Claims for Patent: 9,562,038

Summary for Patent: 9,562,038

Title:	Bifunctional molecules with antibody-recruiting and entry inhibitory activity against the human immunodeficiency virus
Abstract:	The present invention is directed to new bifunctional compounds and methods for treating HIV infections. The bifunctional small molecules, generally referred to as ARM-HI\'s, function through orthogonal pathways, by inhibiting the gp120-CD4 interaction, and by recruiting anti-DNP antibodies to gp120-expressing cells, thereby preventing cell infection and spread of HIV. It has been shown that ARM-HI\'s bind to gp120 and gp-120 expressing cells competitively with CD4, thereby decreasing viral infectivity as shown by an MT-2 cell assay, the binding leading to formation of a ternary complex by recruiting anti-DNP antibodies to bind thereto, the antibodies present in the ternary complex promoting the complement-dependent destruction of the gp120-expressing cells. 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:	13/988,251
Patent Claims:	1. A compound according to the chemical structure: ##STR00070## Where ##STR00071## is an antibody binding terminus (moiety) comprising a moiety according to the chemical structure; ##STR00072## ##STR00073## wherein said DNP group is a dinitrophenyl group linked through the amino group or a thio group to the amino acid; Y' is H or NO.sub.2; X is O, CH.sub.2, NR.sup.1, S(O), S(O).sub.2, --S(O).sub.2O, --OS(O).sub.2, or OS(O).sub.2O; R.sup.1 is H, a C.sub.1-C.sub.3 alkyl group, or a --C(O)(C.sub.1-C.sub.3) group; Xs is OH or NHAc; X.sub.R is O or S; X.sub.M is O or S; X' is CH.sub.2, O, N--R.sup.1' or S; R.sup.1' is H or C.sub.1-C.sub.3 alkyl; Z is a bond, a monosaccharide, disaccharide, oligosaccharide, glycoprotein or glycolipid; Xs is OH or NHAc; X.sup.b is a bond, O, CH.sub.2, NR.sup.1 or S; X'' is O, CH.sub.2, NR.sup.1; and ##STR00074## is a linker molecule which chemical links ABT to R.sup.Y and which optionally includes a connector group CT; ##STR00075## optionally substituted is an aromatic or heteroaromatic group; R.sup.Y is an optionally substituted heteroaryl, or is an optionally substituted aryl group wherein said optionally substituted heteroaryl or said optionally substituted aryl group is selected from the group consisting of imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, indole, quinoline, pyridone, pyridazine, pyrazole, triazine, tetrazole, isoindole, indolizine, purine, indazole, isoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, perimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, pyridopyrimidine; thiophene, benzothiophene; furan, pyran, cyclopentapyran, benzofuran, isobenzofuran; thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine, phenyl, naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl, 2-thiazole, 4-thiazole, 5-thiazole, isothiazolyl, oxazole, 2-oxazole, 4-oxazole, 5-oxazole, isoxazolyl, furanyl, 2-furan, 3-furan or thiophenyl, 2-thiophene, 3-thiophene, a bicyclic aryl, benzyl, anthracenyl, and phenanthrenyl; X.sub.2 is --(CH.sub.2).sub.nO--(C.sub.1-C.sub.6 alkyl), --(OCH.sub.2).sub.nO--(C.sub.1-C.sub.6 alkyl), H, --(CH.sub.2).sub.nOH, --(CH.sub.2).sub.nCOOH, optionally substituted C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.nC(O)--(C.sub.1-C.sub.6 