SE457641B - EBURNANOXIMIZE DERIVATIVES, PROCEDURES FOR PREPARING THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOSITIONS - Google Patents

Description

According to a further aspect of the invention there is provided a process for the preparation of racemic or optically active eburnanoxime derivatives of formulas Ia and / or Ib, wherein R and the configuration of the 3-hydrogen and R are as defined above. ) and acid addition salts thereof, which process involves oxidizing a racemically or optically active eburnamonine derivative of formula II in II wherein R and its configuration with respect to the 3-hydrogen are as defined above, and separating, if desired, the resulting ZE isomeric mixture of the eburanane oxime derivatives of formulas Ia and / or Ib or, if desired, converting a Z isomer of formula Ia into an E isomer of formula Ib and / or, if desired, , cleaves a racemic eburnanoxime derivative of the formula Ia or Ib and / or, if desired, a racemically or optically active eburnanoxime derivative of the formula Ia or Ib is treated with an acid.

The novel compounds of formula Ia exhibit valuable antihypoxic activity.

The term "alkyl group having 1-6 carbon atoms" as used herein means straight or branched chain aliphatic hydrocarbon groups having 1-6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc.

The starting compounds of formula II are prepared, for example, according to Belgian Patents 776,337 or 802,387 or as described in French Patent Specification 10 15 20 25 30 35 3 457641 2 268 016.

The oximation of the compounds of formula II is generally carried out with a tertiary C 4-8 alkyl nitrite such as tert-butyl nitrite, tert-amyl nitrite or isoamyl nitrite in the presence of a strong base such as, an alkali metal alcoholate, for example potassium or sodium tert .-butylate, sodium or potassium isoamylate or potassium tert-amylate, an alkali metal amide such as lithium diisopropylamide or an organic metal compound such as butyllithium. The oximation is preferably carried out in a non-polar organic solvent which is inert under the reaction conditions, preferably in an aromatic hydrocarbon such as benzene, toluene or xylene.

The oximation gives a mixture of the Z-isomer of formula Ia and the E-isomer of formula Ib, in which mixture the Z-isomer is the main component, if the reaction temperature is moderate, preferably between 15 and 50 ° C, and the pH of the reaction mixture is neutral or slightly acidic and is preferably between 3 and 7. If, for example, the oxidation reaction mixture is decomposed with an aqueous solution of ammonium chloride at room temperature, the Z isomer of formula Ia is mainly obtained, while if a dilute aqueous solution of sulfuric acid the two isomers obtained The Z-isomer of the formula can be re-isomerized in approximately equal proportions.

Ia is a kinetic product which is part of the thermodynamically more stable E-isomer of formula Ib by heating, especially in the presence of protons. In the starting compounds of formula II, the mutual configuration between the 3-hydrogen and the R-substituent does not change during the process according to the invention. Therefore, the configuration of the 3-hydrogen and R in the starting compounds of formula II and 1 shnrmom fl denri of formulas Ia and / or Ib is the same.

For the preparation of salts of the compounds of formula I, for example, the following acids may be used: inorganic acids such as hydrogen halides, for example hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or perhalic acids such as perchloric acid; organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, ascorbic acid, salicylic acid, lactic acid, cinnamic acid, benzoic acid, phenylacetic acid, p-hydrobenzoic acid, -aminobenzoic acid, p-aminosalicylic acid, etc .; alkylsulfonic acids such as methanesulfonic acid, ethanesulfonic acid, etc .; cycloaliphatic sulfonic acids such as cyclohexanesulfonic acid; arylsulfonic acids such as p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, etc .; amino acids such as aspartic acid, glutamic acid, etc.

The salts are prepared in an inert organic solvent, for example an aliphatic alcohol having 1 to 6 carbon atoms, for example by dissolving a racemic or optically active compound of the formula Ia or Ib in said solvent and adding a corresponding acid to the resulting solution as such or in in the form of a solution with the above solvents until the mixture becomes slightly acidic (pH about 5-6).

The precipitated acid addition salt can then be separated from the rectin mixture by conventional techniques, for example by filtration.

The racemic compounds of formula Ia or Ib can be cleaved in a known manner, but optically active starting materials of formula II can also be used when it is desired to obtain optically active end products. Preferably, racemic compounds of formula Ia or Ib are prepared starting from racemic compounds of formula II, while optically active compounds of formula Ia or Ib are obtained starting from optically active compounds of formula II.

