JPS6011898B2 - New benzenesulfonamide derivatives, their production methods and pharmaceutical compositions containing them - Google Patents

Description

[Detailed description of the invention]

The present invention relates to new benzenesulfonamide derivatives, processes for their preparation, and pharmaceutical compositions containing them. The inventors have discovered that certain benzenesulfonamide derivatives are useful in treating myocardial dysfunction diseases such as angina and hypertension due to their ability to block B-adrenoceptors. Furthermore, many of these compounds have effective blocking effects on the Q-adrenoceptor, and the combined Q- and 8-blocking effects of these compounds make them particularly useful in the treatment of hypertension. These compounds are also useful in the treatment of peripheral muscle diseases such as Raynaud's disease and in the treatment of arrhythmias. According to the invention, therefore:
A compound represented by the general formula '1} [wherein R is chlorine, fluorine, amino,
C, ~C4 alkylamino, diC, ~C4 alkylamino, piberidino or pyrrolidino, and X is -CH2
1, 10- or 1N (C ratio) 1, R5 is hydrogen or fluorine, and Y is S02NH2]. Preferred compounds according to the invention are those in which R is chlorine, fluorine, amino, C, to C4 alkylamino or diC, to C4 alkylamino, especially a jetylamino group. R5 is hydrogen or fluorine, and when R5 is fluorine it is in the p- or m-position. x is preferably CH2. Particularly preferred compounds consist of the following compounds, which particularly exhibit the ability to block both Q and 8-adrenoceptors. 2-fluoro-5-[1-hydroxy-2-[3-(4
-fluorophenyl)-1-methylpropyl]amino]
ethyl]benzenesulfonamide 2-fluoro-5-[
1-Hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide 2-
dimethylamino-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide 2-amino-5-[1-hydroxy-2-[(1-methylm3-phenyl) Propyl)amino]ethyl]benzenesulfonamide 5-[1-hydroxy-2-[(1-methyl-3-phenylpyl)amino]ethyl]-2-methylaminobenzenesulfonamide 2-(butylmethylamino)-5-[ 1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide 2-fluoro5-[1-hydroxy-2-[[3-(3-fluorophenyl)-1-methylpropyl]amino [ethyl]benzenesulfonamide 21 (ethylmethylamino)
15-[1-Hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide The compounds of the present invention include all possible diastereomers and optical enantiomers and mixtures thereof. The compounds of the present invention also include physiologically acceptable abiotic salts of the aforementioned compounds, such as acid addition salts with inorganic or organic acids. Specific salts include hydrochlorides, maleates, tartrates, etc. Blocking effects on Q- and 8-adrenoceptors have been demonstrated in bilaterally vagus-cut and anesthetized dogs. Compounds were administered by injection through a cannulated femoral vein. The B-flocking effect of the compound is due to (1) the healing frequency induced by intravenous injection of isoprenaline;
From the results obtained, the DR for each compound, determined from the ability of the compound to counteract the increase in a). The value was calculated. DR. The value is the dose of compound required to produce a shift of 1 note to the right of the isoprenaline dose-response curve for an increase in rod frequency. The Q-flocking effect of the compound may be due to the diastolic blood pressure induced by intravenous injection of phenylephrine.
cbloodpressure). The Q-70 docking effect was quantified as the DR,o value described above. Compounds of the invention can be made by various methods. In one method, the compounds of the present invention can be prepared by reacting a ketone of the general formula (b), in which Y and R have the meanings given above, with a halogen, preferably bromine, to form a compound of the formula (b).
m) and then convert this haloketone to the formula NH
An amine represented by R7R3 (wherein R7 is pendyl or a group R in which R is a group represented by formula (W) (wherein X and R5 have the abovementioned meanings), and R3 is hydrogen or pendyl) to give an aminoketone of the formula (V) (wherein Y, R,, R? and R8 have the above-mentioned meanings).The ketone group in the compound of formula (V) is then subjected to a suitable reduction. treatment with an agent, for example a complex metal hydride such as sodium borohydride, to reduce the CHOH group to a compound of formula (machi), where Y, R, , R7 and R8 have the meanings given above. Compounds of formula () in which R7 is a radical R and R8 is hydrogen are compounds of the invention. Alternatively, the reduction can be carried out by catalytic hydrogenation in the presence of a noble metal catalyst such as platinum or palladium or mixtures thereof. 1 indicated by the expression (skin)
-phenyl-2-aminoethanol derivative (wherein R9 is hydrogen or a group R) is produced. Compounds of formula (W) in which R9 represents a group R are compounds of the invention. When the aminoketone of formula (V) is reduced using a non-catalytic reduction method, the penzyl group in the molecule is not affected. In order to convert this penzyl group into a hydrogen atom, catalytic hydrogenolysis can be subsequently performed to obtain the compound of the present invention. Catalytic hydrogenolysis can be carried out using hydrogen and a palladium oxide catalyst. In order to convert compounds of the formula (W) in which R7 represents pendyl and compounds of the formula (skin) in which R9 represents hydrogen into compounds according to the invention, a radical R must be introduced. The introduction of the group R is carried out by reacting a compound of formula () in which R7 is a pendyl group and R8 has the above-mentioned meaning with a suitable ketone, for example a ketone of formula (side), hydrogen and a suitable catalyst, for example supported on activated carbon. This can be carried out by reductive alkylation in the presence of a special platinum or activated carbon supported palladium catalyst. An alternative method is to use an amine of formula (戊) and condense it with a suitable ketone to introduce an R group, such as a group of formula (hada);
The product is then reduced using catalytic hydrogenation or a reducing agent such as sodium borohydride and the formula according to the invention (
1). Ketones of the formula (X) (wherein R8 has the abovementioned meaning) can also be directly reductively alkylated to give the compounds of formula (1) of the invention.An alternative method for preparing the compounds of the invention is Glyoxal represented by the formula (phantom) (in which R and Y have the meanings given above) can be used as a starting material. When this glyoxal is condensed with an amine represented by the formula (kari), the formula ( Xm). This intermediate is then reduced by a rust metal hydride such as sodium borohydride or by hydrogen and a noble metal catalyst to give the compound of formula (1). Alternative method A halohydrin represented by formula (XW) or formula (XV)
An epoxide of the formula (in which R and Y have the meanings given above and Hal represents a halogen atom) is reacted with an amine of the formula (dish). When R is a halogen atom, it is generally convenient for the halogen atom to be present in the starting material. When R, is NR2R3, this group is replaced with a compound of formula (JP) and (X) in which R, is halogen in ammonia or an amine HNR2R3 in a solvent, preferably ethanol.
