Novel mercapto-acylamino acids useful in the treatment of hypertension and combinations of mercapto-acylamino acids and atrial natriuretic peptides useful for treating hypertension are disclosed.

SUMMARY OF THE INVENTION 
The present invention relates to mercapto-acylamino acids useful in the 
treatment of hypertension and congestive heart failure. 
The invention also relates to the treatment of hypertension and congestive 
heart failure with a combination of a mercapto-acylamino acid and an 
atrial natriuretic peptide. 
Other aspects of the invention relate to pharmaceutical compositions 
comprising the mercapto-acylamino acids of this invention, alone or in 
combination with atrial natriuretic peptides, and to methods of treatment 
of hypertension and congestive heart failure comprising administering a 
mercapto-acylamino acid of this invention, alone or in combination with an 
atrial natriuretic peptide, to a mammal in need of such treatment. 
BACKGROUND OF THE INVENTION 
Human hypertension represents a disease of multiple etiologies. Included 
among these is a sodium and volume dependent low renin form of 
hypertension. Drugs that act to control one aspect of hypertension will 
not necessarily be effective in controlling another. 
A variety of mercapto-acylamino acids are known as enkephalinase inhibitors 
useful as analgesics and in the treatment of hypertension. 
U.S. Pat. No. 4,513,009 to Roques et al discloses, inter alia, compounds of 
the formula. 
##STR1## 
wherein n is 0 to 1; R.sup.1 includes hydrogen, optionally substituted 
alkyl, optionally substituted phenyl, cyclohexyl and thienyl; and R.sup.2 
includes hydrogen optionally substituted alkyl, optionally substituted 
benzyl, phenyl, phenoxyalkyl and optionally substituted mercaptoalkyl. The 
compounds are disclosed as principally having enkephalinase activity, but 
also are said to be antihypertensives. 
U.S. Pat. No.4,401,677 to Greenberg et al discloses compounds of a scope 
similar to Roques et al as having analgesic activity, while U.S. Pat. No. 
4,053,651 to Ondetti et al discloses the use of similar compounds in the 
treatment of renin-angiotensin related hypertension. 
It has recently been discovered that the heart secretes a series of peptide 
hormones called atrial natriuretic factors (ANF) which help to regulate 
blood pressure, blood volume and the excretion of water, sodium and 
potassium. ANF were found to produce a short-term reduction in blood 
pressure and to be useful in the treatment of congestive heart failure. 
See P. Needleman et al, "Atriopeptin: A Cardiac Hormone Intimately 
Involved in Fluid, Electrolyte and Blood-Pressure Homeostasis", N. Engl. 
J. Med., 314, 13 (1986) pp. 828-834, and M. Cantin et al in "The Heart as 
an Endocrine Gland", Scientific American, 254 (1986) pg. 76-81. 
DETAILED DESCRIPTION 
Novel antihypertensive compounds of the present invention are represented 
by the following formulae: 
##STR2## 
wherein R.sup.1 is phenyl substituted by one or more substituents 
independently selected from alkyl, alkoxy, cycloalkyl, cyano and 
aminomethyl, Y--C.sub.6 H.sub.4 S--, Y--C.sub.6 H.sub.4 O--, 
##STR3## 
.alpha.-naphthyl, .beta.-naphthyl, furyl, benzofuryl, benzothienyl, 
H.sub.2 N(CH.sub.2).sub.m --, diphenylmethyl, 
##STR4## 
R.sup.2 is alkyl, alkyl-S(O).sub.0-2 (CH.sub.2).sub.q --, R.sup.5 
(CH.sub.2).sub.k S(O).sub.0-2 (CH.sub.2).sub.q --, alkyl-O(CH.sub.2).sub.q 
--, R.sup.5 (CH.sub.2).sub.k -O(CH.sub.2).sub.q --, R.sup.5 
(CH.sub.2).sub.q --, H.sub.2 N(CH.sub.2).sub.q --, 
cycloalkyl(CH.sub.2).sub.k --, R.sup.13 CONH(CH.sub.2).sub.q --, R.sup.13 
NHCO(CH.sub.2).sub.q -- or R.sup.6 OCO(CH.sub.2).sub.q --; 
R.sup.3 is --OR.sup.7, 
##STR5## 
R.sup.4 and R.sup.13 are independently hydrogen, alkyl or Y.sup.1 --C.sub.6 
H.sub.4 --; 
R.sup.5 is Y.sup.2 --C.sub.6 H.sub.4 --, Y.sup.2 --C.sub.6 H.sub.4 S--, 
Y.sup.2 --C.sub.6 H.sub.4 O--, .alpha.-naphthyl, .beta.-naphthyl, furyl, 
thienyl, benzofuryl, benzothienyl, indolyl or 
##STR6## 
provided that when R.sup.5 is Y.sup.2 --C.sub.6 H.sub.4 S-- or Y.sup.2 
--C.sub.6 H.sub.4 O--, k is 2 or 3; 
R.sup.6, R.sup.7 and R.sup.8 are independently H, alkyl, hydroxyalkyl, 
alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or arylalkyl, 
or R.sup.7 and R.sup.8 together with the nitrogen to which they are 
attached complete a 5-7 membered ring, wherein one of the 4-6 ring members 
comprising R.sup.7 and R.sup.8 may be a nitrogen atom, an 
alkyl-substituted nitrogen atom or an oxygen atom, and wherein the ring 
may be substituted on the ring carbon atoms with substituents chosen from 
alkyl and hydroxy groups; 
R.sup.9 is hydrogen, alkyl, carboxyalkyl, mercaptoalkyl, alkylthioalkyl, 
aminoalkyl, hydroxyalkyl, phenylalkyl, hydroxyphenylalkyl, guanidinoalkyl, 
imidazolylalkyl, indolylalkyl or carbamoylalkyl; 
n is 0-2; 
m and k are independently 0-3; 
q is 1-4; 
X and X.sup.1 are independently a bond, --O--, --S--, or --CH.sub.2 --; 
Q is hydrogen or R.sup.10 CO--; 
R.sup.10 is alkyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, Y.sup.3 
--C.sub.6 H.sub.4 -alkyl, alkoxy, Y.sup.3 --C.sub.6 H.sub.4 --, naphthyl, 
furyl, thienyl or pyridyl; 
Y, Y.sup.1, Y.sup.2 and Y.sup.3 independently represent one or more 
substituents selected from H, alkyl, cycloalkyl, alkoxy, OH, F, Cl, Br, 
CN, --CH.sub.2 NH.sub.2, --CO.sub.2 H, --CO.sub.2 alkyl, --CONH.sub.2 and 
phenyl; 
R.sup.1a is Y--C.sub.6 H.sub.4 --, Y--C.sub.6 H.sub.4 S--, Y--C.sub.6 
H.sub.4 O--, 
##STR7## 
.alpha.-naphthyl, .beta.-naphthyl, furyl, thienyl, benzofuryl, 
benzothienyl, H.sub.2 N(CH.sub.2).sub.m --, diphenylmethyl, 
##STR8## 
R.sup.2a .sbsp.R.sup.5a (CH.sub.2).sub.k S(O).sub.0-2 (CH.sub.2).sub.q --, 
R.sup.5a (CH.sub.2).sub.k -O(CH.sub.2).sub.q --, R.sup.5a (CH.sub.2).sub.q 
---, or cycloalkyl-(CH.sub.2).sub.k, and when R.sup.3 is --NR.sup.7 
R.sup.8, 
##STR9## 
R.sup.2a may also be indolyl-(CH.sub.2).sub.q --, R.sup.13 
CONH(CH.sub.2).sub.q --, R.sup.13 NHCO(CH.sub.2).sub.q -- or R.sup.6 
OCO(CH.sub.2).sub.q --; 
R.sup.3a is 
##STR10## 
R.sup.11 is hydroxyalkyl or substituted phenylalkyl wherein the phenyl 
group is substituted by one or more groups selected from alkyl, alkoxy, 
cycloalkyl and cyano; R.sup.12 is H or selected from the same group as 
R.sup.11 ; or R.sup.11 and R.sup.12 together with the nitrogen to which 
they are attached complete a 5-7 membered ring wherein one of the 4-6 ring 
members comprising R.sup.11 and R.sup.12 may be a nitrogen atom, an 
alkyl-substituted nitrogen atom or an oxygen atom, and wherein the ring 
may be substituted on the ring carbon atoms with substituents chosen from 
alkyl and hydroxy groups; 
R.sup.5a is Y.sup.2 --C.sub.6 H.sub.4 provided Y.sup.2 is not H or OH, 
Y.sup.2 --C.sub.6 H.sub.4 S--, Y.sup.2 --C.sub.6 H.sub.4 O--, 
.alpha.-naphthyl, .beta.-naphthyl, furyl, thienyl, benzofuryl, 
benzothienyl or 
##STR11## 
provided that when R.sup.5a is Y.sup.2 --C.sub.6 H.sub.4 --S-- or Y.sup.2 
--C.sub.6 H.sub.4 O--, k is 2 or 3; 
and the pharmaceutically acceptable addition salt thereof. 
As used herein the term "alkyl" means straight or branched alkyl chains of 
1 to 6 carbon atoms, and "alkoxy" similarly refers to alkoxy groups having 
1 to 6 carbon atoms. "Cycloalkyl" means cyclic alkyl groups of 3-6 carbon 
atoms. 
"Aryl" means mono-cyclic or fused ring bicyclic aromatic groups having 5 to 
10 ring members wherein 0-2 ring members may independently be nitrogen, 
oxygen or sulfer and wherein the ring members may be substituted by one to 
three substituents chosen from group Y defined above. Examples of aryl 
groups are phenyl, .alpha.-naphthyl, .beta.-naphthyl, furyl, thienyl, 
benzofuryl, benzothienyl, indolyl and pyridyl. 