If desired, the optically active or racemic compounds of formula Ia or Ib or acid addition salts thereof may then be subjected to further purification, for example recrystallization.

The solvents used for the recrystallization are selected depending on the solubility and crystallization ability of the crystallization compounds; According to a further aspect of the present invention there are provided pharmaceutical compositions which comprise as active ingredient at least one racemic or optically active compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof in admixture with inert solids or liquid the pharmaceutical carriers and / or additives.

The pharmaceutical compositions may be formulated in forms suitable for parenteral or enteral administration. As carrier, it is possible to use, for example, water, gelatin, lactose, milk sugar, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil, etc. The compositions can be prepared in the form of solid preparations, for example tablets, lozenges, dragees, capsules such as hard gelatine capsules, suppositories, etc., or in the form of liquid preparations, for example oily or aqueous solutions, suspensions, emulsions, syrups, soft gelatine capsules, injectable oily or aqueous solutions or suspensions, etc.

The amount of solid carrier can vary within wide limits but is preferably from about 25 mg to 1 g. The pharmaceutical compositions may optionally also contain conventional pharmaceutical additives such as preservatives, stabilizers, wetting agents, emulsifying agents, salts having the ability to control the osmotic pressure, buffer substances, flavoring substances, flavoring substances, etc. Additional pharmaceutically active compounds may be present in the formulations.

The pharmaceutical compositions are preferably prepared in dosage units suitable for the desired route of administration. The pharmaceutical compositions may be prepared by conventional techniques including, for example, sieving, mixing, granulating, pressing or dissolving the components. The resulting compositions can be subjected to additional treatments conventionally used in the pharmaceutical industry, for example sterilization.

The invention is further illustrated by the following working examples. Example 1 (+) - 14-oxo-15-hydroxyiminofeburnan (3a, 16d) - (Zfisomer) and dgss hydrochloride "" "" "To a solution of 4.0 g ( (-) rvinoamone (3w, 16 fi) in 80 ml of absolute benzene is added 13.6 ml (148 mmol) of freshly distilled tert-butyl nitrite and a few minutes later 3.8 g (34 mmol) of potassium tert-butylate; The solution is stirred for 1-1.5 hours at room temperature under a nitrogen atmosphere. The reaction mixture is decomposed with a solution of 15 g of ammonium. ,. . . . . . . -. . . . . . chloride in 150 ml of water under ice-cooling. The organic phase is separated and the aqueous phase is shaken with three 3D ml portions of dichloromethane. The organic phases are combined, dried over solid anhydrous magnesium sulphate and filtered and the solvent is removed from the filtrate by distillation in vacuo. The residual oil is crystallized from methanol.

2.05 g of the intended compound are obtained in a yield of 47%.

According to thin layer chromatography, the Rf value of the final product is higher than that of the starting compound (KG-G, dichloromethane / methanol). Melting point 158-15900 (methanol).

(GUD = + 7s, 4 ° (c = 1.1s, chloroform).

Analysis for C 19 H 21 N 3 O 2 (323.38): Calculated: C 70.57%, H 6.54%, N 12.99%; Found: C 70.60%, H 6.60%, N 12.92%.

IR spectrum (KBr): 3200-2600 (broad, chelate OH), 1710 (co), 1630 cm -1 (c = N) .- Mass spectrum (m / e,%): 324 (M + 1.24), 323 (M +, 100), 306 (15), 294 (40), 277 (53), 276 (42), 264 (10), 253 (J2) ...

1 H-NMR Spectrum (cnc13, @ f) = 14.47 (1H, s, N-one), 8.40-7.27 (4H, m, aromatic), 4.26 (1H, s, 3 -H), 1.03 (3H, t, j = 3Hz, CH 13 C-NMR spectrum (cnc13,; F) = 1ss, ø (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 (cs), 44.8 (c-19), 44.2 f (c-16), 31.0 (c-20), 23.5 (C-17), 20.6 (C-18), 16.3 (C-6), 9.0 (C-21).

To the mother liquor from the methanolic crystallization is added hydrochloric acid in methanol to pH = 3 to obtain 2-cg3>. 4576411 an additional 0.9 g (18.3%) of the intended compound as hydrochloride. Total yield: 65.3%.

