WO2015196137A1 - Crystalline forms of (2r,5s,13ar)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido [1',2':4,5] pyrazino [2,1-b] [1,3] oxazepine-10-carboxamide - Google Patents
Crystalline forms of (2r,5s,13ar)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido [1',2':4,5] pyrazino [2,1-b] [1,3] oxazepine-10-carboxamide Download PDFInfo
- Publication number
- WO2015196137A1 WO2015196137A1 PCT/US2015/036784 US2015036784W WO2015196137A1 WO 2015196137 A1 WO2015196137 A1 WO 2015196137A1 US 2015036784 W US2015036784 W US 2015036784W WO 2015196137 A1 WO2015196137 A1 WO 2015196137A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dioxo
- crystalline form
- xrpd
- polymorphic
- pattern
- Prior art date
Links
- SOLUWJRYJLAZCX-LYOVBCGYSA-N bictegravir Chemical compound C([C@H]1O[C@@H]2CC[C@@H](C2)N1C(=O)C1=C(C2=O)O)N1C=C2C(=O)NCC1=C(F)C=C(F)C=C1F SOLUWJRYJLAZCX-LYOVBCGYSA-N 0.000 title description 2
- 239000013078 crystal Substances 0.000 claims abstract description 173
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 45
- 150000001875 compounds Chemical class 0.000 claims description 205
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 168
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 108
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 92
- 239000003814 drug Substances 0.000 claims description 86
- 239000003112 inhibitor Substances 0.000 claims description 83
- 238000000034 method Methods 0.000 claims description 81
- 229940124597 therapeutic agent Drugs 0.000 claims description 71
- 239000011591 potassium Substances 0.000 claims description 68
- 229910052700 potassium Inorganic materials 0.000 claims description 68
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 63
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims description 57
- 229960004556 tenofovir Drugs 0.000 claims description 43
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 38
- 229940116315 oxalic acid Drugs 0.000 claims description 36
- 235000006408 oxalic acid Nutrition 0.000 claims description 36
- 238000004519 manufacturing process Methods 0.000 claims description 35
- 241000282414 Homo sapiens Species 0.000 claims description 30
- 208000031886 HIV Infections Diseases 0.000 claims description 29
- 208000037357 HIV infectious disease Diseases 0.000 claims description 29
- 102100034343 Integrase Human genes 0.000 claims description 29
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 29
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 claims description 28
- 239000002777 nucleoside Substances 0.000 claims description 28
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 28
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 23
- 239000002773 nucleotide Substances 0.000 claims description 22
- 125000003729 nucleotide group Chemical group 0.000 claims description 22
- 239000001530 fumaric acid Substances 0.000 claims description 15
- 229960001355 tenofovir disoproxil Drugs 0.000 claims description 15
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 claims description 15
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 14
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 13
- 239000002552 dosage form Substances 0.000 claims description 11
- 238000001179 sorption measurement Methods 0.000 claims description 11
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000004030 hiv protease inhibitor Substances 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 5
- 101100326215 Pseudomonas aeruginosa bla gene Proteins 0.000 claims description 4
- FJNCXZZQNBKEJT-UHFFFAOYSA-N 8beta-hydroxymarrubiin Natural products O1C(=O)C2(C)CCCC3(C)C2C1CC(C)(O)C3(O)CCC=1C=COC=1 FJNCXZZQNBKEJT-UHFFFAOYSA-N 0.000 claims description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 abstract description 8
- WJNFBIVCQMPPJC-FQYDJHLKSA-M bictegravir sodium Chemical group O=C1C=2N(C[C@H]3O[C@@H]4CC[C@H](N31)C4)C=C(C(C=2[O-])=O)C(NCC1=C(C=C(C=C1F)F)F)=O.[Na+] WJNFBIVCQMPPJC-FQYDJHLKSA-M 0.000 abstract 1
- 235000013350 formula milk Nutrition 0.000 description 230
- 239000000203 mixture Substances 0.000 description 159
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 91
- 239000002904 solvent Substances 0.000 description 86
- 241000725303 Human immunodeficiency virus Species 0.000 description 71
- 239000011734 sodium Substances 0.000 description 71
- 229910052708 sodium Inorganic materials 0.000 description 71
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 49
- 238000002424 x-ray crystallography Methods 0.000 description 41
- -1 Formulas (I) Chemical class 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- 239000012535 impurity Substances 0.000 description 36
- 229940126656 GS-4224 Drugs 0.000 description 26
- 239000007787 solid Substances 0.000 description 26
- 239000002253 acid Substances 0.000 description 20
- 150000003857 carboxamides Chemical group 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 19
- 239000000725 suspension Substances 0.000 description 19
- 238000011282 treatment Methods 0.000 description 17
- 239000008186 active pharmaceutical agent Substances 0.000 description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- 230000002194 synthesizing effect Effects 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 229940079593 drug Drugs 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 14
- 208000015181 infectious disease Diseases 0.000 description 14
- 229960001627 lamivudine Drugs 0.000 description 14
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 14
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 description 14
- 229960004946 tenofovir alafenamide Drugs 0.000 description 14
- 238000004458 analytical method Methods 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 229960000531 abacavir sulfate Drugs 0.000 description 12
- 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 12
- 230000008901 benefit Effects 0.000 description 12
- 239000000825 pharmaceutical preparation Substances 0.000 description 12
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 12
- 230000008569 process Effects 0.000 description 12
- 239000003826 tablet Substances 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
- 241000700605 Viruses Species 0.000 description 11
- 239000000356 contaminant Substances 0.000 description 11
- 239000007857 degradation product Substances 0.000 description 11
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 11
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 10
- 239000006227 byproduct Substances 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 229960000366 emtricitabine Drugs 0.000 description 10
- 239000003623 enhancer Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229960002402 cobicistat Drugs 0.000 description 9
- 229940126534 drug product Drugs 0.000 description 9
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 9
- 230000003612 virological effect Effects 0.000 description 9
- 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 9
- 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 8
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 229940124524 integrase inhibitor Drugs 0.000 description 8
- 239000002850 integrase inhibitor Substances 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- 229960005486 vaccine Drugs 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 229960004748 abacavir Drugs 0.000 description 7
- 101150049515 bla gene Proteins 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 7
- 239000011521 glass Substances 0.000 description 7
- SFJGCXYXEFWEBK-UHFFFAOYSA-N oxazepine Chemical group O1C=CC=CC=N1 SFJGCXYXEFWEBK-UHFFFAOYSA-N 0.000 description 7
- 229960002555 zidovudine Drugs 0.000 description 7
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 6
- 229960003277 atazanavir Drugs 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
- 125000004429 atom Chemical group 0.000 description 6
- 210000000234 capsid Anatomy 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- ZCIGNRJZKPOIKD-CQXVEOKZSA-N cobicistat Chemical compound S1C(C(C)C)=NC(CN(C)C(=O)N[C@@H](CCN2CCOCC2)C(=O)N[C@H](CC[C@H](CC=2C=CC=CC=2)NC(=O)OCC=2SC=NC=2)CC=2C=CC=CC=2)=C1 ZCIGNRJZKPOIKD-CQXVEOKZSA-N 0.000 description 6
- 238000002050 diffraction method Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 235000011056 potassium acetate Nutrition 0.000 description 6
- 229940121649 protein inhibitor Drugs 0.000 description 6
- 239000012268 protein inhibitor Substances 0.000 description 6
- 229960000311 ritonavir Drugs 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- SVUJNSGGPUCLQZ-FQQAACOVSA-N tenofovir alafenamide fumarate Chemical compound OC(=O)\C=C\C(O)=O.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 SVUJNSGGPUCLQZ-FQQAACOVSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- 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
- 229940099797 HIV integrase inhibitor Drugs 0.000 description 5
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- 229960005107 darunavir Drugs 0.000 description 5
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir 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]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 description 5
- 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 5
- 238000011161 development Methods 0.000 description 5
- 229960003804 efavirenz Drugs 0.000 description 5
- 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 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000003084 hiv integrase inhibitor Substances 0.000 description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 5
- 229940011051 isopropyl acetate Drugs 0.000 description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 5
- 229960000689 nevirapine Drugs 0.000 description 5
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000001757 thermogravimetry curve Methods 0.000 description 5
- YSIBYEBNVMDAPN-CMDGGOBGSA-N (e)-4-oxo-4-(3-triethoxysilylpropylamino)but-2-enoic acid Chemical compound CCO[Si](OCC)(OCC)CCCNC(=O)\C=C\C(O)=O YSIBYEBNVMDAPN-CMDGGOBGSA-N 0.000 description 4
- ZIAOVIPSKUPPQW-UHFFFAOYSA-N 3-chloro-5-[1-[(4-methyl-5-oxo-1h-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)pyridin-3-yl]oxybenzonitrile Chemical compound N1C(=O)N(C)C(CN2C(C(OC=3C=C(C=C(Cl)C=3)C#N)=C(C=C2)C(F)(F)F)=O)=N1 ZIAOVIPSKUPPQW-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 108010010369 HIV Protease Proteins 0.000 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 4
- 241000208125 Nicotiana Species 0.000 description 4
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 4
- 102000003923 Protein Kinase C Human genes 0.000 description 4
- 108090000315 Protein Kinase C Proteins 0.000 description 4
- 229960001997 adefovir Drugs 0.000 description 4
- 108700025316 aldesleukin Proteins 0.000 description 4
- 229960003796 atazanavir sulfate Drugs 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- YDDGKXBLOXEEMN-IABMMNSOSA-N chicoric acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)\C=C\C=1C=C(O)C(O)=CC=1)C(O)=O)C(=O)\C=C\C1=CC=C(O)C(O)=C1 YDDGKXBLOXEEMN-IABMMNSOSA-N 0.000 description 4
- 238000007405 data analysis Methods 0.000 description 4
- 229960002656 didanosine Drugs 0.000 description 4
- 229960002542 dolutegravir Drugs 0.000 description 4
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 229960004525 lopinavir Drugs 0.000 description 4
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 4
- 229910052753 mercury Inorganic materials 0.000 description 4
- 230000009897 systematic effect Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 125000006510 trifluorobenzyl group Chemical group 0.000 description 4
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 3
- 241001135569 Human adenovirus 5 Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000013590 bulk material Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000000539 dimer Substances 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 229950003141 doravirine Drugs 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 238000001415 gene therapy Methods 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 229960001936 indinavir Drugs 0.000 description 3
- 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 3
- 239000004615 ingredient Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- SWUARLUWKZWEBQ-VQHVLOKHSA-N phenethyl caffeate Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)OCCC1=CC=CC=C1 SWUARLUWKZWEBQ-VQHVLOKHSA-N 0.000 description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 description 3
- 235000011009 potassium phosphates Nutrition 0.000 description 3
- 238000004886 process control Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 229960004742 raltegravir Drugs 0.000 description 3
- 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 3
- 230000010076 replication Effects 0.000 description 3
- 229960002814 rilpivirine Drugs 0.000 description 3
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 description 3
- 229960001852 saquinavir Drugs 0.000 description 3
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- MLGCXEBRWGEOQX-UHFFFAOYSA-N tetradifon Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)C1=CC(Cl)=C(Cl)C=C1Cl MLGCXEBRWGEOQX-UHFFFAOYSA-N 0.000 description 3
- CNPVJJQCETWNEU-CYFREDJKSA-N (4,6-dimethyl-5-pyrimidinyl)-[4-[(3S)-4-[(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl]-3-methyl-1-piperazinyl]-4-methyl-1-piperidinyl]methanone Chemical compound N([C@@H](COC)C=1C=CC(=CC=1)C(F)(F)F)([C@H](C1)C)CCN1C(CC1)(C)CCN1C(=O)C1=C(C)N=CN=C1C CNPVJJQCETWNEU-CYFREDJKSA-N 0.000 description 2
- CUFQBQOBLVLKRF-RZDMPUFOSA-N (4r)-3-[(2s,3s)-2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-phenylbutanoyl]-5,5-dimethyl-n-[(2-methylphenyl)methyl]-1,3-thiazolidine-4-carboxamide Chemical compound CC1=CC=CC=C1CNC(=O)[C@@H]1C(C)(C)SCN1C(=O)[C@@H](O)[C@@H](NC(=O)C=1C(=C(O)C=CC=1)C)CC1=CC=CC=C1 CUFQBQOBLVLKRF-RZDMPUFOSA-N 0.000 description 2
- NUBQKPWHXMGDLP-UHFFFAOYSA-N 1-[4-benzyl-2-hydroxy-5-[(2-hydroxy-2,3-dihydro-1h-inden-1-yl)amino]-5-oxopentyl]-n-tert-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide;sulfuric acid Chemical compound OS(O)(=O)=O.C1CN(CC(O)CC(CC=2C=CC=CC=2)C(=O)NC2C3=CC=CC=C3CC2O)C(C(=O)NC(C)(C)C)CN1CC1=CC=CN=C1 NUBQKPWHXMGDLP-UHFFFAOYSA-N 0.000 description 2
- RGHYDLZMTYDBDT-UHFFFAOYSA-N 2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)-7-pyrido[2,3-d]pyrimidinone Chemical compound O=C1N(CC)C2=NC(N)=NC(C)=C2C=C1C=1C=CNN=1 RGHYDLZMTYDBDT-UHFFFAOYSA-N 0.000 description 2
- KRZBCHWVBQOTNZ-PSEXTPKNSA-N 3,5-di-O-caffeoyl quinic acid Chemical compound O([C@@H]1C[C@](O)(C[C@H]([C@@H]1O)OC(=O)\C=C\C=1C=C(O)C(O)=CC=1)C(O)=O)C(=O)\C=C\C1=CC=C(O)C(O)=C1 KRZBCHWVBQOTNZ-PSEXTPKNSA-N 0.000 description 2
- DQEFVRYFVZNIMK-FEDPJRJMSA-N 4-amino-5-fluoro-1-[(2r,5s)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one;[[(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate;(e)-but-2-enedioic acid;4-[[4-[4-[(e)-2-cyanoe Chemical compound OC(=O)\C=C\C(O)=O.C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1.CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N DQEFVRYFVZNIMK-FEDPJRJMSA-N 0.000 description 2
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 description 2
- OLROWHGDTNFZBH-XEMWPYQTSA-N Alisporivir Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N(CC)C(=O)[C@@H](C)N(C)C1=O OLROWHGDTNFZBH-XEMWPYQTSA-N 0.000 description 2
- UXCAQJAQSWSNPQ-XLPZGREQSA-N Alovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](F)C1 UXCAQJAQSWSNPQ-XLPZGREQSA-N 0.000 description 2
- 108091005625 BRD4 Proteins 0.000 description 2
- 102100029895 Bromodomain-containing protein 4 Human genes 0.000 description 2
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 2
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- YDDGKXBLOXEEMN-IABMMNSOSA-L Chicoric acid Natural products C1=C(O)C(O)=CC=C1\C=C\C(=O)O[C@@H](C([O-])=O)[C@H](C([O-])=O)OC(=O)\C=C\C1=CC=C(O)C(O)=C1 YDDGKXBLOXEEMN-IABMMNSOSA-L 0.000 description 2
- YDDGKXBLOXEEMN-UHFFFAOYSA-N Di-E-caffeoyl-meso-tartaric acid Natural products C=1C=C(O)C(O)=CC=1C=CC(=O)OC(C(O)=O)C(C(=O)O)OC(=O)C=CC1=CC=C(O)C(O)=C1 YDDGKXBLOXEEMN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 206010013710 Drug interaction Diseases 0.000 description 2
- 102100025027 E3 ubiquitin-protein ligase TRIM69 Human genes 0.000 description 2
- 241000448280 Elates Species 0.000 description 2
- 108010032976 Enfuvirtide Proteins 0.000 description 2
- 229940033330 HIV vaccine Drugs 0.000 description 2
- 108010033040 Histones Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000830203 Homo sapiens E3 ubiquitin-protein ligase TRIM69 Proteins 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- OFFWOVJBSQMVPI-RMLGOCCBSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O.N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 OFFWOVJBSQMVPI-RMLGOCCBSA-N 0.000 description 2
- 101150068888 MET3 gene Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 102100025207 Mitogen-activated protein kinase kinase kinase 11 Human genes 0.000 description 2
- 108010007843 NADH oxidase Proteins 0.000 description 2
- 101100022915 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cys-11 gene Proteins 0.000 description 2
- 108090001074 Nucleocapsid Proteins Proteins 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 101710149951 Protein Tat Proteins 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- IRHXGOXEBNJUSN-YOXDLBRISA-N Saquinavir mesylate Chemical compound CS(O)(=O)=O.C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 IRHXGOXEBNJUSN-YOXDLBRISA-N 0.000 description 2
- 101100022918 Schizosaccharomyces pombe (strain 972 / ATCC 24843) sua1 gene Proteins 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- SUJUHGSWHZTSEU-UHFFFAOYSA-N Tipranavir Natural products C1C(O)=C(C(CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)C(=O)OC1(CCC)CCC1=CC=CC=C1 SUJUHGSWHZTSEU-UHFFFAOYSA-N 0.000 description 2
- RLAHNGKRJJEIJL-RFZPGFLSSA-N [(2r,4r)-4-(2,6-diaminopurin-9-yl)-1,3-dioxolan-2-yl]methanol Chemical compound C12=NC(N)=NC(N)=C2N=CN1[C@H]1CO[C@@H](CO)O1 RLAHNGKRJJEIJL-RFZPGFLSSA-N 0.000 description 2
- IBHARWXWOCPXCR-WELGVCPWSA-N [(2s,3s,5r)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl (2-decoxy-3-dodecylsulfanylpropyl) hydrogen phosphate Chemical compound C1[C@H](N=[N+]=[N-])[C@@H](COP(O)(=O)OCC(CSCCCCCCCCCCCC)OCCCCCCCCCC)O[C@H]1N1C(=O)NC(=O)C(C)=C1 IBHARWXWOCPXCR-WELGVCPWSA-N 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 229960003205 adefovir dipivoxil Drugs 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229960005310 aldesleukin Drugs 0.000 description 2
- 108010058359 alisporivir Proteins 0.000 description 2
- 229950004424 alovudine Drugs 0.000 description 2
- 229950005846 amdoxovir Drugs 0.000 description 2
- 229960001830 amprenavir Drugs 0.000 description 2
- 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 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 150000005840 aryl radicals Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- WWVKQTNONPWVEL-UHFFFAOYSA-N caffeic acid phenethyl ester Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCC1=CC=CC=C1 WWVKQTNONPWVEL-UHFFFAOYSA-N 0.000 description 2
- 229940124765 capsid inhibitor Drugs 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229930016920 cichoric acid Natural products 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 229940029487 complera Drugs 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 229960005319 delavirdine Drugs 0.000 description 2
- 238000003795 desorption Methods 0.000 description 2
- YDDGKXBLOXEEMN-PMACEKPBSA-N dicaffeoyl-D-tartaric acid Natural products O([C@H](C(=O)O)[C@H](OC(=O)C=CC=1C=C(O)C(O)=CC=1)C(O)=O)C(=O)C=CC1=CC=C(O)C(O)=C1 YDDGKXBLOXEEMN-PMACEKPBSA-N 0.000 description 2
- YDDGKXBLOXEEMN-WOJBJXKFSA-N dicaffeoyl-L-tartaric acid Natural products O([C@@H](C(=O)O)[C@@H](OC(=O)C=CC=1C=C(O)C(O)=CC=1)C(O)=O)C(=O)C=CC1=CC=C(O)C(O)=C1 YDDGKXBLOXEEMN-WOJBJXKFSA-N 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 238000000375 direct analysis in real time Methods 0.000 description 2
- 238000012063 dual-affinity re-targeting Methods 0.000 description 2
- 229960003586 elvitegravir Drugs 0.000 description 2
- JUZYLCPPVHEVSV-LJQANCHMSA-N elvitegravir Chemical compound COC1=CC=2N([C@H](CO)C(C)C)C=C(C(O)=O)C(=O)C=2C=C1CC1=CC=CC(Cl)=C1F JUZYLCPPVHEVSV-LJQANCHMSA-N 0.000 description 2
- 229960002062 enfuvirtide Drugs 0.000 description 2
- 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 2
- 238000011067 equilibration Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229960002049 etravirine Drugs 0.000 description 2
- PYGWGZALEOIKDF-UHFFFAOYSA-N etravirine Chemical compound CC1=CC(C#N)=CC(C)=C1OC1=NC(NC=2C=CC(=CC=2)C#N)=NC(N)=C1Br PYGWGZALEOIKDF-UHFFFAOYSA-N 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- OSYWBJSVKUFFSU-SKDRFNHKSA-N festinavir Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@](CO)(C#C)O1 OSYWBJSVKUFFSU-SKDRFNHKSA-N 0.000 description 2
- 229960003142 fosamprenavir Drugs 0.000 description 2
- MLBVMOWEQCZNCC-OEMFJLHTSA-N fosamprenavir Chemical compound C([C@@H]([C@H](OP(O)(O)=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 MLBVMOWEQCZNCC-OEMFJLHTSA-N 0.000 description 2
- 229950011117 fozivudine tidoxil Drugs 0.000 description 2
- 229940124784 gp41 inhibitor Drugs 0.000 description 2
- 238000009499 grossing Methods 0.000 description 2
- 239000002835 hiv fusion inhibitor Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229960004243 indinavir sulfate Drugs 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 229960005386 ipilimumab Drugs 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- 230000007775 late Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 description 2
- 229960004710 maraviroc Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000035800 maturation Effects 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- HYVVJDQGXFXBRZ-UHFFFAOYSA-N metam Chemical compound CNC(S)=S HYVVJDQGXFXBRZ-UHFFFAOYSA-N 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 108010041596 mitogen-activated protein kinase kinase kinase 11 Proteins 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229950007856 mofetil Drugs 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000032696 parturition Effects 0.000 description 2
- 229940023041 peptide vaccine Drugs 0.000 description 2
- 230000005551 perinatal transmission Effects 0.000 description 2
