JPH0212216B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel phenethylamine derivative represented by the following general formula (I) and an acid addition salt thereof. (In the formula, R is a lower alkyl group, a lower alkoxy group, or a hydroxyl group, R ₁ is a hydrogen atom, a hydroxyl group, or a halogen atom, R ₂ is a hydrogen atom or a lower alkyl group, and R ₃ is a hydrogen atom or a lower alkyl group. However, when R is a hydroxyl group, R ₃ means a hydrogen atom. The same shall apply hereinafter) In the definition of the group in the above general formula (I) and the general formula below, the word "lower" refers to a group having 1 to 5 carbon atoms. means a straight or branched carbon chain having Therefore, examples of lower alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, amyl group, etc., and examples of lower alkoxy groups include methoxy group, ethoxy group, propoxy group. , isopropoxy group, butoxy group, etc. Further, specific examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and the like. The compound of the present invention represented by the above general formula (I) forms an acid addition salt. The present invention also includes pharmacologically acceptable acid addition salts of the compound of general formula (I), and specific examples of such acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, Acid addition salts with mineral acids such as phosphoric acid and organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, etc. Can be done. Further, the compounds of the present invention include compounds having an asymmetric carbon atom, and such compounds exist in various optical isomers. The present invention includes all such isomers. The compound represented by the above general formula (I) and its acid addition salt can be produced by the methods exemplified below. First manufacturing method (manufacturing method of primary amino compound) (In the formula, X and Y mean the same or different halogen atoms. The same applies hereinafter.) Here, specific examples of the halogen atom represented by X include an iodine atom, a bromine atom, and a chlorine atom. Moreover, Y means the same group as the halogen atom represented by R ₁ . Each step will be sequentially explained below. First step This step involves reacting the α-halogenoacetophenone derivative represented by the general formula () with sodium azide () to form the α-halogenoacetophenone derivative represented by the general formula ().
- This is a process for producing an azidoacetophenone derivative. The reaction is usually carried out in a water-containing organic solvent of methanol, ethanol, isopropanol, dioxane, diethylene glycol monoethyl ether, etc. and water, preferably methanol-water (e.g., volume ratio 5:1).
The reaction is carried out in a mixed solvent of , by heating on a water bath or a steam bath. Second Step The compound represented by the general formula (V) can be produced by reducing the compound () obtained in the first step. Examples of the reducing agent used here include complex metal hydrides such as sodium borohydride and diborane. The reaction is preferably carried out in an organic solvent inert to the reaction at room temperature or cooling. Suitable examples of such organic solvents include methanol, ethanol, isopropanol, dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran. Third step 5- represented by general formula (Ia) in the compound of the present invention
The (2-amino-1-hydroxy)benzenesulfonamide derivative is produced by reducing compound (V). In this reduction reaction, it is advantageous to carry out hydrogenation in an organic solvent such as methanol, ethanol, toluene, acetonitrile, or tetrahydrofuran in the presence of a reduction catalyst such as platinum, palladium, or palladium-carbon. The reaction is usually carried out at room temperature and pressure, and can also be carried out by adding a small amount of acid to promote the reaction. In addition, the compound (Ic) in which R ₁ is a hydrogen atom in the general formula (I) can also be produced by the same treatment using the corresponding azide compound as a raw material for this reaction. Fourth step 5- represented by general formula (Ib) in the compound of the present invention
The (2-amino-1-halogeno)benzenesulfonamide derivative is the compound (Ia) obtained in the third step.
It is produced by halogenating. The reaction is carried out in an organic solvent inert to the reaction, such as toluene, xylene, acetone, methyl ethyl ketone, acetonitrile, and tetrahydrofuran, at room temperature or at elevated temperatures, using thionyl chloride, hydrochloric acid, hydrobromic acid,
This is carried out by treatment with a halogenating agent such as phosphorus pentachloride, phosphorus trichloride, or thionyl bromide. Fifth Step The compound of the present invention represented by the general formula (Ic) can be produced by reducing the compound (Ib). This reaction is carried out in the same manner as the third step. Second manufacturing method (manufacturing method of secondary amino compound) (In the formula, R ₄ represents a lower alkyl group, and Z represents a hydrogen atom or a benzyl group. The same applies hereinafter.) Each step will be explained in sequence below. First step Among the compounds of the present invention, the compound represented by the general formula (Id) is produced by reducing the α-secondary amino-substituted acetophenone compound represented by the general formula (). When a compound in which Z is a hydrogen atom is used as a raw material, as in the second step of the first production method, it is heated in an organic solvent inert to the reaction, such as methanol, ethanol, isopropanol, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, etc., under cooling. It is appropriate to treat with a reducing agent such as sodium borohydride or a complex metal hydride such as diborane at room temperature. When Z is a benzyl group, it is reduced using a reducing agent such as a complex metal hydride in the same manner as in the above reaction, and then catalytic hydrogenolysis is carried out by a conventional method using palladium-carbon as a catalyst, or the compound ( ) can be reduced in one step by catalytic hydrogenation in the presence of a catalyst such as palladium-carbon to produce compound (Id). Second step This step is a step of halogenating the compound (Id) obtained in the first step to produce the corresponding halogen compound (Ie) of the present invention, and can be carried out in exactly the same manner as the fourth step of the first production method. Can be done. Third step The compound represented by general formula (If) is produced by reducing compound (Ie). This reaction is also carried out in exactly the same manner as the third and fifth steps of the first production method. In addition to the first and second production methods described above, the compounds of the present invention can also be produced by various methods in consideration of the characteristics of each substituent. For example, the compound represented by the general formula (Id) can also be produced by reacting a corresponding halohydrin compound or epoxide compound with a lower alkylamine in an organic solvent such as ethanol at room temperature or under heating, preferably under reflux. sell. The object compound of the present invention thus produced is isolated and purified as it is or in the form of its acid addition salt. Isolation and purification are performed by applying any conventional chemical operations such as concentration, crystallization, extraction, column chromatography, etc. The compound represented by the general formula (I) and its acid addition salt provided by the present invention exhibit a pressor effect without side effects such as increased heart rate and heart palpitations, and can be used to treat diseases such as hypotension. It is useful as an advantageous pressor agent. These pharmacological effects of the compounds of the present invention were confirmed by the following test methods. Test method Male Wistar rats (weighing around 300g) were given
The animals were anesthetized by intraperitoneally administering 1 g/Kg of urethane. A cannula was inserted into the femoral artery, blood pressure was measured with a pressure transducer (MPU-0.5, manufactured by Nihon Kohden), and heart rate was recorded using a blood pressure pulse wave with a heart rate monitor (RT-5, manufactured by Nihon Kohden). did. To induce hypotension, 5 mg/Kg of pentolinium was administered intravenously, and the test drug was administered through the femoral vein. Results The test results are shown in Table 1.

