Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
-- 113~4~'
~IA179a
_ I _
('arl)amale l)(~ri~lcltiv(~i of Merca~)toacyl llyclrox~l'rol illCS
This invention relates to new carbamate derivatives
of mercaptoacyl hydroxy prolines which have the formula
Ro
13 12 ~ CO-N
R4 - S (CH)n CH CO N COOR
wherein R, R2 and R3 each is hydrogen, lower alkyl, or
trifluoromethyl; Ro and Rl each is hydrogen, lower alkyl,
cyclo-lower alkyl, allyl, propargyl, phenyl or
substituted phenyl; or R and Rl can join with the
nitrogen to form a S- or 6-membered heterocyclic;
R4 is hydrogen or a hydrolyzable organic protecting
group of the formula R5-CO- or
Ro
OCO-N
3 12 ~ \R
-S (CH)n -- H CO N COOR
R5 is lower alkyl, phenyl, substituted phenyl, phenyl-
lower alkyl, substituted phenyl-lower alkyl, cycloalkyl,
thienyl or furyl; n is 0, 1 or 2; and salts thereof,
as well as novel intermediates therefor.
The asterisks indicate centers of asymmetry. The
carbon in the acyclic side chain is asymmetric when R2
and/or R3 is other than hydrogen. Each of the centers
of asymmetry provide D and L forms which can be
separated by conventional methods as described below.
The carbamate group / R also gives rise to
-OCON \
cis-trans isomerism.
. ..
' ' ` 113~345Z
11~179a
-2-
This invention relates to new compounds
which have the formula
(I)
R
R3 R2 ~ ~ R
R -S-(C1~) - CH CO - N OOR
and to salts thereof, to compositions containing
such compounds and to the method for using such
compounds as anti-hypertensive agents. The symbols
have the meanings defined above.
The lower alkyl groups represented by any of
the variables include straight and branched chain
hydrocarbon radicals having up to seven carbons, for
example, methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, t-butyl, pentyl, isopentyl and the like.
The lower alkyl groups having up to four carbons and
especially the Cl and C2 members are preferred.
The cyclo-lower alkyl groups are the alicyclic
groups having up to seven carbons, i.e., cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Cyclopentyl and cyclohexyl are preferred.
The substituted phenyl groups include monosub-
stituted phenyl rings wherein the phenyl substituent is
halogen, lower alkyl, lcwer alkoxy, lower alkylthio or trifluoro-
methyl. The lower alkoxy and lower alkylmercaptogroups include lower alkyl groups of the type described
above. Exemplary are methoxy, ethoxy, propoxy, iso-
113~45Z Ill~l 79a
--3--
propoxy, butoxy, t-butoxy, methylthio, ethylthio,
propylthio, isopropylthio and the like. The Cl-C4
and Cl-C2 preferences described above also apply.
The halogens are the four common halogens, preferably
5 chlorine and bromine, providing such radicals as
o-, m- and p-chlorophenyl, o-, m- and p-bromophenyl
and the like. The phenyl and substituted phenyl can
also be described as R6 ~ wherein R6 is hydrogen,
10 halogen, lower alkyl, lower alkoxy, lower alkylthio
or trifluoromethyl.
The phenyl-lower alkyl groups include lower
alkyl groups of the type described above attached
to the phenyl ring. Phenylmethyl and phenylethyl
15 are the preferred phenyl-lower alkyl groups,
especially phenylmethyl.
The preferred groups of the formula R5-CO-
are those wherein R5 is lower alkyl, phenyl, or
phenyl-lower alkyl.
The lower alkanoyl groups represented by
R5-CO- are those having the acyl radicals of the lower
(C2-C7) fatty acids, for example, acetyl, propionyl,
butyryl, isobutyryl and the like. Those lower
alkanoyl groups having up to four carbons, and
25 especially acetyl, are preferred. The same preferences
apply to the phenyl-lower alkanoyl groups when R5 in
the group R5-CO- is phenyl-lower alkyl. Benzoyl is
especially preferred.
The carbamate group on the pyrrolidine ring
30 can be acyclic including, for example, the radicals
carbamoyl, lower alkylcarbamoyl like methylcarbamoyl,
ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl,
di(lower alkyl)carbamoyl like dimethylcarbamoyl,
- 113E~4SZ
liAl 79a
--4--
diethylcarbamoyl, proi)ar(3ylcart)am0yl~ or allyl-
carbamoyl. It also includes cycloalkylcarbamoyl
groups like cyclopentylcarbarnoyl, dicyclopentylcar-
bamoyl, cyclohexylcarbamoyl, dicyclohexylcarbamoyl and
the like. In addition it includes phenyl- and
substituted phenylcarbamoyl groups like phenylcar-
bamoyl, 4-chlorophenylcarbamoyl, 3-ethylphenyl-
carbamoyl, 4-methoxyphenylcarbamoyl, 4-(trifluoro-
methyl)phenylcarbamoyl and the like. Preferably
only one of Ro and Rl is a cycloalkyl, phenyl or
substituted phenyl radical.
The -N'R can also form a 5-membered or
6-membered heterocyclic of the group pyrrolidine,
piperidine or morpholine.
lS Preferably only one of Ro and Rl is other than
hydrogen except when both Ro and Rl are lower alkyl.
Preferred compounds of formula I are those
wherein R is hydrogen or lower alkyl; Ro and Rl each
is independently Cl-C4-lower alkyl; R2 and R3 each
is hydrogen or cl-C4-lower alkyl; R4 is hydrogen,
lower alkanoyl, or benzoyl; and n is 0 or 1.
The carbamate group is in the 3- or 4-
position of the pyrrolidine ring, preferably the
4-position.
Especially preferred are compounds of formula
I wherein R is hydrogen; Ro and Rl each is Cl-C4
lower alkyl, most especially Cl-C3-lower alkyl;
R2 is methyl; R3 is hydrogen; R4 is hydrogen;
n is l; and the carbamate group is in the 4-position.
.
113~4SZ HA179 a
--5--
The preferred method of synthesiziny compoun~s
of formula 1 utilizes as starting material a l~ydroxy-
proline of the formula
(II) ~
HN COOH
The nitrogen is first protected, e g., with a
nitrogen protecting group of the type commonly used
in peptide synthesis like carbobenzoxy, p-toluene-
sulfonyl, acetyl or the like to obtain a protected
compound such as
(III) ~ H
Cbz-N COOH
wherein CBz is the carbobenzyoxy
protecting group.
