Compounds and compositions for treatment of breathing control disorders or diseases
The present invention includes compounds, and compositions comprising the same, that are useful in the treatment of breathing control diseases or disorders in a subject in need thereof. The present invention also includes a method of treating a respiratory disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention. The present invention further includes a method of preventing destabilization or stabilizing breathing rhythm in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention.
1. A composition comprising N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXV) or a salt thereof, wherein 4,6-bis-(n-propylamino)-1,3,5-triazin-2-ol (CLXXVIII) is essentially absent from the composition or is present in the composition at a level equal to or lower than about 1% (w/w) with respect to (XXXV) or the salt thereof.
2. The composition of claim 1 , wherein 4,6-bis-(n-propylamino)-1,3,5-triazin-2-ol (CLXXVIII) is present at a level equal to or lower than about 0.5% (w/w) with respect to (XXXV) or the salt thereof.
3. The composition of claim 2 , wherein 4,6-bis-(n-propylamino)-1,3,5-triazin-2-ol (CLXXVIII) is present at a level equal to or lower than about 0.2% (w/w) with respect to (XXXV) or the salt thereof.
4. The composition of claim 3 , wherein 4,6-bis-(n-propylamino)-1,3,5-triazin-2-ol (CLXXVIII) is present at a level equal to or lower than about 0.15% (w/w) with respect to (XXXV) or the salt thereof.
5. The composition of claim 4 , wherein 4,6-bis-(n-propylamino)-1,3,5-triazin-2-ol (CLXXVIII) is present at a level equal to or lower than about 0.1% (w/w) with respect to (XXXV) or the salt thereof.
6. The composition of claim 5 , wherein 4,6-bis-(n-propylamino)-1,3,5-triazin-2-ol (CLXXVIII) is essentially absent from the composition.
7. The composition of claim 1 , further comprising a buffer and a liquid carrier.
8. The composition of claim 7 , wherein the salt of (XXXV) is the hydrogen sulfate salt (XXXVI).
9. The composition of claim 7 , further comprising citric acid.
10. The composition of claim 7 , wherein the pH of the composition is adjusted with a base.
11. The composition of claim 10 , wherein the base comprises sodium hydroxide.
12. The composition of claim 7 , wherein the liquid carrier comprises water.
13. The composition of claim 7 , wherein the pH of the composition ranges from about 2.5 to about 5.
14. The composition of claim 7 , wherein the concentration of (XXXV) or the salt thereof in the composition is about 1-10 mg/mL.
15. The composition of claim 14 , wherein the concentration of (XXXV) or the salt thereof in the composition is about 5-10 mg/mL.
16. The composition of claim 15 , wherein the concentration of (XXXV) or the salt thereof in the composition is about 10 mg/mL.
17. The composition of claim 7 , comprising less than 0.5% (w/w) (CLXXVIII) with respect to (XXXV).
18. The composition of claim 17 , wherein less than 0.5% (w/w) of N-(4,6-Bis-n-propylamino)-[1,3,5]-triazin-2-ol (CLXXVIII) with respect to (XXXV) forms over a six-month period of storage of the composition at 2-8° C.
19. The composition of claim 18 , wherein less than 0.5% (w/w) of N-(4,6-Bis-n-propylamino)-[1,3,5]-triazin-2-ol (CLXXVIII) with respect to (XXXV) forms over a twenty-four-month period of storage of the composition at 2-8° C.
20. A crystalline free base of N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXV), Form A, having the XRPD spectrum of FIG. 22 .
21. At least one crystalline salt of N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXV) selected from the group consisting of:
(i) crystalline hydrogen sulfate salt (XXXVI) Form A, having the XRPD spectrum of FIG. 14 ;
(ii) crystalline hydrogen sulfate salt (XXXVI) comprising a mixture of Form A and Form B, having the XRPD spectrum of FIG. 23 ;
(iii) crystalline hydrogen sulfate salt (XXXVI) Form C, having the XRPD spectrum of FIG. 24 ;
(iv) crystalline hydrogen sulfate salt (XXXVI) Form D, having the XRPD spectrum of FIG. 25 ;
(v) crystalline hydrogen sulfate salt (XXXVI) comprising a mixture of Form A and Form D, having the XRPD spectrum of FIG. 26 ;
(vi) crystalline phosphoric acid salt (CLXXX) Form A, having the XRPD spectrum of FIG. 27 ;
(vii) crystalline phosphoric acid salt (CLXXX) Form C, having the XRPD spectrum of FIG. 28 ;
(viii) crystalline phosphoric acid salt (CLXXX) comprising a mixture of Form A and Form B, having the XRPD spectrum of FIG. 29 ;
(ix) crystalline phosphoric acid salt (CLXXX) comprising a mixture of Form C and Form D, having the XRPD spectrum of FIG. 30 ;
(x) crystalline phosphoric acid salt (CLXXX) comprising a mixture of Form C and Form E, having the XRPD spectrum of FIG. 31 ;
and any mixtures thereof.
22. A salt of N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXV), comprising about one mole equivalent of sulfuric acid.
23. The salt of claim 22 , further comprising one mole equivalent of water.
24. A salt of N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXV), comprising at least one mole equivalent of phosphoric acid.
25. The salt of claim 24 , comprising about one mole equivalent of phosphoric acid.
26. A method of increasing minute ventilation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXV) or a salt thereof, wherein 4,6-bis-(n-propylamino)-1,3,5-triazin-2-ol (CLXXVIII) is essentially absent from the composition or is present in the composition at a level equal to or lower than about 1% (w/w) with respect to (XXXV) or the salt thereof.
27. The method of claim 26 , wherein the pharmaceutical formulation is administered via intravenous infusion.
28. The method of claim 26 , wherein the infusion dose of the pharmaceutical formulation is at least about 0.016 mg/kg/min of N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXV).
29. The method of claim 26 , wherein the infusion dose of the pharmaceutical formulation is about 0.016 mg/kg/min of N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXV).
30. The method of claim 26 , wherein the infusion dose of the pharmaceutical composition produces a plasma concentrations of at least about 726 ng/mL of N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXV) in the subject.
31. The method of claim 26 , wherein the subject is a mammal.
32. The method of claim 31 , wherein the mammal is human.
33. The method of claim 26 , wherein the infusion dose of the pharmaceutical formulation is about 0.012 mg/kg/min of N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXV).