JPS63435B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to heterocyclic amino alcohol derivatives, including substituted amino-alcohols, their esters and their salts, and processes for their preparation, as well as to pharmaceutical compositions containing at least one such derivative. Conventionally, amino alcohol derivatives have the formula shown in British Patent No. 1013224: A compound of formula: The compound shown in this formula (2) is described.
R ¹ is hydrogen, and both of the above compounds (1) and (2) are ethanol amino type derivatives, and R ₂ in the general formula described below is not always hydrogen, that is,
The chemical structure is different from the derivatives of the present invention, which are directed toward higher alkanol and amino derivatives. For this reason, the conventional compounds mentioned above have β-blocking activity, but
Significant anti-hypertensive activity (anti-
hypertensive activity). On the other hand, the compounds of the present invention, which will be described later, do not have β-blocking activity and, moreover, have anti-hypertensive activity, so they are useful for treating various pathological conditions such as hypertension. Such amino alcohol derivatives of the invention have the following general formula: (In the formula, (a) R ₁ represents hydrogen, one or two straight chain or branched alkyl groups (C ₁ to C ₃ ), phenyl group or carboxy group. (b) R ₂ represents a straight chain or Branched alkyl group ( _C1 - _C3 )
shows. (c) R ₃ is: - mono- or polyunsaturated alkenyl group (C ₃ -
C ₁₈ ); - Mono- or polyunsaturated alkenyl groups (C 3 to C 12 ) substituted with oxygen, sulfur or phenyl groups; - Mono- or polyunsaturated alkynyl groups (C _{3 to} C ₁₂ );
_C18 ) - Mono- or polyunsaturated alkynyl groups substituted with oxygen, sulfur or phenyl groups ( _C3 - _C12 ) - Cycloalkyl groups ( _C3 - _C10 ) - Straight-chain or branched alkyl groups (C2 ₎ ~ _C20 ) - indicates a straight-chain or branched alkyl group ( _C2 - _C18 ) substituted with at least one atom and/or group selected from the following groups: (1) oxygen or sulfur; 2) Alkoxycarbonyl group (C ₁ - _{C 3} ), pyrrolidine, pyrrolidinone or imidasolidone (3) Phenyl, phenoxy, phenylthio, benzoyl, indanyloxy, naphthyloxy group (4) One or more alkyl groups (C ₁ - _C4 )
or an alkoxy (C ₁ -C ₄ ) group with 1 or 2 halogen atoms, nitrile, hydroxy, amino, alkanoyl (C ₂ -C ₆ ), acylamino (C ₂ -C ₄ ), alkoxycarbonyl (C ₁ -C ₄ ) or phenyl, phenoxy, phenylthio, benzoyl group substituted with an alkylsulfonamide (C ₁ -C ₄ ) group (d) R ₄ represents hydrogen, or when the nitrogen atom adjacent to R ₃ is condensed is a morpholine, pyrrolidine, piperidine group, or a piperidine group substituted with one or two alkyl ( _C1 - _C4 ), phenyl or phenylalkyl ( _C1 - _C4 ) groups,
or a piperazine group substituted at the 4-position with a phenyl group, or (1) one or two alkyl (C _1
-C4 ) or alkoxy ( _C1 - _C4 ) group, (2)1
4 or 2 halogen atoms, or (3) a phenyl group itself substituted with a trifluoromethyl group.
form a piperazine group substituted at the position. (e) _R5 represents hydrogen or an alkyl ( _C1 - _C3 ) group. (f) R ₆ represents hydrogen or a linear or branched alkanoyl (C ₁ -C ₁₀ ) group or a cycloalkanoyl (C ₃ -C ₈ ) group. (g) n represents an integer of 1, 2 or 3. (h) X represents sulfur or oxygen. (i) Y represents a CH ₂ group. (j) At the same time, X is oxygen, Y is CH ₂ group, n is 2, and R ₁
And when R ₅ is hydrogen, R ₂ is a methyl group, and R ₆ is water or an alkanoyl group, R ₄ does not form a substituted piperazine group with R ₃ and the adjacent nitrogen atom. The invention advantageously encompasses derivatives of the general formula having the following atoms and groups: (a) R ₁ represents hydrogen or an alkyl (C ₁ -C ₃ ) group. (b) _R2 represents an alkyl ( _C1 - _C3 ) group. (c) _R3 is: -mono- or polyunsaturated alkenyl ( _C3 - _C18 )
Group - mono- or polyunsaturated alkynyl ( _C3 - _C18 )
Group - Cycloalkyl (C ₃ - _{C 8} ) group - Alkyl (C ₂ - C ₁₈ ) group - (1) Phenylthio group, alkoxy (C ₁ - C ₆ )
(2) phenyl, benzoyl, each substituted with an alkyl (C ₁ -C ₃ ) group or a halogen, by one or two phenyl groups, an alkylthio (C ₁ -C ₆ ) group, a phenoxy group, a benzoyl group, By phenylthio or phenoxy group,
or (3) nitrile or alkanoyl (C ₂ ~
It represents an alkyl ( _C2 - _C16 ) group substituted with a phenoxy group substituted with a C3 ₎ group. (d) R ₄ represents hydrogen, or (1) alkyl (C ₁ to C ₃ ) when R ₃ and the adjacent nitrogen atom are condensed;
form a piperazine group substituted with a phenyl group substituted with (2) a piperidine group substituted with an alkyl (C ₁ -C ₃ ) group substituted with a phenyl group. (e) _R5 represents hydrogen or alkyl ( _C1 to _C3 ). (f) R ₆ is hydrogen, a straight or branched alkanoyl (C ₁ -C ₈ ) group or a cycloalkanoyl (C _{3 -C 8} ) group;
C ₆ ) group. (g) n represents an integer of 1, 2 or 3. (h) X represents sulfur or oxygen. (i) Y represents a CH ₂ group. A preferred group of compounds represented by the general formula is R ₁
is hydrogen or a methyl group; R ₂ is a methyl or ethyl group; R ₃ is an alkyl (C ₂ - C ₁₈ ) group; or (1) a phenyl, phenylthio, phenoxy or benzoyl group; or (2) one or two alkyl groups. (C ₁
~ _C3 ) groups or alkyl ( _C2 - _C10 ) groups substituted with phenyl, phenylthio, phenoxy or benzoyl, respectively substituted with halogen;
R ₄ and R ₅ are hydrogen; R ₆ is hydrogen, an alkanoyl (C ₁ -C ₄ ) group or a cycloalkanoyl (C ₃ -
C ₆ ) group; n is an integer of 1, 2 or 3; X is sulfur; and Y is a CH ₂ group. Examples of the derivatives according to the present invention are as follows: 1-(6-thiochromanyl)-2-n-octylamino-1-propanol, 1-(6-thiochromanyl)-2-(4-phenylbutylamino) )-1-propanol, 1-(6-thiochromanyl)-2-[2-(phenoxy)ethylamino]-1-propanol, 1-(2,3-dihydro-5-benzo[b]thienyl)-2- n-octylamino-1-propanol, 1-(2,3-dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1
