GB2111477A - Eburnane derivatives - Google Patents

Abstract

Compounds of general formula <IMAGE> wherein <IMAGE> R1 and R2 which may be the same or different each represents a C1-6 alkyl group; and R3 represents a C1-8 alkyl, C6-14 aryl, C7-20 aralkyl, C5-14 cycloalkyl or an acyl group (each of which may be optionally substituted by one or more substituents selected from halogen atoms and C1-6 alkoxy, nitro, amino and trifluoromethyl groups); and salts thereof which are not only themselves biologically active but are also of use in the preparation of apovincaminic acid esters having vasodilatory activity.

Description

SPECIFICATION Eburnane derivatives This invention relates to new oxyaminoeburnane derivatives which are not only themselves biologically active but are also of use in the preparation of apovincaminic acid ester derivatives.

As is known, apovincaminic acid esters, particularly the ethyl ester, possess significant vasodilatory activity.

According to the methods known hitherto, apovincaminic acid esters are prepared by subjecting vincamine, which itself also possesses valuable therapeutical activity, to hydrolysis; converting the resulting vincaminic acid into the desired ester; and subjecting the ester to dehydration to obtain the respective apovincaminic acid ester. According to an alternative method vincamine is first subjected to dehydration, the resulting apovincamine is hydrolyzed, and the resulting apovincaminic acid is converted into the desired ester. Both methods are described in Hungarian Patent Specification No. 1 63,434.

These methods, however, have the disadvantage that vincamine must first be synthesized, and then this compound with valuable therapeutical properties must be subjected to further reactions with yields not exceeding 60%.

We have now found that apovincaminic acid esters may be obtained in high purity and with good yields using certain new oxyaminoeburnane derivatives which may themselves be obtained from simple and easily avaiiable starting materials. Furthermore the synthesis is carried out using simple chemical operations.

Our copending Application No. 7941361 of even date herewith describes and claims compounds of general formula (IV),

wherein: R2 represents a C16 alkyl group; and R3 represents a C18 alkyl, C6~,4 aryl, C720 aralkyl, Cm~14 cycloalkyl or an acyl group (each of which may be optionally substituted by one or more substituents selected from halogen atoms and C 1-6 alkoxy, nitro, amino and trifluoromethyl groups); and salts thereof.

In the compounds of general formula (IV) R2 may represent any straight-chained or branched C16 alkyl group, e.g. a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl or isohexyl group. Such groups may also be represented by R3 when this represents a C16 alkyl group. As a C6~,4 aryl group R3 may represent a mono- or polycyclic (separate or fused) aryl group, such as e.g. a phenyl, diphenyl or naphthyl group. The C7 20 aralkyl groups represented by Ra may contain one or more monocyclic or polycylic (separate or fused) aryl groups containing, for example, 6 to 14 carbon atoms, and a straight-chained or branched alkyl group e.g. containing from 1 to 6 carbon atoms.Such aralkyl groups may include, for example, the benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl and naphthylbutyl groups. The Cs-14 cycloalkyl groups represented by R3 may be monocyclic or polycyclic groups, such as e.g. a cyclopentyl or cyclohexyl group, The acyl groups represented by R3 may be derived from various organic carboxylic acids.Of these acyl groups for example those derived from C C,~8 a aliphatic mono- carboxylic acids, such as e.g. formyl, acetyl, propionyl and valeroyl, groups; those derived from unsaturated monocarboxylic acids of up to 8 carbon atoms, such as e.g. acroyl, methacroyl and vinylacetyl groups; those derived from mono- or poly-cyclic C6~,0 aromatic monocarboxylic acids, such as e.g. benzoyl and naphthoyl groups; those derived from C720 aral kylcarboxylic acids, such as e.g. phenylacetyl, phenylpropionyl, naphthylacetyl and naphthylpropionyl groups; and those derived from mono- or polycyclic Cs-14 cycloaliphatic carboxylic acids may particularly be mentioned.

The alkyl, aryl, aralkyl and acyl groups in R3 may optionally be substituted by one or more substituents, selected from halogen atoms, i.e.

fluorine, chlorine, bromine and iodine atoms; straight-chained and branched C16 alkoxy groups, such as e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert.-butoxy groups; and nitro, amino and trifluoromethyl groups.

