CS228110B2 - Production of novel derivatives of 3-/4-phenoxymethylpi - Google Patents

Description

(54) A process for the preparation of new 3- (4-phenoxymethylpiperidino) propanol derivatives

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

where

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 \

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 5 is hydrogen or -O-R 8, wherein

R is hydrogen, an alkanoyl group having 1-8 carbon atoms or benzoyl or naphthoyl group optionally substituted with halogen, ^and! (C 1 -C 6) alkyl, (C 1 -C 6) alkyloxy, (C 1 -C 2) alkoxycarbonyl, hydroxy, (C 1 -C 6) alkylthio, nitrile, nitro or trifluoromethyl group,

R d and R s can be the same or different from each other and are hydrogen, halogen, hydroxyl, benzyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylthio, carboxyl, benzyloxycarbonyl or (C 1 -C 2) alkoxycarbonyl,

X and Y are the same or can be different from each other and are a nitrogen atom or a group —C = i

R9 where

R 8 is hydrogen, C 1 -C 6 alkyl optionally substituted with -O-R 6 where R 8 is as defined above, or is -CO-Z wherein Z is as defined above, or a pharmacologically acceptable salt thereof , processes for their preparation and pharmaceutical compositions containing compounds of 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, marked vasodilatory properties, which are mainly manifested in a decrease in blood pressure. In addition, suppression of adrenergic, d-receptors has been observed.

Alkyl groups R 1, R a, R 4, R 5, R 6, R 7, R a and R 9 are straight or branched groups having 1 to 6, preferably 1 to 4, carbon atoms such as methyl, ethyl, isopropyl, propyl, butyl , isobutyl, tert-butyl or n-hexyl. However, methyl and ethyl are particularly suitable.

Hydroxyalkyl groups R 1, R a, R 6 and R 7 contain 1 to 4 carbon atoms and are, in particular, 2-hydroxyethyl and hydroxymethyl.

The alkoxy groups represented by 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 @ 4, R @ 5 and R @ 8 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.

Alkanoyl groups in the meaning of R 5 contain 1 to 8, preferably 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 by methyl, halogen and methoxy.

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 (IV) in a manner known per se

in which

X, Y, R 1 and R 2 are as defined above, and

R10 is hydrogen or the residue of acetyl, benzoyl, benzyl or tetrahydropyranyl, wherein in case indazoles capable of tautomerism can rest acetyl, benzoyl, benzyl or tetrahydropyranyl also on the second nitrogen atom of X, is reacted with a compound of the formula V ^U *, _V] in which

A, B, Rd, and R5 are as defined above, and when A is \

0 = 0 /

the reaction product is then reduced, where, when Ra is C1-C8 alkanoyl or optionally substituted benzoyl or naphthoylo228110, the hydroxyl optionally present as R3 is esterified or R 5 is hydrogen, then the ester group, which is optionally R 3, is hydrolyzed and the optionally present acetyl, benzoyl, benzyl or tetrahydropyranyl group is removed as the capping group, or when one or more of R 1, R 2 and R 9 represent hydroxymethyl, prepared from a hydroxymethyl, acyl-oxymethyl or alkoxycarbonyl group having 1 to 2 carbon atoms in the alkoxy moiety by reduction or from an alkanoyloxymethyl group having 1 to 6 carbon atoms by hydrolysis or a methyl group obtained by reduction from an alkoxycarbonyl group having 1 to 2 carbon atoms in alkoxy and the resulting compounds are optionally converted into their pharmacologically useful salts.

The reactive radicals B in the compounds of the formula V are in particular acid radicals, for example hydrohalic acids and sulfonic acids.

The process according to the invention is conveniently carried out in an organic solvent which is inert under the reaction conditions, for example in toluene, dioxane, ethylene glycol dimethyl ether, ethanol, n-butanol or dimethylformamide, optionally in the presence of an acid binding agent.

The reaction of the compounds of formula IV with 3 with the compounds of formula V is conveniently carried out with the exclusion of oxygen in the presence of an acid binding agent. It is also possible to use alkali metal salts of the hydroxy compounds of the formula IV.

