CHIMERIC SMALL MOLECULES FOR THE RECRUITMENT OF ANTIBODIES TO CANCER CELLS

• US 20110201563A1
• Filed: 05/13/2009
• Published: 08/18/2011
• Est. Priority Date: 05/13/2008
• Status: Active Grant

• Current Assignee: Yale University
• Original Assignee: Yale University
• Inventors: Zhang, Andrew, Spiegel, David, Murelli, Ryan
• Granted Patent: US 8,859,509 B2
• Time in Patent Office: Days
• US Class Current: 514/25
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/555 pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
• CPC Class Codes: A61K 47/646 the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07K 16/44 against material not provided for elsewhere , e.g. haptens, metals, DNA, RNA, amino acids

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.

Claims

1. A compound according to the chemical structure:

2. The compound according to claim 1 wherein

A is an antibody binding moiety according to the chemical formula:

3. The compound according to claim 2 wherein A is

4. The compound according to claim 1 wherein A is

5. The compound according to claim 3 wherein A is

8. The compound according to claim 3 wherein A is

9. The compound according to claim 5 wherein Z is a monosaccharide selected from the group consisting of aldoses, ketoses and aminosugars.

10. The compound according to claim 5 wherein Z is a monosaccharide selected from the group consisting of D-glyceraldehdye, D-erythrose, D-Threose, D-ribose, D-arabinose, D-xylose, D-lyxose, D-allose, D-altrose, D-Glucose, D-Mannose, D-gulose, D-idose, D-galactose, dihydroxyacetone, D-erythrulose, D-ribulose, D-xylulose, D-Psicone, D-Fructose, D-Sorbose, D-Tagatose, galactoseamine, sialic acid and N-acetylglucosamine.

11. The compound according to claim 5 wherein Z is a disaccharide selected from the group consisting of sucrose, which may be optionally N-acetylated, lactose, which may be optionally N-acetylated, maltose, which may be optionally N-acetylated, trehalose, which may be optionally N-acetylated, cellobiose, which may be optionally N-acetylated, kojibiose, which may be optionally N-acetylated, nigerose, which may be optionally N-acetylated, isomaltose, which may be optionally N-acetylated, β

,β

-trehalose, which may be optionally N-acetylated, sophorose, which may be optionally N-acetylated, laminaribiose, which may be optionally N-acetylated, gentiobiose, which may be optionally N-acetylated, turanose, which may be optionally N-acetylated, maltulose, which may be optionally N-acetylated, palatinose, which may be optionally N-acetylated, gentiobiluose, which may be optionally N-acetylated, mannobiose, melibiose, which may be optionally N-acetylated, melibiulose, which may be optionally N-acetylated, rutinose, which may be optionally N-acetylated, rutinulose and xylobiose.

12. The compound according to claim 2 wherein said linker is group according to the chemical formula:

13. The compound according to claim 1 wherein [CON] is a bond or a

14. The compound according to claim 1 wherein said linker is a group according to the formula:

15. A compound according to claim 2 wherein A is

16. A compound according to claim 2 as set forth in attached FIG. 7.

17. A compound according to claim 1 as set forth in attached FIG. 8.

18. A pharmaceutical composition comprising an effective amount of a chimeric compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient.

19. The composition according to claim 18 wherein said composition further comprises an effective amount of an additional anticancer agent.

20. The composition according to claim 19 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof.

21. The composition according to claim 19 wherein said agent is aldesleukin;

aemtuzumab;

alitretinoin;

allopurinol;

altretamine;

amifostine;

anastrozole;

arsenic trioxide;

aparaginase;

BCG 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;

domostanolone propionate;

eliott'"'"'s B soution;

epirubicin;

eoetin alfa estramustine;

etoposide phosphate;

etoposide (VP-16);

exemestane;

flgrastim;

floxuridine (intraarterial);

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;

nfetumomab;

LOddC;

orelvekin;

oxaliplatin;

paclitaxel;

pamidronate;

pegademase;

Pegaspargase;

Pegfilgrastim;

pentostatin;

pipobroman;

plicamycin;

mithramycin;

porfimer sodium;

procarbazine;

quinacrine;

Rasburicase;

Rituximab;

Sargramostim;

streptozocin;

talbuvidine (LDT);

talc;

tamoxifen;

temozolomide;

teniposide (VM-26);

testolactone;

thioguanine (6-TG);

thiotepa;

topotecan;

toremifene;

Tositumomab;

Trastuzumab;

tretinoin (ATRA);

Uracil Mustard;

vairubicin;

valtorcitabine (monoval LDC);

vinblastine;

vinorelbine;

zoledronate; and

mixtures thereof.

22. The composition according to claim 18 or 19 further comprising at least one antiandrogen compound.

23. The composition according to claim 18 or 19 further comprising at least one GNRh modulator.

24. The composition according to claim 18 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.

25. The composition according to claim 18 further comprising at least one agent selected from the group consisting of an enlarged prostate agent, eulexin, flutamide, goserelin, leuprolide, lupron, nilandron, nilutamide, zoladex and mixtures thereof.

26. The composition according to claim 18 in oral dosage form.

27. The composition according to claim 18 in parenteral dosage form.

28. The composition according to claim 27 wherein said parenteral dosage form is an intravenous dosage form.

29. The composition according to claim 18 in topical dosage form.

30. A method of treating prostate cancer in a patient in need thereof comprising administering to said patient an effective amount of a compound according to claim 1.

31. The method according to claim 30 wherein said prostate cancer is metastatic prostate cancer.

32. A method of treating prostate cancer in a patient in need thereof comprising administering to said patient an effective amount of a composition according to claim 18.

33. A method of inhibiting metastasis of prostate cancer in a patient in need thereof comprising administering to said patient an effective amount of a compound according to claim 1 to said patient.

34. A method of treating cancer in a patient in need thereof comprising administering to said patient a composition according to claim 18.

35. The method according to claim 34 wherein said cancer is stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, testis, bladder, renal, brain/CNS, head and neck, throat, Hodgkin'"'"'s disease, non-Hodgkin'"'"'s lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing'"'"'s sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms'"'"' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx, esophagus, larynx, kidney cancer or lymphoma.

36. A method of treating prostate cancer in a patient wherein said patient also has another form of cancer said method comprising administering to said patient an effective amount of a composition according to claim 19.

37. The method according to claim 36 wherein said other form of cancer is stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, testis, bladder, renal, brain/CNS, head and neck, throat, Hodgkin'"'"'s disease, non-Hodgkin'"'"'s lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing'"'"'s sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms'"'"' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx, esophagus, larynx, kidney cancer or lymphoma.

6-7. -7. (canceled)

38-43. -43. (canceled)