-propanol, 1-(2,3-dihydro-5-benzo[b]thienyl)-2-[4-(p-chlorophenyl)butylamino]-1-propanol, 1-(2-methyl-2,3- dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1-propanol, 1-(2-methyl-2,3-dihydro-5-benzo[b]furanyl)-2- n-octylamino-1-propanol, 1-(2,3,4,5-tetrahydrobenzo[b]thiepin-7-yl)-2-(4-phenylbutylamino)-1-propanol, 1-( 2,3-dihydro-5-indolyl)-2
-n-octylamino-1-propanol, 1-(2,3-dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1
-propionyloxypropane, and 1-(2,3-dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1
- Cyclohexanoyloxypropane. Derivatives of the formula which can be present as salts include in particular salts of inorganic acids such as hydrochlorides, phosphates, sulfates or oxalates, lactates, tartrates, acetates, citrates, maleates, glucuronides. Examples include salts of organic acids such as acid salts and gluconate salts. Many of the active products according to the invention with two asymmetric centers, two racemic compounds corresponding to the erythro and threo configurations, respectively, can be obtained, both racemic compounds being, for example, tartaric acid, diacetyltartaric acid, tartranil. diastereomeric salts are formed by the action of optically active acids such as dibenzoyltartaric acid and ditoluoyltartaric acid,
Such diastereomeric mixtures are crystallized, distilled,
Chromatographic separation and subsequent isolation of the optically active base from such salts can be obtained in the usual manner. The same method can also be used in the case of compounds according to the invention having two or more asymmetric centers. Many of the active derivatives of the invention can be used as racemates in the erythro or threo configuration, as mixtures of these forms, or as individual optically active compounds in both forms. In general, the aminoalcohol derivatives of the present invention have an activity in the cardiovascular system such as antihypertensive and/or anticonvulsant activity, peripheral vasodilatory activity, protective activity against cardiomyopathy, fat depletion activity, antithrombotic activity, analgesic activity. activity in the central nervous system, such as platelet aggregation inhibitory activity and/or tranquilizing activity. Compounds of the invention having these properties can be used in the treatment of hypertension and cardiovascular diseases such as atherosclerosis. In particular, it has been established that the derivatives of the invention exhibit extremely high antihypertensive, fat deficiency and antithrombotic activity. The active compounds of the invention can be administered via various pharmaceutical suppositories, orally or parenterally. For oral administration, dragees, pills, tablets, capsules, solutions with additives and adjuvants used in galenic pbarmacy;
Syrups, emulsions and suspensions can be used. For suppository administration, sterile water or liquids such as peanut oil or ethyl oleate can be used. These active compounds according to the invention alone are:
Or it can be used in combination with other active substances with similar or different activities. The novel compounds of this invention can be made by general methods as described below. The novel derivative of the present invention has the general formula: (wherein R ₁ , R ₅ , Y, X and n have the same meanings as above, and Q is the following group:

【formula】

【formula】

【formula】

It is produced from a compound represented by the formula: (wherein R ₂ , R ₃ and R ₄ have the same meanings as described above, and Z represents a halogen atom such as Cl or Br). This general method can be carried out in two ways depending on the starting materials, ie primarily defined by Q in formula (). In the first manufacturing method, Q is: (wherein R ₂ and R ₃ have the same meaning as given above, and R ₇ has the same meaning as R ₄ , or
or a protecting group that can be removed by hydrolysis or hydrogenolysis, such as benzyl, trityl, acetyl, formyl, benzhydryl group, etc.). This reduction is carried out, for example, by the action of an alkali metal hydride, such as sodium borohydride, in a solvent such as methanol or ethanol, preferably at low temperature, or of aluminum and lithium hydride in a solvent such as diethyl ether or tetrahydrofuran. This can be conventionally carried out by the action of an aluminum alkoxide, such as aluminum isopropoxide, or by the action of an aluminum alkoxide, such as aluminum isopropoxide, in a solvent such as isopropanol at reflux. Reduction is also carried out by hydrogenation in a solvent such as methanol, ethanol, dioxane and acetic acid in the presence of a catalyst such as palladium on carbon, Raney nickel, or platinum oxide. As mentioned above, the most interesting compounds of the invention have two configurations: erythro and threo.
The choice of the starting aminoketone and the reducing conditions allows to obtain either of these two forms stereoselectively.

Reduction of the aminoketone with the formula and R ₄ = hydrogen produces compounds with erythro configuration under the general conditions described above. To obtain a compound with threo configuration, reduction is performed to an aminoketone.

[Formula] (where R ₂ and R ₃ have the same meaning as described above,
and R ₇ represents a protecting group that can be removed by hydrolysis or hydrogenolysis, such as benzyl, trityl, acetyl, formyl, benzhydryl group. This reduction can preferably be carried out by the action of alkali metal hydrides such as sodium borohydride, or aluminum hydride and lithium hydride. The starting aminoketones are e.g.
