CA1271966A

CA1271966A - Aryl and aralkyl sulfonyl l-prolines

Info

Publication number: CA1271966A
Application number: CA000615516A
Authority: CA
Inventors: John Krapcho
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1983-04-25
Filing date: 1984-04-17
Publication date: 1990-07-24
Anticipated expiration: 2007-07-24
Also published as: CA1271966C; CA1266661A; CA1266661C

Abstract

ABSTRACT
This invention provides new aryl and aralkyl sulfonyl L-prolines of the formula wherein:
R is hydrogen or lower alkyl;
m is zero or an integer from 1 to 4;

R1 , a 1- or 2-naphthyl of the formula , or which are useful as intermediates in the preparation of new acyl mercaptoalkanoyl and mercaptoalkanoyl derivatives of aryl and aralkyl sulfonyl prolines of the formula IMG>
which possess angiotensin converting enzyme inhibition activity and thus are useful as anti-hypertensive agents.

Description

~ b ARYL AND ARALKYL SULFONYL L-PROLINES

This invention relates to new acylmercaptoalkanoyl and mercaptoalkanoyl derivatlves of aryl and aralkyl sulfinyl or sulfonyl prolines of the formula (I) ()n S--(CH2)m-R
3 ~
I 11 r ~

and pharmaceutically accep~able salts thereof.
R is hydrogen, lower alkyl, or a salt forming ion.
n is one or two.
m is zero or an integer from 1 to 4.

Rl is ~ , a 1- or 2-naphthyl of the formula ~ R2 or biphenyl.

R2 i5 hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, acetyloxy, or hydroxy. The hydroxy substituted compounds are obtained by hydrolysis of the corresponding acetyloxy compound as ~he last step in the synthetic procedure.
R3 is hydrogen, lower alkyl, or trifluoromethyl.

1~7~36~

HA~85

-2-R4 is hydrogen or R5-C- .

R5 i5 lower alkyl, -(CH2)p ~ , -(CH2) ~ , -(CH2~ ~ , or - (CH2) j~) N

p is zerb or an integer from 1 to 4.

This invention in its broadest aspects relates to the .substituted proline compounds of formula I above, to compositions containing such compounds and to the method of using ~uch compounds a~ anti-h.ypertensive agents.
The term lower alkyl represents straight or branched chain hydroca.rbon radicals having up to seven carbons, for exampie, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, etc. The preferred lower alkyl groups are up to four carbons with methyl and ethyl being most preferred. Similarly, the term lower alkoxy represents such lowex alkyl groupq bonded to an oxygen.

1~7~

The symbols -(CHz)p ~ ~ -(CH2)pt o ~

and -~C~2)p ~ represent that the alkylene bridge is attached to an available carbon atom.

Ondetti et al. in U.S. Pa~ent 4,105,776 disclose that various acylmercaptoalkanoyl and mercaptoalkanoyl derivatives of proline, hydroxy substituted proline, and alkyl substituted proline possess angiotensin converting enzyme inhibition activity and thus are useful as anti-hypertension agents.
Ondetti et al. in U.S. Patent 4,316,906 discloses that various acylmercaptoalkanoyl and mercaptoalkanoyl derivatives of various ether and thioether 3- or 4-substituted prolines also possess angiotensin converting enzyme inhibition activity. ~nong the compounds disclosed by Ondetti et al. are arylthio and aralkylthio 4-substituted prolines.

' ~.; ~.. ;
.
, -'': '` . .

7~L~6~i The compounds of formula I can be prepared as follows. The 4-substituted proline of the formula (II) ' ( 2)m ~J~

HN ¦ COOR
H(L) is coupled with an acid o~ its chemical equivalent of the formula (III) Il I

to yield the compound of the formula ;' ~.

