# US 2016/0355485 A9 · Benzimidazole derivatives as selective blockers of persistent sodium current

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- Number: US 2016/0355485 A9
- Document ID: US20160355485A9
- Status: Published application
- Kind: A9
- Application number: 14/494,734
- Filed: 2014-09-24
- Published: 2016-12-08
- Earliest claimed: 2011-12-28
- Assignees: Allergan, Inc.
- Applicants: Allergan, Inc.
- Inventors: George R. Ehring; Ellen Chao; Herman Ng; Hau Ton; Jia Chian Li; Joseph S. Adorante; Michael E. Garst; Howard B. Rind; Mark R. Hansen; Alfred Arthur Avey, JR.; Lloyd Jay Dolby; Shervin Esfandiari; Vivian R. MacKenzie; Jeremiah Andrew Marsden; David Charles Muchmore
- Web page: https://patentgrep.com/patent/US20160355485A9

## CPC

- C07D 235/12: Radicals substituted by oxygen atoms
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 235/06: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D 235/08: Radicals containing only hydrogen and carbon atoms
- C07D 235/14: Radicals substituted by nitrogen atoms (by nitro radicals C07D235/10)
- C07D 235/20: Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is directed to a compound of Formula I or a pharmaceutically acceptable salt thereof; wherein R, R1, R2, R3, R4, m, and n are as defined herein, to pharmaceutical compositions comprising said compound, and to methods of treating diseases or conditions mediated by elevated persistent sodium current, such as an ocular disorder, multiple sclerosis, seizure disorder, and chronic pain.

## Claims

### Claim 1

A compound of Formula I
or a pharmaceutically acceptable salt thereof; wherein:
R is selected from the group consisting of C1-6 alkyl which is unsubstituted or substituted with a substituent selected from the group consisting of —N(C1-6 alkyl)2, C6-12 aryl, C6-12 aryloxy and heteroaryl;
each R1 and R2 are independently H or C1-6 alkyl;
R3 is selected from the group consisting of C6-12 aryl and heteroaryl;
each R4 independently is selected from the group consisting of C1-6 alkyl, and C1-6 alkoxy, wherein said C1-6 alkyl and the alkyl portion of said C1-6 alkoxy are independently unsubsubstituted or substituted with a substituent selected from the group consisting of hydroxyl, —C(═O)OH, —C(═O)O—C1-6 alkyl, —C(═O)-heterocyclyl, and —N(C1-6 alkyl)2;
R5 is H or C1-6 alkyl;
X is selected from the group consisting of a covalent bond, O, NR5, —S(═O)—, and —S(═O)2—;
m is 1 or 2; and
n is 0 or 1;
with the proviso that when R is an unsubstituted C1-6 alkyl, then either (1) X is other than a covalent bond, or (2) R4 is C1-6 alkoxy, wherein the alkyl portion of said C1-6 alkoxy is substituted with a —N(C1-6 alkyl)2 substituent.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R is and unsubstituted straight chain or branched C1-6 alkyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R is C1-6 alkyl which is substituted with a C6-12 aryloxy group.

### Claim 4 (depends on 3)

The compound of claim 3, wherein the “aryl” portion of said C6-12 aryloxy group is unsubstituted or substituted with 1-2 C1-6 alkyl or C1-6 alkoxy substitutents.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R is C1-6 alkyl which is substituted with a heteroaryl substitutent, wherein said heteroaryl group is five- to six-membered ring containing 1-2 ring N atoms, and wherein when said five- to six-membered ring containing 1-2 ring N atoms has two substituents on adjacent carbon atoms, said substituents together with the carbon atoms to which they are attached can optionally form a phenyl ring, and wherein said six-membered ring containing 1-2 ring N atoms, optionally with said phenyl ring is optionally further substituted with a ring system substituent.

### Claim 6 (depends on 5)

The compound of claim 5, wherein said five- to six-membered ring containing 1-2 ring N atoms, optionally with said phenyl ring is selected from the group consisting of pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, and benzimidazolyl.

### Claim 7 (depends on 6)

The compound of claim 6, wherein said five- to six-membered ring containing 1-2 ring N atoms, optionally with said phenyl ring is selected from the group consisting of is imidazolyl and benzimidazolyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R is C1-6 alkyl which is substituted with a —N(C1-6 alkyl)2 substituent.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R is selected from the group consisting of:

### Claim 10 (depends on 1)

The compound of claim 1, wherein R1 and R2 are both H.

### Claim 11 (depends on 10)

The compound of claim 10, wherein m is 1 or 2.

### Claim 12 (depends on 10)

The compound of claim 10, wherein m is 1, and X is O.

### Claim 13 (depends on 10)

The compound of claim 10, wherein m is 2, and X is a covalent bond.

### Claim 14 (depends on 10)

The compound of claim 10, wherein m is 1, and X is —S(═O)—.

