MXPA97004040A

MXPA97004040A - Quinazolines as inhibitors of endotel converter enzyme

Info

Publication number: MXPA97004040A
Application number: MXPA/A/1997/004040A
Authority: MX
Inventors: Marian Doherty Annette; Cheng Xuemin; Ahn Kyunhgye; Edward Kornberg Brian; M Leonard Daniele; Faith Elslager Edward; Lee Chitase; Shribhar Nikam Sham; Morton Werbel Leslie
Original assignee: Warnerlambert Company
Priority date: 1994-12-22
Filing date: 1997-05-30
Publication date: 1998-07-03

Abstract

Novel quinazoline inhibitors of endothelin-converting enzymes are described, as well as methods for the preparation and pharmaceutical compositions thereof, which are useful in the treatment of high levels of endothelin and in the control of hypertension, myocardial infarctions and ischemias, metabolic disorders , endocrinological and neurological, congestive failures of the heart, endotoxic and hemorrhagic attacks, septic attacks, subarachnoid hemorrhages, arrhythmias, asthma, acute and chronic renal failure, nephrotoxicity induced by cyclosporin-A, angina, gastric mucosal damage, ischemic bowel disease , cancer, pulmonary hypertension, preclaimsia, atherosclerosis disorders including Raynaud's disease and restenosis, cerebral ischemia and vasospasms and diabetics

Description

QUINAZOLINES AS INHIBITORS OF ENDOTHELINE CONVERTIBLE ENZYME BACKGROUND OF THE INVENTION The present invention relates to novel quinazoline inhibitors of endothelin-converting enzymes useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions including these compounds and a pharmaceutically acceptable carrier and to pharmaceutical methods of treatment. More particularly, the novel compounds of the present invention are inhibitors of endothelin-converting enzymes useful in the treatment of high levels of endothelin and to control hypertension, myocardial infarctions and ischemia, metabolic, endochronological and neurological disorders, congestive heart failures , endotoxic and hemorrhagic attacks, septic attacks, subarachnoid hemorrhages, arrhythmias, asthma, acute and chronic renal failure, cyclosporine-A-induced nephrotoxicity, angina, gastric mucosal damage, ischemic bowel disease, cancer, pulmonary hypertension, preclaimsia, atherosclerotic disorders including Raynaud's disease and restenosis, cerebral ischemia and vasospasms and diabetes.

Endothelin-1 (ET-1), a potent vasoconstrictor, is an amino acid bicyclic peptide 21 that was first isolated from cultured porcine aortic endothelial cells. Endothelin-1 is one of a family of structurally similar bicyclic peptides that includes: ET-2, ET-3, vasoactive intestinal contractor (VIC), and sarafotóxinas (SRTXs). The unique bicyclic structure and the corresponding arrangement of the disulfide bridges of ET-1, which are the same for endothelin, VIC and sarafotoxins, has led to significant speculation as to the importance of the resulting induced secondary structure for activity. of the link receiver and functional. The ET-1 analogs with incorrect disulfide pairs exhibit at least 100-fold less vasoconstrictor activity.

Endothelin-1 is generated from a 203 amino acid peptide known as preproendotalin by an unknown dibasic endopeptidase. This enzyme divides the prepropeptide into an amino acid peptide 38 (human) or 39 (porcine) known as large endothelin or proendothelin. The large ET is then divided by an enzyme, known as an endothelin converting enzyme or ECE, to produce the biologically active molecule ET-1. The large ET is only 1% as potent as ET-1 to induce vasoconstrictor activity in vascular strips but is equally potent in vivo in raising blood pressure, presumably by rapid conversion to ET-1 (Kimura S., Kasuya Y ., Sawamura T., et al., "The conversion of large endothelin-1 to endothelin-1 of residue 21 is essential for the expression of complete vasoconstrictor activity: Structure-activity relationship of the large endothelin-1", J. Cardiovasc Pharmacol., 1989; 13: S5). There have been numerous reports describing possible proteases in both cell-binding fractions of either the cytoplasm and the membrane (Ikegawa R., Matsumura Y., Takaoka M., et al., "Evidence of pepstatin-sensitive conversion of large endothelin- 1 porcine to endothelin-1 by the endothelial cell extract ", Biochem Biophys, Res. Commun. 1990; 167: 860; Sawamura T., Kimura S., Shinrni O., et al.," Characterization of the activities of the endothelin-converting enzyme in soluble fraction of cultured bovine endothelial cells ", Biochem Biophys., Commun., 1990; 169: 1138; Sawamura T., Shinmi O., Kishi N., et al.," Analysis of the digestion of large endothelin-1 by cathepsin D. "Biochem, Biophys, Res. Commun. 1990; 172: 883; Shields PP, Gonzales TA, Charles D., et al.," Accumulation of pepstatin in cultured endothelial cells and their effect in the endothelin process ", Biochem Biophys, Res. Commun., 1991; 177: 1006; Matsamura Y., Ikegawa R., Tsukahara Y., et al., "Conversion of large endothelin-1 to endothelin-1 by two types of metalloproteinases derived from porcine aortic endothelial cells", FEBS Lett, 1990; 272: 166; Sawamura T., Kasuya Y., Matsushita S.N., et al., "Phosphoramidon inhibits the intercellular conversion of large endothelin-1 into endothelin-1 in cultured endothelial cells", Biochem Biophys. Res. Commun., 1991; 176: 860; Ahn K., Beningo K., Olds G., Hupe D., "Endothelin-converting enzyme of porcine and human endothelial cells", J. Vasc. Res., 1991; 29:76, 2nd International Symposium on vasoactive factors derived from the endothelium). Many groups have chosen to isolate ECE from endothelial cells of several species, since endothelin is known to be synthesized and secreted by this type of cell. It was initially reported that two types of protease activity were present in the bovine porcine endothelial cells that could cause the conversion of the large ET into ET in vitro (Ikegawa R., supra, Sawamura T., supra, Matsumara Y., supra, Takada J., supra; Ahn K., supra). However, it was eventually discovered that the aspartic protease activity of porcine endothelial cells, despite being predominantly cathepsin D, also causes further degradation of ET-1 and was therefore unlikely to be the real ECE (Sawamura T, supra) . Moreover, human cathepsin D also causes rapid degradation of ET-1. In addition, there has been a study showing that the intercellular accumulation of pepstatin, an aspartic protease inhibitor, did not inhibit the production of ET-1 in cultured bovine aortic endothelial cells (Shields PP, supra). Stronger evidence that ECE is indeed a neutral metalprotease has appeared (Matsumura Y, supra, Sawamura T., supra, Takada J, supra, Ahn K., supra) and, recently, ECE rat and bovine genes have been dyed and expressed, confirming that ECE is a metalloprotease sensitive to phosphoramidon (Shimada, K., Tanzawa, K., J. Biol. Chem., 1994, 269, 18275) (Dong, X., Emoto, N., Giaid, A., Slaughter, C, Kaw, S., deWit, D., Yanagisawa, M., Cell 1994, 78, 1-20). However, the non-specific metalproteinase inhibitor, phosphoramidon, has been shown to inhibit the intercellular conversion of large ET-1 into ET-1 in cultured vascular endothelial cells and smooth muscle cells (Sawamura T, supra).

The transforming activity of ET has been detected in both membranous and cytosolic fractions of porcine, bovine and human endothelial cells (Matsamura Y, supra). Micromolar concentrations of phosphoramidon have been shown to block the large ET pressor response in both in vitro and in vivo (Takada J, supra, Fukorada T, Noguchi K., Tsuchida S., et al., "Inhibition of biological actions in large endothelin-1 by phosphoramidon "Biochem Biophys., Res. Commun., 1990; 172: 390; Matsumura Y., Hisaki K., Takaoka M., Marimoto S.," Phosphoramidon, a metalproteinase inhibitor, suppresses the hypertensive effect of large endothelin-1"Eur J Pharmacol., 1990: 185; 103; McMahon EG., Palomo MA., Moore MW., et al.," Phosphoramidon blocks the pressor activity of the large porcine endothelin-1 (1-39). ) in vivo and the conversion of the large endothelin-1 (1-39) into endothelin-1 (1-21) in vitro "Proc. Nati. Acad. Sci. USA., 1981; 88: 703). It has been recently reported that phosphoramidon is able to inhibit the vasoconstrictor effects invoked by intravenous injections of large ET-1 in anesthetized pigs, but had no effect on plasma ET-1 level (Modin A., Pernow J., Lundberg JM., "Phosphoramidon inhibits the vasoconstrictor effects invoked by the large endothelin-1 but not the elevation of plasma endothelin-1 in vivo" Life Sci 1991; 49: 1619). It should be noted that phosphoramidon is more of a general metalloproteinase inhibitor and clearly the discovery of specific ECE inhibitors such as those described in the present invention is important.

The importance of ECE inhibitors is further supported by recent reports. Several studies demonstrating the inhibition of ECE by metalloprotease inhibitors such as phosphoramidon in vivo have been published (Doherty, AD, Endothelin: A New Challenge, J. Med. Chem., 1992, 35, 1493; Simonson, JS, Endothelins: Multirunal Renal Peptides, Physiological Journals, 1993, 73, 375, Opgenorth, TJ, Wu-Wong, JR, Shiosaki K., Endothelin-converting enzymes, FASEB, J., 1992, 6, 2653-2659; Pollok, D.M., Opgenorth, T.J., Evidence for the intervention of metalloprotease in the in vivo effects of the great endothelin-1, Am. J. Physiol., 1991, 261, 257-263). These studies have also been followed by in vivo studies in which the effects of ET in physiological conditions have been blocked by ECE inhibitors. For example, several reports have shown that phosphoramidon (IC50 = ~ lμM) inhibits ECE in vitro. In rats anesthetized with the blocked ganglion the large ET-1 pressor response was blocked with phosphoramidon in a dose-dependent manner (McMahon, EG, Palomo MA, Moore, WM, Phosphoramidon blocks the pressor activity of the large endothelin (1 -39) and lowers blood pressure in spontaneously hypertensive rats J. Cardiovasc Pharmacol., 1991, 17 (Suppl 17), S29-S33; McMahon, EG, Palomo, MA, Moore, WM, McDonald, JF, Stern , MK, Phosphoramidon blocks the pressor activity of the large porcine endothelin-1 (1-39) in vivo and the conversion of large endothelin-1 (1-39) into endothelin-1 (1-21) in vitro Proc. Nati Acad. Sci. USA., 1991, 88, 703-707). Phosphoramidon has also been shown to inhibit the effects of large endothelin-1 in the microvasculature of anesthetized hamsters and has also been used to suppress the lethality induced by intravenous infusion of large ET-1 (Lawrence, E; Brain, SD, La Large endothelin-1 and large endothelin-3 are constrictor agents in the micro-vasculature: evidence of high-endothelin-1 local phosphoramidon-sensitive conversion, Eur. J. Pharmacol., 1993, 233, 243-250). In all cases it has been shown that phosphoramidon inhibited the effects of the large ET-1 and not ET-1 indicating that it did not behave as a receptor antagonist. Intracisternal administration of large ET-1 in anesthetized dogs decreased caliber of the basilar artery on the angiogram and systemic blood pressure was also elevated. These effects were blocked by phosphoramidon (Shinyama, H., Uchida, T., Kido, H., Hayashi, K., Watanabe, M., Matsumura Y., Ikegawa, R., Takaoka, M., Morimoto, S. Phosphoramidon inhibits the conversion of large endothelin administered intracisternally to endothelin-1 (Biochem Biophys Res. Commun., 1991 , 178, 24-30). Similar enzyme inhibitory activity has been reported in studies involving the phosphoramidon-sensitive inhibition of hemodynamic actions of large ET-1 in rat brains (Hashim, MA, Tadepalli) Functional evidence for the presence of a phosphoramidon-sensitive enzyme in the brain of rat that converts the great endothelin-1 into endothelin-1, Life Sci., 1991, 49, 207-211).

Endothelin is involved in many states of human diseases.

Several in vivo studies with ET antibodies have been reported in disease models. Ligation of the left coronary artery and reperfusion to induce myocardial infarctions in the heart of the rat caused a four- to seven-fold increase in endogenous endothelin levels. It was reported that the administration of the ET antibody reduces the size of the infarct in a manner that depends on the dose (Watanabe, T., et al., "Endothelin in Myocardial Infarction", Nature (London) 1990; 344: 114). Thus, ET may be involved in the pathogenesis of congestive heart failure and myocardial ischemia (Margulies KB, et al., "Greater Endothelin in Experimental Cardiac Failure" Circulation 1990; 82: 2226).

The studies of Kon and colleagues using anti-ET antibodies in an ischemic kidney model, to deactivate endogenous ET, indicated the involvement of the peptide in acute renal ischemic injury (Kon V, et al., "Endothelial glomerular actions in alive "J. Clin. Invest., 1989; 83: 1762). In isolated kidneys, preexposed to specific anti-endothelin antibodies and then attacked by cyclosporine, renal perfusate flow and glomerular filtration rate increased, whereas renal resistance decreased compared to isolated kidneys pre-exposed to non-immunized rabbit serum. The effectiveness and specificity of the anti-ET antibody were confirmed by its ability to prevent renal deterioration caused by a single dose of bolus (150 pmol) of synthetic ET, but not by infusion of angiotensin II, norepinephrine or thromboxane A2 mimetic U -46619 on isolated kidneys (Perico N., et al., "Endothelin mediates renal vasoconstriction induced by Ciclosporin in the rat", J. Am. Soc. Nephrol., 1990; 1:76).

Others have reported the inhibition of vasoconstriction induced by ET-1 or ET-2 in isolated thoracic aortas of rat using a monoclonal antibody for ET-1 (Koshi T., et al., "Inhibition of vasoconstriction induced by Endothelin (ET ) and ET-2 by antiET-1 monoclonal antibodies "Chem. Pharm. Bull., 1991; 39: 1295).

Combined administration of ET-1 and ET-1 antibody to rabbits demonstrated significant inhibition of blood pressure and responses in renal blood flow (Miyamori I, et al., Systemic and regional effects of endothelin in rabbits: effects of the endothelin antibody "Clin. Exp. Pharmacol. Physiol. 1990; 17: 691).

