# US 11,298,344 B2 · Composition for inhibiting sodium leak channel (NALCN), comprising n-benzhydryl quinuclidine derivatives

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- Number: US 11,298,344 B2
- Document ID: US11298344B2
- Status: Granted
- Kind: B2
- Application number: 16/392,680
- Filed: 2019-04-24
- Published: 2020-01-16
- Granted: 2022-04-12
- Earliest claimed: 2018-07-10
- Assignees: Research & Business Foundation Sungkyunkwan University
- Applicants: Research & Business Foundation Sungkyunkwan University
- Inventors: Myoung Kyu Park; Hyun Jin Kim; Suyun Hahn; So Woon Kim
- Web page: https://patentgrep.com/patent/US11298344B2

## CPC

- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61P 25/00: Drugs for disorders of the nervous system
- 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

## Abstract

A composition for inhibiting sodium leakage channel (NALCN), including as an active ingredient N-benzhydryl quinuclidine (NBQN) or a N-benzhydryl quinuclidine derivative represented by the following Formula 1, wherein in the following Formula 1, R is an unsubstituted or substituted benzyl group

## Claims

### Claim 1

A method for inhibiting a sodium leak channel, comprising:
treating a cell comprising a mutation of a gene encoding the sodium leak channel with a pharmaceutical composition comprising as an active ingredient N-benzhydryl quinuclidine, a N-benzhydryl quinuclidine derivative represented by the following Formula 1, or a pharmaceutically acceptable salt thereof; and
detecting and measuring a change of an electrical current through the sodium leak channel in the cell,
wherein in the following Formula 1, R is an unsubstituted or substituted benzyl group, and
wherein the N-benzhydryl quinuclidine, a N-benzhydryl quinuclidine derivative or a pharmaceutically acceptable salt thereof inhibits a sodium leak channel in the individual in need thereof:

### Claim 2 (depends on 1)

The method according to claim 1,
wherein R1 is hydrogen, halogen, or methoxy, and
R2 is hydrogen or C1-4 alkyl.

### Claim 3 (depends on 1)

The method according to claim 1,
wherein the N-benzhydryl quinuclidine derivative is
2-(diphenylmethyl)-N-(2-iodobenzyl)quinuclidin-3-amine,
2-(diphenylmethyl)-N-(2-methoxybenzyl)quinuclidin-3-amine, or
(2S,3S)-2-(diphenylmethyl)-N-[2-methoxy-5-(2-methyl-2-propanyl)benzyl]quinuclidin-3-amine.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the cell is obtained from a subject suffering from a disease resulting from abnormality of the sodium leak channel.

### Claim 5 (depends on 4)

The method according to claim 4, wherein the disease is one or more diseases selected from the group consisting of infantile neuroaxonal dystrophy (INAD), neurodevelopmental autosomal syndromes with severe hypotonia, speech impairment, cognitive delay, cervical dystonia, pancreatic cancer, non-small cell lung cancer, glioblastoma, 13q deletion syndrome, restless legs syndrome, and autism.

### Claim 6

A method for treating a disease resulting from abnormality of sodium leak channels, comprising:
administering, to an individual with the disease resulting from abnormality of sodium leak channels, a pharmaceutical composition comprising as an active ingredient N-benzhydryl quinuclidine, a N-benzhydryl quinuclidine derivative represented by the following Formula 1, or a pharmaceutically acceptable salt thereof; and
detecting and measuring a change of an electrical current through the sodium leak channel to confirm inhibition of the sodium leak channel,
wherein in the following Formula 1, R is an unsubstituted or substituted benzyl group,
wherein the disease is one or more diseases selected from the group consisting of infantile neuroaxonal dystrophy (INAD), neurodevelopmental autosomal syndromes with severe hypotonia, speech impairment, cognitive delay, cervical dystonia, pancreatic cancer, non-small cell lung cancer, glioblastoma, 13q deletion syndrome, restless legs syndrome, and autism:
and
wherein the abnormality of sodium leak channels is caused by a mutation of a gene encoding the sodium leak channel.

### Claim 7 (depends on 6)

The method according to claim 6, wherein
R1 is hydrogen, halogen, or methoxy, and
R2 is hydrogen or C1-4 alkyl.

### Claim 8 (depends on 6)

The method according to claim 6,
wherein the N-benzhydryl quinuclidine derivative is 2-(diphenylmethyl) -N-(2-iodobenzyl)quinuclidin-3-amine, 2-(diphenylmethyl)-N-(2-methoxybenzyl)quinuclidin-3-amine, or (2S,3S)-2-(diphenylmethyl)-N-[2-methoxy-5-(2-methyl-2-propanyl)benzyl]quinuclidin-3- amine.

### Claim 9 (depends on 6)

The method according to claim 6,
wherein the disease resulting from abnormality of sodium leak channel is one or more diseases selected from the group consisting of sodium leak channel is one or more diseases selected from the group consisting of infantile neuroaxonal dystrophy (INAD), neurodevelopmental autosomal syndromes with severe hypotonia, speech impairment, cognitive delay, cervical dystonia, pancreatic cancer, non-small cell lung cancer, glioblastoma, 13q deletion syndrome, restless legs syndrome, and autism.

### Claim 10

A method for inhibiting a sodium leak channel, comprising:
treating a cell comprising a mutation of a gene encoding the sodium leak channel or an with a pharmaceutical composition comprising as an active ingredient N-benzhydryl quinuclidine, a N-benzhydryl quinuclidine derivative represented by the following Formula 1, or a pharmaceutically acceptable salt thereof; and
detecting and measuring a change of an electrical current through the sodium leak channel in the cell:
wherein R is
wherein R1 is hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxy, and R2 is hydrogen, halogen, or C1-4 haloalkyl, and
wherein the N-benzhydryl quinuclidine, a N-benzhydryl quinuclidine derivative or a pharmaceutically acceptable salt thereof inhibits the sodium leak channel.

### Claim 11 (depends on 10)

The method according to claim 10, wherein
R1 is hydrogen, halogen, or methoxy, and
R2 is hydrogen.

### Claim 12 (depends on 10)

The method according to claim 10,
wherein the N-benzhydryl quinuclidine derivative is
2-(diphenylmethyl)-N-(2-iodobenzyl)quinuclidin-3-amine, or 2-(diphenylmethyl)-N-(2-methoxybenzyl)quinuclidin-3-amine.

### Claim 13 (depends on 10)

The method according to claim 10, wherein the cell is obtained from a subject suffering from a disease resulting from abnormality of the sodium leak channel.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the disease is one or more diseases selected from the group consisting of infantile neuroaxonal dystrophy (INAD), neurodevelopmental autosomal syndromes with severe hypotonia, speech impairment, cognitive delay, cervical dystonia, pancreatic cancer, non-small cell lung cancer, glioblastoma, 13q deletion syndrome, restless legs syndrome, and autism.