Ion channel modulating compounds and uses thereof

• US 7,534,790 B2
• Filed: 11/21/2007
• Issued: 05/19/2009
• Est. Priority Date: 04/01/1998
• Status: Expired due to Term

• Current Assignee: Correvio International SARL (ADVANZ PHARMA Corp. Ltd.)
• Original Assignee: Cardiome Pharma Corp. (ADVANZ PHARMA Corp. Ltd.)
• Inventors: Bain, Allen I., Plouvier, Bertrand M. C., Zolotoy, Alexander B., Sheng, Tao, Wall, Richard A., Zhu, Jeff Jiqun, Yong, Sandro L., Longley, Cindy J., Walker, Michael J. A., Beatch, Gregory N.
• Primary Examiner(s): Saeed; Kamal A
• Assistant Examiner(s): BIANCHI, KRISTIN A
• Application Number:
  US11/944,282
• Publication Number:
  US 20080070911A1
• Time in Patent Office: 545 Days
• Field of Search: 514/231.2, 514/359, 514/365, 514/424, 514/235.2, 514/231.5, 514/239.5, 514/255.01, 514/409, 514/429, 544/106, 544/143, 544/154, 544/166, 544/146, 544/391, 548/146, 548/400, 548/541, 548/409
• US Class Current: 514/231.2
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous 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 25/16 Anti-Parkinson drugs
• 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 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• 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: C07C 217/52 : having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07D 207/12 : Oxygen or sulfur atoms
• CPC Class Codes: C07D 207/27 : with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 277/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 295/08 : substituted by singly bound oxygen or sulfur atoms
• CPC Class Codes: C07D 295/096 : with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/14 : substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 295/15 : to an acyclic saturated chain
• CPC Class Codes: C07D 295/185 : from aliphatic carboxylic acids
• CPC Class Codes: C07D 333/54 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 333/56 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems

Abstract

Ion channel modulating compounds are disclosed. The compounds of the present invention may be incorporated in compositions and kits. The present invention also discloses a variety of in vitro and in vivo uses for the compounds and compositions, including the treatment of arrhythmia and the production of analgesia and local anesthesia.

Claims

1. A compound of formula (I), or pharmaceutically acceptable salt thereof:

2. A compound according to claim 1 having formula (IX), or pharmaceutically acceptable salt thereof:

3. A compound of claim 1 having formula (X), or pharmaceutically acceptable salt thereof:

4. A compound of claim 1 having formula (XI), or pharmaceutically acceptable salt thereof:

5. A compound of claim 1 having formula (XII), or pharmaceutically acceptable salt thereof:

6. A compound of claim 1 having formula (XIII), or pharmaceutically acceptable salt thereof:

7. A compound of claim 1 having formula (XIV), or pharmaceutically acceptable salt thereof:

8. A compound of claim 1 having formula (XV), or pharmaceutically acceptable salt thereof:

9. A compound of claim 1 having formula (XVI), or pharmaceutically acceptable salt thereof:

10. A compound of claim 1, or mixture comprising compounds of claim 1, selected from the group consisting of:

(+)-trans-[2-(4-morpholinyl)-1-(2-naphthenethoxy)]cyclohexane;

(−

)-trans-[2-(4-morpholinyl)-1-(2-naphthenethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(1-naphthenethoxy)]cyclohexane;

(−

)-trans-[2-(4-morpholinyl)-1-(1-naphthenethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(4-bromophenethoxy)]cyclohexane;

(−

)-trans-[2-(4-morpholinyl)-1-(4-bromophenethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-[2-(2-naphthoxy)ethoxy)]cyclohexane;

(−

)-trans-[2-(4-morpholinyl)-1-[2-(2-naphthoxy)ethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-[2-(4-bromophenoxy)ethoxy]cyclohexane;

(−

)-trans-[2-(4-morpholinyl)-1-[2-(4-bromophenoxy)ethoxy]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(3,4-dimethoxyphenethoxy)]cyclohexane;

(−

)-trans-[2-(4-morpholinyl)-1-(3,4-dimethoxyphenethoxy)]cyclohexane;

(+)-trans-[2-(1-pyrrolidinyl)-1-(1-naphthenethoxy)]cyclohexane;

(−

)-trans-[2-(1-pyrrolidinyl)-1-(1-naphthenethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophen-3-yl)ethoxy)]cyclohexane;

(−

)-trans-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophen-3-yl)ethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophen-4-yl)ethoxy)]cyclohexane;

(−

)-trans-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophen-4-yl)ethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(3-bromophenethoxy)]cyclohexane;

(−

)-trans-[2-(4-morpholinyl)-1-(3-bromophenethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(2-bromophenethoxy)]cyclohexane;

(−

)-trans-[2-(4-morpholinyl)-1-(2-bromophenethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(3-(3,4-dimethoxyphenyl)-1-propoxy)]cyclohexane;

(−

)-trans-[2-(4-morpholinyl)-1-(3-(3,4-dimethoxyphenyl)-1-propoxy)]cyclohexane;

(1R,2R)/(1S ,2S)-2-(4-morpholinyl)-1-(3,4-dichlorophenethoxy)cyclohexane;

(1R,2R)/(1S ,2S)-2-(3-ketopyrrolidinyl)-1-(1-naphthenethoxy)cyclohexane;

(1R,2R)/(1S ,2S)-2-(1-acetylpiperazinyl)-1-(2-naphthenethoxy)cyclohexane;

(1R,2R)/(1S ,2S)-2-(3-ketopyrrolidinyl)-1-(2,6-dichlorophenethoxy)cyclohexane;

(1R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro[4.4]non-7-yl]-1-(1-naphthenethoxy)cyclohexane;

(1R,2S)/(1S,2R)-2-(4-morpholinyl)-1-[(2-trifluoromethyl)phenethoxy]cyclohexane;

(1R,2R)/(1S,2S)-2-(3-ketopyrrolidinyl)-1-[3-(cyclohexyl)propoxy]cyclohexane;

(1R,2R)/(1S,2S)-2-(3-acetoxypyrrolidinyl)-1-(1-naphthenethoxy)cyclohexane;

(1R,2R)/(1S,2S)-2-(3-hydroxypyrrolidinyl)-1-(2,6-dichlorophenethoxy)cyclohexane;

(1R,2R)/(1S ,2S)-2-(3-ketopyrrolidinyl)-1-(2,2-diphenylethoxy)cyclohexane;

(1R,2R)/(1S,2S)-2-(3-thiazolidinyl)-1-(2,6-dichlorophenethoxy)cyclohexane; and

(1R,2S)/(1S,2R)-2-(3-ketopyrrolidinyl)-1-(1-naphthenethoxy)cyclohexane; and

including isolated enantiomeric and diastereomeric isomers thereof, and mixtures thereof; and

pharmaceutically acceptable salts thereof.

11. A composition comprising a compound according to any one of claims 1-10 in combination with a pharmaceutically acceptable carrier, excipient or diluent.