"Halo" refers to fluorine, chlorine, bromine or iodine radicals. The term 
"poly", when used to describe substitution in a phenyl, alkylphenyl or 
alkoxyphenyl group, means 2 to 5 substituents. 
Groups R.sup.3 and R.sup.3a comprising the partial structure 
##STR12## 
are derived from amino acids of formula 
##STR13## 
Examples of such amino acids are alanine, arginine, asparagine, aspartic 
acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, 
leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, 
tyrosine and valine. 
Preferred embodiments of compounds of formula I are compounds wherein 
R.sup.2 is alkyl, alkyl-S(O).sub.0-2 (CH.sub.2).sub.q --, R.sup.5 
(CH.sub.2).sub.k S(O).sub.0-2 (CH.sub.2).sub.q -- or R.sup.5 
(CH.sub.2).sub.q --, wherein R.sup.5, q and k are as defined above. Also 
preferred are compounds of formula I wherein R.sup.1 is naphthyl, furyl, 
benzofuryl, benzothienyl, diphenylmethyl, aminoalkyl, Y--C.sub.6 H.sub.4 
--X--C.sub.6 H.sub.4 --, R.sup.4 CONH(CH.sub.2).sub.m -- or R.sup.4 
NHCO(CH.sub.2).sub.m --, wherein Y, X, R.sup.4 and m are as defined above. 
A third group of preferred compounds in that wherein R.sup.1 is 
substituted phenyl. Still another group of preferred compounds of formula 
I is that wherein R.sup.3 is --OR.sup.7 or --NR.sup.7 R.sup.8, wherein 
R.sup.7 and R.sup.8 are as defined above. 
Preferred compounds of formula II are those wherein R.sup.2a is R.sup.5 
(CH.sub.2).sub.k S(O).sub.0-2 (CH.sub.2).sub.q -- wherein R.sup.5, q and k 
are as defined above. Also preferred are compounds of formula II wherein 
R.sup.la is naphthyl, furyl, thienyl, benzofuryl, benzothienyl, 
diphenylmethyl, aminoalkyl, Y--C.sub.6 H.sub.4 --X--C.sub.6 H.sub.4 --, 
R.sup.4 CONH(CH.sub.2).sub.m -- or R.sup.4 NHCO(CH.sub.2).sub.m -- wherein 
Y, X, R.sup.4 and m are as defined above. A third group of preferred 
compounds is that wherein R.sup.1a is Y--C.sub.6 H.sub.4. Still another 
group of preferred compounds of formula II is that wherein R.sup.3 is 
--OR.sup.7 or --NR.sup.7 R.sup.8, wherein R.sup.7 and R.sup.8 are as 
defined above. 
Preferred compounds of formula III are those wherein R.sup.3a is 
--NHCH.sub.2 CONH.sub.2, arylalkoxy or arylalkylamino. Also preferred are 
compounds of formula III wherein R.sup.1a is naphthyl, furyl, thienyl, 
benzofuryl, benzothienyl, diphenylmethyl, aminoalkyl, Y--C.sub.6 H.sub.4 
--X--C.sub.6 H.sub.4 --, R.sup.4 CONH(CH.sub.2).sub.m --or R.sup.4 
NHCO(CH.sub.2).sub.m -- wherein Y, X, R.sup.4 and m are as defined above. 
A third group of preferred compounds is that wherein R.sup.1a is 
substituted phenyl. 
Preferred compounds of formulae I-III are those wherein Q is hydrogen or 
R.sup.10 CO-- wherein R.sup.10 is alkyl. 
Compounds of this invention may, depending on the nature of functional 
groups, form addition salts with various inorganic and organic acids and 
bases. Such salts include salts prepared with organic and inorganic acids, 
e.g. HCl, HBr, H.sub.2 SO.sub.4, H.sub.3 PO.sub.4, methanesulfonic acid, 
toluenesulfonic acid, maleic acid, furmaric acid and camphorsulfonic acid. 
Salts prepared with bases include ammonium salts, alkali metal salts, e.g. 
sodium and potassium salts, and alkaline earth salts, e.g. calcium and 
magnesium salts. 
The salts may be formed by conventional means, as by reacting the free acid 
or base forms of the product with one or more equivalents of the 
appropriate base or acid in a solvent or medium in which the salt is 
insoluble, or in a solvent such as water which is then removed in vacuo or 
by freeze-drying or by exchanging the cations of an existing salt for 
another cation on a suitable ion exchange resin. 
Compounds of formulae I-III have two or more asymmetrical carbon atoms and 
therefore include various stereoisomers. All stereoisomers are included 
within the scope of the present invention. 
Compounds of the present invention may be prepared by using coupling 
reactions well known in the peptide art to join a 
3-acetylthio-2-(substituted)-propionic acid of formula 1 with an amino 
acid ester of formula 2. The following reaction Scheme 1 is an example: 
##STR14## 
In the above scheme, R.sup.p =R.sup.1 and R.sup.1a ; R.sup.r =R.sup.2 and 
R.sup.2a ; R.sup.t is methyl, ethyl, t-butyl or aralkyl (e.g. benzyl); Ac 
is acetyl; n is 0-2; DEC is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 
hydrochloride; HOBT is 1-hydroxybenzotriazole hydrate; NMM is 
N-methylmorpholine; and DMF is dimethylformamide. 
As Scheme 1 shows, an amino acid ester of formula 2 and a 3-acetylthio 
propionic acid of formula 1 are reacted at room temperature in an inert 
solvent such as DMF in the presence of coupling agents such as DEC and 
HOBT in the presence of a base such as NMM. The resultant isomers are 
separated by chromatography and the isomers are deprotected at the acid 
and mercapto positions. 
Alternatively, a propionic acid of formula 1 may be reacted with thionyl 
chloride to prepare the corresponding propionyl chloride, which may then 
be reacted with an amino acid ester of formula 2 or with the corresponding 
free acid 2a in an inert solvent such as acetonitrile in the presence of a 
base such as triethylamine to give isomers of formula 3, which may be 
separated as in Scheme 1. The following Scheme 2 is an example: 
##STR15## 
wherein n, Ac, R.sup.p, R.sup.r and R.sup.t are as defined above, and 
wherein R.sup.t may also be hydrogen. 
Compounds of formulae I-III wherein R.sup.3 or R.sup.3a is --NR.sup.7 
R.sup.8 are prepared by coupling reactions as described above in Schemes 1 
and 2 by replacing the amino acid ester 2 with an amide or substituted 
amide as shown in Scheme 3: 
##STR16## 
Alternatively, compounds of formulae I-III wherein R.sup.3 or R.sup.3a is 
--NR.sup.7 R.sup.8 may be prepared by coupling a propionyl chloride of 
formula 8 with an amino acid of formula 2a in the presence of a base and 
then coupling the desired --NR.sup.7 R.sup.8 group to the carboxylic group 
using a typical peptide-coupling reaction. Scheme 4 shows an example of 
such a procedure: 
##STR17## 
A third method for preparing compounds of formulae I-III wherein R.sup.3 or 
R.sup.3a is --NR.sup.7 R.sup.8 comprises reacting a propionic acid of 
formula 1 with an amino acid t-butyl ester of formula 2, removing the 
t-butyl ester and coupling the --NR.sup.7 R.sup.8 group to the carboxylic 
acid group as above. Compounds wherein R.sup.3 and R.sup.3a are 
##STR18## 
are prepared analogously to those wherein R.sup.3 and R.sup.3a are 
--NR.sup.7 R.sup.8. 
Compounds wherein Q is R.sup.10 CO-- may be prepared by known methods, for 
example by adding a mercaptoacid of formula R.sup.10 -COSH to an acrylic 
acid to obtain a thio-substituted propionic acid analogous to compounds of 
formula 1. 
Starting materials of formulae 1 and 2 are known in the art or may be 
prepared by methods well known to those skilled in the art. Examples of 
typical preparations of starting materials and specific examples of 
compounds of formulae I-III are provided at the end of the specification. 
A second aspect of the invention is the administration of a combination of 
an atrial natriuretic peptide and a compound of the following formula IV 
##STR19## 
wherein n, R.sup.1a, R.sup.2, R.sup.3 and Q are as defined above, for the 
treatment of hypertension. Compounds of formula IV have chiral centers and 
form addition salts as described above for compounds of formulae I-III, 
and may be prepared by similar methods. 
As indicated by Needleman et al., a number of atrial peptides have been 
isolated so far, all having the same core sequence of 17 amino acids 
within a cysteine disulfide bridge, but having different N-termini 
lengths. These peptides represent N-terminal truncated fragments (21-48 
amino acids) of a common preprohormone (151 and 152 amino acids for man 
and rats, respectively). Human, porcine and bovine carboxy-terminal 
28-amino acid peptides are identical and differ from similar peptides in 
rats and mice in that the former contain a methionine group at position 12 
while the latter contain isoleucine. Various synthetic analogs of 
naturally occurring atrial peptides also have been found to have 
comparable biological activity. Examples of atrial peptides contemplated 
for use in this invention are .alpha. human AP 21 (atriopeptin I), .alpha. 
human AP 28, .alpha. human AP 23 (atriopeptin II or APII), .alpha. human 
AP 24, .alpha. human AP 25, .alpha. human AP 26, .alpha. human AP 33, and 
the corresponding rat sequence of each of the above wherein Met 12 is Ile. 
See Table 1 for a comparison of the peptides. 
3 TABLE 1 
HUMAN PEPTIDE 
AP 33 . . . 
##STR20## 
AP 28 . . . 
##STR21## 
AP 26 . . . 
##STR22## 
AP 25 . . . 
##STR23## 
AP 24 . . . 
##STR24## 
AP 23 . . . 
##STR25## 
AP 21 . . . 
