JPS6024100B2 - Method for producing aminopropanol derivatives - Google Patents

Description

Detailed Description of the Invention The present invention relates to the general formula: [wherein R represents a lower alkyl group, a cycloalkyl group, or an alkylmercaptoalkyl group, and R represents a hydrogen atom, a lower alkyl group, a hydroxyalkyl group, a pivalo yloxyalkyl group, alkoxyalkyl group, alkoxycarbonyl group, carboxyl group or group -CONR3R4
, in which R3 and R4 may be the same or different and represent a hydrogen atom or a lower alkyl group, and R2 is a lower alkyl group, a hydroxyalkyl group, a pivaloyloxyalkyl group, or R is an alkylmercaptoalkyl group. group or R. When represents a pivaloyloxyalkyl group, it also represents a hydrogen atom]
The present invention relates to derivatives and pharmacologically acceptable salts thereof.

The novel compounds and their pharmacologically acceptable salts inhibit adrenergic 3-receptors and are therefore suitable for the treatment or prevention of cardiac and circulatory diseases. The new compound is prepared by a method known per se, 'a} General formula (b): A compound of the general formula m: Z-R (m) [wherein R and R2 represent the above-mentioned ones, and R' is mercaptoalkyl] or the same as R, one of the groups Y and Z represents an amino group and the other a reactive group, × represents the group >C:○ or >CH-A, in which case A may represent a hydroxyl group or an oxygen atom together with Y, or 'b' with a compound of general formula N: [wherein R and R2 represent the above] is reacted with a compound of the general formula V: Y'-CH2-X-C string-NHR' (V) [wherein R' and × represent the above-mentioned ones, and Y' represents a reactive group], or {c- When R represents an alkyl group and a mercaptoalkyl group, the general formula W: [wherein R,
and R2 represent the above, B represents a lower alkylene group, and X' represents a group >C=○ or >CHOH], a compound of the general formula: HS-R5
(Punishment) React with the compound [in the formula, R5 represents a hydrogen atom or a lower alkyl group], or {d} R
, and/or R2 represents a pivaloyloxyalkyl group, the general formula side: 2, in which one of the groups R' or R'2 may represent R or R2] is reacted with pivalic acid or a reactive derivative thereof, and R' is a mercabutalkyl group. or, if R5 represents a hydrogen atom, subsequent alkylation with a sulfur atom; if X or X' represents a group >C=○, subsequent reduction; and, if desired, The compound is produced by subsequently converting one substituent R into another substituent R by saponification, esterification, ester substitution, acylation or alkylation.

The compounds of general formula 1 obtained by process {a}, {b}, (c} or [d}' can subsequently optionally be converted into their pharmacologically acceptable salts.

The alkyl radicals in the definition of the substituents R, R,, R2, R3, R4, R5 and B contain 1 to 6, preferably 1 to 5, carbon atoms and may be straight-chain or branched, The alkyl groups in the substituents R, R5 and B are preferably branched.

The cycloalkyl radical R may contain 3 to 6, preferably 3 to 4 carbon atoms. The reactive groups Y, Z and Y' in the compounds of the formulas 0, m and V are in particular acid groups, for example of hydrohalic acids and sulfonic acids.

The compound of general formula D is, for example, Helv 54th lid, 24th lid
18 (1971), amines of the general formula m are described in DE-OS 2045905.

A compound of formula 0 can be obtained, for example, by reacting a compound of formula 0 with a compound of formula:

The process to obtain the compounds of the invention is advantageously carried out in an inert organic solvent such as toluene, dioxane, ethylene glycol dimethyl ether, ethanol, n-butanol or dimethylformamide under reaction conditions, optionally in the presence of an acid binder. be.

However, the reaction can be triggered by standing at room temperature or heating after mixing the reaction components. The reaction of compounds of formula W with substances of formula V according to process {b} is advantageously carried out in the presence of an acid acceptor under oxygen exclusion. However, alkali metal salts of hydroxy compounds of formula W may also be used. method'd
The introduction of a pivaloyl group into the hydroxyalkyl group of a compound of the formula can be carried out under customary acylation conditions, for example by reacting the compound of the formula with pivaloyl chloride in the presence of a base, such as pyridine, with cooling.

S-Alkylation - If R in the formulas m, V and the valence represents a mercaptoalkyl group or R5 in the formula represents a hydrogen atom, the reaction with normal S-Alkylation may be carried out in a solvent of the type mentioned above, with exclusion of oxygen. - Advantageously, it is carried out using alkylating agents.

The optional reduction of the group >C=◯ is carried out using sodium shelphide hydride or by catalytic hydrogenation using noble metal catalysts. Groups R to be implemented as desired
, into other radicals R, may be carried out in the customary manner by saponification, esterification, ester substitution, acylation or alkylation.

