RU2076098C1 - 3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfoneanilide and agent for enuresis treatment - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: 3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfoneamide or its optically active isomers, pharmacological salts, m. p. is 176-179 C, empirical formula is C₉H₁₃FN₂O₃. Reagent 1: 3'-(2-aminoacetyl)-4'-fluoromethanesulfone anilide. Reagent 2: sodium borohydride. Reaction condition: in methanol medium, at heating. Synthesized compound is used in medicine. EFFECT: improved method of synthesis. 2 cl, 5 tbl

Description

 The invention relates to compounds belonging to the group consisting of compounds of the general formula [I] or their optical isomers, or their salts suitable for pharmacological use.

Соединение согласно настоящему изобретению может применяться при лечении недержания мочи.The compound of General formula [I]

The compound of the present invention can be used in the treatment of urinary incontinence.

 Urinary incontinence is associated with a symptom consisting in the inability to drain urine through the bladder and urethra at the request of the patient.

 Many years have passed since the time when it became necessary for older people to have higher-quality therapy, which is associated with a significant increase in life expectancy, while the incidence of urinary incontinence in older people, all the time in bed, reaches about 75 % In this regard, the development of treatment tools for urinary incontinence is urgently needed in terms of facilitating the tasks of personnel serving elderly people with urinary incontinence.

 Women also often have urinary incontinence, especially those who have had a pregnancy, it is a factor that impedes the participation of women in public life and, therefore, there is an increasing need for treatment for urinary incontinence.

 Conventional urinary incontinence treatments, such as flavoxate, can reduce the incidence of urinary incontinence. They act on the bladder and contribute to its relaxation when urinary incontinence is expected.

 Another type of medication that prevents the onset of urinary incontinence is based on the use of a completely different mechanism for stimulating alpha-1 receptors. They accelerate the compression of the smooth muscles of the urethra, thereby mitigating the symptom of incontinence. For example, outside of Japan, mainly used are midodrine (a means of lowering pressure) and norephedrine (a means of calming a cough).

в которой Х представляет собой атом водорода, гидроксил, аминогруппу, низший алкоксил, бензилокси-группу, атом галогена, метильную группу или группу R²SO₂NH-; R¹ и R² представляет собой низший алкил, фенильный или толильный радикал; R³ представляет собой атом водорода или метильный радикал; Z представляет собой

или

; R⁴ в группе -NR⁵(R⁴) представляет собой атом водорода, низший алкильный или бензильный радикал; R⁵ представляет собой атом водорода, низший алкильный аралкильный, замещенный по кольцу аралкильный, арилоксиалкильный или замещенный по кольцу арилоксиалкильный радикал (где указанные заместители в кольце принадлежат к группе, состоящей из гидроксила, метокси- или метилендиокси-группы; указанные низший алкильный и низший алкоксильный радикалы содержат 4 или менее атомов углерода; и указанный алкильный, замещенный по кольцу аралкильный и замещенный по кольцу арилоксиалкильный радикалы содержат 10 или менее атомов углерода); и R⁴ и R⁵ могут образовывать пирролидиновый, морфолиновый или пиперидиновый радикалы вместе с атомом азота, причем структура их соответствует сульфананилидным производным.Patent applications (Japan No. 15101/66, No. 06169/67 and No. 19500/70) describe compounds of the following general formula, some of which have a wide range of useful pharmacological properties; these compounds can be used as anti-inflammatory drugs to prevent anaphylaxis, as well as hypertonic drugs for blood vessels, hypotonic drugs for blood vessels, as analgesics, bronchodilators, alpha receptor stimulants, alpha receptor blockers, beta receptor stimulants, beta receptor blockers and smooth muscle relaxants (such as papaverine):

in which X represents a hydrogen atom, hydroxyl, amino group, lower alkoxyl, benzyloxy group, halogen atom, methyl group or R ² SO ₂ NH- group; R ¹ and R ² represents lower alkyl, phenyl or tolyl radical; R ³ represents a hydrogen atom or a methyl radical; Z represents

or

; R ⁴ in the group —NR ⁵ (R ⁴ ) represents a hydrogen atom, a lower alkyl or benzyl radical; R ⁵ represents a hydrogen atom, lower alkyl aralkyl, ring-substituted aralkyl, aryloxyalkyl or ring-substituted aryloxyalkyl radical (wherein said substituents on the ring belong to the group consisting of hydroxyl, methoxy or methylenedioxy; said lower alkyl and lower alkoxy radicals contain 4 or less carbon atoms; and said alkyl, ring-substituted aralkyl and ring-substituted aryloxyalkyl radicals contain 10 or less carbon atoms); and R ⁴ and R ⁵ can form pyrrolidine, morpholine or piperidine radicals together with a nitrogen atom, and their structure corresponds to a sulfananilide derivative.

Однако фармакологический эффект соединений, описанный в приведенных выше литературных источниках согласно имеющемуся уровню техники соответствует только общему свойству сокращения гладкой мускулатуры. Соответственно трудно получить на их основе фармацевтические средства, которые могут быть полезны именно для лечения недержания мочи.In addition, in the application (Japan No. 15101/66, left column p. 12), 2-fluoro-5- (2-methylamino-1-hydroxyethyl) methanesulfonanilide is described which has the following structural formula (X):

However, the pharmacological effect of the compounds described in the above literature according to the prior art corresponds only to the general property of smooth muscle contraction. Accordingly, it is difficult to obtain pharmaceuticals based on them that may be useful specifically for the treatment of urinary incontinence.

 For the drugs used in the treatment of urinary incontinence, it is important that even when they have the property of stimulating contraction on the smooth muscles of the urethra, they (1) have a selective strong effect on the contraction of a strictly defined organ (i.e., smooth muscles of the urethra ) compared with exposure to other organs, such as peripheral blood vessels, etc. (that is, so that these agents exhibit so-called selectivity with respect to certain organs); so that they have a relatively prolonged effect, even when administered orally; so that their toxicity to living tissue is low.

 The aim of the present invention is to obtain a substance with the specified characteristics.

 A distinctive feature of the compounds of the present invention is their chemical structure per se.

 A distinctive feature of the compounds of the present invention is their chemical structure per se.

; R³, R⁴ и R⁵ атом водорода. Далее соединения общей формулы (1) согласно настоящему изобретению представляют собой соединения, отличные от соединений общей формулы (Х) в том, что (1) вместо замещения сторон в положении 2, вместо чего имеется замещение фтором в положении 4; и (2) в аминогруппе отсутствует замещение на метильную группу, вместо чего в аминогруппе остается атом водорода.Obviously, the compound of general formula (1) according to the present invention corresponds to compounds according to Japanese Patent Application No. 15101/66, for which R ¹ is a methyl radical; X is fluorine; Z group

; R ³ , R ⁴ and R ^{5 are} hydrogen. Further, compounds of general formula (1) according to the present invention are compounds different from compounds of general formula (X) in that (1) instead of substituting the sides in position 2, instead there is fluorine substitution in position 4; and (2) there is no substitution on the methyl group in the amino group, instead of which a hydrogen atom remains in the amino group.

