CA1146949A - 2-(2-chloro-4-cyclopropyl-phenylimino)- imidazoidine, their acid addition salts, pharmaceuticals containing same and processes for production thereof - Google Patents
2-(2-chloro-4-cyclopropyl-phenylimino)- imidazoidine, their acid addition salts, pharmaceuticals containing same and processes for production thereofInfo
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- CA1146949A CA1146949A CA000360243A CA360243A CA1146949A CA 1146949 A CA1146949 A CA 1146949A CA 000360243 A CA000360243 A CA 000360243A CA 360243 A CA360243 A CA 360243A CA 1146949 A CA1146949 A CA 1146949A
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Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to 2-(2-chloro-4-cyclopropyL-phenylimino)-imidazolidine of the formula I
and the acid addttion salts thereof.
The novel compounds possess strong bradycardial activity and are of interest in the treatment of coronary disease.
Pharmaceutical compositions containing the compound of the invention as active ingredient and processes for the preparation of the novel compound are described and exemplified.
The invention relates to 2-(2-chloro-4-cyclopropyL-phenylimino)-imidazolidine of the formula I
and the acid addttion salts thereof.
The novel compounds possess strong bradycardial activity and are of interest in the treatment of coronary disease.
Pharmaceutical compositions containing the compound of the invention as active ingredient and processes for the preparation of the novel compound are described and exemplified.
Description
~ 6~ffl -- 2 ~
The present invention relates to 2(2-chloro-4-cyclopropyl-phenylimino)-imida~olidine and the acid - addition salts thereof as well as to processes for the preparation thereof, pharmaceutical compositions containing the said compound and its physiologically compatible acid addi-tion salts and me-thods for their use. Thc novel compoun~ po5Ses5 interesting physiological activity.
According to one feature of the present invention there is ~rovided 2-(2~chloro-4-cyclopropyl-phenylimino)-imidazolidine of the formula:
Cl / H
N = / ~ I
H
and ~he acid addition salts thereof.
It will be appreciated that the compounds of formula I may exist in different tautomeric forms. Both such tautomeric forms fall within the scope of the present invention.
The acid addition salts for incorporation in pharmaceutical compositions are the physiologically compatible acid addition salts. Other acid addition salts mayj however, be useful in the preparation of the compound of formula I and the physiologically compatible acid addition saltsthereof.
As stated above the compound of formula I and its ~5 physiologically compatible acid addition salts possess interesting physiological activity,and in particular have been found to possess a strong bradycardiac activity. The bradycardiac activity of the compound of .
' ' ' .
.' - ' ,, ~ ,.
: .
: ~ w~
formula I and the physiologically compatible acid addition salts thereof render it of in-terest in the treatment of coronary disease where reduction of the heart beat frequency may be advantageous~
The compound of formula I and the acid addition salts thereof may, for example, be prepared by one of the following processes ~a) to (c), which processes constitute further features of the present invention:-a) reacting a compound of the formula:
, Cl /
~ ~ N - A II
(wherein A represents a cyano group or the r~dical -COY, , NH
-CSY or - C in which Y represents a leaving atom or Y
group) or a salt thereof w.ith ~ethylene diamine or an acid addition salt thereof and where a compound of : 15 formula I is obtained if desired converting said compound of formula I into an acid addition salt thereof.
A compound of formula II is advantageously used in which A represents the raaical -COY, -CSY or C wherein Y represents an alkoxy or alkylthio \ y group, preferably with I to 4 carbon atoms or a sulfhydryl : or amino group. A compound of formula II is preferably . . , ~H
used in which A represents the radical - C ~
. ~ ~__, __ ~ ,~
'.: ':. ~
-- 4 -- .
The reaction is conveniently effected at a temperature of from 100 to 250C. Polar protic, polar aprotic or non-polar solvents may, for example, be used as solvent. The reaction mayj howe~.er be effected ~ithout the use of a solvent in which case the reactlon i5 preferably effected at an.elevated tempe~atuEe. The reaction time varies from a few minutes to several hours.
b) reac7tion of a compound of the formula:
., .
Cl ~ N = C III
X
(wherein X and Z, which may be the same or diffe:rent, each represent a leaving atom or grou~) or a salt thereof with ethylene diamine or an acid addition salt thereo~
and where a compound of formula I is obtained, if desired, ~ 15 convertlng said compound of formula I into an acid ; addition ~alt thereof.
