FI85465C - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA 4-FENYLPROPYL-INDOLDERIVAT. - Google Patents

Description

1 85465

Process for the preparation of therapeutically useful 4-phenylpropylindole derivatives

The invention relates to a process for the preparation of therapeutically useful 4-phenylpropylindole derivatives of the formula I

Ri „r Vi / 1 y H-O-A-N.

JL \

X-R

10 Γ (I)

15 I

B

wherein R and R 1 independently represent a hydrogen atom, a straight-chain alkyl radical containing 1 to 5 carbon atoms, a branched alkyl radical containing 3 to 5 carbon atoms, a together with b forms an oxo group, or together with c a carbon -b carbon bond, b is a hydrogen atom, or together with a forms an oxo group, c is a hydrogen atom or together with a forms a carbon-carbon bond, the dashed line is a possible carbon-carbon bond, A is 25 - (CH2) n-, where n is 2 or 3, x is a hydrogen atom or a hydroxy group, or forms an oxo group with y, and y is a hydrogen atom, or together with x forms an oxo group, and salts thereof.

The process is characterized in that the compound of formula II

N 2 -] 0-A-Hal. 35 y (II) 1

: H

2 85465

wherein Hal is a chlorine, bromine or iodine atom and A is as defined above is reacted with a derivative of formula III

5. R '! H-N <^ (III) R '

wherein R 'and R' are as defined for R and Rx, to give compound 10 of formula IA

/ R, i \ R.

15 dA) to

20 H

wherein A, R 'and R'j are as defined above and the compound of formula IA is either reduced with gaseous hydrogen in the presence of a platinum or palladium based catalyst in a solvent such as an alkanol containing 1-5 carbon atoms or with gaseous hydrogen Raney' n in the presence of nickel in a solvent such as ethyl acetate or for up to three hours with sodium in ammonia in a solvent to give a compound of formula IB 30; Y: ΓΓ ^ Ί ^ R1

Il - O-A-N

N R

f '35 UB>

. ·. : I

·. : H

3 B 5 4 65 wherein A, R and Rx are as defined above, which compound is isolated and, if desired, purified or reduced with alkaline borohydride or cyanoborohydride to give a compound of formula Ic 5 R i --OAN ^ H0 JsL \ <IC )

B

wherein A, R and Rx are as defined above, which compound is isolated and, if desired, purified or reduced with sodium in ammonia to give a compound of formula ID

j0) ~ o-a- <1

20 R

(ID)

On 25 X / '"N /

B

wherein A, R and R 1 are as defined above, which compound is isolated and, if desired, purified, or the compound of formula IA is reacted with a complex formed between the early boron hydride and pyridine to give a compound of formula IB

n / Ri H — o-a-n ^ • HO I * \

R

* 35 \ A [(IE> ä n r t 4 85465

wherein A, R and Rj are as defined above, which compound is isolated or reduced with sodium in ammonia to give a compound of formula ID which is isolated and, if desired, purified, or a compound of formula Ιλ is reduced with sodium in ammonia to give a compound of formula 1D, which is isolated and, if desired, purified, the compounds of formula Ix, IB, Ic, ID and IB are, if desired, reacted with a halogenating agent to give a compound of formula 10

x y * 1 --O-A-N r

y-Z ^^ N

15 J '<IV |

Jv. /"Oh

B

Wherein Hal is a bromine or chlorine atom, and x, y, A, R, Rx, R2 and the dashed line have the same meaning as above, which compound is hydrolyzed to give a compound of formula Ip ·. **! y (½) «Cd

B

wherein x, y, A, R, Rx and the dashed line have the same meaning as above, which compound is isolated and, if desired, purified.

s 85465

Derivatives of formula I are described in French Application No. 85-06135, filed April 23, 1985, which relates to novel derivatives of 4-phenylpropylindole, their salts, processes for their preparation, 5 medical applications and compositions containing these compounds.

The reaction of a product of formula II with a creepy derivative of formula III is carried out e.g. in an inert organic solvent such as dioxane, benzene, toluene, or especially dimethylformamide, preferably a condensing agent such as an alkali metal carbonate or bicarbonate such as potassium carbonate, alkali metal hydroxide e.g. in the presence of sodium or potassium hydroxide, or a tertiary amine such as triethylamine. It is also possible to act using the amine of the formula III as solvent as such.