- SWUARLUWKZWEBQ-UHFFFAOYSA-N phenylethyl ester of caffeic acid Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCCC1=CC=CC=C1 SWUARLUWKZWEBQ-UHFFFAOYSA-N 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 238000012877 positron emission topography Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 150000003243 quercetin Chemical class 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 231100000205 reproductive and developmental toxicity Toxicity 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 229960003542 saquinavir mesylate Drugs 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 229940070590 stribild Drugs 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 229960003560 tenofovir alafenamide fumarate Drugs 0.000 description 2
- 229960000838 tipranavir Drugs 0.000 description 2
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 2
- 229940111527 trizivir Drugs 0.000 description 2
- 229950009860 vicriviroc Drugs 0.000 description 2
- SVNJBEMPMKWDCO-KCHLEUMXSA-N (2s)-2-[[(2s)-3-carboxy-2-[[2-[[(2s)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yl]methoxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]-3-hydroxypropanoate Chemical compound C=1C(=O)C2=CC=CC(C=3C=CC=CC=3)=C2OC=1[N+]1(COC(=O)CCC(=O)N[C@@H](CCCNC(=N)N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C([O-])=O)CCOCC1 SVNJBEMPMKWDCO-KCHLEUMXSA-N 0.000 description 1
- AKWRNBWMGFUAMF-ZESMOPTKSA-N (2s)-n-[(2s)-1-[[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-2-[[(2s,3r)-2-[[(2s,3r)-2-[[(2s,3r)-2-[[(2s)-2-[[(2r)-2-aminopropanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxybutanoyl]amin Chemical compound C[C@@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H]([C@H](O)C)C(N)=O)CC1=CC=C(O)C=C1 AKWRNBWMGFUAMF-ZESMOPTKSA-N 0.000 description 1
- PNIFFZXGBAYVMQ-RKKDRKJOSA-N (2s)-n-[(2s,3r)-4-[(3-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]-2-[[2-[(3-fluorophenyl)methylamino]acetyl]amino]-3,3-dimethylbutanamide Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=C(N)C=CC=1)NC(=O)[C@@H](NC(=O)CNCC=1C=C(F)C=CC=1)C(C)(C)C)C1=CC=CC=C1 PNIFFZXGBAYVMQ-RKKDRKJOSA-N 0.000 description 1
- IXZYCIFRVZKVRJ-RKKDRKJOSA-N (2s)-n-[(2s,3r)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]-2-[[2-[(3-fluorophenyl)methylamino]acetyl]amino]-3,3-dimethylbutanamide Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)[C@@H](NC(=O)CNCC=1C=C(F)C=CC=1)C(C)(C)C)C1=CC=CC=C1 IXZYCIFRVZKVRJ-RKKDRKJOSA-N 0.000 description 1
- JLUPGSPHOGFEOB-WQLSENKSSA-N (2z)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-ylidene)-n-[(4-fluorophenyl)methyl]-n-methoxyacetamide Chemical compound O\1C(C)(C)OC(=O)C/1=C/C(=O)N(OC)CC1=CC=C(F)C=C1 JLUPGSPHOGFEOB-WQLSENKSSA-N 0.000 description 1
- QRBIFAKBTSNLCS-ZTFBILFISA-N (3s,4as,8as)-n-tert-butyl-2-[(2r,3s)-2-hydroxy-3-[[(2r)-3-methyl-3-methylsulfonyl-2-[(2-pyridin-3-yloxyacetyl)amino]butanoyl]amino]-4-phenylbutyl]-3,4,4a,5,6,7,8,8a-octahydro-1h-isoquinoline-3-carboxamide Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@@H](NC(=O)COC=1C=NC=CC=1)C(C)(C)S(C)(=O)=O)C1=CC=CC=C1 QRBIFAKBTSNLCS-ZTFBILFISA-N 0.000 description 1
- AQHMBDAHQGYLIU-XNFHFXFQSA-N (3s,6s,9s,12r,15s,18s,21s,24s,27r,30s,33s)-27-[2-(dimethylamino)ethylsulfanyl]-30-ethyl-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-24-(2-hydroxy-2-methylpropyl)-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18-tris(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10, Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)(C)O)N(C)C(=O)[C@@H](SCCN(C)C)N(C)C1=O AQHMBDAHQGYLIU-XNFHFXFQSA-N 0.000 description 1
- JNSKQYZFEVKYDB-UVMMSNCQSA-N (4-nitrophenyl)methyl n-[1-[[(3s,4r)-1-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl]methyl]piperidin-4-yl]-n-prop-2-enylcarbamate Chemical compound C([C@H]1CN(C[C@]1(O)C=1C=CC=CC=1)C(=O)C1CCCC1)N(CC1)CCC1N(CC=C)C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 JNSKQYZFEVKYDB-UVMMSNCQSA-N 0.000 description 1
- DJIGFNCGXOAXOW-WTPNCWHFSA-N (4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-4-carboxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-carboxypropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-carboxybutanoyl]amino]-3-methylpentanoyl]amino]-4-amino-4-oxobutanoyl]amino]-4-amino-4-oxobutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxybutanoyl]amino]-6-[[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethoxy]acetyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]-4-carboxybutanoyl]amino]-4-carboxybutanoyl]amino]-3-hydroxypropanoyl]amino]-5-amino-5-oxopentanoyl]amino]-4-amino-4-oxobutanoyl]amino]-5-amino-5-oxopentanoyl]amino]-5-amino-5-oxopentanoyl]amino]-5-[[(2S)-6-amino-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-oxopentanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(C)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCNC(=O)COCCOCCNC(=O)CCN1C(=O)C=CC1=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCC(O)=O)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(N)=O DJIGFNCGXOAXOW-WTPNCWHFSA-N 0.000 description 1
- QCNJQJJFXFJVCX-ZDUSSCGKSA-N (4s)-4-(2-cyclopropylethynyl)-5,6-difluoro-4-(trifluoromethyl)-1,3-dihydroquinazolin-2-one Chemical compound C([C@@]1(NC(=O)NC2=CC=C(C(=C21)F)F)C(F)(F)F)#CC1CC1 QCNJQJJFXFJVCX-ZDUSSCGKSA-N 0.000 description 1
- JJWJSIAJLBEMEN-ZDUSSCGKSA-N (4s)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1,3-dihydroquinazolin-2-one Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)N1)C(F)(F)F)#CC1CC1 JJWJSIAJLBEMEN-ZDUSSCGKSA-N 0.000 description 1
- UXDWYQAXEGVSPS-GFUIURDCSA-N (4s)-6-chloro-4-[(e)-2-cyclopropylethenyl]-4-(trifluoromethyl)-1,3-dihydroquinazolin-2-one Chemical compound C(/[C@]1(C2=CC(Cl)=CC=C2NC(=O)N1)C(F)(F)F)=C\C1CC1 UXDWYQAXEGVSPS-GFUIURDCSA-N 0.000 description 1
- JUYWDXUELATAOI-UHFFFAOYSA-N 1,3-oxazepine Chemical compound O1C=CC=CN=C1 JUYWDXUELATAOI-UHFFFAOYSA-N 0.000 description 1
- DBPMWRYLTBNCCE-UHFFFAOYSA-N 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1h-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione Chemical compound C1=2C(OC)=CN=C(OC)C=2NC=C1C(=O)C(=O)N(CC1)CCN1C(=O)C1=CC=CC=C1 DBPMWRYLTBNCCE-UHFFFAOYSA-N 0.000 description 1
- SOJJMSYMCLIQCZ-CYBMUJFWSA-N 1-[(2r)-4-[2-(2-aminopyrimidin-5-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)purin-8-yl]-2-methylpiperazin-1-yl]ethanone Chemical compound C1CN(C(C)=O)[C@H](C)CN1C1=NC2=C(N3CCOCC3)N=C(C=3C=NC(N)=NC=3)N=C2N1CC(F)(F)F SOJJMSYMCLIQCZ-CYBMUJFWSA-N 0.000 description 1
- JPOJKNJIKXMZRB-UHFFFAOYSA-N 1-[1-(3-chloro-4-fluorophenyl)-5-(3-chloro-5-fluorophenyl)pyrazole-3-carbonyl]imidazolidin-4-one Chemical compound FC1=CC(Cl)=CC(C=2N(N=C(C=2)C(=O)N2CC(=O)NC2)C=2C=C(Cl)C(F)=CC=2)=C1 JPOJKNJIKXMZRB-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- BEMBRAMZGVDPMH-UHFFFAOYSA-N 11-ethyl-5-methyl-8-[2-(1-oxidoquinolin-1-ium-4-yl)oxyethyl]dipyrido[2,3-d:2',3'-h][1,4]diazepin-6-one Chemical compound CN1C(=O)C2=CC(CCOC=3C4=CC=CC=C4[N+]([O-])=CC=3)=CN=C2N(CC)C2=NC=CC=C21 BEMBRAMZGVDPMH-UHFFFAOYSA-N 0.000 description 1
- ZOAIEFWMQLYMTF-UHFFFAOYSA-N 18-(4-iodophenyl)octadecyl 2-(trimethylazaniumyl)ethyl phosphate Chemical compound C[N+](C)(C)CCOP([O-])(=O)OCCCCCCCCCCCCCCCCCCC1=CC=C(I)C=C1 ZOAIEFWMQLYMTF-UHFFFAOYSA-N 0.000 description 1
- VNIWZCGZPBJWBI-UHFFFAOYSA-N 2-(1,1-dioxothiazinan-2-yl)-n-[(4-fluorophenyl)methyl]-5-hydroxy-1-methyl-6-oxopyrimidine-4-carboxamide Chemical compound OC=1C(=O)N(C)C(N2S(CCCC2)(=O)=O)=NC=1C(=O)NCC1=CC=C(F)C=C1 VNIWZCGZPBJWBI-UHFFFAOYSA-N 0.000 description 1
- IUVCFHHAEHNCFT-INIZCTEOSA-N 2-[(1s)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one Chemical compound C1=C(F)C(OC(C)C)=CC=C1C(C1=C(N)N=CN=C11)=NN1[C@@H](C)C1=C(C=2C=C(F)C=CC=2)C(=O)C2=CC(F)=CC=C2O1 IUVCFHHAEHNCFT-INIZCTEOSA-N 0.000 description 1
- UAXHPOBBKRWJGA-ZDUSSCGKSA-N 2-[2-[(2s)-2-methyl-2,3-dihydroindol-1-yl]-2-oxoethyl]-6-morpholin-4-yl-1h-pyrimidin-4-one Chemical compound C([C@@H]1C)C2=CC=CC=C2N1C(=O)CC(NC(=O)C=1)=NC=1N1CCOCC1 UAXHPOBBKRWJGA-ZDUSSCGKSA-N 0.000 description 1
- RTJUXLYUUDBAJN-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-fluoro-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1C[C@H](F)[C@@H](CO)O1 RTJUXLYUUDBAJN-KVQBGUIXSA-N 0.000 description 1
- MWYDSXOGIBMAET-UHFFFAOYSA-N 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro-1H-imidazo[1,2-c]quinazolin-5-ylidene]pyrimidine-5-carboxamide Chemical compound NC1=NC=C(C=N1)C(=O)N=C1N=C2C(=C(C=CC2=C2N1CCN2)OCCCN1CCOCC1)OC MWYDSXOGIBMAET-UHFFFAOYSA-N 0.000 description 1
- QINPEPAQOBZPOF-UHFFFAOYSA-N 2-amino-n-[3-[[3-(2-chloro-5-methoxyanilino)quinoxalin-2-yl]sulfamoyl]phenyl]-2-methylpropanamide Chemical compound COC1=CC=C(Cl)C(NC=2C(=NC3=CC=CC=C3N=2)NS(=O)(=O)C=2C=C(NC(=O)C(C)(C)N)C=CC=2)=C1 QINPEPAQOBZPOF-UHFFFAOYSA-N 0.000 description 1
- XTKLTGBKIDQGQL-UHFFFAOYSA-N 2-methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-morpholin-4-ylbenzimidazole-4-carboxylic acid Chemical compound CC1=NC2=C(C(O)=O)C=C(N3CCOCC3)C=C2N1CC1=CC=CC(C(F)(F)F)=C1C XTKLTGBKIDQGQL-UHFFFAOYSA-N 0.000 description 1
- BCSVCWVQNOXFGL-UHFFFAOYSA-N 3,4-dihydro-4-oxo-3-((5-trifluoromethyl-2-benzothiazolyl)methyl)-1-phthalazine acetic acid Chemical compound O=C1C2=CC=CC=C2C(CC(=O)O)=NN1CC1=NC2=CC(C(F)(F)F)=CC=C2S1 BCSVCWVQNOXFGL-UHFFFAOYSA-N 0.000 description 1
- MVCIFQBXXSMTQD-UHFFFAOYSA-N 3,5-dicaffeoylquinic acid Natural products Cc1ccc(C=CC(=O)OC2CC(O)(CC(OC(=O)C=Cc3ccc(O)c(O)c3)C2O)C(=O)O)cc1C MVCIFQBXXSMTQD-UHFFFAOYSA-N 0.000 description 1
- HDXDQPRPFRKGKZ-INIZCTEOSA-N 3-(3-fluorophenyl)-2-[(1s)-1-(7h-purin-6-ylamino)propyl]chromen-4-one Chemical compound C=1([C@@H](NC=2C=3NC=NC=3N=CN=2)CC)OC2=CC=CC=C2C(=O)C=1C1=CC=CC(F)=C1 HDXDQPRPFRKGKZ-INIZCTEOSA-N 0.000 description 1
- XDMUFNNPLXHNKA-ZTESCHFWSA-N 4-[(1r,3as,5ar,5br,7ar,11as,11br,13ar,13br)-3a-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethylamino]-5a,5b,8,8,11a-pentamethyl-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,11,11b,12,13,13a,13b-tetradecahydrocyclopenta[a]chrysen-9-yl]benzoic acid Chemical compound C([C@]1(C)[C@H]2CC[C@H]3[C@@]([C@@]2(CC[C@H]1C1(C)C)C)(C)CC[C@]2(CC[C@H]([C@H]32)C(=C)C)NCCN2CCS(=O)(=O)CC2)C=C1C1=CC=C(C(O)=O)C=C1 XDMUFNNPLXHNKA-ZTESCHFWSA-N 0.000 description 1
- ILAYIAGXTHKHNT-UHFFFAOYSA-N 4-[4-(2,4,6-trimethyl-phenylamino)-pyrimidin-2-ylamino]-benzonitrile Chemical compound CC1=CC(C)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 ILAYIAGXTHKHNT-UHFFFAOYSA-N 0.000 description 1
- GWNOTCOIYUNTQP-FQLXRVMXSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]benzoic acid Chemical compound N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C(O)=O)C=C1 GWNOTCOIYUNTQP-FQLXRVMXSA-N 0.000 description 1
- DSNMRZSQABDJDK-PZFKGGKESA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-3a-[(1r)-2-[(3-chlorophenyl)methyl-[2-(dimethylamino)ethyl]amino]-1-hydroxyethyl]-5a,5b,8,8,11a-pentamethyl-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dime Chemical compound C([C@H](O)[C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)N(CCN(C)C)CC1=CC=CC(Cl)=C1 DSNMRZSQABDJDK-PZFKGGKESA-N 0.000 description 1
- HSBKFSPNDWWPSL-CAHLUQPWSA-N 4-amino-5-fluoro-1-[(2r,5s)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1C=C[C@@H](CO)O1 HSBKFSPNDWWPSL-CAHLUQPWSA-N 0.000 description 1
- ADGGYDAFIHSYFI-UHFFFAOYSA-N 5-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine Chemical compound C1=NC(N)=CC(C(F)(F)F)=C1C1=NC(N2CCOCC2)=NC(N2CCOCC2)=N1 ADGGYDAFIHSYFI-UHFFFAOYSA-N 0.000 description 1
- LGWACEZVCMBSKW-UHFFFAOYSA-N 5-(6,6-dimethyl-4-morpholin-4-yl-8,9-dihydropurino[8,9-c][1,4]oxazin-2-yl)pyrimidin-2-amine Chemical compound CC1(C)OCCN(C2=N3)C1=NC2=C(N1CCOCC1)N=C3C1=CN=C(N)N=C1 LGWACEZVCMBSKW-UHFFFAOYSA-N 0.000 description 1
- XWHARLVGMNPKNZ-UHFFFAOYSA-N 6-N-cyclopropyl-2-N-quinolin-6-yl-7H-purine-2,6-diamine methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.C1CC1Nc1nc(Nc2ccc3ncccc3c2)nc2nc[nH]c12 XWHARLVGMNPKNZ-UHFFFAOYSA-N 0.000 description 1
- UBLOHCIYTDRGJH-UHFFFAOYSA-N 6-[2-[[4-amino-3-(3-hydroxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-3-[(2-chlorophenyl)methyl]-4-oxoquinazolin-5-yl]-n,n-bis(2-methoxyethyl)hex-5-ynamide Chemical compound C=1C=CC=C(Cl)C=1CN1C(=O)C=2C(C#CCCCC(=O)N(CCOC)CCOC)=CC=CC=2N=C1CN(C1=NC=NC(N)=C11)N=C1C1=CC=CC(O)=C1 UBLOHCIYTDRGJH-UHFFFAOYSA-N 0.000 description 1
- LMJFJIDLEAWOQJ-CQSZACIVSA-N 8-[(1r)-1-(3,5-difluoroanilino)ethyl]-n,n-dimethyl-2-morpholin-4-yl-4-oxochromene-6-carboxamide Chemical compound N([C@H](C)C=1C2=C(C(C=C(O2)N2CCOCC2)=O)C=C(C=1)C(=O)N(C)C)C1=CC(F)=CC(F)=C1 LMJFJIDLEAWOQJ-CQSZACIVSA-N 0.000 description 1
- SJVQHLPISAIATJ-ZDUSSCGKSA-N 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]-1-isoquinolinone Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=CC2=CC=CC(Cl)=C2C(=O)N1C1=CC=CC=C1 SJVQHLPISAIATJ-ZDUSSCGKSA-N 0.000 description 1
- OZOGDCZJYVSUBR-UHFFFAOYSA-N 8-chloro-n-[4-(trifluoromethoxy)phenyl]quinolin-2-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC=C(C=CC=C2Cl)C2=N1 OZOGDCZJYVSUBR-UHFFFAOYSA-N 0.000 description 1
- 229940023859 AIDSVAX Drugs 0.000 description 1
- WVLHHLRVNDMIAR-IBGZPJMESA-N AMD 070 Chemical compound C1CCC2=CC=CN=C2[C@H]1N(CCCCN)CC1=NC2=CC=CC=C2N1 WVLHHLRVNDMIAR-IBGZPJMESA-N 0.000 description 1
- 229960005531 AMG 319 Drugs 0.000 description 1
- 102100033391 ATP-dependent RNA helicase DDX3X Human genes 0.000 description 1
- 101710156069 ATP-dependent RNA helicase DDX3X Proteins 0.000 description 1
- 102100034544 Acyl-CoA 6-desaturase Human genes 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- 102000005590 Anaphylatoxin C5a Receptor Human genes 0.000 description 1
- 229940124527 BI 224436 Drugs 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101000780199 Bos taurus Acyl-coenzyme A synthetase ACSM1, mitochondrial Proteins 0.000 description 1
- 0 C1[C@@]2C1*C*2 Chemical compound C1[C@@]2C1*C*2 0.000 description 1
- 102100024310 COMM domain-containing protein 1 Human genes 0.000 description 1
- 101710155310 COMM domain-containing protein 1 Proteins 0.000 description 1
- 101100383153 Caenorhabditis elegans cdk-9 gene Proteins 0.000 description 1
- 101100420681 Caenorhabditis elegans tir-1 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 108090000565 Capsid Proteins Proteins 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 102100023321 Ceruloplasmin Human genes 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108010078546 Complement C5a Proteins 0.000 description 1
- 102000016550 Complement Factor H Human genes 0.000 description 1
- 108010053085 Complement Factor H Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 108010041986 DNA Vaccines Proteins 0.000 description 1
- 229940021995 DNA vaccine Drugs 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 101100223822 Dictyostelium discoideum zfaA gene Proteins 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 101710177291 Gag polyprotein Proteins 0.000 description 1
- 108060003393 Granulin Proteins 0.000 description 1
- 101000848255 Homo sapiens Acyl-CoA 6-desaturase Proteins 0.000 description 1
- 108700020134 Human immunodeficiency virus 1 nef Proteins 0.000 description 1
- 235000008694 Humulus lupulus Nutrition 0.000 description 1
- 244000025221 Humulus lupulus Species 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- VEBVPUXQAPLADL-UHFFFAOYSA-N Ingenol Natural products C1=C(CO)C(O)C2(O)C(O)C(C)=CC32C(C)CC2C(C)(C)C2C1C3=O VEBVPUXQAPLADL-UHFFFAOYSA-N 0.000 description 1
- 108010061833 Integrases Proteins 0.000 description 1
- 108010064600 Intercellular Adhesion Molecule-3 Proteins 0.000 description 1
- 102100037871 Intercellular adhesion molecule 3 Human genes 0.000 description 1
- 108010054698 Interferon Alfa-n3 Proteins 0.000 description 1
- 108010078049 Interferon alpha-2 Proteins 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 241000272168 Laridae Species 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- 101710125418 Major capsid protein Proteins 0.000 description 1
- YFGBQHOOROIVKG-FKBYEOEOSA-N Met-enkephalin Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 YFGBQHOOROIVKG-FKBYEOEOSA-N 0.000 description 1
- 101100434906 Mus musculus Angptl8 gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229940087098 Oxidase inhibitor Drugs 0.000 description 1
- 239000012828 PI3K inhibitor Substances 0.000 description 1
- QIUASFSNWYMDFS-NILGECQDSA-N PX-866 Chemical compound CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2C2=C1[C@@]1(C)[C@@H](COC)OC(=O)\C(=C\N(CC=C)CC=C)C1=C(O)C2=O QIUASFSNWYMDFS-NILGECQDSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- NUQJULCGNZMBEF-UHFFFAOYSA-N Prostratin Natural products COC(=O)C12CC(C)C3(O)C(C=C(CO)CC4(O)C3C=C(C)C4=O)C1C2(C)C NUQJULCGNZMBEF-UHFFFAOYSA-N 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 101710150344 Protein Rev Proteins 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 102000015097 RNA Splicing Factors Human genes 0.000 description 1
- 108010039259 RNA Splicing Factors Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 108010090287 SCY-635 Proteins 0.000 description 1
- 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 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 108010008038 Synthetic Vaccines Proteins 0.000 description 1
- 102000002689 Toll-like receptor Human genes 0.000 description 1
- 108020000411 Toll-like receptor Proteins 0.000 description 1
- 101800001690 Transmembrane protein gp41 Proteins 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 229940127507 Ubiquitin Ligase Inhibitors Drugs 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- 101710201961 Virion infectivity factor Proteins 0.000 description 1
- 108010042365 Virus-Like Particle Vaccines Proteins 0.000 description 1
- 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 1
- UGWQMIXVUBLMAH-IVVFTGHFSA-N [(1s,4r)-4-[2-amino-6-(cyclopropylamino)purin-9-yl]cyclopent-2-en-1-yl]methanol;4-amino-1-[(2r,5s)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 UGWQMIXVUBLMAH-IVVFTGHFSA-N 0.000 description 1
- JHXLLEDIXXOJQD-VBWFMVIDSA-N [(2r)-2-decoxy-3-dodecylsulfanylpropyl] [(2r,3s,5r)-3-fluoro-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl hydrogen phosphate Chemical compound C1[C@H](F)[C@@H](COP(O)(=O)OC[C@H](CSCCCCCCCCCCCC)OCCCCCCCCCC)O[C@H]1N1C(=O)NC(=O)C(C)=C1 JHXLLEDIXXOJQD-VBWFMVIDSA-N 0.000 description 1
- WXJFKKQWPMNTIM-VWLOTQADSA-N [(2s)-1-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxypropan-2-yl]oxymethyl-(3-hexadecoxypropoxy)phosphinic acid Chemical compound CCCCCCCCCCCCCCCCOCCCOP(O)(=O)CO[C@H](CO)CN1C=CC(N)=NC1=O WXJFKKQWPMNTIM-VWLOTQADSA-N 0.000 description 1
- BINXAIIXOUQUKC-UIPNDDLNSA-N [(3as,4r,6ar)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl] n-[(2s,3r)-3-hydroxy-4-[(4-methoxyphenyl)sulfonyl-(2-methylpropyl)amino]-1-phenylbutan-2-yl]carbamate Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(CC(C)C)C[C@@H](O)[C@@H](NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)CC1=CC=CC=C1 BINXAIIXOUQUKC-UIPNDDLNSA-N 0.000 description 1
- VJLRLTSXTLICIR-UHFFFAOYSA-N [8-[6-amino-5-(trifluoromethyl)pyridin-3-yl]-1-[6-(2-cyanopropan-2-yl)pyridin-3-yl]-3-methylimidazo[4,5-c]quinolin-2-ylidene]cyanamide Chemical compound N#CN=C1N(C)C2=CN=C3C=CC(C=4C=C(C(N)=NC=4)C(F)(F)F)=CC3=C2N1C1=CC=C(C(C)(C)C#N)N=C1 VJLRLTSXTLICIR-UHFFFAOYSA-N 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 238000011374 additional therapy Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 108010011303 albuvirtide Proteins 0.000 description 1
- 229950004789 alisporivir Drugs 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 108010050122 alpha 1-Antitrypsin Proteins 0.000 description 1
- 102000015395 alpha 1-Antitrypsin Human genes 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229950006356 aplaviroc Drugs 0.000 description 1
- RYMCFYKJDVMSIR-RNFRBKRXSA-N apricitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1S[C@H](CO)OC1 RYMCFYKJDVMSIR-RNFRBKRXSA-N 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229940068561 atripla Drugs 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- 229950007843 bavituximab Drugs 0.000 description 1
- 235000013405 beer Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 229950009079 brecanavir Drugs 0.000 description 1
- JORVRJNILJXMMG-OLNQLETPSA-N brecanavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=C2OCOC2=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C(C=C1)=CC=C1OCC1=CSC(C)=N1 JORVRJNILJXMMG-OLNQLETPSA-N 0.000 description 1
- WCWSTNLSLKSJPK-LKFCYVNXSA-N cabotegravir Chemical compound C([C@H]1OC[C@@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F WCWSTNLSLKSJPK-LKFCYVNXSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- PMDQGYMGQKTCSX-HQROKSDRSA-L calcium;[(2r,3s)-1-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-[[(3s)-oxolan-3-yl]oxycarbonylamino]-4-phenylbutan-2-yl] phosphate Chemical compound [Ca+2].C([C@@H]([C@H](OP([O-])([O-])=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 PMDQGYMGQKTCSX-HQROKSDRSA-L 0.000 description 1
- 229940023860 canarypox virus HIV vaccine Drugs 0.000 description 1
- YQXCVAGCMNFUMQ-UHFFFAOYSA-N capravirine Chemical compound C=1C(Cl)=CC(Cl)=CC=1SC1=C(C(C)C)N=C(COC(N)=O)N1CC1=CC=NC=C1 YQXCVAGCMNFUMQ-UHFFFAOYSA-N 0.000 description 1
- 229950008230 capravirine Drugs 0.000 description 1
- 125000005521 carbonamide group Chemical group 0.000 description 1
- PNDKCRDVVKJPKG-WHERJAGFSA-N cenicriviroc Chemical compound C1=CC(OCCOCCCC)=CC=C1C1=CC=C(N(CC(C)C)CCC\C(=C/2)C(=O)NC=3C=CC(=CC=3)[S@@](=O)CC=3N(C=NC=3)CCC)C\2=C1 PNDKCRDVVKJPKG-WHERJAGFSA-N 0.000 description 1
- 229950011033 cenicriviroc Drugs 0.000 description 1
- 229950002672 censavudine Drugs 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229950002550 copanlisib Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 229950006497 dapivirine Drugs 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- MEPNHSOMXMALDZ-UHFFFAOYSA-N delavirdine mesylate Chemical compound CS(O)(=O)=O.CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 MEPNHSOMXMALDZ-UHFFFAOYSA-N 0.000 description 1
- 229960000475 delavirdine mesylate Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 101150024031 dio3 gene Proteins 0.000 description 1
- SDIXRDNYIMOKSG-UHFFFAOYSA-L disodium methyl arsenate Chemical compound [Na+].[Na+].C[As]([O-])([O-])=O SDIXRDNYIMOKSG-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960001976 dolutegravir sodium Drugs 0.000 description 1
