Claims for Patent: 8,859,509

Summary for Patent: 8,859,509

Title:	Chimeric small molecules for the recruitment of antibodies to cancer cells
Abstract:	The present invention relates to chimeric chemical compounds which are used to recruit antibodies to cancer cells, in particular, prostate cancer cells or metastasized prostate cancer cells. The compounds according to the present invention comprise an antibody binding terminus (ABT) moiety covalently bonded to a cell binding terminus (CBT) through a linker and optionally, a connector molecule.
Inventor(s):	Spiegel; David (New Haven, CT), Murelli; Ryan (Torrington, CT), Zhang; Andrew (New Haven, CT)
Assignee:	Yale University (New Haven, CT)
Application Number:	12/991,926
Patent Claims:	1. A compound according to the chemical structure: ##STR00039## wherein A is an antibody binding moiety according to the chemical formula: ##STR00040## 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; 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; 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; X.sup.b is a bond, O, CH.sub.2, NR.sup.1or S; X'' is O, CH.sub.2, NR.sup.1; 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; n is 1 or 2; n.sup.1 is 1; B is a cell binding moiety according to the chemical formula: ##STR00041## Where X.sub.1 and X.sub.2 are each independently CH.sub.2, O, NH or S; X.sub.3 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; k is an integer from 0 to 20; L is a linker according to the chemical formula: ##STR00042## Or a linker based upon polyethylene glycol, polypropylene glycol or polypropylene-co-polyethylene glycol linker having between 1 and 100 glycol units; Where R.sub.a is H, C.sub.1-C.sub.3 alkyl or alkanol or forms a cyclic ring with R.sup.3 resulting in a proline side chain and R.sup.3 is a side chain derived from an amino acid wherein said amino acid is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, trvptophan, tyrosine and valine; and m is an integer from 1 to 45, or L is a linker according to the chemical formula: ##STR00043## 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, ##STR00044## wherein said --(CH.sub.2), group, if present in Z or Z', is bonded to [CON] if present, antibody binding terminus (ABT) or cell binding terminus (CBT); Each R is independently 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 0 to 100; D is ##STR00045## 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; and X.sup.1 is O, S or N--R, R is as defined above; and The connector moiety [CON] is an optional moiety according to the chemical structure: ##STR00046## Where X.sup.2 is O, S, NR.sup.4, S(O), S(O).sub.2, --S(O).sub.2O, --OS(O).sub.2, or OS(O).sub.2O; X.sup.3 is NR.sup.4, O or S; and R.sup.4 is H, a C.sub.1-C.sub.3 alkyl or alkanol group, or a --C(O)(C.sub.1-C.sub.3) group; or a pharmaceutically acceptable salt, solvate or polymorph thereof. 2. The compound according to claim 1 wherein A is ##STR00047## X is O or NH; Y' is H; X' is O; and Z is a bond, a monosaccharide or a disaccharide. 3. The compound according to claim 1 wherein A is ##STR00048## where X is O or NR.sup.1; and R.sup.1is H, a C.sub.1-C.sub.3 alkyl group, or a --C(O)(C.sub.1C.sub.3) group, or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1 wherein said linker is a group according to the chemical formula: ##STR00049## Where R.sub.a is H 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 10. 5. The compound according to claim 1 wherein [CON] is ##STR00050## group where X.sup.2 is a NR.sup.4 group and R.sup.4 is H or a C.sub.1-C.sub.3 alkyl group. 6. The compound according to claim 1 wherein said linker is a group according to the formula: ##STR00051## Wherein m is an integer from 1 to 15. 7. A compound according to claim 1 wherein A is ##STR00052## X is O or NH; L is a ##STR00053## group; where m is an integer from 5 to 15; and [CON] is attached to A or B through linker L. 8. A pharmaceutical composition comprising an anti-cancer effective amount of a chimeric compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient. 9. The composition according to claim 8 wherein said composition further comprises an effective amount of an additional anticancer agent. 10. The composition according to claim 9 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof. 11. The composition according to claim 9 wherein said agent is aldesleukin; aemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; aparaginase; Bacillus Calmette-Guerin Live; bexarotene capsules; bexarotene gel; bleomycin; busulfan intravenous; busulfan oral; calusterone; capecitabine; carboplatin; carmustine; carmustine with poifeprosan 20 iplant; celecoxib; chlorarnbucil; cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin; actinomycin D; dabepoetin alfa; daunorubicin liposomal; daunorubicin, daunomycin; denileukin diftitox, dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; domostanoione propionate; eliott's B soution; epirubicin; eoetin alfa estramustine; etoposide phosphate; etoposide (VP-16); exemestane; flgrastim; floxuridine; fludarabine; fluorouracil (5-FU); fulvestrant; gemtuzumab ozogamicin; goserelin acetate; hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide; imatinib mesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan; letrozole; leucovorin; levamisole; lomustine (CCNU); rneclorethamine (nitrogen mustard); megestrol acetate; melphalan (L-PAM); mercaptopurine (6-MP); mesna; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; nofetumomab; L-O-dideoxy cytidine; orelvekin; oxaliplatin; paclitaxel; pamidronate; pegademase; Pegaspargase; Pegfilgrastim; pentostatin; pipobroman; plicamycin; mithramycin; porfimer sodium; procarbazine; quinacrine; Rasburicase; Rituximab; Sargrarnostim; streptozocin; telbivudine (LDT); talc; tarnoxifen; temozolomide; teniposide (VM-26); testolactone; thioguanine (6-TG); thiotepa; topotecan; toremifene; Tositurnornab; Trastuzumab; tretinoin (ATRA); Uracil Mustard; valrubicin; valtorcitabine (monoval LDC); vinblastine; vinorelbine; zoledronate; and mixtures thereof. 