Deuterated pyrazino[2,1-a]isoquinoline compounds and methods of treatment using the same
This invention in one embodiment is directed to a compound of Formula Ia; where the designation (R) indicates that the designated carbon has the (R) stereochemistry; and wherein Z 1 is hydrogen or fluorine; Z 2 is hydrogen, deuterium, or fluorine; Z 3 is deuterium; Z 4 is fluorine; m is an integer from 0 to 10; n is an integer from 0 to 2; provided that: the sum of m+n does not exceed 10; and when both Z 1 and Z 2 are hydrogen, the sum of m+n is greater than 0, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering an antihelminthic agent, such as praziquantel.
1. A compound selected from:
or a pharmaceutically acceptable salt thereof, wherein the compound has a deuterium incorporation at each designated deuterium atom of at least 90%.
2. The compound of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.
3. The compound of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 97%.
4. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. A compound selected from:
or a pharmaceutically acceptable salt thereof, wherein the compound has a deuterium incorporation at each designated deuterium atom of at least 90%.
6. The compound of claim 5 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.
7. The compound of claim 5 , wherein the deuterium incorporation at each designated deuterium atom is at least 97%.
8. A pharmaceutical composition comprising a compound of claim 5 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9. A method of treating schistosoma infections, infections due to Clonorchis sinensis or Opisthorchis viverrini , cysticercosis, neurocysticercosis, or malaria in a patient comprising administering to a patient in need thereof an effective amount of a compound of Formula Ia:
or a pharmaceutically acceptable salt thereof, wherein:
Z 1 is hydrogen or fluorine;
Z 2 is hydrogen, deuterium, or fluorine;
Z 3 is deuterium;
Z 4 is fluorine;
m is 2, 4, 6, 8 or 10; and
n is 0 or 2;
provided that:
the sum of m and n does not exceed 10;
wherein the compound has a deuterium incorporation at each designated deuterium atom of at least 90%.
10. The method of claim 9 , wherein 2, 4, 6, 8 or 10 geminal Z 3 are present.
11. The method of claim 9 , wherein Z 2 is hydrogen.
12. The method of claim 9 , wherein Z 2 is deuterium.
13. The method of claim 9 , wherein 2 geminal Z 4 are present.
14. The method of claim 9 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
15. The method of claim 9 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
16. The method of claim 14 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.
17. The method of claim 14 , wherein the deuterium incorporation at each designated deuterium atom is at least 97%.
18. The method of claim 15 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.
19. The method of claim 15 , wherein the deuterium incorporation at each designated deuterium atom is at least 97%.