A compound of:formula III is preferably used in which X and Z, which may be the same or different, each represent a halogen atom, e.g. chlorine, or an a:Lkoxy or alkylthio group e . g. with l to 4 carbon atoms.
If X and Z represent a halogen atom, preferably a : ch~Lorine atom, the reaction is preferably effected at a temperature of from 0C to ambient temperature.
Tnert solvents such as for example ethers e.g. diethyl ether, ketones, esters or aliphatic or aromatic .____ _ ,.
.
., -~
~ ~ 7~ . 7~. , ~'''. -~' ;-'^';
hydrocarbons may conveniently be used as solvent~
If X and Z represent alkoxy or alkylthio groups, the reaction is preferably effected at an elevated tempera-ture, preferably at the reflux temperature of the reaction mix~ure. Polar protic/ polar aprotic or non-polar solvents may conveniently be used as solvent, c) . .deacylation of a compound of the formula:
., .
Cl ¦ IV
_ N - -CH
Acyl (wherein Acyl represents an aliphatic or aromatic acyl group~ and i desired convert,ing a compound of formula I
obtained into an acid addition salt thereof.
The deacylation is conveniently effected in the presence of an aliphatic alcohol e.g. with l to 4 carbon atoms, such as methanol. The deacylation may also be effected by acid hydrolysis e.g. by the use of a dilute acid.
Compounds of formula II may, for example, be obtained reactiny 2~chloro-4-cyclopropylaniline with a cyanate or thiocyanate, a urea or thiourea being formed. The urea or thiourea may then be converted into the corresponding isouronium salt or isothiouronium salt for example, by the use of an alkylating agent. The corresponding isourea or isothiourea may be obtained from these acid addition compounds with bases. By dehydration of the urea,or by removal of H2S from the thiourea, ~or example in the presence of lead or ~ ~ ' ' ' .
.. . ____ ; ~ ~ r~
mercury salts 2-chloro-4-cyclopropyl-phenylcyanamide is obtained, with which ammonia may be reacted to form
The present invention relates to 2(2-chloro-4-cyclopropyl-phenylimino)-imida~olidine and the acid - addition salts thereof as well as to processes for the preparation thereof, pharmaceutical compositions containing the said compound and its physiologically compatible acid addi-tion salts and me-thods for their use. Thc novel compoun~ po5Ses5 interesting physiological activity.
According to one feature of the present invention there is ~rovided 2-(2~chloro-4-cyclopropyl-phenylimino)-imidazolidine of the formula:
Cl / H
N = / ~ I
H
and ~he acid addition salts thereof.
It will be appreciated that the compounds of formula I may exist in different tautomeric forms. Both such tautomeric forms fall within the scope of the present invention.
The acid addition salts for incorporation in pharmaceutical compositions are the physiologically compatible acid addition salts. Other acid addition salts mayj however, be useful in the preparation of the compound of formula I and the physiologically compatible acid addition saltsthereof.
As stated above the compound of formula I and its ~5 physiologically compatible acid addition salts possess interesting physiological activity,and in particular have been found to possess a strong bradycardiac activity. The bradycardiac activity of the compound of .
' ' ' .
.' - ' ,, ~ ,.
: .
: ~ w~
formula I and the physiologically compatible acid addition salts thereof render it of in-terest in the treatment of coronary disease where reduction of the heart beat frequency may be advantageous~
The compound of formula I and the acid addition salts thereof may, for example, be prepared by one of the following processes ~a) to (c), which processes constitute further features of the present invention:-a) reacting a compound of the formula:
, Cl /
~ ~ N - A II
(wherein A represents a cyano group or the r~dical -COY, , NH
-CSY or - C in which Y represents a leaving atom or Y
group) or a salt thereof w.ith ~ethylene diamine or an acid addition salt thereof and where a compound of : 15 formula I is obtained if desired converting said compound of formula I into an acid addition salt thereof.
A compound of formula II is advantageously used in which A represents the raaical -COY, -CSY or C wherein Y represents an alkoxy or alkylthio \ y group, preferably with I to 4 carbon atoms or a sulfhydryl : or amino group. A compound of formula II is preferably . . , ~H
used in which A represents the radical - C ~
. ~ ~__, __ ~ ,~
'.: ':. ~
-- 4 -- .
