HU192096B - Process for production of derivatives of optically active 9-/indole-2-il/-1-azobyciclo /3.3.1/nonane and medically applicable acidadditive salts - Google Patents

Abstract

9-(indol-2-il)-1-azabicyclo(3.3.1.) nonane derivs. (I) and their salts, where R is 1-4 C atom alkyl gp. and R' is H+ Or i-cyanoethyl gp. can be prepd. from 1-alkyl-1,2,3,4,6,7,12,12b-octahy dro-1,5 -propano-indolo(2,3a)quinolizine deriv. (II) where R is as above and X is an acid anion or OH- by reaction (a) with NaOH at 200 deg.C in a high boiling point organic solvent to produce (I) where R is as above and R' is H+. Salts can be pptd. with an acid; (b) with KCN at 200 deg.C in a high boiling point organic solvent to produce an epimer mixt., where R is as above and R' is 1-cyano-ethyl gp. After sepn. the epimer can be pptd. with an acid. Application: antihypoxi and lipid decreasing effect.

Description

The present invention relates to novel optically active 9- (indol-2-yl) -1-azabicyclo (3.3.1) nonane derivatives and their pharmaceutically acceptable acid addition salts, wherein

R 1 is C 1 -C 4 alkyl and R 1 is hydrogen, or

R is a C14 alkyl group and R 'is a 1-cyanoethyl group, such that an optically active 1-alkyl-1,23,4,6,7,12,12b of the formula (II) an octahydro-1,5-propanoindole (2,3-a) quinolysinium derivative, wherein -

R is C 1 -C 4 alkyl,

X is an acid residue anion or hydroxide ion

the. ) in the preparation of derivatives containing R 'in the hydrogen atom, an alkali metal hydroxide, preferably sodium hydroxide, in an inert organic solvent having a boiling point at or above the reaction temperature of 120 to 230 ° C, preferably 200 ° C, is prepared; optionally converted into an acid addition salt,

b. ) in the preparation of derivatives containing R 'as 1-cyanoethyl group, heating with an alkali metal cyanide, preferably potassium cyanide, in an inert organic solvent having a boiling point or above, at a temperature of from 120 to 230 ° C, preferably 200 ° C, then separating the resulting mixture of epimers, if desired, and converting the epimers, if desired, into pharmaceutically acceptable acid addition salts.

In the compounds of formula (I) according to the invention, R 1 is a C 4 -C 4 alkyl group such as methyl, ethyl, n-propyl, η-butyl, i-butyl, sec-butyl, tert-butyl. may.

The compounds of formula (I) are novel and possess valuable therapeutic effects, namely, partly antihypoxic and sympathetic beta-receptor blocking and partly lipid-lowering effects. Antihypoxic activity was assessed in CFLP (LATI) mice and Hann.-Wistar rats. The sympathetic beta-blocking effect was demonstrated in the right atrium of spontaneously isolated isolated guinea-pig heart. Normal and cholesterol-fed non-anesthetized male Wistar rats were used to investigate the lipid-lowering effect.

There are no known references in the literature concerning the compounds of formula (I) or their preparation. Conversions of a similar type but with other starting materials are described in J.P. Kutney, Ka Kong Chan, A. Failli, J.M. Fromson, C.Gletsos, A. Leutwiller, V.R. Nelson, and J.P. de Souza (Helv. Chim. Acta58, 1648 (1975)).

The novel 1-alkyl-1,2,3,4,6,7,12,12b-octahydro-1,5-propanoindolo (2,3-a) quinolizinium used as starting material in the process of the present invention The preparation of derivatives is described in our patent application Serial No. 4783/84, published under the number T / 38939. According to this (Example 11), a quinoline lysine derivative of 1 (3-hydroxypropyl) -1,2,3,4,6,7,12,12b-octahydroindole (2,3-a) in an inert organic solvent in the presence of an acid scavenger reaction with a lower alkanesulfonic acid chloride and, if desired, converting the resulting compound by anion exchange.

According to the invention, the process according to the invention comprises the use of a 1-alkyl-1,2,3,4,6,7,12,12b-octahydro-1,5-propano-indolo A quinolizinium derivative (2,3-a) - aalol R is a C 1 -C 4 alkyl group, X is an acid residue in an anion or lydroxide ion in ethylene glycol or diethylene glycol at about 200 ° C with an alkali metal hydroxide such as potassium or sodium. heating with hydroxide, preferably sodium hydroxide, results in a previously unknown skeleton of the compound of formula I wherein R is C 1-4 alkyl and R 'is hydrogen. The reaction is also carried out at temperatures below 200 ° C, but the reaction time is substantially prolonged. The product is obtained by pouring the reaction mixture into ice water, extracting with chloroform, evaporating the organic phase and drying the product by column chromatography, preferably on a silica gel column with ethyl acetate containing diethylamine. The bases of formula (I) are optionally converted into acid addition salts.

