CA1081709A - Phenylamidino urea compounds - Google Patents
Phenylamidino urea compoundsInfo
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- CA1081709A CA1081709A CA231,435A CA231435A CA1081709A CA 1081709 A CA1081709 A CA 1081709A CA 231435 A CA231435 A CA 231435A CA 1081709 A CA1081709 A CA 1081709A
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- guanidine
- loweralkyl
- dichlorophenyl
- carbon atoms
- chloro
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Abstract
ABSTRACT OF THE DISCLOSURE
Novel phenlamidinourea compounds and processes for their preparation are described. These compounds have an effective degree of anti-hypertensive pro-perties and exert activities on the cardiovascular system. A method for treatment of hypertensive disorders is also described.
Novel phenlamidinourea compounds and processes for their preparation are described. These compounds have an effective degree of anti-hypertensive pro-perties and exert activities on the cardiovascular system. A method for treatment of hypertensive disorders is also described.
Description
10~ 9 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 substituted amidinourea chain. This results in urea and substituted urea type compounds having a phenylamidino or a substi-tuted phenylamidino group attached at one of the nitrogen atoms. This invention also describes the non-toxic pharmaceutically acceptable salts and the method of preparing these substituted phenylamidinourea compounds.
The novel compounds of this invention are described by the structural formula I:
X
~ N-C-I-C-N \ 1.
where:
X is hydrogen, -loweralkyl, halo;
Y is hydrogen, halo, haloloweralkyl, nitro, loweralkyl or loweralkoxy;
Z is halo, loweralkoxy, loweralkyl, nitro, cyano, haloloweralkylj haloloweralkoxy or loweralkylsulfonyl;
: .
~8~709 Rl, R2 and R3 are hydrogen or loweralkyl;
R' and R" are hydrogen, loweralkyl, :~
intermediate alkyl, loweralkenyl, cycloalkyl, cycloalkylloweralkyl, aralkyl, cycloalkenyl or R' and R" together are loweralkylidenyl or heteroloweralkylidenyl, provided Rl, R2, R3, R' and R" are not all hydrogen at the same time; and the non-toxic acid addition salts thereof.
A special embodiment of this invention is described where X is hydrogen, Y is 2-chloro and Z is 6-chloro.
Another special embodiment is described where X and Y are hydrogen and Z is 4-fluoro. -.
A further special embodiment is described where ~ :
X is 2-methyl or 2-ethyl; Y is hydrogen; and Z is in the 6-position and is chloro, bromo, fluoro, methyl or ethyl. . Another special embodiment is described where X is in the 6-position and is chloro, bromo or fluoro; Y
is in the 4-position and is methyl, ethyl 7 chloro, bromo or fluoro; and Z is in the 2-position and is chloro, bromo or fluoro.
A further embodiment is described where X is -
This invention describes a class of novel chemical compounds which comprises a substituted phenyl radical which is further attached to a substituted amidinourea chain. This results in urea and substituted urea type compounds having a phenylamidino or a substi-tuted phenylamidino group attached at one of the nitrogen atoms. This invention also describes the non-toxic pharmaceutically acceptable salts and the method of preparing these substituted phenylamidinourea compounds.
The novel compounds of this invention are described by the structural formula I:
X
~ N-C-I-C-N \ 1.
where:
X is hydrogen, -loweralkyl, halo;
Y is hydrogen, halo, haloloweralkyl, nitro, loweralkyl or loweralkoxy;
Z is halo, loweralkoxy, loweralkyl, nitro, cyano, haloloweralkylj haloloweralkoxy or loweralkylsulfonyl;
: .
~8~709 Rl, R2 and R3 are hydrogen or loweralkyl;
R' and R" are hydrogen, loweralkyl, :~
intermediate alkyl, loweralkenyl, cycloalkyl, cycloalkylloweralkyl, aralkyl, cycloalkenyl or R' and R" together are loweralkylidenyl or heteroloweralkylidenyl, provided Rl, R2, R3, R' and R" are not all hydrogen at the same time; and the non-toxic acid addition salts thereof.
A special embodiment of this invention is described where X is hydrogen, Y is 2-chloro and Z is 6-chloro.
Another special embodiment is described where X and Y are hydrogen and Z is 4-fluoro. -.
A further special embodiment is described where ~ :
X is 2-methyl or 2-ethyl; Y is hydrogen; and Z is in the 6-position and is chloro, bromo, fluoro, methyl or ethyl. . Another special embodiment is described where X is in the 6-position and is chloro, bromo or fluoro; Y
is in the 4-position and is methyl, ethyl 7 chloro, bromo or fluoro; and Z is in the 2-position and is chloro, bromo or fluoro.
A further embodiment is described where X is -
2-methyl or 2-ethyl; Y is in the 4-position and is methyl, ethyl, chloro, bromo or fluoro; and Z is in the 6-position and is methyl, ethyl, chloro, bromo or fluoro.
In the descriptive portions of this invention, . .
the following definitions apply:
The nomenclature applied to the compounds of this invention:
' :, ~8~ ~9 ~ , ~
'.
NHI O
~ ~U-C-N-C-N~
The term "loweralkyl" refers to an alkyl hydro-carbon group containing from 1 to 5 carbon atoms which may be straight chained or branched.
The term "intermediate alkyl" refers to an alkyl hydrocarbon group conta~ning from 6 to 12 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 hydroxy group such as benzoyl, toluyl, etc.
The "loweralkoxy" radical signifies an alkoxy group containing from 1 to about 6 carbon atoms which can be straight chained or branched.
The "loweralkenyl" group refers to an alkenyl hydrocarbon group containing from 2 to about 6 carbon atoms which may be straight chained or branched.
"Cycloalkyl" refers to a cycloalkyl hydrocarbon ring having from 3 to 8 carbon atoms.
"Cycloalkenyl" refers to a cycloalkenyl hydro-carbon ring having from 3 to 8 carbon atoms.
The "loweralkylidenyl" radical refers to analkylidene~hydrocarbon radical containing from 2 to 8 carbon atoms thus forming a ring.
The "heteroloweralkylidenyl" radical refers to an alkylidene hydrocarbon radical containing from 2 to 8 carbon atoms and one or more hetero atoms selected from oxygen,-nitrogen and sulfur, thus forming a hetero ring.
~ "Aryl" refers to an aromatic ring preferably phenyl.
~ It is well known in the pharmacological arts ~ that non-tox1c acid addition salts of pharmacologically .
:
17~9 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 inorsanic acids, organic acids, higher fatty acids, high molecular weight acids, etc., and include such as:
hydrochloric acid, succinic acid, hydrobromic acid, glycolic acid, sulfuric acid, lactic acid, nitric acid, salicylic acid, phosphoric acid, benzoic acid, methanesulfonic acid, nicotinic acid, benzenesulfonic acid, phthalic acid, acetic acid, stearic acid, propionic acid, oleic acid, malic acid, abietic acid, etc.
The compounds of this invention exert activity on the cardiovascular system. They possess blood-pressure lowering effects and are useful as antihyper-tensive agents.
For these purposes, the amidinoureas of this invention can be normally administered orally or par-enterally. Orally they may be administered as tablets, aqueous or oily suspensions, 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 from the group consisting of sweetening agents, flavoring "' ' .
.
1~i8~7'~1~
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 thera-peutic response until improvement is obtained and there-after the minimum effective level which gives relief.
Thus, in general, the dosages are those that are thera-peutically effective in the alleviation of hypertensive disorders. In general, the daily dose can be between about 0.~5 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, e~ aZ., 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 anti-hypertensives in man have been shown to be active in lowering blood pressure in this animal model. In view of the results of this rest, the amidinoureas of this invention can be considered to be active antihypertensive agents.
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 phenyl-guanidine.
'~
.~8~9 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 tempera-ture. The more preferred solvents are water or alcohol but other solvents may be used such as DMSO, diethylene-glycol, ethyleneglycol, tetrahydrofuran, dimethyl-formamide, etc. The most preferred solvent is a mildly acidic solvent which is non-nucleophilic such as phenol, cresol, xylenol, etc. The reaction should 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 the substituted phenylguanidine is reacted with a substituted isocyanate of the formula R'NCO, then -the product formed is a l-substituted phenylamidino-3-R' urea. This reaction is preferably carried out in a non-polar medium using solvents such as benzene, toluene, xylene, etc. The reaction is also carried out as above at raised temperatures.
The following reaction equations illustrate this synthesis:
- , , ; , - . ., ~ ~ ,, - .
L7~
N
z ~ ~ NH HX' + C-NH2 X
NH-C-NH2 ~ HX' z R'NCO
X ~ /
NH
Z ~ ~ NH-C-NH-C-NHR' where:
HX' is a mineral acid and R' is other than hydrogen.
When Rl substitution is desired, it is con-venient to carry out the condensation using the appropri-ately N-substituted aniline. Thus, for example, N-methyl-2,6-dichloroaniline would result in the 1-(2,6-dichlorophenyl)-l-methylguanidine. This is then reacted as above with the isocyanate to form the amidinourea.
X
3H ~ HX' + C-NHR3 X ~ ' Rl R'NCO
X \ /
Y~T 1I N 11 -NHR'
In the descriptive portions of this invention, . .
the following definitions apply:
The nomenclature applied to the compounds of this invention:
' :, ~8~ ~9 ~ , ~
'.
NHI O
~ ~U-C-N-C-N~
The term "loweralkyl" refers to an alkyl hydro-carbon group containing from 1 to 5 carbon atoms which may be straight chained or branched.
The term "intermediate alkyl" refers to an alkyl hydrocarbon group conta~ning from 6 to 12 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 hydroxy group such as benzoyl, toluyl, etc.
The "loweralkoxy" radical signifies an alkoxy group containing from 1 to about 6 carbon atoms which can be straight chained or branched.
The "loweralkenyl" group refers to an alkenyl hydrocarbon group containing from 2 to about 6 carbon atoms which may be straight chained or branched.
"Cycloalkyl" refers to a cycloalkyl hydrocarbon ring having from 3 to 8 carbon atoms.
"Cycloalkenyl" refers to a cycloalkenyl hydro-carbon ring having from 3 to 8 carbon atoms.
The "loweralkylidenyl" radical refers to analkylidene~hydrocarbon radical containing from 2 to 8 carbon atoms thus forming a ring.
The "heteroloweralkylidenyl" radical refers to an alkylidene hydrocarbon radical containing from 2 to 8 carbon atoms and one or more hetero atoms selected from oxygen,-nitrogen and sulfur, thus forming a hetero ring.
~ "Aryl" refers to an aromatic ring preferably phenyl.
~ It is well known in the pharmacological arts ~ that non-tox1c acid addition salts of pharmacologically .
:
17~9 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 inorsanic acids, organic acids, higher fatty acids, high molecular weight acids, etc., and include such as:
hydrochloric acid, succinic acid, hydrobromic acid, glycolic acid, sulfuric acid, lactic acid, nitric acid, salicylic acid, phosphoric acid, benzoic acid, methanesulfonic acid, nicotinic acid, benzenesulfonic acid, phthalic acid, acetic acid, stearic acid, propionic acid, oleic acid, malic acid, abietic acid, etc.
The compounds of this invention exert activity on the cardiovascular system. They possess blood-pressure lowering effects and are useful as antihyper-tensive agents.
For these purposes, the amidinoureas of this invention can be normally administered orally or par-enterally. Orally they may be administered as tablets, aqueous or oily suspensions, 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 from the group consisting of sweetening agents, flavoring "' ' .
.
1~i8~7'~1~
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 thera-peutic response until improvement is obtained and there-after the minimum effective level which gives relief.
Thus, in general, the dosages are those that are thera-peutically effective in the alleviation of hypertensive disorders. In general, the daily dose can be between about 0.~5 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, e~ aZ., 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 anti-hypertensives in man have been shown to be active in lowering blood pressure in this animal model. In view of the results of this rest, the amidinoureas of this invention can be considered to be active antihypertensive agents.
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 phenyl-guanidine.
'~
.~8~9 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 tempera-ture. The more preferred solvents are water or alcohol but other solvents may be used such as DMSO, diethylene-glycol, ethyleneglycol, tetrahydrofuran, dimethyl-formamide, etc. The most preferred solvent is a mildly acidic solvent which is non-nucleophilic such as phenol, cresol, xylenol, etc. The reaction should 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 the substituted phenylguanidine is reacted with a substituted isocyanate of the formula R'NCO, then -the product formed is a l-substituted phenylamidino-3-R' urea. This reaction is preferably carried out in a non-polar medium using solvents such as benzene, toluene, xylene, etc. The reaction is also carried out as above at raised temperatures.
The following reaction equations illustrate this synthesis:
- , , ; , - . ., ~ ~ ,, - .
L7~
N
z ~ ~ NH HX' + C-NH2 X
NH-C-NH2 ~ HX' z R'NCO
X ~ /
NH
Z ~ ~ NH-C-NH-C-NHR' where:
HX' is a mineral acid and R' is other than hydrogen.
When Rl substitution is desired, it is con-venient to carry out the condensation using the appropri-ately N-substituted aniline. Thus, for example, N-methyl-2,6-dichloroaniline would result in the 1-(2,6-dichlorophenyl)-l-methylguanidine. This is then reacted as above with the isocyanate to form the amidinourea.
X
3H ~ HX' + C-NHR3 X ~ ' Rl R'NCO
X \ /
Y~T 1I N 11 -NHR'
3 ~ -- .
.
. : ~ . ::. - . , : : . , - . ~ : . .. . . : .. ,, ., :.: . .
. ., , , : .
.. .... . , , ~
~8~
It is convenient to use t-butylisocyanate in the above reaction when R3 is not desired. This may then be selectively hydrolyzed off.
When R3 substitution is desired, it is con-venient to carry out the condensation using the appropri-ately substituted cyanamide of the formula NHNHR3. Thus, for example, methylcyanamide condensed with 2,6-dichloro-aniline would result in the corresponding 1-(2,6-dichlorophenyl)-3-ethylguanidine. This is then reacted as above with the isocyanate to form the amidinoureas.
X
NH2 HX' + C-NHR3 X ~ /
NH-C-NHR3 HX' R'NCO
X ~ / ,-~N3--C-N--C-NI:R' Condensation of an aniline with benzoylthiourea results in the l-substitutedphenyl-3-benzoylthiourea.
This may then be hydrolyzed to the l-substitutedphenyl-thiourea and treated with iodomethane to obtain the 1-substitutedphenyl-2-methyl-pseudothiouronium iodide.
When the latter is treated with an amine of the formula NH2Rl, the resultant displacement yields a l-substituted-phenyl-3-Rl guanidine which may then be reacted as above to form the amidinourea.
, .
:
7~9 NH4 SCN + ~ COCl --- > ~ CONCS
X X
CONCS + ~ NH2 - > ~ NH-C-NHCO
10% NaOH
Me X NH-C-NH2 I ~ ~ NH-C-NH2 3 -:
z ~ lI NHR R'NCO > ~ NH-C-N-C-NHR' These compounds may also be prepared by con-densing the desired aniline with a substituted isothio- , `
urea or with a thiocyanate of the formula SCNR3. The ~ -latter reaction product is the thiourea which is then 1:
treated with iodomethane and reacted with an amine of the formula NH2R2 to obtain the desired guanidine. The above guanidine compounds are reacted with an isocyanate as above to obtain the amidinourea. -X ~:
NH2 HX~ + S-C-NER3 Z I ' :' -.
: - -': `, - : ~
:
L7~g~
,;
~J<J )--NH-C-NHR3 Z/~
RINCO
X \ /
~ NH-C-N~-C-NHR' Z 13 ;
:, .
X ' ~\ : :' ' ~ NH2 HX' + S=C=NR3 Z ,~: ' X \ ~ .
MeI
X N}~ISI_NHR I~
Z : :~
: 2 2 X ~ ' ':
Z
~ R I NCO
X
~NH 1I N 1I NHR' : Z
:- : R3 ~ :
:: :
:
8~7~9 When R2 substitution is desired the aniline is condensed with t-butyl thiocyanate of the formula SCN-t-butyl to form the thiourea. The t-butyl group is then hydrolyzed off with conc. HCl. The product is reacted with an isocyanate to obtain the carbamylthio-urea, which is treated with iodomethane and reacted with an amine of the formula NHR2 to obtain the desired amidinourea. :
X
NH2 HX' ~ SCN~t-butyl X \ /
~ NH-C-NH-t-butyl ~NH-C-NH2 R'NCO
X .
NH-C-NH-C-NHR' ¦MeI
X ~3 NH-C-NH-C-NHR' I
¦NHR2 NH-C-NH-C-NHR' .
~L~8~7~9 When R' and R" substitution is desired the appropriate guanidine is reacted with the acid chloride of the amine of the formula ClC-N . The latter is \ R" ~ R' made by the reaction of the amine of the formula HR \
with phosgene in an inert solvent. The reaction of the acid chloride and guanidine is carried out in a polar medium and inert conditions at moderate temperatures.
~NH + COCl > ClC- N~
2 ~ R"
X X
y ~ NH 1I R' Y ~ ll ¦¦ ~R' ~ NH-C-NH2 + ClC-N\ - 3 ~ NH-C-NH-C-N
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 prepa-ration 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 inert 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 monochloride (ClI).
Alkylation may be carried out on an acetanilide using an alkyl halide and aluminum chloride under Friedel-Crafts conditions to obtain desired alkyl substi-tution.
Nitration may be carried out using fuming nitric acid at about 0C.
:~ ' A nitro compound may be hydrogenated to the corresponding 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 corresponding alkylsulfonyl substituent.
A halo compound in which halo is chloro or bromo or iodo 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 trifluoromethyliodide and copper powder at about 150C in dimethylformamide to obtain a trifluoro-methyl compound ~etrahedron Letters: 47, 4095 (1959 ~.
A halo compound may also be reacted with cuprous methanesulfinate in quinoline at about 150C to obtain a methylsulfonyl compound.
Of course the above reaction may also be carried out on acetophenone in order to direct substi-tution. Formation of an oxime followed by Beckmann 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 .
~l~8~7~9 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 phenylguanidine or amidinourea 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 0.4 moles 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 2,6-dichlorophenylguanidine hydro-chloride.
The free base is prepared by dissolving 2,6-dichlorophenylguanidine hydrochloride in 10% sodium hydroxide solution and extracting with ether. The ether is dried and evaporated to dryness to obtain 2,6-dichlorophenylguanidine.
When the above procedures are followed usingthe amines of Table I, below, then the corresponding product of Table II, below, is prepared.
.. . . . , - , . . . , . - . , . - . , ~ .
~{~8~7~9 TABLE I TABLE II
o-chloroaniline o-chlorophenylguanidine m-chloroaniline m-chlorophenylguanidine p-chloroaniline p-chlorophenylguanidine 2,3-dichloroaniline 2,3-dichlorophenylguanidine 2,4-dichloroaniline 2,4-dichlorophenylguanidine 2,5-dichloroaniline 2,5-dichlorophenylguanidine 3,4-dichloroaniline 3,4-dichlorophenylguanidine 3,5-dichloroaniline 3,5-dichlorophenylguanidine 2,3,4-trichloroaniline 2,3,4-trichlorophenyl-guanidine 2,3,5-trichloroaniline 2,3,5-trichlorophenyl-guanidine 2,3,6-trichloroaniline 2,3,6-trichlorophenyl-guanidine 2,4,5-trichloroaniline 2,4,5-trichlorophenyl-guanidine 2,4,6-trichloroaniline 2,4,6-trichlorophenyl-guanidine 3,4,5-trichloroaniline 3,4,5-trichlorophenyl-guanidine o-bromoaniline o-bromophenylguanidine ::
m-bromoaniline m-bromophenylguanidine p-bromoaniline p-bromophenylguanidine 2,3-dibromoaniline 2,3-dibromophenylguanidine 2,4-dibromoaniline 2,4-dibromophenylguanidine 2,5-dibromoaniline 2,5-dibromophenylguanidine 2,6-dibromoaniline 2,6-dibromophenylguanidine 3,4-dibromoaniline 3,4-dibromophenylguanidine 3,5-dibromoaniline 3,5-dibromophenylguanidine 2-chloro-3-bromoaniline 2-chloro-3-bromophenyl-guanidine 2-chloro-4-bromoaniline 2-chloro-4-bromophenyl-guanidine 2-chloro-5-bromoaniline 2-chloro-5-bromophenyl-guanidine 2-chloro-6-bromoaniline 2-chloro-6-bromophenyl-guanidine 3-chloro-2-bromoaniline 3-chloro-2-bromophenyl- -guanidine ~' . ,. : . . . . ..
~8:L7~9~
3-chloro-4-bromoaniline 3-chloro-4~bromophenyl-guanidine 3-chloro-5-bromoaniline 3-chloro-5-bromophenyl-guanidine 3-chloro-6-bromoaniline 3-chloro-6-bromophenyl-guanidine
.
. : ~ . ::. - . , : : . , - . ~ : . .. . . : .. ,, ., :.: . .
. ., , , : .
.. .... . , , ~
~8~
It is convenient to use t-butylisocyanate in the above reaction when R3 is not desired. This may then be selectively hydrolyzed off.
When R3 substitution is desired, it is con-venient to carry out the condensation using the appropri-ately substituted cyanamide of the formula NHNHR3. Thus, for example, methylcyanamide condensed with 2,6-dichloro-aniline would result in the corresponding 1-(2,6-dichlorophenyl)-3-ethylguanidine. This is then reacted as above with the isocyanate to form the amidinoureas.
X
NH2 HX' + C-NHR3 X ~ /
NH-C-NHR3 HX' R'NCO
X ~ / ,-~N3--C-N--C-NI:R' Condensation of an aniline with benzoylthiourea results in the l-substitutedphenyl-3-benzoylthiourea.
This may then be hydrolyzed to the l-substitutedphenyl-thiourea and treated with iodomethane to obtain the 1-substitutedphenyl-2-methyl-pseudothiouronium iodide.
When the latter is treated with an amine of the formula NH2Rl, the resultant displacement yields a l-substituted-phenyl-3-Rl guanidine which may then be reacted as above to form the amidinourea.
, .
:
7~9 NH4 SCN + ~ COCl --- > ~ CONCS
X X
CONCS + ~ NH2 - > ~ NH-C-NHCO
10% NaOH
Me X NH-C-NH2 I ~ ~ NH-C-NH2 3 -:
z ~ lI NHR R'NCO > ~ NH-C-N-C-NHR' These compounds may also be prepared by con-densing the desired aniline with a substituted isothio- , `
urea or with a thiocyanate of the formula SCNR3. The ~ -latter reaction product is the thiourea which is then 1:
treated with iodomethane and reacted with an amine of the formula NH2R2 to obtain the desired guanidine. The above guanidine compounds are reacted with an isocyanate as above to obtain the amidinourea. -X ~:
NH2 HX~ + S-C-NER3 Z I ' :' -.
: - -': `, - : ~
:
L7~g~
,;
~J<J )--NH-C-NHR3 Z/~
RINCO
X \ /
~ NH-C-N~-C-NHR' Z 13 ;
:, .
X ' ~\ : :' ' ~ NH2 HX' + S=C=NR3 Z ,~: ' X \ ~ .
MeI
X N}~ISI_NHR I~
Z : :~
: 2 2 X ~ ' ':
Z
~ R I NCO
X
~NH 1I N 1I NHR' : Z
:- : R3 ~ :
:: :
:
8~7~9 When R2 substitution is desired the aniline is condensed with t-butyl thiocyanate of the formula SCN-t-butyl to form the thiourea. The t-butyl group is then hydrolyzed off with conc. HCl. The product is reacted with an isocyanate to obtain the carbamylthio-urea, which is treated with iodomethane and reacted with an amine of the formula NHR2 to obtain the desired amidinourea. :
X
NH2 HX' ~ SCN~t-butyl X \ /
~ NH-C-NH-t-butyl ~NH-C-NH2 R'NCO
X .
NH-C-NH-C-NHR' ¦MeI
X ~3 NH-C-NH-C-NHR' I
¦NHR2 NH-C-NH-C-NHR' .
~L~8~7~9 When R' and R" substitution is desired the appropriate guanidine is reacted with the acid chloride of the amine of the formula ClC-N . The latter is \ R" ~ R' made by the reaction of the amine of the formula HR \
with phosgene in an inert solvent. The reaction of the acid chloride and guanidine is carried out in a polar medium and inert conditions at moderate temperatures.
~NH + COCl > ClC- N~
2 ~ R"
X X
y ~ NH 1I R' Y ~ ll ¦¦ ~R' ~ NH-C-NH2 + ClC-N\ - 3 ~ NH-C-NH-C-N
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 prepa-ration 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 inert 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 monochloride (ClI).