It is convenient to introduce it by processing. When preparing compounds of formula (1) where R2 is day and R3 is a group other than H, the amine HN(R3)CH2Ph can be used and the penzyl group subsequently removed. The compounds of the present invention can be isolated as such or in the form of non-toxic salts that can be used in medicine. The compounds of the invention can be formulated into therapeutic or prophylactic medicines for human and household use. Therefore, pharmaceutical compositions containing the compound of general formula (1) or a medically usable addition salt as a medicinal ingredient are also included within the scope of the present invention. As mentioned above, preferred salts include hydrochloride, maleate, tartrate, and the like. Pharmaceutical compositions of this type can be prepared for use in the conventional manner using a carrier or suppository and optionally a pharmaceutical preparation, using the compound of the invention alone or in combination with adjuvants. These compositions include, for example, solid and liquid preparations for oral, suppository and injectable use. For oral administration, it is most conveniently in the form of tablets, which may be prepared by conventional methods and optionally coated. Injectables can be prepared as solutions or suspensions using a compatible carrier and pharmaceutical agent, or as a dry preparation for reconstitution before use. The dosage of the medicinal ingredient that can be used can vary over a wide range, but in general suitable dosage units are from 5 to 1000 doses, preferably from 20 to 200 doses. The preferred dose/indication varies depending on the age and weight of the patient and the severity of the symptoms, but is 300-3000 9/day for oral administration. In order that the present invention may be more fully understood, the following examples are set forth, but are intended to be illustrative only. Example 1 2-chloro-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide, hydrochloride (a} 5-(2-bromoacetyl)-2-chlorobenzene sulfone) Amide glacial acetic acid 1
While stirring vigorously at 50oC, 3.2 parts of bromine in 20 parts of glacial acetic acid was added dropwise to a solution of 4.7 parts of 5-acetyl-2-chlorobenzenesulfonamide in 20% of glacial acetic acid. After an initial induction period of 5 minutes, the bromine color disappeared. Bromine was added in third batches and the resulting solution was stirred for 15 minutes before the acetic acid was removed under reduced pressure. The resulting white mass was dissolved in 30 parts of acetone, diluted with 250 parts of benzene, and concentrated to a solution volume of 150 parts. When this is cooled, white crystals of the desired product with a melting point of 168-17
．． It was raining overnight. (b) 2-Chloro-5-[1-hydroxy-2-[N-(1-methyl-3-phenylpropyl)N-(phenylmethyl)amino]ethyl]benzenesulfonamidobutanone -bromoacetyl)-2-chlorobenzenesulfonamide 3.1
3 and N-(1-methyl-3-phenylpropyl)
-2-(phenylmethyl)amine was heated at reflux for 30 minutes, the solvent was removed under reduced pressure, and the residue was triturated with dry ether and removed. The ether solution was evaporated to dryness, the residue was dissolved in 50' of ethanol, the solution was treated with 0.3 ml of sodium borohydride, the mixture was stirred for 30 min, and another 0.3 ml of sodium borohydride was added. and the reaction mixture was diluted with 2N
It was acidified with hydrochloric acid and the ethanol was removed under reduced pressure. The resulting concentrate was made basic with sodium hydroxide, the mixture was extracted twice with 50 parts of ethyl acetate, the extract was washed twice with 50 parts of water, dried at an M ratio of 04, and evaporated to dryness. This gave 4.6 kg of the desired product as a yellowish substance, which was chromatographed on a preparative chromatographic plate (silica, CHC 13/5% MeOH) and converted into the hydrochloride salt, mp 120-125 qo. (c) 2-chloro-5-[1-hydroxy-2
-[(1-methyl-3-phenylpropyl)-amino]
Ethyl]benzenesulfonamide, hydrochloride 2-chloro5-[1-hydroxy-2-[N-(1-methyl-3-phenylpropyl)-N-(phenylmethyl)amino]
Hydrogenate a solution of 0.5 ml of ethyl benzenesulfonamide with 0.05 ml of palladium oxide for 18 hours to obtain hydrogen 64%
of

[(theoretical value 48') was absorbed. The catalyst was filtered off, washed with ethanol, and the resulting liquid was dried under reduced pressure to obtain the target product in the form of a white sponge with a melting point of 88-94°C. Example 2 2-fluoro5-[1-hydroxy-2-[[3-(
4-fluorophenyl)-1-methylpropyl]amino]ethyl]benzenesulfonamide, hydrochloride'a) 5-(2-bromoacetyl)-12-fluorobenzeso sulfosoamide acetic acid 30 5-acetyl-2-fluorobenzene in the ground A solution of 1.0 ml of sulfonamide in acetic acid
In the presence of a few drops of % hydrogen bromide solution, a solution of 0.736% bromine in 4.5% acetic acid was added dropwise, stirred for 15-20 minutes, then the solvent was removed under reduced pressure and the resulting residue 8% solution of sodium bicarbonate dissolved in ethyl acetate for 50 min.
The organic layer was then washed with 50 parts of water and the organic layer was dried with 0.4 M and concentrated to give a pale brown oil which, when crystallized from benzene and acetone, had a melting point of 129-13. ○
1.2 hours of the desired product were obtained. {b) 2-fluoro5-[[bis(phenylmethyl)
Amino]acetyl]benzenesulfonamide, hydrochloride A solution of 1.0% of butanone (bromoacetyl)-2-fluorobenzesulfonamide (1.0%) was added to this while stirring. Amine 1
．． 94 Kite' was added dropwise, stirring was continued for 3 hours at room temperature, the precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was converted to the hydrochloride to obtain 1.01% of the hydrochloride with a melting point of 198-200%. {c1 2-fluoro5
-[1-Hydroxy-2-[[3-(4-fluorophenyl)-1-methylpropyl]amino]ethyl]benzenesulfonamide, hydrochloride ethanol 50 2-fluoro-5-[(bis(phenylmethyl) ) A mixture of 2.2 parts of amino]acetyl]benzenesulfonamide and 3.48 parts of 4-[4-fluorophenyl)-butan-2-one was mixed with 0.2 parts of prereduced 10% palladium oxide supported on activated carbon.
Hydrogenation was carried out at room temperature and pressure in the presence of 0.42 g of 5% platinum oxide supported on activated carbon and 0.42 g of 5% platinum oxide supported on activated carbon until hydrogen absorption ceased. Remove the catalyst and solvent, dissolve the residue in ethyl acetate,
Petroleum ether having a boiling point of 60-80% was added to cause precipitation.
The crude product was mixed with Merck's silica (70-230 mesh) 35
The product was chromatographed in the evening and eluted with ethyl acetate containing 1 tsubo of ammonium hydroxide to 250 ml.
