RENIN INHIBITORY PEPTIDES CONTAINING A SUBSTITUTED PHENOXYACETYLE GROUP

Abstract: The present invention provides novel peptides. These peptides are useful as renin inhibitors and have a non-cleavable transition state insert corresponding to the 10,11- position of the renin substrate (angiotensinogen) and a mono- or di-substituted phenoxyacetic acid moiety corresponding to the 8- position of the renin substrate. Renin inhibitors are useful for the diagnosis and control of renin-dependent hypertension, congestive heart failure, renin dependent hyperaldosterism, other renin dependent cardiovascular disorders and ocular disorders. These peptides are also useful as inhibitors of HIV-I protease. Inhibitors of HIV-I protease are useful for treating human acquired immunodeficiency disease syndrome (AIDS).

Description: Renin inhibitory peptides containing a substituted phenoxyacetyl group. DESCRIPTION BACKGROUND OF THE INVENTION The present invention provides novel compounds. More par¬ ticularly, the present invention provides novel peptide analogs. The peptides of the present invention are useful as renin inhibitory peptides and contain a non-cleavable transition state insert corre¬ sponding to the 10,11-position of the renin substrate (angio ensino- gen) and a mono- or di-substituted phenoxyacetic acid moiety corre¬ sponding to the 8-position of the renin substrate. Renin inhibitors are useful for the diagnosis and control of renin-dependent hyperten¬ sion, congestive heart failure, renin dependent hyperaldosterism, and other renin dependent cardiovascular disorders. The peptides of the present invention are also useful as inhibitors of HIV-I protease. Inhibitors of HIV-I protease are useful for treating human acquired immunodeficiency disease syndrome (AIDS) . Renin is an endopeptidase which specifically cleaves a par¬ ticular peptide bond of its substrate (angiotensinogen) , of which the N-terminal sequence in equine substrate is for example: Renin 4 Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser- IA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 as found by L.T. Skeggs, et al. , J. Exper. Med. 106, 439 (1957). Human renin substrate has a different sequence as recently discovered by D.A. Tewkesbury, et al., Biochem. Biophys. Res. Comm. 99, 1311 (1981). It may be represented as follows: Renin 4 -Val-Ile-His- 11 12 13 IB and having the sequence to the left of the arrow (4-) being as designated in formula IA above. Renin cleaves angiotensinogen to produce angiotensin I, which is converted to the potent pressor angiotensin II. A number of an¬ giotensin I converting enzyme inhibitors are known to be useful in the treatment of hypertension. Inhibitors of renin are also useful in the treatment of hypertension. A number of renin-inhibitory peptides have been disclosed. Thus, U.S. patent 4,424,207; European published applications 45,665; 104,041; and 156,322; and U.S. patent application, Serial No. 825,250, filed 3 February 1986; disclose certain peptides with the dipeptide at the 10,11-position containing an isostere bond. A number of statine derivatives stated to be renin inhibitors have been disclosed, see, e.g., European published applications 77,028; 81,783; 114,993; 156,319; and 156,321; and U.S. patents 4,478,826; 4,470,971; 4,479,941; and 4,485,099. Terminal disulfide cycles have also been disclosed in renin inhibiting peptides; see, e.g., U.S. patents 4,477,440 and 4,477,441. Aromatic and aliphatic amino acid residues at the 10,11 position of the renin substrate are disclosed in U.S. patents 4,478,827 and 4,455,303. C-terminal amide cycles are disclosed in U.S. patent 4,485,099 and European published applica¬ tions 156,320 and 156,318. Certain tetrapeptides are disclosed in European publications 111,266 and 77,027. Further, European pub¬ lished application No. 118,223 discloses certain renin inhibiting peptide analogs where the 10-11 peptide link is replaced by a one to four atom carbon or carbon-nitrogen link. Additionally, Holladay, et al. , in "Synthesis of Hydroxyethylene and Ketomethylene Dipeptide Isosteres", Tetrahedron Letters, Vol. 24, No. 41, pp. 4401-4404, 1983 disclose various intermediates in a process to prepare stereo-di- rected "ketomethylene" and "hydroxyethylene" dipeptide isosteric functional groups disclosed in the above noted U.S. Patent No. 4,424,207. Additionally, published European Applications 45,161 and 53,017 disclose amide derivatives useful as inhibitors of angiotensin converting enzymes. Certain dipeptide and tripeptides are disclosed in U.S. patents 4,514,332; 4,510,085; and 4,548,926 as well as in European published applications 128,762; 152,255; and 181,110. Pepstatin derived renin inhibitors have been disclosed in U.S. patent 4,481,192. Retro- inverso bond modifications at positions 10-11 have been disclosed in U.S. patent 4,560,505 and in European published applications 127,234 and 127,235. Derivatives of isosteric bond replacements at positions 10-11 have been disclosed in European published applications 143,746 and 144,209; and U.S. patent application, Serial No. 833,993, filed 27 February 1986. Isosteric bond modifications at positions 11-12 and 12-13 have been disclosed in European published application 179,352. Certain peptides containing 2-substituted statine analogues have been disclosed in European published application 157,409. Certain peptides containing 3-aminodeoxystatine have been disclosed in European published application 161,588. Certain peptides contain¬ ing l-amino-2-hydroxybutane derivatives at positions 10-11 have been disclosed in European published application 172,346. Certain peptides containing l-amino-2-hydroxypropane derivatives at positions 10-11 have been disclosed in European published application 172,347. Certain peptides containing N-terminal amide cycles have been disclosed in U.S. patent application, Serial No. 844,716, filed 27 March 1986. Certain peptides containing dihalostatine have been disclosed in PCT application, Serial No. 000,713, filed 7 April 1986. European published applications 156,322; 114,993; and 118,223; and U.S. patent application, Serial No. 798,459, filed 15 November 1985; U.S. patent application, Serial No. 825,250, filed 3 February 1986; U.S. patent application, Serial No. 833,993, filed 27 February 1986; and U.S. patent application, Serial No. 844,716, filed 27 March 1986; disclose hydroxamic acids or esters at the C-terminus. INFORMATION DISCLOSURE J. Boger, et al., Nature, Vol. 303, 5 May 1983, pages 81-84, discloses novel renin inhibitors containing the amino acid statine as the transition-state analog and containing unsubstituted phenoxy¬ acetic acid as the N-terminal protecting group. J. Boger, et al., "Peptides, Structure and Function, Proceedings of the Ninth American Peptide Symposium, " Deber, CM.; Hruby, V.J.; Kopple, K.D. , Eds.; Pierce Chemical Co., Rockford, IL, 1985, pages 747-750, disclose renin inhibitors containing a novel analog of statine, such as (3S,4S)-4-amino-3-hydroxy-5-cyclohexylpentanoic acid as the transition-state analog and containing unsubstituted phenoxy¬ acetic acid as the N-terminal protecting group. DE 3438545-A1 (an English-language equivalent is U.S. Patent 4,709,010) discloses 3-(2-,3-, or 4-substituted phenyl)-propionyl substituted peptides and unsubstituted-pheriyloxyacetyl substituted peptides having statine or analogs thereof as the transition state insert. DE 3512128-A1 (an English-language equivalent is Australian Patent Application 55302/86) discloses 3-(2-,3- or 4-substituted phenyl)-propionyl substituted peptides and unsubstituted-phenyloxy- acetyl substituted peptides having two transition state inserts, amino-statine and statine, or analogs thereof. It also discloses unsubstituted-phenyloxyacetyl substituted peptides having statine or analogs thereof as the transition state insert and pyrrolidone at the C-terminus. Phenoxyacetyl-His-LVA-Ile-NHOMe is generically disclosed and Phenoxyacetyl-His-LVA-Ile-Amp is specifically disclosed in European published application number 0173481. SUMMARY OF THE INVENTION The present invention particularly provides: A peptide of the formula I wherein Y is a moiety of the formula Y; wherein R50 is (a) chloro, (b) fluoro, (c) methyl, (d) ethyl, (e) isopropyl, (f) methyloxy, or (g) nitro; wherein j is 1 or 2; wherein the phenyl ring of formula Y is mono-substituted by R 5u at the 2- or 3-position or is disubstituted by R50 at the 2,3- position, 2,5-position, 2,6-position, 3,5-position or 3,6-position; provided that when the phenyl ring of formula Y is mono-sub¬ stituted with methyl, R 5 Q is 2-methyl; wherein D9 is a divalent moiety of the formula XL3; wherein ~ _o-~__ is a divalent moiety of the formula XL5; wherein * indicates an asymmetric center which is either in the R or S configuration; wherein G^2 is absent or a divalent moiety of the formula XL4; wherein H^3 is absent; wherein 1^ is absent; wherein Z is (a) -N(R 10 )(0R 14 ) , (b) -0-R 10 , (c) -N(R 4 )R 14 , or (d) C4-C3cyclic amino; wherein R is (a) isopropyl, (b) isobutyl, (c) phenylmethyl, or (d) - CH2) p -C3-C cycloalk l; wherein R^ Is (a) hydrogen, (b) Ci-Csalk l, (c) aryl, (d) C3-C7c cloalkyl, (e) -Het, (f) C 1 -C 3 alkoxy, or (g) Cι-C3alk lthio; wherein R is (a) hydrogen, or (b) -CH(R 3 )R 4 ; wherein R3 is (a) hydrogen, (b) hydroxy, (c) Cι-C 5 alkyl, (d) C3-C7cycloalkyl, (e) aryl, (f) -Het, (g) C^-C3alko y, or (h) C 1 -C 3 alkylthio; wherein R4 at each occurrence is the same or different and is (a) hydrogen, or (b) Csalkyl; wherein R7 is (a) hydrogen, (c) hydroxy, (d) amino C^-C4alkyl- , (e) guanidinyl C^-C3alkyl- , (f) aryl , -6- (g) -Het, αo methylthio, (i) -(CH2) p -C3-C cycloalkyl, or ϋ) amino; wherein Rg is (a) hydrogen, (b) Cχ-C5al yl, (c) hydroxy, (d) aryl, (e) -Het, ( g) - CH2)p-C3-C 7 cycloalkyl; wherein W-j_ is (a-) hydrogen, or (b) C -C5 lkyl; wherein ~-__ is -R or -R2; wherein ~-_ι\ Is (a) C -C oal yl, (b) -(CH 2 ) n -aryl, (c) -(CH 2 ) n -Het, (d) -(CH 2 ) XH .2- l8. (e) -CCH 2 ) n+2 -Rl9. (f) (hydroxy-C -Cgalkyl) , or (g ) (C^-C3alkoxy)C^-Cgalkyl; wherein R^g is (a) amino, (b) mono-, or di-C -C3alkyla__d.no, (c) C4-C cyclic amino, or (d) C4-C c cloal l mino; wherein R^g is (a) aryl, (b) -Het, (c) tri-C^-G3alkylamino, (d) G3-^cycloalkyl, (e) C2-C5 lkenyl, (f) C3-C c cloalken l, (g) hydroxy, (h) C -C3alkox , (i) c l'C3alkanoyloxy, (j) mercapto, αo C -C3alkylthio, (1) -C00H, ( ) -CO-0-Ci-Cgalkyl, (n) -C0-0-CH2-(C 1 -C3alkyl)-N(C 1 -C 3 alkyl)2, (o) -C0-NR 22 R25- (P) guanidyl, (q) cyano, (r) N-cyanoguanidyl, (s) cyanoamino, (t) (hydroxy-C2-C4alkyl amino, (u) di-(hydroxy-C2"C alkyl)amino, or (v) S0 3 H wherein R22 s (a) hydrogen, or (b) C -C3alkyl; wherein R25 is (a) hydrogen, (b) C -C3alkyl, or (c) phenyl-0 -C3alk l; wherein for each occurrence n is independently an integer of zero to five, inclusive; wherein ~ is zero to two, inclusive; wherein aryl is phenyl or naphthyl substituted by zero to 3 of the following . (a) Ci-Csalkyl, (b) hydroxy, (c) C^-C3alkoxy, (d) halo, (e) amino, (f) mono- or di-C^-C3alkylamino, <g) -CHO, (h) -COOH, (i) COOR25, (j) CONHR25, ( ) nitro, (1) mercapto, -8- ( ) Cι-C3al yl hio, (n) Cχ-C3allylsulfinyl, (o) C -C3alkylsulfonyl, (p) -N(R4)-C 1 -G 3 alkylsulfonyl, (q) S0 3 H, (r) S0 2 NH 2 , (s) -CN, or (t) -CH 2 NH 2 ; wherein -Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring, which heterocyclic moiety is substituted with zero to 3 of the following: (i) Cx-Cgalkyl, (ii) hydroxy, (iii) trifluoromethyl, (iv) C^-C 4 alkoxy, (v) halo, (vi) aryl, (vii) aryl-C 1 -C4al-cyl-, (viii) amino, or (ix) mono- or di-CL-C 4 alkylamino; or a carboxy-, amino-, or other reactive group-protected form thereof; or a pharmaceutically acceptable acid addition salt thereof. These compounds are shown in relation to the human renin substrate as follows: 6 7 8 9 10 11 12 13 -His Pro Phe His Leu Val He His- X A 6 B 7 Cg D 9 E 10 F U G 12 H 13 I 14 Z, The present invention provides peptide inhibitors of renin and HIV-I protease which contain a mono- or di-substituted phenoxyacetic acid moiety. This moiety is preferably at the N-terminus of the peptide. The phenyl ring of this moiety is preferably substituted at the 2- or 3- position. Examples of pharmaceutically acceptable acid addition salts include: acetate, adipate, alginate, aspartate, benzoate, ben- zenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsul- fonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane- sulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix (C^-Cj) indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus (C^-C4)al yl refers to alkyl of one to 4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, and isomeric forms thereof. C4-C7c clic amino indicates a monocyclic group containing one nitrogen and 4 to 7 carbon atoms. Examples of (C3-C g)cycloalkyl, which include alkyl-substituted cycloalkyl containing a total of up to 10 total carbon atoms, are cyclopropyl, 2-methylcyclopropyl, 2.2-dimethylcyclopropyl, 2,3- diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methyl- cyclobutyl, 3-propylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, cyclohexyl, cycloheptyl. cyclooctyl, cyclononyl, cyclodecyl and isomeric forms thereof. Examples of aryl include phenyl, naphthyl, (o-, m- , or p-)tolyl, (o-, m-, or p-)ethylphenyl, 2-ethyl-tolyl, 4-ethyl-o-tolyl, 5- ethyl-m-tolyl, (o-, m- , or p-)propylphenyl, 2-propyl-(o- , m- , or p-)tolyl, 4-isopropyl-2,6-xylyl, 3-ρropyl-4-ethylphenyl, (2,3,4- 2,3,6-, or 2,4,5-)trimeth lphenyl, (o-, m- , or p-)fluorophenyl, (o-, m-, or p-trifluoromethyl)phenyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenyl, (o-, m- , or p-)chlorophenyl, 2- chloro-p-tolyl, (3-, 4-, 5- or 6-)chloro-o-tolyl, 4-chloro-2-propyl- phenyl, 2-isopropyl-4-chlorophenyl, 4-chloro-3-fluorophenyl, (3- or 4-)chloro-2-fluorophenyl, (o-, m- , or p-)trifluoro-methylphenyl, (o-, m- , or p-)ethoxyphenyl, (4- or 5-)chloro-2-methoxy-phenyl, and 2,4- dichloro(5- or 6-)methylphenyl, and the like. Examples of -Het include: 2-, 3-, or 4-pyridyl, imidazolyl, indolyl, N in -formyl-indolyl, N in -C 1 -C 5 alkyl-C(0)-indolyl, 1,2,4- triazolyl, 2-, 4-, or 5-pyrimidinyl, 2- or 3-thienyl, piperidinyl, pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidi- nyl, imidazolinyl, imidazolidinyl, pyrazinyl, piperazinyl, pyridazin- yl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolldinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, and benzothienyl. Each of these moieties may be substituted as noted above. As would be generally recognized by those skilled in the art of organic chemistry, a heterocycle as defined herein for -Het would not be bonded through oxygen or sulfur or through nitrogen which is within a ring and part of a double bond. Halo is halogen (fluoro, chloro, bromo, or iodo) or tri- fluoromethyl. Examples of pharmaceutically acceptable cations include: pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations. Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium, and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron are also within the scope of this invention. Phar¬ macologically acceptable amine cations are those derived from primary, secondary, or tertiary amines. The novel peptides herein contain both natural and synthetic amino acid residues. These residues are depicted using standard amino acid abbreviations (see, e.g., IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN) , "Nomenclature and Symbolism for Amino Acids and Peptides," Eur. J. Biochem. 138:9-37 (1984) unless otherwise indicated. The peptides of this invention are useful for treating any medi- cal condition for which it is beneficial to reduce the levels of active circulating renin. Examples of such conditions include renin- dependent hypertension, hypertension, hypertension under treatment with another antihypertensive and/or a diuretic agent, congestive heart failure, renin-dependent hyperaldosterism, angina, post-myo- cardial Infarction, other renin-dependent cardiovascular disorders and ocular disorders. The renin-aπgiotension system may play a role in maintenance of intracellular homeostasis: see Clinical and Experimental Hypertension, 86, 1739-1742 (1984) at page 1740 under Discussion. The peptides of the present invention are preferably orally administered to humans to effect renin inhibition for the purpose of favorably affecting blood pressure. For this purpose, the compounds are administered from 0.1 mg to 1000 mg per kg per dose, administered from 1 to 4 times daily. Equivalent dosages for other routes of administration are also employed. For example, renin-associated hypertension and hyperaldosteronism are effectively treated by the administration of from 0.5 to 100 milligrams of the compound per kilogram of body weight per day. The exact dose depends on the age, weight, and condition of the patient and on the frequency and route of administration. Such variations are within the skill of the practitioner or can readily be determined. The peptides of the present invention to effect renin inhibition may be in the form of pharmaceutically acceptable salts both those which can be produced from the free bases by methods well known in the art and those with which acids have pharmacologically acceptable conjugate bases. Conventional forms and means for administering renin-inhibiting compounds may be employed and are described, e.g., in U.S. Patent No. 4,424,207 which is incorporated by reference herein. Likewise, the amounts disclosed in the U.S. Patent No. 4,424,207 are examples applicable to the peptides of the present invention. The peptides of the present invention to effect renin inhibition are preferably orally administered in the form of pharmacologically acceptable acid addition salts. Preferred pharmacologically accept¬ able salts for oral administration include the citrate and aspartate salts, although any pharmacologically acceptable salt is useful in this invention, including those listed above. These salts may be in hydrated or solvated form. For renin inhibition, the peptides of the present invention may be administered topically, parenterally, by inhalation spray, or rectally in dosage unit formulations containing conventional non- toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the peptides of the -12- invention are effective in the treatment of humans. The pharmaceutical compositions of the peptides of the present invention for renin inhibition may be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated accord¬ ing to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenteral- ly-acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or digly- cerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The peptides of this invention for renin inhibition may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. The peptides of this invention for renin inhibition