CA1119177A - Compounds and method for alleviating angiotensin related hypertension - Google Patents

Abstract

ABSTRACT A method for alleviating or reducing angiotensin related hypertension in hypertensive mammals comprises admin-istering to such hypertensive mammals an effective amount of an angiotensin converting enzyme inhibitor selected from a group of mercaptoacyl aminoacids of the formula (I) or a salt thereof, wherein n is 0, 1 or 2 and R5 is hydrogen, lower alkanoyl, benzoyl or

Description

" 11~9~77 Angiotensin II is a powerful vasoconstrictor agent that has been implicated as the main causative agent in the etiology of renovascular hypertension.
Angiotensin II is formed from angiotensin I by the action of angiotensin converting enzyme. Angiotensin I
is a biologically inert decapeptide cleaved from the blood protein angiotensinogen by the action of the enzyme renin [OFaril et al. New England J. of Med., 291, 389-457 (1974)].
Angiotensinogen and renin are also biologically inert.
Angiotensin converting enzyme is also responsible for the inactivation of bradykinin, a vasodilator agent that has been implicated in the regulation of renal function [Erdos, Circulation Research 36, 247 (1975)].
Agents that inhibit angiotensin converting enzyme can therefore counteract the pressor effect of angiotensin since this is due only to its conversion to angiotensin II.
These agents can be used therapeutically in the treatment of forms of renovascular and malignant hypertension as well as other forms of angiotensin dependent hypertension lGavras et al., New England J. of Med. 291, 817 (1974)].
According to Oparil et al., supra, angiotensin II
has a major role in maintaining circulatory homeostasis in the sodium depleted animal, but in the normal animal on a normal salt intake, angiotensin II is not required for the acute maintenance of blood pressure. In a variety of conditions that stress the renin-angiotensin system, acute administration of an Angiotension Converting Enzyme inhibitor or an angiotensin II blocker lowers blood pressure and causes a rise in plasma renin activity.
Certain mercaptoacyl amino acids have been disclosed in the literature. U.S. Patent 3,246,025, April 12, 1966, shows mercaptopropionyl glycine derivatives which are useful for stregthening function of the liver and as antidotes for such poisons as mercury and organoarsenic compounds. See also German Offenlegungsschrift 2,349,707. U.S. Patent 3,897,480, July 29, 1957, shows N-(a-mercaptoacyl)amino acids useful for prophylaxis and therapy in treating a metabolic disorder, such as nosotoxicosis due to a heavy metal, radiation disorder, diabetes or hepatitis. U.S. Patent 3,857,951, December 31, -1974, shows the use of 2-mercaptopropionylglycine and its alkali metal salts in treating respiratory diseases.
It has been reported that 2-mercaptopropionylglycine, known as a liver protecting agent, produced lowering of the blood pressure upon intravenous injection to anesthetized -normotensive rats [Schulze, Arzneim. Forsch. 22, 1433 (1972)], an unreliable model [Schwarts, Methods in Pharmacology, Vol. 1, 125 (1971); Berger, Selected Pharmacological Testing Methods, Vol. 3, 171, 194 (1968)]; while others have reported no noticeable effects on blood pressure, etc., [Fujimura et al., Nippon Yakurigaku Zasshi 60, 278-92 (1964)]. See also Ripa, Proc. Int. Symp. Thiola, Osaka, Japan 1970, p. 226-230, who reported that in normotensive rats a-mercaptopropionylglycine increases angiotensinogen and lowers renin blood levels by a ,~

feed-back homeostatic mechanism.
It has now been found that certain mercapto acyl amino acids are angiotensin converting enzyme inhibitors and when administered to species of hypertensive mammals they reduce or relieve angiotensin related hypertension.

This invention relates to certain compounds as well as a method for reducing or relieving angiotensin related hypertension in mammalian species. The method comprises administering to the hypertensive mammal an angiotensin converting enzyme inhibitor from the group consisting of Compounds having the formula (I) 14 13 12 1l R5-S-(CH)n- CH-CO-N - CH -COOH

or a salt thereof.
Rl is hydrogen, lower alkyl, phenyl-lower alkylene, ~0 hydroxy-lower alkylene, amino-lower alkylene, yuanidino-lower alkylene, imidazolyl-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkylmercapto-lower alkylene carbamoyl-lower alkylene or carboxy-lower alkyl.
R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene;
R5 is hydrogen, lower alkanoyl, benzoyl or R IR3 12 1l -S-(CH)n CH- CO- N - CH - COOH;
n is 0, 1 or 2.
'l~he asteri.~ks (I(~ Le c~ntcrs o~ asymm~y.

_ ~_ . ~.

17~

Compounds of formula I, and salts thereof, wherein n is ; ~1 is hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, imidazolyl-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkylmercapto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl;and R2, R3,R4 and R5 each has the -meaning defined above, compounds of formula I, and salts thereof, wherein n is l; Rl is lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower ~
alkylene, amino-lower alkylene, guanidino-lower alkylene, -;
imidazolyl-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkylmercapto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2 and R3 each is hydrogen, lower alkyl or phenyl-lower alkylene; R4 lS hydrogen; and R5 has the "
meaning defined above, and compounds of formula I, and salts thereof, wherein n is 2 and Rl, R2, R3, R4 and R5 each has -the meaning defined above, are new compounds. Members in the groups remaining are known.
'~

This invention comprises compounds and a method for the reduction or alleviation of renin-angiotensin related hypertension in mammals, such as rats, dogs, etc. Such renin-angiotensin related types of hypertension include, for example, renovascular hypertension and malignant hypertension. This invention therefore relates to the new ; compounds described above and to the method for relieving or alleviating renin-angiotensin related hypertension by the administration of a compound or compounds of formula I above.

The method com~rises the administration to the mammal suffering 1~19177 from renin-angiotensin related hypertension an effective amount of an angiotensin converting enzyme inhibitor from the group consisting of compounds having formula I above.
The lower alkyl groups are straight or branched chain hydrocarbon radicals having up to seven carbon atoms like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, heptyl and the like. The lower alkylene groups are of the same kind. The Cl-C4 lawer alkyl and lower alkylene groups and especially the Cl-C2 lower alkyl and lower alkylene groups are preferred. The phenyl-lower alkylene groups include such lower alkylene groups having a phenyl group attached. Benzyl and phenethyl are especially preferred, most especially the former. The lower alkanoyl groups are the acyl radicals of the lower fatty acids like acetyl, propionyl, butyryl and the like. The C2-C4 members are preferred.
Compounds in the group represented by formula I
which are derived from or include the structure of the amino acids alanine, leucine, phenylalanine, arginine, sarcosine, serine, asparagine, lysine, glutamine, histidine, tryptophane, cysteine, methionine, threonine, lysine, tyrosine, leucine, valine or aspartic acid are preferred, especially arginine.
alanine, phenylalanine and leucine. R5 is preferably hydrogen.
Experimental evidence indicates that N -(3-mercapto-

2-methylpropanoyl)-L-arginine, N -(3-mercaptopropanoyl)-L-arginine, N-(3-mercaptopropanoyl)-L-phenylalanine and N-(3-mercaptopropanoyl-L-leucine are the most potent members of the group and they constitute an especially preferred group and especially preEcrred embodiments.

Thc compounds or formula I also form salts with various _rJ_ 11~9~77 inorganic and organic bases which are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts, alkaline earth metal salts, like calcium and magnesium salts, salts with `
organic basesi e.g., dicyclohexylamine, benzathne, hydrabamine and N-methyl-D-glucamine salts.
The compounds of this invention have one, two or three asymmetric carbons if Rl, R3 and R4 are other than ~ hydrogen. These carbons are indicated by an asterisk in - 10 formula I. The compounds accordingly exist in diastereoiso-meric forms or in racemic mixtures thereof. All of these are within the scope of the invention.
It has been found that to attain a significant degree of biological activity the asymmetric carbon bearing the Rl residue should be of the L-configuration, a stereospecificity ~ .
4 that is not apparent in previously reported applications of mercapto acylamino acids. These accordingly are preferred.
7, The inhibition of the angiotensin converting enzyme by compounds of formula I can be measured in vitro with i 20 isolated angiotensin converting enzyme from rabbit lungs following the procedure described by Cushman and Cheung [Biochem. Pharmacol., 20, 1637 (1971)], and with an excised smooth muscle assay [E. O'Keefe, et al., Federation Proc.
~ 31, 511 (1972)] in which these compounds have been shown to i be powerful inhibitors of the contractile activity of , angiotensin I and potentiators of the contractile activity of bradykinin.
By administering a composition containing one or a combination of the angiotensin converting enzyme inhibitor or 30 physiologically acceptable salt thereof, to the hypertensive _ (, _ mammal suffering from angiotensin dependent hypertension, it intervenes in the renin ~ angiotensin I ~ angiotensin II
sequence and the condition is reduced or alleviated.
A single dose, or preferably two to four divided daily doses, provides on a basis of about 1 to 1000 mg. per kilogram per day, preferably about 10 to 500 mg. per kilogram per day and especially 30 to 300 mg. per kilogram per day is appropriate to reduce angiotensin related elevated blood pressure. The animal model experiments described by S.L.
Engel, T.R. Schaefer, M. H. Waugh and R. Rubin, Proc. Soc.
Exp. Biol. Med. 143, 483 (1973) provide a valuable guide.
The composition is preferably administered orally, but ; parenteral routes such as subcutaneously, intramuscularly, intra-venously or intraperitoneally can also be employed.
The compounds of formula I can be prepared by several alternate procedures. A thio acid of the formula (II) R6cosH
wherein R6 is lower alkyl or phenyl, is made to react with an acrylic acid of the formula (III) IR3 CH2=C_cooH
to obtain the product of the formula (IV) IR3 and this acid is coupled to the amino acid of the formula (V) ~R2 ll HN -CE~-COOH
yieldin~3 a ~roduct o~ L lle l-OrlllUla 1~9~77 (VI ) I 3 1 2 1 1 which can then be converted to the product (VII) l3 12 1l by ammonolysis.
In an alternate procedure, the amino acid of formula V is coupled with a haloalkanoic acid of the formula (VIII) I 4 1 3 X- ( CH) -CH-COOH
wherein X is a halogen, preferably chlorine or bromine, by one of the known procedures in which the acid VIII is activated, prior to reaction with the amino acid V, involving formation of a mixed anhydride, symmetrical anhydride, acid chloride, active ester or the like. The product of this -reaction is a compound of the formula (IX) 14 13 12 1l X- (CH) n-CH-CO-N--CH-COOH
This product is subjected to a displacement reaction with the anion of a thioacid of formula II to give the compound of formula VI. I 4 13 1 2 1l When R5 in formula I is -S- (CH) -CH-CO-N - Cl~-COOH, this product is a dimer of the formula (X) 14 1 3 1 2 1l [S- (CH) n-CH-CO-N--CH-cooH] 2 which is produced by oxidation of a compound of formula VII with an alcoholic solution of iodine. This product can also be obtained by treating the halo compound of formula IX
with sodium disulfide.

7~

The compounds of formula I are utilized to alleviate the angiotensin related hypertension by formulating in a composition such as tablet, capsule or elixir for oral adminiStration. Sterile solutions or suspensions can be use~
for parenteral administration. About 10 to 500 mg. of a compound or mixture of compounds of formula I or physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, 1avor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in the composition is such that dosage in the range indicated is obtained.
Illustrative of the adjuvants which may be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin;
an excipient such as dicalcium phosphate; a disintegrating f agent such as corn starch, potato starch, alginic acid andthe like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise enhance the pharmaceutical elegance of the preparation. For instance, tablets may be coated with shellac, sugar or the like. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Sterile compositions for injection can be formulated _g_ 91~7 according to conventional pharmaceutical practice by dissolving or suspending the active substance in a conventional vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehlcle like ethyl oleate or the like. Buffers, preservatives, anti-oxidants and the like can be incorporated as required.
The following examples are illustrative of the invention. Temperatures are in degrees celsius.

Example 1 , N-(3-Benzoylthiopropanoyl)-L-alanine L-alanine (4.45 g.) is dissolved in aqueous N-sodium hydroxide (50 ml.) and the solution is chilled in the ice bath with stirring. 2N sodium hydroxide (27 ml.) and 3-bromo-propionyl chloride (8.5 g.) are added in that order and the mixture is removed from the ice bath and stirred at room temperature for three and one half hours. A mixture o~
thiobenzoic acid (7.5 g.) and potassium carbonate (4.8 g.) in water (50 ml.) is added and the mixture is stirred at room temperature overnight. After acidification with concentra-ted hydrochloric acid the aqueous solution is extracted with ethyl acetate, and the organic phase is washed with water, dried and concentrated to dryness. The residue (14.9) is !
cry~tallized from ether to yield 7.1 g. of N-(3-benzoylthio-propanoyl)-L-alanine, m.p. 99-100.
Example 2 N-(3-mercaptopropanoyl)-L-alanine N-(3-benzoylthiopropanoyl)-L-alanine (4.2 g.) is dis~olved in a mixture of water (7.5 ml.) and concentrated ammonium hydroxidc (G ml.). ~ter one hour, the mixture is --:10--.

1~19~77 diluted with water, filtered and the filtrate is extracted with ethyl acetate. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and concentrated to dryness in vacuo. The residue is crystallized from ethyl acetate-hexane to yield 1.87 g. of N-(3-mercaptopropanoyl)-L-alanine, m.p. 79-81 .
Example 3 N-(3-Benzoylthiopropanoyl)-L-leucine By substituting L-leucine (6.55 g.) for the L-alanine in the procedure of Example 1, 16.7 g. of crude N-(3-benzoyl-thiopropanoyl)-L-leucine is obtained. This material is dissolved in a mixture of ethyl acetate (200 ml.) and dicyclo-hexylamine. The crystalline salt is filtered and dried.
Yield 19.5 g., m.p. 178-180. This dicyclohexylammonium salt is treated with a mixture of ethyl acetate (200 ml.) and 10% aqueous potassium bisulfate (50 ml.). The organic phase is dried over magnesium sulfate, concentrated to dryness in vacuo and the residue crystalli~ed from ethyl acetate-hexane to yield 8.8 g. of pure N-(3-benzoylthiopropanoyl)-L-leucine, m p 99-101.
Example 4 N-(3-Mercaptopropanoyl)-L-leucine By substituting N-(3-benzoylthiopropanoyl)-L-leucine (6.46 g.) for the N-(3-benzoylthiopropanoyl)-L-alanine in the procedure of Example 2, 2.75 g. of N-(3-mercaptopro-panoyl)-L-leucine are obtained, m.p.131-132 . This material is recrystallized from acetonitrile.
;

_ I I _ 93~77 Example 5 N-(3-senzoylthiopropanoyl)-L-Phenylalanine By substituting L-phenylalanine (8.25 g.) for the L-alanine in the procedure of Example 1, 18.8 g. of crude N-(3-benzoylthiopropanoyl)-L-phenylalanine is obtained.
This material is crystallized from acetonitrile to yield 11.1 g. of product, m.p. 123-124.
Example 6 N-(3-Mercapto ro anoyl)-L- hen lalanine P P P Y
N-(3-benzoylthiopropanoyl)-L-phenylalanine (1.78 g.) is dissolved in a mixture of water (20 ml.) and N sodium hydroxide (5.5 ml.). To this solution concentrated ammonium hydroxide (20 ml.) is added followed by water (20 ml.).
After three hours, the reaction mixture is extracted with ethyl acetate, acidified with concentrated hydrochloric acid and reextract'ed with ethyl acetate. The second ethyl acetate extract is washed with water,,dried over magnesium sulfate and concentrated to dryness in vacuo. The residue is chromatographed on a column of silica gel with a mixture of benzene-acetic acid to yield 0.47 g. of N-(3-mercaptopro-panoyl)-L-phenylalanine, m.p. 106-107 .
Example 7 N -(3-Benzoylthiopropanoyl)-L-arginine L-arginine (8.7 g.) is dissolved in aqueous N sodium hydroxide (50 ml.) and the solution is chilled in the ice bath with stirring. 2N sodium hydroxide (25 ml.) and

3-bromopropionyl chloride (8.5 g.) are added in that order and the mixture is removed from the ice bath and stirred at room temperature for 2 hours. A mixture of thiobenzoic acid (7.5 g.) and potassium carbonate (2.4 g.) in water (10 ml.) is addcd and the mixture is stirred overniqllt at 11~917~7 room temperature. Ion-exchange resin [polystyrene sulfonic acid resin Dowex 50 (Mikes, Laboratory Handbook of Chroma-tographic Methods, Van Nostrand, 1961, page 256)] (100 ml.) is added and the suspension is applied to a column of the ;
same resin (300 ml.). After washing off acidic materials with water, the N -(3-benzoylthiopropanoyl)-L-arginine is eluted with a buffer of pyridine-acetic acid-water, pH 6.5. ;
The fractions containing the desired material are pooled, concentrated to dryness and the residue is triturated with ether to yield 7 g., m.p. 345 (dec.).
Example 8 N -(3-Mercaptopropanoyl)-L-arginine N -(3-benzoylthiopropanoyl)-L-arginine (1 g.) is dissolved with vigorous stirring in a mixture of water (5 ml.) and concentrated ammonia (5 ml.). After one hour, the solution is extracted with ethyl acetate and concentrated to dryness in vacuo. The residue is chromatographed on a column of DEAE Sephadex [anion exchange resin derived from dextran (Mikes, supra, page 328)] (85 ml.) with a buffer of 0.005 M ammonium bicarbonate. The fractions containing the N -(3-mercaptopropanoyl)-L-arginine (as indicated by positive thlol and Sakaguchi Reaction) are pooled and lyophiliæed to remove ammonium bicarbonate, yield 200 mg., m.p. 230 (starts decomposing at 200).
Example 9 N-(3-Benzoylthiopropanoyl)sarcosine By substituting sarcosine (4.45 g.) for L-alanine in the procedure of Example 1, 7.9 g. of N-(3-benzoylthio-propanoyl)sarcosine, m.p. 139-140 are obtained.

, -~ 77 HA136 E mple 10 N-(3-Mercaptopropanoyl)sarcosine By substituting N-(3-benzoylthiopropanoyl)sarcosine (2.8 g.) for N-(3-benæoylthiopropanoyl)-L-alanine in the procedure of Example 2, 1.65 g. of crude N-(3-mercapto-propanoyl)sarcosine is obtained. This material is converted to the dicyclohexylammonium salt (2.7 g.), m.p. 157-158 and the purified salt is converted to the free acid by distribution between ethyl acetate and 10~ potassium ; 10 bisulfate.
Example 11 N-(3-Mercapto ropano l)-L-serine P Y
By substituting L-serine for the L-alanine in the procedure of Example 1, and then treating the product by the procedure of Example 2, N-(3-benzoylthiopropanol)-L-serine and N-(3-mercaptopropanoyl)-L-serine are obtained.
Example 12 N-(3-Mercaptopropanoyl)-L-asparagine By substituting L-asparagine for the L-alanine in the procedure of Example 1, and then treating the product by the procedure of Example 2, N-(3-benzoylthiopropanoyl)-L-asparagine and N-(3-mercaptopropanoyl)-L-asparagine are obtained.
Example 13 N -(3-Mercaptopropanoyl)-L-lysine By substituting N -tert-butyloxycarbonyl-L-lysine [R. Schwyzer and W. Rittel, Helv. Chim. Acta 44, 159 (1961)~
for L-alanine in the procedure of Example 1, and then treating the product by the procedure of Example 2, N -(3-benzoylthiopropanoyl)-N -tert-butyloxycarbonyl-L-~1~9177 HA136 ,, lysine and N -(3-mercaptopropanoyl)-N~-tert-butyloxycarbonyl-L-lysine are obtained. By treating this material with tri-fluoroacetic acid at room temperature for 15 minutes, N -(3-benzoylthiopropanoyl)-L-lysine and N -(3-mercaptopropanoyl)-- L-lysine are obtained.
Example 14 N -(3-Mercaptopropanoylj-L-histidine By substituting L-histidine for the L-alanine in ~ the procedure of Example 1, and then treating the product by ; 10 the procedure of Example 2, N -(3-benzoylthiopropanoyl)-L-histidine and N -(3-mercaptopropanoyl~-L-histidine are obtained.
Example 15 ,~ N-(3-Nercaptopropanoyl)glycine By substituting glycine for the L-alanine in the procedure of Example 1, and then treating the product by the '~ procedure of Example 2, (3-benzoylthiopropanoyl)glycine and ; N-(3-mercaptopropanoyl)glycine are obtained.
Example 16 N-(3-Mercaptopropanoyl)-L-tryptophane ' 20 By sub~tituting L-tryptophane for the L-alanine " ' in the procedure of Example 1, and then treating the product by the procedure of Example 2, N-(3-benzoylthiopropanoyl)-L-tryptophane and N-(3-mersaptopropanoyl)-L-tryptophane are obtained.
~ Example 17 ., N-(3-Mercaptopropanoyl)-L-cysteine By susbtituting L-cystein'e for the L-alanine in the procedure of Example 1, and then treating the praduct by the procedure of Example 2, N-(3-benzoylthiopropanoyl)-L-cysteine and N-(3-mercaptopropanoyl)-L-cysteine are obtained.

, .
:
, - -, ~1~9~7~ HA136 Example 18 ~-(3-Mercaptopropanoyl)-L-methionine By substituting L-methionine for the L-alanine in the procedure of Example 1, and then treating the product by the procedure of Example 2, N-(3-benzoylthiopropanoyl)-L-methionine, and N-(3-mercaptopropanoyl)-L-methionine are obtained.
Example l9 N-(3-Mercaptopropanoyl)-N-methyl-L-leucine By substituting N-methyl-L-leucine for the L-alanine in the procedure of Example l, and then treating the product by the procedure of Example 2, N-(3-benzoylthiopropanoyl)-N-methyl-L-leucine, and N-(3-mercaptopropanoyl)-N-methyl)-L-leucine are obtained.
Example 20 N -t3-Acetylthio-2-methylpropanoyl)-L-arginine L-Arginine (2.61 g.) is dissolved in a mixture of sodium carbonate (3.2 g.) and water (30 ml.) and the solution iB chilled in an ice bath. 3-Acetylthio-2-methylpropanoyl chloride (2.7 g.) is added and the reaction mixtuxe is stirred at room temperature for 1.5 hours. Ion exchange resin (AG S0 W) 50 ml. is added and the suspension is applied to a column of the same resin (80 ml.). After washing with water, the N -(3-acetylthio-2-methylpropanoyl)-L-arginine i8 eluted with a pyridine-acetic acid buffer pH 6.5, the solvent is removed in vacuo, the residue is dissolved in methanol and precipitated with ether to yield 3.86 g. of N -(3-acetylthio-2-methylpropanoyl)-L-arginine, m.p. 133.

~1~9177 Example 21 N -(3-Mercapto-2-methylpropanoyl)-L-arginine N -(3-Acetylthio-2-methylpropanoyl)-L-arginine (1 g.) is dissolved in a mixture of water (5 ml.) and concentrated ammonia (S ml.). After one hour at room temperature the solution is concéntrated to 3 ml. in vacuo (no heat) and ion exchange resin AG-50 W is added until the pH of approximately

4. The suspension is applied to a column of the same resin and the N -(3-mercapto-2-methylpropanoyl)-L-arginine is eluted with pyridine-acetate buffer pH 6.5. The solvent is removed in vacuo and the residue is freeze dried, yield 0.86 g., m.p. 100.
Example 22 N-(3-Acetvlthio-2-methvl~ro~anoYl)-L-valine ~ ..
L-valine ~88 g.) and sodium carbonate (40 g.) are dissolved in water (1 1.) andthe solution is chilled ; in an ice bath with vigorous stirring. 3-Acetylthio-2-methyl-propanoyl chloride (135 g.) and a solution of sodium carbonate (120 g.) in 500 ml. of water are added in five equal portions over a 15 minute period. After 1.5 hours the reaction mixture is extracted with ethyl acetate, the aqueous phase is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated to dryness to yield 190 g. of N-(3-acety thio-2-methylpropanoyl)-L-valine.
Example 23 N-(3-Mercapto-2-methylpropanoyl)-L-valine N-~3-Acetylthio-2-methylpropanoyl)-L-valine (20 g.) is dissolved in a mixture of water(46 ml.) and concentrated .

-- 111`9177 HAl 3 6 ammonia (31 ml.). After one hour at room temperature the reaction mixture is extracted with ethyl acetate, the aqueous phase is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to yield 19 g. of N-(3-mercapto-2-methylpropanoyl)-L-valine.
Example 24 N-(3-Merca~to-2-methvl~ropanovl)-L-phenvlaianine .. . .
By substituting L-phenylalanine for the L-valine in the procedure of Example 22, and then treating the product by the procedure of Example 23, N- (3-acetylthio-2-methylpropan-oyl)-L-phenylalanine and N- ( 3-mercapto-2-methylpropanoyl)-L-phenylalanine are obtained.
Example 25 N-(3-Mercapto-2-methylpropanoyl)-L-threonine By substituting L-threonine for the L-valine in the procedure of Example 22, and then treating the product by the procedure of Example 23, N- (3-acetylthio-2-methylpropanoyl)-L-threonine and N-(3-mercapto-2-methyl-~0 propanoyl)-L-threonine are obtained.
Example 26 N-(3-Mercapto-2-methylpropanoyl)-L-glutamine By substituting L-glutamine for the L-valine in the procedure of Example 22 and then treating the product by the procedure of Example 23, N-(3-acetylthio-2-methyl-propanoyl)-L-glutamine and N-(3-mercapto-2-methylpropanoyl)-L-glutamine are obtained.
Example 27 N -(3-Mercapto-2-methylpropanoyl)-L-lysine By substituting~N -tert-butyloxycarbonyl-L-lysine ~ 177 HA136 for the L-valine in the procedure of Example 22, and then treating the product by the procedure of Example 23, Na-(3-acetylthio-2-methylpropanoyl)-N -tert-butyloxycarbonyl-L-lysine and N -(3-mercapto-2-methylpropanoyl)-N -tert-butyloxycarbonyl-L-lysine are obtained. By treating these ~' products with trifluoroacetic acid at room temperature for 15 minutes, N ~(3-acetylthio-2-methylpropanoyl)-L-lysine and N -(3-mercapto-2-methylpropanoyl)-L-lysine are obtained.
Example 28~
N-(3-Merca to-2-methvlpropanoyl)-L-tyrosine P
By substituting L-tyrosine for the L-valine in the , procedure of Example 22, and then treating the product by the procedure of Example 23, N-(3-acetylthio-2-methylpro-panoyl)-L-tyrosine and N-(3-mercapto-2-methylpropanoyl)-L-tyrosine are obtained.
Example 29 N-(3-Mercapto-2-methylpropanoyl ? -L-tryptophane By substituting L-tryptophane for the L-valine in the procedure of Example 22, and then treating the product by the procedure of Example 23, N-(3-acetylthio-2-methyl-propanoyl)-L-tryptophane and N-(3-mercapto-2-methylpropanoyl)-L-tryptophane are obtained.
Example 30 N-(3-mercapto-2-methylpropanoyl)-L-methionine By substituting L-methionine for the L-valine in the procedure of Example 22, and th,en treating the product by the procedure of Example 23, N-~3-acetylthio-2-methyl-propanoyl)-L-methionine and N-(3-mercapto-2-methylpro-panoyl)-L-methionine are obtained.

' ` ~119~7q Example 31 N-(3-Mercapto-2-methylpropanoyl)-N-methyl-L-phenylalanine By substituting N-methyl-L,phenylal ~ ne for the L,valine in the procedure of Example 22, and then treating the product by the procedure of Example 23, N-(3-acetylthio-2-methyl-propanoyl)-N-methyl-L-phenylalanine and N-(3-mercapto-2-methylpropanoyl)-N-methyl-L-phenylalanine are obtained.
~ ExamPle 32 ; 3-Acetylth1o-2-benzy1propanoic acid chloride 2-Benzylacrylic acid (8.1 g.) and thiolacetic acid (5.3 g.) are mixed and heated on the steam bath for one hour. After cooling to room temperature, thionyl chloride (9.75 g.) is added and the mixture is stored overnight at room temperature. The excess thionyl chloride is removed in vacuo and the residue is distilled to obtain 3-acetylthio-2-benzylpropanoic acid chlorlde bo o5:120-122 .
Example 33 -N -(3-Acetylthio-2-benzylpropanoyl)-L-arginine By substituting 3-acetylthio-2-benzylpropanoic acid chloride for the 3-acetylthio-2-methylpropanoic acid chloride in the procedure of Example 20, N -(3-acetylthio-2-benzyl-propanoyl)-L-arginine, m.p. 253-295 , is obtained.
Example 34 _-(3-mercapto-2-benzylpropanoyl)-L-arginine By substituting N -(3-acetylthio-2-benzylpropanoyl)-L-arginine for the N -(3-acetylthio-2-methylpropanoyl)-L-arginine in the procedure of Example 21, N -(3-mercapto-2-benzylpropanoyl)-L-arginine, m.p. 135 , is obtained.
Examples 35 - 48 By substituting the amino acid of column I for ~7 ~ HA136 the L-alanine and chloroacetyl chloride for the 3-bromo-propionyl chloride in the procedure of Example 1, then treating the product by the procedure of Example 22, the compounds of column II are obtained.
Example I II
Glycine N-2-Mercaptoacetylglycine 36 L-Alanine N-2-Mercaptoacetyl-L-alanine 37 L-Valine N-2-Mercaptoacetyl-L-valine 38 L-Leucine N-2-Mercaptoacetyl-L-leucine 39 L-Serine N-2-Mercaptoacetyl-L-serine L-Asparagine N-2-Mercaptoacetyl-L-asparagine 41 N -Boc-L-Lysine N -2-Mercaptoacetyl-N -Boc-L-lysine 42 L-Histidine N-2-Mercaptoacetyl-L-histidine 43 L-Phenylalanine N-2-Mercaptoacetyl-L-phenylalanine 44 L-T~yptophane N-2-Mercaptoacetyl-L-tryptophane L-Cysteine N-2-Mercaptoacetyl-L-cysteine 46 L-Methionine N-2-Mercaptoacetyl-L-methionine 47 Sarcosine N-2-Mercaptoacetylsarcosine 48 N-Methyl-L-Leucine N-2-Mercaptoacetyl-N-Methyl-lrleucine Example 49 N-2-Mercaptoacetyl-L-lysine By treating N -2-mercaptoacetyl-N -Boc-L-lysine with trifluoroacetic acid at room temperature for 15 minutes, Na-2-mercaptoacetyl-L-lysine is obtained.
Example 50 N -2-Mercaptoacetyl-L-arginine By substituting chloroacetyl chloride for the 3-bromopropionyl chloride in the procedure of Example 7, and treating the product by the procedure of Example 8, N -2-benzoylthioacetyl-L-arginine and N -2-mercaptoacetyl-L-1119~77 HAl36 arginine are obtained.

