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Generated: August 23, 2019

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Claims for Patent: 8,703,801

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Summary for Patent: 8,703,801
Title:Pyridinone hydroxycyclopentyl carboxamides: HIV integrase inhibitors with therapeutic applications
Abstract: New chiral and achiral oxy-substituted cyclopentyl pyridinone diketocarboxamides and their derivatives and methods for their preparations are disclosed. The compounds include tautomers, regioisomers and geometric isomers. These complex carboxamides are designed as inhibitors of HIV replication through inhibition of HIV integrase. The compounds are useful in the prevention or treatment of infection by HIV and in the treatment of AIDS and ARC, either as the compounds, or as pharmaceutically acceptable salts, with pharmaceutically acceptable carriers, used alone or in combination with antivirals, immunomodulators, antibiotics, vaccines, and other therapeutic agents, especially other anti-HIV compounds (including other anti-HIV integrase agents), which can be used to create combination anti-HIV cocktails. Methods of treating AIDS and ARC and methods of treating or preventing infection by HIV are also described.
Inventor(s): Nair; Vasu (Athens, GA), Okello; Maurice O. (Athens, GA), Nishonov; Abdumalik A. (Boulder, CO), Mishra; Sanjaykumar (Pune, IN)
Assignee: University of Georgia Research Foundation, Inc. (Athens, GA)
Application Number:13/513,448
Patent Claims:1. A compound according to the structural formula I: ##STR00026## Wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are each independently H or a halogen; X is CH or N; and Z is OH or .dbd.O, or a chiral isomer, geometric isomer, tautomer, regioisomer or a pharmaceutically acceptable salt or ester thereof.

2. A compound according to claim 1 wherein said halogen is F.

3. A compound according to claim 1 wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are substituted according to the following alternative sequences: R.sub.1=o-F, R.sub.2=H, R.sub.3 p-F, R.sub.4=o-F R.sub.1=p-F, R.sub.2=H, R.sub.3=p-F, R.sub.4=o-F R.sub.1=o-F, R.sub.2=o-F, R.sub.3=o-F, R.sub.4=H R.sub.1=o-F, R.sub.2=H, R.sub.3=o-F, R.sub.4=o-F o-F, R.sub.2=H, R.sub.3=p-F, R.sub.4=H R.sub.1=o-F, R.sub.2 p-F, R.sub.3=p-F, R.sub.4=o-F or R.sub.1=o-F, R.sub.2=o-F, R.sub.3=o-F, R.sub.4=o-F.

4. A compound according to claim 1 wherein X is CH.

5. A compound according to claim 1 wherein X is N.

6. A compound according to claim 1 where Z is OH.

7. A compound according to claim 1 wherein Z is .dbd.O.

8. A compound according to claim 1 wherein the said compound is a pharmaceutically acceptable salt.

9. A pharmaceutical composition for treating an HIV infection, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier, additive or excipient.

10. The pharmaceutical composition of claim 9 wherein said composition treats said HIV infection by inhibiting HIV integrase, both wild type and mutants, in the human host.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 in combination with a therapeutically effective amount of at least one compound selected from the group consisting of i) an additional anti-HIV agent, ii) an anti-infective agent other than an anti-HIV agent; and iii) an immunomodulator and a pharmaceutically acceptable carrier, additive or excipient.

12. The composition of claim 11 wherein said anti-infective agent is an antiviral agent selected from the group consisting of a protease inhibitor, a reverse transcriptase inhibitor, an additional integrase inhibitor or a combination thereof.

13. The composition of claim 12 wherein said reverse transcriptase inhibitor is a nucleoside compound.

14. The composition of claim 13 wherein said reverse transcriptase inhibitor is a non-nucleoside compound.

15. The composition of claim 12 wherein the said additional integrase inhibitor is a compound other than a pyridinone hydroxycyclopentyl carboxamide compound according to claim 1.

16. The composition according to claim 11 in oral or parenteral dosage form.

17. The composition according to claim 11 formulated for administration as an inhalation spray or a rectal suppository.

18. A method of treating an HIV infection in a patient, said method comprising administering to said patient an effective amount of a composition according to claim 11.

19. A method of reducing the likelihood of an HIV infection in a patient at risk for said infection, said method comprising administering to said patient an effective amount of a composition according to claim 11.

20. A method of treating a patient with AIDS or ARC comprising administering to said patient a therapeutically effective amount of the composition according to claim 1.

21. A method of inhibiting HIV integrase in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound according to claim 1.

22. The method of claim 21 wherein said subject is a human.

23. The method according to claim 18, wherein said compound according to the structure: ##STR00027## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are each independently H or a halogen; X is CH or N; and Z is OH or .dbd.O or a chiral isomer, geometric isomer, tautomer, regioisomer or a pharmaceutically acceptable salt or ester thereof, is combined with a therapeutically effective amount of at least one additional compound selected from the group consisting of i) an additional anti-HIV agent, ii) an anti-infective agent other than an anti-HIV agent and iii) an immunomodulator, in combination with a pharmaceutically acceptable carrier, additive or excipient.

24. The method according to claim 20, wherein said the compound according to the structure: ##STR00028## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are each independently H or a halogen; X is CH or N; and Z is OH or .dbd.O or a chiral isomer, geometric isomer, tautomer, regioisomer or a pharmaceutically acceptable salt or ester thereof, is combined with a therapeutically effective amount of at least one additional compound selected from the group consisting of i) an additional anti-HIV agent, ii) an anti-infective agent other than an anti-HIV agent and iii) an immunomodulator, in combination with a pharmaceutically acceptable carrier, additive or excipient.

25. A method of treating an HIV infection in a human host comprising administering to said host in combination, an effective amount of a compound according to the structure: ##STR00029## in combination with a therapeutically effective amount of at least one additional compound selected from the group consisting of i) an additional anti-HIV agent, ii) an anti-infective agent other than an anti-HIV agent and iii) an immunomodulator, in combination with a pharmaceutically acceptable carrier, additive or excipient.

