Phosphodiesterase-1 inhibitors and their use in treatment of cardiovascular diseases

A method of treatment or prophylaxis of a disease or disorder which is ameliorated by modulating cGMP/PKG-dependent signaling pathways comprising administration of a phosphodiesterase 1 (PDE1) inhibitor to a human patient in need thereof, wherein the disease or disorder is selected from the group consisting of:

• cardiac hypertrophy, angina, stroke characterized as a transient ischemic attack, renal failure, essential hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, renovascular hypertension, myocardial infarction, cardiovascular disease characterized by cardiac hypertrophy, congestive heart failure characterized by cardiac hypertrophy, and pulmonary hypertension characterized by cardiac hypertrophy;
• wherein the PDE1 inhibitor is a compound of Formula VII:
• (i) X is C1-6alkylene;
• (ii) Y is a single bond, alkynylene, arylene, or heteroarylene;
• (iii) Z is H, aryl, heteroaryl, halo, haloC1-6alkyl, —C(O)—R1, —N(R2)(R3), or C3-7cycloalkyl optionally containing at least one atom selected from a group consisting of N or O;
• (iv) R1 is C1-6alkyl, haloC1-6alkyl, —OH or —OC1-6alkyl;
• (v) R2 and R3 are independently H or C1-6alkyl;
• (vi) R4 and R5 are independently H, C1-6alky or aryl optionally substituted with one or more halo, hydroxy or C1-6alkoxy;
• (vii) wherein X, Y and Z are independently and optionally substituted with one or more halo, C1-6alkyl, haloC1-6alkyl,
• in free or salt form.