Crystalline form of (S)-(2-(6-chloro-7-methyl-1H-benzo[D]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and its use as orexin receptor antagonists

Patent metadata

Field	Value
Publication number	US-9914720-B2
Application number	US-201415101768-A
Country	US
Kind code	B2
Filing date	Dec 2, 2014
Priority date	Dec 3, 2013
Publication date	Mar 13, 2018
Grant date	Mar 13, 2018

Abstract

The invention relates to crystalline forms of (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone, processes for the preparation thereof, pharmaceutical compositions containing such crystalline forms, pharmaceutical compositions prepared from such crystalline forms, and their use as a medicament, especially as orexin receptor antagonists.

First claim

The invention claimed is:

1. A crystalline form of the compound (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone comprising:
the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 8.6°, 11.5°, 13.4°, 14.6°, 15.2°, 15.5°, 19.3°, 21.3°, 22.4°, and 26.4°; or
the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 10.9°, 13.4°, 14.3°, 14.9°, 18.3°, 20.9°, 21.1°, 21.8°, 24.0°, and 30.1°.

2. A crystalline form of the compound (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone according to claim 1 , comprising peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: θ: 8.6°, 11.5°, 13.4°, 14.6°, 15.2°, 15.5°, 19.3°, 21.3°, 22.4°, and 26.4°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.

3. A crystalline form of the compound (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone according to claim 2 , which shows the X-ray powder diffraction pattern as depicted in FIG. 2 .

4. A crystalline form of the compound (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone according to claim 2 , obtainable by:
a) mixing 2 g of COMPOUND as amorphous material with 8 mL of an ethanol/water mixture with volume/volume ratio of 1/4;
b) adding about 0.05 g seed crystals of COMPOUND in crystalline form 1;
c) shaking at 300 rpm for about 16 hours at room temperature;
d) filtering and washing the cake with 2 mL ethanol/water 1/4 (v/v) and drying the product at room temperature and reduced pressure of about 10 mbar for 4 hours; and
e) open equilibration at room temperature and about 60% relative humidity for 2 hours.

5. A crystalline form of the compound (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone according to claim 1 , comprising peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 10.9°, 13.4°, 14.3°, 14.9°, 18.3°, 20.9°, 21.1°, 21.8°, 24.0°, and 30.1°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 20 values is in the range of 20+/−0.2°.

6. A crystalline form of the compound (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone according to claim 5 , which shows the X-ray powder diffraction pattern as depicted in FIG. 3 .

7. A crystalline form of the compound (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone according to claim 5 , obtainable by:
a) mixing 10 mg of COMPOUND in crystalline form 1 in 0.05 mL acetonitrile;
b) stirring in a closed 4 mL vial for up to three days;
c) isolating; and drying at reduced pressure and room temperature for 2 hours.

8. A pharmaceutical composition comprising as active ingredient a crystalline form of the compound (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone according to claim 1 , and at least one pharmaceutically acceptable carrier.

9. A method of treatment of sleep disorders or anxiety disorders; comprising administering to a patient an effective amount of a crystalline form of the compound(S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone according to claim 1 .

10. The method of claim 9 , wherein the sleep disorders are selected from the group consisting of dyssomnias, parasomnias, sleep disorders associated with a general medical condition and substance-induced sleep disorders.

11. A method of treatment of sleep disorders or anxiety disorders; comprising administering to a patient an effective amount of a pharmaceutical composition according to claim 8 .

12. The method of claim 11 , wherein the sleep disorders are selected from the group consisting of dyssomnias, parasomnias, sleep disorders associated with a general medical condition and substance-induced sleep disorders.

Assignees

• Idorsia Pharmaceuticals Ltd

Inventors

• Boss Christoph
• Brotschi Christine
• Gude Markus
• Heidmann Bibia
• Sifferlen Thierry
• Von Raumer Markus
• Williams Jodi T

Classifications

• A61P25/28

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• A61P25/24

  Antidepressants · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title