- UGWJRRXTMKRYNK-VSLILLSYSA-M dolutegravir sodium Chemical compound [Na+].C([C@@H]1OCC[C@H](N1C(=O)C1=C([O-])C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F UGWJRRXTMKRYNK-VSLILLSYSA-M 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 229950004949 duvelisib Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 229940019131 epzicom Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004175 fluorobenzyl group Chemical group 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229950003232 fosalvudine tidoxil Drugs 0.000 description 1
- 229960002933 fosamprenavir calcium Drugs 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 101150049033 haao gene Proteins 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- 229950010245 ibalizumab Drugs 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- VEBVPUXQAPLADL-POYOOMFHSA-N ingenol Chemical compound C1=C(CO)[C@@H](O)[C@]2(O)[C@@H](O)C(C)=C[C@]32[C@H](C)C[C@H]2C(C)(C)[C@H]2[C@H]1C3=O VEBVPUXQAPLADL-POYOOMFHSA-N 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 229950000038 interferon alfa Drugs 0.000 description 1
- 229960003507 interferon alfa-2b Drugs 0.000 description 1
- 229940109242 interferon alfa-n3 Drugs 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- PGHMRUGBZOYCAA-ADZNBVRBSA-N ionomycin Chemical compound O1[C@H](C[C@H](O)[C@H](C)[C@H](O)[C@H](C)/C=C/C[C@@H](C)C[C@@H](C)C(/O)=C/C(=O)[C@@H](C)C[C@@H](C)C[C@@H](CCC(O)=O)C)CC[C@@]1(C)[C@@H]1O[C@](C)([C@@H](C)O)CC1 PGHMRUGBZOYCAA-ADZNBVRBSA-N 0.000 description 1
- PGHMRUGBZOYCAA-UHFFFAOYSA-N ionomycin Natural products O1C(CC(O)C(C)C(O)C(C)C=CCC(C)CC(C)C(O)=CC(=O)C(C)CC(C)CC(CCC(O)=O)C)CCC1(C)C1OC(C)(C(C)O)CC1 PGHMRUGBZOYCAA-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 229940112586 kaletra Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 229940023832 live vector-vaccine Drugs 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical class O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 229960005011 metenkefalin Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- KHASNRBNVBIREH-IZEXYCQBSA-N methyl n-[(2s)-1-[[(5s)-5-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-6-phosphonooxyhexyl]amino]-1-oxo-3,3-diphenylpropan-2-yl]carbamate Chemical compound C=1C=CC=CC=1C([C@H](NC(=O)OC)C(=O)NCCCC[C@@H](COP(O)(O)=O)N(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)C1=CC=CC=C1 KHASNRBNVBIREH-IZEXYCQBSA-N 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 description 1
- LNLJHGXOFYUARS-OAQYLSRUSA-N n-[(1r)-1-[8-chloro-2-(1-oxidopyridin-1-ium-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl]pyrido[3,2-d]pyrimidin-4-amine Chemical compound [O-][N+]1=CC=CC(C=2C(=CC3=CC=CC(Cl)=C3N=2)[C@@H](NC=2C3=NC=CC=C3N=CN=2)C(F)(F)F)=C1 LNLJHGXOFYUARS-OAQYLSRUSA-N 0.000 description 1
- KWRYMZHCQIOOEB-LBPRGKRZSA-N n-[(1s)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7h-purin-6-amine Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=CC2=CC=C(F)C=C2N=C1C1=CC=CC=N1 KWRYMZHCQIOOEB-LBPRGKRZSA-N 0.000 description 1
- VWDUPUFYZJZZLS-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]butanamide Chemical compound CCCC(=O)NCCN(CC)CC VWDUPUFYZJZZLS-UHFFFAOYSA-N 0.000 description 1
- JOWXJLIFIIOYMS-UHFFFAOYSA-N n-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl-methylamino]pyrimidine-5-carboxamide Chemical compound C1=NC(OC)=CC=C1C1=NC(N2CCOCC2)=C(SC(CN(C)C=2N=CC(=CN=2)C(=O)NO)=C2)C2=N1 JOWXJLIFIIOYMS-UHFFFAOYSA-N 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- 229960005230 nelfinavir mesylate Drugs 0.000 description 1
- NQHXCOAXSHGTIA-SKXNDZRYSA-N nelfinavir mesylate Chemical compound CS(O)(=O)=O.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 NQHXCOAXSHGTIA-SKXNDZRYSA-N 0.000 description 1
- JWNPDZNEKVCWMY-VQHVLOKHSA-N neratinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 JWNPDZNEKVCWMY-VQHVLOKHSA-N 0.000 description 1
- 229950008835 neratinib Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- CGBJSGAELGCMKE-UHFFFAOYSA-N omipalisib Chemical compound COC1=NC=C(C=2C=C3C(C=4C=NN=CC=4)=CC=NC3=CC=2)C=C1NS(=O)(=O)C1=CC=C(F)C=C1F CGBJSGAELGCMKE-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- FPOHNWQLNRZRFC-ZHACJKMWSA-N panobinostat Chemical compound CC=1NC2=CC=CC=C2C=1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FPOHNWQLNRZRFC-ZHACJKMWSA-N 0.000 description 1
- 229960005184 panobinostat Drugs 0.000 description 1
- 229950004852 panulisib Drugs 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- SZFPYBIJACMNJV-UHFFFAOYSA-N perifosine Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OC1CC[N+](C)(C)CC1 SZFPYBIJACMNJV-UHFFFAOYSA-N 0.000 description 1
- 229950010632 perifosine Drugs 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 229950004941 pictilisib Drugs 0.000 description 1
- LHNIIDJUOCFXAP-UHFFFAOYSA-N pictrelisib Chemical compound C1CN(S(=O)(=O)C)CCN1CC1=CC2=NC(C=3C=4C=NNC=4C=CC=3)=NC(N3CCOCC3)=C2S1 LHNIIDJUOCFXAP-UHFFFAOYSA-N 0.000 description 1
- 229950005769 pilaralisib Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960002169 plerixafor Drugs 0.000 description 1
- YIQPUIGJQJDJOS-UHFFFAOYSA-N plerixafor Chemical compound C=1C=C(CN2CCNCCCNCCNCCC2)C=CC=1CN1CCCNCCNCCCNCC1 YIQPUIGJQJDJOS-UHFFFAOYSA-N 0.000 description 1
- 108010089520 pol Gene Products Proteins 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 150000003109 potassium Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 229940099982 prolastin Drugs 0.000 description 1
- 229940087463 proleukin Drugs 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- BOJKFRKNLSCGHY-HXGSDTCMSA-N prostratin Chemical compound C1=C(CO)C[C@]2(O)C(=O)C(C)=C[C@H]2[C@@]2(O)[C@H](C)C[C@@]3(OC(C)=O)C(C)(C)[C@H]3[C@@H]21 BOJKFRKNLSCGHY-HXGSDTCMSA-N 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 229940023143 protein vaccine Drugs 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- OWBFCJROIKNMGD-BQYQJAHWSA-N rigosertib Chemical compound COC1=CC(OC)=CC(OC)=C1\C=C\S(=O)(=O)CC1=CC=C(OC)C(NCC(O)=O)=C1 OWBFCJROIKNMGD-BQYQJAHWSA-N 0.000 description 1
- 229950006764 rigosertib Drugs 0.000 description 1
- VLQLUZFVFXYXQE-USRGLUTNSA-M rigosertib sodium Chemical compound [Na+].COC1=CC(OC)=CC(OC)=C1\C=C\S(=O)(=O)CC1=CC=C(OC)C(NCC([O-])=O)=C1 VLQLUZFVFXYXQE-USRGLUTNSA-M 0.000 description 1
- 229960004481 rilpivirine hydrochloride Drugs 0.000 description 1
- KZVVGZKAVZUACK-BJILWQEISA-N rilpivirine hydrochloride Chemical compound Cl.CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 KZVVGZKAVZUACK-BJILWQEISA-N 0.000 description 1
- KNUXHTWUIVMBBY-JRJYXWDASA-N rintatolimod Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(O)=O)O1.O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1.O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(NC=NC2=O)=C2N=C1 KNUXHTWUIVMBBY-JRJYXWDASA-N 0.000 description 1
- 229950006564 rintatolimod Drugs 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- 229960003452 romidepsin Drugs 0.000 description 1
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 1
- 108010091666 romidepsin Proteins 0.000 description 1
- 238000011452 sequencing regimen Methods 0.000 description 1
- BLGWHBSBBJNKJO-UHFFFAOYSA-N serabelisib Chemical compound C=1C=C2OC(N)=NC2=CC=1C(=CN12)C=CC1=NC=C2C(=O)N1CCOCC1 BLGWHBSBBJNKJO-UHFFFAOYSA-N 0.000 description 1
- 108010048106 sifuvirtide Proteins 0.000 description 1
- WIOOVJJJJQAZGJ-ISHQQBGZSA-N sifuvirtide Chemical compound C([C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)CO)[C@@H](C)O)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)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](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(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)=O)C1=CC=C(O)C=C1 WIOOVJJJJQAZGJ-ISHQQBGZSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- MIXCUJKCXRNYFM-UHFFFAOYSA-M sodium;diiodomethanesulfonate;n-propyl-n-[2-(2,4,6-trichlorophenoxy)ethyl]imidazole-1-carboxamide Chemical compound [Na+].[O-]S(=O)(=O)C(I)I.C1=CN=CN1C(=O)N(CCC)CCOC1=C(Cl)C=C(Cl)C=C1Cl MIXCUJKCXRNYFM-UHFFFAOYSA-M 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 229950007865 sonolisib Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229940008349 truvada Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 101150059019 vif gene Proteins 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000008299 viral mechanism Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
Classifications
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring 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
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- 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
- 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
- C07D498/12—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 three hetero rings
- C07D498/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D498/12—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 three hetero rings
- C07D498/18—Bridged 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to novel crystalline forms and co-crystals of (2R,5SJ3aR)-8-hydroxy-7, ⁇
- Human immunodeficiency vims infection and related diseases ate a major public health problem worldwide.
- Human immunodeficiency virus type 1 (ffiV-1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, arid integrase.
- reverse transcriptase a enzyme which is required for viral replication
- protease a substrate for converting viral genome to a virus.
- arid integrase integrase
- drags targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palclla, et al. N. Engl. J Med. (1998) 333:853-860; Richman, D, D. Nature (2001 ) 410:995-1001).
- a goal of antiretrovira! therapy Is to achieve viral suppression in the HIV infected patient.
- Treatment guidelines published by the United States Department of Health and Human Services provide that achievement of viral suppression requires the use of combination therapies, i.e., several drags from at least two or more drug classes.
- decisions regarding the treatment of HIV infected patients are complicated when the patient requires treatment for other medical conditions. Because the standard of care requires the use of multiple different drugs to suppress HIV, as well as to treat other conditions the patient may be experiencing, the potential for drug interaction is a criterion for selection of a drug regimen. As such, there is a need for antirstroviral therapies having a decreased potential for drug interactions.
- the present invention is directed to novel forms of (2R.5SJ 3a ⁇ -8- hydroxy-7,9 lioxG-N-(2,4 5 6-?TM ⁇
- the present invention is directed to (2R,5S, 13aR)-S-hydroxy-
- fee present invention is directed to i2 .SS, 13a V8- hydroxy-7,9 ⁇ ioxo-N ⁇
- the present invention is directed to (2R,SS 5 13aR)-8-
- the present invention is directed to (2R s 5S,13aR)- ⁇ hydroxy-7 5 9-dioxo ⁇ N ⁇ (2,4,0 rifiuQre ⁇
- the present invention is directed to (2R,5S,1 aR) ⁇ 8 ⁇ hydroxy-7,9 ⁇ dioxo-N ⁇ (2,4,6-trifluorobenzyl)-2 s 3,4,5,7 s 9, 13,13 a ⁇ oeiahydre-2,5 ⁇
- the present invention is directed to (2R,SS, 13aR)-8- hydroxy-7,9-dioxO"N-(2,4,6 rifluorobenzyl) ⁇ 2 ? 3 ! 4 s 5.7,9J.3 5 13a-ocfebydrO"2,5 »
- the present invention Is directed to (2R,5S, 13 ⁇ -8- bydroxy ⁇ 7 s 9-dioxo-N-(2,4,6 rit1uorokinzyi ⁇ -2,3,4,5,7,9, ! 3, 13a-octahydro-2.5- methanopyrido[ I ⁇ 2':4,5]pyrazino[2,l -b] [ 1 s 3]oxazepine- i 0-catboxamide Form VII.
- the present invention is directed to (2R 5 5S,13aR)-8- h dro ⁇ -dio o-N ⁇ -triflisorobeaxy ⁇ J ⁇ ,? ⁇ .13, ] 3a-octahydro ⁇ 2,5- ffiethanopyrido[172 ⁇ 4,S]pyrazmoP ⁇ Form VIII.
- present Invention Is directed to a fnmarle acid co- cr ⁇ of (2R,5S 3aR) ⁇ 8-hydroxy-7 ⁇
- the present invention is directed to a citric acid co-erystal of (2R,5S,13aR)-8 tydrox ⁇
- the present invention is directed to an oxalic acid co- crystal of (2R,5S, 13aR)-8-hydroxy-7,9 ⁇ i-oxo-N ⁇
- the present Invention is directed to crystalline forms and co-crystals of (2R s 5S 5 13aR)-8-hydroxy-7 ) 9"dioxo-N- ⁇ 2,4 5 6 ⁇ trii1.uorobenzyi) ⁇
- the present invention is directed to novel forms of sodium
- the present invention is directed to sodium.
- the present invention is directed to novel forms of potassium (2R ! 5S, 13aR)-7 5 9 ⁇ dioxo-10-( ⁇ 2 J 4,6-trifiuorobenzyl)carbam.oyl)-2 s 3,4,5 s 7,9 5 I3, I 3a- octahydro ⁇ 2 > 5 ⁇ methaBopyrido[ l ⁇ 2 I :4 s 5]pyrazino[2J. ⁇ b][l s 3]oxaz €pin-S-oiaie, having the following structure (Formula ill):
- the present invention is directed to potassium
- the present invention is directed to potassium
- the present invention is directed to hydraied potassium (2R,5S, .1 ;1 ⁇ 4R)"7,9-dioxo-10- ⁇ 2 3 4 5 6 fifluorobenzyi)ca banioyl) » 2 ; 3 5 4,S s 7,9, 13, 13a- octahydrO"2 > 5 ⁇ r eihanopyrido[ I ! ,2 ! A5]pyrazino[2, 1 -b] [ 1 ,3]oxa2;epm-8-olate.
- the present invention is directed to methods of treating or prophyiactically preventing an HIV Infection by administering compound (e.g. Formulas (I), (II), and/or (III)) provided herein.
- compound e.g. Formulas (I), (II), and/or (III) provided herein.
- the present invention s directed to a compound (e.g. Formulas (I), (II), and/or (III)) provided herein for use in methods of treating or
- the present invention is directed to the use of a compound (e.g. Formulas (I), ( ⁇ ), and/or (III)) provided herein in the manufacture of a medicament for treating or prophyiactically preventing HIV infection.
- a compound e.g. Formulas (I), ( ⁇ ), and/or (III) provided herein in the manufacture of a medicament for treating or prophyiactically preventing HIV infection.
- Figure 6 Actual and calculated XRPD pattern for (2R,5S,13aR)-8-hydroxy ⁇ 7 s 9» dio o-N ⁇ lfluoro iizylJ ⁇ ⁇ JS.Da-ociahydro- ⁇ S- methairopyTldo[r > 2 , :4 s 5]pyra2ino[2 -b][l,3]oxazepke ⁇ !0-carboxamide oxalic acid co- crystal Form I.
- Fsg?ire 10 TGA for (2R.5S, 13aR>8-hydroxy-7.9-dioxo-N-(2,4,6-
- Figure 14 DVS for (2R,5SJ3 ⁇ R) ⁇ S- ydrox --7 J 9-dloxo « N ⁇ (2,4,6-.
- Figure 15 DVS for sodium (2R,5S 5 13aR)-7 s 9-dioxo ⁇ I0 ⁇ ((2 > 4,6- udil «orobenzj.'i)carbamoyl)-2 ! ,3 J 4 i 5 i 7,9,13,13a-octahydro ⁇ 2,5 ⁇
- the invention disclosed herein is also meant to encompass all pharmaceutically acceptable compounds of Formulas (I), ( ⁇ ), and (III) being isotonics! ly-Ja beled by having one or more atoms replaced by an atom having a different atomic mass or mass number.
- isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 3 ⁇ 4 3 ⁇ 4 U C, i3 C, M C, 3 ⁇ 4, 15 N, i5 0, 37 0, 38 G, 33 P, 3 3 ⁇ 4 3S S, l % 3 ⁇ 4 n ⁇ and % respectively.
- These radiolabeled compounds could he useful to help determine or measure the
- Isotopically-labeled compounds of Formulas (f) (II) and (III), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
- the radioactive isotopes tritium, i n 3 ⁇ 4 and carbon- 14. i.e. i4 C, are particularly useful for this purpose in view of their ease of i ncorporation and ready means of detection.
- Substitution with heavier isotopes such as deuterium, i.e. 3 ⁇ 4 may afford certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half- life may increase or dosage requirements may be reduced. Thus, heavier Isotopes may he preferred In some circumstances.
- isoiopicaUy-labeled compounds of Formulas (I), (II), (III) can generally be prepared by conventional techniques known to those skilled in the art or by processes ' analogous to those described in the Examples as set out below using an appropriate
- “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an. efficacious therapeutic agent.
- ' ptional or “optionally” means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
- “optionally substituted aryi” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
- 'Thannaccutically acceptable carrier, diluent or excipient includes without limitation any adjuvant, carrier, excipient, glidant sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or ernuisifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
- a "pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans.
- a medium includes ail pharmaceutically acceptable carriers, diluents or excipients therefor.
- Effective amount refers to an amount of a compound according to the invention, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician.
- the amount of a compound according to the invention which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological acti vity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidental! ⁇ ' with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient.
- a therapeutically effective amount can be determined routinely by one of ordinary skill in the art. having regard to their own knowledge, the state of the ait, and this disclosure,
- treatment is intended to mean the
- treatment also encompasses the administration of a compound or composition according to the present invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching deteetible levels in the blood, and the admins stratioa of a compound or composition according to the present invention to prevent perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life.
- the term "treatment” as used herein is intended to mean the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of HIV infection and/or to reduce viral load in a patient.
- the term “'treatment” as used herein is further or alternatively intended to mean the administration of a compound or composition according to the present Invention to maintain a reduced viral load in a patient.
- treatment also encompasses the administration of a compound or composition according to the present invention postexposure of the individual to the virus but before the appearance of symptoms of the disease; and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching deteetible levels in the blood, and the administration of a compound or composition according to the present invention to prevent perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life, in certain embodiments, the term “treatment” as used herein is further or alternatively intended to mean the administration of a compound or composition according to the present invention post-exposure of the individual to the virus as a subsequent or additional therapy to a first-line therapy (e.g., for maintenance of low viral load), [0060] "Prevention” or "preventing *5 means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop.
- prevention also encompasses the administration of a compound or composition according to the present inventio pre ⁇ exposure of the individual to the virus ⁇ e.g., pre ⁇ exposure prophylaxis), to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detect! hie levels in the blood.
- Subject refers to an animal, such as a mamma! (including a human), that has been or will be the object of treatment observation or experiment.
- the methods described herein may be useful in human therapy and''or veterinary applications.
- the subject is a mammal (or the patient).
- the subject (or the patient) is human, domestic animals (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats and pigs), and/or laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys).
- the subject (or the patient) is a human.
- “Human (or patient) in need thereof 5 refers to a human who may have or is suspect to have diseases or conditions that would benefit from certain treatment; for example, being treated with the compounds disclosed herein according to the present application.
- antiviral agent as used herein is intended to mean an agent (compound or biological) that is effective to inhibit the formation and/or replication of a virus in a human being, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a human being.
- inhibitor of HIV replication is intended to mean an agent capable of reducing or eliminating the ability of HIV to replicate in a host ceil, whether in vitro, ex vivo or in vivo.
- a "tasjtomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
- the present invention includes tantomers of any said compounds.
- “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human
- Unit dosage forms are physically discrete units suitable as unitary dosages for subjects (e.g.. human subjects and other mammals), each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
- earboxamide may be an intermediate to the synthesis of (2R,5S,I3aR)-S-hydroxy-7,9-dioso- " N-(2,4,6 rinuorobenzyl)-2,3,4,5,7,9, 13,1 a ⁇ oc ⁇ ahydro-2,5 ⁇
- a polymorphic form or polymorph or eocrystal may have properties such as bioavaiiabiiity and stability at certain conditions that may be suitable for medical or pharmaceutical uses.
- a crystalline form of (2R J 5S,13aR)-8 « hydroxy-7,9-dioxo-N-(2,4 > 6- trifluorobenzyl) ⁇ 2,3,4,5,7,9, 13, 13a-octahydro-2,5 ⁇ meihanopyrido[ 1 ',2';4,5]pyrazino[2, 1 - b][l i 3]oxazepine-10 ⁇ carboxamide may provide the advantage of bioavailability and stability, suitable for use as an active ingredient in a pharmaceutical composition.
- Variations in the crystal structure of a pharmaceutical drug substaxs.ee or active ingredient may affect the dissolution rate (which may affect bioavailability, etc.), manufactiirabiilty (e.g., ease of handling, ability to consistently prepare doses of known strength) and stability' (e.g.. thermal stability, shelf life, etc.) of a pharmaceutical drug product or active ingredient.
- dissolution rate which may affect bioavailability, etc.
- manufactiirabiilty e.g., ease of handling, ability to consistently prepare doses of known strength
- stability' e.g. thermal stability, shelf life, etc.
- Such variations may affect the preparation or formulation of pharmaceutical compositions in different dosage or delivery forms, such as solid oral dosage form including tablets and capsules.
- crystalline forms may provide desired or suitable hygroscopicity, particle size controls, dissolution rate, solubility, purity, physical and chemical stability, ma ufacturabiiity, yield, and/or process control.
- Carboxamide may provide advantages such as; improving the manufacturing process of an active agent or the stabiiiiy or storability of a drug product form of the compound or an acti ve ingredient and/or having suitable bioavailability and/or stability as an active agent,
- the compound name provided above is named using ChemBioDraw Ultra and one skilled in the art understands that the compound structure may be named or identified using other commonly recognized nomenclature systems and symbols.
- the compound may be named or identified with common names, systematic or non- systematic names.
- the nomenclature systems and symbols that are commonly recognized in the art of chemistry including but not limited to Chemical Abstract Service (CAS) and International Union of Pure and Applied Chemistry (IUPAC).