alkyl), --(CH.sub.2).sub.nNHC(O)--R.sub.1, --(CH.sub.2).sub.nNR.sub.1R.sub.2, --(CH.sub.2).sub.nC(O)--NR.sub.1R.sub.2, --(CH.sub.2O).sub.nH, --(CH.sub.2O).sub.nCOOH, --(CH.sub.2O).sub.nC(O)--(C.sub.1-C.sub.6 alkyl), --(OCH.sub.2).sub.nNHC(O)--R.sub.1, --(CH.sub.2O).sub.nC(O)--NR.sub.1R.sub.2, NO.sub.2, CN or halogen; X.sub.3 is H, --(CH.sub.2).sub.nOH, --(CH.sub.2).sub.nCOOH, optionally substituted C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.nO--(C.sub.1-C.sub.6 alkyl), --(CH.sub.2).sub.nC(O)--(C.sub.1-C.sub.6 alkyl), --(CH.sub.2).sub.nNR.sub.1R.sub.2, --(CH.sub.2).sub.nNHC(O)--R.sub.1, --(CH.sub.2).sub.nC(O)--NR.sub.1R.sub.2, --(CH.sub.2O).sub.nH, --(CH.sub.2O).sub.nCOOH, --(OCH.sub.2).sub.nO--(C.sub.1-C.sub.6 alkyl), --(CH.sub.2O).sub.nC(O)--(C.sub.1-C.sub.6 alkyl), --(OCH.sub.2).sub.nNHC(O)--R.sub.1, --(CH.sub.2O).sub.nC(O)--NR.sub.1R.sub.2, NO.sub.2, CN, halogen or a monocyclic aryl or heteroaryl group which itself is optionally substituted; R.sup.1 is H or a C.sub.1-C.sub.3 alkyl group; R.sub.1 and R.sub.2 are each independently H or a C.sub.1-C.sub.6 alkyl group; i is 1 or 0; k is 0, 1, 2 or 3; n is 0, 1, 2, 3, 4, 5, 6; Y.sub.3 is H or a C.sub.1-C.sub.3 alkyl group; and R.sup.N is H or a C.sub.1-C.sub.3 alkyl group which is optionally substituted with one or two hydroxyl groups or up to three halogen groups, or a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof, wherein the term "substituted" shall mean substituted at a carbon or nitrogen position with hydroxyl, carboxyl, cyano (C.ident.N), nitro (NO.sub.2), halogen, C.sub.1-C.sub.10 alkyl, substituted phenyl, benzyl, benzoyl, C.sub.1-C.sub.6 alkoxy, aryl ester, C.sub.1-C.sub.6 alkylene ester, where substitution occurs on the alkylene group, rather than at the ester function, aryl, a five- or six-membered cyclic alkylene amine, a C.sub.1-C.sub.6 alkyl amine, a C.sub.1-C.sub.6 dialkyl amine which alkyl groups may be substituted with one or two hydroxyl groups, an amido group substituted with one or two C.sub.1-C.sub.6 alkyl groups, carboxamide, which is substituted with one or two C.sub.1-C.sub.6 alkyl groups, C.sub.1-C.sub.6 alkyl or aryl alkanol or C.sub.1-C.sub.6 alkyl or aryl alkanoic acid. 2. The compound according to claim 1 according to the formula: ##STR00076## where ##STR00077## is a monocyclic or bicyclic aryl or heteroaryl group according to the chemical structure: ##STR00078## Where W is H, --(CH.sub.2).sub.nOH, --(CH.sub.2)--COOH, C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.nO--(C.sub.1-C.sub.6 alkyl), --(CH.sub.2).sub.nC(O)--(C.sub.1-C.sub.6 alkyl), --(CH.sub.2).sub.nNHC(O)--R.sub.1, --(CH.sub.2).sub.nC(O)--NR.sub.1R.sub.2, --(CH.sub.2O).sub.nOH, --(CH.sub.2O).sub.nCOOH, --CH.sub.2O).sub.nO--(C.sub.1-C.sub.6 alkyl), --(CH.sub.2O).sub.nC(O)--(C.sub.1-C.sub.6 alkyl), --(CH.sub.2O).sub.bNHC(O)--R.sub.1, --(CH.sub.2O).sub.nC(O)--NR.sub.1R.sub.2, NO.sub.2, CN, halogen (F, Cl, Br, I) or a monocyclic aryl or heteroaryl group which itself is optionally substituted; W' is H, --(CH.sub.2).sub.nOH, --(CH.sub.2).sub.nCOOH, C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.nO--(C.sub.1-C.sub.6 alkyl) or halogen; ##STR00079## is a group according to chemical structure: ##STR00080## Where W.sup.2 is H, --(CH.sub.2).sub.nOH, --(CH.sub.2).sub.nCOOH, C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.nO--(C.sub.1-C.sub.6 alkyl), --(CH.sub.2).sub.nC(O)--(C.sub.1-C.sub.6 