26. A pharmaceutical composition according to claim 9 further comprising at least one additional compound selected from the group consisting of (-)bDioxolane-G; DXG (-)b-Arctigenin; Arctigenin (-)-Carbovir; (-)--C-D4G; (-)-Carbovir (-)-b-D-2,6-Diaminopurine dioxolane; Amdoxovir; DAPD; APD (+)-2'-Deoxy-3'-oxa-4'-thiocytidine; dOTC (+) (+)-2'-Deoxy-3'-oxa-4'-thio-5-fluorocytidine; dOTFC (+) (+/-)-Cyclobut-G; A-69992; (+/-)-Lobucavir; C-Oxt-G; Cyclobut-G; C-Oxetanocin-G (R)-2QuinCOAsnPhe[CHOHCH2]PipCONHtBu (R)-3,6-Diamino-N-(aminomethyl)hexanamide; Bellenamine (R)-PMPA; (R)-9-(2-Phosphonylmethoxypropyl)adenine; PMPA-(R); Tenofovir (R)-PMPDAP; PMPDAP-(R) (S)-PMPA; (S)-9-(2-Phosphonylmethoxypropyl)adenine; PMPA(S) (S)-9-(2-Phosphonylmethoxypropyl)adenine; (S)-PMPA a-APA; R89439; Loviride a-APA derivative; R87232 a-APA derivative; R88703 a-APA enantiomer; R90385 a-L-AZT; AZT-a-L a-L-DXC; a-L-Dioxalane-C; DXC-a-L- a-L-FTC; FTC-a-L- a-Monofluoromethyldehydroornithine methyl ester; MFMOME 1,1'-Azobisformamide; ADA; Azodicarbonamide 1-(11-Octylamino-10-hydroxyundecyl)-3,7-dimethylxanthine; CT-2576 1-(2',3'-Dideoxy-2'-fluoro-b-D-threo-pentofuranosyl)cytosine; Ro 31-6840 1-(2'-Fluoro-2',3'-dideoxy-B-D-erythro-pentofuranosyl)thymine; 2'FddT 1-(2OHPr)-4-Substit-piperazine, thienyl carbamate derivative 1-(2OHPr)-4-Substit-piperazine, thienyl carbamate derivative 1-(2OHPr)-4-Substit-piperazine, thienyl carbamate derivative 1-(2OHPr)-4-Substit-piperazine, thienyl carbamate derivative 1-[(2-Hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine; HEPT-M 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine; HEPT-S 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine; HEPT 1-Deoxynojirimycin; Deoxynojirimycin 141W94; VX-478; Amprenavir 1592U89 Succinate; Abacavir Succinate 1-Aminooxyethylamine; AEA 1-Methoxyoxalyl-3,5-dicaffeoylquinic acid; 1-MO-3,5-DCQA; Dicaffeoylquinic acid derivative 1OH-2(Cbz-Tle)3PhPr [14]paracyclophane derivative 1OH-2(Cbz-ValNH)3PhPr [13]metacyclophane derivative 1OH-2(Cbz-ValNH)3PhPr [13]paracyclophane derivative 1OH-2(Cbz-ValNH)3PhPr [14]paracyclophane derivative 1OH-2(Cbz-ValNH)3PhPr [17]paracyclophane derivative 12-Deoxyphorbol-[3-(3E,5E-decadienoate); Phorbol derivative 16-alpha-Bromoepiandrosterone; Epi-Br; Inactivin; HE2000; PPB2; DHEA derivative 1-b-D-arabinofuranosyl-5-(2-bromovinyl)uracil; BV-ara-U; BVaraU; BV ara-U; Sorivudine; SQ-32756; Bravavir; Brovavir; Usevir; YN-72; Bromovinyl araU; BVAU 2',3'-Didehydro-3'-deoxycytidine; D4C 2',3'-Dideoxydidehydroguanosine; D4G 2',3'-Didehydro-3'-deoxythymidine; D4T; Stavudine 2',3'-Dideoxy-3'-fluoro-4-thiothymidine; 3'-F-4-Thio-ddT 2',3'-Dideoxy-3'-fluoro-5-bromouridine; FddBrU 2',3'-Dideoxy-3'-fluoro-5-chlorocytidine; 3'-F-5-Cl-ddC 2',3'-Dideoxy-3'-fluoro-5-chlorouridine; 935U83; 5-Chloro-2',3'-dideoxy-3'-fluorouridine; FddClU; Raluridine 2',3'-Dideoxy-5-ethylcytidine; 5-Et-ddC 2',3'-D1deoxyadenosine; D2A; ddAdo; ddA 2',3'-Dideoxydidehydroadenosine; d4A 2',3'-D1deoxyguanosine; D2G; ddG 2',3'-Dideoxy-3'-hydroxymethyl cytidine; 3'-Hydroxymethyl-ddC; BEA-005 2,5'-Anhydro-3'-azido-2',3'-dideoxyuridine; AZU-2,5'-anhydro 2,5'-Anhydro-3'-azido-3'-deoxythymidine; AZT-2,5'-anhydro 2',5'diSilySpiroT; TSAO-T; 2',5'diSilySpiroT; TSAO-me^3T 2,6-Diamino-2',3'-dideoxypurine-9-ribofuranoside; ddDAPR; DAPDDR; 2,6-Diamino-ddP 2,6-Diaminopurine-2',3'-dideoxydidehydroriboside; ddeDAPR 2,6-Diaminopurine-3'-fluoro-2',3'-dideoxyriboside; 3'-F-ddDAPR 2-Aminobenzylstatine Valyl Cbz derivative; Statine derivative 2-Glycine amide-5-chlorophenyl 2-pyrryl ketone; GCPK [2-PyridCH2NCH3CO-Val-NHCH(Bz)]CHOHCHOH; A-77003 2'-Azido-2',3'-dideoxyadenosine; 9-(2'-Azido-2',3'-dideoxy-B-D-erythropentofuranosyl)adenine; 2'-N3ddA 2'-FddA(B-D-threo); F-ddA; 2'-F-dd-ara-A; 9-(2'-Fluoro-2',3'-dideoxy-B-D-threopentafuranosyl)adenine; Lodensine 2'-N3ddA (B-D-threo); 9-(2'-Azido-2',3'-dideoxy-b-threopentafuranosyl)adenine 2-NaphCOAsnPhe[CHOHCH2]Pro-OtBu 2-Nitrophenylphenylsulfone; NPPS 3-(3-Oxo-1-propenyl)-3'-azido-3'-deoxythymidine; 3-(3-Oxo-1-propenyl)AZT 3-(Phenylsulfonyl)-indole derivative; L-737,126 3,5-DCQA; 3,5-Dicaffeoylquinic acid; Dicaffeoylquinic acid 3'-Azido-2',3'-dideoxy-5-[(cyanomethyl)oxy]uridine; 3'-N3-5-Cyanomethyloxy-ddU 3'-Azido-2',3'-dideoxy-5-aminouridine; 3'-N3-5-NH2-ddU 3'-Azido-2',3'-dideoxy-5-aza-6-deazauridine; C-analog of 3'-N3-ddU 3'-Azido-2',3'-dideoxy-5-bromouridine; 3'-N3-5-Br-ddU; AZddBrU 3'-Azido-2',3'-dideoxy-5-chlorocytidine; 3'-Az-5-Cl-ddC 3'-Azido-2',3'-dideoxy-5-dimethylaminouridine; 3'-N3-5-NMe2-ddU 3'-Azido-2',3'-dideoxy-5-ethyluridine; 3'-N3-5-EtddU; CS-85; AZddEtU 3'-Azido-2',3'-dideoxy-5-fluorocytidine; 3'-N3-5-F-ddC 3'-Azido-2',3'-dideoxy-5-fluorouridine; AZddFU 3'-Azido-2',3'-dideoxy-5-hydroxyuridine; 3'-N3-5-OH-ddU 3'-Azido-2',3'-dideoxy-5-iodouridine; 3'-N3-5-1-ddU; AZddIU 3'-Azido-2',3'-dideoxy-5-methyaminouridine; 3'-N3-5-NHMe-ddU 3'-Azido-2',3'-dideoxy-5-methylcytidine; CS-92; 3'-N3-5-Me-ddC 3'-Azido-2',3'-dideoxy-5-thiocyanatouridine; 3'-N3-5-SCN-ddU 3'-Azido-2',3'-dideoxy-5-trifluoromethyluridine; 3'-N3-5-CF3-ddU 3'-Azido-2',3'-dideoxycytidine; CS-91; 3'-N3-ddC 3'-Azido-2',3'-dideoxyguanosine; AZG; 3'-N3ddG 3'-Azido-2',3'-dideoxy-N4-5-dimethylcytidine; 3'-N3-N4-5-diMe-ddC 3'-Azido-2',3'-dideoxy-N4-OH-5-methylcytidine; 3'-N3-N4-OH-5-Me-ddC 3'-Azido-2',3'-dideoxyuridine; CS-87; 3'-N3ddU; AZdU; Uravidine 3'-Azido-3'-deoxy-6-azathymidine; 3'AZ-6AzaT 3-Azido-3'-deoxythymidilyl-(5',5')-2',3'-dideoxy-5'-adenylic acid; AZT-P-ddA 3'-Azido-3'-deoxythymidilyl-(5',5)-2',3'-dideoxy-5'-adenylic acid, 2-cyanoethyl ester; AZT-P(CyE)-ddA 3'-Azido-3'-deoxythymidilyl-(5',5)-2',3'-dideoxy-5'-inosinic acid; AZT-P-ddI 3'-Azido-3'-deoxythymidine-5'-(butylmethoxyvalinyl)phosphate; 5'MeOValPO3(Bu)AZT 3'-Azido-5-chloro-2',3'-dideoxyuridine; AzddClUrd; AzddClU 3'-Deoxythymidine; ddT 3'-FddA (B-D-Erythro); 9-(3'-Fluoro-2',3'-dideoxy-B-D-erythropentafuranosyl)adenine 3'-FddC; 3'-Fluoro-2',3'-dideoxycytidine 3'-FddG; 3'-Fluoro-2',3'-dideoxyguanosine 3'-FddT; Alovudine; FddT; FddThD; 3'-FLT; FLT 3'-FddU; 3'-Fluoro-2',3'-dideoxyuridine 3'-Fluoro-2',3'-dideoxy-5-iodouridine; FddIU 3'-N3-ddA; 9-(3'-Azido-2',3'-dideoxy-B-D-erythropentafuranosyl)adenine 3TC; Lamivudine Lamivudine & Zidovudine 4-Acetoamidophenyl-4-guadinobenzoate; AGB 4'-Az-3'-dT; 4'-Azido-3'-deoxythymidine 4'-Az-5CldU; 4'-Azido-5-chloro-2'-deoxyuridine 4'-AzdA; 4'-Azido-2'-deoxyadenosine 4'-AzdC; 4'-Azido-2'-deoxycytidine 4'-AzdG; 4'-Azido-2'-deoxyguanosine 4'-AzdI; 4'-Azido-2'-deoxyinosine 4'-AzdU; 4'-Azido-2'-deoxyuridine 4'-Azido-2'-deoxy-b-D-erythro-pentofuranosyl-5-methyl-2,4-dioxopyrimidine- ; 4'-Azidothymidine 4'-Cyanothymidine; 4'-CN-T 