. HA285 S--(IV) 2 m Il I ll I
R5~C-CH2-CH- C - N - COOR
H

This reaction can be performed in the presence of a coupling agent such as dicyclohexyl-carbodiimide or the like, or by conversion Or the acid of formula III to its mixed anhydride, symmetrical anhydride, acid halide, active ester or by use of Woodward reagent K, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline or the like. For a review of the methods of acylation see Methoden der Organishchen Chemie (Houben-Weyl), Vol. XV, part II, page 1 et seq. (1974). Preferably, the acid halide, especially the acid chloride, of formula III is reacted with the acid of formula II.
Oxidation of the compound of formula IV, for example, with.sodium metaperiodate yields the sulfinyl compound of the formula ,"';: '' , (V) o Il ( 2)m P
R5-C-S-CH2-CH- C - N _ (L)COOR
H
Similarly, oxidation of the compound of formula IV, for example, with two equivalents of hydrogen peroxide or metachloroperbenzoic acid yields the sulfonyl compound of the formula (VI) O O
( 2)m o R3 R5-C-S-CH2-CH - C - - N - ~ COOR
(L) H

Hydrolysis or ammonolysis of the compounds of formula V or VI yields the corresponding suIfinyl or sulfonyl compounds wherein R4 is hydrogen.
Also, the suIfinyl and sulfonyl products of formula I wherein R4 is hydrogen can be acylated with an acid halide, preferably acid ~L~7~

chloride, o~ the formula (VII) o R5-C-Cl to yield products having other RS-C- groups.
The sulfonyl products of formula I can - also be prepared as follows. An N-protected proline of the formula (VIII) I ( ~)m R

Prot-N - COOR
(L) H
wherein Prot i5 a group such as benzyloxycarbonyl, is oxidized, ~or example, by treatment with hydrogen peroxide or metachloroperbenzoic acid to give tha N-protected sulfonyl proline of the formula tIX) O O

tC~z)m R

Prot-N COOR
(L) [

9~

Removal of the N-protecting group by treatment with hydrogen bromide followed by coupling with the acid of formula III or its chemical equivalent yields the suIfonyl compound of S formula VI.
The esters of formula I wherein R is lower alkyl can be obtained from the carboxylic acid compounds, i.e., wherein R is hydrogen, by conventional esterification procedures, e. g., by esterification with a diazoalkane such as diazomethane, l-alXyl-3-p-tolyltriazine such as l-n-butyl 3-p-tolyltria~ine, or the like. The esters can also be obtained by treating the acid with an alcohol of the formula R-OH in the presence of a Lewis acid such as sulfuric acid, boron trifluoride, etc., at room temperature.
If the compounds of formuIa I are obtained in the ester ~orm they can be converted to the carboxylic acid by conventional means. For example, if R is t-butyl treatment with trifluoro-acetic acid and anisole gives the carboxylic acid compound, i.e., R is hydrogen.
The compounds o ormula I wherein R3 is other than hydrogen contain an asymmetric center.
These compounds can accordingly exist in stereoisomeric forms or as racemic mixtures thereof. The synthesis described below can utilize the racemate or one of the enantiomers as starting materials. When the racemic starting material is used in tha synthesis, the 6~

_g stereoisomers obtained in the final product can be separated by conventional chromatographic or fractional crystallization procedures.
(0)~
The -S-(C~2)m-Rl substituent on the L-proline ring also gives rise to isomers referred to as a- and ~-.
Preferably, if there is an asymmetric center in the acylmercaptoalkanoyl or mercapto-alkanoyl sidechain it is in the D-configuration.
The compounds of this invention form basic salts with various inorganic and organic bases which are also ~ithin the scope of the invention.
Such salts include ammonium salts, alkali metal salts like lithium, sodium and potassium salts (which are preferred), alkaline earth metal salts like calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salt, l-adamantanamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, salts with amino acids like arginine, lysine and the like. The non-toxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g~, in isolating or purifying the product.
The salts are formed using conventional techniques.
Preferred compounds of this invention are those of formula I wherein:
R is hydrogen or an alkali metal ion;

Rl is ~ R2 wherei~ R2 is hydrogen, .

. HA285 methyl, methoxy, chloro or fluoro, especially hydrogen;
m is zero, one or two, especially zero;
R3 is methyl; and R4 is hydrogen, ll or H C C-o ~C- .