##STR26## 
*Ile in the rat peptide 
We have found that the novel compounds Of the present invention are 
effective in treating congestive heart failure and various types of 
hypertension, particularly volume expanded hypertension. These novel 
compounds as well as other mercapto-acylamino acids known in the art have 
been found to enhance both the magnitude and duration of the 
antihypertensive and natriuretic effects of edogenous atrial natriuretic 
peptides. Administration of a combination of a mercapto-acylamino acid of 
formula IV and an exogenous atrial peptide is therefore particularly 
useful in treating hypertension. 
In addition to the compound aspect, the present invention therefore also 
relates to treating hypertension with a mercapto-acylamino acid or with a 
mercapto-acylamino acid in combination with an atrial peptide, which 
methods comprise administering to a mammal in need of such treatment an 
antihypertensive effective amount of the mercapto-acylamino acid or the 
combination of a mercapto-acylamino acid and atrial peptide. The drug or 
combination of drugs is preferably administered in a pharmaceutically 
acceptable carrier, e.g. for oral or parenteral administration. The 
combination of drugs may be co-administered in a single composition, or 
components of the combination therapy may be administered separately. 
Where the components are administered separately, any convenient 
combination of dosage forms may be used, e.g. oral mercapto-acylamino 
acid/oral atrial peptide, oral mercapto-acylamino acid/parenteral atrial 
peptide, parenteral mercapto-acylamino acid/oral atrial peptide parenteral 
mercapto-acylamino acid/parenteral atrial peptide 
When the components of a combination of a mercapto-acylamino acid and an 
atrial peptide are administered separately, it is preferred that the 
mercapto-acylamino acid be administered first. 
The present invention also relates to a pharmaceutical composition 
comprising a mercapto-acylamino acid for use in treating hypertension and 
to a pharmaceutical composition comprising both a mercapto-acylamino acid 
and an atrial peptide. 
The antihypertensive effect of mercapto-acylamino acids was determined 
according to the following procedure: Male Sprague Dawley rats weighing 
100-150 g were anesthetized with ether and the right kidney was removed. 
Three pellets containing Doc acetate (desoxycorticosterone acetate, DOCA, 
25 mg/pellet) were implanted subcutaneously. Animals recovered from 
surgery, were maintained on normal rat chow and were allowed free acess to 
a fluid of 1% NaCl and 0.2% KCl instead of tap water for a period of 25-30 
days. This procedure results in a sustained elevation in blood pressure 
and is a slight modification of published procedures (e.g. Brock et al., 
1982) that have been used to produce DOCA salt hypertension in the rat. 
On the day of study, animals were again anesthetized with ether and the 
caudal artery was cannulated for blood pressure measurement. Patency of 
the caudal artery cannula was maintained with a continuous infusion of 
dextrose in water at a rate of 0.2 ml/hr. Animals were placed into 
restraining cages where they recovered consciousness. Blood pressure was 
measured from caudal artery catheter using a Statham pressure transducer 
attached to a Beckman oscillographic recorder. In addition, a 
cardiovascular monitoring device (Buxco Electronics, Inc.) and a digital 
computer were used to calculate average blood pressures. 
After an equilibration period of at least 1.5 hr., animals were dosed 
subcutaneously (1 ml/kg) with vehicle (methylcellulose, hereinafter MC) or 
mercapto-acylamino acid and blood pressure was monitored for the next 4 
hours. 
The antihypertensive effect of mercapto-acylamino acids in combination with 
atrial peptides was determined according to the following procedures: 
Male spontaneously hypertensive rats (SHR), 16-18 weeks old, 270-350 g, 
were anesthetized with ether and the abdominal aorta was cannulated 
through the tail artery. The animals were then placed into restrainers to 
recover from anesthesia (in less than 10 min.) and remained inside 
throughout the experiments. Through a pressure transducer (Gould P23 
series) analog blood pressure signals were registered on a Beckman 612 
recorder. A Buxco digital computer was used to obtain mean arterial 
pressures. Patency of the arterial cannula was maintained with a 
continuous infusion of 5% dextrose at 0.2 ml/hr. Animals were allowed a 
90-min equilibration period. The animals first underwent a challenge with 
an atrial peptide such as atriopeptin II (AP II) or AP28 30 .mu.g/kg iv 
and at the end of 60 min. were treated with MC vehicle or a 
mercapto-acylamino acid subcutaneously. A second atrial peptide challenge 
was administered 15 min. later and blood pressure was monitored for the 
next 90 min. 
The antihypertensive effect in SHR of mercapto-acylamino acids was 
determined as follows: 
Animals were prepared for blood pressure measurement as described above. 
After stabilization, animals were dosed subcutaneously with test drugs or 
placebo and blood pressure was monitored for the next 4 hr. 
The compositions of this invention comprise a mercapto-acylamino acid or a 
mercapto-acylamino acid and an atrial peptide in combination with a 
pharmaceutically acceptable carrier for administration to mammals. A 
variety of pharmaceutical forms is suitable, preferably for oral or 
parenteral administration, although mechanical delivery systems such as 
transdermal dosage forms are also contemplated. 
The daily antihypertensive dose of the compound or combinations of this 
invention is as follows: for mercapto-acylamino acids alone the typical 
dosage is 1 to 100 mg/kg of mammalian weight per day administered in 
single or divided dosages; for the combination of mercapto-acylamino acid 
and an atrial peptide, the typical dosage is 1 to 100 mg of 
mercapto-acylamino acid/kg mammalian weight per day in single or divided 
dosages plus 0.001 to 0.1 mg atrial peptide/kg of mammalian weight per 
day, in single or divided dosages. The exact dose of any component or 
combination to be administered is determined by the attending clinician 
and is dependent on the potency of the compound administered, the age, 
weight, condition and response of the patient. 
Generally, in treating humans having hypertension, the compounds or 
combinations of this invention may be administered to patients in a dosage 
range as follows: for treatment with mercapto-acylamino acids alone, about 
10 to about 500 mg per dose given 1 to 4 times a day, giving a total daily 
dose of about 10 to 2000 mg per day; for the combination of 
mercapto-acylamino acid and atrial peptide, about 10 to about 500 mg 
mercapto-acylamino acid per dose given 1 to 4 times a day and about 0.001 
to about 1 mg atrial peptide given 1 to 6 times a day (total daily dosage 
range of 10 to 2000 mg day and 0.001 to 6 mg/day, respectively). Where the 
components of a combination are administered separately, the number of 
doses of each component given per day may not necessarily be the same, 
e.g. where one component may have a greater duration of activity, and will 
therefore need to be administered less frequently. 
Typical oral formulations include tablets, capsules, syrups, elixirs and 
suspensions. Typical injectable formulations include solutions and 
suspensions. 
The typical acceptable pharmaceutical carriers for use in the formulations 
described above are exemplified by: sugars such as lactose, sucrose, 
mannitol and sorbitol, starches such as cornstarch, tapioca starch and 
potato starch; ceullulose and derivatives such as sodium carboxymethyl 
cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such 
as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium 
sufate; polyvinylpyrrolidone, polyvinyl alcohol; stearic acid; alkaline 
earth metal stearates such as magnesium stearate and calcium stearate, 
stearic acid, vegetable oils such as peanut oil, cottonseed oil, sesame 
oil, olive oil and corn oil; non-ionic, cationic and anionic surfactants; 
ethylene gylcol polymers; betacyclodextrin; fatty alcohols and hydrolyzed 
cereal solids; as well as other nontoxic compatible fillers, binders, 
disintegrants, buffers, preservatives, antioxidants, lubricants, flavoring 
agents, and the like commonly used in pharmaceutical formulations. 
Since the present invention relates to treatment of hypertension with a 
combination of active ingredients wherein said active ingredients may be 
administered separately, the invention also relates to combining separate 
pharmaceutical compositions in kit form. That is, a kit comprising a 
mercapto-acylamino acid and an atrial peptide in separate pharmaceutical 
compositions. The kit form is particularly advantageous when the separate 
components must be administered in different dosage forms (e.g. oral and 
parenteral) or are administered at different dosage intervals.

Following are descriptions of preparations of typical starting materials 
and examples of procedures for preparing compounds of formulae I-IV. 
Temperature designations, i.e. reaction conditions and melting points, are 
in .degree.C. 
PREATION 1 
L-Cysteine Esters 
Method 1: S-(4-Methylbenzyl)-L-Cysteine, Methyl Ester, Hydrochloride: 
At room temperature, add thionyl chloride (2.8 ml, 2.2 equiv.) dropwise to 
N-t-butyloxycarbonyl-S-(4-methylbenzyl)-L-cysteine (5.0g) in methanol (500 
ml) and heat the resulting mixture under reflux for 90 minutes. Cool the 
reaction mixture to room temperature and concentrate in vacuo to give the 
title compound, a white solid (4.31g), m.p. 158.degree.-160.degree., 
[.alpha.].sub.D.sup.26 =-22.9.degree. (MeOH). 
By the same method, other amino acid esters are prepared: 
S-Benzyl-D-cysteine ethyl ester hydrochloride, a while solid, m.p. 
149.degree.-151.degree., [.alpha.].sub.D.sup.26 =+15.5.degree. (H.sub.2 
O); 
S-(4-Methoxybenzyl)-L-cysteine methyl ester hydrochloride, a white solid, 
m.p. 145.degree.-6.degree., [.alpha.].sub.D.sup.26 =-23.2.degree. (MeOH); 
S-(3,4-Dimethylbenzyl)-L-cysteine ethyl ester hydrochloride, white solid, 
m.p. 161.degree.-167.degree., [.alpha.].sub.D.sup.26 =-26.6.degree. 
(MeOH); and 
S-t-Butyl-L-cysteine methyl ester, an oil. 