Other researchers have reported that the infusion of ET-specific antibodies in spontaneously hypertensive rats (SHR) decreased actual blood pressure (MAP) and increased the rate of glomerular filtration and renal blood flow. In the control study with Wistar-Kyoto rats (WKY) of normal tension, there were no significant changes in these parameters (Ohno A., "Effects of endothelin-specific antibodies and endothelin in spontaneously hypertensive rats" J Tokyo Women's Med Coll., 1991; 61: 951).

In addition, high levels of endothelin have been reported in several disease states (see Table I below).

Table I. Concentrations of ET-1 Plasma in Humans Condition Reported Condition Normal ET Plasma Levels (pg / ml) Atherosclerosis 1.4 3.1 pmol / L Surgical operation 1.5 7.3 Buerger's disease 1.6 4.8 Takayasu's arteries 1.6 5.3 Cardiogenic attack 0.3 3.7 Congestive heart failure (CHF) 9.7 20.4 Mild CHF 7.1 11.0 Severe CHF 7.1 13.8 Dilated cardiomyopathy 1.6 7.1 Preclamsia 10.4 pmol / L 22.6 pmol / L Pulmonary hypertension 1.45 3.5 Acute myocardial infarction 1.5 3.3 (Several reports) 6.0 11.0 0.76 4.95 0.50 3.8 Subarachnoid hemorrhage 0.4 2.2 Crohn's disease 0-24 Fmol / mg 4-64 Fmol / mg Ulcerative colitis 0-24 Fmol / mg 20-50 Fmol / mg Cold pressure test 1.2 8.4 Raynaud's phenomenon 1.7 5.3 Raynaud's cold hands 2.8 5.0 Hemodialysis < 7 10.9 (Several reports) 1.88 4.59 Chronic renal failure 1.88 10.1 Acute renal failure 1.5 10.4 Uremia before hemodialysis 0.96 1.49 Uremia after hemodialysis 0.96 2.19 Essential hypertension 18.5 33.9 Sepsis syndrome 6.1 19.9 Postoperative cardiac 6.1 11.9 inflammatory arthritis 1.5 4.2 Malignant hemangioendothelin 4.3 16.2 (after removing) Burnett and his colleagues recently demonstrated that the exogenous infusion of ET (2.5 ng / kg / ml) to anesthetized dogs, which produces a doubling of the circulating concentration, had biological actions (Lerman A., et al., "Endothelin has biological actions in pathophysiological concentrations" Circulation 1991; 83: 1808 ). Thus, the heart rate and the output of the heart decreased in association with increased renal and systemic resistance to renal and systemic antinatriuresis. These studies support a role of endothelin in the regulation of cardiovascular, renal and endocrine function.

In the anesthetized dog with congestive heart failure, a significant two to three-fold elevation of circulating ET levels has been reported (Cavero PG., Et al., "Endothelin in experimental congestive heart failure in the anesthetized dog" m. J. Physiol., 1990; 259: F312) and studies in humans have shown similar increases (Rodeheffer RJ., Et al., "Circulating plasma endothelin correlates with the severity of congestive heart failure in humans", Am. J. Hypertension 1991; 4: 9A). When ET was chronically infused into male rats, to determine whether a long-term increase in circulating ET levels would cause a sustained rise in arterial blood pressure, significant, sustained, and dose-dependent increases in arterial blood pressure were observed real. Similar results were observed with ET-3 despite the fact that large doses were required (Mortenson LH., Et al., "Chronic hypertension produced by infusion of endothelin in rats" Hypertension, 1990; 15: 729). Recently, the non-peptide endothelin antagonist RO 46-2005 has been reported as effective in models of acute renal ischemia and subarachnoid hemorrhages in rats (3rd International Conference on Endothelin, Houston, Texas, February 1993). In addition, the ETA antagonist BQ-153 has also been shown to prevent early cerebral vasospasms after subarachnoid hemorrhages after intracisternal injection (Clozel M., et al., Life Sciences 1993; 52: 825); prevents increases in pressure in spontaneously hypertensive rats with probabilities of attacks (Nishibike M., et al., Life Sciences, 1993; 52: 717); and attenuate the renal vascular effects of ET-1 in anesthetized pigs (Cirino M., et al., J. Pharm Pharmacol 1992; 44: 782).

Levels of plasma endothelin-1 increased dramatically in a patient with malignant hemangioendothelioma (Nakagawa K., et al., Nippon Hifuka Gakkai Zasshi, 1990; 100: 1453).

The ET BQ-123 receptor antagonist has been shown to block ET-1-induced bronchoconstriction and contraction of mild tracheal muscles in allergic sheep, which provides evidence of efficacy expected in bronchopulmonary diseases such as asthma (Noguchi, et al. , Am Rev Respir Dis 1992; 145 (4 part 2): A858).

Circulating endothelin levels rise in women with preclamias and correlate closely with serum uric acid levels and renal dysfunction measures. These observations indicate a role of ET in renal constriction in preclamias (Clark BA, et al., Am. J. Obstet Gynecol, 1992; 166: 962).

Plasma immunoreactive endothelin-1 concentrations are elevated in patients with sepsis and correlated with the degree of disease and depression of cardiac output (Pittett J., et al., Ann. Surg., 1991; 213 (3): 261).

In addition, the ET-1 antagonist BQ-123 has been evaluated in a mouse model of endotoxic attack. This ETA antagonist significantly increased the survival rate in this model (Toshiaki M., et al., 20.12.90, EP 0 436 189 Al).

Endothelin is a potent agonist in the liver that causes both vasoconstriction of the hepatic vasculature and a significant increase in hepatic glucose output (Gandhi CB., Et al., J. Biol. Chem., 1990; 265 (29 ): 17432). In streptozotocindiabetic rats, there is an increased sensitivity to endothelin-1 (Tammesild PJ., Et al., Clin Exp Pharmacol Physiol., 1992; 19 (4): 261). In addition, increased plasma ET-1 levels have been observed in patients with diabetes mellitus dependent on microalbuminuric insulin, which indicates a role for ET in endocrine disorders such as diabetes (Collier A., et al., Diabetes Care 1992; 15 (8): 1038).

It has been found that blockade of the ETA antagonist receptor produces an antihypertensive effect in normal to low renal models and hypertension with a time course similar to the inhibition of ET-1 pressor responses (Basil MK., Et al., J. Hypertension 1992; 10 (Suppl 4): S49). Endothelins have been shown to be arrhythmogenic and have positive chronotropic and inotropic effects, thus blockage of the ET receptor would be expected to be useful in arrhythmia and other cardiac disorders (Han S-P, et al., Life Sci., 1990; 46: 767).

The broad localization of endothelins and their receptors in the central nervous system and cerebrovascular circulation have been described (Nikolov RK., Et al., Drugs today 1992; 28 (5): 303). Intracerebroventricular administration of ET-1 in rats has been shown to invoke effects on behavior. These factors strongly suggest a role for endothelin in neurological disorders. The potent vasoconstrictor action of ETs in isolated cerebral arterioles suggests the importance of these peptides in the regulation of cerebrovascular tone. Increased levels of ET have been reported in some CNS disorders, that is, in the CSFs of patients with subarachnoid hemorrhages and in the plasma of women with preclaimsia. Stimulation with ET-3 under hypoglycemic conditions has been shown to accelerate the development of striatal damage as a result of an influx of extracellular calcium. It has been suggested that circulating or locally produced ET contributes to the circulation of brain fluid balance through effects on the choroidal plexus and the production of CSF. The development of lesions induced by ET-1 in a new model of local ischemia in the brain has been described.

The immunoreactivity of circulating and tissue endothelin increases by more than two in patients with advanced atherosclerosis (Lerman A., et al., New England J Med., 1991; 325: 997). The increased immunotherability of endothelin has also been associated with Buerger's disease (Kanno K., et al., J. Amer Med Assoc 1990; 264: 2868) and Raynaud's phenomenon (Zamora MR., Et al., Lancet 1990; 336: 1144). Similarly, higher concentrations of endothelin were observed in hypercholesterolemic rats (Horio T., et al., Atherosclerosis 1991; 89: 239).

An increase in circulating endothelin levels was observed in patients who underwent percutaneous transluminal coronary angioplasty (PTC A) Tahara A., et al., Metab Clin Exp 1991; 40: 1235; Sanjay K., et al., Circulation 1991; 84 (Su? 4): 726).

The highest levels of endothelin plasma have been measured in rats (Stelzner TJ., Et al., Am J Physiol 1992; 262: L614) and humans (Myyauchi T, et al., Jpn J Pharmaciol 1992; 58: 279P: Stewart DJ., Et al., Ann Internal Medicine 1991; 114: 464) with pulmonary hypertension.

High levels of endothelin have also been measured in patients suffering from ischemic heart disease (Yasuda M., et al., Amer heart J 1990; 119: 801; Ray SG., Et al., Br Heart J 1992; 67: 383) and stable or unstable angina (Stewart JT., Et al., Br Heart J, 1991; 66: 7).

Infusion of an endothelin antibody 1 hour before and 1 hour after a 60 minute period of renal ischemia that results in changes in renal function against control. In addition, an increase in glomerular platelet activation factor was attributed to endothelin (Lopez-Farre A., et al., J Physiology 1991; 444: 513-). In patients with chronic renal failure as well as in patients undergoing regular hemodialysis, actual plasma endothelin levels increased significantly (Stockenhuber F., et al., Clin Sci (London) 1992; 82: 255). In addition, it has been suggested that the proliferative effect of endothelin on mesangial cells may be a contributing factor in chronic renal failure (Schultz PJ., J Lab Clin Med 1992; 119: 448).

Also, Haleen, S., et al., Faseb J., April 1994, demonstrated the efficacy of an ETA ETB antagonist, PD 145065, which essentially also blocks all ET function (similar to an ECE inhibitor) in a model. Severe acute renal failure.

The effects of blockade of the endothelin receptor on acute renal failure and mortality induced by ischemia were evaluated in rats suffering from unilateral nephrectomy and global ischemia in the remaining kidney. Male Sprague Dawley rats were housed (300-400 g) metabolic cages for 2 days before and 7 days after the kidney injury; urine output and plasma creatinine levels were monitored daily. On the day of the kidney injury, the rats were anesthetized with sodium pentobarbital (50 mg / kg, LP), heparanized (50 units, IV) and instrumented with a tail vein cannula for drug or vehicle infusion. Both kidneys were exposed via an incision in the flank and the right kidney was removed. The left renal artery was squeezed for 60 minutes and released. PD 145065 was infused 60 minutes before and after the ischemic period. The renal lesion was evident 1 and 2 days after the ischemia from a ten-fold increase in plasma creatinine levels and significant decreases in urine output. Mortality occurred first between the second and third days after the injury. However, mortality was significantly lower (52%, N = 23) in rats treated with PD 145065 compared to vehicle rats (83%, N-23). In addition, the urine output on the second day after the kidney injury was significantly different between the treatment groups on any of the first and second days after the injury. Thus blockade of endothelin receptors with PD 145065 significantly decreases mortality in rats subject to renal failure induced by ischemia.

It has been shown that local intra-arterial administration of endothelin induces little damage to the intestinal mucosa in rats in a dose-dependent manner (Mirua S., et al., Digestion 1991; 48: 163). The administration of endothelin-1 in the range of 50-500 pmol / kg within the left gastric artery increased the release of tissue-type plasminogen activator and platelet-activating formation and induced gastric mucosal hemorrhagic change in a manner dependent on dose (Kurose I., et al., GUT 1992; 33: 868). Furthermore, it has been shown that an anti-ET-1 antibody reduced the vasoconstriction induced by ethanol in a concentration-dependent manner (Masuda E., et al., Am J Physiol 1992; 262: G785). Elevated endothelin levels have been observed in patients suffering from Crohn's disease and ulcerative colitis (Murch SR., Et al., Lancet 1992; 339: 381).

Additionally, there is a correlation between the inhibition of ECE in an in vitro assay, as used and described for the quinazolines of the present invention and the demonstration of in vivo activity in various pathophysiological conditions. For example, Grover G.J., et al., J. Pharmacol. Exp. Ther. 1992; 263, 1074-1082, tested the effect of phosphoramidon, an ECE inhibitor, in a rat model of ischemia. Thus, Grover G.J., et al., Determined the effect of endothelin (ET-1) and large ET-1 on coronary flow and concentration function in hearts of isolated non-ischemic and ischemic rats. Both ET-1 (IC50 = 12 pMol) and large ET-1 (IC50 = 2 nMol) reduced coronary flow in a concentration-dependent manner. Both treatments with ET-1 of 30 pMOL and large ET-1 of 10 nMol significantly reduced the contraction time in globally ischemic rat hearts, suggesting a proischemic effect. Phosphoramidon (IC50 = 100 μM) and BQ-123 (0.3 μM, ETA receptor antagonist) abolished the preischemic increase in coronary perfusion pressure by large ET-1 as well as its proischemic effect. Phosphoramidon was also given IV to rats subject to infarct sizes significantly reduced 24 hours post-ischemia. Phosphoramidon has been reported to be an effective ECE inhibitor. IC50 - lμM, (Published European Patent Application EP 0518299 and Published InternatioPatent Application WO 92/13944).

Depending on the nature of the appended substitutes, quinazolines have been described, for example, as fungicides, insecticides, bronchodilators, hypotensive agents, aesics and active against trachoma virus. See, for example, German patents 1,800,709, 4,208,254, the description of the United Kingdom patent 1,199,768, US patents 3,340,260, United Kingdom patent 857,362, Patterson, S.E., et al., J. Heterocycl. Chem (1992) 29 (4), 703-6, Brown D.J., et al., Aust. J. Chem (1985) 38 (3) 467-74, Genther, C.S., et al., J. Med. Chem. (1977), 20 (2), 237-43 and the Russian patent SU-466,233. European Patent Publication No. 057946A1 also discloses 4-aminoquinazolines which have an inhibitory effect on cGMP-PDE or additioy synthetase TXA2. The inhibition of cGMP-PDE is considered useful in diseases induced by increases in the metabolism of cGMP, such as hypertension, heart failure, myocardial infarction, angina, atherosclerosis, cardiac edema, pulmonary hypertension, refailure, nephrotic edema, hepatis edema, asthma, bronchitis, dementia and immunodeficiency. The inhibition of thromboxane A2 (TXA2) synthetase is said to be useful for inflammation, hypertension, thrombosis, arteriosclerosis, cerebral stroke, asthma, myocardial infarction, cardiostenosis and cerebral infarction.