alkyl), --(CH.sub.2).sub.nNHC(O)--R.sub.1, --(CH.sub.2).sub.nC(O)--NR.sub.1R.sub.2, --(CH.sub.2O).sub.nOH, --(CH.sub.2O).sub.nCOOH, C.sub.1-C.sub.6 alkyl, --(CH.sub.2O).sub.nO--(C.sub.1-C.sub.6 alkyl), --(CH.sub.2O).sub.nC(O)--(C.sub.1-C.sub.6 alkyl), --(CH.sub.2O).sub.nNHC(O)--R.sub.1, --(CH.sub.2O).sub.nC(O)--NR.sub.1R.sub.2, NO.sub.2, CN or halogen; X in ##STR00081## is a group --(CH.sub.2).sub.n'NHC(O)--, --(CH.sub.2).sub.n'NH--, --(CH.sub.2).sub.n'O--, --(CH.sub.2).sub.m--, --(CH.sub.2).sub.n'S--, --(CH.sub.2).sub.n'S(O)--, --(CH.sub.2).sub.n'SO.sub.2-- or --(CH.sub.2).sub.n'NH--C(O)--NH-- which links ##STR00082## to the linker; Y is O, S or N--R where R is H or a C.sub.1-C.sub.3 alkyl group; X.sub.2 is --(CH.sub.2O).sub.nO--(C.sub.1-C.sub.6 alkyl), H, --(CH.sub.2).sub.nOH, --(CH.sub.2).sub.nCOOH, C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.nO--(C.sub.1-C.sub.6 alkyl), --(CH.sub.2).sub.nC(O)--(C.sub.1-C.sub.6 alkyl), --(CH.sub.2).sub.nNHC(O)--R.sub.1, --(CH.sub.2).sub.nC(O)--NR.sub.1R.sub.2, --(CH.sub.2O).sub.nOH, --(CH.sub.2O).sub.nCOOH, C.sub.1-C.sub.6 alkyl, --(CH.sub.2O).sub.nC(O)--(C.sub.1-C.sub.6 alkyl), --(CH.sub.2O).sub.nNHC(O)--R.sub.1 or --(CH.sub.2O).sub.nC(O)--NR.sub.1R.sub.2, NO.sub.2; R.sub.1 and R.sub.2 are each independently H or a C.sub.1-C.sub.6 alkyl group; Y.sub.3 is H or a C.sub.1-C.sub.3 alkyl group disposed out of or into the plane on the chiral carbon; and R.sup.N is H or a C.sub.1-C.sub.3 alkyl group which is optionally substituted with one or two hydroxyl groups or up to three halogen groups; i is 1 or 0; and m is 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4, 5 or 6; and n' is 0, 1, 2 or 3; ##STR00083## is the same as in claim 1; and ##STR00084## is a linker molecule which links ##STR00085## to X and optionally includes a connector group CT; or a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof. 3. The compound according to claim 1 wherein ABT is a) a moiety according to the chemical structure; ##STR00086## where X.sup.b is a bond, 0, CH.sub.2, NR.sup.1 or S; or b) a moiety according to the chemical structure: ##STR00087## Where Y' is H or NO.sub.2; X is O, CH.sub.2, NR.sup.1, S(O), S(O).sub.2, --S(O).sub.2O, --OS(O).sub.2, or OS(O).sub.2O; and R.sup.1 is H, a C.sub.1-C.sub.3 alkyl group, or a --C(O)(C.sub.1-C.sub.3) group; or c) a chemical group according to the chemical structure: ##STR00088## where DNP is a dinitrophenyl group linked to the amino acid through an amine or thio group or d) a group according to the chemical structure: ##STR00089## Where X.sub.R is O or S; and X.sub.M is O or S. 4. The compound according to claim 1 wherein R.sup.Y is an optionally substituted furanyl, tetrazolyl, phenyl, naphthyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, or thiophenyl group. 5. The compound according to claim 1 wherein said ARYL group is an optionally substituted phenyl group. 6. The compound to claim 1 wherein R.sup.N is H, X.sub.2 is H or OCH.sub.3; X.sub.3 is H, OCH.sub.3, CH.sub.3 or NO.sub.2; Y.sub.3 is H or CH.sub.3 (racemic or enantiomeric); and k and i are each 1, or a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof. 7. The compound according to claim 1 wherein Y.sub.3 is a CH.sub.3 group and said CH.sub.3 group is disposed outward from the plane. 8. The compound according to claim 1 wherein R.sup.Y is an optionally substituted furanyl group. 