For example, general formula 1 where R represents an alkoxycarbonyl group
can be subsequently hydrogenated to the corresponding carboxylic acids of the general formula 1 in which R, represents a carboxyl group; this is carried out in the customary manner, preferably in a dilute alkali metal hydroxide solution. do. For the conversion of a compound of general formula 1 into its pharmacologically safe salt, it is preferably added in an organic solvent to an equivalent amount of an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid. , reacted with citric acid, maleic acid, benzoic acid.

For the production of pharmaceutical preparations, the substance 1 is mixed in a manner known per se with suitable pharmaceutical carrier substances, fragrances, flavors and colorants and shaped, for example, as tablets or bran pills, or in a corresponding manner. Suspended or dissolved in water or in an oil, for example olive oil, with the addition of auxiliaries.

The novel substance 1 according to the invention and its salts can be applied orally or parenterally in liquid or solid form.

As injection medium it is advantageous to use water, which contains the additives customary in injection solutions, such as stabilizers, solubilizers or buffers. Such additives include, for example, tartrate salts.
and citrate buffers, ethanol, rust forming agents (e.g. ethylenediaminetetraacetic acid and non-toxic salts thereof),
A viscosity-adjusting polymer (for example, liquid polyethylene oxide). Solid killer substances are, for example, starch, lactose, mannite, methylcellulose, talc, highly disperse silicic acid, polymeric fatty acids (eg stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solids. There are high molecular weight polymers, such as polyethylene glycol, and preparations suitable for oral application may contain flavoring and sweetening agents as desired. Within the scope of the present application, in addition to the following examples, the following may also be advantageously provided: 4-[2-Hydroxy-3-(1-propylmercapto-2-methyl-isopropylamino)-propoxy]-indole 4-[2- Hydroxy-3-(1-
Methylmercapto-isopropylamino)-propoxy]-indole 4-[2-hydroxy-3-(2-methylmercapto-2-methyl-propylamino)-propoxy]-indole 4-[2-hydroxy-3-(1-
Methylmercaptoisopropylamino)-propoxy]-2-methyl-indole 4-[2-hydroxy-3
1-(1-methylmercaptoisopropylamino)-propoxy]-2-hydroxymethyl-indole 4-[
2-Hydroxy-3-(1-methylmercapto-isopropylamino)-propoxy]-2-ethoxycarbonylindole-4-[2-hydroxy-3-(1-methylmercapto-isopropylamino)-propoxy]-2-triol/ゞMoiruindole 4-[2-hydroxy-3-(1-methylmercaptoisopropylamino)
-propoxy]-2-dimethylaminocarbonylindole 4-[2-hydroxy-3-(1-methylmercaptoisopropylamino)-propoxy]-2-dimethylmercaptoisopropylamino)-2-hydroxy-indole 4-[2-hydroxy-3-(1-
Methylmercaptoisopropylamino)-propoxy]-12-methoxymethyl-indole 4-(2-hydroxy-3-sec-butylaminopropoxy)-12-pivaloyloxymethyl-indole 4-(2-hydroxy- 3-cyclobutylaminopropoxy)-2-pivaloyloxymethyl-indole 4-(2-hydroxy-3-tertiarybentylaminopropoxy)-2-pivaloyloxymethyl-indole 4-(2- hydroxy-3-sec-butylaminopropoxy)-6-hydroxymethyl-indole 4-[2-hydroxy-3-(
1-methylmercaptoisopropylamino)-propoxy]-6-hydroxymethyl-indole 4-[2-
Hydroxy-3-(1-methylmercapto-2-methyl-isopropylamino)-propoxy]-6-hydroxymethyl-indole-4-(2-hydroxy-3-(1)
-ethylmercapto-2-methyl-isopropylamino)-propoxy]-6-hydroxymethyl-indole4-[2-hydroxy-3-(1-inpropylmercapto-2-methyl-isopropylamino)-propoxy]-6-hydroxymethyl-indole 4-(2-hydroxy-3-sec-butylaminoproboxy)-6
-Methyl-indole 4-[2-hydroxy-3-(1
-methylmercapto-isopropylamino)-propoxy]-16-methyl-indole 4-[2-hydroxy-3-(1-ethylmercapto-2-methyl-isopropylamino)-propoxy]-6-methyl-indole 4
-[2-Hydroxy-3-(1-isopropylmercaf.

