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US6017951A - Butenolide endothelin antagonists - Google Patents
Butenolide endothelin antagonists Download PDF
US6017951A
US6017951A US09247534 US24753499A US6017951A US 6017951 A US6017951 A US 6017951A US 09247534 US09247534 US 09247534 US 24753499 A US24753499 A US 24753499A US 6017951 A US6017951 A US 6017951A
US09247534
Bill R. Reisdorph
Joseph T. Repine
Novel nonpeptides characterized as having a carbamic group which are antagonists of endothelin I are described, as well as methods for their preparation and pharmaceutical compositions containing the same. The compounds are useful in treating elevated levels of endothelin and are therefore useful in the treatment of hypertension, myocardial infarction, diabetes, cerebral vasospasm, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythminas, asthma, chronic and acute renal failure, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, stroke, head injury, and ischemic bowel syndrome.
This application is a Div. of Ser. No. 08/981,059 filed Dec. 15, 1997 which is a 371 of PCT/US96/10651 filed Jun. 21, 1996 and claims priority of provisional application No. 60/000,904 filed Jul. 6, 1995
The present invention relates to novel antagonists of endothelin useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the compounds of the present invention are antagonists of endothelin useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction and myocardial ischemia, cerebral vasospasm, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, and diabetes.
Also, the compounds will be useful in cerebral ischemia or cerebral infarction resulting from a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, head injury, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma.
Several studies have been reported with both peptide and nonpeptide ET antagonists showing efficacy in various models of subarachnoid hemorrhage (SAH). For example, BQ-123-prevents early cerebral vasospasm following SAH in various rat (Clozel M., et al., Life Sci., 1993;52:825) and rabbit (Lee K. S., et al., Cerebral Vasospasm, 1993:217; and Neurosurgery, 1994; 34:108) models. FR 139317 significantly inhibited the vasoconstriction of the basilar artery after 7 days in a canine two-hemorrhage model of SAH (Nirei H., et al., Life Sci., 1993;52:1869). BQ-485 also significantly inhibited the vasoconstriction of the basilar artery after 7 days in a canine two-hemorrhage model of SAH (Yano, et al., Biochem Biophys. Res Commun., 1993; 195:969). Ro 46-2005 (Clozel M., et al., Nature, 1993;365:759) has been shown to prevent early cerebral vasospasm following SAH in the rat with no significant effect on systemic arterial blood pressure. Treatment with Ro 47-0203=Bosentan (Clozel, et al., Circulation, 1993;88(4) part 2:0907) to rabbits with SAH had a 36±7% reduction of basilar artery cross-sectional area compared to sham rabbits. All of these studies show in vivo efficacy of endothelin antagonists in cerebral vasospasm resulting from SAH.
Endothelin-1 (ET-1), a potent vasoconstrictor, is a 21 amino acid bicyclic peptide that was first isolated from cultured porcine aortic endothelial cells. Endothelin-1, is one of a family of structurally similar bicyclic peptides which include; ET-2, ET-3, vasoactive intestinal contractor (VIC), and the sarafotoxins (SRTXs).
Studies by Kon and colleagues using anti-ET antibodies in an ischemic kidney model, to deactivate endogenous ET, indicated the peptide's involvement in acute renal ischemic injury (Kon V., et al., "Glomerular Actions of Endothelin In Vivo," J. Clin. Invest., 1989;83:1762). In isolated kidneys, preexposed to specific antiendothelin antibody and then challenged with cyclosporine, the renal perfusate flow and glomerular filtration rate increased, while renal resistance decreased as compared with isolated kidneys preexposed to a nonimmunized rabbit serum. The effectiveness and specificity of the anti-ET antibody were confirmed by its capacity to prevent renal deterioration caused by a single bolus dose (150 pmol) of synthetic ET, but not by infusion of angiotensin II, norepinephrine, or the thromboxane A2 mimetic U-46619 in isolated kidneys (Perico N., et al., "Endothelin Mediates the Renal Vasoconstriction Induced by Cyclosporine in the Rat," J. Am. Soc. Nephrol., 1990;1:76).
Others have reported inhibition of ET-1 or ET-2-induced vasoconstriction in rat isolated thoracic aorta using a monoclonal antibody to ET-1 (Koshi T., et al., "Inhibition of Endothelin (ET)-1 and ET-2-Induced Vasoconstriction by Anti-ET-1 Monoclonal Antibody," Chem. Pharm. Bull., 1991;39:1295).
Combined administration of ET-1 and ET-1 antibody to rabbits showed significant inhibition of the blood pressure (BP) and renal blood flow responses (Miyamori I., et al., Systemic and Regional Effects of Endothelin in Rabbits: Effects of Endothelin Antibody,° Clin. Exp. Pharmacol. Physiol., 1990;17:691).
