Title of Invention

"AMINOETHYLPHENOXYACETIC ACID COMPOUND AND PHARMACEUTICAL COMPOSITION THEREOF"

Abstract

An aminoethylphenoxyacetic acid compound represented by the general formula: wherein R1 represents a hydrogen atom, a lower alkyl group or an aralkyl group; R2 represents a hydrogen atom or a halogen atom; the carbon atom marked with (R) represents a carbon atom in (R) configuration; the carbon atom marked with (S) represents a carbon atom in (S) configuration and a pharmaceutically acceptable salt thereof.

Full Text

Technical Field The present invention relates to aminoethylphenoxyacetic acid derivatives and phannaceutically acceptable salts thereof which are useful as medicaments. Background Art Urolithiasis is a disease generating calculi in the lumen of the entire urinary tract from the kidney to the urethra. The calculi is thought to be formed in a series of events such as nucleation of the urinary component, crystallization, aggregation, concretion, and enlargement. Urinary flow is often obstructed by calculi, which results in the rise of intra-ureteral pressure, leading to pain. An analgesic and an antispastic are prescribed for the pain. However, the use of the analgesic is only a temporary symptomatic therapy for the pain, and is not expected to treat urolitiasis fundamentally at all. The effectiveness of an anti-cholinergic, one of the antispastic, is also not satisfactory. Therefore, the drugs which relieve pain and promote the removal of calculi by widening the ureter with their strong relaxing effects are desired (The Journal of Urology, Vol.152, pp.1095-1098 (1994)). It was recently confirmed that both ß2- and ß3-adrenoceptors are present in human ureter as ß-adrenoceptor subtypes. It is reported that a drug having stimulating effects on both ß2- and ß3-adrenoceptors is extremely useful as an agent for relieving pain and promoting the removal of calculi in urolithiasis because a compound having stimulating effects on both ß2- and ß3-adrenoceptors shows potent relaxing efffceta on uiretsr (Inter-national applicat).on publication^ W097/197UUJ Disclosure of the Invention The present inventors have studied extensively to find compounds beiag useful as agents for relieving paiu. and promoting the removal of calculi in urolithia«i.s, A.S a result;, it was found that certain aminoethylphenoxyaciatic add derivativess Lave potent stimulating effects pn both ß2- and ß3-adrenoceptors and show excellent ureteral relaxation effects, thereby forming 1 the basis of the present invention. Accordingly, the present invention relates to arainoethy'phenrccyacetie acid derivatives represeakedjby the general formula: (Formula Removed) (wherein R1 represents a hydrogen atom, a lower alkyl group or an aralkl group; Ra represents a hydrogen atom or a halogen atom; the carbon atom marked with (R) reprefsentii a carbon ' atom in (R) config~cinition; and the carbon, stem unarmed with (S) representii a carbon atom in (S) configuration) and phs.nnacevitically acceptable salts thereof. The present invention relates to a pharmaceutical composition comprising the aminoethylphencryapetic acid derivative represented by the general formula (L) above or pharmaceutically acceptable salt thereof. Th«i present invention relates to an agent for relieving pair and promoting the removal of calculi which comprises as the active ingredient the amioethylhenosyacetic acid derivative represented by the general formula (I) above or pharmaceutically acceptable salt thereof. The present invention relates to a method for relieving pain and promoting the removal of calculi in urolitbiasis which comprises administering a therapeutically effective amount of the ammpethylphenoxyacetic acid derivative represented by the general formula (I) above or 'pharmaceutically acceptable salt thereof, The present invention relates to a 'use of the aminos'rhylphenoxyncetic acid derivative represented, by the general formula (I) above or pha:nnaceuticaLly acceptable salt thereof