Chimeric small molecules for the recruitment of antibodies to cancer cells

Patent metadata

Field	Value
Publication number	US-12084517-B2
Application number	US-202318206937-A
Country	US
Kind code	B2
Filing date	Jun 7, 2023
Priority date	May 13, 2008
Publication date	Sep 10, 2024
Grant date	Sep 10, 2024

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.

First claim

The invention claimed is:

1. A composition in pharmaceutical dosage form in combination with a pharmaceutically acceptable carrier, additive or excipient, comprising an anticancer effective amount of a compound according to the chemical structure:

Wherein each 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 b is a bond, O, CH 2 , NR 1 or S;
B is a cell binding moiety according to the chemical formula:

Wherein 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 10;
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;
Wherein R a is H, C 1 -C 3 alkyl or alkanol or together with R a forms a proline side chain with R 3 ;
R 3 forms a proline side chain with R a or R 3 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 12; 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 15;
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 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 composition according to claim 1 wherein A is

Where Y′ is H;
X is O, CH 2 , 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.

3. The composition 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 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 12.

4. The composition 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 group.

5. The composition according to claim 1 wherein said linker is a group according to the formula:

Wherein m is an integer from 1 to 8.

6. The composition 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 12; and
[CON] is attached to A or B through linker L.

7. The composition according to claim 1 according to the chemical structure:

Where n is an integer from 1 to 12; and
X is

Where Y N , Y N1 and Y′ is H or NO 2 ; with the proviso that at least two of Y N , Y N1 and Y′ is NO 2 , or a pharmaceutically acceptable salt thereof.

8. The composition according to claim 7 wherein X is

and Y′ is H or NO 2 .

9. The composition according to claim 8 wherein n is an integer from 1-8.

10. The composition according to claim 1 in combination with an additional anticancer agent.

11. The composition according to claim 2 in combination with an additional anticancer agent.

12. The composition according to claim 4 in combination with an additional anticancer agent.

13. The composition according to claim 10 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof.

14. The composition according to claim 11 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof.

15. The composition according to claim 12 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof.

16. The composition according to claim 1 in parenteral dosage form.

17. The composition according to claim 2 in parenteral dosage form.

18. The composition according to claim 16 wherein said parenteral dosage form is an intravenous dosage form.

19. The composition according to claim

Assignees

• Univ Yale

Inventors

• Spiegel David
• Murelli Ryan
• Zhang Andrew

Classifications

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title

• A61K47/6869

  the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate · CPC title

• A61K47/68

  the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment · CPC title

• A61K47/646

  the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines · CPC title

• A61K47/6873

  the antibody targeting an immunoglobulin; the antibody being an anti-idiotypic antibody · CPC title