It is easily obtained by reacting R ₃ R ₄ NH with an α-halogen ketone in a solvent such as ether, benzene, chloroform, dioxane, methanol, isopropanol or acetonitrile. However, it is well known that this reaction produces many by-products and is insoluble in α-aminoketones, resulting in low yields. In the present invention, it has been found that amino alcohols of the general formula can be obtained in extremely excellent yields without liberating intermediate aminoketones. Particularly suitable solvents for this type of reaction are alcohols such as methanol, ethanol or isopropanol. For this purpose, in the present invention, the formula ()

The α-halogenoketone of [formula] is reacted with the amine R ₃ R ₄ NH to form the formula ()

An aminoketone corresponding to the formula is obtained which is then reduced as described above without prior separation. In the second manufacturing method, Q is

[Formula] (wherein R ₂ and Z have the same meanings as above) A compound of the general formula () is converted into an amine R ₃ R ₄ NH (wherein R ₃ to _{R 4} have the same meanings as above) ). This reaction can be easily carried out in a solvent such as alcohols, chloroform, dioxane, carbon tetrachloride, and in the presence of a reagent capable of scavenging the hydrogen halide formed, such as a tertiary inorganic or organic base. In these cases, first

[Formula] reacts with amino compounds

Produces oxirane of formula. The method also includes a method for producing an amino alcohol from oxirane, and this method can be advantageously used for producing an amino alcohol derivative having a threo configuration. Salts of amino alcohols of general formula () can be prepared as described above by the general methods described above. There are various methods for this. Generally, these salts are prepared by reacting equal amounts of an amino alcohol and an acid in a suitable solvent such as an alcohol, then mixing with the amino alcohol and adding another solvent, such as an ether, which is insoluble in the salt. It can be produced by well-known methods such as precipitation or neutralization of an ethereal solution of the acid or base with the base or acid. The acids used can be organic acids or inorganic acids. Preferred inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and perchloric acid. Organic acids include formic acid, propionic acid, glycolic acid, lactic acid, citric acid, ascorbic acid, fumaric acid, maleic acid, pamoic acid, succinic acid, tartaric acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, Examples include anthranilic acid, p-hydroxybenzoic acid, salicylic acid, and glucuronic acid. Esters of amino alcohols of the general formula (wherein R ₆ is an alkanoyl or cycloalkanoyl group) are prepared by mixing the amino alcohol or its salt with an excess of the appropriate acid chloride or anhydride at 50°C or more. It can be made by reaction at temperatures in the reflux temperature range. In another method, the amino alcohol or salt thereof is reacted with an equal or slight excess of the appropriate acid chloride or anhydride in a solvent such as acetonitrile, benzene and toluene. Next, Examples relating to the production of amino alcohol derivatives of the present invention will be described. Example 1 1-(6-thiochromanyl)-2-n-octylamino-1-propanol (a) 35 g of aluminum chloride was mixed with 500 ml of 1,2-
To a mixture of dichloroethylene and 19.7 ml of propionyl chloride, a mixture of 36.5 g of thiochroman in 150 ml of 1,2-dichloroethylene was added with stirring while maintaining a temperature of about 10°C. After addition, bring the mixture to room temperature for 3
Stirred for an hour and then decomposed by adding ice and hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with 1,2-dichloroethylene. The organic phase was dried over _MgSO4 , filtered and the solvent was evaporated in vacuo. The residue thus obtained was solidified by addition of petroleum ether, yielding 32.5 g of 6-propionyl-thiochroman. MP (melting point) (℃): 63-65, yield: 69% (b) 32 g of 6-propionyl-thiochroman
8 ml of bromine was added dropwise to the solution in 400 ml of anhydrous ether, maintaining the temperature at ±5°C. After the addition, the mixture was stirred at ambient temperature for 2-3 hours, then saturated aqueous NaHCO ₃ solution was added slowly. The aqueous phase was extracted twice with 100 ml of ether,
The organic phase was evaporated in vacuo. 100ml of the resulting residue
of petroleum ether to produce 38 g of α-bromo
6-propiniol-thiochroman was obtained. MP (°C): 71-73, yield: 86% (c) 20 g of the obtained thiochroman, 15 ml of n-octylamine and 200 ml of ethanol were refluxed for 4 hours. The mixture was cooled to ±5°C and 5.2g of sodium borohydride was added slowly to it. After addition, keep the mixture at room temperature for 1~
Stirred for 2 hours, then the solvent was evaporated in vacuo. The residue was treated with 200 ml of water and extracted three times with 100 ml of chloroform. The organic phase was washed with water, dried over _MgSO4 , filtered and
The solvent was evaporated in vacuo. The obtained residue was recrystallized from acetone to obtain 13.3 g of 1-(6-thiochromanyl)-2-n-octylamino-1-propanol. MP (°C): 115-116, yield: 60% Elemental analysis: C H N Calculated value %: 71.58 9.91 4.17 Actual value %: 71.70 9.85 4.05 Example 2 1-(2,3-dihydro-5-benzo b]Thienyl-2-(4-phenylbutylamino)-1
-Propanol (a) 500ml of 0.3M aluminum chloride 1.2-
Add 0.21 M propionyl chloride to the solution in dichloroethylene, then add with stirring
0.2M of 2,3-dihydrobenzo[b]thiophene was added slowly maintaining the temperature at about 10°C. The mixture was stirred at ambient temperature for 3 hours and then decomposed with a mixture of ice and hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with 1,2-dichloroethylene. The organic phase was dried over _MgSO4 , filtered and the solvent was evaporated in vacuo. The resulting residue was solidified by addition of petroleum ether to obtain 25 g of 5-propionyl-2,3-dihydrobenzo[b]thiophene. MP (°C): 50-52, yield: 55% (b) 3.3 ml of bromine was added to a solution of 12.5 g of the above product dissolved in 150 ml of anhydrous tetrahydrofuran.
It was added gradually with stirring at a temperature of 10°C. Stirring was continued for 1 hour at room temperature, then 50 ml
A 10% aqueous solution of _NaHCO3 was added. The organic phase was separated, dried and evaporated. The resulting oily residue was solidified by adding petroleum ether to give 30 g of 5
-(α-bromopropionyl)-2,3-dihydrobenzo[b]thiophene was obtained. MP (℃): 64-66 (c) 15 g of 5-(α-bromopropionyl)-2.
3-dihydrobenzo[b]thiophene, 16 g of 4-phenylbutylamine and 150 ml of methanol were refluxed for 3 hours. solution ±5
It was cooled to 0.degree. C. and 5 g of sodium borohydride was slowly added thereto. After addition, stir at room temperature for 3 minutes.
Continued for ~4 hours, then the solvent was evaporated in vacuo. The residue was treated with 200ml of water and extracted with chloroform. The organic phase was washed with water, dried over _MgSO4 , filtered and the solvent was evaporated in vacuo. The solid residue was recrystallized from acetone to obtain 9.9 g of the desired product. MP (°C): 113-115, yield: 55% Elemental analysis: C H N Calculated value %: 73.85 7.97 4.10 Actual value %: 73.50 7.95 3.90 Example 3 1-(2.3.4.5-tetrahydrobenzo [b] Thiepin-7-yl)-2-(4-phenylbutylamino)-1-propanol (a) Add 0.27M aluminum chloride to 500ml of 1.2
- 0.25M propionyl chloride is added to the solution in dichloroethylene and then slowly, with stirring, 0.25M 2,3,4,5-tetrahydrobenzo[b]thiepin is added at a temperature maintained at about 10°C. Added. Then, the mixture is heated at room temperature for 3~
Stirred for 4 hours then decomposed with a mixture of ice and hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with 1,2-dichloroethylene. The organic phase was dried over _MgSO4 , filtered and the solvent was evaporated in vacuo. The residue was vacuum distilled to obtain 30 g of dense oil. Yield: 60%, boiling point (BP): 130-135 (0.4 mm) NMR spectrum (nuclear magnetic resonance) shows structure 7-propionyl-2.
It corresponded to 3,4,5-tetrahydrobenzo[b]thiepin. (b) 2.6 ml of bromine was added dropwise to a solution of 11 g of the above product in 150 ml of anhydrous tetrahydrofuran (THF) at a temperature of ±10°C. The mixture was stirred at room temperature for 1 hour, then 30 ml of 10%
Aqueous _NaHCO3 solution was added. Separate the organic phase;
Drying and evaporation gave 13.2 g of 7-(α-bromopropionyl)-2,3,4,5-tetrahydrobenzo[b]thiepin (flowable, yellow oil). The homogeneity of the product was confirmed by TIC (thin layer chromatography). (c) 10 g of 7-(α-bromopropionyl)-2.