It has now been discovered that certain known and novel quinazolin derivatives possess a new property not previously reported for this class of compounds, which are inhibitors of the endothelin-converting enzyme. The endothelin compounds of the present invention are thus useful in the treatment of diseases associated with high levels of endothelin as mentioned above.

SUMMARY OF THE INVENTION According to the foregoing, the present invention is a compound of Formula I: where A is N, CH or S (0) n where n is 0, 1 or 2; R is lower alkyl, lower halo alkyl, aryl lower aryl alkyl, heteroaryl or lower heteroaryl alkyl; Ri is hydroxyalkyl containing at least 2 carbon atoms when A is N or S, lower alkoxyalkyl, thioalkyl containing at least 2 carbon atoms when A is N or S, thioalkyl lower alkyl, carboxyalkyl, an aminoalkyl group R7-Rs in wherein R and Rg are each independently hydrogen, or less alkyl or when taken together with amino form a saturated 5- to 7-membered heterocyclic chain optioy interrupted by a second heteroatom chosen from nitrogen, oxygen and sulfur and where the heteroatom is nitrogen , said nitrogen atom can be substituted with alkyl, carboxyalkyl, or carboxyalkyl lower alkyl and wherein said chain can be further substituted at a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, diaqylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, wherein the alkyl portion of the Ri groups defined above can be further substituted in the alkyl chain by aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl , alkylcarboxylalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl or alkoxyalkyl, a saturated or monounsaturated carbocyclic chain of 5 to 7 members optionally fused to a benzene chain or a 6,6-membered bicyclic carbocyclic chain, said chains attached directly to A or by a group alkyl, or a saturated 5- to 7-membered heterocyclic chain optionally fused to a benzene chain, having at least 1 heteroatom, wherein said chain is directly attached with A or through an alkyl group linking A with the chain in an atom of carbon, said chains are subst optionally with alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxylalkyl, thio, thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, OR9 wherein R9 is hydrogen or lower alkyl, NR9R10 wherein Ra and Rio are each independently hydrogen or lower alkyl, CO2R9 wherein R is as defined above, when A is N, a lower alkyl side chain carboxy of a natural or unnatural a-amino acid or; when A is S and n is zero, a hydrogen atom; R2 is absent when A is S, a hydrogen atom or lower alkyl and when A is N, Ri and R2 can be combined together to form a 5- or 6- membered saturated chain optionally containing an additional nitrogen atom in the chain in the 3- or 4- position and the additional nitrogen atom can optionally be replaced by alkyl, carboxyalkyl or lower alkylcarboxyalkyl and the chain can be further substituted in a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl; R3, R4, R5RR are each independently hydrogen, halo, lower alkyl, cycloalkyl, lower haloalkyl, minor alkoxy, hydroxyalkyl, aminoalkyl, aminoalkyl lower alkyl, aminoalkyl lower alkyl, nitro, cyano, S02NRnR? 2, SO2R9, CO2R9, CONR? R? 2, NRuR? 2 in which Rn and R? 2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl, or two of the adjacent members of R3 to Re can be combined together to form a methylenedioxy group and ethylenedioxy group or a benzene chain or a pharmaceutically acceptable acid addition or basic salt thereof of the same; with the following provisions: (a) when A is N and Ri is aminoalkyl, aminoalkyl lower alkyl, aminoalkyl lower alkyl or hydroxyalkyl, then R4 is iodo or R5 is lower haloalkyl; (b) when A is N and Ri is pyrrolidine optionally substituted by alkyl or minor carboxy alkyl and R3 and R§ are as defined above, then R is lower halo alkyl, aryl, minor aryl alkyl, heteroaryl or lower heteroaryl alkyl and ( c) when A is N, R3 and Re are as defined above and Ri and R2 with form a piperazine chain, then R is aryl, aryl lower alkyl, heteroaryl or heteroaryl lower alkyl or when, in addition, R4 is halo, R can be lower halo alkyl.

Since elevated levels of endothelin have been shown to be involved in a number of pathophysiological states, a second aspect of the present invention is a method for treating diseases associated with high levels of endothelin comprising administration to a host suffering therefrom. therapeutically effective amount of an endothelin-converting enzyme inhibitor of the Formula I where A is N, CH or S (0) "where n is 0, 1 or 2; R is lower alkyl, lower halo alkyl, aryl lower aryl alkyl, heteroaryl or lower heteroaryl alkyl; Ri is hydroxyalkyl containing at least 2 carbon atoms when A is N or S, lower alkoxyalkyl, thioalkyl containing at least 2 carbon atoms when A is N or S, thioalkyl lower alkyl, carboxyalkyl, an aminoalkyl group R7-Rg in wherein R7 and Rg are each independently hydrogen, or less alkyl or when taken together with amino form a saturated 5- to 7-membered heterocyclic chain optionally interrupted by a second heteroatom chosen from nitrogen, oxygen and sulfur and where the heteroatom is nitrogen , said nitrogen atom can be substituted with alkyl, carboxyalkyl, or carboxyalkyl lower alkyl and wherein said chain can be further substituted at a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, diaqylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, wherein the alkyl portion of the Ri-defined above can be further substituted in the alkyl chain by aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkylcarboxylalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl or alkoxyalkyl, a saturated or monounsaturated carbocyclic chain of 5-7 membered optionally fused to a benzene chain or a 6,6-membered bicyclic carbocyclic chain, said chains attached directly with A or by an alkyl group, or a 5- to 7-membered saturated heterocyclic chain optionally fused to a benzene chain, having at least 1 heteroatom, wherein said chain is directly attached with A or through an alkyl group linking A with the chain on a carbon atom, said chains are optionally substituted with alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxylalkyl, thio, thioalkyl, alkylthioalkyl , hydroxy, hydroxy alkyl, alkoxy or alkoxyalkyl, OR9 wherein R9 is hydrogen or lower alkyl, NR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl, C02R9 wherein R9 is as defined above, when A is N, a side chain of lower alkyl carboxy of a natural or non-natural a-amino acid or; when A is S and n is zero, a hydrogen atom; R2 is absent when A is S, a hydrogen atom or lower alkyl and when A is N, Ri and R2 can be combined together to form a 5- or 6- membered saturated chain which optionally contains an additional nitrogen atom in the chain in the 3- position. 4- and the additional nitrogen atom can optionally be replaced by alkyl, carboxyalkyl or lower alkylcarboxalkyl and the chain can be further substituted at a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio , thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl; R3, R4, RsRR are each independently hydrogen, halo, lower alkyl, cycloalkyl, lower haloalkyl, minor alkoxy, hydroxyalkyl, aminoalkyl, aminoalkyl lower alkyl, aminoalkyl lower alkyl, nitro, cyano, S? 2NRpR? 2, SO2R9, C02R9, CONRnRp, NRpR? 2 in which Rn and Ri2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl, or two of the adjacent members of R3 to Re can be combined together to form a methylenedioxy group and ethylenedioxy group or a benzene chain or a pharmaceutically acceptable acid addition or base salt thereof.

These diseases include acute and chronic renal failure, hypertension, myocardial infarction and myocardial ischemia, cerebral vasospasm, cirrhosis, septic seizures, congestive heart failure, endotoxic attacks, subarachnoid hemorrhages, arrhythmias, asthma, preclaimsia, atherosclerosis disorders, including Raynaud's disease. and restenosis, angina, cancer, pulmonary hypertension, ischemic diseases, damage to the gastric mucosa, hemorrhagic attacks, ischemic bowel disease, diabetes, cerebral ischaemia or cerebral infarction resulting from a variety of conditions such as thromboembolic or hemorrhagic attacks, vasospasm cerebral, head injuries, hypoglycemia, heart attacks, epileptic states, perinatal asphyxia, anoxia as a result of drowning, lung surgery and brain trauma.

A third aspect of the present invention is a pharmaceutical composition for administering an effective amount of a compound of Formula I in admixture with a pharmaceutically acceptable carrier in the above-mentioned treatment methods in the form of dose per unit.

DETAILED DESCRIPTION OF THE INVENTION In the compounds of the present invention, the term "alkyl", in general and unless specifically limited, means a straight or branched hydrocarbon radical having from 1 to 12 carbon atoms and includes, for example , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl , dodecil and similar. The term "alkyl" also has the same meaning when used as a suffix for "aminoalkyl", "hydroxyalkyl", "thioalkyl", "carboxyalkyl" and the like.

The term "minor" that precedes "alkyl" means only those straight or branched hydrocarbon radicals defined above having from 1 to 7 carbon atoms.

The term "alkoxy" is 0-alkyl as defined above for alkyl or minor alkyl.

The term "aryl" means an aromatic radical that is a phenyl group, a naphthyl group, a biphenyl group, a pyrenic group, an anthracenyl group, 3,3-diphenylalanyl, 10, l-dihydro-5H-dibenzo- [a , d] - (cyclohepten-5-yl) glycyl or a fluorenyl group and the like, unsubstituted or substituted by from 1 to 4 minor alkyl substituted substitutes as defined above, lower alkoxy as defined above, trifluoromethyl, nitro, halogen , CN, S03H, S02NH2, S02CH, COOH, lower COO alkyl, CONH2, lower alkyl, NH2, lower alkyl, N, N-di minor, aralkyl NH-, aralkyl N-di-, alkyl- N, N- lower aralkyl, in which aralkyl is as defined below.

The term "arylalkyl" or "aralkyl" means an aromatic radical attached to an alkyl radical wherein aryl and alkyl are as defined above, for example, benzyl, fluorenylmethyl and the like.

The term "heteroaryl" means a heteroaromatic radical including 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4-. or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridinyl, 3-, 4- or 5-pyridazinyl, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, N-formyl-1-, 3-, 4-, 5-, 6-, 7-indolyl, 2-, 3-, 4-, 5-, 6-, 7-benzo [b] thienyl or 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7- benzimidazolyl, 2-, 4-, 5-, 6-, 7-benzothiazolyl, unsubstituted or substituted by 1 or 2 substitutes chosen from those defined above for aryl.

"Halogen" or "halo" is fluorine, chlorine, bromine or iodine.

A "5- to 7-membered saturated heterocyclic chain optionally interrupted by a second hetero atom chosen from nitrogen, oxygen and sulfur" includes, for example, pyrrolidine, pyrrazolidine, imidazolidine, oxazolidine, thiaoxazolidine, piperidine, piperazine, morpholine, thiamorpholine, homopiperidine and the like . When the second nitrogen atom is, for example, an imidazolidine or piperazine, said second nitrogen atom can be replaced by lower alkyl, carboxyalkyl or carboxyalkyl. The carbon atoms of the above 5- to 7-membered heterocyclic chain can be independently substituted by alkyl, amino, aminoalkyl, ammonioalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl.

For the purposes of the present invention, the above definitions apply to the compounds of the formula I wherein Ri is R Rg aminoalkyl and wherein R and Rg are taken together with the nitrogen atom. Said nitrogen atom is bound to "A" in Formula I.

A "saturated or monosaturated 5 to 7 membered carbocyclic chain optionally fused to a benzene chain" includes, for example, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, indane, tetralin and benzosuberane.

"Bicyclic carbocyclic chains of 5,6 or 6,6-members" include, for example, bicyclo [3.2.1] octane or bicyclo [2.2.2] octane.

The carbocyclic and heterocyclic chains defined above come under the definition of Ri in the compounds of Formula I and, as such, are radicals wherein a carbon atom of said chain is directly linked to "A" of the formula loa through an alkyl chain linking the chain at a carbon atom with "TO".

The above-defined carbocyclic and heterocyclic chains can be optionally substituted on a carbon chain atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl.

The following table provides a representative list of natural and modified or unsaturated amino acids with the abbreviations used in the present invention.

Abbreviation Amino Acid Ala Alanine Arg Arginine Asn Asparagine Asp Aspartic Acid Cys Cysteine Glu Glutamic Acid Gln Glutamine Gly Glycine His Histidine He Isoleucine Leu Leucine Lys Lysine Met Methionine Phe Phenylalanine Pro Proline Ser Serine Thr Threonine Trp Tryptofan Tyr Tyrosine Val Valine * If the optical activity of the amino acid is different from L (S), the amino acid or abbreviation is preceded by the appropriate configuration D (R) or DL (RS).

Abbreviation Amino Modified and Non-Natural Acid Nva Norvaline Nle Norleucine Alg 2-amino-4-pentanoic acid (aliglicine) Cpn 2-amino-3-cyclopropane propane acid (Cyclopropylalanine) Chx Cyclohexylalanine (Hexahydrophenylalanine) His (Dnp) Nim-2,4-Dinitrophenyl-histidine HomoPhe 2-amino-5-phenylpentanoic acid (homophenylalanine) I-Nal 3- (1-Naphthyl) alanine 2-Nal 3- (2 ' -Naphthyl) alanine Pgy 2-aminopentanoic acid (propylglycine) Pyr 2-amino-3- (3-pyridyl) -propanoic acid Tza 2-amino-3- (4-thiazolyl) -propanoic acid Tyr (Ot-Bu) Butyltyrosine O -tertiary Tyr (OMe) O-methyltyrosine Tyr (OEt) O-ethyltyrosine Trp (For) N? n-formyltriptofan His (t-Bu) Butylhistidine His (Cf3) Nim-triphenylmethyl-histidine (Nim-tritylhistidine) Trp (Me) N-methyltriptofan Asp (Ot-Bu) 4-tertiary butyl ester of aspartic acid Asp (OMe) 4-methyl ester of aspartic acid Asp (OBn) 4-benzyl ester of aspartic acid Glu (Ot-Bu) Butyl ester 5- tertiary glutamic acid Glu (OMe) 5-methyl glutamic acid ester Bta 3-Benzothienyl alanine Bfa 3-Benzofuranyl alanine * If the optical activity of the amino acid is different from L (S), the amino acid or abbreviation is preceded by the appropriate configuration D (R) or DL (RS).

