Derivatives of N-(arylamino) sulfonamides including polymorphs as inhibitors of MEK as well as compositions, methods of use and methods for preparing the same
View Patent ↗This invention concerns N-(2-arylamino) aryl sulfonamide compounds which are inhibitors of MEK including crystalline polymorphic forms which exhibit a specific powder x-ray diffraction profile and/or a specific differential scanning calorimetry profile. This invention also concerns pharmaceutical compositions comprising the compounds described herein and methods of use of the compounds and compositions described herein, including the use in the treatment and/or prevention of cancer, hyperproliferative diseases and inflammatory conditions. The invention also concerns methods of making the compounds and compositions described herein.
1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and
2. The pharmaceutical composition of claim 1 , which is substantially free of the S-isomer of the compound
3. The pharmaceutical composition of claim 1 , which is substantially free of the R-isomer of the compound
4. The pharmaceutical composition of claim 1 , which contains less than 10% of the S-isomer of the compound
5. The pharmaceutical composition of claim 1 , which contains less than 10% of the R-isomer of the compound
6. The pharmaceutical composition of claim 1 , comprising about 1-100 mg of a compound having the following structure:
7. The pharmaceutical composition of claim 1 , comprising: about 1-50 mg of a compound having the following structure
wherein the composition allows for modified release of the drug.
8. The pharmaceutical composition of claim 1 , further comprising microcrystalline cellulose.
9. The pharmaceutical composition of claim 1 , comprising about 1 mg of a compound of structure
about 222.2 mg of microcrystalline cellulose;
about 12.0 mg of croscarmellose sodium;
about 2.4 mg of sodium lauryl sulfate; and
about 2.4 mg of magnesium stearate.
10. The pharmaceutical composition of claim 1 , comprising about 10 mg of a compound of structure
about 213.2 mg of microcrystalline cellulose;
about 12.0 mg of croscarmellose sodium;
about 2.4 mg of sodium lauryl sulfate; and
about 2.4 mg of magnesium stearate.
11. The pharmaceutical composition of claim 1 , comprising about 20 mg of a compound of structure
about 203.2 mg of microcrystalline cellulose;
about 12.0 mg of croscarmellose sodium;
about 2.4 mg of sodium lauryl sulfate; and
about 2.4 mg of magnesium stearate.
12. The pharmaceutical composition of claim 1 , comprising about 40 mg of a compound of structure
about 183.2 mg of microcrystalline cellulose;
about 12.0 mg of croscarmellose sodium;
about 2.4 mg of sodium lauryl sulfate; and
about 2.4 mg of magnesium stearate.
13. A method for inhibiting an MEK enzyme comprising contacting said MEK enzyme with an effective amount of a pharmaceutical composition according to claim 1 to inhibit said enzyme by at least 25%.
14. A method of treatment of a MEK mediated disorder in an individual suffering from said disorder, comprising administering to said individual an effective amount of a pharmaceutical composition according to claim 1 .
15. A method for the treatment of a proliferative disease in an individual, wherein prophylaxis is excluded, comprising administering to said individual an effective amount of a pharmaceutical composition according to claim 1 , wherein said proliferative disease is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, leukemia, myeloid leukemia, glioblastoma, follicular lymphoma, pre-B acute leukemia, chronic lymphocytic B-leukemia, stomach cancer, mesothelioma, non-small cell lung carcinoma, small cell lung cancer or liver cancer.
16. A method for the treatment of a proliferative disease in an individual, wherein prophylaxis is excluded, comprising administering to said individual an effective amount of a pharmaceutical composition according to claim 1 , wherein said proliferative disease is lung cancer, pancreatic cancer, colorectal cancer, non-small cell lung carcinoma, small cell lung cancer or liver cancer.
17. A method for degrading, inhibiting the growth of or killing cancer cells comprising contacting the cells with an effective amount of a pharmaceutical composition according to claim 1 to degrade, inhibit the growth of or kill cancer cells.
18. A pharmaceutical composition according to claim 1 , wherein upon administration to a subject, the compound
reaches a C max between about 0.01 μg/ml to about 1.0 μg/ml on day 1.
19. A pharmaceutical composition according to claim 1 , wherein upon administration to a subject, the compound
has an AUC between about 0.1 μg hr/mL to about 5.0 μg hr/mL from 0-12 hours.
20. A pharmaceutical composition according to claim 1 , wherein upon administration to a subject, the compound
has a T max between 0.5 and 5.0 hours.
21. A method for the treatment of stomach cancer, brain cancer, breast cancer, lung cancer, non small cell lung cancer, ovarian cancer, pancreatic cancer, liver cancer, prostate cancer, renal cancer, colorectal cancer or leukemia in an individual, wherein prophylaxis is excluded, comprising administering to said individual an effective amount of a pharmaceutical composition according to claim 1 .
22. A method for the treatment of rheumatoid arthritis in an individual, wherein prophylaxis is excluded, comprising administering to said individual an effective amount of a pharmaceutical composition according to claim 1 .
23. A pharmaceutical composition according to claim 1 , wherein upon administration to a human subject, the compound
reaches a C max between about 0.01 μg/ml to about 1.0 μg/ml on day 1.
24. A pharmaceutical composition according to claim 1 , wherein upon administration to a human subject, the compound
has an AUC between about 0.1 μg hr/mL to about 5.0 μg hr/mL from 0-12 hours.
25. A pharmaceutical composition according to claim 1 , wherein upon administration to a human subject, the compound
has a T max between 0.5 and 5.0 hours.