A method of stimulating histamine H.sub.2 -receptors in mammals employing imidazole amidinoureas.

SUMMARY OF THE INVENTION 
This invention describes a method of treating mammals with imidazole 
amidinoureas in order to stimulate histamine H-2 receptors for the 
treatment of gastrointestinal disorders and diseases. 
It has long been postulated that many of the physiologically active 
substances within the animal body, in the course of their activity, 
combine with certain specific sites known as receptors. Histamine is a 
compound which is believed to act in such a way but since the actions of 
histamine fall into more than one type, it is believed that there is more 
than one type of histamine receptor. The type of action of histamine which 
is blocked by drugs commonly called "antihistamines" (of which mepyramine 
is a typical example) is believed to involve a receptor which has been 
designated by Ash and Schile (Brit. J. Pharmac. Chemother, 27:427, 1966) 
as H-1. The substances and pharmaceutical compositions of the present 
invention are distinguished by the fact that they act at histamine 
receptors other than the H-1 receptor, that is they act at H-2 histamine 
receptors which are described by Black et al. Nature 236, 385 (1972), 
Black et al cited above, page 390, column 2, state the following: 
"Mepyramine has been defined as an H.sub.1 -receptor antagonist and 
burimamide has now been defined as an H.sub.2 -receptor antagonist. Used 
alone, burimamide can antagonize those responses to histamine, such as 
stimulation of acid gastric secretion, which cannot be blocked by 
mepyramine; histamine apparently activates H.sub.2 -receptors to produce 
these effects." 
Thus, from the Black et al paper, H-2 histamine receptors are those 
histamine receptors which are not inhibited by mepyramine but are 
inhibited by burimamide. Thus they are of utility in inhibiting certain 
actions of histamine which are not inhibited by the above mentioned 
"antihistamines". Agonists of H-2 histamine receptors are useful, for 
example, as enhancers of histamine activity in the same manner as 
4-methylhistamine as described by Levi et al in Pharmacological 
Characterization of Cardiac Histamine Receptors: Sensitivity to H.sub.1 - 
and H.sub.2 Receptor Agonists and Antagonists, European Journal of 
Pharmacology 30 (1957) 328-335. 
The compounds of the present invention may be used in the treatment of 
gastrointestinal disorders such as achlorhydria. Also, because of the 
compounds ability to enhance H.sub.2 - receptor activity and thus inhibit 
contractions of the uterus, it can be used in the treatment of 
dysmenorrhea. 
Also the administration of the compounds of this invention can serve as a 
pharmacological tool in the testing of antihistamine activity. In this 
respect, it has been found that the compounds of this invention are 
selective stimulants of histamine H.sub.2 -receptors with no side 
reactions, especially in having no effect on the histamine H.sub.1 
-receptors. The selectivity is especially important in pharmacological 
studies of compounds which are intended for use as antihistamines or with 
respect to the study of the cardiac histamine effects.

DESCRIPTION AND PREFERRED EMBODIMENT 
This invention relates to a new method of treating gastrointestinal 
disorders and diseases, and of gastrointestinal therapeutic compositions, 
which comprises the utilization of imidazole amidinoureas having the 
structural formula as shown in Formula I. 
##STR1## 
where: n is 1-3, and 
R is hydrogen or lower alkyl. 
The term "lower alkyl" refers to an alkyl hydrocarbon group containing from 
1 to about 8 carbon atoms which may be straight chained or branched. 
It is well known in the pharmacological arts that non-toxic acid addition 
salts of pharmacologically active amine compounds do not differ in 
activities from their free base. The salts merely provide a convenient 
solubility factor. 
The amines of this invention may be readily converted to their non-toxic 
acid addition salts by customary methods in the art. The non-toxic salts 
of this invention are those salts the acid component of which is 
pharmacologically acceptable in the intended dosages; such salts would 
include those prepared from inorganic acids, organic acids, higher fatty 
acids, high molecular weight acids, etc. and include such as: hydrochloric 
acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, 
methane sulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, 
malic acid, oxalic acid, succinic acid, glycolic acid, lactic acid, 
salicylic acid, benzoic acid, nicotinic acid, phthalic acid, stearic acid, 
oleic acid, abietic acid, etc. 