Method 2: S-Phenethyl-L-Cysteine Ethyl Ester Hydrochloride: 
Add thionyl chloride (2.0 ml) to absolute ethanol (25 ml) at 
0.degree.-5.degree.. To this solution add S-phenethyl-L-cysteine (2.5 g, 
1.11 mmole). Warm the resulting mixture to room temperature, and then heat 
at 60.degree. for 5 hours. Concentrate the reaction mixture in vacuo, 
dissolve the resultant residue in dichloromethane (CH.sub.2 Cl.sub.2), and 
concentrate the solution in vacuo. Dissolve the residue in absolute 
ethanol, treat with DARCO, filter and concentrate in vacuo to give the 
title compound, a white solid (2.90 g) m.p. 155.degree.-156.degree., 
[.alpha.].sub.D.sup.26 =-1.5.degree. (MeOH). 
By the same method, other amino acid esters are prepared: 
O-Benzyl-L-tyrosine methyl ester hydrochloride, a white solid, m.p. 
189-190, [.alpha.].sub.D.sup.26 =+6.9.degree. (MeOH); 
S-Methyl-L-cysteine ethyl ester, an oil, [.alpha.].sub.D.sup.26 
=+25.1.degree. (MeOH); 
S-Ethyl-L-cysteine ethyl ester hydrochloride, a white solid, m.p. 
130.degree.-3.degree.[.alpha.].sub.D.sup.26 =-11.0.degree. (MeOH); and 
Ethionine ethyl ester, hydrochloride, clear oil, [.alpha.].sub.D.sup.26 
=+15.5.degree. (MeOH). 
PREATION 2 
3-Acetylthio-2-(Arylmethyl)Propionic Acids 
3-Acetylthio-2-(4-phenylbenzyl)propionic acid: 
Step 1: 4-Biphenylmethylenemalonic acid: Heat 4-biphenyl carboxaldehyde 
(18.0 g, 9.89 mmole) and malonic acid (10.8 g, 10.4 mmole) in glacial 
acetic acid (6 ml) at approximately 100.degree. for 2 hours. Cool the 
reaction mixture, dilute with dichloromethane and filter to give a white 
solid (8.76 g). Concentrate the filtrate, add malonic acid (1.5 g) and 
heat the resulting mixture at 100.degree. for 2 hours. Cool the reaction 
mixture, dilute with CH.sub.2 Cl.sub.2 and filter to give a white solid 
(3.44 g). Suspend the combined solids (12.20 g) in water and filter to 
give the title compound, a pale yellow solid (9.56 g), m.p. 
208.degree.-9.degree..uparw.. 
By this method other aryl methylene malonic acids are prepared, for 
example: 
.beta.-Naphthylmethylene malonic acid, a white solid, m.p. 
204.degree.-205.degree.. 
Step 2: (4-Phenylbenzyl)malonic acid: Hydrogenate the product of Step 1 
(9.50 g, 3.5 mmole) in ethyl acetate (200 ml) in the presence of 10% 
palladium-on-charcoal (0.80 g) at 50 psi for 3 hours. Filter and 
concentrate the reaction mixture in vacuo to give the title compound, a 
white solid (8.16 g) m.p. 180.degree.-181.degree.. 
By this method other arylmethyl malonic acids are prepared, for example: 
.beta.-Naphthylmethyl malonic acid, a white solid, m.p. 
150.degree.-152.degree.. 
Step 3: 2-(4-Phenylbenzyl)acrylic acid: Treat a portion of the product of 
Step 2 (4.05 g, 1.50 mmole) in water (20 ml) at 0.degree.-5.degree. with 
40% dimethylamine in water to pH 7-8. Add the remaining product of Step 2 
(4.05 g, 1.50 mmole). After 15 minutes, add aqueous formaldehyde (10.0 ml, 
38%). Slowly warm the resulting mixture to room temperature and stir for 
18 hours. Filter the reaction mixture, wash the white solid with water, 
and suspend the solid in water (150 ml). Heat this suspension at 
100.degree. for 3 hours until the solution is almost clear. Cool the 
solution and add concentrated hydrochloric acid to pH 2 to give a white 
precipitate. Filter the mixture and dry the white solid. Dissolve this 
white solid in hot methanol, filter and concentrate in vacuo to give the 
title compound, a white solid (6.68 g) m.p. 168.degree.-170.degree.. 
By this method other 2-(aryl)acrylic acids are prepared, for example: 
2-(.beta.-naphthylmethyl)acrylic acid, a white solid m.p. 
83.degree.-84.degree.. 
Step 4: 3-Acetylthio-2-(4-phenylbenzyl)propionic acid: Add thioacetic acid 
(8.0 ml) to the product of Step 3 (6.0 g, 2.77 mmole) in CH.sub.2 Cl.sub.2 
(30 ml) and ethyl acetate (100 ml) and stir the resulting mixture at room 
temperature for 72 hours. Concentrate the reaction mixture in vacuo. 
Dissolve the residue in toluene (100 ml), and concentrate in vacuo (3 
times) to give a yellow oil (6.0 g). Chromatograph the oil on a column of 
silica gel (1.6L), eluting with CH.sub.2 Cl.sub.2 (4L) CH.sub.2 Cl.sub.2: 
methanol 1000:1 (3L), and 1000:5 (15L) to give the title compound, a white 
solid (3.44 g), m.p. 101.degree.-103.degree.. 
By this method, other 3-acetylthio-2-(aryl methyl)propionic acids are 
prepared: 
3-Acetylthio-2-(4-chlorobenzyl)propionic acid, an oil. 
3-Acetylthio-2-(.alpha.-naphthylmethyl)propionic acid, a white solid, m.p. 
94.degree.-7.degree.; and 
3-Acetylthio-2-(.beta.-naphthylmethyl)propionic acid, a white solid, m.p. 
103.degree.-106.degree.. 
PREATION 3 
1-(.alpha.-Naphthylmethyl)Acrylic Acid 
Step 1: Diethyl .alpha.-naphthylmethyl malonate: Add sodium metal (11.0 g, 
0.478 mole) to absolute ethanol (650 ml) with cooling and stirring until 
the sodium is dissolved. Add diethyl malonate (75.6 g, 0.473 mole) over 15 
minutes at room temperature. After 30 min., add 
.alpha.-bromomethylnaphthalene (100 g, 0.452 mole) in absolute ethanol 
(400 ml). Heat the resulting mixture under reflux for 5 hours. Keep at 
room temperature for 20 hours, and concentrate in vacuo. Partition the 
residue between water (500 ml) and diethyl ether (700 ml). Extract the 
diethyl ether solution with water (200 ml), and brine (200 ml), then dry 
the organic layer (MgSO.sub.4) and concentrate in vacuo to give the title 
compound, an oil (133.7 g). 
Step 2: 3-(1-Naphthyl)-2-ethoxycarbonylpropionic acid: To the product of 
Step 1 (133.7 g, 0.446 mole) in absolute ethanol (400 ml) add a solution 
of potassium hydroxide (24.9 g, 0.445 mole) in absolute ethanol (400 ml) 
and stir the resulting mixture at room temperature for 20 hours. 
Concentrate the reaction mixture in vacuo and partition the residue 
between ice water (lL) and diethyl ether (500 ml). Cool the aqueous 
solution to 0.degree.-5.degree. C. and acidify to approximately pH 2 with 
2N hydrochloric acid, keeping the temperature at 0.degree.-5.degree.. 
Extract the mixture with diethyl ether, dry the organic layer (MgSO.sub.4) 
and concentrate in vacuo to give the title compound, an oil (100 g). 
Step 3: Ethyl 1-(.alpha.-naphthylmethyl)acrylate: Add to the product of 
Step 2 (100 g, 0.367 mole) and diethylamine (39 ml) a 37% aqueous solution 
of formaldehyde (38 ml) over 30 min. at 0.degree.-5.degree. C. with 
vigorous stirring. Stir the mixture at room temperature for 7 hours and 
then extract with diethyl ether (3.times.500 ml). Extract the organic 
layer with 2N hydrochloric acid (2.times.500 ml), saturated aqueous sodium 
bicarbonate solution (500 ml) and brine (500 ml). Dry the organic layer 
(MgSO.sub.4) and concentrate in vacuo to give the title compound, an oil 
(58.6 g). 
Step 4: 1-(.alpha.-Naphthylmethyl)acrylic acid: Treat the product of Step 3 
(12.0 g, 50 mmole) in dioxane (50 ml) with lN sodium hydroxide (60 ml) and 
stir the resulting mixture at room temperature for 18 hours. Concentrate 
the reaction mixture under nitrogen, dilute with water and extract with 
ethyl acetate. Cool the aqueous solution to 0.degree.-5.degree. and add 
concentrated hydrochloric acid slowly to pH 3-4 to give a white solid. 
Filter the reaction mixture, wash the resultant white solid with water and 
dry to give the title compound, a white solid (9.62 g), m.p. 
115.degree.-117.degree.. 
PREATION 4 
L-Bishomophenylalanine t-Butyl Ester [(2S)-AMINO-5-PHENYLPENTANOIC ACID, 
t-BUTYL ESTER] 
Step 1: 4-Benzoyl-2(S)-trifluoroacetamidobutyric acid: Heat at reflux for 3 
hours a mixture of N-trifluoroacetyl-L-glutamic anhydride (18.0 g, 80 
mmol) and AlCl.sub.3 (23.5 g, 177 mmol) in dry benzene (400 ml). Allow to 
cool, treat with ice (400 ml), conc. HCl (100 ml), and ethylacetate 
(EtOAc) (400 ml). Dry the organic layer and concentrate to obtain the 
title compound as a brown crystalline solid (25 g). 
Step 2: 5-Phenyl-2(S)-trifluoroacetamidopentanoic acid: Reduce the product 
of Step 1 (9.7 g) with Pearlman's catalyst (3.5 g) in EtOAc (75 ml) and 
ethanol (25 ml) at 50 psi H.sub.2 for 3 hours. Filter, concentrate and 
wash the resultant residue with 3:1 hexane:diethyl ether to give the title 
compound (7.8 g). 
