CS199606B2 - Method of producing derivatives of 4-/2-hydroxy-3-aminopropoxy/indole - Google Patents

Description

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

R represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or an alkylmercaptoalkyl group containing 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, wherein each of R 3 and R 1, which may be the same or different, represents a vo199606 radical or an alkyl group having 1 to 6 carbon atoms, and

R2 is C1 -C6 alkyl, C1 -C6 hydroxyalkyl, C1 -C6 alkoxyalkyl, C1 -C6 pivaloyloxyalkyl or, in the case of C1 -C6 alkyl, or when R is as defined above alkylmercaptoalkyl or R1 is as defined above pivaloyloxyalkyl, R2 is also hydrogen, provided that at least one of R1 and R2 is hydrogen; represents a pivaloyloxyalkyl group as defined above and pharmacologically tolerable salts thereof.

The novel compounds of the present 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

S in which

R @ 1 represents a mercaptoalkyl group having 1 to 6 carbon atoms or has the same meaning as R @ 1,

X stands for \

C = O

Z or \

CH — OH,

OF

R 1 'and / or R 2' represents a C 1 -C 6 hydroxyalkyl group, one of which R 1 'and R 2' may also have the meaning of R 1 and R 2, respectively, reacted with pivalic acid or a reactive derivative thereof, when R 'is a mercaptoalkyl group, the compound obtained is additionally alkylated on a sulfur atom, in the case where X represents a group \

C = O,

Z is additionally reduced, and in the compounds of formula I thus obtained, optionally an R 1 substituent is additionally converted by saponification, esterification, re-esterification, acylation, or alkylation to another R 1 substituent.

The alkyl and alkoxy groups R, R 1, R 2, R 3 and R 4 preferably contain 1 to 5 carbon atoms and may be straight or branched, the alkyl groups R being preferably branched. The cycloalkyl groups R preferably contain 3 to 4 carbon atoms.

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 introduction of the pivoyl moiety to the hydroxyalkyl group or groups of compounds of formula II above is carried out under conventional acylation conditions, for example by reacting compounds of formula II with pivaloyl chloride under cooling in the presence of a base such as pyridine.

The aforementioned sulfur alkylation, when R, represents a mercaptoalkyl group, is conveniently also carried out in solvents of the above type with the exclusion of oxygen, using conventional S-alkylating agents.

Optional reduction of the grouping is effected 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 may be carried out in a conventional manner by saponification, eBterification, 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 are processed, for example, into tablets or dragees, or suspended or dissolved in water or in water oils, such as 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 to control the viscosity of high molecular weight polymers (such as liquid polyethylene oxide). Solid carriers are, for example, starches, lactose, mannitol, methylcellulose, talc, highly dispersed silicas, higher molecular weight fatty acids (such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular polymers). (such as polyethylene glycol). 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-tert-butylaminopropoxy) -6-pivaloyloxymethylindole

To a solution of 1.0 g of 4- (2-hydroxy-3- tert -butylaminopropoxy) -6-hydroxymethylindole in 25 ml of absolute pyridine was added dropwise 0.86 ml of pivaloyl chloride with stirring and cooling to 0-5 ° C. The reaction mixture was allowed to stand overnight at room temperature, then evaporated in vacuo and the residue partitioned between 50 ml of aqueous sodium bicarbonate solution and ethyl acetate. The organic phase was washed with water, dried and evaporated in vacuo. The residue is taken up in about 20 ml of ethyl acetate and a solution of 0.5 g of benzoic acid in 10 ml of ethyl acetate is added to the solution. The precipitate was filtered off with suction and dried to give 0.5 g (ca. 30% of theory) of chromatographically pure 4- (2-hydroxy-3-tert-butylaminopropoxy) -6-pivaloyloxymethylindole as the benzoate. The product melts at 193-195 ° C. Example 2

4- (2-hydroxy-3-tert-butylaminopropoxy) -2-pivaloyloxymethylindole

By analogy to the previous example, 1.0 g of 4- (2-hydroxy-3-t-butylaminopropoxy) -2-hydroxymethyl-indole and 0.86 ml of pivaloyl chloride are obtained after precipitation of the crude base from an ether solution by adding 0.5 g of acid. benzoic acid 0.83 g (ca. 50% theory) of chroimatographically pure 4- (2-hydroxy-3-tert-butylaminopropoxy) -2-plvaloyloxymethylindole as the benzoate, m.p. 149-151 ° C.

