# US 11,028,050 B2 · Salts and polymorphs of a PDE4 inhibitor

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- Number: US 11,028,050 B2
- Document ID: US11028050B2
- Status: Granted
- Kind: B2
- Application number: 16/851,203
- Filed: 2020-04-17
- Published: 2020-10-22
- Granted: 2021-06-08
- Earliest claimed: 2019-04-18
- Assignees: Tetra Discovery Partners, LLC
- Applicants: Tetra Discovery Partners, Inc.
- Inventors: Mark E. Gurney; Jon P. Lawson; Stephan D. Parent; Richard James Ely
- Web page: https://patentgrep.com/patent/US11028050B2

## CPC

- C07D 213/55: Acids; Esters
- A61P 25/28: 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
- 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 free base crystalline forms and crystalline salts of Compound 1.

## Claims

### Claim 1

A crystalline form of free base Compound 1 (Form A), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.72, 15.90, 19.39, 20.80, 20.98, 23.15, and 26.08,±0.2° 2θ using Cu Kα radiation.

### Claim 2 (depends on 1)

The crystalline form of claim 1, further characterized by XRPD pattern peaks at 4.63, 17.40, 19.85, 20.07, 22.84, 25.10, and 27.47, and optionally further comprising 8.24, 9.29, 16.97, 18.65, 21.19, 21.59, 23.89, 24.20, 25.55, 25.82, and 28.14±0.2° 2θ using Cu Kα radiation.

### Claim 3 (depends on 1)

The crystalline form of claim 1, having an endothermic transition at 125° C. to 135° C., as measured by differential scanning calorimetry (“DSC”).

### Claim 4 (depends on 3)

The crystalline form of claim 3, wherein the endothermic transition is at 131° C.±3° C.

### Claim 5 (depends on 1)

The crystalline form of claim 1, having a dynamic vapor sorption (“DVS”) substantially as a shown in FIG. 4.

### Claim 6

A crystalline form of Compound 1 selected from the group consisting of
(a) Compound 1 and p-dioxane (Form B), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 20.02, 20.29, 21.32, 21.51, and 23.57,±0.2° 2θ using Cu Kα radiation,
(b) Compound 1 and dichloromethane (Form C), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.59, 13.00, 19.09, 21.74, 22.27, 23.82, and 24.11,±0.2° 2θ using Cu Kα radiation;
(c) Compound 1 calcium salt (Form D), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.10, 9.17, 15.68, 19.86, and 26.46,±0.2° 2θ using Cu Kα radiation;
(d) Compound 1 potassium salt (Form E), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.02, 3.88, 6.07, 7.01, and 8.32,±0.2° 2θ using Cu Kα radiation;
(e) Compound 1 potassium salt (Form F), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.8, 7.1, 7.5, 8.6, 9.4, 18.1, and 23.5, ±0.2° 2θ using Cu Kα radiation;
(f) Compound 1 sodium salt (Form G), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.93, 19.66, 20.48, and 21.10,±0.2° 2θ using Cu Kα radiation; and
(b) Compound 1 sodium salt (Form H), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.09, 8.39, 19.56, 23.64, and 24.70,±0.2° 2θ using Cu Kα radiation.

### Claim 7 (depends on 6)

The crystalline form of claim 6, wherein Compound 1 and p-dioxane (Form B) is further characterized by XRPD pattern peaks at 4.90, 16.46, 18.03, 18.74, 18.89, 19.39, 19.71, and 21.75, and optionally further comprising 18.03, 21.14, 22.43, 22.93, 23.29, 23.83, 24.22, 25.65, 26.02, and 26.77±0.2° 2θ using Cu Kα radiation.

### Claim 8 (depends on 6)

The crystalline form of claim 6, wherein Compound 1 and dichloromethane (Form C) is further characterized by XRPD pattern peaks at 9.50, 16.44, 18.01, 18.38, 20.11, 21.13, 22.51, 22.80, and 28.46, and optionally further comprising 7.82, 9.20, 10.50, 14.81, 17.05, 19.38, 20.87, 21.36, 24.63, 24.87, 28.79, and 29.80±0.2° 2θ using Cu Kα radiation.

### Claim 9 (depends on 6)

The crystalline form of claim 6, wherein the crystalline form of Compound 1 and dichloromethane (Form C) is a ratio of 1 to 1 of Compound 1 to dichloromethane.

### Claim 10 (depends on 6)

The crystalline form of claim 6, wherein Compound 1 calcium salt (Form D) is further characterized by XRPD pattern peaks at 5.41, 6.49, 7.70, 8.60, 10.86, 12.84, 15.46, 15.68, 19.86, 21.62, 21.84, 22.03, 23.57, 23.75, 24.53, 25.67, and 26.46, and optionally further comprises 13.43, 15.03, 16.32, 17.80, 18.13, 19.00, 19.51, 20.45, 20.83, 22.82, and 28.89±0.2° 2θ using Cu Kα radiation.

### Claim 11 (depends on 6)

The crystalline form of claim 6, wherein the Compound 1 potassium salt (Form E) is further characterized by XRPD pattern peaks at 6.86, 15.63, 18.35, 19.00, 19.64, 20.22, 21.08, 21.79, 22.03, 22.60, 22.93, 23.61, and 24.71, and optionally further comprises 7.79, 8.87, 9.12, 9.51, 9.77, 10.44, 12.19, 14.85, 16.08, 16.36, 17.10, 17.30, 25.29, and 25.99±0.2° 2θ using Cu Kα radiation.

### Claim 12 (depends on 6)

The crystalline form of claim 6, wherein the Compound 1 potassium salt (Form F) is further characterized by XRPD pattern peaks at 10.3, 11.2, 11.5, 13.1, 13.7, 14.0, 15.0, 16.1, 17.2, 17.7, 18.6, 19.5, 20.3, 20.8, 21.1, 21.5, 22.1, 25.9, 28.7 and 29.4,±0.2° 2θ using Cu Kα radiation.

### Claim 13 (depends on 6)

The crystalline form of claim 6, wherein Compound 1 sodium salt (Form G) is further characterized by XRPD pattern peaks at 13.70, 18.12, 19.28, 22.90, 24.01, 25.99, and 26.64, and optionally further comprises 4.53, 7.83, 12.37, 16.31, 20.17, 20.77, 21.62, 21.96, 24.41, 24.76, 26.45, 28.83, and 29.32±0.2° 2θ using Cu Kα radiation.

### Claim 14 (depends on 6)

The crystalline form of claim 6, wherein Compound 1 sodium slat (Form H) is further characterized by XRPD pattern peaks at 4.01, 6.17, 14.94, 15.87, 18.38, 21.06, 22.51, 22.80, 23.02, and 26.05, and optionally further comprises 6.68, 9.00, 9.65, 10.46, 12.39, 19.07, 19.33, 19.94, 20.20, 20.38, 20.81, 21.35 22.03, 24.04, 25.39, 26.48, and 28.42±0.2° 2θ using Cu Kα radiation.

### Claim 15 (depends on 6)

The crystalline form of claim 6, wherein Compound 1 sodium salt (Form H) has an endothermic transition at 110° C. to 120° C. and 200° C. to 210° C., as measured by differential scanning calorimetry (“DSC”).

### Claim 16 (depends on 15)

The crystalline form of claim 15, wherein the endothermic transition is at 116° C.±3° C. and 206° C.±3° C.