US2016017323A1PendingUtilityA1

Conjugated antisense compounds and their use

71
Assignee: ISIS PHARMACEUTICALS INCPriority: May 1, 2013Filed: Jun 19, 2015Published: Jan 21, 2016
Est. expiryMay 1, 2033(~6.8 yrs left)· nominal 20-yr term from priority
Inventors:Thazha P. PrakashPunit P. SethEric E. Swayze
A61K 47/59A61P 43/00A61P 25/00C12Y 301/03048A61K 31/713C12N 15/113C07H 21/04C12N 15/111A61K 47/549A61K 31/7088C12N 2310/321C12N 2310/315C12N 2310/341C12N 2310/31C12N 2320/32C12N 2310/3511C12N 2310/3341C12N 2310/322C12N 2310/11C12N 2310/3231C12N 2310/353C12N 2310/351C12N 2310/17C12N 2310/3513C12N 2310/346C12N 2310/3515C12N 2310/3525C12N 2310/113C07H 21/00C12N 2310/35C12N 2310/32A61K 48/00A61K 31/7125C12N 2310/34C12N 2310/14A61K 31/7105C12N 15/1137
71
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Claims

Abstract

Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.

Claims

exact text as granted — not AI-modified
1 .- 296 . (canceled) 
     
     
         297 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein one of T 3  or T 4  is selected from among: GalNAc 3 -1a, GalNAc 3 -2a, GalNAc 3 -3a, GalNAc 3 -4a, GalNAc 3 -5a, GalNAc 3 -6a, GalNAc 3 -7a, GalNAc 3 -8a, GalNAc 3 -9a, GalNAc 3 -10a, GalNAc 3 -11a, GalNAc 3 -12a, GalNAc 3 -13a, GalNAc 3 -14a, GalNAc 3 -15a, GalNAc 3 -16a, GalNAc 3 -17a, GalNAc 3 -18a, GalNAc 3 -19a, GalNAc 3 -20a, GalNAc 3 -21a, GalNAc 3 -22a, GalNAc 3 -23a, GalNAc-24a, GalNAc-25a, GalNAc-26a, GalNAc-27a, GalNAc-28a, GalNAc-29a, GalNAc-30a, GalNAc-31a, and GalNAc-32a, 
         and the other of T 3  or T 4  is selected from among: a hydroxyl, a hydroxyl protecting group, a nucleoside, an oligonucleotide, a monomeric subunit, or an oligomeric compound; wherein Bx is a heterocyclic base moiety; and wherein Q or Q 13  is selected from among: a hydrogen, halogen, OCH 3 , OCF 3 , OCH 2 CH 3 , OCH 2 CF 3 , OCH 2 —CH═CH 2 , O(CH 2 ) 2 —OCH 3  (MOE), O(CH 2 ) 2 —O(CH 2 ) 2 —N(CH 3 ) 2 , OCH 2 C(═O)—N(H)CH 3 , OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 , and OCH 2 —N(H)—C(═NH)NH 2 ; 
         and where X is selected from among O or S. 
       
     
     
         298 . The compound of  claim 297 , wherein X is S. 
     
     
         299 . The compound of  claim 297 , wherein Q or Q 13  is OCH 3 . 
     
     
         300 . The compound of  claim 297 , wherein Q or Q 13  is O(CH 2 ) 2 —OCH 3 . 
     
     
         301 . The compound of  claim 300 , wherein Q 13  is O(CH 2 ) 2 —OCH 3    
     
     
         302 . The compound of  claim 297 , wherein T 3  is selected from among: GalNAc 3 -1a, GalNAc 3 -2a, GalNAc 3 -3a, GalNAc 3 -4a, GalNAc 3 -5a, GalNAc 3 -6a, GalNAc 3 -7a, GalNAc 3 -8a, GalNAc 3 -9a, GalNAc 3 -10a, GalNAc 3 -11a, GalNAc 3 -12a, GalNAc 3 -13a, GalNAc 3 -14a, GalNAc 3 -15a, GalNAc 3 -16a, GalNAc 3 -17a, GalNAc 3 -18a, GalNAc 3 -19a, GalNAc 3 -20a, GalNAc 3 -21a, GalNAc 3 -22a, GalNAc 3 -23a, GalNAc-24a, GalNAc-25a, GalNAc-26a, GalNAc-27a, GalNAc-28a, GalNAc-29a, GalNAc-30a, GalNAc-31a, and GalNAc-32a. 
     
     
         303 . The compound of  claim 298 , wherein T 3  is selected from among: GalNAc 3 -1a, GalNAc 3 -2a, GalNAc 3 -3a, GalNAc 3 -4a, GalNAc 3 -5a, GalNAc 3 -6a, GalNAc 3 -7a, GalNAc 3 -8a, GalNAc 3 -9a, GalNAc 3 -10a, GalNAc 3 -11a, GalNAc 3 -12a, GalNAc 3 -13a, GalNAc 3 -14a, GalNAc 3 -15a, GalNAc 3 -16a, GalNAc 3 -17a, GalNAc 3 -18a, GalNAc 3 -19a, GalNAc 3 -20a, GalNAc 3 -21a, GalNAc 3 -22a, GalNAc 3 -23a, GalNAc-24a, GalNAc-25a, GalNAc-26a, GalNAc-27a, GalNAc-28a, GalNAc-29a, GalNAc-30a, GalNAc-31a, and GalNAc-32a. 
     
