CA1081711A - 1-phenylguanidines - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

There is disclosed novel compounds of the formula:

Description

~8~L7~ :

SUMMARY OF THE INVENTION
This invention describes new substituted phenyl-guanidine compounds and processes for their preparation. This invention further provides valuab:Le pharmaceutical prepa-rations which contain substituted phenylguanidine compounds which possess an effective degree of antihypertensive proper-ties and exert activities on the cardiovascular system. A
method for the treatment of hypertensive disorders by the administration of a substituted phenylguanidine compound is also described.
BACKGROUND OF THE INVENTION
,, , The pharmaceutical compositions which have been used as antihypertensive agents have included such as the thi-azides, reserpine, hydralazine, ~-methyl dopa, guanethidine and the like. These compounds, however, while being effective produce undesirable side effects such as electrolyte in-balance, orthostatic hypertension, and gastric secretory and spasmolytic properties. ~ -~
We have unexpectedly found that guanidine compounds exhibit valuable pharmacologic properties.
We have unexpectedly found that the guanidines of this invention are useful antihypertensive agents.
We have also unexpectedly found that guanidines of this invention are also useful intermediates for the prepa-ration of amidinourea compounds which are also useful anti- -hypertensive ayents.
We have further found that the guanidine compounds of this invention are novel and can easily be prepared.
We have also found that the compounds of this invention have a minimum of the side effects which accompany . .
antihypertensive agents.

- - 1 - ~ ;,,.. ".,.. , .' We have still further found a simple and effective method for the treatment of cardiovascular disorders such as hypertensive disorders.
DESCRIPTION AND PREFERRED EMBODIMENT
This invention describes a class of novel chemical compounds which comprises a substituted phenyl radical which is further attached to a guanidine chain. This invention also describes the non-toxic pharmaceutically acceptable salts and the method of preparing these substituted phenylguanidine compounds.
The novel compounds of this invention are described by the structural formula I:

R ~ NH

R4 ~ 0 ~ ¦N-e N~ R'' 1- ;

where:
R2, R3, R4, R5 and R6 stand for hydrogen, halogen and loweralkyl of 1 to 5 carbon atoms; R is hydrogen or loweralkyl; R' and R" are hydrogen, loweralkyl or -:-acyl, wlth the proviso that R2 and R6 may not be chloro when R' and R" are the same or different and stand for hydrogen or methyl;
and the non-toxic acid addltion salts thereof.
Compounds of this invention which are preferred are described by general formula I
where:
R2 and/or R3 is hydrogen or halo;

- 2 -_~, ~ 7 R4 and/or R5 is hydrogen, halo or loweralkyl;
R6 is halo or loweralkyl, provided R2, R3, R4 and R5 are not al1 hydrogen R is hydrogen or loweralkyl; and R' and R" are hydrogen, loweralkyl or ~:
acyl.
The more preferred compounds of this inVention include those compounds !~
where: :
R2 or R3 is hydrogen, chloro, bromo or .
fluoro; :-R4 or R5 is hydrogen, chloro, :
bromo, fluoro, methyl or .:
trifluoromethyl;
R6 is chloro provided R2, R3, R4 and R5 are not all hydrogen, ~ :
bromo provided R2, R3, R4 and R5 are not all hydrogen, fluoro provided R2, R3, R4 and R5 are not all hydrogen, -~ . --. -: methyl provided R2, R3, R4 and R5 are not all hydrogen;
R is hydrogen or -methyli R' is hydrogen;

- 3 - `

1~ 8 1 7 R" is hydrogen, methyl, ethyl, propyl, i-propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or acetyl.
A special embodiment of this invention is described where X is hydrogen, R2 is chloro and R6 is 6-chloro provided R' and R" each stand for hydrogen.
In the descriptive portions of this invention, the following definitions apply:
The term "loweralkyl" refers to an alkyl hydrocarbon `~
group containing from l to 5 carbon atoms which may be `;
straight chained or branched. ~`~
The "acyl" radical may be any organic radical derived from an organic acid by its removal of the hydroxyl group such as acetyl, propionyl, etc.
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 solubillty ~factor.
The amines~ of this invention may be readily con-:
verted to their non-toxic acid addition salts by customary methods in the~art.~The non-toxic salts of this i~nvention are those salts the acid component of which is pharmacologically acceptable in the intended dosages; such salts would include `:

- 4 -: ' : , . .. .. . . .
... ... , . . .. . . .. .. . . .: ~ . .. . . .

