WO1994014843A1 - Endothelin antagonists - Google Patents

Endothelin antagonists Download PDF

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Publication number
WO1994014843A1
WO1994014843A1 PCT/US1993/012377 US9312377W WO9414843A1 WO 1994014843 A1 WO1994014843 A1 WO 1994014843A1 US 9312377 W US9312377 W US 9312377W WO 9414843 A1 WO9414843 A1 WO 9414843A1
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asp
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lie
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PCT/US1993/012377
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French (fr)
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Wayne Livingston Cody
Patricia Depue
Annette Marian Doherty
John Xiaoqiang He
Michael Douglas Taylor
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Warner-Lambert Company
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Priority to EP94904089A priority Critical patent/EP0675902A1/en
Priority to JP51534794A priority patent/JP3494649B2/en
Priority to AU58280/94A priority patent/AU679712B2/en
Publication of WO1994014843A1 publication Critical patent/WO1994014843A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/57536—Endothelin, vasoactive intestinal contractor [VIC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel
  • 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, neurological disorders, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma,
  • transluminal coronary angioplasty and restenosis angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, 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
  • bicyclic peptides which include; ET-2, ET-3, vasoactive intestinal contractor (VIC), and the sarafotoxins (SRTX' s ) .
  • VOC vasoactive intestinal contractor
  • SRTX' s sarafotoxins
  • ET-1 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.
  • Trp-21 C-terminal amino acid
  • Endothelin is involved in many human disease states.
  • ET may be involved in the pathogenesis of congestive heart failure and myocardial ischemia
  • 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.
  • SHR hypertensive rats
  • MAP mean arterial pressure
  • WKY normotensive Wistar-Kyoto rats
  • heart rate and cardiac output decreased in association with increased renal and systemic vascular resistances and antinatriuresis.
  • ET A and ET B 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 used.
  • N-Acetyl-ET[10-21, 11, 15-Ala] caused vasorelaxation in isolated, endothelium- intact porcine pulmonary
  • 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
  • the ET receptor antagonist BQ-123 has been shown to block ET-1 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.
  • Circulating endothelin levels are elevated in women with preeclampsia and correlate closely with serum uric acid levels and measures of renal
  • Plasma immunoreactive endothelin-1 concentrations are elevated in patients with sepsis and correlate with the degree of illness and depression of cardiac output (Pittett J., et al, Ann Surg., 1991, 213(3), 262).
  • 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.
  • 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).
  • streptozotocin-diabetic rats there is an increased sensitivity to endothelin-1 (Tammesild P.J., et al, Clin. Exp. Pharmacol. Physiol., 1992, 19(4), 261).
  • 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,
  • 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).
  • 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
  • ET-1 induced lesion development in a new model of local ischemia in the brain has been
  • 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.
  • endothelin-1 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 haemorrhagic change in a dose dependent manner (I. Kurose, et al, Gut, 1992, 33, 868-871).
  • an anti-ET-1 antibody reduced ethanol- induced vasoconstriction in a concentration-dependent manner (E.
  • the present invention is a compound of Formula I
  • AA 1 is R-CH-C-
  • R 3 and R 4 are each the same or
  • R 3 or different and each is as
  • R 3 or different and each is as defined above, but R 4 is not hydrogen
  • R 3' is F, Cl, Br, or I, or
  • n is zero or an integer of 1, 2, 3, 4, 5, or 6 and
  • R 2 is hydrogen
  • R 3 and R 4 are each the same or
  • R 4 different and each is as defined above, NH
  • R 4 same or different and each is as
  • n and n' are each the same or different and each is as defined above for n,
  • 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, wherein R 2 , R 2 ', and R 2 '' are each the same or different and each is as defined above for R 2 , R, and n are defined as above,
  • n and n' are each the same or different and each is as defined above for n,
  • R 2 , 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,
  • R 8 and R 9 are each the same or different and each is as defined above for R 8
  • R 7 , R 8 , and R 9 are as defined above or
  • R 7 and R 7' are each the same or different and each is as defined above 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
  • R 3 and R 4 are each the same or
  • R 3 and R 4 are each the same R 4 or different and each is as defined above,
  • R 3 is as defined above where R 3 is not hydrogen
  • R 11 is hydrogen, alkyl, or aryl
  • n is as defined above, wherein n and n' 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, wherein p is an integer of 1, 2, 3, 4, 5, or 6 and R 11 is as defined above, wherein q is zero or an integer of
  • R 2 and R 2 ' are each the same or different and each is as defined above for R 2 , and
  • n is as defined above, or
  • R 12 is
  • n and n' are each the same or different and each is as defined above for n
  • R 12 and R 12 ' are each the same or different and each is as defined above for R 12 and R 11
  • R 13 are as defined above
  • 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 , R 13 and n are as defined above
  • 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,
  • R 11 and R 13 are as defined above,
  • R 11 and R 13 are as defined above, wherein R 11 and R 13 are as defined above,
  • R 8 and R 9 are each the same or different and each is as defined above for R 8 and R 9
  • R 13 is as defined above
  • R 8 and R 9 are each the same or different and each is as defined above for R 8 and R 9
  • R 13 is as defined above
  • R 8 , R 11 , and R 13 are as defined above, and
  • CH is D stereochemistry
  • AA 2 is -NH-CH-C- wherein CH is L stereochemistry
  • AA 3 is -NH-CH-C- wherein CH is L stereochemistry
  • AA 4 and AA 5 are each -NHCH-C- wherein CH is L
  • AA 6 is -NH-CH-C-OH wherein CH is L
  • the compounds of Formula I are useful in the treatment of elevated levels of endothelin, acute and chronic renal failure,
  • transluminal coronary angioplasty and restenosis angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, ischemic bowel disease, and diabetes.
  • invention is a pharmaceutical composition for
  • 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.
  • alkenyl means a straight or branched unsaturated hydrocarbon radical having from 2 to
  • 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,
  • cycloalkyl means a saturated
  • hydrocarbon ring which contains from 3 to 12 carbon atoms, for example, cyclopropyl, cyclobutyl,
  • 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,
  • alkoxy and thioalkoxy are O-alkyl or S-alkyl as defined above for alkyl.
  • 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,
  • alkyl is as defined above, -C-O-alkyl wherein
  • alkyl is as defined above, -C-alkyl wherein alkyl is as defined above, or aryl.
  • 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, 1 - , 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
  • alkyl is as defined above, -C-O-alkyl wherein alkyl
  • alkyl is as defined above or phenyl.
  • heterocycloalkyl means 2- or
  • Halogen is fluorine, chlorine, bromine or iodine.
  • 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,
  • 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.
  • salts of amino acids such as arginate and the like and gluconate, galacturonate
  • 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.
  • 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
  • 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,
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,
  • 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.
  • 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.
  • 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
  • R 3 and R 4 are each the same or different and each is hydrogen
  • R 3 and R 4 are each the same or different and each is as defined above or
  • R 3 and R 4 are each the same R or different and each is as defined above,
  • R 3 ' is F, Cl, Br, or I, n is zero,
  • R 2 is hydrogen or methyl
  • n' is zero or an integer of 1, 2, or 3
  • R 2 ' is hydrogen
  • R 3 and R 4 are each the same or different and each is as defined above or
  • R 8 and R 9 are each the same or different and
  • R 2'' , R 2"' , and R 2 ''' are each the same or different and each is hydrogen
  • R 2''' , and R 2''' is aryl or heteroaryl and R 2 , n, and n' are as defined above, or
  • R 7 and R 7 ' are each the same or different and each is hydrogen
  • AA 2 , AA 3 , AA 4 , and AA 5 are each independently absent or each independently;
  • n zero
  • R 10 is hydrogen or methyl
  • n' is zero or an integer of 1, 2, 3, or 4 and
  • R 10 ' is hydrogen
  • R 3'' and R 4' are each the same or different and each is as defined above for R 3" ,
  • R 3'' is as defined above, -S(O) m R 3'' wherein m is zero or an integer of
  • R 3" is as defined above except that R 3" is not hydrogen, or
  • R 11 is hydrogen or methyl
  • n zero
  • R 12 is hydrogen, or methyl
  • n' is zero or an integer of 1, 2, or 3
  • R 12 ' is aryl or heteroaryl
  • R 13 is -(CH 2 ) n -CO 2 H wherein n is as defined
  • n is as defined above or
  • R 8 and R 9 are each the same or different and each is as defined above for 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 2 , AA 3 , AA 4 , or A A5 is D, L, or DL, and stereochemistry at
  • R 4 each the same or different and each is
  • R 3 or different and each is as
  • R 3 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
  • R 2 , R 2 ', and R 2 " is aryl or heteroaryl
  • R 2 "' is hydrogen or methyl
  • R 3 ' is F, Cl, Br, or I
  • R 2 is hydrogen or methyl
  • n zero
  • n' is zero or an integer of 1, 2, or 3, or AA 2 is
  • R 11 is hydrogen or methyl
  • n zero
  • R 10 is hydrogen or methyl, n' is zero or an integer of 1, 2, 3, 4, or 5, and
  • R 10 is alkyl
  • R 4' each the same or
  • R 3'' is as defined above except that R 3" is not hydrogen; AA 3 is
  • R 11 is hydrogen or methyl
  • n zero
  • R 10 is hydrogen or methyl, n" is zero or an integer of 1, 2, or 3, and
  • R 11' is alkyl
  • AA 4 and AA 5 are each
  • R 11 is hydrogen or methyl
  • n zero
  • R 10 is hydrogen or methyl, n' is zero, and
  • R 10 ' is alkyl
  • R 11 is hydrogen or methyl
  • n 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 -CO 2 H wherein n is zero or an integer of 1, 2, 3, 4, 5, or 6,
  • n is zero or an integer of 1, 2, 3, 4, 5, or
  • R 14 hydrogen or
  • stereochemistry at C in AA 2 , AA 3 , AA 4 , or AA 5 is D or L and
  • a more preferred compound of Formula I is one wherein AA 1 is
  • Ada-D-2-Nal Ada-D-1-Nal
  • Ada-D-Trp(For) Ada-D-Tic
  • AA 2 is absent; AA 3 is Asn,
  • AA 3 is absent; AA 4 is Ala,
  • AA 4 is absent; AA 5 is Ala,
  • AA 5 is absent; and AA 6 is 2-Nal,

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, Raynaud's disease, percutaneous transluminal coronary angioplasty or restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, ischemic bowel disease, and diabetes.

Description

ENDOTHELIN ANTAGONISTS
This application is a continuation-in-part of United States Patent Application Serial
No. 07/809,746, filed December 18, 1991, now pending; which is a continuation-in-part of United States
Application Serial No. 07/701,274, filed May 16, 1991, now pending.
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, neurological disorders, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma,
preeclampsia, Raynaud's disease, percutaneous
transluminal coronary angioplasty and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, 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 (SRTX' s ) . The unique bicylicc 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.
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," 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 A2 mimetic U-46619 in isolated kidneys (Perico, N., et al, "Endothelin Mediates the Renal Vasoconstriction Induced by Cyclosporine in the Rat," J. Am. Soc.
Nephrol. 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)-1 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 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 (WKY) there were no significant changes in these parameters (Ohno, A.
"Effects of Endothelin-Specific Antibodies and
Endothelin in Spontaneously Hypertensive Rats,"
J. Tokyo Women's Med. Coll., 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 ETA and ETB, have been studied extensively (Arai, H., et al, Nature 348:730 (1990), Sakurai, T., et al, Nature 348:732 (1990)). The ETA, or vascular smooth muscle receptor, is widely
distributed in cardiovascular tissues and in certain regions of the brain (Lin, H.Y., et al, Proc. Natl. Acad. Sci. 88:3185 (1991)). The ETB receptor,
originally cloned from rat lung, has been found in rat cerebellum and in endothelial cells, although it is not known if the ETB receptors are the same from these sources. The human ET receptor subtypes have been cloned and expressed (Sakamoto, A., et al, Biochem.
Biophys. Res. Chem. 178:656 (1991), Hosoda, K., et al, FEBS Lett. 287:23 (1991)). The ETA receptor clearly mediates vasoconstriction and there have been a few reports implicating the ETB receptor in the initial vasodilatory response to ET (Takayanagi , R . , et al ,
FEBS Lett. 282:103 (1991)). However, recent data has shown that the ETB receptor can also mediate
vasoconstriction in some tissue beds (Panek, R.L., et al, Biochem. Biophys. Res. Commun. 183(2):566
(1992)).
Comparison of the receptor affinities of the ET's and SRTX's in rats and atria (ETA) or cerebellum and hippocampus (ETB), indicate that SRTX-c is a selective ETB ligand (Williams, D.L., et al, Biochem. Biophys. Res. Commun.. 175:556 (1991)). A recent study showed that selective ETB agonists caused only vasodilation in the rat aortic ring, possibly through the release of EDRF from the endothelium (ibid). Thus, reported selective ETB agonists, for example, the linear analog ET [1,3,11, 15-Ala] and truncated analogs ET[6-21, 1,3,11,15-Ala], ET[8-21,11,15-Ala], and
N-Acetyl-ET[10-21, 11, 15-Ala] caused vasorelaxation in isolated, endothelium- intact porcine pulmonary
arteries (Saeki, T., et al, Biochem. Biophys. Res. Commun. 179:286 (1991)). However, some ET analogs are potent vasoconstrictors in the rabbit pulmonary artery, a tissue that appears to possess an ETB 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-1 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. Dis., 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. Gynecol., 1992, 166, 962-968).
Plasma immunoreactive endothelin-1 concentrations are elevated in patients with sepsis and correlate with the degree of illness and depression of cardiac output (Pittett J., et al, Ann Surg., 1991, 213(3), 262).
In addition the ET-1 antagonist BQ-123 has been evaluated in a mouse model of endotoxic shock. This ETA antagonist significantly increased the survival rate in this model (Toshiaki M., et al, 20.12.90.
EP 0 436 189 A1).
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).
ETA antagonist receptor blockade has been found to produce an antihypertensive effect in normal to low renin models of hypertension with a time course similar to the inhibition of ET-1 pressor responses (Basil M.K., et al, J. Hypertension. 1992,
10(Suppl 4), S49). The endothelins have been shown to be arrhythmogenic, and to have positive chronotropic and inotropic effects, thus ET receptor blockade would be expected to be useful in arrhythmia and other cardiovascular disorders (Han S.-P., et al, Life Sci., 1990, 46, 767).
The widespread localization of the endothelins and their receptors in the central nervous system and cerebrovascular circulation has been described
(Nikolov R.K., et al, Drugs of Today, 1992, 28(5), 303-310). Intracerebroventricular administration of ET-1 in rats has been shown to evoke several
behavioral effects. These factors strongly suggest a role for the ETs in neurological disorders. The potent vasoconstrictor action of ETs on isolated cerebral arterioles suggests the importance of these peptides in the regulation of cerebrovascular tone. Increased ET levels have been reported in some CNS disorders, i.e., in the CSF of patients with
subarachnoid hemorrhage and in the plasma of women with preeclampsia. Stimulation with ET-3 under conditions of hypoglycemia have been shown to
accelerate the development of striatal damage as a result of an influx of extracellular calcium.
Circulating or locally produced ET has been suggested to contribute to regulation of brain fluid balance through effects on the choroid plexus and CSF
production. ET-1 induced lesion development in a new model of local ischemia in the brain has been
described.
Circulating and tissue endothelin
immunoreactivity is increased more than twofold in patients with advanced atherosclerosis (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. Exp., 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, 114 464-469) 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 cells may be a contributing factor in chronic renal failure (P.J. 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 haemorrhagic 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).