for the manufacture of a pharm.acenti.cal composition tor like trca.tment of urolithiasis. The present invention relates to a use of the aroinuebylpheiwxyacetic acid derivative represented.by the gjenoral formula (I) above or phanuceuticslly acceptable salt thereof as an agent for relieving pain an:! prorooting the removal of culculi in urolithiasis, The present invention relates to a. procass for the manufacture of B pbarcnaceutical composition for the treatment of urolithiasiEi, characteiiired in bht uiis, aii an t ssential constitueitit of naid pharmaceutical composition;, of tha aminoetliylp'benox.yiicfltic acid derivative represented by the jreteral formula (1) above or phamtjicautLcaily acceptable salt thereof. In the present invention, the term "lower alkyl fro up" rcoans a:::. ali:yl group having fi'om 1 to 6 carbon atoms such &s a mathyl group, an ethyl, irrouji, a pnipyl group, an isopropyl group, a butyl group, an iwjbutyl group, a *sec-butyl igtrou ip, a f«u-f-bul;yl group, a pemtyl group «nd a fc,exyl group; the tprm "aralkyl group" means; jiaid luwmr tdJsyl group substituted by etn aryl group s\|icb as a phenyl gi-oup and a uapht/l jjroup; and the tencn "halogen atom" meansi a fluoride atom, a. chlorine atom, a bromine ato::o nncl an iodine atom. The compound!! represented by the general formula (1) above o;!' thti present invention can be prepared according to the following procedure. For example, the compounds of the present invention can be prepared by subjecting a phenylpropanol-amine derivative represented by the formula: (Formula Removed) (wherein the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as denned above) to alkylation using an alkylating agent represented by the general formula: (Formula Removed) (wherein Rla represents a lower alkyl group or an aralkyl group; X1 represents a chlorine atom or a bromine atom; and R2 has the same meaning as defined above), and hydrolyzing the ester group of the resulting compound in the usual way as occasion demands. Of the aminoethylphenoxyacetic acid derivatives represented by the general formula (I) above of the present invention, compounds represented by the general formula: (Formula Removed) (wherein Ru , R2, the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as defined above) can be also prepared by esterification of the corresponding aminoethylphenoxyacetic acid derivative. The phenylpropanolamine derivative represented by the formula (II) above used as a starting material in the above production process can be prepared by optical resolution of a commercially available enantiomeric mixture in the usual way or a method described in a literature (J. Med. Chem., Vol. 20, No. 7, pp. 978-981(1977)). Alkylating agents represented by the general formula (III) above used as starting materials in the above production process can be prepared by allowing an anisole derivative represented by the general formula: (Formula Removed) (wherein R2 has the same meaning as defined above) to react with a compound represented by the general formula: (Formula Removed) (wherein X2 represents a chlorine atom or a bromina atom; and X1 has the same meaning as defined above) in the presence of Lewis acid such as aluminum chloride, if necessary, removing the methyl group, reducing the carbonyl group using a reducing agent such as triethylsilane to give a phenol derivative represented by the general formula: (Formula Removed) (wherein R2 and X1 have the same meanings as defined above), and allowing the resulting compound to renct with an alkyl halogenoacetate in tbe presence of the base such as potassium carboaatit. The aminoethylphenoxyacetic acid derivatives represented by the general formula (I) above of the present invention obtained by the- above production processes can be easily isolated and purified by conventional (separation means aueh aa fractional recrystallization, purification usinjf column ch'romatography and solverit'fla.t:raction. The aminoethylphenoxyacetic acid derivatives