~C~81711 those prepared from inorganic acids, organic acids, higher fatty acids, high molecular weight acids, etc.
The compounds of this invention exert activity on the cardiovascular system. They possess blood-pressure lowering effects and are useful as antihypertensive agents.
For these purposes, the guanidines of this invention can be normally administered orally or parenterally. Orally they may be administered as tablets, aqueous or oily sus-pensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known in the art for ~
the manufacture of pharmaceutical compositions and such ;
compositions may contain one or more agents selected :

.. ;.,.
.

:~, ' ' : ~ .. '':'.
~3~

~8:L711 from the group consisting of sweetening agents, flavoring agents, coloring agents, preserving agents and the like, in order to provide a pharmaceutically elegant and palatable preparation.
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 alleviation of hypertensive disorders. In general, the daily dose can be between about 0.05 mg/kg/day and 70 mg/kg/ -day (preferably in the range of 1-25 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.
Various tests in animals have been carried out to show the ability of the compounds of this invention to exhibit reactions that can be correlated with activity in humans.
One such test is the ability of the compound to lower blood pressure in the spontaneous hypertensive rat (Ryo Tabei, et ~Z., Clin. Pharm. & Therap. 11: 269-274, 1970).
Blood pressure measurements are recorded by both the tail cuff method and by direct cannulation of a common carotid artery. -Compounds that are effective antihypertensives in man have been shown to be active in lowering blood pressure in this animal model. In view of the results of this test, the guanidines of this invention can be considered to be active antihypertensive agents.
The compounds of this invention are also useful as intermediates for the preparation of pharmaceutically active .~ .

- 6 - `

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agents. Thus, for example, the compounds of this invention may be used to prepare those pharmaceutically active amidino-urea compounds disclosed in Can. Pat. 1,041,908, Nov. 7, 1978.
The compounds of this invention may be prepared by the following general synthesis:
Condensation of cyanamide and a substituted aniline results in the corresponding substituted phenylguanidine.
The reaction is preferably carried out on the aniline salt either in a polar medium or heat and using increased temperatures. The salt used may be any acid addition amine salt but preferably the salt of a mineral acid.
The polar medium may be aqueous, partially aqueous or a non-aqueous solution. It is convenient to choose a solvent that will reflux at the desired reaction temperature. The more preferred solvents are water or alcohol but other solvents may be used such as DMSO, diethyleneglycol, ethyleneglycol, tetra-hydrofuran, dimethylformamide, etc. The most preferred solvent is a mildly acidic solvent which is non-nucleophilic ~-such as phenol, cresol, xylenol, etc. The reaction should 2Q also be carried out at a temperature which is high enough so that condensation takes place readily, but not sufficient to decompose the guanidine formed. The reaction temperature can vary from room temperature to about 250C although it is preferable to run the reaction at temperatures from about 50C
. ~ -to 150C. The guanidine salt which is formed can be converted to the free base with a metal hydroxide or alkoxide solution.
. .
The isolation of the desired guanidine can be carried out by any method known in the art.

When R substitution is desired, it is convenient to carry out the condensation using the appropriately N-substi-tuted aniline. Thus, for example, N-methyl-2,6-diahloro-~ ,, . ' .

,. . . . . .

7~1 aniline would result in the 1-(2,6-dichlorophenyl)-1-methyl-guanidine.
X
_-- N
z 3~NH ' ~ + C--NH2 z ~ ~ N-C-NH2 HX' The following reaction equations illustrate this synthesis:
X

~--NH2 HX + C NH2 ,~NH--C--NH2 HX ' where:
10HX' is a mineral acid.
When R' and/or R" substitution is desired, it is convenient to carry out the condensation using the appropri- .
ately substituted cyanamide. Thus, for example, ethyl or .
diethylcyanamide condensed with 2,6-dichloroaniline would : I
result in the corresponding 1-(2,6-dichlorophenyl)-3-diethyl- ~ :
guanidine.

~ , ::

1~8~

NH2 HX' + C-N

~ NH-C-N \

Condensation of an aniline with benzoylthiourea results in the l-substitutedphenyl-3-benzoylthiourea. This may then be hydrolyzed to the l-substitutedphenylthiourea and treated with iodomethane to obtain the l-substitutedphenyl-2- -methylpseudothiouronium iodide. When the latter is treated with an amine of the formula NHR'R", the resultant dis-placement yields the l-substitutedphenyl-3-R'R" guanidine.