4-Methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione; Oltipraz 5'-[(1,4-Dihydro-1-methyl-3-pyridinylcarbonyl)oxy]-3'-azido-2',3'-deoxyth- ymidine; DP-AZT; HP-AZT; AZT Prodrug; AZT-DHP 5'-[[(Z)-4-amino-2-butenyl]methylamino]-5'-deoxyadenosine; MDL 73811 5'-Alkylglycosidecarbonate of 3'-azido-3'-deoxythymidine; AcNHGlc-hexyl-CO3 AZT 5Cl3PhS-2IndolCONH2 5-Fluoro-2',3'-dideoxycytidine; 5-F-ddC 5-Methyl-3'-azido-2',3'-dideoxyisocytidine; MeAZddIsoC 6-O-Butanoylcastanospermine; BuCast; MDL 28,574; Celgosivir 6-Chloro-9-(2,3-dideoxy-b-D-glyceropentofuranosyl)-9H-purine; D2ClP; 6-Chloro-ddP; CPDDR; 6Cl-ddP 6-Dimethylaminopurine-2',3'-dideoxyriboside; N-6-dimethylddA; DMAPDDR 7-Chloro-N-methyl-5-(1H-pyrrol-2-yl)-3H-1,4-benzodiazepin-2-amine; Ro 24-7429 7-Chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2(H)-one; Ro 5-3335 8-Chloro-TIBO; Tivirapine; R86183 9-(2,3-Dideoxy-b-D-ribofuranosyl)-6-(methylthio)purine; D2SMeP 9-[Bis(OHMe)cBu]A; A-69463; Cyclobutyl-A; Cyclobut-A; C-oxetanocin A A-76890 A-77212 A-80987; Ritonavir derivative A-81525; Ritonavir derivative A-83962; Ritonavir derivative A-98881; Azacyclic urea derivative AA; L-ascorbic acid; Calcium Ascorbate AAP-BHAP; U-104489; PNU-104489 Abacavir & Lamivudine & Zidovudine ABT-378; Lopinavir ABT-378 & ABT-538; Lopinavir & Ritonavir ABT-538; Ritonavir Acemannan Adefovir; PMEA; GS-0393 Adefovir dipivoxil; BisPom PMEA; GS-840 AG-1343; Nelfinavir AG1350; LY316957; Nelfinavir-octahydro-thienopyridine analog AHPBA analog; R-87366 Alpha-lipoic acid; a-Lipoic acid; Thioctic acid ALX40-4C AMD3100; JM3100 Amprenavir phosphate; VX-175; GW433908; GW433908A (*Sodium Salt*); GW433908G (*Calcium Salt*); Fosamprenavir Ancer 20; Z-100 Anti-sense 25-mer phosphorothioate; GEM91 Atazanavir; CGP-73547; BMS-232632; BMS 232632; Zrivada; Latazanavir Atevirdine; U-87201E; BHAP derivative Aurintricarboxylic acid; Dupont ATA; Dupont DA639; SD-095345; ATA AY 9944; trans-1,4-Bis(2-dichlorobenzylaminoethyl)cyclohexane dichlorhydrate AZT; Zidovudine; Azidothymidine AZT-PO3(CH3)-AZT; O,O'-Bis(3'-azido-3'-deoxythymidin-5'-yl)methylphosphonate Baicalin; TJN-151 Betulinic acid; Mairin Betulinic acid, 3-O-(3',3'-dimethylsuccinate) BHAP derivative Delavirdine; U-90152 U-88204E BI-RG-587; Nevirapine BILA 1906 BS BILA 2011 BS; Palinavir BILA 2185 BS Bis(2-nitrophenyl)sulfone; Bis(2NO2Ph)SO2; NSC633001 bis-ValHOEt-N2aza-peptide isostere; CGP 53820 bis-ValHOEt-N2aza-peptide isostere; CGP 53820 analog BMS-186318 BocPhe[CHOH(CH2)3CH.dbd.CHPhCO]IleAMBI; L-687,908 BzOCValPhe[diCHOH(RR)]PheValBzOC BzOCValPhe[diCHOH(SS)]PheValBzOC C2-Sym Phosphinic amide derivative (HOECHST AG) Calanolide A; NSC675451 Calanolide B Capravirine; S-1153 Castanospermine CbzAF(CHOHCH2)AVVOMe Cbz-Asn-Apns-Pro-NH-tBu; KNI-102 CGP 61755; Lasinavir CGP 64222 CNI-H0294 Coactinon; I-EBU; HEPT derivative; MKC-442; Emivirine Conocurvone; NSC650891 Coviracil; (-)FTC; (-)-2',3'-Dideoxy-5-fluoro-3'-thiacytidine; Emtricitabine; Emtriva C-Oxetanocin-G; A-69992; (+-)Lobucavir; C-Oxt-G; Cyclobut-G; (+-)Cyclobut-G Indinavir; MK639; L-735,524 Curdlan Sulfate CV-N; Cyanovirin-N Cyclic Urea Amide; SD146 Cyclosporin A [Me-Ile-4]Cyclosporin A; SDZ NIM 811 D4A (L); L-2',3'-Didehydro-2',3'-dideoxyadenosine D4FC; D-D4FC; 2',3'-Didehydro-2',3'-dideoxy-5-fluorocytidine; DPC 817 D4FC (L); L-2',3'-Didehydro-2',3'-dideoxy-5-fluorocytidine D4G (L); L-2',3'-Didehydro-2',3'-dideoxyguanosine D4I (L); L-2',3'-Didehydro-2',3'-dideoxyinosine DABO ddC; Dideoxycytidine; Zalcitabine ddI; Dideoxyinosine; Didanosine Dehydroepiandrosterone; DHEA; Prasterone; Dehydroisoandrosterone; EL-10 Dextran Sulfate Dicaffeic acid ester; L-Chicoric acid DMP-266; Efavirenz; Approved DMP-323; XM-323 DMP-450 Docosanol; n-Docosanol dOTC (-); (-)-2'-Deoxy-3'-oxa-4'-thiocytidine dOTFC (-); (-)-2'-Deoxy-3'-oxa-4'-thio-5-fluorocytidine DP-178; Pentafuside; T-20; GP41 127-162 AA; Enfuvirtide E-BPTU; HEPT derivative; NSC 648400 E-EBU; HEPT derivative; MKC-442 derivative E-EBU-dM; HEPT derivative; MKC-442 derivative E-EPSeU; HEPT derivative; MKC-442 derivative E-EPU; HEPT derivative; MKC-442 derivative Ebselen Etoposide Epoxy steroid derivative; (4a,5a,17b)-17-Hydroxy-3-oxo-4,5-epoxyandrostane-2-carboxamide Eulicin Fenalamide A1; Phenalamide A1; Stipiamide Fleephilone Fluoroquinolone derivative; K-12 Saquinavir; Ro31-8959; Approved Foscarnet; Phosphonoformic acid; Foscavir FPMDAP FPMPA FPMPG GPGRAF Octomer; SPC3 Hammerhead anti-gag RNA Ribozyme B Harziphilone HBY 097; Quinoxaline derivative HEPT derivative; MKC-442 derivative LY326188 HPMPA HPMPDAP HU; Hydroxyurea; Hydrea Hydroxocobalamin Hypericin Ingenol 3,5,20-triacetate; ITA; RD3-2118 Ingenol derivative; RD4-2138 Inophyllum B Inophyllum P iQoa-Mta-Apns-Thz-NH-tBu; KNI-272 Isentress (Raltegravir) IsoquinCON furanyl urethane analog IsoquinCON thienyl urethane analog KNI-154; Noa-Asn-Apns-Thz-NH-tBu KNI-174; Noa-Asn-Apns-Dmt-NH-tBu KNI-227; Qoa-Mta-Apns-Thz-NH-tBu L-685,434 L-685, 434-6-Hydroxy derivative L-685,434-sOEtMorphderivative; L-689,502 L-685,434-OEtNMe2 L-685,434-OPrMorph derivative L-697,593; 2-Pyridinone derivative L-697,639; 2-Pyridinone derivative L-697,661; 2-Pyridinone derivative L-FddC; b-L-5F-ddC Lamivudine & Zidovudine; 3TC & AZT; Approved LY289612 LY289612 analog LY-300046-HCl; PETT derivative; Trovirdine LY314163; Saquinavir/Nelfinavir derivative LY-73497; N-(2-Phenethyl)-N'-(2-thiazolyl)thiourea; PETT MAP; Methyl acetylenic putrescine Michellamine A; NSC650898 Michellamine B; NSC649324 Michellamine F N-6-Et-ddA; N-Ethyl-2',3'-dideoxyadenosine N-6-methyl ddA; N6-Methyl-2',3'-dideoxyadenosine Naphthalene 2-sulphonate polymer; PRO2000 Nelfinavir-octahydro-thienopyridine analog Nonoxynol 9 NSC625487; Thiazolobenzimidazole; TBZ Oxathiin derivative; UC-38 Oxathiin derivative; UC-84 P9941 Penicillin Et(NH)2 Sym dimer Penicillin G, ET(NH)2 derivative Penicillin, 2Isoquin-OHPrNH2 analog Pentosan Sulfate; Elmiron; SP54; Xylan Sulfate PETT Cl, F derivative PETT derivative Phenoxan Phorbol derivative; Prostratin Platanic acid PMEDAP PMEG PMEHx; PMEI PMEMAP PMET PNU-140690; U-140690; Tipranavir Pyridinone derivative Quinoxalin2thione derivative; S-2720 R14458; TIBO derivative R82150; TIBO derivative R82913; TIBO derivative Resobene Ribavirin; Virazole Ro 31-8959-bis-thf derivative Saquinavir/Nelfinavir derivative SB-205569; Val-Phe-Phe-HOCH2CH2 isostere analog SC-52151; Telinavir SDZ PRI 053 Suramin Sodium T22 Thalidomide Thiangazole; (-)-Thiangazole Thiazoloisoindol-5-one Thiazoloisoindol-5-one, derivative Tle-Val-Sta, 5PhBuCOOH derivative; Statine derivative UC-781 Val-Val-Sta, 5PhBuCOOH derivative; Statine derivative VB-11,328 and Tenofovir Disoproxil.