In the process (b) of the present invention, a 1-alkyl-1,2,3,4,6,7,12,12b-octahydro-1,5-propano-indolo (2,3-a) quinolizinium of formula II The derivative wherein R and X are as defined above is preferably heated in an ethylene glycol, diethylene glycol or dimethylformamide solution in an ethylene glycol solution at about 200 ° C with an alkali metal cyanide, preferably potassium cyanide. The reaction proceeds within a few hours to give a new compound of formula I wherein R is as defined above and R 'is 1-cyanoethyl.

The reaction results in an epimeric mixture of the compounds of formula I wherein the epimers differ only in the relative chirality of the carbon atom bearing the cyanide group. The epimer mixture is separated and, if desired, the epimers can be converted into pharmaceutically acceptable acid addition salts. After completion of the reaction, the reaction mixture is worked up by pouring the reaction mixture into water at room temperature, filtering off the precipitate and extracting the aqueous mother liquor with chloroform.

After drying the organic phase, the residue and the filtered precipitate are combined, dissolved in a lower alcohol, preferably methanol, clarified, dried again and finally evaporated to give the crude epimer mixture. Separation of the epimers can be accomplished by column chromatography. Preferably, a silica gel column is used, eluting with ethyl acetate containing diethylamine. Later, the epimer A with higher Rf first descending upon separation is called epimer B with lower Rf.

The compounds of formula (I) obtained by processes (a) and (b) of the present invention may be converted into pharmaceutically acceptable acid addition salts, if desired. For the formation of salts, inorganic acids such as hydrogen halides, e.g. , salicylic acid, lactic acid, cinnamic acid, benzoic acid, alkylsulfonic acids such as methanesulfonic acid, ethanesulfonic acid, arylsulfonic acids such as p-toluenesulfonic acid, sulfanylic acid, amino acids such as aspartic acid, glutamic acid.

Salt formation in some inert organic solvent,

192,096, for example, in a C 1 -C 6 aliphatic alcohol, dioxane, acetone, the compound of formula (I) obtained by processes (a) and (b) of the present invention is dissolved in one of the solvents mentioned above. solution of the acid in one of the solvents mentioned above, the mixture does not become slightly acidic. This is about pH 5-6. The salt formation may also be carried out by adding to the solution a calculated amount of the desired acid in one of the solvents mentioned above. The precipitated acid addition salt may then be isolated from the reaction mixture by any suitable means, such as filtration.

The following Examples (a) and (b) of the present invention are illustrated by the following examples, but are not limited to these examples:

Example 1 (+) - (12bS) -1-Ethyl-1,2,3,4,6,7,12,12b-octahydro-1,5-propanoindole (2,3-a) quinolysinium methanesulfonate

5.9 g (0.019 moles of (-) {1S: 12bS) -1-ethyl-1- (3-hydroxypropyl) -1,2,3,4,6,7,12,12b-octahydro-indole ( Quinolizine 2,3-a) is dissolved in 65 ml of absolute tetrahydrofuran, 4.0 g (0.039 mol) of absolute triethylamine are added and cooled to -15 ° C. At this temperature, while stirring, a solution of methanesulfonic acid chloride (2.36 g, 0.02 mol) in absolute tetrahydrofuran (33 mL) was added dropwise to the reaction mixture over ca. In 30 minutes. The mixture was then boiled for 30 minutes at -15 ° C and for 2 days at room temperature.

The precipitate was filtered off, washed with a little tetrahydrofuran and dried. The resulting solid was boiled with about 45 mL of chloroform to transfer to the remaining triethylamine hydrochloride solution. After cooling, the precipitate is filtered off, washed with a little ether and dried. If necessary, recrystallize from methanol.

