MXPA00000869A - Aminoethylphenoxyacetic acid derivatives and drugs for pain remission and calculi removal promotion in urinary lithiasis - Google Patents

Abstract

Novel aminoethylphenoxyacetic acid derivatives represented by general formula (I) and pharmacologically acceptable salts thereof, which have effects of stimulating both of b2- and b3-adrenergic receptors and are useful in the pain remission and calculi removal promotion in urinary lithiasis;wherein R1 represents hydrogen, lower alkyl or aralkyl;R2 represents hydrogen or halogeno;and the carbon atoms with the marks of (R) and (S) are those having the (R)- and (S)-configurations respectively.

Description

DERIVATIVES OF AMINOETHYLPHENOXYACTIC ACID AND DRUGS FOR THE REMISSION OF PAIN AND PROMOTION FOR THE ELIMINATION OF CALCULATIONS IN THE URINARY LITHIASIS Technical Field The present invention relates to the arainoethyl phenoxyacetic acid derivatives and the pharmaceutically acceptable salts thereof, which are useful as medicaments.

BACKGROUND ART Urolithiasis is a disease that generates calculations through a series of events, such as the nucleation of the urinary component, crystallization, aggregation, concretion and lengthening of the lumen of the entire urinary tract from the kidney to the urethra. Urinary flow is frequently obstructed by stones, which results in the origin of intra-ureteral pressure, which leads to pain. At present, an analgesic and an antispastic is prescribed for pain, however, the use of the analgesic is only a temporary symptomatic therapy for pain, and it is not expected to treat urolithiasis fundamentally at all. Neither is the effectiveness of the antispastic, such as an anti-cholinergic, satisfactory. Therefore, drugs useful for the causal treatment of urolithiasis are desirable, for example, drugs that relieve pain and promote the elimination of stones by widening the ureter with its powerful relaxing effects (The Journal of Urology , volume 152, pages 1095-1098 (1994)). It was recently confirmed that both β2 and β3 adrenoreceptors are present in the human ureter as subtypes of the β-adrenoreceptor. It is reported that a drug that has stimulant effects on the ß2 and / 33 adrenoreceptors, is extremely useful as an agent to relieve pain and promote stone removal in urolithiasis, because a compound that has stimulating effects on the two adrenoreceptors ß2 and jS3 shows potent relaxing effects in the ureter (International Application Publication Number O97 / 19700).