 As clearly indicated below, the compound according to the present invention includes a compound belonging to the number described in the aforementioned patent application, according to the prior art, although there is no indication that the compound according to the present invention is specifically or actually noted in the specified source. In addition, it should be emphasized that this invention is the result of the activities of its authors, who undertook a targeted search for compounds with a specific pharmacological effect.

 Thus, the present invention is the so-called invention resulting from selection, and, therefore, differs from the inventions described in the patents according to the prior art. Further, the present invention is not obvious from the inventions described in the above patents according to the prior art.

 From the above structural formula, it is clear that the compound according to the present invention contains 1 asymmetric carbon atom, which corresponds to the presence of 2 optical isomers. Obviously, any optical isomer, as well as mixtures thereof, are also included in the scope of this invention.

Соединение формулы (I) согласно настоящему изобретению может быть получено, например, в результате восстановления соединения общей формулы (XII) или их солей.Compound (1) according to the present invention corresponds to the following general formula:

A compound of formula (I) according to the present invention can be obtained, for example, by reducing a compound of general formula (XII) or salts thereof.

Восстановление можно осуществлять с использованием известных способов. Так например, соединение общей формулы (XII) или его соль восстанавливают металлом, например натрием или цинком, комплексом водорода с металлом, например боргидридом натрий или литийалюминийгидридом; или с использованием катализатора, например палладия или никеля Ренея, в результате чего получают рацемат соединения формулы (I) согласно настоящему изобретению.

Recovery can be carried out using known methods. For example, a compound of general formula (XII) or a salt thereof is reduced with a metal, for example sodium or zinc, a hydrogen complex with a metal, for example sodium borohydride or lithium aluminum hydride; or using a catalyst, for example palladium or Raney nickel, whereby a racemate of the compound of formula (I) according to the present invention is obtained.

The reduction of a compound of formula (XII) or its salt with a metal, for example sodium or zinc, can be carried out, for example, by reaction with an alkali metal together with a lower alcohol. Examples of suitable alkali metals are sodium or lithium in an amount of from 1 to 20 equivalents when using a lower alcohol, for example ethanol, tert-butanol or tert-amyl alcohol in an amount from 1 to 100 times the amount of metal; the reaction is carried out at a temperature of from -10 ^o C to 120 ^o C for 2 to 30 hours, obtaining the compound of formula (I) according to the present invention.

Alternatively, an amphoteric metal, such as zinc or aluminum, may be used together with a neutral or alkaline solution. Zinc, aluminum, etc. used in an amount of 1 to 20 equivalents, while taking from 5 to 150 times more than a 0-50% aqueous solution of sodium hydroxide, potassium oxide hydrate, and the like. and carrying out the reaction at a temperature of 5-100 ^o C for 1-20 hours to obtain the compounds according to the present invention.

The reduction of the compound of general formula (XII) or its salt with a hydrogen complex with a metal, for example sodium borohydride or lithium aluminum hydride, can be carried out, for example, by dissolving it from 2 to 100 times more proton solvent, for example water, methanol, ethanol or isopropanol, by reaction with 0.25 1 mol of sodium borohydride at a temperature of from -50 to 80 ^{° C.} for 0.5 to 3 hours, whereby a compound of formula (I) according to the present invention is obtained.

 In the case of using lithium aluminum hydride instead of lithium borohydride, ethers, for example diethyl ether, tetrahydrofuran, 1,4-dioxane or dimethoxyethane, are used instead of the flowing solvents mentioned above, carrying out the reaction under the same conditions.

 In addition to the reagents described above, diborane, sodium cyanoborohydride, lithium aluminum triethoxyhydride and the like complexes can be used as hydrogen complexes with metals.

In the case of catalytic hydrogenation of the compounds of formula (XII) or its salt, take 0.5-50 wt. a catalyst, for example palladium, Raney nickel, platinum oxide, chromium oxide, etc. in the form of a suspension, from 5 to 100 times more aprotic solvent, for example ether, dixane, tetrahydrofuran or ethyl acetate, or protic solvent, for example water, methanol, ethanol, isopropanol or acetic acid, carrying out the catalytic hydrogenation reaction in a hydrogen atmosphere at a pressure of 1- 200 atm. and a temperature of 0-200 ^{° C.} for 5-50 hours, whereby a compound of formula (I) according to the present invention is obtained.

 A compound of general formula (XII) or a salt thereof can be subjected to asymmetric reduction using an asymmetric ligand, for example, MCPCM, BINAP or BPREON in accordance with the method (Japanese application No. 01/216963) and (Journal of American Chemical Society, vol. 100, p. 629, 1988) or (Tetrahedron Letters, p. 425, 1979) to obtain an optically active compound of formula (I).

 So for example, you can use 0.001-10 mol. the catalyst MSSRM-rhodium in solution from 5 to 200 times more water, methanol, ethanol or another proton solvent, carrying out the reaction with 0.01-10 mol. triethylamine in a hydrogen atmosphere at 2-150 atm. within 1-100 hours to obtain the compounds of formula (I) according to the present invention.

More preferred reaction conditions consist in the use of 0.01-0.1 mol. the catalyst MSSRM-rhodium in a solution of methanol and 0.05-0.5 mol. triethylamine in a hydrogen atmosphere at 15-35 atm. at a temperature of 40-70 ^o C for 15-30 hours

 Instead of the above-mentioned MSSRM-rhodium catalyst, the same reaction can be carried out using an asymmetric catalyst such as BINAP-ruthenium or BPPFOH-rhodium. If the antipode of the asymmetric orientation is properly selected, optical isomers, for example, (R) or (S) compounds, can be obtained.

 The above-mentioned optical isomers can be obtained by resolving the racemates into optical isomers using optically active acids, for example tartaric acid, dibenzoyl tartaric acid or mandelic acid.

 In more detail, the compounds according to the present invention can be obtained, for example, according to the following methods (1) to (10).

где R²¹ представляет собой атом водорода, или бензильный радикал;
R²² атом водорода или бензильный радикал.In the formulas below, Ar has the following meaning,

where R ²¹ represents a hydrogen atom, or a benzyl radical;
R ^{22 is} a hydrogen atom or a benzyl radical.

In the case where R ²¹ or R ²² is a benzyl radical, debenzylation is carried out together with the reduction of the carbonyl, after which the target compound can be obtained. In some cases, carbonyl reduction may be carried out after debenzylation, or alternatively, debenzylation may be carried out after reduction of the carbonyl group.