3,4,5-tetrahydrobenzo[b]thiepin, 150 ml of methanol and 10 g of 4-phenylbutylamine were refluxed for 4 hours.
The solution was cooled to ±5° C. and 4 g of sodium borohydride was added slowly with stirring. After the addition, the mixture was left at ambient temperature overnight and then the solvent was evaporated in vacuo. The resulting oily residue was treated with 200 ml of water and extracted with chloroform. The organic phase was washed with water, dried over _Na2SO4 , filtered and the solvent was evaporated _in vacuo. The resulting residue was recrystallized from acetone to obtain 7.5 g of the desired product. MP (°C): 87-89, yield: 53% Elemental analysis: C H N Calculated value %: 74.74 8.45 3.79 Actual value %: 74.85 8.65 3.70 Example 4 1-(2-methyl-2,3-dihydrobenzo [b]Thienyl)-2-[2-(chlorophenoxy)-ethylamino]-1-propanol (a) 0.1M 2-methyl-2,3-dihydrobenzo[b]-thiophene (by the method of Petropaulos) J.Am.Chem.Soc., 75.
1130, 1953) with 0.15M aluminum chloride,
0.11M propionyl chloride and 150ml 1.
It was slowly added to 2-dichloroethylene at a temperature maintained at ±10°C. After addition, let the mixture stand at room temperature for 3 minutes.
Stir for an hour and then add a mixture of ice and HCl. The mixture was extracted with 1,2-dichloroethylene, dried over MgSO ₄ and the solvent was evaporated. The oily residue was removed in vacuo. 14g
5-propyniol-2-methyl-2,3-dihydrobenzo[b]thiophene was obtained. BP (0.2mm): 110-115, yield: 70% NMR spectrum matched the structure. (b) 7 g of the above product thus obtained is
ml of anhydrous THF and 1.8 ml of bromine was added dropwise to this solution with stirring while maintaining the temperature at about 10°C. After the addition, the mixture was stirred at room temperature for 1 hour,
Then an aqueous solution of _NaHCO3 was added. The organic phase was separated, dried and evaporated to yield 8.5 g of 5-(α
-bromopropionyl)-2-methyl-2,3
-dihydrobenzo[b]thiophene was obtained. MP (℃): 52-54, yield: 88% NMR spectrum is consistent with the structure, the product is
It was homogeneous in TIC (silica gel-
_{C6H6 )} . (c) 16 g of the above product, 12 g of α-(p-chlorophenoxy)-ethylamine and 200 ml of ethanol were refluxed for 3 hours. solution ±5
Cooled to <0>C, the solvent was evaporated and the residue was extracted with _CHCl3 . The organic phase was dried over _MgSO4 , filtered and
Evaporate and the resulting residue is recrystallized from acetone. 5.5 g of the desired product were thus obtained. MP (°C): 108-109 Elemental analysis: C H N % calculated: 63.56 6.40 3.70 % found: 63.70 6.45 3.85 The structure of the product was confirmed by mass, NMR and IR spectra. Example 5 1-(3-methyl-6-thiochromanyl)-2-
[2-(Phenoxy)ethylamino]-1-propanol (a) Add 0.1 M (16.4 g) of 3 to a solution of 0.13 M AlCl ₃ and 0.12 M propionyl chloride in 150 ml of 1,2-dichloroethylene. -Methyl-thiochroman was added dropwise at a temperature of ±5°C. After the mixture was stirred at ambient temperature for 3 hours, a mixture of ice and HCl was added to it and extracted with CHCl ₃ . The organic phase was dried over MgSO ₄ , filtered and evaporated to give 17.3 g of 6-propionyl-3-methylthiochroman. The homogeneity of this product
It was confirmed by TLC and its structure was confirmed by NMR spectrum. (b) To a solution of 22 g of the above product in 150 ml of THF, 5.2 ml of bromine was added dropwise with stirring at a temperature of ±5°C. Treat the solution as described above and
26 g of 6-(α-bromopropionyl)-3-methylthiochroman were obtained. MP (°C): 60-63 (MeOH), yield 85% NMR spectrum matched the structure. (c) 11 g of the above product, 15 g of 2-phenoxy-
Ethylamine and 150ml of ethanol were refluxed for 2 hours. The mixture was cooled to ±5° C. and 6 g of NaBH ₄ was added slowly. The solution was worked up as described above and recrystallized from acetone to give 5 g of the desired product. MP (°C): 85-87 Elemental analysis: C H N % calculated: 70.54 7.61 3.91 % found: 70.42 7.60 3.90 NMR, IR and mass spectra were consistent with the structure. Example 6 1-(8-methyl-6-thiochromanyl)-2-
n-Octylamino-1-propanol (a) 165 g of 8-methyl-thiochroman were treated with propionyl chloride in the presence of AlCl ₃ in 1,2-dichloroethylene as described in the example above. 107.4 g of product was obtained. BP: 140-155 (0.50mm), solidified the product. MP (°C): 48-51, yield: 50% NMR spectrum fit the structure. (b) 107.4 g of the above product was added to 800 ml of THF and brominated with 25 ml of bromine as described above. 91.7 g of 6-(α-bromopropionyl)-
8-Methyl-thiochromanil was obtained. MP (°C): 79-80 (petroleum ether), yield: 63% NMR spectrum fit the structure. (c) 20 g of the above product, 20 g n-octylamine and 300 g methanol were refluxed for 4 hours. The mixture was cooled to ±0°C and 9.5 g
_NaBH4 was added slowly. Work-up as usual gave 14 g of desired product. MP (°C): 129-130 ( _CHCl3 ) Elemental analysis: C H N % calculated: 72.15 10.09 4.01 % found: 72.05 9.75 3.85 NMR, mass and IR spectra fit the structure. Example 7 1-(2-methyl-2,3-dihydro-5-benzo[b]furanyl-2-[4-(p-chlorophenyl)butylamino]-1-propanol (a) 100 g (0.075 mol) 2-methyl-2・3-
108 g (0.8 mol) of aluminum chloride and 71.6 g (0.75 mol) of propionyl chloride were added to dihydrobenzo[b]furan with stirring at 10°C.
1000ml of dichloromethane was added to the resulting mixture. After the addition, stirring was continued for 3 hours at ambient temperature. The final medium was carefully dripped onto ice mixed with a small amount of concentrated hydrochloric acid. The organic phase was decanted, dried and then evaporated to dryness. The oily residue was distilled. 91.3 g (0.48 mol) of cetonic derivative was recovered. BP: 119°C/0.5 Torr, NMR spectrum consistent with structure. (b) A solution of 57 g (0.3 mol) of 2-methyl-5-propionyl-2,3-dihydrobenzo[b]furan in 600 ml of diethyl ether is prepared.
Maintained at 10°C, a trace amount of benzoyl peroxide was added to this solution, then 47·9 g (0.3
mol) of bromine was added. The mixture was stirred at ambient temperature for 2 hours. The final medium was washed with 10% aqueous sodium bicarbonate solution, further washed with water, then dried and evaporated to dryness. The solid residue was recrystallized from a 1:1 hexane/cyclohexane mixture. In this way, 67.3g (0.25 mol,
83%) of cetone bromide was obtained. MP (°C): 79.6, NMR spectrum was consistent with the expected structure. (c) A solution of 8.2 g (45 mol) of p-chlorophenylbutylamine in 100 ml of acetonitrile is stirred to reflux, 12.4 g (90 mmol) of potassium carbonate is added, and 80 ml of 12 g (45 mmol) of the above setone bromide
in acetonitrile was added over 1 hour. Reflux was maintained for 1.5 hours after the addition. A solution of 1.8 g (48 mmol) of sodium borohydride dissolved in 10 ml of water, which had been made basic by dropping a 40% NaOH aqueous solution into the medium, was added dropwise at room temperature. The solids were filtered and the filtrate was evaporated to dryness. The residue was solid. This residue is 1:1
Recrystallization from a hexane/cyclohexane mixture gave 5.1 g (14 mmol, 31%) of the desired product. The melting point of this product was 107.8°C.
The NMR spectrum was consistent with the expected structure. Elemental analysis: C H N Calculated value %: 70.70 7.60 3.73 Actual value %: 70.40 7.60 3.60 Example 8 1-(2-methyl-6-thiochromanyl)-2-
(4-Phenylbutylamino)-1-propanol (a) 83 g (0.5 M) of 2-methyl-thiochroman was mixed with 750 ml of 1.2 as described in the example above.
- 73g AlCl ₃ (0.55M) in dichloroethylene
43.2ml propyl chloride (0.5M) in the presence of
64 g of 2-methyl-6-propionyl-thiochroman was obtained. MP (°C): 65-66 (petroleum ether), yield: 58% NMR spectrum fit the structure. (b) 64 g of the above product were treated as described above with 14.9 ml of bromine in 500 ml of absolute methanol to give 82 g of 6-(α-bromopropionyl)-2-
Methyl-thiochroman was obtained. MP (°C): 78-79, yield: 95% NMR spectrum matched the structure. (c) 15 g of the above product, 9 g of 4-phenylbutylamine and 200 ml of methanol were refluxed for 4 hours. Cool the mixture to ±0 °C and
g of _NaBH4 was slowly added. After working up as usual and recrystallizing from methanol, 6 g of 1-(2-methyl-6-thiochromanyl)-2-
(4-phenylbutylamino)-1-propanol was obtained. MP (°C): 118-119, yield: 35% Elemental analysis: C H N % calculated: 74.74 8.45 3.79 % found: 74.80 8.45 3.70 NMR, mass and IR spectra fit the structure. Example 9 1-(2,3-dihydro-5-benzo[b]furanyl)-2-(4-phenylbutylamino)-
1-Propanol (a) 8.8 g of 2,3-dihydro-6-propionylbenzo[b]furan were treated with 2.6 ml of bromine in 50 ml of anhydrous THF as described above. The product thus obtained was recrystallized from methanol to obtain 8 g of 6-(α-bromopropionyl)-2,3-dihydrobenzo[b]furan. MP (°C): 65-66, yield: 40% (b) 10 g of the above product, 6 g of 4-phenylbutylamine and 100 ml of methanol were refluxed for 3 hours. Cool the mixture to ±0 °C and
g of _NaBH4 was slowly added. Work-up as usual and recrystallization from acetone gave 7.7 g of desired product. MP (°C): 131-133, yield: 50% Elemental analysis: C H N % calculated: 77.49 8.36 4.30 % found: 77.25 8.25 4.10 NMR, mass and IR spectra fit the structure. Example 10 1-[(1,4-benzodithien)-6-yl]-
2-(4-phenylbutylamino)-1-propanol (a) Add 0.12M aluminum chloride to 250ml of 1.2
-0.12M to the mixture added to dichloroethylene
of propionyl chloride and then to this
A mixture of 100 ml of 1,2-dichloroethylene and 0.1 M of 1,4-benzodithiene was mixed with ±
It was added gradually with stirring at a temperature of 15°C. After the addition, the mixture was stirred at room temperature for 1 hour,
Then, after decomposition with a mixture of ice and hydrochloric acid and the usual treatment, 12 g of 6-propionyl-
1,4-benzothiene was obtained. BP: 145-150 (0.2 mm), Yield: 60% (b) 10 g of the above product was dissolved in 100 ml of anhydrous THF, and 2.3 ml of bromine was added dropwise to this solution with stirring at a temperature of ±10°C. did. After working up as usual, 11 g of 6-(α-bromopropionyl)-
1,4-benzothiene was obtained. MP (°C): 72-73, yield: 80% (c) 10 g of the above product, 100 ml of methanol and 10 g of 4-phenylbutylamine were refluxed for 3 hours. Cool the solution to ±50°C and add 7g
of _NaBH was added. The solvent is then evaporated,
The residue was diluted with water and extracted with chloroform.
