Salt of EGFR inhibitor, crystalline form and uses thereof
The invention relates to a salt, a hydrate or a crystalline form of an EGFR inhibitor, and use thereof. Specifically it relates to 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-[3-[(1R,6S)-2,5-dioxa-8-azabicyclo [4.3.0] nonan-8-yl] propoxy] quinazoline dimethanesulfonate, hydrate and a crystalline form thereof; the invention also relates to a preparation method of the crystalline form disclosed herein, a pharmaceutical composition containing the crystalline form, and uses thereof for treating proliferative disorders.
1. A compound having Formula (I):
2. A hydrate of a compound having formula (I).
3. The hydrate of claim 2 , wherein the hydrate is a monohydrate of the compound having formula (I).
4. A crystalline form of a monohydrate of a compound having formula (I):
wherein the crystalline form is form I having one or more of following characteristics:
i) an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 14.88°±0.2°, 18.05°±0.2°, 20.84°±0.2°, 21.34°±0.2°, 24.39°±0.2° and 25.18°±0.2°; or/and
ii) the following structure parameters analyzed from monocrystalline:
Crystallographic System:
monoclinic system
Space Groups:
C2/c;
Cell Parameters:
a = 27.3004(5) Å, α = 90°,
b = 16.2882(3) Å, β = 103.3439(17)°,
c = 14.3529(2) Å, γ = 90°;
Volume:
6210.01(18) Å 3 ;
Molecules number of
8.
each unit cell (Z):
5. The crystalline form of claim 4 having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 9.47°±0.2°, 14.88°±0.2°, 16.58°±0.2°, 17.15°±0.2°, 17.46°±0.2°, 18.05°±0.2°, 20.46°±0.2°, 20.84°±0.2°, 21.34°±0.2°, 22.71°±0.2°, 23.16°±0.2°, 24.39°±0.2°, 25.18°±0.2°, 25.46°±0.2°, 26.29°±0.2° and 28.01°±0.2°.
6. The crystalline form of claim 4 having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 6.36°±0.2°, 6.66°±0.2°, 9.47°±0.2°, 10.82°±0.2°, 11.70°±0.2°, 13.31°±0.2°, 14.88°±0.2°, 15.86°±0.2°, 16.58°±0.2°, 17.15°±0.2°, 17.46°±0.2°, 18.05°±0.2°, 19.30°±0.2°, 20.46°±0.2°, 20.84°±0.2°, 21.34°±0.2°, 21.76°±0.2°, 22.28°±0.2°, 22.71°±0.2°, 23.16°±0.2°, 24.07°±0.2°, 24.39°±0.2°, 25.18°±0.2°, 25.46°±0.2°, 26.29°±0.2°, 26.78°±0.2°, 27.15°±0.2°, 28.01°±0.2°, 28.80°±0.2°, 29.77°±0.2°, 30.44°±0.2°, 31.06°±0.2°, 32.05°±0.2°, 33.01°±0.2°, 33.51°±0.2°, 33.84°±0.2°, 34.90°±0.2°, 38.03°±0.2°, 38.58°±0.2° and 39.48°±0.2°.
7. The crystalline form of claim 4 having an X-ray powder diffraction (XRPD) pattern as shown in FIG. 1 .
8. The crystalline form of claim 4 having a monocrystalline structure as shown in FIG. 3 .
9. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
10. The pharmaceutical composition of claim 9 further comprising a therapeutic agent, wherein the therapeutic agent is a chemotherapeutic agent used for treating proliferative disease or cancer, an antiproliferative agent, a cytotoxic agent, a signal transduction inhibitor, an agent used for treating non-small cell lung cancer or skin cancer or a combination thereof; and wherein the therapeutic agent is adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabine, cyclophosphamide, dexamethasone, etoposide, fluorouracil, imatinib mesylate, dasatinib, nilotinib, erlotinib, lapatinib, gefitinib, sorafenib, sunitinib, interferon, carboplatin, topotecan, paclitaxel, vinblastine, vincristine, temozolomide, tositumomab, trabedectin, bevacizumab, trastuzumab, cetuximab, panitumumab, icotinib, icotinib hydrochloride, matuzmab, neratinib, canertinib, vandetanib, cediranib, vatalanib, axitinib, motesanib, nimotuzumab, theliatinib, epitinib, simotinib, poziotinib, varlitinib, rociletinib, pelitinib, osimertinib, PKI-166, PD 158780, MDX447, Mab425, HM-61713, TAS-121, seribantumab, naquotinib, or a combination thereof.