When it is desired to prepare a product of formula IB starting from a product of formula IA using sodium in an ammonia-20 cat, the contact time is preferably about 1 hour; when it is desired to prepare a product of formula ID, the contact time is preferably about 6 hours. It is preferably carried out using a solvent such as tetrahydrofuran.

The alkaline borohydride or cyanoborohydride used in the reduction of the product of formula 1B is, for example, potassium or sodium cyanoborohydride, or preferably sodium borohydride.

The alkaline borohydride complexed with the pyridine is preferably sodium borohydride. As the reaction medium, an alkanol containing up to 5 carbon atoms, such as ethanol, is preferably used.

The halogenation of the ____ products of formulas (IA), (IB), (lc), (iD) and (IE) can be carried out, for example, by means of a brominated complex of pyridine with the formula: ‘1 35 6 85465 5’ 5γ2 ’HEr in the case of bromination. It is best accomplished with N-halosuccinimide, preferably N-bromo or N-chlorosuccinimide; operated in dioxane or preferably in acetic acid. The product of formula (IV) obtained is preferably a chlorinated product.

The hydrolysis of the product of formula (IV) is preferably carried out with the aid of a mineral acid such as phosphoric acid, sulfuric acid or, preferably, hydrochloric acid in aqueous solution. This solution can be used as a concentrated but preferably diluted e.g. IN solution. In addition, a solvent such as an aliphatic alcohol, e.g., ethanol, can be used.

The derivative of formula II is preferably prepared by the reaction of an indole of formula V; H \ r ^ ° i (V) ..o 25 Οζρ

: '- · H

with a derivative of the formula VI 30 CH3n ^ P <^ ° Q- ™ (VI> 35 to obtain a derivative of the formula VII: 7 85465 J (VII) • &

B

Which is reacted with a chlorine derivative of an alkylene halide of formula VIII, a hydroxy derivative or a sulfonate of said chlorine or hydroxy derivative 15 -A-Hal (VIII) wherein A and Hal are as defined above to give the desired derivative of formula II.

The reaction between the indole of formula V and the derivative of formula VI is preferably carried out in an alkanol, in particular ethanol, in the presence of an alkaline substance such as sodium hydroxide or, preferably, potassium hydroxide. Quaternary ammonium soda is best used. 25 lan, such as in the presence of triethylbenzylammonium chloride.

The reaction between the indole of formula V and the derivative of formula VI can also be carried out by phase transfer using preferably an aqueous solution of an al-30 potassium metal hydroxide such as potassium or sodium hydroxide as the aqueous phase and a solvent such as benzene using a phase transfer agent such as benzene as the organic water insoluble phase. a quaternary ammonium salt, especially bromide or hydrogen sulfate. When a halogen derivative of an alkylene halide of formula VIII is used, it is preferable to use two different halogens in order to avoid condensation of two molecules of the product of formula VII. Therefore, for example, when Hal represents a chlorine atom, a more reactive derivative such as bromide is selected as the halogen derivative.

It is also possible to use a hydroxyl derivative of an alkylene halide of formula VIII corresponding to formula VIII ': HO-A-Hal VIII' wherein A and Hal are as defined above to react with a derivative of formula VII. It is preferably carried out in the presence of triphenylphosphine and azodi-carboxylate in tetrahydrofuran.

Preferably a sulfonate of a derivative of formula VIII 'is used; in this case, the tosylate of formula VIII 'is preferably used as the sulfonate of the hydroxyl derivative of the alkylene halide of formula VIII:

Ta0-A-Hal Vili "where Ts represents a tosyl radical, and A and Hai are already •: *: 25 as defined above.

Thus, operate under the conditions described by phase transfer.

A derivative of formula II can also be prepared by the reaction of an indole of formula V: VV 30 H 0 φ On

B

9 85465 with a derivative of formula IX: 5 Jk I jJ-O-A-Hal (IX) wherein Hal is as defined above, to give the desired derivative of formula II-10.

The reaction of an indole of formula V with a derivative of formula IX is preferably carried out in the presence of a base such as sodium or potassium hydroxide.

The derivatives of formula I have a basic nature. The addition salts of the derivatives of formula I can best be prepared by reacting a mineral acid or an organic acid with the above-mentioned derivative of formula I in suitable stoichiometric ratios. The salts can be prepared without isolating the corresponding bases. Addition salts with mineral acids or organic acids can be formed, for example, with the following acids: hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric , succinic, tartaric, citric, oxalic, glycolic, aspartic, alkanesulfonic acids such as methane and ethanesulfonic acids, arylsulfonic acids such as benzene and paratoluene sulfonic acids and arylcarboxylic acids.