[Table] A pharmaceutical composition containing as a main component the compound (I) of the present invention and one or more of its acid addition salts can be prepared by any conventional method using any conventional excipients or carriers. Clinical administration is usually by intravenous injection or orally. The dosage depends on the age of the recipient,
The dosage is determined as appropriate considering gender, severity of disease, etc., but the usual daily dose for adults is 1 to 10 mg by intravenous injection, or by oral administration.
The dose is 10 to 100 mg, which is administered in 1 to 3 divided doses. EXAMPLES The present invention will be described in further detail by way of Examples below. Note that mp in the text means melting point. Example 1 (a) 4'-methoxy-3'-sulfamoyl-2-bromopropiophenone 7g, sodium nitride
Dissolve 3.5 g, 50 ml of methanol, and 10 ml of water by heating at 50°C on a water bath. The reaction solution was cooled, the crystals formed were collected, washed with water, and then added with 50 ml of isopropanol.
The residue was washed with water and dried to obtain 6 g of 4'-methoxy-3'-sulfamoyl-2-azidopropiophenone with a mp of 141 to 142°C. (b) 18 g of 4'-methoxy-3'-sulfamoyl-2-azidopropiophenone and 200 ml of methanol
Suspend sodium borohydride under cooling stirring
Add 3g. After standing at room temperature for 15 hours, methanol was distilled off under reduced pressure and 100ml of ethyl acetate and 100ml of water were added.
The ethyl acetate layer was subjected to silica gel column chromatography, eluted with ethyl acetate, and the 5-(2-azido-1-hydroxy-2-methylethyl)- 2-
12 g of methoxybenzenesulfonamide was obtained. (c) 5-(2-azido-1-hydroxy-2-
Dissolve 8.3 g of (methylethyl)-2-methoxybenzenesulfonamide in 100 ml of methanol to give a 10%
- Hydrogenation using 0.2 g of palladium on carbon.
Separate palladium on carbon, neutralize with ethanol and hydrochloric acid, remove methanol under reduced pressure, and add 20ml of ethanol.
Recrystallization was performed to obtain 5.8 g of 5-(2-amino-1-hydroxy-2-methylethyl)-2-methoxybenzenesulfonamide hydrochloride. This product has the following physical and chemical properties. (i) Melting point 208-210℃ (ii) Elemental analysis value (as C ₁₀ H ₁₇ N ₂ O ₄ SCl) C (%) H (%) N (%) Calculated value 40.47 5.77 9.44 Actual value 40.27 5.83 9.22 ( iii) Nuclear magnetic resonance spectrum ( _CD3OD ) δ: 1.05-1.17 (3H, q, CH- CH3 ) 3.38-3.60 ( _1H , m, _CH3 - CH ) 3.98 (3H, s, O-C H ₃ ) 4.54-5.04 (1H, q, O-C H ) Example 2 5-(2-amino-1-hydroxy-2-methylethyl)-2-methoxybenzenesulfonamide hydrochloride (5 g) was suspended in 500 ml of acetonitrile and 5 ml of thionyl chloride was added at room temperature with stirring. Once dissolved, crystals formed. Crystallizes. After stirring for an additional 3 hours, it was cooled and collected to give 5-(2-amino-
4.1 g of 1-chloro-2-methylethyl)-2-methoxybenzenesulfonamide hydrochloride was obtained. This product has the following physical and chemical properties. (i) Melting point 216℃ (decomposition) (ii) Elemental analysis value (as C ₁₀ H ₁₆ N ₂ O ₃ SCl ₂ ) C (%) H (%) N (%) Calculated value 38.10 5.12 8.89 Actual value 37.94 5.16 9.16 (iii) Nuclear magnetic resonance spectrum (d ₆ -DMSO) δ: 1.08 (3H, d, CH- CH ₃ ) 3.82 (3H, s, O- CH ₃ ) 5.35 (1H, d, Cl- CH ) Example 3 2.5 g of 5-(2-amino-1-chloro-2-methylethyl)-2-methoxybenzenesulfonamide hydrochloride is dissolved in 200 ml of methanol and hydrogenated using 0.1 g of 10% palladium on carbon. After separating the palladium on carbon and distilling off the methanol under reduced pressure, it was recrystallized from methanol to give 5-(2-amino-
1.5 g of 2-methylethyl)-2-methoxybenzenesulfonamide hydrochloride was obtained. This product has the following physical and chemical properties. (i) Melting point 305℃ (ii) Elemental analysis value (as C ₁₀ H ₁₇ N ₂ O ₃ SCl) C (%) H (%) N (%) Calculated value 42.78 6.10 9.98 Actual value 42.63 6.13 9.82 (iii) Nuclear magnetic resonance spectrum (CD ₃ OD) δ: 1.25 (3H, d, CH- CH ₃ ) 3.96 (3H, s, O- CH ₃ )