Ниже приведены примеры, описанных выше способов получения соединения согласно настоящему изобретению, а также ряд других предпочтительных способов.

The following are examples of the methods described above for preparing the compounds of the present invention, as well as a number of other preferred methods.

В предмет настоящего изобретения входят пригодные с фармакологической точки зрения соли соединения формулы (1).

The subject of the present invention is pharmacologically acceptable salts of the compounds of formula (1).

 Examples of such salts include salts of mineral acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, or salts of organic acids, for example acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acids and methanesulfonic acids. Preferred salts are hydrochlorides and tartrates.

 In the case when the compounds according to the present invention are administered as a medicine, they are administered to animals, including humans, either in pure form or in the form of pharmaceutical compositions containing, for example, 0.1-99.5% (preferably 0.5 -90%) of the compound in admixture with a pharmaceutically acceptable methoxy and inert carrier.

 Examples of such carriers include solid, semi-liquid or liquid diluents, excipients and other auxiliary agents for the manufacture of pharmaceutical compositions; they can be used either individually or in combination, the pharmaceutical compositions are preferably administered through the mouth, tissues (eg, through veins), certain parts of the body (eg, skin) or through the anus. It should be noted that it is necessary to adapt this composition for a specific type of administration. Especially preferred is, for example, an oral route of administration.

 It is recommended that the dose of the urinary incontinence treatment agent be determined depending on the condition of the particular patient (for example, factors such as age and body weight), route of administration and the nature and extent of the development of the disease, however, usually the effective dose of the compound according to the present invention ranges from 0 , 01 mg to 1.0 g / day, or, preferably in the range from 0.1 mg to 300 mg / day in the treatment of humans. In some cases, smaller doses are sufficient, while in other cases large quantities of medication are needed. It is desirable that the drug composition is administered in parts, for example, from 2 to 3 times per day.

 Oral administration is carried out using unit dosage forms in solid or liquid form, for example, in the form of powders, diluted powders, tablets, sugar coated tablets, capsules, granules, suspensions, solutions, syrups, drops, under the tongue tablets and other formulations .

 Powders can be obtained by processing the active component into a finely divided state.

 Diluted powders can be obtained by processing the active component into a finely divided state, followed by mixing with edible carbohydrates, such as starch, mannitol, etc. If necessary, seasonings, preservatives, dispersants, dyes, perfumes and other auxiliary agents can be added to the mixture.

 Capsules can be prepared as follows. The powder or diluted powder obtained according to the previously described method or granules (which can be formed into tablets) are placed in capsules, for example gelatin capsules. Lubricants and liquefiers (e.g. colloidal silicon dioxide, talc, magnesium stearate, calcium stearate and solid polyethylene glycol) can also be mixed with the powdery substance before filling the capsules. The effectiveness of the active component in capsules can be improved by the introduction of disintegrants or solubilizers, for example, such as carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, unsubstituted hydroxypropyl cellulose, calcium carbonate, sodium carbonate, and the like.

 It is also possible to transfer the fine powder of the compound according to the present invention into a suspension or dispersion in vegetable oil, polyethylene glycol, glycerin or a surfactant, after which the resulting suspension or dispersion is placed on a gelatin sheet to form soft capsules.

 Tablets are prepared as follows. First, a powder mixture is prepared, after which granules or semi-finished tablets are obtained, then a disintegrator or lubricant is added to them and formed into tablets.

 Powdered mixtures are obtained by mixing appropriately ground compounds with the diluents or bases mentioned above and, if necessary, with a binder (e.g. sodium carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone and polyvinyl alcohol), solubilizing inhibitors (e.g. paraffin), reagents ( for example, quaternary salts) and adsorbents (for example, bentonite, kaolin and disubstituted calcium phosphate). The powder mixture is first wetted with a binder in the form of a syrup, starch paste, gum arabic, a cellulose solution or a polymer solution, and then forced through a sieve to obtain granules. In the case of granulating the powder itself, said powder is initially pelletized and the resulting prefabricated tablets of a different shape are sprayed to form granules.

 The granules obtained by themselves can be mixed with lubricants, for example stearic acid, stearates, talc, mineral oil or the like, in order to prevent mutual curing. Then the lubricant mixture is formed into tablets.

 Alternatively, the drug can be mixed with a flowable inert carrier, followed by direct molding of the tablets instead of the intermediate production of granules and semi-finished tablets in accordance with the method described above. You can also use transparent or translucent protective coatings, including closed membranes of alkali, coatings of sugar or polymeric materials, or coatings of an irregular type, including wax.

 Other compositions for oral administration, such as solutions, syrups and elixirs, can be obtained in the form of dosages in which a certain amount of the composition contains a given amount of the drug.

 Syrups are obtained by dissolving the compound in an appropriate aqueous solution having a pleasant sweet taste, while the elixir is obtained using a non-toxic alcohol carrier.

 The suspension can be obtained by dispersing the compound in a non-toxic carrier. If necessary, you can use solubilizers or emulsifiers (for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitan esters), preservatives and seasonings (for example, peppermint and saccharin), as well as other additives.

 If necessary, unit dosages for oral administration can be obtained in the form of microcapsules. In addition, these compositions can be coated with polymers or wax so that the duration of the drug is prolonged or its delayed effect is ensured.

 Compositions for parenteral administration may exist in liquid dosage forms (e.g., solutions or suspensions) for subcutaneous, intramuscular or intravenous injection. They can be prepared by dispersing or dissolving a certain amount of the compound in a non-toxic liquid carrier (for example, an aqueous or oily medium) suitable for injection, followed by sterilization of the suspension or solution. Alternatively, a certain amount of the compound of the present invention is taken into a test tube and then the test tube is sterilized together with its contents, after which it is tightly closed. For the purpose of dissolving or mixing, immediately before use, a carrier or a tube may be pre-added to the powdered or lyophilized active component.

 To obtain a solution for injection, an isotonic non-toxic salt or its solution is added to the active component. If this becomes necessary, additional stabilizers, preservatives, emulsifiers and the like additives can be used.

 Perrectal administration can be carried out using suppositories obtained by mixing the compound of the present invention with low melting water soluble or water insoluble solids such as, for example, polyethylene glycol, cocoa butter, higher esters (e.g. myristyl palmitate) and mixtures thereof.

 The medicines of the present invention can be used or combined with other medicines and treatments for urinary incontinence and polysacuria.

 The test results of the pharmacological properties of the compounds according to the present invention and comparative compounds are given below.

 1. The effect of the composition on the smooth muscles of the urethra and femoral artery.

 The experiment is carried out using female rabbits with a body weight of 2 to 3.5 kg.

