2-IMIDAZOLINE DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF AND THE PHARMACEUTICAL COMPOSITION OF THE SAME

Abstract: Compounds of the general formula: wherein R¹ is aryl which may have 1 to 5 substituent(s) selected from the groups consisting of halogen, lower alkyl, lower alkoxy, lower alkanesulfonamido, mono(or di or tri)-halo(lower)alkyl, carbomoyl, hydroxy, nitro, amino, cyano, sulfamoyl, N,N-di(lower)alkylsulfamoyl, and di(lower­ )alkylamino which may form a 3 to 7-membered ring with or without an oxygen or nitrogen atom;

Description: 2-IMIDAZOLINE DERIVATIVES, PROCESS FOR PREPARATION THEREOF AND PLIARMACEUTICAL COMPOSITION OF THE SAblE This invention relates to 2-imidazoline derivatives. Nore particularly, it relates to new 2-imidazoline derivatives which have antihypertensive, anti-inflammatory, analgesic and anti-ulcer activities, to processes for the preparation thereof, and to pharmaceutical composition comprising tile same for therapeutical treatment of hyper- tensive, inflammatory and gastrointestinal disorder and for relief from pain of various origins in human being. Accordingly, one object of this invention is to provide new and useful 2-imidazoline derivatives. Another object of this invention is to provide processes for the preparation of 2-imidazoline derivatives. A further object of this invention is to provide useful pharmaceutical composition comprising said 2imidazoline derivatives as antihypertensive, antiinflammatory, analgesic and anti-ulcer agents. Still further object of the present invention is to provide a therapeutical method of treating hypertensive, inflammatory and gastrointestinal disorder and of relieving pain of various origins. The object imidazoline derivatives of the present invention are novel and include the compound of the formula (I): EMI2.1 wherein R1 is aryl which may have 1 to 5 substituent(s) selected from the groups consisting of halogen, lower alkyl, lower alkoxy, lower alkanesulfonamido, mono(or di or tri)-halo (lower)alkyi, carbamoyl, hydroxy, nitro, amino, cyano, sulfamoyl, N,N-di (lower)alkyl- sulfamoyl and di(lower)alkylamino which may form a 3 to 7-membered ring with or without an oxygen or another nitrogen atom; ; R2 and R3 are each hydrogen, halogen, lower alkyl, lower alkoxy, lower alkanesulfonamido, mono (or di or tri)-lialo(lower)alkyl, carbamoyl, hydroxy, nitro, amino, cyano, sulfamoyl, N,N-di(lower)alkylsulfamoyl or di(lower) alkylamino which may form a 3 to 7-membered ring with or without an oxygen or nitrogen atom; A is -1)-, -S- or -CE12-; and n is an integral number of (3 or 1. and pharmaceutically acceptable salt thereof. As to the object compound (I), the following points are to be noted. That is, the "2-imidazline- 2-ylamino group in the object compound (I) can be alternatively represented by its tautomeric group, i.e. "imidazolidin-2-ylideneamino group, and both of the said groups are in the state of tautomeric equilibrium which can be represented by the following equilibrium: EMI3.1 These types of tautomerism between "2-imidazolin-2ylamino" group and "imidazolidin-2-ylideneamino" group have been well known in the arts, and it is obvious to a person skilled in the arts that both of the tautomeric isomers are equilibrated and lie in the reciprocally convertible state, and accordingly it is to be understood that such isomers are included within the same category of the object compound ti) per se. Accordingly, the both of the tautomeric forms are clearly included within the scope of the present invention . In the present specification, the object compound (I) including the group of such tautomeric isomers is represented by using one of the expressions, i.e. "2-imidazolin-2-ylamino" group and the formula: EMI3.2 only for the convenient sake. The object compound (I) of the present invention can be prepared by the following processes. EMI4.1 or a salt thereof or a salt thereof Process 2 EMI4.2 or a salt thereof or a salt thereof Process 3 EMI5.1 or a salt thereof or a salt thereof wherein R1, R2, R3, A and n are each as defined above; R4 is hydrogen or acyl; x2 and X5 are each an acid residue; Y is lower alkyl; and RaÚ is the same as RÚ, and Ra is hydrogen or nitro, provided that RaÚ is aryl substituted with nitro when Ra is hydrogen; and RbÚ is the same as RÚ, and Rb is hydrogen or amino, provided that Rb is aryl substituted 3 with amino when Rb is hydrogen. Suitable pharmaceutically acceptable salts of the object compounds (I) are conventional non-toxic salts and may include an inorganic acid salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), an organic acid salt (e.g. oxalate, maleate, fumarate, tartrate, methanesulfonate, lactate, benzenesulfonate, toluenesulfonate, etc.) or a salt with an amino acid (e.g. arginine, aspartic acid, lysine, glutamic acid, etc.) and the like. In the above and subsequent description of the present specification, suitable examples and illustrations for the various definitions to be incluted within the scope of the invention are explained in details as follows. The term "lower" is intended to mean 1 to 6 carbon atom(s) and the term "higher" is intended to mean 7 to 18 carbon atoms, unless otherwise indicated. Suitable "aryl" may include phenyl, naphthyl and the like. Suitable "halogen" may include fluorine, chlorine, bromine and iodine. Suitable "lower alkyl" may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like. Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy and the like. Suitable "lower alkanesulfonamido" may include methanesulfonamido, ethanesulfonamido, p-ropanesulfonamido, isopropanesulfonamido, butanesulfonamido, hexanesulfonamido and the like. Suitable "mono(or di or tri)-halo(lower)alkyl" may include chloromethyl, dibromomethyl, trifluoromethyl, dichloroethyl and the like. "Suitable N,N-di(lower)alkylsulfamoyl" may include N,N-dimethylsulfamoyl, N-methyl-N-ethylsulfamoyl, N,Ndipropylsulfamoyl, N,N-diisopropylsulfamoyl, N,N- dibutylsulfamoyl, N+N-dipentylsulfamoyl, N,Ndihexylsulfamoyl and the like. Suitable "di(lower)alkylamino which may form a 3 to 7-membered ring with or without an oxygen or another nitrogen atom" may include di (lower) alkylamino (e.g. dimethylamino, methylethylamino, dipropylamino, diisopropylamino, dibutylamino, dipentylamino, dihexylamino, etc.), l-aziridinyl, l-pyrrolidinyl, piperidino, morpholino, l-imidazolidinyl, l-piperazinyl, 4-lower alkyl-l-piperazinyl (e.g. 4-methyl-l-piperazinyl, 4-ethyl-l-piperazinyl, 4-propyl-l-piperazinyl, 4-butyl l-piperazinyl, etc.), and the like. Suitable "an acid residue" may include halogen as aforementioned, azido, acyloxy (e.g. benzenesulfonyloxy, tosyloxy, etc.), and the like. Suitable "acyl" may include aliphatic acyl group, acyl group containing an aromatic ring (hereinafter referred to as aromatic acyl), acyl group containing a heterocyclic ring (hereinafter referred to as heterocyclic acyl), and the like. Suitable example of said acyl may be illustrated as follows: Aliphatic acyl such as lower or higher alkanoyl (e.g. formyl, acetyl, succinyl, hexanoyl, heptanoyl, stearoyl, etc.);. lower or higher alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); lower or higher alkanesulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.); or the like. Aromatic acyl such as aroyl (e.g. benzoyl, toluoyl, naphthoyl, etc.); phenyl (lower) alkanoyl (e.g. phenylacetyl, phenylpro- pionyl, etc.); aryloxycarbonyl (e.g. phenoxycarbonyl, naphthyloxy carbonyl, etc.); phenoxy(lower)alkanoyl (e.g. phenoxyacetyl, phenoxy propionyl, etc.); arylglyoxyloyl (erg. phenylglyxyloyl, naphthylglyoxy loyl, etc.); arenesulfonyl (e.g. benzenesulfonyl, p-toluenesulfonyl, etc.); or the like; Heterocyclic acyl such as heterocycliccarbonyl (e.g. thenoylX furoyl, nicotinoyl, etc.); heterocyclic (lower) alkanoyl (e.g. thienylacetyl, thiazolylacetyl, tetrazolylacetyl, etc.); heterocyclicglyoxylcyl (e.g. thiazolylglyoxyloyl, thienylglyoxyloyl, etc.); or the like. The acyl moiety as stated above may have one or more, same or different, suitable substituent(s) such as lower alkyl as aforementioned; lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.); lower alkylthio (e.g. methylthio, ethylthio, etc.); lower alkylamino (e.g. methylamino, etc.); cyclo(lower)alkyl (e.g. cyclopentyl, cyclohexyl, etc.); cyclo(lower)alkenyl (e.g. cyclohexenyl; cyclohexadienyl, etc.); halogen as aforementioned; amino; hydroxy; cyano; nitro; carboxy; sulfo; sulfamoyl; imino; oxo; amino(lower)alkyl (e.g. Åaminomethyl, aminoethyl, etc.), or