Hydrazine derivatives useful as anti-hypertensives

The invention provides novel hydrazine derivatives of the formula: ##STR1## in which R is a variously substituted oxy or thio substituted phenyl radical, 2-oxobenzimidazol-5-yl radical or 3-pyridyl radical; PA1 R' is a radical of formula: ##STR2## in which R.sub.5 and R.sub.6 taken separately are each hydrogen, and taken together form, with the nitrogen atoms to which they are attached, an imidazolinyl radical of formula; ##STR3## and R" is hydrogen or lower alkyl, and the pharmaceutically acceptable addition salts, with non-toxic acids, of these hydrazine derivatives. These compounds are useful as anti-hypertensive agents.

The present invention provides, as new compounds, the hydrazine derivatives 
of the formula: 
##STR4## 
in which R is either (a) a substituted phenyl radical of formula: 
##STR5## 
wherein A is O, S, or a direct bond, R.sub.1 is lower alkyl, lower 
alkenyl, lower alkynyl, benzyl, or cyclopropyl (by "lower" is meant of up 
to 4 carbon atoms) and R.sub.2 is hydrogen or halogen, or (b) the radical 
of formula: 
##STR6## 
wherein R.sub.3 is hydrogen, methyl or methoxy, or (c) a radical of 
formula: 
##STR7## 
wherein R.sub.4 is halogen, alkylthio or benzylthio; R' is a radical of 
formula: 
##STR8## 
in which R.sub.5 and R.sub.6 taken separately are each hydrogen, and taken 
together form, with the nitrogen atoms to which they are attached, an 
imidazolinyl radical of formula: 
##STR9## 
and R" is hydrogen or lower alkyl, and the pharmaceutically acceptable 
addition salts, with non-toxic acids, of these hydrazine derivatives. 
The invention also provides a process for the preparation of the compounds 
of formula (I), which comprises reacting an aldehyde or ketone of the 
formula R--CO--R" (R and R" having the meanings given above) with a salt 
of a hydrazine derivative of formula: H.sub.2 N--NH--R', wherein R' is as 
defined above, especially aminoguanidine sulphate or with 
hydrazinoimidazoline hydrobromide in an organic polar solvent, preferably 
a lower alcohol solvent, especially methanol or ethanol, or a glycol, 
optionally diluted with water, preferably at the reflux temperature of the 
solvent. 
The compounds of formula (I) and their salts possess pharmacological 
properties which make them of value in therapy. In particular, they are 
active on the cardiovascular system, especially as hypotensive agents. 
The invention thus includes within its scope pharmaceutical compositions 
comprising a compound of formula I or a non-toxic acid addition salt 
thereof in association with a pharmaceutical carrier, e.g. in the form of 
a tablet, pill, capsule, powder, syrup, elixir, or sterile injectable 
solution or suspension.

The invention is illustrated in the following Examples. 
EXAMPLE 1 
N-[o-(Prop-2-Y-noxy)-Benzylidene]-N'-Amidino-Hydrazine 
##STR10## 
A mixture of 0.1 mol of o-(prop-2-ynoxy)-benzaldehyde, 0.05 mol of neutral 
aminoguanidine sulphate and 200 cm.sup.3 of ethanol is heated under reflux 
for 6 hours. 
The solvent is evaporated in vacuo, the residue is taken up in 300 cm.sup.3 
of water, the solution is rendered alkaline with concentrated ammonia and 
extracted with ether, the ether extract is dried over sodium sulphate and 
the solvent is then evaporated in vacuo. 
The corresponding maleate salt is prepared as follows: the residue is 
dissolved in 150 cm.sup.3 of ethyl acetate and mixed with a solution of 
0.1 mol of maleic acid in 100 cm.sup.3 of ethyl acetate, the mixture is 
left to stand for 2 hours and is filtered, and the filter residue is 
washed with ethyl acetate and dried to give 24 g of 
N-[o-(prop-2-ynoxy)-benzylidene]-N'-amidino-hydrazine maleate. 
Melting point = 157.degree. C. 
EXAMPLE 2 
N-[o-(Prop-2-Enoxy)-Benzylidene]-N'-Amidino-Hydrazine 
##STR11## 
The procedure of Example 1 is repeated, but using 0.1 mol of 
o-(prop-2-enoxy)-benzaldehyde in place of o-(prop-2-ynoxy)-benzaldehyde. 