Animals are sacrificed by blood drainage during phenobarbital anesthesia (30 mg / kg when administered intravenously) and smooth muscle samples of the urethra and femoral artery are excised. Each of the samples is placed in a Magnus vessel filled with a modified Krebs solution (at 37 ^° C; in a mixture of gases) and samples of smooth muscles of the urethra and femoral artery are transferred into a suspension under a load of 1 g.

 The test drug is administered with accumulation until muscle contraction occurs, obtaining curves in the concentration / recall coordinates, from which, in turn, the value of the 50% effective dose of ED-50 (M) and pD2 are obtained and the selectivity of the effect on the smooth muscles of the urethra is determined channel. The results are shown in table. one.

 The compound of the present invention used in the above experiment is a compound (49B) or (R) - (-) - 3 ′ - (2-amino-1-hydroxyethyl) -4′-fluoromethanesulfonanilide (hydrochloride) (compound according to example 5), the description of which is given above.

 The selectivity of the compound according to the present invention, in its action on the smooth muscles of the urethra, is 4-6 times higher than the selectivity of phenyletherin and amidephrine. Therefore, the compound according to the present invention has reliable selectivity for action on organs, and its usefulness as a treatment for urinary incontinence is quite obvious.

 2. Effects on alpha-1-adrenergic receptors.

The receptor membrane is prepared as follows. Rats are decapitated, the brain is cut out (with the exception of the cerebellum), weighed, a 40-fold amount of 50 mM Tris hydrochloric acid buffer solution (pH 7.4) is added to it, and the mixture is homogenized using a Polytron homogenizer, after which it is centrifuged for 20 minutes at 39000 g. A buffer solution is added to the precipitate, and the resulting suspension is again centrifuged for 20 minutes. After that, the precipitate is suspended in 40 volumes of a Tris hydrochloric acid buffer solution to obtain a receptor sample. All the above operations are carried out at a temperature of 4 ^o C.

The alpha-1-adrenoceptor binding experiment was carried out using [ ³ H] -prazoline as a radioactive ligand.

Initially, the receptor sample obtained according to the method described above is kept in a 50 mM buffer solution of a mixture of TRIS hydrochloric acid (pH 7.4) with [ ³ H] -prazosin (0.2 mM) at 25 ^{° C.} for 30 minutes. After drawing out, the reaction mixture is filtered through glass fiber filter paper (Whatman GF / B) in vacuo. The filter paper is washed three times with 3 ml of ice-cold buffer, placed in a flat-bottom tube and 10 ml of scintillator is added. The mixture is left at room temperature for about for 10 hours and measure the radioactivity by means of a liquid scintillation counter, obtaining the value of complete binding.

 A similar process is carried out in the presence of 1 μM prazosin and the radioactivity of the mixture is determined as a characteristic of non-specific binding. The difference between complete and non-specific binding corresponds to specific binding. All the experiments described above are performed twice.

The inhibitory activity of a test agent for binding of [ ³ H] -prazosin is calculated in the presence of various concentrations of the compounds of the present invention. The concentration of the compound at which the specific binding of [ ³ H] -prazosin is inhibited by 50% is defined as a 50% inhibitory concentration of IC ₅₀ . The results are shown in table. 2.

 The compound of the present invention used in the above experiment is a compound (49B) or (R) - (-) - 3 ′ - (2-amino-1-hydroxyethyl) -4′-fluoromethanesulfonanilide (hydrochloride) (compound according to example 5).

The inhibitory effect of the compound according to the present invention on the binding of [ ³ H] -prazosin is very large, about twice and five times that of amidephrine and phenylephrine, respectively. Thus, the presence of a significant affinity of the compound according to the present invention for alpha-1-adrenoceptors is quite obvious.

 3. Effects on urethral pressure and blood pressure.

 The experiment is carried out using male rabbits with a body weight of 1.4-3.1 kg, maintained without food intake. Animals are fixed during anesthesia with urethane (1.2 g / kg body weight, subcutaneously), the abdominal cavity is incised along the midline and the bladder is exposed. In order to prevent the influence of urine contained in the bladder on the pressure in the urethra, urine from the bladder is forcibly pumped out. After that, a catheter is inserted into both ureters and urine excreted from the kidney is introduced from the outside.

 The pressure inside the urethra (IUP) is measured at a distance of about 0.5-1 cm from the neck of the bladder using a microsensor equipped at the end with a ball (filled with physiological saline). A polyethylene tube is then inserted into the femoral vein to measure blood pressure (BP).

 The same experience with intravenous administration.

 The test drug is administered by injection into the ear vein every 15 minutes and, for each dose, the maximum response is measured for an increase in pressure within the urethra and an increase in blood pressure. Depending on the maximum revocation value for each dose, the indicated dose is increased to 150% of this value [IUP (ED-150%)] and the dose that increases blood pressure by 30% [BP (ED-30%)] is calculated by the method least squares. The results obtained are contained in table. 3.

Each of the compounds (table 3) is respectively:
Compounds of the invention:
(49A): (±) -3 '- (2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide (hydrochloride) (compound according to example 2);
(49B) (R) - (-) - 3 '- (2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide (hydrochloride) (compound according to example 5);
(49K): (R) - (-) - 3 '- (2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide L - (+) - tartrate (compound according to example 4);
Comparison Compounds:
(24A): (±) -3 '- (2-amino-1-hydroxyethyl) methanesulfonanilide (hydrochloride);
(24B): (R) - (-) - 3 '- (2-amino-1-hydroxyethyl) methanesulfonanilide (hydrochloride);
(59A): (±) -erythro-3 '- (2-amino-1-hydroxypropyl) -4'-fluoromethanesulfonanilide (hydrochloride) (compound according to example 6);
(61A): (±) -2'-fluoro-5 '- (1-hydroxy-2-methylaminoethyl) methanesulfonanilide (hydrochloride);
(63A): (±) -5 '- (2-amino-1-hydroxyethyl) -2', 4'-difluoromethanesulfonanilide (hydrochloride) (compound according to example 9);
(67A): (±) -4-chloro- (1-hydroxy-2-methylaminoethyl) methanesulfonanilide (hydrochloride);
(70A): (±) -erythro-5 '- (2-amino-1-hydroxyethyl) -2'-fluoromethanesulfonanilide (hydrochloride) (compound according to example 8);
(71A): (±) -2 ', 4'-difluoro-5' - (1-hydroxy-2-methylaminoethyl) methanesulfonalide (hydrochloride) (compound according to example 7);
(73A): (±) -3 '- (2-amino-1-hydroxyethyl) -5'-fluoromethanesulfonanilide (hydrochloride) compound according to example 11).