Description of the Invention The present inventors have studied intensively to find compounds that are useful as pain relieving agents and promote stone removal in urolithiasis. As a result, it was found that certain aminoethyl phenoxyacetic acid derivatives have potent stimulatory effects on both β2 and β3 adrenoreceptors and exhibit excellent ureteral relaxation effects, thereby forming the bases of the present invention. The present invention relates to the aminoethyl phenoxyacetic acid derivatives, which are represented by the general formula: (wherein R 1 represents a hydrogen atom, a lower alkyl group or an aralkyl group, R 2 represents a hydrogen atom or a halogen atom, the carbon atom marked with (R) represents a carbon atom in the configuration (i?), and the carbon atom marked with (S) represents a carbon atom in the configuration (£)) and pharmaceutically acceptable salts thereof. The present invention relates to pharmaceutical compositions comprising an aminoethyl phenoxyacetic acid derivative which is represented by the general formula (I) above or a pharmaceutically acceptable salt thereof. The present invention relates to agents for relieving pain and promoting stone removal, which comprises as the active ingredient an aminoethyl phenoxyacetic acid derivative, represented by the above general formula (I) or a pharmaceutically acceptable salt thereof. The present invention relates to methods for relieving pain and promoting the removal of stones in urolithiasis, which comprises the administration of a therapeutically effective amount of an aminoethyl phenoxyacetic acid derivative represented by the general formula (I) above or a salt pharmaceutically acceptable thereof. The present invention relates to the use of an aminoethyl phenoxyacetic acid derivative represented by the general formula (I) above or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of urolithiasis. The present invention relates to the uses of an aminoethyl phenoxyacetic acid derivative, represented by the general formula (I) above or a pharmaceutically acceptable salt thereof as agents for relieving pain and promoting the removal of stones in urolithiasis. The present invention relates to processes for the manufacture of a pharmaceutical composition for the treatment of urolithiasis, which is characterized by the use, as an essential constituent of that pharmaceutical composition, of a derivative of aminoethyl phenoxyacetic acid, represented by the general formula (I) above or a pharmaceutically acceptable salt thereof. In the present invention, the term "lower alkyl group" means an alkyl group having from 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and a hexyl group; the term "aralkyl group" means the above lower alkyl group substituted by an aryl group, such as a phenyl group and a naphthyl group; and the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The compounds represented by the general formula (I) above of the present invention can be prepared according to the following procedures. For example, the compounds of the present invention can be prepared by subjecting a phenylpropane-lamellar derivative, represented by the formula: (wherein the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as defined above) alkylation, using an alkylating agent represented by the general formula: (III) (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 hydrolyze the ester group of the resulting compound in the usual way that the occasion demands. Of the compounds represented by the general formula (I) above of the present invention, the compounds represented by the general formula can also be prepared: (where Rla, R2, the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as defined above) by means of the esterification of the corresponding aminoethyl phenoxyacetic acid derivative (compounds represented by the general formula (Ib) which is described below). The phenylpropanolamine derivative represented by the above formula (II), which is used as a starting material in the above production process, can be prepared by optical resolution of an enantiomerically available mixture commercially in the usual manner or by a method described in the literature (J. Med. Chem., volume 20, number 7, pages 978-981 (1977)). The alkylating agents represented by the general formula (III) above, which are used as starting materials in the above production process, can be prepared by allowing an anisole derivative, represented by the general formula: (where R has the same meaning as defined above), react with a compound represented by the general formula: (wherein X2 represents a chlorine atom or a bromine atom, and X1 has the same meaning as defined above), in the presence of a Lewis acid such as aluminum chloride, remove the methyl group as the occasion demands , reducing the carbonyl group using a reducing agent such as triethylsilane, to give a phenol derivative represented by the general formula: (wherein R2 and X1 have the same meanings as defined above), and allowing the resulting compound to react with alkyl halogenoacetate in the presence of a base, such as a potassium carbonate. The aminoethyl phenoxyacetic acid derivatives represented by the above general formula (I) of the present invention, which was obtained by the above production processes, can be easily isolated and purified by conventional separation elements, such as fractional recrystallization, purification using chromatography column and solvent extraction. The aminoethyl phenoxyacetic acid derivatives represented by the general formula (I) above of the present invention can be converted into their pharmaceutically acceptable salts in the usual manner. Examples of these salts include the acid addition salts, which are formed with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, acid addition salts that are formed with organic acids such as acid formic, acetic acid, propionic acid, citric acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, succinic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, inorganic base salts such as a sodium salt, a potassium salt, a calcium salt and an ammonium salt, and salts that are formed with organic bases such as triethylamine, piperidine, morpholine, pyridine and lysine. In addition, the compounds represented by the general formula (I) above of the present invention, they also include their solvates with pharmaceutically acceptable solvents, such as water and ethanol. The stimulatory effects of the β2-adrenoreceptor of the compounds represented by the above general formula (I) of the present invention can be measured by the use of the pregnant rat uterus. For example, the EC50 value (the concentration that inhibits 50 percent of spontaneous contraction) of 2- [4- [2- [[1S, 2R) -2-hydroxy-2- (4-hydroxy-phenyl)] -1-methylethyl] mino] ethyl] phenoxy] -acetic was 3. lxlO ~ 8M. The stimulatory effects of the β2-adrenoreceptor of the compounds represented by the general formula (I) above of the present invention can be measured by the use of the pregnant ferret uterus. For example, the EC50 value (the concentration that inhibits 50 percent of spontaneous contraction) of 2- [4- [2- [[13, 2R) -2-hydroxy-2- (4-hydroxy-phenyl)] -1-methylethyl] amino] ethyl] phenoxy] -acetic was 1.4xl0"8M In this way, the compounds represented by the general formula (I) above of the present invention have potent stimulant effects in the two β2-adrenoreceptors. ß3 and are useful as agents for relieving pain and promoting the removal of stones, such as the spontaneous passage of stones and the removal of stones after extracorporeal shock lithotripsy in urolithiasis. less stimulatory effects of the ßx-adrenoreceptor, compared to the stimulatory effects of the β2 and β3-adrenoreceptors, are thus preferred to reduce loads on the heart and not to induce side effects such as tachycardia. The present invention is a stimulator of β2 and β3-adrenoreceptors with less stimulating effects of the ßx-adrenoreceptor. As examples of these compounds, the compounds represented by the general formula can be illustrated: (wherein R2, the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as defined above) and the pharmaceutically acceptable salts thereof. As the most preferred compounds in the present invention, 2- [4- [2- [[1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] can be illustrated] phenoxy] -acetic, 2- [3-fluoro-4- [2- [[1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] -acetic acid and the pharmaceutically acceptable salts thereof. For example, in the experiment to measure the stimulatory effects of the β1-adrenoreceptor using the rat atrium, the acid 2- [4- [2- [[1S, 2R) -2 ~ hydroxy-2- (4-hydroxyphenyl) -1 -methylethyl] amino] ethyl] phenoxy] -acetic showed an EC value of 20 (the concentration to increase the heart rate to 20 beats per minute), at a concentration of 1.3xl0_6M. Additionally, the compounds represented by the general formula (I) above of the present invention are highly safe. For example, in the acute toxicity tests using rats, no dead rat was observed by a single administration of 1,000 milligrams / kilogram of 2- [4- [2- [[1S, 2R) -2-hydroxy-2- (4-Hydroxyphenyl) -1-methylethyl] -amino] ethyl] phenoxy] -acetic. Accordingly, the compounds represented by the general formula (I) above of the present invention and the pharmaceutically acceptable salts thereof, have potent and extremely useful stimulant effects on both β2 and β3 adrenoreceptors. When the aminoethylphenoxyacetic acid derivatives represented by the general formula (I) above of the present invention and the pharmaceutically acceptable salts thereof are used in the practical treatment, these are administered orally or parenterally in the form of appropriate pharmaceutical compositions such as tablets, powders, fine granules, capsules, injections and the like. These pharmaceutical compositions can be formulated in accordance with conventional methods using pharmaceutical carriers, excipients and other conventional additives. The dose is decided appropriately depending on the sex, age, body weight, degree of symptoms and others of each patient to be treated, which is within the range of from 1 to 1,000 milligrams per day per adult human in the case of oral administration, and approximately in the range of from 0.1 to 100 milligrams per day per adult human, in the case of parenteral administration, and the daily dose can be divided into one or several doses per day.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is further illustrated in more detail by means of the following Reference Examples, Examples and Test Examples. The present invention is not limited thereto.

