Novel dual mode of action of soluble guanylate cyclase activators and phosphodiesterase inhibitors and uses thereof

摘要

The present invention relates to a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, solvate or hydrate thereof; Pharmaceutical compositions thereof and their use in methods of treating or preventing diseases ameliorated by inhibition of PDE5 in a human or non-human mammal. during the meal, each compound of Formula I or Formula II comprises at least one covalently bonded ONO ₂ or ONO moiety; R ₁ is C ₁ -C ₃ alkyl; R ₂ is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ haloalkyl, C ₁ -C ₂ alkoxy, C ₂ -C ₄ alkenyl; R ₃ is C ₁ -C ₂ alkoxy, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkyl, which is optionally substituted by C ₂ -C ₄ alkenyl; R ₄ and R _{5are each independently H or C 1} -C ₆ alkyl optionally substituted with F, OH, ONO, ONO ₂ , COOH, C ₁ -C ₃ alkoxy, C ₃ -C _{6 cycloalkyl;} or together with the nitrogen atom to which they are attached form a heterocyclic ring, preferably said heterocyclic ring is aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homo-piperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, wherein the heterocyclic ring is independently selected from one or more R ₆ . substituted; R ₆ is one or more independently of _{halogen, OH, ONO, ONO 2,} C 1 -C 3 alkoxy, C ₁ -C _{3haloalkoxy, COOR 7, NR 8 R 9} , C = NR 10 optionally being substituted with C ₁ -C ₆ alkyl; R _{7is H, or C 1} -C ₄ alkyl optionally substituted with F, OH, ONO, ONO ₂ , NR ₈ R _{9 ;} R ₈ and R ₉ are independently H, or _{C 1} -C ₄ alkyl optionally substituted with _{ONO, ONO 2 ;} R _{10is C 1} -C ₄ alkyl optionally substituted with F, ONO, ONO _{2 ;} C ₃ -C ₆ cycloalkyl.