The protected compound III is then esterified,
for example, by reaction with a diazoalkane, such as
diazomethane to form an ester of the structure
(IV) "~OH
r
Cbz-N I COOR
wherein R is lower alkyl like methyl or
isobutyl, preferably methyl.
The carbamate group OCO-N / , wherein
Rl
- 30 Ro is hydrogen and Rl is other than hydrogen, can
then be introduced by reacting the compound of
formula IV with an isocyanate (Rl-NCO) in an inert
organic solvent like benzene, and the like to obtain
the next intermediate having the formula
113845'~
1 7 9
(V) R
~ON~
Cbz-N COOR
5 In the preparation of the cis isomer, the
above reaction is carried out in the presence of a
catalytic amount of a base, such as pyridine or
triethylamine.
Alternatively, compounds of formula V may be
prepared by reacting the protected compound IV with
phosgene to form an intermediate of formula Vl
(VI) ~ OCOCl
Cbz-N l COOR
(which is not necessarily isolated), which is then
reacted with the appropriate amine HN / or NH3
(where both Ro and Rl are to be hydrogen) to form
the formula V compound.
20 When Ro and Rl (in formula V) are both to be
other than hydrogen or together complete a hetero-
cyclic, then the protected compound of formula IV is
made to react with the carbamoyl halide
(VII) /Ro
hal-CO-N
\Rl
wherein hal is halogen, preferably chlorine.
Alkaline hydrolysis of the compound of
formula V with a base like sodium hydroxide, barium
hydroxide, potassium hydroxide or the like yields
the acid having the formula
(VIII) ~Ro
OCON
~ 1
Cbz-N COOH
. :
.
11384SZ
~IA179a
-7--
The com~ound of formula VIII in acid or
ester form can then be deprotected, e.q., by the
convention~l procedure of hyclroqenation in the
presence of palladium-carbon to obtain the compound
S havinq the formula
R
(IX) ~ OCO-N
HN COOH
The next stage of the synthesis entails
coupling the proline derivative IX with an
acid having the formula
(X)
IR3 lR2
R5- CO- S -(CH)n CH- COOH
most conveniently in th~ form of an acid
chloride, yielding a ~ro~ct of the formula
(XI)R OCo-N
3 R2 ~ ~ R
R5- CO- S- (CH)n- CH-CO-N l COOH
The proline derivative XI is preferably
isolated and purified by crystallization, e.g.,
by forming a salt like the dicyclohexylamine salt
and then converting the salt to the free acid form
by treatment with an aqueous solution of an acid,
such as potassium acid sulfate.
2:
HA179a
--8--
The pro~uct of formula Xl bearing the acyl
group R5-CO can be converted, if desired, to the
product of formula I wherein R4 is hydrogen by
hydrolysis with ammonia, sodium hydroxide or the like.
~sters of formula I wherein R is lower alkyl
can be obtained by conventional esterification
procedures, e.g., by esterification with a diazo-
alkane like diazomethane, l-alkyl-3-p-tolyltriazene,
like l-n-butyl-3--p-tolyltriazene, or the like,
preferably after the completion of the sequence of
reactions described above. However, earlier esteri-
fication and omission of the alkaline hydrolysis can
also be practiced.
The compounds of formula I wherein R4 forms
lS the symmetrical bis compound are obtained by directly
oxidizing with iodine a product of formula I wherein
R4 is hydrogen.
Reference is also made to the following
publications for additional illustrative informa-
tion with respect to the production of starting
materials and intermediates: U.S. Patents 4,046,889
and 4,105,776; J. Chem. Soc., 1945, 429-432;
J. Amer. Chem. Soc. 79, 185-192 ~1957); J. Amer. Soc.
85, 3863-3865 (1963). The procedures illustrated
therein can be utilized as general methods for the
synthesis and stereoconversion of compounds utili-
zable in theinvention of this application.
Additional experimental details are found in
the examples which are preferred embodiments and
also serve as models for the preparation of other
members of the group.
1~3E~ i2
~IA179a
_9_
As indicated above, the compounds of this
invention have several centers of asymmetry. These
compounds accordingly exist in stereoisomeric forms
or in racemic mixtures thereof. The various
stereoisomeric forms and mixtures thereof are all
within the scope of this invention. The above
described methods of synthesis can utilize the
racemate or one of the enantiomers as starting material.
When a mixture of stereoisomers is obtained as the
product, the stereoisomeric forms can be separated,
if desired, by conventional chromatographic or
fractional crystallization methods or by conversion
to a salt with an optically active base, followed
by fractional crystallization or similar known
methods. In general, those compounds are preferred
wherein the proline moiety is in the L-configuration,
the carbamate group is cis and the acyl side chain
has the D-configuration.
The compounds of this invention form basic
salts with a variety of inorganic or organic bases.
The salt forming ion derived from such bases can
be metal ions, e.g., aluminum, alkali metal ions,
such as sodium or potassium, alkaline earth metal
ions such as calcium or magnesium, or an amine
salt ion, of which a number are known for this
purpose, for example, aralkylamines like, dibenzyl-
amine, N.N-dibenzylethylenediamine, lower alkyl-
amines like methylamine, triethylamine,
t-butylamine, procaine, lower alkylpiperidines
like N-ethylpiperidine, cycloalkylamines like
cyclohexylamine, dicyclohexylamine, l-adamantaneamine,
1138452 11A179 a
- 1 0 -
benzathine, or salts dcrived ~rom amino acids likc
arginine, lysine or thc like. Thc physiologically
ace~)table salts like thc sodium or potassium salts
can be used medicinally as described below and are
preferred. These and other salts which are not
necessarily physiologically acceptable are useful
in isolating or purifying a product acceptable for the
purposes described below as well as purifying or
isolating intermediates, as illustrated in the examples.
The salts are produced by reacting the acid form of
the compound with an equivalent of the base supplying
the desired basic ion in a medium in which the salt
precipitates or in aqueous medium and then lyophili-
zing. The free acid form can be obtained from the
salt by conventional neutralization techniques, e.g.,
with potassium bisulfate, hydrochoric acid, etc.
The compounds of this invention inhibit the
conversion of the decapeptide angiotensin I to angio-
tensin II by angiotensin converting enzyme and there-
fore are useful in reducing or relieving hypertension
in various mammalian species, e.g., cats, dogs, mice,
rats, etc., having elevated blood pressure. Thus
by administration of a hypotensively effective amount
of a composition containing one or a combination of
compounds of formula I or physiologically acceptable
salt thereof, hypertension in the species of mammal
suffering therefrom is reduced or alleviated.