Reference Example 1 2 '-fluoro-47-hydroxyphenacyl bromide Bromoacetyl bromide (3.8 milliliters) was added to a stirred suspension of aluminum chloride (17.5 grams) in 1,2-dichloroethane (146 milliliters) under ice-cooling. After the mixture was stirred for 30 minutes, 3-fluoro-anisole (5.0 milliliters) 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 and dried over anhydrous magnesium sulfate. After the solvent was removed in vacuo, purification of the residue by liquid column chromatography of intermediate pressure on silica gel (diluent: hexane / ethyl acetate = 4/1) gave the 2'-fluoro-4 'bromide -hydroxyphenacyl (518 milligrams). ^ • H-NMR (CDC13) dppm: 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, 2.4 Hz), 7.92 (1H, t, J = 8.7Hz) Reference Example 2 2'-Chloro-4 '-hydroxyphenacyl Bromide 2'-Chloro-4'-methoxyphenacyl bromide was prepared using 3-chloroanisole in accordance with a manner similar to that described in Reference Example 1.

XH-NMR (CDC13) dppm: 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) The 2'-chloro-4'-methoxyphenacyl bromide (415 milligrams) was dissolved in 1,2-dichloroethane (8.6 milliliters). Aluminum chloride (690 milligrams) was added to the solution at room temperature with stirring, and the mixture was stirred for 3 hours at 60 ° C. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with saline and dried over anhydrous magnesium sulfate. After the solvent was removed in vacuo, purification of the residue by liquid column chromatography of intermediate pressure on silica gel (diluent: hexane / ethyl acetate = 3/1) gave the 2'-chloro-4 'bromide -hydroxyphenacyl (295 milligrams). ^? - NM (CDCI3) dppm: 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 Trifluoroacetic acid (900 μl) and triethylsilane (610 μl) were added to a stirred solution of 2'-chloro-4'-hydroxyphenacyl bromide (291 milligrams) in dichloromethane (6.0 milliliters) at room temperature, and the mixture was heated under reflux for 3 hours. A solution of saturated aqueous sodium bicarbonate was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After the solvent was removed in vacuo, purification of the residue by liquid column chromatography of intermediate pressure on silica gel (diluent: exano / ethyl acetate = 5/1) gave 4- (2-bromoethyl) -3 -chlorophenol (183 milligrams). ^ -H-NMR (CDC13) dppm: 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-fluoro-phenol was prepared using 2 '-fluoro-4' -hydroxyphenacyl bromide, in accordance with a similar manner to that which was described in the Example of Reference 3. ^ -NMR (CDCI3) dppm: 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 2- T4- (2-bromoethyl) -3-chlorophenoxy] ethyl acetate Potassium carbonate (139 milligrams) and ethyl bromoacetate (89 μl) were added to a stirred solution of 4- (2-bromoethyl) -3-chlorophenol (158 milligrams) in acetone (7 milliliters), at room temperature. After the mixture was stirred for 20 hours at room temperature, the insoluble material was filtered and the filtrate was concentrated in vacuo. Purification of the residue by intermediate pressure liquid column chromatography on silica gel (diluent: hexane / ethyl acetate = 7/1) gave 2- [4- (2-bromoethyl) -3-chlorophenoxy] ethyl acetate ( 193 milligrams). ^ -H-NMR (CDC13) dppm: 1.30 (3H, t, J = 7.1Hz), 3.22 (2H, t, J = 7.5Hz), 3.55 (2H, t, J = 7.5Hz), 4.28 (2H, q, J = 7.1Hz), 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 = 8.5 Hz) Reference Example 6 The following compounds were prepared using the corresponding bromoacetic acid derivative and the corresponding phenol derivative, in accordance with a manner similar to that described in Reference Example 5. 2- f4- (2-bromoethyl) phenoxyethyl acetate ^ -H-NMR (CDCl 3) dppm: 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 ) 2- f4- (2-bromoethyl) -3-fluorophenoxy] ethyl acetate, _ ^ -NMR (CDCI3) dppm: 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 (2H, t, J = 8.6 Hz) 2- [4- (2-bromoethyl) -3-fluorophenoxy benzyl acetate ^? NMR (CDC13) dppm: 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) Ex e plo 1 2- [3-chloro-4- \ 2- \\ (1S, 2R) -2-hydroxy-2- (-hydroxyphenyl) -1-methyl-ethylamino] ethyl] phenoxyethyl acetate (Compound 1) A solution of was stirred. { IR, 2S) -2-amino-1- (4-hydroxyphenyl) propan-1-ol (97 milligrams), 2- [4- (2-bromoethyl) -3-chlorophenoxy] ethyl acetate (187 milligrams) and IV N-diisopro-pylethylamine (203 μl) in N / N-dimethylformamide (3 milliliters) for 10 hours at 60 ° C. After cooling, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After the solvent was removed in vacuo, purification of the residue by intermediate pressure liquid column chromatography on aminopropyl silica gel (diluent: ethyl acetate / ethanol = 30/1) gave the 2- [3-chloro -4- [2- [[US, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] ethyl acetate (75 milligrams).

