IL29692A - 2-(halophenoxy methyl)-2-imidazolines - Google Patents

Description

C O H E N Ζ Ε ¾ DTE & □ S P I S B A C H R E G D. P ATE N T ATT O R N E YS 24, LEVONTIN; STR., P. O. 8. 1169 • T E L - A V I V P A T E N T S & D E S I'O N' S' O R D I N A N C E 1769V68 SPECIFICATION 2- ^HA L0PHE¾0XY METHYL^2~IMIDA ZOLINES ο^,?ιτη Β'κ~2-('>'>ηΒ¾ρρι 3-ΐ,>>>η)-2 We, THE DOW CHEMICAL COMPANY, a oorporation under the laws of the State of Delaware, and having an office and place of bu aineas at Midland , County of Midland, State of Michigan, TJr.S.A . , ■ ' . - ■. ' · ■ I, . ■ ■ ■ DO HEREBY DECLARE Ihe nature of this invention and in what manner the same is to be performed to be particularly described and ascertained in and by the following statement : This invention is concerned with aryloxyimidazolines and is particularly directed to 2- (phenoxymethyl)-2-imidazolines substituted in the phenoxy group, and the physiologically- acceptable salts thereof having the formula wherein Z rep e formulae : rine or bromine, X' represents chlorine, bromine or methyl, X^ and X2 each independently represent chlorine or bromine, A represents acetamido or amino, R represents trifluoromethyl, chlorine or The term "physiologically-acceptable salt" as herein employed refers to salts of the 2- (substituted phenoxymethyl)-2-imidazolines which are substantially non-toxic at dosage rates consistent with good pharmacological activity. Such physiolo-gically-acceptable salts include non-toxic acid addition salts with inorganic acids such as hydrochloric, hydrobromic, sulfuric or phosphoric acid, or with organic acids such as acetic, succinic, malic, maleic, tartaric or citric acid, or with organic sulfonic acids such as methanesulfonic or p-toluene-sulfonic acid. The 2- (substituted phenoxymethyl)-2-imidazolines are crystalline solids and oils which are of varying degrees of solubility in organic solvents such as 1 ,2-dichlorobenzene , 1,2-dimethoxyethane, methylene chloride and alcohols and only slight ly soluble in water. The physiologically-acceptable salts of the 2- (substituted phenoxymethyl)-2-imidazolines such as 2- [ (2,6-dibromophenoxy)methyl]-2-imidazoline hydrochloride, 2[(4-amino-3 ,5-dichlorophenoxy)methyl]-2-imidazoline dihydrochloride and 2 [ (3,4-dichlorophenoxy)methyl]-2- imidazoline hydrochloride are soluble in water and slightly soluble in organic solvents such as acetone, benzene and alcohols.

The novel compounds have been found to be useful for administration o laboratory animals in studying the behavior thereof and in studying drug effects on the central and peripher al nervous system. The compounds corresponding to the above Formulae I through VI wherein A is amino when Z corresponds to Formula IV, V, or VI have been found to be particularly useful as analgesic agents. These of the above compounds belonging to Formula IV also have utility as diuretics. Those belonging to Formula V or VI are particularly useful as antidepressants. por such uses, the preferred form of the compounds wherein Z salt thereof and the hydrochloride salts are preferred. Other salts, and particularly the tosylate (p-toluenesulfonate) , can also be used in the preparation and purification of the compounds and can be converted to the preferred hydrochloride salt. The compound wherein is hydrogen and X and X' are both chlorine is especially preferred as an antidepressant and as an analgesic. The compounds wherein Z corresponds to Formula IV or VI when. A is acetamido are particularly useful as intermediates in the preparation, of the compounds wherein A is amino. For such uses, the preferred form of the 2- (substituted phenoxymethyl)-2-imidazoline compounds in general is a physiologically-acceptable salt thereof, and the compounds are generally employed in the form of their hydrochloride salts. Other salts, and particularly the tosylate (p-toluenesulfonate), can also be used in the preparation and purification of the 2- (substituted phenoxymethyl)-2-imidazoline and can be converted to the preferred hydrochloride salts.

The compounds wherein Z corresponds to Formula III are prepared by the reaction of ethylenediamine monotosylate with an ethyl 2,6-dihalo-3-methylphenoxyacetimide hydrochloride wherein "halo" refers to chlorine or bromine. The compounds wherein Z corresponds to Formula IV or VI when A is amino are prepared by the hydrolysis in acid media of a compound wherein A is acetamido. In all other cases, the compounds of the invention are prepared by the reaction of a substituted phenoxy-acetonitrile in compliance with VII P.A, 2 6 2 II N a C - CH2 - 0~/ Formulae I through VI with ethylenediamine monotosylate to form a 2- (substituted phenoxymethyl)-2-imidazoline tosylate, and the subsequent hydrolysis of the tosylate in aqueous base to liberate the 2-(substituted phenoxymethyl)-2-imidazoline in the free base form. The reaction proceeds with the evolution of ammonia when the substituted phenoxyacetonitrile and the ethy- lenediamine monotosylate are contacted and mixed, preferably in an inert organic solvent as a reaction medium. Representative and suitable inert organic solvents which can be employed as reaction media include xylenes, alkylbenzenes and halobenzenes , preferably 1,2-dichlorobenzene. The reaction is preferably carried out under an inert atmosphere with.an inert gas being passed through the reaction mixture to carry off ammonia of reaction. The reaction proceeds readily at temperatures from 140° to 180°C. and the reaction is preferably carried out under reflux at the boiling temperature of the reaction mixture. In most cases, the 2- (substituted phenoxymethyl)-2-imidazoline product precipitates in the reaction mixture as its tosylate (p-toluenesulfonate) salt, and the salt can be separated by conventional methods as filtration, centrifugation or decanta-tion. When no precipitate forms, the salt can be separated by evaporation. The 2- (substituted phenoxymethyl)-2-imidazoline tosylate can be purified by conventional procedures such as recrystallization and washing. The 2- (substituted phenoxymethyl)-2-imidazoline tosylate can be converted to the free base form by hydrolysis in aqueous base. The free base 2- (substituted phenoxymethyl)-2-imidazoline is then separated by extraction form followed by evaporation of the solvent. The product can be purified by conventional methods such as recrystallization, or it can be converted to a physiologically-acceptable salt.

