Derivatives aminomethylpropanol acids and drugs to soothe the pain and facilitate the discharge of stones urolithiasis

 

(57) Abstract:

The invention relates to the group's derivative aminomethylpropanol acid represented by the following formula:

< / BR>
where R1represents a hydrogen atom, a lower alkyl group or aracelio group; R2represents a hydrogen atom or a halogen atom; the carbon atom marked with (R) denotes the carbon atom in (R)-configuration; the carbon atom marked with (S) means a carbon atom in (S)-configuration, or their pharmaceutically acceptable salts, pharmaceutical compositions, a stimulating effect on 2and3-adrenoceptor, comprising as an active ingredient derived aminomethylpropanol acid, a means to soothe pain and the way to calm the pain. 4 C. and 5 C.p. f-crystals, 1 table.

The invention relates to a derivative aminomethylpropanol acids and their pharmaceutically acceptable salts that can be used as medicines.

Art

Urolithiasis is a disease in which there is a formation of rocks due to a number of processes such as nucleation components of urine, crystallization, aggrega the flow of urine due to concretions often difficult which leads to an increase of pressure inside the ureter, causing pain. Currently, to soothe pain prescribed analgesic and anti-spastic funds. However, the use of analgesics is only temporary symptomatic treatment, eliminate pain, and, as suggested, mostly not cure kidney stones. The effectiveness of antispastic means, such as anticholinergics, also not satisfactory. Therefore, necessary medicines, suitable for targeted treatment of urolithiasis, for example medicines that relieve pain and facilitate the passage of stones through the expansion of the ureter, as well as have a strong effect relaxation (The Journal of Urology, Vol. 152, pp. 1095-1098 (1994)).

Recently it was confirmed that as2- and3-adrenergic receptors are present in the ureter of man as a species-adrenergic receptors. It was reported that drug possessing stimulant as2- and3-adrenergic receptors, is extremely useful as a means to soothe pain and facilitate the discharge of stones urolithiasis because soedineniya effect on the ureter (Published international application W097/19700).

Description of the invention

The present invention was designed primarily to search for compounds that can be used as a means to soothe pain and facilitate the discharge of stones urolithiasis. The result found that some derivatives of aminomethylpropanol acids have a strong stimulating effect as2- and3-adrenergic receptors and have a wonderful relaxing effect on the urinary tract. The present invention relates to a derivative aminomethylpropanol acid represented by the General formula

< / BR>
where R1represents a hydrogen atom, a lower alkyl group or aracelio group; R2represents a hydrogen atom or halogen; 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; or their pharmaceutically acceptable salts.

The present invention relates to pharmaceutical compositions comprising a derivative aminomethylpropanol acid represented by the above General formula (I) or its pharmaceutically acceptable salt.

Nastawieni, which comprise as an active ingredient derived aminomethylpropanol acid represented by the above General formula (I) or its pharmaceutically acceptable salt.

The present invention relates to methods to soothe pain and facilitate the discharge of stones urolithiasis, which includes the introduction of a therapeutically effective amount of a derivative aminomethylpropanol acid represented by the above General formula (I) or its pharmaceutically acceptable salt.

The present invention relates to the use of derivative aminomethylpropanol acid represented by the above General formula (I) or its pharmaceutically acceptable salts for the preparation of pharmaceutical compositions for the treatment of urolithiasis.

The present invention relates' to the use of derivative aminomethylpropanol acid represented by the above General formula (I) or its pharmaceutically acceptable salt as a means to soothe pain and facilitate the discharge of stones urolithiasis.

The present invention relates to a method of manufacturing fortunago specified component of the pharmaceutical composition used is derived aminomethylpropanol acid, represented by the above General formula (I) or its pharmaceutically acceptable salt.