Alkylation may be carried out on an acetanilide using an alkyl halide and aluminum chloride under Friedel-Crafts conditions to obtain desired alkyl substi-tution.
Nitration may be carried out using fuming nitric acid at about 0C.
:~ ' A nitro compound may be hydrogenated to the corresponding 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 corresponding alkylsulfonyl substituent.
A halo compound in which halo is chloro or bromo or iodo 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 trifluoromethyliodide and copper powder at about 150C in dimethylformamide to obtain a trifluoro-methyl compound ~etrahedron Letters: 47, 4095 (1959 ~.
A halo compound may also be reacted with cuprous methanesulfinate in quinoline at about 150C to obtain a methylsulfonyl compound.
Of course the above reaction may also be carried out on acetophenone in order to direct substi-tution. Formation of an oxime followed by Beckmann 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 .
~l~8~7~9 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 phenylguanidine or amidinourea 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 0.4 moles 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 2,6-dichlorophenylguanidine hydro-chloride.
The free base is prepared by dissolving 2,6-dichlorophenylguanidine hydrochloride in 10% sodium hydroxide solution and extracting with ether. The ether is dried and evaporated to dryness to obtain 2,6-dichlorophenylguanidine.
When the above procedures are followed usingthe amines of Table I, below, then the corresponding product of Table II, below, is prepared.
.. . . . , - , . . . , . - . , . - . , ~ .
~{~8~7~9 TABLE I TABLE II
o-chloroaniline o-chlorophenylguanidine m-chloroaniline m-chlorophenylguanidine p-chloroaniline p-chlorophenylguanidine 2,3-dichloroaniline 2,3-dichlorophenylguanidine 2,4-dichloroaniline 2,4-dichlorophenylguanidine 2,5-dichloroaniline 2,5-dichlorophenylguanidine 3,4-dichloroaniline 3,4-dichlorophenylguanidine 3,5-dichloroaniline 3,5-dichlorophenylguanidine 2,3,4-trichloroaniline 2,3,4-trichlorophenyl-guanidine 2,3,5-trichloroaniline 2,3,5-trichlorophenyl-guanidine 2,3,6-trichloroaniline 2,3,6-trichlorophenyl-guanidine 2,4,5-trichloroaniline 2,4,5-trichlorophenyl-guanidine 2,4,6-trichloroaniline 2,4,6-trichlorophenyl-guanidine 3,4,5-trichloroaniline 3,4,5-trichlorophenyl-guanidine o-bromoaniline o-bromophenylguanidine ::
m-bromoaniline m-bromophenylguanidine p-bromoaniline p-bromophenylguanidine 2,3-dibromoaniline 2,3-dibromophenylguanidine 2,4-dibromoaniline 2,4-dibromophenylguanidine 2,5-dibromoaniline 2,5-dibromophenylguanidine 2,6-dibromoaniline 2,6-dibromophenylguanidine 3,4-dibromoaniline 3,4-dibromophenylguanidine 3,5-dibromoaniline 3,5-dibromophenylguanidine 2-chloro-3-bromoaniline 2-chloro-3-bromophenyl-guanidine 2-chloro-4-bromoaniline 2-chloro-4-bromophenyl-guanidine 2-chloro-5-bromoaniline 2-chloro-5-bromophenyl-guanidine 2-chloro-6-bromoaniline 2-chloro-6-bromophenyl-guanidine 3-chloro-2-bromoaniline 3-chloro-2-bromophenyl- -guanidine ~' . ,. : . . . . ..
~8:L7~9~
3-chloro-4-bromoaniline 3-chloro-4~bromophenyl-guanidine 3-chloro-5-bromoaniline 3-chloro-5-bromophenyl-guanidine 3-chloro-6-bromoaniline 3-chloro-6-bromophenyl-guanidine
4-chloro-2-bromoaniline 4-chloro-2-bromophenyl-guanidine 4-chloro-3-bromoaniline 4-chloro-3-bromophenyl-guanidine 2-fluoro-4-chloroaniline 2-fluoro-4-chlorophenyl-guanidine 2-fluoro-6-chloroaniline 2-fluoro-6-chlorophenyl-guanldine 2-chloro-4-bromoaniline 2-chloro-4-fluorophenyl-guanidine 2-fluoro-6-bromoaniline 2-fluoro-6-bromophenyl-guanidine 2-bromo-4-fluoroaniline 2-bromo-4-fluorophenyl-guanidine 2-iodo-4-chloroaniline 2-iodo-4-chlorophenyl-guanidine 2-iodo-6-chloroaniline 2-iodo-6-chlorophenyl-guanidine ;
2-chloro-4-iodoaniline 2-chloro-4-iodophenyl-guanidine 2-iodo-4-bromoaniline 2-iodo-4-bromophenyl-guanidine o-fluoroaniline o-fluorophenylguanidine m-fluoroaniline m-fluorophenylguanidine p-fluoroaniline p-fluorophenylguanidine p-iodoaniline p-iodophenylguanidine 2,4-difluoroaniline 2,4-difluorophenylguanidine 2,5-difluoroaniline 2,5-difluorophenylguanidine 2,6-difluoroaniline 2,6-difluorophenylguanidine .
2,4-diiodoaniline 2,4-diiodophenylguanidine 2-iodo-6-bromoaniline 2-iodo-6-bromophenyl- -:
guanidine 2-bromo-4-iodoaniline 2-bromo-4-iodophenyl-guanidine 2-fluoro-4-iodoaniline 2-fluoro-4-iodophenyl-guanidine .~
: ~ :
,:
~8~ 39 2-iodo-4-fluoroaniline 2-iodo-4-fluorophenyl-guanidine o-trifluoromethylaniline ~-trifluoromethylphenyl-guanidine m-trifluoromethylaniline m-trifluoromethylphenyl-guanidine p-trifluoromethylaniline p-trifluoromethylphenyl-guanidine p-trifluoromethoxyaniline p-trifluoromethoxyphenyl-guanidine p-methylsulfonylaniline p-methylsulfonylphenyl-guanidine o-nitroaniline o-nitrophenylguanidine m-nitroaniline m-nitrophenylguanidine p-nitroaniline p-nitrophenylguanidine 2-chloro-4-nitroaniline 2-chloro-4-nitrophenyl guanidine 2-bromo-4-nitroaniline 2-bromo-4-nitrophenyl-guanidine 20 2-iodo-4-nitroaniline 2-iodo-4-nitrophenyl-guanidine 2-fluoro-4-nitroaniline 2-fluoro-4-nitrophenyl-guanidine 2-nitro-4-chloroaniline 2-nitro-4-chlorophenyl-guanidine 2-nitro-4-bromoaniline 2-nitro-4-bromophenyl-guanidine 2-nitro-4-fluoroaniline 2-nitro-4-fluorophenyl-guanidine 30 2-nitro-4-trifluoromethyl- 2-nitro-4-trifluoromethyl-aniline phenylguanidine 2-nitro-4-methoxyaniline 2-nitro-4-methoxyphenyl-~ guanidine :: 2-cyano-4-chloroanil.ine 2-cyano-4-chlorophenyl-. guanidine 2~chloro-4-cyanoaniline 2-chloro-4-cyanophenyl-guanidine 2-methyl-4-chloroaniline 2-methyl-4-chlorophenyl-guanidine ; 40 2-methyl-4-bromoaniline 2-methyl-4-bromophenyl-guanidine 2-methyl-4-fluoroaniline 2-methyl-4-fluorophenyl-guanidine . - .
...
: , . .... . .
. - - -: . . ~ ~ ... .: .
7~9 2-chloro-4-methylaniline 2-chloro-4-methylphenyl-guanidine 2-bromo-4-methylaniline 2-bromo-4-methylphenyl-guanidine 2-fluoro-4-methylaniline 2-fluoro-4-methylphenyl-guanidine 2-cyano-4-methylaniline 2-cyano-4-methylphenyl-guanidine 2-trifluoromethyl-4-methyl- 2-trifluoromethyl-4-methyl-aniline phenylguanidine 2-methyl-4-nitroaniline 2-methyl-4-nitrophenyl-guanidine 2-methyl-4-cyanoaniline 2-methyl-4-cyanophenyl-guanidine 2-methyl-4-trifluoromethyl- 2-methyl-4-trifluoromethyl-aniline phenylguanidine 2-chloro-6-nitroaniline 2-chloro-6-nitrophenyl-guanidine 2-bromo-6-nitroaniline 2-bromo-6-nitrophenyl-guanidine 2-iodo-6-nitroaniline 2-iodo-6-nitrophenyl-guanidine 2-fluoro-6-nitroaniline 2-fluoro-6-nitrophenyl-guanidine 2-nitro-6-trifluoromethyl- 2-nitro-6-trifluoromethyl-aniline phenylguanidine 2-nitro-6-methoxyaniline 2-nitro-6-methoxyphenyl-guanidine : 2-cyano-6-chloroaniline 2-cyano-6-chlorophenyl-guanidine 2-methyl-6-chloroaniline 2-methyl-6-chlorophenyl-guanidine 2-methyl 6-bromoaniline 2-methyl-6-bromophenyl-- guanidine ~- 2-methyl-6-fluoroaniline 2-methyl-6-fluorophenyl-guanidine 2-methyl-6-nitroaniline 2-methyl-6-nitrophenyl-: guanidine ~ 2-methyl-6-trifluoromethyl- 2-methyl-6-trifluoromethyl-- 40 aniline phenylguanidine 2-methyl-6-cyanoaniline 2-methyl-6-cyanophenyl-guanidine :~ :
,;-., .
~81'7~
2-methyl-6-methylsulfonyl 2-methyl-6-methylsulfonyl-aniline phenylguanidine 2,4-dimethylaniline 2,4-dimethylphenylguanidine 2,6-dimethylaniline 2,6-dimethylphenylguanidine 2-trifluoromethyl-6-chloro- 2-trifluoromethyl-6-chloro-aniline phenylguanidine 2-trifluoromethyl-6-bromo- 2-trifluoromethyl-6-bromo-anillne phenylguanidine 2-trifluoromethyl-6-fluoro- 2-trifluoromethyl-6-fluoro-aniline phenylguanidine 2-trifluoromethyl-6-nitro- 2-trifluoromethyl-6-nitro-aniline phenylguanidine . .
2-trifluoromathyl-4-chloro- 2-trifluoromethyl-4-chloro-aniline phenylguanidine 2-trifluoromethyl-4-bromo- 2-trifluoromethyl-4-bromo-aniline phenylguanidine 2-trifluoromethyl-4-fluoro- 2-trifluoromethyl-4-fluoro-aniline phenylguanidine 4-trifluoromethyl-2-chloro- 4-trifluoromethyl-2-chloro-anillne phenylguanidine 4-trifluoromethyl-2-bromo- 4-trifluoromethyl-2-bromo-aniline phenylguanidine 4-trifluoromethyl-2-fluoro- 4-trifluoromethyl-2-bromo-aniline phenylguanidine :
2,4-dichloro-6-methyl- 2,4-dichloro-6-methyl-aniline phenylguanidine 2,6-dichloro-4-methyl- 2,6-dichloro-4-methyl-aniline phenylguanidine 3,5-ditrifluoromethyl- 3,5-ditrifluoromethyl-3~ aniline phenylguanidine 2-methoxy-4-nitroaniline 2-methoxy-4-nitrophenyl-guanidine 2-trifluoromethyl-4-nitro- 2-trifluoromethyl-4-nitro-aniline phenylguanidine - . .
