CN105311033A - 抗病毒治疗 - Google Patents
抗病毒治疗 Download PDFInfo
- Publication number
- CN105311033A CN105311033A CN201510619148.8A CN201510619148A CN105311033A CN 105311033 A CN105311033 A CN 105311033A CN 201510619148 A CN201510619148 A CN 201510619148A CN 105311033 A CN105311033 A CN 105311033A
- Authority
- CN
- China
- Prior art keywords
- compound
- coupling medicine
- hiv
- medicine
- coupling
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002560 therapeutic procedure Methods 0.000 title description 19
- 230000000840 anti-viral effect Effects 0.000 title description 6
- 239000003814 drug Substances 0.000 claims abstract description 105
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 238000011282 treatment Methods 0.000 claims abstract description 26
- 230000008878 coupling Effects 0.000 claims description 62
- 238000010168 coupling process Methods 0.000 claims description 62
- 238000005859 coupling reaction Methods 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 46
- 239000008194 pharmaceutical composition Substances 0.000 claims description 38
- 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 claims description 8
- 229960002814 rilpivirine Drugs 0.000 claims description 7
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- 238000004806 packaging method and process Methods 0.000 claims description 4
- 208000031886 HIV Infections Diseases 0.000 claims description 3
- 208000037357 HIV infectious disease Diseases 0.000 claims description 3
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 abstract description 34
- 208000030507 AIDS Diseases 0.000 abstract description 16
- 208000015181 infectious disease Diseases 0.000 abstract description 5
- 230000002265 prevention Effects 0.000 abstract description 5
- 229940099797 HIV integrase inhibitor Drugs 0.000 abstract description 4
- 239000003084 hiv integrase inhibitor Substances 0.000 abstract description 4
- 230000005764 inhibitory process Effects 0.000 abstract 1
- 230000010076 replication Effects 0.000 abstract 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 40
- 238000000034 method Methods 0.000 description 35
- 229960004748 abacavir Drugs 0.000 description 33
- 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 33
- 210000004027 cell Anatomy 0.000 description 29
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 24
- 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 23
- 229960004525 lopinavir Drugs 0.000 description 23
- 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 22
- 229960003277 atazanavir Drugs 0.000 description 22
- 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 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 22
- 201000010099 disease Diseases 0.000 description 21
- -1 sodium) Chemical class 0.000 description 20
- 229960004556 tenofovir Drugs 0.000 description 13
- 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 description 13
- CGBYTKOSZYQOPV-ASSBYYIWSA-N 5-chloro-3-[[3-[(e)-2-cyanoethenyl]-5-methylphenyl]-methoxyphosphoryl]-1h-indole-2-carboxamide Chemical compound C1([P@](=O)(C=2C3=CC(Cl)=CC=C3NC=2C(N)=O)OC)=CC(C)=CC(\C=C\C#N)=C1 CGBYTKOSZYQOPV-ASSBYYIWSA-N 0.000 description 12
- MCPUZZJBAHRIPO-UHFFFAOYSA-N Lersivirine Chemical compound CCC1=NN(CCO)C(CC)=C1OC1=CC(C#N)=CC(C#N)=C1 MCPUZZJBAHRIPO-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 229960001627 lamivudine Drugs 0.000 description 11
- 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 11
- 229950004188 lersivirine Drugs 0.000 description 11
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 239000002585 base Substances 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- 208000036142 Viral infection Diseases 0.000 description 9
- 230000009385 viral infection Effects 0.000 description 9
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 8
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 8
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 7
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 241000700605 Viruses Species 0.000 description 5
- 230000008485 antagonism Effects 0.000 description 5
- 239000003067 chemokine receptor CCR5 antagonist Substances 0.000 description 5
- 229960002656 didanosine Drugs 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000002773 nucleotide Substances 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 208000011580 syndromic disease Diseases 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000003612 virological effect Effects 0.000 description 5
- 108020004414 DNA Proteins 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
- 102100034343 Integrase Human genes 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- 239000004365 Protease Substances 0.000 description 4
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 4
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000012752 auxiliary agent Substances 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000002576 chemokine receptor CXCR4 antagonist Substances 0.000 description 4
- 229940121384 cxc chemokine receptor type 4 (cxcr4) antagonist Drugs 0.000 description 4
- 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 4
- 239000002552 dosage form Substances 0.000 description 4
- 229940125777 fusion inhibitor Drugs 0.000 description 4
- 229940124524 integrase inhibitor Drugs 0.000 description 4
- 239000002850 integrase inhibitor Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229960004710 maraviroc Drugs 0.000 description 4
- 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 4
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- BEUUJDAEPJZWHM-COROXYKFSA-N tert-butyl n-[(2s,3s,5r)-3-hydroxy-6-[[(2s)-1-(2-methoxyethylamino)-3-methyl-1-oxobutan-2-yl]amino]-6-oxo-1-phenyl-5-[(2,3,4-trimethoxyphenyl)methyl]hexan-2-yl]carbamate Chemical compound C([C@@H]([C@@H](O)C[C@H](C(=O)N[C@H](C(=O)NCCOC)C(C)C)CC=1C(=C(OC)C(OC)=CC=1)OC)NC(=O)OC(C)(C)C)C1=CC=CC=C1 BEUUJDAEPJZWHM-COROXYKFSA-N 0.000 description 4
- 229960002555 zidovudine Drugs 0.000 description 4
- 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 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 3
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 3
- 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 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 238000002835 absorbance Methods 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 229950004697 lasinavir Drugs 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 230000001566 pro-viral effect Effects 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000001117 sulphuric acid Substances 0.000 description 3
- 235000011149 sulphuric acid Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- OKGPFTLYBPQBIX-CQSZACIVSA-N 1-[(2r)-4-benzoyl-2-methylpiperazin-1-yl]-2-(4-methoxy-1h-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione Chemical compound C1=2C(OC)=CC=NC=2NC=C1C(=O)C(=O)N([C@@H](C1)C)CCN1C(=O)C1=CC=CC=C1 OKGPFTLYBPQBIX-CQSZACIVSA-N 0.000 description 2