In the description of the present invention, the term "lower alkyl group" means an alkyl group containing from one to six carbon atoms, such as methyl group, ethyl group, through the group, isopropyl group, bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, Amelina group or exilda group; the term "kalkilya group" means the above lower alkyl group, a substituted aryl group such as phenyl group or naftalina group, and the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Compounds that are the subject of the present invention can be obtained according to the following methods. For example, compounds that are the subject of the present invention can be obtained by alkylation derivative phenyl-propanolamine represented by the formula

< / BR>
where the carbon atom marked with (R) and the carbon atom marked with (S) are as defined above; using an alkylating agent represented by the General formula

< / BR>
where R1arepresent bromine; and R2has the same meanings as defined above; and hydrolysis of the ester groups of the compounds obtained in the usual way, under the right conditions.

Compounds according to the present invention represented by the above General formula (I) include compounds represented by the General formula

< / BR>
where R1aR2the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as defined above; these compounds can also be obtained by esterification of the corresponding derived aminomethylpropanol acid (compound represented by following General formula (Ib)).

Derived phenylpropanolamine represented by the above General formula (II) used as starting compound in the above method of production, can be obtained by the optical separation of a commercially available mixture of enantiomers in the usual way or by the method described in literature (J. Med. Chem., Vol. 20, No. 7, pp. 978-981 (1977)).

Alkylating agents represented by the above General formula (III) used as starting compounds in the above-described method of production, can be obtained by the interaction preeedenee above, with a compound represented by the General formula

< / BR>
where X2represents a chlorine atom or a bromine atom; and X1has the same meanings as defined above, in the presence of a Lewis acid such as aluminum chloride, followed by removal of the methyl group in a suitable way, the recovery of the carbonyl group using a reducing agent such as triethylsilane, obtaining a derivative of phenol represented by the General formula

< / BR>
where R2and X1have the same meanings as defined above, and the subsequent interaction of the compounds with alkylhalogenide in the presence of a base such as potassium carbonate.

Derivatives aminomethylpropanol acid represented by the above General formula (I), which is the subject of the present invention obtained as described above can be easily isolated and purified by conventional methods of separation, such as fractional crystallization, purification using column chromatography and solvent extraction.

Derivatives aminomethylpropanol acid represented by the above formula (I) according to the present invention can be PR is prisoedinenia acids, formed with mineral acids such as chloromethane acid, Hydrobromic acid, iodomethane acid, sulfuric acid, nitric acid and phosphoric acid, and salt - addition products of acids derived from such organic acids as formic acid, 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, methanesulfonate acid, benzolsulfonat acid, n-toluensulfonate acid, and also salts of inorganic bases such as sodium salt, potassium salt, calcium salt, ammonium salt, and salts formed with organic bases such as triethylamine, piperidine, morpholine, pyridine and lysine.

In addition, the compounds represented by the above General formula (I), which is the subject of the present invention, also includes a solvate of these compounds with pharmaceutically acceptable solvents such as water and ethanol.

The stimulating effect of the compounds, which Ave the market can be measured using mares pregnant rats. For example, the value of EC50(the concentration at which inhibited 50% of spontaneous contractions) 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl] amino] ethyl] phenoxy] acetic acid is 3,110-8M

The stimulating effect of the compounds that are the subject of the present invention and represented by the above General formula (I)3-adrenergic receptors can be measured using the ureters ferrets. For example, the value of EC50(the concentration at which inhibited 50% of spontaneous contractions) 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl] amino] ethyl] phenoxy]acetic acid is l, 410-8M.

Thus, compounds which are the subject of the present invention represented by the above General formula (I), have a stimulating effect as2- and3-adrenergic receptors and can be used as a means to soothe pain and facilitate the discharge of stones urolithiasis as the spontaneous passage of stones, and the removal of stones extracorporeal shock wave lithotripsy.

According to the present invention is preferable from the above-described action2and3-adrenergic receptors, in order to reduce the workload of the heart and not cause such side effects as tachycardia. Examples of such compounds are compounds represented by the General formula

< / BR>
where R2the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as defined above; and their pharmaceutically acceptable salts.

Examples of most preferred compounds according to the present invention are 2-[4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl] amino] ethyl]phenoxy]acetic acid, 2-[3-fluorescent-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl] amino] ethyl] phenoxy] acetic acid and their pharmaceutically acceptable salts.

