RENIN-INHIBITORY PEPTIDES HAVING AN EPOXIDE OR GLYCOL MOIETY

Abstract: Novel renin-inhibitory peptides of the formula X-A6-B7-C8-D9-E10-F11, containing C-terminus truncated epoxy or azido or cyano groups or containing a position 10-11 diol and a position 11-12 retro bond. The present invention further provides novel transition-state analogue inserts which are useful as intermediates for the preparation of renin-inhibitory peptides.

Description: RENIN-INHIBITORY PEPTIDES HAVING AN EPOXIDE OR GLYCOL MOIETY DESCRIPTION BACKGROUND OF THE INVENTION The present invention provides novel compounds. More particularly, the present invention provides novel renin inhibitory peptides and intermediates thereto. Most particularly, the present invention provides renin-inhibitory peptides containing C-terminus truncated epoxy or azido or cyano groups or containing a position 1011 diol and a position 11-12 retro bond as compared to the renin substrate. These renin-inhibitory peptides are useful for the diagnosis and control of renin-dependent hypertension. The present invention further provides novel transition-state analogue inserts which are useful as intermediates to renin-inhibitory peptides. 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: Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His EMI1.1 <tb> Renin <tb> <SEP> # <tb> Leu-Leu <tb> -Val-Tyr-Ser- IA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 as found by L.T. Skeggs et al., J. Exper. Med. 106, 439 (1957). Human renin substrate has a different sequence as recently discovered by D.A. Tewkesbury et al., Biochem. Biophys. Res. Comm. 99, 1311 (1981). It may be represented as follows: EMI1.2 <tb> Renin <tb> <SEP> 4 <SEP> <tb> <SEP> -Val <tb> -Ile-His 11 12 13 IB and having the sequence to the left of the arrow (4) being as designated in formula IA above. Renin cleaves angiotensinogen to produce angiotensin I, which is converted to the potent pressor angiotensin II. A number of an gio tens in I converting enzyme inhibitors are known to be useful in the treatment of hypertension. Inhibitors of renin are also useful in the treatment of hypertension. A number of renin-inhibitory peptides have been disclosed. Thus, U.S. patent 4,424,207; European published applications 45.665; 104,041; and 156,322; and U.S. patent application, Serial No. 825,250, filed 3 February 1986 (Case 4119.2.1); disclose certain peptides with the dipeptide at the 10,11-position containing an isostere bond. A number of statine derivatives stated to be renin inhibitors have been disclosed, see, e.g., European published applications 77,028; 81,783; 114,993; 156,319; and 156,321; and U.S. patents 4,478,826; 4,470,971;- 4,479,941; and 4,485,099. Terminal disulfide cycles have also been disclosed in renin inhibiting peptides; see, e.g., U.S. patents 4,477,440 and 4,477,441. Aromatic and aliphatic amino acid residues at the 10,11 position of the renin substrate are disclosed in U.S. patents 4,478,827 and 4,455,303. C-terminal amide cycles are disclosed in U.S. patent 4,485,099 and European published applications 156,320 and 156,318. Certain tetrapeptides are disclosed in European publications 111,266 and 77,027. Further, European published application No 118,223 discloses certain renin inhibiting peptide analogs where the 10-11 peptide link is replaced by a one to four atom carbon or carbonnitrogen link. Additionally, Holladay et al;, in "Synthesis of Hydroxyethylene and Ketomethylene Dipeptide Isosteres", Tetrahedron Letters, Vol. 24, No. 41, pp. 4401-4404, 1983 disclose various intermediates in a process to prepare stereo-directed "ketomethylene" and "hydroxyethylene" dipeptide isosterie 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. Retroinverso bond modifications at positions 10-11 have been disclosed in U.S. patent 4,560,505 and in European published applications 127,234 and 127,235. Derivatives of isosteric bond replacements at positions 10-11 have been disclosed in European published applications 143,746 and 144,209; and U.S. patent application, Serial No. 833,993, filed 27 February 1986 (Case 4212). Isosteric bond modifications at positions 11-12 and 12-13 have been disclosed in European published application 179,352. Certain peptides containing 2-substituted statine analogues have been disclosed in European published application 157,409. Certain peptides containing 3-aminodeoxystatine have been disclosed in European published application 161,588. Certain peptides 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 U.S. patent application, Serial No. 844,716, filed 27 March 1986 (Case 4293). Certain peptides containing dihalostatine have been disclosed in PCT application, Serial No. 000,713, filed 7 April 1986 (Case 4156.P). European published applications 156,322; > 114,993; and 118,223; and U.S. patent application, Serial No. 798,459, filed 15 November 1985 (Case 4137); U.S. patent application, Serial No. 825,250, filed 3 February 1986 (Case 4119.2.1); U.S. patent application, Serial No. 833,993, filed 27 February 1986 (Case 4212); and U.S. patent application, Serial No. 844,716, filed 27 March 1986 (Case 4293); disclose hydroxamic acids or esters at the C-terminus. INFORMATION DISCLOSURE E.P. 189,203 discloses new N-dihydroxyalkyl peptide derivatives which are useful as inhibitors of renin for treating hypertension. E.P. 184,855 discloses new hydroxy substituted-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 have been disclosed in U.S. patent application, Serial No. 833,993, filed 27 February 1986 (Case 4212). SUMMARY OF THE INVENTION The present invention particularly provides: A renin inhibitory pep tide of the formula I X-A6-37-C8-D9-E10-F11 I wherein X is (a) hydrogen, (b) C1-Cgalkyl (c) Rs-O-(CH2)q-C(0)-, (d) Rs-(CH2)q-0-C(0)-, (e) R5-0-C(O)-, (f) Rs-(CH2)n-C(0)-, (g) R4N(R4)-(CH2)n-C(O)-, (h) R5-SO2-(CH2)q-C(O)-, (i) R5-SO2-(CH2)q-O-C(O)-, (j) R5-S-(CH2)q-C(O)-, (k) R5-(CH2)q-S-(CH2)q-C(O)-, (l) R5-(CH2)q-O-(CH2)q-C(O)-, or (m) (R3)p+C(H)2-p-NH-C(O)-; wherein Y is (a) -0-, (b) -NH-, or (c) -ONHZ-; wherein A6 is absent or a divalent moiety of the formula XL1, XL2, or XL2a; wherein B7 is absent or a divalent moiety of the formula XLb; ; wherein C8 is absent or a divalent moiety of the formula XL1, XL2 or XL7; or wherein C8 is a monovalent moiety of the formula XL2a, when X, A6 and B7 are all absent; wherein Dg is a divalent moiety of the formula XL3 or XL2a; or wherein C8-D9 is a divalent moiety of the formula XL4 or XL4a, or wherein Cg-Dg is a monovalent