Burnett and coworkers recently demonstrated that exogenous infusion of ET (2.5 ng/kg/mL) to anesthetized dogs, producing a doubling of the circulating concentration, did have biological actions (Lerman A., et al., "Endothelin has Biological Actions at Pathophysiological Concentrations," Circulation, 1991; 83:1808). Thus heart rate and cardiac output decreased in association with increased renal and systemic vascular resistances and antinatriuresis. These studies support a role for endothelin in the regulation of cardiovascular, renal, and endocrine function.
In congestive heart failure in dogs and humans, a significant 2- to 3-fold elevation of circulating ET levels has been reported (Rodeheffer R. J., et al., "Circulating Plasma Endothelin Correlates With the Severity of Congestive Heart Failure in Humans," Am. J. Hypertension, 1991;4:9A).
The distribution of the two cloned receptor subtypes, termed ETA and ETB, have been studied extensively (Arai H., et al., Nature, 1990;348:730, Sakurai T., et al., Nature, 1990;348:732). The ETA, or vascular smooth muscle receptor, is widely distributed in cardiovascular tissues and in certain regions of the brain (Lin H. Y., et al., Proc. Natl. Acad. Sci., 1991;88:3185). The ETB receptor, originally cloned from rat lung, has been found in rat cerebellum and in endothelial cells, although it is not known if the ETB receptors are the same from these sources. The human ET receptor subtypes have been cloned and expressed (Sakamoto A., et al., Biochem. Biophys. Res. Chem., 1991;178:656, Hosoda K., et al., FEBS Lett., 1991;287:23). The ETA receptor clearly mediates vasoconstriction and there have been a few reports implicating the ETB receptor in the initial vasodilatory response to ET (Takayanagi R., et al., FEBS Lett., 1991;282:103). However, recent data has shown that the ETB receptor can also mediate vasoconstriction in some tissue beds (Panek R. L., et al., Biochem. Biophys. Res. Commun., 1992;183(2):566).
A recent study showed that selective ETB agonists caused only vasodilation in the rat aortic ring, possibly through the release of EDRF from the endothelium (ibid). Thus, reported selective ETB agonists, for example, the linear analog ET[1,3,11,15-Ala] and truncated analogs ET[6-21, 1,3,11,15-Ala], ET[8-21,11,15-Ala], and N-Acetyl-ET[10-21,11,15-Ala] caused vasorelaxation in isolated, endothelium-intact porcine pulmonary arteries (Saeki T., et al., Biochem. Biophys. Res. Commun., 1991;179:286). However, some ET analogs are potent vasoconstrictors in the rabbit pulmonary artery, a tissue that appears to possess an ETB, nonselective type of receptor (ibid).
Plasma endothelin-1 levels were dramatically increased in a patient with malignant hemangioendothelioma (Nakagawa K. et al., Nippon Hifuka Gakkai Zasshi, 1990;100:1453-1456).
Circulating endothelin levels are elevated in women with preeclampsia and correlate closely with serum uric acid levels and measures of renal dysfunction. These observations indicate a role for ET in renal constriction in preeclampsia (Clark B. A., et al., Am. J. Obstet. Qynecol., 1992;166:962-968).
Plasma immunoreactive endothelin-1 concentrations are elevated in patients with sepsis and correlate with the degree of illness and depression of cardiac output (Pittett J., et al., Ann Surg., 1991;213(3):262).
In addition the ET-1 antagonist BQ-123 has been evaluated in a mouse model of endotoxic shock. This ETA antagonist significantly increased the survival rate in this model (Toshiaki M., et al., 20.12.90. EP 0 436 189 A1).
ETA antagonist receptor blockade has been found to produce an antihypertensive effect in normal to low renin models of hypertension with a time course similar to the inhibition of ET-1 pressor responses (Basil M. K., et al., J. Hypertension, 1992;10(Suppl 4): S49). The endothelins have been shown to be arrhythmogenic, and to have positive chronotropic and inotropic effects, thus ET receptor blockade would be expected to be useful in arrhythmia and other cardiovascular disorders (Han S.-P., et al., Life Sci., 1990;46:767).
The widespread localization of the endothelins and their receptors in the central nervous system and cerebrovascular circulation has been described (Nikolov R. K., et al., Drugs of Today, 1992;28(5): 303-310). Intracerebroventricular administration of ET-1 in rats has been shown to evoke several behavioral effects. These factors strongly suggest a role for the ETs in neurological disorders. The potent vasoconstrictor action of ETs on isolated cerebral arterioles suggests the importance of these peptides in the regulation of cerebrovascular tone. Increased ET levels have been reported in some CNS disorders, i.e., in the CSF of patients with subarachnoid hemorrhage and in the plasma of women with preeclampsia. Stimulation with ET-3 under conditions of hypoglycemia have been shown to accelerate the development of striatal damage as a result of an influx of extracellular calcium. Circulating or locally produced ET has been suggested to contribute to regulation of brain fluid balance through effects on the choroid plexus and CSF production. ET-1 induced lesion development in a new model of local ischemia in the brain has been described.