Compounds of formula (IV) are described in Helv Chim Acta 54, 2411 (1971) in case X and Y are - C (R 9) =, in case X is N and Y is - C (R 9) ) = also described, in case Y is a nitrogen atom and X is a group —C (R9) ==, described in Helv Chim Acta 35, 1740 (1952), in case X and Y are a nitrogen atom, described in J. Chem. Soc., 1956, 569.

Group reduction, if any \

C = O /

is carried out, for example, by complex metal hydrides, such as sodium hydride, or by catalytic hydrogenation using noble metal catalysts.

Optionally, the reduction of R 1, R 2, and R 8 in the compounds of formula I is carried out by complex metal hydrides such as lithium aluminum hydride or by catalytic hydrogenation using noble metal catalysts or Raney nickel.

The hydrolysis of the groups R 1, R 2 and R 9 of the compounds of formula I can be carried out in a manner known per se under acidic or basic conditions.

The esterification of the hydroxyl group R 5 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.

Suitable protecting groups for R 10 are lower alkanoyl groups, for example acetyl, aroyl groups, for example benzoyl, arylmethyl groups, for example benzyl or cyclic ethers, for example tetrahydopyranyl. The cleavage of the protecting groups in the substituent R10 may be carried out in a known manner corresponding to their nature, hydrolytically or by hydrogen glycol.

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 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 the active acids, 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) for the purpose of regulating obesity. Solid carriers are, for example, starches, lactose, mannitol, methylcellulose, talc, highly disperse silicic acid, high 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); for oral administration, suitable preparations are, for example, those which may optionally contain flavoring and sweetening agents.

For the purposes of the present invention, the following compounds are preferred in addition to the compounds exemplified:

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-tert-butylindole

4- [2-hydroxy-3- (4-phenoxymethylpiperldino) propoxy] -6-methylbenzimidazole

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

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -3-methylindazole.

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] -2-ethoxycarbonylindole

A mixture of 0.9 g of 2-ethoxycarbonyl-4-hydroxyinExample 3 below, 1.7 g of N- (2,3-epoxypropyl) -4-phenoxymethylpiperidine, 1.2 g of potassium carbonate and 50 ml of acetoniltril is heated at reflux for 10 hours. After cooling, the filtrate was allowed to cool overnight and 0.3 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-ethoxycarbonylindole (15% of theory) crystallized, m.p. 168 to 170 ° C.

Example 2

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

A solution of 4.5 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-ethoxycarbonylindole in 25 ml of absolute tetrahydrofuran is added dropwise at 0 [deg.] C. to a suspension of 0.95 g of lithiamalticillin anhydride in 45 ml of absolute tetrahydrofuran, The mixture was stirred at room temperature for 1 hour, then quenched with cooling with brine, filtered, and after washing with tetrahydrofuran, 0.01 mol of benzoic acid was added to the combined filtrates. Recrystallization of the benzoate from 25 ml of ethyl acetate gave 2.5 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-hydroxymethylindole benzoate (47% of theory), m.p. 145-146 ° C.

In an analogous manner to that described in Example 2, the following compounds are obtained:

designation yield melting point ° C (solvent)

(a) 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-hydroxymethylindole benzoate

4- [2-hydroxy-3- (4-phenoxymethylpiperldino) propoxy] -6-17

-methoxycarbonylindole

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

153 to 155 (ethyl acetate)

4- [2-hydroxy-3- (4-phenoxymethyl-piperidino) propoxy] -6-methoxycarbonyl-5-methylindole

Example 4

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

To a suspension of 2.0 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-ethoxycarbonylindole in 50 ml of dioxane is added a solution of 0.5 g of potassium hydroxide in 25 ml of water, the mixture is stirred for 16 hours at 50 DEG C., concentrated, the residue is taken up in water and the aqueous solution is neutralized with dilute sulfuric acid. 1.8 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino-propoxy) -indole-2-carboxylic acid (96% of theory) is isolated, m.p. 218 DEG-220 DEG C. (decomposition).

