Compounds, compositions and methods

Patent metadata

Field	Value
Publication number	US-10710976-B2
Application number	US-201916272788-A
Country	US
Kind code	B2
Filing date	Feb 11, 2019
Priority date	Dec 23, 2014
Publication date	Jul 14, 2020
Grant date	Jul 14, 2020

Abstract

The disclosed subject matter provides certain polymorphic forms of Compound (I) as well as pharmaceutical compositions comprising Compound (I) or such polymorphic forms, and methods of using or making such compounds and pharmaceutical compositions. It has now been discovered that Compound (I) can exist in multiple crystalline forms (polymorphs). One particular crystalline form, Form II, has been found to be more thermodynamically stable and, thus, likely more suitable for bulk preparation and handling than other polymorphic forms. Efficient and economic methods have been developed to prepare Compound (I) and Form II in high purity on a large scale. In animal studies, Form II has demonstrated safety and efficacy in treating depressive disorders and, when micronized, improved absorption compared to non-micronized Form II.

First claim

What is claimed is:

1. A crystalline Form II of Compound I

wherein Form II is obtained by converting Form I of Compound 1 having an X-ray powder diffraction pattern as shown in FIG. 1B to Form II having an X-ray powder diffraction pattern substantially as shown in FIG. 1A .

2. The crystalline Form II of claim 1 wherein Form I of Compound I is converted to form II of Compound I by heating Form I in its solid form to a temperature of up to 150° C.

3. The crystalline Form II of claim 2 wherein Form I of Compound I is heated to a temperature from about 50° C. to about 150° C.

4. The crystalline Form II of claim 3 wherein Form I of Compound I is heated to a a temperature from about 70° C. to about 135° C.

5. The crystalline Form II of claim 4 wherein Form I of Compound I is heated to a a temperature from about 90° C. to about 135° C.

6. The compound crystalline Form II of claim 2 wherein Form I of Compound I is converted to Form II of Compound I by heating Form I for up to 24 hours.

7. The compound crystalline Form II of claim 3 wherein Form I of Compound I is converted to Form II of Compound I by heating Form I for up to 10 hours.

8. The compound crystalline Form II of claim 4 wherein Form I of Compound I is converted to Form II of Compound I by heating Form I for up to 3 hours.

9. The compound crystalline Form II of claim 5 wherein Form I of Compound I is converted to Form II of Compound I by heating Form I for up to 5 hours.

10. The compound crystalline Form II of claim 1 wherein Form I of Compound I is converted to Form II of Compound I by slurring slurrying and suspending Form I of Compound I in water at ambient temperature.

11. The compound crystalline Form II of claim 10 wherein Form I of Compound I is suspended in water for up to 40 hours.

12. A method of preparing crystalline Form II of Compound I

wherein Form II has an X-ray powder diffraction pattern substantially as shown in FIG. 1A ; comprising:
(i) reacting Compound (8)

with triflic anhydride to yield a triflate;
(ii) reacting the triflate with ammonia to yield Compound (9)

(iii) reacting the Compound (9) with 2-chloropyrimidine to yield a crude form of Compound I;
(iv) purifying said crude form of Compound I by dissolving the crude form of Compound I in ethyl acetate at a temperature above 35° C., followed by partially or completely replacing the ethyl acetate with heptane;
(v) collecting the purified Form I of Compound I, having an X-ray powder diffraction pattern as shown in FIG. 1B ; and
(vi) suspending the purified Form I of Compound I in water to obtain crystalline Form II of Compound I.

13. The method of claim 12 further comprising heating the heptane solution to a temperature above 50° C. but below the boiling point of heptane followed by cooling the heptane solution to room temperature.

14. A method of preparing crystalline Form II of Compound I

wherein Form II has an X-ray powder diffraction pattern substantially as shown in FIG. 1A ;
comprising:
(i) reacting Compound (8)

with triflic anhydride to yield a triflate;
(ii) reacting the triflate with ammonia to yield Compound (9)

(iii) reacting the Compound (9) with 2-chloropyrimidine to yield a crude form of Compound I;
(iv) purifying said crude form of Compound I by dissolving the crude form of Compound I in ethyl acetate at a temperature above 35° C., followed by partially or completely replacing the ethyl acetate with heptane;
(v) collecting the purified Form I of Compound I, having an X-ray powder diffraction pattern as shown in FIG. 1B ; and
(vi) heating Form I of Compound I in its solid form to a temperature above 50° C. to obtain crystalline Form II of Compound 1.

15. The method of claim 14 further comprising heating the heptane solution to a temperature above 50° C. but below the boiling point of heptane followed by cooling the heptane solution to room temperature.

16. The method of claim 14 wherein Form I of Compound I is heated to a temperature above 100° C. to obtain crystalline Form II of Compound I.

17. The method of claim 16 further comprising heating the heptane solution to a temperature above 50° C. but below the boiling point of heptane followed by cooling the heptane solution to room temperature.

Assignees

• Cerecor Inc
• Merck Sharp & Dohme

Inventors

• Mazhari Reza
• Mezaache Djelila
• Paterson Blake M
• Vornov James
• Garner Rachel M
• Nelson Todd

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P29/02

  without antiinflammatory effect · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title