The reaction is conveniently effected at a temperature of from 100 to 250C. Polar protic, polar aprotic or non-polar solvents may, for example, be used as solvent. The reaction mayj howe~.er be effected ~ithout the use of a solvent in which case the reactlon i5 preferably effected at an.elevated tempe~atuEe. The reaction time varies from a few minutes to several hours.
b) reac7tion of a compound of the formula:
., .
Cl ~ N = C III
X
(wherein X and Z, which may be the same or diffe:rent, each represent a leaving atom or grou~) or a salt thereof with ethylene diamine or an acid addition salt thereo~
and where a compound of formula I is obtained, if desired, ~ 15 convertlng said compound of formula I into an acid ; addition ~alt thereof.
A compound of:formula III is preferably used in which X and Z, which may be the same or different, each represent a halogen atom, e.g. chlorine, or an a:Lkoxy or alkylthio group e . g. with l to 4 carbon atoms.
If X and Z represent a halogen atom, preferably a : ch~Lorine atom, the reaction is preferably effected at a temperature of from 0C to ambient temperature.
Tnert solvents such as for example ethers e.g. diethyl ether, ketones, esters or aliphatic or aromatic .____ _ ,.
.
., -~
~ ~ 7~ . 7~. , ~'''. -~' ;-'^';
hydrocarbons may conveniently be used as solvent~
If X and Z represent alkoxy or alkylthio groups, the reaction is preferably effected at an elevated tempera-ture, preferably at the reflux temperature of the reaction mix~ure. Polar protic/ polar aprotic or non-polar solvents may conveniently be used as solvent, c) . .deacylation of a compound of the formula:
., .
Cl ¦ IV
_ N - -CH
Acyl (wherein Acyl represents an aliphatic or aromatic acyl group~ and i desired convert,ing a compound of formula I
obtained into an acid addition salt thereof.
The deacylation is conveniently effected in the presence of an aliphatic alcohol e.g. with l to 4 carbon atoms, such as methanol. The deacylation may also be effected by acid hydrolysis e.g. by the use of a dilute acid.
Compounds of formula II may, for example, be obtained reactiny 2~chloro-4-cyclopropylaniline with a cyanate or thiocyanate, a urea or thiourea being formed. The urea or thiourea may then be converted into the corresponding isouronium salt or isothiouronium salt for example, by the use of an alkylating agent. The corresponding isourea or isothiourea may be obtained from these acid addition compounds with bases. By dehydration of the urea,or by removal of H2S from the thiourea, ~or example in the presence of lead or ~ ~ ' ' ' .
.. . ____ ; ~ ~ r~
mercury salts 2-chloro-4-cyclopropyl-phenylcyanamide is obtained, with which ammonia may be reacted to form
2-chloro~4-cyclopropyl-phenvl-~uanidine.
The isocyanide dichloride of formula III may, for example, be obtained by reaction of 2-chloro-4-cycloprop~laniline with formic acid followed by reaction of th~ formanilide obtained with a mixture of thionyl chloride and sulphuryl chloride.
Other starting c-ompounds of formula III may for example be obtained by reacting the isocyanide dichloride with an alcohol or thioalcohol~
The starting compounds of formula IV may, for ~xample, be prepared by reacting 2-chloro-4-cyc~opropylaniline with an N-acyl-imidazolidinone-(2) in the presence of phosphorus oxychloride.
- The 2-phenylimino-imidazolidine of the present invention may, if desired, be converted into an acid addition salt e.g. a Rhysiologically compatible acid addit~on salt by conventi.onal methods. Acids suitable for salt formation include for example hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulphuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, valeric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acidj benzoic acid, ~-hydroxybenzoic acid, p-aminobenzolc acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulphonic acid and 8~chlorotheophylline.
As stated above the compound of formula I (as hereinbefore defined) and the physiologically compatible acid addition salts possess a strong bradycardiac activity. The influence of the said compound on the heart beat requency has been investigated in rabbits . .
.
~ ~ ~_ :~ , ~ . .'~
.: D~ ~ i.. ' ' ~ ~
~ _ 7 _ and in spinal rats as well as in live anaest~etised rats.
Thus according to a still further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient the compound of formula I as herein~lore defined or a physiologically compatib].e acid addition salt -thereof in association with a pharmaceutical carrier or excipient.
The compositions according to t~e invention may be presented, for example, in a form suitable for oral, . parenteral or rectal administration.