After evaporation of the ether, the base is recrystallised from a 70/30 
mixture of isopropanol/petroleum ether to give 16 g of 
N-[o-(prop-2-enoxy)-benzylidene]-N'--amidino-hydrazine. 
Melting point = 124.degree. C. 
EXAMPLE 3 
N-[o-(Prop-2-Enethio)-Benzylidene]-N'-Amidino-Hydrazine 
##STR12## 
The procedure of Example 1 is repeated, but using 0.1 mol of 
o-(prop-2-enethio)-benzaldehyde in place of o-(prop-2-ynoxy)-benzaldehyde. 
Finally, 26 g of N-[o-(prop-2-enethio)-benzylidene]-N'-amidino-hydrazine 
maleate are obtained. 
Melting point = 145.degree. C. 
EXAMPLE 4 
N-[o-(Prop-2-Ynoxy)-Benzylidene]-N'-Imidazolino-Hydrazine 
##STR13## 
A mixture of 0.1 mol of o-(prop-2-ynoxy)-benzaldehyde, 0.1 mol of 
hydrazino-imidazoline hydrobromide and 200 cm.sup.3 of ethanol is heated 
under reflux for 6 hours. 
It is allowed to return to ambient temperature and the product obtained is 
filtered off, washed with 50 cm.sup.3 of ethanol and dried, to give 29 g 
of N-[o-(prop-2-ynoxy)-benzylidene]-N'-imidazolino-hydrazine hydrobromide. 
Melting point = 231.degree. C 
EXAMPLE 5 
N-[o-(Prop-2-Enoxy)-Benzylidene]-N'-Imidazolino-Hydrazine Hydrobromide 
##STR14## 
The procedure of Example 4 is repeated, but using 0.1 mol of 
o-(prop-2-enoxy)-benzaldehyde in place of o-(prop-2-ynoxy)-benzaldehyde, 
to give 26 g of N-[o-(prop-2-enoxy)-benzylidene]-N'-imidazolino-hydrazine 
hydrobromide. 
Melting point = 172.degree. C. 
EXAMPLE 6 
N-[o-(Prop-2-Enethio)-Benzylidene]-N'-Imidazolino-Hydrazine Hydrobromide 
##STR15## 
The procedure of Example 4 is repeated, but using 0.1 mol of 
o-(prop-2-enethio)-benzaldehyde in place of o-(prop-2-ynoxy)-benzaldehyde, 
to give 25 g of 
N-[o-(prop-2-enethio)-benzylidene]-N'-imidazolino-hydrazine hydrobromide. 
Melting point = 187.degree. C. 
EXAMPLE 7 
N-(2-Methylthio-3-Pyridylidene)-N'-Imidazolino-Hydrazine Hydrobromide 
##STR16## 
A mixture of 13.4 g of 2-methylthio-nicotinaldehyde and 15.8 g of 
hydrazino-imidazoline hydrobromide in 160 cm.sup.3 of ethanol and 100 
cm.sup.3 of water is heated under reflux for 7 hours. 
The mixture is then concentrated in vacuo and the residue obtained is 
recrystallised from ethanol. 15.5 g of 
N-(2-methylthio-3-pyridylidene)-N'-imidazolino-hydrazine hydrobromide are 
thus obtained in the form of white crystals. 
Melting point = 250.degree.-251.degree. C. 
EXAMPLE 8 
N-(2-Benzylthio-3-Pyridylidene)-N'-Amidino-Hydrazine Dihydrochloride 
##STR17## 
A mixture of 15 g of 2-benzylthio-nicotinaldehyde and 8.7 g of neutral 
aminoguanidine sulphate in 120 cm.sup.3 of ethanol and 120 cm.sup.3 of 
water is heated under reflux for 12 hours. 
The reaction mixture is then cooled, mixed with ice and rendered alkaline 
with concentrated ammonia. 
The organic products are extracted with chloroform and the extract is 
washed with water and dried over sodium sulphate. 
The residue obtained after evaporation of the chloroform in vacuo is taken 
up in a mixture of methanol and ether; a solution of hydrogen chloride in 
ether is added thereto, in the cold. The precipitate obtained is filtered 
off, washed with ether and then recrystallised from methanol. 12 g of 
N-(2-benzylthio-3-pyridylidene)-N'-amidino-hydrazine hydrochloride are 
thus obtained in the form of white crystals. 