- HSBKFSPNDWWPSL-VDTYLAMSSA-N 4-amino-5-fluoro-1-[(2s,5r)-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-VDTYLAMSSA-N 0.000 description 2
- 0 C[C@@](CCO[C@@]1(*)CN(C=*(C(C=C)NCC(C(F)=CC=C2)=CCC=C2F)C2=O)C3=*2O)N1C3=O Chemical compound C[C@@](CCO[C@@]1(*)CN(C=*(C(C=C)NCC(C(F)=CC=C2)=CCC=C2F)C2=O)C3=*2O)N1C3=O 0.000 description 2
- 102000009410 Chemokine receptor Human genes 0.000 description 2
- 108050000299 Chemokine receptor Proteins 0.000 description 2
- 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 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 229930182566 Gentamicin Natural products 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- 208000008771 Lymphadenopathy Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 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
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 2
- 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 2
- 229960003205 adefovir dipivoxil Drugs 0.000 description 2
- 239000003513 alkali Substances 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
- 230000003042 antagnostic effect Effects 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- YJEJKUQEXFSVCJ-WRFMNRASSA-N bevirimat Chemical compound C1C[C@H](OC(=O)CC(C)(C)C(O)=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C YJEJKUQEXFSVCJ-WRFMNRASSA-N 0.000 description 2
- 229950002892 bevirimat Drugs 0.000 description 2
- 239000012472 biological sample Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 235000008429 bread Nutrition 0.000 description 2
- 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 2
- 229950008230 capravirine Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 229940104302 cytosine Drugs 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 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 2
- 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 2
- 238000013461 design Methods 0.000 description 2
- 229950006528 elvucitabine Drugs 0.000 description 2
- 229960000366 emtricitabine Drugs 0.000 description 2
- 239000000839 emulsion Substances 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
- 230000003203 everyday effect 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
- 229950011117 fozivudine tidoxil Drugs 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 229950010245 ibalizumab Drugs 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- CJPLEFFCVDQQFZ-UHFFFAOYSA-N loviride Chemical compound CC(=O)C1=CC=C(C)C=C1NC(C(N)=O)C1=C(Cl)C=CC=C1Cl CJPLEFFCVDQQFZ-UHFFFAOYSA-N 0.000 description 2
- 229950006243 loviride Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- CKNAQFVBEHDJQV-UHFFFAOYSA-N oltipraz Chemical compound S1SC(=S)C(C)=C1C1=CN=CC=N1 CKNAQFVBEHDJQV-UHFFFAOYSA-N 0.000 description 2
- 229950008687 oltipraz Drugs 0.000 description 2
- RXBWRFDZXRAEJT-SZNOJMITSA-N palinavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)C=1N=C2C=CC=CC2=CC=1)C(C)C)[C@H](O)CN1[C@@H](C[C@@H](CC1)OCC=1C=CN=CC=1)C(=O)NC(C)(C)C)C1=CC=CC=C1 RXBWRFDZXRAEJT-SZNOJMITSA-N 0.000 description 2
- 229950006460 palinavir Drugs 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 150000003009 phosphonic acids Chemical class 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 239000002574 poison Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 229960004742 raltegravir Drugs 0.000 description 2
- 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 2
- 229960000311 ritonavir Drugs 0.000 description 2
- 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 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229960001203 stavudine Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000002562 thickening agent Substances 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
- 210000001519 tissue Anatomy 0.000 description 2
- 210000001215 vagina Anatomy 0.000 description 2
- 230000029812 viral genome replication Effects 0.000 description 2
- 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 1
- GXINKQQWHLIBJA-UCIBKFKQSA-N (z)-but-2-enedioic acid;(4,6-dimethylpyrimidin-5-yl)-[4-[(3s)-4-[(1r)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl]-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl]methanone Chemical compound OC(=O)\C=C/C(O)=O.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 GXINKQQWHLIBJA-UCIBKFKQSA-N 0.000 description 1
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-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
- WVXRAFOPTSTNLL-NKWVEPMBSA-N 2',3'-dideoxyadenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1CC[C@@H](CO)O1 WVXRAFOPTSTNLL-NKWVEPMBSA-N 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- MKJMTKSTMONLDG-UHFFFAOYSA-N 4H-pyrido[1,2-a]pyrazine-8-carboxamide Chemical compound C1=C2N(CC=N1)C=CC(=C2)C(=O)N MKJMTKSTMONLDG-UHFFFAOYSA-N 0.000 description 1
- 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 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- 108010036239 CD4-IgG(2) Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 108010002459 HIV Integrase Proteins 0.000 description 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 1
- 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 1
- 108010061833 Integrases Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000007542 Paresis Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 206010038997 Retroviral infections Diseases 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
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010043561 Thrombocytopenic purpura Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- JQUNFHFWXCXPRK-AMMMHQJVSA-N [(3as,4r,6ar)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl] n-[(2s,3r)-4-[[2-[(1-cyclopentylpiperidin-4-yl)amino]-1,3-benzothiazol-6-yl]sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=C2SC(NC3CCN(CC3)C3CCCC3)=NC2=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 JQUNFHFWXCXPRK-AMMMHQJVSA-N 0.000 description 1
- IOYGCIOOMSKGEY-GTYOFVGBSA-N [4-[(3s)-4-[(r)-(1-cyclopropylsulfonylpiperidin-4-yl)-(3-fluorophenyl)methyl]-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl]-(4,6-dimethylpyrimidin-5-yl)methanone Chemical compound C1CC([C@@H](N2CCN(C[C@@H]2C)C2(C)CCN(CC2)C(=O)C=2C(=NC=NC=2C)C)C=2C=C(F)C=CC=2)CCN1S(=O)(=O)C1CC1 IOYGCIOOMSKGEY-GTYOFVGBSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 229960001997 adefovir Drugs 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229950004424 alovudine Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012805 animal sample Substances 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 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
- 229950007936 apricitabine Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 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
