ENDOTHELIN ANTAGONISTS II

Abstract: Novel antagonists of endothelin are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction, metabolic, endocrinological, neurological disorders, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease, restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, and diabetes. In the claimed new compounds, the N-terminal 16-His is replaced by a building-block of formula ( alpha ).

Description: ENDOTHELIN ANTAGONISTS II BACKGROUND OF THE INVENTION 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 novel compounds of the present invention are antagonists of endothelin useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction, metabolic, endocrinological and neurological disorders, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease, restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, and diabetes. 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) . The unique bicyclic structure and corresponding arrangement of the disulfide bridges of ET-1, which are the same for the endothelins, VIC, and the sarafotoxins, has led to significant speculation as to the importance of the resulting induced secondary structure to receptor binding and functional activity. ET-1 analogues with incorrect disulfide pairings exhibit at least 100-fold less vasoconstrictor activity. The flexible C-terminal hexapeptide of ET-1 has been shown to be important for binding to the ET receptor and functional activity in selected tissues. Additionally, the C-terminal amino acid (Trp-2l) has a critical role in binding and vasoconstrictor activity, since ET[l-20] exhibits approximately 1000-fold less functional activity. Endothelin is involved in many human disease states_ Several in vivo studies with ET antibodies have been reported in disease models. Left coronary artery ligation and reperfusion to induce myocardial infarction in the rat heart, caused a four- to sevenfold increase in endogenous endothelin levels. Administration of ET antibody was reported to reduce the size of the infarction in a dose-dependent manner (Watanabe, T. , et al, "Endothelin in Myocardial Infarction, π Nature (Lond.) 344:114 (1990)). Thus, ET may be involved in the pathogenesis of congestive heart failure and myocardial ischemia (Margulies, K.B., et al, "Increased Endothelin in Experimental Heart Failure," Circulation 82:2226 (1990)) . 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. 83:1762 (1989)). 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 A 2 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. 1:76 (1990)). 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)-l and ET-2- Induced Vasoconstriction by Anti-ET-1 Monoclonal Antibody," Chem. Pharm. Bull.. 39:1295 (1991)). 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.. 17:691 (1990)) . Other investigators have reported that infusion of ET-specific antibodies into spontaneously hypertensive rats (SHR) decreased mean arterial pressure (MAP) , and increased glomerular filtration rate and renal blood flow. In the control study with normotensive Wistar-Kyoto rats ( KY) there were no significant changes in these parameters (Ohno, A. Effects of Endothelin-Specific Antibodies and Endothelin in Spontaneously Hypertensive Rats," J. Tok o Women's Med. Coll.. 61:951 (1991)). In addition, elevated levels of endothelin have been reported in several disease states (see Table I below) . Burnett and co-workers 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 83:1808 (1991)). 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 the anesthetized dog with congestive heart failure, a significant two- to threefold elevation of circulating ET levels has been reported (Cavero, P.G. , et al, "Endothelin in Experimental Congestive Heart Failure in the Anesthetized Dog, " Am. J. Physiol. 259:F312 (1990)), and studies in humans have shown similar increases (Rodeheffer, R.J., et al, "Circulating Plasma Endothelin Correlates With the Severity of Congestive Heart Failure in Humans, " Am. J. Hypertension 4:9A (1991)) . When ET was chronically infused into male rats, to determine whether a long-term increase in circulating ET levels would cause a sustained elevation in mean arterial blood pressure, significant, sustained, and dose- dependent increases in mean arterial BP were observed. Similar results were observed with ET-3 although larger doses were required (Mortenson, L.H., et al, "Chronic Hypertension Produced by Infusion of Endothelin in Rats," Hypertension. 15:729 (1990)). The distribution of the two cloned receptor subtypes, termed ET A and ET B , have been studied extensively (Arai, H. , et al, Nature 348:730 (1990), Sakurai, T. , et al, Nature 348:732 (1990)). The ET A , 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. 88:3185 (1991)). The ET B receptor, originally cloned from rat lung, has been found in rat cerebellum and in endothelial cells, although it is not known if the ET B 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. 178:656 (1991), Hosoda, K. , et al, FEBS Lett. 287:23 (1991)). The ET A receptor clearly mediates vasoconstriction and there have been a few reports implicating the ET B receptor in the initial vasodilatory response to ET (Takayanagi, R. , et al, FEBS Lett. 282:103 (1991)). However, recent data has shown that the ET B receptor can also mediate vasoconstriction in some tissue beds (Panek, R.L., et al, Biochem. Biophys. Res. Commun. 183(2):566 (1992)) . Comparison of the receptor affinities of the ETs and SRTXs in rats and atria (ET A ) or cerebellum and hippocampus (ET B ) , indicate that SRTX-c is a selective ET B ligand (Williams, D.L., et al, Biochem. Biophys. Res. Commun.. 175:556 (1991)). A recent study showed that selective ET B agonists caused only vasodilation in the rat aortic ring, possibly through the release of EDRF from the endothelium (ibid) . Thus, reported selective ET B agonists, for example, the linear analog ET[l,3,ll,15-Ala] and truncated analogs ET[6-21, 1,3,11,15-Ala] , ET[8-21,ll,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. 179:286 (1991)). However, some ET analogs are potent vasoconstrictors in the rabbit pulmonary artery, a tissue that appears to possess an ET B y, nonselective type of receptor (ibid) . Plasma endothelin-1 levels were dramatically increased in a patient with malignant hemangioendothelioma (K. Nakagawa et al, Nippon Hifuka Gakkai Zasshi. 1990, 100, 1453-1456). The ET receptor antagonist BQ-123 has been shown to block ET-l induced bronchoconstriction and tracheal smooth muscle contraction in allergic sheep providing evidence for expected efficacy in bronchopulmonary diseases such as asthma (Noguchi, et al, Am. Rev. Respir. Pis.. 1992, 145 (4 Part 2), A858) . 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. Gvnecol., 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 Surσ.. 1991, 213(3), 262) . In addition the ET-1 antagonist BQ-123 has been evaluated in a mouse model of endotoxic shock. This ET A 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 eliciting both sustained vasoconstriction of the hepatic vasculature and a significant increase in hepatic glucose output (Gandhi C.B., et al, Journal of Biological Chemistry. 1990, 265(29), 17432). In streptozotocin-diabetic rats there is an increased sensitivity to endothelin-1 (Tammesild P.J., et al, Clin. Exp. Pharmacol. Physiol.. 1992, 19(4), 261). In addition increased levels of plasma ET-1 have been observed in microalbuminuric insulin-dependent diabetes mellitus patients indicating a role for ET in endocrine disorders such as diabetes (Collier A. , et al. Diabetes Care, 1992, 15(8), 1038). ET A 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 (A. Lerman, et al, New England J. Med.. 1991, 325, 997-1001). Increased endothelin immunoreactivity has also been associated with Buerger's disease (K. Kanno, et al, J. Amer. Med. Assoc. 1990, 264, 2868) and Raynaud's phenomenon (M.R. Zamora, et al, Lancet, 1990, 336, 1144-1147) . Likewise, increased endothelin concentrations were observed in hypercholesterolemic rats (T. Horio, et al, Atherosclerosis. 1991, 89, 239- 245) . An increase of circulating endothelin levels was observed in patients that underwent percutaneous transluminal coronary angioplasty (PTCA) (A. Tahara, et al, Metab. Clin. Eχp_. 1991, 40, 1235-1237, K. Sanjay, et al, Circulation. 1991, 84(Suppl. 4), 726). Increased plasma levels of endothelin have been measured in rats (T.J. Stelzner, et al. Am. J. Physiol.. 1992, 262, L614-L620) and individuals (T. Miyauchi, et al, Jpn. J. Pharmacol.. 1992, 58, 279P, D.J. Stewart, et al, Ann. Internal Medicine. 