ENDOTHELIN ANTAGONISTS

Abstract: Novel antagonists of endothelin are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in controlling hypertension, myocardial infarction, metabolic, endocrinological, and neurological disorders, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrythmias, asthma, acute renal failure, preeclampsia, and diabetes.

Description: ENDOTHELIN ANTAGONISTS 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 controlling hypertension, myocardial infarction, metabolic, endocrinological, and neurological disorders, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, acute renal failure, preeclampsia, 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 (SRTX's). 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-21) has a critical role in binding and vasoconstrictor activity, since ET[1—20] exhibits approximately 1000—fold less functional activity. 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. Phar . 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. 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. 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 wh „erei ■ n AA i i . s wherein R is hydrogen alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, fluorenylmethyl, -N-R 3 wherein R 3 and R 4 are each the same or R 4 different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, or fluorenylmethyl, -OR 3 wherein R 3 is as defined above, O -C II-OR * - 3 . wherein R * - 5 x is as defined above, 0 -N-C-R 4 wherein R 3 and R 4 are each the same R or different and each is as defined above, wherein R 3 and R 4 where R 4 is not hydrogen are each the same or different and each is as defined above, 0 If , -C-R wherein R° is as defined above, or -CH 2 0R 3 wherein R 3 is as defined above, n is zero or an integer of l, 2, 3, 4, 5, or 6 and R 2 is hydrogen, alkyl, -N-R 3 wherein R 3 and R 4 are each the same or R 4 different and each is as defined above, -NH- HC"-NH-Rs 5 wherein R 5 is hydrogen, p-toluenesulfonyl, nitro or 0 -C-OR 6 wherein R 6 is alkyl, cycloalkyl, aryl, or heteroaryl. 0 N-C-OR 6 -NH-C-NH-C-O-R 6 wherein R 6 is as defined IIII 00 above. -N-C-NH-R 3 wherein R 3 and R 4 are each the R 4 same or different and each is as defined above, aryl, heteroaryl, or heterocycloalkyl, wherein n and n' are each the same and each is as defined above are each the same or and each is as defined above for R 2 , and R is as defined above. * ?ι —CH—C- I wherein R 2 , R 2 ', and R 2 " are each the (CH 2 ) n same or different and each is as R 2 -C-R 2 ' I defined above for R 2 , R and n. R 2 " o * II wherein n and n' are each the same or t and each is as defined above and R 2 " are each the same or t and each is as defined above for R 2 and R is as defined above. wherein R is as defined above. wherein R is as defined above. wherein R is as defined above. wherein R is hydrogen, or alkyl, and R is as defined above. wherein R 7 is hydrogen, alkyl, cycloalkyl, aryl, or heteroacyl, R 8 and R 9 are each the same or different and each is as defined above for R 8 wherein R 7 , R 8 , and R 9 are as defined above or 0 II wherein R 7 and R 7 ' are each the same or R-C—C- II different and each is as defined above .c s \ for R , and R is as defined above; R 7 AA 2 , AA *3 , AA 4 , and AA 5 are each independently absent or each independently hydrogen, alkyl, aryl, cycloalkyl, alkenyl, alkynyl, -OR 3 wherein R 3 is as defined above, -N-R 3 wherein R 3 and R 4 are each the same or R 4 different and each is as defined above, wherein R 3 and R 4 are each the same or different and each is as defined above, -S(O) R 3 wherein m is zero or an integer of 1 or 2, and R 3 is as defined above where R is not hydrogen, Q -C-R° wherein R° is as defined above. 0 II - , . -C-OR *5 wherein R° is as defined above. R 11 is hydrogen, alkyl, or aryl, and n is as defined above. * ιι wherein n and τι r are each the same or different and each is as defined above for n, R 10 and R 10 ' are each the same or different and each is as defined above for R 10 , and R 11 is as defined above, 0 II wherein p is an integer of l, 2, -T: < OH 2'P -c- 3, 4, R 5, or 6 and R 11 is as defined above. ero or an integer of wherein R 2 and R 2 are each the same or different and each is as defined above for R , and wherein R 13 is -(CH 2 ) n -C0 2 H wherein n is as defined above, -(CH 2 ) n -OH wherein n is as defined above, or 0 II -C-NH-CH-C0 2 H wherein R >14 * is hydrogen or _." -CH 2 -C0 2 H R 12 is aryl, heteroaryl, or heterocycloalkyl, and R 11 and n are as defined above, * —N c— R 13 wherein n and n' are each the same I S* \ R ** (CH _)n (CH 2 ) n . or different and each is as R Ii2 R Ii2< defined above for n, and and R 12 ' are each the same or different and each is as defined above for R 12 and R 11 , and R 13 are as defined above. wherein R 12 , R 12 ', and R 12 " are —N—CH—R 13 each the same or different and R 12_ C _ R 12' each is as defined above for R 12 R I12- and R 11 , R 13 and n are as defined above. wherein n and n' are each the same or different and each is as defined above for n, R 12 , R 12 ', and R 12 " are each the same or different and each is as defined above for R 12 , and R 11 and ,13 are as defined above. wherein R 11 and R 13 are as defined above. C— R 13 wherein R >n xx and R 1 ** "3 3 are as defined I R 11 , CH 2 ι_ above. wherein R >n xx and R > 13 Λ are as defined above. wherein R 8 and R 9 are each the same or different and each is as defined above for R 8 and R 9 , and R 13 is as defined above, wherein R 8 and R 9 are each the same or different and each is as defined above for R 8 and R 9 , and R 13 is as defined above, wherein R , R 11 , and R 13 are as defined above, and -N— - wherein R ,11 and p are as defined above; I >- < CH 2>p 4 n stereochemistry at CH or C in AA 1 is D, * * stereochemistry at CH or C in AA 2 , AA 3 , AA 4 , or AA 5 is D, L, or DL and * * stereochemistry at CH or C in AA 6 is L; and with the exclusion of the compound wherein AA 1 is 0 o II * II H 3 C — C -NH — CH— C - wherein CH is D stereochemistry, O ,2 . * II AA is -NH-CH-C- wherein CH is L stereochemistry. O 3 * If AA is — H-CH-C- wherein CH is L stereochemistry, CH, I 2 C0 2 H 0 * II * AA 4 and AA5 are each -NHCH-C- wherein CH is L CH-CH.- stereochemistry, I 3 CH 2 CH 3 and 0 * II AA is wherein CH is L stereochemistry; 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, acute renal failure, preeclampsia, 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-nonyl, 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, 1-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 O-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, 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 II hydroxy, thiol, nitro, halogen, amino, —NH-C-alkyl 0 II wherein alkyl is as defined above, -C-O-alkyl wherein 0 H alkyl is as defined above, —C—alkyl wherein alkyl is as defined above, or aryl. 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— sothiazolyl, 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 2 substituents selected from alkyl as defined above, aryl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, thiol, 0 II nitro, halogen, formyl, amino, -NH-C-alkyl wherein 0 II alkyl is as defined above, —C-O-alkyl wherein alkyl 0 s as defined above, — ICI—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 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 Bip (Paraphenyl)phenylalanine Dip 3,3-Diphenylalanine ** 3Hyp 3-Hydroxyproline 4Hyp 4-Hydroxyproline N-MePhe N-Methylphenylalanine N-MeAsp N-Methylaspartic acid Nva Norvaline Nle Norleucine Orn Omithine Abu 2—Aminobutyric acid Alg 2-Amino-4-pentenoic acid (Allylglycine) Arg(N0 2 ) N G —nitroarginine Atm 2-Amino-3-(2-amino-5- thiazole)propanoic acid Cpn 2-Amino-3-cyclopropanepropanoic acid (Cyclopropylalanine) Chx Cyclohexylalanine (Hexahydrophenyl- alanine) Ξmg 2-Amino-4,5 (RS)-epoxy-4-pentenoic acid His (Dnp) N * " 1* ^,4-Dinitrophenylhistidine HomoGlu 2-Aminoadipic acid HomoPhe 2-Amino-5-phenylpentanoic acid (Homophenylalanine) Met(0) Methionine sulfoxide Met(0 2 ) Methionine sulfone Synthesis can be accomplished according to the procedure described by Josien, H., et al. Tetrahedron Letters. 