Solid form of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)phenyl]-(6-methoxy-pyridazin-3-yl)-methanol

Patent metadata

Field	Value
Publication number	US-11053233-B2
Application number	US-201816498905-A
Country	US
Kind code	B2
Filing date	Mar 28, 2018
Priority date	Mar 30, 2017
Publication date	Jul 6, 2021
Grant date	Jul 6, 2021

Abstract

An anhydrous disordered crystalline (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol can be used in pharmaceutical compositions.

First claim

The invention claimed is:

1. An anhydrous disordered crystalline (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol.

2. The anhydrous disordered crystalline (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 1 , which is characterized by a powder X-ray diffraction pattern having at least two peaks at degrees two theta selected from the group consisting of 3.9, 5.1, 6.1, 8.4, 10.7, 12.7, 14.6, and 22.8, each ±0.3 degrees two theta, wherein each of the at least two peaks is characterized by having a full width at half maximum of equal to or greater than 0.2 degrees two theta.

3. The anhydrous disordered crystalline (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 2 , wherein the powder X-ray diffraction pattern has at least one further peak at degrees two theta selected from 3.1, 9.9, 13.5, 16.0, 16.5, 18.0, 19.0, 20.9, 21.9, 22.8, 24.0, 24.9, and 25.4 each ±0.2 degrees two theta.

4. The anhydrous disordered crystalline (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 1 , which is characterized by a powder X-ray diffraction pattern substantially in accordance with FIG. 1 or 2 .

5. The anhydrous disordered crystalline (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 1 , which is characterized by a differential scanning calorimeter profile substantially in accordance with FIG. 3 .

6. The anhydrous disordered crystalline (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 1 , which has a solubility in a simulated gastric fluid without pepsin at a pH of 1.2 of at least about 1900 μg/ml.

7. The anhydrous disordered crystalline (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 1 , which is obtainable by antisolvent precipitation.

8. A process for preparing anhydrous disordered crystalline (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol, comprising:
antisolvent precipitating of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol.

9. The process according to claim 8 , wherein the antisolvent precipitating comprises:
a) preparing a clear solution of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol in a solvent or solvent mixture, optionally with heating,
b) combining the clear solution with an antisolvent to generate a suspension of (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol in a solvent/antisolvent mixture,
c) separating the obtained anhydrous disordered crystalline (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methox-pyridazin-3-yl)-methanol from the solvent/antisolvent mixture, and
d) drying the anhydrous disordered crystalline (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol.

10. The process according to claim 9 , wherein the solvent or solvent mixture is selected from the group consisting of dimethyl sulfoxide, dichloromethane, methanol, 1,4-dioxane, tetrahydrofuran, and mixtures thereof.

11. The process according to claim 9 , wherein the antisolvent is at least one selected from the group consisting of acetone, n-heptane and water.

12. The process according to claim 9 , wherein the solvent is at least one selected from the group consisting of dichloromethane, methanol and 1,4-dioxane, and the antisolvent is water; or
the solvent is tetrahydrofuran and the antisolvent is n-heptane.

13. A pharmaceutical composition, comprising:
the anhydrous disordered crystalline (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 1 , and
optionally at least one excipient.

14. A method for inhibiting DNA-dependent protein kinase in a cancer that expresses DNA-PK, comprising:
administering the anhydrous disordered crystalline (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol to a patient in need thereof, optionally in combination with at least one selected from the group consisting of chemotherapy and radiotherapy.

15. A pharmaceutical composition, comprising:
the anhydrous disordered crystalline (S)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)-methanol according to claim 1 , and
at least one excipient.

16. The pharmaceutical composition according to claim 15 , wherein the at least one excipient is selected from the group consisting of a filler, a binder, a humectant, a disintegrating agent, a wicking agent, a matrix former and a lubricant.

Assignees

• Merck Patent Gmbh

Inventors

• Lange Michael
• Kuehn Clemens
• Fuchss Thomas
• Maillard David
• Breuníng Marcel
• Poma Marco
• Burini Edoardo

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D403/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61P35/00

  Antineoplastic agents · CPC title