2,4-dichloro-6-methoxy- 2,4-dichloro-6-methoxy-aniline phenylguanidine 2,6-dimethyl-4-chloro- 2,6-dimethyl-4-chloro-aniline phenylguanidine 2,6-dimethyl-4-fluoro- 2,6-dimethyl-4-fluoro-aniline phenylguanidine 2,6-dimethyl-4-bromoaniline 2,6-dimethyl-4-bromophenyl-guanidine 1~17~
2,6-dimethyl-4-nîtroaniline 2,6-dimethyl-4-nitrophenyl-guanidine 2,6-dimethyl-4-trifluoro- 2,6-dimethyl-4-trifluoro-methylaniline methylphenylguanidine 2-ethyl-4-nitroaniline 2-ethyl-4-nitrophenyl-guanidine 2-ethyl-4-chloroaniline 2-ethyl-4-chlorophenyl-guanidine 2-ethyl-4-bromoaniline 2-ethyl-4-bromophenyl-guanidine 2-ethyl-4-fluoroaniline 2-ethyl-4-fluorophenyl-guanidine 2-ethyl-4-trifluoromethyl- 2-ethyl-4-trifluoromethyl-aniline phenylguanidine 2-ethyl-4-cyanoaniline 2-ethyl-4-cyanophenyl-guanidine 2-ethyl-4-methylsulfonyl- 2-ethyl-4-methylsulfonyl-aniline phenylguanidine 2,4-dichloro-6-bromoaniline 2,4-dichloro-6-bromophenyl-guanidine 2,6-dichloro-4-bromoaniline 2,6-dichloro-4-bromophenyl-guanidine 2,4-dibromo-6-chloroaniline 2,4-dibromo-6-chlorophenyl-guanidine 2,6-dibromo-4-chloroaniline 2,6-dibromo-4-chlorophenyl-guanidine 2,4-dichloro-6-fluoro- 2,4-dichloro-6-fluoro-aniline phenylguanidine 2-chloro-4-methyl-6-fluoro- 2-chloro-4-methyl-6-fluoro-aniline phenylguanidine 2,4-dimethyl-6-chloro- 2,4-dimethyl-6-chloro-aniline phenylguanidine 2,4-dimethyl-6-fluoro- 2,4-dimethyl-6-fluoro-aniline phenylguanidine 2-chloro-4-fluoro-6-methyl- 2-chloro-4-fluoro-6-methyl-aniline phenylguanidine 2,6-dichloro-4-fluoro- 2,6-dichloro-4-fluoro-aniline phenylguanidine 2,5-dichloro-4-fluoro- 2,5-dichloro-4-fluoro-aniline phenylguanidine 2,4-dichloro-6-iodoaniline 2,4-dichloro-6-iodophenyl-guanidine .
71~9 2,6-dichloro-4-iodoaniline 2,6-dichloro-4-iodophenyl-guanidine 2,4-dibromo-6-iodoaniline 2,4-dibromo-6-iodophenyl-guanidlne 2,4-dibromo-6-fluoroaniline 2,4-dibromo-6-fluorophenyl-guanidine 2,6-dibromo-4-fluoroaniline 2,6-dibromo-4-fluorophenyl-guanidine 2-chloro-4-bromo-6-fluoro- 2~chloro-4-bromo-6 fluoro-aniline phenylguanidine 2-bromo-4-fluoro-6-chloro- 2-bromo-4-fluoro-6-chloro-aniline phenylguanidine 2-bromo-4-chloro-6-fluoro- 2-bromo-4-chloro-6-fluoro-aniline phenylguanidine 2-chloro-4-iodo-6-bromo- 2-chloro-4-iodo-6-bromo-aniline phenylguanidine 2,4,6-tribromoaniline 2,4,6-tribromophenyl-guanidine 2,4,6-trifluoroaniline 2,4,6-trifluorophenyl-guanidine 1-(2,6-dichlorophenyl)-1-methylguanidine To 55.4 g (0.315 mole) of N-methyl-2,6-di-chloroaniline is added 0.4 moles 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 hydro-gen 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 l-(2,6-di- :
chlorophenyl)-l-methylguanidine hydrochloride.
The free base is prepared by dissolving 1-(2,6-dichlorophenyl)-l-methylguanidine hydrochloride in 10% -sodium hydroxide~solution and extracting with ether. The . , ,. .. .. . . . . . . ,; ~ .. : . ~ ,, , -743~
ether is dried and evaporated to dryness to obtain 1-(2,6-dichlorophenyl~ methylguanidine~
When the N-methylaniline in the above pro-cedures is replaced by the N-loweralkylanilines of this invention then the corresponding product is obtained.
When the above procedures are followed then the corresponding products are prepared.
1-(2,6-dichlorophenyl)-3-methylguanidine To 51 g (0.315 mole) of 2,6-dichloroaniline is added 0.4 moles 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 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 l-(2,6-dichloro-phenyl)-3-methylguanidine hydrochloride.
The free base is prepared by dissolving 1-(2,6-dichlorophenyl)-3-methylguanidine hydrochloride to 10%
sodium hydroxide solution and extracting with ether. The ether is dried and evaporated to dryness to obtain 1-(2,6-dichlorophenyl)-3-methylguanidine.
When the above procedures are followed using 3Q the cyanamides of Table III below, then the corresponding products are prepared.
TABLE III
ethylcyanamide propylcyanamide ~ :
i-propylcyanamide butylcyanamide pentylcyanamide hexylcyanamide heptylcyanamide octylcyanamide vinylcyanamide propargylcyanamide methallylcyanamide 2,4-pentadienylcyanamide 2-pentenylcyanamide cyclopropylcyanamide cyclobutylcyanamide cyclopentylcyanamide cyclohexylcyanamide phenylcyanamide -benzylcyanamide phenethylcyanamide cyclohex-2-enylcyanamide cyclopropylmethylcyanamide cyclobutylmethylcyanamide cyclopropylethylcyanamide 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 4 . .
1-(p-fluorophenyl)-3-methylthiourea To~a mixture of 55.5 g (0.5 mole) of p-fluoro-aniline and 100 ml of xylene is added 36.5 g (0.5 mole) of methylisothiocyanate and the mixture is refluxed for 2 hours.: The reaction product is cooled, triturated with .
heptane and filtered. Recrystallization from 1:1 iso-propanol/water results in l-(p-fluorophenyl)-3-methyl , ~ .
: .
1~817~9 thiourea.
When the above procedure is followed using 2,6-dichloroaniline then the product prepared is l-(2,6-di-chlorophenyl)-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 isothiocyanates of Table IV below, then the corresponding product is obtained.
TABLE IV
.. . . .
ethylisothiocyanate propylisothiocyanate i-propylisothiocyanate butylisothiocyanate pentylisothiocyanate hexylisothiocyanate heptylisothiocyanate octylisothiocyanate vinylisothiocyanate propargylisothiocyanate methallylisothiocyanate cyclopropylisothiocyanate cyclobutylisothiocyanate cyclopentylisothiocyanate cyclohexylisothiocyanate cyclohex-2-enylisothiocyanate phenylisothiocyanate ben7.ylisothiocyanate 3D phenethylisothiocyanate cyclopropylmethylisothiocyanate cyclobutylmethylisothiocyanate cyclopropylethylisothiocyanate .
~, ' 1-(2,6-dichlorophenyl)-3-methylguanidine 1-(2,6-dichlorophenyl)-3-benzoylthiourea To 51.8 g (0.68 mole) of ammonium thiocyanate in 300 ml acetone is added 86.~ g (0.62 mole) of ben~oyl chloride. The reaction mixture is refluxed for about
2-chloro-4-iodoaniline 2-chloro-4-iodophenyl-guanidine 2-iodo-4-bromoaniline 2-iodo-4-bromophenyl-guanidine o-fluoroaniline o-fluorophenylguanidine m-fluoroaniline m-fluorophenylguanidine p-fluoroaniline p-fluorophenylguanidine p-iodoaniline p-iodophenylguanidine 2,4-difluoroaniline 2,4-difluorophenylguanidine 2,5-difluoroaniline 2,5-difluorophenylguanidine 2,6-difluoroaniline 2,6-difluorophenylguanidine .
2,4-diiodoaniline 2,4-diiodophenylguanidine 2-iodo-6-bromoaniline 2-iodo-6-bromophenyl- -:
guanidine 2-bromo-4-iodoaniline 2-bromo-4-iodophenyl-guanidine 2-fluoro-4-iodoaniline 2-fluoro-4-iodophenyl-guanidine .~
: ~ :
,:
~8~ 39 2-iodo-4-fluoroaniline 2-iodo-4-fluorophenyl-guanidine o-trifluoromethylaniline ~-trifluoromethylphenyl-guanidine m-trifluoromethylaniline m-trifluoromethylphenyl-guanidine p-trifluoromethylaniline p-trifluoromethylphenyl-guanidine p-trifluoromethoxyaniline p-trifluoromethoxyphenyl-guanidine p-methylsulfonylaniline p-methylsulfonylphenyl-guanidine o-nitroaniline o-nitrophenylguanidine m-nitroaniline m-nitrophenylguanidine p-nitroaniline p-nitrophenylguanidine 2-chloro-4-nitroaniline 2-chloro-4-nitrophenyl guanidine 2-bromo-4-nitroaniline 2-bromo-4-nitrophenyl-guanidine 20 2-iodo-4-nitroaniline 2-iodo-4-nitrophenyl-guanidine 2-fluoro-4-nitroaniline 2-fluoro-4-nitrophenyl-guanidine 2-nitro-4-chloroaniline 2-nitro-4-chlorophenyl-guanidine 2-nitro-4-bromoaniline 2-nitro-4-bromophenyl-guanidine 2-nitro-4-fluoroaniline 2-nitro-4-fluorophenyl-guanidine 30 2-nitro-4-trifluoromethyl- 2-nitro-4-trifluoromethyl-aniline phenylguanidine 2-nitro-4-methoxyaniline 2-nitro-4-methoxyphenyl-~ guanidine :: 2-cyano-4-chloroanil.ine 2-cyano-4-chlorophenyl-. guanidine 2~chloro-4-cyanoaniline 2-chloro-4-cyanophenyl-guanidine 2-methyl-4-chloroaniline 2-methyl-4-chlorophenyl-guanidine ; 40 2-methyl-4-bromoaniline 2-methyl-4-bromophenyl-guanidine 2-methyl-4-fluoroaniline 2-methyl-4-fluorophenyl-guanidine . - .
...
: , . .... . .
. - - -: . . ~ ~ ... .: .
7~9 2-chloro-4-methylaniline 2-chloro-4-methylphenyl-guanidine 2-bromo-4-methylaniline 2-bromo-4-methylphenyl-guanidine 2-fluoro-4-methylaniline 2-fluoro-4-methylphenyl-guanidine 2-cyano-4-methylaniline 2-cyano-4-methylphenyl-guanidine 2-trifluoromethyl-4-methyl- 2-trifluoromethyl-4-methyl-aniline phenylguanidine 2-methyl-4-nitroaniline 2-methyl-4-nitrophenyl-guanidine 2-methyl-4-cyanoaniline 2-methyl-4-cyanophenyl-guanidine 2-methyl-4-trifluoromethyl- 2-methyl-4-trifluoromethyl-aniline phenylguanidine 2-chloro-6-nitroaniline 2-chloro-6-nitrophenyl-guanidine 2-bromo-6-nitroaniline 2-bromo-6-nitrophenyl-guanidine 2-iodo-6-nitroaniline 2-iodo-6-nitrophenyl-guanidine 2-fluoro-6-nitroaniline 2-fluoro-6-nitrophenyl-guanidine 2-nitro-6-trifluoromethyl- 2-nitro-6-trifluoromethyl-aniline phenylguanidine 2-nitro-6-methoxyaniline 2-nitro-6-methoxyphenyl-guanidine : 2-cyano-6-chloroaniline 2-cyano-6-chlorophenyl-guanidine 2-methyl-6-chloroaniline 2-methyl-6-chlorophenyl-guanidine 2-methyl 6-bromoaniline 2-methyl-6-bromophenyl-- guanidine ~- 2-methyl-6-fluoroaniline 2-methyl-6-fluorophenyl-guanidine 2-methyl-6-nitroaniline 2-methyl-6-nitrophenyl-: guanidine ~ 2-methyl-6-trifluoromethyl- 2-methyl-6-trifluoromethyl-- 40 aniline phenylguanidine 2-methyl-6-cyanoaniline 2-methyl-6-cyanophenyl-guanidine :~ :
,;-., .
~81'7~
2-methyl-6-methylsulfonyl 2-methyl-6-methylsulfonyl-aniline phenylguanidine 2,4-dimethylaniline 2,4-dimethylphenylguanidine 2,6-dimethylaniline 2,6-dimethylphenylguanidine 2-trifluoromethyl-6-chloro- 2-trifluoromethyl-6-chloro-aniline phenylguanidine 2-trifluoromethyl-6-bromo- 2-trifluoromethyl-6-bromo-anillne phenylguanidine 2-trifluoromethyl-6-fluoro- 2-trifluoromethyl-6-fluoro-aniline phenylguanidine 2-trifluoromethyl-6-nitro- 2-trifluoromethyl-6-nitro-aniline phenylguanidine . .