^ -H-NMR (CDCI3) dppm: 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 = 9.2Hz) Example 2 The following compounds were prepared using the corresponding phenoxyacetate derivative, in accordance with a manner similar to that described in Example 1. 2- T4- T2- rr (15, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl aminol ethyl phenoxy] ethyl acetate (Compound 2) XH-NMR (CDCI3) dppm: 0.97 (3H , d, J = 6.4Hz), 1.33 (3H, t, J = 7.1Hz), 2.60-2.80 (4H, m), 2.90-3.05 (1H, m), 4.31 (2H, q, J = 7.1Hz) , 4.47 (1H, 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) 2-3 fluoro-r2-rr (lg, 2J?) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl aminol ethyl] phenoxy] ethyl acetate (Compound 3) ^ -H-NMR ( DMSO-dg) dppm: 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) 2- r 3 -fluoro-4 \ 2 - \ (1S, 2 R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl phenoxy benzyl acetate (Compound 4) ^ -NMR (DMSO -d6) dppm: 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 2- r3-Chloro-4 \ 2 - [[(1S, 2R) -2-hydroxy-2- (4-hydroxy-enyl) -1-methyl-ethyl-amino] -ethyl-phenoxy] ethyl acetate (Compound 5 ) A solution of 4N hydrogen chloride ethylacetate (220 μl) was added to a stirred solution of 2- [3-chloro-4- [2- [[(1S, 2R) -2-hydroxy-2- (4- hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] ethyl acetate (120 milligrams) in ethyl acetate (2.0 milliliters) under ice cooling, and the mixture was stirred vigorously for one hour at room temperature. Collection of the resulting precipitates by filtration gave 2- [3-chloro-4 [2- [[(13, 2 R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] hydrochloride] ethyl] phenoxy] ethyl acetate (110 milligrams). ^ - MR (DMSO-d6) dppm: 0.96 (3H, d, J = 6.9Hz), 1.22 (3H, t, J = 7.2Hz), 3.05-3.20 (4H, m), 3.25-3.40 (1H, m ), 4.17 (2H, q, J = 7.2Hz), 4.82 (2H, s), 5.06 (1H, br), 5.97 (1H, d, J = 3.8Hz), 6.76 (2H, d, J = 8.2Hz ), 6.95 (1H, dd, J = 8.8, 2.7Hz), 7.08 (1H, d, J = 2.7Hz), 7.17 (2H, d, J = 8.2Hz), 7.33 (1H, d, J = 8.8Hz) ), 8.89 (2H, br), 9.42 (1H, s) Specific rotation: [a] D25 = -9.2 ° (c = 0.50, methanol) Example 4 The following compounds were prepared according to a manner similar to that described in Example 3, using the corresponding phenoxyacetic acid derivatives. 