The compounds of general formula (IV) and their salts may exist in the form of optically active and/or geometrical isomers.

Our said copending Application No. 79141361 describes and claims a process for the preparation of compounds of formula IV and also describes and claims a process for the preparation of compounds of formula (i),

(wherein R2 is as hereinbefore defined and R, represents a C16 alkyl group, e.g. as exemplified above for R2 and which may be the same as or different from R2) or an acid addition salt thereof which comprises reacting a compound of formula (IV) as hereinbefore defined or a salt thereof with an alcohol of formula R1-OH (wherein R, is as defined above) in the presence of an acid followed where required by separation of the product obtained into optically active isomers and/or by conversion of a compound of formula (I) into an acid addition salt thereof, whereby the desired product is obtained.

The desired compounds of general formula (I) are prepared from the intermediates of general formula (IV) by an elimination reaction. The presence of bulky groups promotes this reaction.

Thus, with regard to this elimination step, the significance of the R3 substituent increases with its size.

When the compounds of the general formula (IV) are reacted with the alcohol of formula R,- OH in the presence of an acid, it is preferred to use a mineral acid together with the minimum possible amount of water e.g. concentrated sulfuric acid or concentrated phosphoric acid.

Strong organic acids, such as e.g. trichloroacetic acid, can alternatively be used if desired. The reaction is conveniently performed so that the compound of formula (IV) or salt thereof, which is either an isomeric mixture or any of the pure isomers, is dissolved in a mixture of the alcohol of formula R1-OH and of the acid,and the solution is boiled for some bours, preferably for 0.5 to 5 hours.

Our investigations have shown that the reaction proceeds through an intermediate of formula (V),

(wherein R1, R2 and Ra are as hereinbefore defined) which intermediate may, under certain conditions be isolated, for example by reacting the compound of formula (IV) or salt thereof with the alcohol of formula R1-OH for 5 to 10 mimutes at 60 to 800C, in the presence of 1 to 20, preferably 6 to 10, molar equivalents of the acid. On applying more acid, higher temperature and longer reaction time, the compound of formula (V) is gradually converted into a compound of formula (I).

The compounds of general formula (V) and their salts are novel compounds and, together with the above process for their preparation, constitute features of the present invention. It will be appreciated that the compounds of formula (V) may exist in the form of single 1 4-epimers and/or of optically active isomers as well as mixtures thereof. The compounds of general formula (V) and their salts are themselves biologically active although it will be appreciated that, for pharmaceutical use, the salts will be physiologically compatible.

According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising, as active ingredient, at least one compound of formula (V) as hereinbefore defined or a physiologically compatible salt thereof in association with a pharmaceutical carrier or excipient.

Particularly preferred compounds are 3(S),1 4(S),1 7(S)-1 4-ethoxywarbonyl- 1 4-(pchlorobenzyloxyamino)-eburnane hydrochloride and 3(S),14(R),17(S)-1 4-ethoxycarbonyl-l 4-(p- chlorobenzyloxyamino)-eburnane hydrochloride.

The compounds of general formula (V) and their salts may be prepared, if desired, not only by reaction of a compound of formula (IV) or salt thereof with an alcohol of formula R1-OH in the presence of an acid but also by reaction of a compound of formula (IV) or salt thereof with an alcohol of formula R1-OH in the presence of an alkaline agent followed, where required, by epimerization and/or resolution and/or by conversion of a compound of formula (V) into a salt, whereby the desired product is obtained.

Such a process constitutes a further feature of the present invention.

Suitable alkaline agents include, for example, alkali metals, such as e.g. potassium, sodium and lithium; alkali metal hydrides, such as e.g.

potassium hydride, sodium hydride and lithium hydride; alkali metal amides such as e.g.

potassium amide, sodium amide and lithium amide; and alkali metal alkoxides. Preferably an alcoholic solution of the respective alkali metal alkoxide with the alcohol of the general formula R1-OH is prepared in excess and the compound of formula (IV) is dissolved in this solution.

The reaction is performed preferably under anhydrous conditions, by boiling the mixture for 0.5 to 3 hours.

