MALIC ACID DERIVATIVE CONTAINING RENIN INHIBITING PEPTIDES

Abstract: The present invention provides novel renin-inhibiting peptides of the formula Z-C(O)-CH(OH)-CH(CH2R1)-C(O)-N(R2)-CH(CH2R3)-C(O)-NH-CH(CH2R4)-X-C(R5) (R2)-C(O)-Y-Z containing malic acid derivatives. Such inhibitors are useful for the diagnosis and control of renin-dependent hypertension and other related diseases.

Description: MALIC ACID DERIVATIVE CONTAINING RENIN INHIBITING PEPTIDES DESCRIPTION BACKGROUND OF THE INVENTION The present invention provides novel compounds. More parricu- larly, the present invention provides novel renin-inhibiting peptid analogs. Most particularly, the present invention provides reτiin- inhibitory compounds malic acid derivatives and having transition state inserts. The renin inhibitors provided herein are useful for the diagnosis and control of renin-dependent hypertension and other related diseases. Renin is an endopeptidase which specifically cleaves a particular peptide bond of its substrate (angiotensinogen) , of which the N-ter- minal sequence in equine substrate is for example: Renin I Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser- IA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 as found by L. T. Skeggs et al, J. Exper. Med. 106, 439 (1957). Human renin substrate has a different sequence as recently discovered by D. A. Tewkesbury et al, Biochem. Biophys. Res. Comm. 99, 1311 (1981). It may be represented as follows: Renin I -Val-Ile-His- 11 12 13 IB and having the sequence to the left of the arrow (I) being as dεsig- nated in formula IA above. Renin cleaves angiotensinogen to produce angiotensin I, which is converted to the potent pressor angiotensin II. A number of angio¬ tensin I converting enzyme inhibitors are known to be useful in the treatment of hypertension. Inhibitors of renin are also useful i 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, file d 3 February 1986; disclose certain peptides with the dipeptide at the 10,11-position containing an isostere bond. A number of statin 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; an 5 4,485,099. Terminal disulfide cycles have also been disclosed in reni 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 th 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 an l_f£ European published applications 156,320 and 156,318. Certain tetra psp.tπ__fes are disclosed in European publications 111,266 and 77,027 Further", European published application No. 118,223 discloses certai renin inhibiting peptide analogs where the 10-11 peptide link i replaced by a one to four atom carbon or carbon-nitrogen link 15 Additionally, Holladay et al. , in "Synthesis of Hydroxyethylene an Ketomethylene Dipeptide Isosteres", Tetrahedron Letters, Vol. 24 No. 41, pp. 4401-4404, 1983 disclose various intermediates in a proces to prepare stereo-directed "ketomethylene" and "hydroxyethylene dipeptide isosteric functional groups disclosed in the above note 20 U.S. Patent No. 4,424,207. Evans, et al. f J. Org. Chem. , 50, 461 (1985) discloses the synthesis of Hydroxyethylene Dipeptide Isosteres See also published European patent application 163,237 which disclose certain renin inhibiting peptides. Additionally, published European Applications 45,161 and 53,01 25 disclose amide derivatives useful as inhibitors of angiotensin convert ing enzymes. Certain dipeptide and tripep ides are disclosed in U.S. patent 4,514,332; 4,510,085; and 4,548,926 as well as in European publishe applications 128,762; 152,255; and 181,110. Pepstatin derived reni 30 inhibitors have been disclosed in U.S. patent 4,481,192. Retroinvers bond modifications at positions 10-11 have been disclosed in U.S patent 4,560,505 and in European published applications 127,234 an 127,235. Derivatives of isosteric bond replacements at positions 10-1 have been disclosed in European published applications 143,746 an 35 144,290; and U.S. patent application, Serial No. 904,149, filed September 1986. Isosteric bond modifications at positions 11-12 an 12-13 have been disclosed in European published application 179,352 Certain peptides containing 2-substituted statine analogues have bee disclosed in European published application 13 " , 09. Certain peptide containing 3-aminodeoxystatine have been disclosed in European pub lished application 161,588. Certain peptides containing l-amino-2 hydroxybutane derivatives at positions 10-11 have been disclosed i European published application 172,346. Certain peptides containing 1 amino-2-hydroxypropane derivatives at positions 10-11 have bee disclosed in European published application 1~2,347. Certain peptide containing N-terminal amide cycles have been disclosed in U.S. paten application, Serial No. 844,716, filed 27 March 1986. Certain peptide containing dihalostatine have been disclosed in PCT application, Seria No. 000,713, filed 7 April 1986. Certain peptides containing C- terminus truncated epoxy or azido or cyano groups or containing position 10-11 diol and a position 11-12 retro bond have been disclose in U.S. patent application, Serial No. 945,34C. filed 22 December 1986. European published applications 156,322; 114,993; and 118,223; an PCT patent application, Serial No. 002,227, filed 21 November 1986 U.S. patent application, Serial No. 825,250. filed 3 February 1986 U.S. patent application, Serial No. 904,149, filed 5 September 1986 and U.S. patent application, Serial No. 844,716, filed 27 March 1986 disclose hydroxamic acids or esters at the C-terminus. 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. 