The comp~unds of formula I, and the pharmaceutically and physiologically acceptable salts thereof, are hypotensive agents. They inhibit the conversion of the decapeptide angio-tensin I to angiotensin II and, therefore, are useful in reducing or relieving angiotensin related hypertension. The action of the enzyme renin on angiotensin, a pseudoglobulin in blood plasma, produces angiotensin I. Angiotensin I is converted by angiotensin converting enzyme (ACE) to angiotensin II. The latter is an active pressor substance which has been implicated as the causative agent in several forms of hypertension in various man~alian species, e.g., humans. The compounds of this invention intervene in the angiotensin ~ (renin) -~ angiotensin I ~ -angiotensin II sequence by inhibiting angiotensin converting enzyme and reducing or eliminating

3~ the formation of the pressor substance angioten~in II. Thus by the administration of a composition containing one (or a combination) of the compounds of this invention, angiotensin dependent hypertension in a species of mammal (e.g., humans) suffering therefrom is alleviated. A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to 100 mg. per kilogram of body weight per day is appropriate to reduce blood pressure. The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, intravenous or intraperitoneal routes can also be employed.
The compounds of this invention can also be formuIated in combination with a diuretic for the treatment of hypertension. A combination product comprising a compound of this invention and a diuretic can be administered in an effective amount which comprises a total daily dosage of about 30 to 600 mg., preferably about 30 to 330 mg. of a compound of this invention, and about 15 to 300 mg., preferably about 15 to 200 mg. of the diuretic, to a mammalian species in need thereof. Exemplary of the diuretics contemplated for use in combination with a compound of this invention are the thiazide diuretics, e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydro-flumethiazide, bendroflumethiazide, methyclothia-zide, trichlormethiazide, polythiazide or .. ....

. .

1~7~6tj ~2-benzthiazide as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds.
S The compounds of formula I can be formulated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration, or in sterile solutions or suspensions for parenteral administration. About 10 to 500 mg. of a compound of formula I is compounded with physiologicallylacceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, e~c., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
The following examples are illustrative of the invention. Temperatures are given in degrees centigrade.

~L~7~96~

Example 1 [l(S),4S~ 3-Merca~o-2-meth~ oxopropyl)-4 (phenylsulfinyl)-L-Proline a) [l(S),4S]-1-[3-(Acetylthio)-2-methyl-1-S oxopropy~-4-(ph n ~ ne A s~irred cooled solution of [l(S~,4S]-l-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-(phenylthio)-L-proline (2.0 g., 5.4 mmole;
prepared as set forth in Example 58 (d) of U.S. Patent 4,316,906~ in 29 ml. of methanol is treated portionwise with sodium metaperiodate (1.4 g., 6.5 mmole) dissolved in 12 ml. of water. The materials remain in solution. The cooling bath is removed and after a few minutes solid sodium iodate begins to separate. After stirring overnight at room temperature (mixture has dar]cened to a reddish-orange color), the solid is filtered off, washed with methanol, and the combined filtrates are concentrated on a rotary evaporator to r~move the bulk of methanol.
The residue is shaken with 80 ml. of ethyl acetate and 20 ml. o~ water, the layers are separated, and the organic ~hase is washed with water (2 x 20 ml.). After back-extracting the combined aqueous layers with 20 ml. of ethyl acetate, the combined organic phases are dried (MgSO~), filtered, and the solvent evaporated to give 1.55 g. of a pale yellow brittle foam.

: .
.

.

This material is dissolved in 15 ml. of ethyl acetate and treated with 0.8 g. of dicyclo-hexylamine to give 2.1 g. of colorless [l(S),4S]-1-[3-(acetyl~hio)~2-methyl-1-oxopropyl]-4-(phenylsulfinyl)-L-proline, dicyclohexylamine salt; m.p. 192-194 (s. 189). [a]DS = -70 (c - 1.0, methanol). This salt is combined with 0.45 g. from a different experiment a~d crystallized from 25 ml. of boiling isopropanol to give 2.05 g. of dicyclohexylamine salt;
m.p. 198-200 (s. 194). [a]25 = -71 (c = 1.0, methanol). A sample recrystallized from ethanol melts at 198-200 (s, 194).
[a]D = -72 (c = 1.0, methanol).
17 21 5 2 C12H23 :
C, 61.67; H, 7.85; N, 4.96; S, 11.3i Found: C, 61.34; H, 7.78; N, 4.97; S, ll.G .
This dicyclohexylamine salt (1.9 g.) is treated with 30 ml. of 10~ potassium bisuIfate and extracted into ethyl acetate to give 1.3 g.
of [l(S),4S]-l-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-(phenylsulfinyl)-L-proline as a colorless amorphous solid. [a]25 = -103 ( c = 1 . n, ethanol).

