CARBOXYMETHYL ESTERS OF MERCAPTOPROPANOIC ACIDS

CARBOXYMETHYLESTERS D'ACIDES MERCAPTOPROPANOIQUES

English Abstract

ABSTRACT
New carboxymethyl esters of mercaptopropanoic
acids,and salts thereof,have the formula
<IMG>
wherein R is hydrogen or lower alkanoyl;
R1 is hydrogen or lower alkyl; and
R2 is hydrogen, lower alkyl, phenyl,
phenyl-lower alkyl, 4-hydroxyphenyl-lower alkyl or
indolyl-lower alkyl.
They are useful as hypotensive agents.

Claims

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
<IMG>
wherein R is hydrogen or lower alkanoyl; R1 is hydrogen or
lower alkyl; R2 is hydrogen, lower alkyl, phenyl, phenyl-
lower alkyl, 4-hydroxyphenyl-lower alkyl or indolyl-lower
alkyl; and salts thereof, characterized by reacting an alpha-
hydroxy acid of the formula
<IMG>
with an acid having the formula
<IMG>
by conventional esterification procedures.
2. A process as in claim 1 wherein R is hydrogen or
lower alkanoyl; R1 is hydrogen or lower alkyl; and R2 is
hydrogen or phenyl-lower alkyl.
3. A process as in claim 1 wherein R is hydrogen.
4. A process as in claim 1 wherein R is lower alkanoyl.
5. A process as in claim 1 wherein R is acetyl.
6. A process as in claim 1 wherein R, R1 and R2 each
is hydrogen.
7. A process as in claim 1 wherein R is lower alkanoyl;
R1 is lower alkyl; and R2 is hydrogen.
8. A process as in claim 1 wherein R is acetyl; R1 is
methyl and R2 is hydrogen.
11

9. A process as in claim 1 wherein R and R2 each is
hydrogen and R1 is methyl.
10. A process as in claim 1 wherein R and R1 each is
hydrogen and R2 is phenyl-lower alkyl.
11. A process as in claim 1 wherein R and R1 each is
hydrogen and R2 is phenylmethyl.
12. A process as in claim 1 wherein R and R1 each is
hydrogen, R2 is phenylmethyl and the product is in the
L-form.
13. A process as in claim 1 wherein R2 is indolylmethyl.
14. A process as in claim 1 wherein R and R1 each is
hydrogen and R2 is 3-indolylmethyl.
15. A process as in claim 1 wherein R is hydrogen, R1
is methyl and R2 is 3-indolylmethyl.
16. A compound of the formula
<IMG>
wherein R is hydrogen or lower alkanoyl; R1 is hydrogen or
lower alkyl; R2 is hydrogen, lower alkyl, phenyl, phenyl-
lower alkyl, 4-hydroxyphenyl-lower alkyl or indolyl-lower
alkyl; and salts thereof, whenever prepared by the process
of claim 1.
17. A compound as in claim 16 wherein R is hydrogen
or lower alkanoyl; R1 is hydrogen or lower alkyl and R2 is
hydrogen or phenyl-lower alkyl, whenever prepared by the
process of claim 2.
18. A compound as in claim 16 wherein R is hydrogen,
whenever prepared by the process of claim 3.
19. A compound as in claim 16 wherein R is lower
alkanoyl, whenever prepared by the process of claim 4.
12

20. A compound as in claim 16 wherein R is acetyl,
whenever prepared by the process of claim 5.
21. A compound as in claim 16 wherein R, R1 and R2
each is hydrogen, whenever prepared by the process of claim 6.
22. A compound as in claim 16 wherein R is lower
alkanoyl; R1 is lower alkyl; and R2 is hydrogen, whenever
prepared by the process of claim 7.
23. A compound as in claim 16 wherein R is acetyl, R1
is methyl and R2 is hdyrogen, whenever prepared by the process
of claim 8.
24. A compound as in claim 16 wherein R and R2 each
is hydrogen and R1 is methyl, whenever prepared by the
process of claim 9.
25. A compound as in claim 16 wherein R and R1 each
is hydrogen and R2 is phenyl-lower alkyl, whenever prepared
by the process of claim 10.
26. A compound as in claim 16 wherein R and R1 each is hydrogen,
and R2 is phenylmethyl; whenever prepared by the process of claim 11.
27. A compound as in claim 16 wherein R and R1 each
is hydrogen, R2 is phenylmethyl and the product is in the
L-form, whenever prepared by the process of claim 12.
28. A compound as in claim 16 wherein R2 is indolyl-
methyl, whenever prepared by the process of claim 13.
29. A compound as in claim 16 wherein R and R1 each
is hydrogen and R2 is 3-indolylmethyl, whenever prepared
by the process of claim 14.
30. A compound as in claim 16 wherein R is hydrogen,
R1 is methyl and R2 is 3-indolylmethyl, whenever prepared
by the process of claim 15.
13