- 229950009079 brecanavir Drugs 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- ILJDFBVQZFJJJS-UHFFFAOYSA-N butyl $l^{1}-oxidanylformate Chemical compound CCCCOC([O])=O ILJDFBVQZFJJJS-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001413 cellular effect Effects 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
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 108010087236 cobra venom endonuclease Proteins 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000009133 cooperative interaction Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 229960005107 darunavir Drugs 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 229960005319 delavirdine Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- AYXBAIULRDEVAS-UHFFFAOYSA-N dimethyl-[[4-[[3-(4-methylphenyl)-8,9-dihydro-7h-benzo[7]annulene-6-carbonyl]amino]phenyl]methyl]-(oxan-4-yl)azanium;iodide Chemical compound [I-].C1=CC(C)=CC=C1C1=CC=C(CCCC(=C2)C(=O)NC=3C=CC(C[N+](C)(C)C4CCOCC4)=CC=3)C2=C1 AYXBAIULRDEVAS-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229960002542 dolutegravir Drugs 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 229960003586 elvitegravir Drugs 0.000 description 1
- 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 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- LLYJISDUHFXOHK-GOCONZMPSA-N ferroptocide Chemical compound C[C@@H]1CC[C@@]23C[C@@H](C(=O)[C@]2([C@@]1([C@@H](C[C@H]([C@@H]3C)C4=CCN5C(=O)N(C(=O)N5C4)C6=CC=CC=C6)OC(=O)CCl)C)O)O LLYJISDUHFXOHK-GOCONZMPSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- LTVDTKRMOQDRCH-UHFFFAOYSA-N furan;1h-pyrrole Chemical compound C=1C=CNC=1.C=1C=COC=1 LTVDTKRMOQDRCH-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- CEAZRRDELHUEMR-UHFFFAOYSA-N gentamicin Chemical class O1C(C(C)NC)CCC(N)C1OC1C(O)C(OC2C(C(NC)C(C)(O)CO2)O)C(N)CC1N CEAZRRDELHUEMR-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- IBXZOZHEVAARJT-UHFFFAOYSA-N imidazo[1,2-a]pyrazine-8-carboxamide Chemical compound NC(=O)C1=NC=CN2C=CN=C12 IBXZOZHEVAARJT-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000007373 indentation Methods 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- 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 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940121292 leronlimab Drugs 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 208000018555 lymphatic system disease Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 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
- 239000007932 molded tablet Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 229940051866 mouthwash Drugs 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000013610 patient sample Substances 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- ZVIWEYTXPYNLGB-UHFFFAOYSA-M potassium;4-[[2-[[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-1,2,4-triazol-3-yl]sulfanyl]acetyl]amino]-3-chlorobenzoate Chemical compound [K+].ClC1=CC(C(=O)[O-])=CC=C1NC(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 ZVIWEYTXPYNLGB-UHFFFAOYSA-M 0.000 description 1
- 229940068586 prezista Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000001177 retroviral effect 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
- 229960001860 salicylate Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- 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 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 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 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 208000009999 tuberous sclerosis Diseases 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 229950009860 vicriviroc Drugs 0.000 description 1
- 229940023080 viracept Drugs 0.000 description 1
- 239000008215 water for injection 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
- A61K31/536—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 carbocyclic 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
-
- 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
- A61K31/4985—Pyrazines or piperazines 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- 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
- A61K31/66—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
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
-
- 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
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Abstract
抗病毒治疗。本发明涉及化合物的联用药，其包含HIV整合酶抑制剂及其它治疗剂。这种联用药可有效用于抑制HIV复制、预防和/或治疗HIV感染和用于治疗AIDS和/或ARC。
Description
本申请是申请日为2011年1月24日的发明名称为“抗病毒治疗”的PCT/US2011/022219号发明专利申请的分案申请，原申请进入中国国家阶段获得的国家申请号为201180015114.8.
本发明的背景.
人类免疫缺陷性病毒(“HIV”)是获得性免疫缺陷综合征(爱滋病,“AIDS”)的病原体，这种疾病的特征为：破坏免疫***，尤其是破坏CD4+T细胞，同时伴随有对机会感染的敏感性，而它的前身AIDS相关的综合症(“ARC”)是一种以下列症状为特征的综合症：例如，持久性的全身***病、发热和体重减轻。HIV是逆转录病毒；它的RNA至DNA的转化是通过酶(逆转录酶)的作用完成的。抑制逆转录酶的功能的化合物可以抑制HIV在受感染细胞中的复制。这种化合物可有效用于预防或治疗人的HIV感染。
除了CD4之外，HIV为进入到靶细胞需要辅助受体。趋化因子受体和CD4一起起到HIV的辅助受体的作用。趋化因子受体CXCR4和CCR5已经被确定为HIV-1的主要辅助受体。CCR5起到嗜巨噬细胞(macrophage-tropic)HIV融合并进入到宿主细胞中的主要辅助受体作用。人们认为这些趋化因子受体在HIV感染的建立和扩散方面起到主要的作用。因此，人们认为CCR5拮抗剂用作抗HIV的活性治疗剂。
正如在一些其它逆转录病毒的情况下那样，HIV编码蛋白酶的生产，该蛋白酶使前体多肽在形成感染性病毒体所必需的过程中实现翻译后断裂。这些基因产物包括pol，其编码病毒体RNA依赖性的DNA聚合酶(逆转录酶)、核酸内切酶、HIV蛋白酶和gag(其编码病毒体的核心蛋白)。
抗病毒药物设计的一个焦点是产生能够通过干扰病毒多蛋白前体的加工来抑制感染性病毒体形成的化合物。这些前体蛋白的加工需要病毒编码的、对复制必不可少的蛋白酶的作用。人们使用肽基抑制剂证明了HIV蛋白酶抑制作用的抗病毒潜力。
在人T细胞中，HIV复制所需要的步骤是通过病毒编码的整合酶使前病毒的DNA***到宿主细胞基因组中。人们认为，整合是在下述过程中通过整合酶介导的,该过程涉及稳定核蛋白与病毒DNA序列的复合物的组装，两个核苷酸从线型前病毒DNA的3'端断裂，以及该前病毒DNA的凹进的3'OH端在宿主靶向位点所产生的交错切口处共价连接。所产生的缝隙的修复合成可以通过细胞酶完成。HIV整合酶的抑制剂可以有效用于治疗AIDS和抑制病毒复制。
在HIV感染和相关病症的治疗过程中，给予治疗化合物的联用药(combinations)可以导致抗病毒活性增强、毒性降低、延迟耐药性的进展和提高药物效果。在单一剂量单位中给予的联用药可以导致患者依从性提高，同时降低药片负荷，并使给药计划简化。然而，不是所有的化合物都适合于以联用形式给药。影响联用药的可行性的因素包括：化合物的化学不稳定性，剂量单位的大小，拮抗潜力或仅仅具有联用化合物的加和活性和获得合适制剂的困难度。
因此还需要发现适合在治疗HIV感染的联用药和合适药物组合物中使用的治疗剂。由于某些HIV整合酶抑制剂的高效能和药物动力学特性，它们作为联合治疗中的组成部分是很有吸引力的。
附图的简要说明
图1∶式(I)化合物GSK1349572A与阿巴卡韦(ABC)的联用药对HIV-1IIIB的抑制。
图2∶式(I)化合物GSK1349572A与依法韦恩茨(EFV)的联用药对HIV-1IIIB的抑制。
图3∶式(I)化合物GSK1349572A与洛匹那韦(LPV)的联用药对HIV-1IIIB的抑制。
本发明概述
本发明涉及化合物的联用药，其包含HIV整合酶抑制剂及其它治疗剂。这种联用药可有效用于抑制HIV复制、预防和/或治疗HIV感染和用于治疗AIDS和/或ARC。本发明的特征还在于含有HIV整合酶抑制剂的药物组合物。
本发明的详细说明
本发明涉及联用药，其包含下列式(I)、(II)或(III)的化合物∶
(I)
(II)
(III)
或其可药用盐，和一或多种选自下列的治疗剂：核苷酸逆转录酶抑制剂，核苷逆转录酶抑制剂(NRTIs)，非核苷逆转录酶抑制剂(NNRTIs)，蛋白酶抑制剂，CCR5拮抗剂，CXCR4拮抗剂，融合抑制剂，成熟抑制剂和整合酶抑制剂。
本发明涉及治疗HIV感染、AIDS和AIDS相关病症的方法，该方法给予患者式(I)、(II)或(III)的化合物和一或多种选自下列的治疗剂：核苷酸逆转录酶抑制剂，核苷逆转录酶抑制剂(NRTIs)，非核苷逆转录酶抑制剂(NNRTIs)，蛋白酶抑制剂，CCR5拮抗剂，CXCR4拮抗剂，融合抑制剂，成熟抑制剂和整合酶抑制剂。
式(I)的化合物还称为GSK1349572。式(I)化合物的化学名称是(4R,12as)-N-[2,4-氟苯基)甲基]-3,4,6,8,12,12a-六氢-7-羟基-4-甲基-6,8-二氧代-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]噁嗪-9-甲酰胺。
式(II)化合物的化学名称是(3S,11aR)-N-[(2,4-二氟苯基)甲基]-2,3,5,7,11,11a-六氢-6-羟基-3-甲基-5,7-二氧代-噁唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺。
式(III)化合物的化学名称是(4aS,13aR)-N-[2,4-二氟苯基)甲基]-10-羟基-9,11-二氧代-2,3,4a,5,9,11,13,13a-八氢-1H-吡啶并[1,2-a]吡咯并[1',2':3,4，]咪唑并[1,2-d]吡嗪-8-甲酰胺。
术语“可药用载体或助剂”是指可以与本发明化合物一起给予患者的载体或助剂，其不会破坏本发明化合物的药理学活性，并且当以足够递送治疗数量的抗病毒剂的剂量给予时，其是无毒的。
本文使用的术语“治疗”是指患者具体病症的症状减轻，或与具体病症有关的可确定的量度的改善，并且可以包括抑制无症状患者的症状复发，例如，具有潜在病毒感染的患者。治疗可以包括预防，这是指预防患者的疾病或病症，或防止这种疾病或病症的症状出现。本文使用的术语“患者”是指哺乳动物，包括人。