11. A method of inhibiting EGFR in a subject, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .
12. A method of treating a proliferative disorder in a patient, comprising administering to the patient a therapeutically effective amount of the compound of claim 1 ; wherein the proliferative disorder is colon cancer lung cancer or malignant glioma.
13. A pharmaceutical composition comprising the hydrate of claim 2 ; and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
14. A pharmaceutical composition comprising the crystalline form of claim 4 ; and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
15. The pharmaceutical composition of claim 13 further comprising a therapeutic agent, wherein the therapeutic agent is a chemotherapeutic agent used for treating proliferative disease or cancer, an antiproliferative agent, a cytotoxic agent, a signal transduction inhibitor, an agent used for treating non-small cell lung cancer or skin cancer or a combination thereof; and wherein the therapeutic agent is adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabine, cyclophosphamide, dexamethasone, etoposide, fluorouracil, imatinib mesylate, dasatinib, nilotinib, erlotinib, lapatinib, gefitinib, sorafenib, sunitinib, interferon, carboplatin, topotecan, paclitaxel, vinblastine, vincristine, temozolomide, tositumomab, trabedectin, bevacizumab, trastuzumab, cetuximab, panitumumab, icotinib, icotinib hydrochloride, matuzmab, neratinib, canertinib, vandetanib, cediranib, vatalanib, axitinib, motesanib, nimotuzumab, theliatinib, epitinib, simotinib, poziotinib, varlitinib, rociletinib, pelitinib, osimertinib, PKI-166, PD 158780, MDX447, Mab425, HM-61713, TAS-121, seribantumab, naquotinib, or a combination thereof.
16. The pharmaceutical composition of claim 14 further comprising a therapeutic agent, wherein the therapeutic agent is a chemotherapeutic agent used for treating proliferative disease or cancer, an antiproliferative agent, a cytotoxic agent, a signal transduction inhibitor, an agent used for treating non-small cell lung cancer or skin cancer or a combination thereof; and wherein the therapeutic agent is adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabine, cyclophosphamide, dexamethasone, etoposide, fluorouracil, imatinib mesylate, dasatinib, nilotinib, erlotinib, lapatinib, gefitinib, sorafenib, sunitinib, interferon, carboplatin, topotecan, paclitaxel, vinblastine, vincristine, temozolomide, tositumomab, trabedectin, bevacizumab, trastuzumab, cetuximab, panitumumab, icotinib, icotinib hydrochloride, matuzmab, neratinib, canertinib, vandetanib, cediranib, vatalanib, axitinib, motesanib, nimotuzumab, theliatinib, epitinib, simotinib, poziotinib, varlitinib, rociletinib, pelitinib, osimertinib, PKI-166, PD 158780, MDX447, Mab425, HM-61713, TAS-121, seribantumab, naquotinib, or a combination thereof.
17. A method of inhibiting EGFR in a subject, comprising administering to the subject a therapeutically effective amount of the crystalline form of claim 4 .
18. A method of inhibiting EGFR in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 14 .
19. A method of treating the severity of a proliferative disorder in a patient, comprising administering to the patient a therapeutically effective amount of the crystalline form of claim 4 , wherein the proliferative disorder is colon cancer lung cancer, or malignant glioma.
20. A method of treating a proliferative disorder in a patient, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 14 ; wherein the proliferative disorder is colon cancer, lung cancer, or malignant glioma.