1991, 32_, 6547-50. Abbreviation 1 ' Modified and Unusual Amino Acid (cont) 1-Nal 3-(1'-Naphthyl)alanine 2-Nai 3-(2 '-Naphthyl)alanine Nia 2-Amino-3-cyanopropanoic acid (Cyanoalanine) Pgl Phenylglycine Pgy 2—Aminopentanoic acid (Propylglycine) 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- isoquinolinecarboxylic acid Tza 2-Amino-3-(4-thiazolyl)-propanoic acid Abbreviation* Protecting Group (cont) TBS tertiary Butyldimethylsilyl Dnp 2,4-Dinitrophenyl For For yl Fmoc 9-Fluorenylmethyloxycarbonyl N0 2 Nitro Tos 4-Toluenesulfonyl (tosyl) Trt Triphenylmethyl (trityl) Abbreviation Solvents and Reagents HOAc Acetic acid CH 3 CN Acetonitrile DCM Dichloromethane DCC N,N'-Dicyclohexylcarbodiimide DIEA N,N-Diisopropylethylamine DMF Di ethylformamide 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 base, 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, 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, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, S. M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66, 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 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 AA 1 is wherein R is hydrogen alkyl. alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, fluorenylmethyl, -N-R 3 wherein R 3 and R 4 are R 4 each the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, or fluorenylmethyl, O -N-C-R *3 wherein R *3 and R are each the same R 4 or different and each is as defined above or 0 -N-C-OR 4 wherein R 3 and R 4 are each the same R- 5 or different and each is as defined above, n is zero, R 2 is hydrogen or methyl, n' is zero or an integer of 1, 2, or 3, and R 2 ' is hydrogen, trityl, aryl, heteroaryl, heterocycloalkyl, -N-R 3 wherein R 3 and R 4 are each the same or I different and each is as defined above or wherein R 7 is hydrogen, alkyl, aryl, or heteroaryl, R 8 and R 9 are each the same or different and each is hydrogen or alkyl. o wherein R 2 ', R 2 ", and R 2 "' are each the same or different and each is hydrogen, alkyl, aryl , or heteroaryl with the proviso that at least one of R R 2 , and R 2 "' is aryl or heteroaryl and R 2 , n, and n' are as defined above, or o II R— H-C—C— II R 7 R 7 ' wherein R 7 and R 7 ' are each the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl. AA 2 , AA 3 , AA 4 , and AA 5 are each independently absent or each independently wherein R 11 is hydrogen or methyl, n is zero, R 10 is hydrogen or methyl, n' is zero or an integer of 1, 2, 3, or 4 and R 10 ' is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, -OR 3 ' wherein R 3 ' is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl, -N-R 3 ' wherein R 3 ' and R 4 ' are each the same R 4 ' or different and each is as defined above for R 3 ', 0 -C-NR 3 ' wherein R 3 ' and R 4 ' are each the R 4 ' same or different and each is as defined above, s as defined above, 0 -C-R 3 ' wherein R 3 ' is as defined above, —S(0) m R 3 ' wherein m is zero or an integer of 1 of 2 and R 3 ' is as defined above except that R 3 ' is not hydrogen, or 0 -C-OR 4 ' wherein R 4 ' is as defined above, wherein R 11 is hydrogen or methyl, n is zero, R 12 is hydrogen, or methyl, n' is zero or an integer of 1, 2, or 3, R is aryl or heteroaryl, R 13 is -(CH 2 ) n —Cθ 2 H wherein n is as defined above. -(CH 2 ) n -OH wherein n is as defined above, or wherein R 14 is hydrogen or -CH 2 -C0 2 H, or wherein R 8 and R 9 are each the same or different and each is as defined above for R 8 and R 9 and R 13 is as defined above, and R 8 is hydrogen, formyl, acetyl, Z, Boc, Bzl, or alkyl; * stereochemistry at C in AA 1 is D, * stereochemistry at C in AA 2 , AA 3 , AA 4 , or AA 5 is D, L, or DL, and stereochemistry at * C in AA 6 is L. Most preferred compounds of Formula I are one wherein AA 1 is " * B R——;C—C (CH 2 ) n ^(CH 2 ) a . R 2 R 2__ C _ R 2" R 2* -- wherein R is hydroge , alkyl. alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, fluorenylmethyl, -N-R 3 wherein R 3 and R 4 are R 4 each the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, or fluoroenylmethyl, O —N-C-OR 4 wherein R *5 and R 4 are each the same or R 4 different and each is as defined above, and R 2 ', R 2 ", and R 2 "' are each the same or different and each is ' hydrogen, alkyl, aryl, or heteroaryl with the proviso that at least one of R 2 , R 2 ', and R 2 " is aryl r or heteroaryl, and R is hydrogen or methyl, R 2 is hydrogen or methyl, n is zero, and n' is zero or an integer of 1, 2, or 3, or AA^ is wherein R 11 is hydrogen or methyl, n is zero, R 10 is hydrogen or methyl, n' is zero or an integer of 1, 2, 3, or 4, and R 10 is alkyl, OH, -N-R 3 ' wherein R 3 ' and R 4' are each R I ,- the same or different and each is hydrogen, alkyl, or aryl, 0 -C-NR 3 ' wherein R 3' and R 4' are as R 4 ' defined above, 0 -C 11 -OR A . wherein R 4 is as defined above; AA *3 is wherein R ,1 x 1 is hydrogen or methyl, n is zero, R 10 is hydrogen or methyl, n" is zero or an integer of 1, 2, or 3, and ,11' is alkyl , aryl, O -C-NR 3 ' wherein R 3 ' and R 4 ' are R 4 ' as defined above, O -C 11 -OR A 4 . wherein R 4 is as defined above, AA 4 and AA 5 are each o wherein R 11 is hydrogen or methyl, n is zero, R 10 is hydrogen or methyl, n' is zero, and R 10 ' is alkyl, or cycloalkyl. AA° is wherein R 11 is hydrogen or methyl, n is zero, R 12 is hydrogen, or methyl, n' is zero or an integer of 1, 2, of 3, R 12 ' is aryl or heteroaryl, R 13 is -(CH 2 ) n -C0 H wherein n is zero or an integer of 1, 2, 3, 4, 5, or 6, -(CH 2 ) n -OH wherein n is zero or an integer of 1, 2, 3, 4, 5, or 6, or O II -C-NH-CH wherein R 14 is hydrogen or —CH CO H, stereochemistry at C in AA 1 is D, stereochemistry at C in AA 2 , AA *3 , AA 4 , or AA 5 is D or L and * stereochemistry at C in AA 6 is L. A more preferred compound of Formula I is one wherein AA 1 is D-Dip, D-Bip, D-His, D-His(Dnp) , D-2-Nal, D-l-Nal, D-Phe, D-Pgl, D-Tyr, D-Tyr(OMe) , D-Tyr(OEt) , D-Tyr(OtBu) , D-Trp, D-Trp(For) , D-Tic, D-Tza, D-Pyr, Ac-D-Dip, Ac-D-Bip, Ac-D-His, Ac-D-His (Dnp) , Ac-D-2-Nal, Ac-D-1-Nal, Ac-D-Phe, Ac-D-Pgl, Ac-D-Tyr, Ac-D-Tyr(OMe) , Ac-D-Tyr(OEt) , Ac-D-Tyr(OtBu) , Ac-D-Trp, Ac-D-Trp(For) , Ac-D-Tic, Ac-D-Tza, Ac-D-Pyr, Ada-D-Dip, Ada-D—Bip, Ada-D-His, Ada-D-His (Dnp) , Ada-D-2-Nal, Ada-D-1-Nal, Ada-D-Phe, Ada-D-Pgl, Ada-D-Tyr, Ada-D-Tyr(OMe) , Ada-D-Tyr(OEt) , Ada-D-Tyr(OtBu), Ada-D-Trp, Ada-D-Trp(For) , Ada-D-Tic, Ada-D-Tza, Ada-D-Pyr, Adoc-D-Dip, Adoc-D-Bip, Adoc—D-His, Adoc-D-His (Dnp) , Adoc-D-2-Nal, Adoc-D-1-Nal, Adoc-D-Phe, Adoc-D-Pgl, Adoc-D-Tyr, Adoc-D-Tyr(OMe) , Adoc-D-Tyr(OEt) , Adoc-D-Tyr(OtBu) , Adoc-D-Trp, Adoc-D-Trp(For) , Adoc-D-Tic, Adoc-D-Tza, Adoc-D-Pyr, Boc-D-Dip, Boc-D-Bip, Boc-D-His, Boc-D-His (Dnp) , Boc-D-2-Nal, Boc-D-1-Nal, Boc-D-Phe, Boc-D-Pgl, Boc-D-Tyr, Boc-D-Tyr (OMe) , Boc-D-Tyr (OEt) , Boc-D-Tyr (OtBu) , Boc-D-Trp, Boc-D-Trp (For) , Boc— D-Tic, Boc-D-Tza, Boc-D-Pyr, Z-D-Dip, Z-D-Bip, Z-D-His, Z-D-His (Dnp) , Z-D-2-Nal, Z-D-1-Nal, Z-D-Phe, Z-D-Pgl, Z -D-Tyr, Z-D-Tyr (OMe) , Z-D-Tyr (OEt) , Z-D-Tyr (OtBu) , Z-D-Trp, Z-D-Trp (For) , Z-D-Tic, Z-D-Tza, Z-D-Pyr, Fmoc-D-Dip, Fmoc-D-Bip, Fmoc-D-His , Fmoc-D-His (Dnp) , Fmoc-D-2-Nal, Fmoc-D-1-Nal, Fmoc-D-Phe, Fmoc-D-Pgl, Fmoc-D-Tyr, Fmoc-D-Tyr(OMe) , Fmoc-D-Tyr(OEt) , Fmoc-D-Tyr(OtBu) , Fmoc-D-Trp, Fmoc-D-Trp(For) , Fmoc-D-Tic, Fmoc-D-Tza, Fmoc-D-Pyr, or s Ala, Alg, Arg Asn, Asp, Dab, Glu, Gin, Gly, homoArg, homoGlu, homoLys, lie, Leu, D-Leu, Lys, Met, Met(0) , et(0 2 ), Nva, Nle, Orn, Phe, Tyr, Val, or AA 2 is absent; Asp, D-Asp, N-MeAsp, Glu, Gin, homoPhe, Phe, Tyr, or AA 3 is absent; AA 4 is Ala, Chx, Gly, Glu, lie, D-Ile, Leu, Nleu, Nval, Val, or AA 4 is absent; AA 5 is Ala, Chx, Gly, lie, D-Ile, Leu, Nleu, Particularly valuable are: D-Phe-Leu-Asp-Ile-Ile-Trp; D-His (Dnp) -Leu-Asp-Ile-Ile-Trp; D-Trp-Leu-Asp-Ile-Ile-Trp; D-Tyr-Leu-Asp-Ile-Ile-Trp; D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp; D-Tyr(OEt) -Leu-Asp-Ile-Ile-Trp; D-2-Nal-Leu-Asp-Ile-Ile-Trp; D-1-Nal-Leu-Asp-Ile-Ile-Trp; D-Pgl-Leu-Asp-Ile-Ile-Trp; D-Pyr-Leu-Asp-Ile-Ile-Trp; D-Tic-Leu-Asp-Ile-Ile-Trp; D-Dip-Leu-Asp-Ile-Ile-Trp; D-Bip-Leu-Asp-Ile-Ile-Trp; Ac-D-Phe-Leu-Asp-Ile-Ile-Trp; Ac-D-His (Dnp)-Leu-Asp-Ile-Ile-Trp; Ac-D-Trp-Leu-Asp-Ile-Ile-Trp; Ac-D-Tyr-Leu-Asp-Ile-Ile-Trp; Ac-D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp; Ac-D-Tyr(OEt)-Leu-Asp-Ile-Ile-Trp; Ac-D-2-Nai-Leu-Asp-Ile-Ile-Trp; Ac-D-1-Nal-Leu-Asp-Ile-Ile-Trp; Ac-D-Pgl-Leu-Asp-Ile-Ile-Trp; Ac-D-Pyr-Leu-Asp-Ile-Ile-Trp; Ac-D-Tic-Leu-Asp-Ile-Ile-Trp; Ac-D-Dip-Leu-Asp-Ile-Ile-Trp; Ac-D-Bip-Leu-Asp-Ile-Ile-Trp; Fmoc-D-Phe-Leu-Asp-Ile-Ile-Trp; F