Claims for Patent: 10,738,037

Summary for Patent: 10,738,037

Title:	Crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2- -(tetrahydro-pyran-4-ylamino)-benzamide
Abstract:	The present invention relates to a new crystalline form of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2- -(tetrahydro-pyran-4-ylamino)-benzamide, process for its preparation, its utility in treating diseases caused by deregulated protein kinase activity and pharmaceutical compositions containing it.
Inventor(s):	Candiani; Ilaria (Busto Arsizio, IT), Ottaiano; Giovanni (Corbetta Milan, IT), Tomasi; Attilio (Milan, IT)
Assignee:	NERVIANO MEDICAL SCIENCES S.R.L. (Nerviano (MI), IT)
Application Number:	16/301,826
Patent Claims:	1. Crystalline Form 4 of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2- -(tetrahydro-pyran-4-ylamino)-benzamide of the following formula (I) ##STR00006## wherein said crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at a 2-theta values of about 8.6, 15.6, 17.9, and 21.3.+-.0.2 degrees. 2. The crystalline Form 4 according to claim 1, wherein said X-ray powder diffraction pattern further comprises the peaks at 2-theta values of about 19.7, 22.1, and 24.3.+-.0.2 degrees. 3. The crystalline Form 4 according to claim 1 or 2 wherein said crystalline form is further characterized by exhibiting a peak in a differential scanning calorimetry scan of from about 200.degree. C. to about 205.degree. C. 4. A pharmaceutical composition comprising a crystalline Form 4 of the compound of formula (I) as defined in claim 1 as active ingredient and a pharmaceutically acceptable excipient, carrier or diluent. 5. The pharmaceutical composition according to claim 4, wherein said composition is in the form of a tablet, a capsule, a suspension, an emulsion, a dispersible powder or granules. 6. The pharmaceutical composition according to claim 5, wherein said composition comprises from about 10 mg to about 1 g of said crystalline Form 4 of compound of formula (I) per dose. 7. A method of treating colorectal cancer in a mammal comprising: administering to said mammal a therapeutically effective amount of crystalline Form 4 as defined in claim 1. 8. A method of treating colorectal cancer in a mammal having at least one genetic alteration in at least one target gene selected from the group consisting of ROS1, NTRK1, NTRK2 and NTRK3, comprising: administering to said mammal a therapeutically effective amount of crystalline Form 4 as defined in claim 1. 9. A process for preparing the crystalline Form 4 of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2- -(tetrahydro-pyran-4-ylamino)-benzamide of the following formula (I) ##STR00007## comprising the following steps: a) adding the acyl chloride of formula (II): ##STR00008## to the indazol-3-ylamine of formula (III): ##STR00009## blocking the addition when the indazol-3-ylamine of formula (III) is completely reacted; b) deprotecting under mild basic conditions the resulting compound of formula (IV): ##STR00010## to obtain the compound of formula (I) as defined above; c) suspending in ethanol the obtained compound of formula (I); d) heating the suspension of step c) to a temperature between about 50.degree. C. and about 70.degree. C. and cooling to room temperature; and e) adding water, filtering and drying to give the crystalline Form 4 of compound of formula (I); or, alternatively: f) heating at reflux temperature a slurry of crystalline Form 2 of compound of formula (I) in ethanol to obtain a solution and cooling the solution to a temperature between about 50.degree. C. and about 65.degree. C.; g) adding an amount of crystalline Form 4 seeds, obtained as defined in steps a) to e) to the solution of step f), followed by adding water; h) heating the mixture of step g) at reflux temperature for a time period ranging from 30 to 90 minutes, followed by cooling the mixture to room temperature and stirring for about 12 hours; i) filtering the mixture of step h) and drying at about 40.degree. C. to obtain the crystalline Form 4 of the compound of formula (I), as defined in claim 1. 10. The process according to claim 9, wherein the solution of step f) is cooled at temperature between 55.degree. C. and 60.degree. C. 11. The process according to claim 9, wherein the mixture of step g) is heated at reflux temperature for 60 minutes. 12. The method of claim 8, wherein the mammal is a human being. 13. The method of claim 9, wherein the mammal is a human being. 14. Crystalline Form 4 of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2- -(tetrahydro-pyran-4-ylamino)-benzamide of the following formula (I) ##STR00011## wherein said crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak at a 2-theta value of about 10.3, 11.0, 11.9, 14.3, 14.6, 15.1, 15.3, 16.1, 17.1, 19.0, 19.2, 19.6, 19.7, 20.1, 20.7, 21.3, 22.1, 22.7, 24.3, 24.6, 25.3, 25.5, 25.9, 26.7, 26.9, 27.3, 27.7, 28.1, 28.6, 29.0, 29.5, 29.9, 30.5, 31.0, 31.6, 32.2, 33.3, 34.0, 35.4, 36.4 and 36.8.+-.0.2 degrees. 15. Crystalline Form 4 of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2- -(tetrahydro-pyran-4-ylamino)-benzamide of the following formula (I) ##STR00012## wherein said crystalline form is characterized by a melting endotherm at a peak temperature of about 200.degree. C. to about 205.degree. C. 16. The crystalline Form 4 according to claim 15, wherein said crystalline form is further characterized by a Delta H in the range 70-82 J/g. 17. The crystalline Form 4 according to claim 2, wherein said X-ray powder diffraction pattern further comprises the peaks at 2-theta values of about 19.6 and 22.7.+-.0.2 degrees. 18. The crystalline Form 4 according to claim 17, wherein said X-ray powder diffraction pattern further comprises the peaks at a reflection angle 2-theta of about 10.3, 11.0, 11.9, 14.3, 14.6, 15.1, 15.3, 16.1, 17.1, 19.0, 19.2, 20.1, 20.7, 24.6, 25.3, 25.5, 25.9, 26.7, 26.9, 27.3, 27.7, 28.1, 28.6, 29.0, 29.5, 29.9, 30.5, 31.0, 31.6, 32.2, 33.3, 34.0, 35.4, 36.4, 36.8, and 39.0 .+-.0.2 degrees.