Description

HA154
This invention relates to new carboxymethyl esters
of mercaptopropanoic acids which have the formula
(I) IRl lR2
R-S-CH2-(~H-CO-O-CH-COOH
and to salts thereof.
In formula I and throughout this specification the
symbols have the meanings described below.
,~ R is hydrogen or lower alkanoyl.
Rl is hydrogen or lower alkyl.
;~ R2 is hydrogen, lower alkyl, phenyl, phenyl-lower
..: .
alkyl, 4-hydroxyphenyl-lower alkyl or indolyl-lower alkyl.
The lower alkyl groups are straight or branched
chain hydrocarbon radicals having up to seven carbon
atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl,
sec.butyl and the like. The Cl-C4 and especially Cl-C2
alkyl groups are preferred. The phenyl-lower alkyl and indolyl-
, lower alkyl groups include lower alkyl groups of the same
type (with the same preferences expressed above.)
: The lower alkanoyl groups are the acyl radicals of the
lower (C2-C7~ fatty acids, e.g., acetyl, propionyl, butyryl,
isobutyryl and the like. The members mentioned, and especially
acetyl, are preferred.
Preferred members of the invention are those compounds
of formula I wherein R is hydrogen or lower alkanoyl,
especially acetyl; Rl is hydrogen or lower alkyl, especially
_ / _
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-~ _ HAl54
methyl; and R2 is hydrogen, phenyl-lower alkyl or indolyl
lower alkyl especially phenylmethyl.
The compounds of formula I are produced by acylation
of an a-hydroxy acid having the formula
(II) 12
HO-CH-COOH
with an acid having the formula
: (III)
Rl
R-S-CH2-CH-COOH
by conventional esterification procedures.
A preferred method comprises activating the acid of
formula III with carbodiimidazole to form the acylimidazole
intermediate having the formula
(IV) R
;. , I ~
, R-S-CH2-CH-CO-N~N
which is used without isolation. It is also preferred to
form a product wherein R is lower alkanoyl, then treat the
` acyl derivative with ammonia or concentrated ammonium
hydroxide to obtain the product wherein R is hydrogen.
The carbon atoms marked with an asterisk in formula I are
asymmetric if Rl and R2 are other than hydrogen. Thus the
compoundswith the asymmetric carbon exist as_diastereoisomers
or in racemic mixtures thereof. All of these are within
the scope of the invention.
The a-hydroxy acids of formula II are well known
~; in the literature and can be produced by the many methods
available.
The mercaptopropanoic acids of formula III can
be produced as described in U.S. Patent No. 4,053,651
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HA154
issued October 11, 1977 and Belgian Patent No. 851,361 granted
August 11, 1977 e.g., by reacting a thioacid of the formula
(VI)
R4-CO-SH
wherein R4 is lower alkyl,
with an acrylic acid having the formula
(VII)
CH2=C-COOH
The R4-CO group can be removed at this stage or
later by treatment with ammonia or concentrated ammonium
hydroxide as described above.
The compounds of formula I form the common (basic)
~; salts of carboxylic acids, e.g., by reaction with inorganic
- or organic bases. Such salts include ammonium salts, alkali
metal salts like sodium and potassium salts, alkaline earth
meta~ like calcium and magnesium salts, salts with organic
bases, e.g., dicyclohexylamine, benzathine, hydrabamine
and N-methyl-D-glucamine salts. Since some of the compounds
of formula I are not readily obtainable as crystalline
; substances with well defined melting points, the salts
(which are not necessarily physiologically acceptable) provide
means to isolate and characterize the product.
Additional experimental details can be found in the
illustrative examples below.
The compounds of this invention are angiotensin
.
converting enzyme inhibitors and are useful as hypotensive
: agents, particularly for the reduction of renin-angiotcnsin
dependent hypertension. By administering a composition
containing one or a combination of angiotensin converting
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enzyme inhibitors of this invention to a hypertensive
mammal, it intervenes in the renin ~ angiotensinogen ~
angiotensin I ~ angiotensin II sequence and the hypertension
is reduced or alleviated.
A singledose, or preferably two to four divided
daily doses, provided on a basis of about 1 to 1000 mg.
per ~ilogram per day and especially about 10 to 100 mg.
per kilogram per day is appropriate to bring about a reduction
in elevated blood pressure. The animal model experiments
described by Engel et al., Proc. Soc. Exp. Biol. Med. 143,
483 (1973) provide a valuable guide.
:
