CA1072962A - Process for preparing amidinoureas - Google Patents
Process for preparing amidinoureasInfo
- Publication number
- CA1072962A CA1072962A CA258,859A CA258859A CA1072962A CA 1072962 A CA1072962 A CA 1072962A CA 258859 A CA258859 A CA 258859A CA 1072962 A CA1072962 A CA 1072962A
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- Prior art keywords
- hydrogen
- loweralkyl
- ch2ch3
- compounds
- acid
- Prior art date
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Abstract
ABSTRACT
The invention describes a novel class of chemical compounds of the formula I or its tautomeric form II when the R radical is hydrogen:
I II
where X, Y and Z may be the same or different and are hydrogen, halo, loweralkyl, haloloweralkyl, nitro loweralkoxy, hydroxy, arloweralkoxy, acyloxy, cyano, haloloweralkoxy or loweralkyl-sulfonyl; R and R' are hydrogen or loweralkyl, R" and R''' are hydrogen, loweralkyl, loweralkenyl, cycloalkenyl up to 9 carbon atoms, cycloalkylloweralkyl, loweralkyl, cycloalkyl, aralkyl or loweralkynyl; R" and R''' together may form a 5-7 atom ring which may include 0-2 heteo atoms of N, O or S; Rn is hydrogen or loweralkyl provided at least one of R, R', R" and R''' is other than hydrogen; and non-toxic acid addition salts thereof. The novel compounds of the invention have valuable spasmolytic (anti-diarrheal), local anaesthetic, anti-arrhythmic and anti-secretory properties.
The invention describes a novel class of chemical compounds of the formula I or its tautomeric form II when the R radical is hydrogen:
I II
where X, Y and Z may be the same or different and are hydrogen, halo, loweralkyl, haloloweralkyl, nitro loweralkoxy, hydroxy, arloweralkoxy, acyloxy, cyano, haloloweralkoxy or loweralkyl-sulfonyl; R and R' are hydrogen or loweralkyl, R" and R''' are hydrogen, loweralkyl, loweralkenyl, cycloalkenyl up to 9 carbon atoms, cycloalkylloweralkyl, loweralkyl, cycloalkyl, aralkyl or loweralkynyl; R" and R''' together may form a 5-7 atom ring which may include 0-2 heteo atoms of N, O or S; Rn is hydrogen or loweralkyl provided at least one of R, R', R" and R''' is other than hydrogen; and non-toxic acid addition salts thereof. The novel compounds of the invention have valuable spasmolytic (anti-diarrheal), local anaesthetic, anti-arrhythmic and anti-secretory properties.
Description
lV~ 36~
The present invention relates to a novel process for preparing amidinourea derivatives of the general formula I or its tautomeric form II when the R radical is hydrogen:
X X
y~ 1l NR' R~ y3~N-c-N-c/
Z Rn R R Z Rn \NR"R"' II
where:
X, Y and Z may be the same or different and are:
hydrogen, halo, loweralkyl, haloloweralkyl, nitro, loweralkoxy, hydroxy, arloweralkoxy, acyloxy, cyano, haloloweralkoxy or loweralkylsulfonyl;
R and R' are hydrogen or loweralkyl, R" and R"'are hydrogen, alkyl, loweralkyl, loweralkenyl, cycloalkyl, cycloalkenyl up to 9 carbon atoms, aralkyl, ~07Z~6~
cycloalkylloweralkyl, loweralkynyl;
R" and R"' together may form a 5-7 atom ring which may include 0-2 hetero atoms of N, 0 or S, Rn is hydrogen or loweralkyl provided at least one of R, R', R" and R"'is other than hydrogen; and the non-toxic acid addition salts thereof.
Compounds of this invention which are preferred include those where:
X, Y and Z are hydrogen, halo, loweralkyl, haloloweralkyl, nitro, hydroxy or loweralkoxy, provided not more than one of X, Y
and Z is hydrogeni and R' and Rn are hydrogen or loweralkyl and R" and R"'are hydrogen or alkyl, provided R, R', R" and R"' are not all hydrogen at the same time.
The compounds of formula I or II of the present invention exist as tautomeric forms when a proton is present on the second nitrogen atom of the amidinourea chain. As with tautomers certain compounds would naturally exist in one form or the other depending on their character as discussed in Journa~ of Organic C~emistry~ 33, 1968 p. 552.
