Thiosaccharide mucolytic agents
There are provided, inter alia, methods for decreasing mucus elasticity or decreasing mucus viscosity in a subject in need thereof, the methods including administering to the subject an effective amount of a thiosaccharide mucolytic agent, and compounds and pharmaceutical compositions useful for the methods.
1. A method for decreasing mucus elasticity or decreasing mucus viscosity in a subject in need thereof, said method comprising administering to said subject in need thereof an effective amount of a thiol saccharide mucolytic agent, wherein said thiol saccharide mucolytic agent has the formula:
wherein,
R 1 is —SH, —OR 1A , —NR 1B or —R 1D , wherein
R 1A is H, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 1B is —C(O)R 1C , substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 1C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 1D is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 2 is —SH, —OR 2A or —NR 2B , wherein
R 2A is H, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 2B is —C(O)R 2C , substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 2C is substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 3 is —SH, —OR 3A or —NR 3B , wherein
R 3A is H, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 3B is —C(O)R 3C , substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 3C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 4 is —SH, —SAc, —OR 4A or —NR 4B , wherein
R 4A is H, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 4B is —C(O)R 4C , substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 4C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 5 is H, —SH, —SAc, —OR 5A , —NR 5B , or —R 5D , wherein
R 5A is H, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 5B is —C(O)R 5C , substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 5C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 5D is substituted or unsubstituted C 1 -C 10 thiol-alkyl; and
R 5′ is H or —OH,
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein R 1 is —OR 1A and R 1A is substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl.
3. The method of claim 1 , wherein
R 1 , R 3 , R 4 and R 5 are —OH;
R 5′ is H;
R 2A is an unsubstituted C 1 -C 10 thiol-alkyl or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 2B is —C(O)R 2C , unsubstituted C 1 -C 10 thiol-alkyl or unsubstituted thiol-heteroalkyl; and
R 2C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl.
4. The method of claim 1 , wherein R 2 , R 3 , R 4 are —OH.
5. The method of claim 1 , wherein
R 3 , R 4 and R 5 are —OH; and
R5′ is H.
6. The method of claim 1 , wherein R 4 is —SH.
7. The method of claim 1 , wherein
R 5 is —SH; and
R 5′ is H.
8. The method of claim 1 , wherein
R 1 is —OR 1A ;
R 2 , R 3 , and R 4 are —OH;
R 5 is H or —OR 5A ; and
R 5′ is H.
9. The method of claim 1 , wherein
R 1 is —OR 1A ;
R 2 , R 3 , and R 4 are —OH;
R 5′ is H; and
R 5 is —SH.
10. The method of claim 1 , wherein
R 1 is —OR 1A ;
R 2 , R 3 , and R 4 are —OH;
R 5 is —SAc; and
R 5′ is H.
11. The method of claim 1 , wherein
R 1 is —OR 1A or —R 1D ,
R 2 is —OH or —NR 2B ;
R 2B is —C(O)R 2C ;
R 2C is substituted or unsubstituted C 1 -C 10 alkyl;
R 3 and R 4 are —OH; and
R 5 is —OR 5A or —R 5D .
12. A pulmonary pharmaceutical composition comprising a pulmonary pharmaceutical carrier and a thiol saccharide mucolytic agent, wherein said thiol saccharide mucolytic agent has the formula:
wherein,
R 1 is —SH, —OR 1A , —NR 1B or —R 1D , wherein
R 1A is H, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 1B is —C(O)R 1C , substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 1C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 1D is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 2 is —SH, —OR 2A or —NR 2B , wherein
R 2A is H, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 2B is —C(O)R 2C , substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 2C is substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 3 is —SH, —OR 3A or —NR 3B , wherein
R 3A is H, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 3B is —C(O)R 3C , substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 3C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 4 is —SH, —SAc, —OR 4A or —NR 4B , wherein
R 4A is H, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 4B is —C(O)R 4C , substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 4C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 5 is H, —SH, —SAc, —OR 5A , —NR 5B , or —R 5D , wherein
R 5A is H, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 5B is —C(O)R 5C , substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 5C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 5D is substituted or unsubstituted C 1 -C 10 thiol-alkyl; and
R 5′ is H or —OH,
or a pharmaceutically acceptable salt thereof.