The organic phase was dried over _MgSO4 , filtered and evaporated. The solid thus obtained was recrystallized from methanol to obtain 7.5 g of the target compound. MP (°C): 138-140, yield: 55% Elemental analysis: C H N Calculated value %: 67.50 7.28 3.75 Actual value %: 67.25 7.45 4.00 Example 11 1-(2,3-dihydro-5-benzo b]Thienyl)-2-(4-phenylbutylamino)-
1-propanol (threo form) 4 g of 1-(2,3-dihydro-5-benzo[b]thienyl-2-bromo-1-propanol,
100 ml of ethanol and 20 g of 4-phenylbutylamine were refluxed for 5 hours. The solvent and excess amine were evaporated in vacuo and the resulting residue was treated with ether. The solid was recrystallized from a mixture of methanol and ether and the corresponding free base was obtained by treatment with dilute NaOH solution and recrystallized from acetone. In this way, 1.05 g of the target compound was obtained. MP (°C): 85-87 Elemental analysis: C H N Calculated %: 73.80 7.95 4.10 Observed %: 73.40 7.90 4.20 The threo configuration of the product was confirmed by NMR spectroscopy (JH ₁ , H ₂ = 9 cps; δH ₁ = 4.04ppm:
CDCl ₃ -1% TMS) Example 12 1-(2,3-dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-
1-Propionyloxypropane 7 ml (7.4 g, 80 moles) of propionyl chloride,
10 g of 1-(2,3-dihydro-5-benzo[b]
thienyl)-2-(4-phenylbutylamino)-
1-Propanol hydrochloride and 10 ml of toluene were heated at reflux temperature for 3 hours. The final medium was evaporated to dryness under reduced pressure and the residue was recrystallized from acetonitrile. In this way, 5.9 g of the desired product was obtained, the structure of which was confirmed by NMR and IR spectroscopy. MP (℃): 169.9 Elemental analysis: C H N Calculated value %: 66.40 7.40 3.10 Actual value %: 66.54 7.60 3.40 Example 13 15 g of 1-(2,3-dihydro-5-benzo[b]thienyl)-2 -(4-phenylbutylamino)-1-propanol in 750 ml of toluene and
Dry gaseous HCl dissolved in 150 ml chloroform
The stream was bubbled for 2 hours. The mixture was stirred at ambient temperature for 2 hours. The resulting precipitate was filtered, washed with ice-cold pentane and dried to yield 15 g of the hydrochloride salt. MP (°C): 208-209 Elemental analysis: C H N Calculated value %: 66.72 7.40 3.70 Actual value %: 66.70 7.50 3.65 Example 14 16 g of 1-(6-thiochromanyl)-2-n-octylamino-1- Propanol was dissolved in 600 ml of toluene and passed through it with a stream of anhydrous HCl for 1.5 hours. The formed precipitate was filtered, washed with water-cold pentane, and dried. 17 g of hydrochloride was obtained. MP (°C): 227 Elemental analysis: C H N Calculated value %: 64.60 9.15 3.77 Actual value %: 64.60 9.15 3.65 Example 15 28.0g (0.144M) of D-glucuronic acid was heated at 50°C
Dissolved in 340 ml of water heated to 34.1
g (0.1 M) of 1-(2,3-dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1-propanol with vigorous stirring,
dripped. Stirring was continued for the time required to completely dissolve. Dilution with distilled water gave a clear solution. The melting points of the compounds described in each of the above examples and the melting points of other compounds obtained according to the present invention are shown in the table. The pharmaceutical effects of a number of compounds according to the invention are shown in the table and in the table. The following effects are listed in the table. (1) Acute toxicity was measured in male rats that had been fasted for 20 days. The test compound was orally administered, and the LD50
The value (lethal dose for 50% of animals) was calculated by the Richfield and Wilcoxon method (J. Pharmacol. exp. Ther. 96, 94-113, 1949).
These LD50 values are expressed in mg/Kg and confidence limits are P=95%. (2) Antihypertensive activity was measured in mice suffering from hypertension. The test compound was orally administered at a rate of 60 mg/Kg. Systolic arterial pressure was measured every 30 minutes for 2 hours before test compound administration and every 30 minutes for 3 hours after test compound administration. The results were expressed in the following stages: 0: Arterial pressure did not decrease. +: Decrease of 10mmHg or less. ++: 10-20mmHg decrease. +++: 20mmHg or more decrease. (3) Vasodilator activity was measured at the level of the femoral artery of anesthetized dogs (perfused paw).
paw) technology). The test compound was intraarterially administered at a rate of 30 mg/Kg. Results were expressed relative to papaverine tested at the same dosage. 0: No effect +: Slightly active ++: Effect equivalent to half of the effect of papaverine +++: Effect equivalent to the effect of papaverine +++++: Effect higher than that of papaverine (4) Anticonvulsant activity was confirmed in vitro in the ileum of guinea pigs. Contractions were produced with histamine (Hist.), acetylcholine (Achol) or barium chloride (BaCl ₂ ). Test compounds were added to the perfusion bath 15 minutes before giving the convulsant. The dosage was expressed in milligrams (g) per ml of bath that completely suppressed spasms. The results are shown in the table according to the following criteria. (1)
Campbell and Richter's method (Acat Phamacol.
Toxicol. 25, 345, 1967) was administered intraperitoneally to 25 g of male mice 30 minutes before observation. This study investigated the LD50 of intraperitoneal administration, changes in animal behavior, and the effective administration of animals by this method. LD50 and MAD values were expressed in mg/Kg. The main symptoms observed in this case showed a depression of the central nervous system, qualitatively compared to the effects of tranquilizers. In the tables and, the numbers in the first column correspond to the numbers in the first column of the table. Like numbers indicate the same compounds. The compounds of the invention can be used in various forms. The following non-limiting examples relate to herbal medicine formulations containing as active compounds indicated by the letter "A": 1-(2,3-dihydro-
5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1-propanol; 1-(6-thiochromanyl)-2-(4-phenylbutylamino)-1-propanol; 1-( 2.3.4.5-
Tetrahydrobenzo[b]thiepin-7-yl)
-2-(4-phenylbutylamino)-1-propanol; 1(2,3-dihydro-5-benzo[b]
Thienyl-2-(4-phenylbutylamino)-1
- Cyclohexanoyloxypropane. Intramuscular injection A 100mg Isopropyl myristate 0.57ml Peanut oil (required amount) 3ml A 50mg Ethyl alcohol 0.50mg Polyethylene glycol 400 0.25ml Propylene glycol 0.50ml 10% acetic acid 1.125ml 70% Sorbitol 0.75ml Distilled water (required amount (qs) ) 3ml Solution A for oral administration 5ml Ethyl alcohol 0.1ml Propylene glycol 0.05ml 10% acetic acid 0.05ml Single reliquary (65% sutucarose) (required amount)
(simple syrup) 1ml A 50mg Aerosil 2.5mg Cornstarch 25mg Lecithin 1.5mg Methylcellulose 2.5mg STA-RX 2mg Avicel 6mg A 50mg Cornstarch 50mg Sodium acetate 15mg Magnesium stearate 2mg Aerosil 3mg Starch STA-RX1500 80mg capsule Selector A 50mg Starch STA -RX1500 94 mg Magnesium stearate 1 mg Laurelle sodium 5mg A 50mg Fine crystal cellulose 70mg Corn starch 30 mg Soderic oil 0.01 mg Sodium laurelil sodium 5mg A 50 mg A 50 mg laurelil sodium sulfate. 5mg Crystal cellulose 70mg magnesium 20mg A 50mg starch STA-RX1500 10mg Magnesium stearate 1mg Sodium lauryl sulfate 10mg Microcrystalline cellulose 30mg Erosil 1mg A 50mg Erosil 2.5mg Corn starch 25mg Lecithin 1.5mg Methylcellulose 2.5mg Soluble starch 13mg Talc 7mg Situated Medicine A 100mg White Psol (triglycerides) )2.3 mg (required amount) (whitepsol) 2.3mg A 100mg Syndermine GIC (triglycerides) 200mg Whitepsol (required amount) 2.3mg A 100mg Polyethylene glycol 6000 1mg Polyethylene glycol 1540 (required amount) 2.7mg A 100mg Peanut oil 1.5mg Soybean Lecithin 5mg 2-octyldotecanol 5mg Gelatin-glycerin (required amount for 1 capsule) Tablet A 50mg Lactose 20mg Erosil 2mg Starch STA-RX1500 18mg Calcium phosphate (CaHPO ₂ ) 25mg Microcrystalline cellulose 100mg Sodium acetate 15mg A 50mg Microcrystalline cellulose 100mg Sodium acetate 15mg A 50mg Crystalline cellulose 80mg Sodium acetate 25mg Aubygel Avicel 6mg A 50mg Corn starch 50mg Sodium acetate 15mg Magnesium stearate 2mg Erosil 3mg Starch STA-RX1500 80mg Among the compounds of the present invention, the compounds with antihypertensive activity can be orally administered to the human body at a dosage of 50 to 3000mg per day. In various animal studies, the side effects observed with these compounds were characterized as sedation. This was confirmed using higher than therapeutic doses. The ratio between the effective dosage and the sedative dosage is α
- These ratios were significantly superior for the compounds of the invention compared to those observed for reference compounds such as α-methyldopa and propanolol.

