JPS607613B2 - New amidinourea and its production method - Google Patents

Description

[Detailed description of the invention] The present invention relates to a new class of compounds and methods for their preparation.

The present invention also relates to new methods for treating diarrheal diseases. The present invention further provides formulations effective in treating diarrheal diseases. The present invention relates to a class of compounds called amidinoureas, which have effective activity capable of producing an antidiarrheal effect in mammals. Diarrhea is common among people around the world. In some diseases, this intestinal disorder can cause severe morbidity and even death. Narcotic analgesics are used as the drug of choice for the treatment of diarrhea and dysentery. However, this group of drugs has significant drawbacks. These drugs are narcotic and produce sleep as well as painlessness.
These are also physically and psychologically dependent susceptibilities. Morphine and codeine are two excellent examples within this group. In 1957, the mevelidine derivative diphenoxylate was introduced into therapeutic regimens for the control of diarrhea.

This drug has anticholinergic properties as well as morphine-like properties, both of which are effective in antidiarrheal action. Due to its narcotic properties, diphenoxylate is capable of supporting the physical dependence of morphine in monkeys. Overdosing in children can lead to symptoms and misfortunes that are characteristic of anesthetics, such as respiratory depression and
There may be a reversal of the pathology with lorphi hypertrophy). All previous attempts to discover non-addictive anti-diarrheal drugs have failed.

However, unexpectedly, the inventors have discovered a powerful antidiarrheal agent.

The inventors have unexpectedly discovered a group of compounds that have antidiarrheal action without the side effects common to antidiarrheal agents.

The inventors have also unexpectedly discovered that amidi/urea is an effective antidiarrheal agent with minimal side effects.

The inventors have also unexpectedly discovered that the administration of amidinourea is a simple and effective method of treating diarrheal symptoms without the ability to become physically addictive.

The inventors have further discovered an effective anti-diarrheal formulation without undesirable side effects and containing an amidinourea compound as an active ingredient.

The present invention is based on the formula (in the above formula, R2 and R6 may be the same or different,
Each represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group, provided that R2 and R6 do not represent a hydrogen atom at the same time; R3 and R5 may be the same or different, and each represents a hydrogen atom. atom, a halogen atom, or a lower alkyl group; R4 represents a hydrogen atom, a halogen atom, a nitro group, an amino group, or a lower alkyl group; R represents a hydrogen atom or a lower alkyl group; R' and R'' are the same; They may be present or different, and each may be a hydrogen atom, an alkyl group, an allyl group,
It represents a propargyl group, a cycloalkyl group, or a lower alkoxy group, or R' and R'' jointly form a pentamethylene chain or a tetramethylene chain; Rn represents a hydrogen atom or a lower alkyl group; the substituent R , R' and R'' is a substituent other than hydrogen.

) or a non-toxic acid addition salt thereof.

The present invention also relates to a method for producing a compound represented by the above formula or a non-toxic acid addition salt thereof.

It is known in the pharmacological art that non-toxic acid addition salts of pharmacologically active amine compounds are no different in activity than the free base.

The salt merely provides an advantageous solubility factor. The method of the present invention can be easily converted into non-toxic acid addition salts by methods conventional in the art.

The non-toxic salts of the present invention are salts that are pharmacologically acceptable at the dosage intended for their brewing ingredients, and such salts include inorganic acids, organic acids, higher fatty acids, high molecular weight acids, etc., such as hydrochloric acid, hydrobromic acid, etc. , sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, malic acid, succinic acid, glycolic acid, lactic acid, salicylic acid, benzoic acid, nicotinic acid, phthalic acid, stearic acid, oleic acid, ajetin Includes salts made from acids. The nomenclature of the compounds of the present invention is as follows.

The term "lower alkyl" means a straight or branched chain alkyl hydrocarbon group of 1 to 5 carbon atoms; A hydrocarbon group. "The term cycloalki'zo means a cycloalkyl group having 3 to 7 carbon atoms.

A "lower alkoxy" group means a straight or branched alkoxy group containing from 1 to about 5 carbon atoms. A preferred "ary'zo group is phenyl.

Preferred "aralky'zo" groups are penzyl and phenethyl. A preferred "halo-lower alkyl" group is trifluoromethyl. A preferred "halo-lower alkoxy" group is trifluoromethoxy.

However, tautomerism must be considered in the true structure of amidinourea.

The amidi/urea head can be reasonably represented by one of its tautomeric and geometric isomers. There are a large number of possible configurations within the structure, and such rearrangements are possible and occur to some extent, especially in solution.

One structure may take precedence over another depending on the type and position of the substituent and the nature of the solvent.

