The invention relates to cyanoguanidine derivatives characterized by an imino-alkyl and amino-nitrile structure having the general formula: ##STR1## in which R.sub.1 is a 2-mercapto-ethyl, 2-hydroxy-ethyl, a 2-((4-methyl-5-imidazolyl)thio-methyl)ethyl, or a 2-((4-methyl-5-imidazolyl)dithioformyloxy-methyl)ethyl radical, and R.sub.2 is the methyl radical. The invention relates to the manufacture of imino-methyl and amino-nitrile cyano-guanidines. One compound of invention: N-methyl-N'-cyano-N"-imino-[2-((4-methyl-5-imidazolyl)thio-methyl)ethyl] guanidine is a histamine antagonist in the H.sub.2 receptors and inhibits the secretion of gastric acid. It can be used therapeutically for the treatment of gastric and duodenal ulcers.

TECHNICAL FIELD 
This invention relates to a novel group of cyanoguanidine derivatives 
characterized by the following imino-alkyl and amino-nitrile structural 
formula: 
##STR2## 
wherein R.sub.1 is a 2-mercapto-ethyl, a 2-hydroxy-ethyl, a 
2-((4-methyl-5-imidazolyl)thio-methyl)ethyl, or a 
2-((4-methyl-5-imidazolyl)dithioformyloxy-methyl)ethyl radical, and 
R.sub.2 represents a methyl radical. 
A particularly advantageous compound of the invention: 
N-methyl-N'-cyano-N"-imino-[2-((4-methyl-5-imidazolyl)thio-methyl)ethyl]gu 
anidine is a histamine antagonist in the H.sub.2 receptors which inhibits 
the secretion of gastric acid, and can be used therapeutically for the 
treatment of gastric and duodenal ulcers. 
This invention also relates to processes for the production of these novel 
cyanoguanidine derivatives. 
BACKGROUND OF THE INVENTION 
Cyanoguanidine derivatives synthesized by known processed are characterized 
by imino-nitrile guanidine structures having the following formula: 
##STR3## 
The stable conformations of the cyanoguanidines of formula II are 
represented by the following structures: 
##STR4## 
Structures IIa and IIb represent the anti(--NHR.sub.2) and syn(--NHR.sub.2) 
geometrical isomers of the formula II cyanoguanidines. These isomers do 
not demonstrate the phenomenon of tautomerism and thus, are not 
intermediates for the production of amino-nitrile and imino-alkyl 
cyanoguanidines having the following formula: 
##STR5## 
In solution, the IIa and IIb isomers do not transform into each other. A 
high energy barrier prevents establishment of either a tautomeric or an E 
to Z isomeric equilibrium. This high energy barrier results from the 
rapidity of inversion of the --NCN group (probably by a rotational-bond 
mechanism) which is greater than the rate of rotation of the --NHR.sub.1 
and --NHR.sub.2 groups. 
SUMMARY OF THE INVENTION 
This invention discloses a group of cyanoguanidine derivatives 
characterized by the following imino-alkyl and amino-nitrile formula: 
##STR6## 
wherein R.sub.1 and R.sub.2 may or may not be identical. The invention 
also relates to a method for producing these novel cyanoguanidines. 
Cyanoguanidines conforming to structure IV are unique, and their 
intermediate guanidines of structure I do not represent tautomers of 
either of the known formula II cyanoguanidines. The phenomenon of 
tautomerism involves the establishment of an equilibrium between the 
tautomers. If the formula I and II cyanoguanidines were in fact tautomers, 
upon dissolving the formula II cyanoguanidine in a suitable solvent, the 
corresponding formula I cyanoguanidine would also be found in the 
solution. It may be hypothesized that the absence of the formula I 
cyanoguanidine is due to an equilibrium situation in which the quantity of 
the formula I cyanoguanidine is reduced to a level at which its presence 
cannot be detected. If this were the case however, upon dissolving a 
formula I cyanoguanidine in the same solvent, it would be expected that it 
would be transformed into the corresponding formula II cyanoguanidine 
until it no longer existed in the solution above a trace amount. This does 
not occur, and it has been established that: 
(1) in solutions of formula II cyanoguanidines, the presence of the 
corresponding formula I cyanoguanidine is not detected; 
(2) in solutions of formula I cyanoguanidines, the presence of the 
corresponding formula II cyanoguanidine is not detected. 
DETAILED DESCRIPTION OF THE INVENTION 
Stable conformations which can be isolated from the formula I 
cyanoguanidines are the following: 
##STR7## 
The absence of a demonstrated tautomerism phenomenon between the formula 
Ia, Ib, Ic cyanoguanidines and the formula IIa or IIb cyanoguanidines is 
due to the respective molecular stability of each of these cyanoguanidine 
groups. The molecular stability of formula Ia and Ib cyanoguanidines is, 
most likely, caused by an interaction of the amino-nitrile component with 
the imino-alkyl component; within a planar structure. This interaction 
leads to a considerable decrease in the electrical moment of the nitrile 
component, as reflected by the disappearance of its infra-red absorption. 
