PEPTIDES CONTAINING DIAMINO-GLYCOLS AS TRANSITION-STATE MIMICS

Abstract: The present invention provides novel peptides. These peptides have a novel non-cleavable transition state insert corresponding to the 10,11-position of the renin substrate (angiotensinogen) of the formula XL8. These peptides are useful as renin inhibitors and as inhibitors of retroviral proteases. 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. Inhibitors of retroviral proteases, such as the HIV-I protease, are useful for treating diseases caused by retroviruses, such as human acquired immunodificiency disease syndrome (AIDS).

Description: PEPΗDES CONTAINING DIAMINO-GLYCOLS AS TRANSITION-STATE MIMICS DESCRIPTION BACKGROUND OF THE INVENTION The present invention provides novel compounds. More particularly, the present invention provides novel peptide analogs. The peptides of the present invention contain a diamino-glycol moiety as a novel non-cleavable transition state insert corresponding to the 10,11-position of the renin substrate (angiotensinogen). These peptides are useful as renin inhibitors and as inhibitors of retroviral proteases. Renin inhibitors are useful for the diagnosis and control of renin-dependent hypertension, congestive heart failure, renin-dependent h peraldosterism, and other renin-dependent cardiovascular disorders. Inhibitors of retroviral proteases, such as the HTV-I protease, are useful for treating diseases caused by retroviruses, such as human acquired immunodeficiency disease syndrome (AIDS). Renin is an endopeptidase which specifically cleaves a particular peptide bond of its substrate (angiotensinogen), of which the N-terminal sequence in equine substrate is for example: Renin A_ιp-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 -Val-De-His- 11 12 13 IB and having the sequence to the left of the arrow (*) being as designated in formula IA above. Renin cleaves angiotensinogen to produce angiotensin I, which is converted to the potent pressor angiotensin π. A number of angiotensin 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 applications 156,320 and 156,318. Certain tetrapeptides are disclosed in European publications 111,266 and 77,027. Further, European published 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-directed "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-aminodeoxyst- atine have been disclosed in European published application 161,588. Certain peptides containing 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 dis¬ closed 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 European patent application 189,203, published 30 July 1986, and European patent application 230,266, published 24 July 1987, disclose N-dihydroxyalkyl peptide derivatives which are useful as inhibitors of renin for treating hypertension. They specifically disclose the intermediate compound, (2S,3R,4S)-l-Amino-2,3-dihydroxy-4- tert-butoxy-«--iκ nylamino-5-cyclohexylpen_ane, and the final compound Boc-Phe-His Amide of (2S,3R,4S)-l-(3-MeΛylbutylcarbonylam__no)-2,3-dihydroxy-4-amino-5- cyclohexylpentane. European patent application 184,855, published 18 June 1986, discloses new hydroxy carbonyl substituted-statine peptide derivatives which are usefiil as inhibitors of renin for treating hypertension. Derivatives of isosteric bond replacements at positions 10,11 as dihydroxy ethylene isosteres are disclosed in International Patent Application, PCT/US87/00291, published 11 September 1987 (Publication No. WO87/05302). International Patent Application, PCT/US 87/03007, published 30 June 1988 (Publication No. WO88/04664) discloses renin inhibitory peptides having an epoxide or glycol moiety at the 10,11-position. Derwent Abstracts, Accession Nos. 89-101394, 89- 101395, 89-101396 and 89-101397, disclose compounds having an amino:diol alkyl moiety as the transition state insert which are useful as renin inhibitors in the treatment of hypertension. SUMMARY OF THE INVENΗON The present invention particularly provides: A peptide having a non-cleavable transition state insert corresponding to the 10,11-position of a renin substrate (angiotensinogen) of the formula XL,, wherein Xj is (a) hydrogen, (b) Y r (CH-).-C(OK (c) (HOCH 2 ) 3 C-NH-C(O)-, (d) (HOCH 2 ) 2 CH-NH-C(O)-, (e) the moiety of formula π, (f) HOH 2 C(CHOH),CH(CH 2 OH)-NH-C(0)-, (g) Na0 3 S(CH 2 ) 2 N(CH 3 )C(O)(CH 2 )iC(O)-, (h) R 2 C(0)-, (i) R 2 -0-C(O)- or 0) Z r C(0)-; wherein Y, is (a) -NH 2 , (c) -CflSH^O^, (d) -CHOrøjXCOjH), or (e) -OP(0)(OHh; wherein Zi is -Het bonded through a nitrogen; wherein t is (a) hydrogen, (b) -C, alkyl, (c) aryl, (d) - cycloalkyl, (e) Het, (f) - alkoxy, or (g) C r C 3 alkylthio; wherein R 2 is (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 rused to a benzene ring, which heterocyclic moiety is substituted with zero to three of the following: (i) - alkyl, (ii) hydroxy, (ϋi) trifluoromethyl, (iv) C r C alkoxy, (v) halo, (vi) aryl, (vii) aryl C r C 4 alkyl-, (viii) amino, (ix) mono- or di-(Cj-C alkyl) amino, or (x) Cj-C 5 alkanoyl; wherein R« is (a) hydrogen, (b) -Cj alkyl, (d) -(CH^-Het. 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 lie His- X A 4 B~ C g D 9 E HJ F U G 12 H u I M Z, The present invention provides peptide inhibitors of renin and retroviral proteases which contain a diamino-glycol moiety as a novel non-cleavable transition state insert corresponding to the 10,11-position of the renin substrate (angiotensinogen). By "renin inhibitory peptide" is meant a compound capable of inhibiting the renin enzyme in mammalian metabolism and having three or more amino acid residues linked by peptidic or pseudo-peptidic bonds. By "a non-cleavable transition state insert" is meant a transition state insert which is not cleavable by a hydrolytic enzyme in mammalian metabolism. A variety of such transition state inserts, corresponding to the 10, 11 -position of the renin substrate, are known in the art, including those disclosed in the following references, which are hereby incorporated by reference: U.S. patent 4,424,207 (Szelke); European patent 104041A (Szelke); European patent application 144,290A (Ciba Geigy AG); European patent 0,156,322 (Merck); European patent 161-588A (Merck); European patent 0,172,347 (Abbott); European patent 172-346-A (Abbott); European patent 156-318 (Merck); European patent 157-409 (Merck); European patent 152-255 (Sankyo); and U.S. patent 4,548,926 (Sankyo); and U.S. patent application, Serial No. 904,149, filed 5 September 1986; U.S. patent application, Serial No. 844,716, filed 27 March 1986; PCT application, Serial No. 000,713, filed 7 April 1986; U.S. patent application, Serial No. 945,340, filed 22 December 1986; and U.S. patent application, Serial No. 825,250, filed 3 February 1986; and A. Spaltenstein, P. Carpino, F. Miyake and P.B. Hysldns, Tetrahedron Letters, 27:2095 (1986); D.H. Rich and M.S. Bernatowicz, J. Med. Chem., 25:791 (1982); Roger, J. Med. Chem., 28: 1062 (1985); D.M. Glick, et al., Biochemistry, 21:3746 (1982); D.H. Rich, Biochemistry, 24:3165 (1985); R.L. Johnson, J. Med. Chem., 25:605 (1982); R.L. Johnson and K. Verschovor, J. Med. Chem., 26:1457 (1983); R.L. Johnson, J. Med. Chem., 27:1351 (1984); P.A. Bartlett, et al., J. Am. Chem. Soc., 106:4282 (1984); and Peptides: Synthesis, Structure and Function (V.J. Hruby; D.H. Rich, eds.) Proc. 8th American Peptide Sym., Pierce Chemical Company, Rockfoid, HI., pp. 511-20; 587-590 (1983). By "derivatives" of amino acids is meant the well known amino acid derivatives commonly employed in renin inhibitors as set forth in the references above. Examples of the peptides of the present invention are represented by formula I. In formula I, the non-cleavable transition state insert, corresponding to the 10,11-position of the renin substrate, is designated Ejn. The present invention provides novel peptides having a diamino-glycol as a novel non-cleavable transition state insert. As is apparent to those of ordinary skill in the art, the renin inhibitory peptides of the present invention can occur in several diastereomeric forms, depending on the configuration around the asymmetric carbon atoms. All such diastereomeric forms are included within the scope of the present invention. Preferably, the stereochemistry of the amino acids corresponds to that of the naturally-occurring amino acids. Renin inhibitory peptides commonly have protecting groups at the N-terminus and the C-terminus. These protecting groups are known in the polypeptide art. Examples of these protecting groups are given below. Any of these protecting groups are suitable for the renin inhibitory peptides of the present invention. Examples of pharmaceutically acceptable acid addition salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane-sulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, πicotinate, 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) indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus ( -CJalkyl refers to alkyl of one to 4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, and isomeric forms thereof. -Crcyclic amino indicates a monocyclic group containing one nitrogen and 4 to 7 carbon atoms. Examples of ( - ^cycloalkyl, which include alkyl-substituted cycloalkyl containing a total of up to 10 total carbon atoms, are cyclopropyl, 2-methylcyclcpropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2- methylcyclobutyl, 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 -)propylphenyl, 2-propyl-(o-, m-, or p-)tolyl, 4-isopropyl-2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4- 2,3,6-, or 2,4,5-)trimethylphenyl, (o-, m-, or p-)fluoroρhenyl, (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-propylphenyl, 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-pyτidyl, imidazolyl, indolyl, N ormyl indolyl, N--C r Cj__lkyl-C(0)-indolyl, 1,2,4-triazolyl, 2-, 4-, or 5-pyrimidinyl, 2- o 3-thienyl, piperidinyl, pyπyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidi nyl, imidazoϋnyl, imidazolidinyl, pyrazinyl, piperazinyl, pyridazinyl, oxazolyl, oxa zolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl isothiazolidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, and benzothienyl. Each of these moieties may be substituted as note 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 sulfu or through nitrogen which is within a ring and part of a double bond. Halo is halogen (fluoro, chloro, bromo, or iodo) or trifluoromethyl. Examples of pharmaceutically acceptable cations include: pharmacologicall 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 an calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron are als within the scope of this invention. Pharmacologically acceptable amine cations are thos 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 an Symbolism for Amino Acids and Peptides," Eur. J. Biochem. 138:9-37 (1984) unles otherwise indicated. The peptides of this invention are useful for treating any medical condition fo which it is beneficial to reduce the levels of active circulating renin. Examples of suc conditions include renin-dependent hypertension, hypertension, hypertension unde treatment with another antihypertensive and/or a diuretic agent, congestive heart failure, renin-dependent hyperaldosterism, angina, post-myocardial infarction, other renin dependent cardiovascular disorders and ocular disorders. The renin-angiotension syste may play a role in maintenance of intracellular homeostasis: see Clinical an 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 0Λ mg to 100 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 50 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 pharma- cologically acceptable conjugate bases. Conventional forms and means for administering r aiin-inhibiting compounds may be employed and are described, e.g., in U.S. Patent No. 4,424,207 which is incorporat¬ ed by reference herein. Likewise, the amounts disclosed in the U.S. Patent No. 4,424,207 are examples applicable to the compounds 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 acceptable 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, in- travenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the compounds of the 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 steril injectable aqueous or oleagenous suspension. This suspension may be formulate according to the known art using suitable dispersing or wetting agents and suspendin agents. The sterile injectable preparation may also be a .sterile injectable solution o suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may b employed are water, Ringer's solution and isotonic sodium chloride solution. I addition, sterile, fixed oils are conventionally employed as a solvent or suspendin medium. For this purpose any bland fixed oil may be employed including syntheti mono- or digly-cerides. In addition, fatty acids such as oleic acid find use in th preparation of injectables. The peptides of this invention may also be administered in the form o suppositories for rectal administration of the drug. These compositions can be prepare by mixing the drug with a suitable non-irritating excipient which is solid at ordinar temperatures but liquid at the rectal temperature and will therefore melt in the rectu to release the drug. Such materials are cocoa butter and polyethylene glycols. The peptides of this invention may be administered in combination with othe agents used in antihypertensive therapy such as diuretics, α and/or ø-adrenergic blockin agents, CNS-acting agents, adrenergic neuron blocking agents, vasodilators, angiotensi I converting enzyme inhibitors, and the like as described for example in publishe European patent application 156,318. The present invention is also directed to combinations of the novel renin inhibitory peptides of Formula I with one or more antihypertensive agents selected fro the group consisting of diuretics, or and/or 0-adrenergic blocking agents, CNS-actin agents, adrenergic neuron blocking agents, vasodilators, angiotensin I converting enzym inhibitors, and other antihypertensive agents. For example, the compounds of this invention can be given in combination wit such compounds or salt or other derivative forms thereof as: Diuretics: acetazolamide; amiloride; bendroflumethiazide; benzthia-zide; bumetanide chlorothiazide; chlorthalidone; cyclothiazide; ethacrynic acid; furosemide; hydrochloro thiazide; hydroflumethiazide; indacrinone (racemic mixture, or as either the (+) or (- enantiomer alone, or a manipulated ratio, e.g., 9:1 of said enantiomers, respectively) metolazone; methyclothiazide; muzolimine; polythiazide; quinethazone; sodiu trichlormethiazide; α-Adrenergic Blocking Agents: dibenamine; phentolamine; phenoxybenzamine; prazosin; tolazoline; S-Adrenergic Blocking Agents: atenolol; metoprolol; nadolol; propranolol; timolol; ((±)-2-[3-(tert-butylammo)-2-hydroxyprorx)xy]-2-fur_man_lide) (ancarolol); (2-acetyl-7-(2-hydroxy-3-isopropylami_-opropoxy)ben∞fi_r_m HCl)(befunolol); ((±)-l-(isopropylamino)-3-(p-(2-cyclopropylmethoxyethyl)-phenoxy)-2-propranol HC1) (betaxolol); (l-[(3,4-dimethoxyρhenethyl)amino]-3-(m-tolyloxy)-2-propanolHCl)(bevantolol); (((±)-l-(4-((2-isopropoxye-hoxy)me_hyl)phenoxy)-3-isopropylamino-2-propanol) 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 Η-indol-4-yl)oxy)-2-pro-panol benzoate) (bopindolol); (l-(2-exobicyclo[2.2.1]-hept-2-ylρhenoxy)-3-[(l-methylethyl)-amino]-2-propanol HC1) (bomaprolol); (o-[2-hydroxy-3-[(2-indol-3-yl-l , l-dimemylethyl)-amino]propoxy]benzonitrile HC1) (bucindolol); (a-[(tert.burylan-__no)methyl]-7-ethyl-2-benzofii-ranmethanol) (bufiir-alol) ; (3-[3-acetyl-4-[3-(tert.butylamino)-2-hydroxypropyl]-ρhenyl]-l , 1-diethylurea HC1) (celiprolol); ((±)-2-p-P-[(l,l-dimethyleAyl)__mino]-2-hydroxypropoxy]phenoxy]-N-methylacetamide HC1) (cetamolol); (2-benzimidazolyl-phenyl(2-isopropylaminopropanol)); ((±)-3'-acetyl-4'-(2-hydroxy-3-isopropylammopropoxy)-acetanilideHCl) (diacetolol); (methyl-4-[2-hydroxy-3-[(l-methylethyl)aminopropoxyl]]-benzene-propanoate HC1) (esmolol); (erythro-DL-l-(7-methylmdan-4-yloxy)-3-isopropylaminobutan-2-ol); (l-(tert.butylamino)-3-[0-(2-propynyloxy)phenoxy]-2-propanol (pargo-lol) ; (l-(tert.butylamino)-3-[o-(6-hydrazino-3-pyridazinyl)phenoxy]-2-propanol diHCl) (prizidilol); ((-)-2-hydroxy-5-[(R)- l-hydroxy-2-[(R)-( l -methyl-3-phenylpropyl) amino]ethyl]ben___amide) ; (4-hydroxy-9-[2-hydroxy-3-(isopropylamino)-propoxy]-7-methyl-5H-furo[3,2-g][l]- benzopyran-5-one) (iprocrolol); ((-)-5-(tert.butylami_no)-2-hydroxyprorx ) xy]-3,4-dihydro-l-(2H)-naphthalenone HCl) Gevobunolol); (4-(2-hydroxy-3-isopropylamino-propoxy)- 1 ,2-benzisothiazole HCl) ; (4-[3-(tert.butylami_no)-2-hydroxypropoxy]-N-memyU_«x_art)ostyril HCl); ((±)-N-2-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]ethyl-N'-isopropylurea) (pafenolol); (3-[[(2-trifluoroacetaπύdo)ethyl]amino]-l-phenoxypropan-2-ol); (N-(3-(o-chlorophenoxy)-2-hydroxypropyl)-N'-(4'-chloro-2,3-dihydro-3-oxo-5- pyτidazinyl)ethylenediamine) ; ((±)-N-[3-acetyl-4-[2-hydroxy-3-[(l-methylethyl)amino]propoxyphenyl3-butanamide) (acebutolol); (( ± )-4 ' -[3-(tert-butylamino)-2-hydroxyproρoxy]sρiro[cyclohexane- 1 ,2 '-indan]- 1 '-one) (spirendolol); (7-[3-[[2-hydroxy-3-[(2-methylindol-4-yl)oxylpropyl]amino]butyl]thio-phylline) (teoprolol); ((±)-l-tert.butylamino-3-(thiochroman-8-yloxy)-2-propanol) (tertato-lol); ((±)-l-tert.butylamino-3-(2,3-xylyloxy)-2-propanol HCl) (xibenolol); (8-[3-(tert.butylamino)-2-hydroxypropoxy]-5-methylcOumarin) (bucumo-lol); (2-(3-(tert.butylan__i_-o)-2-hydroxy-propoxy)benzonitrile HCl) (bunitro-lol); ((±)-2 , -[3-(tert-butylam o)-2-hydroxypropoxy-5'-fluorobutyrophenone)(butofilolol); (l-(c_utazol-4-yloxy)-3-(isopropylamino)-2-propanol) (carazolol); (5-(3-tert.butylam__no-2-hydroxy)propoxy-3,4-dihydrocarbotyril HCl) (carteolol); (l-(tert.burylan__ino)-3-(2,5-dichlorophenoxy)-2-propanol) (clorano-lol); (l-(inden-4(or 7)-yloxy)-3-(isoρropylamino)-2-propanol HCl) Ondeno-lol); (l-isopropyl_unino-3-[(2-methylindol-4-yl)oxy]-2-propanol) (mepindo-lol); (1 -(4-acetoxy-2, 3 ,5-trimemylphenoxy)-3-isopropylaminopropan-2-ol) (metipranolol); (l-(isopropylamino)-3-(o-methoxyρhenoxy)-3-[(l-methylethyl)amino]-2-propanol) (moprolol); ((l-tert.buryl_ιmino)-3-[(5,6,7,8-tetr__hydro as-6,7-d__hydroxy-l-n_φhthyl)oxy]-2-p^^ (nadolol); ((S)-l-(2-cyclopentylphenoxy)-3-[(l , l-dimethylethyl)amino]-2-propanol sulfate (2: 1)) (penbutolol); (4'-[l-hydroxy-2-(ami_no)ethyl]me _ esulfonanilide) (sotalpl); (2-methyl-3-[4-(2-hydroxy-3-tert.butylaminopropoxy)phenyl]-7-methoxy-isoquinolin-l- (2H)-one); (l-(4-(2-(4-fluorophenyloxy)ethoxy)phenoxy)-3-i-»propylamino-2-propanol HCl) ; ((- p-[3-[(3,4-dime_hoxyphenethyl)ammo]-2-hydroxypropoxy]-/3-memyl-ci__-namonit_^ (pacrinolol); ((±)-2-(3'-tert.butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl)thiazole HCl) (arotinolol); ((±)-l-[p-[2-(cyclopropylmethoxy)ethoxy]phenoxy]-3-(isopropylamino)-2-propanol) (cicloprolol); ((±)-l-[(3-chloro-2-methylindol-4-yl)oxy]-3-[(2-phenoxyethyl)amino]-2-propanol) (indopanolol); ((±)-6-[[2-[[3-(p-butoxyphenoxy)-2-hydroxypropyl]amino]ethyl]amino]-l,3- dimethyluracil) (pirepolol); (4-(cyclohexylamino)-l-(l-naphtholenyloxy)-2-butanol); (l-phenyl-3-[2-[3-(2-cyanophenoxy)-2-hydroxypropyl]aminoethyl]hydan-toinHα); (3,4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy-2H-l-benzopyran) (nipradolol); Angiotensin I Converting Enzyme Inhibitors: l-(3-mercapto-2-methyl- l-oxopropyl)-L-proline (captopril) ; (l-(4-ethoxycariκ ) nyl-2,4(R,R)-dimemylbutanoyl)__ndoline-2(S)-car-boxy_icacid); (2-[2-[(l-(ethoxycarbonyl)-3-phenyl-propyl]amino]-l-oxopropyl]-l,2,3,4-tetrahydro-3- isoquinoline carboxylic acid); ((S)-l-p-[(l-(etlκ ) xyca_iκ ) nyl)-3-phenylpropyl]__mmo]-l-oxoproρyl]oct_ώydro-lH-mdole- 2-carboxylic acid HCl); (N-cyclopentyl-N-(3-(2,2-dimethyl-l-oxopropyl)thiol-2-methyl-l-oxo-proρyl)glycine) (pivalopril); ((2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-tW__zoUdme-carboxylicacid); (l-(N-[l(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl)-cis,syn-octa-hydroindol-2(S)- carboxylic acid HCl); ((-)-(-)- 1 -[(S)-3-mercapto-2-methyl- 1 -oxopropyl]indoline-2-carboxylic acid) ; ([ 1 (S) ,4S]- 1 -[3-(benzoylthio)-2-methyl- 1 -oxopropyl]-4-phenylthio-L-proline; (3-([l -ethoxycarbonyl-3-phenyl-( 1 S)-proρyl]amino)-2 , 3 , 4 ,5-tetrahydro-2-oxo- 1 -(3S) benzazepine-1-acetic acid HCl); (N-(2-benzyl-3-mercaptopropanoyl)-S-ethyl-L-cysteine) and the S-methyl analogue; (N-(l(S)-e_hoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prol__ne maleate) (enalapril); N-[l-(S)-carboxy-3-phenylpropyl]-L-alanyl-l-proline; N 2 -[l-(S)-c_uiκ)xy-3-phenylpropyl]-L-lysyl-L-pro-ine (lysinopril); Other Antihypertensive Agents: aminophylline; cryptenamine acetates and tannates; deserpidine; meremethoxylline procaine; pargyϋne; tri-methaphan camsylate; and the like, as well as admixtures and combinations thereof. Typically, the individual daily dosages for these combinations can range fro 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 coadministration are, o course, possible. Thus, the novel peptides of the present invention possess an excellent degree o activity in treating renin-associated hypertension and hyperaldosteronism. Renin inhibitors have also been disclosed to control the rise in intraocular pressure associated with the use of steroidal anti-inflammatory drugs as described in International Application PCT/US86/02291 (International Publication Number WO 87/02581 dated 7 May 1987). The peptides of the present invention are also useful as novel human retroviral protease inhibitory peptide analogs. Therefore, the peptides of the present invention inhibit retroviral proteases and thus inhibit the replication of the virus. They are useful for treating human patients infected with a human retrovirus, such as human immunode¬ ficiency virus (strains of HIV-1 or HTV-2) or human T-cell leukemia viruses (HTLV-I or HTLV-II) which results in acquired immunodeficiency syndrome (AIDS) and/or related diseases. The capsid and replicative enzymes (i.e. protease, reverse transcriptase, integrase) of retroviruses are translated from the viral gag and pol genes as polyproteins that are further processed by the viral protease (PR) to the mature proteins found in the viral capsid and necessary for viral functions and replication. If the PR is absent or nonfunctional, the virus cannot replicate. The retroviral PR, such as HTV-1 PR, has been found to be an aspartic protease with active site characteristics similar to those exhibited by the more complex aspartic protease, renin. The term human retrovirus (HRV) includes human immunodeficiency virus type I, human immunodeficiency virus type π, or strains thereof, as well as human T cell leukemia virus 1 and 2 (HTLV-1 and HTLV-2) or strains apparent to one skilled in the art, which belong to the same or related viral families and which create similar physiological effects in humans as various human retroviruses. Patients to be treated would be those individuals: 1) infected with one or more strains of a human retrovirus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) in the case of HIV, having either a symptomatic AIDS defining infection such as i) disseminated histoplasmosis, ii) isopsoriasis, iii) bronchial and pulmonary candidiasis including pneumocystic pneumonia iv) non- Hodgkin's lymphoma or v) Kaposi's sarcoma and being less than sixty years old; or having an absolute CD4 lymphocyte count of less than 200/m 3 in the peripheral blood. Treatment would consist of maintaining an inhibitory level of the peptide used according to this invention in the patient at all times and would continue until the occurrence of a second symptomatic AIDS defining infection indicates alternate therapy is needed. More specifically, an example of one such human retrovirus is the human immunodeficiency virus (HTV, also known as HTLV-m or LAV) which has been recognized as the causative agent in human acquired immunodeficiency disease syndrome (AIDS), P. Duesberg, Proc. Nad. Acad. Sci. USA, 86:755 (1989). HTV contains a retro viral encoded protease, HIV-I protease, that cleaves the fusion polypeptides into the functional proteins of the mature virus particle, E.P. Lillehoj, et al., J. Virology, 62:3053 (1988); C. Debuck, et al., Proc. Nail. 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. Nail. 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. , Biochem. 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 diseases caused by retroviruses, such as human acquired immunodeficiency disease syndrome (AIDS), using dosages, forms and modes of administration equivalent to those described abov for renin inhibition. 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 peptides of the present invention are also useful for treating non-human animals infected with a retrovirus, such as cats infected with feline leukemia virus. Other viruses that infect cats include, for example, feline infectious peritonitis virus, calicivirus, rabies virus, feline immunodeficiency virus, feline parvovims (panleukopenia virus), and feline chlamydia. Exact dosages, forms and modes of administration of the peptides of the present invention to non-human animals would be apparent to one o ordinary skill in the art, such as a veterinarian. The compounds of the present invention are prepared as depicted in the charts and as described more fully in the Preparations and Examples. In these charts, the variables are as defined above. CHART A Chart A describes the preparation of the novel transition state analog insert, 1- cyclohexyl-2S,6-diammo-3R,4S-dihydroxy-6-memy_lιeptane.Thisappropriatelyprotected building block is utilized in the construction of some of the peptides of the present invention. The preparation of the allylic alcohol of formula A-l is described in U.S. patent application, Serial No. 234,413, filed 19 August 1988. This alcohol is oxidized to the corresponding enone of formula A-2 with either manganese dioxide in hexane or 2,3- dichloro-5,6-dicyano-l,4-benzoquinone in dioxane. 1,4- Addition of gaseous ammonia in ethanol leads to the amino ketone of formula A-3 which is then protected under appropriate conditions (CbzCl, PrNEtz) on the amino group with a Z x group as in compound A-4 wherein Zj is carbobenzyloxy. The ketone is then reduced with sodium borohydride in the presence of cerium (ID) chloride, as described in G. Gajewsld, et al. , Syn. Commun. 10, 623 (1980), to give an 85:15 mixture ( 13 C-NMR) of epimeric alcohols of formula A-5. The acid labile protecting groups are then removed using hydrochloric acid in methanol to give the free amine of formula A-6. CHART B Chart B illustrates the preparation of the novel peptides N-tert-Butyloxycarbonyl- L-pheny_alanyl-L-histidyl-2S,6-diam__no-l-cyclohexyl-3R,4R-dihydroxy-6-methylheptane and N-tert-Butyloxycarixmyl-L-phenylalany^ dihydroxy-6-methylheptane of the present invention. The epimeric mixture of formula B-l (A-6), prepared as the compound of formula A-6 in Chart A, is coupled to Boc-His(Ts)-OH with diethylphosphoryl cyanide as the condensing agent to give the two epimeric compounds of formula B-2a (Rj =H, R 2 =OH) and B-2b (Rj=OH, R 2 =H) which are separated by column chromatography on silica gel. Each epimer is then carried on through the syntheses separately. Removal of the tert- butyloxy-carbonyl group with trifluoroacetic acid and coupling of the resulting amines to Boc-Phe-OH with diethylphosphoryl cyanide as the condensing agent gives the two epimers of formula B-3a and B-3b. The tosyl protecting group is then removed with 1- hydroxybenzotriazole to give the two epimers of formula B-4a and B-4b. Finally, the benzyloxycarbonyl protecting group is hydrogenolyzed (5% Pd/C, H 2 , ethanol) to give the final peptides of formula B-5a and B-5b. CHART C Chart C describes the preparation of the peptide BVal-Phe-His-X of the present invention. The peptide of formula C-l (wherein X is l-cyclohexyl-2S,6-diamino-3R,4S- dihydroxy-6-methylheptane; Cbz is carbobenzyloxy), prepared as the compound of formula B-3a or B-3b in Chart B, is deprotected with trifluoroacetic acid and the resulting amine is coupled to Boc-β-Val-OH to give the peptide of formula C-2. The tosyl group is removed with 1-hydroxybenzotriazole to give the compound of formula C-3. The Cbz group is removed by hydrogenolysis with palladium on charcoal and ammonium formate to give the compound of formula C-4. The Boc group is removed with trifluoroacetic acid to give the desired final peptide of formula C-5, which is isolated as the tris trifluoroacetate salt. CHART D Chart D describes the preparation of the peptide jSVal-Phe-N-Me-His-X of the present invention. The Boc-N-MeHis(Ts)-OH, obtained from as described in U.S. patent application, Serial No. 147,073, filed 20 January 1988, and in published European patent application, Serial No. 0 173 481, published 5 March 1986, is coupled to the transition-state-insert building block of formula A-6, prepared as described in Chart A, with diethylphosphoryl cyanide (DEPC) to give the compound of formula D-l (wherein X is l-cyclohexyl-2S,6- diamino-3R,4S-dihydroxy-6-methylheptane; Cbz is carbobenzyloxy). The Boc group is removed with acid and the resulting amine is coupled to Boc-Phe-OH employing bis(2- oxo-3-oxazolidinyl)phosphinic chloride (BOPC1) to give the peptide of formula D-2. The Boc group is removed under acidic conditions and the amine is then coupled to Boc- /..Val-OH to give the peptide of formula D-3. The tosyl group is removed with 1- hydroxybenzotriazole in methanol to give the compound of formula D-4. The Cbz group is removed with phase transfer hydrogenolysis to give the compound of formula D-5. Finally, the Boc group is removed with trifluoroacetic acid to give the desired final peptide of formula D-6 which is isolated as the tris trifluoroacetate salt. CHART E Chart E describes the preparation of the renin inhibitory peptide γGlu-Pro-Phe-N- Me-His-X of the present invention. Coupling of the amine from the peptide of formula E-l (D-2), prepared as the compound of formula D-2 in Chart D, with Boc-Pro-OH gives the compound of formula E-2. The Boc group is removed with acid and the resulting amine is coupled to Boc- γGlu(Boc)-OH to give the peptide of formula E-3. The tosyl group is removed with 1- hydroxybenzotriazole to give the compound of formula E-4. The Cbz group is removed with catalytic hydrogenolysis to give the compound of formula E-5. Finally, the Boc groups are removed with trifluoroacetic acid to give the final peptide of formula E-6, which is isolated as the tris trifluoroacetate salt. CHART F Chart F describes the preparation of the peptide Boc-0-MeTyr-His-X of the present invention. Coupling of the amine from the peptide of formula F-l (wherein X is 1- cyclohexyl-2S,6-diamino-3R,4S-dihydroxy-6-methylheptane; Cbz is carbobenzyloxy), prepared as the compound B-2a in Chart B, with Boc-O-Me-Tyτ-OH, obtained from Boc protection of commercial O-Me-Tyr-OH, gives the compound of formula F-2. The tosyl group is removed with 1-hydroxybenzotriazole to give the compound of formula F-3. The Cbz group is removed with catalytic hydrogenolysis to give the final peptide of formula F-4. CHART G Chart G describes the preparation of the peptide 7Glu-Pro-O-MeTyr-His-X of the present invention. The compound of formula G-l (F-2) is deprotected with trifluoroacetic acid. The resulting amine is coupled with Boc-Pro-OH using diethylphosphoryl cyanide to give the compound of formula G-2. The Boc group is removed with trifluoroacetic acid and the resulting amine is then coupled to Boc-τGlu(Boc)-OH using diethylphosphoryl cyanide to give the compound of formula G-3. The tosyl group is removed with 1- hydroxybenzotriazole to give the compound of formula G-4. The Cbz group is hydrogenolyzed to give the compound of Formula G-5. The two Boc groups are removed with trifluoroacetic acid to give the compound of formula G-6 which is isolated as the tris(trifluoroacetate) salt. CHART H Chart H describes the preparation of the peptide Glc-Pro-O-MeTyr-His-X of the present invention. The compound of formula H-l (F-2) is deprotected with trifluoroacetic acid. The resulting amine is coupled with the compound of formula 1-4 using diethylphosphoryl cyanide to give the compound of formula H-2. The acetyl and the tosyl groups are removed with methanolic ammonia to give the compound of formula H-3. The Cbz group is hydrogenolyzed to give the compound of formula H-4. CHART I Chart I describes the preparation of the compound of the formula 1-4, abbreviated as Glc(per Ac)-Pro-OH, which is used in the preparation of the intermediate compound of formula H-2 in Chart H. The compound of the formula 1-1, prepared as described in International Patent Application, PCT/US 89/00247, filed 27 January 1989, is reacted with proline benzyl ester hydrochloride of formula 1-2, which is commercially available, to give the compound of formula 1-3. Catalytic hydrogenolysis removes the benzyl ester protecting group to give the acid of formula 1-4. Generally, the renin inhibiting polypeptides may be prepared by solution phase peptide synthetic procedures analogous to those described hereinafter or to those methods known in the art. Appropriate protecting groups, reagents, and solvents for the solution phase method can be found in "The Peptides: Analysis, Synthesis, and Biology," Vols. 1-5, eds. E. Gross and T. Meienhofer, Academic Press, NY, 1979-1983; "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 N β -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 or peptide using a conventional coupling protocol such as dicyclohexyl- carbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) or diethylphosphoryl cyanide (DEPC) and triethylamine (Et 3 N) 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% diisopropylethylamine or sodium bicarbonate in methylene chloride. 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), benzyloxycaibonyl, acetyl, allyl, phthalyl, benzyl, benzoyl, trityl and the like. The following compounds of the present invention are preferred: /SVal-Phe-N-Me-His-X; 7Glu-Pro-0-MeTyr-His-X; N-tert-Butyloxycarbonyl-L-phenylalanyl-L-Wstidyl-2S,6-diamino-l-cyclohexyl- 3R,4S-dihydroxy-6-methylheptane; SVal-Phe-His-X; γGlu-Pro-Phe-N-Me-His-X; N-tert-Butyloxycartrønyl-L-phenyla_anyl-L-Wstidyl-2S,6-diaπ_ino-l-cyclohexyl- 3R,4R-dihydroxy-6-methylheptane; and Boc-O-MeTyr-His-X. The following compounds of the present invention are more preferred: /SVal-Phe-His-X; τGlu-Pro-Phe-N-Me-His-X; N-tert-Butyloxycart ) onyl-L-phenyl_danyl-L-histidyl-2S,6-d_amino-l-cyclohexyl- 3R,4R-dihydroxy-6-methylheptane; and Boc-O-MeTyr-His-X. The following compounds of the present invention are most preferred: N-tert-Butyloxycarbonyl-L-phenyla_anyl-L-_ύstidyl-2S,6-diamino-l-cyclohexyl- 3R,4R-dihydroxy-6-methylheptane; and Boc-O-MeTyr-His-X. DESCRIPTION OF THE PREFERRED EMBODIMENTS The following Preparations and Examples illustrate the present invention. In the Preparations and Examples below and throughout this document: 'H-NMR is nuclear magnetic resonance BOC is t-butoxycarbonyl Bz is benzyl C is centigrade Cbz is benzyloxycarbonyl CDC1 3 is deuteriochloroform Celite is a filter aid CVA is Cha^[CH(OH)CHJVal DCC is dicyclohexylcarbodiimide DEPC is diethylphosphoryl cyanide EtOAc is ethyl acetate g is grams γ-Glu is γ-glutamic acid His is histidine N-MeHis is Not-methyl histidine HOBT is 1-hydroxybenzotriazole HPLC is high performance liquid chromatography IR is infrared spectra LVA is Leuφ(CH(0H)CH 2 )Val with the S configuration at C4 (the hydroxyl bearing carbon atom) M or mol is mole Me is methyl min is minute mL is milliliter MPLC is medium pressure liquid chromatography MS is mass spectroscopy Ph is phenyl Phe is phenylalanine Pro is proline 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-inhibiting peptide TEA is triethylamine TFA is trifluoroacetic acid THF is tetrahydrofuran TLC is thin layer chromatography Tos is p-toluenesulfonyl TsOH is p-toluenesulfonic acid Tyr is tyrosine (OCH 3 )Tyr is O-methyl tyrosine /S-Val is jS-Valine. 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. In the examples below, the renin inhibitory activity of the compounds of the present invention ( Vs) are determined using the in vitro test described in U.S. patent application, Serial No. 07/147,073, filed 20 January 1988, and in published European patent application 0 173 481, published 5 March 1986, pages 103-105, which arc hereby incorporated by reference. Compounds of the present invention have also exhibited renin-inhibitory activity during in vivo testing. In the examples below, HPLC is high pressure liquid chromatography and k' is the partition ratio obtained. The solvent system used is indicated in parentheses after the partition ratio. HPLC is performed on a Perlrin-Elmer Series IV liquid chromatograph operating at 1.5 mlJmin through a Brownlee RP-18 10 micron column, with UV monitoring by a Kratos Spectroflow 773 detector. A Perkin-Elmer LCI-100 integrator is used for peak data. Solvent A is 90% by volume Burdick & Jackson water, 10% acetonitrile, and 0.1% trifluoroacetic acid; solvent B is 10% by volume Burdick & Jackson water, 90% acetonitrile, and 0.1% trifluoroacetic acid. Preparation 1 l-[3-tert-Butyloxycarbonyl-4S-cyclohexyl-methyl-2,2- dime_hyl-5R-oxazolidinyl]-3-methyl-l-oxo-trans-2- butene (Formula A-2) Refer to Chart A. To a stirred solution of 5.51 g of the allylic alcohol of formula A-l in 50 mL of hexane is added 24 g of manganese dioxide. After stirring for 2 days, the mixture is filtered through Celite with hexane and then dichloromethane washings. The filtrate is concentrated and the residue chromatographed on silica gel with 5%-10% ether in hexane to give 1.3 g of the title product. Continued elution with 15% ethyl acetate in hexane gives 1.88 g of the major, less polar allylic alcohol and 1.19 g of the minor, more polar allylic alcohol (A-l). Alternatively, to a stirred solution of 2.0 g of the allylic alcohol of formula A-l in 20 mL of dioxane is added 4.0 g of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone. After stirring at room temperature for 4 days, the mixture is diluted with dichloromethane and then washed with aqueous sodium bicarbonate. The aqueous phase is extracted with several portions of dichloromethane and the organic phase is then dried (magnesium sulfate) and concentrated. The residue is chromatographed on silica gel with 10% ethyl acetate in hexane to give 1.076 g of the title product. Physical characteristics are as follows: Η NMR (CDC1 3 ): δ 1.34, 1.36, 1.45, 1.83, 2.07, 4.0, 4.3, 6.4. IR (mull, cm 1 ): 1702, 1625. [α] D = -8° (C=1.011, chloroform). HRMS: Found 379.2749. Anal.: Found C, 69.59; H, 9.36; N, 3.74. Preparation 2 3- Amino- 1 -[3-tert-butyloxycarbonyl-4S-cyclohexyl-methyl-2,2-dimethyl 5R-oxazolidinyl]-3-methyl- 1-oxo-butane (Formula A-3) Refer to Chart A To a solution of 1.18 g of the title product of Preparation 1 in 10 mL of absolut ethanol at -15° C is passed gaseous ammonia until saturated.. The container is sealed an the content allowed to warm to room temperature. After a few hours, the container i recooled to -15 °C and a stream of nitrogen is passed through the content while th container is allowed to warm to room temperature. The content is concentrated and th residue flash-chromatographed on silica gel with 3% methanol (saturated with ammonia in dichloromethane to give 1.24 g of the title product. Physical characteristics are as follows: Η NMR (CDC1 3 ): δ 1.20, 1.21, 1.47, 1.48, 1.52, 2.68, 2.80, 4.09, 4.35. Preparation 3 3-Benzyloxycarbonylamino-l-[3-tert-butyloxycarbonyl-4S-cycloh exyl-methyl-2,2-dimethyl-5R-oxazolidinyl]-3-methyl-l-oxo-butan (Formula A-4: Z, is benzyloxycarbonyl) Refer to Chart A. To a stirred solution of 1.11 g of the title product of Preparation 2 in 30 mL o dichloromethane is added 0.7 mL of diisopropylethylamine and then 0.55 mL o benzylchloroformate. After stirring at room temperature for 3 hours, the mixture i diluted with dichloromethane and then washed successively with aqueous citric acid saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. Th organic phase is dried (magnesium sulfate) and then concentrated. The residue i chromatographed on silica gel with 10%-20% ethyl acetate in hexane to give 1.24 g o the title product. Physical characteristics are as follows: »H NMR (CDC1 3 ): δ 1.40, 1.42, 1.46, 1.51, 1.57, 3.1, 4.07, 4.32, 5.03, 7.34 IR (neat, cm 1 ): 1724, 1701. [d] D =+8° (C=0.391, chloroform). HRMS: Found 531.3436. Anal.: Found C, 67.45; H, 8.19; N, 5.67. Preparation 4 3-Benzyloxycarbonylamino- l-[3-tert-butyloxycarbonyl-4S-cyclohexyl methyl-2,2-dimethyl-5R-oxazolidinyl]-3-methyl-lR and lS-butano (Formula A-5: Zj is benzyloxycarbonyl) Refer to Chart A. To a stirred solution of 712 mg of the title product of Preparation 3 and 550 m of cerium (HI) chloride heptahydrate in 15 mL of methanol at 0°C under argon is adde 80 mg of sodium borohydride. After 1.5 hours, 10 mL of water is added and the mixture is partitioned between water and diethylether. The organic phase is dried (magnesium sulfate) and then concentrated. The residue is chromatographed on silica gel with 15% ethyl acetate in hexane to give 670 mg of the title product. Physical characteristics are as follows: Η NMR (CDC1 3 ): δ 1.37, 1.42, 1.48, 1.51, 1.54, 3.55, 3.79, 4.10, 5.03, 7.33. IR (mull, cm' 1 ): 3364, 1728, 1701, 1671. HRMS: Found 533.3599. Anal.: C, 67.69; H, 9.12; N, 5.25. Preparation 5 2S-Ammo-6-benzyloxycarrx)nylamino-l-cyclohexyl-3R,4R and 4S- dihydroxy-6-methylheptane (Formula A-6: Zj is benzyloxycarbonyl) Refer to Chart A. A solution of 0.14 mL of acetyl chloride in 2 mL of methanol is allowed to stir for 15 minutes; then 120 mg of the title product of Preparation 4 is dissolved and allowed to stir at room temperature. After 4 hours, 350 mg of solid sodium bicarbonate is slowly added. After stirring for 30 minutes, the mixture is filtered with dichloro¬ methane washings. The concentrated residue is triturated with ether and then filtered through Celite. The filtrate is concentrated to give 92 mg of the title product. Physical characteristics are as follows: Η NMR (CDC1 3 ): δ 1.37, 5.03, 7.32. Preparation 6 N-tert-Butyloxycartronyl--^-tosyl-L-histid ylamino-l-cyclohexyl-3R,4Rand4S-dihydroxy-6-methylheptane(Foπnula B-2a and B-2b: Z t is Cbz) Refer to Chart B. To a stirred solution of 92 mg of the title product of Preparation 5 and 100 mg of N-tert-butyloxycarbonyl-N- > -tosyl-L-histidine in 2 mL of dichloromethane is added 0.07 mL of diisopropyldiethylamine and 0.04 mL of diethylphosphoryl cyanide. After stirring overnight, the concentrated mixture is chromatographed on silica gel with 30%- 50% ethyl acetate in dichloromethane to give 47.8 mg of the less polar title product of formula B-2a and 35 mg of the more polar title product of formula B-2b. Physical characteristics are as follows: FAB-HRMS: Found 784.3963. *H NMR (CDC1 3 ) is consistent with structure. Preparation 7 N-tert-Butyloxycariκ ) nyl-L-phenyl_danyl-N"-tosyl-L-histidyl-2S-amino-6- benzyloxycart)onylamino-l-cyclohexyl-3R,4R and 4S-dihydroxy-6- methylheptane (Formula B-3a and B-3b: Z, is Cbz) Refer to Chart B. A solution of 47.8 mg of the less polar title product of formula B-2a o Preparation 6 in 1 mL of 1:1 = trifluoroacetic acid:dichlρromethane is allowed to stir for 45 minutes. The mixture is then partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase is dried (magnesium sulfate) and then concentrated to give 41.5 mg of the corresponding amine. To a stirred solution of this amine and 19 mg of N-tert-butyloxycarbonyl-L-phenylalanine in 0.5 mL of dichloromet¬ hane is added 0.03 mL of diisopropylethylamine and 0.012 mL of diethyl-phosphoryl cyanide. After stirring overnight, concentrated mixture is then chromatographed on silica gel with 1:1 = ethylacetate: dichloromethane to give 49 mg of the title product o formula B-3a. By the same procedure 35 mg of the more polar title product of formula B-2b o Preparation 6 is converted to 32 mg of the title product of formula B-3b. Physical characteristics are as follows: FAB-HRMS: Found 931.4641. l H NMR (CDC1 3 ) is consistent with structure. Preparation 8 N-tert-Butyloxyc_ιιtonyl-L-phenylalanyl-L-histidyl-2S-ammo-^benzyloxy- carbonylamino-l-cyclohexyl-3R,4R and 4S-dihydroxy-6-methylheptane (Formula B-4a and B-4b: Z, is Cbz) Refer to Chart B. A solution of 49 mg of the title product of formula B-3a of Preparation 7 and 30 mg of l-hydroxybenzotriazole in 0.5 mL of methanol is allowed to stir at room temperature for 4 hours. The concentrated mixture is then chromatographed on silica gel with 4% -8% methanol (saturated with ammonia) in dichloromethane to give 40 mg of the title product of formula B-4a. By the same procedure 32 mg of the title product of formula B-3b of Preparation 7 is converted to 25 mg of the title product of formula B-4b. Physical characteristics are as follows: ! H NMR (CDC1 3 ) is consistent with structure. Examples 1 and 2 L-Histidinamide, N-[(l,l-dimethylethoxy)carbonyl]-L-phenylal- anyl-N-[5-amino- 1 -(cyclohexylmethyl)-2 , 3-d_hydroxy-5-methylhe- xyl]-, or N-tert-Butyloxycarbonyl-L-phenylalanyl-L-histidyl-2S,6- diamino-l-cyclohexyl-3R,4R and 4S-dihydroxy-6-methylheptane (Formula B-5a and B-5b) Refer to Chart B. A mixture of 40 mg of the title product of formula B- a of Preparation 8 and 30 mg of 5% palladium on charcoal in 1 mL of absolute ethanol is shaken under 50 psi of hydrogen for 3 hours. The mixture is filtered through Celite with ethanol washings and the filtrate is then concentrated to give 28 mg of the title product of formula B-5a. By the same procedure 25 mg of the title product of formula B-4b of Preparation 8 is converted to 18 mg of the title product of formula B-5b. Physical characteristics are as follows: Formula B-5a: FAB-HRMS: Found 643.4202. I oCM): 3,2 x 10 "9 . Formula B-5b: FAB-HRMS: Found 643.4183. IC»(M): 6.4 x 10 4 . Preparation 9 Boc-3Val-Phe-His(Ts)-X(Cbz) (Formula C-2: X is 1-cyclohexyl- 2S ,6-diam__no-3R,4S-dihydroxy-6-methylheptane; Cbz is benzylox- ycarbonyl.) Refer to Chart C. To a solution of 168 mg of Boc-Phe-His(Ts)-X(Cbz) of Preparation 7 in 1.5 mL of dichloromethane is added 1.5 mL of trifluoroacetic acid and then allowed to stir at room temperature. After 45 minutes, the reaction mixture is diluted with dichloromet¬ hane and then added slowly to a saturated aqueous solution of sodium bicarbonate. The resulting mixture is separated and the aqueous layer extracted with several portions of dichloromethane. The combined organic phase is dried (magnesium sulfate) and then concentrated to give the free amine. . To a stirred solution of 126 mg of H-Phe-His(Ts)-X(Cbz) and 50 mg of Boc- β Val-OH in 2 mL of dichloromethane is added 50 μl of dϋsopropylethylamine, followed by 35 μL of diethylphosphoryl cyanide. The reaction mixture is stirred for 15 hours and then flashed chromatographed on silica gel with 3% to 4% methanol in dichloromethane to afford 143 mg of the title compound as a glassy white solid. Physical characteristics are as follows: FAB-HRMS: (m+H)= 1030.535. Preparation 10 Boc-3Val-Phe-His-X(Cbz) (Formula C-3: X is l-cyclohexyl-2S,6 diaminc-3R,4S-dihydroxy-6-methylheptane; Cbz is benzylox¬ ycarbonyl.) Refer to Chart C. To a flask containing 143 mg of the title product of Preparation 9 and 85 mg of 1-hydroxybenzotriazole hydrate is added 1.5 mL of methanol. After dissolution, the flask is capped and left to stir at room temperature. After 2.5 days, the reaction mixture is then concentrated under reduced pressure. Chromatography of the residue on silica with 3% to 5% methanol (saturated with ammonia) in dichloromethane affords 120 mg of the title product as a glassy white solid. Physical characteristics are as follows: FAB-HRMS: (m+H) =876.5247. Preparation 11 Boc-βVal-Phe-His-X (Formula C-4: X is 1-cyclohexyl- 2S,6-diamino-3R,4S-dihydroxy-6-methylheptane; Cbz is benzyloxycarbonyl.) Refer to Chart C. To a mixture of 120 mg of the title product of Preparation 10, 75 mg of 5% Pd C, and 195 mg of ammonium formate is added 1.5 mL of dimethylformamide. The resulting black slurry is back-filled with argon gas and rapidly stirred at room temperature. After 40 hours, the reaction mixture is diluted with dichloromethane and then filtered through Celite with methanol/methylene chloride washings. The filtrate is concentrated and dimethylformamide removed under high vacuum. The residue is chromatographed on silica gel with 10% to 20% methanol (saturated with ammonia) in dichloromethane to afford 79 mg of the title compound as a white solid. Physical characteristics are as follows: FAB-HRMS: (m+H) =742.4851. Example 3 L-Arabino-heptitol, 6-amino-2-[[N-[N-(3-amino-3-methl-l- oxobutyl)-L-phenylalanyl]-L-Wstidyl]amino]-l-cyclohexyl-l,2,5- ,6,7-pentadeoxy-6-C-methyl-, tris(trifluoroacetate) (salt) or 0Val- Phe-His-X (Formula C-5: X is l-cyclohexyl-2S,6-diamino-3R,4S- dihydroxy-6-methylheptane; Cbz is benzyloxycarbonyl.) Refer to Chart C. A solution of 79 mg of the title product of Preparation 11 in 1.0 mL of 1:1 trifluoroacetic acid-dichloromethane is allowed to stir for one hour and is dripped slowly into a rapidly stirred 1:2 ether-hexane solution. The precipitated solid is spun down, washed trice with 1:2 ether-hexane and dried under both house and high vacuum to afford 95 mg of the title product as a white solid. Physical characteristics are as follows: FAB-HRMS: (m+H) =642.4363. HPLC (20/80 A/B; 225 nm) k'=5.21. I oCM). 2.4 x 10 . Preparation 12 Boc-N-Me-His(Ts)-X(Cbz) (Formula D-l: X is 1-cyclohexyl- 2S,6-diamino-3R,4S-dihydroxy-6-methylheptane; Cbz is benzylox- ycarbonyl.) Refer to Chart D. To a stirred solution of 470 mg of H-X(Cbz) and 800 mg of Boc-N-Me-His(Ts)- OH in 10 mL of dichloromethane is added 0.38 mL of diisopropylethylamine, followed by 0.29 mL of diethylphosphoryl cyanide. The reaction mixture is stirred overnight, then flash chromatographed on silica gel with 25% to 50% ethyl acetate in dichlorome- thane to afford 685 mg of the title compound as a pale tan solid. Physical characteristics are as follows: FAB-HRMS: (m+H) =798.4094. Preparation 13 Boc-Phe-N-Me-His(Ts)-X(ebz) (Formula D-2: X is 1- cycIohexyl-2S,6-diamino-3R,4S-dihydroxy-6-methylhep- tane; Cbz is benzyloxycarbonyl.) Refer to Chart D. To a solution of 685 mg of the title product of Preparation 12 in 5 mL of dichloromethane is added 5 mL of trifluoroacetic acid. The solution is allowed to stir for one hour. The reaction mixture is diluted with dichloromethane and then added to a stirring solution of saturated aqueous sodium bicarbonate. The resulting mixture is separated and the aqueous layer extracted with several portions of dichloromethane. The combined organic phase is dried (magnesium sulfate) and then concentrated to give 610 mg of the free amine. To a stirred solution of 610 mg of H-N-Me-His(Ts)-X(Cbz) and 330 mg of Boc- Phe-OH in 9 mL of dichloromethane is added 0.27 mL of diisopropylethylamine, followed by 320 mg of bis(2-oxo-3-oxazoUdinyl)pho_φhinic chloride (BOPCl). The reaction mixture is stirred overnight and then flash chromatographed on silica gel with 0% to 5% methanol in dichloromethane to afford 690 mg of the title compound as a pale yellow solid. Physical characteristics are as follows: FAB-HRMS: (m+H) =945.4805. Preparation 14 Boc-/SVal-Phe-N-Me-His(Ts)-X(Cbz) (Formula D-3: X is l-cyclohexyl-2S,6-diamino-3R,4S-dihydroxy-6-methylhep- tane; Cbz is benzyloxycarbonyl.) Refer to Chart D. To a solution of 690 mg of the title product of Preparation 13 in 4 mL of dichloromethane is added 4 mL of trifluoroacetic acid. The solution is allowed to stir for 1.5 hours. The reaction mixture is diluted with dichloromethane and then added to a stirring solution of saturated aqueous sodium bicarbonate. The resulting mixture is separated and the aqueous layer extracted with several portions of dichloromethane. The combined organic phase is dried (magnesium sulfate) and then concentrated to give 593 mg of the free amine. To a stirred solution of 200 mg of H-Phe-N-Me-His(Ts)-X(Cbz) and 75 mg of Boc-jSVal-OH in 3 mL of dichloromethane is added 75 μL of diisopropylethylamine, followed by 55 μL of diethylphosphoryl cyanide. The reaction mixture is stirred overnight, then flash chromatographed on silica with 20% to 50% ethyl acetate in hexane to afford 181 mg of the title compound as a tan solid. Physical characteristics are as follows: FAB-HRMS: (m+H)=1044.551. Preparation 15 Boc-3Val-Phe-N-Me-His-X(Cbz) (Formula D-4: X is 1- cyclohexyl-2S,6-diamino-3R,4S-dihydroxy-6-methylhep- tane; Cbz is benzyloxycarbonyl.) Refer to Chart D. A solution of 181 mg of the title product of Preparation 14 and 150 mg of 1- hydroxybenzotriazole hydrate in 2 mL of methanol is allowed to stir for 3.5 days and is then concentrated under reduced pressure. Chromatography of the residue on silica with 5% to 7% methanol (saturated with ammonia) in dichloromethane affords 128 mg of the title peptide as a white solid. Physical characteristics are as follows: FAB-HRMS: (m+H) =890.5379. Preparation 16 Boc-0Val-Phe-N-Me-His-X (Formula D-5: X is 1-cycloh- exyl-2S,6-diamino-3R,4S-dihydroxy-6-methylheptane;Cbz is benzyloxycarbonyl.) Refer to Chart D. To a flask containing 128 mg of the title product of Preparation 15, 75 mg of 5% Pd/C, and 210 mg of ammonium formate is added 1.5 mL of dimethylformamide. After stirring 2 days under an argon atmosphere, the reaction mixture is diluted with dichloromethane and then filtered through Celite cotton plug with dichloromethane washings of the filter cake. The filtrate is concentrated and dimethylformamide removed on high vac. The residue is chromatographed on silica gel with 10% to 20% methanol (saturated with ammonia) in dichloromethane to afford 74 mg of the title product as a white solid. Physical characteristics are as follows: FAB-HRMS: (m+H) =756.5021. Example 4 L-Arabino-heptitol, 6-ammo-2-[P^-r^-(3-amino-3-methyl-l-oxobutyl)-L- phenylalanyl]-N-methyl-L-histidyl]amino]- 1,2,5,6, 7-pentadeoxy- 1 - cyclohexyl-6-methyl-, tris (trifluoroacetate) (salt) or j8Val-Phe-N-Me-His- X (Formula D-6: X is l-cyclohexyl-2S,6-diamino-3R,4S-dihydroxy-6- methylheptane; Cbz is benzyloxycarbonyl.) Refer to Chart D. A solution of 74 mg of the title product of Preparation 16 in 1 mL of 1:1 tetrahydrofuran-dichloromethane is allowed to stir for one hour and is then dripped slowly into 90 mL of rapidly stirred 1:2 ether-hexane. The solution immediately begins to turn cloudy and the flocculent white product is allowed to form over 0.5 hour. The precipitated solid is spun down, washed twice with 1:2 ether-hexane, and carefully dried under both house and high vacuum to afford 90 mg of the title product as a white solid. Physical characteristics are as follows: FAB-HRMS: (m+H) =656.4495. HPLC (20/80 AJB; 225 nm) k'=7.35. IC 5 o(M): 1.5 x 10 "7 . Preparation 17 Boc-Pro-Phe-N-Me-His(Ts)-X(Cbz) (Formula E-2: X is l-cyclohexyl-2S,6-di__ιmino-3R,4S-dilιydroxy-6-methylhep- tane; Cbz is benzyloxycarbonyl.) Refer to Chart E. To a stirred solution of 200 mg of the deprotected title product of formula E-l, i.e., H-Phe-N-Me-His(Ts)-X-(Cbz), prepared as described in the first paragraph of Preparation 13, and 75 mg of Boc-Pro-OH in 3 mL of dichloromethane is added 75 μL of dusoprcφylethylamine, followed by 55 μL of diethylphosphoryl cyanide. The reaction mixture is stirred for 20 hours, then flash chromatographed on silica with 0% to 5% methanol in dichloromethane to afford 240 mg of d e title product. Physical characteristics are as follows: FAB-HRMS: (m+H) =1042.537. Preparation 18 Boc-γGlu(Boc)-Pro-Phe-N-Me-His(Ts)-X(Cbz) (Formula E- 3: X is l-cyclohexyl-2S,6-diamino-3R,4S-dihydroxy-6- methylheptane; Cbz is benzyloxycarbonyl.) Refer to Chart E. A solution of 240 mg of the title product of Preparation 17 in 1.5 mL of dichloromethane is added 1.5 mL of trifluoroacetic acid and then allowed to stir at room temperature. After two hours, the reaction mixture is diluted with dichloromethane and then slowly to a saturated aqueous solution of sodium bicarbonate. The resulting mixture is separated and the aqueous layer extracted with several portions of dichloromethane. The combined organic phase is dried (magnesium sulfate) and then concentrated to give the free amine. To a stirred solution of 204 mg of H-Pro-Phe-N-Me-His(Ts)-X(Cbz) and 160 mg of Boc-τGlu(Boc)-OH dicyclohexylamine salt in 3 mL of dichloromethane is added 70 μL of diisopropylethylamine, followed by 50 μL of diethylphosphoryl cyanide. The reaction mixture is stirred for 3.5 days and then flash chromatographed on silica gel with 0% to 5% methanol in dichloromethane to afford 246 mg of the title product as a pale orange foam. Physical Characteristics are as follows: FAB-HRMS: (m+H) =1227.636 Preparation 19 Boc-7Glu(Boc)-Pro-Phe-N-Me-His-X(Cbz) (Formula E-4: X is l-cyclohexyl-2S,6-diamino-3R,4S-dihydroxy-6- methylheptane; Cbz is benzyloxycarbonyl.) Refer to Chart E. To a flask containing 246 mg of the title product of Preparation 18 and 123 mg of 1-hydroxybenzotriazole hydrate is added 2 mL of methanol. After dissolution, the flask is allowed to stir for 24 hours and is then concentrated under reduced pressure. Chromatography of the residue on silica with 5% to 10% methanol (saturated with ammonia) in dichloromethane affords 163 mg of the title product as a glassy white solid. Physical Characteristics are as follows: FAB-HRMS: (m+H) =1073.638. Preparation 20 Boc-γGlu(Boc)-Pro-Phe-N-Me-His-X (Formula E-5: X is l-< clohexyl-2S,6-diamino-3R,4S-dihydroxy-6-methylhep- tane; Cbz is benzyloxycarbonyl.) Refer to Chart E. To a flask containing 163 mg of the title product of Preparation 19, 100 mg of 5% Pd C, 150 mg of ammonium formate is added 2 mL of dimethylformamide. After stirring for 5 days, the reaction mixture is diluted with dichloromethane and filtered through Celite. The filter cake is washed with methanol/methylene chloride. The combined filtrates are concentrated and dimethylformamide removed under high vacuum. The residue is chromatographed on silica gel with 10% to 20% methanol (saturated witii ammonia) in dichloromethane to afford 69 mg of die title product. Physical Characteristics are as follows: FAB-HRMS: (m+H) =939.5910. Example 5 L-A_r._bmo-heptitol -ammo-l,2,5,6,7-pentadeoxy-l-cyclohexyl-2-[lN-[N- (l-L-γ-glutamyl-L-prolyl)-L-phenyla_anyl]-N-methyl-L-histidyl]amino]-6- methyl-tris(trifluoroacetate) (salt) or γGlu-Pro-Phe-N-Me-His-X (Formula E-6: X is l-cyclohexyl-2S,6-diamino-3R,4S-dihydroxy-6-methylheptane; Cbz is benzyloxycarbonyl.) Refer to Chart E. To a flask containing 69 mg of the title product of Preparation 20 is added 1 mL of trifluoroacetic acid. After one hour the reaction mixture is slowly dripped into 90 mL of a rapidly stirred 1:2 ether-hexane. After 0.5 hour the precipitated solid is spun down, washed twice with 1:2 ether-hexane, and dried under both house and high vacuum to afford 74 mg of the title product as a creme-white solid. Physical Characteristics are as follows: FAB-HRMS: (m+H) =783.4758; HPLC (20/80 A/B; 225 nm) k' =7.35. IC JO (M):2.6 x 10 4 . Preparation 21 Boc-0-MeTyr-His(Ts)-X(Cbz) (Formula F-2: X is 1- cyclohexyl-2S,6-diamino-3R,4S-dihydroxy-6-methylhep- tane; Cbz is benzyloxycarbonyl.) Refer to Chart F. To a flask containing 90 mg of the deprotected compound of formula F-l of Preparation 6, i.e., H-His(Ts)-X(C_bz) and 80 mg of Boc-Tyr(OMe)-OH dicyclohexyl- amine salt is added 2 mL of dichloromethane. After dissolution of the solids, 35 μL of diisopropylethylamine and 25 μL of diethylphosphoryl cyanide are added. The reaction mixture is stirred overnight and tiien the solvent is removed at reduced pressue. The residue is chromatographed on silica gel with 40% ethyl acetate in hexane to afford 104 mg of me title product as a light brown solid. Physical Characteristics are as follows: FAB-HRMS: (m+H) =961.4742. Preparation 22 Boc-0-MeTyr-His-X(Cbz) (Formula F-3: X is 1-cyclo exyl-2S,6-diaιn o-3R,4S-dihydroxy-6-methylheptane;C is benzyloxycarbonyl.) Refer to Chart F. To a flask containing 104 mg of the title product otPreparation 21 and 66 mg 1-hydroxybenzotriazole hydrate is added 1.5 mL of methanol. After dissolution, t flask is allowed to stir for 15 hours and is then concentrated under reduced pressu Chromatography of the residue on silica with 5% to 7% methanol (saturated wi ammonia) in dichloromethane affords 54 mg of the title product as a white solid. Physical Characteristics are as follows: FAB-HRMS: (m+H)=807.4640. Example 6 L-Arabino-heptitol^ammc>-l-cyclohexyl-l,2,5,6,7-pentadeoxy-2-[IN-r [( 1 , 1 -dimethylethoxy)C-_rbonyl]-0-methyl-L-tyrosyl]-L-Wstidyl]amino- methyl-, or Boc-O-MeTyr-His-X (Formula F-4: X is l- yclohexyl-2S, diamino-3R,4S-dihydroxy-6-methylheptane; Cbz is benzyloxycarbonyl Refer to Chart F. To a Parr pressure test tube containing 40 mg of 5 % pallidium on carbon is adde 54 mg of the title product of Preparation 22 as a solution in 2 mL of absolute ethano The resulting black slurry is placed on a Parr shaker at a hydrogen gas pressure of @5 psi. After shaking for 5 hours, the reaction mixture is filtered through Celite. The filt cake is washed with absolute ethanol and the combined filtrates concentrated at reduc pressure. Further concentration of the reaction mixture under high vacuum affords 4 mg of the title product as a white solid. Physical Characteristics are as follows: FAB-HRMS (m+H)=673.4293; HPLC (60/40 AJB; 225 nm) k' = 10.07. ICso M): 3.4 x lO . Preparation 23 Boc-Pro-O-MeTyr-His(Ts)-X(Cbz) (Formula G-2: X is cyclohexyl-2S,6-diamino-3R,4S-dihydroxy-6-methylhe tane; Cbz is benzyloxycarbonyl.) Refer to Chart G. A solution of 118 mg of Boc-0-MeTyr-His(Ts)-X(Cbz) of formula G-l in 1 m of dichloromethane is added 1 mL of trifluoroacetic acid and then allowed to stir at roo temperature. After one hour, the reaction mixture is diluted with dichloromediane an then added slowly to a saturated aqueous solution of sodium bicarbonate. The resultin mixture is separated and d e aqueous layer extracted with several portions of dichlorome¬ thane. The combined organic phase is dried (magnesium sulfate) and then concentrated to give 102 mg of me free amine. To a stirred solution of 51 mg of H-O-MeTyr-His(T_s)-X(Cbz) and 18 mg of Boc- Pro-OH in 1 mL of dichloromethane is added 19 μL of diisopropylethylamine, followed by 13 μL of diethylphosphoryl cyanide. The reaction mixture is stirred overnight and then flask chromatographed on silica gel with 5% methanol in dichloromethane to afford 63 mg of the title product. Physical Characteristics are as follows: FAB-HRMS: (m+H) =1058.528. Preparation 24 Boc-7Glu(Boc)-Pro-O-MeTyr-His(Ts)-X(Cbz)(FormulaG- 3: X is l-cyclohexyl-2S,6-diamino-3R,4S-dihydroxy-6- methylheptane; Cbz is benzyloxycarbonyl.) Refer to Chart G. A solution of 63 mg of the title product of Preparation 23 in 0.5 mL of dichloromethane is added 0.5 mL of trifluoroacetic acid and then allowed to stir at room temperature. After one hour, the reaction mixture is diluted with dichloromethane and then added slowly to a saturated aqueous solution of sodium bicarbonate. The resulting mixture is separated and the aqueous layer extracted witii several portions of dichlorome- thane. The combined organic phase is dried (magnesium sulfate) and tiien concentrated to give the free amine. To a stirred solution of 52 mg of H-Pro-O-MeTyr-His(Ts)-X(Cbz) and 34 mg of Boc-τGlu(Boc)-OH dicyclohexylamine salt in 2 mL of dichloromethane is added 15 μL of diisopropylethylamine, followed by 11 μL of diethylphosphoryl cyanide. The reaction mixture is stirred overnight and then flash chromatographed on silica gel with 5% methanol in dichloromethane to afford 49 mg of me title product. Physical Characteristics are as follows: FAB-HRMS: (m+H) =1243.629. Preparation 25 Boc-γGlu(Bc )-Pro-C ) -MeTyr-His-X(Cbz) (Formula G-4: X is l-cyclohexyl-2S,6-diamino-3R,4S-dihydroxy-6- methylheptane; Cbz is benzyloxycarbonyl.) Refer to Chart G. To a flask containing 49 mg of the title product of Preparation 24 and 24 mg of 1-hydroxy-benzotriazole hydrate is added 2 mL of methanol. After dissolution, die flask is allowed to stir for 24 hours and is then concentrated under reduced pressure. Chromatography of the residue on silica with 5% methanol (saturated with ammonia) in dichloromethane affords 36 mg of the title product as a glassy white solid. Physical Characteristics are as follows: FAB-HRMS: (m+H) = 1089.625. Preparation 26 Boc-7Glu(Boc)-Pro-O-MeTyr-His-X (Formula G-5: X is l-cyclohexyl-2S,6-diamino-3R,4S-dihydroxy-6-methylhq)- tane; Cbz is benzyloxycarbonyl.) Refer to Chart G. To a flask containing 36 mg of the title product of Preparation 25, 20 mg of 5 % Pd/C, 31 mg of ammonium formate is added 2 mL of dime ylformamide. After stirring for one day, die reaction mixture is diluted with dichloromethane and filtered tiirough Celite. The filter cake is washed with methanol/methylene chloride. The combined filtrates are concentrated and dimemylformamide removed under high vacuum. The residue is chromatographed on silica gel with 10% to 15% methanol (saturated with ammonia) in dichloromethane to afford 24 mg of the title product . Physical Characteristics are as follows: FAB-HRMS: (m+H) =955.5872. Example 7 L-Arabino-heptitol -_unino-l,2,5,6,7-pentadeoxy-l-cyclohexyl-2-[[N-[N- (l-L-γ-glutamyl-L-prolyl)-O-methyl-L-tyrosyl]-L-histidyl]-amino]-6- methyl-, tris(trisluoroacetate) salt, or γGlu-Pro-O-MeTyr-His-X (Formula G-6: X is l-cyclohexyl-2S,6-diamino-3R,4S-dihydroxy-6-methylheptane; Cbz is benzyloxycarbonyl.) Refer to Chart G . To a flask containing 24 mg of the title product of Preparation 26 is added 1 mL of trifluoroacetic acid. After one hour the reaction mixture is slowly dripped into 50 mL of a rapidly stirred 1:2 ether-hexane. After 0.5 hour the precipitated solid is spun down, washed twice with 1:2 ether-hexane, and dried under high vacuum to afford 28 mg of the tide product as a white solid. Physical Characteristics are as follows: FAB HRMS: (m+H)=799.4731. HPLC (20/80 A/B; 225 nm) k'=7.82. IC JO (M): 34% inhibition at 10-*M. Preparation 27 Glc(perAc)-Pro-0-MeTyr-His(Ts)-X(Cbz) (Formula H-2: X is l-cyclohexyl-2S,6-d-_-unino-3R,4S-dihydroxy-6- methylheptane; Cbz is benzyloxycarbonyl.) Refer to Chart H. To a stirred solution of 51 mg of deprotected Boc-_O-MeTyr-His(Ts)-X(Cbz) of formula H-l, i.e., H-O-MeTyr-His(Ts)-X(Cbz) prepared as described in the first paragraph of Preparation 23, and 41 mg of Glc(perAc)-Pro-OH of formula 1-4, prepared as described in Chart I, in 2 mL of dichloromethane is added 19 μL of dϋsopropyletiiyla- mine, followed by 13 μL of diethylphosphoryl cyanide. The reaction mixture is stirred overnight and tiien chromatographed on silica gel with 5% methanol in dichloromethane to afford 29 mg of the tide product. Physical characteristics are as follows: The proposed structure is supported by Η-NMR. Preparation 28 Glc-Pro-O-MeTyr-His-X(Cbz) (Formula H-3: X is 1- cyclohexyl-2S,6-diamino-3R,4S-dihydroxy-6-methylhep- tane; Cbz is benzyloxycarbonyl.) Refer to Chart H. A solution of 29 mg of the title product of Preparation 27 is allowed to stand in 1 mL of saturated ammonia in methanol overnight. The mixture is concentrated and d e residue chromatographed on silica gel with 10% to 20% methanol (saturated with ammonia) in dichloromethane to give 14 mg of the title product. Physical Characteristics are as follows: FAB-HRMS: (m+H) =1009.527. Example 8 L-Aι___b-__-θ-heptitol,6-an^o-l, 2,5,6,7-^^ (2-deoxy-glu∞py_^ose-2-aπ_i_-oc-_rt y histidyl]amino]-6-methyl, tris(trifluoroacetate) salt, or Glc-Pro-O-MeTyr- His-X (Formula H-4: X is l-cyclohexyl-2S,6-diamino-3R,4S-dihydroxy- 6-memylheptane; Cbz is benzyloxycarbonyl.) Refer to Chart H. To a flask containing 14 mg of the title product of Preparation 28, 10 mg of 5 % Pd/C, 15 mg of ammonium formate is added 1 mL of dimemylformamide. After stirring for overnight, the reaction mixture is diluted with dichloromethane and filtered through Celite. The filter cake is washed with methanol/methylene chloride. The combined filtrates are concentrated and dimethylformamide removed under high vacuum. The residue is treated witii 1 mL of acetic acid/methylene chloride which is then added to ether. The mixture is spun down to afford 11 mg of me title product. Physical Characteristics are as follows: FAB-HRMS: (m+H)=875.4895. HPLC (10/90 A B; 225 nm) k'=8.16. Preparation 29 l,3,4,6-Tetra-acetyl-2-deoxy-glucopyranose-2-amino carbonyl-L-prolyl-benzyl ester (Formula 1-3: Ac is acetyl Bzl is benzyl.) Refer to Chart I. A solution of 0.935 g of the compound of formula 1-1, 0.484 g of proline benzy ester hydrochloride of formula 1-2 and 0.7 mL of diisopropylethylamine in 2 mL o dioxane is stirred in an oil bath at 70°C for three hours. The reaction mixture i chromatographed on silica gel with 50%-70% etiiyl acetate in hexane to give 0.84 g o the tide product. Physical Characteristics are as follows: Η-NMR spectrum is consistent with the structure. Preparation 30 l,3,4,6-Tetra-acetyl-2-deoxy-glucopyranose-2-amino carbonyl-L-proline (Formula 1-4: Ac is acetyl.) Refer t Chart I. A mixture of 0.55 g of the title product of Preparation 29 and 50 mg of 5 palladium on charcoal in 10 mL of ethyl acetate is shaken under 50 psi of hydrogen fo three hours. The mixture is then filtered through Celite with ethyl acetate washings The filtrate is concentrated to give 0.34 g of the title product. Physical characteristics are as follows: Η-NMR spectrum is consistent with the structure. FORMULA CHART *3 CH XL, I .CH 0 -0 / \«c- FORMULA CHART (continued) CH 0 X I II • N-CH ■ c- I *6 FORMULA CHART (continued) - HOH 2 C A-3 CHART A (continued) B-3a, B-3b CHART B (continued) B-5a, B-5b -47- CHART C Boc-Phe-His(Ts)-X(Cbz) C-1 (B=3a) Boc-βVal-Phe-HisfTs>X(Cbz) C-2 Boc-øVal-Phe-H I is-X(Cbz) C-3 Boc-øVal-Ph J e-His-X C-4 £Val-Phe-His-X C-5 CHART D Boc-N-Me-HisfTs)-X(Cbz) D-l Boc-Phe-N-Me-H I is(Ts)-X(Cbz) D-2 Boc-j5Val-Phe-N-Me J -His(Ts>-X(Cbz) D-3 Boc-|8Val-Phe-N-M i e-His-X(Cbz) D-4 Boc-øVal-Phe-N I -Me-His-X D-5 øVal-Phe-N-Me-His-X D-6 -49- CHART E Boc-Phe-N-Me-His(Ts)-X(Cbz) E-l (D-2) Boc-Pro-Phe-N-Me- J His(T*)-X(Cbz) E-2 Boc-τGlu(Boc)-Pro-Phe-N I -Me-ffis(Ts)-X(Cbz) E-3 Boc-τGlu(Boc)-Pro-Phe J -N-Me-His-X(Cbz) E-4 Boc-γGlu(Boc Pro-P J he-N-Me-His-X E-5 τGlu-Pro-Phe-N J -Me-His-X E-6 CHART F Boc-Hi__(Ts)-X(Cbz) F-1 (B-2a) Boc-0-MeTyr-IB I s(Ts)-X(Cbz) F-2 Boc-0-MeTyr- I His-X(Cbz) F-3 Boc-O-MeTy I r-His-X F-4 CHART G Boc-O-MeTyr-His(Ts)-X(Cbz) G-I Boc-P iO -0-MeTyr-His(Ts)-X(Cbz) G-2 Bc -7Glu(Boc>Pro-0-MeTyr-His(Ts)-X(Cbz) G-3 Boc-τGlu(Boc)-Pro-0-M J eTyr-His-X(Cbz) G-4 ! Boc- Glu(Boc)-Pro-O-MeTyr-His-X G-5 7Glu-Pro-0-MeTyr-His-X G-6 CHART H Boc-O-MeTyr-His(Ts)-X(Cbz) H-l (G-1) Glc(per Ac)-Pro-0-MeTyr-His<Ts)-X(Cbz) H-2 Glc-Pro-0-MeTyr I -His-X(Cbz) H-3 Glc-Pro-0-Me I Tyr-His-X H-4 CHARTI 1-1 1-2

Claims: CLAIMS 1. A peptide having a non-cleavable transition state insert corresponding to die 10, 11 -position of a renin substrate (angiotensinogen) of the formula XL, - XL, wherein X t is (a) hydrogen, (b) Y (CR .-C(0)-, (c) (HOCH 2 ) 3 C-NH-C(O)-, (d) (HOCH 2 )-CH-NH-C(O)-, (f) HOH 2 C(CHOH).CH(CH 2 OH)-NH-C(O)-, (g) Na0 3 S(CH 2 ) 2 N(CH 3 )C(0)(CH 2 )^C(O)-, (h) R 2 C(O)-, (i) R 2 -0-C(0)- or 0) Zr O)-; wherein Y ! is (a) -NH 2 , ( ) -CO-H, (c) -C(NH 2 )(CH 3 ) 2 , (d) -CH(NH 2 )(C0 2 H), or (e) -OP^XOH) wherein Zx is -Het bonded through a nitrogen; wherein j is (a) hydrogen, (b) -C, alkyl, (c) aryl, (d) C--C. cycloalkyl, (o) - alkylsulfonyl, (p) -N(Re)-C r C 3 alkylsulfonyl, (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 rused to a benzene ring, which heterocyclic moiety is substituted witii zero to three of the following: CO ( - alkyl, (ϋ) hydroxy, (ϋi) trifluoromethyl, (iv) -C 4 alkoxy, (v) halo, (vi) aryl, (vii) arylC,-C 4 alkyl-, (viii) amino, (ix) mono- or di-(Cj-C 4 alkyl) amino, or (x) C 1 -C 5 alkanoyl; wherein R* is (a) hydrogen, (b) - alkyl, (d) -(CH-VHet. 2. In a renin inhibitory peptide, die improvement which comprises inclusion in the renin inhibitory peptide of a non-cleavable transition state insert corresponding to the 10, 11 -position of a renin substrate (angiotensinogen) of the formula XL, wherein -Het is a 5- or 6-membered saturated or unsaturated ring containing from o to tiiree heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfu and including any bicyclic group in which any of the above heterocyclic rings is rus to a benzene ring, which heterocyclic moiety is substituted with zero to three of t following: (i) Q-C, alkyl, (ii) hydroxy, (iii) trifluoromethyl, øv) C,-C 4 alkoxy, (v) halo, (vi) aryl, (vii) aryl C,-C 4 alkyl-, (viii) amino, (ix) mono- or di-(CrC 4 alkyl) amino, or (x) C alkanoyl; wherein R« is (a) hydrogen, (b) C- alkyl, (c) -(CH^-aryl, or (d) -(CH^-Het. (e) - , (f) HOH 2 C(CHOH).CH(CH 2 OH)-NH-C(0)-, (g) Na0 3 S(CH 2 ) 2 N(CH 3 )C(0)(CH 2 )^C(0)-, (h) R 2 C(0)-, CO R 2 -0-C(0)- or 0) 2,-0(0)-; wherein B 7 is absent or a divalent moiety of the formula XL*; wherein d is absent or a divalent moiety of me formula XL,, XL j or XI^; or wherein C s is a monovalent moiety of the formula XL,, or X when X and B 7 are absent; *ryl - XL wherein D, is absent or a divalent moiety of the formula XL,; R 3 \ / A CH 0 I II -N-CH-C- X I *6 or wherein C,-D 9 is XL-, or when X, B, are absent, XL,, X I I I R- (CH 2 ) m — CH 2 wherein E, 0 is a monovalent moiety of the formula XL,; wherein W is H or OH; wherein Y, is (a) -NH 2 , (b) -CO-H, (j) amino, wherein aryl is phenyl or naphthyl substituted by zero to three of the following: (a) -C, alkyl, (b) hydroxy, (c) -Cj alkoxy, (d) halo, (e) amino, (f) mono- or di-C,-^ alkylamino, (g) -CHO, (h) -COOH, CO -CONHj, 0) -CONH(Cι-C 5 alkyl) (k) -nitro, (i) mercapto, (m) C,-Cj alkylthio, (n) Cj-Cj alkylsulfinyl, (o) C,-Cj alkylsulfonyl, (p) -N^- - alkylsulfonyl, (q) SO 3 H, (r) SO-NH 2 , (s) -CN, or (t) -CH-NH,; 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 three of the following: CO - alkyl, (ii) hydroxy, (iϋ) trifluoromethyl, (iv) C,-C 4 alkoxy, (v) halo, (vi) aryl, (vii) aryl C,-C 4 alkyl-, (viii) amino, (ix) mono- or di (C,-C 4 alkyl)amino, or (x) Cj- alkanoyl; or a carboxy, amino or other reactive group protected form thereof; or a pharmaceutically acceptable acid or base addition salts thereof. 4. A peptide of claim 3 wherein X, at N-terminal is t-butyloxycarbonyl, β-valyl, τ-glutamyl, or 2-deoxy- glucopyrano_^2-aminocarbonyl; wherein B ? is absent, Pro or a derivative thereof; wherein C, is Phe, OMe-Tyr or a derivative thereof; wherein D, is His, N(Me)His or a derivative thereof; wherein E is l-cyclohexyl-2S,6-diammo-3R,4S-dihydroxy-6-me ylheptane; or a pharmaceutically acceptable salt thereof. 5. A peptide of claim 4 selected from the group consisting of: L-Histidinamide,N-[(l,l-dimemyletiioxy)carbonyl]-L-pheny_alanyl-N-[5-an^ (cyclohexylmethyl)-2,3-dihydroxy-5-memylhexyl]-, or N-tert-Butyloxycarbonyl-L- phenyl__Uanyl-L-Wstidyl-2S,6-diammo-l-cyclohexy^ L-Histidinamide,N-[(l , l-dimemylethoxy)carbonyl]-L-pheny____lanyl-N-[5-amino-l- (cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-, or N-tert-Butyloxycarbonyl-L- phenylalanyl-L-histidyl-2S,6-diamho-l-cyclohexyW^ L-Arabino-heptitol, 6-amino-2-[[N-[N-(3-amino-3-methyl- 1 -oxobutyl)-L- phenylalanyl]-L-histidyl]amino]- 1 -cyclohexyl- 1,2,5 , 6,7-pentadeoxy-6-C-methyl, tris(trifluoroacetate) (salt), or øVal-Phe-His-X; L-Arabino-heptitol, 6-amino-2-[[N-[N-(3-amino-3-methyl- 1 -oxobutyl)-L- p__enyl_danyl]-N-methyl-L-W_ttidyl]aιnino]l,2,5,6,7-pentadeoxy-l-< clohexyl-6-m tris(trifluoroacetate) (salt), or /3Val-Phe-N-Me-His-X; L-Arabino-heptitol, 6-amino-l,2,5,6,7-pentadeoxy-l-cyclohexyl-2-[rN-[N-(l-L- 7glutamyl-L-prolyl L-phenyM_ yl]-N-methyl-L-histidyl]_ ιino]-6-memyl-,tris(trifluoro- acetate) (salt), or τGlu-Pro-Phe-N-Me-His-X; L-Arabino-heptitol, 6-amino-l-cyclohexyl-l ,2,5,6,7-pentadeoxy-2-[[N-[N-[(l , 1- dimemylethoxy)C-_rtx ) nyl]-0-memyl-L-tyrosyl3-L-_ustidyl]amino]-6-methyl-, or Boc-O- MeTyr-His-X; L-Arabino-heptitol,6-amino-l ,2,5 ,6,7-pentadeoxy-l-cyclohexyl-2-[[N-[N-(l-L-7- glu___myl-L-prolyl)-CHnemyl-L-ty_O^ tris(trifluoroacetate) salt, or TGlu-Pro-O-MeTyr-His-X; and L-Arabino-heptitol, 6-amino-l,2,5,6,7-pentadeoxy-l-cyclohexyI-2-[[N-[N-(2- deoxy-glucoρyra_κ>se-2-am-nocaΛonyl-L-p^^ 6-methyl-, tris(trifluoroacetate) salt, or Glc-Pro-0-MeTyr-His-X.

Inventors: THAISRIVONGS SUVIT, THAISRIVONGS, SUVIT
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1990
Main classification: A61K37
IPC codes: A61K38, A61P9, A61P31, A61P43, C07C237, C07C275, C07C309, C07F9, C07K5, C07K9, C07K14