2-trifluoromathyl-4-chloro- 2-trifluoromethyl-4-chloro-aniline phenylguanidine 2-trifluoromethyl-4-bromo- 2-trifluoromethyl-4-bromo-aniline phenylguanidine 2-trifluoromethyl-4-fluoro- 2-trifluoromethyl-4-fluoro-aniline phenylguanidine 4-trifluoromethyl-2-chloro- 4-trifluoromethyl-2-chloro-anillne phenylguanidine 4-trifluoromethyl-2-bromo- 4-trifluoromethyl-2-bromo-aniline phenylguanidine 4-trifluoromethyl-2-fluoro- 4-trifluoromethyl-2-bromo-aniline phenylguanidine :
2,4-dichloro-6-methyl- 2,4-dichloro-6-methyl-aniline phenylguanidine 2,6-dichloro-4-methyl- 2,6-dichloro-4-methyl-aniline phenylguanidine 3,5-ditrifluoromethyl- 3,5-ditrifluoromethyl-3~ aniline phenylguanidine 2-methoxy-4-nitroaniline 2-methoxy-4-nitrophenyl-guanidine 2-trifluoromethyl-4-nitro- 2-trifluoromethyl-4-nitro-aniline phenylguanidine - . .
2,4-dichloro-6-methoxy- 2,4-dichloro-6-methoxy-aniline phenylguanidine 2,6-dimethyl-4-chloro- 2,6-dimethyl-4-chloro-aniline phenylguanidine 2,6-dimethyl-4-fluoro- 2,6-dimethyl-4-fluoro-aniline phenylguanidine 2,6-dimethyl-4-bromoaniline 2,6-dimethyl-4-bromophenyl-guanidine 1~17~
2,6-dimethyl-4-nîtroaniline 2,6-dimethyl-4-nitrophenyl-guanidine 2,6-dimethyl-4-trifluoro- 2,6-dimethyl-4-trifluoro-methylaniline methylphenylguanidine 2-ethyl-4-nitroaniline 2-ethyl-4-nitrophenyl-guanidine 2-ethyl-4-chloroaniline 2-ethyl-4-chlorophenyl-guanidine 2-ethyl-4-bromoaniline 2-ethyl-4-bromophenyl-guanidine 2-ethyl-4-fluoroaniline 2-ethyl-4-fluorophenyl-guanidine 2-ethyl-4-trifluoromethyl- 2-ethyl-4-trifluoromethyl-aniline phenylguanidine 2-ethyl-4-cyanoaniline 2-ethyl-4-cyanophenyl-guanidine 2-ethyl-4-methylsulfonyl- 2-ethyl-4-methylsulfonyl-aniline phenylguanidine 2,4-dichloro-6-bromoaniline 2,4-dichloro-6-bromophenyl-guanidine 2,6-dichloro-4-bromoaniline 2,6-dichloro-4-bromophenyl-guanidine 2,4-dibromo-6-chloroaniline 2,4-dibromo-6-chlorophenyl-guanidine 2,6-dibromo-4-chloroaniline 2,6-dibromo-4-chlorophenyl-guanidine 2,4-dichloro-6-fluoro- 2,4-dichloro-6-fluoro-aniline phenylguanidine 2-chloro-4-methyl-6-fluoro- 2-chloro-4-methyl-6-fluoro-aniline phenylguanidine 2,4-dimethyl-6-chloro- 2,4-dimethyl-6-chloro-aniline phenylguanidine 2,4-dimethyl-6-fluoro- 2,4-dimethyl-6-fluoro-aniline phenylguanidine 2-chloro-4-fluoro-6-methyl- 2-chloro-4-fluoro-6-methyl-aniline phenylguanidine 2,6-dichloro-4-fluoro- 2,6-dichloro-4-fluoro-aniline phenylguanidine 2,5-dichloro-4-fluoro- 2,5-dichloro-4-fluoro-aniline phenylguanidine 2,4-dichloro-6-iodoaniline 2,4-dichloro-6-iodophenyl-guanidine .
71~9 2,6-dichloro-4-iodoaniline 2,6-dichloro-4-iodophenyl-guanidine 2,4-dibromo-6-iodoaniline 2,4-dibromo-6-iodophenyl-guanidlne 2,4-dibromo-6-fluoroaniline 2,4-dibromo-6-fluorophenyl-guanidine 2,6-dibromo-4-fluoroaniline 2,6-dibromo-4-fluorophenyl-guanidine 2-chloro-4-bromo-6-fluoro- 2~chloro-4-bromo-6 fluoro-aniline phenylguanidine 2-bromo-4-fluoro-6-chloro- 2-bromo-4-fluoro-6-chloro-aniline phenylguanidine 2-bromo-4-chloro-6-fluoro- 2-bromo-4-chloro-6-fluoro-aniline phenylguanidine 2-chloro-4-iodo-6-bromo- 2-chloro-4-iodo-6-bromo-aniline phenylguanidine 2,4,6-tribromoaniline 2,4,6-tribromophenyl-guanidine 2,4,6-trifluoroaniline 2,4,6-trifluorophenyl-guanidine 1-(2,6-dichlorophenyl)-1-methylguanidine To 55.4 g (0.315 mole) of N-methyl-2,6-di-chloroaniline is added 0.4 moles 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 hydro-gen 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 l-(2,6-di- :
chlorophenyl)-l-methylguanidine hydrochloride.
The free base is prepared by dissolving 1-(2,6-dichlorophenyl)-l-methylguanidine hydrochloride in 10% -sodium hydroxide~solution and extracting with ether. The . , ,. .. .. . . . . . . ,; ~ .. : . ~ ,, , -743~
ether is dried and evaporated to dryness to obtain 1-(2,6-dichlorophenyl~ methylguanidine~
When the N-methylaniline in the above pro-cedures is replaced by the N-loweralkylanilines of this invention then the corresponding product is obtained.
When the above procedures are followed then the corresponding products are prepared.
1-(2,6-dichlorophenyl)-3-methylguanidine To 51 g (0.315 mole) of 2,6-dichloroaniline is added 0.4 moles 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 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 l-(2,6-dichloro-phenyl)-3-methylguanidine hydrochloride.
The free base is prepared by dissolving 1-(2,6-dichlorophenyl)-3-methylguanidine hydrochloride to 10%
sodium hydroxide solution and extracting with ether. The ether is dried and evaporated to dryness to obtain 1-(2,6-dichlorophenyl)-3-methylguanidine.
When the above procedures are followed using 3Q the cyanamides of Table III below, then the corresponding products are prepared.
TABLE III
ethylcyanamide propylcyanamide ~ :
i-propylcyanamide butylcyanamide pentylcyanamide hexylcyanamide heptylcyanamide octylcyanamide vinylcyanamide propargylcyanamide methallylcyanamide 2,4-pentadienylcyanamide 2-pentenylcyanamide cyclopropylcyanamide cyclobutylcyanamide cyclopentylcyanamide cyclohexylcyanamide phenylcyanamide -benzylcyanamide phenethylcyanamide cyclohex-2-enylcyanamide cyclopropylmethylcyanamide cyclobutylmethylcyanamide cyclopropylethylcyanamide 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 4 . .
1-(p-fluorophenyl)-3-methylthiourea To~a mixture of 55.5 g (0.5 mole) of p-fluoro-aniline and 100 ml of xylene is added 36.5 g (0.5 mole) of methylisothiocyanate and the mixture is refluxed for 2 hours.: The reaction product is cooled, triturated with .
heptane and filtered. Recrystallization from 1:1 iso-propanol/water results in l-(p-fluorophenyl)-3-methyl , ~ .
: .
1~817~9 thiourea.
When the above procedure is followed using 2,6-dichloroaniline then the product prepared is l-(2,6-di-chlorophenyl)-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 isothiocyanates of Table IV below, then the corresponding product is obtained.
TABLE IV
.. . . .
ethylisothiocyanate propylisothiocyanate i-propylisothiocyanate butylisothiocyanate pentylisothiocyanate hexylisothiocyanate heptylisothiocyanate octylisothiocyanate vinylisothiocyanate propargylisothiocyanate methallylisothiocyanate cyclopropylisothiocyanate cyclobutylisothiocyanate cyclopentylisothiocyanate cyclohexylisothiocyanate cyclohex-2-enylisothiocyanate phenylisothiocyanate ben7.ylisothiocyanate 3D phenethylisothiocyanate cyclopropylmethylisothiocyanate cyclobutylmethylisothiocyanate cyclopropylethylisothiocyanate .
~, ' 1-(2,6-dichlorophenyl)-3-methylguanidine 1-(2,6-dichlorophenyl)-3-benzoylthiourea To 51.8 g (0.68 mole) of ammonium thiocyanate in 300 ml acetone is added 86.~ g (0.62 mole) of ben~oyl chloride. The reaction mixture is refluxed for about
5 min. 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 liters of ice and water, filtered to obtain 1-(2,6-dichlorophenyl)-3-benzoylthiourea.
2,6-dichlorophenylthiourea 182.8 g (0.56 mole) of the latter is heated with 260 ml 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-dichloro-phenylthiourea is filtered off.
1-(2,6-dichlorophenyl)-2-methylpseudothiouronium iodide 20 g (0.09 mole) of 2,6-dichlorophenylthiourea is combined with 200 ml methanol and 12.9 g (0.09 mole) iodomethane 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-methylpseudothiouronium iodide.
1-(2,6-dichIorophenyl)-3-methylguanidine hydrochloride 32.8 g (0.09 mole) of the latter is added to 300 ml of n-butanol. Methylamine gas is bubbled through this solution while refluxing for 24 hours. The reaction mixture is evaporated to dryness and extracted with 10%
sodium hydroxide solution and ether. The ether is washed with 10% sodium hydroxide and then with water, dried and filtered. To this is added ethereal HCl and the precipi-tate 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 1-(2,6-dichlorophenyl)-3-methylguanidine.
When the above procedures are followed using the anilines of Examples 1 and 2, then the corresponding product is obtained.
When the above procedures are followed and methylamine is replaced with the amines of Table V below, then the corresponding product is obtained.
TABLE V
ethylamine propylamine i-propylamine butylamine pentylamine hexylamine heptylamine `
octylamine propargylamine methallylamine 2,4-pentadienylamine cyclopropylamine cyclobutylamine cyclopentylamine - -cyclohexylamine propionamide aniline benzylamine phenethylamine cyclohex-2-enylamine cyclopropylmethylamine cyclobutylmethylamine cyclopropylethylamine N-benzylaniline azetidine : - .
." .
1~8~7~
piperidine homopiperidine morpholine pyrrolidine piperazine 2-methyl-1-azacyclooctane When the above procedures are followed using the anilines of Examples 1 and 2 and the amines of Table I above the corresponding products are obtained.
When the thiourea compounds prepared of Example 4 are substituted in the above procedure, then the corre-sponding products are obtained.
1-(2,6-dichlorophenylamidino)-3-(t-butyl)urea To a mixture of 10 g (0.05 mole) of 2,6-dichlorophenylguanidine and 10 ml xylene is added 5 g of t-butylisocyanate (0.05 mole) and the mixture is refluxed for 2 hours. The reaction product is cooledj triturated with heptane and filtered. Recrystallization from 1:1 isopropanol/water results in 1-(2,6-dichlorophenyl-amidino)-3-(t-butyl)urea, m.p. 161-163C.
When the above procedure is followed using the guanidines of Example 1, then the corresponding products are prepared.
When t-butylisocyanate in the above procedure is repIaced by the isocyanates of Table VI below, then the corresponding product is prepared.
TABLE VI -methylisocyanate ethylisocyanate propylisocyanate i-propylisocyanate butylisocyanate ~
pentylisocyanate ~ -hexylisocyanate heptylisocyanate , ::
L7~3 octylisocyanate propargylisocyanate methallylisocyanate cyclopropylisocyanate cyclobutylisocyanate cyclopentylisocyanate cyclohexylisocyanate cyclohex-2-enylisocyanate phenylisocyanate benzylisocyanate phenethylisocyanate cyclopropylmethylisocyanate cyclobutylmethylisocyanate cyclopropylethylisocyanate When the above procedure is followed using the guanidines of Example 1 and 3 and the isocyanates of Table VI above, then the corresponding product is prepared.