The rate at which one structure is converted to another depends on the nature of the solvent, the degree of hydrogen bonding allowed, the temperature and possible other factors such as pH, traces of impurities, etc. In order to illustrate the above, structures that can be taken by one compound of the present invention are listed below.

Of course, other structures are also possible if hydrogen bonds are present.

Since there are many possible structures, it is not possible to list all possible structures. The above compounds are representative and represent the compounds of the present application. Under physiological conditions, any or all of these structures may be present, and the sites of action of these molecules can be predicted.

By definition, tautomerism applies only when protons are involved, and does not apply to other groups.

Therefore, in the above description, we have cited those that are smoothly and freely translocated by the translocation of one proton. If other substituents are involved, they are outside the scope of tautomerism. For example, if all are substituted and no protons are present, only one structure will exist (as shown below). The compounds of the present invention can be produced by the following general synthetic method.

Condensation of a substituted phenyl isocyanate (prepared in conventional manner from aniline and phosgene) with guanidine gives a 1-monosubstituted phenyl-3-amidinourea.

This reaction is carried out in a polar medium using solvents such as dimethylformamide, tetrahydrofuran, etc. It is convenient to carry out the reaction by preparing the isocyanate in the reaction soot and then hydrolyzing the guanidine carbonate in situ with chlorine to form the guanidine. When guanidine is produced, condensation of isocyanate takes place and an amidinourea compound is obtained. Compounds of the invention can also be prepared by decomposition of the corresponding biguanides.

Hydrolysis of 1-monosubstituted phenylbiguanide compounds with acid at elevated temperatures provides 1-substituted phenyl-3-amidinoureas.

This reaction is preferably carried out using hydrochloric acid; the reaction time and reaction temperature will of course depend on the particular biguanide used and the acid concentration present. Generally, high acid concentrations do not require high temperatures or long reaction times. If it is desired to have R substitution at N-3, the starting material is of course aniline with N-alkyl substitution.

Reaction with phosgene gives carbamoyl chloride, which then reacts with guanidine to give amidinourea. The starting anilines are known or can be prepared by known methods, or references to their preparation are given.

Thus, chlorination or bromination of acetanilide or aniline can be carried out in acetic acid or in the presence of a small amount of dissolved iodine in an inert solvent such as carbon tetrachloride. Next, a solution of chlorine or bromine is added while maintaining the temperature around 0°C. Iodination can also be carried out by known methods using iodine monochloride (CII). Alkylation of acetanilide can be carried out using an alkyl halide and aluminum chloride under Friedel-Krach conditions to obtain the desired alkyl substitution.

Nitration can be carried out using fuming nitric acid at about 0°C.

Nitro compounds can be hydrogenated to the corresponding amines, which can then be diazotized and heated in an alcoholic medium to form alkoxy compounds.

Amino compounds can also be diazotized to give diazonium fluoroshelate salts, which can then be salt decomposed to give fluoro compounds.

A bromine, chloro or iodo compound can be obtained by carrying out a Sandmeyer type reaction after diazotization.

Diazotization of the amino compound followed by reaction with potassium ethylxanthate and subsequent hydrolysis yields the mercapto compound. The mercapto compound can also be alkylated to an alkylthio group, which can be further oxidized to the corresponding alkylsulfonyl substituent.
Chlor, bromo or iodo compounds can also be reacted with trifluoromethyl iodide and copper powder in dimethylformamide at about 150°C to give trifluoromethyl compounds [Tetrahedron Letters: 47, 4095
~4096 (1969)]. Halo compounds can also be reacted with cuprous methanesulfonate at 15,000 °C in quinoline to give methylsulfonyl compounds. If a final product containing hydroxy groups is desired, it is preferred that the starting aniline contains the corresponding acyloxy or alkoxy group.

These compounds are prepared in the conventional manner by acylation of the starting hydroxyaniline compound with an acyl halide or acid anhydride in the presence of a tertiary amine, or alternatively by aralkylation with an aralkyl halide or an aralkyl sulfate. be able to. Of course, the amine functionality should be protected in the usual manner. After the amidinourea is formed, hydrogenation to the desired hydroxy compound can be carried out. This hydrogenation is performed using sacrificial solvents (ethanol, TMF).
etc.), sodium in liquid ammonia, etc.). Thus, for example, 3,4-dihydroxyamidi/urea compounds can be prepared from the corresponding 3,4-dibenzyloxyanilines. Hydroxy compounds can also be prepared by hydrolysis of acyl or aralkoxy compounds. The reaction can also be carried out in other synthetic steps depending on the substituents present and desired.