The compounds of Formula I are also capable of forming both basic salts and / or pharmaceutically acceptable acid addition. All these forms are within the scope of the present invention.

The pharmaceutically acceptable acid addition salts of the compounds of the Formula I include salts derived from non-toxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous and the like as well as salts derived from non-toxic organic acids such as acids mono- and dicarboxylic aliphatics, alkane acids substituted with phenyl, hydroxy acids alkanoic acids, alkanedioic acids, aromatic acids, aliphatic sulfonic acids and aromatics, etc. Said salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate, n-methyl glucamine (see, for example, SM Berge, et al, "Pharmaceutical Salts" Journal of Pharmaceutical Science 66, 1-19 (1977) ): The acid addition salts of said basic compounds are prepared by contacting the free base with a sufficient amount of the desired acid to produce the salt in the conventional manner. Preferably a compound of Formula I can be converted to an acidic salt by treating it with an aqueous solution of the desired acid, so that the resulting pH is less than 4. The solution can be passed through a C18 cartridge to absorb the compound, wash with copious amounts of water, the compound eluted with a polar organic solvent such as, for example, methanol, acetonitrile and the like and be isolated by concentration under reduced pressure by lysis. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner or as above. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free bases for the purposes of the present invention.

The pharmaceutically acceptable basic addition salts are formed with metals or amines, such as the alkali and alkali metals or organic amines. Examples of the metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are N-N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine (see, for example, S.M.

Berge, et al., "Pharmaceutical Sales", Journal of Pharmaceutical Science 66, 1-19 (1977)).

The basic addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. Preferably, a compound of Formula I can be converted to a base salt by treating it with an aqueous solution of the desired base, so that the resulting pH is greater than 9. The solution can be passed through a C18 cartridge to absorb the compound, wash with copious amounts of water, elute the compound with an organic polar solvent such as, for example, methanol, acetonitrile and the like, and isolate by concentration under reduced pressure followed by lyophilization. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner or as above. The free acid forms differ from their respective salt forms somewhat in certain physical characteristics such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acids for the purposes of the present invention.

Certain compounds of the present invention can exist in undissolved forms as well as dissolved forms, including hydrated forms. In general, dissolved forms, including hydrated forms, are equivalent to undissolved forms and are intended to be within the scope of the present invention.

Certain compounds of the present invention possess one or more chiral centers and each center may exist in the R (D) or S (L) configuration. The present invention includes all enantiomeric and epimeric forms as well as appropriate mixtures thereof.

Of the above compounds of Formula I, those which are preferred are: (1) wherein A is N; (2) wherein Ri is aminoalkyl, aminoalkyl lower alkyl, alkylaminoalkyl dimenor, hydroxyalkyl or thioalkyl and R is lower halo alkyl and (3) wherein R4 is iodo and / or R5 is halo. other preferred compounds are the compounds of Formula II: II wherein R13 and Ri4 are each independently hydrogen, alkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkylcarboxyalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl or alkoxyalkyl; n 'is O, 1, 2 or 3 and R, R2, R3, R4, R5, Re, 7 and e are as defined above, provided that when R7 and R "are each independently hydrogen or lower alkyl and R3 and R they are hydrogen, then R4 is iodine or R5 is halo and R is lower halo alkyl.

Particularly valuable compounds of Formula I are, for example, N- (6-iodo-2-trichloromethyl-quinazoline-4-yl) -ethane-1,2-diamine, N- (6-iodo-2-trichloromethyl- quinazolin-4-yl) -N-methyl-ethane-1,2-diamine, N- (6-iodo-2-trichloromethyl-quinazoline-4-yl) -N ', N'-dimethyl-ethane-1, 2 -diamine, N- (7-chloro-2-trichloromethyl-quinazoline-4-yl) -N'.N'-diisopropyl-ethane-1,2-diamine, (6-iodo-2-trichloromethyl-quinazoline-4-) il) - (2-piperidine-1-ethyl-ethyl) -amine, (6-iodo-2-trichloromethyl-quinazoline-4-yl) - (2-morpholine-4-yl-ethyl) -amine and N'- (6-iodo-2-trichloromethyl-quinazoline-4-yl) -N, N, N ", N" -tetramethyl-propane-1,2,3-triamine Another preferred aspect of the present invention is a compound of Formula III III where A is N, CH or S (0) n where n is 0, 1 or 2; and q is 0, 1 or 2; (a) B, C, D and E are CH2 or NR in which only one of B, C, D or E is NRi3 wherein R? 3 is hydrogen, minor alkyl, aralkyl, - (CH2) mC02R9 in which Rg is hydrogen or lower alkyl or - (CH2) mNR9R? Or in which R9 and Ri0 are each independently hydrogen or lower alkyl and m is integer from 0 to 6, p is an integer from 0 to 2 and r is an integer of 0 up to 2 or (b) A is N, C, D and E are absent, p is 0 and B is NR? 3 or -CH2NR? 3 and annexed to R2 to form a 5- or 6- member chain, in which R? 3 is as defined above; R is lower alkyl, lower halo alkyl, phenyl or phenyl substituted by lower alkyl, lower alkoxy, trifluoromethyl, halo, N02, CN, S03H, S02NH2, S02CH3, COOR9 in which R9 is hydrogen or lower alkyl, CONR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl or NRnR? 2 wherein Ru and R? 2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralalkyl or heteroaryl; R2 is absent when A is S, a hydrogen atom or lower alkyl; R3 and Re are each independently hydrogen, lower alkyl or lower alkoxy and R "and R5 are each independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, halo, N02, CN, S03H, S02NH2, S02CH3, COOR9 in the which R9 is hydrogen or lower alkyl, CONR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl or NRnR? wherein R n and R 2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl or R 4 and R 5 can be attached to form a methylenedioxy group or benzene chain or a pharmaceutically acceptable acid or basic addition salt thereof, with the following provisions: (i) when A is N, R3 to Re are as defined above and B, C, D and E are as defined in (a) above, then R is lower alkyl, phenyl or substituted phenyl as defined above or heteroaryl and (ii) when A is N, R3 to Rd are as defined above and B, C, D and E are as defined in (b) above, R is phenyl or substituted phenyl as defined above or heteroaryl or when, in addition, R »is halo, R may be lower halo alkyl.

Preferred compounds of Formula II are those that: (1) wherein A is N; (2) where C, D and E are absent; p is 0; B is NR? 3 or -CH2NRi3 and annex to R2 to form a 5- or 6- membered chain; R is phenyl or substituted phenyl or lower alkyl, lower alkoxy, trifluoromethyl, halo, N02, CN, S03H, S02NH2, S02CH3, COORg in which R9 is hydrogen or lower alkyl, CONR9R10 wherein R9 and R10 are each independently hydrogen or minor alkyl or NRnR? 2 wherein Rn and R? 2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl; or, alternatively wherein R 4 is halo and R is lower halo alkyl, for example, 6-iodo-4- (4-methyl-piperazin-1-yl) -2-trichloromethyl-quinazoline or 6-iodo-4-piperazin- 1 -yl-2-trichloromethyl-quinazoline.

Still another preferred aspect of the present invention is a compound of Formula III, wherein A is N, CH or S (0) "wherein n is 0, 1 or 2; B, C, D, E are CH2 or NR13 in which only one of B, C, D or E is NRi3 wherein R? 3 is hydrogen, lower alkyl, aralkyl, - (CH2) mC02R9 wherein R9 is hydrogen or minor alkyl or - (CH2) m-NR9R? or in which R9 and Rio are each independently hydrogen or lower alkyl and m is an integer from 0 to 6 and p is an integer from zero to 2; R is lower alkyl, lower halo alkyl, phenyl or phenyl substituted by lower alkyl, lower alkoxy, trifluoromethyl, halo, N02, CN, S03H, S02NH2, S02CH3, COOR9 in which R9 is hydrogen or lower alkyl, CONR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl or NRnR? 2 wherein Rp and Ri2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl or heteroaryl; R2 is absent when A is S, a hydrogen atom or lower alkyl; R3 and Re are each independently hydrogen, lower alkyl or lower alkoxy and R4 and R5 are each independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, halo, N02, CN, S03H, S02NH2, S02CH3, COOR9 in which R9 is hydrogen or lower alkyl, CONR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl or NRnR? 2 wherein Rn and R? 2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl or R4 and R5 can be join together to form a methylenedioxy group or a benzene chain or an acid or pharmaceutically acceptable basic addition salt thereof, provided that when A is N and p is 0, R is lower halo alkyl, phenyl or substituted phenyl as defined above or heteroaryl.

Still another preferred specimen is a compound of Formula III where A is N, B, D and E are CH2, C is N, p is 1, q is 0 and r is 2, which is (l-aza-bicyclo [2 , 2,2] oct-3-yl) - (6-iodo-2-trichloromethyl-quinazoline-4-yl) -amine.

A more preferred aspect of the present invention is a compound of Formula IV: where q is 0, 1 or 2 and p is 0 or 1; R is lower alkyl, lower halo alkyl, phenyl or phenyl substituted by lower alkyl, minor alkoxy, trifluoromethyl, halo, N02, CN, SO3H, S02NH2, S02CH3, COOR9 in which R9 is hydrogen or lower alkyl, CONR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl or NRpR? 2 wherein Rp and R? 2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl or heteroaryl; R 2 is a hydrogen atom or lower alkyl; R3 and Re are each independently hydrogen, lower alkyl or lower alkoxy and R4 and Rs are each independently hydrogen, lower alkyl, minor alkoxy, trifluoromethyl, halo, N02, S03H, S02NH2, S02CH3, COOR9 in which R9 is hydrogen or lower alkyl, CONR9R10 wherein R9 and Rio are each independently hydrogen or minor alkyl or NRnRp wherein R n and R 2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl or R 4 and R 6 can be joined to form a methylenedioxy group or a benzene chain; R7 is hydrogen, lower alkyl, aralkyl, - (CH2) m-NR9R? Or in which R9 and Rio are each independently hydrogen or lower alkyl and m is an integer of 1 to 6 or a pharmaceutically acceptable salt of acid or basic addition thereof; provided that when p is 0, q is 1 or 2.

The most preferred compounds of Formula IV are those in which Rt and R5 are each independently hydrogen, trifluoromethyl, halo, N02, CN, SO3H, S02NH2, S02CH3, COOR9 in which R9 is hydrogen or lower alkyl or CONR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl and R is lower alkyl, lower halo alkyl, phenyl or phenyl substituted by lower alkyl, lower alkoxy or halo.

The most preferred compounds of Formula IV are those in which R 4 and R 5 are each independently hydrogen, halo or N 0 and R is lower halo alkyl.

Particularly valuable compounds of Formula III are: (1-ethyl-piperidin-3-yl) - (6-iodo-2-p-tolyl-quinazolin-4-yl) -amine (1-ethyl-piperidin-3 - il) - (6-iodo-2- (4-methoxy-phenyl) -quinazolin-4-yl) -amine [2- (4-chloro-phenyl) -6-iodo-quinazoline-4-yl] - (l -ethyl-piperidin-3-yl) -amine [2-tert-butyl-6-iodo-quinazoline-4-yl) - (1-ethyl-piperidin-3-yl) -amine (1-ethyl-piperidin-3) -yl) - (6-iodo-2-phenyl-quinazoline-4-yl) -amine (1-ethyl-piperidin-3-yl) - (6-iodo-2-trichloromethyl-quinazoline-4-yl) -amine [3 - (6-iodo-2-trichloromethyl-quinazoline-ylamine) -piperidin-1-yl] -acetic acid-l-ethyl-piperidin-3-yl) - (6-chloro-2-trichloromethyl-quinazoline-4-yl) ) -amine l-ethyl-piperidin-3-yl) - (6-nitro-2-trichloromethyl-quinazoline-4-yl) -amine 1-ethyl-piperidin-3-yl) - (2-trichloromethyl-quinazoline-4) -yl) -amino-l-ethyl-piperidin-3-yl) - (7-chloro-2-trichloromethyl-quinazoline-4-yl) -amine (1-ethyl-piperidin-3-yl) - (6-iodo- 2-trifluoromethyl-quinazolin-4-yl) -amine and (l-ethyl-pyrrolidin-2-yl-methyl) - (6-iodo-2-trichloride romethyl-quinazolin-4-yl) -amine.

The compounds of the present invention are valuable inhibitors of the endothelin-converting enzyme. The tests used indicate that said compounds possess inhibitory activity towards an endothelin-converting enzyme.

MONITORING OF THE INHIBITORS OF THE ENDOTHELIN CONVERTER ENZYME (ECE) Cell Culture A permanent human cell line (EA.hy926), derived by fusing human umbilical vein endothelial cells with the permanent human cell line A549 (derived from a human lung carcinoma) was cultured as it is described, except that the medium also contained HAT supplements (100 μM hypoxanthine, 0.4 μM aminopterin, 16 μM thymidine). Edgell, C.-J.S., McDonald, C.C. and Graham, J.B. (1983) Proc. Nati Acad. Sci. USA 80, 3734-3737. Cells from passages 40 to 50 were used. Subcultures were prepared by treating confluent cells with trypsin ((0.5%) and sowing them either on 24-well platforms for a cell-based assay or roller bottles for a partial purification of the enzyme.