 In the above compound numbers, index (A) refers to racemate hydrochlorides; (B) to hydrochlorides of (R) - (-) - isomers; and (K) to tartrates of (R) - (-) - isomers, and the numbering corresponds to the following compounds (49): of the present invention, compounds (1); (24): compound (XX); (59): compound (II); (61): compound (X); (63): compound (III); (67): compound (XXX); (70): compound (IV); (71): compound (V); (73): compound (VI).

Тот же опыт при введении в двенадцатиперстную кишку.

The same experience with the introduction into the duodenum.

 The abdominal cavity immediately above the stomach is incised along the midline, after which the test drug, suspended in a 0.5% solution of methylcellulose (0.5% MS), is injected in an amount of 0.5 ml / kg into the duodenum. After administration, the change in intravenous pressure in the urethra (IUP) and blood pressure (BP) over time is measured; the results are shown in table 4. The introduction to the duodenum described above corresponds to oral administration, as does the administration of an anesthetized animal into the digestive organ (Table 4).

 4. Toxicity.

 The number of mice (variety dd males, age 6-8 weeks) and mice (type SD males, age 6-7 weeks) in each of the groups in the experiments were 4 and 6 animals, respectively.

 The test drug was administered to animals that were not given food during the previous day (for 16-18 hours), orally in an amount of 10 ml / kg of body weight using an oral probe. After the introduction of the drug, the animals are again given access to food and water, checking their general condition and deaths (if any) within 2 weeks. The drug is transferred into a suspension in physiological saline containing 0.5% methylcellulose (0.5% MS) and the suspension is administered orally to animals. The results are shown in table. 5.

 A general assessment of drugs is carried out according to test results 3 (effects on pressure in the urethra and blood pressure) and 4 (toxicity).

 Compounds (1) [(49A), (49B) and (49K)] have a selectivity of 6.6, which corresponds to the highest selectivity for specific organs. In addition, their effect on the internal pressure in the urethra corresponds to the highest value (at a dose of 0.009 mg / kg). Thus, they have a satisfactory effect and fairly low toxicity.

 Compounds (X) [(61A) and (61B)] cannot be used as pharmaceuticals and are not considered in the present invention because the selectivity of compound (61A) is not high enough (1,2), and compound (61B) is too high toxicity (LD-50 is 36.1 mg / kg).

 The selectivity of compound (III) [(63A)] is 2.9, which is about 6 times higher than the selectivity of phenylephrine. In addition, its effect on the internal pressure in the urethra corresponds to a good level (at a dose of 0.065 mg / kg), and its toxicity also remains quite low.

 The selectivity of compound (XXX) [(67A)] corresponds to a good value of 4.2. However, its effect on the internal pressure in the urethra corresponds to a low level (at a dose of 0.70 mg / kg), which corresponds to only about 1/20 of the corresponding exposure to a known drug. Accordingly, although its toxicity is kept at a sufficiently low level, they do not fall within the scope of the present invention.

 The selectivity of compound (IV) [70A)] is 3.6, which is about 7 times higher than the selectivity of phenylephrine. In addition, its effect on the internal pressure in the urethra corresponds to a good level (0.028 mg / kg), and toxicity is also quite low.

 The selectivity of compound (V) [71A)] is 2.1, which is about 4 times higher than the selectivity of phenylephrine.

 In experiments on the administration of drugs to the digestive organs to verify the results obtained by oral administration, the dose of the representative compound according to the present invention (49B) leads to about 10 times stronger effect on the increase in the internal pressure in the urethra compared to the well-known amidefrine. In addition, the effect on blood pressure is negligible and thus the effect of the drug is extended over a long period of time.

 When analyzing the above test results, the following compounds (49A), (49B), (49K) can be selected.

 The present invention is further illustrated by the following comparative examples and working examples related to methods for producing compounds according to the present invention and comparison compounds, as well as examples for producing drugs according to the present invention.

 Comparative example 1.

(1) 5'-amino-2'-fluoroacetophenone (28 g) was dissolved in a mixture of 100 ml of ethyl acetate and 15.9 g of pyridine, a solution of 23 g of methanesulfonyl chloride in 50 ml of ethyl acetate was added to the resulting mixture under cooling with ice and stirring, and the reaction mixture was left to leave the reaction mixture at room temperature for 3 hours. The reaction mixture was washed with water, dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography, eluting with chloroform, to give 33.7 g of 3'-acetyl-4'-fluoromethanesulfonanilide with a melting point 120-123 ^o C.

(2) 3'-Acetyl-4'-fluoromethanesulfonanilide (32 g) was dissolved in 250 ml of acetic acid, after which 22.1 g of bromine was gradually added dropwise to the solution at room temperature, after which the reaction mixture was left at room temperature for 3 h. Then the reaction mixture is added to a mixture of ice water and extracted with ethyl acetate. The extract is washed first with an aqueous solution of sodium bicarbonate, then with water, dried and the solvent is distilled off from it, after which the residue is crystallized from diisopropyl ether to obtain 38 g of 3 '- (2-bromoacetyl) -4'-fluoromethanesulfonanilide with a melting point of 110-113 ^o C .

(3) 3 '- (2-Promacetyl) -4'-fluoromethanesulfonanilide (30 g) was dissolved in 200 ml of N, N-dimethylformamide, after which a solution of 38 g of dibenzylamine in N, N-dimethylformamide was added to the solution under ice-cooling and stirring. and then the reaction mixture was left at room temperature for 1 hour. Then the reaction mixture was added to water and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was removed from it, after which the residue was crystallized from diisopropyl ether to obtain 35 g of 3 '- (2-dibenzylaminoacetyl) -4'-fluoromethanesulfonanilide. The crystals are converted into the hydrochloride in the usual way, obtaining 35 g of crystalline hydrochloride with a melting point of 185-188 ^o C.

(4) 3 '- (Dibenzylaminoacetyl) -4'-fluoromethanesulfonanilide (as hydrochloride) (10 g) is suspended in 100 ml of methanol, 1.0 g of 5% palladium on activated carbon is added and the reaction mixture is reduced at room temperature temperature and hydrogen pressure of 8 atm. Then, the catalyst was removed, the solvent was distilled off, and the precipitated crystals were collected by filtration to obtain 4.6 g of 3 '- (2-aminoacetyl) -4'-fluoromethanesulfonanilide (as hydrochloride) with a melting point of 177-181 ^o С.

NMR spectrum (in DMSP-d ₆ ) δ: 2.96 (3H, singlet), 4.23-4.5 (2H, multiplet), 7.0-8.0 (3H, multiplet), 8.2- 8.9 (3H, broad signal), 9.55-10.2 (1H, broad signal).

 The following compounds are prepared according to a method similar to that described in sections (1) to (3) of comparative example 1.

 Comparative Example 2

 3 '- (2-Dibenzylaminopropionyl) -4'-fluoromethanesulfonanilide.