The compounds according to the invention may be presented in the conventional pharmacological forms of administration, such as tablets, coated tab~ets, pills, solutions, suspension, emulsions, powders r capsules tinctures, injection solutions or sustai~ed release forms-. Conventional pharmaceutical excipients as well as the usual methods of production may be employed for the preparation of these forms. Tablets may be produced, for example, by mixing the active ingredient or ingredients with known excipients, such as for example with diluents, such as calcium carbonate, calcium phosphate or lactose t disintegrants such as corn starch or gelatin, lubricants such as magnesium stearate or talcum, and~or agents for obtaining sustained release, such as carboxypolymethylene, carboxymethyl cellulose, cellulose phthalatel or polyvinylacetate.
The tablets may if desired consist of several layers. Coated tablets may be produced by coating cores, obtained in a similar manner to the tablets, with agents commonly used for tablets coatings for example polyvinyl pyrrolidone or shellac, gum arabic, talcum, titanium dioxide or sugar. In order to obtain sustained .release or to avoid incompatibilities, the core may also consist o several layers. The tablet-coat may also consist of several layers in order to obtain sustained release,~in which case the excipients mentioned above in relation to tablets may be used. Syrups o the , . .
:~ .
. ~ ~_ active ingredient according to the invention or combina-tions of active ingredients may additionally contain a sweetenerrsuch as saccharin, cyclamate, glycerln or sugar, and/or taste improving agents such as flavourings, e.g. vanillin or orange extract. They may also contain suspension agents or thickeners, such as sodium carboxymethyl cellulose, wetting agents, such as for example condensation products of fa-tty alcohols with ethylene oxide, or preservatives, such as ~-..10 hydroxybenzoates.
Injection solutions may, for example, be produced in the conventional manner, su¢h as by the addition of preservatives~ such as ~-hydroxybenzoates, or s~abilizers, such as Complexons, e.g. ethylenediamine tetraacetic acid. The solutions are then filled into injection vials or ampoules.
Capsules containing one or several active ingredients may be produced for example by mixing the active ingredients with insert carriers, such as :Lactose or sorbitol, and filling the mixture into gelatin capsules.
Suitable suppositories may, for example, be produced by mixing the active ingredient or active ingredient combinations with the conventional carriers ~5 envisaged for this purpose, such as neutral fats or polyethyleneglycol or derivatives thereof.
Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Tablets, coated tablets, capsules, suppositories and ampoules are examples of suitable dosage unit forms. Each dosage unit preferably contains 0.1 to 80 mg especially 1 to 30 my of the said active ingredient.
According to a still further feature of the present invention there is provided a method of reducing the .
11 ~__ ~
:, .
~-JJL46a~9 heart bea-t frequency oE a patient suffer:ing from coronary disease which comprises administering to the said patient an efective amount of a pharmaceutical composition as hereinbefore deined.
The following Examples illustrate the prepara-tion of the co~pound according to the invention, and also pharmaceutical compositions containing the said compound . as active lngredient'-.
.
~ .
.
.
~"~
:~ ~ ~ J' :c .~
~6~
Example 1 2-(2-Chloro-4-cyclopropyl~ imino)-imidazolidirle ~ 0,~>--N =~<
Molecular weight: 235.7 5 Molecular formula: C12H14ClN3 Melting point~ 135.5 - 138.5 C
Elementary analysis. C H Cl N
Calculated 61.15 5~99 15.04 17.83 Found 61.07 6.05 15.42 17.66 a) N-(2-Chloro-4-cyclopropyl-phenyl)~S-methyl-isothio-' uronium_iodide 4-Cyclopropylaniline is acet~lated to 4-cyclopropyl-acetanilide ~m.p. 111-113.5C) and is chlorinated and saponified to 2-chloro~4-cyclopropylaniline as described in J. Amer. Chem. Soc. 62 (1940), 21Q3. The -title compound is obtained by reaction of the aniline with ammonium thiocyanate followed by methylation of the resulting N-~2-chloro-4-cyclopropyl-phenyl)-thiourea with methyl iodide.
b) 2-(2-Chloro-4 cyclopropyl-phenylimino)-imldazolidine 8.30 g of N-(2-chloro-4-cyclopropyl-phenyl)-S-methyl-isothiouronium iodide are refluxed for 15 hours in 25 ml of methanol together with 2.3 ml (150%) of ethylene diamine. The clear reaction mixture is then evaporated in vacuo and a honey-like residue i9 left. This is dissolved in lN HCl and the hydrochloric acid solution is extrarted twice wlth ether. The aqueous phase is ~. ~_ _ .