A person skilled in the art can also determine various combinations of the above reactions to obtain the desired product. Thus, the phenylamidinourea can be halogenated or nitrated as described above. The biguanide starting materials are also known compounds, or can be prepared by known methods, or can be prepared by the following general synthetic methods.
Condensation of cyanoguanidine and aniline in the presence of equimolar amounts of hydrochloric acid gives the corresponding phenyl biguanide.

This reaction is preferably carried out on the aniline salt in a polar solvent or in pure form at elevated temperature.

When the above reaction is carried out on biguanides or amidinoureas, it is possible to obtain products with appropriate substituents. The compounds described in this application are useful antidiarrheal agents. These compounds are administered orally for this purpose;
Can be administered parenterally or rectally. Oral administration is preferred. For oral administration, these compounds can be presented in the form of tablets, hard or soft capsules, aqueous or oily suspensions, dispersible powders or tablets, emulsions, syrups or elixirs. The optimal dosage will, of course, depend on the particular compound used and the type and severity of the condition being treated. In particular cases, the appropriate dosage will also depend on patient factors that influence sensitivity to the drug used, such as general health, age, weight, etc. The optimal amount of the compound of the present invention to be used as an antidiarrheal agent will vary depending on the compound used and the particular disease being treated, but when administered to mammals, it is recommended to
Oral administration of the preferred compounds in amounts of 0.01 to 500 parts per nine is particularly useful.

A preferred dosage range is 0.05 to 200 9'k9. It can be administered parenterally or rectally in corresponding doses. Oral preparations can be prepared by methods known in Qin.

Such formulations may contain one or more additives selected from the group consisting of sweeteners, colorants, preservatives, etc. to improve appearance and flavor. Additionally, the activated amidinocarbons of the present invention may be administered alone or in admixture with other drugs having the same or different pharmacological properties. The formulation contains inert diluents such as calcium carbonate, lactose, etc., granules or disintegrants such as corn starch, alginic acid, etc.: lubricants such as magnesium stearate, binders such as starch, gelatin, etc., methylcellulose, Suspending agents such as vegetable oils, non-irritating excipients such as lecithin, and the like may be included.

Also, when formulated, there may be from 5 to 95 parts by weight of active ingredient per part by weight of formulation 10.

Dosage unit forms generally contain from 0.1 to about 50% of the active ingredient of the invention.
Contains 0m9. A preferred unit dose is 1 to about 50 doses. The formulation may be administered from 1 to 8 times per day, depending on the required dosage unit. Various tests can be conducted in animal experiments to demonstrate the ability of the amidinourea of the present invention to exhibit a response that correlates with antidiarrheal activity in humans.

The following test demonstrates the ability of the compounds of the present invention to suppress diarrhea in animals, and this test is known to correlate well with antidiarrheal ability in animals. These tests are considered the standard tests used to measure antidiarrheal efficacy. This correlation can be demonstrated by the activity of compounds known to be clinically active. In view of the test results, the amidinourea of the present invention can be considered as an antidiarrheal agent. 1 Rat feces 9E pond test: Oral ED5o
(dose expected to reduce fecal excretion volume by 50%) is determined using the method of Bass et al. (1972).

Briefly, this method is performed by dosing rats and collecting feces from their ponds for 8 hours (4 p.m. to 1 p.m.) in a dark room starting at 4 p.m. (3 p.m.). References: Bass, P. Kennedy, J.
A. and Willey, J. N. , “Measurement of excreted amount of feces in rats” (AmJ. Dig. 01s.1 Li925-Shigeru &
1972).

2 Castor oil test in mice: Several groups of mice are orally administered the test compound, and 30 minutes later all mice are administered 0.3' castor oil.

Three hours after administration of castor oil, all mice were checked for diarrhea symptoms, and the dose of the test compound that did not cause diarrhea in 50% of the mice was determined. o. 3 Castor oil test on rats: This test was performed using Njermegeer.
) et al. (1972).

Rats are administered various doses of the test compound, and 1 hour later, all rats are orally administered with 1 part of castor oil. Examine excreted feces 1, 2, 3, 4, 6, and 8 hours after castor oil administration. References: Niameguia, C. J. E. , Lena Arts, F.M. and Jjansen, P. A. J. “Difunoxin, a potent orally active and safe antidiarrheal agent for rats” [DrugRes. 22, N
o. 3 516-5181972].

Detailed examples illustrating the properties of the compounds of the invention are presented below. These compounds are listed as examples of the compounds of the present invention and are not intended to limit the present invention. Example 1 1-(N-methyl-amidi/)-3-(2,6-dimethylphenyl)urea and its hydrochloride anhydrous benzene 300
To a solution containing 12.1 liters (0.1 mol) of 2,6-dimethylaniline in 32.5% benzene solution of phosgene is added 325 ml (0.395 mol) of a 12.5% solution of phosgene in benzene.

