Novel tetrahydrocarbazole derivatives with improved biological action and improved solubility as ligands for G protein-coupled receptors (GPCRs)

摘要

Tetrahydrocarbazole compounds (I) and their salts, derivatives or analogues; or their racemates, pure enantiomers and/or diastereomers, tautomers, solvates and hydrates, or polymorphic forms are new, where the salts are obtained by neutralizing the bases with inorganic or organic acids or by neutralizing the acids with inorganic or organic bases. Tetrahydrocarbazole compounds of formula (I) and their salts, derivatives or analogues; or their racemates, pure enantiomers and/or diastereomers, tautomers, solvates and hydrates, or polymorphic forms are new, where the salts are obtained by neutralizing the bases with inorganic or organic acids or by neutralizing the acids with inorganic or organic bases. X1 : S or O; X2, X3 : O or geminally linked H 2; R1, R2 : H (preferred), aryl, alkyl or arylalkyl radicals (optionally substituted in the alkyl and/or aryl group by up to 3 substituents of -hal, -CN or -O-alkyl); R3 : alkyl, arylalkyl or heteroarylalkyl radical (optionally substituted by up to 3 substituents -hal, -CN, -CO-O-R12, -CO-NR12R12a, -OH, -O-R13, -O-CO-R13, -O-SO 2, -OR12, -O-SO 2-R12, -SO 2, -SO-R12, -SO-R12, -O-PO(OR12)(OR12a), -O-PO(NR12R12a) 2, -O-CO-O-R13, -O-CO-NR12R12a, -O-CS-NR12R12a, -S-R12, -NR12R12a, -NH-CO-R13, -NH-SO 2-R12, -NH-CO-O-R13, -NH-CO-NHR12 or -NH-C(NH)-NH 2); R4-R7 : H, -Hal, -CN, -CONH 2, -COOH, -CF 3, -O-alkyl, -OCF 3, -NO 2, alkyl, arylalkyl or heteroarylalkyl radicals; R9 : H, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl radical; R10 : H or -R11, -CO-R11, -CO-OR11, -CO-NHR11, -C(NH)-NHR11, -SO 2-R11 or -SO 2-NHR11; R11 : alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl radical (optionally substituted by one or more -hal, -CN, -alkyl, -CF 3, -OCF 3, -OH, -O-alkyl or -O-(CH 2CH 2-O) n-CH 3); R8 : 1-6C alkyl-aryl or 1-6C-alkyl-heteroaryl (where the aryl or heteroaryl group is substituted by 1-3 substituents of -O-(CH 2CH 2O) n-CH 3, -O-CO-R 12, -O-CO-(CH 2CH 2-O) n-CH 3, -O-SO 2-OR12, -O-SO 2-R12, -O-PO(OR12)(OR12a), -O-PO(NR12R12a) 2, -O-CO-OR13, -O-CO-NR12R12a or -O-CS-NR12R12a); R12, R12a : H, alkyl, arylalkyl, aryl, heteroarylalkyl, or heteroaryl radicals; R13 : alkyl, arylalkyl, aryl, heteroarylalkyl, heteroaryl radical, or -(CH 2CH 2-O) n-CH 3; and n : 1-10. When X1 is S or R10 is not H, and R11 is an arylalkyl or heteroarylalkyl radical (substituted in the aryl or heteroaryl group by one or more halo, -CN, -alkyl, -CF 3, -OCF 3, -OH, -O-alkyl or -O-(CH 2CH 2-O) n-CH 3, then R8 also assumes R3. An independent claim is also included for a pharmaceutical composition comprising at least one (I). [Image] ACTIVITY : Cytostatic; Antiinfertility; Endocrine-Gen.; Contraceptive; Gynecological; Analgesic; Hemostatic; Depilatory; Anti-HIV; Neuroleptic; Neuroprotective; Nootropic; Antiemetic; Antiinflammatory; Antiarthritic. MECHANISM OF ACTION : LHRH receptor antagonist; Neurokinin-1 (NK-1) receptor antagonist; NK-2 receptor antagonist. The ability of (I) (3.3 x 10 - 8 M) to inhibit LHRH-induced LH secretion was assessed in rat pituitary cells in vitro. The results showed that the percentage inhibition of LHRH-induced LH secretion was 83%.