The first fraction 300' was discarded 9E and the next fraction 375' was evaporated to a colorless oil o. 8 evenings passed,
Convert this into hydrochloride, melting point 95-10500 hydrochloride 0
．． I got 85 evenings. In the same manner, 2-fluoro-5-[[bis(phenylmethyl)amino]acetyl]benzenesulfonamide 2.5 and 4-phenyl-butan-2-one were converted into 2-fluoro-5-[[bis(phenylmethyl)amino]acetyl]benzenesulfonamide and 4-phenylbutan-2-one with a melting point of 80-960.
0.4 of 1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide, hydrochloride was converted. Example 3 2-dimethylamino-5-[1-hydroxy-2-[(
1-Methyl-3-phenylpropyl)amino]ethyl]
Benzenesulfonamide, dihydrochloride [a} 5-acetyl-2-dimethylaminobenzenesulfonamide A mixture of 5-acetyl-2-chlorobenzenesulfonamide in 10 parts of ethanol and 5 parts of a 33% dimethylamine solution in ethanol. 1 in a steam bath in an airtight container.
Heating for an hour, the solvent was removed in vacuo, and the residue was crystallized from ethanol to give 0.31 g of the desired product, mp 184-18500. b) 5-Bromoacetyl-2-dimethylaminobenzenesulfonamide A solution of 5-acetyl-2-dimethylaminobenzenesulfonamide in 1 hour of chloroform, 0.75 hours of bromine in 1 hour of chloroform and 48% in acetic acid. Drop the mixture over 2 parts of the hydrogen bromide solution.
It was stirred for an hour and then filtered. The product was a bright yellow solid that decolorized rapidly in sunlight for 2.04 hours. The compound was partitioned between 100' of ethyl acetate and 100' of aqueous sodium carbonate, the organic layer was separated, washed with water, dried over MgSO4, evaporated to dryness, and the residue was recrystallized from ethyl acetate. 1.1 volumes of the desired bromoacetyl compound having a melting point of 142-143°C were obtained. (c1 2-dimethylamino-5-[1-hydroxy-[bis(phenylmethyl)amino]ethyl)benzenesulfonamide, 5-furomoacetyl-2- in butanone hydrochloride 100'
A solution of 2.4 parts of dimethylaminobenzenesulfonamide and 1.5 parts of dibenzylamine and 10 parts of propylene oxide was added.
4. After heating at reflux for an hour, the solvent was removed under reduced pressure. The resulting yellow oil was dissolved in absolute ethanol and treated with sodium borohydride for 1 hour, then the mixture was acidified with dilute hydrochloric acid and the ethanol was removed in vacuo. The residue was extracted three times with 150 parts of ethyl acetate, the organic layer was washed with 100 parts of sodium bicarbonate solution and then with 100 parts of water, then dried over MgSO4, evaporated to dryness, and the residue was dissolved in hydrochloride. After conversion, 1.5% of the hydrochloride salt was obtained, melting point 180-18yo (decomposition). (d) 2-dimethylamino-5-[
1-Hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide, dihydrochloride 2-dimethylamino-5-[1-hydroxy-2-[bis(phenylmethyl)amino] in 300% absolute ethanol) A solution of 4.4 ml of ethylbenzenesulfonamide was mixed with 4-phenylbutan-2-one in a Cook hydrogenation reactor with 0.5 ml of palladium on activated carbon catalyst.
Hydrogenate 3.5 kg/g of the activated carbon-supported platinum catalyst (50 psi) for 1 hour at room temperature, filter off the catalyst, remove the solvent under reduced pressure, and dissolve the resulting residual oil in ethyl acetate. 10 and add 400' of petroleum ether with a boiling point of 60-80 qo to precipitate. The resulting oil was chromatographed on silica (manufactured by Merck) for 30 minutes and dissolved in ethyl acetate containing 10 drops of aqueous ammonia with a specific gravity of 0.88 per 200 mm. The target compound was isolated in the form of a sponge, which was converted to the hydrochloride salt with a melting point of 12
0 to 13,000 hydrochloride salts were obtained. Similarly, 2-dimethylamino-5-[1-hydroxy-2-[bis(phenylmethyl)amino]ethyl]benzenesulfonamide (compound A) was reductively alkylated with the corresponding ketone to obtain the following compound. Compound A2.2 and 1-phenoxypropan-2-one 2.7, melting point 120-130
2-dimethylamino-5-[1-hydroxy-2-[(1-methyl-2-phenoxyethyl)amino]ethyl]benzenesulfonamide, dihydrochloride 1.2 hours and compound A hydrochloride 4.45 hours and 1-(Methylphenylamino)-2-propanone Melting point 130-140 from 7.4 days
2-dimethylamino-5-[1-hydroxy-2
-[(1-Methyl-(methylphenyl)amino)ethyl]amino]ethyl]benzenesulfonamide, trihydrochloride 2.6 hours, compound A hydrochloride 3.9 hours, and 4-fluorobenzylacetone 6.6 hours Melting point 126-1 from evening
34% of 2-dimethylamino-5-[1-hydroxy-2-[(4-fluorophenyl)-1-methylpropyl]amino]ethyl]benzenesulfonamide, dihydrochloride 2.0%. In the case of the last compound, the hydrogenation was carried out for 6 hours instead of 1 hour. Example 4 5-[1-Hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-2-(1-piveridinyl)benzenesulfonamide, dihydrochloride, monohydrate [
a] 5-acetyl-2-(1-piveridinyl)benzenesulfonamide ethanol 50 5-acetyl-2 in the ground
- A solution of 1 part of fluorobenzenesulfonamide and 0.98 parts of piverizine was heated under reflux for 3.5 hours, the solvent was removed and the residue was dissolved in ethyl acetate and 100 parts of water.
Washed twice on each plate, dried at M 04, concentrated and the product crystallized from isopropanol, melting point 130.5~
131.5 ml of the desired product was obtained in 0.92 ml. (b} 5-(2-7lomoacetyl)-2-(1-piveridinyl)benzenesulfonamide, hydrobromide chloroform 100%

[While heating under reflux a suspension of 2 volumes of 5-acetyl-2-(1-piveridinyl)benzenesulfonamide and 2.3 volumes of 48% hydrobromic acid in acetic acid,
A solution of 23 parts of chloroform and 1.13 parts of bromine was added dropwise to this, and the suspension was then stirred for 1 hour, the chloroform was removed with a tumbleweed, and the residue was recrystallized from ethanol and ethyl acetate. A hydrobromide salt of 185-189°C (decomposition) was obtained. While vigorously stirring the suspension of 100 [5-(2-furomoacetyl)-121-(1-piveridinyl)benzenesulfonamide, hydrobromide], add 3-3 of dibenzylamine and 10 of butanone. After 3 hours, the mixture was filtered and the filtrate was concentrated to give a yellow oil. The oil was dissolved in 100% of ethanol and 0.42% of sodium borohydride was added at room temperature. After 1 hour the excess borohydride was destroyed with hydrochloric acid, the ethanol was removed and the residue was made basic with 8% sodium bicarbonate solution and extracted three times with 100 parts of ethyl acetate. The extract was washed with 100 g of water, dried and concentrated, and the resulting pale yellow oil was 2.7 g.