Step 3: N-Trifluoroacetyl-L-bishomophenylalanine, t-butyl ester: Treat the 
product of Step 2 (11.3 g) with isobutylene (25 ml) and conc. H.sub.2 
SO.sub.4 (1.0 ml) in CH.sub.2 Cl.sub.2 (100 ml) for 16 hours. Partition 
between diethyl ether and 1N NaHCO.sub.3, dry, concentrate, and 
chromatograph the resultant residue on silica gel, eluting with 2:1 
hexane:diethyl ether to obtain 11.3 g of the title compound as a colorless 
oil. 
Step 4: L-Bishomophenylalanine, t-butyl ester, hydrochloride: To the 
product to Step 3 in EtOH (120 ml) add NaBH.sub.4 (5.2 g) portionwise over 
30 min. Stir another 1.5 hours, concentrate, and partition between diethyl 
ether and H.sub.2 O. Dry and concentrate to obtain an oil (8.lg). Treat 
with HCl:diethyl ether to give the hydrochloride salt of the title 
compound, white crystals (4.0 g), m.p. 161.degree.-2.degree., 
[.alpha.].sub.D.sup.26 =+15.6.degree. (MeOH, c=0.5). 
PREATION 5 
S-(4-Methylbenzyl)-L-Cysteine Amide 
Step 1: N-t-Butyloxycarbonyl-S-(4-methylbenzyl)-L-cysteine amide: React 
N-t-butyloxycarbonyl-S-(4-methylbenzyl)-L-cysteine (6.50 g) with 
triethylamine (4.44 g, 6.16 ml) in tetrahydrofuran (THF). Cool the mixture 
to 0.degree.-5.degree.. Add ethyl chloroformate (4.77 g, 3.41 ml) in THF 
(5 ml) dropwise over 5 min. and stir the reaction mixture for 15 min. Add 
ammonium hydroxide (28%, 2.0 ml) in THF (5 ml) dropwise. Allow the 
reaction mixture to warm to room temperature and stir for 18 hr. Filter 
the reaction mixture and concentrate the filtrate in vacuo to give a pale 
yellow solid. Dissolve this solid in CH.sub.2 Cl.sub.2 and extract with 
H.sub.2 O. Concentrate the dried (MgSO.sub.4) CH.sub.2 Cl.sub.2 solution 
in vacuo to give a pale yellow solid (6.41 g). Recrystallize this solid 
from EtOAc to give the title compound, a white solid (2.82 g), m.p. 
140.degree.-141.degree., [.alpha.].sub.D.sup.26 =-7.5.degree. (MeOH). 
Step 2: S-(4-Methylbenzyl)-L-cysteine amide: Treat the product of Step 1 
(2.79 g) in CH.sub.2 Cl.sub.2 (40 ml) with trifluoroacetic acid (10 ml) at 
room temperature for 18 hr. Concentrate the reaction mixture in vacuo. 
Dissolve the residue in CH.sub.2 Cl.sub.2 and concentrate in vacuo 
(twice). Dissolve the white solid in EtOAc and extract with 10% sodium 
bicarbonate solution. Dry (MgSO.sub.4) the EtOAc and concentrate in vacuo 
to give the title compound, a white solid (1.53 g) m.p. 
94.degree.-95.degree., [.alpha.].sub.D.sup.26 =-1.3.degree. (MeOH). 
PREATION 6 
S-(4-Methylbenzyl)-L-Cysteine t-Butyl Ester 
To a cold solution of isobutylene (50 ml) in dioxane (80 ml), add 
S-(4-methylbenzyl)-L-cysteine (5.0 g) and concentrated H.sub.2 SO.sub.4 
(10 ml). Seal the vessel, allow to warm to room temperature, and stir for 
18 hr. Pour into 5% NaOH (500 ml), extract with Et.sub.2 O (3.times.400 
ml), dry (MgSO.sub.4) and concentrate the Et.sub.2 O in vacuo to give an 
oil. Treat the oil with HCl in Et.sub.2 O to give the title compound, 
white needles (2.76 g) m.p. 218.degree. (dec). 
EXAMPLE 1 
N-(2-Benxyl-3-Mercaptopropionyl)-S-(4-Methylbenzyl)-L-Cysteine (Isomers A 
and B) 
Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-S-(4-Methylbenzyl)-L-Cysteine 
Methyl Ester (Isomers A and B): Add S-(4-methylbenzyl)-L-cysteine methyl 
ester, hydrochloride (1.85 g, 0.77 mmole) to 3-acetylthio-2benzyl 
propionic acid (1.93 g, 0.81 mmole), DEC (1.46 g, 0.76 mmole), HOBT (1.18 
g, 0.76 mmole) and NMM (2.30 g, 2.5 ml, 2.27 mmole) in DMF (20 ml) and 
stir the resulting mixture at room temperature for 20 hours. Concentrate 
the reaction mixture in vacuo and partition the residue between EtOAc and 
water. Concentrate the dried (MgSO.sub.4) ethyl acetate solution in vacuo 
to give an amber oil (3.85 g). Chromatograph the oil on silica gel (Baker, 
60-200 mesh) (1.5L) using EtOAc:hexane 4:21 as eluent to give Isomer A, 
white solid (0.64g), m.p. 101.degree.-104.degree., [.alpha.].sub.D.sup.26 
=-76.2.degree. (MeOH); overlap Isomer A and Isomer B (0.40 g); and Isomer 
B, white solid (0.67 g), m.p. 52.degree.-55.degree.[.alpha.].sub.D.sup.26 
=-4.9.degree. (MeOH). 
Step 2: N-(2-Benzyl-3-Mercaptopropionyl)-(S)-(4-Methylbenzyl)-L-Cysteine 
(Isomer B): Dissolve Isomer B (0.66 g, 1.6 mmole) in methanol (20 ml) 
under a nitrogen atmosphere, cool to 0.degree.-5.degree., add 1N sodium 
hydroxide (4.8 ml), stir the mixture at 0.degree.-5.degree. for 6 hours 
and then keep at that temperature for 18 hours. Concentrate the reaction 
mixture under nitrogen, dilute the resultant oil with water (200 ml) and 
ethyl acetate (200 ml) and acidify to pH 2-4 with 1N hydrochloric acid. 
Dry (MgSO.sub.4) the ethyl acetate solution and concentrate in vacuo to 
give the title compound (Isomer B), a viscous oil (0.45 g), 
[.alpha.].sub.D.sup.26 =-56.3.degree. (MeOH). 
Step 3: N-(2-Benzyl-3-Mercaptopropionyl)-(S)-4-Methylbenzyl)-L-Cysteine 
(Isomer A): By a procedure similar to that of Step 2 react Isomer A (0.63 
g) and 1N sodium hydroxide (4.5 ml) to give the title compound (Isomer A), 
a viscous clear oil (0.165 g), [.alpha.].sub.D.sup.26 =-8.8.degree. 
(MeOH). 
In a similar manner, according to Example 1, Step 1, using the appropriate 
propionic acid, prepare: 
N-[3-Acetylthio-2-(.alpha.-naphthylmethyl)propionyl]-S-(4-methylbenzyl)-L-c 
ysteine ethyl ester, Isomer A, m.p. 71.degree.-74.degree., 
[.alpha.].sub.D.sup.26 =-40.6.degree. (MeOH); 
N-[3-Acetylthio-2-(.alpha.-naphthylmethyl)propionyl]S-(4-methylbenzyl)-L-cy 
steine ethyl ester, Isomer B, m.p. 88.degree.-90.degree., 
[.alpha.].sub.D.sup.26 =-58.8.degree. (MeOH); 
N-[3-Acetylthio-2(8-naphthylmethyl)propionyl]-S-(4-methylbenzyl)-L-cysteine 
ethyl ester, Isomer A, m.p. 74.degree.-77.degree., [.alpha.].sub.D.sup.26 
=-61.0.degree. (MeOH); 
N-[3-Acetylthio-2(.beta.-naphthylmethyl)propionyl]-S-(4-methylbenzyl)-L-cys 
teine ethyl ester, Isomer B, m.p. 86.degree.-88.degree., 
[.alpha.].sub.D.sup.26 =-20.7.degree. (MeOH); 
N-[3-Acetylthio-2-(4-chlorobenzyl)propionyl]-S- benzyl-L-cysteine ethyl 
ester (Isomer A), m.p. 89.degree.-90.degree.; 
N-[3-Acetylthio-2-(4-chlorobenzyl)propionyl]-S-benzyl-L-cysteine ethyl 
ester (Isomer B), m.p. 103.degree.-4.degree.; and 
N-[3-Acetylthio-2-(4-chlorobenzyl)propionyl]-L-tryptophan methyl ester 
(Isomers A and B). 
Using the procedure of Example 1, Step 2, treat the above 3-acetylthio 
compounds to obtain the following 3-mercaptopropionyl compounds: 
N-[2-(.alpha.-Naphthylmethyl)-3-mercaptopropionyl]-S-(4-methylbenzyl)-L-cys 
teine Isomer A, m.p. 70.degree.-75.degree., [.alpha.].sub.D.sup.26 
=+18.3.degree. (MeOH); 
N-[2-(.alpha.-Naphthylmethyl)-3-mercaptopropionyl]-S-(4-methylbenzyl)-L-cys 
teine Isomer B, m.p. 48.degree.-55.degree., [.alpha.].sub.D.sup.26 
=-102.3.degree. (MeOH); 
N-[2-(.beta.-Naphthylmethyl)-3-mercaptopropionyl]-S-(4-methylbenzyl)-L-cyst 
eine, Isomer A, a white foam, [.alpha.].sub.D.sup.26 +9.9.degree. (MeOH); 
N-[2-(.beta.-Naphthylmethyl)-3-mercaptopropionyl]-S-(4-methylbenzyl)-L-cyst 
eine, Isomer B, a white foam, [.beta.].sub.D.sup.26 =-50.1.degree. (MeOH); 
N-[2-(4-chlorobenzyl)-3-mercaptopropionyl]-S-benzyl-L-cysteine (Isomer A), 
[.alpha.].sub.D.sup.26 =-3.0.degree. (EtOH, c=1); 
N-[2-(4-chlorobenzyl)-3-mercaptopropionyl]-S-benzyl-L-cysteine (Isomer B), 
[.alpha.].sub.D.sup.26 =-48.7.degree. (EtOH, c=1); 
N-[2-(4-chlorobenzyl)-3-mercaptopropionyl]-L-tryptophan (Isomer A), 
[.alpha.].sub.D.sup.26 =+18.1.degree. (EtOH, c=0.5); and 
N-[2-(4-chlorobenzyl)-3-mercaptopropionyl]-L-tryptophan (Isomer B), 
[.alpha.].sub.D.sup.26 =-22.5.degree. (EtOH, c=0.5). 
