Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof
Inventors
Liu, Ziping • PAGE DANIEL, null • Pagé, Daniel • Walpole, Christopher • Yang, Hua
Assignees
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Publication Number
US-8633235-B2
Publication Date
2014-01-21
Expiration Date
Abstract
Compounds of Formula (I) or pharmaceutically acceptable salts thereof; wherein R1, R2, R3, and R4 are as defined in the specification as well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.
Core Innovation
The disclosed invention provides benzimidazole-containing compounds of Formula I, including pharmaceutically acceptable salts, solvates, and pharmaceutical compositions comprising a pharmaceutically acceptable carrier. The compounds are defined by constrained substituent patterns for R1, R2, R3, R4, R5, R6, R8, and R9, with the C3-6 heterocycloalkyl group containing at least one nitrogen ring atom and the radical located on the nitrogen ring atom.
The claim scope also includes explicit exclusions of a defined list of specific benzimidazole-containing sulfamide and sulfonamide embodiments. The disclosure further describes benzimidazole-derived cannabinoid receptor ligands intended to act on CB1 and/or CB2 receptors, including CB1 agonist, partial agonist, inverse agonist, and antagonist activities as stated.
The invention is presented in a pharmaceutical context and addresses pain management, with applicability to other CB1-related diseases. Biological evaluation is described at a human receptor level using radioligand binding to human CB1 and human CB2 receptors, including 3H-CP55,940 and GTPγS assays.
Claims Coverage
The consolidated claim set includes two independent compound claims directed to Formula I benzimidazole-containing compounds and one dependent claim directed to a pharmaceutical composition. Across the independent claims, the inventive features are the constrained Formula I substituent selections and the explicit exclusions of listed sulfamide and sulfonamide embodiments.
Formula I benzimidazole scaffold with constrained substituents
A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3 are defined by selected groups from enumerated cycloalkyl, alkyl, aryl, and heterocycloalkyl sets with optional substitution patterns, wherein the C3-6 heterocycloalkyl contains at least one nitrogen ring atom with the radical located on the nitrogen ring atom, and wherein each of R8 and R9 is independently selected from H, C1-6 alkyl, morpholinyl-C1-3 alkyl, pyrrolidinyl-C1-3 alkyl, and piperidinyl-C1-3 alkyl, and wherein R4, R5 and R6 are independently selected from H and C1-3 alkyl.
Enumerated R1 and R2 selections with defined R3 and R4
A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R1 is selected from cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl, 4,4-difluorocyclohexanemethyl, cyclohexylethyl, cyclopentylethyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl, 1-piperidinylethyl, N-methyl-2-piperidinyl-methyl and benzyl; R2 is selected from t-butyl, n-butyl, 2-methyl-2-butyl, isopentyl, 2-methoxy-2-propyl, 2-hydroxy-propyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 1-cyclopropyl-ethyl, 1-methyl-propyl, 1,1-dimethyl-propyl, 1,1-dimethyl-3-buten-1-yl, ethyl, and 2-propyl; R3 is C2-5 alkyl and R8R9N— with R8 and R9 independently selected from H and C1-3 alkyl; and R4 is selected from H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-6 alkyl, and C4-8 cycloalkenyl-C1-6 alkyl.
Excluded specific sulfamide and sulfonamide embodiments
The compound is not N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N,N',N'-trimethylsulfamide; N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N',N'-diethyl-N-methylsulfamide; N'-[1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-yl]-N,N-dimethyl-sulfamide; N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylbutane-1-sulfonamide; N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methyl-2-pyrrolidin-1-ylethanesulfonamide; N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methyl-2-morpholin-4-ylethanesulfonamide; N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methyl-2-piperidin-1-ylethanesulfonamide; N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-2-methoxy-N-methylethanesulfonamide; N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-2-[(2-hydroxyethyl)amino]-N-methylethanesulfonamide; 2-(2-Aminoethoxy)-N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylethanesulfonamide; N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-methylethylenesulfonamide; N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N-methylbutane-1-sulfonamide; and N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N-methyl-2-piperidin-1-ylethanesulfonamide, and pharmaceutically acceptable salts thereof.
The claim coverage centers on benzimidazole Formula I compounds defined by specific allowable substituent patterns and by explicit exclusions of particular sulfamide and sulfonamide embodiments. A dependent claim covers pharmaceutical compositions that include one of the defined compounds together with a pharmaceutically acceptable carrier.
Stated Advantages
Pain management, including CB1 agonist, partial agonist, inverse agonist, and antagonist activity as stated.
Applicability to other CB1-related diseases, as stated.
Documented Applications
Therapeutic use for pain management, including acute, chronic, neuropathic, cancer, and visceral pain as referenced in the document summary.
Treatment of other CB1-related diseases, as stated.
Pharmaceutical compositions containing the compounds for administration.
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