Small molecule conjugates for intracellular delivery of biologically active compounds

Patent metadata

Field	Value
Publication number	US-9301990-B2
Application number	US-201313917524-A
Country	US
Kind code	B2
Filing date	Jun 13, 2013
Priority date	Dec 29, 2010
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

Abstract

The invention provides novel compounds and conjugates of these compounds useful for the delivery of biologically active substances. Further novel design criteria for chemically stabilized siRNA particular useful when covalently attached to a delivery polymer to achieve in vivo mRNA knock down are disclosed therein.

First claim

What is claimed is:

1. A compound of formula (I):

wherein
Y is a linker group selected from —(CH 2 ) 3 — or —C(O)—NH—(CH 2 —CH 2 —O) p —CH 2 —CH 2 —;
R 1 is —(C1-6) alkyl;
—(CH 2 )-naphthyl; or
—(CH 2 ) m -phenyl, which phenyl is unsubstituted or up to four times substituted with a substituent independently selected from
—NO 2 ,
—CN,
Halogen,
—O—(CH 2 )-phenyl,
—O—(C1-6) alkyl, or
—C(O)—NH 2 ;

R 2 is hydrogen;
—(CH 2 ) k —NH—C(Ph) 3 , which phenyl rings are unsubstituted or independently substituted with —O—(C1-4)alkyl;
—(CH 2 ) k —C(O)—NH 2 ;
—(CH 2 ) k -phenyl;
—(C1-6) alkyl, which is unsubstituted or once substituted with —S—CH 3 ;

R 3 is —NH-phenyl, which phenyl group is further substituted with a substituent independently selected from
—(CH 2 )—OH; or
—(CH 2 )—O—C(O)—O-(4-nitro-phenyl);

k is 1, 2, 3, 4, 5 or 6;
m is 1, 2, 3 or 4;
n is 0 or 1; and
p is an integer from 1 to 20.

2. The compound of claim 1 , having the conformation as shown in formula (Ia):

3. The compound of claim 1 wherein Y is —(CH 2 ) 3 —.

4. The compound of claim 3 , wherein:
Y is —(CH 2 ) 3 —;
R 2 is —(CH 2 ) k —NH—C(Ph) 3 , which phenyl rings are unsubstituted or independently substituted with —O—(C1-4)alkyl; and
R 3 is —NH-phenyl, which phenyl group is further substituted with —(CH 2 )—O—C(O)—O-(4-nitro-phenyl);
n is 0; and
R 1 and k are as defined in claim 1 .

5. The compound of claim 1 , wherein Y is —C(O)—NH—(CH 2 —CH 2 —O) p —CH 2 —CH 2 —.

6. The compound of claim 5 , wherein:
Y is —C(O)—NH—(CH 2 —CH 2 —O) p —CH 2 —CH 2 —;
R 2 is —(CH 2 ) k —NH—C(Ph) 3 , which phenyl rings are unsubstituted or independently substituted with —O—(C1-4)alkyl; and
R 3 is —NH-phenyl, which phenyl group is further substituted with —(CH 2 )—O—C(O)—O-(4-nitro-phenyl);
n is 0; and

R 1 , k and p have the meanings given above.

Assignees

• Hoffmann La Roche
• Hoffmann La Roche

Inventors

• Hadwiger Philipp
• Hoffmann Torsten
• Jahn-Hofmann Kerstin
• Kitas Eric A
• Lewis David L
• Mohr Peter
• Mueller Hans Martin
• Ott Guenther
• Roehl Ingo
• Rozema David B

Classifications

• C12N2310/321

  2'-O-R Modification · CPC title

• C12N15/87 Primary

  Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation · CPC title

• A61K47/18

  Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids · CPC title

• C12N2310/322

  2'-R Modification · CPC title

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title