2-methyl-isopropylamino)-propoxy]
-6-methyl-indole 4-(2-hydroxy-3-
isobropylaminopropoxy)-6-pivaloyloxymethyl-indole 4-(2-hydroxy-3-sec-butylaminopropoxy)-16-pivaloyloxymethyl-indole 4-[2-hydroxy-3- (1
-Methylmercaptoisopropylamide/)-propoxy]-6-pivaloyloxymethyl-indole4-[
2-Hydroxy-3-(1-methylmercapto-2-methyl-isopropylamine/)-propoxy]-6-pivaloyloxymethyl-indole 4-[2-hydroxy-3-(1-ethylmercapto-2-methyl Example 1 4-[2-Hydroxy-3-(1-methylmercapto-2-methyl-isopropylamino) )-propoxy]-indole modification 1 4-(2,3-epoxypropoxy)-isodole5.
A mixture of 79 and 1-methylmercapto-2-methylpropylamine-27.1 was stirred at room temperature.

This viscous mixture is dissolved in about 50% of the mixture, followed by the addition of the ligroin. At this time, the precipitated crystals are vacuumed and
and after drying chromatographically pure melting point 119
~120 qo of 4-[2-hydroxy-3-(1-methylmercapto-2m-methyl-isopropylamide/)-propoxy]-indole 8.5 qo (92% of theory) are obtained. Variant 0 4-(2,3-epoxypropoxy)-indole 1.
The mixture consisting of 9 ml and 2,2-dimethyl-aziridine 5' was stirred overnight at room temperature and then for a further 40 to 50 ml.

Excess 2,2-dimethylaziridine is removed in vacuo. Take the residue in isopropanol 15. This solution is added to a solution of methyl mercaptan in about 150 g of saturated isopropanol at 0°C while slowly cooling to 0-5°C. After standing at about divalent room temperature, excess methyl mercaptan is removed by passing nitrogen through. Add 1.39% of benzoic acid to this isopropanol solution, and then add [
Dilute with After suction filtration and drying of the precipitate that separates out, 2.9 g of product with a melting point of 155 to 157 C0 is obtained. A second crystal is obtained by partially evaporating the mother liquor (0.8 ml, melting point 155-156 oz). 4
-[2-Hydroxy-3-(1-methylmercapto-2
The total yield of methyl-isopropylamino)-propoxy-indole amounts to 37 units (86% of theory).

Production of benzoate 41 [2-hydroxy-31 (1-methylmercapto-
2-Methyl-isopropylamino)-propoxy]-indole (0.01 mol) was mixed with 50 mol of acetate.
Add an equivalent amount of benzoic acid dissolved in a small amount of acetate.

After 2-3 hours, the slowly precipitated precipitate is sucked out and dried. The melting point is 4-[2-hydroxy-3] with a melting point of 155 qo.
-(1-Methyl-2-methyl-isopropylamino)-propoxy]-indole-benzoate4.
0 min (93% of theory) is obtained. Example 24-[2-hydroxy-3-(1-ethylmercapto-2-methyl-isopropylamino)-propoxy]-indole 4-
A mixture consisting of 1.9 mol of (2,3-epoxypropoxy)-indole and 3.5 ml of 212-dimethylaziridine is left at room temperature for 3 days.

Excess 2,2-dimethylaziridine is removed in vacuo.
The residual light is taken up in 10 ml of ethyl mercaptan and the solution is stored at room temperature for 2 days. It is then concentrated by evaporation in vacuo and the residue is dissolved in ether and a little acetate. After adding 1.2 parts of benzoic acid dissolved in 20 parts of ether, a precipitation occurs. This is filtered by suction and recrystallized from isopropanol. 4-[ as a benzoate salt with a melting point of 161°C
2.4 units (54% of theory) of 2-hydroxy-3-(1-ethylmercapto-2-methyl-isopropylamino)-propoxy]-indole are obtained. Example 3 4-[2-hydroxy-3-(inpropylmercapto-2-methyl-isopropylamino)-propoxy]-indole 4-(2,3-epoxybropoxy)-indole 1.7 and 2,2-dimethyl aziridine 3.5
The mixture consisting of is left at room temperature for 3 days.

Excess 2,2-dimethylaziridine is removed in vacuo.
The remaining liquid was poured into inpropyl mercapto 20ml, and the solution was heated for 2 hours to boil. It is then concentrated by evaporation in vacuo and worked up as in Example 2. Melting point 1 as benzoate
32 to 133 ○ 4-[2-hydroxy-3-(1-
1.52 (% of theoretical speck) of isopropylmercapto-2-methyl-isopropylamino)-propoxy]-indole is obtained. Example 44-[2-Hydroxy-3-(
1-Methylmercapto-2-methyl-isopropylamino)-bropoxy]-2-methyl-indole 4-(2
3-Epoxypropoxy) A mixture of 2-methyl-indole 5.1 and 212-dimethylaziridine 5 is kept at room temperature for 3 days.