C, 52.02; H, 5.65; N, 3.57; S, 16.34 Found: C, 52.01; ~, 5.58; N, 3.67; S, 16.07.

- 1~7~6~
~ HA285 ~5- , b) [l(S),4S]-1-(3-Mercapto-2-methyl-1-oxo-~ropyl)-4-(phenylsulfinyl)-L-proline The [l(S),4S]-1-[3-(acetylthio)-2-methyl-l-oxopropyl]-4-(phenylsulfinyl)-L-proline from part (a) (1.3 g., 3.4 mmole) is hydrolyzed by treatment with 2.5 ml. of concentrated ammonia in 6 ml. of water for one hour according to the procedure of Example 2 in U.S. Paten~

4,316,906 to yield 1.05 g. of [l(S),4S]-l-(3-mercapto-2-methyl-1-oxopropyl)-4-(phenylsulfinyl~-L-proline as a colorless feathery solid (residue from ethyl acetate is rubbed under ether and evaporation repeated); m.p. 47-50 (s. approxi-mately 37o) [~]25 = -67 (c = 1.0, ethanol). Rf 0.37 (silica gel;dichloromethane/methanol/acetic acid:
90:5:5)-15 19 4S2 0.5 H2O:
C, 51.40; H, 5.75; N, 4.00; S, 18.23 Found:C, 51.75; H, 5.72; N, 4.08; S, 17.89.
Treatment with l-adamantanamine in ethyl ac~tate yields [l(S),4S]-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(phenylsulfinyl)-L-proline, 1-adamantanamine qalt; m.p. 193-195~ (dec.).
Anal- calc'd- for C15H19N4S2 ClO 17 2 C, 60.39; H, 7.40; N, 5.64; S, 12.90 Found: C, 60.37, H, 7.40; N, 5.67; S, 13.08.

, , ,: . .
' ,'` , ~
. ~ .
.. .. .
- .; : .
:., , ~.

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Examples 2 - 18 Following the procedure of Example 1 the acylmercaptoalkanoyl-4-(arylthio or aralkyl-thio)-L-proline shown i~ Col. l is oxidized to ~he sulfinyl compound shown in Col. II.
Treakment with concentrated ammonia yields the mercaptoalkanoyl compound shown in Col. III.

Col. I

S- (CH2)m~Rl O R O
ll 13 ~ I
R5-C-S-CH2-CH- C - N _ - COOH
(L) Col. II
o (CH2)m O R O
~13 P

5 2 C C N COOH
(L) 1~7~

Col. III

2 ) m r (L) , . "
:, : ~ . :

~ : '' '`'" :

6~

Ex. Rl m R3 R5 2 ~ zero -CH

3 ~ Cl zaro -c~3 -CH3 4 ~ F zerO -CH3 -C2H5 ~ 3 zero -CH3 -CH3 6 ~ OCH3 -CH3 -CH3

7 ~ one -CH3 -CH3

8 ~ F two -H -c~3 ~ H3 three -CH3 -CH3 ~ ~our -CH3 -C~3 11 ~ CF3 zero -CF3 -CH3 12 ~ ~ zero -CH3 -CH3 13 ~ F one -CH

14 ~ two -CH3 -(CH2) -- " .

': ~
. ~ .,.;, .

: ~
. ;"