1991, 114464-469) with pulmonary hypertension. Elevated levels of endothelin have also been measured in patients suffering from ischemic heart disease (M. Yasuda, et al, Amer. Heart J.. 1990, 119 801-806, S.G. Ray, et al, Br. Heart J.. 1992, 67, 383- 386) and either stable or unstable angina (J.T. Stewart, et al, Br. Heart J.. 1991, 66, 7-9) . Infusion of an endothelin antibody lh prior to and lh after a 60 minute period of renal ischaemia resulted in changes in renal function versus control. In addition, an increase in glomerular platelet- activating factor was attributed to endothelin (A. Lopez-Farre, 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 (F. Stockenhuber, et al, Clin. Sci. (Lond.). 1992, 82, 255-258) . In addition it has been suggested that the proliferative effect of endothelin on mesangial ceils may be a contributing factor in chronic renal failure (P.iT. Schultz, J. Lab. Clin. Med.. 1992, 119, 448- 449) . Local intra-arterial administration of endothelin has been shown to induce small intestinal mucosal damage in rats in a dose-dependent manner (S. Mirua, et al, Digestion. 1991, 48, 163-172) . Administration of endothelin-1 in the range of 50-500 pmol/kg into the left gastric artery increased the tissue type plasminogen activator release and platelet activating formation, and induced gastric mucosal hemorrhagic change in a dose dependent manner (I. Kurose, et al, Gut. 1992, 33, 868-871). Furthermore, it has been shown that an anti-ET-1 antibody reduced ethanol- induced vasoconstriction in a concentration-dependent manner (E. Masuda, 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 (S.H. Murch, et al, Lancet, 1992, 339, 381-384) . Recently the nonpeptide endothelin antagonist RO 46-2005 has been reported to be effective in models of acute renal ischemia and subarachnoid hemorrhage in rats (3rd International Conference on Endothelin. Houston, Texas, February 1993) . In addition, the ET A antagonist BQ-123 has been shown to prevent early cerebral vasospasm following subarachnoid hemorrhage (M. Clozel and H. Watanabe, Life Sci.. 52 . :825-834 (1993)) . TABLE I. Plasma Concentrations of ET-1 in Humans Rovero, P., et al, British Journal of Pharmacology 101. pages 232-236 (1990) disclosed various analogs of the C-terminal hexapeptide of ET-1, none of which were reported to be antagonists of ET-1. Doherty, A. M., et al, Abstract, Second International Conference on Endothelin, Tsukuba, Japan, December 9, 1990, and the published manuscript (J. Cardiovasc- Pharm. 17 (Suppl. 7) , 1991, pp. 559-561) disclosed various analogs of the C-terminal hexapeptide of ET-1, none of which exhibited any functional activity. Copending United States Patent Application Serial Number 07/995,480 discloses a series of novel antagonists of endothelin. However, we have surprisingly and unexpectedly found that a series of C-terminal hexapeptide and related analogs of ET-1 are receptor antagonists of endothelin. Additional data for the activity of this series of peptides is found in the following references (W.L. Cody, et al, J. Med. Chem.. 1992, 35, 3301-3303., D.M. LaDouceur, et al, FASEB, 1992) . SUMMARY OF THE INVENTION Accordingly, the present invention is a compound of Formula I AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 wherein AA 1 is wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, fluorenylmethyl, TS.T __) _5 , wherein R and R are each the same or Rl 3 different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, or fluorenylmethyl, 0 -C-OR 2, wherein R2 is as defined "~ above, -OR 2 , wherein R 2 is as defined above, 0 -N-C-N-R 3 , wherein R 2 and R 3 are as defined 2 R2 above, 0 -C-C(R ) 3 , wherein R is F, Cl, Br, or I, -CH 2 -0R 2 , wherein R 2 is as defined above, wherein R a and R 3 are as defined above excluding R 3 is hydrogen, or -C 11 -R2, wherein R" 1 is as defined above, R 1 is hydrogen or alkyl, Z is -0-, -s(o> fi , wherein m is zero or an integer of 1 or 2, -N-, wherein R 2 is as defined above, R l 2 ^ -(CH 2 ) n -, wherein n is zero or an integer of 1, 2, 3, or 4, -(CH 2 ) n -CH=CH-(CH 2 ) n -, wherein n is as defined above, O -C-, -, wherein R 1 and R 2 are as defined above, or wherein R 2 and R 3 are each the same or different and each is as defined above, X and Y are the same and substituted at the same position on the aromatic ring and each may be one, two, three, or four substituents selected from the group consisting of hydrogen, halogen, alkyl, -C0 2 R 2 , wherein R 2 is as defined above, -CONR 2, wherein R2 and R3 are as defined R ι 3 above, -NR 2, wherein R2 and R3 are as defined R ι 3 above, or n tro or wherein R, Z, X, and Y are as defined above; A ^ is wherein R 4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, are each the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, or hetero . aryl, -0R 2b , wherein R 2b is as defined above, wherein R 2b and R 3b are each the same or different and each is as defined above for R 2b and R 3b , C-R , wherein R is as defined above, NH -NH-C-NH-R 2b wherein R 2b is as defined above, or is as defined above, and R 1 and n are as defined above, or AA 2 is absent; wherein R 5 is hydrogen, alkyl, aryl, heteroaryl, are each the same or different and each is as defined above, C-R , wherein R is as defined above, or -C-OR , wherein R is as defined above, and R 1 and n are as defined above, or AA 3 is absent; AA 4 and AA 5 are each independently absent or each is independently wherein R 6 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, and R 1 and n are as defined above; AA 6 is R 1 -N--C*-R 8 R 1 ( a 2 ) n R 7 wherein R 7 is aryl or heteroaryl, R 8 is 0 -C ιι-0R i x , wherein R is as defined above. -0R 1 , wherein R 1 is as defined above, C-N-R 1 , wherein R 1 is as defined ii above, or -C^-OR 1 , wherein R 1 is as defined above, and R 1 and n are as defined above; * stereochemistry at C in AA 1 , AA 2 , AA 3 , AA 4 , or AA 5 is D, L, or DL and * stereochemistry at C in AA 6 is L; or a pharmaceutically acceptable salt thereof. 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, metabolic, endocrinological and neurological disorders, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, and chronic and acute renal failure, preeclampsia, atherosclerotic disorders including Raynaud's disease, restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, and diabetes. A still further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of a compound of Formula I in unit dosage form in the treatment methods mentioned above. Finally, the present invention is directed to methods for production of a compound of Formula I. DETAILED DESCRIPTION OF THE INVENTION In the compounds of Formula I, the term "alkyl" 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- onyl, n-decyl, undecyl, dodecyl, and the like. The term "alkenyl" means a straight or branched unsaturated hydrocarbon radical having from 2 to 12 carbon atoms and includes, for example, ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 3-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl, and the like. The term "alkynyl" means a straight or branched triple bonded unsaturated hydrocarbon radical having from 2 to 12 carbon atoms and includes, for example, ethynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 3-heptynyl, 1-octynyl, 2-octynyl, l-nonynyl, 2-nonynyl, 3-nonynyl, 4-nonynyl, 1-decynyl, 2-decynyl, 2-undecynyl, 3-undecynyl, 3-dodecynyl, and the like. The term "cycloalkyl" means a saturated hydrocarbon ring which contains from 3 to 12 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like. The term "cycloalkylalkyl" means a saturated hydrocarbon ring attached to an alkyl group wherein alkyl is as defined above. The saturated hydrocarbon ring contains from 3 to 12 carbon atoms. Examples of such are cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, adamantylmethyl and the like. The terms "alkoxy" and "thioalkoxy" are 0-alkyl or S-alkyl as defined above for alkyl. 