[Table] Example 7 5-promoacetyl-2-methylbenzenesulfonamide 4.4g, N-benzylmethylamine 3.6g
and 50ml of ethanol, stirring for 20 minutes.
Heat to reflux for minutes. After cooling, ethanol was distilled off under reduced pressure, ethyl acetate was added to the resulting residue, the precipitated N-benzylmethylamine hydrobromide was separated, ethyl acetate was distilled off, and the resulting oil was added with ethanol. Add 20ml and stir under ice cooling to precipitate crystals. Separately, dissolve it as it is in 50 ml of methanol, add 0.4 g of sodium borohydride under ice cooling, stir at room temperature for 20 minutes, and then distill off the methanol under reduced pressure. The residue was dissolved in ethyl acetate, the ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give an oily 5-{[1-hydroxy-2-
(N-benzyl-N-methyl)amino]ethyl}-
2.2 g of 2-methylbenzenesulfonamide is obtained.
Dissolve this in 25 ml of methanol, add 0.3 g of 10% palladium on carbon, and perform catalytic reduction at room temperature and pressure. After absorbing the theoretical amount of hydrogen, the palladium on carbon is separated, a solution of 0.6 g of oxalic acid dissolved in 6 ml of methanol is added to the solution, and the solvent is distilled off under reduced pressure to obtain 2.1 g of colorless crystals. Recrystallize from 30ml of ethanol,
1.8 g of colorless crystals of 5-[(1-hydroxy-2-methylamino)ethyl]-2-methylbenzenesulfonamide oxalate are obtained. This material has the following physical and chemical properties. (i) Melting point 112-115℃ (ii) Elemental analysis value (as C ₁₂ H ₁₈ N ₂ O ₇ S) C (%) H (%) N (%) Calculated value 43.11 5.43 8.38 Actual value 43.49 5.30 8.17 ( iii) Nuclear magnetic resonance spectrum ( _d6 -DMSO) δ: 2.44 (3H, s,

[Formula] or N- C H ₃ ) 2.54 (3H, s,

[Formula] or N- C H ₃ ) 4.86 (1H, m, > C H OH)

Claims (1)

[Claims] 1. General formula (In the formula, R is a lower alkyl group, a lower alkoxy group, or a hydroxyl group, R ₁ is a hydrogen atom, a hydroxyl group, or a halogen atom, R ₂ is a hydrogen atom or a lower alkyl group, and R ₃ is a hydrogen atom or a lower alkyl group. (However, when R is a hydroxyl group, R ₃ means a hydrogen atom.) A phenethylamine derivative or an acid addition salt thereof.