Figure imgf000012_0001
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. 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
AA1 -AA2 -AA3 -AA4 -AA5 -AA6
Figure imgf000013_0001
wherein AA1 is R-CH-C-
Figure imgf000013_0002
(CH2)n
Figure imgf000013_0003
R2
wherein R is
hydrogen
alkyl,
alkenyl,
alkynyl,
cycloalkyl,
cycloalkylalkyl,
aryl,
heteroaryl,
fluorenylmethyl,
-N-R3 wherein R3 and R4 are each the same or
Figure imgf000013_0004
R 4 different and each is
hydrogen,
alkyl,
alkenyl,
alkynyl, cycloalkyl,
cycloalkylalkyl,
aryl,
heteroaryl, or
fluorenylmethyl,
-OR3 wherein R3 is as defined above,
Figure imgf000014_0001
-C-OR3 wherein R3 is as defined above,
Figure imgf000014_0002
-N-C-R4 wherein R3 and R4 are each the same
R 3 or different and each is as
defined above,
Figure imgf000014_0003
-N-C-OR4 wherein R3 and R4 are each the same
Figure imgf000014_0007
R3 or different and each is as defined above, but R4 is not hydrogen,
Figure imgf000014_0004
-C-R5 wherein R3 is as defined above,
Figure imgf000014_0005
-N-C-N-R4 wherein R3 and R4 are defined
R3
Figure imgf000014_0008
R3 above,
Figure imgf000014_0006
-C-C(R3')3 wherein R3' is F, Cl, Br, or I, or
-CH2OR3 wherein R3 is as defined above, n is zero or an integer of 1, 2, 3, 4, 5, or 6 and
R2 is hydrogen,
alkyl,
trityl,
-N-R3 wherein R3 and R4 are each the same or
Figure imgf000014_0009
R4 different and each is as defined above, NH
Figure imgf000014_0010
-NH-C-NH-R5 wherein R5 is
hydrogen, p-toluenesulfonyl,
nitro or
Figure imgf000015_0003
-C-OR6 wherein R6 is
alkyl,
cycloalkyl,
aryl, or
heteroaryl,
Figure imgf000015_0004
N-C-OR6
Figure imgf000015_0006
-NH-C-NH-C-O-R6 wherein R6 is as defined
Figure imgf000015_0005
above,
Figure imgf000015_0002
-N-C-NH-R3 wherein R3 and R4 are each the
Figure imgf000015_0007
R 4 same or different and each is as
defined above,
aryl,
heteroaryl, or
heterocycloalkyl, wherein n and n' are each the same or different and each is as defined above for n,
R2 and R2' are each the same or different and each is as defined above for R2, and R is as defined above, wherein R2, R2', and R2'' are each the same or different and each is as defined above for R2, R, and n are defined as above,
Figure imgf000015_0001
wherein n and n' are each the same or different and each is as defined above for n,
R2, R2', and R2" are each the same or different and each is as defined above for R2 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 R8 is
hydrogen, or
alkyl,
and R is as defined above,
wherein R7 is
hydrogen,
alkyl,
cycloalkyl,
Figure imgf000016_0001
aryl, or heteroaryl,
R8 and R9 are each the same or different and each is as defined above for R8
wherein R7, R8, and R9 are as defined above or
wherein R7 and R7' are each the same or different and each is as defined above for R7, and R is as defined above;
Figure imgf000017_0001
AA2, AA3, AA4, and AA5 are each independently absent or each independently
Figure imgf000017_0002
wherein R10 is
hydrogen,
alkyl,
aryl,
cycloalkyl,
alkenyl,
alkynyl,
-OR3 wherein R3 is as defined above,
-N-R3 wherein R3 and R4 are each the same or
Figure imgf000017_0003
R4
different and each is as defined above,
Figure imgf000018_0003
-C-N-R3 wherein R3 and R4 are each the same R 4 or different and each is as defined above,
Figure imgf000018_0004
-NH-C-NH-R5 wherein R5 is as defined above, -S(O)mR3 wherein m is zero or an integer of
1 or 2, and R3 is as defined above where R3 is not hydrogen,
Figure imgf000018_0005
- C- R3 wherein R3 is as defined above,
Figure imgf000018_0006
-C-OR3 wherein R3 is as defined above,
R11 is hydrogen, alkyl, or aryl, and
n is as defined above, wherein n and n' are each the same or different and each is as defined above for n,
Figure imgf000018_0002
R10 and R10' are each the same or different and each is as defined above for R10, and R11 is as defined above, wherein p is an integer of 1, 2, 3, 4, 5, or 6 and R11 is as defined above, wherein q is zero or an integer of
1, 2 , or 4,
Figure imgf000018_0001
wherein R2 and R2' are each the same or different and each is as defined above for R2, and
Figure imgf000019_0001
wherein R13 is
- (CH2)n-CO2H wherein n is as defined above,
- (CH2)n-OH wherein n is as defined above, or
- (CH2)n
Figure imgf000019_0002
-C-N-R3 wherein n, R3, and R4 are as defined above,
Figure imgf000019_0003
Figure imgf000019_0004
-C-NH-CH-CO2H wherein R14 is hydrogen or
Figure imgf000019_0005
-CH2-CO2H
R12 is
aryl,
heteroaryl, or
heterocycloalkyl, and R11 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 R12 and R12' are each the same or different and each is as defined above for R12 and R11, and R13 are as defined above, wherein R12, R12' , and R12'' are each the same or different and each is as defined above for R12 and R11, R13 and n are as defined above,
— wherein n and n' are each the same or different and each is as defined above for n,
R12, R12' , and R12" are each the same or different and each is as defined above for R12, and R11 and R13 are as defined above,
wherein R11 and R13 are as defined above,
wherein R11 and R13 are as defined above,
Figure imgf000020_0001
wherein R11 and R13 are as defined above,
wherein R8 and R9 are each the same or different and each is as defined above for R8 and R9, and R13 is as defined above, wherein R8 and R9 are each the same or different and each is as defined above for R8 and R9, and R13 is as defined above,
wherein R8, R11, and R13 are as defined above, and
Figure imgf000021_0001
N - (CH2 )p - C- wherein R11 and p are as defined above ;
Figure imgf000021_0002
* *
stereochemistry at CH or C in AA1 is D,
* *
stereochemistry at CH or C in AA2 , AA3 , AA4 , or AA5 is
D, L, or DL and
* *
stereochemistry at CH or C in AA6 is L; and with the exclusion of the compounds wherein AA1 is *
wherein CH is D stereochemistry, or
*
wherein CH is D stereochemistry,
Figure imgf000022_0001
*
Figure imgf000022_0003
*
AA2 is -NH-CH-C- wherein CH is L stereochemistry,
I
Figure imgf000022_0002
*
Figure imgf000022_0005
*
AA3 is -NH-CH-C- wherein CH is L stereochemistry,
Figure imgf000022_0004
Figure imgf000022_0006
AA4 and AA5 are each -NHCH-C- wherein CH is L
stereochemistry, and
Figure imgf000022_0007
Figure imgf000023_0002
*
AA6 is -NH-CH-C-OH wherein CH is L
Figure imgf000023_0001
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 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, Raynaud' s disease, percutaneous
transluminal coronary angioplasty and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, 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-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,
Figure imgf000025_0001
hydroxy, thiol, nitro, halogen, amino, -NH-C-alkyl
Figure imgf000025_0002
wherein alkyl is as defined above, -C-O-alkyl wherein
Figure imgf000025_0003
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, 1 - , 4-, or 5-thiazolyl, 3-, 4-, or
5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2, 4-triazolyl, 4- or
5-1,2, 3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridinyl, 3-, 4-, or 5-pyridazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or
8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or
8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo [b] thienyl, or 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or
7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl, unsubstituted or substituted by l to 2 substituents selected from alkyl as defined above, aryl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, thiol,
Figure imgf000025_0004
II
nitro, halogen, formyl, amino, -NH-C-alkyl wherein
Figure imgf000026_0001
II
alkyl is as defined above, -C-O-alkyl wherein alkyl
Figure imgf000026_0002
is as defined above, -C-alkyl wherein alkyl is as defined above or phenyl.
The term "heterocycloalkyl" means 2- or
3-tetrahydrσthieno, 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.
Figure imgf000026_0003
* 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 Amino Acid
(cont)
Lys Lysine
Met Methionine
Phe Phenylalanine
Pro Proline
Ser Serine
Thr Threonine
Trp Tryptophan
Tyr Tyrosine
Val Valine
Abbreviation* Modified and Unusual Amino Acid
Adm Adamantyl alanine
Ahp 7-Amino heptanoic acid
Ana 9 -Anthracene alanine
Apa 5-Amino pentanoic acid
Bip (Paraphenyl) phenylalanine
Dip 3,3-Diphenylalanine**
3Hyp 3 -Hydroxyproline
4Hyp 4 -Hydroxyproline
N-MeAsp N-Methyl-Aspartic acid
N-MeDip N-Methyl-3,3-Diphenylalanine
N-Melle N-Methyl-Isoleucine
N-MeLeu N-Methyl-Leucine
N-MePhe N-Methyl-Phenylalanine
N-MeTrp N-Methyl-Tryptophan
Nva Norvaline
Nle Norleucine
Orn Ornithine
Abu 2-Aminobutyric acid ** Synthesis can be accomplished according to the procedure described by Josien, H., et al,
Tetrahedron Letters, 1991, 32, 6547-50. Abbreviation* Modified and Unusual Amino Acid
(cont)
Alg 2-Amino-4-pentenoic acid
(Allylglycine)
Arg(NO2) NG-nitroarginine
Atm 2-Amino-3-(2-amino-5- thiazole)propanoic acid
Cpn 2-Amino-3-cyclopropanepropanoic acid
(Cyclopropylalanine)
Chx Cyclohexylalanine (Hexahydrophenyl - alanine)
Dopa 3,4-Dihydroxyphenylalanine
Emg 2 -Amino-4,5(RS)-epoxy-4-pentenoic
acid
His (Dnp) Nim-2 ,4-Dinitrophenylhistidine
HomoArg Homoarginine
HomoGlu 2-Aminαadipic acid
HomoPhe 2-Amino-5-phenylpentanoic acid
(Homophenylalanine)
HomoLys 2,7-Diamino-Heptanoic acid
(Homolysine)
Met (O) Methionine sulfoxide
Met (O2) Methionine sulfone
1-Nal 3-(1'-Naphthyl)alanine
2-Nal 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 Pmp Pentamethylphenylalanine
Pyr 2-Amino-3-(3-pyridyl)-propanoic acid
(3-Pyridylalanine)
Tic 1,2,3,4-Tetrahydro-3- isoquinolinecarboxylic acid Abbreviation* Modified and Unusual Amino Acid (cont)
Tza 2-Amino-3-(4-thiazolyl)-propanoic acid
Tyr (Ot-Bu) O-tertiary butyl-tyrosine
Tyr (OMe) O-Methyl-tyrosine
Tyr(OEt) O-Ethyl-tyrosine
Trp(For) Nin-Formyltryptophan
Trp-NH2 Tryptophan carboxamide
Abbreviation Protecting Group
Ac Acetyl
Ada 1-Adamantyl acetic acid
Adoc Adamantyloxycarbonyl
Bppa 2,2-Diphenylpropionyl
Bz Benzylcarbonyl
Bzl Benzyl
CF3CO Trifluoroacetyl
Cxl Cyclohexylacetyl
Cxl (U) Cyclohexylurea
Et Propionyl
Pya 3-Pyridylacetyl
MeBzl 4-Methylbenzyl
Me(U) Methylurea
Z Benzyloxycarbonyl
2-Br-Z ortho-Bromobenzyloxycarbonyl
2-Cl-Z ortho-Chiorobenzyloxycarbonyl
Bom Benzyloxymethyl
Boc tertiary Butyloxycarbonyl
tBu t-Butylcarbonyl
TBS tertiary Butyldimethylsilyl
Dnp 2,4-Dinitrophenyl
For Formyl
Fmoc 9- Fluorenylmethyloxycarbonyl Abbreviation Protecting Group
(cont)
NO2 Nitro
Tos 4-Toluenesulfonyl (tosyl)
Trt Triphenylmethyl (trityl)
Abbreviation Solvents and Reagents
HOAc Acetic acid
CH3CN Acetonitrile
DCM Dichloromethane
DCC N,N'-Dicyclohexylcarbodiimide
DIEA N,N-Diisopropylethylamine
DMF Dimethylformamide
HCl 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 alkaooic 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
AA1 is
Figure imgf000033_0001
wherein R is
hydrogen
alkyl,
alkenyl,
alkynyl,
cycloalkyl,
cycloalkylalkyl,
aryl,
heteroaryl,
fluorenylmethyl,
-N-R3 wherein R3 and R4 are
Figure imgf000033_0002
each the same or different and each is hydrogen,
alkyl,
alkenyl,
alkynyl,
cycloalkyl,
cycloalkylalkyl,
aryl, heteroaryl, or
fluorenylmethyl,
Figure imgf000034_0009
II
-N-C-R3 wherein R3 and R4 are each the same or different and each is as defined above or
Figure imgf000034_0007
-N-C-OR4 wherein R3 and R4 are each the same
Figure imgf000034_0006
R or different and each is as defined above,
Figure imgf000034_0005
-N-C-N-R4 wherein R3 and R4 are defined
above, or
Figure imgf000034_0004
Figure imgf000034_0003
-C-C(R3')3 wherein R3' is F, Cl, Br, or I, n is zero,
R2 is hydrogen or methyl,
n' is zero or an integer of 1, 2, or 3, and
R2' is hydrogen,
trityl,
aryl,
heteroaryl,
heterocycloalkyl,
-N-R3 wherein R3 and R4 are each the same or
Figure imgf000034_0002
different and each is as defined above or
Figure imgf000034_0001
wherein R7 is
hydrogen,
alkyl aryl, or
heteroaryl,
R8 and R9 are each the same or different and
each is
hydrogen or
alkyl,
Figure imgf000035_0001
wherein R2'', R2"', and R2'''' are each the same or different and each is hydrogen,
alkyl,
aryl, or
heteroaryl with the proviso that at least one of R2",
R2''' , and R2''' is aryl or heteroaryl and R2, n, and n' are as defined above, or
Figure imgf000035_0002
wherein R7 and R7' are each the same or different and each is hydrogen,
alkyl,
cycloalkyl,
aryl, or
heteroaryl;
AA2, AA3, AA4, and AA5 are each independently absent or each independently;
Ahp, Dip,
Apa,
Pro,
Phe, or
Figure imgf000036_0001
wherein R11 is
hydrogen or methyl,
n is zero,
R10 is hydrogen or methyl,
n' is zero or an integer of 1, 2, 3, or 4 and
R10' is hydrogen,
alkyl,
cycloalkyl,
alkenyl,
alkynyl,
-OR3'' wherein R3'' is
hydrogen,
alkyl,
alkenyl,
cycloalkyl,
aryl, or
heteroaryl,
-N-R3'' wherein R3'' and R4' are each the same
Figure imgf000036_0002
or different and each is as defined above for R3",
Figure imgf000036_0004
-C-NR3'' wherein R3'' and R4' are each the
Figure imgf000036_0003
same or different and each is as defined above for R3",
Figure imgf000037_0005
-C-NH wherein R3'' is as defined above,
Figure imgf000037_0004
-NH-C-NH-R5 wherein R3 is defined as above,
Figure imgf000037_0003
-C-R3'' wherein R3'' is as defined above, -S(O)mR3'' wherein m is zero or an integer of
1 of 2 and R3" is as defined above except that R3" is not hydrogen, or
Figure imgf000037_0002
-C-OR4' wherein R4' is as defined above,s
Figure imgf000037_0001
wherein R11 is hydrogen or methyl,
n is zero,
R12 is hydrogen, or methyl,
n' is zero or an integer of 1, 2, or 3,
R12' is aryl or heteroaryl,
R13 is -(CH2)n-CO2H wherein n is as defined
above,
-(CH2)n-OH wherein n is as defined above or
Figure imgf000037_0009
- (CH2)n-C-N-R3 wherein n, R3, and R4 are
I defined above,
Figure imgf000037_0008
Figure imgf000037_0006
-C-NH-CH-CO2H wherein R14 is hydrogen or
I -CH2-CO2H, or
Figure imgf000037_0007
Figure imgf000038_0002
wherein R8 and R9 are each the same or different and each is as defined above for and R9 and R13 is as defined above, and R8' is hydrogen, formyl, acetyl, Z, Boc, Bzl, or alkyl;
*
stereochemistry at C in AA1 is D,
*
stereochemistry at C in AA2, AA3, AA4, or AA5 is D, L, or DL, and stereochemistry at
*
C in AA6 is L.