Circulating and tissue endothelin immunoreactivity is increased more than twofold in patients with advanced atherosclerosis (Lerman A., et al., New England J. Med., 1991;325:997-1001). Increased endothelin immunoreactivity has also been associated with Buerger's disease (Kanno K., et al., J. Amer. Med. Assoc., 1990;264:2868) and Raynaud's phenomenon (Zamora M.R., et al., Lancet, 1990;336:1144-1147).
Increased plasma levels of endothelin have been measured in rats and humans (Stewart D. J., et al., Ann, Internal Medicine, 1991;114:464-469) with pulmonary hypertension.
Elevated levels of endothelin have also been measured in patients suffering from ischemic heart disease (Yasuda M., et al., Amer. Heart J., 1990;119:801-806) and either stable or unstable angina (Stewart J.T., et al., Br. Heart J., 1991;66:7-9).
Infusion of an endothelin antibody 1 hour prior to and 1 hour after a 60 minute period of renal ischaemia iresulted in changes in renal function versus control. In addition, an increase in glomerular platelet-activating factor was attributed to endothelin (Lopez-Farre A., et al., J. Physiology, 1991;444:513-522). In patients with chronic renal failure as well as in patients on regular hemodialysis treatment mean plasma endothelin levels were significantly increased (Stockenhuber F., et al., Clin. Sci. (Lond.), 1992;82:255-258).
Local intra-arterial administration of endothelin has been shown to induce small intestinal mucosal damage in rats in a dose-dependent manner (Mirua S., et al., Digestion, 1991;48:163-172). Furthermore, it has been shown that an anti-ET-1 antibody reduced ethanol-induced vasoconstriction in a concentration-dependent manner (Masuda E., et al., Am. J. Physiol., 1992;262:G785-G790). Elevated endothelin levels have been observed in patients suffering from Crohn's disease and ulcerative colitis (Murch S. H., et al., Lancet, 1992;339:381-384).
At the 3rd International Conference on Endothelin, Houston, Tex., February 1993, the nonpeptide endothelin antagonist RO 46-2005 has been reported to be effective in models of acute renal ischemia and subarachnoid hemorrhage in rats (Clozel M., et al., "Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist," Nature, 1993;365:759). In addition, the ETA antagonist BQ-123 has been shown to prevent early cerebral vasospasm following subarachnoid hemorrhage (Clozel M. and Watanabe H., Life sci., 1993;52:825-834.
Recently, an ETA selective antagonist demonstrated an oral antihypertensive effect (Stein P. D., et al., "The Discovery of Sulfonamide Endothelin Antagonists and the Development of the Orally Active ETA Antagonist 5-(Dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide," J. Med. Chem., 1994;37:329-331.
Table I below summarizes some of the conditions in which ET-1 is involved.
TABLE I______________________________________Plasma Concentrations of ET-1 in Humans                           ET Plasma    Levels   Normal Reported  Condition Control (pg/mL)______________________________________Atheroscierosis  1.4        3.2 pmol/L  Surgical operation 1.5 7.3  Buerger's disease 1.6 4.8  Takayasu's arteritis 1.6 5.3  Cardiogenic shock 0.3 3.7  Congestive heart failure (CHF) 9.7 20.4  Mild CHF 7.1 11.1  Severe CHF 7.1 13.8  Dilated cardiomyopathy 1.6 7.1Preeclampsia     10.4 pmol/L                       22.6 pmol/LPulmonary 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 2.2Crohn's Disease  0-24 fmol/mg                       4-64 fmol/mgCold pressor test            1.2        8.4  Raynaud's phenomenon 1.7 5.3  Raynaud's/hand cooling 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 arthritides 1.5 4.2  Malignant 4.3 16.2hemangioendothelioma            (after   removal)______________________________________
Copending U.S. application Ser. No. 08/384,083 covers nonpeptide endothelin antagonists of formula ##STR1## or a tautomeric open chain keto-acid form thereof or a pharmaceutically acceptable salt thereof wherein
R1 is cycloalkyl substituted or unsubstituted of from
3 to 12 carbon atoms, phenyl substituted with from 1 to 5 substituents, naphthyl unsubstituted or substituted with from
1 to 5 substituents, or heteroaryl unsubstituted or substituted with from
1 to 5 substituents;
R2 is alkyl substituted or unsubstituted straight, or branched of from 1 to 12 carbon atoms, cycloalkyl substituted or unsubstituted of from
3 to 12 carbon atoms, aryl which is unsubstituted or substituted with
from 1 to 5 substituents, heteroaryl which is unsubstituted or substituted
with from 1 to 3 substituents;
R3 is alkyl substituted or unsubstituted straight, or branched, of from 1 to 12 carbon atoms, cycloalkyl substituted or unsubstituted of from