本文使用的术语“患者”是指病人、动物或生物样品。
按照本发明化合物的可药用盐包括衍生自可药用无机和有机酸和碱的那些盐。合适的酸的例子包括盐酸，氢溴酸，硫酸，硝酸，高氯酸，富马酸，马来酸，磷酸，乙二醇酸，乳酸，水杨酸，琥珀酸，对甲苯磺酸，酒石酸，乙酸，柠檬酸，甲磺酸，乙磺酸，甲酸，苯甲酸，丙二酸，萘-2-磺酸和苯磺酸。其它酸，例如草酸，尽管本身不是可药用的，但可以在得到本发明化合物和其可药用酸加成盐的过程中用作中间体的盐的制备中使用。衍生自合适的碱的盐包括碱金属(例如钠)、碱土金属(例如镁)、铵、NW4 +(其中W是C1-4烷基)及其它胺盐。优选的盐是钠盐。
本发明化合物的盐可以利用本领域技术人员已知的方法来制备。例如，在合适的溶剂中，用合适的碱或酸处理本发明的化合物，可以得到相应的盐。
本发明涉及治疗或预防人的病毒感染的方法，例如HIV感染，该方法包括：给予人治疗有效量的式(I)、(II)或(III)的化合物或其可药用盐与一或多种选自下列的治疗剂的联用药：核苷酸逆转录酶抑制剂，核苷逆转录酶抑制剂(NRTIs)，非核苷逆转录酶抑制剂(NNRTIs)，蛋白酶抑制剂，CCR5拮抗剂，CXCR4拮抗剂，融合抑制剂，成熟抑制剂和整合酶抑制剂。可以同时或顺序给予联用药。
式(I)、(II)和(III)的化合物尤其适合于治疗或预防HIV感染和有关的病症。本文谈到的治疗可以延伸至预防以及确定感染、症状和相关的临床病症的治疗，例如AIDS相关症(ARC)、卡波济氏肉瘤和AIDS痴呆。
联合治疗包括：给予本发明的化合物或其可药用盐和另一种药学活性剂。活性组分和药学活性剂可以在相同或不同的药物组合物中同时(即并行)给予，或以任何次序顺序给予。为了获得目标联合治疗效果，可以选择活性组分和药学活性剂的数量和给药的相对时间。
这种治疗剂的例子包括但不局限于：有效治疗病毒感染或相关病症的药剂。在这些药剂之中有核苷酸逆转录酶抑制剂，无环核苷膦酸酯，例如(S)-1-(3-羟基-2-膦酰基-甲氧基丙基)胞嘧啶(HPMPC)，[[[2-(6-氨基-9H-嘌呤-9-基)乙氧基]甲基]氧亚膦基(phosphinylidene)]二(氧甲撑)-2,2-二甲基丙酸(bis-POMPMEA，阿德福韦酯)，阿德福韦，[[(1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基乙氧基]甲基]膦酸(泰诺福韦)，泰诺福韦二吡呋酯富马酸盐和(R)-[[2-(6-氨基-9H-嘌呤-9-基)-1-甲基乙氧基]甲基]膦酸双(异丙氧羰基氧基甲基)酯(bis-POC-PMPA)；核苷逆转录酶抑制剂，例如3'-叠氮基-3'-脱氧胸苷(AZT，叠氮胸苷)，2',3'-双脱氧胞苷(ddC，扎西他滨)，2',3'-二脱氧腺苷，2',3'-去羟肌苷(ddI，去羟肌苷)，2',3'-双脱氧胸苷(d4T，双脱氧胸苷)，(-)-顺式-1-(2-羟甲基)-1,3-氧硫杂环戊烷-5-基)-胞嘧啶(拉米夫定)，顺式-1-(2-(羟甲基)-1,3-氧杂硫杂环戊烷-5-基)-5-氟胞嘧啶(FTC，恩曲他滨(emtricitabine))，(-)-顺式-4-[2-氨基-6-(环丙氨基)-9H-嘌呤-9-基]-2-环戊烯-1-甲醇(阿巴卡韦)，福齐夫定替酯(fozivudinetidoxil)，阿洛夫定，氨多索韦(amdoxovir)，艾夫他滨(elvucitabine)，阿立他滨(apricitabine)和festinavir(OBP-601)；蛋白酶抑制剂，例如茚地那韦，利托那韦，奈非那韦，安普那韦，沙奎那维，佛萨普那韦，洛匹那韦，阿扎那韦(atazanavir)，替拉那韦(tipranavir)，达芦那韦(darunavir)，贝卡那韦(brecanavir)，帕利那韦(palinavir)，拉西那韦(lasinavir)，TMC-310911，DG-17，PPL-100和SPl-256；非核苷逆转录酶抑制剂(NNRTIs)，例如内维拉平，地拉韦啶，依法韦恩茨，GSK2248761(IDX-12899)，来司韦林(lersivirine)(UK-453,061)，利匹韦林(rilpivirine)(TMC-278)，依曲韦林(etravirine)，洛韦胺(loviride)，immunocal，奥替普拉(oltipraz)，卡普韦林(capravirine)和RDEA-806；整合酶抑制剂，例如雷特格韦(raltegravir)，埃替拉韦(elvitegravir)和JTK-656；CCR5和/或CXCR4拮抗剂，例如，马拉维若(maraviroc)，vicriviroc(Sch-D)，TBR-652(TAK-779)，TAK-449，PRO-140，GSK706769和SCH-532706；融合抑制剂，例如恩夫韦地(T-20)，T-1249，PRO-542，ibalizumab(TNX-355)，BMS-378806(BMS-806)，BMS-488043，KD-247，5-螺旋抑制剂和HIV连接抑制剂；和成熟抑制剂，例如，贝韦立马(bevirimat)(PA-344和PA-457)。
本发明的特征在于联用药，其包含式(I)的化合物
(I)
或其可药用盐和一或多种选自下列的治疗剂：拉米夫定，阿巴卡韦，泰诺福韦，依法韦恩茨，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦(atazanavir)。
本发明的特征还在于联用药，其包含式(I)的化合物或其可药用盐和一或多种选自下列的治疗剂：阿巴卡韦、依法韦恩茨或洛匹那韦。本发明的特征在于联用药，其包含式(I)的化合物或其可药用盐和阿巴卡韦。
本发明的特征在于HIV感染的治疗方法，包括：给予患者式(I)的化合物或其可药用盐和一或多种选自下列的治疗剂：拉米夫定，阿巴卡韦，泰诺福韦，依法韦恩茨，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦(atazanavir)。
本发明的特征在于HIV感染的治疗方法，包括：给予患者式(I)的化合物或其可药用盐与一或多种选自下列的治疗剂：阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征在于HIV感染的治疗方法，包括：给予患者式(I)的化合物或其可药用盐和阿巴卡韦。
本发明的特征在于药物组合物，其包含式(I)的化合物或其可药用盐和一或多种选自下列的治疗剂以及此种情况下可药用的载体∶拉米夫定，阿巴卡韦，依法韦恩茨，泰诺福韦，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦(atazanavir)。
本发明的特征在于药物组合物，其包含式(I)的化合物或其可药用盐和一或多种选自下列的治疗剂以及此种情况下可药用的载体∶阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征在于药物组合物，其包含式(I)的化合物或其可药用盐和阿巴卡韦以及此种情况下可药用的载体。
本发明的特征在于联用药，其包含式(II)的化合物
(II)
或其可药用盐和一或多种选自下列的治疗剂：拉米夫定，阿巴卡韦，泰诺福韦，依法韦恩茨，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦(atazanavir)。
本发明的特征还在于联用药，其包含式(II)的化合物或其可药用盐和一或多种选自下列的治疗剂：阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征在于联用药，其包含式(II)的化合物或其可药用盐和阿巴卡韦。
本发明的特征在于HIV感染的治疗方法，包括：给予患者式(II)的化合物或其可药用盐和一或多种选自下列的治疗剂：拉米夫定，阿巴卡韦，泰诺福韦，依法韦恩茨，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦(atazanavir)。
本发明的特征在于HIV感染的治疗方法，包括：给予患者式(II)的化合物或其可药用盐与一或多种选自下列的治疗剂：阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征在于HIV感染的治疗方法，包括：给予患者式(II)的化合物或其可药用盐和阿巴卡韦。
本发明的特征在于药物组合物，其包含式(II)的化合物或其可药用盐和一或多种选自下列的治疗剂以及此种情况下可药用的载体∶拉米夫定，阿巴卡韦，依法韦恩茨，泰诺福韦，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦阿扎那韦(atazanavir)。
本发明的特征在于药物组合物，其包含式(II)的化合物或其可药用盐和一或多种选自下列的治疗剂以及此种情况下可药用的载体∶阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征在于药物组合物，其包含式(II)的化合物或其可药用盐和阿巴卡韦以及此种情况下可药用的载体。
本发明的特征在于联用药，其包含式(III)的化合物
(III)
或其可药用盐和一或多种选自下列的治疗剂：拉米夫定，阿巴卡韦，泰诺福韦，依法韦恩茨，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦(atazanavir)。
本发明的特征还在于联用药，其包含式(III)的化合物或其可药用盐和一或多种选自下列的治疗剂：阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征还在于联用药，其包含式(III)的化合物或其可药用盐和阿巴卡韦。
本发明的特征在于HIV感染的治疗方法，包括：给予患者式(III)的化合物或其可药用盐和一或多种选自下列的治疗剂：拉米夫定，阿巴卡韦，泰诺福韦，依法韦恩茨，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦(atazanavir)。
本发明的特征在于HIV感染的治疗方法，包括：给予患者式(III)的化合物或其可药用盐与一或多种选自下列的治疗剂的联用药：阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征在于HIV感染的治疗方法，包括：给予患者式(III)的化合物或其可药用盐和阿巴卡韦。
本发明的特征在于药物组合物，其包含式(III)的化合物或其可药用盐和一或多种选自下列的治疗剂以及此种情况下可药用的载体∶拉米夫定，阿巴卡韦，依法韦恩茨，泰诺福韦，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦阿扎那韦(atazanavir)。
本发明的特征在于药物组合物，其包含式(III)的化合物或其可药用盐和一或多种选自下列的治疗剂以及此种情况下可药用的载体∶阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征在于药物组合物，其包含式(III)的化合物或其可药用盐和阿巴卡韦以及此种情况下可药用的载体。
本发明的特征在于上述的联用药、治疗方法和药物组合物，其中式(I)、(II)或(III)化合物的可药用盐是钠盐。
本发明的特征在于上述联用药、治疗方法和药物组合物，其中一或多种治疗剂是所述治疗剂的可药用盐，例如，阿巴卡韦半硫酸盐，佛萨普那韦钙，硫酸阿扎那韦(atazanavir)，硫酸泰诺福韦二吡呋酯，vicriviroc马来酸盐或贝韦立马(bevirimat)二甲葡胺。
本发明的特征在于上述治疗方法，其中患者是人。
本发明的特征在于上述联用药、治疗方法和药物组合物，其中顺序给予联用药。
本发明的特征在于上述联用药、治疗方法和药物组合物，其中同时或并行给予联用药。
式(I)、(II)和(III)的化合物可以利用WO2006/116764、U.S.61/193,634(WO2010/068253)或61/193,636(WO2010/068262)(本文以引证的方式将它们结合到本文中)公开的方法来制备。
阿巴卡韦可以利用公开在下列中的方法来制备：美国专利US5,034,394；5,089,500；6,294,540；5,641,889；5,840,990；5,919,941；5,808,147；6,392,085；6,448,403；5,917,041；6,087,501；5,917,042；6,555,687；6,552,193；6,870,053；6,294,540；6,340,587；或6,646,125。
拉米夫定可以利用公开在下列中的方法来制备：美国专利US5,047,407；7,119,202；5,905,082；5,696,254；5,663,320；5,693,787；6,051,709；或6,329,522。
泰诺福韦可以利用美国专利US5,922,695、5,935,946、5,977,089、6,043,230、6,069,249来制备。
依法韦恩茨可以利用公开在下列中的方法来制备：美国专利US5,519.021；5,663,169；5,811,423；6,555,133；6,639,071；或6,939,964。
GSK2248761可以利用公开在美国专利US7,534,809中的方法来制备。
来司韦林(Lersivirine)可以利用公开在美国专利US7,109,228中的方法来制备。
洛匹那韦可以利用公开在美国专利US5,914,332中的方法来制备。
佛萨普那韦可以利用公开在美国专利US6,436,989、6,514,953或6,281,367中的方法来制备。
阿扎那韦(atazanavir)可以利用公开在美国专利US5,849,911或6,087,383中的方法来制备。
联用药的治疗剂可以按照公开的方法或利用本领域技术人员已知的任何方法来制备。
在本发明的一个方面，可以将式(I)、(II)或(III)的化合物或其可药用盐与一或多种治疗剂一起配制为组合物。该组合物可以是药物组合物，其包含式(I)、(II)或(III)的化合物、一或多种治疗剂和可药用载体、助剂或赋形剂。在一个实施方案中，该组合物包含有效治疗或预防生物样品或病人中的病毒感染(例如HIV感染)数量的本发明的联用药。在另一个实施方案中，可以将本发明的联用药和其药物组合物进行配制，用于给予病人，例如，口服给药，其中该药物组合物包含有效抑制病毒复制或治疗或预防病毒感染或疾病或病症(例如HIV感染)数量的本发明的联用药和可药用载体、助剂或赋形剂。
本发明的特征在于用于医学治疗的按照本发明的联用药，例如，用于治疗或预防病毒感染，例如HIV感染和相关病症。按照本发明的化合物尤其可用于治疗AIDS和相关的临床病症，例如AIDS相关综合症(ARC)，渐进性的全身化***病(PGL)，卡波济氏肉瘤，血小板减少性紫癜，AIDS相关的神经病症，例如AIDS痴呆综合症、多发性脑硬化或热带轻瘫（paraperesis），抗HIV抗体阳性和HIV-阳性病症，包括无症状患者中的这种病症。
按照另一个方面，本发明提供了治疗或预防受感染患者(例如，哺乳动物，包括人)中的病毒感染的症状或影响的方法，该方法包括：给予所述患者药学有效量的按照本发明的联用药。按照本发明的一个方面，病毒感染是逆转录病毒感染，尤其是HIV感染。
本发明进一步包括按照本发明的联用药在制备药物中的用途，该药物用于同时(并行)或顺序给予被治疗病毒感染的患者，尤其是HIV感染。
本发明进一步提供了治疗患者(例如，哺乳动物，包括人)的临床病症的方法，其中临床病症包括上文讨论的那些病症，该方法包括：用药学有效量的按照本发明的化合物治疗所述患者。本发明还包括治疗或预防任何上述疾病或病症的方法。
本发明的化合物可以与已知能够抑制或降低化合物代谢的药剂(例如利托那韦)一起给予。相应地，本发明的特征在于治疗或预防上文所描述疾病的方法，该方法给予本发明化合物与代谢抑制剂的联用药。这种联用药可以同时或顺序给予。