9. The compound according to claim 2 wherein [ARYL2] is a ##STR00090## group. 10. The compound according to claim 2 wherein said linker comprises a group according to the formula: ##STR00091## where each n is independently 0, 1, 2, 3, 4, 5 or 6 or a polyethylene glycol having from 1 to 12 glycol units. 11. A compound according to claim 10 according to the chemical structure: ##STR00092## or a pharmaceutically acceptable salt thereof. 12. The compound according to claim 10 wherein said polyethylene glycol linker has 1 to 10 glycol units. 13. The compound according to claim 10 wherein said polyethylene glycol linker has 1 to 6 glycol units. 14. The compound according to claim 2 wherein said [ARYL1] group is selected from the group consisting of phenyl, o-, m-, or p-toluyl, o-, m- or p-ethylphenyl, o-, m- or p-isopropylphenyl, naphthyl, o-, m- or p-phenol, 3,5-dihydroxylphenyl, o-, m- or p-hydroxymethylphenyl or a 2-, 3-, or 4-pyridyl group. 15. The compound according to claim 1 wherein said [ARYL] group is selected from the group consisting of phenyl, o-, m-, or p-toluyl, o-, m- or p-ethylphenyl, o-, m- or p-isopropylphenyl, naphthyl, o-, m- or p-phenol, 3,5-dihydroxylphenyl, o-, m- or p-hydroxymethylphenyl or a 2-, 3-, or 4-pyridyl group. 16. The compound according to claim 1 wherein said ABT moiety comprises a group according to the chemical formula: ##STR00093## Where Y' is H or NO.sub.2; X is NR.sup.1, O, CH.sub.2, S(O), S(O).sub.2, --S(O).sub.2O, --OS(O).sub.2, or OS(O).sub.2O; and X.sub.R is O or S. 17. The compound according to claim 1 wherein said linker is ##STR00094## Where R.sub.a is H, C.sub.1-C.sub.3 alkyl or alkanol or forms a cyclic ring with R.sup.3 and R.sup.3 is a side chain derived from an amino acid; and m is an integer from 1 to 15. 18. The compound according to claim 9 according to the chemical structure: ##STR00095## where each n is independently 0, 1, 2, 3, 4, 5 or 6. 19. The compound according to claim 1 wherein said linker is a compound according to the chemical formula: ##STR00096## where Z and Z' are each independently a bond, --(CH.sub.2).sub.i--O, --(CH.sub.2).sub.i--S, --(CH.sub.2).sub.i--N--R, ##STR00097## wherein said --(CH.sub.2).sub.i group, if present in Z or Z', is bonded to a connector, ABT or CBT; Each R is H, or a C.sub.1-C.sub.3 alkyl or alkanol group; Each R.sup.2 is independently H or a C.sub.1-C.sub.3 alkyl group; Each Y is independently a bond, O, S or N--R; Each i is independently 1 to 50; D is ##STR00098## or a bond, with the proviso that Z, Z' and D are not each simultaneously bonds; j is 1 to 100; m' is 1 to 100; n is 1 to 100; X.sup.1 is O, S or N--R; and R is as described above, or a pharmaceutically acceptable salt, solvate or polymorph thereof. 20. The compound according to claim 2 wherein said linker is a compound according to the chemical formula: ##STR00099## where Z and Z' are each independently a bond, --(CH.sub.2).sub.i--O, --(CH.sub.2).sub.i--S, --(CH.sub.2).sub.i--N--R, ##STR00100## wherein said --(CH.sub.2).sub.i group, if present in Z or Z', is bonded to a connector, ABT or CBT; Each R is H, or a C.sub.1-C.sub.3 alkyl or alkanol group; Each R.sup.2 is independently H or a C.sub.1-C.sub.3 alkyl group; Each Y is independently a bond, O, S or N--R; Each i is independently 1 to 50; D is ##STR00101## or a bond, with the proviso that Z, Z' and D are not each simultaneously bonds; j is 1 to 100; m' is 1 to 100; n is 1 to 100; X.sup.1 is O, S or N--R; and R is as described above, or a pharmaceutically acceptable salt, solvate or polymorph thereof. 