NH45CN + ~ -COCl ~ ~ CORC5 ~

X X . ' -CONCS + ~ ~R2 > ~ N~CNNCO ~

X S ¦ : ~
} ~ 10~ ~a ~ ~ ~ I

N~-C=N~2 I NHR R > ~ NH-C-N

. .

~. , ,.' 9 _ . :
~ . ... .
'`' '' ''""' -- - , - ~ . . . .

3l~8~7~L

When the above benzoyl group is replaced by any R"' group, condensation with the desired aniline results in a 1-substitutedphenyl-3-R"' thiourea. Treatment with iodomethane gives the l-substitutedphenyl-2-methyl-3-R"' pseudothiouronium iodide. Replacement with an amine of the formula NHR'R"
results in the l-substitutedphenyl-2-R"'-3-R',R" guanidine.

R"' NCS + ,~UH2 > 3~--RH--C-NHR"' X X ~ CH3 \ R"l ~ NH-C-NHR"' I

Condensation may also take place between an aniline and a substituted pseudothiourea under the above reaction conditions. ;
X .

~NH2 ~ HX~ + Me-S-C- ~

X ,.

R"' These compounds may also be prepared by reacting the desired aniline~with an R', R" substituted thiocyanate to form : ~ .
the thioguanidine. This is then reacted with a loweralkyl iodide to ~form the thiouronium salt and condensation with an amine of the formula NHR"' results in the desired guanidine. -. .

:: :
: ~ : , ~ ~ lQ -: ~ ` ' .

7~1 `

3~NH2 HX ' + Hal-C-N\ :

X \ ~ .

3~NH-C-N~ ~, alkyl I
X ~ / ,`. :~' Il -alkyl I~
z ~ \R "
NHR "' X ,:

Z ~ \R
Treatment of a l-substitutedphenylguanidine with an anhydride affords the diacylguanidine. Selective hydrolysis -~
with acid yields the l-substitutedphenyl-3-acyl guanidine. ;
Appropriately desired end products having various X, Y and Z substituents may be prepared at various steps of synthesis using suitable reactions in order to convert one group to another.
The starting anilines are either known, may be prepared by known techniques or reference to the preparation is shown. Thus, chlorination or bromination of an acetanilide .. . .
or aniline may be carried out in acetic acid, or in the presence~of a small amount of iodine dissolved in an lnert solvent such as carbon tetrachloride. A solution of chlorine or bromine is then~added while the temperature is held near 0C. Iodination may also be carried out by known methods using iodine monoohloride (Cl I).

- 11 - .
~ ' .

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Alkylation may be carried out on an acetanilide using an alkyl halide and aluminum chloride under Friedel-Crafts conditions to obtain desired alkyl substitution.
Nitration may be carried out using fuming nitric acid at about 0C.
A nitro compound may be hydrogenated to the corre-sponding amine which may then be diazotized and heated in an alcohol medium to form the alkoxy compound.
An amino compound may also be diazotized to the diazonium fluoroborate which is then thermally decomposed to the fluoro compound. Diazotization followed by a Sandmeyer type reaction may yield the bromo, chloro or iodo compound.
Diazotization of an amino compound followed by addition of cuprous cyanide may result in the desired cyano compound. -When an amino compound is diazotized followed by reaction with potassium ethylxanthate and then hydrolyzed, the mercapto compound results. This in turn may be alkylated to the alkylthio group which is then oxidized to the correspond-ing alkylsulfonyl substituent.
A halo compound in which halo is chloro or bromo oriodo may be reacted with cuprous cyanide in guanidine at about ~-150C to produce a cyano compound.
A chloro, bromo or iodo compound may also be reacted with t~ifluoromethyliodide and copper powder at about 150C in dimethylformamide to obtain a trlfluoromethyl compound ~etrahedron Letters:47, 4095 (1959 ~.
~ A halo compound may also be reacted with cuprous methanesulfinate in quinol1nè at about 150C to obtain a 3~ methylsulfonyl compound.
O~f course, the above reactions may also be carried ~ - 12 -~,-~8~71~

out on acetophenone in order to direct substitution. For-mation of an oxime followed by seckmann Rearrangement results in the acetamide which is then deacylated to the aniline.
Reactions may also be carried out on the substituted anilines which would result in di- and tri- substituted anilines.
Reactions may also be carried out at other stages of synthesis depending on the substituents present and the substituents desired and various combinations of the foregoing reactions will be determined by one skilled in the art in order that the desired product results. Thus, a phenyl-guanidine may be halogenated or nitrated as above, etc.
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.

