Salt forms and polymorphs of (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

Patent metadata

Field	Value
Publication number	US-10899740-B2
Application number	US-201916241596-A
Country	US
Kind code	B2
Filing date	Jan 7, 2019
Priority date	Dec 22, 2015
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

Disclosed herein is the compound (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide, and salt forms and polymorphs thereof demonstrating improved exposure after oral dosing. Methods of inhibition GLS1 activity in a human or animal subject are also provided.

First claim

What is claimed is:

1. A method of inhibiting GLS1 activity in a biological sample comprising contacting the biological sample with a salt or a polymorph of the compound

wherein the salt is of structural Formula I:

R − is chosen from Cl − , Br − , I − , HSO 4 − , SO 4 2− , NO 3 − , CH 3 SO 3 − , PhSO 3 − , 4-MePhSO 3 − , Naphthalene SO 3 − ;
n is an integer from 1 to 2; and
the polymorph is the Polymorph D having one or more x-ray powder diffraction peaks chosen from about 4.0, about 8.0, about 11.6, about 11.9, about 14.9, about 15.9, about 17.6, about 19.9, about 20.2, about 22.4, about 23.7, and about 23.9 degrees 2-theta.

2. The method as recited in claim 1 , comprising the step of administering to the subject a salt of the compound

wherein the salt is of structural Formula I:

R − is chosen from Cl − , Br − , I − , HSO 4 − , SO 4 2− , NO 3 − , CH 3 SO 3 − , PhSO 3 − , 4-MePhSO 3 − , Naphthalene SO 3 − ; and
n is an integer from 1 to 2.

3. The method as recited in claim 2 , wherein n is 1.

4. The method as recited in claim 3 , wherein R − is chosen from Cl − , HSO 4 − , CH 3 SO 3 − , 4-MePhSO 3 − .

5. The method as recited in claim 4 , wherein R − is CH 3 SO 3 − .

6. The method as recited in claim 5 , wherein the mesylate salt is characterized by having one or more x-ray powder diffraction peaks chosen from about 9.2, about 10.8, about 13.8, about 16.7, about 17.3, about 18.4, about 18.7, about 19.9, about 20.6, about 21.4, about 22.1, about 22.3, about 22.6, about 22.9, about 24.1, and about 32.1 degrees 2-theta.

7. The method as recited in claim 4 , wherein R − is chosen from Cl − .

8. The method as recited in claim 7 , wherein the chloride salt is characterized by having one or more x-ray powder diffraction peaks chosen from about 4.6, about 9.26, about 11.0, about 12.6, about 13.2, about 13.8, about 16.5, about 19.0, about 20.8, about 22.0, about 22.4, about 22.7, about 24.2, about 25.0, and about 33.4 degrees 2-theta.

9. The method as recited in claim 4 , wherein R − is, 4-MePhSO 3 − .

10. The method as recited in claim 9 , wherein the tosylate salt is characterized by having one or more x-ray powder diffraction peaks chosen from about 4.5, about 9.0, about 10.3, about 10.5, about 10.7, about 11.1, about 11.7, about 13.6, about 14.3, about 17.1, about 17.3, about 17.6, about 18.5, about 18.9, about 19.0, about 19.2, about 19.8, about 20.1, about 20.4, about 20.8, about 21.4, about 21.8, about 22.4, about 22.6, about 23.4, about 24.3, about 25.1, about 26.0, about 26.3, about 27.2, about 27.4, and about 28.2 degrees 2-theta.

11. The method as recited in claim 4 , wherein R − is HSO 4 − .

12. The method as recited in claim 1 , wherein the Polymorph D is characterized by having two, three, four, five or more x-ray powder diffraction peaks chosen from about 4.0, about 8.0, about 11.6, about 11.9, about 14.9, about 15.9, about 17.6, about 19.9, about 20.2, about 22.4, about 23.7, and about 23.9 degrees 2-theta.

13. The method as recited in claim 1 , wherein the Polymorph D is characterized by having five or more x-ray powder diffraction peaks chosen from about 4.0, about 8.0, about 11.6, about 11.9, about 14.9, about 15.9, about 17.6, about 19.9, about 20.2, about 22.4, about 23.7, and about 23.9 degrees 2-theta.

14. The method as recited in claim 1 , wherein the Polymorph D is anhydrous.

15. The method as recited in claim 1 , wherein the Polymorph D displays an endothermic peak in DSC with onset of 197° C.±1° C.

Assignees

• Univ Texas

Inventors

• Jones Philip
• Soth Michael J
• Burke Jason P
• Le Kang
• Liu Gang

Classifications

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/501 Primary

  not condensed and containing further heterocyclic rings · CPC title