     
         304 . The compound of  claim 299 , wherein T 3  is selected from among: GalNAc 3 -1a, GalNAc 3 -2a, GalNAc 3 -3a, GalNAc 3 -4a, GalNAc 3 -5a, GalNAc 3 -6a, GalNAc 3 -7a, GalNAc 3 -8a, GalNAc 3 -9a, GalNAc 3 -10a, GalNAc 3 -11a, GalNAc 3 -12a, GalNAc 3 -13a, GalNAc 3 -14a, GalNAc 3 -15a, GalNAc 3 -16a, GalNAc 3 -17a, GalNAc 3 -18a, GalNAc 3 -19a, GalNAc 3 -20a, GalNAc 3 -21a, GalNAc 3 -22a, GalNAc 3 -23a, GalNAc-24a, GalNAc-25a, GalNAc-26a, GalNAc-27a, GalNAc-28a, GalNAc-29a, GalNAc-30a, GalNAc-31a, and GalNAc-32a. 
     
     
         305 . The compound of  claim 300 , wherein T 3  is selected from among: GalNAc 3 -1a, GalNAc 3 -2a, GalNAc 3 -3a, GalNAc 3 -4a, GalNAc 3 -5a, GalNAc 3 -6a, GalNAc 3 -7a, GalNAc 3 -8a, GalNAc 3 -9a, GalNAc 3 -10a, GalNAc 3 -11a, GalNAc 3 -12a, GalNAc 3 -13a, GalNAc 3 -14a, GalNAc 3 -15a, GalNAc 3 -16a, GalNAc 3 -17a, GalNAc 3 -18a, GalNAc 3 -19a, GalNAc 3 -20a, GalNAc 3 -21a, GalNAc 3 -22a, GalNAc 3 -23a, GalNAc-24a, GalNAc-25a, GalNAc-26a, GalNAc-27a, GalNAc-28a, GalNAc-29a, GalNAc-30a, GalNAc-31a, and GalNAc-32a. 
     
     
         306 . The compound of  claim 300 , wherein T 4  is an oligomeric compound. 
     
     
         307 . The compound of  claim 297 , wherein each B x  is independently selected from adenine, guanine, thymine, uracil, cytosine, or 5-methyl cytosine. 
     
     
         308 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein one of T 3  or T 4  is selected from among: GalNAc 3 -1a, GalNAc 3 -2a, GalNAc 3 -3a, GalNAc 3 -4a, GalNAc 3 -5a, GalNAc 3 -6a, GalNAc 3 -7a, GalNAc 3 -8a, GalNAc 3 -9a, GalNAc 3 -10a, GalNAc 3 -11a, GalNAc 3 -12a, GalNAc 3 -13a, GalNAc 3 -14a, GalNAc 3 -15a, GalNAc 3 -16a, GalNAc 3 -17a, GalNAc 3 -18a, GalNAc 3 -19a, GalNAc 3 -20a, GalNAc 3 -21a, GalNAc 3 -22a, GalNAc 3 -23a, GalNAc-24a, GalNAc-25a, GalNAc-26a, GalNAc-27a, GalNAc-28a, GalNAc-29a, GalNAc-30a, GalNAc-31a, and GalNAc-32a; 
         and the other of T 3  or T 4  is selected from among: a hydroxyl, a hydroxyl protecting group, a nucleoside, an oligonucleotide, a monomeric subunit, or an oligomeric compound; wherein Bx is a heterocyclic base moiety; and wherein Q 13  is selected from among: a hydrogen, halogen, OCH 3 , OCF 3 , OCH 2 CH 3 , OCH 2 CF 3 , OCH 2 —CH—CH 2 , O(CH 2 ) 2 —OCH 3  (MOE), O(CH 2 ) 2 —O(CH 2 ) 2 —N(CH 3 ) 2 , OCH 2 C(═O)—N(H)CH 3 , OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 , and OCH 2 —N(H)—C(═NH)NH 2 ; 
         and where X is selected from among O or S 
         and where Z is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, substituted C 1 -C 6  alkyl, substituted C 2 -C 6  alkenyl, substituted C 2 -C 6  alkynyl, halogen, hydrogen, acyl, substituted acyl, substituted amide, thiol or substituted thio. 
       
     
     
         309 . The compound of  claim 308 , wherein X is S. 
     
     
         310 . The compound of  claim 308 , wherein Q 13  is OCH 3 . 
     
     
         311 . The compound of  claim 308 , wherein Q 13  is O(CH 2 ) 2 —OCH 3 . 
     
     
         312 . The compound of  claim 308 , wherein T 4  is an oligomeric compound. 
     
     
         313 . The compound of  claim 308 , wherein each B X  is independently selected from adenine, guanine, thymine, uracil, cytosine, or 5-methyl cytosine. 
     
     
         314 . The compound of  claim 311 , wherein T 3  is selected from among: GalNAc 3 -1a, GalNAc 3 -2a, GalNAc 3 -3a, GalNAc 3 -4a, GalNAc 3 -5a, GalNAc 3 -6a, GalNAc 3 -7a, GalNAc 3 -8a, GalNAc 3 -9a, GalNAc 3 -10a, GalNAc 3 -11a, GalNAc 3 -12a, GalNAc 3 -13a, GalNAc 3 -14a, GalNAc 3 -15a, GalNAc 3 -16a, GalNAc 3 -17a, GalNAc 3 -18a, GalNAc 3 -19a, GalNAc 3 -20a, GalNAc 3 -21a, GalNAc 3 -22a, GalNAc 3 -23a, GalNAc-24a, GalNAc-25a, GalNAc-26a, GalNAc-27a, GalNAc-28a, GalNAc-29a, GalNAc-30a, GalNAc-31a, and GalNAc-32a. 
     
     
         315 . The compound of  claim 311 , wherein T 4  is an oligomeric compound. 
     
     
         316 . The compound of  claim 311 , wherein each B X  is independently selected from adenine, guanine, thymine, uracil, cytosine, or 5-methyl cytosine.

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