27. A pharmaceutical composition according to claim 9 further comprising at least one additional compound selected from the group consisting of ACV; AK602; AMD070; APV; ATV; ATZ; AVX754 (apricitabine); AZT; Abacavir; Abacavir/Lamivudine/Zidovudine; Abacavir sulfate; Abacavir sulfate/Lamivudine; Abacavir/Lamivudine; Abelecet; Acyclovir; Adefovir dipivoxil; Adriamycin; Agenerase; Aldesleukin; Alovudine; Aluvia; AmBisome; Amdoxovir; Amphocin; Amphotec; Amphotericin B; Ampligen; Amprenavir; Androderm; Androgel; Apricitabine; Aptivus; Atazanavir; Atripla; Azithromycin; BMS-378806; BMS-488043; Bactrim; Baraclude; Bevirimat; Biaxin; Brecanavir; BufferGel; C31G; CD4-IgG2; CS; CV-N; Calanolide A; Calcium hydroxylapatite; Carbopol 974P; Carrageenan; Carraguard; Cellulose sulfate; Clarithromycin; Copegus; Cotrimoxazole; Crixivan; Cyanovirin-N; Cytovene; DAPD; DLV; DS; Darunavir; Delavirdine; Depo-Testosterone; Dextran sulfate; Didanosine; Diflucan; Doxil; Doxorubicin (liposomal); Dronabinol; EFV; Efavirenz; Elvucitabine; Emtricitabine; Emtricitabine; Tenofovir disoproxil fumarate; Emtriva; Enfufirtide; Entecavir; Epivir; Epoetin alfa; Epogen; Epzicom; Etopophos (phosphate salt); Etoposide; Etravirine; FTC; Fluconazole; Fortovase; Fosamprenavir; Foxivudine tidoxil; Fungizone; Fuzeon; GS 9137; GSK-873,140 (aplaviroc); GW433908; GW640385 (brecanavir); Ganciclovir; Globulin, Immune; Growth hormone (human); Hepsera; Hivid; Human growth hormone; IL-2; INH; Immune Globulin Intravenous (Human); Indinavir; Interferon alfa-2; Interleukin-2, recombinant human; Intron A (2b); Invirase; Isentress; Isoniazid; Itraconazole; KP-1461; Lamivudine/Zidovudine; Lexiva; Lopinavir/Ritonavir; MK-0518; Nebupent; Nelfinavir, Neutrexin; Nevirapine; Norvir; Nydrazid; Peptide T; PMPA Prodrug (Viread)' Prezista (Darunavir); PRO 140; PRO 2000; PRO 542 (CD4 IGg2); Procrit (Epoetin); Proleukin; Racivir; Radiesse; Rrebetol; Rescriptor; Retrovir; Reyataz; Ribavirin; Rifabutin; Rifadin; Rifampin; Rimactane; Ritonavir; Roferon-A (2a); Saquinavir; SCH-D (vicriviroc); Somatropin; Stavudinie; Sulfamethoxazole/Trimethoprim; Sustanon; Sustiva; TNX-355; Taxol; Tenofovir, Tenofovir disoproxil fumarate; Testosterone; Tipranavir; Toposar; Trimetrexate; Trizivir; Truvada (Erotriva and Viread combination); U-90152S (Delaviridine); UC-781; UK-427,857 (maraviroc); Valcyte; Valganciclovir, Valproic acid; VePesid; Vicriviroc; Videx; Viracept (Tennofovir DF); Viramune; Virazole; Viread; Vitrasert; Zalcitabine; Zerit; Ziagen; Zidovudine; Zithromax; Zovirax, and mixtures thereof.