The most preferred compounds of this invention are those where:
X is methyl, ethyl, methoxy, chloro or bromo;
Y is methyl, ethyl, hydroxy, methoxy, chloro or bromo;
Z is hydrogen, methyl, ethyl, nitro, methoxy, ethoxy~
l~qZ9~
chloro, bromo or fluoroi R, R' and Rn are hydrogen, methyl or ethyl; and R" and R"'are hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, t-butyl, pentyl, hexyl or heptyl, provided R, R', R" and R"' are not all hydrogen at the same time.
It is well known in the pharmacological arts that non-toxic acid addition salts of pharmacologically active amine compounds do not differ in activities from their free base.
The salts merely provide a convenient solubility factor.
The amines of this invention may be readily converted to their non-toxic acid addition salts by customary methods in the art. The non-toxic salts of this invention are those salts the acid component of which is pharmacologically acceptable in the intended dosages, such salts would include those prepared from inorganic acids, organic acids, higher fatty acids, high molecular weight acids, etc., and include such as:
hydrochloric acid, succinic acid, hydrobromic acid, glycolic acid, sulfuric acid, lactic acid, nitric acid, salicylic acid, phosphoric acid, benzoic acid, ~ 962 methane sulfonic acid, nicotinic acid, benzene sulfonic acid, phthalic acid, acetic acid, stearic acid, propionic acid, oleic acid, malic acid, abietic acid, etc.
The nomenclature applied to the compounds of this invention is as follows:
~3 : - C - N C ~ N~
urea amidino The term "loweralkyl" refers to an alkyl hydrocarbon group from 1 to 5 carbon atoms which may be straight chained or branched while "alkyl" refers to an alkyl 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 "aralkyl" groups are benzyl and phenethyl.
The preferred "haloloweralkyl" group is trifluoro-methyl.
The preferred "haloloweralkoxy" group is trifluoro-methoxy.
In accordance with the present invention it has be2n observed that the compounds having anti-diarrheal or spasmo-lytic properties are preferably those compounds wherein X,Y,Z, R,R',R",R"' and Rn represent a total number of carbon atoms .
10~962 -lower than seven. On the other hand, when the total number of carbon atoms of those substituents is 3 or more the products are found to possess both spasmolytic activity and surprisingly high significant local anaesthetic and anti-arrhythmic activi-ties.
The novel process of the present invention comprises reacting a carbamoyl derivative of the formula:
X
~I e OR~
wherein X, Y, Z and Rn are as previously defined and R8 stands for loweralkyl, phenyl or phenylloweralkyl, with a guanidine of the formula:
R"' wherein R, R', R" and R"'are as previously defined, thereby to obtain an amidinourea of the formula:
X 1l NR' /R~ X I /NRR' N-C-N-e-N ~ < _ _ > ~ I-l-N=C~
Rn R R"' Z Rn NR"R"' wherein X, Y, Z, Rn~ R, R', R" and R"'are as defined previously.
The reaction is carried out in the presence of an inert solvent such as a lower alcohol, for example ethanol or isopropanol, toluene or phenol. The choice of the proper solvent will depend on the substituents on the guanidine and the selection is within the ability of one skilled in the art.
The reaction is also conveniently carried out at room tempera-ture.
The compounds described in this application are ' 1~7~6~
useful anti-diarrheal agents. For these purposes they can 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 elixers. 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.
Compositions intended for oral use may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, preserving agents, etc. in order to provide a pharmaceutically elegant and palata-ble preparation.
Further the active amidinourea may be administered alone or in admixture with other agents having the same or different pharmacological properties.
The composition may contain selected excipients such as inert diluents such as calcium carbonate, lactose, . ., ~ . ~ . .
l~q296Z
ete.; granulating and disintegrating agents such as maize starch, alginic acid, etc.; lubricating agents such as mag-nesium stearate, etc.; binding agents such as starch gelatin, ete.; suspending agents such as methylcell-lose, vegetable oil, ete.; dispersing agents such as lecithin, etc.; thickening agents such as beeswax, hard paraffin, etc.; emulsifying agents such as naturally-occurring gums, etc.; non-irritating excipi-ents 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 mg. and about 500 mg. of the active ingredients of this invention. The preferred unit dose is between 1 mg. and about 50 mg. The compositions may be taken 1-8 times daily depending on the dosage unit required.
