RENIN INHIBITORY PEPTIDES CONTAINING MALEAMIDE SUBSTITUENTS

Abstract: The present invention provides novel renin-inhibiting peptides having a non-cleavable transition state insert corresponding to the 10,11-position of the renin substrate (angiotensinogen) and having a maleic acid derived moiety or derivatives thereof of the formula R20N(R30)-(O)CCH=CHC(O)- corresponding to the 8,9-position of the renin substrate, preferably at the N-terminus of the peptide. Such inhibitors are useful for the diagnosis and control of renin-dependent hypertension, congestive heart failure, renin dependent hyperaldosterism, other renin dependent cardiovascular disorders and ocular disorders.

Description: RENIN INHIBITORY PEPTIDES CONTAINING MALEAMIDE SUBSTITUENTS DESCRIPTION BACKGROUND OF THE INVENTION The present invention provides novel compounds. More particu- larly, the present invention provides novel renin-inhibiting peptide analogs. Most particularly, the present invention provides renin- inhibitory peptides containing a non-cleavable transition state insert corresponding to the 10,11-position of the renin substrate (angiotensinogen) and containing a maleic acid derived moiety corre- sponding to the 8,9-position of the renin substrate and which is preferably at the N- erminus of the peptide. The renin inhibitors provided herein are useful for the diagnosis and control of renin- dependent hypertension, congestive heart failure, renin dependent hyperaldosterism, and other renin dependent cardiovascular disorders. Renin is an endopeptidase which specifically cleaves a particu¬ lar peptide bond of its substrate (angiotensinogen) , of which the N-terminal 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. Co m. 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 desig¬ nated in formula IA above. Renin cleaves angiotensinogen Co produce angiotensin I, which is converted to the potent pressor angiotensin II. A number of angio¬ tensin I converging enzyme inhibitors are known to be useful in the treatment of hypertension. Inhibitors of renin are also useful in the treatment of hypertension. A number of renin-inhibitory peptides have been disclosed. Thus, U.S. patent 4,424,207; European published applications 45,665; 104,041; and 156,322; and European application 0173481, published 5 March 1986; disclose certain peptides with the dipeptide at the 10,11-position containing an isostere bond. A number of statine derivatives stated to be renin inhibitors have been disclosed, see, e.g., European published applications 77,028; 81,783; 114,993; 156,319; and 156,321; and U.S. patents 4,478,826; 4,470,971; 4,479,941; and 4,485,099. Terminal disulfide cycles have also been disclosed in renin inhibiting peptides; see, e.g., U.S. patents 4,477,440 and 4,477,441. Aromatic and aliphatic amino acid residues at the 10,11 position of the renin substrate are disclosed in U.S.. patents 4,478,827 and 4,455,303. C- erminal amide cycles are dis¬ closed 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 appli¬ cation No. 118.223 discloses certain renin inhibiting peptide analogs where the 10-11 peptide link is replaced by a one to four atom carbon or carbon-nitrogen link. Additionally, Holladay et al., in "Synthe¬ sis of Hydroxyethylene and Ketomethylene Dipeptide Isosteres", Tetra¬ hedron Letters, Vol. 24, No. 41, pp. 4401-4404, 1983 disclose various intermediates in a process to prepare stereo-directed "ketomethylene" and "hydroxyethylene" dipeptide isosteric functional groups disclosed in the above noted U.S. Patent No. 4,424,207. Additionally, published European Applications 45,161 and 53,017 disclose amide derivatives useful as inhibitors of angiotensin con¬ verting enzymes. Certain dipeptide and tripeptides are disclosed in U.S. patents 4,514,332; 4,510,085; and 4,548,926 as well as in European published applications 128,762; 152,255; and 181,110. Pepstatin derived renin inhibitors have been disclosed in U.S. patent 4,481,192. Retro- i verso 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 PCT Application International Publication Number WO87/05302, published 11 September 1987. Isosteric bond modifica- tions at positions 11-12 and 12-13 have been disclosed in European published application 179,352. Certain peptides containing 2-substi- tuted 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. Cer¬ tain peptides containing l-amino-2-hydroxybutane derivatives at posi¬ tions 10-11 have been disclosed in European published application 172,346. Certain peptides containing l-amino-2-hydroxypropane deriv- atives at positions 10-11 have been disclosed in European published application 172,347. Certain peptides containing N-terminal amide cycles have been disclosed in PCT Application International Publica¬ tion Number WO87/05909, published 8 October 1987. Certain peptides containing dihalostatine have been disclosed in European application 0218688, published 22 April 1987. European published applications 156,322; 114,993; and 118,223; and PCT Application International Publication Number WO87/02986, pub¬ lished 21 May 1987; European Application 0173487, published 5 March 1986; PCT Application International Publication Number WO87/05302, published 11 September 1987; and PCT Application International Publi¬ cation Number O87/05909, published 8 October 1987; disclose hydrox- amic acids or esters at the C-terminus. INFORMATION DISCLOSURE PCT patent application, PCT/US89/00247, filed 27 January 1989, discloses renin inhibitory peptides having a variety of polar end groups at the N-terminus and/or the C-terminus. PCT Application International Publication Number WO89/01488, published 23 February 1989, discloses renin inhibitory peptides having aryl acid derived moieties substituted for Phe^-His^ (angio- tensinogen numbering) positions. SUMMARY OF THE INVENTION The present invention particularly provides: A renin inhibitory peptide having a non-cleavable transition state insert corresponding to the 10,11-ρosition of a renin substrate (angiotensinogen) and having a moiety of the formula I at the N- er¬ minus; wherein 20 is (a) -C<R 21 )(R22>-C<0)-0R 2 3, or wherein R is (a) hydrogen, or (b) C 1 -C 5 alkyi; wherein R22 is (b) -(CH 2 ) p -Het; wherein 23 is (a) hydrogen, or (b) Ci-C^al yl; wherein R2 is (a) -(_H 2 ) p -aryl, or (b) -(CH 2 ) p -Het; wherein 30 is (a) hydrogen, (b) CiL-Csalkyl, (c) - (CH 2 ) p -aryl , or (d) -(CH 2 ) p -Het; wherein n is 1 to 5, inclusive; wherein p is 0 to 5, inclusive. By "renin inhibitory peptide" is meant a compound capable of inhibiting the renin enzyme in mammalian metabolism and having three or more amino acid residues linked by peptidic or pseudo-peptidic bonds. By "a non-cleavable transition state insert" is meant a transi¬ tion state insert which is not cleavable by a hydrolytic enzyme in mammalian metabolism. A variety of such transition state inserts, corresponding to the 10,11-position of the renin substrate, are known in the art, including those disclosed in the following references, which are hereby incorporated by reference: U.S. Patent 4,424,207 (Szelke) ; European Patent 104041A (Szelkε) ; European Patent Application 144,290A (Ciba Geigy AG) ; European Patent 0.156,322 (Merck); European Patent 161-588A (Merck); European Patent 0,172,347 (Abbott); European Patent 172-346-A (Abbott); European Patent 156-318 (Merck); European Patent 157-409 (Merck); European Patent 152-255 (Sankyo); and U.S. Patent 4,548,926 (Sankyo) ; and PCT Application International Publication Number 087/05302, published 11 September 1987; PCT Application International Publica- tion Number WO87/05909, published 8 October 1987; European