12. The composition according to claim 8 or 9 further comprising at least one antiandrogen compound. 13. The composition according to claim 8 or 9 further comprising at least one Gonadotropin releasing hormone (GNRh) modulator. 14. The composition according to claim 8 further comprising at least one agent selected from the group consisting of flutamide, bicalutamide, nilutamide, cyproterone acetate, ketoconazole, aminoglutethimide, abarelix, leuprolide, goserelin, triptorelin, buserelin, abiraterone acetate, sorafenib and mixtures thereof. 15. The composition according to claim 8 further comprising at least one agent selected from the group consisting of eulexin, flutamide, goserelin, leuprolide, lupron, nilandron, nilutamide, zoladex and mixtures thereof. 16. The composition according to claim 8 in oral dosage form. 17. The composition according to claim 8 in parenteral dosage form. 18. The composition according to claim 17 wherein said parenteral dosage form is an intravenous dosage form. 19. The composition according to claim 8 in topical dosage form. 20. A compound according to the chemical structure: ##STR00054## where n is 1 to 15, or a pharmaceutically acceptable salt thereof. 21. A compound of claim 20 according to the chemical structure: ##STR00055## or a pharnaceutically acceptable salt thereof. 22. A pharmaceutical composition comprising an anti-cancer effective amount of a chimeric compound according to claim 20 in combination with a pharmaceutically acceptable carrier, additive or excipient. 23. A pharmaceutical composition comprising an anti-cancer effective amount of a chimeric compound according to claim 21 in combination with a pharmaceutically acceptable carrier, additive or excipient. 24. The composition according to claim 22 wherein said composition further comprises an anti-cancer effective amount of an additional anticancer agent. 25. The composition according to claim 23 wherein said composition further comprises an anti-cancer effective amount of an additional anticancer agent. 26. The composition according to claim 24 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof. 27. The composition according to claim 24 wherein said agent is aldesleukin; aemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; aparaginase; Bacillus Calmette-Guerin Live; bexarotene capsules; bexarotene gel; bleotnycin; busulfan intravenous; busulfan oral; calusterone; capecitabine; carboplatin; carmustine; carmustine with poifeprosan 20 iplant; celecoxib; chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin; actinomycin D; dabepoetin alfa; daunorubicin liposomal; daunorubicin, daunomycin; denileukin diftitox, dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; domostanolone propionate; eliott's B soution; epirubicin; eoetin alfa estramustine; etoposide phosphate; etoposide (VP-16); exemestane; figrastim; floxuridine fludarabine; fluorouracil (5-FU); fulvestrant; gemtuzumab ozogamicin; goserelin acetate; hydroxyurea; Ibritumornab Tiuxetan; idarubicin; ifosfarnide; imatinib mesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan; letrozole; leucovorin; levamisole; lomustine (CCNU); meclorethamine (nitrogen mustard); megestrol acetate; melphalan (L-PAM); mercaptopurine (6-MP); mesna; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; nofetumomab L-O-dideoxy cytidine; orelveldn; oxaliplatin; paclitaxel; pamidronate; pegademase; Pegaspargase; Pegfilgrastim; pentostatin; pipobroman; plicamycin; mithramycin; porfimer sodium; procarbazine; quinacrine; Rasburicase; Rituximab; Sargramostim; streptozocin; telbivudine (LDT); talc; tamoxifen; temozolomide; teniposide (VM-26); testolactone; thioguanine (6-TG); thiotepa; topotecan; toremifene; Tositumomab; Trastuzumab; tretinoin (ATRA); Uracil Mustard; valrubicin; valtorcitabine (monoval LDC); vinblastine; vinorelbine; zoledronate; and mixtures thereof. 28. The composition according to claim 22 further comprising at least one antiandrogen compound. 29. The composition according to claim 22 further comprising at least one GNRh modulator. 30. The composition according to claim 22 further comprising at least one agent selected from the group consisting of an eulexin, flutamide, bicalutarnide, nilutamide, cyproterone acetate, ketoconazole, aminoglutethimide, abarelix, leuprolide, lupron, nilandron, nilutamide, zoladex, goserelin, triptorelin, buserelin, abiraterone acetate, sorafenib and mixtures thereof. 31. The composition according to claim 22 in parenteral dosage form. 32. The compound according to claim 1 wherein A is ##STR00056## B is a ##STR00057## group, where k is an integer from 1 to 6; L is a linker based upon polyethylene glycol having from 1 to 15 ethylene glycol units; and [CON] is a ##STR00058## group, or a pharmaceutically acceptable salt thereof. 