NOVEL COMPLEX AMIDO AND IMIDO DERIVATIVES OF CARBOXYALKYL PEPTIDES AND THIOETHERS AND ETHERS OF PEPTIDES

Abstract: Novel inhibitors of angiotensin converting enzyme are disclosed which have the general formula wherein R₁ and/or R₃ form complex amides and imides thereof, X = S, O or NR₉, R₄ and R₅ form with -N-C- a 4-6 membered ring structure as described and the other R substituents are selected from a variety of disclosed groups.

Description: Background of the Invention Angiotensin converting enzyme (peptidyldipeptide hydrolase, hereinafter referred to as ACE) occupies a central role in the physiology, of hypertension. The enzyme is capable of converting the decapeptide angiotensin I, having the sequence AspArgValTyrIleHisProPheHisLeu to an octapeptide, angiotensin II, by removal of the: carboxy-terminal HisLeu. The symbols for the foregoing chemical moieties -and' others used throughout this application are explained in the following table: Arg = arginine Asp = aspartic acid Boc = t-butyloxycarbonyl Cbo = carbobenzyloxy > Glu=pyro-L-glutamic acid Gly = glycine Hip = Hippuric acid (Benzoyl-glycine) His = histidine Ile = isoleucine Leu = leucine Phe = phenylalanine Pro = proline #Pro = 3,4-dehydroproline Ser = serine Tos = tosyl Trp. = tryptophan Tyr = tyro3ine Val '= valine Pht = phthaloyl ACE = angiotensin converting enzyme Hepes = N-2-hydroxyethylpiperazine N'-2-ethanesulfonic acid In each instance the symbol for any amino acid is also used herein at times to refer to a mono-or-di-valent radical of such acid and those of ordinary skill in the art will readily understand the context of each specific use. Angiotensin I is formed by the action of the enzyme renin, an endopeptida'se found in kidney, other tissues and plasma, on a serum &alpha;-2 globulin. Blood pressure is affected by certain pep-tides found in the blood. One of these angiotensin II, is a powerful pressor @ (blood pressure elevating) agent. Another, brady- kinin, a nonapeptide with the sequence ArgProProGlyPheSer ProPheArg is a powerful depressor (blood pressure lowering) agent. In addition to a direct pressar effect, angiotensin II stimulates release of aldosterone which tends to elevate blood pressure by causing, retention' of extracellular 'salt and fluids. Angiotensin II is found in measurable amount in the blood of normal humans However, it is found at elevated concentrations in the blood of patients with renal hypertension. The level of ACE activity is ordinarily in excess, in both normal and hypertensive humans, of the amount needed to maintain observed levels of angiotensin II. However, it ha's -been found that significant blood pressure lowering is achieved in hypertensive patients by treatment with ACE inhibitors. [Gavras, I. et al., New Engl. J. Med. 291, 817 (1974)]. ACE is a peptidyldipeptide hydrolase. It catalyzes the hydrolysis of the penultimate peptide bond at 'the C-terminal end of a variety of acyl-ated- tripeptides and larger poly- peptides having an unblocked &alpha;-carboxyl group. The action of ACE results in hydrolytic cleavage of the penultimate peptide bond from the 'carbox'yl-terminal 'end yielding as reaction products a dipeptide and a remnant. -The reactivity of the enzyme varies markedly. depending on the substrate. At least one-type of pepti-de bon'd, having the nitrogen supplied by proline, is not hy'drol'yzed at all. The' appa'rent -Micha'elis constant (Km) varies from'- substrate to- substrate over several orders of magnittrde'. For general discussion of the kinetic parameters of enzyme catalyzed reactions, see Lehninger, A., Biochemistry, 2nd. Ed., Worth Publishers, Inc., New Yark, 1975, pp. 189-195. Many pep tides which 'are called inhibitors of the enzymatic conversion of.- angiotansin I to 'angiotensin II are in fact substrates having a lower Km than angiotensin I. Such peptides are more properly termed competitive substrates. @ Examples of complete itive substrates include bradykinin, and the peptide BPP 5a (also called SQ20475) from snake venom, whose sequence is GluLysTrpAlaPro. Numerous synthetic peptide derivatives have been shown to be ACE inhibitors by 'Ondetti', et al. in U.S. patent 3,832,337 issued Augst 27, 1974. The role of ACE in the pathogenesis of hypertension has prompted a search. for inhibitors of the enzyme that could act as.antihypertensive.dru.gs... See for example U.S. Patents 3,891,616, 3,947,575, 4,052,511 and 4,053,651. A highly. effective inhibitor, with high biological activity when orally administered, is 0-3-mercapto-2-methylpropanoyl L-proline, designated SQ14225, or "captopril" disclosed in U.S. patent 4,046,889 to Ondetti et al., issued Septamber 6, 1977, and in scientific articles by Cushman, D.W. et al., Biochemistry 16, 5484 (1977), and by Ondetti, M. et al., Science 196, 441 (1977). The inhibitor SQ14225 reportedly has an I@@ value of 2.3 x 10-8M. The I5(3 value reported by Cushman, et al. 'su'r'a' is the concentration of inhibitor required to produ,ce 50% inhibition of the enzyme under a standard assay system containing substrate at a leve sub- stantially above Km. It will be understood that I50 values are directly' comparable' when. all potential 'factors affecting the "reaction' are kept constant. The'se factor's include the source of enzyme, its purity, the substrate used and its concentration', and the composition of the assay buffer. All I50 data reported herein have been parformed with the same assay system and 'same enzyme (human urinary ACE) and with the. same level 'of substrate and are therefore internally consistent. The mode of action of SQ14225 has b'een based upon a model of the active site of ACE developed by analogy with the better known related enzyme, carboxypeptidase A. The active site was postulated to have a cationic site for binding the' -carb'ox'yl end group of the' substra'te and a pocket or cleft capable of binding the side chain of the C-terminal 'amino acid and providing especially tight bind- ing for the heterocyclic ring of a terminal proline residue. A similar pocket for the penultimate amino 'acid residue was postulated, and the published data suggested a rather stringent steric requirement, since the D-form of the inhibitor was substantially more potent than its stereo- isomer or the 3-methyl and unsubstituted analogs.The sulfhydryl group on the inhibitor, postulated to be bÏund at the active site near the catalytic 'center, was believed to play a centraL role' in inactivation of the enzyme. by combining with the zinc moiety known to be essential for catalytic activity. Substituents on the sulfhydryl, such as a methyl group, and a S-acetyl derivative, substantially reduced potency of the inhibitor. See Cushman, D.W., et al., Biochemistry, supra. In vitro study of the mechanism by which SQ14225 and its analogs act to inhibit ACE has b'een somewhat hampered by the instability of these molacules under ambient cnditions. For example, it has been observed that a fresh aqueous solution of concentration, e.g., 1 mg per ml of SQ14225 et a' pH of about 8 becomes substantially less active upon standing for as little as 30 minutes, and that activity continues to decrease as the solution stands for longer-- periods. It is believed that this loss in activity is mainly the result of dimerization of SQ14225 occurring at the sulfhydrylend groups, whereby a disulfide is formed which is largely inactive a-s an inhibitor; Since the free sulfhydryl group is highly reactive and may be readily oxidized to polar acidic moieties such as sulfone and sulfoxide groups, it may also be that the observed 'in' vitro loss of activity of aqueous solutions of SQ14225 on standing is in some part a consequence of one or more such oxidation reactions, with formation of a sulfone or sulf- oxide which does not function effectively as an inhibitor for ACE. Such -reports of SQ14225 clinical testing ,as are currently available, some of which refer to the' compound under th.e' name "Captopril" or' Capoten", suggest that the product is sufficiently stable in. the normal gastric and intestinal environments of most patients to be an effective inhibitor of ACE when administered orally It is not yet clear, how ever, whether there may be a group of patients for which SQ14225 is substantially ineffective. Because of the high reactivity of the free sulfhydryl group, SQ14225 could readily form mixed disulfides with serum, cellular proteins, pep tide or other free sulhydryl group-containing substances in. the gastric or intestinal environments, in addition to the possibility for dimer formation or oxidative degradation reactions. A mixed disulfide with protein may be antigenic and, indeed, occaional allergic reactions have been clinically observed. See Gavras, et al., New England J. Med. 298, 991 (1978). Disulfides and oxidative degradation products of SQ14225, if formed, may at best be expected to be largely ineffective. as inhibitors. It 'may be postulated accordingly that dose response to SQ14225 may vary with conditions of administration and among individual patients. Moreoever, in at least some patients, unwanted side effects may occur and maintenance of an effective concentration of the inhibitor in the body may be difficult to control; Adverse effects or 5014225 in man include fevers and rashes (Gavras et al. surpa). Hoorntje et al.', The Lancet, i@, 1212-1214 (1980) describe the performance of renal biopsies on 13 patients treated with SQ14225. All biopsies showed evidence of immune complex deposition aldng 'the glomerular basement membranes, although 9 of 13 patients were asymptomatic at the. time of the biopsy. These authors also discussed simila'rities of their findings with those induced by another drug with a free mercapto group, D-penicill amine. In- an effort etc devise better inhibitors of angiotensin converting enzyme that are more stable than captopril and less likely. 'to induce D-penicillamine-like adverse effects, applicants have prepared a series of compounds having side chain structure analogous to an effective substrate for the enzym'e, be.nzoyl-Phe-Ala-Pro and disclosed them in cop'enduing U.S. application Ser. No. J87992 filed September 17, 1980. Also relevant are the class of carboxyalkyldipeptides derivatives disclosed in European publishe'd application of Patchett et al. published on or about aune 25, t980. The present application defines compounds such' as N-[L-1-carboxy 3-(carbonalide)propyl]D,L-Ala-L-Pro, N-[L-1-carboxy-3-(carbo 4-iodoanilide)propyl]-D, L-Ala-L-Pro, and analogs i.e., amides and imides of N-(Iawer alkylene)Ala-Pro. The'se two named compounds were found to be unexpectedly effective in inhibiting angio'tensin converting enzyme in vitro, that is they have a very low I50, in the order of 10-9M. In contrast another closely: related analog of the two hammed compounds, i.e., N-[L-1-carboxy-2-(carbopyrrolide)ethyl]-D,L-Ala-Pro, was found to have a much higher I50, in the order of 10-7M, a potency of inhibitor likely to be too low for anti-hyper tensive effectiveness. It is believed, therefore, that amides and imides of N-(lower alkylene)-Ala-Pro and related compounds have unpredictable effects on angiotensin converting enzyme In addition', the removal of iodine from N-(L-1-carboxy-3- (carbo-4-iodoanilide)propyl]-D,L-Ala-L-Pro increases intra venous effectiveness three-feld, an unexpectedly' large difference in the in vivo effect of the anti-hypertensive compounds of @ this Invention. Hence, amides and imides of N-(lower alkylene)-D,L-Ala-Pro and related compounds are new agents with surprising effectiveness in lowering blood pressure in vivo. Moreover, since the compounds of this invention do not have the free sulfhydryl group. of SQ14225, they are most likely to be stable and' have durations of action much longer than that of SQ14225. Thus, inhibitors af this invention' may -be used for treating hypertension' with less f'r'equ'ent dosage schedules than required for SQ14225 and may be capable of administration under less rigorously controlled conditions. Brief description of the invention Novel inhibitors of ACE are disclosed which base the general formula (vii) alkoxyphenyl or alkoxybenzyl in which the alkoxy group has 1 - 3 carbons, phenoxyphenyl, phenoxybenzyl, benzyloxybenzyl or benzyloxyphenyl or a thioether analog of any of them; EMI7.1 wherein n = 0-4 and B = H or a 1 - 6 carbon alkyl group, or an -SB analog thereof; (ix) (CH2)pCOOZ or (CH2)p COSZ wherein p = 0 - 3 and Z is H, phenyl, benzyl, a 1 - 5 carbon alkyl group, or an anion of a physiologically acceptable salt; ; EMI7.2 wherein n is O to 4- and Z each have the same significance as above, EMI7.3 wherein n = 0 - 4, D is phenyl, thienyl or a 1 - 3 carbon alkyl group (xii) HO - (CH2)o - C(CH3)2 -, HS - (CH2)n - C(CH3)2 -, p-hydroxyphenyl -CCH2) - - C (cH,3)2 - or -p-mercaptophenyl (CH2)n - CCCH3) - wherein n has the same significance as above; (xiii) p -mercaptopheayl - (CH2) - CH2 - or p-hydroxyphenyl - (CH2)n - CH2 -- wherein the phenyl ring has one or two nitro or amino substituents and n has the same significance as above: EMI7.4 wherein n has the same significance as above; (xv). NH2 - alkylene or NO2 - alkylene or NO2 - alkylene containing one hydroxy or mercapto substituent and having 1 - 6 carbon atoms; Cxvi) hydroxy- or mercapto-phenoxybenzyl; EMI8.1 EMI8.2 w@erein q = 1 - -5 and n is from 0 to 4 and Z has the same significance as above; EMI8.3 wherein @ and n all have the same significance as above; EMI8.4 it; being understood that any of these structures may be monosubstituted with '-OH, -OCH3, F, EMI9.1 