Ex. Rl m R3 R5 15 _~ zero -CH3 ~ (CH2 ) 2 ~ON

16 ~ zero -CH3 -C~3 lû 17` ~ one -C~3 18 _~ three -c~3 -C~12~

Similarly, by employing two equivalents of hydrogen peroxide in place of the sodium metaperiodate in the procedure of Examples 1 to 18, the corresponding sulfonyl compounds would be obtained.
Exa_ple 19 [l(S?L4S]-l-t3-Mercapto-2- ethyl-1-oxopropyl) 4-~phenylsu'fonyl)-L-proline a) N-Carbobenz~loxy-cis-4-~phenylsulfonyl)-L-proline A stirred solution of N-carbobenzyloxy-cis-4-(phenylthio)-L-proline (8.2 g., 23 mmole;
prepared as set foxth in Example 58 (b) of U.S. Patent 4,316,906) in 95 ml. of acetic acid is treated portionwise with 30% hydrogen peroxide (15.6 g., 140 mmole). The temperature ,, ., .: ~, ~0-drops from 26 to 24 then gradually rises to 30. After standing overnight at room temperature, the solution is concentrated to approximately 50% of its volume on a rotary evaporator at 0.2 mm. (water bath temperature less than 30). The residue is diluted with 300 ml. of dichloromethane, washed with water (3 x 100 ml.), a~d after back-extracting the combined washes with 100 ml. of dichloro-methane, the combined organic layers are dried (MgSO4) and evaporated, finally at 0.2 mm., to give 8.0 g. of N-carbobenzyloxy-cis-4-(~henyl-suIfonyl)-L-proline as a colorless brittle foam.
The above N-carbobenzyloxy-cis-4-(phenyl-sulfonyl)-L-proline is dissolved in 60 ml. of ethyl acetate and treated with 3.1 g. of l-adamantanamine to precipitate, after cooling overnight, 10.2 g. of N-carbobenzyloxy-cis-4-(phenylsulfonyl)-L-proline, l-adamantanamine salt;
m.p. 225-227 (dec.). ~a]DS = - 31 (c = 1.0, methanol). A sample stirred with boiling ethanol and cooled shows no change in m.p. or ~a]D .
19 19 6 Clo 17 C, 64.42; H, 6.71; N, 5.18; S, 5.98 Found: C, 64.57; H, 6.96; N, 5.18; S, 5.68.

., .

6~

This l-adamantanamine salt (3.0 g.) is suspended in 15 ml. of ethyl acetate, stirred, and treated with 8 ml. of N hydrochloric acid~
When two clear layers are obtained, they are separated and the aqueous phase is extracted with additional ethyl acetate (3 x 15 ml.).
The combined organic layers are dried (MgSO4) and the solvent evaporated to give 2.3 g. of N-carbobenzyloxy-cis-4-(phenylsuIfonyl)-L-proline as a colorless sticky foam.
b) cis-4-(Phenylsulfonyl)-L-prollne, hxdrobromide The above N-carbobenzyloxy-cis-4-(phenylsulfonyl)-L-proline (2.0 g., 5 mmole) is treated with 10 ml. of hydrogen bromide in acetic acid (30-32%), stoppered loosely, and swirled to obtain a yellow-orange solution.
After 30 minutes, the solution is diluted with several volumes of ether to precipitate an oil which crystallizes on rubbing. Following cooling for one hour, the colorless solid is filtered under nitrogen, washed with ether, and dried ln~vacuo to give 1.6 g. of cis-4-(phenylsulfonyl)-L-proline, hydrobromide; m.p.
200-202 (s 195). [a]2 = +7o (c = 1.0, methanol).
A~al- calc'd. for CllH13N04S HBr C, 39.29; H, 4.20; N, 4.17; S, 9.54;
Br, 23.77 Found: C, 39.12; H, 4.13; N, 4.13; 5, 9.51;
~r, 23.69.

''; ' ~'~7~9~i c) [l(S),4S]-1-[3-(Acetylthlo)-2-methyl-1-oxoPropy1]-4-(phenylsulfonyl)-L-proline Interaction of cis-4-(phenylsulfonyl)-- L-proline, hydrobromide (3.1 g., 9.2 mmole) and D-3-acetylthio-2-methylpropionyl chloride (2.0 g., 11 mmole) in 40 ml. of water in the presence of sodium carbonate according to the procedure of Example l(d) of U.S. Patent 4,316,906 (using approximately 13 ml. of 20%
sodium carbonate solution to maintain the pH
at 8.0 to 8.4) yields 3.7 g. of a colorless s-ticky product.' The dicyclohe~ylamine salt (prepared in 30 ml. of ethyl acetate employing 1.7 g~ of dicyclohexylamine) weighs 4.3 g.i m.p. 235-237~ (dec.) (s. 225). [~]D = -71 (c = 1.0, methanol). Following trituration with 20 ml. of acetonitrile one obtains 4.0 g.
of colorless solid dicyclohexylamine salt;
m.p. 236-238 (dec.) (s. 228). [~]25 = -71 (c - 1.0, methanol).
Anal- calc'd- ~or C17~I21N6S2 C12H23~
C, 59.97 H, 7.64 N, 4.82 S, 11.04 Found: C, 59.87; H, 7.71; N, 4.71; S, 10.87.
This dicyclohexylamine salt is treated with 50 ml. of 10% potassium bisulfate and extracted into ethyl acetate to yield 2.8 g.
of ~l(S),4S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-(phenylsulfonyl)-L-proline as a colorless amorphous solid; m.p. 55-58.