represented by the pinera! formula (I) above of the present invention can be converted their pharmaceutically acceptable salts in title usual way. Examples of tbe such suits include acid .addition saltfi formed with minoral acids such as hydrochloric acid, hydrobromic; acid, hydroiociic; ucid, sulfun'c acid, nitric acid s.nd phosphoric acid, acid addition salts formed with orgai!.k ucids; such aa formic acid, acetic acjid, propionic acid, citric add, tartaric acid, fu:a:falie acid, butyric acid, oxalic acid, aucciuic acid, malonic acid, maleic acid, lactic acid, melic acid carbonic acid, glutamic acid, aspartic acid, methaaesufomc acid, benzenf!&al,foaj((:: acid and p-toluenesulfonic acid, inorganic base salts such tia a sodium sai.lt, a potassium salt, a calcivooa salt and a:ti ammonium salt, and gaits formed with organic bases such as triethylanaine, piperidine, morphob'ine, pyridine and lysine. In addition, the compounds represented by the general formula (I) above of the present invention also include their solvates with pharmaceutically ffiKceptE-blo solvents such as water and ethanol. ß2-Adrenoceptbr-iStimulatipg effects of the compoaods repres-unteql by the general formula (1) above of the present invention can be measured by using progimnt rat uterus. For example, EC50 value (the concentration inhibiting 50% of the spontaneous contraction) of 2-(4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxypheny])-l-methylethyl'lamino]-ethyl]pheiioxy]aceticj acid was 3.1xlO-8M. formula (I) above of the present invention can be measured by using ferret ureter. For example, EC50 value (the concentration inhibiting 50% of the spontaneous contraction) of 2-[4-[2-[[(1S',2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyl]amino]ethyl]phenoxy]-acetic acid was 1.4xlO"8M. Thus, the compounds represented by the general formula (I) above of the present invention have potent stimulating effects on both ß2- and ß3-adrenoceptors and are useful as agents for relieving pain and promoting the removal of calculi in urolithiasis such as spontaneous passage of calculi and the removal of the 'calculi after extracorporeal shock wave lithotripsy. In the present invention, compounds with less ß1-adrenoceptor-stimulating effects in comparison with the above ß2- and ß3-adrenoceptor-stimulating effects are preferable in order to reduce burdens on the heart and so as not to induce side effects such as tachycardia. Some compounds of the present invention are ß2-. and ß3-adrenoceptor-stimulants with less ß1-adrenoceptor-stimulating effects. As examples of such compounds, compounds represented by the general formula: (Formula Removed) (wherein R2, the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as defined above) and pharmaceutical acceptable salts thereof can be illustrated. As more preferable compounds in the present invention, 2-[4-[2-[[(1Sr,2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyl]amino]ethyl]phenoxy]acetic acid and 2-[3-fluoro-4-[2-[[(1S',2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyl]amino]ethyl]-phenoxy]acetic acid and pharmaceutically acceptable salts thereof can be illustrated. For examples, in the experiment for measuring ß1-adrenoceptor-stimulating effects using rat atrium, 2-[4-[2-[[(1S',2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyl]amino]-ethyl]phenoxy]acetic acid showed ECΔ20 (the activity to increase the heart rate by 20 beats per minute) at a concentration of l.3xl0-6 M. Furthermore, the compounds represented by the general formula (I) above of the present invention are highly safe. For example, in acute toxicity test using rats, any dead rats were not observed by a single administration of 1,000 rng/kg of 2-[4-[2-[[(S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyI]amino]ethyl]phenoxy]acetic acid. In consequence, the compounds represented by the general formula (I) above of the present invention and pharmaceutically acceptable salts thereof have potent and extremely useful stimulating