moiety of the formula XL4b when X, A6, and B7 are all absent; wherein Elo-Fll is a divalent moiety of the formula XL6, XL6a, XL6b, or XL6c; wherein * indicates an asymmetric center which is either in the R or S configuration; wherein G12 is absent or a divalent moiety of the formula XL5, XLsa or XL5b; wherein H13 is absent or a divalent moiety of the formula XL5, XL5a or XL5b; ; wherein R1 is (a) hydrogen, (b) C1-C5alkyl, (c) aryl, (d) C3-C7cycloalkyl, (c) -Het, (f) C1-C3alkoxy, or (g) C1-C3alkylthio; wherein R2 is (a) hydrogen, (b) C1-C5 alkyl, or (c) aryl-C1-C5 alkyl; wherein R3 is (a) -(CH2)q-OH, (b) -(CH2)q-NH2, or (c) -(Ch2)q-CO2H; wherein R4 at each occurrence is the same or different and is (a) hydrogen, or (b) C1-C5akyl; wherein R5 is (a) C1-C6alkyl, (b) C3-C7cycloalkyl, (c) aryl, (d) -Het, or (e) 5-oxo-2-pyrrolidinyl; wherein R6 is (a) hydrogen, (b) C1-C5alkyl, (c) -(CH2)p-aryl, (d) -(CH2)p-Het, (e) C3-C7cycloalkyl, (f) 1- or 2-adamantyl, or (g) -C(CH20H)3; wherein R7 is (a) hydrogen, (b) C1-C5alkyl, (c) hydroxy, (d) amino C1-C4alkyl-, (e) guanidinyl C1-C3alkyl-, (f) aryl, (g) -Het, (h) methylthio, (i) C3-C7cycloalkyl, (j) amino, or (k) -(CH2)nCO2H; wherein R6-Y taken together can be (a) -NR2R6, (b) N-morpholino, (c) N-piperidyl, (d) N-prolinol, (e) N-proline-Y-R6, wherein m is one or two; wherein for each occurrence n is independently an integer of zero to five, inclusive; wherein p is zero to 2, inclusive; wherein q is 1 to 5, inclusive; wherein Q is (a) -CH2-, (b) -CH(OH)-, (c) -O-, or (d) -S-; wherein M is (a) -CO-, or (b) -CH2-; ; wherein aryl is phenyl or naphthyl substituted by zero to 3 of the following (a) C1-C3alkyl, (b) hydroxy, (c) C1-C3alkoxy, (d) halo, (e) amino, (f) mono- or di-C1-C3alkylamino, (g) -CHO, (h) -COOH, (i) COOR2, (j) CONHR2, (k) nitro, (1) mercapto, (m) C1-C3alkylthio, (n) C1-C3alkylsulfinyl, (o) C1-C3alkylsulfonyl, (p) C1-C3alkylsulfonyl-N(R4) (q) S03H, (r) SO2NH2, (s) -CN, or (t) -CH2NH2; wherein -Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring, which heterocyclic moiety is substituted with zero to 3 of the following: (i) C1-C6alkyl, (ii) hydroxy, (iii) trifluoromethyl, (iv) C1-C4alkoxy, (v) halo, (vi) aryl, (vii) aryl-C1-C4alkyl-, (viii) amino, or (ix) mono- or di-C1-C4alkylamino; or a carboxy-, amino-, or other reactive group-protected form thereof; or a pharmaceutically acceptable acid addition salt thereof; with the overall provisos that (1) when Elo-Fll is XL6a and C8 is XL2, then B7 must be present, and M must be -CH2-; (2) when E10-F11 is XL6a, C8 is XL1 and both A6 and B7 are absent, then X in formula I is not hydrogen; (3) when E10-F11 is XL6b, C8 is XL2, both G12 and H13 are absent, and X in XL6b is hydrogen, C1-C5 alkyl, or Rs-(CH2)n-C(0)-, then B7 must be present and M must be -CH2-; (4) when E10-F11 is XL6b, C8 is XL1, both G12 and H13 are absent, X in XL6b is hydrogen, C1-C5 alkyl, or R5-(CH2)n-C(O)-m, and both A6 and B7 are absent, then X in formula I is not hydrogen, C1-C5 alkyl, or R5-(CH2)n-C(O)-; and (5) when Elo-Fll is XLs and C8 is XL2, then R6 in XL2 of Cg is neither hydrogen nor C1-C5 alkyl. 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 Ile His X A6 B7 C8 Dg E10 F11 The present invention provides peptide inhibitors of renin which contain right-hand-terminating epoxy or azido or cyano groups or containing a position 10-11 diol and a position 11-12 retro bond as compared to the renin substrate. Examples of pharmaceutically acceptable acid addition salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanspropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2hydroxyethanesulfonate, 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 CCi-Cj) indicates a moiety of the integer i" to the integer "j" carbon atoms, inclusive. Thus (Cl-C4)alkyl refers to alkyl of one to 4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, and isomeric forms. thereof. C4-C7cyclic amino indicates a monocyclic group containing one nitrogen and 4 to 7 carbon atoms. Examples of (C3-C10)cycloalkyl, which includealkyl-substituted cycloalkyl containing a total of up to 10 total carbon atoms, are cyclopropyl, 2-methylcyclopropyl, 2, 2-dimethylcyclopropyl, 2,3diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3 -propylcyclobutyl, cyclopentyl, 2, 2-dimethylcyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and isomeric forms thereof. Examples of aryl include phenyl, naphthyl, (o-, m--, or p-)tolyl, (o-, m-, or p-)ethylphenyl, 2-ethyl-tolyl, 4-ethyl-o-tolyl, 5ethyl-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, 2chloro-p-tolyl, (3-, 4-, 5- or 6-)chloro-o-tolyl, 4-chloro-2-propylphenyl, 2-isopropyl-4-chlorophenyl, 4-chloro-3-fluorophenyl, (3- or 4-)chloro-2-fluorophenyl, (o-, m-, or p-)trifluoro-methylphenyl, (o-, m-, or p-)ethoxyphenyl, (4- or 5-)chloro-2-methoxy-phenyl, and 2,4dichloro(5- or 6-)methylphenyl, and the like. Examples of -Het include: 2-, 3-, or 4-pyridyl, imidazolyl, indolyl, Nin-formyl-indolyl, Nin-Cl-Csalkyl-C(0)-indolyl, 1,2,4triazolyl, 2-, 4-, or 5-pyrimidinyl, 2- or 3-thienyl, piperidinyl, pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrazinyl, piperazinyl, pyridazinyl, 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 those skilled in the art of organic chemistry, a heterocycle as defined herein for -Het would not be bonded through oxygen or sulfur or through nitrogen which is within a ring and part of a double bond. Halo is halogen (fluoro, chloro, bromo, or iodo) or 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. Pharmacologically 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 renin inhibitors 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 another antihypertensive and/or a diuretic agent, congestive heart failure, renin-dependent hyperaldosterism, angina, post-myocardial infarction and other renin-dependent cardiovascular 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 compounds of the present invention are preferably orally administered to humans to effect renin inhibition for the purpose of favorably affecting blood pressure. For this purpose, the compounds are administered from 0 1 mg to 1000 mg per kg per dose, administered from 1 to 4 times daily. Equivalent dosages for other routes of administration are also employed. The exact dose depends on the age, weight, and condition of the patient and on the frequency and route of administration. Such variations are within the skill of the practitioner or can readily be determined. The compounds of the present invention may