2,6-Dichlorophenylguanidine .
To 51 g (0.315 mole) of 2,6-dichloroaniline is added ;
2Q 0.4 mole of ethèreal HCl and 200 ml of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 13.3 g (0.315 mole) of cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2 x 1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with 3Q ether and dried to obtain 2,6-dichlorophenylguanidine hydro-chloride, m.p. 244-5C.

~ 13 : ' ', ''' ' ~317~1 The free base is prepared by dissolving 2,6-dichlorophenylguanidine hydrochlo:ride in 10% sodium hydroxide :-solution and extracting with ether. The ether is dried and evaporated to dryness to obtain 2,6-dichlorophenylguanidine, m.p. 212-213C.
When the above procedures are followed using the amines of Table I, below, then the corresponding product prepared is:
TABLE I
10 o-chloroaniline -m-chloroaniline p-chloroaniline 2,3-dichloroaniline 2,4-dichloroaniline 2,5-dichloroaniline 3,4-dichloroaniline 3,5-dichloroaniline 2,3,4-trichloroaniline 2,3,5-trichloroaniline 2,3,6-trichloroaniline 2,4,5-trichloroaniline 2,4,6-trichloroaniline 3,4,5-trichloroaniline o-bromoaniline m-bromoaniline p-bromoaniline ~ .
2,3-dibromoaniline `~
2,4-dibromoaniline 2,5-dibromoaniline 3Q 2,6-dlbromoaniline ~ ~
3,4-dibromoaniline :

- 14 - ~
... . ..

1~8~7~

3,5-dibromoaniline 2-chloro-3-bromoaniline 2-chloro-4-bromoaniline p-trifluoromethoxyaniline 2-chloro-5-bromoaniline p-methylsulfonylaniline 2-chloro-6-bromoaniline o-nitroaniline 3-chloro-2-bromoaniline m-nitroaniline 3-chloro-4-bromoaniline ~ .
p-nitroaniline 3-chloro-5-bromoaniline 2-chloro-4-nitroaniline 3-chloro-6-bromoaniline :
10 2-bromo-4-nitroaniline 4-chloro-2-bromoaniline -2-iodo-4-nitroaniline 4-chloro-3-bromoaniline ~:
2-fluoro-4-nitroaniline 2-fluoro-4-chloroaniline 2-nitro-4-chloroaniline 2-fluoro-6-chloroaniline :
2-nitro-4-bromoaniline 2-chloro-4-fluoroaniline .
2-nitro-4-fluoroaniline 2-fluoro-6-bromoaniline ~ . -2-nitro-4-trifluoromethyl- 2-bromo-4-fluoroaniline aniline 2-nitro-4-methoxyaniline 2-iodo-4-chloroaniline 2-cyano-4-chloroaniline 2-iodo-6-chloroaniline 20 2-chloro-4-cyanoaniline 2-chloro-4-iodoaniline 2-methyl-4-chloroaniline 2-iodo-4-bromoaniline 2-methyl-4-bromoaniline o-fluoroaniline 2-methyl-4-fluoroaniline m-fluoroaniline ~ :
2-chloro-4-methylaniline p-fluoroaniline 2-fluoro-4-methylaniline p-iodoaniline 2-cyano-4-methylaniline 2,4-difluoroaniline 2-trifluoromethyl-4-methyl- 2,5-difluoroaniline aniline 2-methyl-4-nitroaniline 2,6-difluoroaniline 30 2-methyl-4-cyanoaniline 2,4-diiodoaniline 2-methyl-4-trifluoromethyl- 2-iodo-6-bromoaniline : -aniline : .
2-chloro-6-nitroaniline 2-bromo-4-iodoaniline 7~L