Nuclear Magnetic Resonance Spectrum (in CDCl ₃ ) d: 1.34 (3H, doublet, J = 6.4 Hz), 3.01 (3H, singlet), 3.59 (4H, singlet), 4.23 (3H, quartet) , J = 6.4 Hz), 6.91 - 7.52 (13H, multiplet).

 Comparative example 3.

 3 '- (2-Dibenzylaminopropionyl) -2'-fluoromethanesulfonanilide.

NMR spectrum (in CDCl ₃ ) d: 1.32 (3H, doublet, J = 7.0 Hz), 2.99 (3H, singlet), 3.59 (4H, multiplet), 4.23-4.33 (2H, multiplet); 7.23 (13H, multiplet).

 Comparative example 4.

5 '- (2-Dibenzylaminoacetyl) -2', 4'-difluoromethanesulfonanilide. Melting point 168-172 ^o C.

 Comparative Example 5

 5 '- (2-Benzylmethylaminoacetyl) -2', 4'-difluoromethanesulfonanilide.

Nuclear Magnetic Resonance Spectrum (in CDCl ₃ , DMSO-d ₆ ) d: 2.34 (3H, singlet), 2.95 (3H, singlet), 3.64-3.98 (4H, multiplet), 7.19-7 31 (7H, multiplet).

 Comparative example 6.

(1) 2-Fluoro-5-nitrobenzoic acid (60 g) is suspended in 300 ml of methanol, 6.0 g of 5% palladium on activated carbon are added and the reaction mixture is reduced at 40 ^{° C.} and a hydrogen pressure of 6.5 atm. Then the catalyst was removed, the solvent was distilled off, and the precipitated crystals were collected by filtration to obtain 42 g of 5-amino-2-fluorobenzoic acid with a melting point of 189-192 ^° C.

NMR spectrum (in DMSO-d ₆ d: 6.65-7.25 (3H, multiplet), 5.5-7.5 (3H, broad signal).

 (2) 5-amino-2-fluorobenzoic acid (100 g) is suspended in 1.3 l of methanol, after which 100 g of concentrated hydrochloric acid are gradually added to the solution and the reaction mixture is heated under reflux for 24 hours. Then, methanol distilled off, and the residue was added to a mixture of water and ice. The mixture was neutralized with sodium bicarbonate and extracted with ethyl acetate. The extract is washed with water, dried and the solvent is distilled off from it. The resulting crystals were separated by filtration to obtain 88 g of methyl 5-amino-2-fluorobenzoate.

NMR spectrum (in CDCl ₃ ) d: 2.9-3.8 (2H, broad signal), 3.92 (3H, singlet), 6.8-7.3 (3H, multiplet).

(3) Methyl 5-amino-2-fluorobenzoate (59 g) and 23.4 g of pyridine are dissolved in 300 ml of ethyl acetate, after which 37 g of methanesulfonyl chloride are added to the solution under ice-cooling and stirring, after which the reaction mixture is left at room temperature temperature for 3 hours. Then the reaction mixture was washed with water, dried and the solvent was distilled off from it, after which the precipitated crystals were separated by filtration, to obtain 72 g of methyl 2-fluoro-5-methanesulfonylaminobenzoate with a melting point of 135-137 ^o C.

NMR spectrum (in CDCl ₃ ) d: 3.02 (3H, singlet), 3.96 (3H, singlet), 6.9-7.9 (3H, multiplet).

(4) Methyl-2-fluoro-5-methanesulfonylaminobenzoate (72 g) and 49 g of potassium hydroxide are dissolved in 400 ml of a 1: 1 mixture of water and methanol and the reaction mixture is heated under reflux for 2 hours. Methanol is then distilled off, and the residue is acidified with hydrochloric acid. The resulting crystals are separated by filtration, washed with water and dried, obtaining 63 g of 2-fluoro-5-methanesulfonylaminobenzoic acid and a melting point of 203-205 ^o C.

NMR (DMSO-d ₆₎ d: 2,98 (3H, s), 7.2-7.8 (3H, m), 9.82 (1H, broad singlet).

(5) 60% sodium hydride (3.0 g) is suspended in 20 ml of N, N-dimethylformamide, after which 8.4 g of nitromethane are gradually added dropwise to the solution under ice-cooling and stirring, and the reaction mixture is stirred at room temperature for 30 minutes 2-fluoro-5-methanesulfonylaminobenzoic acid (8.0 g) and 6.7 g of N, N-carbonyldiimidazole are dissolved in 30 ml of N, N-dimethylformamide and the reaction is carried out in the resulting solution for 1 h. Then the reaction mixture is added while cooling ice to the previously obtained solution and the reaction mixture is stirred at room temperature for 2 hours. After this, the reaction mixture is poured into a mixture of ice water, acidified with hydrochloric acid and the precipitated crystals are separated by filtration, washed with a small amount of ethanol and dried, obtaining 8.2 g 4'-fluoro- 3 '- (2-nitroacetyl) methanesulfonanilide with a melting point of 174-176 ^o C.

NMR spectrum (in DMSO-d ₆ ) d: 2.97 (3H, singlet), 5.87 (2H, doublet, J = 3.5 Hz), 7.0-8.0 (3H, multiplet), 9 81 (IN, broad singlet).

(6) 4'-fluoro-3 '- (2-nitroacetyl) methanesulfonanilide (0.5 g) is dissolved in 10 ml of methanol, 2 ml of a 10% solution of hydrochloric acid in methanol and 50 mg of 5% palladium per activated carbon and restore the reaction mixture at room temperature, stirring and a hydrogen pressure of 1 atm for 21 hours. Then the catalyst is removed, the solvent is distilled off and the precipitated crystals are collected by filtration after adding a small amount of ethanol, yielding 0.4 g of 3 '- (2-aminoacetyl ) -4'-fluoromethanesulfonanilide melting point 179-181 ^o C.

NMR spectrum (in DMSO-d ₆ ) d: 2.96 (3H, singlet), 4.23-4.5 (2H, multiplet), 7.0-8.0 (3H, multiplet), 8.2- 8.9 (3H, broad signal), 9.55-10.2 (1H, broad signal).

 The following compounds are prepared according to a method similar to that described in sections (1) (6) of Reference Example 6.

 Reference example 7.

3 '- (2-aminoacetyl) -5'-fluoromethanesulfonanilide (hydrochloride). Melting point 190-200 ^o C (with decomposition). The results of elemental analysis based on C ₉ H ₁₁ FN ₂ O ₃ S • HCl:
Calculated: C 38.24; H 4.28; N, 9.81.

 Found: C, 38.04; H 4.15; N, 9.66.