0) Melting point 133-14 after chromatographing at 50 min.
Two white solids of the desired product were obtained. [d} 5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-2-(1-piveridinyl)benzenesulfonamide, dihydrochloride, monohydrate ethanol 200 underground 4-phenylbutan-2-one 1.7
A solution of 3 and 5-[1-hydroxy-2-[bis(phenylmethyl)]amino]ethyl]-2-(1-piveridinyl)benzenesulfonamide and 1.4 mol of ester was heated on activated carbon in a Cooke hydrogenation reactor. Special 10% palladium catalyst 0
．． The mixture was hydrogenated for 2 hours at 40 psi with a mixture of 2.8 kg and 0.28 kg of 5% platinum catalyst on activated carbon. The residual liquid obtained after removal of the catalyst and solvent was dissolved in 5 ml of ethyl acetate, precipitated using 300 ml of petroleum ether having a boiling point of 60 to 80 CO, and the oil was dissolved on silica (Merck) for 30 min. It was chromatographed and eluted with methyl acetate to which was added 1 part aqueous ammonia with a specific gravity of 0.88 to 200'. Isolate the target compound in a sponge-like manner,
This was converted into a hydrochloride to obtain a hydrochloride 800 female with an unclear melting point of 114°C or higher. Elemental analysis value, C, 52.
4%, day, 6.7%, N, 8.0% (C spot day 33N30
3S・Field CI・Ratio Calculated value from 0, C, 52.8%, day, ma. 1%, N, 8.05%) Example 52-diethylamino-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide, dihydrochloride 'a'5-acetyl 2-diethylaminobenzenesulfonamide absolute ethanol 200
A solution of 6.5 ml of 5-acetyl-2-fluorobenzenesulfonamide and 7.0 ml of diethylamine was added to the solution.
Heat under reflux for a while, concentrate the solution under reduced pressure, divide the resulting gum into 100 parts of ethyl acetate and 1 part of water, separate the organic phase and evaporate to dryness to obtain a residue. When ground in isopropanol, the melting point is 103-105
00 Objective Cream-colored crystals of diethylamine compound 5
．． I got 9 nights. {b' 5-Bromoacetyl-2-diethylaminobenzesulfonamide, hydrobromide 5-acetyl-2-
Diethylaminobenzenesulfonamide 5.5 ml, chloroform 275 ml and 48% hydrogen bromide solution in acetic acid 1 ml
1.19 parts of bromine in 110 parts of chloroform was added dropwise to the 3.75% mixture while stirring over a period of 2 hours, the reaction mixture was stirred at room temperature for 1 hour, the chloroform was filtered from the precipitated semi-solid, and The semi-solid was washed with 300 parts of chloroform and then with 400 parts of ethyl acetate.
PurposeWhite crystalline solid of hydrobromide salt of bromoketone8.
Get 4 evenings. This was recrystallized from ethanol and ethyl acetate and had a melting point of 135-13. {c'2-diethylamino-5-[1-hydroxy-2-(dibenzylamino)ethyl]benzenesulfonamide 5-promoacetyl-2-diethylaminobenzenesulfonamide hydrobromide 4.5 hours, dibenzylamine 2 .5', propylene oxide. A solution of 5 and 250 of butanone was heated at reflux for 4 hours, then the solvent was removed under reduced pressure, the residue was dissolved in 150 of absolute ethanol, 0.7 of sodium borohydride was added, and the mixture was brought to room temperature. Stirred overnight, evaporated to dryness in vacuo, acidified with hydrochloric acid, then made basic with sodium bicarbonate, and acetic acid. Extracted with ethyl. The residue obtained by evaporating the extract 6.2 minutes is dissolved in ethanol, treated with an ethereal solution of hydrogen chloride, then evaporated to dryness under reduced pressure, the resulting solid is triturated with ethyl acetate, and the resulting solid is dissolved in ethanol. and ethyl acetate to give 5.02 kg of crude hydrochloride with a melting point of 230-240 qo.
I got the evening. Dissolve 5.02 hours of this salt in warm water, filter it,
Make basic with sodium bicarbonate and dilute the cold solution with ethyl acetate.
Extracted 4 times with 0 birds each, removed the solvent, and obtained a melting point of 133 ~
2.17 hours of a cream solid of the free base was obtained at 135°C. (d} 2-diethylamino-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]
Ethyl]benzenesulfonamide, dihydrochloride 2-diethylamino-5-[1-hydroxy-2-(dibenzylamino)ethyl]benzenesulfonamide 1.17 hours, activated carbon supported 10% palladium oxide catalyst 0.2 hours, activated carbon supported Special 5% platinum oxide catalyst 0.2 hours, 4-phenylbutane-2
- Cook a mixture of 1.48 g and 500' of absolute ethanol at room temperature and 3.5 k9 in a hydrogenation reactor.
Hydrogenation was carried out overnight at 500 ml of water and the catalyst and solvent were removed to give a free-flowing oil. This was chromatographed on a column of silica (70-230 mesh manufactured by Merck) for 35 minutes, and 250 minutes of ethyl acetate was added.
Elution was carried out with ethyl acetate containing 1 pcm of aqueous ammonia with a specific gravity of 0.88. of the first fraction 200'
was discarded, and the next fraction, 270', was concentrated under reduced pressure to give 1.0% of a colorless oil, which was converted to the hydrochloride to give 0.7% of the salt with a melting point of 140-150°C. Similarly, 2-jethylamino-5-[1-hydroxy-2-(dibenzylamino)ethyl]benzenesulfonamide (compound B
) was reductively alkylated with the corresponding ketone to give the following compound. Compound B 2.25 mm and 1-(methylphenylami/)-2-propanone 3.25 mm, melting point 140~
2-jethylamino-5-[1-hydroxy-2-[(1-methyl-2-(methylphenylamino).thyl]amino]ethyl]benzenesulfonamide, trihydrochloride 0.87 at 150°C (decomposition) From compounds BI.9 and 4-fluorobenzylacetone 4.02, 2-jethylamino-5-[1-hydroxy-2-[[1-methyl-]
3-(4-Fluorophenyl)propyl[amino]ethyl]benzenesulfonamide ○-5. The only catalyst for both of these reactions was 10% palladium oxide supported on activated carbon. Example 6 2-Amino-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide, dihydrochloride (a} 5-acetyl-2-aminobenzenesulfonamide ammonia A solution of 0.5 ml of 5-acetyl-2-fluorobenzenesulfonamide in 40 ml of ethanol saturated with 100 ml of ethanol was added in a bomb.