The reaction mixture is refluxed for 2 hours, the benzene is distilled off under reduced pressure to remove the phosgene, and the residue is purified by distillation. This was 2,6-dimethylphenylisocyanate, which was then dissolved in 50 parts of tetrahydrofuran, and this solution was mixed with 11.2 parts of potassium hydroxide and 18 parts of methylguanidine sulfate in 250 parts of tetrahydrofuran. Add dropwise into the heterogeneous mixture containing. After the mixture has been allowed to stand for 8 hours, 35 g of concentrated hydrochloric acid is added, and then the mixture is placed in a cold water bath and, while keeping it at a low temperature, 40 g of concentrated sodium hydroxide solution is added. The mixture is then poured onto 1500 g of water and the tetrahydrofuran is removed under reduced pressure. Next, the mixture was extracted with ether, and the ether extract was dried and evaporated to dryness.
- Obtain 6-dimethylphenyl)urea. The hydrochloride salt is prepared by dissolving the free base in methanol and adding a methanol solution of hydrogen chloride.

The mixture obtained here was concentrated, ether was added, and 1-(N
-Methyl-amidino)-131 (2,6-dimethylphenyl) urea hydrochloride is collected in an oven. Melting point of hydrochloride: 197-1
97.5q0. The corresponding compound of the present invention can be obtained by using aniline shown in Table 1 below in place of 2,6-dimethylaniline in the above method.

Table 1 2-Methyl-6-chloroaniline 2-methyl-6-fluoroaniline 2-methyl-6-bromoaniline 2-methyl-6-iodoaniline 2-methyl-6-methoxyaniline 2-methyl-6-ethoxyaniline 2-methyl-6-ethylaniline 2-methyl-6-propyl Aniline 2-methyl-6-1-propylaniline 2-methyl-6-butylaniline 2-methyl-6-cyananiline 2-methyl-6-trifluoromethylaniline 2-methyl-6 nitroaniline 2-methyl-6-methylsulfonylaniline 2-ethyl-6 -Chloraniline 2-ethyl-6-fluoroaniline 2-ethyl-6-fromaniline 2-ethyl-6-methoxyaniline 2-ethyl-6-ethoxyaniline 2,6-diethylaniline 2-ethyl-6-propylaniline 2-ethyl-6 -trifluoromethylaniline 2-propyl-6-chloroaniline 2-propyl-6-fluoroaniline 2-propyl-6-bromoaniline 2-propyl-6-methoxyaniline 2-bropyl-6-ethoxyaniline 2,6-dipropylaniline 2-1-Propyl-6-Chloraniline 2-1-Propyl-6-Fluoraniline 2-1-Propyl-6-Methoxyaniline 2-Butyl-6-Chloraniline 2-Methyl-3-Chloraniline 2-Methyl-5-Chloraniline 2,4-Dichloroaniline 2,5- Dichloroaniline 2,6-dichloroaniline 2-chloro-3-methylaniline 2-chloro-4-methylaniline 2-chloro-5-methylaniline 2-chloro-5-fluoroaniline 2-chloro-5-bromoaniline 2-chloro-5-trifluoromethylaniline 2 -fluoro-5-chloroaniline 2-chloro-6-fluoroaniline 2,6-difluoroaniline 2-methylaniline 2-ethy'reaniline 2-propylaniline 4-trifluoromethoxyaniline 4-methylsulfonylaniline 4-trifluoromethylaniline 3・4-dimethoxyaniline 3,4,5-trimethoxyaniline 3,4-diacetyloxyaniline 3,4-dibenzyloxyaniline 3,4,5-tribenzyloxyaniline 3,4-diethoxyaniline 2,4- Dimethylaniline 2,4-diethylaniline 2-methyl-4-ethylaniline 2-ethyl-4-methylaniline 2-methyl-4-chloroaniline 2-methyl-4-bromoaniline 2-methyl-4-fluoroaniline 2-ethyl-4- Chloraniline 2-ethyl-4-fluoroaniline 2-methyl-4-methoxyaniline 2-ethyl-4-methoxyaniline 2,4,6-trimethylaniline 2,4-dimethyl-6-ethylaniline 2,4-dimethyl-6-chloroaniline 2,4-dimethyl-6 -promaniline 2,4-dimethyl-6-fluoroaniline 2,4m dimethyl-6-trifluoromethylaniline 2,4 days dimethyl-6 nitroaniline 2,4 m dimethyl-6-methoxyaniline 2,6 days dimethyl-4-ethylaniline 2,6 m dimethyl-4 -Chloraniline 2,6m dimethyl-4-promaniline 2,6m dimethyl-4-fluoroaniline 2,6-dimethyl-4-methoxyaniline 2-methyl-4,6-dichloroaniline 2-methyl-4,6-difluoroaniline 2-methyl-4- Fluoro-6-bromoaniline 2-methyl-4-fluoro-6-chloroaniline 2-methyl-4-bromo-4-chloroaniline-2-methyl-4-chloro-6-fluoroaniline 2-methyl-4-chloro-6-promoaniline 2-methyl-4-methoxy6-chloroaniline 2
-Methyl-4-ethyl-6-chloroaniline 2-Methyl-4-chloro-6-trifluoromethylaniline 2-Methyl-4-trifluoromethyl-6-chloroaniline 2
-Ethyl-4,6-dichloroaniline 2-ethyl-416-difluoroaniline 2-ethyl-4-fluoro-6-bromoaniline 2-ethyl-4-fluoro-6-chloroaniline 2-ethyl-4-prom-
6-Chloraniline 2-ethyl-4-chloro-6-fluoroaniline 2-ethyl-4-chloro-6-bromoaniline 2,6-diethyl-4-chloroaniline 2,6-diethyl-4-bromoaniline 2,6-diethyl-4-fluoroaniline 2,4-dimethyl-6-nitroaniline 1-amidino-3-(3,4-diacetyloxyphenyl)urea and 1-amidino-3-(3,4-dibenzyloxyphenyl)urea in ethanol with Pd/
Hydrogenation at C gives 1-amidino-3-(3,4-dihydrophenyl)urea.

