CA1230886A - Amidinourea process and pharmaceutical composition - Google Patents
Amidinourea process and pharmaceutical compositionInfo
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- CA1230886A CA1230886A CA000474424A CA474424A CA1230886A CA 1230886 A CA1230886 A CA 1230886A CA 000474424 A CA000474424 A CA 000474424A CA 474424 A CA474424 A CA 474424A CA 1230886 A CA1230886 A CA 1230886A
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- methylamidinourea
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Abstract
Abstract An improved process for the preparation of an amidinourea of the formula
Description
lZ30886 AMIDINOUREA PROCESS AND PHAR~CEl~TICAL COMPOSITION
Field of the Invention This invention relates to amidinoureas, improved processes for their preparation, and pharmaceutical compositions.
Reported Developments The amidinoureas prepared by the present invention have been reported to be effective anti-diarrheal agents.
In US. Patent No. 4,060,635, amidinourea compounds and a method for the treatment of diarrhea by administering these compounds are described. Methods by which these compounds have been prepared include the following general syntheses.
Condensation of a substituted phenol isocyanate prepared from an aniline and phosgene in the customary manner) with guanidine results in a l-substituted phenol-3-amidinourea as shown in Scheme I below. It it convent tent to carry cut the reaction by preparing the issues-:: :
1 . . .
....... . ...
Nate in the reaction media and then forming guanidine in situ by hydrolyzing guanidine carbonate with base. Con-sensation of the isocyanate takes place when the guano-dine forms and the amidinourea compound results.
R4 - NH2 COOK R4 _ NO
A
NH NH
~NH2 C NH2)2 H2CO3 + KOCH NH2-C-NH2 O NH
A B > R4 NH-C-NH-C-NH2 SCHEME I
The amidinoureas may also be prepared by degradation of the corresponding biguanide as shown in Scheme II below. When a l-substituted phenylbiguanide compound is hydrolyzed in acid at raised temperature, then the resultant product is l-substituted phenyl-3-amidinourea.
I , :.. . , . . . . . . . ...
~Z3~886 4~N-C-N-C-N Lowe nil R4 N-C-N-C-~
SCHEME II
: When it is desired to have Run substitution, the starting material of course will by an aniline having N-al~yl substitution. Reaction with phosgene results in the carbamoyl chloride which is then reacted with the guanidine to prepare the amidinourea as shown in Scheme III below.
R 3 R 2 Jo _/ O
/ _ NH + COOK R4 Run .,, C
NO R ' NO R ' (NH2-C-N ) 2 }KIWI + KOCH > NH2_c_N
D
' ;
... . . . . . ...
,:.... ... ... . . .
lZ30886 C + D R 4 -C -NH -C -N
SCHEME III
The reported processes for the preparation of these compounds are plagued by the presence of side products which require tedious and expensive additional purification steps.
It has been found surprisingly that a modification of the reported process results in the formation of the desired products as a crystalline precipitate which may be easily and inexpensively separated from the reaction.
It has also been reported that the amidinourea compounds may be formulated into anti-diarrheal compositions. However, it has been found that liquid compositions including the amidinourea compounds degrade over prolonged periods of time, thereby limiting their use.
Summary of the Invention This invention relates to an improved process for the preparation of a compound ox Formula I
O Nil N-c-NH-c-NR2R3 Formula I
/'--\ H
.
' , lZ30886 comprising the reaction of an isocyanate of Formula II
NO Formula II
<
Z Y
with a guanidine of Formula III
Nil ~-C-NR2R3 Formula III
said guanidine being prepared in situ by the treatment of the salt of Formula IV
Nil (H2N-C-NR2R3)2 H2S4 Formula IV
with aqueous base, wherein:
X, Y and Z are hydrogen, alkyd, alkoxy, cyan, ; acyloxy, alkenyl, alkynyl, halo, haloalkyl, haloalkoxy, amino, azalea, carbamoyl, vitro, hydroxy, arylalkoxy or alk~lsulfonyl;
Al, R2 and R3 are each independently hydrogen, alkyd, cycloalkyl or aralkyl;
or R2 and R3 together with the nitrogen atom to which they are attached form a S, 6, or 7 member Ed ring which may include 0-2 additional heteroatoms of N, O or S;
provided that at least one of Al R2 or R3 is other than hydrogen;
the improvement comprising the use of a kitten as the reaction medium, with a lower alkyd kitten being preferred.
Jo This invention also relates to a method for the preparation of a liquid pharmaceutical composition comprising a compound of Formula I.
.
.. . .. . . .
.. ,, .. . , , . , . . . .
.. .. ... . .
12:~08~36 Detailed Description of the Invention The process according to this invention comprises the use of a kitten as the reaction medium. It has been found that the use of such reaction medium results in formation of a crystalline precipitate of an amidinourea of Formula I, which can be easily separated and purified for use as a pharmaceutical product. The most desired kitten is acetone, although other lower alkyd kittens such as methyl ethyl kitten and ethyl ethyl kitten may be utilized in the reaction process.
The nomenclature applied to the compounds of this invention is as follows.
NO CON
\' (I
urea amidino The term "lo reralkyl" refers to an alkyd hydrocar-bun group of from 1 to 5 carbon atoms which may be straight chained or branched, while "alkyd" refers to an alkyd hydrocarbon group which may have as many as ten carbon atoms.
The term "cycloalkyl" refers to a cycloalkyl group - having 3-7 carbon atoms.
The "loweralkoxy" radical signifies an alkoxy group containing from 1 to about 5 carbon atoms which may be straight chained or branched.
The preferred "aureole" group is phenol.
The preferred "aralkyl" groups are bouncily and pen-ethyl.
.. . - -.
"' 1230886 The preferred "halo loweralkyl" group is trifler-methyl.
The preferred "halo loweralkoxy" group is in-fluoromethoxy.
The most preferred process is a process for the preparation of a compound of Formula V
X
o NH
-N-c-NH-c-NR2R3 Y Formula V
wherein a compound of Formula VI
NO Formula VI
,.
is added to a reaction solution prepared by mixing a compound of Formula VII
NH
(NH2-C-NR2R3)2 H2S4 Formula VII
and a neutralizing quantity of aqueous base in a kitten solvent;
wherein X and Y are hydrogen, alkyd, halo, alkoxy, haloalkyl or haloalkoxy;
and R2 and R3 are hydrogen, alkyd, cycloalkyl, aralkyl or alkoxy;
provided that at least one of R2 and R3 is ether than hydrogen.
. .
~Z~0886 The following is a detailed example which shows the process according to the present invention This is to be construed as an illustration of this process and not as a limitation thereof.
., "I
. .
... .. ,_. . .
~Z308~36 EXAMPLE
PREPARATION OF 1-(2,6-DIMETHYLPHENYL)-3-METHYL~MIDINOUREA
736 g ox 50% w/w aqueous sodium hydroxide are added to 1,123.6 g of methylguanidine sulfate suspended in 5.2 1 of acetone (reagent grade). the mixture is stirred for 3 his. To the rapidly stirred suspension there is added drops over a period of 4 hours a mixture of 1,176.0 g of 2,6-dimethylphenylisocyanate and 350 ml of acetone. During the addition a cold water bath is used to maintain the temperature at approximately 25C.
After the addition is complete the reaction mixture is stirred overnight.
The mixture is chilled to 10C in an ice bath and the solid collected by filtration. The filter cake is washed with 2 1 of cold acetone. The solid is suspended in 4 1 of water and stirred for 30 minutes.
The suspension is filtered and the solid washed on the filter with 4 1 of water. The solid is suspended in
Field of the Invention This invention relates to amidinoureas, improved processes for their preparation, and pharmaceutical compositions.
Reported Developments The amidinoureas prepared by the present invention have been reported to be effective anti-diarrheal agents.
In US. Patent No. 4,060,635, amidinourea compounds and a method for the treatment of diarrhea by administering these compounds are described. Methods by which these compounds have been prepared include the following general syntheses.
Condensation of a substituted phenol isocyanate prepared from an aniline and phosgene in the customary manner) with guanidine results in a l-substituted phenol-3-amidinourea as shown in Scheme I below. It it convent tent to carry cut the reaction by preparing the issues-:: :
1 . . .
....... . ...
Nate in the reaction media and then forming guanidine in situ by hydrolyzing guanidine carbonate with base. Con-sensation of the isocyanate takes place when the guano-dine forms and the amidinourea compound results.
R4 - NH2 COOK R4 _ NO
A
NH NH
~NH2 C NH2)2 H2CO3 + KOCH NH2-C-NH2 O NH
A B > R4 NH-C-NH-C-NH2 SCHEME I
The amidinoureas may also be prepared by degradation of the corresponding biguanide as shown in Scheme II below. When a l-substituted phenylbiguanide compound is hydrolyzed in acid at raised temperature, then the resultant product is l-substituted phenyl-3-amidinourea.
I , :.. . , . . . . . . . ...
~Z3~886 4~N-C-N-C-N Lowe nil R4 N-C-N-C-~
SCHEME II
: When it is desired to have Run substitution, the starting material of course will by an aniline having N-al~yl substitution. Reaction with phosgene results in the carbamoyl chloride which is then reacted with the guanidine to prepare the amidinourea as shown in Scheme III below.
R 3 R 2 Jo _/ O
/ _ NH + COOK R4 Run .,, C
NO R ' NO R ' (NH2-C-N ) 2 }KIWI + KOCH > NH2_c_N
D
' ;
... . . . . . ...
,:.... ... ... . . .
lZ30886 C + D R 4 -C -NH -C -N
SCHEME III
The reported processes for the preparation of these compounds are plagued by the presence of side products which require tedious and expensive additional purification steps.
It has been found surprisingly that a modification of the reported process results in the formation of the desired products as a crystalline precipitate which may be easily and inexpensively separated from the reaction.
It has also been reported that the amidinourea compounds may be formulated into anti-diarrheal compositions. However, it has been found that liquid compositions including the amidinourea compounds degrade over prolonged periods of time, thereby limiting their use.
Summary of the Invention This invention relates to an improved process for the preparation of a compound ox Formula I
O Nil N-c-NH-c-NR2R3 Formula I
/'--\ H
.
' , lZ30886 comprising the reaction of an isocyanate of Formula II
NO Formula II
<
Z Y
with a guanidine of Formula III
Nil ~-C-NR2R3 Formula III
said guanidine being prepared in situ by the treatment of the salt of Formula IV
Nil (H2N-C-NR2R3)2 H2S4 Formula IV
with aqueous base, wherein:
X, Y and Z are hydrogen, alkyd, alkoxy, cyan, ; acyloxy, alkenyl, alkynyl, halo, haloalkyl, haloalkoxy, amino, azalea, carbamoyl, vitro, hydroxy, arylalkoxy or alk~lsulfonyl;
Al, R2 and R3 are each independently hydrogen, alkyd, cycloalkyl or aralkyl;
or R2 and R3 together with the nitrogen atom to which they are attached form a S, 6, or 7 member Ed ring which may include 0-2 additional heteroatoms of N, O or S;
provided that at least one of Al R2 or R3 is other than hydrogen;
the improvement comprising the use of a kitten as the reaction medium, with a lower alkyd kitten being preferred.
Jo This invention also relates to a method for the preparation of a liquid pharmaceutical composition comprising a compound of Formula I.
.
.. . .. . . .
.. ,, .. . , , . , . . . .
.. .. ... . .
12:~08~36 Detailed Description of the Invention The process according to this invention comprises the use of a kitten as the reaction medium. It has been found that the use of such reaction medium results in formation of a crystalline precipitate of an amidinourea of Formula I, which can be easily separated and purified for use as a pharmaceutical product. The most desired kitten is acetone, although other lower alkyd kittens such as methyl ethyl kitten and ethyl ethyl kitten may be utilized in the reaction process.
The nomenclature applied to the compounds of this invention is as follows.
NO CON
\' (I
urea amidino The term "lo reralkyl" refers to an alkyd hydrocar-bun group of from 1 to 5 carbon atoms which may be straight chained or branched, while "alkyd" refers to an alkyd hydrocarbon group which may have as many as ten carbon atoms.
The term "cycloalkyl" refers to a cycloalkyl group - having 3-7 carbon atoms.
The "loweralkoxy" radical signifies an alkoxy group containing from 1 to about 5 carbon atoms which may be straight chained or branched.
The preferred "aureole" group is phenol.
The preferred "aralkyl" groups are bouncily and pen-ethyl.
.. . - -.
"' 1230886 The preferred "halo loweralkyl" group is trifler-methyl.
The preferred "halo loweralkoxy" group is in-fluoromethoxy.
The most preferred process is a process for the preparation of a compound of Formula V
X
o NH
-N-c-NH-c-NR2R3 Y Formula V
wherein a compound of Formula VI
NO Formula VI
,.
is added to a reaction solution prepared by mixing a compound of Formula VII
NH
(NH2-C-NR2R3)2 H2S4 Formula VII
and a neutralizing quantity of aqueous base in a kitten solvent;
wherein X and Y are hydrogen, alkyd, halo, alkoxy, haloalkyl or haloalkoxy;
and R2 and R3 are hydrogen, alkyd, cycloalkyl, aralkyl or alkoxy;
provided that at least one of R2 and R3 is ether than hydrogen.
. .
~Z~0886 The following is a detailed example which shows the process according to the present invention This is to be construed as an illustration of this process and not as a limitation thereof.
., "I
. .
... .. ,_. . .
~Z308~36 EXAMPLE
PREPARATION OF 1-(2,6-DIMETHYLPHENYL)-3-METHYL~MIDINOUREA
736 g ox 50% w/w aqueous sodium hydroxide are added to 1,123.6 g of methylguanidine sulfate suspended in 5.2 1 of acetone (reagent grade). the mixture is stirred for 3 his. To the rapidly stirred suspension there is added drops over a period of 4 hours a mixture of 1,176.0 g of 2,6-dimethylphenylisocyanate and 350 ml of acetone. During the addition a cold water bath is used to maintain the temperature at approximately 25C.
After the addition is complete the reaction mixture is stirred overnight.
The mixture is chilled to 10C in an ice bath and the solid collected by filtration. The filter cake is washed with 2 1 of cold acetone. The solid is suspended in 4 1 of water and stirred for 30 minutes.
The suspension is filtered and the solid washed on the filter with 4 1 of water. The solid is suspended in
2.5 1 of water at 60C. 670 ml of concentrated hydrochloric acid are added to the suspension while stirring. after dissolution is complete 360 g of sodium chloride ~USP--crystal) is added in portions. Using a water bath the mixture is cooled to 18C over a period of 1 hr. The suspension is filtered and the solid washed with 1 1 of a cold I solution of sodium chloride in 0.36 molar hydrochloric acid. The material is partially dried on the filter.
An Alcott ~100 9) of the filter cake is removed to prepare a final wash solution. This Alcott is dissolved in 800 ml of water, the solution is filtered j and diluted to 1 1. The solution is stored at 5~C until the bulk of the material is processed as follows:
i ,, . . . . .. . .. ...
. . .
10 1z30886 The remainder of the filter cake is dissolved in 2.5 1 of water (60C) and the solution is filtered. 250 ml of concentrated hydrochloric acid are added to the stirred filtrate at 35C which induces crystallization.
218 g of sodium chloride (USP--crystal) are added to the stirred suspension in portions. The mixture is stirred for 1 hr. while a cold water bath is used to reduce the temperature to 18C. The suspension is filtered and the solid washed with 2 1 of a cold 4% solution of sodium chloride in 0.36 molar hydrochloric acid and then with the 1 1 of cold wash solution prepared above. The solid is left on the filter until no additional filtrate can be collected. The filter cake is spread on a tray and dried at 50C in a mechanical convection oven for 24 his. This yields 1480.3 g of 1-(2,6-dimethylphenyl)-3-methyl amid-Norway hydrochloride, MOP. 200-203C.
The dried product is examined by TLC (1:1, SCHICK:
EtOCHO, Silica). The presence of mobile materials ~Rf>0.1) requires that the product be washed with methyl tone chloride as follows:
1-~2,6-dimethylphenyl)-3-methylamidinourea hydra-chloride ~1,267 g, greater than 0.1% N,N"-bis Dow-methylphenylcarbamoyl)-N'-methylguanidine hydrochlclride) is suspended in 2,534 ml of ethylene chloride at RUT and stirred for 2 his. The suspension is filtered and the filter cake is washed with 2 1 of ethylene chloride.
The solid is air dried to obtain 1,194 g ~94.2%) of 1-~2,6-dimethylphenyl)-3-methylamidinourea hydrochloride, MOP. 200-203C. TLC ~1:1, CHC13:EtOCHO, Silica) shows no mobile materials. The product obtained by this procedure can be precipitated further from aqueous hydrochloric acid - sodium chloride if desired.
: - - .
., ~Z30886 When 2,6-dimethylphenyl isocyanate is replaced by one of the isocyanates of Table I below, then the core-sponging product of Table II is prepared when reacted with methylguanidine.
TABLE I
2-methyl-6-chlorophenylisocyanate 2-methyl-6-fluorophenylisocyanate 2-methyl-6-bromophenylisocyanate 2-methyl-6-iodophenylisocyanate 2-methyl-6-methoxyphenylisocyanate 2-methyl-6-ethoxyphenylisocyanate 2-methyl-6-ethylphenylisocyanate 2-methyl-6-propylphenylisocyanate 2-methyl-6-i-propylphenylisocyanate 2-methyl-6-butylphenylisocyanate 2-methyl-6-cyanophenylisocyanate 2-methyl-6-trifluoromethylphenylisocyanate 2-methyl-6-nitrophenylisocyanate 2-methyl-6-methylsulfonylphenylisocyanate 2-ethyl-6-chlorophenylisocyanate 2-ethyl-6-fluorophenylisocyanate 2-ethyl-6-bromophenylisocyanate 2-ethyl-6-methoxyphenylisocyanate 2-ethyl-6-ethoxyphenylisocyanate 2,6-dlethylphenylisocyanate 2-ethyl-6 propylphenylisocyanate 2-ethyl-6-trifluoromethylphenylisocyanate 2-propyl-6-chlorophenylisocyanate 2-propyl-6-fluorophenylisocyanate 2-propyl-6-bromophenylisocyanate ... ...
- ` I, ' ` ` ' :
~Z3088~
2-propyl-6-methoxyphenylisocyanate 2-propyl-6-ethoxyphenylisocyanate 2,6-dipropylphenylisocyanate 2-i-propyl-6-chlorophenylisocyanate 2-i-propyl-6-fluorophenylisocyanate 2-i-propyl-6-methoxyphenylisocyanate 2-butyl-6-chlorophenylisocyanate 2,6-dichlorophenylisocyanate 2-chloro-6-fluorophenylisocyanate 2,6-di~luorophenylisocyanate 2,4,6-trimethylphenylisocyanate 2,4-dimethyl-6-ethylphenylisocyanate 2,4-dimethyl-6-chlorophenylisocyanate 2,4-dimethyl-6-bromophenylisocyanate 2,4-dimethyl-6-fluorophenylisocyanate 2,4-dimethyl-6-trifluorophenylisocyanate 2,4-dimethyl-6-nitrophenylisocyanate 2,4-dimethyl-6-methoxyphenylisocyanate 2,6-dimethyl-4-ethylphenylisocyanate 2,6-dimethyl-4-chlorophenylisocyanate 2,6-dimethyl-4-bromophenylisocyanate 2,6-dimethyl-4-fluorophenylisocyanate 2,6-dimethyl-4-methoxyphenylisocyanate 2-methyl-4,6-dichlorophenylisocyanate 2-methyl-4,6-difluorophenylisocyanate.
2-methyl-4-fluoro-6-bromophenylisocyanate 2-methyl-4-fluoro-6-chlorophenylisocyanate 2-methyl-4-bromo-6-chlorophenylisocyanate 2-methyl-4-chloro-6-fluorophenylisocyanate 2-methyl-4-chloro-6-bromophenylisocyanate 2-methyl-4-methoxy-6-chlorophenylisocyanate 2-methyl-4-ethyl-6-chlorophenylisocyanate 2-methyl-4-chloro-6-trifluoromethylphenylisocyanatlo .
lZ30886 2-methyl-4-trifluormethyl-6-chlorophenylisocyanatee 2-ethyl-4,6-dichlorophenylisocyanate 2-ethyl-4,6-difluorophenylisocyanate 2-ethyl-4-fluoro-6-bromophenylisocyanate .
2-ethyl-4-fluoro-6-chlorophenylisocyanate 2-ethyl-4-bromo-6-chlorophenylisocyanate 2-ethyl-4-chlo~o-6-fluorophenylisocyanate 2-ethyl-4-chloro-6-bromophenylisocyanate 2,6-diethyl-4-chlorophenylisocyanate 2,6-diethyl-4-bromophenylisocyanate 2,6-diethyl-4-fluorophenylisocyanate 2,4-dimethyl-6-nitrophenylisocyanate TABLE II
l-t2-methyl-6-chlorophenyl)-3-methylamidinourea 1-~2-methyl-6-fluorophenyl)-3-methylamidinourea 1-~2-methyl-6-bromophenyl)-3-methylamidinourea 1-~2-methyl-6-iodophenyl)-3-methylamidinourea 2-methyl-6-methoxyphenyl)-3-methylamidinourea -methyl-6-ethoxyphenyl)-3-methylamidinourea l-t2-methyl-6-ethylphenyl)-3-methylamidinourea 1-~2-methyl-6-propylphenyl)-3-methylamidinourea 1-~2-methyl-6-i-propylphenyl)-3-methylamidinourea 1-~2-methyl-6-butylphenyl)-3-methylamidin~urea 1-(2-methyl-6-cyanophenyl)-3-methylamidinourea 2-methyl-6-trifluoromethylphenyl)-3-methylamidin~uurea 1-~2-methyl-6-nitrophenyl)-3-methylamidinourea 2-methyl-6-methylsulfonylphenyl)-3-methylamidinourfee 1-~2-ethyl-6-chlorophenyl)-3-methylamidinourea 1-(2-ethyl-6-fluorophenyl)-3-methylamidinourea , .
.... . .. .. .. . . - -. ....... . .
~230886 1-(2-ethyl-6-bromophenyl~-3-methylamidinourea 1-(2-ethyl-6-methoxyphenyl)-3-methylamidinourea 1-(2-ethyl-6-ethoxyphenyl)-3-methylamidinourea 1-~2,6-diethylphenyl)-3-methylamidinourea 1-~2-ethyl-6-propylphenyl)-3-methylamidinourea l-t2-ethyl-6-trifluoromethylphenyl)-3-methylamidinNorway 1-(2-propyl-6-chlorophenyl)-3-methylamidinourea 1-(2-propyl-6-fluorophenyl)-3-methylamidinourea 1-(2-propyl-6-bromophenyl)-3-methylamidinourea 1-~2-propyl-6-methoxyphenyl)-3-methylamidinourea 1-(2-propyl-6-ethoxyphenyl)-3-methylamidinourea 1-(2,6-dipropylphenyl)-3-methylamid.inourea 1-(2-i-propyl-6-chlorophenyl)-3-methylamidinourea 1-(2-i-propyl-6-fluorophenyl)-3-methylamidinourea 1-(2-i-propyl-6-methoxyphenyl)-3-methylamidinoureaa 1-(2-butyl-6-chlorophenyl)-3-methylamidinourea 1-(2,6-dichlorophenyl)-3-methylamidinourea 1-(2-chloro-6-fluorophenyl)-3-methylamidinourea 1-(2,6-difluorophenyl)-3-methylamidinourea 1-~2,4,6-trimethylphenyl)-3-methylamidinourea 1-(2,4-dimethyl-6-ethylphenyl)-3-methylamidinoureaa 1-(2,4-dimethyl-6-chlorophenyl~-3-methylamidinoureeta 1-(2,4-dimethyl-6-bromophenyl)-3-methylamidinoureaa 1-(2,4-dimethyl-6-fluorophenyl)-3-methylamidinoureeta 1-(2,4-dimethyl-6-trifluorophenyl)-3-methylamidinourea 1-(2,4-dimethyl-6-nitrophenyl)-3-methylamidinoureaa 1-(2,4-dimethyl-6-methoxyphenyl)-3-methylamidinourfee 1-(2,6-dimethyl-4-ethylphenyl)-3-methylamidinoureaa 1-(2,6-dimethyl-4-chlorophenyl)-3-methylamidinoureeta 1-(2,6-dimethyl-4-bromophenyl)-3-methylamidinoureaa 1-(2,6-dimethyl-4-fluorophenyl)-3~methylamidinoureeta 1-~2,6-dimethyl-4-methoxyphenyl)-3-methylamidinourfee 1-~2-methyl-4,6-dichlorophenyl)-3-methylamidinoureeta .
.
.
.. . . .
Jo . ... , .... . . .
~230886 1-(2-methyl-4,6-difluorophenyl)-3-methylamidinoureeta 1-(2-methyl-4-fluoro-6-bromophenyl)-3-methylamidinNorway 1-(2-methyl-4-fluoro-6-chlorophenyl)-3-methylamidiinure 1-(2-methyl-4-bromo-6-chlorophenyl)-3-methylamidinNorway 1-(2-methyl-4-chloro-6-fluorophenyl)-3-methylamidiinure l-(2-methyl-4-chloro-6-bromophenyl)-3-methylamidinNorway l-(2-methyl-4-methoxy-6-chlorophenyl)-3-methylamiddowner 1-~2-methyl-4-ethyl-6-chlorophenyl)-3-methylamidinNorway 1-~2-methyl-4-chloro-6-trifluoromethylphenyl)-3-meethyl-amidinourea 1-~2-methyl-4-trifluoromethyl-6-chlorophenyl)-3-meethyl-amidinourea 1-~2-ethyl-4,6-dichlorophenyl)-3-methylamidinoureaa 1-(2-ethyl-4,6-difluorophenyl)-3-methylamidinoureaa 1-(2-ethyl-4-fluoro-6-bromophenyl)-3-methylamidinourea l-(2-ethyl-4-fluoro-6-chlorophenyl)-3-methylamidinNorway 1-(2-ethyl-4-bromo-6-chlorophenyl)-3-methylamidinourea 1-~2-ethyl-4-chloro-6-fluorophenyl)-3-methylamidinNorway 1-(2-ethyl-4-chloro-6-bromophenyl)-3-methylamidinourea l-~2,6-diethyl-4-chlorophenyl)-3-methylamidinoureaa l-~2,6-diethyl-4-bromophenyl)-3-methylamidinourea 1-(2,6-diethyl-4-fluorophenyl)-3-methylamidinoureaa l-t2,4-dimethyl-6-nitrophenyl)-3-methylamidinoureaa The isocyanates of Table I may be prepared as described above from the corresponding aniline which are either known, or may be prepared by known techniques.
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 bromide is then added while the temperature it held near 0C. Iodination may also be carried out by known methods using iodine monochloride clue I).
O' I ' ' ' ' I.
. .
.. ..... Jo --to ~Z30886 Alkylation may be carried out on an acetanilide using an alkyd halide and aluminum chloride under Friedel-Crafts conditions to obtain desired alkyd substitution.
Nitration may be carried out using fuming nitric acid at about 0C.
A vitro compound may be hydrogenated to the corresponding amine which may then be diazotized and heated in an alcohol medium to form the alkoxy compound.
n amino compound may also be diazotized to the diazonium fluoroborate which is then thermally decomposed to the flyer compound.
Diazotization followed by a Sand Meyer type reaction may yield the broom, sheller or idea compound.
When an amino compound is diazotized followed by reaction with potassium ethylxanthate and then hydrolyzed, the Marquette compound results. This in turn may be alkylated to the alkylthio group which is then oxidized to the corresponding alkylsulfonyl substituent.
A sheller, broom or idea compound may also be reacted with trifluoromethyliodide and copper powder at about 150C in ~imethylformamide to obtain a trifluoromethyl compound [Tetrahedron Letters: 47,4095 ~1959)]. A halo compound may also be reacted with cuprous methanesulfinate in quinoline at about 150C to obtain a methylsulfonyl compound.
When it it desired that the final product contain a hydroxy group, it is preferred that the starting aniline contain the corresponding acyloxy or aralkyloxy groups. These may be prepared in the usual fashion by assaulting the starting hydroxy aniline compound with an azalea halide or android in the presence of a tertiary amine or aralkylating with an aralkyl halide or sulfate.
Of course the amine function would be protected in the ;:
, .
. .
lZ30886 customary manner. Hydrogenation to the desired hydroxy compound may then take place after the formation of the amidinourea. This may be accomplished with a metal catalyst (Pd/C, Pi etc.) in a polar medium (ethanol, THY, etc.), sodium in liquid ammonia, etc. Thus, for example, the 3,4-dihydroxy amidinourea compound may be prepared from the corresponding 3,4-dibenzyloxyaniline. The hydroxy compounds may also be prepared by hydrolysis of the azalea or alkoxy compounds with acid.
Reactions may also be carried out at other stages of synthesis depending on the substituents present and the substituents desired, and various combinations of the foregoing reactions will be determined by one skilled in the art in order that the desired product results. Thus, a phenylamidinourea may be halogenated or nitrated as above, etc.
The compounds of Formula I are useful anti-diarrheal agents. Various tests can be carried out in animal models to show the ability of the compounds of Formula I to exhibit reactions that can be correlated with anti-diarrheal activity in humans. The following tests show the ability of the compounds of this invention to inhibit diarrhea in animals and are known to correlate well with anti-diarrheal activity in humans. These are considered to be standard tests used to determine anti-diarrhea properties. This correlation can be shown by the activities of compounds known to be clinically active. In view of the results of these tests, the amidinoureas of this invention can be considered to be anti-diarrheal agents.
1. Focal output in rat.
Rev: - Bass, P., Kennedy, JOY. and Witty, JON.:
Measurement of local output in rats. Am. J. Dig. Disk 10: 925-928, 1972.
:
. .
: ' .
... . . , .. . .
,. . . - - , 2. Castor oil test in mice.
Rev: - Niemegeers, CUE Lenaerts, EM and Janssen, PUDGY. Difenoxine, a potent, orally active and safe anti-diarrheal agent in rats. Arzneim-Forscth (Drug Ryes.) 22, 516-1518, 1972.
The compounds of Formula I may be administered orally, parenterally or rectally. Administration by the oral route is preferred. Orally, these compounds may be administered in tablets, hard or soft capsules, aqueous or oily suspensions, dispersible powders or granules, emulsions, syrups or elixirs. The optimum dosage, of course, will depend on the particular compound being used and the type and severity of the condition being treated.
In any specific case the appropriate dosage selected will further depend on factors of the patient which may influence response to the drug; for example, general health, age, weight, etc. of the subject being treated.
Although the optimum quantities of the compounds of this invention to be used as anti-diarrheal agents will depend on the compound employed and the particular type of disease condition treated, oral dose levels of preferred compounds when administered to a mammal in dosages of 0.01 to 500 milligrams per kilogram of body weight per day are particularly useful. The preferred range is 0.05 to 200 mg/kg. Comparative dosages may be used in parenteral or rectal administration.
The composition may contain such selected excipients as inert delineates such as calcium carbonate, lactose, etc.;granulating and disintegrating agents such as maize starch, alginic acid, etc.; lubricating agents such as magnesium Stewart, etc.; binding agents such as starch gelatin, etc.; suspending agents such as methyl cellulose, vegetable oil, etc.; dispersing agents such as lecithin, etc.; thickening agents such as beeswax, hard ..... . Jo . . ........ .
, . .. ... . . . .
.. I_ Jo .... I.. _ .. _.. _ ._ . .... _._._ __ _ .. _ _ _ Jo .. _~__._.. ,____.__ _ _ _. __ _.. _ . . _ . ._ _, ~___~_ _ .. _ .. ...
_ lZ3088~
Jo paraffin, etc.; emulsifying agents such as naturally-occurring gums, etch; non-irritating excipients such as cocoa butter, polyethylene glycols, etc.; and the like. Further, in formulating these compounds for every 100 parts by weight of the composition, there may be present between 5 and 95 parts by weight of the active ingredient. The dosage unit form will generally contain between 0.1 my and about 500 my of the active ingredients of this invention. The preferred unit dose is between 1 my and about 50 my. The compositions may be taken 1-8 times daily depending on the dosage unit required.
Further the active amidinourea may be administered alone or in admixture with other agents having the same or different pharmacological properties.
The debilitating effects of diarrhea result partially from electrolyte imbalance in the patient, so that it is recommended that a solvent or delineate forming the carrier of the liquid pharmaceutical compositions, whether designed for injection or oral administration, should incorporate electrolyte balance. The precise composition of the electrolyte replenisher incorporated in the liquid compositions will depend on the age and the genera health and condition of the patient, but in many cases it is appropriate to use a commercially available electrolyte replenisher. These generally include sodium chloride alone or in combination with potassium salts, calcium salts, lactates or bicarbonates, and typical examples are Ringer's Solution, Doris Solution for injection), Ringer's Injection and Lactated Ringers Injection. These and other examples of commercially available electrolyte replenishers may be found in the "Pharmacopoeia of the United States.
A particularly preferred liquid anti-diarrheal composition is one in which the couriers a solvent or ... . .. I. . , ~230886 delineate comprising a saline solution of substantially isotonic concentration.
Liquid compositions for oral use are preferably aqueous, so as to permit the inclusion of an electrolyte.
Ingredients suitable for incorporation in the carrier of an aqueous liquid suspension are for example suspending agents such as sodium carboxymethylcellulose, methylcelluiose, hydroxypropylmethylcellulose, sodium allegiant, polyv;nylpyrrolidine, gum tragacanth and gum r Acadia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, condensation products of an alkaline oxide with fatty acids, for example polyoxyethylene Stewart, condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxyethanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example polyoxyethylene sorbitol moonlit or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol androids, for example polyoxyethylene sorbitan moonlit. Aqueous suspensions may also in particular contain one or more preservatives, for example ethyl- or n-propyl-p-hydroxy-bonniest, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose.
Oily suspensions may be formulated by suspending the amidinourea in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or Seattle alcohol. Sweetening agents, such as those set forth above, and flavourinq agents may here also be added to provide a palatable oral .
... . . . ... .
- 12:~0886 preparation. These compositions may also be preserved by the addition of an anti-oxidant such as ascorbic acid.
Where the liquid compositions are in the form of oil-in-water emulsions, the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these.
The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs in particular may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
The liquid compositions, as herei~before described, may be formulated for injection. For example they may take the form of a sterile injectable aqueous suspension formulated according to the known art and containing those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
An injectable composition is preferably a sterile ; injectable solution or suspension of the amidinourea in a parenterally acceptable delineate or solvent, for example a sterile aqueous solution buffered to a pi of 4.0 to 7.0 and made isotonic with sodium chloride.
It has been found that the liquid compositions including an anti-diarrheal composition of Formula I
degrade over a period of time. Accordingly, the present invention relates to a method of providing a stable dosage form for preparation into a liquid form :
::
~3088 immediately prior to its use. More particularly the present invention is a method for the preparation of a liquid pharmaceutical composition suitable for oral administration or parenteral injection, said composition comprising a pharmaceutically acceptable liquid vehicle and from 1 to 25 my of a compound of the Formula I
.
X
Jo 0, I
N-C-NH-C-NR2R3 Formula I
H
z y wherein X, Y and Z are hydrogen, alkyd, alkoxy, cyan, acyloxy, alkenyl, alkynyl, halo, haloalkyl, haloalkoxy, amino, azalea, carbamoyl, vitro, hydroxy, arylalkoxy or alkylsulfonyl;
Al, R2 and R3 are each independently hydrogen, alkyd, cycloalkyl or aralkyl;
or R2 and R3 together with the nitrogen atoms to which they are attached form a 5, 6, or 7 member Ed ring which may include 0-2 additional heteroatoms of N, O or S;
provided that at least one of Al, R2 or R3 is other than hydrogen;
which method comprises combining the compound of Formula I with the vehicle by the steps of:
a) dissolving an effective anti-diarrheal dosage amount of a salt of said compound in a liquid vehicle comprising either sterile water or a sterile electrolyte replenisher solution;
by sterilizing the solution by means of micro filtration;
, .
, .
` ~230886 (c) freeze-drying the sterilized solution to form a dissected composition; and (d) preparing the liquid composition for administration by dissolving the dissected composition in a dosage volume of liquid vehicle comprising either sterile water or a sterile electrolyte replenisher solution;
the said dosage amount and volume being for either single or multiple doses, and in the latter case a preservative being added in step (a) or step (d).
The following formulations are given in illustration of the compositions prepared from the `
compounds of Formula I.
Formulation 1.
An aqueous solution for parenteral administration is prepared as follows:
50 g of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride and 5 g of propel p-hydroxybenzoate are dissolved and diluted to 5,000 cm3 with twice-distilled water after the addition of modified Sorensen buffer soul-lion in an amount sufficient to adjust the pi value to a pi of 6Ø Sodium chloride is dissolved therein in an amount sufficient to render the resulting solution is-tonic. The resulting solution is passed through a beater-illogical filter, the filtrate distributed to 1000 stern tie ampules, the contents of each ampule is freeze-dried and sealed for later use. Reconstitution with 5 cm3 of sterile water results in a parenterally applicable solution which contains 50 my of 1-(2,6-dimethylphenyl)-
An Alcott ~100 9) of the filter cake is removed to prepare a final wash solution. This Alcott is dissolved in 800 ml of water, the solution is filtered j and diluted to 1 1. The solution is stored at 5~C until the bulk of the material is processed as follows:
i ,, . . . . .. . .. ...
. . .
10 1z30886 The remainder of the filter cake is dissolved in 2.5 1 of water (60C) and the solution is filtered. 250 ml of concentrated hydrochloric acid are added to the stirred filtrate at 35C which induces crystallization.
218 g of sodium chloride (USP--crystal) are added to the stirred suspension in portions. The mixture is stirred for 1 hr. while a cold water bath is used to reduce the temperature to 18C. The suspension is filtered and the solid washed with 2 1 of a cold 4% solution of sodium chloride in 0.36 molar hydrochloric acid and then with the 1 1 of cold wash solution prepared above. The solid is left on the filter until no additional filtrate can be collected. The filter cake is spread on a tray and dried at 50C in a mechanical convection oven for 24 his. This yields 1480.3 g of 1-(2,6-dimethylphenyl)-3-methyl amid-Norway hydrochloride, MOP. 200-203C.
The dried product is examined by TLC (1:1, SCHICK:
EtOCHO, Silica). The presence of mobile materials ~Rf>0.1) requires that the product be washed with methyl tone chloride as follows:
1-~2,6-dimethylphenyl)-3-methylamidinourea hydra-chloride ~1,267 g, greater than 0.1% N,N"-bis Dow-methylphenylcarbamoyl)-N'-methylguanidine hydrochlclride) is suspended in 2,534 ml of ethylene chloride at RUT and stirred for 2 his. The suspension is filtered and the filter cake is washed with 2 1 of ethylene chloride.
The solid is air dried to obtain 1,194 g ~94.2%) of 1-~2,6-dimethylphenyl)-3-methylamidinourea hydrochloride, MOP. 200-203C. TLC ~1:1, CHC13:EtOCHO, Silica) shows no mobile materials. The product obtained by this procedure can be precipitated further from aqueous hydrochloric acid - sodium chloride if desired.
: - - .
., ~Z30886 When 2,6-dimethylphenyl isocyanate is replaced by one of the isocyanates of Table I below, then the core-sponging product of Table II is prepared when reacted with methylguanidine.
TABLE I
2-methyl-6-chlorophenylisocyanate 2-methyl-6-fluorophenylisocyanate 2-methyl-6-bromophenylisocyanate 2-methyl-6-iodophenylisocyanate 2-methyl-6-methoxyphenylisocyanate 2-methyl-6-ethoxyphenylisocyanate 2-methyl-6-ethylphenylisocyanate 2-methyl-6-propylphenylisocyanate 2-methyl-6-i-propylphenylisocyanate 2-methyl-6-butylphenylisocyanate 2-methyl-6-cyanophenylisocyanate 2-methyl-6-trifluoromethylphenylisocyanate 2-methyl-6-nitrophenylisocyanate 2-methyl-6-methylsulfonylphenylisocyanate 2-ethyl-6-chlorophenylisocyanate 2-ethyl-6-fluorophenylisocyanate 2-ethyl-6-bromophenylisocyanate 2-ethyl-6-methoxyphenylisocyanate 2-ethyl-6-ethoxyphenylisocyanate 2,6-dlethylphenylisocyanate 2-ethyl-6 propylphenylisocyanate 2-ethyl-6-trifluoromethylphenylisocyanate 2-propyl-6-chlorophenylisocyanate 2-propyl-6-fluorophenylisocyanate 2-propyl-6-bromophenylisocyanate ... ...
- ` I, ' ` ` ' :
~Z3088~
2-propyl-6-methoxyphenylisocyanate 2-propyl-6-ethoxyphenylisocyanate 2,6-dipropylphenylisocyanate 2-i-propyl-6-chlorophenylisocyanate 2-i-propyl-6-fluorophenylisocyanate 2-i-propyl-6-methoxyphenylisocyanate 2-butyl-6-chlorophenylisocyanate 2,6-dichlorophenylisocyanate 2-chloro-6-fluorophenylisocyanate 2,6-di~luorophenylisocyanate 2,4,6-trimethylphenylisocyanate 2,4-dimethyl-6-ethylphenylisocyanate 2,4-dimethyl-6-chlorophenylisocyanate 2,4-dimethyl-6-bromophenylisocyanate 2,4-dimethyl-6-fluorophenylisocyanate 2,4-dimethyl-6-trifluorophenylisocyanate 2,4-dimethyl-6-nitrophenylisocyanate 2,4-dimethyl-6-methoxyphenylisocyanate 2,6-dimethyl-4-ethylphenylisocyanate 2,6-dimethyl-4-chlorophenylisocyanate 2,6-dimethyl-4-bromophenylisocyanate 2,6-dimethyl-4-fluorophenylisocyanate 2,6-dimethyl-4-methoxyphenylisocyanate 2-methyl-4,6-dichlorophenylisocyanate 2-methyl-4,6-difluorophenylisocyanate.
2-methyl-4-fluoro-6-bromophenylisocyanate 2-methyl-4-fluoro-6-chlorophenylisocyanate 2-methyl-4-bromo-6-chlorophenylisocyanate 2-methyl-4-chloro-6-fluorophenylisocyanate 2-methyl-4-chloro-6-bromophenylisocyanate 2-methyl-4-methoxy-6-chlorophenylisocyanate 2-methyl-4-ethyl-6-chlorophenylisocyanate 2-methyl-4-chloro-6-trifluoromethylphenylisocyanatlo .
lZ30886 2-methyl-4-trifluormethyl-6-chlorophenylisocyanatee 2-ethyl-4,6-dichlorophenylisocyanate 2-ethyl-4,6-difluorophenylisocyanate 2-ethyl-4-fluoro-6-bromophenylisocyanate .
2-ethyl-4-fluoro-6-chlorophenylisocyanate 2-ethyl-4-bromo-6-chlorophenylisocyanate 2-ethyl-4-chlo~o-6-fluorophenylisocyanate 2-ethyl-4-chloro-6-bromophenylisocyanate 2,6-diethyl-4-chlorophenylisocyanate 2,6-diethyl-4-bromophenylisocyanate 2,6-diethyl-4-fluorophenylisocyanate 2,4-dimethyl-6-nitrophenylisocyanate TABLE II
l-t2-methyl-6-chlorophenyl)-3-methylamidinourea 1-~2-methyl-6-fluorophenyl)-3-methylamidinourea 1-~2-methyl-6-bromophenyl)-3-methylamidinourea 1-~2-methyl-6-iodophenyl)-3-methylamidinourea 2-methyl-6-methoxyphenyl)-3-methylamidinourea -methyl-6-ethoxyphenyl)-3-methylamidinourea l-t2-methyl-6-ethylphenyl)-3-methylamidinourea 1-~2-methyl-6-propylphenyl)-3-methylamidinourea 1-~2-methyl-6-i-propylphenyl)-3-methylamidinourea 1-~2-methyl-6-butylphenyl)-3-methylamidin~urea 1-(2-methyl-6-cyanophenyl)-3-methylamidinourea 2-methyl-6-trifluoromethylphenyl)-3-methylamidin~uurea 1-~2-methyl-6-nitrophenyl)-3-methylamidinourea 2-methyl-6-methylsulfonylphenyl)-3-methylamidinourfee 1-~2-ethyl-6-chlorophenyl)-3-methylamidinourea 1-(2-ethyl-6-fluorophenyl)-3-methylamidinourea , .
.... . .. .. .. . . - -. ....... . .
