CH656881A5 - NEW EBURNANE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF. - Google Patents

Description

The invention relates to new racemic and optically active eburnan derivatives of the general formula (Ia) and / or (Ib) and a process for the preparation thereof

wherein R is an alkyl group with 1-6 carbon atoms, where the space position of the hydrogen atom in position 3 and that of R a, a and / or ß, ß or a, ß and / or ß, a can be, and their acid addition salts.

2. A process for the preparation of racemic and optically active eburnan derivatives of the general formula (Ia) and / or (Ib) according to claim I, characterized in that a racemic or optically active eburnamonin derivative of the general formula (II),

(Ia)

35

NU

HO '^

(II)

(Ib)

in which R and its position in relation to the hydrogen atom in position 3 are defined as in the general formulas (Ia) and (Ib), is oximated, and if desired the racemic or optically active eburnan oxime derivative of the general formula (Ia) or (Ib ) is treated with an acid.

3. The method according to claim 2, characterized in that the obtained Eburnan derivative-Z, E-isomer mixture of the general formula (Ia) and (Ib) is separated.

4. A process for the preparation of optically active Ebur-nan derivatives according to claim 1, characterized in that an Eburnan derivative Z isomer of the general formula (Ia) is prepared by the process according to claim 2 and this to an Eburnan derivative. E isomer of the general formula (Ib) is formed.

50

- wherein R is an alkyl group with 1-6 carbon atoms, where the space position of the hydrogen atom in position 3 and that of R a, a and / or ß, ß or a, ß and / or ß, a can be - and their acid addition salts , wherein a razemi-55 or optically active eburnamonin derivative of the general formula (II)

60

65

(II)

R

- In which R and its position in relation to the hydrogen atom are defined as in the general formulas (Ia) and (Ib)

3,656,881

are - is oximated, and if desired the lactic acid, cinnamic acid, benzoic acid, phenylacetic acid, p-

Eburnan derivative ZE isomer mixture of the general for aminobenzoic acid, p-hydroxybenzoic acid, p-amino-sali-

mel (Ia) and (Ib) is separated or, if desired, the acrylic acid etc., alkylsulfonic acids, such as methanesulfonic acid,

holding Eburnan derivative Z isomer of the general formula ethanesulfonic acid, etc., cycloaliphatic sulfonic acids, such as

(Ia) to an Eburnan derivative E isomer of the general 5 cyclohexylsulfonic acid, arylsulfonic acids, such as p-toluenesulfon

Formula (Ib) is formed and / or if desired the erfonic acid, naphthylsulfonic acid, sulfanylic acid etc., amino

racemic Eburnan derivative of the general formula acids, such as aspartic acid, glutamic acid, N-acetyl

(la) or (Ib) resolves and / or, if desired, the aspartic acid, N-acetyl-glutaric acid etc.

The racemic or optically active Eburnan derivative of all- The salt formation can in a neutral organic Lö-general formula (Ia) or (Ib) treated with an acid, e.g. in 1-6 carbon aliphatic alcohol. atoms of matter take place, the racemic or optically ac-

The new compounds of the general formula (Ia) active compound of the general formula (Ia) or (Ib) in the above

add significant antihypoxic effects. solvent is dissolved, then the corresponding acid

In the above general formula, R as alkyl or the solution grappe with 1-6 carbon atoms prepared with the above solvent stands for straight or mixed 15 of the acid in the first solution until the second groups, e.g. Methyl, ethyl, n-propyl, i-propyl, reaction of the mixture becomes slightly acidic (up to a pH

n-butyl, sec.-butyl, tert.-butyl, n-pentyl, i-pentyl, n-He value of about 5-6). Then the separated acid ad-

xyl groups. dition salt from the reaction mixture to a suitable

The starting materials of the general formula (II) can be e.g. by filtration.

as in the Hungarian patent specification No. 151 295 or the 20 The racemic compounds of the general formulas in the patent specification No. 776 337 or 802 387 or the fran- (Ia) or (Ib) can be resolved in a manner known per se No. 2 268 016 can be produced, but one can also proceed in such a way that

will. Process according to the invention as an optically active starting material

The oximation of the compounds of the general formula Compounds of the general formula (II) can be used

(II) can with a tert .- (C4 8 alkyl) nitrite, such as tert-butylni-. However, the method according to the invention can be

trite, tert-amyl nitrite or isoamyl nitrite, in the presence of a moderately so that when racemic strong base such as alkali metal alcoholates, e.g. Potassium or compounds of the general formula (Ia) or (Ib)

Sodium tert-butoxide, sodium or potassium isoamylate, potassium, racemic starting materials of the general lium tert-amylate, alkali metal amides, e.g. Lithium isopro formula (II) can be used. However, if optically active pylamide or organometallic compounds, such as butyl-li compounds of the general formula (Ia) or (Ib)

thium. The oximation can be suitably made, is assumed from optically active compounds sig in a neutral, apolar general formula (II) for the reactions.