Excess 2,2-dimethylaziridine is distilled off in vacuo. Qianlien is dissolved in a solution of methyl mercaptan in saturated isopropanol at 0-5°C. The mixture is kept at room temperature for 2 days and then concentrated by evaporation. Dissolve Zanwan in 30 parts of ester acetate, and add 10 parts of ether to the solution.
Add 3.0 ml of benzoic acid. The deposited precipitate is suctioned and recrystallized from about 30 g of isopropanol. After suction filtration and drying, 4-[2-hydroxy-3-(1-methylmercapto-2-methyl-isopropylamide/)-propoxy]-2-methyl-indole as a benzoate salt with a melting point of 151-1520 was obtained. (18% of theory) is obtained. Example 5 4-[2-hydroxy-3-(1-methylmercapto-2-methyl-isopropylamino)].

poxy-]-2-hydroxymethyl-indo--4
A mixture consisting of 8.2% of 1[2,3-epoxypropoxy)-2-hydroxymethyl indole and 25.35% of 1-methylmercapto-2-methylpropylamine was stored at room temperature for 2 hours and then ether and acetate.

The organic phase is shaken out with dilute acetic acid and discarded. The acetic acid aqueous phase is made alkaline and extracted with ether/acetate. The solution is washed with water, dried and evaporated.
The residue was dissolved in 25 parts of acetate, and 4.1 parts of benzoic acid to 25 parts of acetate was added to the solution. The first crystals consist almost exclusively of the benzoate salt of 1-methylmercapto-2-methylpropylamine-2 and are discarded. After partial evaporation of the mother liquor and addition of a small amount of ether, 5.2 g of crude product is obtained. This is recrystallized from 100% acetate. After suction and drying, melting point 124-1
As the benzoate of 2 and 0, 4-[2-hydroxy-3-(1-methylmercapto-2-methyl-isopropylamino)-propoxy]-2-hydroxymethyl-indole 3.5 (% of theoretical amount) can get. Example 6 4-[2-hydroxy-3-(1-methylmercapto-2-methyl-isopropylamino)propoxy]-2-pivaloyloxymethyl-indole 4-(2,3-epoxypropoxy)-2-pivaloyl Oxymethyl indole 5.3 times and 1-methylmercapto 2-methylpropylamine-2 2.5 times isopropanol 5 times
Be sure to flood to 50℃ for 3 sections.

It is then concentrated by evaporation in vacuo and the residue is partitioned between ether and dilute acetic acid. The acetic acid phase is made alkaline and extracted with ether. The ether solution is dried, nearly evaporated and benzoic acid is added. The solution is concentrated in vacuo and the residue is recrystallized from a small amount of isopropanol.
After suction and drying, 4-[2-hydroxy-3-(1-methylmercapto-2-methyl-isopropylamino)-proboxy]-2-pivaloyloxymethyl as the benzoate salt with a melting point of 119-121°C. Endor 1.
5 ml (~16% of theory) is obtained. Example 7 4-[2-Hydroxy-3-(1-methylmercapto-2-methyl-isopropylamide/)propoxy]-2-ethoxycarbonyl-indo--/4-(2,3-epoxypropoxy)- 5.2 hours of ethoxycarbonyl-indole and 22.6 hours of 1-methylmercapto-2-methylpropylamine are mixed under mild warming until a homogeneous mixture forms.

After standing overnight at room temperature, the batch is partitioned between ether/acetate and dilute acetate. The acid phase is made alkaline with potassium carbonate and extracted with acetate/ether. The extract is dried and concentrated by evaporation, toluene is subsequently added twice to the residue and concentrated by evaporation. Dissolve the residue in about 50 ml of acetic acid ester and add 1 ml of benzoic acid.
．． Add 7 evenings. Suction and sieve the precipitate and dry. 4-[2-
Hydroxy-3-(1-methyl-mercapto-2-methyl-isopropylamino)-propoxy]-2-ethoxycarbonylindole 4.1 units (~40% of theory)
) is obtained. Example 84-[2-hydroxy-3-(1-methylmercapto-2-methyl-isopropylamino)
-propoxy] 12-carbamoyl indole 41 (
2.3-epoxypropoxy)-2-carbamoyl indole 9.5 hours and 1-methylmercapto 2-methylpropylamine-2 4.4 hours under mild heating until a homogeneous mixture is formed. Worship the dolls.

The batch is kept overnight at room temperature and then triturated with ether. The solid residual light is filtered with suction and taken up in 100ml of isopropanol. For this purpose, a solution of 3.5 parts of maleic acid in 50 parts of isopropanol is obtained. The slowly precipitated precipitate is sucked up and dried. 4-[2-Hydroxy-3-(1-methylmercapto-2-methyl-isopropylamino) as a maleate salt with a melting point of 119-121°C
-propoxy]-2-carbamoyl indole 3.8
23% of theory is obtained. Example 94-[2-Hydroxy-3-(1-methylmercapto-2-methyl-isopropylamine/)-propoxy]-2-dimethylaminocarbonylindole 4-(2,3-epoxypropoxy)-2-dimethylfuminocarbonyl 9.2 ml of indole and 2 ml of 1-methylmercapto-2-methylpropylamine are mixed together under mild warming until a homogeneous mixture results.