Yield: 5.2 g of _p decomposes above (70.5%), m.p .: 330 ° C. (a) f) ³ = + 13.4 ° (c = 1.0, water). Its elemental analysis and its NMR spectrum clearly confirmed its structure. Elemental analysis for C ₂₁ H ₃₀ N ₂ O ₃ S (Ms: 390.54):

H, 7.74; N, 7.17; S, 8.21%. Found: C, 64.76; H, 7.62; N, 7.18; S, 8.04. %. 1 H-NMR (DMSO-d ₆ + CDCl ₃ , 3: 1): γ 1.10 (3H, t, J = 7.5 Hz, C ₁ -CH ₂ -CH ₃ ), 2.48 (3H, 2 , CH ₃ SO ₃ ), 4.94 (1H, broad s, C 12b-H), 6.95-7.65 (4H, m, aromatic protons), 9.94 (1H, broad s, NH) ppm.

¹³ C-NMR (DMSO-d 6 + CDCl 3, 3: 1): δ 7.32 (Cl-CH2 -CH3), 17.29 (C7), 20.33 * (Cl4), 20.46 *, ( C3), 28,3R * (C13), 32.05 * ^(C1-CH2 CH3), 33.16 * (C 2), 36.45 (Cl), 39.40 (CH ₃ SO _3), 51 , 22 (C15), 63.12 ° (C4), 64.72 ° (C6), 69.14 (C12b), 107.38 (C7a),

112.66 (Cll), 117.87 (C8), 119.73 (C9), 122.64 (C10), 125.38 * (C12a), 125.94 * (C7b), 137.37 (Cl 1a) ) ppm.

Example 2 (+) - (9S) -5-eyl-9- (indol-2'-yl) -1-azabidklo (3.3.1) nonane

10.0 g (0.0256 mol) of (+) - (12bS) -1-ethyl-1,2,3,4,6,7,12,12b-octahydro-1,5-propanoindole (2, 3-a) Quinolysinium methanesulfonate was dissolved in 150 ml of ethylene glycol. 8.0 g (0.2 mol) of sodium hydroxide was added and refluxed for 1 hour. The mixture is poured into ice water and quenched with chloroform. The organic phase is washed with water, clarified and, after drying, concentrated to dryness on a rotary evaporator. The crude product obtained (6.0 g) was purified by column chromatography (500 g Kieselgel 60, 0.063 0.2 mm; 1% diethylamine in ethyl acetate). The fractions containing 0.20 Rf material were collected and evaporated. The resulting base was 5.4 g (79%) of a light yellow oil.

¹ H-NMR (CDCl ₃ ): 0.84 (3H, t, J = 7.5 Hz, C 5 Cl ₁₂ CH ₃ ), 3.88 (1H, broad s, C 9 -H), 6.53 (1 H, s, C 3 'II) 6.9-7.6 (4H, m, aromatic protons), 8.93 (1H, broad, s, NH) ppm.

¹³ C NMR (CDCl3): 6.87 (C5-Cíl2 Cfl3) 23 ^x 10 (C7), 24.17 * (C3), 31.33 (C6), 31.54 (C5), 34 , 44 (C 5 -CH 2 -CH _3), 36.42 (C4), 45.95 (C2), 54.77 (C8>, 62.50 (C9), 101.72 (C3 '), 110.59 ( C7 '), 119.08 * (C6 ^; ) 119.94 * (C4'), 121.18 <C5 '), 128.59 (¢ 33 ^, 135.06 (C2'), 137.07 (C7a) ') ppm.

Hydrochloride and:

2.68 g (0.01 mol) of the above base in 15 ml of abs. dissolved in acetone, 3.3 ml (0.011 mol) of 3.35 molar hydrochloric acid were added with stirring and ice-cooling. The precipitated crystals are filtered off, washed with a little cold acetone and dried.

Yield: 1.54 g (50.6%), m.p. 284-288 ° C (sublimation from 220 ° C).

(a) ²⁴ ] 5 = + 28.4 ° (c = 1.0, water).

Analysis calculated for C ₁₈ H ₂₅ ClN ₂ (Ms: 304.85):

Theory:% C70,91, H8,27% N9,19% Clösszl 1.63% Found: C 70.80%, H 8.25%, N 9.21%, Cl 11.56% _total. Methanesulfonate formation:

The above base (1.34 g, 0.005 mol) was dissolved in acetone (4 ml) and methanesulfonic acid (0.48 g, 0.005 mol) was added under ice-cooling. After evaporation, it crystallizes on digestion in ether.