Example 5

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

A mixture of 5.9 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-hydroxymethyl Example 6 indole, 114 ml of acetic anhydride and 55 ml of pyridine was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue is taken up in ethyl acetate, the ethyl acetate solution is washed with water and concentrated. The bisacetyl compound (8.0 g) thus obtained was dissolved in 100 ml of methanol and hydrogenated using 2.0 g of 10% palladium on carbon at 1 atm of hydrogen pressure.

After the calculated amount of hydrogen has been consumed, the mixture is filtered, the filtrate is concentrated to half its original volume, the pH is adjusted to 9 by addition of 2N sodium methoxide solution, refluxed for 10 minutes, poured into water and extracted. chloroform. After concentration of the extract, the residue is taken up in ethyl acetate, 0.01 mol of benzoic acid is added and the precipitated benzoate is recrystallized from 25 ml of isopropanol. There were obtained 1.6 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-methylindolbenzoate (28% of theory), m.p. 145-148 ° C.

The following compounds were obtained in an analogous manner to that described in Example 5:

designation yield% melting point (solvent)

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

4- [2-hydroxy-3- (4-phenoxymethylpiperidin-o) propoxy] -6-hydroxymethylindole

b) 4- (2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy) -5,6-dimethylindole;

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

122-123 (ethyl acetate)

Example 7

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

A mixture of 4.4 g of 4- [2-hydroxy-3- (4-phenoxymethylplperidino) propoxy] indolacetate, 10.2 g of pivalic acid and 2.0 g of pivalic anhydride is stirred until dissolved and then the reaction mixture is left for 2 days. at room temperature. The reaction mixture is then poured onto ice, adjusted to pH 9 with aqueous ammonia solution, extracted with methylene chloride, concentrated and the residue triturated with ether. 3.2 g of 4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] indole (69% of theory) are isolated, m.p. 103-105 ° C.

Example 8

The following compounds were obtained in an analogous manner to that described in Example 7:

designation yield% melting point ° C (solvent)

a) 4- / 2-Pivaloyloxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / indole 66

107 (ether) 2

4- / 2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / indole and pivalic anhydrides

b) 4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methylindole

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methylindole and pivalic anhydrides

c) 4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] -23

-6-pivaloyloxymethylindole z

(mixture of Igroin and ether) to 78 (from a mixture of heptane and ether)

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-hydroxymethylindole and pivaloyl chloride

d) 4- [2-benzoyloxy-3- (4-phenoxymethylpiperidino) propoxy] -40 indole

108 to 110 (ether)

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

e) 4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] -24

-2-pivaloyloxymethylindole z

up to 95 (from a mixture of heptane and ether)

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-p-valoyloxymethylindole and pivalic anhydride designation yield% melting point ° C (solvent)

f) 4- [2-Pivaloyloxy-3- [4- (2-methylphenoxymethyl) piperidino] propoxy] -2-methylindiol

4- [2-hydroxy-3- [4- (2-methylphenoxymethyl) piperidino] propoxy] -2-methylindole and pivalic anhydride

Example 9

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

13.8 g of 4- (2-hydroxy-3- [4- (2-benzyloxyphenoxymethylpiperidino) propoxy / indole) are hydrogenated in 250 ml of methanol at room temperature and at 10 bar of hydrogen pressure using 3 bar of hydrogen. g of 5% palladium on carbon, then the reaction mixture is filtered, the filtrate is concentrated and the residue is crystallized from ethyl acetate to give 4.7 g of 4- / 2-hydroxy-3- [4- (2-hydroxyphenoxymethyl) piperidino] propoxy / indole (42% of theory), m.p. 119-121 ° C;

The following compounds were obtained in an analogous manner to that described in Example 9:

designation yield% melting point ° C (solvent) aj 4- / 2-hydroxy-3- [4- (4-hydroxyphenoxymethyl) piperidino] propoxy / indole from

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

4- / 2-hydroxy-3- [4- (2-benzyloxycarbonylphenoxymethylpiperidino) propoxy] indole