The derivatives of formula I have very interesting pharmacological properties; they have particularly remarkable antiarrhythmic and blocking properties of slow calcium sodium channels. The properties are illustrated in the experimental part of the invention.

Derivatives of the formula I are applied e.g.

: 35 in the treatment of heart failure, angina in all its ____ forms and in the treatment of arrhythmia.

10 85465

The usual dosage may vary, for example, from 50 mg to 1 g per day, depending on the derivative used, the subject and the cause of the disease. When administered orally to a human, the derivative of Example 8 may be administered in a daily dose of 200 mg to 800 mg, e.g. for the treatment of ventricular, supraventricular and ionic arrhythmias, about 3 mg to 12 mg per kilogram of body weight.

In medical use, the derivatives of formula I and their addition salts with pharmaceutically acceptable acids may be included in pharmaceutical compositions for digestive or parenteral administration.

The pharmaceutical compositions may be, for example, solids or solutions and in the pharmaceutical forms commonly used in human medicine, such as, for example, compacts as such or in sugar form, gelatin capsules, pills, suppositories, injectables; they are prepared according to commonly used methods. The active ingredient or ingredients may be incorporated into excipients commonly used in pharmaceutical compositions, such as talc, acacia, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, animal or vegetable fatty substances, various glycerol derivatives, paraffin derivatives. 25 substances, disintegrants or emulsifiers and preservatives.

The following examples illustrate, but do not limit, this invention.

Example No. 1: (E) -1- [2- [2 - [(1,1-dimethylethyl) amino] -30 ethoxy] phenyl] -3- [1H-indol-4-yl] -2-propen-1 -one and its (t) 2,3-dihydroxybutanedioic acid A mixture of 71 mg of 1- [2- (2-chloroethoxy) phenyl] -3- [1H-indol-4- * is heated at 120 ° C for 17 hours. yl] -2-propen-1-one, 30 mg of potassium carbonate and 0.23 cm 3 of 35 tert-butylamine in 1.5 cm 3 of Ν, Ν-dimethylformamide, diluted with water, extracted with ethyl acetate, washed with water, dried , evaporated to dryness, purified by chromatography on silica (eluent: ethyl acetate-triethylamine 9: 1) to give the desired product 40 mg.

Formation of (±) -2,3-dihydroxybutanedioic acid:

1.24 g of DL-tartaric acid are added with stirring at 80 ° C to a solution of 3 g of the above base in 159 cm 3 of iso-10 propanol and 50 cm 3 of methanol, the temperature is maintained at 80 ° C for 20 minutes, evaporated solvent, the residue is dissolved in a mixture of 45 cm3 of methanol and 50 cm3 of isopropanol and a little pentane and allowed to crystallize.

The obtained crystals are filtered and dried at 80 ° C under reduced pressure, and 2.83 g of the desired product are obtained from two crystallizations.

Melting point ~ 172 ° C

Analysis (Crystallization 1) C 23 H 26 N 2 O 2, C 4 H 6 O 6: 512.564 Calculated C% 63.27 H% 6.29 N% 5.46 20 Found 63.3 6.6 5.5

Example No. 2: 1- [2- (3-chloropropyl) phenyl] -3- [1H-indol-4-yl] -2-propen-1-one

Step A: 3- (1H-Indol-4-yl) -1- (2-hydroxyphenyl) -2-propen-1-one Add with stirring at 30 ° C under an inert atmosphere 0.5 cm 3 38% of potassium hydroxide to a mixture of 0.132 g of indole-4-carboxaldehyde, 0.1 cm 3 of 2-hydroxyacetophenone and 0.189 g of triethylbenzylammonium chloride in 2 cm 3 of ethanol. After stirring for 23 hours at 30 [deg.] C., the mixture is diluted with water, extracted with ethyl acetate, washed with water, dried, evaporated to dryness and purified by chromatography on silica (eluent: methylene chloride) to give 159 mg of the expected product. Molten

mp 164 ° C

* * · • «· i2 85465

Step B: 1- [2- (3-Chloropropoxy) phenyl] -3- [1H-indol-4-yl] -2-propen-1-one

2 cm3 of 50% sodium hydroxide are added to a mixture of 100 mg of the product of step A, 94 mg of 3-chloro-5-propylparatoluenesulphonate and 54 mg of tert-butylammonium sulphate in 2 cm3 of benzene and 2 cm3 of acetonitrile.