28. The composition according to claim 27 in oral or parenteral dosage form.

29. The composition according to claim 27 formulated for administration as an inhalation spray or a rectal suppository.

30. A method of treating an HIV infection in a patient, said method comprising administering to said patient an effective amount of a composition according to claim 27.

31. A method of reducing the likelihood of an HIV infection in a patient at risk of said infection, said method comprising administering to said patient an effective amount of a composition according to claim 27 to said patient.

32. A method of treating a patient with AIDS or ARC comprising administering to said patient a therapeutically effective amount of a composition according to claim 27.

33. A method of inhibiting HIV integrase in a subject, said method comprising administering to said subject a therapeutically effective amount of a composition according to claim 27.

34. The method according to claim 30 wherein said patient or subject is a human.

35. A method of treating an HIV infection in a human host comprising administering to said host in combination, an effective amount of a first compound according to the structure: ##STR00030## where R.sub.1=o-F, R.sub.2=H, R.sub.3=p-F, R.sub.4=o-F R.sub.1=p-F, R.sub.2=H, R.sub.3=p-F, R.sub.4=o-F R.sub.1=o-F, R.sub.2=o-F, R.sub.3=o-F, R.sub.4=H R.sub.1=o-F, R.sub.2=H, R.sub.3=o-F, R.sub.4=o-F R.sub.1=o-F, R.sub.2=H, R.sub.3=p-F, R.sub.4=H R.sub.1=o-F, R.sub.2=p-F, R.sub.3=p-F, R.sub.4=o-F, or R.sub.1=o-F, R.sub.2=o-F, R.sub.3=o-F, R.sub.4=o-F X is CH or N; and Z is OH or .dbd.O; in combination with an effective amount at least one additional agent set forth below: (-)bDioxolane-G; DXG (-)b-Arctigenin; Arctigenin (-)-Carbovir; (-)--C-D4G; (-)-Carbovir (-)-b-D-2,6-Diaminopurine dioxolane; Amdoxovir; DAPD; APD (+)-2'-Deoxy-3'-oxa-4'-thiocytidine; dOTC (+) (+)-2'-Deoxy-3'-oxa-4'-thio-5-fluorocytidine; dOTFC (+) (+/-)-Cyclobut-G; A-69992; (+/-)-Lobucavir; C-Oxt-G; Cyclobut-G; C-Oxetanocin-G (R)-2QuinCOAsnPhe[CHOHCH2]PipCONHtBu (R)-3,6-Diamino-N-(aminomethyl)hexanamide; Bellenamine (R)-PMPA; (R)-9-(2-Phosphonylmethoxypropyl)adenine; PMPA-(R); Tenofovir (R)-PMPDAP; PMPDAP-(R) (S)-PMPA; (S)-9-(2-Phosphonylmethoxypropyl)adenine; PMPA(S) (S)-9-(2-Phosphonylmethoxypropyl)adenine; (S)-PMPA a-APA; R89439; Loviride a-APA derivative; R87232 a-APA derivative; R88703 a-APA enantiomer; R90385 a-L-AZT; AZT-a-L a-L-DXC; a-L-Dioxalane-C; DXC-a-L- a-L-FTC; FTC-a-L- a-Monofluoromethyldehydroornithine methyl ester; MFMOME 1,1'-Azobisformamide; ADA; Azodicarbonamide 1-(11-Octylamino-10-hydroxyundecyl)-3,7-dimethylxanthine; CT-2576 1-(2',3'-Dideoxy-2'-fluoro-b-D-threo-pentofuranosyl)cytosine; Ro 31-6840 1-(2'-Fluoro-2',3'-dideoxy-B-D-erythro-pentofuranosyl)thymine; 2'FddT 1-(2OHPr)-4-Substit-piperazine, thienyl carbamate derivative 1-(2OHPr)-4-Substit-piperazine, thienyl carbamate derivative 1-(2OHPr)-4-Substit-piperazine, thienyl carbamate derivative 1-(2OHPr)-4-Substit-piperazine, thienyl carbamate derivative 1-[(2-Hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine; HEPT-M 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine; HEPT-S 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine; HEPT 1-Deoxynojirimycin; Deoxynojirimycin 141W94; VX-478; Amprenavir 1592U89 Succinate; Abacavir Succinate 1-Aminooxyethylamine; AEA 1-Methoxyoxalyl-3,5-dicaffeoylquinic acid; 1-MO-3,5-DCQA; Dicaffeoylquinic acid derivative 1OH-2(Cbz-Tle).sub.3PhPr [14]paracyclophane derivative 1OH-2(Cbz-ValNH).sub.3PhPr [13]metacyclophane derivative 1OH-2(Cbz-ValNH).sub.3PhPr [13]paracyclophane derivative 1OH-2(Cbz-ValNH).sub.3PhPr [14]paracyclophane derivative 1OH-2(Cbz-ValNH).sub.3PhPr [17]paracyclophane derivative 12-Deoxyphorbol-[3-(3E,5E-decadienoate); Phorbol derivative 16-alpha-Bromoepiandrosterone; Epi-Br; Inactivin; HE2000; PPB2; DHEA derivative 1-b-D-arabinofuranosyl-5-(2-bromovinyl)uracil; BV-ara-U; BVaraU; BV ara-U; Sorivudine; SQ-32756; Bravavir; Brovavir; Usevir; YN-72; Bromovinyl araU; BVAU 2',3'-Didehydro-3'-deoxycytidine; D4C 2',3'-Dideoxydidehydroguanosine; D4G 2',3'-Didehydro-3'-deoxythymidine; D4T; Stavudine 2',3'-Dideoxy-3'-fluoro-4-thiothymidine; 3'-F-4-Thio-ddT 2',3'-Dideoxy-3'-fluoro-5-bromouridine; FddBrU 2',3'-Dideoxy-3'-fluoro-5-chlorocytidine; 3'-F-5-Cl-ddC 2',3'-Dideoxy-3'-fluoro-5-chlorouridine; 935U83; 5-Chloro-2',3'-dideoxy-3'-fluorouridine; FddClU; Raluridine 2',3'-Dideoxy-5-ethylcytidine; 5-Et-ddC 2',3'-D1deoxyadenosine; D2A; ddAdo; ddA 2',3'-Dideoxydidehydroadenosine; d4A 2',3'-D1deoxyguanosine; D2G; ddG 2',3'-Dideoxy-3'-hydroxymethyl cytidine; 3'-Hydroxymethyl-ddC; BEA-005 2,5'-Anhydro-3'-azido-2',3'-dideoxyuridine; AZU-2,5'-anhydro 2,5'-Anhydro-3'-azido-3'-deoxythymidine; AZT-2,5'-anhydro 2',5'diSilySpiroT; TSAO-T; 2',5'diSilySpiroT; TSAO-me^3T 2,6-Diamino-2',3'-dideoxypurine-9-ribofuranoside; ddDAPR; DAPDDR; 2,6-Diamino-ddP 2,6-Diaminopurine-2',3'-dideoxydidehydroriboside; ddeDAPR 2,6-Diaminopurine-3'-fluoro-2',3'-dideoxyriboside; 3'-F-ddDAPR 2-Aminobenzylstatine Valyl Cbz derivative; Statine derivative 2-Glycine amide-5-chlorophenyl 2-pyrryl ketone; GCPK [2-PyridCH2NCH3CO-Val-NHCH(Bz)]CHOHCHOH; A-77003 2'-Azido-2',3'-dideoxyadenosine; 9-(2'-Azido-2',3'-dideoxy-B-D-erythropentofuranosyl)adenine; 2'-N3ddA 2'-FddA(B-D-threo); F-ddA; 2'-F-dd-ara-A; 9-(2'-Fluoro-2',3'-dideoxy-B-D-threopentafuranosyl)adenine; Lodensine 2'-N3ddA (B-D-threo); 9-(2'-Azido-2',3'-dideoxy-b-threopentafuranosyl)adenine 2-NaphCOAsnPhe[CHOHCH2]Pro-OtBu 2-Nitrophenylphenylsulfone; NPPS 3-(3-Oxo-1-propenyl)-3'-azido-3'-deoxythymidine; 3-(3-Oxo-1-propenyl)AZT 3-(Phenylsulfonyl)-indole derivative; L-737,126 3,5-DCQA; 3,5-Dicaffeoylquinic acid; Dicaffeoylquinic acid 3'-Azido-2',3'-dideoxy-5-[(cyanomethyl)oxy]uridine; 3'-N3-5-Cyanomethyloxy-ddU 3'-Azido-2',3'-dideoxy-5-aminouridine; 3'-N3-5-NH2-ddU 3'-Azido-2',3'-dideoxy-5-aza-6-deazauridine; C-analog of 3'-N3-ddU 3'-Azido-2',3'-dideoxy-5-bromouridine; 3'-N3-5-Br-ddU; AZddBrU 3'-Azido-2',3'-dideoxy-5-chlorocytidine; 3'-Az-5-Cl-ddC 3'-Azido-2',3'-dideoxy-5-dimethylaminouridine; 3'-N3-5-NMe2-ddU 3'-Azido-2',3'-dideoxy-5-ethyluridine; 3'-N3-5-EtddU; CS-85; AZddEtU 3'-Azido-2',3'-dideoxy-5-fluorocytidine; 3'-N3-5-F-ddC 3'-Azido-2',3'-dideoxy-5-fluorouridine; AZddFU 3'-Azido-2',3'-dideoxy-5-hydroxyuridine; 3'-N3-5-OH-ddU 3'-Azido-2',3'-dideoxy-5-iodouridine; 3'-N3-5-1-ddU; AZddIU 3'-Azido-2',3'-dideoxy-5-methyaminouridine; 3'-N3-5-NHMe-ddU 3'-Azido-2',3'-dideoxy-5-methylcytidine; CS-92; 3'-N3-5-Me-ddC 3'-Azido-2',3'-dideoxy-5-thiocyanatouridine; 3'-N3-5-SCN-ddU 3'-Azido-2',3'-dideoxy-5-trifluoromethyluridine; 3'-N3-5-CF3-ddU 3'-Azido-2',3'-dideoxycytidine; CS-91; 3'-N3-ddC 3'-Azido-2',3'-dideoxyguanosine; AZG; 3'-N3ddG 3'-Azido-2',3'-dideoxy-N4-5-dimethylcytidine; 3'-N3-N4-5-diMe-ddC 3'-Azido-2',3'-dideoxy-N4-OH-5-methylcytidine; 3'-N3-N4-OH-5-Me-ddC 3'-Azido-2',3'-dideoxyuridine; CS-87; 3'-N3ddU; AZdU; Uravidine 3'-Azido-3'-deoxy-6-azathymidine; 3'AZ-6AzaT 3-Azido-3'-deoxythymidilyl-(5',5')-2',3'-dideoxy-5'-adenylic acid; AZT-P-ddA 3'-Azido-3'-deoxythymidilyl-(5',5)-2',3'-dideoxy-5'-adenylic acid, 2-cyanoethyl ester; AZT-P(CyE)-ddA 3'-Azido-3'-deoxythymidilyl-(5',5)-2',3'-dideoxy-5'-inosinic acid; AZT-P-ddI 3'-Azido-3'-deoxythymidine-5'-(butylmethoxyvalinyl)phosphate; 5'MeOValPO3(Bu)AZT 3'-Azido-5-chloro-2',3'-dideoxyuridine; AzddClUrd; AzddClU 3'-Deoxythymidine; ddT 3'-FddA (B-D-Erythro); 