oc—D-His-Leu-Asp-Ile-Ile-Trp; Fmoc-D-Trp-Leu-Asp-Ile-Ile-Trp; Fmoc-D-Tyr-Leu-Asp-Ile-Ile-Trp; Fmoc-D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp; Fmoc-D-Tyr(OEt)-Leu-Asp-Ile-Ile-Trp; Fmoc-D-2-Nai-Leu-Asp-Ile-Ile-Trp; Fmoc-D-1-Nal-Leu-Asp-Ile-Ile-Trp; Fmoc-D-Dip-Leu-Asp-Ile-Ile-Trp; Fmoc-D-Bip-Leu-Asp-Ile-Ile-Trp; Ada-D-Phe-Leu-Asp-Ile-Ile-Trp; Ada-D-His-Leu-Asp-Ile-Ile-Trp; Ada-D-Trp-Leu-Asp-Ile-Ile-Trp; Ada-D-Tyr-Leu-Asp-Ile-Ile-Trp; Ada-D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp; Ada-D-Tyr(OEt)-Leu-Asp-Ile-Ile-Trp; Ada-D-2-Nal-Leu-Asp-Ile-Ile-Trp; Ada-D-1-Nal-Leu-Asp-Ile-Ile-Trp; Ada-D-Dip-Leu-Asp-Ile-Ile-Trp; Ada-D-Bip-Leu-Asp-Ile-Ile-Trp ; Ac-D-Phe-D-Leu-Asp-Ile-Ile-Trp ; Ac-D-His-D-Leu-Asp-Ile-Ile-Trp; Ac-D-Trp-D-Leu-Asp-Ile-Ile-Trp ; Ac-D-Tyr-D-Leu-Asp-Ile-Ile-Trp ; Ac-D-Tyr (OMe) -D-Leu-Asp-Ile-Ile-Trp; Ac-D-Tyr (OEt) -D-Leu-Asp-Ile-Ile-Trp; Ac-D-2-Nal-D-Le -Asp-Ile-Ile-Trp; Ac-D-1-Nal-D-Leu-Asp-Ile-Ile-Trp; Ac-D-Dip-D-Leu-Asp-Ile-Ile-Trp; Ac— D-Bip-D— Leu-Asp-Ile-Ile-Trp ; Ac-D-Phe-Ile-Asp-Ile-Ile-Trp ; Ac-D-His -Ile-Asp-Ile-Ile-Trp; Ac-D-Trp-Ile-Asp-Ile-Ile-Trp; Ac-D-Tyr-Ile-Asp-Ile-Ile-Trp; Ac-D-Tyr (OMe) -Ile-Asp-Ile-Ile-Trp; Ac-D-Tyr (OEt ) -Ile-Asp-Ile-Ile-Trp; Ac-D-2-Nal-Ile-Asp-Ile-Ile-Trp; Ac-D-1-Nal-Ile-Asp-Ile-Ile-Trp ; Ac-D-Dip-Ile-Asp-Ile-Ile-Trp; Ac-D-Bip-Ile-Asp-Ile-Ile-Tr ; Ac-D-Phe-Val-Asp-Ile-Ile-Tr ; Ac-D-His -Val -Asp-Ile-Ile-Trp; Ac-D-Trp-Val-Asp-Ile-Ile-Trp ; Ac-D-Tyr-Val-Asp-Ile-Ile-Trp; Ac-D-Tyr (OMe) -Val -Asp-Ile-Ile-Trp; Ac-D-Tyr (OEt) -Val-Asp-Ile-Ile-Trp; Ac-D-2-Nal-Val-Asp-Ile-Ile-Trp; Ac-D-1-Nal-Val-Asp-Ile-Ile-Trp ; Ac-D-Dip-Val-Asp-Ile-Ile-Trp; Ac-D-Bip-Val -Asp-Ile-Ile-Trp; Ac-DPhe-Dab-Asp-Ile-Ile-Trp; Ac-DHis-Dab-Asp-Ile-Ile-Trp; Ac-DTrp-Dab-Asp-Ile-Ile-Trp; Ac-DTyr(OMe)-Dab-Asp-Ile-Ile-Trp; Ac-DTyr(OEt) -Dab-Asp-Ile-Ile-Trp; Ac-D2Nal-Dab-Asp-Ile-Ile-Trp; Ac-D3Nal-Dab-Asp-Ile-Ile-Trp; Ac-DDip-Dab-Asp-Ile-Ile-Trp; Ac-DBip-Dab-Asp-Ile-Ile-Trp; Ac-DPhe-Arg-Asp-Ile-Ile-Trp; Ac-DHis-Arg-Asp-Ile-Ile-Trp; Ac-DTrp-Arg-Asp-Ile-Ile-Trp; Ac-DTyr(OMe) -Arg-Asp-Ile-Ile-Trp; Ac-DTyr(OEt)-Arg-Asp-Ile-Ile-Trp; Ac-D2Nal-Arg-Asp-Ile-Ile-Trp; Ac-D3Nal-Arg-Asp-Ile-Ile-Trp; Ac-DDip-Arg-Asp-Ile-Ile-Trp; Ac-DBip-Arg-Asp-Ile-Ile-Trp; Ac-DPhe-hLys-Asp-Ile-Ile-Trp; Ac-DHis-hLys-Asp-Ile-Ile-Trp; Ac-DTrp-hLys-Asp-Ile-Ile-Trp; Ac-DTyr(OMe)-hLys-Asp-Ile-Ile-Trp; Ac-DTyr(OEt)-hLys-Asp-Ile-Ile-Trp; Ac-D2Nal-hLys-Asp-Ile-Ile-Trp; Ac-D3Nal-hLys-Asp-Ile-Ile-Trp; Ac-DDip—hLys-Asp-Ile-Ile-Trp; Ac-DBip—hLys— sp-Ile-Ile-Trp; Ac-DPhe-hGlu-Asp-Ile-Ile-Trp; Ac-DHis-Glu-Asp-Ile-Ile-Trp; Ac-DTrp-Glu-Asp-Ile-Ile-Trp; Ac-DTyr(OMe) -Glu-Asp-Ile-Ile-Trp; Ac-DTyr(OEt)-Glu-Asp-Ile-Ile-Trp; Ac-D2Nal-Glu-Asp-Ile-Ile-Trp; Ac-D3Nal-Glu-Asp-Ile-Ile-Trp; Ac-DDip-Glu-Asp-Ile-Ile-Trp; Ac-DBip-Glu-Asp-Ile-Ile-Trp; Ac-DPhe-hGlu-Asp-Ile-Ile-Trp; Ac-DHis-hGlu-Asp-Ile-Ile-Trp; Ac-DTrp-hGlu-Asp-Ile-Ile-Trp; Ac-DTyr(OMe) -hGlu-Asp-Ile-Ile-Trp; Ac-DTyr(OEt) -hGlu-Asp-Ile-Ile-Trp; Ac-D2Nal-hGlu-Asp-Ile-Ile-Trp; Ac-D3Nal-hGlu-Asp-Ile-Ile-Trp; Ac-DDip-hGlu-Asp-Ile-Ile-Trp; Ac-DBip-hGlu-Asp-Ile-Ile-Trp; Ac-DPhe-Asp-Asp-Ile-Ile-Trp; Ac-DHis-Asp-Asp-Ile-Ile-Trp; Ac-DTrp-Asp-Asp-Ile-Ile-Trp; Ac-DTyr(OMe) -Asp-Asp-Ile-Ile-Trp; Ac-DTyr(OEt)-Asp-Asp-Ile-Ile-Trp; Ac-D2Nal-Asp-Asp-Ile-Ile-Trp; Ac-D3Nal-Asp-Asp-Ile-Ile-Trp; Ac-DDip-Asp-Asp-Ile-Ile-Trp; Ac-DBip-Asp-Asp-Ile-Ile-Trp; Ac-D-Phe-Lys-Asp-Ile-Ile-Trp; Ac-D-His-Lys-Asp-Ile-Ile-Trp; Ac-D-Trp-Lys-Asp-Ile-Ile-Trp; Ac-D-Tyr-Lys-Asp-Ile-Ile-Trp; Ac-D-Tyr (OMe) -Lys-Asp-Ile-Ile-Trp; Ac-D-Tyr (OEt) -Lys-Asp-Ile-Ile-Trp; Ac-D-2-Nal-Lys-Asp-Ile-Ile-Trp; Ac-D-1-Nal-Lys-Asp-Ile-Ile-Trp; Ac-D-Phe-Orn-Asp-Ile-Ile-Trp; Ac-D-His-Orn-Asp-Ile-Ile-Trp; Ac-D-Trp-Orn-Asp-Ile-Ile-Trp; Ac-D-Tyr-Orn-Asp-Ile-Ile-Trp; Ac-D-Tyr(OMe) -Orn-Asp-Ile-Ile-Trp; Ac-D-Tyr (OEt) -Orn-Asp-Ile-Ile-Trp; Ac-D-2-Nal-Orn-Asp-Ile-Ile-Trp; Ac-D-1-Nal-Or -Asp-Ile-Ile-Trp; Ac-D-Phe-Gln-Asp-Ile-Ile-Trp; Ac-D-His-Gln-Asp-Ile-Ile-Trp; Ac-D-Trp-Gln-Asp-Ile-Ile-Trp; Ac-D-Tyr-Gln-Asp-Ile-Ile-Trp; Ac-D-Tyr(OMe) -Gln-Asp-Ile-Ile-Trp; Ac-D-Tyr(OEt) -Gln-Asp-Ile-Ile-Trp; Ac-D-2-Nal-Gln-Asp-Ile-Ile-Trp; Ac-D-1-Nal-Gln-Asp-Ile-Ile-Trp; Ac-D-Phe-Leu-Glu-Ile-Ile-Trp; Ac-D-His-Leu-Glu-Ile-Ile-Trp; Ac-D-Trp-Leu-Glu-Ile-Ile-Trp; Ac-D-Tyr-Leu-Glu-Ile-Ile-Trp; Ac-D-Tyr(OMe)-Leu-Glu-Ile-Ile-Trp; Ac-D-Tyr(OEt) -Leu-Glu-Ile-Ile-Trp; Ac-D-2-Nal-Leu-Glu-Ile-Ile-Trp; Ac-D-1-Nal-Leu-Glu-Ile-Ile-Trp; Ac-D-Phe-Leu-Asn-Ile-Ile-Trp; Ac-D-His-Leu-Asn-Ile-Ile-Trp; Ac-D-Trp-Leu-Asn-Ile-Ile-Trp; Ac-D-Tyr-Leu-Asn-Ile-Ile-Trp; Ac-D-Tyr(OMe)-Leu-Asn-Ile-Ile-Trp; Ac-D-Tyr(OEt)-Leu-Asn-Ile-Ile-Trp; Ac-D-2-Nal-Leu-Asn-Ile-Ile-Trp; Ac-D-1-Nal-Leu-Asn-Ile-Ile-Trp; Ac-D-Dip-Leu-Asn-Ile-Ile-Trp; Ac-D-Bip-Leu-Asn-Ile-Ile-Trp; Ac-DPhe-Leu-Phe-Ile-Ile-Trp; Ac-DHis-Leu-Phe-Ile-Ile-Trp; Ac-DTrp-Leu-Phe-Ile-Ile-Trp; Ac-DTyr(OMe)-Leu-Phe-Ile-Ile-Trp; Ac-DTyr(OEt)-Leu-Phe-Ile-Ile-Trp; Ac-D2Nal-Leu-Phe-Ile-Ile-Trp; Ac-D3Nal-Leu-Phe-Ile-Ile-Trp; Ac-DDip-Leu-Phe-Ile-Ile-Trp; Ac-DBip-Leu-Phe-Ile-Ile-Trp; Ac-D-Phe-Glu-Asp-Ile-Ile-Trp; Ac-D-Phe-Leu-Asp-Val-Ile-Trp ; Ac-D-His-Leu-Asp-Val-Ile-Trp; Ac-D-Trp-Leu-Asp-Val-Ile-Trp ; Ac-D-Tyr-Leu-Asp-Val-Ile-Trp; Ac-D-Tyr (OMe) -Leu-Asp-Val-Ile-Trp; Ac-D-Tyr (OEt) -Leu-Asp-Val-Ile-Trp; Ac-D-2-Nal-Leu-Asp-Val-Ile-Trp; Ac-D-1-Nal-Leu-Asp-Val-Ile-Trp; Ac-D-Dip-Leu-Asp-Val-Ile-Trp; Ac-D-Bip-Leu-Asp-Val-Ile-Trp ; Ac-D-Phe-Leu-Asp-Chx-Ile-Trp ; Ac-D-His-Leu-Asp-Chx-Ile-Trp; Ac-D-Trp-Leu-Asp-Chx-Ile-Trp ; Ac-D-Tyr-Leu-Asp-Chx-Ile-Trp; Ac-D-Tyr (OMe) -Leu-Asp-Chx-Ile-Trp; Ac-D-Tyr (OEt) -Leu-Asp-Chx-Ile-Trp; Ac-D-2— al-Leu-Asp-Chx-Ile-Trp; Ac-D-1-Nal-Leu-Asp-Chx-Ile-Trp; Ac-D-Dip-Leu-Asp-Chx-Ile-Trp; Ac— D-Bip— Leu— Asp-Chx-Ile— Trp ; Ac-D-Phe-Leu-Asp-D-Ile-Ile-Trp ; Ac-D-His -Leu -Asp-D-Ile-Ile-Trp ; Ac-D-Trp-Leu-Asp-D-Ile-Ile-Trp ; Ac-D-Tyr-Leu-Asp-D-Ile-Ile-Trp ; Ac-D-Tyr (OMe) -Leu-Asp-D-Ile-Ile-Trp; Ac-D-Tyr (OEt) -Leu-Asp-D-Ile-Ile-Trp; Ac-D-2-Nal-Leu-Asp-D-Ile-Ile-Trp; Ac-D-1-Nal-Leu-Asp-D-Ile-Ile-Trp; Ac-D-Dip-Leu-Asp-D-Ile-Ile-Trp; Ac-D-Bip-Leu-Asp-D-Ile-Ile-Trp; Ac-D-Phe-Leu-Asp-Ile-D-Ile-Trp; Ac-D-His-Leu-Asp-Ile-D-Ile-Trp; Ac-D-Trp-Leu-Asp-Ile-D- le-Trp; Ac-D-Tyr-Leu-Asp-Ile-D-Ile-Trp ; Ac-D-Tyr (OMe) -Leu-Asp-Ile-D-Ile-Trp; Ac-D-Tyr (OEt) -Leu-Asp-Ile-D-Ile-Trp; Ac-D-2-Nal-Leu-Asp-Ile-D-Ile-Trp; Ac-D-1-Nal-Leu-Asp-Ile-D-Ile-Trp; Ac-D-Dip-Leu-Asp-Ile-D-Ile-Trp ; Ac-D-Bip-Leu-Asp-Ile-D-Ile-Trp ; Ac-D-Phe-Leu-Asp-Ile-Val-Trp; Ac-D-His -Leu-Asp-Ile-Val-Trp; Ac-D-Trp-Leu-Asp-Ile-Val-Trp; Ac-D-Tyr-Leu-Asp-Ile-Val-Trp ; Ac-D-Tyr (OMe) -Leu-Asp-Ile-Val-Trp; Ac-D-Tyr (OEt) -Leu-Asp-Ile-Val-Trp; Ac-D-2-Nal-Leu-Asp-Ile-Val-Trp ; Ac-D-1-Nal-Leu-Asp-Ile-Val-Trp; Ac-D-Dip-Leu-Asp-Ile-Val-Trp ; Ac-D-Bip-Leu-Asp-Ile-Val-Trp ; Ac-D-Phe-Leu-Asp-Ile-Chx-Trp ; Ac-D-His -Leu-Asp-Ile-Chx-Trp; Ac-D-Trp-Leu-Asp-Ile-Chx-Trp; Ac-D-Tyr-Leu-Asp-Ile-Chx-Trp ; Ac-D-Tyr (OMe) -Leu-Asp-Ile-Chx-Trp; Ac-D-Tyr (OEt) -Leu-Asp-Ile-Chx-Trp; Ac-D-2-Nal-Leu-Asp-Ile-Chx-Trp; Ac-D-1-Nal-Leu-Asp-Ile-Chx-Trp; Ac-D-Dip-Leu-Asp-Ile-Chx-Trp ; Ac— D— Bip— Leu— Asp-Ile— Chx— rp ; Ac-D-Phe-Leu-Asp-Ile-Ile-2 -Nai ; Ac-D-His -Leu-Asp-Ile-Ile-2 -Nai ; Ac-D-Trp-Leu-Asp-Ile-Ile-2-Nal; Ac-D-Tyr-Leu-Asp-Ile-Ile-2-Nal ; Ac-D-Tyr (OMe) -Leu-Asp-Ile-Ile-2-Nal; Ac-D-Tyr (OEt) -Leu-Asp-Ile-Ile-2-Nal; Ac-D-2-Nal-Leu-Asp-Ile-Ile-2-Nal; Ac-D-l-Nal-Leu-Asp-Ile-Ile-2-Nal ; Ac-D-Dip-Leu-Asp-Ile-Ile-2-Nal; Ac-D-Bip-Leu-Asp-Ile-Ile-2-Nal; Ac-D-Phe-Leu-Asp-Ile-Ile-1-Nal ; Ac-D-His-Leu-Asp-Ile-Ile-1-Nal; Ac-D-Trp-Leu-Asp-Ile-Ile-1-Nal ; Ac-D-Tyr-Leu-Asp-Ile-Ile-1-Nal; Ac-D-Tyr (OMe) -Leu-Asp-Ile-Ile-1-Nal; Ac-D-Tyr (OEt) -Leu-Asp-Ile-Ile-1-Nal; Ac-D-2-Nal-Leu-Asp-Ile-Ile-l-Nal; Ac-D-1-Nal-Leu-Asp-Ile-Ile-l-Nal ; Ac-D-Dip-Leu-Asp-Ile-Ile-1-Nal ; Ac-D-Bip-Leu-Asp-Ile-Ile-1-Nal ; Ac-D-His-Leu-D-Asp-Ile-D-Ile-Trp; Ac-D-Phe-Leu-D-Asp-Ile-D-Ile-Trp; Ac-D-Bip-Leu-D-Asp-Ile-D-Ile-Trp; Ac-D-Dip-Leu-D-Asp-Ile-D-Ile-Trp; Ac-D-2-Nal-Leu-D-Asp-Ile-D-Ile-Trp; Ac-D-1-Nal-Leu-D-Asp-Ile-D-Ile-Trp; Ac-D-Trp-Leu-D-Asp- le-D-Ile-Trp ; Ac-D-Dip-Asn-Ile-Ile-Trp; Ac-D-Dip-Phe-Ile-Ile-Trp ; Ac-D-Dip-Ile-Ile-Trp; Ac-D-Dip-Asp-Ile-Ile-Trp ; Ac-D (NMe) -Dip-Leu-Asp-Ile-Ile-Trp; Ac-D-Dip-Leu-Asp-Ile-Ile- (NMe) Trp; Ac-D-Dip-Leu-Asp-Ile- (NMe) Ile-Trp; Ac-D-Dip-Leu-Asp- (NMe) Ile-Ile-Trp; Ac-D-Dip-Leu- (NMe) Asp-Ile-Ile-Trp; Ac-D-Dip- (NMe ) Leu-Asp-Ile-Ile-Trp ; Ac-D-Phe-Asp-Ile-Ile-Trp ; Ac-D-His-Asp-Ile-Ile-Trp; Ac-D-Trp-Asp-Ile-Ile-Trp ; Ac-D-Tyr-Asp-Ile-Ile-Trp ; Ac-D-Tyr (OMe) -Asp-Ile-Ile-Trp; Ac-D-Tyr (OEt) -Asp-Ile-Ile-Trp; Ac-D-2-Nal-Asp-Ile-Ile-Trp ; Ac-D-1-Nal-Asp-Ile-Ile-Trp ; Ada-D-Phe-Asp-Ile-Ile-Trp; Ada-D-His-Asp-Ile-Ile-Trp ; Ada-D-Trp-Asp-Ile-Ile-Trp ; Ada-D-Tyr-Asp-Ile-Ile-Trp ; Ada-D-Tyr (OMe) -Asp-Ile-Ile-Trp; Ada-D-Tyr (OEt) -Asp-Ile-Ile-Trp; Ada-D-2-Nal-Asp-Ile-Ile-Trp; Ada-D-1-Nal-Asp-Ile-Ile-Trp; Ada-D-Dip-Asp-Ile-Ile-Trp ; Ada-D-Bip-Asp-Ile-Ile-Trp ; Ac-D-Phe-Asp-Ile-Ile-2-Nal; Ac-D-Phe-Asp-Ile-Ile-1-Nal ; Ac-D-His -Asp-Ile-Ile-2 -Nai ; Ac-D-His-Asp-Ile-Ile-1-Nal ; Ac-D-Tyr-Asp-Ile-Ile-2-Nal ; Ac-D-Tyr-Asp-Ile-Ile-1-Nal; Ac-D-Trp-Asp-Ile-Ile-2-Nal ; Ac-D-Trp-Asp-Ile-Ile-1-Nal ; Ac-D-Dip-Asp-Ile-Ile-2-Nal ; Ac-D-Dip-Asp-Ile-Ile-1-Nal ; Ac-D-Bip-Asp-Ile-Ile-2-Nal; Ac-D-Bip-Asp-Ile-Ile-1-Nal ; Ac-D-Phe-Leu-Asp-Ile-Trp ; Ac— D— His— Leu-Asp-Ile-Trp; Ac-D-Tyr-Leu-Asp-Ile-Trp ; Ac-D-Dip-Leu-Asp-Ile-Trp; Ac-D-Trp-Leu-Asp-Ile-Trp ; Ac-DPhe-Leu-Asp-Ile-Ile-Trp-Gly; Ac-DHis-Leu-Asp-Ile-Ile-Trp-Gly; Ac-DTrp-Leu-Asp-Ile-Ile-Trp-Gly; Ac-DTyr(OMe) -Leu-Asp-Ile-Ile-Trp-Gly; . Ac-DTyr(OEt)-Leu-Asp-Ile-Ile-Trp-Gly; Ac-D2Nal-Leu-Asp-Ile-Ile-Trp-Gly; Ac-D3Nal-Leu-Asp-Ile-Ile-Trp-Gly; Ac-DDip-Leu-Asp-Ile-Ile-Trp-Gly; Ac-DBip-Leu-Asp-Ile-Ile-Trp-Gly; Ac-DPhe-Leu-Asp-Ile-Ile-Trp-Asp; Ac-DHis-Leu-Asp-Ile-Ile-Trp-Asp; Ac-DTrp-Leu-Asp-Ile-Ile-Trp-Asp; Ac-DTyr(OMe) -Leu-Asp-Ile-Ile-Trp-Asp; Ac-DTyr(OEt) -Leu-Asp-Ile-Ile-Trp-Asp; Ac-D2Nal-Leu-Asp-Ile-Ile-Trp-Asp; Ac-D3Nal-Leu-Asp-Ile-Ile-Trp-Asp; Ac-DDip-Leu-Asp-Ile-Ile-Trp-Asp; and Ac-DBip-Leu-Asp-Ile-Ile-Trp-Asp-Asp; 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-l([ 125 I]-Endothelin-l) binding in a receptor assay. The binding of the compounds of Formula I is determined by incubation (37°C, 2 hours) of a compound of Formula I with [ 125 I]-ET-1 and the tissue (rat heart ventricle (10 μg) ) in 50 mM Tris (hydroxy- methyl) aminomethane hydrochloride (Tris-HCl) (pH 7.4), 5 mM ethylenediamine tetraacetic acid (EDTA) , 2 mM ethylene glycol bis (β-aminoethyl ether)N,N,N',N'-tetraacetic acid (EGTA) , 100 μM phenylmethylsulfonyl fluoride (PMSF) , and 100 μM bacitracin containing protease inhibitors (total volume of 0.5 mL) . 1 50 values are calculated by weighing nonlinear regression curve—fitting to the mass-action (Langmuir) equation. The functional activity of compounds of Formula I is determined in Rat—1 cells by measuring intracellular levels of second messengers. Thus, cells were prelabeled with [ 3 H]—inositol and endothelin-stimulated accumulation of total [ 3 H]-inositol phosphates in the presence of Li + is monitored using anion exchange chromatography as described by Muldoon, L. L., et al. Journal of Biological Chemistry, Volume 264, pages 8529-8536 (1989) and Dudley, D. T., et al. Molecular Pharmacology, Volume 38, pages 370-377 (1990) . Antagonist activity is assessed as the ability of added compounds to reduce endothelin-stimulated inositol phosphate accumulation. Antagonist activity was also measured by the ability of added compounds to reduce endothelin-stimulated arachidonic acid release in cultured vascular smooth muscle cells as (AAR) described in Reynolds, E., Mok, L., Faseb J. , 1991, 5., A1066. The data in the table show the endothelin antagonist activity of representative compounds of Formula I. TABLE 1. Biological Activity of Compounds of Formula I (Page 1 of 2) IP (Inositol Example Binding Assay in Rat Phosphate) Number Compound Heart Ventricle IC 50 Accumulation, AAR (μM) or % Inhibition IC 50 (μM) or IC 50 (μM) % Inhibition 1 Ac-D-Phe-Leu-Asp-Ile-Ile-Trp 4 jD-1-Nal-Leu-Asp-Ile-Ile-Trp 5 Ac-D-1-Nal-Leu-Asp-Ile-Ile-Trp 1 . 9 6 Ac-jD-Phe-Leu-Asp-Ile-Trp 7 Ac-D-His-Leu-D-Asp-Ile-D-Ile-Trp 10 8 Ac-D-Phe-Orn-Asp-Ile-Ile-Trp 9 Ac-D-Phe-Glu-Asp-Ile-Ile-Trp 0 . 60 10 Ac-E)-Tyr-Leu-Asp-Ile-Ile-Trp 0 . 25 11 Ac-D-Phe-Asp-Ile-Ile-Trp 12 Fmoc-D-Phe-Leu-Asp-Ile-Ile-Trp 15 13 Ac-D-Dip-Leu-Asp-Ile-Ile-Trp 0 . 07 16 Ac-D-Dip-Leu-Phe-Ile-Ile-Trp 1 . 8 17 Ac-D-Dip-Leu-Asp-Ile-Lys-Trp 18 Ac-D-Dip-Leu-Asp-Ile-Glu-Trp 19 Ac-D-Dip-Leu-Asp-Glu-I le-Trp TABLE 1. Biological Activity of Compounds of Formula I (Page 2 of 2) IP (Inositol Example Binding Assay in Rat Phosphate) Compound Heart Ventricle IC 50 AAR Number Accumulation, (μM) or % Inhibition IC 50 (μM) or IC 50 (μM) % Inhibition 20 Ac-D-Dip-Glu-Asp-Ile-Ile-Trp 0 . 085 21 Ac-D-Dip-Orn-Asp-Ile-Ile-Trp 79% @ 0 .05 μM 0 . 02 23 Ac-D-Dip-D-Leu-Asp-Ile-Ile-Trp 41 .3% @ 10 μM 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: Bzl(Asp, 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, subcutaneously, intraduodenally, 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-Phe-Leu-Asp-Ile-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 and are not further purified. The protected peptide resin is prepared on an Applied Biosystems 430A Peptide Synthesizer, utilizing protocols supplied for a dicyclohexylcarbodiimide mediated coupling scheme (Standard 1.0, Version 1.40). Starting with 0.560 g of N-α-Boc-Trp(For)-PAM resin (0.88 meq/g, 0.43 meq 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-D-Phe, N-α-Boc-Leu-H 2 0, N-α-Boc-Asp(Bzl) , and N-α-Boc-Ile * 0.5 H 2 0. 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-D-Phe, the Boc group is removed with the end-NH 2 cycle and the free amine is acetylated with N-acetylimidazole (1.0 g, 120 minutes) in 20 mL of dichloromethane (DCM) . The resin is washed with DCM (3 x 20 mL) and dried under reduced pressure (0.878 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 (1.0 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 (320 mg) . To remove the formyl protecting group, the crude peptide is suspended in 50 mL of aqueous 0.1 N KOH at 0°C for 2 minutes. The pH of the solution is adjusted to less than 4.0 with 10% HC1/H 2 0 and passed through a C 18 (60 cc) cartridge. The cartridge is washed with H 2 0 (50 mL) , eluted with 0.1% TFA, 70% CH 3 CN in H 2 0, the eluants combined, concentrated under reduced pressure (10 mL) , diluted with H 2 0, and lyophilized to yield 153 mg of a white powder. The crude peptide is dissolved in 4.0 mL of 50% TFA/H 2 0, filtered through a 0.4 μM 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 50% B over 120 minutes) . Individual fractions are collected and combined based upon analysis by analytical HPLC. The combined fractions are concentrated under reduced pressure (10 mL) , diluted with H 2 0 (50 mL) , and lyophilized (14.8 mg) . The homogeneity and structure of the resulting peptide is confirmed by analytical HPLC, capillary zone electrophoresis. Proton Nuclear Magnetic Resonance Spectroscopy (H 1 -NMR) and Fast Atom Bombardment Mass Spectroscopy (FAB-MS), MH + 848.4. 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-2-Nal-Leu-Asp-Ile-Ile-Trp; FAB-MS, MH + 856.3. EXAMPLE 3 Ac-D-2-Nal-Leu-Asp-Ile-Ile-Trp; FAB-MS, MH + 898.5. EXAMPLE 4 D-1-Nal-Leu-Asp-Ile-Ile-Tr ; MH + 856.3, MNa + 878.2. EXAMPLE 5 Ac-D-1-Nal-Leu-Asp-Ile-Ile-Trp; MH + 898.5, MNa + 920.5. EXAMPLE 6 Ac-D-Phe-Leu-Asp-Ile-Tr ; MH + 735.5, MNa + 757.8. EXAMPLE 7 Ac-D-His-Leu-D-Asp-Ile-D-Ile-Trp; MH + 838.5, MNa + 860.40. EXAMPLE 8 Ac-D-Phe-Om-Asp-Ile-Ile-Tr ; MH + 849.1, MNa + 871.0. EXAMPLE 9 Ac-D-Phe-Glu-Asp-Ile-Ile-Trp; MH + 864.1, MNa + 886.0. EXAMPLE 10 Ac-D-Tyr-Leu-Asp-Ile-Ile-Trp; MH + 864.0, MNa + 886.3. EXAMPLE 11 Ac-D-Phe-Asp-Ile-Ile-Tr ; MH + 735.1, MNa + 757.3. EXAMPLE 12 Fmoc-D-Phe-Leu-Asp-Ile-Ile-Trp; MH + 1028.1, MNa + 1050.3. EXAMPLE 13 Ac-D-Dip-Leu-Asp-Ile-Ile-Trp; FAB-MS, MNa + 946.6. EXAMPLE 14 Ac-D-Dip-Ile-Ile-Tr ; FAB-MS, MH + 696.5, MNa + 718.5 EXAMPLE 15 Ac-D-Dip-Asp-Ile-Ile-Trp; FAB-MS, MH + 810.4, MNa + 833.5. EXAMPLE 16 Ac-D-Dip-Leu-Phe-Ile-Ile-Trp; FAB-MS, MNa + 978.3. EXAMPLE 17 Ac-D-Dip-Leu-Asp-Ile-Lvs-Trp; FAB-MS, MH + 939.6. EXAMPLE 18 Ac-D-Dip-Leu-Asp-Ile-Glu-Trp; FAB-MS, MH + 940.9, MNa + 963.3. EXAMPLE 19 Ac-D-Dip-Leu-Asp-Glu-Ile-Trp; FAB-MS, MH + 938.2. EXAMPLE 20 Ac-D-Dip-Glu-Asp-Ile-Ile-Trp; FAB-MS, MH + 940.5. EXAMPLE 21 Ac-D-Dip-Om-Asp-Ile-Ile-Trp; FAB-MS, MH + 925.1. EXAMPLE 22 Ac-D-Dip-Leu-Asp(NMe)-Ile-Ile-Trp; FAB-MS, MNa + 960.7. EXAMPLE 23 Ac-D-Dip-D-Leu-Asp-Ile-Ile-Trp; FAB-MS, MH + 924.12, M + Na 946.0. EXAMPLE 24 N-Methyl—glucamine salt of Ac-D—Phe-Leu-Asp-Ile-Ile- Trp A saturated solution of N-methyl-glucamine in water is prepared, diluted with water (1:10), chilled to 0°C, and 10 mL of the solution is added to 20.45 mg of Ac-D-Phe-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.

