NOVEL AROMATIC HETEROCYCLIC CARBOXYLIC ACID AMIDE DERIVATIVES USEFUL AS POTASSIUM CHANNEL MODULATORS

• US 20100137312A1
• Filed: 05/13/2008
• Published: 06/03/2010
• Est. Priority Date: 05/15/2007
• Status: Abandoned Application

• Current Assignee: Neurosearch AS
• Original Assignee: Neurosearch AS
• Inventors: Nielsen, Elsebet Østergaard, Christophersen, Palle, Nardi, Antonio, Strøbæk, Dorte, Christensen, Jeppe Kejser, Madsen, Lars Siim, Jones, David Spencer
• Application Number:
  US12/600,159
• Publication Number:
  US 20100137312A1
• Time in Patent Office: Days
• US Class Current: 514/236.200
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: 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
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/12 : for electrolyte homeostasis
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/24 : of the sex hormones
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

This invention relates to novel aromatic heterocyclic carboxylic acid amide derivatives of formula (I) 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.

Claims

1. An aromatic heterocyclic carboxylic acid amide derivative of Formula I

a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, wherein

X represents alkyl, cycloalkyl, alkenyl, alkynyl, methoxyiminomethyl, amino, N-alkyl-amino, N,N-dialkyl-amino, N-aryl-amino, N,N-diaryl-amino, alkyl-sulfonyl-amino, aryl-sulfonyl-amino, alkyl-carbonyl-amino, aryl-carbonyl-amino, phenyl or a five- or six-membered heterocyclic group selected from imidazolyl, 2-oxopyrrolidin-1-yl, piperidinyl, morpholin-4-yl and pyridinyl, which phenyl and heterocyclic group are optionally substituted one or more times with substituents selected from the group consisting of alkyl, halo, trifluoromethyl, cyano, hydroxy, phenyl and alkoxy-carbonyl;

L is absent (i.e. representing a covalent bond), or represents the linking group —

CH₂—

or —

CONH—

;

HET represents a five-membered aromatic heterocyclic group selected from furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl and triazolyl, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, halo, trifluoromethyl and cyano;

R¹ represents tetrazolyl, tetrazolyl-alkoxy, N-phenyl-carbamoyl, alkyl-sulfonyl-amino-carbonyl, N-alkyl-sulfonyl-carboxamide, N-phenyl-sulfonyl-carboxamide, carboxy, N-cyano-carboxamide, sulfamoyl, sulfonic acid, sulfonic acid alkyl ester, sulfonic acid phenyl ester, or a oxadiazolyl oxo- or thio-derivative selected from 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl and 5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl;

R² represents halo or trifluoromethyl; and

R³ represents hydrogen, halo, trifluoromethyl, amino, N-alkyl-amino, N,N-dialkyl-amino, piperidinyl or morpholinyl.

2. The aromatic heterocyclic carboxylic acid amide derivative of claim 1, or a pharmaceutically-acceptable addition salt thereof, wherein X represents alkyl, cycloalkyl, alkenyl, alkynyl, methoxy-iminomethyl, amino, N-alkyl-amino, N,N-dialkyl-amino, N-aryl-amino, N,N-diaryl-amino, alkyl-sulfonyl-amino, aryl-sulfonyl-amino, alkyl-carbonyl-amino, aryl-carbonyl-amino, phenyl or a five- or six-membered heterocyclic group selected from imidazolyl, 2-oxopyrrolidin-1-yl, piperidinyl, morpholin-4-yl and pyridinyl, which phenyl and heterocyclic groups are optionally substituted one or more times with substituents selected from the group consisting of alkyl, halo, trifluoromethyl, cyano, hydroxy, phenyl and alkoxy-carbonyl.

3. The aromatic heterocyclic carboxylic acid amide derivative of either one of claims 1-2, or a pharmaceutically-acceptable addition salt thereof, wherein L is absent (i.e. representing a covalent bond), or represents the linking group —

CH₂—

or —

CONH—

.

4. The aromatic heterocyclic carboxylic acid amide derivative of any one of claims 1-3, or a pharmaceutically-acceptable addition salt thereof, wherein HET represents a five-membered aromatic heterocyclic group selected from furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl and triazolyl, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, halo and trifluoromethyl.

5. The aromatic heterocyclic carboxylic acid amide derivative of any one of claims 1-4, or a pharmaceutically-acceptable addition salt thereof, wherein R¹ represents tetrazolyl, tetrazolyl-alkoxy, N-phenyl-carbamoyl, alkyl-sulfonyl-amino-carbonyl, N-alkyl-sulfonyl-carboxamide, N-phenyl-sulfonyl-carboxamide, carboxy, N-cyano-carboxamide, sulfamoyl, sulfonic acid, sulfonic acid alkyl ester, sulfonic acid phenyl ester, or a oxadiazolyl oxo- or thio-derivative selected from 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl and 5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl.

