Compounds having cGMP-PDE inhibitory effect

Details Compounds having cGMP-PDE inhibitory effect Compounds having cGMP-PDE inhibitory effect

2000-05-26

2002-11-05

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S229500, C514S284000, C514S287000, C514S288000, C544S014000, C544S031000, C544S099000, C546S064000, C546S066000, C546S068000, C546S072000

Reexamination Certificate

active

06476021

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel condensed tetracyclic hetero-ring compounds having action in inhibiting strongly and highly selectively cyclic GMP-phosphodiesterase (hereinafter abbreviated as cGMP-PDE), featuring high safety, processes for producing such compounds, pharmaceuticals containing at least one of such compounds as an active ingredient, in particular, agents for preventing and/or treating pulmonary hypertension, ischemic heart diseases, erectile dysfunction, female sexual dysfunction or diseases against which the cGMP-PDE inhibition is effective, and intermediates useful for the production of the condensed tetracyclic hetero-ring compounds.
BACKGROUND ART
The identity of vascular endothelial cell derived relaxing factors has been found to be nitric oxide (hereinafter abbreviated as NO) which, like nitroglycerin used to treat angina pectoris, manifests its vascular relaxing action as mediated by the increase in cyclic GMP (hereinafter abbreviated as cGMP). Briefly, nitrites-like relaxing factors exist endogenously and counteract catecholamine and other endogenous vasoconstricting factors to adjust the tone of blood vessels and contribute to the retention of adequate blood flow. Therefore, the decrease in NO or cGMP is believed to enhance vasotonia and reduce the blood flow in tissue, eventually causing circulatory disorders or ischemic heart diseases. Increase in vasotonia resulting from damage to coronary endothelial cells which are in the class of NO producing cells is believed to induce insufficiency in the blood flow in myocardial tissue, thereby causing anginal attacks. This results from disorders in the NO-cGMP system working as an endogenous relaxing factor. The vasodilating action of nitrites depends on the diameter of blood vessels for the degree of relaxation and because of their active site specificity (i.e., thicker coronary arteries are relaxed more intensely), nitrites have so far been in common use. However, the nitrites have a disadvantage in that their action is transient and attenuated during prolonged use. In addition, it has been pointed out that among vasodilators, adenosine enhancers such as dipyridamole which dilate narrow portions of coronary arteries to increase the coronary blood flow increase the myocardial blood flow at normal sites rather than at the lesion, thereby aggravating the ischemia (this phenomenon is generally referred to as “steal”) and, hence, showing side effects such as aggravation of angina pectoris and pectoralgia.
While no effective therapeutics have been available for the various pathogenic conditions that manifest pulmonary hypertension, it has recently been reported that NO gas inhalation therapy has certain utility. Since NO gas relaxes blood vessels and lower the pulmonary arterial pressure through the increase in cGMP, it is anticipated that activation of the cGMP producing system dilates selectively pulmonary arteries in the pulmonary circulation, thereby contributing to the treatment of pulmonary hypertension. Calcium blockers and many other vasodilating drugs have so far been used in attempts to treat pulmonary hypertension, none have been commercialized since every one of them is more potent in lowering the systemic blood pressure than the pulmonary arterial pressure. An oxygen therapy has been verified to be effective in achieving improvements after its application. However, oxygen intoxication occurs as a serious side effect and the occurrence of pulmonary lesions such as pulmonary edema and fibrosis has been reported with patients who were on prolonged oxygen therapy at home. The NO gas inhalation therapy is not an exception and the NO gas used in this therapy is one of the air pollutants NO
x
and will easily generate NO
2
in the presence of oxygen, thereby potentially causing adverse effects on the airway and lungs; hence, utmost care is required in applying the NO gas and many problems are involved in its prolonged use. On the other hand, suppressing the cGMP degradation system is believed another way to maintain the concentration of cGMP, thereby allowing for selective decrease in the pulmonary arterial pressure. Briefly, an inhibitor of phosphodiesterase (hereinafter abbreviated as PDE) which is an enzyme catalyzing specific hydrolyzation of cyclic GMP holds promise as a new therapeutic free from the aforementioned side effects.
With the inhibition of PDE, cGMP increases, possibly leading to the treatment of these diseases. As of today, PDE has been verified to exist in at least seven isozyme types (Physiological Reviews, 75, 725-748, 1995). Of these, five types of isozymes distribute in many diverse tissues. Two isozymes are capable of selective hydrolyzation of cGMP and they are PDE type I (calmodulin-dependent PDE) and PDE type V (cGMP-PDE). On the other hand, PDE types III and IV hydrolyse cyclic AMP (hereinafter abbreviated as cAMP) selectively and PDE type II has no substrate selectivity. If the last three isozymes are inhibited, cAMP is increased to cause various obvious side effects including enhanced myocardial contraction and heart rate and depression of systemic blood pressure. Among other things, it is well known that with the inhibition of type III PDE, cAMP increases resulting in enhanced myocardial contraction. It has been also reported that increased cGMP in cardiac muscle reduced myocardial contraction but the distribution of PDE type V has not been recognized in cardiac muscle. Furthermore, PDE type VI is distributed in the retina, and it is expected that the inhibition of this PDE type VI will cause defect in vision such as changes in blue/green color and increased sensitivity to light. Therefore, it is anticipated that selective inhibition of PDE type V will produce selective action that is limited in the decrease in systemic blood pressure and side effects on the heart and the retina. It has recently been found that NO releasing compounds show an inhibition of vascular smooth muscle cell proliferation with the intermediary of cGMP. For example, Garg et al. (J. Clin. Invest., 83, 1774-1777, 1989) and Nakaki et al. (Eur. J. Pharmacol., 189, 347-353, 1990) reported that the proliferation of cultured vascular smooth muscle cells isolated from aortic media in rats was suppressed by the treatment of NO releasing compounds nitroprusside, nitroglycerin, isosorbide dinitrate or 8-bromo-cGMP. Therefore, it is suggested that increased cGMP could suppress the proliferation of vascular smooth muscle cells in arteriosclerosis and post-PTCA restenosis. It is also known that the NO-cGMP system is involved in the mechanism of penile erection. When the sexual center in the brain is excited by sexual stimulation from the eyes or ears or by direct stimulation of the penis, the stimulation is transmitted to the nerves in corpus cavernosum penis via parasympathetic pelvic nerves, whereupon acetylcholine, vasoactive intestinal peptides and nitrogen monoxide (hereinafter abbreviated as NO) are released from the corpus cavernosum to relax the smooth muscle forming the valve structure in the spiral artery so that the arterial blood supplied from the penile deep artery and dorsal artery suddenly flows into the cavities of corpora cavernosa, causing the pressure in the corpus cavernosum penis to rise so that the fibrous trabeculae that have relaxed under the action of acetylcholine, vasoactive intestinal peptides and NO clog the flux veins or the cavities of corpora cavernosa will themselves increase in volume. In addition, the tension under the pressure of the tunica albuginea compresses the veins running obliquely across the tunica albuginea to obstruct the blood outflow. As the result, blood stays within the cavities of corpora cavernosa and the tunica albuginea becomes rigid under tension to establish penile erection.
It has been unravelled that the entity of the vascular endothelial cell derived relaxing factor is NO and develops its vasohypotonic action with the intermediary of an increased cGMP level. Therefore, it is postulated that suppressing the CGMP decomposing system is another wa

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