The resulting solution was concentrated and the resulting product was crystallized from ethanol to give the desired compound as a yellow crystalline solid with a melting point of 263-264. {b) 2-Amino-5-[2-furomoacetyl]benzenesulfonamide 0.25% of 2-amino-5-acetylbenzenesulfonamide and 0.523% of cupric bromide in 15% of ethyl acetate and 15% of chloroform The suspension was refluxed overnight, the cuprous bromide was filtered off, the filtrate was concentrated, and the concentrate was dissolved in 20 parts of ethyl acetate and 20 parts of water.
The organic phase was dried and concentrated to give 0 colorless solids.
．． I got 3 nights. Nuclear magnetic resonance spectroscopy of this solid showed it to be a 3:1 mixture of bromoketone and starting material. This solid was used in the next step without further purification. (c'2-amino-5-[1-hydroxy-2-[N
1-(1-Methyl-3-phenylpropyl) 1N-(phenylmethyl)amino]ethyl]benzenesulfonamide 2-amino-5 in 30 units of 2-butanone 1-(2-furomoacetyl)benzenesulfonamide 0.5 units, N-( 1
-Methyl-3-phenylpropyl)-N-(phenylmethyl)amine 0.45% and propylene oxide 2. The solution on the ridge was heated to reflux for 3 hours and then concentrated to give a reddish-brown oil. This was dissolved in 30 parts of absolute ethanol and treated with 258 parts of sodium borohydride for 2 hours at room temperature, then the excess hydride was destroyed with hydrochloric acid and the ethanol was removed under reduced pressure. The residue was made basic with 8% aqueous sodium bicarbonate,
Extracted 3 times with 50 parts of ethyl acetate, and diluted the extract with 10 parts of water.
Washed with [0], dried and concentrated to an orange oily liquid
．． I got 63 nights. This was dissolved in acetone and petroleum ether having a boiling point of 60 to 80 degrees was added to obtain 340 parts of an orange solid. This solid was purified by chromatography on silica plates (Merck ST17) eluting with a 5:1 mixture of chloroform:methanol, converting the product to the hydrochloride salt and yielding 0.2% of the desired compound with a melting point of 133-136°C. I got the evening. [d' 2-amino-5-[
1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino)ethyl]benzenesulfonamide, dihydrochloride ethyl acetate 50' and acetic acid 1' in 2-amino-5-[1-hydroxy-2- A solution of [N-(1-methyl-3-phenylpropyl)-N-(phenylmethyl)amino]ethyl]benzenesulfonamide of 0.2 hours was hydrogenated over a 10% palladium oxide catalyst supported on activated carbon for 200 minutes. did. Hydrogen absorption was 13.5 skin over 80 minutes (theoretical value was 10.6 skin). The catalyst was filtered off, the filtrate was diluted with 150' of dry ether and an ethereal solution of hydrochloric acid was added to give the hydrochloride salt 130'9 of melting point 129-136° (decomposed). Example 7 2-ethylamino-5-[1-hydroxy-2-[(1
-Methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide, sesquihydrochloride'a) 5-acetyl-2-ethylamino-benzenesulfonamide 5-acetyl-2-fluorobenzenesulfonamide 6 in 100% absolute ethanol .0 and 7 of ethylamine
0% aqueous solution 25 mounds of solution in a cylinder at 100 oo
Heat for an hour, concentrate the resulting yellow solution to a small volume, and crystallize the residue from ethanol, melting point 201-204.
An off-white crystalline solid of the desired compound was obtained at 6.0 oz. 'b'5 -(bromoacetyl)-2-ethylbenzenesulfonamide ethyl acetate 100 and chloroform 1
A solution of 2.4% of 5-acetyl-2-ethylaminobenzenesulfonamide in No. 00 was stirred and heated under reflux for 18 hours in the presence of 4.4% cupric bromide, the precipitate was filtered off, and the filtrate was The solvent was removed under reduced pressure. Dissolve the resulting cutlet-colored solid in 200M ethyl acetate,
Washed twice with 10 parts of water, dried and evaporated to dryness. The residue is recrystallized twice from chloroform, melting point 156
1.6 g of an off-white crystalline solid of the desired compound of ~1570 was obtained. {c) 2-ethylamino-5-[1-hydroxy-2-[(1-methyl-3-phenylbropylamino]ethyl]benzenesulfonamide, sesquihydrochloride butanone 70 5-bromoacetyl-2- Ethylaminobenzenesulfonamide 0.96%, N-(1-methyl-3-phenylpropyl)-N-(phenylmethyl)
A solution of 1.4 mol of amino acid and 5 ml of propylene oxide
．． The pale yellow oily liquid obtained by heating under reflux for an hour and removing the solvent under reduced pressure was dropped into 200ml of petroleum ether having a boiling point of 60 to 80 qo to obtain a gummy solid. This was dissolved without further purification over 100 ml of ethyl acetate and 0% palladium on activated carbon catalyst in the presence of 2 chlorides of acetic acid.
．． Hydrogenation was carried out for 18 hours over 3 nights and activated carbon-supported platinum catalyst for 0.3 nights, the catalyst was filtered off, and the resulting colorless solution was treated with an ethereal solution of hydrogen chloride to give a solution with a melting point of 120-12500.
