Potassium ion channel modulators and uses thereof

• US 9,675,567 B2
• Filed: 09/08/2016
• Issued: 06/13/2017
• Est. Priority Date: 07/22/2008
• Status: Active Grant

• Current Assignee: Ramot at Tel Aviv University Limited (Tel Aviv University)
• Original Assignee: Ramot at Tel Aviv University Limited (Tel Aviv University)
• Inventors: Edwards, Simon, Kimberley, Ruth Meriel, Armer, Richard Edward, Khan, Mohammed Nawaz
• Primary Examiner(s): Javanmard, Sahar
• Application Number:
  US15/259,064
• Publication Number:
  US 20160374969A1
• Time in Patent Office: 278 Days
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/22 Anxiolytics
• 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 27/16 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 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: C07C 237/20 : the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07D 213/40 : Acylated substituent nitrogen atom

Abstract

Compounds of formula (I):

and pharmacologically acceptable salts and pro-drugs thereof, wherein the variables are as defined in the specification, are potassium ion channel modulators, making them particularly useful in treating and preventing conditions such as pain, lower urinary tract disorders and the like.

Claims

1. A method of enhancing KCNQ2/KCNQ3 voltage-dependent potassium channels, wherein diseases treatable by such enhancement are selected from the group consisting of Lower Urinary Tract Disorders, Gynaecological Pain, Cardiac Arrhythmias, Thromboembolic Events, Cardiovascular Diseases, Gastrointestinal Disorders and Visceral Smooth Muscle Disorders, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I):

2. The method according to claim 1, wherein V is (CR^3aR^3b)_pCON(R^3b)X, wherein said groups is in the 3-(meta) or 4-(para) position with respect to the substituent Z, wherein p is an integer of 0 or 1, each of R^3a and R^3b is hydrogen, and X is selected from the group consisting of alkyl having 1 or 2 carbon atoms which are substituted with a group selected from hydroxyl groups, methoxy groups, ethoxy groups, carboxy groups, methoxycarbonyl groups and ethoxycarbonyl groups.

3. A compound according to claim 1 or a pharmacologically acceptable salt or prodrug thereof, selected from the group consisting of:

{2-[5-(3,5-dichlorophenylamino)-2-fluorophenyl]-acetylamino}acetic acid;

2-[5-(2,6-dichloro-4-trifluoromethoxy-phenylamino)-2-fluoro-phenyl]-N-(2-hydroxy-ethyl)acetamide;

5-(2,6-dichloro-4-trifluoromethyl-phenylamino)-2-fluoro-N-(2-hydroxy-ethyl)-benzamide;

2-[5-(2,6-dichloro-4-trifluoromethyl-phenylamino)-2-fluoro-phenyl]-N-(2-hydroxy-2-methyl-propyl)acetamide; and

2-[4-(2,6-dichloro-4-trifluoromethoxy-phenylamino)-2-fluoro-phenyl]-N-(2-hydroxy-ethyl)propionamide.

4. The method according to claim 1, wherein said compound forms a part of a pharmaceutical composition which further comprises a pharmacologically acceptable diluent or carrier.

5. The method according to claim 4, wherein said pharmaceutical composition further comprises at least one compound selected from the group consisting of muscarinic receptor antagonists, β

3 adrenergic receptor agonists, neurokinin K receptor antagonists, vanilloid VR1 agonists, calcium channel α

2 δ

ligands, potassium channel activators, calcium channel inhibitors, sodium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), 5-HT antagonists, alpha-1 adrenoceptor antagonists, tricyclic antidepressants, N-methyl-D-aspartate (NMDA) receptor antagonists, cannabinoid receptor agonists, anti-convulsants, aldose reductase inhibitors, opioids, alpha adrenoceptor agonists, P2X receptor antagonists, acid-sensing ion channel modulators, NGF receptor modulators, nicotinic acetylcholine receptor modulators, synaptic vesicle protein 2A ligands and non-steroidal anti-inflammatory drugs (NSAIDs).