# US 2014/0194427 A1 · Deuterium Substituted Fumarate Derivatives

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- Number: US 2014/0194427 A1
- Document ID: US20140194427A1
- Status: Published application
- Kind: A1
- Application number: 14/201,380
- Filed: 2014-03-07
- Published: 2014-07-10
- Earliest claimed: 2012-12-21
- Assignees: Biogen Idec MA Inc.
- Applicants: Biogen IDEC MA Inc.
- Inventors: Jianhua CHAO
- Web page: https://patentgrep.com/patent/US20140194427A1

## CPC

- C07C 69/60: Maleic acid esters; Fumaric acid esters
- A61K 31/225: Polycarboxylic acids
- A61K 31/235: having an aromatic ring attached to a carboxyl group
- A61K 31/24: having an amino or nitro group
- A61K 31/5375: 1,4-Oxazines, e.g. morpholine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/12: Antihypertensives
- A61P 11/06: Antiasthmatics
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/04: Antipruritics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- 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 25/14: 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07B 59/001: {Acyclic or carbocyclic compounds}
- C07C 69/533: Monocarboxylic acid esters having only one carbon-to-carbon double bond
- C07C 69/76: Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C 229/36: with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
- C07D 295/145: with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided is a compound of formula (I): or a pharmaceutically acceptable salt thereof. Also provided is a method of treating, prophylaxis, or amelioration of a disease, comprising administering to a subject in need of treatment for the disease an effective amount of a compound of formula (I) described herein. In one embodiment, the method is a neurodegenerative disease, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, or Alzheimer's disease.

## Claims

### Claim 1

A compound of formula (I)
(a) or a pharmaceutically acceptable salt thereof, wherein
(b) each, of R1 and R2, independently, is hydrogen, deuterium, deuterated methyl, deuterated ethyl, C1-6 aliphatic, phenyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and
(c) each of R3 and R4, independently, is hydrogen or deuterium, wherein at least one of R3 and R4 is deuterium and provided R1 and R2 are not hydrogen at the same time.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is hydrogen or —CH3.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R2 is —CH2D, —CHD2, or —CD3.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R1 is —CD3.

### Claim 5 (depends on 4)

The compound of claim 4, wherein R2 is —CH2D, —CHD2, or —CD3.

### Claim 6

(canceled)

### Claim 7 (depends on 1)

The compound of claim 1, wherein both of R3 and R4 are deuterium.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R2 is hydrogen or —CH3, —CH2D, —CHD2, or —CD3.

### Claim 9

(canceled)

### Claim 10

(canceled)

### Claim 11

A compound of formula (I) wherein the compound is (2H6)dimethyl fumaric acid ester, (2H3)methyl fumaric acid ester, (2H3)dimethyl fumaric acid ester, dimethyl fumaric(2,3-2H2) acid ester, methyl fumaric(2,3-2H2) acid ester, ethyl fumaric(2,3-2H2) acid ester, (2H3)methyl fumaric(2,3-2H2) acid ester, (2H6)dimethyl fumaric(2,3-2H2) acid ester, methyl (2-morpholino-2-oxoethyl) fumaric(2,3-2H2) acid ester, methyl (4-morpholino-1-butyl) fumaric(2,3-2H2) acid ester, 2-(benzoyloxy)ethyl methyl fumaric(2,3-2H2) acid ester, 2-(benzoyloxy)ethyl (2H3)methyl fumaric acid ester, (S)-2-((2-amino-3-phenylpropanoyl)oxy)ethyl methyl fumaric(2,3-2H3) acid ester, or (S)-2-((2-amino-3-phenylpropanoyl)oxy)ethyl (2H3)methyl fumaric acid ester.

### Claim 12 (depends on 1)

A method of activating the Nrf2 pathway, comprising contacting cells with a sufficient amount of a compound of claim 1.

### Claim 13 (depends on 1)

A method of treating, prophylaxis, or amelioration of one or more neurodegenerative diseases, comprising administering to a subject, in need of treatment for the neurodegenerative disease an effective amount of a compound of claim 1.

### Claim 14 (depends on 13)

The method of claim 13, wherein the neurodegenerative disease is one or more diseases selected from the group consisting of Multiple Sclerosis, Amyotrophic Lateral Sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, acute haemorrhagic leucoencephalomyelitis, Hurst's disease, acute disseminated encephalomyelitis, optic neuritis, spinal cord lesions, acute necrotizing myelitis, transverse myelitis, chronic progressive myelopathy, progressive multifocal leukoencephalopathy (PML), radiation myelopathy, HTLV-1 associated myelopathy, monophasic isolated demyelination, central pontine myelinolysis, and leucodystrophy, chronic inflammatory demyelinating polyneuritis (CIDP), and acute inflammatory demyelinating polyneuropathy (AIDP).

