Auristatin compounds and conjugates thereof

Patent metadata

Field	Value
Publication number	US-10226535-B2
Application number	US-201314651097-A
Country	US
Kind code	B2
Filing date	Dec 10, 2013
Priority date	Dec 10, 2012
Publication date	Mar 12, 2019
Grant date	Mar 12, 2019

Abstract

An auristatin compound conjugate is provided herein. The conjugate comprises a protein based recognition-molecule (PBRM) and a polymeric carrier substituted with one or more -LD-D, the protein based recognition-molecule being connected to the polymeric carrier by LP. Each occurrence of D is independently an auristatin compound having a molecular weight ≤5 kDa. LD and LP are distinct linkers connecting the auristatin compound and PBRM to the polymeric carrier respectively. Also disclosed are polymeric scaffolds useful for conjugating with a PBRM to form a polymer-auristatin compound-PBRM conjugate described herein, compositions comprising the conjugates, methods of their preparation, and methods of treating various disorders with the conjugates or their compositions.

First claim

What is claimed is:

1. A polymeric scaffold of Formula (Ibb) useful to conjugate with a protein based recognition-molecule (PBRM):

wherein:
the scaffold comprises poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF) having a molecular weight ranging from 2 kDa to 40 kDa when the PBRM to be conjugated has a molecular weight of greater than 40 kDa, or the scaffold comprises PHF having a molecular weight ranging from 20 kDa to 300 kDa when the PBRM to be conjugated has a molecular weight of less than 80 kDa;
each occurrence of D is independently an auristatin compound of Formula (Ib):

wherein:
R 2 is H or C 1-8 alkyl;
R 3 is H, C 1-8 alkyl, C 3-8 carbocycle, X 4 —C 3-8 carbocycle, C 6-10 aryl, X 4 —C 6-10 aryl, C 3-8 heterocycle, or X 4 —C 3-8 heterocycle;
R 4 is H, C 1-8 alkyl, C 3-8 carbocycle, X 4 —C 3-8 carbocycle, C 6-10 aryl, X 4 —C 6-10 aryl, C 3-8 heterocycle, or X 4 —C 3-8 heterocycle;
R 5 is H or methyl; or
R 4 and R 5 together with the carbon atom to which they are attached form a carbocyclic ring having the formula —(CR a R b ) n —wherein each of R a and R b independently is H, C 1-8 alkyl or C 3-8 carbocycle;
R 6 is H or C 1-8 alkyl;
R 7 is H, C 1-8 alkyl, C 3-8 carbocycle, X 4 —C 3-8 carbocycle, C 6-10 aryl, X 4 —C 6-10 aryl, C 3-8 heterocycle, or X 4 —C 3-8 heterocycle;
each R 8 independently is H, OH, C 1-8 alkyl, C 3-8 carbocycle or O—(C 1-8 alkyl);
each X 4 independently is C 1-10 alkylene or C 3-10 cycloalkylene;
R 9 is H or C 1-8 alkyl;
R 18 is —C(R 8 ) 2 —C(R 8 ) 2 —C 6-10 aryl, —C(R 8 ) 2 —C(R 8 ) 2 —(C 3-8 heterocycle), —C(R 8 ) 2 —C(R 8 ) 2 —(C 3-8 carbocycle), or selected from

