GB2124215A

GB2124215A - Eburnane-oxime derivatives

Info

Publication number: GB2124215A
Application number: GB08317612A
Authority: GB
Inventors: Csaba Szantay; Lajos Szabo; Gyorgy Kalaus; Janos Sapi; Eva Palosi; Bela Kiss; Maria Zajer; Egon Karpati; Laszlo Szporny
Original assignee: Richter Gedeon Vegyeszeti Gyar RT
Current assignee: Richter Gedeon Vegyeszeti Gyar Nyrt
Priority date: 1982-06-30
Filing date: 1983-06-29
Publication date: 1984-02-15
Also published as: GB8317612D0; BE897148A; AU1639683A; DE3323606A1; PT76951B; NL8302298A; ES8500619A1; IL69107A; SE8303719L; AU554196B2; GR77525B; DK300583A; FR2529551B1; ES523695A0; NZ204754A; SE457641B; SE8303719D0; HU190400B; FR2529551A1; GB2124215B

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

SPECIFICATION Eburnane-oxime derivatives This invention relatesto new eburnane-oxime derivatives and to pharmaceutical compositions containing them as well as to a process for preparing them.

More particularlythe invention concerns new eburnane-oxime derivatives offormulae (la) and/or (Ib),

R represents an alkyl group having 1 to 6 carbon atoms, the configuration ofthe hydrogen atom in the 3-position and R being a,a and/or ss,ss and/or oc,P and/or ss, and acid addition salts thereof.

The compounds according to the invention may exist in a number ofsteroisomeric forms and all such forms as well as mixtures thereofareto be be consi- dered within the scope of this invention. Thus not only may the compounds exist in a cis (Z) and trans (E) form due to the oxime group but they may also exist in a number of optically active forms depending on the configuration of the hydrogen atom in the 3-position and the group R which may be atom or ss,ss or oc,P or plcx.

The compounds according to the invention possess interesting pharmacological activity and in particular antihypoxial activity. It will be appreciated that, for pharmaceutical use, the salts referred to above will be pharmaceutically acceptable but other acid addition salts may find use,forexample, in the preparation of compounds of formulae (la) and (Ib) and their pharmaceutically acceptable acid addition salts.

According to a further aspect of the invention there is provided a processforthe preparation of eburnaneoxime derivatives of the formulae (la) and/or (Ib) as defined above and acid addition salts thereof, which process comprises oximating an eburnamonine derivativeofformula (II)

(wherein R is as defined above) followed, if desired, in any appropriate order by separation of a desired stereoisomer and/or by conversion of a Z-isomer into the corresponding E-isomer and/or by conversion of a compound of formula (la) or (Ib) into an acid addition salt thereof.

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

The starting compounds offormula (II) may be prepared for example according to the method disclosed in Belgian PatentSpecifications Nos.

776,337 or 802,387 or as described in French Patent Specification No. 2,268,016.

The oximation ofthe compounds of formula (II) is generally carried out with a tertiary C4~e-alkyl nitrite, such as tert.-butyl nitrite,tert.-amyl nitriteorisoamyl nitrite and in the presence of a strong base, such as an alkali metal alcoholate, e.g. potassium or sodium tert.-butylate, sodium or potassium isoamylate or potassium tert.-amylate, an alkali metal amide, e.g.

lithium diisopropyl amide, or organic metal compounds, e.g. butyl-lithium. The oximation is preferably performed in an apolar organic solvent inert under the reaction conditions, preferably in an aromatic hydrocarbon, such as benzene, toluene or xylene.

The oximation generally yields a mixture of the Z-isomerofformula (la) and the E-isomerofformula (Ib). The Z-isomer is the major 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 preferably is between 3 and 7. For example, if the reaction mixture of oximation is decomposed with an aqueous ammonium chloride solution at room temperature, essentiallythe Z-isomerofformula (la) is obtained, while if a dilute aqueous sulfuric acid solution is used for the decomposition, the two isomers are obtained in about equal proportion.The Z-isomer oaf formula (la) is a kinetic product, which can be partially transisomerized into the thermodynamically more stable E-isomer oftheformula (Ib) by heating, especially in the presence of protons.

The configuration of the 3-hydrogen and the R substituent in the starting compounds offormula (II) is not changed during the process of the present invention. Therefore, the configuration of the 3hydrogen and R in the starting compounds of formul (II) and the end products offormulae (la) and/or (Ib) is the same.

For the preparation of salts, the compounds of the formula (la) or (lb) may be reacted with acids according to conventional methods. Suitable acids include inorganic acids, such as for example hydrohalic acids e.g. hydrochloric acid and hydrobromic acid; sulfuric acid; phosphoric acid; nitric acid; and perhalic acids e.g. perchloricacid: organic acids, such asfor example formic acid, acetic acid, propionic acid, glycolicacid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, ascorbic acid, salicylic acid, lactic acid, cinnamic acid, benzoic acid, phenylacetic acid, p-amino-benzoic acid, p-hydroxy benzoic acid, p-amino-benzoic acid, p-amino-salicylic acid, etc.: alkyl-sulfonic acids, such as for example methanesulfonic acid, ethanesulfonic acid, etc.; cyc loaliphatic sulfonic acids, such as for example cyclohexanesulfonic acid; arylsulfonic acids, such as for exa m ple p-toluene-sulfonic acid, naphthylsulfo nic acid, sulfanilic acid, etc.; and amino acids, such as for example asparaginic acid, glutaminic acid, etc.