Representative compounds of this invention which are particularly useful 
are as follows: 
1-[(4-imidazolyl)methylamidino]urea 
1-[2-(4-imidazolyl)ethylamidino]urea 
1-[3-(4-imidazolyl)propylamidino]urea 
1-[(5-methyl-4-imidazolyl)methylamidino]urea 
1-[2-(5-methyl-4-imidazolyl)ethylamidino]urea 
1-[3-(5-methyl-4-imidazolyl)propylamidino]urea 
1-[(5-ethyl-4-imidazolyl)methylamidino]urea 
1-[2-(5-ethyl-4-imidazolyl)ethylamidino]urea 
1-[3-(5-ethyl-4-imidazolyl)propylamidino]urea 
1-[(5-propyl-4-imidazolyl)methylamidino]urea 
1-[2-(5-propyl-4-imidazolyl)ethylamidino]urea 
1-[3-(5-propyl-4-imidazolyl)propylamidino]urea 
1-[(5-butyl-4-imidazolyl)methylamidino]urea 
1-[2-(5-butyl-4-imidazolyl)ethylamidino]urea 
1-[3-(5-butyl-4-imidazolyl)propylamidino]urea 
1-[(5-pentyl-4-imidazolyl)methylamidino]urea 
1-[2-(5-pentyl-4-imidazolyl)ethylamidino]urea 
1-[3-(5-pentyl-4-imidazolyl)propylamidino]urea 
1-[(5-hexyl-4-imidazolyl)methylamidino]urea 
1-[2-(5-hexyl-4-imidazolyl)ethylamidino]urea 
1-[3-(5-hexyl-4-imidazolyl)propylamidino]urea 
1-[(5-heptyl-4-imidazolyl)methylamidino]urea 
1-[2-(5-heptyl-4-imidazolyl)ethylamidino]urea 
1-[3-(5-heptyl-4-imidazolyl)propylamidino]urea 
1-[(5-octyl-4-imidazolyl)methylamidino]urea 
1-[2-(5-octyl-4-imidazolyl)ethylamidino]urea 
1-[3-(5-octyl-4-imidazolyl)propylamidino]urea 
The compounds of this invention may be prepared by the following general 
procedures: 
Reaction of a substituted [4(5)-imidazolyl] alkylamine with 
O-m-tolyl-N-cyanoisourea results in the formation of a substituted 
1-[4(5)-imidazolyl] alkyl-3-cyanoguanidine. This condensation can be 
carried out in an inert solvent at raised temperatures. It is preferably 
carried out in an alcohol such as isopropanol at reflux. 
##STR2## 
where n=1-3. 
The substituted 1-[4(5)-imidazolyl] alkyl-3-cyanoguanidine may also be 
prepared by condensation of the corresponding substituted 
[4(5)-imidazolyl] alkylamine with sodium dicyanamide. This reaction can be 
carried out in an inert solvent at raised temperatures. 
##STR3## 
The O-m-tolyl-N-cyanoisourea of the above condensation may be prepared by 
reacting m-cresol with cyanogenbromide to obtain the m-tolyl cyanate. 
Treatment with cyanamide results in the O-m-tolyl-N-cyanoisourea. 
##STR4## 
Hydrolysis of a substituted 1-[4-(5)-imidazolyl]alkyl-3-cyanoguanidine with 
aqueous mineral acid results in the formation of the corresponding 
substituted 1-[4(5)-imidazolyl]alkyl amidinourea. This reaction is 
preferably carried out in a polar medium such as alcohol and at 
temperatures which may range from room temperature to reflux. Isopropanol 
is a preferred solvent. 
##STR5## 
When the starting imidazolylalkylamine material is histamine then 
condensation with O-m-tolyl-N-cyanoisourea in an inert solvent at raised 
temperatures results in the formation of 
1-(2-[4-(5)-imidazolyl]ethyl)-3-cyanoguanidine. Hydrolysis of the latter 
in a polar medium with an aqueous mineral acid results in the formation of 
the 1-(2-[4(5)-imidazolyl ]ethylamidino)urea. The latter reaction is 
preferably carried out in an alcohol such as isopropanol at temperatures 
ranging from room temperature to reflux. 
##STR6## 
The starting materials of this invention are either known compounds or 
their method of preparation is described. 
We have found that the compounds of this invention have a useful degree of 
gastric secretory activity and are effective in the treatment of some 
gastrointestinal disorders. It should further be noted that these 
compounds are also characterized by their low acute toxicity. 
For all these purposes, the compounds of this invention can be normally 
administered parenterally. The term "parenteral" as used herein, includes 
subcutaneous injection, intravenous, intramuscular or intrasternal 
injection or infusion techniques. 
