(e) Methods for preparing N - (4 - (3 - Chloro - 4 - (2 - piridinilmetoxi) anilino) - ethoxy - 3 - cyano - 7 - 6 quinolinil) - 4 - (dimethylamino) - 2 / - as maleate Salt, Pharmaceutical compositions for the inhibition of the kinase activity her - isolated 2 and Crystal forms of these salts maleate

摘要

Forms of maleate Salt of (e) - N - (4 - [3 - (4 - (2 - chlorine - piridinilmetoxi) anilino] - 3 - cyano - ethoxy - 6 - 7 - quinolinil} - 4 - (dimethylamino) - 2 - /, Methods for preparing forms of maleate Salt Crystal Associated Compounds, and Pharmaceutical compositions containing the salts maleate.Maleate salts are useful in the treatment of cancer, particularly those affected by Family Kinases of the epidermal growth factor receptor.Claim 1: a method for the preparation of (e) - N - (4 - [3 - (4 - (2 - chlorine - piridinilmetoxi) anilino] - 3 - cyano - ethoxy - 6 - 7 - quinolinil} - 4 - (dimethylamino) - 2 / - as maleate Salt,Characterized by understanding the mixing Stage: (e) - N - (4 - [3 - (4 - (2 - chlorine - piridinilmetoxi) anilino] - 3 - cyano - ethoxy - 6 - 7 - quinolinil} - 4 - (dimethylamino) - 2 - / and Maleic acid in a Water alcohol Solution a high temperature. Claim: a compound characterized by 14 belong to the set consisting of: group of formulas (1).A method for preparing claim 17: maleate monohydrate (e) - N - (4 - [3 - (4 - (2 - chlorine - piridinilmetoxi) aniiino] - 3 - cyano - ethoxy - 6 - 7 - quinolinil) - 4 - (dimethylamino) - 2 - / understand the selected stages characterized by the Group consisting of:.Dissolves maleate (e) - N - (4 - [3 - (4 - (2 - chlorine - piridinilmetoxi) anilino] - 3 - cyano - ethoxy - 6 - 7 - quinolinil} - 4 - (dimethylamino) - 2 - / with an anhydrous Organic Solvent, adding Water, and filtered; b.Dissolves maleate (e) - N - (4 - [3 - (4 - (2 - chlorine - piridinilmetoxi) anilino] - 3 - cyano - ethoxy - 6 - 7 - quinolinil} - 4 - (dimethylamino) - 2 - / with an anhydrous Organic Solvent, adding a solution of a Second Organic Solvent yagua,C is dissolved and filtered; maleate (e) - N - (4 - (3 - Chloro - 4 - (2 - piridinilmetoxi) anilino] - 3 - cyano - ethoxy - 6 - 7 - quinolinil} - 4 - (dimethylamino) - 2 - / with an anhydrous Organic Solvent containing Water,And filtered; and D redissolve maleate (e) - N - (4 - [3 - (4 - (2 - chlorine - piridinilmetoxi) anilino] - 3 - cyano - ethoxy - 6 - 7 - quinolinil} - 4 - (dimethylamino) - 2 - / with an anhydrous Organic Solvent containing water during a period of days, and filter.Claim 1: Isolation of a Crystalline form maleate monohydrate (e) - N - (4 - [3 - (4 - (2 - chlorine - piridinilmetoxi) anilino] - 3 - cyano - ethoxy - 6 - 7 - quinolinil} - 4 - (dimethylamino) - 2 - / characterized by diffraction Peaks x-ray in the Following Angles (+ - 2 Theta 0.20u00b0) in their pattern X-ray diffraction: 6.53, 8.43, 10.16, 12.19, 1247, 13.01, 15.17, 16.76, 17.95, 19.86, 21.11, 21.88, 23.22, 23.78, 25.69, 26.17, 27.06, 28.17, 28.26, 31.03 and 29.92. Claim 31: a Crystalline form isolated maleate (e) - N - (4 - [3 - (4 - (2 - chlorine - piridinilmetoxi) anilino] - 3 - cyano - ethoxy - 6 - 7 - quinolinil} - 4 - (dimethylamino) - 2 - / anhydrous, characterized by diffraction Peaks x-ray in the Following Angles (+ - 2 Theta 0.20u00b0) in their pattern of dif Reaction of x-ray: 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 16.47.Claim 1: a Crystalline form isolated maleate (e) - N - (4 - [3 - (4 - (2 - chlorine - piridinilmetoxi) anilino] - 3 - cyano - ethoxy - 6 - 7 - quinolinil} - 4 - (dimethylamino) - 2 - / anhydrous, characterized by a starting temperature of 196u00b0C and the final temperature of 204u00b0C, as measured by the calorimetru00ed A differential Scanning.Claim: a Crystalline form of 34 isolated maleate monohydrate (e) - N - (4 - [3 - (4 - (2 - chlorine - piridinilmetoxi) anilino] - 3 - cyano - ethoxy - 6 - 7 - quinolinil} - 4 - (dimethylamino) - 2 - /, which has a Water content 2.5 to 2.7% in weight.Claim 35: a partially hydrated Crystalline form isolated maleate (e) - N - (4 - [3 - (4 - (2 - chlorine - piridinilmetoxi) anilino] - 3 - cyano - ethoxy - 6 - 7 - quinolinil} - 4 - (dimethylamino) - 2 - /, which has a Content of Water from 1.5% to 2.3% in weight.