Those products of the present invention which are found to possess local anaesthetic or anti-arrhythmic activi-ties are preferably administered in any of the well known forms for subcutaneous administration while those products possessing especially anti-arrhythmic activity may be administered orally, parenterally or rectally.
Various tests can be carried out in animal models to show the ability of the amidinoureas of this invention 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 .
~ 96'~
active. In view of the results of these tests, the amidino-ureas of this invention can be considered to be anti-diarrheal agents.
1. Fecal output in rat: - The oral ED50 (that dose which would be expected to reduce fecal output by 50%) is de-termined by a method described by Bass et aZ., 1972. Briefly, the method involves dosing the rats and collecting the fecal output over an 8 hour period (4 P.M. - 12 midnight) with the room darkened starting at 4:30 P.M.
Ref: - Bass, P., Kennedy, J.A. and Willy, J.N.:
Measurement of fecal output in rats. Am. J. Dig. Dis. 10:
925-928, 1972.
The present invention relates to a novel process for preparing amidinourea derivatives of the general formula I or its tautomeric form II when the R radical is hydrogen:
X X
y~ 1l NR' R~ y3~N-c-N-c/
Z Rn R R Z Rn \NR"R"' II
where:
X, Y and Z may be the same or different and are:
hydrogen, halo, loweralkyl, haloloweralkyl, nitro, loweralkoxy, hydroxy, arloweralkoxy, acyloxy, cyano, haloloweralkoxy or loweralkylsulfonyl;
R and R' are hydrogen or loweralkyl, R" and R"'are hydrogen, alkyl, loweralkyl, loweralkenyl, cycloalkyl, cycloalkenyl up to 9 carbon atoms, aralkyl, ~07Z~6~
cycloalkylloweralkyl, loweralkynyl;
R" and R"' together may form a 5-7 atom ring which may include 0-2 hetero atoms of N, 0 or S, Rn is hydrogen or loweralkyl provided at least one of R, R', R" and R"'is other than hydrogen; and the non-toxic acid addition salts thereof.
Compounds of this invention which are preferred include those where:
X, Y and Z are hydrogen, halo, loweralkyl, haloloweralkyl, nitro, hydroxy or loweralkoxy, provided not more than one of X, Y
and Z is hydrogeni and R' and Rn are hydrogen or loweralkyl and R" and R"'are hydrogen or alkyl, provided R, R', R" and R"' are not all hydrogen at the same time.
The compounds of formula I or II of the present invention exist as tautomeric forms when a proton is present on the second nitrogen atom of the amidinourea chain. As with tautomers certain compounds would naturally exist in one form or the other depending on their character as discussed in Journa~ of Organic C~emistry~ 33, 1968 p. 552.
The most preferred compounds of this invention are those where:
X is methyl, ethyl, methoxy, chloro or bromo;
Y is methyl, ethyl, hydroxy, methoxy, chloro or bromo;
Z is hydrogen, methyl, ethyl, nitro, methoxy, ethoxy~
l~qZ9~
chloro, bromo or fluoroi R, R' and Rn are hydrogen, methyl or ethyl; and R" and R"'are hydrogen, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, t-butyl, pentyl, hexyl or heptyl, provided R, R', R" and R"' are not all hydrogen at the same time.
It is well known in the pharmacological arts that non-toxic acid addition salts of pharmacologically active amine compounds do not differ in activities from their free base.
The salts merely provide a convenient solubility factor.
The amines of this invention may be readily converted to their non-toxic acid addition salts by customary methods in the art. The non-toxic salts of this invention are those salts the acid component of which is pharmacologically acceptable in the intended dosages, such salts would include those prepared from inorganic acids, organic acids, higher fatty acids, high molecular weight acids, etc., and include such as:
hydrochloric acid, succinic acid, hydrobromic acid, glycolic acid, sulfuric acid, lactic acid, nitric acid, salicylic acid, phosphoric acid, benzoic acid, ~ 962 methane sulfonic acid, nicotinic acid, benzene sulfonic acid, phthalic acid, acetic acid, stearic acid, propionic acid, oleic acid, malic acid, abietic acid, etc.
The nomenclature applied to the compounds of this invention is as follows:
~3 : - C - N C ~ N~
urea amidino The term "loweralkyl" refers to an alkyl hydrocarbon group from 1 to 5 carbon atoms which may be straight chained or branched while "alkyl" refers to an alkyl 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 "aralkyl" groups are benzyl and phenethyl.
The preferred "haloloweralkyl" group is trifluoro-methyl.
The preferred "haloloweralkoxy" group is trifluoro-methoxy.
In accordance with the present invention it has be2n observed that the compounds having anti-diarrheal or spasmo-lytic properties are preferably those compounds wherein X,Y,Z, R,R',R",R"' and Rn represent a total number of carbon atoms .
10~962 -lower than seven. On the other hand, when the total number of carbon atoms of those substituents is 3 or more the products are found to possess both spasmolytic activity and surprisingly high significant local anaesthetic and anti-arrhythmic activi-ties.
The novel process of the present invention comprises reacting a carbamoyl derivative of the formula:
X
~I e OR~
wherein X, Y, Z and Rn are as previously defined and R8 stands for loweralkyl, phenyl or phenylloweralkyl, with a guanidine of the formula:
R"' wherein R, R', R" and R"'are as previously defined, thereby to obtain an amidinourea of the formula:
X 1l NR' /R~ X I /NRR' N-C-N-e-N ~ < _ _ > ~ I-l-N=C~
Rn R R"' Z Rn NR"R"' wherein X, Y, Z, Rn~ R, R', R" and R"'are as defined previously.
The reaction is carried out in the presence of an inert solvent such as a lower alcohol, for example ethanol or isopropanol, toluene or phenol. The choice of the proper solvent will depend on the substituents on the guanidine and the selection is within the ability of one skilled in the art.
The reaction is also conveniently carried out at room tempera-ture.
The compounds described in this application are ' 1~7~6~
useful anti-diarrheal agents. For these purposes they can 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 elixers. 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.
Compositions intended for oral use may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, preserving agents, etc. in order to provide a pharmaceutically elegant and palata-ble preparation.
Further the active amidinourea may be administered alone or in admixture with other agents having the same or different pharmacological properties.
The composition may contain selected excipients such as inert diluents such as calcium carbonate, lactose, . ., ~ . ~ . .
l~q296Z
ete.; granulating and disintegrating agents such as maize starch, alginic acid, etc.; lubricating agents such as mag-nesium stearate, etc.; binding agents such as starch gelatin, ete.; suspending agents such as methylcell-lose, vegetable oil, ete.; dispersing agents such as lecithin, etc.; thickening agents such as beeswax, hard paraffin, etc.; emulsifying agents such as naturally-occurring gums, etc.; non-irritating excipi-ents 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 mg. and about 500 mg. of the active ingredients of this invention. The preferred unit dose is between 1 mg. and about 50 mg. The compositions may be taken 1-8 times daily depending on the dosage unit required.
Those products of the present invention which are found to possess local anaesthetic or anti-arrhythmic activi-ties are preferably administered in any of the well known forms for subcutaneous administration while those products possessing especially anti-arrhythmic activity may be administered orally, parenterally or rectally.
Various tests can be carried out in animal models to show the ability of the amidinoureas of this invention 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 .
~ 96'~
active. In view of the results of these tests, the amidino-ureas of this invention can be considered to be anti-diarrheal agents.
1. Fecal output in rat: - The oral ED50 (that dose which would be expected to reduce fecal output by 50%) is de-termined by a method described by Bass et aZ., 1972. Briefly, the method involves dosing the rats and collecting the fecal output over an 8 hour period (4 P.M. - 12 midnight) with the room darkened starting at 4:30 P.M.
Ref: - Bass, P., Kennedy, J.A. and Willy, J.N.:
Measurement of fecal output in rats. Am. J. Dig. Dis. 10:
925-928, 1972.
2. Castor oil test in mice: - Groups of mice are orally dosed with test compound and half an hour later all mice are given 0.3 ml. of castor oil. Three hours after castor oil administration, all mice are checked for diarrhea and the dose of testing compound which protected 50% of mice from diarrhea is the ED50 dose.
3. Castor oil test in rats: - The test is conducted according to Niermegeers et aZ.~ 1972. The rat is orally dosed with graded doses of test compound. One hour after dosing, each animal is challenged with 1 ml. of castor oil orally.
Fecal output is examined 1, 2, 3, 4, 6 and 8 hours after castor oil. Absence of diarrhea is criterion of drug effectiveness.
Ref: - Niemegeers C.J.E., Lenaerts, F.M. and Janssen, P.A.J. Difenoxine, a potent, orally active and safe anti-diarrheal agent in rats. Arzneim-Forssth (~rug Res.) 22, 516-1518, 1972.