This application for patent is hereby incorporated by reference. ##STR2## wherein:
__________________________________________________________________________R.sub.1                    R.sub.2 R.sub.3__________________________________________________________________________phenyl                     phenyl  phenyl  phenyl  phenyl p-chlorophenyl  phenyl  phenyl p-bromophenyl   - piperonyl                                phenyl p-chlorophenyl   - phenyl  o-chlorophenyl phenyl  phenyl  phenyl p-phenyl-phenyl  anisyl (p-methoxyphenyl)  phenyl phenyl  anisyl  α-furyl phenyl  phenyl  piperonyl p-chlorophenyl  anisyl  o-chlorophenyl phenyl  anisyl  o-methoxyphenyl phenyl  phenyl  phenyl mesityl  phenyl  phenyl p-methylphenyl  phenyl  o-chlorophenyl p-chlorophenyl  phenyl  phenyl p-methoxy-phenyl  anisyl  o-methylphenyl phenyl  phenyl  piperonyl p-bromophenyl  phenyl  piperonyl p-methoxy-phenyl__________________________________________________________________________
Japanese Patent Application Number 5[1993]178706 covers compounds of formula ##STR4## where R2 represents a 1 to 10 carbon alkyl group, 3 to 6 carbon cycloalkyl group, 2 to 10 carbon alkenyl group, 2 to 10 carbon alkynyl group, or phenylalkyl group with a total of less than 10 carbons,
R2 represents a hydrogen atom or hydroxyl group,
R3 and R4 each represent a lower alkyl group, or R3 and R4 together represent an alkylene group with a total of 3 to 6 carbons. The compounds are disclosed as insect repellents.
The present invention includes compounds of Formula I ##STR5## or a pharmaceutically acceptable salt thereof wherein: R1 is cycloalkyl substituted or unsubstituted of from
or branched, of from 1 to 12 carbon atoms,
heteroaryl which is unsubstituted or substituted with from 1 to 5 substituents,
R3 is alkyl substituted or unsubstituted straight,
heteroaryl which is unsubstituted or substituted with from 1 to 5 substituents;
R4 is alkyl, substituted or unsubstituted with from 1 to 5 substituents;
aryl unsubstituted or substituted with from 1 to 5 substituents;
R1 is phenyl substituted with from 1 to 5 substituents, naphthyl unsubstituted or substituted with from 1 to 5 substituents, or heteroaryl unsubstituted or substituted with from 1 to 5 substituents;
R2 is alkyl substituted or unsubstituted straight, or branched, of from 1 to 7 carbon atoms,
R3 is aryl substituted or unsubstituted, heteroaryl substituted or unsubstituted;
R4 is alkyl, unsubstituted or substituted with from 1 to 5 substituents;
heteroaryl unsubstituted or substituted with from 1 to 5 substituents; and
R1 is 4-piperonyl,
3,5 dimethyl,
3,5-dimethoxyphenyl, ##STR6## 3-methoxy-4,5-methylenedioxyphenyl; R2 is benzyl,
44-piperonylmethyl,
4-Me2 aminobenzyl,
3-Me2 aminobenzyl,
3-chlorobenzyl,
3,4-dimethoxy-5-(2-morpholin-4-yl-ethoxy)-benzyl,
3,4-dimethoxy-5-(3-morpholin-4-yl-propoxy)-benzyl,
3,4-dimethoxy-5-(2-dimethylaminoethoxy)-benzyl,
3,4-dimethoxy-5-(3-dimethylaminopropoxy)-benzyl,
3,4-dimethoxy-5-(2-(4-methylpiperazin)-1-yl- ethoxy)-benzyl,
3,4-dimethoxy-5-(3-(4-methylpiperazin)-l-yl-propoxy)-benzyl, or
4-methoxyphenyl, ##STR7## 3-methoxyphenyl, 3-methyl-4-methoxyphenyl,
3,4-dimethoxyphenyl, or
(1-Phenyl-ethyl)-carbamic acid-4-benzo[1,3]dioxol-5-yl-3-benzyl-2-(4-methoxy-phenyl)-5-oxo-2,5-dihydro-furan-2-yl ester,
(1-Naphthalen-1-yl-ethyl)-carbamic acid-4-benzo[1,3]dioxol-5-yl-2-(4-methoxy-phenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yl ester,
[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxy-phenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-acetic acid ethyl ester,
(1-Phenyl-ethyl)-carbamic acid 4-benzo[1,3]dioxol-5-yl-3-benzyl-2-(4-methoxyphenyl)-5-oxo-2,5-dihydro-furan-2-yl ester,
(1-Naphthylen-1-yl-ethyl)[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-,
[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-acetic acid ethyl ester,
2-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-3-phenyl-propionic acid ethyl ester,
Methyl-carbamic acid 4-benzo[1,3]dioxol-5-yl-3-(3,4,5-trimethoxy-benzyl)-2-(4-methoxyphenyl)-5-oxo-2,5-dihydro-furan-2-yl ester,
3-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-propionic acid ethyl ester,
Allyl-carbamic acid 4-benzo[1,3]dioxol-5-yl-3-(3,4,5-trimethoxy-benzyl)-2-(4-methoxyphenyl)-5-oxo-2,5-dihydro-furan-2-yl ester,
2-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-acetic acid,
2-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-acetaldehyde,
2-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-3-methyl-butryic acid ethyl ester,
3-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-propionic acid,