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, 3,3-diphenylalanyl, 10,ll-dihydro-5H-dibenzo[a,d] - (cyclohepten-5-yl)glycyl, or a fluorenyl group and the like, unsubstituted or substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, 0 hydroxy, thiol, nitro, halogen, amino, -NH-C-alkyl 0 wherein alkyl is as defined above, -C-O-alkyl wherein 0 alkyl is as defined above, -C-alkyl wherein alkyl is as defined above, or aryl. The term "arylalkyl" 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 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-benzotb]thienyl, or 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6- t or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl, unsubstituted or substituted by 1 to 2 substituents selected from alkyl as defined above, aryl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, thiol, 0 nitro, halogen, formyl, amino, -NH-C-alkyl wherein 0 alkyl is as defined above, -C-O-alkyl wherein alkyl O is as defined above, -C-alkyl wherein alkyl is as defined above or phenyl. The term "heterocycloalkyl" means 2- or 3-tetrahydrothieno, 2- or 3-tetrahydrofurano, 2- or 3-pyrrolidino, 2-, 4-, or 5-thiazolidino, 2-, 4-, or 5-oxazolidino, 2-, 3-, or 4-piperidino, N-morpholinyl or N-thiamorpholinyl. "Halogen" is fluorine, chlorine, bromine or iodine. The following table provides a list of abbreviations and definitions thereof used in the present invention. TABLE Abbreviation Amino Acid Bhg 10,ll-Dihydro-5H-dibenzo[a,d] - (cyclohepten-5-yl)glycine or α-Amino-10,ll-dihydro-5H-dibenzo- [a,d]cycloheptene-5-acetic acid Bip . (Paraphenyl)phenylalanine If the optical activity of the amino acid is other than L(S), the amino acid or abbreviation is preceded by the appropriate configuration D(R) or DL(RS) . Abbreviation* Modified and Unusual Amino Acid (cont) Dip 3,3-Diphenylalanine 3Hyp 3-Hydroxyproline 4Hyp 4-Hydroxyproline N-MePhe N-Methylphenylalanine N-MeAsp N-Methylaspartic acid Nva Norvaline Nle Norleucine Orn Ornithine Abu 2-Aminobutyric acid Alg 2-Amino-4-pentenoic acid (AllyIglycine) Arg(N0 2 ) IS^-nitroarginine Atm 2-Amino-3- (2-amino-5- thiazole)propanoic acid Cpn 2-Amino-3-cyclopropanepropanoic acid (Cyclopropylalanine) Chx Cyclohexylalanine (Hexahydrophenyl- alanine) Emg 2-Amino-4,5(RS) -epoxy-4-pentenoic acid His(Dnp) N ιm -2,4-Dinitrophenylhistidine HomoGlu 2-Aminoadipic acid HomoPhe 2-Amino-5-phenylpentanoic acid (Homophenylalanine) Me (0) Methionine sulfoxide Met(0 2 ) Methionine sulfone 1-Nal 3- (1' -Naphthyl)alanine 2-Nal 3- (2 τ -Naphthyl)alanine Nia 2-Amino-3-cyanopropanoic acid (Cyanoalanine) Pgl Phenylglycine Pgy 2-Aminopentanoic acid (Propylglycine) Abbreviation* Modified and Unusual Amino Acid (cont) Pha 2-Amino-6- (1-pyrrolo) -hexanoic acid Pyr 2-Amino-3- (3-pyridyl) -propanoic acid (3-Pyridylalanine) Tic 1,2,3,4-Tetrahydro-3- isoguinolinecarboxylic acid Tza 2-Amino-3- (4-thiazolyl) -propanoic acid Tyr(Ot-Bu) 0-tertiary butyl-tyrosine Tyr(OMe) 0-Methyl-tyrosine Tyr(OEt) 0-Ethyl-tyrosine Trp(For) N ιn -Formyl-tryptophan Bheg 5H-Dibenzo[a,d] cycloheptene glycine Txg 9H-Thioxanthene glycine Abbreviation Protecting Group Ac Acetyl Ada l-Adamantyl acetic acid Adoc Adamantyloxycarbonyl Bzl Benzyl MeBzl 4-Methylbenzyl Z Benzyloxycarbonyl 2-Br-Z ortho-Bromobenzyloxycarbonyl 2-C1-Z ortho-Chiorobenzyloxycarbonyl Bom Benzyloxymethyl Boc tertiary Butyloxycarbonyl TBS tertiary Butyldimethylsilyl Dnp 2,4-Dinitrophenyl For Formyl Fmoc 9-Fluorenylmethyloxycarbonyl N0 2 Nitro Tos 4-Toluenesulfonyl (tosyl) Abbreviation Protecting Group (cont) Trt Triphenylmethyl (trityl) Ada 1-Adamantyl acetic acid Bz Benzylcarbonyl tBu t-Butylcarbonyl CF 3 CO Trifluoroacetyl Cxi Cyclohexylacetyl Cxi(U) Cyclohexylurea Et Propionyl Pya 3-Pyridylacetyl Me(U) Methylurea Abbreviation Solvents and Reagents HOAc Acetic acid CH 3 CN Acetonitrile DCM Dichloromethane DCC N,N' -Dicyclohexylcarbodiimide DIEA N,N-Diisopropylethylamine DMF Dimethylformamide HC1 Hydrochloric acid HF Hydrofluoric acid HOBt 1-Hydroxybenzotriazole KOH Potassium hydroxide TFA Trifluoroacetic acid MBHA Resin Methylbenzhydrylamine resin PAM Resin 4- (Oxymethyl) -phenylacetamidomethyl resin The compounds of Formula I are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. All of these forms are within the scope of the present invention. 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, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge, S. M. , et al, "Pharmaceutical Salts, " Journal of Pharmaceutical Science. 66. pp. 1-19 (1977)). The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. Preferably a peptide of Formula I can be converted to an acidic salt by treating with an aqueous solution of the desired acid, such that the resulting pH is less than 4. The solution can be passed through a C18 cartridge to absorb the peptide, washed with copious amounts of water, the peptide eluted with a polar organic solvent such as, for example, methanol, acetonitrile, aqueous mixtures thereof, and the like, and isolated by concentrating under reduced pressure followed by lyophilization. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. 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 base for purposes of the present invention. 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, dicyclohexyla ine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, S. M. , et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, , pp. 1-19 (1977)). The base 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 peptide of Formula I can be converted to a base salt by treating with an aqueous solution of the desired base, such that the resulting pH is greater than 9. The solution can be passed through a C18 cartridge to absorb the peptide, washed with copious amounts of water, the peptide eluted with a polar organic solvent such as, for example, methanol, acetonitrile, aqueous mixtures thereof, and the like, and isolated by concentrating under reduced pressure followed by lyophilization. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid 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 acid for purposes of the present invention. Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain of the 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 the appropriate mixtures thereof. A preferred compound of Formula I is one wherein wherein R is -N-R 2 , R 3 wherein R 2 and R 3 are each the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, or fluorenylmethyl, -N-C-N-R 3 , wherein R 2 and R 3 are as λμ J j 2 defined above. -C-C(R 9 ) 3 , wherein R 9 is F, Cl, Br, or I, 0 -NH-C-R 3, wherei.n R3 is as defined above, or is as defined above excluding R is hydrogen, Z is -0-, "S(0) ώ , wherein m is zero or an integer of 1 or 2, -N-, wherein R 2 is as defined above, ~(CH 2 ) ή , wherein n is zero or an integer of 1, 2, 3, or 4, - (CH2) (CH2_)n ...-, wherein n is as defined above, 0 -C-, -CH-, wherein R 1 is hydrogen or alkyl, OR 1 wherein R 2 and R 3 are each the same or different and each is as defined above and X and Y are the same and substituted at the same position on the aromatic ring and each substituent is selected from the group consisting of hydrogen, halogen, or alkyl; wherein R 4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,_ heteroaryl, wherein R 2b and R 3b are each the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl, -0R 2b , wherein R 2b is as defined above, . 0 -C-N-R 3b , R 2b wherein R 2b and R 3b are each the same or different and each is as defined above for R 2b and R 3b , 0 II 2b -.v. -C-R , wherein ^ D is as defined above, NH -NH-C-NH-R 2b , wherein R 2b is as defined above, or 0 wherein R 5 is aryl, heteroaryl, wherein R and R are each the same or different and each is as defined above, 0 II - 2b •.v. " -C-R , wherein R o is as defined above, or C-OR , wherein R 2b is as defined above, and n is as defined above, or AA 3 is absent; AA 4 and AA 5 are each independently absent or each is * stereochemistry at CH m AA 1, AA2, AA3, AA4, or AA5 is D,L, or DL, and * g stereochemistry at CH in AA is L; or a pharmaceutically acceptable salt thereof. A more preferred compound of Formula I is one wherein AA 1 is wherein R is -N-R 2, - k- wherein R 2 and R3 are each the same or different and each is hydrogen, alkyl, aryl, or fluorenylmethyl, 0 -N-C-N-R 3 , wherein R 2 and R 3 are '2 τ j 2 as defined above. -C-C(R 9 ) 3 ,wherein R 9 is F, Cl, Br, or I, or 0 -NH-C-OR , wherein R 10 is hydrogen, alkyl, aryl, or arylalkyl, excluding R 10 is hydrogen, Z is -0-, -S-, -NH-, -(CH 2 ) n , wherein n is zero or an integer of 1, 2, 3, or 4, or -(CH 2 ) n -CH=CH-(CH 2 ) ή , wherein n is zero or an integer of 1 or 2 and X and Y are each the same and substituted at the same position on the aromatic ring and each substituent is selected from the group consisting of hydrogen, halogen, or alkyl; wherein R 4 is hydrogen, alkyl, aryl, heteroaryl, -U-R 3b . 2b wherein R and R are each the same or different and each is hydrogen or alkyl, wherein R _,2b and- „R3b are each the same or different and each is hydrogen or alkyl, NH -NH-C-NH-R 2b wherein R 2b is as defined above, or II 2b 2b -C-OR , wherein R is as defined above, and n is an integer of 1, 2, 3, or 4 or wherein R 3 is aryl, heteroaryl, 0 -C-NHR , wherein R is hydrogen or alkyl. -C-R , wherein R is hydrogen or alkyl, or -C- is hydrogen or alkyl, and n is an integer of 1, 2, 3, or 4; AA 4 and AA 5 are each independently wherein R 6 is hydrogen, alkyl, cycloalkyl, or aryl, and n is an integer of 1, 2, 3, or 4; AA χ 6° is wherein R 7 is aryl or heteroaryl, and n is zero or an integer of 1, 2, 3, or 4, or 0 -NH- * CH-C--N-R 1 I I wherein R 7 , R 1 , and n are as ( H 2 ) n R defined above, R 7 stereochemistry at CH m AA 1, AA2, AA3, AA4, or AA5 i.s D, L, or DL and * g stereochemistry at CH in AA is L; or a pharmaceutically acceptable salt thereof. Particularly valuable are: L-Bhg-Leu-Asp-Ile-Ile-Trp; D-Bhg-Leu-Asp-Ile-Ile-Trp; Ac-L-Bhg-Leu-Asp-Ile-Ile-Trp; Ac-D-Bhg-Leu-Asp-Ile-Ile-Trp; Ac-D-Bhg-Orn-Asp-Ile-Ile-Trp; Ac-D-Bhg-Lys-Asp-Ile-Ile-Trp; Ac-D-Bhg-Asp-Asp-Ile-Ile-Trp; Ac-D-Bhg-Glu-Asp-Ile-Ile-Trp; Ac-D-Bhg-Phe-Asp-Ile-Ile-Trp; Ac-D-Bhg-Arg-Asp-Ile-Ile-Trp; Ac-D-Bhg-Asp-Ile-Ile-Trp; Fmoc-D-Bhg-Leu-Asp-Ile-Ile-Trp; Fmoc-D-Bhg-Orn-Asp-Ile-Ile-Trp; Rrtoc-D-Bhg-Lys-Asp-lie-lie-Trp; Fmoc-D-Bhg-Asp-Asp-Ile-Ile-Trp; Fmoc-D-Bhg-Glu-Asp-Ile-Ile-Trp; Emoc-D-Bhg-Phe-Asp-Ile-Ile-Trp; Fmoc-D-Bhg-Arg-Asp-Ile-Ile-Trp; Fmoc-D-Bhg-Asp-lie-Ile-Trp; Ac-D-Bhg-Leu-Phe-Ile-Ile-Trp; Ac-D-Bhg-Leu-Asn-lie-Ile-Trp; Ac-D-Bhg-Leu-Glu-Ile-Ile-Trp; Ac-D-Bhg-Leu-Gln-Ile-Ile-Trp; Ac-D-Bhg-Leu-Tyr-Ile-Ile-Trp; Ac-D-Bhg-Leu-1-Nal-Ile-Ile-Trp; Ac-D-Bhg-Leu-2-Nal-lie-Ile-Trp; Ac-D-Bhg-Leu-Trp-lie-lie-Trp; Ac-D-Bhg-Leu-Asp-Val-Ile-Trp; Ac-D-Bhg-Leu-Asp-lie-Val- Trp; Ac-D-Bhg-Leu-Asp-Chx-Ile-Trp; Ac-D-Bhg-Leu-Asp-Ile-Chx-Trp; Ac-D-Bhg-Arg-Asp-Ile-Chx-Trp; Ac-D-Bhg-Lys-Asp-Ile-Chx-Trp; Ac-D-Bhg-Orn-Asp-Ile-Chx-Trp; Ac-D-Bhg-Asp-Asp-Ile-Chx-Trp; Ac-D-Bhg-Glu-Asp-Ile-Chx-Trp; Fmoc-D-Bhg-Leu-Phe-lie-Ile-Trp; Emoc-D-Bhg-Leu-Asn-Ile-Ile-Trp; Fmoc-D-Bhg-Leu-Glu-lie-Ile-Trp; Fmoc-D-Bhg-Leu-Gln-lie-Ile-Trp; Fmoc-D-Bhg-Leu-Tyr-Ile-Ile-Trp; Fmoc-D-Bhg-Leu-Asp-Val-Ile-Trp; Fmoc-D-Bhg-Leu-_sp-Ile-Val-Tι_p; Fmoc-D-Bhg-Leu-Asp-Chx-Ile-Trp; Fmoc-D-Bhg-Arg-Asp-Chx-Ile-Trp; Fmoc-D-Bhg-Lys-Asp-Chx-Ile-Trp; Fmoc-D-Bhg-Orn-Asp-Chx-Ile-Trp; Fmoc-D-Bhg-Asp-Asp-Chx-Ile-Trp; Fmoc-D-Bhg-Glu-Asp-Chx-Ile-Trp; Fmoc-D-Bhg-Leu-Asp-Ile-Chx-Trp; Fmoc-D-Bhg-Arg-Asp-lie-Chx-Trp; Fmoc-D-Bhg-Lys- sp-lie-Chx-Trp; Fmoc-D-Bhg-Orn-Asp-Ile-Chx-Trp; Fmoc-D-Bhg-Asp-Asp-lie-Chx-Trp; Fmoc-D-Bhg-Glu-Asp-Ile-Chx-Trp; Ac-D-Bheg-Leu-Asp-lie-Ile-Trp; Ac-D-Bheg-Orn-Asp-lie-Ile-Trp; Ac-D-Bheg-Lys-Asp-lie-Ile-Trp; Ac-D-Bheg-Asp-Asp-lie-lie-Trp; Ac-D-Bheg-Glu-Asp-lie-Ile-Trp; Ac-D-Bheg-Phe-Asp-lie-Ile-Trp; Ac-D-Bheg-Arg-Asp-lie-Ile-Trp; Ac-D-Bheg-Asp-lie-Ile-Trp; Fmoc-D-Bheg-Leu-Asp-lie-Ile-Trp; Fmoc-D-Bheg-Orn-Asp-lie-Ile-Trp; Fmoc-D-Bheg-Lys-Asp-lie-lie-Trp; Fmoc-D-Bheg-Asp-Asp-lie-lie-Trp; Fmoc-D-Bheg-Glu-Asp-lie-Ile-Trp; Fmoc-D-Bheg-Phe-Asp-lie-Ile-Trp; Fmoc-D-Bheg-Arg-Asp-lie-Ile-Trp; Fmoc-D-Bheg-Asp-lie-Ile-Trp; Ac-D-Bheg-Leu-Phe-lie-Ile-Trp; Ac-D-Bheg-Leu-Asn-lie-Ile-Trp; Ac-D-Bheg-Leu-Glu-lie-Ile-Trp; Ac-D-Bheg-Leu-Gln-Ile-Ile-Trp; Ac-D-Bheg-Leu-Tyr-lie-Ile-Trp; Ac-D-Bheg-Leu-1-Nal-lie-Ile-Trp; Ac-D-Bheg-Leu-2-Nal-lie-Ile-Trp; Ac-D-Bheg-Leu-Trp-lie-Ile-Trp; Ac-D-Bheg-Leu-Asp-Val-Ile-Trp; Ac-D-Bheg-Leu-Asp-Ile-Val-Trp; Ac-D-Bheg-Leu-Asp-Chx-Ile-Trp; Ac-D-Bheg-Leu-Asp-Ile-Chx-Trp; Ac-D-Bheg-Arg-Asp-lie-Chx-Trp; Ac-D-Bheg-Lys-Asp-Ile-Chx-Trp; Ac-D-Bheg-Orn- sp-lie-Chx-Trp; Ac-D-Bheg-Asp-Asp-lie-Chx-Trp; Ac-D-Bheg-Glu-Asp-Ile-Chx-Trp; Fmoc-D-Bheg-Leu-Phe-Ile-Ile-Trp Emoc-D-Bheg-Leu-Asn-lie-Ile-Trp Fmoc-D-Bheg-Leu-Glu-lie-Ile-Trp Fmoc-D-Bheg-Leu-Gln-lie-Ile-Trp Fmoc-D-Bheg-Leu-Tyr-lie-Ile-Trp Fmoc-D-Bheg-Leu-Asp-Val-Ile-Trp Fmoc-D-Bheg-Leu-Asp-Ile-Val-Trp Fmoc-D-Bheg-Leu-Asp-Chx-Ile-Trp Fmoc-D-Bheg-Arg-Asp-Chx-lie-Trp Fmoc-D-Bheg-Lys-Asp-Chx-Ile-Trp Fmoc-D-Bheg-Orn-Asp-Chx-Ile-Trp Fmoc-D-Bheg-Asp-Asp-Chx-Ile-Trp Fmoc-D-Bheg-Glu- sp-Chx-Ile-Trp Fmoc-D-Bheg-Leu-Asp-Ile-Chx-Trp Fmoc-D-Bheg-Arg-Asp-lie-Chx-Trp Emoc-D-Bheg-Lys-Asp-Ile-Chx-Trp Fmoc-D-Bheg-Orn-Asp-lie-Chx-Trp Fmoc-D-Bheg-Asp-Asp-lie-Chx-Trp Fmoc-D-Bheg-Glu-Asp-lie-Chx-Trp Ac-D-Txg-Leu-Asp-lie-Ile-Trp; Ac-D-Txg-Orn-Asp-Ile-Ile-Trp; Ac-D-Txg-Lys-Asp-lie-lie-Trp; Ac-D-Txg-Asp-Asp-Ile-Ile-Trp; Ac-D-Txg-Glu-Asp-Ile-Ile-Trp; Ac-D-Txg-Phe-Asp-lie-Ile-Trp; Ac-D-Txg-Arg-Asp-lie-Ile-Trp; Ac-D-Txg-Asp-Ile-Ile-Trp; Fmoc-D-Txg-Leu-Asp-lie-lie-Trp; Fmoc-D-Txg-Orn-Asp-Ile-Ile-Trp; Fmoc-D-Txg-Lys-Asp-Ile-Ile-Trp; Fmoc-D-Txg-Asp-Asp-Ile-Ile-Trp; Fmoc-D-Txg-Glu-Asp-Ile-Ile-Trp; Fmoc-D-Txg-Phe-Asp-Ile-Ile-Trp; Fmoc-D-Txg-Arg-Asp-Ile-Ile-Trp; Fmoc-D-Txg-Asp-Ile-Ile-Trp; Ac-D-Txg-Leu-Phe-Ile-Ile-Trp; Ac-D-Txg-Leu-Asn-lie-Ile-Trp; Ac-D-Txg-Leu-Glu-lie-Ile-Trp; Ac-D-Txg-Leu-Gln-lie-Ile-Trp; Ac-D-Txg-Leu-Tyr-lie-Ile-Trp; Ac-D-Txg-Leu-1-Nal-lie-Ile-Trp; Ac-D-Txg-Leu-2-Nal-lie-Ile-Trp; Ac-D-Txg-Leu-Trp-lie-Ile-Trp; Ac-D-Txg-Leu-Asp-Val-Ile-Trp; Ac-D-Txg-Leu-Asp-Ile-Val-Trp; Ac-D-Txg-Leu-Asp-Chx-Ile-Trp; Ac-D-Txg-Leu-Asp-Ile-Chx-Trp; Ac-D-Txg-Arg-Asp-Ile-Chx-Trp; Ac-D-Txg-Lys-As -lie-Chx-Trp; Ac-D-Txg-Orn-Asp-lie-Chx-Trp; Ac-D-Txg-Asp-Asp-lie-Chx-Trp; Ac-D-Txg-Glu-Asp-Ile-Chx-Trp; Fmoc-D-Txg-Leu-Phe-lie-Ile-Trp Fmoc-D-Txg-Leu-Asn-lie-Ile-Trp Fmoc-D-Txg-Leu-Glu-lie-Ile-Trp Fmoc-D-Txg- eu-Gin-lie-Ile-Trp Fmoc-D-Txg-Leu-Tyr-lie-Ile-Trp Fmoc-D-Txg-Leu- sp-Val-Ile-Trp Fmoc-D-Txg-Leu-Asp-Ile-Val-Trp Fmoc-D-Txg-Leu-Asp-Chx-lie-Trp Fmoc-D-Txg-Arg-Asp-Chx-Ile-Trp Fmoc-D-Txg-Lys-Asp-Chx-Ile-Trp Fmoc-D-Txg-Orn-Asp-Chx-Ile-Trp Fmoc-D-Txg-Asp-Asp-Chx-lie-Trp Fmoc-D-Txg-Glu-Asp-Chx-Ile-Trp Fmoc-D-Txg-Leu-Asp-Ile-Chx-Trp Fmoc-D-Txg-Arg-Asp-Ile-Chx-Trp Fmoc-D-Txg-Lys-Asp-lie-Chx-Trp Fmoc-D-Txg-Orn-Asp-Ile-Chx-Trp Fmoc-D-Txg-Asp-Asp-lie-Chx-Trp Fmoc-D-Txg-Glu-Asp-lie-Chx-Trp Et-D-Bhg-Leu-Asp-lie-Ile-Trp; Bz-D-Bhg-Leu-Asp-lie-Ile-Trp; Pya-D-Bhg-Leu-Asp-Ile-Ile-Trp; Cxi-D-Bhg-Leu-Asp-Ile-Ile-Trp; Ada-D-Bhg-Leu-Asp-Ile-Ile-Trp; Cxi(U) -D-Bhg-Leu-Asp-Ile-Ile-Trp; Me(U) -D-Bhg-Leu-Asp-Ile-Ile-Trp; tBu-D-Bhg-Leu-Asp-lie-lie-Trp; CF 3 CO-D-Bhg-Leu-Asp-Ile-Ile-Trp; Et-D-Bheg-Leu-Asp-Ile-Ile-Trp; Bz-D-Bheg-Leu-Asp-Ile-Ile-Trp; Pya-D-Bheg-Leu-Asp-Ile-Ile-Trp; Cxl-D-Bheg-Leu-Asp-Ile-Ile-Trp; Ada-D-Bheg-Leu-Asp-Ile-Ile-Trp; Cxl(U) -D-Bheg-Leu-Asp-Ile-Ile-Trp; Me(U) -D-Bheg-Leu-Asp-Ile-Ile-Trp; tBu-D-Bheg-Leu-Asp-Ile-Ile-Trp; CF 3 CO-D-Bheg-Leu-Asp-lie-Ile-Trp; Ac-D-Bhg-Leu-Asp-Phe-Ile-Trp; Ac-D-Bhg-Orn-Asp-Phe-Ile-Trp; Ac-D-Bhg-Lys-Asp-Phe-Ile-Trp; Ac-D-Bhg-Asp-Asp-Phe-Ile-Trp; Ac-D-Bhg-Glu-Asp-Phe-lie-Tr ; Ac-D-Bhg-Phe-Asp-Phe-Ile-Trp; Ac-D-Bhg-Arg-Asp-Phe-Ile-Trp; Ac-D-Bheg-Leu-Asp-Phe-Ile-Trp; Ac-D-Bheg-Orn-Asp-Phe-Ile-Trp; Ac-D-Bheg-Lys-Asp-Phe-lie-Trp; Ac-D-Bheg-Asp-Asp-Phe-Ile-Trp; Ac-D-Bheg-Glu-Asp-Phe-Ile-Trp; Ac-D-Bheg-Phe-Asp-Phe-lie-Trp; and Ac-D-Bheg-Arg-Asp-Phe-Ile-Trp; or a pharmaceutically acceptable acid or base addition salt thereof. The compounds of Formula I are valuable antagonists of endothelin. The tests employed indicate that compounds of Formula I possess endothelin antagonist activity. Thus, the compounds of Formula I were tested for their ability to inhibit [ 125 I] -ET-1( [ 125 I] -Endothelin-1) binding in a receptor assay according to the following procedures: ENDOTHELIN RECEPTOR BINDING ASSAY-A (ERBA-A) INTACT CELL BINDING OF [ 125 I] -ET-1 Materials and Terms Used: Cells The cells used were rabbit renal artery vascular smooth muscle cells grown in a 48-well dish (1 cm 2 ) (confluent cells) . Growth Media The growth media was Dulbecco's Modified Eagles/Ham's F12 which contained 10% fetal bovine serum and antibiotics (penicillin/streptomycin/ fungizone) . Assay Buffer 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 (l mg/mL) . [ 125 I] -ET-1 Amersham radioiodinated endothelin-1 [ 125 I]-ET-1 was used at final concentration of 20,000 cpm/0.25 mL (25 pM) . Protocol 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 μ 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 Used: Tissue Buffer The tissue is made up of 20 M tris(hydroxy- methyljaminomethane hydrochloride (Trizma) buffer, 2 mM ethylenediaminetetra acetate, 100 μM phenylmethylsulfonyl fluoride. Tissue Preparation First, thaw one aliquot of frozen rat cerebellar membranes (2 mg protein in 0.5 mL) . Next, add 0.5 mL membrane aliquot to 4.5 mL cold tissue buffer, polytron at 7,500 revolutions per minute for 10 seconds. Finally, dilute tissue suspension 1/100 (0.1 mL suspension + 9.9 mL tissue buffer), polytron again, and place ice. Dilution Buffer Medium 199 with Hank's salts plus 25 mM Hepes + 1 mg/mL bovine serum albumin. [ 125 I]-ET-1 Amersham [ 125 I] -ET-1 (aliquots of 2 x 10 e 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) . Protocol 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 μ ) . 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. Count filters for radioactivity in gamma counter. IN VITRO INHIBITION OF ET-1 STIMULATED ARACHIDONIC ACID RELEASE (AAR) IN CULTURED RABBIT VASCULAR SMOOTH MUSCLE CELLS BY COMPOUNDS OF FORMULA I 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 x 0.25 mCi/mL [ 3 H] arachidonic acid (A ersham) . 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% C0 2 . 