A single dose, or preferably two to four
divided daily doses, provided in a basis of
about 0.1 to 100 mg. per kilogram per day, preferably
113~Z 11~179a
-I 1-
about 1 to 15 mg. E~er kilogra~ )cr day, is appropriaLe
to reduce blood pressure as indicated in the animal
model experiments described by S. L. ~ngel, T. R.
Schaeffer, M. 1~. Waugh and B. Rubin, Proc. Soc.
Exp. Biol. Med. 143, 483 (1973). The substance is
preferably administered orally, but parenteral routes
such as subcutaneously, intramuscularly, intravenously
or intraperitoneally can also be employed.
The compounds of this invention can also be
formulated 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 (for a 70 kg. mammal) a total daily
dosage of about 30 to 600 mg., preferably about 30 to
300 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, ~ , chlorthiazide, hydrochlor-
thiazide, flumethiazide, hydroglumethiazide, bendroflu-
methiazide, methylchlorthiazide, trichlormethiazide,
polythiazide or benzthiazide, as well as ethacrynic
acid, ticrynafen, chlorthalidone, furosemide,
bumetanide, triamterene, amiloride and spirono-
lactone, and salts of such compounds.
The compounds of this invention can be utilized
to achieve the reduction of blood pressure by formu-
lating in compositions such as tablets, capsules orelixirs for oral administration or in sterile
1~3~41~
11~17')~
solutions or suspcnsions for parenteral administra-
tion. ~bout lO to 500 my. of a compound or mixture
of compounds of formula I or physiologically
acceptable salt is compounded wi-th a physiologically
acceptable vehicle, carrier, excipient, binder,
preservative, stabilizer, flavor, etc., 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 suitable
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 or microcrystalline cellulose;
a disintegrating agent such as corn starch, potato
starch, alginic acid and the 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 modify
the physical form of the dosage unit. For instance,
tablets may be coated with shellac, sugar or both.
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.
~3~4~2 ~IA179a
-13-
Sterile compositions for injection can be
formulated according to conventional pharmaceutical
practice by dissolving or suspending the active
substance in a vehicle such as water for injection,
a naturally occurring vegetable oil like sesame oil,
coconut oil, peanut oil, cottonseed oil, etc. or
synthetic like ethyl oleate.
The following examples are illustrative of
the invention and constitute preferred embodiments.
They also serve as models for the preparation of
other members of the group which can be produced
by replacement of the given reactants with suitably
substituted analogs. All temperatures are in
degrees Celsius.
1~31~9~52
~IA179a
-l4-
Exampl e
trans-l- ¦D- (3-Acetylthio)-2-methyl-1-oxoPropyl]-4-
[[(methylamino)carbonyl]oxy]-L-proline
_ _
a) N-Carbobenzyloxy-trans-4-hydroxy-L-proline
26.5 y. (0.20 mole) of trans-4-hydroxy-L-
proline and 32.8 ml. (0.23 mole) of benzyl chloro-
formate are reacted in 200 ml. of water and 100 ml. of
acetone in the presence of 20 g. (0.20 mole)
of potassium bicarbonate and 69.2 g. (0.50 mole) of
potassium carbonate and worked up with 90 ml. of
concentrated hydrochloric acid as described in Can. J.
Biochem. & Physiol. 37, 584 (1959). The product is
reacted with cyclohexylamine to form the cyclohexyl-
amine salt, yield 69 g., m.p. 193-195. The salt
(34 g.) is neutralized with N hydrochloric acid to
obtain 27 g. of the free acid as a colorless glass
[tl ] 26 -70 (c, ]% in chloroform).
b) N-Carbobenzyloxy-trans-4-hydroxy-L-proline, methyl
ester
12.4 g. (0.047 mole) of N-carbobenzyloxy-trans-
4-hydroxy-L-proline is esterified with diazomethane
~ in dioxane-ether as described in J.A.C.S. 79,
; 191 (1957). To avoid freezing of the dioxane the
addition of the diazomethane is begun at 10 and
completed at 0-2. The yield of N-carbobenzyloxy-
trans-4-hydroxy-L-proline, methyl ester as a nearly colorless
viscous oil is 14.6 g. (100%). [rl]D6 -62 (c, 1% in chloroform).
c) trans-N-Carbobenzyloxy-4-[[(methylamino)carbonyl]-
. _ .. _ . . . . .. .
oxy]-L-proline, methyl ester
. _
To a stirred solution of 6.0 g. (0.021 mole)
of N-carbobenzyloxy-trans-4-hydroxy-L-proline, methyl
ester (J.A.C.S. 79 supra) in 120 ml. of benzene is
added 6 ml. (0.10 mole) of methylisocyanate and
~ '
.
~.~ 3~4~iZ
~l~179a
the reaction mixture ke~t ovcrnigh~ at room telllpera-
ture. ~fter refluxin(J ror onf hol~r, the solvcnt is
removed on a rotary eva~orator, finally at 0.2 mm
and 50 . The viscous residue is taken up in 150 ml.
of ether, washed with water (3 x 50 ml.), dried
(MgSO4), and the ether is evaporated to yield
6.5 g. (90~) of syrupy product, trans-N-carbobenzyloxy-
4-[[(methylamino)carbonyl]oxy]-L-proline, methyl ester.
d) trans-N-Carbobenzyloxy-4-[1(methylamino)carbonyl]-
oxy]-L-proline
_ . . _ .
The crude ester from part c (7.6 g., 0.023 mole)
is dissolved in 60 ml. of methanol, treated dropwise at
-1 to 4 with 14 ml. (0.028 mole) of 2N sodium
hydroxide, kept at 0 for one hour, and at room
temperature overnight. After removing about 1/2 of
the solvent on a rotary evaporator, the solution is
diluted with 160 ml. of water, washed with ether
(wash discarded), acidified,while cooling,with
5.5 ml. of 1:1 hydrochloric acid to pH 2, and
extracted with ethyl acetate (4 x 75 ml.). The
combined extracts are washed with 50 ml. of saturated
sodium chloride, dried (MgSO4) and the solvent
evaporated to give 7.2 g. of a very viscous
syrup. The syrup is dissolved in 30 ml. of ethanol,
treated with 2.3 g. of cyclohexylamine in 5 ml. of
ethanol and diluted to 600 ml. with ether. On
seeding and rubbing, the crystalline cyclohexylamine
salt separates; weight after cooling overnight,
o [ ]25 20 (c, 1~ in ethanol).
Following crystallization from 25 ml.
of isopropanol, the colorless solid
.