The following are detailed examples which show the properties of the compounds of this invention. They are to be construed as illustrations of said compounds and not as limi-tations thereof.
i~'7Z96Z
The following are detailed examples which show the preparation of the compounds in accordance with the process of the present invention. They are to be construed as illus-trations only and not as limitations.
1-(2',6'-dimethylphenyl~-3-methylamidinourea hydrochloride With gentle warm;ng 300 ml of dry isopropanol was treated with 4.6 9 of clean sodium metal (0.2 g-atms). When the mixture was homogeneous there was added portionwise 24.4 9 (0.10 moles) of methylguanidine sulfate. The suspension was stirred at room temperature for three hours.
To the above mixture at room temperature there was added a solution of 48.3 9 (0.20 moles) of phenyl N-(2,6-dimethylphenyl)carbamate in 100 ml of dry isopropanol. The mixture was stirred at room temperature overnight and the solvent removed in vao~o. The residue dissolved in ether and the ether solution washed with 10% hydrochloric acid until the wash was acidic. The acidic aqueous extracts combined and washed once with ether. The aqueous solution made just basic with 10% sodium hydroxide solution, cooled and filtered to give the desired 1-(2,6-dimethylphenyl)-3-methylamidinourea free base. The white solid dissolved in methanol and the solution dried with anhydrous sodium sulfate. The filtered solution made acidic with methanolic hydrogen chloride and evaporated to a glass in vacuo. The glass was broken up and triturated with a large volume of ether, the suspension filtered and the solid dried to give 1-(2,6-dimethylphenyl)-3-methylamidinourea hydro-chloride, m.p. 193-5C. Recrystallization from acetonitrile containing some methanol gives analytically pure material m.p.
198-200C.
g .:
~7~6Z
By proceeding in the same manner as in Example 1 and using the appropriate carbonate and guanidine the compounds of Table I are obtained.
lV'~296Z
~, ~ ~ ~ ., ~ V
~ -- , S S S S S -- -- S
._ ~
o o o o 1. o O~ O O
~: Y C _ o o o o o , o _ ~ o o Z Z -- A a~ C~Lt') C~J oQ ~
_ I~ o ~ co o~:) o c~ J 1~ O
Z
O =~ :
Z--~
~ ~Y I S S S S S -r S S ~ -- = = "
x~ s s s s ~ T I
s~ s ~ ~s~ .
S ~ S 3~ S ~ S -- S
Z
cr Z
Z--~
0=~ ~1 Z--Cl CC ¦ T -- -- S T _ I t~ -~ I --X~O~
~ r S S -- S -- -- -- -- S = =
-- S -- -- - X I - S ~ S S
S X _ T I S ~ S ~--~ o o o _ ~
. C~
o ~, o o o o o o CJl ~ ~ 0~ ~ ~ ~ C~ ~ ~ ~ O~ ~ O
C o o o ~ o o o o o o o .~ o~ o~ o o _ U~ U O ~D ~ ~ ~ ~ ~ C`~ _ 03 _ C~ O
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-- S S S S I S S S S -- S
C~ I Y S :~ -- -- -- S -- S S S S
.
-O -~ISSSSSS--SSSSSS---rS
_ I~ I I
~J ~I~
J ~ S
'Si -- Ss s S S T I S S~ ~ ~ ~ C~. =
~~r I ~~ ~ ~ ~ ~ ~~ s L~J L.J
C
llll llll S ~Cl: ~ CC ~:SS ~ S I S = S
+ I ~ ~
I ~ S Ss ~r S S S-- S S S S S
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TI I I I ~ I
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~ î S TS ~ S S S S S S S S T T S
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S SS S S :~C S S S = T
_ C~l ~ ~ ~ C~ ~
J S T ~
et: 3~ S S S ~ S S SC~ S -- S ~ ~ I C`J
-- ~) I ~ ~ ~ T
~ .
S, ~S S S S S S S S S T S T T
~1 ~ -- ~ 3: s s s :~: s s -- s s s s ~
L T T ~ T _ _S T _ S_ S T T
~n ~ ~ vv ~ ~ cn ~ <~
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S S ~ ~ ~ ~ ~ ~ ~
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~ ~ ~ ~ ~I N N ~ C~ J N C~J N N
:
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l(~';~Z~6Z
_ _______ ________ :
~7 I S S -- -- -- S X -- ~r ~ T
C~
C O C~
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Cl O ~ O . O O O O
C O 0 0~ 0 0 1 0 CO r~ ~ O O
o ~ ~ o r~ ~ _ c 'I ~ .
S -- ~ ~ S S -- -- S S S S S S S
~ S S-- -- -- -- S S -- S S S -- ~
~ .
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I S S S S S ~r S ---- -- S S S S
_ 1~1 N ~ C~l C~
J -- -- S O
~e S S ~e~ ~ -- ~ S S S ~- S S ~ S S
~_ ~ ~ ~ S ~ ~ O
C C
S
S ~
~Y ¦ S S S S --r S S SCS: S S S T
-~1 ~ S S ~ S + ~ S + S
I
~ ~ ~O .
T _ I X S ~ O ~ L
L _ ~ T ~ S S ~ ~ ~ S + O
Xl ~ ~ ~ ~L~ ~ ~ S~ ~ ~ ~ ~ ~ LLI ~D Z
... . ...... . .
1{)';t;~96~ _ o ~ = ~ ~
_ -- _ o _ _ _ X ~ ~ ~
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O
S
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O O O O O O O O
C ~ o O 1~ ~ U~ r~ O O O O
_ _ l~ C ~ ~> C 1~ 1 CJ C~J ~ ~ O ~ C~J
~: __ _ _ _ _ _ _ --c _ s~ a~ ' S -- -- -- _ ~ C Z
C~l S--S~:SSS--SSSS ...
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-_ _ >, _ ~ O
et~ ~ ~ ~ ~ ~ ~ I ~
C~ G <~ ~ ~ ~ O ~ S
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S T -- S S -- -- S ~ S S S
.
:~ S I -- S + -- ~ S 4 ~ 2 S S = ~ -- ~ ~ `
.,, ~ .
.. . .
Fecal output is examined 1, 2, 3, 4, 6 and 8 hours after castor oil. Absence of diarrhea is criterion of drug effectiveness.
Ref: - Niemegeers C.J.E., Lenaerts, F.M. and Janssen, P.A.J. Difenoxine, a potent, orally active and safe anti-diarrheal agent in rats. Arzneim-Forssth (~rug Res.) 22, 516-1518, 1972.
The following are detailed examples which show the properties of the compounds of this invention. They are to be construed as illustrations of said compounds and not as limi-tations thereof.
i~'7Z96Z
The following are detailed examples which show the preparation of the compounds in accordance with the process of the present invention. They are to be construed as illus-trations only and not as limitations.
1-(2',6'-dimethylphenyl~-3-methylamidinourea hydrochloride With gentle warm;ng 300 ml of dry isopropanol was treated with 4.6 9 of clean sodium metal (0.2 g-atms). When the mixture was homogeneous there was added portionwise 24.4 9 (0.10 moles) of methylguanidine sulfate. The suspension was stirred at room temperature for three hours.
To the above mixture at room temperature there was added a solution of 48.3 9 (0.20 moles) of phenyl N-(2,6-dimethylphenyl)carbamate in 100 ml of dry isopropanol. The mixture was stirred at room temperature overnight and the solvent removed in vao~o. The residue dissolved in ether and the ether solution washed with 10% hydrochloric acid until the wash was acidic. The acidic aqueous extracts combined and washed once with ether. The aqueous solution made just basic with 10% sodium hydroxide solution, cooled and filtered to give the desired 1-(2,6-dimethylphenyl)-3-methylamidinourea free base. The white solid dissolved in methanol and the solution dried with anhydrous sodium sulfate. The filtered solution made acidic with methanolic hydrogen chloride and evaporated to a glass in vacuo. The glass was broken up and triturated with a large volume of ether, the suspension filtered and the solid dried to give 1-(2,6-dimethylphenyl)-3-methylamidinourea hydro-chloride, m.p. 193-5C. Recrystallization from acetonitrile containing some methanol gives analytically pure material m.p.
198-200C.
g .:
~7~6Z
By proceeding in the same manner as in Example 1 and using the appropriate carbonate and guanidine the compounds of Table I are obtained.