~230886 1-(2-ethyl-6-bromophenyl~-3-methylamidinourea 1-(2-ethyl-6-methoxyphenyl)-3-methylamidinourea 1-(2-ethyl-6-ethoxyphenyl)-3-methylamidinourea 1-~2,6-diethylphenyl)-3-methylamidinourea 1-~2-ethyl-6-propylphenyl)-3-methylamidinourea l-t2-ethyl-6-trifluoromethylphenyl)-3-methylamidinNorway 1-(2-propyl-6-chlorophenyl)-3-methylamidinourea 1-(2-propyl-6-fluorophenyl)-3-methylamidinourea 1-(2-propyl-6-bromophenyl)-3-methylamidinourea 1-~2-propyl-6-methoxyphenyl)-3-methylamidinourea 1-(2-propyl-6-ethoxyphenyl)-3-methylamidinourea 1-(2,6-dipropylphenyl)-3-methylamid.inourea 1-(2-i-propyl-6-chlorophenyl)-3-methylamidinourea 1-(2-i-propyl-6-fluorophenyl)-3-methylamidinourea 1-(2-i-propyl-6-methoxyphenyl)-3-methylamidinoureaa 1-(2-butyl-6-chlorophenyl)-3-methylamidinourea 1-(2,6-dichlorophenyl)-3-methylamidinourea 1-(2-chloro-6-fluorophenyl)-3-methylamidinourea 1-(2,6-difluorophenyl)-3-methylamidinourea 1-~2,4,6-trimethylphenyl)-3-methylamidinourea 1-(2,4-dimethyl-6-ethylphenyl)-3-methylamidinoureaa 1-(2,4-dimethyl-6-chlorophenyl~-3-methylamidinoureeta 1-(2,4-dimethyl-6-bromophenyl)-3-methylamidinoureaa 1-(2,4-dimethyl-6-fluorophenyl)-3-methylamidinoureeta 1-(2,4-dimethyl-6-trifluorophenyl)-3-methylamidinourea 1-(2,4-dimethyl-6-nitrophenyl)-3-methylamidinoureaa 1-(2,4-dimethyl-6-methoxyphenyl)-3-methylamidinourfee 1-(2,6-dimethyl-4-ethylphenyl)-3-methylamidinoureaa 1-(2,6-dimethyl-4-chlorophenyl)-3-methylamidinoureeta 1-(2,6-dimethyl-4-bromophenyl)-3-methylamidinoureaa 1-(2,6-dimethyl-4-fluorophenyl)-3~methylamidinoureeta 1-~2,6-dimethyl-4-methoxyphenyl)-3-methylamidinourfee 1-~2-methyl-4,6-dichlorophenyl)-3-methylamidinoureeta .
.
.
.. . . .
Jo . ... , .... . . .
~230886 1-(2-methyl-4,6-difluorophenyl)-3-methylamidinoureeta 1-(2-methyl-4-fluoro-6-bromophenyl)-3-methylamidinNorway 1-(2-methyl-4-fluoro-6-chlorophenyl)-3-methylamidiinure 1-(2-methyl-4-bromo-6-chlorophenyl)-3-methylamidinNorway 1-(2-methyl-4-chloro-6-fluorophenyl)-3-methylamidiinure l-(2-methyl-4-chloro-6-bromophenyl)-3-methylamidinNorway l-(2-methyl-4-methoxy-6-chlorophenyl)-3-methylamiddowner 1-~2-methyl-4-ethyl-6-chlorophenyl)-3-methylamidinNorway 1-~2-methyl-4-chloro-6-trifluoromethylphenyl)-3-meethyl-amidinourea 1-~2-methyl-4-trifluoromethyl-6-chlorophenyl)-3-meethyl-amidinourea 1-~2-ethyl-4,6-dichlorophenyl)-3-methylamidinoureaa 1-(2-ethyl-4,6-difluorophenyl)-3-methylamidinoureaa 1-(2-ethyl-4-fluoro-6-bromophenyl)-3-methylamidinourea l-(2-ethyl-4-fluoro-6-chlorophenyl)-3-methylamidinNorway 1-(2-ethyl-4-bromo-6-chlorophenyl)-3-methylamidinourea 1-~2-ethyl-4-chloro-6-fluorophenyl)-3-methylamidinNorway 1-(2-ethyl-4-chloro-6-bromophenyl)-3-methylamidinourea l-~2,6-diethyl-4-chlorophenyl)-3-methylamidinoureaa l-~2,6-diethyl-4-bromophenyl)-3-methylamidinourea 1-(2,6-diethyl-4-fluorophenyl)-3-methylamidinoureaa l-t2,4-dimethyl-6-nitrophenyl)-3-methylamidinoureaa The isocyanates of Table I may be prepared as described above from the corresponding aniline which are either known, or may be prepared by known techniques.
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 bromide is then added while the temperature it held near 0C. Iodination may also be carried out by known methods using iodine monochloride clue I).
O' I ' ' ' ' I.
. .
.. ..... Jo --to ~Z30886 Alkylation may be carried out on an acetanilide using an alkyd halide and aluminum chloride under Friedel-Crafts conditions to obtain desired alkyd substitution.
Nitration may be carried out using fuming nitric acid at about 0C.
A vitro compound may be hydrogenated to the corresponding amine which may then be diazotized and heated in an alcohol medium to form the alkoxy compound.
n amino compound may also be diazotized to the diazonium fluoroborate which is then thermally decomposed to the flyer compound.
Diazotization followed by a Sand Meyer type reaction may yield the broom, sheller or idea compound.
When an amino compound is diazotized followed by reaction with potassium ethylxanthate and then hydrolyzed, the Marquette compound results. This in turn may be alkylated to the alkylthio group which is then oxidized to the corresponding alkylsulfonyl substituent.
A sheller, broom or idea compound may also be reacted with trifluoromethyliodide and copper powder at about 150C in ~imethylformamide to obtain a trifluoromethyl compound [Tetrahedron Letters: 47,4095 ~1959)]. A halo compound may also be reacted with cuprous methanesulfinate in quinoline at about 150C to obtain a methylsulfonyl compound.
When it it desired that the final product contain a hydroxy group, it is preferred that the starting aniline contain the corresponding acyloxy or aralkyloxy groups. These may be prepared in the usual fashion by assaulting the starting hydroxy aniline compound with an azalea halide or android in the presence of a tertiary amine or aralkylating with an aralkyl halide or sulfate.
Of course the amine function would be protected in the ;:
, .
. .
lZ30886 customary manner. Hydrogenation to the desired hydroxy compound may then take place after the formation of the amidinourea. This may be accomplished with a metal catalyst (Pd/C, Pi etc.) in a polar medium (ethanol, THY, etc.), sodium in liquid ammonia, etc. Thus, for example, the 3,4-dihydroxy amidinourea compound may be prepared from the corresponding 3,4-dibenzyloxyaniline. The hydroxy compounds may also be prepared by hydrolysis of the azalea or alkoxy compounds with acid.
Reactions may also be carried out at other stages of synthesis depending on the substituents present and the substituents desired, and various combinations of the foregoing reactions will be determined by one skilled in the art in order that the desired product results. Thus, a phenylamidinourea may be halogenated or nitrated as above, etc.
The compounds of Formula I are useful anti-diarrheal agents. Various tests can be carried out in animal models to show the ability of the compounds of Formula I to exhibit reactions that can be correlated with anti-diarrheal activity in humans. The following tests show the ability of the compounds of this invention to inhibit diarrhea in animals and are known to correlate well with anti-diarrheal activity in humans. These are considered to be standard tests used to determine anti-diarrhea properties. This correlation can be shown by the activities of compounds known to be clinically active. In view of the results of these tests, the amidinoureas of this invention can be considered to be anti-diarrheal agents.
1. Focal output in rat.
Rev: - Bass, P., Kennedy, JOY. and Witty, JON.:
Measurement of local output in rats. Am. J. Dig. Disk 10: 925-928, 1972.
:
. .
: ' .
... . . , .. . .
,. . . - - , 2. Castor oil test in mice.
Rev: - Niemegeers, CUE Lenaerts, EM and Janssen, PUDGY. Difenoxine, a potent, orally active and safe anti-diarrheal agent in rats. Arzneim-Forscth (Drug Ryes.) 22, 516-1518, 1972.
The compounds of Formula I may be administered orally, parenterally or rectally. Administration by the oral route is preferred. Orally, these compounds may be administered in tablets, hard or soft capsules, aqueous or oily suspensions, dispersible powders or granules, emulsions, syrups or elixirs. The optimum dosage, of course, will depend on the particular compound being used and the type and severity of the condition being treated.
In any specific case the appropriate dosage selected will further depend on factors of the patient which may influence response to the drug; for example, general health, age, weight, etc. of the subject being treated.
Although the optimum quantities of the compounds of this invention to be used as anti-diarrheal agents will depend on the compound employed and the particular type of disease condition treated, oral dose levels of preferred compounds when administered to a mammal in dosages of 0.01 to 500 milligrams per kilogram of body weight per day are particularly useful. The preferred range is 0.05 to 200 mg/kg. Comparative dosages may be used in parenteral or rectal administration.
The composition may contain such selected excipients as inert delineates such as calcium carbonate, lactose, etc.;granulating and disintegrating agents such as maize starch, alginic acid, etc.; lubricating agents such as magnesium Stewart, etc.; binding agents such as starch gelatin, etc.; suspending agents such as methyl cellulose, vegetable oil, etc.; dispersing agents such as lecithin, etc.; thickening agents such as beeswax, hard ..... . Jo . . ........ .