Melting point = 182.degree.-6.degree. C. 
EXAMPLE 9 
N-(o-Cyclopropylbenzylidene-N'-Amidino-Hydrazine 
##STR18## 
A mixture of 0.1 mol of o-cyclopropylbenzaldehyde, 0.05 mol of neutral 
aminoguanidine sulphate and 200 cm.sup.3 of ethanol is heated under reflux 
for 6 hours. 
A mixture is taken up in 400 cm.sup.3 of water and rendered alkaline with 
concentrated ammonia, stirred for one hour and then filtered, and the 
filter residue is washed with water until the pH is neutral, and is dried. 
After recrystalliation from ether, 17 g of 
N-(o-cyclopropylbenzylidene)-N'-amidino-hydrazine are obtained. 
Melting point = 139.degree. C. 
The corresponding maleate is prepared as follows: 0.05 mol of base is 
dissolved in 100 cm.sup.3 of ethyl acetate, and the solution thus obtained 
is added to a solution of 0.05 mol of maleic acid in 100 cm.sup.3 of ethyl 
acetate; the mixture is left to stand for 4 hours and is filtered; and the 
filter residue is washed with 50 cm.sup.3 of ethyl acetate and dried to 
give 15.4 g of N-(o-cyclopropylbenzylidene)-N'-amidino-hydrazine maleate. 
Melting point = 170.degree. C. 
EXAMPLE 10 
N-[2-(Prop-2'-Ynoxy)-5-Bromo-Benzylidene]-N'-Amidino-Hydrazine 
##STR19## 
A mixture of 0.1 mol of 2-(prop-2'-ynoxy)-5-bromo-benzaldehyde, 0.05 mol of 
neutral aminoguanidine sulphate and 200 cm.sup.3 of ethanol is heated 
under reflux for 6 hours. 
The mixture is taken up in 400 cm.sup.3 of water, rendered alkaline with 
ammonia, stirred for one hour and the filtered, and the filter residue is 
washed with water until the pH is neutral, and is dried. 
After recrystallisation from toluene, 25 g of 
N-[2-(prop-2'-ynoxy)-5-bromo-benzylidene]-N'-amidinohydrazine are 
obtained. 
Melting point = 153.degree. C. 
EXAMPLE 11 
N-(1,3-Dimethyl-2-Oxo-5-Benzimidazolylidene)-N'-Amidino-Hydrazine 
##STR20## 
15.5 g (0.08 mol) of 5-carboxaldehyde-1,3-dimethyl-benzimidazolone and 10.7 
(0.04 mol) of amidino-hydrazine sulphate are added to 300 cm.sup.3 of 50% 
strength ethanol and this mixture is then heated under reflux for 13 
hours, after which it is evaporated to dryness and the residue is treated 
with sodium hydroxide. A yellow solid is obtained which is filtered off, 
washed with water and dried. 
The base thus obtained is recrystallised from methanol. 11 g of 
N-(1,3-dimethyl-2-oxo-5-benzimidazolylidene)-N'-amidino-hydrazine are thus 
obtained. 
Melting point = 238.degree. C. 
EXAMPLE 12 
N-(1,3-Dimethyl-2-Oxo-5-Benzimidazolylidene)-N'-Imidazolino-Hydrazine 
##STR21## 
15.5 g (0.08 mol) of 5-carboxaldehyde-1,3-dimethyl-benzimidazolone and 14.6 
g (0.08 mol) of imidazolino-hydrazine hydrobromide are added to 300 
cm.sup.3 of 50% strength ethanol. This mixture is heated under reflux for 
7 hours after which it is evaporated to dryness and treated with sodium 
hydroxide. A yellow solid is obtained, which is filtered off, washed with 
water and dried. 
The base thus obtained is washed with hot methanol to give 13.5 g of 
N-(1,3-dimethyl-2-oxo-5-benzimidazolylidene N'-imidazolino-hydrazine. 
Melting point = 275.degree. C. 
EXAMPLE 13 
N-(2-Chloro-3-Pyridylidene)-N'-Amidino-Hydrazine 
##STR22## 
A mixture of 13.5 of 2-chloro-nicotinaldehyde and 12.6 g of neutral 
aminoguanidine sulphate in 200 cm.sup.3 of ethanol and 50 cm.sup.3 of 
water is heated under reflux for 4 hours. 