~ . ~ ~';'',".-'~ '~'.~.,-.~.'''.. ' ' ,. . ~ . ~ : . , .~ ~ ~ Q ~ ,1 ~ubsequently buffered to pH 6 with 2N NaOH and extracted with ether (50-ml portions) in fractions with rising pH
values (fractionated alkalisation with 2N NaOM). The approximately uniform ether fractions are combined (by a thin-layer chromatogram check), dried over MgSO4 and evaporated in vacuo. For further purification the crude 2-(2-chloro-4-cyclopropyl-phenylimino)-imidazolidine is chromatographed over silica gel.
Eluant: isopropanol: ethyl aceta~e: concentrated ammonia = 50:50~1. Yieldo 1.3 g (corresponding to 23.6% of theory).
Melting point: 135,5 to 138.5C.
Thin-layer chromatogram:
System:isopropanol:ethyl acetate:concentrated ammonia (50:50:1).
Carrier: silical gel plates by Merck-Darm~tadt No.
60F254.
Detector~ (a) UV, (b) po~assium iodopla-tinate according to Schlittler.
R~: 0.3.
Pharmaceutical Composition Examples Example A: Coated tablets Active substance according to invention 5 mg 25 Lactose 65 mg Corn starch 130 mg Seconda~y calcium phosphate 40 mg Soluble starch 3 mg Magnesium stearate 3 mg 30 Colloidal silicic acid 4_m~
Total 250 mg PreE~ration:
The active substance is mixed with a part of the excipie~ts, kneaded intensively ~ith an aqueous solution __ ~___ ~' ~'" , .. . ....
4~
of the soluble starch and granulated in conventional ma~ner by means of a sieve. The granulate is mixed with the rest of the excipients and pressed into coated tablet cores weighing 250 mg which are then coated in a conventional manner with a coating of sugarl talcum and gum arabic.
Example B: Ampoules Active substance according to the invention 1.O mg Sodium chloride 18.0 mg . 10 Distilled water sufficient to make 200 ml Preparation:
The active substance and sodium chloride are dissolved in water and filled, under nitrogen/ into glass ampoules.
~xample_C: Drops Active substance according to the invention 0.02 g Methyl~~ hydroxybenzoate 0.07 g Methyl-~-hydroxybenzoat~ 0.03 g Demineralised water sufficient to make 100 ml , .
: ~ ~ .r , ..
The isocyanide dichloride of formula III may, for example, be obtained by reaction of 2-chloro-4-cycloprop~laniline with formic acid followed by reaction of th~ formanilide obtained with a mixture of thionyl chloride and sulphuryl chloride.
Other starting c-ompounds of formula III may for example be obtained by reacting the isocyanide dichloride with an alcohol or thioalcohol~
The starting compounds of formula IV may, for ~xample, be prepared by reacting 2-chloro-4-cyc~opropylaniline with an N-acyl-imidazolidinone-(2) in the presence of phosphorus oxychloride.
- The 2-phenylimino-imidazolidine of the present invention may, if desired, be converted into an acid addition salt e.g. a Rhysiologically compatible acid addit~on salt by conventi.onal methods. Acids suitable for salt formation include for example hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulphuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, valeric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acidj benzoic acid, ~-hydroxybenzoic acid, p-aminobenzolc acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulphonic acid and 8~chlorotheophylline.
As stated above the compound of formula I (as hereinbefore defined) and the physiologically compatible acid addition salts possess a strong bradycardiac activity. The influence of the said compound on the heart beat requency has been investigated in rabbits . .
.
~ ~ ~_ :~ , ~ . .'~
.: D~ ~ i.. ' ' ~ ~
~ _ 7 _ and in spinal rats as well as in live anaest~etised rats.
Thus according to a still further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient the compound of formula I as herein~lore defined or a physiologically compatib].e acid addition salt -thereof in association with a pharmaceutical carrier or excipient.
The compositions according to t~e invention may be presented, for example, in a form suitable for oral, . parenteral or rectal administration.