Example 3

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

In analogy to the previous examples, 1.5 g of 4- [2-hydroxy-3- (1-methylmercapto-2-methylisopropylamino) propoxy] -2-hydroxymethylindole and 1.08 ml of pivaloyl chloride are obtained after precipitation of the crude base from ether. solution by adding 0.7 g of benzoic acid and after recrystallization of the precipitated precipitate from isopropanol, 1.0 g (ca. 42% of theory) of chromatographically pure 4- [2-hydroxy-3- (1-methylmercapto-2-methylisopropylamino) propoxy] - 118 DEG-120 DEG C. 2-pivaloyloxymethylindole in the form of benzoate.

He attaches

4- [2-hydroxy-3- (1-methylmercapto-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. The solution was allowed to stand for 24 hours at room temperature, then for a further 3 hours at 50 ^° C, and then acidified with 2N hydrochloric acid to about pH 3.5. An oil precipitated which, after trituration with ethyl acetate and n-butanol, crystallized. After suctioning and drying, 1.6 g (65% of theory) of 4- [2-hydroxy-3- (1-methylmercapto-2-methylisopropylamino) propoxy] -2-carboxyindole hydrate are obtained.

Example 5

Preparation of benzoate

3.1 g (0.01 mole) 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 of ethyl acetate is added. The slowly precipitating precipitate is suctioned off after a while and dried. There were obtained 4.0 g (93%) of 4- [2-hydroxy-3- (1-methylmercapto-2-methylisopropylamino) propoxy] indole benzoate, m.p. 155 ^DEG C.

Claims (3)

1. A process for the preparation of the 4- (2-hydroxy-3-aminopropoxy) indole derivatives of the general formula I according to the invention which contain up to 6 carbon atoms or an alkylmercaptoalkyl group containing from 1 to 6 carbon atoms in each alkyl moiety; R 1 represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group, a C 1 -C 6 pivaloyloxyalkyl group in the alkyl moiety, and an C 1 -C 6 alkoxyalkyl group each in the alkoxy and alkyl moieties, (C 2 -C 7) alkoxycarbonyl, carboxyl or -CONR 3 R 4 radical, where each of R 3 and R 4, which may be the same or different, represents an atom in which: R represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 residues or an alkyl group having 1 to 6 carbon atoms, and R2 is C1 -C6 alkyl, C1 -C6 hydroxyalkyl, C1 -C6 alkoxyalkyl, C1 -C6 pivaloyloxyalkyl, or, in the case of C1 -C6 alkyl, or when R is as defined above alkylmercaptoalkyl or R1 is as defined above pivaloyloxyalkyl, Ra is also hydrogen, provided that at least one of R1 and R2 is as defined above as pivaloyloxyalkyl and pharmacologically tolerable salts thereof, the compound of formula II R @ 1 represents a mercaptoalkyl group having 1 to 6 carbon atoms or has the same meaning as R @ 1, X is a group C = O 2. The process of item 1, for the preparation of compounds of formula Ia OH AND O-CH 2 CH-CH 2 NH-R H (laj in which R is as defined in point 1, with the exception of the alkylmercaptoalkyl group, and their pharmacologically tolerable salts, characterized in that compounds of the formula IIIa are used as starting materials. OCH2X-CH-NH3 CHgH (HaJ in which X is as in 1, and R is as defined in this point. 3. The process of item 1, for producing compounds of formula 1b OH l,, O-CHrCH-CHrN-A-B-Ry or CH — OH, OF Rs (lb) R 1 'and / or R 2' represents a C 1 -C 6 hydroxyalkyl group, one of which R 1 'and R 2' may also have the meaning of R 1 or R 2, respectively, reacted with pivalic acid or a reactive derivative thereof, If R 'is a mercaptoalkyl group, the compound obtained is additionally alkylated on a sulfur atom when X is a group C = O, the compound obtained is additionally reduced, and in the compounds of the formula I thus obtained, optionally a R 1 substituent is subsequently converted by saponification, esterification, re-esterification, acylation or alkylation to another R 1 substituent, pharmacologically compatible salts. in which A * represents an alkylene group having 2 to 6 carbon atoms, B ‘represents a sulfur atom or the continuation of a single bond between R7 and A‘, R 7 represents a straight or branched alkyl group having 1 to 4 carbon atoms, and Re represents a pivaloyloxymethyl group, and pharmacologically tolerable salts thereof, characterized in that compounds of formula IIb are used as starting materials. O-C (X-CH) NH-A-B-R (b) HOCH in which X is as defined in point 1, and A ‘, B‘ and R 7 have the meanings indicated. Severography, n. P., Plant 7, N