# US 11,304,914 B2 · Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,304,914 B2
- Document ID: US11304914B2
- Status: Granted
- Kind: B2
- Application number: 16/919,044
- Filed: 2020-07-01
- Published: 2021-01-21
- Granted: 2022-04-19
- Earliest claimed: 2014-12-16
- Assignees: PTC Therapeutics, Inc.
- Applicants: PTC Therapeutics, Inc.
- Inventors: Paul Mollard; Peter Giannousis; Shazad Suchit; Mahmoud Mirmehrabi
- Web page: https://patentgrep.com/patent/US11304914B2

## CPC

- A61K 31/122: having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
- A61K 31/164: of a carboxylic acid with an aminoalcohol, e.g. ceramides
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/02: Nutrients, e.g. vitamins, minerals
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/12: of the kidneys
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- 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 27/06: Antiglaucoma agents or miotics
- A61P 27/16: Otologicals
- A61P 35/00: Antineoplastic agents
- A61P 39/02: Antidotes
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07B 57/00: Separation of optically-active compounds
- C07C 215/08: with only one hydroxy group and one amino group bound to the carbon skeleton
- C07C 215/28: and containing six-membered aromatic rings
- C07C 215/30: containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
- C07C 231/12: by reactions not involving the formation of carboxamide groups
- C07C 235/78: the carbon skeleton containing rings
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07C 2601/16: the ring being unsaturated
- 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)
- 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)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

Disclosed herein are polymorphic and amorphous forms of anhydrate, hydrate, and solvates of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide and methods of using such compositions for treating or suppressing oxidative stress disorders, including mitochondrial disorders, impaired energy processing disorders, neurodegenerative diseases and diseases of aging. Further disclosed are methods of making such polymorphic and amorphous forms.

## Claims

### Claim 1

A polymorph of a solvate of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide, wherein the polymorph is selected from the group consisting of Forms IV, V, and VI wherein a powder X-ray diffraction pattern for polymorph Form IV comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ±0.2: 4.31, 12.97, and 13.20; wherein a powder X-ray diffraction pattern for polymorph Form V comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ±0.2: 9.61, 11.49, and 15.45; and wherein a powder X-ray diffraction pattern for polymorph Form VI comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ±0.2: 6.27, 9.91, and 12.94.

### Claim 2 (depends on 1)

The polymorph of claim 1, wherein the polymorph is Form V.

### Claim 3 (depends on 1)

The polymorph of claim 1, wherein the polymorph is Form V, wherein a powder X-ray diffraction pattern for the polymorph comprises characteristic peaks at the following angular positions, wherein the angular positions may vary by ±0.2: 9.61, 11.49, 12.93, 15.45, and 26.05.

### Claim 4 (depends on 2)

A composition comprising the polymorph claim 2, wherein the composition is essentially free of Forms I-IV and VI, wherein; wherein a powder X-ray diffraction pattern for polymorph Form I comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ±0.2: 12.06, 17.03, and 17.26; wherein a powder X-ray diffraction pattern for polymorph Form III comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ±0.2: 14.02, 15.23, and 21.10; and wherein a powder X-ray diffraction pattern for polymorph Form II comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ±0.2: 9.63, 11.33, and 19.33.

### Claim 5 (depends on 2)

A composition comprising the polymorph of claim 2, wherein at least about 95% by mole of the composition is the polymorph Form V, exclusive of any solvents, carriers or excipients.

### Claim 6 (depends on 1)

The polymorph of claim 1, wherein the polymorph is Form IV.

### Claim 7 (depends on 1)

The polymorph of claim 1, wherein the polymorph is Form IV, wherein a powder X-ray diffraction pattern for the polymorph comprises characteristic peaks at the following angular positions, wherein the angular positions may vary by ±0.2: 4.31, 8.76, 12.97, 13.20, and 16.66.