effects on both ß2- and. ß3-adrenoceptors. When the aminoethylphenoxyacetic acid derivatives represented by the general formula (I) above of the present invention and pharmaceutically acceptable salts thereof are employed in the practical treatment, they are administered orally or parenterally in the form of appropriate compositions such as tablets, powders, fine granules, granules, capsules, injections and the like. These pharmaceutical compositions can be formulated in accordance with conventional methods using conventional pharmaceutical carriers, excipients and other additives. The dosage is appropriately decided depending on the sex, age, body weight, degree of symptoms and the like of each patient to be treated, which is approximately within the range of from 1 to 1,000 mg per day per adult human in the case of oral administration and approximately within the range of from 0.01 to 100 mg per day per adult human in the case of parenteral administration, and the daily dose can be divided into one to several doses per day. Accordingly, the present invention relates to the aminoethylphenoxyacetic acid compound represented by the general formula: (Formula Removed) (wherein R1 represents a hydrogen atom, a lower alkyl group or an aralkyl group; R2 represents a hydrogen atom or a halogen atom; the carbon atom marked with (R) represents a carbon atom in (R) configuration; the carbon atom marked with (S) represents a carbon atom in (S) configuration) and a pharmaceutically acceptable salt thereof, Best Mode for Carrying Out the Invention The present invention is further illustrated in more detail by way of the following Reference Examples, Examples and Test Examples. The present invention is not limited thereto. Reference Example 1 2'-Fluoro-4'-hydroxyphenacyl bromide To a stirred suspension of aluminum chloride (17.5 g) in 1,2-dichloroethane (146 ml) was added bromoacetyl bromide (3.8 ml) under ice-cooling. After the mixture was stirred for 30 minutes, 3-fluoroanisole (5.0 ml) was added to the reaction mixture and the resulting mixture was stirred for 12 hours at room temperature. The reaction mixture was poured into ice-water and extracted with dichloromethane. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacua. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane / ethyl acetate =4/1) gave 2'-fluoro-4'-hydroxyphenacyl bromide (518 mg). 1H-NMR (CDCl3) δ ppm: 4.78 (2H, s), 5.74 (1H, br s), 6.63 (1H, dd, J=12.5, 2.4Hz), 6.73 (1H, dd, J=8.7, 2.4Hz), 7.92 (1H, t, J=8.7Hz) Reference Example 2 2'-Chloro-4'-hydroxyphenacyl bromide 2'-Chloro-4'-methoxyphenacyl bromide was prepared according to a similar manner to that described in Reference Example 1 using 3-chloroanisole. 1H-NMR (CDC13) δ ppm: 3.86 (3H, s), 4.54 (2H, s), 6.88 (1H, dd, J=8.7, 2.5Hz), 6.96 (1H, d, J=2.5Hz), 7.69 (1H, d, J=8.7Hz) To a stirred solution of 2'-chloro-4'-methoxyphenacyl bromide (451 mg) in 1,2- dichloroethane (8.6 ml) was added aluminum chloride (690 mg) at room temperature. After the mixture was stirred for 3 hours at 60t, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacua. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane / ethyl acetate = 3/1) gave 2'-chloro-4'-hydroxyphenacyl bromide (295 mg). 1H-NMR (CDCl3) δppm: 4.54 (2H, s), 5.77 (1H, s), 6.82 (1H, dd, J=8.6, 2.4Hz), 6.94 (1H, d, J=2.4Hz), 7.65 (1H, d, J=8.6Hz) Reference Example 3 4-(2-Bromoethyl)-3-chlorophenol To a stirred solution of 2'-chloro-4'-hydroxyphenacyl bromide (291 mg) in dichloromethane (6.0 ml) were added trifluoroacetic acid (900 µl) and triethylsilane (610 µl) at room temperature, and the mixture was heated under reflux for 3 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacua. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane / ethyl acetate = 5/1) gave 4-(2-bromoethyl)-3-chlorophenol (183 mg). 