6. The aromatic heterocyclic carboxylic acid amide derivative of any one of claims 1-5, or a pharmaceutically-acceptable addition salt thereof, wherein R² represents halo or trifluoromethyl.

7. The aromatic heterocyclic carboxylic acid amide derivative of any one of claims 1-6, or a pharmaceutically-acceptable addition salt thereof, wherein R³ represents hydrogen, halo, trifluoromethyl, amino, N-alkyl-amino, N,N-dialkyl-amino, piperidinyl or morpholinyl.

8. The aromatic heterocyclic carboxylic acid amide derivative of claim 1, which is

5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2-(1H-tetrazol-5-yl)-phenyl]-amide;

1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid [5-chloro-2-(1H-tetrazol-5-yl)-phenyl]-amide;

1-(4-Bromo-benzyl)-5-methyl-1H-[1,2,3]triazole-4-carboxylic acid [5-chloro-2-(1H-tetrazol-5-yl)-phenyl]-amide;

5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid (5-chloro-2-phenylcarbamoyl-phenyl)-amide;

5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid (5-chloro-2-methanesulfonylaminocarbonyl-phenyl)-amide, 4-Chloro-2-{[5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-benzenesulfonic acid;

5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2-(1H-tetrazol-5-ylmethoxy)-phenyl]-amide;

4,5-Dichloro-2-{[5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-benzenesulfonic acid;

4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid [5-chloro-2-(1H-tetrazol-5-yl)-phenyl]-amide;

4-Chloro-2-{[5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-benzoic acid;

4-Chloro-2-{[5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-benzoylcyanamide;

5-(4-Chloro-phenyl)-2-methyl-furan-3-carboxylic acid [5-chloro-2-(1H-tetrazol-5-yl)-phenyl]-amide;

2-{[5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-4,5-difluoro-benzoic acid;

4,5-Dichloro-2-{[5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-benzenesulfonic acid methyl ester;

5-Methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid [5-chloro-2-(1H-tetrazol-5-yl)-phenyl]-amide;

5-Trifluoromethyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid [5-chloro-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide;

5-Trifluoromethyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid [5-chloro-2-(1H-tetrazol-5-yl)-phenyl]amide;

5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide;

5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid [4,5-dichloro-2-(1H-tetrazol-5-yl)-phenyl]-amide;

5-(4-Chloro-phenyl)-2-methyl-furan-3-carboxylic acid [5-chloro-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide;

2-(4-Chloro-benzyl)-thiazole-4-carboxylic acid [5-chloro-2-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide;

1-(4-Bromo-benzyl)-5-methyl-1H-[1,2,3]triazole-4-carboxylic acid [5-chloro-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide;

4-Methyl-2-morpholin-4-yl-thiazole-5-carboxylic acid [5-chloro-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide;

4-Methyl-2-morpholin-4-yl-thiazole-5-carboxylic acid [5-chloro-2-(1H-tetrazol-5-yl)-phenyl]-amide;

2-(3-Chloro-phenyl)-5-methyl-2H-[1,2,3]triazole-4-carboxylic acid [5-chloro-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide;

4-{5-[5-Chloro-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenylcarbamoyl]-4-methyl-thiazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester;

4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid [5-chloro-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide;

5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-4-morpholin-4-yl-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide;

5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-4-dimethylamino-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide;

5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-4-piperidin-1-yl-phenyl]-amide;

2-(3-Chloro-phenyl)-5-methyl-2H-[1,2,3]triazole-4-carboxylic acid [5-chloro-2-(1H-tetrazol-5-yl)-phenyl]-amide;

4-Methyl-2-pyridin-4-yl-thiazole-5-carboxylic acid [5-chloro-2-(1H-tetrazol-5-yl)-phenyl]-amide;

4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid [5-chloro-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-4-piperidin-1-yl-phenyl]-amide;

5-(Cyclopentanecarbonyl-amino)-3-methyl-thiophene-2-carboxylic acid [5-chloro-2-(1H-tetrazol-5-yl)-phenyl]amide;

or

2,4-Dichloro-6-[(4-methyl-2-morpholin-4-yl-thiazole-5-carbonyl)-amino]-benzoic acid;

or a pharmaceutically-acceptable addition salt thereof.

9. A pharmaceutical composition comprising a therapeutically effective amount of the aromatic heterocyclic carboxylic acid amide derivative of any one of claims 1-8, or a pharmaceutically-acceptable addition salt thereof, or a prodrug thereof, together with one or more adjuvants, excipients, carriers and/or diluents.

10. Use of an aromatic heterocyclic carboxylic acid amide derivative of any one of claims 1-8, 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.

11. The use according to claim 10, 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 diarrhea, 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, Sjogren'"'"'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, rhinorrhea, ocular hypertension (glaucoma) or baldness.

12. 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 the aromatic heterocyclic carboxylic acid amide derivative according to any one of claims 1-8.