IE55818B1

IE55818B1 - Pharmaceuticaly active n-acyl dipeptides

Info

Publication number: IE55818B1
Application number: IE1655/83A
Authority: IE
Original assignee: Squibb & Sons Inc
Priority date: 1982-07-19
Filing date: 1983-07-15
Publication date: 1991-01-30
Also published as: IT8322114A0; ES8707549A1; ES539084A0; GB2123834A; DK330683D0; KR840005709A; FI832620A0; JPH0526775B2; HU187090B; JPH0517420A; FR2540867B1; JPH0653713B2; JPH0532601A; IL69136A0; GB2123834B; JPH0645582B2; AU1643283A; BE897327A; SE8304031L; PT77045A

Abstract

Substituted peptide compounds of the formula are disclosed. These compounds are useful as hypotensive agents due to their angiotensin converting enzyme inhibition activity and depending upon the definition of X may also be useful as analgesics due to their enkephalinase inhibition activity.

Description

Phareaceutically active M-acyl dlpeptide» This invention is directed to substituted peptide conpounds. of formula I and salts thereof (!) R R, O I ? I R,-CH-C-CH,—N - CB 3 I 2 ' (U NH ' I C-0 I "2 C-X X is an amino or Imino add of the formula -M—C-COOR/v*·.

-N—C-COOR. |(U β H -H — e-WML |U) 6 H -2*10^*10 ί p»’ . -Μ— C-COOR, I (L) 6 R N—C-COOR. I (L) 1 R -N — c-cocftc I tt) R o-cocxl • tt)® C-COOR, I tt) 6 H or N-CH-COOR, ’ R4 *5 H -3R7 la hydrogen, lower alkyl, halogen, keto, « Ae hydroxy, -NH-C-lower alkyl, azido, amino, -N ? *" (R13'p XO -(CB a'iiTjJ - -'«a'sfj) · "W-fO) · a 1- or 2-naphthyl of the formula -«mp ΊξΙοΗ.., , -(CHp^-cycloalkyl l| /*15 -O-C-H , -Olower alkyl, -O-(C^bTXO Χ*ϋ a 1- or 2-naphthyloxy of the formula -O-(CB.) 'W......' , -S-lower alkyl, 14Jp or a 1- or 2-naphthylthio IS of the formula -s-cch2)> -4Re Is keto, halogen, || / IS 8 -O-C-R -0-(CHj)j/oj * -0-lower alkyl, a J 2-naphthyloxy of the formula -S-lower alkyl, s(CH2^b^OX · or a 1- or 2-naphthylthio of the formula -8- (CHj); .- or Rg Is keto or -(CHj) -5R10 ifl halogen or "^*15· Rxx' 8xi' *x2 R'i2 are JLndePendently selected from hydrogen and lower alkyl or R’1X » rX2 and R’12 are hydrogen and Ru is ^<1,, XO R^2 Is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of .1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, hromo, fluoro, trifluoronethyl, hydroxy, phenyl, phenoxy, phenylthio, or ptuftiy ImethylR^4 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons,* lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoronethyl, or hydroxy. n is taro, one, two, three, or four, p is one, two or three provided that p is nore than one only if R^ or R^ is hydrogen, methyl, methoxy, chloro, or fluoro.

R^j is hydrogen or lower alkyl of 1 to 4 carbons.

Y is oxygen or sulfur· R^c is lower alkyl of 1 to 4 carbons, · or the groups join to ^13¼ conplete aa unsubstituted 5- or 6-membered ring I© or said ring in which one or more of the carbons has a lower alkyl of 1 to 4 carbons or a di (lower alkyl of 1 to 4 carbons) substituent· is hydrogen, lower alkyl.

(CH,) IS -(CH2)B-cycloalkyl, -(CHjIj^jJ , *(CH2)5^]J ‘"ζ’Κδ)' * · or <Ι§) · »5 1· hydrogen, lower alkyl, R is hydrogen, lower alkyl, cyclo?lkyl.

-(CH2’i-© ' -2)2-nh2, -2)3-tm2 , -(CH2)4-nb2, -(CH2) 2-OH, - (CH2)3-oh, -CCH2)4-oh, -(ch2>2-sb, -2)3-sh, or -2)4-SH.

IS Rj is hydrogen, lower alkyl, halo substituted lower alkyl.

(CH2»F© * -(CH2) OR rQ’,,(qH2,riS?0B ' -(CH2 OB (CH,), nJ · - (CH2)r-WH2 , - (CHj) r-SH (CHjJ^-OH, - (CHj) ^-S-lower alkyl, NB (CH.) -NH-C 2 r NB. , or -(CHj)r-C-NH2 -gw provided that R^ ig hydrogen Only If R Is other than hydrogen.. *2 le ' -] - " - -(CHjIrfnj . -(CHa>i{S) , halo substituted lower alkyl, -(CHp^-cycloalkyl, -(CHp , -(CH, 'τ® -tCH2»r '"O ' H I H -9-2»r-NH2, -(CH2»r-SH. -(CH2)r-S-lower alkyl, zNa ! -(CR.) -NH-CZ , or -(CH2)r-C-NHj \ XNH„ wherein m, R^, P a»* * a*® as ae£ined above.

R- is hydrogen, lower alkyl* benzyl, * o o ' »2X * benzhydryl.

-CH-O-C-R I R?3 Is lower alkyl.

Rg* is hydrogen, lower alkyl, ~Q. Ό " -Φ , I -10This invention in its broadest aspects relates to the substituted peptide compounds of formula Z above, to compositions and the. method of using such compounds da pharmaceutical agents, and to intermediates useful in preparing these compounds.

The term lower alkyl used in defining various symbols refers to straight or branched chain radicals having up to seven carbons. The 1° preferred lower alkyl groups are up to four carbons with methyl and ethyl most preferred. Similarly the terms lower alkoxy and lower alkylthio refer to such lower alkyl groups attached to an oxygen or sulfur.

XS The term cycloalkyl refers to saturated rings of 3 to 7 carbon atoms with cyclopentyl and cyclohexyl being most preferred.

The term halogen refers to chloro, bromo and fluoro.

The term halo substituted lower alkyl refers .. to such lower alkyl groups described above in which one or more hydrogens have been replaced by chloro, bromo or fluoro groups such as, for example, trifluoromethyl, which is preferred, penta25 fluoroethyl, 2,2,2-trichloroethyl, chloromethyl and bromomethyl. -11The symbols -(CH.

M3' represent that the alkylene bridge is attached to an available carbon atom.

The compounds of formula X wherein R is hydrogen can be prepared by converting a carboxymethyl peptide ester of the formula (IX) "l 0 r fl HO-C-CH.-H-CH-C-X I (1*1 *40 to its acid chloride and then reacting with an oxasolone of the formula (XII) C-R C-0 wherein and Rg (in the definition of X) are protecting groups such as, for example, wherein R40 1b benzyloxycarbonyl and Rg is benzyl. Removal of the Rg0 and protecting group, *or example, by hydrogenation yields the products of formula X wherein Rg is hydrogen. -12•i The carboxymethyl peptide ester of formula II is prepared by reacting the peptide ester of the formula <**> IL O r p c-x 2 tt> with tert-butyl bromoacetate and then introducing the *40 protecting group, for example, by treating with benzyl chloroformat·.

The compounds of formula I can also be prepared by reacting a ketone of the formula (V) 0 H I Rj-C-HH-CH-C-Cfij-halo . wherein halo is Cl or Br with the peptide ester of the formula (VI) MX. O I ? ί or-cb-c** (U in the presence of base such as sodium bicarbonate followed by removal of the R* ester group.

The ketone Intermediate of formula V can be prepared by treating a ketone of the formula (VII) IS P R*n-NH-CH-C-CH,-halo 40 | 2 «3 wherein R^o is a protecting group auch aa benzyloxycarbonyl with hydrogen bromide and acetic acid followed by reaction with tha acid halide of the formula (VIII) < I R^-C-halo in the presence of base such es sodium bicarbonate.

The compounds of formula X can also be prepared by reacting an amlnoketone of the formula (IX) H BI particularly the hydrochloride salt thereof with the haleacetyi amino or imino sold ester of ths formula *· I -14(X) halo-CH—C-X. tt) wherein Rg in the definition of X is an easily removable ester protecting group and halo is Cl or Br.

The cosipounds of formula X ean also be prepared by coupling an eminofcetone carboxylic acid of the formula (XI) 15 Ο o R R- O H > II I R,-C-NH-CH-C-CH,-N - CH - C-OH 2 | 2 (M «3 with the amino or imino acid ester of the formula (XXX) in the presence of a coupling agent such as dicyclo25 hexylcarbodilmide wherein Rg in the definition of X is an easily removable protecting group.

Removal of the Rg protecting group yields the products of formula X wherein Rg is hydrogen.

Tte aminoketone of formula XX can te prepared by converting tte cartexyalkylamine of tte formula (XXXX) BO-C-CB2-«-R40 o wherein R40 le a protecting group such as benxyloxy10 carbonyl, to Its add chloride and then reacting with an oxasolone of formula XXX to yield (XIV) * 0 0 R fi fi I R2-C-Ma-CX-C-CR2-MHR40 *3 Removal of tte R4q protecting group such as by hydrogenation yields tte reactant of formula xx.

Tte aminoketone of formula XX wherein R is otter than hydrogen can also te prepared by reacting tte ketone of formula v with a substituted amine Qg the formula (XV) -16Tbe aminoketone carboxylic acid of formula XZ can be prepared by reacting the aminoketone of formula XX with a haloacetic acid ester of the formula (Wl) halo-CH — C-O-Prot W wherein Prot is an easily removable eater protecting group such as. t-butyl to yield the ester (XVXI) *3 Removal of the ester protecting group gives the reactant of formula XX· Xn the above reactions if any or all of R, R^, Rj and R$ are 1710 -(CH.

’•-Q- I -2)r-OT· OX ‘-(CHj^-NH-C^ 9 -r-SB, .NB 88. then the hydroxyl, amino, imidazolyl, mercaptan or guanidinyl function should be protected during the reaction. Suitable protecting groups include e.g. benzyloxycarbonyl,. t-butoxycarbonyl, benzyl, benzhydryl and trityl, and nitro in the case of guanidinyl. The protecting group la removed by hydrogenation, treatment with acid, or other known methods following completion of the reaction.

The ester products of formula X wherein Rg is lower alkyl, benzyl or benzhydryl can be chemically treated such as with sodium hydroxide ia aqueous dioxane or with trimethylsilylbramide to yield the products of formula X wherein Rg is hydrogen. The benzyl and benzhydryl esters can also be hydrogenated, for example, by treating with hydrogen in the presence ef a 18palladium on carbon catalyst.

Tha eater products of formula I wherein Rg is -CR-O-C-Rjg may be obtained by employing the peptide of formula IV or VI or the haloacetyl amino or imino acid ester of formula X in the above reactions with such ester group already in place. Such ester reactants can be prepared by treating the peptide of formula ZV or VI or the haloacetyl amino or imino acid ester of formula X wherein Rg is hydrogen with an acid chloride auch as CH2-O-C-C1 or (HjOj-C-O-C-Cl so as to protect the N-atom. The protected compound is then reacted in the presence of a base vith a compound of the formula (XVXXX) ll Χτγι-0-c-Rie *17 -1910 wherein Lisa leaving group such as, for exanple, chlorine, bromine and tolylsulfonyl, followed by removal of the N-protecting group such as by treatment with acid or hydrogenation.

The ester products of formula X wherein Rg is O can also be obtained -CH-O-C-R, .

I 18 *17 by treating tha product of formula I wherein Rg is hydrogen with a molar excess of the conpound of formula XVIIl.

Tha aster products of formula I wherein Rc is ΪΗ 2 -C —— C-O-Rjj can be prepared by treating the product of formula X wherein Rg is hydrogen with a molar excase of the compound of the formula (XXX) I I C-O-Bjj .

The ester products of formula χ wherein Rg la -CH-(CHjOH)2 or -CHj-CH—-CH2 can OB OB -20• be prepared by coupling the product of formula I wherein Rfi is hydrogen with a molar excess of the compound of the formula (XX) •CH -(CH^OProt)2 OH or the formula (XXX) CHj-CH--CH.

I I I OH OProt OProt 15 in the presence of a coupling agent such as dicyclohexylcarbodiimide followed by removal of the hydroxyl protecting groups.

The esters of formula X wherein R^ is lower alkyl can be obtained from the carboxylic acid compounds, i.e., wherein R$ is hydrogen, by conventional esterification procedures, e.g., treatment with an alkyl halide of the formula Rg~halo or an alcohol of the formula The peptide esters of formulas XV and vx may be obtained by coupling the hydrochloride salt of the amino or imino acid ester of formula XXX wherein R$ is, for example, benzyl with the Ν-protected amino acid of the formula -21(XXXX) Prot-N-CH-COOH (I·) wherein Prot is a protecting group euch as O ll -C-O-(CHj)j. Preferably, this reaction is performed in the presence of a coupling agent such as dicyclohexylcarbodiimide. Removal of the N-protecting group, for example, by treatment with trifluoroacetic acid yields the peptide esters of formulas XV and VX.

The haloacetyl amino or imino acid ester of formula X can be prepared by reacting the amino or Imino acid ester of formula XXX with a haloacetylhalide of. the formula (XXXXX) O I halo-CTj-C-halo .

The product* of formula I wherein R? le amino may be obtained by reducing the corresponding products of formula X wherein R? is azido.

Preferred compounds of this invention with respect to the peptide part of the structure of formula I are those wherein the variable substituents, alone or together, may be: R is hydrogens straight or branched chain lower alkyl of 1 to 4 carbons, especially -C(CHj)^; or phenyl.

Rx is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, -CPg, . . wherein r is an integer from 1 to 4, -22-Oif® » -C»2-©-OH , -CTa-^- OI OH ^"ζΤΘ)' 'CTrCJ ’ _CH?'SH' NH (CH2>2-S-CH3, -(.ch2)3nrc O O n H -CH2-C-NH2, or -(CH2)2-C-NH2 provided that is hydrogen only lf R is other than hydrogen.

R2 is -(CH2)n -© wherein m is zero* one or two and R^ is hydrogen, methyl, methoxy» methyl thio, chloro, broeo, fluoro or hydroxy.

R3 is straight or branched chain lover alkyl of 1 to 4 carbon atoms, -(CH2)r -NH2, or ~(CH2)B ~·{θ) wherein r is an integer fronJf to 4 and m and R^ were as defined above.

R^ is hydrogen, cyclohexyl or phenyl.

Rj Is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, -CH2OR, -CH r© · -o’f©-011' OH OH ’"qr^Q) ' 9 -<«ψ4-«η2 I I Η B NH -ch2-sh, -(ch2)2-s-ch3, -2)3nhc^ NR. -23Ο -CHj-C-NHj or -(CT2)2-c-nh2 Rg is hydrogen, lower alkyl of 1 to 4 salt, θ -CH-O-C-Rjg straight or branched chain carbons, alkali metal -CH2-C-OR 23 , -CH-(CH2-OH)2 . -CH2-2. -(CH2)2-N(CH3)2, or OH OH -0*2 Rj3 Is straight or branched chain lower alkyl of 1 to 4 carbons, especially -c3)3 Rj7 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl· A>le straight or branched chain lower alkyl of 1 to 4 carbons or phenyl.

My ia hydrogen.

Ry is hydroxyRy is straight or branched chain lower alkyl of 1 to 4 carbons or cyclohexyl. 24Rj is aaino.

Bj is -O-lower alkyl wherein lower alkyl is straight or branched chain of 1 to 4 carbons. -Λ®.

R13 wherein m is zero, one or two and R^3 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.

IS 1-naphthyloxy or 2-naphthyloxy wherein m is zero, one, or two and Rjj is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.

Rj is -8-lower alkyl wherein lower alkyl is straight or branched chain of 1 to 4 carbons.

Rj is -S-JCBj 1-naphthyl thio, or 2-naphthylthio wherein m is zero, one, or two and R^j la hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.

Rg is -O-lower alkyl wherein lower alkyl is straight or branched chain of 1 to 4 carbons. -2510 *e 1β wherein m Is zero, one, pr two and is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.

Rg is -S-lower alkyl wherein lower alkyl is straight or branched chain of 1 to 4 carbons. wherein m is zero, one or two and R13 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro or hydroxy.

Rg is phenyl, 2-hydroxyphenyl, or 4-hydroxyphenyl.

R^o are both fluoro or chloro. are both -Y-R^g wherein Y is O or S, R^g is straight or branched chain lower alkyl of 1 to 4 carbons or the R^g groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the available carbons has.a methyl or dimethyl substituent. *ii' *ii* *12 *12 we a11 or R^2 is phenyl, 2-hydroxyphenyl, or 4-hydroxyphenyl and R|2« R^j an^ *4.2 hydrogen. #24 is phenyl.

Most preferred conpounds of this Invention with respect to the peptide part of tbe structure of foraula X are those wherein the variable substituents, alone or together, aay be: -26X Ιβ -M-CBj-COORg, B-C " CH. 2t , < -H-C-COOR l(W B s s i? Pi -N-C-COOR- , or l(L> ® B -H R ia hydrogen or methyl.

R^ is hydrogen, methyl, or -(CHjIjNHj, especially methyl, provided that R^ ia hydrogen only if R la other than hydrogen.

Rg la hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or an alkali metal salt. Rg is cyclohexyl or phenyl. -27Ry ie hydrogen, cyclohexyl, lower alkoxy of 1 te 4 carbons. wherein a ie zero, one, or two and ηχ3 is IO hydrogen, methyl, methoxy, methylthio, Cl, Br, F, or hydroxy, especially preferred wherein Rj ia hydrogen. t is two or three, especially where t is two. Preferred compounds of this invention with respect to the keto portion of the structure of formula X are those wherein: *2 S~~\ *14 (wherein is zero, one, or two end Su le hydrogen, nethvl, methoxy, .ethylthio. Cl, Br, F, or hydroxy), end Rj is especially phenyl.

Rj ie straight or branched chain lower 25 alkyl of 1 to 4 carbons, -(CHj^-RHj, -(CHj) , or -(CHy) *14 · (wherein m is' zero, one, or two, Rj4 is hydrogen,methyl, methoxy, methylthio, CX, Br, F, or hydroxy, and r is an integer from X to 4), and R^ is especially benzyl.

. The compounds of formula X wherein R- is hydrogen form salts with a variety of s inorganic or organic bases. The nontoxic, pharmaceutically acceptable salts are preferred, although other salts are also useful in isolating or purifying the product. Such pharmaceutically acceptable salts Include metal salts such as sodium, potassium or lithium, alkaline earth metal salts such as calcium or magnesium, and salts derived from aaino acids such as, for example, arginine and lysinei The salts are obtained by reacting the acid form of the compound with an equivalent of the base supplying the desired ion in a medium in which the salt precipitates or in aqueous medium and then lyophilising. * Similarly, the compounds of formula X, especially wherein R$ is an ester group, form salts with a variety of inorganic and organic acids. Again, the non-toxic pharmaceutically acceptable salts are preferred, although other salts are also useful In Isolating or purifying the product.

Such pharmaceutically acceptable salts include those formed with e.g. hydrochloric acid.

A 29methanesulfonic acid, sulfuric acid and maleic acid. The salts are obtained by reacting the product with an equivalent amount of the acid in a medium in which the salt precipitates· As shown above» tbe peptide portion of the molecule of the products of formula X represented by R IL 0 ι r » -N-CH-C-X (I·) is ia the L-conf iguration. An asymmetric center is also present in the keto portion of the molecule when R^ is other than hydrogen. Thus, IS the compounds of formula X can exist in diastereoisomeric forms or in mixtures thereof. The above described processes can utilise racemates* enantiomers or diastereomars as starting materials· * When dlasterecmsric products are prepared, they can be separated by conventional chromatographic or fractional crystallisation methods· -30. The products of formula X wherein the imino acid ring is monosubstituted give rise to cis- . trans isomerism. The configuration ot the final product will depend upon the configuration of the Rj, Rg and Rg substituent in the starting'material of formula xxx.

The compounds of formula I, and the pharmaceutically acceptable salts thereof, are hypotensive agents. They inhibit the conversion of the decapeptide angiotensin I to angiotensin il and, therefore, are useful in reducing or relieving angiotensin related hypertension.

The action of the ensyme renin on angiotensinogen, a pseudoglubulin in blood, produces angiotensin X. Angiotensin X is converted by angiotensin converting ensyme (ACE) to angiotensin XX. The latter is an active pressor substance which haa been implicated as the causative agent in several forms of hypertension in various mammalian species, e.g., humans.

The compounds of this invention intervene in the angiotensinogen * (renin) * angiotensin X * angiotensin XX sequence by inhibiting angiotensin converting enzyme and reducing or eliminating the formation of the pressor substance angiotensin XX. Thus by the administration of a composition containing one (or a combination) of the compounds of this invention, angiotensin dependent hypertension in a species of mammal 30 (e.g., humans) suffering therefrom is alleviated. -31• A single dose, or preferably two to four divided dally doses, on a basis of about 0.1 to 100 mg·, preferably about 1 to 50 mg·, per kg. of body weight per day is appropriate to reduce blood pressure.

The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, intravenous or intraperitoneal routes can also be employed.

The compounds of this invention can also be 10 formulated ia combination with a diuretic for the treatment of hypertension, λ combination product comprising a conpound of this invention and a diuretic can be administered in an effective amount which comprises a total daily dosage of about 30 to COO mg., preferably about 30 to 330 mg. of a compound of this invention, and about 15 to 300 mg.« preferably about 15 to 200 mg. of the diuretic, to a mammalian species in need thereof· Xxenplary of the diuretics contemplated for use in combination with a compound of this invention axe the thiaside diuretics, e.g., chlorothiazide, hydrochlorothiazide, flvmethiaside, hydroflumethiazide, hendroflunethiazide, methyclothiazlde, trichloromethiazide, poly25 thiazide or bensthiaslde as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, ausolimine, bumetanide, triamterene, emiloride and spironolactone and salts of such conpounds.

