Immune response modifier compositions and methods

Patent metadata

Field	Value
Publication number	US-10005772-B2
Application number	US-51946307-A
Country	US
Kind code	B2
Filing date	Dec 20, 2007
Priority date	Dec 22, 2006
Publication date	Jun 26, 2018
Grant date	Jun 26, 2018

Abstract

The present invention provides an immune response modifier (IRM) composition that includes an IRM moiety and a second active moiety covalently linked to the IRM moiety, wherein the covalent link comprises a labile bond directly attached to the IRM moiety.

First claim

What is claimed is:

1. An immune response modifier (IRM) conjugate of the Formula:

wherein:
when taken together, R A and R B form a fused aryl ring wherein the aryl ring is unsubstituted;
R 1 is selected from the group consisting of:
—R 4 ,
—X—R 4 ,
—X—Y—R 4 ,
—X—Y—X—Y—R 4 , and
—X—R 5 ;

R 2 is selected from the group consisting of:
—R 4 ,
—X—R 4 ,
—X—Y—R 4 , and
—X—R 5 ;

R 3 is selected from the group consisting of:
—Z—R 4 ,
—Z—X—R 4 ,
—Z—X—Y—R 4 ,
—Z—X—Y—X—Y—R 4 , and
—Z—X—R 5 ;

X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more —O— groups;
Y is selected from the group consisting of:
—O—,
—S(O) 0-2 —,
—S(O) 2 —N(R 8 )—,
—C(R 6 )—,
—C(R 6 )—O—,
—O—C(R 6 )—,
—O—C(O)—O—,
—N(R 8 )-Q-,
—C(R 6 )—N(R 8 )—,
—O—C(R 6 )—N(R 8 )—,
—C(R 6 )—N(OR 9 )—,
—O—N(R 8 )-Q-,
—O—N═C(R 4 )—,
—C(═N—O—R 8 )—,
—CH(—N(—O—R 8 )-Q-R 4 )—,

Z is a bond or —O—;
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
R 5 is selected from the group consisting of

R 6 is selected from the group consisting of ═O and ═S;
R 7 is C 2-7 alkylene;
R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R 10 is C 3-8 alkylene;
A is selected from the group consisting of —O—, —C(O)—, —S(O) 0-2 —, and N(R 4 )—;
A′ is selected from the group consisting of —O—, —S(O) 0-2 —, —N(-Q-R 4 )—, and —CH 2 —; Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, —C(R 6 )—S—, and —C(R 6 )—N(OR 9 )—;
V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;
W is selected from the group consisting of a bond, —C(O)—, and S(O) 2 —;
a and b are independently integers from 1 to 6 with the proviso that a+b is ≤7;
SAM is a second active moiety wherein the SAM is other than a second IRM moiety;
FG C is selected from the group consisting of

Linker C is the reaction product of Linker A-FG A and Linker B-FG B ;
Linker A is C 1-10 alkylene, alkylene-arylene, arylene-C 1-10 alkylene, C 3 -C 8 heterocyclene, C 1-10 alkylene-C 3-8 heterocyclene, or C 3-8 heterocyclene-C 1-10 alkylene;
Linker B is C 1-10 alkylene, O—C 1-8 alkylene-arylene, alkylene-arylene, arylene-C 1-10 alkylene, C 3 -C 8 heterocyclene, alkylene-C 3-8 heterocyclene, or C 3-8 heterocyclene-C 1-10 alkylene;
p is an integer from 1 to 20; and
FG A and FG B are capable of reacting with each other to form a covalent bond.

2. The conjugate of claim 1 wherein the second active moiety comprises a targeting moiety.

3. The conjugate of claim 2 wherein the targeting moiety comprises an active targeting moiety.

4. The conjugate of claim 3 wherein the targeting moiety comprises an antibody, LHRH receptor ligand, or folic acid receptor ligand.

5. The conjugate of claim 2 wherein the targeting moiety comprises a passive targeting moiety.

6. The conjugate of claim 2 wherein the targeting moiety comprises a nanoparticle having a diameter of from about 50 nm to about 200 nm.

7. The conjugate of claim 1 wherein FG C is

8. The conjugate of claim 1 , wherein FG A is a nucleophilic group that is reactive to FG B , and FG B is an electrophilic group.

9. The conjugate of claim 1 , wherein FG A is an electrophilic group that is reactive to FG B , and FG B is a nucleophilic group.

10. The conjugate of claim 1 , wherein FG A is selected from the group consisting of

wherein LG is a leaving group selected from Cl, Br, I, O-mesyl or O-tosyl, and AAG is an acid activating group selected from N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide activated acids, N-hydroxysuccinimide, sulfo-N-hydroxysuccinimide, 4-nitrophenyl, chloride, bromide, anhydride, mixed anhydride, pehtaflurophenyl ester, and tetraflurophenyl ester.

11. The conjugate of claim 1 , wherein FG B is selected from the group consisting of

Assignees

• Stoermer Doris
• Griesgraber George W
• Kshirsagar Tushar A
• 3M Innovative Properties Co

Inventors

• Stoermer Doris
• Griesgraber George W
• Kshirsagar Tushar A

Classifications

• A61P37/00

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• C07D471/04 Primary

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