1 k 1 and cl 11

4- [2-pivaloxyloxy-3- (4-phenoxymethylpiperidino) propoxy] benzimidazole

3.8 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] benzimidazole and 1.3 g of pivaloyl chloride are refluxed in 25 ml of pyridine for 2 hours. After evaporation

167 (isopropanol) of the solvent is taken up in 100 ml of chloroform. The chloroform solution is washed thoroughly with water, dried over sodium sulfate and finally 50 ml of ethereal hydrochloric acid solution are added. After concentration, 4- [2-pivaloyloxy] -3- (4-phenoxymethylpiperidino) propoxy] benzimidazole hydrochloride crystallizes from ethanol, m.p. 132-134 ° C.

melting point ° C (solvent)

Example 12

In an analogous manner to that described in Example 11:

designation yield

4- / 2- (3,4,5-trimethoxybenzyloxy) -3- (4- (2-chlorophenoxymethyl) piperidino] propoxy) benzimidazole

4- / 2-hydroxy-3- [4- (2-chlorophenoxymethyl) piperidino) propoxy / benzimidazole and 3,4,5-trimethoxybenzoyl chloride

Example 13

4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] benzotriazole

A mixture of 5.1 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] benztriazole hydrochloride, 6.7 g of pivalic anhydride and 33.3 g of molten pivalic acid is stirred for 3 days at room temperature,

158-160 (ethanol) is then poured onto ice, neutralized with a solution of ammonia in water and extracted with methylene chloride. After concentrating the extract, the oily residue is taken up in methanol and the solution is slightly acidified with dilute hydrochloric acid. Evaporation of the solvent gave 2.53 g of 4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxy] benzotriazole hydrochloride (38%), m.p. 131-133 ° C.

Example 14

The following compounds were obtained in an analogous manner to that described in Example 13:

designation yield% melting point ° C (solvent)

a) 4- / 2- (4-Methylbenzoyloxy) -3- (4- (2-methoxyphenoxymethyl) piperidino] propoxy / benztriazole from

4- / 2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / benzotriazole and 4-methylbenzoic anhydride in dioxane

b) 4- / 2- (2-Chlorobenzoyloxy) -3- [4- (3-methylphenoxymethyl) piperidino] pnopoxy / benztriazole from

4- / 2-hydroxy-3- [4- (3-methyphenoxymethyl) piperidino] propoxy / benztriazole and 2-chlorobenzoic anhydride in dioxane

226116

Example 15

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -3-hydroxymethylindazole dihydrochloride

3-Acetoxymethyl-4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indazole is treated with excess ethanolic hydrogen chloride, then the product is precipitated with ether and recrystallized from ethanol. It is isolated in 48% yield of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -3-hydroxymethyldiazole dihydrochioride as pale yellow crystals of m.p. 183 DEG C. (decomposition).

Example 16

4- [2-pivaloyloxy-3- (4-phenoxymethyl piperidino) propoxy) indazole

A mixture of 2.2 g of 4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxyindazole, 1.25 g of pivalic anhydride and 10 g of pivalic acid is heated to 40 ° C. The reaction mixture was poured into 2N sodium hydroxide solution, extracted with methylene chloride, the extract was concentrated and the residue was recrystallized from isopropanol / water. 1.3 g of 4- [2-pivaloyloxy-3- (4-phenoxymethylpiperidino) propoxyindazole (48% of theory) are obtained in the form of colorless crystals, m.p. 116 DEG-118 DEG.

The following compounds were also prepared in an analogous manner to those described above:

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indole, acetate, mp 127-129 ° C, benzoate mp 146-147 ° C.

S (-) -4- (2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indole acetate, mp 121-124 degrees C, [α-] _D ²⁰ - 8.3 ° (1.5 % solution in methanol).

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-ethoxycarbonylindole, m.p. 170 [deg.] C. (isopropyl alcohol).

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-carbamoylindole, m.p. 182 [deg.] C. (ethyl acetate).

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxyl-2-dimethylaminocarbonylindole, 1.1. 178 ° C (isopropyl alcohol).