2- T3-fluoro-4 [2- f [(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methyl-ethyl-aminol-ethyl-phenoxyethyl acetate (Compound 6) -H-NMR Hydrochloride (DMSO-d6) dppm: 0.95 (3H, d, J = 6.6Hz), 1.22 (3H, t, J = 7.1Hz), 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 (1H, br s), 5.97 (1H, d, J = 3.8Hz), 6.70-6.85 (3H, m), 6.87 (1H , dd, J = 12.0, 2.3Hz), 7.17 (2H, d, J = 8.4Hz), 7.27 (1H, t, J = 8.7Hz), 8.75 (2H, br), 9.41 (1H, s) Specific rotation : [a] D32 = -10.0 ° (c = 0.74, methanol) 2- (3-Fluoro-4 \ 2 - \\ (1S.2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl phenoxy] benzyl acetate hydrochloride (Compound 7) ^ - H-NMR (DMSO-dg) dppm: 0.95 (3H, d, J = 6.6Hz), 2.95-3.45 (5H, m), 4.90 (2H, s), 5.03 (1H, br s), 5.20 (2H, s), 5.98 (1H, br s), 6.70-6.85 (3H, m), 6.88 (1H, dd, J = 12.0, 2.2Hz), 7.17 (2H, d, J = 8.4Hz), 7.26 (1H, t, J = 8.8Hz), 7.30-7.45 (5H, m), 8.80 (2H, br), 9.41 (1H, s) Specific rotation: [a] D32 = -8.7 ° (c = 1.20, methanol) EXAMPLE 5 2- [3-Chloro-4 \ 2 - \\ (13, R) -2-Hydroxy-2- (4-hydroxyphenyl) -1-methyl-ethyl-aminol-ethyl-phenoxy-acetic acid (Compound 8) A solution of 1N aqueous sodium hydroxide to a stirred solution of 2- [3-chloro-4- [2- [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] -acetic acid (63 milligrams) in ethanol (775 μl) at room temperature. After the mixture was stirred for 20 hours, 1N hydrochloric acid (465 μl) was added to the reaction mixture under ice cooling with stirring. Collection of the resulting precipitates gave 2- [3-chloro-4 [2- [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic (44 milligrams) XH-NMR (DMS0-d6 + D20) dppm: 0.90 (3H, d, J = 6.6Hz), 2.30-2.80 (2H, m), 2.90-3.05 (2H, m), 3.20-3.35 (1H, m), 4.30-4.45 (2H, m), 5.05-5.15 (1H, m), 6.70-6.80 (3H, m), 6.86 (1H, d, J = 2.5Hz), 6.94 (1H, d) , J = 8.6Hz), 7.16 (2H, d, J = 8.5Hz) Specific rotation: [a] D25 = -5.7 ° (c = 0.56, 1N hydrochloric acid) Example 6 The following compounds were prepared using the acid derivative corresponding phenoxyacetic, in accordance with a manner similar to that described in Example 5.

