HU190400B - Process for preparing new eburnan-oxime derivatives - Google Patents

Abstract

Eburnane-oxime derivatives of formulae (Ia) and/or (Ib> <IMAGE> wherein R represents an alkyl group having 1 to 6 carbon atoms and acid addition salts thereof, which compounds are pharmaceutically active, possessing in particular anti- hypoxial activity.

Description

The present invention relates to novel racemic and optically active ebumannoxime derivatives of formula Ia and / or Ib, wherein R is ethyl, and to their acid addition salts by reacting a racemic or optically active ebummonoxin compound of formula II in which R is reacted with a tertiary (C4-C8) -alkyl nitrite as defined above and optionally separating the resulting ZE-isomeric mixture of eburnanoxime la and Ib and / or optionally forming the racemic or optically active la or an eburnan oxime derivative of the formula Ib or Ib.

The novel compounds of formula Ia have significant antihypoxic activity.

For example, starting materials of formula II are disclosed in U.S. Patent No. 151,295. Hungarian or 776 337 or 802 387 Belgian or U.S. Patent No. 2,268,016. can be prepared as described in French Patent No. 5,198,198.

Reaction of compounds of Formula A with tertiary C4-C8 alkyl nitrite such as tert-butyl nitrite, tertiary amyl nitrite, or isoamyl nitrite, a strong base such as alkali metal alcoholates, for example, potassium or sodium tertiary butylate, sodium or potassium isoamylate, potassium tertiary amylate, alkali metal amides such as lithium diisopropylamide or organometallic compounds such as butyllithium. The reaction may conveniently be carried out in a reaction-inert organic apolar solvent, preferably an aromatic hydrocarbon such as benzene, toluene or xylene.

The reaction results in a mixture of the Z-isomer of formula Ia and the E-isomer of formula Ib in which the Z-isomer of formula Ia is predominant when the temperature of the reaction mixture is not too high, preferably 15-50 ° C. the pH of the reaction mixture is neutral or slightly acidic, preferably 3-7. For example, when the reaction mixture is quenched with aqueous ammonium chloride solution at room temperature, the Z-isomer of Formula Ia is predominantly formed, whereas when dilute aqueous sulfuric acid is used, the two isomers are formed in approximately equal proportions. The Z-isomer of formula Ia is a kinetic product and can be partially re-isomerized by heating, especially in the presence of a proton, to the E-isomer of formula Ib, which is more thermodynamically stable.

For example, the following acids may be used to form the acid addition salts of the compounds Ia and Ib. Inorganic acids such as hydrogen halides such as hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perhalic acids such as perchloric acid, and the like. Organic carboxylic acids such as formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, fumaric acid, succinic acid, ascorbic acid, citric acid, malic acid, salicylic acid, lactic acid, cinnamic acid, benzoic acid, p-phenylacetic acid, amino salicylic acid, etc. Alkylsulfonic acids such as methanesulfonic acid, ethanesulfonic acid, etc. Cycloaliphatic sulfonic acids such as cyclohexylsulfonic acid. Arylsulfonic acids such as p-toluenesulfonic acid, naphthylsulfonic acid, sulfanylic acid, and the like. Amino acids such as aspartic acid, glutamic acid, N-acetyl aspartic acid, N-acetylglutaric acid and the like.

The salt formation may be carried out in an inert organic solvent, such as an aliphatic alcohol having 1 to 10 carbon atoms, by dissolving the racemic or optically active compound of formula Ia or Ib in the above solvent and then adding the appropriate acid or acid to the solution. until the pH of the mixture becomes slightly acidic (about pH 5-6). The precipitated acid addition salt may then be isolated from the reaction mixture by any suitable means, such as filtration.

The process of the present invention may conveniently be carried out by using racemic II starting materials when preparing racemic compounds of formula Ia or Ib, if desired to prepare optically active compounds of formula Ia or Ib from optically active compounds of formula II let's start.

The optically active compounds of formula Ia or Ib, or their racemates or acid addition salts, obtained by the process of the invention may, if desired, undergo further purification, such as recrystallization. The range of solvents suitable for recrystallization is determined by the solubility and crystallization properties of the material to be crystallized.