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 μh ET-1 (0.3 nM) and the incubation was extended for 30 minutes. This solution was then collected, 10 μh 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 IN THE RABBIT FEMORAL ARTERY (ET A ) AND SARAFOTOXIN 6c STIMULATED VASOCONSTRICTION IN THE RABBIT PULMONARY ARTERY (ET B ) 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 guage for femoral rings and 28 guage for pulmonary rings, Small Parts, Ine, Miami, Florida) and gently rolling them. Denuded rings were mounted in 20 mL organ baths containing Krebs-bicarbonate buffer (composition in mM: NaCl, 118.2; NaHC0 3 , 24.8; C1, 4.6; MgS0 4 7-H 2 0, 1.2; H 2 P0 4 , 1.2; CaCl 2 -2H 2 0; Ca-Na 2 EDTA, 0.026; dextrose, ICO), that was maintained at 37°C and gassed continuously with 5% C0 2 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 pA 2 values were calculated (Table I) . The data in Table I below show the endothelin receptor binding and antagonist activity of representative compounds of Formula I. TABLE I. Biological Activity of Compounds of Formula I Example ERBA-A ERBA-B AAR ____2 Compound Number IC 50 , ) IC 50 (/XM) IC 50 (μM) Femoral Pulmonary 1 Ac-D-Bhg-Leu-Asp-Ile-Ile-Trp 2 D-Bhg-Leu-Asp-Ile-Ile-Trp 3 -Bhg-Leu-Asp-Ile-Ile-Trp 4 Ac-L-Bhg-Leu-Asp-Ile-Ile-Trp 5 Ac-D-Txg-Leu-Asp-Ile-I e-Trp 10 6 Ac-D-Bheg-Leu-Asp-Ile-Ile-Trp 6.8 7.4 7 Ac-D-Bhg-Om-Asp-Ile-Ile-Trp 6.5 8 Ac-D-B g-Glu-Asp-Ile-Ile-Trp 6.5 7.0 9 Ac-D-Bhg-Leu-Asp-Ile-Ile-Trp, 2Na + 6.9 7.X 15 General Method for Preparing Compounds of Formula I The compounds of Formula I may be prepared by solid phase peptide synthesis on a peptide synthesizer, for example, an Applied Biosystems 430A peptide synthesizer using activated esters or anhydrides of N-alpha-Boc protected amino acids, on PAM or MBHA resins. Additionally, the compounds of Formula I may also be prepared by conventional solution peptide synthesis. Amino acid side chains are protected as follows: BzKAsp, Glu, Ser) , 2-Cl-Z(Lys), 2-Br-Z(Tyr), Bom(His) , For(Trp), and MeBzl(Cys). Each peptide resin (1.0 g) is cleaved with 9 mL of HF and 1 mL of anisole or p-cresol as a scavenger (60 minutes, 0°C) . The peptide resin is washed with cyclohexane, extracted with 30% aqueous HOAc, followed by glacial HOAc, concentrated under reduced pressure, and lyophilized. (A peptide containing For(Trp) is dissolved in 0°C, the pH is adjusted to 12.5 with IN KOH (2 minutes), neutralized with glacial HOAc, desalted on C 18 (as described below) , and lyophilized. The crude peptide is purified by preparative reversed phase high performance liquid chromatography (RP-HPLC) on a C 18 column (2.2 x 25.0 cm, 15.0 mL/min) with a linear gradient of 0.1% TFA in water to 0.1% TFA in acetonitrile and lyophilized. The homogeneity and composition of the resulting peptide is verified by RP-HPLC, capillary electrophoresis, thin layer chromatography (TLC) , proton nuclear magnetic resonance spectrometry (NMR) , and fast atom bombardment mass spectrometry (FAB-MS) . 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, that is, intravenously, intramuscularly, intracutaneously, s bcutaneously, mtraduodenally, or intraperitoneally. Also, the compounds of the present invention can be administered by inhalation, for example, intranasally. Additionally, 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 Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I. For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid which 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 suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. 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 formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection 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 colorants, flavors, stabilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. The pharmaceutical preparation is preferably in unit dosage form. 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 containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsules, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents. In therapeutic use as antagonist of endothelin, the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.01 mg to about 20 mg per kilogram daily. A daily dose range of about 0.01 mg to about 10 mg per kilogram is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. . The following nonlimiting examples illustrate the inventors' preferred methods for preparing the compounds of the invention. EXAMPLE 1 Ac-D-Bhq-Leu-Asp-lie-Ile-Trp The linear hexapeptide is prepared by standard solid phase synthetic peptide methodology utilizing a Boc/benzyl strategy (Stewart, J. M. and Young, J. D., Solid Phase Peptide Synthesis. Pierce Chemical Co., Rockford, IL, 1984) . All protected amino acids and reagents are obtained from commercial sources with the exception of N-α-Boc-DL-Bhg and are not further purified. The protected peptide resin is prepared on an Applied Biosystems 430A Peptide Synthesizer, utilizing protocols supplied for a dicyclohexyl- carbodiimide-mediated coupling scheme (Standard 1.0, Version 1.40) . Starting with 0.710 g of N-α-Boc-Trp-PAM resin (0.70 meq/g, 0.497 eq of Boc-Trp(For) total) the protected peptide is prepared by the stepwise coupling of the following amino acids (in order of addition) : N-α-Boc-Ile « 0.5H 2 O, N-Q!-Boc-Ile-0.5H 2 0, N-α-Boc-Asp(Bzl) , N-α-Boc-Leu-H 2 0, and N-α-Boc-DL-Bhg. A typical cycle for the coupling of an individual amino acid residue is illustrated below (reproduced from the ABI manual) : All the single couple RV cycles conform to the following pattern: 1) 33% TFA in DCM for 80 seconds 2) 50% TFA in DCM for 18.5 minutes 3) Three DCM washes 4) 10% DIEA in DMF for 1 minute 5) 10% DIEA in DMF for 1 minute 6) Five DMF washes 7) Coupling period 8) Five DCM washes After the coupling of N-α-Boc-DL-Bhg, the Boc group is removed with the end-NH 2 cycle (1.012 g) . The peptide is liberated from the solid support, and the carboxylate of aspartic acid deprotected by treatment with anhydrous hydrogen fluoride (9.0 mL) , anisole (0.5 mL) , and dimethyl sulfide (0.5 mL) (60 minutes, 0°C) . After removing the hydrogen fluoride under a stream of nitrogen, the resin is washed with diethyl ether (3 x 30 mL) and extracted with 20% HOAc in water (3 x 30 mL) and glacial HOAc (2 x 30 mL) . The aqueous extractions are combined, concentrated under reduced pressure, and lyophilized (360 mg) . The crude peptide is dissolved in 4.0 mL of 50% TFA/H 2 0, filtered through a 0.4 L syringe filter, and chromatographed on a Vydac 218TP 1022 column (2.2 x 25.0 cm, 15.0 mL/min, A: 0.1% TFA/H 2 0, B: 0.1% TFA/CH 3 CN, Gradient; 0% B for 10 minutes, 10% to 40% B over 120 minutes) . Two individual fractions are collected and combined based upon analysis by analytical HPLC. The combined fractions are concentrated separately under reduced pressure (10 mL) , diluted with H 2 0 (50 mL) , and lyophilized (40_0 mg/ea) . Separation into the two diastereomers (Isomers A and B) is effected under these conditions (t R = Isomer A 15.63 min., Isomer B 16.79 min.) . The late running peak fractions (Isomer B) are repurified under the same experimental conditions with a gradient of 30% to 50% B over 120 minutes at 15 mL/min to afford purified product. Acetylation is carried out with 20 mg of Isomer B in 90% acetic acid followed by addition of acetic anhydride (5 mL) and stirring overnight. After evaporation and drying the product Ac-D-Bhg-Leu-Asp-lie-Ile-Trp is 99% pure by HPLC. [Vydac 218 TP 1022 column (2.2 x 25.0 cm, 15.0 mL/min. A: 0.1% TFA/CH 3 CN, Gradient 20% to 86% B over 22 min.)] t R = 18.66 minutes. The homogeneity and structure of the resulting peptide is confirmed by analytical HPLC. Proton Nuclear Magnetic Resonance Spectroscopy (H 1 -NMR) and Fast Atom Bombardment Mass Spectroscopy (FAB-MS), M+Na 972.0, M+2Na + 995.9. In a process analogous to Example 1 using the appropriate amino acids, the corresponding compounds of Formula I are prepared as follows: EXAMPLE 2 D-Bhq-Leu-ASD-He-Ile-Trp: FAB-MS, M+l 907.4. EXAMPLE 3 L-Bhg-Leu-Asp-He-Ile-Trp: FAB-MS, M+l 907.4. EXAMPLE 4 Ac-L-Bhq-Leu-Asp-lie-Ile-Trp: FAB-MS, M+l 950.0. EXAMPLE 5 Ac-D-Txq-Leu-Asp-He-Ile-Trp; FAB-MS, M+Na 977.0. EXAMPLE 6 Ac-D-Bheg-Leu-Asp-lie-Ile-Trp: FAB-MS, M+l 970.3. EXAMPLE 7 Ac-D-Bhg-Orn-Asp-He-Ile-Trp: FAB-MS, M+l 951.2. EXAMPLE 8 Ac-D-Bhq-Glu-Asp-lie-Ile-Trp; FAB-MS, M+Na 988.8. EXAMPLE 9 Disodium salt of Ac-D-Bhg-Leu-Asp-Ile-Ile-Trp A saturated solution of sodium bicarbonate in water is prepared, diluted with water (1:10), chilled to 0°C, and 10 mL of the solution is added to approximately 50 mg of Ac-D-Bhg-Leu-Asp-Ile-Ile-Trp (Example 1) with stirring. The pH of the solution is greater than 9. After 10 minutes, the solution is passed through a C18 cartridge, washed with water (100 mL) , and the absorbed peptide is eluted with methanol (50 mL) , concentrated under reduced pressure, resuspended in water (50 mL) , and lyophilized (three times) to give the title compound. Ac-D-Bhg-Leu-Asp-Ile-Ile-Trp, disodium salt; FAB-MS, M+l 950.4, M+Na 972.1, M+2Na 994.3. EXAMPLE 10 Boc-Bhg Bhg-HCl (1.70 g, 5.43 mmol) is suspended in 150 mL of p-dioxane:H 2 0 (2:1) at room temperature. To the stirred solution is added 1.40 g (6.42 mmol) of di-tert butyldicarbonate. The pH of the solution is adjusted to >9.0 with IN NaOH and maintained at between pH 9 and 10 with aliquot additions of IN NaOH, until the pH is constants The solution is concentrated under reduced pressure to approximately 75 mL, overlain with ethyl acetate (50 mL) , and acidified to approximately pH 2.5 with 10V aqueous HC1. The organic layer is separated, washed successively with 10% aqueous HC1 (2 x 50 mL) , brine (2 x 50 mL) , H 2 0 (3 x 50 mL) , and dried with MgS0 4 . The solution is filtered, concentrated under reduced pressure, and the oil is recrystallized from ethyl acetate:heptane (1.82 g) . The white solid is characterized by proton NMR, fast atom bombardment mass spectrometry (M+l=368) , and elemental analysis.