1.0% of the hydrochloride was obtained. Example 8 5-[1-Hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-2-methylaminobenzenesulfonamide, dihydrochloride {a} 5-acetyl-2-[N-methyl- N-phenylmethyl)amino]benzenesulfonamide A solution of 40 ethanol, 0.7 ml of 5-acetyl-2-chlorobenzesulfonamide and 1.1 ml of pendylmethylamine was heated in a bomb at 120 qo for 3 days to produce The red solution was evaporated to a small volume to precipitate pale yellow crystals of the desired compound. This solid was recrystallized twice from absolute ethanol to give 0.4 g of an off-white crystalline solid with a melting point of 159-16 RO. 'b) 5-bromoacetyl-2-methylamine/benzenesulfonamide ethyl acetate 50 [in cupric bromide 1
．． While stirring the suspension heated under reflux for 4 days, a solution of 0.96 parts of 5-acetyl-2-(N-methyl-N-phenylmethylamino)benzenesulfonamide in 40 parts of chloroform was added little by little over 3 minutes. and the resulting mixture was stirred for an additional hour while heating to reflux. The precipitated cuprous bromide was filtered off, the solution was evaporated to dryness, and the resulting dark-colored oil was filtered through 50% chloroform diatomaceous solution, and the filtrate was evaporated to dryness to give a yellow color. 0.9% of the sponge was obtained. This was recrystallized twice with chloroform to obtain 0.6% of the target compound with a melting point of 170-17〆C (decomposition). {c) 5-[1-Hydroxy-2 one〔
(1-Methyl-3-phenylpropyl)amino]ethyl]-2-methylaminobenzenesulfonamide, 5-bromoacetyl-2-methylaminobenzenesulfonamide in dihydrochloride butanone 70% and N-benzyl 4. A solution of 1.2 ml of 2-amino-4-phenylbutane was mixed with 5 ml of propylene oxide. After heating under reflux for a period of time, the solvent was removed under reduced pressure, and the resulting pale yellow liquid had a boiling point of 60~
Dropwise into 800C petroleum ether loo to obtain a gummy solid. This solid was not purified and was directly diluted with 100% ethyl acetate [
and dissolved in acetic acid, 0% palladium catalyst supported on activated carbon.
．． Hydrogenation was carried out for 3 nights and 0.3 nights using a special platinum catalyst supported on activated carbon for 1 hour. Hydrogen absorption is 200 pine [(theoretical absorption value is 1
It was 45 [). The catalyst was filtered off and the resulting colorless solution was treated with an ethereal solution of hydrogen chloride to precipitate a white solid. The solid turned pink after a few minutes. When this solid is filtered and dried under vacuum, it has a melting point of 115-125q.
1.0 kg of a brown solid of the desired compound was obtained. Example
9 2-chloro-5-[2-[[3-(4-fluorophenyl)-1-methylpropyl]amino-1-hydroxyethyl]benzenesulfonamide, hydrochloride, hydrate [a
]2-chloro5-[2-([3-(4-fluorophenyl)-1-methylpropyl]phenylmethyl]amino]-1-hydroxyethyl]benzenesulfonamide,
A solution of 2.0 mol of 5-furomoacetyl-2-chlorobenzenesulfonamide in 60 mol of hydrochloride acetone was prepared from N-[31(4
-fluorophenyl)-1-methylpropyl]-N-(
After treatment with phenylmethyl)amine for 1 hour at about 20:00, the acetone was removed in vacuo and the resulting oil was triturated with dry ether. The solid hydrobromide was filtered, the ether solution was evaporated to dryness, and the resulting residue was dissolved in 40 mL of ethanol.
The mixture was treated with 1.0 mL (4.0 eq.) of sodium borohydride and the mixture was stirred at room temperature for 2 hours before being acidified with hydrochloric acid and the ethanol was removed under reduced pressure. The pH was immediately adjusted to 10 by adding sodium hydroxide solution, the mixture was extracted three times with 100 ml of ethyl acetate, the organic layer was washed twice with 30 parts of water, dried with M 0.4 and evaporated to dryness. After solidification, the resulting oil was washed with preparative silica brate. matographed,
The main components were separated and treated with an ethereal solution of hydrogen chloride to give the desired compound as a white solid with a melting point of 110-120 qo.
I got 7 nights. {b1 2-chloro-5-[2-[[3-(4-fluorophenyl)-1-methylpropyl]amino]-1-. Hydroxyethyl]benzenesulfonamide, hydrochloride, hydrate 2-chloro-5-[2-[[3-(4-fluorophenyl)-1] in absolute ethanol 30%
-Methylpropyl]phenylmethyl]amino]-1-hydroxyethyl]benzenesulfonamide, hydrochloride 0.
The 2-day solution was mixed with a 10% palladium oxide catalyst supported on activated carbon.
Using 9 of 0, the absorption rate of hydrogen virtually ceases, and hydrogen 1
Hydrogenation was carried out until 5% of the solution was absorbed, and the filtrate was evaporated under reduced pressure to obtain 0.13% of the desired compound as a white brittle solid. Elemental analysis C, 47.5%, day, 5.3%, N, 5.9%
(Calculated value from C, 8th 22CIFN203S・HC1・day 20, C, 47.7%, day, 5.5%, N, 6.1
%) Example 102-dimethylamino-5-[2-[[
3-(3-fluorophenyl)-1-methylpropyl]
Amino]-1-hydroxyethyl]benzenesulfonamide, dihydrochloride 5-[2-
[Bis(phenylmethyl)amino]-1-hydroxyethyl]121[dimethylamino]benzenesulfonamide 2.2 times the amount of 41(3-fluorophenyl)-butan-2-one 3.3 times the activated carbon-supported palladium catalyst. Hydrogenation was carried out for 1 hour at 3.5 k9/ground (50 PSi) using 0.5 min and activated carbon-supported platinum catalyst for 1 hour.
The catalyst was filtered off, and the solvent was evaporated under reduced pressure. The resulting colorless oil was chromatographed on a silica gel column and eluted with ethyl acetate containing 1 quot of ammonia per 250 ml of ethyl acetate. A spongy target product was obtained. This was dissolved in ethyl acetate, dissolved in ether of hydrogen chloride, and treated with an ethereal solution of hydrogen chloride, melting point 115-
1.25 quarts of a white amorphous solid of 1125 quarts of hydrochloride was obtained. Example 112-(butylmethylamine/)-5
-[1-Hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide, dihydrochloride 5-[[bis(phenylmethyl)amino)acetyl]-2-fluorobenzene in 150 ml of ethanol A solution of the sulfonamide, hydrochloride salt, 3 parts and methylbutylamine, 2 parts was heated under reflux for 1 hour, the ethanol was removed and the resulting residue was dissolved in 150 parts of ethyl acetate and 20 parts of 8% aqueous sodium bicarbonate. ', then water 20
The solution was concentrated to a small volume and 520 kg of petroleum ether, boiling point 60-80 qo, was added to precipitate 1.8 qo of a reddish-brown gum. This was dissolved in 150 parts of ethanol, and this solution was dissolved in 4-phenylbutan-2-one 4 in 150 parts of ethanol.
．． In addition to the solution of 10% palladium oxide on activated carbon, 0.7% palladium oxide catalyst on activated carbon and 0.7% platinum oxide catalyst on activated carbon.