may be administered in combination with other agents used in antihyperten- sive therapy such as diuretics, α and/or ^-adrenergic blocking agents, CNS-acting agents, adrenergic neuron blocking agents, vasodilators, angiotensin I converting enzyme inhibitors, and the like as described for example in published European patent applica- tion 156,318. For example, the peptides of this invention can be given in combination with such compounds or salt or other derivative forms thereof as: Diuretics: acetazolamide; amiloride; bendroflumethiazide; benzthia- zide; bumetanide; chlorothiazide; chlorthalidone; cyclothiazide; ethacrynic acid; furosemide; hydrochlorothiazide; hydroflumethiazide; indacrinone (racemic mixture, or as either the (+) or (-) enantiomer alone, or a manipulated ratio, e.g., 9:1 of said enantiomers, respec- tively) ; metolazone; methyclothiazide; muzolimine; polythiazide; quinethazone; sodium ethacrynate; sodium nitroprusside; spironol- actone; ticrynaten; trimaterene; trichlormethiazide; α-Adrenergic Blocking Agents: dibenamine; phentolamine; phenoxyben- za ine; prazosin; tolazoline; iS-Adrenergic Blocking Agents: atenolol; metoprolol; nadolol; propranolol; timolol; ((±)-2-[3- (tert-butylamino) -2-hydroxypropoxy] -2-furananilide) (ancarolol) ; (2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran HCl)(befun- olol) ; ((±) -1-(isopropylamino)-3-(p-(2-cyclopropylmethoxyethyl)-phenoxy)-2- propranol HCl) (betaxolol) ; (1-[(3,4-dimethoxyphenethyl)amino] -3-(m-tolyloxy)-2-propanol HCl) (be- vantolol) ; (( (±)-1- (4-((2-isopropoxyethoxy)methyl)phenoxy)-3-isopropylamino-2- proρanol)fumarate) (bisoprolol) ; (4-(2-hydroxy-3-[4-(phenoxymethyl)-piperidino] -propoxy)-indole) ; (carbazolyl-4-oxy-5,2-(2-methoxyphenoxy)-ethylamino-2-propanol) ; (l-((l,l-dimethylethyl)amino)-3-((2-methyl 'H-indol-4-yl)oxy)-2-pro- panol benzoate) (bopindolol) ; (1- (2-exobicyclo[2.2.1]-hept-2-ylphenoxy)-3- [(1-methylethyl)-amino] - 2-propanol HCl) (bornaprolol) ; (o- [2-hydroxy-3-[(2-indol-3-yl-1,1-dimethylethyl)-amino]propoxy]ben- zonitrile HCl) (bucindolol) ; (α-[(tert.butylamino)methyl] -7-ethyl-2-benzofuranmethanol) (bufur- alol) ; (3 - [ 3 - acetyl -4- [ 3 - (tert . butylamino) - 2 -hydroxypropyl] -phenyl] -1 , 1- diethylurea HCl) (celiprolol) ; ( (±) -2 - [ 2- [3- [ (1 , 1-dimethylethyl) amino] -2-hydroxypropoxy ] phenox ] -N- methylacetamide HCl) (cetamolol) ; (2-benzimidazolyl-ρhenyl(2-isopropylaminopropanol) ) ; ( (±) - 3 ' - acetyl -4 ' - (2 -hydroxy- 3 - isopropylaminopropoxy) -acetanilide HCl) (diacetolol) ; (methyl-4- [ 2 -hydroxy- 3 - [ (l -methylethyl) aminopropoxyl ] ] -benzene- propanoate HCl) (esmolol) ; (erythro-DL-l- (7-methylindan-4-yloxy) -3-isopropylaminobutan-2-ol) ; (1-(tert.butylamino)-3- [0-(2-propynyloxy)phenoxy] -2-propanol (pargo- -14- lol) ; (1-(tert.butylamino)-3-[o-(6-hydrazino-3-pyridazinyl)phenoxy]-2- propanol diHCl) (prizidilol) ; ((-) -2-hydroxy-5-[ (R) -1-hydroxy-2- [(R) -(l-methyl-3-phenylpropyl)- amino]ethyl]benzamide); (4-hydroxy-9- [2-hydroxy-3- (isopropylamino) -propoxy]-7-methyl-5H- furo[3,2-g] [1]-benzoρyran-5-one) (iprocrolol) ; ( (-) -5- (tert.butylamino)-2-hydroxypropoxy] -3,4-dihydro-l- (2H) - naphthalenone HCl) (levobunolol) ; (4-(2-hydroxy-3-isopropylamino-propoxy)-l,2-benzisothiazole HCl) ; (4- [3- (tert.butylamino)-2-hydroxypropoxy] -N-methylisocarbostyril HCl); ((±)-N-2- [4- (2-hydroxy-3-isopropylaminopropoxy)phenyl]ethyl-N' - isopropylurea) (pafenolol) ; (3-[[(2-trifluoroacetamido)ethyl]amino]-l-phenoxypropan-2-ol) ; (N-(3-(o-chlorophenoxy)-2-hydroxypropyl)-N'-(4' -chloro-2,3-dihydro-3- oxo-5-pyridazin 1)ethylenedlamine) ; ((±)-N-[3-acetyl-4-[2-hydroxy-3-[(l-methylethyl)amino]propoxyphenyl]- butanamlde) (acebutolol); ((±)- '-[3-( ert-butylamino)-2-hydroxypropox ]spiro[cyclohexane-1,2'- indan]-l'-one) (spirendolol) ; (7-[3-[ [2-hydroxy-3-[(2-methylindol-4-yl)oxylpropyl]amino]butyl]thio- phylline) (teoprolol) ; ((±)-1-tert.butylamino-3-(thiochroman-8-yloxy)-2-propanol) (tertato- lol) ; ((±)-1-tert.butylamino-3-(2,3-xylyloxy)-2-propanol HCl) (xibenolol) ; (8-[3-(tert.butylamino)-2-hydroxypropoxy]-5-methylcoumarin) (bucumo- - lol); (2-(3-(tert.butylamino)-2-hydroxy-propoxy)benzonitrile HCl) (bunitro- lol) ; ((±)-2'-[3-(tert-butylamino)-2-hydroxypropoxy-5' -fluorobutyrophenone) (butofilolol) ; (l-(carbazol-4-yloxy)-3-(isopropylamino)-2-propanol) (earazolol) ; (5-(3-tert.butylamino-2-hydroxy)propoxy-3,4-dihydrocarbotyril HCl) (carteolol) ; (1-(tert.butylamino)-3-(2,5-dichlorophenoxy)-2-propanol) (clorano- lol) ; (l-(inden-4(or 7)-yloxy)-3-(isopropylamino)-2-propanol HCl) (indeno- lol); (l-isopropylamino-3-[(2-methylindol-4-yl)oxy] -2-propanol) (mepindo- lol); (l-(4-acetoxy-2, 3 , 5- trimethylphenoxy)-3-isopropylaminopropan-2-ol) (metipranolol) ; (l-( isopropylamino) -3- (o-methoxyphenoxy) -3- [ (l-methylethyl)amino] -2- propanol) (moprolol) ; ((1-tert. butylamino) -3- [ (5 , 6 ,7 , 8-tetrahydro-cis-6 , 7-dihydroxy-l- naphthyl)oxy] -2-propanol) (nadolol) ; ((S)-l-(2-cyclopentylphenoxy)-3- [ (1,1 -dime thylethyl) amino] -2-proρanol sulfate (2:1)) (penbutolol) ; (4' - [l-hydroxy-2-(amino)ethyl]methanesulfonanilide) (sotalol) ; (2-methyl-3- [4- (2 -hydroxy- 3- tert. butylaminopropoxy) phenyl] -7-methoxy- isoquinolin-1- (2H) -one) ; (l-(4-(2- (4- fluorophenyloxy)ethoxy) phenoxy) -3- isopropylamino- 2- propanol HCl) ; ((-)-p-[3-[(3,4-dimethoxyphenethyl)amino] -2-hydroxypropoxy] -β-methyl- cinnamonitrile) (pacrinolol) ; ((±)-2-(3' -tert.butylamino-2' -hydroxypropylthio)-4-(5'-carbamoyl-2' - thienyl)thiazole HCl) (arotinolol) ; ((±) -1- [p- [2-(cyclopropylmethoxy)ethoxy]phenoxy] -3-(isopropylamino)- 2-propanol) (cicloprolol) ; ((±) -1- [ (3-chloro-2-methylindol-4-yl)oxy] -3- [(2-phenoxyethyl)amino] - 2-propanol) (indopanolol) ; ((±)-6-[[2-[ [3-(p-butoxyphenoxy)-2-hydroxypropyl]amino]ethyl]amino] - 1,3-dimethyluracil) (pirepolol) ; (4-(cyclohexylamino)-1-(1-naphtholenyloxy)-2-butanol) ; (1-phen l-3-[2-[3-(2-cyanophenoxy)-2-hydroxypropyl]aminoethyl]hydan- toin HCl) ; (3,4-dihydro-8- (2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy-2H-1- benzopyran) (nipradolol) ; Angiotensin I Converting Enzyme Inhibitors: l-(3-mercapto-2-methyl-l-oxopropyl)-L-proline (captopril) ; (1- (4-ethoxycarbonyl-2 ,4(R,R) -dimethylbutanoyl)indoline-2(S) -car- boxylic acid) ; (2- [2- [ (1- (ethoxycarbonyl) -3-phenyl-propyl]amino] -1-oxopropyl] - l,2,3,4-tetrahydro-3-isoquinoline carboxylic acid); ((S)-l-[2- [(1- (ethoxycarbonyl) -3-phenylpropyl] amino] -l-oxopropyl]oc- -16- tahydro-lH-indole-2-carboxylic acid HCl); (N-cyclopentyl-N-(3- (2,2-dimethyl-l-oxopropyl)thiol-2-methyl-l-oxo- propyl)glycine) (pivalopril) ; ((2R,4R) -2-(2-hydroxyρhenyl)-3-(3-mercaptopropionyl)-4-thiazolidine- carboxylic acid); (1-(N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl)-cis,syn-octa- hydroindol-2(S)-carboxylic acid HCl); ((-)-(S)-1-[(S)-3-mercapto-2-methyl-1-oxopropyl]indoline-2-carboxylic acid) ; (_1(S) ,4S] -l-[3-(benzoylthio)-2-methyl-l-oxopropyl]-4-phenylthio-L- proline; (3-([l-ethoxycarbonyl-3-phenyl-(IS)-propyl]amino)-2,3,4,5-tetrahydro- 2-oxo-l-(3S)-benzazepine-l-acetic acid HCl); (N-(2-benzyl-3-mercaptopropanoyl)-S-ethyl-L-cysteine) and the S- methyl analogue; (N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate) (enalapril) ; N-[1-(S)-carboxy-3-phenylpropyl]-L- lanyl-1-proline; V-~[1-(S)-carboxy-3-phenylpropyl] -L-lysyl-L-proline (lysinopril) ; Other Antihyper ensive Agents: aminophylline; cryptenamine acetates and tannates; deserpidine; meremethoxylline procaine; pargyline; tri- methaphan camsylate; and the like, as well as admixtures and combina¬ tions thereof. Typically, the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly. Coadministration Is most readily accomplished by combining the active ingredients Into a suitable unit dosage form containing the proper dosages of each. Other methods of coad- ministration are, of course, possible. Thus, the novel peptides of the present invention possess an excellent degree of activity in treating renin-associated hyperten¬ sion and hyperaldosteronism. The peptides of the present invention are also useful as novel HIV-I protease inhibitory peptide analogues. It has been recognized that human immunodeficiency virus (HIV, also known as HTLV-III or LAV) is the causative agent in human acquired immunodeficiency disease syndrome (AIDS), P.Duesberg, Proc. Natl. Acad. Sci. USA, 86, 755 (1989). HIV contains a retro viral encoded protease, HIV-I protease, that cleaves the fusion polypep- tides into the functional proteins of the mature virus particle, E.P. Lillehoj, et al., J. Virology, 62, 3053 (1988); C. Debuck, et al. , Proc. Natl. Acad. Sci, 84, 8903 (1987). This enzyme, HIV-I protease, has been classified as an aspartyl protease and has a demonstrated homology to other aspartyl proteases such as renin, L.H. Pearl, et al., Nature, 329, 351 (1987); I. Katoh, et al., Nature, 329, 654 (1987). Inhibition of HIV-I protease blocks the replication of HIV and thus is useful in the treatment of human AIDS, E.D. Clerq, J. Med. Chem. , 29, 1561 (1986). Inhibitors of HIV-I protease are useful in the treatment of AIDS. Pepstatin A, a general inhibitor of aspartyl proteases, has been disclosed as an inhibitor of HIV-I protease, S. Seelmeier, et al. , proc. Natl. Acad. Sci. USA, 85, 6612 (1986). Other substrate derived inhibitors containing reduced bond isosteres or statine at the scissle position have also been disclosed, M.L. Moore, et al., Bio- chem. Biophys. Res. Commun. , 159, 420 (1989); S. Billich, et al., J. Biol. Chem., 263, 17905 (1988); Sandoz, D.E. 3812-576-A. Thus, the peptides of the present invention are useful for treating human acquired immunodeficiency disease syndrome (AIDS) , using dosages, forms and modes of administration equivalent to those described above. Exact dosages, forms and mode of administration would be apparent to one of ordinary skill in the art such as a physician or pharmacologist. The compounds of the present invention are prepared as depicted in the charts and as described more fully in the Preparations and Examples. The process of the present invention is more completely under- stood by reference to the charts below. In these charts, the variables are as defined above. CHART A Chart A describes the preparation of the renin inhibitory peptides of the present invention. In Chart A, X is chloro, fluoro, methyl, ethyl, isopropyl, methyloxy, or nitro. The compound of formula A-l is coupled with HCIΗ2N-OCH3 using triethylamine and diethylphosphoryl cyanide in methylene chloride to give the compound of formula A-2. -18- The compound of formula A-2 is first treated with trifluoro- acetic acid in methylene chloride to remove the Boc- protecting group and then coupled with Boc-Leuψ[CH0-TBS-CH 2 ]Val-0H using diethyl- phosphoryl cyanide and triethylamine to give the compound of formula A-3. The compound of formula A-3 is first treated with trifluoro- acetic acid in methylene chloride to remove the Boc- protecting group and then coupled with Boc-His(Tos)OH using diethylphosphoryl cyanide and triethylamine to give the compound of formula A-4. The compound of formula A-4 is first treated with trifluoro- acetic acid and methylene chloride to remove the Boc- protecting group and then coupled with X-POA-para-nitrophenyl ester (ONp) using dimethylformamide and triethylamine to give the compound of formula A-5. The compound of formula A-5 is treated with sodium ethoxide in ethanol to remove the Tos- protecting group and to give the renin inhibitory peptide of formula A-6. Using di-substituted-POA-ONp, the compounds of the present invention wherein the phenoxyacetic acid moiety is disubstituted may be prepared by following procedures analogous to those described in Chart A. Boc-His(Tos)-LVA(OTBS)-He-Amp, which is an intermediate to some of the compounds of the present invention, is prepared as described in the following references: TenBririk, R.E. ; Pals, D.T.; Harris, D.W. ; Johnson, G.A. , J. Med. Chem., 1988, 31:671; and Thaisrivongs, S.; Pals, D.T. ; Harris, D.W. ; Kati, W.M. ; Turner, S.R. , J. Med. Chem., 1986, 29:2088. Generally, the renin inhibiting polypeptides may be prepared by either polymer assisted or solution phase peptide synthetic procedu- res analogous to those described hereinafter or to those methods known in .the art. Appropriate protecting groups, reagents, and solvents for both the solution and solid phase methods can be found in "The Peptides: Analysis, Synthesis, and Biology," Vols. 1-5, eds. E. Gross and T. Meienhofer, Academic Press, NY, 1979-1983; "Solid Phase Peptide Synthesis", J.M. Stewart and J.D. Young, Pierce Chemical Company, Rockford, 111., 1984; "The Practice of Peptide Synthesis", M. Bodansky and A. Bodansky, Springer-Verlag, New York, 1984; "The Principles of Peptide Synthesis", M. Bodansky, Springer- Verlag, New York, 1984. Thus, for example, the carboxylic moiety of ϊ -t-butyloxycarbonyl (Boc)-substituted amino acid derivatives having suitable side chain protecting groups, if necessary, may be condensed with the amino functionality of a suitably protected amino acid, peptide or polymer-bound peptide using a conventional coupling protocol such as dicyclohexylcarbodiimide (DCC) and 1-hydroxyben- zotriazole (HOBT) or diethylphosphoryl cyanide (DEPC) and triethylam¬ ine (Et3N) in methylene chloride or dimethylformamide. Following coupling reaction completion, the N α -Boc moiety may be selectively removed with 50% trifluoroacetic acid with or without 2% anisole (v/v) in methylene chloride. Neutralization of the resultant trifluoroacetate salt may be accomplished with 10% diisopropyl- ethylamine or sodium bicarbonate in methylene chloride. In the case of polymer-assisted peptide synthesis, this stepwise, coupling strategy may be partially or completely automated to provide the desired peptide-polymer intermediates. Protecting group removal may be accomplished while the peptide is bound to the polymeric support. Methanolysis or other cleavage methodologies known in the art may be used to cleave the peptide from its polymeric support. Variations in the above description for starting materials, reactants, reaction conditions and required protecting groups to obtain other such N-alkylated compounds are known to an ordinarily skilled chemist or are readily available in the literature. The compounds of the present invention may be in either free form or in protected form at one or more of the remaining (not previously protected) peptide, carboxyl, amino, hydroxy, or other reactive groups. The protecting groups may be any of those known in the polypeptide art. Examples of nitrogen and oxygen protection groups are set forth in T.W. Greene, Protecting Groups in Organic Synthesis, Wiley, New York, (1981); J.F.W. McOmie, ed. Protective Groups in Organic Chemistry, Plenum Press (1973); and J. Fuhrhop and G. Benzlin, Organic Synthesis, Verlag Chemie (1983). Included among the nitrogen protective groups are t-butoxycarbonyl (Boc) , ben- zyloxycarbonyl, acetyl, allyl, phthalyl, benzyl, benzoyl, trityl and the like. The following compounds of the present invention are preferred: 2-Methylphenoxyacetyl-His-LVA-Ile-NH0CH3, 2-Methylphenoxyacetyl-His- LVA-Ile-Amp, 2-Fluorophenoxyacetyl-His-LVA-Ile-NH0CH3, 3-Fluorophen- oxyacetyl-His-LVA-Ile-NHOCH 3 , 2-Ethylphenoxyacetyl-His-LVA-Ile- NHOCH3 and 2-Methylphenoxyacetyl-His-CVA-Ile-NH0CH 3 . The most preferred compounds are 2-Methylphenoxyacetyl-His-LVA-Ile-NHOCH3, 2- Methylphenoxyacetyl-His-LVA-Ile-Amp and 2-Methylphenoxyacetyl-His- CVA-Ile-NH0CH 3 . DESCRIPTION OF THE PREFERRED EMBODIMENTS The following Preparations and Examples illustrate the present invention. In the Preparations and Examples below and throughout this document: ■ 1-NMR is nuclear magnetic resonance Amp is 2-(aminomethyl)pyridinyl Bn is benzylester BOC is t-butoxycarbonyl Bz is benzyl C is centigrade Cbz is benzyloxycarbonyl CDCI3 is deuteriochloroform Celite is a filter aid CVA is ChaΦ[CH(OH)CH 2 ]Val DCC is dicyclohexylcarbodiimide DEPC is diethylphosphoryl cyanide EtOAc is ethyl acetate FTrp is N itl -formyl-Trp g is grams His is histldine HOBT is 1-hydroxybenzotriazole HPLC is high performance liquid chromatography Iba is isobutylamine He is isoleucine IR is infrared spectra LVA is LeuτKCH(0H)CH 2 )Val with the S configuration at C4 (the hydroxyl-bearing carbon atom) . M or mol is mole Me is methyl mln is minute ml is milliliter MPLC is medium pressure liquid chromatography MS is mass spectroscopy Ph is phenyl Phe is phenylalanine RIP means a compound having the formula H-Pro-His-Phe-His-Phe- Phe-Val-Tyr-Lys-0H.2(CH 3 C(0)0H).XH 2 0 which is a known renin-inhibit¬ ing peptide. Sta is statine TBS is tert-butyldimethylsilyl TEA is triethylamine TFA is trifluoroacetic acid THF is tetrahydrofuran TLC is thin layer chromatography Tos is p-toluenesulfonyl TsOH is p-toluenesulfonic acid. The wedge-shape line indicates a bond which extends above the plane of the paper relative to the plane of the compound thereon. The dotted line indicates a bond which extends below the plane of the paper relative to the plane of the compound thereon. Preparations 1-6 General Procedure for the Synthesis of Sub¬ stituted Phenoxyacetic Acids A slurry of the requisite phenol, chloroacetic acid, and sodium hydroxide in water (100 ml) is refluxed in air for 4 hr, cooled to room temperature, and washed with diethyl ether. The aqueous layer is cooled to 0 β C, acidified to pH-2, and extracted with dichloro- methane. The dichloromethane extracts are combined, dried with anhydrous magnesium sulfate, and concentrated. The resulting solid is recrystallized from ethyl acetate/hexane to give the desired purified acid. 1) Physical characteristics of 2-Fluorophenoxyacetic acid are as follows: Yield: 1.97 g. Mp: 137-9°C. MS (El, m/z): 170, 112, 125, 95. IR (mull, cm -1 ): 2807, 1736, 1712, 1504, 1431, 1260. Anal. Found: C, 56.56; H, 4.16. 2) Physical characteristics of 3-Fluorophenoxyacetic acid are as follows: -22- Yield: 2.18 g. Mp: 113-5°C. MS (El, m/z): 44, 125, 170, 95, 94. IR (mull, cm -1 ): 1723, 1612, 1492, 1294, 1229. 5 Anal. Found: C, 56.31; H, 4.30. 3) Physical characteristics of 2,6-Dimethylphenoxyacetic acid are as follows; Yield: 3.7 g. MS (El, m/z): 121, 180, 77, 91, 105. 10 IR (mull, cm' 1 ): 1732, 1710, 1263, 1199, 1066. Anal. Found: C, 66.78; H, 7.04. 4) Physical characteristics of 2-Ethylρhenoxyacetic acid are as follows: Yield: 2.47 g. 15 Mp: 137-9 β C. MS (El, m/z): 121, 107, 180, 77, 91. IR (mull, cm" 1 ): 1740, 1706, 1496, 1426, 1240. Anal. Found: C, 66.90; H, 6.93. 5) Physical characteristics of 2-Propylphenoxyacetic acid are 20 as follows: Yield: 2.62 g. Mp: 101-3 β C. MS (El, m/z): 107, 165, 194, 91, 57. IR (mull, cm" 1 ): 1741, 1706, 1498, 1239, 1136. 25 Anal. Found: C, 68.22; H, 7.44. 6) Physical characteristics of 2-Isopropylphenoxyacetic acid are as follows: Yield: 5.29 g. Mp: 131-3 β C. 30 MS (El, m/z): 179, 133, 194, 105, 91. IR (mull, cm "1 ): 1741, 1707, 1492, 1426, 1235. Anal. Found: C, 68.53; H, 7.20. Preparation 7 4-Nitrophenyl 3-Fluorophenoxyacetate A slurry of 3-fluorophenoxyacetic acid of Preparation 2 (1.02 g) 35 and 4-nitrophenol (0.84 g) in tetrahydrofuran (15 ml) is stirred at 0°C and a solution of dicyclohexylcarbodiimide (1.38 g) in tetrahy¬ drofuran (10 ml) is added via syringe. The reaction mixture is stirred at 0°C for 40 min, and allowed to warm to room temperature and stir overnight. The reaction mixture is filtered and the filtrate concentrated to give a yellow solid. The material is recrystallized from 95% ethanol/1% acetic acid to give 1.14 g of the title product as a white solid. Physical characteristics are as follows: MS (El, m/z): 125, 95, 97, 291, 152. IR (mull, cm -1 ): 3327, 3117, 3081, 1785, 1594, 1522, 1349, 1160. NMR (CDC1 3 , 5): 8.29, 7.33, 7.30-7.25, 6.78-6.69, 4.91. Preparation 8 4-Nitrophenyl 2-Fluorophenoxyacetate A slurry of 2-fluorophenoxyacetic acid of Preparation 1 (1.08 g) and 4-nitrophenol (0.88 g) in tetrahydrofuran (15 ml) is stirred at 0°C and a solution of dicyclohexylcarbodiimide (1.45 g) in tetrahy¬ drofuran (10 ml) is added via syringe. The reaction mixture is stirred at 0°C for 40 min, and allowed to warm to room temperature and stir overnight. The reaction mixture is filtered and the filtrate concentrated to give a yellow solid. The material is recrystallized from 95% ethanol/1% acetic acid to give 1.27 g of the title product as a white solid. Physical characteristics are as follows: MS (El, m/z): 125, 95, 97, 291, 152. IR (mull, cm -1 ): 3113, 3079, 1778, 1526, 1509, 1345, 1176, 1170. NMR (CDCI3, 5): 8.28, 7.32, 7.18-7.00, 4.99. Preparation 9 4-Nitrophenyl 2,6-Dimeth lphenoxyacetate A slurry of 2,6-dimethylphenoxyacetic acid of Preparation 3 (1.03 g) and 4-nitrophenol (0.80 g) in tetrahydrofuran (15 ml) is stirred at 0°C and a solution of dicyclohexylcarbodiimide (1.31 g) in tetrahydrofuran (10 ml) is added via syringe. The reaction mixture is stirred at 0°C for 45 min, and allowed to warm to room temperature and stir overnight. The reaction mixture is filtered and the filtrate concentrated to give a yellow solid. The material is recrystallized from 95% ethanol/1% acetic acid to give 1.47 g of the title product as a white solid. Physical characteristics are as follows: MS (El, m/z): 135, 105, 301, 77, 121. IR (mull, cm -1 ): 3117, 3084, 1790, 1522, 1349, 1212, 1150, 1068. NMR (CDCI3, 5) : 8.31, 7.38, 7.07-6.96, 4.40, 2.36. Preparation 104-Nitrophenyl 2-Methylphenoxyacetate A slurry of 2-meth lphenoxyacetic acid, which is commercially available, (0.69 g) and 4-nitrophenol (0.58 g) in tetrahydrofuran (5 ml) is stirred at 0°C and a solution of dicyclohexylcarbodiimide (0.95 g) in tetrahydrofuran (5 ml) is added via syringe. The reaction mixture is stirred at 0 β C for 30 min, and allowed to warm to room temperature and stir overnight. The reaction mixture is filtered and the filtrate concentrated to give a yellow oil. Attempts to recrystallize the material were unsuccessful and the material was utilized in crude form. Preparation 114-Nitrophenyl 3-Methylphenoxyacetate A slurry of 3-methylphenoxyacetic acid, which is commercially available, (0.78 g) and 4-nitrophenol (0.65 g) in tetrahydrofuran (5 ml) Is stirred at 0 β C and a solution of dicyclohexylcarbodiimide (1.10 g) in tetrahydrofuran (5 ml) Is added via sjrringe. The reaction mixture is stirred at 0 β C for 30 min, and allowed to warm to room temperature and stir overnight. The reaction mixture is filtered and the filtrate concentrated to give a yellow solid. Attempts to recrystallize the material were unsuccessful and the material was utilized in crude form. Preparation 12 4-Nitrophenyl 2-Ethylphenoxyacetate A slurry of 2=ethylphenoxyacetic acid of Preparation 4 (1.10 g) and 4-nitrophenol (0.85 g) in tetrahydrofuran (15 ml) is stirred at 0°C and a solution of dicyclohexylcarbodiimide (1.40 g) in tetrahy¬ drofuran (10 ml) is added via syringe. The reaction mixture is stirred at 0 β C for 30 min, and allowed to warm to room temperature and stir for 72 hr. The reaction mixture is filtered and the filtrate concentrated to give a yellow solid. The material is recrystallized from 95% ethanol/1% acetic acid to give 0.96 g of the title product as a white solid. Physical characteristics are as follows: MS (El, m/z): 135, 56, 99, 55, 105, 310. IR (mull, cm "1 ): 3326, 3077, 1785, 1522, 1492, 1348, 1208, 1122. NMR (CDC1 3 , : 8.28, 7.31, 7.26-6.80, 4.94, 2.74, 1.24. Preparation 13 4-Nitrophenyl 2-Methoxyphenoxyacetate A slurry of 2-methoxyphenoxyacetic acid, which is commercially available, (1.10 g) and 4-nitrophenol (0.84 g) in tetrahydrofuran (15 ml) is stirred at 0°C and a solution of dicyclohexylcarbodiimide (1.34 g) in tetrahydrofuran (10 ml) is added via syringe. The reaction mixture is stirred at 0°C for 30 min, and allowed to warm to room temperature and stir for 72 hr. The reaction mixture is filtered and the filtrate concentrated to give a yellow solid. The material is recrystallized from 95% ethanol/1% acetic acid to give 1.03 g of the title product as a white solid. Physical characteristics are as follows: MS (El, m/z): 137, 122, 77, 303, 92. IR (mull, cm" 1 ): 3084, 3018, 1767, 1531, 1344, 1208, 1159, 1131. NMR (CDC1 3 , 5): 8.27, 7.31, 7.07-6.90, 4.97, 3.91. Preparation 144-Nitrophenyl 2-Isopropylphenoxyacetate A slurry of 2-isopropylphenoxyacetic acid of Preparation 6 (1.14 g) and 4-nitrophenol (0.86 g) in tetrahydrofuran (15 ml) is stirred at 0 β C and a solution of dicyclohexylcarbodiimide (1.41 g) in tetrahydrofuran (10 ml) is added via syringe. The reaction mixture is stirred at 0°C for 30 min, and allowed to warm to room temperature and stir overnight. The reaction mixture is filtered and the filtrate concentrated to give a yellow solid. The material is recrystallized from 95% ethanol/1% acetic acid to give 0.97 g of the title product as a white solid. Physical characteristics are as follows: MS (El, m/z): 315. IR (mull, cm -1 ): 3395, 3038, 1786, 1711, 1524, 1450, 1351, 1142. NMR (CDCI3, 5): 8.28, 7.32, 7.29-6.76, 4.94, 3.49-3.40, 1.26. Preparation 15 4-Nitrophenyl 2-Chlorophenoxyacetate A slurry of 2-chlorophenoxyacetic acid, which is commercially available, (0.61 g) and 4-nitrophenol (0.45 g) in tetrahydrofuran (10 ml) is stirred at 0°C and a solution of dicyclohexylcarbodiimide (0.74 g) in tetrahydrofuran (5 ml) is added via syringe. The reaction mixture is stirred at 0°C for 30 min, and allowed to warm to room temperature and stir for 72 hr. The reaction mixture is filtered and the filtrate concentrated to give a yellow solid. The material is recrystallized from 95% ethanol/1% acetic acid to give the title product as a white solid. Physical characteristics are as follows: MS (El, m/z): 141, 111, 113, 143, 75, 307. IR (mull, cm -1 ): 3117, 3086, 1771, 1521, 1485, 1346, 1205, 1155. NMR (CDC1 3 , 5): 8.28, 7.33, 7.44-6.96, 5.00. Preparation 164-Nitrophenyl 3-Chlorophenoxyacetate A slurry of 3-chlorophenoxyacetic acid, which is commercially available, (0.56 g) and 4-nitrophenol (0.42 g) in tetrahydrofuran (10 ml) is stirred at 0 β C and a solution of dicyclohexylcarbodiimide (0.68 g) in tetrahydrofuran (5 ml) is added via syringe. The reaction mixture is stirred at 0°C for 30 min, and allowed to warm to room temperature and stir for 72 hr. The reaction mixture is filtered and the filtrate concentrated to give a yellow solid. The material is recrystallized from 95% ethanol/1% acetic acid to give the title product as a white solid. Physical characteristics are as follows: MS (El, m/z): 141, 111, 143, 113, 307. IR (mull, cm" 1 ): 3118, 3082, 1780, 1526, 1216, 1088. NMR (CDCI3, δ): 8.29, 7.33, 7.30-6.86, 4.91. Preparation 17 Boc-His(Tos)-LVA(OTBS)-He-NHOCH 3 . A. Boc-Ile-NH0CH 3 A slurry of Boc-He-OH (2.66 g) , O-methylhydroxylamine hydro- chloride (1.16 g) , and dieth lphosphoryl cyanide (2.25 g) in di- chloromethane (30 ml) is stirred at CG under argon and triethylamine (5.31 ml) added via syringe over a period of 5 min. The reaction mixture is stirred at 0°C for 1 hr and allowed to warm to room temperature and stir overnight. The reaction mixture is poured into water, extracted with ethyl acetate, washed with brine, dried (anhydrous sodium sulfate) and concentrated. The solid residue is recrystallized from diethyl ether to give the title intermediate (1.9 g) as a fluffy white solid. Physical characteristics are as follows: Mp 119-121°C. [α] D 25 -37.5° (c 0.64, MeOH) . IR (cm -1 , mull) 3330, 3236, 1669, 1524, 1500. MS (CI, isobutane, m/z) 205, 261 [M+H] + , 130, 262, 206. Anal. Found: C.55.22; H.9.42; N.10.76. B. Boc-LVA(0TBS)-Ile-NH0CH 3 To a well stirred solution of the title intermediate of Part A (450 mg) in dichloromethane (5 ml) at room temperature is added trifluoroacetic acid (5 ml) . The reaction mixture is stirred at room temperature for 1 hr, the solvents removed in vacuo, and the residue redissolved in dichloromethane. The solution is washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate, and concentrated. The residue is dissolved in dichloromethane (10 ml) , Boc-LVA(0TBS)-0H (700 mg) , triethylamine (1.0 ml), and diethyl- phosphoryl cyanide (0.32 ml) added and the reaction stirred at room temperature for 18 hr. The reaction mixture is diluted with dichloro¬ methane, washed with water, saturated sodium bicarbonate solution, and brine. The organic layers are combined, dried with anhydrous sodium sulfate, and concentrated to give a residue which affords the title intermediate (600 mg) as an oil after chromatography on silica gel (elution with 25% ethyl acetate/hexane) . Physical characteristics are as follows: MS (FAB, m/z) 584 [M+H] + . C. Boc-His(Tos)-LVA(0TBS)-He-NH0CH 3 To a well stirred solution of the title intermediate of Part B (3.04 g) in dichloromethane (7 ml) at room temperature is added trifluoroacetic acid (7 ml) . The reaction mixture is stirred at room temperature for 1 hr, the solvents removed in vacuo, and the residue redissolved in dichloromethane (12 ml) . The solution is neutralized by the dropwise addition of triethylamine (monitored with Fisher's Universal Indicating Reagent), Boc-His(Tos)-OH (2.3 g) , triethylamine (0.8 ml), and diethylphosphoryl cyanide (1.2 ml) added and the reaction stirred at room temperature for 24 hr. The solvent is removed in vacuo, the residue dissolved in ethyl acetate, washed with water, saturated sodium bicarbonate solution, and brine. The organic layers are combined, dried with anhydrous sodium sulfate, and concentrated to give a residue which affords the title product (1.99 g) as an oil after chromatography on silica gel (elution with 70% ethyl acetate/hexane) . Physical characteristics are as follows: MS (FAB, m/z) 893 [M+HJ + . Preparation 18 Boc-His(Tos)-LVA(0TBS)-Iba A. Boc-LVA(0TBS)-Iba To a cold (0°C), well stirred solution of Boc-LVA(OTBS)-OH, prepared as described in European published application number 0173481, (1.0 g) in dichloromethane (10 ml) is added isobutylamine- (Iba) (241 mg) , triethylamine (0.63 ml) , and diethylphosphoryl cyanide (0.51 ml) via syringe. The reaction mixture is allowed to warm to room temperature and stir overnight. The reaction is poured into brine, extracted with dichloromethane, dried with anhydrous sodium sulfate and concentrated. Chromatography on silica gel (elution with 25% ethyl acetate/hexane) gives the title intermediate (1.0 g) as an oil. Physical characteristics are as follows: NMR (300MHz, CDC1 3 ) δ 5.2, 4.43, 3.57, 3.11, 2.50, 1.98, 1.34, 1.60-1.20, 0.91-0.78, 0.80, 0.02, 0.01. B. Boc-His(Tos)-LVA(OTBS)-Iba To a well stirred solution of the title intermediate of Part A (500 mg) in dichloromethane (5 ml) at room temperature is added trifluoroacetic acid (5 ml) . The reaction mixture is stirred at room temperature for 1 hr, the solvents removed in vacuo, and the residue redissolved in dichloromethane. The solution is washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate, and concentrated. The residue is dissolved in freshly distilled dichloro¬ methane (10 ml), Boc-His(Tos)-OH (818 mg) , triethylamine (0.55 ml), and diethylphosphoryl cyanide (0.32 ml) added and the reaction stirred at room temperature for 18 hr. The solvent is removed in vacuo, the residue dissolved in ethyl acetate, washed with water, saturated sodium bicarbonate solution, and brine. The organic layers are combined, dried with anhydrous sodium sulfate, and concentrated to give a residue which affords the title product (452 mg) as an oil after chromatography on silica gel (elution with 2.5% methanol/di- chloromethane) . Physical characteristics are as follows: MS (FAB, m/z) 792 [M+H] + . Example 1 2,6-Dimethylphenoxyacetyl-His-LVA-He-NH0CH3 (Formula A-6: X is 2,6-dimethyl) Refer to Chart A. To a well stirred solution of Boc-His(Tos)-LVA(0TBS)-He-NH0CH3 of Preparation 17 (152 mg) in dichloromethane (2 ml) at room tempera¬ ture is added trifluoroacetic acid (2 ml) . The reaction mixture is stirred at room temperature for 1 hr, the solvents removed in vacuo, and the residue redissolved in dimethylformamide (2 ml) . The solution is neutralized by the dropwise addition of triethylamine (monitored with Fisher's Universal Indicating Reagent), 4-nitrophenyl 2,6-dimeth lphenoxyacetate of Preparation 9 (65 mg) and additional triethylamine is added (0.025 ml) and the reaction stirred at room temperature for 18 hr. The solvent is removed in vacuo, the residue suspended in dry ethanol (2 ml) at room temperature, and sodium ethoxide (1M) is added via syringe. The solution is stirred at room temperature for 3 hr, neutralized with glacial acetic acid (monitored with Fisher's Universal Indicating Reagent) , filtered through scintered glass, and concentrated. The residue is chromatographed on silica gel (Merck Lobar B, elution with 10% methanol (saturated with gaseous ammonia)/- dichloromethane) to deliver 110 mg of the title product as an amorphous solid. Physical characteristics are as follows: MS (FAB, m/z): 673. Exact Mass Found: 673.4293. Example 2 2-Chlorophenoxyacetyl-His-LVA-He-NHOCH3 (Formula A- 6: X is 2-chloro) Refer to Chart A. To a well stirred solution of Boc-His(Tos)-LVA(OTBS)-He-NHOCH 3 of Preparation 17 (157 mg) in dichloromethane (2 ml) at room tempera¬ ture is added trifluoroacetic acid (2 ml) . The reaction mixture is stirred at room temperature for 1 hr, the solvents removed in vacuo, and the residue redissolved in dimethylformamide (2 ml) . The solution is neutralized by the dropwise addition of triethylamine (monitored with Fisher's Universal Indicating Reagent), 4-nitrophenyl 2-chlorophenoxyacetate of Preparation 15 (67 mg) and additional triethylamine is added (0.025 ml), and the reaction stirred at room temperature for 18 hr. The solvent is removed in vacuo, the residue suspended in dry ethanol (2 ml) at room temperature, and sodium ethoxide (1M) is added via syringe. The solution is stirred at room temperature for 5 hr, neutralized with glacial acetic acid (monitored with Fisher's Universal Indicating Reagent) , filtered through scintered glass, and concentrated. The residue is chromatographed on silica gel (Merck Lobar B, elution with 10% methanol (saturated with gaseous ammonia)/- dichloromethane) to deliver the title product as an amorphous solid. Physical characteristics are as follows: MS (FAB, m/z): 679. Exact Mass Found: 679.3617. Example 3 2-Methylphenoxyacetyl-His-LVA-He-NHOCH3 (Formula A-6: X is 2-methyl) Refer to Chart A. To a well stirred solution of Boc-His(Tos)-LVA(OTBS)-He-NHOCH 3 of Preparation 17 (217 mg) in dichloromethane (2 ml) at room tempera¬ ture is added trifluoroacetic acid (2 ml) . The reaction mixture is stirred at room temperature for 2 hr, the solvents removed in vacuo, and the residue redissolved in dimethylformamide (2.5 ml). The solution is neutralized by the dropwise addition of triethylamine (monitored with Fisher's Universal Indicating Reagent), 4-nitrophenyl 2-methylphenoxyacetate of Preparation 10 (110 mg) and additional triethylamine is added (0.035 ml), and the reaction stirred at room temperature for 66 hr. The solvent is removed in vacuo, the residue suspended in dry ethanol (2 ml) at room temperature, and sodium ethoxide (1M) is added via syringe. The solution is stirred at room temperature for 5 hr, neutralized with glacial acetic acid (monitored with Fisher's Universal Indicating Reagent) , filtered through scintered glass, and concentrated. The residue is chromatographed on silica gel (Merck Lobar B, elution with 10% methanol (saturated with gaseous ammonia)/- dichloromethane) to deliver the title product as an amorphous solid. Physical characteristics are as follows: MS (FAB, m/z): 659. Exact Mass Found: 679.4175. Example 4 2-Methoxyphenoxyacetyl-His-LVA-He-NHOCH3 (Formula A- 6: X is 2-methoxy) Refer to Chart A. To a well stirred solution of Boc-His(Tos)-LVA(OTBS)-He-NHOCH 3 of Preparation 17 (169 mg) in dichloromethane (2 ml) at room tempera- ture is added trifluoroacetic acid (2 ml). The reaction mixture is stirred at room temperature for 1.5 hr, the solvents removed in vacuo, and the residue redissolved in dimethylformamide (2 ml). The solution is neutralized by the dropwise addition of triethylamine (monitored with Fisher's Universal Indicating Reagent), 4-nitrophenyl 2-methoxyphenoxyacetate of Preparation 13 (70 mg) and additional triethylamine is added (0.027 ml), and the reaction stirred at room temperature for 18 hr. The solvent is removed in vacuo, the residue suspended in dry ethanol (2 ml) at room temperature, and sodium ethoxide (IM) is added via syringe. The solution is stirred at room temperature for 5 hr, neutralized with glacial acetic acid (monitored with Fisher's Universal Indicating Reagent) , filtered through scintered glass, and concentrated. The residue is chromatographed on silica gel (Merck Lobar B, elution with 10% methanol (saturated with gaseous ammonia)/- dichloromethane) to deliver 43 mg of the title product as an amor¬ phous solid. Physical characteristics are as follows: MS (FAB, m/z): 675. Exact Mass Found: 675.4083. Example 5 2-Fluorophenoxyacetyl-His-LVA-He-NH0CH3 (Formula A-6: X is 2-fluoro) Refer to Chart A. To a well stirred solution of Boc-His(Tos)-LVA(OTBS)-He-NH0CH 3 of Preparation 17 (158 mg) in dichloromethane (2 ml) at room tempera¬ ture is added trifluoroacetic acid (2 ml) . The reaction mixture is stirred at room temperature for 2.5 hr, the solvents removed in vacuo, and the residue redissolved in dimethylformamide (2 ml). The solution is neutralized by the dropwise addition of triethylamine (monitored with Fisher's Universal Indicating Reagent), 4-nitrophenyl 2-fluorophenoxyacetate of Preparation 8 (65 mg) and additional triethylamine is added (0.025 ml), and the reaction stirred at room temperature for 66 hr. The solvent is removed in vacuo, the residue suspended in dry ethanol (2 ml) at room temperature, and sodium ethoxide (IM) is added via syringe. The solution is stirred at room temperature for 4 hr, neutralized with glacial acetic acid (monitored with Fisher's Universal Indicating Reagent) , filtered through scintered glass, and concentrated. The residue is chromatographed on silica gel (Merck Lobar B, elution with 10% methanol (saturated with gaseous ammonia)/- dichloromethane) to deliver the title product as an amorphous solid. Physical characteristics are as follows: MS (FAB, m/z): 663. Exact Mass Found: 663.3896. Example 6 2-Ethylphenoxyacetyl-His-LVA-He-NHOCH 3 (Formula A-6: X is 2-ethyl) Refer to Chart A. To a well stirred solution of Boc-His(Tos)-LVA(0TBS)-He-NH0CH 3 of Preparation 17 (157 mg) in dichloromethane (2 ml) at room tempera- ture is added trifluoroacetic acid (2 ml) . The reaction mixture is stirred at room temperature for 1.5 hr, the solvents removed in vacuo, and the residue redissolved in dimethylformamide (2 ml). The solution is neutralized by the dropwise addition of triethylamine (monitored with Fisher's Universal Indicating Reagent), 4-nitrophenyl 2-ethylphenoxyacetate of Preparation 12 (65 mg) and additional triethylamine is added (0.025 ml), and the reaction stirred at room temperature for 18 hr. The solvent is removed in vacuo, the residue suspended in dry ethanol (2 ml) at room temperature, and sodium ethoxide (IM) is added via syringe. The solution is stirred at room temperature for 5 hr, neutralized with glacial acetic acid (monitored with Fisher's Universal Indicating Reagent) , filtered through scintered glass, and concentrated. The residue is chromatographed on silica gel (Merck Lobar B, elution with 8% methanol (saturated with gaseous ammonia)/- dichloromethane) to deliver the title product as an amorphous solid. Physical characteristics are as follows: MS (FAB, m/z): 673. Exact Mass Found: 673.4326. Example 7 2-Isopropylphenoxyacetyl-His-LVA-He-NH0CH3 (Formula A-6: X is 2-isopropyl) Refer to Chart A. To a well stirred solution of Boc-His(Tos)-LVA(0TBS)-He-NH0CH3 of Preparation 17 (160 mg) in dichloromethane (2 ml) at room tempera¬ ture is added trifluoroacetic acid (2 ml) . The reaction mixture is stirred at room temperature for 1 hr, the solvents removed in vacuo, and the residue redissolved in dimethylformamide (2 ml) . The solution is neutralized by the dropwise addition of triethylamine (monitored with Fisher's Universal Indicating Reagent), 4-nitrophenyl 2-isopropylphenoxyacetate of Preparation 14 (69 mg) and additional triethylamine is added (0.026 ml) , and the reaction stirred at room temperature for 18 hr. The solvent is removed in vacuo, the residue suspended in dry ethanol (2 ml) at room temperature, and sodium ethoxide (IM) is added via syringe. The solution is stirred at room temperature for 66 hr, neutralized with glacial acetic acid (monitored with Fisher's Universal Indicating Reagent), filtered through scintered glass, and concentrated. The residue is chromatographed on silica gel (Merck Lobar B, elution with 8% methanol (saturated with gaseous ammonia)/- dichloromethane) to deliver 66 mg of the title product as an amor¬ phous solid. Physical characteristics are as follows: MS (FAB, m/z): 687. Exact Mass Found: 687.4454. Example 8 2-Methylphenoxyacetyl-His-LVA-Ile-Amp To a well stirred solution of Boc-His(Tos)-LVA(OTBS)-He-Amp, which can be prepared by procedures known in the art, (149 mg) in dichloromethane (2 ml) at room temperature is added trifluoroacetic acid (2 ml) . The reaction mixture is stirred at room temperature for 0.5 hr, the solvents removed in vacuo, and the residue redissolved in dimethylformamide (2 ml) . The solution is neutralized by the dropwise addition of triethylamine (monitored with Fisher's Universal Indicating Reagent) , 4-nitrophenyl 2-meth lphenoxyacetate of Prepara- tion 10 (62 mg) and additional triethylamine is added (0.025 ml), and the reaction stirred at room temperature for 18 hr. The solvent is removed in vacuo, the residue suspended in dry ethanol (2 ml) at room temperature, and sodium ethoxide (IM) is added via syringe. The solution is stirred at room temperature for 2 hr, neutralized with glacial acetic acid (monitored with Fisher's Universal Indicating Reagent), filtered through scintered glass, and concentrated. The residue is chromatographed on silica gel (Merck Lobar B, elution with 6% methanol (saturated with gaseous ammonia)/- dichloromethane) to deliver 22 mg of the title product as an amor- phous solid. Physical characteristics are as follows: MS (FAB, m/z): 720. Exact Mass Found: 720.4435. Example 9 3-Chlorophenoxyacetyl-His-LVA-He-NHOCH3 (Formula A-6: X is 3-chloro) Refer to Chart A. To a well stirred solution of Boc-His(Tos)-LVA(0TBS)-He-NH0CH 3 of Preparation 17 (162 mg) in dichloromethane (2 ml) at room tempera¬ ture is added trifluoroacetic acid (2 ml) . The reaction mixture is stirred at room temperature for 1 hr, the solvents removed in vacuo, and the residue redissolved in dimethylformamide (2 ml) . The solution is neutralized by the dropwise addition of triethylamine (monitored with Fisher's Universal Indicating Reagent), 4-nitrophenyl 3-chlorophenoxyacetate of Preparation 16 (66 mg) and additional triethylamine is added (0.025 ml), and the reaction stirred at room temperature for 18 hr. The solvent is removed in vacuo, the residue suspended in dry ethanol (2 ml) at room temperature, and sodium ethoxide (IM) is added via syringe. The solution is stirred at room temperature for 1 hr, neutralized with glacial acetic acid (monitored with Fisher's Universal Indicating Reagent), filtered through scintered glass, and concentrated. The residue is chromatographed on silica gel (Merck Lobar B, elution with 10% methanol (saturated with gaseous ammonia)/- dichloromethane) to deliver 114 mg of the title product as an amorphous solid. Physical characteristics are as follows: MS (FAB, m/z): 679. Exact mass Found: 679.3598. Example 10 3 -Fluorophenoxyacetyl-His-LVA-Ile-NHOCH 3 (Formula A-6: X is 3-fluoro) Refer to Chart A. To a well stirred solution of Boc-His(Tos)-LVA(0TBS)-He-NH0CH3 of Preparation 17 (163 mg) in dichloromethane (2 ml) at room tempera¬ ture is added trifluoroacetic acid (2 ml) . The reaction mixture is stirred at room temperature for 3 hr, the solvents removed in vacuo, and the residue redissolved in dimethylformamide (2 ml) . The solution is neutralized by the dropwise addition of triethylamine (monitored with Fisher's Universal Indicating Reagent), 4-nitrophenyl 3-fluorophenoxyacetate of Preparation 7 (66 mg) and additional triethylamine is added (0.025 ml), and the reaction stirred at room temperature for 66 hr. The solvent is removed in vacuo, the residue suspended in dry ethanol (2 ml) at room temperature, and sodium ethoxide (IM) is added via syringe. The solution is stirred at room temperature for 4.5 hr, neutralized with glacial acetic acid (monitored with Fisher's Universal Indicating Reagent), filtered through scintered glass, and concentrated. The residue is chromatographed on silica gel (Merck Lobar B, elution with 10% methanol (saturated with gaseous ammonia)/- dichloromethane) to deliver 38 mg of the title product as an amor- phous solid. Physical characteristics are as follows: MS (FAB, m/z): 66-3 [M+H]+. Exact Mass Found: 663.3863. Example 11 2-Methylphenoxyacetyl-His-LVA-Iba To a well stirred solution of Boc-His(Tos)-LVA(OTBS)-Iba of Preparation 18 (197 mg) in dichloromethane (2 ml) at room temperature is added trifluoroacetic acid (2 ml) . The reaction mixture is stirred at room temperature for 2 hr, the solvents removed in vacuo, and the residue redissolved in dimethylformamide (2 ml) . The solution is neutralized by the dropwise addition of triethylamine (monitored with Fisher's Universal Indicating Reagent), 4-nitrophenyl 2-methylphenoxyacetate of Preparation 10 (87 mg) and additional triethylamine is added (0.035 ml), and the reaction stirred at room temperature for 18 hr. The solvent is removed in vacuo, the residue suspended in dry ethanol (2 ml) at room temperature, and sodium ethoxide (IM) is added via syringe. The solution is stirred at room temperature for 18 hr, neutralized with glacial acetic acid (monitored with Fisher's Universal Indicating Reagent), filtered through scintered glass, and concentrated. The residue is chromatographed on silica gel (Merck Lobar B, elution with 5% methanol (saturated with gaseous ammonia)/- dichloromethane) to deliver 19 mg of the title product as an amor- phous solid. Physical characteristics are as follows: MS (FAB, m/z): 572 [M+H]+. Exact Mass Found: 572.3806. Preparation 19 Boc-CVA(OTBS)-He-NHOCH 3 To a well stirred solution of Boc-He-NH0CH3 in dichloromethane (2 ml) is added trifluoroacetic acid (2 ml) . The reaction mixture is stirred at room temperature for 2 hours, the solvents removed in vacuo and the residue redissolved in dichloromethane (5.3 ml). The solution is neutralized by dropwise addition of triethylamine (mon- itored with Fisher's Universal Indicating Regent). Boc-CVA(0TBS)-0H (0.414 g) , prepared as described in PTC patent application, Serial No. PCT/US89/00247, filed 27 January 1989, which is hereby incorpor¬ ated by reference, additional triethylamine (0.24 ml), and diethyl- cyanophosphonate (0.260 ml) is added and the reaction mixture stirred at room