2-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-3-methyl-butryic acid,
2-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-3-phenyl-propionic acid,
2-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-4-methyl-pentanoic acid ethyl ester,
2-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-4-methyl-pentanoic acid,
2-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-4-methyl-pentanoic acid t-butyl ester,
2-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-4-methyl-pentanoic acid benzyl ester,
2-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-4-methyl-pentanoic acid methyl ester,
2-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-4-methyl-pentanoic acid (2,2,2-trichlorethyl ester),
2-[4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylamino]-3-carboxyethyl propionic acidethyl esteracetic acid, and
3-Phenyl propionic acid [4-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yl] ester.
Elevated levels of endothelin have been postulated to be involved in a number of pathophysiological states including diseases associated with the cardiovascular system as well as various metabolic and endocrinological disorders. As antagonists of endothelin, the compounds of Formula I are useful in the treatment of hypertension, myocardial infarction, diabetes, cerebral vasospasm, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, chronic and acute renal failure, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, stroke, head injury, and ischemic bowel disease.
In the compounds of Formula I, the term "alkyl" means a straight or branched hydrocarbon radical having from 1 to 12 carbon atoms unless otherwise specified and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, allyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, and dodecyl. The alkyl group is unsubstituted or substituted by from 1 to 6 substituents selected from alkyl, alkoxy, thioalkoxy all as defined herein, hydroxy, thiol, nitro, halogen, amino, monosubstituted amino, disubstituted amino, formyl, cycloalkyl, sulfonic acid, ##STR8## aryl, or heteroaryl wherein alkyl, aryl, and heteroaryl are defined as herein.
The term "cycloalkyl" means a saturated hydrocarbon ring which contains from 3 to 12 carbon atoms unless otherwise specified, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl. The cycloalkyl ring may be unsubstituted or substituted by from 1 to 3 substituents selected from alkyl, cycloalkyl, cycloalkoxy, alkoxy, thioalkoxy all as defined herein, hydroxy, thiol, nitro, halogen, amino, monosubstituted amino, disubstituted amino, formyl, sulfonic acid, carboxyl, nitrile, alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl, arylsulfonyl, ##STR9## aryl, or heteroaryl wherein alkyl, aryl, and heteroaryl are defined as herein.
Two alkoxy or thioalkoxy groups can be taken together to form a cyclic group such as ##STR10## where X and Y are independently either O or S and n=1, 2, 3, or 4.
The term "aryl" means an aromatic radical which is a phenyl group, a benzyl group, a naphthyl group, a biphenyl group, a pyrenyl group, an anthracenyl group, or a fluorenyl group and the like, unsubstituted or substituted by 1 to 5 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, thiol, nitro, halogen, sulfonic acid, amino, monosubstituted amino, disubstituted amino, formyl, carboxy, nitrile, arylsulfoxyl, alkylsulfoxyl, arylsulfonyl, alkylsulfonyl, ##STR11## or heteroaryl wherein alkyl, aryl, and heteroaryl are defined as above.
The term "heteroaryl" means a heteroaromatic radical which is 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, 3- 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-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, or 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl, unsubstituted or substituted by 1 to 3 substituents selected from alkyl as defined above, aryl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, thiol, nitro, halogen, formyl, amino, monosubstituted amino, disubstituted amino, carboxyl, sulfonic acid, ##STR12## alkyl is as defined above or phenyl.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, 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, isethionic and the like. Also contemplated are salts of amino acids such as lysinate, arginate, and the like and gluconate, galacturonate (see, for example, Berge S. M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977;66:1-19).
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, piperazine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge S. M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977;66:1-19).
