# US 2010/0168192 A1 · Benzisoxazole derivatives as potassium channel modulators for the treatment of e.g. respiratory diseases, epilepsy and convulsions

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- Number: US 2010/0168192 A1
- Document ID: US20100168192A1
- Status: Published application
- Kind: A1
- Application number: 12/601,482
- Filed: 2008-05-22
- Published: 2010-07-01
- Earliest claimed: 2007-05-24
- Assignees: NeuroSearch A/S
- Inventors: Antonio Nardi; Claus Mathiesen; Jeppe Kejser Christensen
- Web page: https://patentgrep.com/patent/US20100168192A1

## CPC

- C07D 261/20: condensed with carbocyclic rings or ring systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 1/10: Laxatives
- A61P 1/12: Antidiarrhoeals
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- 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 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/10: for impotence
- A61P 17/14: for baldness or alopecia
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- 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 27/00: Drugs for disorders of the senses
- 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 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention relates to novel benzisoxazole derivatives that are found to be potent modulators of potassium channels and, as such, are valuable candidates for the treatment of diseases or disorders as diverse as those which are responsive to the modulation of potassium channels e.g. a respiratory disease, epilepsy or convulsions. X represents a substituent selected from the group consisting of CO—NR′R″, CO—O—R′, CO—NH—S, CO—NH—SO2R″′, CO—NH—C═N, SO2—NR′R″, 2,3-dihydro-1-H-tetrazol-5-yl and [1,2,4]oxadiazolidin-5-one; wherein R′ and R″, independently of each other, represent hydrogen or alkyl or phenyl; and R″′ represents alkyl, cycloalkyl, haloalkyl or phenyl, which phenyl may optionally be substituted one or more times with substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano and nitro.

## Claims

### Claim at position 1

1-14. (canceled)

### Claim 15

A benzisoxazole derivative of Formula I
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein
X represents a substituent selected from the group consisting of CO—NR′R″, CO—O—R′, CO—NH—S, CO—NH—SO2R′″, CO—NH—C≡N, SO2—NR′R″, 2,3-dihydro-1H-tetrazol-5-yl and [1,2,4]oxadiazolidin-5-one; wherein
R′ and R″, independently of each other, represent hydrogen or alkyl or phenyl; and
R″′ represents alkyl, cycloalkyl, haloalkyl or phenyl, which phenyl may optionally be substituted one or more times with substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano and nitro.

### Claim 16 (depends on 15)

The benzisoxazole derivative of claim 15, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein X represents CO—NR′R″, wherein R′ and R″, independently of each other, represent hydrogen or alkyl.

### Claim 17 (depends on 15)

The benzisoxazole derivative of claim 15, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein X represents CO—O—R′, wherein R′ represents hydrogen or alkyl.

### Claim 18 (depends on 15)

The benzisoxazole derivative of claim 15, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein X represents CO—NH—S.

### Claim 19 (depends on 15)

The benzisoxazole derivative of claim 15, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein X represents CO—NH—SO2R′″, wherein R′″ represents alkyl or phenyl.

### Claim 20 (depends on 15)

The benzisoxazole derivative of claim 15, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein X represents CO—NH—C≡N.

### Claim 21 (depends on 15)

The benzisoxazole derivative of claim 15, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein X represents SO2—NR′R″, wherein R′ and R″, independently of each other, represent hydrogen or alkyl.

### Claim 22 (depends on 15)

The benzisoxazole derivative of claim 15, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein X represents 2,3-dihydro-1H-tetrazol-5-yl.

### Claim 23 (depends on 15)

The benzisoxazole derivative of claim 15, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein X represents [1,2,4]oxadiazolidin-5-one.

### Claim 24 (depends on 15)

The benzisoxazole derivative of claim 15, which is
3-(2,3-Dihydro-1H-tetrazol-5-yl-methyl)-benzo[d]isoxazole;
3-Benzo[d]isoxazol-3-yl-methyl-[1,2,4]oxadiazolidin-5-one,
N-(2-Benzo[d]isoxazol-3-yl-acetyl)-methanesulfonamide;
N-(2-Benzo[d]isoxazol-3-yl-acetyl)-trifluoro-methanesulfonamide;
Cyclopropanesulfonic acid (2-benzo[d]isoxazol-3-yl-acetyl)-amide;
N-(2-Benzo[d]isoxazol-3-yl-acetyl)-benzenesulfonamide; or
N-(2-Benzo[d]isoxazol-3-yl-acetyl)-4-chloro-benzenesulfonamide;
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof.

### Claim 25 (depends on 15)

A pharmaceutical composition comprising a therapeutically effective amount of the benzisoxazole derivative of claim 15, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, together with one or more adjuvants, excipients, carriers and/or diluents.

### Claim 26 (depends on 15)

A method of treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to modulation of potassium channels, which method comprises the step of administering to such a living animal body in need thereof, a therapeutically effective amount of a benzisoxazole derivative of claim 15, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, for the manufacture of a pharmaceutical composition/medicament for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to modulation of potassium channels.

### Claim 27 (depends on 26)

The method according to claim 26, wherein the disease, disorder or condition is a respiratory disease, epilepsy, convulsions, seizures, absence seizures, vascular spasms, coronary artery spasms, motor neuron diseases, myokymia, renal disorders, polycystic kidney disease, bladder hyperexcitability, bladder spasms, urinogenital disorders, urinary incontinence, bladder outflow obstruction, erectile dysfunction, gastrointestinal dysfunction, gastrointestinal hypomotility disorders, gastrointestinal motility insufficiency, postoperative ileus, constipation, gastroesophageal reflux disorder, secretory diarrhoea, an obstructive or inflammatory airway disease, ischaemia, cerebral ischaemia, ischaemic heart disease, angina pectoris, coronary heart disease, ataxia, traumatic brain injury, stroke, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, autism, anxiety, mood disorders, depression, manic depression, psychotic disorders, dementia, learning deficiencies, age related memory loss, memory and attention deficits, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea, narcolepsy, sleeping disorders, sleep apnea, Reynaud's disease, intermittent claudication, Sjögren's syndrome, xerostomia, cardiovascular disorders, hypertension, myotonic dystrophy, myotonic muscle dystrophia, spasticity, xerostomi, diabetes Type II, hyperinsulinemia, premature labour, cancer, brain tumors, inflammatory bowel disease, irritable bowel syndrome, colitis, colitis Crohn, immune suppression, hearing loss, migraine, pain, neuropathic pain, inflammatory pain, trigeminal neuralgia, vision loss, rhinorrhoea, ocular hypertension (glaucoma) or baldness.