The processes of the invention yield the new compounds of general formula (V) as mixtures of 1 4-epimers. The epimeric mixtures can be used directly to prepare the compounds of general formula (I), if desired, or the individual epimers can be separated first.

The mixture of epimers of general formula (V), or any of the individual epimers may be converted into compounds of general formula (I) or their acid addition salts by reaction with an alcohol of formula R1 -OH in the presence of an acid followed where required by resolution and/or conversion of a compound of formula (I) into an acid addition salt thereof. The reaction conditions are the same as described above in connection with the reaction of the compounds of general formula (IV) with an alcohol of formula R,--OH.

Alternatively the compounds of general formula (I) or an acid addition salt thereof may be obtained by reacting the compound of formula (V) or salt thereof with a dilute aqueous solution of a mineral acid, in which case a vincaminic acid ester of formula (VI),

(wherein R, and R2 are as hereinbefore defined) is formed in addition to the desired compound of formula (I), which ester may be separated from the desired ester by, for example, fractional crystallization and subjected to dehydration and, if desired, subjected to transesterification according to methods known per se to obtain further quantities of the desired compound of formula (I).

Any compound of formula (Vl) obtained when a compound of formula (IV) or a salt thereof is reacted with an alcohol of formula R1-OH in the presence of an acid may also be treated in this way to yield further compound of formula (I).

The compounds of general formula tl), prepared according to the above-described processes may if desired be converted into their acid addition salts by reaction with an acid according to methods known per se. Such acids include, amongst others, mineral acids such as, for example hydrohalic acids (e.g. hydrochloric and hydrobromic acids), sulfuric acid and phosphoric acid; organic carboxylic acids such as for example formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, benzoic acid and cinnamic acid; alkylsulfonic acids, such as, for example methanesulfonic acid; arylsulfonic acids, such as for example, ptoluenesulfonic acid; cyclohexylsulfonic acids; and aspartic acid, glutamic acid, N-acetyl-aspartic acid and N-acetyl-glutamic acid.

Salt formation can be carried out, for example, in an inert organic solvent such as a C16 aliphatic alcohol, so that the racemic or optically active compound of formula (I) is dissolved in the solvent and the selected acid or a solution thereof formed with the same solvent is added to the first solution until it becomes slightly acidic (pH-5 to 6). Thereafter the acid addition salt separates out and may be removed from the reaction mixture e.g. by filtration.

The compounds of general formula (I) and their acid addition salts, when obtained in the form of a racemate, can if desired be resolved in a manner known per se. However, any of the intermediates obtained in the above process can be resolved, and the further steps of the process can be carried out with the required optically active substances.

Based on the results of elementary analysis, and on IR and mass spectral data, both the endproducts and the new intermediates of the process of the invention are easily identifiable substances.

The invention is elucidated in detail by the aid of the following non-limiting Examples.

Example 1 Preparation of 3(S).1 4(S),1 7(S)-i 4- ethoxyca rbonyl-l 4-( p-chlorobenzyloxya mino)- eburnane and 3(S),14(R),17(S)-14 ethoxycarbonyl-i 4-(p-chlorobenzyloxyamino)- eburnane 0.20 g (0.43 mmoles) of (+)-3(S),17(S)-14 oxo-1 5-(p-chlornbenzyloxyimino)-E-homo- eburnane, prepared as described in Example 3 of our copending Application No.7941361 are dissolved in a solution of 20 mg of metallic sodium in 4 ml. of absolute ethanol. A tube filled with calcium chloride is attached to the flask in order to exclude atmospheric moisture, and the mixture is boiled for 1.5 hours on a steam bath.

The progress of the reaction can be monitored by thin layer chromatography (adsorbent: silica gel G, solvent: a 14:2 mixture of benzene and methanol; the Rf value of the starting substance is higher than that of the product). When the reaction terminates, a few drops of glacial acetic acid are added to the mixture to adjust the pH to 6, and the solvent is distilled off in vacuo. The residue is admixed with water, the solution is rendered alkaline (pH=8) with 5% aqueous sodium hydrocarbonate solution, and the aqueous phase is extracted thrice with 5 ml of dichloromethane, each. The dichloromethane solutions are combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate is evaporated.

