# US 10,118,932 B2 · Solid state forms of spiro-oxindole compounds

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- Number: US 10,118,932 B2
- Document ID: US10118932B2
- Status: Granted
- Kind: B2
- Application number: 15/625,724
- Filed: 2017-06-16
- Published: 2018-01-18
- Granted: 2018-11-06
- Earliest claimed: 2016-06-16
- Assignees: Xenon Pharmaceuticals Inc.
- Applicants: Xenon Pharmaceuticals Inc.
- Inventors: Ronen Ben-David; Stephen Bierlmaier; Ralph Curtis Haltiwanger; Alexandr Jegorov; Raeann Ruiyun Wu; Mehran Yazdanian
- Web page: https://patentgrep.com/patent/US10118932B2

## CPC

- C07D 491/20: Spiro-condensed systems
- A61P 9/06: Antiarrhythmics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention provides solid state forms of certain spiro-oxindole compounds, such as funapide and the racemic mixture of funapide and its corresponding (R) enantiomer, pharmaceutical compositions comprising the solid state forms and processes for preparing the solid state forms and the pharmaceutical compositions.

## Claims

### Claim 1

A crystalline form of funapide, designated as Form A0, characterized by one or more of the following: a powder X-ray diffraction pattern having peaks at 10.10°, 10.69°, 20.59°, 22.69° and 33.12° θ±0.2° θ; a powder X-ray diffraction pattern substantially as depicted in FIG. 1; and any combination of these data.

### Claim 2 (depends on 1)

The crystalline form of claim 1, characterized by a powder X-ray diffraction pattern having peaks at 10.10°, 10.69°, 20.59°, 22.69° and 33.12° θ±0.2° θ, further characterized by an additional one, two, three, four or five powder X-ray diffraction pattern peaks selected from 15.94°, 17.77°, 20.26°, 23.79°, and 30.84° θ±0.2° θ.

### Claim 3 (depends on 1, 2)

The crystalline form of funapide according to claim 1 or claim 2, further characterized by one or more of the following: a DSC thermogram substantially as depicted in FIG. 2; an endothermic onset at 109° C. and a peak max at 114° C., or combinations thereof.

### Claim 4 (depends on 1)

A pharmaceutical composition comprising the crystalline form of funapide according to claim 1.

### Claim 5 (depends on 1)

A pharmaceutical formulation comprising the crystalline form of funapide according claim 1 and at least one pharmaceutically acceptable excipient.

### Claim 6 (depends on 4)

A pharmaceutical formulation comprising the pharmaceutical composition of claim 4 and at least one pharmaceutically acceptable excipient.

### Claim 7 (depends on 4)

A method of treating a subject suffering from sodium channel-mediated diseases and conditions, wherein the method comprises administering to the subject a pharmaceutical composition according to claim 4.

### Claim 8 (depends on 5)

A method of treating a subject suffering from sodium channel-mediated diseases and conditions, wherein the method comprises administering to the subject the pharmaceutical formulation according to claim 5.

### Claim 9 (depends on 1)

A method of treating a subject suffering from sodium channel-mediated diseases and conditions, comprising administering to the subject a therapeutically effective amount of the crystalline form of funapide according to claim 1.

### Claim 10 (depends on 1)

A method of preparing a pharmaceutical composition comprising combining the crystalline form of funapide according to claim 1 with a one or more pharmaceutically acceptable excipients.

### Claim 11

A method of preparing a crystalline form of funapide designated as Form A0, wherein the method comprises one of the following methods to obtain the crystalline form of funapide designated as Form A0:
(a) equilibrating funapide at 25±3° C. with a mixture of solvents, filtering the resulting solutions; and drying the resulting solids;
(b) equilibrating funapide at 50° C. with a solvent or mixture of solvents, filtering the resulting solutions and drying the resulting solids;
(c) dissolving funapide in methyl tert-butyl ether at 22-25° C., cooling the resulting solution to 5° C., filtering the resulting solution and drying the resulting solids;
(d) dissolving funapide in a solvent or a mixture of solvents at 22-25° C., cooling the resulting solutions to 5° C., maintaining the temperature and allowing the solvent or mixture of solvents to slowly evaporate;
(e) mixing funapide with a mixture of solvents at 22-25° C., rapidly heating the resulting solutions to 50° C., maintaining the temperature and allowing the mixture of solvents to rapidly evaporate; and
(f) dissolving funapide in a first solvent, in which funapide is soluble, adding a second solvent, in which funapide is insoluble or poorly soluble, and filtering the resulting solutions.