Substituted dioxopiperidinyl phthalimide derivatives
This invention relates to novel substituted dioxopiperidinyl phthalimide derivatives and pharmaceutically acceptable acid addition salts thereof. The invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions beneficially treated by an immunomodulatory agent.
1. A compound of Formula Ia:
or a pharmaceutically acceptable salt thereof, wherein:
each of W 1 , W 2 , and W 3 is independently selected from hydrogen or deuterium;
each of Y 1 and Y 2 is independently selected from hydrogen or deuterium; and
each of Z 1 Z 2 , Z 3 and Z 4 is independently selected from hydrogen or deuterium;
wherein the compound comprises less than 25% of the other enantiomer, and wherein each position designated as D or deuterium has at least 75% incorporation of deuterium, and wherein any atom not designated as deuterium is present at its natural isotopic abundance.
2. The compound of claim 1 , wherein Z 3 and Z 4 are deuterium; W 1 , W 2 and W 3 are simultaneously hydrogen or simultaneously deuterium; Z 1 and Z 2 are simultaneously hydrogen; and Y 1 and Y 2 are simultaneously hydrogen.
3. The compound of claim 1 , wherein Z 3 and Z 4 are deuterium; W 1 , W 2 and W 3 are simultaneously hydrogen or simultaneously deuterium; Z 1 and Z 2 are simultaneously hydrogen; and Y 1 and Y 2 are simultaneously deuterium.
4. The compound of claim 1 , wherein W 1 , W 2 and W 3 are the same.
5. The compound of claim 4 , wherein W 1 , W 2 and W 3 are simultaneously hydrogen.
6. The compound of claim 5 , wherein Z 1 , Z 2 , Z 3 and Z 4 are the same.
7. The compound of claim 6 , wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are simultaneously deuterium.
8. The compound of claim 7 , wherein each Y is simultaneously deuterium.
9. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
12. A pyrogen-free pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.
13. The composition of claim 12 , additionally comprising a second therapeutic agent selected from pemetrexed, topotecan, doxorubicin, bortezomib, gemcitabine, dacarbazine, dexamethasone, biaxin, doxil, vincristine, decadron, azacitidine, rituximab, prednisone, docetaxel, melphalan, and combinations thereof.
14. A method of treating a disease or condition selected from myelodysplastic syndromes, multiple myeloma, Non-Hodgkins lymphoma; chronic lymphocytic leukemia, amyloidosis, malignant gliomas, chronic myelomonocytic leukemia, follicular lymphoma, myeloid leukemia, mantle cell lymphoma, non-small cell lung cancer, Hodgkin's lymphoma, large cell lymphoma, and Waldenstrom's macroglobulinemia in a patient in need thereof, the method comprising the step of administering to the patient a composition of claim 12 .
15. The method of claim 14 , wherein the disease is selected from myelodysplastic syndromes and multiple myeloma.
16. The compound of claim 1 , wherein the compound comprises less than 10% of the other enantiomer.
17. The compound of claim 1 , wherein the compound comprises less than 5% of the other enantiomer.
18. The compound of claim 1 , wherein the compound comprises less than 2% of the other enantiomer.
19. The compound of claim 1 , wherein each position designated as D or deuterium has at least 90% incorporation of deuterium.
20. The compound of claim 1 , wherein each position designated as D or deuterium has at least 95% incorporation of deuterium.
21. The compound of claim 1 , wherein the compound comprises less than 10% of the other enantiomer and wherein each position designated as D or deuterium has at least 90% incorporation of deuterium.
22. The compound of claim 1 , wherein the compound comprises less than 5% of the other enantiomer and wherein each position designated as D or deuterium has at least 90% incorporation of deuterium.
23. The compound of claim 1 , wherein the compound comprises less than 2% of the other enantiomer and wherein each position designated as D or deuterium has at least 95% incorporation of deuterium.