Claims: CLAIMS 1. A compound of Formula I AA 1 - AA 2 - AA 3 - AA 4 - AA 5 - AA 6 wherein AA 1 is wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, fluorenylmethyl, ■N-R 2, wherein R2 and R3 are each the same or Rl 3 different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, or fluorenylmethyl, -C-OR 2, wherein R2 is as defined above, -OR 2 , wherein R 2 is as defined above, 0 -N-C-N-R 3 , wherein R 2 and R 3 are as defined 2 R 2 abOVe ' -C-C(R 9 ) 3 , wherein R 9 is F, Cl, Br, or I, -CH 2 -0R 2 , wherein R 2 is as defined above. wherein R 2a is hydrogen or alkyl and R 3 is as defined above, wherein R 2 and R 3 are as defined above excluding R 3 is hydrogen, or 0 -C I-R2, wherein R^ is as defined above, R 1 is hydrogen or alkyl, Z is -0-, -S(0) fi , wherein m is zero or an integer of 1 or 2, -N-, wherein R 2 is as defined above, R l 2 ^ -(CH 2 ) n -, wherein n is zero or an integer of 1, 2, 3, or 4, -(CH 2 ) n -CH=CH-(CH 2 ) n -, wherein n is as defined above, 0 -C-, -CR 1 -, wherein R 1 and R 2 are as defined above, or wherein R 2 and R 3 are each the same or different and each is as defined above, X and Y are the same and substituted at the same position on the aromatic ring and each may be one, two, three, or four substituents selected from the group consisting of hydrogen, halogen, alkyl, -C0 2 R 2 , wherein R 2 is as defined above, -CONR 2, wherein R2 and R3 are as defined Rl 3 above, -NR 2, wherein R2 and R3 are as defined Rl 3 above, or nitro or wherein R, Z, X, and Y are as defined above; 100 wherein R 4 is hydrogen, alkyl, alkenyl, alkynyl, 105 cycloalkyl, aryl, heteroaryl, wherein R and R are each the same or different and each is hydrogen, alkyl, 115 cycloalkyl, aryl, or heteroaryl, -OR 2b , wherein R 2b is as defined above, wherein R and R are each 125 the same or different and each is as defined above for R 2b and R 3b , 130 -C II -R- 2b, wherei.n R2b ' i.s as d"efi.ned above, NH -NH-C-NH-R 2b wherein R 2b is as defined 135 above, or is as defined above, and 140 R 1 and n are as defined above, AA 2 is absent; wherein R 5 is hydrogen, 145 alkyl, aryl, heteroaryl, wherein R and R are each the same or 155 different and each is as defined above, -C-R , wherein R is as 160 defined above, or -C 11 -OR2b, wherein R2b is as defined above, and 165 R 1 and n are as defined above, or AA 3 is absent; AA 4 and AA 5 are each independently absent or each is independently wherein R 6 is hydrogen, 170 alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or 175 heteroaryl, and R 1 and n are as defined above; AA b is 185 wherein R 7 is aryl or heteroaryl, R 8 is 0 190 1 -C-OR , wherein R^ is as defined above, -OR 1 , wherein R 1 is as defined above, 195 0 -C-N-R 1 , wherein R 1 is as defined 'i above, or 200 -C^-OR 1 , wherein R 1 is as defined above, and R 1 and n are as defined above; * stereochemistry at C in AA 1 , AA 2 , AA 3 , AA 4 , or AA 5 is 205 D, L, or DL and * stereochemistry at C in AA 6 is L; or a pharmaceutically acceptable salt thereof. 2. A compound according to Claim 1, in which AA 1 is wherein R is -N-R 2, R ι 3 - 3 5 wherein R 2 and R 3 are each the same or different and each is hydrogen, alkyl, alkenyl, 10 alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, 15 heteroaryl, or fluorenylmethyl, 0 -N-C-N-R 3 , wherein R 2 and R 3 are as 20 12 J,2 defined above, 0 -C I'-C(R9 a ) 3 , wherein R* is F, Cl, Br, or I, 0 -NH-C I'-R3, wherein R3 i.s as defined above, or is as defined above 3 excluding R is hydrogen, Z is -0-, -S(0)m' wherein m is zero or an integer of 1 or 2, -N-, wherein R 2 is as defined above, R I 2 - -(CH 2 ) jj , wherein n is zero or an integer of 1, 2, 3, or 4, -(CH ) -CH=CH-(CH ) -, wherein n is as defined above, -C-, -CH-, wherein R 1 is hydrogen or alkyl, or OR 1 wherein R 2 and R 3 are each the same or different and each is as defined above and X and Y are the same and substituted at the same position on the aromatic ring and each substituent is selected from the group consisting of hydrogen, halogen, or alkyl; wherein R 4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, wherein R 2b and R 3b are each the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl, -OR 2b , wherein R 2b is as defined above, wherein and are each the same or different and each is as defined above for R 2b and R 3b 0 I! v_ -C-R , wherein R 2b is as defined 100 above, NH -NH-C-NH-R 2b wherein R 2b is as defined above, or s as defined above, and n is as defined above or 110 AA 2 is absent; AA 3 is wherein R 5 is aryl, heteroaryl, 0 115 ιι v, -C-N-R 3b , R 2b wherein R and R are each the 120 same or different and each is as defined above, 0 II 2b _ _, -C-R , wherein R D is as defined 125 above, or -C-OR , wherein R 2b is as defined above, and 130 n is as defined above, or AA 3 is absent; AA 4 and AA 5 are each independently absent or each is wherein R is hydrogen alkyl, 135 alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, and 140 n is as defined above; AA 6 is wherein R 7 is aryl or heteroaryl, and n is as defined above, or _ stereochemistry at CH in AA 1, AA2, AA3, AA4, or AA5 is D,L, or DL, and 160 * _ stereochemistry at CH in AA is L; or a pharmaceutically acceptable salt thereof. 3. A compound according to Claim 2, in which AA 1 is wherein R is -N-R 2, R ι 3 - wherein R 2 and R3 are each the same or different and each is hydrogen, alkyl, aryl, or fluorenylmethyl, O -N-C-N-R 3 , wherein R 2 and R 3 are as '2 I2 defined above, 0 -C 'I-C(R9 3 ) 3 , wherei ■ n R9 y i•s F, Cl, Br, or I, or s hydrogen, alkyl, aryl, or arylalkyl, excluding R 10 is hydrogen, Z is -0-, -S-, -NH-, - (CH 2 ) n , wherein n is zero or an integer of 1, 2, 3, or 4, or - (CE 2 ) n -CE--CR- (Cl- 2 ) h , wherein n is zero or an integer of 1 or 2 and X and Y are each the same and substituted at the same position on the aromatic ring and each substituent is selected from the group consisting of hydrogen, halogen, or alkyl; AA' 1 is wherein R 4 is hydrogen, alkyl, aryl, heteroaryl, wherein R and R are each the same or different and each is hydrogen or alkyl, 0 75 II b 2b -C-OR , wherein R is as defined above, and n is an integer of 1, 2, 3, or 4 or AA 2 is absent; 80 AA 3 is 0 II -NH-CH-C- , I 85 (C ■ H _. n R ς wherein R 5 is aryl, •heteroaryl, . wherei.n „R3b i.s hydrogen or alkyl, 95 0 -C-R , wherein R is hydrogen or alkyl, or 100 -C r.-O ΛT R,2b, wh,erei.n „R2b i.s hydrogen or alkyl, and 105 n is an integer of 1, 2, 3, or 4; AA 4 and AA 5 are each independently wherein R 6 is hydrogen, 115 alkyl, cycloalkyl, or aryl, and n is an integer of 1, 2, 3, or 4; AA° is 120 125 _ stereochemistry at CH in AA 1, AA2, AA3, AA4, or AA5 is D, L, or DL and * g 140 stereochemistry at CH in AA is L; or a pharmaceutically acceptable salt thereof. 