1H-NMR (CDC13) δ ppm: 3.21 (2H, t, J=7.5Hz), 3.55 (2H, t, J=7.5Hz), 5.01 (1H, s), 6.70 (1H, dd, J=8.3, 2.6Hz), 6.88 (1H, d, J=2.6Hz), 7.12 (1H, d, J=8.3Hz) Reference Example 4 4-(2-Bromoethyl)-3-fluorophenol 4-(2-Bromoethyl)-3-fluorophenol was prepared according to a similar manner to that described in Reference Example 3 using 2'-fluoro-4'-hydroxyphenacyl bromide. 1H-NMR (CDC13) δ ppm: 3.12 (2H, t, J=7.5Hz), 3.53 (2H, t, J=7.5Hz), 6.50-6.60 (2H, m), 7.00-7.10 (1H, m) Reference Example 5 Ethyl 2-[4-(2-bromoethyl)-3-chlorophenoxy1acetate To a stirred solution of 4-(2-bromoethyl)-3-chlorophenol (158 mg) in acetone (7.0 ml) were added potassium carbonate (139 mg) and ethyl bromoacetate (89µl) at room temperature. After the mixture was stirred for 20 hours at room temperature, the insoluble material was filtered off and the filtrate was concentrated in vacua. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane / ethyl acetate = 7/1) gave ethyl 2-[4-(2-bromoethyl)-3-chloro-phenoxylacetate (193 mg). 1H-NMR (CDC13) δ ppm: 1.30 (3H, t, J=7.lHz), 3.22 (2H, t, J=7.5Hz), 3.55 (2H, t, J=7.5Hz), 4.28 (2H, q, J=7.lHz), 4.59 (2H, s), 6.78 (1H, dd, J=8.5, 2.7Hz), 6.94 (1H, d, J=2.7Hz), 7.17 (1H, d, J=8.5Hz) Reference Example 6 The following compounds were prepared according to a similar manner to that described in Reference Example 5 using the corresponding bromoacetic acid derivatives and phenol derivatives. Ethyl 2-r4-(2-bromoethyl)phenoxy1acetate 1H-NMR (CDCl3)δ ppm: 1.30 (3H, t, J=7.1Hz), 3.10 (2H, t, J=7.6Hz), 3.53 (2H, t, J=7.6Hz), 4.27 (2H, q, J=7.1Hz), 4.61 (2H, s), 6.86 (2H, d, J=8.5Hz), 7.13 (2H, d, J=8.5Hz) Ethl 2-[4-(2-bromoethyl)-3-fluorohenox1acetate 1H-NMR (CDC13) δ ppm: 1.30 (3H, t, J=7.1Hz), 3.13 (2H, t, J=7.5Hz), 3.53 (2H, t, J=7.5Hz), 4.28 (2H, q, J=7.1Hz), 4.59 (2H, s), 6.60-6.70 (2H, m), 7.12 (1H, t, J=8.6Hz) Benzyl 2-r4-(2-bromoethyl)-3-fluorophenoxy1acetate - 1H-NMR (CDC13) δ ppm: 3.13 (2H, t, J=7.5Hz), 3.53 (2H, t, J=7.5Hz), 4.64 (2H, s), 5.24 (2H, s), 6.55-6.70 (2H, m), 7.11 (1H, t, J=8.7Hz) Example 1 Ethyl 2-[3-chloro-4-[2-[[(1S',2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyl1amino1- ethyllphenoxylacetate (Compound 1) A solution of (1R ,2S)2-amino-l-(4-hydroxyphenyl)propan-l-ol (97 mg), ethyl 2-[4-(2-bromoethyl)-3-chlorophenoxy]acetate (187 mg) and ,N,N-diisopropylethylamine (203(il) in N,N-dimethylfonnamide (3 ml) was stirred for 10 hours at 60t. After cooling, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacua. Purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: ethyl acetate / ethanol = 30/1) gave ethyl 2-[3-chloro-4-[2-[[(LSr,2ff)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyl]-amino]ethyl]phenoxy]acetate (75 mg). 1H-NMR (CDCl3) δ ppm: 0.93 (3H, d, J=6.4Hz), 1.33 (3H, t, J=7.1Hz), 2.75-3.05 (5H, m), 4.31 (2H, q, J=7.1Hz), 4.53 (1H, d, J=5.2Hz), 4.60 (2H, s), 6.65-6.80 (3H, m), 6.88 (1H, d, J=2.7Hz), 7.03 (1H, d, J=8.5Hz), 7.10 (2H, d, J=8.2Hz) Example 2 The following compounds were prepared according to a similar manner to that described in Example 1 using the corresponding phenoxyacetic acid derivatives. Ethyl 2-[4-[2-[[1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethvl1amino1ethyn-phenoxylacetate (Compound 2) 1H-NMR (CDCl3)δppm: 0.97 (3H, d, J=6.4Hz), 1.33 (3H, t, J=7.1Hz), 2.60-2.80 (4H, m), 2.90-3.05 (IH, m), 4.31 (2H, q, J=7.1Hz), 4.47 (IH, d, J=5.6Hz), 4.62 (2H, s), 6.69 (2H, d, J=8.6Hz), 6.76 (2H, d, J=8.6Hz), 7.01 (2H, d, J=8.6Hz), 7.05 (2H, d, J=8.6Hz) Ethyl 2-[3-fluoro-4-[2-[[1S'r2R)-2-hydroxy-2-f4-hydroxyphenyI')-l-methylethynainino1-ethyllphenoylacetate (Compound 3) 1H-NMR (DMSO-d6)δ ppm: 0.81 (3H, d, J=6.3Hz), 1.22 (3H, t, J=7.1Hz), 2.55-2.80 (5H, m), 4.18 (2H, q, J=7.1Hz), 4.35-4.45 (1H, m), 4.78 (2H, s), 4.80-4.90 (1H, m), 6.65-6.80 (4H, m), 7.05-7.20 (3H, m), 9.18 (1H, br) Benzyl 2-[3-fluoro-4-[2-[[(1S'.2R)-2-hydroxy-2-(4-hydroxvphenyn-l-methyIethynamino1-ethyllphenoxylacetate (Compound 4) 1H-NMR (DMSO-D6) δ ppm: 0.80 (3H, d, J=6.4Hz), 1.30 (1H, br), 2.55-2.80 (5H, m), 4.41 (1H, br s), 4.80-4.95 (3H, m), 5.20 (2H, s), 6.60-6.80 (4H, m), 7.00-7.20 (3H, m), 7.25-7.45 (5H, m), 9.20 (1H, br) Example 3 Ethyl 2-[3-chloro-4-[2-[[(1S.2R)-2-hvdroxy-2-(4-hydroxyphenyl)-l-methylethyl1aminol- ethvllphenoxylacetate hvdrochloride (Compound 5) To a stirred solution of ethyl 2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-l-methylethyl]amino]ethyl]phenoxy]acetate (120 ing) in ethyl acetate (2.0 ml) was added 4 N hydrogen chloride ethyl acetate soluion (220(0.1) under ice-cooling, and the mixture was vigorously stirred for an hour at room temperature. Collection of the resulting precipitates by filtration gave ethyl 2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyl]amino]ethyl]phenoxy]acetate hydrochloride (110 mg). 