CS228108B2 - Production of novel derivatives of 3-/4-phenoxymethylpiperidino/propanol - Google Patents

Description

The present invention relates to a process for the preparation of novel 3- (4-phenoxymethylpiperidino) propanol derivatives of the general formula I (> -,

where

R1 and R2 are the same or different and are hydrogen, (C1-C6) alkyl, (C1-C4) hydroxyalkyl, (C1-C6) alkanoyloxyalkyl or -CO-Z, wherein:

Z is hydroxy, C 1 -C 6 alkoxy or a group of formula

Ríi

Z —N \

R7

R 6 and R 7 may be the same or different and are hydrogen, C 1 -C 6 alkyl or C 1 -C 4 hydroxyalkyl,

R 3 is hydrogen or -O-R e, wherein

R 8 is hydrogen, C 1 -C 8 alkanoyl or benzoyl or naphthoyl optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 1 -C 2 alkoxycarbonyl , hydroxy, (C1 -C6) alkylthio, mini, nitro or trifluoromethyl;

R 4 and R 5 may be the same or different from each other and are hydrogen, halogen, hydroixyl, benzyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylthio, carboxyl, benzyloxycarbonyl or an alkoxycarbonyl group having 1 to 2 carbon atoms in the alkoxy group, their pharmacologically acceptable salts, the process for their preparation, and pharmaceutical preparations containing the compounds of the formula I.

Since the compounds of formula I, when R 5 is not hydrogen, contain an asymmetric carbon atom, the invention further provides optically active forms and racemic mixtures of these compounds.

The compounds of formula I and their pharmacologically usable salts have, at low toxicity, significant vasodilatory properties, which are mainly manifested in a decrease in blood pressure. In addition, suppression of adrenergic (3-receptors) has been observed.

Alkyl groups R 1, R 2, Rd, R 5, R 6, R 7 and R 8 are straight or branched groups having 1 to 6, preferably 1 to 4, carbon atoms such as methyl, ethyl, isopropyl, propyl, butyl, isobutyl , t-butyl or n-hexyl. However, methyl and ethyl are particularly suitable.

Hydroxyalkyl groups R 1, R 2, R e and R y contain 1 to 4 carbon atoms, preferably 2-hydroxyethyl and hydroxymethyl.

Alkoxy groups R 4, R 5, R 5 and Z contain 1 to 6, preferably 1 to 4 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, butoxy or pentyloxy. However, methoxy and ethoxy are preferred.

Suitable alkoxycarbonyl groups R @ 1, R @ 5 and R @ 6 in particular are methoxy and ethoxycarbonyl.

Alkylthio groups R @ 4, R @ 5 and R @ 8 are groups having from 1 to 6, preferably from 1 to 4, carbon atoms. Methyl mercapto is preferred.

The alkanoyl groups R @ 1 contain from 1 to 8, preferably from 1 to 6, carbon atoms, the alkyl groups having a straight, branched or cyclic chain. Acetyl and pivaloyl residues are preferred.

The alkanoyloxyalkyl radicals R 1 and R 2 are radicals having 1 to 6 carbon atoms, in particular an acetoxymethyl radical.

Aroyl groups R 5 are benzoyl and naphthoyl, which may preferably be substituted with methyl, halogen and methoxy groups.

For the purposes of the invention, halogen is fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine and bromine.

The novel compounds of the formula (I) according to the invention are prepared by the preparation of a compound of the formula (VIII) in a known manner

in which

R 1 and R 5 are as defined above, reduced and cyclized, and when R 6 represents an alkanoyl group having 1 to 8 carbon atoms or an optionally substituted benzoyl or naphthoyl group, the hydroxyl group optionally present as R 5 is esterified, or in the case where R 8 is hydrogen, an ester group optionally in the meaning of R 5 is hydrolyzed, or when one or more of R 1 and R 2 are hydroxymethyl, such a group is prepared from a hydroxymethyl, acyloxymethyl or alkoxycarbonyl group with C 1 -C 2 alkoxy by reduction or from C 1 -C 6 alkanoyloxymethyl by hydrolysis or by methyl reduction from C 1 -C 2 alkoxycarbonyl and optionally converting the obtained compounds to their pharmacologically useful salts.

Optionally, the reduction of the R 1 and R 2 substituents in the compounds of formula I is accomplished by complex metal hydrides such as lithium aluminum hydride or catalytic hydrogenation using noble metal catalysts or Raney nickel.

The hydrolysis of the groups R 1 and R 2 in the compounds of the formula I can be carried out in a manner known per se under acidic or basic conditions.

The esterification of the hydroxyl group R 3 may be carried out in a conventional manner by reaction with an acid halide or anhydride, optionally in the presence of an acid-binding agent, such as pyridine.

In order to convert the compounds of formula I into their pharmacologically acceptable salts, the compounds are reacted preferably in an organic solvent with an inorganic or organic acid, for example with hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, maleic acid. or benzoic acid.