Partial Purification of ECE from EA.hy926 All operations were carried out at 0-4 ° C unless noted otherwise. The cells in each roller bottle were washed with phosphate buffered saline and gently scraped. These cells were further washed with phosphate-buffered saline followed by 10 mM Tris-HCl, pH 7.5 / 0.25 M sucrose 20 mM KC1 (regulator A) and immediately frozen in liquid nitrogen. Cells of 150 roller bottles were suspended in 100 ml of buffer A containing protease inhibitor cocktail (1 mM phenylmethylsulfonyl fluoride / 0.5 mM pepstatin A / 0.1 mM leupeptin) and homogenized via nitrogen cavitation (600 psi, 10 minutes) and centrifuged at ,000 x g for 20 minutes. This process was repeated with the palette resuspended in 100 ml of regulator A containing cocktail of protease inhibitors. The combined supernatant was then centrifuged at 20,000 x g for 35 minutes. The resulting supernatant was further centrifuged at 100,000 x g for 1 hour. The paddle was washed with 120 ml of 20 mM Tris-HCl, pH 7.5 / 0.02% NaN3 (regulator B), was resuspended in 40 ml of regulator B containing 0.5% Triton X-100 (hydrogenated) and cocktail of protease inhibitors and gently stirred for 1 hour (fraction membrane). The clear supernatant was obtained by centrifugation at 100, 000 x g for 1 hour (detergent extract). For the Ricinus communis agglutinin chromatography (RC AI), the detergent extract was applied at a flow rate of 0.15 ml / minute on a 4 ml RCA-I column (0.5 x 20 cm) equilibrated with 50 mM Tris-HCl , pH 7.2 / 50 mM NaCl 0.02% NaN3 / 0.2 triton X-100 (hydrogenated) (regulator C) including cocktail of protease inhibitors. The column was washed with the equilibrium regulator until A2 onm of the eluate was less than 0.03 and the activity was eluted with buffer C containing 0.5 M galactose at a flow rate of 0.15 ml / minute. Fractions of 4 ml were collected and maximum fractions were pooled (RCA-I fraction, 20 ml) (See Table II).

The above procedure produced 35.6-fold purification of ECE from the membrane fraction (Table II) that was used to monitor the ECE inhibitors. This enzyme has an optimum neutral pH and is sensitive to phosphoramidon with an IC50 value of 1.8 μM. The enzyme is also inhibited by EDTA, EGTA and 1,10-phenanthroline but was not inhibited by pepstatin A, leupeptin, phenylmethylsulfonyl fluoride, sunflower triprione inhibitor, E-64, bestatin, captopril, enalprilat or thiorphan.

The cell line, EA.hy926, contains neutral endopeptidase 24.11 (NEP 24.11) which also divides the large ET-1 into ET-1 and C-terminal fragment (submitted manuscript). Therefore, for all ECE assays, 100 μM of thiorpan or 100 nM of phosphoramidon were added. Under these conditions, NEP 24.11 is completely inhibited without affecting the activity of ECE. All data were obtained in the linear range of the curves of the time course.

Table II. Partial Purification of ECE from EA.h 926a Fraction Volume Concentration of protein Activity Total specific activity mi (Absorbency (280 nm) total (unit of / mL / A28o unitsD m Membrane 40.0 0.902c 382 1.1 Extract of 39.4 0.387c 301 2.0 detergent RCA-I 20.0 0.386 275 35.6 a ECE was partially purified from EA.hy926 grown in 150 roller bottles to confluence. b One unit of enzyme is defined as the unit that generates 1 pmol of immunoreactive ET-1 (ir) per minute. c The illustrated Absorbency was measured after dissolution in ten points.

ECE assay The assay measured the production of ET-1 essentially as described with minimal modifications. Ahn, K., Benigno, K., Olds, G. and Hupe, D. (1982) Proc. Nati Acad. Sci. USA 89, 8606-8610 The typical reaction mixture (50 μL) contained 10 μM large ET-1, 100 nM Hepes-KOH (pH 7.0), 0.25% Triton X-100, 0.01% NaN3, 0.1 mM of thiorfan, 0.2 mM of phenylmethylsulfonyl fluoride, 0.02 M of pepstatin A, 0.1 mM of leupeptin and the enzyme. To monitor the inhibitors, the indicated concentration of a drug (or DMSO for control) dissolved in DMSO was added and the final concentration of DMSO remained at 3%. After incubation for 1.5 hours at 37 aC, the reaction was stopped by the addition of EDTA to give a final concentration of 10 mM. This final mixture was diluted with 60 mM KP +, pH 7.4 / 10 mM EDTA / 8 mM NaN3 / 0.1% bovine serum albumin / 0.1% Tween 20/3% DMSO (regulator D) and the ET- 1 generated was measured by radioimmunoassay (RIA).

Radioimmunoassay (RIA) ET-1 was measured by radioimmunoassay (RIA) as previously described with minimal modifications. Ahn, K., Benigno, K., Olds, G. and Hupe, D. (1982) Proc. Nati Acad. Sci. USA 89, 8606-8610. Briefly, the RIA mixture (250 μl) contained the antibody against ET-1, a sample of ET-1 and [125I] ET-1 (1500 cpm) in regulator D. For the analysis of ET-1 of the assays based on cells, the final 6% bovine serum albumin was added. The order of the additions was the sample of ET-1, antibody and then [1 5I] ET-1. After incubating at 4 ° C for 16 hours, the unbound ET-1 was coprecipitated by the addition of carbon (2.4%, weight / volume) / dextran (0.24%, weight / volume) suspension (125 μl) in 60 mM of KP pH 7.4 / 10 mM EDTA 8 mM NaN3 / 0.25% gelatin (weight / volume). The amount of interactive ET-1 (ir) was measured by counting the supernatant and determined by the standard curve. Cross reactivity for the great ET-1 was less than 0.01% and the detection limit was 1 fmol.

HI table. Biological Activity of Compounds of the Present Invention Example Ic50 μM 1 4.2 ± 0.5 2 9.2 ± 0.8 3 14.1 ± 1.5 4 29.1 ± 5.4 5 17.6 ± 1.7 6 29.6 ± 6 7 22.1 ± 4.8 8 11.1 ± 2.7 9 3.7 ± 1.6 10 25.4 ± 4.2 11 12.4 ± 1 11.1 ± 12 1.7 66.6 ± 13 11.8 75.5 ± 14 11.6 15 11.1 ± 1.7 16 8.4 ± 1.4 17 2.3 ± 0.3 Procedure for a cell-based assay EAhy926 cells (0.2-4 x 104) were planted on platforms of 24 and cultured as described above. At a confluence of 90% -100%, the cells were washed with the same medium and were treated with medium containing drugs (or DMSO for control) in the indicated concentrations and 10 μM of phosphoramidon (for inhibition of NEP 24.11) (0.5 ml / well). The final concentration of DMSO for all the experiments was 0.5%. After After incubating for 18-24 hours, the medium was cooled and centrifuged at 10,000 x g for 5 minutes to remove cell debris. The resulting supernatant was used to measure the ET-1 through RIA. The ET-1 level of these samples was measured by RIA described previously. Ahn, K., Benigno, K., Olds, G. and Hupe, D. (1982) Proc. Nati Acad. Sci. USA 89, 8606-8610.

Table IV.

Example ICjo (μM) 6.6 ± 1.5 14.4 ± 1.1 The compounds of the present invention can be prepared generally as shows Scheme I. Even though Scheme I shows the preparation of the compounds where A is N, step (a) can also be carried out when A is CH or S (0) "as defined above.

SCHEME I (5) (1) Step (a) involves the reaction of an anthranilic acid derivative of the formula (1) with appropriately substituted imidates illustrated in formula (2) in ethanol or other hydroxylated solvents at elevated temperatures preferably between 50-70 ° C. The reaction is carried out for 8-24 hours preferably from 16 to 17 hours. The product, quinazoline 4-substituted one is shown in the formula (3) separated as a crystalline solid. The reaction mixture is cooled to below room temperature preferably between 0-5 ° C and filtered. The product is washed with water until neutral and air-dried.

Step (b) involves the reaction of the quinazoline-4-one illustrated in formula (3) with chlorinating agents such as phosphorus oxychloride, phosphorus pentachloride or thionyl chloride, preferably phosphorus oxychloride at elevated temperatures preferably at reflux for periods ranging from 6 to 20 hours, preferably 14 to 16 hours. The reaction mixture is cooled to room temperature and poured continuously onto broken ice under vigorous stirring and keeping it at temperatures below 5 ° C. The solid that separates is filtered and washed with water until neutral. The air-dried solid is extracted with inert solvents such as benzene, toluene or xylene, preferably toluene and filtered. The filtrate is evaporated in vacuo to give 4-chloro-quinazolines illustrated in formula (4).

Step (c) involves the reaction of 4-chloro-quinazolines illustrated in formula 84) with several primary or secondary amines (equivalents 1-2) in ethyl acetate, preferably diethyl ether at temperatures between 15-25 ° C, preferably at room temperature. environment for periods ranging from 16 to 24 hours, preferably 20 hours to give a suspension. The suspension is filtered to give 4-quinazolines illustrated in formula 85) as a solid. In some cases, the reaction mixture is poured into water and the product is extracted into ethyl acetate or chloroform, preferably ethyl acetate. The organic extracts are collected and dried over magnesium sulfate. The solvent is removed under vacuum and 4-aminoquinazolines (5) are isolated by chromatography, preferably silica gel using a mixture of petrolatum ether and ethyl acetate in the ratio of 8: 2 to 1: 1.

The anthranilic acids and the starting compounds of the formula (2) can be purchased commercially or prepared from commercially available materials by known methods.

Schemes II, III and IV illustrate preferred process routes for particular compounds of the present invention. However, these routes can also be used generally to prepare compounds of the present invention with certain limitations. For example, Scheme II illustrates a preferred route for compounds of the invention in general but where R is trichloromethyl. Scheme III can also be used generally but where R is lower halo alkyl, in this case, trifluoromethyl. Scheme IV illustrates the preferred route for compounds of Formula III starting with 3-aminopyridine.

SCHEME H ( 5 ) SCHEME (n í 9 SCHEME IV (10) (1 I) SCHEME V Scheme V illustrates an alternative route for the synthesis of 2-substituted 4-chloro-quinazoline.

Step (a) involves the reaction of an anthranilic acid derivative of Formula (1) with appropriately substituted anhydrides (2), in this case trifluoroacetate anhydride, in the presence of tertiary bases such as triethylamine at elevated temperatures preferably at reflux during 1-6 hours, preferably 2 hours. The volatile components are removed under reduced pressure and the residue is treated with an ether solvent such as diethyl ether and water. The ether layer is separated, dried with MgSO 4 and concentrated to give the benzo [d] [1,3] oxazine derivative. -4-one appropriate as the product.

Step (b) involves the reaction of benzo [d] [1,3] oxazine-4-one illustrated in Formula (3) with saturated ammonia water at elevated temperatures preferably at 40 ° C for 4-8 hours, preferably 5 hours. The reaction mixture is cooled below room temperature, preferably between 0 ° -5 ° C and the precipitate obtained, filtered and dried under reduced pressure (0.1 - 0.5 mm). The product is crystallized from a mixture of petrolatum ether and ethyl acetate.

Step (c) and step (d) are carried out as described in step (b) and (c) of Scheme I.

The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, i.e., intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally or intraperitonally. Also, the compounds of the present invention can be administered by inhalation, for example, intranasally. In addition, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of the present invention, as a compound of Formula I, II or III or a pharmaceutically acceptable salt of a compound of Formula I, II or III.

To prepare pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either liquid or solid.

The solid form preparations include powders, tablets, pills, capsules, lozenges, suppositories and dispersible granules. A solid carrier can be one or more substances which can also act as diluents, flavoring agents, bonds, preservatives, tablet disintegrating agents or a encapsulating material In powders, the carrier is a finely divided solid that is in a mixture with the finely divided active component.

In tablets, the active component is mixed with the carrier having the necessary binding properties in appropriate proportions and compacted in the desired shape and size.

The powders and tablets preferably contain from 5 or 10 up to about 70 percent of the active component. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "preparation" is intended to include the formula of the active compound with encapsulating material as a carrier that produces a capsule in which the active component with or without other carriers is surrounded by a carrier, which is in turn in relation thereto. Similarly, pills and tablets are included. The tablets, powders, capsules, pills, pills and tablets can be used as solid dosage forms suitable for oral administration.

To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, melts first and the active component is dispersed homogeneously therein, by stirring. The melted homogeneous mixture is then poured into molds of suitable size, allowed to cool and thus solidify.

Liquid form preparations include solutions, suspensions and emulsions, for example, water or water glycol propylene solutions. For parenteral injections, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable coloring, flavoring, stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, carboxymethylcellulose and other well-known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, into liquid form preparations for oral administration. Said liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, dyes, flavors, stabilizers, regulators, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.

The pharmaceutical preparation is preferably in the form of a unit dose. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package contains discrete quantities of the preparation, such as tablets, capsules and powders in packaged vials or ampoules. Also, the unit dosage form can be a capsule, tablet, tablet, or tablet itself or you can see the appropriate number of any of these in packaged form.

The amount of active component in a unit dose preparation can be varied or adjusted from 0.1 mg to 200 mg preferably 0.5 mg to 100 mg according to the particular application and potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

In therapeutic use as inhibitors of the endothelin-converting enzyme the compounds used in the pharmaceutical method of this invention are administered in the initial dose of from about 0.01 mg to about 500 mg / kg daily. A daily dosage range of about 0.01 mg to about 100 mg / kg is preferred. The doses, however, may vary depending on the patient's requirements, the severity of the condition being treated and the compound used. The determination of the appropriate dose for a particular situation is within those skilled in the art. Generally, treatment starts with smaller doses that are less than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimal effect under the circumstances is reached. For convenience, the total daily dose can be divided and administered in portions during the day, if desired.

The following non-limiting examples illustrate the inventors' preferred methods for preparing the compounds of the invention.

EXAMPLE 1 (1-ethyl-piperidin-3-ylV (6-iodo-2-trichloromethyl-quinazolma-4-yD-amine) monohydrochloride Step 1: Preparation of 6-iodo-2-trichloromethyl-1,2-dihydro-quinazoline -4-one.

To a solution of 5-iodoanthranilic acid (131.5 g, 500 mmol) in ethanol (700 ml), 2,2,2-trichloroacetimidate (88.2 g, 500 mmol) were added. The reaction mixture was heated at 45 ° C for 3 days by stirring. The solid formed was filtered and washed with fresh ethanol and air dried. The production of 129.51 g (66.4%). Melting point 224-225 ° C? -NMR (DMSO) 7.59 (d, lh, J = 8.6 Hz), 8.21 (dd, 1H, J = 2 Hz, J = 7.5 Hz), 8.44, 1H, J = 1.9 Hz), 13.55 (bs, 1H). MS (SCI); M + = 499. CHN calculated for C16H, gCl13rN4-hcL; C: 35.84, H.3.57, N: 10.45; Found: C: 35.81, H: 3.35, N: 10.44.