0.20 g of the title compounds are obtained as an oil.

The 0.20 g of the product are dissolved in 1 ml of ethanol, the pH of the solution is adjusted to 5 with ethanolic hydrochloric acid, and then 1.0 ml of ether is added to the solution. The separated substance, which is a mixture of the hydrochlorides of the title 1 4-epimers, is filtered off, washed with ether, and dried.

0.17 g of the mixed salt are obtained; m.p: from 1350C; yield: 76%.

IR spectrum (KBr): 3200 (NH), 1718 (ester CO) cm-'.

Mass spectrum, m/e (%): 507 (M+ 20).

The hydrochloride of the mixture of the 14epimers can be applied directly in the next reaction step.

Example 2 Preparation of (+)-apovincaminic acid ethyl ester 0.17 g (0.31 mmoles) of(+)-3(S)-14- ethoxycarbonyl- 1 4-(p-chlorobenzyloxya mino)- eburnane hydrochloride (mixture of 1 4-epimers; prepared as described in Example 1) are dissolved in 4 ml of ethanolic sulfuric acid. The solvent is prepared by dissolving 6.5 ml of concentrated sulfuric acid in 1 8.5 ml of absolute ethanol. The reaction mixture is boiled for 45 minutes on a steam bath, then it is poured onto ice water, and the mixture is rendered alkaline (pH=8) with concentrated aqueus ammonia. The alkaline solution is extracted thrice with 4 ml of dichloromethane, each. The dichloromethane extracts are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated. The obtained 0.1 5 g of oily residue is purified by preparative layer chromatography (adsorbent: silica gel PF254+366, solvent: a 14:3 mixture of benzene and methanol, elution with acetone). 80 mg (73%) of (+)-apovincaminic acid ethyl ester are obtained; m.p.: 149-1520C (from ethanol).

No depression of melting point can be observed when admixing the product with an authentic sample of (+)-apovincaminic acid ethyl ester.

IR spectrum (KBr): 1722 (ester CO), 1622 (C=C) cm-l.

[ez]C2,0=+ 142 (C=1, chloroform).

Claims (21)

Claims

1. Compounds of general formula (V)

wherein R, and R2, which may be the same or different, each represents a C16 alkyl group and R3 represents a C18 alkyl, C6~,4 aryl, C,~20 aralkyl, Cs-14 cycloalkyl or an acyl group (each of which may be optionally substituted by one or more substituents selected from halogen atoms and C16 alkoxy, nitro, amino and trifluoromethyl groups).

2. Compounds as claimed in claim 1 wherein R3 represents a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutul, tert.-butyl, n-pentyl, isopenyl, nhexyl or isohexyl group; a phenyl, diphenyl or naphthyl group; a benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl or naphthylbutyl group; a cyclopentyl or cyclohexyl group; or a formyl, acetyl, propionyl, valeroyl, acroyl, methacroyl, vinylacetyl, benzoyl, naphthoyl, phenylacetyl, phenylpropionyl, naphthylacetyl or naphthylpropionyl group; each said group being optionally substituted by one or more substituents selected from halogen atoms and C 1-6 alkoxy, nitro, amino and trifluoromethyl groups.

3. A compound as claimed in claim 1 or claim 2 in the form of a single epimer.

4. A compound as claimed in claim 1 or claim 2 in the form of an optically active isomer.

5. 3(S), 14(S), 17(S)- 1 4-Ethoxycarbonyl- 14-(p- chlorobenzyloxyamino)-eburnane hydrochloride.

6. 3(5)14(R), 17(S)- 1 4-Ethoxycarbonyl- 14-(p- chlorobenzyloxyamino)-eburnane hydrochloride.

7. Physiologicaliy compatible salts of compounds of general formula (V) as defined in any one of claims 1 to 4.

8. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula (V) as defined in claim 1 or a physiologically compatible salt thereof in association with a carrier or excipient.

