KR840001284B1 - Process for preparation of 2-imidazoline derivatives - Google Patents

Abstract

Anilinoimidazolines(I; R1=substituted aryl; R2, R3=H, halogen, alkyl, alkoxy, alkanesulfonamido, haloalkyl, cabamoyl, NO2, amino, cyano, SO2NH2; A-O, CH2; n-1-2) used as antihypertensive, anti-inflammatory, analgesia, were prepd. by the reaction of III or its salt with ethylenediamine. In an example, 8.7g 1-[2-(3,5-dicholorophenoxy)Phenyl thiourea and 4.8g methyliodide in 100ml CH3OH was refluxed and stirred 1hr. A mixt. of the residue and 5.1g of ethylenediamine in 100cc methanol was refluxed and stirred 3hr. The product(X) was purified by recrystallization from ethylacetate gave 5.1g. (m.p 168-170≰C)

Description

[Name of invention]

Method for preparing 2-imidazoline derivatives

Detailed description of the invention

The present invention relates to a method for preparing 2-imidazoline derivatives, which provides useful pharmaceutical compositions of novel 2-imidazoline derivatives which are antihypertensive anti-inflammatory, analgesic and anti-ulcer agents.

The imidazoline derivatives, which are the target compounds of the present invention, are novel and represent the following general formula (I) compounds and their pharmaceutically acceptable salts.

In the above structural formula

R ¹ is halogen, lower alkyl, lower alkoxy, mono (or di or tri) -halo (lower) alkyl, nitro, amino, cyano, sulfamoyl, N, N-di (lower) alkylsulfamoyl and di (lower) Phenyl or naphthyl having 1-5 substituents selected from alkylamino and the like;

R ² and R ³ are each hydrogen, halogen, lower alkyl, lower alkoxy, lower alkanesulfonamido, mono (or di or tri) -halo (lower) alkyl, carbamoyl, hydroxy, nitro, amino, cyano , Sulfamoyl, N, N-di (lower) alkylsulfamoyl, or di (lower) alkylamino capable of forming a 3 to 7-membered ring with or without oxygen or nitrogen atoms;

A is -0-, or -CH _2- ;

n is 0 or 1.

With regard to the target compound (I), the following points should be noted. That is, in the target compound (I), the "2-imidazolin-2-ylamino group" may be represented by a tautomeric group, that is, "imidazoline-2-ylideneamino group" and is in the state of tautomer equilibrium. The above mentioned groups may be represented by the next parallelism.

The above forms of tautomerism between the "2-imidazolin-2-ylamino" group and the "imidazoline-2-ylideneamino" group are well known in the art and those skilled in the art are familiar with the tautomers. It can be clearly seen that they are in a parallel and interconvertible state. These isomers therefore fall within the same category of target compound (I). Accordingly, tautomers are expressly within the scope of this invention.

에 의해 표시되는 호변이성체의 그룹을 표함한다.In the present specification, the target compound (I) is a structural formula of the "2-imidazolin-2-ylamino" group

Group of tautomers represented by.

The target compound (I) of the present invention is prepared by the following method.

[Method 1]

In the above structural formula

R ¹ , R ² , R ³ , A and n are each as defined above;

R ⁴ is hydrogen or acyl;

X ² is acid residue;

Y is lower alkyl;

Suitable pharmaceutically suitable salts of the desired compound (I) are conventionally non-toxic salts such as inorganic acid salts (i.e. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), organic acids (i.e. oxalate, malate, puma). Latex, tartrate, metalsulfonate, lactate, benzenesulfonate, toluenesulfonate and the like or salts with amino acids (ie, arginine, aspartic acid, lysine, glutamic acid, etc.). In the foregoing and subsequent descriptions of this specification, the preferred embodiments to be covered within the scope of the invention and the description for the various definitions are described in detail as follows.

The term "lower" means 1-6 carbon atoms, and "advanced" means 7-18 carbon atoms, unless otherwise noted.