Ren solvent, advantageously in an aromatic hydrocarbon, such as benzene, toluene or xylene, obtained with the process according to the invention. optically active compounds of the general formula (Ia)

As a result of the oximation reaction, the mixture 35 or (Ib) or their racemates or acid addition salts can

a Z isomer of the general formula (Ia) and an E isone, if desired, a further purification operation,

obtained of the general formula (Ib), in which the Z-iso- e.g. Recrystallize, be subjected. The range of mer of the general formula (Ia) predominates when the solvent suitable for recrystallization is obtained by

Temperature of the reaction mixture is not too high, the solubility and crystallization properties of the moderately 15-50 ~ C is appropriate and the pH of the reaction to crystallizing substance fixed.

Mix is neutral or slightly acidic, a value is expedient. The active ingredient of the general formula (Ia) or (Ib) is between 3 and 7. For example, if the oximation reaction mixture with that customary in medicine, for parenteral or enteral mixing with an aqueous one Ammonium chloride solution with administration, suitable, non-toxic, inert, is split in sol-room temperature, mainly Z-Iso preparations usually solid or liquid carrier of the general formula (Ia) arises, but a thin «and / or auxiliaries are mixed into one Pharmaceutical aqueous sulfuric acid solution is used to form the molded product. As a carrier, e.g. Water, charged isomers in almost the same ratio. The Z-isomer of tine, lactose, milk sugar, starch, pectin, magnesium ste general formula (Ia) is a kinetic product, and can arate, stearic acid, talc, vegetable oils such as peanut oil, oli by heating, especially in the presence of protons veno oil etc. can be used. The active ingredient can be partially in the form of a thermodynamically more stable E-isomer such as that of conventional pharmaceutical preparations, e.g. are isisomerized in solid general formula (Ib). (round or angular tablets, coated tablets, capsules, such as the solid In the process according to the invention, the gelatin capsule, pills, suppositories, etc. changes) or in liquid form, the position of the hydrogen atom in position 3 and that of (e.g. oily or aqueous solution, suspension, Emulsion, Si-R to each other in the starting compounds of the general rup, soft gelatin capsule, injectable oily or aqueous formula (II) is not, so in the final product of the general 55 solution or suspension etc.) are prepared. The amount of formula (Ia) and / or (Ib), the spatial position of the hydrogen of the solid carrier can vary between wide limits of atoms in position 3 and that of R relative to one another, a value between 25 mg and 1 g being advantageous. the starting compounds of the general formula (II) The preparations can, if appropriate, also be the usual phar-identical. pharmaceutical excipients, e.g. Preservatives, stabilizers

For the acid addition salt formation of the compounds of the 60 sators, wetting agents, emulsifiers, salts for the general formulas (Ia) and (Ib), e.g. the following acid levels of the osmotic pressure, buffers, flavors, or be used: inorganic acids, such as hydrogen odorants, etc. contain. The preparations can be further halides, e.g. Hydrochloric acid or hydrogen bromide, sulfur and optionally also other pharmaceutically valuable acids, phosphoric acid, nitric acid, perhalic acids, e.g. Known compounds contain, so that synergistic Wir-perchloric acid, organic carboxylic acids, such as formic acid, 65 kung occurs. The preparation is advantageously produced in those dose acetic acid, propionic acid, glycolic acid, maleic acid, hydrounits which correspond to the desired route of administration xymaleic acid, fumaric acid, succinic acid, tartaric acid. The pharmaceutical preparations can be prepared with ascorbic acid, citric acid, malic acid, salicylic acid, the usual methods, e.g. that she-

656 881

practicing, mixing, granulating and pressing the components, which is necessary to form a corresponding preparation. The preparations can be subjected to further usual pharmaceutical operations (e.g. sterilization).

The invention is illustrated by the following examples, without thereby restricting the scope of protection.

example 1

(+) - 14-Oxo-15-hydroxyimino-eburnan (3a, 16a) (Z-isomer) and its hydrochloric acid sah

The solution of 4.0 g (13.6 mmol) (-) - Vincamon (3a, 16a) prepared with 80 ml of absolute benzene is mixed with 13.6 ml (148 mmol) of freshly distilled tert-butyl nitrite and after a few minutes 3 8 g (34 mmol) of potassium tert-butoxide were added. The solution is stirred in a nitrogen atmosphere for 1-1.5 hours at room temperature. The reaction mixture is cleaved under ice cooling with the solution of 15 g of ammonium chloride prepared with 150 ml of water. The organic phase is separated off, then the aqueous phase is extracted three times with 30 ml of dichloromethane. The organic phases are combined, dried over solid anhydrous magnesium sulfate, filtered and the solvent is removed from the filtrate in vacuo by distillation. The remaining oil is crystallized from methanol.

Weight of the title compound obtained: 2.05 g. Yield: 47%.

Based on thin-layer chromatography investigations, it was found that the Rr value of the end product is higher than that of the starting material (KG-G, dichloromethane-methanol mixture).

Melting point: 158-159 ° C (methanol).

(a) D = + 78.4 ° (c = 1.15, chloroform).