After 2 days at room temperature, the batch is triturated three times with ether. Discard the ether extract and dissolve the residue in acetate and treat with activated charcoal. After adding 2.1 g of benzoic acid dissolved in a small amount of acetate, a precipitation occurs.
It is filtered with suction and recrystallized twice from a little isopropanol with a little methanol. Melting point 114-1
2.7 (18% of theory) of 4-[2-hydroxy-3-(1-methylmercapto-2-methylisopropylamino)-propoxy]-12-dimethylaminocarbonylindole was obtained as a benzoate with 1 being C. It will be done. Example 10 4-[2-hydroxy-3-(1-methylmercapto-2-methyl-isopropylami/)propoxy]-2-carboxyindole 4-[2-hydroxy-3-(
A mixture of 2.7 parts of 1-methylmercapto (2-methyl-isopropylamino)-propoxy]-2-ethoxycarbonyl indole (see Example 7) and 0.4 parts of potassium hydroxide, 25 parts of ethanol and 5 parts of water. dissolve in

The solution is kept at room temperature for 2 hours and with a further 5000 hours of water.
Subsequently, the pH was adjusted to about 3.5 with hydrochloric acid. The oil produced at this time is crystallized by crushing the bonito flakes with acetate and n-butanol. After suction and drying, 4-[
2-Hydroxy-3-(1-methylmercapto-2-methyl-isopropylamino)-propoxy]-2-carboxyindole hydrate (theoretical amount of 6
5%) is obtained. Example il 4-[2-hydroxy-3-(1-methylmercapto-2-methyl-isopropylamino)-propoxy]-2
-methoxymethyl-indole/shi4-(2,3-epoxypropoxy)-2-methoxymethyl-indole1.
4 ml and 1-methylmercapto-2-methylpropylamine-20.72 ml were mixed under mild heating to form a homogeneous mixture.

After 2 days at room temperature, dissolve in ether and extract the ether phase with IN-tartaric acid. The organic phase is discarded, the aqueous phase is made slightly alkaline with sodium bicarbonate solution and extracted with ether. After drying and evaporating the solution, the residue is dissolved in a small amount of ether/acetate 1:1 and 0.6 parts of benzoic acid in 5 parts of ether is added to the solution. First, remove the precipitate that is precipitated in the form of oil. This oil crystallizes out on trituration with acetate (0.5 min). After inoculation, an additional 0.8 g of crude product crystallizes from the lagoon material. The combined crude product was diluted with 10% of isopropanol [
After recrystallization from 4-[2-hydroxy-3-(1-methylmercapto-2-methyl-isopropylamino)-propoxy]-12-methoxymethyl-indole as a benzoate salt with a melting point of 104-1070. 0 min (35% of theory) is obtained. Example 12 4-[2-hydroxy-3-tert-butylaminopropoxy)-2-pivaloyloxymethyl-indole 4
3.19 of 1(2,3-epoxypropoxy)-2-pivaloyloxymethyl-indole is dissolved in 25' of tert-butylamine.

The mixture is kept at room temperature for 2 days and then concentrated by evaporation in vacuo. Partition the retentate between dilute acetic acid and ether.
The ether phase is discarded, the acetic acid solution is made slightly alkaline and extracted several times with ether. The ether solution is dried and concentrated by evaporation. The crystalline residue (1.9 hours) is taken up again in ether and 0.63 hours of benzoic acid is added to the solution. After 2-3 hours, the slowly precipitated precipitate is suctioned and dried. Chromatographically pure 4-(2-hydroxy-3-tert-butylaminopropoxy)-2-pivaloyloxymethyl-indole (a theoretical amount of 40%) is obtained. The 4-(213-epoxypropoxy)-2-pivaloyloxymethyl-indole used as starting material is prepared as follows: 4-[2,3-epoxypropoxy)-2-hydroxy 11.5 ml of methyl-indole (see US Pat. No. 3,705,907) is dissolved in 100 ml of pyridine.

To this was added 6.5 minutes of pivaloyl chloride (6.5 hours) while cooling to 0-5℃.
．． 7 secretion). After 1 hour, the mixture is poured onto ice and extracted with ether.

The ether solution is washed successively with dilute sulfuric acid, bicarbonate solution and water. After drying and treatment with activated carbon, the solution is concentrated by evaporation. Residue (13th evening, 82% of theoretical amount) is ether/
Crystallizes during grinding with ligroin; melting point 129-13
100. Example 13 4-[2-Hydroxy-3-isopropylaminopropoxy)-2-pivaloyloxymethyl-indole 4-(2,3-epoxypropoxy)-2-pivaloyloxy 4-(2-hydroxy-3-isopropylaminopropoxy)-2 as a benzoate with a melting point of 1 to 135 qo from methyl-indole 2.6 and isopropylaminol/10
1.1 kg (27% of theory) of -pivaloyloxymethyl-indole are obtained.