Z 1 is O, S, or NR 34 ;
R 31 is H, OH, N(R 34 ) 2 , C 1-8 alkyl, C 3-8 carbocycle, O—(C 1-8 alkyl), C 6-10 aryl, X 4 —C 6-10 aryl, X 4 —(C 3-8 carbocycle), C 3-8 heterocycle, X 4 —(C 3-8 heterocycle), C 1-8 alkylene-NH 2 , or (CH 2 ) 2 SCH 3 ; or R 31 is an oxygen atom which forms a carbonyl unit (C═O) with the carbon atom to which it is attached and one hydrogen atom on this carbon atom is replaced by one of the bonds in the (C═O) double bond;
R 32 is C 6-10 -aryl or C 3-8 heterocycle;
R 33 is H, OH, N(R 34 ) 2 , C 1-8 alkyl, C 3-8 carbocycle, O—(C 1-8 alkyl), C 6-10 aryl, C 1-8 alkyl-C 6-10 aryl, C 1-8 alkyl-(C 3-8 carbocycle), C 3-8 heterocycle, or C 1-8 alkyl-(C 3-8 heterocycle);
each R 34 independently is H or C 1-8 alkyl;
R 11 is H, OH, N(R 34 ) 2 , C 1-20 alkyl, C 6-10 aryl, C 3-8 heterocycle, —(R 13 O) s —R 14 , —(R 13 O)s—CH(R 15 ) 2 or —[C(R 50 R 51 )] b —R 52 ;
R 13 is C 2-8 alkyl;
R 14 is H or C 1-8 alkyl;
R 15 is H, COOH, —(CH 2 ) o —N(R 16 ) 2 , —(CH 2 ) o —SO 3 H, or —(CH 2 ) o —SO 3 —C 1-8 alkyl;
R 16 is H, C 1-8 alkyl, or —(CH 2 ) o —COOH;
each of R 50 and R 51 independently is hydrogen, C 1-6 alkyl, C 6-10 aryl, hydroxylated C 6-10 aryl, polyhydroxylated C 6-10 aryl, 5 to 12-membered heterocycle, C 3-8 cycloalkyl, hydroxylated C 3-8 cycloalkyl, polyhydroxylated C 3-8 cycloalkyl or a side chain of a natural or unnatural amino acid;
R 52 is OH, NHR 53 , COOH, R 82 —C(O)(CH 2 ) c —C(H)(R 53 )—N(H)(R 53 ), R 82 —C(O)(CH 2 ) d —(O—CH 2 —CH 2 ) h —N(H)(R 53 ) or R 82 —(C(O)—CH(X 2 )—NH) d —R 77 ;
each R 53 independently is hydrogen, C 1-6 alkyl, C 6-10 aryl, C 3-8 cycloalkyl, COOH, or COO—C 1-6 alkyl;
X 2 is a side chain of a natural or unnatural amino acid;
R 77 is hydrogen or X 2 and NR 77 form a nitrogen containing cyclic compound;
R 82 is NH or oxygen;
n is an integer from 2 to 7;
s is an integer from 0 to 1000;
o is an integer from 0 to 6;
b is an integer from 1 to 6;
c is an integer from 0 to 3;
d is an integer from 1 to 3; and
h is an integer from 1 to 12;
L D1 is a carbonyl-containing moiety;
L D2 is a moiety of Formula (Iaa):
-A a -W w —Y y —   (Iaa)

in which
-A- is a Stretcher unit and is proximal to the polymeric carrier;
a is an integer 0 or 1;
each —W— is independently an amino acid unit;
w is an integer from 0 to 12;
—Y— is a self-immolative or non-self-immolative Spacer unit and is proximal to D; and
y is an integer from 0 to 2;
wherein at least one of a, w, and y is not 0;
each occurrence of

 in

 is independently a first linker that contains a biodegradable bond so that when the bond is broken, D is released in an active form for its intended therapeutic effect; in which the

 in

 between L D1 and L D2 denotes direct or indirect attachment of L D2 to L D1 ;
each occurrence of

 is independently a second linker not yet connected to the PBRM, in which L P2 is a moiety containing a functional group that is capable of forming and not yet formed a covalent bond with a functional group of a PBRM, and the

 in

 between L D1 and L P2 denotes direct or indirect attachment of L P2 to L D1 , and each occurrence of the second linker is distinct from each occurrence of the first linker;
m is an integer from 1 to 2200,
m 1 is an integer from 1 to 660,
m 2 is an integer from 1 to 300,
m 3 is an integer from 1 to 110, and
the sum of m, m 1 , m 2 and m 3 ranges from 15 to about 2200.

2. The scaffold of claim 1 , wherein -A- is

wherein
R 48 is proximal to D and is —C(O), NH or O;
X 3 is —O—or —NH;
R 17 is —C 1-10 alkylene-, —C 3-8 carbocyclo-, C 1-30 heteroalkylene, —O—(C 1-8 alkyl)-, -arylene-, —C 1-10 alkylene-arylene-, -arylene-C 1-10 alkylene-, —C 1-10 alkylene-(C 3-8 carbocyclo)-, —(C 3-8 carbocyclo)-C 1-10 alkylene-, —C 3-8 heterocyclo-, —C 1-10 alkylene-(C 3-8 heterocyclo)-, —(C 3-8 heterocyclo)-C 1-10 alkylene-, and —(CH 2 CH 2 O) h —(CH 2 ) c , in which c is an integer from 0 to 3 and h is an integer from 1 to 12; and
ring A is cycloalkyl or heterocycloalkyl.

3. The scaffold of claim 2 , wherein -A- is

4. The scaffold of claim 1 , wherein W is

in which the carbonyl group is proximal to D and the amino group is proximal to the PHF; and R 19 is hydrogen, methy

Assignees

• Mersana Therapeutics Inc

Inventors

• Yurkovetskiy Aleksandr V
• Yin Mao
• Lowinger Timothy B
• Stevenson Cheri A
• Conlon Patrick R

Classifications

• C07K17/08

  the carrier being a synthetic polymer · CPC title

• C08G4/00

  Condensation polymers of aldehydes or ketones with polyalcohols; Addition polymers of heterocyclic oxygen compounds containing in the ring at least once the grouping —O—C—O— (of cyclic oligomers of aldehydes C08G2/00) · CPC title

• A61K47/59 Primary

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes · CPC title

• A61K47/48192 Primary

  Human Necessities · mapped topic