The compounds wherein Z corresponds to Formula III are prepared by substantially the same method described above with the exception that an alkyl 2,6-dihalo-3-methylphenoxy- acetamide hydrochloride is employed in lieu of the substituted phenoxyacetonitrile and the use of a lower reaction temperature.

In a convenient procedure, ethyl 2,6-dihalo-3-methylphenoxy- acetamide hydrochloride, ethylenediamine monotosylate and an inert organic solvent are mixed together and heated at a temperature of 75°-90°C. The product is obtained as the tosylate salt and can be separated and purified or converted to the free base as described above.

The compounds wherein Z corresponds to Formula IV or VI when A is amino are prepared by hydrolysis of a compound wherein Z corresponds to Formula IV or VI when A is acetamido in excess aqueous acid media. The hydrolysis takes place in a few hours at a temperature of 90°- 100°C. In the preferred procedure, hydrochloric acid is employed as the acid medium.

The product precipitates in the acidic reaction mixture as the hydrochloride salt and can be separated and purified by conventional procedures such as filtration, washing and recrystallization. The product can be further purified or it can be con- verted to the free base. reaction proceeds when the reactants are contacted and mixed, preferably in the presence of water as a solvent. The exact some of the desired product being produced when the reactants are mixed in any proportions. However, the reaction consumes equimolar amounts of the reactants, and the reactants are preferably employed in equimolar proportions. The reaction proceeds at temperatures of from about 25° to 75 °C. Heat is evolved in the initial stages of the reaction and the evolved heat is generally sufficient to bring the reaction mixture to a temperature within the reaction temperature range. The reaction mixture is held at a temperature within the reaction temperature range for up to 2-3 hours. At the end of the reaction period, the mixture is made strongly basic by the addition of sodium hydroxide. The product is then extracted with a chlorinated hydrocarbon solvent. The l-methyl-2- [ (3,4-dihalo-phenoxy)methyl]-2-imidazoline product can be separated by conventional methods such as evaporation of the solvent. The product can be further purified by conventional methods such as recrystallization or it can be converted to a pharmaceutically-acceptable salt.

The physiologically-acceptable salts of the 2- (substituted phenoxymethyl)-2-imidazoline compounds can be prepared by dissolving 2- (substituted phenoxymethyl)-2-imidazoline in a minimal amount of alcohol and adding an alcohof"°solution of an acid such as hydrochloric acid, hydrobromic acid, malic acid, maleic acid or succinic acid until precipitation of the corresponding salt is complete. The salt can further be purified by recrystallization or converted to the free base form of 2- (substituted phenoxymethyl)-2-imidazoline .

The free base can be prepared by hydrolysis of the salt in aqueous base. The salt is mixed with an aqueous solution of sodium hydroxide (about 4 normal), after which the free base solvent. The solvent can be removed by conventional methods such as evaporation or distillation and the 2- (substituted phenoxymethyl)-2-imidazoline can be purified by methods such as recrystallization.

In preparing the compounds of the invention, a suitable substituted phenoxyacetonitrile phenoxyacetimide hydrochloride, ethylenediamine monotosylate and an inert organic solvent, preferably 1 , 2-dichlorobenzene , are mixed together. The exact proportions of the reactants to be employed are not critical, some of the desired product being obtained when the reactants are combined in any proportions. However, the reaction consumes the reactants in equimolar proportions and the use of the reactants in such proportions is preferred. Nitrogen is directed through the mixture and the mixture is heated to a temperature within the reaction temperature range for 1 to 10 hours. In a convenient procedure, the reaction vessel is vented to a trap containing aqueous hydrochloric acid to react with the ammonia of reaction. The reaction mixture is then cooled and filtered. The 2- (substituted phenoxymethyl)-2-imidazoline tosylate filter cake can be further purified by recrystallization or it can be converted to the free base by hydrolysis in aqueous base.

The following examples illustrate the invention.

EXAMPLE 1 2,6-Dlbromophenoxyacetonitrile (58.2 grams; 0.20 mole) was mixed with ethylenediamine monotosylate (47 grams; 0.20 mole) and 200 milliliters of 1, 2-dichlorobenzene. Nitrogen gas was directed through the mixture while the mixture was heated at a temperature of 150°C. for one hour. The ammonia of reaction was collected by passing the exit gases through a gas scrubber containing dilute aqueous hydrochloric acid. The dibromophenoxy)methyl] -2-imidazoline tosylate, having a molecular weight of 506.2, as a filter cake. The 2- [ (2,6-dibromo-phenoxy)methyl]-2-imidazoline tosylate filter cake was mixed with a mixture of methylene chloride and water to form a slurry. The slurry was made basic by the addition of about 8 grams of sodium hydroxide in water. The organic layer was separated and evaporated in vacuo to leave 2- [ (2,6-dibromophenoxy)methyl]-2-imidazoline, having a molecular weight of 334.0, as a residue. The 2- [ (2,6-dibromophenoxy)methyl]-2-imidazoline was dissolved in about 100 milliliters of isopropyl alcohol. The alcohol solution was acidified by the addition of 5 normal hydrochloric acid in isopropyl alcohol until precipitation was complete. The mixture was filtered and the; 2- [ (2,6-dibromophenoxy)methyl]-2-imidazoline hydrochloride product was collected as a filter cake and found to melt at 230°-231°C.

In substantially the same procedure described above, employing similar inert organic solvents and substituting for the hydrochloric acid an acid capable of forming a physiologically-acceptable salt, the following 2- [ (2,6-dibromophenoxy) methyl] -2-imidazoline salts are prepared; 2- [ (2 ,6-dibromophenoxy) methyl] -2-imidazoline hydrobromide, 2- [ (2,6-dibromophenoxy) methyl] -2- imidazoline sulfate, 2- [ (2,6-dibromophenoxy)methyl]-2-imidazoline succinate, 2- [ (2,6-dibromophenoxy)methyl]-2-imidazoline maleate, 2- [ (2,6-dibromophenoxy)methyl]-2-imidazo-line malate.

