# US 10,870,644 B2 · Crystalline forms of 4-(5-(4,7-dimethylbenzofuran-2-yl)-l,2,4-oxadiazol-3-yl)benzoic acid and processes for their preparation

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- Number: US 10,870,644 B2
- Document ID: US10870644B2
- Status: Granted
- Kind: B2
- Application number: 16/311,318
- Filed: 2017-06-16
- Published: 2019-11-14
- Granted: 2020-12-22
- Earliest claimed: 2016-06-22
- Assignees: King's College London
- Applicants: King's College London
- Inventors: Ronnie Maxwell Lawrence; Edwin Aret; Alan David Borthwick; Jane Theresa Brown; Jonathan Patrick Thomas Corcoran; Maria Beatriz de Castro Vasconcelos Goncalves; Sarkis Barrett Kalindjian
- Web page: https://patentgrep.com/patent/US10870644B2

## CPC

- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- A61P 15/10: for impotence
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- 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
- A61P 27/02: Ophthalmic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

The present invention pertains generally to the field of therapeutic compounds, and more specifically to crystalline forms of 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid (referred to herein as “BHBA-001”), which, inter alia, is a (selective) retinoic acid receptor beta (RARβ) (e.g., RARβ2) agonist. The present invention also pertains to pharmaceutical compositions comprising such crystalline forms, and the use of such crystalline forms and compositions, both in vitro and in vivo, to (selectively) activate RARβ (e.g., RARβ2), to cause or promote neurite development, neurite outgrowth, and/or neurite regeneration, and in the treatment of diseases and conditions that are mediated by RARβ(e.g., RARβ2), that are ameliorated by the activation of RARβ (e.g., RARβ2), etc., including, e.g., neurological injuries such as spinal cord injuries.

## Claims

### Claim 1

A crystalline form of 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid having an X-ray powder diffraction which exhibits characteristic scattering angles (2θ) at least at: 14.8° 0.2°, 20.7°±0.2°, and 9.5°±0.2°.

### Claim 2 (depends on 1)

The crystalline form according to claim 1, wherein the X-ray powder diffraction exhibits characteristic scattering angles (2θ) at least at: 14.8°±0.2°, 20.7°±0.2°, 9.5θ±0.2°, and 16.4°±0.2°.

### Claim 3 (depends on 1)

The crystalline form according to claim 1, wherein the X-ray powder diffraction exhibits characteristic scattering angles (2θ) at least at: 14.8°±0.2°, 20.7°±0.2°, 9.5°±0.2°, 16.4°±0.2°, 13.1°±0.2°, 24.6°±0.2°, 26.7°±0.2°, and 21.0°±0.2°.

### Claim 4 (depends on 1)

The crystalline form according to claim 1, wherein the X-ray powder diffraction exhibits characteristic scattering angles (2θ) at least at: 14.8°±0.2°, 20.70±0.2°, 9.5°±0.2°, 16.4°±0.2°, 13.1°±0.2°, 24.6°±0.2°, 26.7°±0.2°, 21.0°±0.2°, 14.4°±0.2°, 12.4°±0.2°, 12.7°±0.2°, and 28.1°±0.2°.

### Claim 5 (depends on 1)

The crystalline form according to claim 1, wherein any peaks at characteristic scattering angles (2θ) between 17.0°±0.2° and 20.0°±0.2° in the X-ray powder diffraction have a peak intensity of less than about 2% of the most intense peak.

### Claim 6 (depends on 1)

The crystalline form according to claim 1, wherein the X-ray powder diffraction is substantially as shown in FIG. 9.

### Claim 7 (depends on 1)

The crystalline form according to claim 1, having a differential scanning calorimetry thermogram comprising an endotherm at about 268±4° C.

### Claim 8 (depends on 1)

The crystalline form according to claim 1, having a differential scanning calorimetry thermogram substantially as shown in FIG. 10.

### Claim 9 (depends on 1)

The crystalline form according to claim 1, having a thermogravimetric analysis thermogram showing a weight loss of less than about 0.5% between 4° C. and 100±4° C.

### Claim 10 (depends on 1)

The crystalline form according to claim 1, having a thermogravimetric analysis thermogram substantially as shown in FIG. 11.

### Claim 11 (depends on 1)

The crystalline form according to claim 1, having a dynamic vapour sorption sorption-desorption profile substantially as shown in FIG. 12.

### Claim 12 (depends on 1)

The crystalline form according to claim 1, having a dynamic vapour sorption mass uptake profile substantially as shown in FIG. 13.

### Claim 13 (depends on 1)

A solid formulation comprising the crystalline form according to claim 1, and a pharmaceutically acceptable carrier or diluent.

### Claim 14 (depends on 13)

The solid formulation according to claim 13, which is substantially free of other crystalline forms of 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid.