Chimeric small molecules for the recruitment of antibodies to cancer cells

1. 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 the chemical structure:

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

Y′ is H or NO 2 ;

X is O, CH 2 , NR 1 , S(O), S(O) 2 , —S(O) 2 O, —OS(O) 2 , or OS(O) 2 O;

R 1 is H, a C 1 -C 3 alkyl group, or a —C(O)(C 1 -C 3 ) group;

X′ is CH 2 , O, N—R 1′ or S;

R 1′ is H or C 1 -C 3 alkyl;

Z is a bond, a monosaccharide, disaccharide, oligosaccharide, glycoprotein or glycolipid;

X b is a bond, O, CH 2 , NR 1 or S;

X″ is O, CH 2 , NR 1 ;

R 1 is H, a C 1 -C 3 alkyl group or a —C(O)(C 1 -C 3 ) group;

n is 1 or 2;

n 1 is 1;

B is a cell binding moiety according to the chemical formula:

Where X 1 and X 2 are each independently CH 2 , O, NH or S;

X 3 is O, CH 2 , NR 1 , S(O), S(O) 2 , —S(O) 2 O, —OS(O) 2 , or OS(O) 2 O;

R 1 is H, a C 1 -C 3 alkyl group, or a —C(O)(C 1 -C 3 ) group;

k is an integer from 0 to 20;

L is a linker according to the chemical formula:

Or a polypropylene glycol or polypropylene-co-polyethylene glycol linker having between 1 and 100 glycol units;

Where R a is H, C 1 -C 3 alkyl or alkanol or forms a proline side chain with R 3 ;

R 3 forms a proline side chain with R a or 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, tryptophan, tyrosine and valine; and

m is an integer from 1 to 45, or

L is a linker according to the chemical formula:

Where Z and Z′ are each independently a bond, —(CH 2 ) i —O, —(CH 2 ) i —S, —(CH 2 ) i —N—R,

wherein said —(CH 2 ) i 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 1 -C 3 alkyl or alkanol group;

Each R 2 is independently H or a C 1 -C 3 alkyl group;

Each Y is independently a bond, O, S or N—R;

Each i is independently 0 to 100;

D is

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; and

X 1 is O, S or N—R,

R is as defined above; and

[CON] is a bond or a moiety according to the chemical structure:

Where X 2 is O, S, NR 4 , S(O), S(O) 2 , —S(O) 2 O, —OS(O) 2 , or OS(O) 2 O;

X 3 is NR 4 , O or S; and

R 4 is H, a C 1 -C 3 alkyl or alkanol group, or a —C(O)(C 1 -C 3 ) group; or

a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 wherein A is

X is O or NH;

Y′ is H;

X′ is O; and

Z is a bond, a monosaccharide or a disaccharide, or

a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 wherein A is

where X is O or NR 1 ; and

R 1 is H, a C 1 -C 3 alkyl group, or a —C(O)(C 1 -C 3 ) group, or

a pharmaceutically acceptable salt thereof.

4. The method according to claim 1 wherein said linker is a group according to the chemical formula:

Where R a is H, C 1 -C 3 alkyl or alkanol or forms a proline side chain with R 3 ;

R 3 forms a proline side chain with R a or 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, tryptophan, tyrosine and valine; and

m is an integer from 1 to 45, or

m is an integer from 1 to 10.

5. The method according to claim 1 wherein [CON] is, a

group or a

group where X 2 is a NR 4 group and R 4 is H or a C 1 -C 3 alkyl group.

6. The method according to claim 1 wherein said linker is a group according to the formula:

wherein m is an integer from 1 to 15.

7. The method according to claim 1 wherein A is

X is O or NH;

L is a

group;

where m is an integer from 5 to 15; and

[CON] is attached to A or B through linker L.

8. The method according to claim 1 wherein said Linker group L is based upon a polyethylene glycol having between 1 and 15 glycol units.

9. The method according to claim 1 wherein said Linker group L is based upon a polyethylene glycol having between 6 and 10 glycol units.

10. The method according to claim 1 wherein A is

B is a

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

group,

or a pharmaceutically acceptable salt thereof.

11. 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 the chemical structure:

where n is 1 to 15, or

a pharmaceutically acceptable salt thereof.

12. 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 the chemical structure:

where n is 0 to 8, or

a pharmaceutically acceptable salt thereof.

13. The method according to claim 1 wherein said prostate cancer is metastatic prostate cancer.

14. The method according to claim 11 wherein said compound is co-administered with an anti-cancer effective amount of an additional anticancer agent.

15. The method according to claim 12 wherein said compound is co-administered with an anti-cancer effective amount of an additional anticancer agent.

16. The method according to claim 13 wherein said compound is co-administered with an anti-cancer effective amount of an additional anticancer agent.

17. The method according to claim 14 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof.

18. The method according to claim 14 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 polifeprosan 20 implant; 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 solution; 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); 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; 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.

19. The method according to claim 1 wherein said compound is co-administered with at least one antiandrogen compound.

20. The method according to claim 1 wherein said compound is co-administered with at least one GNRh modulator.

21. The method according to claim 1 wherein said compound is co-administered with at least one agent selected from the group consisting of eulexin, flutamide, bicalutamide, nilutamide, cyproterone acetate, ketoconazole, aminoglutethimide, abarelix, leuprolide, lupron, nilandron, nilutamide, zoladex, goserelin, triptorelin, buserelin, abiraterone acetate, sorafenib and mixtures thereof.

22. The method according to claim 1 wherein said compound is administered in parenteral dosage form.

23. The method according to claim 11 wherein said compound is administered in parenteral dosage form.

24. The method according to claim 12 wherein said compound is administered in parenteral dosage form.

25. 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 as set forth in claim 1 .

26. 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 as set forth in claim 11 .

27. 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 as set forth in claim 12 .