EXAMPLE 2 2,6-Dichlorophenoxyacetonitrile (80.8 grams; 0.40 mole) was mixed with ethylenediamine monotosylate (94 grams; 0.40 mole) and 200 milliliters of 1,2-dichlorobenzene. Nitrogen gas was directed through the mixture while the mixture was ammonia of reaction was collected by passing the exit gases through a gas scrubber containing dilute aqueous hydrochloric acid. The reaction mixture was cooled and filtered to obtain 2- [ (2,6-dichlorophenoxy)methyl]-2-imidazoline tosylate, having a molecular weight of 417.3, as a filter cake. The 2- [ (2,6-dichlorophenoxy)methyl]- 2-imidazoline tosylate filter cake was dissolved in water. The solution was made basic by the addition of about 16 grams of sodium hydroxide in aqueous solution. The mixture was extracted with methylene chloride and the organic layer was separated and evaporated in vacuo to leave 2- [ (2,6-dichlorophenoxy)methyl]~2-imidazoline, having a mole- ■ cular weight of 245.1, as a residue. The 2- [ (2,6-dichloro-phenoxy)methyl]- 2-imidazoline was dissolved in 100 milliliters of isopropyl alcohol. The alcohol solution was acidified by the addition of 5 normal hydrochloric acid in isopropyl alcohol until precipitation was complete. The mixture was filtered and the 2- [ (2, 6-dichlorophenoxy)methyl] -2-imidazoline hydrochloride product was collected as a filter cake and found to melt at 221°-222°C. The structure of the product was confirmed by nuclear magnetic resonance spectroscopy.

In substantially the same procedure described above, employing similar inert organic solvents and substituting for the hydrochloric acid an acid capable of forming a physiologically-acceptable salt, the following 2- [ (2,6-dichlorophenoxy) methyl].-2-imidazoline salts are prepared; 2- [ (2,6-dlchlorophenoxy)methyl]-2-imidazoline hydro-bromide, 2- [ (2,6-dichlorophenoxy)methyl]-2-imidazoline sulfate, 2- [ (2, 6-dichlorophenoxy)methyl] -2-imidazoline succinate, 2- [ (2,6-dichlorophenoxy)methyl] -2-imidazoline maleate, 2- [ (2,6-dichloro-phenoxy)methyl]-2- imidazoline malate. chloride (17.8 grams; 0.06 mole) was mixed with ethylenediamine monotosylate (14.1 grams; 0.06 mole) and 100 milliliters of 1,2-dichlorobenzene. Nitrogen gas was directed through the mixture while the mixture was heated for about four hours at a temperature of about 82°C. The ammonia of reaction was collected by passing the exit gases through a gas scrubber containing dilute aqueous hydrochloric acid. The reaction mixture was evaporated in vacuo to obtain 2- [ (2 ,6-dichloro-3-methylphenoxy) methyl] -2-imidazoline tosylate, having a molecular weight of 431.3, as a residue. The 2- [ (2,6-dichloro-3-methylphenoxy) methyl ]-2-imidazoline tosylate residue was dissolved in water acidified to pH 4 with hydrochloric acid. The solution was made basic by the addition of aqueous sodium hydroxide to a pH of about 13. The solution was extracted with methylene chloride and the extract was evaporated in vacuo to leave 2-[(2,6-dichloro-3"»methylphenoxy)methyl]-2-imidazoline, having a molecular weight of 259.1, as a residue. The 2- [ (2,6-dichloro-3-methylphenoxy)methyl] -2-imidazoline was dissolved in about 100 milliliters of dimethoxyethane . The solution was acidified by the addition of about 6 normal hydrochloric acid in isopropyl alcohol until precipitation was complete. The mixture was filtered and the 2- [ (2,6-dichloro-3-methylphenoxy)methyl]-2-imldazoline hydrochloride product was collected as a filter cake and found to melt at 229°-230°C. The structure of the product was confirmed by nuclear magnetic, resonance spectroscopy.

In substantially the same procedure, 2- [ (2,6-dibromo-3-methylphenoxy)methyl]-2-imidazoline hydrochloride, having a molecular weight of 384.5, is prepared.

EXAMPLE 4 . 2-Chloro-6-meth lphenoxyacet.onitrile (54.5 grams; grams; 0.30 mole) and 100 milliliters of 1, 2-dichlorobenzene . Nitrogen gas was directed through the mixture while the mixture was heated at a temperature of 130°-145°C. for two hours. The ammonia of reaction was collected by passing the exit gases through a gas scrubber containing dilute aqueous hydrochloric acid. The reaction mixture was cooled and filtered to obtain 2- [ (2-chloro-6-methylphenoxy)methyl]-2-imidazoline tosylate, having a molecular weight of 396.8, as a filter cake. The 2- [ (2-chloro-6-methylphenoxy)methyl]- 2-imidazoline tosylate filter cake was mixed with water and the mixture was made basic by the addition of about 12 grams of sodium hydroxide in water. The mixture was extracted with methylene chloride and the organic layer was separated and evaporated in vacuo to leave 2- [ (2-chloro-6-methylphenoxy)methyl]-2-imidazoline, having a molecular weight of 224.6, as a residue. The 2- [ (2-chloro-6-methylphenoxy)methyl]-2-imidazoline was dissolved in about 100 milliliters of isopropyl alcohol. The alcohol solution was acidified by the addition of 5 normal hydrochloric acid in isopropyl alcohol until precipitation was complete. The mixture was filtered and the 2- [ (2~chloro-6-methylphenoxy)methyl]-2-imidazoline hydrochloride product was collected as a filter cake and found to melt at 218°-219°C. The product was found to have a chloride equivalent weight of 261 as compared with the chloride equivalent weight of 261 calculated for the named structure.