Examples 51 - 64 ` By substituting the amino acid of column I for the '- L-alanine and 2-bromopropionyl chloride for the 3-bromo- -propionyl chloride in the procedure of Example l, then treating the product by the procedure of Example 2, the compounds of column II are obtained.
Example I II
51 Glycine N-2-Mercaptopropanoylglycine 52 L-Alanine N-2-Mercaptopropanoyl-L-alanine 53 L-Valine N-2-Mercaptopropanoyl-L-valine 54 L-Leucine N-2-Mercaptopropanoyl-L-leucine L-Serine N-2-Mercaptopropanoyl-L,serine 56 L-Glutamine N-2-Mercaptopropanoyl-L-glutamine 57 N -Boc-L-Lysine N -2-MercapOcprqyL~l-N -Boc-lysine 58 L-Histidine N-2-Mercaptopropanoyl-L,histidine 59 L-Phenylalanine N-2-Mercaptopropanoyl-L,phenylalanine L-Tryptophane N-2-Mercaptopropanoyl-L-tryptophane 61 L-Cysteine N-2-Mercaptopropanoyl-L-cysteine 62 L-Methionine N-2-Mercaptopr~noyl-L-methionine 63 Sarcosine N-2-Mercaptopropanoylsarcosine 64 N-Methyl-L-Phenylalanine N-2-Mercaptopropanoyl-N-methyl-L-, phenylalanine i Example 65 , ~
~ N -2-Mercaptopropanoyl-L-lysine , .
By treating N -2-mercaptopropanOyl- N -Boc-L-lysine with trifluoroacetic acid at room temperature for 15 minutes, N -2-mercaptopropanoyl- L-lysine is obtained.

.

- ~

Example 66 N~-2-Mercaptopropanoyl-L-arginine By substituting 2-bromopropionyl chloride for the 3-bromopropionyl chloride in the procedure of Example 7 and then treating the product by the procedure of Example 8, N~-2-benzoylthiopropanoyl-L-arginine and N -2-mercapto-propanoyl-L-arginine are obtained.
Example 67 Na-4-Mercaptobutanoyl-L-arginine _ By substituting 4-chlorobutyryl chloride for the 3-bromopropionyl chloride in the procedure of Example 7, and then treating the product by the procedure of Example 8, N~-4-benzoylthiobutanoyl-L-arginine and N~-4-mercaptobutanoyl-L-arginine are obtained.
The racemic forms of the final products in each of the foregoing examples are produced by utilizing the DL-form of the startingamino acid instead of the L-form.
Similarly the D-form of the final products in each of the foregoing examples is produced by utilizing the D-form of the starting amino acid instead of the L-form.
Example 68 N~,N~ -[Dithio-3,3'-bis(2-methylpropanoyl)]-bis-L-arginine N~-(3-mercapto-2-methylpropanoyl)-L-arginine is dissolved in water and the pH is adjusted to 7 with N sodium hydroxide. A 0.5 M iodine solution in 95~ ethanol is added dropwise while maintaining the pH between 6 and 7 by careful addition of N sodium hydroxide. When a permanent (5 minutes) yellow color is formed, the solution of iodine is stopped, the color is discharged by addition of sodium thiosulfate and the solution is concentrated to 1/10 of ~;

~ 77 HA136 the original volume in vacuo. The resulting solution is applied to a column of ion exchange resin Dowex 50 and the N -N -ldithio-3,3'-bis(2-methylpropanoyl)]-bis-L-arginine is eluted with pyridine acetate buffer, pH 6.5.
Example 69 N-N'-tDithio-3,3'-bis[2-methylpropanoyl)]-bis-L-valine N-(3-mercapto-2-methylpropanoyl)-L-valine is dissolved in water and the pH is adjusted to 7 with N-sodium hydroxide.
A 0.5 M iodine solution in 95% ethanol is added dropwise while maintaining the pH between 6 and 7 by careful addition of N-sodium hydroxide. When a permanent (5 minutes) yellow color is obtained, the addition of iodine is discontinued and the yellow color is discharged with sodium thiosulfate.
The aqueous alcoholic solution is acidified with N
hydrochloric acid and the N-N'-[dithio-3,3-bis-(2-methyl-propanoyl)]-bis-L-valine is extracted with ethyl acetate.
E~le 70 N-(3-r~ercaptopropanoyl)-N-benzylglycine By substituting N-benzylglycine for the L-alanine in the procedure of Example 1, and then treating the product by the procedure of Example 2, N-(3-benzoylthiopropanoyl)-N~
benzylglycine and N-(3-mercaptopropanoyl)-N-benzylglycine are obtained.
Example 71 N-(3-Mercaptopropanoyl)-N-benzyl-L-leucine By substituting N-benzyl-L-leucine for the L-alanine in the procedure of Example 1, and then treating the product by the procedure of Example 2, N-(3-benzoylthiopropanoyl)-N-benæyl-L-leucine and N-(3-mercaptopropanoyl)-N-benzyl-L-leucine are obtained.

-- .

~9~7q HA136 .
N-(3-Mercaptopro~anoyl ? -L-aspartic acid ~ y substituting L-aspartic acid for L-alanlne in the pro-cedure of Example l, and then treating the product by the procedure of Example 2, N-(3-benzoylthiopropanoyl)-L-aspartic acid ~nd N-(3-mercaptopropanoyl)-L-aspartic acid are obt`ained.
Example 73 lOO0 tablets each containing lO0 mg. of N-(3-mercaptopropanoyl)-L-phenylalanine are produced from the following ingredients:
N-(3-mercaptopropanoyl)-L-phenyl-alanine lO0 g.
Corn starch 50 g.
Gelatin 7.5 g.
Avicel (microcrystalline cellulose) 25 g.
Magnesium stearate 2.5 g.
The N-(3-mercaptopropanoyl)-L-phenylalanine and corn starch are admixed with an aqueous solution of the gelatin. The mixture is dried and ground to a fine powder.

The Avicel and then the magnesium stearate are admixed with , . the granulation. This is then compressed in a tablet press to form 1000 tablets each containing 100 mg. of active ~ ingredient.
L Example 74 1000 tablets each containing 200 mg. of N-2-mercapto-propanoylglycine are produced from the following ingredients:
N-2-mercaptopropanoylglycine 200 g.
Lactose 100 g.
- Avicel 150 g.
,i 10 Corn starch 50~ g Magnesium stearate 5 g.
The N-2-mercaptopropanoylglycine, lactose and ;
Avicel are admixed, then blended with the corn starch.
Magnesium stearate is added. The dry mixture is compressed , in a tablet press to form 1000 505 mg. tablets each tablet -- containing 200 mg. of active ingredient. The tablets are coated with a solution of Methocel E 15 (methyl cellulose) including as a color a lake containing yellow #6.
, Example 75 An injectable solution is produced as follows:
N-(3-mercaptopropanoyl)-L-phenyl-alanine 500 g.
Methyl paraben 5 g.
Propyl paraben 1 g.
Sodium chloride 25 g.
Water for injection qs. 5 ,~ The active substance, preservatives and sodium chloride are dissolved in 3 liters of water for injection and then the volume is brought up to 5 liters~ The solution is filtered through a sterile filter and aseptically filled into pre-;1 -77 HAl36 sterilized vials which are then closed with presterilized rubber closures. Each vial contains S ml. of solution in a concentration of 100 mg. of active ingredient per ml. of solution for injection.
Example 76 Although conversion of angiotensin I to angiotensin II
by angiotensin-converting enzyme is probably the reaction of most importance in the pathology of hypertension, the activity of the isolated enzyme is more conveniently and accurately assayed by measuring its rate of cleavage of a simpler peptide substrate, hippuryl-L-histidyl-L-leucine. For determination f I50 values (concentrations of compounds expressed in micrograms/ml producing a 50% inhibition of angiotensin-converting enzyme) various concentrations of each compound are added to 13 x 100 mm tubes along with the following components at the indicated final concentrations in a final volume of 0.25 ml: 100 mM potassium phosphate buffer, pH 8.3; 300 mM
sodium chloride; 5 mM hippuryl-L-histidyl-L-leucine; and

5 milliunits of angiotensin-converting enzyme of rabbit lung.