For example, in experiments on the measurement of stimulating action on the1-adrenergic receptors using females rats for 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl] amino] ethyl]phenoxy] acetic acid EC20(the concentration at which the heart rate increases by 20 beats per minute) corresponds to the concentration of l,310-6M

In addition, the compounds according to the present invention represented by the above General formula (I), are the[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-phenoxy] acetic acid in the amount of 1000 mg/kg mortality of rats was observed.

Thus, the compounds according to the present invention represented by the above General formula (I) and their pharmaceutically acceptable salts have a strong and positive impact on2- and3-adrenergic receptors.

When using derivatives aminomethylpropanol acid according to the present invention represented by the above General formula (I) and their pharmaceutically acceptable salts to soothe pain and facilitate the breaking of stones urolithiasis they are administered orally or parenterally in the form of appropriate pharmaceutical compositions such as tablets, powders, fine granules, granules, capsules, injections, etc., Such pharmaceutical compositions can be prepared using conventional pharmaceutical carriers, fillers and other additives.

The appropriate dosage is determined depending on sex, age, weight of the patient, and the severity of the patient's symptoms to be treated, and is sootwetstwii mg per day for adults in the case of parenteral administration, the daily dose can be divided into several doses per day.

The best way of carrying out the invention

Further, the present invention is illustrated in more detail by the following reference examples, examples, and sample tests. However, the invention is not limited with this.

Reference example 1

2'-fluorescent-4'-hydroxybenzylated

To a stirred suspension of aluminium chloride (17.5 g) in 1, 2-dichloroethane (146 ml) under cooling with ice add bromoacetamide (3.8 ml). After stirring the reaction mixture for 30 min there was added 3-Floransa (5.0 ml) and the resulting mixture is stirred for 12 hours at room temperature. The reaction mixture was poured into ice water and extracted with dichloromethane. The extract is washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent in vacuo and purification of the residue liquid column chromatography with an average pressure on silica gel (eluent: hexane/ethyl acetate=4/1) to obtain 2'-fluorescent-4'-hydroxyphenazine (518 mg).

1H-NMR (Dl3) , M. D.: 4,78 (2H, s), 5,74 (1H, Shir. C) 6,63 (1H, DD, J=12,5, 2.4 Hz), was 6.73 (1H, DD, J=8,7, 2.4 Hz), 7,92 (1H, t, J=8.7 Hz).

Reference example 2

2'-chloro-4'-hydroxybenzyl is the example 1, using 3-chloroanisole.

1H-NMR (Dl3) , M. D.: 3,86 (3H, s), of 4.54 (2H, s), to 6.88 (1H, DD, J= 8,7, 2,5 Hz), of 6.96 (1H, d, J=2.5 Hz), 7,69 (1H, d, J=8.7 Hz).

2'-chloro-4'-methoxybenzylamine (451 g) dissolved in 1, 2-dichloroethane (8.6 ml). To this solution under stirring at room temperature added aluminium chloride (690 mg), then stirred the mixture for 3 hours at 60oC. the Reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After removal of the solvent in vacuo and purification of the residue liquid column chromatography with an average pressure on silica gel (eluent: hexane/ethyl acetate= 3/1) to obtain 2'-chloro-4'-hydroxyphenazine (295 mg).

1H-NMR (Dl3) , M. D.: of 4.54 (2H, s), 5,77 (1H, s), PC 6.82 (1H, DD, J= 8,6, 2.4 Hz), 6,94 (1H, d, J=2.4 Hz), the 7.65 (1H, d, J=8.6 Hz).

Reference example 3

4-(2-bromoethyl)-3-chlorophenol

To a stirred solution of 2'-chloro-4'-hydroxybenzamide (291 mg) in dichloromethane (6.0 ml) at room temperature add triperoxonane acid (900 ml) and triethylsilane (610 ml) and heat the mixture under reflux for 3 hours. To the reaction mixture add NAT with water and dried over anhydrous magnesium sulfate. After removal of the solvent in vacuo and purification of the residue liquid column chromatography with an average pressure on silica gel (eluent: hexane/ethyl acetate=5/1) to obtain 4-(2-bromoethyl)-3-chlorophenol (183 mg).