11384t~
HA179a
-16-
trans-N-car~)obcllz.yloxy-4-[[(mcthyl-llni.no)carbonyl]oxy]-
L-proline cycloll(~xyl.lrlline salt wei(JIls 7.8 y., m.p.
174-176. [~]25 -18 (c, 1~, in ethanol).
The cyclohexylamine salt is suspended in 60 ml.
of ethyl acetate, stirred, and treated with 40 ml. of
N hydrochloric acid. When two clear layers are
obtained they are separated, the aqueous phase is
extracted with additional ethyl acetate (3 x 60 ml.),
the combined organic layers are dried (MgSO4),
and the solvent evaporated. The yield of glass-like
free acid is 5.5 g. (81%).
e) trans-4-[[(Methylamino)carbonyl]oxy]-L-proline
A solution of 2.7 g. (0.0084 mole) of trans-N-
carbobenzyloxy]-4-[[(methylamino)carbonyl]oxy]-L-
proline in 100 ml. of methanol-water (2:1) is treated
wi~ 1 g. of 5~O palladium-carbon and 45 lb. of hydrogen and
shaken on a Parr hydroyenator for 6 hours. The
catalyst is filtered off under nitroyen, washed
with methanol and the combined filtrates are evapora-
ted, finally at 0.1-0.2 mm,to give 1.5 g. (96~) of
a residue which gradually crystallizes to give trans-
4-[[(methylamino)carbonyl]oxy]-L-proline as a
greyish solid; m.p. 213-215 (dec.), preceded by
gradual darkening and sintering. [~]26 -12
tc, 0.25% in 1:3 ethanol-methanol).
f) trans-1-[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-
4-[[(methylamino)carbonyl]oxy]-L-proline
A stirred solution of 2.9 g. (0.0154 mole)
of trans-4-[[(methylamino)carbonyl]oxy]-L-proline
in 45 ml. of water is cooled to 5 and treated
113~S,~
-17~ l79a
portionwise with solid sodium carbonate to p~8.5;
(approx. 0.4 g. required). Tilen while continuing
stirring and cooling, a solution of 3.1 g. (0.017 mole)
of D-3-acetylthio-2-methylpropanoyl chloride in 4 ml.
of ether is added portionwise by means of a pipette
while maintaining the pH at 7.0 - 8.0 by dropwise
addition of 25~, (w/v) sodium carbonate. After about
10 minut~s, the pH stabilizes at 8.1 - 8.3 (about
14 ml. of the sodium carbonate solution has been
added). ~fter continued stirring and cooling for
a total ~f 1.25 hours, the solution is washed
with ethyl acetate (50 ml.), layered over with
50 ml. of ethyl acetate, stirred, cooled, acidified
carefully with 1:1 hydrochloric acid to pH 2.0,
saturated with sodium chloride and the layers are
separated. The aqueous phase is extracted with
additional ethyl acetate (3 x 50 ml.), the combined
organic layers are dried (MgSO4) and the solvent
evaporated, finally at 0.2 mm., to give 5.3 g. of a
glass-like residue. The latter is dissolved in
40 ml. of ethyl acetate and treated with a solution
of 2.8 g. of dicyclohexylamine in 15 ml. of
ethyl acetate. On seeding and rubbing, the
crystalline trans-l-[D-(3-acetylthio)-2-methyl-1-
oxopropyl]-4-[[(methylamino)carbonyl]oxy]-L-proline
dicyclohexylamine salt separates, weight after
cooling overnight 5.8 g. (colorless); m.p. 187-189
(s.183 ) [a]D -64 (c, 1% in MeOH). Following
recrystallization from 15 ml. of methanol - 100 ml.
of ether, the colorless solid weighs 4.5 g., m.p.
45iZ
ll~l79a
1'~0-192 ~ 0-1 (c, 1'1 in Me()ll).
The clicyclohexylamin( .saL~ is convc~rtc(l ~o
thc frce acid by sus[~entliny in 50 m]. of otllyL acetatc,
cooling, treating with 50 rnl. of 10~ potassium
bisulfate and stirring until two clear layers are
obtained. After separating, the aqueous phase is
extraeted with ethyl acetate (3 x 50 ml.), the
combined organic layers are dried tMgSO4), and the
solvent evaporated to give 2.8 g. (55%) of trans-l-
~D-(3-acetylthio)-2-methyl-1-oxopropyl]-4-[1(methyl-
amino)carbonyl]oxy]-L-proline as a foamy hygroscopic
residue.
Example 2
trans-l-(D-3-Mercapto-2-methyl-1-oxopropyl)-4-
_ _
[[(methylamino)carbonyl]oxy]-L-proline
Argon is passed through a cold solution of
6 ml. of concentrated ammonium hydroxide in 4 ml.
of water for 10 minutes. The latter is then added
while cooling and under a blanket of argon to the
product of Example 1 and the mixture is swirled in an
icebath until a pale yellow solution is obtained
(about 3 minutes). Stirring under argon is continued
at room temperature for a total of 2 hours, then the
solution is extracted with 20 ml. of ethyl acetate
(this and subsequent operations are carried out as
much as possible under an argon atmosphere). The
aqueous layer is cooled, stirred, layered over with
20 ml. of ethyl acetate and acidified portionwise with
approximately 13 ml. of 1:1 hydrochloric acid. The
layers are separated, the aqueous phase is extracted
113845Z ",~, 79
I (~
with additional ethyl acetate (3 x 20 ml.), the com-
bined ethyl acetate layers are dried (MgSO4), and the
solvent evaporated to give trans-l-(D-3-mercapto-2-
methyl-l-oxopropyl)-4-[[(methylamino)carbonyl]oxy]-L-
proline as a sticky foamy residue. The latter is
rubbed under ether and the evaporation repeated,
finally at 0.1 - 0.2 mm., to yield 2.2 g. (9096) of
the product as a colorless, somewhat hygroscopic,
amorphous solid, m.p. 54-57 (S, 45). [(Y]D -53
(c, 1% in EtOH).
The racemic forms of the final products in
each of the foregoing examples are produced by
utilizing the DL-form of the starting amino 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 3
a) N-Carbobenzyloxy-cis-4-hydroxy-L-proli`ne,
methyl ester
6.5 g (0.024 mole) of N-carbobenzyloxy-cis-
4-hydroxy-L-proline [J.A.C.S., 79, 189 (1957)] is
dissolved in 65 ml. of methanol, stirred, and treated
with 0.65 ml. of concentrated sulfuric acid. After
stirring at room temperature for one-half hour, the
solution is allowed to stand overnight. The bulk
of solvent is removed on a rotary evaporator and the
oily residue (13 g.) is taken up in 70 ml. of ether
and washed with 35 ml. of 10% sodium bicarbonate
~ 84SZ H~]79~
--;~0-
solution. The wash is back extracted with 35 ml.
of ether. The combined organic layers are dried
(MgSO4), and the ether is evaporated to give 6.5 g.