Cl, Br, I, phenyl, hydroxyphenyl, -SH, -SCH3, EMI9.2 EMI9.3 -NHCH3, -CH2NH2, - CH3, -CH2OH, propyl, guanidino, nitroguanidino or thioguanidino and that. any of the 5- or 6-membered rings may be disubstituted with -OH, F, Cl, Br, I, OH3 or any combination of two of this group of substitutents; R6 is -OM or -SM, wherein M may be X, an alkyl group of 1-3 carbon atoms or any other ester moiety hydrolyzable under mammalian in vivo conditions to -OH, or an ionically bonded anion of a physiologically acceptable' nontoxic salt; R7 is H-, CH3-, halomethyl, hydroxymethyl; aminomethyl or mercaptomethyl; R8 is H-, CH3-, amino, halomethyl, hydroxymethyl, aminmethyl, dihalomethyl, trihalomethyl, mercaptomethyl, methoxymethyl, methylthiomethyl, methoxycarbonylmethyl, cyanomethyl, benzyl, acetoxymethyl, CH2=CH-CH2-, isobutyl, mercaptoalkyl of 2-3 carbon atoms, hydroxyalkyl of 2-3 carbon atoms,.. acetylthioethyl, benzamido, acetamido, phehaloylaminoalkylene wherein the alkylene group has 1-4 carbon atoms, &alpha;-alkoxycarbonyl isoalkylene wherein the alkyl 'group -contains 1-5 carbons the isoalkylene group containe 3 - 5 carbons, benzoylamine, alkanoylamine of 1 - 5 carbons, alkylamide of 1 - 5 carbone, phenylamine, alkyl amino of 1 - 5 carbons, or ethyl; and A. R1 and R3 may each be of the general formula EMI9.4 wherein A3 i.s: (i) alkylene of .1-6 carbons, branched chain alkyl of 1-6 carbon's, cycloalkyl 'alkylene, alkylc'ycloalkylalkylene, or alkylcycloalkylene; (ii) aralkylene wherein the alkyl group is 1-6 carbons or alkylaryl; (iii) phenyl; (iv) alkylaralkylene wherein the alkyl groups may be the same or different and are 1-6 carbons in length; ; (v) substituted alkylene, substituted branched chain alkyl, substituted cycloaikylalkyle'ne, substituted alkyl cycloalkyl al kyl ene ,substituted al kylcycloal ethyl a'ne substituted alkylaryl, substituted aralkylene, substituted aralkylene, substituted phenyl or substituted alkylaralkylene wherein the subatituent or substituents may be the same or different,' may be included in an alkylene chain or pendent thereto, and are 'selected from amino, hald, hydroxy, mercapto, NO2, carboxy, CONH2, lower alkyl, halomethyl, hydroxymethyl, aminomethyl, dihalomethyl, trihalomethyl, cyano, mercaptomethyl, methoxy methyl, methylthiomethyl, methoxycarbonylmethyl, cyanomethyl, benzyl, acetoxymethyl, CH2=CH-CH2-, isobutyl, mercaptoalkyl of 2-3 carbon atoms, hydroxyalkyl of 2-3 carbon atoms, acetylthioethyl, benamido, acetamido, phthaloylaminoalkylene wherein the alkylene group has 1-4 carbon atoms -alkoxy- carbonyl isoalkylene wherein the alkyl group contains 1-5, carbons and the isoalkylene group contains 3-5 c rbons, benzoylamino, alkanoylamino of 1-5 carbons, alkylamide of 1-5 carbons, phenylamine, alkylamine of 1-5 carbons, lower alkoxy, aryloxy, lower alkylamino, diloweralkylamino, acyl amino, arylamino, guanidino, imidazolyl, indolyl, lower alkylthio, arylthio, carboxy amido and carbolower alkoxy; (vi) alkylenethio- or alkylenethioalkylene of 1-6 carbons, alkylthioalkylene of 1-6 carbons; ; (vii) alkylenoxy or alkyleneoxyalkylene wherein the alkyl groups may be the same or different and are 1-6 carbons; (viii) alkoxyphenyl or alkoxybenzyl in which the alkoxy group has 1-3 carbons, phenoxyphenyl, phenoxybenzyl, benzyl oxybenzyl or benzyloxyphenyl or a thioether analog of any of them; EMI10.1 wherein n=0-4, m=s-4 and 8=H or a 1-5 carbon alkyl group; or an -58 analog thereof; EMI11.1 wherein n and m have the same significance as above, Y is phenyl. benzyl or a 1-5 carbon alkyl 'group; EMI11.2 EMI11.3 wherein T and W may be the same or different and are alkylene, aryl, benzyl or cycloalkyl; and P and Q may be the same, or one of them may be H or they may combine to form a ring with the nitrogen to which they are attached. Either or both of P and Q may be selected from any of the following: (a) C1-C6 straight or branched chain alkyl 'groups or C1 -,,C;6 straight or branched chain alkenyl igroups, any one of which may be substituted with any of halo, hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, alkylacylamino, arylamino, guanidino, thioguanidino, nitroguanidino, hydrazino, ureido, nitro, mercaptocarbonyl, hydroxyamino, histidinyl, cyano, imidazolyl, indolyl, mercapto, alkylthio, arylthio, carboxy amido or carboalkoxy, wherein the alkyl groups contain 1-6 carbon atoms; ; (b) cycloalkyl or cycloalkyl alkylene wherein cyclo alkyl has 4-12 carbon's, and alkylene 1-5 carbons, which may be substituted with any of -OH, -SH, halo, COOH, COSH, CONH2, NO2NH2, NO2, CH3, -OCH3, -SCH3, EMI12.1 hydrazino, ureido, hydroxyamino, cyano, guanidino, thioguanidino or nitroguanidino groups; (c) aralkyl or alkaryl groups which may be ring substituted with one or more of the following: : SH, halo, CH2COOH, CH2CONH, CH2CONH-alkyl, COSH, COOH CONH2, CONH-alkyl, CH2COSH, CH2SH, CH2OH, OH, NO2, amino, alkyl, alkoxy, aralkyloxy, alkylthio and aralkylthio groups, wherein the alkyl. groups contain 1-6 carbons and may also or alternatively be chain substituted with -CH3, -OH, -OCH3, halo, -SCH3, EMI12.2 -NH2, -NO2, -CN, -SH, -NHOH, - NHNH2, EMI12.3 or a thio or nitro derivative thereof, -COOH or COSH; ; (d) an aryl, heterocyclic or adamentanyl group which may be ring-substituted with at least one group selected from halo, -OH, -O-alkyl, -O-aryl, NH2, NH-arkyl, N-(alkyl)2 EMI12.4 aryl-NH2, guanidino, thioguanidino, nitro-guanidino, hydrazino, ureido, nitro, mercaptocarbonyl, hydroxyamino, cyano imidazolyl, indanyl, histidinyl, -SH, -S-alkyl, S-aryl, EMI12.5 EMI12.6 -C-5-aryl and -NO2 when P and Q join with N th form a ring, the ring may be any 4-10 membered heterocyclic ring which contains a nitrogen with only two of its valences attached to other ring members B. Alternatively R1 may be EMI12.7 and R3 may be'- (i) mono-N substituted alk.ylene of -2-4 carbons wherein th'e N substituent is benzoyl, Boc, CbO, Tos, formyl or acetyl; (ii) hydrox@phenyl or hydroxyphenyl-(1-6C)-alkylene or a thiol analog of either, (iii) mercaptoalkylene of 1-6 carbons; (iv) phenylalkylene wherein the alkylene group has 1-6 carbons; (v) phenylthioalkylene or benzylthioalkylene wherein the alkyl'e'ne 'group has 1-6 carbons; (viN alkylthioaikylene wherein the alkyl and, alkylene groups have 1-3 carbons; ; (vii) alkoxyphenyl or alkoxybenzyl in which the alkoxy group@ has 1-3 carbons, phenoxyphenyl, phenoxybenzyl, benzyloxybenzyl or benzyloxyphenyl or a thioether analog of any of them; EMI13.1 wherein n=@=4 and 8=H or a 1-6 carbon alkyl group; or an -SB analogs thereof; (ix) (CH2)pCOOZ or (CH2)p COSZ wherein p = 0 - 3 and Z is H, phenyl, benzyl,' a 1 - 5 carbon alkyl group, or an anion of.a physiologically acceptable salt; EMI13.2 wherein n is 0 to 4 and Z each have the same significance EMI13.3 wherein n = 0 - 4, D is phenyl, thienyl or a 1 - 3 carbon alkyl group; (xii) HO - (CH2)n - C(CH3)2 -, H@ - (CH2)n - C(CH3)2 -, p-hydroxyphenyl - (CH2)n - C(CH3)2 - or -p-mercaptophenyl (CH2)n - C(CH3)2 - wherein n has the same significance as above; ; (xiii) p -mercaptophenyl - (CH2)@ - CH2 - or p-hydroxyphenyl - (CH2)n - CH2 - wherein the phenyl ring has one or two nitro or amino substituents and n has the same signifi EMI14.1 wherein n has the same significance as above; (xv) NH2 - alkylene or NO2 - alkylene containing one hydroxy or mercapto substituent and having 1 - 6 carbon atoms; (xvi) hydroxy - or mercapto-phenoxybenzyl; EMI14.2 EMI14.3 wherein q = I - -5 and n is from 0 to 4 and Z has the same significance as above; EMI14.4 wherein q and n all have the same significance as above; ; EMI14.5 wherein C is an alkacyl or alkacyloxy group of f - 6 carbon's, a benzoyl or benzoyloxy group, or a phenylalkacyl or phenylalkacyloxy group wherein the alkacyl or alkacyloxy group contains 2 - 6 carbons and q 'and n have the same significance as set forth above; EMI15.1 wherein n has the significance stated above and K is select- ed from carboxyphenyl', aminoopyhenyl, nitrophenyl ,. halphenyl, hydroxyphenyl, alkylthiophenyl, alkylphenyl, mercaptophenyl, cyanophenyl, mercapto-carbonylphenyl, alkylcarbonylphenyl, alkylcarbonyloxyphenyl, hydriazinophenyl, oreidephenyl, alkylcarbonylaminophenyl, alkylcarbonylthiophenyl, alkyloxy phenyl and hydroxy-aminophenyl, wherein all alkyl groups contain 1 - 6 carbon atoms; ; EMI15.2 wherein n has the significance stated above and L is selected from cycloalkyl groups of 3 - 7 carbons which may be unsubstituted or substituted with up to two groups selected from among carboxy, amino, nitro, halo, hydroxy, mercapto, mercaptocarbonyl, hydroxyamino, alkyl, alkylcarbonyl, alkyl carbonyloxy, alkylthio, alkylcarbonylamino, alkylcarbonylthio cyanohydrazino, ureido and alkyloxy, wherein all alkyl groups contain. J: - 6 carbon: atoms; (xxii) guanidino alkylene, thioguanidinoalkylene or nitroguanidino alkylene in which the alkylene groups'contain I 6 6 carbon atoms; (xxiii) ring substituted aryl gorups in which the ring substituents may be the same or different and may comprise up to five per ring of the following; - NH2, -OZ, -SZ, halogen, -CN, -NO2, -COOZ, -COSZ, CONH2, - NHNH2, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkyl, dihaloalkyl, trihalomethyl, hydroxyamino, alkyl carbonylthio, phenoxy, and benzyloxy wherein the alkyl groups contain 1 - 6 carbon atoms and Z has the same significance ,,as above; (xxiv) amidoalkylene or alkylcarbonyl-aminoalkylene wherein the alkyl and alkylene groups contain t < - 5 6 carbon atoms, (xxv) hydroxyaminoalkylene of 1 - 6 carbons; (xxvi) vinyl and, substituted vinyl groups in which the substituents may be alkyl, aryl, cycloalkyl or heterocyclic groups; ; (xxvii) unsubstituted heterocyclic groups from among phenothiazinyl, pyrrolidinyl, pyrrolyl, quinolinyl, imidazoly pyridyl, thyminyl, benzothiazinyl, indolyl, thienyl, porinyl, piperidinyl, morpholinyl, azaindolyl, pyrazinyl, pyrimidyl, piperonyl, piperazinyl, furanyl, thiazolyl and thiazolidinyl, cytosinyl; (xxviii) alkylene or alkenyl groups of 1 - 6 carbons substituted with one of the heterocyclic' rings from (xxvii) above (xxix) groups from (xxvii) or (xxviii) above containing up to four ring substituents on the heterocyclic ring select from among - OZ - SZ, - COOZ, - NO2, - NH2, - COSZ, halogen, haloalkyl, dihaloalkyl, trihalomethyl, cyano, CONH2, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino, alkylcarbonlythio- phenoxy, benzyloxy, EMI16.1 -NHNH2 and HONH -, wherein Z has the same significance as above; ; (xxx) grups from (xxvii), (xxviii) or (xxix) attached to one valence of an etheric -0- or -S-; (xxxi) mano-, di- or tri-alkyl, alkenyl - or phenyl-silyl or -selenyl wherein the alkyl or alkenyl groups contain 1 - 6 carbons (xxxii) any of H, 1 - 5 carbons straight or branched chain alkyl, phenyl, -OH, alkoxy of 1 - 6 carbons, benzyloxy, benzyloxyalkylene or phenoxyalkylene wherein the alkylene has 1 - 5 carbons, alkoxyalkylene having 1 - 5 carbons in the alkoxy and alkylene groups, aminoalkylene of 1 - s carbons, alkenyl of 1 - 6 carbons, benzyl, hydroxyalkyl of 1 - 6 carbons, mercaptoalkyl of 1 - 6 carbons, histidinyl, halo'alkyl of 1 - 6 carbons, 4 - aminomethyl-benzyl, acetamidoalkyl of 1 - 5 carbons, benzylthiomethylene, or dimethylaminoalkyl of I - 5 ,carbons. C. Alternatively, R3 may be EMI17.1 and, may be any of groups (i) - (xxxi) above or any of H, C1 r r8 straight or branched chain alkyl, phenyl, benzyl,: unsubstituted aminoalkylene of 2 - 6 carbons, Xiydroxyalkylene of 1 -- 6 carbons, hydroxyphenyl, phenoxy- alkylene or benzyloxyalkylene wherein the alkylene group has 1 - 6 carbons, cycloalkyl of 3 - 6 carbons, cycloalkyl methyl, 3 indolyl-, phenylethyl, methylthioethyl 3 indolyl alkyl wherein the alkyl group contains 7 - 5 carbon's, imidazolyl, imidazolylalkyl wherein the alkyl group contains 1 - 5 carbons, phenoxymethyl, phenylthiomethyl, 4-aminomethyl benzyl, 2-amino phenethyl, naphthylethyl, 4-halophenethyl, 3,4-dihalophenethyl or phenoxyphenethyl, or R1 and R2 together may form with -CH a lactone ring of the formula EMI17.2 or an analogous six-membered ring. In the 'general formula above, asterisks indicate possible asymmetric enters. These centers may be racemized or in any optically active form. However, the S-form is preferred The' inhibitor's are useful as orally effective anti-hyper tensive agents. Detailed description of the invention The pre'sent invention in its broad aspects relates to thioether, ether and secondary amino compounds containing at least one amino acid or related structure containing ,the sequence EMI18.1 preferably EMI18.2 and includes at least one group of the general formula EMI18.3 in the R1 or R3 position. The compounds of this invention wherein X = NR9 may be made in a variety of ways. For example an alpha keto carboxylic acid of the general formula EMI18.4 may be coupled EMI18.5 to- give a product EMI18.6 using a conventional coupling agent such as dicyclohexyl- carboiimide ("DCC") or diphenylphosphorylazide ("DPPA") This product in turn may be coupled, in the presence of a reducing agent such as sodium cyanoborohydride to a compound of the- general formula EMI18.7 to give the desired compound, In such an instance EMI18.8 may, e.g. be first reacted with an appropriate @ - carboxylated compound, e.g., EMI18.9 In thi's particular scheme, e.g., EMI19.1 may alternatively first be coupled with EMI19.2 and the, product then coupled with EMI19.3 in such instances 9 - N - P may be reacted with the COOH attached to A3 after the first or second coupling step. Similarly, EMI19.4 may be coupled to EMI19.5 and Q - N - P may the'n be 'reacted with 'the' COOH adja'cent to A3. As those of ordinary skill in the art will readily under stand, conventional blocking groups such as BOC, CbO,' etc. may be introduced at appropriate stages to protect reactive groups and may be removed when protection is no'lo'nge,r n'eeded or wanted. It is within ordinary skill, e.g., to use in lieu of EMI19.6 a compound EMI19.7 protect either of the COOH groups as desired in the particul-ar reaction scheme preferred and prepare, EMI20.1 Similarly if EMI20.2 wh@rein is other than EMI20.3 is chosen.and EMI20.4 is used in lieu of EMI20.5 the reactions may be manipul-ated with appropriate blocking and eoupling,' steps to yield a product¯ EMI20.6 Among suitable #-carboxylic acids of the general formula EMI20.7 are glutamic acid &alpha;-benzyl ester glutamic acid &alpha; ;-methyl ester glu@amic acid a-methyl ester glutamic acid a¯ t - butyl ester aspartic -&alpha; - benzyl ester 2-amino - 5 -carboxy - indan - 2-carboxylic acid para-carboxy phenyl alanine &alpha;-methyl ester ortho-carboxy tyrosine &alpha;- methyl-ester 2-amino malinic acid monoethyl ester 2-amino adipic acid 1 methyl ester 2-amino pimelic acid 1-ethyl ester 2-amino suberic acid 1-ethyl ester 2-amino azelaic acid 1-ethyl ester 2-amino sebacic acid 1-ethyl ester and others which will readily occur to those of ordinary skill in the art.'