the like. The processes for preparing the object compounds (I) of the present invention are explained in details in the following. Process 1 (1) Preparation of The intermediate (IV) The compound (IV) or a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the isothiocyanate compound (V). The suitable salts of the compound (VI) can be referred to those exemplified for the compound (I). The present reaction is usually carried out in the precence of a solvent such as acetone, methanol, tetrahydrofuran, chloroform, benzene or any other solvents which do not adversely affect the reaction. The reaction temperature is not critical and the reaction is preferably carried out at ambient temperature or under heating. Thus obtained compound (IV) can be used in the next step reaction without isolation. (2) Preparation of the intermediate (III) The compound (III) or a salt thereof can be prepared by subjecting the compound (IV) wherein R4 is acyl or a salt thereof to deacylation reaction. The suitable salt of the compound (IV) can be re ferred to those exemplified for the compound (I). The present deacylation reaction is carried out in accordance with a conventional method such as hydrolysis, reduction, elimination using a LewiS acid, or the like. Among these methods, hydrolysis is one of the common and preferable method, and the hydrolysis can preferably be carried out in the presence of a base or an acid. Suitable base may include an organic or inorganic base such as tri(lower)alkylamine (e.g. trimethylamine, triethylamine, etc.), pyridine, picoline, 1,5diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]- octane, 1,5-diazabicyclo[5,4,0lundecene-5, alkali metal acetate (e.g. sodium acetate, potassium acetate etc.), alkali metal lower alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc .),.alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), or the like. Suitable acid may include an organic or inorganic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid,p-toluenesulfonic acid, hydrochloric acid or the like. The present reaction is usually carried out in a solvent such as water, methanol, ethanol and the like. The reaction temperature is not critical and the reaction is preferably carried out at ambient temperature or under warming. (3) Preparation of the intermdiate (II) The compound (11) or a salt thereof can be prepared by reacting the compound (III) or a salt thereof with the compound (VIII). Suitable salts of the compound (III) can be refer red to those exemplified for the compound (I). The present reaction is usually carried out in a solvent such as methanol, ethanol or any other solvents which do not adversely affect the reaction. The present reaction can be carried out in the presence of a base as aforementioned. The reaction temperature is not critical and the reaction is preferably carried out at ambient temperature or under warming. The obtained product can be used directly in the next step reactions without isolation. (4) Preparation of the object comnound (I) The object compound (I) or a salt thereof can be prepared by reacting the compound (11) or (I II) or a salt thereof with ethylenediamine or a salt thereof. Suitable salts of the compound (II) can be referred to those exemplified for the compound (I). The present reaction is usually carried out in a solvent such as methanol, ethanol or any other solvents which do not adversely affect the reaction. The reaction teierature is not critical and the reac tion is preferably carried ou at ambient temperature or under warming. Process 2 The compound (I) or a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the compound (VII). The present reaction is usually carried out in a solvent such as methanol, diethyl ether or any other solvents which do not adversely affect the reaction. The present reaction can be carried out in the presence of a base as aforementioned. The reaction temperature is not critical and the reaction is preferably carried out at ambient temperature or under warming. Process 3 The compound (Ia) or its salt can be prepared by reducing the compound (Ib) or a salt thereof. The reduction is conducted by a conventional method which can be applied for the reduction of a nitro group into an amino group, such as reduction of using a metal (e.g. iron, zinc, etc.) and an acid (e.g. hydrochloric acid, etc.); reduction in the presence of a metallic catalyst. The metallic catalysts for the catalytic reduction include, for example, platinum catalyst (e.g. platinum wire, spongy platinum, platinum black, platinum colloid, etc.), palladium catalyst (e.g. palladium spongy, palladium black, palladium oxide, palladium on barium sulfate, palladium on barium carbonate, palladium on charcoal, palladium on silica gel, palladium colloid, etc.), nickel catalyst (e.g. reduced nickel, nickel oxide, Raney nickel, Urushibara nickel, etc.), and the like. The present reaction is usually carried out in a solvent such as methanol, ethanol or any other solvents which do not adversely affect the reaction. The reaction temperature is not critical and the reaction is preferably carried out under cooling, at ambient temperature or under warming. The following pharmacological test data show that the object compound (I) of the present invention exhibits high and long lasting antihypertensive, anti-inflammatory analgesic and anti-ulcer activities and are accordingly useful in the treatment of hypertensive, inflammatory and gastrointestinal disorder and in the relief from pain of various origins. 1. Antihypertensive activity Test method: Five Wistar rats were used per group. Each animal was immobilized in a cage sized to the body. Blood pressure was measured at the femoral artery by means of a pressure transducer and recorded as electrically integrated values of mean arterial pressure, and heart rate was determined by a pulse wave detector. Operation for the catheterization was performed under light anesthesia with ether. The test compound (10 mg/kg) was administered orally 3 hours after completion of the operation. Test compound: Compound A : 2-(2-Phenoxy-5-chlorophenyl)amino-2 imidazoline Compound B : 2-(2-Phenoxy-5-methylphenyl)amino-2- imidazoline Test results: Mean ratios of A maximum decrease of blood pressure (mmHg) were shown in the following table. (Table 1) EMI13.1 <tb> Test <SEP> compound <SEP> Effect <SEP> () <SEP> <tb> <SEP> Compound <SEP> A <SEP> 57 <tb> <SEP> Compound <SEP> B <SEP> 53 <tb> 2. Anti-inflammatory activity Test method: Ten Sprague-Dawley rats were used per group. The right hind paw of the rat was injected subcutaneously under the plantar surface with 0.1 ml of carrageenin .5%). After 3 hours, the animals were sacrificed. The normal and edematous hind paws were cut off at the tibio-dorsal joint and weighed. The difference in the weight of edematous paw and that of normal paw was a measure of the edema. The test compound (100 mg/kg) was administered orally 60 minutes before the irritating agent. Paw swelling of treated animals was compared with that of control animals. Test results: 2- (2-Phenoxy-4-methylphenyl) amino-2-imidazoline. Inhibitory effect : 48.4% 3. Analgesic activity Test method: Ten male ddy strain mice were used for each dose. To estimate the frequency of writhing syndrome, the animals were observed from 3 to 13 minutes after an intraperitoneal injection of 0.2 my/10 g of 0.6t acetic acid. The drugs were given orally 60 minutes before acetic acid. The frequency of writhing syndrome in the treated animals was compared with that in the non-treated control animals. Test results: The ED50 value was calculated according to Litchfield Wilcoxon method. 