Most preferred compounds of Formula I are one wherein AA1 is
Figure imgf000038_0001
wherein R is
hydrogen,
alkyl,
alkenyl,
alkynyl,
cycloalkyl,
cycloalkylalkyl,
aryl,
heteroaryl,
fluorenylmethyl, -N-R3 wherein R3 and R4 are
Figure imgf000039_0001
R4 each the same or different and each is
hydrogen,
alkyl,
alkenyl,
alkynyl,
cycloalkyl,
cycloalkylalkyl,
aryl,
heteroaryl, or
fluorenylmethyl,
Figure imgf000039_0002
-N-C-R4 wherein R3 and R4 are each the same
Figure imgf000039_0003
R3 or different and each is as
defined above,
Figure imgf000039_0004
-N-C-OR4 wherein R3 and R4 are each the same or
Figure imgf000039_0005
R4 different and each is as defined above, and R2', R2", and R2"' are each the same or different and each is
hydrogen ,
alkyl,
aryl, or
heteroaryl with the proviso that at least one of R2, R2', and R2" is aryl or heteroaryl, and R2"' is hydrogen or methyl,
Figure imgf000039_0006
-N-C-N-R4 wherein R3 and R4 are defined
Figure imgf000039_0007
Figure imgf000039_0008
R3 R3 above, or
Figure imgf000039_0009
-C-C(R3')3 wherein R3' is F, Cl, Br, or I,
R2 is hydrogen or methyl,
n is zero, and
n' is zero or an integer of 1, 2, or 3, or AA2 is
Apa,
Aha,
Dip,
D-Phe,
Phe,
HomoArg,
Arg, or
Figure imgf000040_0001
wherein R11 is hydrogen or methyl,
n is zero,
R10 is hydrogen or methyl, n' is zero or an integer of 1, 2, 3, 4, or 5, and
R10 is alkyl,
OH,
-N-R3" wherein R3'' and R4' are
Figure imgf000040_0002
R4' each the same or
different and each is hydrogen,
alkyl, or
aryl,
Figure imgf000040_0003
-C-N-R3'' wherein R3" and R4' are
Figure imgf000040_0004
R4' as defined above,
Figure imgf000040_0005
-C-OR4' wherein R4 ' is as defined above;
-S(O)mR3'' wherein m is zero or an integer of
1 of 2 and R3'' is as defined above except that R3" is not hydrogen; AA3 is
Lys ,
Tyr,
Phe , or
Figure imgf000041_0001
wherein R11 is hydrogen or methyl,
n is zero,
R10 is hydrogen or methyl, n" is zero or an integer of 1, 2, or 3, and
R11' is alkyl,
aryl,
Figure imgf000041_0002
-C-N-R3" wherein R3" and R4' are
Figure imgf000041_0003
as defined above,
Figure imgf000041_0004
-C-OR4' wherein R4' is as
defined above,
AA4 and AA5 are each
Phe,
Lys,
Glu,
Pro, or
Figure imgf000041_0005
wherein R11 is hydrogen or methyl,
n is zero,
R10 is hydrogen or methyl, n' is zero, and
R10' is alkyl,
or cycloalkyl,
AA6 is
Figure imgf000042_0001
wherein R11 is hydrogen or methyl,
n is zero,
R12 is hydrogen, or methyl,
n' is zero or an integer of 1, 2, of 3, R12' is aryl or heteroaryl,
R13 is -(CH2)n-CO2H wherein n is zero or an integer of 1, 2, 3, 4, 5, or 6,
- (CH2)n-OH wherein n is zero or an integer of 1, 2, 3, 4, 5, or
6, or
Figure imgf000042_0002
- (CH2)n- C-N-R3 wherein n, R3, and R4 are
Figure imgf000042_0003
defined above,
Figure imgf000042_0004
-C-NH-CH-CO2H wherein R14 is
Figure imgf000042_0005
~
R14 hydrogen or
- CH2CO2H,
*
stereochemistry at C in AA1 is D,
*
stereochemistry at C in AA2, AA3, AA4, or AA5 is D or L and
*
stereochemistry at C in AA6 is L. A more preferred compound of Formula I is one wherein AA1 is
D-Adm,
D-Ana,
D-Chx,
D-Dip,
D-Dopa,
D-Bip,
D-His,
D-His (Dnp),
D-2-Nal,
D-1-Nal,
D-Phe,
D-Pmp,
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-Adm,
Ac-D-Ana,
Ac-D-Chx,
Ac-D-Dip,
Ac-D-Dopa,
Ac-D-Bip,
Ac-D-His,
Ac-D-His (Dnp),
Ac-D-2-Nal,
Ac-D-1-Nal,
Ac-D-N-MeDip,
Ac-D-Phe,
Ac-D-Pgl, Ac-D-Pmp,
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-Adm,
Ada-D-Ana,
Ada-D-Chx,
Ada-D-Dip,
Ada-D-Dopa,
Ada-D-Bip,
Ada-D-His,
Ada-D-His(DnDp) ,
Ada-D-2-Nal, Ada-D-1-Nal,
Ada - D - Pmp,
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-Adm,
Adoc-D-Ana, Adoc-D-Chx,
Adoc-D-Dip,
Adoc-D-Dopa, Adoc-D-Bip,
Adoc-D-His,
Adoc-D-His(Dnp),
Adoc-D-2-Nal, Adoc-D-1-Nal,
Adoc-D-Phe,
Adoc-D-Pmp,
Adoc-D-Pgl,
Adoc-D-Tyr,
Adoc-D-Tyr(OMe),
Adoc-DOTyr(OEt),
Adoc-D-Tyr(OtBu),
Adoc-D-Trp,
Adoc-D-Trp(For), Adoc-D-Tic,
Adoc-D-Tza,
Adoc-D-Pyr,
Boc-D-Adm,
Boc-D-Ana,
Boc-D-Chx,
Boc-D-Dip,
Boc-D-Dopa,
Boc-D-Bip,
Boc-D-His,
Boc-D-His(Dnp),
Boc-D-2-Nal,
Boc-D-1-Nal,
Boc-D-Phe,
Boc-D-Pmp,
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-Adm,
Z-D-Ana,
Z-D-Chx,
Z-D-Dip,
Z-D-Dopa,
Z-D-Bip,
Z-D-His,
Z-D-His(Dnp) ,
Z-D-2-Nal,
Z-D-1-Nal,
Z-D-Phe,
Z-D-Pmp,
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-Adm,
Fmoc-D-Ana,
Fmoc-D-Chx,
Fmoc-D-Dip,
Fmox-D-Dopa, Fmoc-D-Bip,
Fmoc-D-His,
Fmoc-D-His(Dnp) ,
Fmoc-D-2-Nal,
Fmoc-D-1-Nal, Fmoc-D-Phe,
Fmoc-D-Pmp,
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,
Et-D-Dip,
Bz-D-Dip,
Pya-D-Dip,
Cxl-D-Dip,
Ada-D-Dip,
Cxl(U)-D-Di-,
Me(U)-D-Dip, tBu-D-Dip,
CF3CO-D-Dip; AA2 is Ala,
Alg,
Aha,
Apa,
Arg,
Asn,
Asp,
Dab,
D-Dip,
Glu,
Gin,
Gly,
HomoArg,
HomoGlu,
HomoLys,
lIe,
Leu,
D-Leu, Lys,
D-N-MeLeu,
Met,
Met(O),
Met(O2O,
Nva,
Nle,
Orn,
Phe,
D-Phe,
Tyr,
Val, or
AA2 is absent; AA3 is Asn,
Asp,
D-Asp,
N-MeAsp,
Glu,
Gln,
Lys,
HomoPhe,
Phe,
Tyr, or
AA3 is absent; AA4 is Ala,
Chx,
Gly,
Glu,
Ile, D-Ile,
Leu,
Lys,
Nle,
N-Melle, Nva,
Phe,
Pro, Val, or
AA4 is absent; AA5 is Ala,
Chx,
Gly,
lIe,
D-Ile,
Leu,
Lys,
Nle,
N-Melle,
Nva,
Phe,
Val, or
AA5 is absent; and AA6 is 2-Nal,
1-Nal,
N-MeTrp,
Phe,
Pyr,
Trp,
Trp-NH2,
Tyr(O(e),
Tyr(OEt),
Tyr(Ot-Bu),
Tyr,
Trp-Gly,
Trp-Asp,
Trp(For),
Dip,
Phe, or
Figure imgf000049_0001
Particularly valuable are:
D-Phe-Leu-Asp-Ile-Ile-Trp;
D-His(Dnp)-Leu-Asp-Ile-Ile-Trp;
D-Trp-Leu-Asp-IIe-lIe-Trp;
D-Tyr-Leu-Asp-Ile-lIe-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-lIe-lIe-Trp;
D-Tic-Leu-Asp-Ile-lIe-Trp;
D-Dip-Leu-Asp-Ile-lIe-Trp;
D-Bip-Leu-Asp-Ile-lIe-Trp;
Ac-D-Phe-Leu-Asp-Ile-Ile-Trp;
Ac-D-His(Dnp)-Leu-Asp-Ile-Ile-Trp; Ac-D-Trp-Leu-Asp-lIe-lIe-Trp;
Ac-D-Tyr-Leu-Asp-Ile-lIe-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-lIe-lIe-Trp;
Ac-D-Pgl-Leu-Asp-Ile-lIe-Trp;
Ac-D-Pyr-Leu-Asp-lIe-lIe-Trp;
Ac-D-Tic-Leu-Asp-Ile-lIe-Trp;
Ac-D-Dip-Leu-Asp-lIe-lIe-Trp;
Ac-D-Bip-Leu-Asp-lIe-lIe-Trp;
Fmoc-D-Phe-Leu-Asp-lIe-lIe-Trp;
Fmoc-D-His-Leu-Asp-Ile-Ile-Trp;
Fmoc-D-Trp-Leu-Asp-Ile-lIe-Trp;
Fmoc-D-Tyr-Leu-Asp-lIe-lIe-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-lIe-Trp;Fmoc-D-1-Nal-Leu-Asp-lIe-lIe-Tip; Fmoc-D-Dip-Leu-Asp-lIe-lIe-Trp;
Fmoc-D-Bip-Leu-Asp-lIe-lIe-Trp; Ada-D-Phe-Leu-Asp-lIe-lIe-Trp;
Ada-D-His-Leu-Asp-Ile-lIe-Trp;
Ada-D-Trp-Leu-Asp-lIe-I Ie -Trp;
Ada-D-Tyr-Leu-Asp-Ile-lIe-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-lIe-lIe-Trp;
Ada-D-1-Nal-Leu-Asp-lIe-lIe-Trp;
Ada-D-Dip-Leu-Asp-Ile-Ile-Trp;
Ada-D-Bip-Leu-Asp-Ile-Ile-Trp;
Ac-D-Phe-D-Leu-Asp-lIe-lIe-Trp;
Ac-D-His-D-Leu-Asp-lIe-lIe -Trp;
Ac-D-Trp-D-Leu-Asp-Ile-lIe-Trp;
Ac-D-Tyr-D-Leu-Asp-Ile-lIe-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-lIe-Trp;
Ac-D-1-Nal-D-Leu-Asp-Ile-lIe-Trp;
Ac-D-Dip-D-Leu-Asp-Ile-Ile-Trp;
Ac-D-Bip-D-Leu-Asp-Ile-Ile-Trp;
Ac-D-Phe-lIe-Asp-lIe-lIe-Trp;
Ac-D-His-lIe-Asp-lIe-lIe-Trp;
Ac-D-Trp-lIe-Asp-lIe-lIe-Trp;
Ac-D-Tyr-lIe-Asp-lIe-lIe-Trp;
Ac-D-Tyr(OMe)-lIe-Asp-Ile-lIe-Trp;
Ac-D-Tyr(OEt)-lIe-Asp-lIe-lIe-Trp;
Ac-D-2-Nal-Ile-Asp-Ile-lIe-Trp;
Ac-D-1-Nal-Ile-Asp-Ile-lIe-Trp;
Ac-D-Dip-lIe-Asp-lIe-lIe-Trp;
Ac-D-Bip-lIe-Asp-lIe-lIe-Trp;
Ac-D-Phe-Val-Asp-lIe-lIe-Trp;
Ac-D-His-Val-Asp-lIe-lIe-Trp;
Ac-D-Trp-Val-Asp-lIe-lIe-Trp;
Ac-D-Tyr-Val-Asp-lIe-lIe-Trp;
Ac-D-Tyr(OMe)-Val-Asp-Ile-lIe-Trp;
Ac-D-Tyr(OEt)-Val-Asp-Ile-lIe-Trp;
Ac-D-2-Nal-Val-Asp-lIe-lIe-Trp; Ac-D-1-Nal-Val-Asp-lIe-Ile-Trp;
Ac-D-Dip-Val-Asp-lIe-lIe-Trp;
Ac-D-Bip-Val-Asp-Ile-lIe-Trp;
Ac-D-Phe-Dab-Asp-Ile-Ile-Trp;
Ac-D-His-Dab-Asp-Ile-Ile-Trp;
Ac-D-Trp-Dab-Asp-lIe-lIe-Trp;
Ac-D-Tyr(OMe)-Dab-Asp-lIe-Ile-Trp;
Ac-D-Tyr(OEt)-Dab-Asp-lIe-lIe-Trp;
Ac-D-2-Nal-Dab-Asp-Ile-lIe-Trp;
Ac-D-1-Nal-Dab-Asp-lIe-Ile-Trp;
Ac-D-Dip-Dab-Asp-Ile-Ile-Trp;
Ac-D-Bip-Dab-Asp-Ile-Ile-Trp;
Ac-D-Phe-Arg-Asp-Ile-Ile-Trp;
Ac-D-His-Arg-Asp-lIe-lIe-Trp;
Ac-D-Trp-Arg-Asp-Ile-Ile-Trp;
Ac-D-Tyr(OMe)-Arg-Asp-Ile-lIe-Trp;
Ac-D-Tyr(OEt)-Arg-Asp-Ile-lIe-Trp;
Ac-D-2-Nal-Arg-Asp-lIe-lIe-Trp;
Ac-D-l-Nal-Arg-Asp-lIe-lIe-Trp;
Ac-D-Dip-Arg-Asp-Ile-Ile-Trp;
Ac-D-Bip-Arg-Asp-Ile-Ile-Trp;
Ac-D-Phe-HomoLys-Asp-IIe-IIe-Trp;
Ac-D-His-HomoLys-Asp-lIe-lIe-Trp;
Ac-D-Trp-HomoLys-Asp-lIe-lIe-Trp;
Ac-D-Tyr(OMe)-HomoLys-Asp-lIe-Ile-Trp;
Ac-D-Tyr(OEt)-HomoLys-Asp-lIe-Ile-Trp;
Ac-D-2-Nal-HomoLys-Asp-lIe-lIe-Trp;
Ac-D-1-Nal-HomoLys-Asp-IIe-IIe-Trp;
Ac-D-Dip-HomoLys-Asp-lIe-lIe-Trp;
Ac-D-Bip-HomoLys-Asp-lIe-Ile-Trp;
Ac-D-His-Glu-Asp-lIe-lIe-Trp;
Ac-D-Trp-Glu-Asp-Ile-Ile-Trp;
Ac-D-Tyr(OMe)-Glu-Asp-Ile-lIe-Trp;
Ac-D-Tyr(OEt)-Glu-Asp-Ile-lIe-Trp;
Ac-D-2-Nal-Glu-Asp-Ile-lIe-Trp;
Ac-D-1-Nal-Glu-Asp-Ile-lIe-Trp;
Ac-D-Dip-Glu-Asp-lIe-Ile-Trp; Ac -D-Bip-Glu-Asp- lIe- Ile- Trp ;
Ac-D-Phe-HomoGlu-Asp-lIe-Ile-Trp;
Ac-D-His-HomoGlu-Asp-lIe-lIe-Trp;
Ac-D-Trp-HomoGlu-Asp-lIe-Ile-Trp;
Ac-D-Tyr(OMe)-HomoGlu-Asp-lIe-Ile-Trp;
Ac-D-Tyr(OEt)-HomoGlu-Asp-lIe-lIe-Trp;
Ac-D-2-Nal-HomoGlu-Asp-lIe-Ile-Trp;
Ac-D-1-Nal-HomoGlu-Asp-Ile-lIe-Trp;
Ac-D-Dip-HomoGlu-Asp-lIe-lIe-Trp;
Ac-D-Bip-HomoGlu-Asp-lIe-Ile-Trp;
Ac-D-Phe-Asp-Asp-lIe-lIe-Trp;
Ac-D-His-Asp-Asp-lIe-lIe-Trp;
Ac-D-Trp-Asp-Asp-lIe-lIe-Trp;
Ac-D-Tyr(OMe)-Asp-Asp-Ile-lIe-Trp;
Ac-D-Tyr(OEt)-Asp-Asp-Ile-lIe-Trp;
Ac-D-2-Nal-Asp-Asp-Ile-lIe-Trp;
Ac-D-1-Nal-Asp-Asp-Ile-lIe-Trp;
Ac-D-Dip-Asp-Asp-lIe-lIe-Trp;
Ac-D-Bip-Asp-Asp-lIe-lIe-Trp;
Ac-D-Phe-Lys-Asp-Ile-lIe-Trp;
Ac-D-His-Lys-Asp-lIe-lIe-Trp;
Ac-D-Trp-Lys-Asp-lIe-lIe-Trp;
Ac-D-Tyr-Lys-Asp-lIe-lIe-Trp;
Ac-D-Tyr(OMe)-Lys-Asp-Ile-lIe-Trp;
Ac-D-Tyr(OEt)-Lys-Asp-Ile-lIe-Trp;
Ac-D-2-Nal-Lys-Asp-lIe-lIe-Trp;
Ac-D-1-Nal-Lys-Asp-lIe-lIe-Trp;
Ac-D-Dip-Lys-Asp-lIe-lIe-Trp;
Ac-D-Bip-Lys-Asp-lIe-lIe-Trp;
Ac-D-Phe-Orn-Asp-Ile-lIe-Trp;
Ac-D-His-Orn-Asp-lIe-lIe-Trp;
Ac-D-Trp-Orn-Asp-lIe-lIe-Trp;
Ac-D-Tyr-Orn-Asp-lIe-lIe-Trp;
Ac-D-Tyr(OMe)-Orn-Asp-Ile-lIe-Trp;
Ac-D-Tyr(OEt)-Orn-Asp-Ile-lIe-Trp;
Ac-D-2-Nal-Orn-Asp-Ile-lIe-Trp;
Ac-D-1-Nal-Orn-Asp-Ile-lIe-Trp; Ac-D-Dip-Orn-Asp-Ile-Ile-Trp;
Ac-D-Bip-Orn-Asp-Ile-lle -Trp;
Ac-D-Phe-Gln-Asp-lle-lle-Trp;
Ac-D-His-Gln-Asp-lle-lle-Trp;
Ac-D-Trp-Gln-Asp-Ile-Ile-Trp;