The salts may be prepared in an inert organic solvent, for example an aliphatic alcohol having 1 to 6 carbon atoms, e.g. by dissolving the compound of the formula (la) or(lb) in said solvent, and adding a corresponding acid to the solution obtained as such or in the form of a solution with the above solvent until the mixture becomes slightly acidic (about pH 5-6). The precipitated acid addition salt can thereafter be seperated from the reaction mixture by conventional technique, e.g. by filtration.

The stereoisomers according to the invention may be separated by conventional techniques. Thusthe Eand Z-oxime isomers may, for example be separated by chromatography.

The racemic compounds according to the invention can also be resolved in a known manner but optically active starting materials of the formula (II) may also be employed when optically active end products are desired. Preferably racemic compounds offormula (la) or (lb) are prepared from racemic compounds of the formula (II), while optically active compounds of the formula (la) or (lb) are obtained starting from optically active compounds of the formula (it).

If desired, the compounds oftheformula (la) or (Ib) or acid addition salts thereof may be subjected to further purification, e.g. recrystallization. The solvents used for recrystallization are selected depending on the solubility and crystallizability of the compounds to be crystallized.

According to a still further aspect of the present invention there are provided pharamaceutical compositions which comprise, as active ingredient, at least one compound of formula (la) or (Ib) or a pharmaceutically acceptable saltthereof, in associatin with a pharmaceutical carrier or excipient.

The pharmaceutical compositions may beformulated in forms suitableforparenteral orenteral administration. As carriersfor example water, gela- tine, lactose, milk sugar, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils, such as peanut oil, olive oil, etc. can be used. The compositions may be finished in the form of solid, e.g. tablets, lozenges, drage'es, capsules, such as hard gelatine capsulses, suppositories, etc., or liquid, e.g. oily or aqueous solutions, suspensions, emulsions, syrups, soft gelatine capsulses, injectable oily or aqueous solutions or suspensions, etc. formulations.The quantity of carrier can be varied within a wide range but preferably is about between 25mg. and 1 g. The pharmaceutical compositions optionally can contain IR spectrum (KBr): 3200-2600 (broad, chelate OH), 1710(cho), (CO),1630cm-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(12),,, 1H-NMR spectrum (CDCI3, 5): 14.47(1 H,s,N-OH), 8.40-7.27 (4H,m,aromatic), 4.26(1H,s,3-H), 1.03 (3H,t,j=3Hz, CH2-CH3).

'jC-N MR spectrum (CDCI3,o): 158.0 (CO),148.0 (C= N), 134.0 (C-13), 130.7 (C-2), 129.9 (C-8), 125.3- 125.0 (C-l O/C-l 1), 118.6(C-9), 116.8(C-t2), 115-1 (C-7), 53.5 (C-3), 50.7 (C-5), 44.8(0-19), 44.2 (C-16), 31.0(0-20),23.5(0-17),20.6(0-18),16.3(0-6),9.0 (C-21).

To the mother liquor of the methanolic crystallization hydrochloric acid in methanol is added until also conventional pharmaceutical additives, such as preservatives, stabilizing, wetting, emulsifying agents, salts capable of adjusting the osmotic pressure, buffers, flavouring agents, aroma agents, etc.

Optionallyfurtherpharmaceutically active compounds can also be present in the formulations.

The pharmaceutical compositions are preferably manufactured in dosage units, suitable forthe desired route of administration. The pharmaceutical compositions may be prepared by conventional techniques, which comprisefor example screening, admixing, granulating, pressing or dissolving ofthe components. The compositions obtained can be subjected to further operations conventionally used in the pharmaceutical industry, for example sterilization.

Further details ofthe present invention are to be found in the following Examples which are, however, by no means intended to limitthe scope ofthe protection sought.

Example 1 (+)-14-Oxo-15-hydroxyimino-eburnane(3a, 16a) (Z-isomer) and its hydrochloride To a solution of 4.09. (13.6 mmoles) of (-)vincamone (3Oc,16Oc) in 80ml. of absolute benzene 13.6mI. (148 mmoles) of freshly distilled tert.-butyl nitrite and some minutes later 3.89. (34 mmoles) of potassium tert.-butylate are added. The solution is stirred at room temperature under nitrogen atmospherefor 1 to 1.5 hours. The reaction mixture is decomposed with a solution of 1 5g. of ammonium chloride in 150m1 of water, under ice cooling. The organic phase is separated, and the aqueous phase is shaken with three 30-mI. portions of dichloromethane. The organic phases are combined, dried over solid, anhydrous magnesium sulfate, filtered and from thefiltratethe solvent is eliminated by distillation in vacuo. The residual oil is crystallized from methanol. 2.05g. ofthe desired compound are obtained.

