Maleate salts of (E)-N-{4[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof

Patent metadata

Field	Value
Publication number	US-10035788-B2
Application number	US-201715463998-A
Country	US
Kind code	B2
Filing date	Mar 20, 2017
Priority date	Oct 17, 2007
Publication date	Jul 31, 2018
Grant date	Jul 31, 2018

Abstract

The present invention relates to maleate salt forms of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-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.

First claim

The invention claimed is:

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-quinolinyl}-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-quinolinyl}-4-(dimethylamino)-2-butenamide maleate is characterized by X-ray diffraction peaks at the following angles)(±0.20° 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-quinolinyl}-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-quinolinyl}-4-(dimethylamino)-2-butenamide maleate is characterized by X-ray diffraction peaks at the following angles)(±0.20° 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-quinolinyl}-4-(dimethylamino)-2-butenamide maleate is characterized by X-ray diffraction peaks at the following angles)(±0.20° 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-quinolinyl}-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-quinolinyl}-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-quinolinyl}-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-quinolinyl}-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-quinolinyl}-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-quinolinyl}-4-(dimethylamino)-2-butenamide and maleic acid in a water-alcohol solution at a temperature in the range of between about 50° C. to about 60° C.;
ii) cooling said solution to a temperature of about 40° C. and maintaining the cooled solution at about 40° C. for about 12 hours to precipitate the maleate salt;
iii) further cooling the cooled solution to room temperature (about 25° C.) over a minimum of 4 hours and maintaining the further cooled solution at room temperature (about 25° 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-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, wherein the crystalline (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate is (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-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-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, monohydrate, under vacuum at a temperature greater than 30° 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-quinolinyl}-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-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, monohydrate, at 50° 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-quinolinyl}-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-quinolinyl}-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-quinolinyl}-4-(dimethylamino)-2-butenamide maleate, monohydrate, is characterized by X-ray diffraction peaks at the following angles)(±0.20° 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-quinolinyl}-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-butenamide maleate, monohydrate, is characterized by X-ray diffraction peaks at the following angles)(±0.20° 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-butenamide maleate, monohydrate, is characterized by X-ray diffraction peaks at the following angles)(±0.20° 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-butenamide maleate, monohydrate, has substantially the X-ray diffraction pattern as shown in FIG. 7 .

Assignees

• Wyeth Llc

Inventors

• Lu Qinghong
• Ku Mannching Sherry
• Chew Warren
• Cheal Gloria
• Hadfield Anthony F
• Mirmehrabi Mahmoud

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• A61P13/12

  of the kidneys · CPC title