Ac-D-Tyr-Gln-Asp-lle-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-Dip-Gln-Asp-Ile-Ile-Trp;
Ac-D-Bip-Gln-Asp-Ile-Ile-Trp;
Ac-D-Phe-Leu-Glu-lIe-lIe-Trp;
Ac-D-His-Leu-Glu-Ile-Ile-Trp;
Ac-D-Trp-Leu-Glu-Ile-Ile-Trp;
Ac-D-Tyr-Leu-Glu-lIe-lIe-Trp;
Ac-D-Tyr(OMe)-Leu-Glu-lIe-lIe-Trp;
Ac-D-Tyr(OEt)-Leu-Glu-Ile-lIe-Trp;
Ac-D-2-Nal-Leu-Glu-Ile-lIe-Trp; Ac-D-1-Nal-Leu-Glu-lIe-Ile-Trp;
Ac-D-Dip-Leu-Glu-Ile-Ile-Trp;
Ac-D-Bip-Leu-Glu-lIe-lIe-Trp;
Ac-D-Phe-Leu-Asn-lIe-lIe-Trp;
Ac-D-His-Leu-Asn-lIe-lIe-Trp;
Ac-D-Trp-Leu-Asn-Ile-Ile-Trp;
Ac-D-Tyr-Leu-Asn-lIe-lIe-Trp;
Ac-D-Tyr(OMe)-Leu-Asn-lIe-lIe-Trp;
Ac-D-Tyr(OEt)-Leu-Asn-lIe-lIe-Trp;
Ac-D-2-Nal-Leu-Asn-lIe-lIe-Trp; Ac-D-1-Nal-Leu-Asn-lIe-lIe-Trp;
Ac-D-Dip-Leu-Asn-lIe-lIe-Trp;
Ac-D-Bip-Leu-Asn-lIe-lIe-Trp;
Ac-D-Phe-Leu-Phe-lIe-lIe-Trp;
Ac-D-His-Leu-Phe-Ile-Ile-Trp;
Ac-D-Trp-Leu-Phe-Ile-Ile-Trp;
Ac-D-Tyr(OMe)-Leu-Phe-Ile-Ile-Trp;
Ac-D-Tyr(OEt)-Leu-Phe-Ile-Ile-Trp; Ac-D-2-Nal-Leu-Phe-lle-Ile-Trp;
Ac-D-1-Nal-Leu-Phe-Ile -Ile -Trp;
Ac-D-Dip-Leu-Phe-Ile-Ile-Trp;
Ac-D-Bip-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-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;
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-Ile-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-lIe-Trp; Ac-D-2-Nal-Leu-Asp-Ile-D-lIe-Trp; Ac-D-1-Nal-Leu-Asp-Ile-D-lIe-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-lIe-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-lIe-Val-Trp;
Ac-D-1-Nal-Leu-Asp-lIe-Val-Trp;
Ac-D-Dip-Leu-Asp-lIe-Val-Trp;
Ac-D-Bip-Leu-Asp-lIe-Val-Trp;
Ac-D-Phe-Leu-Asp-Ile-Chx-Trp;
Ac-D-His-Leu-Asp-lIe-Chx-Trp;
Ac-D-Trp-Leu-Asp-lIe-Chx-Trp;
Ac-D-Tyr-Leu-Asp-Ile-Chx-Trp;
Ac-D-Tyr(OMe)-Leu-Asp-lIe-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-lIe-Chx-Trp;
Ac-D-Dip-Leu-Asp-lIe-Chx-Trp;
Ac-D-Bip-Leu-Asp-lIe-Chx-Trp;
Ac-D-Phe-Leu-Asp-lIe-lIe-2-Nal, Ac-D-His-Leu-Asp-lIe-lIe-2-Nal, Ac-D-Trp-Leu-Asp-Ile-Ile-2-Nal, Ac-D-Tyr-Leu-Asp-Ile-lIe-2-Nal;
Ac-D-Tyr(OMe)-Leu-Asp-lIe-Ile-2-Nal; Ac-D-Tyr(OEt)-Leu-Asp-lIe-lIe-2-Nal; Ac-D-2-Nal-Leu-Asp-lIe-lIe-2-Nal; Ac-D-1-Nal-Leu-Asp-lIe-lIe-2-Nal; Ac-D-Dip-Leu-Asp-lIe-lIe-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 -1-Nal;
Ac-D-1-Nal-Leu-Asp-Ile-Ile-1-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-Ile-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-N-MeDip-Leu-Asp-Ile-Ile-Trp;
Ac-D-Dip-Leu-Asp-Ile-Ile-N-MeTrp;
Ac-D-Dip-Leu-Asp-Ile-N-Melle-Trp;
Ac-D-Dip-Leu-Asp-N-Melle-Ile-Trp;
Ac-D-Dip-Leu-N-MeAsp-Ile-Ile-Trp;
Ac-D-Dip-N-MeLeu-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-Nal;
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-D-Phe-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-His-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-Trp-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-Tyr(OEt)-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-2-Nal-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-1-Nal-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-Dip-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-Bip-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-Phe-Leu-Asp-Ile-Ile-Trp-Asp;
Ac-D-His-Leu-Asp-Ile-Ile-Trp-Asp; Ac-D-Trp-Leu-Asp-Ile-Ile-Trp-Asp;
Ac-D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp-Asp;
Ac-D-Tyr(OEt)-Leu-Asp-Ile-Ile-Trp-Asp;
Ac-D-2-Nal-Leu-Asp-Ile-lIe-Trp-Asp; Ac-D-1-Nal-Leu-Asp-Ile-Ile-Trp-Asp;
Ac-D-Dip-Leu-Asp-Ile-Ile-Trp-Asp;
Ac-D-Dip-Leu-Asp-lIe-lIe-Trp-NH2;
Ac-D-His-Leu-Asp-Ile-Ile-Trp;
Bppa-Leu-Asp-Ile-Ile-Trp;
Ada-D-Phe-Leu-Asp-Ile-Ile-Trp;
Fmoc-D-Dip-Leu-Asp-Ile-Ile-Trp;
Et-D-Dip-Leu-Asp-lIe-lIe-Trp;
Bz-D-Dip-Leu-Asp-lIe-lIe-Trp;
Pya-D-Dip-Leu-Asp-lIe-lIe-Trp;
Cxi-D-Dip-Leu-Asp-lIe-lIe-Trp;
Ada-D-Dip-Leu-Asp-Ile-Ile-Trp;
Cxi (U)-D-Dip-Leu-Asp-lIe-Ile-Trp;
Me (U) -D-Dip-Leu-Asp-Ile-Ile-Trp;
tBu-D-Dip-Leu-Asp-Ile-Ile-Trp;
CF3CO-D-Dip-Leu-Asp-Ile-Ile-Trp;
Ac-D-Chx-Leu-Asp-lIe-lIe-Trp;
Ac-D-Dopa-Leu-Asp-Ile-Ile-Trp;
D-Pmp-Leu-Asp-lIe-lIe-Trp;
Ac-D-Pmp-Leu-Asp-lIe-lIe-Trp;
D-Ana-Leu-Asp-Ile-lIe-Trp;
Ac-D-Ana-Leu-Asp-IIe-IIe-Trp;
Ac-D-Adm-Leu-Asp-IIe-IIe-Trp;
Ac-D-Phe-Ala-Asp-lIe-lIe-Trp;
Ac-D-Phe-Phe-Asp-lIe-lIe-Trp;
Ac-D-Phe-D-Phe-Asp-lIe-lIe-Trp;
Ac-D-Dip-D-Phe-Asp-Ile-lIe-Trp;
D-Dip-Leu-Asn-lIe-lIe-Trp;
Ac-D-Dip-Leu-Tyr-Ile-Ile-Trp;
Ac-D-Phe-Leu-Asp-Ala-lIe-Trp;
Ac-D-Dip-Leu-Asp-Glu-Ile-Trp;
Ac-D-Dip-Leu-Asp-Phe-lIe-Trp;
Ac-D-Dip-Leu-Asp-N-Melle-Ile-Trp; Ac -D-Dip- Leu-Asp- Lys - Ile - Trp ;
Ac -D-Dip - Leu -Asp-Ala-Ile- Trp ,
Ac -D- Phe - Leu-Asp-Ile-Ala- Trp ;
Ac -D-Dip- Leu-Asp- Ile - Lys - Trp ;
Ac-D-Dip-Leu-Asp-lIe-Phe-Trp;
Ac-D-Dip-Leu-Asp-Ile-Leu-Trp;
Ac~D-Dip-Leu-Asp-Ile-Ile-Phe;
Ac-D-Dip-Leu-Asp-Ile-Ile-Tyr;
Ac-D-Phe-Leu-Asp-Ile-Ile-Tyr;
Ac-D-Phe-Leu-Asn-Pro-Ile-Trp;
Ac-D-Phe-Leu-Asp-Ala-Ile-Tyr;
Ac-D-Dip-Leu-Asn-Pro-Ile-Trp;
Ac-D-Phe-Asp-Phe-Ile-Trp;
D-Dip-Tyr-Ile-lIe-Trp;
Ac-D-Dip-Apa-lIe-lIe-Trp;
Ac-D-Dip-D-Dip-Asp-Ile-Trp; and
Ac-D-Dip-Ahp-Ile-lIe-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.
Rat Heart Ventricle Binding Assay
Thus, the compounds of Formula I were tested for their ability to inhibit [125I] -ET-1 ( [125I] -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
[125I]-ET-1 and the tissue (rat heart ventricle
(10 μg)) in 50 mM Tris (hydroxymethyl) 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). 1C50 values are calculated by weighing nonlinear regression
curve-fitting to the mass-action (Langmuir) equation.
Endothelin Receptor Binding Assay-A (ETA)
Intact Cell Binding of [125I] -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 cm2) (confluent cells). Growth Media
The growth media was Dulbeccos 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 Hank's salts and 25 mM Hepes buffer
(Gibco 380-2350AJ), supplemented with penicillin/ streptomycin/fungizone (0.5%) and bovine serum albumin (1 mg/mL).
[125I]-ET-1
Amersham radioiodinated endothelin-1 [125I] -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 μL of cold assay buffer described above to each well. Third, add 50 mL each of cold [125I]-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 M sodium hydroxide, agitate for 1 hour on rotator, and then transfer the sodium hydroxide extract to gamma counting tubes and count the radioactivity.
Endothelin Receptor Binding Assay-B (ETB)
[125I] -ET-1 Binding in Rat Cerebellar Membranes
Materials and Terms Used:
Tissue Buffer
The tissue is made up of 20 mM
tris (hydroxymethyl)aminomethane hydrochloride (Trizma) buffer, 2 mM ethylenediaminetetraacetate, 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. [125I] -ET- 1
Amersham [125I]-ET-1 (aliquots of 2 x 106 cpm per 100 mL aliquot of [125I]-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 [125I] -ET-1 and competing ligand to tubes on ice. Mix in 150 μL of tissue to each tube, vortex briefly, then tap to force all liquids to bottom (total assay volume = 250 μL). Then place the tubes in a 37°C water bath for 2 hours.
Add 2.5 mL cold water 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. Inositol Phosphate Accumulation
The functional activity of compounds of Formula I is determined in Rat-1 cells by measuring intra- cellular levels of second messengers. Thus, cells were prelabeled with [3H] -inositol and
endothelin-stimulated accumulation of total
[3H] -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. Arachidonic Acid Release Assay
Antagonist activity was also measured by the ability of added compounds to reduce endothelin- stimulated arachidonic acid release (AAR) in cultured vascular smooth muscle cells as described in
Reynolds, E., Mok, L., FASEB J., 1991, 5, A1066.
Briefly, 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. [3H] Arachidonic Acid Loading Media (LM) is DME/F12 + 0.5% FCS x 0.25 mCi/mL [3H]
arachidonic acid (Amersham). Confluent monolayers of cultured rabbit renal artery vascular smooth muscle cells were incubated in 0.5 mL of the LM over
18 hours, at 37°C, in 5% CO2. The LM was aspirated and the cells were washed once with the assay buffer (Hank's BSS + 10 mM HEPES + fatty acid- free BSA
(1 mg/mL), and incubated for 5 minutes with 1 mL of the prewarmed assay buffer. This solution was
aspirated, followed by an additional 1 mL of prewarmed assay buffer, and further incubated for another
5 minutes. A final 5-minute incubation was carried out in a similar manner. The same procedure was repeated with the inclusion of 10 μL of the test compound (1 nM to 1 μM) and 10 μL ET-1 (0.3 nM) and the incubation was extended for 30 minutes. This solution was then collected, 10 μL of scintillation cocktail was added, and the amount of [3H] arachidonic acid was determined in a liquid scintillation counter.
The data in Table II and IIa below show the endothelin antagonist activity of representative compounds of Formula I .
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
In Vitro (Isolated Vessel) Studies
Male New Zealand rabbits were killed by cervical dislocation and exsanguination. Femoral and pulmonary arteries were isolated, cleaned of connective tissue, and cut into 4 mm rings. The endothelium was denuded by placing the rings over hypodermic tubing (32 gauge for femoral rings and 28 gauge for pulmonary rings, Small Parts Inc., Miami, FL) and gently rolling them. Denuded rings were mounted in 20 mL organ baths containing Krebs-bicarbonate buffer (composition in mM: NaCl, 118.2; NaHCO3 , 24.8; KCl, 4.6; MgSO4, 7.H2O, 1.2; KH2PO4, 1.2; CaCl2.2H2O; Ca-Na2 EDTA, 0.026;
Dextrose, 10.0), that was maintained at 37°C, and gassed continuously with 5% CO2 in oxygen (pH 7.4).
Resting tension was adjusted to 3.0 g for femoral and 4.0 g pulmonary arteries; the rings were left for 90 minutes to equilibrate. Tension was monitored with force displacement transducers (Grass FT03, Quincy, MA) and recorded on a polygraph (Gould 2108,
Cleveland, OH) recorder.