Suitable “aryls” include phenyl, naphthyl; Suitable “lower alkyls” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl; "Lower alkoxy" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy; “Lower alkanesulfon amidos” include methanesulfonamido, ethanesulfonamido; Suitable “mono (or di or tri) -halo (lower) alkyl” include chloromethyl, dibromomethyl, trifluoromethyl, dichloroethyl; "N, N-di (lower) alkylsulfamoyl" means N, N-dimethylsulfamoyl, N-methyl-N-ethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-diisoprosulfamoyl , N, N-dibutylsulfamoyl, N, N-dipentylsulfamoyl, N, N-dihexylsulfamoyl; “Di (lower) alkylamino capable of forming a 3-7-membered ring with or without oxygen or nitrogen atoms” is di (lower) alkylamino (ie dimethylamino, methylethylamino, dipropylamino, diisopropylamino , Dibutylamino, dipentylamino, dihexylamino, etc.), 1-aziridinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-imidazolidinyl, 1-piperazinyl, 4- Loweralkyl-1-piperazinyl (ie 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-propyl-1-piperazinyl, 4-butyl-1-piperazinyl; Suitable “acid residues” refer to the halogens, azido, acyloxys (ie benzene sulfonyloxy, soil oxy) already mentioned and the like.

Suitable “acyl” includes acyl groups containing aliphatic acyl group aromatic rings (hereinafter referred to as aromatic acyl), acyl groups representing heterocycling (hereinafter referred to as heterocyclic acyl), and the like.

Examples of such acyl are as follows;

Aliphatic acyls such as lower or higher alkanoyl (ie formyl, acetyl, succinyl, hexanoyl, heptanoyl, stearoyl, etc.);

Lower or higher alkoxycarbonyl, ie methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); Aliphatic acyl such as lower or higher alkanesulfonyl (ie, methanesulfonyl, ethanesulfonyl, etc.); Aroyl (ie benzoyl, toloyl, taftoyl, etc.); Phenyl (lower) alkanoyl (ie, phenylacetyl, phenylpropionyl, etc.); Aryloxycarbonyl (ie, phenoxycarbonyl, naphthyloxycarbonyl, etc.); Phenoxy (lower) alkanoyl (ie, phenoxyacetyl, phenoxypropionyl, etc.) arylglyoxyloyl (ie, phenylglyoxyloyl, naphthylglyoxyloyl, etc.); arensulfonyl (ie, Aromatic acyls such as benzenesulfonyl, P-toluenesulfonyl, etc .; heterocyclic carbonyl (ie, tennoyl, furoyl, nicotinoyl, etc.); heterocyclic (lower) alkanoyl (ie, thienyl) Acetyl, thiazolylacetyl, tetrazolylacetyl, etc.), heterocyclic acyl such as heterocyclicglyoxyloyl (ie, thiazolylglyoxyloyl, thienylglyoxyloyl, etc.).

The acyl moieties as mentioned above may have one or multiple, same or other suitable substituents, such as lower alkyl, as already mentioned: lower alkoxy (ie methoxy, ethoxy, propoxy, etc.); Lower alkylthio (ie, methylthio, ethylthio, etc.); Lower alkylamino (ie, methylamino, etc.); Cyclo (lower) alkyl (ie cyclopentyl, cyclohexyl, etc.); Cyclo (lower) alkenyl (ie, cyclohexenyl, cyclosesadienyl, etc.); Halogen as already mentioned; Amino; Hydroxy; Cyano; Nitro; Carboxybox; Sulfo; Sulfamoyl; Imino; Oxo; Amino (lower) alkyl (ie, aminomethyl, aminoethyl, etc.);

The preparation method of the target compound (I) of the present invention is described in detail below.

[Method 1]

(1) Preparation of Intermediate (IV)

Compound (IV) or salts thereof can be prepared by reacting compound (VI) or salts thereof with isothiocyanate compound (V). Suitable salts of compound (VI) are illustrated for compound (I). The reaction is carried out in the presence of solvents or other solvents such as acetone, methanol, tetrahydrofuran, chloroform, benzene, which have no adverse effect on the reaction. The reaction is preferably carried out at ambient temperature or under warming. The obtained compound (IV) can be used in the next step reaction without separation.

(2) Preparation of Intermediate (III)

Compound (III) or salts thereof can be prepared by diacylating a compound (IV) wherein R ⁴ is acyl or a salt thereof.

Suitable salts of compound (III) are exemplified for general formula (I).

The diacylation reaction is carried out by conventional methods such as hydrolysis, reduction and desorption using Lewis acids.