Example 2 (+) - 14-Oxo-15-hydroxyimino-eburnan (3§916WJ (Z-isomer) to (.-1-1 4-axo-1 si à-yafo] imino-ezuran (au. 1000 (E-isomer) The procedure of Example 1 is repeated until the decomposition of the reaction mixture with ammonium chloride. After decomposition of the reaction mixture, the dose-separated benzene phase is extracted with three 15 ml portions of a 2.5% aqueous solution of sulfuric acid, the extract is alkalized to pH 9 with a concentrated aqueous solution of ammonium hydroxide under ice-cooling and then extracted with three 30 ml portions of dichloromethane, the organic phases are combined, dried over solid anhydrous magnesium sulphate and filtered and the solvent is distilled off from the filtrate in vacuo to give 2.4 g ( 55%) of an oily product The product is separated by thin layer chromatography into two components (KG-PF254 + 366, dichloromethane methanol = 20: 2, elution with acetone, Rf value of the Z-isomer higher than for the E-isomer).

By crystallizing the components with a higher Rf value from methanol, 1.04 g of the title Z isomer are obtained in a yield of 24%.

The material with a lower Rf value is transferred to a filterable state with petroleum ether, filtered and dried. 0.9 g of the title E-isomer are obtained in a yield of 20.5%. Melting point 202-203 ° C (petroleum ether).

H36 = -1ee ° Analysis for C19H21N3O2 (323, $ 8): Calculated: N 12.99%, Found: N 12.80%. 1n-Nnn spectrum (cnc13, nnso-avá 1; s, 3s-7.27 (4n, m, aromatic), 4.30 (1n, s, 3-H), io, 9s (311, t ,; r = s11z, c112cg3).

Bc-Nmrucnciy nMso-ayà fi; 156.8 (co), 150.7 (c = 7), 134.6 (13-c), 130.9 (cz), 130.3 (ca), 124.0 (c-10), 123, 9 (c-11), 118.2 (cs), 11s ', o (c-121, 112.4 (c-7), 52.0 (cs), 51.4 (c ~ s),' 4s, 3 (c-19), 45.1 (c-16), 28.3 (c-zo), 25.7 (c-17), 20.3 (c-1s), 16, 0. (c.-s), 10.2 (c-z1). ': Za spectrum (man: 32so (on, med), 1700 (co), 163m cmq (c = N). em: 324 (M + 1.24), 323 (f, 100), 306 (27), 294 (46), 277 (se), 276 (62), 264 (16), 253 (13)

Claims (4)

457641 EATENTKRAV Racemic or optically active eburnanoxime derivatives of the formulas Ia and / or Ib JN Ia o / å \ NR / Q HO Ib wherein R is an alkyl group having 1 to 6 carbon atoms and the configuration of the hydrogen atom in the 3-position and R fi {and / or 5.19 or: me and / or ß ,, (, and syraaaaíuians salts thereof. Pharmaceutical compositions, characterized in that they comprise as active ingredient at least one racemic or optically active compound of formula Ia or Ib according to claim 1 or a pharmaceutically acceptable acid addition salt thereof in admixture with inert solid or liquid pharmaceutical carriers and / or additives. A process for the preparation of racemic or optically active eburnanoxime derivative according to claim 1 of the formulas Ia and / or Ib Ia 0 1 'INR / Q HO _11 »wherein R is an alkyl group having 1 to 6 carbon atoms and the configuration of the hydrogen atom in the 3-position and R. are'QQx 'and / or ß or and / or / íøf and acid addition salts thereof, characterized in that a racemically or optically active eburnamonine derivative of the formula II is 457641 II wherein R and its configuration with respect to the 3-hydrogen are as defined above and that, if desired, the resulting ZE isomeric mixture of the eburanane oxime derivatives of formulas Ia and / or Ib is separated or, if desired, a Z-isomer is converted and / or that, if desired, a racemic eburnanoxime derivative of the formula Ia or Ib is cleaved and / or, if desired, a racemically or optically active eburnanoxime derivative of the formula Ia is treated. or Ib with an acid. ' 4. A process according to claim 3, characterized in that the oximation is carried out with a tert-C 4 -alkyl nitrite in the presence of a strong base.