By hydrogenating 1-amidino-3-(3,4,5-tribenzyloxyphenyl)urea with Pd/C in ethanol, 1-amidino-3-(3,4,5-trihydroxyphenyl)urea was obtained. can get.

Example 2 1-[N-butyl-N-(2,6-diethylphenyl)
[carbamoyl]-3-methylguanidine succinate Methylguanidine sulfate 36.5 mol (0.15 mol) of tetrahydrofuran (300% suspension at 50% (w/w)
It was treated with 24.0 molar (0.30 mol) of sodium hydroxide aqueous solution and kept lit for 1 hour.

20.0 liters of anhydrous sodium sulfate was added and stirred for an additional 30 minutes. A solution of 20.6 moles (0.077 moles) of N-butyl-N-(2,6-diethyl phenyl)rubamoyl chloride in tetrahydrofuran (50 moles) was added for 1 hour and 30 minutes.
It was dripped over several minutes. After feeding for another 2 hours, the solvent was removed under reduced pressure, and the residue was partitioned between ether (400 ships) and dilute aqueous sodium bicarbonate solution. The ether layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was dissolved in 250 ml of hot isopropanol and treated with 9.5 ml of succinic acid (0.08 mol). Add this solution to 20
The mixture was boiled until the temperature reached 0.0 and left overnight to cool. The suspension was filtered and the solid material was vacuum dried at 70:00 for 2 hours and 3 minutes to obtain 1-[N-butyl-N-(2,6-diethylphenyl)rubamoyl]-3-methylguanidine succinate. Acid salt 14.8 mol (0.035 mol, yield 46%, m.p.
．． 123-124 qo) were obtained. Example 31-(
N・N'-dimethyl-amide/)-3-(2-chloro-
6-Methylphenyl)urea and 200ml of 11(2-chloro-6-methylphenyl)-4,5-dimethylbiguanide were added to 200ml of 10% hydrochloric acid, and the mixture was refluxed for 3 hours.

Next, this reaction mixture is heated through a furnace and then cooled. The separated material is collected in an oven and recrystallized from isopropanol/water to obtain 11N.N'-dimethyl-amidino-3-(2-chloro-6-methylphenyl)urea hydrochloride. Melting point of hydrochloride: 200-20 ○. Dissolve this hydrochloride in 200 g of water and add 10% sodium hydroxide solution until alkaline. The reaction mixture was then extracted with chloroform and the chloroform extract was dried and evaporated to dryness.
6-methylphenyl)urea is obtained. By substituting the biguanides of Table 2 below for 1-(2-chloro-6-methylphenyl)-4,5-dimethylbiguanide in the examples above, the respective corresponding products are obtained.