通常，对于每个上述病症，合适的剂量在每千克接受者(例如人)体重每天0.01至250mg范围内、在每千克体重每天0.1至100mg范围内、在每千克体重每天1至30mg范围内、在每千克体重每天0.5至20mg范围内。除非另有陈述，否则，活性组分的所有重量以式(I)、(II)或(III)的母体化合物及其它治疗剂的形式来计算。对于其盐，重量可以按比例提高。目标剂量可以以每天以合适的间隔时间给予的一个、两个、三个、四个、五个、六个或更多个子剂量形式提供。在某些情况下，目标剂量可以隔天给予。可以用单位剂型给予这些子剂量，例如，每个单位剂型含有1至2000mg、5至500mg、10至400mg、20至300mg每种活性组分。
可以给予联用药，获得每个活性组分的峰值血浆浓度。
尽管可以单独给予活性组分，但优选以药物组合物形式提供。本发明的组合物包含上述活性组分以及一或多种其可接受的载体和一或多种其它治疗剂。每个载体在与组合物的其它组分相容的意义上必须是可接受的，并且对患者无害。
药物组合物包括适合于口服、直肠、鼻部、局部(包括透皮、口腔和舌下)、***或肠胃外(包括皮下、肌内、静脉内、皮内和眼内)给药的那些药物组合物。组合物可以方便地存在于单位剂型中，并且可以用药学领域任何众所周知的方法来制备。这种方法代表本发明的进一步特征，并且包括下列步骤：使活性组分与构成一或多种助剂成分的载体结合。通常，如下制备组合物：使活性组分与液体载体或细碎的固体载体或两者均匀和密切地结合，而后，如有必要，使产品成型。
本发明进一步包括上文所定义的药物组合物，其中以组件的试剂盒形式相互分离地提供本发明的化合物或其可药用衍生物和另一种治疗剂。
适合于透皮给药的组合物可以以离散贴片形式提供，这种贴片适合于保持与接受者的表皮长时间地密切接触。这种贴片合适地含有活性化合物：1)在任选缓冲的水溶液中，或2)溶解和/或分散在粘附剂中，或3)分散在聚合物中。活性化合物的合适浓度大约为1%至25%，优选大约3%至15%。作为一种具体可能性，利用通常在PharmaceuticalResearch3(6)，318(1986)中所描述的电迁移或离子电渗方法，活性化合物可以从贴片中输送。
适合于口服给药的本发明药物组合物可以以下列形式提供：离散单位形式，例如胶囊剂、小胶囊、扁囊剂或片剂，其中每个优选含有预定数量的活性组分；粉剂或颗粒剂形式；在水或非水液体中的溶液剂或混悬剂形式；或水包油型液体乳剂或油包水型液体乳剂形式。活性组分还可以以丸剂(bolus)、膏剂或糊剂形式提供。
片剂可以通过压制或模制来制备，任选与一或多种助剂成分一起压制或模制。压制片可以如下制备：在合适的机械中，压制自由流动形式的(例如粉末或颗粒)活性组分,任选与粘合剂(例如，聚维酮，明胶，羟基丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如，淀粉乙醇酸钠，交联聚维酮，交联羧甲基纤维素钠)、表面活性剂或分散剂混合。模制片可以如下制备：在合适的机械中，将用惰性液体稀释剂湿润的粉末化合物混合物模制。可以任选将片剂包衣或刻痕，并且可以使用例如变化比例的羟基丙基甲基纤维素配制，以便使其中的活性组分缓慢或控制释放，从而提供目标释放特性。片剂可以任选拥有肠溶衣，以便在胃以外的肠管部分中释放。
适合于口腔局部给药的药物组合物包括：含有活性组分(在调味基质中，通常是蔗糖和***胶或黄芪胶)的糖锭；包含活性组分(在惰性基质中，例如明胶和丙三醇，或蔗糖和***胶)的软锭剂；和包含活性组分(在合适的液体载体中)的漱口药。
适合于***给药的药物组合物可以以***栓、塞、乳膏剂、凝胶剂、糊剂、泡沫体或喷雾剂形式提供。除了活性组分之外，药物组合物还可以含有本领域已知的合适载体。
直肠给药的药物组合物可以以含有合适载体(包括，例如，可可脂或水杨酸酯或本领域通常使用其它物质)的栓剂形式提供。栓剂可以方便地如下形成：将活性联用药与软化或熔融载体混合，而后在模具中冷却并成型。
适合于肠胃外给药的药物组合物包括水和非水等渗无菌注射溶液剂，其可以含有抗氧化剂、缓冲剂、抑菌剂和能够使该药物组合物与目标接受者的血液等渗的溶质；和水和非水的无菌混悬剂，其可以包含悬浮剂和增稠剂；和脂质体或其它微粒***，可以对其进行设计，使化合物靶向血液组分或一个或多个器官。药物组合物可以提供于单位剂量或多剂量密封容器中，例如，安瓿和小瓶，并且可以保存在冷冻干燥(冻干)条件下，只需要在临近使用之前加入无菌的液体载体即可，例如注射用水。可以用先前所描述种类的无菌粉剂、颗粒剂和片剂来制备临时注射溶液剂和混悬剂。
单位剂量药物组合物包括含有上文列举的活性组分的日剂量或日子剂量或其合适部分的那些药物组合物。
本发明的药物组合物可以以患者包装形式提供，在单个包装(例如，泡罩包装)中含有一个或多个疗程的药物组合物。可以理解，借助于单个患者包装或每个组合物的患者包装来给予本发明的联用药是本发明的另外的特征。
应该理解，根据所述药物组合物的类型，除了上面具体提及的组分之外，本发明的药物组合物还可以包含本领域的其它常规药剂，例如，适合于口服给药的那些药物组合物可以进一步包含例如甜味剂、增稠剂和调味剂。
实施例
实施例1∶生物活性
试验
方法
借助于基于四唑盐的比色方法，在人T细胞白血病毒(HTLV-1)转变的细胞系MT-4中，测定抗病毒HIV活性。将试验化合物的等分样品在深孔主试验板的纵向上(vertically)稀释于培养基(RPMI1640，10%vol./vol.胎牛血清(FBS)和10(μg/mL庆大霉素)中，浓度比最终试验浓度大约高40倍。以1:2或1:3.16的比例进行系列稀释。将HIV抑制剂在主试验板的横向上(horizontally)加以稀释，浓度还是比最终试验浓度大约高40倍。使用自动的96孔移液***(RapidPlate-96，ZymarkCorp.)，将纵向稀释和横向稀释的化合物的少量等分样品在子板中混合。将棋盘式稀释物进行排列，以便在存在和不存在每个浓度的HIV抑制剂条件下试验每个浓度的试验化合物。对于每个联用药，一式三份地进行抗HIV活性试验，或进行更多的试验。采集指数(Exponentially)生长的MT-4细胞，并在Jouan离心机(ModelCR412)中、在1,000rpm下离心10分钟。将细胞球粒重新悬浮在新的培养基(RPMI1640，20%vol./vol.FBS，20%vol./vol.IL-2和10μg/mL庆大霉素)中，密度为1.25x106个细胞/mL。通过加入稀释的HIV-1(菌株IIIB)，使细胞等分样品感染，得到每1x104个细胞73pfU的病毒多重性感染(MOI)。用培养基稀释类似的细胞等分样品，提供模拟感染(mock-infected)对照物。在37℃，在含有湿润的5%CO2氛围的组织培养箱中，使细胞感染进行1小时。培养1小时之后，将病毒/细胞悬液加入到含有预先稀释的化合物的板的每个孔中。然后将板放入含有湿润的5%CO2的组织培养箱中，保持5天。在培养期的最后，将40μLCellTiter96MTS试剂(PromegaNo.G3581)加入到培养板的每个孔中。将板在37℃下培养2至3小时，使其显色。使用微板吸光度读数器(TecanNo.20-300)在492nM测定吸光度O.D.。
使用的病毒
HIV-1菌株IIIB，野生型实验室菌株，病毒滴度=6.896E4TCID50/mL。
数据分析
虽然一些试验形式理论上可能失去拮抗作用(由于联合细胞毒性)，但本文所描述的方法不应该失去拮抗效应。在MT-4细胞试验中的读出数据使用MTS(基于四唑盐的染色剂)，其中该试剂的吸光度(O.D.)变化用于估计处理后的总的细胞数目。由于两种影响，最终的MT-4细胞数目可能减少。首先，当在感染之后5天期间HIV杀死75%以上的MT-4细胞时，可能出现HIV引起的细胞毒性。其次，可能出现化合物引起的细胞毒性，在这种的情况下，化合物直接杀死MT-4细胞，或在感染或未感染的细胞中妨碍细胞生长(停滞)5天。在这些情况中的任何一种情况下，与抗HIV-1化合物保护的受感染细胞相比较，或相对于未经处理的和未感染的对照细胞，O.D.降低。由于抗HIV活性的细胞毒性效果和拮抗作用两者导致O.D.降低，我们不应该由于联合细胞毒性而忽视(miss)拮抗效应，但可能低估协同作用的联用药。
在试验过程中，可以如下评价联合细胞毒性：将含有未感染的MT-4细胞(源自于含有最高浓度试验化合物或比较化合物的试验板)的孔与含有HIV-1感染的MT-4细胞(在相应的最高联用药浓度下)的孔进行比较。对于这些数值中的每个数值，每个试验板有一个孔，并由此每个联用药试验中至少有3个孔。虽然它们不包括正式的联合细胞毒性分析，但联用药中的化合物与单独化合物的比例可以提供在检验浓度范围内化合物联合细胞毒性的度量。
利用Selleseth，D.W.等人，(2003)AntimicrobialAgentsandChemotherapy47:1468-71所描述的方法，分析每对化合物联用药的相互作用。协同作用和拮抗作用定义为自剂量加合值的偏离值，剂量加和值发生在当两种药物如同它们是相同的药物一样相互作用时。自加和值的平均偏离值在-0.1至-0.2范围内表示弱协同作用，接近-0.5的数值表示强协同的相互作用。反之，0.1至0.2的正值表示在治疗之间存在弱的拮抗作用。
结果
发现式(I)的化合物与雷特格韦(raltegravir)、阿德福韦和马拉维若(maraviroc)具有加和效果，并且不受利巴韦林的存在的影响。发现式(I)的化合物与双脱氧胸苷(stavudine,司他夫定)、阿巴卡韦、依法韦恩茨、内维拉平、洛匹那韦、安普那韦、恩夫韦地具有协同作用。
Claims (18)
1.联用药，其包含式(I)的化合物
或其可药用盐与利匹韦林(rilpivirine)或其可药用盐。
2.按照权利要求1的联用药，其中式(I)化合物的可药用盐是钠盐。
3.按照权利要求1或2的联用药，其中利匹韦林的可药用盐是盐酸盐。
4.按照权利要求1-3的任一项的联用药，其用于医学治疗。
5.按照权利要求1-3的任一项的联用药，其用于治疗HIV感染。
6.按照权利要求1-3的任一项的联用药，其用于预防HIV感染。
7.药物组合物，其包含按照权利要求1-3中任一项的联用药以及其可药用载体。
8.按照权利要求1-3的任一项的联用药，其中同时给予该联用药。
9.按照权利要求1-3的任一项的联用药，其中顺序给予该联用药。
10.按照权利要求1-3的任一项的联用药在制备用于治疗或预防HIV感染的药物中的用途。
11.按照权利要求10的用途，其中式(I)化合物和利匹韦林同时给予。
12.按照权利要求10的用途，其中式(I)化合物和利匹韦林顺序给予。
13.一种患者包装，其包括按照权利要求1-3的任一项的联用药。
14.按照权利要求1的联用药，其基本上如本文中所描述或举例说明的。
15.按照权利要求7的药物组合物，其基本上如本文中所描述或举例说明的。
16.按照权利要求10的用途，其基本上如本文中所描述或举例说明的。
17.按照权利要求13的患者包装，其基本上如本文中所描述或举例说明的。
18.本文中所公开的任何新特征或多种特征的新组合。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US29858910P | 2010-01-27 | 2010-01-27 | |
| US61/298589 | 2010-01-27 | ||
| CN201180015114.8A CN102791129B (zh) | 2010-01-27 | 2011-01-24 | 抗病毒治疗 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201180015114.8A Division CN102791129B (zh) | 2010-01-27 | 2011-01-24 | 抗病毒治疗 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105311033A true CN105311033A (zh) | 2016-02-10 |
| CN105311033B CN105311033B (zh) | 2019-05-07 |
Family
ID=44319704
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510619148.8A Active CN105311033B (zh) | 2010-01-27 | 2011-01-24 | 抗病毒治疗 |
| CN201180015114.8A Active CN102791129B (zh) | 2010-01-27 | 2011-01-24 | 抗病毒治疗 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201180015114.8A Active CN102791129B (zh) | 2010-01-27 | 2011-01-24 | 抗病毒治疗 |
Country Status (45)
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT2531027E (pt) | 2010-01-27 | 2015-09-16 | Viiv Healthcare Co | Combinação terapêutica compreendendo dolutegravir, abacavir e lamivudina |
| US10004721B2 (en) | 2012-10-23 | 2018-06-26 | Cipla Limited | Pharmaceutical antiretroviral composition |
| RS54873B1 (sr) | 2012-12-21 | 2016-10-31 | Gilead Sciences | Policiklična-karbamoilpiridonska jedinjenja i njihova farmaceutska upotreba |
| EP2767272A1 (en) * | 2013-02-18 | 2014-08-20 | Ratiopharm GmbH | Solid pharmaceutical dosage form of dolutegravir |
| EP2956123A1 (en) * | 2013-02-18 | 2015-12-23 | ratiopharm GmbH | Solid pharmaceutical dosage form of dolutegravir |
| EP3252058B1 (en) | 2013-07-12 | 2021-01-20 | Gilead Sciences, Inc. | Polycyclic-carbamoylpyridone compounds and their use for the treatment of hiv infections |
| NO2865735T3 (zh) | 2013-07-12 | 2018-07-21 | ||
| JP6081662B2 (ja) | 2013-09-27 | 2017-02-15 | メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． | Ｈｉｖインテグラーゼ阻害薬として有用な置換されたキノリジン誘導体 |
| IN2014MU00916A (zh) | 2014-03-20 | 2015-09-25 | Cipla Ltd | |
| EP3151920A4 (en) | 2014-06-04 | 2017-12-27 | Sanford-Burnham Medical Research Institute | Use of inhibitor of apoptosis protein (iap) antagonists in hiv therapy |
| TWI744723B (zh) | 2014-06-20 | 2021-11-01 | 美商基利科學股份有限公司 | 多環型胺甲醯基吡啶酮化合物之合成 |
| NO2717902T3 (zh) | 2014-06-20 | 2018-06-23 | ||