The compounds of Formula I are valuable antagonists of endothelin. The tests employed indicate that compounds of the invention possess endothelin antagonist activity. Thus, the compounds were tested for their ability to inhibit [125 I]-ET-1([125 I]-Endothelin-1) binding in a receptor assay. Selected compounds were also tested for antagonist activity by inhibition of ET-1 stimulated arachidonic acid release and ET-1 stimulated vasoconstriction. The following testing procedures were used (Doherty A. M., et al., "Design of C-Terminal Peptide Antagonists of Endothelin: Structure-Activity Relationships of ET-1 [16-21, D-His16 ]", Bioorganic and Medicinal Chemistry Letters, 1993;3:497-502).
ENDOTHELIN RECEPTOR BINDING ASSAY-A (ERBA-A) INTACT CELL BINDING OF [125 I]-ET-1
Materials and Terms Used:
The growth media was Dulbecco's Modified Eagles/Ham's F12 which contained 10% fetal bovine serum and antibiotics (penicillin/streptomycin/fungizone).
The assay buffer was a medium 199 containing Hanks salts and 25 mM Hepes buffer (Gibco 380-2350AJ), supplemented with penicillin/streptomycin/fungizone (0.5%) and bovine serum albumin (1 mg/mL).
First, add 0.5 mL warm assay buffer (described above) to the aspirated growth media and preincubate for 2 to 3 hours in a 37° C. water bath (do not put back in the 5% carbon dioxide). Second, remove the assay buffers, place the dish on ice, and add 150 μL of cold assay buffer described above to each well. Third, add 50 mL each of cold [125 I]-ET-1 and competing ligand to the solution (at the same time if possible). Next, place dish in a 37° C. water bath for about 2 hours and gently agitate the dish every 15 minutes. Discard the radioactive incubation mixture in the sink and wash wells 3 times with 1 mL of cold phosphate buffered saline. Last, add 250 mL of 0.25 molar sodium hydroxide, agitate for 1 hour on a rotator, and then transfer the sodium hydroxide extract to gamma counting tubes and count the radioactivity.
ENDOTHELIN RECEPTOR BINDING ASSAY-B (ERBA-B) [125 I]-ET-1 BINDING IN RAT CEREBELLAR MEMBRANES
Materials and Terms 2sed:
The tissue is made up of 20 mM tris(hydroxy-methyl)aminomethane hydrochloride (Trizma) buffer, 2 mM ethylenediaminetetra acetate, 100 μM phenylmethyl-sulfonyl fluoride.
Amersham [125 I]-ET-1 (aliquots of 2×106 cpm per 100-mL aliquot of [125 I]-ET-1 with 5.2 mL dilution buffer, place on ice until use (final concentration will be 20,000 cpm per tube, or 25 pM).
Add 50 μL each of cold [125 ]-ET-1 and competing ligand to tubes on ice. Mix in 150 μL of tissue to each tube, vortex briefly, then tap to force all liquids to bottom (total assay volume=250 μL). Then place the tubes in a 37° C. water bath for 2 hours.
Add 2.5 mL cold wash buffer (50 mM Trizma buffer) to each tube, filter, and then wash tube with additional 2.5 mL wash buffer and add to filter. Finally, wash filters with an additional 2.5 mL of cold wash buffer.
The above process has also been modified by using human recombinant CHO-K1 cells.
The tissue used for human ETB was recombinant human ETB receptor expressed in CHO-K1 cells (chinese hamster ovary cells). The gene for human ETB receptor was cloned and inserted into the pRc-CMW expression vector, then transfected into CHO-K1 cells by electroporation. For binding assays, membranes (0.7 mg protein) of CHO-K1 cells expressing recombinant human ETB receptor were used.
IN VITRO INHIBITION OF ET-1 STIMULATED ARACHIDONIC ACID RELEASE (AAR) IN CULTURED RABBIT VASCULAR SMOOTH MUSCLE CELLS (ETA) BY THE COMPOUNDS OF THE INVENTION
Antagonist activity is measured by the ability of added compounds to reduce endothelin-stimulated arachidonic acid release in cultured vascular smooth muscle cells as arachidonic acid release (AAR). [3 H] Arachidonic Acid Loading Media (LM) is DME/F12+0.5% FCS×0.25 mCi/mL [3 H] arachidonic acid (Amersham). Confluent monolayers of cultured rabbit renal artery vascular smooth muscle cells were incubated in 0.5 mL of the LM over 18 hours, at 37° C., in 5% CO2. The LM was aspirated and the cells were washed once with the assay buffer (Hank's BSS+10 mM HEPES+fatty acid-free BSA (1 mg/mL)), and incubated for 5 minutes with 1 mL of the prewarmed assay buffer. This solution was aspirated, followed by an additional 1 mL of prewarmed assay buffer, and further incubated for another 5 minutes. A final 5-minute incubation was carried out in a similar manner. The same procedure was repeated with the inclusion of 10 μL of the test compound (1 nM to 1 μM) and 10 μL ET-1 (0.3 nM) and the incubation was extended for 30 minutes. This solution was then collected, 10 μL of scintillation cocktail was added, and the amount of [3 H] arachidonic acid was determined in a liquid scintillation counter.