- the compound structure provided above may also be named or identified as (2R,5S,13aR)-8-hydJx>xy-7,9- dloxo ⁇ N ⁇ (2,4J-triilnorobenz)d)-2 ; 3,4,5,7,9, 13, i 3a-oetahydro ⁇ 2 5 5- methanopyrido[r,2 i :4,5]p>'razmo[2,l-b][1 ,3]oxazepine-10-carboxaniide under IUPAC and 2,S-Methanopyrido[ 1 ',2 ! :4,5] ⁇ > ⁇ 3 ⁇ [2, 1 ⁇ b] [ 1 ,3 Joxazepine- 10-carboxamide, 2 ⁇ 4,5, , , 13, 13a-oetahydro-8-hydro.xy ⁇ 7 5 ⁇
- crystalline forms and co-crystals of (2 5 5S,13aR)-8 ⁇ hydiOxy ⁇ 7 s 9-di xo-N ⁇ (2 J 4,6-tri !uorobeiizyl)-2,3 s 4,5,7 s 9 ⁇ 13, 13a-octahydro-2,5- methanopyrido[r s 2 t :4 5]p) ' Tazino[2J -b][l ,3]oxazeplne 0-carboxamide are disclosed.
- Polymorphic Form I exhibits an X-ray powder diffraction (XRPD) pattens substantially as shown in FIG. L
- Polymorphic Form I may exhibit a differential scanning ealorimetry (DSC) thermogram substantially as shown in FIG. 7
- Polymorphic Form I may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 10.
- Polymorphic Form I may exhibit dynamic vapour sorption (DVS) graphs substantially as shown in FIG. 13.
- terns "substantially as shown in” when referring, for example, to an XRPD pattern, a DSC thermogram, or a TGA graph includes a pattern, thermogram, or graph that i not necessarily identical to those depicted herein, but that falls within the limits of experimental error or deviations when considered by o e of ordinary skill in the art.
- polymorphic Form I at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or all of the following (a)-(k) apply: (a) polymorphic Form I has an XRPD pattern substantially as shown in FIG. 1 ; (b) polymorphic Form ⁇ has a DSC thermogram
- polymorphic Form I has a TGA graph substantially as shown In FIG, 10;
- polymorphic Form I has DVS graphs substantially as shown in FIG. 13;
- polymorphic Form I has an endomermie event onset;
- polymorphic Porta I has a moBociimc crystal system.;
- polymorphic Form ⁇ has a P2(l) space group;
- polymorphic Form I has a volume of 1855.44( 12) A 3 ;
- polymorphic Fonn I has a Z value of 4; and
- polymorphic Form ⁇ has a
- polymorphic Form I has at. least one, at least two, at. least three, or all of the following properties:
- polymorphic Form I has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2e-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. I ,
- polymorphic Form I has an XRPD pattern comprising degree 20-refiections ( ⁇ / ⁇ 0.2 degrees 2 ⁇ ) at 27.4, 13.1, and 17.4. In one embodiment, polymorphic Form I has an XRPD pattern comprising degree 28 ⁇ refleetions ( ⁇ /- 0.2 degrees 2 ⁇ ) at 27,4, 13.1, and 17.4 and one or more of the degree 28-reffeeiions (+/- 0.2 degrees 28) at 10.5, 20.6. and 25.0.
- polymorphic Form ⁇ has an XRPD pattern comprising degree 29-re flections (+/- 0.2 degrees 28) at 27.4, 13,1, and 17.4 and one of the degree 28-ret3 ⁇ 4ctiorjs (+/- 0.2 degrees 20) at 10,5, 20.6, and 25.0.
- polymorphic Form I has an XRPD pattern comprising degree 28 ⁇ ref1ections (+/- 0,2 degrees 20) at 27.4, 13,1, and 17.4 and two of the degree 28-reilectlons (+/- 0.2 degrees 2 ⁇ ) at 10.5, 20.6, and 25.0.
- polymorphic Form I has an XRPD pattern comprising degree 28 -reflections ⁇ ⁇ ? ⁇ / ⁇ 0.2 degrees 20) at 27.4, 13.1, and 17,4 and three of the degree 2 ⁇ - reflections ⁇ - ⁇ -/- 0,2 degrees 28) at 10.5, 20.6, and 25.0, In one embodiment, polymorphic Form I has an XRPD pattern comprising degree 20 -reflections (+/- 0,2 degrees 2 ⁇ ) at 27.4,
- polymorphic Form I has an XRPD pattern comprising degree 28-refiections (+/- 0.2 degrees 28) at 27.4, 13.1, 17.4, 10.5, 20.6, 25.0 , 16.2, and 22.3. In one embodiment, polymorphic Form I has an XRPD pattern comprising any three degree 29-reflections (+/- 0,2 degrees 28) selected from the group consisting of 27.4, 13.1, 17.4, 10.5, 20.6, 25.0, 16.2, 22.3, 13.9, ⁇ 1.4, and 9.3.
- polymorphic Form II at leas one, at least two, at least three, at least four, at least five, at least six, or all of the following (a)-(g) apply: (a) polymorphic Form II has an XRPD pattern substantially as shown in FIG.
- polymorphic Form II has at least one. or all of the following properties:
- polymorphic Form II has an X PD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 2e-refkctions with the greatest intensity as the XRPD pattern substantially as shown in FIG. 2,
- polymorphic Form H has an XRPD pattern comprising degree 2 ⁇ - eflections (+/ ⁇ 0.2 degrees 2 ⁇ ) at 6,6, 21.4, and 10.6.
- polymorphic Form II has an XRPD pattern comprising degree 20-reflections (+/- 0.2 degrees 2 ⁇ ) at 6.6, 21.4, and 10.6 and one or m.ore of the degree 28-refiectioris ⁇ +/- 0.2 degrees 2 ⁇ ) at 12.5, 16.2, and 14.3.
- polymorphic Form II has an XRPD pattern comprising degree 20-reflections ⁇ /- 0.2 degrees 2 ⁇ ) at 6.6, 21.4, and 10.6 and one of the degree 29-reflections (+/- 0,2 degrees 2 ⁇ ) at 12.5, 16.2, and 14.3, In one embodiment, polymorphic Form II has an XRPD pattern comprising degree 20 ⁇ reflections ( ⁇ * ⁇ /- 0.2 degrees 2 ⁇ ) at 6.6, 21.4, and 10.6 and two of the degree 20- reflections (+/- 0,2 degrees 20) at 12,5,
- polymorphic Form II lias an XRPD pattern comprising degree 20-refiections ( ⁇ /- 0.2 degrees 2 ⁇ ) at 6.6, 21.4, and 10.6 and three of the degree 20- refiectlons (+/- 0,2 degrees 28) at 12.5, 16,2, and 14.3.
- polymorphic Form II has an XRPD pattern comprising degree 28-reflections (+/- 0.2 degrees 28) at 6,6, 21,4, 10,6, 12.5, 16.2, and 14.3,
- polymorphic Form II has an XRPD pattern comprising degree 2e ⁇ refleetions ( ⁇ /- 0.2 degrees 20) at 6.6, 21.4, 10,6, 12,5, 16.2,
- polymorphic Form II has an XRPD pattern comprising any three degree 20 ⁇ f jections ⁇ +/- 0,2 degrees 2 ⁇ ) selected .from the group consisting of 6.6, 21.4, 10.6, 12.5, 16.2, 14.3, 25.6, and 23,5.
- XRPD X-ray powder diffraction
- Polymorphic Form III may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG, 8, Polymorphic Form.
- ⁇ may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG, 11.
- Polymorphic- Form III may exhibit dynamic vapour sorption (DVS) graphs substantially as shown in FIG. 14.
- polymorphic Form ⁇ at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or all of the following (a)-(k) apply: (a) polymorphic Form III has an XRPD pattern substantially as shown in FIG. 3; (b) polymorphic Form III has a DSC thermogram substantially as shown in FIG. 8; (c) polymorphic Form ⁇ has a TGA graph substantially as shown in FIG. 11; (d) polymorphic Form has DVS graphs substantially as shown in FIG.
- polymorphic Form I has an endothermic event onset
- polymorphic Form III has a monoelinic crystal system
- polymorphic Form III has a P2(l) space group
- polymorphic Form ⁇ has a volume of 3884,0(8) A 3
- polymorphic Form III has a 2 value of 8
- polymorphic Form III has a density of 1 ,537 g/cra 3 .
- polymorphic Form III has at least one, at least two, at least three, or ail of the following properties:
- polymorphic Form III has an XRPD pattern displaying at least two, at least three, at least four, at least fi ve, or at least six of the degree 2G ⁇ refieetion,s with the greatest intensity as the XRPD pattern substantially as shown in FIG. 3.
- polymorphic Form III has an XRPD pattern comprising degree 28-reilections (-f/ ⁇ 0.2 degrees 20) at 20.0, 18.5, and 9,6.
- polymorphic Form III has an XRPD pattern comprising degree 28-reflectioras (+/ ⁇ 0.2 degrees 20) at 20.0, 18,5, and 9.6 and one or more of the degree 29-refkctions (+/- 0.2 degrees 20) at 22.5, 14.0, and 25,0.
- polymorphic Form III has an XRPD pattern comprising degree 20-re flections (-17- 0.2 degrees 20) at 20.0, 18.5, and 9,6 and one of the degree 28-refiections (+/ ⁇ 0.2 degrees 28) at 22.5 S 14,0, and 25.0.
- polymorphic Form III has an XRPD pattern comprising degree 2B-reflections (+/- 0,2 degrees 20) at 20.0, 18.5, and 9.6 and two of the degree 28 ⁇ refleciions (+/ ⁇ 0.2 degrees 2 ⁇ ) at 22.5, 14.0, and 25.0.
- polymorphic Form III has an XRPD pattern comprising degree 28-refiections ( ⁇ -/- 0.2 degrees 20) at 20.0, 18.5, and 9.6 and three of the degree 28- reflections (+/- 0.2 degrees 28) at 22.5, 14.0, and 25.0
- polymorphic Form HI has an XRPD pattern comprising degree 28 ⁇ refieolions (+/- 0.2 degrees 20) at 20,0, 18.5, 9.6, 22.5, 14.0, and 25.0
- polymorphic Form III has an XRPD pattern comprising degree 20-reflections (+/- 0.2 degrees 28) at 20,0, 18.5, 9.6, 22,5, .14.0, 25.8, 12.1, and 27.0
- polymorphic Form 111 has an XRPD pattern comprising any three degree 28 ⁇ ref lections (+/ ⁇ 0.2 degrees 20) selected from the group consisting of 20,0, 18.5, 9,6, 22.5, 1.4,0, 25.0, 12.1, 27.0, 16.2, and 29.0
- at least one, at least two, at least three, at least four, at least five, at least sis, or all of the following (a)-(g) apply: (a) polymorphic Form IV has an XRPD pattern substantially as shown in FIG, 4; (b)
- polymorphic Form IV has at least one, or all of the following properties:
- polymorphic Form IV has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the degree 29 ⁇ reiIectio «s with the greatest Intensity as the XRPD pattern substantially as shown in FIG, 4,
- polymorphic Form IV has an XRPD pattern comprising degree 26 ⁇ reflections ( ⁇ * ⁇ /- ⁇ .2 degrees 20) at 16,3, 6.2, and 8,6,
- polymorphic Form. IV has an XRPD pattern comprising degree 28 ⁇ reflections ⁇ +/- 0.2 degrees 20) at 16.3, 6.2, and 8,6 and one or more of the degree 20 ⁇ refiections ( ⁇ -/- 0.2 degrees 26) at 22.7, 22.3, and 25.8.
- polymorphic Form IV has an. XRPD pattern, comprising degree 20-re flections ( ⁇ ⁇ -/- 0.2 degrees 20) at 16.3.
- polymorphic Form IV has an XRPD pattern comprising degree 20-reflectIons (+/- 0,2 degrees 20) at 16,3, 6.2, and 8.6 and two of the degree 28-refleetions (+/- 0,2 degrees 20) at 22.7, 223, and 25.8.
- polymorphic Form IV has an XRPD pattern comprising degree 20-reflections (+/- 0,2 degrees 28) at 16,3, 6.2, and 8,6 and three of the degree 20- reflections (+/- 0,2 degrees 2 ⁇ ) at 22.7, 22.3, and 25.8.
- polymorphic Form IV has an XRFD pattern comprising degree 2G-re.0ecisons (+/- 0.2 degrees 20) at 16,3, 6.2, 8.6, 22.7, 22,3, and 25.8.
- polymorphic Form ⁇ has an XRPD pattern comprising degree 2e ⁇ refleetions (+/- 0.2 degrees 20) at 16,3, 6.2, 8.6, 22.7, 22,3, 25.8, 20.0, arid 8.7
- polymorphic Form IV has an XRFD pattern comprising any three degree 26-reflections ( ⁇ * ⁇ /- 0.2 degrees 28) selected from the group consisting of 16.3, 6.2, 8.6, 22.7, 22.3, 25.8 20,0, 18.7, 27.7, and 13.2,
- polymorphic Form V at least one, at least two, at least three, at least four, at least five, or all of the following, (a)-(f) apply:
- polymorphic Form V has a triclinic crystal system;
- polymorphic Form V has a 1*2(1) space group; (d) polymorphic Form V has a volume of 970.18(14) A 3 ; (e) polymorphic Form V has a Z value of 2; a d (f) polymorphic Fonts V has a density of 1.573 Mg m 3 .
- polymorphic Form V has the following properties:
- polymorphic Form VI has the following properties:
- polymorphic Form VII at least one. at least two, at least three, at least four, at least five, or all of the following (a)-(f) apply;
- polymorphic Form VII has a monoclinic crystal system;
- polymorphic Form VII has a P2(l) space group;
- polymorphic Form Vi has a votome of 12666(8) A ' ';
- polymorphic Form VII has a Z value of 24; and
- polymorphic Form VII has a density of 1.468 Mg.1 ⁇ 2 3 .
- polymorphic Form VI has the following properties:
- polymorphic Form VOL at least one, at least two, at least three, at least four, at least five, or all of the following (a)-(f) apply;
- polymorphic Form VIII has a monoclinic crystal system;
- polymorphic Form VIII has a C2 space group;
- polymorphic Form VIII has a volume of 1913.9(6) A 3 ;
- polymorphic Form VIII has a Z value of 4; and
- polymorphic Form VIII has a density of 1.560 Mg m 3 .
- polymorphic Form VET has the following properties:
- a form of sodium (2R,SS s I3aR)-7,9-dioxo-I0- ⁇ (2 5 4 5 6 rifliioroberizyl)caibamoyl)- 2,3,4,5,7,9,13,13a ⁇ aetahydro-2, 5 -methanopyrido [ 1 ⁇ 2':4,5]pyrazino 2., 1 -b] 1 ,3 ]oxazeph 8- oiate may be an intermediate to the synthesis of sodium (2R,5 S, 13aR) ⁇ 7,9-dioxo- 10-((2,4,6- trifl «oroben3 ⁇ 44)carbaffioyl)-2,3,4,5,7,9 s 13 s 13a ⁇ oetahydro-2,5 ⁇
- 2 5 5 ⁇ msthanopyrido[1 ⁇ 2 ! :4,5]pyra2;ino[2,l-h][l,3]oxazepin-'8 ⁇ oIate may be the final product in the synthesis of sodium (2R,5 S, 13 aR)-7,9-dsoxo- 10-((2,4,6 ⁇ trifluorobenzyi)carbamoyl)- 2,3,4,5,7.9, 13,13a ⁇ octahydro ⁇ 2,5-me&anopyrido[ 1 s ,2 ! :4,5]pyrazino(2, 1 -b][ 1 ,3]oxazepin-8- olate.
- a polymorphic form or polymorph or eocrystal may have properties such as bioavailability and stability at certain conditions that may be suitable for medical or pharmaceutical uses,
- a crystalline form of sodium (2R s 5SJ 3a )-7,9-dioxo-10-((2,4,6- trifluoroben yl)carbamoyl)-2,3,4,5J J 9 9 13, 13a-oetahydro-2,5- methanopyrido[r i 2':4 ; ,5]pyraziuo[2J-bl[! ! 3]oxazepin-8-okte may provide the advantage of bioavailability and stability, suitable for use as an active Ingredient in a pharmaceutical composition.
- a crystalline forro sodium (2R,5S, 13aR)-7,9-dioxo- 10- ( ⁇ 2 , ,6-trifluorobenxy i)carbamoyi) » 2,3,4 J 5,7,9, 13, i 3a-octahydro-2,5- inethanop>Tidoi l',2 , :4,5]pyrazirio[2, 1 -b] ⁇ l,3]oxazcpu 8-olate provides an advantage of improved bioavailability (Table 3) and/or stability (Table 4), Variations in die crystal structure of a pharmaceutical drug substance or active ingredient may affect the dissolution rate (which may affect bioavailability, etc.), anufaciurabi ⁇ ity (e.g., ease of handling, ability to consistently prepare doses of known strength) and stability (e.g., thermal stability, shelf life, etc) of a pharmaceutical drug product or active ingredient.
- Such variations may affect the preparation or formulation of pharmaceutical compositions in different dosage or deliver ⁇ ' forms, such as solid oral dosage form including tablets and capsules.
- crystalline forms may provide desired or suitable h groseopidty. particle size controls, dissolution rate, solubility, purity; physical and chemical stability; manufact rabiiity, yield, and/or process control
- advantages such as: improving the manufacturing process of an active agent or the stability or storability of a drug product form of the compound or an active ingredient, and/or having suitable bioavailability and/or stability as an active agent.
- the compound name provided above is named using ChemBioDra Ultra and one skilled in the art understands that the compound structure may be named or identified using other commonly recognized nomenclature systems and symbols.
- the compound may be named or identified with common names, systematic or non- systematic names, The nomenclature systems and symbols that are commonly recognized in the art of chemistry including but not limited to Chemical Abstract Service (CAS) and International Union of Pure and Applied Chemistry (iUPAC), Accordingly the compound structure provided above may be named or identified as sodium (2R,5S 5 13aR ⁇ -7,9 ⁇ dioxo-10- ( ⁇ 2,4,64rifluorobes3 ⁇ 43 ⁇ 4'l)carbasBoyl) ⁇ 2 s 3,4 s 5 3 7,9 J 13,13a-octahydro--2 5 S- meihanopyrido[f 5 2 ! :4,S)pyrazino[2,i-b][l,3joxazepin ⁇ 8-oiate under IUPAC.
- meihanopyrido[r 5 2 , :4,5]pyrazmo[2 5 ' i ⁇ b][l 5 3]c*xa2ep ⁇ -3 ⁇ 4-olats 8 having the following structure (Formul II) are disclosed:
- crystalline forms of sodium (2R,5S s 13aR)-7 s 9 ⁇ di !xo-10- ((2,4,6 ⁇ trifiuoroberi2yi)cafba£noyl)-2,3 s 4,5 s 7 5 9 s 13, 13a ⁇ octahydro-2 s 5- methanop rido[l V2':4,5]pyra;dri [2,l-b][l J]c>xazepin-S-olate are disclosed.
- Polymorphic sodium Form I may exhibit a differential scanning ca!orimetry (DSC) thermogram substantially as shown in FIG, 9, Polymorphic sodium Form I may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 12, Polymorphic sodium Form I may exhibit dynamic vapour sorption (DVS) graphs substantially as shown in FIG. 15,
- polymorphic sodium Form I at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or all of the following (a)-(j) apply: (a) polymorphic Form I has an XRPD pattern substantially as shown in FIG. 5 and/or FIG, 16; (b) polymorphic sodium Form I has a DSC thermogram substantially as shown in FIG, 9; (c) polymorphic sodium Form I has a TGA graph substantially as shown in FIG.
- polymorphic sodium Form I has DVS graphs substantially as shown in FIG, IS;
- polymorphic sodium Form ⁇ has an orthorhombic crystal system;
- polymorphic sodium Form I has a P212I21 space group;
- polymorphic sodium Form I has a volume of 3879.2 A 3 ;
- polymorphic Form I has a Z value of 4; and
- polymorphic Form I has a density of L61.4
- polymorphic sodium Form I has at least one, at least two, at least three, at least four, or all of the following properties:
- polymorphic sodium Form I has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of fee degree 20-refiections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 1 and/or FIG, 8,
- polymorphic sodium Form I has an XRPD pattern comprising degree 2CJ ⁇ refieetions (-! ⁇ /- 0.2 degrees 2 ⁇ ) at 5.5, 16.1, and 23,3.
- polymorphic sodium Form I has an XRPD pattern comprising degree 2 ⁇ - reflections (+/- 0,2 degrees 2 ⁇ ) at 5.5, 16.1, and 23.3 and one or more of the degree 20- refleetions (+/- 0,2 degrees 20) at 22.1, 28.5, and 22.5.
- polymorphic sodium Form I has an XRPD pattern comprising degree IB-reflections (+/- 0.2 degrees 28) at 5.5, 16.1, and 23.3 and one of the degree 29-reflections (+/- 0.2 degrees 20) at 22,1, 28.5, and 22,5,
- polymorphic sodium Form I has an XRPD pattern comprising degree 28-refleetions (+/- 0.2 degrees 20) at 5,5, 16.1 , and 23,3 and two of the degree 2 ⁇ - reflectkms (+/- 0.2 degrees 20) at 22.1, 28,5, and 22.5.
- polymorphic sodium Pons I has an XRPD pattern comprising degree 20-refleciions (+/- 0.2 degrees 2 ⁇ ) at 5.5, 16.1, and 23,3 and three of the degree 20-rsSections 0.2 degrees 2 ⁇ ) at 22.1, 28.5, and 22.5.
- polymorphic sodium. Form I has an XRPD pattern comprising degree 20-reflections ⁇ +/- 0.2 degrees 20) at 5.5, 16,1, 23.3, 22.1, 28.5, and 22.5.
- polymorphic sodium Form I has an XRPD pattern comprising degree 20- refleciions 0.2 degrees 20) at 5.5, 16.1, 23.3, 22.1, 28.5, 22.5, 19.5, and 26.6
- polymorphic sodium Form I has an XRPD pattern comprising any three degree 20-reflections (+/- 0.2 degrees 2 ⁇ ) selected from the group consisting of 5.5, 16.1, 23.3, 22.1, 28,5, 22.5, 19.5, 26.6, and 17.9.
- oiate A form of a potassium ⁇ 2R,5S,13aR)-7,9-dioxo-I0-((2,4,6 ⁇ trifluorobenzyl)earhamoyl)- 2,3,4,5,7,9,13, 13a ⁇ oetahydro-2,5 ⁇ methanopyrido[I ⁇ 2':4,5]pys-azino[24-b][1 .
- a polymorphic form or polymorph or cocrystal may have properties such as bioavailability and stability at certain conditions that may be suitable for medical or pharmaceutical uses.
- trifluorobeiizy 3)carbamoyl) ⁇ 2 5 3.4,5,7,9,13, 13 a-ociahy dro-2, 5 - metMnopyrido r,2':4,5]pyrazirio[2, l-b][l,3]oxazepiri-8-oiale may provide the advantage of bioavailability and stability; suitable for use as an active ingredient in a pharmaceutical composition.
- Variations in the crystal structure of a pharmaceutical drug substance or active ingredient may affect the dissolution rate ⁇ which may affect bioavailability, etc.), manufaet rabllity ⁇ e.g., ease of handling, ability to consistently prepare doses of known strength) and stability ⁇ e.g., thermal stability, shelf life . , etc) of a pharmaceutical drug product or active ingredient
- dissolution rate which may affect bioavailability, etc.
- manufaet rabllity e.g., ease of handling, ability to consistently prepare doses of known strength
- stability e.g., thermal stability, shelf life . , etc
- Such variations may affect the preparation or formulation of pharmaceutical compositions in different dosage or delivery forms, sack as solid oral dosage form including tablets and capsules.
- crystalline forms may provide desired or suitable hygroscopieity, particle size controls, dissolution rate, solubility, purity, physical and chemical stability,
- (2R,5S, 13a )-7,9-dioxo- 10-i(2 5 4,6 rifluorobeii2 4)carban ⁇ yl)-2,3,4,5,7 i 9 ; 13, 13a-octahydro ⁇ 2 , 5 ⁇ methanopy ki [ 1 ',2 * :4 , 5 ]pyrazi n [2, 1 -b J [ 1 , ]oxazepin ⁇ 8-oiaie may provide advantages such as: improving the manufacturing process of an active agent or the stability or storability of a drug product form of the compound or an active ingredient, and/or having suitable bioavailability and/or stability as an active agent.
- polymorphic Forms I, II, and III which may exhibit one or more favorable characteristics described above.
- the processes for the preparation of the polymorphs described herein, and characterization of these polymorphs are described in greater detail below.
- the compound name provided above is named using ChemBioDraw Ultra and one skilled in the art understands that the compound structure may be named or identified using other commonly recognized nomenclature systems and symbols.
- the compound may be named or Identified with common names, systematic or non- systematic names.
- T he nomenclature systems and. symbols that are commonly recognized in the art of chemistry Including but not limited to Chemical Abstract Service (CAS) and Internationa! Union of Pure and Applied Chemistry (iUPAC). Accordingly, the compound structure provided above may be named or identified as potassium.
