Chimeric small molecules for the recruitment of antibodies to cancer cells
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.
1. A compound for use in the treatment of prostate cancer in a patient according to the chemical structure:
Wherein n is independently 1 or 2;
A is an antibody binding moiety according to the chemical structure:
Where 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 a 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;
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 1 to 15;
L is a linker according to the chemical formula:
Or L is a polyethylene glycol, polypropylene glycol or polypropylene-co-polyethylene glycol linker having between 1 and 20 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 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 and valine; and
Each m is independently an integer from 1 to 30; 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], 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 an integer from 0 to 100;
D is
or a bond,
with the proviso that Z, Z′ and D are not each simultaneously bonds;
j is an integer from 1 to 100;
m′ is an integer from 1 to 100;
n′ is an integer from 1 to 100; and
X″ 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 , —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 compound according to claim 1 wherein A is
Where Y′ is H;
X is O, CH 2 or NR 1 ;
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 or oligosaccharide;
X b is a bond, O, CH 2 , NR 1 or S; and
Each n is 1, or
a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 wherein A is
4. The compound according to claim 2 wherein X′ is O or N—R 1 ′ and R 1 ′ is H.
5. The compound according to claim 2 wherein X′ is O.
6. The compound according to claim 3 wherein A is
7. The compound according to claim 3 wherein Z is a monosaccharide selected from the group consisting of aldoses, ketoses and aminosugars.
8. The compound according to claim 3 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-Psicose, D-Fructose, D-Sorbose, D-Tagatose, galactoseamine, sialic acid and N-acetylglucosamine.
9. The compound according to claim 1 wherein Z is a disaccharide selected from the group consisting of sucrose, lactose, maltose, trehalose, cellobiose, kojibiose, isomaltose, β,β-trehalose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, palatinose, mannobiose, melibiose, melibiulose, rutinose, rutinulose, and xylobiose.
10. The compound according to claim 1 wherein said linker is group according to the chemical formula:
Where R a is H or forms a proline side chain with R 3 and R 3 forms a proline side chain with R a or is a side chain derived from an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acied, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan and valine; and
Each m is independently an integer from 1 to 15.
11. The compound according to claim 1 wherein [CON] is a
group,
where X 2 is O, S or NR 4 ; and
R 4 is H or a C 1 -C 3 alkyl or alkanol group.
12. The compound according to claim 1 wherein said linker is a group according to the formula:
Wherein m is an integer from 1 to 10.
13. A compound according to claim 1 wherein A is
where X is O or NH;
L is a
group;
where m is an integer from 2 to 15; and
[CON] is attached to A or B through linker L.
14. A compound according to claim 1 according to the chemical structure:
Where n is an integer from 2 to 15; and
X is
Where Y N , Y N1 and Y′ is H or NO 2 ; with the proviso that at least one of Y N , Y N1 and Y′ is NO 2 , or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 14 wherein X is
and Y′ is H or NO 2 .
16. The compound according to claim 15 wherein Y′ is H.
17. The compound according to claim 14 wherein n is an integer from 1-8.
18. The compound according to claim 14 wherein n is an integer from 1-4.
19. A pharmaceutical composition comprising an anticancer effective amount of a chimeric compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient, optionally in combination with an anticancer effective amount of an additional anticancer agent.
20. The composition according to claim 19 wherein said composition further comprises an anticancer effective amount of an additional anticancer agent.
21. The composition according to claim 20 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof.
22. The composition according to claim 19 in parenteral dosage form.
23. The composition according to claim 22 wherein said parenteral dosage form is an intravenous dosage form.
24. 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 19 .
25. The method according to claim 24 wherein said prostate cancer is metastatic prostate cancer.
26. 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 20 .