. Th'e,se acids may be purchased in. ,many instances from, e.g. Aldrich Chemical Co. or Chemical Dynamics. Co. It is also well known that amino. acids of the formula EMI21.1 wherein R, is COOH or, another carboxyl function may be obtained from &alpha;-keto dicarboxylic acids using methods described by Waters, K.L., Chem. Rev. 41, 585-98 (1947). Among suitable compounds of the general formula EMI21.2 referred to above are: &alpha;-keto glutaric acid oxalacetic acid ketomalonic acid 4-keto pimele acid para-carboxy phenyl pyruvic acid indole-1-carboxy-3-pyruvic acid ss-carboxy-DL-lactic acid 2-ketoadipic acid It is to be understood that whe'n EMI22.1 the compound of the general formula EMI22.2 can be selected from a very wide group. Suitable R1 compounds of the general formula EMI22.3 NHR9 for use in making the compounds of the invention include, but are not limited to tert. Laucine, 2-methylglutamic acid, &alpha;-amino-&gamma;-guanidino butyric acid, &alpha;-amino-ss-guanidino- propionic acid, ss-fluorophenylalanine, ss-hydroxyvaline, &alpha; ;-oxa- lysine, #-hydroxy ornithine, N@-hydroxylysine, -N@ methyl arginine, N@-hydroxyarginine, canvanin, 5,5Ú-dihydroxyleucine, ss-carboxyaspartic acid, ss-fluoroaspartic acid, ss-methylaspartic acid, ss-methylene aspartic acid, p-amino phenyl alanine, p-guanidinophenyl alani ne, p methyl, -phenyl al aniRe, 2-ethoxy-5-nitrophenyl-alanine, 2-hydroxy-5-nitrophenyl alanine, 4-mercaptophenylalanine, 2-amino-2-indolsacetic acid, 2-amino-3-adamantylpropionic acid, ss-methylene norvaline, &alpha;-amino- -(4 carboxythiazolyl)-butyric acid) 3-chloroglutamic acid, &alpha;-amino-&gamma; ;-nitrovaleric acid, 4-azalysine, ss-(2,4,5 trihydroxyphenyl)-alanine, ss-(3-bromo-5-methoxyphenyl) alanine, ss- (3,5 dimethyl - 4 methoxypheny) alanine, 3,5-di (ethylthio) 4-(4' hydroxph,enoxy) - phenylalanine, 3,5-di (ethylthio) -4(3' -isopropyl-4'-methoxyphenoxy)-phenylalanine, ss-pyrrolyl-alanine, 2-amino-4-pyrrolyl-butyric acid, 2-amino -5-pyrrolyl-valeric acid, ss-(2 pyridyl) alanine, ss-(3 pyridyl alanine, ss (6-aminopurin - 9yl) alanine, ss-(4-amino-2-hydroxy pyrimidin -1-yl) alanine, ss-(2,4 hydroxy - 5 methyl pyrimidin-1-yl) alanine, ss-(6-hydroxy-purin -9-yl) alanine, ss(6-dimethylamino-purin -9 yl) alanine, B-(6-mercaptopurin- 9 yl) alanine, ss-(6-methylthiopurin -9yl) alanine, 4-ezatrypto phan, 4-methyl- 6-chloro-7-azatryptophan, N#-(1,4-dehydro -6 methyl -3-hydroxy -4-oxo- 1 pyridyl) lysine, 5-(2-hydroxy -2-carboxyethanethiomethyl) -cysteine, 2-amino -3- (6-thieno [3,2-b] pyrrolyl) propionic acid, 3,3', 5,5' tetr@@@@@@@@@@ thyronine, 3-hydroxy - L-lysine, 2-aminohex-4-ynoic acid, N-hydroxyornithine, 4-piperazinobut - 2-ynoic acid, 4-piperidinobut - 2-ynoic acid, 4-pyrrolidinobut - 2-ynoic acid, &alpha;-amino -N&gamma; - nitroguanidinobutyric acid, &alpha;-amino ss(1-imidazolyl) propionic acid, 4-nitrohistidine, 2-methyl -3 (2', 4'-diiodo 5' -hydroxyphenyl) alanine, 4-(3'amino2', 4', 6'-triiodophenyl) - isovaline, 4-(3' acetamido -2', 4', 6' - triiodophenyl) - isovaline, 4- (3'-hydroxy -2'; 4', 6'-triiodophenyl) isovaline, 2-amino-4-thiosulfobutyr@@ acid, @-(3-aminopropyl) homecysteine, @-(cyclopentyl methyl) homocysteine, @ - guanosyl homocysteine, ss (cytosin-1-yl)- alanine, @-[(diphenyl -&alpha; ;-naphthyl) methyl]-L-cysteine, @-[(diphenyl-ss-naphthyl) methyl]-L-cysteine, 2-amino-6-(methylthio) caproic acid, NGNG - dimethyl - L-arginine, NGNG - dimethyl - L-arginine, N#N#N#-trimethyl -#-hydroxy-L-lysine, N#-(5-amino-5-carboxypentyl) -5-hydroxy-L-lysine, ## -dihydroxy-L-norleucine, cis-1-amino-1,3-dicarboxycyclohexane, trans-1-amino-1,3-dicarboxycyclohexane, 3,3,4,4,4,-pentafluoro-2-aminobutyric acid, 3,3,4,4,5,5,5,- heptafluoro-2-aminovaleric acid, #-fluoro-DL-and L-allo-isoleucine, 2,6-diamino-4-hexynoic acid, @-(&alpha; ;-D-glucopyranoxyl)-L-serine, 2-amino-5,6-dihydroxyindan-2-carboxylic acid, 3-(m-fluorophenyl)-2-methylalanine, 3-(m-bromophenyl)-2-methylalanine, 3-(m-iodophenyl)-2-methylalanine, 2-[(m-iodophenyl)methyl]glycine, 4-(m-iodophenyl)-2-methyl-2-aminobutyric acid 3,5,3'-tri-isopropyl-DL-thyronine, 3,5-dimethyl-3'-isopropyl-thyronine 3,5-di-isopropyl-thyronine, 3,5-di-isopropyl-4'-amino-thyronine, 3,5-di-isopropyl-3'-bromo-thyronine, 3,5-di-isopropyl-3'-methyl-thyronine, 3,5-di-s-butyl-thyronine, 3,5-di-s-butyl-4'-amino- thyronine, 3,5-di-s-butyl-3'-bromo-thyronine, 3,5-di-s-butyl-3'-iodo-thyronine, 4-fluoro-tryptophan, 5-fluoro-tryptophan, 6-fluoro-tryptophan, ss-5(-hydroxy-6-iodo-2-pyridyl)-alanine, ss-(benzimidazol-5-yl)-alanine, ss-(2-amino-6-hydroxypurin-9-yl)-alanine, ss-(2-amino-6-mercaptopurin-9-yl)-alanine, N#-(5-Amino-6-chloro-4-pyrimidyl)lysine, &alpha;-Amino-#-(6-chloro-9-purinyl)caproic acid, 4-Fluoro-DL-histidine, 5-methyl-2-methyl-cysteine, 5-Ethyl-2-methyl-cysteine, 5-propyl-2-methyl-cysteine, 5-Isopropyl-2-methyl-cysteine, 5-Butyl-2-methyl-cysteine, 5-Isobutyl-2-methyl-cysteine, 5-t-Butyl-2-methyl-cysteine, 5-Amyl-2-methyl-cysteine, 5-Isoamyl-2-methyl-cysteine, 5-Allyl-2-methyl-cysteine, 5-(ss-Aminoethyl)homocysteine, &gamma;#, #'-trihydroxy-leucine, N#-(indole-3-acetyl)-lysine, p-hydroxymethylphenylalanine, O-ethylhomoserine, 5-methyl-2-aminohex-4-enoic acid, &alpha;-(3-hydroxyphenyl)glycine, &alpha; ;-(3,5-dihydroxyphenyl)glycine, ss-(cyclohexa-1,4-dienyl)alanine, ss-(cyclohex-1-enyl)-alanine, ss-(1-hydroxycyclohexyl)-alanine, 4-bromoacetyl-phenylalanine, 4-bromoacetamido-phenylelanine, 3-chloroacetamido-phenylalanine, 4-fluoro-3-chloroacetamido-phenylalanine, 3,4,5-tri-iodo-phenylalanine, 3,5-di-isopropyl-3'-iodo-thyronine, ss-(4-methoxy-1-naphthyl)-&alpha;-methylalanine, ss-(4-hydroxy-1-naphthyl)-&alpha;-methylalanine, &alpha;-(2-indanyl)glycine, ss-tri methyl sil yl -al ani ne, &alpha;-amino-ss-(methylamino)propionic acid, N#N#-bis(2-cyanoethyl)-lysine, a,y--di methyl no rl eu ci ne, &alpha;-methyl-N#N#-diethylornithine, &alpha;-ethyl-3,4-dimethoxy-phenylalanine, &alpha; ;-methyl-4-morpholino-phenylalanine, ss-(2-amino-4-pyrimidinyl)alanine, 3-(2-Methyl-4,5-dihydroxyphenyl)-alanine, 3-(2-Ethyl-4,5-dihydroxyphenyl)-alanine, 3-(2-Isopropyl-4,5-dihydroxyphenyl)-alanine, 3-(2-t-Butyl-4,5-dihydroxyphenyl)-alanine, 3-(2,5-Dimethoxy-4-methylphenyl)-alanine, 3-Ethyl-&alpha;-methyl-tyrosine, 2-amino-3,3-dimethylhex-5-enoic acid 2-aminohexa-4,5-dienoic acid 2-amino-3,3-dimethylhepta-4,5-dienoic acid, 2-amino-3,3-dimethylnona-4,5-dienoic acid, 2-aminohepta-5,6-dienoic acid, 2-amino-3-methylhepta-5,6-dienoic acid, 2-amino-5-t-butyl-6,6-dimethylhepta-3,4-dienoic acid 2-amino-5-methylhepta-3,4-dienoic acid 2-aminohept-4-en-6-ynoic acid #-hydroxy-ss-carboxy-norleucine, ss-carboxy-lysine, ss-(3,4-dihydroxyphenyl)-&alpha;-methyl-serine 5-benzyl-ss, &gamma; ;-dimethyl-homocysteine, 5-benzyl-&alpha;-&gamma;&gamma;-trimethyl-homocysteine, ss-methyl-methionine, &alpha;-methyl-selenomethionine, ss-methyl-L-selenomethionine, &gamma;-methyl-selenomethionine, &gamma;,&gamma;'-difluoro-leucine, #,#'-difluoro-leucine, &gamma;-fluoro-allothreonine, ss-hydroxy-asparagine, ss-hydroxy-isoleucine, ss-methoxy-isoleucine, &alpha;amino-&gamma;-(methylamino)butyric acid, &alpha;-amino-ss-(ethylamino)propionic acid, 3-Isopropyl-&alpha;-methyl-tyrosine, 3-t-Butyl-&alpha; ;-methyl-tyrosine, 2-Amino-5-hydroxy-indan-2-carboxylic acid, 2-Amino-5-methoxy-indan-2-carboxylic acid, 2-Amino-5-carboxy-indan-2-carboxylic acid, 2-Amino-5-chloro-indan-2-carboxylic acid, 2-Amino-5-bromo-indan-2-carboxylic acid, 2-Amino-5-iodo-indan-2-carboxylic acid, 3-(2,4-Difluorophenyl)-alanine, 3-(3,4-Difluorophenyl)-alanine, 3-(3,5-Difluorophenyl)-alanine, 3-(2,5-Difluorophenyl)-alanine, 3-(2,6-Difluorophenyl)-alanine, 3-(2,3,5,6-Tetrafluorophenyl)-alanine, 3-(3,5-Dichloro-2,4,6-trifluorophenyl)-alanine, 3-(2,3,4,5,6-Pentafluorophenyl)-alanine, ss-(1,2-Dihydro-2-oxo-3-pyridyl)-alanine, ss-(1,2-Dihydro-2-oxo-4-pyridyl)-alanine, ss-(1,2-Dihydro-2-oxo-5-pyridyl)-alanine, ss-(1,2-Dihydro-2-oxo-6-pyridyl)-alanine, ss-(2-Fluoro-3-pyridyl)-alanine, ss-(2-Fluoro-5-pyridyl)-alanine, ss-(2-Fluoro-6-pyridyl)-alanine, ss-(2-Bromo-3-pyridyl)-alanine, ss-(2-Bromo-4-pyridyl)-alanine, ss-(2-Bromo-5-pyridyl)-alanine, ss-(2-Bromo-6-pyridyl)-alanine, ss-(2-Chloro-3-pyridyl)-alanine, ss-(2-Chloro-4-pyridyl)-alanine, ss-(2-Chloro-5-pyridyl)-alanine, ss-(2-Chloro-6-pyridyl)-alanine, ss-(Thymin-1-yl)-alanine, It, is further contemplated that EMI27.1 may be selected from among any of the known amino acids or esters or from amides thereof in which, when R1 is any of' CH3, NH2-(CH2)3, (NH2(CH2)4-, CH3S(CH2)2-, benzyl-, p-hydroxy benzyl, 3,4-dimethoxybenzyl, EMI27.2 or EMI27.3 R8 is selected from among CH3-, (CH3)2CH-CH2-, Pht N(CH2)@-, CH2 = CH - CH2-, benzyl-, nitrilomethylene-, ethyl EMI27.4 CH3OCH2-, CH3SCH2-, -CH2F, - CHF2, -CF3, -CH2Cl, -CF2Br, PhtN (CH2)2), EMI27.5 H5(CH2)3-, or EMI27.6 There are also known aminoacids, and esters or primary amides thereof in which, when R8 is hydroxymethyl, R1 may be methyl, ethyl, isopropyl, isobutyl, phenyl benzyl or methylthiothyl. It is also contemplated that reactants of the general formula EMI28.1 wherein R2 is COOX may be utilized in lieu of EMI28.2 in the coupling reaction with EMI28.3 or its coupling product already described. In such case, EMI28.4 may be, e.g., dehydroalanine, &alpha;,ss-dehydrophenylalanine, vinyl glycine or a known compound in which Ra and Rb are both methyl or ethyl or Ra is phenyl or a substituted phenyl grout such as 3,4-dimethoxyphenyl and Rb is methyl. In" this instance various functional groups such as halo, hydroxy or mercapto groups and their methylene analogs, may later be added to, one or both carbons of the unsaturated bond via well known and conventional organic chemical - procedures. Many suitable variations in EMI29.1 will readily occur to those of ordinary skill in the art. Another general method for synthesizing compounds of this invention is to couple a suitable a keto carboxylic acid with a suitable dipeptide derivative. A,suitable a keto acid can be formed in the reaction, EMI29.2 in the presence of a conventional coupling agent An appropriate dipeptide derivative can be formed in the reaction EMI29.3 C@@pounds of this invention are then obtain@d by reacting I and II. Alternative schemes are readily apparent, for example, EMI29.4 may be reacted with ' EMI30.1 and the product then reacted with EMI30.2 Suitable compounds of the formula EMI30.3 for use in this synthesis method include, but are in no sense limited to, acetoacetic acid, 5-aminolevulinic acid, acetobutyric acid, acetyl cyclopentanecarboxylic acid, chloromethylketocyclopentane carboxylic acid, dibromomethyl- ketocyclohexanecarboxylic acid, 1-acetyl-4-piperidinecarboxylic acid, N-acetyltryptophan, p-carboxyphenoxyacetic acid, 2-benoylbenzoic acid,. 4-benzoylbenzoic- acid, 4-benzoylbutyric acid, 3-benzoylpropionic acid, mercaptoaceto phenone-4-; ;arboxylic acid, hydroxyethylbenzoyl banzoic acid, the pyruvoyl 'alkyl carboxylic acids, and others which will readily occur to those of ordinary skill in the art.' Suitable compounds of the formula, EMI30.4 include, but are by no means limited to 2-methalalanine, histidine, N -acetyl-lysine, tryptophan, &alpha;-methyltryptophan, albizziin, 2-amino-adipic acid, p-aminophenylalanine, phenylalanine, arginine, aspartic acid, asparagine, 2-methylglutamic acid, N-hydorxylysine, 2-amino-3-adamantyl propionic acid, &alpha;-hydroxymethyl- alanine, &alpha;-methyl methionine, &alpha;-Methyl-N,N-diethylornithine, &alpha; ;-methyl-4 morpholinophenylalanine, ss-(4 methoxy-1-naphthoyl &alpha;-methylalanine, and ss-(hydorxy-1 naphthoxyl)&alpha;-methylalanine, &alpha;-ethyl3,4-dimethoxy phenylalanine and others which will readily occur to those of ordinary skill in the art. So lang as R1 is of the for EMI31.1 any compound of the general formula given above1 wherein R9 = H,- and R2 = COOH may be used as EMI31.2 In these cases R1 becomes R3, R8 becomes R7 and m '= 0. Useful compounds of the type EMI31.3 include amino acenaphthene, para-morpholinoaniline, piperidine, phenyl piperidine, hydantoin, alloxazine, rhodanine, morpholine, aminophenanthrene, adenosine, adamantanamine, adenine, C-aminoacridine, C-aminopyrimidine, aminoanthracene, amino enthraquinone, aminoantipyrine, aminophenol, aminonaphthalene, aminobenzophenone, C-aminobenzothiadiazole, C-aminobenzo thiazole, benzothiazole, aminobiphenyl, C-aminopyridine, C-aminothiazolet pyrazole, C-aminopyrazol'e', C-aminobenzox azole, C-aminopurine, aminochrysene, aminocyclo'pentane, aminocyclopropane, aminocyclobutane, aminocyclohexane, aminocycloheptane, aminocyclooctane, aminocyclononane, aminocyclodecane, C-amino-benizmidazole, C-aminopteridine, N-aminopiperidine, C-amino-1,2,4-triazine, C-aminouracil, uracil, C-amino,N,N-dimethyluracil, aminodiphenylmethane, N-aminoethylimidazoline, N-aminoethylmorpholine, C-amino morpholine, N-aminoethylpiperazine, C-aminopiperazine, N aminoethylpiperidine, 3-amino-N-ethylpiperidine, 2-amino ethylpyridine, N(aminoethyl)-pyrrolidine, pyrrolidine, aminofluoranthene, 1-, 2-, or 4-aminofluoroenone, aminohexane, aminopentane, N-aminohomopiperidine, bomopiperidine, 1-amino, 4-(ss-hydroxyethyl) piperazine, amino-9-hydroxyfluorene, 2-amino-4-hydroxy-6-methylpyrimidine, 4-amino-6-hydroxy pyrazole, 4-aminoimidazole, aminoindan, C-aminoindazole, C-aminoindole, 1- or 5- aminoisoquinoline, 3-amino-mercapto-1 2, 4-triazolë, 4-aminobutanol-1, 5-aminopentanol-1, 2-amino methyl-1-ethylpyrrolidine, 5-aminoisothiazole, 2-amino-6 methylmercaptopurine, 6-aminohexanol-1, 1-amino-4-methyl piperazine, 4-aminomethylpiperidine, 2-amino-1, 3, 4-thia diazole, 2-amino-4-methyl thiazole, N-aminomorpholine, 2-amino-4-morpholine-s-triazine, 4-amino-1,8-naphthalimide, 6-aminonicotinamide, 5-amino-6-nitroquinoline, 2-amino-5 nitrothiazole, 6-aminopenicillanic acid, 4-aminophenyl ether, 2(p-aminophenyl)-6-methylbenzothiazole, 3-amino-1 phenyl-2pyrazoline-5-one, 3-aminophthalhydrazide, N-amino phthalimide, 2-aminopecoline, N-aminopiperidine, 3-amino propanol-1, N-(3aminopropyl) morpholine, N-(3 aminopropyl), ethanolamine, N(3-aminopropyl) pyrrolidinone, 2-amino-6 purinethiol, aminopyrazine, 3-aminopyrazole, 4-aminopyrazolopyrimidine, aminopyrene, 4-aminoquinaldine, N-aminorhodanine, 4- or 5-aminosalicylic acid, 5-aminotetrazole, tetrazole, 2-aminothiazoline, aminovaleric acid, aniline, 3,4-dimethoxy aniline, aminoxylene, benzisooxazole, o- or p- aminobenzamide, o- or p- aminobenzoic acid, o- or p-aminobenzonitrile, ss-aza 6-amin@purine, 2-azacyclooctanone, 3-azabicyclononane, 2 azacytidine, 5-azacytosine, cytosine, 6-azacytosine, 5- or 6-azauracid, Azetidine, aminoazulene, barbituric acid, aminobenzofluorene, C-aminobenzofuran, benzothiazinone, benzylpiperazine, bis (2-ethoxyethyl)amine, bromoguanine, bromoisatin, #-caprolactam, carbazole, tryptophan, glycine, glycinamide, glycinanilide, oxazolidine, oxazolidinone, 8-chlorotheophylline, chlorzoxazone, creatinine, aminocyclo heptadiene, aminocyclooctatriene, aminocyclooctratetraene, cycloserine, cytidine, cytosinecarboxylic acid, dehydeo abietylamine, 4,5-diaminoacenaphthene, aminobenzidine, aminothiophene, dimethyhydantoin, aminofuran, N,N-diethyl ethylenediamine, aminotoluene, aminoindenone, ethyl-4-amino 5-imidazole carboxylate, &alpha;-methyltryptamine, glutamine, glutathione, glutarimide, guanine, guanosine, histamine, dodecamethyleneimine, homocarnosine, dithiouracil., 2,2' dipyridylamine, 2,5-dimethyl-3-pyrroline, 2,6-dimethyl piperazine, isoamarine, glycouril, leucinol, leucenol, myrtanylamine, nicotinamide, homopiperazine, isonicotinamide, 6-ss-hydroxyethylamino pureine, aminonorbornane, aminonorbornene, orotic acid, oxindole, phenoxazine, proline, phthalimide, pyrimidone, pyrole, < Clu, thiazolidine, triacanthine, and 1,2,4-triazole. The various compounds' named can be substituted with, e.g., -OH, halo, dihalomethyl, trihalomethyl, -SH, 0-alkyl, 5-alkyl, phenyl, 0-phenyl, 5-phenyl, COOY, alkylcarbonyloxy, uraido, cyano, hydroxylamino, alkyl, alkoxyalkyl, alkoxyphenyl, phenoxyphenyl and the like. These compounds are illustrative, rather than limiting, as to suitable EMI33.1 compounds It will be understood that EMI33.2 may be utilized in this particular scheme and the A3COOH converted to EMI33.3 at any desired stage of the synthesis process. -- A variety of known methods can be employed to esterify or block any carboxyl group of a multi-carboxyl amino acid or an &alpha;-keto carboxylic acid. See, for example, Schroder E. et al, The Peptides Vol 1, Academic Press (1965) pp. 181-207, and Merrifield, R.8., Adv. Enzym. 32, 221 (1969). Furthermore, many of these- precursors can be obtained commercially, eg., from Chemical Dynamics, South Plainfield, N.J. or from Bachem Chemical Co., Torrance, California. Another method for synthesizing compounds of Formuia I involves the use of a diagomethyl intermediate. See, for example, Boyer, J.H. et al Chem. Rev. 54, 1-57 (1954); Aldrichimica Acta, 3(4) 9 (1 970) an article available from Aldrich Chemical Co., Milwaukee, Wisconsin; Lieber, E. et al, Chem.. Rev. 65;377-384 (1965); L L'Abbe: G. Chem. Rev.. 69. 345363 (1969). This method is especially useful for synthesizing compounds of the invention wherein A3 w C,H2-. Typically a carboxylic acid is reacted with diazomethane via a mixed anhydride reaction, e.g., EMI34.1 'the product is then reacted with an acid such as HBr or HCl, in a solvent such as ethyl acetate, to form an &alpha;-haloketone as follows: : EMI34.2 The o-haloketone can then be reacted with an equivalent of diethylformamidomalonate, then decarboxyleted in aqueous HCl to form derivatives af 2-amino-4-keto carboxylic acid, that is compounds of the formula EMI34.3 Compounds of this general formula can then be coupled with compounds or general formula EMI34.4 in the presence of a reducing agent such. as sodium cyanoborohydride in aqueous solution with an organic solvent (for example CH2Cl2 or CHCl3) to form compounds of the invention. Alternatively, EMI34.5 can be coupled with EMI35.1 to form EMI35.2 which in turn is coupled with EMI35.3 in the presence of, DCC or DPPA.to form a compound of this invention. The' 'di'azomethyl intermediate can be formed with virtually any carboxylated organic compound. Thus, EMI35.4 can- be a difunctional or trifunctional amino acid, any dicarboxylic acid or any carboxylic acid. Appropriate protecting groups may also be necessary. The thioether compounds of this invention can be produced by several methods of synthesis. In the examples of synthesis which follow for the thioether as well as the ether and secondary amine compounds, proline- will be utilized as prototype amino acid moiety. It is to be understood that this is done for illustration purposes only and. that the other ring structures EMI35.5 can be substituted for proline in these methods unless noted otherwise. According to one preferred'method the compound EMI35.6 is reacted with P2S5 to form the compound EMI35.7 The compound EMI36.1 is reacted with Pro to form EMI36.2 The two products of these reactions are reacted together to yield the compounds EMI36.3 Sapon@@fication removes the ethyl alcohol radical and forms the'corresponding salt.' The free acid can be formed- there .from by acidification. In this method, A-Pro cannot be sub stituted for Pro. In a second preferred method, the compound EMI36.4 is, reacted with isobutylene in the presence of sulfuric acid to form the t-butyl ester of EMI36.5 This compound is then reacted with EMI36.6 form the product: EMI36.7 Next, the t-butyl ester of Pro is coupled to this product using conventional coupling methods, such as the dicyclohexylcarbodiimide (DCC) method. Other useful coupling methods include the mixed anhydride, symmetrical anhydride, acid chloride, active ester, Woodward reagent K, or the like, methods. For a review of the coupling methods, see Methoden der Organischen Chemie (Houben-Weyl), Vol. XV, part IS, page 1 et seq. (1974). The product formed, EMI37.1 ester, is deprotected, i.e., the t-butyl ester groups are removed by conventional means such as treatment with trifluoroacetic acid' (TFA) and anisole to produce the desired product. For a review of other deprotecting methods, see Methoden der Orqanischen Chemie (Houben-Weyl, Vol. XV, part I, page 376 et 'seq. (1974). An alternative method is the reaction of EMI37.2 to form the desired product. This alternative method will not work for # Pro although the original method will. EMI37.3 HBr in the presence of NaNO2 or with KBr in 2.5 N H2S04 in the presence of NaN02 to yield the desired product. The ether compounds of formula I can also be prepared by several other methods. According to one preferred method, the compound R1CH2C1 is reacted with the diethyl ester of malonic acid to yield R1-CH(COOC2H5)2. This product is then reacted with bromine to produce R1-C(Br)(COOC2H5)2. The compound EMI38.1 is couplod to an ester of Pro using conventional coupling means These two products are then reacted to form the compound EMI38.2 ester, The vorious ester groups are removed by conventional means and one carboxyl group is removed by acidf'ication and heat produce the desired product. By substituting EMI38.3 and following this procedure, the thioether compounds can be formed but this will not work with # Pro. In still another method, the compound EMI38.4 is reacted with EMI38.5 t-butyl ester to produce EMI38.6 t-butyl ester The ester is removed, the product reacted with Pro, and the blocking group is removed to yield a final product s according to this invention. The secondary amino compounds of this invention wherein R8 is H and X is NH can also be synthesized by the II following method. the compound EMI39.1 is coupled with thiophenol using the, mixed anhydride method to produce EMI39.2 This product is then ,reacted with EMI39.3 to yield EMI39.4 This compound is reacted with NaSH to form EMI39.5 Compoundsof this- Invention in which R1 and R2 are bridged to form a lactone ring can be prepared using 2-hal.olactones, e.g., &alpha; -Br-&gamma;-valerolactone and &alpha; -Br-&gamma; -butylrolactone. The c-bromo group is reactive with EMI39.6 or those analogs in which an, Nh2- or OH-group is substituted for the HS-group ta form compounds in which X is -S, -0- or -NH- in the general formula for compounds of. this invention. Pro cannot be used in. this procedure unless added as EMI40.1 as a final step, i.e., after the EMI40.2 bond has been formed. The lactone ring can be opened, e.g., kith a base such as Ba(CH)2 to -form the corresponding &gamma; -OH-1-carboxymethul compounds. The hydroxy-group can be converted ta a salt'with sodium, potassium or an organic cation such as that from arginine, or can be converted to an ethyl or methyl ester. Compounds EMI40.3 used in any of the procedures disclosed herein may be selected from known ketocarboxylic acids, including, but not limited to, -pyruvic acid, phenylpyruvic acid. 3-c,ycloh exyl -2-oxop ropionic acid, 6-methyl-2-oxoheptanoic acid, 4-methyl-2-oxopentano'ic acid, 2-oxobutyric acid, 3-methyl-Z-axobutyric acid, 2-exoglutaric acid, 2-oxoadipic- acid, Z-oxo-4-phenylbutyric acid, 4-(3-indolyl)-2-oxobutyric acid, N-acetylaminoethyl-2-oxo-4-phenylbutyrate, dimethylaminoethyl-2-oxo-4-phenylbutyrate, 2-oxo-5-methylhexanate, phenoxypyruvic acid, phenylthiopyruvic acid, 4-p-chlorophenyl-2-oxobutyrate, indole-3-pyruvic acid, 2-oxo-3-p-cyanophenylpropionate, 4-&alpha;-naphthyl-2-oxobutyrate, 4-(3,4-dichlorophenyl)-2-oxo-butyrate), or 2-oxo-4-p-phenoxyphenylbutyric acid. The compounds of this.invention have one or more asymmetric carbons as indicated by the asterisks in the general formula. The compounds accordingly exist in stereoisomeric forms or in racemic mixtures thereof. All of these are within the scope of f the invention. The above described syntheses can utilize a racemate or one of the enantiomers as starting material. When the racemic starting material is used in the synthetic procedure or a racemic mixture results from the. synthesis, the stereoisomers obtained in the product can be separated by conventional chromatographic or fractional crystallization methods. In general the S- isomer with respect to. the carbon bearing R1 constitutes the preferred isomeric form. Also the-. S-isomer of the carbon bearing R5 is preferred. The compounds of this invention form basic salts with various inorganic and organic bases which are also within the scope of the invention. Such salts include ammonium salts alkali metal salts like sodium and potassium salts (which are preferred), and -alkaline, earth metal salts like the calcium megnesium salts, salts with organic basis, e.g., dicyclohexylamine, benzathine, N-methyl-D-glucamine, procaine salts, salts with amino--acids like arginine, lysine, and the like. The non-txic, physiologically acceptat.e salts are preferred. The salts are formed in conventional manner- by reacting the free acid- form of the product with one or more equivalents of the appropriate base providing' the desired cation i.n a solvent or medium in which the salt is in soluble, or in water and removing the water by freeze drying. By neutralizing the salt with an insoluble acid like a cation exchange, resin, in the hydrogen form (e.g., polystyrene suifonic acid resin like Dowex 50) or @i th aqueous acid and extraction with an organic solvent, e.g., ethyl acetate, dichloromethane or the like, the free acid form can be obtained, and, if desired, another salt formed. Additional experimental details are found in the examples which are preferred embodiments and also serve as models for the- preparation of other members of the group. The compounds o? this invention inhibit the conversion of the decapeptide angiotensin I to angiotensin- II and there fore are useful in. reducing or relieving angiotensin related hypertension. The action of the enzyme renin on angiotens- inogen, a pseudoglobulin in blood plasma, produces angiotensin I. An,giotensi I is converted by angiotensin converting enzyme -CACE) to angiotensin II. The latter is an active ,pr'essor substance which has been implicated as the causative agent in various forms of hypertension in various mammalian species, e.g., -rats and dogs. The compounds of this invention (renin) (ACE) intervene in the angiotensin EMI42.1 angiotensin I EMI42.2 angiotensin 11 sequence by inhibiting angiotensin converting enzyme and reducing or eliminating the formation of the presscr substance angiotensin IT. Thus the administration of a compositio containing one or a combination of compounds of formula I including their physiologically acceptable salts, angiotensin-dependent hypertension in the species of mammal suffering therefrom is alleviated. A single dose, or in some cases up to two to f four divided daily doses, provided on a basis of about 0.03 to 20 mg per kilogram per day, is appropriate to reduce blond pressure The substance is preferably administered orally, but parenteral routes such as subcutaneous7 intra-muscular, intravenous or intrape,ritoneal can also be-employed. The compounds of this invention can be utilized to achieve the reduction of blood pressure by formulating them in compositions such as tablets, capsules or elixirs for oral administration. or in. sterile solutions or suspensions for parenteral administration. About 10 to 500 mg of a compound or mixture of compounds of formula I, including the physiologically acceptable salts thereof, is compounded with a physiologically acceptable vehicle, carrier, excipient, binder preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of activ.e substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained. Illustrative of the adjuvants which 'may be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, gum acacia, corn starch or gelatin; an excipi.ent such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like;- a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose, or saccharin; a flavoring agent, such as peppermint, oil of wintergreen or cherry. When the- dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. 'for instance,, tablets may be, coated with shellac,, sugar ar both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye. and a flavoring such as cherry or orange flavor Anti-oxidants may also be added. Suitable antioxidants are c-tocopherol nicotinate, vitamin A, C, E and analogs of vitamin ± known in the art, retinal palmitate and other antioxidaats known in the art as food additives such as the gallates. ¯ Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut 'oil, cottonseed oil, etc., or a synthetic fatty vehicle li.ke ethyl oleate or the like. Buffers, preservatives, and the like can be incorporated as required. The present invention will be further -described by the following examples. All temperature are in degrees Celsius unless otherwise indicated. Molar equivalents of the reactants as usually utilized. Example t Synthesis of 3-N-(1-carboxy-2-(praa-ethylamino carbons phenyl ) ethyl 1-aminopropanoyl-L-5-keto- proline A.. 20 mmoles of 3-N-(benzyloxycarbonyl)-aminopropanoic acid is dissolved in CH2Cl2 at OOC. 20 mmoles of N-hydroxy succinimide is added and then 20 mmoles of DCC is added drop wise to this mixture. The reaction mixture is stirred for 30 minutes at 0 C and then overnight at 4 C. Crystalline dicyclohexylurea is removed by filtration. The solvent from the filtrate is removed under reduced pressure. The result- ing product is dissolved in cold THF and then the solution. is added to a cold solution of 20 mmoles of L-glutamic acid and 40 mmoles of NaHCO3 in THF/water.- The reaction mixture is stirred overnight at room temperature and then the THF is removed with a rotary evaporator. The glutamyl residue is cyclized to give the L-5-keto-proline residue according to Gibian H. and Klieger E*, Justus Liebiq's Ann.Chemie 640, -145 (1961). 'The benzyloxycarbonyl group is removed by treat ment with hydrogenolysis. 8. A solution of 10 mmoles af this product and 50 mmoles of 2-keto-3-(4-ethylaminocarbonyl-phenyl) propionic tert butyl ester in ethanol is stirred with powdered molecular sieves at room temperature for 1/2 hour. A solution of 40 mmoles of sodium cyanobo.rohydride in ethanol is slowly added over the course of six hours. The reaction mixture is filtered. The "t-butyl ester is removed by treatment with trifluoro acetic acid in anisole. The named product is obtained after removal of the solvent with a rotary evaporator. Example 2 Synthesis of N-[L-1- carboxyl (2-proplyaminocarbonyl-, ethyl)-l-carboxyethyll-D,L-Ala-t-Pro ' -A. 200 mmoles of propylamine and 150 mmoles of the methyl ester of N -80c aspartic acid are dissolved in 600 ml of cold dimethyl formamide and 125 mmoles of DPPA. A volume of 25 ml of triethylamine in DMF is added drop-wise, hold ing the temperature at about -100C for two hours. The reaction is stored overnight at room temperature and rotary evaporated to remove DHF. The product is 3-(propylamino carbonyl )-2-aminopropanoic acid ethyl ester. The Boc group is removed with TFA. B. A solution of 60 mmoles of pyruvic acid plus 60 mmoles of L-proline ethyl ester in redistilled chloroform is cooled to -50 C in an acetone-dry ice bath. To this solution is added 60 mmoles of a precooled solution of dicyclohexyl carbodiimide (DCC) in chloroform and the mixture is stirred at -5 C for 1 hour. The reaction mixture is slowly warmed to room temperature and stirred for an additional 2 hours and then stirred at 40C overnight. The mixture is filtered to remove dicyclohexylurea, then cooled in an ice bath. The organic phase is washed with cold water, cold 1N NaHCO3 and finally with cold saturated NaCl. The organic phase is dried over anhydrous MgSO, and filtered. The solvent is removed with a rotary evaporator yielding N-p,yruvoyl-L- proline ethyl esters C. 40 mmoles of the product of Step A is reacted with 200 mmoles of the product of Step B in ethanol with stirring in tha presence of molecular sieves at room temperature. A solution of 40 mmoles of sodiu.m cyanoborohydride in ethanol is then slowly added over the course of 6 hours. The reaction mixture is filtered and the solvent removed by a rotary evaporator. The product is purified by partition chroma tography (Sephadex G-25), developed with butanol/acetic acid/ H2Ö (4:1:5). The ethyl esters are removed by saponification to yield the named product. Example 3-16 By substituting any one. of the reactants for propyl amine of Example 2, aad following the procedures of Example 2, compounds are obtained with R1 groups as shown in the Table. TABLE EMI46.1 <tb> <SEP> Example <SEP> Reactant <tb> <SEP> 3 <SEP> ' <SEP> butyaine <SEP> -CH, <SEP> LB-CH-2-CH,-CH2-CH3 <tb> <SEP> '.4 <SEP> cyc1opentylaine <tb> <SEP> 5' <SEP> 1a-pr'oiina <SEP> -CEPCOOET <tb> <SEP> 6 <SEP> r <SEP> adenina <SEP> -CR <SEP> g <tb> <SEP> '2 <tb> <SEP> 7 <SEP> indolina <SEP> <tb> <SEP> - <SEP> 0, <SEP> (CR) <tb> <SEP> 8 <SEP> 2-azacyclooctanona <SEP> -CR <SEP> -C- <SEP> ) <tb> <SEP> 2 <tb> <SEP> 0 <tb> <SEP> 9 <SEP> anilifla <SEP> -e, <SEP> ' <tb> <SEP> 9' <tb> <SEP> 1(3 <SEP> 2-a=ino-5-br=o' <tb> <SEP> pyrfdre <SEP> 2 <SEP> ,11,,,r <tb> <SEP> Cl <tb> <SEP> 11-, <SEP> 2-2mno-5- <SEP> ciiloro- <SEP> -fJ?,-C <tb> <SEP> 0 <SEP> "3 <SEP> <tb> .12 <SEP> 'N'-ainino <SEP> ,pipendina <SEP> -CR2 <tb> <SEP> 0 <tb> <SEP> isobutyrtide <tb> <SEP> -2C'NI- <SEP> CMZ <SEP> CH <SEP> (CH3 <SEP> 2 <tb> EMI47.1 <tb> Example. <SEP> . <SEP> Reactant <SEP> > , <tb> <SEP> C} <tb> <SEP> 14 <SEP> malelvde <SEP> -CH <tb> <SEP> -CH, <tb> <SEP> 2 <tb> <SEP> to <tb> <SEP> 0 <tb> <SEP> 15 <SEP> diacetan-ide <SEP> -- <SEP> CH,2-C-'H1-CH2-CH(CH)2 <tb> <SEP> . <SEP> , <SEP> . <tb> <SEP> 76 <SEP> diallyl2m.ine <SEP> -CH2-C-N- <SEP> CCH2CR=CH2)2 <tb> Example 17 Synthesis of N-[(Z-butylaminocarbonyl-1-carboxy-ethyl thio)-2-D-methyloropanoyl]-L-proline A. 0.25 mmoles of 3-mercapto-2-D-methylpropanoly-L-proline ethyl ester, G.28 mmoles of 2-b,romosuccinic acid monoethylester (esterified at CI) and .16 mmole of K2C03 were added to 0.6 ml of a 50:50 mixture of absolute ethanol and water. The suspension was stirred overnight at room temperature. 0.25 mmoles of K2CO3 in 0.1-5 ml of water was then added and the reaction mixture was stirred for an additional 24 hours, This mixture was then, acidified to pH 2.0 with HC1 and the product was extracted with ethyl acetate. The organic phase was- washed with saturated NaCl. The product appeared to be pure and behaved as a- single substance on thin layer chromatography in two separate solvent systems. The ethyl acetate phase was dried over anhydrous MgS04 and the solvent - was removed with a rotary evaporator to yield the N-[3-(1carboxyethylthyio)-2-D-methylpropancyl]--L-proline ethyl ester as a colorless oil. B. A quantity of 0,15 mmoles of butylamine and 0.15 mmoles of the product of Synthesis A are dissolved in 0.6 ml of cold DMF and 0.05 ml DPPA. A volume of 0.025 ml of triethylamine in DMF is added, holding the temperature at about -100C for 2 hours. - The reaction. is stored overnight at room temperature, rotary evaporated to remove DMF, then the residue is partitioned between water and ethyl acetate. The organic layer is chromatographed to obtain the named product. Example 18 Synthesis of N-[1-carbethoxy-3-(methylaminocarbonyl) propyl]-D,L-Ala-L-Pro A solution of 50 mmoles of 4-methylaminocarbonyl-2-oxo- butyric acid ethyl easter and 10 mmoles of L-Ala-L-Pro butyl ester in ethanol is stirred with powdered molecular sieves at room temperature for 30 minutes. A solution of sodium cyanoborohydride, 10 mmoles, in ethanol is added- slowly over the next 5 hours; The mixture is filtered, and the, solvent of the filtrate is removed with a rotary evaporator and deprotected by treatment with TFA. The product,' an diethyl ester of N-[1-carbethoxy-3-methylaminocarbonyl-butyl]-alanylproline, is obtained after partition column chromatography [butannl/acetic acid/H2O (4:1:5 by vol.)] Example 19 Synthesis of N-[(1-carboxy-3-carboanilide)propyl]-#-propyl- amido-L-glutamyl-L-pro A. 175 mmoles of propylamine and 150 mmoles of the methyl ester of-Bo.c-glu-tamic acid are dissolved in 600 ml of DMF and 125 mmoles of DPPA. A. volume of 25 ml of triethylamine- is added drop-wise, holding the-temperature at about -10 C for 2.5 hours. The reaction is stored overnight at room temperature, rotary evaporated to ramove DMF, thenthe product, #-propyl- amido-L-Boc-glutamic acid ethyl ester, is saponified and then purified by chromatography on silica gel. B. 100 mmoles of the product is then reacted with 100 mmoles of L-proline-t-butyl ester in. redi stilled di chloromethane, precooled to -5 C. To this solution is added 100 mmoles of a precooled solution of dicyclohexylcarbodiimide in dichloro methane and the mixture is stirred in an ice bath for 2 hours. The reaction mixture is slowly warmed to room temperature and their, stirred at 40C overnight. The mixture is filtered to remove dicyclohexylurea, then cooled in an ice bath. The organic phase is washed with cold 1 N HCl cold iN NaHCO3 and finally with cold saturated NaCl. The organic phase is dried over an aahydrous MgSO4 and filtered. The solvent is removed with a rotary evaporation yielding #-propylamido-Boc- L-glutamyl-L-pro-t-butyl ester. The t-butyl ester and Boc group is removed with TFA. C. 50 mmoles of the product of Synthesis A of Example 9 and 250 mmoles of the product of Synthesis B of Examp'le 19 are condensed in the presence of 50 mmoles sodium cyano- . borohydride by the method daascribed in Synthes'is 8 of Example 1 plus 300 mmoles of NaHCO3 in water to yield an esterified compound. Examples 20-26 By substituting propylamine and the methyl ester of Boc-glutamic acid in Synthesis A of Example 19 with each pair of reactant compounds in the Table, then reacting the product with L-proline-tert-butyl ester according to Synthesis a of Example 19, and finally reacting the resulting compound with 5-carboanilide-2-ketobutyric acid ethyl ester according to Synthesis 8;of Example: a series of analogs of the product of Example 19 are obtained, which products have R3 and R7 groups given in the Table. TABLE EMI50.1 <tb> Example <SEP> Pair <SEP> of <SEP> Reactants <SEP> R7 <SEP> 23 <tb> <SEP> P, <tb> <SEP> 20 <SEP> methyl2mine, <SEP> R <SEP> -(CH2)2-C-N-CH3 <tb> <SEP> methyl <SEP> ester <SEP> of <tb> <SEP> Boc-glutanic <SEP> ac,id <tb> <SEP> o <SEP> F <tb> <SEP> 21 <SEP> -mathylamine, <SEP> -C-N-CH3 <tb> <SEP> l-ethyl <SEP> ester <SEP> of <tb> <SEP> Boc-2-amino-mnlonic <SEP> acid <tb> <SEP> gu <tb> <SEP> 22 <SEP> methylanme, <SEP> K <SEP> -CH <tb> <SEP> . <SEP> l-ethyl <SEP> ester <SEP> of <SEP> 2 <SEP> 3 <tb> <SEP> Boc-aspar"tic <SEP> acid <tb> <SEP> 23 <SEP> anili?1e <SEP> of <SEP> E <tb> <SEP> methyl <SEP> ester <tb> <SEP> 3oc-2-amno <SEP> adipic <SEP> acid <tb> <SEP> 24 <SEP> aniline <tb> <SEP> I-vthy7 <SEP> ester <SEP> of <SEP> p <tb> <SEP> occarboxyphenyIglycine <SEP> o <tb> <SEP> 25 <SEP> propyS=ne <SEP> K <SEP> ,-cH <SEP> 2 <tb> <SEP> l-ethy' <SEP> ester <SEP> of <SEP> p- <SEP> p- <tb> <SEP> Boc < =ozo-?hny <SEP> ' <SEP> aX <SEP> an:;:P <SEP> CHZCH3 <tb> <SEP> L <tb> <SEP> 26 <SEP> Lins <SEP> -CH3I <SEP> Hz <tb> <SEP> l-e¯aya <SEP> ester <SEP> of <SEP> Z <SEP> <tb> <SEP> 3oc-=iathyl <SEP> aspartic <SEP> acid <tb> Example 27 Preparation of N-[L-1-benzyloxycarbonyl-3-(carbo-4iodoenrlied)propyl]-Alanyl-L-Proline A. Synthesis of L-glutamic acid-&alpha;-benzyl ester-ö-4 iodoanilide. A solution of 4 mmoles of N&alpha;-Boc-L-Glu-#-2-ND2-phenyl ester-&alpha;-benzyl ester in. 3 ml of CH2Cl2 was added to a solution. of 4.1 mmoies of 4-iodo-aniline in 3 ml of CH2Cl2 and the resulting solution was stirred at room temperature overnight. (The reaction was judged to be complete by thin layer chromatography). An oily residue was obtained after work-up. The product was dissolved in 4 ml of anhydrous trifluoroacetic acid. After 45 minutes at room temperature, the solvent was removed by rotary evaporation at 40 C. White crystals were formed after the addition of 4.5 mi M HCl in ethyl acetate. The mixture was left at 0 C for one hour and was filtered. The precipitate was washed with cold ethyl acetate in ether and then dried over P205 and NaOH in a vacuum desiccator. Yield 0.79 g; d.p. 119- 1200C; second crop yield I.1,t g; d.p. 119-120.5 C. The material was recrystallized from CHCl3/isopropyl ether; d.p. 119.5 - 120.5 C. Elemental analysis for C18H10N2ICIO3: Calculated C 45.54; H 4.24; N 5.90; I 26.73 Cl 7.47; 0 10.11.' Pound: C 45.55; H 4.19; N 5.92; I 26.53; Cl 7.34. B. Synthesis of N-L-]-benzyloxycarbonyl-3-(carbo-4-iodoanilide) propyl]-Ala-L-Pro-t-butyl ester A. solution of the-product of A (1 mmole in 7 ml of ethanol) . is added. with stirring. to, J mmole of NaHCO3 in 0.2 ml of H2 0.. To the resulting solution was added 5 mmoles of N-pyruvoyl L-proline-t-butyl ester in,2 ml of ethanol plus 1.6 9 of molecular sieves. The mixture was stirred for 30 minutes at room temperature. Sodium cyanoborohydride, 65 mg in 1.5 ml of ethanol, was added, drop-wise, over a period of 4 hours. The reaction mixture was. left at room. temperature overnight. The.mixture was filtered, the filtrate saved, and the precipitate was washed several times with ethanol. Solvent of the combined filtrates was removed by rotary evaporation at'300C to yield a yellow oil. The crude product was purified on Sephadex LH-20 (2.22 x 99 cm column) developed with THF/iso- propanol (3:7 by vol.); 250 drops (5.8 ml/fraction). Fractions 33-35 contained the desired product. C. The named compound of this Example was obtained by dissolving the desired product of B in 2 ml of anhydrous TFA. The solution, was allowed to stand at room temperature for 30 minutes and then. the trifluoroacetic acid was removed by rotary evaporation. at 30ïC. The residue was dissolved in a small amount of ethanol, and the solution was applied to a column (1.2 x 43 cm) of AG1-X2 (OH. form) in H20. The column was developed with H2(3, 62 ml, and then a linear gradient was developed between H2O and O.5M ammonium acetate (2 liters total). The column was washed with O.5M ammonium acetate (1 liter), 1.OM ammonium acetate (200 ml) and then with 1.OM ammonium acetate/ethanol t1:2 by vol). The desired product was aluted with the last-named solution. Solvent volume was reduced by rotary evaporation and then ammonium acetate was removed by lyophilization and sublimation. Example 28, Preparatiom. of N-[L-1-carboxy-3-(carbo-anilide) propyl] Alanyl-L-Proline The product of Example 2T, 4O mg, in 3 ml of methanol, was reacted with 20 mg of 10 palladium on carbon and H2 at room atmosphere for a hours at room temperature. The precipi tate was removed by filtration, and the solvent of the filtrate was removed by rotary evaporation The- desired product was obtained by chromatography on Sephadex G-10 (1-2 x 96 cm column developed and eluted with 2% pyridine in water (yield 12.1 mg). Example 29 Preparation of N-[L-1-carboxy-3-(carbo-4-iodo-anilide) propyl Alanyl-L-Proline The product of Example 27, 60 mg, was treated with 3 ml of anhydrous HF i@@ the presence of anisole for 1 hr. The desired product wa.s obtained by the chromatographic system of Example 28. Yield 22.15 mg. Example 30 Preparatiom of N-[L-1-carboxy-2-(carbooyrrolide) ethyl] Alanyl-L-Proline A. Synthesis of L-aspartic acid-ss-pyrrolide-&alpha;-ethyl ester. N&alpha;-Cbo-L-aspartic acid-a-ethyl ester, 8 ,mmoles, in 5 ml of CH2Cl2 was cooled to -5 C. A,cold solution of DCC, 8 mmoles in-3 ml of CH2Cl2 was added with stirring. To this soultion: was added 0.67 ml af pyrrolidine. Stirring was continued at -5 C for 30 minutes and at 40C overnight The mixture was filtered, and the precipitate was washed with ethyl acetate. The combined filtrate was washed until neutral. The organic phase was dried over MgSO4 and then. filtered. The solvent of the filtrate was removed under vacuum to yield 1.85 of a yellow oil. The oil, 1.5 g, was dissolved in 20 ml of methanol and the Cbo-protecting group was removed, by hydrogenolysis (150 mg of 10% palladium on carbon with H2 at 10 pounds per square inch for 90 minutes). The mixture was filtered, and solvent was removed under vacuum- to yield white crystals. Recrystallization was effected from, methanol/isopropyl ether. The desired product remained in the mother liquid and was converted to its HCl salt by adding HCl in ethyl acetate. Solvent was removed and the residue was dried over P2O5 and KOH in a vacuum desiccator to yield a hydroscopic foam.- Crystals, 0.47 g, were obtained from CHCl3/ethyl acetate. H. Alkylation of. pyruvoyl-L-proline with the product of A (Example 30) Molecular sieves (1.312 g) were added with stirring to a mixture of Q.206 g. of HCl.L-Asp-@-pyrrolide-&alpha;-ethyl ester, 0.073 g of NaHCO3 and 0.986 g of N-pyruvoyl-L-proline-t butyl ester in 0.1 ml of H2O and 2.0 ml of ethanol at room temperature- The-. mixture was stirred for 30 minutes and then 0.054 g of sodium cyanoborohydride in 1.0 ml of ethanol -was added drop-wise over a period of 4 hours. Stirring was cootinued for another 18 hours. The mixture was filtered and the precipitate was washed with ethanol. Solvent of the combined filtrates was removed by rotary evaporation to yield a yellow cil. The material was chromatographed on LH-20 (2.2 x 9,9 cm) dev.eloped with THF/isopropanol (3:7 by vol). The residue obtained by rotary evaporation was dissolved in. I-.Z ml of TFA After 45 minutes at room temp- erature, TFA,was removed and the material was purified by chromatography on AGl-X2 (1.2 x 38 cm developed first with H2O and then with a linear gradient between H2O and 0.5M ammonium acetate. Apparently pure product, 31.5 mg, was obtained by chromatography on Sephadex G-1,0 (1.2 c 97 cm column) developed with 2% pyridine. The ethoxy group was removed by saponification. Example 31 In: vitro assays of the potency of selscted compounds as inhibitors of angiotensin converting enzyme. Compounds of this invention were- assayed through the following protocol: 25 microliters of buffer (0.05M Hepes buffer, pH 3.0, plus 0.1 M NaCl and 0.75 M Na2SO4) or 25 microliters. of an inhibitor in buffer was added to the bottom-of a 7 ml liquid scintillation viaL. To this was added 100 microliters of buffered substrate [S], [3H] benzoyl-Gly-His Leu, 80 oM (25 Ci/mmole). The reaction was started by adding 100 microliters--of partially-purifie'd human plasma angiotensin: converting enzyme, or 100 microliters o-f buffer alone. The cancentration: of anzyme [E] used was that required to hydrolyze 8--2 of substrate when incubated at 370C for 1S.minutes, The scintillation vials and their contents were incubated at 370C for 15 minutes, and the reactions were- stopped by adding 200 microliters of 0.5 M CHl to each vial. The radioactive reaction product, [3H] benzoyl-Gly (hippuric acid), was separated from unhydrolyzed substrate by adding and mixing (by inversion) 3 ml of Ventrex Cocktail No. 1 (Ventrex Laboratories, Inc., Portland, Maine), a fluid disclosed in copending U.S. patent application No. 184, 653, filed September 6, 1980. Extractable 3H was. quantified by liquid scintillation counting. Substrate, in c-p-m-, was quantified by sciatillation counting of a vial cootaining 100@l: of buffered substrate in 5 ml of RIAfluor (New England Nuclear). The reaction mixture containing all constituents except for inhibitor was termed the control. (C). The reaction mixture lacking enzyme and inhibitor was called the blank (B). Reaction mixtures containing inhibitor (varied over the range of 304 - 10-12M) were called the teat (T) reactions. Under the conditions of this assay, the reaction: obeys first order enzyme kinetics, thus the con centration of inhibitor required to inhibit the rate of hydrolysis by half (I50) approximate the Ki value. The results were estimated by use of the formula: [E] = C - B x 100 x 1 [5] 15 min where C = control c.p.m. ; B = blank c.p.m.; [S] = substrate c.p.m. The factor 100 converts fractional substrate utilization into percentage utilization, and 1/15 minute connects to percentage substrate utilization/minute. Thus, È) is enzyme activity in percentage substrate utilization/ minute. By substituting T for C, hydrolysis rates are computed for the test reaction mixtures. By comparing a given test rate against the control rate, the degree of inhibition can, be computed Compound Product of Example No. 50 28 5.2 X 10 9-M 29 2-.3 X 10-10M 30 1.4 X 10 7,M Example 32 Intravenous effactiveness of N-[L-1-carboxy-3-(carbo-4iodoanilide) propyl]-D,L-Ala-L-Pro. Rats- (190 - 29a g body weight were fasted overnight and then anesthetized with intraperitoneal pentobarbital, 50-60 mg/kg. Tracheostomy was performed and the animals were ventilated mechanically. A canoula was inserted into a femoral vein for injection of angiotensin I, and a second cannula was inserted into a common carotid artery for direct measurement of arterial blood pressure. heparin, 1,000 units, was iaje"cted via the- femoral vein td prevent coagulation. Blood pressure was measured with a pressure transducer connected to a polygraph. The rats were injected with 400 mg/kg of angiotensin- I in 20 l: of.0.9 g @ NaCI, an amount of angiotensin. I sufficient to raise mean arterial blood pressure by approximately 48 mm Hg. After the responsiveness of a given rat to angiotensin I was "esàblished, the named compound at 0.5 micromole/kg (drug dissolved in 15 microliters of 0.9 NaCl) was given intravenously. At timed intervals, the effects of 400 ng/kg of angiotensin I on. mean arterial blood pressure were tested. Results are shown below: Time after IV Blood Pressure Reponse to Administration 400 ng/kg of Angiotensin I (minutes) (% of Control) -5 100% (48 mm hG.) +1 33% 5 42% 10 46% 15 52% 20 60% 25 67% 30 71% 35 71% 50 83% 60 92Z 70 100% 80 min 104% Example .33 - "Intravenous Effectiveness of N-[L-1-carboxy-3 (carboanilide) propyl]-D,L-Ala-L-Pro" Experiments *were carried out using rats according to example 32 The results are shown below: TABLE EMI56.1 <tb> <SEP> E.Y21npl <SEP> eto <SEP> carboxylic <SEP> acid <SEP> R3 <tb> 34 <SEP> ' <SEP> pyruvic <SEP> acid- <SEP> C3 <tb> <SEP> 35 <SEP> phenylpyrusic <SEP> acid <tb> <SEP> 36 <SEP> . <SEP> 3-cycr <SEP> oSexs <SEP> 2-oxo- <SEP> ¯ <tb> <SEP> propionic <SEP> 2cid <SEP> OUCU2- <tb> <SEP> 37 <SEP> 6-rneyi-2-oxo- <SEP> heptanoi <tb> <SEP> acid <SEP> 6-net'iyl-2-o-hetanoic <SEP> -,C(CR2)3 <tb> <SEP> ca3 <tb> S-benzyl-cysteine-t-butyl ester ester S-benzyl-homocysteine-t-butyl ester S-methyl-homocysteine ethyl ester S-ethyl-homocysteine-ethyl ester S-t-butyl-homocysteine-t-butyl ester 0-t-butyl-homoserin'e-t-butyl ester O-benzyl-homoserine-benzyl ester O-methyl-homoserine-methyl ester 0-ethyl-homoseri'ne-ethyl ester O-phenyl-homoserine-ethyl ester O-phenyl-serine-ethyl ester S-phenyl-cysteine-ethyl ester B-fluoro-phenylalanine ethyl ester B-CH-phenylalanine-methyl ester B-Br-alanine-methyl ester B-thienylserine-t-butyl ester 3,5-dimethyl-tyrosine-t-butyl ester B -hydroxynorv.aline ethyl ester W - benzyloxynorvaline-ethyl ester Nê-Boc-hydroxylysine t-butyl ester 3-Boc-amino-tyrosine-ethyl ester a -methyl-pheny7alanime-ethyi ester t-lescine methyl ester 8-methyl gultamine methyl ester Nê-hydroxylysine t-butyl ester B-N-methyl-lysine-methyl ester 5,5-'-dihydroxy-leucine-ethyl ester a -fluoro-asparagine-ethyl ester B-methyl-asparagine-ethyl ester & N-methyl-lysine-methyl ester B-methyl-B-benzylamido-aspartic acid-B-ethyl ester 2-ethoxy-5-NO2-phenylalanine ethyl ester B-ethoxy-phenylalanine-t-butyl ester a-methyl-serine-t-butyl ester O-benzyl-&alpha;-methyl-serine-t-butyl ester O-benzyl-&alpha; ;-methyl-serine-t-butyl ester C Any of the a-a,mides or &alpha;-imides of D-cysteine-&alpha;-benzyl ester of Synthesis B of this example are then used to alkyl ate any of the &alpha; -keto carboxylic acids i in Table II, immediately below. A quantity of 5 mmoles of any of the- &alpha; amides or &alpha;-imides o.f D-cysteine--benzyl ester of Synthesis B is dissolved in 1 ml of ethanol and added with stirring to 5 mmoles of NaHCO3in 0.2 ml H2O. To the resulting solution is added 25 mmoles of any c-keto carboxylic acid of Table II in Z ml of ethanol plus 1.6 g of molecular sieves. The mixture is stirred for 1 hour at room temperature, then 5 males of- sodium cyanoborohydride, in 1.5 ml of ethanol, is added drop-wise over a period of-4 hrs. The reaction, mixture is left et romm temperature overnight. After filtration, solvent is removed from the filtrate, and. the product purified by column chromatography. The products. are compounds of the formula: EMI58.1 TABLE II: &alpha; KETO CARBOXYLIC ACIDS pyruvic acid phenylpyruvic acid 3-cyclohexyl-2-oxopropionic acid (cyclohexylpyruvic acid) 6-methyl-2-oxoheptanoic acid 4-methyl-2-oxopentaoic acid 2-oxobutyric acid 3-methyl-2-oxobutyric acid 2-oxoglutanic acid 2-oxoadipic acid 2-oxo-4-phenylbutyric acid (and its t-butyl ester) 4-(3-indolyl)-2-oxobutyric acid N-acetylaminoethyl-2-oxo-4-phenylbutyrate dimethylaminoethyl-2-oxo-4-phenylbutyrate EMI59.1 <tb> <SEP> E.^camp1 <SEP> e <SEP> -keto <SEP> carboxylic <SEP> acid <tb> <SEP> 38 <SEP> 4-mot'n.yl-2-oxo-nen.82noic <SEP> CE3 <tb> <SEP> acid <SEP> C'2- <SEP> <tb> <SEP> 3 <tb> <SEP> 39 <SEP> 2-oxo-butyric <SEP> acid <SEP> CE <SEP> CII <tb> <SEP> 32 <tb> <SEP> 40 <SEP> 3-;aethy7-2-cxo- <SEP> 3\ <tb> <SEP> btityric <SEP> acid <SEP> CR <tb> <SEP> CR3 <tb> <SEP> ' <SEP> . <SEP> CH3 <tb> <SEP> 41 <SEP> 2-oxo-glu.a <SEP> ic <SEP> acid- <SEP> EtOOC-CH2-CH2-' <tb> <SEP> L <SEP> L <tb> <SEP> 42 <SEP> 2-oxo-adipic <SEP> acid <SEP> X <SEP> t0OC-CR2( <SEP> H2CR2 <tb> <SEP> 43 <SEP> ' <SEP> '2-'OXo-4p'iLefly1 <SEP> butyric <SEP> 2-CHz <tb> <SEP> acid <tb> P,, <SEP> - <SEP> <tb> <SEP> 44 <SEP> 4- <SEP> (3-'ndolyl <SEP> -2-oxo <tb> <SEP> buty-'ic <SEP> 'acid <SEP> ' <SEP> OCg2-CH2 <tb> <SEP> 2 <SEP> - <SEP> 2 <tb> <SEP> 45 <SEP> phenoxypyrussric <SEP> acid <SEP> - <SEP> O-CH2 <tb> <SEP> 46 <SEP> 3henylthio'pyruvic <SEP> acid <SEP> S-CH2 <tb> <SEP> &num; <SEP> . <SEP> . <SEP> . <SEP> ¯ <tb> <SEP> 4i <SEP> 4-p <SEP> -chlor'ophenyl-'2-oxo- <SEP> /= <tb> <SEP> butyric <SEP> acid <SEP> ( <SEP> \/2 <SEP> C'1 <SEP> 2 <tb> Time After IV Blood Pressure Reponse to Administration 400 ng/kg of Angiotensin I (minutes) % of Control) -5 100% (48 mm Hg.) +1 42% 5 37% 10 37% 15 40% 20 40% 25 40% 30 35% 40 35% 50 46% 60 46% 70 48% 80 52% 90 54% 102% min. 62.5% Examoles 34-52 By substituting pyruvic acid in Synthesis B of Example 2 with any of the &alpha;-keto carboxylic acids (appropriately protected) in the Table, and reacting the product with 3 Cpropyl ämino-carbonyl)-2-amino-propanoci acid ethyl ester as in Synthesis A of Example 2, products with R3; groups in the Table are formed. Table EMI60.1 <tb> 1 <SEP> '-.- <SEP> -, <tb> ±x mple <SEP> =-keto <SEP> carboxylic <SEP> acid <SEP> R3 <tb> <SEP> : <SEP> 3-4 <SEP> pyrusric <SEP> acid <tb> <SEP> 3 <SEP> 5 <SEP> phenylpyruric <SEP> a < : <SEP> a <SEP> OCE2 <tb> <SEP> 36 <SEP> 3-cyclohexyl-2-oxo- <SEP> 0- <SEP> <tb> <SEP> prop <SEP> ionic <SEP> acid <SEP> 2 <tb> EMI61.1 <tb> Example <SEP> keto <SEP> carboxylic <SEP> acid <tb> <SEP> 37 <SEP> 6-methyl-2-oxo- <SEP> 3CB(CH,)3' <tb> <SEP> CR3 <tb> <SEP> 3 & 4-methyl <SEP> -2-oxo-pantanoi <SEP> c <SEP> CH3 <tb> <SEP> 'acid <tb> <SEP> CH3 <tb> <SEP> 3 <tb> <SEP> 3 <SEP> ..2-oxo-butyric <SEP> acid <SEP> CR3CR2, <tb> <SEP> CH3 <tb> <SEP> 40 <SEP> methyl-2-oxo <tb> <SEP> ' <SEP> .bu'tyric <SEP> acid <tb> <SEP> CR3. <tb> <SEP> Z <SEP> s <tb> <SEP> 4t <SEP> .,' <SEP> :!-ouco-gluta2ric <SEP> acid <SEP> EtOOC-CH, <SEP> -CH2 <tb> <SEP> L <tb> <SEP> 42: <SEP> ' <SEP> 2-oxo-adipic <SEP> acid <SEP> EtooC-CX2Cz2CX2 <tb> <SEP> L <tb> <SEP> cl'cxo-'4;-phenyl <SEP> but;rric <SEP> SOCH2 <SEP> 2 <tb> <SEP> 44 <SEP> 4-(3-i,=doly'l,)'-Z-cxo-, <tb> <SEP> EUm1C <SEP> acid <SEP> sCFI <SEP> -CH2 <tb> <SEP> 4,5 <SEP> p'henrxyyruvic <SEP> acid <SEP> O-CH2 <tb> 46 <SEP> phenylthio <SEP> pyruvic <SEP> acid <SEP> O-S-CH2 <tb> 47 <SEP> 4-fl <SEP> - <SEP> chorophenyl- <SEP> 2-oxo <tb> <SEP> butyric <SEP> acid <SEP> Cl/-CH2-C}I <SEP> <tb> <SEP> 2, <tb> EMI62.1 <tb> <SEP> E:xample <SEP> a-keto <SEP> carboxylic <SEP> acid <SEP> R, <tb> <SEP> : <SEP> . <SEP> . <SEP> . <tb> . <SEP> . <tb> <SEP> 48 <SEP> indole-3-pq,z-uut <SEP> acid <tb> <SEP> 49 <SEP> 2-.oXo-3-p-cyaflo?''ieflYI <tb> <SEP> propioflic <SEP> acid <SEP> NC <tb> <SEP> 50 <SEP> 4-2lph2-naD <SEP> yt-2 <tb> <SEP> oxo-bu°Snc <SEP> 2cs <SEP> CE2 <SEP> Ch <tb> <SEP> u <SEP> /r <tb> <SEP> 51 <SEP> 4-(3,4-dicMo.ophenyl)- <SEP> Ci <tb> <SEP> 2-oxo-buXyX <SEP> c <SEP> acid <SEP> --C2- <SEP> - <SEP> CE2 <SEP> <SEP> 2-oxo-butyle <SEP> 2cld <SEP> C, <SEP> -. <SEP> Cfi2 <tb> <SEP> Ci <tb> <SEP> . <SEP> <tb> <SEP> 52 <SEP> 2oxo4pp.?.0x <tb> <SEP> - <SEP> phenyL <SEP> butyrxc <SEP> acid <SEP> CH2' <SEP> CliZ Example 53 Synthesis of 2-keto-butyryl-L- < Glu. L-pyroglutamic acid (35 mmoles) is suspended in a mixture of 35 ml of propyl.ne oxide and 210 ml of dry acetonitrile at romm temperature. Bis-trimethylsilyl tri-fluoro acetamide (-77 mmole) is added and the stopped reaction is stirred at room temperature for 15 minutes. 2-keto-butyric acid mixed carbonic anhydride (prepared by 2-keto-butyric acid, 36.8 mmole, triethylamine in iso- butyl chloro formate) is added and the reaction is stirred at room temperature overnight, Acetonitrile is then removed in vacuoand the resulting residue is dissolved in ethyl acetate. The organic phase is washed with H20, then saturated NaCI, dried over anhydrous Na2SO4 and filtered, and the solvent removed with a rotary evaporator. 8. Synthesis of: N-2-(1-anilinocarbonyl-2-benzylthioethyl)- butyryl-L-pyroglutamic acid. Na-Boc-S-bezyl-D-cysteine 100 mmoles is reacted with an, equivalent of aniline in. the presence of a slight excess of one equivalent of DCC (105 mmoles) by the method described in Synthesis B of Example 2. The Boc group is then removed with anhydrous TFA. 50 mmoles of the product is then coupled to 10 mmoles z-keto-butyryl-L- < Glu (Synthesis A) with 10 mmoles of cyanoborohydride according to Example 18 to yield the named compound. Example 54 Synthesis of N-2-(1-anilinocarbonyl-2-benzylthioethyl)propanoyl-L-pro. By substituting pyruvoyl-L-pro (Example 2) for 2-ketobutyryl-L- < Glu (Synthesis A of Example 53), and following the procedure of Synthesis B of Example 53, the named product is obtained. Example 55 Synthesis of N-[1-(N-acetylaminoethoxy carobnyl)-3 (carboanilide) propyl]-D,L-Ala-L-Pro-ethyl ester. A solution of 50 mmoles, of 2-Boc-amino-4-c,arboxy butyric acid N-acetyl aminoethyl ester is coupled to 50 mmoles of aniline in the presence of an equivalent of DCC according to Synthesis s of Example 2. The Boc group is then removed with anhydrous TFA., 40 mmoles of the product is then reacted with ZOO mmoles of N-pyruvoyl-L-Pro-ethyl ester, then 4-2 mmoles of sodium cyanoborohydride in ethanol is slowly added over the course o-f 6 hours. The reaction mixture is filtered and the solvent removed by a rotary evaporator, yielding the named compound. Example 56 Synthesis of N-[L-1-(dimethylaminoethoxycarbonyl)-3 (carbonylmethylamino)propyl]-D.L.-Ala-L-Pro ethylester. By substituting 2-amino-4-carboxy butyric acid dimethyl aminoethyl ester for 2-amino-4-carboxy butyric acid of Example- 55, he named compound is synthesized. Example 57 A By substituting L-proline-tert butyl ester for L-proline ethyl ester in- Synthesis B of Example 2, the procedure of Synthesis B of Example 2 yields the pyruvoyl-L-Pro-tert butyl ester The tert butyl ester can be- removed by treatment with TFA in anisole. B- A solution of 10 mmoles of N&alpha;-Boc-S-benzyl-D-cysteine-&alpha;- NO@-phenyl ester it 3 ml of CH2Cl2 is added to a solution of 10.5 mmoles of any of the amine or imine compounds (listed in Table I, below) in 3 ml of CH?C12, and the resulting solution is stirred overnight at room temperature. The reaction is judged to be complete by thin layer chroma tography. The resulting mixture is dissolved in 4 ml of TFA to remov.e the Boc blocking group, rotary evaporated and crystallized, to yield 2-amides and &alpha;-imides of D-cysteine a-benzyl ester as the product. TABLE I: AMINE AND IMINE COMPOUNDS aniline benzylamine methylamine ethyl amine 1-aminopropane 2-aminopropane 2-aminobutane 1-amino-2-butanone t-butylamine cyclopentylamide cyclohexylamine #-aminocapric acid henzyl ester #-@minocaproamide 3-amino-2-methyl-propionic acid ethyl ester 2-amino-propionic acid ethyl ester glycine-t-butyl ester valine-benzyl ester p-OH-aniline p-OH-m-iodo-aniline p-carboxy-thienyl ester of aniline m-F-benzylami ne 4-OH-3,3'-Br-benzylamine 4-Cl-benzylamine 3 ,4-dichloro-benzylami ne 3-NO2-benzylamine 3-phenylpropylamine 2-indolylethylamine 2-amino-pyridine adenine- Cytidine pyrrotine 4-phenylbutylamine &alpha; ;-methyl-alanine ethyl ester 3-hydroxy-propylamine 3-Boc-amino-propylamine 1-amino-3-hydroxy-butane 1-adamantanamine 2-adamantanamine 1-adamantanemethyl amine N# -@oc-lysine-ethylester N a -B,oc-lysine-t-butyl aster N# hydroxy-arginine-ethyl ester N# methyl-homoarginine-t-butyl ester Nim-benzyl-histidine-t-butyl ester Ieucine-t-butyl ester isoleucine-t-butyl ester norvaline-ethyl ester norleucine-methyl ester glucine-p-m,ethyl benzyl ester &alpha; ;-methyl-alanine-diphenylmethyl ester glycyl-benzylamide #-methyl-alanyl-4-OH-benzylamide Nim-benzyl-histidinyl-3-iodo-anilide glycyl-pyrrolide glycyl-1-adamantanamide glutamine-ethyl ester asparagine-t-butyl ester &alpha;-methyl-valine-t-butyl ester &alpha; ;-methyl-phenylalanine-t-butyl ester tyrosine-t-butyl ester O-benzyl-tyrosine-t-butyl ester 4-iodo-phenylalanine ethyl ester 3,5-dibromotyrosine-ethyl ester thyronine-ethyl ester vinyl glycine ethyl ester B-fluoro-alanine ethyl ester serine ethyl ester threonine t-butyl ester O-t-butyl-threonine-t-butyl ester O-t-butyl-serine-ethyl ester O-benzyl-serine-ethyl ester O-methyl -seri ne-methyl ester O-ethyl-serine-ethyl ester S-ethyl-c,ysteine-ethyl ester S-t-butyl-cysteine-t-butyl ester 2-oxo-5-methylhexonic acid phenoxypyruvic acid phenylthiopyruvic acid 4-p-chlorophenyl-2-oxobutyric acid indole-3-pyruvic acid 2-oxo-3-p-cyanophenylpropionic acid 4-&alpha;-naphthyl-2-oxobutyric acid 4-(3,4-dichlorophenyl)-2-oxo-butyric acid 2-oxo-4-p-phenoxyphenylbutyric acid D. Any of the products of synthesis C of this example are reacted with L-proline ethyl ester, or L-proline-tert butyl ester or an &alpha;-ethyl ester of any of the L-p-roline analogs listed in. Table III, immediately below. The reaction is carried ou,t according to the coupling procedures of Synthesis B in: Example 2 or Synthesis A-in Example 53. Table III 3,4-dehydroproline 2,3-dehydroproline, 4,5-dehydroproline 2-OH-proline 3,4-di-OH-proline 3-metho xyp roli ne 2 -metho xyp roli ne 3,4-dimethoxy proline 4-fluoro-p,roliat 3-fluoro-p,roline 2-fluoro-proline3,4-di-OH-proline 3-methoxyp roline 2-methoxyproline 3,4-dimethoxyproline 4-fluoro-p roline 3-fluoro-proline 2-fluoro-proline 3,4-fluoroproline 2,3-difluoro-proline 3 ,4-di fluoro-proli ne 4-Cl-proline 3-Cl-proline 2-Cl -9 roli ne 3,4-dichloro-proline 2,3-dichloro-proline 3-@r-proline 2-@r-proline 3,4-dibromo-proline 2,3-dibromo-proline 4-iodo-proline 3-iodo-proline 2-iodo-proline 3,4-diiodo-proline 5-phenyl-thioproline 5-hydroxyphenyl-thioproline (o-, m- or p-) 4-mercapto-prohne-proline 3-mercapto-proline 4-methylthio-proline 3-methylthio-proline 4-aminomethyl-proline 3-aminomethyl-proline #-thioproline &alpha;-methyl-proline 3-OH-5-methyl-proline 4-methylene proline 4-hydroxymethyl-proline 4-propyl-proline 3-propyl-proline L-proline L-pyroglutamic acid 4-keto-L-proline 3-keto-L-proline 4-hydroxy-L-proline 3-hydroxy-L-proline L-pipecolic acid 4-methoxy-L-proline 4-bromo-L-proline L-thiazolidine-4-cartoxylic acid 5-@etoproline L-2-azetidine carboxylic acid Products of Synthesis D of this example are sapo@ified to remove the ethyl ester. They are treated with anhydrous HF in" the presence of anisole to remove the S-benzyl pro tecting group. If the ethyl ester or benzyl ester groups are removed, the final product of Synthesis D of this example has the formula: EMI69.1 Example 58 . By substituting the N&alpha;-Boc-&alpha;-methyl-S-benzyl-D-cysteine a-N02-phenyl ester for -Boc -S-benztyl-D-cysteine-&alpha;-NO2 - phenyl ester of Synthesis 8 of Example 57, and following the procedures of Example 57, compounds of the formula: EMI69.2 are isolated. Example 59 By substituting N&alpha;-Bac-S-benzyl-D-homocysteine-&alpha;- NO2 phenyl ester for N&alpha; - Boc-S-benzyl-D-cysteine-&alpha;-NO2-phenyl ester of Synthesis s of Example 57, and following the procedures of Example 57, compoundsof the formula EMI70.1 are obtained. Example 60 By substituting N&alpha; -Boc - S - benzyl - methyl - D homocysteine - c - N02 phenyl ester for N&alpha; - ,Boc - S - benzyl - D - cysteine - &alpha; - N02 - phenyl ester of Synthesis 8 in Example 57, and following. th, procedures of Example 57, compounds of the formula: EMI70.2 are obtained. Example 61 By substituting N&alpha; - Boc - D aspartic acid - &alpha; - NO2 phenyl- ester - @ - ethyl ester for N0- - Boc - S - benzyl D - cysteine - &alpha; - NO2 - phenyl ester of Synthesis B in Example 57, and following the procedure of Example 57, with selected deprotection steps, compounds of the formula: EMI71.1 are obtained, Example 62 By substituting N&alpha; - Boc - &alpha; - methyl - D - aspartic acid - &alpha; - NO2 - phenyl ester - ss - ethyl ester for N&alpha; - Boc - S - benzyl - D - cysteine - &alpha; - NO2 - phenyl ester of Synthesis B in Example 57, and following the procedures of Example 57, with selected deprotection steps, compounds of the formula EMI71.2 are obtained. Example 63 By substituting Na - Boc - a -'methyl- D - aspartic - a - p NO2 - phenyl ester - ss - athyl ester for N&alpha; - Boc - S benzyl - D cysteine - t - NO2 - phenyl ester of Synthesis E in Example 57, and by adding N-pyruvoyl - c - methyl - L proline - t - butyl ester as the 2-keto - acyl -- proline ester analog in Example 57, and following the procedures of Example 57, with selected deprotection steps, compounds of the formula: EMI72.1 are obtained. Example 64 By substi-tu-ting N&alpha; - Boc - a - methyl - D - ,aspartic - &alpha; - ND2 - phenyl ester - ss - thiophenol ester for N&alpha; Boc - S - benzyl - D - cysteine - a - NO2 - phenyl ester of Synthesis B in Example 57, and following the procedures of Example 57 with selected deprotection steps, including treatment with NaSH, compounds of the formula EMI72.2 are obtained. The foregoing examples are intended to be illustrative, not limiting. Many other variations of the present invention will readily occur to those of ordinary skill in the art; and it -is intended that such variations are within the scope of the invention and the appended claims.

Claims: 1. Novel compounds of the general formula: EMI73.1 wherein x and y are 0 or t, X may be S, O or N-R9 and R9 may be -H or -CH3, R10 is H,. CH3, F, Cl or Br; m is O or 1; R2 is COOH, CH2COOH, COSH, CH2COSH, CH2SH, CH2CH2SH, a physiologically acceptable nontoxic salt of any of them; COOY, CH2COOY, COSY, CHzSY, or CH2CH2SY wherein Y phenyl, benzyl or a 1 - 5 carbon alkyl group; or EMI73.2 wherein eithér of A1 and A2 may be H, phenyl, b@nzyl or a 1 - 5 carbon alkyl group; R4 and R5 together form a ring with the nitrogen and carbon atoms to which they are respectively attached, which ring is one of the structures: EMI73.3 EMI74.1 it being understood that any of these structures may be onosubstituted with - OH, -OCH3, F, EMI74.2 CI, Br I, phenyl, hydroxyphenyl, -SH, -SCH3, EMI74.3 -NHCH, -CH2NH2, - CH3, -CH2OH, propyl, guanidino, nitro guanidion or thioguanidino and that any af the- 5- or 6- membered rings may be disubstituted with OH, F, CI, Br, I, OCH3 or any combination of two of this group of substituents; ; R6 is OM or -SM, wherein M may.be H, an alkyl group of 1-3 carbon atoms or any other ester moiety hydrolizable under mammalian in v.iv.o conditions to OH, ar an ionically bonded anion of a physiologically acceptable nontoxic salt; R7 is H-, CH3 -, halomethylt hydroxymethyl, aminomethyl or mercaptomethyl; R8 is H-, CH3- amino, halomethyl, hydroxymethyl, aminomethyl, dihalomethyl, trihalomethyl, mercaptomethyl, methoxymethyl, methylthiomethyl, methoxycarbonylmethyl, cyanomethyl, benzyl, acetoxymethyl, CH2=CH-CH2-, isobutyl, mercaptoalkyl of, 2-3 carbon atoms, hydroxyalkyl of 2-3 carbon atoms, acetylthioethyl, benzamido, acetamido, phthaloylaminoalkylene wherein the alkylene group has 1-4 carbon atoms, &alpha; ;-alkoxycarbonyl isoalkylene wherein the alkyl group contains 1-5 carbons and the isoalkylene group contains 3 - 5 carbons, benzoylamine, alkanoylamine of 1 - 5 carbons, alkylamide of 1 - 5 carbons, phenylamine, alkylamine of 1 - 5 carbons, or ethyl; and A R1 and R3 may each be of the general formula EMI75.1 wherein A3 is: : I. alkylene of 1-6 carbons, branched chain alkyl of 1-6 carbons, cycloalkyl alkylene, alkylcycloalkylalkylene, or alkylcycloalkylene; - aralkylene wherein the alkyl groups 1-6 carbons or alkylaryl; III phenyl; IV. alkylaralkylene wherein the alkyl groups may be the same or different and are 1 ó carbons in length; ; V. substituted alkylene, substituted branched chain alkyl, substituted cycloalkylalkylene, substituted alkyl cycloalkylalkylene, substituted alkylcycloalkylene, substituted alkylaryl, substituted aralkylene, substituted phenyl or substituted alkylaralkylene wherein the substituent or substituents may be the same or different, may be included in an alkylene chain or pendent thereto, and are selected from amino, halo, hydroxy, mercapto, NO2, carboxy, CONH2, lower alkyl, halomethyl, hydroxymethyl, aminomethyl, dihalomethyl, trihalomethyl, cyano, mercaptomethyl, methoxy methyl, methylthiomethyl, methoxycarbonylmethyl, cyanomethyl, benzyl, acetoxymethyl, CH2=CH-CH2-, isobutyl, mercaptoalkyl of 2-3, carbon atoms, hydroxyalkyl of 2-3 carbon@atoms, acetylthioethyl, benzamido, acetamido, phthaloylamino alkylene wherein the alkylene group has 1-4 carbon atoms, &alpha;-alkoxycarbonyl isoalkylene wherein the alkyl group contains 1-5 carbons and the isoalkylene groiup contains 3-5 carbons, benzoylamino, alkanoylamino of 1-5 carbons, alkylamide of 1-5 carbons, phenylamine, alkylamine of 1-5 carbons, lower alkoxy, aryloxy, lower alkylamino, diloweralkylamino, acylamino, arylamino, guanidino, imidazolyl, indolyl, lower alkylthio, arylthio, carboxy amido and -carbolower alkoxy; VI. alkylenethio- or alkylenethioalklene of 1-6 carbons, alkylthioalkylene of 1-6 carbons; VII. alkyl eneoxy or alkyleneoxyalkylene wherein the alkyl groups may be the sameor different and are 1-6 carbons; ; VIII.- alkoxyphenyl or alkoxybenzyl in which the alkoxy groupchas 1-3 carbons, phenoxyphenyl, phenoxybenzyl, benzyloxybenzyl or benzyloxypheyl or a thioether analog of any of them; EMI76.1 wherein n=0-4, m=0-4, and B=H or a 1-5 carbon alkyl group; or an -SB analog thereof; EMI76.2 wherein n and m have the same significance as above, Y is phenyl, benzyl or a 1-5 carbon alkyl group; EMI77.1 EMI77.2 wherein T and W noy be the same or different and are alkylene, aryl, benzyl. or cycloalkyl; and P and Q may be the same,or one of them may be H or they may combine to form a ring with the nitrogen to which they are attached. Eithet or both of P and Q may be selected from any of the following : (a) C1-C6 straight or branched chain alkyl groups or C1-C6 straight. or branched chain alkenyl groups,- any one of which may be substituted with any of hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, alkylacylamino, arylamino, guanidino, thioguanidino, nitroguanidino, hydrazino, ureido, nitro, mercaptocarbonyl, hydroxyamino, histidinyl, cyano, imidazolyl, indolyl, mercapto, alkylthio, arylthio, carboxy amido or carboalkoxy, wherein the alkyl groups contain 1-6 carbon atoms; ; (b) cycloalkyl or cycloakyl alkylene wherein cyc@o- alkyl has 4-12 carbons, and alkylene 1-5 ca.rbons, which may be substituted with any of -OH, -SH, halo, COQH,. COSH, CONH2, NO2NH2, NO2, CH3, -OCH3, EMI77.3 hydrazine, ureido, -SCH3, hydroxysmino, cyano, guanidino, thioguanidino or nitroguanidino groups; (c) aralkyl or -alkaryl groups' which may be ring substituted with one or more of the following: SH, halo, CH2COOH, CH2CONH2, CH2CONH-alkyl, COSH, COOH, CONH2, CONH-alkyl; CH2COSH, CH2SH, CH2CH, OH, NO2, amino, alkyl, alkoxy, aralkyloxy, alkylthio, and walkylthio groups, wherein the alkyl groups contain 1--6 carbons and may also alternatively be chain. substituted with -CH3, -OH, -OCH3, halo, -SCH3, EMI78.1 -NH2, NO2; -CN, -SH, -NHNH2, EMI78.2 -NHOH or a thio or nitro derivative thereof, COSH, or COSH; (d) an aryl, hetarocyclic or adamantanyl group which may be ring-substituted with at least one group selected from halo, -OH, - O-alkyl, -O-aryl, NH2, NH-alkyl, N-C:alk W EMI78.3 aryl-NH2, guanidino, thioguanidino, nitroguanidino, hydrazino, ureido, nitro, mercaptocarbonyl, hydroxyamino, cyano imidazolyl, indanyl, histidinyl, -@H, -@-alkyl, @-aryl, EMI78.4 EMI78.5 when P and @ join with N to form a ring, the ring may be any 4 - 10 membered heterocyclic ring which contains a nitrogen with only two of its valences attached to other ring members. B. Alternatively R1 may be EMI78.6 and R3 may be (i) mono-N substituted alkylene of 2 - 4 carbons 'wher'ein'- the. N substituent is- benzoyl, Boc, CbO, Tos, formyl or acetyl;. (ii) hydroxyphenyl or hydroxypenyl-(1-6C)-alkylene or a thiol analog of either; Ciii) mercaptoalkylene of 1 - 6 carbons; (iv) phenylakylene wherein the alkylene group has 1-6 carbons; (u) phenylthioalkylene or b'enzyl thioalkyl ene wherein the alkylene group has 1. - 6 carbons; (vi) alkylthioalkylene wherein the alkyl and alkylene groups have 1 - 3 carbons; EMI79.1 Wherein x and y are 0 or 1, X nay be S, O or N-Rq and R may be -H or R10 is H, CH3, F, Cl or Br; m is O or 7, R2 is COOH, CH2 COOH, COSH, CH2COSH, CH2SH, CH2, CH2SH, a physiologically acceptable nontoxic salt of any of them; COOY, CH2 COOY, COSY, CH2SY, or CH2CH2SY wherein Y is phenyl; benzyl or a 1-5 carbon alkyl group, or EMI79.2 wherein either of A1 and A2 may be H, phenyl, benzyl or a 1-5 carbon alkyl group; R4 R4 and R5 together form a ring with the nitrogen and carbon atoms to which they are respectively attached, which ring is one of the structures: : EMI79.3 EMI80.1 EMI81.1 wherein G is an alkacyl or alkacyloxy group of 1 - 6 carbons, a benzoyl or benzoyloxy group or a phenylalkacyl or phenylalkacyloxy group wherein the alkacyl or alkacyloxy group contains 2 - 6 carbons and q and n have the same significance as set forth above; ; EMI81.2 wherein n has the significance stated above and K is selected from carboxypheyl, aminophenyi, nitrophenyl, halophenyl, hydroxyphenyl, alkylthiophenyl, alkylphenyl, mercaptophenyl, cyanophenyl, mercapto-carbonylphenyl, alkylcarbonylphenyl, alkylcarbonyloxyphenyl, hy,drazinophenyl,- ureidophenyl, alkylcarbohylaminophenyl, alkylcarbonylthiophenyl, alkyloxyphenyl and hydroxyaminophenyl, wherein all alkyl groups contain 1 - 6 carbon, atoms; ; EMI81.3 wherein n has the significance stated above and L is selected from cycloalkyl groups of 3 - 7 carbons which may be unsubstituted or substituted with up to two groups selected from among carboxy, amino, nitro, halo, hydroxy, mercapto, mercaptocarbonyL,' frydroxyamioo, alkyl, alkylcarbonyl, alkyl carbonyloxy, alkylthio, alkylcarbonylamina, alkylcarbonyl- thio, cyanohydrazino, ureido and alkyloxy, wherein all alkyl groups contain 1 - ,6 carbon atoms: (xxii) guanidino alkylene, thioguanidinoalkylene, or nitorguanidino alkylene in which the alkylene groups contain 1 - 6 carbon. atoms; (xxiii) ring substituted aryl groups in which the ring substituents may be the same or different and may comprise up to fiv.e per ring of the, following: - ,NH2, . -OZ, . -SZ, halogen, -CNC, -NO2, -COOZ, COSZ, CONH2, - NHNH2, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkyl, dihaloalkyl, trihalomethyl, hydroxyamino, alkylcarbonylthio, phenoxy, and benzyloxy wherein the alkyl groups contain 1 -. 6 carbon atoms and Z has the same signify cance as above ; (xxiv) amidoalkylene or alkylcarbonyl-aminoalkylene wherein. the al,wyl and alkylene groups contain 1 - 6 carbon atoms; (xxv) hydroxyaminoalkylene of 1 - 6 carbons; (xxvi) vinyl and substituted vinyl groups in which the substituents may be alkyl, aryl, cycoalkyl or heterocyclic groups; ; (xxvii) unsubstituted heterocyclic groups from among phenothiazioyl, pyrrolidinyl, pyrrolyl, quinol'inyl, imidazolyl, pyridyl, thyminyl, benzothiazinyl, indolyl, thienyl, purinyl, piperidinyl, morpholinyl, azaindolyl, pyrazinyl, pyrimidyl, piperonyl, piperazinyl, furanyl, thiazolyl and thiazolidinyl, cytosinyl; ; (xxviii) alkylene or alkenyl groups 1 - 6 carbons substituted with one of the hete,rocyclic rings from (xxvii) above (xxix) groups from (xxvii) or (xxviii) above containing up to four ring substituents on the heterocyclic ring selected from among - OZ, - SZ, - COOZ, - NO2, - NH2, -COSZ, halogen, haloalkyl, dihaloalkyl, trihalomethyl, cyano, CONH2, alkyl, alkylcarboayl, alkylcarbonyloxy, alkylcarbonylthio, phenoxy, benzyloxy, EMI82.1 - NHNH2 and HONH -, wherein, Z has the same significance as above; (xxx) groups from (xxvii), (xxviii) or (xxix) attached to one valence of an etheric. -0- or -S-; ; (xxxi) monc-, di- or tri-alkyl, alkenyl. - or phenylsilyl or - selenyl wherein. the alkyl or alkenyl groups cantain 1 - 6 carbons; (xxxiii) any of H, 1 - 5 carbon straight or branched chain alkyl, phenyl, -OH, alkoxy of 1 - 6 carbons, benzyloxy, benzyloxyalkylene or phenoxyalkylene wherein the alkylene has 1,- 5 carbons, alkoxyalkylene having 1 - 5 carbons in the alkoxy and alkelene groups, aminoalkylene of 1 - 6 carbons, alkenyl of 1 - 6 carbons, benzyl, hydroxyalkyl of 1 - 6 carbons, mercaptoalkyl of 1 - 6 carbons, histidinyl, haloalkyl of 1 - 6 carbons, 4 - aminomethyl-benzyl, acetamidoalkyl of 7 - 5 carbons, benzylthiomethylene, or do methyl aminoalkyl of t 1 - 5 5 carbons. C. Alternatively, R3 may be EMI83.1 2nd R1 may be, any of groups (i) - (xxxii) above or any of H, C1 - C8 straight or branched chain alkyl, phenyl, benzyl, unsubstituted aminoalkyleon of 2 - 6 carbons, hydroxyalkylene of 1 - 6 carbons, hydroxyphenyl, phenoxyalkylene or benzyloxyalkylene wherein the alkylene group has 1 - 6 carbons, cycloalkyl of 3 - 6 carbons, cycloelkyl methyl, 3 indolyl, phenylethyl, methylth oethyl, 3 indolyl alkyl wherein -the alkyl group contains 1.- 5 carbons. imidazolyl, imidazolylalkyl wherein the alkyl group -contains 1 - 5 carbons, phenoxymethyl, phenylthicmethyl, 4-aminomethyl benzyl, 2-aminophenethyl, naphthylethyl, 4-halophenthyl, 3,4-dihalophenethyl or pheno,xyphenethyl, or, R1 and R2 together may form with -CH a lactone fing or the 'formula: EMI84.1 or an-analogous six-membered ring. 2. A compound according to claim 1 wherein x is -NH-, -S- or -O-. 3. A compound according to claim 1 or 2 wherein R and R3 are each of the general formula EMI84.2 and P and Q may be the same, or one of them may be H or they may combine to form a ring, with the- nitrogen to which they are attached, wherein P- and Q may be selected from any of the radicals of the groups (a) - (d). 4. A compound according to claim 1 or 2 wherein R1 is of the general formula EMI84.3 R3 is a radical of groups (i) - (xxxii); and 'P -and Q may be the same, or one of them may be H or they may combine to form a -ring with the nitrogen to which they are attached, wherein P and Q may be selected from any of the radicals of groups (a-) - (d). 5. A compound according to any of claims 1 to 4 wherein m is O; X is N-R9 and R9 is H; R4 and R5 together form a ring with the nitrogen and . carbon atoms to 'which they are respectively attached, which ring is one of the structures: EMI85.1 R7 is H- or CH3 R8 is H- or CH3-; and R10 is H- or CH3-. 6. A compound according to claim 5 wherein A3 is a radical of groups I - 'V'; and P, and, Q are the same or different 'and are selected from H and any radical of groups, (a)- - (d). 7. A compound according to claim 5 wherein A3 is a radical of groups I - V; P and Q are the' same or different and are selected from radicals of the groups (b) - (d), when P and 9 joinito form a ring, the ring is any 4. - 10 membered heterocyclic ring which contains a nitrogen with only two of its valences attached to other ring numbers. 8. A compound according to any of claims 1 - 7 wherein R4 and R5, form one of the structures EMI85.2 EMI86.1 (where h is Cl, F, Br or I), and R6 is -OH, or a lower alkyl ester or physiologically acceptable salt thereof. 9. A compound according to any of claims 1 - 7 wherein R4 and R5 and R6 together form substituted proline, or a lower. alkyl ester thereof and physiologically acceptable saltsthere of, wherein the substituent is selected -from the group consist ing of Cl, Br, F or: I. 10. A compound according to any of claims 1 - 9 wherein P-N-Q form the structure EMI86.2 and x = 1, y = 1, X = N-R9, m = O, R8 = H, R3 = CH3, R4 and R5 together form the structure EMI86.3 R6 = OH, R7 = H and R2 = COOH, R9 = H, R10 = H or physiologically acceptable salts thereof. 11.. A compound according to any of claims 7 '- 9 wherein . P = H, q = phenyl or iodo-phenyl , x = 1, y -= 1, X = NR9, m = 0, R8 = H, R3 = CH3, R4 and R5 together form the structure EMI86.4 R6 = OH, R7 = H and R2 = COOH, R9 = H, R10 = H or physiologically acceptable salts thereof. IZ. Acompound according to claim 1 wherein R2 is COOH, COOEt, COOMe, COSH, COSH, CH2SH; or wherein P-N-O forms structures selected from the group consisting of anilino, benzylamino, 2-amino pyridyl amino, 3-amino pyridyl amino, 4-amino pyridyl amino, 3-indolyl amino, and histaino; or Wherein R3 is CH3. 13. A compound according to any of claims t - ,12 wherein P of R1 is H; Q of R2 is aminoalkylens; A3 of R1 is alkylene; and P-N-Q of R3 forms sturctures selected form the group consisting of anilino, benzylamino, 2-amino pyridyl amino, 3-amino pyridyl amino, 4-aminopyridyl amino, 3-indolyl and histamino; or wherein P .of R3 is H, 9 of R3 is aminoalkylene; A3 of R3 is alkylene; P-N-Q of R1 forms structures selected from the group consisting of anilino, benztlamino, 2-amino pyridyl amino, 3-amino pyridyl amino, 4-amino pyridyl amino, 3-indolyl amino, and histamino; ; or wherein R1 is EMI87.1 R3 is phenyloxyat kylene, benzyloxyalkylene, benzylalkyleneoxyalkylene, wherein the alkylene group has 1 '- 5 carbons; or wherein R1 is phenyloxyalkylene, benztyloxyalkylene, benzylalkylene oxyalkylene, wherein the alkylene group has 7 - 5 carbons; R3 is EMI87.2 14. A composition of of matter effective to inhibit angiotensin converting enzyme in vivo . or to reduce the, blood pressure in vivo of a mammal in a hypertensive state which contains as its essential active ingredient a therapeutically effective amount of a compound of any of claims 1 - 13. 15.. A compound of any of claims 1 - 13 for use in treating hypertension or abnormal serum levels of angiotensin II in mammals.

Inventors: CHUNG, ALFRED, RYAN, JAMES WALTER
Applicants: RYAN, JAMES WALTER
Application year: 1982
Main classification: C07K5
IPC codes: C07K5, C07D207, C07K14, A61K38, A61P9, A61P43