Of these methods, hydrolysis is a common and preferred method, and hydrolysis can be preferably carried out in the presence of a base or an acid.

Suitable bases include tri (lower) alkylamines (ie trimethylamine, triethylamine, etc.), pyridine, picoline, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4- Diazabicyclo [2,2,2] octane, 1,5-diazabicyclo [5,4,0] undecene-5, alkalimethylacetate (ie sodium acetate, potassium acetate), alkali metal lower alkoxide (I.e. sodium methoxide, sodium ethoxide, potassium tert-butoxide), alkali metal hydrides (i.e. sodium hydride, potassium hydride, etc.), alkali metal hydroxides (i.e. sodium hydroxide, potassium Hydroxides, etc.), alkali earth metal hydroxides (ie, magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonates (ie, sodium carbonate, potassium carbonate, etc.), alkali metal carbonates Nate (ie magnesium carbonate, calcium carbonate Sites, etc.), alkali metal bicarbonate (i. E., Containing an organic or inorganic base such as sodium bicarbonate, potassium bicarbonate).

Suitable acids include organic or inorganic acids such as formic acid, trifluoroacetic acid, benzenesulphonic acid, P-toluenesulphonic acid hydrochloric acid. The reaction is carried out in solvents such as water, methanol and ethanol. The reaction is carried out at ambient temperature and warming.

(3) Preparation of Intermediate (II)

Compound (II) or salts thereof can be prepared by reacting compound (III) or salts thereof with compound (iii).

Suitable salts of compound (III) are illustrated for compound (I). The reaction is usually carried out in solvents such as methanol, ethanol or other solvents which have no adverse effect on the reaction, and the reaction can be carried out in the presence of a base as already mentioned.

The reaction is carried out at ambient temperature or under warming. The product obtained can be used directly in the next reaction without separation.

(4) Preparation of the target compound (I).

The desired compound (I) or salts thereof can be prepared by reacting compound (II) or (III) or salts thereof with ethylenediamine or salts thereof.

Suitable salts of compound (II) are illustrated for compound (I). The reaction is usually carried out in solvents such as methanol, ethanol or other solvents which have no adverse effect on the reaction.

The reaction is carried out at ambient temperature or under warming.

The following pharmaceutical test data shows that the target compound (I) of the present invention has high and persistent antihypertensive, anti-inflammatory, analgesic and anti-ulcerative effects and is useful for treating hypertension, inflammation, gastrointestinal disorders and pain of various causes. have.

1. Antihypertensive activity

[Test Methods]

Five Vista rats are used per group. Each animal is secured in a cage suitable for its body. Blood pressure is measured in the femoral artery by a pressure artificial transducer and recorded as an electrically complete value of mean arterial pressure, and the beat rate is determined by a Pals wavelength detector. Manipulation for catheterization proceeds under mild anesthesia with ether. Test compound (10 mg / kg) is administered orally 3 hours after the operation is completed.

[Test Compound]

Compound A: 2- (2-phenoxy-5-chlorophenyl) amino-2-imidazoline

Compound B: 2- (2-phenoxy-5-methylphenyl) amino-2-imidazoline

[Test result]

The average ratio of Δ maximum decrease in blood pressure (mmHg) is shown in the following table.

TABLE 1

2. Anti-inflammatory activity

Test Methods :

Ten Sprague-Dieurey rats are used per group. 0.1 ml of carrageenan (1.5%) is injected subcutaneously in the rat's right paw. Three hours later the animals were lethal. Weigh the normal and swelling soles.

The difference in weight between the swelling sole and the normal sole is measured.

Test compound (100 mg / kg) is administered orally 60 minutes prior to stimulant administration. The swollen paw of the treated animal is compared to the control animal.

Test result :

2- (2-phenoxy-4-methylphenyl) amino-2-imidazoline

Inhibitory effect: 48.4%

3. Analgesic activity

Test Methods :

10 female ddy strain mice are used to administer each. To estimate the frequency of writhing syndrome, animals were observed 0.2 ml / 10 g of 0.6% acetic acid after 3-13 minutes intraperitoneal injection. The drugs were administered orally 60 minutes before the injection of acetic acid. The frequency of warping syndrome in treated animals was compared to untreated animals.

Test result :

ED ₅₀ values were calculated according to the Richfield Wilcoxon method. 2-2- (3,4,5-trimethoxyphenoxy) phenyl amino-2-imidazoline.

ED ₅₀ value: 50.1 mg / kg

4. Antiulcer activity

Test Methods :

HEIDENHAIN porches were prepared in a healthy beagle system several weeks before the experiment. No food was given but water was supplied for 18-24 hours before the experiment. During the experiment, catheter was inserted with care to prevent bacteria from entering the vein.

Pentagastrin is injected at 10 μg / kg / hour via catheter to obtain the lowest gastric secretions. Once the secretion of Plato is obtained, the test compound (1 mg / kg) is injected intravenously. The volume of secretions is measured at 15 minute intervals and the corresponding acid emissions are calculated at μEqH + / 15 minutes.

[Test Compound]

Compound A: 2- (2-biphenylyl) amino-2-imidazoline

Compound B: 2- (2-phenylthiophenyl) amino-2-imidazoline

[Test result]

The results are calculated as% reduction of gastric acid secretion and are shown in the following table.

TABLE 2

As can be seen from the test results, the target compound (I) of the present invention is useful for antihypertensive, anti-inflammatory, analgesic and anti-ulcer drugs. Effective ingredients are taken at 0.1-500 mg / kg 1-4 times a day in preparations such as tablets, granules, powders, tests, injections, supplements.

However, the dosage may be increased or decreased depending on age, weight or patient's condition or method of administration.

The above-mentioned formulations can be prepared by conventional methods using conventional carriers and additives.

The invention is illustrated by the following examples.

The temperature unit used is Celsius (° C).

[Production of Starting Compound]

[Manufacture 1]

To a solution of ammonium thiocyanate (7.2 g) dissolved in dry acetone (70 mL) is added benzoyl chloride (12.1 g) with stirring at 50-55 °. The reaction is continued for 1 hour at this temperature. To a mixture containing benzoyl isothiocyanate is added dropwise, 2-phenoxy-5-methoxyaniline (17.6 g) dissolved in dry acetone (180 mL), while stirring at room temperature. The reaction mixture is refluxed for one hour with stirring to remove the solvent, and then water is added to the residue.

The precipitated crystals are collected by filtration, washed sequentially with water and a small amount of methanol and dried to give 1- (2-phenoxy-5-methoxyphenyl) -3-benzoylthiourea (28.9 g). Melting Point 163-165 °

[Manufacture 2]

The following compounds are obtained following a method analogous to Preparation 1.

[Manufacture 3]

Reflux for 3 days with stirring a suspension of 1- (2-phenoxy-6-chlorophenyl) -3-benzoylthiourea (8.6 g) dissolved in a solution of water (50 mL) and sodium hydroxide (2.0 g) Let's do it.

The reaction mixture is acidified with concentrated hydrochloric acid and extracted with chloroform (200 mL). The extract is washed sequentially with a 4% aqueous ammonia (twice) solution and a saturated aqueous solution of sodium chloride, dried over magnesium and sulphate and evaporated under reduced pressure. To the residual oil is added a mixture of n-hexane and petroleum ether.

Collected by filtration of precipitated crystals and dried to give 1- (2-phenoxy-6-chlorophenyl) thiaurea (5.9 g). Melting Point 107-120 °

[Manufacture 4]

50-60 ° of a solution of 1- (2-phenoxy-5-methoxyphenyl) -3-benzoylthiourea (28.6 g) dissolved in a solution of methanol (290 mL) and potassium hydroxide (4.2 g) Stir for 10 minutes. The reaction mixture is cooled and then evaporated.

The residue is washed with water and dried to give 1- (2-phenoxy-5-methoxyphenyl) thiourea (21.0 g). Melting Point 143-167 °

[Manufacture 5]

The following compounds are obtained following methods analogous to preparations 3 and 4.

[Manufacture 6]

To a solution of ammonium thiocyanate (4.55 g) dissolved in dry acetone (100 mL) is added benzoyl chloride (7.4 g) over 5 minutes with stirring at 50 °.

The mixture is refluxed with stirring for 40 minutes. To the resulting mixture containing benzoyl isothiocyanate, 2-phenoxaniline (7.2 g) dissolved in dry acetone (50 mL) was added dropwise over 10 minutes with stirring at 50 °, and then the mixture was stirred for 30 minutes. Reflux with stirring. After removing the solvent, water (100 mL) is added.

A precipitate comprising 1- (2-phenoxyphenyl) -3-benzoylthiourea is collected by filtration and washed with water.

The precipitate is added to a mixture of 10% sodium hydroxide (100 mL) aqueous solution and methanol (80 mL) with stirring at 50 ° and then stirring is continued at this temperature for 30 minutes. The reaction mixture is cooled to precipitate crystals, collected by filtration, washed with water and dried to obtain 1- (2-phenoxyphenyl) thiourea (8.5 g). Melting Point 122-125 °

[Manufacture 7]

The following compounds are obtained following methods analogous to preparation 6.

[Preparation of target compound]

Example 1

A solution of 1- [2- (3,5-dichlorophenoxy) phenyl] thiourea (8.7 g) and methyl iodide (4.8 g) in dry methanol (100 mL) was refluxed with stirring for 1 hour. . The reaction mixture is cooled and then evaporated under reduced pressure.

Methanol (100 mL) and ethylenediamine (5.1 g) are added to the residue, and the mixture is refluxed with stirring for 3 hours.

The reaction mixture is evaporated under reduced pressure and an aqueous solution of sodium carbonate and methylene chloride is added to the residue. The methylene chloride layer is separated, washed with water, dried over magnesiumsulfate and evaporated. The residue is recrystallized from ethyl acetate to give 2- [2- (3,5-dichlorophenoxy) phenyl] -2-imidazoline (5.1 g). Melting point 168 to 170 °

Elemental Analysis:

Calculated Value: C 55.92, H 4.07, N 13.04

Found: C 55.88, H 4.01, N 12.92

Example 2

The following compounds are obtained following the method analogous to Example 2.

Elemental Analysis:

Calculated Value: C 52.07, H 3.91, N 9.59

Found: C 52.22, H 3.80, N 9.61

Elemental Analysis:

Calculated Value: C 71.89, H 6.41, N 15.72

Found: C 71.50, H 6.38, N 15.54

Elemental Analysis:

Calculated Value: C 71.89, H 6.41, N 15.72

Found: C 72.06, H 6.41, N 15.55

Elemental Analysis:

Calculated Value: C 69.05, H 5.07, N 29.13

Found: C 68.98, H 4.70, N 19.81

Elemental Analysis:

Calculation: C 63.68, H 5.34, N 13.93

Found: C 63.51, H 5.30, N 13.89

Elemental Analysis:

Calculation: C 68.89, H 6.80, N 18.91

Found: C 68.81, H 6.74, N 18.72

Elemental Analysis:

Calculation: C 68.89, H 6.80, N 18.91

Found: C 68.72, H 6.77, N 18.92

59) 2- [2-phenoxy-5- (1-pyrrolidinyl) phenyl] amino-2-imadazoline, melting point 203 to 208 °

Elemental Analysis:

Calculated Value: C 70.78, H 6.88, N 17.38

Found: C 70.61, H 6.83, N 17.23

Elemental Analysis:

Calculation: C 56.65, H 5.95, N 15.55

Found: C 56.91, H 5.60, N 15.52

Claims (1)

A method for producing 2-imidazoline derivatives of general formula (I) by reacting a compound of general formula (III) or a salt thereof with ethylenediamine or a salt thereof.

Wherein R ¹ is halogen, lower alkyl, lower alkoxy, mono (or di or tri) -halo (lower) alkyl, nitro, amino, cyano, sulfamoyl, N, N-di (lower) alkylsulfamoyl and Phenyl or naphthyl having 1-5 substituents of di (lower) alkyl amino; R ² and R ³ are hydrogen, halogen, lower alkyl, lower alkoxy, lower alkanesulfonamido, mono (or di or tri) -halo (lower) alkyl, carbamoyl, hydroxy, nitro, amino, cyano , Sulfamoyl, N, N-di (lower) alkylsulfamoyl, or di (lower) alkylamino capable of forming a 3 to 7 membered ring with or without oxygen or nitrogen atoms; A is -0- or -CH _2- ; n is 0 or 1;