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Claims (21)
1. A process for preparing a compound of the formula I or its tautomeric form II:
I II
wherein:
X, Y and Z may be the same or different and are:
hydrogen, halo, loweralkyl, nitro, loweralkoxy;
R and R' are hydrogen or loweralkyl;
R" and R''' are hydrogen, alkyl, loweralkyl, loweralkenyl, cycloalkyl, cycloalkenyl up to 9 carbon atoms, aralkyl, cycloalkylloweralkyl, loweralkynyl;
R" and R''' together with the nitrogen atom form the pyrrolidine or piperidine ring;
Rn is hydrogen or loweralkyl provided at least one of R, R', R" and R''' is other than hydrogen; and the non-toxic acid addition salts thereof, which comprises reacting a carbamoyl derivative of the formula:
wherein X, Y, Z and Rn are as defined previously and R8 stands for loweralkyl, phenyl or phenylloweralkyl, with a guanidine of the formula:
wherein R, R', R" and R''' are as previously defined.
I II
wherein:
X, Y and Z may be the same or different and are:
hydrogen, halo, loweralkyl, nitro, loweralkoxy;
R and R' are hydrogen or loweralkyl;
R" and R''' are hydrogen, alkyl, loweralkyl, loweralkenyl, cycloalkyl, cycloalkenyl up to 9 carbon atoms, aralkyl, cycloalkylloweralkyl, loweralkynyl;
R" and R''' together with the nitrogen atom form the pyrrolidine or piperidine ring;
Rn is hydrogen or loweralkyl provided at least one of R, R', R" and R''' is other than hydrogen; and the non-toxic acid addition salts thereof, which comprises reacting a carbamoyl derivative of the formula:
wherein X, Y, Z and Rn are as defined previously and R8 stands for loweralkyl, phenyl or phenylloweralkyl, with a guanidine of the formula:
wherein R, R', R" and R''' are as previously defined.
2. The process of Claim 1, wherein methylguanidine sulfate is reacted with phenyl N-(2,6-dimethylphenyl)carbamate to form the 1-(2',6'-dimethylphenyl)-3-methylamidinourea.
3. The process of Claim 1, wherein X is 2-CH3;
Y is 6-CH3;
R', R" and R''' are each CH3;
Z, Rn and R are each hydrogen.
Y is 6-CH3;
R', R" and R''' are each CH3;
Z, Rn and R are each hydrogen.
4. The process of Claim 1, wherein X is 2-CH3;
Y is 6-CH3;
R, R', R" and R''' are each CH3;
Z and Rn are each hydrogen.
Y is 6-CH3;
R, R', R" and R''' are each CH3;
Z and Rn are each hydrogen.
5. The process of Claim 1, wherein X is 2-CH3;
Y is 6-CH3;
R''' is -CH2CH3;
Z, R, R', R" and Rn are each hydrogen.
Y is 6-CH3;
R''' is -CH2CH3;
Z, R, R', R" and Rn are each hydrogen.
6. The process of Claim 1, wherein X is 2-CH2CH3;
Y is 6-CH2CH3;
R''' is -CH2CH3;
Z, R, R', R" and Rn are each hydrogen.
Y is 6-CH2CH3;
R''' is -CH2CH3;
Z, R, R', R" and Rn are each hydrogen.
7. The process of Claim 1, wherein X is 2-Cl;
Y is 6-CH3;
R''' is n-propyl;
Z, R, R', R" and Rn are each hydrogen.
Y is 6-CH3;
R''' is n-propyl;
Z, R, R', R" and Rn are each hydrogen.
8. The process of Claim 1, wherein X is 2-Cl;
Y is 6-CH3;
R''' is -CH2CH3;
Z, R, R', R" and Rn are each hydrogen.
Y is 6-CH3;
R''' is -CH2CH3;
Z, R, R', R" and Rn are each hydrogen.
9. The process of Claim 1, wherein X is 2-CH3;
y is 4-CH3;
Z is 6-CH3;
R''' is n-propyl;
R, R', R" and Rn are each hydrogen.
y is 4-CH3;
Z is 6-CH3;
R''' is n-propyl;
R, R', R" and Rn are each hydrogen.
10. The process of Claim 1, wherein X is 2-CH2CH3;
Y is 4-Br;
Z is 6-CH2CH3;
R''' is CH3;
R, R', R" and Rn are each hydrogen.
Y is 4-Br;
Z is 6-CH2CH3;
R''' is CH3;
R, R', R" and Rn are each hydrogen.
11. The process of Claim 1, wherein X is 2-OCH3;
Y is 6-CH3;
R''' is CH3;
Z, R, R', R" and Rn are each hydrogen.
Y is 6-CH3;
R''' is CH3;
Z, R, R', R" and Rn are each hydrogen.
