CS199605B2 - Method of producing derivatives of 4-/2-hydroxy-3-aminopropoxy/indole - Google Patents

Description

The present invention relates to a process for the preparation of novel 4- (2-hydroxy-3-aminopropoxy) indole derivatives of the general formula I

OH i

O-CH 2 CH 2 -NH 2 NHR

R is an alkylmercaptoalkyl group containing from 1 to 6 carbon atoms in each alkyl moiety,

R1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms, a pivaloyloxyalkyl group having 1 to 6 carbon atoms in the alkyl moiety, an alkoxyalkyl group having 1 to 6 carbon atoms in both the alkoxy and alkyl moieties; (C 2 -C 7) alkoxycarbonyl, carboxyl or -CONR 3 R 4 radical, where each of R 3 and R 1, which may be the same or different, represents a hydrogen atom or a C 1 -C 6 alkyl group, and aa

R2 is C1 -C6 alkyl, C1 -C6 hydroxyalkyl, C1 -C6 alkoxyalkyl, C1 -C6 pivaloyloxyalkyl or, in the case of C1 -C6 alkyl, when R1 is a pivaloyloxyalkyl group as defined above, R2 is also a hydrogen atom, and a pharmacologically tolerable salt thereof.

The novel compounds of the invention and their pharmacologically tolerable salts block adrenergic β-receptors and are therefore suitable for the treatment or prophylaxis of heart and circulatory diseases.

The novel compounds of the invention are prepared by the preparation of a compound of formula II

H in which

R1 and R2 are as defined above,

B represents an alkylene group having 1 to 6 carbon atoms, and

X stands for \

C = O

Z or \

CHOH,

Z is reacted with a compound of formula III

HS-R 5, (III) wherein R 5 represents a hydrogen atom or a C 1 -C 6 alkyl group, when R 5 represents a hydrogen atom, the compound obtained is additionally alkylated on a sulfur atom when X represents a group \

C = O,

Z is additionally reduced, and in the compounds of formula I thus obtained, optionally a R 1 substituent within the above definition of R 1 is additionally converted by saponification, esterification, reesterification, acylation or alkylation to another R 1 substituent, followed by If appropriate, they are also converted into their pharmacologically compatible salts.

The alkyl, alkylene and alkoxy groups R, R 1, R 2, R 5, R 4, R 5 and B preferably contain 1 to 5 carbon atoms and may be straight or branched, wherein the alkyl and alkylene radicals R, R 5 and B they are preferably branched.

The starting materials of the formula II are obtained, for example, by reacting the compounds of the formula IV

in which

R 1 and R 2 are as defined above, X ‘represents a group \

c = o

Z or \

CH-A,

Wherein A represents a hydroxyl group or together with Y represents an oxygen atom, and

Y represents a reactive acid residue, with compounds of formula V (V) in which:

B is as defined above.

The reaction according to the invention is conveniently carried out in organic solvents inert under the reaction conditions, for example toluene, dioxane, ethylene glycol dimethyl ether, ethanol, n-butanol or dimethylformamide, optionally in the presence of acid binding agents. However, the reaction can also be carried out by allowing the mixture to stand at room temperature or with heating after mixing the reaction components.

The aforementioned sulfur alkylation, when R @ 5 in the general formula (III) represents a hydrogen atom, is conveniently also carried out in solvents of the above type with the exclusion of oxygen, using the usual S-alkylating agents.

Possible grouping reduction \

C = O

Z is carried out by treatment with sodium borohydride or by catalytic hydrogenation in the presence of noble metal catalysts.

Any additional conversions of R 1 to another R 1 can be carried out in a conventional manner by saponification, esterification, reesterification, acylation or alkylation. For example, a compound of formula I wherein R 1 is alkoxycarbonyl can be saponified to the corresponding carboxylic acid of formula I wherein R 1 is carboxyl. This saponification is carried out in a customary manner, preferably in a dilute alkali metal hydroxide solution.

The compounds of formula (I) are preferably converted into their pharmacologically acceptable salts in an organic solvent by treatment with an equivalent amount of an inorganic or organic acid, for example hydrochloric, hydrobromic, phosphoric, sulfuric, acetic, citric, maleic or benzoic acids.

For the preparation of medicaments, the compounds of the formula I are admixed in a manner known per se with suitable pharmaceutical carriers, flavoring agents, flavoring agents and coloring agents and processed, for example, into tablets or dragees, or suspended or dissolved in water or in oil with the addition of corresponding excipients. , for example in olive oil.

The novel compounds of the formula I and their salts can be administered in liquid or solid form enterally or parenterally. Water which contains additives usually added to injectable solutions, such as stabilizing agents, solubilizers or buffers, is preferably suitable as an injectable preparation medium. Such additives are, for example, tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) to control the viscosity. Solid carriers are, for example, starches, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acids, higher molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight. polymers (such as polyethylene glycols). Preparations suitable for oral administration may optionally contain flavoring and sweetening agents.

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention in any way.