### Claim 8 (depends on 6)

A composition comprising the polymorph of claim 6, wherein the composition is essentially free of Forms I-III and V-VI, wherein a powder X-ray diffraction pattern for polymorph Form I comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ±0.2: 12.06, 17.03, and 17.26; wherein a powder X-ray diffraction pattern for polymorph Form III comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ±0.2: 14.02, 15.23, and 21.10; and wherein a powder X-ray diffraction pattern for polymorph Form II comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ±0.2: 9.63, 11.33, and 19.33.

### Claim 9 (depends on 6)

A composition comprising the polymorph of claim 6, wherein at least about 95% by mole of the composition is the polymorph Form IV, exclusive of any solvents, carriers or excipients.

### Claim 10 (depends on 1)

The polymorph of claim 1, wherein the polymorph is Form VI.

### Claim 11 (depends on 1)

The polymorph of claim 1, wherein the polymorph is Form VI, wherein a powder X-ray diffraction pattern for the polymorph comprises characteristic peaks at the following angular positions, wherein the angular positions may vary by ±0.2: 6.27, 9.41, 9.91, 12.94, and 13.29.

### Claim 12 (depends on 10)

A composition comprising the polymorph of claim 10, wherein the composition is essentially free of Forms I-V, wherein a powder X-ray diffraction pattern for polymorph Form I comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ±0.2: 12.06, 17.03, and 17.26; wherein a powder X-ray diffraction pattern for polymorph Form III comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ±0.2: 14.02, 15.23, and 21.10; and wherein a powder X-ray diffraction pattern for polymorph Form II comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ±0.2: 9.63, 11.33, and 19.33.

### Claim 13 (depends on 10)

A composition comprising the polymorph of claim 10, wherein at least about 95% by mole of the composition is the polymorph Form VI, exclusive of any solvents, carriers or excipients.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising the polymorph of claim 1, and a pharmaceutically acceptable carrier.

### Claim 15 (depends on 14)

The pharmaceutical composition of claim 14, wherein the pharmaceutical composition has an HPLC purity of more than about 95% for the solvate of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide, exclusive of any solvents, carriers or excipients.

### Claim 16 (depends on 14)

The pharmaceutical composition of claim 14, wherein the pharmaceutical composition has an HPLC purity of more than about 99% for the solvate of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide, exclusive of any solvents, carriers or excipients.

### Claim 17 (depends on 14)

The pharmaceutical composition of claim 14, wherein the pharmaceutical composition has an HPLC purity of more than about 99.9% for the solvate of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide, exclusive of any solvents, carriers or excipients.

### Claim 18 (depends on 1)

A method of treating or suppressing an oxidative stress disorder, modulating one or more energy biomarkers, normalizing one or more energy biomarkers, or enhancing one or more energy biomarkers, comprising administering to an individual in need thereof a therapeutically effective amount or effective amount of the polymorph of claim 1.