, . .. ... . . . .
.. I_ Jo .... I.. _ .. _.. _ ._ . .... _._._ __ _ .. _ _ _ Jo .. _~__._.. ,____.__ _ _ _. __ _.. _ . . _ . ._ _, ~___~_ _ .. _ .. ...
_ lZ3088~
Jo paraffin, etc.; emulsifying agents such as naturally-occurring gums, etch; non-irritating excipients such as cocoa butter, polyethylene glycols, etc.; and the like. Further, in formulating these compounds for every 100 parts by weight of the composition, there may be present between 5 and 95 parts by weight of the active ingredient. The dosage unit form will generally contain between 0.1 my and about 500 my of the active ingredients of this invention. The preferred unit dose is between 1 my and about 50 my. The compositions may be taken 1-8 times daily depending on the dosage unit required.
Further the active amidinourea may be administered alone or in admixture with other agents having the same or different pharmacological properties.
The debilitating effects of diarrhea result partially from electrolyte imbalance in the patient, so that it is recommended that a solvent or delineate forming the carrier of the liquid pharmaceutical compositions, whether designed for injection or oral administration, should incorporate electrolyte balance. The precise composition of the electrolyte replenisher incorporated in the liquid compositions will depend on the age and the genera health and condition of the patient, but in many cases it is appropriate to use a commercially available electrolyte replenisher. These generally include sodium chloride alone or in combination with potassium salts, calcium salts, lactates or bicarbonates, and typical examples are Ringer's Solution, Doris Solution for injection), Ringer's Injection and Lactated Ringers Injection. These and other examples of commercially available electrolyte replenishers may be found in the "Pharmacopoeia of the United States.
A particularly preferred liquid anti-diarrheal composition is one in which the couriers a solvent or ... . .. I. . , ~230886 delineate comprising a saline solution of substantially isotonic concentration.
Liquid compositions for oral use are preferably aqueous, so as to permit the inclusion of an electrolyte.
Ingredients suitable for incorporation in the carrier of an aqueous liquid suspension are for example suspending agents such as sodium carboxymethylcellulose, methylcelluiose, hydroxypropylmethylcellulose, sodium allegiant, polyv;nylpyrrolidine, gum tragacanth and gum r Acadia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, condensation products of an alkaline oxide with fatty acids, for example polyoxyethylene Stewart, condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxyethanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example polyoxyethylene sorbitol moonlit or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol androids, for example polyoxyethylene sorbitan moonlit. Aqueous suspensions may also in particular contain one or more preservatives, for example ethyl- or n-propyl-p-hydroxy-bonniest, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose.
Oily suspensions may be formulated by suspending the amidinourea in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or Seattle alcohol. Sweetening agents, such as those set forth above, and flavourinq agents may here also be added to provide a palatable oral .
... . . . ... .
- 12:~0886 preparation. These compositions may also be preserved by the addition of an anti-oxidant such as ascorbic acid.
Where the liquid compositions are in the form of oil-in-water emulsions, the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these.
The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs in particular may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
The liquid compositions, as herei~before described, may be formulated for injection. For example they may take the form of a sterile injectable aqueous suspension formulated according to the known art and containing those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
An injectable composition is preferably a sterile ; injectable solution or suspension of the amidinourea in a parenterally acceptable delineate or solvent, for example a sterile aqueous solution buffered to a pi of 4.0 to 7.0 and made isotonic with sodium chloride.
It has been found that the liquid compositions including an anti-diarrheal composition of Formula I
degrade over a period of time. Accordingly, the present invention relates to a method of providing a stable dosage form for preparation into a liquid form :
::
~3088 immediately prior to its use. More particularly the present invention is a method for the preparation of a liquid pharmaceutical composition suitable for oral administration or parenteral injection, said composition comprising a pharmaceutically acceptable liquid vehicle and from 1 to 25 my of a compound of the Formula I
.
X
Jo 0, I
N-C-NH-C-NR2R3 Formula I
H
z y wherein X, Y and Z are hydrogen, alkyd, alkoxy, cyan, acyloxy, alkenyl, alkynyl, halo, haloalkyl, haloalkoxy, amino, azalea, carbamoyl, vitro, hydroxy, arylalkoxy or alkylsulfonyl;
Al, R2 and R3 are each independently hydrogen, alkyd, cycloalkyl or aralkyl;
or R2 and R3 together with the nitrogen atoms to which they are attached form a 5, 6, or 7 member Ed ring which may include 0-2 additional heteroatoms of N, O or S;
provided that at least one of Al, R2 or R3 is other than hydrogen;
which method comprises combining the compound of Formula I with the vehicle by the steps of:
a) dissolving an effective anti-diarrheal dosage amount of a salt of said compound in a liquid vehicle comprising either sterile water or a sterile electrolyte replenisher solution;
by sterilizing the solution by means of micro filtration;
, .
, .
` ~230886 (c) freeze-drying the sterilized solution to form a dissected composition; and (d) preparing the liquid composition for administration by dissolving the dissected composition in a dosage volume of liquid vehicle comprising either sterile water or a sterile electrolyte replenisher solution;
the said dosage amount and volume being for either single or multiple doses, and in the latter case a preservative being added in step (a) or step (d).
The following formulations are given in illustration of the compositions prepared from the `
compounds of Formula I.
Formulation 1.
An aqueous solution for parenteral administration is prepared as follows:
50 g of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride and 5 g of propel p-hydroxybenzoate are dissolved and diluted to 5,000 cm3 with twice-distilled water after the addition of modified Sorensen buffer soul-lion in an amount sufficient to adjust the pi value to a pi of 6Ø Sodium chloride is dissolved therein in an amount sufficient to render the resulting solution is-tonic. The resulting solution is passed through a beater-illogical filter, the filtrate distributed to 1000 stern tie ampules, the contents of each ampule is freeze-dried and sealed for later use. Reconstitution with 5 cm3 of sterile water results in a parenterally applicable solution which contains 50 my of 1-(2,6-dimethylphenyl)-
3-methylamidinourea hydrochloride in 5 cm3 of the solution.
:
~L230886 Formulation 2.
A sterilized aqueous solution for oral administer-lion containing l-(2,6-dimethylphenyl)-3-amidinourea hydrochloride is made up from the following ingredients:
1-~2,6-dimethylphenyl)-3-amidinourea hydrochloride my Sodium chloride 86 my Potassium chloride 3 my Calcium chloride 2H20 3.3 my Deionized water TV 100 cm3 Formulation 3.
A sterile solution suitable for inter peritoneal injection, containing 10 my of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride in each 10 ml (1:1 wt/vol), is prepared from the following ingredients:
1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 10 g Bouncily bonniest 100 cm3 Methylparaben 1 g Propylparaben 0.5 g Cottonseed oil us SO cm3 .
Formulation 4.
500 ampules, each with 2 ml of solution containing 15 my of 1-~2,6-dimethylphenyl)-3-methylamidinourea hydra-chloride, are prepared from the following types and amount of materials.
,.. . .
.. , . .. ,... .
- i.;230886 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 7 5 g Ascorbic acid 1 g Sodium bisulphite 0.5 g Sodium sulfite 1 g Deionized water us 1000 cm3 Formulation 5.
Tablets of 850 my are prepared by maximum compression of a mixture of the following ingredients:
l-t2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 500 my Tricalcium phosphate 200 my Talc . 50 my Magnesium Stewart 10 my Polyvinyl acetate 40 my Protective excipients such as ethyl cellulose, dibutylphthalate, propylene glycol, wax (white and/or carnauba), spermaceti, ethylene chloride and rectified .: deathly ether may optionally be included among the ingredients.
Formulation 6.
. A lot of tablets, each containing 20 my of 1-~2,6-dlmethylphenyl)-3-methylamidinourea hydrochloride are prepared from the following ingredients:
1-~2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 1 kg Dicalcium phosphate 1 kg Methyl cellulose US 75 kg : Talc 150 g Cornstarch 200 g Magnesium Stewart 10 g ,::
I: ' :: :
._ . .
. . , ~Z30886 The amidinourea and dicalcium phosphate are mixed thoroughly and granulated with a 7.5~ solution of methyl cellulose in water and Sassed through a #8 screen and air-dried. The dried granules are passed through a ~12 screen and combined with the talc, starch and magnesium Stewart with thorough mixing, after which the composition is compressed into tablets.
Formulation 7:
A lot of two-piece hard gelatin capsules, each containing 25 my of 1-(2,6-di~ethylphenyl)-3-methyl amidinourea hydrochloride, are prepared from the following types and amounts of ingredients:
1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 500 g Dicalcium phosphate 500 g Talc 150 g Magnesium Stewart 5 g The ingredients are mixed thoroughly and filled into capsules for oral administration to animals at the rate of about one every four hours. If desired, slow release or delay release forms can be provided, depending on choice of capsules and formulating ingredients.
Formulation 8:
Tablets for oral administration, each containing 25 my of 1-~2,6-dimethylphenyl)-3-methylamidinourea hydrochloride, are prepared prom a mixture of the following ingredients:
1-~2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 500 g Lactose US 350 g Potato starch US 346 g .
. . .
i2~0886 The mixture is moistened with an alcoholic solution of 20 g of Starkey acid and granulated through a sieve. After drying, the following ingredients are added:
Potato starch US 320 g Talc 400 g Magnesium Stewart 500 g Colloidal silicum dockside g and the whole is thoroughly mixed and compressed into tablets.
Formulation 9:
Capsules are prepared from the following mixture:
1-~2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 15 g Magnesium Stewart 3 g Finely divided silica sold under the trademark CAB-O-SIL by Godfrey L.
Cabot, Inc., Boston, MA 2 g : Lactose 369 g The mixture is filled into gelatin capsules, each capsule containing 500 my of the mixture and thus 15 my of 1-~2,6-dimethylphenyl)-3-methylamidinourea hydrochloride.
By analogous procedures, other amidinoureas of general Formula I above can be formulated in a similar manner for either oral or parenteral administration as injectable or infusible solutions. The solid or liquid formulations can also be dispersed in the food or dissolved in the drinking water or the liquid diet of the patient.
:
~L230886 Formulation 2.
A sterilized aqueous solution for oral administer-lion containing l-(2,6-dimethylphenyl)-3-amidinourea hydrochloride is made up from the following ingredients:
1-~2,6-dimethylphenyl)-3-amidinourea hydrochloride my Sodium chloride 86 my Potassium chloride 3 my Calcium chloride 2H20 3.3 my Deionized water TV 100 cm3 Formulation 3.
A sterile solution suitable for inter peritoneal injection, containing 10 my of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride in each 10 ml (1:1 wt/vol), is prepared from the following ingredients:
1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 10 g Bouncily bonniest 100 cm3 Methylparaben 1 g Propylparaben 0.5 g Cottonseed oil us SO cm3 .
Formulation 4.
500 ampules, each with 2 ml of solution containing 15 my of 1-~2,6-dimethylphenyl)-3-methylamidinourea hydra-chloride, are prepared from the following types and amount of materials.
,.. . .
.. , . .. ,... .
- i.;230886 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 7 5 g Ascorbic acid 1 g Sodium bisulphite 0.5 g Sodium sulfite 1 g Deionized water us 1000 cm3 Formulation 5.
Tablets of 850 my are prepared by maximum compression of a mixture of the following ingredients:
l-t2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 500 my Tricalcium phosphate 200 my Talc . 50 my Magnesium Stewart 10 my Polyvinyl acetate 40 my Protective excipients such as ethyl cellulose, dibutylphthalate, propylene glycol, wax (white and/or carnauba), spermaceti, ethylene chloride and rectified .: deathly ether may optionally be included among the ingredients.
Formulation 6.
. A lot of tablets, each containing 20 my of 1-~2,6-dlmethylphenyl)-3-methylamidinourea hydrochloride are prepared from the following ingredients:
1-~2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 1 kg Dicalcium phosphate 1 kg Methyl cellulose US 75 kg : Talc 150 g Cornstarch 200 g Magnesium Stewart 10 g ,::
I: ' :: :
._ . .
. . , ~Z30886 The amidinourea and dicalcium phosphate are mixed thoroughly and granulated with a 7.5~ solution of methyl cellulose in water and Sassed through a #8 screen and air-dried. The dried granules are passed through a ~12 screen and combined with the talc, starch and magnesium Stewart with thorough mixing, after which the composition is compressed into tablets.
Formulation 7:
A lot of two-piece hard gelatin capsules, each containing 25 my of 1-(2,6-di~ethylphenyl)-3-methyl amidinourea hydrochloride, are prepared from the following types and amounts of ingredients:
1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 500 g Dicalcium phosphate 500 g Talc 150 g Magnesium Stewart 5 g The ingredients are mixed thoroughly and filled into capsules for oral administration to animals at the rate of about one every four hours. If desired, slow release or delay release forms can be provided, depending on choice of capsules and formulating ingredients.
Formulation 8:
Tablets for oral administration, each containing 25 my of 1-~2,6-dimethylphenyl)-3-methylamidinourea hydrochloride, are prepared prom a mixture of the following ingredients:
1-~2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 500 g Lactose US 350 g Potato starch US 346 g .
. . .
i2~0886 The mixture is moistened with an alcoholic solution of 20 g of Starkey acid and granulated through a sieve. After drying, the following ingredients are added:
Potato starch US 320 g Talc 400 g Magnesium Stewart 500 g Colloidal silicum dockside g and the whole is thoroughly mixed and compressed into tablets.
Formulation 9:
Capsules are prepared from the following mixture:
1-~2,6-dimethylphenyl)-3-methylamidinourea hydrochloride 15 g Magnesium Stewart 3 g Finely divided silica sold under the trademark CAB-O-SIL by Godfrey L.
Cabot, Inc., Boston, MA 2 g : Lactose 369 g The mixture is filled into gelatin capsules, each capsule containing 500 my of the mixture and thus 15 my of 1-~2,6-dimethylphenyl)-3-methylamidinourea hydrochloride.
By analogous procedures, other amidinoureas of general Formula I above can be formulated in a similar manner for either oral or parenteral administration as injectable or infusible solutions. The solid or liquid formulations can also be dispersed in the food or dissolved in the drinking water or the liquid diet of the patient.
Claims (6)
1. In a process for the preparation of a compound of Formula I:
comprising the reaction of an isocyanate of Formula II:
II
with a guanidine of Formula III:
I I I
said guanidine being prepared m situ by the treatment of the salt of Formula IV
IV U
with aqueous base, wherein:
X, Y and Z are hydrogen, lower alkyl, lower alkoxy, cyano, lower acyloxy, lower alkenyl, lower alkynyl, halo, lower haloalkyl, lower haloalkoxy, amino, lower acyl, lower carbamoyl, nitro, hydroxy, lower arylalkoxy or lower alkylsulfonyl;
R1, R2 and R3 are each independently hydrogen, lower alkyl, cycloalkyl or lower aralkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a 5, 6 or 7 membered ring which may include 0-2 additional heteroatoms of N, O or S;
provided that at least one of R1, R2 or R3 is other than hydrogen;
the improvement comprising the use of a ketone as the reaction medium.
comprising the reaction of an isocyanate of Formula II:
II
with a guanidine of Formula III:
I I I
said guanidine being prepared m situ by the treatment of the salt of Formula IV
IV U
with aqueous base, wherein:
X, Y and Z are hydrogen, lower alkyl, lower alkoxy, cyano, lower acyloxy, lower alkenyl, lower alkynyl, halo, lower haloalkyl, lower haloalkoxy, amino, lower acyl, lower carbamoyl, nitro, hydroxy, lower arylalkoxy or lower alkylsulfonyl;
R1, R2 and R3 are each independently hydrogen, lower alkyl, cycloalkyl or lower aralkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a 5, 6 or 7 membered ring which may include 0-2 additional heteroatoms of N, O or S;
provided that at least one of R1, R2 or R3 is other than hydrogen;
the improvement comprising the use of a ketone as the reaction medium.
2. In a process according to Claim 1, the improvement comprising the use of acetone as the reaction medium.
3. In a process according to Claim 2, the improvement comprising removing the reaction product of Formula I from the reaction mixture by filtration.
4. In a process according to Claim 3, wherein the filtered reaction product is 1-(2,6-dimethylphenyl)-3-methyl amidinourea.
5. A process for the preparation of a compound of Formula V:
V
wherein a compound of Formula VI:
VI
is added to a reaction solution prepared by mixing a compound of Formula VII:
VII
and a neutralizing quantity of aqueous base in a ketone solvent;
wherein X and Y are hydrogen, lower alkyl, halo, lower alkoxy, lower haloalkyl or lower haloalkoxy; and R2 and R3 are hydrogen, lower alkyl, cycloalkyl, lower aralkyl or lower alkoxy; provided that at least one of R2 and R3 is other than hydrogen.
V
wherein a compound of Formula VI:
VI
is added to a reaction solution prepared by mixing a compound of Formula VII:
VII
and a neutralizing quantity of aqueous base in a ketone solvent;
wherein X and Y are hydrogen, lower alkyl, halo, lower alkoxy, lower haloalkyl or lower haloalkoxy; and R2 and R3 are hydrogen, lower alkyl, cycloalkyl, lower aralkyl or lower alkoxy; provided that at least one of R2 and R3 is other than hydrogen.
6. The process according to Claim 5, wherein the compound of Formula I is 1-(2,6-dimethylphenyl)-3-methylamidino-urea.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000474424A CA1230886A (en) | 1985-02-15 | 1985-02-15 | Amidinourea process and pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000474424A CA1230886A (en) | 1985-02-15 | 1985-02-15 | Amidinourea process and pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1230886A true CA1230886A (en) | 1987-12-29 |
Family
ID=4129844
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000474424A Expired CA1230886A (en) | 1985-02-15 | 1985-02-15 | Amidinourea process and pharmaceutical composition |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1230886A (en) |
-
1985
- 1985-02-15 CA CA000474424A patent/CA1230886A/en not_active Expired
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