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Claims (1)

[Claims] 1. General formula: (In the formula, (a) R ₁ is hydrogen, one or two methyl groups (C ₁ )
(b) R ₂ represents an alkyl group (C ₁ -C ₂ ); (c) R ₃ represents: - a mono- or polyunsaturated alkenyl group (C ₈ -
_C12 ); -mono- or polyunsaturated alkynyl group ( _C3 ~
_C12 ); - mono- or polyunsaturated alkynyl groups containing an oxygen atom ( _C3 - _C12 ); - straight-chain or branched alkyl groups ( _C2 - _C14 ); - selected from the group: Indicates a straight-chain or branched alkyl group ( _C2 - _C7 ) substituted with at least one atom and/or group: (1) oxygen or sulfur, (2) phenyl, phenoxy, phenylthio, benzoyl group, ( 3) 1 methyl (C ₁ ) or methoxy (C ₁ )
phenyl substituted with one or two halogen atoms or with nitrile, alkanoyl (C ₂ ) or acylamino (C ₂ ) groups,
phenoxy, benzoyl group; (d) R ₄ represents hydrogen; or morpholine group when R ₃ and the adjacent nitrogen atom are condensed, or phenyl or phenylalkyl (C ₁ -C ₄ )
a piperidine group substituted with a group, or a piperazine group substituted in the 4-position with a phenyl group, or a phenyl group itself substituted with one methyl (C ₁ ) group to form a piperazine group substituted in the 4-position; R ₅ represents hydrogen or a methyl (C ₁ ) group; (f) R ₆ represents hydrogen or a straight-chain or branched alkanoyl (C ₁ -C ₈ ) group or a cycloalkanoyl (C ₃ -C ₆ ) group; (g) n represents an integer of 1, 2 or 3; (h) X represents sulfur or oxygen; and (i) Y represents a CH ₂ group and salts thereof. 2 In the general formula (a) R ₁ is hydrogen, 1 or 2 methyl (C ₁ )
group; (b) _R2 is an alkyl ( _C1 - _C2 ) group; (c) _R3 is: -alkenyl ( _C8 - _C12 ) group, -alkynyl ( _C4 - _C12 ) group, -oxygen substitution Alkynyl (C ₆ to C ₁₀ ) group, -alkyl (C ₂ to _{C 14} ) group, -substituted alkyl (C ₂ to _{C 7} ) group, (d) R ₄ is hydrogen, or a nitrogen atom adjacent to R ₃ (e) R _{5 is} hydrogen or a methyl (C ₁ ) group; (f) R ₆ is hydrogen or a straight-chain or branched alkanoyl (C ₁ -C ₈ ) group or a cycloalkanoyl (C ₃ -C ₆ ) group; (g) n is 1 , 2 or 3; (h) X is sulfur or oxygen; (i) Y represents a CH ₂ group; and the amino alcohol derivative and its salts according to claim 1. 3 In the general formula, R ₁ is hydrogen or methyl; R ₂ is a lower alkyl (C ₁ -C ₂ ) group; R ₃ is a mono- or polyunsaturated alkenyl (C ₈ -C ₁₂ ) group, an alkynyl (C ₈ -C 2 ) group; ₁₂ ) groups, straight-chain or branched alkyl (C ₂ -C ₁₄ ) groups, or (1) one or two phenyl, phenoxy or benzoyl groups, or (2) one methyl (C ₁ ) or halogen, alkyl ( _C2 - _C7 ) substituted with phenyl, phenoxy or benzoyl, respectively
group; R ₄ and R ₅ are hydrogen; R ₆ is hydrogen, a straight-chain or branched alkanoyl (C ₁ -C ₄ ) group or a cycloalkanoyl (C ₃ -C ₆ ) group; n is 1, 2 or 3; integer; X is oxygen or sulfur; and Y is CH ₂
Amino alcohol derivatives and salts thereof according to claim 1 or 2, which represent a group. 4 In the general formula, R ₁ is hydrogen or a methyl group, R ₂ is a methyl or ethyl group; R ₃ is an alkyl (C ₂ - _{C 14} ) group, or (1) phenyl, phenylthio, phenoxy or benzoyl group, or (2 )1
Alkyl (C _{2 -
C7} ) group; _R4 and _R5 are hydrogen; _R6 is hydrogen, alkanoyl ( _C1 - _C4 ) group or cycloalkanoyl ( _C3 - _C6 ) group; n is an integer of 1, 2 or 3; Claim 3 represents sulfur and Y represents CH ₂ group.