| 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 |
| CN107074875B (zh) | 2014-07-29 | 2019-03-29 | 斯洛文尼亚莱柯制药股份有限公司 | 度鲁特韦钠的新水合物 |
| TWI695003B (zh) | 2014-12-23 | 2020-06-01 | 美商基利科學股份有限公司 | 多環胺甲醯基吡啶酮化合物及其醫藥用途 |
| EP3466490B1 (en) | 2015-04-02 | 2020-10-21 | Gilead Sciences, Inc. | Polycyclic-carbamoylpyridone compounds and their pharmaceutical use |
| EP3334419A1 (en) * | 2015-08-14 | 2018-06-20 | Sandoz AG | Solid pharmaceutical composition of abacavir, lamivudine, and efavirenz |
| WO2017205585A1 (en) * | 2016-05-27 | 2017-11-30 | Viiv Healthcare Company | Combinations and uses treatments thereof |
| WO2018028841A1 (en) * | 2016-08-12 | 2018-02-15 | Sandoz Ag | Solid pharmaceutical composition of abacavir, lamivudine, and efavirenz |
| WO2018042332A1 (en) * | 2016-08-31 | 2018-03-08 | Glaxosmithkline Intellectual Property (No.2) Limited | Combinations and uses and treatments thereof |
| US20200138845A1 (en) * | 2017-07-18 | 2020-05-07 | Viiv Healthcare Company | Combination Drug Therapy |
| EP3654980A1 (en) | 2017-07-21 | 2020-05-27 | VIIV Healthcare Company | Regimens for treating hib infections and aids |
| US20200147092A1 (en) * | 2017-07-21 | 2020-05-14 | Viiv Healthcare Company | Regimens for treating hiv infections and aids |
| MX2020003377A (es) * | 2017-10-13 | 2020-09-28 | Viiv Healthcare Co | Formulacion de tableta farmaceutica de dos capas. |
| CA3128961A1 (en) | 2019-03-22 | 2020-10-01 | Hang CHU | Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use |
| US20230270677A1 (en) * | 2020-01-09 | 2023-08-31 | University Of Washington | Long-acting therapeutic agent combinations and methods thereof |
| CR20220418A (es) | 2020-02-24 | 2022-10-10 | Gilead Sciences Inc | Compuestos tetracíclicos para el tratamiento de infecciones por vih |
| LT4196479T (lt) | 2021-01-19 | 2023-12-11 | Gilead Sciences, Inc. | Pakeistieji piridotriazino junginiai ir jų panaudojimo būdai |
| WO2023164293A1 (en) * | 2022-02-28 | 2023-08-31 | Jericho Sciences, Llc | Methods for viral infections |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6544961B1 (en) * | 1996-06-25 | 2003-04-08 | Smithkline Beecham Corporation | Combinations comprising VX478, zidovudine, FTC and/or 3TC for use in the treatments of HIV |
| US20060084627A1 (en) * | 2002-06-27 | 2006-04-20 | Medivir Ab | Synergistic interaction of abacavir and alovudine |
| US20080076738A1 (en) * | 2004-04-14 | 2008-03-27 | Cai Zhenhong R | Phosphonate Analogs Of Hiv Integrase Inhibitor Compounds |
| US20090318421A1 (en) * | 2005-04-28 | 2009-12-24 | Brian Alvin Johns | Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity |
Family Cites Families (70)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7119202B1 (en) | 1989-02-08 | 2006-10-10 | Glaxo Wellcome Inc. | Substituted-1,3-oxathiolanes and substituted-1,3-dioxolanes with antiviral properties |
| US5047407A (en) | 1989-02-08 | 1991-09-10 | Iaf Biochem International, Inc. | 2-substituted-5-substituted-1,3-oxathiolanes with antiviral properties |
| GB8815265D0 (en) | 1988-06-27 | 1988-08-03 | Wellcome Found | Therapeutic nucleosides |
| GB9009861D0 (en) | 1990-05-02 | 1990-06-27 | Glaxo Group Ltd | Chemical compounds |
| ZA923641B (en) | 1991-05-21 | 1993-02-24 | Iaf Biochem Int | Processes for the diastereoselective synthesis of nucleosides |
| GB9111902D0 (en) | 1991-06-03 | 1991-07-24 | Glaxo Group Ltd | Chemical compounds |
| GB9204015D0 (en) | 1992-02-25 | 1992-04-08 | Wellcome Found | Therapeutic nucleosides |
| US5665720A (en) | 1992-08-07 | 1997-09-09 | Merck & Co., Inc. | Benzoxazinones as inhibitors of HIV reverse transcriptase |
| IL106507A (en) | 1992-08-07 | 1997-11-20 | Merck & Co Inc | Pharmaceutical compositions containing benzoxazinones and some novel compounds of this type |
| GB9402161D0 (en) | 1994-02-04 | 1994-03-30 | Wellcome Found | Chloropyrimidine intermediates |
| IL113432A (en) | 1994-04-23 | 2000-11-21 | Glaxo Group Ltd | Process for the diastereoselective synthesis of nucleoside analogues |
| UA49803C2 (uk) | 1994-06-03 | 2002-10-15 | Дж.Д. Сьорль Енд Ко | Спосіб лікування ретровірусних інфекцій |
| MY115461A (en) | 1995-03-30 | 2003-06-30 | Wellcome Found | Synergistic combinations of zidovudine, 1592u89 and 3tc |
| US5914332A (en) | 1995-12-13 | 1999-06-22 | Abbott Laboratories | Retroviral protease inhibiting compounds |
| US5849911A (en) | 1996-04-22 | 1998-12-15 | Novartis Finance Corporation | Antivirally active heterocyclic azahexane derivatives |
| US5922695A (en) | 1996-07-26 | 1999-07-13 | Gilead Sciences, Inc. | Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability |
| US5965729A (en) | 1997-02-05 | 1999-10-12 | Merck & Co., Inc. | Process for the crystallization of a reverse transcriptase inhibitor using an anti-solvent |
| GB9709945D0 (en) | 1997-05-17 | 1997-07-09 | Glaxo Group Ltd | A novel salt |
| US5935946A (en) | 1997-07-25 | 1999-08-10 | Gilead Sciences, Inc. | Nucleotide analog composition and synthesis method |
| GB9717928D0 (en) | 1997-08-22 | 1997-10-29 | Glaxo Group Ltd | Process for the enatioselective hydrolysis of n-derivatised lactams |
| GB9721780D0 (en) | 1997-10-14 | 1997-12-10 | Glaxo Group Ltd | Process for the synthesis of chloropurine intermediates |
| US6436989B1 (en) | 1997-12-24 | 2002-08-20 | Vertex Pharmaceuticals, Incorporated | Prodrugs of aspartyl protease inhibitors |
| US6087383A (en) | 1998-01-20 | 2000-07-11 | Bristol-Myers Squibb Company | Bisulfate salt of HIV protease inhibitor |
| GB9805898D0 (en) | 1998-03-20 | 1998-05-13 | Glaxo Group Ltd | Process for the sythesis of hiv protease inhibitors |
| AU3366899A (en) | 1998-03-27 | 1999-10-18 | Regents Of The University Of California, The | Novel hiv integrase inhibitors and hiv therapy based on drug combinations including integrase inhibitors |
| UA72207C2 (uk) | 1998-04-07 | 2005-02-15 | Брістол- Майєрс Сквібб Фарма Компані | Фармацевтична композиція ефавіренцу з добавкою дезінтегруючих агентів у вигляді швидкорозчинних капсул або таблеток та спосіб її виготовлення |
| GB9809213D0 (en) * | 1998-04-29 | 1998-07-01 | Glaxo Group Ltd | Pharmaceutical compositions |
| GB9815567D0 (en) | 1998-07-18 | 1998-09-16 | Glaxo Group Ltd | Antiviral compound |
| EP1255510B3 (en) | 2000-01-31 | 2009-03-04 | Cook Biotech, Inc. | Stent valves |
| ME00558A (en) | 2001-04-10 | 2011-12-20 | Pyrazole derivatives for treating hiv | |
| JO3429B1 (ar) | 2001-08-13 | 2019-10-20 | Janssen Pharmaceutica Nv | مشتقات برميدينات مثبطة فيروس الايدز |
| MY169670A (en) | 2003-09-03 | 2019-05-08 | Tibotec Pharm Ltd | Combinations of a pyrimidine containing nnrti with rt inhibitors |
| US7638522B2 (en) * | 2001-08-13 | 2009-12-29 | Janssen Pharmaceutica N.V. | Salt of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino] benzonitrile |
| AR040242A1 (es) * | 2002-06-04 | 2005-03-23 | Glaxo Group Ltd | Composiciones farmaceuticas |