The composition is preferably administered orally,
but it can also be administered subcutaneously, intramuscularly,
intravenously or intraperitoneally. The compound or
; compounds of formula I can be formulated as tablets,
capsules or elixirs for oral administration. Sterile
solutions or suspensions can be used for parenteral use.
About 20 to 1000 mg. of a compound or compounds of
formula I or physiologically acceptable salt thereof can be
compounded with a physiologically acceptable vehicle,
carrier, excipient, binder, preservative, stabilizer,
flavor, etc., in a conventional unit dosage form as called
for by accepted pharmaceutical practice. The amount
of active substance is selected so as to provide a dosage
in the range indicated.
The following examples are illustrative of the invention -
and represent preferred embodiments. All temperatures are
in degrees Celsius.
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~ HA154
Example 1
o-(3-Acetylthiopropanoyl)glycolic Acid
3-(Acetylthio)propanoic acid (2.96 g.) and l,l'-car-
bonyldiimidazole (3.24 g.) are dissolved in 20 ml. of dry
tetrahydrofuran with stirring at room temperature. After
twenty minutes,a solution of glycolic acid (1.52 g.) and
- 2.80 ml. of triethylamine in 15 ml. of dry tetrahydrofuran
are added. The reaction mixture is stored overnight at room
temperature. The tetrahydrofuran is removed in vacuo, the
crude residue taken up into ethyl acetate, washed with lN
hydrochloric acid and three times with water, dried over
magnesium sulfate and the 0-(3-acetylthiopropanoyl)glycolic
acid is concentrated to dryness in vacuo, yield 3.9 g.
` This is dissolved in ether and dicyclohexylamine is added.
The dicyclohexylamine salt precipitates, yield 2.85 g.;
m.p. 150-157. The salt is converted to the free acid by
adding to ethyl acetate and adding 10% potassium bisulfate
solution, yield 1.5 g.
: Example 2
0-(3-Mercaptopropanoyl)~lycolic Acid
0-~3-acetylthiopropanoyl)glycolic acid from Example 1
' (1.3 g.), under a blanket of argon is treated for fifteen
- minutes with a cold solution of 7 ml. of water and 7 ml. of
concentrated ammonium hydroxide. This is chilled, acidified
with concentrated hydrochloric acid and extracted into ethyl
acetate, yield: 1.2 g. This product 0-(3-mercaptopropanoyl)-
glycolic acid is chromatographed on DEAE Sephadex A25
~Polidextrane* anion exchange resin) with a linear gradient of
ammonium bicarbonate. The desired fractions (45-70; U.V.
peak at 254 nm.) are pooled, concentrated and lyophilized.
* -5-
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A154
This ammonium salt of 0-(3-mercaptopropanoyl)glycolic acid
is converted to the free acid by treatment with Dowex 50WX2
cation exchange resin, yield 320 mg. The 0-(3-mercapto-
- propanoyl)glycolic acid is converted to the dicyclo-
hexylamine salt by dissolving in ether and precipitating
by the addition of dicyclohexylamine, m.p. 143-144 .
Example 3
0-[3-(Acetylthio)-2-Methylpropanoyl]Glycolic Acid
A mixture of thioacetic acid (50 g.) and methacrylic
acid (40.7 g.) is heated on the steam bath for one hour and
then stored at room temperature for 18 hours. After confirming
by nmr spectroscopy that complete reaction of the methacrylic
acid has been achieved, the reaction mixture is distilled
in vacuo and the desired 3-acetylthio-2-methylpropanoic --
acid is separated in the fraction with boiling point 128.5-131
(2.6 mmHg.), yield 64 g.
3-Acetylthio-2-methylpropanoic acid (6.48 g.) is taken
into 40 ml. of dry tetrahydrofuran. To this l,l'-carbonyl-
diimidazole (0.48 g.) is added and stirred for 30 minutes
at room temperature. Glycolic acid (6.08 g.) and 11.2 ml.
of triethylamine in 60 ml of dry tetrahydrofuran are added. !~
After several minutes, the imidazole salt of glycolic acid
begins to come out of solution. The reaction is permitted to
run overnight at room temperature. The crystalline salt
is filtered and the filtrate concentrated to dryness in vacuo.
The residue is taken up into ethyl acetate, washed with lN
hydrochloric acid and three times with water, dried over
magnesium sulfate and concentrated to dryness in vacuo.
This product is converted to its dicycloehxylamine salt by
dissolving in ether/hexane and precipitating by the addition
*
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~ o~
IIA154
of dicyclohexylamine. The salt is recrystallized from
ether, m.p. 120-122 . This salt is then converted to the
free acid, 0-[3-(acetylthio)-2-methylpropanoyl]glycolic acid,
by adding to ethyl acetate, addin~ 10~ potassium bisulfate