Table 2 1-(3,4-dibenzyloxyphenyl)-5-methylbiguanide 1-(3,4-dibenzyloxyphenyl)-5,5-dimethylpiguanide 1-(3,4- dibenzyloxyphenyl)-4,5-dimethylbiguanide 1
-(3,4-dibenzyloxyphenyl)-3-methylbiguanide 1-(3,4-dibenzyloxyphenyl)
-1,5-dimethylbiguanide 1-(3,4,5-tribenzyloxyphenyl)-5-methylbiguanide 1-(3,4,5-tribenzyloxyphenyl)-5,5
-dimethylbiguanide 1-(3,4,5-tribenzyloxyphenyl)-4,5-dimethylbiguanide 1-(
3,4,5-tribenzyloxyphenyl)-3-methylpiguanide 1-(3,4,5-tribenzyloxyphenyl)-1,5-dimethylbiguanide 1-,(2,6
-dimethylphenyl)-5-methylbiguanide 1-(2
・6-dimethylphenyl)-5,5-dimethylbiguanide 1-(2,6-dimethylphenyl)-4,5-ditylbiguanide 1-(2,6-dimethylphenyl)-4,5
・5-Trimethylpiguanide 1-(2,6-dimethylphenyl)-1-3-methylbiguanide 1-(2,6-dimethylphenyl)-1-1,3-dimethylbiguanide 1-(2.
6-dimethylphenyl)-3,5-dimethylbiguanide 1-(2,6-dimethylphenyl)-3,5,5-trimethylbiguanide 1-(2,6-dimethylphenyl)-3,4,5 -trimethylbiguanide 1-(2,6-dimethylphenyl)-1,5-dimethylpiguanide 1-(2
・6-dimethylphenyl)-1,3,5-trimethylbiguanide 1-(2,6-dimethylphenyl)-1,3,5
・5-tetramethylbiguanide 1-(2.6-dimethylphenyl)-1.3.4.5-tetramethylbiguanide 1-(2.6-dimethylphenyl)-1.3.4.5.
5-pentamethylbiguanide 1-(2,6-diethylphenyl)-5-methylbiguanide 1-(2-methyl-6
-methoxyphenyl)-5-methylbiguanide 1-(2
-methyl-6-chlorophenyl)-5-methylbiguanide 1-(2-methyl-6-ethylphenyl)-5-methylbiguanide 1-(2-methylphenyl)-5-methylbiguanide 1-(2,4,6-trimethylphenyl) 1-5-Methyl biguanide 1-(2-methyl-4-bromo-
6-chlorophenyl)-5-methylbiguanide 1-(2
-chloro-6-fluorophenyl)-5-methylbiguanide 1-(2,5-dichlorophenyl)-15-methylbiguanide-1-(2-chloro-6-fromphenyl)-5
-Methylbiguanide 1-(2-chloro-5-fromphenyl)-5-methylbiguanide 1-(2-chloro-5-
Fluorophenyl)-5-methylbiguanide 1-(2-
Fluoro-5-chlorophenyl)-5-methylbiguanide 1-(2-fluor-5-fromphenyl)-5-methylbiguanide 1-(2,4,6-triethyl)-5-methylbiguanide 1-(2,4-dimethyl-6-ethylphenyl) )-5-methylbiguanide 1-(2,6-dimethyl-4-ethylphenyl)-5-methylbiguanide 1
-(2-ethyl-6-chlorophenyl)-5-methylbiguanide 1-(2-ethylphenyl)-5-methylbiguanide 1-(2-ethyl-4-from-6-chlorophenyl)-5-methylbiguanide 1-(2-ethyl-6 -methoxyphenyl)-5-methylbiguanide 1-(2-methyl-6-ethoxyphenyl)-5-methylbiguanide 1-(2,6-diethylphenyl)-3-methylbiguanide 1-(2-methyl- 6-methoxyphenyl)-3
-Methylbiguanide 1-(2-methyl-6-chlorophenyl)-3-methylbiguanide 1-(2-methyl-6-
ethyl phenyl)-3-methylbiguanide 1-(2-methylphenyl)-3-methylbiguanide 1-(2.4.
6-trimethylphenyl)-3-methylbiguanide 1-
(2-methyl-4-from-6-chlorophenyl)-3
- Methyl biguanide 1-1 (2-k.

1-(2,5-dichlorophenyl)-13-methylbiguanide 1-(2,6-dimethylphenyl)-15-ethylbiguanide 1-(216- dimethylphenyl)-5-propylpiguanide 1-(2,6-dimethylphenyl)-5
1-1-Propylpiguanide 1-(2,6-dimethylphenyl)-5-butylbiguanide 1-(2,6-dimethylphenyl)-5-1-phthylbiguanide 1-. (2・
6-dimethylphenyl)-15-sec-butylpiguanide 1-(2,6-dimethylphenyl)-5-t-butylpiguanide 1-(2,6-dimethylphenyl)-15-bentylbiguanide 1-(2 -6-dimethylphenyl)-15-hexylbiguanide 1-(2,6-dimethylphenyl)-15-heptylbiguanide 1-(2,6-dimethylphenyl)-15-sic.