9-(3'-Fluoro-2',3'-dideoxy-B-D-erythropentafuranosyl)adenine 3'-FddC; 3'-Fluoro-2',3'-dideoxycytidine 3'-FddG; 3'-Fluoro-2',3'-dideoxyguanosine 3'-FddT; Alovudine; FddT; FddThD; 3'-FLT; FLT 3'-FddU; 3'-Fluoro-2',3'-dideoxyuridine 3'-Fluoro-2',3'-dideoxy-5-iodouridine; FddIU 3'-N3-ddA; 9-(3'-Azido-2',3'-dideoxy-B-D-erythropentafuranosyl)adenine 3TC; Lamivudine Lamivudine & Zidovudine 4'-Acetoamidophenyl-4-guadinobenzoate; AGB 4'-Az-3'-dT; 4'-Azido-3'-deoxythymidine 4'-Az-5CldU; 4'-Azido-5-chloro-2'-deoxyuridine 4'-AzdA; 4'-Azido-2'-deoxyadenosine 4'-AzdC; 4'-Azido-2'-deoxycytidine 4'-AzdG; 4'-Azido-2'-deoxyguanosine 4'-AzdI; 4'-Azido-2'-deoxyinosine 4'-AzdU; 4'-Azido-2'-deoxyuridine 4'-Azido-2'-deoxy-b-D-erythro-pentofuranosyl-5-methyl-2,4-dioxopyrimidine- ; 4'-Azidothymidine 4'-Cyanothymidine; 4'-CN-T 4-Methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione; Oltipraz 5'-[(1,4-Dihydro-1-methyl-3-pyridinylcarbonyl)oxy]-3'-azido-2',3'-deoxyth- ymidine; DP-AZT; HP-AZT; AZT Prodrug; AZT-DHP 5'-[[(Z)-4-amino-2-butenyl]methylamino]-5'-deoxyadenosine; MDL 73811 5'-Alkylglycosidecarbonate of 3'-azido-3'-deoxythymidine; AcNHGlc-hexyl-CO3 AZT 5Cl3PhS-2IndolCONH2 5-Fluoro-2',3'-dideoxycytidine; 5-F-ddC 5-Methyl-3'-azido-2',3'-dideoxyisocytidine; MeAZddIsoC 6-O-Butanoylcastanospermine; BuCast; MDL 28,574; Celgosivir 6-Chloro-9-(2,3-dideoxy-b-D-glyceropentofuranosyl)-9H-purine; D2ClP; 6-Chloro-ddP; CPDDR; 6Cl-ddP 6-Dimethylaminopurine-2',3'-dideoxyriboside; N-6-dimethylddA; DMAPDDR 7-Chloro-N-methyl-5-(1H-pyrrol-2-yl)-3H-1,4-benzodiazepin-2-amine; Ro 24-7429 7-Chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2(H)-one; Ro 5-3335 8-Chloro-TIBO; Tivirapine; R86183 9-(2,3-Dideoxy-b-D-ribofuranosyl)-6-(methylthio)purine; D2SMeP 9-[Bis(OHMe)cBu]A; A-69463; Cyclobutyl-A; Cyclobut-A; C-oxetanocin A A-76890 A-77212 A-80987; Ritonavir derivative A-81525; Ritonavir derivative A-83962; Ritonavir derivative A-98881; Azacyclic urea derivative AA; L-ascorbic acid; Calcium Ascorbate AAP-BHAP; U-104489; PNU-104489 Abacavir & Lamivudine & Zidovudine ABT-378; Lopinavir ABT-378 & ABT-538; Lopinavir & Ritonavir ABT-538; Ritonavir Acemannan Adefovir; PMEA; GS-0393 Adefovir dipivoxil; BisPom PMEA; GS-840 AG-1343; Nelfinavir AG1350; LY316957; Nelfinavir-octahydro-thienopyridine analog AHPBA analog; R-87366 Alpha-lipoic acid; a-Lipoic acid; Thioctic acid ALX40-4C AMD3100; JM3100 Amprenavir phosphate; VX-175; GW433908; GW433908A (*Sodium Salt*); GW433908G (*Calcium Salt*); Fosamprenavir Ancer 20; Z-100 Anti-sense 25-mer phosphorothioate; GEM91 Atazanavir; CGP-73547; BMS-232632; BMS 232632; Zrivada; Latazanavir Atevirdine; U-87201E; BHAP derivative Aurintricarboxylic acid; Dupont ATA; Dupont DA639; SD-095345; ATA AY 9944; trans-1,4-Bis(2-dichlorobenzylaminoethyl)cyclohexane dichlorhydrate AZT; Zidovudine; Azidothymidine AZT-PO3(CH3)-AZT; O,O'-Bis(3'-azido-3'-deoxythymidin-5'-yl)methylphosphonate Baicalin; TJN-151 Betulinic acid; Mairin Betulinic acid, 3-O-(3',3'-dimethylsuccinate) BHAP derivative Delavirdine; U-90152 U-88204E BI-RG-587; Nevirapine BILA 1906 BS BILA 2011 BS; Palinavir BILA 2185 BS Bis(2-nitrophenyl)sulfone; Bis(2NO2Ph)SO2; NSC633001 bis-ValHOEt-N2aza-peptide isostere; CGP 53820 bis-ValHOEt-N2aza-peptide isostere; CGP 53820 analog BMS-186318 BocPhe[CHOH(CH2)3CH.dbd.CHPhCO]IleAMBI; L-687,908 BzOCValPhe[diCHOH(RR)]PheValBzOC BzOCValPhe[diCHOH(SS)]PheValBzOC C2-Sym Phosphinic amide derivative (HOECHST AG) Calanolide A; NSC675451 Calanolide B Capravirine; S-1153 Castanospermine CbzAF(CHOHCH2)AVVOMe Cbz-Asn-Apns-Pro-NH-tBu; KNI-102 CGP 61755; Lasinavir CGP 64222 CNI-H0294 Coactinon; I-EBU; HEPT derivative; MKC-442; Emivirine Conocurvone; NSC650891 Coviracil; (-)FTC; (-)-2',3'-Dideoxy-5-fluoro-3'-thiacytidine; Emtricitabine; Emtriva C-Oxetanocin-G; A-69992; (+-)Lobucavir; C-Oxt-G; Cyclobut-G; (+-)Cyclobut-G Indinavir; MK639; L-735,524 Curdlan Sulfate CV-N; Cyanovirin-N Cyclic Urea Amide; SD146 Cyclosporin A [Me-Ile-4]Cyclosporin A; SDZ NIM 811 D4A (L); L-2',3'-Didehydro-2',3'-dideoxyadenosine D4FC; D-D4FC; 2',3'-Didehydro-2',3'-dideoxy-5-fluorocytidine; DPC 817 D4FC (L); L-2',3'-Didehydro-2',3'-dideoxy-5-fluorocytidine D4G (L); L-2',3'-Didehydro-2',3'-dideoxyguanosine D4I (L); L-2',3'-Didehydro-2',3'-dideoxyinosine DABO ddC; Dideoxycytidine; Zalcitabine ddI; Dideoxyinosine; Didanosine Dehydroepiandrosterone; DHEA; Prasterone; Dehydroisoandrosterone; EL-10 Dextran Sulfate Dicaffeic acid ester; L-Chicoric acid DMP-266; Efavirenz; Approved DMP-323; XM-323 DMP-450 Docosanol; n-Docosanol dOTC (-); (-)-2'-Deoxy-3'-oxa-4'-thiocytidine dOTFC (-); (-)-2'-Deoxy-3'-oxa-4'-thio-5-fluorocytidine DP-178; Pentafuside; T-20; GP41 127-162 AA; Enfuvirtide E-BPTU; HEPT derivative; NSC 648400 E-EBU; HEPT derivative; MKC-442 derivative E-EBU-dM; HEPT derivative; MKC-442 derivative E-EPSeU; HEPT derivative; MKC-442 derivative E-EPU; HEPT derivative; MKC-442 derivative Ebselen Etoposide Epoxy steroid derivative; (4a,5a,17b)-17-Hydroxy-3-oxo-4,5-epoxyandrostane-2-carboxamide Eulicin Fenalamide A1; Phenalamide A1; Stipiamide Fleephilone Fluoroquinolone derivative; K-12 Saquinavir; Ro31-8959; Approved Foscarnet; Phosphonoformic acid; Foscavir FPMDAP FPMPA FPMPG GPGRAF Octomer; SPC3 Hammerhead anti-gag RNA Ribozyme B Harziphilone HBY 097; Quinoxaline derivative HEPT derivative; MKC-442 derivative LY326188 HPMPA HPMPDAP HU; Hydroxyurea; Hydrea Hydroxocobalamin Hypericin Ingenol 3,5,20-triacetate; ITA; RD3-2118 Ingenol derivative; RD4-2138 Inophyllum B Inophyllum P iQoa-Mta-Apns-Thz-NH-tBu; KNI-272 Isentress (Raltegravir) IsoquinCON furanyl urethane analog IsoquinCON thienyl urethane analog KNI-154; Noa-Asn-Apns-Thz-NH-tBu KNI-174; Noa-Asn-Apns-Dmt-NH-tBu KNI-227; Qoa-Mta-Apns-Thz-NH-tBu L-685,434 L-685, 434-6-Hydroxy derivative L-685,434-sOEtMorphderivative; L-689,502 L-685,434-OEtNMe2 L-685,434-OPrMorph derivative L-697,593; 2-Pyridinone derivative L-697,639; 2-Pyridinone derivative L-697,661; 2-Pyridinone derivative L-FddC; b-L-5F-ddC Lamivudine & Zidovudine; 3TC & AZT; Approved LY289612 LY289612 analog LY-300046-HCl; PETT derivative; Trovirdine LY314163; Saquinavir/Nelfinavir derivative LY-73497; N-(2-Phenethyl)-N'-(2-thiazolyl)thiourea; PETT MAP; Methyl acetylenic putrescine Michellamine A; NSC650898 Michellamine B; NSC649324 Michellamine F N-6-Et-ddA; N-Ethyl-2',3'-dideoxyadenosine N-6-methyl ddA; N6-Methyl-2',3'-dideoxyadenosine Naphthalene 2-sulphonate polymer; PRO2000 Nelfinavir-octahydro-thienopyridine analog Nonoxynol 9 NSC625487; Thiazolobenzimidazole; TBZ Oxathiin derivative; UC-38 Oxathiin derivative; UC-84 P9941 Penicillin Et(NH)2 Sym dimer Penicillin G, ET(NH)2 derivative Penicillin, 2Isoquin-OHPrNH2 analog Pentosan Sulfate; Elmiron; SP54; Xylan Sulfate PETT Cl, F derivative PETT derivative Phenoxan Phorbol derivative; Prostratin Platanic acid PMEDAP PMEG PMEHx; PMEI PMEMAP PMET PNU-140690; U-140690; Tipranavir Pyridinone derivative Quinoxalin2thione derivate; S-2720 R14458; TIBO derivative R82150; TIBO derivative R82913; TIBO derivative Resobene Ribavirin; Virazole Ro 31-8959-bis-thf derivative Saquinavir/Nelfinavir derivative SB-205569; Val-Phe-Phe-HOCH2CH2 isostere analog SC-52151; Telinavir SDZ PRI 053 Suramin Sodium T22 Thalidomide Thiangazole; (-)-Thiangazole Thiazoloisoindol-5-one Thiazoloisoindol-5-one, derivative Tle-Val-Sta, 5PhBuCOOH derivative; Statine derivative UC-781 Val-Val-Sta, 5PhBuCOOH derivative; Statine derivative VB-11,328 and Tenofovir Disoproxil and mixtures thereof.