EXAMPLE 5 2-Bromo-6-chlorophenoxyacetonitrile (74 grams; 0.30 mole) was mixed with ethylenediamine monotosylate (70.5 grams; 0.30 mole) and 200 milliliters of 1, 2-dichlorobenzene . Nitrogen gas was passed through the mixture while the mixture was heated of reaction was collected by passing the exit gases through a gas scrubber containing dilute aqueous hydrochloric acid. The reaction mixture was cooled and filtered to obtain 2- [ (2-bromo-6-chlorophenoxy)methyl] -2-imidazoline tosylate, having a molecu-lar weight of 461.8, as a filter cake. The 2- [ (2-bromo-6-chlorophenoxy)methyl] -2-imidazoline tosylate filter cake was mixed with a mixture of methylene chloride and water to form a slurry. The slurry was made basic by the addition of about 12 grams of sodium hydroxide in water. The organic layer was separated and evaporated in vacuo to leave 2- [ (2-bromo-6-chloro-phenoxy)methyl ] -2-imidazoline , having a molecular weight of 289.6, as a residue. The 2- [ (2-bromo-6-chlorophenoxy)methyl]-2-imidazoline was dissolved in about 100 milliliters of isopropyl alcohol. The alcohol solution was acidified by the addition of 5 normal hydrochloric acid in isopropyl alcohol until precipitation was complete. The mixture was filtered and the 2-[(2-bromo-6-chlorophenoxy)methyl] ÷2-imidazoline hydrochloride product was collected as a filter cake and found to melt at 214°-215°C. The structure of the product was confirmed by nuclear magnetic resonance spectroscopy.

In substantially the same procedure and employing similar inert organic solvents, 2- [ (4-acetamido-2,6-dibromo-phenoxy)methyl] -2-imidazoline hydrochloride, melting at 235°-236 °C. , was prepared by mixing together equimolar proportions of 4-acetamido-2,6-dibromophenoxyacetonitrile and ethylene-diamine monotosylate, separating the tosylate salt, libertaing the free base by treatment with sodium hydroxide and preparing the hydrochloride by treatment with alcoholic hydrochloric acid. 2- [ (4-Acetamido-2 , 6-dichlorophenoxy)methy1] -2-imida-zoline hydrochloride is prepared in a similar manner. imidazoline hydrochloride (34.2 grams; 0.08 mole) was dissolved in 100 milliliters of aqueous 5 normal hydrochloric acid. The solution was heated on a steam bath for about 2.5 hours during which time a precipitate formed. The mixture was cooled and filtered and the filter cake was washed with aqueous 5 normal hydrochloric acid. The filter cake was dried and the 2- [ (4-amino-2, 6-dibromophenoxy)methyl] -2-imidazoline hydrochloride product was found to melt at 235°-236°C. The structure of the product was confirmed by nuclear magnetic resonance spectroscopy In substantially the same procedure, 2- [ (4-amino-2,6-dichlorophenoxy)methyl]-2-imidazoline hydrochloride, having a molecular weight of 296.5, is prepared.

The novel compounds corresponding to Formula I wherein Z corresponds to one of Formulae II, III, IV, V and VI and where in A is amino when Z corresponds to Formula IV or VI are useful as analgesics. Groups of mice were administered one of the test compounds at various dosage rates. The mice were subsequently challenged by the intraperitoneal injection of aqueous 0.1 percent hydrochloric acid at a dosage rate of 0.01 milliliter per gram. The mice were then placed in clear plastic cages and observed. In untreated mice, the intraperitoneal injection of this dosage of hydrochloric acid is followed by characteristic writhing of the mice, that is, flattening of the abdomen against the floor of the cage accompanied by rotation of the spine and pelvis. The dosage of each 2- (substituted phenoxy-methyl)-2-imidazoline hydrochloride which was effective to prevent writhing in 50 percent of the mice (ED 50) was calculated. The ED 50 's for the compounds tested and the routes of administration are set out in the following table.

TABLE I ED 50 in Milligrams Route of Compound Per Kilogram Administration 2- [ (2,6-Dibromophenoxy)-methyl] -2- imidazoline subcutaneous hydrochloride 0.54 injection 2- [ (2,6-Dichlorophenoxy)-methy1 ] -2-imidazoline subcutaneous hydrochloride 1.1 injection 2- [ (4-Amino-2,6-dibromo-phenoxy)methyl] -2- subcutaneous imidazoline hydrochloride 3.0 injection 2- [ (2,6-Dichloro-3-methyl-phenoxy)methyl] -2- subcutaneous imidazoline hydrochloride 0.9 injection 2- [ (2-Bromo-6-chlorophenoxy)-methyl] -2-imidazoline hydrochloride 2.0 oral In similar operations, representative compounds of the invention were administered to mice at dosage levels of 1, 2.5 or 25 milligrams per kilogram. For purposes of comparison, other 2- (substituted phenoxymethyl)- 2-imidazoline compounds were administered to separate groups of mice at a dosage level of 10 milligrams per kilogram. The mice were then challenged with hydrochloric acid as described above. The dosage rate for each compound and the percentage of mice in each group protected from writhing are set out in Table II.

TABLE II Compound 2- [ (2, 6-Dibromophenoxy)methyl] -2- imidazoline hydrochloride 2- [ (2,6-Dichlorophenoxy)methyl]-2-imidazoline hydrochloride 2- [ (2-Bromo-6-chlorophenoxy)methyl ] -2-imidazoline hydrochloride 2- [ (4-Amino-2,6-dibromophenoxy)methyl]-2-imidazoline hydrochloride 2- [ (2 ,6-Dichloro-3-methylphenoxy)methyl] -2- imidazoline hydrochloride 2- [ (2-Chloro-6-methylphenoxy)methyl]-2-imidazoline hydrochloride 2- [ (2 ,4-Dichlorophenoxy)methyl] -2- imidazoline hydrochloride 2- [ (2-Bromophenoxy)methyl] -2-imidazoline hydrochloride 2- [ (2-Chlorophenoxy)methyl]-2-imidazoline hydrochloride The ethyl 2 , 6-dihalo-3-methylphenoxyacetimide hydrochloride employed as a starting material herein can be prepared according to known procedures. In a representative operation, 0.07 mole of 2,6-dichloro-3-methylphenoxyacetonitrile, 4.4 milliliters of ethanol and 250 milliliters of diethyl ether were mixed together. The mixture was saturated with hydrochloric acid for about one hour at 0°-5°C. The mixture was concentrated by evaporation and filtered, and the ethyl 2 ,6-dichloro-3-methylphenoxyacetimide hydrochloride was collected as a filter cake. The substituted phenoxyacetonitriles employed as starting materials are likewise prepared by conventional methods. In a representative operation, 2,6-dibromophenol (101 grams; 0.40 mole) was mixed with 55 grams (0.40 mole) of anhydrous potassium carbonate and 200 milliliters of dimethylsulfoxide. The mixture was stirred at 70°C. while chloroacetonitrile (32 grams; 0.42 mole) was added dropwise over a 15 minute period. The mixture was held at a temperature of 75°C. for three hours after which it was cooled and filtered. The filtrate was distilled and the 2,6-dichlorophenoxyacetonitrile product was collected as a fraction boiling at 135°-138°C. under a pressure of 2-3 millimeters of mercury. The product was recrystallized from cyclohexane and the 2,6-dichlorophenoxyacetonitrile product was found to melt at 63°-63.5°C.

EXAMPLE 7 4-Acetamido-3-chlorophenoxyacetonitrile (17.5 grams; 0.083 mole) is mixed with ethylenediamine p-toluenesulfonate (20 grams; 0.086 mole) and 100 milliliters of 1,2-dichlorobenzene. Nitrogen is passed through the mixture while the mixture is heated at the boiling temperature under reflux for about 1 hour. The ammonia of reaction is collected by passing the exit gases neutralized with dilute aqueous hydrochloric acid. The reaction mixture is cooled and the solvent is decanted off to obtain 2- [ (4-acetamido-3-chlorophenoxy)methyl ] -2-imidazoline p- toluenesulfonate as a residue. The 2- [ (4-acetamido-3-chloro-phenoxy)methyl] -2- imidazoline p-toluenesulfonate is dissolved in water and the solution is made basic by the addition of about 20 milliliters of aqueous 5 normal sodium hydroxide. The mixture is extracted with methylene chloride to separate the 2- [ (4-acetamido-3-chlorophenoxy)methyl] -2-imidazoline as a solution of the free base in methylene chloride. The methylene chloride extract is acidified by the addition of excess gaseous hydrogen chloride until precipitation is complete. The mixture is filtered and the 2- [ (4-acetamido-3-chlorophenoxy)methyl]r2-imidazoline hydrochloride product is collected as a filter cake.

The 2- [ (4-acetamido-4-chlorophenoxy)methylJ-2-imidazoline hydrochloride is dissolved in 100 milliliters of aqueous 5 normal hydrochloric acid. The mixture is heated on a steam bath for about 2.5 hours, during which time a precipitate forms. The mixture is cooled and filtered. The filter cake is washed with aqueous 5 normal hydrochloric acid and dried. The 2- [ (4-amino-3-chlorophenoxy)methyl] -2-imidazoline dihydrochloride product is found to melt at 285°C. The structure of the product is confirmed by infrared spectroscopy.

In substantially the same procedure described above and employing similar inert organic solvents, 2- [ (4-amino-3-chlorophenoxy)methyl] -2-imidazoline dihydrobromide is prepared. EXAMPLE 8 4-Acetamido-3,5-dichlorophenoxyacetonitrile (22 grams; 0.10 mole) is mixed with ethylenediamine p-toluenesulfonate (23.5 grams; 0.10 mole) and 100 milliliters of 1,2-dichloro- mixture is heated at the boiling temperature under reflux for about 2 hours. The ammonia of reaction is collected by passing the exit gases through a gas scrubber containing dilute aqueous hydrochloric acid. The reaction mixture is cooled and filtered to obtain 2- [ (4-acetamido-3,5-dichlorophenoxy)methyl]-2-imida-zoline p-toluenesulfonate as a filter cake. The filter cake is mixed with water and the mixture is made basic by the addition of about' 3.2 grams of sodium hydroxide in aqueous solution.

The mixture is then extracted with methylene chloride and the organic layer is evaporated in vacuo to leave 2- [ (4-acetamido-3,5-dichlorophenoxy)methyl]-2-imidazoline as a residue. The 2- [ (4-acetamido-3,5-dichlorophenoxy)methyl]-2-imidazoline is dissolved in about 100 milliliters of isopropyl alcohol.and excess alcoholic hydrochloric acid is added until precipitation is complete. The mixture is filtered and the 2- [ (4-acetamido-3 ,5-dichlorophenoxy)methyl] -2-imidazoline hydrochloride product is collected as a filter cake.

The 2- [ (4-acetamidO-3,5,-dichlorophenoxy)methyl]-2-imidazoline hydrochloride is dissolved in about 100 milliliters of aqueous 5 normal hydrochloric acid. The mixture heated on a steam bath for about 2.5 hours. The mixture is cooled and filtered, and the filter cake is washed with aqueous hydrochloric acid and dried. The 2- [ (4-amino-3,5,-dichlorophenoxy)methyl]-2-imidazoline dihydrochloride product is found to melt at 232°-234°C.

In substantially the same procedure described above and employing similar inert organic solvents but substituting for the 4-acetamido-3 ,5-dichlorophenoxyacetonitrile, an appropriate substituted phenoxyacetonitrile , the following halophenoxymethylimidazoline salts are formed; 2- [ (4-Amino-3 ,5-dibromophenoxy)methyl] -2-imidazoline EXAMPLE 9 4-Acetamido-3-trifluoromethylphenoxyacetonitrile (21.9 grams; 0.1 mole) is mixed with ethylenediamine p-toluene-sulfonate (23.5 grams; 0.1 mole) and about 100 milliliters of 1, 2-dichlorobenzene . Nitrogen gas is passed through the mixture while the mixture is heated at the boiling temperature under reflux for about 2 hours. The ammonia of reaction is collected by passing the exit gases through a gas scrubber containing dilute aqueous hydrochloric acid. The reaction mixture is cooled and filtered to obtain 2- [ (4-acetamido-3-trifluoromethyl-phenoxy)methyl]-2-imidazoline p-toluenesulfonate as a filter cake. The filter cake is dissolved in water and the solution is made basic by the addition of about 20 milliliters of aqueous 5 normal sodium hydroxide. The mixture is extracted with methylene chloride and the extract is evaporated in vacuo to leave 2- [ (4-acetamido-3-trifluoromethylphenoxy)methyl] -2-imidazoline as a residue. The residue is dissolved in about 100 milliliters of isopropanol and an isopropanol solution of hydrochloric acid is added until precipitation is complete.

The mixture is filtered and the 2- [ (4-acetamido-3-trifluoro-methylphenoxy)methyl] -2-imidazoline hydrochloride product is collected as a filter cake.

The 2- [ (4-acetamido-3-trifluoromethylphenoxy)methyl]-2-imidazoline hydrochloride is dissolved in about 100 milli-liters of aqueous 5 normal hydrochloric acid. The mixture heated on a steam bath for about 2.5 hours. The mixture is cooled and aqueous sodium hydroxide is added to bring the pH of the resulting mixture to about 13. The mixture is extracted with methylene chloride and the methylene chloride extract is evaporated in vacuo to leave the product as a residue. The In substantially the same procedure described above and employing similar inert organic solvents, 2- [ (4-amino-3-bromophenoxy)methyl]-2-imidazoline is prepared.

Antidepressant activity of the new compounds was indicated by reversal of reserpine-induced depression in mice. In representative operations, separate halophenoxymethylimida-zolihe compounds were administered to separate groups of mice at various dosage rates by intraperitoneal injection. One hour after the dose of the halophenoxymethylimidazoline compound, reserpine was administered to each mouse at a dosage rate of 5 milligrams per kilogram by intraperitoneal injection. The administration of 5 milligrams per kilogram of reserpine intra-peritoneally to mice results in a progression of signs starting with drooping of the eyelids (ptosis) and pilo-erection and culminating in a generalized depression with decreased spontaneous motor activity and decreased responsiveness to auditory or tactile stimuli.

Following the administration of the reserpine, the test animals were observed for the above signs of depression. A reversal of reserpine depression was indicated when the mice were observed to exhibit increased spontaneous motor activity and increased responsiveness to stimuli. The dosage of representative halophenoxymethylimidazoline compounds effective to reverse reserpine depression in 50 percent of the mice (ED 50) was calculated. 2- [ (4-Amino-3-chlorophenoxy)methyl]-2-imida-zoline dihydrochloride was found to have an ED 50 of 0.9 milligram per kilogram. 2- [ (4-Amino-3,5-dichlorophenoxy)methyl]-2- imidazoline dihydrochloride was found to have an ED 50 of 2.5 milligrams per kilogram. The ED 50 for 2- [ (4-amino-3-trifluoromethylphenoxy)methyl]-2-imidazoline was found to be In other operations, 2- [ (4-amino-3 ,5 ,-dichlorophenoxy) methyl] -2-imidazoline dihydrochloride was found to block convulsions induced by Metrazol (pentylenetetrazol) in mice with an ED 50 of 2.75 milligrams per kilogram by intraperitoneal injection.

EXAMPLE 10 3,4-Dichlorophenoxyacetonitrile (20.2 grams; 0.10 mole) was mixed with ethylenediamine monotosylate (23.5 grams; 0.10 mole) and 75 milliliters of 1,2-dichlorobenzene. Nitrogen gas was directed through the mixture while the mixture was heated at the boiling temperature under reflux for three hours. The ammonia of reaction was collected by passing the exit gases through a gas scrubber containing dilute aqueous hydrochloric acid. The reaction mixture was cooled and filtered to obtain 2- [ (3,4-dichlorophenoxy)methyl]-2-imidazoline tosylate as a filter cake. The 2- [ (3,4-dichlorophenoxy)methyl]-2-imidazoline tosylate filter cake was mixed with a mixture of methylene chloride and water to form a slurry and the slurry was made basic by the addition of about 0.10 mole of sodium hydroxide in aqueous solution. The organic layer was separated and evaporated in vacuo to leave 2- [ (3,4-dichlorophenoxy)methyl]-2-imidazoline as a residue. The 2- [ (3,4-dichlorophenoxy)methyl]-2 imidazoline was dissolved in 100 milliliters of isopropyl alcohol. The alcohol solution was acidified by the addition of 5 normal hydrochloric acid in isopropyl alcohol until precipitation was complete. The mixture was filtered and the 2- [ (3, -dichlorophenoxy)methyl] -2-imidazoline hydrochloride product was collected as a filter cake and found to melt at 244°-245°C. The product was found to have a neutral weight of 280 as compared with the equivalent weight of 281.5 calculated In substantially the same procedure described above, employing similar inert organic solvents and substituting for the hydrochloric acid an acid capable of forming a pharmaceu-tically-acceptable salt, the following 2- [ (3 ,4-dichlorophenoxy) methyl] -2-imidazoline salts are prepared; 2- [(3, , -Dichlorophenoxy)methyl]- 2-imidazoline hydrobromide , 2- [ (3,4-dichlorophenoxy)methyl]-2- imidazoline sulfate, 2- [ (3,4-dichlorophehoxy)methyl]-2-imidazoline succinate, 2- [ (3,4-dichlorophenoxy)methyl]-2-imidazoline maleate, 2- [ (3,4-dichlorophenoxy)methyl]- 2-imidazoline malate.