### Claim 15 (depends on 10)

The compound of claim 10, wherein m is 1 and X is NR5, wherein R5 is H.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R3 is C6-12 aryl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of: C1-6 alkoxy, halo, and haloalkyl,

### Claim 17 (depends on 16)

The compound of claim 16, wherein:
the C1-6 alkoxy substituent is selected from the group consisting of methoxy, ethoxy, isobutoxy;
the halo substituent is selected from the group consisting of: fluoro and chloro; and
the haloalkyl group is trifluoromethyl.

### Claim 18 (depends on 16)

The compound of claim 16, wherein said C6-12 aryl is a unsubstituted or substituted phenyl or naphthyl.

### Claim 19 (depends on 1)

The compound of claim 1, wherein R3 is heteroaryl, wherein said heteroaryl is pyridyl.

### Claim 20 (depends on 1)

The compound of claim 1, wherein R4 is an unsubstituted or substituted C1-6 alkoxy, which is selected from the group consisting of: ethoxy, —OCH2CH2CH(CH3)CH3, —O—CH2CH2CH3, —O—CH2CH2—N(CH2CH3)2, —O—CH2CH2-pyrazolyl, —O—CH2—C(═O)-pyrrolidinyl, —O—CH2—C(═O)—O—CH2CH3, and —O—CH2—C(═O)—OH.

### Claim 21 (depends on 1)

The compound of claim 1, wherein R4 is an unsubstituted or substituted C1-6 alkyl which is propyl.

### Claim 22 (depends on 1)

The compound of claim 1, selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 1)

A pharmaceutical composition comprising at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

### Claim 24

A method of blocking persistent sodium current without affecting transient current in a mammal comprising administering to said mammal in need thereof a therapeutically effective amount of the compound of Formula I
or a pharmaceutically acceptable salt thereof; wherein:
R is selected from the group consisting of C1-6 alkyl which is unsubstituted or substituted with a substituent selected from the group consisting of —N(C1-6 alkyl)2, C2-6 alkenyl, C6-12 aryl, C6-12 aryloxy and heteroaryl;
each R1 and R2 are independently H or C1-6 alkyl;
R3 is selected from the group consisting of C6-12 aryl and heteroaryl;
each R4 independently is selected from the group consisting of C1-6 alkyl, and C1-6 alkoxy, wherein said C1-6 alkyl and the alkyl portion of said C1-6 alkoxy are independently unsubsubstituted or substituted with a substituent selected from the group consisting of hydroxyl, —C(═O)OH, —C(═O)O—C1-6 alkyl, —C(═O)-heterocyclyl, and —N(C1-6 alkyl)2;
R5 is H or C1-6 alkyl;
X is selected from the group consisting of a covalent bond, O, S, NR5, —S(═O)—, and —S(═O)2—;
m is 1 or 2; and
n is 0 or 1.

### Claim 25

A method of treating a disease or condition in a mammal, wherein said disease or condition is mediated by elevated persistent sodium current, comprising administering to said mammal in need thereof an effective amount of a compound of Formula I
or a pharmaceutically acceptable salt thereof; wherein:
R is selected from the group consisting of C1-6 alkyl which is unsubstituted or substituted with a substituent selected from the group consisting of —N(C1-6 alkyl)2, C2-6 alkenyl, C6-12 aryl, C6-12 aryloxy and heteroaryl;
each R1 and R2 are independently H or C1-6 alkyl;
R3 is selected from the group consisting of C6-12 aryl and heteroaryl;
each R4 independently is selected from the group consisting of C1-6 alkyl, and C1-6 alkoxy, wherein said C1-6 alkyl and the alkyl portion of said C1-6 alkoxy are independently unsubsubstituted or substituted with a substituent selected from the group consisting of hydroxyl, —C(═O)OH, —C(═O)O—C1-6 alkyl, —C(═O)-heterocyclyl, and —N(C1-6 alkyl)2;
R5 is H or C1-6 alkyl;
X is selected from the group consisting of a covalent bond, O, S, NR5, —S(═O)—, and —S(═O)2—;
m is 1 or 2; and
n is 0 or 1.

### Claim 26 (depends on 25)

The method of claim 25, wherein said disease or condition is selected from the group consisting of chronic pain, ocular disorder, multiple sclerosis, and seizure disorder.

### Claim 27 (depends on 26)

The method of claim 26, wherein the ocular disorder is selected from the group consisting of age related macular degeneration, geographic atrophy (GA), retinitis pigmentosa, Stargardt's disease cone dystrophy, and pattern dystrophy of the retinal pigmented epithelium, macular edema, retinal detachment, retinal trauma, retinal tumors and retinal diseases associated with said tumors, congenital hypertrophy of the retinal pigmented epithelium, acute posterior multifocal placoid pigment epitheliopathy, optic neuritis, acute retinal pigment epithelitis, optic neuropathies and glaucoma; the chronic pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, post-operative pain, pain resulting from cancer or cancer treatment, headache pain, irritable bowel syndrome pain, fibromyalgia pain, and pain resulting from diabetic neuropathy; and the seizure disorder is selected from the group consisting of epilepsy and chemically-induced seizure disorder.

### Claim 28 (depends on 25)

The method of claim 25, wherein said compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.