After stirring for 6 hours at 80 [deg.] C., the mixture is decanted, extracted with ethyl acetate, washed with water, dried, evaporated to dryness and purified by chromatography on silica (methylene chloride as eluent) to give 68 mg of the expected product.

UV spectrum: (ethanol) max 218 nm Ej 951 f - 32 300 15 "266 nm Ej 390 £ = 13 300 infl 342 nm E \ 269 max 389 nm Ej 424» 14 400

Example No. 3: 1- [2- (2-chloroethoxy) phenyl] -3- [1H-indol-4-yl] -2-propen-1-one 20 0.4 cm 3 of 50% are added under an inert atmosphere: sodium hydroxide to a solution of 278 mg of 1- [2- (2-chloroethoxy) phenyl] ethanone in 3 cm 3 of ethanol, followed by the addition of 200 mg of indole-4-carboxaldehyde. After stirring for 30 hours, the mixture is diluted with water, extracted with ethyl acetate, washed with water, dried, kept dry, purified by chromatography on silica (methylene chloride as eluent) to give 142 mg of the expected product.

UV spectrum: (ethanol) 30 max 215 nm E \ 925 £ = 30 100 max 268 nm Ej 397 £ = 12,900 infl 340 nm Ej 255 *: '' = max 390 nm e} 434 £ - 14 100 • • · 13 85465

Example No. 4; 1- [2- [2 - [(1,1-dimethylethyl) amino] ethoxy] phenyl] -3- [1H-indol-4-yl] -1-propanone, 1α its hydrochloride

3.218 g of the base of Example 1 are hydrogenated in the presence of 1.1 g of 10% palladium on carbon in 350 cm3 of methanol, filtered, evaporated to dryness under reduced pressure, washed with 7 cm3 of isopropanol, filtered, dried under reduced pressure to give 2.35 g of crystallization. g of the desired product. Melting point 112 ° C 10 Hydrochloride formation:

4 cm3 of a solution of ethyl acetate in hydrochloric acid are added to a suspension of 2.25 g of the above base in 70 cm3 of isopropanol, stirred, filtered, dried at 80 ° C to give 2.38 g of the desired product. Melting point-250 ° C

Example No. 5: g- [2- [2 - [(1,1-dimethylethyl) amino] ethoxy] phenyl] -1H-indol-4-propanol and its neutral (E) -butenedioate

0.934 g of sodium borohydride are added to a solution of 3 g of the base of Example 4 in 90 cm3 of methanol, stirred for 20 min under an inert atmosphere, ice water is added, extracted with ethyl acetate, washed with water, dried to give 2.79 g of the expected product.

Formation of neutral (E) -butenedioate: Add, with stirring, 0.862 g of fumaric acid to a solution of 2.73 g of the above base in 70 cm3 of isopropanol, add again 20 cm3 of isopropanol and begin crystallization. Hold at + 4 ° C for 16 hours, then filter, dry at 80 ° C under reduced pressure to give 2.5 g of the desired product.

Melting point - 190 ° C

. Analysis (C23H30N2O2) 2, C4H404 = 849.089 ... Calculated C% 70.73 H% 7.60 N% 6.60

Found 70.5 7.8 6.5 14 85465

Example No. 6: N- [2- [2- [3- (1H-indol-4-yl) propyl] phenoxy] ethyl] -2-methyl-2-propanamine

A solution of 31 mg of the base of Example 5 in 2 cm3 of tetrahydrofuran is added to 3 cm3 of ammonia at 5-78 ° C and 100 mg of sodium are added at -40 ° C under inert solution.

in this atmosphere. After stirring for 1 hour, 800 mg of ammonium chloride are added at -40 [deg.] C., evaporated to ambient temperature, diluted with water, extracted with ethyl acetate, washed with water, dried, filtered, the solvent is evaporated off, a little pentane is added, filtered and dried to give 22 mg desired product. Melting point - 112 ° C

Example No. 7: 1- [2- [2 - [(1,1-dimethylethyl) amino] ethoxy] phenyl] -3- [1H-indol-4-yl] -2-propen-1-ol 15 is added. , 1 cm 3 of pyridine and 624 mg of sodium borohydride in an inert atmosphere to a solution of 1.5 g of the base of the product of Example 1 in 35 cm 3 of ethanol are stirred for 15 min at 70 ° C, water is added, cooled, extracted with ethyl acetate, washed with water, dried over drying agent, evaporated to dryness, purified by chromatography on silica (eluent: ethyl acetate / triethylamine 9: 1) to give 1.32 g of the expected product.