2-bromo-6-nitroaniline 2-fluoro-4-iodoaniline 2-iodo-6-nitroaniline 2-iodo-4-fluoroaniline 2-fluoro-6-nitroaniline o-trifluoromethylaniline 2-nitro-6-trifluoromethyl- m-trifluoromethylaniline aniline 2-nitro-6-methoxyaniline p-trifluoromethylaniline 2-cyano-6-chloroaniline 2-ethyl-4-nitroaniline 2-methyl-6-chloroaniline 2-ethyl-4-chloroaniline 2-methyl-6-bromoaniline 2-ethyl-4-bromoaniline 10 2-methyl-6-fluoroaniline 2-ethyl-4-fluoroaniline 2-methyl-6-nitroaniline 2-ethyl-4-trifluoromethyl-aniline 2-methyl-6-trifluoromethyl- 2-ethyl-4-cyanoaniline aniline 2-methyl-6-cyanoaniline 2-ethyl-4-methylsulfonyl-aniline 2-methyl-6-methylsulfonyl- 2,4-dichloro-6-bromoaniline aniline 2,4-dimethylaniline 2,6-dichloro-4-bromoaniline 2,6-dimethylaniline 2,4-dibromo-6-chloroaniline 2-trifluoromethyl-6-chloro- 2,6-dibromo-4-chloroaniline anlline 2-trifluoromethyl-6-bromo- 2,4-dichloro-6-fluoroaniline aniline 2-trifluoromethyl-6-fluoro- 2,6-dichloro-4-fluoroaniline aniline 2-trifluoromethyl-6-nitro- 2,5-dichloro~4-fluoroaniline aniline 2-trifluoromethyl-4-chloro- 2,4-dichloro-6-iodoaniline ~0 aniline -2-trifluoromethyl-4-bromo- 2,6-dichloro-4-iodoaniline :.
aniline :
2-trifluoromethyl-4-fluoro- 2,4-dibromo-6-iodoaniline --~
aniline 4-trifluoromethyl-2-chloro- 2,4-dibromo-6-fluoroaniline : -:
aniline 4-trifluoromethyl-2-bromo- 2,6-dibromo-4-fluoroaniline aniline ~817~

4-trifluoromethyl-2-fluoro- 2-chloro-4-bromo-6-fluoro-aniline aniline 2,4-dichloro-6-methylaniline 2-bromo-4-fluoro-6-chloro-aniline 2,6-dichloro-4-methylaniline 2-bromo-4-chloro-6-fluoro-aniline 3,5-ditrifluoromethylaniline 2-chloro-4-iodo-6-bromoaniline 2-methoxy-4-nitroaniline 2,4,6-tribromoaniline 2-trifluoromethyl-4-nitro- 2,4,6-trifluoroaniline aniline 2,4-dichloro-6-methoxyaniline 2,6-dimethyl-4-chloroaniline ... .....
2,6-dimethyl-4-fluoroaniline 2,6-dimethyl~-4-bromoaniline 2,6-dimethyl-4-nitroaniline 2,6-dimethyl-4-trifluoro-methylaniline 1-(2,6-Dichlorophenyl)-l-methylguanidine To 55.4 g (0.315 mole) of N-methyl-2,6-dichloro-aniline is added 0.4 mole of ethereal HCl and 200 ml of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 13.3 g (0.315 mole) of cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml of conc.
sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2 x 1 liter of water, dried over sodium sulfate, charcoaled and evaporated.
The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 1-(2,6-dichlorophenyl)-1-methylguanidine hydrochloride, m.p.
308-9C. ~ `
The free base is prepared by dissolving 1-(2,6-.' :: .
- 17 - ~
' ':
. . . . , ,, . , . , ~ . .. .

~8:L7~

dichlorophenyl)-l-methylguanidine hydrochloride in 10% sodium hydroxide solution and extracting with ether. The ether is dried and evaporated to dryness to obtain l-~2,6-dichloro-phenyl)-l-methylguanidine, m.p. 160C.
When the N-methylaniline in the above procedures are replaced by the N-loweralkylanilines of this invention then the corresponding product is obtained.
When the above procedures are followed using repre-sentative amines then the corresponding product is prepared.