(96~) of product as a pale yellow viscous oil.
[~]D -24 (c, 1~ in chloroform).
b) cis-N-Carbobenzyloxy-4-[[(methylamino)carbonyl]-
oxy]-L-proline, methyl ester
To a stirred solution of 5.4 g. (0.019 mole)
of N-carbobenzyloxy-cis-4-hydroxy-L-proline, methyl
ester, in 120 ml. of acetonitrile is added 5.4 ml.
of triethylamine, followed by 5.4 ml. of methyl
isocyanate. After keeping overnight at room tempera-
ture and refluxing for two hours, the reaction mixture
is worked up as in Example lc to give 5.6 g (86~)
of a pale yellow viscous oil.
c) cis-N-Carbobenzyloxy-4-[[(methylamino)carbonyl]-
oxy]-L-proline
The crude ester from part b (5.6 g; 0.017 mole)
is saponified with 11 ml. (0.022 mole) of 2N sodium
hydroxide in 45 ml. of methanol as in Example ld
to give 5.1 g of a foamy residue. The colorless
-~ cyclohexylamine salt, prepared in 25 ml. of ethanol
and 400 ml.of ether employing 1.7 g. of cyclohexyl-
amine, weighs 4.8 g.; m.p. 171-173 [~]D -16
(c, 1% in ethanol). A sample recrystallized from
ethanol-ether shows no change in melting point or
optical rotation.
The cyclohexylamine salt yields 3.5 g. (65%)
of the free acid as a colorless foamy residue.
... . .
11384~2 ilA179a
d) cis-4-[[(Methylamino)carb(~ y~-L-proline
3.5 ~3 (0.011 mole) of cis-N-carbobenzyloxy-
4-[[(methylamino)carbonyl]oxyl-L-proline is hydro-
genated in 130 ml . of 2 :1 methanol-water employing
1.3 g of 2:1 methanol-water employing 1.3 g. of
5% palladium-carbon as in Example le to give 1.~ g.
(95%) of product as a greyish solid; m.p. 232-234
(dec.), preceded by gradual darkening and sintering.
[~]D -42 (c, 0.5% in 1:1 methanol-water).
e) cis-1-[D-(3-~cetylthio)-2-methyl-1-oxopropyl]-
4-[[(methylamino)carbonyl]oxy]-L-proline
Interaction of 1.85 g (0.0098 mole) of
cis-4-[[(methylamino)carbonyl]oxy]-L-proline and
2.0 g (0.011 mole) of D-3-acetylthio-2-methyl-
lS propanoyl chloride in 30 ml. of water in the presenceof sodium carbonate as in Example lf yields 3.35 g.
of a gummy product. The dicyclohexylamino salt,
prepared in 35 ml. of ethyl acetate employing
1.8 g. of dicyclohexylamine, weighs 4.0 g.;
m.p. 177-179 . [~]D ~54 (c, 1% in methanol).
Following trituration with 20 ml. of acetonitrile
and cooling, the colorless solid weighs 3.6 g.;
o [ ]25 54 ~c, 1~ in methanol).
Treatment with 10% potassium bisulfate and extraction
into ethyl acetate yields 2.5 g. (76%) of the free
acid as a colorless foamy residue.
~13845iZ E1~179a
-2~-
Example 4
. _
cis-l-(D-3-Merc~ o-2-m thyl-1-oxo~ 4-
~ . ...
[[(methylamino)c~rbr~ oxy -B-proline
By treating thc material oE Example 3 with
5.5 ml. of concentrated ammonium hydroxide in
12.5 ml. of water according to the procedure
described in Example 2, 1.8 g. t82%) of the product
is obtained as a colorless, hygroscopic, sticky
foam. [~]D5 ~59 (c, 1~ in ethanol)
Example 5
cis-l-[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-4-
[[(ethylamino?carbonyl]oxy]-L-proline
~tilizing the procedure of Example 3 but
; 15 substituting ethylisocyanate for the methylisocyanate
in part b, cis-l-[D-(3-acetylthio)-2-methyl-1-
oxopropyl]-4-[[(ethylamino)carbonyl]oxy]-L-proline
is obtained.
Example 6
cis-l-(D-3-Mercapto-2-methyl-l-oxopropyl)-4
[[(ethylamino)carbonyl]oxy]-L-proline
By treating the material of Example 5 with
ammonia according to the procedure described in
Example 4, cis-1-(D-3-mercapto-2-methyl-1-oxopropyl)-
4-[[(ethylamino)carbonyl]oxy]-L-proline is obtained.
Example 7
. _
cis-l-[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-4-
. .
[[(propylamino)carbonyl]oxy]-L-proline
Utilizing the procedure of Example 3 but
substituting n-propylisocyanate for the methyl-
1~.384~ 179a
isocyanate in part b, cis-l-[D-(3-acetylthio)-2-
methyl-l-oxopropyl]-4-[[(propylamino)carbonyl]oxy]-
L-proline is obtained.
Example 8
cis-l-(D-3-Mercapto-2-methyl-1-oxopropyl)-4-
[[(propylamino)carbonyl]oxy]-L-proline
By treating the material of Example 7 with
ammonia according to the procedure described in
10 Example 4, cis-1-(D-3-mercapto-2-methyl-1-
oxopropyl)-4-[[(propylamino)carbonyl]oxy]-L-proline
is obtained.
Example 9
15 cis-1-[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-4-
[[(phenylamino)carbonyl]oxy]-L-proline
Utilizing the procedure of Example 3 but
substitutiny phenylisocyanate for the methyl-
isocyanate in part b, cis-l-[D-(3-acetylthio)-2-
methyl-1-oxopropyl]-4-ff(phenylamino)carbonyl]oxy]-
L-proline is obtained.
Example 10
cis-l-(D-3-Mercapto-2-methyl-1-oxopropyl)-4-
[[(phenylamino)carbonyl]oxy]-L-proline
By treating the material from Example 9
with ammonia according to the procedure described in
Example 4, cis-1-(D-3-mercapto-2-methyl-1-oxopropyl)-
4-[[(phenylamino)carbonyl]oxy]-L-proline is obtained.
.
