# US 11,993,586 B2 · Crystalline forms of potassium channel modulators

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- Number: US 11,993,586 B2
- Document ID: US11993586B2
- Status: Granted
- Kind: B2
- Application number: 17/287,907
- Filed: 2019-10-21
- Published: 2021-12-23
- Granted: 2024-05-28
- Earliest claimed: 2018-10-22
- Assignees: Novartis AG
- Applicants: Novartis AG
- Inventors: Gregg F. Keaney; Jun Xu; Wenfeng Xue
- Web page: https://patentgrep.com/patent/US11993586B2

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- A61P 25/00: Drugs for disorders of the nervous system
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Provided herein are crystalline and amorphous forms of a compound having structural formula (1). Also provided are pharmaceutical compositions comprising the crystalline and amorphous forms, methods for their manufacture, and uses thereof for treating a variety of diseases, disorders or conditions, associated with potassium channels.

## Claims

### Claim 1

A single crystalline Form B of a compound having structural formula 1:
wherein the crystalline form is characterized by at least three x-ray powder diffraction peaks at 2 Θ angles selected from 7.2°, 17.7°, 20.1°, 23.3°, and 23.2°.

### Claim 2 (depends on 1)

The single crystalline Form B of claim 1, wherein the crystalline form is characterized by at least four x-ray powder diffraction peaks at 2Θ angles selected from 7.2°, 15.5°, 17.7°, 18.9°, 20.1°, 22.3°, and 23.2°.

### Claim 3 (depends on 1)

The single crystalline Form B of claim 1, wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2Θ angles selected from 7.2°, 15.5°, 17.7°, 18.9°, 20.1°, 22.3°, and 23.2°.

### Claim 4 (depends on 1)

The single crystalline Form B of claim 1, wherein the crystalline form is characterized by at least six x-ray powder diffraction peaks at 2Θ angles selected from 7.2°, 15.5°, 17.7°, 18.9°, 20.1°, 22.3°, and 23.2°.

### Claim 5 (depends on 1)

The single crystalline Form B of claim 1, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2Θ angles selected from 7.2°, 15.5°, 17.7°, 18.9°, 20.1°, 22.3°, and 23.2°.

### Claim 6 (depends on 1)

The single crystalline Form B of claim 1, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2Θ angles selected from 7.2°, 9.2°, 10.9°, 13.1°, 14.6°, 15.5°, 17.7°, 18.9°, 20.1°, 20.6°, 21.4°, 22.0°, 22.3°, and 23.2°.

### Claim 7 (depends on 1)

The single crystalline Form B of claim 1, wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2Θ angles selected from 7.2°, 9.2°, 10.9°, 11.5°, 12.2°, 13.1°, 13.7°, 14.0°, 14.6°, 15.5°, 16.9°, 17.7°, 18.4°, 18.9°, 19.1°, 20.1°, 20.6°, 20.9°, 21.4°, 22.0°, 22.3°, 23.2°, 24.0°, 24.5°, 25.2°, 25.9°, 26.4°, 27.1°, 28.1°, 28.9°, 29.7°, 33.9°, 34.7°, 35.2°, 37.3°, and 38.9°.

### Claim 8

A single crystalline Form C, single crystalline Form D, single crystalline Form E, or single crystalline Form F of a compound having structural formula 1:
wherein the single crystalline Form C is characterized by at least three, at least four, five, x-ray powder diffraction peaks at 2 Θ angles selected from 4.2°, 8.5°, 17.00, 20.20, and 21.40; wherein the single crystalline Form D is characterized by at least three, at least four, at least five, at least six, or at least seven x-ray powder diffraction peaks at 2 Θ angles selected from 4.90, 99°, 11.10, 17.40, 21.30, 22.20, and 24.8°; wherein the single crystalline Form E is characterized by at least three, at least four, at least five, at least six, or at least seven x-ray powder diffraction peaks at 2Θ angles selected from 8.0°, 16.00, 16.80, 17.10, 18.80, 19.30, and 23.4°; and wherein the single crystalline Form F is characterized by at least three, at least four, at least five, at least six, or at least seven x-ray powder diffraction peaks at 2 Θ angles selected from 7.1°, 17.90, 18.80, 21.40, 22.10, 24.40, and 28.80.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising the crystalline Form B of claim 1; and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 1)

A method of treating a disease or condition responsive to modulation of the small conductance calcium-activated potassium channel (SK channel) in a subject comprising the step of administering to the subject a therapeutically effective amount of the crystalline Form B of claim 1.

### Claim 11 (depends on 1)

A method of preparing the crystalline Form B of claim 1, said method comprising:
dissolving Form A in 2-MeTHF at elevated temperature to form a solution;
adding heptane to the solution; and
reducing the temperature of the solution, thereby precipitating Form B.

### Claim 12 (depends on 8)

A pharmaceutical composition comprising the crystalline Form C, Form D, Form E, or Form F of claim 8, and a pharmaceutically acceptable carrier.

### Claim 13 (depends on 8)

A method of treating a disease or condition responsive to modulation of the small conductance calcium-activated potassium channel (SK channel) in a subject comprising the step of administering to the subject a therapeutically effective amount of the crystalline Form C, Form D, Form E, or Form F of claim 8.