solution, then crystallizing from ethyl/hexane, yield
2.96 g., m.p. 50-51.
Example 4
O-(DL-3-Mercapto-2 Methylpropanoyl)Glycolic Acid
0-[3-(Acetylthio)-2-methylpropanoyl]glycolic acid
(1.5 g.) is placed under a blanket of argon. To this a
cold solution of 7.5 ml. of concentrated ammonium hydroxide and
.~,.
~,l 7.5 ml. of water is added and the mixture is stored for
; 15 minutes at room temperature. This is then acidified
with concentrated hydrochloric acid and extracted with ethyl
acetate, yield 1.3 g. This product is dissolved in
ether/hexane and dicyclohexylamine is added to precipitate
the dicyclohexylamine salt, yield 2.24 g., m.p. 96-98.
A 1.9 g. aliquot of the salt is converted to the free
O-(DL-3-mercapto-2-methylpropanoyl)glycolic acid by adding
to ethyl acetate and adding 10~ potassium bisulfate ~solution,
yield 0.9 g. The product is a heavy oil which is chromatographed
on silica gel (benzene 7:2 acetic acid), Rf=0.49, traces Rf=0.32
and 0.57.
Example 5
O-L-[3-(Acetylthio)propanoyl]-3-Phenyllactic Acid
3-(Acetylthio)propanoic acid (1.48 g.) is added to
10 ml. of dry tetrahydrofuran with stirring. To this
l,l'-carbonyldiimidazole (1.62 g.) is added ~nd the mixture
stirred for twenty minutes at room temperature. L-(-)-
3-phenyllactic acid (1.66 g.) is added in a solution of
-7-
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HA154
7.5 ml. of dry tetrahydrofuran and 1.4 ml. of triethyl-
amine. The reaction mixture is stored overnight at room
temperature. The tetrahydrofuran is removed in vacuo, the
residue is taken up into ethyl acetate, washed with lN
hydrochloric acid, three times with water, dried over
magnesium sulfate and concentrated to dryness in vacuo,
yield 2.8 g. The O-L-[3-(Acetylthio)propanoyl]-3-pheny~actic
acid is purified on a silica gel column,eluting with benzene
7:1 acetic acid, yield 1.7 g. -
Example 6
O-L-(3-Merca~topropanoyl)-3-Phenyllactic Acid
To 1.5 g. of O-L-[3-(acetylthio)propanoyl]-3-phenyllactic
acid a solution of 7.5 ml. of water and 7.5 ml. of concentrated
ammonium hydroxide is added under an argon blanket. After
fifteen minutes, the reaction mixture is chilled, acidified
- with concentrated hydrochloric acid and extracted into
ethyl acetate, yield 1.1 g. The product, O-L-(3-mercapto-
propanoyl)-3-phenyllactic acid is purified on a silica gel
column, eluting with benzene 14:1 acetic acid, yield 357 mg.
A small portion of the semi-solid product is converted to its
dicyclohexylamine salt by dissolving in ether/hexane and
precipitating with dicyclohexylamine, m.p. 100.
Example 7
O-DL-(3-Acetylthiopropanoyl)-3-Indolelactic Acid
By substituting DL-3-indolelactic acid for the L-~-
- phenyllactic acid in the procedure of Example 5, O-DL-
(3-acetylthiopropanoyl)-3-indolelactic acid is obtained.
Example 8
O-DL-(3-Mercaptopro~ano~1)-3-Indolelactic Acid
- 30 By substituting O-DL-(3-acetylthiopropanoyl)-3-
--8--
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J~ HA154
indolelactic acid for the O-L-(3-acetylthiopropanoyl)-3-phenyl-
lactic acid in the procedure of Example 6, O-DL-(3-mercapto-
propanoyl)-3-indolelactic acid is obtained, as the dicyclohexyl-
- amine salt, m.p. 151-153C.
Example 9
O-DL-(3-Mercapto-2-Methylpropanoyl)-3-Indolelactic Acid
;~' .
, By substituting 3-indolelactic acid for the glycolic acid in
,~i the procedure of Example 3 and then submitting the product to the
procedure of Example 4, O-DL-[3-(acetylthio)-2-methylpropanoyl]-
3-indolelactic acid and O-DL-(3-mercapto-2-methylpropanoyl)-3-
indolelactic acid are obtained.
Example 10
' O-L-(3-Mercaptopropanoyl)lactic Acid
~ By substituting L-lactic acid for the glycolic acid in the
- procedure of Example 1 and then submitting the product to the
~- procedure of Example 2, O-L-(3-acetylthiopropanoyl)lactic acid
;~ and O-L-(3-mercaptopropanoyl)lactic acid are obtained.
,',:
Example 11
O-L-(3-Mercaptopropanoyl)--Hydroxyisocaproic Acid
By substituting L-~-hydroxyisocaproic acid [Winitz, et al.,
J. Am. Chem. Soc. 78, 2423 (1956)] for the glycolic acid in the
procedure of Example 1 and then submitting the product to the
procedure of Example 2, O-L-(3-acetylthiopropanoyl)-a-hydroxy-
isocaproic acid and O-L-(3-mercaptopropanoyl)-~-hydroxyisocaproic
acid are obtained.
~- Example 12
;~ O-L-(3-Acetylthiopropanoyl)-3-(p-tert-butoxyphenyl)lactic Acid
By substituting 3-(p-tert-butoxyphenyl)lactic acid
, [obtained from O-tert-butyl-L-tyrosine by the procedure
described by H.D. Dakin and H.W. Dudley in J. Biol. Chem.,
18, 29 (1914) for the preparation of 3-L-phenyllacetic acid]
, .
.:
. .,
_ g _
. ', .
' .