be in the form of pharmaceutically acceptable salts both those which can be produced from the free bases by methods well known in the art and those with which acids have pharmacologically acceptable conjugate bases. Conventional forms and means for administering renin-inhibiting compounds may be employed and are described, e.g., in U.S. Patent No. 4,424,207 which is incorporated by reference herein. Likewise, the amounts disclosed in the U.S. Patent No. 4,424,207 are examples applicable to the compounds of the present invention. The compounds of the present invention are preferably orally administered in the form of pharmacologically acceptable acid addition salts. Preferred -pharmacologically acceptable salts for oral administration include the citrate and aspartate salts, although any pharmacologically acceptable salt is useful in this invention, including those listed above. These salts may be in hydrated or solvated form. For these purposes the compounds of the present invention may be administered 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 the invention are effective in the treatment of humans. The pharmaceutical compositions 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 the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3butanediol. 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 the preparation of injectables. The peptides of this invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable nonirritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. The renin-inhibiting compounds of this invention may be administered in combination with other agents used in antihypertensive therapy such as diuretics, a and/or ss-adrenergic blocking agents, CNS-acting agents, adrenergic neuron blocking agents, vasodilators, angiotensin I converting enzyme inhibitors, and the like as described for example in published European patent application 156,318. The present invention is also directed to combinations of the novel renin-inhibitory peptides of Formula I with one or more antihypertensive agents selected from the group consisting of diuretics, a and/or ss-adrenergic blocking agents, CNS-acting agents, adrenergic neuron blocking agents, vasodilators, angiotensin I converting enzyme inhibitors, and other antihypertensive agents. For example, the compounds of this invention can be given in combination with such compounds or salt or other derivative forms thereof as: Diuretics: acetazolamide; amiloride; bendroflumethiazide; benzthiazide; bumetanide; chlorothiazide; chlorthalidone; cyclothiazide; ethacrynic acid; furosemide; hydrochlorothiazide; hydroflumethiazide; indacrinone (racemic mixture, or as either the (+) or (-) enantiomer alone, or a manipulated ratio, e.g., 9:1 of said enantiomers, respectively); metolazone; methyclothiazide; muzolimine; polythiazide; quinethazone; sodium ethacrynate; sodium nitroprusside; spironolactone; ticrynaten; trimaterene; trichlormethiazide; a-Adrenergic Blocking Agents: dibenamine; phentolamine; phenoxybenzamine; prazosin; tolazoline; p-Adrenergic Blocking Agents: atenolol; metoprolol; nadolol; propranolol; timolol; ((+)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-2-furananilide) (ancarolol); C2.acetyl-7- (2.hydroxy.3 -isopropylaminopropoxy)benzofuran HCl) (befun- olol); ((+)-1-(isopropylamino)-3-(p-(2-cyclopropylmethoxyethyl)-phenoxy)-2propranol HC1) (betaxolol); (1-[(3,4-dimethoxyphenethyl)amino]-3-(m-tolyloxy)-2-propanol HCl)(bevantolol); (((+)-I-(4-((2-isopropoxyethoxy)methyl)phenoxy)-3-isopropylamino-2propanol)fumarate) (bisoprolol); (4-(2-hydroxy-3-[4-(phenoxymethyl)-piperidino]-propoxy)-indole); (carbazolyl-4-oxy-5,2-(2-methoxyphenoxy)-ethylamino-2-propanol); ; (1-((1,1-dimethylethyl)amino)-3-((2-methyl 'H-indol-4-yl)oxy)-2-propanol benzoate) (bopindolol); (1-(2-exobicyclo[2.2.1]-hept-2-ylphenoxy)-3-[(1-methylethyl)-amino]2-propanol HC1) (bornaprolol) (o-[2-hydroxy-3-[(2-indol-3-yl-1,1-dimethylethyl)-amino]propoxy]benzonitrile HCl) (bucindolol); (Q-[(tert.butylamino)methyl]-7-ethyl-2-benzofuranmethanol) (bufuralol); (3-[3-acetyl-4.[3-Ctert.butylamino)-2-hydroxypropylj-phenyl]-l,l. diethylurea HC1) (celiprolol); ((#)-2-[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenoxy]-N- methylacetamide HC1) (cetamolol); (2-benzimidazolyl-phenyl(2-isopropylaminopropanol)); ((#)-3'-acetyl-4'-(2-hydroxy-3-isopropylaminopropoxy)-acetanilide HC1) (diacetolol); (methyl-4-[2-hydroxy-3-[(1-methylethyl)aminopropoxyl]]-benzene- propanoate HC1) (esmolol); (erythro-DL-1-(1-methyliden-4-yloxy)-3-isopropylaminobutan-2-ol); (l-(tert.butylamino)-3-[0-(2-propynyloxy)phenoxy]-2-propanol (pargo- lol); (l-(tert.butylamino)-3-[o-(6-hydrazino-3-pyridazinyl)phenoxy]-2propanol diHCl) (prizidilol); ; ((-)-2-hydroxy-5-[(R)-l-hydroxy-2-[(R)-(l-methyl-3-phenylpropyl)- amino] ethyl] benzamide); (4-hydroxy-9-[2-hydroxy-3-(isopropylamino)-propoxy]-7-methyl-5H furo[3,2-g] [1]-benzopyran-5-one) (iprocrolol); ((-)-5-(tert.butylamino)-2-hydroxypropoxy]-3,4-dihydro-1-(2H)- naphthalenone HC1) (levobunolol); (4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benzisothiazole HC1); (4-[3-(tert.butylamino)-2-hydroxypropoxy]-N-methylisocarbostyril HCl); ((+)-N-2-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]ethyl-N'isopropylurea) (pafenolol); (3-[[(2-trifluoroacetamido)ethyl]amino]-1-phenoxypropan-2-ol); (N-(3-(o-chlorophenoxy)-2-hydroxypropyl)-N'-(4'-chloro-2,3-dihydro-3oxo-5-pyridazinyl)ethylenediamine); ; ((#)-N-[3-acetyl-4-[2-hydroxy-3-[(1-methylethyl)amino]propoxyphenyl]- butanamide) (acebutolol); ((#)-4'-[3-(tert-butylamino)-2-hydroxypropoxy]spiro8cyclohexane-1,2 - indan]-l'-one) (spirendolol); (7-[3-[[2-hydroxy-3-[(2-methylidol-4-yl)oxylpropyl]amino]butyl]thio phylline) (teoprolol); ((#)-1-tert.butylamino-3-(thiochroman-8-yloxy)-2-propanol) (tretato- lol); ((+)-l-tert.butylamino-3-(2,3-xylyloxy)-2-propanol HCl) (xibenolol); (8-[3-(tert.butylamino)-2-hydroxypropoxy]-5-methylcoumarin) (bucumo- lol); (2-(3-(tert.butylamino)-2-hydroxy-propoxy)benzonitrile HC1) (bunitro lol); ((#)-2'-[3-(tert-butylamino)-2-hydroxypropoxy-5'-fluorobutyrophenone) (butofilolol); ; (l-(carbazo1-4-yloxy)-3-(isopropylamino)-2-propanol) (carazolol); (5-(3-trt.butylamino-2-hydroxy)propoxy-3,4-dihydrocarbotyril HCl) (carteolol); (l-(tert.butylamino)-3-(2,5-dichlorophenoxy)-2-propanol) (cloranolol); CI- Cinden-4Cor 7)-yloxy)-3-(isopropylamino)-2-propanol