Vascular rings were tested for a 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, for femoral artery rings and SRTX-6C for pulmonary artery rings (one peptide per
experiment), were cumulatively added at 10-minute intervals. In separate experiments, the test
compounds (ET antagonists), were added 30 minutes prior to adding the agonist as indicated above.
For the in vitro experiments compounds were dissolved in 0.1% acetic acid in distilled water. The maximum concentration of DMSO in the bath was 0.1% which did not significantly affect developed tension in response to ET-1, ET-3, or SRTX-6c. The antagonist activity of various compounds are expressed as pA2 values in Table III.
Figure imgf000073_0001
In Vivo Studies
Male Sprague Dawley rats (300 to 500 g) were anesthetized (Inactin, 120 mg/kg IP) and acutely instrumented for measurement of systemic hemodynamics. Cannulae (PE 50) were placed in the left carotid artery to measure mean arterial blood pressure (MABP) and left and right jugular veins for drug
administration. The trachea was cannulated (PE 240) for artificial respiration (Harvard Apparatus,
Model 681, South Natick, MA) at a rate of 100
cycles/min and a tidal volume of 3.0 mL/kg. Cardiac output was measured using a thoracic aortic flow probe (Transonics, probe size 1RB, Ithaca, NY).
In separate experiments regional hemodynamics were assessed. To monitor regional blood flow rats were similarly anesthetized and instrumented for measurement of MABP and intravenous (IV) drug
administration. The trachea was cannulated and the rats were allowed to breathe spontaneously. In addition, flow probes (Transonics, probe size 1RB, Ithaca, NY) were placed on the left renal, left iliac, right carotid, and/or mesenteric arteries. All rats were ganglionic blocked with mecamylamine (1.25 mg/kg, IV) to block hemodynamic reflexes and allowed to stabilize for 5 minutes.
Responses to rising doses (0.03, 0.1, 0.3,
1.0, and 3.0 nmol/kg, IV bolus) of ET-1 or SRTX-6c were measured continuously and averaged at 1-second intervals during the depressor phase and at 5 -second intervals during the pressor phase. Agonists were administered at 5-minute intervals. Changes in SVR and regional vascular resistances were calculated for individual rats based on blood flow and arterial blood pressure measurements at the peak of depressor and pressor responses. The effects of test compounds (ET antagonists) on the hemodynamic responses to ET-1 and S6c were determined in separate experiments. Infusion of the test compounds (1.0 μmol/kg/5 min) were
initiated 5 minutes prior to the first ET-1 or SRTX-6C challenge and maintained throughout the agonist dose response curve. Data points for global and regional hemodynamics represent the mean of four to eight rats. For in vivo experiments compounds were dissolved in 0.1% acetic acid in distilled water.
To determine in vivo endothelin antagonism by Ac-D-Dip-Leu-Asp- lIe- Ile-Trp, male Sprague Dawley rats (300-500 g) were anesthetized (Inactin, 120 mg/kg, IP) and instrumented to measure mean arterial blood pressure, and renal and hind limb blood flow.
Ganglionic blockade (mecamylamine, 1.25 mg/kg, IV) was produced to prevent hemodynamic reflexes. ET-1
(0.3-3.0 nM/kg, IV bolus 5 minutes apart) caused transient dose dependent depressor responses followed by slowly (~2 minutes to max.) developing pressure responses. Predominant vasodilator responses to ET-1 were observed in the hind limb versus predominant vasoconstrictor responses in the renal bed.
Pretreatment with Ac-D-Dip-Leu-Asp-Ile-Ile-Trp
(1.0 μM/kg/5 minutes, IV infusion) significantly attenuated the systemic depressor responses to ET-1, but had no effect on pressor responses. In the regional beds, pretreatment with Ac-D-Dip-Leu-Asp-lIe- Ile-Trp significantly attenuated (-50%) the
vasodilatation to ET-1 in the hind limb, whereas the vasoconstriction to ET-1 in the renal bed was
unchanged.
As in vivo test bases on the peak effect of single bolus doses of ET antagonists on depressor and pressor responses to ET has been developed in
conscious rats. This model is able to provide both potency and duration of action information. Duration of action studies were carried out in the conscious chronically prepared normotensive rats with a 5 -day treatment protocol. There were 5 groups of animals with dosing regimen of drug at (10 μM/kg IV bolus) 0, 5, 20, 60, and 120 minutes before the ET-1 challenge. In the control set of animals vehicle was administered instead of drug. There was no repetitive dosing of ET-1 due to the inability to wash out the response. These studies were carried out with the ET antagonist Ac-D-Dip-Leu-Asp-Ile-Ile-Trp. The results indicate that Ac-D-Dip-Leu-Asp-Ile-Ile-Trp showed blocking of the depressor component of the ET-1 challenge 2 hours postdose.
Statistics
An F test for parallelism was used to evaluate the effects of antagonist pretreatment on the
contractile activity of ET-1 in isolated vessels.
Statistical differences between parallel curves were determined using t-test on EC50 values. An F test was used to assess significant differences among treatment groups for systemic and regional hemodynamic
parameters.
Paired t- tests, corrected for multiple comparison with the Bonferroni inequality adjustment, were used to determine significant differences from control values within treatment groups.
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 AppIled 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 1N KOH (2 minutes), neutralized with glacial HOAc, desalted on C18 (as described below), and lyophilized. The crude peptide is purified by preparative reversed phase high
performance liquid chromatography (RP-HPLC) on a C18 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, 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-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-cv-Boc-D-Phe, N-α-BOC- Leu-H2O, N-α-Boc-Asp(Bzl), and N-C--Boc-lIe- 0.5 H2O. 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-NH2 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% HCl/H2O and passed through a C 18 (60 cc) cartridge. The cartridge is washed with H2O (50 mL), eluted with 0.1% TFA, 70% CH3CN in H2O, the eluants combined, concentrated under reduced pressure (10 mL), diluted with H2O, and lyophilized to yield 153 mg of a white powder. The crude peptide is dissolved in 4.0 mL of 50% TFA/H2O, 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/H2O, B: 0.1% TFA/CH3CN, 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 H2O (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 (H1-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-Trp; MH+ 856.3, MNa+ 878.2.
EXAMPLE 5
Ac-D-1-Nal-Leu-Asp-lle-Ile-Trp; MH+ 898.5, MNa+ 920.5. EXAMPLE 6
Ac-D-Phe-Leu-ASP-Ile-Trp; 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-Orn-Asp-Ile-Ile-Trp: 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-Trp: 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-Trp: FAB-MS, MH+ 696.5, MNa+ 718.5.
EXAMPLE 15
Ac-D-DJP-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-Lys-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-Orn-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
Disodium salt of Ac-D-Dip-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-Dip-Leu-Asp-Ile-Ile-Trp
(Example 16) 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-Dip-Leu-Asp-Ile-Ile-Trp; FAB-MS, MH+ 924.6,
MNa+ 946.6, M2Na+ 968.6.

Claims

1. A compound of Formula I
AA1-AA2 -AA3 -AA4 -AA5 -AA6
wherein AA1 is
Figure imgf000085_0001
wherein R is
hydrogen
alkyl,
alkenyl,
alkynyl,
cycloalkyl,
cycloalkylalkyl,
aryl,
heteroaryl,
fluorenylmethyl,
-N-R3 wherein R3 and R4 are each the same or
Figure imgf000085_0002
different and each is
hydrogen,
alkyl,
alkenyl,
alkynyl,
cycloalkyl,
cycloalkylalkyl,
aryl,
heteroaryl, or
fluorenylmethyl,
-OR3 wherein R3 is as defined above,
Figure imgf000085_0003
-C-OR3 wherein R3 is as defined above,
Figure imgf000086_0010
-N-C-R4 wherein R3 and R4 are each the same
Figure imgf000086_0009
or different and each is as
defined above,
Figure imgf000086_0008
-N-C-OR4 wherein R3 and R4 are each the same
Figure imgf000086_0007
L or different and each is as defined above, but R4 is not hydrogen,
Figure imgf000086_0006
-C-R3 wherein R3 is as defined above,
Figure imgf000086_0005
-N-C-N-R4 wherein R3 and R4 are defined
R3 R3 above,
Figure imgf000086_0004
-C-C(R3')3 wherein R3' is F, Cl, Br, or I, or -CH2OR3 wherein R3 is as defined above, n is zero or an integer of 1, 2, 3, 4, 5, or 6 and
R2 is hydrogen,
alkyl,
trityl,
-N-R3 wherein R3 and R4 are each the same or
Figure imgf000086_0003
different and each is as defined above,
Figure imgf000086_0002
-NH-C-NH-R5 wherein R5 is
hydrogen,
p-toluenesulfonyl,
nitro or
Figure imgf000086_0001
-C-OR6 wherein R6 is
alkyl,
cycloalkyl,
aryl, or
heteroaryl,
Figure imgf000087_0001
-NH-C-NH-C-O-R6 wherein R6 is as defined
Figure imgf000087_0002
above,
Figure imgf000087_0003
-N-C-NH-R3 wherein R3 and R4 are each the
Figure imgf000087_0004
same or different and each is as
defined above,
aryl,
heteroaryl, or
heterocycloalkyl, wherein n and n' are each the same or different and each is as defined above for n,
Figure imgf000087_0005
R2 and R2' are each the same or different and each is as defined above for R2, and R is as defined above, wherein R2, R2', and R2'' are each the same or different and each is as defined above for R2, R, and n are defined as above, wherein n and n' are each the same or different and each is as defined above for n,
R2, R2', and R2" are each the same or different and each is as defined above for R2 and R is as defined above,
wherein R is as defined above,
Figure imgf000087_0006
wherein R is as defined above,
wherein R is as defined above,
wherein R8 is
hydrogen, or
alkyl,
and R is as defined above,
wherein R is
hydrogen,
alkyl,
cycloalkyl,
aryl, or
Figure imgf000088_0001
heteroaryl,
R8 and R9 are each the same or different and each is as defined above for R8 wherein R7, R8, and R9 are as defined above or
wherein R7 and R7' are each the same or different and each is as defined above for R7, and R is as defined above;
Figure imgf000089_0001
AA2, AA3, AA4, and AA5 are each independently absent or each independently
Figure imgf000089_0002
wherein R10 is
hydrogen,
alkyl,
aryl,
cycloalkyl,
alkenyl,
alkynyl,
-OR3 wherein R3 is as defined above,
-N-R3 wherein R3 and R4 are each the same or
Figure imgf000089_0006
different and each is as defined above,
Figure imgf000089_0003
-C-N-R3 wherein R3 and R4 are each the same
Figure imgf000089_0005
or different and each is as defined
above,
Figure imgf000089_0004
-NH-C-NH-R3 wherein R3 is as defined above, -S(O)mR3 wherein m is zero or an integer of 1 or 2, and R3 is as defined above where R3 is not hydrogen,
Figure imgf000090_0004
-C-R3 wherein R3 is as defined above,
Figure imgf000090_0003
-C-OR3 wherein R3 is as defined above,
R11 is hydrogen, alkyl, or aryl, and
n is as defined above, wherein n and n' are each the same or different and each is as defined
Figure imgf000090_0002
above for n,
R10 and R10' are each the same or different and each is as defined above for R10, and R11 is as defined above, wherein p is an integer of 1, 2, 3, 4, 5, or 6 and R11 is as defined above, wherein q is zero or an integer of 1, 2, 3, or 4,
Figure imgf000090_0001
wherein R2 and R2' are each the same or different and each is as defined above for R2, and
Figure imgf000091_0001
wherein R13 is
- (CH2)n-CO2H wherein n is as defined above,
- (CH2)n-OH wherein n is as defined above, or
Figure imgf000091_0002
- (CH2)n-C-N-R3 wherein n, R3, and R4 are as defined above,
Figure imgf000091_0003
Figure imgf000091_0004
C-NH-CH-CO2H wherein R14 is hydrogen or
Figure imgf000091_0005
-CH2-CO2H
R12 is
aryl,
heteroaryl, or
heterocycloalkyl, and
R11 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 R12 and R12' are each the same or different and each is as defined above for R12 and R11, and R13 are as defined above, wherein R12, R12', and R12" are each the same or different and each is as defined above for R12 and R11, R13 and n are as defined above, wherein n and n' are each the same or different and each is as defined above for n,
R12, R12', and R12" are each the same or different and each is as defined above for R12, and R11 and R13 are as defined above,
wherein R11 and R13 are as defined above,
wherein R11 and R13 are as defined above,
wherein R11 and R13 are as defined above,
Figure imgf000092_0001
wherein R8 and R9 are each the same or different and each is as defined above for R8 and R9, and R13 is as defined above, wherein R8 and R9 are each the same or different and each is as defined above for R8 and R9, and R13 is as defined above,
wherein R8, R11, and R13 are as defined above, and
Figure imgf000093_0001
N- (CH2) p-C- wherein R11 and p are as defined above;
Figure imgf000093_0002
stereochemistry at CH or C in AA1 is D,
* *
stereochemistry at CH or C in AA2, AA3, AA4, or AA5 is
D, L, or DL and
* *
stereochemistry at CH or C in AA6 is L; and with the exclusion of the compounds wherein AA1 is *
wherein CH is D stereochemistry, or
*
wherein CH is D stereochemistry,
Figure imgf000094_0001
*
Figure imgf000094_0008
*
AA2 is -NH-CH-C- wherein CH is L stereochemistry,
Figure imgf000094_0006
*
Figure imgf000094_0007
*
AA3 is -NH-CH-C- wherein CH is L stereochemistry,
Figure imgf000094_0003
*
Figure imgf000094_0004
*
AA4 and AA5 are each -NHCH-C- wherein CH is L
stereochemistry, and
Figure imgf000094_0005
*
AA6 is wherein CH is L
Figure imgf000094_0002
stereochemistry; or a pharmaceutically acceptable salt thereof.
2. A compound according to Claim 1, in which AA1 is
Figure imgf000095_0001
wherein R is
hydrogen
alkyl,
alkenyl,
alkynyl,
cycloalkyl,
cycloalkylalkyl,
aryl,
heteroaryl,
fluorenylmethyl,
-N-R3 wherein R3 and R4 are
Figure imgf000095_0002
R4 each the same or different and each is hydrogen,
alkyl,
alkenyl,
alkynyl,
cycloalkyl,
cycloalkylalkyl,
aryl,
heteroaryl, or
fluorenylmethyl,
Figure imgf000096_0010
-N-C-R3 wherein R3 and R4 are each the same
Figure imgf000096_0009
R4 or different and each is as defined above or
Figure imgf000096_0008
-N-C-OR4 wherein R3 and R4 are each the same
Figure imgf000096_0007
l
R3 or different and each is as def ined above,
Figure imgf000096_0004
-N-C-N-R4 wherein R3 and R4 are defined
Figure imgf000096_0005
Figure imgf000096_0006
R3 R3 above, or
Figure imgf000096_0003
-C-C(R3')3 wherein R3 'is F, Cl, Br, or I, n is zero,
R2 is hydrogen or methyl,
n' is zero or an integer of 1, 2, or 3, and
R2' is hydrogen,
trityl,
aryl,
heteroaryl,
heterocycloalkyl,
-N-R3 wherein R3 and R4 are each the same or R4 different and each is as defined
Figure imgf000096_0002
above or
Figure imgf000096_0001
wherein R7 is
hydrogen,
alkyl,
aryl, or
heteroaryl, R8 and R9 are each the same or different and each is
hydrogen or
alkyl,
Figure imgf000097_0001
wherein R2", R2'", and R2'"' are each the same or different and each is hydrogen,
alkyl,
aryl, or
heteroaryl with the proviso that at least one of R2",
R2'", and R2" '' is aryl or heteroaryl and R2, n, and n' are as defined above, or
Figure imgf000097_0002
wherein R7 and R7' are each the same or different and each is hydrogen,
alkyl,
cycloalkyl,
aryl, or
heteroaryl;
AA2, AA3, AA4, and AA5 are each independently absent or each independently;
Ahp,
Dip,
Apa, Pro ,
Phe , or
Figure imgf000098_0001
wherein R11 is
hydrogen or methyl,
n is zero,
R10 is hydrogen or methyl,
n' is zero or an integer of 1, 2, 3, or 4 and
R10' is hydrogen,
alkyl,
cycloalkyl,
alkenyl,
alkynyl,
-OR3'' wherein R3'' is
hydrogen,
alkyl,
alkenyl,
cycloalkyl,
aryl, or
heteroaryl,
wherein R3'' and R4' are each the same or different and each is as defined
Figure imgf000098_0002
above for R3",
Figure imgf000098_0003
-C-NR3" wherein R3" and R4' are each the
Figure imgf000098_0004
same or different and each is as defined above for R3",
Figure imgf000098_0005
-C-NH wherein R3'' is as defined above,
Figure imgf000098_0006
Figure imgf000099_0004
-NH-C-NH-R-R5 wherein R5 is defined as above,
Figure imgf000099_0003
-C-R3'' wherein R3'' is as defined above, -S(O)mR3" wherein m is zero or an integer of
1 of 2 and R3'' is as defined above except that R3'' is not hydrogen, or
Figure imgf000099_0002
-C-OR4, wherein R4' is as defined above,
AA6 is
Figure imgf000099_0001
wherein R11 is hydrogen or methyl,
n is zero,
R12 is hydrogen, or methyl,
n' is zero or an integer of 1, 2, or 3,
R12' is aryl or heteroaryl,
R13 is - (CH2)n-CO2H wherein n is as defined
above,
- (CH2)n-OH wherein n is as defined above, or
Figure imgf000099_0005
- (CH2)n-C-N-R3 wherein n, R3, and R4 are
defined above,
Figure imgf000099_0007
Figure imgf000099_0006
-C-NH-CH-CO2H wherein R14 is hydrogen or
-CH2-CO2H, or
Figure imgf000099_0008
Figure imgf000100_0001
wherein R8 and R9 are each the same or different and each is as defined above for and R9 and R13 is as defined above, and R8' is hydrogen, formyl, acetyl, Z, Boc, Bzl, or alkyl;
*
stereochemistry at C in AA1 is D,
*
stereochemistry at C in AA2, AA3, AA4, or AA5 is D, L, or DL, and stereochemistry at
*
C in AA6 is L.
