2-phenyl-3,4-dihydropyrrolo[2,1-f] [1,2,4]triazinone derivatives as phosphodiesterase inhibitors and uses thereof

Abstract

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein Ris C-Calkyl optionally substituted with F, C-Ccycloalkyl, C-Calkoxy; X represents a bond or C-Calkylene optionally substituted with OH, ONO, ONO; Ris H, OH, ONO, ONO, C(O)OH, C(O)OC-Calkyl, CHO, CN, C-Calkoxy, OC(O)H, OC(O)—C-Calkyl, C(O)N(R)OR, OC-Calkylene-C(O)OH, OC-Calkylene-C(O)OC-Calkyl, OC-Calkylene-C(O)N(R)OR, S(O)C-Calkyl, CR═N—OR, CR═N—NRR, CR═NRor CR═N—ONO; Ris C-Calkyl optionally substituted with F, OH, ONO, ONO, C-Calkoxy, C-Ccycloalkyl; C-Ccycloalkyl, C-Calkenyl, C-Calkynyl; Ris C-Calkyl optionally substituted with C-Ccycloalkyl, C-Calkoxy, F, ONO, ONO; C-Calkenyl, C-Calkynyl, C-Ccycloalkyl; Ris H, SON—RR, NHSONRR; Ris H or C-Calkyl; Ris H, C-Calkyl, C-Calkoxy, C-Calkyl substituted with phenyl, benzyl or a heterocyclic ring, wherein said phenyl, benzyl or said heterocyclic ring are independently optionally substituted by C-Calkyl, F; Ris H, CHor CH; R: H, C-Calkyl optionally substituted with OH, ONO, ONO, CN, COOH, COOC-Calkyl, C-Calkoxy, OC(O)H, OC(O)—C-Calkyl, C(O)N(R)OR, OC-Calkylene-C(O)OH, OC-Calkylene-C(O)OC-Calkyl, OC-Calkylene-C(O)N(R)OR, S(O)C-Calkyl; Rand Rare each independently H, C-Calkyl optionally substituted with OH, ONO, ONO, CN, COOH, COOC-C, C-Calkoxy, OC(O)H, OC(O)—C-Calkyl, C(O)N(R)OR, OC-Calkylene-C(O)OH, OC-Calkylene-C(O)OC-Calkyl, OC-Calkylene-C(O)N(R)OR, S(O)C-Calkyl; i or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrolidine, piperidine, morpholine, piperazine and homopiperazine, wherein said heterocyclic ring is optionally substituted with C-Calkyl; Ris C-Calkyl optionally substituted with OH, ONO, ONO, CN, COOH, COOC-Calkyl, C-Calkoxy, OC(O)H, OC(O)—C-Calkyl, C(O)N(R)OR, OC-Calkylene-C(O)OH, OC-Calkylene-C(O)OC-Calkyl, OC-Calkylene-C(O)N(R)OR, S(O)C-Calkyl; Rand Rare each independently H or C-Calkyl optionally substituted with F, OH, ONO, ONO, COOH, C-Calkoxy, C-CCycloalkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring is optionally substituted with R; Ris C-Calkyl optionally substituted with halogen, OH, ONO, ONO, C-Calkoxy, C-Chaloalkoxy, COOR, NRR, C═NR, or with a tetrazole group which is optionally substituted with C-Calkyl; or a heteroaryl ring which is optionally substituted with F, wherein the at least one heteroatom of said heteroaryl ring is nitrogen; Ris H, or C-Calkyl optionally substituted with F, OH, ONO, ONO, NRR, or with a heteroaryl ring, wherein the at least one heteroatom of said heteroaryl ring is nitrogen, and wherein preferably said heteroaryl ring is selected from pyrrolidine, piperidine, piperazine, morpholine, pyrrole, and imidazole, wherein nitrogen atom is directly bound to C-Calkyl; Rand Rare each independently H or C-Calkyl optionally substituted with ONO, ONO; Ris C-Calkyl optionally substituted with F, ONO, ONO; C-CCycloalkyl; and their use in methods of treating or preventing a disease alleviated by inhibition of PDE-5 in a human or in a non-human mammal.