1H-NMR (Dl3) , M. D.: is 3.21 (2H, t, J=7.5 Hz), 3,55 (2H, t, J=7.5 Hz), free 5.01 (1H, s) 6,70 (1H, DD, J=8,3, and 2.6 Hz), to 6.88 (1H, d, J=2.6 Hz), 7,12 (1H, d, J=8,3 Hz).

Reference example 4

4-(2-bromoethyl)-3-Floriana

4-(2-bromoethyl)-3-Floriana receive in a manner analogous to the method described in reference example 3, using 2'-fluorescent-4'-hydroxybenzylated.

1H-NMR (Dl3) , M. D.: of 3.12 (2H, t, J=7.5 Hz), 3,53 (2H, t, J=7.5 Hz), 6,50-6,60 (2H, m), 7,00-7,10 (1H, m).

Reference example 5

Ethyl-2-[4-(2-bromoethyl)-3-chlorophenoxy]acetate

To a stirred solution of 4-(2-bromoethyl)-3-chlorophenol (158 mg) in acetone 17 ml) at room temperature add potassium carbonate (139 mg) and ethylbromoacetate (89 μl). After stirring the mixture at room temperature for 20 hours, the insoluble material is filtered and the filtrate concentrated in vacuo. After purification of the obtained residue liquid column chromatography on silica gel under medium pressure (eluent: hexane/ethyl acetate= 7/1) to obtain ethyl-2-[4-(2-bromate t, J=7.5 Hz), 4,28 (2H, q, J=7,1 Hz), 4,59 (2H, s), is 6.78 (1H, DD, J=8,5, 2.7 Hz), 6,94 (1H, d, J=2.7 Hz), 7,17 (1H, d, J=8,5 Hz).

Reference example 6

The following compounds are produced by the method similar to the method described in reference example 5, using the appropriate derivative bromoxynil acid and the corresponding derivative of phenol.

Ethyl-2-[4-(2-bromoethyl)-phenoxy]acetate

1H-NMR (Dl3) , M. D.: of 1.30 (3H, t, J=7,1 Hz), 3,10 (2H, t, J=7,6 Hz), 3,53 (2H, t, J=7,6 Hz), 4,27 (2H, q, J=7,1 Hz), br4.61 (2H, s) 6,86 (2H, d, J=8.5 Hz), 7,13 (2H, d, J=8,5 Hz).

Ethyl-2-[4-(2-bromoethyl)-3-perience]acetate

1H-NMR (Dl3) , M. D.: of 1.30 (3H, t, J=7,1 Hz), of 3.13 (2H, t, J=7.5 Hz), 3,53 (2H, t, J= 7.5 Hz), 4,28 (2H, q, J=7,1 Hz), 4,59 (2H, s), 6,60-6,70 (2H, m), 7,12 (1H/ t, J=8.6 Hz).

Benzyl-2-[4-(2-bromoethyl)-3-perience]acetate

1H-NMR (Dl3) , M. D.: 3,13 (2H, t, J=7.5 Hz), 3,53 (2H, t, J=7.5 Hz), with 4.64 (2H, s), of 5.24 (2H, s), 6,55-6,70 (2H, m), 7,11 (1H, t, J=8.7 Hz).

Example 1

Ethyl-2-[3-chloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetate (compound 1)

A solution of (1R, 2S)-2-amino-1-(4-hydroxyphenyl) propan-1-ol (97 mg), ethyl-2-[4-(2-bromoethyl)-3-chlorophenoxy] acetate (187 mg) and N,N-diisopropylethylamine (203 μl) in N,N-dimethylformamide (3 ml) was stirred at 60oWith 10 hours is washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent in vacuo and purification of the residue liquid column chromatography with an average pressure on aminopropiophenone silica gel (eluent: ethyl acetate/ethanol=30/1) to obtain ethyl-2-[3-chloro-4-[2-[[(1S/2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl] amino] ethyl] phenoxy] acetate (75 mg).

