Compounds, compositions and methods

Patent metadata

Field	Value
Publication number	US-12410153-B2
Application number	US-202217934772-A
Country	US
Kind code	B2
Filing date	Sep 23, 2022
Priority date	Dec 23, 2014
Publication date	Sep 9, 2025
Grant date	Sep 9, 2025

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 method of treating a depressive disorder in a human patient in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a compound having the formula

and a melting point of 123-124° C.

2. The method of claim 1 , wherein the compound is an anhydrate.

3. The method of claim 1 , wherein the depressive disorder is major depressive disorder.

4. The method of claim 3 , wherein the pharmaceutical composition is administered as an adjunct to a serotonin reuptake inhibitor or a serotonin and norepinephrine reuptake inhibitor.

5. The method of claim 1 , wherein the compound is present in the pharmaceutical composition in particulate form with an X50 particle size of about 5 μm or less.

6. The method of claim 1 , wherein the compound is present in the pharmaceutical composition in particulate form with an X90 particle size of about 10 μm or less.

7. A method of treating a post-traumatic stress disorder in a human patient in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a compound having the formula

and a melting point of 123-124° C.

8. The method of claim 7 , wherein the compound is an anhydrate.

9. The method of claim 7 , wherein the pharmaceutical composition is administered as an adjunct to a serotonin reuptake inhibitor or a serotonin and norepinephrine reuptake inhibitor.

10. The method of claim 7 , wherein the compound is present in the pharmaceutical composition in particulate form with an X50 particle size of about 5 μm or less.

11. The method of claim 7 , wherein the compound is present in the pharmaceutical composition in particulate form with an X90 particle size of about 10 μm or less.

12. A method of treating a depressive disorder or post-traumatic stress disorder, or a bipolar disorder with depressive features in a human patient in need thereof comprising administering a pharmaceutical composition comprising an effective amount of a compound having the formula

and the differential scanning calorimetry thermogram of the compound comprises an endothermic peak at a temperature of about 124° C.

13. The method of claim 12 , wherein the compound is an anhydrate.

14. The method of claim 12 , wherein the patient has a depressive disorder.

15. The method of claim 14 , wherein the depressive disorder is major depressive disorder.

16. The method of claim 15 , wherein the pharmaceutical composition is administered as an adjunct to a serotonin reuptake inhibitor or a serotonin and norepinephrine reuptake inhibitor.

17. The method of claim 12 , wherein the patient has post-traumatic stress disorder.

18. The method of claim 12 , wherein the compound is present in the pharmaceutical composition in particulate form with an X50 particle size of about 5 μm or less.

19. The method of claim 12 , wherein the compound is present in the pharmaceutical composition in particulate form with an X90 particle size of about 10 μm or less.

20. The method of claim 12 , wherein the patient has a bipolar disorder with depressive features.

21. A method of treating a bipolar disorder with depressive features in a human patient in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a compound having the formula

and a melting point of 123-124° C.

Assignees

• Avalo Therapeutics Inc
• Merck Sharp & Dohme Llc

Inventors

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

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/24

  of the sex hormones · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title