Example 14 4-[2-hydroxy-3-cyclop.

pyraminopropoxy)-2-pivaloyloxymethyl-indole by the method described in Example 12.
- 4-(2-Hydoxypropoxy) 4-(2-hydroxypropoxy) as the benzoate salt with a melting point of 146-147q0 from 2-pivaloyloxymethyl-indole 2.0 and cyclopropylamine 4. 2.7 units (85% of theory) of 2-bivaloyloxymethyl-indole (pyraminopropoxy) are obtained. Example 15 4-[2-Hydroxy-3-tertiary butylaminopropoxy)-6-hydroxymethyl-indole 4-(2
Dissolve 3-epoxypropoxy-16-hydroxymethyl-indole 5 in tertiary butylamine 25.

The mixture is stored for 2 days at room temperature, then gently heated to the boil for about an additional hour and then concentrated by evaporation in vacuo. Partition the total residue between diluted acetic acid and ether. Discard the Table phase, adjust the acetic acid solution to alkalinity and shake out with ether. After drying and evaporating the ether phase, the base obtained is recrystallized from a small amount of acetate/ether (3.3 pm, mp 129-13100). 3.0 parts of this base is dissolved in a mixture of about 10 parts acetate and 20 parts isopropanol. Addition of 1.2 hours of benzoic acid causes slow precipitation of the benzoate salt. After suction filtration and drying, 4-(2
-Hydroxy-3-tert-butylamino-propoxy)
3.4 units (41% of theory) of 1-6-hydroxymethyl indole are obtained. 4- used as starting material
(2,3-epoxypropoxy)-16-hydro.

Oxymethyl-indole is produced as follows:
N. R. J. prakt. Che by EL-Rayyes
m. ), No. 315, p. 295 (King, 1973), 4-acetoxy-6-methoxycarbonylindole was saponified with sodium methylate under oxygen exclusion to give 4-hydroxy-6. -Methoxycarbonylindole.

4-Hydroxy-6-methoxycarbonyl indole thus obtained 22.2 hours, dried potassium carbonate 1
6.5 minutes and 15.9 degrees of pendyl chloride were heated in 200 degrees of anhydrous dimethylformamide (DMF) at 80-90 qo for 3 hours. Approximately 100-150 DMs
F is evaporated off in vacuo and water and ether are added to the residue. The ether phase is separated and the aqueous phase is extracted several times with ether. The combined ether extracts are dried, clarified with activated charcoal and concentrated by evaporation. The crystallized residue is recrystallized from ethanol with the addition of activated carbon. 18.0 kg (53.5% of theory) of almost colorless crystals with a melting point of 160-16°C are obtained. The 4-benzyloxy-6-methoxycarbonyl indole thus obtained was slowly evaporated with 24.8 ml of solution in anhydrous tetrahydrofuran (THF) and 1
Add dropwise to a suspension of 5.3 ml of aluminum hydride in 150 ml of anhydrous THF while cooling to 5-20 ml.

After 4 hours, excess reducing agent was removed by adding 25 ml of saturated saline solution.
Decomposes by adding.

The precipitate that separates out is suction filtered and washed with ether. The oak liquor is dried, treated with activated carbon and concentrated by evaporation. The remaining brown oil crystallizes upon trituration with ether/ligroin. After filtration with suction and drying, 18.6 slightly colored crystals (83% of theory) with a melting point of 118-12000 are obtained. 18.5 ml of the 4-benzyloxy-6-hydroxymethyl indole thus obtained was mixed with 20 ml of methanol.
Palladium-carbon catalyst (10:90) in 0'3
．． Hydrogenation is carried out at normal pressure and room temperature after 0 hours of addition.

After 2 hours, starting material is no longer observed in the thin layer chromatogram.

The catalyst is filtered off with suction and the oak liquor is concentrated by evaporation in vacuo. The solid residue is ground with ether and passed through a suction filter. Melting point 1
10.0 units (84% of theory) of 4-hydroxy-6-hydroxymethyl-indole of 68 to 16 units are obtained. 3.3 times of the 4-hydroxy-6-hydroxymethyl-indole thus obtained was added to epichlorohydride.
Dissolve to 0M. To this solution, 20 g of sodium methylate solution was added dropwise under a saucepan at room temperature for about 1 hour. After about 5 hours, the starting materials are reacted. The solution is concentrated in vacuo and water and a mixture of ether and acetate are added to the remaining bamboo. The organic phase is shaken several times with water, then dried, treated with activated charcoal and concentrated by evaporation. The crude 4-(2,3-epoxypropoxy)-6 thus obtained
-Hydroxymethylindole (brown oil - 50%) contains a small amount of 4-(2-hydroxy-3-chloropropoxy)-16-hydroxymethyl-indole as a by-product and is used after purification. Example 16 4-(2-Hydroxy-3-isopropylaminopropoxy)-6-hydroxymethyl-indole In the same manner as described in Example 15, 4-(2,3-epoxypropoxy)-6-hydroxymethyl-indole 5.19 and isopropylamine 25% melting point 171-17〆0
4-(2-hydroxy-3-isopropylaminopropoxy)-6-hydroxymethyl-indole (41% of theory) is obtained as the benzoate salt.