4. A compound according to Claim 3 selected from the group consisting of: L-Bhg-Leu-Asp-Ile-Ile-Trp; D-Bhg-Leu-Asp-He-Ile-Trp; 5 Ac-L-Bhg-Leu-Asp-lie-Ile-Trp; Ac-D-Bhg-Leu-Asp-He-Ile-Trp; Ac-D-Bhg-Orn-Asp-He-Ile-Trp; Ac-D-Bhg-Lys-Asp-He-Ile-Trp; Ac-D-Bhg-Asp-Asp-lie-lie-Trp; 10 Ac-D-Bhg-Glu-Asp-Ile-He-Trp; Ac-D-Bhg-Phe-Asp-He-Ile-Trp; Ac-D-Bhg-Arg-Asp-He-Ile-Trp; Ac-D-Bhg-Asp-He-Ile-Trp; Fmoc-D-Bhg-Leu-Asp-He-Ile-Trp; 15 Fmoc-D-Bhg-Orn-Asp-Ile-He-Trp; Fmoc-D-Bhg-Lys -Asp-He- Ile-Trp; Fmoc-D-Bhg -Asp-Asp- He-Ile-Trp; Fmoc-D-Bhg-Glu-Asp-Ile-Ile-Trp; Fmoc-D-Bhg-Phe-Asp-Ile-Ile-Trp; Fmc-D-Bhg-Arg-Asp-Ile-Ile-Trp; Fmoc-D-Bhg-Asp-Ile-Ile-Trp; Ac-D-Bhg-Leu-Phe-Ile-Ile-Trp; Ac-D-Bhg-Leu-Asn- He- Ile-Trp ; Ac-D-Bhg-Leu-Glu-Ile- Ile-Trp; Ac-D-Bhg-Leu-Gln-Ile-Ile-Trp; Ac-D-Bhg-Leu-Tyr- He- Ile-Trp; Ac-D-Bhg-Leu-1-Nal-Ile-Ile-Trp; Ac-D-Bhg-Leu-2 -Nal-Ile-Ile-Trp; Ac-D-Bhg-Leu-Trp-Ile-Ile-Trp; Ac-D-Bhg-Leu-Asp-Val-Ile-Trp; Ac-D-Bhg-Leu-Asp-Ile-Val-Trp; Ac-D-Bhg- Leu- Asp-Chx- Ile-Trp; Ac-D-Bhg-Leu-Asp-Ile-Chx-Trp; Ac -D -Bhg- Arg -Asp - He - Chx-Trp ; Ac -D-Bhg- Lys -Asp -lie- Chx- Trp; Ac-D-Bhg-Orn-Asp-Ile-Chx-Trp; Ac-D-Bhg- Asp-Asp-Ile-Chx-Trp; Ac-D-Bhg-Glu-Asp-Ile-Chx-Trp; Fmoc-D-Bhg-Leu-Phe- lie - lie -Trp; Fmoc-D-Bhg-Leu-Asn-Ile-Ile-Trp; Fmoc-D-Bhg-Leu-Glu-Ile-Ile-Trpr Fmoc-D-Bhg-Leu-Gln- lie- Ile-Trp ; Fmoc-D-Bhg-Leu-Tyr- lie- Ile-Trp; Fmoc-D-Bhg- Leu -Asp-Val -He -Trp; Fmoc-D-Bhg-Leu-Asp-Ile-Val-Trp; Fmoc-D-Bhg-Leu-Asp-Chx- Ile-Trp; Fmoc-D-Bhg-Arg -Asp-Chx- Ile-Trp; Fmoc-D- Bhg ^ Lys -Asp- Chx- He -Trp ; Fmoc- -Bhg-Orn-Asp-Chx-lie-Trp; Fmoc-D-Bhg-Asp-Asp-Chx- Ile-Trp; Fmoc- D-Bhg-Glu -Asp -Chx- Ile-Trp; Fmoc-D -Bhg - Leu-Asp - He - Chx- Trp ; Fmoc-D-Bhg-Arg-Asp- Ile-Chx-Trp; Fmoc-D-Bhg-Lys -Asp- lie- Chx-Trp; Fmoc-D-Bhg-Orn-Asp- Ile-Chx-Trp; Fmoc-D- Bhg- Asp- Asp- He- Chx-Trp; Fmoc-D- Bhg- Glu- Asp- He- Chx-Trp; Ac-D-Bheg- Leu-Asp- He- Ile-Trp ; Ac-D-Bheg- Orn-Asp- He- Ile-Trp; Ac -D-Bheg- Lys -Asp- lie - Ile-Trp ; Ac -D-Bheg- Asp-Asp- He- Ile-Trp ; Ac -D-Bheg-Glu-Asp- lie- Ile-Trp ; Ac -D-Bheg- Phe -Asp- lie - lie -Trp; Ac-D-Bheg-Arg-Asp- He- Ile-Trp; Ac-D-Bheg-Asp- Ile- Ile-Trp; Fmoc-D-Bheg-Leu-Asp- He - He -Trp; Fmoc-D-Bheg-Orn-Asp-Ile- Ile-Trp; Fmoc -D-Bheg- Lys -Asp- He- Ile-Trp ; Fmoc -D-Bheg-Asp-Asp- lie- lie -Trp; Fmoc -D-Bheg -Glu -Asp- He- Ile-Trp; Fmoc-D-Bheg- Phe-Asp- He- Ile-Trp ; Fmoc-D-Bheg-Arg-Asp- He- Ile-Trp; Fmoc-D-Bheg-Asp- He- Ile-Trp; Ac-D-Bheg-Leu- Phe- He- Ile-Trp; Ac-D-Bheg-Leu-Asn- Ile- Ile-Trp; Ac -D-Bheg- Leu-Glu- He - He -Trp; Ac-D-Bheg-Leu-Gln- He- Ile-Trp; Ac-D-Bheg- Leu-Tyr- He- Ile-Trp; Ac -D-Bheg- Leu- 1 -Nal - lie- Ile-Trp; Ac -D-Bheg- Leu- 2 -Nal - He- Ile-Trp ; Ac -D-Bheg- eu-Trp- He- Ile-Trp; Ac-D-Bheg-Leu-Asp-Val- Ile-Trp; Ac-D-Bheg-Leu-Asp- Ile-Val-Trp; Ac-D-Bheg-Leu-Asp- Chx- Ile-Trp; Ac-D-Bheg-Leu-Asp- Ile-Chx-Trp; Ac-D-Bheg-Arg-Asp- Ile-Chx-Trp; Ac-D-Bheg-Lys -Asp- He- Chx-Trp ; Ac-D-Bheg- Orn-Asp- He- Chx-Trp ; Ac-D-Bheg- Asp-Asp- He- Chx-Trp; 90 Ac-D-Bheg-Glu-Asp-Ile-Chx-Trp; Fmoc-D-Bheg-Leu-Phe-He-Ile-Trp; Fmoc-D-Bheg-Leu-Asn-Ile-Ile-Trp; Fmoc-D-Bheg-Leu-Glu-He-Ile-Trp; Fmoc-D-Bheg-Leu-Gln-He-Ile-Trp; 95 Emoc-D-Bheg-Leu-Tyr-Ile-Ile-Trp; Fmoc-D-Bheg-Leu-Asp-Val-Ile-Trp; Fmoc-D-Bheg-Leu-Asp-He-Val-Trp; Fmoc-D-Bheg-Leu-Asp-Chx-Ile-Trp; Fmoc -D-Bheg -Arg-Asp -Chx- lie- Trp; 100 Fϊrioc -D-Bheg- Lys -As -Chx- Ile-Trp; Emoc-D-Bheg-Orn- sp-Chx- Ile-Trp; Fmoc-D-Bheg -Asp-Asp- Chx- Ile-Trp; Fmoc-D-Bheg-Glu-Asp-Chx-Ile-Trp; Fmoc-D-Bheg-Leu-Asp-Ile-Chx-Trp; 105 Fmoc-D-Bheg-Arg-Asp-Ile-Chx-Trp; Fmoc-D-Bheg-Lys-Asp- He- Chx-Trp; Fmoc-D-Bheg-Orn-Asp-Ile-Chx-Trp; Fmoc-D-Bheg-Asp-Asp Ile-Chx-Trp; Fmoc-D-Bheg-Glu-Asp- He- Chx-Trp ; 110 Ac-D-Txg-Leu-Asp-Ile-Ile-Trp; Ac-D-Txg-Orn-Asp-Ile-Ile-Trpr Ac -D- Txg-Lys -Asp- He-Ile-Trp ; Ac-D-Txg-Asp-Asp-Ile-Ile-Trp; Ac-D-Txg-Glu-Asp- He- Ile-Trp; 115 Ac-D-Txg-Phe-Asp-Ile- Ile-Trp; Ac-D-Txg -Arg-Asp- He- Ile-Trp; Ac-D-Txg-Asp-Ile-Ile-Trp; Fmoc-D-Txg- Leu-Asp-Ile- Ile-Trp; Fmoc-D-Txg- Orn-Asp- Ile-Ile-Trp; 120 Fmoc-D-Txg-Lys-Asp-Ile- Ile-Trp; Fmoc-D-Txg- Asp- Asp- He- Ile-Trp; Fmoc-D-Txg-Glu-Asp-Ile-Ile-Trp; Fmoc-D-Txg- Phe-Asp- Ile-Ile-Trp; Fmoc -D-Txg-Arg -Asp- He- Ile-Trp ; 125 Fmoc-D-Txg- Asp- He- Ile-Trp; Ac-D-Txg-Leu-Phe-Ile- Ile-Trp; Ac-D-Txg-Leu-Asn-He-He-Trp; Ac-D-Txg-Leu-Glu-He-He-Trp; Ac-D-Txg-Leu-Gin-He-He-Trp; 130 Ac-D-Txg-Leu-Tyr-Ile-Ile-Trp; Ac-D-Txg-Leu-1-Nal-Ile-He-Trp; Ac-D-Txg-Leu-2-Nal-lie-lie-Trp; Ac-D-Txg-Leu-Trp-He-Ile-Trp; Ac-D- xg-Leu-Asp-Val-lie-Trp; 135 Ac-D-Txg-Leu-Asp-Ile-Val-Trp; Ac-D-Txg-Leu-Asp-Chx-Ile-Trp; Ac-D-Txg-Leu-Asp-lie-Chx-Trp; Ac-D-Txg-Arg-Asp-Ile-Chx-Trp; Ac-D-Txg-Lys-Asp-He-Chx-Trp; 140 Ac-D-Txg-Orn-Asp-Ile-Chx-Trp; Ac-D-Txg-Asp-Asp-Ile-Chx-Trp; Ac-D-Txg-Glu-Asp-He-Chx-Trp; Fmoc-D-Txg-Leu-Phe-He-Ile-Trp; Fmoc-D-Txg-Leu-Asn-He-Ile-Trp; 145 Fmoc-D-Txg-Leu-Glu-He-Ile-Trp; Fmoc-D-Txg-Leu-Gin-He-Ile-Trp; Fmoc-D-Txg-Leu-Tyr-He-Ile-Trp; Fmoc-D-Txg-Leu-Asp-Val-He-Trp; Fmoc-D-Txg-Leu-Asp-Ile-Val-Trp; 150 Fmoc-D-Txg-Leu-Asp-Chx-Ile-Trp; Fmoc-D-Txg-Arg-Asp-Chx-Ile-Trp; Fmoc-D-Txg-Lys-Asp-Chx-Ile-Trp; Fmoc-D-Txg-Orn-Asp-Chx-He-Trp; Fmoc-D-Txg-Asp-Asp-Chx-Ile-Trp; 155 Fmoc-D-Txg-Glu-Asp-Chx-Ile-Trp; Fmoc-D-Txg-Leu-Asp-He-Chx-Trp; Fmoc-D-Txg-Arg-Asp-IIe-Chx-Trp; Fmoc-D-Txg-Lys-Asp-He-Chx-Trp; • Fmoc-D-Txg-Orn-Asp-Ile-Chx-Trp; 160 Fmoc-D-Txg-Asp-Asp-Ile-Chx-Trp; Fmoc-D-Txg-Glu-Asp-He-Chx-Trp; Et-D-Bhg-Leu-Asp-Ile-He-Trp; Bz-D-Bhg-Leu-Asp-He-Ile-Trp; Pya-D-Bhg-Leu-Asp-Ile-Ile-Trp; 165 Cxl-D-Bhg-Leu-Asp-Ile-Ile-Trp; Ada-D-Bhg-Leu-Asp-He-Ile-Trp; Cxl(U) -D-Bhg-Leu-Asp-Ile-Ile-Trp; Me(ϋ) -D-Bhg-Leu-Asp-lie-Ile-Trp; tBu-D-Bhg-Leu-Asp-Ile-Ile-Trp; 170 CF 3 CO-D-Bhg-Leu-Asp-He-Ile-Trp; Et-D-Bheg-Leu-Asp-Ile-He-Trp; Bz-D-Bheg-Leu-Asp-Ile-Ile-Trp; Pya-D-Bheg-Leu-Asp-Ile-Ile-Trp; Cxi-D-Bheg-Leu-Asp-He-Ile-Trp; 175 Ada-D-Bheg-Leu-Asp-Ile-Ile-Trp; Cxi(U) -D-Bheg-Leu-Asp-Ile-Ile-Trp; Me(U)-D-Bheg-Leu-Asp-He-Ile-Trp; tBu-D-Bheg-Leu-Asp-He-Ile-Trp; CF 3 CO-D-Bheg-Leu-Asp-Ile-Ile-Trp; 180 Ac-D-Bhg-Leu-Asp-Phe-He-Trp; Ac-D-Bhg-Orn-Asp-Phe-Ile-Trp; Ac-D-Bhg-Lys-Asp-Phe-He-Trp γ Ac-D-Bhg-Asp-Asp-Phe-Ile-Trp; Ac-D-Bhg-Glu-Asp-Phe-Ile-Trp; 185 Ac-D-Bhg-Phe-Asp-Phe-Ile-Trp; Ac-D-Bhg-Arg-Asp-Phe-He-Trp; Ac-D-Bheg-Leu-Asp-Phe-Ile-Trp; Ac-D-Bheg-Orn-Asp-Phe-Ile-Trp; Ac-D-Bheg-Lys-Asp-Phe-Ile-Trp; 190 Ac-D-Bheg-Asp-Asp-Phe-Ile-Trp; Ac-D-Bheg-Glu-Asp-Phe-He-Trp; Ac-D-Bheg-Phe-Asp-Phe-Ile-Trp; and Ac-D-Bheg-Arg-Asp-Phe-Ile-Trp. 5. A method of inhibiting elevated levels of • endothelin comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit 5 dosage form. 6. A pharmaceutical composition adapted for administration as an antagonist of endothelin comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 7. A method of treating hypertension comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 8. A pharmaceutical composition adapted for administration as an antihypertensive agent comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 9. A method of treating metabolic and endocrine disorders comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 10. A pharmaceutical composition adapted for administration as an agent for treating metabolic and endocrine disorders comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 11. A method of treating congestive heart failure and myocardial infarction comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 12. A pharmaceutical composition adapted for administration as an agent for treating congestive heart failure and myocardial infarction comprising a therapeutically effective amount of a compound according to Claim l in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 13. A method of treating endotoxic shock comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 14. A pharmaceutical composition adapted for administration as an agent for treating endotoxic shock comprising a therapeutically effective amount of a compound according to Claim l in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 15. A method of treating subarachnoid hemorrhage comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 16. A pharmaceutical composition adapted for administration as an agent for treating subarachnoid hemorrhage comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 17. A method of treating arrhythmias comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 18. A pharmaceutical composition adapted for administration as an agent for treating arrhythmias comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 