Claims for Patent: 9,745,334

Summary for Patent: 9,745,334

Title:	Cytotoxic-drug delivering molecules targeting HIV (CDM-Hs), cytotoxic activity against the human immunodeficiency virus and methods of use
Abstract:	The present invention is directed to new bifunctional compounds and methods for treating HIV infections. The bifunctional small molecules, generally referred to as CDM-Hs, function through orthogonal pathways, by inhibiting the gp120-CD4 interaction, and by introducing cytotoxic moieties to gp120-expressing cells, thereby causing cell death and preventing cell infection and spread of HIV. It is shown that CDM-Hs bind to gp120 and gp-120 expressing cells competitively with CD4, and these compounds cause cell death of HIV-infected cells, thereby decreasing viral infectivity. Compounds and methods are described herein.
Inventor(s):	Spiegel; David (New Haven, CT), Parker; Christopher (Medina, OH)
Assignee:	YALE UNIVERSITY (New Haven, CT)
Application Number:	14/396,956
Patent Claims:	1. A compound according to the chemical structure: ##STR00094## Where X.sub.2 is H, C.sub.1-C.sub.6 alkyl, O--C.sub.1-C.sub.6 alkyl or halogen; ##STR00095## is ##STR00096## W or W' is each independently H, --(CH.sub.2).sub.n''OH, --(CH.sub.2).sub.n''COOH, --(CH.sub.2).sub.n''O--(C.sub.1-C.sub.6 alkyl), NO.sub.2, CN or halogen; n and n' are each independently 2-8; Each n'' is independently 0, 1, 2, 3, 4, 5, or 6; i is 0 or 1; [LL] is a labile linker according to the chemical structure: ##STR00097## where R is an ethylene glycol group, or a methylene group and n in this labile linker is from 0 to 10; X is O, N--R.sup.AL or S; R.sup.AL is H or a C.sub.1-C.sub.3 alkyl group; Y is O or S and Z=Me, Et, iPr, tBu, Ph, each of which may be optionally substituted with one or more halogen groups and where said Ph group may be further optionally substituted with OMe or a C.sub.1-C.sub.3 alkyl group which itself may be substituted with up to three halogens; or [LL] is a group according to the chemical formula: ##STR00098## and R is an ethylene glycol group, or a methylene group and n in this labile linker is from 0 to 10; or [LL] is an enzymatically cleaved labile linker according to the chemical structure: ##STR00099## Where the protease substrate is a peptide containing from 2 to 50 amino acid units, and R is an ethylene glycol group, or a methylene group; and n in this labile linker is from 0 to 10; or [LL] is a group according to the chemical structure: ##STR00100## Where the points of attachment in each of the labile linkers as indicated are joined to other portions of the molecule as indicated; [NLL] when present is a (poly)ethylene glycol linker of from 2 to 8 ethylene glycol units, or [NLL] is a group: ##STR00101## where each X.sup.S is independently S, O or N--R.sup.S; R.sup.S is H or C.sub.1-3 alkyl; S.sub.c is CH.sub.2; CH.sub.2O; or CH.sub.2CH.sub.2O; i is 0 or 1; and m.sup.S is 0, 1, 2, 3, 4, 5, or 6; and [CYT] is a group according to the chemical structure: ##STR00102## ##STR00103## ##STR00104## ##STR00105## wherein X is a group --NR.sup.1N--, --NR.sup.1NCO--, --O--, --CH.sub.2--, --S--, --OCONH-- or --NHCONH-- where R.sup.1N is H or a C.sub.1-C.sub.3 alkyl group optionally substituted with one or two hydroxyl groups, and the symbol signifies a chemical attachment point of the cytotoxic moiety to a labile linker which is linked through X, or a pharmaceutically acceptable salt or stereoisiomer thereof. 2. A compound according to claim 1 which is ##STR00106## or a pharmaceutically acceptable salt or stereoisomer thereof. 3. The compound according to claim 2 wherein CYT is doxorubicin or daunorubicin. 4. The compound according to claim 3 wherein CYT is doxorubicin. 5. The compound according to claim 3 wherein CYT is daunorubicin. 6. A compound according to the chemical structure: ##STR00107## or the free amine or alternative pharmaceutical salt thereof. 7. A compound according to claim 6 having the chemical structure: ##STR00108## or the free amine or alternative pharmaceutical salt thereof. 8. A compound of claim 6 having the chemical structure: ##STR00109## or the free amine or alternative pharmaceutical salt thereof. 9. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient. 10. A pharmaceutical composition comprising an effective amount of a compound according to claim 2 in combination with a pharmaceutically acceptable carrier, additive or excipient. 11. A pharmaceutical composition comprising an effective amount of a compound according to claim 3 in combination with a pharmaceutically acceptable carrier, additive or excipient. 12. A pharmaceutical composition comprising an effective amount of a compound according to claim 4 in combination with a pharmaceutically acceptable carrier, additive or excipient. 13. A pharmaceutical composition comprising an effective amount of a compound according to claim 5 in combination with a pharmaceutically acceptable carrier, additive or excipient. 