The active ingredient of Formula Ia or Ib is formulated in pharmaceutical compositions with non-toxic, inert, solid or liquid carriers and / or excipients suitable for parenteral or enteral administration in pharmaceutical formulations. Suitable carriers include, for example, water, gelatin, lactose, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil, and the like. It can be used. The active ingredient may be in the form of standard pharmaceutical compositions, for example solid (round or square tablets, dragees, capsules, such as hard gelatin capsules, pills, suppositories, etc.) or liquid (e.g., oily or aqueous solution, suspension, emulsion, syrup, capsules, injectable oily or aqueous solutions or suspensions, etc.). The amount of solid carrier can vary widely, preferably from about 25 mg to about 1 g. The compositions may optionally contain conventional pharmaceutical excipients such as preservatives, stabilizers, wetting agents, emulsifying agents, salts for adjusting the osmotic pressure, buffering agents, flavoring agents, perfumes, and the like. may also be included. The compositions may also optionally contain other pharmaceutically acceptable compounds of known value without exhibiting synergistic effects. Preferably, the composition is formulated in dosage units appropriate to the desired route of administration. Pharmaceutical compositions may be prepared by conventional methods, which may include, for example, sifting, mixing, granulating and compressing or dissolving the ingredients in the appropriate compositions. The compositions may be subjected to other conventional pharmaceutical operations (e.g., sterilization).

The invention is illustrated in more detail by the following non-limiting examples.

Example 1 (+) -14-Oxo-15-hydroxyimino-eburnan (3a, 16a) (Z-isomer) and its hydrochloride salt

To a solution of (-) - vincamone (3a, 16a) (4.0 g, 13.6 mmol) in absolute benzene (80 mL) was freshly distilled tert-butyl nitrite (13.6 mL, 148 mmol) followed by 3.8 g (34 mmol) of potassium tert-butylate was added. The solution was under nitrogen

Stir at room temperature for 1-1.5 hours. The reaction mixture was quenched with a solution of 15 g of ammonium chloride in 150 mL of water under ice-cooling. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3 x 30 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent removed from the filtrate by distillation in vacuo. The residual oil was crystallized from methanol.

The title compound was weighed 2.05 g.

Yield: 47%.

TLC showed the final product to have an R _f greater than its starting material (KG-G, dichloromethane / methanol).

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

[α] _D = + 78.4 ° (c = 1.15, chloroform).

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

IR (KBr): 3200-2600 (wide 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). ·.

1 H-NMR (CDCl ₃ , δ): 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).}

¹³ C-NMR (CDCl 3, δ): 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 TC-17), 20.6 (C-18), 16.3 (C-6), 9.0 (C-21).

HCl methanol was added to the mother liquor of the methanol crystallization to give an additional 0.9 g (18.3%) of the title compound as the hydrochloride 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)

All were carried out as described in Example 1 up to the decomposition with ammonium chloride. After the reaction mixture was quenched, the separated benzene phase was extracted three times with 15 ml of 2.5% aqueous sulfuric acid solution, and the sulfuric acid extract was basified to pH 9 with concentrated aqueous ammonium hydroxide solution under ice-cooling, and extracted three times with 30 ml of dichloromethane. The organic phases were combined, dried over solid anhydrous magnesium sulfate, filtered and the solvent removed from the filtrate by distillation in vacuo. That's how it got

2.4 g of an oil (55%) were separated by preparative thin-layer two materials (KG-PF _{2j4 + JÍ6} dichloromethane. Methanol = 20: 2, elution with acetone, the Z-isomer R _f is greater than the E-izomerénél).

The material _Rf value greater crystallized from methanol to give the Z-isomer of the title compound, 1.04 g.

Yield: 24%.

The lower R _f material is brought to a well-filterable state with petroleum ether, filtered and dried.

0.9 g of the title E isomer is obtained.

Yield: 20.5%.

Mp 202-203 ° C (petroleum ether).

[?] D ⁼ -198 '(c = 1, chloroform).

Elemental analysis based on C ₁₉ H ₂₁ N ₃ O ₂ (MW 323.38):

Calculated: N, 12.99; Found: N, 12.80.

Ή NMR (CDCl₃, DMSO-d _e): 8 8.38 to 7.27 (4H, m, aromatic), 4.30 (lH, s, 3H), 0.98 (3H, t, J = 8Hz CH ₂ CH) * ^'3 C-NMR (CDC1 _3, DMSO-d _e, δ): 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 (C -11), 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 '(C = N)

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

Claims (3)

Claims A process for the preparation of novel racemic and optically active ebumannoxime derivatives of the formulas Ia and / or Ib wherein R is ethyl and the acid addition salts thereof, characterized in that a racemic or optically active ebumannone derivative of the formula II is wherein R is as defined above, by reaction with a tertiary (C4-C8) -alkylnitrite and optionally separating the resulting mixture of eburnanoxime, Ζ, iz-isomers of formula Ia and Ib and / or, if desired, the resulting racemic or optically active 190,400 of the ebuman oxime derivative of formula Ia or Ib is treated with an acid. The process of claim 1, wherein the reaction is carried out in the presence of an alkali metal alcohol. 3. A process for the preparation of a pharmaceutical composition comprising the racemic or optically active ebuman oxime derivative of the formula Ia or Ib, wherein R is ethyl, or a pharmaceutically acceptable acid addition salt thereof with a pharmaceutically acceptable carrier and / or or mixed with excipients to form a pharmaceutical composition.