Note: Descriptions are shown in the official language in which they were submitted.
11~7~
The present invention is related to substituted
N-aniline-4-chloro-3-sulphamoyl benzamides of general
formula I
Cl~ONHN~ II)
S2NH2
wherein R represents a hydrogen atom or a methyl radical
and Rl is a radical selected from the group consisting of
methyl, ethyl, isopropyl, 2-hydroxyethyl and phenyl, and to
a process for preparation thereof.
The present invention, in particular, relates to
benzamides of general formula I above andtheir process of
preparation wherein R is hydrogen and Rl is selected from
methyl and ethyl.
In the literature a number of substituted hydra-
zides of 4-chloro-3-sulphamoyl benzoic acid has been
described which exhibit aiuretic and saliuretic activity.
Thus for example in the U.S. Patent no. 3 119 847 phenyl-
hydrazides of 4-chloro-3-sulphamoyl benzoic acid with various
substituents on the benzene ring of the phenylhydrazine group
were described which phenylhydrazides exhibited diuretic and
saliuretic activity. The same activity was found in the
case of dialkyl hydrazides of 4-chloro-3-sulphamoyl benzoic
acid which are described in the U.S. Patent no. 3 043 874.
It has been found that the new hydrazides of
general formula (I) above exhibit in addition to high
diuretic and saliuretic activity a significant antihyperten-
sion.
A compound of formula (I), in which formula R
represents a hydrogen atom and Rl stands for the methyl
group, is especially advantageous in this sense.
Diuretic and saliuretic activity or this compound
~ ~789~
in the dose 0.2 mg applied perorally to rat is the same as
the effect of peroral dose 0.5 mg/rat of known and clini-
cally employed diuretics clopamide.
- la -
~78~9
Antihypertension ac-tivity of this compound was
established on the one hand with rats with experimental
hypertension induced by subcutaneous implantation of DOCA
pellet after unilateral nephrectomy and on the o-ther hand
with Macac rhesus monkeys ~macaca mulatta). The effect was
compared with the activity of known clinically used diure-tics
indapamide. In -the dose 10 mg/kg p.o. for rats the compound
presented reduced blood pressure by 10 to 15 ~l the ma~imum
reduction taking place in the -third hour after administra-
tion. In this test the compound was at leas-t equally effec-
-tive as the indapamide mentioned. For monkeys the effect
of the compound according to -the invention was compared with
indapamide in the dose 2x25 mg/kg p.o. Approximately equal
suppression of pressure took place in both cases.
The compound additionally has a low toxicity. At a
dosage of 2.5 g/kg it does not evoke any signs of toxicity
in rats. It thus has preconditions for clinical employment
for curing hypertension disease.
The invention is also related to a process for
producing compounds of general formula I. They can be pro-
duced by acylation of substituted hydrazines of general
formula (II)
R ~ llH2 (II),
wherein R and Rl represent the same as in -the formula I,
with a halogenide (preEerably a chloride) of ~-chloro-3-
sulphamoyl benzoic acid (British Patent no. 915 259). The
acylation can be carried out in an inert organic solvent
and in the presence of an agen-t which is able to bind halo-
genide resulting from the reac-tion. The acylation can be
carried out at a temperature of 10 to 30C.
Substituted hydrazines of general formula (II) are
~7i~9
altogether known compounds.
Acylation of substitutea hydrazines of general
formula (II) can be realized by the addition of 4-chloro-3-
sulphamoyl benzoyl chloride or its solution in tetrahydro-
furan to a solution of substituted hydrazine of general
Eormula (II) in a suitable inert solven-t, for example in
chloroform or tetrahydrofuran, without cooling or under
cooling wi-th ice water. The reaction is then finished by
s-tanding the reaction mixture at room tempera-ture for 2 to
16 hours. Solvents employed are evaporated under reduced
pressure and evaporation residue is mixed between water and
water-immiscible solvent, for example ethyl acetate. Sepa-
rated organic solution is dried with anhydroux potassium
carbonate or anhydrous sodium sulphate and the solvent is
evaporated. The evaporation residue is either directly
crystallized from organic solvent or a mixture of solvents
or it ispreviouslypurified by chromatography using an alumina
column, less polar impurities being separated by elution
with benzene. Compounds of general formula (I) are then
eluted with a mixture of chloroform and methanol.
