Pyrazole derivatives and their use as cannabinoid receptor mediators
Inventors
Kunos, George • Iyer, Malliga • Cinar, Resat • Rice, Kenner C.
Assignees
US Department of Health and Human Services
Publication Number
US-10329259-B2
Publication Date
2019-06-25
Expiration Date
2035-05-08
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of: wherein X and Y are each independently selected from optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted cycloalkyl, optionally-substituted heterocycloalkyl, or optionally-substituted alkyl; Q is H, hydroxyl, or optionally-substituted alkoxy;R1, R2, and R3 are each independently selected from H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, aminocarbonyl, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, aralkyl, optionally-substituted thiol, or R2 and R3 together with Z form an optionally-substituted cycloalkyl ring or an optionally-substituted heterocycloalkyl ring;Z is B, N, —CH—, or P;D is —S(O)2— or —C(O)—; andn is 0 to 5.
Core Innovation
The invention relates to novel peripherally restricted cannabinoid receptor mediating compounds, particularly those targeting CB1 receptors, for the treatment of conditions such as fibrosis, diabetes, obesity, and liver cancer. The compounds disclosed include structures where substituents X, Y, R1, R2, R3, and others vary among optionally-substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, and other functional groups to provide cannabinoid receptor mediation. The invention also encompasses pharmaceutically acceptable salts, esters, prodrugs, and compositions containing these compounds, along with methods of use in treating metabolic and associated diseases.
The problem addressed concerns the limitations of existing CB1 receptor blocking drugs, such as the prototype compound rimonabant, which was effective for metabolic syndrome treatment but caused neuropsychiatric side effects leading to its market withdrawal. The invention aims to provide compounds that selectively target peripheral CB1 receptors, thus minimizing central nervous system side effects. Furthermore, it tackles the limited metabolic efficacy of existing drugs by developing dual activity compounds acting on CB1 receptors and other intracellular targets like inducible nitric oxide synthase (iNOS) or adenosine monophosphate kinase (AMPK) to improve insulin resistance, fibrosis, and inflammation.
The disclosed compounds are characterized by low brain penetrance, evidenced by a brain to plasma maximum concentration ratio less than 0.1, preferably less than 0.05 or 0.025, reducing neuropsychiatric side effects while maintaining beneficial peripheral metabolic effects. The compounds may be CB1 inverse agonists or neutral antagonists, showing selectivity for CB1 versus CB2 receptors and having improved chemical stability with plasma half-lives in the range of 1 to 16 hours. Hybrid compounds combining a CB1 receptor mediating scaffold and a second therapeutic scaffold, such as an antidiabetic agent like metformin, are also disclosed, enhancing therapeutic efficacy through dual mechanisms.
Claims Coverage
The patent contains 34 claims focusing on chemical compounds with specific structural features, pharmaceutical compositions, and methods for treatment based on these compounds. The analysis identifies 3 independent claims centered on compound structures and their use in therapy.
Specific structural features of the compounds
The compounds have a defined chemical structure with substituents X and Y independently selected from optionally-substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkyl; Q as H, hydroxyl, or optionally-substituted alkoxy; R1, R2, R3 as various optionally-substituted groups or forming rings with Z being B, N, —CH—, or P; D is —S(O)2— or —C(O)—; and n is 0 to 5. Particular embodiments involve the exclusion of ring formation by R2, R3, and Z, specific lower alkyl substitutions, and specified values of these entities to modulate receptor interaction.
Pharmaceutical compositions including the compounds
Pharmaceutical compositions comprising therapeutically effective amounts of the disclosed compounds or their pharmaceutically acceptable salts or esters together with pharmaceutically acceptable additives are claimed. These compositions are formulated for administration to subjects in need of treatment.
Methods of treatment using the compounds
Methods for treating obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, dyslipidemias related to arteriosclerotic heart disease, diabetic nephropathy, gout, and co-morbidities of obesity are claimed. The methods include administering effective amounts of the disclosed compounds to subjects, leading to therapeutic benefits with minimal or no neuropsychiatric side effects and having a brain to plasma maximum concentration ratio below 0.1. Prevention or reversal of adipose tissue deposition is also claimed.
The claims cover novel cannabinoid receptor mediating chemical structures with tailored substituents to achieve peripheral selectivity, pharmaceutical formulations containing these compounds, and therapeutic methods utilizing them to treat metabolic and related diseases, emphasizing reduced central nervous system side effects and improved treatment outcomes.
Stated Advantages
Reduced neuropsychiatric side effects due to peripheral selectivity and low brain penetrance of the compounds.
Improved efficacy in treating metabolic syndrome aspects such as obesity, insulin resistance, fibrosis, and fatty liver disease.
Dual activity compounds may improve metabolic efficacy by targeting additional intracellular pathways like iNOS inhibition or AMPK activation.
Improved chemical stability resulting in suitable plasma half-life ranges (1-16 hours) facilitating dosing.
Potential for minimal drug-to-drug interactions due to low or no cytochrome P450 activity.
Documented Applications
Treatment of obesity, diabetes including type 1 and type 2, and non-alcoholic and alcoholic fatty liver disease.
Treatment of co-morbidities of obesity such as arteriosclerotic heart disease, diabetic nephropathy, gout, dementia, hypertension, gallbladder disease, gastrointestinal disorders, and various cancers.
Prevention or reversal of adipose tissue deposition to reduce obesity and related complications.
Use as pharmaceutical compositions formulated for various administration routes including oral, parenteral, transdermal, and others.
Interested in licensing this patent?