1-(2,6-dichlorophenyl-N-methylamidino)urea 1-(2,6-dichlorophenyl-N-methylamidino)-3-(t-butyl)urea To a mixture of 10.9 g (0.05 mole) of 1-(2,6-dichlorophenyl)-l-methylguanidine and 10 ml xylene is added 5 g of t-butylisocyanate (0.05 mole) and the mixture is refluxed for 2 hours. The reaction product is cooled, triturated with heptane and filtered. Re-crystallization from 1:1 isopropanol/water results in 1-(2,6-dichlorophenyl-N-methylamidino)-3-(t-butyl)urea, m.p. 157-159C, while its hydrochloride has a m.p. of ~ 192C.
1-(2,6-dichlorophenyl-N-methylamidino)urea A mixture of 33.7 g (0.106 mole) of 1-(2,6-dichlorophenyl-N-methylamidino)-3-(t-butyl)urea and 200 ml of conc. hydrochloric acid is refluxed for 1/2 hour.
The reaction mixture is cooled, filtered and washed with lO ml of l:l HCl/H2O and dried. The product is then ' : :
recrystallized from ethanol-ether to obtain 1-(2,6-dichlorophenyl-N-methylamidino)urea. Its hydrochloride melts at 203-204C.
When the above procedure is followed using 1-(2,6-dichlorophenyl)-3-methylguanidine and 1-(2,6-dichlorophenyl)-1,3-dimethylguanidine then the products prepared are 1-(2,6-dichlorophenylamidino)-1-methylurea (m.p. 120C) and 1-(2,6-dichlorophenyl-N-methylamidino)-l-methylurea.
When the above procedure is followed using the guanidines of Examples 2, 3 and 5, then the corresponding products are prepared.
1-(2,6-dichlorophenyl)-3-carbamylthiourea 1-(2,6-dichlorophenyl)-3-(t-butylcarbamyl)thiourea To a mixture of 11 g (0.05 mole) of 1-(2,6-dichlorophenyl)thiourea and 10 ml of xylene is added 5 g of t-butylisocyanate (0.05 mole) and the mixture is refluxed for 2 hours. The reaction product is cooled, triturated with heptane and filtered. Recrystallization from 1:1 isopropanol/water results in 1-(2,6-dichloro-phenyl)-3-(t-butylcarbamyl)thiourea.
1--(2,6-dichlorophenyl)-3-carbamylthiourea A mixture of 32 g (0.1 mole) of 1-(2,6-dichlorophenyl)-3-(t-butylcarbamyl)thiourea and 200 ml of conc. hydrochloric acid is refluxed for 1/2 hour. The reaction mixture is cooled, filtered and washed with 10 ml of 1:1 HCl/H2O and dried. The product is then re-crystallized from ethanol-ether to obtain 1-(2,6-dichlorophenyl)-3-carbamylthiourea.
When the above procedure is followed using 1-(2,6-dichlorophenyl)-1-methylthiourea; 1-(2,6-dichloro-phenyl)-3-methylthiourea; 1-(2,6-dichlorophenyl)-1,3-dimethylthiourea; l-(p-fluorophenyl)-3-methylthiourea then the products obtained are l-(2,6-dichlorophenyl)-1-methyl-3-carbamylthiourea; 1-(2,6-dichlorophenyl)-3-7~
methyl-3-carbamylthiourea; 1-(2,6-dichlorophenyl)-1,3-dimethyl-3-carbamylthiourea; and 1-(p-fluorophenyl)-3-methyl-3-carbamylthiourea.
When the above procedure is followed using the thiourea compounds of Examples 4 and 5 then the corre-sponding product is obtained.
When the above procedure is followed using the substituted isocyanate compounds of Table II, Example 6, then the corresponding product is obtained.
When the above procedure is followed using the thiourea compounds of Examples 4 and 5 and the substi-tuted isocyanate compounds of Table II, Example 6, then the corresponding product is obtained.
1-(2,6-dichlorophenyl-N'-methylamidino)urea 1-(2,6-dichlorophenyl)-3-carbamyl-2-methylthiouronium iodide 26.4 g (0.1 mole) of 1-(2,6-dichlorophenyl)-3-carbamylthiourea is combined with 200 ml of methanol and 14.1 g (0.1 mole) of iodomethane and refluxed for 4 hours. This is then evaporated to dryness and 100 ml of hexane is added. The mixture is filtered to obtain 1-(2,6-dichlorophenyl)-3-carbamyl-3-methylthiouronium iodide.
1-(2,6-dichlorophenyl-N'-methylamidino)urea 40.5 g of 1-(2,6-dichlorophenyl)-3-carbamyl-2-methylthiouronium iodide (0.1 mole) is added to 300 ml of n-butanol. Methylamine gas is bubbled through this solution while refluxing for 24 hours. The reaction mixture is evaporated to dryness and extracted with 10%
sodium hydroxide solution and ether. The ether is washed with 10% sodium hydroxide and then with water; dried and filtered. To this is added ethereal HCl and the precipi-tate is collected to obtain l-(~,6-dichlorophenyl-N'-methylamidino)urea hydrochloride, m.p. 203-204C.
The ~ree base is prepared by dissolving the . ,:
- ~ -. ,.
above hydrochloride in 10% sodium hydroxide solution and extracting with ether. The ether is dried and evaporated to dryness to obtain l-(2,6-dichlorophenyl-N'-methyl-amidino)urea.
When the above procedure is followed using the thiourea compounds prepared by Example 8, then the corre-sponding amidinourea is prepared.
When the above procedure is followed and methylamine is replaced with the amines of Table I, Example 5, then the corresponding product is obtained.
When the above procedure is followed using the thiourea compounds prepared by Example 8 and the amines of Table I, Example 5, then the corresponding product is prepared.
EXA~IPLE 10 1-(2,6-dichlorophenylamidino)-3,3-(~,~'-dimethylpenta-methylene)urea _ A. 2,6-dimethylpiperidinoyl chloride To a solution of 50 g of 2,6-dimethylpiperidine in 300 ml of benzene is added 60 g of phosgene and the mixture is refluxed for 3 hours. The solid which had separated was filtered and the filtrate was concentrated and distilled under vacuum to obtain 2,6-dimethyl-piperidinoyl chloride.
B. 1-(2,6-dichlorophenylamidino)-3,3-(~,~'-dimethyl-pentamethylene)urea -To a mixture of 20.4 g (0.1 mole) of 2,6-dichlorophenylguanidine in 250 ml of dimethylformamide is added dropwise with~stirring a solution of 17.5 g (0.1 mole) of 2,6-dimethylpiperidinoyl chloride in 150 ml of tetrahydrofuran. The mixture is stirred for 6 hours, poured onto ice, acidified with conc. HCl basified with sodium hydroxide and extracted with ether. The ether is washed with water~and saturated sodium chloride solution and dried over magnesium sulfate. The filtered solution is evaporated to dryness~to obtain 1-(2,6-dichloro-phenyl)-3,3-(~,~'-dimethylpentamethylene)urea.
.
1~8~L7~39 The hydrochloride salt is prepared by dis-solving the above free base in ether and adding ethereal hydrochloric acid. The formed hydrochloride is separated and recrystallized from acetonitrile/water/conc. HCl.
When 2,6-dimethylpiperidine is replaced in the above example by the amines of Table VII below, then the corresponding product is prepared.
TABLE VII
piperidine 4-methylpiperidine N-methylpiperazine N-methylhomopiperazine morpholine thiazolidine octamethyleneamine 2-methylazacyclooctane pyrrolidine dimethylamine diethylamine methylethylamine ethylpropylamine ethylcyclopropylamine ethylbenzylamine dibenzylamine dicyclopropylamine methylcyclobutylamine methyl-t-butylamine ethyl-t-butylamine cyclopropyl-t-butylamine methyl(cyclopropylmethyl)amine When 2,6-dichlorophenylguanidine in the above Example is replaced by the guanidines prepared in Examples 1, 2, 3 and 5, then the corresponding product is obtained.
When the above procedure is followed, and 2,6-dichlorophenylguanidine is replaced by the guanidines of 1~8:~L7~
Examples 1, 2, 3 and 5 and 2,6-dimethylpiperidine is replaced by the amines of Table I above, then the corre-sponding product is prepared.
EXAMP~E 11 1-(2,6-dichlorophenyl-N'-methylamidino)-3,3-diethylurea A. 1-(2,6-dichlorophenyl)-3,3-diethylcarbamylthiourea . . _ To a mixture of 11 g (0.05 mole) of 1-(2,6-dichlorophenyl)thiourea in 150 ml of dimethylformamide is added dropwise with stirring a solution of 6.75 g (0.01 mole) of diethylcarbamyl chloride in 100 ml of tetra-hydrofuran (prepared from diethylamine and phosgene according to Example 10). The mixture is stirred for 10 hours, poured onto ice, acidified with conc. HCl while keeping the mixture at ice temperature and basified with sodium hydroxide and extracted with ether. The ether is washed, dried and evaporated to obtain l-(2,6-dichloro-phenyl)-3,3-diethylcarbamylthiourea.
B. 1-(2,6-dichlorophenyl)-3-(N,N-diethylcarbamyl)-2-methylthiouronium iodide (0.1 mole) of 1-(2,6-dichlorophenyl)-3-(N,N-diethylcarbamyl)thiourea is combined with 200 ml of methanol and 14.1 g (0.1 mole) of iodomethane and reflux-ed for 4 hours. This is then evaporated to dryness and 100 ml of hexane is added. The mixture is filtered to obtain l-(2,6-dichlorophenyl)-3-(N,N-diethylcarbamyl)-2-methylthiouronium iodide.
C. 1-(2,6-dichlorophenyl-N'-methylamidino)-3,3-diethyl-urea Of 1-(2,6-dichlorophenyl)-3-(N,N-diethyl-carbamyl)-2-methylthiouronium iodide (0.1 mole) is added to 300 ml of n-butanol. Methylamine gas is bu~bled through this solution while refluxing for 24 hours. The reaction mixture is evaporated to dryness and extracted ;
with 10% sodium hydroxide solution and ether. The ether is washed with 10% sodium hydroxide and then with water;
dried filtered and evaporated to dryness to obtain 1-(2,6-dichlorophenyl-N'-methylamidino)-3,3-diethylurea.
The hydrochloride salt is prepared by dis-solving the above free base in ether and adding ethereal hydrochloric acid. The ~ormed hydrochloride is separated and recrystallized from acetonitrile/water conc. EICl.
By proceeding in the same manner as in Examples
The mixture is refluxed for 1-1/2 hours, cooled, poured into 1-1/2 liters of ice and water, filtered to obtain 1-(2,6-dichlorophenyl)-3-benzoylthiourea.
2,6-dichlorophenylthiourea 182.8 g (0.56 mole) of the latter is heated with 260 ml 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-dichloro-phenylthiourea is filtered off.
1-(2,6-dichlorophenyl)-2-methylpseudothiouronium iodide 20 g (0.09 mole) of 2,6-dichlorophenylthiourea is combined with 200 ml methanol and 12.9 g (0.09 mole) iodomethane 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-methylpseudothiouronium iodide.
1-(2,6-dichIorophenyl)-3-methylguanidine hydrochloride 32.8 g (0.09 mole) of the latter is added to 300 ml of n-butanol. Methylamine gas is bubbled through this solution while refluxing for 24 hours. The reaction mixture is evaporated to dryness and extracted with 10%
sodium hydroxide solution and ether. The ether is washed with 10% sodium hydroxide and then with water, dried and filtered. To this is added ethereal HCl and the precipi-tate 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 1-(2,6-dichlorophenyl)-3-methylguanidine.
When the above procedures are followed using the anilines of Examples 1 and 2, then the corresponding product is obtained.
When the above procedures are followed and methylamine is replaced with the amines of Table V below, then the corresponding product is obtained.
TABLE V
ethylamine propylamine i-propylamine butylamine pentylamine hexylamine heptylamine `
octylamine propargylamine methallylamine 2,4-pentadienylamine cyclopropylamine cyclobutylamine cyclopentylamine - -cyclohexylamine propionamide aniline benzylamine phenethylamine cyclohex-2-enylamine cyclopropylmethylamine cyclobutylmethylamine cyclopropylethylamine N-benzylaniline azetidine : - .
." .
1~8~7~
piperidine homopiperidine morpholine pyrrolidine piperazine 2-methyl-1-azacyclooctane When the above procedures are followed using the anilines of Examples 1 and 2 and the amines of Table I above the corresponding products are obtained.
When the thiourea compounds prepared of Example 4 are substituted in the above procedure, then the corre-sponding products are obtained.