### Claim 15 (depends on 14)

The method of claim 14, wherein the one or more neurodegenerative diseases is selected from the group consisting of Multiple Sclerosis, Amyotrophic Lateral Sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's disease.

### Claim 16 (depends on 15)

The method of claim 15, wherein the neurodegenerative disease is Multiple Sclerosis.

### Claim 17 (depends on 1)

A method for the treatment or prophylactic treatment of one or more diseases or disorders in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1, wherein the disease or disorder is one or more diseases, or disorders selected from the group consisting of multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, acute haemorrhagic leucoencephalomyelitis, Hurst's disease, encephalomyelitis, optic neuritis, spinal cord lesion, acute necrotizing myelitis, transverse myelitis, chronic progressive myelopathy, progressive multifocal leukoencephalopathy, radiation myelopathy, HTLV-1associated myelopathy, monophasic isolated demyelination, central pontine myelinolysis, leucodystrophy, inflammatory demyelinising polyneuropathy, acute Guillain-Barre syndrome, polyneuritis, myasthenia gravis, Eaton Lambert Syndrome, encephalomyelitis, inflammatory bowel disease, Crohn's disease, lupus, systemic Lupus erythematodes, asthma, Leber's disease, Devic's disease. Friedrich's Ataxia, a mitochondrial Central Nervous System disease, scleroderma, uveitis, anti-phospholipid antibody syndrome, polyarthritis, polyarticular juvenile idiopathic arthritis, sickle cell disease, ankylosing spondylitis, myositis, atherosclerosis, diabetic peripheral neuropathy, head injury, stroke, HIV-dementia, myocardial infarction, angina pectoris, cardiac insufficiency, psoriasis, psoriatic arthritis, Sjogren's syndrome, diabetes, blistering skin diseases, sarcoidosis, osteoarthritis, ulcerative colitis, vasculitis, lung fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, kidney fibrosis, acute kidney injury, chronic kidney disease, diabetic nephrophathy, graft-versus-host reactions, Hashimoto's thyroiditis, Grave's disease, pernicious anaemia, hepatitis, neurodermatitis, retinopathia pigmentosa, a mitochondrial encephalomyopathy, osteochondritis syphilitica (Wegener's disease), cutis marmorata (livedo reticularis), Behcet disease, panarteriitis, osteoarthritis, gout, artenosclerosis, Reiter's disease, pulmonary granulomatosis, encephalitis, endotoxic shock (septic-toxic shock), sepsis, pneumonia, anorexia nervosa, Rennert T-lymphomatosis, mesangial nephritis, post-angioplastic restenosis, reperfusion syndrome, cytomegaloviral retinopathy, adenoviral diseases, AIDS, post-herpetic neuralgia, post-zoster neuralgia, mononeuropathia multiplex, mucoviscidosis, Bechterew's disease, Barett oesophagus, Epstein-Barr virus infection, cardiac remodeling, interstitial cystitis, human tumour radiosensitisation, multi-resistance of malignant cells to eheraotherapeutic agents, granuloma annulare, a cancer, chronic obstructive pulmonary disease, PDGF induced thymidine uptake of bronchial smooth muscle cells, bronchial smooth muscle cell proliferation, Adrenal Leukodystrophy, Alcoholism, Alper's disease, Ataxia telangiectasia, Batten disease, Bovine spongiform encephalopathy, Cerebral palsy, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, Familial Fatal Insomnia, Frontotemporal lobar degeneration, Kennedy's disease, Lewy body dementia, Neuroborreliosis, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple System Atrophy, Narcolepsy, Niemann Pick disease, Pick's disease, Primary lateral sclerosis, a Prion disease, Progressive Supranuclear Palsy, Refsum's disease, Sandhoff disease, Schilder's disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Spinocerebellar ataxia, Spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabes dorsalis, Toxic encephalopathy, MELAS (Mitochondrial Encephalomyopathy; Lactic Acidosis; Stroke), MERRF (Myoclonic Epilepsy; Ragged Red Fibers), PEG (Progressive External Opthalmoplegia), Leigh's Syndrome, MNGIE (Myopathy and external ophthalmoplegia; Neuropathy; Gastro-Intestinal; Encephalopathy), Kearns-Sayre Syndrome, NARP, Hereditary Spastic Paraparesis, Mitochondrial myopathy, optic neuritis, progressive multifocal, leucoencephalopathy, Pyoderma Gangrenosum, Erosive Pustular Dermatosis of the Scalp, Sweet's Syndrome, Bowel-associated Dermatosis-arthritis Syndrome, Pustular Psoriasis, Acute Generalized Exanthematous Pustulosis, Keratoderma Blenorrhagicum, Sneddon-Wilkinson Disease. Amicrobial Pustulosis of the Folds, Infantile Acropustulosis, Transient Neonatal Pustulosis, Neutrophilic Eccrine Hidradenitis, Rheumatoid Neutrophilic Dermatitis, Neutrophilic Urticaria, Still's Disease, Erythema Marginatum, Unclassified Periodic Fever Syndromes/Autoinflammatory Syndromes, Bullous Systemic Lupus Erythematosus, Neutrophilic Dermatosis of the Dorsal Hands (Pustular Vasculitis), anaphylaxis, allergic rhinitis, allergic asthma, lung cancer, severe asphyxic episodes of asthma, acute lung injury, Acute Respiratory Distress Syndrome, ischemia reperfusion injury, septicemia with multiorgan failure, inderteminate colitis, sickle cell crisis, acute chest syndrome, Scleroderma lung disease, Chronic Asthma, Radiation-Induced Fibrosis Sarcoidosis, Pulmonary Hypertension, Bronchopulmonary Dysplasia (BPD), Lung Transplant Rejection, Pulmonary GVHD Complications, Interstitial pneumonia Syndrome (IPS) in transplant recipients, COPD, Silicosis, Asbestosis, Primary sclerosing cholangitis (PSC), Alcohol-induced hepatic fibrosis, Autoimmune hepatitis, Chronic viral hepatitis (HepB,C), Primary biliary cirrhosis (PBC), Non-alcohol Steatohepatitis (NASH), Liver transplant rejection, Hepatic complications of GVHD, Veno-occlusive disease in transplant recipients, Focal Segmental Glomerular Sclerosis (FSGS), Diabetic nephropathy, IgA nephropathy, Renal complications of GVHD (AKI delayed graft function), Acute renal failure post CABG (AKI post CABG), Lupus nephritis, Hypertension-induced Renal Fibrosis, HIV-associated nephropathy, Peritoneal dialysis-induced peritoneal fibrosis, Retroperitoneal fibrosis, Idiopathic Glomerulosclerosis, Kidney transplant rejection, Alport syndrome, Restenosis, Subarachnoid hemorrhage (SAH), Heart transplant rejection, Cosmetic surgery, Chronic wounds, Burns, Surgical adhesions, Keloids, Donor graft re-epithelialization, Myelofibrosis, Corneal transplant, LASIX, Trabeculectomy, Systemic sclerosis, Radiation induced fibrosis, Peripatellar Fibrosis, and Dupuytren's Contractures.