1H-NMR (Dl3) , M. D.: of 0.93 (3H, d, J=6,4 Hz) of 1.33 (3H, t, J=7,1 Hz), 2,75 was 3.05 (5H, m), or 4.31 (2H, q, J=7,1 Hz), a 4.53 (1H, d, J=5,2 Hz), 4,60 (2H, s), 6,65-to 6.80 (3H, m), to 6.88 (1H, d, J=2.7 Hz), 7,03 (1H, d, J=8.5 Hz), 7,10 (2H, d, J=8,2 Hz).

Example 2

The following compounds are produced by the method similar to the method described in example 1 using the appropriate derived phenoxyacetate.

Ethyl-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino] ethyl]phenoxy]acetate (compound 2)

1H-NMR (Dl3) , M. D.: of 0.97 (3H, d, J=6,4 Hz) of 1.33 (3H, t, J=7,1 Hz), 2,60 is 2.80 (4H, m), 2,90 was 3.05 (1H, m), or 4.31 (2H, q, J=7,1 Hz), 4,47 (1H, d, J= 5, 6 Hz), to 4.62 (2H, s), 6,69 (2H, d, J=8.6 Hz), 6,76 (2H, d, J=8.6 Hz), 7,01 (2H, d, J=8.6 Hz), 7,05 (2H, d, J=8.6 Hz).

Ethyl-2-[3-fluorescent-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetate (compound 3)

1H-NMR (DMSO-d6) , M. D.: 0,81 (3H, d, J=6.3 Hz), to 1.22 (3H, t, J=7,1 Hz), 2,55 is 2.80 (5H, m), 4,18 (2H, q, J=7,1 Hz), 4,35 is 4.45 (1H, m), 4,78 (2H, s), 4.80 to the 4.90 (1H, m), 6,65-to 6.80 (4H, m), 7,05-7,20 (3H, m), 9,1 the t (compound 4)< / BR>
1H-NMR (DMSO-d6) , M. D. : the 0.80 (3H, d, J=6.4 Hz), 1,30 (1H, Shir), 2,55 is 2.80 (5H, m) to 4.41 (1H, Shir), 4,80-of 4.95 (3H, m), 5,20 (2H, s), 6,60-to 6.80 (4H, m), 7,00-7,20 (3H, m), 7,25 was 7.45 (5H, m), 9,20 (1H, Shir).

Example 3

Ethyl-2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl) -1-methylethyl]amino]ethyl]phenoxy]acetate hydrochloride (compound 5)

To a stirred solution of ethyl-2-[3-chloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl] amino] ethyl] -phenoxy] acetate (120 mg) in ethyl acetate (2.0 ml) under cooling with ice add 4n. a solution of hydrogen chloride in ethyl acetate (220 ml) and the mixture vigorously stirred at room temperature for one hour. The resulting precipitate is collected by filtration and obtain ethyl-2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]-ethyl]phenoxy]acetate hydrochloride (110 mg).

1H-NMR (DMSO-d6) , memorial plaques as 0.96 (3H, d, J=6,9 Hz) to 1.22 (3H, t, J=7.2 Hz), 3,05-3,20 (4H, m), 3.25 to 3.40 in (1H, m) to 4.17 (2H, q, J=7.2 Hz), 4,82 (2H, s), is 5.06 (1H, Shir), 5,97 (1H, d, J=3.8 Hz), 6,76 (2H, d, J=8,2 Hz), to 6.95 (1H, DD, J= 8,8, 2.7 Hz), was 7.08 (1H, d, J=2.7 Hz), 7,17 (2H, d, J=8,2 Hz), 7,33 (1H, d, J=8,8 Hz), 8,89 (2N, W), 9,42 (1H, s).

Specific rotation: []32D= 9.2 per(C=0,50, methanol).

Example 4

The following compounds are produced by the method similar to the method described is, R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetate hydrochloride (compound 6)

1H-NMR (DMSO-d6) , M. D.: of 0.95 (3H, d, J=6.6 Hz), to 1.22 (3H, t, J=7,1 Hz), 2,90 was 3.05 (2H, m), 3,10 is 3.40 (3H, m) to 4.17 (2H, q, J=7,1 Hz), to 4.81 (2H, s), of 5.03 (1H, Shir) 5,97 (1H, d, J=3.8 Hz), 6,70-6,85 (3H, m), 6.87 in (1H, DD, J= 12,0, 2.3 Hz), 7,17 (2H, d, J=8,4 Hz), 7,27 (1H, t, J=8.7 Hz), the rate of 8.75 (2H, Shir), 9,41 (1H, s).