Yield: 1.7 g (93.4%), mp 194-199 ° C. Elemental analysis: C ₁₉ H ₂₈ N ₂ O ₃ S (Ms: 364.50):

H, 7.74; N, 7.69; S, 8.80. Found: C, 62.58; H, 7.79; N, 7.70; S, 8.92. %. Ethane sulfonate formation:

To a solution of the above base (1.34 g, 0.005 mol) in acetone (4 ml) was added ethanesulfonic acid (0.55 g, 0.005 mol) under ice-cooling. After evaporation, it crystallizes on digestion in ether.

Yield: 1.8 g (95.0%); mp 184-188 ° C. ANALYSIS; based on C ₂₀ H ₃₀ N ₂ O ₃ S (Ms: 378.53):

Calculated: C 63.45%, H 7.99%, N 7.40%, S 8.47%, Tahitian: C 63.44%, H 7.96%, N 7.26%, S 8.56%. .

Example 3 Epimer A and B of (9S) -5-ethyl-9- (3 '- (1-cyanoethyl) -indol-2'-yl) -1-azabicyclo (3.3.1) nonane

10.0 g (0.0256 mol) of (+) - (12bS) -1-ethyl-1,2,3,4,6,7,

12,12b-octahydro-1,5-propanoindole (2,3-a) quinolysinium methanesulfonate in 200 mL of ethylene glycol solution was treated with 13.0 g (0.2 mol) of potassium cyanide under nitrogen at reflux for 4 hours.

The dark brown reaction mixture was poured into water (500 mL), the precipitate was filtered off, the aqueous mother liquor was extracted with chloroform and the organic phase was evaporated to dryness over anhydrous magnesium sulfate. A at-31

The combined organic extracts and the precipitate (192.096) were combined with charcoal in methanol, dried over anhydrous magnesium sulfate and evaporated. The crude product (9.5 g) was chromatographed on 500 g silica gel (Kieselgel 60, particle size 0.063-0.2 mm) with 10% diethylamine in ethyl acetate. The 0.72 Rf fractions were collected and evaporated to give epimer A and the 0.64 Rf fractions were collected to yield epimer B.

Epimer A: Yield 3.5 g (42%; light yellow oil, Rf = 0.72 (Poligram SILG / UV ₂₅₄ , 10% diethylamine in ethyl acetate, UV light) 1 H-NMR (CDCl 3): 0.75 (3H, t, J = 7.2Hz, C5-CH ₂ CH _3), 1.20 (2H, m, C5-CH ₂ -CH _3), 1.70 (3H, d, J = 7.4 Hz, CH _3), 3.98 (1H, s, C9-H), 4.25 (1H, q, C H), 7.0-7.9 (4H, m, aromatic protons) , 8.24 (1H, broad, s, indole-NH) ppm.

¹³ C-NMR (CDCl 3): 6.65 (C 5 -CH 2 -CH 3), 20.05 (C), 22.10 ^x (C 14), 22.40 (C), 23.9 & (C 3), , 18 (C5), 31,60 (C6), 34.58 _{(C5-CH2-CH3),} 37.59 (C4), 46.19 (C2), 55.10 (C8), 60.43 (C9 ), 109.91 (C 3 -C ^5), 111.29 (C7), 118.74 ⁺ (C4 '), 119.86 ⁺ (C5'), 121.96 ⁺ (C6 '), 122.20 (-CN ), 125.20 (C3a '), 134.88 (C2'), 135.24 (C7a ') ppm.

B-epimer: Yield 2.2 g (26%), mp 89-94 ° C (from methanol) Rf = 0.64 (Poligram SIL G / UV _²⁵⁴⁾ 10% diethylamine in ethyl acetate, UV light) ¹ H-NMR (CDCl ₃ ): 0.74 (3H, t, J = 7.2 Hz, C 5 -CH ₂ CH ₃ ), 1.1-1.3 (2H, m, C 5 -CH ₂ -CH ₃ ), 1.69 (3H, d, J = 7.4 Hz, CH ₃ ), 4.10 (1H, s, C 9 -H), 4.35 (1H, q, C-H). , 7.0-7.8 (4H, m, aromatic protons), 8.25 (1H, broad, s, indole-NH) ppm.

Example 4

Ethanesulfonic acid salt of epimer A

To a solution of 6.3 g (0.0194 moles) of A-epimer base in 30 ml of anhydrous isopropanol was added dropwise 2.14 g (0.0194 moles) of ethanesulfonic acid under stirring and evaporation on a rotary evaporator. The residue is treated with acetone to crystallize into white crystals.

Yield: 4.73 g (68%), (a) ²⁴ D ⁵ = ₊ 103 ° (c = 1.0 in DMF) Melting point: not typical, mp 190 ° C, crystallizes at 300 ° C It re-melts at 335 ° C.