The pharmaceutical compositions may be in the form of a sterile injectable 
preparation, for example, as a sterile injectable aqueous suspension. This 
suspension may be formulated according to the known art using those 
suitable dispersing or wetting agents and suspending agents which have 
been mentioned above. The sterile injectable preparation may also be a 
sterile injectable solution or suspension in a non-toxic parenterally 
acceptable diluent or solvent, for example, as an aqueous solution 
buffered to a pH of 4.0 to 7.0 and made isotonic with sodium chloride. 
Further, these compounds may be formulated so that for every 100 parts by 
weight of the compositions, there are present between 5 and 95 parts by 
weight of the active ingredient. The dosage unit form will generally 
contain between about 1 mg. and about 500 mg. of the active ingredients of 
this invention. The preferred unit dose is between about 10 mg. and about 
100 mg. 
The dosage regimen in carrying out the methods of this invention is that 
which insures maximum therapeutic response until improvement is obtained 
and thereafter the minimum effective level which gives relief. Thus, in 
general, the dosages are those that are therapeutically effective in the 
treatment of gastrointestinal disease conditions or symptoms. In general, 
the daily dose can be between about 0.5 mg/kg and 70 mg/kg (preferably in 
the range of 2-25 mg/kg/day), bearing in mind, of course, that in 
selecting the appropriate dosage in any specific case, consideration must 
be given to the patient's weight, general health, age and other factors 
which may influence response to the drug. 
The following are detailed Examples which show the preparation of the 
compounds of this invention. They are to be construed as illustrations of 
said compounds and not as limitations thereof. 
EXAMPLE I 
A. N-cyano-N'-[(5-methyl-4-imidazolyl)methyl]guanidine 
5.16 g. (0.0280 mole) 5-methyl-4-(aminomethyl)imidazole dihydrochloride is 
converted to the free base with K.sub.2 CO.sub.3. A solid free base is 
taken up in 70 ml. isopropyl alcohol. 4.90 g. (0.0280 mole) 
O-m-tolyl-N-cyanoisourea is added, heated 30 minutes to reflux, then 
refluxed for one hour. The mixture is then cooled, and a small amount of 
the white solid is filtered off. The filtrate is then stripped to give a 
solid-cresol mixture, triturated in benzene, and filtered. The collected 
solid is recrystallized from MeOH/CH.sub.3 CN to obtain 
N-cyano-N'-[(5-methyl-4-imidazolyl)methyl] guanidine having a m.p. of 
216.degree.-221.degree. C. 
B. 1-[(5-methyl-4-imidazolyl)methylamidino]urea dihydrochloride 
1.80 g. (0.0101 mole) N-cyano-N'-[(5-methyl-4-imidazolyl) methyl] guanidine 
is taken up in 100 ml. isopropanol. 2.5 ml. conc. HCl is added. The 
reaction mixture is then heated for 20 minutes to reflux and refluxed for 
65 minutes to obtain complete hydrolysis. The mixture is then cooled and 
filtered. The material is then recrystallized from MeOH/CH.sub.3 CN to 
obtain 1-[(5-methyl-4-imidazolyl)methylamidino]urea dihydrochloride with a 
m.p. of 214.degree.-214.5.degree. C. 
EXAMPLE II 
A. N-cyano-N'-[(4-imidazolyl)methyl]guanidine. 
5.48 g. (0.0322 mole) 4-aminomethylimidazole dihydrochloride is converted 
to the free base using Na.sub.2 CO.sub.3. The solid base is combined with 
5.64 g. (0.0322 mole) O-m-tolyl-N-cyanoisourea in 82 ml. isopropanol. This 
mixture is then heated for 15 minutes to reflux, and refluxed for one 
hour. The mixture is then cooled to room temperature, filtered to remove 
cloudiness, and stripped to obtain a cloudy oil of cresol mixed with the 
product. 
B. 1-[(4-imidazolyl)methylamidino]urea dihydrochloride 
A cresol-cyanoguanidine mixture is taken up in 322 ml. isopropanol. 15.8 
ml. conc. HCl is added, heated 18 minutes to reflux, and refluxed for 30 
minutes. The reaction mixture is then cooled in ice and refrigerated 
overnight. The mixture is then filtered, and a yellowish solid is 
collected. The mixture is recrystallized from MeOH/CH.sub.3 CH, to obtain 
1-(4-imidazolyl)methylamidino]urea dihydrochloride with a m.p. of 
203.5.degree.-204.5.degree. C. 