Example 17 4-(2-hydroxy-3-tertiary butylaminope).

Poxy)-16-methyl-indole 4-(2,3-epoxypropoxy)-16-methyl-indole 2.39 is dissolved in tert-butylamine. The mixture is stored for 3 days at room temperature and then concentrated by evaporation in vacuo. The afterlight is subjected to monoacid separation as described in Example 15. The residue obtained at this time (2.2 nights) was dissolved in a small amount of acetate. Upon addition of 1.0 μl of benzoic acid, a crystalline precipitate slowly separates out. After suction filtration and drying, melting point 198-2
4-(2-hydroxy-3) as the benzoate of 00oo
1.5 units (33% of theory) of 6-methyl-indole (-tert-butylaminopropoxy) are obtained. The 4-(2,3-epoxypropoxy)-6-methyl-indole used as starting material is obtained in the following way: 4-benzyloxy-6-hydroxymethyl-indole (starting from Example 15) in pyridine 50. (See Material Preparation) 10. Carefully add 50M acetic anhydride to the solution.

This mixture was stored overnight at room temperature and subsequently in vacuo for 40 minutes.
Evaporate and concentrate at 00. Take the remaining part. The ether phase is washed successively with water, IN-sulfuric acid and again with water. The dry solution is treated with activated carbon and concentrated by evaporation. 4-benzyloxy-6-acetoxymethyl-indole 9.9 hours (
~80% of theory) is obtained, which is worked up as crude product (melting point ~100° C.).

9.8 hours of the 4-penzyloxy-6-acetoxymethyl-indole thus obtained is hydrogenated in 200 g of methanol with the addition of 2 g of palladium-carbon catalyst (10:90).

After about 3 hours, starting material is no longer present. The catalyst is filtered off with suction and the liquor is concentrated in vacuo. actually 100%
4-Hydroxy-6 obtained as a pale yellow oil in a yield of
-Methyl-indole reacts further after purification. Coarse 4
-Hydroxy-6-methyl-indole 6.4 days Example 1
React with epichlorohydrin and work up as described in 5. 4-(2,3-epoxypropoxy)-16-methyl-indole and 4-(2-epoxypropoxy) obtained at this time.
-Hydroxy-3-chloropropoxy)-6-methyl-indole is chromatographed on a silicic acid gel column (methylene chloride/methanol 99:1~
95:5 to Hina). Thus, 4-(2,3-epoxybropoxy)-6-methyl-indole (relative to 4-benzyloxy-6-acetoxymethyl-indole) was obtained as a chromatographically pure, almost colorless oil. 41.5% of theory) is obtained. Example 18 4-(2-Hydroxy-3-isopropylaminopropoxy)-6-methyl-indole 4-(2,3-epoxypropoxy)-6
-Methyl-indole 4.0 and isopropylamine 25' to give 4-(2-hydroxy-3-isopropylaminopropoxy)-6-methyl-indole 3.
0 (41% of theory) is obtained as the benzoate salt with a melting point of 182-184q.

Example 19 4-[2-hydroxy-3-(1-methylmercapto-
2-Methyl-isopropylamino)-p.

[poxy]-6-methyl-indole 4-(2,3-epoxypropoxy)-6-methyl-indole and 3.0 ml of 2,2-dimethyl-aziridine were heated at room temperature for 2 days. Store in.

Excess 2,2-dimethylaziridine is removed in vacuo. Dissolve the pickles in a small amount of isopropanol, and then
Add 50 parts of a solution of methyl mercaptan in isopropanol saturated at 0°C. After 2 days it is concentrated by evaporation in vacuo.

The residue was dissolved in 35 ml of acetate. ether 10
After adding a solution of 1.7 g of benzoic acid, a precipitate forms, which is filtered off with suction and recrystallized from about 50 g of isopropanol. 4-[2-Hydroxy-3-(1-methylmercapto-2-methyl-isopropylamino)-propoxy]-6-methyl-indole (50% of theory) is benzoic acid with a melting point of 174-175°C Obtained as salt.