Elemental analysis: C ₂₃ H ₃₃ N ₃ O ₃ S (Ms: 431.58):

H, 7.70; N, 9.74; S, 7.43. Found: C, 64.12; H, 7.59; N, 9.69; S, 7.54. %.

Example 5

Ethanesulfonic acid salt of epimer B

6.3 g (0.0194 mole) of epimer B were prepared as in Example 2.

Yield: 69 g (99%), m.p. 272-278 ° C, (a) ² V = -7.7 ° (c = 1.0, DMF)

Elemental analysis: C ₂₃ H ₃₃ N ₃ O ₃ S (Ms: 431.58):

H, 7.70; N, 7.74; S, 7.43. Found: C, 63.95; H, 7.62; N, 9.81; S, 7.45. .

Example 6> Methanesulfonic acid salt of epimer A -0.643 g (0.002 mol) of epimeric base A was dissolved in 5 ml of propyl alcohol and 0.192 g (0.002 mol) of methanesulfonic acid was added under stirring and ice-cooling. The precipitated crystals were filtered the next day, washed, and dried. Yield: 0.65 g (78.0%); Melting point: 289-292 ° C Elemental analysis: Calculated for C ₂₂ H ₃ N ₃ O ₃ S (Ms: 417.56):

H, 7.48; N, 10.06; S, 7.68; Found: C, 63.07; H, 7.52; N, 9.91; S, 7.60. %.

Example 7

Hydrochloric acid salt of epimer

To a solution of 0.643 g (0.002 mol) of A-epimer base in 3 ml of acetone was added 0.319 ml (0.002 mol) of 6.2 M hydrochloric acid dioxane under stirring and ice-cooling. The next day, the precipitated crystals are born, washed, and dried. Yield: 0.58 g (81.7%); Melting point: 290-293 ° C Molecular formula Based Analysis: for C ₂₁ H _{2 3} 8C1N (357.92 Ms):

Found: C, 70.47; H, 7.88; N, 11.74; Cl, R: Calcd: C, 70.47; H, 7.88; N, 11.74; Cl, Only 9.90; 70.42%, H 7.93%, N11.69%, Cl only 9.83%.

Example 8

Methanesulfonic acid salt of epimer B

Dissolve 0.643 g (0.002 mol) of B-epimer base in 5 ml of isopropanol and add 0.192 g (0.002 mol) of methanesulfonic acid under stirring and ice-cooling. The next day, the precipitated crystals were filtered, washed, and dried.

Yield: 0.79 g (94.6%) Melting point: 274-279 ° C Elemental analysis: C ₂₂ H ₃₁ N ₃ O ₃ S (Ms: 417.56):

H, 7.48; N, 10.06; S, 7.68; Found: C, 63.31; H, 7.55; N, 9.98; S, 7.62. %.

Example 9

Hydrochloric acid salt of epimer B

To a solution of 0.643 g (0.002 mol) of B-epimer base in 3 ml of acetone was added 0.319 ml (0.002 mol) of 6.2 M hydrochloric acid in ice-cooling. The precipitated white crystals were born the next day, washed, and dried. Yield: 0.68 g (95.0%); Melting point: sublimates from 250 ° C and then decomposes above 320 ° C with decomposition. Elemental analysis for C ₂₁ H ₂₈ ClN ₃ (Ms: 357.92):

Calculated: C 70.47%, H 7.88%, N 11.74%, Clösszes 9.91%, found: C 7038%, H 7.86%, N1136%, Cl 10.05% _ÖS communication equipment.

Example 10

B-epimer D-maleic acid salt

To a solution of 0.643 g (0.002 mol) of B-epimer base in 4 ml of ethanol was added 0.3 g (0.002 mol) of D-tartaric acid in 3 ml of alcohol while stirring under ice-cooling. The material that crystallized overnight was filtered, washed, dried.

Yield: 0.73 g (77.5%); Melting point: 175-180 ° C Calculated: C 63.67%, H 7.05%, N 8.91%, found C 63.72%, H 7.19%, N 9.02%.