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

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

2-Ethoxycarbonyl-4- [2-hydroxy-3- (4-phenoxymethylpiperidino] propoxy] -6-methylindole benzoate, m.p. 189 ° C (isopropyl alcohol).

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

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

4- [2-hydroxy-3- [4- (4-chlorophenoxymethyl) piperidino] propoxy] indole benzoate, m.p. 156-158 [deg.] C. (ethyl acetate).

4- [2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / indole benzoate, m.p. 115 DEG-117 DEG C. (ethyl acetate).

4- [2-hydroxy-3- [4- (2-methylphenoxymethyl) piperidino] propoxy] indole benzoate, m.p. 128-129 [deg.] C. (ethyl acetate).

4- [2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidino] propoxy] indol benzoate, m.p.

154 ° C (ethyl acetate).

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

4- [2-hydroxy-3- [4- (4-fluorophenoxymethyl) piperidino] propoxy] -6-methylindole, mp 137-139 [ ^deg. ] C (ethyl acetate).

4- [2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidino] propoxy] -6-methylindole benzoate, m.p. 138-140 [deg.] C. (ethyl acetate).

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

4- [2-hydroxy-3- [4- (4-benzyloxyphenoxymethyl) piperidino] propoxy] indole, mp 113 ^DEG C. (ether).

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -2-pivaloyloxymethylindole, m.p. 130 DEG-132 DEG C. (ethyl acetate).

4- [2-hydroxy-3- (4- (2-methoxyphenoxymethyl) piperidino] propoxy) -2-methylindole, m.p. 137 DEG-138 DEG C. (ethyl acetate).

4- [2-hydroxy-3- [4- (2-chlorophenoxymethyl) piperidino] propoxy] -2-methylindole.

4- / 2-hydroxy-3- [4- (2,5-dimethylphenoxymethyl) piperidino | propoxy / indole, m.p.

155 A1 (ethyl acetate).

5- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indole, mp 121-123 ° C (ethanol).

1B

6- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indole, m.p. 144-145 ° C (ethanol).

4- (3- (4-phenoxymethylpiperidino) propoxy] indole, mp 118-119 ° C.

5- (3- (4-phenoxymethylpiperidino) propoxy) indole, m.p. 107-108 ° C (ethyl acetate).

6- (3- (4-phenoxymethylpiperidino) propoxy] indole, m.p. 123-124 ° C (isopropyl alcohol).

4- [3- (4-Phenoxymethyl-piperidino) -propoxy] -benzimidazole dihydrochloride, m.p. 144-146 ° C.

4- (2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] benzimidazole dihydrochloride, m.p. 123-125 ° C (ethanol).

4- [2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy] benzimidazole dihydrochloride, m.p. 144 DEG-145 DEG C. (ethanol).

4- [2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidino] propoxy] benzimidazole dihydride, m.p. 118-120 [deg.] C. (ethanol).

4- [2-hydroxy-3- [4- (2-chlorophenoxymethyl) piperidino] propoxy] benzimidazole dihydrochloride, m.p. 140 DEG-142 DEG C. (ethanol).

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) poropoxy] -6-methylbenzimidazole dihydrochloride.

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] benzotriazole hydrochloride, m.p. 187-189 ° C.

4- [2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy] benzotriazole hydrochloride, m.p. 161-162 ° C.

4- [2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidino] propoxy / benzotriazole hydrochloride, m.p. 206 DEG-208 DEG.

4- (3- (4-phenoxymethylpiperidino) propoxy) benzotriazole hydrochloride, m.p. 259-260 ° C.

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy Jindazole, mp 142-143 ° C, hydrochloride mp 220-222 ° C.

4- [2-hydroxy-3- [4- (2-chlorophenoxymethyl) piperidino] propoxy / indazole, m.p. 154 [deg.] C. (isopropyl alcohol).

4- (2-hydroxy-3- [2-methylphenoxymethyl) piperidino] propoxy / indazole, m.p. 127-129 degrees C (isopropyl alcohol).