9. A process for the preparation of a compound of general formula (V) as defined in claim 1 or a salt thereof which comprises reacting a compmnd of formula (IV)

(wherein R2 and R3 are as defined in claim 1) or a salt thereof with an alcohol of formula R1-OH (wherein R, is as defined in claim 1) either in the presence of 1 to 20 molar equivalents of an acid for 5 to 10 minutes at 60 to 80 C or in the presence of an alkaline agent followed, where required, by epimerization and/or resolution and/or byconversion of a compound of formula (V) into a salt thereof, whereby the desired product is obtained.

10. A process as claimed in claim 9 wherein the reaction is effected in the presence of an alkaline agent.

11. A process as claimed in claim 10 wherein the alkaline agent is an alkali metal, an alkali metal hydride, an alkali metal amide or an alkali metal alcoholate.

12. A process as claimed in claim 11 wherein the alkaline agent is an alkali metal alkoxide of formula R1-OMe (wherein R, is as defined in claim 9 and Me represents an alkali metal atom).

1 3. A process for the preparation of compounds of general formula (V) as defined in claim 1 or salts thereof substantially as herein described.

14. A process for the preparation of compounds of general formula (V) as defined in claim 1 or salts thereof substantially as herein described with reference to Example 1.

1 5. Compounds of general formula (V) as defined in claim 1 and salts thereof whenever prepared by a process as claimed in any one of claims 9 to 14.

1 6. A process for the preparation of a compound of general formula (I)

(wherein R1 and R2 are as defined in claim 1) or an acid addition salt thereof which comprises reacting a compound of formula (V) as defined in claim 1 or salt thereof either with an alcohol of formula R1-OH (wherein R, is as defined in claim 1) in the presence of an acid or with a dilute aqueous solution of a mineral acid, followed where required, by resolution and/or by conversion of a compound of formula (I) into an acid addition salt thereof whereby the desired product is obtained.

1 7. A process as claimed in claim 16 wherein the compound of formula (V) is obtained by a process as claimed in any one of claims 9 to 14.

18. A process as claimed in claim 1 6 or claim 17 wherein a dilute aqueous solution of a mineral acid is used and the compound of formula (VI),

(wherein R1 and R2 are as defined in claim 1) formed as a by-product, is separated and subjected to treatment with a dehydrating agent and, if desired, to transesterification to obtain an additional quantity of the desired compound of formula (V) or acid addition salt thereof.

19. A process as claimed in any one of claims 9, 1 6 and 17 wherein the reaction of the compound of formula (IV) or (V) with the alcohol of formula R1-0H is effected in the presence of concentrated sulfuric acid, concentrated phosphoric acid or trichloroacetic acid.

20. A process for the preparation of a compound of general formula (I) as claimed in claim 16 or an acid addition salt thereof substantially as herein described.

20. A process for the preparation of a compound of general formula (I) as defined in claim 1 6 or an acid addition salt thereof substantially as herein described.

21. A process for the preparation of a compound of general formula (I) as defined in claim 1 6 or an acid addition salt thereof substantially as herein described with reference to Example 2.

22. Compounds of general formula (I) as defined in claim 1 6 and acid addition salts thereof whenever prepared by a process as claimed in any one of claims 16 to

21.

New claims or amendments to claims filed on 15.12.82 and 14.1.83.

Superseded claims 2, 18 and 20.

New or amended claims:

2. Compounds as claimed in claim 1 wherein R3 represents a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, n-pentyl, isopentyl, nhexyl or isohexyl group; a phenyl, diphenyl or naphthyl group; a benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl or naphthylbutyl group; a cyclopentyl or cyclohexyl group; or a formyl, acetyl, propionyl, valeroyl, acryloyl, methacryloyl, vinylacetyl, benzoyl, naphthoyl, phenylacetyl, phenylpropionyl, naphthylacetyl or naphthylpropionyl group; each said group being optionally substituted by one or more substituents selected from halogen atoms and C16 alkoxy, nitro, amino and trifluoromethyl groups.

18. A process as claimed in claim 16 or claim 17 wherein a dilute aqueous solution of a mineral acid is used and the compound of formula (VI),

(wherein R, and R2 are as defined in claim 1) formed as a by-product, is separated and subjected to treatment with a dehydrating agent and, if desired, to transesterification to obtain an additional quantity of the desired compound of formula (I) or acid addition salt thereof.