Controls containing no inhibitor (100% activity), and those acidified before addition of the enzyme (0% activity) are similarly prepared. All of the enzymatic reactions are initiated by addition of the enzyme component; tubes are incubated for 30 minutes at 37 C; and reactions are terminated by addition of 0.25 ml. of lN HCl. The hippuric acid formed by action of angiotensin-converting enzyme on hippuryl-L-histidyl-L-leucine is extracted into ethyl acetate, evaporated : to dryness, redissolved in water and quantitated from its absorbance at 228 nm. The percent inhibition by each con-centration of compound is calculatcd by comparison with the 0% and 100% activity controls. The concentrations of representative compounds of the present invention which inhibit activity of angiotension-converting enzyme by 50%
are shown in the following table:
Compound of Example I50(~g/ml) ;
2 1.'2 4 1.8 -: 6 0.86 8 0.17 1.8 2.0 51 2.6 Example 77 The procedure for evaluating the inhibition of :
angiotensin I converting enzyme in excised guinea pig ileum is carried out as follows: varying concentrations of the compound are added to an excised guinea pig ileum bath in Krebs solution at 37 , aerated with a mixture of 95% 2-5% CO2. After two minutes, angiotensin I (25 ng~ml) is added and the isotonic contractions are measured. The conc~tration of representative compounds of the present invention (in micrograms/ml) which inhibit the contractile activity of angiotensin I by 50~ (IC50) are shown in the following table:
Compound of Example IC50(~g/ml) ' 2 0.94 4 2.0

6 0.52 8 0.9 . . , , -~119177 Compounds of Example IC50(~g/ml) 4.5 34 4.1 51 2.0 Example 78 Representative compounds of the present invention are administered orally to unanesthet~ ed male rats of the Sprague-Dawley strain, weighing about 200 g., followed by an injection of 0.31 ~g/kg of angiotensin I. The following table indicates the degree of inhibition obtained.
Compound Dose No. of % maximum inhibition of of mg/kg animals angiotensin I pressor Example response + SE

2 34.2 + 6.7%
100 2 61.5 + 1.2%

51 10 2 29.9 + 3.1%
2 52.9 + 15.8%
100 2 64.9 + 12.3%
Example 79 Male rats of the CF Nelson strain are anesthetized with ether and each left renal artery is partially con~tricted with a silver clip (i.d. 0.22 mm). The right kidney and renal artery are left intact. This model, which is commonly designated as the "2-kidney Goldblatt renal hypertensive rat", has been considered typical of renin-angiotensin dependent hypertension [(Gavras, et al., Science 188, 1316 (1975)]. The abdominal aortas are cannulated 5 weeks after clipping the left renal artery.
One week after cannulation mean blood pressures and heart 11~9177 HA136 rates are recorded directly for 4-8 hours during which time the rats are dosed orally every 24 hours for two consecutive days with 300 mg. of the compound of Example 51.
~ The following table shows the lowering of blood pressure in s two different rats at th~ second dosage day.
Mean blood pressure mm Hg.
Rat # 9Rat # 10 Before drug administration 222 206 After drug administration 1 h 206 203 2 h 173 190 3 h 157 189 4 h 184 199 ;-5 h 206 195 6 h 199 197 ; When the same dose is administered orally to a normotensive rat no significant effects on blood pressure are observed. .

.: . :

Claims (56)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for preparing a compound of the formula (I) or a salt thereof, wherein n is 0, 1 or 2; and when n is 0, R1 is hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is hydrogen, lower alkan-oyl, benæoyl or and when n is 1, Rl is lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene or carboxyl lower alkyl; R2 and R3 each is hydrogen, lower alkyl or phenyl-lower alkylene; R4 is hydrogen; and R5 has the same meaning as hereinabove defined and when n is 2, R1 is hydrogen, lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkylmercapto-lower alky-lene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 has the same meaning as hereinabove de-fined, characterized by either (a) coupling an acid of the formula wherein R6 is lower alkyl or phenyl to an amino acid of the formula to form a compound of formula (I) wherein R5 is lower alkanoyl or benzoyl and n is 1 or (b) reacting a compound of the formula wherein X is halogen with a compound of the formula wherein R6 is lower alkyl or phenyl to form a compound of for-mula (I) wherein R5 is lower alkanoyl or benzoyl and optionally (c) subjecting said compound of formula (I) from (a) or (b) to ammonolysis to form a compound of formula (I) wherein R5 is hydrogen, and further optionally (d) oxidizing said compound of formula (I) from (c) wherein R5 is hydrogen, by treatment with an alcoholic sol-ution of iodine to form a compound of formula (I) wherein R5 is or (e) subjecting a compound of the formula wherein R5 is lower alkanoyl or benzoyl to ammonolysis to form a compound of formula (I) wherein R5 is hydrogen or (f) oxidizing a compound of the formula wherein R5 is hydrogen, by treatment with an alcoholic so-lution of iodine to form a compound of formula (I) wherein R5 is

2. A process for preparing a compound of the formula (I) or a salt thereof, wherein n is 0, 1 or 2; and when n is 0, R1 is hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is hydrogen, lower alkan-oyl, benzoyl or and when n is 1, R1 is lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkylmer-capto-lower alkylene, carbamoyl-lower alkylene or carboxyl lower alkyl; R2 and R3 each is hydrogen, lower alkyl or phenyl-lower alkylene; R4 is hydrogen; and R5 has the same meaning as hereinabove defined and when n is 2, R1 is hy-drogen, lower alkyl, phenyl lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alky-lene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkylmercapto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alky-lene; and R5 has the same meaning as hereinabove defined, characterized by either (a) coupling an acid of the formula wherein R6 is lower alkyl or phenyl to an amino acid of the formula to form a compound of formula (I) wherein R5 is lower al-kanoyl or benzoyl and n is 1 or (b) reacting a compound of the formula wherein X is halogen with a compound of the formula wherein R6 is lower alkyl or phenyl to form a compound of formula (I) wherein R5 is lower alkanoyl or benzoyl.

3. A process for preparing a compound of the for-mula (I) or a salt thereof, wherein n is 0, 1 or 2; and when n is 0, R1 is hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is hydrogen, lower alka-noyl, benzoyl or and when n is 1, R1 is lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene or carboxyl lower alkyl; R2 and R3 each is hydrogen, lower alkyl or phenyl-lower alkylene; R4 is hydrogen; and R5 has the same meaning as hereinabove defined and when n is 2, R1 is hydrogen, lower alkyl, phenyl lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alky-lene, mercapto-lower alkylene, lower alkylmercapto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 has the same meaning as hereinabove defined, characterized by either (a) coupling an acid of the formula wherein R6 is lower alkyl or phenyl to an amino acid of the formula to form a compound of formula (I) wherein R5 is lower alkanoyl or benzoyl and n is 1 or (b) reacting a compound of the formula wherein X is halogen with a compound of the formula wherein R6 is lower alkyl or phenyl to form a compound of for-mula (I) wherein R5 is lower alkanoyl or benzoyl and optionally (c) subjecting said compound of formula (I) from (a) or (b) to ammonolysis to form a compound of formula (I) wherein R5 is hydrogen.