Propyl biguanide 1-(2,6-dimethylphenyl)
1-5-cyclobutyl biguanide 1-(2,6-dimethylphenyl)-5-cyclobentyl biguanide 1-(2,
6-dimethylphenyl)-5-cyclohexylbiguanide 1-(2,6-dimethylphenyl)-5-phenylbiguanide 1-(2,6-dimethylphenyl)-5-benzylbiguanide 1-(2,6 -dimethylphenyl)-5
-phenethyl biguanide 1-(2,6-dithylphenyl)-15-(2,6-dimethylphenyl) biguanide 1-(2,6-dimethylphenyl)-15-(2-methylphenyl) biguanide 1-(2・6-dimethylphenyl)-5-(2,6-diethylphenyl) biguanide 1-(2
・6-dimethylphenyl)-5-(2-methyl-6-chlorophenyl) biguanide 1-(2,6-dimethylphenyl)-15-(2,406-trimethylphenyl) biguanide 1-(2,6- dimethylphenyl)-5,5-bentamethylene biguanide) biguanide 1-(2,6-dimethylphenyl)-5,5-(N-methyl-3'-azabesotamethylene) biguanide 1-(2,6- dimethylphenyl)-5,5-(N-methyl-3'-azaheptamethylene) bigufnide 1-(2,6-dimethylphenyl)
-5,5-(3'-oxobentamethylene) biguanide 1-(2,6-dimethylphenyl)-5,5-(2-thiatetramethylene) biguanide 1-(2,6-dimethylphenyl)- 5-methyl-5-ethyl biguanide 1-(
2,6-dimethylphenyl)-5,5-dimethylbiguanide 1-(2.

6-dimethylphenyl)-15-methyl-5-penzylbiguanide 1-(2,6-dimethylphenyl)-15,5-dibenzylbiguanide The physical properties of the compound of the present invention are shown below.

Table 3 Furthermore, physical property values of the compound of the present invention are shown.

Table 4 [Toxicity test] The LD5o values of the compounds described in JP-A-50-140544, JP-A-50-140545 and JP-A-50-140546 (hereinafter referred to as "cited compounds") and the compounds of the present invention were investigated. .

Swiss Webster (Tac, Tac)
50, 82, 1 dose of the test compound to each group of 5 or 10 male mice (weight 18-22 days).
35 222, 365 and 600 9/k9 administered;
LD5. The value of was calculated. 0.5% methylcellulose was used as the vehicle. The results are shown in the table below. The substituents X, Y, and Rn of the cited example compound are the same as the substituents of the corresponding compound of the present invention, and the substituents R' and R'' are both hydrogen atoms. From the above toxicity test results, It can be seen that the amidino group-substituted compound of the present invention has significantly lower toxicity than the unsubstituted amidino group compound of the cited example, and is a pharmacologically useful compound.Related matters of the present application are inserted below. .

Formula 1 (in the above formula, R2, R3, R4, R5, and R6 may be the same or different, and each represents hydrogen, halo-lower alkyl, halo-lower alkyl, nitro, lower alkoxy, hydroxy,
al-lower alkoxy, acyloxy, cyan, halo-lower alkoxy or lower alkylsulfonyl; R and Rn are hydrogen or lower alkyl; R' and R'' are hydrogen, alkyl, cycloalkyl or aralkyl; R' and R'' can together form a ring of 5 to 7 atoms, which ring may contain 0 to 2 heteroatoms N, 0 or S) or non-toxic acids thereof Added salt 0.01-500 kites per day9
A method of treating diarrhea in humans and mammals comprising administering /k9.

Claims (1)