NMR spectrum (in DMSO-d ₆ ) d: 3.09 (3H, singlet), 4.53 (2H, singlet), 7.37 (1H, double triplet, J 11 Hz, 1.5 Hz), 7, 54-7.68 (2H, multiplet), 8.3-10.6 (4H, broad signal).

 Example 1

3 '- (2-aminoacetyl) -4'-fluoromethanesulfonanilide (hydrochloride) (3 g) was dissolved in 30 ml of methanol, 0.20 g of sodium borohydride was added to the solution at 0-5 ^° C and the reaction was carried out at the same temperature for 1 h. The solvent was distilled off and the residue was transferred to the free base using an ion exchange resin (Dovex 50W X2 "), concentrated to dryness and the residue was recrystallized from methanol to obtain 2.4 g of (±) -3 '- (2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide with a melting point of 176-179 ^o C.

 Example 2

(±) -3 '- (2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide (2.3 g) was treated with a 20% solution of hydrochloric acid in ethanol to obtain 2.4 g of (±) -3'- (2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide as a hydrochloride with a melting point of 178-181 ^o C. The results of elemental analysis based on C ₉ H ₁₃ FN ₂ O ₃ S • HCl:
Calculated: C 37.96; H 4.96; N, 9.84.

 Found: C, 37.97; H 5.06; N, 9.59.

 Example 3

3 '- (2-aminoacetyl) -4'-fluoromethanesulfonanilide (hydrochloride) (21 g) is suspended in 210 ml of methanol, then a catalyst of 50 mg (2R, 4R) -N-methylcarbamoyl-4-dicyclohexylphosphino-2- diphenylphosphinomethylpyrrolidine and 18 mg of di-m-chlorobis (cyclooctadiene) dirodium (1), which are added to the suspension together with 19 mg of triethylamine and the reaction mixture is reduced at 50 ^{° C.} in a hydrogen atmosphere at a pressure of 20 atm. The reaction mixture was concentrated and transferred to the free base using an ion exchange resin ("Dovex 50W X2") to obtain 15.8 g of crude (R) - (-) - 3 '- (2-amino-1-hydroxyethyl) -4'- fluoromethanesulfonanilide.

NMR spectrum (in DMSO-d ₆ ) d: 2.4-2.76 (2H, multiplet), 2.92 (3H, singlet), 3.9-4.6 (2H, broad signal), 4.65 -4.74 (1H, multiplet), 5.2-5.6 (1H, broad signal), 7.03-7.12 (2H, multiplet), 7.28-7.37 (1H, multiplet).

 Example 4

15.8 g of crude (R) - (-) - 3 '- (2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide and 9.6 g of L - (+) - tartaric acid are dissolved in water, added to the mixture ethanol, precipitated crystals are separated and crystallized several times sequentially from a mixture of ethanol with water, obtaining 16 g of (R) - (-) - 3 '- (2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide in the form of L - (+ ) -tartrate with a melting point of 91-91 ^o C. The results of elemental analysis based on C ₉ H ₁₃ FN ₂ O ₃ S • C ₄ H ₆ O ₆ • H ₂ O:
Calculated: C 37.49; H 5.02; N, 6.73.

 Found: C, 37.67; H 5.22; N, 6.65.

 Example 5

(R) - (-) - 3 '- (2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide (L - (+) - tartrate) (2.0 g) was transferred to the free base using an ion exchange resin (" Dovex 50W X2 "), after which it is treated with a 20% solution of hydrochloric acid in ethanol. The crystals liberated in this case are collected, yielding 1.1 g of (R) - (-) - 3 '- (2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide as a hydrochloride with a melting point of 181-191 ^o C.

The results of elemental analysis based on C ₉ H ₁₃ FN ₂ O ₃ S • HCl:
Calculated: C 37.96; H 4.96; N, 9.84.

 Found: C, 37.85; H 4.96; N, 9.80.

[α] _D = - 22.33 ^° (water, s 1.012).

Nuclear Magnetic Resonance Spectrum (in DMSO-d ₆ ) δ: 2.73-3.07 (2H, multiplet), 2.97 (3H, singlet), 5.0-5.13 (1H, multiplet), 6.21- 6.30 (1H, broad signal), 7.35-7.45 (1H, multiplet), 7.9-8.9 (4H, broad signal).

 Example 6

3 '- (2-Dibenzylaminopropionyl) -4'-fluoromethanesulfonanilide (hydrochloride) (0.8 g) was suspended in 8 ml of methanol, 0.08 g of 5% palladium on activated carbon was added to the mixture, and the mixture was restored at room temperature temperature for 15 hours at a hydrogen pressure of 8 atm. The catalyst was removed, then the solvent was distilled off to obtain 0.5 g of crystals. These crystals were dissolved in 40 ml of methanol, 0.32 g of sodium borohydride was added to the solution with stirring and cooling with ice, and the mixture was left for 15 minutes. The solvent was distilled off from the reaction mixture, and the residue was transferred to the free base using an ion exchange resin (Dovex 50W X2), after which the indicated free base was recrystallized from methanol and treated with a 20% solution of hydrochloric acid in ethanol, releasing 0.27 g ( -) - erythro-3 '- (2-amino-1-hydroxypropyl) -4'-fluoromethanesulfonanilide as a hydrochloride with a melting point of 239-241 ^o C. The results of elemental analysis based on C ₁₀ H ₁₅ FN ₂ O ₃ S • HCl :
Calculated: C 40.20; H 5.40; N, 9.38
Found: C, 39.81; H 5.35; N, 9.47.

NMR spectrum (in DMSO-d ₆ ) d: 0.95 (3H, doublet, J = 7.0 Hz), 2.94 (3H, singlet), 2.25-2.39 (1H, multiplet), 5, 12-5.20 (1H, broad signal), 6.24 (1H, doublet, J 4.0 Hz), 7.13-7.18 (2H, multiplet), 7.38-7.42 (1H, multiplet), 8.02-8.54 (3H, broad signal), 9.61-9.90 (1H, broad signal).

 Example 7

5 '- (2-Benzylmethylaminoacetyl) -2', 4'-difluoromethanesulfonanilide (2.5 g) is dissolved in 10 ml of tetrahydrofuran, then 0.28 g of sodium borohydride in 2 ml of water is added to the solution with stirring and cooling with ice and the mixture is left to leave a mixture for 15 minutes. The solvent was distilled off from the reaction mixture, and the residue was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off to obtain 2.7 g of (±) -5 '- (2-benzylmethylamino-1-hydroxyethyl) -2', 4'-difluoromethanesulfonanilide, which was suspended in 90 ml of methanol. To the suspension add 0.5 g of 5% palladium on activated carbon and restore the mixture at 30 ^o C for 15 hours at a hydrogen pressure of 8 ATM. The catalyst was removed and the residue was treated with a 20% solution of hydrochloric acid in ethanol to obtain 1.25 g of (±) -2 ', 4'-difluoro-5' - (1-hydroxy-2-methylaminoethyl) methanesulfonanilide as a hydrochloride with temperature melting point 192-194 ^o C. The results of elemental analysis based on C ₁₀ H ₁₄ F ₂ N ₂ O ₃ S • HCl:
Calculated: C 37.92; H 4.77; N 8.84
Found: C, 37.98; H 4.80; N 8.79
NMR spectrum (in CDCl ₃ , DMSP-d ₆ ) d: 2.46 (3H, singlet), 2.55 - 2.80 (2H, multiplet), 3.00 (3H, singlet), 4.80-5 19 (1H, multiplet); 6.67-7.01 (1H, multiplet); 7.67-7.80 (1H, multiplet).