Specific rotation: []32D= -10,0(s=0,74, methanol).

Benzyl-2-[3-fluorescent-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetate hydrochloride (compound 7)

1H-NMR (DMSO-d6) , M. D.: of 0.95 (3H, d, J=6.6 Hz), 2.95 and is-3.45 (5H, m), the 4.90 (2H, s), of 5.03 (1H, Shir) 5,20 (2H, s), 5,98 (1H, Shir) 6,70-6,85 (3H, m), to 6.88 (1H, DD, J=12,0, 2.2 Hz), 7,17 (2H, d, J=8,4 Hz), 7,26 (1H, t, J=8,8 Hz), 7,30 was 7.45 (5H, m), 8,80 (2N, W), 9,41 (1H, s).

Specific rotation: []32D= -8,7(C=1,20, methanol).

Example 5

2-[3-chloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl] amino]ethyl]phenoxy]acetic acid (compound 8)

To a stirred solution of ethyl-2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl] amino] ethyl] -phenoxy] acetate (63 mg) in ethanol (775 μl) is added at room temperature for 1H. an aqueous solution of sodium hydroxide (465 μl). After stirring the GTC (465 μl). The resulting precipitate is collected by filtration and receive 2-[3-chloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid (44 mg).

1H-NMR (DMSO-d6+D2O) , M. D.: of 0.90 (3H, d, J=6.6 Hz), 2,30 is 2.80 (2H, m), 2,90 was 3.05 (2H, m), 3,20-to 3.35 (1H, m), 4,30-4,45 (2H, m), of 5.05-of 5.15 (1H, 10 m) 6,70-to 6.80 (3H, m) 6,86 (1H, d, J=2.5 Hz), 6,94 (1H, d, J=8, 6 Hz), 7,16 (2H, d, J=8,5 Hz).

Specific rotation: []25D= -5,7(C=0,56, 1H. chloromethane acid).

Example 6

The following compounds are produced by the method similar to the method described in example 5 using the corresponding derived phenoxyalkanoic acid.

2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl] phenoxy]acetic acid (compound 9)

1H-NMR (DMSO-d6) , M. D.: of 0.91 (3H, d, J=6.6 Hz), 2,55 is 2.75 (2H, m), 2,90 was 3.05 (2H, m), 3.15 and is 3.25 (1H, m), 4,34 (2H, s), 5,00-5,10 (1H, m), 6,65-to 6.80 (4H, m) 6,91 (2H, d, J=8.6 Hz), 7,13 (2H, d, J=8.6 Hz), 9,40 (1H, Shir).

Specific rotation: []25D= -10,0(C=1,06, 1H. chloromethane acid).

2-[3-fluorescent-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl] amino]ethyl]phenoxy]acetic acid (compound 10)

1H-NMR (DMSO-d6) , M. D.: of 0.87 (3H, d, J=6, 6 Hz), 2,30-2,70 (2H, m), 2,85-of 3.00 (2H, m), 3,15-3,30 Specific rotation: []25D= -6,6(C=1,19, acetic acid).

Example 7

Benzyl-2-[3-chloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetate hydrochloride (compound 11)

A solution of 2-[3-chloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl] amino] ethyl] phenoxy]acetic acid (200 mg) and methanesulfonate (38 μl) in benzyl alcohol (1.0 ml) was stirred at room temperature for 2 days. After purification of the reaction mixture using liquid column chromatography with an average pressure on aminopropiophenone silica gel (eluent: ethyl acetate/ethanol= 20/1) to obtain benzyl-2-[3-chloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl] amino] ethyl] phenoxy] acetate (136 mg).