Claims: CLAIMS 1. A compound of Formula I AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 0 II wherein AA 1 is R-CH-C- wherein R is hydrogen alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, fluorenylmethyl, -N-R 3 wherein R 3 and R 4 are each the same or R 4 different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, or fluorenylmethyl, —OR 3 wherein R 3 is as defined above. 0 II , , -C-OR *3 wherein R *3 is as defined above, wherein R 3 and R 4 are each the same or different and each is as defined above, 0 -N-C-OR 4 wherein R 3 and R 4 where R 4 is not R *3 hydrogen are each the same or different and each is as defined above, 0 II , -C-R- 3 wherein R *3 is as defined above, or -CH OR 3 wherein R 3 is as defined above, n is zero or an integer of 1, 2, 3, 4, 5, or 6 and R 2 is hydrogen, alkyl, -N-R 3 wherein R 3 and R 4 are each the same or I. R 4 different and each is as defined above, NH -NH-C-NH-R 5 wherein R 5 is hydrogen, p-toluenesulfonyl, nitro or 0 -C-OR 6 wherein R 6 s alkyl, cycloalkyl, aryl, or heteroaryl, N -.-OR c -NH- -C-NH-C-O-R 6 wherein R 6 iis as defined 0 above. -N-C-NH-R 3 wherein R 3 and R 4 are each the i- same or different and each is as defined above, aryl, heteroaryl, or heterocycloalkyl, wherein n and ' are each the same R-C -C - different and each is as defined above (CH 2 ) n (CH 2 ) n . for n, R 2 R 2 ' R 2 and R 2 ' are each the same or different and each is as defined above 0 * II for R 2 , and R is as defined above, R— CH— C - I (CH 2 ) n wherein R 2 , R 2 ', and R 2 " are each the R 2_C — R2 " same or different and each is as defined above for R 2 , R and n, 0 * II R-^C — C — wherein n and n' are each the same or <CH 2 ) n (CH 2 ) n . different and each is as defined above R 2 -C-R 2 ' R ** -C-R 2 ' for n, R 2 " R 2 " R 2 , R 2 ', and R 2 " are each the same or different and each is as defined above 0 for R 2 and R is as defined above, wherein R is as defined above, wherein R is as defined above, wherein R is as defined above, wherein R 8 is hydrogen, or 95 alkyl, and R is as defined above. wherein R 7 is hydrogen, alkyl, 100 cycloalkyl, aryl, or heteroacyl, R 8 and R 9 are each the same or different and each is as defined 105 above for R 8 wherein R 7 , R 8 , and R 9 are as defined above or wherein R 7 and R 7 ' are each the same or different and each is as defined above 110 for R 7 , and R is as defined above; AA 2 , AA 3 , AA 4 , and AA 5 are each independently absent or each independently 0 * II —N CH-C- R" wherein R 10 is hydrogen, 115 alkyl, aryl, cycloalkyl, alkenyl, alkynyl, 120 —OR 3 wherein R 3 is as defined above, -N-R 3 wherein R 3 and R 4 are each the same or R * - different and each is as defined above, 125 0 II -C-N-R 3 wherein R 3 and R 4 are each the same R or different and each is as defined above, —S (0) R 3 wherein m is zero or an integer of 130 1 or 2, and R 3 is as defined above where R 3 is not hydrogen, O — "C—R3 wherein R3 *3 i.s as defined above, 0 135 - 'Ci-OR * - 5 . wherei.n R * 3 3 is as defined above, R 11 is hydrogen, alkyl, or aryl, and n is as defined above, * 0 11 —N ■* " ? £ ■ —C— wherein n and n' are each the same R11 (CH 2 ) n ( CH 2 ) n . or different and each is as 140 R" R 10 ' defined above for n, R 10 and R 10 ' are each the same or different and each is as defined above for R 10 , and R 11 is as defined above, wherein p is an integer of 1, 2, 3, 4, 5, or 6 and R i i is as defined above, ero or an integer of 0 II 150 -ι_5 o II wherein R >2 a _ _ndJ r R>2 ' are each the same or different and each is as 155 defined above for R 2 , and wherein R 13 is -(CH 2 ) n -C0 2 H wherein n is as defined above, -(CH 2 ) n -OH wherein n is as defined above, or 165 0 II -C-NH-CH-C0 2 H wherein R 14 is hydrogen or R 14 170 -CH 2 -C0 2 H R 12 is aryl, heteroaryl, or heterocycloalkyl, and 175 R 11 and n are as defined above, e same and 180 different and each is as defined above for R 12 and R 11 , and R 13 are as defined above, — N — CH— R 13 wherein R 12 , R 12 ' , and R ~ are .11 (CH 2 ) , each the same or different and 185 Rl2 _ C _ R 12 * each is as defined above for R 12 R 12" and R 11 , R 13 and n are as defined above, wherein n and n' are each the same or different and each is as defined above for n, R 12 , R 12 ', and R 12 ' ' are each the same or different and each is as defined above for R 12 , and R 11 and R 13 are as defined above. 195 wherein R 11 and R 13 are as defined above. —N- :C—R 13 wherein R 11 and R 13 are as defined R CH 2 CH, above. x y wherein R 11 and R 13 are as defined 200 above, wherein R 8 and R 9 are each the same or different and each is as defined above for R 8 and R 9 , and ,13 is as defined above. 205 wherein R 8 and R 9 are each the same or different and each is as defined above for R 8 and R 9 , and R 13 is as defined above. wherein R 8 , R 11 , and R 13 are as 210 defined above, and 0 II - —(CH.-) -C- wherein R >1-"1 1 and p .are as defined above; R 11 * * 215 stereochemistry at CH or C in AA 1 is D, stereochemistry at CH or C in AA 2 , AA 3 , AA 4 , or AA 5 is D, L, or DL and * * 220 stereochemistry at CH or C in AA 6 is L; and with the exclusion of the compound wherein AA 1 is o 0 II * II H 3 C—C-NH—CH—c— wherein CH is D stereochemistry. 225 0 2 . II AA is -NH-CH-C- wherein CH is L stereochemistry, CH ? I 2 CH / 230 CH. CH. 0 AA 3 is -NH-C*H-CII- wherein CH is L stereochemistry, CH 2 35 C0 2 H 0 s L • emistry, stereochemistry; or a pharmaceutically acceptable salt thereof. 2. A compound according to Claim 1, in which AA 1 is wherein R is hydrogen alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, fluorenylmethyl, -N-R 3 wherein R 3 and R 4 are R 4 each the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, or fluorenylmethyl, 0 -N-C-R 3 wherein R 3 and R 4 are each the same R 4 or different and each is as defined above or wherein R 3 and R 4 are each the same or different and each is as defined above. n is zero, R .2 is hydrogen or methyl, n r is zero or an integer of 1, 2, or 3, and R is hydrogen, trityl, aryl, heteroaryl, heterocycloalkyl, -N-R 3 wherein R 3 and R 4 are each the same or R 4 different and each is as defined above or wherein R 7 is hydrogen, alkyl, a. ~ ~γl, or heteroaryl, R 8 and R 9 are each the same or different and each is hydrogen or alkyl, wherein R 2 ', R 2 ", and R 2 "' are each the same or different and each is hydrogen, alkyl, aryl, or heteroaryl with the proviso that at least one of R 2 ', R 2 "', and R 2 "' is aryl or heteroaryl and R , n, and n' are as defined above, or 0 II R—C—C- II wherein R 7 and R 7 ' are each the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl. AA 2 , AA 3 , AA 4 , and AA 5 are each independently absent or each independently wherein R 11 is hydrogen or methyl, n is zero, R 10 is hydrogen or methyl, Ω. r is zero or an integer of 1, 2, 3, or 4 and R 10 ' is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, -OR 3 ' wherein R 3 ' is hydrogen, alkyl, alkenyl, cycloalkyl , aryl, or heteroaryl, -N-R 3 ' wherein R 3 ' and R 4 ' are each the same R 4 ' or different and each is as defined above for R 3 ', wherein R 3 ' and R 4 ' are each the same or different and each is as defined above, 0 — ICI—NH wherein R *3 i .s as defined above, R '3 -3. 