- potassium (2R,5S,I 3a )-7,9-dioxo-10 ⁇ ((2,4 5 6- trifiuorobenz 4)carbarnoyl)-2 ; 3 s 4 3 5,7J 5 13,13a ⁇ oetaliydro-2 s 5- methanopyrido[r,2':4 5 5]pyrazlno[2,l-b][l,3]oxazepiri"8"Olate Form II is disclosed.
- hydrated potassium (2R,5S, 1 3aR)-7,9-dioxo- 10- ((2 > 4,6 Tifluorobenzyl)carbamoyl)-2 s 3 5 4 s 5 s 7,9 3 13, 13a-octahydn 2,5- methaiiopyr Ido[ 1 ',2' :4,5]pyraz.ino[2 5 1 ⁇ b] [ 1 , 3 ] oxazepin-8 -olate Is disclosed.
- potassium Form I has an orthorhombic crystal system;
- polymorphic potassium Form I has a P 21 21 2 space group;
- polymorphic potassium Form I has a volume of 5101.9(4) A 3 ;
- polymorphic potassium Form I has a Z value of 8; and
- potassium Form I has a density of 1.498 Mg m 3 ,
- polymorphic potassium Form 1 has the following properties:
- polymorphic potassiwm Form ⁇ has a P 21 21 2 space group;
- polymorphic potassium Form II has a volume of 5126,8(6) A 3 ;
- polymorphic potassiwm Form II has a Z value of 4;
- polymorphic potassium Form ⁇ has a density of 1.336 Mg1 ⁇ 2 3 .
- polymorphic potassium Form II has the following properties:
- polymorphic potassium Form III at least one, at least two, at least three, at least four, at least five, or all of the following (a)-(f) apply: (a) polymorphic potassium Form ⁇ has a unit cell, as determined by crystal X-ray
- polymorphic potassium Form HI has a volume of 1230.86 (8) A 3 ;
- polymorphic potassium Form III has a Z value of 2; and
- potassium Form IU has a density of 1,483 Mg/m
- polymorphic potassium Form III has the following properties:
- metham3 ⁇ 4pyrido[i , ,2 f :4 s S]pyrazmo[2J-b][L3]oxazepine-I O-carbo3 ⁇ 4amide is disclosed.
- Formula ⁇ citric acid co-crystal has all of the following properties:
- Formula I fumaric acid co-cry tal s at least one, at least two, at least three, at least four, at least five, or ail of the following (a)-(f) apply;
- Formula ⁇ fumaric acid co-crystal has a monoclmic crystal system;
- (c) Formula I fumaric acid co-crystal has a C2 space group;
- (d) Formula I fumaric acid co-crystal has a volume of 5237.9(16) A 3 ;
- (e) Formula i fumaric acid co-crystal has a
- Formula I fumark acid co-crystal has all of the following properties:
- Formula I oxalic acid co-crystal of (2R,5S J 3aR)- S- ydroxy-T ⁇ -dio ⁇
- Formula i oxalic acid eo-crystal at least one, at least two, at least three, at least four, at least five, or ail of the following (a)-(f) apply:
- Formula ⁇ oxalic acid co-crystal has a rnonoclink crystal system;
- (d) Formula ⁇ oxalic acid co-crystal has a volume of 2231.95(14) A 5 ;
- Formula I oxalic acid co-crystal has the following properties:
- Formula I oxalic acid co-crystal has an XRPD pattern comprising degree 29-reflections (+/- 0.2 degrees 29) at 19.1. 14,5, and 9.1.
- Formula I oxalic acid co-crystal has an XRPD pattern comprising degree 20- refleetions (+/- 0.2 degrees 20) at 1.9.1 , 14.5, and 9,1 and one or more of the degree 29- reflections (+/- 0.2 degrees 2 ⁇ ) at 7.6, 26.5, and 17.1.
- Formula I oxalic acid co-crystal has an XRPD pattern comprising degree 28-reflectlons (+/- 0,2 degrees 2 ⁇ ) at 19.1, 14.5, and 9/1 and one of the degree 20-reflections ( ⁇ ⁇ ⁇ /- 0.2 degrees 2 ⁇ ) at 7.6, 26.5, and 17.1.
- Formula I oxalic acid co-crystal has an XRPD pattern comprising degree 28-reilectiorts (+/- 0.2 degrees 20) at 19.1, 14.5, and 9,1 and two of the degree 20- reflections (+/- 0,2 degrees 2 ⁇ ) at 7,6, 26.5, and 17.1,
- Formula I oxalic acid co-crystal has an XRPD pattern comprising degree 29-reflections (+/ ⁇ 0.2 degrees 28) at 19.1, 14.5, and 9.1 and three of the degree 20-reflections (+/- 0.2 degrees 2 ⁇ ) at 7.6, 26.5, and 17,1.
- Formula I oxalic acid co-crystal has an XRPD pattern comprising degree 28 ⁇ refleetions ( ⁇ /- 0,2 degrees 2 ⁇ ) at 19.1, 14.5 » 9.1, 7,6, 26.5, and 17,1.
- Formula 1 oxalic acid co-crystal has an XRPD pattern comprising degree 29- reflections (+/- 0.2 degrees 2 ⁇ ) at 19.1, 14,5, 9.1, 7.6, 26,5, 17.1, 21.8, and 39.4.
- polymorphic Formula 1 oxalic- acid co-crystal has an XRPD pattern comprising any three degree 20-refiections ⁇ +!- 0.2 degrees 2 ⁇ ) selected from the group consisting of .19.1., 1.4.5, 9.1, 7.6, 26.5, 17.1, 21.8, 39.4, 29.7, and 11.6.
- compositions of the present Invention comprise a compound of Formulas (I). (I ) or (ill), including forms and co-crystals thereof, and a pharmaceutically acceptable earrier, diluent or excipient
- the compound of Formulas ( ⁇ ), (II), or (III) is present in the composition in an amount which is effective to treat a particular disease or condition of interest.
- the activity of compounds of Formulas (I), (II), and (III) can be determined by one skilled in the art, for example, as described in co-pending application. U.S.
- PHARMACEUTICAL USE Appropriate concentrations and dosages can be readily- determined by one skilled in the art.
- a compound of Form ulas (I) s (H), and/or (III) is present in the pharmaceutical composition in an amount from about 25 mg to about 500 mg.
- a compound of Formulas (I), (II), and/or (III) is present in the pharmaceutical composition in an amount of about 100 mg to about 300 mg.
- a compound of Formulas (I), (II), and/or ( ⁇ ) is present in the pharmaceutical composition in an amoun t of about 5 mg to about 00 mg.
- a compound of Formulas (I), (IT), and/or (III) is present in the pharmaceutical composition in an amount of about 25 mg to about 100 mg. In certain embodiments, a compound of Formulas (I), (II), and/or (III) is present In the pharmaceutical composition in an amount of about 50 mg to about 1.00 mg. In certain embodiments, a compound of Formula (1), ( ⁇ ), and/or (III) Is present in the pharmaceutical composition in an amount of about 5 mg, 25 mg, 50 mg, 75, mg, 100 mg, 200 mg, 300 mg, 400 mg or about 500 mg.
- compositions comprising at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of polymorphs ⁇ e.g., any one or more of Formula ⁇ polymorphic Forms I, U, III, IV, V, VI, VII and VIII) as described herein.
- a composition comprising one of Formula I polymorphic Forms I, II, III, IV, V, VI, VII, and VIII described herein is provided.
- a composition comprising two of Formula I polymorphic Forms I, II, III, IV, V, VI, VII, and VIII described herein is provided.
- a composition comprising three of Formula I is provided.
- polymorphic Forms L II, III, IV, V, VI, VII, and VIII described herein is provided.
- a composition comprising four of Formula 1 polymorphic Forms 1, XL III, IV, V» VI, VII, and VIII described herein is provided.
- a composition comprising five of Formula I polymorphic Forms I, II, III. IV, V VI, VII, and VIII described herein is provided.
- a composition comprising six of Formula I polymorphic Forms I, II, III, IV, V, VI, VII, and VIII described herein is provided.
- a composition comprising seven of Formula I polymorphic Forms I, II, III, IV, V, VI, VII, and VIII described herein is provided.
- compositions described herein comprising eight of Formula I polymorphic Forms I, II, HI, IV, V, VI, VII, and VIII described herein is provided.
- the compositions described herein may comprise substantially pisre polymorphic forms, or may be substantially free of other polymorphs and/or impurities.
- the composition comprises a polymorphic form of (2 ,5S S i S ⁇ -g-hydroxy-T ⁇ -dlo o-N-CZ ⁇ -iTiil ioro sn ⁇ 'O ⁇ J ⁇ .SJ ⁇ , 13,13a ⁇ oe ⁇ ahydn 2,5 ⁇ methanopytido[ I ! ,2' :4 5 5
- compositions comprising a polymorphic form as described herein, wherein the (2R,5S, 1 Sa ⁇ -S-hydrox -T ⁇ -di so-N-C ⁇ -t fluoroben yl) ⁇ ,;? ⁇ ,?, 1 ⁇ , 13,13a- octa ydro-2,5-methanopyrido[ 1 ' s 2 ! :4,S]pyr azino[2, 1 -b] [ 1 5 3]oxa epis e ⁇ 10-carboxamidc within the composition is substantially pure (i.e., substantially pure Form i. Form II, Form Hi, Form ⁇ ', Form V.
- compositions comprising a polymorphic form of (2R,5S, 13aIt)-8-hydroxy-7,9-dioxo-N- (2,4 s 6-trIf!uorobenzyl)-2,3,4,5 5 7,9 5 i3,I 3a-octahydro-2,5- methanopyrido[1 ⁇ 2';4,5]pyrazlno[2,l-h][l ,3]oxa i;pirie-i0-carboxaniide, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%
- the carboxamide present in the composition is one of the polymorphic forms disclosed herein.
- the composition includes at least about 50%, at least about 60%, at least about 70%. at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of one of the polymorphic forms of (2R,5S, 13aR)-8 iydroxy-7,9-dioxo-N-(2,4,6-irif]uorobenzyl)- 2,3,4,5,7,9, .13, 13a-octahydro-2,5-methar!Op>'Tido[i , ,2 , :4,5]pyrazino[2, 1 -b][.l ,3]oxazepke-10 ⁇ carboxamide.
- compositions comprising a polymorphic form disclosed herein, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of (2R,5 S, 1 ;1 ⁇ 2R ⁇ -8-hydrox.y-7,9-dioxo ⁇ ⁇
- impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic forms present
- im urities may, for example, include by-products from synthesizing (2R S 5 S, 13aR)-81 ⁇ 2droxy-7.9-dioxo ⁇ - ⁇ 2A ⁇
- impurities include by-products from the process of synthesizing i2R,5S 5 13aR) ⁇ 8-hydroxy-?,9 ⁇ dio3 ⁇ 4o ⁇ N-(2,4 s 6 ⁇ trifto ⁇
- Impurities include contaminants from the process of syHthesteing (2R,5S 3aR) ⁇ 8-hydrGx
- impurities include degradation products of
- impurities include other polymorphic forms of (2R,5S,13aR)-8-hydrox r y-7 s 9- dioxo-N"(2,4 ⁇ 6 rif!uorobenzyi) ⁇ 2 s 3 ; 4,5,7,9 5 13, 13a-octahydro--2,5- methanopyrido[ 1 ',2' :4, 5]pyrazino[2, I -b] [ I,3]oxazepine- !
- impurities include water or solvent.
- impurities are selected from the group consisting of by-products from synthesizing (2R,5S,13aR) ⁇ S ⁇ hydroxy ⁇ 7 s 9 ⁇ dioxo ⁇ M ⁇ (2 s 4,6- trifjuorobenzy!)-2,3 s 4,S,? ⁇
- the composition comprising a polymorphic form disclosed herein has less than about 5%, less man about 4%, less than about 3%, less than about 2%. or less than about 1% by weight of amorphous or non -crystalline (2R,5S, 13aR)-8- d o ⁇ -dio o-N ⁇ .
- compositions comprising at least one polymorph ⁇ e.g., any one or more of Formula II polymorphic Forms ⁇ ) as described herein.
- a composition comprising Formula ⁇ polymorphic Form 1, described herein is provided, in other embodiments, the compositions described herein may comprise substantially pure polymorphic forms, or may be substantially free of other polymorphs and/or impurities,
- the composition comprises a polymorphic form of sodium (2R,5S 5 13aR) ⁇ 7,9-dioxo ⁇ 10-( ⁇ 2 3 4 : ,6-trifJuoroberiz 'l)carbanioyl) ⁇ 2 s 3,4 s 5,7 5 9, 13,13a ⁇ oetahydro- 2,5"meihanopyrido[1 ⁇ 2 , :4,5]pyrazmo[2,l-b3[l,31oxazepin-8 «oiate.
- compositions comprising a polymorphic form as described herein, wherein the sodium (2R,SS 3aR)-7 s 9-dioxo-10-((2 5 4,0-tri ⁇
- compositions comprising a polymorphic form, of sodium (2R s 5SJ3aR)-7,9 ⁇ dioxo-lG- ( ⁇ 2 A6 ⁇ tr3f1uorobenzy l)eatbamoyl)-2,3 AS.,7,9, 13, 13a ⁇ octahydro-2,5 ⁇
- meihanopyrido[r s 2 , :4 ? 5]pyrazmo[2,l-b][.U3]oxazepin-8-olate at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% ot ⁇ sodium (2R,SS,13aR) ⁇ 7 s 9-d ⁇
- the composition includes at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least, about 98%, or at least about 99% of Form I of sodium (2R,5S,!3aR)-7,9 ⁇ dioxO"10-((2,4,6- ⁇
- compositions comprising a polymorphic form disclosed herein, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of sodium (2R,5S, 13aJl)-7,9-dioxo ⁇ i 0-((2,4.6- trifluorohenzyi)cai-bamoyl)-2,3,4,5,7,9, 13,13a ⁇ octahydro-2,5- methaiiopysido[l ! ,2 ?
- composition are other polymorphs of sodium (2R,5S 5 13aR)-7,9"dioxo ⁇ iO-((2,4,6-triOuorohenzyl)carbanioyl) ⁇ 2,3,4,5,7,9, 13, 13a ⁇ oetahydro-2,5-metbanopyrido[ l ! ,2 f :4,5]pyrazino[2, 1 -b][1 ,3]oxazepin ⁇ 8 ⁇ elate and/or impurities.
- impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic forms present.
- Impurities may. for example, include by-products from synthesizing sodium (2 s 5SJ3a )-7,9-diaxo-10-((2,4,0 ⁇
- impurities include by-products from the process of synthesizing sodium ⁇ 2R,5S i 13aR.)-7 5 9"dIoxo-10- ⁇ (2,4,6 rifluoroben£yi)carbamoyi)- 2.3,4 J,7,9 ! i343a-octahydro-2,5-Biethanopyrido 3 2':4,5]pyi-azino[2, l ⁇ b][!,3]oxazepm-8- olate.
- impurities include contaminants from the process of synthesizing sodium (2R,5S, 33aR)-7,9-dioxo- 10-((2A6-triftuorobenzy ⁇ carbam ⁇
- impurities include degradation products of sodium
- impurities include other polymorphic forms of sodium (2R,5S, 13aR ⁇ 7,9-dk>xo-10 ⁇ ((2,4,6 - trifluorobefizyl)carbamoyl)-2,3,4,5,? 5 9, 13,13a-ociahydro-2,5- methan ridol ⁇ '. ⁇ jpyra irjo ⁇ j l-bjl l ⁇ joxaze isi-S-olaie,
- impurities include water or solvent.
- impurities are selected from the group consisting of by* products from synthesizing sodium (2 ,5S,13aR)-7,9 ⁇ dioxo-I0-((2,4,6- trifluoroben2;yl)carbamoyl)-2 3 3,4 s 5,7 s 9,13 s l3a-octahydro-2 5 5 ⁇
- the composition comprising Formula II, Form I disclosed herein has less than about 5%, iess than about 4%. less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline sodium
- the term "substantially pure” or “substantially free” with respect to a particular polymorphic form of a compound means that the composition comprising the polymorphic form contains less than 95%, less than 90%, less than 80%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% by weight of other substances, including other polymorphic forms and/or impurities.
- "substantially pure” or “substantially free of refers to a substance free of other substances, including other polymorphic forms and/or impurities. Impurities may, for example, include by-products or left over reagents from chemical reactions, contaminants, degradation products, other polymorphic forms, water, and sol vents.
- compositions comprising at least one, or all of polymorphs ⁇ e.g. , any one or more of Formula III polymorphic Forms I, II, and III) as described herein.
- a composition comprising one of Formula III polymorphic Forms I, II, and III described herein is provided.
- a composition comprising two of Formula ⁇ polymorphic Forms I, II, and III described herein is provided,
- the compositions described herein may comprise substantially pure polymorphic forms, or may be substantially free of other polymorphs and/or impurities.
- the composition comprises a polymorphic form of potassium (2R,5S, 13aR)-7,9 ⁇ dioxo-l O- ⁇ -rulluorobe ⁇ ca b moyl) ⁇ ,? ⁇ , 13,13a- oe-tahydro ⁇ 2,5-methanopyrido[! ⁇ 2':4,S]p ⁇
- compositions comprising a polymorphic form as described herein, wherein the potassium (2R,5S, 13aR) ⁇ ?,9 ⁇ dioxo- 10- ⁇ (2,4,6-trifluorobenz l ⁇ c6.rba oyl)- 2 s 3A5,7,9 5 I3,13a ⁇ Q Ctahydr0-2,5 ⁇ meta
- compositions comprising a polymorphic form of potassium (2R,5S, 13aR)-7,9-dioxo- 10-i(2 5 4,6-trifluoroben:3 ⁇ 44)eaA ⁇
- octahydro ⁇ 2,5-metha3 ⁇ 4opyrido[r,2':4,5]pyraK?no[2, l-h ' ][l ,3]oxa ⁇ pin ⁇ 8 ⁇ olate at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of potassium (2 5 5S,13aR)-7,9-dioxo-10-( ⁇ 2,4 5 6- irifiuoroben l)carbamoyi)-2 5 3 :i 4,5,7,9,13,13a-octahydro-2 ;!
- the composition includes at least, about 50%. at least about 60%, at least about 70%, at least about 80%, at least about 85%. at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of one of the polymorphic forms potassium (2 ,5S, 13aR)-7,9 ⁇ dioxG- 10-((2 ,5S, 13aR)-7,9 ⁇ dioxG- 10-((2
- compositions comprising a polymorphic form disclosed herein, less than about 50%. less than about 40%, less than about 30% 5 less than about 20%, less than about 10%, less than about 5%. less than about 4%, less than about 3%, less than about 2% or less than about 1% of potassium (2R 5 5S,13aR)-7,9-dioxo-10-((2 ! 4,6- trifiuorobe3 ⁇ 1)carhaBioyi)-2,3,4 ?
- impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphic forms present, impurities may, for example, include by-products from synthesizing potassium (2R.5SJ 3aR) ⁇ 7,9 ⁇ diGXQ-10-((2,4 s 6 riflu ⁇
- impurities include by-products from the process of synthesizing potassium (2R 5 5 S, 13 aR)-7,9 ⁇ dioxo- 10-((2,4,6»trifluorobenzyl)carbamoyi)-2 5 3 ,4, 5 ,7,9, 13,13a- octah ⁇ 'dro-2 s 5-metha.nopyrido[r,2 i ;4 J 5]pyTazino[2,l-b][l s 3]oxazepk-8-oiate.
- impurities include contaminants from the process of synthesizing potassium (2R,5S, 13aR)-7,9-dioxo- 10-((2,4 s 6-trifluofoben2yl)earbamoyl)-2 5 3,4,5 5 7,9, 13, 13a ⁇ octahydro ⁇ 2,5"S3 ⁇ 4ethanopyrido[r,2 , :4,5]pyrazino[2, i ⁇ b][ 1 ,3]oxazeph ⁇ -olate.
- impurities include degradation products of potassium (2R.5S, 13aR) « ?,9 ⁇ dioxo - 10- ⁇ (2,4,6- U-ifluorobeRzy!carbamoy])-2,3,4,S,7,9 > 13, 13a ⁇ oeiahydro-2,5 ⁇
- impurities include other polymorphic forms of potassium (2R «5S, i 3a ) ⁇ 7,9-dioxo ⁇ I0 ⁇ ( ⁇ 2,4,6- trifl uorobenzyl) arbamoyl) ⁇ 2, 3,4,5,7,9,13,13 a-octahydro-2,5 - methaiK)p rido ,2':4.S]p azmo[2,1 ⁇ b][l ,3]oxazepin-8-oiate.
- Impurities include water or solve t
- impurities are selected from, the group consisting of byproducts from synthesizing potassium (2 ,5S,13aR) ⁇ 7,9-"dioxo ⁇ 10 ⁇ 2,4,6 ⁇
- the composition comprising a polymorphic form disclosed herein has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline potassium (2R,5S.13aR) ⁇ 7,9-dioxo- 10-((2,4,6-trifi orobeii3 ⁇ 4'l)carbamoyl)-2,3,4,5,7 s 9 ! 13,13a-octahydro- 2 J 5»methanopyrido[lV2 ! :4,5]py a7ino[2,l "b][l,3]oxazepin ⁇ 8--olaie.
- compositions comprising at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or ail of polymorphs ⁇ e.g., any one or more of Formula I polymorphic Forms I, II, ill, IV, V, VI, VI , and VIII, Formula II polymorphic Form I, and/or Formula IH polymorphic Forms 1, 11, aud III) as described herein.
- a composition comprising one of Formula I polymorphic Forms I, II, III, IV, V, VI, VII, and VIII, Formula II polymorphic Form 1, and/or Formula III polymorphic Forms 1, 11, and III described herein is provided.
- a composition comprising two of Formula I polymorphic Forms I, II, III, IV, V, VI, VII, and VIII, Formula II polymorphic Form ⁇ , and/or Formula III polymorphic Forms I, II, and III described herein is provided,
- a composition comprising three of Formula I polymorphic Forms I, II, III, IV, V, VI, VII, and VIII, Formula II polymorphic Form 1, and/or Formula II polymorphic Forms I, II, and III described herein is provided,
- a composition comprising four of Formal Formula 1 polymorphic Forms I, II, III, IV, V, VI, VII, and VIII, Formula II polymorphic Form I, and/or Formula III polymorphic Forms L
- a composition comprising five of Formula I polymorphic Forms I, II, IIL IV, V, VI, VII, and VIII, Formula II polymorphic Form I, and/or Formula III polymorphic Forms I, II, and III described herein is provided.
- a composition comprising six of Formula I polymorphic Forms I, ⁇ , III, IV, V, VI, VII, and VEIL Formula II polymorphic Form I, and/or Formula III polymorphic Forms I, II, and III described herein is provided.
- composition comprising seven of Formula I polymorphic Forms I, ⁇ , III, IV, V, VI, VII, and VIII, Formula II polymorphic Form I, and/or Formula III polymorphic Forms I, II, and HI described herein is provided.
- compositions comprising eight of Formula I polymorphic Forms I, II, III, IV, V, VI, VII, and VIII, Formula II polymorphic Form I, and/or Formula III polymorphic forms I, II, and III described herein is provided, In a particular embodiment a composition comprising nine of Formula I polymorphic Forms I, II, III, IV, V, VI, VII, and VIII, Formula II polymorphic Form I s and/or Formula 111 polymorphic Forms I, II, and III described herein is provided.
- compositions comprising ten of Formula I polymorphic Forms L ⁇ , III, IV, V, VI, VII, and VIII, Formula II polymorphic Form I, and/or Formula III polymorphic Forms I, II, and HI described herein is provided.
- a composition comprising eleven of Formula I polymorphic Forms I, II, III, IV, V, VI, VII, and VIII, Formula II polymorphic Form I, and/or Formula III polymorphic Forms I, II, and III described herein is provided.
- the compositions described herein may comprise substantially pure polymorphic forms, or may be substantially free of other polymorphs and/or impurities.
- the tem "substantially pure” or “substantially free” with respect to a particular polymorphic form of a compound means that the composition comprising the polymorphic form contains less than 95%, less than 90%, less than 80%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% by weight of other substances, including other polymorphic forms and/or impurities.
- "substantially pure” or “substantially free of 5 refers to a substance free of other substances, including other polymorphic forms and/or impurities. Impurities may, for example, include by-products or left over reagents from chemical reactions, contaminants, degradation products, other polymorphic forms, water, and solvents.
- compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
- compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as solid dispersions and solid solutions.
- Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
- the pharmaceutical compositions is prepared for oral administration.
- the pharmaceutical composition is a tablet.
- Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the compositio to a patient.
- compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units.
- dosage forms are known, or will be apparen t, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000),
- the composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention for treatment of a disease or condition of Interest in accordance with the teachings of this invention,
- compositions of the invention may be prepared by methodology well known in the pharmaceutical art.
- a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution, A surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
- Surfactants are compounds that non-covalentiy interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous de lively system.
- a solid pharmaceutical composition intended for oral administration can be prepared by mixing a compound of the invention with at least one suitable pharmaceutical excipient to form a solid eformulation composition, which then may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- a pharmaceutical composition is provided, which includes a compound of Formula ( ⁇ ), (II), or (III) and a pharmaceutical exe-ipient.
- the compounds of the invention are administered in a therapeutically effecti ve amount which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy, in some embodiments, the compounds of the in ention can be administered alone or is combination with other antiviral agents once or twice daily for as long as the patient is infected, latently infected, or to prevent infection (e.g. for multiple years, months, weeks, or days).
- a method for treating or preventing an HIV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
- a method for treating an HIV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one. two, three, one or two, or one to three) additional therapeutic agents.
- a method for treating an HIV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound or composition disclosed herei In combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
- a therapeutically effective amount of a compound or composition disclosed herei In combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
- the present invention provides a method for treating an HI infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition disclosed herein in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.
- One embodiment provides a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents for use in a method for treating or preventing an HIV infection in a human having or at risk of having the Infection,
- One embodiment provides a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents for use in a method for treating an HIV Infection in a human having or at risk of having the infection.
- One embodiment provides a compound disclosed herein for us in a method for treating or preventing a HIV infection in a human having or at risk of having the infection, wherein the compound is administered in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
- One embodiment provides a compound disclosed herein for use in a method for treating an HIV infection in a human having or at risk of having the infection, wherein the compound is administered in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
- the present invention provides a compound disclosed herein in combination with one or more additional therapeutic agents which are suitable for treating an HIV infection, for nse in a method for treating an HIV infection, in certain embodiments, the present invention provides a compound disclosed herein for use in a method for treating an HIV infection, wherein the compound is administered in combinatio with one or more additional therapeutic agents which are suitable for treating an HIV infection.
- One embodiment provides the use of a compound disclosed herein thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents in the manufacture of a medicament for treating or preventing an HIV infection in a human having or at risk of having the Infection.
- One embodiment provides the use of a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents in the manufacture of a medicament for treating an HIV infection in a human having or at risk of having the infection.
- One embodiment provides the use of a compound disclosed herein in the manufacture of a medicament for treating or preventing an HIV infection in a human having or at risk of having the Infection, wherein the compound Is administered in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
- One embodiment provides the use of a compound disclosed herein thereof, in the manufacture of a medicament for treating an HIV infection in human having or at risk of having the infection, wherein the compound is administered in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, in certain embodiments, the present invention provides the use of a compound disclosed herein thereof, in
- the present invention provides the use of a compound disclosed herein thereof for treating an HIV infection, wherein the compound is administered in combination with one or more additional therapeutic agents which are suitable for treating an HIV infection.
- a compound as disclosed herein may be combined with one or more additional therapeutic agents in any dosage amount of the compound of Formulas ( ⁇ ), (II), and/or (III) (e.g., from 50 mg to 1000 mg of compound),
- compositions comprising a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutical ly acceptable carrier, diluent or exeipient are provided.
- combination pharmaceutical agents comprising a compound disclosed herein in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided.
- kits comprising a compound disclosed herein in combination with one or more (e.g., one. two, three, one or two, or one to three) additional therapeutic agents are provided.
- the additional therapeutic agent may be an aod-HIV agent.
- the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non-nndeoside inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV mtegrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp!20 inhibitors, G6PD and NA.DH-oxida.se inhibitors, compounds that target the HIV capsid ("capsid inhibitors"; e.g., capsid polymerization inhibitors or capsid disrupting compounds such as those disclosed Irs WO 2013/006738 (Giiead Sciences),
- the additional therapeutic agent may be an and- HIV agent.
- the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non-nuc!eoside or non-nucleoiide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or aliosteric) integrase inhibitors, HIV entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp!20 inhibitors, G6PD and NADH-oxidase Inhibitors, HIV vaccines, HIV maturation inhibitors, latency reversing agents (e.g., histone deacety!ase inhibitors, proteasoroe Inhibitors, protein kinase C (PKC
- capsid polymerization inhibitors or capsid disrupting compounds HIV nucleocapsid p7 (NCp?) inhibitors, HIV p24 capsid protein inhibitors), pharmacokinetic enhancers, immune-based therapies (e.g., Pd-1 modulators, Pd-Ll modulators, toil like receptors modulators,, IL-15 agonists, ), HIV antibodies, bispeeific antibodies and "antibody-like" therapeutic proteins (e.g., DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives) including those targeting HIV gp!20 or gp4i, combination drags for HIV, HIV pi 7 matrix protein inhibitors, IL-13 antagonists, Peptidyl -prolyl cis-trans isoraerase A modulators.
- Pd-1 modulators e.g., Pd-Ll modulators, toil like receptors modulators,, IL-15 agonists
- HIV antibodies bispe
- Protein disulfide isomera.se inhibitors, Complement C5a receptor antagonists, DNA methyitransferase inhibitor, HIV vif gene modulators, Vif dhiierization antagonists, HW-1 viral infcetivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-l splicing inhibitors, Rev protein Inhibitors, Integrin antagonists, Nucleoprotein inhibitors, Splicing factor modulators, COMM domain containing protein 1 modulators, HIV ibonuclease H inhibitors, Retrocyelin modulators, CDK-9 inhibitors, Dendritic ICAM-3 grabbing nonintegrln 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, Ubiquitin ligase inhibitors, Deoxycytidme kinase inhibitors, Cy
- the additional therapeutic is selected from tbe group consisting of HIV protease inhibitors, H1Y non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosterie) integrase Inhibitors,
- a compound of Formulas (I), (II), and/or (III) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV.
- the tablet can contain another active ingredient for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide Inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosterie) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.
- the tablet can contain one or more active ingredients for treating HIV, such as HIV nucleoside or nucleotide Inhibitors of reverse transcriptase.
- such tablets are suitable for once daily dosing,
- the additional therapeutic agent is selected from one or more of:
- HIV nucleoside or nucleotide inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emfridtahine, didanosine, stavudins, xale-iiabine, lamivudine, abacavir, abacavir sulfate, aradoxovir, elvucit&bine, alovudine, MIV-210, ⁇ -FTC, D ⁇ d4FC, emtricitabine, phosphatide, fozivudine tidoxil, aprieitlbine (AVX754), KIM 461, GS-9131
- HIV integrase inhibitors selected from the group consisting of ciircumin, derivatives ofcurcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicafFeoylquinic acid, derivatives of 3,5-dicaffeoyiquInie acid, aurintriearboxyfie acid, derivatives of
- aarintricarboxylic acid caffeic acid phenethyl ester, derivatives of caffeie acid phenethyi ester, iyrphostin, derivatives of iyrphostin, quercctin, derivatives of quercetin, S-1360, AR- 177, L-870812, and L-870810, raitegra , BMS-538158, GSK364735C, BMS-707035, MK- 2048, BA 01 1, elvitegravir, dolutegravir, dolutegravir sodium, and GSK-744;
- NTNI HIV fion-catalyiic .site, or allosterk, integrase inhibitors
- gp4i inhibitors selected from the group consisting of enfuvirtide, sifuvtrtide, a!buvirtlde, FB006M, and TRM 144;
- CCRS Inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, ccnicriviroc, PRG-I 40, INCB.I 5050, PF-232798 (Pfizer), and CCR5mAb004;
- CD4 attachment inhibitors selected from the group consisting of ibalizumab (TMB-355) and BMS-068 (BMS-663068);
- phamiacokmetic enhancers selected from the group consisting of cobicistai and SPI-452;
- other drugs for treating HIV selected from the group consisting of BAS-I00, SPI- 452, REP 9, SP-Gi A, TNX-3SS, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevMmat), HRG214, VGX-410, D-247, AMZ 0026, CYT 99007A-221 HIV, DEBiO-025, BAY 50- 4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1G5QQ40 (PA-040), and combinations thereof.
- drugs for treating HIV selected from the group consisting of BAS-I00, SPI- 452, REP 9, SP-Gi A, TNX-3SS, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevMmat), HRG214, VGX-410, D-247, AMZ 0026, CYT 99007A-221 HIV, DEBiO-025, BAY 50-
- die additional therapeutic agent is selected from one or more of:
- HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir, fesamprenavir calcium, indinavir, indinavir sulfate, lopinavir, ritonavir, nelflnavir, nelfinavir mesylate, saquinavir, saquinavir mesylate, tipranavir, breeanavir, darunavir, DG-17, TMB-657 (FPL-100) and T C-31091 1 ;
- HIV non-nuc!eoside or non-nncleotide inhibitors of reverse transcriptase selected from the group consisting of delavirdine, delavirdine mesylate, nevirapine, etravirine, dapivirine, doravirine, rilpivirine, efavirenz, M-G23, VM-1500, lentinan and AIC-292;
- HIV nucleoside or nucleotide inhibitors of reverse transcriptase selected from the group consisting of VIDEX® and VIDEX® EC (didanasine. ddl) 5 zido vudine, emtricitabine, dldanosine, stavudine, zalcitabine, lamivudine, censavudine, abacavir, abacavir sulfate, amdoxovir, el ucitabine, alovudine, phosphazid, fozivudine tidoxil, aprkitabine, amdoxovir .
- KP-1461 fosa!vudine tidoxil, ienofovir, tenofovir disoproxil, ienofovir disoproxil fumarate, tenofovir disoproxil hemifi.mia.rate, tenofovir alafenamide, tenofovir alafenamide
- HIV integrase inhibitors selected from the group consisting of ewcwniin, derivatives of curcu in, chicoric acid, derivatives of chicoric acid, 3 ,5 -dicaffeoylquin ic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxyiic acid, derivatives of
- aurintricarboxyiic acid caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of lyrphostin, qoercetin, derivatives of quercetin, raltegravir, dvitegravir, do!utegravir and eabotegravir;
- NCINI HIV non-catalytic site, or allosterie, integrase inhibitors (NCINI) selected from the group consisting of CX-05168, CX-05045 and CX-14442;
- HIV gp4.l inhibitors selected from the group consisting of enfovixtide, sifuvirtide and albuvirtide; (8) HIV entry inhibitors selected from the group consisting of cenicriviroc;
- HIV g i O inhibitors selected from the group consisting of Radha-108 (Reeeptol) and BMS-663068;
- CCR.5 inhibitors selected from the group consisting of apiaviroc, vicriviroc, rnaraviroe, cemcriviroc, PRO- 140, Adaptavir (RAP-J O 1 ), nifeviroc (TD-0232), TD-0680, and vMIP (Haimipu);
- CD4 attachment inhibitors selected from the group consisting of ibalkuniab;
- CXCR4 inhibitors selected from the group consisting of plerixafor, ALT- 1188, vMIP and Hairnipu;
- Pharmacokinetic enhancers selected from the group consisting of cobicistat and ritonavir;
- Immune-based therapies selected from the group consisting of dermaVir, interkukin-7, plaqnenll (hydroxychloroquine), proleukin (aldesleukin, if . -2), interferon alia, interferon alfa-2b, interferon alfa-n3, pegylated interferon alfa, interferon gamma, hydroxyurea, myeoplienoiate mofetil (MP A) and its ester derivative mycoptienolate mofetil (MMF), WF-10, ribavirin, l ' L-2, IL-12, polymer polyeffayleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936S59, toll-like receptors modulators (tkl, ilr2, tlr3, tir4, tlr5, tlr6, tlr7, tlrS, tir9, tlrlO, tir1 1 , tirl2 and t
- HIV vaccines selected from the group consisting of peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, virus-like particle vaccines (pseudovirion vaccine), CD4-derived peptide vaccines, vaccine combinations, rgpl2Q (AIDSVAX), ALVAC HIV (vCP! S2i)/AIBSVAX B/E (gp!20) (RV144), monomelic gp l 20 IHV-1 subtype C vaccine (Novartis), Remnne, ITV-l . Contre Vir, Ad5 ⁇ ENVA-48, DCVax- 001 (CDX-24G1), PEP-6409,Vacc-4x.
- TVI-HIV-1, Ad-4 Ad4-env Clade C + Ad4-mGag
- Ad-4 Ad4-env Clade C + Ad4-mGag
- PrcVaxTat TL-01
- SAV- 001 SAV- 001
- AE-H SAV- 001
- MYM-YIGl CombiHIVvac
- ADVAX ADVAX
- MYM-V201 MVA-CMDR
- ETV-01 CDX-I4G1, rcAd26.MOS l .HiV-Env and DNA ⁇ Ad5 gag/pof/nef/nev (HYTN505);
- HIV antibodies, bispecific antibodies and "antibody-ilke” therapeutic proteins such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ® strictly Fab derivatives
- BMS-936559, TMB-360 and those targeting HIV gp!20 or gp41 selected from the group consisting of bavituximab, UB-42L C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC- 1 17 , PGT145, PGT12L DX01 Q (ipilim ma ).
- latency reversing agents selected from the group consisting of Histone deaeetylase inhibitor such as Romidepsin, vorinostai panobinostat; Proteasome inhibitors such as Yeleade; protein kinase C (PKC) activators such as indolaetam, Prostratin, Ingenol B and DAG-lactones, Ionomycin, GS -343, PMA, SAHA, BRD4 inhibitors, IL-15, JQI , disulfram, and amphotericin B;
- Histone deaeetylase inhibitor such as Romidepsin, vorinostai panobinostat
- Proteasome inhibitors such as Yeleade
- protein kinase C (PKC) activators such as indolaetam, Prostratin, Ingenol B and DAG-lactones, Ionomycin, GS -343, PMA, SAHA, BRD4 inhibitors,
- Np7 HIV nucleocapsid p7 (NCp7) inhibitors selected from the group cons sting of azod carbonamide
- HIV maturation inhibitors selected from the group consisting of BMS-955176 and GSK-2838232;
- PI3K inhibitors selected from the group consisting of sacredalisib, AZD-8186, bupariisib, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, aipelisib, duvelisib, UCB-5857, tase!isib, XL-765, gedatoiisib, VS-5584, copanlisib, CA?
- (22) other drugs for treating HIV selected from the group consisting of BanLee, MK ⁇ 8507, AG- 1105, TR-452, M -8591 , REP 9, CYT-107, alisporivir, NOV-205, IND-02, metenkefalin, PGN-007, Aeemannan, Gamimune, Prolastin, 1,5-dicaiFeoylquinic acid, ⁇ - 225, RPI-MN, VSSP.
- a compound disclosed herein Is combined with two. three, four or more additional therapeutic agents in certain embodiments, a compound disclosed herein Is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein Is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein is combined with four additional therapeutic agents.
- the two, three four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, or they can be selected from different classes of therapeutic agents, in a specific embodiment, a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non ⁇ nucleoside inhibitor of reverse transcriptase, in another specific
- a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
- a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucieoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
- a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HTV non-nucleoside inhibitor of reverse transcriptase, and a
- a compound disclosed herein is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.
- a compound disclosed herein is combined with one, two, three, four or more additional therapeutic agents.
- a compound dssciosed herein is combined with one additional therapeutic agent.
- a compound disclosed herein is combined with two additional therapeutic agents.
- a. compound disclosed herein is combined with three additional therapeutic agents.
- a compound disclosed herein is combined with four additional therapeutic agents.
- the one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from d ifferent, classes of therapeutic agents.
- a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase
- a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound
- a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, ami an HIV protease inhibiting compound.
- a compound disclosed herein is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer.
- a compound disclosed herein is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer,
- a compound disclosed herein is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.
- a compound disclosed herein is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer.
- a compound disclosed herein is combined with abacavir, abacavir sulfate, tenofovir, tenofovir disoproxlf &marate s tenofovir alafenamide, or tenofovir alafenamide hemifumarate,
- a compound disclosed herein is combined with tenofovir, tenofovir disoproxil fimnarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate, [0211]
- a compound disclosed herein is combined with a first additional therapeutic agent selected from the group consisting of: abacavir, abacavi sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenoibvir alafenamide hemifumaraie and a second additiosal therapeutic agent selected from the group consisting of emtricitibirse and lamivudine.
- a compound disclosed herein is combined with a first additional, therapeutic agent selected from the group consisting of: tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemlfumarate and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtrichibine.
- a compound disclosed herein is combined with one, two, three, four or more additional therapeutic agents selected from Ttiumeq®
- a compound disclosed herein is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumaraie, tenofovir aiafenamide, or tenofovir aiafenamide hemifumarate.
- a compound, disclosed herein is combined with a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumaraie, tenofovir aiafenamide. and tenofovir aiafenamide hemi fumaraie and a second additional therapeutic agent selected from the group consisting of erntrieitabine and laxnivudine.
- a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumaraie, tenofovir aiafenamide. and tenofovir aiafenamide hemi fumaraie
- a second additional therapeutic agent selected from the group consisting of erntrieitabine and laxnivudine.
- a compound disclosed herein Is combined with a -first additional therapeutic agent selected from the group consisting of: tenofovir, tenofovir disoproxil, tenofovir disoproxil fumaraie, tenofovir aiafenamide, and tenofovir aiafenamide hemifnmarate and a second additional therapeutic agent, wherein the second additional therapeutic agent, is emtricitablne.
- a compound disclosed herein is combined with 5-30 mg tenofovir aiafenamide fumaraie, tenofovir aiafenamide hemifumarate, or tenofovir aiafenamide and 200 mg emtrlcitablne, in certain embodiments, a compound disclosed herein is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir aiafenamide fumaraie, tenofovir aiafenamide hemi fumaraie. or tenofovir akfenamide and 200 mg emtricitablne.
- a compound disclosed herein is combined with 10 mg tenofovir aiafenamide fumaratc, tenofovir aiafenamide hemlfumaraie, or tenofovir aiafenamide and 200 mg emtricitablne. in certain embodiments, a compound disclosed herein is combined with 25 mg tenofovir aiafenamide fumaraie, tenofovir aiafenamide hemifumarate, or tenofovir aiafenamide and 200 mg emtricitablne.
- a compound as disclosed herein may be combined with the agents provided herein in any dosage am ount of the compound (e.g., from 50 mg to 500 nig of compound) the same as if each combination of dosages were specifically and individually listed.
- a compound disclosed herein is combined with 200-400 nig tenofovir disproxIL tenofovir disoproxil fumarate, or tenol vir disoproxii hemifurnarate and 200 mg emtrieitabine.
- a compound disclosed herein is combined with 200-250; 200-300; 200-350; 250-350; 250-400; 350-400; 300-400; or 250» 400 mg tenofovir disoproxii, tenofovir disoproxii fumarate, or tenofovir disoproxil hemifurnarate and 200 nig emtrieitabine, In certain embodiments, a compound disclosed herein is combined with 300 mg tenofovir disoproxii fumarate, tenofovir disoproxii hemifumarate, or tenofovir disoproxii and 200 mg emtrlcitahlne.
- a compound as disclosed herein may be combined with the agents provided herein m any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
- the components of the composition are administered as a simultaneous or sequential regimen.
- the combination may be administered in two or more administrations.
- a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.
- a compound disclosed herein is administered with one or more additional therapeutic agents.
- Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and one or more additional therapeutic agents are both present in the body of the patient.
- Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents,
- a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents.
- a unit, dose of one or more additional therapeutic agents is administered first, followed fay administration of a unit dose of a compound disclosed herein within seconds or minutes.
- a unit dose of a compound disclosed herein is administered first, followed, after a period of hours ⁇ e.g..
- a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound disclosed herein.
- the crystalline forms are characterized by the interiattlce plane intervals determined by an X-ray powder diffraction pattern (XRPD).
- XRPD X-ray powder diffraction pattern
- diffractogram of XR PD is typically represented by a diagram plotting the intensity of the peaks versus the location of the peaks, i.e., diffraction angle 20 (two-theta) in degrees,
- the intensities are often given in parenthesis with the following abbreviations; very strong - vst; strong - st; medium - m; weak ⁇ w; and very weak - vw.
- the characteristic peaks of a given XRPD can be selected according to the peak locations and their relative intensity to conveniently distinguish this crystalline structure from others.
- the measurements of the XRPD peak locations and/or intensity for a given crystalline form of the same compound will vary within a margin of error.
- the values of degree 2 ⁇ allow appropriate error margins.
- tha error margins are represented by
- the degree 20 of about "8.7 ⁇ G.3" denotes a range from about 8,7- 0.3» i.e., about 9.0, to abont 8.7-0.3, i.e., about 8.4,
- the appropriate error of margins for a XRPD can be ⁇ 0.5; ⁇ 0.4; ⁇ 0.3; ⁇ 0.2; ⁇ 0.1; ⁇ 0.05; or less.
- the XRPD margin of error is ⁇ 0.2
- a method of producing a composition comprising one or more polymorphs of ⁇ 2R,5S,13a )- ⁇ Hydroxy-7 > 9-dioxo- - ⁇ 2,4 ) 6 ⁇ trifi uof Plumbing3 ⁇ 4i)"2 A ⁇ hjP.SJoxazepinc ⁇ O-carboxamide, wherein the method comprises combining a compoimd of Formula (I) with a suitable solvent or a mixture of suitable solvents to produce a composition comprising one or more polymorphs of the. compound of Formula (I).
- composition comprising one or more polymorphs of (2R,5S, i :3 ⁇ 4R)-8-iiydroxy.7 s 9"dioxo ⁇ N 2,4 > 6 rifluorobenzyl).2.
- Solvents suitable for polymorph formation may include, for example, methanol, ethanoi, water, isopropyl acetate, acetonitrile, tetrahydrofurao, methyl isobutyl ketone, and any mixtures thereof,
- methanopyrido[l ⁇ 2';4,5]p ⁇ ajzino[2J-b][1 ]ox&zepine-10 ⁇ carboxamide produced according to any of the methods described herein.
- the methods for preparing the polymorphs described herein may yield quantity and quality differences compared to the methods for preparing (2R,SS,13aR)-8-Hydroxy-7 5 9 ⁇ dioxo-N-(2 5 4 5 6"trifluoroben3 ⁇ 44)-23 s 4,5 : ,7 5 9 3 13,13a-octahYdrQ-2 ) 5- methanopyrido[ 1 ° s 2 ! :4 3 5]pyrazino[2, 1 -b] [ l 5 3] ixa/epine-' I G-earboxamide produced on laboratory scale.
- a method of producing a composition comprising polymorphic Form I, Form ⁇ , or a mixture thereof, of (2R,5S, 13aR ⁇ -8- Iiydroxy-7,9 ⁇ dioxo ⁇ - (2A6 rifiuorabenzyl) ⁇ 2 ; 3,4,5,7,9, 13, ! 3a-octahydro ⁇ 2,5 ⁇
- composition comprising polymorphic Form III of (2R J 5S ⁇ 3aR)-8 ⁇ Hydroxy ⁇ 7 5 9-dioxo-N-(2 > 4 5 6 ⁇ fluoroberizyl)-
- carboxamidc wherein the method comprises combining (2R,5S,I3aR) ⁇ 8 ⁇ Hydroxy"7,9-dioxo- N-(2,4,6 ' rifdiorobeB S'l)-2,3 5 4,5,7,9 :i 13,I3a-octahydro--2,5- methanopyrido[1 ⁇ 2 !
- composition comprising polymorphic Form IV, Form VII, and Form VIII, or a mixture thereof, of (2R 5 5S,!3aR)-8- Hydroxy-7.9 ⁇ ioxo-N-(2A6- ⁇
- composition comprising polymorphic Form V of (2R,5S S 13aR)-8-Hydroxy-7,9 ⁇ toxo-N 2A ⁇
- composition comprising polymorphic Form VI of(2R,5S, 13aR 8 : iydroxy-7,9Hiioxo-Ni:2 ; ⁇
- the solvent is selected from the group consisting of methanol, water, and any mixtures thereof, In an embodiment, the solvent is a mixture of water and methanol.
- oetahydro «2,5-metfaanopyrido[i ',2 ! :4,,5 jpyrazino[2, 1 ⁇ h][ 1 ,3 joxazepine- 10-carboxamide with a solvent, wherein the solvent is selected from the group consisting of methanol, water, aad any mixtures thereof, Irs an embodiment, the solvent is a mixture of water and methanol
- olate e.g. a compound of Formula (If) is described herein.
