# US 8,785,443 B2 · Methods of using prodrugs of methyl hydrogen fumarate and pharmaceutical compositions thereof

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- Number: US 8,785,443 B2
- Document ID: US8785443B2
- Status: Granted
- Kind: B2
- Application number: 13/274,284
- Filed: 2011-10-14
- Published: 2012-04-19
- Granted: 2014-07-22
- Earliest claimed: 2008-08-19
- Assignees: XenoPort, Inc.
- Applicants: Archana Gangakhedkar; Xuedong Dai; Noa Zerangue; Peter A. Virsik
- Inventors: Archana Gangakhedkar; Xuedong Dai; Noa Zerangue; Peter A. Virsik
- Web page: https://patentgrep.com/patent/US8785443B2

## CPC

- C07C 235/06: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07C 69/60: Maleic acid esters; Fumaric acid esters
- C07C 69/75: of acids with a six-membered ring
- C07C 69/78: Benzoic acid esters
- C07C 69/96: Esters of carbonic or haloformic acids
- C07C 235/08: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C 235/10: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07C 235/12: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C 259/06: having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C 271/64: Y being a hydrogen or a carbon atom, e.g. benzoylcarbamates
- C07C 275/50: Y being a hydrogen or an acyclic carbon atom
- C07D 207/16: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 263/20: attached in position 2
- C07D 285/12: 1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D 295/18: by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D 295/185: from aliphatic carboxylic acids
- C07C 2601/14: The ring being saturated
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Prodrugs of methyl hydrogen fumarate, pharmaceutical compositions comprising prodrugs of methyl hydrogen fumarate, and methods of using prodrugs of methyl hydrogen fumarate and pharmaceutical compositions thereof for treating diseases such as psoriasis, asthma, multiple sclerosis, inflammatory bowel disease, and arthritis are disclosed.

## Claims

### Claim 1

A method of treating a patient suffering from a disease selected from psoriasis, multiple sclerosis, Huntington's disease, asthma, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, ulcerative colitis and psoriatic arthritis, comprising administering to a patient in need thereof a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R1 and R2 are independently chosen from hydrogen, C1-6 alkyl, and substituted C1-6 alkyl;
R3 and R4 are independently chosen from hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C1-6 heteroalkyl, substituted C1-6 heteroalkyl, C4-12 cycloalkylalkyl, substituted C4-12 cycloalkylalkyl, C7-12 arylalkyl, and substituted C7-12 arylalkyl; or R3 and R4 together with the nitrogen to which they are bonded form a ring chosen from a C5-10 heteroaryl, substituted C5-10 heteroaryl, C5-10 heterocycloalkyl, and substituted C5-10 heterocycloalkyl; and
R5 is methyl;
wherein each substituent group is independently chosen from halogen, —OH, —CN, —CF3, ═O, —NO2, benzyl, —C(O)NR112, —R11, —OR11, —C(O)R11, —COOR11, and —NR112 wherein each R11 is independently chosen from hydrogen and C1-4 alkyl.

### Claim 2 (depends on 1)

The method of claim 1 wherein the disease is selected from psoriasis and multiple sclerosis.

### Claim 3 (depends on 1)

The method of claim 1 wherein the disease is psoriasis.

### Claim 4 (depends on 1)

The method of claim 1 comprising administering a second therapeutic agent effective in treating psoriasis.

### Claim 5 (depends on 1)

The method of claim 1 wherein the disease is multiple sclerosis.

### Claim 6 (depends on 1)

The method of claim 1 comprising administering a second therapeutic agent effective in treating multiple sclerosis.

### Claim 7 (depends on 1)

The method of claim 1 wherein the disease is selected from Huntington's disease, asthma, Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease.

### Claim 8 (depends on 1)

The method of claim 1 wherein the disease is selected from rheumatoid arthritis and Crohn's disease.

### Claim 9 (depends on 1)

The method of claim 1 wherein the disease is selected from ankylosing spondylitis and ulcerative colitis.

### Claim 10 (depends on 1)

The method of claim 1, wherein each of R1 and R2 is hydrogen.