[Claims] 1 Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the above formula, R_2 and R_6 may be the same or different, and each represents a hydrogen atom, a halogen atom, a lower alkyl group, or Represents a lower alkoxy group, provided that R_2 and R_6 do not represent a hydrogen atom at the same time; R_3 and R_5 may be the same or different, and each represents a hydrogen atom, a halogen atom, or a lower alkyl group; R_4 represents a hydrogen atom, a halogen atom, a nitro group, an amino group, or a lower alkyl group; R represents a hydrogen atom or a lower alkyl group; R' and R'' may be the same or different, and each represents hydrogen. atom, an alkyl group, an allyl group, a propargyl group, a cycloalkyl group, or a lower alkoxy group, or R' and R'' together form a pentamethylene chain or a tetramethylene chain; Rn is a hydrogen atom or a lower 1-amidino-3-substituted phenyl urea or a non-toxic acid addition salt thereof, represented by the following formula (representing an alkyl group; at least one of the substituents R, R' and R'' is a substituent other than a hydrogen atom).2 R_2 is a methyl group or an ethyl group; R_3 is a hydrogen atom, R_4 is a hydrogen atom, a bromine atom, or a methyl group; R_5 is a hydrogen atom; R_6 is a chlorine atom, a bromine atom, a methyl group, an ethyl group; or a methoxy group; R is a hydrogen atom, a methyl group, or an ethyl group; Rn is a hydrogen atom or a methyl group; R' and R'' may be the same or different, and each is a hydrogen atom , methyl, ethyl, propyl or isopropyl; substituents R, R' and R''
2. The compound according to claim 1, wherein at least one of the substituents is a substituent other than a hydrogen atom. 3. The compound according to claim 1 or 2, wherein R_2 and R_6 may be the same or different, and each is a methyl group or an ethyl group. 4. The compound according to any one of claims 1 to 3, wherein R_3, R_4 and R_5 are each a hydrogen atom. 5 The compound according to any one of claims 1 to 4, wherein one of R, R' and R'' is a methyl group. 6 1-(N-methylamidino)-3-(2. The compound according to claim 1, which is 6-dimethylphenyl)-urea or a nontoxic acid addition salt thereof.7 1-(N-Methylamidino)-3-(2,6-diethylphenyl)-
The compound according to claim 1, which is urea or a non-toxic acid addition salt thereof. 8 1-(N-methylamidine)-3-(2-methyl-
6-ethylphenyl)-urea or a non-toxic acid addition salt thereof. 9 There are formulas, mathematical formulas, chemical formulas, tables, etc. that are characterized by reacting a substituted phenyl isocyanate with guanidine. (In the above formula, R_2 and R_6 may be the same or different, and each hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group, provided that R_2 and R_6 do not simultaneously represent a hydrogen atom; R_3 and R_5 may be the same or different, and each represents a hydrogen atom, a halogen atom, Represents an atom or a lower alkyl group; R_4 represents a hydrogen atom, a halogen atom, a nitro group, an amino group, or a lower alkyl group; R represents a hydrogen atom or a lower alkyl group; R' and R'' may be the same They may be different, and each represents a hydrogen atom, an alkyl group, an allyl group, a propargyl group, a cycloalkyl group, or a lower alkoxy group, or R' and R'' jointly represent a pentamethylene chain or a tetramethylene chain. at least one of the substituents R, R' and R'' is a substituent other than a hydrogen atom. 10 Formulas characterized by reacting substituted phenylcarbamoyl chloride with guanidine: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the above formula, R_2 and R_6 may be the same or different, and each represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group, provided that R_2 and R_6 do not represent a hydrogen atom at the same time; R_3 and R_5 may be the same or different, and each represents a hydrogen atom. , represents a halogen atom or a lower alkyl group; R_4 represents a hydrogen atom, a halogen atom, a nitro group, an amino group or a lower alkyl group; R represents a hydrogen atom or a lower alkyl group; R' and R'' are the same; may be different, and each represents a hydrogen atom, an alkyl group, an allyl group, a propargyl group, a cycloalkyl group, or a lower alkoxy group, or R' and R'' jointly represent a pentamethylene chain or tetramethylene chain. 1-amidino-3-substituted compound, which forms a chain; Rn represents a hydrogen atom or a lower alkyl group; at least one of the substituents R, R' and R'' is a substituent other than a hydrogen atom. A method for producing phenylurea or its nontoxic acid addition salt. 11 Formulas that are characterized by hydrolyzing biguanides: ▲Mathematical formulas, chemical formulas, tables, etc.▼ (In the above formula, R_2 and R_6 may be the same or different, and each represents a hydrogen atom, a halogen atom, lower alkyl group, or lower alkoxy group, provided that R_2 and R_6 do not simultaneously represent a hydrogen atom; R_3 and R_5 may be the same or different, and each represents a hydrogen atom, a halogen atom, or a lower Represents an alkyl group; R_4 represents a hydrogen atom, a halogen atom, a nitro group, an amino group, or a lower alkyl group; R represents a hydrogen atom or a lower alkyl group; R' and R'' may be the same or different; Each may represent a hydrogen atom, an alkyl group, an allyl group, a propargyl group, a cycloalkyl group or a lower alkoxy group, or R' and R'' may jointly form a pentamethylene chain or a tetramethylene chain; Rn represents a hydrogen atom or a lower alkyl group; at least one of the substituents R, R' and R'' is a substituent other than a hydrogen atom.) 1-amidino-3-substituted phenyl urea or its non-toxic Method for producing acid addition salts.