The reaction mixture is then concentrated in vacuo and thereafter rendered 
alkaline, in the cold, with concentrated ammonia, whilst stirring. The 
crystals obtained are filtered off, washed with water and dried. 
12.1 g of N-(2-chloro-3-pyridylidene)-N'-amidino-hydrazine are thus 
obtained in the form of white crystals. 
Melting point = 201.degree.-202.degree. C. 
EXAMPLE 14 
6-Methoxy-1,3-Dimethyl-Benzimidazolone-5-Carboxaldehyde 
14.7 g. (0.16 mole) of phosphorus oxychloride are added slowly to 12.5 
cm.sup.3 of dimethylformamide. To the complex thus formed is added 28 g. 
(0.145 mole) of 5-methoxy-1,3-dimethylimidazolone in solution in 75 
cm.sup.3 of methylene chloride. The reaction mixture is heated to 
100.degree. C for three hours, cooled and hydrolysed by adding ice. The 
product which precipitates is filtered off and washed with water and hot 
methanol. 22.5 g. of 
6-Methoxy-1,3-dimethyl-benzimidazolone-5-carboxaldehyde, m.p. 
240.degree.-242.degree. C. are obtained. 
EXAMPLE 15 
N-(6-Methoxy-1,3-Dimethyl-2-Oxo-5-Benzimidazolylidene)-N'-Amidino Hydrazine 
##STR23## 
17.4 g of 6-methoxy-1,3-dimethylbenzimidazolone-5-carboxaldehyde and 10.4 g 
of amidino hydrazine sulphate are added to a mixture of 500 cm.sup.3 of 
dioxane and 100 cm.sup.3 of water. The mixture is heated under reflux for 
8 hours. The product which has precipitated is filtered off and made 
alkaline in the cold with concentrated ammonia solution. The base 
precipitates. It is separated and recrystallised from a mixture of 
methanol and isopropanol (50:50). 10.5 g of 
N-(6-methoxy-1,3-dimethyl-2-oxo-5-benzimidazolylidene)-N'-amidinohydrazine 
, m.p. 260.degree. C., are obtained. 
EXAMPLE 16 
N-(6-Methyl-1,3-Dimethyl-2-Oxo-5-Benzimidazolylidene)-N'-Amidino Hydrazine 
Neutral Sulphate 
##STR24## 
19.6 g. of 6-Methyl-1,3-dimethylbenzimidazolone-5-carboxaldehyde and 12.7 g 
of amino guanidine sulphate are added to a mixture of 200 cm.sup.3 of 
methanol and 100 cm.sup.3 of water. The mixture is heated under reflux for 
7 hours. The product which has precipitated is filtered off and washed 
with methanol. 24 g of the neutral sulphate of 
N-(6-methyl-1,3-dimethyl-2-oxo-5-benzimidazolylidene)-N'-amidino hydrazine 
are obtained m.p. 315.degree. C. 
EXAMPLE 17 
N-[Methyl-o-(Prop-2-Ynoxy)-Benzylidine]-N'-Amidino Hydrazine 
##STR25## 
A mixture of 0.1 mole of o-(prop-2-ynoxy)-acetophenone, 0.05 mole of amino 
guanidine neutral sulphate, and 80 cm.sup.3 of ethylene glycol is heated 
at 130.degree. C., for 6 hours. The mixture is then diluted by adding 300 
cm.sup.3 of water and extracted with ether. The aqueous phase is made 
alkaline by addition of sodium hydroxide and extracted with chloroform. 
The chloroform phase is separated, dried over anhydrous magnesium 
sulphate, and evaporated in vacuo. 
The residue thus obtained (12 g) is taken up in 60 cm.sup.3 of ethyl 
acetate, and a solution of 5.4 g of oxalic acid in 60 cm.sup.3 of ethyl 
acetate is added. The mixture is allowed to stand for 6 hours. The 
precipitate is filtered off, washed with ethyl acetate, dried, and 
recrystallised from isopropanol. 5.8 g of the expected product, m.p. 
138.degree. C., are obtained. 
The anti-hypertensive activity of the compounds according to the invention 
is shown by the pharmacological experiments which follow. 