12. The process of Claim 1, wherein X is 2-OCH3;
Y is 6-CH3;
R''' is -CH2CH3;
Z, R, R', R" and Rn are each hydrogen.
Y is 6-CH3;
R''' is -CH2CH3;
Z, R, R', R" and Rn are each hydrogen.
13. The process of Claim 1, wherein X is 2-CH3;
Y is 6-CH3;
R''' is CH3;
Z, R, R', R" and Rn are each hydrogen.
Y is 6-CH3;
R''' is CH3;
Z, R, R', R" and Rn are each hydrogen.
14. The process of Claim 1, wherein X is 2-CH3;
Y is 6-CH3;
R''' is -CH2CH3;
Z, R, R', R" and Rn are each hydrogen.
Y is 6-CH3;
R''' is -CH2CH3;
Z, R, R', R" and Rn are each hydrogen.
15. The process of Claim 1, wherein X is 2-Br;
Y is 6-CH3;
R''' is CH3;
Z, R, R', R" and Rn are each hydrogen.
Y is 6-CH3;
R''' is CH3;
Z, R, R', R" and Rn are each hydrogen.
16. The process of Claim 1, wherein X is 2-CH3;
Y is 6-CH3;
R''' is -CH2CH=CH2;
Z, R, R', R" and Rn are each hydrogen.
Y is 6-CH3;
R''' is -CH2CH=CH2;
Z, R, R', R" and Rn are each hydrogen.
17. The process of Claim 1, wherein X is 2-CH2CH3;
Y is 6-CH2CH3;
R''' is CH3;
Z, R, R', R" and Rn are each hydrogen.
Y is 6-CH2CH3;
R''' is CH3;
Z, R, R', R" and Rn are each hydrogen.
18. The process of Claim 1, wherein X is 2-Cl;
Y is 6-CH3;
R''' is CH3;
Z, R, R', R" and Rn are each hydrogen.
Y is 6-CH3;
R''' is CH3;
Z, R, R', R" and Rn are each hydrogen.
19. The process of Claim 1, wherein X is 2-CH3;
Y is 6-CH3;
R''' is n-butyl;
Z, R, R', R" and Rn are each hydrogen.
Y is 6-CH3;
R''' is n-butyl;
Z, R, R', R" and Rn are each hydrogen.
20. The process of Claim 1, wherein X is 2 CH3;
Y is 6-CH3;
R and R" are each -CH3;
Z, R', R''' and Rn are each hydrogen.
Y is 6-CH3;
R and R" are each -CH3;
Z, R', R''' and Rn are each hydrogen.
21. The process of Claim 1. wherein X is 2-CH3;
Y is 6-CH3;
R" and R''' are each -CH3;
Z, R, R' and Rn are each hydrogen.
Y is 6-CH3;
R" and R''' are each -CH3;
Z, R, R' and Rn are each hydrogen.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA258,859A CA1072962A (en) | 1976-08-11 | 1976-08-11 | Process for preparing amidinoureas |
| ZA00781574A ZA781574B (en) | 1976-08-11 | 1978-03-17 | Amidinoureas |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA258,859A CA1072962A (en) | 1976-08-11 | 1976-08-11 | Process for preparing amidinoureas |
| ZA00781574A ZA781574B (en) | 1976-08-11 | 1978-03-17 | Amidinoureas |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1072962A true CA1072962A (en) | 1980-03-04 |
Family
ID=25668338
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA258,859A Expired CA1072962A (en) | 1976-08-11 | 1976-08-11 | Process for preparing amidinoureas |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA1072962A (en) |
| ZA (1) | ZA781574B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4332814A (en) | 1979-08-23 | 1982-06-01 | Beecham Group Limited | Treatment of diarrhoea |
| US11465989B2 (en) | 2014-04-17 | 2022-10-11 | ImmunoMet Therapeutics, Inc. | Guanidine compounds and use thereof |
-
1976
- 1976-08-11 CA CA258,859A patent/CA1072962A/en not_active Expired
-
1978
- 1978-03-17 ZA ZA00781574A patent/ZA781574B/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4332814A (en) | 1979-08-23 | 1982-06-01 | Beecham Group Limited | Treatment of diarrhoea |
| US11465989B2 (en) | 2014-04-17 | 2022-10-11 | ImmunoMet Therapeutics, Inc. | Guanidine compounds and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA781574B (en) | 1979-03-28 |
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