Vanilloid receptor ligand compounds, pharmaceutical compositions containing them, a method of producing them and the use thereof to treat pain and various other conditions

• US 8,252,816 B2
• Filed: 04/11/2008
• Issued: 08/28/2012
• Est. Priority Date: 04/13/2007
• Status: Expired due to Fees

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: Frank, Robert, Bahrenberg, Gregor, Christoph, Thomas, Schiene, Klaus, De Vry, Jean, Saunders, Derek, Lee, Jeewoo
• Primary Examiner(s): Chang, Celia
• Application Number:
  US12/081,174
• Publication Number:
  US 20080269289A1
• Time in Patent Office: 1,600 Days
• Field of Search: 514/212, 514/237.8, 514/255, 514/318, 514/331, 514/605, 540/311, 544/106, 544/124, 546/193, 546/229, 548/565, 564/99
• US Class Current: 514/331
• 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 11/02 Nasal agents, e.g. decongestants
• 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 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 23/02 Local anaesthetics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 25/32 : Alcohol-abuse
• CPC Class Codes: A61P 25/36 : Opioid-abuse
• 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 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 311/08 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 323/41 : Y being a hydrogen or an acyclic carbon atom
• CPC Class Codes: C07D 211/08 : with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
• CPC Class Codes: C07D 211/14 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 213/70 : Sulfur atoms
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond

Abstract

Compounds corresponding to formula I:

which act as vanilloid receptor ligands, pharmaceutical composition s containing such compounds, a method for producing the compounds, and the use of such compounds to treat pain and various other conditions.

Claims

1. A compound corresponding to formula I:

2. A compound according to claim 1, wherein said compound is in the form of an isolated stereoisomer.

3. A compound according to claim 1, wherein said compound is in the form of a mixture of stereoisomers in any mixing ratio.

4. A compound according to claim 1, wherein said compound is in the form of a racemic mixture.

5. A compound according to claim 1, wherein said compound corresponds to formula Ia:

6. A compound according to claim 1, wherein said compound corresponds to formula Ib:

7. A compound according to claim 1, wherein said compound is selected from the group consisting of:

[12] 2-(3-fluoro-4-(N-methylmethylsulfonamido)phenyl)-N-(2-(4-methylpiperidin-1-yl)-4-(trifluoromethyl)benzyl)propanamide,

[13] N-(2-(cyclohexylthio)-4-(trifluoromethyl)benzyl)-2-(3-fluoro-4-(N-methylmethylsulfonamido)phenyl)propanamide,

[14] N-(4-tert.-butyl-2-(4-methylpiperidin-1-yl)benzyl)-2-(3-fluoro-4-(N-methylmethylsulfonamido)phenyl)propanamide, and

[15] N-(4-tert.-butyl-2-(cyclohexylthio)benzyl)-2-(3-fluoro-4-(N-methylmethylsulfonamido)phenyl)propanamide,

or a salt thereof.

8. A compound according to claim 1, wherein, in a FLIPR assay with CHO K1 cells transfected with the human gene VR1, said compound at a concentration of less than 2000 nM, brings about a 50% displacement of capsaicin which is present in a concentration of 100 nM.

9. A compound according to claim 8, wherein said compound at a concentration of less than 300 nM, brings about a 50% displacement of capsaicin which is present in a concentration of 100 nM.

10. A compound according to claim 8, wherein said compound at a concentration of less than 75 nM, brings about a 50% displacement of capsaicin which is present in a concentration of 100 nM.

11. A compound according to claim 8, wherein said compound at a concentration of less than 10 nM, brings about a 50% displacement of capsaicin which is present in a concentration of 100 nM.

12. A pharmaceutical composition comprising a compound according to claim 1, and at least one pharmaceutically acceptable carrier or pharmaceutical auxiliary substance.

13. A method of producing a compound according to claim 1, said method comprising:

reacting a compound corresponding to formula II;

14. A method according to claim 13, wherein the compound of formula II is reacted in the presence of at least one reducing agent selected from the group consisting of sodium hydride, sodium, potassium hydride, lithium aluminium hydride, sodium borohydride and di(isobutyl)aluminium hydride;

or wherein the compound of formula IV is reacted in the presence of at least one reducing agent selected from the group consisting of sodium hydride, potassium hydride, lithium aluminium hydride, sodium borohydride and di(isobutyl)aluminium hydride;

or wherein the compound of formula IV is reacted in the presence of a platinum or palladium catalyst;

or wherein a compound corresponding to formula VI is reacted in the presence of a palladium or platinum catalyst and of hydrochloric acid;

or wherein LG denotes a chlorine or bromine atom;

or wherein each of the phenyl groups in the compound of formula IX is substituted by 1 or 2 phenoxy or methoxy residues.

15. A method of producing a compound according to claim 1, said method comprising:

reacting a compound corresponding to formula X;

16. A method according to claim 15, wherein LG denotes a chlorine or bromine atom;

or wherein each of the phenyl groups in the compound of formula IX is substituted with 1 or 2 phenoxy or methoxy residues;

or wherein each of the phenyl groups in the compound of formula IX is substituted with a methoxy residue in the para position.

17. A method of treating or inhibiting pain in a subject, said method comprising administering to said subject a pharmacologically effective amount of a compound according to claim 1.

18. A method according to claim 17, wherein said pain is selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain, joint pain, hyperalgesia, allodynia, causalgia and migraine.