Example 1

4- [2-hydroxy-3- (1-methylmercapto-2-methylsopropylamino) propoxy] indole

A mixture of 1.9 g of 4- (2,3-epoxypropoxy) indole and 5 ml of 2,2-dimethylaziridine was stirred at room temperature overnight and then at 40-50 ° C for 4 hours. The excess 2,2-dimethylaziridine was evaporated in vacuo and the residue taken up in 15 ml of isopropanol. This solution is slowly added to about 15 ml of isopropanol saturated at 0 ^° C with methyl mercaptan while cooling to 0-5 ° C. After standing at room temperature for about 20 hours, excess methyl mercaptan was removed by purging with nitrogen, 1.3 g of benzoic acid was added to the isopropanol solution, and the resulting solution was diluted with 100 mL of ether. The precipitate is filtered off with suction and dried, yielding 2.9 g of product, m.p. 155-157 ^° C. Partial concentration of the mother liquors yields 0.8 g of a second crystallizate, m.p. 155-156 ° C. A total of 3.7 g (86% of theory) of 4- [2-hydroxy-3- (1-methylmercapto-2-methylisopropylamino-propoxy) indole is obtained.

Preparation of benzoate

3.1 g (0.01 mol) of 4- [2-hydroxy-3- (1-methylmercapto-2-methylisopropylamino) propoxy] indole are dissolved in 50 ml of ethyl acetate and an equivalent amount of benzoic acid dissolved in a small amount is added. ethyl acetate. The slowly precipitating precipitate is suctioned off after a while and dried. 4.0 g (93% of theory) of 4- [2-hydroxy-3- (1-methylmercapto-2-methylisopropylamino) propoxyindole benzoate, m.p.

Example 2

4- [2-hydroxy-3- (1-ethylmercapto-2-methylisopropylamino) propoxy] indole

Mixture of 1.9 g of 4- (2,3-epoxypropoxy) indole a

3.5 ml of 2,2-dimethylaziridine was allowed to stand at room temperature for 3 days, then the excess 2,2-dimethylaziridine was evaporated under vacuum. The residue is taken up in 10 ml of ethyl mercaptan, the solution is left to stand at room temperature for 2 days and then evaporated in vacuo. The residue was dissolved in ether and a small amount of ethyl acetate, and 1.2 g of benzoic acid dissolved in 20 ml of ether was added. A precipitate formed which was filtered off with suction and recrystallized from isopropanol. 2.4 g (54% of theory) of 4- [2-hydroxy-3- (1-ethylmercapto-2-methylsopropylamino) propoxy] indole are obtained in the form of the benzoate, m.p.

Example 3

4- [2-Hydroxy-3- (1-isopropylmercapto-2-methylisopropylamino) propoxy] indole

A mixture of 1.7 g of 4- (2,3-epoxypropoxy) indole a

3.5 ml of 2,2-dimethylaziridine are allowed to stand at room temperature for 3 days, then the excess 2,2-dimethylaziridine is evaporated off under vacuum, the residue is taken up in 20 ml of isopropylmercaptan and the solution is heated to boiling for 20 hours. is worked up analogously to Example 2. It is obtained

1.5 g (34% of theory) of 4- [2-hydroxy-3- (1-isopropylmercapto-2-methylisopropylamino) propoxy] indole in the form of benzoate, m.p. 132-133 ^° C.

Example 4

4- [2-hydroxy-3- (1-methylmercapto-2-methylisopropylamino) propoxy] -2-methylindole

A mixture of 5.1 g of 4- (2,3-epoxypropoxy) -2-methylindole and 5 ml of 2,2-dimethylaziridine was allowed to stand at room temperature for 3 days, then the excess 2,2-dimethylaziridine was evaporated in vacuo. The residue is dissolved in 20 ml of a saturated isopropanolic solution of methyl mercaptan prepared at 0-5 ^° C. The mixture is allowed to react at room temperature for 2 days and then evaporated. The residue was dissolved in 30 ml of ethyl acetate and 3.0 g of benzoic acid in 10 ml of ether was added. The precipitate formed is filtered off with suction and recrystallized from approximately 30 ml of isopropanol. After aspiration and drying, 2.0 g (18% of theory) of 4- [2-hydroxy-3- (1-methylmercapto-2-methylisopropylamino) propoxy] -2-methylindole are obtained in the form of the benzoate, m.p. 151-152. ^; C.

Example 1 a d 5

4- [2-hydroxy-3- (1-methylmercapto-2-2-methylisopropylamino) propoxy] -2-carboxyindole

2.7 g of 4- [2-hydroxy-3- (1-methylmercapto-2-methylisopropylamino-propoxy) -2-ethoxycarbonylindole and 0.4 g of potassium hydroxide are dissolved in a mixture of 25 ml of ethanol and 5 ml of water. standing at room temperature for 24 hours, then at 50 ° C for a further 3 hours, then acidified to about pH 3.5 with 2N hydrochloric acid, and an oil precipitated upon trituration with ethyl acetate and n-butanol. 1.6 g (65% of theory) of 4- [2-hydroxy-3- (1-methylmercapto-2-methylisopropylamino) propoxy] -2-carboxyindole hydrate are obtained.