UV spectrum: (ethanol) 25 max: 221 nm E \ 685 6 - 24 968 infl: 233 nm E \ 533 infl: 276 nm E | 151 infl: 285 nm E \ 186 infl: 292 nm E \ 219 30 max: 308 nm 267 £ = 9 732

Example No. 8; N- [2- [2- [3- (1H-indol-4-yl) propyl] phenoxy] ethyl] -2-methyl-2-propanamine and its neutral (E) -butenedioate in 30 cm3 of ammonia - At 78 [deg.] C., a solution of 3.94 g of the product of Example 7 in 25 cm <3> of tetrahydro-85465 furan is added, the mixture is kept at -40 [deg.] C., 4.2 g of sodium are added, stirring is continued for 2 hours under an inert atmosphere. , 36 g of ammonium chloride are added at -40 [deg.] C., the mixture is allowed to evaporate, diluted with water while cooling, the extra 5 is treated with ethyl acetate, washed with water, dried,

filtered, dried, washed with isopropanol, dried under reduced pressure to give 2.43 g of the desired product. Melting point ^ 114 ° C

Formation of neutral (E) -butenedioate To a stirred solution of 2.4 g of the above base in 90 cm3 of ethanol add 0.795 g of fumaric acid, concentrate, start crystallization, leave for 16 hours at +4 ° C, filter, dried under reduced pressure to give 1.67 g of the desired product.

Melting point ^ 190 ° C

Analysis for C 23 H 30 N 2 O, δ (C 4 H 4 O 4) = 408.545 Calculated C% 73.50 H% 7.89 N% 6.86

Found 73.3 7.9 7.2

Example No. 9: 1- [2-hydroxyphenyl] -3- [1H-indol-4-20 yl] -1-propanone

Hydrate until absorption is completed 200 mg of the product of Example 2 of Step A in 10 cm3 of methanol in the presence of palladium on carbon, filtered, evaporated with methanol, purified by chromatography on silica (eluent: cyclohexane-dichloromethane-triethylamine 6: 3: 1) 143 mg of the expected product are obtained.

Melting point ^ 143 ° mg.

UV spectrum: (ethanol) max 214 nm Ej 2 080 £ - 55 200 30 max 254 nm Ej 555 £ «14 700 lnfl 275 nm E3 295 infl 286 nm E * 220 max 323 nm Ej 117 £ - 4 700

Compounds (I) may be used in the preparation of extrudates according to the following instructions: 16 85465

Instruction 1: N- [2- [2- [3- (1H-indol-4-yl) propyl] phenoxy] ethyl] -2-methyl-2-propanamine neutral (E) -butenedioate 100 mg; 5 binders a.d. 150 mg.

(list of binders: lactose, starch, talc, magnesium stearate).

Instruction 2: 1- [2- [2 - [(1,1-dimethylethyl) amino] ethoxy] -10-phenyl] -3- [1H-indol-4-yl] -1-propanone hydrochloride 100 mg; binder a.d. 150 mg.

(List of binders: lactose, starch, talc, magnesium stearate) 15 Pharmacological study 1) Antiarrhythmic effect in rats The trachea of male anesthetized rats weighing 300-350 g is opened intraperitoneally (intraperitoneally) using 1.20 g / kg of urethane and 20 (3 ml / min blowing 40-50)

The needles are placed subcutaneously so that the electrocardiograms of the rats deviate from the DII signal.

25 Test products are administered intravenously or orally.

5 min after dosing of the product, 10 pg / min of the rat carotid artery solution is perfused (drip) and the time of onset of cardiac arrhythmias is taken into account (10 pg of aconitine corresponds to a volume of 0.2 ml solution perfusion).

Results are expressed as a percentage of the prolongation of the onset time of cardiac arrhythmias compared to control animals and as a function of test substance dose.

I? 85465

The figures described in the table below show that the compounds of formula (I) have significant antiarrhythmic properties.