Yield: 47%.

According to thin layer chromatography the Rfvalue ofthe end product is higherthan that ofthe starting compound (KG-G, dichloromethane/ methanol).

Melting point: 158 to 159'0(methanol).

[OciD = +78.4 (c=1.15,chloroform).

Analysis for C1gH21 N302 (323.38): calculated: C70.57%, H 6.54%, N 12.99%; found: C 70.60%, H 6.60%, N 12.92%.

pH=3to yield a further 0.9g. batch (18.3%) of the desired compound as a hydrochloride.

Total yield: 65.3%.

Example 2 (+)-14-Oxo-15-hydroxyimino-eburnane(3α,16α) (Zisomer) and (-)-oxo-15-hydroxyimino-eburnane (3a,160c) (E-isomer) The procedure described in Example 1 is followed until the decomposition of the reaction mixture with ammonium chloride. After decomposition of the reaction mixture the separated benzene phase is extracted with three 15-ml. portions of a 2.5% aqueous sulfuric acid solution, the extract is alkalized until pH 9 with a concentrated aqueous ammonium hydroxide solution under cooling with ice, whereupon it is extracted with three 30-ml. portions of dichloromethane. The organic phases are combined, dried over solid, anhydrous magnesium sulfate, filtered and from the filtrate the solvent is distilled off in vacuo. 2.49 of an oily product (55%) are obtained.

The product is seperated bythin layer chromatography into two components (KG-PF2s4+366, dichloromethane: methanol = 20:2, elution with acetone, the Rrvalue of the Z-isomer is higherthan that of the E-isomer).

By crystallization of the components having a higher Revalue from methanol 1 .04g. ofthe Z-isomer given in the title are obtained.

Yield: 24%.

The material having a lower Rrvalue is brought into a filterable state with petroleum ether, filtered and dried. 0.9g. ofthe E-isomergiven inthetitle are obtained.

Yield: 20.5%.

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

[a]546 = -1980 (c=1, chloroform).

Analysis for C19H21 N302 (323.38): calculated: N 12.99%, found: N 12.80%.

1H-NMRspectrum (CDCl3, DMSO-d6,5): 8.38-7.27 (4H,m,aromatic),4.30 H,s,3-H), 0.98 (3H,t,J=8Hz,CH2CH3).

13C-N MR(CDCl3, DMSO-d6,5):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(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(0-16), 28.3(C-20),25.7(C-17),20.3(C-18),16.0(C-6),10.2 (C-21).

IR spectrum (KBr): 3250(OH,broad),1700(CO),1630 cm- (C=N).

Mass spectrum (m/e,%): 324 (M+1.24), 323 (M+,1 00), 306(27), 294(46), 277(66), 276(62), 264(16), 253 (13)...

Claims

CLAIMS 1. Eburnane-oxime derivatives offormulae (la) and/or (Ib),

1 N N (Ib) 0 R wherein R represents an alkyl group having 1 to 6 carbon atoms, the configuration ofthe hydrogen atom in the 3-position and R being cs and/or ss,ss and/or a,ss and/or ss,os and acid addition salts therof.

2. Compounds as claimed in claim 1 in stereoisomericform.

3. (+)-14-oxo-1 5-hydroxyimino-eburnane (3cx,l 60() in E and/or Z form and the hydrochloride thereof.

4. Pharmaceutically acceptable acid addition salts of compounds of formula (la) and/or (lb) as claimed in any preceding claim.

5. Compounds offormulae (la) and/or (lb) as defined in claim 1 and their pharmaceutically acceptable acid addition salts for use as antihypoxial agents.

6. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula (la) or (lb) as defined in claim 1 ora pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrierorexcipient.

7. Pharmaceutical compositions as claimed in claim 6 in a form suitable for parental or enteral administration.

8. Pharmaceutical compositions as claimed in claim 6 or claim 7 in dosageunitform.

9. Pharmaceutical compositions as claimed in claim 6 substantially as herein described.

10. A process for the preparation of eburnaneoxime derivatives as defined in claim 1 which comprises oximating an eburnamonine derivative of formula (II)

(wherein R is as defined in claim 1), followed, if desired in any appropriate order by separation of a desired stereoisomer and/or by conversion of a Z-isomer into the corresponding E-isomerand/orby conversion of a compound offormula (la) or (lb) into an acid addition salt thereof.

11. A process as claimed in claim 10 wherein the oximation is carried out with a tert.-C4~8-alkyl nitrite in the presence of a strong base.

12. A process forthe preparation of compounds as claimed in claim 1 substantially as herein described.

13. A process forthe preparation of compounds as claimed in claim 1 substantially as herein described in Example 1 or Example 2.

14. Compounds as claimed in claim 1 whenever prepared buy a process as claimed in any one of claims 10to13.

15. A process forthe preparation of pharmaceutical compositions as claimed in claim 6 which comprises mixing at least one compound offormula (la) or (Ib) as defined in claim 1 ora pharmaceutically acceptable acid addition salt thereof with a pharmaceutical carrier or excipient.

16. Each and every novel method, process, compound and composition herein disclosed.