Potassium ion channel modulators and uses thereof

• US 9,464,052 B2
• Filed: 07/20/2009
• Issued: 10/11/2016
• 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: Kimberley, Meriel Ruth, Edwards, Simon David, Armer, Richard Edward, Khan, Nawaz Mohammed
• Primary Examiner(s): Javanmard, Sahar
• Application Number:
  US13/054,960
• Publication Number:
  US 20110245250A1
• Time in Patent Office: 2,640 Days
• Field of Search: 514/619, 564/164
• US Class Current: 1/1
• 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:

• Ar¹ and Ar² are aryl or heteroaryl;
• a is 0 to 5;
• R¹ is alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, carboxyl, hydroxyl, amino, monoalkylamino, dialkylamino, nitro, acylamino, alkoxycarbonylamino, alkylsulphonyl, alkylsulphonylamino or cyano and, where a is greater than 1, each substituent R¹ may be the same or different;
• b is 0 to 5;
• R² is alkyl, halogen, haloalkyl, haloalkoxy, alkoxy, alkoxycarbonyl, carboxyl, hydroxyl, amino, monoalkylamino, dialkylamino, nitro, acylamino, alkoxycarbonylamino, alkylsulphonyl, alkylsulphonylamino or cyano and where b is greater than 1, each substituent R² may be the same or different;
• V is selected from the group consisting of (CR^3aR^3b)_pCON(R^3b)X and (CR^3aR^3b)_pN(R^3b)CO(X), wherein said groups are in the 3- (meta) or 4- (para) position with respect to the substituent Z;
• W is selected from the group consisting of NR^4a, O, S, S═O, SO₂ and C(R^4aR^4b)₂;
• X is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, cycloalkyl, aryl, heteroaryl, polyalkylene glycol, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkyl that is substituted with a groups of formula of formula NR8R9 wherein R8 and R9 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated heterocyclic group, carboxyalkyl, alkoxycarbonylalkyl, haloalkoxycarbonylalkyl or aralkyloxycarbonylalkyl;
• Y and Z are the same or different and each is a substituent selected from the group consisting of (CR^5aR^5b)_n1, C═O, SO₂, C(═O)NR^5a; C(═O)NR^5aSO₂ and C═O(R^5aR^5b)_n2;
• R^3a, R^3b, R^4a, R^4b, R^5a and R^5b are the same or different and each is selected from the hydrogen, alkyl, cycloalkyl, aryl and heteroaryl;
• n1 and n2 are the same or different and each is 0 to 2; and
• p is 0 to 2;
• 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 compound of formula (I) or a pharmacologically acceptable salt or pro-drug thereof wherein:

2. A compound according to claim 1 or a pharmacologically acceptable salt or pro-drug thereof, 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 pro-drug thereof, wherein:

Ar¹ and Ar² are each phenyl;

a is 0 or 1;

R¹ is halogen;

b is 0 to 3;

R² is selected from the group consisting of alkyl having from 1 to 3 carbon atoms, halogen, haloalkyl having from 1 to 3 carbon atoms, alkoxy having from 1 to 3 carbon atoms, haloalkoxy having from 1 to 3 carbon atoms, carboxyl, amino, hydroxyl and cyano;

W is a group of formula NR^4a, wherein R^4a is selected from the group consisting of hydrogen, alkyl having from 1 to 3 carbon atoms and phenyl;

Y and Z are each a group of formula (CR^5aR^5b)_n1 wherein each n1 is 0; and

V is (CR^3aR^3b)_pCON(R^3b)X, wherein said group 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 a 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, methoxy, ethoxy, carboxy, methoxycarbonyl and ethoxycarbonyl.

4. A compound according to claim 1 or a pharmacologically acceptable salt or pro-drug 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.

5. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and an active ingredient, wherein said active ingredient is a compound according to claim 1 or a pharmacologically acceptable salt or prodrug thereof.

6. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and an active ingredient, wherein said active ingredient is a compound according to claim 1 or a pharmacologically acceptable salt or prodrug thereof for use in the treatment of a disease of any disease or condition in which KCNQ2, KCNQ3 or KCNQ2/3 channels are involved or which is ameliorated by KCNQ2, KCNQ3 or KCNQ2/3 channel opening, and/or which is selected from the group consisting of Anxiety and Anxiety-Related Conditions, Epilepsy, Pain Disorders, Disorders of the Auditory System, Migraine, Inflammatory and Immunological Diseases, Cell Proliferative Disorders, Metabolic Disorders, Memory Loss, CNS-Mediated Motor Dysfunction Disorders, and Ophthalmic Disorders.

7. A pharmaceutical composition comprising a pharmacologically acceptable diluent or carrier and at least two active ingredients, wherein said active ingredients comprise at least one compound according to claim 1 in combination with 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).

8. A pharmaceutical composition according to claim 7 for the treatment of any disease or condition in which KCNQ2, KCNQ3 or KCNQ2/3 channels are involved or which is ameliorated by KCNQ2, KCNQ3 or KCNQ2/3 channel opening, or which is selected from the group consisting of Anxiety and Anxiety-Related Conditions, Epilepsy, Pain Disorders, Disorders of the Auditory System, Migraine, Inflammatory and Immunological Diseases, Cell Proliferative Disorders, Metabolic Disorders, Memory Loss, CNS-Mediated Motor Dysfunction Disorders, Ophthalmic Disorders, Lower Urinary Tract Disorders, Gynaecological Pain, Cardiac Arrhythmias, Thromboembolic Events, Cardiovascular Diseases, Gastrointestinal Disorders and Vascular and Visceral Smooth Muscle Disorders.

9. The compound of claim 1, being: