PEPTIDES CONTAINING AMINO-POLYOLS 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 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 immunodeficiency disease syndrome (AIDS).

Description: PEPTIDES CONTAINING AMINO-POLYO S 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 an amino-polyol 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 hyperaldosterism, and other renin-dependent cardiovascular disorders. Inhibitors of retroviral proteases, such as the HIV-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 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. S eggs, 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. Bio¬ phys. Res. Comm. 99, 1311 (1981). It may be represented as follows: Renin -Val-Ile-His- 11 12 13 IB and having the sequence to the left of the arrow (1) 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 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 European published application 0173481, published 5 March 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 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 lsosteres", Tetrahedron Letters, Vol. 24, No. 41, pp. 4401-4404, 1983 disclose various intermediates in a process to prepare stereo-directed "keto ethylene" 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 European published application 237202, published 16 September, 1987. Isosteric bond modifica- tions 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 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 disclosed in PCT application, Publication No. WO 87/05909, published 8 October 1987. Certain peptides containing dihalostatine have been disclosed in PCT application, Publication No. WO 86/06379, published 6 November 1986. European published applications 156,322; 114,993; and 118,223; and PCT application, Publication No. WO 87/02986, published 21 May 1987; European published application 0173481, published 5 March 1986; European published application 237202, published 16 September 1987; and PCT application, Publication No. WO 87/05909, published 8 October 1987; 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)- 1 -amino-2 , 3-d ihydroxy-4-t -butoxy-carbonylamino-5- cyclohexylpentane, and the final compound Boc-Phe-His Amide of (2S,3R,4S)-l-(3- Methylbutylcarbonylamino)-2,3-dihydroxy-4-amino-5-cyclohexylpentane. European patent application 184,855, published 18 June 1986, discloses new hydroxy carbonyl substiruted-statine peptide derivatives which are useful 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. International Application PCT/US90/03754, filed 9 July 1990, discloses peptides having a diamino glycol moiety as die non-cleavable transition state insert corresponding to the 10,11- position of the renin substrate (angiotensinogen). These peptides are disclosed as being useful as renin inhibitors and as inhibitors of retroviral proteases. Ciba-Gigy has described a compound that is reported to exhibit good oral activity and it includes 3-t-butylsulfonyl-2-benzylpropionic acid as the N-terminal group. P. Buhlmayer et al., J. Med. Chem 31: 1839 (1988). 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 INVENTION 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 8 wherein R j is (a) hydrogen, (b) Cj-C 10 alkyl, (c) aryl, (d) C 3 -C 7 cycloalkyl, (e) Het, (f) C r C 3 alkoxy, or (g) C r C 3 alkylthio; wherein each R 2 is independently (a) hydrogen, (b) C r C 5 alkyl, (c) -(CH 2 ) p -aryl, or (d) -(CH 2 ) p -Het; wherein p is O to 2 inclusive; wherein q is three to six, inclusive; wherein aryl is phenyl or naphthyl substituted by zero to three of the following: (a) C r C 3 alkyl, (b) hydroxy, (c) C j -C 3 alkoxy, (d) halo, (e) amino, (f) mono- or alkylamino, (g) -CHO, (h) -COOH, (i) -CONH 2 , (j) -CONH(C r C 5 alkyl), (k) -nitro, (1) mercapto, ( ) C r C 3 alkylthio, (n) C r C 3 alkylsulfinyl, (o) j -C 3 alkylsulfonyl, (p) -N(Rg)-C r C 3 alkylsulfonyl, (q) SO 3 H, (r) SO 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 three of the following: or a carboxy, amino or other reactive group protected form or a pharmaceutically acceptable acid or base 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 C 8 D 9 E 10 F π G 12 H 13 I 14 Z, The present invention provides peptide inhibitors of renin and retroviral proteases which contain an amino-polyol 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. Renin inhibitory peptides having 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 p? nt 0,172,347 'Abbott); European patent 172-346-A (Abbott); European patent 156-318 (Merck); European patent 157-409 (N.^rck); European patent 152-255 (Sankyo); and U.S. patent 4,548,926 (Sankyo); and PCT application, Publication No. WO 87/05302, published 11 September 1987; PCT application, Publication No. WO 87/05909, published 8 October 1987; PCT application, Publication No. WO 86/06379, published 6 November 1986; PCT application, Publication No. WO 88/04664, published 30 June 1988; and European published application 0173481, published 5 March 1986; and A. Spaltenstein, P. Carpino, F. Miyake and P.B. Hyskins, 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, Rockford, 111., 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 die 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 sub¬ strate, is designated E 10 - Most renin inhibitory peptides known in the art are highly lipophilic and have low water solubility. There is a need in this field for renin inhibitory peptides with increased hydrophilicity and thus higher water solubility. In general, peptides which are water soluble are readily adaptable to oral administration. The peptides of the present invention meet this need by having a novel amino-polyol moiety as their non-cleavable transition state insert. This insert results in peptides having increased hydrophilicity and d us higher water solubility. Some of the peptides of the present invention also contain other modifications, r as a beta-valine group or a glucosamine carbohydrate group at the N-terminus, which further .iiiproves their hyprophilicity and water solubility. Another advantage of these peptides is their small size since the polyhydroxylated unit is part of the transition state insert. This unit is C-terminally truncated which further reduces the overall size of the final peptides. In the peptides of the present invention, tetraols are the preferred transition state analog inserts. 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, 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 j -C j ) indicates a moiety of the integer "i" to die integer "j" carbon atoms, inclusive. Thus (C j -C^alkyl refers to alkyl of one to 4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, and isomeric forms thereof. C 4 -C 7 cyclic amino indicates a monocyclic group containing one nitrogen and 4 to 7 carbon atoms. Examples of (C 3 -C 10 )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-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-, -, 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-propyl-4-ethylphenyl, (2,3,4- 2,3,6-, or 2,4,5-)trimethylphenyl, (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-methyl phenyl, (o-, m-, or p-)ethoxyphenyl, (4- or 5-)chloro-2-methoxy-phenyl, and 2,4-dichloro(5- or 6-)methyl phenyl, and the like. Examples of -Het include: 2-, 3-, or 4-pyridyl, imidazolyl, indolyl, N m -formyl-indolyl, N in -C r C 5 alkyl-C(0)-indolyl, 1 ,2,4-triazolyl, 2-, 4-, or 5-pyrimidinyl, 2- or 3-thienyl, piperidinyl, pyrryl, pyrrolinyl.pyrrolidinyl yrazolyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrazinyL iperazinyl, pyrida__. .yl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, 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 diose 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 trifluoromethyl. 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 medical 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 anodier antihypertensive and/or a diuretic agent, congestiveheart failure, renin-dependent hyperaldosterism, angina, post-myocardial infarction, other renin-dependent cardiovascular disorders and ocular disorders. The renin-angiotension 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 purpos. , the compounds are administered from 0.1 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 wiύYin the skill of the practitioner or can readily be determined. The peptides of die 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 die U.S. Patent No. 4,424,207 are examples applicable to the compounds of the present invention. The peptides of die present invention to effect renin inhibition are preferably orally administered in the form of pharmacologically acceptable acid addition salts. Preferred pharma¬ cologically 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, 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 compounds of die 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 according to die 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 parenterally- 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 diglycerides. In addition, fatty acids such as oleic acid find use in die preparation of injectables. The peptides of this invention may also be administered in the form of suppositories for rectal administration of die drug. These compositions can be prepared by mixing the drug widi a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will dierefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. The peptides of this invention may e administered in combination with odier agents used in antihypertensive therapy such as diuretics, a and/or S-adrenergic blocking agents, CNS-actiπg agents, adrenergic neuron blocking agents, vasodilators, angiotensin I converting enzyme inhibitors, and the like as described for example in published European patent application 156,318. The present invention is also directed to combinations of die novel renin-inhibitory peptides of Formula I widi one or more antihypertensive agents selected from die group consisting of diuretics, a and/or /S-adrenergic blocking agents, CNS-acting agents, adrenergic neuron blocking agents, vasodilators, angiotensin I converting enzyme inhibitors, and odier antihypertensive agents. For example, the compounds of this invention can be given in combination with such compounds or salt or odier derivative forms thereof as: Diuretics: acetazolamide; amiloride; bendroflumethiazide; benzthia-zide; bumetanide; chlorothiazide; chlorthalidone; cyclothiazide; ediacrynic 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, respectively); metolazone; methyclodiiazide; muzolimine; polythiazide; quinediazone; sodium ethacryπ :e; sodium nitroprusside; spironolactone; ticrynaten; trimaterene; trichlormediiazide; α-Adrenergic Blocking Agents: dibenamine; phentolamine; phenoxybenzamine; prazosin; tolazoline; /S-Adrenergic Blocking Agents: atenolol; metoprolol; nadolol; propranolol; timolol; ((±)-2-[3-( / -butylamino)-2-hydroxypropoxy]-2-furananilide) (ancarolol); (2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran HCl)(befunolol); ((±)-l-(isopropylamino)-3-(p-(2-cyclopropylme-hoxyethyl)-phenoxy)-2-proprano_HC (betaxolol); (l-[(3,4-dimethoxyphenedιyl)amino]-3-(m-tolyloxy)-2-propanol HCl)(bevantolol); (((±)-l-(4-((2-isopropoxyethoxy)methyl)phenoxy)-3-isopropylamino-2-propanol) fumarate) (bisoprolol); (4-(2-hydroxy-3-[4-(phenoxymediyl)-piperidino]-propoxy)-indole); (carbazolyl-4-oxy-5,2-(2-medιoxyphenoxy)-ethylamino-2-propanol); (1-((1 , 1 -dimethyl ethyl)amino)-3-((2-methyl 'H-indol-4-yl)oxy)-2-pro-panol benzoate) (bopindolol); (l-(2-exobicyclo[2.2. l]-hept-2-ylphenoxy)-3-[(l-methyledιyl)-amino]-2-propanol HC1) (bomapro- lol); (o-[2-hydroxy-3-[(2-indol-3-yl-l,l-dimethyledι imino]propoxy]benzonitrile HC1) (bucindolol); (α-[(re7T.butylamino)me-hyl]-7-edιyl-2-benzofuranmedιanol) (bufur-alol); (3-[3-acetyl-4-[3-(tc'/7:.butylamino)-2-hydroxypropyl]-phenyl]-l , 1-diethylurea HC1) (celiprolol); ((±)-2-[2-[3-[(l , l-dime_hylethyl)amino]-2-hydroxypropoxy]phenoxy]-N-med ylacetamide HC1) (cetamolol); (2-benzimidazolyl-phenyl(2-isopropylaminopropanol)); ((-j.).3'. ace tyi-4'-(2-hydroxy-3-isopropylaminopropoxy)-acetanilide HCl) (diacetolol); (methyl-4-[2-hydroxy-3-[(l -methylethyI)aminopropoxyl]]-benzene-propanoate HC1) (esmolol); (erythro-DL-l-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol); (l-(rerr.butylamino)-3-[0-(2-propynyloxy)phenoxy]-2-propanol (pargo-lol); (l-( e / t.butylamino)-3-[o-(6-hydrazino-3-pyridazinyl)phenoxy]-2-propanol diHCl) (prizidilol); ((-)-2-hydroxy-5-[(R)-l-hydroxy-2-[(R)-(l-medιyl-3-phenylpropyl)-amino]ethyl]benzamide); (4-hydroxy-9-[2-hydroxy-3-(isopropylamino)-propoxy]-7-methyl-5H-furo[3,2-g][l]-benzopyran-5- one) (iprocrolol); ((.).5-( g rϊ .butylamino)-2-hydroxypropoxy]-3,4-dihydro-l-(2H)-naphdιalenoneHCl)0evobunolol); (4-(2-hydroxy-3-isopropylamino-propoxy)-l,2-benzisodιiazole HCl); (4-[3-(terr.butylamino)-2-hydroxypropoxy]-N-methylisocarbostyril HCl); ((±)-N-2-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]ethyl-N'-isopropylurea) (pafenolol); (3-[[(2-trifluoroacetamido)edιyl]amino]-l-phenoxypropan-2-ol); (N-(3-(o-chlorophenoxy)-2-hydroxypropyl)-N'-(4'-chloro-2,3-dihydro-3-oxo-5-pyridazinyl)- ethylenediamine); ((±)-N-[3-acetyl-4-[2-hydroxy-3-[(l-methylethyl)amino]propoxyphenyl]-butanamide) (acebutolol); ((+)_4'-[3-(/er/-butylamino)-2-hydroxypropoxy]spiro[cyclohexane-l,2'-indan]- -one) (spirendolol); (7-[3-[[2-hydroxy-3-[(2-methylindol-4-yl)oxylpropyl]amino]butyl]thio-phylline) (teoprolol); ((±)-l-t .butylamino-3-(thiochroman-8-yloxy)-2-propanol) (tertato-lol); ((±)-l-t .butylamino-3-(2,3-xylyloxy)-2-propanol HCl) (xibenolol); (8-[3-(re/T.butylamino)-2-hydroxypropoxy]-5-methylcoumarin) (bucumo-lol); (2-(3-(rer/.butylamino)-2-hydroxy-propoxy)benzonitrile HCl) (bunitro-lol); ((±)-2'-[3-(rerr-butylamino)-2-hydroxypropoxy-5'-fluorobutyrophenone) (butofiloloI); (1 -(carbazol-4-yloxy)-3-(isopropylamino)-2-propanol) (carazolol); (5-(3-t .butylamino-2_hydroxy)propoxy-3,4-dihydrocarbotyril HCl) (carteolol); (l-(/e/τ.butylamino)-3-(2,5-dichlorophenoxy)-2-propanol) (clorano-lol); (l-(inden-4(or 7)-yloxy)-3-(isopropylamino)-2-propanol HC1) (indeno-lol); (l-isopropylamino-3-[(2-methylindol-4-yl)oxy]-2-propanol) (mepindo-lol); (l-(4-acetoxy-2,3,5-trimemylphenoxy)-3-isopropylaminopropan-2-oI) (metipranolol); (l-(isopropylamino)-3-(o-methoxyphenoxy)-3-[(l-me-hylethyl)amino]-2-propanol) (moprolol); ((l-te/*T.butylamino)-3-[(5,6,7,8-tetrahydro-c_s-6,7-dihydroxy-l-n_iphthyl)oxy]-2-propanol) (nadolol); ((S)-l-(2-cyclopentylphenoxy)-3-[(l , l-dimethyledιyl)amino]-2-propanol sulfate (2: 1)) (penbutolol); (4'-[l-hydroxy-2-(amino)ethyl]methanesulfonanilide) (sotalol); (2-medιyl-3-[4-(2-hydroxy-3-rerr.butylaminopropoxy)phenyl]-7-medιoxy-isoquinolin-l-(2H)-one); (l-(4-(2-(4-fluorophenyloxy)efhoxy)phenoxy)-3-isopropylamino-2-propanol HCl); ((-)-p-t3-[(3,4-dimethoxyphenethyl)amino]-2-hydroxypropoxy]-/S-methyl-cinnamonitrile) (pacrinolol); ((±)-2-(3'-f^rt.butylamino-2'-hydroxypropylthio)-4-(5 , -carbamoyl-2'-thienyl)thiazole HCI) (arotinolol); ((+)-l-[p-[2-(cyclopropylmethoxy)edιoxy]phenoxy]-3-(isopropylamino)-2-propanol) (cicloprolol); ((±)-l-[(3-chloro-2-methylindol-4-yl)oxy]-3-[(2-phenoxyedιyl)amino]-2-propanol) (indopanolol); ((±)-6-[[2-[[3-(p-butoxyphenoxy)-2-hydroxypropyl]amino]ethyl]amino]-l,3-dimethyluracil) (pirepolol); (4-(cyclohexylamino)-l-(l-naphdιolenyloxy)-2-butanol); (l-phenyl-3-[2-[3-(2-cyanophenoxy)-2-hydroxypropyl]aminoethyl]hydan-toin HCl); (3,4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy-2H-l-benzopyran) (nipradolol); Angiotensin I Converting Enzyme Inhibitors: l-(3-mercapto-2-medιyl-l-oxopropyl)-L-proline (captopril); (l-(4-ethoxycarbonyl-2,4(R,R)-dimethylbutanoyl)indoline-2(S)-car-boxylic acid); ^-[2-[(l-(edιoxycarbonyl)-3-phenyl-propyl]amino]-l-oxopropyI]-l,2,3,4-tetrahydro-3-isoquinoline carboxylic acid); ((S)-l-[2-[(l-(ethoxycarbonyl)-3-phenylpropyl]amino]-l-oxopropyl]octahydro-lH-indole-2- carboxylic acid HCI); (N-cyclopentyl-N-(3-(2,2-dur_ethyl- 1 -oxopropyl)thiol-2-methyl- 1 -oxo-propyl)glycine) (pivalopril); ((2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidine-carboxylic acid); (l-(N-[l(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl)-cis,syn-octa-hydroindol-2(S)-carboxylic acid HCI); ((-)-(S)-l-[(S)-3-mercapto-2-methyl-l-oxopropyl]indoline-2-carboxylic acid); ([l(S),4S]-l-[3-(benzoylthio)-2-methyl-l-oxopropyl]-4-phenyldιio-L-proline; (3-([l-ethoxycarbonyl-3-phenyl-(lS)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-l-(3S)-benzazepine-l- acetic acid HCI); (N-(2-benzyl-3-mercaptopropanoyl)-S-ethyl-L-cysteine) and die S-methyl analogue; (N-(l(S)-edιoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate) (enalapril); N-[ 1 -(S)-carboxy-3-phenylpropyl]-L-alanyl- 1 -proline; N 2 -[l-(S)-carboxy-3-phenylpropyl]-L-lysyl-L-proIine 0ysinopril); Other Antihypertensive Agents: aminophylline; cryptenamine acetates and tannates; deserpidine; meremethoxylline procaine; pargyline; tri-methaphan camsylate; and die like, as well as admixtures and combinations 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 tiiey are given singly. Coadministration is most readily accomplished by combining die active ingredients into a suitable unit dosage form containing the proper dosages of each. Other methods of coadministration are, of course, possible. Thus, the novel peptides of the present invention possess an excellent degree of 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 prote¬ ases and thus inhibit the replication of the virus. They are useful for treating human patients infected widi a human retrovirus, such as human immunodeficiency virus (strains of HIV-1 or HIV-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 die viral protease (PR) to the mature proteins found in die 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 HIV-1 PR, has been found to be an aspartic protease widi 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 II, 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 diose individuals: 1) infected with one or more strains of a human retrovirus as determined by the presence of eidier measurable viral antibody or antigen in the serum and 2) in die 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 dian 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 die peptide used according to this invention in die patient at all times and would continue until die 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 (HIV, also known as HTLV-III or LAV) which has been recognized as 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 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. 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 ie 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, 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 diose described above for renin inhibition. Exact dosages, forms and mode of administration would be apparent to one of ordinary skill in die art such as a physician or pharmacologist. The peptides of die present invention are also useful for treating non-human animals infected wid a retrovirus, such as cats infected widi feline leukemia virus. Other viruses that infect cats include, for example, feline infectious peritonitis virus, calicivirus, rabies virus, feline immunodeficiency virus, feline parvovirus (panleukopenia virus), and feline chlamydia. Exact dosages, forms and modes of administration of die peptides of die present invention to non-human animals would be apparent to one of ordinary skill in the art, such as a veterinarian. The compounds of die present invention are prepared as depicted in the charts and as described more fully in the Preparations and Examples. In diese charts, the variables are as defined above. CHART A Chart A describes the preparation of l-cyclohexyl-2S-amino-3R,4,5,6-tetrahydroxyhexane in protected form which is incorporated into certain peptides of die present invention as the novel transition state analog insert. The syntheses of this insert starts with die aldehyde of formula A-l, obtained from International Application, Publication No. WO 88/04664, published 30 June 1988. Reaction widi carbomedioxymediylenetriphenylphosphorane gives the unsaturated ester of formula A-2. This compound is reduced widi diisobutylaluminum hydride to die corresponding alcohol of formula A 3. Reaction with osmium tetroxide affords the -hydroxylated products of formula A-5a (wherein Xi and X 2 are each α-OH) and formula A-5b (wherein X j and X 2 are each /S-OH), as a mixture of diastereomers. The compound of formula A-3 is also reacted widi wi-chloroperbenzoic acid to give the epoxides of formula A-4a and A-4b as a mixture of diastereomers which are hydrolyzed to a mixture of compounds of formula A-6a (wherein X j is α-OH and X is /S-OH) and formula A- 6b (wherein X 2 is /S-OH and X 2 is α-OH). CHART B Chart B illustrates the preparation of the novel peptides N- rr-butyloxycarbonyl-L- phenylaIanyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane of formula B-7a (wherein Xi and X 2 are each α-hydroxy) and N-t -butyloxycarbonyl-L-phenylalanyl-L-histidyl- 2S-amino-l-cyclohexyl-3R,4S,5S,6-tertahydroxyhexane of formula B-7b (wherein X j and X 2 are each /S-hydroxy) of the present invention. The mixture of formula B-la,b prepared as die compounds of formula A-5a,b in Chart A, is treated widi potassium hydride and benzyl bromide to give the mixture of tri-benzyl ethers of formula B-2a (wherein Y j and Y 2 are each α-O-benzyl) and formula B-2b (wherein Y and Y 2 are each /S-O-benzyl). The acid labile protecting groups are removed with medianolic hydrogen chloride to give the mixture formula B-3a,b. Coupling with N-/err-butyloxycarbonyl-N ιm -tosyl-L- histidine using diethylphosphoryl cyanide affords the compounds of formula B-4a,b which are readily separated. The compound of formula B-4a (wherein Y j and Y 2 are each α-O-benzyl) is treated with trifluoroacetic acid and the resulting amine is coupled with N-r -butyloxycarbonyl-L- phenylalanine using diethylphosphoryl cyanide to give die compound of formula B-5a (wherein j and Y are each α-O-benzyl). The tosyl protecting group is removed with 1-hydroxybenzotriazole to give the compound of formula B-6a (wherein Y 1 and Y 2 are each α-O-benzyl) which is then hydrogenolyzed using palladium catalyst to give the desired final compound of formula B-7a (wherein X- and X 2 are each α-hydroxy). In a similar manner, the diastereomer of formula B-4b (wherein Y j and Y 2 are each /S-O- benzyl) is converted in the sequence of reactions to the desired final compound of formula B-7b (wherein X l and X 2 are each j8-hydroxy). CHART C Chart C illustrates the preparation of the novel peptides N-r -butyloxycarbonyl-L- phenylalanyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4R,5S,6-tertahydroxyhexane of formula C-7a (wherein X j is α-hydroxy and X 2 is /S-hydroxy) and N-r -butyloxycarbonyl-L-phenylalanyl-L- histidyl-2S-amino-l-cyclohexyl-3R,4S,5R,6-tetrahydroxyhexaneof formula C-7b(wherein X j is β- hydroxy and X 2 is α-hydroxy) of the present invention. The mixture of formula C-la,b prepared as the compounds of formula A-6a,b in Chart A, is treated wid potassium hydride and benzyl bromide to give die mixture of tri-benzyl ethers of formula C-2a (wherein Y j is α-O-benzyl and Y 2 is /S-O-benzyl) and formula C-2b (wherein Y l is /S-O-benzyl and Y 2 is α-O-benzyl). The acid labile protecting groups are removed widi methanolic hydrogen chloride to give a mixture of compounds of formula C-3a,b. Coupling with N-tert- butyIoxycarbonyl-N ιm" tosyl-L-histidine using diediylphosphoryl cyanide affords a mixture of compounds of formula C-4a,b. This mixture is treated widi trifluoroacetic acid and die resulting amines are coupled widi N-re/ -butyloxycarbonyl-L-phenylalanine using diethylphosphoryl cyanide to give a mixture of compounds of formula C-5a,b. The tosyl protecting group is removed widi 1-hydroxybenzotriazole to give a mixture of compounds of formula C-6 a,b which is then hydrogenolyzed using palladium catalyst to give die desired compounds of formula C-7a (wherein X, is α-hydroxy and X 2 is /S-hydroxy) and formula C-7b (wherein X j is /S-hydroxy and X 2 is α- hydroxy) as two separable diastereomers. CHART D Chart D describes the preparation of 2S-amino-l-cyclohexyl-6-methyl-3R,4S,5,6- tetrahydroxyheptane in protected form which is used as a transition-state-analogue insert for the construction of certain peptides of die present invention. The synthetic route begins from the allylic alcohol of formula D-l which is prepared from the Grignard reaction between d e corresponding aldehyde of formula A-l of Chart A and 2- methyl-1-propenyl magnesium bromide. The olefin of formula D-l is treated widi a solution of osmium teroxide in t-butanol employing N-mediylmorpholine N-oxide as an internal oxidation source to afford the cw-hydroxylated tri-ols of formula D-2. The alcohols are then protected as benzyl ethers by treatment wid potassium hydride followed by addition of benzyl bromide. The resulting benzyl ethers of formula D-3 are reacted widi medianolic hydrogen chloride to remove die acid labile groups. The free amine of formula D-4 is tiien utilized in die construction of other peptides of die present invention. CHART E Chart E illustrates the preparation of the peptide N-r -butyloxycarbonyl-L-phenylalanyl-L- histidyl-2S-amino-l-cyclohexyl-6-medιyl-3R,4R,5S,6-tetrahydroxyheptane of formula E-5 of the present invention. The free amine of formula E-l, prepared as the compound of formula D-4 in Chart D is reacted with Boc-His(Ts)-OH employing diethylphosphoryl cyanide as the coupling agent and diisopropylethyl amine as the hindered base. The resulting peptide of formula E-2 is treated with trifluoroacetic acid to remove die fe/T-butyloxy carbonyl group and die resulting amine is coupled to Boc-Phe-OH to afford the peptide of formula E-3. The major iso er is separated from a mixture of minor components and is subsequently treated with 1-hydroxybenzotriazole to remove the tosyl protecting group from histidine. In die final synthetic step, the peptide of formula E-4 is subjected to hydrogenolysis with palladium black to afford die final peptide of formula E-5. CHART F Chart F describes the preparation of the novel peptide /SVal-Phe-His-Y of formula F-3 (wherein Y is 2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane), also known as /S-Valyl-L- phenylalanyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane, bis tri- fluoroacetate of the present invention. The peptide of formula F-l, prepared as die compound of formula B-7a in Chart B, is deprotected with trifluoroacetic acid and die resulting amine is coupled to Boc-/SVal-OH with diethyl cyanophosphonate to give the peptide of formula F-2. The final step is removal of the tert- butyloxy carbonyl group with trifluoracetic acid to give the desired peptide of formula F-3 which is isolated as the bis trifluoroacetate salt. In Chart F, Y is 2S-amino-l-cyclohexyl-3R,4R,5R,6- tetrahydroxyhexane. CHART G Chart G describes the preparation of the novel peptide Boc-Tyr(OMe)-His-Y of formula G-4 (wherein Y is 2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane), also known as N-tert- butyloxycarbonyl-O-methyl-L-tyrosyl-L-histidyl-2S-amino-l -cyclohexyl-3R,4R,5R,6- tetrahydroxyhexane of d e present invention. The peptide of formula G-l, prepared as die compounds of formula B-4a in Chart B, is deprotected with trifluoroacetic acid and the resulting amine is then coupled to Boc-Tyr(OMe) DCHA salt widi DEPC and to afford die compound of formula G-2. The protecting groups must be removed to yield the desired final product. The tosyl group is removed widi 1- hydroxybenzotriazole in methanol to give the compound of formula G-3. Finally, the benzyl protecting groups are removed by hydrogenolysis with palladium black to afford the desired compound of formula G-4. In Chart G, Y is 2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane and X is 2S- amino-l-cyclohexyl-3R-hydroxy-4R,5R,6-tribenzyloxyhexane. CHART H Chart H describes the preparation of the novel peptide /SVal-Tyr (OMe)-His-Y of formula H-5 (wherein Y is 2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane), also known as β- Valyl-O-methyl-L-tyrosyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane, bis trifluoroacetate of the present invention. Coupling of the amine from the peptide of formula H-l, prepared as the compound of formula G-2 in Chart G, with Boc-/3Val-OH gives die compound of formula H-2. The protecting groups must be removed to yield the desired peptide. The tosyl group is removed widi 1- hydroxybenzotriazole to give the peptide of formula H-3. The benzyl protecting groups are removed by hydrogenolysis with palladium black to afford the compound of formula H-4. Finally, the Boc group is removed widi trifluoroacetic acid to give die desired peptide of formula H-5 which is isolated as the bis trifluoroacetate salt. In Chart H, Y is 2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane and X is 2S- amino-l-cycIohexyl-3R-hydroxy-4R,5R,6-tribenzyloxyhexane. CHART I Chart I describes die preparation of the novel peptide Glc-Pro-Tyr (OMe) His-Y of formula 1-4 (wherein Y is 2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane) or 2-Deoxy-D- glucopyranos-2-aminocarbonyl-L-prolyl-O-methyl-L-tyrosyl-L-histidyl-2S-amino-l-cyclohexyl- 3R,4R,5R,6-tetrahydroxyhexane of the present invention. Coupling of the amine from the peptide of formula 1-1, prepared as the compound of formula G-2 in Chart G, widi per acetylated glucosamine-Pro-OH gives the compound of formula 1-2. The protecting groups must be removed to yield the desired peptide. The tosyl group and the carbohydrate acetates are removed by treatment with methanol saturated with ammonia to give the compound of formula 1-3. Finally, die benzyl ethers are removed by hydrogenolysis with palladium black to give die desired compound of formula 1-4. In Chart I, Y is Y is 2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane and X is 2S- amino-l-cyclohexyl-3R-hydroxy-4R,5R,6-tribenzyloxyhexane. CHART J Chart J describes die preparation of the novel peptides SPP-His-Y of formula J-4a,b (wherein Y is 2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane), also known as 2R-ferf- Butylsulfonylmethyl-3-phenyl-propionyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4R,5R,6- tetrahydroxyhexane and 2S-/ -butylsulfonylmethyl-3-phenylpropionyl-L-histidyl-2S-amino-l- cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane of the present invention. Coupling of the amine from the peptide of formula J-l, prepared as the compounds of formula B-4a of Chart B, widi d e epimeric mixture of tert-butylsulfonylmethyl-3-phenylpropionic acid (abbreviated as SPP) widi DEPC affords d e peptides of formula J-2a,b as a separable mixture. They are independently carried on to final products. The protecting groups must be removed to yield the desired peptides. The tosyl group is removed from die less polar peptide of formula J-2a by treatment with 1-hydroxybenzotriazole in methanol to afford die compound of formula J-3a. Finally, the benzyl ethers from the peptide of formula J-3a are removed by hydrogenolysis with palladium black to give die desired compound of formula J-4a. Using the procedures for the preparation of J-4a, the more polar diastereomer of formula J-2b, is converted to die desired compound of formula J-4b, which is 2S-tert-butylsulfonylmethyl-3- phenylpropionyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane. In Chart J, Y is 2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane and X is 2S- amino-l-cyclohexyl-3R-hydroxy-4R,5R,6-tribenzyloxyhexane. Using procedures analogous to diose described in die charts above, the other peptides the present invention may be prepared. Generally, the renin inhibiting polypeptides may be prepared by solution phase peptid synthetic procedures analogous to diose described hereinafter or to diose mediods known in th art. Appropriate protecting groups, reagents, and solvents for the solution phase method can b found in "The Peptides: Analysis, Synthesis, and Biology," Vols. 1-5, eds. E. Gross and T. Mei enhofer, Academic Press, NY, 1979-1983; "The Practice of Peptide Synthesis", M. Bodansky an 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 o N α -t-butyloxycarbonyl (BOC)-substituted amino acid derivatives having suitable side chain protecting groups, if necessary, may be condensed widi 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 diediylphosphoryl cyanide (DEPC) and triediylamine (Et 3 N) in methylene chloride or dimediylformamide. Following coupling reaction completion, the N α -BOC moiety may be selectively removed widi 50% trifluoroacetic acid with or without 2% anisole (v/v) in methylene chloride. Neutral¬ ization of the resultant trifluoroacetate salt may be accomplished widi 10% diisopropylediylamine or sodium bicarbonate in methylene chloride. Variations in die above description for starting materials, reactants, reaction conditions and required protecting groups to obtain odier such N-alkylated compounds are known to an ordinarily skilled chemist or are readily available in die 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 odier 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 die nitrogen protective groups are t-butoxycarbonyl (BOC), benzyloxycarbonyl, acetyl, allyl, phdialyl, benzyl, benzoyl, trityl and the like. The following compounds of the present invention are preferred: N-tert-Butyloxycarbonyl-L-phenylalanyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4R,5R,6- tetrahydroxy-hexane; Boc-Tyr(OMe)-His-Y (wherein Y is 2S-amino-l-cyclohexyl-3R-4R,5R,6-tetrahydroxy- hexane) or N-t -Butyloxycarbonyl-O-memyl-L-tyrosyl-L-histidyl-2S-amino-l-cyclohexyl- 3R,4R,5R,6-tetrahydroxy-hexane; SPP-His-Y (wherein Y is 2S-amino-l-cyclohexyl-3R-4R,5R,6-tetrahydroxyhexane) or 2S- «rf-Butylsulfonylmethyl-3-phenyl-propionyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4R,5R,6- tetrahydroxy-hexane; and N-terr-butyloxycarbonyl-L-phenylalanyl-L-histidyl-2S-amino-l-cyclohexyl-6-methyl- 3R,4R,5S,6-tetrahydroxyheptane. DESCRIPTION OF THE PREFERRED EMBODIMENTS The following Preparations and Examples illustrate the present invention. In the Preparations and Examples below and diroughout this document: *H-NMR is nuclear magnetic resonance BOC is t-butoxycarbonyl BOPCL is bis (2-oxo-3-oxazolidinyl) phosphinic chloride Bz is benzyl C is centigrade Cbz is benzyloxycarbonyl CDC1 3 is deuteriochloroform Celite is a filter aid CVA is Cha^[CH(OH)CH 2 ]Val DCC is dicyclohexylcarbodiimide DEPC is diediylphosphoryl cyanide EtOAc is ediyl acetate g is grams γ-Glu is γ-glutamic acid His is histidine N-MeHis is Nα-mediyl histidine HOBT is 1-hydroxybenzotriazole monohydrate HPLC is high performance liquid chromatography IR is infrared spectra LVA is Leu (CH(OH)CH 2 )Val with the S configuration at C4 (the hydroxyl- bearing carbon atom) M or mol is mole Me is ediyl 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 SPP is the racemic acid, 2-t-butylsulfonylmedιyl-3-phenylpropionic acid 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-mediyl tyrosine /S-Val is /S-Valine. The wedge-shape line indicates a bond which extends above die plane of die paper relative to the plane of die compound thereon. The dotted line indicates a bond which extends below the plane of the paper relative to die plane of die compound diereon. In die examples below, the renin inhibitory activity of ie compounds of the present invention (IC 50 's) are determined using d e in vitro test described in published European patent application 0 173 481, published 5 March 1986, pages 103-105, which are hereby incorporated by reference. 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 Perkin-Elmer Series IV liquid chromatograph operating at 1.5 mL/min 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 MethyH-[3-re/T-Butyloxycarbonyl-4S-cyclohexyl-methyl-2,2-dimethyl-5R- oxazolidinylj-propenoate (Formula A-2) Refer to Chart A. To a flame-dried flask under an argon atmosphere is charged 5.00 g of aldehyde of formula A-l in Chart A, 6.50 g of (carbethoxymethylene)-triphenylphosphorane and 150 mL of dry toluene. The solution is placed in an 80°C oil bath and heated for 20 hours. The suspension of a white solid in an orange solution is dien cooled to room temperature and treated with diediyl edier. The mixture is filtered and the white solid washed with diethyl ether. The filtrate is concentrated under reduced pressure and th -esidue is triturated widi diediyl edier, filtered and then concentrated. The trituration process is .epeated and the resulting viscous orange oil is flash chromatographed on silica gel widi 10% to 15% diediyl edier in hexane to afford 5.34 g of die title product as a clear, tan oil which solidifies upon standing. Physical characteristics are as follows: FAB HRMS: C-gl^gN j Os (m+H)=396.2753. Preparation 2 l-[3-rer -Butyloxycarbonyl-4S-cyclohexyl-methyl-2,2-dimethyl-5R- oxazolidinyl]-3-propenol (Formula A-3) Refer to Chart A. To a stirring solution of 5.0 g of die title product of Preparation 1 in 25 mL of anhydrous diediyl edier under an argon atomsphere at -78°C is added 26 mL of diisobutylaluminum hydride in toluene (1.5 M) slowly via cannula. The first drop of the hydride solution causes a yellow color to appear which increases in intensity during the addition of die first equivalent. The color gradually decreased during the remainder of the addition period. After 1 hour, the solution is warmed to -6O°C for 30 minutes and dien recooled to -78°C. The reaction mixture is slowly treated widi 5 mL of methanol and warmed to ambient temperature. The mixture is dien treated widi 80 mL of 1 M sodium potassium tartrate, stirred vigorously for 45 minutes, and dien diluted wid diediyl ether. The layers are separated and die aqueous layer is extracted with diediyl edier. The organic layers are combined, washed widi brine, and dien concentrated under reduced pressure. The residue is flash chromatographed on silica gel with 30% ethyl acetate in hexanes to afford 3.92 g of die title product as a pale tan oil which solidifies upon standing. Physical characteristics are as follows: FAB HRMS: C 20 H 36 N 1 O 4 (m+H)=354.2628. Preparation 3 l-[3-fer/-ButyloxycarbonyI-4S-cyclohexyl-methyl-2,2-dimethyl-5R- oxazoliidinyl]-2,3-dihydroxy-l-propanol (Formula A-5a: X j and X 2 are each α-hydroxy; Formula A-5b: X j and X 2 are each /S-hydroxy) Refer to Chart A. To a stirring solution of 1.40 g of the title product of Preparation 2 in 5.0 mL of acetone is added 5.0 mL of water dropwise. The cloudy mixture is placed under an argon atomsphere and then treated widi 734 mg of N-methy norpholine N-oxide dihydrate. After 15 minutes, 0.40 mL (1 M _n r -butanol) of osmium tetroxide is added. The reaction mixture becomes black dien gradually changes to dark green finally resulting in a light green suspension with a voluminous precipitant. The reaction mixture is vigorously stirred at ambient temperature overnight. During die reaction time, die mixture becomes difficult to stir and is dien diluted widi dichloromediane. The reaction is treated widi 10% aqueous sodium bisulfite, filtered through Celite, and die filter cake washed wid dichloromediane-methanol. The layers are separated and die aqueous layer is repeatedly extracted widi dichloromediane. The combined organic layers are dried (magnesium sulfate) and then concentrated under reduced pressure. The resulting white soli is adsorbed onto silica gel with methanol and die solvent is removed under high vacuum. Th material is chromatographed on silica gel widi 75% ediyl acetate in hexane to afford 1.09 g of th tide products. Physical characteristics are as follows: The proposed structure was supported by H NMR Preparation 4 l-Benzyloxy-[3-te/ -butyloxycarbonyl-4S-cyclohexyl-methyl-2,2-dimedιyl- 5R-oxazolidinyl]-2,3-dibenzyloxypropane (Formula B-2a: Y j and Y 2 are each α-O-benzyl; Formula B-2b: Y j and Y 2 are each /S-O-benzyl) Refer to Chart B. To a flask containing 170 mg of the title products of Preparation 3 as a suspension in 2 mL of dry tetrahydrofuran at 0°C under an argon atomsphere is added 245 mg (35% by weight in oil) of washed, oil-free potassium hydride suspended in 1 mL of dry tetrahydrofuran. The initial light green suspension becomes more cloudy and deepened in color as the mixture is warmed to ambient temperature. After a short time at room temperature, 0.55 mL of benzyl bromide is added and die reaction mixture is left to stir overnight. The cloudy suspension is diluted widi dichloromediane and partitioned with saturated aqueous sodium bicarbonate. The aqueous layer is extracted widi dichloromethane and die combined organic layers are washed with brine, dried (magnesium sulfate), and dien concentrated under reduced pressure. The residue is chromatographed on silica gel with 10% ediyl acetate in hexane to afford 284 mg of the title products as a pale oil. Physical Characteristics are as follows: FAB HRMS: C 41 H 56 NO 6 (m+H)=658.4149. Preparation 5 2S-amino-l-cyclohexyl-3R-hydroxy-4,5,6-tribenzyloxyhexane (Formula B-3a: Y-and Y 2 are each α-O-benzyl; Formula B-3b: Y j and Y 2 are each /S-O-benzyl) Refer to Chart B. To a flask containing 4.0 mL of methanol at 0°C is slowly added 0.25 mL of acetyl chloride and tightly capped. After 15 minutes, die solution is warmed to ambient temperature. After an additional 15 minutes, the medianolic hydrogen chloride is added to flask containing 284 mg of the title products of Preparation 4. After 3 hours, the solution is treated wid 0.85 g of solid sodium bicarbonate in portions to control gas evolution. The resulting suspension is stirred for 30 minutes and die volatiles are dien removed widi die aid of a stream of nitrogen gas. The resulting white residue is triturated widi dichloromediane, filtered with dichloromethane washings, and then concentrated under reduced pressure. The resulting pale oil is used directly in the next reaction and no further purification is performed. Physical characteristics are as follows: The proposed structure was supported by *H NMR. Preparation ό N-rerr-Butyloxycarbonyl-N ιm" tosyl-L-histidyl-2S-amino-l-cyclohexyl-3R- hydroxy-4,5,6-tribenzyloxyhexane (Formula B-4a: Y j and Y 2 are each α- O-benzyl; Formula B-4b: Yi and Y 2 are each /S-O-benzyl) Refer to Chart B. To a stirred solution of 211 mg of die tide products of Preparation 5 and 220 mg of Boc- His(Ts)-OH in 3 ml of dry dichloromethane is added 120 uL of diisopropylediylamine, followed by 80 uL of DEPC. The solution is stirred overnight and dien concentrated under reduced pressure. Chromatography of die residue on silica with 30% to 50% ediyl acetate in hexane provides 205 mg (0.225 mmol) of the less polar title product of formula B-4a as a glassy solid and 80 mg of the more polar title product of formula B-4b as a glassy solid. Physical Characteristics for the title product of formula B-4a are as follows: FAB HRMS: C 51 H 65 N 4 O 9 S (m+H)-=909.4454. Physical Chacteristics for the title product of formula B-4b are as follows: FAB HRMS: C 51 H 65 N 4 O 9 S (m+H)=909.4436. Preparation 7 N-rerf-Butyloxycarbonyl-L-phenylalanyl-N ιm" tosyl-L-histidyl-2S-amino-l- cyclohexyl-3R-hydroxy-4,5,6-tribenzyloxyhexane (Formula B-5a: Y j and Y 2 are each α-O-benzyl) Refer to Chart B. A solution of 205 mg of the less polar title product formula B-4a of Preparation 6 in 3 mL of 1:1 TFA-dichloromethane is allowed to stand for 1.5 hour at room temperature, en diluted widi more dichloromethane and slowly added to excess stirred, saturated aqueous sodium bicarbon¬ ate. After 30 minutes, die aqueous layer is extracted widi additional dichloromediane and die combined organic extracts are dried (magnesium sulfate) and are dien concentrated under reduced pressure to give die free amine. To a stirred solution of 178 mg of die amine and 80 mg of Boc-Phe-OH in 2.0 ml of dry dichloromediane is added 65 uL of diisopropylediylamine, followed by 45 uL of DEPC. The solution is stirred overnight at ambient temperature and dien concentrated under reduced pressure. Flash chromatography of die residue on silica gel widi 50% ediyl acetate in hexane provides 210 mg of die title product. Physical characteristics are as follows: FAB HRMS: C 50 H 74 N 5 O 10 S (m+H)= 1056.519. Preparation 8 N-t -ButyloxyC-_rbonyl-L-phenylalanyl-N ιm" tosyl-L-histidyl-2S-amino-l- cyclohexyl-3R-hydroxy-4,5,6-tribenzyloxyhexane (Formula B-5b: Y j and Y 2 are each S-O-benzyl) Refer to Chart B. A solution of 80 mg of die more polar title product of formula B-4b of Preparation 6 in 1 L of 1:1 TFA-dichloromethane is allowed to stand for 1.5 hour at room temperature, dien diluted with more dichloromediane and slowly added to excess stirred, saturated aqueous sodium bicarbonate. After 30 minutes, die aqueous layer is extracted with additional dichloromethane an the combined organic extracts are dried (magnesium sulfate) and are then concentrated und reduced pressure to give die free amine. To a stirred solution of 66 mg of die amine and 30 mg of Boc-Phe-OH in 0.8 ml of dr dichloromediane is added 25 uL of diisopropylediylamine, followed by 17 uL of DEPC. Th solution is stirred overnight at ambient temperature and then concentrated under reduced pressure Chromatography of die residue on silica gel widi 50% ethyl acetate in hexanes provides 76 mg o die title product. Physical characteristics are as follows: FAB HRMS: C 60 H 74 N 5 O 10 S (m+H)= 1056. Preparation 9 N-/f τ-Butyloxycarbonyl-L-phenylalanyl-L-histidyl-2S-amino-l-cyclohexyl 3R-hydroxy-4R,5R,6-tribenzyloxyhexane (Formula B-6a: Y j and Y 2 are each α-O-benzyl) Refer to Chart B A solution of 210 mg of the title product of Preparation 7 and 127 mg of HOBT hydrate in 2.0 mL of methanol is allowed to stir at room temperature overnight. The reaction mixture is then concentrated under reduced pressure and die residue chromatographed on silica gel widi 4% methanol saturated widi ammonia in dichloromethane to afford 157 mg of die title product. Physical characterics are as follows: FAB HRMS: C 53 H 68 N 5 O 8 (m+H)= 902.5061. Preparation 10 N-r -Butyloxycarbonyl-L-phenylalanyl-L-histidyl-2S-amino-l-cyclohexyl- 3R-hydroxy-4S,5S,6-tribenzyloxyhexane (Formula B-€b: Y j and Y 2 are each /S-O-benzyl) Refer to Chart B. A solution of 76 mg of the title product of Preparation 8 and 44 mg of HOBT hydrate in 0.7 mL of methanol is allowed to stir at room temperature overnight. The reaction mixture is then concentrated under reduced pressure and the residue chromatographed on silica gel with 4% medianol saturated with ammonia in dichloromediane to afford 64 mg of the title product. Physical characteristics are as follows: FAB HRMS: C 53 H 68 N 5 O 8 (m+H)= 902.5044. Example 1 N-/ -Butyloxycarbonyl-L-phenylalanyl-L-histidyl-2S-amino-l-cyclohexyl- 3R,4R,5R,6-tetrahydroxyhexane (Formula B-7a: X j and X are each α- hydroxy) Refer to Chart B. To a solution of 109 mg of the title product of Preparation 9 in 1 mL of acetic acid is added 200 mg of palladium black catalyst. The suspension is placed on a Parr apparatus at 50 psi of hydrogen gas and allowed to shake overnight. The reaction mixture is diluted with dichloro- mediane/medianol and dien filtered through Celite widi dichloromediane/medianol to pure methanol washings [Note: washing the catalyst under diese conditions can cause an exothermic reaction to occur, therefore suitable precautions should be taken]. The filtrates are concentrated under reduced pressure and die residual acetic acid azeotroped wid the aid of toluene. The resulting white solid is chromatographed on silica gel widi 10% to 20% medianol saturated widi ammonia in dichloromediane to afford 68 mg of the tide product. The product is lyophilized widi die aid of medianol as a co-solvent to afford a white solid. Physical characteristics are as follows: FAB HRMS: C 32 H 49 N 5 O 8 (m+H)=632 HPLC (60:40, A:B) (225 nm) k'=4.65. IC50 value of 6.8 nM. Example 2 N-re τ-Butyloxycarbonyl-L-phenylalanyl-L-histidyl-2S-amino-l-cyclohexyl- 3R,4S,5S,6-tertahydroxyhexane (Formula B-7b: X j and X 2 are each β- hydroxy) Refer to Chart B. To a solution of 64 mg of the title product of Preparation 10 in 2 mL of acetic acid is added 200 mg of palladium black catalyst. The suspension is placed in a high pressure bomb at 1200 psi of hydrogen gas and allowed to stir overnight. The reaction mixture is diluted widi dichloromediane and then filtered dirough Celite with dichloromediane/medianol to pure methanol washings. The filtrates are concentrated under reduced pressure and the residual acetic acid azeotroped with die aid of toluene. The resulting white solid is chromatographed on silica gel widi 10% to 20% medianol saturated with ammonia in dichloromediane to afford 9 mg of die title product. The product is lyophilized wid die aid of medianol as a co-solvent to afford white, fluffy solid. Physical characteristics are as follows: FAB HRMS: C 32 H 49 N 5 O 8 (m+H)-=632. HPLC (60:40, A:B) (225 nm) k'=4.94 9% renin inhibition at 10 "8 M. Preparation 11 l-[3-t -ButyIoxycarbonyl-4S-cyclohexyl-methyl-2,2-dimethyl-5R- oxazolidinyl]-l,2-epoxy-3-hydroxypropane (Formula A-4a: α-epoxide; Formula A^b: /S-epoxide). Refer to Chart A. To a stirring solution of 1.21 g of the title product of Preparation 2 in dry dichloromethane is added 0.71 g (70%) of m-chloroperbenzoic acid and 0.50 g of solid sodium bicarbonate as a buffer. The reaction mixture is vigorously stirred under an argon atomsphere for 15 hours. The mixture is then treated widi 1.7 g of solid sodium sulfite and die suspension left to stir at ambient temperature. After 1 hour, the reaction mixture is filtered and die filtrate is concentrated under reduced pressure. The resulting white foam is flash chromatographed on silica gel widi 25% to 30% ediyl acetate in hexane to afford 1.26 g of the title products as a clear, colorless oil which solidifies upon standing. Physical characteristics are as follows: FAB HRMS: C 20 H 36 NO 5 (m+H)= 370.2571. Preparation 12 l-[3-t -Butyloxycarbonyl-4S-cyclohexyl-methyl-2,2-dimethyl-5R oxazolidinyl]-2,3-dihydroxy-l-propanol (Formula A-6a: X t is α-hydroxy and X 2 is / S-hydroxy; Formula A-6b:X j is /S-hydroxy and X 2 is α- hydroxy) Refer to Chart A. To a stirring solution of 1.25 g of the tide products of Preparation 11 in 10 mL of dioxane is added 3.5 mL (40% in water) of tetrabutylammonium hydroxide. The reaction mixture immediately begins to turn yellow. The flask is equipped widi a reflux condenser and dien placed in an 110°C oil bath. After 38 hours, the pale brown solution is cooled to ambient temperature, diluted with dichloromediane and dien partitioned widi pH=7 phosphate buffer. The aqueous layer is extracted with dicholoromethane and the organic layers are combined, washed with brine, dried (magnesium sulfate) and dien concentrated under reduced pressure. The residue is flash chromatographed with 30% ediyl acetate in hexane to afford 546 mg of the title products as a pale yellow solid. Physical characteristics are as follows: FAB HRMS: C 20 H 38 NO 6 (m+H)=388.2698. Preparation 13 l-Benzyloxy-[3-ferr-butyloxycarbonyl-4S-cyclohexyl-methyl-2,2-dimedιyl- 5R-oxazolidinyl]-2,3-dibenzyloxy-propane (Formula C-2a: Y j is α-O- benzyl and Y 2 is /S-O-benzyl; Formula C-2b: Y j is /3-O-benzyl and Y 2 is α-O-benzyl) Refer to Chart C. To a stirring suspension of 485 mg of the title products of Preparation 12 in 1.25 mL of dry tetrahydrofuran is added 300 mg of sodium hydride (50% by weight in oil) as a suspension in tetrahydrofuran (2 mL and 3 x 1 mL rinses). After the initial evolution of gas, the suspension is left to stir under an argon atomsphere. After 10 minutes, 0.75 mL of benzyl bromide is added and the mixture left to stir at ambient temperature. After 2.5 days, the reaction mixture is diluted widi dichloromethane and pardoned against saturated aqueous sodium bicarbonate. The aqueous layer is extracted with dichloromediane and the combined organic layers are washed widi brine, dried (magnesium sulfate) and dien concentrated under reduced pressure. The residue is flash chromatographed on silica gel widi 10% to 50% ethyl acetate in hexane to afford 530 mg of die title products as a crystalline solid. Physical characteristics are as follows: FAB HRMS: C 41 H 56 NO 6 (m+H)=658.4118. Preparation 14 2S-amino-l-cyclohexyl-3R-hydroxy-4,5,6-tribenzyloxyhexane(FormulaC- 3a: Y-, is α-O-benzyl and Y 2 is jS-O-benzyl; Formula C-3b: Y j is /S-O- benzyl and Y 2 is α-O-benzyl) Refer to Chart C. To a flask containing 8.0 mL of methanol at 0°C is slowly added 0.51 L of acetyl chloride and is then tightly capped. After 15 minutes, the solution is warmed to ambient temperature. After an additional 15 minutes, the methanolic hydrogen chloride solution is added to a flask containing 0.53 g of die title products of Prepartion 13. After 3 hours, the solution is treated with 0.90 g of solid sodium bicarbonate in portions to control gas evolution. The resulting suspension is stirred for 30 minutes and die volatiles are removed with the aid of a stream of nitrogen gas. The white residue is triturated widi dichloromethane, filtered widi dichloromediane washings, and then concentrated under reduced pressure. The resulting pale foam is used direcdy in the next reaction and no further purification is performed. Physical characteristics are as follows: The proposed structure was supported by *H NMR. Preparation 15 N-rert-Butyloxycarbonyl-N ιm" tosyl-L-histidyl-2S-amino-l-cyclohexyl-3R- hydroxy-4,5,6-tribenzyloxyhexane (Formula C-4a: Y^ is α-O-benzyl and Y 2 is / S-O-benzyl; Formula C-4b: Y j is /S-O-benzyl and Y 2 is α-O-benzyl) Refer to Chart C. To a stirred solution of 160 mg of the title products of Preparation 14 and 170 mg of Boc- His(Ts)-OH in 3 ml of dry dichloromediane is added 90 uL of diisopropylediylamine, followed by 65 uL of DEPC. The solution is stirred overnight and then concentrated under reduced pressure. Gravity chromatography of d e residue on silica gel with 30% to 50% ethyl acetate in hexane provides 205 mg of the title products as a pale viscous oil. Physical Characteristics are as follows: FAB HRMS: C 51 H 65 N 4 O 9 S (m+H)= 909.4498. Preparation 16 N-r-?/T-Butyloxycarbonyl-L-phenylalanyl-N ,m" tosyl-L-histidyl-2S-amino-l- cyclohexyl-3R-hydroxy-4,5,6-tribenzyloxyhexane (Formula C-5a: Y j is α- O-benzyl and Y 2 is /S-O-benzyl; Formula C-5b: Y- is /S-O-benzyl and Y 2 is α-O-benzyl) Refer to Chart C. A solution of 205 mg of die title products of Preparation 15 in 3 mL of 1:1 TFA- dichloromediane is allowed to stir for one hour at room temperature, then diluted with more dichloromethane and slowly added to excess stirred, saturated aqueous sodium bicarbonate. After 30 minutes, die aqueous layer is extracted with add.tional dichloromethane and die combined organic extracts are dried (magnesium sulfate) and are then concentrated under reduced pressure to give the free amines. To a stirred solution of 140 mg of the amines and 65 mg of Boc-Phe-OH in 1.5 ml of dry dichloromediane is added 55 uL of diisopropylediylamine, followed by 37 uL of DEPC. The solution is stirred for 3 days and was dien concentrated under reduced pressure. Chromatography of the residue on silica gel with 30% to 50% ediyl acetate in hexane provides 157 mg of die titl products. Physical characteristics are as follows: FAB HRMS: C 60 H 74 N 5 O 10 S (m+H)= 1056.514. Preparation 17 N-terr-Butyloxycarbonyl-L-phenylalanyl-N ιm tosyl-L-histidyl-2S-amino-l cyclohexyl-3R-hydroxy-4,5,6-tribenzyloxyhexane (Formula C-6a: Y j is α-O-benzyl and Y 2 is /S-O-benzyl; Formula C-6b: Y j is /S-O-benzyl and Y 2 is α-O-benzyl) Refer to Chart C. A solution of 157 mg of the title products of Preparation 16 and 90 mg of HOBT hydrate in 1.25 mL of medianol is allowed to stir at room temperature. After 15 hours, the reaction mixture is concentrated under reduced pressure and the residue chromatographed on silica gel with 3% to 4% methanol saturated widi ammonia in dichloromethane to afford 127 mg of the title products. Physical characteristics are as follows: FAB HRMS: C 53 H 68 N 5 O 8 (m+H)=902.5106. Example 3 N-te/τ-Butyloxyc-_τbonyl-L-phenylalanyl-L-histidyl-2S-amino-l-cyclohexyl- 3R,4R,5S,6-tetrahydroxyhexane (Formula C-7a: X j is α-hydroxy and X 2 is /S-hydroxy) and N-t -butyloxycarbonyl-L-phenylalanyl-L-histidyl-2S- amino-l-cyclohexyl-3R,4S,5R,6-tetrahydroxyhexane (Formula C-7b: X j is /S-hydroxy and X 2 is α-hydroxy). Refer to Chart C. To a solution of 45 mg of die title products of Preparation 17 in a small amount of acetic acid is added 105 mg of palladium black catalyst. The suspension is placed in a high pressure bomb at 1250 psi of hydrogen gas and allowed to stir overnight. The reaction mixture is removed from the bomb and diluted with dichloromethane/methanol. The mixture is filtered through Celite widi dichloromethane/medianol to pure medianol washings. The filtrates are concentrated under reduced pressure and the residual acetic acid azeotroped widi the aid of toluene. The resulting white solid is chromatographed on silica gel widi 5% to 20% methanol saturated widi ammonia in dichloromethane to afford 6 mg of pure less polar isomer title product of formula C-7a, 6 mg of more polar title product of formula C-7b and 7 mg of mixed products. The products are lyophilized with the aid of medianol as a co-solvent to afford white, fluffy solids. Physical characteristics of the title product of formula C-7a are as follows: FAB HRMS: C 32 H 50 N 5 O 8 (m+H)= 632.3690. HPLC (60:40, A:B) (225 n ) k'=6.06 13% renin inhibition at 10 "8 M. Physical Characteristics of the title product of formula C-7b are as follows: FAB HRMS: C 32 H 50 N 5 O 8 (m+H)= 632. HPLC (60:40, A:B) (225 nm) k'=4.41 24% renin inhibition at 10 ~8 M. Preparation 18 lR-[3-rert-Butyloxycarbonyl-4S-cyclohexyl-methyl-2,2-dimethyl-5R- oxazolidinyl]-3-med yl-2,3-dihydroxy-l-butanol (Formula D-2) Refer to Chart D. To a stirring solution of 495 mg of allylic alcohol of formula D-l in 1.5 mL of acetone is added 1.5 mL of water dropwise. The cloudy mixture is placed under an argon atmosphere and dien treated widi 291 mg of N-mediylmorpholine N-oxide dihydrate. After 15 minutes, 0.15 mL (1 M in re/τ-butanol) of osmium tetroxide is added. The reaction mixture becomes black then gradually changes to dark green finally resulting in a light green suspension. The reaction mixture is vigorously stirred at ambient temperature overnight. During the reaction time, the mixture becomes difficult to stir and is then diluted with dichloromethane. The reaction is treated with solid sodium bisulfite and allowed to stir for 15 minutes. The layers are separated ana the aqueous layer is repeatedly extracted widi dichloromediane. The combined organic layers are dried (magnesium sulfate) and dien concentrated under reduced pressure. The resulting tan solid is flash chromatographed on silica gel with 50% ethyl acetate in hexane to afford 380 mg of the title products. Physical Characteristics are as follows: The proposed structure was supported by l H NMR. Preparation 19 lR-[3-fert-Butyloxycarbonyl-4S-cyclohexyl-methyl-2,2-dimethyl-5R- oxazolidinyl]-3-medιyl-l-2,3-tribenzyloxybutane (Formula D-3) Refer to Chart D. To a flask containing 124 mg of the tide products of Preparation 18 as a suspension in 0.5 mL of dry tetrahydrofuran at 0°C under an argon atmosphere is added 174 mg (35% by weight in oil) of washed, oil-fre^ potassium hydride suspended in 1 mL of dry tetrahydrofuran with 2 x 0.25 mL rinses. The initial light green suspension becomes gel-like and unstirrable. The paste is diluted widi an additional 2 mL of dry terahydrofuran. The resulting slurry is treated widi 0.7 mL of benzyl bromide and the reaction mixture is left to stir and warm to room temperature overnight. The pale, cloudy s '^nension is diluted widi dichloromediane and slowly treated widi 1 mL of methanol to contn. as evolution. After a short time the reaction mixture is partitioned against half-saturated aqueous sodium bicarbonate. The aqueous layer is extracted with dichloromethane and the combined organic layers are washed widi brine, dried (magnesium sulfate), and dien concentrated under reduced pressure. The residue is flash chromatographed on silica gel wid 5% to 10% ediyl acetate in hexane to afford 227 mg of the title product as a pale oil. Physical characteristics are as follows: FAB HRMS: C 43 H 59 NO 6 (m+H)=686. Preparation 20 2S-amino-l-cyclohexyl-3R-hydroxy-6-medιyMR,5,6-tribenzyloxyheptane • (Formula D-4) Refer to Chart D. To a flask containing 3.0 mL of methanol at 0°C is slowly added 0.20 mL of acetyl chloride and tighdy capped. After 15 minutes, the solution is warmed to ambient temperature. After an additional 15 minutes, die medianolic hydrogen chloride is added to a flask containing 227 mg of the title product of Preparation 19. After 3 hours, the solution is treated widi solid sodium bicarbonate in portions to control gas evolution. The resulting suspension is stirred for 30 minutes and d e volatiles are then removed with die aid of a stream of nitrogen gas. The resulting white residue is triturated widi dichloromediane, filtered widi dichloromethane washings, and dien concentrated under reduced pressure. The resulting white solid is used directly in the next reaction and no further purification is performed. Physical characteristics are as follows: The proposed structure was supported by *H NMR. Preparation 21 N-r -Butyloxycarbonyl-N^-tosyl-L-histidyl^S-amino-l-cyclohexyl-SR- hydroxy-6-medιyl-4R,5,6-tribenzyloxyheptane (Formula E-2) Refer to Chart E. To a stirred solution of 168 mg of die title product of Preparation 20 and 171 mg of Boc- His(Ts)-OH in 3 ml of dry dichloromethane is added 93 uL of diisopropylediylamine, followed by 63 uL (0.42 mmol) of DEPC. The solution is stirred for 2 days and dien concentrated under reduced pressure. Chromatography of the residue on silica widi 10% to 20% ediyl acetate in dichloromethane provides 138 mg of the title product as a pale foam. Physical characteristics are as follows: FAB HRMS: C^H^N^S (m+H) =937.4781. Preparation 22 N-;£/7-Butyloxycarbonyl-L-phenylalanyl-N t -tosyl-L-histidyl-2S-amino-l- cyclohexyl-3R-hydroxy-6-methyl-4R,5S,6-tribenzyloxyheptane (Formula E-3) Refer to Chart E. A solution of 138 mg of the title product of Preperation 21 in 1.5 mL of 1:1 TFA-dichloro¬ methane is allowed to stir for 1 hour at room temperature, then diluted widi more dichloromediane and slowly added to excess stirred, saturated aqueous sodium bicarbonate. After 30 minutes, the aqueous layer is extracted with additional dichloromethane and die combined organic extracts are dried (magnesium sulfate) and are dien concentrated under reduced pressure to give the free amine. To a stirred solution of 121 mg of die amine and 55 mg of Boc-Phe-OH in 1.5 ml of dry dichloromediane is added 46 uL of diisopropylediylamine, followed by 31 uL of DEPC. The solution is stirred overnight at ambient temperature and then concentrated under reduced pressure. Chromatography of the residue on silica gel widi ediyl acetate in dichloromediane provides 74 mg of die title product as the major isomer. Physical Characteristics are as follows: FAB HRMS: 62 1 Ατi^S 0 lO s (m+H) = 1084.547. Preparation 23 N-K/T-Butyloxycarbonyl-L-phenylalanyl-L-histidyl-2S-amino-l -cyclohexyl- 3R-hydroxy-6-medιyl-4R,5S,6-tribenzyloxyhexane (Formula E-4) Refer to Chart E. A solution of 74 mg of the title product of Preparation 22 and 42 mg of HOBT hydrate in 1.0 mL of methanol is allowed to stir at room temperature overnight. The reaction mixture is then concentrated under reduced pressure and die residue gravity chromatographed on silica gel widi 2% to 6% medianol saturated widi ammonia in dichloromethane to afford 57 mg of die tide product. Physical Characteristics are as follows: FAB HRMS: C 55 H 71 N 5 O 8 (m+H)=930.5371. Example 4 N-re/T-Butyloxycarbonyl-L-phenylalanyl-L-histidyl-2S-amino-l-cyclohexyl- 6-methyl-3R,4R,5S,6-tetrahydroxyheptane (Formula E-5) Refer to Chart E. To a solution of 57 mg of the title product of Preparation 23 in a small amount of acetic acid is added 100 mg of palladium black catalyst. The suspension is placed on a Parr apparatus at 50 psi of hydrogen gas and allowed to shake overnight. The reaction mixture is diluted widi dichloromethane/methanol and then filtered through Celite widi dichloromediane/medianol to pure methanol washings [Note: washing the catalyst under these conditions can cause an exodiermic reaction to occur, dierefore suitable precautions should be taken]. The filtrates are concentrated under reduced pressure and die residual acetic acid azeotroped wid die aid of toluene. The resulting white solid is chromatographed on silica gel widi 10% to 30% medianol saturated widi ammonia in dichloromediane to afford 37 mg of die title product as a white solid. Physical Characteristics are as follows: FAB HRMS: C 34 H 53 N 5 O 8 (m+H)=660.3°61. HPLC (60:40, A:B) (225 nm) k'=6.25 IC 50 Value of 0.7 nM. Preparation 24 Boc-/3Val-Phe-His-Y (Formula F-2: Y is 2S-amino-l-cyclohexyl-3R- 4R,5R,6-tetrahydroxyhexar : . Refer to Chart F. To a flask containing 0.7 mL of methanol at 0°C is slowly added 0.041 mL of acetyl chloride and then tightly capped. After 15 minutes, die solution is warmed to room temperature and stirred for an additional 15 minutes. The medianolic hydrogen chloride is then added to a vial containing 42 mg of the title product of Example 1 and d e acidic flask is rinsed widi 0.3 mL of additional medianol before addition to die compound vial. The peptide is slow to dissolve and a cloudy mixture results. After 2 hours, the reaction mixture is diluted with dichloromediane and diin layer chromatography suggests a significant amount of unreacted starting material is stil present. The mixture is concentrated by treatment with a stream of nitrogen gas to remove the solvents. The resulting residue is treated widi 1 mL of a solution of 1 : 1 trifluoroacetic acid-dichloro- methane and allowed to stir at room temperature for 1.25 hours. The mixture is then slowly dripped into 60 mL of a stirring solution of 1:2 diediyl ed er-hexane. The resulting cloudy suspension is stirred for 0.5 hours, divided into two centrifuge tubes, spun down, decanted, and finally dried. The resulting tan solid is used directly in the next reaction and no further purification is performed. The structure was supported by H-NMR. To a stirred solution of 45 mg of H-Phe-His-Y and 14 mg of Boc-/SVal-OH in 0.5 ml of dimediylformamide is added 36 μl* of diisopropylediylamine, followed by 10 uL of DEPC. The reaction mixture is stirred overnight and dien chromatographed on silica gel with 2% to 20% medianol saturated wid ammonia in dichloromediane to afford 14 mg of the title product as a white solid. Physical characteristics are as follows: FAB HRMS: C 37 H 58 N 6 O 9 (m+H)=731.4318. Example 5 /SVal-Phe-His-Y (Formula F-3: Y is 2S-amino-l-cyclohexyI-3R-4R,5R,6- tetrahydroxyhexane) or j8-Valyl-L-phenylalanyl-L-histidyl-2S-amino-l- cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane,bis trifluoroacetate. Refer to Chart F. A solution of 15 mg of the title product of Preparation 24 in 1.0 mL of 1:1 TFA- dichloromediane is allowed to stir for 1 hour and is then dripped slowly into 50 mL of a rapidly stirred 1:2 edier-hexane solution. The precipitated solid is spun down, washed twice with 1:2 edier-hexane, and dried under air followed by bodi house and high vacuum to afford 13 mg of die title product as a white solid. Physical characteristics are as follows: FAB HRMS: C-* 4 μ 5β * η 5 (m + H) = 631.3810. HPLC (10/90 A/B; 225 nm) k'=6.33. 21% renin inhibition at 10 "8 M. Preparation 25 Boc-Tyr(OMe)-His(Ts)-X (Formula G-2: X _s2S-amino-l-cyclohexyl-3R- hydroxy-4R,5R,6-tribenzyloxyhexane) Refer to Chart G. To a flask containing of 810 mg of the title products B-4a of Preparation 6 is added 10 mL of a solution of 1 : 1 trifluoroactice acid-dichloromediane, tightly capped and allowed to stir at room temperature. After 1.5 hours, the reaction mixture is diluted widi dichloromediane and dien added slowly to 120 mL of a saturated aqueous solution of sodium bicarbonate. The resulting mixture is stirred for 15 minutes, separated and die aqueous layer extracted widi several portions of dichloromediane. The combined organic phase is dried (magnesium sulfate) and then concentrated to give the free amine. To a stirred solution of 245 mg of H-His(Ts)-X and 149 mg of Boc-Tyr(OMe)-OH dicyclohexylamine salt in 3 ml of dichloromethane is added 75 uL of diisopropylediylamine, followed by 48 uL of DEPC. The reaction mixture is stirred overnight and dien chromatographed on silica gel widi 50% ediyl acetate in hexanes to afford 233 mg of the title as a pale foam. Physical characteristics are as follows: FAB-HRMS: C 61 H 75 N 5 O u S (m+H)= 1086.529. Preparation 26 Boc-Tyr(OMe)-His-X (Formula G-3: X is 2S-amino-l-cyclohexyl-3R- hydroxy-4R,5R,6-tribenzyloxyhexane) Refer to Chart G. A solution of 112 mg of the title product of Preparation 25 and 69 mg of HOBT hydrate in 1 mL of methanol is allowed to stir overnight. The solution is then concentrated under a stream of nitrogen gas and die resulting residue is gravity chromatographed on silica widi 4% to 5% medianol (saturated widi ammonia) in dichloromediane. The purification affords 89 mg of die title product as a glassy solid. Physical characteristics are as follows: FAB-HRMS: C 54 H 69 N 5 O 9 (m+H)=932.5157. Example 6 Boc-Tyr(OMe)-His-Y (Formula G-4: Y is 2S-amino-l-cyclohexyl-3R- 4R,5R,6-tetrahydroxyhexane) or N-t -Butyloxycarbonyl-O-methyl-L- tyrosyl-L-h_stidyl-2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane. Refer to Chart G. To a solution of 89 mg of die title product of Preparation 26 in a small amount of acetic acid is added 180 mg of palladium black catalyst. The suspension is placed on a Parr apparatus at 50 psi of hydrogen gas and allowed to shake overnight. The reaction mixture is diluted with dichloromethane/medianol and dien filtered through Celite with dichloromediane/medianol to pure medianol washings [Note: washing die catalyst under diese conditions can cause an exodiermic reaction to occur, dierefore suitable precautions should be taken]. The filtrates are concentrated under reduced pressure and die residual acetic acid azeotroped widi die aid of toluene. The resulting white solid is chromatographed on silica gel widi 10% to 20% medianol saturated widi ammonia in dichloromethane to afford 60 mg of the title product as a white solid. The solid is lyophilized with die aid of medianol to a fluffy white compound. Physical characteristics are as follows: FAB HRMS: C 33 H 51 N 5 O 9 (m+H)=662.3771. IC 50 value of 5.3 nM. HPLC (60:40, A:B) (225 nm) k'=3.87 Preparation 27 Boc-/SVal-Tyr(OMe)-His(Ts)-X (Formula H-2: X is 2S-amino-l- cyclohexyl-3R-hydroxy-4R,5R,6-tribenzyloxyhexane) Refer to Chart H. To a flask containing of 333 mg of the tide product of Preparation 25 is added 3 mL o a solution of 1:1 trifluoroacetic acid-dichloromethane, then tightly capped and allowed to stir at room temperature. After 1 hour, the reaction mixture is diluted with dichloromethane and dien added slowly to a saturated aqueous solution of sodium bicarbonate. The resulting mixture is stirred for 30 minutes, separated and die aqueous layer extracted with several portions of dichloromediane. The combined organic phase is dried (magnesium sulfate) and dien concentrated to give the free amine. To a stirred solution of 121 mg of H-Tyr(OMe)-His(Ts)-X and 32 mg of Boc-/SVal-OH in 1 ml of dichloromethane is added 33 uL of diisopropylediylamine, followed by 23 uL of DEPC. The reaction mixture is stirred overnight, dien chromatographed on silica with 5% medianol in dichloromediane to afford 140 mg of die title product as a pale foam. Physical characteristics are as follows: FAB-HRMS: C 66 Hg4N 6 O 12 S (m+H)= 1185. Preparation 28 Boc-/SVal-Tyr(OMe)-His-X (Formula H-3: X is 2S-amino-l-cyclohexyl- 3R-hydroxy-4R,5R,6-tribenzyloxyhexane) Refer to Chart H. A solution of 140 mg of die title product of Preparation 27 and 75 mg of HOBT hydrate in 1 mL of methanol is allowed to stir overnight and is then concentrated under reduced pressure. Chromatography of die residue on silica wid 5% medianol (saturated widi ammonia) in dichloromediane affords 125 mg of the title product as a white foam. Physical characteristics are as follows: FAB-HRMS: C 59 H 78 N 6 O- 0 (m+H)= 1031.582. Prepartion 29 Boc-/SVal-Tyr(OMe)-His-Y (Formula H-4: Y is 2S-amino-l-cyclohexyl- 3R-4S,5S,6-tetrahydroxyhexane). Refer to Chart H. To a solution of 125 mg of die title product of Preparation 28 in a small amount of acetic acid is added 375 mg of palladium black catalyst. The suspension is placed on a high pressure bomb under 1250 psi of hydrogen gas and allowed to stir overnight. The reaction mixture is diluted with dichloromethane/medianol and dien filtered dirough Celite with dichloromediane/medianol to pure methanol washings. The filtrates are concentrated under reduced pressure and die residual acetic acid azeotroped widi the aid of toluene. The resulting white solid is chromatographed on silica gel wid 10% to 20% medianol saturated widi ammonia in dichloromediane to afford 64 mg of the title product as a white solid. Physical characteristics are as follows: FAB HRMS: (m+H) =761.4442. Exa ple 7 /SVal-Tyr(OMe)-His-Y (Formula H-5: Y is 2S-amino-l-cyclohexyl-3R- 4R,5R,6-tetrahydroxyhexane)or/S-Valyl-O-methyl-L-tyrosyl-L-histidyl-2S- amino-l-cyclohexyI-3R,4R,5R,6-tetrahydroxyhexane, bis trifluoroacetate. Refer to Chart H. A solution of 64 mg of the title product of Preparation 29 in 1 mL of 1:1 TFA- dichloromethane is allowed to stir for 1.5 hours and is dien dripped slowly into 40 ml of rapidly stirred 1:2 diediyl edier-hexane. The solution begins to turn cloudy and the white suspension is allowed to form over 0.5 h. The precipitated solid is spun down, washed twice with 1:2 edier- hexane, and carefully dried under bodi house and high vacuum to afford 67 mg of the title product as a white solid. Physical characteristics are as follows: FAB HRMS: C 33 H 52 N 6 O 8 (m+H) =661.3942. HPLC (10/90 A/B; 225 nm) k'= 7.56. 21% renin inhibition at 10 ~8 M. Preparation 30 Glc(per Ac)-Pro-Tyr(OMe)-His(Ts)-X (Formula 1-2: X is 2S-amino-l- cyclohexyl-3R-hydroxy-4R,5R,6-tribenzyloxyhexane ethers). Refer to Chart I. To a stirred solution of 161 mg of die deprotected title product of Preparation 25 and 108 mg of Glc(per Ac)-Pro-OH in 1.5 ml of dichloromethane is added 48 uL of diisopropylediylamine, followed by 34 uL of DEPC. The reaction mixture is stirred overnight and dien chromatographed on silica widi 5% medianol in dichloromediane to afford 240 mg of the title product as a white foam. Physical characteristics are as follows: FAB-HRMS: C 76 H 93 N 7 O 20 S (m+H)= 1456. Preparation 31 Glc-Pro-Tyr(OMe)-His-X (Formula 1-3: X is 2S-amino-l-cyclohexyl-3R- hydroxy-4R,5R,6-tribenzyloxyhexane) Refer to Chart I. A solution of 240 mg of the title product of Preparation 30 in 2 mL of methanol saturated widi ammonia is allowed to stir overnight and is then concentrated under reduced pressure. Chromatography of die residue on silica widi 10% to 20% medianol (saturated widi ammonia) in dichloromethane affords 101 mg of the title proc ;t as a white solid. Physical characteristics are as follows: The proposed structure was supported by ^-NMR Example 8 Glc-Pro-Tyr(OMe)-His-Y (Formula 1-4: Y is 2S-amino-l-cyclohexyl-3R- 4R,5R,6-tetrahydroxyhexane) or 2-Deoxy-D-glucopyranos-2-aminocarbo- nyl-L-prolyl-O-medιyl-L-tyrosyl-L-histidyl-2S-amin. , -l-cyclohexyl-3R,4R,- 5R,6-tetrahydroxyhexane. Refer to Chart I. To a solution of 101 mg of the title product of Preparation 31 in a small amount of acetic acid is added 200 mg of palladium black catalyst. The suspension is placed on a Parr apparatus at 50 psi of hydrogen gas and allowed to shake for 18 hours. The reaction mixture is diluted widi dichloromediane/methanol and then filtered dirough Celite widi dichloromethane/methanol to pure medianol washings. The filtrates are concentrated under reduced pressure and the residual acetic acid azeotroped with the aid of toluene. The resulting white solid is gravity chromatographed on silica gel with 20% to 50% medianol saturated with ammonia in dichloromethane to afford 32 mg of die title product as a pale solid. Physical characteristics are as follows: FAB HRMS: C 40 H 61 N 7 O 14 (m+H) =864.4399. HPLC (10:90, A:B) (225 nm) k' = 8.94. 21% renin inhibition at 10 "8 M. Preparation 32 SPP-His(Ts)-X (Formulas J-2a,b: X is 2S-amino-l-cyclohexyl-3R- hydroxy-4R,5R,6-tribenzyloxyhexane) Refer to Chart J. To a stirred solution of 97 mg of die deprotected title products of Preparation 6 and 49 mg of 2-r -butylsulfonylmedιyl-3-phenyl-propionic acid in 1 ml of dichloromethane is added 38 uL of diisopropylediylamine, followed by 24 uL of DEPC. The reaction mixture is stirred overnight and dien chromatographed on silica widi 20% to 40% ethyl acetate in dichloromethane to afford 69 mg of the title product of formula J-2a as a pale oil and 53 mg of the title product of formula J-2b also as a pale oil. Physical characteristics for die compound of formula J-2a are as follows: FAB-HRMS: C 60 H 74 N 4 O 10 S 2 (m + H)= 1075.484 Physical characteristics for the compound of formula J-2b are as follows: FAB-HRMS: C 60 H 74 N 4 O 10 S 2 (m+H)= 1075.489 Preparation 33 SPP-His-X (Formula J-3a: X is 2S-amino-l-cyclohexyl-3R-hydroxy- 4R,5R,6-tribenzyloxyhexane) Refer to Chart J. A solution of 69 mg of die title product J-2a of Preparation 32 and 39 mg of HOBT hydrate in 0.65 mL of medianol is allowed to stir overnight and is dien concentrated under reduced pressure. Chromatography of die residue on silica widi 2% to 6% medianol (saturated widi ammonia) in dichloromediane affords 45 mg of die title product as a pale glassy solid. Physical characteristics are as follows: FAB-HRMS: C 53 H 68 N 4 O 8 S (m+H)=921.4823 Example 9 SPP-His-Y (Formula J-4a: Y is 2S-amino-l-cyclohexyl-3R-4R,5R,6- tetrahydroxyhexane)or2R-rerr-butylsulfonylmethyl-3-phenyl-propionyl-L- histidyl-2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane. Refer to Chart J. To a solution of 45 . mg of die title product of Preparation 33 in a small amount of acetic acid is added 44 mg of palladium black catalyst. The suspension is placed on a Parr apparatus at 45 psi of hydrogen gas and allowed to shake for 3 days. The reaction mixture is diluted widi dichloromediane/methanol and dien filtered through Celite widi dichloromediane/medianol to pure methanol washings. The filtrates are concentrated under reduced pressure and die residual acetic acid azeotroped widi die aid of toluene. The resulting white solid is chromatographed on silica gel widi 10% to 20% methanol saturated widi ammonia in dichloromethane to afford 22 mg of the title product as a white solid. Physical characteristics are as follows: FAB HRMS: C^H^^OgS (m+H)=651.3465. 34% renin inhibition at 10 "7 M. Preparation 34 SPP-His-X (Formula J-3b: X is 2S-amino-l-cyclohexyl-3R-hydroxy- 4R,5R,6-tribenzyloxyhexane). Refer to Chart J. A solution of 53 mg of the title product of formula J-2b of Preparation 32 and 30 mg (0.196 mmol) of HOBT hydrate in 0.5 mL of medianol is allowed to stir overnight and is dien concentrated under reduced pressure. Chromatography of die residue on silica widi 2% to 6% medianol (saturated widi ammonia) in dichloromediane affords 28 mg of the title product as a white glassy solid. Physical characteristics are as follows: FAB-HRMS: C 53 H 68 N 4 O 8 S (m+H) =921.4823. Example 10 SPP-His-Y (Formula J-4b: Y is 2S-amino-l-cyclohexyl-3R-4R,5R,6- tetrahydroxyhexane)or2S-r -butylsulfonylmethyl-3-phenyl-propionyl-L- histidyl-2S-amino-l -cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane. Refer to Chart J. To a solution of 28 mg of die title product of Preparation 34 in a small amount of acetic acid is added 24 mg of palladium black catalyst. The suspension is placed on a Parr apparatus at 45 psi of hydrogen gas and allowed to shake for 3 days. The reaction mixture is diluted widi dichloromediane/medianol and d en filtered tiirough Celite with dichloromediane/medianol to pure methanol washings. The filtrates are concentrated under reduced pressure and die residual acetic acid azeotroped widi die aid of toluene. The resulting white sc'id is gravity chromatographed on silica gel widi 10% to 20% medianol saturated widi ammonia in dichloromethane to afford 18 mg of the title product as a white solid. Physical characteristics are as follows: FAB HRMS: C^H^OgS (m+H)=651.3465. IC 50 value of 3.8 nM. Examples 11-16 Following chemical processes and procedures analogous to those described above and using starting materials and reactants which are commercially available or readily prepared by methods known in the art, the following compounds of die present invention, having the indicated physical characteristics, are prepared: Example 11 N-^rT-Butyloxycarbonyl-L-phenylalanyl-N-methyl-L-histidyl-2S-amino-l- cyclohexyl-3R,4S,5S,6-tetrahydroxy-hexane. FAB-HRMS: C 33 H 52 N 5 O 8 (m + H) = 646.3811. HPLC (A): 14.62 min. 0% renin inhibition at 10 "8 M;Expected to have activity at a higher dose. Example 12 N-r -Butyloxcarbonyl-L-phenylalanyl-N-meΛyl-L-histidyl-2S--_mino-l- cyclohexyl-3R,4R,5R,6-tetrahydroxy-hexane. FAB-HRMS: C 33 H 52 N 5 O 8 (m + H) = 646. HPLC (A): 11.26 min. 9% renin inhibiton at 10 "8 M. Example 13 2R-Hydroxy-3-(tetrahydro-2-naphdιyl)-propanoyl-L-histidyl-2S-amino-l- cyclohexyl-3R,4R,5R,6-tetrahydroxy-hexane. FAB-HRMS: C 31 H 47 N 4 O 7 (m + H) = 587.3453. HPLC (B): 20.62 min. 8% renin inhibition at 10 "8 M. Example 14 N-/e/ -Butyloxycarbonyl-L-phenylalanyl-N-methyl-L-histidyl-2S-amino-l- cyclohexyl-3R,4S,5R,6-tetrahydroxy-hexane. FAB-HRMS: C 33 H 52 N 5 0 8 (m + H) = 640.3805. HPLC (A): 11.36 min. 15% renin inhibition at 10 "8 M. Example 15 Tetrahydro-l-naphthoxyacetyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4R,5- R,6-tetrahydroxy-heptane. FAB-HRMS: C^H^N^ (m + H) = 572. Example 16 Tetrahydro-l-naphdιoxyacetyl-L-histidyl-2S-amino-l-cyclohexyl-6-methyl- 3R,4R,5S,6-tetrahydroxy-heptane. FAB-HRMS: C 32 H 48 N 4 0 7 (m + H) = 601.3642 For the HPLC's in examples 11-16 above, the retention time is given and the solvent system used is indicated in parendieses. Solvent A is 60% of 90:10 = water: acetonitrile, 0.1% trifluoroacetic acid; and 40% of 10:90 = water: acetonitrile, 0.1% trifluoroacetic acid. Solvent B is 70% of 90:10 = water: acetonitrile, 0.1% trifluoroacetic acid; and 30% of 10:90 = water: acetonitrile, 0;1 % trifluoroacetic acid. FORMULA CHART R3 10 R3 \ / 15 CH XL, I _CH 0 -0 / \« c- 20 30 COoH 0 I II XL, -NH-C-(CH 2 ) m -C- 35 -41- FORMULA CHART (continued) 0 II 9- S0 2 -CH 2 -CH-C XL la I CH R 3 * 10 0 V. 0 0 II I 1 II II • C-CH-CH-C-C- 15 I CH XL2a R 3 R<, 20 *3 *7 \ / CH 0 II H-CH-C- χL 4 25 30 XL- FORMULA CHART (continued) 20 II CHART A 10 / 20 A-4a,b CHART A (continued) 15 20 Chart B (continued) QBenzyl B-6a,b 25 CHART C 25 i Chart C (continued) 20 ChartD ChartE 20 30 35 Chart E (continued) E-5 Chart F Boc-Phe-His-Y F-l (B-7a) Boc-i8Val-Phe-His-Y F-2 /SVal-Phe-His-Y F-3 15 Chart G Boc-His(Ts)-X G-l B-4a) 10 Boc-Tyr(O 1 Me)-His(Ts)-X Boc-Tyr 1 (OMe)-His-X G " 3 Boc-Ty I r(OMe)-His-Y G-4 20 Chart H Boc-Tyr(OMe)-His(Ts)-X H-l (G-2) H-2 10 Boc-/SVal-Ty I r(OMe)-His(Ts)-X 15 Boc-/3Val-Tyr(OMe)-His-X H-3 20 Boc/SVal-Ty 1 r(OMe)-His-Y H^ 25 /SVal-Tyr(OMe)-His-Y H-5 Chart l Boc-Tyr(OMe)-His(Ts)-X M ( -2) Glc(per Ac)-Pro-T 1 yr(OMe)-His(Ts)-X 1-2 10 Glc-Pro-Tyr(OMe)-His-X I_3 15 Glc-Pro-Tyr( 1 OMe)-His-Y I" 4 Chart J Boc-His(Ts)-X M &- $ SPP-His(Ts)-X J - a - b 10 SPP Y J→a,b 20 i -His-

Claims: CLAIMS 1. A peptide having a non-cleavable transition state insert corresponding to the 10, 11 -position of a renin substrate (angiotensinogen) of the formula XL 8 wherein each R 2 is independently (a) hydrogen, (b) C r C 5 alkyl, (c) -(CH 2 ) p -aryl, or (d) -(CH 2 ) p -Het; wherein p is O to 2 inclusive; wherein q is diree to six, inclusive; wherein aryl is phenyl or naphthyl substituted by zero to diree of the following: (a) C r C 3 alkyl, (b) hydroxy, (c) 1-C3 alkoxy, (d) halo, (e) amino, (0 mono- or di-C 1 -C 3 alkylamino, (g) -CHO, (h) -COOH, (i) -CONH 2 , (j) -CONH(C r C 5 alkyl), (k) -nitro, (1) mercapto, (m) C r C 3 alkylthio, (n) C r C 3 alkylsulfinyl, (o) C--C 3 alkylsulfonyl, (p) -N(R 8 )-C--C 3 alkylsulfonyl, (q) SO 3 H, (r) SO j NH j , (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 widi zero to three of the following: (a) C r C 6 alkyl, (b) hydroxy, or a carboxy, amino or other reactive group protected form or a pharmaceutically acceptable acid or base addition salt diereof. 2. In a peptide, die improvement which comprises inclusion in die peptide of a non-cleavable transition state insert corresponding to die 10,11-position of a renin substrate (angiotensinogen) of the formula XL 8 wherein R j is (a) hydrogen, (b) C--C- Q alkyl, (c) aryl, (d) C 3 -C 7 cycloalkyl, (e) Het, (f) C r C 3 alkoxy, or (g) C r C 3 alkylthio; wherein each R 2 is independently (a) hydrogen, (b) C r C 5 alkyl, (c) -(CH 2 ) p -aryl, or (d) -(CH 2 ) p -Het; wherein p is O to 2 inclusive; wherein q is three to six, inclusive; wherein aryl is phenyl or naphthyl substituted by zero to diree of the following: (a) C r C 3 alkyl, (b) hydroxy, (c) C j -C 3 alkoxy, (d) halo, (e) amino, (f) mono- or di-C 1 -C 3 alkylamino, (g) -CHO, (h) -COOH, (i) -CONH 2 , 0) -CONH(C r C 5 alkyl), (k) -nitro, (1) mercapto, (m) C r C 3 alkylthio, (n) C r C 3 alkylsulfinyl, (o) C r C 3 alkylsulfonyl, (p) -N(R 8 )-C--C 3 alkylsulfonyl, (q) SO 3 H, (r) SO 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 -60- bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring, whic heterocyclic moiety is substituted widi zero to three of the following: (a) C r C 6 alkyl, (b) hydroxy, (c) trifluoromediyl, (d) C r C 4 alkoxy, (e) halo, (f) aryl, (g) aryl C^ alkyl-, Oi) amino, (i) mono- or di-(C 1 -C 4 alkyl) amino, or (j) C1-C5 alkanoyl; wherein Rg is (a) hydrogen, (b) C r C 5 alkyLor (c) (CH^p-phenyl; or a carboxy, amino or other reactive group protected form or a pharmaceutically acceptable acid or base addition salt diereof. 3. The peptide of claim 1 of die formula I I (f) HOH 2 C(CHOH) n CH(CH 2 OH)-NH-C(O)-, (g) NaO 3 S(CH 2 ) 2 N(CH 3 )C(O)(CH 2 ) 6 C(O)-, (h) R 5 C(O)-, (i) R 5 -O-C(O)-, 0) Z r C(O)-, (k) tetrahydro-naphdιyl-(CH 2 ) n -CH(OH)-C(O)-, or 0) tetrahydro-naphthyl-O-(CH 2 ) n -C(O)-; wherein B 7 is absent or a divalent moiety of die formula XL ; l 3 wherein Cg is absent or a divalent moiety of the formula XL j , XL^ or XL3; or wherein C 8 is a monovalent moiety of the formula XL la or XL^ when X j and B 7 are absent; /\ R 3 R< 0 V 0 0 II I 1 II II Z^C-CH-CH-C-C- CH / \ XL^ wherein D 9 is absent or a divalent moiety of die formula XL : XL, or wherein C 8 -D 9 is XL 7 , or when X and B 7 are absent, XL 7a ; \ / \ ' CH 0 CH 0 I il l il • N — C — C-— N — CH— C« X 7 wherein E 10 is a monovalent moiety of the formula XL 8 ; (a) ^C jQ alkyl, or (b) aryl; wherein aryl is phenyl or naphthyl substituted by zero to three of die following: (a) C r C 3 alkyl, (b) hydroxy, (c) C j -C 3 alkoxy, (d) halo, (e) amino, (f) mono- or di-C j -C 3 alkylamino, (g) -CHO, (h) -COOH, (i) -CONH 2 , 0) -CONH(C r C 5 alkyl) (k) -nitro, (i) mercapto, (m) C r C 3 alkylthio, (n) C r C 3 alkylsulfinyl, (o) C j -C β alkylsulfonyl, (p) -N(R 8 )-C r C 3 alkylsulfonyl, (q) SO 3 H, (r) SO 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 die 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 widi zero to diree of die following: (a) C r C 6 alkyl, (b) hydroxy, (c) trifluoromediyl, (d) C r C 4 alkoxy, (e) halo, (f) aryl, (g) aryl C r C 4 alkyl-, (h) amino, (i) mono- or di (Cγ-C 4 alkyl)amino, or (j) C j -Cs alkanoyl; or a carboxy, amino or other reactive group protected form thereof; or a pharmaceutically acceptable acid or base addition salt thereof. 4. A peptide of claim 3 wherein X j is (a) t-butyl-O-C(O)-, 00 t-butyl-CH 2 -C(O)-, (c) tetrahydro-naphthyl-CH 2 -CH(OH)-C(O)-, (d) tetrahydro-naphthyl-O-CH 2 -C(O)-, (e) (f) / 8-valine; wherein \ * η is (a) absent, or 00 Pro; wherein C 8 is (a) absent, 00 Phe, (c) (OCH 3 )-Tyr, or (d) when X χ and B 7 are absent, t-butyl-SO 2 -CH 2 -CH-(CH 2 -phenyl)-C(O)-; wherein D 9 is (a) His, or (b) (N-Me) His; wherein R j is cyclohexyl; wherein R 2 is (a) hydrogen, or 00 methyl; wherein q is three; or a pharmaceutically acceptable salt thereof. 5. A peptide of claim 4 selected from the group consisting of: N-^r/-butyloxycarbonyI-L-phenylalanyl-L-histidyI-2S-amino-l-cyclohexyl-3R,4R,5R,6- tetrahydroxyhexane; N-tfrf-butyloxycarbonyl-L-phenylalanyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4S,5S,6- tertahydroxyhexane; N-t-?rr-butyloxycarbonyl-L-phenylalanyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4R,5S,6- tertahydroxyhexane; N-tfrf-butyloxycarbonyl-L-phenylalanyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4S,5R,6- tetrahydroxyhexane; /SVal-Phe-His-Y (wherein Y is 2S-amino-l-cyclohexyl-3R-4R,5R,6-tetrahydroxyhexane) or /3-Valyl-L-phenylalanyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxyhexane,bis trifluoroacetate; Boc-Tyr(OMe)-His-Y (wherein Y is 2S-amino-l-cyclohexyl-3R-4R,5R,6-tetrahydroxy- hexane) or N-tfrt-butyloxycarbonyl-O-mediyl-L-tyrosyl-L-histidyl-2S-amino-l-cyclohexyl- 3R,4R,5R,6-tetrahydroxyhexane; /3Val-Tyr(OMe)-His-Y (wherein Y is 2S-amino-l-cyclohexyl-3R-4R,5R,6-tetrahydroxy- hexane)or/S-Valyl-O-methyl-L-tyrosyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydrox- yhexane, bis trifluoroacetate; Glc-Pro-Tyr(OMe)-His-Y (wherein Y is 2S-amino-l-cyclohexyl-3R-4R,5R,6-tetrahydroxy- hexane) or 2-Deoxy-D-glucopyranos-2-aminocarbonyl-L-prolyI-O-methyl-L-tyrosyl-L-histidyl-2S- amino-l-cycohexyl-3R,4R,5R,6-tetrahydroxyhexane; SPP-His-Y (wherein Y is 2S-amino-l-cyclohexyl-3R-4R,5R,6-tetrahydroxyhexane) or 2R- r -butylsulfonylmethyl-3-phenyl-propionyl-L-histidyI-2S-amino-l-cyclohexyl-3R,4R,5R,6- tetrahydroxyhexane; SPP-His-Y (wherein Y is 2S-amino-l-cyclohexyl-3R-4R,5R,6-tetrahydroxyhexane) or 2S- rert-butylsulfonylmethyl-3-phenyl-propionyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4R,5R,6- tetrahydroxyhexane; N-rerr-Butyloxycarbonyl-L-phenylalanyl-N-methyl-L-histidyl-2S-amino-l-cyclohexyl- 3R,4S,5S,6-tetrahydroxy-hexane; N-t -Butyloxycarbonyl-L-phenylaIanyl-N-methyl-L-histidyl-2S-amino-l-cyclohexyl- 3R,4R,5R,6-tetrahydroxy-hexane; 2R-Hydroxy-3-(tetrahydro-2-naphthyl)-propanoyl-L-histidyl-2S-amino-l-cyclohexyl- 3R,4R,5R,6-tetrahydroxy-hexane; N-rerr-Butyloxycarbonyl-L-phenylalanyl-N-methyl-L-histidyI-2S-amino-l-cyclohexyl- 3R,4S,5R,6-tetrahydroxy-hexane; Tetrahydro-l-naphdιoxyacetyl-L-histidyl-2S-amino-l-cyclohexyl-3R,4R,5R,6-tetrahydroxy- hexane; Tetrahydro-l-naphthoxyacetyl-L-histidyl-2S-amino-l-cyclohexyl-6-methyl-3R,4R,5S,6- tetrahydroxy-heptane; and N-terr-ButyIoxycarbonyl-L-phenylalanyI-L-histidyl-2S-amino-l-cyclohexyl-6 methyl- 3R,4R,5S,6-tetrahydroxyheptane.

Inventors: THAISRIVONGS SUVIT, THAISRIVONGS, SUVIT
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1991
Main classification: C07D233
IPC codes: A61K31, A61K38, A61P9, A61P31, A61P43, C07D233, C07D263, C07H5, C07K5, C07K9, C07K14