 Example 8

5 '- (2-Dibenzylaminopropionyl) -2'-fluoromethanesulfonanilide (hydrochloride) (2.6 g) was dissolved in 50 ml of methanol, then 0.26 g of 5% palladium on activated carbon was added and the mixture was reduced at 30 ^{° C.} 15 hours at a hydrogen pressure of 7 atm. The catalyst was removed and 0.41 g of sodium borohydride was added to the mixture with stirring and ice-cooling, after which the mixture was left for 2 hours at room temperature. The solvent was distilled off from the reaction mixture, and the residue was purified by silica gel column chromatography, eluting with chloroform and methanol. The resulting oil is treated with a 20% solution of hydrochloric acid in ethanol to obtain 0.7 g of (±) -erythritol-5 '- (2-amino-1-hydroxypropyl) -2'-fluoromethanesulfonanilide as a hydrochloride with a melting point of 235 ^° C. The results of elemental analysis based on C ₁₀ H ₁₅ FN ₂ O ₃ S • HCl:
Calculated: C 40.20; H 5.40; N, 9.38
Found: C, 40.03; H 5.67; N, 9.38
Nuclear Magnetic Resonance Spectrum (in CDCl ₃ , DMSO-d ₆ ) d: 0.93 (3H, doublet, J = 7.0 Hz), 2.96 (3H, singlet), 2.55-3.28 (1H, multiplet) 4.00-4.39 (4H, multiplet); 4.39-4.50 (1H, multiplet); 7.04 - 7.48 (3H, multiplet).

 Example 9

5 '- (2-Dibenzylaminoacetyl) -2', 4'-difluoromethanesulfonanilide (1.8 g) was dissolved in 35 ml of methanol, then 0.16 g of sodium borohydride was added to the solution with stirring at room temperature and the mixture was left for 1 h at the same temperature. The solvent was distilled off from the reaction mixture, and the residue was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography, eluting with a mixture of n-hexane and ethyl acetate, to thereby obtain 1.6 g of an oil. The specified oil is dissolved in 30 ml of methanol, 160 mg of 5% palladium on activated carbon are added to it and the mixture is reduced at 30 ^{° C.} for 15 hours at a hydrogen pressure of 7 atm. The catalyst was removed, the solvent was distilled off, and the residue was treated with a 20% solution of hydrochloric acid in ethanol to obtain 0.53 g of (-) - 5 '- (2-amino-1-hydroxyethyl) -2', 4'-difluoromethanesulfonanilide as the hydrochloride with a melting point of 209-211 ^o C. The results of elemental analysis based on C ₉ H ₁₂ F ₂ N ₂ O ₃ S • HCl:
Calculated: C 35.71; H 4.33; N, 9.25
Found: C, 35.73; H 4.59; N, 9.01.

Nuclear Magnetic Resonance Spectrum (in CDCl ₃ , DMSO-d ₆ ) d: 2.57-2.88 (2H, multiplet), 2.97 (3H, singlet), 4.20 (3H, singlet), 4.74-4 83 (1H, multiplet); 6.71-7.04 (1H, multiplet); 7.47-7.75 (2H, multiplet).

 Example 10

3 '- (2-aminoacetyl) -5'-fluoromethanesulfonanilide (hydrochloride) (1.7 g) is suspended in 70 ml of methanol, 114 mg of sodium borohydride are added to the solution with stirring at a temperature of 5-10 ^° C and the reaction is carried out at room temperature for 30 minutes The solvent was distilled off and the residue was transferred to the free base using an ion exchange resin (Dobex 50W X2), after which the residue was recrystallized from a mixture of ethanol and methanol to obtain 1.07 g of (±) -3 '- (2-amino-1-hydroxyethyl ) -5'-fluoromethanesulfonanilide with a melting point of 167-169 ^o C. The results of elemental analysis based on C ₉ H ₁₃ FN ₂ O ₃ S:
Calculated: C 43.54; H 5.28; N, 11.28
Found: C, 43.55; H 5.33; N, 11.39
Example 11

The compound obtained according to example 10 (0.70 g) was treated with a 20% solution of hydrochloric acid in ethanol to obtain 0.72 g of (±) -3 '- (2-amino-1-hydroxyethyl) -5'-fluoromethanesulfonanilide in as hydrochloride with a melting point of 183-186 ^o C. The results of elemental analysis based on C ₉ H ₁₃ FN ₂ O ₃ S • HCl:
Calculated: C 37.96; H 4.96; N 9.84
Found: C, 37.72; H 5.18; N 9.97
NMR spectrum (in DMSO-d ₆ ) d: 2.74-3.1 (2H, multiplet), 3.04 (3H, signal), 4.57-4088 (1H, multiplet), 6.12-6, 28 (1H, broad signal), 6.86-7.12 (3H, multiplet), 8.24-8.86 (4H, broad signal).

 An example of the composition 1.

The compound of the present invention (compound (49B)) is used to prepare a pharmaceutical composition using known methods for preparing tablets from the following components:
1 tablet contains; mg:
The compound according to the invention 1
Lactose 60
Corn Starch 30
Crystalline Cellulose 20
Oxypropyl cellulose 7
Magnesium Stearate 2
Total: 120
An example of composition 2.

The compound of the present invention (compound (49B)) is used to prepare a pharmaceutical composition in the form of a diluted powder using known methods for preparing similar compositions from the following components; mg:
The compound according to the invention 2
Lactose 988
Aqueous Silica 10
Total: 1000
An example of composition 3.

The compound of the present invention (compound (49B)) is used to prepare a pharmaceutical composition in the form of an injectable solution using known methods for preparing similar compositions from the following components:
The compound according to the invention 1 mg
Physiological saline to the required volume
Total: 5 ml

Claims (2)

1. 3 '- (2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanide of the formula

or its optical isomers, or pharmacologically acceptable salts.  2. An agent for treating urinary incontinence, comprising an active substance and a carrier, characterized in that the active substance contains a compound of the formula according to claim 1 in an effective amount.

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