METHOD 
Male rats aged 16 to 20 weeks and exhibiting a spontaneous genetically 
transmissible hypertension are placed in a heated box at 38.degree. C. The 
arterial pressure is measured by a "Narco Bio System" sphygmomanometer. A 
sleeve is placed over the base of the tail and a detector records the 
pulse downstream from the sleeve. The sleeve is then inflated until the 
pulse is stopped, thus indicating the systolic pressure. The rate of 
heartbeat is also recorded. 
The products to be studied are converted to a suspension by means of "Tween 
80" and administered intraperitoneally in a volume of 1 cm.sup.3 per 100 
grams of body weight. 
The measurements are repeated at regular intervals. 
The Table which follows shows the percentage variation and the mean 
deviation of the systolic arterial pressure and of the rate of heartbeat, 
30 to 60 minutes after treatment. 
__________________________________________________________________________ 
Doses mg/kg 
given intra- 
Arterial pressure 
Rate of heartbeat 
Ex. peritoneally 
T + 30 mins 
T + 60 mins 
T + 30 mins 
T + 60 mins 
__________________________________________________________________________ 
1 40 -52 .+-. 3.4 
- 56 .+-. 4.3 
- 19 .+-. 2.1 
- 17 .+-. 3.2 
2 20 - 49 .+-. 5.0 
- 48 .+-. 1.8 
- .+-. 5.0 
- 12 .+-. 7.6 
3 10 - 26 .+-. 5.8 
- 11 .+-. 1.2 
- 2 .+-. 3.1 
- 1 .+-. 1.1 
4 40 - 44 .+-. 8.2 
- 30 .+-. 5.2 
- 20 .+-. 4.3 
- 13 .+-. 1.6 
5 40 - 34 .+-. 4.1 
- 22 .+-. 3.0 
- 7 .+-. 5.4 
- 9 .+-. 3.4 
6 10 - 30 .+-. 6.4 
- 17 .+-. 4.0 
- 3 .+-. 2.1 
- 3 .+-. 3.1 
7 40 - 29 .+-. 4.5 
- 15 .+-. 1.8 
- 9 .+-. 7.8 
- 1 .+-. 4.5 
8 20 - 23 .+-. 1.3 
- 22 .+-. 2.8 
- 6 .+-. 1.1 
- 10 .+-. 4.3 
9 10 - 28 .+-. 5.4 
- 10 .+-. 4.5 
- 7 .+-. 2.3 
- 5 .+-. 2.7 
10 10 - 28 .+-. 5.3 
- 20 .+-. 4.0 
- 4 .+-. 3.6 
- 2 .+-. 2.9 
11 40 - 38 .+-. 4.8 
- 28 .+-. 4.4 
- 2 .+-. 5.8 
+ 8 .+-. 3.8 
12 40 -39 .+-. 7.4 
- 12 .+-. 3.8 
- 12 .+-. 3.8 
- 4 .+-. 3.7 
13 20 - 29 .+-. 4.2 
- 18 .+-. 4.1 
- 5 .+-. 2.2 
- 3 .+-. 1.3 
15 20 - 42 .+-. 7.0 
- 38 .+-. 4.26 
- 12 .+-. 8.97 
- 13 .+-. 6.34 
16 40 - 49 .+-. 4.37 
- 49 .+-. 3.75 
- 21 .+-. 4.63 
- 17 .+-. 6.68 
17 20 - 29 .+-. 5.31 
- 30 .+-. 6.16 
- 14 .+-. 3.56 
- 10.+-. 3.04 
Dihydra- 
lazine 
1.25 - 35 .+-. 5.21 
- 34 .+-. 8.33 
+ 37 .+-. 9.61 
+ 21 .+-. 5.83 
__________________________________________________________________________ 
The animals show normal behaviour. 
The compounds described show an anti-hypertensive activity which is 
noteworthy in that it does not cause sedation or tachycardia, which 
distinguishes these products from currently used therapeutic agents. They 
have low toxicity, the lethal doses (LD.sub.50) following intraperitoneal 
administration in the rat, are between 100 and 500 mg/kg. The active doses 
in this animal are between 20 and 40 mg./kg. following oral 
administration. 
The compounds of Examples 1 to 13 and 15 to 17 can be used in hypertension 
therapy, e.g. in the form of pills or capsules containing 25 and 50 mg 
each of active principle, in a daily dose of 50 to 150 mg for an adult.