Chimeric small molecules for the recruitment of antibodies to cancer cells

Patent metadata

Field	Value
Publication number	US-9296708-B2
Application number	US-201414480204-A
Country	US
Kind code	B2
Filing date	Sep 8, 2014
Priority date	May 13, 2008
Publication date	Mar 29, 2016
Grant date	Mar 29, 2016

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 compound according to the chemical structure:

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

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 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 1 to 15;
L is a linker according to the chemical formula:

Or L is a polyethylene gycol, 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 acied, cysteine, glutamine, glutamic acid, glycine, histicine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan and valine; and
m is 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] 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 compound 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; and
Where X b is a bond or O, or
a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein A is

4. The compound according to claim 1 wherein A is

5. The compound according to claim 4 wherein X′ is O or N—R 1 ′ and R 1 ′ is H.

6. The compound according to claim 4 wherein X′ is O.

7. The compound according to claim 2 wherein A is

8. The compound according to claim 4 wherein Z is a monosaccharide selected from the group consisting of aldoses, ketoses and aminosugars.

9. The compound according to claim 4 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.

10. The compound according to claim 4 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, mannobiose, which may be optionally N-acetylated, melibiose, which may be optionally N-acetylated, melibiulose, which may be optionally N-acetylated, rutinose, which may be optionally N-acetylated, rutinulose, which may be optionally N-acetylated and xylobiose, which may be optionally N-acetylated.

11. 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, histicine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan and valine; and
m is an integer from 1 to 10.

12. 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.

13. 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.

Assignees

• Univ Yale

Inventors

• Spiegel David
• Murelli Ryan
• Zhang Andrew

Classifications

• A61K47/48092

  Human Necessities · mapped topic

• C07D249/04 Primary

  1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles · CPC title

• A61K31/4192

  1,2,3-Triazoles · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07K16/44 Primary

  against material not provided for elsewhere {, e.g. haptens, metals, DNA, RNA, amino acids} · CPC title