(S)(-)-2-(7-chloro-6-fluoro-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}acetamide; treatment of pain; vanilloid receptor inhibitor; Antagonists maintain analgesic properties, but avoid pungency and neurotoxicity side effects of agonists
Inventors
Brown, William • Johnstone, Shawn • Labrecque, Denis
Assignees
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Publication Number
US-7906654-B2
Publication Date
2011-03-15
Expiration Date
Abstract
Provided herein are compounds in accord with Formula I: that are useful in the treatment of pain.
Core Innovation
The invention is directed to the compound (S)(−)-2-(7-Cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}acetamide, and also to pharmaceutically acceptable salts thereof. The disclosed compounds are benzimidazole acetamide analogs defined using variable substituents within a structural framework, with certain compounds excluded, and include related enantiomeric pairs of substituted benzimidazole acetamide structures.
The core inventive aspect includes stereochemical definition and selection of the (−)/(S) enantiomer as more active for VR1 antagonism. The description states VR1 antagonist activity thresholds, including selected compounds with activity <100 nM, and connects the (−)/(S) stereochemistry to improved activity.
The disclosure includes chiral separation and characterization of enantiomeric benzimidazole acetamide derivatives, including chiral HPLC separation, confirmation of absolute configuration by Vibrational Circular Dichroism (VCD), and characterization by 1H NMR, MS, and optical rotation. A pharmacology section introduces a human TRPV1 calcium mobilization FLIPR assay concept using capsaicin-stimulated Ca2+ signaling and IC50 determination to assess inhibition.
Claims Coverage
The claim set centers on one specified chiral compound and its pharmaceutically acceptable salt, with one dependent pharmaceutical composition claim. The inventive features covered are the enantiomeric compound identity, the salt option, and the composition framing.
Specified chiral benzimidazolyl acetamide compound and salts
The compound (S)(−)-2-(7-Cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}acetamide or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with carrier or excipient
A pharmaceutical composition comprising the compound (or a pharmaceutically acceptable salt thereof) together with a pharmaceutically acceptable carrier or excipient.
Overall, the claims coverage is directed to a specific (S)(−) chiral 2-(7-cyano-1H-benzimidazol-1-yl)acetamide derivative, expressly including pharmaceutically acceptable salts, and further extends to a pharmaceutical composition comprising that compound (or its salt) with a pharmaceutically acceptable carrier or excipient.
Stated Advantages
Improved VR1/TRPV1 antagonism associated with selection of the (−)/(S) enantiomer, reflected by VR1 antagonist activity thresholds including selected compounds with activity <100 nM.
Documented Applications
Pain treatment applications, including chronic nociceptive pain disorders and related conditions such as osteoarthritis, chronic tendinitis, pelvic pain, and peripheral neuropathy including PHN.
Disease states implicated with VR1/TRPV1 antagonism, including GERD, IBS, and overactive bladder.
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