Example Dosage Method Dose Prolonged product Intravenous «Incidence% _Oral_ = 0_ 1 S 0.5 mg / kg 26 O 10 mg / kg 41 10 4 S 2.5 mg / kg 40 0 25 mg / kg 32 5 S 0.05 mg / kg 36 O 5 mg / kg 38 15 8 S 2.5 mg / kg 49 O 25 mg / kg 40 ie 85465

When a stable response is obtained, a procedure is performed between the Ca 2+ ion series and the different concentrations of the test product until a stable response is obtained.

Arterial contractions depend on the si-5 weathering of Ca 2+ ions into smooth muscle cells and are mediated by depolarization of smooth muscle by K * ions and by the action of noradrenaline released at the presynaptic level. Restarting the procedure with arteries deprived of nerve with 6-OH-dopamine 10 prevents noradrenaline from acting on its own.

The results are expressed in CI 50 (inhibitory concentration 50), i.e. the concentration of the test product which inhibits 50% of the contractions due to K + ions.

Based on the results in the table below, it is found that the compounds of formula (I) have potent anti-calcium activity.

Cl 50

Product of Example (μΜ) 1 1.9 20 4 0.8 5 1.9 8 0.8 3) Acute Toxicity Study 25 Lethal doses of test compounds DLq have been estimated by oral administration to mice.

DL0 is the maximum dose that will not cause any deaths within 8 days.

The results obtained are shown in the following table: 30 Product of Example DLq (mg / kg) 1> 400 4 200 5 10 35 8 200

Claims (7)