temperature for 66 hours. The mixture is poured into satu¬ rated sodium bicarbonate solution and extracted 3 times with dichlor¬ omethane. Combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is chromatographed on silica gel (Merck Lobar B, elution with 40% ethyl acetate in hexane), to yield the title product (0.515 g) as a white solid. Physical characteristics are as follows: MS (FAB, m/z) 628 [M+H] + , 73, 57, 86, 528, 75. Preparation 20 Boc-His(Tos)-CVA(0TBS)-Ile-NH0CH 3 To a well stirred solution of the title product of Preparation 19 (0.509 g) in dichloromethane (2.5 ml) is added trifluoroacetic acid (2.5 ml) . The reaction mixture is stirred at room temperature for 0.75 hour, the solvents removed in vacuo and the residue redis- solved in dichloromethane (8 ml) . The solution is neutralized by dropwise addition of triethylamine (monitored with Fisher's Universal Indicating Reagent) . Boc-His(Tos)-OH (0.663 g) , additional triethyl¬ amine (0.225 ml) and diethylcyanophosphonate (0.245 ml) is added and the reaction mixture stirred at room temperature for 4 days. Saturated sodium bicarbonate solution (2 ml) is added. The mixture is stirred vigorously for five minutes, transferred to a separatory funnel and extracted twice with dichloromethane. Combined extracts are dried over anhydrous magnesium sulfate, filtered and concen¬ trated. The residue is chromatographed on silica gel (Merck Lobar B, elution with 70% ethyl acetate in hexane) to yield the title product (0.573 g) as a solid. Physical characteristics are as follows: MS (FAB, m/z) 919 [M+H] + , 110, 264, 919, 765, 73. Preparation 21 4-Nitrophenyl-2-methylphenoxyacetate A slurry of 2-methylphenoxyacetic acid (1.12 g) and 4-nitro- phenol (0.951 g) in tetrahydrofuran (15 ml) is stirred at 0°C and a solution of dicyclohexylcarbodiimide (1.54 g) in tetrahydrofuran (10 ml) is added via syringe. The reaction mixture is stirred at 0 β C for one hour followed by room temperature overnight. The reaction mixture is filtered and the filtrate concentrated to yield a yellow oil. The crude product is crystallized from 95% ethanol/1% acetic acid to yield the title product (0.790 g) as an'off-white solid. Physical characteristics are as follows: MS (El, m/z) 121, 91, 287, 65, 122. NMR (300 MHz, CDC1 3 ) δ 8.27, 7.31, 7.21-7.16, 6.95, 6.81, 4.94, 2.32. IR (mull, cm "1 ) 3328, 1769, 1527, 1497, 1346, 1208, 1167, 1131, 1077. Example 12 2-Methylphenoxyacetyl-His-CVA-He-NHOCH 3 or 1-H- Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-2- hydroxy-4- [ [ [1- [ (methoxyamino)carbonyl] -2-methylbut- yl]amino]carbonyl] -5-methylhexyl] -a- [ [ (2-meth lphen- oxy)acetyl]amino] - , [IS- [IR*(R*) ,2R*,4R*] ] - To a well stirred solution of the title product of Preparation 20 (0.268 g) in dichloromethane (2 ml) is added trifluoroacetic acid (2 ml) . The reaction mixture is stirred at room temperature for one hour, the solvents removed in vacuo and the residue redissolved in dimethylformamide (3 ml) . The solution is neutralized by dropwise addition of triethylamine (monitored with Fisher's Universal Indicat¬ ing Reagent). The title product of Preparation 21 (0.146 g) and additional triethylamine (0.040 ml) are added and the reaction mixture is stirred at room temperature for 20 hours. The dimethyl- formamide is removed in vacuo, the residue resuspended in dry ethanol (2 ml) and sodium ethoxide (0.6 ml, IM) is added via syringe. The reaction mixture is stirred at room temperature for 3 hours, neutral¬ ized with glacial acetic acid (monitored with Fisher's Universal Indicating Reagent) , filtered through scintered glass and concen- trated. The residue is chromatographed on silica gel (Merck Lobar B, elution with 10% methanol saturated with gaseous ammonia in dichloro¬ methane) , to deliver the title product as a white solid. Physical characteristics are as follows: MS (FAB, m/z) 699 [M+H] + . Exact Mass found: 699.4440. FORMULA CHART Y-D9-E_.0-Fn-G_.2-H__3-I_.4-Z CHART A Boc-Ile-OH A-l Boc-Ile-NH-OCH 3 A-2 Boc-Leu^[CHOTBS-CH 2 ]Val-Ile-NH-OCH 3 A-3 Boc-His(Tos)Leu^[CHOTBSCH 2 ]Val-Ile-NH-OCH 3 A-4 X-POA-His(Tos)Leu^[CHOH-CH 2 ]Val-He-NH-OCH3 A-5 X-POA-His-Leu 1 6[CHOHCH 2 ]Val-He-NH-OCH3 A-6

Claims: CIAIMS 1. A peptide of the formula I Y-D9-E_.0-Fn-G__2-H__3 -I_.4-Z - wherein Y Is wherein R50 is (a) chloro, (b) fluoro, (c) methyl, (d) ethyl, (e) isopropyl, (f) methyloxy, or (g) nitro; wherein j is 1 or 2 ; wherein the phenyl ring of formula Y is mono-substituted by R50 at the 2- or 3-posItion or is disubstituted by R50 at the 2,3- posltion, 2,5-positlon, 2,6-position, 3,5-position or 3,6-position; provided that when the phenyl ring of formula Y is mono-sub¬ stituted with methyl, R50 is 2-methyl; wherein D9 is a divalent moiety of the formula XL3; wherein E o*Tχχ is a divalent moiety of the formula XLg; wherein * indicates an asymmetric center which is either in the R or S configuration; wherein G 2 i absent or a divalent moiety of the formula XL4; wherein H 3 is absent; wherein I 4 is absent; wherein Z is (a) -N(R 10 )(0R 14 ), (b) -0-R 10 , (c) -N(R )R 14 , or (d) C4-Cgcyclic amino; wherein R is (a) isopropyl, (b) isobutyl, (c) phenylmethyl, or (d) -(CH2)p-C3-C7cycloalkyl; wherein R is (a) hydrogen, (b) Cx-Csalkyl, (c) aryl, (d) C3-C7cycloalkyl, (e) -Het, (f) C -C3alkoxy, or (g) C 1 -C 3 alkylthio; wherein R2 is (a) hydrogen, or (b) -CH(R 3 )R ; wherein R3 is (a) hydrogen, (b) hydroxy, (c) Cχ-C 5 alkyl, (d) C3-C 7 cycloalkyl, (e) aryl, (f) -Het, (g) C -C3alkox , or (h) Cχ-C 3 alkylthio; wherein R4 at each occurrence is the same or different and is (a) hydrogen, or (b) Cx-Csalkyl; wherein R7 is (a) hydrogen, (b) Cx-Csalk l, (c) hydroxy, (d) amino C -C4alkyl-, (e) guanidinyl C -C3alkyl-, (f) aryl, (g) -Het, (h) methylthio, (1) -(CH2)p-C3-C 7 cycloal yl, or ( ) amino; wherein Rg is (a) hydrogen, (b) Cx-Cgalkyl, (c) hydroxy, (d) aryl, (e) -Het, (f) guanidinyl-Cχ-C3alkyl-, or (g) -(CH 2 ) p -C 3 -C 7 cycloalkyl; wherein R o (a) hydrogen, or (b) C -Csalkyl; wherein R^χ is -R or -R 2 ; wherein R 4 is (a) Cx-Cxoalk l, (b) -(CH 2 ) n -aryl, (c) -(CH 2 ) n -Het, (d) -(CH 2 ) n+2 -R 18 , (e) -(CH 2 ) n+ 2-R 19 , (f) (hydroxy-Cχ-Cgalkyl), or (g) (C 1 -C 3 alkoxy)C 1 -Cgalkyl; wherein g is (a) amino, (b) mono-, or di-Cχ-C3alkylamino, (c) C4-G cyclic amino, or (d) C4-G cycloalkyla ino; wherein Rχ 9 is (a) aryl, (b) -Het, (c) tri-Cχ-C3alkylamino, (d) C3-C7cycloalkyl, (e) C 2 -C5alkenyl, (f) C3-C7c cloalkenyl, (g) hydrox , 00 C -C3alkoxy, (i) 0 -C3alkanoyloxy, (j) mercapto, 00 C -C3alkylthio, (1) -C00H, (m) -C0-0-Cχ-Cgalkyl, (n) -C0-0-CH2-(C 1 -C 3 alkyl)-N(C 1 -C 3 alkyl)2, (o) -C0-NR 22 R25. ( P ) guanidyl, (q) cyano, <r) N-cyanoguanidyl, (s) cyanoamino, (t) (hydroxy-C2-C4alkyl)amino, (u) di-(hydroxy-C2-C4alkyl)amino, or (v) S0 3 H wherein ] R 22 is (a) hydrogen, or (b) Cχ-C3alk l; wherein : Et 25 is (a) hydrogen, (b) C -C al yl, or (c) phenyl-C 1 -C3alkyl; wherein for each occurrence n is independently an integer of zero to five, inclusive; wherein p is zero to two, inclusive; wherein aryl is phenyl or naphthyl substituted by zero to 3 of the following (a) C1-C3alkyl, (b) hydroxy, (c) C -C3alkoxy, (d) halo, (e) amino, (f) mono- or di-Cx-C3alkylann.n0, (g) -CH0, 00 -C00H, (i) C00R 25 , (j) C0NHR 25 , (k) nitro, (1) mercapto, (m) Cχ-C 3 alkylthio, (n) Cχ-C3alkylsulfinyl, (o) Cχ-C3alkylsulfonyl, (p) -N(R 4 )-C 1 -C 3 al_ςylsulfonyl, (q) S0 3 H, (r) S0 2 NH 2 , (s) -CN, or (t) -CH 2 NH 2 ; wherein -Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring, which heterocyclic moiety is substituted with zero to 3 of the following: (i) Cx-Cgalkyl, (ii) hydroxy, (iii) trifluoromethyl, (iv) C -C4alkoxy, (v) halo, (vi) aryl, (vii) aryl-C 1 -C alkyl-, (vlii) amino, or (ix) mono- or di-Cχ-C4alkylamino; or a carboxy-, amino-, or other reactive group-protected form thereof; or a pharmaceutically acceptable acid addition salt thereof. 2. The peptide of claim 1 wherein R50 is 2-methyl; wherein D 9 is His or a derivative thereof; wherein Eχ Q -Fχχ is LVA, CVA or a derivative thereof; wherein G j _ 2 is absent, He or a derivative thereof; wherein Z is (a) -NH-OCH3, (b) 2-(Aminomethyl)pyridinyl, or (c) -NH-CH 2 -CH(CH 3 )-CH3. 3. The peptide of claim 2 selected from the group consisting of: 2-Methylphenoxyacetyl-His-LVA-He-NH0CH 3 ; 2-Methylphenoxyacetyl-His-LVA-He-Amp; 2-Methylphenoxyacetyl-His-LVA-Iba; and 2-Methylphenoxyacetyl-His-CVA-He-NH0CH 3 . 4. The peptide of claim 1 wherein R50 is (a) 2-chloro, (b) 3-chloro, (c) 2-fluoro, (d) 3-fluoro, (e) 2-ethyl, (f) 2-isopropyl, (g) 2, 6 -dimethyl, or (h) 2-methyloxy; wherein D 9 is His or a derivative thereof; wherein E ø-F is LVA or a derivative thereof; wherein G 2 is H e or a derivative thereof; wherein Z is (a) -NH-OCH3, (b) 2-(Aminomethyl)pyridinyl, or (c) -NH-CH 2 -CH(CH3)-CH 3 . 5. The peptide of claim 4 selected from the group consisting of: 3-Chlorophenoxyacetyl-His -LVA- He-NH0CH3 ; 2-Chlorophenoxyacetyl-His-LVA-He-NHOCH 3 ; 2,6-Dimeth lphenoxyacetyl-His-LVA-He-NHOCH3; 3-Fluorophenoxyacetyl-His-LVA-He-NH0CH3; 2 -Methoxyphenoxyacetyl -His -LVA- He -NHOCH3 ; 2 - Fluorophenoxyacetyl -His - LVA- He -NHOCH3 ; 2-Ethylphenoxyacetyl-His-LVA-He-NHOCH 3 ; and 2-Isopropylphenoxyacetyl-His-LVA-Ile-NH0CH3.

Inventors: SCHOSTAREZ HEINRICH J, SCHOSTAREZ, HEINRICH, J.
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1989
Main classification: C07D233
IPC codes: A61K38, A61P5, A61P9, A61P43, C07D213, C07D233, C07D401, C07K5, C07K14