### Claim 11 (depends on 1)

The method of claim 1, wherein one of R1 and R2 is hydrogen and the other of R1 and R2 is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.

### Claim 12 (depends on 1)

The method of claim 1, wherein R3 and R4 are independently chosen from hydrogen and C1-6 alkyl.

### Claim 13 (depends on 1)

The method of claim 1, wherein R3 and R4 together with the nitrogen to which they are bonded form a C5-10 heterocycloalkyl ring.

### Claim 14 (depends on 1)

The method of claim 1, wherein one of R1 and R2 is hydrogen and the other of R1 and R2 is chosen from hydrogen and C1-6 alkyl; and R3 and R4 together with the nitrogen to which they are bonded form a ring chosen from morpholine, piperazine, and N-substituted piperazine.

### Claim 15 (depends on 1)

The method of claim 1, wherein one of R1 and R2 is hydrogen; and the other of R1 and R2 is chosen from hydrogen and C1-6 alkyl; R3 is hydrogen; and R4 is chosen from hydrogen, C1-6 alkyl, and benzyl.

### Claim 16 (depends on 1)

The method of claim 1, wherein the compound is chosen from:
(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;
methyl [N-benzylcarbamoyl]methyl (2E)but-2-ene-1,4-dioate;
methyl 2-morpholin-4-yl-2-oxoethyl (2E)but-2-ene-1,4-dioate;
(N-butylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;
[N-(2-methoxyethyl)carbamoyl]methyl methyl (2E)but-2-ene-1,4-dioate;
2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}acetic acid;
4-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}butanoic acid;
(N,N-dimethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;
bis-(2-methoxyethylamino)carbamoyl]methyl methyl (2E)but-2-ene-1,4-dioate;
[N-(methoxycarbonyl)carbamoyl]methyl methyl (2E)but-2ene-1,4-dioate;
methyl 2-oxo-2-piperazinylethyl (2E)but-2-ene-1,4-dioate;
methyl 2-oxo-2-(2-oxo(1,3-oxazolidin-3-yl)ethyl (2E)but-2ene-1,4-dioate;
{N-[2-(dimethylamino)ethyl]carbamoyl}methyl methyl (2E)but-2ene-1,4 dioate;
methyl 2-(4-methylpiperazinyl)-2-oxoethyl (2E)but-2-ene-1,4-dioate;
methyl {N-[(propylamino)carbonyl]carbamoyl}methyl (2E)but-2ene-1,4-dioate;
2-(4-acetylpiperazinyl)-2-oxoethyl methyl (2E)but-2ene-1,4-dioate;
{N,N-bis[2-(methylethoxy)ethyl]carbamoyl}methyl methyl (2E)but-2-ene-1,4-dioate;
methyl 2-(4-benzylpiperazinyl)-2-oxoethyl (2E)but-2-ene-1,4-dioate;
[N,N-bis(2-ethoxyethyl)carbamoyl]methyl methyl (2E)but-2-ene-1,4-dioate;
2-{(2S)-2-[tert-butyl)oxycarbonyl]pyrrolidinyl}-2-oxoethyl methyl (2E)but-2ene-1,4-dioate;
1-{2-{(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetyl}(2S)pyrrolidine-2-carboxylic acid;
(N-{[tert-butyl)oxycarbonyl]methyl}-N-methylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;
{N-(ethoxycarbonyl)methyl]-N-methylcarbamoyl}methyl methyl (2E)but-2-ene-1,4-dioate;
methyl 1-methyl-2-morpholin-4-yl-2-oxoethyl(2E)but-2-ene-1,4-dioate;
[N,N-bis(2-methoxyethyl)carbamoyl]ethyl methyl (2E)but-2-ene-1,4-dioate;
(N,N-dimethylcarbamoyl)ethyl methyl (2E)but-2-ene-1,4-dioate;
2-{2-[(2E)-3-(methoxy carbonyl)prop-2-enoyloxyl]-N-methylacetylamino}acetic acid;
(N-{[(tert-butyl)oxycarbonyl]methyl}carbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;
methyl (N-methyl-N-{[(methylethyl)oxycarbonyl]methyl}carbamoyl)methyl (2E)but-2-ene-1,4-dioate;
{N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}methyl methyl (2E)but-2-ene-1,4-dioate;
{N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}ethyl methyl (2E)but-2-ene-1,4-dioate;
{N-[(ethoxycarbonyl)methyl]-N-methylcarbamoyl}ethyl methyl (2E)but-2-ene-1,4-dioate;
(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl methyl (2E)but-2-ene-1,4-dioate;
(1S)-1-[N,N-bis(2-methoxyethyl)carbamoyl]ethyl methyl (2E)but-2-ene-1,4-dioate;
(1R)-1-(N,N-diethylcarbamoyl)ethyl methyl (2E)but-2-ene-1,4-dioate;
(N-[(methoxycarbonyl)ethyl]carbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;
2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}propanoic acid; and
pharmaceutically acceptable salts of any of the foregoing.