1-(2,6-dichlorophenylamidino)-3-(t-butyl)urea To a mixture of 10 g (0.05 mole) of 2,6-dichlorophenylguanidine and 10 ml xylene is added 5 g of t-butylisocyanate (0.05 mole) and the mixture is refluxed for 2 hours. The reaction product is cooledj triturated with heptane and filtered. Recrystallization from 1:1 isopropanol/water results in 1-(2,6-dichlorophenyl-amidino)-3-(t-butyl)urea, m.p. 161-163C.
When the above procedure is followed using the guanidines of Example 1, then the corresponding products are prepared.
When t-butylisocyanate in the above procedure is repIaced by the isocyanates of Table VI below, then the corresponding product is prepared.
TABLE VI -methylisocyanate ethylisocyanate propylisocyanate i-propylisocyanate butylisocyanate ~
pentylisocyanate ~ -hexylisocyanate heptylisocyanate , ::
L7~3 octylisocyanate propargylisocyanate methallylisocyanate cyclopropylisocyanate cyclobutylisocyanate cyclopentylisocyanate cyclohexylisocyanate cyclohex-2-enylisocyanate phenylisocyanate benzylisocyanate phenethylisocyanate cyclopropylmethylisocyanate cyclobutylmethylisocyanate cyclopropylethylisocyanate When the above procedure is followed using the guanidines of Example 1 and 3 and the isocyanates of Table VI above, then the corresponding product is prepared.
1-(2,6-dichlorophenyl-N-methylamidino)urea 1-(2,6-dichlorophenyl-N-methylamidino)-3-(t-butyl)urea To a mixture of 10.9 g (0.05 mole) of 1-(2,6-dichlorophenyl)-l-methylguanidine and 10 ml xylene is added 5 g of t-butylisocyanate (0.05 mole) and the mixture is refluxed for 2 hours. The reaction product is cooled, triturated with heptane and filtered. Re-crystallization from 1:1 isopropanol/water results in 1-(2,6-dichlorophenyl-N-methylamidino)-3-(t-butyl)urea, m.p. 157-159C, while its hydrochloride has a m.p. of ~ 192C.
1-(2,6-dichlorophenyl-N-methylamidino)urea A mixture of 33.7 g (0.106 mole) of 1-(2,6-dichlorophenyl-N-methylamidino)-3-(t-butyl)urea and 200 ml of conc. hydrochloric acid is refluxed for 1/2 hour.
The reaction mixture is cooled, filtered and washed with lO ml of l:l HCl/H2O and dried. The product is then ' : :
recrystallized from ethanol-ether to obtain 1-(2,6-dichlorophenyl-N-methylamidino)urea. Its hydrochloride melts at 203-204C.
When the above procedure is followed using 1-(2,6-dichlorophenyl)-3-methylguanidine and 1-(2,6-dichlorophenyl)-1,3-dimethylguanidine then the products prepared are 1-(2,6-dichlorophenylamidino)-1-methylurea (m.p. 120C) and 1-(2,6-dichlorophenyl-N-methylamidino)-l-methylurea.
When the above procedure is followed using the guanidines of Examples 2, 3 and 5, then the corresponding products are prepared.
1-(2,6-dichlorophenyl)-3-carbamylthiourea 1-(2,6-dichlorophenyl)-3-(t-butylcarbamyl)thiourea To a mixture of 11 g (0.05 mole) of 1-(2,6-dichlorophenyl)thiourea and 10 ml of xylene is added 5 g of t-butylisocyanate (0.05 mole) and the mixture is refluxed for 2 hours. The reaction product is cooled, triturated with heptane and filtered. Recrystallization from 1:1 isopropanol/water results in 1-(2,6-dichloro-phenyl)-3-(t-butylcarbamyl)thiourea.
1--(2,6-dichlorophenyl)-3-carbamylthiourea A mixture of 32 g (0.1 mole) of 1-(2,6-dichlorophenyl)-3-(t-butylcarbamyl)thiourea and 200 ml of conc. hydrochloric acid is refluxed for 1/2 hour. The reaction mixture is cooled, filtered and washed with 10 ml of 1:1 HCl/H2O and dried. The product is then re-crystallized from ethanol-ether to obtain 1-(2,6-dichlorophenyl)-3-carbamylthiourea.
When the above procedure is followed using 1-(2,6-dichlorophenyl)-1-methylthiourea; 1-(2,6-dichloro-phenyl)-3-methylthiourea; 1-(2,6-dichlorophenyl)-1,3-dimethylthiourea; l-(p-fluorophenyl)-3-methylthiourea then the products obtained are l-(2,6-dichlorophenyl)-1-methyl-3-carbamylthiourea; 1-(2,6-dichlorophenyl)-3-7~
methyl-3-carbamylthiourea; 1-(2,6-dichlorophenyl)-1,3-dimethyl-3-carbamylthiourea; and 1-(p-fluorophenyl)-3-methyl-3-carbamylthiourea.
When the above procedure is followed using the thiourea compounds of Examples 4 and 5 then the corre-sponding product is obtained.
When the above procedure is followed using the substituted isocyanate compounds of Table II, Example 6, then the corresponding product is obtained.
When the above procedure is followed using the thiourea compounds of Examples 4 and 5 and the substi-tuted isocyanate compounds of Table II, Example 6, then the corresponding product is obtained.
1-(2,6-dichlorophenyl-N'-methylamidino)urea 1-(2,6-dichlorophenyl)-3-carbamyl-2-methylthiouronium iodide 26.4 g (0.1 mole) of 1-(2,6-dichlorophenyl)-3-carbamylthiourea is combined with 200 ml of methanol and 14.1 g (0.1 mole) of iodomethane and refluxed for 4 hours. This is then evaporated to dryness and 100 ml of hexane is added. The mixture is filtered to obtain 1-(2,6-dichlorophenyl)-3-carbamyl-3-methylthiouronium iodide.
1-(2,6-dichlorophenyl-N'-methylamidino)urea 40.5 g of 1-(2,6-dichlorophenyl)-3-carbamyl-2-methylthiouronium iodide (0.1 mole) is added to 300 ml of n-butanol. Methylamine gas is bubbled through this solution while refluxing for 24 hours. The reaction mixture is evaporated to dryness and extracted with 10%
sodium hydroxide solution and ether. The ether is washed with 10% sodium hydroxide and then with water; dried and filtered. To this is added ethereal HCl and the precipi-tate is collected to obtain l-(~,6-dichlorophenyl-N'-methylamidino)urea hydrochloride, m.p. 203-204C.
The ~ree base is prepared by dissolving the . ,:
- ~ -. ,.
above hydrochloride in 10% sodium hydroxide solution and extracting with ether. The ether is dried and evaporated to dryness to obtain l-(2,6-dichlorophenyl-N'-methyl-amidino)urea.
When the above procedure is followed using the thiourea compounds prepared by Example 8, then the corre-sponding amidinourea is prepared.
When the above procedure is followed and methylamine is replaced with the amines of Table I, Example 5, then the corresponding product is obtained.
When the above procedure is followed using the thiourea compounds prepared by Example 8 and the amines of Table I, Example 5, then the corresponding product is prepared.
EXA~IPLE 10 1-(2,6-dichlorophenylamidino)-3,3-(~,~'-dimethylpenta-methylene)urea _ A. 2,6-dimethylpiperidinoyl chloride To a solution of 50 g of 2,6-dimethylpiperidine in 300 ml of benzene is added 60 g of phosgene and the mixture is refluxed for 3 hours. The solid which had separated was filtered and the filtrate was concentrated and distilled under vacuum to obtain 2,6-dimethyl-piperidinoyl chloride.
B. 1-(2,6-dichlorophenylamidino)-3,3-(~,~'-dimethyl-pentamethylene)urea -To a mixture of 20.4 g (0.1 mole) of 2,6-dichlorophenylguanidine in 250 ml of dimethylformamide is added dropwise with~stirring a solution of 17.5 g (0.1 mole) of 2,6-dimethylpiperidinoyl chloride in 150 ml of tetrahydrofuran. The mixture is stirred for 6 hours, poured onto ice, acidified with conc. HCl basified with sodium hydroxide and extracted with ether. The ether is washed with water~and saturated sodium chloride solution and dried over magnesium sulfate. The filtered solution is evaporated to dryness~to obtain 1-(2,6-dichloro-phenyl)-3,3-(~,~'-dimethylpentamethylene)urea.
.
1~8~L7~39 The hydrochloride salt is prepared by dis-solving the above free base in ether and adding ethereal hydrochloric acid. The formed hydrochloride is separated and recrystallized from acetonitrile/water/conc. HCl.
When 2,6-dimethylpiperidine is replaced in the above example by the amines of Table VII below, then the corresponding product is prepared.
TABLE VII
piperidine 4-methylpiperidine N-methylpiperazine N-methylhomopiperazine morpholine thiazolidine octamethyleneamine 2-methylazacyclooctane pyrrolidine dimethylamine diethylamine methylethylamine ethylpropylamine ethylcyclopropylamine ethylbenzylamine dibenzylamine dicyclopropylamine methylcyclobutylamine methyl-t-butylamine ethyl-t-butylamine cyclopropyl-t-butylamine methyl(cyclopropylmethyl)amine When 2,6-dichlorophenylguanidine in the above Example is replaced by the guanidines prepared in Examples 1, 2, 3 and 5, then the corresponding product is obtained.
When the above procedure is followed, and 2,6-dichlorophenylguanidine is replaced by the guanidines of 1~8:~L7~
Examples 1, 2, 3 and 5 and 2,6-dimethylpiperidine is replaced by the amines of Table I above, then the corre-sponding product is prepared.
EXAMP~E 11 1-(2,6-dichlorophenyl-N'-methylamidino)-3,3-diethylurea A. 1-(2,6-dichlorophenyl)-3,3-diethylcarbamylthiourea . . _ To a mixture of 11 g (0.05 mole) of 1-(2,6-dichlorophenyl)thiourea in 150 ml of dimethylformamide is added dropwise with stirring a solution of 6.75 g (0.01 mole) of diethylcarbamyl chloride in 100 ml of tetra-hydrofuran (prepared from diethylamine and phosgene according to Example 10). The mixture is stirred for 10 hours, poured onto ice, acidified with conc. HCl while keeping the mixture at ice temperature and basified with sodium hydroxide and extracted with ether. The ether is washed, dried and evaporated to obtain l-(2,6-dichloro-phenyl)-3,3-diethylcarbamylthiourea.
B. 1-(2,6-dichlorophenyl)-3-(N,N-diethylcarbamyl)-2-methylthiouronium iodide (0.1 mole) of 1-(2,6-dichlorophenyl)-3-(N,N-diethylcarbamyl)thiourea is combined with 200 ml of methanol and 14.1 g (0.1 mole) of iodomethane and reflux-ed for 4 hours. This is then evaporated to dryness and 100 ml of hexane is added. The mixture is filtered to obtain l-(2,6-dichlorophenyl)-3-(N,N-diethylcarbamyl)-2-methylthiouronium iodide.
C. 1-(2,6-dichlorophenyl-N'-methylamidino)-3,3-diethyl-urea Of 1-(2,6-dichlorophenyl)-3-(N,N-diethyl-carbamyl)-2-methylthiouronium iodide (0.1 mole) is added to 300 ml of n-butanol. Methylamine gas is bu~bled through this solution while refluxing for 24 hours. The reaction mixture is evaporated to dryness and extracted ;
with 10% sodium hydroxide solution and ether. The ether is washed with 10% sodium hydroxide and then with water;
dried filtered and evaporated to dryness to obtain 1-(2,6-dichlorophenyl-N'-methylamidino)-3,3-diethylurea.
The hydrochloride salt is prepared by dis-solving the above free base in ether and adding ethereal hydrochloric acid. The ~ormed hydrochloride is separated and recrystallized from acetonitrile/water conc. EICl.
By proceeding in the same manner as in Examples
6, 7, 8, 9, 10 and 11 and using the appropriate starting materials the following amidino ureas of Table VIII are obtained.