Acid 2-4 \ 2 - [[(lff, 2J) -2-hydroxy -2- (4-hydroxyphenyl) -1-methylethyl aminol etyl phenoxyl acetic acid (Compound 9) ^? - NMR (DMSO-dg) dppm: 0.91 (3H, d, J = 6.6Hz), 2.55-2.75 (2H, m), 2.90-3.05 (2H, m), 3.15-3.25 (1H, m), 4.34 (2H, s), 5.00-5.10 (1H , m), 6.65-6.80 (4H, m), 6.91 (2H, d, J = 8.6Hz), 7.13 (2H, d, J = 8.6Hz), 9.40 (1H, br) Specific rotation: [a] 25 D -10.0 ° (c = 1.06, 1N hydrochloric acid) 2- [3-Fluoro-4 [2- ((1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methyl-ethyl-amino] -ethyl] -phenoxyl-acetic acid (Compound 10) ^? - NMR ( DMSO-dg) dppm: 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: [a;] D25 = -6.6 ° (c = 1.19, 1N acetic acid) Example 7 Hydrochloride of 2-r3-chloro-4 \ 2 -? f (1S.2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] aminol etyl phenoxy benzyl acetate (Compound 11) A solution of 2- [3-chloro-4 [2- [[(1 S, 2 R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (200 milligrams) and methanesulfonic acid (38 μl) in benzyl alcohol (1.0 milliliters) ) for 2 days at room temperature. Purification of the residue by liquid column chromatography of intermediate pressure on aminopropyl silica gel (diluent: ethyl acetate / ethanol = 20/1) gave 2- [3-chloro-4- [2- [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] ethyl acetate (136 milligrams). ^ -NMR (CDC13) dppm: 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) A solution of 4N hydrogen chloride ethylacetate (161 μl) was added to a stirred solution of 2- [3-chloro-4- [2- [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) Ethyl-1-methylethyl] amino] ethyl] phenoxy] acetate (136 milligrams) in ethyl acetate (2.0 milliliters) under ice-cooling, and the mixture was stirred vigorously for one hour at room temperature. Collection of the resulting precipitates by filtration gave 2- [3-chloro-4 [2- [[(1 S) hydrochloride, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] ethyl acetate (137 milligrams). XH-NMR (DMSO-dg) dppm: 0.96 (3H, d, J = 6.9Hz), 3.00-3.20 (4H, m), 3.30-3.45 (1H, m), 4.92 (2H, s), 5.03 (1H , br), 5.20 (2H, s), 5.97 (1H, br s), 6.76 (2H, d, J = 8.8Hz), 6.96 (1H, dd, J = 8.2, 2.7Hz), 7.09 (1H, d , J = 2.7Hz), 7.18 (2H, d, J = 8.8Hz), 7.30-7.45 (6H, m), 8.75 (2H, br), 9.38 (1H, s) Specific rotation: [ex] D25 = - 6.4 ° (c = 0.53, methanol) Example 8 The following compounds were prepared using 2- [2- [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid in accordance with a similar to that described in Example 7. 2-4 [2- f [(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] aminol ethyl] phenoxy] benzyl acetate (Compound 12) XH-NMR (CDC13) dppm: 0.93 (3H, d, J = 6.5Hz), 2.65-2.85 (4H, m), 2.90-3.05 (1H, m), 4.49 (1H, 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) Hydrochloride 2-4 [2- [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl aminol etyl phenoxy] benzyl acetate (Compound 13) ^ -H-NM (DMSO-dg) dppm: 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 (1H, br s), 5.19 (2H , s), 5.97 (1H, d, J = 4.0Hz), 6.76 (2H, d, J = 8.5Hz), 6.91 (2HT, 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 (1H, s) Specific rotation: [a] D25 = -8.3 ° (c = 0.51, methanol) Test Example 1 Stimulatory Effects of ß2 Adrenoreceptor Uteruses from pregnant SD rats were isolated (day 21 of pregnancy) and longitudinal soft muscle strips approximately 15 millimeters long and approximately 5 millimeters wide, free of the basal plate were prepared. The experiment was conducted in accordance with the Magnus method. The preparations were exposed with a tension of 1 gram to a Locke-Ringer solution which was maintained at 37 ° C and saturated with gas with a mixture of 95 percent oxygen and 5 percent carbon dioxide. The spontaneous contractions of the myometrium were measured in a isometric manner with a force displacement transducer and were recorded by means of a rectiometer.The drug was added cumulatively to the Magnus bath every 5 minutes.The efficacy of the drug was evaluated since it was required that the concentration of the drug produced 50 percent of the inhibition of uterine contractions (ie, the EC50 value) by comparing the sum of uterine contractions for 5 minutes after the addition of the drug, with the sum of the uterine contractions for 5 minutes before the addition of the drug (100 percent) The result is shown in the following Table.

