Crystalline form of a 7H-benzo[7]annulene-2-carboxylic acid derivative

Patent metadata

Field	Value
Publication number	US-12528768-B2
Application number	US-202017783364-A
Country	US
Kind code	B2
Filing date	Dec 8, 2020
Priority date	Dec 9, 2019
Publication date	Jan 20, 2026
Grant date	Jan 20, 2026

Abstract

The present disclosure relates to a compound of formula (1) as an anhydrate which is in a crystalline Form 2, characterized by having a powder-X-ray diffractogram displaying peaks expressed as degree 2-Theta angles at about 9.5; 11.8; 14.1; 14.6; 17.7 and 18.5 and a solid form thereof. The present disclosure also relates to processes for its preparation, as well as a medicament and a pharmaceutical composition comprising it. The present disclosure further concerns the anhydrate crystalline Form 2 of compound of formula (1) for use as a medicine and more particularly in the treatment of cancer.

First claim

The invention claimed is:

1 . An anhydrate crystalline form, which is Form 2 of compound of formula (1)

characterized by having a powder-X-ray diffractogram displaying peaks expressed as degree 2-Theta angles at about 9.5; 11.8; 14.1; 14.6; 17.7 and 18.5.

2 . The anhydrate crystalline Form 2 of compound of formula (1) according to claim 1 , which further shows the following peaks expressed as degree 2-Theta angles: at about 15.5; 15.9; 16.6 and 22.2.

3 . The anhydrate crystalline Form 2 of compound of formula (1) according to claim 2 , wherein a differential scanning calorimetry (DSC) shows a melting endotherm at about 204° C. onset.

4 . The anhydrate crystalline Form 2 of compound of formula (1) according to claim 3 , characterized by showing a weight gain of less than 0.2 weight % based on the weight of the crystalline Form 2 anhydrate, as determined by Dynamic Vapor Sorption (DVS) in the range of from 0% to 95% relative humidity at a temperature of about 25° C.

5 . A process for the preparation of the anhydrate crystalline Form 2 of compound of formula (1) according to claim 1 , comprising at least the following steps:
1) solubilizing the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones, acetates, ethers and acetonitrile, optionally in admixture with water, at a set temperature ranging from 18° C. to 80° C.; 2) leaving the solution obtained in step 1) at the same temperature as the one set in step 1) for almost complete evaporation; and 3) isolating the anhydrate crystalline Form 2 of compound of formula (1) formed in step 2).

6 . The process according to claim 5 , wherein the solvent is selected from methanol, methanol/water mixture, ethanol, ethanol/water mixture, 2-propanol, 1-propanol, 1-propanol/water mixture, 1-butanol, 1-butanol/water mixture, acetone, acetone/water mixture, 2-butanone, 2-butanone/water mixture, methyl isobutyl ketone, methyl isobutyl ketone/water mixture, methyl acetate, methyl acetate/water mixture, ethyl acetate, ethyl acetate/water mixture, isopropyl acetate, isopropyl acetate/water mixture, isobutyl acetate, isobutyl acetate/water mixture, acetonitrile, and methyl tert-butyl ether.

7 . The process according to claim 5 , wherein the set temperature of step 1) and step 2) is selected from a range of temperature from 20° C. to 80° C.

8 . A process for the preparation of the anhydrate crystalline Form 2 of compound of formula (1) according to claim 1 , comprising at least the following steps:
1) solubilizing or suspending the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones, acetates, ethers and acetonitrile, at room temperature; 2) optionally purifying the solution or suspension obtained in step 1) by heating at a set temperature ranging from 60° C. to 80° C., stirring and filtering the solution or suspension; 3) heating the solution or suspension obtained in step 1) or in step 2) at a set temperature ranging from 60° C. to 80° C.; 4) cooling the solution or suspension obtained in step 2) to a set temperature ranging from −20° C. to 25° C.; and 5) isolating the anhydrate crystalline Form 2 of compound of formula (1) formed in step 4).

9 . The process according to claim 8 , wherein the solvent is selected from ethanol, 2-propanol, 1-propanol, 1-butanol, acetone, 2-butanone, methyl isobutyl ketone, isopentyl methyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, acetonitrile, and methyl tert-butyl ether.

10 . A process for the preparation of the anhydrate crystalline Form 2 of compound of formula (1) according to claim 1 , comprising at least the following steps:
1) solubilizing or suspending the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones, acetates, and diethyl-ether, at room temperature; 2) optionally filtering the solution or suspension obtained in step 1); 3) adding water as a non-solvent; and 4) isolating the anhydrate crystalline Form 2 of compound of formula (1) formed in step 3).

11 . The process according to claim 10 , wherein the solvent is selected from 2-propanol, 1-propanol, 1-butanol, acetone, 2-butanone, methyl isobutyl ketone, isopentyl methyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, and diethyl ether.

12 . A process for the preparation of the anhydrate crystalline Form 2 of compound of formula (1) according to claim 1 , comprising at least the following steps:
1) solubilizing or suspending the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones, and acetates, at a set temperature which is room temperature; 2) optionally filtering the solution or suspension obtained in step 1); 3) adding heptane as a non-solvent; and 4) isolating the anhydrate crystalline Form 2 of compound of formula (1) formed in step 3).

13 . The process according to claim 12 , wherein the solvent is selected from ethanol, 2-propanol, 1-propanol, 1-butanol, acetone, 2-butanone, methyl isobutyl ketone, isopentyl methyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, and isobutyl acetate.

14 . A process for the preparation of the anhydrate crystalline Form 2 of compound of formula (1) according to claim 1 , comprising at least the following steps:
1) solubilizing or suspending the compound of formula (1) in amorphous form in an organic solvent; and 2) adding seeds of anhydrate crystalline Form 2 of the compound of formula (1).

15 . The process according to claim 14 , wherein steps 1) and 2) are followed by the step of adding a non-solvent, then performing distillation, followed by cooling and drying.

16 . A medicament, characterized in that it comprises the anhydrate crystalline Form 2 of compound of formula (1) according to claim 1 .

17 . A pharmaceutical composition comprising the anhydrate crystalline Form 2 of compound of formula (1) according to claim 1 , and at least one pharmaceutically acceptable excipient.

18 . The pharmaceutical composition according to claim 17 , wherein said anhydrate crystalline Form 2 is substantially pure and substantially free of alternative forms.

19 . The pharmaceutical composition according to claim 17 , wherein said anhydrate crystalline Form 2 is at least 90 percent by weight of all forms.

20 . A method of treating cancer comprising administering to a subject in need thereof a pharmaceutically effective amount of anhydrate crystalline Form 2 of compound of formula (1) according to claim 1 .

21 . The process according to claim 5 , wherein the set temperature of step 1) and step 2) is selected from a range of temperature from 25° C. to 80° C.

Assignees

• Sanofi Sa

Inventors

• Billot Pascal
• Robert Benoît

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4015

  having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D207/12 Primary

  Oxygen or sulfur atoms · CPC title