4- [2-hydroxy-3- [4- (3-methylphenoxymethyl) piperidin] propoxy / indazole, m.p. 158-159 DEG C. (isopropyl alcohol).

4- / 2-hydroxy-3- [4- (2-methoxyphenoxymethyl) piperidino] propoxy / indazole, m.p. 151-153 degrees C (isopropyl alcohol).

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -5-methylindazole, m.p. 156-157 ° C (isopropyl alcohol).

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-methylindazole, m.p. 152-153 ° C.

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indazole, m.p. 141-142 ° C.

3-Acetoxymethyl-4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] indazole hydrochloride, m.p. 203-204 ° C.

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -7-methylindazole, m.p. 132-135 ° C (isopropyl alcohol).

4- (3- (4-phenoxymethylpiperidino) propoxy] indaol, m.p. 160-161 ° C.

4- [2-hydroxy-3- (4-phenoxymethylpiperidino) propoxy] -6-tert-butylindazole, mp 130-131 degrees Celsius.

Claims (2)

A process for the preparation of the novel 3- (4-phenoxymethylpiperidino) propanol derivatives of the general formula I wherein: R 1 and R 2 are the same or different and are hydrogen, C 1 -C 6 alkyl, C 1 -C 4 hydroxyalkyl, alkanoyloxyalkyl a group of up to 6 carbon atoms or a group --C - Z, wherein Z is hydroxy, (C1-C6) alkoxy or formula Re / —N \ R7 where R e 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, (C 1 -C 6) alkylthio, nitrile, nitro or trifluoromethyl, R 4 and R 6 may be the same or different from each other and are hydrogen, halogen, hydroxyl, benzyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylthio, carboxyl, benzyloxycarbonyl or lower alkoxycarbonyl having 1 to 2 carbon atoms in the alkoxy group, X and Y are the same or can be different from each other and are a nitrogen atom or a group R9 where R 9 is hydrogen, C 1 -C 6 alkyl optionally substituted with -O-R 5, wherein R 5 is as defined above, or is -CO-Z, wherein Z is as defined above, and their pharmacologically usable a salt, characterized in that the compound of formula (IV): wherein: X, Y, R 1 and R 2 are as defined above, and R 10 is hydrogen or an acetyl, benzoyl, benzyl or tetrahydropyranyl radical, and in the case of imidazoles capable of tautomerism, the radical acetyl, benzoyl, benzyl or tetrahydropyranyl may also be on the second nitrogen atom X, in reaction with a compound of formula V 8-CHfA-C / γ-němž wherein A, B, R 4 and R 5 are as defined above, and when A represents a group \ C = O / the reaction product is then reduced and, when R 5 is C 1 -C 8 alkanoyl or an optionally substituted benzoyl or naphthoyl group, the hydroxyl optionally present as R 5 is esterified, or when R 5 is is hydrogen, then the ester group optionally present in R3 is hydrolyzed and the optionally present acetyl, benzoyl, benzyl or tetrahydropyranyl group is removed as the capping group, or when one or more of R1, R2 and R9 are present are hydroxymethyl, prepared from hydroxymethyl, acyloxymethyl or alkoxycarbonyl of 1 to 2 carbon atoms in the alkoxy moiety by reduction or from alkanoyloxymethyl groups of up to 6 carbon atoms by hydrolysis, or methyl groups obtained by reduction from alkoxycarbonyl of 1 to 2 carbon atoms in alkoxy no and the resulting compounds are optionally converted into their pharmacologically useful salts. 2. The process of item 1 for producing 4- / 2-hydroxy-3- [4- (phenoxymethyl) piperidino] propoxy / indole of formula I OH O-CH 2 CH-CH ₂ and its pharmacologically usable salts, characterized in that the compound of formula IV OH reacts with a compound of formula V A stands for \ C = O / or \ CH-E / wherein E represents a hydroxyl group or also together with B may represent an oxygen atom, B is as defined in 1 and when A is a group S-CH _W -A-CH _W · CH 2 O 0 = 0 (V) wherein the reaction product is then reduced, and the compound of formula I thus obtained is optionally converted into pharmacologically useful salts.