, ~L~71~

Rf 0.03 (silica gel;toluene/acetic acid; 85:15);
Rf 0.30 (sillca gel; dichloromethane/
methanol/acetic acid; 90:5:5).
d) _[l(S),4S]-1-(3-Merca~to-_-methYl-l-oxopro~yl)-4-(phenylsu-lfonyl)-L-prol _e The above [l(S~,4S]-1-[3-(acetylthlo)-2-methyl-l-oxopropyl]-4-(phenylsulfonyl)-L-proline (2.8 g., 7.0 mmole) is hydrolyzed with 5 ml. of concentrated ammonia in 12 ml. of water over a period of one hour according to the procedure of Example 2 in U.S. Patent 4,316,906 to yield 2.5 g. of [l(S)~,4S]-1-(3-mercapto-2-methyl-l-oxopropyl)-4-(phenylsulfonyl)-L-proline as a color-less feathery amorphous solid; m.p. 59-62 (s. 50)-[~]D = -64 (c = l.0, ethanol). Rf 0.24 (silica gel; dichloromethanetmethanol/acetic acid;
90:5:5).
Anal. calc~d. for C15H19N5S2 25H2 C, 49.77; H, 5.43; N, 3.87; S, 17.72 Found: C, 49.62; H, 5.58; N, 3.92; S, 17.40.
Examples 20 - 30 Following the procedure of Example 19 but employing the N-protected proline shown in Col. I one obtains, after oxidation with ~5 2 equivalents of hydrogen peroxide and removal of the protecting group, the suIfonyl substituted proline shown in Col. II. Coupling with the acid chloride (or other acid activated form) of Col. III yields the acylmercaptoalkanoyl product of Col. IV. Hydrolysis wi~h concen~rated ..'' :, ' ~

~;~7~
~A285 ammonia gives the mercaptoalkanoyl product of Col. V.

Col. I
. _ S- ( CH2 ) m~Rl CH2-O-C - N ¦ COOH
~(L) Col. II

~ 2)m ,~
HN ¦ COOH
(L) Col. _II

O R O
1 13 1~
R5-C-S-C~I2-CH__C--Cl ~.~7~6~

Co l . IV

O O

2 m O ~ O ~
ll 1 3 11 ~ 1 R5 -C-S-CH2 CH--C ~N--tCOOH
H (L) Col. ~7 -O O

S-- (CH2)m-R
13 ~ ~

HS-CH2-CH--C--N - ¦ COOH
H (L) L9~

~x. Rl m R3 5 20. ~ zero -CH

21 ~ Cl one -CH3 -CH3 22 ~ F two -CH

23 _ ~ - CH3 zero -CH

24 ~ OCH3 one -CH3 -CH3 ~ four -CH3 -CH3 26 ~ ~ three -CH3 -CH3 O
27 ~ O-C-CH zero -H -c~3 28 ~ one . CF -CH3 Ex. Rl m R3R5 29 ~ two -C2H5 N

~--Cl zero C~I3 _~3 1;~7~ 6 ~ 28-Example 31 [l(S),4S]~ 3-Mercap o _-methyl-l-oxopropyl~-4-.
tPhenvlsuIfinyl)-L-proli-n-e~ sodium salt An aqueous solution o~ the product from Example 1 i5 treated with sodium bicarbonate and lyophilized to give [l(S),4S]-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(phenylsulfinyl)-~-proline, ~odium salt.
Similarly, by ~mploying potassium bicarbonate in the above procedure, one obtains the corresponding oota~sium alt.
In an an~logous mannex, sodium or potassium 3alt~ of the product o~ Examples 2 to 30 can be prapared.
Example 32 1000 tablet3 each containing 100 mg.
of [l(S),4S]-1-(3-mercapto-2-methyl-1-oxooropyl)-4-(phenylsulfinyl)-L-proline, sodium salt are prepared containing the following ingredients:
~l~S),4S]-1-(3-Mercapto-2-methyl-l-oxopropyl)-4~
(phenylsul~inyl)-L-proline, 30dium salt 100 mg.
. Corn starch 50 mg.
Gelatin 7.5 mg.
A~icel (microcry~talline cellulo~Q) 25 mg.
Magnesium 3tearate 2.5 mq.
185 mg.