TABLE VIII
Ex. CompoundMelting Point 12 1-(2~6-Dichlorophenylamidino)-3-(t-butyl)urea Hydrochloride207C
13 1-(2,6-Dimethylphenylamidino)-3-(t-butyl)urea 189-191C
14 1-(2,6-Dichlorophenylamidino)-3-methylurea 196C
1-(2,6-Dichlorophenylamidino)-l-methylurea 120C
16 1-Phenylamidino-3-(t-butyl)urea178C
17 1-(3,5-Dichlorophenylamidino)-3-(t-butyl)urea Hydrochloride201C
18 1-(p-Chlorophenylamidino)-3-(t-butyl)urea Hydrochloride170-171C
19 1-(2,6-Dimethylphenylamidino)-3-methylurea 105-107C
l-(p-Fluoro-~-methylbenzylamidino)-urea Hydrochloride 185C
21 1- ~-(2,6-Dimethylphenyl)-N-methyl-amidin ~urea Hydrochloride192-193C
22 1-(2-Methyl-4-bromophenylamidino)-3-(t-butyl)urea 207C
23 1-(t-Butyl)-3-(4'-bromo-2'-methyl-phenylamidino)urea nitrate123-124C
24 1-(t-Butyl)-3-(2'-ethyl-6'-methyl- ~-phenylamidino)urea 149-150C
1-(2'-E'thyl-6'-methylphenyl)amidino-3-(2',6'-dimethylphenyl)urea O
Hydrochloride 203.5-203.6 C
TABLE VIII - Cont'd.
Ex. CompoundMelting Point 26 1-(3-Chloro-4-fluorophenylamidino)-3-(t-butyl)urea 175C
27 1-(2,3,4,5,6-Pentafluorophenyl-O
amidino)-3-(t-butyl)urea21~-215 C
28 1-(2,6-Difluorophenylamidino)-3-(t-butyl)urea 182C
29 1-(2,6-Difluorophenylamidino)-3O
(t-butyl)urea HCl 164 C
1-(2-Chloro-6-fluorophenylamidino)-3-(t-butyl)urea 178dec.
31 1-(4-Chlorophenylamidino)-3-(t-butyl)urea 170-171C
32 1-(2,6-Dichlorophenylamidino)-3-(n-propyl)urea 168-169C
33 1-(3,5-Dichlorophenylamidino)-3-O
(t-butyl)urea 182 183 C
34 1-(4-Chlorophenylamidino)-3-(t-butyl)urea Hydrochloride170-171C
1-(t-Butyl)-3- ~-(2,6-dichloro- -~
phenyl)-l-methylamidin ~urea192dec.
36 1- ~2,6-Dimethylphenyl)-l-methyl-O
amidin ~urea HCl 192-193 C
37 1- ~4-Fluorophenyl)-l-methylamidin ~-urea HCl 185 C
38 l-Methyl-l- ~-(2,6-dichlorophenyl)-amidin ~urea 118-121C
39 1-(t-Butyl)-3-methyl-3- ~-(2,6- O
dichlorophenyl)amidin~7urea 157-159 C
1-Methyl-l-(t-butyl)-3- ~-(2,6-dichlorophenyl)amidin~7urea 181-182C
41 1-(t-Butyl)-3- ~-(2j6-dichloro-phenyl)amidin ~urea 180-181C
42 3-(t-Butyl)-l- ~-bromo-2-methyl- O
phenylamidin~7urea 209 dec.
43 1-(4-Chlorophenylamidino)-3-(t-butyl)urea Hydrochloride170-171C
When diethylamine is replaced in the above example by the amines of Table VII, Example 10, then the -corresponding product is obtained.
.
~OB1709 When 1-(2,6-dichlorophenyl)thiourea is replaced with the thioureas prepared in Examples 4 and 5 then the corresponding product is obtained.
When 1-(2,6-dichlorophenyl)thiourea is replaced with the thioureas of Examples 4 and 5 and diethylamine is replaced by the amines of Table VII, Example 10, then the corresponding product is obtained.
, . .. .
..... .:
TABLE VIII
Ex. CompoundMelting Point 12 1-(2~6-Dichlorophenylamidino)-3-(t-butyl)urea Hydrochloride207C
13 1-(2,6-Dimethylphenylamidino)-3-(t-butyl)urea 189-191C
14 1-(2,6-Dichlorophenylamidino)-3-methylurea 196C
1-(2,6-Dichlorophenylamidino)-l-methylurea 120C
16 1-Phenylamidino-3-(t-butyl)urea178C
17 1-(3,5-Dichlorophenylamidino)-3-(t-butyl)urea Hydrochloride201C
18 1-(p-Chlorophenylamidino)-3-(t-butyl)urea Hydrochloride170-171C
19 1-(2,6-Dimethylphenylamidino)-3-methylurea 105-107C
l-(p-Fluoro-~-methylbenzylamidino)-urea Hydrochloride 185C
21 1- ~-(2,6-Dimethylphenyl)-N-methyl-amidin ~urea Hydrochloride192-193C
22 1-(2-Methyl-4-bromophenylamidino)-3-(t-butyl)urea 207C
23 1-(t-Butyl)-3-(4'-bromo-2'-methyl-phenylamidino)urea nitrate123-124C
24 1-(t-Butyl)-3-(2'-ethyl-6'-methyl- ~-phenylamidino)urea 149-150C
1-(2'-E'thyl-6'-methylphenyl)amidino-3-(2',6'-dimethylphenyl)urea O
Hydrochloride 203.5-203.6 C
TABLE VIII - Cont'd.
Ex. CompoundMelting Point 26 1-(3-Chloro-4-fluorophenylamidino)-3-(t-butyl)urea 175C
27 1-(2,3,4,5,6-Pentafluorophenyl-O
amidino)-3-(t-butyl)urea21~-215 C
28 1-(2,6-Difluorophenylamidino)-3-(t-butyl)urea 182C
29 1-(2,6-Difluorophenylamidino)-3O
(t-butyl)urea HCl 164 C
1-(2-Chloro-6-fluorophenylamidino)-3-(t-butyl)urea 178dec.
31 1-(4-Chlorophenylamidino)-3-(t-butyl)urea 170-171C
32 1-(2,6-Dichlorophenylamidino)-3-(n-propyl)urea 168-169C
33 1-(3,5-Dichlorophenylamidino)-3-O
(t-butyl)urea 182 183 C
34 1-(4-Chlorophenylamidino)-3-(t-butyl)urea Hydrochloride170-171C
1-(t-Butyl)-3- ~-(2,6-dichloro- -~
phenyl)-l-methylamidin ~urea192dec.
36 1- ~2,6-Dimethylphenyl)-l-methyl-O
amidin ~urea HCl 192-193 C
37 1- ~4-Fluorophenyl)-l-methylamidin ~-urea HCl 185 C
38 l-Methyl-l- ~-(2,6-dichlorophenyl)-amidin ~urea 118-121C
39 1-(t-Butyl)-3-methyl-3- ~-(2,6- O
dichlorophenyl)amidin~7urea 157-159 C
1-Methyl-l-(t-butyl)-3- ~-(2,6-dichlorophenyl)amidin~7urea 181-182C
41 1-(t-Butyl)-3- ~-(2j6-dichloro-phenyl)amidin ~urea 180-181C
42 3-(t-Butyl)-l- ~-bromo-2-methyl- O
phenylamidin~7urea 209 dec.
43 1-(4-Chlorophenylamidino)-3-(t-butyl)urea Hydrochloride170-171C
When diethylamine is replaced in the above example by the amines of Table VII, Example 10, then the -corresponding product is obtained.
.
~OB1709 When 1-(2,6-dichlorophenyl)thiourea is replaced with the thioureas prepared in Examples 4 and 5 then the corresponding product is obtained.
When 1-(2,6-dichlorophenyl)thiourea is replaced with the thioureas of Examples 4 and 5 and diethylamine is replaced by the amines of Table VII, Example 10, then the corresponding product is obtained.
, . .. .
..... .:
Claims (6)
1. A process for the preparation of a compound of the formula:
wherein:
X is hydrogen, loweralkyl of 1 to 5 carbon atoms or halo;
Y is hydrogen, loweralkyl of 1 to S carbon atoms or halo;
Z is hydrogen, loweralkyl of 1 to 5 carbon atoms or halo;
R1, R2 and R3 stand for hydrogen or loweralkyl of 1 to 5 carbon atoms;
R' stands for loweralkyl of 1 to 5 carbon atoms; and R" stands for loweralkyl of 1 to 5 carbon atoms; or R' and R" together form an alkylidene chain, and the non-toxic acid addition salts which comprises (a) reacting a substituted guanidine or a mineral acid salt thereof of the formula:
where X, Y, Z, R1, R2 and R3 are as described above with an acid chloride of the formula:
(b) reacting a substituted carbamylthiouronium salt of the formula:
wherein X, Y, Z, R1, R3 and R' are as described above and R is loweralkyl and X ? is halide with an amine of the formula NHR2 where R2 is as desbribed above.
wherein:
X is hydrogen, loweralkyl of 1 to 5 carbon atoms or halo;
Y is hydrogen, loweralkyl of 1 to S carbon atoms or halo;
Z is hydrogen, loweralkyl of 1 to 5 carbon atoms or halo;
R1, R2 and R3 stand for hydrogen or loweralkyl of 1 to 5 carbon atoms;
R' stands for loweralkyl of 1 to 5 carbon atoms; and R" stands for loweralkyl of 1 to 5 carbon atoms; or R' and R" together form an alkylidene chain, and the non-toxic acid addition salts which comprises (a) reacting a substituted guanidine or a mineral acid salt thereof of the formula:
where X, Y, Z, R1, R2 and R3 are as described above with an acid chloride of the formula:
(b) reacting a substituted carbamylthiouronium salt of the formula:
wherein X, Y, Z, R1, R3 and R' are as described above and R is loweralkyl and X ? is halide with an amine of the formula NHR2 where R2 is as desbribed above.
2. The process for preparing 1-(2,6-dichlorophenyl-amidino)-3,3(.alpha.,.alpha.'-dimethylpentamethylene) urea which comprises reacting 2,6-dichlorophenylguanidine with 2,6-dimethylpiperi-dinoyl chloride and isolating the reaction product.
3. The process for preparing 1-(2,6-dichlorophenyl-N'-methylamidino)-3,3-diethylurea which comprises reacting 1-2,6-dichlorophenyl)-3-(N,N-diethylcarbamyl)-2-methyl-thiouronium chloride with methylamine and isolating the desired reaction product.
4. A compound of the formula:
wherein:
X is hydrogen, loweralkyl of 1 to 5 carbon atoms or halo;
Y is hydrogen, loweralkyl of 1 to 5 carbon atoms or halo;
Z is hydrogen, loweralkyl of 1 to 5 carbon atoms or halo;
R1, R2 and R3 stand for hydrogen or loweralkyl of 1 to 5 carbon atoms;
R' stands for loweralkyl of 1 to 5 carbon atoms; and R" stands for loweralkyl of 1 to 5 carbon atoms; or R' and R" together form an alkylidene chain, and the non-toxic acid addition salts when prepared by the process defined in Claim 1 or 2 or by an obvious chemical equivalent.
wherein:
X is hydrogen, loweralkyl of 1 to 5 carbon atoms or halo;
Y is hydrogen, loweralkyl of 1 to 5 carbon atoms or halo;
Z is hydrogen, loweralkyl of 1 to 5 carbon atoms or halo;
R1, R2 and R3 stand for hydrogen or loweralkyl of 1 to 5 carbon atoms;
R' stands for loweralkyl of 1 to 5 carbon atoms; and R" stands for loweralkyl of 1 to 5 carbon atoms; or R' and R" together form an alkylidene chain, and the non-toxic acid addition salts when prepared by the process defined in Claim 1 or 2 or by an obvious chemical equivalent.
5. The 1-(2,6-dichlorophenylamidino)3,3-(.alpha.,.alpha.'-dimethylpentamethylene) urea when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.
6. The 1-(2,6-dichlorophenyl-N'-methylamidino)-3,3-diethylurea, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA231,435A CA1081709A (en) | 1975-07-11 | 1975-07-11 | Phenylamidino urea compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA231,435A CA1081709A (en) | 1975-07-11 | 1975-07-11 | Phenylamidino urea compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1081709A true CA1081709A (en) | 1980-07-15 |
Family
ID=4103605
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA231,435A Expired CA1081709A (en) | 1975-07-11 | 1975-07-11 | Phenylamidino urea compounds |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1081709A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2015518855A (en) * | 2012-05-23 | 2015-07-06 | セリックスビオ プライヴェート リミテッド | Compositions and methods for the treatment of mucositis |
-
1975
- 1975-07-11 CA CA231,435A patent/CA1081709A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2015518855A (en) * | 2012-05-23 | 2015-07-06 | セリックスビオ プライヴェート リミテッド | Compositions and methods for the treatment of mucositis |
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