113845Z ilA179a
E:xarllL)lc 1 1
cis-l-[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-4-
___ _ __
~[(4-chlorop_enyl)carbor,yl]oxy]-r.-proline
Utilizing the procedure of Example 3 but
substituting 4-chlorophenylisocyanate for the
methylisocyanate in part b, cis-l-[D-(3-acetylthio)-
2-methyl-1-oxypropyl]-4-[[(4-chlorophenyl)carbonyl]-
oxy3-1.-proline is obtained.
~xample 12
cis-l-(D-3-Mercapto-2-methyl-1-oxopropyl)-4-
[[(4-chlorophenyl)carbonyl]oxy]-L-proline
By treating the material from Example 11
with ammonia according to the procedure described
in Example 4, cis-1-(D-3-mercapto-2-methyl-1-
oxopropyl)-4-[[(4-chlorophenyl)carbonyl]oxy]-L-
proline is obtained.
Example 13
cis-l-[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-4-
_[(3-trifluoromethylphenyl)carbonyl]oxy]-L-proline
Utilizing the procedure of Example 3 but
substituting 3-trifluoromethylphenylisocyanate in
place of the methylisocyanate in part b, cis-l-[D-(3-
acetylthio)-2-methyl-1-oxopropyl]-4-[[(3-trifluoro-
methylphenyl)carbonyl]oxy]-L-proline is obtained.
Example 14
cis-l-[D-(Acetylthio)-2-methyl-1-oxopropyl]-4-
[[(2-methoxyphenyl)carbonyl]oxy]-L-proline
Utilizing the procedure of Example 3 but
substituting 2-methoxyphenylisocyanate for methyliso-
cyanate in part b, cis-l-[D-(acetylthio)-2-methyl-1-
oxopropyl]-4-[[(2-methoxyphenyl)carbonyl]oxy]-L-
proline is obtained.
li3t~S;~
IIA179a
_~r)_
I~lx;IrllL)~
tran.s-l-[L~ oy~ -m(~ y~ )
[ [ (2-ethyl!~hetlyl)carbony] 1_y_,-r)ro:l l.ne
Utilizing the procedure of Example 1 but
substituting 2-ethylphenylisocyanate for the
methylisocyanate in part c and D-3-benzoylthio-2-
methylpropanoyl chloride for the D-3-acetylthio-2-
methylpropanoyl chloride in part f, trans-l-[D-
(benzoylthio)-2-methyl-1-oxopropyl]-4-[[(2-ethyl-
phenyl)carbonyl]oxy]-L-proline is obtained.
Example 16
trans-l-[D-(Phenacetylthio)-2-methyl-1-oxopropyl]-
4-[[(4-methylthiophenyl)carbonyl]oxy]-L-proline
Utili~ing the procedure of Example 1
but substituting 4-methylthiopheny~isocyanate for
the methylisocyanate in part c, and D-phenylacetyl-
thio-2-methylpropanoyl chloride for the D-(3-
acetylthio)-2-methylpropanoyl chloride in part f,
trans-1-[D-(phenacetylthio)-2-methyl-1-oxopropyl]-
4-[[(4-methylthiophenyl)carbonyl]oxy]-L-proline is :~:
obtained.
: Example 17
trans-1-[D-(3-Phenylpropionylthio)-2-methyl-1-
oxopropyl]-4-[[(3-bromophenyl)carbonyl]oxy]-L-proline
Utilizing the procedure of Example 1 but
substituting 3-bromophenylisocyanate for the methyl-
isocyanate in part c, and D-(3-phenylpropionylthio)-
2-methylpropanoyl chloride for the D-(3-acetylthio)-
2-methylpropanoyl chloride in part f, trans-l-[D-
(3-phenylpropionylthio)-2-methyl-1-oxopropyl]-4-
[[(3-bromophenyl)carbonyl]oxy]-L-proline is obtained.
1~38452
11~179 a
-~6-
r~xam~le 18
trans-l-[D (3-Acetylthio)-2-methyl-1-oxopropyl]-
4-[[(cyclopentylamino)carbonyl]oxy -L-proline
Utilizing the procedure of Example 1 but
substituting cyclopentylisocyanate for the methyl-
isocyanate in part c, trans-l-[D-(3-acetylthio)-2-
methyl-l-oxopropyl]-4-[[(cyclopentylamino)carbonyl]-
oxy]-L-proline is obtained.
Example 19
trans-l--[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-
4-[[(cyclohexylamino)carbonyl]oxy]-L-proline
Utilizing the procedure of Example 1 but
substituting cyclohexylisocyanate for the
methylisocyanate in part c, trans-1-[D-(3-acetyl-
thio)-2-methyl-1-oxopropyl]-4-[[(cyclohexylamino)-
carbonyl]oxy]-L-proline is obtained.
Example 20
_
cis-1-[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-
. . ~
4-[[(allylamino)carbonyl]oxy]-L-proline
Utilizing the procedure of Example 3
but substituting allylisocyanate
for the methylisocyanate in part b, cis-l-[D-
(3-acetylthio)-2-methyl-1-oxopropyl]-4-[[(allyl-
amino)carbonyl]oxy]-L-proline is obtained.
Example 21
cis-1-(D-3-Mercapto-2-methyl-1-oxopropyl)-4-
[[(allylamino)carbonyl]oxy]-L-proline
. . _ .
By treating the material from Example 20
11389~5A~
- ~ 7 ~ 7 9a
with an~onia accor(lin~J to the r)rocedure described
in Example 4, cis-l-(D-3-mercapto-2-methyl-1-oxo-
propyl)-4-[l(allylamino)carbonyl]oxy]-L-proline
is obtained.
Example 22
trans-1-[D-(3-~cetylthio)-2-methyl-1-oxopropyl]-4-
[[(dimethylamino)carbonyl]oxy]-L-proline
_
_) trans-N-Carbobenzyloxy-4-[[(dimethylamino)-
carbonyl]oxy]-L-proline, methyl ester
/, solution of N-carbobenzyloxy-trans-4-hydroxy-
L-proline methy] ester (Example 1, part b) in chloroform
is treated dropwise with an equivalent quantity of
dimethylcarbamyl chloride. The mixture is stirred
for two hours, washed with water and the organic
phase is dried over MgSO4. The solution is filtered
and solvent evaporated to give trans-N-carboben
4-[[(dimethylamino)carbonyl]oxy]-L-proline, methyl
ester.
b) trans-N-Carbobenzyloxy-4-~[(dimethylamino)-
carbonyl]oxy]-L-proline
Hydrolysis of the methyl ester from part a
with sodium hydroxide solution in the manner described
in Example 1, part d, gives trans-N-carbobenzyloxy-
4-[[(dimethylamino)carbonyl]oxy]-L-proline.
c)_trans-4-[[(Dimethylamino)carbonyl]oxy]-L-proline
Hydrogenation of the material from part b
according to the procedure described in Example 1,
part e, gives trans-4-[[(dimethylamino)carbonyl]-
oxy]-L-proline.