1H-NMR (CDCl3) , M. D.: of 0.95 (3H, d, J=6.3 Hz), 2,75 was 3.05 (5H, m), of 4.54 (1H, d, J=5.0 Hz), 4,63 (2H, in), 5.25 (2H, s), 6,65 to 6.75 (3H, m) 6,86 (1H, d, J=2.5 Hz), 7,00 (1H, d, J=8.5 Hz), was 7.08 (2H, d, J=8.5 Hz), 7,30 was 7.45 (5H, m).

To a stirred solution of benzyl-2-[3-chloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl] amino] ethyl]-phenoxy] acetate (136 mg) in ethyl acetate (2.0 ml) under cooling with ice add 4n. a solution of hydrogen chloride in ethyl acetate (161 ml), and vigorously stirred the mixture at room temperature for one hour. Forming the yl]amino]ethyl]-phenoxy]acetate hydrochloride (137 mg).

1H-NMR (DMSO-d6) , memorial plaques as 0.96 (3H, d, J=6, 9 Hz), 3,00-3,20 (4H, m), 3,30 is-3.45 (1H, m) to 4.92 (2H, s), of 5.03 (1H, Shir), 5,20 (2H, s), 5,97 (1H, Shir) 6,76 (2H, d, J=8,8 Hz), of 6.96 (1H, DD, J=8,2, 2.7 Hz), to 7.09 (1H, d, J=2.7 Hz), 7,18 (2H, d, J=8,8 Hz), 7,30 was 7.45 (6N, m), is 8.75 (2H, Shir), 9,38 (1H, s).

Specific rotation: []25D= sphere-6,4(=of 0.53, methanol).

Example 8

The following connections receive in a manner analogous to the method described in example 7 using 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy] acetic acid.

Benzyl-2-[4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl] amino]ethyl]phenoxy]acetate (compound 12)

1H-NMR (CDCl3) , M. D. : of 0.93 (3H, d, J=6.5 Hz), 2,65-to 2.85 (4H, m), 2,90 was 3.05 (1H, m), 4,49 (1H, d, J=5,2 Hz), of 4.66 (2H, s), at 5.27 (2H, s) 6,70 (2H, d, J=8.6 Hz), 6,76 (2H, d, J=8.6 Hz), 7,01 (2H, d, J=8.6 Hz), 7,06 (2H, d, J=8.6 Hz), 7,30-7,40 (5H, m).

Benzyl-2-[4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl] amino]ethyl]phenoxy]acetate hydrochloride (compound 13)

1H-NMR (DMSO-d6) , M. D.: of 0.95 (3H, d, J=6,7 Hz), 2,90-of 3.00 (2H, m), 3,10 is 3.40 (3H, m), is 4.85 (2H, s), of 5.03 (1H, Shir), 5,19 (2H, s), 5,97 (1H, d, J= 4.0 Hz), 6,76 (2H, d, J=8.5 Hz), 6,91 (2H, d, J=8.7 Hz), 7,16 (2H, d, J= 8.5 Hz), 7,19 (2H, d, J=8.7 Hz), 7,30 was 7.45 (5H, m), to 8.70 (2H, Shir), 9,41 (1H, s).

Specific rotation: []25D= -8,3(C=leraut uterus of pregnant rats 3D (pregnancy day 21) and prepare a smooth strips of longitudinal muscle layer of the shell is approximately 15 mm in length and about 5 mm wide, available from the basal plates. The experiment is carried out according to the method of Magnus). Drugs under a load of 1 g was placed in the solution, Locke-ringer (the Locke-Ringer), stored at 37oWith saturated gas mixture containing 95% oxygen and 5% carbon dioxide. Spontaneous contractions of myometrium measure isometrically using measuring transducer force-displacement and write using rectigraph. Every 5 minutes in a bath Magnus (Magnus) add cumulative drug. The effectiveness of the drugs is estimated by the concentration of drug required to reduce the number of uterine contractions by 50% (i.e. the value EC50by comparing the total number of uterine contractions for 5 minutes after adding the drug, and the total number of uterine contractions for 5 minutes before adding the drug (100%). The results are shown in the table.