IN VITRO ANTAGONISM OF ET-1 STIMULATED VASOCONSTRICTION (VERA-A) IN THE RABBIT FEMORAL ARTERY (ETA) AND SARAFOTOXIN 6c STIMULATED VASOCONSTRICTION IN THE RABBIT PULMONARY ARTERY (ETB)
Male New Zealand rabbits were killed by cervical dislocation and exsanguination. Femoral and pulmonary arteries were isolated, cleaned of connective tissue, and cut into 4-mm rings. The endothelium was denuded by placing the rings over hypodermic tubing (32 gauge for femoral rings and 28 gauge for pulmonary rings, Small Parts, Inc, Miami, Fla.) and gently rolling them. Denuded rings were mounted in 20 mL organ baths containing Krebs-bicarbonate buffer (composition in mM: NaCl, 118.2; NaHCO3, 24.8; KCl, 4.6; MgSO4 7. H2 O, 1.2; KH2 PO4, 1.2; CaCl2. 2H2 O; Ca-Na2 EDTA, 0.026; dextrose, 10.0), that was maintained at 37° C. and gassed continuously with 5% CO2 in oxygen (pH 7.4). Resting tension was adjusted to 3.0 g for femoral and 4.0 g pulmonary arteries; the rings were left for 90 minutes to equilibrate. Vascular rings were tested for lack of functional endothelium (i.e., lack of an endothelium-dependent relaxation response to carbachol (1.0 μM) in norepinephrine (0.03 μM) contracted rings. Agonist peptides, ET-1 (femoral), and S6c (pulmonary), were cumulatively added at 10- minute intervals. The ET antagonists were added 30 minutes prior to adding the agonist and pA2 values were calculated (Table II).
The data in Table II below show the endothelin receptor binding and antagonist activity of representative compounds of the instant invention.
TABLE II______________________________________Example ERBA-A.sup.a            ERBA-B.sup.a                       AAR-A.sup.c                              VERA-A.sup.b______________________________________1       18.0.sup.c            >2500.sup.c                       --     6.1  2  1.0.sup.c >2500.sup.c -- --  3  0.35.sup.c 1800.sup.c 3.4 7.3______________________________________ .sup.a IC.sub.50 values in nM .sup.b pA2 values .sup.c Human cloned receptor data
As can be seen in Table II above, the compounds of Formula I bind to the endothelin receptors ETA (ERBA-A) and ETB (ERBA-B) in the μM to nM range.
Furthermore, in vitro activity is demonstrated by the antagonism of endothelin-stimulated vasoconstriction of rabbit femoral artery.
The compounds of Formula I may be prepared as in Scheme I.
Condensation of the alcohol of the generic α-hydroxybutenolide with an isocyanate in a nonprotic solvent (such as methylenechloride, acetonitrile, ethylacetate) with or without a catalyst (such as DMAP, CuCl2). ##STR13##
EXAMPLE 1 ##STR14## (1-Phenyl-ethyl)-carbamic acid-4-benzo[1,3]dioxol-5-yl-3-benzyl-2-(4-methoxy-phenyl)-5-oxo-2,5-dihydro-furan-2-yl ester
To 15 mL dichloromethane was added 3-benzo[1,3] dioxol-5-yl-5-hydroxy-5-(4-methoxyphenyl)-4-(benzyl)-5H-furan-2-one 416 mg (1.00 mmol) and stirred to dissolve. To this was added (S)-1-(1-phenyl)ethyl isocyanate 162 mg (1.1 mmol), and the mixture was stirred at room temperature for 24 hours. To the mixture was added a catalytic amount of 4-dimethylaminopyridine 15 mg (0.123 mmol). The mixture was stirred at room temperature for 24 hours. The solution was washed with 25 mL water and 25 mL brine, and the organic phase was separated and dried over magnesium sulfate, then evaporated to dryness. The crude product was then purified by flash chromatography (70 g silica gel, 33% EtOAc/Hexane). The product was isolated by evaporation of the appropriate fractions to give 310 mg (55%) as a white foam. The product was identified by 1 H NMR, IR, MS, [M+H]+ =546 Da. and microanalysis.