3. A compound according to Claim 2 in which AA1 is
Figure imgf000101_0001
wherein R is
hydrogen,
alkyl,
alkenyl,
alkynyl,
cycloalkyl,
cycloalkylalkyl,
aryl,
heteroaryl,
fluorenylmethyl,
-N-R3 wherein R3 and R4 are
Figure imgf000101_0004
each the same or different and each is
hydrogen,
alkyl,
alkenyl,
alkynyl,
cycloalkyl,
cycloalkylalkyl,
aryl,
heteroaryl, or
fluorenylmethyl,
Figure imgf000101_0002
-N-C-R4 wherein R3 and R4 are each the same
Figure imgf000101_0003
or different and each is as
defined above, wherein R3 and R4 are each the same or
Figure imgf000102_0004
different and each is as defined above, and R2', R2", and R2"' are each the same or different and each is hydrogen,
alkyl,
aryl, or
heteroaryl with the proviso that at least one of R2, R2', and R2" is aryl or heteroaryl, and R2"' is hydrogen or methyl,
Figure imgf000102_0003
-N-C-N-R4 wherein R3 and R4 are defined
Figure imgf000102_0005
R3
Figure imgf000102_0006
R3 above, or
-
Figure imgf000102_0002
C-C(R3')3 wherein R3' is F, Cl, Br, or I,
R2 is hydrogen or methyl,
n is zero, and
n' is zero or an integer of 1, 2, or 3 , or AA2 is
Apa,
Aha,
Dip,
D-Phe,
Phe,
HomoArg,
Arg, or
Figure imgf000102_0001
wherein R11 is hydrogen or methyl,
n is zero, R10 is hydrogen or methyl,
n' is zero or an integer of 1, 2, 3, 4, or 5, and
R10 is alkyl,
OH,
-N-R3'' wherein R3" and R4' are
Figure imgf000103_0005
R4' each the same or
different and each is hydrogen,
alkyl, or
aryl,
Figure imgf000103_0003
-C-N-R3" wherein R3" and R4' are
Figure imgf000103_0004
R4' as defined above,
Figure imgf000103_0002
-C-OR4' wherein R4' is as defined above;
-S(O) 1 mR3" wherein m is zero or an integer of
1 of 2 and R3'' is as defined above except that R3'' is not hydrogen;
AA3 is
Lys,
Tyr,
Phe, or
Figure imgf000103_0001
wherein R11 is hydrogen or methyl,
n is zero,
R10 is hydrogen or methyl, n" is zero or an integer of 1, 2, or 3, and
R11' is alkyl,
aryl, -C-N-R3" wherein R3" and R4' are
Figure imgf000104_0004
R4' as defined above,
Figure imgf000104_0003
-C-OR4' wherein R4' is as
defined above,
AA4 and AA5 are each
Phe,
Lys,
Glu,
Pro, or
Figure imgf000104_0001
wherein R11 is hydrogen or methyl,
n is zero,
R10 is hydrogen or methyl,
n' is zero, and
R10' is alkyl,
or cycloalkyl,
AA6 is
Figure imgf000104_0002
wherein R11 is hydrogen or methyl,
n is zero,
R12 is hydrogen, or methyl,
n' is zero or an integer of 1, 2, of 3, R12' is aryl or heteroaryl, R13 is -(CH2)n-CO2H wherein n is zero or an integer of 1, 2, 3, 4, 5, or 6,
- (CH2)n-OH wherein n is zero or an integer of 1, 2, 3, 4, 5, or
6, or
Figure imgf000105_0001
- (CH2)n-C-N-R3 wherein n, R3, and R4 are
Figure imgf000105_0002
R4 defined above,
Figure imgf000105_0003
-C-NH-CH-CO2H wherein R14 is
Figure imgf000105_0004
R 14 hydrogen or
- CH2CO2H,
*
stereochemistry at C in AA1 is D,
*
stereochemistry at C in AA2, AA3, AA4, or AA5 is D or L and
*
stereochemistry at C in AA6 is L.
4. A compound according to Claim 3 in which
AA1 is
D-Adm,
D-Ana,
D-Chx,
D-Dip,
D-Dopa,
D-Bip,
D-His,
D-His(Dnp),
D-2-Nal,
D-1-Nal,
D-Phe,
D-Pmp,
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-Adm,
Ac-D-Ana,
Ac-D-Chx,
Ac-D-Dip,
Ac-D-Dopa,Ac-D-Bip,
Ac-D-His,
Ac-D-His(Dnp), Ac-D-2-Nal, Ac-D-1-Nal,Ac-D-N-MeDip, Ac-D-Phe,
Ac-D-Pgl,
Ac-D-Pmp,
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-Adm,
Ada-D-Ana, Ada-D-Chx,
Ada-D-Dip,
Ada-D-Dopa,
Ada-D-Bip, Ada-D-His,
Ada-D-His(Dnp), Ada-D-2-Nal, Ada-D-1-Nal, AdaaD-Pmp,
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-Adm,
Adoc-D-Ana,
Adoc-D-Chx,
Adoc-D-Dip,
Adoc-D-Dopa,Adoc-D-Bip,
Adoc-D-His,
Adoc-D-His(Dnp), Adoc-D-2-Nal, Adoc-D-1-Nal,Adoc-D-Phe,
Adoc-D-Pmp,
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-Adm,
Boc-D-Ana,
Boc-D-Chx,
Boc-D-Dip,
Boc-D-Dopa,
Boc-D-Bip,
Boc-D-His,
Boc-D-His(Dnp),Boc-D-2-Nal, Boc-D-1-Nal, Boc-D-Phe,
Boc-D-Pmp,
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-Adm,
Z-D-Ana,
Z-D-Chx,
Z-D-Dip,
Z-D-Dopa,
Z-D-Bip,
Z-D-His,
Z-D-His(Dnp), Z-D-2-Nal,
Z-D-1-Nal,
Z-D-Phe,
Z-D-Pmp,
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-Adm,
Fmoc-D-Ana,
Fmoc-D-Chx,
Fmoc-D-Dip,
Fmox-D-Dopa, Fmoc-D-Bip,
Fmoc-D-His,
Fmoc-D-His(Dnp), Fmoc-D-2-Nal,Fmoc-D-1-Nal, Fmoc-D-Phe,
Fmoc-D-Pmp,
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, Et-D-Dip,
Bz-D-Dip,
Pya-D-Dip,
Cxl-D-Dip,
Ada-D-Dip,
Cxl(U)-D-Dip,
Me(U)-D-Dip, tBu-D-Dip,
CF3CO-D-Dip;
AA2 is Ala,
Alg,
Aha,
Apa,
Arg,
Asn,
Asp,
Dab,
D-Dip,
Glu,
Gln,
Gly,
HomoArg, HomoGlu,
HomoLys, lIe,
Leu,
D-Leu,
Lys,
D-N-MeLeu,
Met,
Met(O),
Met(O2),
Nva,
Nle,
Orn,
Phe,
D-Phe,
Tyr,
Val, or
AA2 is absent; AA3 is Asn,
Asp,
D-Asp, N-MeAsp,
Glu,
Gln,
Lys,
HomoPhe,
Phe,
Tyr, or
AA3 is absent;
AA4 is Ala,
Chx,
Gly,
Glu,
lIe,
D-Ile,
Leu,
Lys,
Nle,
N-Melle,
Nva,
Phe,
Pro,
Val, or
AA4 is absent;
AA5 is Ala,
Chx,
Gly,
lIe,
D-Ile,
Leu,
Lys,
Nle,
N-Melle,
Nva,
Phe,
Val, or
AA5 is absent; and AA6 is 2-Nal, 1-Nal,
N-MeTrp,
Phe,
Pyr,
Trp,
Trp-NH2,
Tyr OMe),
Tyr(OEt),
Tyr(Ot-Bu),
Tyr,
Trp-Gly,
Trp-Asp,
Trp(For),
Dip,
Phe,
Figure imgf000112_0001
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-l-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-lIe-lIe-Trp;
Fmoc-D-Phe-Leu-Asp-lIe-lIe-Trp;
Fmoc-D-His-Leu-Asp-lIe-lIe-Trp;
Fmoc-D-Trp-Leu-Asp-lIe-lIe-Trp;
Fmoc-D-Tyr-Leu-Asp-lIe-lIe-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-lIe-lIe-Trp; Fmoc-D-1-Nal-Leu-Asp-lIe-lIe-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-lIe-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-lIe-Trp; Ada-D-1-Nal-Leu-Asp-lIe-lIe-Trp; Ada-D-Dip-Leu-Asp-Ile-lIe-Trp;
Ada-D-Bip-Leu-Asp-IIe-IIe-Trp;
Ac-D-Phe-D-Leu-Asp-lIe-lIe-Trp;
Ac-D-His-D-Leu-Asp-lIe-lIe-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-Ale-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-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-Trp;
Ac-D-Dip-Val-Asp-Ile-Ile-Trp;
Ac-D-Bip-Val-Asp-Ile-Ile-Trp;
Ac-D-Phe-Dab-Asp-Ile-Ile-Trp;
Ac-D-His-Dab-Asp-Ile-Ile-Trp;
Ac-D-Trp-Dab-Asp-Ile-Ile-Trp;
Ac-D-Tyr(OMe)-Dab-Asp-Ile-Ile-Trp; Ac-D-Tyr(OEt)-Dab-Asp-Ile-Ile-Trp; Ac-D-2-Nal-Dab-Asp-Ile-Ile-Trp;
Ac-D-1-Nal-Dab-Asp-Ile-Ile-Trp;
Ac-D-Dip-Dab-Asp-Ile-Ile-Trp;
Ac-D-Bip-Dab-Asp-Ile-Ile-Trp;
Ac-D-Phe-Arg-Asp-Ile-Ile-Trp;
Ac-D-His-Arg-Asp-Ile-Ile-Trp; Ac -D-Trp-Arg-Asp- Ile - Ile-Trp ;
Ac -D-Tyr (OMe) -Arg-Asp-Ile- Ile -Trp ; Ac -D-Tyr (OEt ) -Arg-Asp- Ile-Ile-Trp;
Ac-D-2 -Nal -Arg-Asp-Ile- Ile-Trp;
Ac-D- 1 -Nal -Arg-Asp-Ile- Ile-Trp;
Ac-D-Dip-Arg-Asp- Ile- Ile-Trp ;
Ac -D-Bip-Arg-Asp-Ile-Ile-Trp ;
Ac-D-Phe-HomoLys-Asp-lIe-lIe-Trp;
Ac-D-His-HomoLys-Asp-lIe-lIe-Trp;
Ac-D-Trp-HomoLys-Asp-lIe-lIe-Trp;
Ac-D-Tyr(OMe)-HomoLys-Asp-Ile-Ile-Trp; Ac-D-Tyr(OEt)-HomoLys-Asp-Ile-Ile-Trp; Ac-D-2-Nal-HomoLys-Asp-Ile-Ile-Trp; Ac-D-1-Nal-HomoLys-Asp-Ile-Ile-Trp; Ac-D-Dip-HomoLys-Asp-Ile-Ile-Trp;
Ac-D-Bip-HomoLys-Asp-lIe-lIe-Trp;
Ac-D-His-Glu-Asp-lIe-lIe-Trp;
Ac-D-Trp-Glu-Asp-Ile-Ile-Trp;
Ac-D-Tyr(OMe)-Glu-Asp-Ile-lIe-Trp;
Ac-D-Tyr(OEt)-Glu-Asp-Ile-lIe-Trp;
Ac-D-2-Nal-Glu-Asp-lIe-Ile-Trp;
Ac-D-1-Nal-Glu-Asp-lIe-lIe-Trp;
Ac-D-Dip-Glu-Asp-lIe-lIe-Trp;
Ac-D-Bip-Glu-Asp-Ile-Ile-Trp;
Ac-D-Phe-HomoGlu-Asp-lIe-lIe-Trp;
Ac-D-His-HomoGlu-Asp-lIe-lIe-Trp;
Ac-D-Trp-HomoGlu-Asp-lIe-Ile-Trp;
Ac-D-Tyr(OMe)-HomoGlu-Asp-lIe-Ile-Trp; Ac-D-Tyr(OEt)-HomoGlu-Asp-lIe-lIe-Trp; Ac-D-2-Nal-HomoGlu-Asp-Ile-Ile-Trp;Ac-D-1-Nal-HomoGlu-Asp-lIe-Ile-Trp; Ac-D-Dip-HomoGlu-Asp-Ile-Ile-Trp;
Ac-D-Bip-HomoGlu-Asp-lIe-lIe-Trp;
Ac-D-Phe-Asp-Asp-lIe-lIe-Trp;
Ac-D-His-Asp-Asp-Ile-Ile-Trp;
Ac-D-Trp-Asp-Asp-Ile-Ile-Trp;
Ac-D-Tyr(OMe)-Asp-Asp-Ile-lIe-Trp; Ac-D-Tyr(OEt)-Asp-Asp-Ile-Ile-Trp; Ac-D-2-Nal-Asp-Asp-Ile-Ile-Trp; Ac-D-1-Nal-Asp-Asp-Ile-Ile-Trp; Ac-D-Dip-Asp-Asp-Ile-Ile-Trp;
Ac-D-Bip-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-Dip-Lys-Asp-Ile-Ile-Trp;
Ac-D-Bip-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-Orn-Asp-Ile-Ile-Trp; Ac-D-Dip-Orn-Asp-Ile-Ile-Trp;
Ac-D-Bip-Orn-Asp-Ile-Ile-Trp;
Ac-D-Phe-Gln-Asp-Ile-Ile-Trp;
Ac-D-His-Gin-Asp-Ile-Ile-Trp;
Ac-D-Trp-Gin-Asp-Ile-Ile-Trp;
Ac-D-Tyr-Gin-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-Dip-Gln-Asp-Ile-Ile-Trp;