4. A process for preparing a compound of the formula (I) or a salt thereof, wherein n is 0, 1 or 2; and when n is 0, R1 is hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is hydrogen, lower alkanoyl, benzoyl or and when n is 1, R1 is lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene or carboxyl lower alkyl; R2 and R3 each is hydrogen, lower alkyl or phenyl-lower alkylene; R4 is hydrogen; and R5 has the same meaning as hereinabove defined and when n is 2, R1 is hy-drogen, lower alkyl, phenyl lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alky-lene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkylmercapto-lower alky-lene, carbamoyl-lower alkylene, or carboxy lower alkyl;
R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 has the same meaning as hereinabove defined, characterized by either (a) coupling an acid of the formula wherein R6 is lower alkyl or phenyl to an amino acid of the formula to form a compound of formula (I) wherein R5 is lower al-kanoyl or benzoyl and n is 1 or (b) reacting a compound of the formula wherein X is halogen with a compound of the formula wherein R6 is lower alkyl or phenyl to form a compound of formula (I) wherein R5 is lower alkanoyl or benzoyl and optionally (c) subjecting said compound of formula (I) from (a) or (b) to ammonolysis to form a compound of for-mula (I) wherein R5 is hydrogen, and further optionally (d) oxidizing said compound of formula (I) from (c) wherein R5 is hydrogen, by treatment with an al-coholic solution of iodine to form a compound of formula (I) wherein R5 is

5. A process for preparing a compound of the for-mula or a salt thereof, wherein n is 0, 1 or 2; and when n is 0, R1 is hydroxy-lower alkylene, hydroxyphenyl-lower al-kylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and when n is 1, R1 is lower alkyl, phenyl-lower alkylene, hydroxy-lower al-kylene, hydroxyphenyl-lower alkylene, amino-lower alky-lene, guanidino-lower alkylene, indolyl-lower alkylene, mer-capto-lower alkylene, lower alkylmercapto-lower alkylene, carbamoyl-lower alkylene or carboxyl lower alkyl; R2 and R3 each is hydrogen, lower alkyl or phenyl-lower alkylene and R4 is hydrogen; and when n is 2, R1 is hydrogen, lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alky-lene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkylmercapto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; and R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene, characterized by sub-jecting a compound of the formula wherein R5 is lower alkanoyl or benzoyl to ammonolysis.

6. A process for preparing a compound of the formula or a salt thereof, wherein n is 0, 1 or 2; and when n is 0, R1 is hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is and when n is 1, R1 is lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower al-kylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene or carboxyl lower alkyl;
R2 and R3 each is hydrogen, lower alkyl or phenyl-lower alk-ylene; R4 is hydrogen and R5 has the same meaning as herein-above, and when n is 2, R1 is hydrogen, lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is as hereinabove defined, characterized by oxidizing a compound of the for-mula by treatment with an alcoholic solution of iodine.

7. The process according to claim 4 wherein n is 0, R1 is hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is hydrogen, lower alkan-oyl, benzoyl or

8. The process according to claim 4 wherein n is 1;
R1 is lower alkyl, phenyl-lower alkylene, hydroxy-lower al-kylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carba-moyl-lower alkylene or carboxyl lower alkyl; R2 and R3 each is hydrogen, lower alkyl or phenyl-lower alkylene; R4 is hydrogen; and R5 is hydrogen, lower alkanoyl, benzoyl or

9. The process according to claim 4 wherein n is 2;
R1 is hydrogen, lower alkyl, phenyl-lower alkylene, hyd-roxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is hydrogen, lower alkanoyl, benzoyl or

10. The process according to claim 4 wherein N-(3-bromopropanoyl)-L-alanine is reacted with thiobenzoic acid to form N-(3-benzoylthiopropanoyl)-L-alanine.

11. The process according to claim 4 wherein N-(3-bromopropanoyl)-L-leucine is reacted with thiobenzoic acid to form N-(3-benzoylthiopropanoyl)-L-leucine.

12. The process according to claim 4 wherein N-(3-bromopropanoyl)-L-phenylalanine is reacted with thioben-zoic acid to form N-(3benzoylthiopropanyl)-L-phenylalanine.

13. The process according to claim 4 wherein N-(3-bromopropanoyl)-L-arginine is reacted with thiobenzoic acid to form N-(3-benzoylthiopropanoyl)-L-arginine.

14. The process according to claim 4 wherein N-(3-bromopropanoyl)-sarcosine is reacted with thlobenzoic acid to form N-(3-benozylthiopropanoyl)sarcosine.

15. The process accoraing to claim 4 wherein 3-ace-tylthio-2-methylpropanoyl chloride is reacted with L-argi-nine to form N-(3-acetylthio-2-methylpropanoyl)-L-arginine.

16. The process according to claim 4 wherein 3-ace-tylthio-2-methylpropanoyl chloride is reacted with L-valine to form N-(3-acetylthio-2-methylpropanoyl)-L-valine.

17. The process according to claim 4 wherein 3-ace-tylthio-2-benzylpropanoic acid chloride is reacted with L-arginine to form N-(3-acetylthio-2-benzylpropanoyl)-L-ar-ginine.

18. The process according to claim 5 wherein n is 0, R1 is hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene.

19. The process as in claim 5 wherein n is 1; R1 is lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guani-dino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-carbamoyl-lower alkylene or carboxyl lower alkyl; R2 and R3 each is hydrogen, lower alkyl or phenyl-lower alkylene and R4 is hydrogen.

20. The process as in claim 5 wherein n is 2; R1 is hydrogen, lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alky-lene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene.

21. The process according to claim 5 wherein N-(3-benzoylthiopropanoyl)-L-alanine is subjected to ammonolysis to form N-(3-mercaptopropanoyl)-L-alanine.

22. The process according to claim 5 wherein N-(3-benzoylthiopropanoyl)-L-leucine is subjected to ammonolysis to form N-(3-mercaptopropanoyl)-L-leucine.

23. The process according to claim 5 wherein N-(3-benzoylthiopropanoyl)-L-phenylalanine is subjected to am-monolysis to form N-(3-mercaptopropanoyl)-L-phenylalanine.

24. The process according to claim 5 wherein N-(3-benzoylthiopropanoyl)-L-arginine is subjected to ammonoly-sis to form N-(3-mercaptopropanoyl)-L-arginine.

25. The process according to claim 5 wherein N-(3-benzoylthiopropanoyl)sarcosine is subjected to ammonolysis to form N-(3-mercaptopropanoyl)sarcosine.

26. The process according to claim 5 wherein N-(3-acetylthio-2-methylpropanoyl)-L-arginine is subjected to ammonolysis to form N-(3-mercapto-2-methylpropanoyl)-L-arginine.

27. The process according to claim 5 wherein N-(3-acetylthio-2-methylpropanoyl)-L-valine is subjected to am-monolysis to form N-(3-mercapto-2-methylpropanoyl)-L-valine.

28. The process according to claim 5 wherein N-(3-acetylthio-2-benzylpropanoyl)-L-arginine is subjected to ammonolysis to form N-(3-mercapto-2-benzylpropanoyl)-L-ar-ginine.

29. A compound of the formula (I) or a salt thereof, wherein n is 0, 1 or 2; and when n is 0, R1 is hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is hydrogen, lower alkan-oyl, benzoyl or and when n is 1, R1 is lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene or carboxyl lower alkyl; R2 and R3 each is hydrogen, lower alkyl or phenyl-lower alkylene; R4 is hydrogen; and R5 has the same meaning as hereinabove defined and when n is 2, R1 is hy-drogen, lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alky-lene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alky-lene; and R5 has the same meaning as hereinabove defined, whenever prepared by the process of claim 1.