EXAMPLE 2 ##STR15## (1-Naphthalen-1-yl-ethyl)-carbamic acid-4-benzo [1,3]dioxol-5-yl-2-(4-methoxy-phenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yl ester
To 15 mL dichloromethane was added 3-benzo[1,3] dioxol-5-yl-5-hydroxy-5-(4-methoxyphenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one 1.00 g (1.98 mmol) and stirred to dissolve. To this was added (S)-1-(1-naphthyl)ethyl isocyanate 414 mg (2.1 mmol) and a catalytic amount of 4-dimethylaminopyridine 20 mg (0.164 mmol). The mixture was stirred at room temperature for 24 hours. The solution was washed with 50 mL water and 50 mL brine, and the organic phase was separated and dried over magnesium sulfate, then evaporated to dryness. The crude product was then purified by flash chromatography (150 g silica gel, 10% EtOAc/CH2 Cl2). The product was isolated by evaporation of the appropriate fractions to give 840 mg (60%) as a white foam. The product was identified by 1 H NMR, MS, [M+H]+ =704 Da. and microanalysis.
EXAMPLE 3 ##STR16## [4-Benzo[1,3]dioxol-5-yl-2-(4-methoxy-phenyl)-5-oxo-3-(3,4,5-trimethoxy-benzyl)-2,5-dihydro-furan-2-yloxycarbonylaminol-acetic acid ethyl ester
To 15 mL dichloromethane was added 3-benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxyphenyl)-4-(3,4,5-trimethoxybenzyl)-5H-furan-2-one 1.00 g (1.97 mmol) and stirred to dissolve. To this was added ethyl isocyanato acetate 284 mg (2.2 mmol) and a catalytic amount of 4-dimethylaminopyridine 10 mg (0.082 mmol). The mixture was stirred at room temperature for 24 hours. The solution was washed with 25 mL 1.0N HCl , 25 mL water, and 25 mL brine, and the organic phase was separated and dried over magnesium sulfate, then evaporated to dryness. The crude product was then purified by flash chromatography (150 g silica gel, 10% EtOAc/CH2 C12). The product was isolated by evaporation of the appropriate fractions to give 122 mg (9.7%) as a white foam. The product was identified by 1 H NMR, MS, [M+H]+ =636 Da. and microanalysis.
1. A method of treating congestive heart failure and myocardial infarction/myocardial ischemia comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of formula I ##STR17## or a pharmaceutically acceptable salt thereof wherein: R1 is cycloalkyl substituted or unsubstituted of from 3 to 12 carbon atoms,
heteroaryl unsubstituted or substituted with from 1 to 5 substituents which heteroaryl has only oxygen as the heteroatom;
R2 is alkyl substituted or unsubstituted straight, or branched, of from 1 to 12 carbon atoms,
heteroaryl which is unsubstituted or substituted with from 1to 5 substituents which heteroaryl has only oxygen as the heteroatom;
R3 is alkyl substituted or unsubstituted straight, or branched, of from 1 to 12 carbon atoms,
heteroaryl which is unsubstituted or substituted with from 1 to 5 substituents which heteroaryl has only oxygen as the heteroatom;
heteroaryl unsubstituted or substituted with from 1 to 5 substituents which heteroaryl has only oxygen as the heteroatom; and
X is O or S with the proviso that (1-phenyl-ethyl)-carbamic acid-4-benzo[1,3]dioxol-5-yl-3-benzyl-2-(4-methoxy-phenyl)-5-oxo-2,5-dihydro-furan-2-yl ester is not included and furthermore, at least one of R1-R4 group represents a heteroaryl group in unit dosage form.
2. A method of treating subarachnoid hemorrhage, cerebral ischemia and/or cerebral infarction; or ischemic disease comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of formula I ##STR18## or a pharmaceutically acceptable salt thereof wherein: R1 is cycloalkyl substituted or unsubstituted of from 3 to 12 carbon atoms,
X is O or S with the proviso that (1-phenyl-ethyl)-carbamic acid-4benzo[1,3]dioxol-5-yl-3-benzyl-2-(4-methoxy-phenyl)-5-oxo-2,5-dihydro-furan-2-yl ester is not included and furthermore, at least one of R1-R4 group represents a heteroaryl group in unit dosage form.
US09247534 1995-07-06 1999-02-10 Butenolide endothelin antagonists Expired - Fee Related US6017951A (en)
US90495 true 1995-07-06 1995-07-06
US08981059 US5922759A (en) 1996-06-21 1996-06-21 Butenolide endothelin antagonists
PCT/US1996/010651 WO1997002265A1 (en) 1995-07-06 1996-06-21 Butenolide endothelin antagonists
US09247534 US6017951A (en) 1995-07-06 1999-02-10 Butenolide endothelin antagonists
US08981059 Division US5922759A (en) 1995-07-06 1996-06-21 Butenolide endothelin antagonists
US6017951A true US6017951A (en) 2000-01-25
ID=25528078
US08981059 Expired - Fee Related US5922759A (en) 1995-07-06 1996-06-21 Butenolide endothelin antagonists
US09247534 Expired - Fee Related US6017951A (en) 1995-07-06 1999-02-10 Butenolide endothelin antagonists
US (2) US5922759A (en)
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