### Claim 19 (depends on 18)

The method of claim 18, wherein the method is a method of treating or suppressing an oxidative stress disorder selected from the group consisting of: a mitochondrial disorder; an inherited mitochondrial disease; Alpers Disease; Barth syndrome; a Beta-oxidation Defect; Carnitine-Acyl-Carnitine Deficiency; Carnitine Deficiency; a Creatine Deficiency Syndrome; Co-Enzyme Q10 Deficiency; Complex I Deficiency; Complex II Deficiency; Complex III Deficiency; Complex IV Deficiency; Complex V Deficiency; COX Deficiency; chronic progressive external ophthalmoplegia (CPEO); CPT I Deficiency; CPT II Deficiency; Friedreich's Ataxia (FA); Glutaric Aciduria Type II; Kearns-Sayre Syndrome (KSS); Lactic Acidosis; Long-Chain Acyl-CoA Dehydrogenase Deficiency (LCAD); LCHAD; Leigh Syndrome; Leigh-like Syndrome; Leber's Hereditary Optic Neuropathy (LHON); Lethal Infantile Cardiomyopathy (LIC); Luft Disease; Multiple Acyl-CoA Dehydrogenase Deficiency (MAD); Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD); Mitochondrial Myopathy, Encephalopathy, Lactacidosis, Stroke (MELAS); Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Mitochondrial Recessive Ataxia Syndrome (MIRAS); Mitochondrial Cytopathy, Mitochondrial DNA Depletion; Mitochondrial Encephalopathy; Mitochondrial Myopathy; Myoneurogastrointestinal Disorder and Encephalopathy (MNGIE); Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP); Pearson Syndrome; Pyruvate Carboxylase Deficiency; Pyruvate Dehydrogenase Deficiency; a Respiratory Chain Disorder; Short-Chain Acyl-CoA Dehydrogenase Deficiency (SCAD); SCHAD; Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD); a myopathy; cardiomyopathy; encephalomyopathy; a neurodegenerative disease; Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis (ALS); a motor neuron disease; a neurological disease; epilepsy; an age-associated disease; macular degeneration; diabetes; metabolic syndrome; cancer; brain cancer; a genetic disease; Huntington's Disease; a mood disorder; schizophrenia; bipolar disorder; a pervasive developmental disorder; autistic disorder; Asperger's syndrome; childhood disintegrative disorder (CDD); Rett's disorder; PDD-not otherwise specified (PDD-NOS); a cerebrovascular accident; stroke; a vision impairment; optic neuropathy; dominant inherited juvenile optic atrophy; optic neuropathy caused by a toxic agent; glaucoma; Stargardt's macular dystrophy; diabetic retinopathy; diabetic maculopathy; retinopathy of prematurity; ischemic reperfusion-related retinal injury; oxygen poisoning; a haemoglobinopathy; thalassemia; sickle cell anemia; seizures; ischemia; renal tubular acidosis; attention deficit/hyperactivity disorder (ADHD); a neurodegenerative disorder resulting in hearing or balance impairment; Dominant Optic Atrophy (DOA); Maternally inherited diabetes and deafness (MIDD); chronic fatigue; contrast-induced kidney damage; contrast-induced retinopathy damage; Abetalipoproteinemia; retinitis pigmentosum; Wolfram's disease; Tourette syndrome; cobalamin c defect; methylmalonic aciduria; glioblastoma; Down's syndrome; acute tubular necrosis; a muscular dystrophy; a leukodystrophy; Progressive Supranuclear Palsy; spinal muscular atrophy; hearing loss; noise induced hearing loss; traumatic brain injury; Juvenile Huntington's Disease; Multiple Sclerosis; NGLY1; Multiple System Atrophy; Adrenoleukodystrophy; and Adrenomyeloneuropathy.

### Claim 20 (depends on 1)

The polymorph of claim 1, wherein the polymorph is Form V and has a DSC thermogram comprises three endothermic peaks at about 67.2, 92.2, and 150.6° C.

### Claim 21 (depends on 1)

The polymorph of claim 1, wherein the polymorph is Form IV and wherein a DSC thermogram comprises three endothermic peaks at about 70.5, 89.1, and 149.7° C.

### Claim 22 (depends on 1)

The polymorph of claim 1, wherein the polymorph is Form VI and a DSC thermogram comprises three endothermic peaks at about 93.2, 135.2, and 151.0° C.

### Claim 23 (depends on 1)

A composition comprising a polymorph of claim 1, wherein the composition comprises Form IV and V.

### Claim 24 (depends on 1)

A composition comprising a polymorph of claim 1, wherein the composition comprises Form IV and VI.

### Claim 25 (depends on 1)

A composition comprising a polymorph of claim 1, wherein the composition comprises Form V and VI.

### Claim 26 (depends on 24)

A composition comprising the polymorph of claim 24, wherein at least about 95% by mole of the composition is the polymorph Form VI, exclusive of any solvents, carriers or excipients.