Preparation of pyrrolecarboxamide derivatives as mineralocorticoid receptor antagonists for use against cancer and other disorders.

Abstract

Pyrrolecarboxamide derivs. (shown as I; other Markush structures for pyrrolecarboxamides are defined in the claims; variables defined below; e.g. 1-[4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid N-[4-(sulfamoyl)phenyl]amide (II)), compns. and methods for modulating the activity of receptors are provided. In particular compds. and compns. are provided for modulating the activity of receptors and for the treatment, prevention, or amelioration of ≥1 symptoms of disease or disorder directly or indirectly related to the activity of the receptors. Semiquant. IC50 values for antagonist activity of 23 examples of I are tabulated and compared to the activity of the Spironolactone control. For I: R1 and R2 = H, halo, cyano, or (un)substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, or -OR9, -SR9, -N(R9)2, -C(O)OR9 or -C(O)N(R9)2; R3 = H, halo, cyano, (un)substituted alkyl, (un)substituted alkenyl or (un)substituted alkynyl; R4 is H, -C(O)R9, -S(O)2R9, or (un)substituted alkyl, alkenyl or alkynyl, or R4 is (un)substituted cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; R6 is H or (un)substituted alkyl; R7 is (un)substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; addnl. details are given in the claims. Although the methods of prepn. are not claimed, prepns. and/or characterization data for many examples of I are included. For example, II was prepd. in 5 steps (50, 37, 62, 64, and 66 % yields, resp.) starting with prepn. of 1-[4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole from 4-fluoro-2-(trifluoromethyl)aniline and 2,5-hexanedione, followed by prepn. of the following intermediates: 1-(4-fluoro-2-trifluoromethylphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxaldehyde, 1-[4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid, and 1-[4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carbonyl chloride and finally amide formation with sulfanilamide. [on SciFinder(R)]