2.8k9/earth (4
Hydrogenation was carried out for 2 hours using a vacuum cleaner. The fluid yellow oil obtained by removing the catalyst and solvent was transferred to a silica column (
Merck, Art 7734) After chromatography at 75°C and eluting with 500°C of ethyl acetate, the desired product was a 9:1 mixture of ethyl acetate and methanol containing traces of aqueous ammonia with a specific gravity of 0.88. By elution with falcon solution, a colorless sponge was obtained in a yield of 0.35 min. This is dissolved in ethyl acetate and treated with an ethereal solution of hydrogen chloride (5) to give a hydrochloride having a melting point of 105-110°C. Example 12 2-fluoro-5-[1-hydroxy-2-[[3-(
3-Fluorophenyl)-1-methylpropyl[amino]ethyl]benzenesulfonamide, hydrochloride, hemihydrate Hot water ethanol 100 must-have 5-[[bis(phenylthyl)amino]acetyl]-2-fluorobenzene A solution of 2.4 mol of the sulfonamide and 2.9 mol of the 4-(3-fluorophenyl)butan-2-one was prepared by prereducing 5
%Pt/CO. 5 and 10% Pd/CO. Hydrogenation was continued for 6 hours using 5 hours and 6 hours until the reaction was judged to be complete by thin layer chromatography. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The resulting blue-white oil was chromatographed on silica (Kieselgel 60, 70, 230 mesh) at 100 mL, and the column was filled with ethyl acetate containing traces of ammonia. The sample was eluted with a mixture of 10% methanol and ethyl acetate at 600 ml. Oily liquid 1 obtained by concentrating the latter dissolved acid solution under reduced pressure
．． When the mixture was triturated with ethyl acetate and petroleum ether having a boiling point of 60-80 ml, a blue-white, highly viscous gum was obtained.
This was dissolved in ethyl acetate and treated with an ethereal solution of hydrogen chloride to give a brittle solid of the desired hydrochloride salt, mp 65-8500. Elemental analysis C, 50.5%, day,
5.7%, N, 6.5%〈C. 8th 22F203S-H
CI-calculated value from back day 20, C, 50.3%, day, 5
．． 4%, N6.5%) Example 13 5-[1-Hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl-21(1-pyrrolidinyl)benzenesulfonamide, dihydrochloride, sesquiwater compound (a} 5-[2-[bis(phenylmethyl)ami/]
-1-hydroxyethyl]-2-(1-pyrrolidinyl)
Benzenesulfonamide, dihydrochloride 5-[[bis(phenylmethyl)amino]acetyl]-12-fluorobenzenesulfonamide, hydrochloride 0.5, pyrrolidine 0.
2033' and anhydrous ethanol 30% mixture
The mixture was refluxed for an hour, an additional 0.101' of pyrrolidine was added, and the solution was heated at reflux for an additional 2 hours. The solution was allowed to cool, 0.168 g of sodium borohydride was added in one portion, and after 2 hours the mixture was evaporated to dryness, acidified with hydrochloric acid, made basic with sodium bicarbonate, and diluted with 40 g of ethyl acetate. Extract 4 times, combine the extracts, wash with 25 cm of water, dry with MgSO4, evaporate to dryness, and transfer the resulting cream-colored sponge-like material to silica gel (Kiesel gel 6, 70-230 mesh). Chromatographing with 250 g of a 1:1 solution of cyclohexane and ethyl acetate and evaporating the solvent gave the desired compound as a pale cream spongy solid with a melting point of 45-55 mm. I got the evening. Others 51 [1-hydroxy-21 [(1-methyl-3-
phenylpropyl)amino]ethyl-2-(1-pyrrolidinyl)benzenesulfonamide, dihydrochloride, sesquihydrate absolute ethanol 400 units
phenylmethyl)amino]-1-hydroxyethyl]-
2-(1-pyrrolidinyl)benzenesulfonamide 3.
After 5 days, a solution of 4.43 parts of 4-phenylbutan-2-one and 1 part of glacial acetic acid was mixed with 0.5 parts of 10% palladium oxide catalyst on activated carbon and 0.5 parts of 5% platinum oxide catalyst on activated carbon.
In the presence of 5 evenings, 3.5 kg/(5 temporary sj), 18-2
Hydrogenation was carried out at 0oo. Formation of the major product was monitored by thin layer chromatography and the reaction was judged to be complete in 118 hours. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the resulting oily liquid was chromatographed on a silica column (Kieselgel 60, 70-230 mesh) for 50 minutes and separated as follows. 1 Ethyl acetate, 450' 2 10% methanol/ethyl acetate + NH40H*45
0 above 3 10% methanol/ethyl acetate 10NH40H
*300' (* stands for 10% methanol/ethyl acetate 25
Ammonium hydroxide fraction 3 with a specific gravity of 0.88 to 0.0 was evaporated to give a cream colored sponge with a melting point of 50-6500. This was dissolved in ethyl acetate and treated with an ethereal solution of hydrogen chloride to obtain 0.4% of the desired dihydrochloride having a melting point of 140-150°C.
I got 5 nights. Example 14 2-(ethylmethylamino)-5-[1-hydroxy-
2-[(1-methyl-3-phenylpropyl)amino]
Ethyl]benzenesulfonamide, dihydrochloride [al 5
1[2-[bis(phenylmethyl)amino]-1-hydroxyethyl]-2-(ethylmethylamino)benzenesulfonamide "5-[[bis(phenylmethyl)amino] in dihydrochloride anhydrous ethanol loo") Acetyl]
A mixture of 1.0 μm of -2-fluorobenzenesulfonamide and 0.53 μm of ethylmethylamine was heated in an autoclave at 10,000 °C overnight. Cool the brown solution and add 0.33% of sodium borohydride.
