IP Library › Granted Patent US 8,742,078
Granted Patent B2
US 8,742,078 · App. 13/741,736 · Granted Jun 3, 2014

Antibacterial 4,6-substituted 6′, 6″ and 1 modified aminoglycoside analogs

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Quick Facts
Patent No.
US 8,742,078
App. No.
13/741,736
Granted
Jun 3, 2014
Kind
B2
Abstract

The present invention is directed to analogs of aminoglycoside compounds as well as their preparation and use as prophylactic or therapeutics against microbial infection.

Claims (41)

1. A compound of formula I:

wherein:

each R 1 and R 2 is, independently, H or an amino protecting group;

each R 3 is, independently, H or a hydroxyl protecting group;

R 4 and R 5 are each, independently, H, amino protecting group, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl or substituted C 2 -C 12 alkynyl;

Q 1 is hydroxyl, a protected hydroxyl, cyano, azido, or NR 8 R 9 ;

R 8 and R 9 are each, independently, H, CN, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 7 -C 9 alicyclic radical, substituted C 7 -C 9 alicyclic radical, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl or substituted C 2 -C 12 alkynyl;

Q 2 is NH 2 or N(CH 2 R 6 )R 7 ;

R 6 and R 7 are each, independently, H, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 7 -C 9 alicyclic radical, substituted C 7 -C 9 alicyclic radical, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl or substituted C 2 -C 12 alkynyl;

wherein said substituents are each, independently, halogen, trifluoromethyl, cyano, OJ 3 , NJ 1 J 2 , C(═O)—NJ 1 J 2 , N(H)C(═O)-J 1 , N(J 1 )—(CH 2 ) n —OJ 3 , N(J 1 )—(CH 2 ) n —NJ 1 J 2 , C 5 -C 20 aryl, C 7 -C 9 alicyclic radical, heterocycle radical, heteroaryl, azido, carboxy, acyl (C(═O)—X), ═O, cyano, sulfonyl (S(═O) 2 —X) or sulfoxyl (S(═O)—X);

each X is, independently, H or C 1 -C 12 alkyl;

each J 1 and J 2 is, independently, H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 20 aryl, acyl (C(═O)—X), a heterocycle radical or heteroaryl;

each J 3 is, independently, H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 aminoalkyl or a hydroxyl protecting group;

each n is, independently, from 1 to 20; and

with the proviso that when Q 1 is hydroxyl or protected hydroxyl, Q 2 is other than NH 2 , NH(CH 3 ) or NH(CH 2 CH 3 ).

2. The compound of claim 1 wherein said substituents are each, independently, OH, NH 2 , N(H)C 1 -C 12 alkyl, C(═O)—N(H)J 2 , N(H)C(═O)-J 1 , N(J 1 )—(CH 2 ) n —OJ 3 , N(J 1 )—(CH 2 ) n —NJ 1 J 2 , C 7 -C 9 alicyclic radical, C 5 -C 20 aryl, a heterocycle radical or heteroaryl.

3. The compound of claim 1 wherein said substituents are each, independently, OH, NH 2 , N(H)C 1 -C 12 alkyl or C 5 -C 20 aryl.

4. The compound of claim 1 wherein each R 1 and R 2 is H.

5. The compound of claim 1 wherein each R 3 is H.

6. The compound of claim 1 wherein Q 1 is hydroxyl.

7. The compound of claim 1 wherein Q 1 is NR 8 R 9 .

8. The compound of claim 7 wherein one of said R 8 and R 9 is H and the other of said R 8 and R 9 is C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 7 -C 9 alicyclic radical or substituted C 7 -C 9 alicyclic radical.

9. The compound of claim 8 wherein the other of said R 8 and R 9 is substituted C 1 -C 12 alkyl wherein each of said substituents is, independently, C 5 -C 20 aryl, C 7 -C 9 alicyclic radical, heterocycle radical or heteroaryl.

10. The compound of claim 1 wherein Q 1 is NH 2 .

11. The compound of claim 1 wherein Q 2 is N(CH 2 R 6 )R 7 and R 7 is H or C 1 -C 12 alkyl.

12. The compound of claim 11 wherein R 6 is C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 7 -C 9 alicyclic radical or substituted C 7 -C 9 alicyclic radical.

13. The compound of claim 11 wherein R 6 is substituted C 1 -C 12 alkyl wherein said substituent is OH, NH 2 , N(H)aC 1 -C 12 alkyl or C 5 -C 20 aryl.

14. The compound of claim 13 wherein said substituent is OH, NH 2 or N(H)C 1 -C 12 alkyl.

15. The compound of claim 11 wherein R 6 is substituted C 1 -C 12 alkyl wherein said substituent is C 5 -C 20 aryl.

16. The compound of claim 1 wherein one of R 4 and R 5 is H and the other of R 4 and R 5 is C 1 -C 12 alkyl or substituted C 1 -C 12 alkyl.

17. The compound of claim 16 wherein the other of R 4 and R 5 is substituted C 1 -C 12 alkyl wherein the substituent is a C 5 -C 9 alicyclic radical, C 5 -C 20 aryl, heterocycle radical or heteroaryl.

18. The compound of claim 17 wherein the substituent is C 5 -C 20 aryl.

19. The compound of claim 1 wherein R 4 , R 5 and each R 1 are each H.

20. The compound of claim 19 wherein Q 1 is OH.

21. The compound of claim 20 wherein Q 2 is N(CH 2 R 6 )R 7 and R 7 is H.

22. The compound of claim 19 wherein Q 2 is NH 2 .

23. The compound of claim 22 wherein Q 1 is NR 8 R 9 and R 8 is H.

24. The compound of claim 23 wherein R 9 is cyclohexyl, (CH 2 ) 2 —C 6 H 5 , CH(CH 3 ) 2 or CH 3 .

25. The compound of claim 1 wherein Q 1 is azido or cyano.

26. The compound of claim 25 wherein Q 2 is N(CH 2 R 6 )R 7 and R 7 is H or C 1 -C 12 alkyl.

27. The compound of claim 1 having the configuration:

Assignments (1)
CHANGE OF NAME Recorded Jun 15, 2017
From: ISIS PHARMACEUTICALS, INC.
To: IONIS PHARMACEUTICALS, INC.
Reel/Frame 042832/0349 →