1 0 -CII-R 3 ' wherein R 3 ' is as defined above, -S(0) m R 3 ' wherein m is zero or an integer of 1 of 2 and R 3 ' is as defined above except that R 3 ' is not hydrogen, or - 8C-OR 4 wherein R 4 is as defined above, 0 * II wherein R >1~1~ is hydrogen or methyl, n is zero, R 12 is hydrogen, or methyl, n' is zero or an integer of 1, 2, or 3, R is aryl or heteroaryl, R 13 is -(CH 2 ) n -C0 2 H wherein n is as defined above, -(CH 2 ) n —OH wherein n is as defined above, or 0 R > 1~4~ is hydrogen or wherein R 8 and R 9 are each the same or different and each is as defined above for R 8 and R 9 and R 13 is as defined above, and R 8 120 is hydrogen, formyl, acetyl, Z, Boc, Bzl, or alkyl; * stereochemistry at C in AA 1 is D, 125 stereochemistry at C in AA 2 , AA 3 , AA 4 , or AA 5 is D, L, or DL, and stereochexnistry at * C in AA 6 is L. 3. A compound according to Claim 2 in which AA 1 is 0 wherein R is hydrogen, alkyl, 5 alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, 10 heteroaryl, fluorenylmethyl, —N-R 3 wherein R 3 and R 4 are R I* each the same or different and each is hydrogen, 15 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl , aryl, heteroaryl, or fluoroenylmethyl, 0 II -N-C-OR 4 wherein R 3 and R 4 are each the same or ■ R different and each is as defined above, and R 2 ', R 2 ", and R 2 "' are each the same or different and each is hydrogen, alkyl, aryl, or heteroaryl with the proviso that at least one of R 2 , R 2 ', and R 2 " is aryl or heteroaryl, and R " is hydrogen or methyl, R 2 is hydrogen or methyl, n is zero, and n' is zero or an integer of 1, 2, or 3, or AA 2 is wherein R is hydrogen or methyl. n is zero r R 10 is hydrogen or methyl, n' is zero or an integer of 1, 2, 3, or 4, and R 10 is alkyl. OH, -N-R 3 ' wherein R 3 ' and R 4 ' are each R 4 ' the same or different and each is hydrogen, alkyl, or aryl. -C-NR 3 ' wherein R 3 ' and R 4 ' are as R 4 defined above, 0 —C-OR 4 ' wherein R 4 ' is as defined above; s wherein R 11 is hydrogen or methyl, n is zero, R 10 is hydrogen or methyl, n" is zero or an integer of 1, 2, or 3, and R 11 ' is alkyl, aryl, 0 || -C-NR 3 ' wherein R 3 ' and R 4 ' are R 4 ' as defined above, O -C 11 -OR A 4 . wherein R 4 is as defined above. AA 4 and AA 5 are each wherein R 11 is hydrogen or methyl. n is zero, 80 R >ιo is hydrogen or methyl, n' is zero, and R 10 ' is alkyl, or cycloalkyl, AA 6 is 85 wherein R 11 is hydrogen or methyl, n is zero, R 12 is hydrogen, or methyl, n' is zero or an integer of 1, 2, of 3, 90 R 12 ' is aryl or heteroaryl, R 13 is -(CH 2 ) n -C0 2 H wherein n is zero or an integer of 1, 2, 3, 4, 5, or 6, -(CH 2 ) n -OH wherein n is zero or 95 an integer of 1, 2, 3, 4, 5, or 6, or 0 -C-NH-CH wherein R 14 is 100 hydrogen or * stereochemistry at C in AA 1 is D, * 105 stereochemistry at C in AA 2 , AA 3 , AA 4 , or AA 5 is D or L and * stereochemistry at C in AA 6 is L. 4. A compound according to Claim 3 in which AA 1 is D-Dip, D-Bip, 5 D-His, D-His (Dnp) , D-2-Nal, D-l-Nal, D-Phe, 10 D-Pgl, D-Tyr, D-Tyr(OMe) , D-Tyr(OEt) , D-Tyr(OtBu) , 15 D-Trp, D-Trp(For) , D-Tic, D-Tza, D-Pyr, 20 Ac-D-Dip, Ac—D-Bip, Ac-D-His, Ac-D—His (Dnp) , Ac-D-2-Nal, Ac-D-1-Nal, Ac-D-Phe, Ac-D-Pgl, Ac-D-Tyr, Ac-D-Tyr (OMe) , Ac-D-Tyr (OEt) , Ac-D-Tyr (OtBu) , Ac-D-Trp, Ac-D-Trp (For) , Ac-D-Tic, Ac-D-Tza, Ac-D-Pyr, Ada-D-Dip, Ada-D-Bip , Ada-D-His, Ada-D-His (Dnp) , Ada-D-2-Nal, Ada-D-1-Nal, Ada-D-Phe , Ada-D-Pgl , Ada-D-Tyr, Ada-D-Tyr (OMe) , Ada-D-Tyr (OEt) , Ada-D-Tyr (OtBu), Ada-D-Trp, Ada-D-Trp (For) , Ada-D-Tic, Ada-D-Tza, Ada-D-Pyr, Adoc-D-Dip, Adoc-D-Bip, Adoc-D-His, Adoc-D-His (Dnp) , Adoc-D-2-Nal, Adoc-D-1-Nal, Adoc-D-Phe, Adoc-D-Pgl, Adoc-D-Tyr, Adoc-D-Tyr(OMe) , Adoc-D-Tyr(OEt) , Adoc-D-Tyr(OtBu) , Adoc-D-Trp, Adoc-D-Trp(For) , Adoc—D-Tic, Adoc-D-Tza, Adoc-D-Pyr, Boc-D-Dip, Boc-D-Bip, Boc-D-His, Boc-D-His (Dnp) , Boc-D-2-Nal, Boc-D-1-Nal, Boc-D-Phe, Boc-D-Pgl, Boc-D-Tyr, Boc-D-Tyr(OMe) , Boc-D-Tyr(OEt) , Boc-D-Tyr(OtBu) , Boc-D-Trp, Boc-D-Trp(For) , Boc-D-Tic, Boc-D-Tza, Boc-D-Pyr, Z-D-Dip, Z-D-Bip, Z-D-His, Z-D-His (Dnp) , Z-D-2-Nal, Z-D-1-Nal, Z-D-Phe, 95 Z-D-Pgl, Z-D-Tyr, Z-D-Tyr(OMe) , Z-D-Tyr(OEt) , Z-D-Tyr(OtBu) , 100 Z-D-Trp, Z-D-Trp(For) , Z-D-Tic, Z-D-Tza, Z-D-Pyr, 105 Fmoc-D-Dip, Fmoc-D—Bip, Fmoc-D-His, Fmoc-D-His (Dnp) , Fmoc-D-2-Nai, 110 Fmoc-D-1-Nal, Fmoc-D-Phe, Fmoc-D-Pgl, Fmoc-D-Tyr, Fmoc-D-Tyr(OMe) , 115 Fmoc-D-Tyr(OEt) , Fmoc-D-Tyr(OtBu) , Fmoc-D-Trp, Fmoc-D-Trp(For) , Fmoc-D-Tic, 120 Fmoc-D-Tza, Fmoc-D-Pyr, or AA -4 is Ala, Alg, Arg 125 Asn, Asp, Dab, Glu, Gin, 130 Gly, homoArg, homoGlu, homoLys, lie, 135 Leu, D-Leu, Lys, Met, Met(O) , 140 Met(0 2 ), Nva, Nle, Orn, Phe, 145 Tyr, Val, or AA 2 is absent; AA 3 is Asn, Asp, 150 D-Asp, N-MeAsp, Glu, Gin, homoPhe, 155 Phe, Tyr, or AA 3 is absent; AA 4 is Ala, Chx, 160 Gly, Glu, lie, D-Ile, Leu, 165 Nleu, Nval, Val, or AA 4 is absent; 170 Chx, Gly, He, D-Ile, Leu, 175 Nleu, Nval, Val, or AA 5 is absent; and AA 6 is 2-Nai, 180 1-Nal, Pyr, Trp, Tyr(OMe) , Tyr(OEt) , SUBSTITUTESHEET 5. A compound according to Claim 4 selected from the groups consisting of: D-Phe-Leu-Asp-Ile-Ile-Trp; D-His (Dnp) -Leu-Asp-Ile-Ile-Trp; D-Trp-Leu-Asp-Ile-Ile-Trp; D-Tyr-Leu-Asp-Ile-Ile-Trp; D-Tyr(OMe) -Leu-Asp-Ile-Ile-Trp; D-Tyr(OEt)-Leu-Asp-Ile-Ile-Trp; D-2-Nal-Leu-Asp-Ile-Ile-Trp; D-1-Nal-Leu-Asp-Ile-Ile-Trp; D-Pgl-Leu-Asp-Ile-Ile-Trp; D-Pyr-Leu—Asp-Ile-Ile-Trp; D-Tic-Leu-Asp-Ile-Ile-Trp; D-Dip-Leu-Asp-Ile-Ile-Trp; D-Bip-Leu-Asp-Ile-Ile-Trp; Ac-D-Phe-Leu-Asp-Ile-Ile-Trp; Ac-D-His (Dnp) -Leu-Asp-Ile-Ile-Trp; Ac-D-Trp-Leu-Asp-Ile-Ile-Trp; Ac-D-Tyr-Leu-Asp-Ile-Ile-Trp; Ac-D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp; Ac-D-Tyr(OEt)-Leu-Asp-Ile-Ile-Trp; Ac-D-2-Nal-Leu-Asp-Ile-Ile-Trp; Ac-D-1-Nal-Leu-Asp-Ile-Ile-Trp; Ac-D-Pgl-Leu-Asp-Ile-Ile-Trp; Ac-D-Pyr-Leu-Asp-Ile-Ile-Trp; Ac-D-Tic-Leu-Asp-Ile-Ile-Trp; Ac-D-Dip-Leu-Asp-Ile-Ile-Trp; Ac-D-Bip-Leu-Asp-Ile-Ile-Trp; Fmoc-D-Phe-Leu-Asp-Ile-Ile-Trp; Fmoc-D-His-Leu-Asp-Ile-Ile-Trp; Fmoc-D-Trp-Leu-Asp-Ile-Ile-Trp; Fmoc-D-Tyr-Leu-Asp-Ile-Ile-Trp; Fmoc-D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp; Fmoc-D-Tyr (OEt)-Leu-Asp-Ile-Ile-Trp; Fmoc-D-2-Nal-Leu-Asp-Ile-Ile-Trp; Fmoc-D-1-Nal-Leu-Asp-Ile-Ile-Trp; Fmoc-D-Dip-Leu—Asp-Ile-Ile-Trp; Fmoc-D-Bip-Leu-Asp-Ile-Ile-Trp; Ada-D-Phe-Leu-Asp-Ile-Ile-Trp; Ada-D-His-Leu-Asp-Ile-Ile-Trp; Ada-D-Trp-Leu-Asp-Ile-Ile-Trp; Ada-D-Tyr-Leu-Asp-Ile-Ile-Trp; Ada-D-Tyr(OMe) -Leu-Asp-Ile-Ile-Trp; Ada-D-Tyr (OEt) -Leu-Asp-Ile-Ile-Trp; Ada-D-2-Nal-Leu-Asp-Ile-Ile-Trp; Ada-D-l-Nal-Leu-Asp-Ile-Ile-Ti-p; Ada-D-Dip-Leu-Asp-Ile-Ile-Trp; Ada-D-Bip-Leu-Asp-Ile-Ile-Trp; Ac-D-Phe-D-Leu-Asp-Ile-Ile-Trp; Ac-D-His-D-Leu-Asp-Ile-Ile-Trp; Ac-D-Trp-D-Leu-Asp-Ile-Ile-Trp; Ac-D-Tyr-D-Leu-Asp-Ile-Ile-Trp; Ac-D-Tyr(OMe) -D-Leu-Asp-Ile-Ile-Trp; Ac-D-Tyr(OEt)-D-Leu-Asp-Ile-Ile-Trp; Ac-D-2-Nal-D-Leu-Asp-Ile-Ile-Trp; Ac-D-1-Nal-D-Leu-Asp-Ile-Ile-Trp; Ac-D-Dip-D-Leu-Asp-Ile-Ile-Trp; Ac-D-Bip-D-Leu-Asp-Ile-Ile-Trp; Ac-D-Phe-Ile-Asp-Ile-Ile-Trp; Ac-D-His-Ile-Asp-Ile-Ile-Trp; Ac-D-Trp-Ile-Asp-Ile-Ile-Trp; Ac-D-Tyr-Ile-Asp-Ile-Ile-Trp; Ac-D-Tyr(OMe) -Ile-Asp-Ile-Ile-Trp; Ac-D-Tyr(OEt) -Ile-Asp-Ile-Ile-Trp; Ac-D-2-Nal-Ile-Asp-Ile-Ile-Trρ; Ac-D-1-Nal-Ile-Asp-Ile-Ile-Trp; Ac-D-Dip-Ile-Asp-Ile-Ile-Trp; Ac-D-Bip-Ile-Asp-Ile-Ile-Trp; Ac-D-Phe-Val-Asp-Ile-Ile-Trp; Ac-D-His-Val-Asp-Ile-Ile-Trp; Ac-D-Trp—Val-Asp-Ile-Ile-Trp; Ac-D-Tyr-Val-Asp-Ile-Ile-Trp; Ac-D-Tyr(OMe) -Val-Asp-Ile-Ile-Trp; Ac-D-Tyr(OEt) -Val-Asp-Ile-Ile-Trp; Ac-D-2-Nal-Val-Asp-Ile-Ile-Trp; Ac-D-1-Nal-Val-Asp-Ile-Ile-Trρ; Ac-D-Dip-Val-Asp-Ile-Ile-Trp; Ac-D-Bip-Val-Asp-Ile-Ile-Trp; Ac-DPhe-Dab-Asp-Ile-Ile-Trp; Ac-DHis-Dab-Asp-Ile-Ile-Trp; Ac-DTrp-Dab-Asp-Ile-Ile-Trp; Ac-DTyr(OMe)-Dab-Asp-Ile-Ile-Trp; Ac-DTyr(OEt) -Dab-Asp-Ile-Ile-Trp; Ac-D2Nal-Dab-Asp-Ile-Ile-Trp; Ac-D3Nal-Dab-Asp-Ile-Ile-Trp; Ac-DDip-Dab-Asp-Ile-Ile-Trp; Ac-DBip-Dab-Asp-Ile-Ile-Trp; Ac-DPhe-Arg-Asp-Ile-Ile-Trp; Ac-DHis-Arg-Asp-Ile-Ile-Trp; Ac-DTrp-Arg-Asp-Ile-Ile-Trp; Ac-DTyr(OMe) -Arg-Asp-Ile-Ile-Trp; Ac-DTyr(OEt)-Arg-Asp-Ile-Ile-Trp; Ac-D2Nal-Arg-Asp-Ile-Ile-Trp; Ac-D3Nal-Arg-Asp-Ile-Ile-Trp; Ac-DDip-Arg-Asp-Ile-Ile-Trp; Ac-DBip-Arg-Asp-Ile-Ile-Trp; Ac-DPhe-hLys-Asp-Ile-Ile-Trp; Ac-DHis-hLys-Asp-Ile-Ile-Trp; Ac-DTrp-hLys-Asp-Ile-Ile-Trp; 100 Ac-DTyr(OMe) -hLys-Asp-Ile-Ile-Trp; Ac-DTyr(OEt) -hLys-Asp-Ile-Ile-Trp; Ac-D2Nal-hLys-Asp-Ile-Ile-Trp; Ac-D3Nal-hLys-Asp-Ile-Ile-Trp; Ac-DDip-hLys-Asp-Ile-Ile-Trp; 105 Ac-DBip-hLys-Asp-Ile-Ile-Trp; Ac-DPhe-hGlu-Asp-Ile-Ile-Trp; Ac-DHis-Glu-Asp-Ile-Ile-Trp; Ac-DTrp-Glu-Asp-Ile-Ile-Trp; Ac-DTyr(OMe) -Glu-Asp-Ile-Ile-Trp; 110 Ac-DTyr(OEt) -Glu-Asp-Ile-Ile-Trp; Ac-D2Nal-Glu-Asp-Ile-Ile-Trp; Ac-D3Nal-Glu-Asp-Ile-Ile-Trp; Ac-DDip-Glu-Asp-Ile-Ile-Trp; Ac-DBip-Glu-Asp-Ile-Ile-Trp; 115 