Test Example 2 Stimulant Effects of the Adrenoreceptor jS3 The ureters of male ferrets were isolated (1100 to 1400 grams of body weight). After the removal of the connective tissue, longitudinal soft muscle strips of approximately 20 millimeters in length were prepared. The experiment was conducted in accordance with the Magnus method. The preparations were exposed with a tension of 0.5 grams to a solution of Krebs-Henseleit which was maintained at 37 ° C and saturated with gas with a mixture of 95 percent oxygen and 5 percent carbon dioxide. The spontaneous contractions of the ureters were measured in an isometric manner with a force displacement transducer and recorded by a rectiometer. The drug was added cumulatively to the Magnus bath every 3 minutes. The efficacy of the drug was evaluated since the concentration of the drug was required to produce 50 percent of the inhibition of ureter contractions (ie, the EC50 value) by comparing the sum of contractions of the ureter for 3 minutes after of the drug addition, with the sum of the contractions of the ureter for 5 minutes before the addition of the drug (100 percent). The result is shown in the following Table.

Test Example 3 Stimulant Effects of the Adrenoreceptor ß The atria of male SD rats (350 to 400 grams body weight) were isolated and the experiment was conducted according to the Magnus methods. The preparations were exposed with a tension of 1 gram to a solution of Krebs-Henseleit which was maintained at 37 ° C and saturated with gas with a mixture of 95 percent oxygen and 5 percent carbon dioxide. Cardiac contractility was measured isometrically with a force displacement transducer and recorded by a rectiometer. The efficacy of the drug was evaluated as the molar concentration that is required to produce an increase of 20 beats / minute in cardiac velocity (ie, the EC value? 20). The result is shown in the following table.

Test Example 4 Acute Toxicity Test 4-week-old male ICR rats were administered 1,000 milligrams / kilogram of 2- [4- [2- [[1S, 2R) -2-hydroxy-2- (4- hydroxy-phenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid intravenously by a single administration. No dead rat was observed during the 24 hours after the administration with the course of time.

Industrial Applicability The aminoethyl phenoxyacetic acid derivatives and the pharmaceutically acceptable salts thereof which are represented by the general formula (I) of the present invention, have stimulatory effects on the two adrenergic receptors jd2 and / 33 and show potent ureteral relaxation effects. Therefore, the compounds of the present invention are compounds extremely useful as medicaments, such as agents for relieving pain and promoting the removal of stones in urolithiasis.

Claims (10)

1. A derivative of aminoethyl phenoxyacetic acid represented by the general formula: (wherein R 1 represents a hydrogen atom, a lower alkyl group or an aralkyl group, R 2 represents a hydrogen atom or a halogen atom, the carbon atom marked with (R) represents a carbon atom in the configuration (R), and the carbon atom marked with (S) represents a carbon atom in the (S) -configuration and the pharmaceutically acceptable salts thereof.

2. A derivative of aminoethylphenoxyacetic acid according to claim 1, characterized in that it is represented by the general formula: (wherein R 2 represents a hydrogen atom or a halogen atom, the carbon atom marked with (R) represents a carbon atom in the (R) configuration, and the carbon atom marked with (S) represents a carbon atom. carbon in the (S) configuration) or a pharmaceutically acceptable salt thereof.

3. 2- [4- [2- [[13, 2R) -2-Hydroxy-2- (4-hydroxy-phenyl) -1-methylethyl] amino] ethyl] phenoxy acetic acid according to claim 2, or a pharmaceutically acceptable salt thereof.

4. 2- [3-Fluoro-4- [2- [[1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid in accordance with claim 2, or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising an aminoethyl phenoxyacetic acid derivative according to claims 1, 2, 3, or 4 or a pharmaceutically acceptable salt thereof.

6. An agent for relieving pain and promoting stone removal in urolithiasis, which comprises as the main ingredient an aminoethyl phenoxyacetic acid derivative according to claims 1, 2, 3, or 4 or a pharmaceutically acceptable salt thereof.

7. A method for relieving pain and promoting stone removal in urolithiasis, comprising administering a therapeutically effective amount of an aminoethyl phenoxyacetic acid derivative according to claims 1, 2, 3, or 4 or a pharmaceutically salt acceptable of it.

8. A use of an aminoethyl phenoxy acetic acid derivative according to claims 1, 2, 3, or 4 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of urolithiasis.

9. A use of an aminoethyl phenoxy-acetic acid derivative according to claims 1, 2, 3, or 4 or a pharmaceutically acceptable salt thereof as an agent for relieving pain and promoting the removal of stones in urolithiasis.

10. A process for the manufacture of a pharmaceutical composition for the treatment of urolithiasis, characterized in use, as an essential constituent of said pharmaceutical composition, of an aminoethyl phenoxyacetic acid derivative according to claims 1, 2, 3, or 4 or a pharmaceutically acceptable salt thereof.