The molecular stability of the formula Ia and Ib cyanoguanidines is also 
attributed to the basicity of the imino-alkyl and the amino-nitrile 
guanidine functional groups, allowing the formation of, for example, 
stable salts such as a hydrochloride of the particular guanidine. This 
interaction, and the effected molecular stability are no longer manifested 
when, for example, a formula I cyanoguanidine is dissolved in acetonitrile 
or dimethylformamide at temperatures between about 50.degree. and 
80.degree. C. and, consequently, infra-red absorption is demonstrated by 
the amino-nitrile component. The disappearance of the molecular stability 
characteristic leads to the establishment of an equilibrium with new 
tautomers. This phenomenon can be effected using the hydrochloride of the 
chosen guanidine, but it appears more rapidly when the corresponding base 
of the guanidine is used. Neutralization of the hydrochloride by an 
equivalent quantity of alkaline alkoxide permits development of the 
infra-red absorption described above. The established equilibrium can be 
depicted as follows: 
##STR8## 
As demonstrated above, it is seen that compounds having the Ia or Ib 
formulas are tautomers of formula III compounds (imino-nitrile tautomers 
demonstrating less stability.) 
The rapidity of inversion of the C.dbd.NR.sub.1 (R.sub.2) group of formula 
Ia and Ib structures is less than that of the rotation of the --NHR.sub.2 
(R.sub.1) and --NHCN groups. This represents an opposite phenomenon to 
that observed with formula IIa and IIb cyanoguanidines. This difference in 
dynamic behavior is the reason why the Ia and Ib cyanoguanidines 
demonstrate tautomery, while formula IIa and IIb cyanoguanidines do not. 
For these reasons, formula I cyanoguanidines cannot be obtained from 
formula II cyanoguanidines by a displacement of equilibrium. Instead, the 
existence of formula I cyanoguanidines depends upon: (1) the invention of 
a reactant which will provide, stereospecifically, the desired 
configuration or (2) the discovery of a reaction characterized by the 
irreversible displacement of the double bond of the guanidine functional 
group. 
According to this invention, a guanidine derivative of the following 
formula, is provided: 
##STR9## 
which is characterized by an imino-alkyl and amino-nitrile components and 
wherein R.sub.1 is a 2-mercapto-ethyl, a 2-hydroxy-ethyl, 
2-((4-methyl-5-imidazolyl)thio-methyl)ethyl, or a 
2-((4-methyl-5-imidazolyl)dithioformyloxymethyl)ethyl radical, and R.sub.2 
represents a methyl radical. 
The compounds of the invention are: 
N-methyl-N'-cyano-N"-imino-(2-mercapto-ethyl)guanidine, 
N-methyl-N'-cyano-N"-imino-(2-hydroxy-ethyl)guanidine, 
N-methyl-N'-cyano-N"-imino-[2-((4-methyl-5-imidazolyl)-thio-methyl)ethyl]gu 
anidine, 
N-methyl-N'-cyano-N"-imino-[2-((4-methyl-5-imidazolyl)-di-thioformyl-oxyme 
thyl)ethyl]guanidine. 
The process for the preparation of the cyanoguanidine compounds of this 
invention includes the irreversible transformation of formula II 
cyanoguanidines into formula I cyanoguanidines by means of an intermediate 
HX reactant, in which X represents Cl.sup.-, Br.sup.-, I.sup.-, PO.sub.4 
H.sub.2.sup.-, SO.sub.4 H.sup.-, 4CH.sub.3 C.sub.6 H.sub.4 SO.sub.3.sup.-. 
The elimination of HX leads to the novel amino-nitrile and imino-alkyl 
structure of formula I cyanoguanidines: 
##STR10## 
A compound having the following formula: 
##STR11## 
may be prepared according to any of the following processes: (1) 
condensing a reactant which already possesses the desired tautomeric form, 
N-methyl-N'-cyano-N"-imino(2-mercapto-ethyl)guanidine, for example, with 
4-methyl-5-chloromethyl-imidazole. 
or, 
(2) condensing a sodium or potassium xanthogenate of 
N-methyl-N'-cyano-N"-imino(2-hydroxy-ethyl)guanidine with 
4-methyl-5-chloromethyl-imidazole and subjecting the obtained xanthate to 
a Chugaev-type transformation. 
or, 
(3) reacting a compound having the following formula: 
##STR12## 
with a hydrogenated mineral acid, such as HCl for example, to give an 
addition intermediary, from which the mineral is then eliminated, to 
yield, for example, a dihydrochloride of the formula V compound. 