2-[2-(3,4,5-Trimethoxyphenoxy)phenyllamino-2-imidazoline ED50 value: 50.1 mg/kg. 4. Anti-ulcer activity Test method: Heidenhain pouches were prepared in healthy beagle dogs several weeks before the experiments. Food was withheld out but water allowed for 18 to 24 hours before each experiment. On the day of the experiment intravenous catheter was inserted with aseptic precautions. Penta gastrin was infused at 10 pg/kg/hour via the catheter to get submaximal gastric secretion. Once a platean of the secretion was obtained, the test compound (1 mg/kg) was injected intravenously. The volume of secretion was measured at 15 minutes intervals and the corresponding acid output was calculated in uEqH+/ 15 minutes. Test compound: Compound A : 2-(2-Biphenylyl)amino-2-imidazoline Compound B : 2-(2-Phenylthiophenyl)amino-2-imidazoline Test results: Results were calculated as maximal % reduction in gastric acid secretion and shown in the following table. (Table 2) EMI15.1 <tb> <SEP> Test <SEP> compound <SEP> | <SEP> Effect <SEP> <SEP> Q <SEP> <tb> Compound <SEP> A <SEP> 73.2% <tb> <SEP> Compound <SEP> B <tb> As being apparent from the above test results, the object compound (I) of the present invention is useful for the antihypertensive, anti-inflammatory, analgesic and anti-ulcer medicines. The effective ingredient may usually be administered with a dose of 0.1 mg/kg to 500 mg/kg, 1 to 4 times a day in a preparations such as tablet, granule, powder, capsule, syrup, injection, suppository and the like. However , the above dosage may be increased or decreased according to the age, weight or conditions of the patient or the administering method. The above mentioned preparations can be prepared in a conventional manner by using conventional carriers and additives. The present invention is illustrated by the following Examples. Preparation of the starting compounds Preparation 1 To a solution of ammonium thiocyanate (7.2 g.) in dry acetone (70 ml.) was added benzoyl chloride (12.1 g.) with stirring at 50 to 550C. The reaction was continued for an hour at this temperature. To the mixture containing benzoyl isothiocyanate was dropwise added a solution of 2-phenoxy-5-methoxy- aniline (17.6 g.) in dry acetone (180 ml.) with stirring at room temperature.. The reaction mixture was refluxed for an hour with stirring. After removal of the solvent, water was added to the residue. The precipitated crystals were collected by filtration, washed successively with water and a small amount of methanol and then dried to give l-(2-phenoxy-5- methoxyphenyl)-3-benzoylthiourea (28.9 g.), mp. 163 to 1650C. Preparation 2 The following compounds were obtained according to the similar manner to that of Preparation 1. 1) l-[2-(3-Chlorophenoxy)phenyl]-3-benzoylthiourea, mp. 112 to 121 C. 2) 1-[2-(4-Chlorophenoxy)phenyl]-3-benzoylthiourea, mp. 149 to 158 C. 3) l-j2-(2,6-Dichlorophenoxy)phenyl]-3-benzoyl- thiourea, mp. 200 to 2050C. 4) 1- [2-(3,4-Dichlorophenoxy)phenyl]-3-benzoyl- thiourea, mp. 141 to 1420C. 5) 1-[2-(3,5-Dichlorophenoxy)phenyl]-3-benzoyl thiourea, mp. 134 to 1350C. 6) 1-[2-(o-Tolyloxy)phenyl]-3-benzoylthiourea, mp. 165 to 1660C. 7) 1-[2-(n-Tolyloxy) phenyl]-3-benzoylthiourea, mp. 144 to 1480C. 8) 1-[2-(n-Tolyloxy) phenyl]-3-benzoylthiourea, nip. 187.5 to 188.50C. 9) 1- [2-(3,4,5-Trimethoxyphenoxy)phenyl]-3- benzoylthiourea, mp. 146 to 1490C. 10) 1-[2-(4-Fluorophenoxy)phenyl]-3-benzoylthiourea, mp. 137 to 1400C. 11) 1-[4-(n-Tolyloxy) phenyl]-3-benzoylthiourea, mp. 170 to 1720C. 12) 1-[2-(4-Tolyloxy) phenyl]-3-benzoylthiourea, mp. 146 to 1480C. 13) 1-(2-phenoxy-3-clorophenyl)-3-benzoylthiourea, mp. 137 to 141 C. 14) 1- (2-Phenoxy-4-chlorophenyl) -3-benzoylthiourea, mp. 164 to 1660C. 15) 1-(2-Phenoxy-5-chlorophentyl)-3-benzoythiourea, mp. 163 to 1660C. 16) l-(2-Phenoxy-6-chlorophenyl)-3-benzoylthiourea, mp. 141 to 1580C. 17) 1-(2-Phenoxy-3-chlorophentyl)-3-benzoythiourea, mp. 146 to 1480C. 18) 1-(2-Phenoxy-5-chlorophentyl)-3-benzoythiourea, mp. 175 to 1800C. 19) 1-(2-Phenoxy-6-chlorophentyl)-3-benzoythiourea, mp. 141 to 1450C. 20) 1-(2-Phenoxy-5-chlorophentyl)-3-benzoythiourea, nip. 183 to 1860C. 21) 1-(2-Phenoxy-5-nitrophenyl)-3-benzoylthiourea, mp. 210 to 2120C. 22) 1- (2-Phenoxy-5-methanesulfonamidophenyl)-3- benzoylthiourea, mp. 231 to 2320C. 23) 1-(2-Phenoxy-5-chlorophentyl)-3-benzoythiourea, mp. 206 to 2080C. 24) 1-(2-Phenoxy-6-chlorophentyl)-3-benzoythiourea, mp. 213 to 215 C. 25) 1-(2-Phenoxy-5-trifluoromethylphenyl)-3 benzoylthiourea, mp. 170 to 1720C. 26) 1-[2-(4-chlorophenoxy)-5-chlorophenyl]-3 benzoylthiourea, mp. 183 to 1890C. 27) 1-[2-(4-chlorophenoxy)-5-methylphenyl]-3 benzoylthiourea, mp. 196 to 197 C. 28) 1-(2-Phenylthiophenyl)-3-benzoylthiourea, mp. 65 to 750C. 29) 1-(2-Phenylthiophenyl)-3-benzoylthiourea, mp. 132 to 133 C. 30) 1-(4-Phenylthiophenyl)-3-benzoylthiourea, mp. 123 to 1260C. 31) 1-(3-Phenylthiophenyl)-3-benzoylthiourea, mp. 71 to 80 C. 32) 1-[2-(1-Naphthiloxy) phenyl]-3-benzoylthiourea, mp. 132 to 160 C. 33) 1-(2-Biphenylyl)-3-benzoylthiourea, mp. 125 to 126 C. 34) 1-[2-(4-Clorophenyl) phenyl]-3-benzoylthiourea, mp. 120 to 122 C. 35) 1-[2-Phenyl-4-chlorophenyl3-3-benzoylthiourea, mp. 190 to 191 C. 36) 1-[2-Phenyl-5-clorophenyl]-3-benzoylthiourea, mp. 138 to 140 C. 37) 1- (2-Phenoxy-5-dimethylaminophenyl) -3- benzoylthiourea, mp. 144 to 1520C. 38) 1-[2-(2-Fluorophenyl)phenyl]-3-benzoylthiourea, mp. 124 to 126 C. 39) 1-[2-(2-Chlorophenyl)phenyl]-3-benzoylthiourea, mp. 163 to 165 C. 40) 1-(2-Phenyl-6-clorophenyl)-3-benzoylthiourea, mp. 197 to 200 C. 41) 1-[4-(2,3-Dimethylphenoxy)-2,6-dichlorophenyl]-3 benzoylthiourea, mp. 166 to 1710C. 42) 1-[2-(3-Fluorophenyl)phenyl]-3-benzoylthiourea, mp. 84 to 1130C. 43) 1-[2-(o-Tolyl)phenyl]-3-benzoylthiourea, mp. 141 to 1460±. 44) 1-[2-(p-Tolyl)phenyl]-3-benzoylthiourea, mp. 118 to 121 C. 45) 1-[2-(4-Fluorophenyl)phenyl]-3-benzoylthiourea, mp. 104 to 1160C. 46) 1-(2-Phenoxy-5-morpholinophenyl)-3- benzoylthiourea, mp. 176 to 1840C. 47) 1-(3-Biphenylyl)-3-benzoylthiourea, mp. 157 to 158 C. 48) 1-(2-Phenyl-3-chlorophenyl)-3-benzoylthiourea, mp. 116 to 129 C. 49) 1-[2-(4-Dimetylaminophenoxy)phenyl)]-3-benzoyl thiourea, mp. 203 to 208 C. 50) 1-[2-Phenoxy-5-(1-pyrrolidini)phenyl]-3 benzoylthiourea, mp. 157 to 165 C. 51) 1-[2-(m-Tolyl)phenyl]-3-benzoylthiourea, mp. 102 to 106 C. 52) 1-[2-(Nitrophenyl)phenyl]-3-benzoylthiourea, mp. 79 to 94 C. I.R. (Nujol) : 3420, 1675 cm 53) 1-[2-(2,4-Difluorophenyl)phenyl]-3-benzoylthiourea, I.R. (Film) : 3415, 3220, 3155, 3040, 3025, 1670 cm 1 54) l-[2-Phenoxy-5-(N,N-dimethylsulfamoyl)ph benzoylthiourea, mp. 140 to 1450±. 55) 1-[2-(2,6-Difluorophenyl)phenyl]-3-benzoylthiourea, mp. 145 to 155 C. 56) 1-(2-Phenyl-5-methylphenyl)-3-benzoylthiourea, mp. 134 to 136 C. 57) 1-[2-(2-Methoxyphenyl)phenyl]-3-benzoylthiourea, mp. 139 to 144 C. (58) l-[2-(2-Trifluoromethylphenyl)phenyl]-3 benzoylthiourea, mp. 139 to 1450±. (59) l-[2-(2-Dimethylaminophenyl)phenyl]-3 benzoylthiourea, mp. 154 to 1640±. (60) 1-[2-(3-Chloro-4-sulfamoylphenoxy)phenyl]-3 benzoylthiourea. I.R. (Nujol) : 3370, 3245, 1670, 1375, 1180 cm Preparation 3 A suspension of 1-(Z-phenoxy-6-chlorophenyl)-3- benzoylthiourea (8.6 g.) in a solution of sodium hydroxide (2.0 g.) in water (50 ml.) was refluxed with stirring for 30 minutes. The reaction mixture was cooled acidified with conc. hydrochloric acid and extracted with chloroform (200 ml.). The extract was washed successively with 4% aqueous solution of ammonia (twice) and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated under reduced pressure. To the residual oil, a mixture of n-hexan and petroleum ether was added. The precipitated crystals were collected by filtration and dried to give l-(2-phenoxy- 6-chlorophenyl) thiourea (5.8 g),mp.107 to 120 C. Preparation 4 A solution of 1-(2-phenoxy-5-methoxyphenyl)-3- benzoylthiourea (28.6 g.) in a solution of potassium hydroxide (4.2 g.) in methanol (290 ml.) was stirred for 10 minutes at 50-600C, The reaction mixture was cooled and then evaporated. The residue was washed with water and dried to give l-(2-phenoxy-5-methoxy- phenyl)thiourea (21.0 g.), mp. 143 to 167 C. Preparation 5 The following compounds were obtained according to the similar manner to those of Preparation 3 and 4. 1) 1-(2-Phenoxyphenyl)thiourea, mp. 122 to 125 C. 2) l-[2-(2-Chlorophenoxy)phenyl]thiourea, mp. 125 to 128 C. 3) 1-[2-(3-Chlorophenoxy)phenyl] thiourea, mp. 102 to 107 C. 4] 1-[2-(4-Chlorophenoxy)phenyl] thiourea, mp. 139 to 1470±. 5) 1-[2-(2,6-Dichlorophenoxy)phenyl] thiourea, mp. 186 to 190 C. 6) 1-[2-(3,4-Dichlorophenoxy)phenyl] thiourea, mp. 147 to 150 C. 7) 1-[2-(3,5-Dichlorophenoxy)phenyl] thiourea, mp. 148 to 150 C. 8) 1- [2-(o-Tolyloxy)phenyl]thiourea, mp. 135 to 136 C. 9) 1-[2-(m-Tolyloxy)phenyl] thiourea, mp. 104 to 1060±. 10) 1-[2-(p-Tolyloxy)phenyl] thiourea, mp. 154 to 155 C. 11) 1-[2-(3,4,5-Trimethoxyphenoxy)phenyl] thiourea, mp. 154 to 158 C. 12) 1-[2-(4-Fluorophenoxy)phenyl] thiourea, mp. 139 to 1410±. 13) 1-[2-(4-Bromophenoxy)phenyl] thiourea, mp. 155 to 157 C. 14) 1-[2-(4-Cyanophenoxy)phenyl] thiourea, mp. 159 to 161 C. 15) l-(2-Phenoxy-3-chlorophenyl)thiourea, mp. 133 to 1420±. 16) 1-(2-Phenoxy- 4-clorophenyl) thiourea, mp. 137 to 138 C. 17) 1-(2-Phenoxy-5-chloropheny)thiourea,mp.140 to 145 C. 18) 1-(2-Phenoxy-3-methylphenyl)thiourea, mp. 141 to 145 C. 19) 1-(2-Phenoxy-4-methylphenyl)thiourea, mp. 131 to 133 C. 20) 1-(2-Phenoxy-5-methylphenyl)thiourea, mp. 161 to 163 C. 21) 1-(2-Phenoxy-6-methylphenyl)thiourea, mp. 137 to 1420±. 22) 1-(2-Phenoxy-5-hydroxyphenyl)thiourea, mp. 174 to 176 C. 23) 1-(2-Phenoxy-5-nytroprohenyl)thiourea, mp. 147 to 157 C. 24) 1-(2-Phenoxy-5-methanesulfonamidophenyl) thiourea, mp. 191 to 195 C. 25) 1-(2-Phenoxy-5-cyanophenyl)thiourea, mp. 187 to 189 C. 26) 1-(2-Phenoxy-5-carbamoylphenyl)thiourea, mp. 195 to 196 C. 27) 1-(2-Phenoxy-5-trifluoromethylphenyl)thiourea, mp. 159 to 160 C. 28) 1-[2-(4-Clorophenoxy-5-clorophenyl]thiourea, mp. 149 to 165 C. 29) 1-[2-(4-Clorophenoxy-5-metylphenyl]thiourea, mp. lo8 to 113 C. 30) 1-(2-Phenylthiophenyl)thiourea,mp. 99 to 103 C. 31) l-(2-Benzylphenyl)thiourea, mp. 125 to 126 C. 32) l-(4-Phenoxyphenyl)thiourea, mp. 181 to 1840±. 33) 1-(3-Phenoxyphenyl)thiourea, mp.98 to 120 C. 34) 1-[2-(1-Naphthyloxy)phenyl]thiourea, mp. 172 to 179 C. 35) 1-(2- Biphenylyl )thiourea, mp. 184 to 185 C. 36) 1-[2-(4-Chlorophenyl)phenyl]thiourea, mp. 199 to 201 C. 37) 1-[2-Phenyl-4-chlorophenyl]thiourea, mp 205 to 206 C. 38) 1-[2-Phenyl-5-chlorophenyl]thiourea, mp. 187 to 189 C. 39) 1-(2-Phenyl-5-dimetylaminophenyl]thiourea, mp. 163 to 1640±. 40) 1-[2-(2-Fluorophenyl)phenyl]thiourea, mp. 195 to 197 C. 41) 1-[2-(2-Clorophenyl)phenyl]thiourea, mp. 190 to 192 C. 42) 1-(2-Phenyl-6-chlorophenyl)thiourea, mp. 171 to 176 C. 43) 1- [4-(2,3-Dimethylphenoxy)-2,6-dichlorophenyl]- thiourea, mp. 93 to 113 C. 44) 1-[2-(3-Fluorophenyl)phenyl]thiourea, mp. 159 to 1620±. 45) l-[2-(o-Tolyl)phenyl]thiourea, mp. 142 to 144 C. 46) l-[2-(p-Tolyl)phenyl]thiourea, mp. 193 to 195 C. 47) 1-[2-(4-Fluorophenyl)phenyl]thiourea, mp. 158 to 161 C. 48) l-(2-Phenoxy-5-sulfamoylphenyl)thiourea, mp. 97 to 102 C. 49) 1-(2-Phenoxy-5-morpholinophenyl]thiourea, mp. 189 to 193 C. 50) l-(3- Biphenylyl)thiourea, mp. 183 to 185 C. 51) l-(2-Phenyl3-chlorophenyl)thiourea, mp. 186 to 188 C. 52) 1-[2-(4-Dimethylaminophenoxy)phenyl]thiourea, mp. 191 to 1940±. 53) l-[2-Phenoxy-5-(1-pyrrolidinyl)phenyl]thiourea, mp. 192 to 196 C. 54) 1-[2-(m-Tolyl)phenyl]thiourea, mp. 128 to 136 C. 55) 1-[2-(2-Nitrophenyl)phenyl]thiourea, mp. 186 to 194 C. 56) l-[2-(2,4-Difluorophenyl)phenyl]thiourea, mp. 153 to 157 C. 57) 1-[2-Phenoxy-5-(N,N-dimethylsulfamoyl)phenyl3- thiourea, mp. 153 to 157 C. 58) 1-[2-(2,6-Difluorophenyl)phenyl]thiourea, mp. 232 to 234 C. 59) 1-(2-Phenyl-5-methylphenyl)thiourea, mp. 187 to 192 C. 60) 1-[2-(2-Methoxyphenyl)phenyl]thiourea, mp. 154 to 158 C. 61) 1-[2-(2-Trifluoromethylphenyl)phenyl]thiourea, mp. 186 to 187 C. 62) 1-[2-(2-Dimethylaminophenyl)pnenyl]thiourea, mp. 151 to 1540±. 63) 1-[2-(3-Chloro-4-sulfamoylphenoxy)phenyl]thiourea, I.R. (Film) : 3325, 3200, 1350, 1170 cm 1 Preparation 6 To a solution of ammonium thiocyanate (4.55 g.) in dry acetone (100 ml.) was added benzoyl chloride (7.4 g.) over a period of 5 minutes with stirring at 50 C. The mixture was refluxed with stirring for 40 minutes. To the resulting mixture containing benzoyl isothiocyanate was dropwise added a solution of 2-phenoxyaniline (7.2 g.) in dry acetone (50 ml.) over a period of 10 minutes with stirring at 50 C and then the mixture was refluxed with stirring for 30 minutes. After removal of the solvent, water (100 ml.) was added. The precipitates containing 1-(2-phenoxyphenyl)-3-benzoylthiourea were collected by filtration and washed with water. The precipitates were added to a mixture of 10% aqueous solution of sodium hydroxide (100 ml.) and methanol (80 ml.) with stirring at 50 C and then stirring was continued for 30 minutes at this temperature. The reaction mixture was chilled to precipitate crystals, which were collected by filtration, washed with water and then dried to give l-(2-phenoxyphenyl)thiourea (8.5 g.), mp. 122 to 125 C. Preparation 7 The following compounds were obtained according to the similar manner to that of Preparation 6. 1) 1-[2-(2-Chlorophenoxy)phenyl]thiourea, mp. 125 to 128 C. 2) 1-[2-(3-Chlorophenoxy)phenyl]thiourea, mp. 102 to 107 C. 3) 1-[2-(4Chlorophenoxy)phenyl]thiourea, mp. 139 to 1470±. 4) 1-[2-(2,6-Dichlorophenoxy)phenyl]thiourea, mp. 186 to 190 C. 5) 1-[2-(3,4-Dichlorophenoxy)phenyl]thiourea, mp. 147 to 150 C. 6) 1-[2-(3,5-Dichlorophenoxy)phenyl]thiourea, mp. 148 to 150 C. 7)- 1- [2- (o-Tolyloxy)phenyl]thiourea, mp. 135 to 136 C. 8) 1- [2- (m-Tolyloxy)phenyl]thiourea, nip. 104 to 106 C. 9) 1-[2-(p-Tolyloxy)phenyl]thiourea, mp. 154 to 155 C. 10) 1-[2-(3,4,5-Trimethoxyphenoxy)phenyl]thiourea, mp. 154 to 1580C. 11) 1-[2-(4-Fluorophenoxy)phenyl]thiourea, mp. 139 to 141 C. 12) 1-[2-(4-Bromophenoxy)phenyl]thiourea mp 155 to 157 C. 13) 1-[2-(4-Cyanophenoxy)phenyl]thiourea, mp. 159 to 161 C. 14) 1-(2-Phenoxy-3-chlorophenyl)thiourea, mp. 133 to 1420±. 15) 1-(2-Phenoxy-4-chlorophenyl)thiourea, mp. 137 to 138 C. 16) 1-(2-Phenoy-5-chlorophenyl)thiourea, mp. 140 to 1450±. 17) 1-(2-Phenoxy-6-chlorophenyl)thiourea, mp. 107 to 1200±. 18) 1- (2-Phenoxy-3-methylphenyl) thiourea, mp. 141 to 1450±. 19) 1-(2-Phenoxy-4-methylphenyl)thiourea, mp. 131 to 133 C. 20) 1-(2-Phenoxy-5-methylphenyl)thiourea, mp. 161 to 163 C. 21) 1-(2-Phenoxy-6-methylphenyl)thiourea, mp. 137 to 1420±. 22) 1-(2-Phenoxy-5-hydroxyphenyl)thiourea, mp. 174 to 176 C. 23) 1-(2-Phenoxy-5-methoxyphenyl)thiourea, mp. 143 to 167 C. 24) 1-(2-Phenoxy-5-nitrophenyl)thiourea, mp. 147 to 157 C. 25) 1-(2-Phenoxy-5-methanesulfonamidophenyl)thiourea, mp. 191 to 195 C. 26) 1-(2-Phenoxy-5-cyanophenyl)thiourea, mp. 187 to 189 C. 27) 1-(2-Phenoxy-5-carbamoylphenyl)thiourea, mp. 195 to 196 C. 28) 1-(2-Phenoxy-5-trifluoromethylphenyl)thiourea, mp. 159 to 160 C. 29) 1-[2-(4-Chlorophenoxy)-5-chlorophenyl]thiourea, mp. 149 to 165 C. 30) 1-[2-(4-Chlorophenoxy)-5-methylphenyl]thiourea, mp. 108 to 113 C. 31) 1-(2-Phenylthiophenyl)thiourea,mp. 99 to 103 C. 32) l-(2-Benzylphenyl)thiourea, mp. 125 to 126 C. 33) 1-(4-Phenoxyphenyl)thiourea, mp. 181 to 184 C. 34) 1-(3-Phenoxyphenyl)thiourea, mp. 98 to 120 C. 35) 1-[2-(1-Naphthyloxy)phenyl]thiourea, mp. 172 to 179 C. 36) 1-t2- Blplienylyl)thiourea, mp. 184 to 185 C. 37) 1-[2-(4-Chlorophenyl)phenyl]thiourea, mp. 199 to 201 C. 38) 1-[2-Phenyl-4-chlorophenyl]thiourea, mp. 205 to 206 C. 39) 1-[2-Phenyl-5-chlorophenyl]thiourea, mp. 187 to 189 C. 40) 1-(2-Phenoxy-5-dimethylaminophenyl)thiourea, mp. 163 to 1640±. 41) 1-[2-(2-Fluorophenyl)phenyl]thiourea, mp. 195 to 197 C. 42) 1-[2-(2-Chlorophenyl)phenyl]thiourea, mp. 190 to 192 C. 43) 1-[2-Phenyl-6-chlorophenyl]thiourea, mp. 171 to 176 C. 44) 1-[4-(2,3-Dimethylphenoxy)-2,6-dichlorophenyl] thlourea, mp. 93 to 113 C. 45) 1-[2-(3-Fluorophenyl)phenyl]thiourea, mp. 159 to 162 C. 46) 1-[2-(o-Tolyl)phenyl]thiourea, mp. 142 to 144 C. 47) 1-[2-(p-Tolyl)phenyl]thiourea, mp. 193 to 195 C. 48) 1-[2-(4-Fluorophenyl)phenyl]thiourea, Trip. 158 to 161 C. 49) 1-(2-Phenoxy-5-sulfamoylphenyl)thiourea, mp. 97 to 102 C. 50) 1-(2-Phenoxy-5-morpholinopheyl)thiourea, mp. 189 to 193 C. 51) 1-(3-Biphenylyl)thiourea,mp. 183 to 185 C. 52) 1-(2-Phenyl-3-chlorophenyl)thiourea, mp. 186 to 188 C. 53) 1-[2-(4-Dimethylaminophenoxy)phenyl]thiourea, mp. 191 to 1940±. 54) 1-[2-Phenoxy-5-(1-pyrrolidinyl)phenyl]thiourea, mp. 192 to 196 C. 55) 1-[2-(m-Tolyl)phenyl]thiourea,mp. 128 to 136 C. 56) 1-[2-(2-Nitrophenyl)phenyl]thiourea, mp. 186 to 194"C. 57) 1 [2-(2,4-Difluorophenyl)phenyl]thiourea, mp. 153 to 157 C. 58) 1-[2-Phenoxy-5-(N,N-dimethylsulfamoyl)phenyl] thiourea, mp. 153 to 157 C. 59) 1-[2-(2,6-Difluorophenyl)phenyl]thiourea, mp. 232 to 234 C. 60) 1-(2-Phenyl-5-methylphenyl)thiourea, nip. 187 to 192 C. 61) 1-[2-(2-Methoxyphenyl)phenyl]thiourea, mp. 154 to 1580±. 62) 1-[2-(2-Trifluoromethylphenyl)phenyl]thiourea, mp. 186 to 187 C. 63) 1-[2-(2-Dimethylaminopheny)phenyl]thiourea, mp. 151 to 154 C. 64) 1-[2-(3-Choro-4-sulfamoyphenoxy)phenyl]thiourea, I.R. (Film) : 3325, 3200, 1350, 1170 cm Preparation 8 A solution of 1-(2-phenoxyphenyl)thiourea (9.6 g.) and methyl iodide (5.6 g.) in methanol (120 ml.) was refluxed for 1.S hours. The reaction mixture was evaporated under reduced pressure. To the residue diethyl ether was added. The precipitates were collected by filtration and dried to give 1-(2phenoxyphenyl)-2-methylisothourea hydroiodide (14.7 g.), mp. 143 to 1470±. Preparation 9 The following compounds were obtained according to the similar manner to that of Preparation 8. 1) 1-[2-(2-Chlorphenoxy)phenyl]-2-methylisothourea hydroiodide, mp. 43 to 53 C. 2) 1-[2-(3-Chlorophenoxt)phenyl]-2-methylisothiourea hydroiodide, mp. i35 to 139 C. 3) 1-[2-(4-Chlorophenoxy)phenyl]-2-methylisothourea hydroiodide, mp. 57 to 77 C. 4) 1-[2-(2,6-Dichlorphenoxy)phenyl]-2-methyl isothiourea hydroiodide, mp. 78 to 115 C. 5) 1-[2-(o-Tolyloxy)phenyl]-2-methylisothourea hydroiodide. I.R. (KBr) : 3300, 3180, 3100, 1630, 1225 cm I 6) 1-[2-(m-Tolyloxy)phenyl]-2-methylisothourea hydroiodide. I.R. (KBr) : 3310, 3210, 3120, 1635, 1265, 12Q5 cm 1 7) 1-[2-(p-Tolyloxy)phenyl]-2-methylisothourea hydroiodide. I.R. (Nujol) : 3305, 3325, 1630, 1210 cm 1 8) 1-[Z-(3,4,5-Trimethoxyphenoxy)phenyl]-2- methylisothiourea hydroiodide, mp. 183 to 190 C. 9) 1-[2-(4-Fluorophenoxy)phenyl]-2-methylisothourea hydroiodide. I.R. (KBr) : 3300, 1625, 1210 cm 10) 1- [2-(4-BromophenoxyZpnenyl]-2-methylisothiourea hydroiodide. I.R. (KBr) : 3300, 1635, 1215 cm 11) 1- [2- (4-±yanophenoxy)phenyl] -2-methylisothiourea hydroiodide. 1.R. (KBr) : 3310, 2250, 1635, 1225 cm 1 12) 1-(2-Phenoxy-3-chlorophenyl)-2-methylisothiourea hydroiodide, mp. 164 to 166 C. 13) 1-(2-Phenoxy-4-chlorophenyl)-2-methylisothiourea hydroiodide, mp. 46 to 820C (dec,). 14) - 1- (2-Phenoxy- 5 -cniorophenyl) -2-methylisothiourea hydroiodide, mp. 152 to 178 C. 15) 1-(2-Phenoxy-6-chlorophenyl)-2-methylisothiourea hydroiodide, mp. 142 to 151 C. 16) 1-(2-Phenoxy- 5 -methylphenyl) - 2 -methylisothiourea hydroiodide. I.R. (film) : 3260, 1625, 1225 cm 1 17) 1-(2-Phenoxy-3-methylphenyl)-2-methylisothiourea hydroiodide, mp. 178 to 188 C. 18) 1-(2-Phenoxy-5-hydroxyphenyl)-2-methylisothiourea hydroiodide. I.R. (film) : 3300, 3200, 1630, 1218 cm 1 19) 1-(2-Phenoxy-3-methoxyphenyl)-2-methylisothiourea hydroiodide, mp. 124 to 129 C. 20) 1-(2-Phenoxy-3-nitrophenyl)-2-methylisothiourea hydroiodide, mp. 53 to 84 C. 21) 1-(2-Phenoxy-5-methanesulfonamidophenyl)-2 methylisothiourea hydroiodide, mp. 61 to 1000±. 22) 1- (2-Phenoxy-5-carbamoylphenyl) -2-methylisothiourea hydroiodide. I.R. (KBr) : 3350, 3200, 3150, 1685, 1660, 1650, 1270, 1225 cm1 23) 1-(2-Phenoxy-5-trifluoromethylphenyl)-2 methylisothiourea hydroiodide, mp. 81 to 91 C. (dec.) 24) 1-[2-(4-Chlorphenoxy)-5-chlorphenyl]-2-methyl isothiourea hydroiodide. I.R. (KBr) : 3300, 3200, 3100, 1630, 1216 cm 1 25) 1- (2-Phenylthiophenyl)-2-methylisothiourea hydroiodide, mp. 133 to 137 C. 26) 1-(2-Benzylphenyl)-2-methylisothiourea hydroiodide. I.R. (KBr) : 3320, 3180, 1635 cm 1 27) 1-(4-Phenoxyphenyl)-2-methylisothiourea hydroiodide, mp. 181 to 185 C. 28) 1-(3-Phenoxyphenyl)-2-methylisothiourea hydroiodide. I.R. (film) : 3260, 3150, 1630, 1215 29) 1-[2-(1-Naphthyloxy)phenyl]-2-methylisothiourea hydroiodide, mp. 57 to 107 C. 30) 1-(2-Biphenylyl)-2-methylisothiourea hydroiodide. 1.R. (KBr) : 33i0, 1635 =1 31) 1-[2-(4-Chlorophenyl)phenyl]-2-methylisothiourea hydroiodide. I.R. (KBr) : 3300, 3200, 1635 cm1 32) 1- [2-Phenyl-4-chlorophenyl]-2-methylisothiourea hydroiodide . -] I.R. (KBr) : 3300, 318O, 1635 cm 33) 1-[2-Phenyl-5-chlorophenyl]-2-methylisothiourea hydroiodide. -1 I.R. (K3r) : 3300, 3190, 1635 cm 1 34) 1-[2-(2-Fluorophenyl)phenyl]-2-methylisothiourea hydroiodide. I.R. (KBr) : 3100, 1635 cm 1 35) 1-[2-(2-Chlorophenyl)phenyl]-2-methylisothiourea hydroiodide. -1 I.R. (KBr) : 3100, 1635 cm 36) 1-(2-Phenyl-6-chlorophenyl)-2-methylisothiourea hydroiodide. I.R. (KBr) : 3100, 1630 cm 37) 1-[4-(2,3-Dimethylphenoxy)-2,6-dichlorophenyl] 2-methylisothiourea hydroiodide, mp. 185 to 195 C. 38) 1- (2-Phenyl-3-chlorophenyl) -2-methylisothiourea hydriodide I.R. (KBr) : 3050, 1620 cm 1 ;39) 1-[2-(m-Tolyl)phenyl]-2-methylisothiourea hydriodide I.R. (KBr) : 3050, 1620 cm-1 40) 1- [2-(2-Nitrophenyl)phenyl]-2-methylisothiourea hydriodide I.R. (Film) : 3080, 1625, 1520, 1350 cm 1 41) 1-[2-(2,4-Difluorophenyl)phenyl]-2-methylisothiourea hydriodide I.R. (Film) : 3080, 1625 cm 1 42) l-[2-(2,6-Difluorophenyl)phenyl]-2-methylisothiourea hydriodide I.R. (Film) : 3260, 3080, 1620 cm 43) 1-(2-Phenyl-5-methylphenyl)-2-methylisothiourea hydriodide I.R. (Film) : 3270, 3170, 3100, 1625 cm 1 44) 1-[2-(2-Methoxyphenyl)phenyl]-2-methylisothiourea hydriodide I.R. (Film) : 3400, 3250, 1620 cm 1 45) 1- [2-(2-Trifluoromethylphenyl)phenyl]-2- methylisothiourea hydriodide I.R. (Film) : 3400, 1625 cm 1 46) 1-[2-(2-Dimethylaminophenyl)phenyl]-2 methylisothiourea hydriodide I.R. (Nujol) : 3250, 3075, 1625 cm 1 47) 1-[2-(3-Chloro-4-sulfamoylphenoxy)phenyl]-2- methylisothiourea hydriodide I.R. (Film) : 3300, 1635, 1350, 1170 cm 1 Preparation of the object compounds Example 1 A solution of 1-(2-pnenoxyphenyl)-2-methyl- isothiourea hydroiodide (16.3 g.) and ethylenediamine (7.6 g.) in dry ethanol (160 ml.) was refluxed for 2 hours. The reaction mixture was cooled and then evaporated under reduced pressure. After addition of ethyl acetate and water to the residue,-the resulting mixture was adjusted to pH 9 to 10 with an aqueous solution of sodium hydroxide and then shaken. The organic layer was separated, washed with water, dried over magnesium sulfate and then evaporated. The residue was recrystallized from a mixture of diisopropyl ether and ethyl acetate to give 2-(2-phenoxyphenyl)amino-2-imidazoline (6.1 g.), mp. 167 to 171 C. Elemental analysis C H N Calcd : 71.12 5.97 16.59 Found : 71.25 5.96 16.44 Example 2 The following compounds were obtained according to the similar manner to that of Example 1. 1) 2-[2-(2-ChlorophenoWy3phenylaamino-Z-imidazoline, mp. 158 to 161 C. Elemental analysis C H N Calcd : 62.61 4.90 14.60 Found : 62.74 4.89 14.45 2) 2-[2-(3-Chlorophenoxy)phenyl]amino-2-imidazoline, mp. 77 to 78 C. Elemental analysis C H N Calcd 62.61 4.90 14.60 Found 62.45 4.83 14.58 3) 2-[2-(3-Chlorophenoxy)phenyl]amino-2-imidazoline, fumarate, mp. 169 to 175 C. N.M.R. (DMSO-d6, d) : 3.60 [4H, s), 6.47 (2H, s), 6.95-7.55 (8H, m), 9.50 (4H, broad s) 4) 2- [2- (4-Chlorophenoxy)phenyl]amino-2-imidazoline, mp. 111 to 119 C. Elemental analysis C H N Calcd : 62.61 4.90 14.60 Found : 62.34 4.76 14.28 5) 2-[2-(2,6-Dichlorophenoxy)phenyl]amino-2 imidazoline, mp. 182 to 185 C. Elemental analysis C H N Calcd : 55.92 4.07 13.04 Found : 56.32 3.94 12.83 6) 2-[2-(3,4-Dichlorophenoxy)phenyl]amino-2 imidazoline fumarate, mp. 166 to 169 C. 7) 2-[2-(3,5-Dichlorophenoxy)phenyl]amino-2- imidazoline, mp. 168 to 170 C. 8) 2-[2-(o-Tolyloxy)phenyl]amino-2-imidazoline, mp. 116 to 117 C. Elemental analysis C H N Calcd : 71.89 6.41 15.72 Found : 71.63 6.22 15.71 9) 2-[2-(m-Tolyloxy)phenyl]amino-2-imidazoline, mp. 85 to 860C. Elemental analysis C H N Calcd : 71.89 6.41 15.72 Found : 71.81 6.32 15.78 10) 2-[2-(p-Tolyloxy)phenyl]amino-2-imidazoline, mp. 126 to 129 C. Elemental analysis C H N Calcd : 71.89 6.41 15.72 Found : 71.81 6.34 15.59 11) 2-[2-(3,4,5-Trimethoxyphenoxy)phenyl]amino-2 imidazoline, mp. 156 to 159 C. Elemental analysis C H N Calcd : 62.96 6.16 12.24 Found : 62.68 6.07 12.15 12) 2-[2-(4-Fluorophenoxy)phenyl]amino-2-imidazoline, mp. 118 to 1210±. Elemental analysis C H N Calcd : 66.41 5.20 15.49 Found : 65.93 5.16 15.41 13) 2-[2-(4-Bromophenoxy)phenyl]amino-2-imidazoline, mp. 68 to 70 C. Elemental analysis C H N Calcd : 54.23 4.25 12.65 Found : 54.51 4.32 12.30 14) 2-[2- (4-CyanophenoWy)pnenyl] amino-Z-imidazoline, mp. 161 to 163 C. Elemental analysis C H N Calcd : 69.05 5.07 20.13 Found : 69.40 4.93 20.12 15) 2-(2-Phenoxy-3-chlorophenyl)amino-2-imidazoline, mp. 150 C to 158 C. Elemental analysis C H N Calcd : 62.61 4.90 14.60 Found : 62.61 4.90 14.51 16) 2-(2-Phenoxy-4-chlorophenyl)amino-2-imidazoline, mp. 163 to 172 C. Elemental analysis C H N Calcd : 62.61 4.90 14.60 Found : 62.51 4.83 14.54 17) 2-(2-Phenoxy-5-chloropheyl)amino-2-imidazoline, mp. 169 to 182 C. Elemental analysis C H N Calcd : 62.61 4.90 14.60 Found : 62.44 4.79 14.73 18) 2-C2-Phenoxy-6-chlorophenyl)amino-2-imidazoline, mp. 167 to 170 C. Elemental analysis C H N Calcd : 62.61 4.90 14.60 Found : 62.58 4.82 14.57 19) 2- (2-Phenoxy- 3-methylphenyl) amino-2-imidazoline mp. 133 to 1340±. 20) 2-(2-Phenoxy-4-methylphenyl)amino-2-imidazoline, mp. 131 to 135 C. 21) 2- (2-Phenoxy-5-methylphenyl) amino-2-imidazoline, mp. 172 to 174 C. Elemental analysis C H N Calcd : 71.89 6.41 15.72 Found : 71.74 6.30 15.74 22) 2-(2-Phenoxy-6-methylphenyl)amino-2-imidazoline, mp. 129 to 133 C. Elemental analysis C H N Calcd : 71.89 6.41 15.72 Found : 72.02 6.36 15.72 23) 2-(2-Phenoxy-5-hydroxyphenyl)amino-2-iinidazoline, mp. 210 to 211 C. Elemental analysis C H N Calcd ; 66.90 5.61 15,60 Found : 67.00 5.47 15.71 24) 2-(2-Phenoxy-5-hydroxyphenyl)amino-2-imidazoline hydrochloride, mp. 223 to 229 C. Elemental analysis C H N Calcd : 58.92 5.27 13.74 11.60 Found : 59.25 5.20 13.42 11.01 25) 2-(2-Phenoxy-5-methoxyphenyl)amino-2-imidazoline, mp. 210 to 217 C (dec.) Elemental analysis C H N Calcd : 67.83 6.05 14.83 Found : 68.05 6.05 14.75 26) 2-(2-Phenoxy-5-nytrophenyl)amino-2-imidazoline, mp. 164 to 166 C. Elemental analysis C H N Calcd : 60.40 4.73 18.78 Found : 60.31 4.64 18.60 27) 2-(2-Phenoxy-S-aminophenyl)amino-2-imidazoline, mp. 153 to 157 C. 28) 2-(2-Phenoxy-5-methanesulfonamidophenyl)amino-2 imidazoline, mp. 199 to Z02 C. Elemental analysis C H N Calcd : 55.48 5.24 16,17 Found : 55.57 4.99 16.12 29) 2-(2-Phenoxy-5-cyanophenyl)amino-2-imidazoline, mp. 168 to 170 C. 30) 2-(2-Phenoxy-5-carbamoylphenyl)amino-2-imidazoline, mp. 236 to 2380±. N.M.R. . (DMSO-d6, d) : 3.28 (4H, s), 6.08 (2H, broad s), 6.78-7.97 (8H, m) 31) 2-(2-Phenoxy-5-trifluoromethylphenyl]amino-2 imidazoline, mp. 165 to 168 C. Elemental analysis C H N Calcd : 59.81 4.39 13.08 Found : 59.83 4.20 13.11 32) 2-[2-(4-Chlorophenoxy)-5-chlorophenyl]amino-2 imidazoline, mp. 147 to 159 C. Elemental analysis C H N Calcd : 55.92 4.07 13.04 Found : 56.09 4.00 12.98 33) 2-[2-(4-Chlorophenoxy)-5-methylphenyl]amino-2 imidazoline, mp. 132 to 135 C. 34) 2-(2-Phenylthiophenyl)amino-2-imidazoline, mp. 150 to 155 C. Elemental analysis C H N Calcd : 66.88 5.61 15.60 Found : 66.85 5.64 15.38 35) 2-(2-Benzylphenyl)amino-2-imidazoline, mp. 112 to 113"C, Elemental analysis C H N Calcd : 76.46 6.82 16.72 Found : 76.46 6 84 16.58 36) 2-(4-Phenoxyphenyl)amino-2-imidazoline, mp. 128 to 135 C. Elemental analysis C H N Calcd : 71.12 5.97 16.59 Found : 70.76 5.99 16.37 37) 2-(4-Phenoxyphenyl)amino-2-imidazoline hydrochloride, mp. 154 to 157 C. Elemental analysis C H N Calcd : 62.17 5.57 14.50 12.24 Found : 61.98 5.48 14.44 12.21 38) 2-(3-Phenoxyphenyl)amino-2-imidazoline, mp. 57 to 75 C. N.M.R. (DMSO-d6, ) : 3.35 (4H, s), 6.40-7.44 (11H, m) 39) 2-(3-Phenoxyphenyl)amino-2-imidazoline hydrochloride, mp. 155 to 1570c. Elemental analysis C H N Calcd : 62.17 5.57 14.50 Found : 62.41 5.52 14.45 40) 2-[2-(1-Naphthyloxy)phenyl]amino-2-imidazoline, mp. 129 to 136 C. Elemental analysis C H N Calcd : 75.22 5.65 13.85 Found : 75.49 5.60 13.91 41) 2-(2- Biphenylyl )amino-2-imidazoline, mp. 170 to 171 C. Elemental analysis C H N Calcd : 75.92 6.37 17.71 Found : 76.56 6.37 17.80 42) 2-[2-(1-Chlorophenyl)phenyl]amino-2 imidazoline, mp. 148 to 150 C. Elemental analysis C H N Calcd : 66.30 5.19 15.46 Found : 66.32 4.98 15.38 43) 2-[2-Phenyl-4-chlorophenyllamino-2-imidazoline, mp. 173 to 1740±. Elemental analysis C H N Calcd : 66.30 5.19 15.46 Found : 66.42 4.87 15.38 44) 2-[2-Phenyl-5-chlorophenyl]amino-2-imidazoline, mp. 160-162"C. Elemental analysis C H N Calcd : 66.30 5.19 15.46 Found : 66.49 4.91 15.39 45) 2-(2-Phenoxy-5-dimethylaminophenyl)amino-2 imidazoline, mp. 164 to 168 C. 46) 2-[2-(2-Fluorophenyl)phenyl]amino-2-imidazoline, mp. 122 to 124 C. Elemental analysis C H N Calcd : 70.57 5.53 16.46 Found : 70.79 5.44 16.54 47) 2-[2-(2-Chlorophenyl)phenyl]amino-2-imidazoline, mp. 150 to 152 C. Elemental analysis C H N Calcd : 66.30 5.19 15.46 Found : 66.41 5.03 15.35 48) 2-(2-Phenyl-6-chlorophenyl)amino-2-imidazoline, mp. 130 to 135 C. Elemental analysis C H N Calcd : 66.30 5.19 15.46 C H ! N Found : 65.32 5.2S 15.21 (H2O : 2.35 %) 49) 2-[4-(2,3-Dimethylphenoxy)-2,6-dichlorophenyl] amino-2-imidazoline, mp. 176 to 179 C. Elemental analysis C H N Calcd : 58.30 4.8 12.00 Found : 57.95 4.79 11.90 50) 2-[2-(3-Fluorophenyl)phenyl]amino-2-imidazoline, mp. 143 to 1450±.. Elemental analysis C H N Calcd : 70.57 5.53 16.46 Found : 70.50 5.20 16.39 51) 2-[2-(o-Tolyl)phenyl]amino-2-imidazoline, mp. 145 to 147 C. Elemental analysis C H N Calcd : 76.46 6.82 16.72 Found : 76.23 6.70 16.73 52) 2-[2-(p-Tolyl)phenyl]amino-2-imidazoline, mp. 175 to 178 C. Elemental analysis C H N Calcd : 76.46 6.82 16.72 Found : 76.17 6.84 16.48 53) 2-[2-(4-Fluorophenyl)phenyl]amino-2-imidazoline, mp. 174 to 176 C. Elemental analysis C H N Calcd : 70.57 5.53 16.46 Found : 70.27 5.22 16.28 54) 2-(2-Phenoxy-5-sulfamoylphenyl)amino-2 imidazoline, mp. 174 to 178 C. Elemental analysis C H N Calcd : 54.20 4.85 16.86 Found : 53.94 4.77 16.27 55) 2- (2-Phenoxy-5-morpholinophenyl) amino-2-imidazoline, mp. 167 to 168 C. Elemental analysis C H N Calcd : 67.43 6.55 16.56 Found : 67.11 6.24 16.32 56) 2-(3- Biphenylyl .)amino-2-imidazoline, mp. 165 to 1670±. Elemental analysis C H N Calcd : 75.92 6.37 17.71 Found : 75.85 6.25 17.68 57) 2-[2-(4-Chlorophenoxy)phenyl]amino-2-imidazoline, sulfate, mp. 167 to 169 C. Elemental analysis C H N S calcd : 46.69 4.18 10.89 8.31 found : 46.67 4.00 10.87 8.29 58) 2-(2-Phenyl-3-chlorophenyl)amino-2-imidazoline, mp. 165 to 167 C. Elemental analysis C H N calcd : 66.30 5.19 15.46 found : 66.73 5.00 15.58 59) 2-[2-(4-Dimethylaminophenoxy)phenyl]amino-2 imidazoline, mp. 143 to 1480±. 60) 2-[2-Phenoxy-5-(1-pyrrolidinyl)phenyl]amino-2 imidazoline, mp. 203 to 208 C. 61) 2-[2-(m-Tolyl)phenyl]amino-2-imidazoline,mp. 150 to 152 C. Elemental analysis C H N calcd : 76.46 6.82 16.72 found : 76.88 6.86 16.71 62) 2-[2-(2-Nitrophenyl)phenyl]amino-2-imidazoline mp. 185 to 188 C. Elemental analysis C H N calcd : 63.82 5.00 19.85 found : 63.73 4.85 19.88 63) 2-[2-(2,4-Difluorophenyl)phenyl]amino-2-imidazoline mp. 131 to 132 C. Elemental analysis C H N calcd : 65.92 4.79 15.38 found : 66.01 4.62 15.40 64) 2-[2-Phenoxy-5-(N,N-dimethylsulfamoyl)phenyl] amino-2-imidazoline, mp. 149 C. 65) 2-[2-(2,6-DifluorophenylDphenylJamino-2-imidazoline, mp. 154 to 156 C. Elemental analysis C H N calcd : 65.92 4.79 15.38 found : 66.20 4.53 15.43 66) 2-(2-Phenyl-5-methylphenyl)amino-2-imidazoline, mp. 177 to 180 C. Elemental analysis C H N calcd : 76.46 6.82 16.72 found : 77.01 6.79 16.77 67) 2-[2-(2-Aminophenyl)phenyl]amino-2-imidazoline, mp. 177 to 179 C. 68) 2-[2-(2-Methoxyphenyl)phenyl]amino-2-imidazoline, mp. 150 to 153 C. Elemental analysis C H N calcd : 71.88 6.41 15.72 found : 71.96 6.10 15.74 69) 2-[2-(2-Trifluoromethylphenyl)phenyl]amino-2 imidazoline, mp. 176 to 180 C. Elemental analysis C H N calcd : 62.94 4.62 13.76 found : 63.10 4.66 13.85 70) 2-[2-(2-Dimethylaminophenyl)phenyl]amino-2 imidazoline, mp. 134 to 137 C. I.R. (Nujol) : 3375, 1665 cm N.M.R. (CDC13, 6) : 2.55 (6H, s), 3.33 (4H, s), 5.63 (2H, s), 6.97 to 7.47 (8H, m) 71) 2-[2-(3-Chloro-4-sulfamoylphenoxy)phenyl]amino-2 imidazoline, mp. 204 to 208 C. Elemental analysis C H N calcd : 49.11 4.12 15.27 found : 49.05 4.07 15.33 Example 3 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 an hour. The reaction mixture was cooled and then evaporated under reduced pressure. After addition of methanol (100 ml.) and ethylenediamine (5.1 g.) to the residue, the mixture was refluxed with stirring for 3 hours. The reaction mixture was evaporated under reduced pressure and to the residue were added an aqueous solution of sodium carbonate and methylene chloride. The methylene chloride layer was separated, washed with water, dried over magnesium sulfate and then evaporated. The residue was recrystallized from ethyl acetate to give 2-[2-(3,5-dichlorophenoxy)phenyl]amino-2-imidazoline (5.1 g.), mp. 168 to 170 C. Elemental analysis C H N Calcd : 55.92 4.07 13.04 Found : 55.88 4.01 12.92 Example 4 The following compounds were obtained according to the similar manner to that of Example 3. 1) 2-(2-Phenoxyphenyl)amino-2-imidazoline, mp. 167 to 171 C. 2) 2-[2-(2-Chlorophenoxy)phenyl]amino-2-imidazoline, mp. 158 to 161 C. 3) 2-[2-(3-Chlorophenoxy)phenyl]amino-2-imidazoline, mp. 77 to 78 C. 4) 2-[2-(3-Chlorophenoxy)phenyl]amino-2-imidazoline, fumarate, mp. 169 to 175 C. 5) 2-r2-(4-ChlorophenoDy)phenyl]amino-2-Imidazoline, mp. 111 to 119 C. 6) 2-[2-(2,6-Dichlorophenoxy)phenyl]amino-2 imidazoline, mp. 182 to 185 C. 7) 2-[2-(3,4-Dichlorophenoxy)phenyl]amino-2 imidazoline fumarate, mp. 166 to 169 C. Elemental analysis C H N Calcd : 52.07 3.91 9.59 Found : 52.22 3.80 9.61 8) 2-[2-(o-Toxylyl)phenyl]amino-2-imidazoline, mp. 116 to 117 C. 9) 2-[2-(m-Toxylyl)phenyl]amino-2-imidazoline, mp. 85 to 860C. 10) 2- [2- (p-Tolyloxy)phenyl]amino-2-imidazoline, mp. 126 to 129 C. 11) 2-[2-(3,4,5-Trimethoxyphenoxy)phenyl]amino-2 imidazoline, mp. 156 to 159 C. 12) 2-[2-(4-FluorophenoxyÇphenylaamino-Z-imidazoline, mp. 118 to 121 C. 13) 2- [2-(4-Bromophenoxy)phenyl]amino-2-imidazoline, mp. 68 to 70 C. 14) 2-[2-(4-Cyanophenoxy)phenyl]amino-2-imidazoline, mp. 161 to 163 C. 15) 2-(2-Phenoxy-3-chlorophenyl)amino-2-imidazoline, mp. 150 to 158 C. 16) 2-(2-Phenoxy-4-chlorophenyl)amino-2-imidazoline, mp. 163 to 172 C. 17) 2-(2-Phenoxy-5-chlorophenyl)amino-2-imidazoline, mp. 169 to 182 C. 18) 2-(2-Phenoxy-6-chlorophenyl)amino-2-imidazoline, mp. 167 to 170 C. 19) 2-(2-Phenoxy-3-methylphenyl)amino-2-imidazoline, mp. 133 to 1340±. Elemental analysis C H N Calcd : 71,89 6.41 15.72 Found : 71.50 6.38 15.54 20) 2-(2-Phenoxy-4-methylphenyl)amino-2-imidazoline, mp. 131 to 135 C. Elemental analysis C H N Calcd : 71.89 6.41 15.72 Found : 72.06 6.41 15.55 21) 2-(2-Phenoxy-5-methylphenyl) amino-2-imidazoline, mp. 172 to 1740±. 22) 2-(2-Phenoxy-6-methylphenyl)amino-2-imidazoline, mp. 129 to 133 C. 23) 2-(2-Phenoxy-5-hydroxyphenyl)amino-2-imidazoline, mp. 210 to 211 C. 24) 2-(2-Phenoxy-5-hydroxyphenyl)amino-2-imidazoline hydrochloride, mp. 223 to 229 C. 25) 2-(2-Phenoxy-5-methoxyphenyl)amino-2-imidazoline, mp. 210 to 217 C (dec.). 26) 2-(2-Phenoxy-5-nitrophenyl)amino-2-imidazoline, mp. 164 to 166 C. 27) 2-(2-Phenoxy-5-aminophenyl)amino-2-imidazoline, mp. 153 to 157 C. 28) 2-(2-Phenoxy-5-methanesulfonamidophenyl) amino 2-imidazoline, mp. 199 to 202 C. 29) 2-(2-Phenoxy-5-cyanophenyl)amino-2-imidazoline, mp. 168 to 17000. Elemental analysis C H N Calcd : 69.05 5.07 20.13 Found : 68.98 4.70 19.81 30) 2- (2-Phenoxy-5-carbamoylphenyl) amino-2- imidazoline, mp. 236 to 238 C. 31) 2-(2-Phenoxy-5-trifluoromethylphenyl)amino-2 imidazoline, mp. 165 to 168 C. 32) 2-[2-(4-Chlorophenoxy)-5-chlorophenyl]amino-2 imidazoline, mp. 147 to 159 C. 33) 2-[2-(4-Chlorophenoxy)-5-methylphenyl]amino-2 imidazoline, mp. 132 to 135 C. Elemental analysis C H N Calcd : 63.68 5.34 13.93 Found :- 63.51 5.30 13.89 34) 2- (2-Phenylthiophenyl) amino-2-imidazoline, mp. 150 to 155 C. 35) 2-(2-Benzylphenyl)amino-2-imidazoline, mp. 112 to 113 C. 36) 2-(4-Phenoxyphenyl)amino-2-imidazoline, mp. 128 to 135 C. 37) 2-(4-Phenoxyphenyl)amino-2-imidazoline hydrochloride, mp. 154 to 157 C. 38) 2-(3-Phenoxyphenyl)amino-2-imidazoline, mp. 57 to 75 C. 39) 2-(3-Phenoxyphenyl)amino-2-imidazoline hydrochloride, mp. 155 to 157 C. 40) 2-[2-(1 -Naphthyloxy)phenyl]amino-2-imidazoliae, mp. 129 to 136 C. 41) 2(2- Biphenylyl) amino-2-imidazoline, mp. 170 to 171 C. 42) 2-[2-(4-Chlorophenyl)phenyl]amino-2-imidazoline, mp. 148 to 150 C. 43) 2-[2-Phenyl-4-chlorophenyl]amino-2-imidazoline, mp. 173 to 174 C. 44) 2-[2-Phenyl-5-chlorophenyl]amino-2-imidazoline, mp. 160 to 1620±. 45) 2-(2-Phenoxy-5-dimethylaminophenyl)amino-2 imidazoline, mp. 164 to 168 C. Elemental analysis C H N Calcd : 68.89 6.80 18.91 Found : 68.81 .6.74 18.72 46) 2-[2-(2-Floorophenyl)phenyllamino-2-imidazoline, mp 122 to 1240±. 47) 2-[2-(2-Chlorophenyl)phenyl]amino-2-imidazoline, mp. 150 to 152 C. 48) 2-(2-Phenyl-6-chlorophenyl)amino-2-imidazoline, mp. 130 to 1350±. 49) 2-[4-(2,3-Dimethylphenoxy)-2,6-dichlorophenyl] amino-2-imidazoline, mp. 176 to 179 C. 50) 2-[2-(3-Fluorophenyl)phenyl]amino-2-imidazoline, mp. 143 to 145 C. 51) 2-[2-(o-Tolyl)phenyl]amino-2-imidazoline, mp. 145 to 147 C. 52) 2-[2-(p-Tolyl)phenyl]amino-2-imidazoline, mp. 175 to 178 C. 53) 2-[2-(4-Fluorophenyl)phenyl]amino-2-imidazoline, mp. 174 to 1760±. 54) 2-(2-Phenoxy-5-sulfamoylphenyl)amino-2 imidazoline, mp. 174 to 178 C. 55) 2-(2-Phenoxy-5-morpholinophenyl)amino-2-imidazoline, mp. 167 to 168 C. 56) 2-(3- Biphenylyl )amino-Z-imidazoline, mp. 165 to 167 C. 57) 2-[2-(4-Chlorophenoxy)phenyl]amino-2-imidazoline sulfate, mp. 167 to 169 C. 58) 2-(2-Phenyl-3-chlorophenyl)amino-2-imidazoline, - mp. 165 to 167 C. 59) 2-[2-(4-Dimethylaminophenoxy)phenyl]amino-2 imidazoline, mp. 143 to 1480±. Elemental analysis C H N calcd : 68.89 6.80 18.91 found : 68.72 6.77 18.92 60) 2-[2-Phenoxy-5-(1-pyrrolidinyl)phenyl]amino-2 imidazoline, mp. 203 to 208 C. Elemental analysis C H N calcd : 70.78 6.88 17.38 found : 70.61 6.83 17.23 61) 2-[2-(m-Tolyl)phenyl]amino-2-imidazoline, mp. 150 to 152 C. 62) 2-[2-(2-Nitrophenyl)phenyl]amino-2-imidazoline, mp. 185 to 188 C. 63) 2-[2-(2,4-Difluorophenyl)phenyl]amino-2-imidazoline, nip. 131 to 132 C. 64) 2-[2-Phenoxy-5-(N,N-dimethylsulfamoyl)phenyl]amino- 2-imidazoline, mp. 1490±. Elemental analysis C H N calcd : 56.65 5.59 15.55 found : 56.91 5.60 15.52 65) 2-[2-(2,6-Difluorophenyl)phenyl]amino-2-imidazoline, mp. 154 to 165 C. 66) 2-(2-Phenyl-5-methylphenyl)amino-2-imidazoline, mp. 177 to 180 C. 67) 2-[2-(2-Aminophenyl)phenyl]amino-2-imidazoline, mp. 177 to 179 C. 68) 2-[2-(2-Methoxyphenyl)phenyl]amino-2-imidazoline, mp. 150 to 153 C. 69) 2-[2-(2-Trifluoromethylphenyl)phenyl]amino-2 imidazoline, mp. 176 to 180 C. 70) 2-[2-(2-Dimethylaminophenyl)phenyl]amino imidazoline, mp. 134 to 137 C. 71) 2-[2-(3-Chloro-4-sulfamoylphenoxy)phenyl]amino-2 imidazoline, mp. 204 to 208 C. Example 5 A solution of 2-chloro-2-imidazoline sulfate (1.0 g.) in 5% aqueous solution of sodium hydroxide (10 ml.) was extracted with methylene chloride (5 ml. x 4). The extracts were combined, dried over magnesium sulfate and filtered for removal of magnesium sulfate. To the methylene chloride solution, 2-(3,4,5-trimethoxyphenoxy)aniline (0.91 g.) was added. The mixture was stirred for 42 hours at ambient temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in dil. hydrochloric acid, washed with ethyl acetate twice, made basic with an aqueous solution of sodium carbonate and then extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and ethanol to give a white powder of 2-[2-(3,4,5-trimethoxy phenoxy)phenyljamino-2-imidazoline (0.3 g.). mp. 156 to 1590C. I.R. (Nujol): 3410, 3140, 1670, 1225, 1200, 1125 cm l N.M.R. (DMSO-d6,6): 3.28 (4H, s), 3.62 (3H, s), 3.68 (6H, s), 5.80 (2H, broad s), 6.22 (2E, s), 6.80-7.23 (4H, m). Example 6 The following compounds were obtained according to the similar manner to that of Example 5. 1) 2-(2-Phenoxyphenyl)amino-2-imidazoline, mp. 167 to 171 C. 2) 2-[2-(2-Chlorophenoxy)phenylaamino-2-imidazoline, mp. 158 to 161 C. 3) 2-[2-(3-Chlorophenoxy)phenyl]amino-2-imidazoline, mp. 77 to 78 C. 4) 2-[2-(3-ChlorophenoxyZphenyl]amino-2-imidazoline fumarate, mp. 169 to 175 C. 5) 2-[2-(4-Chlorophenoxy)phenyl]amino-2-imidazoline, mp. 111 to 119 C. 6) 2-[2-(2,6-Dichlorophenoxy)phenyl]amino-2 imidazoline, mp. 182 to 185 C. 7) 2-[2-(3,4-Dichlorophenoxy)phenyl]amino-2 imidazoline fumarate, mp. 166 to 169 C. 8) 2-[2-(3,5-Dichlorophenoxy)phenyl]amino-2 imidazoline, mp. -168 to 170 C. 9) 2-[2-(o-Tolyloxy)phenyl]amino-2-imidazoline, mp. 116 to 117 C. 10) 2-[2-(m-Tolyloxy)phenyl]amino-2-imidazoline, mp. 85 to 860C. 11) 2-[2-(p-Tolyloxy)phenyl]amino-2-imidazoline, mp. 126 to 129 C. 12) 2-[2-(4-Fluorophenoxy)phenyl]amino-2 imidazoline, mp. 118 to 121 C. 13) 2- [2-(4-Bromophenoxy)phenyl]amino-2- imidazoline, mp. 68 to 70 C. 14) 2-[2-(4-Cyanophenoxy)phenyl]amino-2-imidazoline, mp. 161 to 163 C. 15) 2-(2-Phenoxy-3-chlorophenyl)amino-2-imidazoline, mp. 150C to 158 C. 16) 2-(2-Phenoxy-4-chlorophenyl)amino-2- imidazoline, mp. 163 to 172 C. 17) 2-(2-Phenoxy-5-chlorophenyl)amino-2-imidazoline, mp. 169 to 182 C. 18) 2-(2-Phenoxy-6-chlorophenyl)amino-2-imidazoline, mp. 167 to 170 C. 19) 2-(2-Phenoxy-3-methylphenyl)amino-2-imidazoline, mp. 133 to 1340±. 20) 2-(2-Phenoxy-4-methylphenyl)amino-2-imidazoline, mp. 131 to 135 C. 21) 2-(2-Phenoxy-5-methylphenyl)amino-2-imidazoline, nip. 172 to 1740C. 22) 2-(2-Phenoxy-6-methylphenyl)amino-2-imidazoline, mp. 129 to 1330C. 23) 2-(2-Phenoxy-5-hydroxyphenyl)amino-2-imidazoline, mp. 210 to 211 C. 24) 2-(2-Phenoxy-5-hydroxyphenyl)amino-2-imidazoline hydrochloride, mp. 223 to 229 C. 25) 2-(2-Phenoxy-S-methoxyphenyl)amino-2-imidazoline, mp. 210 to 217 C (dec.). 26) 2-(2-Phenoxy-5-nitrophenyl)amino-2-imidazoline, mp. 164 to 166 C. 27) 2-(2-Phenoxy-5-aminophenyl)amino-2-imidazoline, mp. 153 to 1570C, 28) 2-(2-Phenoxy-5-methanesulfonamidophenyl)amino 2-imidazoline, mp. 199 to 202 C. 29) 2-(2-Phenoxy-5-cyanophenyl)amino-2-imidazoline, mp. 168 to 170 C. 30) 2-(2-Phenoxy-5-carbamoylphenyl)amino-2-imidazoline, mp. 236 to 238 C. 31) 2-(2-Phenoxy-5-trifluoromethylphenyl)amino-2 imidazoline, mp. 165 to 168 0C. 32) 2-[2-(4-Chlorophenoxy)-5-chlorophenyl]amino-2 imidazoline, mp. 147 to 159 C. 33) 2 - [2-(4-Chlorophenoxy)-5-methylphenyl)amino-2 imidazoline, mp. 132 to 1350C. 34) 2- (2-Phenylthiophenyl)amino-2-imidazoline, mp. 150 to 155 C. 35) 2-(2-Benzylphenyl)amino-2-imidazoline, mp. 112 to 1130±. 36) 2-(4-Phenoxyphenyl)amino-2-imidazoline, mp. 128 to 1350±. 37) 2-(4-Phenoxyphenyl)amino-2-imidazoline hydrochloride, mp. 154 to 1570±. 38) 2-(3-Phenoxyphenyl)amino-2-imidazoline, mp. 57 to 75 C. 39) 2-(3-Phenoxyphenyl)amino-2-imidazoline hydrochloride, mp. 155 to 1570±. 40) 2-[2-(1-Nphthyoloxy)phenyl]amino-2-imidazoline, mp. 129 to 136 C. 41) 2-(2-Biphenylyl ) amino-2-imidazoline, mp. 170 to 1710±. 