EXAMPLE 11 3 ,4-Dibromophenoxyacetonitrile (0.1 mole) was mixed with ethylenediamine monotosylate (0.1 mole) and 100 milliliters of 1,2-dichlorobenzene. Nitrogen gas was directed through the mixture while the mixture was heated at a temperature of about 180°C. for about 3 hours. The ammonia of reaction was collected by passing the exit gases through a gas scrubber containing dilute aqueous hydrochloric acid. The reaction mixture was cooled and filtered to obtain 2- [ (3,4-dibromophenoxy)methyl]-2-imidazoline tosylate as a filter cake. The filter cake was mixed with a mixture of methylene chloride and water to form a slurry and the slurry was made basic by the addition of about 0.10 mole of sodium hydroxide in aqueous solution. The organic layer was separated and evaporated in vacuo to leave 2- [(3,4-dibromophenoxy)methyl]- 2-imidazoline as a residue. The 2-[(3,4-dibromophenoxy)methyl]-2-imidazoline was dissolved in about 100 milliliters of isopropyl alcohol. The alcohol solution was acidified by the addition of 5 normal hydrochloric acid in isopropyl alcohol until precipitation was complete. The mixture Was filtered and the 2- [ (3,4-dibromophenoxy)methyl] -2-imida In substantially the same procedure described above and employing similar inert organic solvents, 2- [ (3-bromo-4-chlorophenoxy)methyl] -2-imidazoline hydrochloride is prepared. EXAMPLE 12 2- [ (3, 4-Dichlorophenoxy)methyl]- 2- imidazoline (24.5 grams; 0.10 mole) was slurried in 50 milliliters of water and dimethylsulfate (9.6 milliliters; 0.10 mole) was added to the slurry with stirring. The temperature of the mixture rose from 25° to 55 °C. and the mixture was then held at 55°C. for one hour. Aqueous sodium hydroxide was added to bring the pH of the mixture to about 13. The mixture was extracted with methylene chloride and the extracts were evaporated in vacuo. The residue was dissolved in a minimal amount of isopropyl alcohol and an isopropyl alcohol solution of hydrochloric acid was added until precipitation was complete. The l-methyl-2-[ (3 ,4-dichlorophenoxy)methy1 ] -2-imidazoline hydrochloride product was recrystalllzed from ethanol and found to melt at 238°-240°C. The structure of the product was confirmed by nuclear magnetic resonance analysis.

In substantially the same procedure, l-methyl-2- [ (3,4-dibromophenoxy)methyl]-2-imidazoline hydrochloride is prepared by mixing together equimolar proportions of 2- [ (3,4-dibromo-phenoxy)methyl] -2-imidazoline and dimethylsulfate and treating the reaction product with hydrochloric acid.

EXAMPLE 13 The novel 2- [ (3,4-dihalophenoxy)methyl]-2-imidazoline compounds have utility as antidepressants as indicated by their antagonism to barbiturate-induced sedation in small rodents. This activity was indicated by their effectiveness in decreasing hexobarbital sleep time in mice. For purposes of comparison, minations, separate groups of mice received a dosage of one of the compounds at a rate of 1, 5 or 25 milligrams per kilogram one hour before intraperitoneal administration of hexobarbital at a dosage rate of 100 milligrams per kilogram. Separate groups of untreated mice were similarly injected with hexobarbital at a dosage rate of 100 milligrams per kilogram to serve as checks.

The hexobarbital injections induced sleep in the mice. All the animals were then placed on their backs and the period of time until each mouse turned over and righted itself was recorded as sleep time. The ratio of the average sleep time for the treated mice to that for the untreated mice is expressed as hexobarbital sleep time ratio in the following table.

TABLE III Dosage Level Hexobarbital Milligrams Per Sleep Time Compound Kilogram Ratio 2- [ (3 ,4-Dichlorophenoxy)-methyl] -2-imidazoline hydrochloride 25 0.37 2- [ (3,4-Dibromophenoxy)-methy1 ] -2-imidazo1ine hydrochloride 25 0.72 2- [ (3-Methyl-4-chlorophenoxy)-methyl] -2-imidazoline hydrochloride 25 1.33 2- [ (3-Chlorophenoxy)methyl] - 2-imidazoline hydrochloride 1 1.29 2- [ (4-Chlorophenoxy)methyl]" 2-imidazoline hydrochloride 5 1.20 EXAMPLE 14 2- [(3, 4-Dichlorophenoxy)methyl] -2-imidazoline also has central nervous system activity as indicated by its effectiveness in increasing the effects of d-amphetamine in mice.

In these operations, groups of mice were administered 2-[(3,4-dichlorophenoxy)methyl] -2-imidazoline hydrochloride at a dosage About 45 minutes after the administration of the test compound, the mice were administered 20 milligrams per kilogram of d-amphetamine sulfate by intraperitoneal injection. Immediately after the administration of amphetamine, the mice were aggre-gated by confining them in a cage small enough to maintain the mice in close proximity to one another. Similar groups of mice were similarly administered known aryloxyimidazoline compounds at dosage rates of 10 or 25 milligrams per kilogram, similarly treated with amphetamine and aggregated for comparison. A separate group of mice not pretreated with an aryloxyimidazoline compound was similarly treated with amphetamine and aggregated to serve as a check. The administration of 20 milligrams per kilogram of amphetamine to mice not pretreated with a compound having central nervous system activity normally results in hyper-excitement , tremors and fighting in the aggregated mice, followed by death. of the mice within about three hours. The ratio of the number of mice surviving for three hours to the total number of mice treated with an aryloxyimidazoline compound is expressed as percentage amphetamine antagonism in Table IV.