Step 2: Preparation of 6-iodo-4-chloro-2-trichloromethyl quinazoline. A suspension of 6-iodo-2-trichloromethyl-1,2-dihydro-quinazoline-4-one (38.9 g = 100 mmol) in POCl3 (500 mL) was heated to reflux for 12 hours. The homogeneous solution was cooled and the excess POCl3 was distilled in vacuo. The ined viscous oil was poured onto crushed ice and vigorously crushed to give a gray solid, which was dissolved in toluene (200 ml), filtered and evaporated in vacuo to give a slightly white crystalline solid. Melting point 154-155 ° C. Elemental analysis: Calculated for C9H3CL4IN2, C: 26.50, H: 0.74, N: 6.87; Found: C: 26.15, H: 0.79, N: 6.68.

Step 3: Preparation of (l-ethyl-piperidin-3-yl) - (6-iodo-2-trichloromethyl-quinazolin-4-yl) -amine-monohydrochloride. 6-iodo-4-chloro-2-trichloromethyl quinazoline (8.14 g, 200 mmol) was dissolved in ether (anhydrous 200 ml) stirring at rt. To this solution 3-amino-1-ethyl-piperidine (2.56 g, 20 mmol) in ether (anhydrous 30 ml) was added at 0 ° C. The reaction mixture was allowed to warm to rt overnight. The separated bright solid color that was filtered, washed with ether (200 ml) and dried in the air. Raw production: 5.1 g. The raw material was suspended in MeOH and stirred vigorously for 0.5 hours and filtered. The solid was dried under vacuum (0.01 mm). Production: 3.72 g, (34.7%). Melting point 265-266 ° C.

In a process analogous to Example 1 using the appropriate starting materials, the following compounds of Formula I are prepared as follows: EXAMPLE 2 (1-ethyl-piperidin-3-yr) - (6-iodo-2-phenyl-quinazoline-4-yl-V-amine MS (SCI) M + l = 459, CHN calculated for C2? H23IN4; C: 55.03 , H: 5.06, N: 12.22; Found: C: 54.99, H: 5.11, N: 11.82.

EXAMPLE 3 (1-ethyl-piperidin-3-ylVf 6-iodo-2-trichloromethyl-quinazoline-4-yl) -amine Melting point 274-276 ° C, CHN calculated for C? 6H18N4? Cl, C: 43.22, H: 4.30, N: 12.00; Found: C: 43.23, H: 4.16, N: 12.47.

EXAMPLE 4 l-Ethyl-piperidin-3-ylVf6-nitro-2-trichloromethyl-quinazolin-4-yl) -amine MS (SCI) M + 1 = 418. CHN calculated for C 14 H 18 C 13 N 502-HC 1; C: 42.22, H: 4.21, N: 15.39; Found: C: 42.30, H: 4.19, N: 15.01.

EXAMPLE 5 (2-tert-Butyl-6-iodo-quinazolin-4-yl) -f 1 -ethyl-piperidin-3-iD-amine MS (SCI) M + l = 439. CHN calculated for C? 9H27IN4.

EXAMPLE 6 N- (6-iodo-2-trichloromethyl-quinazoline-4-yl-methane-1,2-diamine hydrochloride MS (SCI) M + l 36.5 = 431.

EXAMPLE 7 N- (6-iodo-2-trichloromethyl-quinazoline-4-ylVN1-methyl-ethane-1,2-diamine MS (SCI) M + 1 = 444.

EXAMPLE 8 N- (6-iodo-2-trichloromethyl-quinazoline-4-ylVN1.N1-dimethyl-ethane-1,2-diamine MS (SCI) M + 1 = 459.

EXAMPLE 9 (6-iodo-2-trichloromethyl-quinazoline-4-yl) - (2-piperidin-1-yl-ethyl) -amine Melting point 254-255 ° C. (dec), MS (SCI): m z (MH) +.

EXAMPLE 10 (6-Iodo-2-trichloromethyl-quinazoline-4-yl) - (2-morpholine-4-yl-ethyl) -amine Melting point 182-183 ° C (dec), MS (SCI): m / z 501 (MH) +.

EXAMPLE 11 (l-Ethyl-pyrrolidin-2-yl-methyl-V (6-iodo-2-trichloromethyl-quinazoline-4-yl) -amine. Melting point 147-153 ° C, MS (SCI): m / z 499 ( MH) +.

EXAMPLE 12 fl-Aza-bicyclo [2.2.2] oct-3-ylV ("6-iodo-2-trichloromethyl-quinazoline-4-yl-Vinyne Melting point> 280 ° C (dec), MS (SCI): m / z 497 (MH) +.

EXAMPLE 13 N- (7-Chloro-2-trichloromethyl-quinazoline-4-ip-N, N'-diisopropyl-ethane-1-diamine Melting point 199-203 ° C. Elemental analysis calculated for Ci 7 H 22 N 4 Cl 5 Cl: C:: 5.2, N: 12.16; Found: C: 44.34, H: 5.30, N: 12.26.

EXAMPLE 14 [3- (6-Iodo-2-trichloromethyl-quinazoline-4-yl-amino) -piperidine-1-yl] -acetic acid potassium salt [0000] Elemental analysis calculated for C? 6H15N402Cl3IK: C: 33.83, H: 2.64, N: 9.86.

Found: C: 33.68, H: 3.01, N: 9.72.

EXAMPLE 15 (l-Aza-bicyclo [2.2.2] oct-3-ip- (6-iodo-2-trichloromethyl-quinazoline-4-yl ') - amine monohydrochloride Melting point> 280 ° C (dec), MS (SCI): M + 1 = 498.

EXAMPLE 16 N '- (6- Iodo-2-trichloromethyl-quinazoline-4-yl-NNN' '. N "-tetramethyl-propane-1,2,3-triamine monohydrochloride Melting point 207-208 ° C (dec), MS (SCI): M + 1 = 517.

EXAMPLE 17 (1-Ethyl-piperidine-3-yl> (6-iodo-2-trifluoromethyl-quinazoline-4-yy-amine Step 1: 6-iodo-2-trifluoromethyl-benzo [d] [1,3] oxazine -4-One 5-iodo-2-aminobenzoic acid (2.1 g, 8 mmol) was mixed with trifluoroacetic anhydride (12 g, 57 mmol) and 2 mL of triethyl amine, heated to reflux for 2 hours. under reduced pressure, the residue was stirred with 25 ml of ether and 5 ml of water The organic layer was separated, dried and concentrated to give 1.92 g of the product, mp 131-132 ° C, MS (SCI): m / z 342 (MH) +.

Step 2: 6-iodo-2-trifluoromethyl-3H-quinazoline-4-one. 6-Iodo-2-trifluoromethyl-benzo [d] [1,3] oxazine-4-one (0.6 g, 1.76 mmole) was stirred with 25 ml of concentrated ammonia water at 40 ° C for 5 hours, cooled to 0 ° C, the precipitate was filtered and dried under vacuum. The product was recrystallized from ethyl acetate and hexanes to give 0.58 g, melting point > 255 ° C (sub), MS (SCI): m / 7 341 (MH) +.

Step 3: 6-iodo-2-trifluoromethyl-4-chloroquinazoline. 6-iodo-2-trifluoromethyl-3H-quinazoline-4-one (3.1 g, 9.1 mmol) was mixed with 20 ml of POC13, heated to reflux for 3 hours, most of the POCl3 was removed without reacting in vacuo. The residue was extracted with 15 mL of NaHCO 3 (sat) and 200 mL of ether, the ether layer was dried with MgSO 4 and concentrated to give the light yellow solid 3.05 g, melting point 145-146 ° C, MS (SCI). ): m / z 359 (MH) +.

Step 4: (1-ethyl-piperidin-3-yl) - (6-iodo-2-trifluoromethyl-quinazolin-4-yl) -amine. 6-Iodo-2-trifluoromethyl-4-chloroquinazoline (1.5 g, 4.2 mmol) was mixed with 3-amino-ethyl-piperidine (0.62 g, 4.8 mmol) and triethyl amine in 200 mL of ether. The product was isolated as the hydrochloride salt by the above method, to give 1.25 g, melting point 196-197 ° C (dec), MS (SCI): M / Z 359 (MH) +.

Claims

The claims are:

1. A compound of the Formula where A is N, CH or S (0) "where n is 0, 1 or 2; R is lower alkyl, lower halo alkyl, aryl lower aryl alkyl, heteroaryl or lower heteroaryl alkyl; Ri is hydroxyalkyl containing at least 2 carbon atoms when A is N or S, lower alkoxyalkyl, thioalkyl containing at least 2 carbon atoms when A is N or S, thioalkyl lower alkyl, carboxyalkyl, an aminoalkyl group R7-R8 in wherein R7 and R "are each independently hydrogen, or less alkyl or when taken together with amino form a saturated 5- to 7-membered heterocyclic chain optionally interrupted by a second heteroatom chosen from nitrogen, oxygen and sulfur and where the heteroatom is nitrogen, said nitrogen atom can be substituted with lower alkyl, carboxyalkyl, or carboxyalkyl lower alkyl and wherein said chain can be further substituted at a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, diaqylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio , thioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, wherein the alkyl portion of the Ri-moieties Ri defined above can be further substituted in the alkyl chain by aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkylcarboxylalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl or alkoxyalkyl, a saturated or monounsaturated carbocyclic chain of 5-7 membered optionally fused to a benzene chain or a 6,6-membered bicyclic carbocyclic chain, said chains attached directly with A or by an alkyl group, or a 5- to 7-membered saturated heterocyclic chain optionally fused to a benzene chain, having at least 1 heteroatom, wherein said chain is directly attached with A or through an alkyl group linking A with the chain on a carbon atom, said chains are optionally substituted with alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxylalkyl, thio, thioalkyl, alkylthioalkyl , hydroxy, hydrox ialkyl, alkoxy or alkoxyalkyl, OR9 wherein R9 is hydrogen or lower alkyl, NR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl, C02Rg wherein R is as defined above, when A is N, a side chain of lower alkyl carboxy of a natural or non-natural a-amino acid or; when A is S and n is zero, a hydrogen atom; R2 is absent when A is S, a hydrogen atom or lower alkyl and when A is N, Ri and R2 can be combined together to form a 5- or 6- membered saturated chain optionally containing an additional nitrogen atom in the chain in the 3- or 4- position and the additional nitrogen atom can optionally be replaced by alkyl, carboxyalkyl or lower alkylcarboxyalkyl and the chain can be further substituted in a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl; R3, R4, R5RR are each independently hydrogen, halo, lower alkyl, cycloalkyl, lower haloalkyl, minor alkoxy, hydroxyalkyl, aminoalkyl, aminoalkyl lower alkyl, aminoalkyl lower alkyl, nitro, cyano, S02NRnR? 2, S02R9, C02R9, CONRnRn, NRnR12 in which Rp and R? 2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl, or two of the adjacent members of R3 to Re can be combined together to form a methylenedioxy group and ethylenedioxy group or a benzene chain or a pharmaceutically acceptable acid addition or base salt thereof; with the following provisions: (a) when A is N and Ri is aminoalkyl, aminoalkyl lower alkyl, aminoalkyl lower alkyl or hydroxyalkyl, then t is iodine or R5 is lower haloalkyl; (b) when A is N and Ri is pyrrolidine optionally substituted by alkyl or lower carboxy alkyl and R3 and Re are as defined above, then R is lower halo alkyl, aryl, minor aryl alkyl, heteroaryl or lower heteroaryl alkyl and ( c) when A is N, R3 and Re are as defined above and Ri and R2 with form a piperazine chain, then R is aryl, aryl lower alkyl, heteroaryl or heteroaryl lower alkyl or when, in addition, R4 is halo, R can be lower halo alkyl.

2. A compound according to Claim 1, wherein A is N.

3. A compound according to Claim 2, wherein R 1 is aminoalkyl, aminoalkyl lower alkyl, aminoalkyl lower alkyl, hydroxyalkyl containing at least 2 carbon atoms or thioalkyl containing at least 2 carbon atoms and R is lower halo alkyl .

4. A compound according to Claim 3, wherein? It is iodine.

5. A compound according to Claim 3, wherein R5 is halo.

6. A compound according to Claim 1 and the formula wherein R 3 and R 4 are each independently hydrogen, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkylcarboxyalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl or alkoxyalkyl; n 'is O, 1, 2 0 3.

7. A compound of Claim 4 and selected from the group consisting of N- (6-iodo-2-trichloromethyl-quinazoline-4-yl) -ethane-1,2-diamine, N- (6-iodo-2-trichloromethyl-quinazoline) -4-yl) -N'-methyl-ethane-1,2-diamine and N- (6-iodo-2-trichloromethyl-quinazoline-4-yl) -N'-N'-dimethyl-ethane-1, 2 -diamina.

8. A compound of Claim 5 and is N- (7-chloro-2-trichloromethyl-quinazoline-4-yl) -N'-N'-diisopropyl-ethane-1,2-diamine.

9. A compound according to Claim 6 and chosen from the group consisting of (6-iodo-2-trichloromethyl-quinazoline-4-yl) - (2-piperidin-1-yl-ethyl-amine, (6-iodo-2- trichloromethyl-quinazoline-4-yl) - (2-morpholine-4-yl-ethyl) -amine and N '- (6-iodo-2-trichloromethyl-quinazoline-4-yl) -N, N, N ", N "-tetramethyl-propane-1,2,3-triamine.

