Modulators of cb1 receptors

Abstract

Compounds of formula (I) suppress the normal signalling activity CB1 receptors, and are thus useful in the treatment of diseases or conditions which are mediated by CB1 receptor signalling activity, such as treatment of obesity and overweight, prevention of weigh gain, treatment of diseases and conditions directly or indirectly associated with obesity and overweight: wherein A1 is hydrogen, -COOH, or tetrazolyl, and A2 is hydrogen, -COOH, or tetrazolyl, provided that one of A1 and A2 is either -COOH or tetrazolyl; p is O or 1 and A3 is phenyl or cycloalkyl, either of which is optionally substituted with R4 and / or R5; q is O or 1; R3 is hydrogen, C1-C4 alkyl, cycloalkyi, -CF3, or -OR9; R4 and R5 independently -R9, -CN, -F, -Cl, -Br, -OR9, - NR7R8, -NR7COR6, -NR7SO2R6, -COR6, -SR9, -SOR9, or -SO2R6; R6 is C1-C4 alkyl, cycloalkyl, -CF3 or -NR7R8; R7 and R8 are independently hydrogen, C1-C4 alkyl, -CF3, or cycloaikyL R9 is hydrogen, C1-C4 alkyl, cycloalkyl, fully or partially fluorinated C1-C4 alkyl; R1 is (i) a bond, or (ii) -(CH2)aB1(CH2)b- wherein a and b are independently O, 1, 2 or 3 provided that a+b is 1, 2 or 3; or (iii) -C(R10)(R11)-*, -C(R10)(R11)-O-*. -C(R10)(R11)CH2-*, -C(R10)(R11)CH2-O-*, - CH2C(R10)(R11)-*, -CH2C(R10)(R11)-O-*, -CH2-O-C(R10)(R11)-* or -C(R10)(R11)-O-CH2-*, wherein the bond indicated by an asterisk is attached to the pyrazole ring; R2 is a divalent radical of formula -Q1A4-[Q2]w- wherein Q1, A4, Q2 and w are as defined in the specification; and R10 is hydrogen and R11 is (C1-C3)alkyl or -OH; or R10 and R11 are both (C1-C3)alkyl; or R10 and R11 taken together with the carbon atom to which they are attached form a (C3- C5)cycloalkyl ring.

Description

[0001] The present invention relates to compounds that act as modulators of the cannabinoid receptor CB1 and inhibit the normal signaling activity of this receptor. The present invention also relates to compositions and methods for using such compounds to treat diseases or conditions mediated by CB1 receptor signal transduction activity, such as treating obesity and overweight, preventing weight gain, treating obesity and overweight directly or indirectly related Diseases and conditions such as metabolic syndrome, type 2 diabetes, cardiovascular disease, abnormal metabolic function in obese, overweight or normal weight individuals, metabolic diseases or disorders, cancer, liver disease and other secondary diseases mentioned below, and treatment Certain diseases not necessarily related to obesity and overweight, such as eating disorder diseases, addictive diseases, mental disorders, neurological disorders, sexual dysfunction, reproductive dysfunction, liver disease, fibrosis-relat...

AI Technical Summary

Problems solved by technology

Although for body weight and metabolic parameters (plasma triglyceride levels, HDL cholesterol levels, plasma insulin levels, HbA 1 c[glycosylated hemoglobin] levels, insulin resistance, and adiponectin levels) are very exciting but also have undesired side effects that may be central nervous system mediated (psychiatric and neurological disorders) such as anxiety, depression, sleep disturbances, nausea, and vomiting (refer to http: / / emc.medicines.org.uk ; http: / / www.emea.europa.eu / humandocs / PDFs / EPAR / acomplia / AcompliaEparScientificD-en.pdf)

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