1-(2,6-Dichlorophenyl)-3-methylguanidine To 51 g (0.315 mole) of 2,6-dichloroaniline is added 0.4 mole of ethereal HCl and 200 ml of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 17.7 g (0.315 mole) of methyl c7anamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2 x 1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 1-(2,6-dichlorophenyl)-3-methylguanidine hydrochloride.
The free base is prepared by dissolving 1-(2,6-dichlorophenyl)-3-methylguanidine hydrochloride in 10~ sodium hydroxide solution and extracting with ether. The ether is dried and evaporated to dryness to obtain l-(2,6-dichloro-phenyl)-3-methylguanidine, m p. 149-150C.
When the above procedures are followed using the cyanamides of Table II, below, then the corresponding products are prepared.

' , ' .

- . . . . . ,:

~8~7~

_ABLE II
ethylcyanamide propylcyanamide i-propylcyanamide butylcyanamide pentylcyanamide hexylcyanamide heptylcyanamide octylcyanamide propargylcyanamide methallylcyanamide 2,4-pentadienylcyanamide cyclopropylcyanamide cyclobutylcyanamide cyclopentylcyanamide cyclohexylcyanamide acetylcyanamide propionylcyanamide - .
benzoylcyanamide phenylcyanamide benzylcyanamide phenethylcyanamide cyclohex-2-enylcyanamide :~:
cyclopropylmethylcyanamide : .
cyclobutylmethylcyanamide cyclopropylethylcyanamide diethylcyanamide methylethylcyanamide ;: ~
methylpropylcyanamide ~ .
methylcyclopropylcyanamide methylbenzylcyanamide .. , -- 19 --~)8~7~L

methylacetylcyanamide ethylacetylcyanamide When the anilines of Examples 1 and 2 are condensed with the above cyanamides using the above procedures, then the corresponding products are obtained.
EXAMPLE ~
1-(2,6-Dichlorophenyl)-3-acetylguanidine A solution of 5 g (0.024 mole) of 2,6-dichloro-phenylguanidine in 50 ml of tetrahydrofuran is chilled in an lQ ice bath while 2.56 g (0.24 mole) of acetic anhydride is added dropwise. The mixture is then stirred for 48 hours and then poured into 1 liter of water. The mixture is then stirred for 8 hours and the precipitate is collected to obtain 1-(2,6-dichlorophenyl)-1,3-diacetylguanidine 3 g of this material is stirred at room temperature with 15 ml of conc. hydrochloric acid. The reaction mixture is poured into ice and basicified with cold conc. sodium hydroxide solution. The precipitate is cooled and recrystallized from ethanol: water to obtain 1-(2,6-dichlorophenyl)-3-acetylguanidine.
2a When acetic anhydride is replaced by propionic anhydride, butyric anhydride, benzoic anhydride, then the products obtained are:
1-(2,6-dichlorophenyl)-3-propionylguanidine 1-(2,6-dichlorophenyl)-3-butyroylguanidine . -1-(2,6-dichlorophenyl)-3-benzoylguanidine When~the above procedures are followed using the anilines of Examples 1 and 2 and the above anhydrides then the corresponding products are obtained.

3Q 1-(p-Fluorophenyl)-3-methylthiourea To a mixture of 55.5 g (0.5 mole) of p-fluoroaniline - 20 - ~
~. .

1~8~7~

and lO0 ml of xylene is added 36.5 g (0.5 mole) of methyliso-thiocyanate and the mixture is refluxed for 2 hours. Re-crystallization from l:l isopropanol/water results in l-(p-fluorophenyl)-3-methylthiourea.
When the above procedure is followed using the anilines of Examples 1 and 2 then the corresponding product is obtained.
When methylisothiocyanate is replaced by the iso-thiocyanates of Table III, below, then the corresponding products are obtained.
TABLE III
ethylisocyanate ::
propylisothiocyanate i-propylisothiocyanate butylisothiocyanate pentylisothiocyanate hexylisothiocyanate :
octylisothiocyanate ~.
propargylisothiocyanate methallylisothiocyanate cyclopropylisothiocyanate cyclobutylisothiocyanate ~ :
cyclopentylisothiocyanate ;
cyclohexylisothiocyanate .
cyclohex-2-enylisothiocyanate acetylisothiocyanate propionylisothiocyanate ;
benzoylisothiocyanate phenylisothiocyanate benzylisothiocyanate : phenethylisothiocyanate ~ . '.