10. A compound according to claim 1 and Formula III where A is N, CH or S (0) n where n is 0, 1 or 2; and q is 0, 1 or 2; (a) B, C, D and E are CH or NRJ3 in which only one of B, C, D or E is NRB where R? 3 is hydrogen, lower alkyl, aralkyl, - (CH2) mC02R9 in which R9 is hydrogen or lower alkyl or - (CH2) mNR9R? Or in which R9 and Rio are each independently hydrogen or lower alkyl and m is integer from 0 to 6, p is an integer from 0 to 2 and r is an integer from 0 to 2 or (b) A is N, C, D and E are absent, p is 0 and B is NRJ3 or -CH2NR? 3 and annex to R2 to form a chain of 5- or 6- members, in which R? 3 is as defined above; R is lower alkyl, lower halo alkyl, phenyl or phenyl substituted by lower alkyl, lower alkoxy, trifluoromethyl, halo, N02, CN, S03H, S02NH2, S02CH3, COOR9 in which R9 is hydrogen or lower alkyl, CONR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl or NR 11 R 12 wherein R n and R 2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralalkyl or heteroaryl; R2 is absent when A is S, a hydrogen atom or lower alkyl; R3 and Re are each independently hydrogen, lower alkyl or lower alkoxy and R? and R5 are each independently hydrogen, lower alkyl, minor alkoxy, trifluoromethyl, halo, N02, CN, S03H, S02NH2, S02CH3, COOR9 in which R9 is hydrogen or lower alkyl, CONR9R? or wherein R9 and Rio are each independently hydrogen or lower alkyl or NRaRp wherein R n and R 2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl or R t and R 5 can be attached to form a methylenedioxy group or benzene chain or an acid addition salt or basic pharmaceutically acceptable thereof, with the following provisions: (i) when A is N, R3 to Re are as defined above and B, C, D and E are as defined in (a) above, then R is alkyl minor halo, phenyl or substituted phenyl as defined above or heteroaryl and (ii) when A is N, R3 to Re are as defined above and B, C, D and E are as defined in (b) above, R is phenyl or substituted phenyl as defined above or heteroaryl or when, in addition, t is halo, R may be haloalkyl; huge

11. A compound of claim 10, wherein A is N.

12. A compound of Claim 10, wherein C, D and E are absent; p is 0 and B is NR? 3 or -CH2NR? 3 and annexed to R2 to form a chain of 5- or 6- members.

13. A compound of Claim 12, wherein R is phenyl or phenyl substituted by lower alkyl, lower alkoxy, trifluoromethyl, halo, N02, CN, S03H, S02NH2, S02CH, COOR9 in which R9 is hydrogen or lower alkyl, CONR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl or NRnR? 2 wherein Rn and R? 2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or araalkyl, heteroaryl or lower heteroaryl alkyl.

14. A compound of Claim 12, wherein R 4 is halo and R is lower halo alkyl.

15. A compound of Claim 14 which is 6-iodo-4- (4-methyl-piperazin-1-yl) -2-trichloromethyl-quinazoline or 6-iodo-4-piperazin-1-yl-2-trichloromethyl-quinazoline.

16. A compound of Claim 11 and is (l-aza-bicyclo [2.2.2 + oct-3-yl) - (6-iodo-2-trichloromethyl-quinazoline-4-yl) -amine.

17. A compound according to Claim 10 and the formula where A is N, CH or S (0) "where n is 0, 1 or 2; B, C, D, E are CH2 or NR? 3 in which only one of B, C, D or E is NRp wherein R? 3 is hydrogen, lower alkyl, aralkyl, - (CH2) mC02R9 wherein R9 is hydrogen or lower alkyl or - (CH2) m-NR9R? 0 in which R9 and Rio are each independently hydrogen or lower alkyl and m is an integer from 0 to 6 and p is an integer from zero to 2; R is lower alkyl, lower halo alkyl, phenyl or phenyl substituted by lower alkyl, lower alkoxy, trifluoromethyl, halo, N02, CN, S03H, S02NH2, S02CH3, COOR9 wherein R9 is hydrogen or lower alkyl, CONR9R? 0 where R9 and Rio are each independently hydrogen or lower alkyl or NRnR? 2 wherein Rn and Rj2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl or heteroaryl; R2 is absent when A is S, a hydrogen atom or lower alkyl; R3 and Re are each independently hydrogen, lower alkyl or lower alkoxy and Rt and Rs are each independently hydrogen, lower alkyl, minor alkoxy, trifluoromethyl, halo, N02, CN, S03H, S02NH2, S02CH3, COOR9 wherein R9 is hydrogen or lower alkyl, CONR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl or NRnR? 2 wherein Rn and R? 2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl or R4 and R5 can be joined together to form a methylenedioxy group or a benzene chain or a acid or basic pharmaceutically acceptable addition thereof, provided that when A is N and p is 0, R is lower alkyl, phenyl or substituted phenyl as defined above or heteroaryl.

18. A compound according to claim 10 and the formula IV where q is 0, 1 or 2 and p is 0 or 1; R is lower alkyl, lower halo alkyl, phenyl or phenyl substituted by lower alkyl, lower alkoxy, trifluoromethyl, halo, N02, CN, S03H S02NH2, S02CH3, COOR9 in which R9 is hydrogen or lower alkyl, CONR9R? 0 where R9 and Rio are each independently hydrogen or lower alkyl or NRnR? 2 wherein R 11 and R 2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl or heteroaryl; R 2 is a hydrogen atom or lower alkyl; R3 and Re are each independently hydrogen, lower alkyl or lower alkoxy and R? and Rj are each independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, halo, N02, S03H, S02NH2, S02CH3, COOR9 in which R9 is hydrogen or minor alkyl, CONR9R? or wherein R and Rio are each independently hydrogen or minor alkyl or NRnR? 2 wherein Rn and RJ2 are each independently hydrogen, minor alkyl, aryl, heteroaryl or aralkyl or? and R5 can join to form a group methylenedioxy or a benzene chain; R7 is hydrogen, lower alkyl, aralkyl, - (CH2) m-NR9R? Or in which R9 and Rio are each independently hydrogen or lower alkyl and m is an integer of 1 to 6 or a pharmaceutically acceptable salt of acid or basic addition thereof; provided that when p is 0, q is 1 or 2.

19. A compound of Claim 18, wherein "and R5 are each independently hydrogen, trifluoromethyl, halo, N02, CN, S03H, S02NH2, S02CH3, COOR in which R9 is hydrogen or lower alkyl, CONR9R? 0 wherein R9 and Rio are each independently hydrogen or lower alkyl.

20. A compound of Claim 19, wherein R is lower alkyl, lower halo alkyl, phenyl or lower alkyl phenyl in which phenyl is substituted or unsubstituted by lower alkyl, lower alkoxy or halo.

21. A compound "of Claim 20, wherein t and Rs are each independently hydrogen, halo or N02.

22. A compound of Claim 21, wherein R is lower halo alkyl.

23. A compound of Claim 21 and is selected from the group consisting of (1-ethyl-piperidin-3-yl) - (6-iodo-2-p-tolyl-quinazolin-4-yl) -amine, (1-ethyl-piperidin-3-yl) - (6-iodo-2) - (4-methoxy-phenyl) -quinazolin-4-yl) -amine, [2- (4-chloro-phenyl) -6-iodo-quinazoline-4-yl] - (1-ethyl-piperidine-3-yl) ) -amine, [2-tert-butyl-6-iodo-quinazoline-4-yl) - (1-ethyl-piperidine-3-yl) -amine and (1-ethyl-piperidin-3-yl) - (6 -Iodo-2-phenyl-quinazoline-4-yl) -amine.

24. A compound of Claim 22 and chosen from the group consisting of (1-ethyl-piperidin-3-yl) - (6-iodo-2-trichloromethyl-quinazoline-4-yl) -amine, [3 - (6- Iodine-2-trichloromethyl-quinazoline-ylamine) -piperidin-1-yl] acetic acid, 1-ethyl-piperidin-3-yl) - (6-chloro-2-trichloromethyl-quinazoline-4-yl) -amine, 1 - ethyl-piperidin-3-yl) - (6-nitro-2-trichloromethyl-quinazolin-4-yl) -amine, 1-ethyl-piperidin-3-yl) - (2-trichloromethyl-quinazoline-4-yl) - amine, 1-ethyl-piperidin-3-yl) - (7-chloro-2-trichloromethyl-quinazoline-4-yl) -amine, (1-ethyl-piperidin-3-yl) - (6-iodo-2- trifluoromethyl-quinazolin-4-yl) -amine and (1-ethyl-pyrrolidin-2-yl-methyl) - (6-iodo-2-trichloromethyl-quinazoline-4-yl) -amine.

25. A pharmaceutical composition adapted for administration as an inhibitor of the endothelin-converting enzyme comprising a therapeutically effective amount of the compound of Claim 1 in admixture with a pharmaceutically acceptable carrier.

26. A method for treating diseases associated with high levels of endothelin comprising administering to a host suffering therefrom a therapeutically effective amount of an inhibitor of the endothelin-converting enzyme of the formula where A is N, CH or S (0) n where n is 0, 1 or 2; R is lower alkyl, lower halo alkyl, aryl lower aryl alkyl, heteroaryl or lower heteroaryl alkyl; Ri is hydroxyalkyl containing at least 2 carbon atoms when A is N or S, lower alkoxyalkyl, thioalkyl containing at least 2 carbon atoms when A is N or S, thioalkyl lower alkyl, carboxyalkyl, an aminoalkyl group R7-Rs in wherein R7 and R "are each independently hydrogen, or less alkyl or when taken together with amino form a saturated 5- to 7-membered heterocyclic chain optionally interrupted by a second heteroatom chosen from nitrogen, oxygen and sulfur and where the heteroatom is nitrogen, said nitrogen atom can be substituted with lower alkyl, carboxyalkyl, or carboxyalkyl lower alkyl and wherein said chain can be further substituted at a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, diaqylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio , thioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, wherein the alkyl portion of the Ri-defined above can be further substituted in the alkyl chain by aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkylcarboxylalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl or alkoxyalkyl, a saturated or monounsaturated carbocyclic chain of 5-7 membered optionally fused to a benzene chain or a 6,6-membered bicyclic carbocyclic chain, said chains attached directly with A or by an alkyl group, or a 5- to 7-membered saturated heterocyclic chain optionally fused to a benzene chain, having at least 1 heteroatom, wherein said chain is directly attached to A or through an alkyl group linking A with the chain at a carbon atom, said chains being optionally substituted with alkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxylalkyl, thio, thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, OR wherein R9 is hydrogen or lower alkyl, NR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl, C02R9 wherein R9 is as defined above, when A is N, a lower alkyl side chain carboxy of a natural or unnatural a-amino acid or; when A is S and n is zero, a hydrogen atom; R2 is absent when A is S, a hydrogen atom or lower alkyl and when A is N, Ri and R2 can be combined together to form a saturated chain of 5- or 6- membered optionally containing an additional nitrogen atom in the chain in the 3- or 4- position and the additional nitrogen atom can optionally be replaced by alkyl, carboxyalkyl or lower alkylcarboxyalkyl and the chain can be further substituted in a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl; R3, Rt, RsRR are each independently hydrogen, halo, lower alkyl, cycloalkyl, lower haloalkyl, minor alkoxy, hydroxyalkyl, aminoalkyl, aminoalkyl lower alkyl, aminoalkyl lower alkyl, nitro, cyano, S02NRnR? 2, S02R9, C02R9, CONRuR? 2, NRnR? 2 in which Rn and Ri2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl, or two of the adjacent members of R3 to Re can be combined together to form a group methylenedioxy and ethylenedioxy group or a benzene chain or a pharmaceutically acceptable acid addition or base salt thereof.

27. A method for treating diseases associated with high levels of endothelin comprising administering to a host suffering therefrom a therapeutically effective amount of an endothelin-converting enzyme inhibitor, such an inhibitor is a compound of claim 1 in the form of dose per unity.

28. A method for treating subarachnoid hemorrhages, cerebral vasospasms, ischemia or cerebral infarcts, attacks or hemorrhagic attacks comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of the formula where A is N, CH or S (0) n where n is 0, 1 or 2; R is lower alkyl, lower halo alkyl, aryl lower aryl alkyl, heteroaryl or lower heteroaryl alkyl; Ri is hydroxyalkyl containing at least 2 carbon atoms when A is N or S, lower alkoxyalkyl, thioalkyl containing at least 2 carbon atoms when A is N or S, thioalkyl lower alkyl, carboxyalkyl, an aminoalkyl group R -Rβ in wherein R7 and Rs are each independently hydrogen, or less alkyl or when taken together with amino form a saturated 5- to 7-membered heterocyclic chain optionally interrupted by a second heteroatom chosen from nitrogen, oxygen and sulfur and where the heteroatom is nitrogen , said nitrogen atom can be substituted with alkyl, carboxyalkyl, or carboxyalkyl lower alkyl and wherein said chain can be further substituted at a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, diaqylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, wherein the alkyl portion of the Ri-moieties Ri defined above can be further substituted in the alkyl chain by aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkylcarboxylalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl or alkoxyalkyl, a saturated or monounsaturated carbocyclic chain of 5-7 membered optionally fused to a benzene chain or a 6,6-membered bicyclic carbocyclic chain, said chains attached directly with A or by an alkyl group, or a 5- to 7-membered saturated heterocyclic chain optionally fused to a benzene chain, having at least 1 heteroatom, wherein said chain is directly attached with A or through an alkyl group linking A with the chain on a carbon atom, said chains are optionally substituted with alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxylalkyl, thio, thioalkyl, alkylthioalkyl , hydroxy, hydrox ialkyl, alkoxy or alkoxyalkyl, OR9 wherein R9 is hydrogen or lower alkyl, NR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl, C02R9 wherein R9 is as defined above, when A is N, a side chain of lower alkyl carboxy of a natural or non-natural a-amino acid or; when A is S and n is zero, a hydrogen atom; R2 is absent when A is S, a hydrogen atom or lower alkyl and when A is N, Ri and R2 can be combined together to form a 5- or 6- membered saturated chain optionally containing an additional nitrogen atom in the chain in the 3- or 4- position and the additional nitrogen atom can optionally be replaced by alkyl, carboxyalkyl or lower alkylcarboxyalkyl and the chain can be further substituted in a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl; R3, t, RsRR are each independently hydrogen, halo, lower alkyl, cycloalkyl, lower haloalkyl, minor alkoxy, hydroxyalkyl, aminoalkyl, aminoalkyl lower alkyl, aminoalkyl lower alkyl, nitro, cyano, S0 NRnR? 2, S02R9, C02R9, CONRuR? 2, NRnR? 2 in which Rn and RJ2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl, or two of the adjacent members of R3 a Re can be combined together to form a methylenedioxy group and ethylenedioxy group or a benzene chain or a pharmaceutically acceptable basic or acid addition salt thereof, provided that R is lower alkyl, lower halo alkyl, aryl or lower aryl alkyl, when A is N and Ri is aminoalkyl, aminoalkyl lower alkyl, aminoalkyl lower alkyl or hydroxyalkyl, in dosage form per unit.