Example 20 4-(2-hydroxy-3-tert-butylaminope.

poxy)-6-pivaloyloxymethyl-indole 4
1 (2.3-epoxypropoxy)-6-piva.

12.7 ml of methyloxymethyl indole is stored in 50 ml of tert-butylamine for 2 days at room temperature. Excess tert-butylamine is removed in vacuo. The residue is dissolved in IN-acetic acid and the solution is extracted with ether. The aqueous phase is made alkaline with dilute potassium carbonate solution and shaken out with an ether/acetate mixture. The organic phase is dried, treated with activated carbon and concentrated by evaporation. The residue is dissolved in 50 parts of acetate and 2.6 parts of benzoic acid dissolved in 30 parts of ether are added to the solution. The precipitate that has separated out is filtered off with suction and recrystallized from a 1:1 mixture of methanol and ethanol. 5.3 (35% of theory) of 4-(2-hydroxy-3-tert-butylaminopropoxy)-6-pivaloyloxymethyl-indole is obtained as the benzoate salt with a melting point of 194-190. .

The 4-(2,3-epoxypropoxy)-6-pivaloyloxymethyl-indole used as starting material is prepared as follows: 4-(2,3-epoxypropoxy)-6- Hydroxymethyl-indole (Example 15
(See Preparation of Starting Materials) 8.7 and 50% of anhydrous pyridine.

To this, add 5 parts of pivalic acid chloride dropwise while cooling for 5 to 1,000 ml of Sumiko. 1.5-2 hours after the addition is complete, pour the mixture into ice water. The aqueous phase is extracted 3-4 times with ether. The ether extract is washed successively with IN-sulfuric acid, saturated sodium bicarbonate solution and water, dried, treated with activated charcoal and bleach and subsequently concentrated by evaporation. Crude 4-(2,3-epoxypropoxy) thus obtained
-6-pivaloyloxymethyl-indole (12.5
(~100% of the theoretical amount) is reacted without further purification. The following experiment was carried out to determine the cardiac 81-receptor inhibitory effect of certain experimental compounds by measuring the inhibition of the increase in cardiac characteristic caused by intravenous application of isoprenaline. Compound 1:4-[2-hydroxy-3-(1-methylmercapto-2-methyl-isopropylamino)propoxy]-indole Compound 0:4-(2-hydroxy-
3-tertiary butylaminopropoxy)-2-pivaloyloxymethyl-indole, compound m: 4-(2-hydroxy-3-isopropylaminopropoxy)-2
-pivaloyloxymethyl-indole, compound W: 4
-(2-hydroxy-3-tert-butylaminopropoxy)-6-hydroxymethyl-indole, compound V
: 4-(2-hydroxy-3-tert-butylamino-bropoxy)-6-methyl-indole, compound W: 4-
(2-Hydroxy-3-isopropylamino/-propoxy)-6-methyl-indole, the following were included as comparative compounds: Compound A: 1-isopropylamino-3-(1-naphthoxy)-2 -Propanol (Propanolol) These compounds were tested in the following manner: The 8-1 receptor inhibitory effect of the test compounds was tested on awake rabbits weighing 2-3.5k9 placed in wooden boxes.

An EKG electrode was inserted subcutaneously into the rabbit, and the heart number was measured as a digital quantity using an integrator (19 sand). Experimental compounds were then injected into the rabbit ear vessels through a thin tube over a period of 18 minutes. After 30 minutes, injection solution isoprenaline (3,4-dihydroxy-Q-[(isopropylamino)-methyl]-penzyl alcohol)
was injected intravenously at 1 mta/k9.

The results are listed in the table below regarding the inhibition of isoprenaline tachycardia: Table 1. It indicates the dose at which the compound is already effective at a dose much lower than the required dose of the comparator.

The compounds according to the invention are therefore surprisingly superior to the known compounds, and the invention therefore makes a significant contribution to the known art. The dosage of the novel compounds according to the invention depends on the age, weight and condition of the patient being treated.

Claims (1)

[Claims] 1 General formula I: ▲ Numerical formulas, chemical formulas, tables, etc. , hydroxyalkyl group, pivaloyloxyalkyl group, alkoxyalkyl group, alkoxycarbonyl group, carboxyl group or group -CONR_3
R_4, R_3 and R_4 may be the same or different and represent a hydrogen atom or a lower alkyl group, and R_2 is a lower alkyl group, a hydroxyalkyl group, a pivaloyloxyalkyl group, or R is an alkylmercaptoalkyl group. or a pharmacologically acceptable salt thereof. 2 4-(2-hydroxy-3-tert-butylamino-
The derivative according to claim 1, which is propoxy)-2-pivaloyloxymethyl-indole. 3 4-(2-hydroxy-3-tert-butylamino-
The derivative according to claim 1, which is propoxy)-6-methyl-indole.