Sample test 2

Stimulating effect on3-adrenergic receptors

Isolate the ureters ferrets male (body weight from 1100 to 1400 g). After removal of connective tissue prepared flat strips of longitudinal muscle layer of the shell primer the BSA-Henseleit (Krebs-Henseleit), aged at 37oWith saturated gas mixture containing 95% oxygen and 5% carbon dioxide. Spontaneous contractions of the ureter measure isometrically using measuring transducer force-displacement and write using rectigraph. Every 3 minutes in a bath Magnus (Magnus) add cumulative drug. The effectiveness of the drugs is estimated by the concentration of drug needed to reduce the number of contractions of the ureter by 50% (i.e. the value of the EU50by comparing the total number of contractions of the ureter within 3 minutes after adding the drug, and the total number of contractions of the ureter in for 3 minutes before adding the drug (100%). The results are shown in the table.

Example test 3

Stimulating effect on1-adrenergic receptors

Isolated Atria of rats 3D, male (body weight from 350 to 400 g) and conducting the test according to the method of Magnus. Drugs under a load of 1 g was placed in a solution of Krebs-Henseleit (Krebs-Henseleit), stored at 37oWith saturated gas mixture containing 95% oxygen and 5% carbon dioxide. Serdivan using rectigraph. Efficacy of medicinal product is assessed according to the molar concentration required to ensure that the heart rate increased by 20 beats per minute (i.e. the value EC20). The results are shown in the table.

Example test 4

Test for acute toxicity

Rats ICR male, age 4 weeks, intravenously was administered 1000 mg/kg 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino] ethyl] phenoxy]acetic acid by a single injection. 24 hours after the introduction of the mortality of rats was observed.

Industrial applicability

Derivatives aminomethylpropanol acids and their pharmaceutically acceptable salts, which are the subject of the present invention represented by the above General formula (I), have a stimulating effect as2- and3-adrenergic receptors, and have a strong relaxing effect on the urinary tract. Therefore, compounds that are the subject of the present invention are extremely useful as drugs to soothe pain and facilitate the discharge of stones urolithiasis.

1. Derived aminomethylpropanol acid, the second group or aracelio group;

R2represents a hydrogen atom or a halogen atom;

moreover, the carbon atom marked with (R) denotes the carbon atom in (R)-configuration;

the carbon atom marked with (S) means a carbon atom in (S)-configuration,

or its pharmaceutically acceptable salt.

2. Derived aminomethylpropanol acid on p. 1 represented by the General formula

< / BR>
where R2represents a hydrogen atom or a halogen atom;

the carbon atom marked with (R) denotes the carbon atom in (R)-configuration;

the carbon atom marked with (S) means a carbon atom in (S)-configuration,

or its pharmaceutically acceptable salt.

3. 2-[4-[2-[[(1S, 2R)-2-hidroxi-2-(4-hydroxyphenyl)-1-methylethyl] amino] ethyl] phenoxy] acetic acid on p. 2 or its pharmaceutically acceptable salt.

4. 2-[3-fluoro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyl-ethyl] amino] ethyl] phenoxy] acetic acid on p. 2 or its pharmaceutically acceptable salt.

5. Pharmaceutical composition, a stimulating effect on2and3-adrenoceptor, including derivative aminomethylpropanol acid on PP. 1-4, or its pharmaceutically acceptable salt.

6. Remedy for soothing pain proizvodnje aminomethylpropanol acid on PP. 1-3 or 4, or its pharmaceutically acceptable salt.

7. The way to calm the pain and facilitate the elimination of stones urolithiasis, which includes the introduction of a therapeutically effective amount of a derivative aminomethylpropanol acid on PP. 1-3 or 4, or its pharmaceutically acceptable salt.

8. Derived aminomethylpropanol acid on PP. 1-3 or 4 or its pharmaceutically acceptable salt for the manufacture of pharmaceutical compositions for the treatment of urolithiasis.

9. Derived aminomethylpropanol acid on PP. 1-3 or 4, or its pharmaceutically acceptable salt as a means to soothe pain and facilitate the elimination of stones urolithiasis.

 

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