applica¬ tion 0218688, published 22 April 1987: PCT Application International Publication Number WO88/04664, published 30 June 1988; and European application 0173481, published 5 March 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 (1985); R.L. Johnson, J. Med. Chem., 25:605 (1982); R.L. Johnson and K. Verschovor, J. Med. Chem., 26:1457 (1983); R.L. John¬ son, J. Med. Chem., 27:1351 (1984); P.A. Bartlett et al. , J. Am. Chem. Soc, 106:4282 (1984); and Peptides: Synthesis, Structure and Function (V.J. Hruby; D.H. Rich, eds.) Proc. 8th American Peptide Sym. , Pierce Chemical Company, Rockford, 111., pp. 511-20; 587-590 (1983). The renin inhibitory peptides of the present invention are represented by formula II. In formula II, the non-cleavable transi¬ tion state insert, corresponding to the 10,11-position of the renin substrate, begins at -NHCH(CH 2 )(R 2 )-Xι, with the variables as defined above. The novel renin inhibitory peptides of the present invention containing a maleic acid derived moiety are potent inhibitors of human plasma renin. The novel non-peptidogenic nature of these inhibitory peptides alters their absorption, distribution, metabo¬ lism, and excretion characteristics. The new maleic acid derived moiety makes these inhibitory peptides unrecognizable to proteinases which would normally rapidly degrade a substrate based inhibitory peptide, particularly at the position corresponding to the 8,9-posi- tion of the renin substrate (angiotensinogen) . As is apparent to those of ordinary skill in the art, the renin inhibitory peptides of the present invention can occur in several isomeric forms. All such isomeric forms are included within the scope of the present invention. Renin inhibitory peptides commonly have protecting groups at the C-terminus. These protecting groups are known in the polypeptide art. Examples of these protecting groups are given below. Any of these protecting groups are suitable for the renin inhibitory pep¬ tides of the present invention. Furthermore, the non α-amino acid moieties of the formula I of the present invention preferably occur at the N-terminus of the renin inhibitory peptide. The present invention provides peptide inhibitors of renin which contain a non -amino acid moiety and have a transition state insert. Examples of pharmaceutically acceptable acid addition salts include: acetate, adipate, alginate, aspartate, benzoate, benzene- sulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfon- ate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane- sulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulf te, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, me hanesulfonate, 2-naph- thalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulf- ate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. The carbon atom content of various hydrocarbon-containing moi¬ eties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix (C^-C*) indi- cates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus (C^-C^ lkyl refers to alkyl of one to 4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, and isomeric forms thereof. C^Cycyclic amino indicates a monocyclic group containing one nitrogen and 4 to 7 carbon atoms. Examples of (C3-C o)c cloalkyl, which include alkyl-substituted cycloalkyl containing a total of up to 10 total carbon atoms, are cyclopropyl. 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-di- ethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, cyclopentyl, 2,2-dime hylcyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and isomeric forms thereof. Examples of aryl include phenyl, naphthyl, (o-, m-, or p-)tolyl, (o-, m- , or p-)ethylphenyl, 2-ethyl-tolyl, 4-ethyl-o-tolyl, 5-ethyl- m-tolyl, (o-, m-, or p-)propylphenyl, 2-propyl-(o- , -, or p-)tolyl, 4-isopropyl-2,ό-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-fIuoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4- , or 3.5-)difluorophenyl, (o- , m-, or p-)chlorophenyl, 2-chloro-p- tolyl, (3-, 4-, 5- or 6-)chloro-o-tolyl, 4-chloro-2-ρropylphenyl, 2- isopropyl-4-chlorophenyl, 4-chloro-3-fIuorophenyl, (3- or 4-)chloro- 2-fluorophenyl, (o- , m- , or p-)trifluoro-methylphenyl, (o-, m-, or p-)ethoxyphenyl, (4- or 5-)chloro-2-methoxy-phenyl, and 2,4-dichloro- (5- or 6-)methylρhenyl, and the like. Exa ples of Het include: 2-, 3-, or 4-pyridyl, imidazolyl, indolyl, N in -formyl-indolyl, N in -C 1 -C 5 alkyl-C(0)-indolyl, 1,2,4- triazolyl, 2-, 4-, or 5-pyrimidinyl, 2- or 3-thienyl, piperidinyl, pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidi- nyl, imidazolinyl, imidazolidinyl, pyrazinyl, piperazinyl, pyridazin- yl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, 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- methyl. Examples of pharmaceutically acceptable cations include: pharmacologically acceptable metal cations, ammonium, a ine 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 cationϊc forms of other metals, e.g., aluminum, zinc, and iron are also within the scope of this invention. Pharma¬ cologically 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 treat¬ ment with another antihypertensive and/or a diuretic agent, congest¬ ive heart failure, renin-dependent hyperaldosterism, angina, post- myocardial infarction, other renin-dependent cardiovascular disorders and ocular disorders. The renin-angiotension system may play a role in maintenance of intracellular hoπteostasis: see Clinical and Exper¬ imental Hypertension, 86, 1739-1742 (1984) at page 1740 under Discus¬ sion. Further, the renin inhibitors of this invention may be useful in the treatment of cerebrovascular disorders and disorders of intracel¬ lular homeotasis. The possible role of the renin-angiotensin system in the maintenance of intracellular homeostasis is disclosed in Clinical and Experimental Hypertension, 86:1739-1742 (1984). Additionally, the renin inhibitors of this invention potentiate the antithrombotic activity of a thromboxane antagonist (U.S. patent 4,558,037). The antihypertensive effect of the renin inhibitors of this invention are potentiated by combination with a thromboxane synthetase inhibitor. 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 100 mg per kg per dose, administered from 1 to 4 times daily. Equivalent dosages for other routes of administration are also employed. For example, renin-associated hypertension and hyperaldosteronism are effectively treated by the administration of from 0.5 to 50 milligrams of the compound per kilogram of body weight per day. The exact dose depends on the age, weight, and condition of the patient and on the frequency and route of administration. Such variations are within the skill of the practitioner or can readily be determined. The 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 βethods 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 phanaacologicall^r 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 coαrpounds of the present invention may be administered topically, parenterally, by inhalation spray, or rectally in dosage unit forπulations 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 accord¬ ing to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenteral¬ ly-acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or digly- cerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The peptides of this invention may also be administered in the form of suppositories for rec_ai administration of the drug. These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. The renin-inhibiting compounds of this invention may be adminis¬ tered in combination with o her agents used in antihypertensive therapy such as diuretics, a and/or 5-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 II with one or more antihypertensive agents selected from the group consisting of diuretics, a and/or ?-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; a iloride; bendroflumethiazide; benzthia- zide; bu etanide; chlorothiazide; chlorthalidone; cyclothiazide; ethacrynic acid; furosemide; hydrochlorothiazide; hydroflumethiazide; indacrinone (racemic mixture, or as either the (+) or (-) enantiomer alone, or a manipulated ratio, e.g., 9:1 of said enantiomers, respec¬ tively); metolazone; methyclothiazide; muzolimine; polythiazide; quinethazone; sodium ethacrynate; sodium nitroprusside; spironol- actone; ticrynaten; tri aterene; trichlormethiazide; αt-Adrenergic Blocking Agents: dibenamine; phentolamine; phenoxyben- zamine; prazosin; tolazoline; -Adrenergic Blocking Agents: atenolol; metoprolol; nadolol; propranolol; timolol; ((±)-2-[3- (tert-butylamino)-2-hydroxypropoxy] -2-furananilide) (ancarolol) ; (2-acetyl-7-(2-hydroxy-3-isopropyl__.inopropoxy)beι__ofuran HC1)(befun- olol); ((±)-1-(isoρropyl__αino)-3-(p-(2-cyciopropylmethoxyethyl)-phenoxy)-2- propranol HC1) (betaxolol) ; (1-[(3, -dimethoxyphenethy1)amino1-3-(m-toLyloxy)-2-proρanol HC1)(be- vantolol) ; (((±)-l-(4-((2-isopropoxyethoxy)πte_hyl)ρhenoxy)-3-isopropylamino-2- propanoDfumarate) (bisoprolol); (4-(2-hydroxy-3-[4-(phenoxyme h l)-piperidinoj-propoxy)-indole); (carbazolyl-4-oxy-5,2-(2-methoxyphenoxy)-ethylamino-2-propanol); (l-((l,l-dimethylethyl)amino)-3-((2-methyl Η-indol-4-yl)oxy)-2-pro- panol benzoate) (bopindolol) ; (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]ben- zonitrile HC1) (bucindolol) ; (α- [(tert.butylamino)methyl] -7-ethyl-2-benzofuranmethanol) (bufur- alol) ; (3- [3-acetyl-4- [3- (tert .butylamino) -2-hydroxypropyl] -phenyl] -1,1- diethylurea HC1) (celiprolol) ; ((±)-2-[2-[3-[ (1,1 -dime thylethyl) amino] -2-hydroxypropoxy]phenoxy] -N- methylacetamide HC1) (cetamolol) ; (2-benzimidazolyl-phenyl(2-isopropylaminopropanol) ) ; ( (±) -3 ' -acetyl-4' - (2-hydroxy-3-isoρropylaminopropoxy) -acetanilide HC1) (diacetolol) ; (methyl -4- [2-hydroxy-3- [ ( 1-methyle thy l)aminopropoxyl] ] -benzene - propanoate HC1) (esmolol) ; (erythro-DL-l-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol) ; (1- (tert. butylamino) -3- [0- (2-propynyloxy)phenoxy] -2-propanol (pargo- l l); (1- (tert. butylamino) -3- [o- (6-hydrazino-3-pyridazinyl)phenoxy] -2- propanol diHCl) (prizidilol) ; ((-)-2-hydroxy-5- [ (R) -l-hydroxy-2- [ (R) - (l-π.e hyl-3-phenylpropyl)- amino]e hyl]benzaaide) ; (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-l- (2H)- naphthalenone HC1) (levobunolol) ; (4 - (2 -hydroxy- 3 - isopropylamino-propox ) -1,2 -benziso thiazole HC1) ; (4- [3- (tert. butylamino) - 2 -hydroxypropoxy ] -N-aethylisocarbostyril HC1) ; ((±.-N-2-[4- (2-h7droxy-3-isopropylaminopropoxy)phenylj ethyl-N' - isopropylurea) (pafenolol) ; (3-[ [ (2-trifiuoroacet__αido)ethyl]__n_no] -l-phenoxypropan-2-ol) ; (N-(3-(o-chlorophenoxy)-2-hydroxypropyl)-N'-(4' -_hloro-2,3-dihydro-3- oxo-5-pyridazinyl)ethylenediamine) ; ((±)-N- [3-acetyi-4- 2-hydroxy-3- [(l-methylethyl)amino]propoxyphenyl]- butanamide) (acebutolol) ; ((±)- ' - [3-(tert-butyla ino)-2-hydroxypropoxy]spiro[cyclohexane-1,2'- indan] -1'-one) (spirendolol) ; (7- [3- [[2-hydroxy-3-[(2-methylindol-4-yl)oxylpropyl]amino]butyl]thio- phylline) (teoprolol) ; ((±)-l-tert.butylamino-3-(thiochroman-8-yloxy)-2-propanol) (tertato- lol); ((±)-l-tert.butylamino-3-(2,3-xylyloxy)-2-proρanol HC1) (xibenolol) ; (8- [3- (tert .butylamino) -2 -hydroxypropoxy] -5-methylcoumarin) (bucumo- lol); (2-(3-(tert.butylamino)-2-hydroxy-proρoxy)benzonitrile HC1) (bunitro- lol); ((±)-2'-[3-(tert-butylamino)-2-hydroxypropoxy-5'-fluorobutyrophenone) (butofilolol) ; (1-(carbazol-4-yloxy)-3-(isopropyla ino)-2-ρropanol) (carazolol); (5-(3-tert.butylamino-2-hydroxy)propoxy-3,4-dihydrocarbo yril HC1) (carteolol) ; (1-(tert.butylamino)-3-(2,5-dichlorophenoxy)-2-propanol) (clorano- lol); (l-(inden-4(or 7)-yloxy)-3-(isopropylamino)-2-propanol HC1) (indeno- lol); (1- isopropylamino- 3- [ (2-methylindol-4-yl)oxy] -2-propanol) (mepindo- lol) ; (1- (4-acetoxy-2, 3, 5- trimethylphenoxy) -3-isopropylaminopropan-2-ol) (metipranolol) ; (1- (isopropylamino)-3-(o-methoxyphenoxy)-3- [(l-methylethyl)amino] -2- propanol) (moprolol) ; ((1- tert. butylamino) -3- [ (5 , 6 , 7 , 8-tetrahydro-cis-6 , 7-dihydroxy-l- naphthyl) ox ] - 2 -propanol) (nadolol) ; ((S) -1- (2-cycloρentylphenoxy) -3- [ (1, 1- dime thylethyl) amino] -2 -propanol sulfate (2:1)) (penbutolol) ; (4' - [l-hydroxy-2- (_mino)ethyl]me_hanesulfonanilide) (sotaloi) ; (2-me_hyl-3- [4- (2-hydroxy-3-tert.butyi___inopropoxy)phenyl] -7-methoxy- isoquinoiin-1- (2H) -one) ; (l-(4- (2- (4-fluorophenyIoxy)ethoxy)phenoxy) -3- isopropylamino -2- propanol HC1) ; ((-)-p-[3- [{3,4-dimethoxyphenethyl)_minoj-2-hydroxypropoxy] -β-nstbyl- cinnamonitrile) (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-methylindol-4-yl)oxy]-3-[(2-phenoxyethyl)amino]- 2-propanol) (indopanolol) ; ((±)-6-[[2-[ [3-(p-butoxyphenoxy)-2-hydroxypropyl]amino]ethyl]amino] - 1,3-dimethyluracil) (pirepolol) ; (4-(cyclohexylamino)-1-(1-naphtholenyloxy)-2-butanol) ; (1-phenyl-3-[2-[3-(2-cyanophenoxy)-2-hydroxypropylJaminoethyl]hydan- toin HC1); (3,4- dihydro - 8 - ( 2 -hydroxy- 3 - isopropylaminopropoxy) - 3 -nitroxy-2H- 1- benzopyran) (nipradolol) ; Angiotensin I Converting Enzyme Inhibitors: l-(3-mercapto-2-methyl-l-oxopropyl) -L-proline (captopril) ; (1- (4-ethoxycarbonyl-2 ,4(R,R) -dimethylbutanoyl)indoline-2(S)-car- boxylic acid) ; (2-[2-[(l- (ethoxycarbonyl) -3 -phenyl -propyl] amino] -1-oxopropyl] - l,2,3,4-tetrahydro-3-isoquinoline carboxylic acid); ((S)-l-[2- [ (1- (ethoxycarbonyl) -3 -phenylpropyl] amino ] - 1 - oxopropyl ] oc- tahydro-lH-indole- 2 -carboxylic acid HC1) ; (N-cyclopentyl-N-(3- (2, 2 -dime thyl -1- oxopropyl) thiol- 2 -me thyl- 1-oxo- propyl) glycine) (pivalopril) ; ( ( 2R , 4R) - 2 - (2-hydroxyphenyl) -3- (3-mercaptopropionyl) -4- thiazolidine- carboxylic acid) ; ( 1 - (N- [ 1 (S ) -ethoxycarbonyl- 3 -phenylpropyl] - (S) -alanyl) -cis , syn-octa- hydroindol-2(S) -carboxylic acid HC1) ; ((-)-(S)-l-[(S)-3-mercapto-2-methyl-l-oxopropyl]indoline-2-carboxylic acid) ; ( [1(S) ,4S] -1- [3-(benzoylthio)-2-methyl-l-oxopropyl]-4-phenylthio-L- proline ; (3- ( [1 -ethoxycarbonyl -3 -phenyl- (IS) -propyl jamino) -2 , 3 ,4 , 5- tetrahydro- 2-oxo-l- (3S)-benzazepine-l-acetic acid HC1) ; (N- (2-benzyl-3-mercaptopropanoyl)-S-ethyl-L-cysteiήe) and the S- methyl analogue; (N-(l(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate) (enalapril) ; N- [l-(S)-carboxy- 3 -phenylpropyl] -L- lanyl -l-proline; N 2 -[l-(S)-carboxy-3-phenylpropyl]-L-lysyl-L-proline (lysinopril) ; Other Antihypertensive Agents: aminophylline ; cryptenamine acetates and tannates; deserpidine; meremethoxylline procaine; pargyline; tri- methaphan camsylate; and the like, as well as admixtures and combina¬ tions thereof. Typically, the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly. Coadainistration 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 hyperaldos eronism. Renin inhibitors have also been disclosed to control the rise in intraocular pressure associated with the use of steroidal anti- inflammatory drugs as described in PCT International Application PCT US86/02291 (PCT International Publication Number WO 87/02581 dated 7 May 1987). The compounds of the present invention are prepared as depicted in the charts and as described more fully in the Preparations and Examples. The process of the present invention is more completely under¬ stood by reference to the charts below. In these charts, the variables are as defined above. All of the starting materials are commercially available or their preparation is described below. Variations to these procedures to prepare other compounds of the present invention would be readily known to one of ordinary skill in the art. CHART A The synthesis of the compound of formula A-6 is given in Chart A. D-Phenylalanine of formula A-l is esterified with isobutylene in methylene chloride using concentrated sulfuric acid as catalyst to give the compound of formula A-2. D-Phenylalanine tert-butyl ester of formula A-2 is then reacted with maleic anhydride of formula A-3 in teεrahydrofuran to give the compound of formula A-4. The compound of formula A-4 is then coupled with 2HC1-LVA-I_e-Amp of formula A-5 (as described in U.S. patent application, Serial No. 147,073, filed 20 January 1988, and in published European patent application 0173481, which are hereby incorporated by reference) using diethyl- phosphoryl cyanide and triethylamine in methylene chloride and dimethylformamide to give the compound of formula A-6. CHART B The synthesis of the compound of formula B-6 is outlined in Chart B. D-Phenylalanine of formula B-l is esterified with ethanol and gaseous hydrochloric acid to give D-phenylalanine ethyl ester hydrochloride of formula B-2. D-Phenylalanine ether ester hydro- chloride of formula B-2 is then reacted with maleic anhydride of formula B-3 in tetrahydrofuran containing triethylamine to give the compound of formula B-4. The compound of formula B-4 is coupled with 2HC1-LVA-Ile-Amp of formula B-5 using diethylphosphoryl cyanide and triethylamine in methylene chloride and dimethylformamide to give the compound of formula B-6. CHART C The synthesis of the compound of formula C-6 is given in Chart C. D-Phenylalanine of formula C-l is esterified with methanol and gaseous hydrochloric acid to give D-phenylanine methyl ester hydro¬ chloride of formula C-2, which is then reacted with maleic anhydride of formula C-3 in tetrahydrofuran containing triethylamine to give the compound of formula C-4. The compound of formula C-4 is coupled with 2HC1-LVA-Ile-Amp of formula C-5 using diethylphosphoryl cyanide and triethylamine in methylene chloride and dimethylformamide to give the compound of formula C-6. CHART D The synthesis of the compound of formula D-2 is given in Chart D. The compound of formula C-6 of Chart C is used as the formula D-l starting material. The compound of formula D-l is hydrolyzed with IN potassium hydroxide in methanol and then neutralized with aqueous hydrochloric acid to give the compound of formula D-2. CHART E The synthesis of the compound of formula E-5 is outlined in Chart Ξ. L-Phenyialanine tert-butyl ester hydrochloride of formula E-l (commercially available) is reacted with maleic anhydride of formula E-2 in the presence of triethylamine and tetrahydrofuran to give the compound of formula E-3. The compound of formula E-3 is coupled with 2HCl-LVA-Iie-Amp of formula E-4 using diethylphosphoryl cyanide and triethylamine in methylene chloride and dimethylformamide as solvents to give the compound of formula E-5. CHART F The synthesis of the compound of formula F-5 is given in Chart F. Phenethylamine of formula F-l is reacted with maleic anhydride of formula F-2 in tetrahydrofuran as solvent to give the compound of formula F-3. The compound of formula F-3 is then coupled with 2HC1- LVA-Ile-Amp of formula F-4 using diethylphosphoryl cyanide and triethylamine in methylene chloride and dimethylformamide to give the compound of formula F-5. CHART.G The synthesis of the compound of formula G-5 is given in Chart G. 2-(2-Aminoethyl)pyridine of formula G-l is reacted with maleic anhydride of formula G-2 in tetrahydrofuran as solvent to give the compound of formula G-3. The compound of formula G-3 is then coupled with 2HC1-LVA-Ile-Amp of formula G-4 using diethylphosphoryl cyanide and triethylamine in methylene chloride and dimethylformamide to give the compound of formula G-5. CHART H The synthesis of the compound of formula H-5 is given in Chart H. Benzylamine of formula H-l is reacted with maleic anhydride of formula H-2 in tetrahydrofuran to give the compound of formula H-3. The compound of formula H-3 is then coupled with 2HC1-LVA-Ile-Amp of formula H-4 using diethylphosphoryl cyanide and triethylamine in methylene chloride and dimethylformajάde to give the compound of formula H-5. CHART I The synthesis of the compound of formula 1-9 is given in Chart I. The amine group of phenethylamine of formula 1-2 is protected as the BOC derivative using di-tert-b__yldicarbonate and potassium carbonate in tetrahydrofuran to give S-Boc- henethylamine of formula 1-2. The compound of formula 1-2 is alkylated using sodium hydride and benzyl bromide of formula 1-3 in dimethylformamide to give N-Boc- N-benzyl-phenethylamine of formula 1-4. The Boc- group of the compound of formula 1-4 is removed vith trifluoroacetic acid in methylene chloride to give N-benzylp enethylamine of formula 1-5, which is then reacted with maleic anhydride of formula 1-6 in tetrahydrofuran to give the compound of formula 1-7. The compound of formula 1-7 is coupled with 2HC1-LVA-Ile-Amp of formula 1-8 using diethylphosphoryl cyanide and triethyisaine in methylene chloride and dimethylformamide to give the compound of formula 1-9. CHART J The compound of formula J- 6 is prepared as shown in Chart J . Tryptamine hydrochloride of formula J- l is stirred in formic acid, and gaseous hydrochloric acid is bubbled in to give N n -formyltrypt- a ine hydrochloride of formula J -2. Biochem. et Biophys . Acta , 147 :453 (1967) . N in -formyl tryptamine hydrochloride of formula J-2 is stirred with maleic anhydride of formula J-3 and triethylamine in tetrahydrofuran to give the compound of formula J-4. The compound of formula J-4 is coupled with 2HCl-LVA-Ile-Amp of formula J-5 using diethylphosphoryl cyanide and triethylamine in methylene chloride and dimethylformamide to give the compound of formula J-6. CHART K The compound of formula K- 7 is prepared as shown in Chart K. Boc-Leu^[CH(0-t-BDMS)CH 2 ]Val-OH of formula K-l (as described in U. S . patent application, Serial No . 147 , 073 , filed 20 January 1988 , and in published European patent application 0173481 , which are hereby incorporated by reference) is coupled with S-2-methylbutylamine of formula K-2 using diethylphosphoryl cyanide and triethylamine in methylene chloride to give Boc-Leu^[CH(0- t-BDHS)CH 2 ]Val-methyl- butylamide of formula K-3. The Boc group of the compound of formula K-3 is removed with trifluoroacetic acid in methylene chloride to give Leu^[CH(0-t-BDMS)CH ]Val-methylbutylamide of formula K-4. The compound of formula K-4 is coupled with the compound of formula K-5 (prepared as the compound of formula A-4 in Chart A) using diethyl¬ phosphoryl cyanide and triethylamine in methylene chloride to give the compound of formula K-6 . The tert-butyldimethylsilyl group of the compound of formula K- 6 is removed with tetra-n-butylammonium fluoride in tetrahydrofuran zo give the compound of formula K- 7. CHART L The compound of formula L-5 , which is named 4- [ (1 ' R- tert- Butoxycarbonyl)phenethylamido] -maleo l -2S -amino -1-cyclohexyi- 3R,4S - diol-6-methylheptane , is prepared as shown in Chart L. The compound of formula L-l (as described in PCT Application International Publi- cation Number W088/04664 , published 30 June 1988 , which is hereby incorporated by reference) is reacted with isobutylaagnesium chloride in tetrahydrofuran and ethylene oxide to give a mixrure of isomers . The isomers are separated and the isomer of formula L-2 (stereochem- istry not specified at indicated center) is deprotected with acetyl chloride-methanol to give l-cyclohexyl-2(S)-amino-3(R) , 4-dihydroxy- 6-methylheρtane of formula L-3. Published European patent applica¬ tion 0189203 (Abbott) discloses the hydrochloride salt of the compound of formula L-3. The compound of formula L-3 is coupled with the compound of formula L-4 (prepared as the compound of formula A-4 in Chart A) using diethylphosphoryl cyanide and triethylamine in methylene chloride as solvent to give the compound of formula L-5. " hen tested, the compound of formula L-5 had an IC5 Q of 1.7 x 10 " ° molar and an FAB mass spec [m + H] at m/z 545. Generally, the renin inhibiting polypeptides may be prepared by solution phase peptide synthetic procedures analogous to those described hereinafter or to those methods known in the art. Appro¬ priate protecting groups, reagents, and solvents for the solution phase method can be found in "The Peptides: Analysis, Synthesis, and Biology," Vols. 1-5, eds. E. Gross and T. Meienhofer, Academic Press, NY, 1979-1983; "The Practice of Peptide Synthesis", M. Bodansky and A. Bodansky, Springer-Verlag, New York, 1984; "The Principles of Peptide Synthesis", M. Bodansky, Springer-Verlag, New York, 1984. Thus, for example, the carboxylic moiety of N α -t-butyloxycarbonyl (Boc)-substituted amino acid derivatives having suitable side chain protecting groups, if necessary, may be condensed with the amino functionality of a suitably protected amino acid or peptide using a conventional coupling protocol such as dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) or diethylphosphoryl cyanide (DEPC) and triethylamine (Et ) 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 European application 0173481, published 5 March 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 α -Boc moiety may be selectively removed with 50% trifluoroacetic acid with or without 2% anisole (v/v) in methylene chloride. Neutralization of the resultant trifluoroacetate salt may be accomplished with 10% diisopropyl- ethylamine or sodium bicarbonate in methylene chloride. Variations in the above description for starting materials, reactants, reaction conditions and required protecting groups to obtain other such N-alkylated compounds are known to an ordinarily skilled chemist or are readily available in the literature. The compounds of the present invention may be in either free form or in protected form at one or more of the remaining (not previously protected) peptide, carboxyl, amino, hydroxy, or other reactive groups. The protecting groups may be any of those known in the polypeptide art. Examples of nitrogen and oxygen protection groups are set forth in T.W. Greene, Protecting Groups in Organic Synthesis, Wiley, New York, (1981); J.F.W. McOmie, ed. Protective Groups in Organic Chemistry, Plenum Press (1973); and J. Fuhrhop and G. Benzlin, Organic Synthesis, Verlag Chemie (1983). Included among the nitrogen protective groups are t-butoxycarbonyl (Boc) , ben- zyloxycarbonyl, acetyl, allyl, phthalyl, benzyl, benzoyl, trityl and the like. The following compounds of the present invention are preferred: 4- [ (l'R-tert-Butoxycarbonyl)phenethylamido]maleoyl-Leu6[CH(0H)- C 2 ]Val-Ile-2-(amidomethyl)pyridine; 4- [ (l'R-Ethoxycarbonyl)phenethylamido]maleoyl-Leu^[CH(0H)CH2]- Val-Ile-2-(amidomethyl)pyridine; 4- [ (l'R-Methoxycarbonyl)phenethylamido]maleoyl-Leu^[CH(OH)CH 2 ] - Val-Ile-2-(amidomethyl)pyridine; and 4-[(l'S-(tert-Butoxycarbonyl)phenethylamido]maleoyl-Leu^[CH(0H)- CH2]Val-Ile-2- (amidomethyl)pyridine. The most preferred compound is 4- [ (l'R-tert-Butoxycarbonyl)phen- ethyla ido]maleoyl-Leu^[CH(OH)C2]Val-1le-2-(amidomethyl)pyridine. DESCRIPTION OF THE PREFERRED EMBODIMENTS . The following Preparations and Examples illustrate the present invention. In the Preparations and Examples below and throughout this document: ^H-NMR is nuclear magnetic resonance 1-HOBt is 1-hydroxybenzotriazole 2-Pya is 3- (2-pyridinyl)alanine 3-Pya is 3- (3-pyridinyl)alanine AcCl is acetyl chloride Amp is 2-(aminomethyl)pyridinyl Bn is benzylester BOC is t-butoxycarbonyl Bz is benzyl C is centigrade Cbz is benzyloxycarbonyl CDCI3 is deuteriochlorofora Celite is a filter aid. CpTSA is p-toluenesulfonic acid CpVA is Cpa[CH(0H)CH 2 ]Val Dap is 2,4-diaminopyrimidin-6-yl DCC is dicyclohexylcarbodiimide DEPC is diethylphosphoryl cyanide DMF is dimethylformamide EtOAc is ethyl acetate FAB is fast atom bombardment, a technique for obtaining mass spectra of large molecules. FTrp is N in "formyl-Trp g is grams h is hour(s) His is histidine HOBT is 1-hydroxybenzotriazole HPLC is high performance liquid chromatography Iba is isobutylamine lie is isoleucine IR is infrared spectra K2CO3 is potassium carbonate LVA is Leu^(CH(0H)CH 2 )Val with the S configuration at C4 (the hydroxyl-bearing carbon atom) . M or mol is mole Me is methyl min is minute ml is millilitεr MPLC is medium pressure liquid chromatography MS is mass spectroscopy NaH is sodium hydride NH4OH is ammonium hydroxide Ph is phenyl Phe is phenylalanine Pla is L-3-phenyllactic acid Poa is phenoxyacetyl RIP means a compound having the formula H-Pro-His-Phe-His-Phe- Phe-Val-Tyr-Lys-0H.2(CH 3 C(O)OH).XH 2 0 which is a known renin-inhibit¬ ing peptide. Sta is statine TBS is tert-butyldimethylsilyl TBDMS is tert-butyldimethylsilyl TEA is triethylamine TFA is trifluoroacetic acid THF is tetrahydrofuran THP is tetrahydropyranyl TLC is thin layer chromatography Tos is p-toluenesulfonyl TsOH is p-toluenesulfonic acid. The wedge-shape line indicates a bond which extends above the plane of the paper relative to the plane of the compound thereon. The dotted line indicates a bond which extends below the plane of the paper relative to the plane of the compound thereon. In the examples below, HPLC is performed using Altex Model 110A pumps, an LDC Spectro Monitor III detector, Altex Model 420 Program¬ mer, and a Hewlett Packard 3390A integrator. The column used is a Brownlee RP-18 Sphere-10, 250 mm x 4.0 mm. The solvent system is solvent A, 50 mM NaH 2 P0 4 (6.9 g/L), 1% H3PO4 (1 ml/L), and 1% CH3CN (10 ml/L) in H 2 0, and solvent B, 12.5 mM NaH 2 P0 4 (1.7 g/L), 0.25% H 3 P0 4 (0.25 ml/L), 25% H 2 0 (250 ml/L), and 75% CH3CN (750 ml/L). 1 H- NMR spectra are recorded on a Bruker 300 MHz instrument. In the examples below, the in vitro IC5 is measured in nano- molars. The in vitro test is performed as described in U.S. patent application, Serial No. 147,073, filed 20 January 1988, and in published European patent application 0173481, which are hereby incorporated by reference. The following general method for coupling was used in the following preparations and examples: To a solution of the acid (1.2 to 1.5 equiv), LVA-Ile-Amp-2HC1 (1 equiv), methylene chloride and dimethylformamide is added first triethylamine (3.25 equiv), followed by diethylphosphorylcyanide (1.20-1.5 equiv). After stirring for 1-24 hours, solvents are removed in vacuo and the residue is partitioned two times with methylene chloride and aqueous sodium bicarbonate. The organic layers are filtered through sodium sulfate, concentrated, and chromatographed on silica gel. Preparation 1 Maleic acid, D-Phenylalanine-tert-butyl ester amide (Formula A-4) Refer to Chart A. A solution of 0.142 g of maleic anhydride and 0.30 g of D-Phe tert-butyl ester in 20 ml of tetrahydrofuran is stirred for 1 hr and is then partitioned between diethyl ether, aqueous hydrochloric acid and brine. The organic layers are dried over magnesium sulfate and taken to dryness to give 0.42 g of a solid. Crystallization from methylene chloride and hexane gives 0.40 of the title product. Physical characteristics are as follows: M.P.: 109-112 β C. [α]D - +8.0 (0.8135, ethanol) . MS: m/z at 319. Anal. Found: C, 63.70; H, 6.91; N, 4.28. X H-NMR (5, CDC1 3 ): 1.43, 3.19, 4.78, 6.24, 6.44, 6.90, 7.11- 7.31. Example 1 4- [l r R-tert-Butoxycarbonyl)phenethylamidoJmaleoyl- Leu^CH^H H^Val-Ile^^amidomethy pyridine (Formula A-6) Refer to Chart A. According to the general coupling procedure given above, 0.061 g of acid of Preparation 1 and 0.0819 g of LVA-Ile-Amp-2HC1 are combined to give, after chromatography with 3% methanol -+ 5% methan- ol-methylene chloride (saturated with ammonium hydroxide), 0.0644 g of the title product. Physical characteristics are as follows: FAB MS: [m + H] at m/z 736. HPLC: 45% A, 55% B, k' - 5.2. ^-H-NMR (S , CDCI3) : 0.34-0.94 , 1.40 , 3.10 , 3.56 , 3.92 , 3 .99 , 4.43 , 4.54, 4.72 , 6.02 , 6.19 . 6.59 , 7.16-8.50. Anal . Found: C , 66.41; H, 8.48 ; ST, 9.53. Ic 50 : 5.4 x 10 *" 9 molar. Example 2 4- [ (l ' R- tert-Butoxycarbony^phenethyiamidoJmaleoyl- Leu [CH(0H)CH 2 jVal-2S-methylbutyl__ιide (Formula K-7) Refer to Chart K. By the method of the general coupling procedure, 0.0644 g of the compound of formula K-5 and 0.0836 g of Leu [CH(0-t-BDMS)CH 2 ]Val- NHCH 2 CH(CH3)CH 2 CH3 of formula K-4 are converted to 0.1341 g of the compound of formula K-6 (chromatography with 4% methanol-methylene chloride). The material is then stirred with 0.5 ml of 1 M (in tetrahydrofuran) tetra-n-butyl ammonium fluoride and 0.5 ml of tetrahydrofuran overnight. The solvent is removed in vacuo and the residue is chromatographed with 4% methanol-methylene chloride to give 0.0714 g of the title product. Physical characteristics are as follows: FAB MS: [m + H] at m/z 602. HPLC: 40% A, 60% B; k' - 6.3. Anal. Found: C, 67.25; H, 9.08; N, 6.77. IC 50 : 4.3 x 10 " - molar. Preparation 2 4-(Phenethylamido)maleic acid (Formula F-3) Refer to Chart F. To 0.62 g of maleic anhydride in 50 ml of tetrahydrofuran is added 0.7 g of phenethylamine. An initial exo herm is observed. The reaction is stirred for 45 min, concentrated, and the residue is partitioned between methylene chloride and diluted aqueous hydro¬ chloric acid. The organic layers are filtered through sodium sulfate and concentrated to give a white solid. Crystallization from methylene chloride and hexane gives 1.08 g of the title product. Physical characteristics are as follows: M.P.: 137-138 β C. Anal. Found: C, 65.53; H, 6.09; N, 6.36. Example 3 4- (Phenethylamido)maleoyl-Leu^[CH(0H)CH 2 ]Val-Ile-2- (amidomethyl)pyridine (Formula F-5) Refer to Chart F. According to the general coupling method, 0.04406 g of the title product of Preparation 2 and 0.0847 g of LVA-Ile-Amp-2HC1 in 10 ml of dimethylformamide and I ml of methylene chloride are coupled to give 0.05«-ό g of the title product after chromatography with 4% methanol- methylene chloride (ammonium hydroxide). Physical characteristics are as follows: FAS MS: [m + H] at m/z 636. HPLC: 40% B-60% A; k' - 6.0. Anal. Found: C, 67.49; H, 8.55; N, 10.92. IC 50 : 1.3 x 10 "7 molar. Preparation 3 4-[(2'-Pyridyl)ethyl__αido]maleic acid (Formula G- 3) Refer to Chart G. To 0.76 g of maleic anhydride in 50 ml of tetrahydrofuran is added 0.93 ml of 2-(2-aminoethyl) pyridine (a slight exotherm occurs). After stirring for 45 min, tetrahydrofuran is removed in vacuo and the residue is partitioned between methylene chloride and aqueous ammonium chloride. The organic layers are filtered through sodium sulfate and concentrated. TLC shows a considerable amount of product remaining in the aqueous layer, so the aqueous layer is continuously extracted with methylene chloride (overnight) . The product fractions are combined to give 1.37 g of the title product. Crystallization from methylene chloride and hexane gives 1.22 g of amber crystals. Physical characteristics are as follows: M.P.: 136-137 β C. Anal. Found: C, 59.60; H, 5.60; N, 12.71. Example 4 4- [(2' -Pyridyl)ethyl___ido]maleoyl-Leu [CH(0H)CH 2 ]Val- Ile-2-(amidomethyl)pyridine (Formula G-5) Refer to Chart G. Using the general coupling procedure, 0.0445 g of the title product of Preparation 3 and 0.0852 g LVA-Ile-Amp-2HCl are coupled to give 0.0577 g of the title product after chromatography with 6% methanol-methylene chloride (ammonium hydroxide) . Physical characteristics are as follows: Rf (8% methanol-methylene chloride-ammonium hydroxide): 0.29. FAB MS: [m + H] at m/z 637. HPLC: 75% A, 25% B, k' - 4.7. Anal. Found: C, 65.89; H, 8.74; N, 12.37. I-5 0 : 1-8 x 10 "7 molar. Preparation 4 Maleic acid, D-Phenylalanine methyl ester amide (Formula C-4) Refer to Chart C. A solution of 0.74 g of D-Phe-0CH 3 and 0.425 g of maleic anhydride in 30 ml of tetrahydrofuran is stirred for 2 hrs, after which it is partitioned between ethyl ether and dilute hydrochloric acid brine. The organic layers are dried over magnesium sulfate and concentrated to give 1.25 g of the title produce as a gum. Physical characteristics are as follows: X H-NMR (.. CDCI3): 3.20, 3.79, 4.91, 6.29, 6.37, 7.07-7.31. Example 5 4- [ (1 'R-Methoxycarbonyl)phenethylamidojmaleoyl- Leu^CH^H H^Val-Ile^-(__f.idomethyl)pyridine (Formula C-6) Refer to Chart C. To 0.1347 g of LVA-Ile-Amp-2HC1 in 5 ml of dimethylformamide and 5 ml of methylene chloride is added 0.0743 ml of triethylamine. To this is then added 0.0886 g of the title product of Preparation 4, followed by 0.0360 g of 1-hydroxybenzotriazole and 0.0824 g of dicyclohexylcarbodiimide in 5 ml of methylene chloride. The reaction is stirred overnight, after which the solvents are removed in vacuo. Ethyl acetate and methylene chloride are added to the residue and dicyclohexylurea is filtered off. The filtrate is partitioned two times between methylene and aqueous sodium bicarbonate and the organic layers are filtered through sodium sulfate, concentrated, and chromatographed using 4% methanol-methylene chloride (ammonium hydroxide) to give 0.1183 g of the title product. Physical characteristics are as follows: FAB MS: [m + H] at m/z 694. HPLC: 60% A, 40% B; k' - 7.4. Anal. Found: C, 65.51; H, 7.71; N, 9.90. IC 50 : 2.6 x 10 "8 molar. Preparation 5 4-(N ιn -formyltryptamido)maleic acid (Formula J-4) Refer " to Chart J. A mixture of 0.1624 g of N ιn -formyltryptamine hydrogen chloride, 0.0780 g of maleic anhydride, 0.101 ml of triethylamine, and 50 ml of tetrahydrofuran is stirred for 45 minutes. The reaction mixture is then concentrated and the residue is partitioned between chloroform and 0.1 N hydrochloric acid and brine. The organic layers are separated, concentrated, and the residue is crystallized from methanol to give 0.1491 g of the title product. Physical characteristics are as follows: M.P.: 163-I65°C. Anal. Found (two runs): C, 57.17, 59.48; H, 4.49, 4.79; N, 8.80, 9.09. Example 6 4- (N in -formyltryptamido)maleoyl-Leu^[CH(0H)CH 2 ]Val- Ile-2-(amidomethyl)pyridine (Formula J-6) Refer to Chart J. Using the standard coupling procedure, 0.0701 g of the title product of Preparation 5 is coupled with 0.1032 g of LVA-Ile-Amp-2HC1 to give, after chromatography with 5% methanol-methylene chloride (ammonium hydroxide), 0.0661 g of the title product. Physical characteristics are as follows: TLC: 8% methanol-methylene chloride (ammonium hydroxide): 0.5. FAB MS: [m + H] at m/z 703. Anal. Found: C, 66.46; H, 7.55; N, 11.21. IC 50 : 2.3 x 10 '7 molar. Preparation 6 N-(tert-Butoxycarbonyl)phenethylamine (Formula I- 2) Refer to Chart I. To 5.13 g of phenethylamine, 5.85 g of potassium carbonate and 100 ml tetrahydrofuran is added 9.70 g of di-tert-butyldicarbonate in several ml of tetrahydrofuran over 5-10 minutes (an ice bath is added at this point to cool the exotherm) . After the addition is complete, about 1 ml of water is added. After 45 min, potassium carbonate is filtered off and the filtrate is partitioned between ethyl ether and IN hydrochloric acid and brine. The organic layers are filtered through sodium sulfate and taken to dryness. The crude product is chromatographed with 5% ethyl acetate-hexane to give 9.24 g of the title product. Physical characteristics are as follows: M.P.: 56-57.5 β C. X H-NMR (., CDC1 3 ): 2.43, 2.80, 3.37, 4.53, 7.18-7.34. Preparation 7 N-Benzyl-N-phenethylamine (Formula 1-5) Refer to Chart I. To 0.100 g of N-Boc-phenethylamine of Preparation 6 and 0.036 g of sodium hydride in 5 ml of dimethylformamide are added 0.107 ml of benzyl bromide. After stirring for 2 hrs, a few drops of aqueous sodium bicarbonate are cautiously added. Dimethylformamide is removed in vacuo and the residue is partitioned between ethyl acetate and brine. The organic layers are dried over magnesium sulfate and the crude product is chromatographed with 5% ethyl acetate-hexane to give 0.129 g of the compound of formula 1-4, with physical charac¬ teristics as follows: MS: m/z at 311. To 0.160 g of N-Boc-N-benzyl-N-phenethylamine is added 10 ml of a 1:1 (v/v) solution of trifluoroacetic acid and methylene chloride. After 15 min, methylene chloride and trifluoroacetic acid are removed in vacuo. The residue is partitioned two times between methylene chloride and aqueous sodium bicarbonate and the organic layers are filtered through sodium sulfate and concentrated to give 0.1032 g of the title product. Physical characteristics are as follows: ^-NMR (δ , CDC1 3 ): 1.52, 2.87, 3.81, 7.21-7.31. Preparation 8 4-(N-Benzyl-N-phenethylamido)maleic acid (Formula 1-7) Refer to Chart I. A solution of 0.1032 g of N-benzyl-N-phenethylamine of Prepara¬ tion 7 and 0.0527 g of maleic anhydride in 5 ml of tetrahydrofuran is stirred overnight. The solvent is then removed and the residue is partitioned between methylene chloride and 0.1 N hydrochloric acid. The organic layers are filtered through sodium sulfate and con¬ centrated. The crude product is crystallized from methylene-hexane to give 0.143 g of the title product. Physical characteristics are as follows: M.P.: 124-125 β C. ^-NMR (_, CDCI3): 2.92, 3.69, 4.58, 6.23, 6.48, 7.10-7.35. Anal. Found: C, 73.84; H, 6.17; N, 5.48. Example 7 4- (N-Benzyl-N-phenethylamido)maleoyl-Leu^[CH(OH)CH ]- Val-Ile-2-(amidomethyl)pyridine (Formula 1-9) Refer to Chart I. Using standard coupling conditions, 0.0533 g of the title product of Preparation 8 and 0.0792 g of LVA-Ile-Amp-2HC1 are coupled to give 0.0942 g of the title product after chromatography with 2% methanol-methylene chloride (ammonium hydroxide) . Physical characteristics are as follows: FAB MS: [m + H] at m/z 726. HPLC: 30% A, 70% B, k' - 8.4. Anal. Found: C, 70.56; H, 8.47; N, 9.25. IC 50 : 1.0 x 10 "7 molar. Preparation 9 Maleic acid, benzyl amide (Formula H-3) Refer to Chart H. To 0.2877 g of benzylamine in 10 ml of tetrahydrofuran is added 0.2764 g of maleic anhydride (exotherm occurs). After 20 min, tetra¬ hydrofuran is removed to give a white solid. The solid is crystal- lized from methanol-methylene chloride-hexane to give 0.517 g of the title product. Physical characteristics are as follows: M.P.: 127-132°C. X H-NMR (S , CDCI3): 4.55, 6.32, 7.33-7.35, 7.55. Anal. Found: C, 63.56; H, 5.54; N, 6.80. Example 8 4- (Benzylamido)maleoyl-Leu [CH(0H)CH 2 ]Val-Ile-2- (amidomethyl)pyridine (Formula H-5) Refer to Chart H. Using standard coupling conditions, 0.0404 g of the title product of Preparation 9 and 0.0829 g of LVA-Ile-Amp-2HC1 are coupled to give 0.0139 g of the title product with chromatography with 5% methanol-methylene chloride-ammonium hydroxide. Physical characteristics are as follows: FAB MS: [m + H] at m/z 622. l R-mm. (., CDCI3): 0.78-0.92, 1.08-2.28, 3.60, 4.95, 4.20, 4.48, 6.10, 6.19, 6.98-7.88, 8.47. IC 50 : 1.7 x 10 "7 molar. Preparation 10 Maleic acid, D-Phenylalamine ethyl ester amide (Formula B-4) Refer to Chart B. To a mixture of 0.5418 g of HCl-D-Phe-0Et, 0.2103 g of maleic anhydride, and 40 ml of tetrahydrofuran is added 0.33 ml of triethyl¬ amine. After 30 min, about 1 ml of ethanol is added to put HC1-D- Phe-OEt in solution. After stirring an additional 15 min, the solvents are removed and the residue is partitioned between methylene chloride and 0.5 N hydrochloric acid. The organic layers are filtered through sodium sulfate and taken to dryness to give 0.51 g of the title product as a gum. Example 9 4- [(1'R-Ethoxycarbonyl)phenethylamido]maleoyl-Leu^- [CH(0H)CH 2 ]VaI-Ile-2-(amidomethyl)pyridine (Formula B- 6) Refer to Chart B. Using standard coupling conditions, 0.0688 g of the title product of Preparation 10 and 0.1085 g of LVA-Ile-A_rp-_HC1 are coupled to give, after chromatography with 3% methanoi-βethylene chloride (ammonium hydroxide). 0.0733 g of the title product. Physical characteristics are as follows: FAB MS: fm + H] at m/z 708. HPLC: 40% A, 60% B, k' - 7.3, 8.4 (ratio of 78 to 22). Anal. Found: C, 65.99; H, 8.16; N, 10.12. IC 50 : 8.6 x 10 "9 molar. Example 10 4- [ (l'R-Carboxy)phenethylamido]maleoyl-Leut>[CH(OH)- CH2jVal-Ile-2-(amidomethyl)pyridine (Formula D-2) Refer to Chart D. To 0.0524 g of the title product of Example 5 in 2 ml of methanol is added dropwise 0.163 ml of 1 N potassium hydroxide. After stirring for 2-1/2 hrs, the solvent is removed in vacuo and the residue is partitioned between ethyl acetate and 0.087 ml of 2 N hydrochloric acid with 0.5 ml of water added. (After several extractions, solid is still visible floating in the aqueous layer) . The organic layers are dried over magnesium sulfate and taken to dryness to give 0.020 g of the title product. Physical characteristics are as follows: FAB MS: [m + H] at m/z 680. Anal. Found: C, 64.17; H, 8.37; N, 9.50. IC 5υ : 5.2 x 10 "7 molar. Preparation 11 Maleic acid, L-Phenylalanine tert-butyl ester amide (Formula E-3) Refer to Chart E. To 0.1526 g of HCl-L-Phe-O-t-Bu, 0.0614 g of maleic anhydride, and 10 ml of tetrahydrofuran is added 0.087 g of triethylamine. After stirring for 45 min, the reaction mixture is partitioned between ethyl ether and acidified brine. The organic layers are filtered through sodium sulfate and taken to dryness to give 0.20 g of the title product as a solid. Physical characteristics are as follows: ^ • H-NMR (., CDC1 3 ): 2.45, 3.18, 4.78, 6.26, 6.38, 7.03, 7.12- 7.33. Example 11 4- [ (1' S- (tert-Butoxycarbonyl)phenethylamido]maleoyl- Leu^[CH(0H)CH ]Val-Ile-2-(amidomethyl)pyridine (Formula E-5) Refer to Chart E. Using standard coupling procedures, 0.0463 g of the title product of Preparation 11 and 0.0666 g of LVA-Ile-Amp-2HC1 are coupled to give (chromatography with 4% methanol-methylene chloride- ammonium hydroxide) 0.0371 g of the title product. Physical characteristics are as follows: FAB MS: [m + HI at m/z 736. ^-NMR (5, CDCI3): 0.86-0.92, 1.40, 1.75, 1.1-2.3, 3.12, 3.58, 3.93, 4.04, 4.42, 4.55, 4.72, 6.03, 6.13, 6.65, 7.17-7.25, 7.37, 7.63, 8.01, 8.47, 3.51. HPLC: 40% A, 60% B, k' - 14.9, 16.1 (8:92 by area %) . IC 50 : 2.9 x 10 "8 molar. FORMULA CHART R 20 N(R 30 )-(0)CCH-CHC(0)- T CHART A A-l A- 2 A-6 CHART B B-l B-2 B-4 CHART C C-l C-2 C-4 _-o CHART D D- * . CHART E E-l E-3 E-5 CHART F F-5 CHART G G-5 CHART H H-l H-2 H-3 H-5 CHART I 1-1 1-2 1-4 1-5 1-7 1-9 CHART J J-l J-2 J-4 J-ό CHART K K-6 K-7 CHART L L-l L-2 L-3 L-5

Claims: CLAIMS 1. A renin inhibitory peptide having a non-cleavable transition state insert corresponding to the 10,11-position of a renin substrate (angiotensinogen) and having a moiety of the formula I R 2 oN(R 3 o)-(0)CCH«CHC(0)- I at the N-terminus; wherein R 2 g is (a) -C(R 21 )(R 2 2)-C(0)-0R 2 3, or (b) -(CH 2 ) n -R 24 ; wherein R 2 ^ is (a) hydrogen, or (b) Cx-Csalkyl; wherein R 22 is (a) -(CH 2 ) p -aryl, or (b) -(CH 2 ) p -Het; wherein R 3 is (a) hydrogen, or (b) C 1 -C 10 alkyl; wherein R 24 is (a) -(CH )p-aryl, or (b) -(CH 2 ) p -Het; wherein R30 is (a) hydrogen, (b) Cx-Csalkyl, (c) -(CH 2 ) p -aryl, or (d) -(CH 2 ) p -Het; wherein n is 1 to 5, inclusive; wherein p is 0 to 5, inclusive. 2. In a renin inhibitory peptide having a non-cleavable transition state insert corresponding to the 10,11-position of a renin substrate (angiotensinogen) and having a moiety of the formula I R 20 N(R 30 )-(0)CCH-CHC(0)- I at the N-terminus; wherein R20 is (a) -C(R 21 )(R 2 2)-C(0)-0R 2 3, or (b) -(CH 2 ) n -R 24 ; wherein R is (a) hydrogen, or (b) Ci-Cs lk l; wherein R 22 is (a) -(CH 2 ) p -aryl, or (b) -(CH 2 ) p -Het; wherein R 3 is (a) hydrogen, or (b) Cx-Cxo lkyl; wherein R 4 is (a) -(CH 2 ) p -aryl, or (b) -(CH 2 ) p -Het; wherein R30 is (a) hydrogen, (b) Cx-Csalkyl, (c) -(CH 2 ) p -aryl, or (d) -(CH 2 ) p -Het; wherein n is 1 to 5, inclusive; wherein p is 0 to 5, inclusive. 3. The renin inhibitory peptide of claim 1 of the formula II *2 CH I * Ag—NH—CH—X L II wherein Ag is a monovalent moiety of the formula I; R 20 N(R 30 )-(0)CCH-CHC(0)- I wherein X^ is (a) -CH(0H)-CH(0H)-CH 2 -Pi, or (b) -L 10 -C(R 1 )(R 4 )-C(0)-F 1 -Z 1 ; wherein P ] _ is (a) -N 3 , (b) -CN, (c) C -Cgalkyl, (d) C -Cgcycloaikyl, (e) aryl, or (f) Het; wherein Lχo is a divalent moiety of the formula (a) -CH(0H)-, (b) -CH(NH 2 )-, (c) -C(0)-, (d) -CH(0H)-C(K 1 )(K 2 )-, (e) -C(0)-C(K 1 )(K 2 )-, (f) -CH(0H)-CH(0H)-, (g) -CH(0H)-CH 2 -, (h) -CH(NH 2 )-CH 2 -, (i) -C(0)-CH 2 -, (j) -CH 2 -NH-, (k) -CH 2 -0-, or (1) -P 1 (0)(G 1 )-I 1 -; wherein F^ is absent or a divalent moiety of the formula L 4 ; wherein G^ is (a) -OH, or (b) -NH 2 ; wherein I is (a) -0-, (b) -NH-, or (c) -CH 2 ; wherein K^ and K 2 are the same or different and are (a) H, (b) F, or (c) Cl; wherein Y^ is (a) hydrogen, (b) alkali metals, (c) alkali earth metals, or (d) pharmaceutically acceptable base addition salts thereof; wherein Z^ is (a) -0-R 5 , or (b) -N(Rχ)R 5 ; wherein R^ is (a) hydrogen, or (b) Cx-Csalkyl; wherein R 2 is (h) -SO3H, or (i) -S0 2 NH 2 ; wherein R9 is (a) hydrogen, or (b) Cx-Csalkyl; wherein R υ - s (a) hydrogen, (b) Cx-Cgalkyl, (c) -(CH 2 ) p -aryl, (d) -(CH 2 ) p -Het, (e) -(CH 2 ) p -C0 2 H, (f) -(CH 2 ) p -NH 2 , (g) -(CH 2 ) p -CH(NH 2 )(C0 2 H), (h) C3-C7cycloalkyl, or (i) 1- or 2-adamantyl; wherein R^ is (a) hydrogen, or (b) Cx-Csalkyl; wherein R 2 Q is (a) -C(R 21 )(R 22 )-C(0)-0R 2 3, or (b) -(CH 2 ) n -R 2 ; wherein R 2 is (a) hydrogen, or (b) Cx-Cgalkyl; wherein R 22 is (a) -(CH 2 ) p -aryl, or (b) -(CH 2 ) p -Het; wherein R 2 3 is (a) hydrogen, or wherein R 24 is (a) -(CH 2 ) p -aryi, or (b) -(CH 2 ) p -Het; wherein R30 is (a) hydrogen, (b) C -Csalkyl, (c) -(CH 2 )p-aryl, or (d) -(CH 2 ) p -Het; 89 -48- wherein n is 1 to 5, inclusive; wherein p is 0 to 5, inclusive; wherein q is 1 to 8, inclusive; wherein aryl is phenyl or naphthyl, optionally substituted by zero to three of the following; (a) C -C5alkyl, (b) hydroxy, (c) hydroxy C -C5alkyl) , (d) halogen, (e) amino, (f) amino (C -C 5 alkyl) , (g) -CH0, (h) -C0 2 H, (i) -C0 2 -(C 1 -C 5 alkyl), (j) -C0NH 2 , (k) -CONH- C -Csalkyl) , (1) nitro, (m) mercapto, (n) mercapto (C -C5alkyl , (o) -S0 3 H, (p) -S0 2 NH 2 , (q) -CN, or (r) -O-Cx-Csalkyl; wherein Het is a 5 or 6-membered saturated or unsaturated ring radi- cal 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 or another heterocycle; and if chemically feasible, the nitrogen and sulfur atoms may be In the oxidized forms; and optional- ly substituted by zero to three of the following; (a) C 1 -C 5 alkyl, (b) hydrox , (c) hydroxy (C 1 -C 5 alkyl) , (d) halogen, (e) amino, (f) amino (^-^alky! , (g) -CH0, (h) -C0 2 H, (I) -C0 2 - (C 1 -C 5 alkyl) , (j ) -C0NH 2 , (k) -CONH- (C 1 -C 5 alkyl) , (1) nitro , (m) mercapto , (n) mercapto (C -C5alkyl) , (o) -S0 3 H, (p) -S0 2 NH 2 , (q) -CN, or (r) -O-Cx-Csalkyl ; or a carboxy- , amino- or other reactive group protected form thereof ; or a pharmaceutically acceptable acid or base addition salts thereof . 4. The renin inhibitory peptide of claim 3 wherein Ag is R 2 QN(R3Q)- (O)CCH-CHC(O)- wherein R 20 is -C(R 21 )(R 2 )-C(0)-0R 23 and R 30 is hydrogen, and wherein R 2 is hydrogen, R 22 is -CH 2 -phenyl and R 2 3 is hydrogen, methyl, ethyl or t-butyl. 5. The renin inhibitory peptide of claim 3 wherein Ag is R 2 QN(R3Q)- (O)CCH-CHC(O)- wherein R 0 is -(CH 2 ) n -R 24 and R 30 is hydrogen or -CH 2 -phenyl, and wherein n is 1 or 2 and R 24 is phenyl, pyridyl or N-formyl-indolyl. 6. The renin inhibitory peptide of claim 4 wherein R 2 is C3-C7- cycloalkyl and XΛ_ is -CH(OH)-CH(OH)-CH 2 -Pχ wherein P χ is Cx-Cgalkyl; or wherein R 2 is C -C5alkyl and X 1 is -L 10 -C(Ri)(R 4 )-C(0)-F 1 -Z 1 wherein L 10 is -CH(0H)-CH 2 - , R^ is hydrogen, R 4 is C^-Cgalkyl, F-^ is absent and Z is N(R )R5 wherein R^ is hydrogen and R5 is C-«_-C Q alkyl; or wherein R 2 is C -C 5 alkyl and X^ is -Lχg-C(R )(R 4 )-C(0)-F -Z wherein L 0 is -CH(0H)-CH 2 - . i is hydrogen, R 4 is C^-Cgalkyl, F^ is the moiety of formula L 4 wherein Rq is hydrogen, R^g is C -Cgalkyl, and R is C-j-Cg; and Z^ is N( ) 5 wherein R . is hydrogen and R is -(CH 2 ) n -Rg. 7. The renin inhibitory peptide of claim 5 wherein R 2 is C^-C5al yl and L is -L 10 -C(R ) (R 4 )-C(0)-F -Z wherein L 10 is -CH(OH) -CH 2 - , R L is hydrogen, R 4 is Cχ-Cgalkyl, F is the moiety of formula L 4 wherein R 9 is hydrogen, R o is Cχ-Cgalkyl and R is Cχ-C 5 alkyl; and Z is N(Rχ)R5 wherein Rx is hydrogen and R5 is -(CH 2 ) n -Rg. 5 8. The renin inhibitory peptide of claim 6 wherein -NH-CH(CH 2 ) (R 2 )- of formula II is 2S -amino- l-cyclohexyl-3R,4S-diol-6-methylheptane; LVA-2S-methylbutylamide; or 10 LVA-Ile-Amp. 9. The renin inhibitory peptide of claim 7 wherein -NH-CH(CH ) (R 2 ) - of formula II is LVA-Ile-Amp. 15 10. A compound of claim 8 selected from the group consisting of: 4- [ (l'R- tert-Butoxycarbonyl)phenethylamido]maleoyl-Leu^[CH(OH)- C 2 ]Val-Ile-2-(amidomethyl)pyridine; 4- [ (1 ' R-Ethoxycarbonyl)phenethylamido]maleoyl-Leu^[CH(0H)CH 2 ] - Val - lie - 2 - (amidome thyl) pyridine ; 20 4- [ (l'R-Methoxycarbonyl)phenethylamido]maleoyl-Leu^[CH(0H)CH 2 ] - Val-Ile-2- (amidomethyl)pyridine ; 4-t(l'R-Carboxy)phenethylamido]maleoyl-Leu^[CH(0H)CH 2 ]Val-Ile-2- (amidomethyl)pyridine ; 4- [ (1 ' S - ( tert-Butoxycarbonyl)phenethylamido]maleoyl-Leu^- - 25 [CH(0H)CH 2 ]Val-Ile-2-(amidomethyl)pyridine; 4-[(l'R-tert- Butoxycarbony 1 ) phene thy lamido ] maleoy 1 - Leu^ CH ( OH ) - CH 2 ] Val - 2S - me thy Ibutylamide ; and 4- [ ( 1 ' R- tert-Butoxycarbonyl)phenethy lamido] -maleoyl-2S -amino- 1 - cyclohexyl-3R,4S-diol-6-methylheptane. 30 11. A compound of claim 9 selected from the group consisting of: 4- (Phene thylamido)maleoyl-Leu^[CH(0H)CH 2 ]Val-Ile-2- (amidome th- yl)pyridine; 4-[(2'-Pyridyl)ethylamido]maleoyl-Leuv[CH(0H)CH 2 ]Val-Ile-2- 35 ( amidome thy 1 ) pyridine ; 4-(Benzylamido)maleoyl-Leuτ6 CH(0H)CH2]Val-Ile-2-(amidoι_eth2^1)- pyr idine ; 4-(N-Benzyl-N-phenethylamido)maleoyl-Leuψ[CH(0H)CH 2 I-Val-Ile-2- ( amidome thyl) pyridine; and 4- ( (NN iinn --ffoorrmmyyll1tryptamido)maleoyl-Leu^[CH(0H)CH 2 ]Val-Ile-2- (amidome thyl)pyridine

Inventors: TENBRINK RUTH E, TENBRINK, RUTH, E.
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1989
Main classification: C07K5
IPC codes: A61K38, A61P9, A61P43, C07C233, C07C237, C07D213, C07D401, C07K5, C07K14