1H-NMR (DMSO-d6)δ ppm: 0.96 (3H, d, J=6.9Hz), 1.22 (3H, t, J=7.2Hz), 3.05-3.20 (4H, m), 3.25-3.40 (IH, m), 4.17 (2H, q, J=7.2Hz), 4.82 (2H, a)-, 5.06 (IH, br), 5.97 (IH, d, J=3.8Hz), 6.76 (2H, d, J=8.2Hz), 6.95 (IH, dd, J=8.8, 2.7Hz), 7.08 (IH, d, J=2.7Hz), 7.17 (2H, d, J=8.2Hz), 7.33 (IH, d, J=8.8Hz), 8.89 (2H, br), 9.42 (IH, s) Specific rotation : [α]DK = -9.2° (c = 0.50, CH3OH) Example 4 The following compounds were prepared according to a similar manner to that described in Example 3 using the corresponding phenoxyacetic acid derivatives. Ethyl 2-[3-fluoro-4-[2-[[(1S,.2R)-2-hydroxy-2[4-hydroxyprhenyl)-l-methylethynamino1- ethyllphenoxylacetate hydrochloride (Compound 6) 1'H-NMR (DMSO-ds) δ ppm: 0.95 (3H, d, J=6.6Hz), 1.22 (3H, t, J=7.lHz), 2.90-3.05 (2H, m), 3.10-3.40 (3H, m), 4.17 (2H, q, J=7.1Hz), 4.81 (2H, s), 5.03 (IH, br s), 5.97 (IH, d, J=3.8Hz), 6.70-6.85 (3H, m), 6.87 (IH, dd, J=12.0, 2.3Hz), 7.17 (2H, d, J=8.4Hz), 7.27 (IH, t, J=8.7Hz), 8.75 (2H, br), 9.41 (IH, s) Specific rotation : [α]D32 = -10.0° (c = 0.74, CH3OH) Benzyl 2-[3-fluoro-4-[2-[[(1S't2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethynamino1-ethyllphenoxylacetate hydrochloride (Compound 7) 1H-NMR (DMSO-d6) δ ppm: 0.95 (3H, d, J=6.6Hz), 2.95-3.45 (5H, m), 4.90 (2H, s), 5.03 (IH, br s), 5.20 (2H, s), 5.98 (IH, br s), 6.70-6.85 (3H, m), 6.88 (IH, dd, J=12.0, 2.2Hz), 7.17 (2H, d, J=8.4Hz), 7.26 (IH, t, J=8.8Hz), 7.30-7.45 (5H, m), 8.80 (2H, br), 9.41 (IH, s) Specific rotation : [α]D32 = -8.7° (c = 1.20, CH3OH) Example 5 2-[3-Chloro-4-[2-[[(1S'r2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethynamino1ethyn-phenoxylacetic acid (Compound 8) To a stirred solution of ethyl 2-[3-chloro-4-[2-[[(1Sr,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-l-methylethyl]amino]ethyl]phenoxy]acetate (63 mg) in ethanol (775 µ1) was added IN aqueous sodium hydroxide solution (465 µl) at room temperature. After the mixture was stirred for 20 hours, IN hydrochloric acid (465 µl) was added to the reaction mixture under ice-cooling with stirring. Collection of the resulting precipitates by filtration gave 2-[3-chloro-4-t2-[[(lS,2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyl]-amino]ethyl]phenoxy]acetatic acid (44 mg). 1H-NMR (DMSO-d6+D2O)δ ppm: 0.90 (3H, d, J=6.6Hz), 2.30-2.80 (2H, m), 2.90-3.05 (2H, m), 3.20-3.35 (IH, m), 4.30-4.45 (2H, m), 5.05-5.15 (IH, m), 6.70-6.80 (3H, m), 6.86 (IH, d, J=2.5Hz), 6.94 (IH, d, J=8.6Hz), 7.16 (2H, d, J=8.5Hz) Specific rotation : [α]DK = -5.7° (c = 0.56, IN hydrochloric acid) Example 6 The following compounds were prepared according to a similar manner to that described in Example 5 using the corresponding aminoethylphenoxyacetic acid derivatives. 2-[4-[2-[[(1S',2R)-2-Hydroxy-2-(4-hydroxyphenyl)-l-methylethynamino1ethynphenoxyl-acetic acid (Compound 9) 1H-NMR (DMSO-d6)δ ppm: 0.91 (3H, d, J=6.6Hz), 2.55-2.75 (2H, m), 2.90-3.05 (2H, m), 3.15-3.25 (IH, m), 4.34 (2H, s), 5.00-5.10 (IH, m), 6.65-6.80 (4H, m), 6.91 (2H, d, J=8.6Hz), 7.13 (2H, d, J=8.6Hz), 9.40 (2H, br) Specific rotation : [α]D26 = -10.0° (c = 1.06, IN hydrochloric acid) 2-f3-Fluoro-4-[2-[[(1S'r2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethynainino1ethyl1- phenoxykcetic acid (Compound 10) 1H-NMR (DMSO-d6) δ ppm: 0.87 (3H, d, J=6.6Hz), 2.30-2.70 (2H, m), 2.85-3.00 (2H, m), 3.15-3.30 (1H, m), 4.30-4.50 (2H, m), 5.00-5.15 (1H, m), 6.55-6.70 (2H, m), 6.71 (2H, d, J=8.6Hz), 