108i7~1 cyclopropylmethylisothiocyanate cyclobutylmethylisothiocyanate cyclopropylethylisothiocyanate 1-(2,6-Dichlorophenyl)-3-methylguanidine To 51.8 g (0.68 mole) of ammonium thiocyanate in 300 ml acetone :is added 86.8 g (0.62 mole) of benzoyl chloride.
The reaction mixture is refluxed for about 5 minutes and then 100 g (0.62 mole) of 2,6-dichloroaniline in 200 ml acetone is added at a rate to maintain reflux. The mixture is refluxed for 1-1/2 hours, cooled, poured into 1-1/2 liter of ice and water, filtered to obtain l-(2,6-dichlorophenyl)-3-benzoyl-thiourea.
182.8 g (0.56 mole) of the latter is heated with 1 liter of 10% sodium hydroxide, filtered, acidified while hot with conc. hydrochloric acid and then made basic with conc.
ammonium hydroxide. The mixture is then chilled in an ice bath and the resultant 2,6-dichlorophenylthiourea is filtered off.
20 g (0.09 mole) of 2,6-dichlorophenylthiourea is combined with 200 ml methanol and 12.9 g (0.09 mole) iodo-methane and refluxed for 4 hours. This is then evaporated to dryness and 100 ml hexane is added and the mixture filtered to obtain l-(2,6-dichlorophenyl)-2-methyl-pseudothiouronium - iodide.
32.8 g (0.09 mole) of the latter is added to 300 ml of n-butanol. Methyl amine gas is bubbled through this solution while refluxing for 24 hours. The reaction mixture .
is evaporated to dryness and extracted with 10% sodium hydrox-ide solution and ether. The ether is washed with 10% sodium hydroxide and then with water, dried and filtered. To this is ~
, .~.

- 22 - ~

1~8~

added ethereal HC1 and the precipitate is collected to obtain 1-(2,6-dichlorophenyl)-3-methylguanidine hydrochloride.
The free base is prepared by dissolving 1-(2,6-dichlorophenyl)-3-methylguanidine hydrochloride in 10% sodium hydroxide solution and extracting with ether. The ether is dried and evaporated to dryness to obtain l-(2,6-dichloro-phenyl)-3-methylguanidine, m.p. 149-150C.
When the above procedures are followed using the anilines of Examples 1 and 2 then the corresponding products are obtained.
When the above procedures are followed and methyl-amine is replaced with the amines of Table IV, below, then the corresponding products are obtained.
T~BLE IV
ethylamine propylamine i-propylamine butylamine pentylamine hexylamine heptylamine octylamine propargylamine methallylamine 2,4-pentadienylamine cyclopropylamine cyclobutylamine cyclopentylamine cyclohexylamine 3Q aniline ~;~
benzylamine - - - .

7~

phenethylamine cyclohex~2-enylamine cyclopropylmethylamine cyclobutylmethylamine cyclopropylethylamine dimethylamine -diethylamine methylethylamine ethylpropylamine ethylcyclopropylamine ethylbenzylamine -dibenzylamine N-benzylaniline azirane azetidine .
piperidine homopiperidine morpholine ~
pyrrolidine ., .
2Q piperazine 2-methyl-1-azacyclooctane ~ -_ . . _ . _ _ When the above procedures are fol].owed using the anilines of Examples 1 and 2 and the amines of Table I, above, then the corresponding products of Table V are obtained.

- 24 ~

7~L~

TABLE V
Ex. Compound ~lelting Point 7 1,2-Diacetyl-3-(2,6-dichlorophenyl)-guanidine 94.5-96C
8 p-Chlorophenylguanidine Hydrochloride 161-4C
9 3,5-Dichlorophenylguanidine O
~ydrochloride 177-8 C
2-Chloro-4-methylphenylguanidine156-7C
11 m-Chlorophenylguanidine 110-12C ~:
1012 m-Chlorophenylguanidine nitrate170-1dec.
13 l-(Pentafluorophenyl)guanidine130-131C ;~
14 1-(4-Bromo-2-methylphenyl)guanidine Hydrochloride 184-5 C
3-Chloro-4-fluorophenylguanidine Hydrochloride 157-9C
16 p-fluorophenylguanidine Hydrochloride 93-5C
17 1-(2-methyl-4-bromophenyl)guanidine139-140C
18 1-(2-chloro-6-methylphenyl)guanidine130-132C
19 1-(2-methyl-6-ethylphenyl)guanidine214-216C
2020 1-(3-chloro-4-fluorophenyl)guanidine163-164C
21 1-(2,3,4,5,6-pentafluorophenyl)- O
guanidine 228-234 C
22 1-(2,6-difluorophenyl)guanidine103-108C
23 1-(2-chloro-6-fluorophenyl)guanidine233-234C
24 1-(4-chlorophenyl)guanidine 101C
1-(2,6-dimethylphenyl)guanidine213-214C
26 l-phenylguanidine 66-67C
27 1-(3,5-dichlorophenyl)guanidine177-179C
28 1-(4-chlorophenyl)guanidine 101-110C - :
30 29 1-(4-chlorophenyl)guanidine O
Hydrochloride 161-164 C
1-(2,6-dichlorophenyl)-3-ethylguanidine 226-229C
31 1-(4-bromo-2-methylphenyl)guanidine139-140C