### Claim 17 (depends on 1)

The method of claim 1, wherein R3 and R4 are independently chosen from methyl, ethyl, methoxyethyl; or R3 and R4 together with the nitrogen to which they are bonded form a 4-morpholinyl group.

### Claim 18 (depends on 1)

The method of claim 1, wherein the compound is (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

### Claim 19 (depends on 18)

The method of claim 18, wherein the disease is psoriasis.

### Claim 20 (depends on 18)

The method of claim 18, wherein the disease is multiple sclerosis.

### Claim 21 (depends on 18)

The method of claim 18, wherein the compound is in an oral formulation.

### Claim 22 (depends on 21)

The method of claim 21, wherein the oral formulation is an oral sustained release formulation.

### Claim 23 (depends on 1)

The method of claim 1, wherein the compound is methyl 2-morpholin-4-yl-2-oxoethyl (2E)but-2-ene-1,4-dioate.

### Claim 24 (depends on 23)

The method of claim 23, wherein the disease is psoriasis.

### Claim 25 (depends on 23)

The method of claim 23, wherein the disease is multiple sclerosis.

### Claim 26 (depends on 23)

The method of claim 23, wherein the compound is in an oral formulation.

### Claim 27 (depends on 23)

The method of claim 23, wherein the oral formulation is an oral sustained release formulation.

### Claim 28 (depends on 1)

The method of claim 1, wherein the compound is bis-(2-methoxyethylamino)carbamoyl]methyl methyl (2E)but-2-ene-1,4-dioate.

### Claim 29 (depends on 28)

The method of claim 28, wherein the disease is psoriasis.

### Claim 30 (depends on 28)

The method of claim 28, wherein the disease is multiple sclerosis.

### Claim 31 (depends on 28)

The method of claim 28, wherein the compound is in an oral formulation.

### Claim 32 (depends on 31)

The method of claim 31, wherein the oral formulation is an oral sustained release formulation.

### Claim 33 (depends on 1)

The method of claim 1, wherein the compound is (N,N-dimethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate.

### Claim 34 (depends on 33)

The method of claim 33, wherein the disease is psoriasis.

### Claim 35 (depends on 33)

The method of claim 33, wherein the disease is multiple sclerosis.

### Claim 36 (depends on 33)

The method of claim 33, wherein the compound is in an oral formulation.

### Claim 37 (depends on 36)

The method of claim 36, wherein the oral formulation is an oral sustained release formulation.

### Claim 38 (depends on 1)

The method of claim 1 wherein the compound is in an oral formulation.

### Claim 39 (depends on 38)

The method of claim 38 wherein the oral formulation is an oral sustained release formulation.

### Claim 40 (depends on 1)

The method of claim 1 comprising administering a second therapeutic agent effective in minimizing an adverse effect associated with the compound of Formula (I).

### Claim 41 (depends on 1)

The method of claim 1 comprising administering a second therapeutic agent selected from a non-steroidal anti-inflammatory agent and a cox-2 inhibitor.

### Claim 42 (depends on 1)

The method of claim 1 comprising administering a second therapeutic agent selected from vitamin E, paroxetine, gabapentin and pentoxifylline.