Ac-DPhe-hGlu-Asp-Ile-Ile-Trp; Ac-DHis-hGlu-Asp-Ile-Ile-Trp; Ac-DTrp-hGlu-Asp-Ile-Ile-Trp; Ac-DTyr(OMe) -hGlu-Asp-Ile-Ile-Trp; Ac-DTyr(OEt) -hGlu-Asp-Ile-Ile-Trp; 120 Ac-D2Nal-hGlu-Asp-Ile-Ile-Trp; Ac-D3Nal-hGlu-Asp-Ile-Ile-Trp; Ac-DDip-hGlu-Asp-Ile-Ile-Trp; Ac-DBip-hGlu-Asp-Ile-Ile-Trp; Ac-DPhe-Asp-Asp-Ile-Ile-Trp; 125 Ac-DHis-Asp-Asp-Ile-Ile-Trp; Ac-DTrp-Asp-Asp-Ile-Ile-Trp; Ac-DTyr(OMe) -Asp-Asp-Ile-Ile-Trp; Ac-DTyr(OEt)-Asp-Asp-Ile-Ile-Trp; Ac-D2Nal-Asp-Asp-Ile-Ile-Trp; 130 Ac-D3Nal-Asp-Asp-Ile-Ile-Trp; Ac-DDip-Asp-Asp-Ile-Ile-Trp; Ac-DBip-Asp-Asp-Ile-Ile-Trp; Ac-D-Phe-Lys-Asp-Ile-Ile-Trp; Ac-D-His-Lys-Asp-Ile-Ile-Trp; 135 Ac—D-Trp-Lys-Asp-Ile-Ile-Trp; Ac-D-Tyr-Lys-Asp-Ile-Ile-Trp; Ac-D-Tyr(OMe)-Lys-Asp-Ile-Ile-Trp; Ac-D-Tyr(OEt) -Lys-Asp-Ile-Ile-Trp; Ac-D-2-Nal-Lys-Asp-Ile-Ile-Trp; 140 Ac-D-1-Nal-Lys-Asp-Ile-Ile-Trp; Ac-D-Phe-Orn-Asp-Ile-Ile-Trp; Ac-D-His-Orn-Asp-Ile-Ile-Trp; Ac-D-Trp-Orn-Asp-Ile-Ile-Trp; Ac-D—Tyr-Orn-Asp-Ile-Ile-Trp; 145 Ac-D-Tyr(OMe)-Orn-Asp-Ile-Ile-Trp; Ac-D-Tyr(OEt)-Orn-Asp-Ile-Ile-Trp; Ac-D-2-Nal-Or -Asp-Ile-Ile-Trp; Ac-D-1-Nal-Orn-Asp-Ile-Ile-Tr ; Ac-D-Phe-Gln-Asp-Ile-Ile-Trp; 150 Ac-D-His-Gln-Asp-Ile-Ile-Trp; Ac-D-Trp-Gln-Asp-Ile-Ile-Trp; Ac-D-Tyr-Gln-Asp-Ile-Ile-Trp; Ac-D-Tyr(OMe) -Gln-Asp-Ile-Ile-Trp; Ac-D-Tyr(OEt) -Gln-Asp-Ile-Ile-Trp; 155 Ac-D-2-Nal-Gln-Asp-Ile-Ile-Trp; Ac-D-1-Nal-Gln-Asp-Ile-Ile-Trp; Ac-D-Phe-Leu-Glu-Ile-Ile-Trp; Ac-D-His-Leu-Glu-Ile-Ile-Trp; Ac-D-Trp-Leu-Glu-Ile-Ile-Trp; 160 Ac-D-Tyr-Leu-Glu-Ile-Ile-Trp; Ac-D-Tyr(OMe)-Leu-Glu-Ile-Ile-Trp; Ac-D-Tyr(OEt)-Leu-Glu-Ile-Ile-Trp; Ac-D-2-Nal-Leu-Glu-Ile-Ile-Trp; Ac-D-1-Nal-Leu-Glu-Ile-Ile-Trp; 165 Ac-D-Phe-Le -Asn-Ile-Ile-Trp; Ac-D-His-Leu-Asn-Ile-Ile-Trp; Ac-D-Trp-Leu-Asn-Ile-Ile-Trp; Ac-D-Tyr-Leu-Asn-Ile-Ile-Trp; Ac-D-Tyr(OMe) -Leu-Asn-Ile-Ile-Trp; 170 Ac-D-Tyr (OEt) -Leu-Asn-Ile-Ile-Trp; Ac-D-2-Nal-Leu-Asn-Ile-Ile-Trp; Ac-D-1-Nal-Leu-Asn-Ile-Ile-Trp; Ac-D-Dip—Leu—Asn-Ile-Ile-Trp; Ac-D-Bip-Leu-Asn-Ile-Ile-Trp; 175 Ac-DPhe-Leu-Phe-Ile-Ile-Trp; Ac-DHis-Leu-Phe-Ile-Ile-Trp; Ac-DTrp-Leu-Phe-Ile-Ile-Trp; Ac-DTyr(OMe)-Leu-Phe-Ile-Ile-Trp; Ac-DTyr(OEt) -Leu-Phe-Ile-Ile-Trp; 180 Ac-D2Nal-Leu-Phe-Ile-Ile-Trp; Ac-D3Nal-Leu-Phe-Ile-Ile-Trp; Ac-DDip-Leu-Phe-Ile-Ile-Trp; Ac-DBip-Leu-Phe-Ile-Ile-Trp; Ac-D-Phe-Glu-Asp-Ile-Ile-Trp; 185 Ac-D-Phe-Leu-Asp-Val-Ile-Trp; Ac-D-His-Leu-Asp-Val-Ile-Trp; Ac-D-Trp-Leu-Asp-Val-Ile-Trp; Ac-D-Tyr-Leu-Asp-Val-Ile-Trp; Ac-D-Tyr (OMe) -Leu-Asp-Val-Ile-Trp; 190 Ac-D-Tyr(OEt) -Leu-Asp-Val-Ile-Trp; Ac-D-2-Nal-Leu-Asp-Val-Ile-Trp; Ac-D-1-Nal-Leu-Asp-Val-Ile-Trp; Ac-D-Dip-Leu-Asp-Val-Ile-Trp; Ac-D-^Bip-Leu-Asp-Val-Ile-Trp; 195 Ac-D-Phe-Leu-Asp-Chx-Ile-Trp; Ac-D-His-Leu-Asp-Chx-Ile-Trp; Ac-D-Trp-Leu-Asp-Chx-Ile-Trp; Ac-D-Tyr-Leu-Asp-Chx-Ile-Trp; Ac-D-Tyr(OMe) -Leu-Asp-Chx-Ile-Trp; 200 Ac-D-Tyr(OEt) -Leu-Asp-Chx-Ile-Trp; Ac-D-2-Nal-Leu-Asp-Chx-Ile-Trp; Ac-D-1-Nal-Leu-Asp-Chx-Ile-Trp; Ac-D-Dip-Leu-Asp-Chx-Ile-Trp; Ac-D—Bip-Leu-Asp-Chx-Ile-Trp; 205 Ac-D-Phe-Leu-Asp-D-Ile-Ile-Trp; Ac-D-His-Leu-Asp-D-Ile-Ile-Trp; Ac-D-Trp-Leu-Asp-D-Ile-Ile-Trp; Ac-D-Tyr-Leu-Asp-D-Ile-Ile-Trp; Ac-D-Tyr(OMe) -Leu-Asp-D-Ile-Ile-Trp; 210 Ac-D-Tyr(OEt)-Leu-Asp-D-Ile-Ile-Trp; Ac-D-2-Nal-Leu-Asp-D-Ile-Ile-Trp; Ac-D-1-Nal-Leu-Asp-D-Ile-Ile-Trp; Ac-D-Dip-Leu-Asp-D-Ile-Ile-Trp; Ac—D—Bip-Leu-Asp—D-Ile-Ile—Trp; 215 Ac-D-Phe-Leu-Asp-Ile-D-Ile-Trp; Ac-D—His-Leu-Asp-Ile-D-Ile-Trp; Ac-D-Trp-Leu-Asp-Ile-D-Ile-Trp; Ac-D-Tyr-Leu-Asp-Ile-D-Ile-Trp; Ac-D-Tyr(OMe)-Leu-Asp-Ile-D-Ile-Trp; 220 Ac-D-Tyr(OEt)-Leu-Asp-Ile-D-Ile-Trp; Ac-D-2-Nal-Leu-Asp-Ile-D-Ile-Trp; Ac-D-1-Nal-Leu-Asp-Ile-D-Ile-Trp; Ac-D—Dip-Leu-Asp-Ile-D-Ile-Trp; Ac-D-Bip-Leu-Asp-Ile-D-Ile-Trp; 225 Ac-D-Phe-Leu-Asp-Ile-Val-Trp; Ac—D-His—Leu-Asp-Ile-Val-Trp; Ac-D-Trp-Leu-Asp-Ile-Val-Trp; Ac-D-Tyr-Leu-Asp-Ile-Val-Trp; Ac-D-Tyr(OMe)-Leu-Asp-Ile-Val-Trp; 230 Ac-D-Tyr(OEt)-Leu-Asp-Ile-Val-Trp; Ac-D-2-Nal-Leu-Asp-Ile-Val-Trp; Ac-D-1-Nal-Leu-Asp-Ile-Val-Trp; Ac-D-Dip-Leu-Asp-Ile-Val-Trp; Ac-D-Bip-Leu-Asp-Ile-Val-Trp; 235 Ac-D-Phe-Leu-Asp-Ile-Chx-Trp; Ac-D-His-Leu-Asp-Ile-Chx-Trp; Ac-D-Trp-Leu-Asp-Ile-Chx-Trp; Ac-D-Tyr-Leu-Asp-Ile-Chx-Trp; Ac-D-Tyr(OMe)-Leu-Asp-Ile-Chx-Trp; 240 Ac-D-Tyr (OEt)-Leu-Asp-Ile-Chx-Trp; Ac-D-2-Nal-Leu-Asp-Ile-Chx-Trp; Ac-D-1-Nal-Leu-Asp-Ile-Chx-Trp; Ac—D-Dip-Leu-Asp-Ile-Chx-Trp; Ac-D-Bip-Leu-Asp-Ile-Chx-Trp; 245 Ac-D-Phe-Leu-Asp-Ile-Ile-2-Nal; Ac-D-His-Leu-Asp-Ile-Ile-2-Nal; Ac-D-Trp-Leu-Asp-Ile-Ile-2-Nal; Ac-D-Tyr-Leu-Asp-Ile-Ile-2-Nal; Ac-D-Tyr(OMe)-Leu-Asp-Ile-Ile-2-Nal; 250 Ac-D-Tyr(OEt)-Leu-Asp-Ile-Ile-2-Nal; Ac-D-2-Nal-Leu-Asp-Ile-Ile-2-Nal; Ac-D-l-Nal-Leu-Asp-Ile-Ile-2-Nal; Ac-D-Dip-Leu-Asp-Ile-Ile-2-Nal; Ac-D-Bip-Leu-Asp-Ile-Ile-2-Nal; 255 Ac-D-Phe-Leu-Asp-Ile-Ile-1-Nal; Ac-D-His-Leu-Asp-Ile-Ile-1-Nal; Ac-D-Trp-Leu-Asp-Ile-Ile-1-Nal; Ac-D-Tyr-Leu-Asp-Ile-Ile-1-Nal; Ac-D-Tyr(OMe) -Leu-Asp-Ile-Ile-1-Nal; 260 Ac-D-Tyr(OEt)-Leu-Asp-Ile-Ile-1-Nal; Ac-D-2-Nal-Leu-Asp-Ile-Ile-l-Nal; Ac-D-1-Nal-Leu-Asp-Ile-Ile-l-Nal; Ac-D-Dip-Leu-Asp-Ile-Ile-1-Nal; Ac-D-Bip-Leu-Asp-Ile-Ile-1-Nal; 265 Ac-D-His-Leu-D-Asp-Ile-D-Ile-Trp; Ac-D-Phe-Leu-D-Asp-Ile-D-Ile-Trp; Ac-D-Bip-Leu-D-Asp-Ile-D-Ile-Trp; Ac-D-Dip-Leu-D-Asp-Ile-D-Ile-Trp; Ac-D-2-Nal-Leu-D-Asp-Ile-D-Ile-Trp; 270 Ac-D-1-Nal-Leu-D-Asp-Ile-D-Ile-Trp; Ac-D-Trp-Leu-D-Asp-Ile-D-Ile-Trp; Ac-D-Dip-Asn-Ile-Ile-Trp; Ac-D-Dip-Phe-Ile-Ile-Trp; Ac-D-Dip-Ile-Ile-Trp; 275 Ac-D-Dip-Asp-Ile-Ile-Trp; Ac-D (NMe) -Dip-Leu-Asp-Ile-Ile-Trp; Ac-D-Dip-Leu-Asp-Ile-Ile-(NMe) Trp; Ac-D-Dip-Leu-Asp-Ile-(NMe) Ile-Trp; Ac-D-Dip-Leu-Asp-(NMe) Ile-Ile-Trp; 280 Ac-D-Dip-Leu-(NMe)Asp-Ile-Ile-Trp; Ac-D-Dip-(NMe)Leu-Asp-Ile-Ile-Trp; Ac-D-Phe-Asp-Ile-Ile-Trp; Ac-D—His—Asp-Ile-Ile-Trp; Ac-D-Trp-Asp-Ile-Ile-Trp; 285 Ac-D-Tyr-Asp-Ile-Ile-Trp; Ac-D-Tyr(OMe)-Asp-Ile-Ile-Trp; Ac-D-Tyr(OEt)-Asp-Ile-Ile-Trp; Ac-D-2-Nal-Asp-Ile-Ile-Trp; Ac-D-1-Nal-Asp-Ile-Ile-Trp; 290 Ada-D-Phe-Asp-Ile-Ile-Trp; Ada-D-His-Asp-Ile-Ile-Trp; Ada-D-Trp-Asp-Ile-Ile-Trp; Ada-D-Tyr-Asp-Ile-Ile-Trp; Ada-D-Tyr(OMe) -Asp-Ile-Ile-Trp; 295 Ada-D-Tyr(OEt) -Asp-Ile-Ile-Trp; Ada-D-2-Nal-Asp-Ile-Ile-Trp; Ada-D-1-Nal-Asp-Ile-Ile-Trp; Ada-D-Dip-Asp-Ile-Ile-Trp; Ada-D-Bip-Asp-Ile-Ile-Trp; 300 Ac-D-Phe-Asp-Ile-Ile-2-Nai; Ac-D-Phe-Asp-Ile-Ile-1-Nal; Ac-D-His-Asp-Ile-Ile-2-Nai; Ac-D-His-Asp-Ile-Ile-1-Nal; - Ac-D-Tyr-Asp-Ile-Ile-2-Nal; 305 Ac-D-Tyr-Asp-Ile-Ile-1-Nal; Ac-D-Trp-Asp-Ile-Ile-2-Nal; Ac-D-Trp-Asp-Ile-Ile-1-Nal; Ac-D-Dip-Asp-Ile-Ile-2-Nal; Ac-D-Dip-Asp-Ile-Ile-1-Nal; 310 Ac-D-Bip-Asp-Ile-Ile-2-Nal; Ac-D-Bip-Asp-Ile-Ile-1-Nal; Ac-D-Phe-Leu-Asp-Ile-Trp; Ac-D-His-Leu-Asp-Ile-Trp; Ac-D-Tyr-Leu-Asp-Ile-Trp; 315 Ac-D-Dip-Leu-Asp-Ile-Trp; Ac-D-Trp-Leu-Asp-Ile-Trp; Ac-DPhe-Leu-Asp-Ile-Ile-Trp-Gly; Ac-DHis-Leu-Asp-Ile-Ile-Trp-Gly; Ac-DTrp-Leu-Asp-Ile-Ile-Trp-Gly; 320 Ac-DTyr(OMe) -Leu-Asp-Ile-Ile-Trp-Gly; Ac-DTyr(OEt) -Leu-Asp-Ile-Ile-Trp-Gly; Ac-D2Nal-Leu-Asp-Ile-Ile-Trp-Gly; Ac-D3Nal-Leu-Asp-Ile-Ile-Trp-Gly; Ac-DDip-Leu-Asp-Ile-Ile-Trp-Gly; 325 Ac-DBip-Leu-Asp-Ile-Ile-Trp-Gly; Ac-DPhe-Leu-Asp-Ile-Ile-Trp-Asp; Ac-DHis-Leu-Asp-Ile-Ile-Trp-Asp; Ac-DTrp-Leu-Asp-Ile-Ile-Trp-Asp; Ac-DTyr(OMe) -Leu-Asp-Ile-Ile-Trp-Asp; 330 Ac-DTyr(OEt) -Leu-Asp-Ile-Ile-Trp-Asp; * Ac-D2Nal-Leu-Asp-Ile-Ile-Trp-Asp; Ac-D3Nal-Leu-Asp-Ile-Ile-Trp-Asp; Ac-DDip-Leu-Asp-Ile-Ile-Trp-Asp; and Ac-DBip-Leu-Asp-Ile-Ile-Trp-Asp-Asp. 6. A compound according to Claim 5 selected from the group consisting of: Ac-D-Phe-Leu-Asp-Ile-Ile-Trp; D-2-Nal-Leu-Asp-Ile-Ile-Trp; Ac-D-2-Nal-Leu-Asp-Ile-Ile-Trp; D_-1-Nal-Leu-Asp-Ile-Ile-Trp; Ac—D—Phe-Leu—Asp-Ile-Trp; Ac-D_-His-Leu-p_-Asp-Ile-D-Ile-Trp; Ac-p_-Phe-Orn-Asp-Ile-Ile-Trp; Ac-D-Phe-Glu-Asp-Ile-Ile-Trp; Ac-D-Tyr-Leu-Asp-Ile-Ile-Trp; Ac-D-Phe-Asp-Ile-Ile-Trp; Fmoc-p_-Phe-Leu-Asp-Ile-Ile-Trp; Ac-D-Dip-Leu-Asp-Ile-Ile-Trp; Ac-D-Dip-Ile-Ile-Trp; Ac-D-Dip-Asp-Ile-Ile-Trp; Ac-D-Dip-Leu-Phe-Ile-Ile-Trp; Ac-D—Dip-Leu-Asp-Ile-Lys-Trp; Ac-D—Dip—Leu-Asp-Ile-Glu-Trp; Ac-D-Dip-Leu-Asp-Glu-Ile-Trp; Ac-D-Dip-Glu-Asp-Ile-Ile-Trp; Ac-D-Dip-Orn-Asp-Ile-Ile-Trp; Ac-D-Dip-Leu-Asp(N-Me)-Ile-Ile-Trp; and Ac-D-Dip-D-Leu-Asp-Ile-Ile-Trp. 7. 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 dosage form. 8. 