EXAMPLE III 
A. N-cyano-N'-[2-(4-imidazolyl)ethyl]guanidine 
3.62 g. histamine (0.0300 mole) and 5.26 g. (0.0300 mole) 
O-m-tolyl-N-cyanoisourea are combined in 75 ml. of isopropanol. The 
mixture is heated 25 minutes to reflux and refluxed 70 minutes. The 
reaction solution is cooled and stripped to a light orange oil, triturated 
in benzene, decanted, and the residue is recrystallized from MeOH/CH.sub.3 
CN to obtain N-cyano-N'-[2-(4-imidazolyl)ethyl] guanidine having a m.p. of 
152.degree.-154.degree. C. 
B. 1-[2-(4-imidazolyl)ethylamidino]urea dihydrochloride 
47.5 g. histamine (0.401 mole) and 71.66 g. (0.409 mole) 
O-m-tolyl-N-cyanoisourea are combined in 500 ml. of isopropanol. The 
mixture is then heated for 10 minutes to reflux, refluxed for one hour, 
and the reaction mixture is stripped to an oil. The oil is taken up in 2 
l. of isopropanol and 102 ml. conc. HCl, heated 25 minutes to reflux, 
refluxed for 35 minutes, cooled slowly, then with ice. The mixture is 
filtered to obtain 1-[2-(4-imidazolyl)ethylamidino]urea dihydrochloride as 
a crude product. This is recrystallized from MeOH/CH.sub.3 CN to obtain 
1-[2-(4-imidazolyl)ethylamidino]urea dihydrochloride with a m.p. of 
180.5.degree.-181.5.degree. C. 
EXAMPLE IV 
A. N-cyano-N'-[2-(5-methyl-4-imidazolyl)ethyl] guanidine 
4.94 g. (0.249 mole) 5-methyl-4-(2-aminoethyl) imidazole dihydrochloride is 
converted to the free base with NaOH. The free base is combined with 4.36 
g. (0.0249 mole) of O-m-tolyl-N-cyanoisourea in 63 ml. isopropanol. This 
mixture is refluxed for one hour. The mixture is then cooled to room 
temperature, filtered to remove insoluble material, and the solvent is 
evaporated to obtain a cloudy oil of the product mixed with m-cresol. 
B. 1-[2-(5-methyl-4-imidazolyl)ethylamidino]urea dihydrochloride 
A cresol-cyanoguanidine mixture is taken up in 225 ml. isopropanol, 6.3 m. 
conc. HCl is added, and this reaction mixture is heated to reflux over 10 
minutes and refluxed for one hour. The isopropanol is evaporated and the 
resulting residue is cooled in an ice-bath, filtered and washed with 
isopropanol/ethylacetate to give crude product. This material is 
recrystallized from MeOH/CH.sub.3 CN to give 
1-[2-(5-methyl-4-imidazolyl)ethylamidino]urea dihydrochloride, having a 
m.p. of 205.5.degree. C. 
EXAMPLE V 
A. N-cyano-N'-[3-(4-imidazolyl)propyl] guanidine 
6.2 g. (0.031 mole) of 4-(3-aminopropyl)imidazole dihydrochloride is 
converted to the free base using NaOH. The free base is combined with 5.4 
g. (0.031 mole) of O-m-tolyl-N-cyanoisourea in 100 ml. isopropanol. This 
mixture is refluxed for 3 hours. The mixture is then cooled to room 
temperature, filtered to remove insoluble material and the solvent is 
evaporated to obtain a cloudy oil of the product mixed with m-cresol. 
B. 1-[3-(4-imidazolyl)propylamidino]urea dioxalate monohydrate 
A cresol-cyanoguanidine mixture is taken up in 300 ml. isopropanol, 8.5 ml. 
conc. HCl is added, and this reaction mixture is heated to reflux over 20 
minutes and refluxed for 30 minutes. The isopropanol is evaporated leaving 
behind an oily residue. The crude dihyrochloride is converted to the free 
base using NaOH. The dioxalate salt is prepared from isopropanol to obtain 
1-[3-(4-imidazolyl)propylamidino]urea dioxalate monohydrate with a m.p. of 
60.degree.-70.degree. C. 