- composition comprising one or more polymorphs of sodium (2R S 5S,13aR.) ⁇ 7,9 ⁇ dioxo-10-((2,4 s 6- xrit1uorobenzyi>carbainoyi)-2,3,4,5,7 ! 9 J 13,13a-octaiiydfo-2 5 ⁇
- the method comprises combining a compound of Formula (II) with a suitable solvent or a mixture of suitable solvents to produce a composition comprising one or more polymorphs of the compound of Formula (II),
- a suitable solvent or a mixture of suitable solvents to produce a composition comprising one or more polymorphs of the compound of Formula (II)
- Solvents suitable for polymorph formation may include, for example, methanol s etharsoL water, isopropyl acetate, acetonitrile, tetrahydrofuran, methyl isohutyl ketone, and any mixtures thereof.
- the methods for preparing the polymorphs described herein may yield quantity and quality differences compared to the methods for preparing sodium (2R,5S 5 13aR)-7,9 ⁇ dioxo-IO-((2,4.6- trifIuoFobenzyl)carhamoyl)-2,3,4,5,7 s 9, 13J 3a-0 €iahydfo-2,5- produced on laboratory seals.
- a method of producing a composition comprising polymorphic Form ! of sodium (2R,5S, 13aR ⁇ -7 5 9-dio3 ⁇ 4>i0- ⁇ (2 ; 4 5 6- trifluorobenzyl)carbamoyl)-2,3 ,4,5,7,9, 13, 13a-octa ydro-2 s 5- metbanopyrido r,2 !
- a composition comprising one or more polymorphs of potassium (2R.5S, 13aR) ⁇ 7,9 ⁇ dioxo ⁇ l 0 ⁇ ((2,4,6 ⁇ criz1uoa>benzyi)carbaTnoyi)-2,3.4 5.7,9, 13, 13a-octa ydro-2 5 5- metha o ido[1 2 ! :4,5]p ziu [2J -b][l !
- the method comprises combining a compound of Formula (III) with a suitable solvent or a mixture of suitable solvents to produce a composition comprising one or more polymorphs of the compound of Formula (III).
- composition comprising one or more polymorphs of potassium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6- tri fluoroberszy S)carbamoyi)-2, 3,4,5,7,9,13, 13 a ⁇ octahydro-2,S - m.ethanopyrido[r,2 , :4,5]p ⁇ i razino[2,l-b][l ⁇ 3]oxazepin ⁇ 8-olate J wherein the method comprises combining potassium (2R ( 5S,13aR)-7,9-dioxo-10-((2 s 4,6-h"jfiyorobenzyl)carbamoy1) ⁇
- Solvents suitable for polymorph formation may include, for example, methanol, etlianol, water, isopropyl acetate, aceionitrile, tetrahydrofuran, methyl isobutyl ketone, and any mixtures thereof.
- the methods for preparing the polymorphs described herein may yield quantity and quality differences compared to the methods for preparing potassium (2R,5S,13aR)-7,9-d oxo ⁇ l 0- ⁇ (2 s 4,6 rifIuorobenzyl)carbamoyi) ⁇ 2 s 3,4 5 5 J 7,9 J I 3J 3a--octahydro-2,5- meihanop rido[r 5 2 ! :4 J S]pyraziao[2,l-b][l,3]oxazspin ⁇ 8 ⁇ olate produced on laboratory scale.
- composition comprising polymorphic Form ⁇ of potassium (2R s 5SJ 3a )-7,9-dioxO"10- ⁇ 2,4,6 ⁇
- a potassium base e.g. potassium acetate
- a potassium base is a solvent to produce a composition comprising polymorphic Form II of potassium (2R,5S 5 13aR) ⁇ 7,9-dioxo ⁇ 10 ⁇ ((2 5 4,6- trifiuorobenzyl)carbamoy!)-2 s 3,4 s 5 5 7,9 s 13,13a--octahydrO'-2,5- methanopyrido[r s 2 , :4,5]p>TazIsio[2 s l--bJ[l i 3]oxa3 ⁇ 4epk-8 ⁇ o!ate )
- the solvent is selected from the group consisting of acetonitriie, water, and any mixtures thereof. la an embodiment, the solvent is a mixture of acetonitriie and water.
- composition comprising polymorphic Form III of potassium (2R ; 5S, 1 aR)-7, -dioxo- 10- ⁇ (2,4,6- trifiuorobenzyI)carbamoyi)-2J s 4,5,7 s 9J 3,13a-oetahyd!O-2,5 ⁇
- potassium phosphate in a solvent to produce a composition comprising polymorphic Form II of potassium (2R, 5 S, 1 aRV7,9-dioxo- 1 £>- ⁇ ( 2,4,6- tritluoro benzy l)carbamoyi) ⁇ 2 5 3 ,4, 5, 7,9, 13,13 a-ociahydro-2,5 - metham-)pyrido[i ! ,2 f :4,5]pyfazko[2 J l4 ⁇ ][i ,3]oxazepin"8-olate J wherein the solvent is methanol,
- pro ided is & method of producing a composition comprising polymorphic ciiric acid co-crystal, fbmaric acid co-crystal oxalic acid co-crystal, or a mixture thereof, of (2R3S, 1 Sal ⁇ -g-H dro y-T ⁇ -dioso-N-C ⁇ -triflu r benEy [)- 2,3,4,5 ,7,9,13 3a ⁇ oetahydro ⁇ 2,5 ⁇ rnet3 ⁇ 4 ⁇
- methanop ⁇ Tido iy2 ⁇ 4,5]pyrazino with an acid e.g. citric acid, fumaric acid, or oxalic acid
- an acid e.g. citric acid, fumaric acid, or oxalic acid
- a solvent e.g. a solvent to produce a composition comprising polymorphic citric acid co-crystal, farrsarie acid co-crystal, oxalic acid co-crystal, or a mixture thereof, of the C2R.58J 3aR) ⁇ 8 ⁇ Hydroxy-7,9-diox0 ⁇
- polymorphs described herein in the manufacture of a drag product
- the one or more of the polymorphic forms described herein ⁇ e.g., one or more of polym orphic Forms I, IL III, IV, V s VI, VII and VIIJ) may be used as an intermediate in the manufacturing process to produce the drug product.
- methanop iido[r,2 f :4,5]pyrazino[2J -fo][l,3]oxazepme ⁇ 10-carboxamide are used in the manufacture of an active pharmaceutical ingredient, fa certain embodiments.
- 2,5-methanopyrido[ 1 ⁇ 2 ! :4,5]p> ⁇ a ⁇ is used in the manufacture of an active pharmaceutical ingredient.
- Form II of (2R.5S, 1 :1 ⁇ 2R)-8 Jydroxy-7,9-dioxo-N--(2 5 4 J 6-triflirorobenz)'-! ⁇ 2 ! 3 > 4 s 5 5 7 5 9 5 13,13 ⁇ octahyd.ro- is used in the manufacture of an active pharmaceutical ingredient.
- polymorphs described herein in the manufacture of a drug product.
- the one or more of the polymorphic forms described herein may be used as an intermediate in fee manufacturing process to produce the drug product.
- polymorphs described herein in the manufacture of a drug product.
- the one or more of the polymorphic forms described herein e.g., one or more of polymorphic Forms I, II, and HI
- 2,5-methanopyrido[i ⁇ 2 ,5]pyrazino[2J-b][i s 3]oxazepin-8 ilatc is used in the manufacture of an active pharmaceutical ingredient.
- compositions comprising one or more of fee polymorphic forms described herein ⁇ e.g., one or more of polymorphic Forms I to VIII of ⁇ 2R,5SJ3aR) ⁇ 8 ⁇ Hydroxy ⁇ 7 s 9 ⁇ dioxo-N ⁇ (2 J 4 ) 6 ⁇ p-ifiuorobenzyi)-2 s 3,4 5 5 J 7 > 9, 13, 13a-octahydro-2,5- methanopyrido[ I !
- an article of manufacture such as a container comprising a dosage form of one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to VIE of ⁇ 2 3 5S > 13aR) » 8-Hydrox5'-7,9-dioxo-N- ⁇ 2,4 J 6.
- the article of manufacture is a container comprising a dosage form, of one or more of the polymorphic forms described herein (e.g., one or more of polymorphic Forms I to VIII of (2R..5S, 13aR)-8-Hydroxy-7,9-dioxo-N-(2 A6- trIfluorohenzyl)-2,3 ,4,5,7,9, !
- the dosage form is a tablet
- kits also are contemplated.
- a kit can comprise a dosage form of a pharmaceutical composition and a package insert, containing instructions for use of the composition in treatment of a medical condition.
- the instructions for use in the kit may be for treating HIV.
- the instructions for use in the kit may be for treating HIV,
- the polymorphic, salt, co-crystal and solvate forms described herein may potentially exhibit Improved properties.
- the polymorphic, salt, co-crystal and solvate forms described herein may potentially exhibit improved stability.
- improved stability could have a potentially beneficial impact on the manufacture of the Compound of Formulas L II, and/or ill, such as for example offering the ability to store process intermediate for extended periods of time.
- Improved stability could also potentially benefit a composition or pharmaceutical composition of the Compound of Formulas I, II, and/or ill.
- solvate forms described herein may also potentially result in improved yield of the Compound of Formulas I, II, and/or III, or potentially result in an improvement of the quality of the Compound of Formulas 1, 11, and/or HI.
- the polymorphic, salt and solvate forms described herein may also exhibit improved
- Citric Acid Co-crystal Form I [0290] C2R,5S,i3aR 8-hydroxy-? 5 9-diox ⁇
- octahydro"2,5-metliaiTopyrkk)[1 ⁇ 2 : :4.5 lpyrazino[2 5 1 -b][ tJJoxazepirse- 10-carboxamide (131 mg) aod fumaric acid (103 mg) were added to a glass vial.
- Te rahydrofura (1 mL) was added, the vial capped, and the suspension stirred at about 21 °C for two days.
- An additional 1 mL of tetrahydrofuran was added, and the mixture was heated to 45 °C. After about 12 hours at 45 ft C the mixture was fou d to be fully dissolved wd was removed from the heat bath.
- octahydro-2 > 5-me&anop ⁇ Tido[l ⁇ (147 mg) arid oxalic acid (134 mg) were added to a glass vial, Tetrahydrofuran (1. mL) was added, the vial capped, and the resulting solution was stirred at about 21 °C for about two days. The vessel was vented, and the solvent was allowed to evaporate at room temperature unassisted. After ne day solids were observed m " the vial and it was re-capped. Two days later large crystals were found in the vial and were identified as a 1 :1 Formula I oxalic acid co-crystal
- octahydro ⁇ 2 5 5 ⁇ methanopyTido[r,2 t :4 ⁇ (1.96 g) was charged to a reaction flask and stirred, followed by etbanol (20 mL), The mixture was stirred at room temperature resulting in a suspension.
- potassium hydroxide (253 mg) was dissolved in deionized water (5 ml,). The potassium hydroxide solution was transferred by syringe pump to the stirring suspension over about 2.5 hours followed by a rinse into the reactor with water (2 mL) after the base solution transfer was completed.
- XRPD X-ray powder diffraction
- DSC differential scanning calorimetry
- TGA thermogravimetric analysis
- DFS dynamic vapor sorption
- Figure 16 compares the calculated XRPD pattern of sodium ⁇ 2R,5S,13aR ⁇ 7 ! 9- io o 0H(2A6-t f iflu roben3 ⁇ 41)c ⁇
- Differential scanning calorimetry Thermal properties were evaluated using a Differential Scanning Calorimetry (DSC) instrument (TA QIGGO, TA instruments, New Castle, DE, USA). Approximately 1 to 10 mg of solid sample was placed in a standard aluminum pan vented with a pinhole for each experiment and heated at a rate of 5 to 10 °C/min under a 50 mL/miii nitrogen purge. Data analysis was conducted using Universal Analysis 2000 Version 4.7A. (TA Instruments, New Castle, DE, USA), Heat of fusion analysis was conducted by sigmoidal integration of the endother ic melting peak.
- DSC Differential Scanning Calorimetry
- Thermogr itmtric analysis was performed on a TGA instrument (TA Q5G0, TA Instruments, New Castle, DE, USA). Approximately 1 to 10 mg of solid sample was placed in an open aluminum pan for each experiment and heated at a rate of 5 to 10 °C/min under a 60 mL/min nitrogen purge using. Data analysis was conducted using Universal Analysis 2000 Version 4.7A (TA Instruments, New Castle, DE, USA),
- Dynamic vapor sorption The hygroscopicity was evaluated at room temperature using a dynamic vapor sorption (DVS) instrument (TGA Q5000 TA Instruments, New Castle, DE), Water adsorption and desorption were studied as a function of relative humidity (RH) over the range of 0 to 90% at 25 8 C. The relative humidity in the chamber was increased by 10% RH and held until the so lid and atmosphere reached equilibration. The equilibrium test was continued until passed or expired after 5 or 10 hours. At this point, RH was raised 10% higher and the process was repeated until 90% RH was reached and equilibrated. During this period, the water sorption was monitored.
- DVS dynamic vapor sorption
- the single crystal X-ray crystallography data for Formula I Forms I -IV are summ rized in Table 2A below.
- the single crystal X-ray crystallography data for Formula I Forms V-VIII are summarized in Table 2 ⁇ - ⁇ below.
- the indexing data for Formula II Form ! is summarized in Table 2C below.
- the single crystal X-ray crystallography data for the co- crystals of the present, in vention summarized in Table 2C below.
- the single crystal X-ray crystallography data for Formula III Forms I ⁇ is summarized in Table 2D-I below. Data from furt her characterization of the crystals ate summarized in Tables 3 A and 38 below. Data from further characterization of the crystals are also summarized in Tables 3A and 3C ⁇ i below.
- Table 3A Crystal Data and Structure Refinement for Formula I Forms ⁇
- Table 3A-I Crystal Data and Structure Refinement for Formula ⁇ Forms V - Vill
- Table 3B Crystal Data and Structure Refinement for Formula I Co-Crystals
- Table 3C-h Crystal Data and Structure Refinement for Formula ⁇ Form I, Formula HI Form II (Dimer), arid Formula III, Form III
- Formula III is bydrated. In certain embodiments, Formula III is hydrated with five to six water molecules.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Tropical Medicine & Parasitology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- AIDS & HIV (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP19167626.1A EP3564244B1 (en) | 2014-06-20 | 2015-06-19 | Crystalline forms of (2r,5s,13ar)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido [1',2':4,5]pyrazino [2,1-b][1,3]oxazepine-10-carboxamide |
CA2950309A CA2950309C (en) | 2014-06-20 | 2015-06-19 | Crystalline forms of (2r,5s,13ar)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide |
NZ726732A NZ726732A (en) | 2014-06-20 | 2015-06-19 | Crystalline forms of (2r,5s,13ar)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido [1’,2’:4,5] pyrazino [2,1-b] [1,3] oxazepine-10-carboxamide |
EP15734504.2A EP3157931A1 (en) | 2014-06-20 | 2015-06-19 | Crystalline forms of (2r,5s,13ar)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido [1',2':4,5]pyrazino [2,1-b][1,3]oxazepine-10-carboxamide |
AU2015276881A AU2015276881B2 (en) | 2014-06-20 | 2015-06-19 | Crystalline forms of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido [1',2':4,5] pyrazino [2,1-b] [1,3] oxazepine-10-carboxamide |
JP2016574182A JP6386104B2 (en) | 2014-06-20 | 2015-06-19 | (2R, 5S, 13AR) -8-hydroxy-7,9-dioxo-N- (2,4,6-trifluorobenzyl) -2,3,4,5,7,9,13,13A-octahydro- Crystal form of 2,5-methanopyrido [1 ′, 2 ′: 4,5] pyrazino [2,1-b] [1,3] oxazepine-10-carboxamide |
EP23195199.7A EP4309736A3 (en) | 2014-06-20 | 2015-06-19 | Crystalline forms of (2r,5s,13ar)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido [1',2':4,5]pyrazino [2,1-b][1,3]oxazepine-10-carboxamide |
AU2018203737A AU2018203737A1 (en) | 2014-06-20 | 2018-05-28 | Crystalline forms of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido [1',2':4,5] pyrazino [2,1-b] [1,3] oxazepine-10-carboxamide |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462015238P | 2014-06-20 | 2014-06-20 | |
US62/015,238 | 2014-06-20 | ||
US201462017183P | 2014-06-25 | 2014-06-25 | |
US62/017,183 | 2014-06-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015196137A1 true WO2015196137A1 (en) | 2015-12-23 |
Family
ID=53514405
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2015/036784 WO2015196137A1 (en) | 2014-06-20 | 2015-06-19 | Crystalline forms of (2r,5s,13ar)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido [1',2':4,5] pyrazino [2,1-b] [1,3] oxazepine-10-carboxamide |
Country Status (12)
Country | Link |
---|---|
US (4) | US9682084B2 (en) |
EP (3) | EP3157931A1 (en) |
JP (4) | JP6386104B2 (en) |
AU (2) | AU2015276881B2 (en) |
CA (1) | CA2950309C (en) |
ES (1) | ES2962291T3 (en) |
MA (1) | MA40236A (en) |
NZ (2) | NZ726732A (en) |
PL (1) | PL3564244T3 (en) |
TW (1) | TW201613936A (en) |
UY (1) | UY36176A (en) |
WO (1) | WO2015196137A1 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017083304A1 (en) * | 2015-11-09 | 2017-05-18 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
US9732092B2 (en) | 2012-12-21 | 2017-08-15 | Gilead Sciences, Inc. | Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]OXAZEPINES and methods for treating viral infections |
WO2018064071A1 (en) * | 2016-09-27 | 2018-04-05 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
WO2019113462A1 (en) | 2017-12-07 | 2019-06-13 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
WO2019207602A1 (en) * | 2018-04-26 | 2019-10-31 | Mylan Laboratories Limited | Polymorphic forms of bictegravir and its sodium salt |
WO2020003151A1 (en) * | 2018-06-28 | 2020-01-02 | Honour Lab Limited | Process for the preparation of sodium (2r,5s,13ar)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1', 2':4,5]pyrazino[2,1-b] [1,3] oxazepin-8-olate and its polymorphic form |
EP3653629A1 (en) | 2018-11-16 | 2020-05-20 | Sandoz AG | Acid addition salts of an integrase strand transfer inhibitor |
WO2020161744A1 (en) | 2019-02-07 | 2020-08-13 | Cipla Limited | Novel polymorphs of integrase inhibitor |
CN111978333A (en) * | 2019-09-30 | 2020-11-24 | 常州制药厂有限公司 | Crystal form A of Bictegravir sodium salt, preparation method and application |
WO2021233434A1 (en) * | 2020-05-22 | 2021-11-25 | 上海迪赛诺生物医药有限公司 | New crystal form of bictegravir sodium and preparation method therefor |
US11628181B2 (en) | 2014-12-26 | 2023-04-18 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
WO2023248240A1 (en) * | 2022-06-21 | 2023-12-28 | Mylan Laboratories Limited | Polymorphic forms of bictegravir sodium |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NO2717902T3 (en) | 2014-06-20 | 2018-06-23 | ||
TWI744723B (en) | 2014-06-20 | 2021-11-01 | 美商基利科學股份有限公司 | Synthesis of polycyclic-carbamoylpyridone compounds |
TW201613936A (en) * | 2014-06-20 | 2016-04-16 | Gilead Sciences Inc | Crystalline forms of(2R,5S,13aR)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide |
TWI794171B (en) | 2016-05-11 | 2023-03-01 | 美商滬亞生物國際有限公司 | Combination therapies of hdac inhibitors and pd-l1 inhibitors |
TWI808055B (en) | 2016-05-11 | 2023-07-11 | 美商滬亞生物國際有限公司 | Combination therapies of hdac inhibitors and pd-1 inhibitors |
DK3749673T3 (en) * | 2018-02-09 | 2022-06-20 | Sandoz Ag | Crystalline form of bictegravir sodium |
CN112996517A (en) * | 2018-09-19 | 2021-06-18 | 吉利德科学公司 | Integrase inhibitors for the prevention of HIV |
WO2021236944A1 (en) | 2020-05-21 | 2021-11-25 | Gilead Sciences, Inc. | Pharmaceutical compositions comprising bictegravir |
US20240208995A1 (en) * | 2021-04-19 | 2024-06-27 | Honour Lab Limited | Polymorphic forms of bictegravir potassium |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006116764A1 (en) * | 2005-04-28 | 2006-11-02 | Smithkline Beecham Corporation | Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity |
WO2014100323A1 (en) * | 2012-12-21 | 2014-06-26 | Gilead Sciences, Inc. | Polycyclic-carbamoylpyridone compounds and their pharmaceutical use |
Family Cites Families (119)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE788516A (en) | 1971-09-10 | 1973-03-07 | Lonza Ag | METHOD OF MANUFACTURING ALCOXYACETYLACETIC ESTERS |
GB1528382A (en) | 1974-12-26 | 1978-10-11 | Teijin Ltd | Cyclopentene diols and acyl esters thereof and processes for their preparation |
DE2658401A1 (en) | 1976-12-23 | 1978-07-06 | Merck Patent Gmbh | CYCLOPENTAN-1-AMINE, METHOD FOR THE PRODUCTION THEREOF AND AGENTS CONTAINING THESE COMPOUNDS |
US4575694A (en) | 1984-03-05 | 1986-03-11 | Allied Corporation | Coaxial connector |
DE3900736A1 (en) | 1989-01-12 | 1990-07-26 | Hoechst Ag | POSITIVELY WORKING RADIATION-SENSITIVE MIXTURE CONTAINING A MULTI-FUNCTIONAL (ALPHA) -DIAZO- (BETA) -KETOESTER, METHOD FOR THE PRODUCTION THEREOF AND RADIATION-SENSITIVE RECORDING MATERIAL COMPRISING THIS MIXTURE |
US6703396B1 (en) | 1990-02-01 | 2004-03-09 | Emory University | Method of resolution and antiviral activity of 1,3-oxathiolane nuclesoside enantiomers |
US5204466A (en) | 1990-02-01 | 1993-04-20 | Emory University | Method and compositions for the synthesis of bch-189 and related compounds |
US5914331A (en) | 1990-02-01 | 1999-06-22 | Emory University | Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane |
DE4014649A1 (en) | 1990-05-08 | 1991-11-14 | Hoechst Ag | NEW MULTIFUNCTIONAL CONNECTIONS WITH (ALPHA) -DIAZO-SS-KETOESTER AND SULPHONIC ACID UNIT UNITS, METHOD FOR THEIR PRODUCTION AND USE THEREOF |
GB9301000D0 (en) | 1993-01-20 | 1993-03-10 | Glaxo Group Ltd | Chemical compounds |
US5922695A (en) | 1996-07-26 | 1999-07-13 | Gilead Sciences, Inc. | Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability |
SE9702772D0 (en) | 1997-07-22 | 1997-07-22 | Astra Pharma Prod | Novel compounds |
US5935946A (en) | 1997-07-25 | 1999-08-10 | Gilead Sciences, Inc. | Nucleotide analog composition and synthesis method |
AU1403099A (en) | 1997-11-14 | 1999-06-07 | Merck & Co., Inc. | Alpha-1a adrenergic receptor antagonists |
JP2002529455A (en) | 1998-11-09 | 2002-09-10 | ジェームズ・ブラック・ファウンデーション・リミテッド | Gastrin and cholecystokinin receptor ligands |
GB2345058A (en) | 1998-12-01 | 2000-06-28 | Cerebrus Pharm Ltd | Hydroxypyridone compounds useful in the treatment of oxidative damage to the central nervous system |
DE69939749D1 (en) | 1998-12-25 | 2008-11-27 | Shionogi & Co | AROMATIC HETEROCYCLES WITH HIV INTEGRASE INHIBITING PROPERTIES |
AU2001262732A1 (en) | 2000-06-14 | 2001-12-24 | Shionogi And Co., Ltd. | Inhibitor for enzyme having two divalent metal ions as active centers |
CN101513402B (en) | 2001-08-10 | 2012-03-21 | 盐野义制药株式会社 | Antiviral agent |