HCl) (indenolol); (1-isopropylamino-3-[(2-methylindol-4-yl)oxy]-2-propanol) (mepindolol); (1-(4-acetoxy-2,3,5-trimethylphenoxy)-3-isopropylaminopropan-2-ol) (metipranolol); (1-(isopropylamino)-3-(o-methoxyphenoxy)-3-[(1-methylethyl)amino]-2propanol) (moprolol); ((1-tert.butylamino)-3-[(5,6,7,8-tetrahydro-cis-6,7-dihydroxy-1 naphthyl)oxy] -2-propanol) (nadolol); ((S)-1-(2-cyclopentylphenoxy)-3-[(1,1-dimethylethyl)amino]-2-propanol sulfate (2: :1)) (penbutolol); (4'-[1-hydroxy-2-(amino)ethyl]methanesulfonanilide) (sotalol); (2-methyl-3-[4-(2-hydroxy-3-tert.butylaminopropoxy)phenyl]-7-methoxyisoquinolin-l-(2H)-one); (1-(4-(2-(4-fluorophenyloxy)ethoxy)phenoxy)-3-isopropylamino-2propanol HC1); ((-)-p-[3-[(3,4-dimethoxyphenethyl)amino]-2-hydroxypropoxy]-ss-methylcinnamonitrile) (pacrinolol); ((#)-2-(3'-tert.butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'- thienyl)thiazole HC1) (arotinolol); ((#)-1-[p-[2-(cyclopropylmethoxy)ethoxy]phenoxy]-3-(isopropylamino)- 2-propanol) (cicloprolol); ((#)-1-[(3-chloro-2-methylindol4-yl)oxy]-3-[(2-phenoxyethyl)amino]- 2-propanol) (indopanolol); ; ((f)-6-[[2-[[3-(p-butoxyphenoxy)-2-hydroxypropyl]amino]ethyl]amino]- 1,3-dimethyluracil) (pirepolol), (4-(cyclohexylamino)-1-(1-naphtholenyloxy)-2-butanol); (1-phenyl-3-[2-[3-(2-cyanophenoxy)-2-hydroxypropyl]aminoethyl]hydantoin HC1); (3,4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy-2H-l- benzopyran) (nipradolol); Angiotensin I Converting Enzyme Inhibitors: : l-(3-mercapto.2-methyl-l-oxopropyl)-L-proline (captopril); (1-(4-ethoxycarbonyl-2,4(R,R)-dimthylbutanoyl)indoline-2(S)-carboxylic acid); (2-[2-[(1-(ethoxyzarbonyl)-3-phenyl-propylJamino]-1-oxopropyl]- 1,2,3 ,4-tetrahydro-3-isoquinoline carboxylic acid); ((S)-1-[2-[(1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]oc tahydro-lH-indole-2-carboxylic acid HC1); (N-cyclopentyl-N-(3-(2,2-dimethyl-1-oxopropyl)thiol-2-methyl-1-oxopropyl)glycine) (pivalopril); ((2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid); (l-(N-[l(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl)-cis,syn-octa- hydroindol-2(S)-carboxylic acid HC1); ; ((-)-(S)-l-[(S)-3-mercapto-2-methyl-1-oxopropyl]indoline-2-carboxylic acid); ([1-(S),4S]-1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-4-phenylthio-Lpro line; (3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro 2-oxo-1-(3S)-benzazepine-l-acetic acid HC1); (N-(2-benzyl-3-mercaptopropanoyl)-S-ethyl-L-cysteine) and the Smethyl analogue; (N-(l(S)-ethoxyearbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate) (enalapril); N-[l-(S)-carboxy-3-phenylpropyl]-L-alanyl-l-proline; N2-{1-(S)-carboxy-3-phenylpropyl]-L-lysyl-L-proline (lysinopril); Other Antihypertensive Agents: aminophylline; cryptenamine acetates and tannates; deserpidine; meremethoxylline procaine; pargyline; trimethaphan camsylate; and the 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 they are given singly. Coadministration is most readily accomplished by combining the active ingredients into a suitable unit dosage form containing the proper dosages of each. Other methods of coad ministration are, of course, possible. The novel peptides of the present invention possess an excellent degree of activity in treating renin-associated hypertension and hyperaldosteronism. The compounds of the present invention are prepared as depicted in the charts and as described more fully in the Preparations and Examples The process of the present invention is more completely understood by reference to- the charts below. In these charts, any variables are as defined above. Chart A Chart A describes the preparation of compounds which are useful as intermediates for the preparation of renin inhibitory peptides. The known aldehyde of formula A-1 is reacted with sulfonium ylide to afford a mixture of epimeric epoxides of formula A-2. Azide opening then proceeds to give an epimeric mixture of alcohols of formula A-3. Chart B Chart B describes the incorporation of amino acids into the- compound of formula- A-3 of Chart A. The compound of formula B-l (A-3) is deprotected with acidic methanol to the corresponding free amine which is coupled to Boc His(Ts)-OH to give an epimeric mixture. The mixture is separated into the compounds of formulas B-2A and B-2B. The stereochemistry at the hydroxyl group at C-2 has not been assigned. The compound of formula B-2A is deprotected and the resulting amine coupled to Boc Phe-OH to give the compound of formula B-3A. Chart C Chart C describes the preparation of the acid of formula C-4. Diastereoselective alkylation of the known dianion of the diester of formula C-1 with l-bromomethylnaphthalene gives the compound of formula- C-2. Selective ester hydrolysis, followed by amide formation with morpholine, gives the ester of formula C-3. Hydrolysis of the ester then affords the acid of formula C-4. Chart D Chart D describes the preparation of a representative renininhibitory peptide of formula D-4. The compound of formula D-l (B-3A) is hydrogenolyzed to the amine of formula D-2. Reaction with isopropylisocyanate gives the compound of formula D-3. Removal of the tosyl group affords the peptide of formula D-4. Chart E Chart E describes the preparation of the compound of formula E-2 and its incorporation into a representative renin-inhibitory peptide. The epimeric epoxides of formula E-1 (A-2) are opened with cyanide to give a mixture of nitriles of formula E-2. The mixture is then deprdtected with acidic methanol to give the corresponding free amine which is coupled to Boc-His(Ts)-OH to give an epimeric mixture. The mixture is separated into the compounds of formulas E-3A and E3B. The assignment of stereochemistry of the C-3 hydroxyl group is tentative. Compound E-3A is deprotected with trifluoroacetic acid in dichloromethane. The corresponding free amine is coupled to Boc-Phe OH to give the compound of formula E-4A. Removal of the tosyl group affords the renin-inhibitory peptide of formula E-5A. Chart F Chart F describes the incorporation of the acid of formula C-4 of Chart C into a representative renin-inhibitory peptide of formula F-3. The compound of formula F-1 (B-2A) is deprotected and the resulting amine is coupled to the acid of formula C-4 to give the compound of formula F-2. Tosyl group removal then gives the peptide of formula F-3. Other renin-inhibitory peptides of this invention can be prepared according to the processes of these charts by using different amino acids known in the art. Generally, the renin inhibiting polypeptides may be prepared by solution phase pep tide synthetic procedures analogous to those described hereinafter or to those methods known in the art. Appropriate protecting groups, reagents, and solvents can be found in "The Peptides: Analysis, Synthesis, and Biology," Vols. 1-5, eds. E. Gross and T. Meienhofer, Academic Press, NY, 1979-1983; "The Practice of Peptide Synthesis", M. Bodansky and A. Bodansky, Springer-Verlag, New York, 1984; "The Principles of Peptide Synthesis", M. Bodansky, Springer-Verlag, New York, 1984. Thus, for example, the carboxylic moiety of N2-t-butyloxyzarbonyl (Boc)-substituted amino acid derivatives having suitable side chain protecting groups, if necessary, may be condensed with the amino functionality of a suitably protected amino acid or peptide using a conventional coupling protocol such as dicyclohexylcarbodiimide and l-hydroxybenzotriazole or diethylphosphoryl cyanide and trialkylamine in methylene chloride or dimethylformamide. Following coupling reaction completion, the NO-Boc moiety may be selectively removed with 508 trifluoroacetic acid with or without 2% anisole (vZv) in methylene chloride Neutralization of the resultant trifluoroacetate salt may be accomplished with 10% diisopropylethylamine or sodium bicarbonate in methylene chloride. The incorporation of Nin formyl-Trp into compounds of the present invention is easily accomplished- because of the commercial availability of N2-Boc-Nin-formyl-Trp-OH. However, the Nin,formyl moiety may be introduced into indolyl-substituted amino acid derivatives or related compounds by reaction with hydrochloric-formic acid as reported in the literature,- see A. Previero et al, Biochim. Biophys. Acta 147, 453 (1967); Y.C.S. Yang et al, Int. J. Peptide Protein Res. 15, 130 (1980). Generally, methods of alkylation useful in alkylating histidine for use in the present invention are found in Cheung, S.T. et al, Can. J. Chem., Vol 55, pp. 906-910 (1977). However it is now found that in the Cheung, S. T. et al, method, it is critical that the reaction conditions for the alkylation of histidine be anhydrous. Further, it is now found also that during work-up instead of adding water directly to the reaction mixture, it is preferred that a buffered aqueous solution be added to the reaction mixture, for example, aqueous sodium or potassium hydrogen sulfate. Variations in the above description for starting materials, reactants, reaction conditions and required protecting groups to obtain other such N-alkylated compounds are known to an ordinarily skilled chemist or are readily available in the literature. The compounds of the present invention may be in either free form or in protected form at one or more of the remaining (not previously protected) peptide, carboxyl, amino, hydroxy, or other reactive groups. The protecting groups may be any of those known in the polypeptide art. Examples of nitrogen and oxygen protection groups are set forth In T.W. Greene, Protecting Groups in Organic Synthesis, Wiley, New York, (1981); J.F.W. McOmie, ed. Protective Groups in Organic Chemistry, Plenum Press (1973); and J. Fuhrhop and G. Benzlin, Organic Synthesis, Verlag Chemie (1983). Included among the nitrogen protective groups are t-butoxycarbonyl (Boc), benzyloxycarbonyl, acetyl, allyl, phthalyl, benzyl, benzoyl, trityl and the like. DESCRIPTION OF THE PREFERRED EMBODIMENTS The following Preparations and Examples illustrate the present invention. In the Preparations and Examples below and throughout this document: 1H-NMR is proton nuclear magnetic resonance CS is relative to tetramethylsilane); 13C-NNR is carbon-13 nuclear magnetic resonance; BOC is t-butoxycarbonyl; C is centigrade; CDC13 is deuteriochloroform; Celite is a filter aid; g is grams; His is histidine; IR is infrared spectra; M or mol is mole; min is minute; ml is milliliter; FAB HRMS is fast-atom bombardment high-resolution mass spectroscopy; Phe is phenylalanine; Ts is p-toluenesulfonyl. The wedge-shape line indicates a bond which extends above the plane of the paper relative to the plane of the compound thereon. The dotted line indicates a bond which extends below the plane of the paper relative to the plane of the compound thereon. Preparation 1 1R and 1S-(3-tert- Butyloxycarbonyl-2, 2-dimethyl- 4S-cyclohexylmethyl-SR-oxazolidinyl) -ethylene oxide formula A-2) Refer to Chart A. To a stirred suspension of 3.3 g of trimethylsulfonium iodide in 14.6 ml of dry dimethylsulfoxide and 14.6 ml of anhydrous tetrahydrofuran, cooled to -5" C, is added dropwise, via addition funnel, 13.5 ml of a 1.0 M solution of sodium bistrimethylsilylamide in tetrahy drofuran. After 1 min, 2.9 g of the aldehyde of formula A-l in 12 ml of anhydrous tetrahydrofuran is added rapidly via cannula. After 2 h, the ice bath is removed and the reaction mixture is stirred at room temperature for 18 h. The reaction mixture is quenched with 30 ml of pH 7 phosphate buffer and then diluted with dichloromethane. The aqueous phase is extracted with four portions of dichloromethane. The combined organics are dried -(magnesium sulfate), -filtered and concentrated. The residue is purified by flash chromatography on silica gel using 5% ethyl acetate in hexane to afford 2.7 g of the title product as a mixture of isomers. Physical characteristics are as follows: 1H-NMR (E, CDC13): 0.96-2.0, 1.48, 1.52, 1.63, 2.66, 2.80, 2.86, 3.06, 4.0. 13C-NMR CS, CDC13): 29.74, 29.97, 30.13, 31.40, 32.10, 36.02, 38.04, 38.66, 38.94, 45 23, 49.37, 56.28, 61.52, 83.29, 85.39, 97.89, 155.07. IR (cm 1 mull): 2950, 2926, 1703. FAB HRMS: [M+H]+ at m/z - 340.2509. Anal. Found: C, 67.65; H, 9.65; N, 4.09. Preparation 2 2-Azido-lR and 1S-(3-tert-butyloxycarbonyl-2,2- dimethyl-4S-cyclohexylmethyl-5R-oxazolidinyl)- ethanol (Formula A-3) Refer to Chart A. To a stirred solution of 2.4 g of the epoxide of formula A-2 of Preparation 1 in 13 ml of dry methanol is added 1.06 g of magnesium sulfate and 1.15 g of sodium azide. The reaction mixture is heated to reflux for 6 h, then cooled to room temperature. The reaction mixture is partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous phase is extracted with four portions of dichloromethane. The combined organics are dried (magnesium sulfate), filtered and concentrated. The residue is purified by flash chromatography on silica gel using 10% ethyl acetate in hexane to afford 2.17 g of the title product as a mixture of isomers. Physical characteristics are as follows: 1H-NMR (E, CDCl3): 0.96-1.0, 1.47, 1.52, 1.58, 3.61, 4.0. IR (cm'l mull): 3393, 2926, 2853, 2099, 1661 FAB HRMS: [M+HJt at m/z - 383.2663. Preparation 3 N&alpha;-tert-Butyloxycarbonyl-Nim-tosyl-L-histidyl-4S- amino-1-azido-(2R and 2S),3R-dihydroxy-5-cyclo hexylpentane (Formulas B-2A and B-2B) Refer to Chart B. To 7.0 ml of dry methanol, cooled to 0 C, is added 0.50 ml of acetyl chloride. After stirring for 10 min at room temperature, this solution is added to 541.1 mg of the azide of formula B-l (A-3) of Preparation 2. After stirring at room temperature for 3 h, 5.0 g of Amberlite exchange resin hydroxide form) is added. After 45 min, the reaction mixture is filtered and the resin is washed with several portions of methanol. The filtrate is concentrated. The residue is chromatographed on 33 g of silica gel using 5% methanol unsaturated with ammonia) in dichloromethane to afford 252.4 mg of a mixture of the title product as a mixture of isOmers. Physical characteristics are as follows: FAB HRMS: [M+H]+ at m/z - 243.1814. To a stirred solution containing 250.1 mg of a mixture of the isomers and 507.6 mg of Boc-His(Ts)-OH in 4.1 ml of dichloromethane is added 0.25 ml of diisopropylethylamine followed by 0.19 ml of diethylcyanophosphonate. After 4 h at room temperature, the reaction mixture is partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous phase is extracted with five portions of dichloromethane. The combined organics are dried magnesium sulfate), filtered and concentrated. The residue is chromatographed on 67 g of silica gel using 40 to 50 to 65% ethyl acetate in hexane to afford 292.9 mg of the title product B-2A and 94.2 mg of the title product B-2B. Note: assignment of 2S to B-2A and 2R to B-2B is tentative. Physical characteristics are as follows: FAB HRMS: [M+H]+ at m/z - 634.3015. Preparation 4 N&alpha;-tert-Butyloxycarbonyl-L-phenylalanyl-Nim- tosyl-L-histidyl-4S-amino-1-azido-2"S",3R-dihy droxy-5-cyclohexylpentane formula B-3A) Refer to Chart B. The peptide of formula B-2A of Preparation 3, 193.9 mg, is dissolved in 1.0 ml of dichloromethane and 1.0 ml of trifluoroacetic acid. After 45 min at room temperature, the reaction mixture is slowly pipetted into a stirred solution containing 1.5 g of solid sodium bicarbonate in 15 ml of water. After 10 min, the aqueous phase is extracted with five portions of dichloromethane. The combined organic phases are dried (magnesium sulfate) filtered and concentrated to afford 150.4 mg of the free amine. A solution of this material and 105.2 mg of Na-tert-butyloxycarbonyl-L-phenylal- anine, 110 p1 of diisopropylethylamine and 70 pl of diethylphosphorylcyanide in 1.2 ml of dichloromethane affords 204.1 mg of the title product after chromatography on silica gel with 50 to 85% ethyl acetate in hexane. Physical characteristics are as follows: FAB HRMS: [M+H]+ at m/z - 781.3678. Preparation 5 Diethyl 3S-hydroxy-2R-(l'-naphthylmethyl)suc cinate (Formula C-2)- Refer to Chart C. A solution of 2.85 g of diethyl S-malate of formula c-l in 5 ml of tetrahydrofuran is slowly added to a solution of 30.6 mmol of lithium diisopropylamide in 20 ml of tetrahydrofuran at -780C under argon. The resulting mixture is stirred at -20 C for 30 min and then recooled to .78cm. A solution of 5 g of 1-bromomethyl-naphthalene in 5 ml of tetrahydrofuran is slowly added to the reaction mixture. The resulting mixture is allowed to warm slowly overnight to -5-C and then quenched with 3 ml of acetic acid. The reaction mixture is partitioned between ether and saturated aqueous sodium bicarbonate. The organic phase is dried (magnesium sulfate), filtered and then concentrated. The residue is chromatographed on silica gel with 2025% ethyl acetate in hexane to give 3.13 g of the title product. Physical characteristics are as follows: 1H-NMR CS, CDCl3): 1.20, 1.22, 1.24, 3.3-3.6, 3.68-3.74, 4.1- 4.3, 7.4-8.2. Preparation 6 Ethyl 3S-hydroxy-4-morpholino-2R-(l'-naphthyl- methyl)-succinate (Formula C-3) Refer to Chart C. A solution of 369 mg of compound of formula C-2 of Preparation 5 in 2.3 ml of tetrahydrofuran is added 1.12 ml of a 1M solution of potassium hydroxide. After stirring at room temperature for 1 h, the reaction mixture is partitioned between dichloromethane and aqueous potassium bisulfate. The organic phase is dried magnesium sulfate), filtered and then concentrated to give 340 mg of an acidic residue. To a stirred solution of this residue in 5 ml of dichloromethane is added 0.13 ml of morpholine, 0.2-1 ml of diisopropylethylamine and 0.21 ml of diethylphosphoryl cyanide. After stirring at room temperature for one day, the reaction mixture is applied to a silica gel column and eluded with 40-50% ethyl acetate in hexane to give 310 mg of the title product. Physical characteristics are as follows: 1H-NMR #, CDC13): 1.20, 1.22, 1.24, 2.8-3.1, 3.2-3.7, 4.0-4.3, 7.4-8.2. Preparation 7 3S-Hydroxy-4-morpho lino- 2R-(1' -naphthylmethyl)- succinic acid formula C-4) Refer to Chart C. A solution of 310 mg of compound of formula C-3 of Preparation 6 in 2 ml of tetrahydrofuran is added 0.91 ml of a 1M solution of aqueous potassium hydroxide. After stirring at room temperature for 2 h, the reaction mixture is partitioned between dichloromethane and aqueous potassium bisulfate. The organic phase is dried magnesium sulfate), filtered and then concentrated to give 280 mg of the title product. Physical characteristics are as follows: 1H-NMR (E, CDC13): 2.4-2.5, 2.8-2.9, 3.0-3.2, 3.4-3.7, 7.3-8.1. Preparation 8 N&alpha;-tert-Butyloxycarbonyl-L-phenylalanyl-Nim- tosyl-L-histidyl-4S-amino-2"S" ,3R-dihydroxy-5 cyclohexylpentamine formula D-2) Refer to Chart D. To 100 mg of the peptide of formula B-3A (D-1) of Preparation 4 in 0.65 ml of dry methanol is added 30 mg of 10% palladium-on-carbon. The reaction mixture is flushed with nitrogen and evacuated several times, and then filled with hydrogen to an initial pressure of 55 psi. The reaction mixture is hydrogenated on a Parr shaker overnight. The reaction mixture is filtered through a pad of Celite. The catalyst is washed with several portions of methanol. The filtrate is concentrated and the residue is purified on 11 g of silica gel using 7% methanol saturated with ammonia in dichloromethane to afford 58.2 mg of the title product. Physical characteristics are as follows: FAB HRMS: [M+H]+ at m/z - 755.3784. Preparation 9 N&alpha;-tert-Butyloxycarbonyl-L-phenylalanyl-Nim- tosyl-L-histidyl-4S-amino-2"S",3R-dihydroxy-5 cyclohexyl-l-isopropylaminocarbonylamino-pentane (Formula D-3) Refer to Chart D. To 72.4 mg of the compound of formula D-2 of Preparation 8 in I ml of dichloromethane at 0 C is added 10 p1 of isopropylisocyanate. After stirring at room temperature for one day, the reaction mixture is then applied to a silica gel column and eluded with 4-6% methanol in dichloromethane to give 42.8 mg of the title product Physical characteristics are as follows: 1H-NMR (E, CDC13-): 1.10, 1.17, 1.38, 2.40, 7.0-8.0. Example 1 Nt-tert-Butyloxycarbonyl-L-phenylalanyl-L-histidyl-4S- amino-2"S",3R-dihydroxy-5-cyclohexyl-1-isopropylamino. carbonylamino-pentane formula D-4) Refer to Chart D. 54 mg of the compound of formula D-3 of Preparation 9 and 34 mg of l-hydroxybenzotriazole are dissolved In 0.5 ml of methanol. After stirring at room temperature overnight, the reaction mixture is concentrated and the residue chromatographed on silica gel with 3-5% methanol (saturated with ammonia) in dichloromethane to afford 31.9 mg of the title product. Physical characteristics are as follows: 1H-NMR ( & CDCl3): 1.10, 1.17, 1.38, 6.83, 7.27, 7.-57. FAB HRMS: [M+H]+ at m/z - 686.4211. Preparation 10 3-(3-tert-Butyloxycarbonyl-2,2-dimethyl-4S cyclohexylmethyl-5R-oxazolidinyl) -3R and 35- hydroxypropionitrile (Formula E-2) Refer to Chart E. To a stirred solution of-4.18 g of the epoxide of formula E-1 (A-2) of Preparation 1 in 25 ml of dry methanol is added 1.85 g of magnesium sulfate and 2.0 g of potassium cyanide. The reaction mixture is heated to reflux for 4 h, then cooled to room temperature. The reaction mixture is partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous phase is extracted with four portions of dichloromethane. The combined organics are dried magnesium sulfate), filtered and concentrated. The residue is purified by flash- chromatography¯ on silica gel using 15% ethyl acetate in hexane to afford 3.65 g of the title product as a mixture of isomers. Physical characteristics are as follows: 1H-NMR CS, CDC13): 1.35, 1.38, 1.39, 1.40, 2.4, 3.5, 3.75. IR (cm-1, mull): 3413, 2924, 2264, 1700. FAB HRMS: jM+H]+ at m/z - 367.2571. Anal. found: C, 65.13; H, 9.41; N, 7.34. Preparation 11 N&alpha;-tert-Butyloxycarbonyl-Nim-tosyl-L-histidyl-5S- amino-6-cyclohexyl-3R and 3S,4R-dihydroxy- hexanenitrile (Formulas E-3A and E-3B) Refer to Chart E. By the same procedure as in the preparation of the compounds of formulas B-2A and B-2B of Preparation 3, 88 mg of the compound of formula E-2 of Preparation 10 is treated with methanol and acetyl chloride to give 53.7 mg of the free amine. A solution of this material, 118.1 mg of Na-tert-butyloxycarbonyl-Ni2-tosyl-L-histidine, 0.08 ml of diisopropylethylamine and 0.05 ml of diethylcyanophosphonate in 0.9 ml of dichloromethane affords 98.5 mg of the title product E-3A and 26.2 mg of the title product E-3B after chromatography on silica gel with 50 to 70% ethyl acetate in hexane. The assignment of stereochemistry to the title products is tentative. Physical characteristics are as follows: FAB HRMS: [M+H]+ at m/z - 618.2953. Preparation 12 N&alpha;-tert-Butyloxycarbonyl-L-phenylalanyl-Nim- tosyl-L-histidyl-5S-amino-6-cyclohexyl-3"S",4R- dihydroxy-hexanenitrile formula E-4A) Refer to Chart E. By the same procedure as in the preparation of the compounds of formula B-3A of Preparation 4, 95.1 mg of the compound of formula E3A of Preparation 11 is treated with trifluoroacetic acid and dichloromethane to give the free amine. A solution of this material, 53.1 mg of Na-tert-butyloxycarbonyl-L-phenylalanine, 56 p1 of diisopropylethylamine and 37 p1 of diethylcyanophosphonate in 0.62 ml of dichloromethane affords 95.7 mg of the title product after chromatography on silica gel with 65 to 70% ethyl acetate in hexane. Physical characteristics are as follows: FAB HRMS: [M+H]+ at m/z - 765.3617. Example 2 Na-tert-Butyloxycarbonyl-L-phenylalanyl-L-histidyl-5S amino-6-cyclohexyl-3"S",4R-dihydroxy-hexanenitrile .Formula E-5A) Refer to Chart E. 91.7 mg of the peptide of formula E-4A of Preparation 12 and 64.8 mg of l-hydroxybenzotriazole hydrate are dissolved in 0.5 ml of dry methanol. After stirring at room temperature overnight, the reaction mixture is concentrated and chromatographed on silica gel with 5% methanol unsaturated with ammonia) in dichloromethane to afford 51.4 mg of the title product. Physical characteristics are as follows: FAB HRMS: [M+H]+ at m/z - 611.3568. Preparation 13 3S-Hydroxy-4-morpholino-2R-(1'-naphthylmethyl) succinoyl-Nim-tosyl-L-histidyl-4S-amino-l-azido 2"S",3R-dihydroxy-5-cyclohexylpentane (Formula F 2) Refer to Chart F. To 89 mg of the amine derived from the compound of formula F-l (B-2A) of Preparation 3 and 52 mg of the compound of formula C-4 of Preparation 7 in 1 ml of dichloromethane is added 29 pl of diisopropylethylamine and 28 pl of diethylphosphoryl cyanide. After stirring at room temperature for one day, the reaction mixture is applied to a silica gel column and eluded with 3-4* methanol in dichloromethane to give 54.5 mg of the title product. Physical characteristics are as follows: 1H-NMR (E, CDC13): 0.8-1.8, 2.36, 2.5-3.8, 4.2-4.4, 4.6-4.8, 7.2-8.2. FAB MS: [M+H]+ at m/z - 860. Example 3 3S-Hydroxy-4-morpholino-2R-(1'-naphthylmethyl)-suc cinoyl-L-histidyl-4S-amino-l-azido-2"S",3R-dihydroxy 5-cyclohexylpentane formula F-3) Refer to Chart F. A solution of 53.8 mg of the compound of formula F-2 of Preparation 13 ¯and 34 mg of l-hydroxybenzotriazole in 0.5 ml of methanol is stirred at room temperature for one day. The concentrated reaction mixture is chromatographed on silica gel with 3-4* methanol (saturated with ammonia) in dichloromethane to give 26.8 mg of the title product. Physical characteristics are as follows: 1H-NMR (E, CDCl3): 0.6-1.8, 2.6-3.8, 4.0-4.5, 4.5-4.8, 6.9-8.5. FAB MS: [M+H]+ at m/z ¯ 706. FORMULA CHART X-A6-B7-C8-D9-E10-F11 EMI27.1 CHART A EMI28.1 CHART B EMI29.1 EMI29.2 CHART C EMI30.1 CHART D EMI31.1 CHART E EMI32.1 CHART F EMI33.1

Claims: CLAIMS 1. A renin inhibitory peptide of the formula I X-A6-B7-C8.D9-E10-F11 wherein X is (a) hydrogen, (b) C1-C5alkyl (c) R5-O-(CH2)q-C(O)-, (d) R5-(CH2)q-O-C(O)-, (e) R5-O-C(O)-, (f) R5-(CH2)n-C(O)-, (g) R4N(R4)-(CH2)n-C(O)-, (h) R5-SO2-(CH2)q-C(O)-, (i) R5-SO2-(CH2)q-O-C(O)-, (j) R5-S-(CH2)q-C(O)-, (k) R5-(CH2)-S-(CH2)q-C(O)-, (l) R5-(CH2)q-O-(CH2)q-C(O)-, or (m) (R3)p+1C(H)2p-NH-C(O)-; wherein Y is (a) -O-, (b) -NH-, or (c) -ONH-; wherein A6 is absent or a divalent moiety of the formula XL1, XL2, or XL2a; EMI34.1 wherein B7 is absent or a divalent moiety of the formula XIb; EMI34.2 wherein C8 is absent or a divalent moiety of the formula XL1, XL2 or XL7; ; EMI35.1 or wherein Cg is a monovalent moiety of the formula XL2a, when X, A6 and B7 are all absent; EMI35.2 wherein Dg is a divalent moiety of the formula XL3 or XL2a; EMI35.3 or wherein Cg-Dg is a divalent moiety of the formula XI4 or XL4a, EMI35.4 or wherein Cg-Dg is a monovalent moiety of the formula XL4b when X, A6, and B7 are all absent; EMI35.5 wherein E10-F11 is a divalent moiety of the formula XL6, XL6a, XL6b, or XL6c; EMI35.6 EMI36.1 wherein * indicates an asymmetric center which is either in the R or S configuration; wherein G12 is absent or a divalent moiety of the formula XL5, XLsa or XL5b; EMI36.2 wherein H13 is absent or a divalent moiety of the formula XL5, XL5a or XL5b; ; EMI36.3 wherein R1 is (a) hydrogen, (b) C1-C5alkyl, (c) aryl, (d) C3-C7cycloalkyl, (e) -Het, (f) C1-C3alkoxy, or (g) C1-C3alkylthio; wherein R2 is (a) hydrogen, (b) C1-C5 alkyl, or (c) aryl-C1-C5alkyl; wherein R3 is (a) -(CH2)q-OH, (b) -(CH2)q-NH2, or (c) -(CH2)q-CO2H; wherein R4 at each occurrence is the same or different and is (a) hydrogen, or (b) C1-C5alkyl; wherein R5 is (a) Cl-C6alkyl, (b) C3-C7cycloalkyl, (c) aryl, (d) -Het, or (e) 5-oxo-2-pyrrolidinyl; wherein R6 is (a) hydrogen, (b) C1-C5alkyl, (c) -(CH2)p-aryl, (d) -(CH2)p-Het, (e) C3-C7cycloalkyl, (f) 1- or 2-adamantyl, or (g) -C(CH20H)3; wherein R7 is (a) hydrogen, (b) C1-C5alkyl, (c) hydroxy, (d) amino C1-C4alkyl-, (e) guanidinyl Cl-C3alkyl-, (f) aryl, (g) -Het, (h) methylthio, (i) C3-C7cycloalkyl, or (j) amino, (k) -(CH2)nC02H; wherein R6-Y taken together can be (a) -NR2R6, (b) N-morpholino, (c) N-piperidyl, (d) N-prolinol, (e) N-proline-Y-R6; wherein m.is one or two; ; wherein for each occurrence n is independently an integer of zero to five, inclusive; wherein p is zero to 2, inclusive; wherein q is 1 to 5, inclusive; wherein Q is (a) -CH2-, (b) -CH(OH)-, (c) -O-, or (d) -S-; wherein M is (a) -CO-, or (b) -CH2-; wherein aryl is phenyl or naphthyl substituted by zero to 3 of the following: (a) C1-C3alkyI, (b) hydroxy, (c) C1-C3alkoxy, (d) halo, (e) amino, (f) mono- or di-C1-C3alkylamino. (g) -CHO, (h) -COOH, (i) COOR2, Ci) CONHR2, (k) nitro, (1) mercapto, (m) C1-C3alkylthio, (n) C1-C3alkylsulfinyl, (o) C1-C3alkylsulfonyl, (p) C1-C3alkylsulfonyl-N(R4)-. (q) SO3H. Cr) S02NH2, (s) -CN, or (t) -CH2NH2; wherein -Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring, which heterocyclic moiety is substituted with zero to 3 of the following: (i) C1-C6alkyl, (ii) hydroxy, (iii) trifluoromethyl, (iv) C1-C4alkoxy, (v) halo, (vi) aryl, (vii) aryl-C1-C4alkyl-, (viii) amino, or (ix) mono- or di-C1-C4alkylamino; or a carboxy-, amino-, or other reactive group-protected form thereof; or a pharmaceutically acceptable acid addition salt thereof; with the overall provisos that (1) when Elo-Fll is XL6a and C8 is XL2, then B7 must be present, and M must be -CH2-; (2) when E10-F11 is XL6a, Cg is XL1 and both A6 and B7 are absent, then X in formula I is not hydrogen; (3) when E10-F11 is XL6b, Cg is XL2, both G12 and H13 are absent, and X in XL6b is hydrogen, Cl-Cs alkyl, or R5-(CH2)n-C(O)-, then B7 must be present and M must be -CH2-; (4) when E10-F11 is XL6b, C8 is XL1, both G12 and H13 are absent, X in XL6b is hydrogen, C1-C5 alkyl, or R5-(CH2)n-C(O)-, and both A6 and B7 are absent, then X in formula I is not hydrogen, C1-C5 alkyl, or R5-(CH2)n-C(O)-; and (5) when Elo-Fll is XL6, and C8 is XL2, then R6 in XL2 of Cg is neither hydrogen nor C1-C5 alkyl. 2. A renin-inhibitory peptide of claim 1 in which A6, B7, G12 and H13 are all absent. 3. A renin-inhibitory peptide of claim 2 in which C8 is XL1, XL2 or XL7; Dg is XL3. 4. A renin-inhibitory peptide of claim 3 in which R4 is hydrogen; R1 is isopropyl or cyclohexyl; and R7 is aryl, -Het, or (CH2)nC02H. 5. N&alpha;-tert-Butyloxycarbonyl-L-phenylalanyl-L-histidyl-5S-amino-6 cyclohexyl-3"S",4R-dihydroxy-hexanenitrile, a compound of claim 4. 6. Na-tert-Butyloxycarbonyl-L-homophenylalanyl-L-histidyl-5S-amino 6-cyclohexyl-3"S",4R-dihydroxy-hexanenitrile, a compound of claim 4. 7. N&alpha;-tert-Butyloxycarbonyl-L-phenylalany-L-histidyl-4s-amino- 2"S",3R-dihydroxy-1-(isopropylaminocarbonylamino)-5-cyclohexylpentane, a compound of claim 4. 8. N-tert-Butyloxyearbonyl-L-phenylalanyl-L-histidyl-4S-amino- 2"S",3R-dihydroxy-1-isobutyloxycarbonylamino-5-cyclohexylpentane, a compound of claim 4. 9. Na-tert-Butyloxycarbonyl-L-phenylalanyl-L-histidyl-4S-amino- 2" S" , 3R-dihydroxy-l - (tris-hydroxymethylmethylaminocarbonylamino) -5 - cyclohexylpentane, a compound of claim 4. 10. 2R-Benzyl-3S-hydroxy-4-morpholinosuccinoyl-L-histidyl-4S-amino1-azido-2"S",3R-dihydroxy-5-cyclohexylpentane, a compound of claim 4. 11. 2R-Benzyl-3S-hydroxy-4-morpholinosuccinoyl-L-histidyl-5S-amino 6-cyclohexyl-3"St,4R-dihydroxy-hexanenitrile, a compound of claim 4. 12. 3S-Hydroxy-4-morpholino-2R-(l' -naphthylmethyl) -succinoyl-L- histidyl-4S-amino-1-azido-2"S",3R-dihydroxy-5-cyclohexylpentane, a compound of claim 4. 13. 3S-Hydroxy-4-morpholino-2R-(l'-naphthylmethyl)-succinoyl-L- histidyl-5S-amino-6-cyclohexyl-3"S",4R-dihydroxy-hexanenitrile, a compound of claim 4. 14. A transition-state analogue insert of the formula II EMI40.1 wherein R1 is (a) hydrogen, (b) C1-C5 alkyl, (c) aryl, (d) C3-C7 cycloalkyl, (e) -Het, (f) C1-C3 alkoxy, or (g) C1-C3 alkylthio; wherein Z is (a) oxirane, (b) -C(H)(OH)CH2N3, or (c) -C(H)(OH)CH2CN. 15. A transition-state analogue insert of the formula III EMI41.1 wherein R4 at each occurrence is the same or different and is (a) hydrogen, or (b) C1-C5 alkyl; wherein R6 is (a) hydrogen, (b) C1-C5 alkyl, (c) -(CH2)p-aryl. (d) -(CH2)p-Het, (e) C3-C7 cycloalkyl, (f) 1- or 2-adamantyl, or (g) -C(CH20H)3; wherein T is (a) hydrogen, or (b) Cl-Cs alkyl; wherein Y is (a) o , (b) -NH-, (c) -ONH-. 16. 1R and 1S-(3-tert-Butyloxycarbonyl-2,2-dimethyl-4S-cyclohexylmethyl-5R-oxazolidinyl)-ethylene oxide, compounds of claim 14. 17. 2-Azido-1R and 1S-(3-tert-butyloxycarbonyl-2,2-dimethyl-4S- cyclohexylmethyl-5R-oxazolidinyl)-ethanol, compounds of claim 14. 18. 3-(3-tert-Butyloxycarbonyl-2,2-dimethyl-4S-cyclohexylmethyl-5R oxazolidinyl)-3R and 3S-hydroxypropionitrile, compounds of claim 14. 19. Ethyl-3S-hydroxy-4-morpholino-2R-(1'-naphthylmethyl)-succinate. a compound of claim 15. 20. 3S-Hydroxy-4-morpholino- 2R- (1 ' -naphthylmethyl) -succinic acid, a compound of claim 15.

Inventors: THAISRIVONGS SUVIT, THAISRIVONGS, SUVIT
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1987
Main classification: C07K5
IPC codes: A61K38, A61P5, A61P9, C07C59, C07C235, C07C237, C07C259, C07D233, C07D263, C07D295, C07D413, C07K5, C07K14