### Claim 18 (depends on 13)

The method of claim 13, wherein the effective amount is about 200 mg to about 800 mg per day.

### Claim 19 (depends on 18)

The method of claim 18, wherein the effective amount is administered in a single administration.

### Claim 20 (depends on 18)

The method of claim 18, wherein the effective amount is administered in separate administrations of 2, 3, 4, or 6 equal doses.

### Claim 21 (depends on 20)

The method of claim 20, wherein the effective amount is administered orally.

### Claim 22 (depends on 13)

The method of claim 13, wherein the subject is administered a first dose for one dosing period and a second dose for a second dosing period.

### Claim 23 (depends on 22)

The method of claim 22, wherein the first dosing period is at least one week.

### Claim 24 (depends on 13)

The method of claim 13, wherein the effective amount is administered in combination with one or more non-steroidal anti-inflammatory drags.

### Claim 25 (depends on 17)

The method of claim 17, wherein the effective amount is about 200 mg to about 800 mg per day.

### Claim 26 (depends on 25)

The method of claim 25, wherein the effective amount is administered in a single administration.

### Claim 27 (depends on 25)

The method of claim 25, wherein the effective amount is administered in separate administrations of 2, 3, 4, or 6 equal doses.

### Claim 28 (depends on 27)

The method of claim 27, wherein the effective amount is administered orally.

### Claim 29 (depends on 17)

The method of claim 17, wherein the subject is administered a first dose for one dosing period and a second dose for a second dosing period.

### Claim 30 (depends on 29)

The method of claim 29, wherein the first dosing period is at least one week.

### Claim 31 (depends on 17)

The method of claim 17, wherein the effective amount is administered in combination with one or more non-steroidal anti-inflammatory drugs.

### Claim 32 (depends on 1)

The compound of claim 1, wherein the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500.