Ac-D-Bip-Gin-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-lIe-lIe-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-Dip-Leu-Glu-lIe-lIe-Trp;
Ac-D-Bip-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-lIe-Trp;
Ac-D-Tyr(OMe)-Leu-Asn-Ile-lIe-Trp;
Ac-D-Tyr(OEt)-Leu-Asn-Ile-lIe-Trp;
Ac-D-2 -Nal-Leu-Asn-lIe-lIe-Trp;
Ac-D-l-Nal-Leu-Asn-lIe-lIe-Trp; Ac-D-Dip-Leu-Asn-lIe-lIe-Trp;
Ac-D-Bip-Leu-Asn-lIe-lIe-Trp;
Ac-D-Phe-Leu-Phe-lIe-Ile-Trp;
Ac-D-His-Leu-Phe-lIe-lIe-Trp;
Ac-D-Trp-Leu-Phe-lIe-lIe-Trp;
Ac-D-Tyr(OMe)-Leu-Phe-Ile-Ile-Trp;
Ac-D-Tyr(OEt)-Leu-Phe-Ile-Ile-Trp;
Ac-D-2-Nal-Leu-Phe-IIe-IIe-Trp;
Ac-D-1-Nal-Leu-Phe-lIe-lIe-Trp;
Ac-D-Dip-Leu-Phe-Ile-Ile-Trp;
Ac-D-Bip-Leu-Phe-lIe-lIe-Trp;
Ac-D-Phe-Glu-Asp-lIe-Ile-Trp;
Ac-D-Phe-Leu-Asp-Val-lIe-Trp;
Ac-D-His-Leu-Asp-Val-lIe-Trp;
Ac-D-Trp-Leu-Asp-Val-Ile-Trp;
Ac-D-Tyr-Leu-Asp-Val-Ile-Trp;
Ac-D-Tyr(OMe)-Leu-Asp-Val-lIe-Trp;
Ac-D-Tyr(OEt)-Leu-Asp-Val-lIe-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-lIe-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-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;
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-Ile-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-lIe-Val-Trp;
Ac-D-Dip-Leu-Asp-Ile- al-Trp;
Ac-D-Bip-Leu-Asp-lIe-Val-Trp;
Ac-D-Phe-Leu-Asp-Ile-Chx-Trp;
Ac-D-His-Leu-Asp-Ile-Chx-Trp;
Ac-D-Trp-Leu-Asp-lIe-Chx-Trp;;
Ac-D-Tyr-Leu-Asp-lIe-Chx-Trp;
Ac-D-Tyr(OMe)-Leu-Asp-lIe-Chx-Trp; Ac-D-Tyr(OEt)-Leu-Asp-lIe-Chx-Trp; Ac-D-2-Nal-Leu-Asp-lIe-Chx-Trp;
Ac-D-l-Nal-Leu-Asp-lIe-Chx-Trp;
Ac-D-Dip-Leu-Asp-Ile-Chx-Trp;
Ac-D-Bip-Leu-Asp-lIe-Chx-Trp;
Ac-D-Phe-Leu-Asp-Ile-lIe-2-Nal;
Ac-D-His-Leu-Asp-Ile-lIe-2-Nal;
Ac-D-Trp-Leu-Asp-Ile-lIe-2-Nal;
Ac-D-Tyr-Leu-Asp-lIe-lIe-2-Nal, Ac-D-Tyr(OMe)-Leu-Asp-lIe-Ile-2-Nal; Ac-D-Tyr(OEt)-Leu-Asp-Ile-lIe-2-Nal; Ac-D-2-Nal-Leu-Asp-lIe-lIe-2-Nal; Ac-D-l-Nal-Leu-Asp-lIe-lIe-2-Nal; Ac-D-Dip-Leu-Asp-lIe-lIe-2-Nal;
Ac-D-Bip-Leu-Asp-Ile-lIe-2-Nal;
Ac-D-Phe-Leu-Asp-Ile-Ile-1-Nal;
Ac-D-His-Leu-Asp-lIe-lIe-1-Nal, Ac-D-Trp-Leu-Asp-lIe-lIe-1-Nal, Ac-D-Tyr-Leu-Asp-lIe-lIe-1-Nal;
Ac-D-Tyr(OMe)-Leu-Asp-Ile-lIe-1-Nal; Ac-D-Tyr(OEt)-Leu-Asp-lIe-lIe-1-Nal; Ac-D-2-Nal-Leu-Asp-lIe-lIe-1-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-lIe-D-lIe-Trp; Ac-D-Phe-Leu-D-Asp-Ile-D-Ile-Trp; Ac-D-Bip-Leu-D-Asp-lIe-D-lIe-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-Ile-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-N-MeDip-Leu-Asp-Ile-Ile-Trp;Ac-D-Dip-Leu-Asp-Ile-Ile-N-MeTrp;Ac-D-Dip-Leu-Asp-Ile-N-Melle-Trp;Ac-D-Dip-Leu-Asp-N-Melle-Ile-Trp;Ac-D-Dip-Leu-N-MeAsp-Ile-Ile-Trp;Ac-D-Dip-N-MeLeu-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-l-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-Nal
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-D-Phe-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-His-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-Trp-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-Tyr(OEt)-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-2-Nal-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-1-Nal-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-Dip-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-Bip-Leu-Asp-Ile-Ile-Trp-Gly;
Ac-D-Phe-Leu-Asp-Ile-Ile-Trp-Asp;
Ac-D-His-Leu-Asp-Ile-Ile-Trp-Asp;
Ac-D-Trp-Leu-Asp-Ile-Ile-Trp-Asp;
Ac-D-Tyr(OMe)-Leu-Asp-Ile-Ile-Trp-Asp;
Ac-D-Tyr(OEt)-Leu-Asp-Ile-Ile-Trp-Asp;
Ac-D-2-Nal-Leu-Asp-Ile-Ile-Trp-Asp;
Ac-D-1-Nal-Leu-Asp-Ile-Ile-Trp-Asp;
Ac-D-Dip-Leu-Asp-Ile-Ile-Trp-Asp;
Ac-D-Dip-Leu-Asp-Ile-Ile-Trp-NH2;
Ac-D-His-Leu-Asp-Ile-Ile-Trp;
Bppa-Leu-Asp-Ile-Ile-Trp;
Ada-D-Phe-Leu-Asp-Ile-Ile-Trp;
Fmoc-D-Dip-Leu-Asp-Ile-Ile-Trp;
Et-D-Dip-Leu-Asp-Ile-Ile-Trp;
Bz-D-Dip-Leu-Asp-Ile-Ile-Trp;
Pya-D-Dip-Leu-Asp-Ile-Ile-Trp; Cxl-D-Dip-Leu-Asp-Ile-Ile-Trp;Ada-D-Dip-Leu-Asp-Ile-lIe-Trp; Cxl(U)-D-Dip-Leu-Asp-Ile-Ile-Trp; Me(U)-D-Dip-Leu-Asp-Ile-Ile-Trp;tBu-D-Dip-Leu-Asp-Ile-Ile-Trp; CF3CO-D-Dip-Leu-Asp-Ile-Ile-Trp;Ac-D-Chx-Leu-Asp-Ile-lIe-Trp;
Ac-D-Dopa-Leu-Asp-Ile-Ile-Trp; D-Pmp-Leu-Asp-Ile-Ile-Trp;
Ac-D-Pmp-Leu-Asp-lIe-lIe-Trp;
D-Ana-Leu-Asp-lIe-lIe-Trp;
Ac-D-Ana-Leu-Asp-lIe-Ile-Trp;
Ac-D-Adm-Leu-Asp-Ile-Ile-Trp;
Ac-D-Phe-Ala-Asp-Ile-lIe-Trp;
Ac-D-Phe-Phe-Asp-Ile-Ile-Trp;
Ac-D-Phe-D-Phe-Asp-Ile-lIe-Trp;Ac-D-Dip-D-Phe-Asp-lIe-lIe-Trp; D-Dip-Leu-Asn-lIe-lIe-Trp;
Ac-D-Dip-Leu-Tyr-lIe-lIe-Trp;
Ac-D-Phe-Leu-Asp-Ala-Ile-Trp;
Ac-D-Dip-Leu-Asp-Glu-lIe-Trp;
Ac-D-Dip-Leu-Asp-Phe-lIe-Trp;
Ac-D-Dip-Leu-Asp-N-Melle-Ile-Trp; Ac-Dip-Leu-Asp-Phe-lIe-Trp;
Ac-D-Dip-Leu-Asp-Lys-lIe-Trp; Ac-D-Dip-Leu-Asp-Ala-lIe-Trp,Ac-D-Phe-Leu-Asp-lIe-Ala-Trp, Ac-D-Dip-Leu-Asp-lIe-Lys-Trp; Ac-D-Dip-Leu-Asp-Ile-Phe-Trp; Ac-D-Dip-Leu-Asp-lIe-Leu-Trp; Ac-D-Dip-Leu-Asp-Ile-Ile-Phe;Ac-D-Dip-Leu-Asp-lIe-Ile-Tyr; Ac-D-Phe-Leu-Asp-lIe-lIe-Tyr; Ac-D-Phe-Leu-Asn-Pro-lIe-Trp; Ac-D-Phe-Leu-Asp-Ala-lIe-Tyr;
Ac-D-Dip-Leu-Asn-Pro-Ile-Trp; Ac-D-Phe-Asp-Phe-Ile-Trp; D-Dip-Tyr-Ile-Ile-Trp;
Ac-D-Dip-Apa-Ile-Ile-Trp;
Ac-D-Dip-D-Dip-Asp-Ile-Trp; and
Ac-D-Dip-Ahp-lIe-Ile-Trp.
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-lIe-lIe-Trp;
Ac-D-Phe-Leu-Asp-Ile-Trp;
Ac-D-His-Leu-D-Asp-Ile-D-Ile-Trp;
Ac-D-Phe-Orn-Asp-Ile-Ile-Trp;
Ac-D-Phe-Glu-Asp-Ile-Ile-Trp;
Ac-D-Tyr-Leu-Asp-lIe-lIe-Trp;
Ac-D-Phe-Asp-Ile-Ile-Trp;
Fmoc-D-Phe-Leu-Asp-lIe-lIe-Trp;
Ac-D-Dip-Leu-Asp-lIe-lIe-Trp;
Ac-D-Dip-lIe-lIe-Trp;
Ac-D-Dip-Asp-lIe-lIe-Trp;
Ac-D-Dip-Leu-Phe-lIe-lIe-Trp;
Ac-D-Dip-Leu-Asp-lIe-Lys-Trp;
Ac-D-Dip-Leu-Asp-lIe-Glu-Trp;
Ac-D-Dip-Leu-Asp-Glu-Ile-Trp;
Ac-D-Dip-Glu-Asp-lIe-Ile-Trp;
Ac-D-Dip-Orn-Asp-Ile-Ile-Trp;
Ac-D-Dip-Leu-Asp(N-Me)-lIe-Ile-Trp;
Ac-D-Dip-D-Leu-Asp-Ile-lIe-Trp;
Bppa-Leu-Asp-lIe-Ile-Trp;
Ada-D-Phe-Leu-Asp-lIe-lIe-Trp;
Fmoc-D-Dip-Leu-Asp-lIe-Ile-Trp;
Et-D-Dip-Leu-Asp-lIe-Ile-Trp;
Bz-D-Dip-Leu-Asp-lIe-lIe-Trp;
Pya-D-Dip-Leu-Asp-Ile-lIe-Trp;
Cxl-D-Dip-Leu-Asp-Ile-Ile-Trp;
Ada-D-Dip-Leu-Asp-Ile-lIe-Trp; Cxl(U)-D-Dip-Leu-Asp-Ile-Ile-Trp; Me(U)-D-Dip-Leu-Asp-Ile-Ile-Trp; tBu-D-Dip-Leu-Asp-Ile-Ile-Trp;
CF3CO-D-Dip-Leu-Asp-Ile-Ile-Trp;
Ac-D-Chx-Leu-Asp-Ile-Ile-Trp;
Ac-D-Dopa-Leu-Asp-Ile-Ile-Trp; D-Pmp-Leu-Asp-Ile-lIe-Trp;
Ac-D-Pmp-Leu-Asp-lIe-lIe-Trp;
D-Ana-Leu-Asp-Ile-Ile-Trp;
Ac-D-Ana-Leu-Asp-lIe-lIe-Trp;
Ac-D-Adm-Leu-Asp-Ile-Ile-Trp;
Ac-D-Phe-Ala-Asp-Ile-lIe-Trp;
Ac-D-Phe-Phe-Asp-lIe-lIe-Trp;
Ac-D-Phe-D-Phe-Asp-lIe-lIe-Trp;
Ac-D-Dip-D-Phe-Asp-lIe-lIe-Tip;
D-Dip-Leu-Asn-lIe-Ile-Trp;
Ac-D-Dip-Leu-Tyr-Ile-Ile-Trp;
Ac-D-Phe-Leu-Asp-Ala-lIe-Trp;
Ac-D-Dip-Leu-Asp-Phe-lIe-Trp;
Ac-D-Dip-Leu-Asp-N-Melle-Ile-Trp;
Ac-D-Dip-Leu-Asp-Lys-Ile-Trp;
Ac-D-Dip-Leu-Asp-Ala-lIe-Trp;
Ac-D-Phe-Leu-Asp-lIe-Ala-Trp;
Ac-D-Dip-Leu-Asp-lIe-Phe-Trp;
Ac-D-Dip-Leu-Asp-lIe-Leu-Trp;
Ac-D-Dip-Leu-Asp-Ile-Ile-Phe; Ac-D-Dip-Leu-Asp-Ile-lIe-Tyr;
Ac-D-Phe-Leu-Asp-lIe-lIe-Tyr;
Ac-D-Phe-Leu-Asn-Pro-lIe-Trp;
Ac-D-Phe-Leu-Asp-Ala-lIe-Tyr;
Ac-D-Dip-Leu-Asn-Pro-lIe-Trp; Ac-D-Phe-Asp-Phe-lIe-Trp;
D-Dip-Tyr-lIe-lIe-Trp;
Ac-D-Dip-Apa-lIe-lIe-Trp;
Ac-D-Dip-D-Dip-Asp-Ile-Trp; and
Ac-D-Dip-Ahp-lIe-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 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 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 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
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 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.
24. 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.
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 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 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.
32. 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.
33. 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.
34. 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.
35. 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.
36. 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.
37. A method of treating atherosclerosis 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.
38. A pharmaceutical composition adapted for
administration as an agent for treating
atherosclerosis 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.