-- ~0'~3~`jf~
HA154
. for, the 3-L-phenyllactic acid in the procedure of Example 5,
O-L-(3-acetylthiopropanoyl)-3-(p-tert-butoxyphenyl)lactic acid
is obtained.
Exampl 13
O-L-(3-Mercaptopropanoyl)-3-p-Hydroxyphenyllactic Acid
;~ O-L-(3-acetylthiopropanoyl)-3-(p-tert-butoxyphenyl)lactic
.~ acid (1.8 g.) is dissolved in trifluoroacetic acid (15 ml.)
~ and the solution is stored at room temperature for
; one hour. After removing the trifluoroacetic acid in vacuo,
the residue is dissolved in a mixture of water (7.5 ml.) and ~`
concentrated ammonium hydroxide (7.5 ml.) under an argon
blanket. After fifteen minutes, the reaction mixture is
- chilled, acidified with concentrated hydrochloric acid and
extracted with ethyl acetate. The organic layer is con-
centrated in vacuo to yield O-L-(3-mercaptopropanoyl)!-3-
p-hydroxyphenyllactic acid.
Example 14
0-(3-Mercaptopropanoyl)mandelic Acid
By substituting mandelic acid for the L-3-ptienyllactic
acid in the procedure of Example 5, and then submitting the
product to the procedure of Example 6, 0-(3-acetylthiopro-
panoyl)mandelic acid and 0-(3-mercaptopropanoyl)mandelic
acid are obtained.
. . .
. ~
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