Oligonucleotide analogues having modified intersubunit linkages and/or terminal groups

Patent metadata

Field	Value
Publication number	US-9469664-B2
Application number	US-201414298655-A
Country	US
Kind code	B2
Filing date	Jun 6, 2014
Priority date	May 28, 2010
Publication date	Oct 18, 2016
Grant date	Oct 18, 2016

Abstract

Oligonucleotide analogs comprising modified intersubunit linkages and/or modified 3′ and/or 5′-end groups are provided. The disclosed compounds are useful for the treatment of diseases where inhibition of protein expression or correction of aberrant mRNA splice products produces beneficial therapeutic effects.

First claim

The invention claimed is:

1. A morpholino subunit, wherein the morpholino subunit has the following structure (XXXI)

or a salt or stereoisomer thereof, wherein:
B is a base-pairing moiety;
W is S or O;
X is —NR 8 R 9 or —OR 3 ; and
Y is O or —NR 10 ,
R 8 is hydrogen or C 2 -C 12 alkyl;
R 9 is hydrogen, C 1 -C 12 alkyl, C 1 -C 12 aralkyl or aryl;
R 10 is hydrogen, C 1 -C 12 alkyl or LNR 4 R 5 R 7 , wherein:

R 4 is, at each occurrence, independently hydrogen, methyl, —C(═NH)NH 2 , —J-L-NHC(═NH)NH 2 or —[C(O)CHR′NH] m H, where —J is carbonyl (C(O)) or a direct bond, R′ is a side chain of a naturally occurring amino acid or a one- or two-carbon homolog thereof, and m is 1 to 6;
R 5 is, at each occurrence, independently hydrogen, methyl, or an electron pair;
R 7 is, at each occurrence, independently C 1 -C 6 alkyl or C 1 -C 6 alkoxyalkyl; and
L is an optional linker up to 18 atoms in length comprising alkyl, alkoxy, or alkylamino groups, or combinations thereof;
wherein R 8 and R 9 , together with the atom to which they are attached, join to form a 5-18 membered mono or bicyclic heterocycle, or
R 8 , R 9 or R 3 , together with the atom to which they are attached, join with R 10 to form a 5-7 membered heterocycle, and wherein when X is 4-piperazinyl, X has the following structure (III):

wherein:
R 11 is C 12 alkyl, C 1 -C 12 aminoalkyl, C 1 -C 12 alkylcarbonyl, aryl, heteroaryl or heterocyclyl, wherein the C 1 -C 12 alkyl of the C 1 -C 12 alkylcarbonyl is not C 1 -C 3 haloalkyl; and
R is an electron pair, hydrogen or C 1 -C 12 alkyl; and
R 12 is at each occurrence, independently, hydrogen, C 1 -C 12 alkyl, C 1 -C 12 aminoalkyl, —NH 2 , —CONH 2 , —NR 13 R 14 , —NR 13 R 14 R 15 , C 1 -C 12 alkylcarbonyl, oxo, —CN, trifluoromethyl, amidyl, amidinyl, amidinylalkyl, amidinylalkylcarbonyl guanidinyl, guanidinylalkyl, guanidinylalkylcarbonyl, cholate, deoxycholate, aryl, heteroaryl, heterocycle, —SR 13 or C 1 -C 12 alkoxy, wherein R 13 , R 14 and R 15 are, at each occurrence, independently C 1 -C 12 alkyl; and
Z is halo or a linkage to a solid support; and
PG is C 7 -C 30 aralkyl.

2. The morpholino subunit of claim 1 , wherein Z is chloro.

3. The morpholino subunit of claim 1 , wherein PG is trityl or methoxy trityl.

4. The morpholino subunit of claim 1 , wherein R 8 and R 9 , together with the atom to which they are attached, join to form a 5-18 membered mono or bicyclic heterocycle, and the morpholino subunit has the following structure (IV′):

wherein Cy represents a 5-18 membered mono or bicyclic heterocycle.

5. The morpholino subunit of claim 4 , wherein the 5-18 membered mono or bicyclic heterocycle has one of the following structures (III), (V), (VI), (VII) or (VIII):

6. The morpholino subunit of claim 5 , wherein the 5-18 membered mono or bicyclic heterocycle has structure (V).

7. The morpholino subunit of claim 5 , wherein at least one R 12 has the following structure (IX):

wherein R 16 is, at each occurrence, independently hydrogen, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, —CN, aryl or heteroaryl.

8. The morpholino subunit of claim 5 , wherein at least one R 12 is —NH 2 , —N(CH 3 ) 2 or —N + (CH 3 ) 3 .

9. The morpholino subunit of claim 5 , wherein at least one R 12 is pyrrolidinyl, piperidinyl or morpholinyl.

10. The morpholino subunit of claim 5 , wherein at least one R 12 is oxo, trifluoromethyl guanidynyl or nitrile.

11. The morpholino subunit of claim 5 , wherein R 11 is ethyl, isopropyl, piperidinyl, pyrimidinyl, cholate, deoxycholate or —C(═O)(CH 2 )—CO 2 H, where n is 1 to 6.

12. The morpholino subunit of claim 4 , wherein the 5-18 membered mono or bicyclic heterocycle is a crown ether.

13. The morpholino subunit of claim 12 , wherein the crown ether has one of the following structures (X) or (XI):

14. The morpholino subunit of claim 1 , wherein R 8 , R 9 or R 3 , together with the atom to which they are attached, join with R 10 to form a 5-7 membered heterocycle, and the morpholino subunit has the following structure (XII′):

wherein Cy′ represents a 5-7 membered heterocycle.

15. The morpholino subunit of claim 14 , wherein the morpholino subunit has the following structure (XIII′):

16. The morpholino subunit of claim 1 , wherein the morpholino subunit has one of the following structures:

17. The morpholino subunit of claim 16 , wherein the morpholino subunit has the following structure:

18. The morpholino subunit of claim 1 , wherein B is selected from adenine (A), guanine (G), cytosine (C), thymine (T), uracil (U), hypoxanthine, and 5-methyl cytosine.

Assignees

• Sarepta Therapeutics Inc

Inventors

• Hanson Gunnar J
• Rudolph Alexander Charles
• Cai Bao Zhong
• Zhou Ming
• Weller Dwight D

Classifications

• A61K31/496 Primary

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C07H21/00 Primary

  Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids · CPC title

• C07F9/24

  Esteramides · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title