39. A method of treating restenosis or percutaneous transluminal coronary angioplasty (PTCA)
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
restenosis or percutaneous transluminal coronary angioplasty (PTCA) 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 angina 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 angina 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 cancer 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 cancer 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
AA1 -AA2 -AA3 -AA4 -AA5 -AA6
Figure imgf000132_0001
wherein AA1 is R-CH-C
Figure imgf000132_0002
(CH2)n
Figure imgf000132_0003
R2
wherein R is
hydrogen
alkyl,
alkenyl,
alkynyl,
cycloalkyl,
cycloalkylalkyl,
aryl,
heteroaryl,
fluorenylmethyl,
-N-R3 wherein R3 and R4 are each the same or
Figure imgf000132_0004
R4 different and each is
hydrogen,
alkyl,
alkenyl,
alkynyl,
cycloalkyl,
cycloalkylalkyl,
aryl,
heteroaryl, or
fluorenylmethyl,
-OR3 wherein R3 is as defined above,
Figure imgf000132_0005
-C-OR3 wherein R3 is as defined above,
Figure imgf000132_0006
-N-C-R4 wherein R3 and R4 are each the same
Figure imgf000132_0007
R3 or different and each is as
defined above,
Figure imgf000133_0001
-N-C-OR4 wherein R3 and R4
Figure imgf000133_0002
are each the same
or different and each is as
defined above, but R4 is not hydrogen,
Figure imgf000133_0003
-C-R3 wherein R3 is as defined above,
Figure imgf000133_0004
-N-C-N-R4 wherein R3 and R4 are defined
Figure imgf000133_0005
R3 R3 above,
Figure imgf000133_0006
-C-C(R3')3 wherein R3' is F, Cl, Br, or I, or
-CH2OR3 wherein R3 is as defined above,
n is zero or an integer of 1, 2, 3, 4, 5, or 6
and
R2 is hydrogen,
alkyl,
trityl,
-N-R3 wherein R3 and R4 are each the same or
Figure imgf000133_0007
R4 different and each is as defined above, NH
Figure imgf000133_0008
-NH-C-NH-R3 wherein R5 is
hydrogen,
p-toluenesulfonyl,
nitro or
Figure imgf000133_0009
-C-OR6 wherein R6 is
alkyl,
cycloalkyl,
aryl, or
heteroaryl,
Figure imgf000134_0002
N-C-OR6
Figure imgf000134_0003
-NH-C-NH-C-O-R6 wherein R6 is as defined
above,
Figure imgf000134_0004
Figure imgf000134_0005
-N-C-NH-R3 wherein R3 and R4 are each the
Figure imgf000134_0006
R4 same or different and each is as
defined above,
aryl,
heteroaryl, or
heterocycloalkyl, wherein n and n' are each the same different and each is as defined above for n,
R2 and R2' are each the same or different and each is as defined above for R2, and R is as defined above, wherein R2, R2' , and R2'' are each the same or different and each is as defined above for R2, R and n, are as defined above,
wherein n and n' are each the same or \ different and each is as defined above . for n,
R2, R2', and R2" are each the same or different and each is as defined above for R2 and R is as defined above,
wherein R is as defined above,
Figure imgf000134_0001
wherein R is as defined above ,
wherein R is as defined above,
wherein R8 is
hydrogen, or
alkyl,
and R is as defined above,
wherein R7 is
hydrogen,
alkyl,
cycloalkyl,
aryl, or
heteroacyl,
R8 and R9 are each the same or
Figure imgf000135_0001
different and each is as defined above for R8 wherein R7, R8, and R9 are as defined above or
wherein R7 and R7' are each the same or different and each is as defined above for R7, and R is as defined above;
Figure imgf000136_0002
AA2, AA3, AA4, and AA5 are each independently absent or each independently
Figure imgf000136_0001
wherein R10 is
hydrogen,
alkyl,
aryl,
cycloalkyl,
alkenyl,
alkynyl,
-OR3 wherein R3 is as defined above,
-N-R3 wherein R3 and R4 are each the same or
Figure imgf000136_0003
different and each is as defined above,
Figure imgf000136_0004
-C-N-R3 wherein R3 and R4 are each the same R4 or different and each is as defined
above,
NH
-NH-
Figure imgf000136_0005
C-NH-R5 wherein R5 is as defined above, -S(O)mR3 wherein m is zero or an integer of 1 or 2, and R3 is as defined above
where R3 is not hydrogen,
Figure imgf000137_0004
-C-R3 wherein R3 is as defined above,
Figure imgf000137_0003
-C-OR3 wherein R3 is as defined above,
R11 is hydrogen, alkyl, or aryl, and
n is as defined above,
V wherein n and n' are each the same or different and each is as defined
Figure imgf000137_0002
above for n,
R10 and R10' are each the same or different and each is as defined above for R10, and R11 is as defined above,
-N-(CH2)p-C- wherein p is an integer of 1, 2, 3, 4,
Figure imgf000137_0005
5, or 6 and R11 is as defined above, wherein q is zero or an integer of 1, 2, 3, or 4,
Figure imgf000137_0001
wherein R2 and R2' are each the same or different and each is as defined above for R2, and
Figure imgf000138_0001
AA6 is
Figure imgf000138_0006
wherein R13 is
- (CH2)n-CO2H wherein n is as defined above,
- (CH2)n-OH wherein n is as defined above, or
- (CH2)n-
Figure imgf000138_0005
C-N-R3 wherein n, R3, and R4 are
Figure imgf000138_0004
R4 defined above,
Figure imgf000138_0002
-C-NH-CH-CO2H wherein R14 is hydrogen or
Figure imgf000138_0003
R14 -CH2-CO2H
R12 is
aryl,
heteroaryl, or
heterocycloalkyl, and
R11 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 R12 and R12' are each the same or different and each is as defined above for R12 and R11, and R13 are as defined above, wherein R12, R12', and R12'' are each the same or different and each is as defined above for R12 and R11, R13 and n are as defined above, wherein n and n' are each the same
B or different and each is as defined above for n,
R12, R12', and R12 '' are each the same or different and each is as defined above for R12, and R11 and R13 are as defined above,
wherein R11 and R13 are as defined above,
wherein R11 and R13 are as defined above,
wherein R11 and R13 are as defined above,
Figure imgf000139_0001
wherein R8 and R9 are each the same or different and each is as defined above for R8 and R9, and R13 is as defined above, wherein R8 and R9 are each the same or different and each is as defined above for R8 and R9, and R13 is as defined above,
wherein R8, R11, and R13 are as defined above, and
Figure imgf000140_0001
-N- (CH ) -C- wherein R11 and p are as defined above;
R11
* *
stereochemistry at CH or C in AA1 is D,
* *
stereochemistry at CH or C in AA2, AA3, AA4, or AA5 is
D, L, or DL and
* *
stereochemistry at CH or C in AA6 is L; and with the exclusion of the compounds wherein AA1 is *
wherein CH is D
stereochemistry, or
*
wherein CH is D
stereochemistry,
Figure imgf000141_0001
*
Figure imgf000141_0008
*
AA2 is -NH-CH-C- wherein CH is L stereochemistry,
Figure imgf000141_0002
*
Figure imgf000141_0003
*
AA3 is -NH-CH-C- wherein CH is L stereochemistry,
I
Figure imgf000141_0004
*
Figure imgf000141_0005
*
AA4 and AA5 are each -NHCH-C- wherein CH is L
stereochemistry, and
Figure imgf000141_0007
*
AA6 is wherein CH is L
Figure imgf000141_0006
stereochemistry; or a pharmaceutically acceptable salt thereof comprising sequential stepwise coupling of the amino acids selected from AA1, AA2, AA3 , AA4 , AA5, or AA6 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.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998035980A1 (en) * 1997-02-14 1998-08-20 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands of cd4
US6180348B1 (en) 1998-04-20 2001-01-30 Weihua Li Method of isolating target specific oligonucleotide ligands
US10278957B2 (en) 2017-09-11 2019-05-07 Protagonist Therapeutics, Inc. Opioid agonist peptides and uses thereof

Families Citing this family (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962490A (en) * 1987-09-25 1999-10-05 Texas Biotechnology Corporation Thienyl-, furyl- and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin
CA2043741C (en) * 1990-06-07 2003-04-01 Kiyofumi Ishikawa Endothelin antagonistic peptide derivatives
US5382569A (en) * 1991-05-16 1995-01-17 Warner-Lambert Company Endotherlin antagonists
GB9116925D0 (en) * 1991-08-06 1991-09-18 Antisoma Ltd Novel reagent for tumour imaging and therapy
US5550110A (en) * 1992-04-22 1996-08-27 Warner-Lambert Company Endothelin Antagonists II
GB9300048D0 (en) * 1993-01-04 1993-03-03 Wellcome Found Endothelin converting enzyme inhibitors
US6613804B2 (en) 1993-05-20 2003-09-02 Encysive Pharmaceuticals, Inc. Biphenylsulfonamides and derivatives thereof that modulate the activity of endothelin
US6541498B2 (en) 1993-05-20 2003-04-01 Texas Biotechnology Benzenesulfonamides and the use thereof to modulate the activity of endothelin
US6342610B2 (en) 1993-05-20 2002-01-29 Texas Biotechnology Corp. N-aryl thienyl-, furyl-, and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin
US6376523B1 (en) 1994-05-20 2002-04-23 Texas Biotechnology Corporation Benzenesulfonamides and the use thereof to modulate the activity of endothelin
US6030991A (en) * 1993-05-20 2000-02-29 Texas Biotechnology Corp. Benzenesulfonamides and the use thereof to modulate the activity of endothelin
CA2142985A1 (en) * 1993-06-25 1995-01-05 Kenji Shibata Endothelin-antagonizing peptide
US6743783B1 (en) * 1993-12-01 2004-06-01 Marine Polymer Technologies, Inc. Pharmaceutical compositions comprising poly-β-1→4-N-acetylglucosamine
US6063911A (en) * 1993-12-01 2000-05-16 Marine Polymer Technologies, Inc. Methods and compositions for treatment of cell proliferative disorders
US6017953A (en) * 1993-12-28 2000-01-25 Allergan Sales, Inc. Thromboxane ligands
US5786335A (en) * 1995-11-06 1998-07-28 Warner-Lambert Company Sulfhydryl containing peptides for treating vascular disease
US5977117A (en) 1996-01-05 1999-11-02 Texas Biotechnology Corporation Substituted phenyl compounds and derivatives thereof that modulate the activity of endothelin
US5688499A (en) 1996-03-13 1997-11-18 Queen's University At Kingston Antagonism of endothelin actions
US5958905A (en) 1996-03-26 1999-09-28 Texas Biotechnology Corporation Phosphoramidates, phosphinic amides and related compounds and the use thereof to modulate the activity of endothelin
US5804585A (en) 1996-04-15 1998-09-08 Texas Biotechnology Corporation Thieno-pyridine sulfonamides derivatives thereof and related compounds that modulate the activity of endothelin
WO1997043307A1 (en) * 1996-05-16 1997-11-20 Warner-Lambert Company Compounds inhibiting the association of the pdgf receptor and phosphatidylinositol 3-kinase and their use
DE19652374A1 (en) * 1996-12-04 1998-06-10 Schering Ag Use of endothelin conjugates in therapy, new endothelin conjugates, agents containing them, and processes for their preparation
US6030975A (en) * 1997-03-14 2000-02-29 Basf Aktiengesellschaft Carboxylic acid derivatives, their preparation and use in treating cancer
US5783705A (en) * 1997-04-28 1998-07-21 Texas Biotechnology Corporation Process of preparing alkali metal salys of hydrophobic sulfonamides
TR200101905T2 (en) 1997-04-28 2002-06-21 Texas Biotechnology Corporation Sulfanoamides used in the treatment of endothelin related diseases.
AU756136B2 (en) * 1997-06-23 2003-01-02 Queen's University At Kingston Microdose therapy
CA2319207A1 (en) * 1998-01-22 1999-07-29 Regents Of The University Of Minnesota Peptides with .beta.1 integrin subunit dependent cell adhesion modulating activity
US6849712B1 (en) 1998-01-22 2005-02-01 Regents Of The University Of Minnesota Peptides with β1 integrin subunit dependent cell adhesion modulating activity
DK1064382T3 (en) 1998-03-17 2008-12-08 Genentech Inc Homologous polypeptides for VEGF and BMP1
DE19814084B4 (en) * 1998-03-30 2005-12-22 Lts Lohmann Therapie-Systeme Ag D2 agonist-containing transdermal therapeutic system for the treatment of Parkinson's syndrome and process for its preparation
US7566452B1 (en) 1999-05-04 2009-07-28 New York University Cancer treatment with endothelin receptor antagonists
CA2378179A1 (en) * 1999-07-12 2001-01-18 Genentech, Inc. Promotion or inhibition of angiogenesis and cardiovascularization by tumor necrosis factor ligand/receptor homologs
US6686382B2 (en) 1999-12-31 2004-02-03 Encysive Pharmaceuticals Inc. Sulfonamides and derivatives thereof that modulate the activity of endothelin
DK1255829T3 (en) 2000-02-11 2009-12-14 Genentech Inc Hepatocyte growth factor activator inhibitor for use in modulating angiogenesis and cardiovascularization
EP2792747A1 (en) 2000-06-23 2014-10-22 Genentech, Inc. Compositions and methods for the diagnosis and treatment of disorders involving angiogenesis
EP2075253A1 (en) 2000-06-23 2009-07-01 Genentech, Inc. Compositions and methds for the diagnosis and treatment of disorders involving angiogensis
US20030224984A1 (en) * 2001-06-20 2003-12-04 Genentech, Inc. Compositions and methods for the diagnosis and treatment of disorders involving angiogenesis
AU2003234712A1 (en) * 2002-04-12 2003-10-27 Pharmacia Corporation Differentially expressed genes involved in angiogenesis, the proteins encoded thereby, and methods of using the same
US7118549B2 (en) * 2003-10-31 2006-10-10 Codman & Shurtleff, Inc. Shunt system including a flow control device for controlling the flow of cerebrospinal fluid out of a brain ventricle
US8076353B2 (en) 2004-03-15 2011-12-13 Ptc Therapeutics, Inc. Inhibition of VEGF translation
US8076352B2 (en) 2004-03-15 2011-12-13 Ptc Therapeutics, Inc. Administration of carboline derivatives useful in the treatment of cancer and other diseases
EA201200555A1 (en) 2004-03-15 2013-01-30 ПиТиСи ТЕРАПЬЮТИКС, ИНК. DERIVATIVES OF CARBOLINE, USEFUL IN THE INHIBITION OF ANGIOGENESIS
US7767689B2 (en) * 2004-03-15 2010-08-03 Ptc Therapeutics, Inc. Carboline derivatives useful in the treatment of cancer
CA2615393C (en) 2005-07-19 2011-09-20 The Population Council, Inc. Methods and compositions for emergency contraception using endothelin receptor antagonists
ES2552842T3 (en) * 2007-02-19 2015-12-02 Marine Polymer Technologies, Inc. Hemostatic compositions and therapeutic regimens
TW201136942A (en) 2009-12-18 2011-11-01 Idenix Pharmaceuticals Inc 5,5-fused arylene or heteroarylene hepatitis C virus inhibitors
AU2011239466B2 (en) 2010-04-15 2015-01-22 Marine Polymer Technologies, Inc. Anti-bacterial applications of poly -N-acetylglucosamine nanofibers
EP3501284A1 (en) 2011-04-15 2019-06-26 Marine Polymer Technologies, Inc. Treatment of skin deseases with poly-n-acetyl glucosamine nanofibers
TWI577697B (en) * 2013-11-28 2017-04-11 國立清華大學 Salt and protease-resistance of antimicrobial peptide and the manufacture thereof
AU2017273857B2 (en) 2016-06-01 2021-08-19 Athira Pharma, Inc. Compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993016104A1 (en) * 1992-02-12 1993-08-19 Roussel-Uclaf New hexapeptidic derivatives, preparation, method and application as medicaments of said new derivatives
WO1993021219A1 (en) * 1992-04-22 1993-10-28 Warner-Lambert Company Endothelin antagonists ii

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0310887B1 (en) * 1987-10-09 1993-06-02 Takeda Chemical Industries, Ltd. Vasoconstrictor peptide
CA2032559C (en) * 1989-12-28 2001-11-06 Kiyofumi Ishikawa Endothelin antagonistic cyclic pentapeptides
US5382569A (en) * 1991-05-16 1995-01-17 Warner-Lambert Company Endotherlin antagonists
JP3294610B2 (en) * 1991-05-16 2002-06-24 ワーナー−ランバート・コンパニー Endothelin antagonist

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993016104A1 (en) * 1992-02-12 1993-08-19 Roussel-Uclaf New hexapeptidic derivatives, preparation, method and application as medicaments of said new derivatives
WO1993021219A1 (en) * 1992-04-22 1993-10-28 Warner-Lambert Company Endothelin antagonists ii

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 117, no. 13, 28 September 1992, Columbus, Ohio, US; abstract no. 125306v, J. Med. Chem. 1992, 35 17), 3301-3303, CODY WAYNE L. ET AL.: "Design of a functional hexapeptide antagonist of endothelin" page 150; *
George R. Pettit,"Synthetic Peptides", 1970, Van Nostrand Reinhold Company page 149, See page 149, peptides no. 6, 16 *
WO, A1, 9220706 (WARNER-LAMBERT COMPANY), 26 November 1992 (26.09.92) *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998035980A1 (en) * 1997-02-14 1998-08-20 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands of cd4
US6180348B1 (en) 1998-04-20 2001-01-30 Weihua Li Method of isolating target specific oligonucleotide ligands
US10278957B2 (en) 2017-09-11 2019-05-07 Protagonist Therapeutics, Inc. Opioid agonist peptides and uses thereof
US10729676B2 (en) 2017-09-11 2020-08-04 Protagonist Theraputics, Inc. Opioid agonist peptides and uses thereof

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EP0675902A1 (en) 1995-10-11
JPH08504823A (en) 1996-05-28
US5382569A (en) 1995-01-17
MX9308191A (en) 1994-06-30
US5773414A (en) 1998-06-30
JP3494649B2 (en) 2004-02-09
AU5828094A (en) 1994-07-19
CA2146874A1 (en) 1994-07-07
US5641752A (en) 1997-06-24
AU679712B2 (en) 1997-07-10

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