36. A method according to claim 35, wherein said first compound is ##STR00031##

37. A method of treating an HIV infection in a human host comprising administering to said host in combination, an effective amount of a first compound according to the structure: ##STR00032## Where R.sub.1=o-F, R.sub.2=H, R.sub.3=p-F, R.sub.4=o-F R.sub.1=p-F, R.sub.2=H, R.sub.3=p-F, R.sub.4=o-F R.sub.1=o-F, R.sub.2=o-F, R.sub.3=o-F, R.sub.4=H R.sub.1=o-F, R.sub.2=H, R.sub.3=o-F, R.sub.4=o-F R.sub.1=o-F, R.sub.2=H, R.sub.3=p-F, R.sub.4=H R.sub.1=o-F, R.sub.2=p-F, R.sub.3 p-F, R.sub.4=o-F or R.sub.1=o-F, R.sub.2=o-F, R.sub.3=o-F, R.sub.4=o-F; X is CH or N; and Z is OH or .dbd.O; or a pharmaceutically acceptable salts thereof, in combination with at least one additional compound selected from the group consisting of ACV; AK602; AMD070; APV; ATV; ATZ; AVX754 (apricitabine); AZT; Abacavir; Abacavir/Lamivudine/Zidovudine; Abacavir sulfate; Abacavir sulfate/Lamivudine; Abacavir/Lamivudine; Abelecet; Acyclovir; Adefovir dipivoxil; Adriamycin; Agenerase; Aldesleukin; Alovudine; Aluvia; AmBisome; Amdoxovir; Amphocin; Amphotec; Amphotericin B; Ampligen; Amprenavir; Androderm; Androgel; Apricitabine; Aptivus; Atazanavir; Atripla; Azithromycin; BMS-378806; BMS-488043; Bactrim; Baraclude; Bevirimat; Biaxin; Brecanavir; BufferGel; C31G; CD4-IgG2; CS; CV-N; Calanolide A; Calcium hydroxylapatite; Carbopol 974P; Carrageenan; Carraguard; Cellulose sulfate; Clarithromycin; Copegus; Cotrimoxazole; Crixivan; Cyanovirin-N; Cytovene; DLV; DS; Darunavir; Delavirdine; Depo-Testosterone; Dextran sulfate; Didanosine; Diflucan; Doxil; Doxorubicin (liposomal); Dronabinol; UV; Efavirenz; Elvucitabine; Emtricitabine; Emtricitabine; Tenofovir disoproxil fumarate; Emtriva; Enfufirtide; Entecavir, Epivir; Epoetin alfa; Epogen; Epzicom; Etopophos (phosphate salt); Etoposide; Etravirine; FTC; Fluconazole; Fortovase; Fosamprenavir; Foxivudine tidoxil; Fungizone; Fuzeon; GS 9137; GSK-873,140 (aplaviroc); GW433908; GW640385 (brecanavir); Ganciclovir, Globulin, Immune; Growth hormone (human); Hepsera; Hivid; Human growth hormone; IL-2; INH; Immune Globulin Intravenous (Human); Indinavir; Interferon alfa-2; Interleukin-2, recombinant human; Intron A (2b); Invirase; Isentress; Isoniazid; Itraconazole; KP-1461; Lamivudine/Zidovudine; Lexiva; Lopinavir/Ritonavir; MK-0518; Nebupent; Nelfinavir; Neutrexin; Nevirapine; Norvir; Nydrazid; Peptide T; PMPA Prodrug (Viread)' Prezista (Darunavir); PRO 140; PRO 2000; PRO 542 (CD4 IGg2); Procrit (Epoetin); Proleukin; Racivir; Radiesse; Rrebetol; Rescriptor, Retrovir, Reyataz; Ribavirin; Rifabutin; Rifadin; Rifampin; Rimactane; Ritonavir, Roferon-A (2a); Saquinavir, SCH-D (vicriviroc); Somatropin; Stavudinie; Sulfamethoxazole/Trimethoprim; Sustanon; Sustiva; TNX-355; Taxol; Tenofovir; Tenofovir disoproxil fumarate; Testosterone; Tipranavir; Toposar; Trimetrexate; Trizivir, Truvada (Emtriva and Viread combination); U-90152S (Delaviridine); UC-781; UK-427,857 (maraviroc); Valcyte; Valganciclovir; Valproic acid; VePesid; Vicriviroc; Videx; Viracept (Tennofovir DF); Viramune; Virazole; Viread; Vitrasert; Zalcitabine; Zerit; Ziagen; Zidovudine; Zithromax; Zovirax and mixtures thereof, further in combination with a pharmaceutically acceptable carrier, additive or excipient.