Details of the process for producing according to
the invention are presented in the examples of embodiment
which are nevertheless only an illustration of possibilities
of the invention without exhausting all the possibilities.
Example l
N-(N-methylaniline)-~-chloro-3 sulphamoyl Benæamide
18 g oE ~-chloro-3-sulphamoylbenzoyl chloride is added in
parts under mixing to a solution of 8.7 g of l-methyl-l-
phenyl hydrazine and 7.l g of trie-thylamine in lO0 ml of
chloroEorm in such way temperature of the reaction mixture
at external cooliny with water would not exceed 20C.
Reaction mix-ture is leEt torest at room t:emperature Eor 16
hours. ChloroEorm is distilled-off under reduced pressure
and evaporation residue is mixed between lO0 ml of ethyl
7~39~ `
aceta-te and 50 ml of water. The organic layer is separated
and the aqueous layer is extracted with 50 ml of ethyl acetate.
United organic solutions are dried with anhydrous sodium
sulphate and ethyl acetate is evaporated under reduced
pressure. The evaporation residue is recrystallized from a
small amount of a mixture of methanol and ether. 12.3 g
(52 % of theory) of product having melting point 224 to
225C is obtained. Analytically pure compound recrystal-
lized from methanol has melting point 225 to 226C.
Example 2
N-(N-ethylaniline)-4-chloro-3-sulphamoyl Benzamide
By an analogous process as in the Example 1 16.3 g of crude
non crystalline evaporation residue is obtained from 6.8 g
of l-ethyl-l-phenylhydrazine and from 12.7 of 4-chloro-3-
sulphamoyl chloride in 80 ml of chloroform in the presence
of 5.1 g of triethylamine, which residue is purified by
chromatography on 500 g alumina column. Less polar impu-
rities are removed by elution with benzene and the product
is obtained by elution with a mixture of chloroform and
methanol (9:1). 6.4 g (36 % of theory) of product is
obtained having melting point 155 to 159DC. The Pure com-
pound has a melting point of 160 to 161C (methanol-ether).
The following compounds were produced by the same process
as in the Example 2:
N-(N-isopropylaniline)-4-chloro-3-sulphamoyl benzamide,
melting point 117 to 119C (methanol-ether),
N-(N-methyl-p-toluidine)-4-chloro-3-sulphamoyl benzamide,
melting point 201 to 203C (ethanol),
N-(diphenylamine)-4-chloro-3-sulphamoyl benzamide, hemi-
hydrate, melting point 200 to 202C (methanol).
Example 3
N-(N-t2-hydroxyethyl) aniline)-4-chloro-3-sulphamoyl
Benzamide
Solu-tion of 10.1 g of 4-chloro-3-sulphamoylbenzoyl chloride
9~
in 80 ml tetrahydrofuran is added dropwise under stirring
within one hour and under external cooling to 10C to a
solution of 6.1 g of l-(2-hydroxyethyl)-l-phenylhydrazine
and 4 g of triethylamine in 120 ml tetrahydrofuran. The
reaction mixture is left to rest at room -temperature for 16
hours, separated triethylamine hydrochloride is sucked oEf
and filtrate is evaporated under reduced pressure. Evapora-
-tion residue (16 g) is puriEied by chromatography on a
col.umn of ~80 g of alumina. Less polar impurities are
separated by elution with benzene. The product is obtained
by elution with a mixture of chloroform and methanol (9:1).
5.8 g (~0 ~ of theory) of pure product having melting point
140 to 1~1C is obtained after crystallization from methanol
under addition of ether.
