NZ194833A

NZ194833A - 2-(2-chloro-4-cyclopropylphenylimino)-imidazolidine and pharmaceutical compositions

Info

Publication number: NZ194833A
Application number: NZ19483380A
Authority: NZ
Inventors: H Stahle; H Koppe; W Kummer; W Hoefke; L Pichler
Original assignee: Boehringer Ingelheim Int
Priority date: 1980-09-03
Filing date: 1980-09-03
Publication date: 1984-07-06

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 1 94833 1 9483 3 PEiortay Data's): Completo Specification Fi5sd: 4'P.°. CI»s£?7A3??; frM ?J/.?(?.. PubHcstion Dcta: ■' 0, Zio: lj;p^ CiWBE OF NAME OF AFPLIGAETT .-HOEHK'MfrER XhiC;HLHEW [XNTeAtm^l, Cr.* y.H- Patents Form NO. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION CHEMICAL COMPOUNDS WE, ^©SHRiN^ER'^BN'GtlLHEa body corporate organised under the laws of the Federal Republic of Germany, of Ingelheim/Rhein, Federal Republic of Germany, hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement - 1 - f 948 10 - 2 - The present invention relates to 2(2-chloro—4— cyclopropy1-phenylimino)-imidazolidine 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 addition salts and methods for their use. The novel compounds possess interesting physiological activity. * ■ • According to one feature of the present invention there is provided 2-(2-chloro-4-cyclopropyl-phenylimino)-imidazolidine of the formula: O N and the acid addition salts thereof. It will be appreciated that the compounds of 15 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 20 compatible acid addition salts. Other acid addition salts may# however, be useful in the preparation of the compound of formula I and the physiologically compatible acid addition salts thereof. As stated above the compound of formula I and its 25 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 formula I and the physiologically compatible acid addition salts thereof render it of interest 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: II (wherein A represents a cyano group or the radical -COY, NH / -CSY or - C in v/hidi y represents a leaving atom or Y 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. A compound of formula II is advantageously used in which A represents the radical -COY, -CSY or XNH - wherein Y represents an alkoxy or alkylthio group; preferably with 1 to 4 carbon atoms or a sulfhydryl or amino group. A compound of formula II is preferably NH used in which A represents the radical -C ^ . $ €$ /: Vr *z "i /J 4nr '•>*' - 4 - The reaction is conveniently effected at a temperature of from .100 to 250°C. Polar protic, polar aprotic or non-polar solvents may, for example, be used as solvent. The reaction may, however be 5 effected without the use of a solvent in which case the reaction is preferably effected at an.elevated temperature. The reaction time varies from a few minutes to several hours. b) reaction of a compound of the formula: 10 N=C JI1 X (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, *5 converting said compound of formula I into an acid addition salt 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 alkoxy 2° or alkylthio group e.g. with 1 to 4 carbon atoms. If X and Z represent a halogen atom, preferably a chlorine atom, the reaction is preferably effected at a temperature of from 0°C to ambient temperature. Inert solvents such as for example ethers e.g. diethyl 25 ether, ketones, esters or aliphatic or aromatic 1 9483 10 - 5 - hydrocarbons may conveniently be used as solvent* If X and Z represent alkoxy or alkylthio groups, the reaction is preferably effected at an elevated temperature, preferably at the reflux temperature of the reaction mixture. Polar protic, polar aprotic or non-polar solvents may conveniently be. used as solvent. c) ' 'deacylation of a compound of the formula: CI 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. The deacylation is conveniently effected in the presence of an aliphatic alcohol e.g. with 1 to 4 carbon atoms, such as methanol. The deacylation may 15 also be effected by acid hydrolysis e.g. by the use of a dilute acid. Compounds of formula II may, for example, be obtained reacting 2-chloro-4-cyclopropylaniline with a cyanate or thiocyanate, a urea or thiourea being formed. The 20 urea or thiourea may then be converted into the corresponding isouroniiim 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 H^S from the thiourea, for example in the presence of lead or 25 mercury salts 2-chloro-4-cyclopropyl-phenylcyanamide is obtained, with which ammonia may be reacted to form 2-chloro-4-cyclopropyl-phenyl-guanidine. The isocyanide dichloride of formula III may, ^ for example, be obtained by reaction of 2-chloro-4- cyclopropylaniline with formic acid followed by reaction of the formanilide obtained with a mixture of thionyl chloride and sulphuryl chloride. Other starting compounds of formula III may for 1® example be obtained by reacting the isocyanide dichloride with an alcohol or thioalcohol<. « The starting compounds of formula IV may, for example, be prepared by reacting 2-chloro-4-cyclopropylaniline with an N-acyl-imidazolidinone-(2) 15 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 physiologically compatible acid addition salt by conventional methods. Acids suitable 20 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, 25 maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulphonic acid and 8-chlorotheophylline. 