* Trade Mark :
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sufficient bulk quantities of the [l(S),4S]-l-(3-merc~pto-2-methyl-1-oxopropyl)-4 (phenyl~ulfinyl)-L-proline, sodium salt and corn starch are admixed with an aqueous solution S of the gelatin. The mixture is dried and ground to a fine powder. The Avicel and then the magnesium teaxate are admixed with the granulation.
Thi~ mixture is then compressed in a tablet pre~ to form 1000 tablet~ each containing 100 mg.
of active ingredient.
In a l~ilar manner, tablet~ can be prepared containing 50 mg. o~ active ingredient.
The products of Examples 2 to 30 can be formulated according to this procedure.
ExamPle 33 Two piece #1 gelatin capsules each containing 100 mg. of [l(S),4S]-1 (3-mercapto-2-methyl-1-oxopropyl)-4-(phenylsulfonyl)-L-proline, sodium salt are filled with a mixture of khe following ingredient3:
~l(S),4S] 1-(3-mercapto-2-mothyl-l-oxopropyl~-4-(phenyl-sul~onyl)-~-proline, sodium ~alt 100 mg.
Magneslum ~tearate 7 mg.
Lactos~ 193 m~
300 mg.
In a sLmilar manner, capsule~ can be prepared containing the product~ o any of Example~ 1 to 18 and 20 to 30.

* Trade Mark ~7~

Example 34 , 1000 tablets each containing the following ingredients:
[l(S),4S~ (3-Mercapto-2-methyl-l-oxopropyl)-4 (phenyl~
sulfinyl)-L-proline, sodium salt 100 mg.
Avicel 100 mg.
Hydrochlorothiazide 12.5 mg.
Lactose 113 mg.
Corn starch 17.5 ~g.
Stearic acid ~ mg.
350 mg.
are produced from su~ficient bulk quantities by slugging the [l(S),4S~ (3-mercapto-2-methyl-l-oxopropyl)-4-(phenylsulfinyl)-L-proline, sodium salt, ~vicel, and a portion of the stearic acid. The 91ug9 are ground and passed through a #2 Ycreen, then ~ixed with the hydrochloro-thiazida, lactose, corn starch, and remainder of the stearic acld. The ~ixture i~ compressed in~o 350 mg. capsul~ shaped tabl2ts in a tablet pres-~O The t~blets are scored for di~iding in half.
Similarly, the products of Examples 2 to 30 can be formu~ated according to this procedure.

* Trade Mark . . .
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.

0 Example 35 An injectable solution is prepared as follows:
[l~S),4S]-1 (3-mercapto 2-methyl 1-oxopropyl)-4-(phenyl-sulfonyl)-L-proline, sodium salt 500 g-Methyl paraben 5 g.
Propyl paraben 1 g.
Sodium chloride 25 g.
Water for injection 5 1.
The active substance, preservatives, and sodium chloride are dissolved in 3 liters of water fox injection and then the volume is brought up to 5 liters. The solution is filtered through a sterile filter and asceptically filled into presterilized vials which are then closed with presterilized rubber closures.
Each vial contains 5 ml. of solution in a concentration o 100 mg. of active ingredient pex ml. of solution for injection.
In a similar manner, the products of Examples 1 to 18 and 20 to 30 can be formulated as described above.

'~

Claims

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

1. A compound of the formula wherein:
R is hydrogen or lower alkyl;
m is zero or an integer from 1 to 4;
R1 is , a 1- or 2-naphthyl of the formula , or ; and R2 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, acetyloxy, or hydroxy.

2. A compound of Claim 1 wherein R is hydrogen;

R1 is ;

R2 is hydrogen, methyl, methoxy, chloro or fluoro;
and m is zero, one or two.

3. A compound of Claim 1 or 2 wherein R1 is phenyl.

4. The compound of the formula wherein m is zero or an integer from 1 to 4.