EXAMPLE VI 
When the procedures of Examples I-V are followed, by substituting the 
starting materials for those below, then the corresponding product is 
obtained: 
______________________________________ 
STARTING MATERIAL 
PRODUCT 
______________________________________ 
5-methyl-4-(3-aminopropyl) 
1-[3-(5-methyl-4-imidazolyl) 
imidazole dihydrochloride 
propylamidino]urea 
5-ethyl-4-(aminomethyl) 
1-[(5-ethyl-4-imidazolyl) 
imidazole dihydrochloride 
methylamidino]urea 
5-ethyl-4-(2-aminoethyl) 
1-[2-(5-ethyl-4-imidazolyl) 
imidazole dihydrochloride 
ethylamidino]urea 
5-ethyl-4-(3-aminopropyl) 
1-[3-(5-ethyl-4-imidazolyl) 
imidazole dihydrochloride 
propylamidino]urea 
5-propyl-4-(aminomethyl) 
1-[(5-propyl-4-imidazolyl) 
imidazole dihydrochloride 
methylamidino]urea 
5-propyl-4-(2-aminoethyl) 
1-[2-(5-propyl-4-imidazolyl) 
imidazole dihydrochloride 
ethylamidino]urea 
5-propyl-4-(3-aminopropyl) 
1-[3-(5-propyl-4-amidazolyl) 
imidazole dihydrochloride 
propylamidino]urea 
5-butyl-4-(aminomethyl) 
1-[(5-butyl-4-imidazolyl 
imidazole dihydrochloride 
methylamidino]urea 
5-butyl-4-(2-aminoethyl) 
1-[2-(5-butyl-4-imidazolyl) 
imidazole dihydrochloride 
ethylamidino]urea 
5-butyl-4-(3-aminopropyl) 
1-[3-(5-butyl-4-imidazolyl) 
imidazole dihydrochloride 
propylamidino]urea 
5-pentyl-4-(aminomethyl) 
1-[(5-pentyl-4-imidazolyl) 
imidazole dihydrochloride 
methylamidino]urea 
5-pentyl-4-(2-aminoethyl) 
1-[2-(5-pentyl-4-imidazolyl) 
imidazole dihydrochloride 
ethylamidino]urea 
5-pentyl-4-(3-aminopropyl) 
1-[3-(5-pentyl-4-imidazolyl) 
imidazole dihydrochloride 
propylamidino]urea 
5-hexyl-4-(aminomethyl) 
1-[(5-hexyl-4-imidazolyl) 
imidazole dihydrochloride 
methylamidino]urea 
5-hexyl-4-(2-aminoethyl) 
1-[2-(5-hexyl-4-imidazolyl) 
imidazole dihydrochloride 
ethylamidino]urea 
5-hexyl-4-(3-aminopropyl) 
1-[3-(5-hexyl-4-imidazolyl) 
imidazole dihydrochloride 
propylamidino]urea 
5-heptyl-4-(aminomethyl) 
1-[5-heptyl-4-imidazolyl) 
imidazole dihydrochloride 
methylamidino]urea 
5-heptyl-4-(2-aminoethyl) 
1-[2-(5-heptyl-4-imidazolyl) 
imidazole dihydrochloride 
ethylamidino]urea 
5-heptyl-4-(3-aminopropyl) 
1-[3-(5-heptyl-4-imidazolyl) 
imidazole dihydrochloride 
propylamidino]urea 
5-octyl-4-(aminomethyl) 
1-[(5-octyl-4-imidazolyl) 
imidazole dihydrochloride 
methylamidino]urea 
5-octyl-4-(2-aminoethyl) 
1-[2-(5-octyl-4-imidazolyl) 
imidazole dihydrochloride 
ethylamidino]urea 
5-octyl-4-(3-aminopropyl) 
1-[3-(5-octyl-4-imidazolyl) 
imidazole dihydrochloride 
propylamidino]urea 
______________________________________ 
EXAMPLE VII 
Five hundred ampoules each with 2 ml. of solution which contain 15 mg. of 
1-[(5-methyl-4-imidazolyl)methylamidino]urea dihydrochloride is prepared 
from the following types and amounts of materials: 
______________________________________ 
Ingredient Grams 
______________________________________ 
1-[(5-methyl-4-imidazolyl) 
7.5 
methylamidino]urea dihydrochloride 
Ascorbic Acid 1.0 
Sodium bisulphite 0.5 
Sodium sulphite 1.0 
______________________________________ 
The previous ingredients are added to distilled water, diluted to 1 liter 
of solution and thoroughly mixed. The solution is used to fill ampoules 
which are sterilized hot in the usual way.