The compounds according to the invention may be presented in the conventional pharmacological forms of administration, such as tablets, coated tab~ets, pills, solutions, suspension, emulsions, powders r capsules tinctures, injection solutions or sustai~ed release forms-. Conventional pharmaceutical excipients as well as the usual methods of production may be employed for the preparation of these forms. Tablets may be produced, for example, by mixing the active ingredient or ingredients with known excipients, such as for example with diluents, such as calcium carbonate, calcium phosphate or lactose t disintegrants such as corn starch or gelatin, lubricants such as magnesium stearate or talcum, and~or agents for obtaining sustained release, such as carboxypolymethylene, carboxymethyl cellulose, cellulose phthalatel or polyvinylacetate.
The tablets may if desired consist of several layers. Coated tablets may be produced by coating cores, obtained in a similar manner to the tablets, with agents commonly used for tablets coatings for example polyvinyl pyrrolidone or shellac, gum arabic, talcum, titanium dioxide or sugar. In order to obtain sustained .release or to avoid incompatibilities, the core may also consist o several layers. The tablet-coat may also consist of several layers in order to obtain sustained release,~in which case the excipients mentioned above in relation to tablets may be used. Syrups o the , . .
:~ .
. ~ ~_ active ingredient according to the invention or combina-tions of active ingredients may additionally contain a sweetenerrsuch as saccharin, cyclamate, glycerln or sugar, and/or taste improving agents such as flavourings, e.g. vanillin or orange extract. They may also contain suspension agents or thickeners, such as sodium carboxymethyl cellulose, wetting agents, such as for example condensation products of fa-tty alcohols with ethylene oxide, or preservatives, such as ~-..10 hydroxybenzoates.
Injection solutions may, for example, be produced in the conventional manner, su¢h as by the addition of preservatives~ such as ~-hydroxybenzoates, or s~abilizers, such as Complexons, e.g. ethylenediamine tetraacetic acid. The solutions are then filled into injection vials or ampoules.
Capsules containing one or several active ingredients may be produced for example by mixing the active ingredients with insert carriers, such as :Lactose or sorbitol, and filling the mixture into gelatin capsules.
Suitable suppositories may, for example, be produced by mixing the active ingredient or active ingredient combinations with the conventional carriers ~5 envisaged for this purpose, such as neutral fats or polyethyleneglycol or derivatives thereof.
Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Tablets, coated tablets, capsules, suppositories and ampoules are examples of suitable dosage unit forms. Each dosage unit preferably contains 0.1 to 80 mg especially 1 to 30 my of the said active ingredient.
According to a still further feature of the present invention there is provided a method of reducing the .
11 ~__ ~
:, .
~-JJL46a~9 heart bea-t frequency oE a patient suffer:ing from coronary disease which comprises administering to the said patient an efective amount of a pharmaceutical composition as hereinbefore deined.
The following Examples illustrate the prepara-tion of the co~pound according to the invention, and also pharmaceutical compositions containing the said compound . as active lngredient'-.
.
~ .
.
.
~"~
:~ ~ ~ J' :c .~
~6~
Example 1 2-(2-Chloro-4-cyclopropyl~ imino)-imidazolidirle ~ 0,~>--N =~<
Molecular weight: 235.7 5 Molecular formula: C12H14ClN3 Melting point~ 135.5 - 138.5 C
Elementary analysis. C H Cl N
Calculated 61.15 5~99 15.04 17.83 Found 61.07 6.05 15.42 17.66 a) N-(2-Chloro-4-cyclopropyl-phenyl)~S-methyl-isothio-' uronium_iodide 4-Cyclopropylaniline is acet~lated to 4-cyclopropyl-acetanilide ~m.p. 111-113.5C) and is chlorinated and saponified to 2-chloro~4-cyclopropylaniline as described in J. Amer. Chem. Soc. 62 (1940), 21Q3. The -title compound is obtained by reaction of the aniline with ammonium thiocyanate followed by methylation of the resulting N-~2-chloro-4-cyclopropyl-phenyl)-thiourea with methyl iodide.
b) 2-(2-Chloro-4 cyclopropyl-phenylimino)-imldazolidine 8.30 g of N-(2-chloro-4-cyclopropyl-phenyl)-S-methyl-isothiouronium iodide are refluxed for 15 hours in 25 ml of methanol together with 2.3 ml (150%) of ethylene diamine. The clear reaction mixture is then evaporated in vacuo and a honey-like residue i9 left. This is dissolved in lN HCl and the hydrochloric acid solution is extrarted twice wlth ether. The aqueous phase is ~. ~_ _ .
