Morphic forms of G1T38 and methods of manufacture thereof

Patent metadata

Field	Value
Publication number	US-11261193-B2
Application number	US-201916721631-A
Country	US
Kind code	B2
Filing date	Dec 19, 2019
Priority date	Jun 29, 2017
Publication date	Mar 1, 2022
Grant date	Mar 1, 2022

Abstract

This invention provides an unexpectedly stable, highly crystalline form of the di-HCl salt of

for advantageous therapeutic pharmaceutical efficacy and dosage form stability.

First claim

We claim:

1. An isolated crystalline Form B of the di-HCl salt of structure:

characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values selected from 6.5±0.2°, 9.5±0.4°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.3±0.2°, 19.9±0.2°, and 22.4±0.2°.

2. The isolated crystalline Form B of claim 1 , wherein the XRPD pattern comprises at least four 2θ values selected from 6.5±0.2°, 9.5±0.4°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.3±0.2°, 19.9±0.2°, and 22.4±0.2°.

3. The isolated crystalline Form B of claim 1 , wherein the XRPD pattern comprises at least the 2θ value of 9.5±0.4°.

4. The isolated crystalline Form B of claim 1 , wherein the XRPD pattern comprises at least a 2θ value of 9.5±0.2°.

5. The isolated crystalline Form B of claim 1 , wherein the XRPD pattern comprises at least the 2θ value of 19.3±0.2°.

6. The isolated crystalline Form B of claim 1 , wherein the XRPD pattern comprises at least the 2θ value of 22.4±0.2°.

7. The isolated crystalline Form B of claim 1 , characterized by an XRPD pattern having the characteristic 2θ values of FIG. 7 .

8. The isolated crystalline Form B of claim 1 characterized by differential scanning calorimetry (DSC) onset endotherms of about 105±20° C., about 220±20° C., and about 350±20° C.

9. The isolated crystalline Form B of claim 1 characterized by differential scanning calorimetry (DSC) onset endotherms of about 105±10° C., about 220±10° C., and about 350±10° C.

10. A pharmaceutical composition comprising the isolated crystalline Form B of claim 1 and a pharmaceutically acceptable excipient for solid dosage delivery.

11. A process for producing crystalline Form B of 2′-((5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)amino)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one di-HCl salt comprising the steps of
(i) heating the free base of 2′-((5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)amino)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′: 1,5]pyrrolo[2,3-d]pyrimidin]-6′-one in aqueous HCl to at least about 45° C.;
(ii) stirring the solution for at least about 15 minutes and filtering the resulting solution;
(iii) adding solvent at a temperature of at least about 45° C. and stirring the solution for at least about 15 minutes;
(iv) decreasing the temperature of the solution to about 25° C. or lower and stirring the solution for at least about 30 minutes; and
(v) filtering the solution and washing the solution with additional solvent to afford the crystalline Form B of 2′-((5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)amino)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′: 1,5]pyrrolo[2,3-d]pyrimidin]-6′-one di-HCl salt;
wherein crystalline Form B of 2′-((5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)amino)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one di-HCl is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values selected from 6.5±0.2°, 9.5±0.4°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.3±0.2°, 19.9±0.2°, and 22.4±0.2°.

12. The process of claim 11 , wherein the solvent used is acetone.

13. The process of claim 11 , wherein the solution is stirred for about 45 minutes in step (ii).

14. The process of claim 11 , wherein the solution is heated to at least about 50° C. in step (i).

15. The process of claim 11 , wherein the solution is heated to about 55° C. in step (i).

16. The process of claim 11 , wherein the solvent is heated to at least about 50° C. in step (iii).

17. The process of claim 11 , wherein the solution is stirred for at least about 1 hour in step (iii).

18. The process of claim 11 , wherein the solution is stirred for at least about 1 hour in step (iv).

19. The process of claim 11 , wherein the solution is stirred for at least about 2 hours in step (iv).

20. The isolated crystalline Form B of claim 1 , wherein the isolated crystalline Form B is a hydrate.

Assignees

• G1 Therapeutics Inc
• Gi Therapeutics Inc

Inventors

• Smith Alexander
• White Hannah S
• Andres Patricia
• Sun Xufeng
• Zhu Lei
• Vlahova Petinka I

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• C07D487/20 Primary

  Spiro-condensed systems · CPC title

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title