32 p-chlorophenylguanidine 101-110C -- ' . - 25 - :
. .

Claims (15)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. A process for the preparation of a guanidine compound of the formula:

where:
R2, R3, R4, R5 and R6 stand for hydrogen, halogen or loweralkyl;
R is hydrogen or loweralkyl;
R' and R" are hydrogen, loweralkyl or a loweracyl of 2 or 3 carbon atoms;
with the proviso that R2 and R6 may not be chloro at the same time when R' and R" are the same or different and stand for hydrogen or methyl, and the non-toxic acid addition salts thereof;
which comprises:
intimately contacting a substituted aniline of the formula:

where R2, R3, R4, R5 and R6 are as described above and HX' is the salt of a mineral acid;
with a cyanamide of the formula:

in the presence of a phenolic solvent selected from the group consisting of:
phenol, cresol and xylenol;
at temperatures from about 25°C to 150°C and isolating said guanidine.

2. A process according to Claim 1 where the reaction is carried out at temperatures between 60°C to 100°C.

3. The process of Claim 1, wherein R2 is chloro, R6 is methyl, R3, R4 and R5 are each hydrogen and R, R' and R"
are each hydrogen and the product obtained is the 1-(2-chloro-6-methylphenyl)guanidine.

4. The process of Claim 1, wherein R2 is methyl, R6 is ethyl, R3, R4 and R5 are each hydrogen and R, R' and R"
are each hydrogen and the product obtained is the 1-(2-methyl-6-ethylphenyl)guanidine.

5. The process of Claim 1, wherein R2, R3, R4, R5 and R6 are each fluoro and R, R' and R" are each hydrogen and the product obtained is the 1-(2,3,4,5,6-pentafluorophenyl)-guanidine.

6. The process of Claim 1, wherein R2 and R6 are each fluoro, R3, R4 and R5 are each hydrogen and R, R' and R"
are each hydrogen and the product obtained is the 1-(2,6-difluorophenyl)guanidine.

7. The process of Claim 1, wherein R2 is chloro, R6 is fluoro, R3, R4 and R5 are each hydrogen and R, R' and R"
are each hydrogen and the product obtained is the 1-(2-chloro-6-fluorophenyl)guanidine.

8. The process of Claim 1, wherein R2 and R6 are each methyl, R3, R4 and R5 are each hydrogen and R, R' and R"
are each hydrogen and the product obtained is the 1-(2,6-dimethylphenyl)guanidine.

9. A guanidine compound of the formula:

wherein R2, R3, R4, R5 and R6 stand for hydrogen, halogen or loweralkyl of 1 to 5 carbon atoms, R stands for hydrogen or loweralkyl and R' and R" stand for hydrogen, loweralkyl of 1 to 5 carbon atoms or a loweracyl of 2 or 3 carbon atoms, with the proviso that R2 and R6 may not be chloro at the same time when R' and R" are the same or different and stand for hydro-gen or methyl, and the non-toxic acid addition salts thereof, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.

10. The 1-(2-chloro-6-methylphenyl)guanidine, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.

11. The 1-(2-methyl-6-ethylphenyl)guanidine, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.

12. The 1-(2,3,4,5,6-pentafluorophenyl)guanidine, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.

13. The 1-(2,6-difluorophenyl)guanidine, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.

14. The 1-(2-chloro-6-fluorophenyl)guanidine, when prepared by the process defined in Claim 7 or by an obvious chemical equivalent.

15. The 1-(2,6-dimethylphenyl)guanidine, when prepared by the process defined in Claim 8 or by an obvious chemical equivalent.