IL160642A0 (en) | 2001-10-03 | 2004-07-25 | Ucb Sa | Pyrrolidinone derivatives |
BRPI0213522C1 (en) | 2001-10-26 | 2021-05-25 | St Di Ricerche Di Biologia Molecolare P Angeletti S P A | hydroxypyrimidinone derivative compounds, pharmaceutical composition, and use of a compound |
US7109186B2 (en) | 2002-07-09 | 2006-09-19 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
AU2003267098B2 (en) | 2002-09-11 | 2008-11-20 | Merck & Co., Inc. | Dihydroxypyridopyrazine-1,6-dione compounds useful as HIV integrase inhibitors |
EP4059923A1 (en) | 2002-11-20 | 2022-09-21 | Japan Tobacco Inc. | 4-oxoquinoline compound and use thereof as hiv integrase inhibitor |
US20040224917A1 (en) | 2003-01-14 | 2004-11-11 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
ATE490788T1 (en) | 2003-04-25 | 2010-12-15 | Gilead Sciences Inc | ANTIVIRAL PHOSPHONATE ANALOGUE |
TW200510425A (en) | 2003-08-13 | 2005-03-16 | Japan Tobacco Inc | Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor |
TW200528440A (en) | 2003-10-31 | 2005-09-01 | Fujisawa Pharmaceutical Co | 2-cyanopyrrolidinecarboxamide compound |
AU2005211349A1 (en) | 2004-01-30 | 2005-08-18 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | N-benzyl-3,4-dihyroxypyridine-2-carboxamide and N-benzyl-2,3-dihydroxypyridine-4-carboxamide compounds useful as HIV integrase inhibitors |
CN101014574A (en) | 2004-03-09 | 2007-08-08 | 默克公司 | HIV integrase inhibitors |
WO2005110399A2 (en) | 2004-04-29 | 2005-11-24 | The Regents Of The University Of California | Zinc-binding groups for metalloprotein inhibitors |
EP1755586A2 (en) | 2004-04-29 | 2007-02-28 | The Regents of the University of California | Hydroxypyridinone, hydroxypyridinethione, pyrone, and thiopyrone metalloprotein inhibitors |
WO2005110414A2 (en) | 2004-05-07 | 2005-11-24 | Merck & Co., Inc. | Hiv integrase inhibitors |
US7273859B2 (en) | 2004-05-12 | 2007-09-25 | Bristol-Myers Squibb Company | HIV integrase inhibitors: cyclic pyrimidinone compounds |
US7531554B2 (en) | 2004-05-20 | 2009-05-12 | Japan Tobacco Inc. | 4-oxoquinoline compound and use thereof as HIV integrase inhibitor |
MY134672A (en) | 2004-05-20 | 2007-12-31 | Japan Tobacco Inc | Stable crystal of 4-oxoquinoline compound |
EP2229945A1 (en) | 2004-05-21 | 2010-09-22 | Japan Tobacco, Inc. | Combinations comprising a 4-isoquinolone derivative and anti-HIV agents |
ES2720618T3 (en) | 2004-07-27 | 2019-07-23 | Gilead Sciences Inc | Phosphonate analogs of HIV inhibitor compounds |
EP1790638B1 (en) | 2004-09-15 | 2013-04-03 | Shionogi Co., Ltd. | Carbamoylpyridone derivative having hiv integrase inhibitory activity |
JP2006118669A (en) | 2004-10-25 | 2006-05-11 | Sanoh Industrial Co Ltd | Resin tube |
CA2634499A1 (en) | 2004-12-23 | 2006-06-29 | Virochem Pharma Inc. | Hydroxydihydropyridopy razine-1,8-diones and methods for inhibiting hiv integrase |
EP1852434B1 (en) | 2005-02-21 | 2011-07-13 | Shionogi Co., Ltd. | Bicyclic carbamoylpyridone derivative having hiv integrase inhibiting activity |
EP1888581A2 (en) | 2005-05-16 | 2008-02-20 | Gilead Sciences, Inc. | Hiv-integrase inhibitor compounds |
CA2616314A1 (en) | 2005-07-27 | 2007-02-01 | Gilead Sciences, Inc. | Antiviral phosphonate conjugates for inhibition of hiv |
CA2626956A1 (en) | 2005-10-27 | 2007-05-03 | Shionogi & Co., Ltd. | Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity |
EP2308490A1 (en) | 2005-12-30 | 2011-04-13 | Gilead Sciences, Inc. | Methods for improving the pharmacokinetics of hiv integrase inhibitors |
US7601844B2 (en) | 2006-01-27 | 2009-10-13 | Bristol-Myers Squibb Company | Piperidinyl derivatives as modulators of chemokine receptor activity |
JP2009525261A (en) | 2006-02-01 | 2009-07-09 | 日本たばこ産業株式会社 | 6- (3-Chloro-2-fluorobenzyl) -1-[(2S) -1-hydroxy-3-methylbutan-2-yl] -7-methoxy-4-oxo for the treatment of retroviral infections Use of -1,4-dihydroquinoline-3-carboxylic acid or a salt thereof |
PL1992607T3 (en) | 2006-03-06 | 2015-05-29 | Japan Tobacco Inc | Method for producing 4-oxoquinoline compound |
CN101437801B (en) | 2006-03-06 | 2013-02-06 | 日本烟草产业株式会社 | Process for production of 4-oxoquinoline compound |
US7893055B2 (en) | 2006-06-28 | 2011-02-22 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
WO2008010953A2 (en) | 2006-07-19 | 2008-01-24 | University Of Georgia Research Foundation, Inc. | Pyridinone diketo acids: inhibitors of hiv replication in combination therapy |
MX2009002689A (en) | 2006-09-12 | 2009-03-26 | Gilead Sciences Inc | Process and intermediates for preparing integrase inhibitors. |
EP2084160A1 (en) | 2006-10-18 | 2009-08-05 | Merck & Co., Inc. | Hiv integrase inhibitors |
ES2603617T3 (en) | 2007-02-23 | 2017-02-28 | Gilead Sciences, Inc. | Modulators of pharmacokinetic properties of therapeutics |
US20080280945A1 (en) | 2007-05-09 | 2008-11-13 | Sachin Lohani | Crystalline forms of an HIV integrase inhibitor |
CN103480000A (en) | 2007-06-29 | 2014-01-01 | 吉里德科学公司 | Therapeutic compositions and the use thereof |
WO2009006203A1 (en) | 2007-06-29 | 2009-01-08 | Gilead Sciences, Inc. | Therapeutic compositions and the use thereof |
WO2009018350A1 (en) | 2007-07-31 | 2009-02-05 | Limerick Biopharma, Inc. | Pyrone analog compositions and methods |
AR068403A1 (en) | 2007-09-11 | 2009-11-18 | Gilead Sciences Inc | PROCESS AND INTERMEDIARIES FOR THE PREPARATION OF INTEGRASA INHIBITORS |
EA201200631A1 (en) | 2007-11-16 | 2012-11-30 | Джилид Сайенсиз, Инк. | Inhibitors of Human Immunodeficiency Virus Replication |
GB0803019D0 (en) | 2008-02-19 | 2008-03-26 | Btg Int Ltd | Fluorinated compounds |
US8129398B2 (en) | 2008-03-19 | 2012-03-06 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US20100272811A1 (en) | 2008-07-23 | 2010-10-28 | Alkermes,Inc. | Complex of trospium and pharmaceutical compositions thereof |
EP2320909B8 (en) | 2008-07-25 | 2016-03-30 | VIIV Healthcare Company | Chemical compounds |
WO2010011819A1 (en) | 2008-07-25 | 2010-01-28 | Smithkline Beecham Corporation | Chemical compounds |
WO2010011818A1 (en) | 2008-07-25 | 2010-01-28 | Smithkline Beecham Corporation | Chemical compounds |
WO2010011816A1 (en) | 2008-07-25 | 2010-01-28 | Smithkline Beecham Corporation | Chemical compounds |
WO2010011815A1 (en) | 2008-07-25 | 2010-01-28 | Smithkline Beecham Corporation | Chemical compounds |
PT2320908E (en) | 2008-07-25 | 2014-03-06 | Shionogi & Co | Dolutegravir prodrugs |
MX2011006241A (en) | 2008-12-11 | 2011-06-28 | Shionogi & Co | Synthesis of carbamoylpyridone hiv integrase inhibitors and intermediates. |
ES2964383T3 (en) | 2008-12-11 | 2024-04-05 | Viiv Healthcare Co | Processes and intermediates for carbamoylpyridone HIV integrase inhibitors |
TWI518084B (en) | 2009-03-26 | 2016-01-21 | 鹽野義製藥股份有限公司 | Process for pyrone and pyridone derivatives |
US8835461B2 (en) | 2009-03-26 | 2014-09-16 | Shionogi & Co., Ltd. | Substituted 3-hydroxy-4-pyridone derivative |
US8338441B2 (en) | 2009-05-15 | 2012-12-25 | Gilead Sciences, Inc. | Inhibitors of human immunodeficiency virus replication |
PT2444400T (en) | 2009-06-15 | 2018-06-06 | Shionogi & Co | Substituted polycyclic carbamoylpyridone derivative |
KR101280198B1 (en) | 2009-09-02 | 2013-06-28 | 이화여자대학교 산학협력단 | pyrazole derivatives, preparation thereof and composition comprising the same for prevention and treatment of osteoporosis |
ES2688925T3 (en) | 2010-01-27 | 2018-11-07 | Viiv Healthcare Company | Antiviral treatment |
WO2011105590A1 (en) | 2010-02-26 | 2011-09-01 | 日本たばこ産業株式会社 | 1,3,4,8-tetrahydro-2h-pyrido[1,2-a]pyrazine derivative and use of same as hiv integrase inhibitor |
TWI582097B (en) | 2010-03-23 | 2017-05-11 | Viiv醫療保健公司 | Process for preparing carbamoylpyridone derivatives and intermediates |
US20130165489A1 (en) | 2010-05-03 | 2013-06-27 | The Trustees Of The University Of Pennsylvania | Small Molecule Modulators of HIV-1 Capsid Stability and Methods Thereof |
CA2798735A1 (en) | 2010-05-19 | 2011-11-24 | Haruki Shibata | Prophylactic and/or therapeutic agent for non-alcoholic steatohepatitis |
JP5806735B2 (en) | 2010-07-02 | 2015-11-10 | ギリアード サイエンシーズ, インコーポレイテッド | 2-Quinolinyl-acetic acid derivatives as HIV antiviral compounds |
US9102614B2 (en) | 2010-07-02 | 2015-08-11 | Gilead Sciences, Inc. | Naphth-2-ylacetic acid derivatives to treat AIDS |
EP2595986A2 (en) | 2010-07-14 | 2013-05-29 | Addex Pharma SA | Novel 2-amino-4-pyrazolyl-thiazole derivatives and their use as allosteric modulators of metabotropic glutamate receptors |
CN106083891B (en) | 2010-08-05 | 2018-03-23 | 盐野义制药株式会社 | The manufacture method of compound with hiv integrase inhibitory activity |
SI2620436T1 (en) | 2010-09-24 | 2018-08-31 | Shionogi & Co., Ltd. | Substituted polycyclic carbamoyl pyridone derivative prodrug |
WO2012106534A2 (en) | 2011-02-02 | 2012-08-09 | The Regents Of The University Of California | Hiv integrase inhibitors |
AP2015008931A0 (en) | 2011-04-21 | 2015-12-31 | Gilead Sciences Inc | Benzothiazole compounds and their pharmaceutical use |
US20140213553A1 (en) | 2011-05-03 | 2014-07-31 | Concert Pharmaceuticals Inc. | Carbamoylpyridone derivatives |
US9328075B2 (en) | 2011-05-05 | 2016-05-03 | St. Jude Children's Research Hospital | Pyrimidinone compounds and methods for treating influenza |
US9121496B2 (en) | 2011-06-29 | 2015-09-01 | Arvinmeritor Technology, Llc | Drive axle system and a method of control |
US9540343B2 (en) | 2011-07-06 | 2017-01-10 | Gilead Sciences, Inc. | Compounds for the treatment of HIV |
CN102863512B (en) | 2011-07-07 | 2016-04-20 | 上海泓博智源医药技术有限公司 | Antiviral compound |
US9206197B2 (en) | 2011-09-14 | 2015-12-08 | Mapi Pharma Ltd. | Amorphous form of dolutegravir |
US9200009B2 (en) | 2011-10-12 | 2015-12-01 | Shionogi & Co., Ltd. | Polycyclic pyridone derivative having integrase inhibitory activity |
WO2013087581A1 (en) | 2011-12-12 | 2013-06-20 | Bayer Intellectual Property Gmbh | Amino-substituted imidazopyridazines |
WO2013091096A1 (en) | 2011-12-20 | 2013-06-27 | Boehringer Ingelheim International Gmbh | Condensed triclyclic compounds as inhibitors of hiv replication |
UY34750A (en) | 2012-04-20 | 2013-11-29 | Gilead Sciences Inc | ? COMPOUNDS FOR HIV TREATMENT, COMPOSITIONS, PREPARATION METHODS, INTERMEDIARIES AND THERAPEUTIC METHODS ?. |
WO2014008636A1 (en) | 2012-07-11 | 2014-01-16 | Merck Sharp & Dohme Corp. | Macrocyclic compounds as hiv integrase inhibitors |
WO2014014933A1 (en) | 2012-07-20 | 2014-01-23 | Merck Sharp & Dohme Corp. | Hiv treatment with amido-substituted pyrimidinone derivatives |
EP2877469A4 (en) | 2012-07-25 | 2016-04-06 | Merck Sharp & Dohme | Substituted naphthyridinedione derivatives as hiv integrase inhibitors |
US8877931B2 (en) | 2012-08-03 | 2014-11-04 | Gilead Sciences, Inc. | Process and intermediates for preparing integrase inhibitors |
WO2014074675A1 (en) | 2012-11-08 | 2014-05-15 | Bristol-Myers Squibb Company | Heteroaryl substituted pyridyl compounds useful as kinase modulators |
JP2016503030A (en) | 2012-12-14 | 2016-02-01 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニーGlaxoSmithKline LLC | Pharmaceutical composition |
WO2014099586A1 (en) | 2012-12-17 | 2014-06-26 | Merck Sharp & Dohme Corp. | 4-pyridinonetriazine derivatives as hiv integrase inhibitors |
EP2934482A4 (en) | 2012-12-21 | 2016-07-20 | Merck Sharp & Dohme | Gastro-retentive formulations |
US20140221355A1 (en) | 2012-12-21 | 2014-08-07 | Gilead Sciences, Inc. | Polycyclic-carbamoylpyridone compounds and their pharmaceutical use |
US20140221380A1 (en) | 2012-12-27 | 2014-08-07 | Japan Tobacco Inc. | SUBSTITUTED SPIROPYRIDO[1,2-a]PYRAZINE DERIVATIVE AND PHARMACEUTICAL USE OF SAME AS HIV INTEGRASE INHIBITOR |
EP3008044B1 (en) | 2013-06-13 | 2018-11-21 | Merck Sharp & Dohme Corp. | Fused tricyclic heterocyclic compounds as hiv integrase inhibitors |
WO2015039348A1 (en) | 2013-09-23 | 2015-03-26 | Merck Sharp & Dohme Corp. | Tetracyclic heterocycle compounds useful as hiv integrase inhibitors |
EA030695B1 (en) | 2013-09-27 | 2018-09-28 | Мерк Шарп И Доум Корп. | Substituted quinolizine derivatives useful as hiv integrase inhibitors |
WO2015089847A1 (en) | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | Spirocyclic heterocycle compounds useful as hiv integrase inhibitors |
EP3096763B1 (en) | 2014-01-21 | 2019-12-25 | Laurus Labs Limited | Novel process for the preparation of dolutegravir and pharmaceutically acceptable salts thereof |
WO2015138933A1 (en) | 2014-03-13 | 2015-09-17 | Assia Chemical Industries Ltd. | Solid state forms of dolutegravir sodium |
TW201613936A (en) * | 2014-06-20 | 2016-04-16 | Gilead Sciences Inc | Crystalline forms of(2R,5S,13aR)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide |
NO2717902T3 (en) | 2014-06-20 | 2018-06-23 | ||
TWI744723B (en) | 2014-06-20 | 2021-11-01 | 美商基利科學股份有限公司 | Synthesis of polycyclic-carbamoylpyridone compounds |
TWI737647B (en) | 2015-11-09 | 2021-09-01 | 美商基利科學股份有限公司 | Therapeutic compositions for treatment of human immunodeficiency virus |
-
2015
- 2015-06-16 TW TW104119402A patent/TW201613936A/en unknown
- 2015-06-17 UY UY0001036176A patent/UY36176A/en not_active Application Discontinuation
- 2015-06-19 NZ NZ726732A patent/NZ726732A/en unknown
- 2015-06-19 AU AU2015276881A patent/AU2015276881B2/en active Active
- 2015-06-19 MA MA040236A patent/MA40236A/en unknown
- 2015-06-19 JP JP2016574182A patent/JP6386104B2/en active Active
- 2015-06-19 WO PCT/US2015/036784 patent/WO2015196137A1/en active Application Filing
- 2015-06-19 US US14/745,121 patent/US9682084B2/en active Active
- 2015-06-19 EP EP15734504.2A patent/EP3157931A1/en not_active Withdrawn
- 2015-06-19 PL PL19167626.1T patent/PL3564244T3/en unknown
- 2015-06-19 ES ES19167626T patent/ES2962291T3/en active Active
- 2015-06-19 EP EP23195199.7A patent/EP4309736A3/en active Pending
- 2015-06-19 CA CA2950309A patent/CA2950309C/en active Active
- 2015-06-19 EP EP19167626.1A patent/EP3564244B1/en active Active
- 2015-06-19 NZ NZ736644A patent/NZ736644A/en unknown
-
2017
- 2017-05-05 US US15/588,346 patent/US10098886B2/en active Active
-
2018
- 2018-05-28 AU AU2018203737A patent/AU2018203737A1/en not_active Abandoned
- 2018-06-14 US US16/008,931 patent/US20190015420A1/en not_active Abandoned
- 2018-08-08 JP JP2018149161A patent/JP6606692B2/en active Active
-
2019
- 2019-09-25 JP JP2019174597A patent/JP2020023509A/en active Pending
-
2020
- 2020-01-10 US US16/740,174 patent/US11202780B2/en active Active
-
2022
- 2022-07-04 JP JP2022107717A patent/JP2022153400A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006116764A1 (en) * | 2005-04-28 | 2006-11-02 | Smithkline Beecham Corporation | Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity |
WO2014100323A1 (en) * | 2012-12-21 | 2014-06-26 | Gilead Sciences, Inc. | Polycyclic-carbamoylpyridone compounds and their pharmaceutical use |
Non-Patent Citations (1)
Title |
---|
CAIRA: "Crystalline Polymorphism of Organic Compounds", TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, January 1998 (1998-01-01), pages 163 - 208, XP008166276, ISSN: 0340-1022 * |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10689399B2 (en) | 2012-12-21 | 2020-06-23 | Gilead Sciences, Inc. | Substituted 3,4,5,6,8,10,14,14a-octahydro-2h-2,6-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazocines and methods for treating viral infections |
US9732092B2 (en) | 2012-12-21 | 2017-08-15 | Gilead Sciences, Inc. | Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]OXAZEPINES and methods for treating viral infections |
US10035809B2 (en) | 2012-12-21 | 2018-07-31 | Gilead Sciences, Inc. | Substituted 2,3,4,5,7,9,13,13a-octahydro-1,5-methanopyrido[1′,2′:4,5]pyrazino[1,2-a][1,3]diazepines and methods for treating viral infections |
US11548901B2 (en) | 2012-12-21 | 2023-01-10 | Gilead Sciences, Inc. | Substituted 1,4-methanopyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidines for treating viral infections |
US11628181B2 (en) | 2014-12-26 | 2023-04-18 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
AU2016354007C1 (en) * | 2015-11-09 | 2020-09-10 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
WO2017083304A1 (en) * | 2015-11-09 | 2017-05-18 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
AU2016354007B2 (en) * | 2015-11-09 | 2019-11-14 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
AU2020200995B9 (en) * | 2015-11-09 | 2022-04-28 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
US10548846B2 (en) | 2015-11-09 | 2020-02-04 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
EP3632415A1 (en) * | 2015-11-09 | 2020-04-08 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
AU2020200995B2 (en) * | 2015-11-09 | 2022-04-07 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
EP3346995B1 (en) | 2015-11-09 | 2019-08-28 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
US11744802B2 (en) | 2015-11-09 | 2023-09-05 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
AU2016354007C9 (en) * | 2015-11-09 | 2020-10-01 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
WO2018064071A1 (en) * | 2016-09-27 | 2018-04-05 | Gilead Sciences, Inc. | Therapeutic compositions for treatment of human immunodeficiency virus |
WO2019113462A1 (en) | 2017-12-07 | 2019-06-13 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
US11903959B2 (en) | 2017-12-07 | 2024-02-20 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
US11331331B2 (en) | 2017-12-07 | 2022-05-17 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
WO2019207602A1 (en) * | 2018-04-26 | 2019-10-31 | Mylan Laboratories Limited | Polymorphic forms of bictegravir and its sodium salt |
US11623933B2 (en) | 2018-06-28 | 2023-04-11 | Honour Lab Limited | Process for the preparation of sodium (2R,5S,13AR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-2,3,4,5,7,9,13,13A-octahydro-2,5-Methanopyrido[1 ′,2′:4,5]pyrazino[2,1 -b] [1,3] oxazepin-8-olate and its polymorphic form |
WO2020003151A1 (en) * | 2018-06-28 | 2020-01-02 | Honour Lab Limited | Process for the preparation of sodium (2r,5s,13ar)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1', 2':4,5]pyrazino[2,1-b] [1,3] oxazepin-8-olate and its polymorphic form |
EP3653629A1 (en) | 2018-11-16 | 2020-05-20 | Sandoz AG | Acid addition salts of an integrase strand transfer inhibitor |
WO2020161744A1 (en) | 2019-02-07 | 2020-08-13 | Cipla Limited | Novel polymorphs of integrase inhibitor |
CN111978333A (en) * | 2019-09-30 | 2020-11-24 | 常州制药厂有限公司 | Crystal form A of Bictegravir sodium salt, preparation method and application |
CN113698420A (en) * | 2020-05-22 | 2021-11-26 | 上海迪赛诺生物医药有限公司 | Novel crystal form of bicalutavir sodium and preparation method thereof |
WO2021233434A1 (en) * | 2020-05-22 | 2021-11-25 | 上海迪赛诺生物医药有限公司 | New crystal form of bictegravir sodium and preparation method therefor |
WO2023248240A1 (en) * | 2022-06-21 | 2023-12-28 | Mylan Laboratories Limited | Polymorphic forms of bictegravir sodium |
Also Published As
Publication number | Publication date |
---|---|
MA40236A (en) | 2017-04-26 |
UY36176A (en) | 2016-01-08 |
CA2950309C (en) | 2019-04-30 |
AU2015276881A1 (en) | 2016-12-15 |
US11202780B2 (en) | 2021-12-21 |
EP4309736A3 (en) | 2024-05-08 |
AU2018203737A1 (en) | 2018-06-21 |
US10098886B2 (en) | 2018-10-16 |
US20200390775A1 (en) | 2020-12-17 |
AU2015276881B2 (en) | 2018-06-07 |
JP6386104B2 (en) | 2018-09-05 |
CA2950309A1 (en) | 2015-12-23 |
US20150366872A1 (en) | 2015-12-24 |
US9682084B2 (en) | 2017-06-20 |
EP3564244A1 (en) | 2019-11-06 |
JP2017518357A (en) | 2017-07-06 |
JP2022153400A (en) | 2022-10-12 |
JP6606692B2 (en) | 2019-11-20 |
EP3157931A1 (en) | 2017-04-26 |
JP2018199687A (en) | 2018-12-20 |
TW201613936A (en) | 2016-04-16 |
EP4309736A2 (en) | 2024-01-24 |
EP3564244C0 (en) | 2023-09-13 |
JP2020023509A (en) | 2020-02-13 |
US20170333438A1 (en) | 2017-11-23 |
PL3564244T3 (en) | 2024-04-08 |
ES2962291T3 (en) | 2024-03-18 |
EP3564244B1 (en) | 2023-09-13 |
NZ726732A (en) | 2018-05-25 |
US20190015420A1 (en) | 2019-01-17 |
NZ736644A (en) | 2023-06-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11202780B2 (en) | Crystalline forms of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide | |
AU2018203175B2 (en) | Sodium (2r,5s,13ar)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin-8-olate | |
AU2018317833B2 (en) | Solid forms of an HIV capsid inhibitor | |
KR102497604B1 (en) | Choline salt forms of an hiv capsid inhibitor |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15734504 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2950309 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2015276881 Country of ref document: AU Date of ref document: 20150619 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2016574182 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REEP | Request for entry into the european phase |
Ref document number: 2015734504 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2015734504 Country of ref document: EP |