THIOPROPANOYLAMINO ACID DERIVATIVES

DERIVES D'ACIDE THIOPROPANOYLAMINE

English Abstract

Abstract
THIOPROPANOYLAMINO ACID DERIVATIVES
New thiopropanoylamino acid derivatives which
have the formula
<IMG>
wherein R3 and R5 each is lower alkyl;
R is hydrogen or lower alkyl;
R4 is hydrogen, lower alkanoyl or benzoyl;
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 having the formula:
I <IMG>
wherein R3 and R5 each is lower alkyl; R is hydrogen or lower
alkyl; R4 is hydrogen, lower alkanoyl or benzoyl which com-
prises either
a) reacting a compound having the formula
IV <IMG>
wherein X is halogen, with a compound having the formula
V R4SH
wherein R4 is lower alkanoyl or benzoyl to obtain a compound
of formula I wherein R4 is lower alkanoyl or benzoyl and R,
R3 and R5 have the meaning defined above; or
b) treating a compound of formula I wherein R4 is lower
alkanoyl or benzoyl with ammonia or concentrated ammonium
hydroxide to obtain a compound of formula I wherein R4 is
hydrogen and R, R3 and R5 have the meaning defined above; or
c) reacting a compound of formula IV with an alkali metal
busulfide to obtain a compound of formula I wherein R4 is

hydrogen and R, R3 and R5 have the meaning defined above.
2. The process as in claim 1 wherein R4 is acetyl.
3. The process as in claim 1 wherein R and R4 each is
hydrogen and R3 and R5 each is lower alkyl.
4. The process as in claim 1 wherein R and R4 each is
hydrogen and R3 and R5 each is lower alkyl.
5. A compound of the formula
I <IMG>
wherein R3 and R5 each is lower alkyl; R is hydrogen or lower
alkyl; and R4 is hydrogen, lower alkanoyl or benzoyl when
prepared by the process of claim 1.
6. A compound as in claim 5 wherein R4 is acetyl when
prepared by the process of claim 2.
7. A compound as in claim 5 wherein R and R4 each is
hydrogen and R3 and R5 each is lower alkyl when prepared by
the process of claim 3.
8. A compound as in claim 5 wherein each lower alkyl
group is methyl and R and R4 each is hydrogen when prepared
by the process of claim 4.

Description

~10~47~ HAl47b
THIOPROPANOYLAMINO ACID DERIVATIVES
This invention relates to new thiopropanoylamino
acid derivatives which have the formula
(I)
R
13 ~
R4 S CH2 C CO N C-COOH
R5 R
In formula I and throughout this specification
the symbols have the meanings described below.
R3 and R5 each is lower alkyl;
R is hydrogen or lower alkyl;
R4 is hydrogen, lower alkanoyl or benzoyl.
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 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.
The compounds of formula I are produced from
amino acid compounds having the formula
(II)
HN - C - COOH
R
by reacting such an acid with a halopropanoyl halide

7S
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having the formula
(III)
13
X--CH -C CO-X
R5
wherein each X is halogen, preferably chlorine or
bromine, to obtain an intermediate having the formula
(IV)
13 ~
X-CH2-f - CO-N f ----COOH
R5 R
Treatment of this intermediate with a mercaptan
(V)
R4 SH
(wherein R4 is other than hydrogen)
20 yields a product having the formula
(VI )R
13
R4-S-CH2-C co ~ f COOH
5 R
R4 in this instance is other than hydrogen, i.e.,
the acyl groups lower alkanoyl or benzoyl. By treating
the acyl derivative of formula IV with ammonia or
concentrated ammonium hydroxide, a compound of
formula VI wherein R4 is hydrogen is derived.

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Alternatively, by treating the intermediate of
formula IV with an alkali metal bisulfide like
sodium bisulfide, a product of formula VI wherein
R4 is hydrogen is directly obtained.
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 hypo-
tensive agents, particularly for the reduction of
angiotensin dependent hypertension. By administering
a composition containing one or a combination of
angiotensin converting enzyme inhibitor of this
invention to a hypertensive mammal, it intervenes in
the angiotensinogen ~ trenin) ~ angiotensin I
angiotensin II sequence and the hypertension is
reduced or alleviated.
A single dose, or preferably two to four divided
daily doses, provided on a basis of about 1 to 1000 mg.
per kilogram per day and especially about 10 to 200
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 patenteral use.
,: - " ~ ' ' '
,:

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About 50 to 1500 mg. of a compound or compounds
of formula I can be compounded with a physiologically
acceptable vehicle, carrier, excipient, binder, pre-
servative, stabilizer, flavor, etc., in a conventional
unit dosage form as called for by accepted pharmaceu-
tical 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.
Example 1
1-(3-Mercapto-2,2-dimethyl-1-oxopropyl-L-proline
a) 1-(3-Chloro-2,2-dimethyl-1-oxopropyl)-L-proline
L-proline (1.15 g.) is dissolved in 11.8 ml.
of 0.85 N sodium hydroxide with vigorous stirring in
an ice-bath. To this solution 5 ml. of 2N sodium
hydroxide is added, followed immediately by ~-chloro-
pivalic acid chloride and 2 ml. of ether. After 3.5hours, the ninhydrin test is almost negative. To
this reaction mixture 12.9 ml. of 0.85 N sodium
hydroxide and 820 mg. of thiolacetic acid are added
and stirred overnight at room temperature. This is
acidified with concentrated hydrochloric acid and
extracted with ethyl acetate. This material is
dissolved in a mixture of ether-hexane (1:10) and the
crystalline product that separates (0.4 g., m.p. 116-
118, tlc identical to mother liquors) is filtered and
the filtrate is concentrated to dryness in vacuo and
; utilized without further purification.

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HA147b
b) l-(3-Mercapto-2,2-dimethyl-l-oxopropyl)-L-proline
The R-chloropivaloyl proline from part a (1.15 g.)
is dissolved in 5 ml. of water and 920 mg. of sodium
bisulfide-H2O under a continuous stream of nitrogen.
The mixture is heated on the steam cone for one hour,
acidified with concentrated hydrochloric acid and
extracted with ethyl acetate, yield 1.1 g. The
product is purified by silica gel chromatography
with benzene-acetic acid (7:1). The product 1-(3-
mercapto-2,2-dimethyl-1-oxopropyl)-L-proline is then
crystallized from ethyl acetate and hexane, yield
180 mg., m.p. 94-96.