Formula V compounds, as well as the therapeutically suitable salts of these 
compounds, antagonize the activity of histamine in the H.sub.2 receptors, 
thus blocking the histamine's stimulation of hydrochloric acid production 
in the stomach. Formula V compounds are also advantageously used for the 
therapeutic treatment of gastric and duodenal ulcers. Suitable excipients 
for pharmaceutical forms of formula V compounds are, for example, lactose, 
saccharose, talcum, gelatine, arabic gum or olive oil.

EXAMPLES 
The following examples are set forth for the purpose of illustration only 
and are not to be construed as limiting the scope of the invention in any 
manner. 
EXAMPLE 1 
Preparation of N-methyl-N'-cyano-N"-imino-(2-mercapto-ethyl)guanidine 
0.76 g of HCl in ether is added to a solution of 2.42 g of 
N-methyl-N'-cyano-N"-imino-(2-tetrahydropyranylthio-ethyl)guanidine in dry 
ethanol. After a reaction time of 40 minutes, infra-red spectrophotometry 
indicates the absence of absorptions by the nitrile component and the 
presence of absorption activity by the addition intermediary. The 
intermediary is precipitated by an ether and the 
imino-(2-mercapto-ethyl)guanidine is crystallized as hydrochloride by 
rubbing. The imino-(2-mercapto-ethyl)guanidine is then transformed in 
water by AgNO.sub.3 into the Ag mercaptide derivative of 
N-methyl-N'-cyano-N"-imino(2-mercapto-ethyl)guanidine as hydrochloride. 
The following are observed: 
Chloride ion titration 99.5% 
IR (film): 1710, 1655 (cm.sup.-1) 1590, 1455, 1380, 1300 
EXAMPLE 2 
Preparation of N-methyl-N'-cyano-N"-imino-(2-hydroxy-ethyl)guanidine as 
hydrochloride 
Two equivalents of HCl in dry ether are added to a solution of 4.26 g of 
N-methyl-N'-cyano-imino-N"-(2-hydroxy-ethyl)guanidine in dry methanol. 
After 30 minutes, there is no infra-red absorption by the nitrile 
component and the IR absorptions of the addition intermediary are as 
follows: 1670, 1630, 1580, 1565 (cm.sup.-1). The intermediary is 
precipitated by an ether and the resulting oil is taken up by methanol. 
The hydrochloride of N-methyl-N'-cyano-N"-imino-(2-hydroxy-ethyl)guanidine 
is crystallized out by rubbing, m.p. 184.degree.-186.degree. C. The 
following are observed: 
C.sub.5 H.sub.10 N.sub.4 O.HCl (178.5) 
______________________________________ 
% C % H % N 
______________________________________ 
Calculated 33.61 5.60 31.37 
Found 33.43 5.72 31.25 
______________________________________ 
IR (nujol): 3250, 3120, 1720 (doublet), (cm.sup.-1) 1665, 1600 (doublet), 
1510, 1400, 1290, 1260, 1105, 995, 950, 900, 850 (doublet), 700. 
EXAMPLE 3(a) 
Preparation of 
N-methyl-N'-cyano-N"-imino[2-((4-methyl-5-imidazolyl)thio-methyl)ethyl]gua 
nidine as dihydrochloride 
3 equivalent parts of HCl in ether are added to a solution of 2.52 g of 
N-methyl-N'-imino-cyano-N"-2-((4-methyl-5-imidazolyl)ethyl guanidine in 
dry ethanol. After 30 minutes, IR absorption activity of the nitrile 
component disappears, and IR absorption activity of the addition 
intermediary is apparent (1665, 1630, 1570 cm.sup.-1.) The intermediary is 
precipitated with ether and the resulting oil is washed by the ether and 
taken up by methanol, from which, by rubbing, the dihydrochloride of the 
N-methyl-N'-cyano-N"imino[2-((4-methyl-5-imidazolyl)thio-methyl)ethyl]guan 
idine is crystallized; m.p. 120.degree.-122.degree. C. The following are 
observed: 
IR (nujol) 3300, 3200, 3100, 2700, 2650, 1700, (cm.sup.-1) 1665, 1590, 
1410, 1400, 1360, 1315, 1290, 1260, 1245, 1210, 1165 (doublet), 1100, 
1025, 935, 870, 780, 700 
EXAMPLE 3(b) 
Preparation of 
N-methyl-N'-cyano-N"-imino-[2-((4-methyl-5-imidazolyl)thio-methyl)ethyl]gu 
anidine as monohydrochloride 
The dihydrochloride of 
N-methyl-N'-cyano-N"-imino-[2-((4-methyl-5-imidazolyl)thio-methyl)ethyl]gu 
anidine as prepared in Ex. 3(a), is mixed with a molar excess of 
triethylamine. A small amount of methanol is added to the mixture in order 
to dissolve it completely. After 20 minutes, the solvent is evaporated 
under reduced pressure and the monohydrochloride of 
N-methyl-N'-cyano-N"-imino-[2-((4-methyl-5-imidazolyl)thio-methyl)ethyl]gu 
anidine is crystallized in acetonitrile; m.p. 174.degree.-176.degree. C. 