~ . ~ ~';'',".-'~ '~'.~.,-.~.'''.. ' ' ,. . ~ . ~ : . , .~ ~ ~ Q ~ ,1 ~ubsequently buffered to pH 6 with 2N NaOH and extracted with ether (50-ml portions) in fractions with rising pH
values (fractionated alkalisation with 2N NaOM). The approximately uniform ether fractions are combined (by a thin-layer chromatogram check), dried over MgSO4 and evaporated in vacuo. For further purification the crude 2-(2-chloro-4-cyclopropyl-phenylimino)-imidazolidine is chromatographed over silica gel.
Eluant: isopropanol: ethyl aceta~e: concentrated ammonia = 50:50~1. Yieldo 1.3 g (corresponding to 23.6% of theory).
Melting point: 135,5 to 138.5C.
Thin-layer chromatogram:
System:isopropanol:ethyl acetate:concentrated ammonia (50:50:1).
Carrier: silical gel plates by Merck-Darm~tadt No.
60F254.
Detector~ (a) UV, (b) po~assium iodopla-tinate according to Schlittler.
R~: 0.3.
Pharmaceutical Composition Examples Example A: Coated tablets Active substance according to invention 5 mg 25 Lactose 65 mg Corn starch 130 mg Seconda~y calcium phosphate 40 mg Soluble starch 3 mg Magnesium stearate 3 mg 30 Colloidal silicic acid 4_m~
Total 250 mg PreE~ration:
The active substance is mixed with a part of the excipie~ts, kneaded intensively ~ith an aqueous solution __ ~___ ~' ~'" , .. . ....
4~
of the soluble starch and granulated in conventional ma~ner by means of a sieve. The granulate is mixed with the rest of the excipients and pressed into coated tablet cores weighing 250 mg which are then coated in a conventional manner with a coating of sugarl talcum and gum arabic.
Example B: Ampoules Active substance according to the invention 1.O mg Sodium chloride 18.0 mg . 10 Distilled water sufficient to make 200 ml Preparation:
The active substance and sodium chloride are dissolved in water and filled, under nitrogen/ into glass ampoules.
~xample_C: Drops Active substance according to the invention 0.02 g Methyl~~ hydroxybenzoate 0.07 g Methyl-~-hydroxybenzoat~ 0.03 g Demineralised water sufficient to make 100 ml , .
: ~ ~ .r , ..
Claims (19)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing 2-(2-chloro-4-cyclopropyl-phenylimino)imidazolidine of the formula:- I
or an acid addition salt thereof, which process comprises:
a) reacting a compound of the formula:- II
(wherein A represents a cyano group or the radical -COY, CSY or in which Y represents a leaving atom or group) or a salt thereof with ethylene diamine of an acid addition salt thereof and where a compound of formula I is obtained, if desired, converting said compound of formula I into an acid addition salt thereof;
b) reacting a compound of the formula:- III
(wherein X and Z, which may be the same or different, each represent a leaving atom or group) or a salt thereof with ethylene diamine or an acid addition salt thereof and where a compound of formula I is obtained if desired converting said compound of formula I into an acid addition salt thereof; or c) deacylating the compound of the formula:- IV
(wherein Acyl represents an aliphatic or aromatic acyl group) and if desired converting a compound of formula I obtained into an acid addition salt thereof.
or an acid addition salt thereof, which process comprises:
a) reacting a compound of the formula:- II
(wherein A represents a cyano group or the radical -COY, CSY or in which Y represents a leaving atom or group) or a salt thereof with ethylene diamine of an acid addition salt thereof and where a compound of formula I is obtained, if desired, converting said compound of formula I into an acid addition salt thereof;
b) reacting a compound of the formula:- III
(wherein X and Z, which may be the same or different, each represent a leaving atom or group) or a salt thereof with ethylene diamine or an acid addition salt thereof and where a compound of formula I is obtained if desired converting said compound of formula I into an acid addition salt thereof; or c) deacylating the compound of the formula:- IV
(wherein Acyl represents an aliphatic or aromatic acyl group) and if desired converting a compound of formula I obtained into an acid addition salt thereof.
2. A process for the preparation of the compound of formula I
as claimed in claim 1 or an acid addition salt thereof, which comprises reacting a compound of the formula:- II
(wherein A represents a cyano group or the radical - COY, -CSY or in which Y represents a leaving atom or group) or a salt thereof with ethylene diamine or an acid addition salt thereof and where a compound of formula I is obtained, if desired converting said compound of formula I into an acid addition salt thereof.
as claimed in claim 1 or an acid addition salt thereof, which comprises reacting a compound of the formula:- II
(wherein A represents a cyano group or the radical - COY, -CSY or in which Y represents a leaving atom or group) or a salt thereof with ethylene diamine or an acid addition salt thereof and where a compound of formula I is obtained, if desired converting said compound of formula I into an acid addition salt thereof.