TABLE IV Dosage Level Amphetamine Milligrams Antagonism Compound Per Kilogram (Percent) 2- [ (3 ,4-Dichlorophenoxy)-methyl] -2-imidazoline hydrochloride 25 0* 2- [ (2,4-Dichlorophenoxy)-methyl] -2-imldazoline hydrochloride 10 50 2- [ (3-Methyl-4-chlorophenoxy)-methyl] -2-imidazoline hydrochloride 25 75 *The mice administered 2- [ (3,4-dichlorophenoxy)methyl]-2- imidazoline hydrochloride survived for a much shorter period - - In similar operations, a group of 10 mice (A) was simultaneously administered 2- [ (3,4-dichlorophenoxy)methyl]-2-imidazoline hydrochloride at a dosage rate of 25 milligrams per kilogram and d-amphetamine sulfate at a dosage rate of 5 milli-grams per kilogram by intraperitoneal injection. A similar group of mice (B) was administered d-amphetamine sulfate alone at a dosage rate of 5 milligrams per kilogram. This dosage rate of amphetamine normally is of minimal toxicity in untreated mice Two other groups of 10 mice (C) and (D) each were administered 31 and 40 milligrams per kilogram, respectively, of 2-[(3,4-dichlorophenoxy)methyl]-2-imidazoline hydrochloride. The four groups of mice were aggregated in small cages substantially as described above. The percentage of deaths for each group of mice is expressed as percent mortality in Table V.

TABLE V Dosage Rate Test Compound Milligrams Percent Group Administered Per Kilogram Mortality A 2-[(3,4-dichlorophenoxy)- 25 100 methyl] -2-imidazoline hydrochloride and d-amphetamine sulfate 5 B d-amphetamine sulfate 5 10 C 2- [ (3,4-dichlorophenoxy)- 31 0 meth l] -2-imidazoline hydrochloride P " . 40 0 In other operations, the intraperitoneal dosage of representative 2- [ (3,4-dihalophenoxy)methyl] -2-imidazoline compounds effective to reverse the antagonism of the anticonvulsant effects of diphenylhydantoin by reserpine in 50 percent of the mice tested (ED 50) was calculated. The ED 50 for reversal of the effect of reserpine by 2- [ (3 ,4-dichloro- be 0.49 milligram per kilogram. The ED 50 for 2- [ (3,4-dibromo-phenoxy)methyl]-2-imidazoline hydrochloride was determined to be 23 milligrams per kilogram. The ED 50 for 1-methyl-2- [ (3 ,4-dichlorophenoxy)methyl] -2~imidazoline hydrochloride was 8.2 milligrams per kilogram.

In other operations, the 50 percent effective dosages (ED 50) of 2- [ (3 ,4-dichlorophenoxy)methyl] -2-imidazoline hydrochloride for protection against the characteristic writhing induced by the intraperitoneal injection of 0.01 milliliter per grain of aqueous 0.1 percent hydrochloric acid were determined to be 11.7 milligrams per kilogram by subcutaneous injection and 31.5 milligrams per kilogram administered orally.

The 3,4-dichlorophenoxyacetonitrile employed as a starting material herein is prepared by known methods. In a representative operation, 3,4-dichlorophenol (81.5 grams; 0.50 mole) was mixed with 40 grams of chloroacetonitrile, 98 grams of anhydrous potassium carbonate and 100 milliliters of dimethyl sulfoxide. The mixture was held at a temperature of 75 °C. for three hours, after which it was cooled and diluted by the addition of about 2 liters of water. A precipitate formed on the addition of the water and the mixture was filtered and the filtrate discarded. The filter cake was recrystallized from cyclohexane and the 3 ,4-dichlorophenoxyacetonitrile product was found to melt at 61°-62°C.

Claims (18)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A member of the group of 2- (substituted phenoxy-methyl)-2-imidazoline compounds, and the physiologically-acceptable salts thereof, the compounds corresponding to the formula wherein Z of radicals corresponding to one of the formulae wherein Χ, Χ·^ and-X each independently represent chlorine or bromine, X' represents chlorine, bromine or methyl and A

2. The compound of Claim 1 wherein the compound is 2- [ (2,6-dibromophenoxy)methyl]-2-imidazoline hydrochloride.

3. The compound of Claim 1 wherein the compound is 2- [ (2,6-dibromophenoxy)methyl] -2-imidazoline.

4. The compound of Claim 1 wherein the compound is 2- [ (2,6-dichlorophenoxy)methyl]-2-imidazoline hydrochloride.

5. The compound of Claim 1 wherein the compound is 2·^ [ (2,6-dichlorophenoxy)methyl] -2-imidazoline.

6.. The compound of Claim 1 wherein the compound is 2-.[ (2 ,6-dichloro-3-methylphenoxy)methy1] -2-imidazoline hydrochloride.

7. ; 7. The compound of Claim 1 wherein the compound is 2- [ (2-chloro-6-methylphenoxy)methyl]-2-imidazoline hydrochloride.

8. The compound of Claim 1 wherein the compound is 2- [ (2-bromo-6-chlorophenoxy)methyl] -2-imidazoline hydrochloride .

9. The compound of Claim 1 wherein the compound is 2- { (2-bromo-6-chlorophenoxy)methy1] -2-imidazoline.

10. The compound of Claim 1 wherein the compound is 2- [ (4-amino-3-chlorophenoxy)methyl]-2-imidazoline dihydrochlor^ ide.

11. The compound of Claim 1 wherein the compound is 2- [ (4-amino-3-chlorophenoxy)methyl] -2-imidazoline .

12. The compound of Claim 1 wherein the compound is 2- [ (4-acetamido-3-chlorophenoxy)methyl] -2-imidazoline.

13. The compound of Claim 1 wherein the compound is 2- [ (4-amino-3,5-dichlorophenoxy)methyl]-2-imidazoline dihydrochloride.

14. The compound of Claim 1 wherein the compound is 2- [ (4-amino-3-trifluoromethylphenoxy)methyl] -2-imidazoline.

15. The compound of Claim 1 wherein the compound is

16. The compound of Claim 1 wherein the compound is 2- [ (3,4-dichlorophenoxy)methyl]-2-imidazoline hydrochloride.

17. The compound of Claim 1 wherein the compound is 2- [ (3 ,4-dichlorophenoxy)meth l] -2-imidazoline p-toluenesulfonate .

18. The compound of Claim 1 wherein the compound is l-methyl-2- [ (3,4-dichlorophenoxy)methyl] -2-imidazoline hydrochloride. DATED P. 0. Box 1169, Tel-Aviv Attorneys for Applicant - 30 -