21. The compound according to claim 2 wherein X.sub.2 is OCH.sub.3 or H; ##STR00102## is a group according to chemical structure: ##STR00103## where Y is O; X is a group --(CH.sub.2).sub.nNHC(O)--, --(CH.sub.2).sub.nNH--, --(CH.sub.2).sub.nO--, --(CH.sub.2).sub.m--, --(CH.sub.2).sub.nS--, --(CH.sub.2).sub.nS(O)--, --(CH.sub.2).sub.n SO.sub.2-- or --(CH.sub.2).sub.nNH--C(O)--NH--; W.sup.2 is H R.sup.N is H; Y.sub.3 is H or a CH.sub.3 group disposed outward from the plane; ABT comprises a ##STR00104## group or a ##STR00105## group where X.sub.R is O or S; ##STR00106## is a linking group comprising a polyethylene glycol having from 1 to 8 glycol units; i is 1; m is 1, 2, 3, 4 or 5; Each n is independently 0, 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof. 22. The compound according to claim 2 wherein X.sub.2 is H or OCH.sub.3; ##STR00107## W is H or NO.sub.2; ##STR00108## Y is O; X is a group --(CH.sub.2).sub.nNH--, --(CH.sub.2).sub.nNHC(O)--, --(CH.sub.2).sub.nO--, --(CH.sub.2).sub.nS--, --(CH.sub.2).sub.nS(O)--, --(CH.sub.2).sub.nSO.sub.2-- or --(CH.sub.2).sub.nNH--C(O)--NH--; R.sup.N is H; Y.sub.3 is H or a CH.sub.3 group disposed outward from the plane; ABT comprises a ##STR00109## group or a or a ##STR00110## group where X.sub.R is O or S; ##STR00111## is a linking group comprising a polyethylene glycol having from 1 to 8 glycol units; i is 1; m is 1, 2, 3, 4 or 5; and Each n is independently 0, 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt thereof. 23. The compound: ##STR00112## where each n is independently 0, 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt thereof. 24. The compound according to claim 22 which is: ##STR00113## 25. A pharmaceutical composition comprising an effective amount of a bifunctional compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient. 26. The composition according to claim 25 wherein said composition further comprises an effective amount of an additional anti-HIV agent. 27. The composition according to claim 26 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 26 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), SP01A, 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. 29. The composition according to claim 26 wherein said additional anti-HIV agent is selected from the group consisting of 3TC (Lamivudine), AZT (Zidovudine), (-)-FTC, ddI (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. 30. The composition according to claim 25 in oral dosage form. 31. The composition according to claim 25 in parenteral dosage form. 32. The composition according to claim 25 in topical dosage form. 33. The composition according to claim 31 wherein said parenteral dosage form is an intravenous dosage form.

Details for Patent 9,562,038

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	HUMATROPE	somatropin	For Injection	019640	06/23/1987		2030-11-18
Eli Lilly And Company	HUMATROPE	somatropin	For Injection	019640	10/16/1986		2030-11-18
Eli Lilly And Company	HUMATROPE	somatropin	For Injection	019640	02/04/1999		2030-11-18
Emd Serono, Inc.	SAIZEN	somatropin	For Injection	019764	10/08/1996		2030-11-18