904,149, filed 5 September 1986. The following references disclose additional substituents at the 10, 11-position: 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 and W.B. Kezer et al., J. Am. Chem. Soc, 106:4282 (1984); 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). INFORMATION DISCLOSURE Certain peptides having cleavable bonds corresponding to the 10,11-position of the renin substrate and containing [malic acid derivatives are disclosed in U.S. Patent 4,629,784 (1986) Stammer; PCT Application WO 85/00809 Stammer] . Different peptides are shown to have different uses such as food additives, analgetics, CNS regulators, renin inhibitors, and antihypertensive agents. SUMMARY OF THE INVENTION The present invention provides: The invention more particularly provides the renin inhibitory peptide of claim 2 of the Formula I wherein X is (a) -CH(OH)-; (b) -CH(NH 2 ) ; (c) -C(0)-; (d) -CH(0H)-CH(0H)-; (e) -CH(OH)-CH 2 -; (f) -CH(NH 2 )-CH 2 ; (g) -C(0)-CH 2 ; (h) -CH 2 -NH-; (i) -CH 2 -0-; or (j) -P(0)(A)B-; wherein A is (a) -OH or (b) -NH 2 ; B is (a) absent; (b) -0-; (c) -NH-; or (d) -CH 2 -; wherein Y is (a) absent or (b) -NHCH(R 5 )C(0)-; wherein Z is (a) -0-R 6 ; (b) -N(R 2 )R 6 ; or (c) Het bonded via a nitrogen atom; wherein ] _ is -5- (a) hydrogen; (b) C -C 5 alkyl; (c) -(CH 2 )p-aryl; (d) -(CH 2 )p-Het; (e) -(CH 2 )p-(C 3 -C 7 )cycloalkyl; (f) -(CH 2 )p-S-aryl; (g) -(CH 2 )p-S-Het; (h) -(CH 2 )p-S-(C 1 -C 5 )alkyl; or (i) -(CH 2 )p-S-(C 3 -C 7 (cycloalkyl); wherein R 2 is (a) hydrogen; or (b) Cχ-C 5 alkyl; wherein R3 is (a) hydrogen; (b) Cχ-C5 alkyl; (c) -(CH 2 )p-0H; (d) -(CH 2 )p-C0 2 H; (e) -(CH 2 )p-NH 2 ; (f) -(CH 2 )p-NH-C(NH 2 ) - NH; (g) -(CH 2 )p-aryl; (h) -(CH 2 )p-Het; or (i) -(CH )p-(C 3 -C 7 )cycloalkyl; wherein R4 is (a) hydrogen; (b) C -C5 alkyl; (c) C3-C7 cycloalkyl; (d) aryl; (e) Het; (f) -(CH 2 )p-0H; or (g) -(CH 2 )p-NH 2 ; wherein R5 is (a) hydrogen; (b) Cχ-05 alkyl; (c) -(CH 2 )p-aryl; (d) -(CH 2 )-p-Het; or (e) -(CH 2 )p-(C 3 -C 7 )cycloalkyl; wherein Rg is (a) hydrogen; -7- rings is fused to a benzene ring or another heterocycle; and, i chemically feasible, the nitrogen and sulfur atoms may be in th oxidized forms ; with the provisos that when X is (a) -CH(OH)-; 5 (b) -CH(NH 2 ) ; and (c) (C(0)-; R 2 and R5 taken together can be -F 2 -; -Cl 2 -; -FH-; or -C1H-, or a carboxy- , amino- or other reactive group protected for thereof; 10 or a pharmaceutically acceptable acid or base addition salt thereof. By "renin inhibitory peptide" is meant a compound capable of inhibiting the renin enzyme in mamnalian metabolism and linked b peptidic or pseudo-peptidic bonds. 15 By "a non-cleavable transition state insert" is meant a transitio state insert which is not cleavable by a hydrolytic enzyme in mammalia metabolism. A variety of such transition state inserts, correspondin to the 10,11-position of the renin substrate, are known in the art, including those disclosed in the following references : 0 U.S. Patent 4,424,207 (Szelke) ; European Patent 104041A (Szelke) ; European Patent Application 144.290A (Ciba Geigy AG) ; European Paten 0,156,322 (Merck); European Patent 161-588A (Merck); European Paten 0,172,347 (Abbott); European Patent 172-346-A (Abbott); European Paten 156-318 (Merck); European Patent 157-409 (Merck); European Patent 152- 5 255 (Sankyo); and U.S. Patent 4,548,926 (Sankyo) ; and U.S. patent application, Serial No. 904,149, filed 5 Septembe 1986; U.S. patent application, Serial No. 844,716, filed 27 March 1986; PCT application, Serial No. 000,713, filed 7 April 1986; U.S. paten application, Serial No. 945,340, filed 22 December 1986; and U.S. 0 patent application, Serial No. 825,250, filed 3 February 1986; and A. Spaltenstein, P. Carpino, F. Miyake and P.B. Hyskins, Tetra¬ hedron 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 5 (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 Chemica Company, Rockford, 111., pp. 511-20; 587-590 (1983). As is apparent to those of ordinary skill in the art, the reni inhibitory peptides of the present invention can occur in severa isomeric forms, depending on the configuration around the asymmetri carbon atoms. All such isomeric forms are included within the scope o the present invention. Preferably, the stereochemistry of the othe amino acids corresponds to that of the naturally-occurring amino acids Renin inhibitory peptides commonly have protecting groups at t N-terminus and the C-terminus. These protecting groups are known i the polypeptide art. Examples of these protecting groups are give below. Any of these protecting groups are suitable for the reni inhibitory peptides of the present invention. Furthermore, the malic acid derivative of Formula I of the prese invention may occur at the N-terminus of the renin inhibitory pepti and, as such, will, when coupled with a suitable protecting group assume the ending position. These compounds are shown in relation to the human renin substrat as follows: 6 7 8 9 10 11 12 13 -His Pro Phe His Leu Val He His- The present invention provides peptide inhibitors of renin whic are malic acid derivatives and contain at least one malic acid ami acid and have transition state inserts. Examples of pharmaceutically acceptable acid addition salt include: acetate, adipate, alginate, aspartate, benzoate, benzenesul fonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate cyclopentanepropionate, digluconate, dodecylsulf te, ethanesulfonate fumarate, glucoheptanoate, glycerophosphate, heπisulfate, heptanoate hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sul onate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate nicotinate, oxalate, pal oate, pectinate, persulfate, 3-phenylpropio nate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate tosylate, and undecanoate. The carbon atom content of various hydrocarbon-containing moietie is indicated by a prefix designating the minimum and maximum number o carbon atoms in the moiety, i.e., the prefix (C j -C,-) indicates a moiet of the integer "i" to the integer "j" carbon atoms, inclusive. Th - 9 - (C -C )alk l refers to alkyl of one to 4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, and isomeric forms thereof. C4-C7 cyclic amino indicates a monocyclic group containing one nitrogen and 4 to 7 carbon atoms. Examples of (C3-Cχø)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-diethyl- cyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3- propylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, cyclohexy1, cycloheptyl,. cyclooctyl, cyclononyl, cyclodecyl and isomeric forms thereof. Examples of aryl include phenyl, naphthyl, (o-, m- , p-)tolyl, (o- , m- , 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-isopro- pyl-2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4- 2,3,6-, or 2,4,5-)- trimethylphenyl, (o-, m- , or p-)fluorophenyl, (o-, - , or p-trifluoro- me h 1)phenyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)di- fluorophenyl, (o-, m-, or p-)chlorophenyl, 2-chloro-p-tolyl, (3-, 4-, 5- or 6-)chloro-o-tolyl, 4-chloro-2-propylphenyl, 2-isoρroρyl-4-chloro- phenyl, 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-π_ethoxy-phenyl, and 2,4-dichloro(5- or 6-)methylphenyl, and the like. Examples of -Het include: 2-, 3-, or 4-pyridyl, imidazolyl, indolyl, N in -formyl-indolyl, N in -C 1 -C 5 alkyl-C(0)-indolyl, [1,2,4]- triazolyl, 2-, 4-, or 5-pyrimidinyl, 2- or 3-thienyl, piperidinyl, pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidi- nyl, imidazolinyl, imidazolidinyl, pyrazinyl, piperazinyl, 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 trifluoro- -10- meth l . Examples of pharmaceutically acceptable cations include: pharm¬ acologically acceptable metal cations, ammonium, amine cations, o quaternary ammonium cations. Especially preferred metal cations ar those derived from the alkali metals, e.g., lithium, sodium, an potassium, and from the alkaline earth metals, e.g. , magnesium an calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron are also within the scope of this invention. Pharmacologi cally acceptable amine cations are those derived from primary, secon- dary, or tertiary amines. The novel peptides herein contain both natural and synthetic amin acid residues. These residues are depicted using standard amino aci abbreviations (see, e.g., Eur. J. Biochem. , 138, 9 (1984)) unles otherwise indicated. In addition to the treatment of warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the compounds of the invention ar effective in the treatment of humans. The renin inhibitors of this invention are useful for treating an medical condition for which it is beneficial to reduce the levels o active circulating renin. Examples of such conditions include renin associated hypertension and hyperaldosteronism, hypertension, hyper tension under treatment with another antihypertensive and/or a diureti agent, congestive heart failure, angina, and post-myocardial infarc tion. The renin-angiotension system may play a role in maintenance o intracellular homeostasisr see Clinical and Experimental Hypertension, 86, 1739-1742 (1984) at page 1740 under Discussion. Further, the renin inhibitors of this invention may be useful i the treatment of cerebrovascular disorders and disorders of intra cellular homeotasis. The possible role of the renin-angiotensin syste in the maintenance of intracellular homeostasis is disclosed i Clinical and Experimental Hypertension, 86:1739-1742 (1984). Addition ally, the renin inhibitors of this invention potentiate the antithrom botic activity of a thromboxane antagonist (U.S. patent 4,558,037) The antihypertensive effect of the renin inhibitors of this inventio are potentiated by combination with a thromboxane synthetase inhibitor The compounds of the present invention are preferably orall administered to humans to effect renin inhibition for the purpose o favorably affecting blood pressure. For this purpose, the compound are administered from 0.1 mg to 1000 mg per kg per dose, administered from 1 to 4 times daily. 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. Other routes of administration include parenteral, 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 tech¬ niques. 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 suspend¬ ing agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-accept¬ able 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 the preparation of injectables. Equivalent dosages for such other routes of administration are thus employed. The exact dose depends on the age, weight, and condi- tion 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, th amounts disclosed in the U.S. Patent No. 4,424,207 are example applicable to the compounds of the present invention. The renin-inhibiting compounds of this invention may be adminis tered in combination with other agents used in antihypertensive therap such as diuretics, a and/or jS-adrenergic blocking agents, CNS- ctin agents, adrenergic neuron blocking agents, vasodilators, angiotensin converting enzyme inhibitors, and the like as described, for example in published European patent application 156 318. For example, the compounds of this invention can be given i combination with such compounds or salts or other derivative form thereof as: Diuretics: acetazolamide; amiloride; bendroflumethiazide benzthiazide; bumetanide; chlorothiazide; chlorthalidone; cyclothia zide; ethacrynic acid; furosemide; hydrochlorothiazide; hydroflume thiazide; indacrinone (racemic mixture, or as either the (+) or (- enantiomer alone, or a manipulated ratio, e.g., 9:1 of said enan tiomers, respectively); metolazone; methyclothiazide; muzolimine polythiazide; quinethazone; sodium ethacrynate; sodium nitroprusside spironolactone; ticrynaten; trimaterene; trichlormethiazide; α-Adrenergic Blocking Agents: dibenamine; phentolamine; phenoxy benzamine; prazosin; tolazoline; 3-Adrenergic Blocking Agents: atenolol; metoprolol; nadolol propranolol; timolol; ((±)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-2-furananilide) (an carolol) ; (2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran HC1) (be funolol); ((±)-1-(isopropyla ino)-3-(p-(2-cyclopropylmethoxyethyl)-phenoxy) 2-propranol HC1) (betaxolol) ; (1- [(3,4-dimethoxyphenethyl)amino] -3-(m-tolyloxy) -2-propano HC1)(bevantolol) ; (((±)-1- (4-((2-isopropoxyethoxy)methyl)phenoxy)-3-isopropylamino 2-propanol)fumarate) (bisoprolol) ; (4-(2-hydroxy-3- [4-(phenoxymeth l -piperidino]-propoxy)-indole) ; (carbazolyl-4-oxy-5,2-(2-methoxyphenoxy)-ethylamino-2-propanol) ; (l-((l,l-dimethylethyl)amino)-3-((2-methyl 'H-indol-4-yl)oxy)-2 propanol benzoate) (bopindolol) ; (l-(2-exobicyclo[2.2.1] -hept-2 -ylphenoxy) -3- [ ( 1-methylethyl) - amino] -2-propanol HCl) (bornaprolol) ; (o- [ 2 -hydroxy- 3- [ (2-indol-3-yl-l,l-dimethylethyl) - amino ]propoxy] - benzonitrile HCl) (bucindolol) ; 5 (α- [ (tert.butylamino)methyl] -7-ethyl-2-benzofuranmethanol) (bufur- alol) ; (3- [3-acetyl-4- [3-(tert.butylamino)-2-hydroxypropyl] -phenyl] -1,1- diethylurea HCl) (celiprolol) ; ((±)-2- [2- [3-[(l,l-dimethylethyl)amino] -2-hydroxypropoxy]phenoxy] - 10 N-methylacetamide HCl) (cetamolol) ; (2-benzimidazolyl-phenyl(2-isopropylaminopropanol) ) ; ( (±) -3 ' -acetyl-4' -(2-hydroxy-3-isopropylaminopropoxy)-acetanilide HCl) (diacetolol) ; (methyl-4- [2-hydroxy-3- [ (l-methylethyl)aminopropoxyl] ] -benzene- 15 propanoate HCl) (esmolol) ; (erythro-DL-l-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol) ; (1- (tert.butylamino) -3- [0- (2-propynyloxy)phenoxy] -2-propanol (pargo- lol); (1- (tert.butylamino) -3- [o-(6-hydrazino-3-pyridazinyl)phenoxy] -2- 20 propanol diHCl) (prizidilol) ; ( ( - ) - 2-hydroxy-5- [ (R) -1 -hydroxy- 2- [ (R) - (1 -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) ; 25 ((-) -5- (tert.butylamino) -2-hydroxypropoxy] -3 , 4 - dihydro - 1 - (2H) - naphthalenone HCl) (levobunolol) ; (4- (2 -hydroxy- 3 -isopropylamino -propoxy )-l, 2 -benzisothiazole HCl) ; (4- [3- (tert.butylamino) -2-hydroxypropoxy] -N-methylisocarbostyril HCl) ; ((±) -N-2- [4- (2-hydroxy-3-isopropylaminopropoxy)phenyl]ethyl-N' - 30 isopropylurea) (pafenolol) ; (3- [ [ (2-trifluoroacetamido)e hyl]amino] -l-phenoxypropan-2-ol) ; (N-(3-(o- chlor ophenoxy ) - 2 -hydroxypropyl ) -N' - (4 ' - chloro -2,3- dihydro - 3 - oxo-5-pyridazinyl)ethylenediamine) ; ( (±) -N- [3-acetyl-4- [ 2-hydroxy- 3- [ ( 1-me h lethyl) amino Jpropoxy- 35 phenyl] -but anamide) (acebutolol) ; ( (±) -4' - [3- (tert-butylamino) -2-hydroxypropoxy]spiro[cyclohexane- 1,2' -indan] -1' -one) (spirendolol) ; (7 - [ 3- [ [2 -hydroxy- 3- [ ( 2 -methyl indol- 4 -yl)oxylpropyl] amino] - -14- butyl]thio-phylline) (teoprolol) ; ((±)-l-tert. butyl amino - 3- (thiochroman-8-yloxy) -2-propar.ol) (tertato-lol) ; ((±)-l-tert.butyla___ino-3-(2,3-xylyloxy)-2-propanol HCl) (xibeno- lol) ; (8- [ 3- (tert .butylamino) -2-hydroxypropoxy] -5-methylcoumarin) (bucumo-lol) ; (2- (3- (tert.butylamino) -2-hydroxy-propoxy)benzonitrile HCl) (bunitro-lol) ; ((±) -2' - [3- (tert -butylamino) -2-hydroxypropoxy-5' - f luorobutvro - phenone) (butof ilolol) ; (l-(carbazol-4-yloxy)-3-(isopropylamino)-2-propanol) (carazolol) ; (5- (3- ter . butylamino -2-hydroxy)propoxy- 3 ,4-dihydrocarbotyril HCl) (carteolol) ; (l-( tert. butylamino) -3- (2, 5-dichlorophenoxy) -2 -propanol) (clorano- lol); (l-(inden-4(or 7)-yloxy)-3-(isopropylamino)-2-propanol HCl) (indeno-lol) ; (l-isopropylamino-3- [ (2-methylindol-4-yl)oxy] -2-propanol) (me- pindo-lol); (1- (4-acetoxy- 2 , 3 , 5 - trimethylphenox ) - 3 - isopropylaminopropan-2-ol) (metipranolol) ; (1- (isopropylamino) -3-(o-methσxyphenoxy) -3- [ (1 -me thylethyl) amino] - 2-propanol) (moprolol) ; ( (1- tert .butylamino) -3- [ (5 , 6 , 7 , 8-tetrahydro-cis-6 , 7-dihydroxy-l- naphthyl)oxy] -2-propanol) (nadolol) ; ((S)-l-(2- cyclopentylphenoxy ) - 3 - [ ( 1 , 1 - dime thylethyl) amino] -2- propanol sulfate (2:1)) (peributolol) ; (4' - [l-hydroxy-2- (amino) ethyl] methanesulfonanilide) (sotalol) ; (2 -methyl- 3- [4- (2-hydroxy-3-tert.butylaminopropoxy)phenyl] -7-methoxy- isoquinolin-1- (2H) -one) ; (1- (4- (2- (4-fluorophenyloxy)ethoxy)phenoxy)-3-isopropylamino-2- propanol HCl) ; ((-)-p-[3-[ (3,4-dimethoxyphenethyl)amino] -2-hydroxypropoxy] -β- methyl -cinnamonitrile) (pacrinolol) ; ((±) -2- (3 ' -tert.butylamino-2'-hydroxypropylthio)-4-(5' -carbaaoyl 2'-thienyl)thiazole HCl) (arotinolol) ; ( (±) -1- [p- [2- (cyclopropylmethoxy)ethoxy]phenoxy] -3- (isopropyl - - amino)-2-propanol) (cicloprolol) ; ((±) -1- [ (3-chloro-2-methylindol-4-yl)oxy]-3-[(2-phenoxyethyl)- amino] -2-propanol) (indopanolol) ; ((±)-6-[[2-[[3- (p-butoxyphenoxy) -2-hydroxypropyl]amino]ethyl] - amino] -1,3-dimethyluracil) (pirepolol) ; (4-(cyclohexylamino)-l-(l-naphtholenyloxy)-2-butanol) ; (1-phenyl-3- [2- [3- (2-cyanophenoxy)-2-hydroxypropyl]aminoethy1] - hydantoin HCl); (3,4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy-2H-1- benzopyran) (nipradolol) ; Angiotensin I Converting Enzyme Inhibitors: 1- (3-mercapto-2-methyl-l-oxopropyl)-L-proline (captopril) ; (1- (4-ethoxycarbony1-2,4(R,R)-dimethylbutanoy1)indoline-2(S)-car- boxylic acid) ; (2-[2-[(l- (ethoxycarbony1) -3-phenyl-propyl]amino] -1-oxopropyl] - l,2,3,4-tetrahydro-3-isoquinoline carboxylic acid); ((S)-l-[2-[(l- (ethoxycarbony1) -3-phenylpropyl]amino] -1-oxopro- pyl]octahydro-lH-indole-2-carboxylic acid HCl); (N-cyclopentyl-N- (3- (2 ,2-dimethyl-l-oxopropyl)thiol-2-methyl-l- oxo-propyl)glycine) (pivalopril) ; ((2R.4R) -2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazoli- dine-carboxylic acid); (1-(N- [l(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl)-cis, syn- octa-hydroindol-2(S)-carboxylic acid HCl); ((-)-(S)-l-[ (S)-3-mercapto-2-methyl-1-oxopropyl] indoline-2- carboxylic acid) ; ([1(S) ,4S]-l-[3-(benzoylthio)-2-methyl-1-oxopropyl] -4-phenylthio- L-proline; (3- ( [1-ethoxycarbony1-3-phenyl-(IS)-propyl]amino)-2,3,4,5-tetra- hydro-2-oxo-l-(3S)-benzazepine-l-acetic acid HCl) ; (N-(2-benzyl-3-mercaptopropanoyl)-S-ethyl-L-cysteine) and the S- methyl analogue; (N- (1 (S) -ethoxycarbonyl-3-phenylpropyl) -L-alanyl-L-proline maleate) (enalapril) ; N- [1- (S) -carboxy-3-phenylpropyl] -L-alanyl-1-proline; N 2 - [l-(S)-carboxy-3-phenylpropyl]-L-lysyl-L-proline (lysinopril) ; Other Antihypertensive Agents: aminophylline; cr ptenamine acetates and tannates; deserpidine; meremethoxylline procaine; par- gyline; tri-methaphan camsylate; and the like, as well as admixtures and combinations thereof. Typically, the individual daily dosages for these combinations ca range from about one-fifth of the minimally recommended clinica dosages to the maximum recommended levels for the entities when the are given singly. Coadministration is most readily accomplished b combining the active ingredients into a suitable unit dosage for containing the proper dosages of each. Other methods of coadminis tration are, of course, possible. The compounds of the present invention are prepared as depicted i the charts and as described more fully in the Preparations and Exam ples. In the charts, Ph is used to represent the phenyl ring. Chart A Chart A describes the preparation of the acid of Formula A-5. Diastereoselective alkylation of the known, dianion of the dieste of Formula A-l with 1-bromomethylnaphthalene gives the compound o Formula A-2. Selective ester hydrolysis, followed by amide formatio with morpholine, gives the ester of Formula A-4. Hydroylsis of th ester then affords the acid of Formula A-5. Chart B Chart B describes the preparation of peptides of Forumlas B-3 an B-4. The compound of Formula B-l(A-5) is coupled with the know amine (B-2) in the presence of diethylphosporyl cyanide to give th compound of Formula B-3. The tosyl group is removed by reacting th compound of Formula B-3 with 1-hydroxybenzotriazole to yield th peptide B-4. The malic acid derivative amino acids are incorporated into peptide using standard coupling procedures. Should the peptide exis in a protected form, the protecting groups are removed prior t coupling. For example, a Boc group is removed from an N-terminus wit trifluoroacetic acid in methylene chloride and then the malic aci derivative acid is introduced. After coupling, any remaining protect ing groups are removed under standard conditions. For example a tosy group is removed from histidine using 1-hydroxybenzotriazole i methanol. Generally, the renin inhibiting polypeptides may be prepared b either polymer assisted or solution phase peptide synthetic procedure analogous to those described hereinafter or to those methods known i - - the art. For example, the carboxylic moiety of N'-'-t-butyloxycarbonyl (Boc)-substituted amino acid derivatives having suitable side chain protecting groups, if necessary, may be condensed with the amino functionality of a suitably protected amino acid, peptide or polymer- bound peptide using a conventional coupling protocol such as dicyclo- hexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) or diethyl- phosphoryl cyanide (DEPC) and triethylaaine (Et3N) in methylene chloride or dimethylformamide. The synthetic procedures used to incorporate the novel moieties herein are analogous to those described, for example, in U.S. patents 4,424,207; 4,470,971; 4,477,440; 4,477,441; 4,478,826; 4,478,827; 4,479,941; and 4,485,099, and copend- ing application Serial No. 753,198 filed 9 July 1985, and copending application Serial No. 825,250 filed 3 February 1986, all of which are expressly incorporated by reference herein. See, also, published European patent applications 45,161; 45,665; 53,017; 77,028; 77,029; 81,783; 104,041; 111,266; 114,993; and 118,223. Following coupling reaction completion, the N'^-Boc moiety may be selectively removed with 45% trifluoroacetic acid with or without 2% anisole (v/v) in methylene chloride. Neutralization of the resultant trifluoroacetate salt may be accomplished with 10% diisopropylethyl- amine or sodium bicarbonate in methylene chloride. In the case of polymer-assisted peptide synthesis, this stepwise, coupling strategy may be partially or completely automated to provide the desired peptide-polymer intermediates. Anhydrous hydrofluoric acid treatment of the peptide-poly er intermediate may then be used to effect simul¬ taneous protecting group removal and cleavage of the peptide from its polymeric support. A notable exception to this includes N ιn -formyl- indolyl-substituted peptides in which the N ι -formyl-indolyl moiety is stable to TFA or HF but may be removed by NH3 or NaOH. Because FTrp is somewhat unstable to base in synthetic procedures, possibly causing lower yields, it may be desirable in solution phase synthesis to introduce the FTrp-containing moiety late in the synthetic sequence so that it is not exposed to such conditions. The incorporation of N ιn -formyl-Trp into compounds of the present invention is easily accomplished because of the commercial availability of N α -Boc-N in -formyl-Trp-OH. However, the N in -formyl moiety may be introduced into indolyl-substituted amino acid derivatives or related compounds by reaction with HCl-formic acid as reported in the liter- ature, 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 foun that in Cheung, S. T. et al, methods it is critical that the reactio conditions for the alkylation of histidine be anhydrous. Further, i is now found also that during work-up instead of adding water directl to the reaction mixture, it is preferred that a buffered aqueou solution be added to the reaction mixture, for example, aqueous sodiu or potassium hydrogen sulfate. Variations in the above description for starting materials, reactants, reaction conditions and required protecting groups to obtai other such N-alkylated compounds are known to an ordinarily skille chemist or are readily available in the literature. These peptides may also be prepared by the standard solid phas techniques of Merrifield. Appropriate protecting groups, reagents, an solvents for both the solution and solid phase methods can be found i "The Peptides: Analysis, Synthesis, and Biology," Vols. 1-5, eds. E. Gross and T. Meienhofer, Academic Press, NY, 1979-1983. The compounds of the present invention may be in either free for or in protected form at one or more of the remaining (not previousl protected) peptide, carboxyl, amino, hydroxy, or other reactiv groups. The protecting groups may be any of those known in th polypeptide art. Examples of nitrogen and oxygen protection groups ar set forth in T.W. Greene, Protecting Groups in Organic Synthesis Wiley, New York, (1981); J.F.W. McOmie, ed. Protective Groups i Organic Chemistry, Plenum Press (1973); and J. Fuhrhop and G. Benzlin Organic Synthesis, Verlag Chemie (1983). Included among the nitroge 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 presen invention. In the Preparations and Examples below and throughout thi document: Ac is acetyl; AMP is 2-(aminomethyl)pyridine; BOC is t-butoxycarbonyl; BOM is benzyloxymeth l; Bz is benzyl; C is centigrade; Celite is a filter aid; DCC is dicyclohexylcarbodiimide; DMF is dimethylformamide; EtOAc is ethyl acetate; g. is grams; HPLC is high performance liquid chromatograph ; I 2 is iodine; IR is infra red spectra; A Lindlar catalyst is a modified 5% palladium on calcium carbonat catalyst, obtained from Engelhard Industries and used for reduction; M or mol is mole; MBA is 2-meth lbutylamino (race ic or optically active) ; MBAS is 2S-methylbutylamino; Me is methyl; min. is minute; ml is milliliter; MS is mass spectroscopy; NMHis is Nα-methyl-L-histidine; NMR is nuclear magnetic resonance; NOAl is (l-naphthyloxy)acetyl; p-TSA salt is para-toluene sulfonic acid salt; Ph is phenyl; POA is phenoxyacetyl; RIP means a compound having the formula H-Pro-His-Phe-His-Phe- Phe-Val-Tyr-Lys-0H.2(CH3C(0)0H).XH 2 0 which is a known renin-inhibiting peptide. Skellysolve B is as defined in the Merck Index, 10th edition; TBDMS is t-butyldimethylsilyl; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TLC is thin layer chromatography; Tos is p-toluenesulfonyl; Tr is trityl (triphenylmethyl) ; 2HPA is (±)-(2-hydroxypropyl)amino; and UV is ultraviolet. 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. 5 Preparation 1 Diethyl 3S-hvdroxy-2R-benzylsuccinate (Formula A-2A (Refer to Chart A) To a stirred solution of 30.6 mmol of lithium diisopropylamide in 20 ml of dry tetrahydrofuran at -78 β C under argon was slowly added a solution of 2.85 g (15 mmol) of diethyl-S-malate in 5 ml of dry ID tetrahydrofuran. The resulting solution was allowed to stir at -25 β C for 30 minutes and then recooled to -78 β C. Benzyl bromide (4.3 ml, 36.1 mmol) was added and the bath was allowed to warm slowly overnight, and then 4.6 ml of acetic acid was added. The solution was partitioned between ethyl acetate and saturated aqueous s odium bicarbonate. The 15 organic phase was dried (magnesium sulfate) and then concentrated. The residue was chromatographed on silica gel with 25% ethyl acetate in hexane to give 2.23 g. (8 mmol, 53%) of the title compound. 1 H-NMR (CDC1 3 ): S 1.25 (q, 6H, J - 7Hz) , 3.15 (m, 3H) , 4.15 ( , 5H) , 7.27 (bs, 5H). 20 Preparation 2 Diethyl 3S-hvdroxy-2R-(l' -naphthylmethvDsuccinate (Formula A-2B (Refer to Chart A) According to the same procedure as in the Preparation 1, 2.85 g (15 mmol) of diethyl S-malate with 30.6 mmol of lithium diisopropyl- 25 amide in tetrahydrofuran with 5 g (23 mol) of 1-bromomethylnaphthalene afforded 3.13 g (9.5 mmol, 63%) of the title compound A. 1 H-NM (CDCI3): δ 1.20 (t, 6H, J - 7Hz), 3.4 (m, 3H) , 3.7 ( , IH) , 4.2 (m, 5H), 7.3-8.2 (m, 7H) . Preparation 3 30 1-Ethyl 3S-hvdroxy-2R-benzylsuccinate (Formula A-3A) (Refer to Chart A) To a stirred solution of 266.6 mg (0.95 mmol) of diethyl-3S- hydroxy-2R-benzylsuccinate (A-2A) in 2 ml of tetrahydrofuran was adde 1 ml of a IH aqueous potassium hydroxide solution. After one hour, the reaction mixture was partitioned between dichloromethane and 1M aqueous 35 potassium hydrogen sulfate. The organic phase was dried (magnesiu sulfate) and then concentrated to give 250 mg. of the title compound. Preparation 4 1-Ethyl 3S-hvdroχy-2R-(l' -naphthylmethyDsuccinate (Formula A-3B) (Refe to Chart A) According to the same procedure as in the Preparation 3, 561 m (2.0 mmol) of diethyl-3S-hydroxy-2R-(1' -naphthyl___ethyl)succinate (A-2B in 4 ml of tetrahydrofuran and 2 ml of a 1M aqueous potassium hydroxid solution gave 443 mg of the title compound. Preparation 5 Ethyl 3S-hvdroxy-4-morpholino-2R-benzylsuccinate (A-4A) (Refer to Char 41 To a stirred solution of 250 mg (0.95 mmol) of 1-ethyl-3S-hydroxy- 2R-benzylsuccinate (A-3A) and 260 μl (3.0 mmol) of morpholine in 4 m of dichloromethane was added 175 μl (1.1 mmol) of diethylphosphory cyanide. After one day, the reaction mixture was partitioned betwee dichloromethane and saturated aqueous sodium bicarbonate. The organi phase was dried (magnesium sulfate) and then concentrated. The residu was chromatographed on silica gel with 1:1 — ethyl acetate:hexane t give 130 mg (0.40 mmol, 43%) of the title compound. 1 H-NMR(CDCl3) : δ 1.2 (t, 3H, J - 7 Hz), 4.15 (q, 2H, J - 7 Hz), 7.3 (bs, 5H) . Preparation 6 Ethyl 3S-hvdroxy-4-morpholino-2R-(1' -naphthylmethvDsuccinate (A- 4B (Refer to Chart A) According to the same procedure as in the Preparation 3, 340 mg. (1.12 mmol) of l-ethyl-3S-hydroxy-2R-(1' -naphthylmethyl)succinate (A- 3b), 130 μl (1.5 mmol) of morpholine, 210 ml (1.2 mmol) of diisopropyl- ethylamine and 210 μl (1.4 mmol) of diethylphosphoryl cyanide in 5 ml of dichloromethane afforded 310 mg (0.83 mmol, 75%) of compound A-4b. ^-NMR (CDC1 3 ): δ 1.22 (t, 3H, J - 7 Hz), 4.15 (q, 2H, J - 7 Hz) 7.4- 8.1 (m, 7H). Preparation 7 3S-Hvdroxy-4-morpholine-2R-benzylsuccinic acid (A-5A) (Refer to Chart A) To a stirred solution of 130 mg (0.4 mmol) of ethyl-3S-hydroxy-4- morpholino-2R-benzylsuccinate (A-4A) in 1 ml of tetrahydrofuran was added 0.5 ml of a 1M aqueous potassium hydroxide solution. After four hours the reaction mixture was acidified with 1M aqueous potassium hydrogen sulfate and then lyophilized. The resulting residue was triturated with dichloromethane to give the title compound (5a) . Preparation 8 3S-Hydroxy-4-morpholino-2R-(l' -naphthylmethvDsuccinic acid (A-5B) (Refer to Chart A) According to the same procedure as in Preparation 7, 310 mg (0.83 mmol) of ethyl-3S-hydroxy-4-morpholine-2R-(1'-naphthylmethyl)succinate (A-4b) in 2 ml of tetrahydrofuran and 0.91 ml of 1 M aqueous potassium hydroxide gave 280 mg of the title compound after extraction of the acidified reaction mixture with 1M aqueous potassium hydrogen sulfate. Preparation 9 3S-Hvdroxy-4-morpholino-2R-benzylsuccinoyl-N j* S-tosyl-L-histidyl-5S- amino-4S-hydroxy-2S-isopropyl-7-methyloctanoyl-L-isoleucyl-2-pyridyl- methylamine (B-3A) (Refer to Chart B) To a stirred solution of 18.7 mg. (64 μmol) of 3S-hydroxy-4- morpholine-2R-benzylsuccinate acid (A-5a) and 46.3 mg (64 μmol) of N lm - tosyl-L-histidyl-5S-amino-4S-hydroxy-2S-isopropyl-7-methyloctanoyl-L- isoleucyl-2-pyridylmethylamine in 0.6 ml of dichloromethane was added 12 μl (69 μmol) of diisopropylethylamine and 11 μl (72 μmol) of diethylphosphoryl cyanide. After 6 hours, the reaction mixture was chromatographed on silica gel with 5%-8% πethanol in dichloromethane gave 25.1 mg (25 μmol, 39%) of the title peptide (B-3a) . 1 H-NMR was consistent with the structure. Preparation 10 3S-Hvdroxy-4-morpholino-2R-(l' -naphthylmethyl)succinoyl-Niffi-tosyl-L- histidyl-5S-amino-4S-hydroxy-2S-isopropyl-7-aethyloctanoyl-L-isoleucyl- 2-pyridylmethylamine (B-3B) (Refer to Chart B) According to the same procedure as in the preparation of compound B-3a, 52.3 mg (0.15 mmol) of the 3S-hydroxy-4-morpholino-2R-(l'- naphth lmethyl)succinic acid (A-5b), 108 mg (0.15 mmol) of the peptidic amine B-2, 29 μl (0.17 mmol) of diisopropylethylamine and 28 μl (0.18 mmol) of diethylphosphoryl cyanide in 1 ml of dichloromethane afforded 61.9 mg (59 μmol, 40%) of the title peptide. -"-H-NMR was consistent with the structure. Example 1 3S -Hydroxy-4-morpholino- 2R-benzylsuccinoyl-L-histidyl-5S-amino-4S- hvdroχy-2S-isopropyl-7 -me thyloctanoyl-L-isoleucyl-2-pyridylmethyl- amine (B-4A) (Refer to Chart B) A solution of 25.1 mg (25 μmol) of the 3S-hydroxy-4-morpholino-2R- benzylsuccinoyl-N lm -tosyl-L-histidyl-5S-amino-4S -hydroxy- 2S- isopropyl - 7-methyloctanoyl-l-isoleucyl-2-pyridyl-methylamine (B-3a) and 14 mg (0.1 mmol) of 1-hydroxybenzotriazole in a few drops of methanol was allowed to stand at room temperature overnight. The reaction mixture was chromatographed on silica gel with 4% -10% methanol (saturated wit ammonia) in dichloromethane to give 11.9 mg (14 μmol, 56%) of th peptide B-4A. ---H-NMR was consistent with the structure. FAB-MS: :M H] + at m/z - 847.5082 (calculated), 847.5089 (found); HPLC - k' - 7.7. Example 2 3S-Hydroxy-4-morpholino-2R-(l' -naphthylmethyl)succinoyl-L-histidyl-5S am ino-4S- hvdroxy- 2S- isopropyl -7 -me thyloctanoyl-L-isoleucyl -2 -pyridyl methyla ine (B-4B) (Refer to Chart B) According tc the same procedure as in Example 1, 61 mg (58 μmol) of the peptide 3S-Hydroxy-4-morpholino-2R- (1' -naphthylI__ethyl)succino l- N il - ■• -tosyl-L-histidyl-5S-amino-4S-hy ro y-2S-isopropyl-7-methyloctanoyl- L-isoleucyl-2-pyridylmethylamine (B-3B) and 31 mg (0.23 mmol) of 1- hydroxybenzotriazole in methanol afforded 32 mg (36 μmol, 62%) of th peptide B-4B. ---H-NMR was consistent with the structure. FAB-MS: [M H] + at m/z - 897.5238 (calculated), 897.5241 (found); HPLC:1' - 8.5. Utilizing procedures similar to those used in Examples 1 and 2 but substituting the appropriate tosylated peptide as a starting material, the following peptides are obtained: 3S- Hydroxy -4-morpholino-2R-benzylsuccinoyl-L-histidyl-5S- amino- 6- cyclohexyl-4S -hydroxy- 2S-isopropylhexanoyl-L-isoleucyl -2 - pyridyl - methylamine, 3S-Hydroxy-4- (N-methylpiperazino) -2R-benzylsuccinoyl-L-histidyl- 5S - amino -4S -hydroxy- 2S- isopropyl -7 -methyloctanoyl-L-isoleucyl -2- pryidylmethylamine , 3S-Hydroxy-4- (N-methylpiperazino) -2R-benzylsuccinoyl-L-histidyl - 5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropylhexanoyl-L-isoleucyl-2- pyridylmethylamine , 3S- Hydroxy -4S -mo rpholino-2R-benzylsuccinoyl-L-histidyl-5S- amino - 4S -hydroxy- 2S - isopropyl -7 -me thyloctanoyl-2S -me thy lbutylamine , 3S -Hydrox -4-morpholino-2R-benzylsuccinoyl-L-histidyl-5S -amino- 6- cyclohexyl - 4S -hydroxy- 2S - isopropylhexanoyl - 2S -me thy lbutylamine , 3S -Hydrox -4- (N-methylpiperazino) -2R-benzylsuccinoyl-L-histidyl- 5S - amino - 4S -hydroxy- 2S - isopropyl - 7 -me thylac tanoyl - 2S -me thy lbutylamine , 3S-Hydroxy-4- (N-methylpiperazino) -2R-benzylsuccinoyl-L-histidyl- 5S -amino -6 -cyclohexyl-4S-hydroxy-2-S - isopropylhexanoyl -23-methyl- butylamine , 3S-Hydroxy-4-morpholino-2R-(l' -naphthylsuccinoyl)-L-histidyl-5S- amino - 6 - cyclohexyl -4S- hydroxy - 2S - isopropylhexanoyl -L- isoleucyl- 2- pyridylmethylamine, 3S-Hydroxy-4- (N-methylpiperazino) -2R- (l r -naphthylsuccinoyl) -L- histidyl-5S -amino -4S -hydroxy- 2S- isopropyl- 7 -me thy loctanoyl-L- isoleucyl- 2-pryidylmethylamine . 3S-Hydroxy-4- (N-methylpiperazino) -2R- (1' -naphthylsuccinoyl)-L- histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropylhexanoyl-L- isoleucyl - 2 -pyridylm th lamine , 3S - Hydrox -4S-morpholino-2R- (1' -naphthylsuccinoyl) -L-histidyl-5S- amino-4S -hydroxy- 2S - isopropyl-7-methyloctanoyl- 2S -methy lbutylamine , 3S-Hydroxy-4-morpholino-2R-(l'-naphthylsuccinoyl-L-histidyl)-5S- amino - 6 - eye lohexyl - 4 S - hydroxy - 2 S - i s op ropy lhexanoy 1 - 2 S - me thy lbutylamine , 3S-Hydroxy-4- (N-methylpiperazino) -2R- (1' -naphthylsuccinoyl) -L- hist idyl- 5S- amino- 4S -hydroxy- 2S- isopropyl -7 -meth lactanoyl-2S -me thyl- butyla ine , 3S -Hydroxy-4- (N-methylpiperazino) -2R- (1' -naphthylsuccinoyl) -L- his t idyl - 5 S - amino - 6 - cyclohexy 1 - 4S - hydroxy- 2 - S - isopropylhexanoyl- 23- me thy lbutylamine . - - CHART A Et0 2 C, ■ C0 2 Et A- OH 15 Et0 2 C C0 2 Et A-2A(R - phenyl A-2B(R - naphthyl) A2 A-3A (R - phenyl) A-3B (R - naphthyl) A-4A (R - phenyl) A-4B (R - naphthyl) A-5A (R - phenyl) A-5B (R - naphthyl) 20 A-5 CHART B le-Amp -Leuf[CHOHCH 2 [Val-He-Amp B-3A (R - phenyl) B-3B (R - naphthyl) [CHOHCH 2 ]Val-lie-Amp B-4A (R - phenyl) B-4B (R - naphthyl)

Claims: CLAIMS 1. The renin inhibitory peptide of the Formula I Z-C(0)-CH(OH)-CH(CH 2 R 1 )-C(0)-N(R 2 )-CH(CH 2 R 3 )-(C(0)-NH-CH(CH 2 R )-X- C(R 5 )(R 2 )-C(0)-Y-Z (e) -(CH 2 )p-(C 3 -C 7 )cycloalkyl; (f) -(CH 2 )p-S-aryl; (g) -(CH 2 )p-S-Het; (h) -(CH 2 )p-S-(C 1 -C 5 )alkyl; or (i) -(CH )p-S-(C 3 -C 7 (cycloalkyl); wherein R 2 is (a) hydrogen; or (b) C -C 5 alkyl; wherein R3 is (a) hydrogen; (b) Cχ-C 5 alkyl; (c) -(CH 2 )p-0H; (d) -(CH 2 )p-C0 2 H; (e) -(CH 2 )p-NH 2 ; (f) -(CH 2 )p-NH-C(NH 2 ) - NH; (g) -(CH 2 )p-aryl; (h) -(CH 2 )p-Het; or (i) -(CH 2 )p-(C 3 -C 7 )cycloalkyl; wherein R4 is (a) hydrogen; (b) C -C5 alkyl; (c) C3-C7 cycloalkyl; (d) aryl; (e) Het; (f) -(CH 2 )p-0H; or (g) -(CH 2 )p-NH 2 ; wherein R5 is (a) hydrogen; (b) C -C5 alkyl; (c) -(CH 2 )p- aryl; (d) -(CH 2 )-p-Het; or (e) -(CH 2 )p-(C 3 -C 7 )cycloalkyl; wherein Rg is (a) hydrogen; (b) aryl; (c) Het; (d) C -C o alkyl; (e) -(CH 2 )p-(C3-C 7 )cycloalkyl; or wherein Het is a 6 or 6-membered saturated or unsaturated ring contain¬ ing from one to three heteroatoms (nitrogen, oxygen, sulfur) ; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle; and, if chemically feasible, the nitrogen and sulfur atoms may be in the oxidized forms; with the provisos that when X is (a) -CH(0H)-; (b) -CH(NH 2 ); and (c) (C(O)-; R and R5 taken together can be -F 2 -; -Cl 2 -; -FH-; or -C1H- , or a carboxy- , amino- or other reactive group protected form thereof; or a pharmaceutically acceptable acid or base addition salts thereof. 2. A compound according to claim 1, 3S-Hydroxy-4-morpholino-2R- benzylsuccinoyl-N- **m -tosyl-L-histidyl-5S-amino-4S-hydroxy-2S-isopropyl- 7-methyloctanoyl-L-isoleucyl-2-pyridylmethylamine. 3. A compound according to claim 1, 3S-Hydroxy-4-morpholino-2R-(l' - naphthylmethyl)succinoyl-N ιm -tosyl-L-histidyl-5S-amino-4S-hydroxy-2S- isopropyl-7-methyloctanoyl-L-isoleucyl-2-pyridylmethylamine. 4. A compound according to claim 1, 3S-Hydroxy-4-morpholino-2R- benzylsuccinoyl-L-histidyl-5S-amino-4S-hydroxy-2S-isopropyl-7-methyl¬ octanoyl-L-isoleucyl-2-pyridylmethylamine. 5. A compound according to claim 2, 3S-Hydroxy-4-morpholino-2R-(1' - naphthylmethyl)succinoyl-L-histidyl-5S-amino-4S-hydroxy-2S-isopropyl-7- methyloctanoyl-L-isoleucyl-2-pyridylmethylamine.

Inventors: THAISRIVONGS SUVIT, THAISRIVONGS, SUVIT
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1988
Main classification: C07D401
IPC codes: A61K31, A61K38, A61P5, A61P9, A61P43, C07D217, C07D233, C07D235, C07D295, C07D401, C07K5, C07K14, C12N9