Methods for treating spinal muscular atrophy using tetracycline compounds
View Patent ↗Methods for using tetracycline compounds for the treatment of spinal muscular atrophy are described.
1. A method for treating a subject for spinal muscular atrophy, comprising: administering to said subject an effective amount of a tetracycline compound of formula I:
wherein
X is CR 6′ R 6 ;
R 2 and R 2′ are each hydrogen;
R 4 ′ and R 4 ″ are each alkyl;
R 3 , R 4a , R 11 and R 12 are each hydrogen;
R 4 is NR 4′ R 4″ ;
R 5 and R 5 ′ are each hydrogen;
R 6 and R 6 ′ are each hydrogen;
R 7 is acyl, amino, phenyl, pyridinyl, furanyl, pyrrolyl, tetrahydropyridinyl, quinolinyl, or aminoalkyl;
R 8 is hydrogen;
R 9 is hydrogen or phenyl; and
R 10 is hydroxyl;
or a pharmaceutically acceptable salt, ester or enantiomer thereof, such that said spinal muscular atrophy in said subject is treated.
2. The method of claim 1 , wherein R 7 is amino.
3. The method of claim 2 , wherein said amino is dialkylamino.
4. The method of claim 3 , wherein said dialkylamino is dimethylamino.
5. The method of claim 1 , wherein R 9 is hydrogen.
6. The method of claim 5 , wherein R 7 is phenyl or pyridinyl, and further wherein said phenyl or pyridinyl is of formula V:
wherein
A g , A i , A j and A k are each C and A h is N or C; and
when A h is C, then R 7g , R 7h , R 7i , R 7j and R 7k are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R 7j and R 7i are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring; or
R 7h is absent when A h is N.
7. The method of claim 6 , wherein A h is C.
8. The method of claim 7 , wherein R 7g , R 7h , R 7i and R 7k are each hydrogen.
9. The method of claim 6 , wherein R 7j is carbonyl, and further wherein said carbonyl is of formula VI:
wherein
R 7s and R 7t are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R 7s and R 7t are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring.
10. The method of claim 9 , wherein R 7t is hydrogen.
11. The method of claim 9 , wherein R 7s is alkyl, and further wherein said alkyl is of formula VII:
wherein
D is O, N, NR 7′ or CR 7′ ;
n is an integer from 0 to 10;
R 7′ is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and
when D is N or CR 7′ , R 71 and R 7m are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R 71 and R 7m are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring; or
when D is O, R 71 is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfonyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic and R 7m is absent.
12. The method of claim 11 , wherein D is N.
13. The method of claim 11 , wherein n is 2.
14. The method of claim 11 , wherein R 71 and R 7m are each alkyl.
15. The method of claim 14 , wherein said alkyl is methyl.
16. The method of claim 9 , wherein R 7s and R 7t are each hydrogen.
17. The method of claim 9 , wherein R 7s and R 7t are each alkyl.
18. The method of claim 17 , wherein said alkyl is methyl.
19. The method of claim 9 , wherein R 7s and R 7t are linked to form a 6-membered heterocyclic ring.
20. The method of claim 11 , wherein D is N or O.
21. The method of claim 11 , wherein n is 1, 2, 3 or 4.
22. The method of claim 11 , wherein R 71 is aryl.
23. The method of claim 21 , wherein R 71 and R 7m are each alkyl.
24. The method of claim 21 , wherein R 71 and R 7m are each hydrogen.
25. The method of claim 21 , wherein R 7m is alkyl or acyl.
26. The method of claim 21 , wherein R 71 and R 7m are linked to form a 5- or 6-membered heterocyclic ring.
27. The method of claim 9 , wherein R 7s is alkyl and further wherein said alkyl is alkoxycarbonyl substituted alkyl, heterocyclic substituted alkyl, or hydroxyl substituted alkyl.