33. The compound according to claim 1 wherein A is ##STR00059## B is a ##STR00060## group where k is an integer from 1 to 6; and L is a linker based upon polyethylene glycol having from 1 to 10 ethylene glycol units. 34. A pharmaceutical composition comprising comprising an anti-cancer effective amount of a chimeric compound according to claim 32 in combination with a pharmaceutically acceptable carrier, additive or excipient and optionally in further combination with an additional anticancer agent. 35. A pharmaceutical composition comprising comprising an anti-cancer effective amount of a chimeric compound according to claim 33 in combination with a pharmaceutically acceptable carrier, additive or excipient and optionally in further combination with an additional anticancer agent. 36. The composition according to claim 34 wherein said additional anticancer agent is antimetabolite, an inhibitor of topoisonierase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof. 37. The composition according to claim 35 wherein said additional anticancer agent is antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof. 38. The composition according to claim 34 wherein said additional anticancer agent is aldesleukin; aemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; aparaginase; Bacillus Calmette-Guerin Live; bexarotene capsules; bexarotene gel; bleomycin; busulfan intravenous; busulfan oral; calusterone; capecitabine; carboplatin; carmustine; carmustine with poifeprosan 20 iplant; celecoxib; chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinornycin; actinomycin D; dabepoetin alfa; daunoruhicin liposomal; daunorubicin, daunomycin; dnileukin diftitox, dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; domostanolone propionate; eliott's B soution; epirubicin; eoetin aifa estramustine; etoposide phosphate; etoposide (VP-16); exemestane; flgrastim; floxuridine; fludarabine; fluorouracil (5-FU); fulvestrant; gemtuzumab ozogamicin; goserelin acetate; hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide; imatinib mesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan; letrozole; leucovorin; levamisole; lomustine (CCNU); meclorethamine (nitrogen mustard); megestrol acetate; melphalan (L-PAM); mercaptopurina (6-MP); mesna; metbotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; nofetumomab; L-O-dideoxy cytidine; orelvekin; oxaliplatin; paclitaxel; pamidronate; pegademase; Pegaspargase; Pegfilgrastim; pentostatin; pipobroman; plicaxnycin; mithramycin; porfimer sodium; procarbazine; quinacrine; Rasburicase; Rituximab; Sargramostini; streptozocin; telbivudine (LDT); talc; tamoxifen; temozolomide; teniposide (VM-26); testolactone; thioguanine (6-TG); thiotepa; topotecan; toremifene; Tositumomab; Trastuzumab; tretinoin (ATRA); Uracil Mustard; valrubicin; valtorcitabine (monoval LDC); vinblastine; vinorelbine; zoledronate; and mixtures thereof. 39. The composition according to claim 35 wherein said additional anticancer agent is aldesleukin; aemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; aparaginase; Bacillus Calmette-Guerin Live; bexarotene capsules; bexarotene gel; bleomycin; busulfan intravenous; busulfan oral; calusterone; capecitabine; carboplatin; carmustine; carmustine with poifeprosan 20 iplant; celecoxib; chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin; actinomycin D; dabepoetin alfa; daunorubicin liposomal; daunorubicin, daunomycin; dnileukin diftitox, dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; domostariolone propionate; eliott's B soution; epinibicin; eoetin alfa estramustine; etoposide phosphate; etoposide (VP-16); exemestane; flgrastim; floxuridine; fludarabine; fluorouracil (5-FU); fulvestrant; gemtuzumab ozogamicin; goserelin acetate; hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide; imatinib mesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan; letrozole; leucovorin; levamisole; lomustine (CCNU); meclorethamine (nitrogen mustard); megestrol acetate; melphalan (L-PAM); mercaptopurine (6-MP); mesna; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; nofetumomab; L-O-dideoxy cytidine; orelvekin; oxatiplatin; paclitaxel; pamidronate; pegademase; Pegaspargase; Pegfligrastim; pentostatin; pipobroman; plicamycin; mithrarmycin; porfimer sodium; procarbazinc; quinacrine; Rasburicase; Rituximab; Sargramostim; streptozocin; telbivudine (LDT); talc; tamoxifen; temozolomide; teniposide (VM-26); testolactone; thioguanine (6-TG); thiotepa; topotecan; toremifene; Tositumomab; Trastuzumab; tretinoin (ATRA); Uracil Mustard; valrubicin; valtorcitabine (monoval LDC); vinblastine; vinorelbine; zoledronate; and mixtures thereof.

Details for Patent 8,859,509

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Teknika Llc	TICE BCG	bcg live	For Injection	102821	06/21/1989		2028-05-13
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2028-05-13
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2028-05-13
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2028-05-13
Clinigen, Inc.	PROLEUKIN	aldesleukin	For Injection	103293	05/05/1992		2028-05-13
Partner Therapeutics, Inc.	LEUKINE	sargramostim	For Injection	103362	03/05/1991		2028-05-13
Partner Therapeutics, Inc.	LEUKINE	sargramostim	Injection	103362	03/05/1991		2028-05-13