Crystalline C21H22Cl2N4O2 malonate

Patent metadata

Field	Value
Publication number	US-9670177-B2
Application number	US-201615011420-A
Country	US
Kind code	B2
Filing date	Jan 29, 2016
Priority date	Jan 30, 2015
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

The present invention provides a malonate salt of a compound of formula (I):

which is a crystalline salt. Also provided are pharmaceutical compositions that include the provided malonate salt and methods of using the provided crystalline forms and pharmaceutical compositions for the treatment of cancer.

First claim

What is claimed is:

1. A malonate salt of a compound of formula (I):

which is a crystalline salt having an X-ray powder diffraction(XRPD) pattern comprising characteristic peaks at about 3.0 and 5.2° 2θ.

2. The malonate salt according to claim 1 having an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks selected from the group consisting of about 3.0, 5.2, 8.0, and 10.9° 2θ.

3. The malonate salt according to claim 1 having an X-ray powder diffraction (XRPD) pattern comprising XRPD 2θ-reflections)(°) at about 3.0. 5.2, 8.0, 10.9, 15.7, 18.4, 23.1, and 25.4.

4. A malonate salt of a compound of formula (I):

having an XRPD pattern substantially as shown in FIG. 7 .

5. Form A crystalline 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide malonate according to claim 1 having an infrared spectroscopy (IR) spectrum comprising one or more peaks at about 1573, 1504, 1475, 1253, 1033, and 883 cm −1 .

6. Form A crystalline 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide malonate according to claim 1 having an IR spectrum substantially as shown in FIG. 8 .

7. Form A crystalline 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H -pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide malonate according to claim 1 having (i) an XRPD pattern comprising one or more peaks at about 3.0. 5.2, 8.0, and 10.9° 2θ; and (ii) an IR spectrum comprising one or more peaks at about 1573, 1504, 1475, 1253, 1033, and 883 cm −1 .

8. Form A crystalline 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide malonate according to claim 1 having a DSC thermogram with an endotherm having an onset temperature of approximately 142.1° C.

9. Form A crystalline 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyI)-2-hydroxyethyl]amide malonate according to claim 1 having a DSC thermogram substantially as shown in FIG. 9 .

10. A pharmaceutical composition comprising a crystalline compound according to any one of claims 1 or 4 - 9 and a pharmaceutically acceptable carrier.

11. A method of treating a cancer in a subject in need thereof comprising administering to the subject an effective amount of a crystalline compound according to any one of claims 1 or 4 - 9 , wherein the cancer is an ERK-dependent cancer associated with an extracellular signal-related kinase (ERK) pathway.

12. The method according to claim 11 , wherein the subject is a mammal.

13. The method according to claim 12 , wherein the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals.

14. The method according to claim 12 , wherein the mammal is a human.

15. The method according to claim 11 further comprising administering to the subject at least one additional anti-cancer agent.

16. A method of treating a cancer in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition according to claim 10 , wherein the cancer is an ERK-dependent cancer associated with an extracellular signal-related kinase (ERK) pathway.

17. The method according to claim 16 , wherein the subject is a mammal.

18. The method according to claim 17 , wherein the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals.

19. The method according to claim 17 , wherein the mammal is a human.

20. The method according to claim 16 further comprising administering to the subject at least one additional anti-cancer agent.

21. A method of making Form A crystalline 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide malonate comprising reacting malonic acid and 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide under conditions suitable to form Form A crystalline 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide malonate.

22. The method according to claim 21 , wherein the malonic acid and 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide are reacted in an ethanol slurry.

Assignees

• Biomed Valley Discoveries Inc
• Albany Molecular Res Inc

Inventors

• Decrescenzo Gary
• Welsch Dean
• Selbo Jon G
• Albert Ekaterina V
• Rigsbee Emily M

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07C55/08

  Malonic acid · CPC title