Amino alcohol derivatives and salts thereof as described in . 5 Compounds described below: 1-(6-thiochromanyl)-2-n-octylamino-1-propanol, 1-(6-thiochromanyl)-2-(4-phenylbutylamino)-1-propanol, 1 -(6-thiochromanyl)-2-[2-(phenoxy)ethylamino]-1-propanol, 1-(2,3-dihydro-5-benzo[b]thienyl)-2-n-octylamino-1- Propanol, 1-(2,3-dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1
-propanol, 1-(2,3-dihydro-5-benzo[b]thienyl)-2-[4-(p-chlorophenyl)butylamino]-1-propanol, 1-(2-methyl-2,3- dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1-propanol, 1-(2-methyl-2,3-dihydro-5-benzo[b]furanyl)-2- n-octylamino-1-propanol, 1-(2,3,4,5-tetrahydrobenzo[b]thiepin-7-yl)-2-(4-phenylbutylamino)-1-propanol, 1-( 2,3-dihydro-5-indolyl)-2
-n-octylamino-1-propanol, 1-(2,3-dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1
-propionyloxypropane, and 1-
(2,3-dihydro-5-benzo[b]thienyl)
The aminoalcohol derivative and its salts according to claim 4, selected from the group consisting of -2-(4-phenylbutylamino)-1-cyclohexanoyloxypropane. 6 Compounds represented by the general formula are hydrochloride, hydrobromide, phosphate, sulfate, oxalate, lactate, tartrate, acetate, citrate, maleate, gluconate and gluguronate. Amino alcohol derivatives and salts thereof according to any one of claims 1 to 5, selected from the group of: 7 General formula: (In the formula, (a) R ₁ is hydrogen, one or two methyl groups (C ₁ )
(b) R ₂ represents an alkyl group (C ₁ -C ₂ ); (c) R ₃ represents: - a mono- or polyunsaturated alkenyl group (C ₈ -
_C12 ); -mono- or polyunsaturated alkynyl group ( _C3 ~
_C12 ); - mono- or polyunsaturated alkynyl groups containing an oxygen atom ( _C3 - _C12 ); - straight-chain or branched alkyl groups ( _C2 - _C14 ); - selected from the group: Indicates a straight-chain or branched alkyl group ( _C2 - _C7 ) substituted with at least one atom and/or group: (1) oxygen or sulfur, (2) phenyl, phenoxy, phenylthio, benzoyl group, ( 3) 1 methyl (C ₁ ) or methoxy (C ₁ )
with one or two halogen atoms, or with nitrile, amino, alkanoyl (C ₂ )
or a phenyl, phenoxy, or benzoyl group substituted with an acylamino (C ₂ ) group; (d) R ₄ represents hydrogen; or a morpholine group, or a phenyl or phenyl group when the nitrogen atom adjacent to R ₃ is fused; Enylalkyl ( _C1 - _C4 )
a piperidine group substituted with a group, or a piperazine group substituted in the 4-position with a phenyl group, or a phenyl group itself substituted with one methyl (C ₁ ) group to form a piperazine group substituted in the 4-position; R ₅ represents hydrogen or a methyl (C ₁ ) group; (f) R ₆ represents hydrogen, or a straight-chain or branched alkanoyl (C ₁ -C ₈ ) group or a cycloalkanoyl (C ₃ -C ₆ ) group; (g) n represents an integer of 1, 2 or 3; (h) X represents sulfur or oxygen; and (i) Y represents a CH ₂ group. : (wherein R ₁ , R ₂ , R ₃ , R ₅ , X and n have the same meanings as above, and R ₇ has the same meaning as R ₄ above, or R ₇ is benzyl, The alpha-aminoketone represented by butyl, acetyl, formyl, benzhydryl (indicating a protecting group which can later be removed by hydrolysis or hydrogenolysis) is dissolved in an alkali such as sodium borohydride in a solvent such as methanol, ethanol or isopropanol. by the action of metal hydrides, or by the action of aluminum hydride and lithium hydride in solvents such as diethyl ether or tetrahydrofuran, by the action of aluminum alkoxides such as aluminum isopropoxide in solvents such as isopropanol under reflux; or A process for the preparation of aminoalcohol derivatives and their salts, characterized by reduction by hydrogenation in a solvent such as methanol, ethanol, dioxane in the presence of catalysts such as palladium on carbon, Raney nickel, and platinum oxide. 8 The compound represented by the general formula is mixed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, etc., or formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, etc. in a suitable solvent such as alcohol. Ascorbic acid, fumaric acid, maleic acid, pamoic acid, succinic acid, tartaric acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydrobenzoic acid, salicylic acid, methanesulfonic acid, ethanedisulfonic acid, reaction with a carboxylic or sulfonic acid, such as glucuronic acid, and then mixing with the first solvent to make the salt formed insoluble; precipitating by addition of another solvent, such as an ether; or an ethereal solution of the acid or base. 8. The method of claim 7, wherein salts of the amino alcohol derivative are produced by neutralizing the amino alcohol derivative with a base or acid to precipitate the salt. 9 In the general formula, R ₆ in the general formula is prepared by reacting an amino alcohol or its salt in which R ₆ is hydrogen with an excess of a suitable acid chloride or anhydride.
9. The production method according to claim 7 or 8, wherein an ester of an amino alcohol in which is different from hydrogen is produced. 10 General formula: (In the formula, (a) R ₁ is hydrogen, one or two methyl groups (C ₁ )
(b) R ₂ represents an alkyl group (C ₁ -C ₂ ); (c) R ₃ represents: - a mono- or polyunsaturated alkenyl group (C ₈ -
_C12 ); -mono- or polyunsaturated alkynyl group ( _C3 ~
_C12 ); - mono- or polyunsaturated alkynyl groups containing an oxygen atom ( _C3 - _C12 ); - straight-chain or branched alkyl groups ( _C2 - _C14 ); - selected from the group: Indicates a straight-chain or branched alkyl group ( _C2 - _C7 ) substituted with at least one atom and/or group: (1) oxygen or sulfur, (2) phenyl, phenoxy, phenylthio, benzoyl group, ( 3) with one methyl ( _C1 - _C4 ) or methoxy ( _C1 ) group, with one or two halogen atoms, or with nitrile, alkanoyl ( _C2 )
or a phenyl, phenoxy, or benzoyl group substituted with an acylamino (C ₂ ) group; (d) R ₄ represents hydrogen; or a morpholine group, or a phenyl or phenyl group when the nitrogen atom adjacent to R ₃ is fused; Enylalkyl ( _C1 - _C4 )
a piperidine group substituted with a group, or a piperazine group substituted in the 4-position with a phenyl group, or a phenyl group itself substituted with one methyl (C ₁ ) group to form a piperazine group substituted in the 4-position; R ₅ represents hydrogen or a methyl (C ₁ ) group; (f) R ₆ represents hydrogen or a straight-chain or branched alkanoyl (C ₁ -C ₈ ) group or a cycloalkanoyl (C ₃ -C ₆ ) group; (g) n represents an integer of 1, 2 or 3; (h) X represents sulfur or oxygen; and (i) Y represents a CH ₂ group; (In the formula, R ₁ , R ₂ , R ₅ , X and n have the same meanings as above, and Z represents a halogen atom such as Cl or Br).
characterized in that it is reacted with R ₃ R ₄ NH (wherein R ₃ and R ₄ have the same meanings as above) in the presence of a compound that scavenges the hydrogen halide formed, such as an inorganic or organic base or an excess amine. A method for producing an amino alcohol derivative and its salts. 11 The compound represented by the general formula is mixed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, etc., or formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, etc. in a suitable solvent such as alcohol. Ascorbic acid, fumaric acid, maleic acid, pamoic acid, succinic acid, tartaric acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydrobenzoic acid, salicylic acid, methanesulfonic acid, ethanedisulfonic acid, reaction with a carboxylic or sulfonic acid, such as glucuronic acid, and then mixing with the first solvent to make the salt formed insoluble; precipitating by addition of another solvent, such as an ether; or an ethereal solution of the acid or base. 10. The method of claim 9, wherein salts of the amino alcohol derivative are produced by neutralizing the amino alcohol derivative with a base or acid to precipitate the salt. 12 In the general formula, an amino alcohol in which R ₆ is hydrogen or a salt thereof is reacted with an excess of a suitable acid chloride or anhydride to obtain the compound in the general formula
Claim 10 or 11 which produces an ester of an amino alcohol in which R ₆ is different from hydrogen.
The method described in section.