| PL378368A1 (pl) * | 2003-01-14 | 2006-04-03 | Gilead Sciences, Inc. | Kompozycje i sposoby wykorzystywane w skojarzonej terapii przeciwwirusowej |
| TW200510425A (en) | 2003-08-13 | 2005-03-16 | Japan Tobacco Inc | Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor |
| CA2555176A1 (en) * | 2004-02-11 | 2005-08-25 | Smithkline Beecham Corporation | Hiv integrase inhibitors |
| EP3287130A1 (en) * | 2004-05-21 | 2018-02-28 | Japan Tobacco Inc. | Combinations comprising a 4-isoquinolone derivative and protease inhibitors |
| US7176196B2 (en) | 2004-05-28 | 2007-02-13 | Bristol-Myers Squibb Company | Bicyclic heterocycles as HIV integrase inhibitors |
| EP1713489B1 (en) | 2004-08-23 | 2011-01-19 | Teva Pharmaceutical Industries Ltd | Crystalline form of ibandronate sodium and processes for preparation thereof |
| CA2577288C (en) | 2004-09-02 | 2010-11-30 | Janssen Pharmaceutica N.V. | Hydrochloride of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile |
| EP1961757B1 (en) | 2004-09-17 | 2010-09-01 | IDENIX Pharmaceuticals, Inc. | Phosphoindoles as HIV inhibitors |
| JP2008531716A (ja) | 2005-03-04 | 2008-08-14 | スミスクライン ビーチャム コーポレーション | 化合物 |
| UA96568C2 (en) * | 2005-04-28 | 2011-11-25 | Глаксосмиткляйн Ллк | Polycyclic carbamoyl pyridone derivative as hiv-integrase inhibitor |
| UA101141C2 (ru) * | 2005-12-30 | 2013-03-11 | Гилиад Сайенсиз, Инк. | Способ улучшения фармакокинетики ингибиторов интегразы вич |
| KR20140082858A (ko) | 2005-12-30 | 2014-07-02 | 길리애드 사이언시즈, 인코포레이티드 | Ｈｉｖ 인테그라제 억제제의 약동학을 개선하기 위한 방법 |
| EP1981506B3 (en) * | 2006-01-20 | 2021-06-09 | Janssen Sciences Ireland Unlimited Company | Long term treatment of hiv- infection with tcm278 |
| US20080039428A1 (en) | 2006-06-29 | 2008-02-14 | Panacos Pharmaceuticals, Inc. | Antiretroviral combination therapy |
| WO2008011117A2 (en) | 2006-07-21 | 2008-01-24 | Gilead Sciences, Inc. | Antiviral protease inhibitors |
| ES2488922T3 (es) | 2006-09-29 | 2014-09-01 | Idenix Pharmaceuticals, Inc. | Fosfoindoles enantiómeramente puros como inhibidores del HIV |
| HUE029866T2 (en) | 2007-02-23 | 2017-03-28 | Gilead Sciences Inc | Modulation of pharmacokinetic parameters of therapeutic agents |
| US20080241289A1 (en) | 2007-02-23 | 2008-10-02 | Auspex Pharmaceuticals, Inc. | Preparation and utility of non-nucleoside reverse transcriptase inhibitors |
| CA2692460A1 (en) | 2007-06-29 | 2009-01-08 | Korea Research Institute Of Chemical Technology | Hiv reverse transcriptase inhibitors |
| KR20100041798A (ko) | 2007-06-29 | 2010-04-22 | 한국화학연구원 | 신규 ｈｉｖ 역전사효소 억제제 |
| AR067412A1 (es) | 2007-07-06 | 2009-10-07 | Gilead Sciences Inc | Moduladores de propiedades farmaceuticas de productos terapeuticos |
| RU2498979C2 (ru) | 2007-07-12 | 2013-11-20 | Тиботек Фармасьютикалз | Кристаллическая форма 4-[[4-[[4-(2-цианоэтенил)-2,6-диметилфенил]амино]-2-пиримидинил]амино]бензонитрила |
| WO2009058923A1 (en) | 2007-10-31 | 2009-05-07 | Smithkline Beecham Corporation | Ccr5 antagonists as therapeutic agents |
| EP2217573A4 (en) | 2007-11-01 | 2011-08-31 | Uab Research Foundation | TREATMENT AND PREVENTION OF VIRUS INFECTIONS |
| US8108055B2 (en) | 2007-12-28 | 2012-01-31 | Larry Wong | Method, system and apparatus for controlling an electrical device |
| WO2009082819A1 (en) * | 2008-01-03 | 2009-07-09 | Virochem Pharma Inc. | Novel lupane derivatives |
| WO2009082818A1 (en) | 2008-01-03 | 2009-07-09 | Virochem Pharma Inc. | Novel c-21-keto lupane derivatives preparation and use thereof |
| PT2231628E (pt) | 2008-01-04 | 2015-12-29 | Gilead Sciences Inc | Inibidores de citocromo p450 |
| JP2011511812A (ja) | 2008-02-14 | 2011-04-14 | バイロケム ファーマ インコーポレイテッド | 新規１７βルパン誘導体 |
| WO2009148600A2 (en) * | 2008-06-06 | 2009-12-10 | Concert Pharmaceuticals, Inc. | Deuterated lysine-based compounds |
| DK2320908T3 (en) * | 2008-07-25 | 2014-03-10 | Viiv Healthcare Co | DOLUTEGRAVIR prodrugs |
| SG171731A1 (en) | 2008-12-11 | 2011-07-28 | Glaxosmithkline Llc | Processes and intermediates for carbamoylpyridone hiv integrase inhibitors |
| CA2955957A1 (en) | 2008-12-11 | 2010-06-17 | Shionogi & Co., Ltd. | Synthesis of carbamoylpyridone hiv integrase inhibitors and intermediates |
| PT2531027E (pt) | 2010-01-27 | 2015-09-16 | Viiv Healthcare Co | Combinação terapêutica compreendendo dolutegravir, abacavir e lamivudina |
| GB201006038D0 (en) | 2010-04-12 | 2010-05-26 | Unilever Plc | Improvements relating to antiviral compositions |
| WO2011160024A2 (en) | 2010-06-17 | 2011-12-22 | Fuzians Biomedicals, Inc. | Compounds useful as antiviral agents, compositions, and methods of use |
-
2011
- 2011-01-24 PT PT117374843T patent/PT2531027E/pt unknown
- 2011-01-24 RS RS20240189A patent/RS65183B1/sr unknown
- 2011-01-24 EA EA201290583A patent/EA025176B1/ru active Protection Beyond IP Right Term
- 2011-01-24 EP EP18161536.0A patent/EP3351249A1/en not_active Withdrawn
- 2011-01-24 DK DK16187411.0T patent/DK3127542T3/en active
- 2011-01-24 DK DK11737484.3T patent/DK2531027T3/en active
- 2011-01-24 BR BR112012018670-1A patent/BR112012018670A2/pt not_active Application Discontinuation
- 2011-01-24 MX MX2014014688A patent/MX367937B/es unknown
- 2011-01-24 PT PT151649316T patent/PT2932970T/pt unknown
- 2011-01-24 SI SI201131593T patent/SI3127542T1/sl unknown
- 2011-01-24 EA EA201690872A patent/EA032868B1/ru active Protection Beyond IP Right Term
- 2011-01-24 PL PL11737484T patent/PL2531027T3/pl unknown
- 2011-01-24 JP JP2012551213A patent/JP2013518107A/ja active Pending
- 2011-01-24 UA UAA201209253A patent/UA105556C2/uk unknown
- 2011-01-24 KR KR1020167025050A patent/KR101883750B1/ko active IP Right Grant
- 2011-01-24 CA CA3003988A patent/CA3003988C/en active Active
- 2011-01-24 EP EP11737484.3A patent/EP2531027B1/en not_active Revoked
- 2011-01-24 SG SG10201509476RA patent/SG10201509476RA/en unknown
- 2011-01-24 CN CN201510619148.8A patent/CN105311033B/zh active Active
- 2011-01-24 EP EP16187411.0A patent/EP3127542B1/en active Active
- 2011-01-24 SI SI201132101T patent/SI3494972T1/sl unknown
- 2011-01-24 LT LTEP19151897.6T patent/LT3494972T/lt unknown
- 2011-01-24 SI SI201131492T patent/SI2932970T1/en unknown
- 2011-01-24 ES ES11737484.3T patent/ES2543066T3/es active Active
- 2011-01-24 HU HUE15164931A patent/HUE037812T2/hu unknown
- 2011-01-24 MA MA35145A patent/MA34002B1/fr unknown
- 2011-01-24 PL PL15164931T patent/PL2932970T3/pl unknown
- 2011-01-24 KR KR1020177017713A patent/KR20170078868A/ko active Application Filing
- 2011-01-24 HU HUE16187411A patent/HUE040554T2/hu unknown
- 2011-01-24 PE PE2016000261A patent/PE20160180A1/es unknown
- 2011-01-24 PT PT16187411T patent/PT3127542T/pt unknown
- 2011-01-24 CA CA2967453A patent/CA2967453C/en active Active
- 2011-01-24 TR TR2018/07704T patent/TR201807704T4/tr unknown
- 2011-01-24 WO PCT/US2011/022219 patent/WO2011094150A1/en active Application Filing
- 2011-01-24 MX MX2014014687A patent/MX367938B/es unknown