I stirred it for 6 nights and an hour. The mixture was evaporated to dryness, acidified with hydrochloric acid, made basic with sodium bicarbonate, extracted four times with 50' of ethyl acetate, the extract was dried, and the solvent was evaporated to give a brown gum. 1. The cream obtained by chromatography on silica gel (Kiesel Gel 60, 70-230 mesh) for 30 days, eluting with 500 g of a mixture of 20% ethyl acetate/cyclohexane, and evaporating the solvent of the melt. 0.5 ml of a colored spongy solid was dissolved in ethyl acetate, treated with an ethereal solution of hydrogen chloride, crystallized from ethanol and ethyl acetate, mp 188-19
0.26 g of an off-white solid of the desired compound of 0.0C was obtained. (b} 2-(ethylmethylamino)-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)]
Amino]ethyl]benzenesulfosamide, dihydrochloride 5-[2-[bis(phenylmethyl)amino]-1-hydroxyethyl)-2-(
Ethylmethylamino)benzenesulfonamide 1.68
1, 2 4-phenylbutane-2-one and 2 glacial acetic acid
Desk mixture on activated carbon with 10% palladium oxide catalyst 0
．． 3.5k9/ground (50psi) in the presence of 2 evenings, 18~
Hydrogenation was carried out at 20q0 for 4 hours. The catalyst was collected by filtration, and the filtrate was evaporated under reduced pressure. The pale brown oily liquid obtained was divided into 25 parts of 8% sodium bicarbonate and 25 parts of ethyl acetate, and the ethyl acetate layer was separated. ,
Washed with 10 parts of water, dried and evaporated in vacuo to give 2.7 parts of a light brown oil. 1.3% of the crude product was mixed with silica (Kieselgel 60, 70~
230 mesh) for 26 days and elution was performed as follows. 1 Ethyl acetate 75' 2 10% methanol/ethyl acetate + NH40H*12
5 Secretion 3 10% methanol/ethyl acetate 10NH40H*
Cream-colored spongy solid obtained by evaporating fraction 3 of 150% (*10% methanol/ethyl acetate 1 part ammonium hydroxide with a specific gravity of 0.880 to 250%) was dissolved in ethyl acetate and treated with an ethereal solution of hydrogen chloride to give 1.10 kg of the desired compound as a yellow solid with a melting point of 130-150 Qo. Elemental analysis, C, 51.7%, Sun, 7.1%, N, 7.8
% (C2, day 3, N30S/plaque Cl/1' spot tOAC:
Calculated value from 2'3 day 20, C, 51.6%, day, 7.
2%, N, 8.1%) Preparation example [a} Tablet {1} Prescription for preparing tablets containing 9 of 20 medicinal ingredients, British Pharmacopoeia microcrystalline cellulose 795 and British Pharmacopoeia Magnesium Stearate are thoroughly mixed and the powder is compressed in a suitable tablet press to produce tablets of 6.5 ribs in diameter and approximately 100 tablets in weight. (2- Tablets containing 9 out of 100 medicinal ingredients, 1000
Prescribed medicinal ingredients for making Tsuchiyado: 1000 yen, British Pharmacopoeia lactose 250 yen, and British Pharmacopoeia dried corn starch 172.5 yen.
Mix well. English corn starch with gelatin added in advance 7
Moisten the powder mixture by dispersing it in cold water to form a moist sticky mass, and mix the moist mass with British standard fluid #
14 and dry the resulting grains at 6000 °C. The dry granules are then passed through a #22 mesh filter using a British standard filter and mixed with 7.5 grams of magnesium stearate. The lubricated granules are compressed in a suitable tablet-making press to produce 9 tablets, each 8 willow in diameter and weighing approximately 150.
Tablets may be coated with a suitable film-forming agent such as methylcellulose or hydroxypropylmethylcellulose using standard techniques. Tablets can also be sugar-coated. (b' Capsules When manufacturing 10,000 capsules each containing 50 parts of the medicinal ingredient, 500 parts of the prescription medicinal ingredient is mixed with 700 parts of microcrystalline cellulose in the British Pharmacopoeia, and each capsule contains about 120 parts of the mixture. Fill into a No. 3 hard gelatin capsule as follows. Dissolve 7.5 ml of sodium chloride and make 1 ml with water for injection. Divide the solution into ampoules of appropriate size, e.g. 1.5 or 10 ml, seal and sterilize by heating in an autoclave. The medicinal ingredient in the composition can be any compound of the present invention.The biological effects are as shown in Table 1 below. -It represents a blocking effect on adrenoreceptors.Anesthetized dogs with bilateral escape nerves cut were used as experimental animals, and each compound was injected through a cannulated femoral vein.8-Flocking of compounds The effect (
1) DR, from the results obtained, as determined from its ability to counteract the increase in cardiac thinness induced by intravenous injection of isoprenaline. The value was calculated. DR. The value is (1) isoprenaline dose-1 to the right side of the response curve for the increase in mandrel frequency.
is the dose of compound required to produce any of the sounds.
TABLE 1 Toxicity The compounds of the invention generally exhibited no toxicity at therapeutically effective doses. The test results are shown in Table 2. No adverse effects were observed on dogs when the compounds of the present invention were administered intravenously to dogs at the doses shown in Table 2. Table 2

Claims (1)

[Claims] 1. A compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 is chlorine, fluorine, amino,
C_1-C_4 alkylamino, di-C_1-C_4 alkylamino, piperidino or pyrrolidino, X is -CH_2-, -O- or -N(CH_3)-, R_5 is hydrogen or fluorine, and Y is SO_
2NH_2] and physiologically acceptable non-toxic salts thereof. 2 Compounds represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [wherein R_1, R_5 and A compound according to claim 1 which is a non-toxic salt. 3. The compound according to claim 1 or 2, wherein R_1 is chlorine, fluorine, amino, C_1-C_4 alkylamino, di-C_1-C_4 alkylamino, piperidino, or pyrrolidino. 4. The compound according to any one of claims 1 to 3, wherein R_5 is hydrogen or fluorine. 5. The compound according to claim 4, wherein R_5 is p-fluoro. 6. A compound according to any one of claims 1 to 5, wherein X is -CH_2-. 7 2-fluoro-5-[1-hydroxy-2-[[3
-(4-fluorophenyl)-1-methylpropyl]-
The compound according to claim 1, which is amino]ethyl]benzenesulfonamide. 8 2-Fluoro-5-[1-hydroxy-2-[(1
-Methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide. 9 2-dimethylamino-5-[1-hydroxy-2-
Claim 1 which is [(1-methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide
Compounds described in Section. 10 2-amino-5-[1-hydroxy-2-[(1
-Methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide. 11 5-[1-hydroxy-2-[(1-methyl-3
-Phenylpropyl)amino]ethyl]-2-methylaminobenzenesulfonamide Claim 1
Compounds described in Section. 12 The compound according to claim 1, which is 2-(butylmethylamino)-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide. 13 2-fluoro-5-[1-hydroxy-2-[[
3-(3-fluorophenyl)-1-methylpropyl)
The compound according to claim 1, which is amino]ethyl]benzenesulfonamide. 14. The compound according to claim 1, which is 2-(ethylmethylamino)-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzenesulfonamide. 15 Active ingredients include one or more compounds represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc.
1-C_4 alkylamino, piperidino or pyrrolidino, and X is -CH_2-, -O- or -N(CH
_3)-, R_5 is hydrogen or fluorine, and Y is SO_2NH_2] or a physiologically acceptable non-toxic salt thereof together with a physiologically acceptable carrier or diluent. - Pharmaceutical compositions for blocking adrenoceptors. 16. The composition of claim 15 in unit dosage form, each unit containing from 5 to 1000 mg of active ingredient. 17. The composition according to claim 16, wherein each unit is 20 to 200 mg.