30. A compound of the formula (I) or a salt thereof, wherein n is 0, 1 or 2; and when n is 0, R1 is hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is hydrogen, lower alkanoyl, benzoyl or and when n is 1, R1 is lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, ami-no-lower alkylene, guanidine-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene or carboxyl lower alkyl; R2 and R3 each is hydrogen, lower alkyl or phenyl-lower alkylene; R4 is hydrogen; and R5 has the same meaning as hereinabove defined and when n is 2, R1 is hydrogen, lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guani-dino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carba-moyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 has the same meaning as hereinabove defined, whenever prepared by the process of claim 2.

31. A compound of the formula (I) or a salt thereof, wherein n is 0, 1 or 2; and when n is 0, R1 is hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is hydrogen, lower alkanoyl, benzoyl or and when n is 1, R1 is lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower al-kylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene or carboxyl lower alkyl;
R2 and R3 each is hydrogen, lower alkyl or phenyl-lower al-kylene; R4 is hydrogen; and R5 has the same meaning as here-inabove defined and when n is 2, R1 is hydrogen, lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alky-lene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alky-lene, or carboxy lower alkyl; R2, R3 and R4 each is hydro-gen, lower alkyl or phenyl-lower alkylene; and R5 has the same meaning as hereinabove defined, whenever prepared by the process of claim 3.

32. A compound of the formula (I) or a salt thereof, wherein n is 0, 1 or 2; and when n is 0, R1 is hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is hydrogen, lower alkan-oyl, benzoyl or and when n is 1, R1 is lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower al-kylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene or carboxyl lower alkyl;
R2 and R3 each is hydrogen, lower alkyl or phenyl-lower al-kylene; R4 is hydrogen; and R5 has the same meaning as here-inabove defined and when n is 2, R1 is hydrogen, lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphe-nyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alky-lene, or carboxy lower alkyl; R2, R3 and R4 each is hydro-gen, lower alkyl or phenyl-lower alkylene; and R5 has the same meaning as hereinabove defined, whenever prepared by the process of claim 4.

33. A compound of the formula (I) or a salt thereof, wherein n is 0, 1 or 2; and when n is 0, R1 is hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and when n is 1, R1 is lower al-kyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydro-xyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower al-kylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene or carboxyl lower alkyl; R2 and R3 each is hydrogen, lower alkyl or phenyl-lower alkylene and R4 is hydrogen; and when n is 2, R1 is hydrogen, lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphe-nyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower al-kylene, or carhoxy lower alkyl; and R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene, whenever prepared by the process of claim 5.

34. A compound of the formula or a salt thereof, wherein n is 0, 1 or 2; and when n is 0, R1 is hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercap-to-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is and when n is 1, R1 is lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower al-kylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene or carboxyl lower alkyl;
R2 and R3 each is hydrogen, lower alkyl or phenyl-lower alkylene; R4 is hydrogen and R5 has the same meaning as here-inabove, and when n is 2, R1 is hydrogen, lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alky-lene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is as hereinabove de-fined, whenever prepared by the process of claim 6.

35. A compound as defined in claim 32, or a salt thereof, wherein n is 0, R1 is hydroxy-lower alkylene, hy-droxyphenyl-lower alkylene, amino-lower alkylene, guani-dino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is hydrogen, lower al-kanoyl, benzoyl or whenever prepared by the process of claim 7.

36. A compound as defined in claim 32, or a salt thereof, wherein n is 1; R1 is lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alky-lene, amino-lower alkylene, guanidino-lower alkylene, indol-yl-lower alkylene, mercapto-lower alkylene, lower alkyl-mer-capto-lower alkylene, carbamoyl-lower alkylene or carboxyl lower alkyl; R2 and R3 each is hydrogen, lower alkyl or phenyl-lower alkylene; R4 is hydrogen; and R5 is hydrogen, lower alkanoyl, benzoyl or whenever prepared by the process of claim 8.

37. A compound as defined in claim 32, or a salt thereof, wherein n is 2; R1 is hydrogen, lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxy-phenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower al-kylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene; and R5 is hydrogen, lower alkanoyl, benzoyl or whenever prepared by the process of claim 9.

38. A compound as defined in claim 32 having the name N-(3-benzoylthiopropanoyl)-L-alanine, whenever prepared by the process of claim 10.

39. A compound as defined in claim 32 having the name N-(3-benzoylthiopropanoyl)-L-leucine, whenever prepared by the process of claim 11.

40. A compound as defined in claim 32 having the name N-(3-benzoylthiopropanoyl)-L-phenylalanine, whenever prepared by the process of claim 12.

41. A compound as defined in claim 32 having the name N-(3-benzoylthiopropanoyl)-L-arginine, whenever prepared by the process of claim 13.

42. A compound as defined in claim 32 having the name N-(3-benzoylthiopropanoyl)sarcosine, whenever prepared by the process of claim 14.

43. A compound as defined in claim 32 having the name N-(3-acetylthio-2-methylpropanoyl)-L-arginine, whenever prepared by the process of claim 15.

44. A compound as defined in claim 32 having the name N-(3-acetylthio-2-methylpropanoyl)-L-valine, whenever prepared by the process of claim 16.

45. A compound as defined in claim 32 having the name N-(3-acetylthio-2-benzylpropanoyl)-L-arginine, whenever prepared by the process of claim 17.

46. A compound as defined in claim 33, or a salt thereof, wherein n is 0, R1 is hydroxy-lower alkylene, hy-droxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alky-lene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hy-drogen, lower alkyl, or phenyl-lower alkylene, whenever pre-pared by the process of claim 18.

47. A compound as defined in claim 33, or a salt thereof, wherein n is 1; R1 is lower alkyl, phenyl-lower al-kylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene or carboxyl lower alkyl;
R2 and R3 each is hydrogen, lower alkyl or phenyl-lower al-kylene; R4 is hydrogen, whenever prepared by the process of claim l9.

48. A compound as defined in claim 33, or salt thereof, wherein n is 2; R1 is hydrogen, lower alkyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alky-lene, indolyl-lower alkylene, mercapto-lower alkylene, lower alkyl-mercapto-lower alkylene, carbamoyl-lower alkylene, or carboxy lower alkyl; R2, R3 and R4 each is hydrogen, lower alkyl or phenyl-lower alkylene, whenever prepared by the pro-cess of claim 20.

49. A compound as defined in claim 33 having the name N-(3-mercaptopropanoyl)-L-alanine, whenever prepared by the process of claim 21.

50. A compound as defined in claim 33 having the name N-(3-mercaptopropanoyl)-L-leucine, whenever prepared by the process of claim 22.

51. A compound as defined in claim 33 having the name N-(3-mercaptopropanoyl)-L-phenylalanine, whenever prepared by the process of claim 23.

52. A compound as defined in claim 33 having the name N-(3-mercaptopropanoyl)-L-arginine, whenever prepared by the process of claim 24.

53. A compound as defined in claim 33 having the name N-(3-mercaptopropanoyl)sarcosine, whenever prepared by the process of claim 25.

54. A compound as defined in claim 33 having the name N-(3-mercapto-2-methylpropanoyl)-L-arginine, whenever pre-pared by the process of claim 26.

55. A compound as defined in claim 33 having the name N-(3-mercapto-2-methylpropanoyl)-L-valine, whenever prepared by the process of claim 27.

56. A compound as defined in claim 33 having the name N-(3-mercapto-2-benzylpropanoyl)-L-arginine, whenever pre-pared by the process of claim 28.