A process for the preparation of therapeutically useful 4-phenylpropylindole derivatives of the formula I 10 yS? ' f (I) H 15 wherein R and R j independently represent a hydrogen atom, a straight-chain alkyl radical containing 1 to 5 carbon atoms, a branched alkyl radical containing 3 to 5 carbon atoms, a together with b forms an ok-20 group, or together c a carbon-carbon bond with, b is a hydrogen atom, or together with a forms an oxo group, c is a hydrogen atom or together with a forms a carbon-carbon bond, the dashed line is a possible carbon-carbon bond, A is - (CH2) n-, wherein n is 2 or 3, x is a hydrogen atom or a hydroxy group, or forms an oxo group with y, and y is a hydrogen atom, or together with x forms an oxo group, and salts thereof, characterized in that the compound of formula II T: γ (id: 35: I ·: H 20 85465 Where Hal is a chlorine, bromine or iodine atom and A is as defined above is reacted with a derivative of formula III 5 R \ H-nC ^ (III) R 'where R' and R'j have the same meaning as R and Rx, to give a compound 10 of formula IA 00 λ ^ r, i Il ~ j— 0-AN ^ 15 of (½) On 20 H where A, R 'and R *! have the same meaning as above and the compound of formula IA is either reduced with gaseous hydrogen in the presence of a platinum or palladium based catalyst in a solvent such as an alkanol containing 1 to 5 carbon atoms or with gaseous hydrogen in the presence of Raney nickel in a solvent such as ethyl acetate, or for up to three hours with sodium in ammonia in a solvent to give a compound of formula IB 30 ^ / X Ri jfl Uoan / • * ηΓ r yo N / NH V-: 35 I (IB) 2i 85465 where A, R and Rj are the same as above, which compound is isolated and, if desired, purified, or reduced with alkaline borohydride or cyanoborohydride to give a compound of formula Ic 5 / MX R, li ^] .M * HO ° "Α-Νχ y N r 10 (lp) όα i H 15 where A, R and Rj are as defined above, which compound is isolated and, if desired, purified or reduced with sodium in ammonia to obtain a compound of formula ID 20 R, h ^ / 1 \ K; CM. ·. : H wherein A, R and Rx are as defined above, which compound is isolated and, if desired, purified, or a compound of formula IA is reacted with a complex formed between an alkaline borohydride and pyridine to give a compound of formula 1B: 35 8 5 465 Ri Π Ν // 1 --OAN ^ HO L \ Nj / R 5 J (½) up 10 'wherein A, R and Rx are as defined above, which compound is isolated or reduced with sodium in ammonia to give a compound of formula 1D which is isolated and, if desired, purified, or the compound of formula IA is reduced with sodium in ammonia to obtain a compound of formula IDD which is isolated and, if desired, purified, compounds of formula IA, IB, Ic, ID and IB are, if desired, reacted with a halogenating agent to give a compound of formula IVx / R 1 -H OAN ^ y- N - 25 (IV) .Hai N - f / tJTT:: _ _ - 30 I::: H where Hai is a bromine or chlorine atom, and x, y, A, R, Rx, R2 · 'and the dashed line denote the same as above, which compound is hydrolyzed to give a compound of formula IF; : 35 23 8 5 4 65 Ri x \] / 1 [--O-A-N 'y — R 5 {IF) 10 H where x, y, A, R, Rx and the dashed line have the same meaning as above, which compound is isolated and, if desired, purified. 15 24 85465 For the preparation of a therapeutically active compound 4-phenylpropyl-indole with the formula I 5 R1 ,, f \ V) / 1 YM Λ-OAN ^ xR 10. c (I) H 15 for R and R2 are used in the form of betecnar en väteatom, en rakkedjad alkylradikal med 1-5 kolatomer, en förgre-nad alkylradikal med 3-5 kolatomer, a tillsammans med b bildar en oxogrupp, eller tillsammans med c en kol-kol-blndnlng, b är en väteatom, eller tillsammans with a picture 20 of an oxo group, with a single atom or a column of the same, with a single column, even with a single column, A is - (CH2) n-, then with 2 or 3, x with a hydrogen atom or a hydroxyl group, with a mixture of oxy groups and oxy groups, with a mixture of 25 species with an oxy group, with an oxy group, with the addition of a formulation II M -) - OA-Hal ; ϊ äo ° γΛ ^ ....:] (II) όπ ·. ·: I ....: H · 25 85465 for Hai är en chlor-, brom- or iodatom, och A betecnar samma som ovan, omsätts med ett derivat, som har formeln III 5 H "N v. (III) ^ R '10 is R' and R'x is the same as R and Rx, for which the formula is Ix 15 fi ^ l / R, i Il - (- 0-AN ^ \ R, 20 ^ i (IA> There are H 25 H of A, R 'and R' x in each case, and in the case of a compound of formula IA, the reducing agent is used in the form of 1 gas form 1 of a platinum- or palladium-based catalyst 1 30 to a solution, preferably 1 of an alkanol , in which case 1-5 cholaters are used, or in the form of a gas form in the nerve of Raney nlckel i et lösnlngsmedel, säsom ethylyletat, eller ”högst 1 tre timmar med sodium sodium 1 ammoniak 1 and lösnlngs medel, för erhällande av en förenlng med form 26 85465 Ri Jj y \ -OAN ^ 0. \ yr 5 s' dB) SO 10 A to A, R and R 1 are selected from the group consisting of 1 and 20, respectively, reduced or reduced with alkaline borohydride or cyanoborohydride to give a mixture of 15 in the form of a mixture of HO 20 s' (Ic) So \ 0 25 H där A, R och Rt betecknar sanuna som ovan, vilken förening lsoleras eller, om s & önskas, renas, eller reducer with sodium 1 ammonia fur & llande av en förening med Formeln ID JQ} ~ oak 1 = 35 Jx_ <lD) GO: 'IH 27 85465 for A, R and Rx of the same mixture as in the case of an isolated form and a mixture of compounds of formula IA which is complexed to a complex of 5 to 11 borohydrides and pyridine , for the purposes of the formulation IE Ri ho jOh ° -a- <io XR J (½) H där A, R and Rj betecknar samma som ovan, vilken förening isoleras eller reducer with sodium i ammonlak for erhäl-20 lande av en förening med formeln ID, som isoleras, och om s & önskas, renas, eller föreningen with formula Ιλ reducing the amount of sodium and ammonium in the formulation with the formulation ID, which is isolated, and is self-contained, renas, fodder-amarna with formulas IA, IB, lc, ID and IE omsätts, to self 25 halogeneringsmedel för erhällande av en förening med formuleln IV x ^ Rl H- OAN. 30 y - \ R. iIV): *: ** __ ^ Hal 35. iT Jj H 28 b 5 4 6 5 där Hal är en brom- eller kl or Atom, och x, y, A, R, Rj R2 och den streckade linjen betecknar samma som ovan, week for hydrolysers for the purposes of formula IF 5 R, x \] / 1 | -] - O-A-N ^ Nk 10 ^ (lp) H 15 där x, y, A, R, Rx and the striking lines of the same sample as above, in the case of isolated isolates, and are self-contained.