13. A compound with the structure of Formula (I):
wherein,
R 1 , R 3 , R 4 and R 5 are —OH;
R 5′ is H; and
R 2 is —SH, —OR 2A or —NR 2B , wherein
R 2A is an unsubstituted C 1 -C 10 thiol-alkyl or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 2B is —C(O)R 2C , unsubstituted C 1 -C 10 thiol-alkyl or unsubstituted thiol-heteroalkyl; and
R 2C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl,
or a pharmaceutically acceptable salt thereof.
14. A compound with the structure of Formula (I):
wherein,
R 1 is —SH, —OR 1A , —NR 1B or —R 1D , wherein
R 1A is substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 1B is —C(O)R 1C , substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 1C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 1D is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 2 is —SH, —OR 2A or —NR 2B , wherein
R 2A is H, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 2B is —C(O)R 2C , substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 2C is substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 3 is —SH, —OR 3A or —NR 3B , wherein
R 3A is H, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 3B is —C(O)R 3C , substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 3C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 4 is —SH;
R 5 is H, —SH, —SAc, —OR 5A , —NR 5B , or —R 5D , wherein
R 5A is H, substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 5B is —C(O)R 5C , substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 5C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 5D is substituted or unsubstituted C 1 -C 10 thiol-alkyl; and
R 5′ is H or —OH,
provided, however, that said structure is not
or a pharmaceutically acceptable salt thereof.
15. The composition of claim 12 , wherein
R 1 , R 3 , R 4 and R 5 are —OH;
R 5′ is H;
R 2A is an unsubstituted C 1 -C 10 thiol-alkyl or unsubstituted 2 to 10 membered thiol-heteroalkyl;
R 2B is —C(O)R 2C , unsubstituted C 1 -C 10 thiol-alkyl or unsubstituted thiol-heteroalkyl; and
R 2C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl.
16. The composition of claim 12 , wherein R 2 , R 3 , R 4 are —OH.
17. The composition of claim 12 , wherein
R 3 , R 4 and R 5 are —OH; and
R5′ is H.
18. The composition of claim 12 , wherein R 4 is —SH.
19. The composition of claim 12 , wherein
R 5 is —SH; and
R 5′ is H.
20. The composition of claim 12 , wherein
R 1 is —OR 1A ;
R 2 , R 3 , and R 4 are —OH;
R 5 is H or —OR 5A ; and
R 5′ is H.
21. The composition of claim 12 , wherein
R 1 is —OR 1A ;
R 2 , R 3 , and R 4 are —OH;
R 5′ is H; and
R 5 is —SH.
22. The composition of claim 12 , wherein
R 1 is —OR 1A ;
R 2 , R 3 , and R 4 are —OH;
R 5 is —SAc; and
R 5′ is H.
23. The composition of claim 12 , wherein
R 1 is —OR 1A or —R 1D ,
R 2 is —OH or —NR 2B ;
R 2B is —C(O)R 2C ;
R 2C is substituted or unsubstituted C 1 -C 10 alkyl;
R 3 and R 4 are —OH; and
R 5 is —OR 5A or —R 5D .
24. The composition of claim 12 , wherein the thiol saccharide mucolytic agent has the structure:
25. The composition of claim 12 , wherein the thiol saccharide mucolytic agent has the structure:
26. The method of claim 1 , wherein the thiol saccharide mucolytic agent has the structure:
27. The method of claim 1 , wherein the thiol saccharide mucolytic agent has the structure:
28. The method of claim 1 , wherein R 1 is —SH.
29. The method of claim 1 , wherein R 5 is —SH.
30. The composition of claim 12 , wherein R 1 is —SH.
31. The composition of claim 12 , wherein R 5 is —SH.