30 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 frequency has been investigated in rabbits - 7 - 1 94S3 and in spinal rats as well as in live anaesthetised 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 hereinbefore defined -or a physiologically compatible acid addition salt' thereof in association with a pharmaceutical carrier or excipient. ' The compositions according to the 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 tablets, pills, solutions, suspension, emulsions, powders, caipsules, tinctures, injection solutions or sustained 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, 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 phthalate, 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 arable, talcum, titanium dioxide or sugar. In order to obtain-sustained release or to avoid incompatibilities, the core may also consist of 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 of the - 8 - 4 //i p- active ingredient according to the invention or combinations of active ingredients may additionally contain a sweetener, such as saccharin, cyclamate, glycerin 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 fatt/ alcohols with ethylene oxide, or preservatives, such as £-hydroxybenzoates. Inje'ction solutions may, for example, be produced in the conventional manner, such as by the addition of preservatives, such as £-hydroxybenzoates, or stabilizers, 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 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 rag of the said active ingredient. According to a still further feature of the present invention there is provided a method of reducing the 194833 9 heart beat frequency of a non-human animal suffering from coronary disease which comprises administering to the said animal an effective amount of a pharmaceutical composition as hereinbefore defined. The following Examples illustrate the preparation of the compound according to the invention, and also pharma-ceutical compositions containing the said compound as active:ingredient!— 3 r E 3 - 10 - Example 1 2- (2-Chloro-4-cyclopropyl-phenyliraino) -imidazolidine CI "H « Molecular weight: 235.7 5 Molecular formula: C, „H, .CIN-. o Melting point: 135.5 - 138*5 C ' Elementary analysis: C H CI N Calculated 61.15 5.99 15.04 17.83 Fo.und 61.07 6.05 15.42 17.66 10 a) N-(2-Chloro-4-cyclopropyl-phenyl)-S-methyl-isothio-uronium iodide 4-Cyclopropylaniline is acetylated to 4-cyclopropyl-acetanilide (m.p. 111-113.5°C) and is chlorinated and saponified to 2-chloro-4-cyclopropylaniline as 15 described in J. Amer. Chem. Soc. 62 (1940). 2103. 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. 20 b) 2-(2-Chloro-4-cyclopropyl-phenylimino)-imidazolidine 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 25 in vacuo and a honey-like residue is left. This is dissolved in IN HC1 and the hydrochloric acid solution is extracted twice with ether. The aqueous phase is subsequently buffered to pH 6 with 2N NaOH and extracted with ether (50-ml portions) in fractions with rising pH values (fractionated alkalisation with 2N NaOH). The approximately uniform ether fractions are combined (by a thin-layer chromatogram check), dried over MgSO^ and evaporated in vacuo. For further purification the crude 2-(2-chloro-4-cyclopropyl-phenylimino)-imidazolidine is chromatographed over silica gel. Elu^nt:: isopropanol: ethyl acetate: concentrated ammonia; = 50:50:1. Yield: 1.3 g (corresponding to 2 3.6% oi; theory) . Melting point: 135.5 to 138.5°C. Thin-layer chromatogram: System:isopropanol:ethyl acetate:concentrated ammonia (50:50:1) . Carrier: silical gel plates by Merck-Darmstadt No. 60F254. Detector: (a) UV, (b) potassium iodoplatinate according to Schlittler. Rf: 0.3. Pharmaceutical Composition Examples Example A: Coated tablets Active substance according to invention 5 mg Lactose 65 mg Corn starch 130 mg Secondary calcium phosphate 40 mg Soluble starch 3 mg Magnesium stearate 3 mg Colloidal silicic acid 4 mg Total . 250 mg Preparation: The active substance is mixed with a part of the excipients, kneaded intensively with an aqueous solution </div>

Claims

<div class="application article clearfix printTableText" id="claims"> of the soluble starch and granulated in conventional manner 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 sugar, talcum and gum arabic. Example"B: Ampoules • Active substance according to the invention 1.0 mg Sodium chloride 18.0 mg Distilled water sufficient to make 2.0 ml Preparation: The active substance and sodium chloride are dissolved in water and filled, under nitrogen, into glass ampoules. Example C: Drops Active substance according to the invention 0.02 g Methyl-£-hydroxybenzoate 0.0 7 g Methyl-£-hydroxybenzoate 0.0 3 g Demineralised water sufficient to make 100 ml 194833 WHAT -47WE CLAIM IS> !• 2-(2-Chloro-4-cyclopropyl-phenylimino)-imidazolidine of the formula:- H N -CD H .and the acid addition salts thereof.
2. The" compound of claim 1 and the physiologically compatible acid addition salts.thereof.
3. 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:- 0- ' ^ N A H (wherein. A represents a cyano group or the radical - COY, -CSY # NH . *" Cx which, Y represents a leaving /atom or group);X Y;or a salt thereof with ethylene diamine or an acid addition salt thereof and where the compound of formula I is obtained, if desired, converting said compound'of formula I into an acid addition salt thereof.;4. A process as claimed in-claim 3 wherein a compound of formula II is used in which A represents-COY, -CSY;✓NH;or ~~:C\S wherein Y represents an alkoxy or alkylthio Y;group.;27FEB1984;5. A process as claimed in claim 4 wherein Y represents an alkoxy or alkylthio group with 1 to 4 carbon atoms.;6. A process as claimed in claim 3 wherein a compound of formula II is used in which A represents the;NH;radical -CQy, -CSY or —q wherein Y represents a;XY;«;sulfhydryl or amino group.;7. A process as claimed in any one of claims 3 to 6;wherein a compound of formula.II is used in which A;'nh represents the radical - C;X;Y;8. A process as claimed in any one of claims 3 to 7 wherein the reaction is effected at a temperature of from 100 to 250°C.;9. 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:-;C1;III;(wherein X and Z, which may be the same or different, each 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.;10. A process as claimed in claim 9 wherein X and Z, which may be the same or different, each represents an alkoxy or alkylthio group.;'94833;- 15 -;ll» A process as claimed in claim 9 wherein X and Zr which may be the same or different, eaph represents an alkoxy or alkylthio group with 1 to 4 carbon atoms or a halogen atom.;12. A process as claimed in claim 11 wherein the halogen atom is chlorine.;13. A process as claimed in claim 11 wherein X and Z each represent a halogen atom and in which the reaction is effected at a temperature of from 0°C to ambient temperature.;14. A process as claimed in claim 10 wherein X and Z each represents an alkoxy or alkylthio group and in which the reaction is effected at about the reflux temperature of the reaction mixture.;15. 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;Acyl;(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.;«;16. A process as claimed in claim 15 wherein the deacylation is effected in the presence of an aliphatic alcohol.;17. A process as claimed in claim 16 wherein the alcohol comprises an aliphatic alcohol with 1 to 4 carbon atoms.;£;to I;18. A process as claimed in any one of claims 15 to 17;wherein the deacylation is effected by acid hydrolysis, 19. A process as claimed in claim 18 wherein the hydrolysis is effected by the use of a dilute acid.;1;I9483o;- 16 -;20. A process as claimed in any one of claims 3 to 19 substantially as herein described.;21. A process for the preparation of a compound as claimed in claim 1 .substantially as herein described in Example 1.;2 2. A compound as claimed in claim 1 when prepared by a process as claimed in any one of claims 3 to 21. 23. • Pharmaceutical compositions comprising as active ingredient the compound of formula I or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient.;2-4. Compositions as claimed in claim 23 in the form of dosage units wherein each dosage unit contains from 0.1 to 80 mg of the said active ingredient.;25. Compositions as claimed in claim 2 4 wherein each dosage unit contains from 1 to 30 mg of the said active ingredient.;26. Pharmaceutical compositions substantially as herein described in any one of Examples A to C.;27. A method of reducing the heart beat frequency of a non-human animal suffering from coronary disease which comprises administering to the said animal an effective amount of a pharmaceutical composition as defined in any one of claims 23-26.;BALDWIN, SON & CAREY;Msd;ATTORNEYS FOR THE APPLICANTS* </div>