6.88 (1H, t, J=8.8Hz), 7.13 (2H, d, J=8.6Hz), 9.40 (2H, br) Specific rotation : [α]D25 = -6.6° (c = 1.19, CH3COOH) Example 7 Benzyl 2-[3-chloro-4-[2-[[(lS,r2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyllamino1- ethyllphenoxylacetate hydrochloride (Compound 11) A solution of 2-[3-chloro-4-[2-[[(lS,2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methyl-ethyl]amino]ethyl]phenoxy]acetic acid (200 mg) and methanesulfonic acid (38 µl) in benzyl alcohol (1.0 ml) was stirred for 2 days at room temperature. Purification of the reaction mixture by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: ethyl acetate / ethanol = 20/1) gave benzyl 2-[3-chloro-4-[2-[[(lS,2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyl]amino]ethyl]phenoxy]acetate (136 mg). 1H-NMR (CDCl3) δ ppm: 0.95 (3H, d, J=6.3Hz), 2.75-3.05 (5H, m), 4.54 (1H, d, J=5.0Hz), 4.63 (2H, s), 5.25 (2H, s), 6.65-6.75 (3H, m), 6.86 (1H, d, J=2.5Hz), 7.00 (1H, d, J=8.5Hz), 7.08 (2H, d, J=8.5Hz), 7.30-7.45 (5H, m) To a stirred solution of benzyl 2-[3-chloro-4-[2-[[(1S',2R)-2-hydroxy-2-(4-hydroxy-phenyl)-l-methylethyl]amino]ethyl]phenoxy]acetate (136 mg) in ethyl acetate (2.0 ml) was added 4 N hydrogen chloride ethyl acetate solution (161 µl) under ice-cooling and the mixture was vigorously stirred for an hour at room temperature. Collection of the resulting precipitates by filtration gave benzyl 2-[3-chloro-4-[2-[[(1S',2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyl]amino]ethyl]phenoxy] acetate hydrochloride (137 nig). 1H-NMR (DMSO-d6)δ ppm: 0.96 (3H, d, J=6.9Hz), 3.00-3.20 (4H, m), 3.30-3.45 (IH, m), 4.92 (2H, s), 5.03 (IH, br), 5.20 (2H, s), 5.97 (IH, br s), 6.76 (2H, d, J=8.8Hz), 6.96 (IH, dd, J=8.2, 2.7Hz), 7.09 (IH, d, J=2.7Hz), 7.18 (2H, d, J=8.8Hz), 7.30-7.45 (6H, m), 8.75 (2H, br), 9.38 (IH, s) Specific rotation : [α]D25 = -6.4° (c = 0.53, CH3OH) Example 8 The following compounds were prepared according to a similar manner to that described in Example 7 using 2-[4-[2-[[(1S',2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methyl-ethyl]amino]ethyl]phenoxy]acetic acid. Benzyl 2-[4-[2-rr(lS',2R)-2-hydroxy-2-(4-hydroxyphenyI)-l-methylethynamino1ethyI1-phenoxylacetate (Compound 12) 1H-NMR (CDC13) δ ppm: 0.93 (3H, d, J=6.5Hz), 2.65-2.85 (4H, m), 2.90-3.05 (IH, m), 4.49 (IH, d, J=5.2Hz), 4.66 (2H, s), 5.27 (2H, s), 6.70 (2H, d, J=8.6Hz), 6.76 (2H, d, J=8.6Hz), 7.01 (2H, d, J=8.6Hz), 7.06 (2H, d, J=8.6Hz), 7.30-7.40 (5H, m) Benzyl 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyl1aminolethyl1-phenoxylacetate hydrochloride (Compound 13) 1H-NMR (DMSO-d6) δ ppm: 0.95 (3H, d, J=6.7Hz), 2.90-3.00 (2H, m), 3.10-3.40 (3H, m), 4.85 (2H, s), 5.03 (IH, br s), 5.19 (2H, s), 5.97 (IH, d, J=4.0Hz), 6.76 (2H, d, J=8.5Hz), 6.91 (2H, d, J=8.7Hz), 7.16 (2H, d, J=8.5Hz), 7.19 (2H, d, J=8.7Hz), 7.30-7.45 (5H, m), 8.70 (2H, br), 9.41 (IH, s) Specific rotation : [α]D25 = -8.3° (c = 0.51, CH3OH) Test Example 1 The experiment for measuring ß2-adrenoceptor-stimulating effects The uterus of pregnant SD rats (pregnancy day of 21) was isolated and longitudinal smooth muscle strips (about 15 mm in length and 5 mm in width) free from the basal plate were prepared. The experiment was conducted according to the Magnus method. The preparations were mounted with an initial resting tension of about 1.0 g in the Locke's-Ringer solution maintained at 37°C and gassed with a mixture of 95 % O2 and 5 % CO2. The spontaneous contraction of the uterus was measured by an isometric force-transducer and recorded by a rectigraph. The drug solution was added cumulatively to the organ bath every 5 minutes. Uterine activities were calculated as the sum of the amplitudes of the spontaneous contraction for 5 minutes, and the percent change before and after the drug application were compared. EC50 value was determined as the molar concentration required to produce 50 % of own maximal relaxation elicited by each drug. The result was shown in the following table. Test Example 2 The experiment for