38. A method according to claim 37 wherein the first compound is ##STR00033##

39. The compound: (1S,2S)-4-(5-(2,4-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyr- idin-3-yl)-2-hydroxy-N-(2-hydroxycyclopentyl)-4-oxobut-2-enamide (1R,2R)-4-(5-(2,4-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyr- idin-3-yl)-2-hydroxy-N-(2-hydroxycyclopentyl)-4-oxobut-2-enamide 4-(5-(2,4-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-y- l)-2-hydroxy-4-oxo-N-(2-oxopyrrolidin-1-yl)but-2-enamide (1S,2S)-4-(5-(2,4-difluorobenzyl)-1-(4-fluorobenzyl)-2-oxo-1,2-dihydropyr- idin-3-yl)-2-hydroxy-N-(2-hydroxycyclopentyl)-4-oxobut-2-enamide (1R,2R)-4-(5-(2,4-difluorobenzyl)-1-(4-fluorobenzyl)-2-oxo-1,2-dihydropyr- idin-3-yl)-2-hydroxy-N-(2-hydroxycyclopentyl)-4-oxobut-2-enamide 4-(5-(2,4-difluorobenzyl)-1-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-y- l)-2-hydroxy-4-oxo-N-(2-oxopyrrolidin-1-yl)but-2-enamide (1S,2S)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin- -3-yl)-2-hydroxy-N-(2-hydroxycyclopentyl)-4-oxobut-2-enamide (1R,2R)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin- -3-yl)-2-hydroxy-N-(2-hydroxycyclopentyl)-4-oxobut-2-enamide 4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-2- -hydroxy-4-oxo-N-(2-oxopyrrolidin-1-yl)but-2-enamide (1S,2S)-4-(1-(2,6-difluorobenzyl)-5-(2-fluorobenzyl)-2-oxo-1,2-dihydropyr- idin-3-yl)-2-hydroxy-N-(2-hydroxycyclopentyl)-4-oxobut-2-enamide (1R,2R)-4-(1-(2,6-difluorobenzyl)-5-(2-fluorobenzyl)-2-oxo-1,2-dihydropyr- idin-3-yl)-2-hydroxy-N-(2-hydroxycyclopentyl)-4-oxobut-2-enamide 4-(1-(2,6-difluorobenzyl)-5-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-y- l)-2-hydroxy-4-oxo-N-(2-oxopyrrolidin-1-yl)but-2-enamide (1S,2S)-4-(1,5-bis(2,4-difluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-h- ydroxy-N-(2-hydroxycyclopentyl)-4-oxobut-2-enamide (1R,2R)-4-(1,5-bis(2,4-difluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-h- ydroxy-N-(2-hydroxycyclopentyl)-4-oxobut-2-enamide 4-(1,5-bis(2,4-difluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-hydroxy-4- -oxo-N-(2-oxopyrrolidin-1-yl)but-2-enamide (1S,2S)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyr- idin-3-yl)-2-hydroxy-N-(2-hydroxycyclopentyl)-4-oxobut-2-enamide (1R,2R)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyr- idin-3-yl)-2-hydroxy-N-(2-hydroxycyclopentyl)-4-oxobut-2-enamide 4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-y- l)-2-hydroxy-4-oxo-N-(2-oxopyrrolidin-1-yl)but-2-enamide (1S,2S)-4-(1,5-bis(2,6-difluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-h- ydroxy-N-(2-hydroxycyclopentyl)-4-oxobut-2-enamide (1R,2R)-4-(1,5-bis(2,6-difluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-h- ydroxy-N-(2-hydroxycyclopentyl)-4-oxobut-2-enamide, or 4-(1,5-bis(2,6-difluorobenzyl)-2-oxo-1,2-6 hydropyridin-3-yl)-2-hydroxy-4-oxo-N-(2-oxopyrrolidin-1-yl)but-2-enamide.

40. A pharmaceutical composition comprising a compound according to claim 39 in combination with a pharmaceutically acceptable carrier, additive or excipient.

41. The composition according to claim 40 in oral or parenteral dosage form.

42. A kit comprising a pharmaceutical composition according to claim 11 and instructions for a medical professional and/or a patient on how to administer said composition.

43. The method according to claim 31 wherein said patient or subject is a human.

44. The method according to claim 32 wherein said patient or subject is a human.

45. The method according to claim 33 wherein said patient or subject is a human.

Summary for Patent:   Try a Free Trial

PCT Information
PCT FiledDecember 07, 2010PCT Application Number:PCT/US2010/059183
PCT Publication Date:June 16, 2011PCT Publication Number:WO2011/071849

Details for Patent 8,703,801

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Schering INTRON A interferon alfa-2b VIAL 103132 001 1986-06-04   Try a Free Trial University of Georgia Research Foundation, Inc. (Athens, GA) 2029-12-07 RX search
Schering INTRON A interferon alfa-2b VIAL 103132 002 1986-06-04   Try a Free Trial University of Georgia Research Foundation, Inc. (Athens, GA) 2029-12-07 RX search
Schering INTRON A interferon alfa-2b VIAL 103132 003 1986-06-04   Try a Free Trial University of Georgia Research Foundation, Inc. (Athens, GA) 2029-12-07 RX search
Amgen EPOGEN/PROCRIT epoetin alfa VIAL; SINGLE-USE 103234 001 1989-06-01   Try a Free Trial University of Georgia Research Foundation, Inc. (Athens, GA) 2029-12-07 RX search
Amgen EPOGEN/PROCRIT epoetin alfa VIAL; MULTIDOSE 103234 002 1989-06-01   Try a Free Trial University of Georgia Research Foundation, Inc. (Athens, GA) 2029-12-07 RX search
Amgen EPOGEN/PROCRIT epoetin alfa VIAL; MULTIDOSE 103234 003 1989-06-01   Try a Free Trial University of Georgia Research Foundation, Inc. (Athens, GA) 2029-12-07 RX search
Amgen EPOGEN/PROCRIT epoetin alfa VIAL; SINGLE-USE 103234 004 1989-06-01   Try a Free Trial University of Georgia Research Foundation, Inc. (Athens, GA) 2029-12-07 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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International Patent Family for US Patent 8,703,801

Country Patent Number Publication Date
South Africa 201204147 Feb 27, 2013
World Intellectual Property Organization (WIPO) 2011071849 Jun 16, 2011
World Intellectual Property Organization (WIPO) 2011071849 Oct 06, 2011
United States of America 2012282218 Nov 08, 2012
Singapore 181524 Jul 30, 2012
New Zealand 600873 Aug 29, 2014
Mexico 2012006485 Aug 23, 2012
>Country >Patent Number >Publication Date

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