The ccnpounds of formula X can be formulated for use in the reduction of blood -325 C · pressure 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 of formula Z is compounded with physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, and/or flavor, in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.

The compounds of formula I wherein X is -NH-CH-COOR also possess enkephalinase I * inhibition activity and are useful as analgesic agents. Thus, by the administration of a composition containing one or a combination of such compounds of formula X or a pharmaceutically acceptable salt thereof, pain is alleviated in the mammalian host. A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to about 100 mg. per kilogram of body weight per day, preferably about 1 to about 50 mg. per kilogram per day, produces the desired analgesic activity.

The composition is preferably administered orally but parenteral routes such as subcutaneous can also be employed.

The following examples are illustrative of the invention. Temperatures are given in degrees centigrade. IA-20 refers to a Sephadex chromatography gel commercially available from Pharmacia Pine Chemicals· AU percentages and ratios are by weight unless specified otherwise. Ether, hexane and’butanol are diethyl ether, n-hexane and n-butanol respectively, unless Indicated otherwise. Sephadex, Millipore· Merck and Avicel are Trade Marks. -34• Example 1 1- [N— (3~* (BenzoVlamino) -2-oxO4-phanylbutyl] -Lalanyl]-L-proline, monohydrochloride a) L-Alanyl-L-proline, phenylmethyl ester, p-toluen sulfonic acid salt N- [ (1,1-Oimethylethoxy) carbonyl ] -Lalanine (310.7 g.), L-proline, phenylmethyl ester, hydrochloride (396.2 g-ί, dicyclohexylcarbodiimide (338.6 g.>, hydroxybenzo10 triazole hydrate (251.5 g.), diisopropylethylamine (285.7 ml·), and tetrahydrofuran (5 liters) are combined at 0* (dicyclohexylcarbodiimide is added last) and stirred at room temperature overnight. The reaction mixture is filtered and concentrated. The residue is dissolved in 4 1. of ethyl acetate and washed with 54 eodium bicarbonate (2x2 1.), potassium bisulfate (2x2 1.) and water.

The ethyl acetate layer ie dried (MgSO^J and concentrated. The residue is dissolved in 3 1. of diethyl ether and left at ff overnight.

The mixture ie filtered and the filtrate concentrated to yield 620 g. of crude N-[(l,ldimethylethoxy) carbonyl] -L-alanyl-L-proline, phenylmethyl ester.

N-1 (1,1-Oimethylethoxy) carbonyl] -L-alanylL-proline, phenylmethyl eater (275 g.) is chilled in an ice bath and treated with 500 ml. of cold trifluoroacetic acid (freshly distilled) under argon and stirred at room temperature for • one hour. The mixture is concentrated in vacuo 5 and azeotroped twice with tdluene. The crude trifluoroacetic acid salt, an oil, is dissolved in 500 ml. of ether and treated slowly with stirring with a solution of p-toluenesulfonic r 10 acid hydrate ( 1 equivalent) dissolved in 6 1. of ether. The resultant precipitate is collected by filtration. The solid is dissolved in 1 1, of methanol and treated with 4 1. of ether and chilled. The resultant preci- 15 pitate ii collected and dried to give 300 g. of L-alanyl-L-proline, phenylmethyl ester, p-toluenesulfonic acid salt; m.p. 156-158 * b) 1-(Ν-Γ2-(1,1-Dimethylethoxy)-2-oxoethylJ- N- f (phenylmethoxy) carbonyl ] -L-a lanyl) -L- proline, phenylmethyl ester A mixture of L-alanyl-L-proline, phenylmethyl ester, p-toluenesulfonic acid salt (32.16 g., 20 72 mmole), tert-butyl bromoacetate (14.2 g·, 72 mmole), triethylamine (20.1 ml·, 144 mmole), and tetrahydrofuran (290 ml.) are stirred 25 at room temperature for 72 hours. Benzyl chloroformate (12.4 ml., 87.8 mmole) and triethylamine (12.5 ml., 87.8 mmole) are added and the mixture atirred overnight. The reaction product ia evaporated, and partitioned ’ between water and ethyl acetate. The ethyl30 acetate solubles are washed with dilute hydrochloric acid And then water. The ethyl acetate solution is then evaporated and chromatographed over silica gel (mesh 230 - 400, U.S. Standard sieve series) using the solvent system ethyl acetate/hexane -36(lsl) (7 χ 10 iLm 10 psi, pressure) to give 19.5 g. of 1-(8-(2-(1,I-dimethylethylethoxy)-2-oxoethyllM-((phenylmethoxy)carbonyl]-L-alanyl]-La proline, phenylmethyl ester. c) 1-(8-(Carboxymathyl) -N-[ (phenylmethoxy) carbonyl]-L-alanyl]-L-proline, phenylmethyl ' ester 1- (N" (2- (1,1-Dime thy lethoxy) -2-oxoethylJN-((phenylmethoxy)carbonyl] -L-alanyl]-L* proline, phenylmethyl ester (18 g·, 34.3 mmole) is dissolved in trifluoroacetic acid (50 ml.) and let stand at room temperature for 1.5 hours.

The mixture is evaporated and filtered through a small column of silica gel (200 g.) using the solvent mixture chloroform/methanol/acctic acid (9.6:0.2:0.2) to give 11.4 g. of 1-(N-(carboxymethyl) -N- [ (phenylmethoxy) carbonyl ] -Lalanyll-L-proline, phenylmethyl ester. d) 1-(8-(3- (Benzoy lamino) -2-oxo-4-phenylbutyl]-W20 f(phenylmethoxy)carbonyl]-L-alanyl]-Lproline, phenylmethyl ester I— (H- (carboxymethyl) -8- ( (phenylmethoxy) carbonyl] -L-alanyl] -L-proline, phenylmethyl ester (7.0 g., 15*0 nmole) is dissolved in dry tetra25 * hydrofuran(50 ml.) and cooled in an ice bath, oxalyl chloride (1.57 ml., 18 mmole) is added followed by 4 drops of dimethylformamide. After 15 minutes, the reaction mixture is stirred at room temperature for an additional period •37of one hour. The mixture is evaporated, redissolved < in tetrahydrofuran (30 ml.) and the solution ia cooled in an ice bath. The solution is added dropwise over a period of 5 minutes to an ice-cold solution of 2-phenyl-4- (phenylmethyl) -5(411)-oxazolone (3.96 g., 15.75 mmole) in tetrahydrofuran (24 ml·). Triethylamine (2.5 ml., 17.1 nmole) is added and the reaction mixture is stirred at room temperature overnight.

The mixture is filtered to remove triethylamine hydrochloride salt and the filtered tetrahydrofuran solution l.s evaporated and redissolved in pyridine (16 ml.)· 4-Dimethylamino pyridine (50 mg.) is added and the solution is stirred at room temperature for 3 hours. Glacial acetic acid (16 ml.) is added and lhe reaction mixture is heated at 100* for 45 minutes. The reaction mixture is then cooled, evaporated under vacuum, dissolved in ethyl acetate and extracted with aqueous sodium bicarbonate and dilute hydrochloric acid.

The ethyl acetate extract after evaporation is chromatographed over silica gel (230-400 mesh, U.S. Standard sieve aeries) using the solvent system ethyl acetate/ benzene (4:6) to obtain 4.9 g. of i-[N-[3-(benzoylanino)-2oxo-4-pttenylbutyll -H- ((pheny lmethoxy) carbonyl] L-alanyU-L-proline, phenylmethyl ester.

Anal, calc'd. for c40H4X»3O7 - 0.42 HjO: C, 70.31: H, 6.15: H, 6.17 Found: C, 70.31; N, 6.13: H, 6.08. -38• e) l-[N-[3-(Banzoylamlno)-2-oxo-4-phenylbutylIL-alanyl]-L-proline, monohydrochlorIda 1-[H-[3- (Benzoylamino) -2-oxo-4-phenylbutylJN-( (phenylmethoxy) carbonyl] -L-alanyl)-L-proline, phenylmethyl ester (1.0 g.) is dissolved in absolute ethanol (30 ml.) and In hydrochloric acid (2.25 ml·). Palladium-carbon catalyst (104, 200 mg.) is added and the solution is stirred under an atmosphere of hydrogen overnight.

* The catalyst is filtered 0ff and the solution Is evaporated. The crude product (700 mg.)is combined with 300 mg. of crude product from a previous small scale reaction and passed through a column of LH-20 (25 no x 380 no, 1 inch x 15 inch) in ceth anol. The fractions containing the desired product are ^pooled, evaporated, dissolved in water and filtered.

The clear aqueous solution is lyophilized to give 800 mg. of 1-(H-(3-(benzoylamino)-2-oxo-4phenyIbuty1 ] -L-alanyl ] -L-proline, monohydro20 chloride; [a)^ * -59.6 (c M 1*4, methanol); m.p. 98-130° (dec.)· Tic (silica gel, n-butanol/acetic acid/water, 4:1:1) Rf - 0.44. l Anal, calc'd. for C25H30H3O5Cl ’ °·75 H2°* C, 59.88; H, 6.33; N, 8.38; Cl, 7.07 Found: C, 59.82; H, 6.30; N, 8.42; Cl, 6.85. 39• Example 2 j- (N- [7-ftmino-3- (benzoy lamino) -2-oxoheptyll-l·alanyll -L-prollne, dihydrochlorlde a) B -Benzoyl-N - [ (phenylmethoxy?carbonyl 1 5 L-lysine To aa ice-cold solution of N6-[(phenyΙα» thoxy) carbony 1]-L-lysine (10.09 g., 36 mmole) in aqueous sodium hydroxide (IN, 26 ml.) is added benzoyl chloride (5 ml·, 43.2 mmole) and aqueous sodium hydroxide (4N, 10.8 ml.) simultaneously in 3 portions over a period of 30 minutes. TM ice bath is removed and stirring is continued,for an additional 1.5 hours at room temperature. The reaction mixture is then extracted with ethyl acetate (discarded), the aqueous mother liquor is acidified with dilute hydrochloric acid and extracted with ethyl acetate· The ethyl acetate extract is concentrated and the residue crystallised from ethyl acetate20 hexane to give 12.9 g. of N^-bensoyl-N®I (phenylmethoxy) carbonyl]-I*-lysine; m.p. 110-112* (109*). b) 2-Phanyl-4-(4-[( (phenylmethoxy)Carbonyllaminolbutyll-3 (4H) -oxazolone N^-Bensoyl-N*-( (phenylmethoxy) carbonyl] lysine (11.53 g., 30 mmole) is dissolved in tetrahydrofuran (55 ml.) and stirred in an ice-bath·. To this reaction mixture a solution of dicyclohexylcarbodiimide (6.8 g., 33 mmole) in tetrahydrofuran is added dropwise over a period -40• of 15 minutes. The ice-bath is removed after an hour and stirring is continued at room temperature for an additional 18 hours. Dicyclohexylurea is filtered off and the tatra5 hydrofuran is concentrated in vacuo. The residue is crystallized from ethyl acetate-hexane to give 9.4 g. of 2-pbenyl-4-(4-(((phenylmethoxy) carbonyl]amino)butyl)-5 (4H) -oxasolone; m.p. 72-73· (68·). c) l-(N-(3-(Bensoylamino)-7-p (phenylmethoxy)carbonyl|amino-2-oxoheptyl] -N- f (phenylmethoxy)carbonyll-L-aXahyD-L-prollne,' phenylmethyl ester 1- [N- (Carboxymethyl) -N- ((phenylmethoxy) carbonyl] -L-alanyl] -L-proline , phenylmethyl ester (2.82 g., 6 mmole), from Example 1(c), is dissolved in totrahydrofuran (20 *1.) and the solution is stirred in an ice-bath. Oxalyl chloride (0.63 ml·, 7.2-mmole) is added followed by four drops of dimethylformamide. After stirring this reaction mixture in an ice-bath for 20 minutes, it is then stirred at ambient temperature for an additional hour. The solvents are removed in vacuo and the residue is redissolved in totrahydrofuran (10 ml.) and cooled in an ice-bath, to this cold stirring solution is added a cold solution 2-phenyl-4-[4-[((phenylmethoxy)carbohyl]amino]butyl]-5 (4H) -oxasolone (2.2 g., 6 mole) in totrahydrofuran (14 ml.), followed by triethylamine (0.85 ml., 6 mmole).

The ice-bath is removed and the reaction mixture . is stirred at ambient temperature overnight.

The precipitated triethylamlne-hydrochloride is removed by filtration and the mother liquor is concentrated in vacuo. It is then redissolved in pyridine (6 ml.), 4-dimethylamino pyridine (30 mg·) is added, and the solution is stirred at room temperature for 3 hours. Acetic acid (6 ml.) is added and the reaction mixture is heated at 105° for 45 minutes, xt is then evaporated, taken up into ethyl acetate, and washed with water, dilute hydrochloric acid, and aqueous sodium bicarbonate. After evaporation of the solvent, Lue crude product (3.8 g.) is chromatographed (silica gel, 230 g.) using ethyl acetate-hexane (4:3) followed by ethyl acetate-hexane (2:1) for elution to give 1.8 g. of 1- (N- (3- (bensOylamino) -7-(((pheny lmethoxy) carbonyl) amino] -2-oxoheptyll -M-l (pheny lmethoxy) carbonyll-L-alanyll-L-proline, phenylmethyl ester. dfr 1- [N- (7-Aminb-3-|ben 1-(11-(3- (Benzoy lamino) -7-( ((pheny lmethoxy) carbonyl] amino] -2-oxoheptyll -M- [ (pheny lmethoxy) carbonyl]-Xralanyl]-b-proline, phenylmethyl ester (1.3 g., 1.6 nmole) is‘dissolved in ethanol (75 ml.) and aqueous hydrochloric acid (IN, 5 ml.). Palladium on carbon catalyst (10%, 450 mg.) is added and the mixture is hydrogenated at atmospheric pressure overnight. The catalyst is filtered off and the solution is evaporated -42* in yacuo. The residue is dissolved in water and lyophilized. The lyophilate is triturated with ether to give 0.6 g. of l-[N-[7-amino-3-(benzoylamino) -2-oxoheptyll -L-alanyl] -L-proline, hydrochloride/ m.p. 80-155°/ (alp^ M -50° (c - 1.1, methanol). R^ 0.09 (silica gel, n-butanol/acetic acid/water, 4:1x1).

Anal, calc’d. for C22H32»4O5 · 2HC1 · 1.3.R2O: C, 49.63/ H, 7.00; N, 10.52; Cl, 13.55 10 Found: C, 49.63; H, 6.82; N, 10.48; Cl, 13.36.

Example 3 1- [N- (3- (Benzoylamino | -2-oxoheptyl] -L-alanyl] -Lproline, monohydrochloride a) M-Benaoyl-D,L-norleucine D/L-Norleucipe (39.3 g., 300 mmole) is taken up into sodium hydroxide (2N, 150 ml.) and while stirring in an ice-bath sodium hydroxide (2N, 150 al.) and benzoyl chloride (330 mmole, 38.3 ml.) are added over a 30 minute period.

The bath is removed and after 1.5 hours the reaction mixture is extracted with ether. The aqueous portion is acidified with 2N hydrochloric acid and the crystals filtered to give 68.9 g. of N-benzoyl-D,L-norleucine; m.p. 131-133° (125°). b) 4-Butyl-2-phenyl-5 (4H) -oxazolone N-Benzoyl-D,L-nprleucine (40 g., 170 mmole) is taken up into tetrahydrofuran (300 ml.) with stirring in an ice-bath. To this reaction mixture a solution of dicyclohexylcarbodiimide 43(38.52 g.f 187 mmole) in tetrahydrofuran (195 ml.) ie added dropwise over a period of 15 minutes. The ice-bath is removed and stirring is continued at room temperature for an additional 18 hours. Dicyclohexylurea is filtered off and the tetrahydrofuran is concentrated in vacuo. The residue (31.7 g.) is purified on silica ia hexane:ether (2:1) to yield 32.1 g. of 4-butyl-2.-phenyl-5(4H)-oxazolone. c) l-fM-p-(Ben»OYlamlnoj-2-oxoheptyl1-N-f (phenylmethoxy)carbonyl!-L-alanyl]-L-proline, phenylmethyl ester < A eolution of 1-[N-(carboxymethyl)-N((phenylmethoxy) carbonyl] -L-alanyl] -L-proline, phenylmethyl ester (1.41 g., 3mmole), from example 1(c), ia tetrahydrofuran (10 ml.) is cooled in an ice-bath. While stirring, oxalyl chloride (0.32 ml., 3.7 mmole) is added followed by 4 drops of dimethylformamide· The reaction mixtufe is stirred in the ice-bath for 20 minutes and then at room temperature for one hour. Xt is evaporated in vacuo, redissolved in tetrahydrofufan (5 ml.) and cooled in an ice-bath. A cold solution of 4-butyl-2-phenylS(4H)-oxazolone (0.65 g., 3 mmole) in tetrahydrofuran (5 mi.) ia added dropwise followed by triethylamine (0.43 ml·, 3.1 mmole). The reaction mixture is' stirred at ambient temperature overnight. After filtering off triethylamine hydrochloride, the tetrahydrofufan solution is -44• concentrated in vacuo. The residue is redissolved ln pyridine (3 ml.), 4-dimethylamino pyridine (15 mg.) is added, and the reaction mixture is stirred at room temperature for 3 hours. Acetic acid (3 ml.) ia added and the reaction mixture is heated at 100* for 40 minutes. It is then evaporated, redissolved in ethyl acetate and washed with water, saturated sodium bicarbonate, dilute hydrochloric acid, and water. After evaporation, the residue is chromatographed over ailica gel using the solvent system ethyl acetate: benzene (4:6) togive 0.8 g. of 1-(8-(3-(benzoylamino) -2-oxoheptyl] -8- ((phenylmethoxy) carbonyl J -Lalanyl]-L-proline, phenylmethyl ester. d) 1-(8-(3-(Benzoylamino)-2-oxoheptyll-L-alanyl]L-proline, monohydrochloride 1-(8-(3- (Benzoylamino) -2-oxoheptyl] -8((phenylmethoxy) carbonyl] -L-alanyl] -L-proline, phenylmethyl ester (0.96 g·, 1.5 mmole) is dissolved in ethanol (75 ml.). Hydrochloric acid (IN,2ml.) ia added followed by palladium on carbon catalyst (104, 200 mg·)· The solution is stirred under an atmosphere of hydrogen overnight. The catalyst ia filtered off, the ethanolic solution is evaporated, and the residue is dissolved in water and lyophilised to give 0.62 g. of 1-(8-(3(benzoy lamino) -2-oxoheptyl] -L-alanyl] -L-proline, monohydrochloride; m.p. 86-123*;< (β)^ e -62.9* (c « 1.05, methanol). R^ °-57 (silica gel, .30 n-butanol/acetic acid/water; 4:1:1). -45Anal. calc’d. for C22H31N3°5 HCl 2H2O: C, 53.85; H, 7.40; N, 8.57; Cl, 7.23 Founds C, 53.85; H, 7.20; N, 8.73; Cl, 7.29. gxampla 4 I- tH- [3- (Benzoylamino} -2-oxo-4- (3-pyridinyl)butyll h-alanylj-L-prollne, dihydrochlorlde a) 2-(Benzoy laaino)-3-(3-pyridinyl)-2-propenoic acid 2-Phenyl-4-(3-pyridinylmethylene)-5<4H)oxazolone (3 g., 12 mnole) (see Griffith et al., J. Org. Chem·, Vol. 29, p. 2659] ia diszolved in acetic acid (24 ml.) and aqueous hydrochloric acid (0.5 M, 150*ml.). The reaction mixture is stirred overnight at room temperature. It is evaporated and reevaporated from absolute ethanol.

Xt is triturated with tetrahydrofuran, filtered, and the filtered solid is retriturated with absolute ethanol to yield 2.8 g. of 2-(benzoylamino) 3- (3-pyridinyl) -2-propenoic acid; m.p. 215-2.16* (203*). b) 2- (Benzoylamino) -3-( 3-pyridinyl) -2-propanolc acid 2- (Benzoylamino) -3- (3-pyridinyl) -2-propenoic acid (14 g., 46 mmol·) is dissolved in water (500 ml.) and hydrogenated using palladium on carbon catalyst (10V i-8 g.) overnight. The catalyst is filtered off, and the reaction mixture is evaporated to a small volume (100 ml.) and lyophilized to give 13.1 g. of product. . The lypphilate ia triturated with absolute ethanol-ether mixture and filtered to give 12 g. of 2-(.benzoylamino)-3-(3-pyridinyl)-ΧΙΟ propanoic acid; m.p. 99S"115·. -46. c) i-rK-(3-(Benzoylamino)-2-oxo-4-(3-pyridinyl) butyl]-H- (f pheny lmethoxy) carbonyl ] -L-alanyl) -Lprollne,phenylmethyl eater 1- (N- (Carboxymethyl) -N- ( (pheny lmethoxy) τ carbonyl]-L-alanyl]-L-proline, phenylmethyl ester (6.2 g., 13.1 mmole), from Example 1(c), Is dissolved in tetrahydrofuran (20 ml.) and the solution is stirred in an ice-bath. Oxalyl chloride la added followed by four drops of dimethylformamide. After stirring this reaction mixture in an ice bath for 20 minutes, it is then stirred at ambient temperature for an additional hour. The solvents are removed In vacuo and this residue is redissolved in tetra15 hydrofuran (20 ml.)· 2- (Benzoylamino) -3- (3-pyridinyl) -2-propanoic acid (4 g., 13 mmole) is suspended in tetrahydrofuran (45 ml.), and while stirring in an ice-bath, triethylamine (1.96 ml., 14 mmole) and dicyclo20 hexylcarbodiimide (2.96 g., 14 nmole) are added.

The reaction mixture is stirred at room temperature overnight. Xt is then filtered, and the filtrate evaporated to dryness. This residue ia dissolved in tetrahydrofuran (30 ml.) and stirred in an ice bath. To this solution is added the above solution of 1- [N- (carboxymethyl) -N- ((phenylmethoxy)carbonyl]-L-alanyl]-L-proline, phenylmethyl ester, acid chloride in tetrahydrofuran (20 ml.)· Triethylamine (1.9 ml., 13.6 mmole) is added, and the reaction mixture is stirred at room temperature 47• overnight. Xt is filtered to remove triethylamine hydrochloride. The filtrate is evaporated in vacuo, redissolved in pyridine (15 ml.), 4-dimethy lamino pyridine <65 mg.) is added, and the reaction mixture is stirred at room temperature for 3 hours. Acetic acid (16 ml.) is added and the reaction mixture is heated at 100° for 45 minutes. Xt Is then evaporated, redissolved ln ethyl acetate, and washed with aqueous sodium bicarbonate and water. After evapora10 tion, the ethyl acetate extract is chromatographed over silica gel using ethyl acetate for elution to give 3.3 g. of l-rN-[.3-(bensoylaaino)-2-oxo-4(3-pyridinyl) butyl] -N- [ (phenylmethoxy) carbonyl] -Lalanyl]-L-proline, phenylmethyl ester. d) l-(N-(3- |BenfOYlamino)-2-oxo-4-(3-pyridinyl) butyll-L-alanyll-L-proline, dihydrochloride The phenylmethyl ester product from part (c) (2.6 g., 3.84 mmole) is dissolved in ethanol (75 ml.) and aqueous hydrochloric acid (IN, 8 ml.) is added followed by palladium on carbon catalyst (104, 0.6 g.)· After hydrogenation for 16 hours, an additional 0.5 g. of catalyst is added and hydrogenation is continued for 6 more hours. The mixture is filtered, evaporated and combined with a similar reaction product obtained by hydrogenation of 0.8 g. of the'ester product of part (c). The hydrogenated material is then chromatographed over LH-20 in water to obtain' the homogeneous product.

An aqueous solution of this material is treated > with aqueous hydrochloric acid* (1 N, 3 ml.) and -48. the solution is lyophilized to give 1.0 g. of 1- IN-1.3- (benzoylamino) -2-oxo-4- (3-pyridinyl) butyl] L-alanyl]-L-proline, dihydrochloride; m.p. 120 - 135·» (a]22 - -55.5· (c - 1.1, methanol).

R* 0.11 (silica gel; n-butanol/acetic acid/water; 4:1:1).

Anal calc'd. for c24H2gN4°5 * 2HC1 * 2H2Oi C, 51.35; H, 5.75; N, 9.98; Cl, 12.63 Found: C, 51.35; R, 5.84; N, 9.96; Cl, 12.84.

Example 5 1-IN-[3-(Benzoylamino)-4-(4-hydroxyphenyl)-2-oxobutyl |-L-alanyl1LL-prollne ? moriohydrochloride a) 2-Phenyi-4-f(4-(phenylmethoxy)phenyl]inethy-ll5(4H)-oxasolone O-Benzyl-L-tyrosine (11.0 g., 40.5 mmole) is taken Into 0.5 N sodium hydroxide (81 ml.) and water (81 ml.) with vigorous stirring in an . ice-bath. To this in' five equal portions is added a total of .52 ml. of benzoyl chloride, 45 ml. of IN sodium hydroxide and an additional 400 ml. of water over a 25 minute period. The bath is removed and the reaction is run for 2 hours at room temperature. The mixture is extracted twice with ethyl acetate. The aqueous portion is filtered, ‘ acidified with IN hydrochloric acid and the crystals filtered to give 12.9 g. of N-behzoyl-O-bcnzyl-Ltyrosine; m.p. 166-168· (162·).

This N-benzoyl-O-benzyl-L-tyrosine (12.76 g., 35 mmole) la taken into dry tetrahydrofuran (50 ml.) with stirring in an ice-bath. To this dicyclonexyl-49carbodiimide (7.7 g., 37.4 mmole) in tetrahydrofuran (18 ml.) is added dropwise. After 20 minutes, the ice-bath is removed and the reaction proceeds overnight at room temperature. The dicyclohexylurea is filtered off and the filtrate is concentrated to dryness. The crude product is crystallized from ether/hexane to, give 10.26 g. of 2-phenyl- * 4-((4- (phenylmethoxy) phenyl (methyl] -5 (4H) -oxazolone; m.p. 85*87° (83°). b) 1* (N- [3- (Benzoylamino) γ2-οχο-4-(4- (phenylmethoxy) - . phenyl] butyl] -N- {(phenylmethoxy) carbonyl ] -L-a lanyl ] L-proline, phenylmethyl ester 1- (N- (Carboxymethyl) -N- ((phenylmethoxy) carbonyl]-L-alanyl]-L-proline, phenylmethyl ester (2.82 g«, 6 mmole), from Example 1(c), is dissolved in tetrahydrofuran (20 ml.) and the solution is stirred in an ice-bath. Oxalyl chloride (0.63 ml·, 7.2 nmole) is added followed by four drops of dimethylformamide. After stirring this reaction aixture in an ice-bath for 20 minutes, it is then stirred at ambient temperature for an additional hour. The solvents are removed In vacuo and the residue is redissolved in tetrahydrofuran (10 al.) and cooled in an ice-bath.

To this ‘cold stirring solution is added a cold solution 2-pheny 1-4-( [4-(phenylmethoxy)phenyl]methyl)-5.(4B)-oxazolone (2.14 g., 6 mmole) in tetrahydrofuran (40 ml.). Triethylamine (0.84 ml., mmole) is added and a basic atmosphere is maintained throughout the reaction by adding -50• additional necessary amounts of triethylamine.

The reaction mixture is stirred at ambient temperature overnight. It is then filtered and the filtrate is evaporated and redissolved in 5 pyridine (7 ml·). 4-Dimethylamino pyridine (30 mg.) is added and the reaction mixture is stirred for 3 hours at room temperature. Acetic acid (7 ml.) is added and the reaction mixture is heated at 100* for 45 minutes. It is then * evaporated, the residue is redissolved in ethyl acetate and washed with saturated eodium bicarbonate and dilute hydrochloric acid. The neutral ethyl acetate extract ia evaporated and chromatographed over silica gel (300* g.) using the solvent system ethyl acetate:bensene (6.5:3.5) to give 2.7 g. of 1- (8-(3- (benzoy lamino) -2-oxo-4- (4-(phenylmethoxy) phenyl ] butyl ] -8- [ (phenylmethoxy) carbony 1 ] -Lelanyl]-L-proline, phenylmethyl ester. c) 1-(8-( 3-(Bensoylamino)-4-(4-hydroxyphenyl)-220 oxobutyl] -L-alanyl ] -L-proline, monohydrochloride .

The ester product from part (b) (1.8 g., 2.26 mnole) is dissolved in ethanol (150 ml.) containing aqueous hydrochloric ’ acid (18, 3.5 ml.). Palladium on carbon catalyst (104, 500 mg.) is -51- added and the solution Is stirred under an atmosphere of hydrogen overnight. Xt is evaporated, dissolved in water, and lyophilised to give l-[N-l3-(benxoylamino)-4-(43 hydroxyphenyl-2-oxobutyl) -L-alanyl) -L-proline, monohydrochlorlde; m.p. 118-152·; (e)£2 » - 43.1* (c " 1.07, methanol).

Rf 0.47 (silica gel, n-butanol/acetie acid/water; 4:lil).

Anal, calc'd. for C25B29N3°6 * HC1 * *20: C, 57.42; H, 6.16; N, 8.04; Cl, 6.78 Founds C, 57.42; H, 6.03'j M, 8.04; Cl, 7.11· -52Examplea 6-62 Following the procedure of Examples 1-3 and 5, the peptide ester shown in Col· X is treated to give the carboxymethyl peptide ester shown in Col. II; Conversion to its acid chloride and further reaction with the oxasoldne of Col. XXX yields the N-protected ester product of Col. IV. Removal of the N-protecting group and the ester group yields the final product of Col. V wherein Rg is hydrogen.

Col. I R. 0 I1 * H.N-CH-C-X 2 Col. IXI — C-0 -53Col. XV Rj-CH I NH I oo I *2 Rl° I H -C-CH--N-CH-C-X | (M C-O-CH I r® Col. V R. O I ri Rj-CH-C-CHj-NH-CH-C-X NH I OO I *2 ♦ i Bxaaple Λ X B C Vl I I κ3° H r3o > CljCH^C10 »3 X <5K- a (°>*ν - .Τ'® TaS^^’a a @r«2- ·—rS··® ♦ h3c13 Vi X H>C15 '· 14 B3C* ΒΧΟφΙβ Β^ r3cΧβ BjC19 HjC- »2 »3 ·* X π ν»-®- 4n® Β ®- Fjt 0 H bb-c-c2b5 H ©- (ry^’r 0 X> ·4γ">© "V. *3 X (0-4--, .B.C0B.C —hrM B B.C- H.CCB, . I Γ© "‘«Λ H C 5 2 Ol H.C<2®, » * « Exaaple E^ BjC24 B3C- X Bxasple *1 » PjC2Ί C28 V>~ »3C" *2 »2 ©- @-‘"2»2- ©- ©*»- ©-'"i'j- (SX ®-(α*Λ- «*—Hcooctcx.).

Jl (M 4-UoOCCBj-^) , »3 2 Η I 114 a *—(ίΕΪ^ζ-® Bxaapla R^ BjO* BjC33 HjC· Ba *3 ©«V X X^tfOOO.-® u ^iS00e»2’© V 8 U- ©V H ©- ©«3- yi-coocHj-© H X Va HjC- Bttapla Ri "a o X @*2®·®"«,«- -»4 Λ (SV,,C· I ΓΓν *§>" ϊ»Γ® a3C-S-(B2C)2- ©- Sxaapls R^ HjC44 HjC- H Bxaopla ftj ·> HjC47 FjC" ©-B2C* 5V ©- -m-CB2-°ooa,2© ©·<«?«- M»-CH-000CH_—/0) |2 ®3 ®- B- -WH-CH-COOCHj^) 1 (L) ?2 CBCCII3)2 ©- -XH-CH-C0OCH_-(O) |2·@ Bxaaple v51 BjC- - @*a- -HB-CH-COOCH -/5) |(L) 2X±y ^Locb2-© "j© I 0» QD 1 ©- "τφ® H ©- (γ)-»,- -HH-CH-COOCH ,-<5> j(L) 2 "ΠΠ °«i© M HjC55 A HjC- *3 X ©- H3C-(HaC)5- •ηϊΤ·»·® · A ©- Ci o -KB-CH-COOCIE_-45) 1ω 1 Olj-e-CHj-© · I <§>»,- • -XH-CH-CO0CH_-/O^ 1« JX *2 3 s NHK>2 ©- -XH-C8-C00CH -(5S I (Ϊ.) 2 2 2 II 2 η ·3ο5» BjOΜ BjC- Χ\ Ο 0 -a—Lc-o-ai-o-is-eA 1 Μ 1 1 * Β ό ©- <Ο>Ι- ι—1 β 8 . >< 0 0 1 •J Ο • ©‘"Λ- 1 <μ ι β «ΐαψ2 ϊ® Η CH.

X ex ajs62 72• The protecting groups in Examples 20,36 to 39 and 41, the Rj protecting groups in Examples 43 and 44, and the Rj protecting groups in Examples 49, 50, and 52 to 55 are removed as the last step in the synthesis. The Rg ester groups shown in Examples 57 to 62 are not removed.

Example 63 1- IW- F (S) -3- (Benzoylamino) -2~oxo-4-phenylbutyl] -Lalanyl) -L-prollne, monohydrochloride ® a) (S) -3-Rmino-l-chloro-4-phenyl-2-butanone * hydroqen bromide (S) - (3-Chloro-2-oxo-l- (phenylmethyl) propyl I carbamic acid, phenylmethyl ester (51.4 g.) is dissolved in a mixture of acetic acid (252 ml.) and hydrogen bromide in acetic acid(3.45 N, 348 al.) and kept at room temperature for 1.5 hours. The reaction mixture is then concentrated in vacuo and precipitated with ether to obtain 36.6 g. of (S)-3-amino-lchloro-4-phenyl-2-butanone, hydrogen bromide; 0 a.p. (175·» 177-17»·. b) (S) 13-Chloro-2-oxo-l- (phenylmethyl) propyl 1 benzamide (8) -3-Amino-l-chloro- 4-phenyl-2-butanone, hydrogen bromide (36.3 g., 130.3 mmole) ie 5 suspended in 520 ml. of dry tetrahydrofuran and 18.2 ml. of triethylamine (130.3 mmole) with stirring for ten minutes. The mixture is placed in an ice bath and 15.2 ml. of benzoyl chloride is added followed by 10.95 g. of sodium bicarbonate.

® After 5 minutes the ice bath is removed and the • reaction mixture ie kept at room temperature for 1.5 hours· The reaction mixture ifl then concentrated in vacuo and the residue taken up in 1 1. of aqueous methanol (10% water).

The precipitate is collected, filtered and washed with methanol to obtain 23.3 g. of (S)-β-l3-chloro2-oxo-l-(phenylmethyl)propylI-benzamide;m.p. (160·) 170°-172· (dec.)f to]23- -129*(c 1.7, dlArtWltenaadde). c) 1- ΓΝ-t (8) -3- (Benzoylamino) -l-oxo-410 phenylbutyll-L-alany11-L-proline, 1,1-dimethylethyl ester L-Alanyl-L-proline, 1,1-dimethylethyl ester (2.42 g., 10 mmole), sodium bicarbonate (840 mg.) and (S)-»-(3-chloro-2-oxo-l15 (phenylmethyl)propyl)benzamide (3.01 g.) «bs combined in SO ml. of dimethylformamide under an argon atmosphere at room tenperature with stirring overnight. The reaction mixture is then concentrated in vacuo to about half its original volume and the residue ia taken «φ in ethyl acetate and washed with saturated sodium bicarbonate to give 2.23 9· of crude product.

This material ie taken up in ethyl acetate: methanol(95:S)and applied to a silica gel column (135 g.) and eluted with ethyl acetate: methanol (93:3)to give 860 mg. of 1-(K-((8)-3(bensoylamino) -2-oxo-4-phenylbutyl] -Lalanyl]-L-proline, l,l-*dimathy lathy 1 ester. -74• d) 1- (N~ ί (S) 3 (Benzoylamino) -2-oxo-4-phenylbutyl) -L-alanyl) -L-proline, monohydrochlorlda 1- [N- ((S) -3- (Benzoylamino) -2-oxo*4phenylbutyl]-L-alanyl)-L-prollne, 1,1-dimethyl5 ethyl ester (740 mg·, 1.46 nmole) is dissolved in a solution of hydrogen chloride in acetic acid (1.5 M, 10 ml.) and kept at room temperature for 30 minutes. Xt is then concentrated, taken into water, filtered and lyophilized to obtain 600 mg. of l-ftN-(S)-3-(benzoylamino)-2-oxo-4phenylbutyl]-L-alanyl]-L-proline, monohydrochloride; m.p. 83 - 163*1 ( [«]" - -109* (c - 1.0«. methanol) Rg 0.6 (silica gel; butanol/acetic acid/water, 4:1:1).

Anal, calc'd. for C25H29N3°5 * 801 * 1,65 R2°: C, 57.99; R, 6.48; R, 8.12; Cl, 6.85 Found: C, 57.99; H, 6.39; V, 8.09; Cl, 6.95.

Example 64 (S) -1- (3- (Benzoylamino) -2-oxo-4-phanylbutyl] -L20 lysyl]-L-prollne, dihydroehloride a) 1- (Ν*- K1 f 1-Plmethylethoxy| carbonyl^ -N*[ (pheny lmethoxy) carbonyl] -L-lysyl] -L-proline, 1,1-dimethylethyl ester H®-[(1,1-Dimethylethoxy) carbonyl] -M2- ((phony 125 methoxy)carbonyl]-L-lysine '(9.51 g.) and hydroxy- . benzotriazole (3.825 g.) are taken into 25 ml. of dimethylformamide with stirring in an ice-bath under an argon atmosphere· To this is added L-proline, 1,1-dimethylethyl ester (4.49 g.) followed by Ν,Ν'-diisopropylethylanine (2.2 ml.) and dicyclo5 ί -75hexyl carbodi Imide (5.15 g.). After 15 minutes tha bath ie removed and the reaction is allowed to proceed for 6.5 hour at room temperature. The dimethylformamide is removed in vacuo. The residue is taken into ethyl acetate and the dicyclohexylurea ie filtered off. The filtrate is washed neutral with 105 potassium bisulfate and saturated sodium bicarbonate. The crude product (13.26 g.) ia purified on silica gel column eluting with ethyl acetateshexane (2:1) to give 13.0 g. of 1- [N*- ((111-dimethy lethoxy) carbonyl] -N2((phenylmethoxyJcarbonyl]-L-lysyl]-L-proline, 1,1-dimethylethyl ester. b) (S)-1-(N2-|3-fBenzovlamino)-2-oxo-4-phenylbutyll-X —f(Ifl^dimethylethoxy|carbonyll-L-Iysyl]L-prollne, 1,1-dimethylathy1 ester The ester product from part (a) is reduced in ethanol with palladium on carbon catalyst (104) to yield 3.99 g. of l-[Me-Il,l-dii».thyl.thoxy)carbonyl]-L- lynyl]-L-proline, 1,1-dimethylethyl ester. This material is taken into 40 ml. of dimethylformamide and treated with (S)-M(3-chloro- 2-oxo-l- (phenylmethyl ) propyl ] benzamide (3.01 g.>, from Example 53(b), and sodium bicarbonate (640 mg.). After stirring for 18 hours at room temperature, the reaction mixture is concentrated in vacuo, taken into ethyl acetate and washed with saturated sodium bicarbonate. The' crude product (7.0g.) is purified on a silica gel column eluting with ethyl acetates14 methanol to give 1.7 g. of I -762 • (S) -1- (N -(3- (benzoylamino) -2-oxo-4-phenylbutyl] X6-( (l,l-dimethylethoxy)carbonyl]-L-lyayl)-Lproline, 1,1-dimethylethyl ester. c) (S) -1-[M2-I3- (Bensoylamino) -2-oxo-4-phenyl5 butyl) -L-lysyl] -L-proline, dihydrochloride The ester product from part (b) (1.6 g.) is treated for 30 minutes at room temperature with 20 ml. of 1.3 B hydrochloric acid:acetic acid, concentrated to dryness, and triturated to a solid with ether to give 1.37 g. of crude product.

This material is taken into water, millipore filtered, and lyophilised to give 1.28 g. of product.

Further purification is performed on an LH20 column in water to give 740 mg. of (S)-l-(N2-[31S (bensoylamino) -2-o.xo-4-phenylbutyl] -L-lysyl] -Lprollne, dihydrochloride; m.p. 120 - 180·; (a)25 - -84.8* (c · 1.05, methanol). Rf 0.61 (trace at 0.9) (silica gel, chloroform/methanol/ acetic ecid, 60, 40, 384 20).

- Anal, calc'd. for C28B36N4°5 * 2HC1 * 3H2O: C, 52.98; B, 6.98; B, 8.83; Cl, 11.17 Founds C, 52.98; B, 6.93; B, 8.66; Cl, 11.31.

Example 65 W-(B-{f(S)-3-(Benzoylamino^-2-oxo-4-yhenvlbutvl125 L-alanyl j -B-cycIoheacyl^lyclney monohydrochloride a) H-Cyclohexylglyclno, 1,1-dimethylethyl ester Cyclohexylaaine (70.35 ml.) and sodium bicarbonate (12.9 g.) are suspended with stirring in 200 ad. of absolute ethanol while stirring in an ice-bath. TO thia is added bromoacetic acid, • 1,1-dime thy lethyl ester (20.78 ml.) dropwise. The ice-bath is removed. After 24 hours at room temperature, the reaction mixture is concentrated to dryness, taken into chloroform and washed with water. The crude product (42 g.) is chromatographed on silica gel eluting with ethyl acetate: hexane (2:1) to give 27.4 g. of N-cyelohexylglycine, 1,1-dlmethy lethyl ester. b) W-Cyclohexyl-W- FM- [ (phenylmethoxy) carbonyl 1 -L10 alanyllglycine, 1,1-dimethy lethyl ester M- ((Fhenylmethoxy)caxbonyl] -L-alanlae (4.46 g.), M-cyclohexylglycine, 1,1-dimethylethyl ester (4.26 g.), hydroxybensotrlaxole (3.06 g.), dicyclohexylcarbodiimide (4.12 g.), and triethyl15 amine (2.8 al.) are stirred in 40 ml. of dimsthylfonunide at roc» temperature for 20 hours. The reaction mixture is then concentrated in vacuo, taken into ethyl acetate, the dicyclohexylurea is filtered off, and the filtrate is washed neutral with 10« potassium bisulfate and saturated sodium bicarbonate to give 5.9 g. of crude product. Crystallisation from «ther:hexane yields 3.97 g. of S-cydohexyl-N- (M- ((phenylmethoxy) carbonyl] -Lalanyl I glycine, 1,1-dimethylethyl ester; m.p. 104 - 105·.................... c^ M-tL-Alanyi)-M-cyclohexylglycine, 1,1dimethylethyl ester The ester product from part (b) (3.9 g.) is taken into methanol with palladium on carbon catalyst (104, 700 mg.) and stirred under v -78• hydrogen atmosphere for 4 hours. The reaction mixture is filtered and concentrated to dryness to give 2.65 g. of crude W-(I»-alanyl)-K-cyclohexylglyclne, 1,1-dimethylethyl ester. d) W- (W- [ [ (S) -3- (Bensoy lamino) -2-oxo-4-Phenylbuty 1] L-alanyil -K-cyclohaxylqlyclne, 1,1-dlmethylethy1 eater The crude ester product from part(c) (2.6 g.), eodium bicarbonate (764 mg.), and (S)-N10 (3-chloro-2-oxo-l- (phenylmethyl) propyl] benzamide (2.75 g.), from Example 63(b), are stirred for 20 hours in 25 ml. of dimethylformamide. The reaction mixture is concentrated to dryness, taken into ethyl acetate, and washed with saturated sodium carbonate to give 4.7 g. of crude product. Purification on a silica gel column eluting with ethyl acetatesmethanol (99:1) yields 1.5 g. of H- (H- ( ((8) -3- (bensoy lamino) -2-oxo-4-phenylbutyl) -Lalanyll-W-cyclohexylglycine, 1,1-dimethyls thyl ester. e) t M-18- f f (8} -3- (Benzoylamino} -2-oxo-4-phanylbutyl}-L-alanyll-B-cyclohexylglvcino, monohydrochlorlde . The ester product from part(d) (500 mg.) is treated for 30 minutes with 5 ml. of 1.5 8 hydrochloric acid:acetic acid and then concentrated to dryness at room temperature. The crude product is taken into methanol and purified on an LH20 column to yield 413 ng. of product. This is made semi-crystalline in acetonitrile:ether to give -79. Η- (Ν-11 (S) -3- (benzoylamino) -2-oxo-4-phenylbutylJ L-alanyl) -fy-cyclohexylglycine, monohydrochloride; m.p. 154 - 157· (132·); (a)23 * -67.4· (c « 1.35, methanol). Rg 0.60 (minor impurity at 0.92) (silica gel, chloroformsmethanols cone, annonia, 30x10x2).

Anal, calc'd. for C28H35K3°5 * HC1 * V C, 61.35; Η, 6.99; N, 7.67; Cl, 6.47 Founds C, 61.08; H, 6.79; Η, 7.65; Cl, 6.46.

Example 66 W-(W-t ί (S) -3-(Benzoylamino) -2-*>xo-4-phanylbufcyllX^alanyll-B-phenylglycine, monohydrochlorlde a) M-Phenylglycine, 1,1-dimethy lethyl ester A solution of triethylamine (11.25 g-, 0.11 mole) and aniline (9.3 g., 0.10 mole) in ether (100 ml.) under an argon atmosphere is cooled to 0· in an ice-bath. TO this is added bromoace tic acid, 1,1-dimethy lethyl ester (18 g·, 0.093 mole) over a period of 30 minutes. The resulting mixture lu stirred at 0· for one hour, then warmed to room temperature, and stirred overnight. The solution is filtered and rinsed with ether and the filtrate concentrated to yield 6.9 g. of a yellow oil. 8^ 0.6, 0.7 (silica gel, ethyl acetate). Chroma25 tography on LF8-1 using hexanes ethyl acetate (7x3) as eluant gives 2.3 g. of H-phenylglycine, 1,1-dimethy lethyl ester as a pale yellow liquid.

Rg 0.7 (silica gel, ethyl acetate). -80. b) N-Phenyl-N- [N- ((phenylmethoxy) carbonyl] -Lalanyl] glycine, 1,1-dimethylethyl ester A solution of H-l (phenylmethoxy) carbonyl ] -Lalanine (2.8, 12.7 mmole) in dry tetrahydrofuran S (50 ml.) under argon is cooled in a dry ice-ethanol bath. To this is added N-methylmorpholine (1.28 g., 12.7 nnole) and ieobutylchlorgformate (1.73 g., 12.7 mmole). After 20 minutes N-phenylglycine, 1,1-dimethylethyl ester (3.7 g., 12.7 mmole) Is added. The resulting mixture is stirred at -20* for one bout, then at room temperature overnight.

The mixture is partitioned between ethyl acetate and IN hydrochloric acid. The organic layer ia washed successively with IN hydrochloric acid and 104 sodium bicarbonate, dried (MgSOg), and concentrated. Chromatography on LPS-1 eluting with a gradient of.ethyl acetate:hexane (3:1 *1:1) gives 4.0 g. of N-phenyl-N-[N-( (phenylmethoxy) carbonyl]-L-alanyl)glycine, 1,1-dimethylethyl ester as a clear oil. 0.4 (silica gel, ethyl acetate). c) N- (l·-Ala nyl) -N-phenylglycine, 1,1-dlmethylethyl ester A solution of the ester product from part (b) (4.0 -g., 9.7 mmole) in ethanol (125 ml.) and 104 palladium on carbon catalyst is stirred under a flow of hydrogen for 18 hours. The solution is filtered, concentrated, dissolved in ethyl acetate and extracted with IN hydrochloric acid. The aqueous layer is treated with sodium bicarbonate until basic and extracted with ethyl acetate. The combined -81• ethyl acetate extract· are dried (MgSO*) and concentrated to give 1.3 g. of M-(L-alanyl)-Nphenylglycino, 1,1-dimethylethyl ester as a white solid. R£ 0.32, minor spot at 0.64 (silica gel, ethyl acetate:methanol; lzl). d) M-tW-t ((8)-3-(Benzoylamino)-2-oxo-4-phenylbutyl] L-alanyl]-W-phenylglyclne, 1,1-dimethylethyl ester To a stirring solution of (S)-N-(3-chloro2-oxo-l-(phenyl»ethyl)propylJbenraaide (1.4 g., 4.7 nmole), from Example 63(h), and N-(L-alanyl)N-phenylglycine, 1,1-dimethylethyl ester (1.3 g., 4.7 mmole) in dry dimethylformamide is added sodium bicarbonate (0.38 g·, 4.7 mmole) and sodium iodide (0.7 g., 4.7 nmole). After stirring overnight at room temperature, the mixture ls concentrated, dissolved in ethyl acetate and filtered. The filtrate le washed with 108 sodium bicarbonate, dried (HgSO^I, and concentrated to a yellow oil. Chromatography on L9S-1 eluting with a gradient of ethyl acetates hexane (lsl) to ethyl acetate gives 1.8 g. of IS-[W-( ((8)-3-(benzoylamino)-2-oxo-4phenylbutyl] -L-alanyl] -N-phenylglycine , 1,1dimethylethyl ester. 0.34 (silica gel, ethyl acetate). e} W-fN-( f (S)-3-(Benzoylamino)-2^oxo-4-^henylbutyll -L-alanyl] -W-Phenylqlvcirte, monohydrochloride A solution of the ester product from part (d) (1.6 g«, 2.9 mmole) in* hydrochloric acid/acetic acid (1.77 V, *17.0 ml.) is stirred at room temperature for 30 minutes. The solution is concentrated and -82• the residue is triturated with ether to give a pale yellow solid. Recrystallization from methanol/ether gives 0.84 g. of H-[H-(I(S)-3(benzoylamino) -2-oxo-4-phenylbutyl] -L-alanyl] -N5 phenyIglyclne, monohydrochlorlde as a white, crystalline solid, m.p. 147 - 159° (dec.).

Rg 0.8 (silica gel, butanol:acetic acid:water; 1:1:1). 12.7* (c - 1.5, methanol).

Anal. calc*d. for C28H29N3O5 - HCl - 0.65 HjOt C, 62.77; Hi 5.89; M, 7.84; Cl, 6.62 Found: C, 62.77; H, 5.70; H, 7.84; Cl, 6.12.

Bxample 67 (8) -1- (Η- ί ( 3- (Benzoylamino) -2-oxo-4-phenylbutyl] N-methyl-L-alanyl] -L-prollne, monohydrochlorlde 15 a) H-( (Phenylmethoxy) carbonyl] -L-alanine L-Alanine (89.1 g·, 1 mole) is dissolved in 2N sodium hydroxide (500 ml.) and chilled to 0·. TO thia is added simultaneously dropwise over a one hour period benzylchloroformate (204.5 g., 1.2 mole) and 4N sodium hydroxide (250 ml.). The reection mixture ia stirred overnight (0® to room temperature), and washed with ethyl acetate (2 x 500 ml·). The.aqueous portion is acidified to pH 2.0 with 6M hydrochloric acid and extracted with ethyl acetate (3 x 600 ml.). The combined ethyl acetate extracts are dried (Ha29O4), concentrated on a rotary evaporator, and the solid residue is triturated with petroleum ether to give 194.0 g. of W-[(pheny lmethoxy Jcarbohyl]-L-alanine as a white solid. . b) N-Methyl-N- ((phenylmethoxy) carbonyl] -L-alanine To a cold (0°) solution of M-( (phenylmethoxy) carbonylI-L-alanine (22.3 g«, 0.1 mole) and methyl iodide (50 ml·, 0.8 mole) in tetrahydrofuran (250 ml.) is added sodium hydride dispersion (14.25 g., 0.3 mole) cautiously with gentle stirring. The suspension is stirred overnight under a nitrogen atmosphere (0· * room temperature), slowly poured into saturated sodium bicarbonate (200 ml.), diluted with ethyl acetate (300 tol.) and the layers separated. The organic layer is extracted once more with saturated sodium bicarbonate. The combined aqueous layers are acidified to pH 2.0 with 104 potassium bisulfate X5 and extracted vith ethyl acetate. The combined ethyl acetate extracts are dried (Ba^SOg) and * concentrated ln vacuo into a dark oily residue (23.0 g.).

This crude acid is treated with dicyclohexyl20 amine (20 ml.) in ether (150 ml.)· The resulting crude dlcyclohexylamine salt is collected (37.0 g.), recrystallised from chloroform/ether (35.0 g·), and converted back to the acid by partitioning between in hydrochloric acld/ethyl acetate, yielding a pale yellow oil, which crystallises on standing (17.4 g.).

Recrystallisation (11.2 g.) from ethyl acetate/petroleum ether gives 4.0 g. of N-methylM-( (phenylmethoxy) carbonyl] -L-alanine as a white crystalline product; m.p. 85 - 66.5·; la)’5 - -31.1· (o - 2, acetic add). —84. c) l-(N-Methyl-N-( (frhenylmethoxy)carbonyl]-Lalanyl]-L-proline, 1,1-dimethylethyl eater To a solution of N-methyl-N-((pheny lmethoxy )carbonyl)-L-alonlne (4.74 g., 20 nmole) in distilled tetrahydrofuran (50 ml.) is added L-proline, 1,1-dimathylethy1 ester (3.42 g., mmole), ftydroxybensotriazole hydrate (3.05 g., nmole) and dicyclohexylcarbodiimide (4.12 g., nmole) · The reaction mixture is stirred overnight, the precipitated dicyclohexylurea is filtered off, and the filtrate is concentrated. The residue ie dissolved in ethyl acetate (50 ml.) and wasued with saturated sodium bicarbonate (twice), 10« potassium bisulfate (twice), and water (twice), dried (Na^SO^), and concentrated to give 0.4 9. of 1-(N-methyl-N-((phenylmethoxy) carbonyl] -L-alanyl] -L-proline, 1,1-dimethylethy1 ester as an oily residue. d) 1- (N-Methyl-L-alanvl) -L-proline, 1,120 dimethylethyl ester A mixture of the ester product from part (c) (6.4 g., 16.4 nmole) and 0.0 g. of 10« palladium on carbon catalyst in ethanol (95«, 150 ml.) ia hydrogenated at atmospheric pressure overnight.

The catalyst is removed by filtration and the filtrate le evaporated. The resulting oily residue solidifies upon drying in high vacuum into an oily solid residue (3.8 g.J. Trituration with ether affords 1.5 g., of l-(N-methyl-L-alanyl)-L-proline, 1,1-dimethylethyl ester, monohydrochloride as -85a white solid; R- 0.44 (silica gel, 204 eethanol/ *25 chloroform). (a)D " -102.1° (c - 2, acetic acid). The ether filtrate affords 2.3 g. of 1-(Nmethyl-L-alanyl)-L-proline, 1,1-dimethy lethyl aster as an oil; Rf 0.44 (silica gel, 204 methanol/ chloroform). IoJq5 -101.6° (c * 2, acetic acid) e) (S) -!-(»-( [3- (Benzoylamino) -2-oxo-4-phenylbutylI 10 M-methyl-L-alanyl 1 -L-proline, 1,1-dimethy lathy 1 ester λ reaction mixture of 1-(N-mothy 1-L-alany 1)-Lproline, 1,1-dimethy lethyl ester (2.1 g·, 8.19 mmole) (S) -M- [3-chloro-2-oxo-l- (phenylmethyl) propyl] benzamide (2.46 g·, 8.19 znole), from Example 63(b), excess sodium bicarbonate, and sodium iodide (1.22 g., 8.10 mmole) in dimethylformamide (15 ml.) is stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture is concentrated, the residue is partitioned between water/ethyl acetate, the layers are separated, and the aqueous layer ia extracted once more with ethyl acetate. The combined organic extracts are washed with saturated sodium bicarbonate and water, dried (Na^SOg), and concentrated into an oily residue (3.5 g.). Flash chromatography (200'g. silica gel, mathanol/ethyl acetate) affords 2.8 g. of (S) —1— (H- ((3- (benzoylamino) -2-oxo-4-pheny Ibutyl] N-me thy 1-L-alany 1] -L-proline, 1,1-dimethy lethyl ester aa a yellow oil. -66. f ) (5) -1- (8- ([ 3- (Benzoylamino) -2-oxo-4-phcnylbutyl] 8-methyl-L-alanyll-L-prollne, monohydrochloride The eater product form part (e) (1.4 g., 2.7 mmole) is treated with 28 hydrochloric acid/ acetic acid (20 ml·)· After stirring for 2 hours at room temperature, the reaction mixture is concentrated under reduced pressure and the resulting oily residue is triturated with ether (four times) to give 1.05 g. of (8)-1-(8-([3-(benzoylamino)-2-oxo10 4-phenylbutyl] -8-methyl-L-alanyl] -L-prolina, monohydrochloride as an off-white solid; m.p. 125 - 135*; Rg 0:24 (silica gel, n-butanol/acetic acid/water; 4:1:1). [ajJ® · - 87* (c - 1, methanol). Anal; calc'd. for C20R3lN3°5 * HCl * 0.7 H^O: C, 60.68; H, 6.41; 8, 8.16; Cl, 6.88 Found: C, 60.68; H, 6.36; 8, 7.95; Cl, 6.48.

Example 68 (S) -1-(8-(3- (Benzoylamino) -2-oxo-4-phenylbutyl)-Hphenylglycyll-L-pJCOilne, hydrochloride. (20:3) a) 1- (Bromoacetyl) -L-prollne, 1,1-dimethylethyl ester TO a chilled (-10*) solution of L-proline, 1,1dimethylethyl ester (34.2 g., 0.2 mole) in methylene chloride (250 ml.) ia added diisopropylethylamine (38.3 ml·, 0.22 mole) and bromoacetyl chloride (16.5 ml·, 0.2 mole) dropwise over a 20 minute period while keeping the temperature between -10* to -5*. The dark reaction mixture is stirred overnight (-10· to room temperature) and concentrated under reduced pressure. The oily residue is • redissolved in ethyl acetate, washed with saturated sodium bicarbonate (twice), 10% potassium bisulfate (twice), and water (twice) , dried (Na^SO^), and concentrated into a dark oily residue (28.0 g.). Flash chromatography (LPS-1 silica gel, 10% ethyl acetate/methylene chloride) affords 11.0 g. of 1-( bromoace tyl) -L-proline, 1,1-dimethylethyl ester as a pale yellow oil. b) 1- (N-Phenylglycyl) -L-proline ^1, l-_ dimethylethyl ester To a solution of l-(bromoacetyl)-L-proline, 1,1-dimethylethyl ester (2.1 g., 7.5 mmole) in distilled totrahydrofuran (40 ml.) is added aniline (1.5 g., 15 mmole) end the reaction mixture is stirred overnight under nitrogen. The reaction mixture ia diluted with ethyl acetate (200 ml.), washed with saturated sodium bicarbonate (2 x 50 ml.) and water (twice), dried (NagSO*), and concentrated in vacuo into a dark oily residue (4.0 g.). Flash chromatography (LPS-1 silica gel, 10% ethyl acetate/methylene chloride) affords 2.2 g. of 1-(N-phenylglycyl)-L-proline, 1,1dimethylethyl ester as a dark oil which solidifies upon drying in high vacuum. ' c) (Sj^l-tM-p-fBenaoylamino)-2-oxo-4-phenylbutyl1W-phenylglycyll-L-proline; l,l^imethylethyl ester A reaction mixture of 1- (N-phenylglycyl) -Lproline, Ι,Γ-dimethylethyl ester (1.06 g., 3.5 mmole), (S)-N-[3-chloro-2-oxo-l-(phenylmsthyl) propyl]benzamide (1.06 g., 3.5 nmole), from * -88, Example 63(b), excess sodium bicarbonate, aftd sodium iodide (0.52 g., 3.5 nmole) in dimethylformamide (10 ml.) is stirred at room temperature under a nitrogen atmosphere overnight. The reaction mixture is poured into water (50 ml.) and extracted with ethyl acetate (3 x 50 ml·). The combined ethyl acetate extracts are washed with saturated sodium bicarbonate (twice) and water (three times), dried (Wa2SOg), and concentrated under reduced pressure to give a dark oily residue (2.0 g·)· Flash chromatography (LFS-1 silica gel, 54 ethyl acetate/ methylene chloride to 154 ethyl acetate/methylene chloride) affords 0.3 g·, of (S)-X-[N-(3-(benzoylamino) -2-oxo-4 -phenyIbu tyl ] -W-phenylglycyl J -L15 proline, 1,1-dimethylethyl ester as a pale yellow foam. d) (S) -I- (B- (3- (Benzoylamino) -2-oxo-4-phenylbutyl] W-phenylglycyll-L-proline, hydrochloride (20sj) The eater product from part (c) (0.28 g., 0.49 nmole) is treated with 2H hydrochloric acid/ acetic acid. After stirring for one hour at room temperature, the reaction mixture ia concentrated under reduced pressure and the resulting oily residue is triturated with ether (4 x) to give 0.14 g: of (S)-1-[N-(.3-(bensoylamino)-2-oxo-4phenylbutyl]-B-phenylglycyl]-L-proline, hydrochloride (20:3) as an off-white solid; m.p. 110 - 140·; 0.76 (minor spot at 0.53) (silica gel, n-butanol/acetic acid/water; 3:1:1). -89. Anal, calc'd. for c30H3iN3O5 * 0-15 HCX ’ 0,5 H20s ¢, 68.22; H, 6.13; N, 7.95; Cl, 1.00 round: C, 68.22; B, 6.00; M, 8.25; Cl, 0.99.

Examples 69 - 90 Following the procedure of Exanples 63 to but employing the ketone shown in Col. I, the acid chloride shown in Col. II , and the peptide ester shown in Col. Ill, one obtains the ester product shown in Col. IV. Removal of the Rfi ester group and aay other protecting groups give the corresponding final product in acid form. ι t Col. I *3 5 H-N-CH-C-CH-Cl 2 11 2 0 Col. II10 0 II Rjj-C-Cl COl. IXI 15 R R. 0 I ii HN— ch-c-x 20 Col. IV O R R. O # I I B R,-CH-C-CH,-N - CH-C-X 3 I 2 (D NH I 0*0 I *2 ©V ©- ©"»- ©«’a ©«">>« V-®- O- <8 >- CH2- X R Sxaaplt Rj *1 B- r3c- H I w M I B3C-(H2C)j- « ©«a ©"a -oooc«a3)3 H78 « Bxaapla *1 ©□J’ Β @-«a®-·ί" @- ©<·,@- (§U 3Ο ,ο-ίοφ. Β<γ°® α 000C(CH3)3 |(L) Β Η-MB-CR-C00C 33 3 CHjOCH -WH-CH-COOCCCHj l CH. 3'3 i Xxanpla *1 ©"a B-BB-CH-COOC (CB.) - HcCo’ |(M 33 53 I V m -KH-CB-COOC (CB J, B- 1 B3c-m-CB-COOC (CH.) , Hl2)4-1MCOC82-Q) 9« Bxoaplo >3 ®-ta9 -m-C8-oooc(ai,). UM 3 3 H•7 ®«2- I · 10 (Fl I @*»2- »3C -8—4—C-O-CH-O-C-CxH I (W I H CH(CH) • I* ©*1 o o II P C-C^CBj-O-C-C (Clip 3 X X- HI «0 *4 I -98• The protecting groups in &xatnplea 74, and 77, the Rj protecting groups in Examples 78 end 80, and the R$ protecting groups in Examples 81 and 83 to 85 are removed aa the last step' in the eyntheeie. The Rfi ester groups shown in. Exanples 87 to 90 are not removed.

Example 91 (1} -1- IM-13- (Benzoylamino}-2-oxo-4-phenylbutyl] -NmethylglYcyl]-L-proline, monohydrochloride 10 a} (3γ ^Benzoylamino)-2-oxo-4-yhenylbutylImethyjcarbaalc acid, phenylmethyl ester M-methyl-N-I (phenylmethoxy) carbonyl] glycine (2.23 g., 10 mmole) is dissolved in 30 al. of tetrahydrofuran and cooled in en ice-bath. Oxalyl chloride (Lml·, 11.5 mole) is added followed by 2 drops of dimethylformamide. After stirring for 30 minutes in the ice-bath, thg mixture is then stirred at room temperature for on hour. To this 0.25 ml. of oxalyl chloride is added. The mixture is evaporated, redissolved ia IS ml. of tetrahydrofuran, and stirred la an ice bath. A solution of 2-pheny 1-4-(phenylmethyl)-5(4B)-oxazolone (3.1 g·, 12.4 mmole) dissolved In 15 ml. of tetrahydrofuran is added to the above solution stirring in the ice-bath. Triethylamine (1.4 ml., 10 mmole) is added and the solution Is stirred at room temperature overnight. The precipitated triethylamine hydrochloride salt is filtered off. Tetrahydrofuran is removed from the residue and it is then redissolved in pyridine (5 ml.) and p-dimethylamino -99• pyridine (20 mg.) ie added. After stirring at room temperature for 3 hours, acetic acid (5 ml.) is added and the reaction mixture is kept at IOS* for 30 minutes. The reaction mixture is then evaporated, the residue is dissolved in ethyl acetate, and washed with aqueous sodium bicarbonate and water. After trituration with ethyl acetate/ hexane, 2.2 g. of homogeneous (3-(benzoylamino)- . 2-exo-4-pheaylbutyl]methylcarbamic add, phenyl10 methyl ester is obtained; m.p. 140^141°. b) f ±)3-{Methvladnoj-2-oxo-l-(phenylmethyl)- . propyl)benzamide j hydrochloride (3- (Benzoylamino) -2-oxo-4-pheny Ibuty 1] methy 1carbamlc acid, phenylmethyl ester (O.S g.) is 15 dissolved in ethanol (50 ml.) containing IB hydrochloric acid (2 ml·)· Palladium carbon catalyst (101, 100 mg.) is added and hydrogenation IS continued overnight. The reaction .mixture is then filtered, evaporated, dissolved in water, and lyophilised to 300 mg. of (1) -11-(3-(methylamino) -2-oxo-l- (phenylmethyl) propyl] benzamide, hydrochloride as a homogeneous white powder. c) <±)-l-(N-[3-(Benzoylamlno}-2-oxo-4-phenyl.butyllN-mathylqlycyl)-L-proline, 1· 1-dimethy lethyl ester A reaction mixture of (4)-B-(3-(»ethylaraino)-2oxo-1-(phenylmethyl)propyllbensamide, hydrochloride (1.65 g·, 5 mmole), 1-(bromoacetyl)-L-proline, 1,1-d,Imethy lethyl ester (2.9 g·, 10 mmole), from Example 66(a), and diisopropylethylamine (1.74 ml., nmole) ia dimethylformamide (20 ml·), is stirred *-100- • at room temperature under nitrogen overnight. The reaction mixture ia partitioned between water/ethyl » 5 acetate and the aqueous layer is extracted once more with ethyl acetate. The ethyl acetate extracts are dried (Ma2SO4) and concentrated to a yellow oily residue (4.0 g·)· Flash chromatography (150 g. of March silica gel 60) affords 0.7 g. of (±)-l- • xo (fl* (3- (benzoylamino) -2-oxo-4 -phenylbutyl] -Mmethylglycyl] -L-proline, 1,1-dime thyl ethyl ester as a yellow foam. d) (t)-1-IN-(3-f Benzoylamino^-2-oxo-4-phanylbuty1]- N-mefhylalvcvl1 -L-proline, monohydrochloride The ester product from part (c) (0.4 g., 15 0.79 mmole) ia treated with 2N hydrochloric acid/acetic acid (5 ml.)· After stirring for 20 45 minutes at room temperature, the reaction mixture is concentrated under reduced pressure and the resulting oily residue is triturated with ether (3x) to give 0.28 g. of (t)-l-(N-[3-(benzoylanino)2-oxo-4-pheny Ibutyl] -H-methylglycyl] -L-proline, monohydrcchloride as a white solid; m.p. 125-130*. Rg 0.73 (silica gel, n-butanol/acetlc acid/water; 3:1:1). Anal, calc'd. for C3$*29N3°5 · HCl * 0.23 HjO: 25 C, 61.01; 6.24; H, 8.54 Found: C, 61.01; fl, 6.10; «, 8.36. -101 • Example 92 (S)-7-([ 13- (Benzoylamino) -2-oxo-4-phenylbutyl] methylamino] acetyl] -1 ,4-dlthia-7-azasplro[4.41nonane-8-carboxylic acid, trlfluoroacetate salt 5 (1:1) . /....... a) (S)-7-(Bromoacetyl)-l,4-dlthia-7-azasplro(4.4] nonane-8-carboxylic acid (S) -1,4-Dlthia-7-asaspiro (4.4] nonane-8carboxyllc acid, hydrochloride (2.1 g., 8.7 mmole) is dissolved in IN sodium hydroxide (25 ml·), chilled to 0· and bromoaeetyl bromide (2.1 g., 0.91 ml.· 10.4 mmole) is added dropwise over a 10 minute period. The reaction mixture is stirred for 2 hours (0· to room temperature), washed with ethyl acetate (twice) · and the aqueous layer is acidified to pH 2 and extracted with ethyl acetate (3 x). The combined organic extracts are dried (Ma^SO^) and concentrated to give 2.25 g. of (8)-7-(bromoaeetyl)-1,4-dithia20 7-aaaspiro(4.4]nonane-8-oarboxylic acid. b] (8) γ7- f ?r?woacety1l T 4-dithla-7-azasplro (4.41nonane-8-carboxylie acid, diphenylmethyl eater (8)-7- (Bromoaeetyl) -l,4-dithia-7-azaspiro(4.4] nonane-8-carboxylie acid (2.25g«, 8.9 nmole) ia dissolved in ethyl acetate (150 ml.). Diphenyldiasomethane (1.3 g·· 6.9 mmole) ia added and the reaction mixture is stirred overnight at room temperature. The decolorized reaction mixture la washed with saturated sodium bicarbonate (twice) · 10» potass ium bisulfate (twice) and water. « 102• dried (NagSO*) , and concentrated to give 2.5 g. of (S) .7- (bromoacetyl) -1 , 4-dithia-7-azaapiro [4.4] nonane8-carboxylic acid,diphenylmethyl ester as a white solid: residue. c) (S) 7-1((3- (Benzoylamino) -2-oxo-4-phenylbutyl ] methy lamino J acetyl] -1,4-dithia-7jazaspiro (4.4] nonane8-carboxyllc acid, diphenylmethyl ester λ mixture of the ester product from part (b) (2.4 g., 4.87 mmole), (±)-N-(3*(methylamino)-2-oxo-l10 (phenylmethyl) propyl Jbenzamide (0.81 g·, 2.43 mmole), prepared as set forth in Example 91 (b), and diisopropylethylamine (0.85 ml·, 4.87 moole) in dimethylformamide (20 ml.) is stirred at r^om ten^orature overnight. The reaction mixture is poured into water (50 ml.), and extracted with ethyl acetate (3 x 100 ml·)· The combined organic extracts are washed with saturated sodium bicarbonate, 10« potassium bisulfate, and water, dried (Na^SO^), and concentrated into a dark oily residue (2.8 g.). Flash chromatography (200 g.

Merck silica gel, 10«' ethyl acetate/methylene chloride, 20« methanol/ethyl acetate) affords 1.1 g. of (S) -7-( ((3-(benzoylamino)-2-oxo-4-phenylbutyl] methylamino] acetyl] -1,4-dithla-7-asaepiro (4.4)25 nonane-8-carboxylic acid, diphenylmethyl ester as a yellow oil. 103 • d) (S) -7-( ((3- (Benzoylamino) "-2-oxo-<-phenylbutyl] me thy lamino] acetyl ] γΐ, 4-dithih-7-azaapiro [4.41 nonane8-carboxylic acid, trifluoroacetate salt (lsl) The eater product from part (c) (10.5 g·, 0.72 nnole) ia added to chilled (0·) trifluoroacetic acid (2 ml.) containing anisole (0.1 ml.). After stirring for one hour, the volatiles are removed in vacuo and the residue is chased with toluene (twice) · The oily residue is triturated with ether (4x) affording 0.36 g. of (S)-7-([[3-(benzoylamino)2- oxo-4-phenylbutyl Imethylamino] acetyl] -1,4-dithia7-azaspiro(4.4]n0nane-8-carboxylic acid, trifluoroacetate salt (1:1); m.p. 120-125*. 0.45 (trailing) (silica gel, n-butanol/acetic acid/water; 4:1:1).

Anal, calc'd. for "lAVz * W C, 53.11; H, 4.92; B, 6.40; S, 9.78 Found: C, 52.68; B, 5.03; H, 6.53; S, 9.97.

Example 93 (8)-2-( ( (3-(Benzoylamino)-2-oxo-4-phenylbutyl] methylamino] acetyl]-1,2f 3,4-tetrahydro-3-lsogulnollnecarboxylie acid, monohydrochloride a) 2-(Bromoacetyl)-1»2 f 3 f 4-tetrahydro-3-lso^ quinoiinecarboxylie acid, 1,1-dimethylethyl ester 25 TO a chilled solution of 1,2,3,4-tetrahydrb3- isoquinolinecarboxylic acid, 1,1-dimethylethyl ester (7.7 g., 33 mmole) in methylene chloride (100 ml.) is added diisopropylethylamine (6.23 ml., 36.3 nnole) and finally over a 15 minute 30 period bromoacetyl bromide (6.6 g., 2.87 ml., 104• 33 mmole) while keeping the temperature at 5®. The reaction mixture is stirred overnight (-5® to room temperature), Concentrated to about 33 1/3« of , its vole», diluted with ethyl acetate (100 ml·), washed with saturated sodium bicarbonate (twice), « potassium bisulfate (twice), and water (twice), dried (Na^SO^), and concentrated into a dark yellow semi-solid residue (11.0 g.). Recrystallization from ethyl acetate/hexane affords 4.2 g. of 2- (bromoacstyl) -1,2,3,4-tetrahydro-3-isoqulnolinecarboxylio acid, 1,1-dimethylethyl ester as a cream colored solid; m.p. 92-95® (85·) · b) (S| -2-1 ((3- (Benzoylamino^ -2-oxo-4-phenylbutyl) methylamino JacetyH -1T 2,3 T4-tetrahydro-3-iso15 qulnolinecarboxylic acid, 1,1-dimethylethyl ester TO a solution of 2-(bromoacetyl)-1,2,3,4tetrahydro-3-isoquinollnecarboxylic acid, 1,1dimethylethyl ester (2.12 g., 6 nmole) in dimethylformamide (20 ml.) is added (t)-K-(3-(methylamino)20 2-oxo-1-(phenylmethyl)propyl]benzamide (2.0 g., nmole), prepared as set forth in Exanple 91(b), and diisopropylethylamine (0.77 g., 1.04 ml., nmole) · The reaction mixture is stirred overnight, poured into water (SO ml.) and extracted with ethyl acetate (3 x 50 ml.). The combined ethyl acetpte extracts are washed with saturated sodium bicarbonate (twice) and water (twice), dried (na^SO*), and concentrated into a yellow oily residue!' (2.9 g.J. Flash chromatography (200 g. Merck silica, 2« mathanol/chloroform) -105. gives 0.68 g. of (S)-2-I[[3-(benzoylamino)-2-oxo4-pheny Ibuty 11 methylamino J acetyl 1-1,2,3,4-tetrahydro-3-isoguinolinecarboxylic acid, 1,1-dimethy1ethyl ester as a yellow dried up foam. c) (S)-2-( f [3-fBenzoylamlnp)-2-oxo-4-phenylbuty 1J methylamino 1 acetyl 1 -1 f 2,3 ·4-tetrahydro3-lsoquinollneoarboxyllc acid,· 'monohydrochloride The ester product from part (b) (1.67 g., 1.17 mmole) is treated with 2B hydrochloric acid/ acetic acid (5 ml·). After stirring for one hour at room temperature, the reaction mixture is concentrated under reduced pressure and the resulting oily residue is triturated with ether (4x) to give 0.55 g. of (8)-2-((( 3-(benzoylamino)-2-oxo-4-phenyl15 butyl]methylaaino]acetyl] -1,2,3,4-tetrahydro-3isoquinolinecarboxylic acid, monohydrochlorlde as an off white solid; m.p. 123-126*. Sg 0.47 (silica gel, n-butanol/acetic acid/water; 4:1:1).

Anal, calc'd. for C3oH3lB3°5 * HCX ’ °"32 B2°5 C, 64.82; B, 5.92; B, 7.56; Cl, 6.38 Found: C, 64.82; H, 6.22; B, 7.55; Cl, 6.13.

Bxamylc 94 {1(4). 4S{ -1- [B- [ 3- f Benzoylamino) -2-oxo-4-pheny Ibuty 1 ] 25 W-methylqlycyll-4- (phenylthio) -L-prollne, aonohydrochloride a) (48) -1- (Bromoacety 1)-4- (pheny lthlo)-L-prollne To a suspension of . (48) -4- (phenylthio) -Lproline (2.2 g., 10 nmole) in methylene chloride (50 ml·, freshly distilled) ls added bis (trimethy 1-106. silyl) acetamide (7.35 ml., 30 mnole). The reaction mixture is stirred at room temperature for 2 hours until it becomes almost clear· The reaction mixture is then cooled to -5· and bromoaeetyl chloride (1.9 g., 1.0 ml·, 12 mmole) la added dropwise keeping the temperature at -5·. After stirring overnight (-5· to room temperature), the reaction mixture ie concentrated to about 506 of its volume, partitioned between saturated sodium bicarbonate/ethyl acetate and the layers are separated. The organic layer le extracted once more with saturated sodium bicarbonate. The combined agueous layers are acidified to pS 2.0 with lot potassium bisulfate and extracted with ethyl acetate (3x). The ethyl acetate fractions are combined, dried (HfcgSOg) and concentrated to give 3.5 g. of (4S) -1- (bromoacetyl) -4- (phenylthio) -L-proline as a viscous oil. b) (43} -1- (Bromoacetyl) -4- (phenyl thio) -L-prollne, diphenylmethyl ester A solution of dlphenyldlasomethane (2.0 g., .2 mmole) in ethyl acetate (50 al.) is added dropwise to a solution of ' (43)-1- (bromoacetate) -4(phenylthio)-L-proline (3.5 g., 10.2 mmole) in ethyl acetate (50 ml.). The purple solution is stirred at room temperature overnight. The decolorised reaction mixture is washed with saturated eodium carbonate (twice) and water (twice), dried (MajSOj), and concentrated to give 4.78 g. of (48)-1-(bromoaeetyl)-4.-(phenylthio)-L-proline, -107. diphenylmethyl ester as a yellow viscous oil. c) [l(±)f4Sj-l-(N-(3-(Benzoylamino)-2-oxo-4phenylbutyl} -N-methylglycyl] -4- (phenylthio) -Lproline, diphenylmethyl ester S TC a solution of (4S)-l-(bromoacetyl)-4-(phenylthio)-L-proline,diphenylmethyl eater(4.78 g., 9.4 mmole)in dimethylformamide (20 ml.) is added (±)-N-(3- » (methylamino) -2-oxo-1- (phenylmethyl) propyl] benzamide (2.42 g., 7.2 Tmols,, 'pcepsxeA asset forth in Example 91(b), and ' dlisopropylethylamine (0.93 g.,1.25 ml·,7.2 nmole). After * stirring overnight at room temperature, the reaction mixture ΐ is poured into water (50 ml.) and extracted with ethyl acetate <3x). The combined ethyl acetate extracts are washed with saturated sodium bicarbonate (tvice) and water (twice), dried (Ma2SOg), and concentrated into a yellow oil (6.2 g.)· Flash chromstdgraphy (Merck silica gel, 24 methanol/methylene chloride) gives 3.2 g. of (1(f) ,4S]-l-£M-(3-(bensoylamino)-2-oxo-420 ’ phenylbutyl] -N-methylglycyl] -4- (phenylthio) -Lproline, diphenylmethyl estar as a pale yellow foam. d) (lfi>, 481-1-(B-f 3-(Benzoylamino)-2-oxo-4phanylbutyH -N-mathylcrlycyl] -4- (phenylthio) -L25 proline, monohydrochloride The eater product from part (c) (1.6 g.-, 2-.2 znole) is treated with 2N hydrochloric acid/acetic acid (20 ml·).' After stirring for 2 hours at room temperature, the reaction mixture is concentrated under reduced pressure and the oily . -108. residue Is triturated with ether overnight to yield 1,2 g. of (1(i),4S)-l-IN-(3-(benzoylamino)-2oxo-4 -phenylhu tyl] -B-mathylglycyl) -4- (phenylthio) -Lproline, monohydrochloride as an off-white solid; m.p. 131-133* Rg 0.38 (silica gel, n-butanol/acetic acid/water; 4tl:l).

Anal, calc'd. for C3lH33N3°5S ' HC1 · °·9 H2°! C, 60.82; R, 5.90; N, 6.87; S, 5.24; Cl, 5.79 Founds C, 60.82; H, 5.74; N, 6.94; S, 5.25; Cl, 5.75. 10 Example 95 (4S) -1- (Ν-(3γ (Benzoylamino) -2-pxo-4-phenylbutyl] -Mmethylglycyll-4-(4-f luorophenoxy)-L-proline, monohydrochloride a) (43) -1- (Bromoacetyl) -4- (fluorophenoxy) -L-proline, 15 1,1-diaethylathy1 eater To a aolution of (S)-4-(fluorophenoxy)-Lproline, 1,1-dimethylethyl ester (2.1 g., 7.5 mmole) in distilled tetrahydrofuran (50 ml.) is added bromoacetic acid (1.04 g·, 7.5 mmole), hydroxy20 bensotriasole hydrate (1.14 g., 7.5 mmole) and dicyclohexylcarbodiimide (1.54 g., 7.5 nmole). The reaction mixture is stirred overnight, the precipitated dicyclohexylurea is filtered off, and the filtrate is concentrated. The residue is dissolved in ethyl acetate (50 ml.) and washed with saturated sodium bicarbonate (twice), 10% potassium bisulfate (twice) and water (twice), dried (NagSOg) and concentrated to give 3.1 g. of (4S) —1— (bromoacetyl) -4- (fluorophenoxy) -L-proline, 1,1-dimethylethyl ester as on oily residue. -109• b) (4S)-1-[N-[3- (Benzoylamino) -2-oxo-4-phenylbutyl]M-methylglycyl] -4- (4-fluorophenoxy) -L-proline, 1,1dimethylethyl eater To a solution of (4S)-1- (bromoacetyl) -4- (fluoro5 phenoxy)-L-proline, 1,1-dimethylethyl ester (3.4 g«, 8.5 mmole) in dimethylformamide (20 ml.) is added (t)-N-13-(methylamino) -2-oxo-l- (phenylmethyl) propyl Jbenzamide (2.83g«, 8.5 mmole), prepared as set forth in Example 91(b), and diisopropylethyΙΙΟ amine (1.43 g., 1.92 ml., 11.0 mmole). After stirring overnight at room temperature, the reaction mixture is poured into water (100 ml.) and - extracted with ethyl acetate (3x). The combined ethyl acetate extracts are washed with saturated IS sodium bicarbonate (twice) , 10« potassium bisulfate (twice), and water (twice), dried (Ha^SO^), and. concentrated Into a dark residue (5.5 g.)· Plash chromatography (LPS-1 silica gel, 50« ethyl acetate/ methylene chloride) gives 1.2. g. of (4S)-l-(N-(320 (benzoylamino) -2-oxo-4-phenylbutyl) -N-methylglycyl] 4- (4-f luorophenoxy) -L-proline, 1,1-dimethylethyl ester as a pale yellow foam. c) (4S)-l-(W-[3-(Benzoylamino)72-oxo-4-phenylbuty1] -N-methylglycyl] -4- (4-f luorophenoxy) -L-proline , monohydrocHlorlde The ester product from part (b) (1.2 g., 1.95 mmole) is treated with 2N hydrochloric acid/ acetic acid (20 ml·). After stirring for 2 hours at roam temperature, the reaction mixture is concentrated under reduced pressure and the oily 110- e residue is triturated with ether overnight to yield . 5 0.92 g. of (4S)-l-[N-(3-(benzoylaniino)-2-oxo-4phenylbutyl]-R-methylglycyl] -4- (4-f luorophenoxy) -Lproline, monohydrochloride as an off-white solid; m.p. 131-140·. 'Rg 0.54 (silica gel, n-butanol/ acetic acid/water; 3:1:1). Anal, calc’d. for CjjH^HjFOg · HCl · 0.55 HjO: C, 61.24; H, 5.65; N, 6.91; Cl, 5.83 10 Found: C, 61.24; H, 5.66; N, 7.09; Cl, 5.70. Xn a similar manner* the procedure of 15 Examples 91 to 95 can be employed to prepare the compoundsof Examples 1 to 90. Example 96 R- [H- ( 3- (Bensoy lamino} -2-oxo-4-phenylbutyl) -N-iuethyl- glycyl] -R-cyclohexylglycine^ monohydrochloride a) (!) -M- (3- (Benzoylamino I -2-exo-4-phenylbuty 1 ] -M- methy Iglyoine, 1,1-dimethylethyl ester To a solution of (i)-R*(3- (methylamino) -2- 20 oxo-1-(phenylmethyl)propyl]benzamide (5.0 g., 15 nmole), prepared aa aet forth in Example 91(b), in dimethylformamide (20 ml.) ia added bromoace tic acid, 1,1-dimethylethyl ester (13.8 g. , 3.15 ml., 19.5 nmole) and diisopropylethylamine (2.5 g., 3.4 ml., 19.5 mole). After 'stirring overnight 25 at room temperature, the reaction mixture is poured into water (100 ml.) and extracted with ethyl acetate <3x). The combined ethyl acetate extracts are washed with saturated sodium bicarbonate 30 (twice), lot potassium bisulfate (twice), and water (twice), dried (Na^SO*), and concentrated into a -111• yellow oil, which becomes a dried up foam upon drying in high vacuum, to give 5.4 g. of (t) [3- (benzoylamino) -2-oxo-4-phenylbutyl)N-methylglycine, 1,1-dimethylethyl ester. b) ft) -N-13- (Benzoylamino) -2-oxo-4-phenyIbutyl I W-methylglycine, monohydrochloride The ester product from part (a) (4.51 g., mmole) is treated with 2N hydrochloric acid/ acetic acid (20 ml.)· After stirring for 2.5 hours at room temperature, the reaction mixture is concentrated under reduced pressure and the oily residue is tritiirated with ether to give 3.3 g. of (t)-N-[3-(benzoylamino)-2-oxo-4-phenyIbutyl]N-methylglycine, monohydrochloride as an off-white IS solid. c) N- |N- f 3- (Benzoylymlno) -2-oxo-4-yhenylbutyl) -Nmethylqlycyl] -N-cyclohexylglycine, 1,1-dimothy lathy 1 ester To a solution of (±)-N-I3-(benzoylamino)-220 oxo-4-pheny Ibutyl] -N-methylglycine, hydrochloride (1.0 g«, 2.6 mmole) in distilled tetrahydrofuran (50 ml.) is added N-cyc lohexy lglycine, 1,1-dimethylethyl ester (0.55 g·, 2.6 mmole), prepared as set forth in Example 65(a), hydroxybenzotriazole hydrate (0.39 g., 2.6 mmole),arid dicyclohexylcarbodiimide (0.55 g·, 2.6 mmole). The reaction mixture is stirred overnight, the precipitated dicyclohexylurea is filtered off, and the filtrate is concentrated. The residue is dissolved in ethyl acetate (50 ml.) and washed with saturated -112. sodium bicarbonate (twice), 104 potassium bisulfate (twice), and water (twice), dried (NagSO*) and concentrated into an oily residue (1.5 9.)· Flash chromatography (100 g., Merck silica gel 60) gives 0.49 g. of N-[H-[3-(benzoylamino)-2-oxo-4-phenylbutyl] -N-methylglycyl] -N-cyclohexy Iglyclne ,1,1dimethylethyl ester as a foam. d) Ν-(Ν-[3γ (Benzoylamino) ^2-oxo-4-phenyIbuty11 N-methylglycyl] -N-cyclohexyIglyclne, monohydro10 chloride The ester product from part (c) (0.48 g., 0.87 mmole) is treated with 2N hydrochloric acid/acetic acid (10 ml.)· After stirring for 2 hours at room temperature, the reaction mixture is concentrated XS under reduced pressure and the oily residue is triturated with ether overnight to give 0.32 g. of Ν- (N- (3- (benzoylamino) -2-oxo-4-ohenyIbuty 11 -Nmefchylglycyl] -N-cyclohexy Iglyclne, monohydrochloride as an off-white solid; m.p. 131-145*.

Mg 0.36 (silica gel, n-butanol/acetic acid/water; 4:1:1).

Anal, calc'd. for C28H35M3°5 * HCX * 0,7 H2O: C, 61.95; fl, 6.95; fl, 7.74; Cl, 6.53 Found: C, 61.95; H, 6.74; N, 7.71; Cl, 6.23. -113• Example 97 (8)-7-[[[(*)-3-(Benzoylamino)-2-oxo-4-phenyIbutyl]methylamino]acetyl]-1,4-dlthia-7-azagpiro [4.41nonane-8-carboxylic acid, methyl ester To a solution of (±)-M-[3-(benzoylamino)-2oxo-4-phenyibutyl]-M-methylglycine, monohydrochloride (1.0 g., 2.5 mmole), prepared as set forth in Example 96(b), in distilled tetrahydrofuran (50 ml.) is added (S)-l,4-dithia-7-azaspiro[4.4]nonane-810 carboxylic acid, methyl ester, monohydrochlorlde (0.66 g., 2.5 znole) , dicyclohexylcarbodiimide (0.54 g., 2.5 mmole), hydroxybenzotriazole hydrate (0.39 g., 2.5 mole) and diisc^ropylethylamine (0.9 ml., 5 mmole). The reaction mixture is IS stirred overnight, the precipitated dicyclohexylurea is filtered Qff, and the filtrate is concentrated.

The residue is dissolved in ethyl acetate (100 ml.) and washed with saturated sodium bicarbonate (twice) and water (twice), dried (Na^SO^), and concentrated into a yellow oily residue <1.3 g.). Flash chromatography (Merck silica gel, 254 ethyl acetate/methylene chloride, 14 methanol/methylene chloride) affords 0.53 g. of (S)-7-[[[(i)-3(benzoylamino) -2-oxo-4-phcnylbutyl]methy lamino] 25 acetyl ] -1,4-dithia-7-azaspiro [4.4] nonane-8carboxylic acid, methyl ester as a white foam; m.p. 60 - 62*. Rg 0.52' (silica gel, 54 methanol/ methylene chloride).

Anal, calc'd. for C28H33M3°5S2 * 0,33 H20: -114. C, 59.87; Η, 6.04; N, 7.48; 8, 11.42 Found: C, 59.87; H, 5.94; N, 7.56; 8, 11.36.

Example 98 CS)-7-(( ((i)-3-(Benzoylamino)-2-oxo-4-phenyIbutyl·]5 methylamino] acetyl] -1, 4-dlthla-7-azaspiro [4.4] nonane8-carboxylic acid, methyl ester, monohydrochloride The methyl eater product from Exaaple 97 (0.26 g., 0.46 mmole) Is treated with 2N hydrochloric acid/acetic acid until homogeneous (2 minutes), concentrated under reduced pressure, and the oily residue is triturated with ether (twice) to give 0.26 g. of (S)-7-((((1)-3(benzoy lamino) -2-oxo-4-phenylbutyl Imethy lamino] acetyl 1 -1,4-dithia-7-azaspiro [4.4] nonane-815 carboxylic acid, methyl ester, monohydrochloride as a white solid; m.p. 79-85*. . Rf 0.53 (silica gel, 5% methenol/methylene chloride).

Anal, calc'd. for ^3*3383 °5S2 * HC1 * 0.56 HgO: C, 55.84; H, 5.88; H, 6.98; S, 10.64; 01,5.88 Found: C, 55.84; H, 5.95; H, 6.78; S, 10.43; 01,5.66. Example 99 (48) -1- [H- f 3- (Benzoylamino) -2-oxo-4-phenylbutyll -HmethylolycYll-4-f4-fluorophenoxy) -L-prollne, methyl eater, monohydrochloride a) (4S)-4-(Fluorophenoxy)-L-proline, methyl ester, monohydrochloride TO a suspension of (4S)-4-(fluorophenoxy)L-proline (2.5 g., 11 mmole) in methanol at -30· under an argon atmosphere is added thionyl chloride (8.09 ml., 11 mmole). The reaction mixture -115• is stirred at -20* for 2 hours, then at room temperature for 16 hours. Solvent is removed at reduced pressure and the residue is redissolved in methylene chloride (150 ml.) and washed with Ifl sodium carbonate (twice) and water (twice).

After drying (MgSO*), excess hydrochloric acid/ methanol is added and solvent is removed at reduced pressure. Addition of ether gives a light brown solid (2.6 g.). Recrystallization from methanol/ ether gives 1.49 g. of (43)-4.-(fluorophenoxy)-Lprollne, methyl ester, monohydrochlorlde as a light brown solid) m.p. 147-148·; (a)^0 46.96° (c - 1.55, methanol). b) (4S) -1-IN-F3- (Benzoylamino) -2-oxo-4-phenylbutylI15 N-aafchylqlycyl] -4-(4-fluorophenoxy) - L-prol Ine, methyl eater To a solution of (±)-N-[3-(benzoylamino)-2oxo-4-phenyIbuty1] -N-methyIglyclne, monohydrochloride (1.17 g·, 3 mmole), prepared as set forth in Example 96(b), ia distilled tetrahydrofuran (20 al.) is added (48)-4-(fluorophenoxy)-L-proline, methyl ester, monohydrochlorlde (0.82 g., 3 mmole), hydroxybenzotriazole hydrate (0.46 g·, 3 mmole) and dicyclohexylcarbodiimide (0.62 g., 3 mmole).

The reaction mixture ls stirred overnight, the precipitated dicyclohexylurea is filtered off, and the filtrate is concentrated. The residue is dissolved in ethyl acetate (50 ml.) and washed with saturated sodium bicarbonate (twice) and water (twice), dried (fla2SO4), and concentrated into an -116• oily residue (1.1 g.). Flash chromatography (200 g., Merck silica gel 60; 3% methanol/chloroform) gives 0.15 g. of (4S)-1-( N-( 3-(benzoylamino)-2oxo-4-phenylbutyl]-N-methylglycyl]-4-(4-fluoro5 phenoxy)-L-proline, methyl ester as a foam. c) (4S) -1- {Mr ] 3- (Benzoylamino) -2-oxo-4-pheriylbutyll -N-methylglycyl] -4- (4-f luorophenoxy) -2proline, methyl ester, monohydrochloride The nethyl ester product fron part (b) (0.15 g., 0.26 mmole) is treated with 2N hydrochloric acid/acetic acid until homogeneous (2 minutes), concentrated under reduced pressure, and the oily residue is triturated with ether (twice) to afford 0.14 g. of (4S)-l-(N-(315 (benzoylamino) -2-oxo-4-pheny Ibuty 1 ] -N-mothy1glycyl]-4-(4-fluorophenoxy)-L-proline, methyl ester, monohydrochloride as an off-white solid; m.p. 105-125*. R^ 0.27 (silica gel, 5% methanol/ chloroform).

Anal, calc'd. for · HCl C, 62.79; H, 5.76; N, 6.86; F, 3.10; Cl,5.79 Founds C, 62.78; H, 5.73; M, 6.87; F, 2.83; Cl,5.33. -117gxample 100 (4S) -1-(W[ (S) -3-(Bensoylamino) -2-pxo-4-phenylbutyl] L-alanyl]-4-(4-fluorophenoxy)-L-proline, monohydrochloride a) (S)-M-(3-(Benzoylamino)-2-oxo-4-phenylbutyl]L-alanine, 1,1-dimethylethyl ester To a stirring solution of (S)-N-[3-chloro2-oxo-l-(phenylmethyl)propyl]benzamide (10.0 g., 33.1 nmole) in dimethylformamide (80 ml.) is added L-alanine, 1,1-dimethylethyl ester, hydrochloride (6.0 g., 33.1 mmole), sodium bicarbonate (6.1 g·, 72 mmole) and sodium iodide (4.9 g·, 33.1 mmole). The resulting solution is stirred overnight at room temperature, poured into ether and washed with water (twice) and 10% sodium bicarbonate. The ether solution is extracted with IN hydrochloric acid (3x,, the combined extracts are made basic by the addition of solid sodium bicarbonate and extracted with ethyl acetate (4x). The organic extracts are combined, dried (MgSOg) and concentrated to give 8.9 g. of pale yellow solid, λ portion of this material is recrystallized from ethyl acetate to give (S)-N-[3(bensoy lamino) -2-oxo-4-phenylbuty 1 ] -L-alanine, 1,1-dimethylethyl eater as a white solid; m.p. 106.5 - 110·. -lie- • b) (S) -N- (3- (Benzoylamino) -2-bxo-4-phenylbutyl] - L-alanine/ monohydrochlorlde A solution of the ester product frorapart(a) (2.95 g., 5.4 mmole) in 1.4 N hydrogen chloride in s acetic acid (39 ml.) is stirred at room temperature for 2 hours. The resulting white precipitate is collected, rinsed with ether and dried to give 2.27 g. of (S)-N-[.3-(benz0ylamino)-2oxo-4,-pheny Ibuty 1]-L-alanine, monohydrochlorlde; 10 D m.p. 208-209* (dec·); * -71· (c 0.388 In methanol). Rg 0.51 (silica gel; chloroform/ methanol/acetic Acid; 4:1:1)·* Anal, calc'd. for C20*22N2°4 ’ HCXs C, 61.64/ H, 5.93; N, 7.17; Cl, 9.07 15 Found: C, 61.33; H, 5.97; N, 7.17; Cl, 8.79. c)* ’ (S)-N-(N-{Benzoylamino)-2-oxo-4-phdnylbutyl]- N- f (phenylmethoxy) carbonyl] -L-alanine Triethylamine (2.1 ml., 15 mmole) is added to a mixtufe of .(S)-N-(.3-(benzOy lamino)- 20 2-oxo-4-phenyIbuty 1]-L-alanine, monohydrochlorlde (2.0 g. , 5.1 mmole), benzyl chloroformate (730 pi., 5.1 mmole), water' (7 ml .J and dioxane* (7 ml.) at 25·. The resulting mixtufe is stirred at 25· for 3 hours, after which it is* pouf ed into 25 5« aqueous, sodium bicarbonate solution and washed with ether. The aqueous layer is acidified (HCl)and extracted, into ethyl acetate (3x). The extract is dried* (MgSO^) and concentrated to give a colorless oil*. Trituration with ether 30 produces a white granular solid’*(150 mg;} which F -119• is collected and discarded. The mother liquor is concentrated in vacuo to give 1.75 g. of (S)-N(N- (benzoylamino) -2-oxo-4-phenylbutyl] -N((phenylmethoxy) carbonyl]-L-alanine as a white glass. d) (4S)-l-(N-[(S)-3-(Benzoylamlno)-2-oxo-4phenylbutyll-N-f (phenylmethoxy)carbony11-Lalanyll-4-(4-fluorophenoxy) -L-proline, phenylmethyl ester A mixture of (S)-N-(N-(benzoylamino)-2oxo-4-phenylbutyl] -N- (‘(phenylmethoxy) carbonyl]-Lalanine (300 mg,>, 0.62 mmole), (4S)-4-(4-fluorophenoxy)-L-proline, pnenylmethyl ester, ptoluenesulfonic acid salt (300 mg., 0.62 mmole), triethylamine (90 yl., 0.62 mmole), dicyclohexylcarbodiimide (130 mg·, 0.62 mmole), and hydroxybenzotriazole hydrate (90 mg., 0.62 mmole) in tetrahydrofuran (7 ml.) is stirred st 25° for 20 hours. The mixture ls then filtered and diluted with ethyl acetate. The resulting solution is washed sequentially with IN hydrochloric acid and 10% aqueous sodium bicarbonate solution, dried (HgSO*), filtered, end conceptrated to give 500 mg. of (4S)-l-(N«((S)-3-(benxoylamino)-2-oxo-425 phenylbutyl]-N-[ (phenylmethoxy) carbonyl I-Lalanyl]-4-(4-fluorophenoxy)-L-proline, phenylmethyl ester as a pale yellow oil. -120• ®) <4S) X ((S) *3- (Benzoy lamino) -2-oxo-4phenylbutyl] -L-alanyl} -4- (4-f luorophenoxy) -Lproline, monohydrochlorlde A mixture of the ester product from part(d) (500 mg., 0.6 mmole), palladium on carbon catalyst (104, 100 mg.), absolute ethanol (15 ml.), and 1.0 9 aqueous hydrochloric acid (800 μΐ., 0.8 mmole) is hydrogenated at 1 atmosphere and 25° for 17 hours, after which it is filtered and concentrated.

X0 The residue is chromatographed on BP-20 a linear gradient from (9:1, 0.0IN aqueous hydrochloric acidzmethanol] to (1:1, 0.019 aqueous hydrochloric acidxmethanol]· Fractions containing the desired product (TLC) are combined and concentrated. The X5 residue is dissolved in a minimum amount of methanol. Ether is added, resulting in a white precipitate which is collected and dried in vacuo to give 200 mg. of (4S)-l-[9-((S)-3-(benzoylamino)2-oxo-4-phenyIbutyl]-L-alanyl] -4-(4-fluorophenoxy) 20 L-proline, monohydrochlorlde; m.p. 152-153* (dec.); (al^5 -50* (c - 0.5, methanol).

Rg 0.75 (silica gel, chloroform/oethanol/acetic acid, 4:1:1).

Anal, calc'd. for C3iH32FS3°e * HCl * ^-5 H20: C, 59.57; H, 5.80; 9, 6.72; Cl, 5.67 Found: C, 59.68; R, 5.56; 9, 6.67; Cl, 5.99. -121Example 101 (1(S),4R]-1-(K-(3-(Benzoylamino)-2-pxo-4-phenylbutyl}L-alany11 -4-pheny1-L-proline, monohydrochlorlda a) (S) -Ν- [N- (Benzoylamino) -2-oxo-4-phenyIbutyl] -N((phenylmethoxy)carbonyll-L-alanine, succinimido eater A mixture of (S) -N-(N- (benzoylamino) -2-oxo4-pheny lbutylj -N- ((pheny lmethoxy) carbonyl ] -Lalanine (800 mg., 1.6 mmole), prepared as aet forth In Example 100 (c), dicyclohexylcarbodiimide (340 mg., 1.6 mmole), and N-hydroxysuccinimide (190 mg·, 1.6 mmole) in tetrahydrofuran (5 ml.) ie stirred at 25? for 18 hours. After this time it is filtered and concentrated'to give 950 mg. of (S) -Ν- (N- (benzoylamino) -2-oxo-4-phenylbutyl J M- [ (phenylmethoxy) carbonyl ] -L-alanine, succinimido ester. b) ptS).4BjTl- f N- (3-(Benzoylamino) -2-oxo-4phenylbutyl]-B- [ (pheny lmethoxy) carbonyl] -Lalanyl 1 -4-phenyl-L-proline TO a solution of (S) -N-[N- (benzoylamino) -2oxo-4-pheny Ibutyl] -N- ((pheny lmethoxy) carbonyl ] -Lalanine, succinimido ester (950 mg., 1.6 mmole) in dimethylformamide (5 ml.) is added (4R)-4phony 1-L-proline, hydrochloride (375 1.7 mmole) end triethylamine (40 pi., 3.2 mmole). The resulting mixture is stirred at 25· for 24 hours, after which it is poured into excess IN hydrochloric acid and extracted with ethyl acetate (3x). The extracts are combined, dried (MgSOj), filtered, and concentrated to give 1.1 g. of < -122.• (1 (S),4R]-1-(N-(3-(benzoylamino)-2-oxo-4-phenylbutyl]-K-((phenyImethoxy)carbony1)-L-alany 11-4phenyl-L-proline. c) (1(8), 4R] -1- (8-(3- (Benzoy lamiito} -2-oxo-43 phenylbutylj-L-alanyl] -4-pheny1-L-prollne, monohydrochloride The product from part (b) (1.0 g., 1.5 nmole), ethanol (20 ml·), water (5 ml·), 1.0 N hydrochloric acid (1.5 ml., 1.5 nmole), and palladium on carbon catalyst (104, 100 mg.) is hydrogenated at one atmosphere and 25* for 18 hours, after which it is filtered and concentrated. The residue is chromatographed on BP-20 using a linear gradient (0.01 8 aqueous hydrochloric acidzmsthanol, 40:60 to 10:90] · Fractions containing the desired product (TLC) are combined and concentrated. The residue is dissolved ia a minimum amount of methanol. Ether is added and the resulting white . precipitate is collected and dried to give 300 mg. of (1(8) ,4R]-1-(8-(3-(bensoylamino)-2-oxo-4-phenylbutyl] -L-elanyl]-4-phenyl-L-proline, monohydrochloride; m.p. 160-162· (£ 0.8 (silica gel; chloroform/methanol/acetic acid; 4:1:1). 2$ Anal, calc'd. for HjOj · HCl - 1.35 HjO: C, 63.27; H, 6.29; 8, 7.14; Cl, 6.02 Found: C, 63.27; H, 6.17; 8, 7.19; Cl, 5.97. 123Exaraple 102 [1(8), 451-1- [B-[3- (Benzoylamino) -2-oxo-4-phenylbutyl]-L-alanyl] -4-phenyl-L-prolina, monohydrochloride Following the procedure of Example 101 but employing (4S)-4-phenyl-L-proline, hydrochloride in part (b), one obtains [1(8),4S]-l-[R-[3-(benzoylamino) -2-oxo-4-phenylbutyl] -L-alanyl*4-phenyl-Lproline, monohydrochloride; m.p. 138-143·; [a]D -61° (c 0.3% in methanol)· Rg 0.84 (silica gel, chloroform/methanol/acetic acid, 4:1:1). . ’ Anal, calc’d. for c3 ^33^5 · BCI · 2.13 HjO: C, 61.80; H, 6.35; R, 6.98; Cl, 5.88 Found: C, 61.80; H, ¢.06/ R, 7.05; Cl, 5.65.

Example 103 [1(8},4R]-1-[R-[3-(Benzoylamino)-2-oxo-4-phenylbutyll -L-alanyl] -4-cyclohexyl-L-proline, monohydrochloride Following the procedure of Example 101 but employing (4R)-4-cyclohexyl-L-proline, hydrochloride in part (b), one obtains (1(S),4RI-1[N-[3- (bensoy lamin^-2-oxo-4-pbenylbutyl] -Lalanyl] -4-cyclohexyl-L-prolina, monohydrochloride; m.p. 140-154· (dec.); [eJ0 « -83· (c - 0.36« in methanol). Rg 0.84 (silica gel; chloroform/ methanol/acetic acid; 4:1:1). -124. Anal, calc'd. for C^H^N^ · HCl · 0.79 HjO: C, 63-71; H, 7.17; N, 7.19; Cl, 6.06 » Found: C, 63.71; H, 7.21; N, 7.05; Cl, 5.82.

Example 104 [1(9) ,4S]-1- [H-[3- (Benzoylamino) -2-oxo-4-phenylbutyl I -L-alanyl 1 -4-cyclohexyl-L-prollne, monohydrochloride Following the procedure of Example 101 but employing (4S)-4-gyclohexyl-L-prolizM, hydrochloride • 10 ia part (b), one obtains il(S) ,4S}-l-[N-[.3(benxqylamino) -2-oxo-4-phenylbutyl] -L-alanyl J -4cyclohexyl-L-proline, monohydrochloride; m.p. 139-141* (dec.)ι (e1D * -80· (c « 0.2% in methanol). Rg 0.83 (silica gel; chloroform/methanol/ acetic acid; 4:1:1)·.

Anal, calc'd. for C3xB3gN3°5 * HC1 * le54 H20: C, 62.28; H, 7.26; M, 7.03; Cl, 5.93 Found: C, 62.28; H, 7.01; », 7.02; Cl, 6.16.

Example 105 (8) -7- (|S) -2- ] [ 3- (Benzoylamino) -2-oxo-4-phenyIbuty 11 amino] -l-exogropyl] -lf 4-dithia^7-azaspiro 14,4] nonane8-carboxyllc acid, monohydrochloride Following the procedure of Example 101 but employing (8) -l,4-dithIa-7-azaapiro [4.4 J nonane-825 carboxylic acid, hydrochloride in part (b) for the L-proline reactant, one obtains (8)-7-((S)-2-((3(benspylamino) -2-oxo-4-phenylbutyl] amino] -1oxopropyl] -1,4-dithia-7-azaspiro (4.4] nonane-8carboxyllc acid', monohydrochloride; m.p. 170-172·; -125* ~2β° Bxainpla 106 [1(5),55}-ΐγ[9-}3-(Banzoylamino)-2-ΟΧΟ-4yhenyIbutyl] -L-alanyl'} y4 f 5-dihydro-3-phenyl- IE- . pyrazole-5-carboicylic acid, monohydrochlorlde Following the procedure of Example 101 but employing (S)-4,5-dihydro-3-phenyl-lH-pyrazole-515 carboxylic acid for the L-proline reactant in part (b), one obtains the above named compound.

Exanple 107 (5} -2- }9- ((8}-3γ (Benzoylamino} -2-oxo-4-phenylbUtyl} L-alanyl]-!, 2 f 3,4-tetrahydro-3-lsoquinollnecarboxylic 20 acid, monohydrochlorlde Following the procedure of Example 101 but employing (S) -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, hydrochloride in part (b) in place of the proline reactant, one obtains (S)-2-[9-((8)25 3- (benzoylamino) -2-oxo-4-phenylbutyl) -L-alanyl] -1, 2,3,4-tatrahydro-3.-'isoguinblinecarboxyllc acid, monohydrochlorlde· -126• Bxample 100 1- (tt- {(S) -3- (Benzoy lamino) -2-oxo-4-pheny Ibuty 11 -Lalanyl) -2- (2-hydroxyphenyl)-4 (R) -thiazolidinecarboxylic add, monohydrochlorlde 5 Following the procedure of Example 101 but employing 2-((2-phanylmethoxy)phenylJ-4(R)-thiazolidinecarboxylic acid, hydrochloride in part (b) In place of the proline reactant, one . obtains after removal of the hydroxy protecting group 1- (Ε-1 (S) -3.- (benzoylamino)-2-oxo-4phenylbutyl] -L-alanyl) -2- (.2-hydrOxyphenyl) . 4 (R)-thiazolidinecarboxylic acid, monohydrochloride.

Za a similar manner, the processes of Examples 96, 97, 99 and 100 to 108 can be employed to prepare the conpounds of Examples 1 to 95. -127. Example 109 (t} -1- (8- (3- (Benzoylamino) -2-oxo-4-phenylbutyl I -Lalanyl]-L-grollne, methyl ester, monohydrochloride a) 1- [8- (2-Etlioxy-2-oxoethyl·) -8- [ (phenylmethoxy) 5 carbonyl1-L-alanyl]-L-proline, 1,1-dimethylethyl eater » L-Alany1-L-proline, 1,1-dimethylethyl ester (25.44 g., 105 mmole) is taken into tetrahydrofuran (400 ml.) with stirring. TO this bromoethyl acetate * (11.64 ml., 105 mmole) and diisopropylethylamine (18.3 ml., 105 mmole) are added. After 6 hours the reaction mixture is chilled in an ice bath and benzyl chloroformate (16.5 ml., 115.5 mmole) and diisopropylethylamine (20.1 ml., 115.5 mmole) are added; After one hour the ice-bath is removed and the reaction mixture is kept overnight at room temperature, it is then concentrated to dryness, taken into ethyl acetate, and washed neutral with 104 potassium bisulfate and saturated sodium bicarbonate. The crude product (52.3 g.) is purified on a silica gel column eluting with ethyl acetate:hexane (1:1) to yield 42.4 g. of l-[N-(2-ethoxy-2-oxoethyl)-8-[ (phenylmethoxy) carbonyl]-L-alanyl]-L-proline, 1,1-dimethylethyl . eater. b) 1- [8- (Carboxymethvl) -8- [ (phenylmethoxy) carbonyl] L-alany11-L-proline, 1,1-dimethylethyl eater The ester product from part (a) (21 g., 45.4 mmole) is taken into methanol (150 ml.) and 18 sodium hydroxide (50 ml., SO mnole) with -128• stirring at room temperature. After 5.5 hours the methanol is removed in vacuo and the aqueous portion is extracted with •thyl acetate. The aqueous portion is acidified with concentrated hydrochloric acid and extracted into ethyl acetate to yield 16.93 g. of l-(N-(carboxyroethyl)-N((phenylmethoxy) carbonyl ] -L-alanyl J -L-proline, 1,1dimethylethyl ester· o) (*) -1- tM- (W- (3- {Benzoylamino) -2-oxo-410 yhenylbutyll -N- {(phenylmethoxy) carbonyl ? -L-alanyl ] L-proline, 1.1-dimethylethyl ester The ester product from part (b) (10.0 g., mmole) is taken into dry tetrahydrofuran (75 ml.) with stirring ini an ice-bath· To this, oxalylchlorlde (2.4 ml., 27.6 nmole) is added dropwise followed by 15 drops of dimethy If onaamide. After 20 minutes the ice-bath is removed and the reaction aixture is kept at room temperature for one hour. The mixture is then concentrated to dryness In vacuo nnd taken into tetrahydrofuran (40 ml.) with stirring in an ice-bath. TO this, 2-phenyl-4(phenyImethyl)-5(4B)-oxasolone (6 g., 23.8 mmole) in tetrahydrofuran (35 ml.) is added dropwise followed by triethylamine (3.22 ml·, 23 mmole).

Additional triethylamine is added to maintain a basic atmosphere. After 20 minutes the ice-bath is removed and the reaction mixture is kept at room temperature overnight. The triethylamine hydrochloride is filtered off and the filtrate is concentrated to dryness in vacuo. The residue isl -129taken into pyridine (25 ml.) and 4-dimethylamino pyridine (75 mg.) ia added and the solution is stirred for 3 hours under an argon atmosphere. Acetic acid (25 ml.) is added and the reaction mixture is stirred for 45 minutes at 100° under a positive flow of argon. The reaction mixture is concentrated to dryness, taken into ethyl acetate, and washed neutral with saturated sodium bicarbonate and dilute hydrochloric acid. The crude product (12.8 g.) is chromatographed on silica gel eluting with ethyl acetate:hexane (1:1) to give 9.05 g. of (i)-l-(N-(N-[3-(benzoylamino)-2oxo-4-phenylbutyl]-H-((phenylmethoxy)carbonyl]-Lalanyl]-L-proline, 1,1-dimethylethyl ester. d) (t)-l-(N-[N-[3-(Benzoylamino)-2-oxo-4phenylbutyl]-H-t(phenylmethoxy)carbonyl]-Lalanyl]-L-proline The ester product from part (c) (11.4 g., 17.7 mmole) Is taken into trifluoroacetic acid (50 ml.) and kept at room temperature for 45 minutes. Xt ie then concentrated to dryness and triturated with ether:hexane to yield 10.3 g. of crude product. This material ia purified on a silica gel column in benzene/acetic acid (8:2) to give 9.7 g. of (i)-l-[M-(N-[3-(benzoylamino)2-oxo-4-phenylbutyl] -M- ((phenylmethoxy) carbonyl] alanyl]-L-proline; m.p. 70 - 91·; fain * -53.0 (c - 1.22, methanol) acetic acid; 8:2).

*LRg 0.41 (silica gel, benzene/ * -130. Anal, calc'd. for C33H35N3°7 C, 67.68; H, 6.02; N, 7.17 Found: C, 67.95; H, 6.02; N, 6.82. e) (t)-1-|N-{M-(3-(Benzoylamino)-2-oxo-4-phenyi- . butyl] -M- [ (pheny Ima thoxy) carbonylT-L-alanyl] L-proline, methyl eater The acid product from part (d) (3.5 g., mmole) in taken into dimethylformamide (12 ml.) with stirring at room temperature. To this sodium bicarbonate (630 mg·, 7.5 mmole) and methyl iodide (0.47 ml·, 7.5 nmole) are added. After 18 hours, additional methyl iodide (7.4 mmole) and sodium . bicarbonate (7.4 nmole) are added. After stirring for an additional 4 hours, the reaction mixture is concentrated to dryness in vacuo, taken into ethyl acetate and washed with saturated sodium bicarbonate. The crude product (3.7 g.) ie purified on a silica gel column in ethyl acetate:hexane (2:1) to give 3.5 g. of (t)-l-(M-[B-[3-(benzoylamino)-2-oxo-420 phenylbutyl]-N-[ (phenylmethoxy)carbonyll-L-alanyl]L-proline, methyl ester. f) (±) -1- 13- (benzoylamino) -2-oxo-4-pheny Ibuty 1 ] L-alanyl1-L-proline,methyl eater, monohydrochlorlde The ester product from (e) (900 mg., 1.5 nmole) is taken into ethanol (954, 100 mX.) and IM hydrochloric acid* (1.8 ml.)· Palladium on carbon catalyst (104, 180 mg.) is added and the reaction mixture is stirred under hydrogen overnight. The reaction mixtufe ia filtered to remove the catalyst, concentrated to dryness end lyophilized -131• twice from water to give 700 mg. of (benzoylamino) -2-oxo-4.-pheny Ibutyl] -L-alanyl] -L-proline, methyl ester,monohydrochloride;m.p. 110-128* (90·); [a)£3 - -69.9* (c - 1.18, methanol).

Rg 0.63 (silica gel, chloroform/methanol/acetic acid; 9:1:1).

Anal, calc'd. for C26H31N3O5 · HCl 0.92 HjO: C, 60.22; R, 6.58; 9, 8.11; Cl, 6.84 Found: C, 60.22; H, 6.28; 9, 8.10; Cl, 7.06.

Example llfl (t)-1-[9-Γ3-(Benzoylamino)-2-oxo-4-phenyIbutyl]L-alanyl]-L-prollne,methyl ester, monomethanesulfonate (t)-1-[Ν-[N-(3-(Benzoylamino)-2-oxo-4phenylbutyl] -9- ((phenylmethoxy) carbonyl) -L15 alanyl)-L-proline, methyl ester (600 mg., 1 mmole), prepared as set forth in Example 109 (e), is taken into methanol (60 ml.) and methanesulfonic acid (0.066 ml., 1 mmole). Palladium on carbon catalyst (108, 120 mg.) is added and tha reaction mixture is stirred under hydrogen for 2.5 hours.

The reaction mixture is- filtered to remove the catalyst and then concentrated in vacuo. The crude product is triturated with ether and filtered.

The precipitate is taken into water and lyophilized to yield 470 mg. of (i)-1-[N-[.3- (benzoylamino) -2oxo-4-phenyIbutyl]-L-alanyl]-L-proline, methyl ester, monomethanesulfonate; m.p. 80 - .140*; [«]q2 " -61.4* (c 1.10, methanol). Rg 0.63 (silica gel, chloroform/methanol/acetic acid; 9:1:1). % -132• Anal, calc'd. for C2$H31N3°5 * CH4°3S C, 56.98; H, 6.34; 8,7.30; S, 5.63 Found: C, 56.98; H, 6.32; 8, 7.47; S, 5.63.

Example 111 (t) -1- [8-(3- (Benzoylamino) -2-oxo-4-phenyibutyl] L-alanyll-L-prollne, methyl eater, hemisulfate (i) -1-(8- [N-{3-(Benzoylamino) -2-oxo-4phenylbutyl] -8- ((phenylmethoxy) carbonyl] -L-alanyl ] L-proline, methyl eater (600 mg., 1 mmole), prepared aa set forth ln Example 109 (e), ia taken into methanol (40 ml.) along with 18 sulfuric acid (0.9 ml.). [s]q2 « -60.3· (c - 1.16, methanol). R£ 0.63 (trailing) (silica gal, chloroform/methanol/ acetic acid; 9:1:1).

Anal, calc'd. for jOj · 0.5 HjSO4 . 0.91H2Os C, 58.81; B, 8.42; N,*7.92; S, 3.01 Founds C, 58.81; B,.6.11; H, 7.91; S, 3.09. -133• Example 112 (4)-1-JM-[3-(Benzoylamino)-2-oxo-4-phenylbutyl]L-alanyl]-L-proline,propyl ester, monomethanesulfonate a) {4)*1(M(M-(3-(Benzoylamino)-2-oxo-45 phenylbutyl]-W-( (phenylmethoxy) carbonyl 1 -L-alanyl]L-proline, propyl ester · (4)-1-[Ν-(N-[3-(Benzoylamino)-2-oxo-4f phenylbutyl] -N- ((phenylmethoxy) carbonyl ] -Lalanyl]-L-proline (1.17 g., 2 mmole), prepared * XO as set forth ln Example 109(d), is taken into tetrahydrofufan (2 ml.) with stirring in an ice-bath.

To this is added'n-propanol (3.0 ml·, 40 mmole) followed by 4-dimethylamino pyridine (122 mg., mmole) and dicyclohexylcarbodiimide (412 mg., 2 mmole). The reaction is allowed to warm to room temperature and to run overnight. The dicyclohexylurea is filtered off and the filtrate is concentrated to dryness in vacuo. The crude product (1.2 g.) is chromatographed on a silica gel column in benzene:acetic acid (9:1) to yield 1.0 g. of (4) -1-[Μ— [H- [3- (benzoylamino) -2-oxo-4-phenyl1 - butyl] -M- ((phenylmethoxy) carbonyl] -L-alanyl] -Lproline, propyl ester. b) (±)^l-fW-(3-(Benxoylarolno)-2-oxo-4-phenylbutyl)25 h-alanylJ-L-proline, propyl ester, monomethaneaulfonate The ester product from part (a) (500 mg., 0.8 mmole) ia taken into methanol (50 ml.).

Methanesulfonic acid' (0.72 ml. of IM solution in methanol) and palladium on carbon catalyst (104, ' » -134• 100 mg.) arm added and the reaction mixture is stirred under hydrogen overnight. The reaction mixture is filtered to remove the catalyst, concentrated to dryness, triturated with ether and filtered to yield 406 mg. of crude product.

This is taken into water, millipore filtered, and lyophilized to yield 390 mg. of (1)-1-(8-(3(bensoy lamino) -2-oxo-4-phenylbutyl] -L-alanyl] L-proline, propyl ester, monomethanesulfonate; B.p. 82-94·(89·)j (a)’3 - -80.3· (e - 0.95, methanol). 0.46 (silica gel, chloroform/ methanol/acetic acid; 90:5:5).

Anal, calc'd. for C28H35N305 CH^S · 0.5 HjOs C, 56.15; H, 6.73; 8, 7.01; S, 5.34 IS Found: C, 58.13; 8, 6.63; 8, 7.05; S, 5.34.

Example 1113 (1) -1- (8- (3- (Benzoylamino) -2-οχθγ4-phenylbutyl 1 L-alanyl 1-L-proline, ethyl eater, monomethanesulfate a) (t) -1- (8- [8-13- (Benzoylamino) -2-oxo-420 pheny lbutyl]-8-|^pheny lme thoxy) carbonyl]-Lalanyl)-L-proline, ethyl eater (1) -1- [V- (8-(3- (Benzoylamino) -2-oxo-4phenylbutyl ] -8- ((phenylmethoxy) carbonyl ] -L-alanyl ] L-proline (1,17 g·, 2 mole), prepared as set forth in Example 109 (d), is taken into tetrahydrofuran (2 al.) with stirring in an lee-bath. To this is added absolute ethanol (2.3 ml·, 40 mmole) followed by 4-dimethylamino pyridine (122 mg., 1 mmole) and dicyclohexylcarbodiimide (412 mg., 2 mmole).

The reaction isLallowed to run overnight at room 135temperature. The dicyclohexylurea is filtered off, the filtrate is concentrated to dryness, the residue is taken into ethyl acetate and washed neutral with 10« potassium bisulfate and saturated sodium carbonate. The crude product (1.2 g.) is purified on silica gel column in benzene; acetic acid (8:2) to yield 1.0 g. of (±)-l(N-1 Μ— 13- (benzoylamino) -2-oxo-4-phenylbutyl J -N((phenylmethoxy) carbonyl] -L-alanyl] -L-proline, ethyl ester. b) (t)-l-lN-(3-(Benzoylamlno)-2-oxo-4-phenylbutylJL-alanyl]-L-proline, athyl ester, monomethancaulfate The ester product form part (a) (500 mg., 0.8147 mmole) is taken into 50 ml. of methanolmethanolic methanesulfonic acid (IM, 0.733 ml·)· Palladium on carbon catalyst (lot, xOO mg.) is added and the reaction mixture is stirred under positive hydrogen pressure for 3 hours. The reaction mixture is filtered to remove the catalyst, concentrated to dryness, triturated with ether and filtered. The precipitate (428 mg.) is taken into water, millipore filtered, and lyophilized to yield 360 mg. of (±)-l(N- (3- (benzoylamino) -2-oxo-4-phenylbutyl ] -L-alanyl] L-proline, ethyl ester, monomethanesulfonate; m.p. 91 - 96· (72·); (a)33 - -57.2· (e - 1.04, methanol). 0.44 (silica gel, chloroform/methanol/ acetic add; 90:5:5).

Anal, calc'd. for £27*33*3°$ * CB^SO^ · 0.6 H20: C, 57.33; H, 6.56; », 7.17; S, 5.47 Found: C, 57.33; H, 6.43; N, 7.12; S, 5.47. -136 • Example 1J.4 (il-1-IN- Γ3-(Benzoylamino)-2-oxo-4-phenyIbutylJ- L-alanylI-L-prollne, 1-methylethyl ester, mono- me tha ne sul f o na te * 5 . a) (t)-1-IN-IN-13-(Benzoylamino)-2-oxo-4-phenyl- butyl] -Ν-1 (phenylmethoxy) carbonyl ] -L-alanyl ] -L- proline, 1-methylethyl ester (1) -1-[Ν- [N- [3- (Benzoylamino) -2-oxo-4-phenyl- 10 buty 1 ]-N-((pheny Imethoxy) carbonyl J-L-e lanyl ]-Lproline (1.17 g., 2 mmole), prepared as set forth in Example 105 (d) , and isopropanol (3.0 ml., 40 mmole) are taken into tetrahydrofuran (2 ml.) with stirring in an ice-bath. To this dicyclohexylcarbodiimide (412 mg., 2 mmole) is added. The 15 reaction is allowed to run overnight at room temperature. Zt ia then concentrated to dryness, taken into ethyl acetate and the dicyclohexylurea filtered off. The filtrate is washed neutral 20 with 10% potassium bisulfate and saturated sodium bicarbonate. The crude product (1.2 g.) is purified on a siliea gel column with benzene:acetic acid 25 (8:2) to yield 1.0 g. of (±)-l-[N-(N-13-(benzoylamino) -2-oxo-4-pheny Ibutyl] -N- ((pheny lmethoxy) carbonyl]-L-alanyl)-L-proline, 1-methy lethyl ester, b) (±) —1— IN-13- (Benzoylamino) -2-oxo-4-pheny Ibutyl] - L-alanyl]-L-proline, 1-methylethyl ester, mono- mathanesulfonate t 30 The ester product from part (a) (815 mg·, 1.3 mmole) is taken into methanol (20 ml.) and methanolic methanesulfonic acid (IM, 1.17 ml.) -137and stirred under hydrogen in the presence of palladium on carbon catalyst (10%, 160 mg.) for 3 hours. The reaction mixture is filtered to remove the catalyst and concentrated to dryness in vacuo. The residue is triturated with ether and the precipitate filtered to yield 704 mg. of crude product. This is taken into 35 ml. of water (2% solution), millipore filtered, and lyophilized to give 600 mg. of (1)-1-(9-(3-(benzoylamino)-210 oxo-4-pheny Ibutyl]-b-alanyl]-L-proline, 1-methylethyl ester, monomethanesulfonate; m.p. 88 - 105*;* (α]θ3 - -55.2* * (c - 1.05, methanol). Rf 0.33 (silica gel, chloroform/methanol/acetic acid; 9:1:1).

Anal, calc'd. for C28*35N3°5 * ^H4°3S * 0-66 C, 57.89; 9, 6.75; 9, 6.99; S, 5.33 Found: C, 57.89; H, 6.62; 6.62; S, 5.32.

Examples 115 - 123 Following the procedure of Examples 109, 112, 313 and 114, (±)-1-(9-(-3-(benzoylamino)-2-oxo-4pheny Ibutyl] -9- ((phenylmethoxy) carbonyl] -Lalanyl]-L-proline is treated with the reagent shown below In Col. X. Removal of the alanyl protecting group yields ths ester product shown below in Col. XX. -138Col. IX Ο 0 /—\ ft 1’ (O/"c"nhm:h— 9-ch2' CH, CH, 0 I 3 ft CH — C CM COORg txaaplo 115 116 117 118 Col. t I Cl-CH-O-C-CjBj CBCCHjij O H Cl-CHj-O-C-CCCHjij CHj-O-C-CBj S o * -CH-O-C7CH I -CH-O-C-C, CH3)2 O I -CBj-O-C-CCCHjJj II -CHj-O-C-CHj *139- Example Col. I 119 0 120 0 1 I-CB3-C-O-C(CH3>3 0 κ -CH3-C-O-C(CB3) 121 CB. 0 1 3 ll x-c— c-o-ca3 CB o ι ι -C-C-O-CH3 I CBj ι. 122 CH-CCH2 *2 -CHtCB^-OH)? 0« X23 CH--CB--CB, -OL-CB—CH, Pi i i ι OB 0 0 OB oa ι I v-® v-@ • Example 124 1- (Ν* ί (S) -3- {Benzoylamino) -2-oxo-4-phenylbutyl) - L-alanyl]-L-proline, sodium salt 5 « 1- [N- [ (S) -3- (Benzoylamino) -2-oxo-4-phenylbutyl]-L-alanyl]-L-proline, hydrochloride (424 mg., 1 nmole) is dissolved ln water (SO ml.)· Aqueous sodium bicarbonate (0·1Μ, 20 ml.) is added and the * 10 aqueous solution is lyophilized. It is then dissolved in water (10 ml.) and applied on a column (5 cm. x 60 cm.) of Sephadex chromatography gel G-10 and eluted with water. Fractions containing 15 the desired product are pooled and lyophilized to obtain l-(M-((S)-3-(benzoylamino)-2-oxo-4phenylbutyll-L-alanylJ-L-proline, sodium salt. 14110 Example 125 1000 tablets each containing the following ingredients l-ίN-I(S>-3-(Benzoylamino) -2-oxo-4-phenylbuty 11 -L-alanyl ] -Lproline, sodium salt 100 mg.

Corn starch 50 mg.

Gelatin 7.5 mg.

Avieel (microcrystalline cellulose) 25 mg.

Magnesium stearate 2.5 mg. are prepared from sufficient bulk quantities by mixing the l-(N-((S)-3-(benzoylamino)-2-oxo-4phenylbutyl]-L-alanyl]-L-proline, sodium salt and corn starch with an agueous solution of the gelatin. The mixture is dried and ground to a fine powder. The Avieel and then the magnesium stearate are admixed with granulation. This mixture is then compressed in a tablet press to form 1000 tablets each containing 100 mg. of active Ingredient.

Xn a similar manner, tablets containing 100 mg. of the product of any of Examples 1 to 123 can be prepared.

A similar procedure can be employed to form tablets containing 50 mg. of active ingredient. -142Example 126 Two piece-tl gelatin capsules each containing 50 mg. of 1-(8-( (S)-3-(benzoylamino)-2-oxo4-phany lbutyl]-L-alanyl]-L-prolinef sodium aalt are filled with a mixture of the following ingredients: 1- (8-( (S) -3-(Benzoylamino) 2- oxo-4-phanylbutyl]-Lalanyl]-L-proline, sodium salt 50 . mg. Magnesium stearate 7 mg. Lactose . 193 mg. 250 mg.

Xa a similar manner capsules containing 50 mg. of the product of any of Examples 1 to 123 can be prepared.

' Example 127 An injectable solution is prepared as follows: 1-[8-((S)-3-(Benzoylamino) -2-oxo-4-phenylbutyl]-L-alanyl]-Lproline, sodium salt 500 g.

Methyl paraben 5 g.

Propyl paraben 1 g.

Sodium chloride 25 g.

Water for injection 5 1.

The active substance, preservatives, and sodium chloride are dissolved in 3 liters of water for injection and then the volume ia -143• brought up to 5 liters. The solution is filtered through a sterile filter and aseptically filled into presterilized vials which are closed with presterilized rubber closures. Each vial contains 5 ml. of solution in a concentration of 100 mg. of active ingredient per ml. of solution for injection.

In a similar manner, an injectable solution containing 100 mg. of active ingredient per ml. of solution can be prepared for the product of any Examples 1 to 123.

Example 128 1000 tablets each containing the following ingredients: 1"(N-[(S)-3-(Benzoylamino) -2-oxo-4-phenylbutyl] -L-alanyl] -Lproline, sodium salt Avicel Hydrochlorothiazide Lactose Cornstarch Stearic acid 100 mg. 100 mg. 12.5 ug. 113 mg. 17.5 mg. mg. 350 mg. are prepared from sufficient bulk quantities by slugging the 1-19-1 (S) -3- (benzoylamino) -2oxo-4-phenylbutyl]-L-alanyl]-L-proline, sodium salt, Avicel, and a portion of the stearic acid.

The slugs are ground and passed through a 82 (approx. ea) screen, then mixed vith the hydrochlorothiazide, lactose. -144• cornstarch, and remainder of the stearic acid.

The mixture is compressed into 350 rag. capsule shaped tablets in a tablet press. The tablets are scored for dividing in half.

Zn a similar manner, tablets can be prepared containing 100 mg. of the product of any of Examples 1 to 123.

Claims

1.CLAIMS 1. A compqund ot the formula 0 R R. 0 » I I 1 ϋ R,-CH-C-CH 3 I 2 (L) CM3 or a pharmaceutically acceptable salt thereof wherein X ia H,C Ί -N-C-COOR I (L) ‘ H -N-C-COOR, H CH. CH. N — C-COORI (I·) 6 H R l°Xx/ *10 H 2f “2 -N-C-COOR, , » (l) Έ u * -146-. ΟΓ -Ν — CH-COOIL· j I I 6 R 4 R 5 R is hydrogen, lower alkyl, cycloalkyl. (CHjIj-NHj, -(C« 2 ) 3 -NH 2 , (ch 2 ) 4 -hh 2 , - 2 ) 2 -oh, -(ch 2 ) 3 -oh, -147 - 2 ) 4 -OH, -(CHjg-SH, or -(CHjl/SHj R x la hydrogen, lower alkyl, halo substituted lower alkyl, -(CBj) i© , “(CHj) f®- 0 »’ OB (CH 2 l r » - 2 ) r -OB , - 2 ) r -HH 2 (CHj) r -SH, - (CHj) r -S-lpwer alkyl, HH -(CHjiy-HH-C , or -(CH 2 ) r -C-NHj , HH. provided that R^ ia hydrogen only when R ia other than hydrogen; -148 ’«αφ,-Π , ir ivr ' , s (εΗ 2’«“ζ5 ' O3E ’ is hydrogen, lower elkyl, -(CH,) i® ‘«xJ: (CH a».-O ' hal ° aubatituted lower alkyl, -(CH.) -cycloalkyl, -(cap OH ,c8a>r U@ ' · ‘“i’qrij' - ( CH 2 ) r -ra 2 , -(CH 2 ) r -SH , -(CH 2 ) r -S-lower alkyl. -149NH r -NH-C , or -(CH 2 ) r -C-NH 2 j NH. r 4 la hydrogen, lower alkyl. -«caa’iT® ' -(CH 2 ) B -cycloallcyl, (CH. ?,Γζί) · or R s Is hydrogen, lower alkyl. - 2 ) “(CHj) or· oh OH I -150- 2 ) ? (CH 2 , r‘ Ofl 9 - (CH 2 l f ra 2' ' 1°¾)r SH * “ tCH 2 ) r ’ s lower alkyl, / ra 1 ° -(CH^-NH-CT * or -(CH 2 ) r -C-»H 2 i r ii ω integer from 1 to 4; Ay is hydrogen, lower alkyl, halogen, keto, -(CH; ι’ίήΓΊ) 151a 1- or 2-naphthyl of the formula -“Va , -(CH^-cycloalkyl, I / “is z-\ -0-C.-8 , -O-lower alkyl, * *15 a 1- or 2-naphthyloxy of the formula -o-coipa , -S-lower alkyl. OlO-hv, -«Vr®. _ «ιΛ , or a 1- or 2-naphthylthio of the formula -S-CCH^ X)IOJ- X4 > p -152 R ] *15 > /15 R e is keto, halogen, -O-C-R, -0-lower alkyl, a 1or * R 13> p 2. -naphthyloxy of the formula ' O ' (CH 2 , i\Zx ' -s-lower -S-(CH 2 )^-6O\ fe i , or a 1- or 2naphthylthio of the formula Rg is keto or lR 13»p « -153is halogen or R ll' R 11 * R 12 and R 12 are inde P en<3entl Y selected from hydrogen and lower alkyl or R’^ , R^j and R'u are hydrogen and R^ is (R 14>p R^ 3 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trif luoromethyl, hydroxy, phenyl, phenoxy, pheny lthio, or phenylmethyl; R^ 4 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trif luoromethyl, or hydroxy; m is kero, one, two, three, or four; p is one, two or three provided that p is mors than one only if R^ 3 or R^ g is hydrogen, methyl, methoxy, chloro, or fluoro; R 15 ie hydrogen or lower alkyl of 1 to 4 carbons; Y is oxygen or sulfur; *1$ le lower alley 1 of 1 to 4 carbons. or the R^ g groups join to -154complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a lower alkyl of 1 to 4 carbons or a di(lower alkyl of 1 to 4 carbons) substituent; R^ is lower alkyl, benzyl, or phenethyl; Is hydrogen, lower alkyl, benzyl or phenethyl; R g is hydrogen, lower alkyl, benzyl, benzhydryl. -CB-O-CI *17 c-o-r 23 , -ch-(ch 2 -oh) 2 , I.-CB-OL , 2 I I 2 (CH 2 ) 2 -N 3 ) 2 , or -CHj{p) R 17 is hydrogen, lower alkyl, cycloalkyl or phenyl; i R^g is hydrogen, lower alkyl, lower alkoxy, phenyl, or R^ and R^g taken together are -(CH^-, Rj! and Rj 2 are independently selected from the group consisting of hydrogen and lower alkyl; and Rjj is lower alkyl. 1552. A compound of Claim 1 wherein: R la hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or phenyl; R^ is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, CF 3< -(CH 2 ) r -NH 2 , -«Γ® , OH , OH - 2 ) 2 -s-ch 3 . 2 > 3 hhc^ NHj -CHj-OH O I -CH 2 -C-MH 2 or P -(CH 2 ) 2 -C-HH 2 provided that R^ Is hydrogen only if R is other than hydrogen; R 4 is hydrogen, cyclohexyl, or phenyl; I -156 Rj is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, : -CH. j-^^-OB , <Η,-(θ^-ΟΗ , -CH„-OH , 'Λ OB ‘ ςΗΓ ζί ' -‘Vr^a ' -CHj-SH, - CCTj) j-S-CHj , - (CH 2 ) j-HHC NH NH, -CH 2 -C-HH 2 or -(CH 2 , 2 -C-HH 2 ; R g is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, an alkali metal salt ion. 0 II -CH-O-C-R. s -CB 2 -C-OR 23 -CH-(CR 2 -OH) 2 , -ch 2 -ch OH CHj , -(CT 2 ) 2 -W(CH 3 ) 2 , OH -157R^ 7 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl; »18 * straight or branched chain lower alkyl of 1 to 4 carbons or phenyl;. is straight or branched chain lower alkyl of 1 to 4 carbons; *2 ia -‘“ζ’ιΓ®. 1« R^ is straight or branched chain lower alkyl of 1 to 4 carbons, -(CH 2 ) r -NH 2 , *14 ° r -(CH 2 ’r@ » a z R 7 Is hydrogen, hydroxy, straight or branched chain lower alkyl of 1 to 4 carbons, cyclohexyl, amino, -O-lower alkyl wherein lower alkyl is straight or branched chain of 1 to 4 carbons, -« α 2»ϊ® > »13 *13 1-naphthyloxy, 2-naphthyloxy, -S-lower alkyl wherein lower alkyl is straight or branched chain of 1 to 4 carbons, - s - (ch 2»£® I 1581-naphthyl thio, or 2-naphthyl thio; R g la -0-lower alkyl, -S-lower alkyl. or -8 ViT© wherein lower alkyl is straight or branched chain of 1 to 4 carbons, Rg is phenyl, 2-hydroxyphenyl or 4-hydroxyphenyl; R^q are both fluoro, both chloro, or both -Y-R^; 1 Y is 0 or S; R 16 etrai 9 ht or branched chain lower alkyl of 1 to 4 carbons or the groups join to complete an unsubstituted 5- or 6-msmbered ring or said ring in which one or nore of the available carbons has a methyl or dimethyl substituent; ^ll' ^11 ' *12 *12* are aXX hydrogen or R^ is phenyl, 2-hydroxyphenyl, or 4hydroxyphenyl and R^ 1 , R^ 2 *12 are all hydrogen; r ls an integer from 1 to 4; m is sero, one, or two; Rj 3 Is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy; *14 Xs hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy; and *24 is phenyl· -159-u 3. λ compound X ie -N-CH o -CO< I 2 ·« H 2 c' chI I 2 ---C-COOR- 9 I (fc) 6 of Claim 2 wherein: *6 ' CH. I I ‘ -»-C-COOR. | (W ' a R is hydrogen or methyl; R^ is hydrogen, methyl, or -(CHp^-NHj provided that R^ is hydrogen only if R is other than hydrogen; R 4 is cyclohexyl or phenyl; Rg is hydrogen, straight or branched chain lover alkyl or 1 to 4 carbons, or an alkali metal salt ion; I -160- . R? is hydrogen, cyclohexyl, lower alkoxy of 1 to 4 carbons. °-< CB 2>r®t 8 ' or - s -< CH 2 , «®. 13 R 13 a la zero, one or two; la hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy; and t ia 2 or 3. 4. A compound of Claim 3 wherein X ia -N-CH.-COOR- . I 2 R « 3. A compound of Claim 4 wherein Rj is phenyl; and Rj Is benzyl. 5. 6. The compound of Claim 5 wherein R is hydrogen; R^ is methyl; R g is cyclohexyl; and R g is hydrogen. 6. 7. The compound of Claim 5 wherein R is hydrogen; Rj is methyl; Rg is phenyl; and Rg is hydrogen. ' -1618. The compound of Claim 5 wherein R is methyl; Rj is hydrogen; R^ is cyclohexyl; and R fi is hydrogen. 7. 9. A coapound of Claim 3 wherein: X is h.c-ca. 2 f , S 8 H 2f -N-C-COOR^ I (L) 6 H 8. 10. A compound of Claim 9 wherein: R^ Is phenyl; and R 3 is benzyl. 9. 11. The compound of Claim 10 wherein: R is methyl; Rj is hydrogen; and . R g is hydrogen; 10. 12. The compound of Claim 10 wherein: R is methyl; Rj is hydrogen; and - Rg is methyl· 11. 13. The compound of Claim 10 wherein: R ia hydrogen; Rj Is methyl; and Rg is hydrogen. -16214. A compound of Claim 3 wherein X is TW COOR. 15. The compound of Claim 14 wherein: Rj is phenyl; and R 3 la benzyl. 16. The compound of Claim 15 wherein: R is methyl; R^ is hydrogen; and Rg is hydrogen. 17. The compound of Claim 15 wherein R is hydrogen; R^ is methyl; and Rg le hydrogen. 18. A compound of Claim 3 wherein: X is -sr— c-cpoR, I (x.) a -16319. λ compound of Claim 18 wherein: R? is hydrogen. 20. The compound of Claim 19 wherein: Rj is phenyl; R 3 is - 2 ) 4 -NH 2< R is hydrogen; Rj is methyl; and R fi is hydrogen. 21. The compound of Claim 19 wherein: Rj is phenyl; Rj is - 2 ) 3 -CH 3 j R is hydrogen; Rj is methyl; and Rg is hydrogen. 22. Thecompound of Claim 19 wherein: Rj is phenyl; is R is hydrogen; Rj is methyl; and Rg is hydrogen, 23. The compound of Claim 19 wfSerein: Rj is phenyl; -164 R is hydrogen; Rj is methyl; and Rg is hydrogen. 24. A compound of Claim 19 wherein: Rj is phenyl; and * R 3 is benzyl. 25. The compound of Claim 24 wherein: R is hydrogen; • Rj is methyl; and Rg ia hydrogen. 26. The compound of Claim 25, 1-(N-((S)3- (benzoylamino) - i 2-oxo-4-phsny lbutyl] -L-alanyl] L-proline, monohydrochlor ide. 27. The compound of Claim 24 wherein: R is hydrogen; Rj is methyl; and Rg is methyl. 28. The compound of Claim 24 wherein: R is hydrogen; Rj is methyl; and Rg is ethyl. 29. The compound of Claim 24 wherein: R is hydrogen; Rj is methyl; and Rg is n-propyl. -16530. The compound of Claim 24 wherein: R is hydrogen; Rg is methyl; and Rg ie isopropyl. 31. The compound of Claim 24 wherein R is methyl; * Rg is hydrogen;- and Rg is hydrogen. 32. The compound of Claim 24 wherein: « R is hydrogen. Rg is - 2 ) 4 -NH 2 ; and Rg is hydrogen. 33. A compound of Claim 18 wherein R? is 34. A ccnpound of Claim 33 wherein: Rg is phenyl; and Rg is benzyl. 35. The compound of Claim 34 wherein: R is methyl; Rg is hydrogen; and Rg is hydrogen. 36. A conpound of Claim 18 wherein R? is -16637. λ compound oi Claim 36 wherein: is phenyl; and R^ is benzyl. 38. The compound of Claim 37 wherein: R is methyl; R^ is hydrogen; and R g ia hydrogen. 39. The compound of Claim 37 wherein: R is methyl; R^ is hydrogen; and Rg is methyl. 40. The compound of Claim 37 wherein: R is hydrogen; R^ is methyl; and Rg is hydrogen. 41. λ compound of Claim 18 wherein R? is phenyl. 42. λ compound of Claim 41 wherein: R^ is phenyl; and is benzyl. 43. The compound of Claim 42 wherein: R is hydrogen; R^ is methyl; and Rg is hydrogen. 44. A compound of Claim 18 wherein R? is cyclohexyl. -16745 · A compound of Claim 44 wherein: R 2 ia phenyl; and Rg ia benzyl. 46. The compound of Claim 45 wherein: R is hydrogen; Rg is methyl; and Rg is hydrogen. 47. A conpound of Claim 1 wherein: R is lower alkyl, cycloalkyl, · - 2 ) 2 -nh 2 , -(cb 2 ) 3 -kh 2 , - (CHg) g-MHg, - (CHg, g-OH, - (CHg) g-OH, -(CHglg-OH, -(CHg)g-SH, -(CHg)g-SH, or -(CHg) 4 -SH; and m is sero, one, two, three or four.' 48. The compound of Claim 47 wherein R is methyl. ι. 16849. A compound of the formula R.-CH-C-CJL· -NH-CH-C-X 3 ι 2 (L) NB I CM} I *2 or a pharmaceutically acceptable salt thereof wherein X -is -M —C-COOR£ <« 6 -Bi—C-COOR, I (L) 1 a CH. ’Ύ CH. “ B —C-COOR-/ ι (U 6 H R 10^ ’10 H-C CH, 2 I I 2 -H— C-COOR- , I (L) ® H ’U'S/u R'n'T N-C-COOR, -N—C-CC&L , I (W * ι ft) 6 H L -169- or -HH-CH-COOR- j I · Rj is lower alkyl, halo substituted lower -170‘“a’nnfol ' ‘‘“a’qrj - -(CH a ). r -o>, ? H (CH 2 ) r -NH 2 , - 2 » r -SH, - 2 ) r -S-lower alkyl. -(CH 2 ) r -UH-C * MB , or -(CB 2 ) r -C-MH 2 ! MB. la ^u’p Ϊ® Rj la hydrogen,lower alkyl. - 2 > a < R 14»p ‘^a’JTinj ' •’a'if] · -< ch 2’»(O) . 171halo substituted lower alkyl, -(CHp^-cycloalkyl -(Οφτ-^Ο^-ΟΗ . . -(CH 2 > r -OH OH lCH 2 ) ry^J * ~(CH 2 ) r -NH 2 , -(CH 2 > r -SH , I - (CH 2 ) r -S-lower alkyl, - (C« 2 ) ^-NH-C II -CCH 2 ) r -C-HH 2 J Rj Is hydrogen, lower alkyl. NH NH, - 2 ) or tCH 2 »£\O)- o H · - 0H ' OH ι -(CH 2 ) r -MH 2 . - 2 ) r -SH, -(CHj) r -S-lower alkyl . NH O -(CH 2 > r -NH-C , or -(CHj) r -C-NHj « NH. r ia an integer fro· 1 to 4» Rj is hydrogen, lower alkyl, halogen, keto. hydroxy, -HH-Olower alkyl, azido, amino, -H, /*19 ‘20 “'U’p (*i3> p 173a 1- pr 2-naphthyl of tha formula -(CHj) % ^§Xs3 ,r w’ , -(CH 2 ) e -cycloalkyl, > /*15 -O-C-M *15 —Q—lower alkyl, -Ο- , & 1- pr 2-naphthyloxy of the formula -8.-lower alkyl. of the formula -S-(CT 2 ) tf -1749 R ί / 15 Rg Is keto, halogen, -O-C-N, “15 , -0-lower alkyl, a 1or 2-naphthyloxy of the formula -0-_ , -S-lower alkyl, - s -< CT 2>r(2\ ( . 1 , or a 1- or 2«“ΐί'ρ naphthylthlo of the formula -S-(CBj) <“h’ Rg Is keto or «* 2 >r(O ‘*13>p -175Rg 0 Is halogen or -V-R^? R ii' R ii * R ia and R ia are ind *p* ndentl y selected from hydrogen and lower alkyl or R'gg , Rgg and R lg are hydrogen and R u i. <*1 J 12. 14 p Rgg Is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl; Rg 4 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, or hydroxy; m is sero, one, two, three, or four; p ia ono, two or three provided that p is more than one only if Rg 3 or Rg 4 is hydrogen, methyl, methoxy, chloro, or fluoro; Rg S is hydrogen or lower alkyl of 1 to 4 carbons; Y is oxygen or sulfur; Rgg is lower alkyl of 1 to 4 carbons, or the Rgg groupe join to <* -176complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a lower alkyl of 1 to 4 carbons or a di(lower alkyl of 1 to 4 carbons) substituent· Rjg is lower alkyl, benzyl, or phenethyl; Rjq is hydrogen, lower alkyl, benzyl or phenethyl; and Rg is hydrogen, benzhydryl, or ι -CH-O-C-Rjg *17 wherein Rj 7 la hydrogen, lower alkyl, cycloalkyl or phenyl, and Rjg is hydrogen, lower alkyl, lower alkoxy, phenyl, or Rj 7 and Rjg taken together are -(CHjIj-, lower alkyl, benzyl, -(CHjij-, or I -17750. A pharmaceutical composition for use in the treatment of hypertension comprising a pharmaceutically acceptable carrier and a hypotensive compound of the formula R,-CH-C-CH,-N 3 I 2 MR I c«o — CH-C-X ’ (L) 'e wherein R, Rg, Rg, Rg and X are as defined in Claim 1. 51. A compound according to any one of claims 1 to 49 for use ln a method of treating hypertension in a mammalian boat· * -17852. A pharmaceutical composition for use as an analgesic comprising a pharmaceutically acceptable carrier and an enkepalinase inhibiting compound c I of the formula 0 R R. O μ ι ι 1 I» „ R,-CH-C-CH, -N - CH - C-NH-CH-COOR 7 3 I 2 <&> ι 6 NB a I 5 a c-o *2 wherein R, R , Rj, Rj, R g and Rg are as defined in Claim 1. 53. A compound as defined in claim 52 for use in a method of relieving pain in a mammalian host which comprises administering an effective amount of the composition of Claim 52. 54. A compound according to claim 1 as herein specifically disclosed. 55. A process for the preparation of compounds according to claim 1 substantially as herein described. 56. A process for the preparation of compounds according to claim 1 substantially as herein described in any one of the Examples. 57. A pharmaceutical composition comprising a compound according to claim 1 substantially aa herein described.