The following results are recorded: 
C.sub.10 H.sub.16 N.sub.6 S.HCl (288.5) 
______________________________________ 
% C % H % N % S 
______________________________________ 
Calculated 41.59 5.85 29.11 
11.09 
Found 41.46 5.95 29.04 
11.12 
______________________________________ 
IR (nujol): 3200, 3080, 1710, 1644, 1605, 1570, (cm.sup.-1) 1480, 1395, 
1340, 1305, 1230, 1150 (doublet), 1080, 1065, 1040, 1010, 1005, 960, 845, 
780 (doublet), 690, 660 
EXAMPLE 4 
Preparation of 
N-methyl-N'-cyano-N"-imino[2-((4-methyl-5-imidazolyl)-thio-methyl)ethyl 
guanidine as monohydrochloride 
0.68 g of sodium hydride and 8 ml of carbon disulfide are added to a 
suspension of 1.80 g of 
N-methyl-N'-cyano-N"-imino-(2-hydroxy-ethyl)guanidine as hydrochloride in 
dry tetrahydrofuran. After a reaction time of 15 hours, 1.52 g of 
4-methyl-5-chloro-methylimidazole in dry ethanol is introduced into the 
medium under agitation. The mixture is taken to reflux and carbon 
oxysulfide is liberated. After the solvent is evaporated, the residue is 
neutralized with an equivalent part of HCl and crystallized in 
acetonitrile as a monohydrochloride with a m.p. 174.degree.-176.degree. C. 
EXAMPLE 5 
Preparation of 
N-methyl-N'-cyano-N"-imino[2-((4-methyl-5-imidazolyl)-thio-methyl)ethyl]gu 
anidine as monohydrochloride 
1.95 g of N-methyl-N'-cyano-N"-imino-(2-mercapto-ethyl)guanidine, as 
hydrochloride, followed by 1.95 g of sodium ethoxide are added to a 
solution of 1.30 g of 4-methyl-5-chloromethyl-imidazole in dry ethanol, 
under inert gas such as argon. After a reaction time of 5 hours, the NaCl 
is separated by filtration and the product is isolated by evaporation of 
the solvent. The monohydrochloride is crystallized after neutralization by 
an equivalent part of HCl in acetonitrile. F. 174.degree.-176.degree.. 
EXAMPLE 6 
Preparation of 
N-methyl-N'-cyano'N"-imino[-2((4-methyl-5-imidazolyl)-thio-methyl)-ethyl]g 
uanidine as dihydrochloride 
1.95 g of hydrochloride of 
N-methyl-N'-cyano-N"-imino-(2-mercapto-ethyl)guanidine is added to a 
solution of 1.90 g of hydrochloride of 4-methyl-5-acetoxy-methyl-imidazole 
in dry ethanol. The mixture is refluxed for 12 hours. The dihydrochloride 
product is crystallized out in methanol, m.p. 120.degree.-122.degree. C. 
EXAMPLE 7 
Preparation of 
N-methyl-N'-cyano-imino-N"-[2-((4-methyl-5-imidazolyl)thio-methyl)-ethyl]g 
uanidine 
The monohydrochloride of 
N-methyl-N'-cyano-N"-imino-2-((4-methyl-5-imidazolyl)thio-methyl)ethyl 
guanidine is refluxed for 16 hours in acetonitrile containing a small 
amount of methanol. After neutralization, the base is isolated as an oil. 
The following are observed: 
IR (film) 3200, 3100, 2150, 1580-1560, 1475, 1440, (cm.sup.-1) 1390, 1285, 
1170, 1080, 790 
EXAMPLE 8 
Preparation of 
N-methyl-N'-cyano-imino-N"[-2-((4-methyl-5-imidazolyl)thio-methyl)-ethyl]g 
uanidine 
3.2 g of the monohydrochloride or 3.6 g of the dihydrochloride of 
N-methyl-N'-cyano-N"-imino-2-((4-methyl-5-imidazolyl)thio-methyl)ethyl 
guanidine is neutralized in ethanol. The NaCl is separated by filtration, 
the solvent is evaporated and the residue is taken up with 
dimethylformamide. This solution is maintained at 62.degree. for 7 hours. 
The solvent is then evaporated under 0.02 T. 
The residue is extracted with acetonitrile and after evaporation under 
reduced pressure, an oil is obtained. The following are observed: 
IR (film) 3200, 3100, 2150, 1580-1560, 1475, 1440 (cm.sup.-1) 1390, 1285, 
1170, 1080, 790