14. A pharmaceutical composition comprising an effective amount of a compound according to claim 6 in combination with a pharmaceutically acceptable carrier, additive or excipient. 15. A pharmaceutical composition comprising an effective amount of a compound according to claim 7 in combination with a pharmaceutically acceptable carrier, additive or excipient. 16. A pharmaceutical composition comprising an effective amount of a compound according to claim 8 in combination with a pharmaceutically acceptable carrier, additive or excipient. 17. The composition according to claim 9 further comprising a latent HIV activator selected from the group consisting of prostratin, bradystatin 1, bryostatin 1, bryostatin 2, IL-7, a histone deacetylase inhibitor, a DNA methylation inhibitor, a compound according to the chemical structure: ##STR00110## where X and Y are H, X is OH and Y is H, X is OAc and Y is H or X is OAc and Y is OH; a compound according to the chemical structure: ##STR00111## where X and Y are H, X is OAc and Y is H or X is OAc and Y is OH, or a mixture thereof. 18. The composition according to claim 10 further comprising a latent HIV activator selected from the group consisting of prostratin, bradystatin 1, bryostatin 1, bryostatin 2, IL-7, a histone deacetylase inhibitor, a DNA methylation inhibitor, a compound according to the chemical structure: ##STR00112## where X and Y are H, X is OH and Y is H, X is OAc and Y is H or X is OAc and Y is OH; a compound according to the chemical structure: ##STR00113## where X and Y are H, X is OAc and Y is H or X is OAc and Y is OH, or a mixture thereof. 19. The composition according to claim 17 wherein said histone deacetylase inhibitor is vorinostat. 20. The composition according to claim 18 wherein said histone deacetylase inhibitor is vorinostat. 21. The composition according to claim 17 wherein said DNA methylation inhibitor is decitabine. 22. The composition according to claim 18 wherein said DNA methylation inhibitor is decitabine. 23. The composition according to claim 9 wherein said composition further comprises an effective amount of an additional anti-HIV agent. 24. The composition according to claim 10 wherein said composition further comprises an effective amount of an additional anti-HIV agent. 25. The composition according to claim 17 wherein said composition further comprises an effective amount of an additional anti-HIV agent. 26. The composition according to claim 18 wherein said composition further comprises an effective amount of an additional anti-HIV agent. 27. The composition according to claim 23 wherein said additional anti-HIV agent is selected from the group consisting of nucleoside reverse transcriptase inhibitors (NRTI), non-nucloeoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors. 28. The composition according to claim 24 wherein said additional anti-HIV agent is selected from the group consisting of nucleoside reverse transcriptase inhibitors (NRTI), non-nucloeoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors. 29. The composition according to claim 23 wherein said additional anti-HIV agent is selected from the group consisting of Amprenivir, Abacavir, Acemannan, Acyclovir, AD-439, AD-519, Adefovir dipivoxil, Alpha Interferon, Ansamycin, 097, AR 177, Beta-fluoro-ddA, BMS-232623 (CGP-73547), BMS-234475 (CGP-61755), CI-1012, Cidofovir, Curdlan sulfate, Cytomegalovirus Immune globin, Ganciclovir, Dideoxyinosine, DMP-450, Efavirenz (DMP-266), EL10, Famciclovir, FTC, GS 840, HBY097, Hypericin, Recombinant Human Interferon Beta, Interferon alfa-n3, Indinavir, ISIS-2922, KNI-272, Lamivudine (3TC), Lobucavir, Nelfinavir, Nevirapine, Novapren, Peptide T Octapeptide Sequence, Trisodium Phosphonoformate, PNU-140690, Probucol, RBC-CD4, Ritonavir, Saquinavir, Valaciclovir, Virazole Ribavirin, VX-478, Zalcitabine, Zidovudine (AZT), Tenofovir diisoproxil fumarate salt, Combivir, Abacavir succinate, T-20), AS-101, Bropirimine, CL246, EL10, FP-21399, Gamma Interferon, Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), HIV Core Particle Immunostimulant, Interleukin-2 (IL-2), Immune Globulin Intravenous, IMREG-1, IMREG-2, Imuthiol Diethyl Dithio Carbamate, Alpha-2 Interferon, Methionine-Enkephalin, MTP-PE (Muramyl-Tripeptide), Granulocyte Colony Stimulating Factor (GCSF), Remune, rCD4 (Recombinant Soluble Human CD4-IgG), rCD4-IgG Hybrids, Recombinant Soluble Human CD4, Interferon Alfa 2a, SK&F1-6528, Soluble T4, Thymopentin, Tumor Necrosis Factor (TNF), AK602, Alovudine, Amdoxovir, AMD070, Atazanavir (Reyataz), AVX754 (apricitabine), Bevirimat, BI-201, BMS-378806, BMS-488043, BMS-707035, C31G, Carbopol 974P, Calanolide A, Carrageenan, Cellulose sulfate, Cyanovirin-N, Darunavir, Delavirdine, Didanosine (Videx), Efavirenz, Elvucitabine, Emtricitabine, Fosamprenavir (Lexiva), Fozivudine tidoxil, GS 9137, GSK-873,140 (aplaviroc), GSK-364735, GW640385 (brecanavir), HG0004, HGTV43, INCB9471, KP-1461, Lopinavir, Mifepristone (VGX410), MK-0518, PPL-100, PRO 140, PRO 542, PRO 2000, Racivir, SCH-D (vicriviroc), SPO1A, SPL7013, TAK-652, Tipranavir (Aptivus), TNX-355, TMC125 (etravirine), UC-781, UK-427,857 (Maraviroc), Valproic acid, VRX496, Zalcitabine, Valganciclovir, Clindamycin with Primaquine, Fluconazole Pastille, Nystatin Pastille, Eflornithine, Pentamidine, Isethionate, Trimethoprim, Trimethoprim/sulfa, Piritrexim, Pentamidine isethionate, Spiramycin, Intraconazole-R51211, Trimetrexate, Daunorubicin, Recombinant Human Erythropoietin, Recombinant Human Growth Hormone, Megestrol Acetate, Testosterone, Aldesleukin (Proleukin), Amphotericin B, Azithromycin (Zithromax), Calcium hydroxyapatite, Doxorubicin, Dronabinol, Entecavir, Epoetin alfa, Etoposide, Fluconazole, Isoniazid, Itraconazole (Sporanox), Megestrol, Paclitaxel (Taxol), Peginterferon alfa-2, Poly-L-lactic acid (Sculptra), Rifabutin (Mycobutin), Rifampin, Somatropin and Sulfamethoxazole/Trimethoprim. 30. The composition according to claim 24 wherein said additional anti-HIV agent is selected from the group consisting of 3TC (Lamivudine), AZT (Zidovudine), (-)-FTC, ddl (Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T (Stavudine), Racivir, L-FddC, L-FD4C, NVP (Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavir mesylate), RTV (Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV (Nelfinavir), APV (Amprenavir), LPV (Lopinavir), T20, fuseon and mixtures thereof. 31. The composition according to claim 9 in oral dosage form. 32. The composition according to claim 9 in parenteral dosage form. 33. The composition according to claim 9 in topical dosage form. 34. The composition according to claim 32 wherein said parenteral dosage form is an intravenous dosage form. 35. A method of treating an HIV infection in a patient in need thereof comprising administering to said patient an effective amount of a pharmaceutical composition according to claim 9. 36. A method of treating an HIV infection in a patient in need thereof comprising administering to said patient an effective amount of a pharmaceutical composition according to claim 10. 37. A method of treating an HIV infection in a patient in need thereof comprising administering to said patient an effective amount of a pharmaceutical composition according to claim 17. 38. A method of treating an HIV infection in a patient in need thereof comprising administering to said patient an effective amount of a pharmaceutical composition according to claim 18. 39. A method of treating an HIV infection in a patient in need thereof comprising administering to said patient an effective amount of a pharmaceutical composition according to claim 29. 40. A method of treating an HIV infection in a patient in need thereof comprising administering to said patient an effective amount of a pharmaceutical composition according to claim 30. 41. The method according to claim 35 wherein an active compound in said composition inhibits entry of HIV into a target cell by binding to a gp120 envelope protein thereof, and recruits antibodies to form a tertiary complex for attacking the bound HIV, leading to HIV and/or cell death. 42. The method according to claim 37 wherein an active compound in said composition inhibits entry of HIV into a target cell by binding to a gp120 envelope protein thereof, and recruits antibodies to form a tertiary complex for attacking the bound HIV, leading to HIV and/or cell death. 43. A method of reducing the likelihood of an HIV infection in a patient at risk for an HIV infection comprising administering to said patient an effective amount of a pharmaceutical composition according to claim 9. 44. The method according to claim 42 wherein said composition is topically administered to said patient in an area at risk for HIV infection. 45. A method of reducing the likelihood of AIDS or ARC in a patient infected with HIV comprising administering to said patient at risk for AIDS or ARC an effective amount of a composition according to claim 9. 46. A method of reducing or abolishing HIV infected CD cells in a patient comprising administering to an HIV infected patient an effective amount of a composition according to claim 9. 47. A method of inhibiting or abolishing HIV in a patient comprising administering to said patient an effective amount of a composition according to claim 9.

Details for Patent 9,745,334

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	HUMATROPE	somatropin	For Injection	019640	06/23/1987		2032-04-26
Eli Lilly And Company	HUMATROPE	somatropin	For Injection	019640	10/16/1986		2032-04-26
Eli Lilly And Company	HUMATROPE	somatropin	For Injection	019640	02/04/1999		2032-04-26
Emd Serono, Inc.	SAIZEN	somatropin	For Injection	019764	10/08/1996		2032-04-26