Claims for Patent: 10,035,788

Summary for Patent: 10,035,788

Title:	Maleate salts of (E)-N-{4[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quino- linyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
Abstract:	The present invention relates to maleate salt forms of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide, methods of preparing crystalline maleate salt forms, the associated compounds, and pharmaceutical compositions containing the same. The maleate salts are useful in treating cancers, particularly those affected by kinases of the epidermal growth factor receptor family.
Inventor(s):	Lu; Qinghong (Suffern, NY), Ku; Mannching Sherry (Thiells, NY), Chew; Warren (Pierrefonds, CA), Cheal; Gloria (Beaconsfield, CA), Hadfield; Anthony F. (St. Petersburg, FL), Mirmehrabi; Mahmoud (Laval, CA)
Assignee:	WYETH LLC (New York, NY)
Application Number:	15/463,998
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,035,788
Patent Claims:	1. A method of treating cancer, comprising: administering to a patient in need thereof neratinib formulated as a crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate; wherein: i) the crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate is characterized by X-ray diffraction peaks at the following angles)(.+-.0.20.degree. of 2Theta in its X-ray diffraction pattern comprising 6.16, 7.38, 8.75, 12.61, 14.65, and 15.75; and ii) when administered to a patient, the formulation of the crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate produces at least a two-fold greater area under the curve, relative to neratinib in a free base formulation. 2. The method of claim 1, wherein the crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate is characterized by X-ray diffraction peaks at the following angles)(.+-.0.20.degree. of 2Theta in its X-ray diffraction pattern comprising 6.16, 7.38, 8.75, 12.24, 12.61, 14.65, 15.75, 17.33, 18.64, 19.99, 21.32, and 22.30. 3. The method of claim 1, wherein the crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate is characterized by X-ray diffraction peaks at the following angles)(.+-.0.20.degree. of 2Theta in its X-ray diffraction pattern comprising 6.16, 7.38, 8.75, 10.20, 12.24, 12.61, 14.65, 15.75, 17.33, 18.64, 19.99, 20.66, 21.32, 22.30, 23.18, 24.10, 24.69, 25.49, 26.09, 26.54, 27.52, 28.62, and 29.43. 4. The method of claim 1, wherein the crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate has substantially the X-ray diffraction pattern as shown in FIG. 6. 5. The method of claim 1, wherein the crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate has substantially the X-ray diffraction pattern as shown in FIG. 1 (lower scan). 6. The method of claim 1, wherein the cancer is selected from the group consisting of: breast cancer, ovarian cancer, epidermoid tumors, colon cancer, prostate cancer, kidney cancer, bladder cancer, larynx cancer, esophagus cancer, stomach cancer, and lung cancer. 7. The method of claim 1, wherein the cancer is breast cancer. 8. The method of claim 1, wherein the cancer is lung cancer. 9. The method of claim 1, wherein when administered to a patient, the formulation of the crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate mitigates interactions with emetic receptors relative to neratinib in a free base formulation. 10. The method of claim 1, wherein when administered to a patient, the formulation of the crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate reduces diarrhea, relative to neratinib in a free base formulation. 11. The method of claim 1, wherein the crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate is prepared according to a method comprising: i) mixing (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide and maleic acid in a water-alcohol solution at a temperature in the range of between about 50.degree. C. to about 60.degree. C.; ii) cooling said solution to a temperature of about 40.degree. C. and maintaining the cooled solution at about 40.degree. C. for about 12 hours to precipitate the maleate salt; iii) further cooling the cooled solution to room temperature (about 25.degree. C.) over a minimum of 4 hours and maintaining the further cooled solution at room temperature (about 25.degree. C.) for at least 2 hours; iv) filtering the maintained, further cooled solution to obtain crystalline (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate, wherein the crystalline (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate is (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate, monohydrate; and v) drying the crystalline (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate, monohydrate, under vacuum at a temperature greater than 30.degree. C. for 12 to 48 hours to obtain said crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate. 12. The method of claim 11, wherein the drying step comprises drying the (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate, monohydrate, at 50.degree. C., 10 mm Hg for 24 hours to obtain said crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate. 13. A method of treating cancer, comprising: administering to a patient in need thereof neratinib formulated as a crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate, monohydrate; wherein: i) the crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate, monohydrate, is characterized by X-ray diffraction peaks at the following angles)(.+-.0.20.degree. of 2Theta in its X-ray diffraction pattern comprising 6.53, 8.43, 12.19, 12.47, 13.01, 16.76, and 21.11; and ii) when administered to a patient, the formulation of the crystalline form of anhydrous (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate, monohydrate, produces at least a two-fold greater area under the curve, relative to neratinib in a free base formulation. 14. The method of claim 13, wherein the crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinyl methoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-buten- amide maleate, monohydrate, is characterized by X-ray diffraction peaks at the following angles)(.+-.0.20.degree. of 2Theta in its X-ray diffraction pattern comprising 6.53, 8.43, 12.19, 12.47, 13.01, 15.17, 16.76, 17.95, 19.86, and 21.11. 15. The method of claim 13, wherein the crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinyl methoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-buten- amide maleate, monohydrate, is characterized by X-ray diffraction peaks at the following angles)(.+-.0.20.degree. of 2Theta in its X-ray diffraction pattern comprising 6.53, 8.43, 10.16, 12.19, 12.47, 13.01, 15.17, 16.76, 17.95, 19.86, 21.11, 21.88, 23.22, 23.78, 25.69, 26.17, 27.06, 27.58, 28.26, 28.73, and 29.77. 16. The method of claim 13, wherein the crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinyl methoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-buten- amide maleate, monohydrate, has substantially the X-ray diffraction pattern as shown in FIG. 7. 17. The method of claim 13, wherein the crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinyl methoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-buten- amide maleate, monohydrate, has substantially the X-ray diffraction pattern as shown in FIG. 1 (upper scan). 18. The method of claim 13, wherein the cancer is selected from the group consisting of: breast cancer, ovarian cancer, epidermoid tumors, colon cancer, prostate cancer, kidney cancer, bladder cancer, larynx cancer, esophagus cancer, stomach cancer, and lung cancer. 19. The method of claim 13, wherein the cancer is breast cancer. 20. The method of claim 13, wherein the cancer is lung cancer. 21. The method of claim 13, wherein when administered to a patient, the formulation of the crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate, monohydrate, mitigates interactions with emetic receptors relative to neratinib in a free base formulation. 22. The method of claim 13, wherein when administered to a patient, the formulation of the crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate, monohydrate, reduces diarrhea, relative to neratinib in a free base formulation. 23. The method of claim 13, wherein the crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate, monohydrate, is prepared according to a method comprising: i) mixing (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide and maleic acid in a water-alcohol solution at a temperature in the range of between about 50.degree. C. to about 60.degree. C.; ii) cooling said solution to a temperature of about 40.degree. C. and maintaining the cooled solution at about 40.degree. C. for about 12 hours to precipitate the maleate salt; iii) further cooling the cooled solution to room temperature (about 25.degree. C.) over a minimum of 4 hours and maintaining the further cooled solution at room temperature (about 25.degree. C.) for at least 2 hours; and iv) filtering the maintained, further cooled solution to obtain said crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-q- uinolinyl}-4-(dimethylamino)-2-butenamide maleate, monohydrate. 24. The method of claim 23, wherein the obtained crystalline form of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin- olinyl}-4-(dimethylamino)-2-butenamide maleate, monohydrate, has a water content of about 2.5 to 2.7%, by weight.