Example 6

4- [2-hydroxy-3- (1-methylmercapto-2-methylsopropylamino) propoxy] -6-methylindole

A mixture of 2.8 g of 4- (2,3-epoxypropoxy) -6-methylindole and 3.0 ml of 2,2-dimethylaziridine was allowed to react at room temperature for 2 days. Excess 2,2-dimethylaziridine was evaporated in vacuo, the residue dissolved in a small amount of isopropanol, and 50 mL of a saturated solution of methyl mercaptan in isopropanol was added at 0 ° C. After 2 days, the reaction mixture was evaporated in vacuo and the residue was dissolved in 35 mL of ethyl acetate. After addition of a solution of 1.7 g of benzoic acid in 10 ml of ether, a precipitate formed which was filtered off with suction and recrystallized from approximately 50 ml of isopropanol. 3.0 g (50% of theory) of 4- [2-hydroxy-3- (1-methylmercapto-2-methylisopropylamino) propoxy] -6-methylindole are obtained in the form of the benzoate, m.p. 174 DEG-175 ^DEG .

Claims (3)

SUBJECT A process for the preparation of 4- (2-hydroxy-3-aminopropoxy) indole derivatives of the general formula I R is an alkylmercaptoalkyl group containing from 1 to 6 carbon atoms in each alkyl moiety, R 1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms, a pivaloyloxyalkyl group having 1 to 6 carbon atoms in the alkyl moiety, an alkoxyalkyl group containing 1 to 6 carbon atoms in both the alkoxy and alkyl moieties; (C 2 -C 7) alkoxycarbonyl, carboxyl or -CONR 3 R 4 radical, wherein each of R 3 and R 6, which may be the same or different, represents a hydrogen atom or a C 1 -C 6 alkyl group, and R2 is C1 -C6 alkyl, C1 -C6 hydroxyalkyl, C1 -C6 alkoxyalkyl, C1 -C6 pivaloyloxyalkyl or, in the case of C1 -C6 alkyl, when R1 is a pivaloyloxyalkyl group as defined above, R2 is also a hydrogen atom, and a pharmacologically tolerable salt thereof; H in which R1 and R2 are as defined above, B represents an alkylene group having from 1 to 2 6 carbon atoms, and X represents a group \ C = O Z or \ CHOH, Z is reacted with a compound of formula III HS-R5, (III) in which R5 represents a hydrogen atom or a C1-6 alkyl group, when R5 represents a hydrogen atom, the compound obtained is additionally alkylated on a sulfur atom, when X represents a group \ C = O, Z is additionally reduced, and in the compounds of formula I thus obtained, optionally an R 1 substituent within the above definition of R 1 is additionally converted by saponification, esterification, reesterification, acylation, or alkylation to another R 1 substituent, followed by If appropriate, they are also converted into their pharmacologically compatible salts. 2. The process of item 1, for the preparation of compounds of formula Ia OH O-CH 2 CH H Ha) in which Z ‘represents an alkylene group having 2 to 6 carbon atoms, and R 6 represents a C 1 -C 4 alkyl group, and pharmacologically tolerable salts thereof, characterized in that compounds of formula IIa in which: X is as in 1, and Z * is as defined herein, and the compounds of formula IIIa HS — Re‘, (lila) in which R 5 is hydrogen or has the same meaning as R 6. 3. The process of item 1 for producing a compound of formula 1b OH O-CH 2 CH-CH 2 N-AH S-R10 containing from 1 to 3 carbon atoms or a pivaloyloxymethyl group in the alkyl and alkoxy moieties and pharmacologically tolerable salts thereof, characterized in that the compounds of the formula IIb are used as starting materials O-CA ^ -X-C / γύΡ < (l / b) ^K SH in which X is as in 1, and A ‘and R 5 are as defined herein, and compounds of formula IIIb HS — R7 ‘, (IIIb) in which R 7 * is hydrogen or has the same meaning as R 2. 4. A zipper according to item 1, for producing compounds of formula Ic Okay O-CH 2 OH-CH-NH-Z-S-R 4 R f ₉ / c). in which Z ‘has the meaning as in point 2, R 7 represents a straight or branched alkyl group having 1 to 4 carbon atoms, and R 8 represents a C 1 -C 4 alkyl group, a C 1 -C 4 hydroxyalkyl group, a C 1 -C 4 pivaloyloxyalkyl group, an C 1 -C 4 alkoxyalkyl group and a C 1 -C 4 alkoxyalkyl group; 2 to 5 carbon atoms, a carboxyl group or a radical of the formula -CO-NR 10 R 11, wherein each of R 10 and R 11, which may be the same or different, represents a hydrogen atom or a C 1 -C 4 alkyl group, and pharmacologically tolerable salts thereof, characterized in that the starting materials used are compounds of the general formula IIc in which: X is as in 1, and R / h white in which A * represents an alkylene group having 2 to 6 carbon atoms, R 7 represents a straight or branched alkyl group having 1 to 4 carbon atoms, and R 5 represents an alkyl group having from 1 to 5 carbon atoms C 3 -C 3 alkoxyalkyl 199B05 R9 and Z * are as defined herein, and compounds of formula IIIc HS-R7 *, [IIIc) wherein R 7 ^l is a hydrogen atom or has the same meaning as R7.