EXAMPLE 2 
N-(2-Benzyl-3-Mercaptopropionyl)-S-Benzyl-L-Cysteine (Isomers A and B) 
Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-S-Benzyl-L-Cysteine, Ethyl Ester 
(Isomers A and B): React S-benzyl-L-cysteine ethyl ester hydrochloride 
(1.38 g) and 3-acetylthio-2-benzyl propionic acid (1.19 g) in a procedure 
similar to that described in Example 1, Step 1 to give a yellow oil. 
Chromatograph the oil on silica gel (1.5L, 60-200 mesh) using CH.sub.2 
Cl.sub.2 ethyl acetate 98:2 as eluant to give Isomer A, white solid (0.49 
g), m.p. 83.degree.-5.degree., [.alpha.].sub.D.sup.26 =-73.5.degree. 
(MeOH); overlap Isomer A and B (0.66 g); and Isomer B, white solid, m.p. 
72.degree.-4.degree., [.alpha.].sub.D.sup.26 =-9.4.degree. (MeOH). 
Step 2: Using the procedure described in Example 1, Step 2, separately 
treat the Isomers of Step 1 above to obtain Isomers A and B of the title 
compound: Isomer A, a colorless oil, [.alpha.].sub.D.sup.26 --2.1.degree. 
(MeOH), and Isomer B, a colorless oil, [.alpha.].sub.D.sup.26 
=-46.7.degree. (MeOH). 
EXAMPLE 3 
N-(2-Benzyl-3-Mercaptopropionyl)-S-Benzyl-D-Cysteine (Isomers A and B) 
Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-S-Benzyl-D-Cysteine, Ethyl Ester 
(Isomers A and B): React S-benzyl-D-cysteine ethyl ester hydrochloride 
(2.05 g) and 3-acetylthio-2-benzylpropionic acid (1.77 g) in a manner 
similar to that described in Example 1, Step 1 to give a light amber oil. 
Place the oil on a column of silica gel (2L, 60-200 mesh) and elute with 
CH.sub.2 Cl.sub.2 :ethyl acetate 98:2 to give Isomer A, white solid (0.70 
g), m.p. 84.degree.-85.degree.; [.alpha.].sub.D.sup.26 =+75 9.degree. 
(MeOH); overlap Isomer A and Isomer B (0.85 g); and Isomer B, white solid 
(0.33 g), [.alpha.].sub.D.sup.26 =0 +15.6.degree. (MeOH). 
Step 2: Using the procedure described in Example 1, Step 2, separately 
treat the Isomers of Step 1 above to obtain Isomers A and B of the title 
compound: Isomer A, a colorless oil, [.alpha.].sub.D.sup.26 =+13.5.degree. 
(MeOH); and Isomer B, a colorless oil, [.alpha.].sub.D.sup.26 
=+38.2.degree. (MeOH). 
EXAMPLE 4 
N-(2-Benzyl-3-Mercaptopropionyl)-S-(4-Methoxybenzyl)-L-Cysteine (Isomers A 
and B) 
Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-S-(4-Methoxybenzyl)-L-Cysteine 
Methyl Ester (Isomers A and B): React S-(4-methoxybenzyl)-L-cysteine 
methyl ester hydrochloride (1.85 g) and 3-acetylthio-2-benzylpropionic 
acid (1.95 g) in the manner described in Example 1, Step 1 to give an 
amber oil. Chromatograph this oil on a column of silica gel (2L, 60-200 
mesh) and elute with ethyl acetate:hexane 5:20 to give Isomer A, a clear 
oil (0.63 g), [.alpha.].sub.D.sup.26 =-66.5.degree. (MeOH), overlap Isomer 
A and Isomer B (0.28 g); and Isomer B, a clear oil (0.67 g), 
[.alpha.].sub.D.sup.26 =+3.0.degree. (MeOH). 
Step 2: Using the procedure described in Example 1, Step 2 separatelv treat 
the isomers of Step 1 above to obtain Isomers A and B of the title 
compound: Isomer A, a viscous oil, [.alpha.].sub.Dphu 26 =-19.3.degree. 
(MeOH); and Isomer B, a viscous oil, [.alpha.].sub.D.sup.26 =-44.2.degree. 
(MeOH). 
EXAMPLE 5 
N-(2-Benzyl-3-Mercaptopropionyl)-S-(3,4-Dimethylbenzyl)-L-Cysteine (Isomers 
A and B) 
Step 1: 
N-(3-Acetylthio-2-Benzylpropionyl)-S-(3,4-Dimethylbenzyl)-L-Cysteine Ethyl 
Ester (Isomers A and B): React S-(3,4-dimethylbenzyl)-L-cysteine ethyl 
ester hydrochloride (2.20 g) and 3-acetylthio-2-benzylpropionic acid (1.74 
g) in the manner described in Example 1, Step 1 to give an amber oil. 
Place the oil on a column of silica gel (lL) and elute with ethyl 
acetate:hexane 25:170 (4L) and then methanol:hexane 25:170 to give a light 
orange oily solid. Repeat the chromatography to give Isomer A, a white 
solid (0.52 g), m.p. 89.5.degree.-92.5.degree., [.alpha.].sub.D.sup.26 
=-71.1.degree. (MeOH) and Isomer B, a white solid (0.60 g), m.p. 
51.degree.-55.degree. , [.alpha.].sub.D.sup.26 =-8.4.degree. (MeOH). 
Step 2: Using the procedure described in Example 1, Step 2, separately 
treat the Isomers of Step 1 above, to obtain Isomers A and B of the title 
compound: Isomer A, a clear viscous oil, [.alpha.].sub.D.sup.26 
=-18.0.degree. (MeOH); and Isomer B, a clear viscous oil, 
[.alpha.].sub.D.sup.26 =-56.5.degree. (MeOH). 
EXAMPLE 6 
N-(2-Benzyl-3-Mercaptopropionyl)-S-Phenethyl-L-Cysteine (Isomers A and B) 
Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-S-Phenethyl-L-Cysteine Ethyl 
Ester, (Isomers A and B): React S-phenethyl-L-cysteine ethyl ester 
hydrochloride (2.85 g) and 3-acetylthio-2-benzylpropionic acid, (2.38 g) 
in a manner similar to that described in Example 1, Step 1 to give an 
amber oil. Chromatograph this oil on Prep 500 (2 silica gel cartridges) 
and elute with CH.sub.2 Cl.sub.2 (4L) and then CH.sub.2 Cl.sub.2 ethyl 
acetate 100:2 to give Isomer A, a white solid (1.32 g), m.p. 
63.degree.-64.degree., [.alpha.].sub.D.sup.26 =-51.2.degree. (MeOH); 
overlap Isomer A and Isomer B (0.63 g); and Isomer B, white solid (1.14 
g), m.p. 84.degree.-86.degree., [.alpha.].sub.D.sup.26 =+5.3.degree. 
(MeOH). 
Step 2: Using the procedure described in Example 1, Step 2, separately 
treat Isomers A and B of Step 1 above to obtain Isomers A and B of the 
title compound. Isomer A, colorless oil, [.alpha.].sub.D.sup.26 
=+4.8.degree. (MeOH); and Isomer B, a colorless oil, 
[.alpha.].sub.D.sup.26 =-39.7.degree. (MeOH). 
EXAMPLE 7 
N-(2-Benxyl-3-Mercaptopropionyl)-S-(t-Butyl)-L-Cysteine (Isomers A and B) 
Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-S-(t-Butyl)-L-Cysteine Methyl 
Ester (Isomers A and B): React S-(t-butyl)-L-cysteine methyl ester (2.32 
g) and 3-acetylthio-2-benzylpropionic acid (3.22 g) in the manner 
described in Example 1, Step 1 to give an orange solid. Chromatograph this 
solid on a column of silica gel (2L, 60-200 mesh) and elute with ethyl 
acetate:hexane 3:17 to give Isomer A, a clear oil (1.09 g), 
[.alpha.].sub.D.sup.26 =-44.9.degree. (MeOH); overlap Isomer A and Isomer 
B (0.52 g); and Isomer B, a clear oil (0.75 g), [.alpha.].sub.D.sup.26 
=+8.3.degree. (MeOH). 
Step 2: Using the procedure described in Example 1, Step 2, separately 
treat the Isomers above to obtain Isomers A and B of the title compound; 
Isomer A, a clear viscous oil, [.alpha.].sub.D.sup.26 =+0.4.degree. 
(MeOH), and Isomer B, a white solid, m.p. 68.degree.-75..degree., 
[.alpha.].sub.D.sup.26 =-32.3.degree. (MeOH). 
EXAMPLE 8 
N-(2-Benzyl-3-Mercaptopropionyl)-L-Ethionine (Isomers A and B) 
Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-L-Ethionine Ethyl Ester (Isomers 
A and B): React L-Ethionine ethyl ester (3.51 g) and 
3-acetylthio-2-benzylpropionic acid (4.37 g) in a manner similar to that 
described in Example 1, Step 1 to give a yellow residue. Chromatograph the 
yellow residue on the Waters Prep 500 (2 silica gel cartridges) and elute 
with ethyl acetate:hexane 2:18 (16L), then ethyl acetate:hexane 3:17. 
Repeat chromatography of the fractions using ethyl acetate:hexane as 
eluant to give Isomer A, a white solid (0.89 g), m.p. 
84.degree.-90.degree., [.alpha.].sub.D.sup.26 =-60.6.degree. (MeOH) and 
Isomer B (0.82 g), m.p. 79.degree.-84.degree., [.alpha.].sub.D.sup.26 
=-0.3.degree. (MeOH). 
Step 2: Using the procedure described in Example 1, Step 2, separately 
treat the Isomers of Step 1 above to obtain Isomers A and B of the title 
compound; Isomer A, a milky viscous oil, [.alpha.].sub.D.sup.26 
=-41.8.degree. (MeOH); and Isomer B, a milky viscous oil, 
[.alpha.].sub.D.sup.26 =-66.0.degree. (MeOH). 
EXAMPLE 9 
N-(2-Benzyl-3-Mercaptopropionyl)-O-Benzyl-L-Tyrosine (Isomers A and B) 
Step 1: N-(3-Acetylthio-2-benzylpropionyl)-O-benzyl-L-tyrosine Methyl Ester 
(Isomers A and B): React O-benzyl-L-tryosine methyl ester hydrochloride 
(2.77 g) and 3-acetylthio-2-benzylpropionic acid (2.05 g) in a manner 
similar to that described in Example 1, Step 1 to give a yellow-orange 
oil. Chromatograph this oil on a column of silica gel (2.5L) and elute 
with CH.sub.2 Cl.sub.2 ethyl acetate 98:2 to give Isomer A, a white solid 
(0.84 g) m.p. 108.degree.-109.degree.; [.alpha.].sub.D.sup.26 
=-39.8.degree. (MeOH); overlap Isomer A and Isomer B (0.80 g); and Isomer 
B, white solid (0.45 g), m.p. 92.degree.-93.degree., 
[.alpha.].sub.D.sup.26 =+19.2.degree. (MeOH). 
Step 2: Using the procedure described in Example 1, Step 2, separately 
treat the Isomers of Step 1 above to obtain Isomers A and B of the title 
compound: Isomer A, an off-white solid, [.alpha.].sub.D.sup.26 
=+4.8.degree. (MeOH); and Isomer B, a viscous colorless oil 
[.alpha.].sub.D.sup.26 +2.4.degree. (MeOH). 
EXAMPLE 10 
N-(2-Benzyl-3-Mercaptopropionyl)-(S)-Bishomophenyl Alanine (Isomers A and 
B) 
Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-(S)-Bishomophenylalanine t-Butyl 
Ester (Isomers A and B): React (S)-bishomophenylalanine t-butyl ester 
hydrochloride (2.49 g) and 3-acetylthio-2-benzylpropionic acid (2.39 g) in 
the manner described in Example 1, Step 1 to give a yellow oil. 
Chromatograph this oil on Waters Prep 500 (2 silica gel cartridges) and 
elute with CH.sub.2 Cl.sub.2 (4L) and then CH.sub.2 Cl.sub.2 :ethyl 
acetate 100:2 to give Isomer A, a colorless oil (0.99 g), 
[.alpha.].sub.D.sup.26 =-54.7.degree. (MeOH), overlap Isomer A and Isomer 
B (0.62 g); and Isomer B, a colorless oil (0.79 g), [.alpha.].sub.D.sup.26 
=+5.1.degree. (MeOH). 
Step 2: N-(3-Acetylthio-2-Benzylpropionyl)-(S)-Bishomophenylalanine (Isomer 
A and B): To Isomer A of the product of Step 1 (0.97 g, 0.21 mmole) in 
CH.sub.2 Cl.sub.2 (10 ml) at 0.degree.-5.degree., add dropwise 
trifluoroacetic acid (10 ml). Warm the resulting mixture to room 
temperature, stir for 18 hours, and concentrate in vacuo. Dissolve the 
residue in CH.sub.2 Cl.sub.2 (10 ml) and concentrate in vacuo. Treat the 
residue with diethyl ether (10 ml) and concentrate in vacuo to give Isomer 
A of the title compound, a light amber oil (0.87 g), 
[.alpha.].sub.D.sup.26 =-43.0.degree. (MeOH). 
By this same method, convert Isomer B of Step 1 to 
N-(3-acetylthio-2-benzylpropionyl)-(S)-bishomophenylalanine Isomer B, a 
light amber oil, [.alpha.].sub.D.sup.26 =+19.6.degree. (MeOH). 
Step 3: N-(2-Benzyl-3-Mercaptopropionyl)-(S)-Bishomophenylalanine (Isomers 
A and B): Dissolve Isomer A of Step 2 in methanol (15 ml) at 
0.degree.-5.degree. under a nitrogen atmosphere and treat with 1N sodium 
hydroxide (6.3 ml). Treat the resulting mixture as described in Example 1, 
Step 2, to give Isomer A of the title compound, a pale yellow viscous oil 
(0.69 g), [.alpha.].sub.D.sup.26 =-25.4.degree. (MeOH). 
By this same method, convert Isomer B of Step 2 to 
N-(2-benzyl-3-mercaptopropionyl)-(S)-bishomophenylalanine Isomer B, a pale 
yellow viscous oil, [.alpha.].sub.D.sup.26 =-50.0.degree. (MeOH). 
In a similar manner, substitute (S)-(4-methylbenzyl)-L-cysteine t-butyl 
ester (Preparation 6) for (S)-bishomophenylalanine in Example 10, Step 1 
to obtain 
N-(3-acetylthio-2-benzylpropionyl)-(S)-(4-methylbenzyl)-L-cysteine t-butyl 
ester, Isomer A, [.alpha.].sub.D.sup.26 =-82.8.degree. (MeOH); and 
N-(3-acetylthio-2-benzylpropionyl)-(S)-(4-methylbenzyl)-L-cysteine t-butyl 
ester, Isomer B, [.alpha.].sub.D.sup.26 =-23.5.degree. (MeOH). 
Treat the above esters in a manner similar to that described in Example 10, 
Step 2 to obtain 
N-(3-acetylthio-2-benzylpropionyl)-(S)-(4-methylbenzyl)-L-cysteine, Isomer 
A, [.alpha.].sub.D.sup.26 =-58.8.degree. (MeOH); and 
N-(3-acetylthio-2-benzylpropionyl)-(S)-(4-methylbenzyl)-L-cysteine, Isomer 
B, [.alpha.].sub.D.sup.26 =-6.6.degree. (MeOH). 
EXAMPLE 11 
N-[3-Mercapto-2(R,S)-Benzylpropionyl]-L-Methionine 
Step 1: N-[3-Acetylthio-2(R,S)-Benzylpropionyl]-L-Methionine Methyl Ester: 
Add methionine methyl ester (2.00 g, 1.23 mmole) to 
3-acetylthio-2-benzylpropionic acid (3.01 g, 1.26 mmole), DEC (2.34 g, 
1.22 mmole), HOBT (1.88 g, 1.23 mmole) and NMM (2.34 g, 2.31 mmole) in DMF 
(12 ml), and treat the resulting mixture as described in Example 1, Step 1 
to give an amber oil (4.36 g). Chromatograph the oil on a column of silica 
gel (lL 60-200 mesh) elute with CH.sub.2 Cl.sub.2 (lL) and then CH.sub.2 
Cl.sub.2 :ethyl acetate 99:1 to give the title compound, a clear oil (2.61 
g), [.alpha.].sub.D.sup.26 =-38.9.degree. (MeOH). 
Step 2: 
N-[3-Mercapto-2(R,S)-Benzylpropionyl]-L-Methionine: Dissolve the product of 
Step 1 in methanol (20 ml) and treat with 1N NaOH (20.4 ml) as described 
in Example 1, Step 2 to give the title compound, a white solid, m.p. 
132.degree.-5.degree., [.alpha.].sub.D.sup.26 =-34.6.degree. (MeOH). 
Using the method of Example 11, Step 1, other 
N-[3-(R,S)-Acetylthio-2-benzylpropionyl]amino acid esters are prepared: 
N-[3-Acetylthio-2(R,S)-benzylpropionyl]-S-methyl-L-cysteine ethyl ester, a 
clear oil, [.alpha.].sub.D.sup.26 =-25.9.degree. (MeOH); 
N-[3-Acetylthio-2(R,S)-benzylpropionyl]-S-trityl-L-cysteine methyl ester, 
an amber oil, [.alpha.].sub.D.sup.26 =+5.9.degree. (MeOH); and 
N-[3-Acetylthio-2(R,S)-benzylpropionyl]-(S)-tryptophan methyl ester, a 
colorless oil, [.alpha.].sub.D.sup.26 =-14.7.degree. (MeOH). 
Using the procedure of Example 11, Step 2, convert the above 3-acetylthio 
comoounds to the following 3-mercaptopropionyl compounds: 
N-[2(R,S)-Benzyl-3-mercaptopropionyl]-S-methyl-L-cysteine, a clear viscous 
oil, [.alpha.].sub.D.sup.26 =-31.1.degree. (MeOH); 
N-[2(R,S)-Benzyl-3-mercaptopropionyl]-S-trityl-L-cvsteine, a white solid, 
[.alpha.].sub.D.sup.26 =+10.5.degree. (MeOH); and 
N-[2(R,S)-Benzyl-3-mercaptopropionyl]-(S)-tryptophan, a white foam, m.p. 
68.degree.-69.degree., [.alpha.].sub.D.sup.26 =-0.5.degree. (MeOH). 