Analysis results based on the formula C19H21N302 (molecular weight: 323.28):

calculated%: C = 70.57; H = 6.54; N = 12.99 found%: C = 70.60; H = 6.60; N = 12.92.

IR (KBr): 3200-2600 (broad chelated OH), 1710 (CO), 1630 cm-1 (C = N).

MS (m) e,%: 324 (M +1.24), 323 (M +, 100), 306 (15), 294 (40), 277 (53), 276 (42), 264 (10), 253 (12) ...

Lh-nmr (CDCI3, §): 14.47 (1H, s, N-OH), 8.40-7.27 (4H, m, aromatic), 4.26 (1H, s, 3-H), 1.03 (3H, t, J = 8Hz, CH2-CH3).

13C NMR (CDC13.5): 158.0 (CO), 148.0 (C = N), 134.0 (C-13), 130.7 (C-2), 129.9 (C-8 ), 125.3-125.0 (C-10 / C-11), 118.6 (C-9), 116.8 (C-12), 115.1 (C-7), 53.5 ( C-3), 50.7 (C-5), 44.8 (C-19), 44.2 (C-16), 31.0 (C-20), 23.5 (C-17), 20.6 (C-18), 16.3 (C-6), 9.0 (C-21).

The mother liquor from the methanol crystallization is added up to a pH of 3 hydrochloric acid methanol, then a further 0.9 g (18.3%) of the title compound can be obtained in the form of a hydrochloric acid salt.

Overall yield: 65.3%.

Example 2

(+) - 14-oxo-15-hydroxyimino-eburnan (3a, 16a) (Z-isomer) and (-) -14-oxo-15-hydroxyimino-eburnan (3a, 16a) (E-isomer)

The procedure is as in Example 1, all the way to ammonium chloride splitting. After the reaction mixture has split, the separated benzene phase is extracted three times with 15 ml of 2.5% strength aqueous sulfuric acid solution, the sulfuric acid extract is alkalized to a pH of 9 with concentrated aqueous ammonium hydroxide solution, and extracted three times with 30 ml of dichloromethane. The organic phases are combined, dried over solid, anhydrous magnesium sulfate, filtered and the solvent is removed from the filtrate in vacuo by distillation. The oil thus obtained, weighing 2.4 g (55%), is separated into two substances by preparative layer chromatography (KG-PF254 + 366: dichloromethane: methanol = 20: 2, eluting with acetone; the Rr value of the Z isomer is higher than that of the E isomer).

The substance with the higher Rr value is crystallized from methanol. 1.04 g of the title compound Z-isomer are thus obtained.

Yield: 24%.

The substance with the lower Rr value is brought into a readily filterable state with petroleum ether, filtered and dried.

0.9 g of the title compound E isomer are thus obtained.

Yield: 20.5%.

Melting point: 202-203 C (petroleum ether).

[a] ^ = - 198: (c = 1, chloroform).

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Analysis results based on the formula C19H21N3O2 (molecular weight: 323.38):

calculated%: N = 12.99

found%: N = 12.80.

'H NMR (CDC13, DMSO-d6, S): 8.38-7.27 (4H, m, aromatic), 4.30 (1H, s, 3-H), 0.98 (3H, t, J = 8Hz, CH2CH3).

13C-NMR (CDC13, DMSO-df), 5): 156.8 (CO), 150.7 (C = 7), 134.6 (13-C), 130.9 (C-2), 130, 3 (C-8), 124.0 (C-10), 123.9 (Cl 1), 118.2 (C-9), 116.0 (C-12), 112.4 (C-7) , 52.0 (C-3), 51.4 (C-5), 45.3 (C-19), 45.1 (C-16), 28.3 (C-20), 25.7 ( C-17), 20.3 (C-18), 16.0 (C-6), 10.2 (C-21).

IR (KBr): 3250 (OH, sharp), 1700 (CO), 1630 cm "1 (C = N).

MS (m / e,%): 324 (M +1.24), 323 (M +, 100), 306 (27), 294 (46), 277 (66), 276 (62), 264 (16), 253 (13) ...

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Claims (5)

656 881 PATENT CLAIMS 1. Racemic or optically active Eburnan derivatives of the general formulas (Ia) (la) and / or (Ib) 5. The method according to any one of claims 2 to 4, characterized in that the racemic Eburnan derivative obtained of the general formula (Ia) or (Ib) is resolved. 6. The method according to any one of claims 2 to 5, characterized 5 characterized that the oximation is carried out with a tert .- (C4_8 alk-yl) nitrite in the presence of a strong base. 7. A process for the preparation of pharmaceutical preparations, characterized in that the racemic or optically active eburnan derivative of the general formula (Ia) io or (Ib) according to claim 1, mixed with the excipients and / or auxiliaries which are acceptable in medicine, and shaped into a pharmaceutical preparation. 8. A pharmaceutical preparation containing a racemic or optically active eburnan derivative according to claim 1 15 or its pharmaceutically acceptable acid addition salt with excipients and / or auxiliaries which are acceptable in medicine. 20th (Ib) 25th