1131~45Z
ll~179a
-28-
d) trans-l-[~-(3-Acetylthio)-2-methyl-1-oxopropyl]-
4-[[(dimethylamino)carbonyl]oxy]-L-proline
Treatment o:f the matcrial from part c with
an equivalent qu~ntity of D-3-acetylthio-2-
methylpropanoyl chloride according to the proceduredescribed in Example 1, part f, gives trans-l-
ED-(3-acetylthio)-2-~ethyl-l-oxopropyl]-4- E E (dimethyl-
amino)carbonyl]oxy]-L-proline.
Example 23
trans-l-[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-
4-1[(pyrrolidino?carbonyl]oxy]-L-~roline
Utilizing the procedure described in the
preparation of Example 22 but substituting
pyrrolidinocarbamyl chloride for the dimethyl-
aminocarbamyl chloride in part a, trans-l-[D-
(3-acetylthio)-2-methyl-1-oxopropyl]-4-[[(pyrroli-
dino)carbonyl]oxy]-L-proline is obtained.
- 20 Example 24
trans-l-[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-
4-E[(piperidino)carbonyl]oxy]-L-proline
Utilizing the procedure described in the
preparation of Example 22, but substituting
piperidinocarbamyl chloride for the dimethylamino-
carbamyl chloride in part a, trans-l-[D-(3-acetyl-
thio)-2-methyl-1-oxopropyl]-4-[[(piperidino)-
carbonyl]oxy]-L-proline is obtained.
Example 25
tr~ns-l-[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-
4-[[(morpholino)carbonyl]oxy]-L-proline
Utilizing the procedure used in the preparation
11~8~5i2'
H~179a
of Exanl~>l~ ~2 ~u~ !;U~t~ lltil~(l mOrl)ll(.)l i~lO('.lrl).llll
chloride for the dimethyla~llinocarbamyl chlori(le
in part a, trans-1-[D-(3-acetylthio)-2-methyl-1-
oxopropyl]-4-[[~morpholino)carbonyl]oxy]-L-proline
is obtained.
Example 26
trans-l-(2-Acetylthio-l-oxoethyl)-4-[[(methylamino)-
carbonyl]oxy]-L-proline
Utilizing the procedure described in the
preparation of Example 1 but substituting 2-acetyl-
thioacetyl chloride for the D-(3-acetylthio)-2-
methylpropanoyl chloride in part f, trans-l-(2-
acetylthio-l-oxoethyl)-4-[[(methylamino)carbonyl]-
oxy]-L-proline is obtained.
Example 27
trans-l-(4-Acetylthio-l-oxobutyl)-4-[[(methylamino)-
_ _
carbonyl]oxy]-D-proline
Utilizing the procedure described in the
preparation of Example 1 but substituting trans-4-
hydroxy-D-proline for the trans-4-hydroxy-L-proline
in part a, and 4-acetylthiobutyroyl chloride for
the D-(3-acetylthio)-2-methylpropanoyl chloride in
part f, trans-1-(4-acetylthio-1-oxobutyl)-4-
[[(methylamino)carbonyl]oxy]-D-proline is obtained.
Example 28
cis-l-(4-Acetylthio-4-methyl-1-oxobutyl)-3-
. . _ _
[[(methylamino)carbonyl]oxy]-L-proline
Utilizing the procedure described in the
preparation of Example 3 but substituting
1138~Z
-30~ 179a
4-acetylthiovalo~oyl chloride ~or th(~
D-3-(acetylthio)-3-methylr~ropiony] chloride in
part e, cis-1-(4-acetylthio-4-methyl-1-oxobutyl)-
3-[[(methylamino)carbonyl]oxy]-L-proline is obtained.
Example 29
t ns-l-[L-(3-Acetylthio)-2-ethyl-l-oxopropyl]-3
[[(methylamino)carbonyl]oxy]-L-proline
Utilizing the procedure of Example 1 but
substituting trans-3-hydroxy-L-proline for trans-4-
hydroxy-L-proline in part a and L-(3-acetylthio)-2-
ethylpropionyl chloride for the D-3-(acetylthio)-
3-methylpropionyl chloride in part f, trans-l-
[L-(3--acetylthio)-2-ethyl-1-oxopropyl]-3-[[(methyl-
amino)carbonyl]oxy]-L-proline is obtained.
Example_30
trans-l-[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-
4-[(aminocarbonyl)oxy]-L-proline
. .
a) trans-N-carbobenzyloxy-4~(aminocarbonyl)oxy]-L-
_oline, methyl ester
A solution of equivalent quantities of
N-carbobenzyloxy-trans-4-hydroxy-L-proline, methyl ester from
Example 1, part b, and dimethylaniline is treated
with a solution of phosgene in toluene. After
standing overnight an equivalent quantity of ammonia
is passed through the solution of trans-N-carbo-
benzyloxy-4-[(chlorocarbonyl)oxy]-L-proline, methyl
ester. After standing for twelve hours at room
temperature, the solution is washed with water,
113~14~'
-31- HA179 a
dried over magnesium sulfate, filtered and the
solvent evaporated to give trans-N-carbobenzyloxy-4-
[(aminocarbonyl)oxyl-L-proline, methyl cster.
_) trans-N-Carbobenzyloxy-4-[(aminocarbonyl)oxy]-L-
proline
Hydrolysis of the methyl ester from part a
with sodium hydroxide solution in the manner
described in Example 1, part d, gives trans-N-
carbobenzyloxy-4-[(aminocarbonyl]oxy]-L-proline.
c) trans-4-[(Aminocarbonyl)oxy]-L-proline
Hydrogenation of the material from part b
according to the procedure described in Example 1,
part e, gives trans-4-[(aminocarbonyl)oxy]-L-
proline.
d) trans-1-[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-
4-[(aminocarbonyl)oxy]-L-proline
Treatment of the material from part c with
an equivalent quantity of D-3-acetylthio-2-methyl-
propanoyl chloride according to the procedure
described in Example 1, part f, gives trans-1-[D-
(3-acetylthio)-2-methyl-1-oxopropyl]-4-[(amino-
carbonyl)oxy]-L-proline.