EXAMPLE 12 
N-[2-(4-Phenylbenzyl)-3-Mercaptopropionyl]-S-(4-Methyl Benzyl)-L-Cysteine 
(Isomers A and B) 
Step 1: 3-Acetylthio-2-(4-Phenylbenzyl)Propionyl Chloride: To 
3-acetylthio-2-(4-phenylbenzyl)propionic acid (3.39 g, 10.8 mmole) in 
toluene (25 ml) add 1% DMF in toluene (2 drops) and thionyl chloride (1.2 
ml, 1.65 g, 13.8 mmoles) and stir the resulting solution at room 
temperature for 18 hours. Concentrate the reaction mixture in vacuo, 
dissolve the residue in toluene (100 ml) and concentrate the solution in 
vacuo to give the title compound, a light brown oil (3.37 g). 
Step 2: 
N-[3-Acetylthio-2-(4-Phenylbenzyl)Propionyl]-S(4-Methylbenzyl)-L-Cysteine 
(Isomers A and B): Add the acid chloride (3.37 g) from Step 1 in 
acetonitrile (25 ml) dropwise to S-(4-methylbenzyl)-L-cysteine 
hydrochloride (2.62 g, 10 mmol) in acetonitrile (30 ml), water (15 ml) and 
triethylamine (2.8 ml), and stir the resulting mixture at room temperature 
for 4 hours. Concentrate the reaction mixture in vacuo and partition the 
residue between ethyl acetate (700 ml) and water (2.times.200 ml) and then 
saturated sodium chloride solution (100 ml). Dry the ethyl acetate 
solution (MgSO.sub.4) and concentrate in vacuo to give a brown solid. 
Chromatograph this solid on a column of silica gel (2L, 60.degree.-200 
mesh) and elute with CH.sub.2 Cl.sub.2 :methanol:glacial acetic acid 
(97.5:2.5:0.25) to give a white foam (2.45 g). Chromatograph this white 
foam on a column of silica gel (1.2L, 60-200 mesh) and elute with CH.sub.2 
Cl.sub.2 :methanol:glacial acetic acid (97.5:2.5:0.25) to give the title 
compound, a white solid (1.04 g), m.p. 123.degree.-125.degree., 
[.alpha.].sub.D.sup.26 =-45.5.degree. (MeOH); overlap Isomers A and B 
(0.19 g); and Isomer B of the title compound, a white solid (0.86 g), m.p. 
131.degree.-135.degree., [.alpha.].sub.D.sup.26 =-7.1.degree. (MeOH). 
Step 3: 
N-[2-(4-Phenylhenzyl)-3-Mercaptopropionyl]-S-(4-Methylbenzyl)-L-Cysteine 
(Isomers A and B): Dissolve Isomer A of Step 2 in methanol saturated with 
ammonia (50 ml) at 0.degree.-5.degree. under a nitrogen atmosphere. After 
35 minutes, bubble nitrogen through the reaction mixture. Dilute the 
reaction mixture with water and acidify to pH 2-4 with 1N hydrochloric 
acid. Extract the acidic solution with ethyl acetate, dry the organic 
layer (MgSO.sub.4) and concentrate in vacuo to give Isomer A of the title 
compound, a white solid (0.73 g). Purify Isomer A by flash chromatography 
on silica gel (Baker flash silica gel, 40 .mu.M) (25 g) eluting with 
CHCl.sub.2 :MeOH:gl.AcOH, 97.5:2.5:0.25, to obtain a white solid (0.549 
g), [.alpha.].sub.D.sup.26 =-2.2.degree. (MeOH). 
In a similar fashion, prepare Isomer B of the title comoound, a white 
solid, [.alpha.].sub.D.sup.26 =-62.2.degree. (MeOH). 
EXAMPLE 13 
N-[2-Benzyl-3-Mercaptopropionyl]-L-Methionine Amide 
Step 1: N-(3-Acetylthio-2-Benzylpropionyl)-L-Methionine Amide: In similar 
fashion to that described in Example 12, Step 2, convert L-methionine 
amide to N-(3-acetylthio-2-benzylpropionyl)-L-methionine amide. 
Recrystallize from hexane:CH.sub.2 Cl.sub.2 to obtain a solid, m.p. 
101.degree.-3.degree.. Chromatograph on silica gel with 4% 
methanol/CH.sub.2 Cl.sub.2 to obtain Isomer A, m.p. 
149.degree.-51.degree., and Isomer B, m.p. 119.degree.-21.degree.. 
Step 2: N-(2-Benzyl-3-Mercaptopropionyl)-L-Methionine Amide: Treat the 
3-acetylthio compound (mixture of Isomer A and B) with NH.sub.3 /MeOH for 
4 hours as in Example 12, Step 3, to give the title compound, 
[.alpha.].sub.D.sup.26 =-53.5.degree. (EtOH, c=1), a mixture of 
diastereomers. 
In a similar manner to that described in Example 13, Step 1, substitute the 
appropriate acetylthio compounds and amides and separate by chromatography 
to obtain: 
N-(3-Acetylthio-2-benzylpropionyl)-S-(4-methylbenzyl)-L-cysteine amide, 
Isomer A, [.alpha.].sub.D.sup.26 =-38.2.degree. (MeOH); 
N-(3-Acetylthio-2-benzylpropionyl)-S-(4-methylbenzyl)-L-cysteine amide, 
Isomer B, [.alpha.].sub.D.sup.26 =]26D=-1.6.degree. (MeOH); 
N-[3-Acetylthio-2-(4-chlorobenzylpropionyl)]-L-methionine amide, Isomer A; 
N-[3-Acetylthio-2-(4-chlorobenzylpropionyl)]-L-methionine amide, Isomer B, 
m.p. 166.degree.-9.degree.; 
Treat the amides obtained above in a manner similar to that described in 
Example 13, Step 2 to obtain: 
N-[2-(4-Chlorobenzyl)-3-mercaptopropionyl]-L-methionine amide, Isomer A, 
m.p. 194.degree., [.alpha.].sub.D.sup.26 =+1.2.degree. (MeOH); 
N-[2-(4-Chlorobenzyl)-3-mercaptopropionyl]-L-methionine amide, Isomer B, 
[.alpha.].sub.D.sup.26 =-65.2.degree. (MeOH); 
N-(2-Benzyl-3-mercaptopropionyl)-S-(4-methylbenzyl)-L-cysteine amide, 
Isomer A, m.o. 130.degree.-2.degree., [.alpha.].sub.D.sup.26 =-4.2.degree. 
(MeOH): and 
N-(2-Benzyl-3-mercaptopropionyl)-S-(4-methylbenzyl)-L-cysteine amide, 
Isomer B, [.alpha.].sub.D.sup.26 =-29.0.degree. (MeOH). 
EXAMPLE 14 
N-(3-Benzoylthio-2-Benzylpropionyl)-L-Methionine Amide 
Prepare the R and S enantiomers of 3-benzoylthio-2-benzylpropionic acid 
according to the procedure described in U.S. Pat. No. 4,329,495, herein 
incorporated by reference. 
In a manner similar to that described in Example 1, Step 1, condense each 
acid separately with L-methionine amide to obtain 
N-(3(S)-benzoylthio-2-benzylpropionyl)-L-methionine amide, m.p. 
178.degree.-180.degree., [.alpha.].sub.D.sup.26 =-97.6.degree. (MeOH); and 
N-(3(R)-benzoylthio-2-benzylpropionyl)-L- C methionine amide, m.p. 
145.degree.-9.degree., [.alpha.].sub.D.sup.26 =+32.9.degree. (CHC13) 
EXAMPLE 15 
N-[2-Benzyl-3-Mercaptipropionyl]-L-Aspartic Acid .beta.-Benzyl Ester 
In similar fashion to that described in Example 12, Step 2, convert 
L-aspartic acid .beta.-benzyl ester to 
N(3-acetylthio-2-benzylpropionyl)-L-aspartic acid, .beta.-benzyl ester. 
Treat with NH.sub.3 /MeOH as in Example 12, Step 3 to give the title 
compound, [.alpha.].sub.D.sup.26 =-5.7.degree. (EtOH, c=0.5). 
EXAMPLE 16 
N-[N-(2-Benzyl-3-Mercaptopropionyl)-L-Phenylalanyl]-L-Alanine 
Using the procedure of Example 1, convert L-phenylalanyl-L-alanine benzyl 
ester hydrochloride to 
N-(N-(3-acetylthio-2-benzylpropionyl)-L-phenylalanyl]-L-alanine, benzyl 
ester. 
Treat with NaOH as in Example 1, Step 2 to give the crude title compound. 
React the product (0.62 g) with zinc powder (0.5 g) and 5N HCl (10ml) in 
20ml MeOH for 1 hour. Concentrate the mixture, extract with CH.sub.2 
Cl.sub.2, dry, and remove the solvent to give the title compound, 
[.alpha.].sub.D.sup.26 =-23.1.degree. (EtOH, c=0.5). 
Use the same procedure to prepare 
N-(N-(2-benzyl-3-mercaptopropionyl)-L-phenylalanyl-L-leucine, 
[.alpha.].sub.D.sup.26 =-20.8.degree. (EtOH, c=0.5). 
EXAMPLE 17 
N-[N-(2-Benzyl-3-Mercaptopropionyl)-L-Alanyl]-L-Proline 
Step 1: N-[N-(3-Acetylthio-2-Benzylpropionyl)-L-Alanyl]-L-Proline: Using 
the procedure of Example 12, Step 2, convert L-alanyl-L- proline to 
N-[N-(3-acetylthio-2-benzylpropionyl)-L-alanyl]-L-proline, a white foam, 
[.alpha.].sub.D.sup.26 =-81.8.degree. (MeOH). 
Step 2: N-[N-(2-Benzyl-3-Mercaptopropionyl)-L-Alanyl]-L-Proline: Treat the 
product from Step 1 with methanol saturated with ammonia as described in 
Example 12, Step 3 (before chromatography). Treat the resultant residue 
with zinc powder as described in Example 17. Chromatograph the product on 
flash grade silica gel using CH.sub.2 Cl.sub.2 MeOH:NH40H (97.5:2.5:0.25) 
to give the title compound, [.alpha.].sub.D.sup.26 =-118.2.degree. (MeOH).