28. The method of claim 6 , wherein R 7i and R 7j are linked to form a 6-membered aryl ring.
29. The method of claim 28 , wherein said aryl ring is a benzene ring.
30. The method of claim 6 , wherein R 7j is acyl.
31. The method of claim 6 , wherein R 7j is carbonyl.
32. The method of claim 31 , wherein said carbonyl is alkoxy substituted carbonyl.
33. The method of claim 6 , wherein A h is N.
34. The method of claim 33 , wherein R 7g , R 7j and R 7k are each hydrogen.
35. The method of claim 5 , wherein R 7 is tetrahydropyridinyl.
36. The method of claim 35 , wherein R 7 is
37. The method of claim 5 , wherein R 7 is quinolinyl.
38. The method of claim 5 , wherein R 7 is furanyl or pyrrolyl, and further wherein said furanyl or pyrrolyl is of formula X:
wherein
G a is N or O;
G b , G c , G d and G e are each CR 7f* ,
R 7f* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl orheterocyclic;
R 7a* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic when G a is N or R 7a* is absent when G a is O;
R 7b* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic;
R 7c* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic;
R 7d* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic orR 7d* is covalently bonded to the 7-position of the tetracycline compound; and
R 7e* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R 7e* is covalently bonded to the 7-position of the tetracycline compound;
provided that one of R 7d* or R 7e* are covalently bonded to the 7-position of the tetracycline compound.
39. A method for treating a subject for spinal muscular atrophy, comprising administering to said subject an effective amount of a tetracycline compound selected from:
and pharmaceutically acceptable salts, esters and enantiomers thereof, such that said spinal muscular atrophy in said subject is treated.
40. The method of claim 1 , wherein said tetracycline compound is of formula XII:
wherein
r is an integer from 1 to 10;
M is OR 7o* or NR 7p* R 7q* ;
Q is hydrogen or alkyl;
R 7o* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and
R 7p* and R 7q* are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R 7p* and R 7q* are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring.
41. The method of claim 1 , wherein said tetracycline compound is of formula XIV:
wherein
t is an integer from 1 to 10;
U is OR 7u* or NR 7v* R 7w* ;
R 7u* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and
R 7v* and R 7w* are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R 7v* and R 7w* are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring.
42. The method of claim 1 , wherein said tetracycline compound is of formula XV:
wherein
u is an integer from 1 to 10;
L is OR 7x* or NR 7y* R 7z* ;
R 7x* is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alloxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and
R 7y* and R 7z* are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R 7y* and R 7z* are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring.
43. The method of claim 1 , wherein said tetracycline compound is of formula XVI:
wherein
v and v* are each independently an integer from 1 to 10;
R 7a** is hydrogen or alkyl;
T is OR 7b** or NR 7c** R 7d** ;
R 7b** is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and
R 7c** and R 7d** are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R 7c** and R 7d** are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring.
44. The method of claim 1 , wherein said tetracycline compound is of formula XVII:
wherein
x and x* are each independently an integer from 1 to 10;
A* is OR 7e** or NR 7f** R 7g**
D* is NH, NCH 3 , O, or CH 2 ;
R 7e** is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and
R 7f** and R 7g** are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R 7f** and R 7g** are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring.
45. The method of claim 1 , wherein said tetracycline is of formula XVIII:
wherein
u is an integer from 1 to 10;
G* is OR 7h** or NR 7i** R 7j** ;
E* is NH, NCH 3 , O, or CH 2 ;
R 7h** is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and
R 7i** and R 7j** are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R 7i** and R 7j** are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring.
46. The method of claim 1 , wherein said tetracycline compound is of formula XIX:
wherein
y is an integer from 1 to 10;
K* is NR 71** R 7m** ;
J* is NH or NCH 3 ;
and
R 71** and R 7m** are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R 71** and R 7m** are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring.
47. The method of claim 1 , wherein said compound is of formula XX:
wherein W″ is O; and
R 7a″ and R 7c″ are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R 7a″ and R 7c″ are linked together to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring; or a pharmaceutically acceptable salt thereof.
48. The method of claim 1 , wherein said subject is a human.
49. The method of claim 1 , further comprising administering said tetracycline compound in combination with a second agent.
50. The method of claim 1 , further comprising administering said tetracycline compound in combination with a pharmaceutically acceptable carrier.
51. The method of claim 1 , wherein said tetracycline compound increases exon 7 inclusion.
52. The method of claim 1 , wherein said tetracycline compound increases intron 6 splicing.
53. The method of claim 1 , wherein said tetracycline compound increases cellular SMN protein levels.
54. The method of claim 1 , wherein said tetracycline compound increases gems in cells of said subject.
55. The method of claim 1 , wherein said tetracycline compound increases FL SMN2 mRNA expression in said subject's liver and/or kidney.
56. The method of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt, ester or enantiomer thereof.
57. The method of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt, ester or enantiomer thereof.
58. The method of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt, ester or enantiomer thereof.
59. The method of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt, ester or enantiomer thereof.
60. The method of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt, ester or enantiomer thereof.
61. The method of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt, ester or enantiomer thereof.
62. The method of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt, ester or enantiomer thereof.
63. The method of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt, ester or enantiomer thereof.