Example 31
trans-1-[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-4-
[[(diisopropylamino)carbonyl]oxy]-L-proline
Utilizing the procedure of Example 30,
but substituting diisopropylamine for the ammonia
in part a, trans-l-[D-[3-acetylthio)-2-methyl-1-
oxopropyl]-4-[[(diisopropylamino)carbonyl]oxy]-L-
proline is obtained.
:
'' 113~4~iZ
-32~ l79a
x~ 32
tran~ [D-(3-Act~tyl l !,i ? -2-metlly~ x~)!)ro!~yl 1-4-
[[(cyclopropylamino)car)on~]oxy]-l,-l?roL-ine
Utilizing the procedure of Example 30, but
substituting cyclopropylamine for the ammonia in
part a, trans-l-[D-(3-acetylthio)-2-methyl-1-
oxopropyl]-4-[[(cyclopropylamino)carbonyl]oxy]-L-
proline is obtained.
Example 33
trans-l-~D-(3-Acetylthio?-2-methyl-1-oxopropyl]-4-
~[(n-butylamino?carbonyl]oxy]-L-proline
Utilizing the procedure of Example 30, but
substîtuting n-butylamine for the ammonia in part a,
trans-1-[D-(3-acetylthio)-2-methyl-1-oxopropyl]-4-
[[(n-butylamino)carbonyl]oxy]-L-proline is obtained.
Example 34
trans-l-[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-4-
[[(propargylamino)carbonyl]oxy]-L-proline
Utilizing the procedure of Example 30, but
substituting propargylamine for the ammonia in
part a, trans-l-[D-(3-acetylthio)-2-methyl-1-
oxopropyl]-4-[[(propargylamino)carbonyl]oxy]-L-
proline is obtained.
Example 35
trans-l-[D-(3-Acetylthio)-2-methyl-1-oxopropyl]-4-
[[(methylamino)carbonyl]oxy]-L-proline,methyl ester
A solution of the material from Example 1
in ether is treated with a slight excess of diazo-
methane. After stirring at room temperature for two
11384~
-83- HA179a
hours, the solvent is evaporated to give trans-l-
[D-(3-acetylthio)-2-methyl-1-oxopropyl]-4-
[[(methylamino)carbonyl~oxyl-L-r)roline, methyl ester.
;
Example 36
S,S-Dimer of trans-l-(D-3-mercapto-2-methyl-1-
oxopropyl)-4-[[(methylamino?carbonylloxy]-L-proline
A solution of the material from Example 2
; is dissolved in ethanol, stirred and treated with
a solution of one equivalent of iodine in ethanol.
The pH of the solution is maintained at 6-7 by
the addition of N sodium hydroxide solution. The
solvent is evaporated and the residue is extracted
with ethyl acetate. After drying over MgSO4,
the solution is filtered and the solvent is removed
to give S,S-dimer of trans-l-(D-3-mercapto-2-
methyl-l-oxopropyl)-4-[[(methylamino)carbonyl]oxy]-
L-proline.
Example_37
S,S-Dimer of cis-l-(D-3-mercapto-2-mcthyl-1-oxopropyl)-
4-[[(methylamino)carbonyl]oxo]-L-proline
Oxidation of the material from Example 4
with a solution of iodine according to the procedure
used in Example 36 gives S,S-dimer of cis-l-(D-3-
mercapto-2-methyl-1-oxopropyl)-4-[[(methylamino)-
carbonyl]oxo]-L-proline.
Example 38
Sodium salt of trans-l-[D-(3-acetylthio)-2-methyl-1-
_ _ _ . _ _
oxopropyl]-4-[[(methylamino)carbonyl]oxy]-L-proline
A solution of 2.9 g of material from Example 1
in 25 ml of water is treated with 0.84 g of sodium
bicarbonate. The solution is freeze-dried to give
-
1~3fl~
HA179a
-34-
the sodium salt of trans-l- ID- t3-acetylthio)-2-
methyl-l-oxopropyl]-4-~l(methylamin~)carbonyl]oxy]-
L-proline.
Example 39
1000 tablets each containing 100 mg. of
active substance are produced from the following
ingredients:
cis-l-(D-3-mercapto-2-
methyl-1-oxopropyl)-4-[[(methyl-
amino)carbonyl]oxy]-L-proline 100 g.
Corn starch 50 g.
Gelatin 7.5 g
Avicel (microcrystalline cellu-
15 lose 25 g.
Magnesium stearate 2.5 g.
The cis-l-(D-3-mercapto-2-methyl-1-
oxopropyl)-4-[l(methylamino)carbonyl]oxy]-L-proline
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.
:
* Trade Mark
.
~ j
., 11384C~2
_ ~r~_ 111~17
l~x~mple 40
1000 tablets each containing 200 mg. of trans-
l-(D-3-mercapto-1-oxopropyl)-4-[[(methylamino)-
carbonyl]oxy]-L-proline are produced from the
following ingredients:
trans-1-(D-3-mercap~l-oxopropyl)-
4-[[(methylamino)carbonyl3Oxy~-
L-proline 200 g.
Lactose 100 g.
Avicel 150 g.
C~rn Starch 50 g.
Magnesium stearate 5 g.
me trans-l-(D-3-mercapto-1-oxo~ropyl)-4-[[(m~thyl-
amino)carbonylloxy]-L-proline~lactose and ~vicel 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 containing 200 mg. of active
ingredient. The tablets are coated with a solution
of Methocel E 15 (methyl eellulose) including as
a color a lake containing yellow #6.
Example 41
Two pieee #l gelatin capsules eaeh eontaining-
250 mg. of trans-1-(D-3-mercapto-2-methyl-1-
oxopropyl)-4-[[(methylamino)carbonyl~oxy~-L-proline
are filled with a mixture of the following ingredients:
trans-l-(D-3-mereapto-2-
methyl-l-oxopropyl)-4-[[(methyl-
amino)carbonyl~oxy~-L-proline 125 mg.
Magnesium stearate 3 mg.
* Trade Mark
. i
- . ' ' ''- ' ' - ~ : ~
- ~13~41~2
11~179 a
USP lactose lOU m-~.
~xample 42
An injectable solution is produced as follows:
trans-l-(D-3-mercapto-2-
methyl-1-oxopropyl-4-[1(methyl-
amino)carbonyl]oxy]-L-proline 500 g.
Methyl paraben 5 g.
Propyl paraben 1 g.
Sodium chloride 25 g.
~ Water for injection qs. 5 1.
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-
sterilized vials which are then closed with
presterilized rubber closures. Each vial contains
5 ml. of solution in a concentration of 100 mg. of
active ingredient per ml. of solution for injection.
:
* Trade Mark
