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,
L 1 and L 5 are independently a bond or methylene;
R 1 is —SH, —OR 1A or —NR 1B , 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;
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 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, —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, —OR 5A or —NR 5B , 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; and
R 5C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl.
2. The method of claim 1 , wherein said method comprises decreasing mucus viscoelasticity in said subject.
3. 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,
L 1 and L 5 are independently a bond or methylene;
R 1 is —SH, —OR 1A or —NR 1B , 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;
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 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, —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, —OR 5A or —NR 5B , 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; and
R 5C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl.
4. The pulmonary pharmaceutical composition of claim 3 , wherein said pulmonary pharmaceutical carrier is a pulmonary pharmaceutical liquid or pulmonary pharmaceutical powder.
5. The pulmonary pharmaceutical composition of claim 4 , wherein said pulmonary pharmaceutical liquid comprises a polar liquid, and said thiol saccharide mucolytic agent is dissolved or suspended in said polar liquid.
6. The pulmonary pharmaceutical composition of claim 5 , wherein said polar liquid is water.
7. The pulmonary pharmaceutical composition of claim 4 , wherein said pulmonary pharmaceutical carrier is lactose, mannitol, a phospholipid or cholesterol.
8. The pulmonary pharmaceutical composition of claim 4 , wherein said pulmonary pharmaceutical carrier is the parent sugar of said thiol saccharide mucolytic agent, said parent sugar lacking a thiol moiety.
9. The pulmonary pharmaceutical composition of claim 3 , wherein said pulmonary pharmaceutical composition is within a pulmonary pharmaceutical delivery device.
10. The pulmonary pharmaceutical composition of claim 9 , wherein said pulmonary pharmaceutical delivery device is a pulmonary pharmaceutical nebulizer, a pulmonary pharmaceutical dry powder inhaler, or a pulmonary pharmaceutical pressurized metered dose inhaler.
11. A thiol saccharide compound with structure of Formula (II):
wherein,
L 1 and L 5 are independently a bond or methylene;
R 1 is —SH, —OR 1A or —NR 1B , 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;
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 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, —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, —OR 5A or —NR 5B , 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 , unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl; and
R 5C is substituted or unsubstituted C 1 -C 10 thiol-alkyl or substituted or unsubstituted 2 to 10 membered thiol-heteroalkyl.