measuring ß3-adrenoceptor-stimulating effects The ferret ureter was isolated and the ring smooth muscle strips were prepared (about 20 mm in length). The experiment was conducted according to the Magnus method. The preparations were mounted with an initial resting tension of about 0.5 g in the Krebs-Henseleit solution maintained at 31°C and gassed with a mixture of 95 % 02 and 5 % C02. The spontaneous contraction of the ureter was measured by an isometric force-transducer and recorded by a rectigraph. The drug solution was added cumulatively to the organ bath every 5 minutes. Ureteral activities were calculated as the sum of the amplitudes of the spontaneous contraction for 5 minutes, and the percent change before and after the drug application were compared. EC50 value was determined as the molar concentration required to produce 50 % of own maximal relaxation elicited by each drug. The result was shown in the following table. Test Example 3 The experiment for measuring ß1-adrenoceptor-stimulating effects The rat atrium (Sprague-Dawley, 350-400g) was isolated and the experiment was conducted according to the Magnus methods. The preparations were mounted with an initial resting tension of about 1.0 g in the Krebs-Henseleit solution maintained at 37°C and gassed with a mixture of 95% 02 and 5% CO2. The spontaneous contraction of the atrium was measured by an isometric force-transducer and recorded by a rectigraph. The drug solution was added cumulatively to the organ bath. EC 4 20 value was determined as the molar concentration required to produce 20 beats/minute increment of the heart rate. The result was shown in the following table. (Table Removed) Test Example 4 Acute toxicity test To male ICR rats of 4 weeks age was administered l,000mg/kg of 2-[4-[[(1S',2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyl]amino]ethyl]phenoxy]acetic acid intravenously by a single administration. Any dead rats were not observed during 24 hours after the administration. WE CLAIM: 1. An aminoethylphenoxyacetic acid compound represented by the general formula: () (Formula Removed) wherein R1 represents a hydrogen atom, a lower alkyl group or an aralkyl group; R2 represents a hydrogen atom or a halogen atom; the carbon atom marked with (R) represents a carbon atom in (R) configuration; the carbon atom marked with (S) represents a carbon atom in (S) configuration and a pharmaceutically acceptable salt thereof of the kind such as herein described. 2. The aminoethylphenoxyacetic acid compound represented by the general formula: (Formula Removed) wherein R2 represents a hydrogen atom, or a halogen atom; the carbon atom marked with (R) represents a carbon atom in (R) configuration; the carbon atom marked with (S) represents a carbon atom in (S) configuration and a pharmaceutically acceptable salt thereof as claimed in claim 1. 3. The aminoethylphenoxyacetic acid compound as claimed in claim 1 and 2, wherein the said compound is 2-[4-[2-[[(lS,2R)-2-Hydroxy-2-(4- hydroxyphenyl) -1 -methylethyl] amino] ethyl] -phenoxy] acetic acid and pharmaceutical acceptable salt thereof. 4. The aminoethylphenoxyacetic acid compound as claimed in claim 1 and 2, wherein the said compound is 2-[3-Fluro-4-[2-[[(lS,2R)-2-hydroxy-2-(4- hydroxyphenyl)-l-methylethyl]amino]-ethyl]-phenoxy]acetic acid and pharmaceutical acceptable salt thereof. 5. A pharmaceutical composition comprising the aminoethylphenoxyacetic acid compound or pharmaceutically acceptable salt thereof as claimed in claim 1 and a pharmaceutically acceptable carrier or diluent wherein the weight ratio of the active ingredient is 0.001 to 20% by weight and weight ratio of pharmaceutically acceptable carrier or diluent is 80 to 99.999% by weight. 6. An aminoethylphenoxyacetic acid substantially as herein described with reference to the foregoing examples. 7. A pharmaceutical composition substantially as herein described with reference to the foregoing examples.

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