The compounds of the formula I according to the invention can be formed in the form of a racemic mixture. The resolution of the racemate into the optically active forms is accomplished by known methods via diastereomeric salts. As active acids ss, predominantly tartaric acid, malic acid, camphoric acid and camphorsulfonic acid can be used.

For the preparation of medicaments, the compound of the formula I is admixed in a manner known per se with suitable pharmaceutical carriers, flavoring agents, flavoring agents and coloring agents, and compressed, for example, tablets or dragees or suspended or dissolved in water with the addition of the appropriate excipients, or in an oil such as olive oil.

The novel compound of the formula I according to the invention and its salts can be administered in liquid or solid form enterally or parenterally. Suitable injectable media are preferably water which, in the case of injectable solutions, contains conventional additives such as stabilizers, co-solvents or buffers. Such additives are, for example, tartrate and citrate buffers, ethanol, complexing agents [such as ethylenediaminetetraacetic acid and non-toxic salts thereof], high molecular weight polymers [such as liquid polyethylene oxide] to control viscosity. Solid carrier substances are, for example, starches, lactose, mannitol, methylcellulose, masquette, highly disperse silicic acid, high molecular weight fatty acids [such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal vegetable fats and solid high molecular polymers (such as polyethylene glycols). For oral administration, suitable preparations are, for example, those which may contain, for example, flavorings and sweeteners.

A preferred compound within the meaning of the present invention is, in addition to the Examples, as follows:

4- [2-hydroxy-3- (4-phenoxymethyl [piperidino] propoxy] -G-tert-butylindole.

The following examples illustrate in more detail the synthesis of the compounds of the invention. However, these examples are not intended to limit the scope of the invention in any way.

Example 1

4- [2-hydroxy-3- (4-phenoxymethylpiperidino] propoxy] indole

The following reaction scheme illustrates the preparation process:

OH i

O'CWrCH-CW _£ N, “Bo

CH *

OH l

, O-CH _? CH-CH-N CI-L0

CH,

AJ

OH

O-CH 2 CH-CH 3 N CH 2 O y a

and.

H

2-methyl-3-nitroepoxyphenol

10.7 g (0.07 mol) of 2-methyl-3-nitrophenol are dissolved in 55 ml of epichlorohydrin, a solution of 7.9 g of sodium methoxide (0.14 mol) in 75 ml of ethanol is added dropwise and the reaction mixture is stirred for 16 hours at room temperature. After removal of excess epichlorohydrin in vacuo, the residue is taken up in ether and extracted three times with water. After drying the organic phase with sodium sulfate and concentrating, 17 g of an oil remain, which crystallizes after trituration with isopropanol and ligroin. Filtration gave 8.6 g of 2-methyl-3-nitroepoxyphenol, m.p. 46-48 ° C (58% of theory).

1- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-methyl-3-nitrobenzene

4.2 g (0.02 mol) of the above compound are dissolved in 100 ml of n-butanol and added

3.8 g (0.02 mol) of 4-phenoxymethylpiperidine. After standing the reaction mixture overnight at room temperature, the formed crystals were filtered off, washed with a small amount of ligroin to give

6.9 g of the title compound, m.p. 103 DEG-104 DEG C. (86% of theory).

1- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-dimethylaminoethyl-3-nitrobenzene

3.0 g (0.0075 mol) of the above compound are dissolved in 20 ml of dimethylformamide, 1.6 ml (0.011 mol) of N, N-dimethylformamide dimethyl acetal are added and the mixture is heated under reflux for 8 hours. . Evaporation in vacuo left 4.0 g of an oily residue which was used for the next reaction without purification.

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indole

4.0 g of the crude product described above was suspended in <150 ml of methanol, 1.0 g of 10% palladium on carbon was added and the mixture was shaken with hydrogen for 2 hours. After the hydrogen uptake is complete, the catalyst is filtered off, concentrated, dissolved in ethyl acetate and the calculated amount of benzoic acid yields the benzoate.

Yield:

1.5 g (39% of theory), m.p. 145-147 ° C.

The following compounds are obtained in an analogous manner:

4- [2-hydroxy-3- [4- (2-chlorophenoxymethyl) piperidino] propoxy] indole benzoate, it. ít. 140-142 ° C (from ethyl acetate),

4- [2-hydroxy-3- [4- (3-chlorophenoxymethyl) piperidino] propoxy] indol benzoate, m.p. 149-151 [deg.] C (from ethyl acetate),

4- / 2-Hydroxy-3- [4- (4-chlorophenoxymethyl) piperidino] propoxy / indole benzoate,

1.1. 156-158 ° C (from ethyl acetate),

4- / 2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / indol benzoate, mp 115-117 ^° C (from ethyl acetate),

4- / 2-hydroxy-3- [4- (2-methylphenoxymethyl) piperidino] propoxy / indol benzoate, m.p. 128-129 ° C (from ethyl acetate),

4- [2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidino] propoxy] indole benzoate, m.p. 152-154 ° C (from ethyl acetate),

4- / 2-hydroxy-3- [4- (2-methylmercaptophenoxymethyl) piperidino] propoxy / indole, m.p. 108-110 ° C (ethyl acetate),