3. A process as claimed in claim 2 wherein a compound of formula II is used in which A represents -COY, -CSY or wherein Y represents an alkoxy or alkylthio group.
4. A process as claimed in claim 3 wherein Y represents an alkoxy or alkylthio group with 1 to 4 carbon atoms.
5. A process as claimed in claim 2 wherein a compound of formula II is used in which A represents the radical -COY, -CSY or wherein Y represents a sulfhydryl or amino group.
6. A process as claimed in claim 2, 3 or 4 wherein a compound of formula II is used in which A represents the radical .
7. A process as claimed in claim 2, 3 or 4 wherein the reaction is effected at a temperature of from 100 to 250°C.
8. A process for the preparation of the compound of formula I as claimed in claim 1 or an acid addition salt thereof, which comprises reacting a compound of the formula:- III
(wherein X and Z, which may be the same or different, each represent a leaving atom or group) or a salt thereof with ethylene diamine or an acid addition salt thereof and where a compound of formula I is obtained if desired converting said compound of formula I into an acid addition salt thereof.
(wherein X and Z, which may be the same or different, each represent a leaving atom or group) or a salt thereof with ethylene diamine or an acid addition salt thereof and where a compound of formula I is obtained if desired converting said compound of formula I into an acid addition salt thereof.
9. A process as claimed in claim 8 wherein X and Z, which may be the same or different, each represent an alkoxy or alkylthio group.
10. A process as claimed in claim 9 wherein X and Z, which may be the same or different each represent an alkoxy or alkylthio group with 1 to 4 carbon atoms or a halogen atom.
11. A process as claimed in claim 10 wherein the halogen atom is chlorine.
12. A process as claimed in claim 10 wherein X and Z each represent a halogen atom and the reaction is effected at a temperature of from 0°C to ambient temperature.
13. A process as claimed in claim 9 wherein X and Z each represent an alkoxy or alkylthio group and the reaction is effected at about the reflux temperature of the reaction mixture.
14. A process for the preparation of the compound of formula I
as claimed in claim 1 or an acid addition salt thereof, which comprises deacylating a compound of the formula:-IV
(wherein Acyl represents an aliphatic or aromatic acyl group) and if desired converting a compound of formula I obtained into an acid addition salt thereof.
as claimed in claim 1 or an acid addition salt thereof, which comprises deacylating a compound of the formula:-IV
(wherein Acyl represents an aliphatic or aromatic acyl group) and if desired converting a compound of formula I obtained into an acid addition salt thereof.
15. A process as claimed in claim 14 wherein the deacylation is effected in the presence of an aliphatic alcohol.
16. A process as claimed in claim 15 wherein the alcohol comprises an aliphatic alcohol with 1 to 4 carbon atoms.
17. A process as claimed in claim 14 wherein the deacylation is effected by acid hydrolysis.
18. A process as claimed in claim 17 wherein the hydrolysis is effected by the use of a dilute acid.
19. 2-(2-Chloro-4-cyclopropyl-phenylimino)imidazolidine of the formula:- I
or an acid addition salt thereof, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.
or an acid addition salt thereof, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000360243A CA1146949A (en) | 1980-09-15 | 1980-09-15 | 2-(2-chloro-4-cyclopropyl-phenylimino)- imidazoidine, their acid addition salts, pharmaceuticals containing same and processes for production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000360243A CA1146949A (en) | 1980-09-15 | 1980-09-15 | 2-(2-chloro-4-cyclopropyl-phenylimino)- imidazoidine, their acid addition salts, pharmaceuticals containing same and processes for production thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1146949A true CA1146949A (en) | 1983-05-24 |
Family
ID=4117882
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000360243A Expired CA1146949A (en) | 1980-09-15 | 1980-09-15 | 2-(2-chloro-4-cyclopropyl-phenylimino)- imidazoidine, their acid addition salts, pharmaceuticals containing same and processes for production thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1146949A (en) |
-
1980
- 1980-09-15 CA CA000360243A patent/CA1146949A/en not_active Expired
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