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 i with a pharmaceutically acceptable excipient, diluent, or carrier. 9. 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. 10. A pharmaceutical composition adapted for administration as an antihypertensive agent comprising a therapeutically effective amount of a compound according to Claim 1 in admixture I with a pharmaceutically acceptable excipient, diluent or carrier. 11. 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 i unit dosage form. 12. 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. 13. 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. 14. 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 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 15. 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. 16. A pharmaceutical composition adapted for administration as an agent for treating endotoxic shock 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 subarachnoid hemorrhage 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 subarachnoid hemorrhage 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 arrhythmias 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 arrhythmias comprising a therapeutically effective amount of a compound according to i Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 21. 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. 22. 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. 23. A method of treating acute renal failure 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 acute renal failure 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 preeclampsia 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 preeclampsia 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 diabetes 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 diabetes 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 neurological disorders comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage 5 form. 30. 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. 31. A method of preparing a compound of Formula I AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 0 wherein AA 1 is R-C *H-CII- ( ? H 2 ) n R 2 wherein R is hydrogen alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, fluorenylmethyl, -N-R 3 wherein R 3 and R 4 are each the same or R 4 different and each is hydrogen. alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, or fluorenylmethyl, -OR 3 wherein R 3 is as defined above, 0 II 3 3 -C-OR *3 wherein R *3 is as defined above, 0 -N-C-R 4 wherein R 3 and R 4 are each the same R- 3 or different and each is as defined above, 0 -N-C-OR 4 wherein R 3 and R 4 where R 4 is not R • 3- 3 hydrogen are each the same or different and each is as defined above, 0 — ICI-R-3 3 wherein R-3 3 i.s as defined above, or -CH 2 OR 3 wherein R 3 is as defined above, n is zero or an integer of l, 2, 3, 4, 5, or 6 and R 2 is hydrogen, alkyl, —N—R 3 wherein R 3 and R 4 are each the same or R 4 different and each is as defined above, NH -NH-C-NH-R 5 wherein R 5 is hydrogen, p-toluenesulfonyl, nitro or 0 -C I'-OR6 0 wherei•n R6° i•s alkyl, cycloalkyl, aryl, or heteroaryl, wherein R fi 6 i.s as defined above, S -N-C-NH-R 3 wherein R 3 and R 4 are each the R • A same or different and each s as defined above, aryl, heteroaryl, or heterocycloalkyl, and n' are each the same and each is as defined above are each the same or different and each is as defined above for R , and R is as defined above, * II wherein R 2 , R 2 ', and R 2 " are each the -CH—C I same or different and each is as <9 H 2 ) n defined above for R 2 , R and n, R 2 -C-R 2 ' I R 2 " T5 , * , °" wherein n and n' are each the same or 85 (CH 2 ) n ( CH 2) t different and each is as defined above R 2 -C—R 2 ' R 2 -c—R 2 ' for n, I R 2 " R 2" R , R 2 ', and R 2 " are each the same or different and each is as defined above for R 2 and R is as defined above, 0 90 wherein R is as defined above. wherein R is as defined above, wherein R is as defined above, wherein R 8 is hydrogen, or 95 alkyl, and R is as defined above, wherein R 7 is hydrogen, alkyl, 100 cycloalkyl, aryl, or heteroacyl, R 8 and R 9 are each the same or different and each is as defined 105 above for R 8 wherein R 7 , R 8 , and R 9 are as defined above or wherein R 7 and R 7 ' are each the same or different and each is as defined above 110 for R 7 , and R is as defined above; AA 2 , AA 3 , AA 4 , and AA 5 are each independently absent or each independently —N CH-C- I R 11 (CH 2 ) n R ιo wherein R 10 is hydrogen, 115 alkyl, aryl, cycloalkyl, alkenyl, alkynyl. 120 -OR 3 wherein R 3 is as defined above, -N-R 3 wherein R 3 and R 4 are each the same or I different and each is as defined above. 125 0 II -C-N-R 3 wherein R 3 and R 4 are each the same R 4 or different and each is as defined above, —S(0) R 3 wherein m is zero or an integer of 130 1 or 2, and R 3 is as defined above where R 3 is not hydrogen, 0 I' 3 3 . —C—R *3 wherein R *3 is as defined above, 0 II 3 3 135 —C-OR wherein R° is as defined above, R 11 is hydrogen, alkyl, or aryl, and n is as defined above, —N c * ?cι wherein n and n' are each the same i y \ R 11 (CH 2 ) n (CH 2 ) n . or different and each is as 140 RIO R io- defined above for n, R 10 and R 10' are each the same or different and each is as defined above for R 10 , and R 11 is as defined above, 145 0 ii -N-(CH 2 ) p -C- wherein p is an integer of 1, 2, 3, 4, R 5, or 6 and R * " * - is as defined above, ero or an integer of wherein R 2 and R 2 ' are each the same or different and each is as defined above for R 2 , and wherein R 13 is -(CH 2 ) n -C0 2 H wherein n is as defined above, -(CH 2 ) n -OH wherein n is as defined above, or 165 0 -C-NH-CH-C0 2 H wherein R is hydrogen or R 14 170 -CH 2 -C0 2 H R 12 is aryl, heteroaryl, or heterocycloalkyl, and 175 R 11 and n are as defined above. wherein n and n' are each the same or different and each is as defined above for n, and R and R 12 ' are each the same or 180 different and each is as defined above for R 12 and R 11 , and R 13 are as defined above. —N—CH—R 13 wherein R 12 , R 12 ', and R 12 " are R (CH 2 ) n each the same or different and 185 R 12 -c—R 12 ' each is as defined above for R 12 R 12 " and R 11 , R 13 and n are as defined above, ch the same s as 190 each the same or different and each is as defined above for R 12 , and R 11 and R 13 are as defined above. 195 wherein R 11 and R 13 are as defined above. wherein R 11 and R 13 are as defined above, wherein R 11 and R 13 are as defined 200 above, wherein R 8 and R 9 are each the same or different and each is as defined above for R 8 and R 9 , and R 13 is as defined above. 205 wherein R 8 and R 9 are each the same or different and each is as defined above for R 8 and R 9 , and R 13 is as defined above. wherein R 8 , R 11 , and R 13 are as 210 defined above, and 0 ENT—(CH-) -C II- wherein R1 * 1 * - and p are as defined above; I 2 P R 11 215 stereochemistry at CH or C in AA 1 is D, stereochemistry at CH or C in AA 2 , AA 3 , AA 4 , or AA 5 is D, L, or DL and 220 stereochemistry at CH or C in AA 6 is L; and with the exclusion of the compound wherein AA 1 is is D stry. CH is L stereochemistry, wherein CH is L stereochemistry, AA 4 and AA5 are each -NHC * H-CII- wherein CH is L "T- CH-CH^ stereochemistry, 240 CH 2 CH 3 and -111- wherein CH is L stereochemistry; or a pharmaceutically acceptable salt thereof comprising sequential stepwise coupling 245 of the amino acids 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 250 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 255 methodology.

Inventors: CODY WAYNE LIVINGSTON, DEPUE PATRICIA, DOHERTY ANNETTE MARIAN, TAYLOR MICHAEL DOUGLAS, CODY, WAYNE, LIVINGSTON, DEPUE, PATRICIA, DOHERTY, ANNETTE, MARIAN, TAYLOR, MICHAEL, DOUGLAS
Applicants: WARNER LAMBERT CO, WARNER-LAMBERT COMPANY
Application year: 1992
Main classification: C07K5
IPC codes: A61K38, A61P3, A61P9, A61P11, A61P13, A61P15, A61P25, C07K5, C07K7, C07K14