- 2011-01-24 SG SG2012053492A patent/SG182614A1/en unknown
- 2011-01-24 HU HUE11737484A patent/HUE026849T2/en unknown
- 2011-01-24 NZ NZ627824A patent/NZ627824A/en unknown
- 2011-01-24 EP EP23214771.0A patent/EP4316599A3/en active Pending
- 2011-01-24 MY MYPI2012003346A patent/MY188334A/en unknown
- 2011-01-24 CA CA3060290A patent/CA3060290C/en active Active
- 2011-01-24 LT LTEP16187411.0T patent/LT3127542T/lt unknown
- 2011-01-24 AU AU2011209788A patent/AU2011209788C1/en active Active
- 2011-01-24 EA EA201892277A patent/EA037601B1/ru active Protection Beyond IP Right Term
- 2011-01-24 SI SI201130539T patent/SI2531027T1/sl unknown
- 2011-01-24 RS RS20181178A patent/RS57728B1/sr unknown
- 2011-01-24 AP AP2012006445A patent/AP3551A/xx active
- 2011-01-24 SG SG10201707183TA patent/SG10201707183TA/en unknown
- 2011-01-24 CN CN201180015114.8A patent/CN102791129B/zh active Active
- 2011-01-24 RS RS20150462A patent/RS54123B1/en unknown
- 2011-01-24 FI FIEP19151897.6T patent/FI3494972T3/fi active
- 2011-01-24 KR KR1020187018909A patent/KR101964923B1/ko active IP Right Grant
- 2011-01-24 CA CA2787691A patent/CA2787691C/en active Active
- 2011-01-24 NO NO15164931A patent/NO2932970T3/no unknown
- 2011-01-24 PE PE2012001082A patent/PE20121524A1/es active IP Right Grant
- 2011-01-24 RS RS20180667A patent/RS57323B1/sr unknown
- 2011-01-24 NZ NZ627827A patent/NZ627827A/en unknown
- 2011-01-24 MX MX2012008774A patent/MX2012008774A/es active IP Right Grant
- 2011-01-24 DK DK19151897.6T patent/DK3494972T3/da active
- 2011-01-24 DK DK15164931.6T patent/DK2932970T3/en active
- 2011-01-24 HR HRP20240168TT patent/HRP20240168T1/hr unknown
- 2011-01-24 NZ NZ601319A patent/NZ601319A/en unknown
- 2011-01-24 PT PT191518976T patent/PT3494972T/pt unknown
- 2011-01-24 NZ NZ627826A patent/NZ627826A/en unknown
- 2011-01-24 ME MEP-2018-131A patent/ME03058B/me unknown
- 2011-01-24 ME MEP-2015-106A patent/ME02182B/me unknown
- 2011-01-24 LT LTEP15164931.6T patent/LT2932970T/lt unknown
- 2011-01-24 KR KR1020127022254A patent/KR101830715B1/ko active IP Right Grant
- 2011-01-24 US US13/575,380 patent/US20120295898A1/en not_active Abandoned
- 2011-01-24 EP EP19151897.6A patent/EP3494972B1/en active Active
- 2011-01-24 EP EP15164931.6A patent/EP2932970B1/en not_active Revoked
- 2011-01-24 EA EA202190473A patent/EA202190473A3/ru unknown
- 2011-01-24 ES ES15164931.6T patent/ES2670811T3/es active Active
- 2011-01-24 PL PL16187411T patent/PL3127542T3/pl unknown
- 2011-01-24 ES ES16187411.0T patent/ES2688925T3/es active Active
- 2011-01-24 MX MX2014014689A patent/MX356891B/es unknown
-
2012
- 2012-07-18 DO DO2012000205A patent/DOP2012000205A/es unknown
- 2012-07-18 IL IL221007A patent/IL221007A/en active IP Right Grant
- 2012-07-24 ZA ZA2012/05586A patent/ZA201205586B/en unknown
- 2012-07-24 TN TNP2012000376A patent/TN2012000376A1/en unknown
- 2012-07-26 CO CO12125933A patent/CO6602152A2/es active IP Right Grant
- 2012-07-26 CL CL2012002080A patent/CL2012002080A1/es unknown
- 2012-08-13 CR CR20120423A patent/CR20120423A/es unknown
- 2012-08-14 EC ECSP12012106 patent/ECSP12012106A/es unknown
-
2013
- 2013-06-06 HK HK18109751.0A patent/HK1250335A1/zh unknown
- 2013-06-06 HK HK15110408.8A patent/HK1209629A1/zh unknown
- 2013-06-06 HK HK13106716.5A patent/HK1179522A1/zh not_active IP Right Cessation
-
2015
- 2015-05-13 US US14/710,952 patent/US20150238496A1/en not_active Abandoned
- 2015-07-14 HR HRP20150770TT patent/HRP20150770T1/hr unknown
- 2015-07-17 CY CY20151100633T patent/CY1116509T1/el unknown
- 2015-07-24 SM SM201500177T patent/SMT201500177B/xx unknown
-
2016
- 2016-01-28 PH PH12016500195A patent/PH12016500195A1/en unknown
- 2016-01-29 JP JP2016015242A patent/JP2016145204A/ja active Pending
- 2016-03-18 US US15/073,728 patent/US20160199379A1/en not_active Abandoned
- 2016-04-18 IL IL245182A patent/IL245182B/en active IP Right Grant
- 2016-08-01 US US15/224,865 patent/US20160339033A1/en not_active Abandoned
- 2016-08-22 JP JP2016161610A patent/JP6268386B2/ja active Active
- 2016-12-01 US US15/366,442 patent/US10426780B2/en active Active
- 2016-12-01 US US15/366,566 patent/US20170119777A1/en not_active Abandoned
-
2017
- 2017-04-19 US US15/490,944 patent/US20170216284A1/en not_active Abandoned
- 2017-06-13 US US15/620,859 patent/US20170281636A1/en not_active Abandoned
- 2017-12-12 US US15/838,738 patent/US20180098992A1/en not_active Abandoned
-
2018
- 2018-01-31 IL IL257267A patent/IL257267B/en active IP Right Grant
- 2018-03-15 US US15/922,240 patent/US20180200254A1/en not_active Abandoned
- 2018-04-05 JP JP2018072861A patent/JP2018127473A/ja active Pending
- 2018-05-23 CY CY20181100548T patent/CY1120457T1/el unknown
- 2018-05-30 HR HRP20180855TT patent/HRP20180855T1/hr unknown
- 2018-09-26 HR HRP20181531TT patent/HRP20181531T1/hr unknown
- 2018-10-15 NO NO2018036C patent/NO2018036I1/no unknown
- 2018-10-15 FR FR18C1043C patent/FR18C1043I2/fr active Active
- 2018-10-16 CY CY2018029C patent/CY2018029I2/el unknown
- 2018-10-22 LT LTPA2018013C patent/LTC2932970I2/lt unknown
- 2018-10-23 CY CY181101087T patent/CY1121040T1/el unknown
- 2018-10-26 HU HUS1800042C patent/HUS1800042I1/hu unknown
- 2018-10-31 LU LU00090C patent/LUC00090I2/en unknown
- 2018-11-26 PH PH12018502489A patent/PH12018502489A1/en unknown
-
2019
- 2019-06-07 JP JP2019106635A patent/JP2019167371A/ja active Pending
- 2019-06-26 IL IL267658A patent/IL267658B/en active IP Right Grant
-
2020
- 2020-03-31 US US16/835,733 patent/US11234985B2/en active Active
-
2021
- 2021-02-26 JP JP2021030306A patent/JP2021091705A/ja active Pending
- 2021-04-01 IL IL281959A patent/IL281959B/en unknown
- 2021-07-14 DO DO2021000147A patent/DOP2021000147A/es unknown
- 2021-09-08 US US17/468,794 patent/US20210401850A1/en active Pending
-
2022
- 2022-03-03 JP JP2022032464A patent/JP2022071126A/ja active Pending
-
2023
- 2023-04-04 JP JP2023060638A patent/JP2023085431A/ja active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6544961B1 (en) * | 1996-06-25 | 2003-04-08 | Smithkline Beecham Corporation | Combinations comprising VX478, zidovudine, FTC and/or 3TC for use in the treatments of HIV |
| US20060084627A1 (en) * | 2002-06-27 | 2006-04-20 | Medivir Ab | Synergistic interaction of abacavir and alovudine |
| US20080076738A1 (en) * | 2004-04-14 | 2008-03-27 | Cai Zhenhong R | Phosphonate Analogs Of Hiv Integrase Inhibitor Compounds |
| US20090318421A1 (en) * | 2005-04-28 | 2009-12-24 | Brian Alvin Johns | Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity |
Non-Patent Citations (1)
| Title |
|---|
| SONG1等: "The effect of ritonavir-boosted protease inhibitors on the HIV integrase inhibitor, S/GSK1349572, in healthy subjects", 《49TH ICAAC》 * |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102791129B (zh) | 抗病毒治疗 | |
| AU2017268621C1 (en) | Antiviral therapy | |
| AU2014202404C1 (en) | Antiviral therapy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |