IE870110L - Substituted peptide compounds - Google Patents

Description

Substituted Peptide Compounds This invention is directed to compounds which ny be useful in the preparation of substituted peptide compounds of formula I and salts thereof IX) O R R, O & ll li r,-ch-c-ch,—n - ch — c-x 3 I - 2 JL) MH I c-o I B2 X is an amino or laino acid of the formula Jb CH Mr* 2r I 8 I ch2 -n-c-coor6 -n-c-coor6 _h_^ H i1 ' MD R. _ R_ M 10^^ 10 H C ,CH 3 I -N— C-COOR, I (10 • ffc) " I (1) H H H *12 . - n . jrc, -M —— C-COOR- -N —C-COCIT, * KM 6 lltl 6 0 • n •$ ^rlrno -H C-COOR, | T L (Ll. -N—C-COOR,.

H H ,(t, H -N—C-COOR, I (L) 6 H C—COOR, %U ct) 6 or -H CB-COOR, i i *4 »5 R? is hydrogen, lower alkyl, halogen, keto, ° /l9 hydroxy, -NH-C-lower alkyl, azido, amino, —H *20 "u'p <«13>, a 1- or 2-naphthyl of the formula ' ~'CH2'm~Cycloalky1' o h /R13 /—\ -O-C-N , -O-lower alkyl, -O-(CH-)—(Qj * N*lS a 1- or 2-naphthyloxy of the formula "0"'CB2'isv^ • -S-lower alkyl, -S- (CHj) "\0>L or a or ^-naphthylthio BX^(813»p of the formula -s-(ch2) o „ R_ is keto, halogen, I / IS 8 -O-C-N ^.r15 -0-(CH2)^-/q\ , -^O-lower alkyl, a <R13lp 2-naphthyloxy of the formula ' -S-lower alkyl, -S-(CH-)—/fSN ^^«R1S»P or a 1- or 2-naphthylthio of the formula -S- (CH2)J 0+- I«lt>p Rj is keto or -(CBj)- '"u'p R10 is halogen or - Y-RU.

R^, R£1# Rl2 and R'12 are independently selected from hydrogen and lower alkyl or R'j^ , r12 and R'^2 are hydrogen and Rj^ is is hydrogen, lower alkyl' of 1 to 4 ' carbons, lower alkoxy of .1 to 4 carbons, lower alkylthio of 1 to 4 carbons, ehloro, bromo, fluoro trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl. 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 zero, one, two, three, or four. p is one, two or three provided that p is more than one only if or R^j is hydrogen, methyl, methoxy, chloro, or fluoro.

R15 is hydrogen or lower alkyl of 1 to 4 carbons.

Y is oxygen or sulfur.

. R^g is lower alkyl of 1 to 4 carbons, -(af2,iT@L ' or *16 9rouP* join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a lowar alkyl of 1 to 4 carbons or a di(lower alkyl of 1 to 4 carbons) substituent.

R. is hydrogen, lower alkyl, <—i 4 - (CHjJ^-cycloalkyl, -(CHjJjjTT) , -^a'irCo) .' "d^) • or ~C(o) • Rj is hydrogen, lower alkyl, -(CH^), oh» -(CH2>r-QH« OH OH ' -(CH2)r-NH.

-(CHjJ^-SH, -(CHj)^-S-lower alkyl, 0 ^ot i -(CH2)r-SH-C , or -(CH2)r-C-HH2 ^ HH2 r is an integer, from 1 to 4.

Rjj is lower alkyl, benzyl, or phenethyl. R20 is hydrogen, lower alkyl, benzyl or phenethyl.

R is hydrogen, lower alkyl, cycloalkyl, ~tCH2)x^) ' -(CH2)2-NH2' -(CH2)3-NH2 , -(CH2J4-NH2, -(CH2)2-OH, -(CH2)3-OH, -(CH2)4-OH, -(CH2)2-SH, -{CH2>3-SH, or -(CH2)4-SH.

Rj is hydrogen, lower alkyl, halo substituted 15 lower alkyl, ■ .—. \ "(CH2,F® -«CH2)J^O/-OH • -(ch2)f€^~0h • ~(cha)nnt§) ' OH ¥ ~(CHz)p , -JCH2)r-HH2, -(CH2)r-SH, I H -(CHjJ^-OH, -{CH2)r-S-lower alkyl, O NH ) -(CH2)r"NH"C^' ' <« -(CH2Jr-C-NH2 NHj provided that is' hydrogen only if R is other than hydrogen.. r2 is , • -(CH2»iro ' 14 p S -(ch2>sr^3j • -<ch2»ir£6) - Rj is hydrogen, lower alkyl, I -'"■s'rfTjl • i halo substituted lower alkyl, -tCH2)B-cycloalkyi, -(CBjlf^-OB OH -(CH, 2,rn§) ' ~'c82,r"OH' -|c"a}qn} ' • ? H 1 -(CH2>r-NH2, -(CH2)r-SH, -(CH2)r-S-lower alkyl, j"" < .

-(CHj)r_NH-C , or -(CH2)r-C-NH2 ^ HHj wherein m, Rj^, p and r are as defined above.

Rfi is hydrogen, lower alkyl, benzyl, benzhydryl, O f *21 j? -CH-O-C-R, _ -C C-O-R ' I " | 23 ,*17 *22 -CH-(CH-OH),, or -CH--CH—CH, 2 2 I I 2 OH OH ^ is hydrogen, lower alkyl, cyeloalkyl, or phenyl.

R is hydrogen,, lower alkyl, lower alkoxy, or phenyl or R^ and R^g taken together are - (CHj) 2~, -CCH2)3-, -CH-CH- ■°*u ■ Rj^ and r22 are independently selected from hydrogen and lower alkyl.

R23 is lower alkyl.

In accordance with the inventioni there is provided a compound of formula (II) 0 0 1 R2- C -NH—CH-C—CH2 - halo where Rj and Rj are as defined above, and halo is CI or Br, with the proviso chat R2 is other than phenyl, when Rj is hydrogen and halo is CI.

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

The term cycloalkyl refers to saturated rings of 3 to 7 carbon atoms with cyclopentyl and cyclohaxyl 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 trifluoromethyl, which is preferred, penta-fluoroethyl, 2,2,2-trichloroethyl, chloromethyl, bromomethyl, etc. bridge is attached to an available carbon atom.

The symbols -(CH2>| and represent that the alkylene The compounds of formula I may be prepared by reacting a compound of the invention with a peptide ester of the formula (III) > 1L O I I1 II HN— CH — c-x (L> in the presence of base such as sodium bicarbonate followed by removal of the Kg ester group.

The compound of the invention can be prepared by treating a ketone of th£ formula 10 (IV) 0 H R4 0-NH-CH-C-CH2-holo v wherein *40 U a protecting group such as benzyl-oxyc&rbonyl with hydrogen bromide and atfetic acid 'followed by reaction with the acid halide of 15 the formula (V) 'Q I Rj-C-halo in the presence of base such as sodium bicarbonate.

The compounds of formula X can also be prepared 20 by reacting an aminoketone of the formula (VI) O O R II J I r_-c-nh-ch-c-ch,~nh. "2 , a "3 particularly the hydrochloride salt thereof with the haloacetyl amino or latino acid ester of 25 the formula (Vll) *1 0 i i halo-CH— C-X.

(L) wherein Rfi in the definition of X is an easily removable ester protecting group and halo is CI or Br.

The aainoketone of formula IX wherein R is other than hydrogen can be prepared by reacting a coapound of the invention with a substituted aaine of the fornula (VIII) r-hh2 In the above reactions if any or all of R, Rj, Rj and are ob -Cch2)^—jj—-0 , -(CB2)r-SH. I - B -(CH2)r-OH, Qr '-(CH2)r-NH-C^ hh2 fchen the hydroxyl, amino, imidazolyl, mercaptan or. guanidinyl function should be protected during the reaction. Suitable protecting groups include benzyloxycarbonyl,.t-butoxycarbony1, benzyl, benzhydryl, trityl, etc., and nitro in the case of guanidinyl. The protecting group Is removed by hydrogenation, treatment with acid, or other known methods following completion of the reaction.

Preferred compounds of this invention are those wherein: ■u wherein a is zero, one, or two and is hydrogen, methyl, methoxy, methylthio, CI, Br, F, or hydroxy, especially phenyl.

Rj is straight or branched chain lower alkyl of 1 to 4 carbons, -(CB2)7HNB2, *14 " wherein* a is' zero, one, or two, *14 is hydrogen,methyl, methoxy, methylthio, CX, Br, F, or hydroxy, and r is an integer from 1 to 4, especially bensyl.

An asymmetric center is present in the compounds of the invention when R^ is other than hydrogen. Thus, the compounds can exist in diastereoisomeric forms or in Mixtures thereof.

The above described processes can utilize racemates, enantiomers or diastereomers as starting materials. ' When diastereomeric products are prepared, they can be' separated by conventional chromatographic or fractional crystallization methods.- The cbmpburids of formula X, and the pharir.a-ceu£ically acceptable salts thereof, are ' hypotensive agents.

The compounds of formula.X wherein X is -HH-CH-COOR also possess enkephalinase I 6 * "5 Inhibition activity and are useful as analgesic agents.

Compounds of formula I, as well as pharmaceutical compositions containing them and additional processes for their preparation, are further described and claimed in parent patent ■ Application No. 1655/83.

The following examples are Illustrative of the preparation of compounds of the invention, as well as their use in the preparation of compounds of formula I.' Temperatures are given in degrees centigrade. LH-20 refers to a Sephadex chromatography gel comerclally available from Pharmacia Fine Chemicals.

Example l 1- TM-1 (S) -3- (Benzovlamino 1 -2-oxo-4-ph»nvlbutvll -L-alanvll-L-prollne. monohydrochlorlde al (S) -3-*mlno-l-chloro-4-phenvl-2-butanone. hydrogen bromide (S) - [3-Chloro-2-oxo-l- (phenylmethyl) propyl J -carbamle acid, phenylmethyl ester (51.4 g.) la dissolved in a mixture of acetic acid (2S2 ml.) and hydrogen bromide in acetic acid(3.45 N, 348 al.) and kept at room temperature for 1.5 hours, llie reaction mixture is then concentrated In vacuo and precipitated with ether to obtain 36.6 g. of (S)-3-amino-l-chloro-4-phenyl-2-butanone, hydrogen bromide; m.p. (175*) 177-179*. b) (S) -N-13-Chloro-2-oxo-l- (phenylmethyl) propyl! -benzaalde (S) -3-Aaino-l-chloro-4-phenyl-2-butanone , hydrogen bromide (36.3 g., 130.3 mnole) is suspended in 520 al. of dry tetrahydrofuran and. 18.2 al. of triethylamine (130.3 mmole) with stirring for ten minutes. The mixture is placed in an ice bath and 15.2 al. of benzoyl chloride is added followed by 10.95 g. of sodium bicarbonate. After 5 ainutes the ice bath is removed and the reaction mixture is kept at room temperature for l.S hours. The reaction mixture is then concentrated in vacuo and the residue taken up in 1 1. of aqueous methanol (101 water). The precipitate is collected, filtered and washed with methanol to obtain 25.3 g. of (S)-N-[3-chloro-2-oxo-l- (phenylmethyl) propyl I -benzamide ; m. p . (160 • ) 170°-172° (dec.) j {«]"- -129(c 1.7, ditetHylfbraiMiide) c) 1- fw-1(SI-3-fBensovlaminol-2-oxo-4-phenv lbutvl 1-L-a lanvl 1 -L-prollne. 1.1-d imethyl-ethyl ester l-Alanyl-l-proline, 1,1-dimethylethyl -ester (2.42 g., 10 mmole), sodium bicarbonate (840 mg.) and (S)-H-[3-chloro-2-oxo-l-(phenylmethyl)propyl]benzamide (3.01 g.) are combined in 50 ml. of dimethylfocmamide under an argon atmosphere at room temperature with stirring overnight. The reaction mixture is then concentrated in vacuo to about half its original volume and the residue is taken up in ethyl acetate and washed with saturated sodium bicarbonate to give 2.25 g. of crude product.

This material is taken 19 in ethyl acetate: methanol (95:5) and applied to a silica gel column (135 g.) and eluted with ethyl acetate: methanol (95:5)to give 860 mg. of l-(N-((S)-3-(benzoy lamino) -2-oxo-4-pheny lbutyl] -L-alanyl] -L-prolina, 1,1-dimethylcthyl ester. . d) 1-[N-t(S)-3-(Benzoylamlno)-2-oxo-4-phenyl-butyll-L-alanyll-L-prollne. monohydrochlorlde 1-[N-[(S)-3-(Benzoylamlno)-2-oxo-4-phenylbutyll-L-alanylJ-L-p'roline, 1,1-dimethyl-' 5 ethyl ester (7'40 mg., 1.46 mmole) is dissolved in a solution o£ hydrogen chloride in acetic acid (1.5 M, 10 ml.) and kept at room temperature for 30 minute's. It is then concentrated, taken into water, filtered and lyophilized to obtain 10 600 mg. of 1- [J»- (S) -3- (benzoylamlno) -2-oxo-4- phenylbuty 1] -L-alanyl] -L-prollne, monohydrochlorlde; m.p. 83 - 163*1 «I»Jo5 " -1.09* (c - 1.04, methanol). Rg 0.6 (silica gel; butanol/acetie acid/water, 4:1:1).

Anal, calc'd. for C25H29M3°5 * RC1 * 1'65 H2°' C, 57.99; R, 6.48; N, 8.12; CI, 6.85 ' Found< . C, 57.99; B, 6.39; H, 8.09; CI, 6.95.

Example 2 tSl -1- f N2- f 3- (Benzoylamlno) -2-oxo-4-phei>Ylbutvll -L-20 lv«y11-L-prollne. dlhydrochlorlde al l-fW6-f(1.1-Dlmathylethoxy)carbonyl| -N2-[(phenylmethoxy)carbonyl!-L-lvayll-L-prollne, 1.1-dimethvlethyl ester N6-[ (1,1-Dimethy lethoxy) carbonyl] -N2- [ (phenyl-25 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-prollne, 1,1-dimethylethyl estez (4.49 g.) followed by 30 NfN'-dii'sbpropylethylamina (2.2 ml.) and dicyclo- hexylcarbodiimide (S.1S 9.). After IS .minutes the bath is 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 dicyclohexylur.ea is filtered off. The filtrate is washed neutral with 10% potassium bisulfata and saturated sodium bicarbonate. The crude product (13.26 g.) is purified on silica gel column eluting with ethyl acetatethexane (2:1) to give 13.0 g. of 1- [N^- ( (1, l-din>ethylethoxy) carbonyl] -H2-[ (phenylmethoxy). carbonyl] -L-lysyl] -L-proline , 1,1-dimethylethyl ester. b) CS) -1- tH2-f3- (Benzoylamlno) -2-OXO-4-phenvl-butvll-M -| f 1 rl-diinethvlethoxvlcarbonyl 1 -L-lvsvll-L-proline. 1,1-dimethylethyl ester The aster product froa part (a) is reduced in ethanol with palladium on carbon catalyst (10%) to yield 3.99 g. of .1-[N®-[ 1,1-dimethylethoxy)-carbonyl] -L-lyayl] -L-proline, 1,1-dime thy lathy 1 ester. ' This material is taken into 40 ml. of dimethylformamide and treated with (S) -H- . (3-chloro-2.-oxo-l- (phenylmethyl) propyl] benz amide (3.01 g.), from Exainple 1 (b), and sodium bicarbonate (840 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.Og.) is purified on a silica gel column eluting with ethyl acetate:it methanol to give 1.7 g. of (S) -1- [N*- J3- (benzoylamlno) -2-oxo-4-phenylbutylJ-n'- 1(1,1-dimethylethoxy ) carbonyl] -L-lysyl] -L-' proline, 1,1-dlroethylethyl ester. *. c) (S) -1- (H2- f 3- (Benzoylamlno) -2-oxo-4-phenvl-butyll-L-lysyl1-L-prollne. dlhydrochloride ' The ester product from part (b) (1.6 9.) 1s treated for 30 minutes at room temperature with 20 ml. of 1.5 M 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 lyophilized to give 1.28 g. of product.

Further purification is performed on an LH20 column in water to give 740 mg. of |S)-l-ln'-|3-(benzoylamlno) - 2-oxo- 4 -pheny lbuty 1 ] -L-lysyl] -L-proline, dlhydrochloride; m.p. 120 - 180*i [a]*5 - -84.8" (e - 1.05, methanol). Rf 0.61 (trace at 0.9) (silica gel, chloroform/methanol/ acetic .acid, 60* 40,'38% 20).

Anal, calc'd. for • 2HCI'• SHjO: C, 52.98; H, 6.98; V, 8.83; Cl, 11.17 Found1 C, 52.98; B, 6.93; R, 8.66; Cl* 11.31.

Example 3 M-fM-f f tS) -3- (Benzoylamlno) -2-dxo-4-ohenylbuty 11 -L-alanyll -N-cyclohexvlqlyclne. monohydrochlorlde al S-Cyclohexvlqlyclne. 1.1-dimethylethyl ester Cyclohexylamina (70.35 ml.) and sodium bicarbonate (12.9 g.) are suspended with stirring la 200 ml. of .absolute ethanol while stirring in an ice-bath. TO this is' added bromoacetic acid. 1,1-dimcthyiethyl ester (20.78 ml.) dropwise. The _ ice-bath is removed.' After 24 hours at .room temperature, the reactioh mixture is concentrated to dryness, taken into chloroform and washed with water. The crude product (42 g.) is chroma to-graphed on silica gel eluting with ethyl acetatei' hexane (2;1) to give 27*4 g. of N-cyclohexyl--glycine, 1,1-dimethylethyl ester. b) N-Cvclohexvl-K- |W-1 tphenvlmethoxv) carbonyl 1 -L-alanvllglycine. 1.1-dlmethylethvl ester H- [ (Phenylmethoxy) carbonyl] -L-alanine (4.46 9-1, H-cyclotiexylglycina, 1,1-dimethylathyl ester (4.26 g.J, hydroxybenzotrlazole (3.06 g.)« dicyclohexylcarbodiimide (4.12 g.), and triethyl-amine (2.8 ml.) are stirred in 40 ml. of dimethylformamide at room temperature for 20 hours That reaction mixture is then concentrated in vacuo taken into ethyl acetate, the dicyclohexylurea La filtered off, and tha filtrate is washed neutral with 16% potassium bisulfate and saturated sodium bicarbonate to give S.9 g. of crude product. Crystallization from ether:hexane yields 3.97 g. of H-cyclohexyl-H- [S- [ (phenylmethoxy) carbonyl] -L-alanyl] glycine, 1,1-dimethylethyl ester; a.p. 104 - ips*. el B- (X.-Alanyl) -K-cycIohSxylglVclne. 1.1- 1 dimethylethvl ester The ester product from part (b) (3.9. g.) is taken into methanol with palladium on carton catalyst (10%, 700 mg.) and stirred under - hydrogen atmosphere for 4- hours. The reaction mixture is filtered and concentrated to dryness to give 2.65 g. of crude H-(L-alanyl)-N-cyclohexy lglycine , 1,1-dimethylethyl ester. d) H-tH-1 [ (S)-3-(Benzoylamlno)-2-oxo-4-pheny.lbutyil-L-alanyl1-N-cyclohexylqlvclne. 1.1-dlmethylethvl ester The crude ester product from'part(c) (2.6 g.) , sodium bicarbonate (764 mg.), and (S)-N-[3-chloro-2-oxo-l- (phenylmethyl) propyl] benzamide (2.75 g.), from Example l (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 acetate:methanol (99:1) yields 1.5 g. of N- [N-[ [ (S) -3- (benzoylamlno) -2-oxo-4-phenylbutyl] -L-alanyl]-N-cyclohexylglycine, 1,1-dimethylethyl ester. e) H- [H- f f (S)-3- (Benzoylamlno} -2-oxo-4-ohenyl-butvlj -L-alanyl 1 -M-cvclohexylqlvclne. monohydrochlorlde The ester product from part(d) (500 mg.) is treated for 30 minutes with 5 ml. of 1.5 N 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 mg. of product. This is made semi-crystallinia in' acetonitrile:ether to give H-l.n-11 (S) -3- (benzoylamlhb} -2-bxb-4-phenylbutyl]-L-alanyl] -N-cyclohexylglycine, monohydrochlorlde; m.p. 154 - 157* (132*); (a)*3 » -67.4* (c ■ 1.35, methanol). Rfi 0.60 (minor impurity at 0.92) (silica gel, chlorbform:mcthanol: cone, ammonia, 30:10:2).

Anal, calc'd. for C28H35f,305 * * "2° "" C, 61.35; H,- 6.99; N, 7.67; Cl, 6.47 Found: C, 61.08; B, 6.79; H, 7.65; Cl, 6.46.

Example i M- [8- f [ (S) -3- (Benzoylamlno) -2-oxo-4-phenylbutyl]-L-alanyll-W-phenylglyclne f monohydrochlorlde a) W-Phenylglycine. 1.1-dlmethylethyl 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 ah ice-bath. To this is added bromoacetic acid, 1,1-dimethylethyl ester (18 g., 0.093 mole) over a period of 30 minutes. The resulting mixture is 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. Xg 0.6, 0.7 (silica gel, ethyl acetate). Chroma- . tography on LPS-1 using hexane:ethyl acetate (7:3) as eluant gives 2.3 g. of N-phenylglycine, 1,1-dimethylethyl ester as a pale yellow liquid. Rg 0.7 (silica gel, ethyl acetate). b) H-Phenyl-N-[N-[(phenylmethoxy)carbonyl]-L-alanyl]glycine. 1.1-dlmethylethvl ester A solution of N-((phenylmethoxy)carbonyl]-L-alanine (2.8, 12.7 mmole) In'dry tetrahydrofuran (50 ml.) under argon is cooled in a dry ice-ethanol bath. To this is added N-methylmorpholine (1.28 g., 12.7 mmole) and isobutylchloroformate (1.73 g., 12.7 cunole). 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 hour, then at room temperature overnight. The mixture is partitioned between ethyl acetate and IN hydrochloric acid. The organic layer is washed successively with IN hydrochloric acid and lOt sodium bicarbonate, dried (MgSO^), and concentrated. Chromatography on LPS-1 eluting with a gradient of .ethyl acetate:hexana (3:1 ♦' 1:1) gives 4.0 g. of N-phenyl-N-[N-[ (phenylmethoxy) carbonyl)-L-alanyl]glycine, 1,1-dimethylethyl ester as • clear oil. R^ 0.4 (silica gel, ethyl acetate). c) N-(L-Alanyl)-N-phenylglycine. 1.1-dlmethyl-ethyl ester A solution of .the ester product from part (b) (4.0 g., 9.7 mmole) in ethanol (125 ml.) and lOt 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 ethyl acetate extracts are dried (MgSO^) and concentrated to give 1.3 g. of N-. (L-alanyl)-M-phenylglycine, 1,1-dimethylethyl ester as a white solid. 0.52, minor spot at 0.64 (silica gel, ethyl acetate:methanol; 1:1). d) H-m-tflSl -3- (Benzoylamlno) -2-oxo-4-phenylbutyll -L-alanyl1-N-phenylqlvclne. 1,1-dimethylethyl ester To a stirring solution of (S)-N-(3-chloro- . 2-oxo-l-(phenylmethyl) propy l]benzataide (1.4 g., 4.7 mmole), from Example l (b) , 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 sodiua iodide (0.7 g., 4.7 mmole). After stirring overnight at room temperature, the mixture is concentrated,' dissolved in athyl acetate and filtered. The filtrate is washed with 101 sodium bicarbonate, dried (HgSO^) , and concentrated to a yellow oil. Chromatography on LPS-1 eluting with a gradient of ethyl acetate:hexane (1«1) to ethyl acetate gives 1.8 g. of N-[N-[[(S)-3- (benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-N-phenylglycine, 1,1-dimethylethyl ester. Rg 0.34 (silica gel, ethyl acetate). e) N-fN-f t(SI-3-(Benzoylamlno)-2-oxo-4-phenvl-butyll-L-alanyl]-N-phenylqlyclne. monohydrochlorlde A solution of the ester product from part (d) (1.6 g., 2.9 mmole) in hydrochloric acid/acetic acid (1.77 N, 17.0 ml.) is stirred at room temperature for 30 minutes. The solution is' concentrated and the residue is triturated with ether to give a pale yellow solid. Recrystallization from methanol/ether gives 0.84 g: of N-[N-[[(S)-3-(benzoylamino) -2-oxo-4-pheny lbutyl] -L-alanyl] -N-phenylglycine, monohydrochlorlde as a white/ crystalline solid, m.p. 147 - 159* (dec.). Rg 0.8 (silica gel, butanol:acetic acid:water? 1:1:1). (a]D » -12.7* (c - 1.5, methanol).

Anal, calc'd. for <:28H29f,305 * HC1 * ®*®s H20: C, 62.77; H> 5.89; H, 7.84; Cl, 6.62 Found: C, 62.77; B, 5.70; N, 7.84; Cl, 6.12.

Example 5 (S) -1- (M-1 f 3- (Benzoylamlno) -2-oxo-4-phenvlbutvl1 -H-methvl-L-alanyl 1 -L-proline. monohydrochlorlde a) N- [ (Phenylmethoxy) carbonyl! -L-alanine L-Alanine (89.1 g., 1 mole) is dissolved in 2N sodium hydroxide (500 ml.) and chilled to 0*. TO this is added simultaneously dropwise over a one hour period benzylchloroforraate (204.5 g., -1.2 mole) and 4N sodium hydroxide (250 ml.). The reaction mixture is stirred overnight (0* to room temperature), and washed with ethyl acetate (2 x 500 ml.). The aqueous portion is acidified to pB 2.0 with 6N hydrochloric acid and extracted with ethyl acetate (3 x 600 ml.). The combined ethyl acetate extracts are dried (Ha^SO^), concentrated on a rotary evaporator, and the solid residue is triturated with petroleum ether to give 194.0 g. of N-1, (phenylmethoxy)carbony 11-L-alanine as a white solid. b) N-Methyl-N-f(phenylmethoxy)carbonyl}-L-alanlne To a cold (0a) solution of N-[(phenylmethoxy) carbonyl]-^alanine (22.3 9., 0.1 nole) and methyl iodide (SO 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 ml.) 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 101 potassium bisulfate and extracted with ethyl acetate. The combined ethyl acetate extracts are dried (Ha^SO^) and -concentrated In vacuo into a dark oily residue (23.0 g.).

This crude acid is treated with dicyclohexyl-oraine (20 ml.) in ether (150 ml.). The resulting crude dicyclohexylamine salt is collected (37.0 g.), recrystallized from chloroform/ether (35.0 9.), and converted back to.the acid by partitioning between IN hydrochloric acid/ethyl acetate, yielding a pale yellow Oil, which crystallizes oa standing (17.4 g.).

Recrystallization (11.2 g.) from ethyl acetate/petroleum ether gives 4.0 g. of N-methyl-H-t(phenylmethoxy)carbonyl]-L-alanine as a white crystalline product; m.p. 65 - 66.5°} folp5 *■* -31.1" (c « 2, acetic acid). . ■' c) l-[N-Methyl-N-f (phenylmethoxy)carbonyl 1 -L-alanyll-L-prollne. 1., 1-dlmethylethvl ester To a solution of N-methyl-N-((phenylmethoxy)-carbonyl]-L-alanina (4.74 3-, 20 mmole) in .

S distilled tetrahydrofuran (50 ml.) is added L-proline, 1,1-dimethylethyl ester (3.42 g., 20 nimole), hydroxybenzotrlazole hydrate (3.06 g., 20 mmole) and dicyclohexylcarbodiimide (4.12 g., 20 mmole). The reaction mixture is stirred 10 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), Id* potassium bisulfate (twice), and IS water (twice) , dried (Ha^SO^) , and concentrated to give 6.4 g. of l-[N-methyl-N-[(phenylmethoxy) carbonyl] -L-alanyl]-L-prollne, 1,1-dimethylethyl ester as an oily residue. d) 1- (N-Methvl-L-alanvl)--L-proIlne. 1.1-20 dimethylethyl ester A mixture of the- ester product from part (c) (6.4 g., 16.4 mmole) and 0.8 g. of lOt palladium on carbon catalyst in ethanol (95%, 150 ml.) is hydrogens ted at atmospheric pressure overnight. 25 The catalyst is removed by filtration and the filtrate is evaporated. The resulting oily residue solidifies upon drying in high vacuum into an oily solid residue (3.8 g.). Trituration with ether affords 1.5 g.Y of .1-(N-oethyl-L-alanyl)-L-proline, 30 1,1-dimethylethyl ester, monohydrochlorlde as a white solid} Rf 0.44. (silica gel, 20% methanol/ chloroform). " 7102.1* (c « 2, acetic acid).

The ether filtrate affords-2.3 g. of 1-(N-methyl-L-alanyl)-L-proline, 1,1-dimethylethyl ester as an oil;. Rj 0.44 (silica gel, 20% methanol/ chloroform). |a]J5 ■ -101.6" (c " 2, acetic acid) e) IS)-l-fM-f f3-tBen»ovlamino)-2-oxo-4-phenvlbutyl)-M-methyl-L-alanvll-L-prollne. 1.1-dlmethylethvl ester A reaction mixture of l-(H-methyl-L-alanyl)-L-proline, 1,1-dimethylethyl ester (2.1 g., 8.19 mmole) (S) -H- [3-chloro- 2-oxo-1- (phenylmethyl) propyl]-henz amide (2.46 g., 8.19 mmole), from Example 1 (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 is extracted once more with ethyl acetate. The combined organic extracts are washed with saturated sodium bicarbonate and water, dried (NtjSO^), and concentrated into an oily residue (3.5 g.). Flash chromatography (200*g. silica gel, 1% methanol/ethyl acetate) affords 2.8 g. of (S) -1- [N- ((3- (benzoylamlno) -2-oxo-4-phenylbutyl] -H-methyl-L-alany1] -L-proline, 1,1-dimethylethyl ester as a yellow oil. •29- t) (SI—1—IM—If3—(Benzoylamlno)-2-oxo-4-phenvlbutvl1 -N-fnethyl-r.-alanvX1 -L-prollne. monohydrochloride The ester product'Com part (e) (1.4 g., 2.7 mmole) 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 resulting oily residue is triturated with ether (four times) to give 1.05 g. of. (S)-1-[N-[[3- (benzoylamlno) -2-oxo-4-phenylbutyl] -N-methyl-L-alanyl] -L-proline, monohydrochlorlde as an off-white solidi m.p. 125 - 13S"| Rg 0.'24 (silica gel, n-butanol/acetic acid/water; 4:1:1). 1°!^ * ~ 87" (c ■ 1, methanol). Anal'. calc*d. for C26H31M3°5 * HC^ * 0.7 H^Oi C, 60.68; B, 6.41; M, 8.16; Cl, 6.88 Foundi C, 60.68; H, 6.36; R, 7.95; Cl, 6.48.

Example 6 (S)-1-[M-f3-(Benzoylaminol-2-oxo-<-phenvlbutvl]-4-phenylqlycylI-L-prollnef hydrochloride (20:31 a) l-(Bromoacetyl)-L-prollne. 1.1-dimethylethyl eater To a chilled (-10*) solution of L-proline, 1,1-dimethylethyl ester (34.2 g., 0.2 mole) in methylene chloride (250 ml.) is added diisppropylethylamine (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 9.). Flash chromatography (LPS-1 silica gel, 10% ethyl acetate/methylene chloride) affords 11.0 g. of l-(bromoacetyl) -L-proline, 1,1-dimethylethyl ester as a pale yellow oil. b) 1- (N-PhenylglvcvH -L-prollne. 1.1- • dimethylethvl eater TO a solution of l-(bromoacetyl)-L-proline, 1,1-dimethylethyl ester (2.1 g., 7.5 nmole) in distilled tetrahydrofuran (40 ml.), is added aniline (1.5 g., 15'mmole) and the reaction mixture is stirred overnight under nitrogen. The reaction mixture is diluted with ethyl acetate (200 ml.), washed with' saturated sodium bicarbonate (2 x 50 ml.) and water (twice), dried (Ha^SO^), 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-prollne, 1,1-dimethylethyl ester as a dark oil which solidifies upon drying in high vacuum. c) (S)-l-fW-r3-tBenzovlamlnol-2-oxo-4-phenvlbutvl1-K-phenylglvcvll-L-prollne; l.l-!dlmethylethvl ester A reaction mixture of 1- (H-phenylglycyl) -L-proline, 1,1-dimethylethyl ester (1.06 g., 3.5 mmole), (S)-H-[3-chloro-2-oxo-1-(phenylmethyl) propyl]benzasd.de (1.06 g., 3.5 mmole), from Example X (b), excess sodium bicarbonate, and sodium iodide (0.S2 g., 3.5 mmole) 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 (Na2S04), and concentrated under reduced pressure to give a dark oily residue (2.0 g.). Flash chromatography (lps-1 silica gel/ 5t ethyl acetate/ methylene chloride to 151 ethyl acetate/methylene chloride) affords 0.3 g., of (S)"-l-[N-[3-(benzoyl-amino) -2-oxo-4-phenylbutyl] -H-phenylglycyl] -l-proline, 1,1-dimethylethyl ester as a pale yellow foam. d) (S) -1- fN- f 3- f Benzoyl amino 1 -2-oxo-4-phenvlbutvl1 -M-phenylqlycyll-L-proline. hydrochloride (20:3) The ester product from part (c) (0.28 g., 0.49 mmole) is treated with 2N hydrochloric acid/ acetic acid. 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 (4 x) to give 0.14 g: of (S)-1-[N-1.3-(benzoylamlno)-2-oxo-4-phenylbutyl] -N-phenylglycyl] -L-proline, hydrochloride (20:3) as an off-white solid; m.p. . 110 - 140"; R£ 0.76 (minor spot at 0.53) (silica gel, n-butanol/acetic acid/water; 3:1:1).

Anal, calc'd. for C30nil*3°S ' 0.15 HC1 • 0.5 H2Oj C, 68.22; H, 6.13; H, 7.95; Cl, 1.00 Foundi C, 68.22; H, 6.00; N, 8.25; Cl, 0.99.

Examples 7-23 Following the procedure of Examples l to 6 but employing the ketone shown in Col. I, the acid chloride shown in Col. XX , and the peptide ester shown in Col. XXX, one obtains the ester product shown in Col. XV. Removal of the R^ ester group and any other protecting groups give the corresponding final product in acid form.

Col. Z H-N-CH-C-CH-Cl 2 II * 0 Col. II o II Rj-C-Cl Col. Ill R R, O I HN— CH-C-X (L) Col. IV O R R. O ii i i b Vp-C-CVH-CH-C-X MB I 00 1 "a o Xxnpla Rj ' Hj • ©- 8 @-«v *©-c"> ' @-«vi v-@- ©■«*>>>- i_L cooc(chj) j *-[5*"** O" CeHj), @^»2- *2cr@ i—j-eeocco.,), H,c -■ c(c»»)aooD-ei«w^' -aen ""^2^ .A 7 * (2h10 -H *jQ m" -H 6(CH3)300J I -y- 7§)- -© JS'W-O'B EI >0 zi n ,en Itdnq o Euaplf (j " r ©■ » <2>*v 16 C-IH-(H C) - / 2 3 OH-HN ©^2- ■ A *1 <^a<w jCUc™, 1 (U 33 s s v.- -m'htgoc{cv OJMM 1 r® -H COOCtCH ) I tt«) 3 H.C- ©-j-,- @haco-®v (ovv hjc-tchjlj- /-"n. ®-v • . "-i:,C00C,CHj)3 h (gk- h- «v<y® ®- ©lev • <§>"■'- 6' -HH-CH-COOC (CH,), lew 33 ch. 0 I ' ► s MaOOHH- (IO) tc «> I (K3)00C»-HD-HH- f-iLv C r (ro)3oa>Kj-H»- I B9 tt tt)l |B3JKX»-H3-H»- •DH -® -'"O ez -OH «— ^O.

-® -"O 11 ■ -'«►© -''"Tut » H r[dmi o The Rj protecting groups in Examples 12, 14 and 15 , the Rj protecting groups in Examples 16 and 18, and the »5 protecting groups in Examples^ 19 and 21 to 23 are removed as the last step in the synthesis. The Rfi ester groups shown in Examples 25 to 28 are not removed.

Example 29 (4S)—1-tNt (S)-3- (Benzoylamlnol -2-oxo-4-phenylbutyl1-L-alanyll-4-(4 -f 1uorophenoxv)-L-prollne. mono-hydrochlorlde al (S)-H-13-(Benzoylamlnol-2-oxo-4-phcnylbutyH-t-alanlne. 1.1-diwethylethyl ester To a stirring solution of (S)-M-(3-chloro-2-oxo-l- (pheny line thy 1) propyl Ibenzamlda (10.0 g., 33.1 mmole) in dimethylfonnamlda (80 ml.) is added L-alanine, 1,1-dimethylathy1 ester, hydrochloride (6.0 g., 33.1 mmole), sodium bicarbonate (6.1 g., 72 mnole) 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 (MgSO^) and concentrated to give 8.9 g. of pale yellow solid, h portion of this material is recrystallized from ethyl acetate to give (S)-N-[3-(benxoylamino) -2-oxo-4-phenylbutyl] -L-alanine, 1,1-dimethylethyl ester as a white solid; m.p. 106.5 - 110*. b.) (S) -N-13- (Bgnzoylamlrio)^2TQxo-4-phenvlbutyll-L-alanlne, monohydrochlorlde A solution of the ester ■ product from part (a) (2.95 g.i 5.4 mmole) in 1.4 N hydrochloric acid in 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-(benzoylamino)'-2-oxo-4-phenylbutyl] -L-a.lanine, monohydrochloride; m.p. 208-2.09" (dec.); [a]p ™ -7.1* (c ■ 0*.38» in methanol). 0.51 (silica gel; chloroform/, methanol/acetic fccid; 4:1:1)." Anal, calc'd. for C20H22N2°4 " HC** C, 6*1.64; H, 5.93;. N, 7.17; CI, 9.07 Founds C, 61.33; H, 5.97; *,7.17; CI, «-79. c)' ' ' (S) -H-fN- (Benzoylaniino)-2-oxo-4-Dhehylbutyl1 -M- f (phenylmethoxy)riarbonyll -L-'alanlne Triethylamine (2.1 ml., IS mmole) is added to a mixture Of (S) (benzdylamino) - 2-oxo-4-phenylbutyl]-L-alanine, monohydrochloride (2.0 g., 5.1 mmole), benzyl chlorofonaate (730 til., 5.1 amole) ," water' (7 ml .J and dioxane' (7 ml.) at 25s. The resulting mixture is stirred at 25" for 3 hours, after which it' is' poured into 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 produces a white granular solid" (150 °mg.)' which . -is collected and discarded. The mother liquor . is concentrated in vacuo to give 1.7S g. of (S) -N-[N- (benzoylamino) -2-oxo-4-phenylbutyl] -N-((phenylmethoxy) earbonyl] -L-alanine as a white S glass. d) (4S)-l-tN-[ (S)-3-(Benzoylamino)-2-OXO-4-phenvlbutvlI-W-f (phenylmethoxy)carbonyll-L-alanvl 1 -4-14-fluorophenoxy) -L-prollne. phenyl-methvl ester A mixture of (S) -N- [N- (benzoylami.no) -2- . oxo-4-phenylbutyl]-K-['(phenylmethoxy) earbonyl]-L-alanine (300 mg.>, 0.62 mmole), (4S)-4-(4-fluorophenoxy )-L-proline, phenylmethyl ester, p-toluenesulfonic acid salt (300 mg., 0.62 mmole), .15 triethylamine (90 yl., 0.62 mmole), dieyclo-hexylcarbodiimide (130 mg., 0.62 mmole), and hydroxybenzotriazole hydrate (90 mg., 0.62 mmole) in tetrahydrofuraa (7 ml.) is stirred at 25" for 20 hours. _ The mixture is then filtered and 20 diluted with ethyl acetate. The resulting solution is washed sequentially with IN hydrochloric acid and 10% aqueous sodium bicarbonate solution, dried (MgSO^), filtered, and concentrated to give S00 mg. of (4S)-l-[N-[(S)-3-(benzoylaraino)-2-OXO-4-25 phenylbutyl]-N-[ (phenylmethoxy) earbonyl]-L- alanyl] -4- (4-fluorophenoxy) -L-proline, phenylmethyl ester as a pale yellow oil. . e) C4SI —1— fW— f (S)-3-(jjcnzoyiamliio)-2-OXO-4-phenylbutyll -L-alanyll -4- (4-f luorophenoxy) -L-prollne. monohydrochloride ' A mixture of the ester product from part(d) 5 (500 mg., 0.6 mmole), palladium on carbon catalyst (104, 100 mg.), absolute ethanol (15 ml.), and 1.0 N aqueous hydrochloric acid (800 ill., 0.8 mmole) is hydrogenated at 1 atmosphere and 25* for 17 hours, efter which it is filtered and concentrated. 10 The residue is chromatographed on HP-20 a linear gradient from [9:1, 0.01N aqueous hydrochloric acid:methanol] to [1:1, 0.0IN aqueous hydrochloric acid:methanol]. Fractions containing the desired product (TLC) are combined and concentrated. The XS 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-[N-[ (S) -3- (bcnzoylamino) -2-oxo- 4 -pheny lbuty 1 ] -L-alanyl] -4- (4-f luorophenoxy) -20 L-proline, monohydrochloride; m.p. 152-153" . (dec.)} [a]J® ■ -50* (c » 0.5, methanol). Rg 0.75 (silica gel, chloroform/methanol/acetic acid, 4:1:1).

Anal, calc'd. for C3iH32E>H306 * HC* * 1*s H2°: 25 C, 59.57; H, 5.80; H, 6.72; Cl", 5.67 Found: C, 59.68; B, 5.56; K, 6.67; Cl, 5.99.

Example 30 [1 (S). 4R1 -1- [N-13- (Benzovlanii.no) -2-oxo-4-phenvlbutyl]-L-alanyll-4-phenyl-L-proline. monohydrochloride a ) (S) -N- [N- (Benzoylamino)-2-oxo-4-phenvlbutyli -N- [ (phenylmethoxy)earbonyl)-L-alanine. succtniwldo ester A mixture of (S)-K-(N-(benzoylamino)-2-oxo-4-phenylbutylJ -N- ((phenylmethoxy) earbonyl]-L-alanlne (800 mg., 1.6 mmole)( prepared as set forth in Example 29 (e), dicyclohexylcarbodiimide (340 mg., 1.6 mmole), and 8-hydroxysuccinimide (190 mg., 1.6 mmole) in tetrahydrofuran (5 ml.) is stirred at 25? for 18 hours. After this time it is filtered and concentrated 'to give 950 mg. of (S) -N- [N- (benzoylamino) -2-oxo-4-phenylbutyl] -N-[(phenylmethoxy)carbonyl]-X>-alanine, succiniaido ester. b) fltS) .4R]-l-[N-[3-(Benzoylamino)-2-OXO-4-phenylbutyl] -H- f (phony line thoxy) earbonyl 1 -L-alanyll-4-phenyl-L-prollne To e solution of (S) (benzoylamino) -2- oxo-4-phenylbutyl] -N- [ (phenylmethoxy) earbonyl] -L-alanine, succinimido ester' (950 mg., 1.6 naole) in dimethylformamide (5 ml.) is added (4R)-4-phonyl-L-prollne, hydrochloride (375 mg., 1.7 mmole) and txlethylamina (40 vA«> 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 (MgSO^) , filtered, end concentrated to give 1.1 g. of (1(S),4R]-l-(N-[3- (benioylamlno)-2-oxo-4-phenyl-butyl]-N-1 (phenylmethoxy)earbonyl]-L-alanyl]-4-phenyl-L-proline. c) fl(S).4Rl-l-[H-[3-(Benzoylamlno)-2-oxo-4-phenvlbutvl] -L-alanvll -4-phenyl-L-prollne. monohydrochloride The product from part (b) (1.0 g., 1.5 mmole) ethanol (20 ml.), water (5 ml.), 1.0 N hydrochloric acid (1.5 ml., 1.5 mmole), and palladium on carbon catalyst (10%, 100 mg.) is hydrogenated at one atmosphere and 25* for 18 hours, after which it is filtered and concentrated. The residue is' chroma to graphed on HP-20 using a linear gradient [0.01 N aqueous hydrochloric acid:methanol, 40:60 to 10:90]. Fractions containing the desired product (TLC) are combined and concentrated. The residue is dissolved in a minimum amount of methanol. Ether is added and the resulting white precipitate is collected and dried to give 300 mg. (1 (S) , 4R] -X- [S- (3- (benzoylamino) -2-oxo-4-phenyl-butyl] -L-alany 11 -4-ph«ny 1-L-proline, monohydrochloride; m.p. 160-162" (dec.); [«]j|5 - -57' (e " X.5., methanol). 0.8 (silica gel; chloroform/methanol/acetic acid; 4:1:1).

Anal, calc'd. for * HC1 • 1.35 RjO: C, 63.27; H, 6.29; M, 7.14; Cl, 6.02* Found: , C, 63.27; H, 6.17; N, 7.X9; Cl, 5.97.

Example 31 [I(S).4S1-X-[W-[3- (Benzoylamino)-2-oxo-4-phenvX-butyll -L-alanyXl -4-phenyl-L-prollne, monohydrochloride Following the procedure of Example 30 but employing (4S)-4-phenyl-L-proXinei hydrochloride in part (b) , one obtains [1(5) ,4S]-l-[N-[3-(benzoyl-amino) -2-oxo-4-phenylbutyX] -X.-alanyl-4-phenyl-I>-proline, monohydrochloride; m.p. 138-143"; [a]D - -61* (c ~ 0.3% in methanol). 0.84 (silica gel, chloroform/methanol/acetic acid, 4:lil). .1 Anal, calc'd. for - HC1 • 2.13 HjO: C, .61.80; H, 6.35; H, 6.98; Cl, 5.88 Founds C, 61.80; H, 6.06; N, 7.05; Cl, 5.65.

Example 32 11 (S) . 4R1 -1- [K- f 3- (Benzoylamlnol -2-oxo-4-phenvl-butyll -L-alanyll -4-cvclohexyl-L-prollne. monohydrochloride Following the procedure of Example 30. but employing (4R)-4-cyelohexyl-L-proline, hydrochloride in part (b), one obtains [1(S),4R]-1-[N-[3- (.bensbylamino-2-oxo-4-phenylbutyl]-L-elanyl] -4-cyciohexyl-L-proline, monohydrochloride; m.p. 140-154* (dec.); [sJD - -83* (c ■ 0.36% in methanol). . Rg 0.84 (silica .gel; chloroform/ methanol/acetic acid; 4>1:1).

Anal, cnlc'd. for C31H39M305 • HC1 - 0.79 HjOs C, 63.71; B, 7.17; N, 7.19; Cl, 6.06- ■ Foundi C, 63.71; B, ?.21; N, 7.05; Cl, 5.82.

' Example 33 [1(S).4S1-1-[N- f 3- (Benzoylamino)-2-oxo-4-phenyl-butvll-L-alanyll-4-cyclohexyl-L-'proline. monohydrochloride Following the procedure of Example 30 but employing (4S)-4-cyclohexyl-L-proline, hydrochloride in part (b), one obtains [1(S) ,4Sj-l,-[N-[.3-(benzoylamino) -2-oxo-4-phenylbutyl] -L-alanyl] -4- . cyclohexyl-Xr-proline, monohydrochloride; m.p. 139-141* (dec.) | [i]D » -80* (c ■ 0.21 in methanol). Rg 0.83 (silica gel; chlorofom/methanol/ acetic acid; 4:1:1)..

Anal, cale'd. for '• HCl - 1.54 HjO; C, 62.28; B, 7.26; N, 7.03; Cl, 5.93 Found: C, 62.28; b, 7.01; B, 7.02; Cl, 6^16.

. Example 34 • (SI -7- f (SI -2- [t3- (Benzoylamino) -2-oxo-4-phenylbutvl1 -amino 1 -l-^xopropyll-l f 4-dlthla-7-azdspiro (4.41 nonane-8-carboxvllc acid, monohydrochloride Following the procedure of Example 30 but employing (S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, hydrochloride in part (b) for the L-prolina reactant, one obtains (S)-7-[(S)-2-tI3-(benzbylamino) -2-oxo-4-phehylbutyl] amino ] -1-oxopropyll -1, 4-d£thia-7-azaspiro [4.4] nonane-8-carboxylic acid1, monohydrochloride; m.p. 170-172*; 1°Jg " -26" (c ™ 1.41 in methanol). R^ 0.78 (silica gel; chlorofprm/methanol/acetlc acid; 6:1:1).

Anal, calc'd. for c27H3lN3°5S2 * HC1 * 0.77h2o': C, 54.77} H,'5.71; N, 7.10} S, 10.83; Ci; 5.99 Found: C, 54.77/ H, 5.70} N, 6.94; S, 10.82} Cl, 6.07.

Example 35 f1(S)f 5Sj-i-{M-f3-(Benzoylamino)-2-oxo-4-phenylbutyll -L-alanyl'^ -4 f 5-dlhydro-3-phenyl-lH- . pyrazole-5-carboxylic" acid, monohydrochloride Following the procedure of Example 30 but employinig (S)-4,5-dihydro-3-phenyl-lH-pyrazole-5-carboxylic acid for the L-proline reactant in part (b), one obtains the above ntuned compound. Example 36 (S)-2-tM-f(S)-3-(Benzoylamino)-2-oxo-4-phenylbutvll-L-alanyl]-1.2.3f 4-tetrahydro-3-lsocruinolinecarboxylic acid, monohydrochloride Following the procedure of Example 30 but employing (S) -1,2 ,3,4-tetrahydro-3-i.soquinoline-carboxylie acid, hydrochloride in part (b) in place of tha proline reactant, one obtains (S) —2— t.N— f.(S) — 3- (benzoylamino) -2-oxo-4.-phenylbutyl] -L-alanyl] -1, 2,3,4-tetrahydro-3.-'isoquinblinecarboxylic acid, monohydrochloride.

Example 37 1-(N-((S)-3- (Benzoylamlnol -2-oxo-4-phenylbutyll -L-alanyl] -2- (2-hvdroxyphenvl1 -4 (Rl -thlazolldlnecar-boxvlle add, monohydrochloride Following the procedure of Example 30 but employing 2-[ (2-phenylmethoxy)phenyl]-4(R)-thia-zolidinecarboxylic acid, hydrochloride in part (b) in place of the proline reactant, one obtains after removal of the hydroxy protecting group 1-IN-1 (S)-3.-(benzoylamino)-2-OXO-4-phenylbutyl] -L-alanyl] -2- (2-hydroxyphenyl) - . , 4 (R) -thiazolidinfeearboxylic acid, monohydrochloride.

Xn a -similar manner, the processes of Examples 29 co 37 can be employed to prepare the .compounds of Examples 1 to 28.

Claims (8)

1. A compound of the formula O O j h R_-C-NH-CH-C-CH,-halo ■ * | 2 *3 wherein halo is Cl or Br; *3 iB ""^(r ) 14 p fch2>«ro ' "(ch2,»~fj) ' or 5 " ■<cvircoj » *3 is hydrogen, lower alXyl, "(CH2,iT^O\ • *VS -(ch j) ' "tCH2)i5~^ji (CHj)^—^Qj , halo substituted lower alkyl, ■ ICTj ) ^-cycloalkyl, - (CHj) ^— ( ■ob ob ■^nno)' -(cH2»r-^' i b -53- "(CH.) 'irTJ M # -(CH2)r-NH2, -(CH2)r-SH H ' -(CH2)r-S-lower alkyl, -(CH'2)r-NH-C » or O ~,CH2,r"c"NH2 ! ' Rj^ Is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower .alkylthlo of 1 to 4 carbons, chloro, brono, fluoro, trlfluoromethyl, or hydroxy; m is zero, one, two, three, or four j p is one, two or three provided that p is more than one only if Rj^ is hydrogen, methyl, methoxy, chloro, or fluoro; and r is aa integer from 1 to 4; with the proviso that Rj is other than phenyl, when is hydrogen and halo is Cl.

2. A compound according to daia 1 wherein I R. 14 X, -la *14 m is zero, one, or two; and is hydrogen, methyl, methoxy, methylthio,' chloro, bromo, fluoro, or hydroxy.

3 . A coopound according to Clalo 2, wherein "a18 Rj' is ~CH2~^Q^ ' and hal° 1( C1*

4. A process for the preparation of a. conpound as defined in claim 1 which comprises treating a compound of formula 0 R^-NH— fH — C — CHj— halo R3 (wherein R-j and halo are as defined in claim 1 and R^q is a protecting group) with hydrogen bromide and acetic acid, followed by reaction with an acid halide of foranila 0 R2 — C — halo (wherein R2 and halo are as defined in dais 1) in the presence of a base.

5. A process according to claim 4 wherein R4q is a benzyloxycarbonyl group. -55-

6. A process according to either of clalns 4 and 5 wherein the base is sodiua bicarbonate.

- 7. A conpound according to daia 1 as herein specifically disclosed.

8. A process for the preparation of a compound according to claim 1. substantially as herein described. MACLACHLAN ft DONALDSON Applicants1 Agents 47 Merrlon Square Dublin 2.