42) 2-[2-(4-Chlorophenyl)phenyl]amino-2-imidazoline, mp. 148 to 150 C. 43) 2-[2-Phenyl-4-chlorophenyl]amino-2-imidazoline, mp. 173 to 1740±. 44) 2-[2-Phenyl-5-chlorophenyl]amino-2-imidazoline, mp. 160 to 162 C. 45) 2- (2-Phenoxy-5-dimethylaminophenyl) amino-2 imidazoline, mp. 164 to 1680±. 46) 2-[2-(2-Fluorophenyl)phenyl]amino-2-imidazoline, mp. 122 to 1240±. 47) 2-[2-(2-Chlorophenyl)phenyl]amino-2-imidazoline, mp. 150 to 1520±. 48) 2-(2-Phenyl-6'-chlorophenyl)amino-2-imidazoline, mp. 130 to 1350±. 49) 2-[4-(2,3-Dimethylphenoxy)phenoxy)-2,6-dichlorophenyl] amino-2-imidazoline, mp. 176 to 1790±. 50) 2-[2-(3-Fluorophenyl)phenyl]amino-2-imidazoline, mp. 143 to 145 C. 51) 2-[2-(o-Tolyl)phenyl]amino-2-imidazoline, mp. 145 to 147 C. 52) 2-[2-(p-Tolyl)phenyl]amino-2-imidazoline, mp. 175 to 178 C. 53) 2-[2-(4-Fluorophenyl)phenyl]amino-2-imidazoline, mp. 174 to 176 C. 54) 2-(2-Phenoxy-5-sulfamoylphenyl)amino-2 imidazoline, mp. 174 to 178 C. 55) 2- (2-Phenoxy-5-morpholinophenyl) amino-2- imidazoline, mp. 167 to 168 C. 56) 2-(3- Biphenylyl Jamino-2-imidazoline, mp. 165 to 167 C. 57) 2- [2-(4-Chlorophenoxy)phenyl]amino-2-imidazoline sulfate, mp. 167 to 169 C. 58) 2-(2-Phenyl-3-chlorophenyl)amino-2-imidazoline, mp. 165 to 167 C. 59) 2-[2-(4-Dimethylaminophenoxy)phenyl]amino-2 imidazoline, mp. 143 to 1480±. 60) 2-[2-Phenoxy-5-(1-pyrrolidinyl)phenyl]amino-2 imidazoline, mp. 203to 2080±.. 61) 2-[2-(m-Tolyl)phenyl]amino-2-imidazoline, mp. 150 to 152 C. 62) 2-[2-(2-Nitrophenyl)phenyl]amino-2-imidazoline, mp. 185 to 188 C. 59) 2-[2-(2,4-Difluorophenyl)phenyl]amino-2 imidazoline, mp. 131 to 132 C. 64) 2-[2-Phenoxy-5-(N,N-dimethylsulfamoyl)phenyl]amino- 2-imidazoline, mp. 1490±. 65) 2-[2-(2,6-Difluorophenyl)phenyl]amino-2 imidazoline, mp. 154 to 156 C. 66) 2-(2-Phenyl-5-methylphenyl)amino-2-imidazoline, mp. 177 to 180 C. 67) 2-[2-(2-Aminophenyl)phenyl]amino-2-imidazoline, mp. 177 to 179 C. 68) 2-[2-(2-Methoxyphenyl)phenyl]amino-2-imidazoline, mp. 150 to 153 C. 69) 2-[2-(2-Trifluoromethylphenyl)phenyl]amino-2 imidazoline, mp. 176 to 180 C. 70) 2-[2-(2-Dimethylaminophenoxy)phenyl]amino-2 imidazoline, mp. 134 to 137 C. 71) 2-[2-(3-Chloro-4-sulfamoylphenoxy)phenyl]amino 2-imidazoline, mp. 204 to 2080±. Example 7. A solution of 2-(2-phenoxy-5-nitrophenyl)amino2-imidazoline (3.0 g.) in dry methanol (240 ml.) was hydrogenated over 10% palladium-carbon (1.2 g.). The reaction mixture was filtered. The filter cake was washed with methanol. The, filtrate and washing were combined and evaporated. The residue was chromatographed over Alumina, using a mixture of chloroform and methanol. as an eluent. The fractions containing the desiredproduct were collected and then evaporated. The residue was recrystallized from a mixture of n-hexane, ethyl acetate and ethanol to give 2-(2-phenoxy-5-aminophenyl)amino-2-imidazoline (1.7 g.), mp. 153 to 157 C. Elemental analysis C H N Calcd : 67.14 6.01 20.88 Found : 67.15 5.89 20.40 The following compounds were obtained according to the similar manner to that of Example 7. (1) 2-[2-(2-Aminophenyl)phenyl]amino-2-imidazoline, mp. 177 to 179 C. Elemental analysis C H N calcd : 71.40 6.39 22.21 found : 71.50 6.37 21.85

Claims: CLAIMS: 1. A compound of the formula: EMI60.1 wherein )? is aryl which may bavc I to 5 substi tuent(s) selected from the groups consisting of halogen, lower alkyl, lower alkoxy, lower alkanesulfo namido, mono(or di or tri)-halo (lower)alkyl, carbamoyl, hydroxy, nitro, amino, cyano, sulfamoyl, N,N-di(lower)alkylsulfamoyl, and di(lower)alkylamino ehich may form a 3 to 7-membered ring with or with out an oxygen or nitrogen atom; ; ê and R are each hydrogen, halogen lower alkyl, lower alkoxy, lower alkanosulfonamido, mono(or di or tri)-halo(lower)alkyl, carbamoyl, hydroxy, nitro, amino, cyano, sulfamoyl, N,N-di(lower)alkyl sulfamoyl, or di(lower)alkylamino which may form a 3 to 7-membered ring with or without an oxygen or another nitrogen atom; A is -0-, -S- or -CH2-; and n is an integral nember of 0 or1 and pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein R1 is phenyl or naphthyl, each of which may have 1 to 5 substituents selected from the groups con sisting of 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, and di (lower) alkylamino which may form a 3 to 7-membered ring with or without an oxygen or another nitrogen atom. 3. The compound of claim 2, wherein n is 1. 4. The compound of claim 3, wherein A is -0-. 5. The compound of claim 4, which is 2-(2-phenoxyphenyl)amino-2-imidazoline. 6. The compound of claim 4, which is 2-[2-(4-chlorophenoxy)phenylamino-2-imidazoline or its sulfate. 7. The compound of claim 4, which is 2-[2-(4-chlorophenoxy)-5-chlorophenyl3amino-2- imidazoline. 8. The compound of claim 4, which is 2-(2-phenoxy-5-chlorophenyl)amino-2-imidazoline. 9. The compound of claim 4, which is 2-(2-phenoxy-5-methylphenyl)amino-2-imidazoline. 10. The compound of claim 4, which is 2-(2-phenoxy-3-methylphenyl)amino-2-imidazoline. 11. The compound of claim 4, which is 2- (2-phenoxy-4-methylphenyl)amino-2-imidazoline. 12. The compound of claim 4, which is 2-' (2-phenoxy-5-trifluoromethylphenyl)amino-2- imidazoline. 13. The compound of claim 4, which is 2-(2-phenoxy-5-nitrophenyl)amino-2-imidazoline. 14. The compound of claim 4, which is 2-[2-(3,4,5-trimethoxyphenoxyjphenylamino-2- imidazoline. 15. The compound of claim 4, which is 2- (2-phenoxy-5-dimethylaminophenyl)amino-2- imidazoline. 16. The compound of claim 3, wherein A is -S-. 17. The compound of -claim 16, which is 2- (2-phenylthiophenyl)amino-2-imidazoline. 18. The compound of claim 3, wherein A is -±H2-. 19. The compound of claim 2, wherein n is 0. 20. The compound of claim 19, which is 2-(2-biphenyl)amino-2-imidazoline. 21. The compound of claim 19, which is 2- [2-(2-chlorophenyl)phenyl]amino-2-imidazoline. 22. The compound of claim 19, which is 2-[2-(2-fluorophenyl)phenyl]amino-2-imidazoline. 23. The compound of claim 19, which is 2-[2-(4-fluoTophenyl)phenyl]amino-2-imidazoline. 24. A process for preparing 2-imidazoline derivatives 6f the formula: EMI63.1 wherein R1 is aryl which may have 1 to 5 sub stituent(s) selected from the groups consisting of halogen, lower alkyl, lower alkoxy, lower alkanesulfonamido, mono(or di qr tri)-halo(lower)alkyl, carbamoyl, hydroxy, nitro, amino, cyano, sulfamoyl, N,N-di(lower) alkylsulfamoyl, and di(lower) alkylamino which may form a 3 to 7 membered ring with or without an oxygen or nitrogen atom; R2 and R3 are each hydrogen, halogen, lower alkyl, lower alkoxy, lower alkane sulfonamido, mono(or di to trij-halo- (lower)alkyl, carbamoyl, hydroxy, nitro, amino, cyano, sulfamoyl, N,N-di(lower)alkylsulfamoyl, or di(lower)alkylamino which may form a 3 to 7-membered ring with or with out an oxygen or another nitrogen atom; A is -0-, -S-, or -CH2-; and n is an integral number of 0 or 1, and pharmaceutically acceptable salt thereof, which comprises; 1) reacting a compound of the formula: EMI64.1 wherein R1, R2, R3, A and n are each as defined above, or a salt thereof, with ethylenediamine or a salt thereof, to give the compound (I), or 2) reacting a compound of the formula: EMI64.2 wherein R1, R2, R3, A and n are each as defined above, and Y is lower alkyl, or a salt thereof, with ethylenediamine or a salt thereof, to give the compound (I), or 3) reacting a compound of the formula: EMI65.1 wherein R1, R2, R3, A and n are each as defined above, or a salt thereof, with a compound of the formula: EMI65.2 wherein X3 is an acid residue, or a salt thereof, to give the compound (I), or 4) reducing a compound of the formula: : EMI65.3 wherein Rê, A and n are dach as defined above, and RaÚ as the same as RÚ (in which RÚ is as defined above), and Ra is hydrogen or nitro, provided that RaÚ is aryl substituted with nitro when Ra is hydrogen, or a salt thereof, to give a compound of the formula: EMI66.1 wherein Rê, A and n are each as defined above, RbÚ is the same as RÚ(in which RÚ is as 3 defined above), and Rb is hydrogen or amino, provided that RbÚ is aryl substituted with amino when Rb is hydrogen, o a salt thereof. 25. A pharmaceutical composition comprising a conpound of claim 1 in association with a pharmaceitically accetable, substantially non-toxic carrier or excipient.

Inventors: KATSURA, YOUSUKE, MATSUO, MASAAKI, TANIGUCHI, KIYOSHI, UEDA, UKUO
Applicants: FUJISAWA PHARMACEUTICAL CO., LTD.
Application year: 1980
Main classification: C07D233
IPC codes: C07D233, A61P1, A61P9, A61K31, A61P29