192 096

Example 11 (t) - (12bS) -1-Ethyl-1,2,3,4,6,7,12,12b-octahydro-15

-propanoindole (2,3-a) quinolysinium methanesulfonate

5.9 g (0.019 mole) of (-) - (lS, 12bS) -l-ethyl-l- (3-hydroxypropyl) -l, _12b-1 2,3,4,6,7,12 oktahidTO- Indolo (2,3-a) quinolizine was dissolved in 65 ml of absolute tetrahydrofur, 4.0 g (0.039 mol) of absolute triethylamine was added and cooled to -15 ° C. At this temperature, while stirring, a solution of 2.36 g (0.02 mol) of methanesulfonic acid chloride in 35 ml of absolute tetrahydrofuran is added dropwise to the reaction mixture. In 30 minutes. The mixture was stirred for 30 minutes at -15 ° C and for 2 days at room temperature. The precipitate was filtered off, washed with a little tetrahydrofuran and dried. The resulting solid was boiled with about 45 mL of chloroform to settle the remaining impurity triethylamine hydrochloride solution. After cooling, the precipitate is filtered off, washed with a little ether and dried. If necessary, recrystallize from methanol.

Yield: 5.2 g (705%); Melting point: Decomposes above 330 ° C. (α / D) = * 13.4 ° (c = 1.0; water),

Its structure and NMR spectra clearly confirmed its structure.

Elemental Analysis: Calculated for C ₂₁ H ₃₀ N ₂ O ₃ S (Ms: 390.54):

H, 7.74; N, 7.17; S, 8.21%. Found: C, 64.76; H, 7.62; N, 7.18; S, 8.04. %. 1 H-NMR (DMSO-D ₆ * CDCl ₃ , 3: 1): γ 1.10 (3H, t, J

7.5 Hz, _{C1-CH2 -CH3),} 2.48 (3H, s, _{CH3 SO3),} 4.94 (1H, broad s, C12b-H), 6.95 to 7.65 ( 4H, m, aromatic protons), 9.94 (1H, broad s, NH) ppm.

¹³ C-NMR (DMSO-d 6 CDCl 3: 1). γ7.32 (C1-CH2 -CH3), 17.29 (C7), 20.33 * (C14), 20.46 * ((C3), 28.38 ⁺ (C13), 32.05 ⁺ (C1- CH 2 -CH ₃ ), 33.16 * (C 2), 36.45 (Cl), 39.40 (CH ₃ SO ₃ ), 51.22 (C 15), 63.12 ° (C 4), 64.72 ° (C6), 69.14 (C12b), 107.38 (C7a), 112.66 (C11), 117.87 (C8), 119.73 (C9), 122.64 (C10), 125.38 ^x (C12a), 125.94 * (C7b), 137.37 (Cila) ppm.

Claims (4)

PATENT CLAIMS A process for the preparation of novel optically active 9- (indol-2-yl) -1-azabicyclo (3.3.1) nonane derivatives of formula I and their pharmaceutically acceptable acid addition salts, wherein: R 1 is C 1 -C 4 alkyl and R 1 is hydrogen, or R represents a C1-C4 alkyl group for the preparation of R * for the 1-cyanoethyl group, wherein 11 is an optically active 1-alkyl-12,3,4,6 of general formula (11), 7,12,12b-ok · tachydro-1,5-propanoindole (2,3-a) clolizinium derivative - where R is C 1 -C 4 alkyl, X represents an acid residue anion or hydroxide ion the. ) in the preparation of derivatives containing R 'in the hydrogen atom, an alkali metal hydroxide, preferably sodium hydroxide, is heated in an inert organic solvent having a boiling point of at or above the reaction temperature of 120 to 230 ° C, preferably 200 ° C. The compound of formula I wherein R is as defined above, R 'is hydrogen is optionally converted to the acid addition salt, b. ) in the preparation of derivatives containing 1 '-cyanoethyl group R' in an inert organic solvent having a boiling point at or above the reaction temperature of 120 ° to 230 ° C, preferably 200 ° C, with an alkali metal cyanide, preferably potassium cyanide then heating the resulting epimeric mixture of formula (I), Where R is as defined above, R 'is 1-cyanoethyl, optionally separated and the epimers optionally converted into pharmaceutically acceptable acid addition salts. Processes a) and b) according to claim 1, wherein the organic solvent is ethylene glycol. Process b) according to claim 1, characterized in that the separation is carried out by column chromatography. A process for the preparation of the compounds of the formula I as claimed in claim 1, wherein R and R 'are as defined in claim 1 for the preparation of a pharmaceutical composition comprising the compounds of formula (I) wherein R and R' are as defined in claim 1 or a pharmaceutically acceptable acid. mixed with excipients and / or excipients commonly used in the pharmaceutical industry to form a pharmaceutical composition.