Derivatives of indole and their use as phosphodiesterase 4 inhibitors

摘要

5- or 6-Hydroxyindole derivatives (I), their optical isomers, racemates and diastereomers, and their acid addition and base salts are new: : 5- or 6-Hydroxyindole derivatives (I), their salts, optical isomers, racemates and diastereomers are new: [Image] A : bond; -(CH 2) m-; -(CH 2) m-(CH=CH) n-(CH 2) p-; -(CHOZ) m-; -C(O)-; -C(S)-; -C(=N-Z)-; -O-; -S-; or -N(Z)-; m, p : 0-3; n : 0-2; Z : H; alkyl; alkenyl; or a heterocycle or carbocycle (both mono-, bi- or tricyclic and saturated or mono- or poly-unsaturated); B : C; S; or S(O); D : O or N-Z or, when B = C, also S or CH 2; E : bond; -(CH 2) m-; -O-; -S-; or -N(Z)-; R 1>, R 5>alkyl, alkenyl, a heterocycle, carbocycle or carbocyclic or heterocyclic spirocycle (all optionally mono- or poly-substituted by Q); Q : OH; SH; NH 2; NH(alkyl); N(alkyl) 2; NH(aryl); N(aryl) 2; N(alkyl)(aryl); NHCOR 6>; NO 2; CN; F; Cl; Br; I; alkoxy; aryloxy; OC(O)R 6>; alkylthio; arylthio; SOR 6>; SO 3H; SO 2R 6>; alkyl-SO 2O; aryl-SO 2O; C(S)R 6>; COOH; C(O)R 6>; or a heterocycle or carbocycle (aryl, heterocycle and carbocycle are optionally mono- or poly-substituted by R 4>); R 2>, R 3>H or OH, but at least one is OH; R 4>H; OH; SH; NH 2; NH(alkyl) N(alkyl) 2; NH(aryl); N(aryl) 2; N(alkyl)(aryl); NHCOR 6>; NO 2; CN; COOH; C(O)R 6>; C(S)R 6>; F: Cl; Br; I; alkoxy; aryloxy; OC(O)R 6>; alkylthio; arylthio; SOR 6>; or SO 2R 6>; R 6>H; NH 2; NH(alkyl); N(alkyl) 2; NH(aryl); N(aryl) 2; N(alkyl)(aryl); alkoxy; aryloxy; alkylthio; arylthio; arylthio-alkyl; alkenyl; or a heterocycle or carbocycle. The full definitions are given in the DEFINITIONS (Full Definitions) Field. Independent claims are also included for the preparation of compounds (I). ACTIVITY : Bronchodilator; neuroprotective. MECHANISM OF ACTION : Phosphodiesterase 4 (PDE 4) inhibitors; TNF-alpha inhibitors. A modification of the method described by Thompson et al. Adv. Cycl. Nucl. Res. 1979, 10, 69-92 was used to determine the inhibition of phosphodiesterase by compounds (I). In this test, compounds (I) exhibited IC 5 0 values of 10 -> 9>-0 -> 5> M. The selectivity over PDE types 2, 3 and 5 was by a factor of 100-10000. Compounds (I) had IC 5 0 values of 10 -> 7>-10 -> 5> M in a test for the inhibition of TNF-alpha release from nasal polyp cells (see Int. Arch. Allergy Immunol., 1993, 101, 308-310). Further, in a test for the inhibition of late phase eosinophilia in ovalubin-sensitized guinea pigs, compounds (I) gave 30-80% inhibition when administered i.p. and 40-70% inhibition when administered p.o. In a test for their effect on allergen-induced vascular permeability in ovalbumin-sensitized rats, compounds (I), administered intranasally exhibited IC 5 0 values of 10 -> 8>-10 -> 5> M.