19. A method of treating asthma comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 20. A pharmaceutical composition adapted for administration as an agent for treating asthma comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 21. A method of treating acute and chronic renal failure comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 22. A pharmaceutical composition adapted for administration as an agent for treating acute and . chronic renal failure comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 23. A method of treating preeclampsia comprising administering to a host suffering therefrom a . therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 24. A pharmaceutical composition adapted for administration as an agent for treating preeclampsia comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 25. A method of treating diabetes comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 26. A pharmaceutical composition adapted for administration as an agent for treating diabetes comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 27. A method of treating neurological disorders comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 28. A pharmaceutical composition adapted for administration as an agent for treating neurological disorders comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 29. A method of treating pulmonary hypertension comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 30. A pharmaceutical composition adapted for administration as an agent for treating pulmonary hypertension comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 31. A method of treating ischemic disease comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 32. A pharmaceutical composition adapted for administration as an agent for treating ischemic disease comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 33. A method of protecting against gastric mucosal damage or treating ischemic bowel disease comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 34. A pharmaceutical composition adapted for administration as an agent for protecting against gastric mucosal damage or treating ischemic bowel disease comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 35. A method of treating atherosclerotic disorders including Raynaud's disease comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 36. A pharmaceutical composition adapted for administration as an agent for treating atherosclerotic disorders including Raynaud's disease comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 37. A method of treating restenosis comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 38. A pharmaceutical composition adapted for administration as an agent for treating restenosis comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 39. A method of treating angina comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 40. A pharmaceutical composition adapted for administration as an agent for treating angina comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 41. A method of treating cancer comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 42. A pharmaceutical composition adapted for administration as an agent for treating cancer comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 43. A method of treating hemorrhagic shock comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form. 44. A pharmaceutical composition adapted for administration as an agent for treating hemorrhagic shock comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 45. A method of preparing a compound of Formula I AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 wherein AA 1 is wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, fluorenylmethyl, -N-R,2 wherein R 2 and R3 are each the same or l. different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, or fluorenylmethyl, -C-OR , wherein R is as defined above, -OR 2 , wherein R 2 is as defined above, 0 -N-C-N-R 3 , wherein R 2 and R 3 are as defined I2 I2 above. -C-C(R 9 ) 3 , wherein R 9 is F, Cl, Br, or I, -CH 2 -OR 2 , wherein R 2 is as defined above, wherein R 2a is hydrogen or alkyl and R 3 is as defined above, wherein R 2a and R 3 are as defined above excluding R 3 is hydrogen, or 0 II -C-R , wherein R 2 is as defined above, R 1 is hydrogen or alkyl, Z is -0-, -S(0) ώf wherein m is zero or an integer of 1 or 2, -N-, wherein R 2 is as defined above, R l 2 ^ -(CH 2 ) n -, wherein n is zero or an integer of 1, 2, 3, or 4, -(CH 2 ) n -CH=CH-(CH 2 ) n -, wherein n is as defined above, 0 II -C-, -CR 1 -, wherein R 1 and R 2 are as defined OR 2 above, or 80 wherein R 2 and R 3 are each the same or different and each is as defined above, X and Y are the same and substituted at the same position on the aromatic ring and each may 85 be one, two, three, or four substituents selected from the group consisting of hydrogen, halogen, alkyl, 90 -C0 2 R 2 , wherein R 2 is as defined above, -CONR 2 , wherein R and R are as defined R L* above, -NR 2 , wherein R 2 and R 3 are as defined 95 R 3 above, or nitro or wherein R, Z, X, and Y are as defined above; 100 wherein R 4 is hydrogen, alkyl, alkenyl, alkynyl, 105 cycloalkyl, aryl, heteroaryl, wherein R and R are each the same or different and each is hydrogen, alkyl, 115 cycloalkyl, aryl, or heteroaryl, -OR 2b , wherein R 2b is as defined above, wherein R and R are each 125 the same or different and each is as defined above for R 2b and R 3b , 130 -C-R , wherein R is as defined above, NH -NH-C-NH-R 2b , wherein R 2b is as defined 135 above, or 0 -C II-OR2b, wherein R2b is as defined above, and 140 R 1 and ri are as defined above, or AA 2 is absent; wherein R 5 is hydrogen, 145 alkyl, aryl, heteroaryl , wherein R and R are each the same or 155 different and each is as defined above, -C- 2b wherein R is as 160 defined above, or -C-OR ,2b, wherein R ,2b ~ is as defined above, and 165 R 1 and n are as defined above, or AA 3 is absent; AA 4 and AA 5 are each independently absent or each is independently wherein R 6 is hydrogen, 170 alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or 175 heteroaryl, and R 1 and n are as defined above; AA 6 is R 1 185 wherein R 7 is aryl or heteroaryl, R 8 is 0 190 || -C-OR 1 , wherein R 1 is as defined above, -OR 1 , wherein R 1 is as defined above, 195 0 -C 'I-N-Ri, wherein R x is as defined ' l above, or 200 -C^-OR 1 , wherein R 1 is as defined above, and R 1 and n are as defined above; * stereochemistry at C in AA 1 , AA 2 , AA 3 , AA 4 , or AA 5 is 205 D, L, or DL and * stereochemistry at C in AA 6 is L; or a pharmaceutically acceptable salt thereof comprising sequential stepwise coupling of the amino acids 210 selected from AA 1 , AA 2 , AA 3 , AA 4 , AA 5 , or AA 6 to the preceding amino acid using conventional peptide synthesis methodology and after conventional deprotection to afford a compound of Formula I and, if desired, converting a compound of Formula I to a pharmaceutically acceptable salt of a compound of Formula I by conventional methodology and, if further desired, converting the obtained pharmaceutically acceptable salt of a compound of Formula I to a compound of Formula I by conventional methodology.

Inventors: CODY WAYNE LIVINGSTON, DOHERTY ANNETTE MARIAN, TOPLISS JOHN GORDON, CODY, WAYNE, LIVINGSTON, DOHERTY, ANNETTE, MARIAN, TOPLISS, JOHN, GORDON
Applicants: WARNER LAMBERT CO, WARNER-LAMBERT COMPANY
Application year: 1993
Main classification: C07K7
IPC codes: A61K38, A61P1, A61P3, A61P9, A61P11, A61P13, A61P15, A61P25, A61P35, C07K7, C07K14