29. A method for treating hypertension, congestive heart failure, myocardial ischemia, myocardial infarction or pulmonary hypertension comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of the formula where A is N, CH or S (0) n where n is 0, 1 or 2; R is lower alkyl, lower halo alkyl, aryl lower aryl alkyl, heteroaryl or lower heteroaryl alkyl; Ri is hydroxyalkyl containing at least 2 carbon atoms when A is N or S, lower alkoxyalkyl, thioalkyl containing at least 2 carbon atoms when A is N or S, thioalkyl lower alkyl, carboxyalkyl, an aminoalkyl group R7-Rg in wherein R7 and Rg are each independently hydrogen, or less alkyl or when taken together with amino form a saturated 5- to 7-membered heterocyclic chain optionally interrupted by a second heteroatom chosen from nitrogen, oxygen and sulfur and where the heteroatom is nitrogen , said nitrogen atom can be substituted with alkyl, carboxyalkyl, or carboxyalkyl lower alkyl and wherein said chain can be further substituted at a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, diaqylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, wherein the alkyl portion of the groups Pos Ri can be further substituted in the alkyl chain by aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkylcarboxylalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl or alkoxyalkyl, a saturated or monounsaturated carbocyclic chain of 5-7 membered optionally fused to a benzene chain or a 6,6-membered bicyclic carbocyclic chain, said chains attached directly with A or by an alkyl group, or a 5- to 7-membered saturated heterocyclic chain optionally fused to a benzene chain, having at least 1 heteroatom, wherein said chain is directly attached with A or through an alkyl group linking A with the chain on a carbon atom, said chains are optionally substituted with alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxylalkyl, thio, thioalkyl, alkylthioalkyl , hydroxy, hydroxy alkyl, alkoxy or alkoxyalkyl, OR9 wherein R9 is hydrogen or lower alkyl, NR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl, C02R9 wherein R9 is as defined above, when A is N, a side chain of lower alkyl carboxy of a natural or non-natural a-amino acid or; when A is S and n is zero, a hydrogen atom; R2 is absent when A is S, a hydrogen atom or lower alkyl and when A is N, Ri and R2 can be combined together to form a 5- or 6- membered saturated chain optionally containing an additional nitrogen atom in the chain in the 3- or 4- position and the additional nitrogen atom can optionally be replaced by alkyl, carboxyalkyl or lower alkylcarboxyalkyl and the chain can be further substituted in a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl; R3, R ?, RsRR are each independently hydrogen, halo, lower alkyl, cycloalkyl, lower haloalkyl, minor alkoxy, hydroxyalkyl, aminoalkyl, aminoalkyl lower alkyl, aminoalkyl lower alkyl, nitro, cyano, S02NRnR? 2 , S02R9, C02R9, CONR? R? 2, NRpR? 2 in which Rn and R? 2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl, or two of the adjacent members of R3 to Re can be combined together to form a methylenedioxy group and ethylenedioxy group or a benzene chain or a pharmaceutically acceptable basic or acid addition salt thereof, provided that R is lower alkyl, lower halo alkyl, aryl or lower aryl alkyl, when A is N and Ri is aminoalkyl, aminoalkyl lower alkyl, aminoalkyl lower alkyl or hydroxyalkyl, in dosage form per unit.

30. A method for treating diabetes or atherosclerosis disorders including Raynaud's disease and restenosis comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of the formula where A is N, CH or S (0) "where n is 0, 1 or 2; R is lower alkyl, lower halo alkyl, aryl lower aryl alkyl, heteroaryl or lower heteroaryl alkyl; Ri is hydroxyalkyl containing at least 2 carbon atoms when A is N or S, lower alkoxyalkyl, thioalkyl containing at least 2 carbon atoms when A is N or S, thioalkyl lower alkyl, carboxyalkyl, an aminoalkyl group R7-Rg in wherein R7 and Rs are each independently hydrogen, or less alkyl or when taken together with amino form a saturated 5- to 7-membered heterocyclic chain optionally interrupted by a second heteroatom chosen from nitrogen, oxygen and sulfur and where the heteroatom is nitrogen , said nitrogen atom can be substituted with alkyl, carboxyalkyl, or carboxyalkyl lower alkyl and wherein said chain can be further substituted at a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, diaqylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, wherein the alkyl portion of the groups Pos Ri can be further substituted in the alkyl chain by aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkylcarboxylalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl or alkoxyalkyl, a saturated or monounsaturated carbocyclic chain of 5-7 membered optionally fused to a benzene chain or a 6,6-membered bicyclic carbocyclic chain, said chains attached directly with A or by an alkyl group, or a 5- to 7-membered saturated heterocyclic chain optionally fused to a benzene chain, having at least 1 heteroatom, wherein said chain is directly attached with A or through an alkyl group linking A with the chain on a carbon atom, said chains are optionally substituted with alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxylalkyl, thio, thioalkyl, alkylthioalkyl , hydroxy, hydroxy alkyl, alkoxy or alkoxyalkyl, OR9 wherein R9 is hydrogen or lower alkyl, NR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl, C02R9 wherein R9 is as defined above, when A is N, a side chain of lower alkyl carboxy of a natural or non-natural a-amino acid or; when A is S and n is zero, a hydrogen atom; R2 is absent when A is S, a hydrogen atom or lower alkyl and when A is N, Ri and R2 can be combined together to form a 5- or 6- membered saturated chain optionally containing an additional nitrogen atom in the chain in the 3- or 4- position and the additional nitrogen atom can optionally be replaced by alkyl, carboxyalkyl or lower alkylcarboxyalkyl and the chain can be further substituted in a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl; R3, Rt, RsRR are each independently hydrogen, halo, lower alkyl, cycloalkyl, lower haloalkyl, minor alkoxy, hydroxyalkyl, aminoalkyl, aminoalkyl lower alkyl, aminoalkyl lower alkyl, nitro, cyano, S02NRnR? 2, S02R9, C02R9, CONR11R12, NRuR? 2 in which Rn and Ru are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl, or two of the adjacent members of R3 to Re can be combined together to form a methylenedioxy group and ethylenedioxy group or a benzene chain or a pharmaceutically acceptable acid addition or basic salt thereof, provided that R is lower alkyl, lower halo alkyl, aryl or lower aryl alkyl, when A is N and Ri is aminoalkyl, aminoalkyl lower alkyl, aminoalkyl di-lower alkyl or hydroxyalkyl, in dosage form per unit.

31. A method for treating acute and chronic renal failure, arrhythmias or angina comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of the formula where A is N, CH or S (0) n where n is 0, 1 or 2; R is lower alkyl, lower halo alkyl, aryl lower aryl alkyl, heteroaryl or lower heteroaryl alkyl; Ri is hydroxyalkyl containing at least 2 carbon atoms when A is N or S, lower alkoxyalkyl, thioalkyl containing at least 2 carbon atoms when A is N or S, thioalkyl lower alkyl, carboxyalkyl, an aminoalkyl group R7-Rg in wherein R7 and Rs are each independently hydrogen, or less alkyl or when taken together with amino form a saturated 5- to 7-membered heterocyclic chain optionally interrupted by a second heteroatom chosen from nitrogen, oxygen and sulfur and where the heteroatom is nitrogen , said nitrogen atom can be substituted with alkyl, carboxyalkyl, or carboxyalkyl lower alkyl and wherein said chain can be further substituted at a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, diaqylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, wherein the alkyl portion of the Ri-defined above can be further substituted in the alkyl chain by aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkylcarboxylalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl or alkoxyalkyl, a saturated or monounsaturated carbocyclic chain of 5-7 membered optionally fused to a benzene chain or a 6,6-membered bicyclic carbocyclic chain, said chains attached directly with A or by an alkyl group, or a 5- to 7-membered saturated heterocyclic chain optionally fused to a benzene chain, having at least 1 heteroatom, wherein said chain is directly attached with A or through an alkyl group linking A with the chain on a carbon atom, said chains are optionally substituted with alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxylalkyl, thio, thioalkyl, alkylthioalkyl , hydroxy, hydroxy alkyl, alkoxy or alkoxyalkyl, OR9 wherein R9 is hydrogen or lower alkyl, NR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl, C02R9 wherein R9 is as defined above, when A is N, a side chain of lower alkyl carboxy of a natural or non-natural a-amino acid or; when A is S and n is zero, a hydrogen atom; R2 is absent when A is S, a hydrogen atom or lower alkyl and when A is N, Ri and R2 can be combined together to form a 5- or 6- membered saturated chain optionally containing an additional nitrogen atom in the chain in the 3- or 4- position and the additional nitrogen atom can optionally be replaced by alkyl, carboxyalkyl or lower alkylcarboxyalkyl and the chain can be further substituted in a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl; R3, Rt, R5RR are each independently hydrogen, halo, lower alkyl, cycloalkyl, lower haloalkyl, minor alkoxy, hydroxyalkyl, aminoalkyl, aminoalkyl lower alkyl, aminoalkyl lower alkyl, nitro, cyano, S02NRnR? 2, S02R9, C02R9, CONRnR? 2, NRnR? 2 in which Rn and Rj2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl, or two of the adjacent members of R3 to Re can be combined together to form a methylenedioxy group and ethylenedioxy group or a benzene chain or a pharmaceutically acceptable basic or acid addition salt thereof, provided that R is lower alkyl, lower halo alkyl, aryl or lower aryl alkyl, when A is N and Ri is aminoalkyl, aminoalkyl lower alkyl, aminoalkyl lower alkyl or hydroxyalkyl, in dosage form per unit.

32. A method for treating cancer, damage to the gastric mucosa, ischemic bowel disease, preclaimsia, septic seizures, asthma or cirrhosis comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of the formula where A is N, CH or S (0) n where n is 0, 1 or 2; R is lower alkyl, lower halo alkyl, aryl lower aryl alkyl, heteroaryl or lower heteroaryl alkyl; Ri is hydroxyalkyl containing at least 2 carbon atoms when A is N or S, lower alkoxyalkyl, thioalkyl containing at least 2 carbon atoms when A is N or S, thioalkyl lower alkyl, carboxyalkyl, an aminoalkyl group R7-Rs in wherein R7 and Rs are each independently hydrogen, or less alkyl or when taken together with amino form a saturated 5- to 7-membered heterocyclic chain optionally interrupted by a second heteroatom chosen from nitrogen, oxygen and sulfur and where the heteroatom is nitrogen , said nitrogen atom can be substituted with alkyl, carboxyalkyl, or carboxyalkyl lower alkyl and wherein said chain can be further substituted at a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, diaqylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl, wherein the alkyl portion of the groups Pos Ri can be further substituted in the alkyl chain by aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkylcarboxylalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl or alkoxyalkyl, a saturated or monounsaturated carbocyclic chain of 5-7 membered optionally fused to a benzene chain or a 6,6-membered bicyclic carbocyclic chain, said chains attached directly with A or by an alkyl group, or a 5- to 7-membered saturated heterocyclic chain optionally fused to a benzene chain, having at least 1 heteroatom, wherein said chain is directly attached with A or through an alkyl group linking A with the chain on a carbon atom, said chains are optionally substituted with alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxylalkyl, thio, thioalkyl, alkylthioalkyl , hydroxy, hydroxy alkyl, alkoxy or alkoxyalkyl, OR9 wherein R9 is hydrogen or lower alkyl, NR9R10 wherein R9 and Rio are each independently hydrogen or lower alkyl, C02R9 wherein R9 is as defined above, when A is N, a side chain of lower alkyl carboxy of a natural or non-natural a * amino acid or; when A is S and n is zero, a hydrogen atom; R2 is absent when A is S, a hydrogen atom or lower alkyl and when A is N, Ri and R2 can be combined together to form a 5- or 6- membered saturated chain optionally containing an additional nitrogen atom in the chain in the 3- or 4- position and the additional nitrogen atom can optionally be replaced by alkyl, carboxyalkyl or lower alkylcarboxyalkyl and the chain can be further substituted in a carbon atom by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl; R3, Rt, RsRR are each independently hydrogen, halo, lower alkyl, cycloalkyl, lower haloalkyl, minor alkoxy, hydroxyalkyl, aminoalkyl, aminoalkyl lower alkyl, aminoalkyl lower alkyl, nitro, cyano, S02NRnR? 2, S02R9, C02R9, CONRnRp, NRnR? 2 in which Rn and R? 2 are each independently hydrogen, lower alkyl, aryl, heteroaryl or aralkyl, or two of the adjacent members of R3 to R «can be combined together to form a methylenedioxy group and ethylenedioxy group or a benzene chain or a pharmaceutically acceptable basic or acid addition salt thereof, provided that R is lower alkyl, lower halo alkyl, aryl or lower aryl alkyl, when A is N and Ri is aminoalkyl, aminoalkyl minor alkyl, aminoalkyl di minor alkyl or hydroxyalkyl, in dosage form per unit. EXTRACT OF THE INVENTION [0002] Novel quinazoline inhibitors of endothelin-converting enzymes are described, as well as methods for the preparation and pharmaceutical compositions thereof, which are useful in the treatment of high levels of endothelin and in the control of hypertension, heart attacks and myocardial ischemia, metabolic, endocrine and neurological disorders, congestive heart failure, endotoxic and hemorrhagic attacks, septic seizures, subarachnoid hemorrhages, arrhythmias, asthma, acute and chronic renal failure, nephrotoxicity induced by cyclosporin-A, angina, mucosal damage gastric, ischemic bowel disease, cancer, pulmonary hypertension, preclaimsia, atherosclerosis disorders including Raynaud's disease and restenosis, cerebral ischemia and vasospasms and diabetes.