4- / 2-hydroxy-3- [4- (2-benzyloxyphenoxymethyl) piperidino] propoxy / indole oil,

4- / 2-hydroxy-3- [4- (4-benzyloxyphenoxymethyl) piperidino] propoxy / indole, mp 1.113 ° C (from ether),

4- / 2-hydroxy-3- [4- (2,5-dimethylphenoxymethyl) piperidino] propoxy / indole,

mp 153-155 ° C (from ethyl acetate),

5- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indole,

mp 121-123 ° C (from ethanol),

6- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indole,

mp 144-145 ° C (from ethanol),

4- (3- (4-phenoxymethylpiperidino) propoxy) indole,

mp 118-119 ° C,

5- [3- (4-Phenoxymethylpiperidino) propoxy] indole

mp, 107-108 ° C (from ethyl acetate),

6- (3- (4-phenoxymethylpiperidino) propoxy] indole,

mp 123-124 ° C (from isopropanol),

4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] indole, mp 103-105 ° C,

4- / 2-plvaloyloxy-3- (4- (2-methoxyphenoxymethyl) piperidino] propoxy / indole, m.p. 107 ° C (from ether),

4- [2-benzoyloxy-3- (4-phenoxymethylpiperidino) propoxyindole,

1.1. 108-100 ° C (from ether),

4- / 2-hydroxy-3- [4- (2-hydroxyphenoxymethyl) piperidino] propoxy / indole, mp 119-121 ° C,

223103

4- / 2-hydroxy-3- [4- (4-hydroxyphenoxymethyl) piperidino] propoxy / indole,

1.1. 167 ° C (from isopropanol),

4- / 2-hydroxy-3- [4- (2-carboxyphenoxymethyl) piperidino] propoxy / indole,

4- [2-hydroxy-3- (4-denoxymethylpiperidinidino) propoxy] -6-methoxycarbonylindole, m.p. 139-140 ° C (from ethyl acetate),

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methylindole, m.p. 122-123 ° C (from ethyl acetate),

2-ethoxycarbonyl-4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methylindole benzoate,

mp 139 ° C (from isopropanol),

4- [2-hydroxy-3- [4- (4-fluorophenoxymethyl) piperidino] propoxy] -6-methylindole, m.p. 137-139 ° C (from ethyl acetate),

4- [2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidino] propoxy] -6-methylindole benzate,

mp 138-140 ° C (from ethyl acetate),

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-hydroxymethylindole benzoate, m.p. 153-155 ° C (from ethyl acetate),

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-hydroxymethyl-5-methylindole;

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propyl] -5,6-dimethylindole; and

4- [2-pivaloyl oxy-3- ^{(4-fenoxymethylpiperid:} amino} propoxy] -6-meithy llndol, mp 81 ° C (from ligroin-ether), and

4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidina) propoxy) -6-pivaloyloxymethylindole, m.p. 76-78 ° C (from heptane / ether).

Claims (3)

Process for the preparation of the novel 3- (4-phe) derivatives of the formula I OF THE INVENTION oxymethylpiperidino is propanol in which: R 1 and R 2 are the same or different and are hydrogen, (C 1 -C 6) alkyl, (C 1 -C 4) hydroxyalkyl, (C 1 -C 6) alkanoyloxyalkyl or -CO-Z, wherein: Z is hydroxy, (C1-C6) alkoxy, or formula Re / —N \ Rz kde R 6 and R 2 may be the same or different and represent hydrogen, an alkyl group having 1 to 5 carbon atoms C 6 or C 1 -C 4 hydroxyalkyl, R 5 is hydrogen or -O-R e, wherein R 5 is hydrogen, C 1 -C 8 alkanoyl or benzoyl or naphthoyl optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 2 alkoxycarbonyl alkoxy, hydroxy, C 1 -C 6 alkylthio, nitrile, nitro or trifluoromethyl, R 4 and R 5 may be the same or different from each other and are hydrogen, halogen, hydroxyl, beinzyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylthio, carboxyl, benzyloxycarbonyl or (C 1 -C 2) alkoxycarbonyl, 220108 And their pharmacologically usable salts, characterized in that the compound of formula (VIII): wherein: R 1 to R 5 are as defined above, reduced and cyclized, and then when R is C 1 -C 8 alkanoyl or optionally substituted benzoyl or naphthoyl, the hydroxyl optionally present as R 3 is esterified or in the case where R 6 is hydrogen, the ester group, which is optionally R 5, is hydrolyzed, or when one or more of R 1 and R 2 are hydroxymethyl, such a group is prepared from a hydroxymethyl, acyloxymethyl or alkoxycarbonyl group having from 1 to 2 carbon atoms in the alkoxy moiety by reduction or from an alkanoyloxymethyl group having from 1 to 6 carbon atoms by hydrolysis or from the ss methyl group obtained by reduction from the alkoxycarbonyl group having 1 to 2 carbon atoms in the alkoxy moiety; .