GB2152499A

GB2152499A - Piperidine derivatives

Info

Publication number: GB2152499A
Application number: GB08431486A
Authority: GB
Inventors: Alan Chapman White
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1984-01-10
Filing date: 1984-12-13
Publication date: 1985-08-07
Also published as: GB2152499B; GB8400537D0; GB8431486D0

Abstract

Piperidine derivatives of the formula <IMAGE> where R<1> is lower alkyl; R<2> is hydrogen, lower alkyl, benzyl, (lower)alkoxymethyl or an acyl group; R<3> is lower alkyl; R<4> is hydrogen or lower alkyl and R<5> is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl(lower)alkyl, 2-tetrahydrofurylmethyl or cycloalkylmethyl and their pharmaceutically acceptable acid addition salts possess analgesic and/or opiate antagonistic activity.

Description

SPECIFICATION Piperidine derivatives This invention relates to piperidine derivatives, more particularly to 5-substituted-3-alkyl-3-(3'substituted phenyl)-piperidines, to processes for their preparation and to pharmaceutical compositions containing them.

The present invention provides novel piperidine derivatives of the general formula (I)

and their pharmaceutically acceptable acid addition salts. In this formula R' represents lower alkyl; R2 represents hydrogen, lower alkyl, benzyl, (lower)alkoxymethyl or an acyl group; R3 represents lower alkyl; R4 represents hydrogen or lower alkyl and R5 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl(lower)alkyl, 2-tetrahydrofurylmethyl or cycloalkylmethyl.

The term "lower" as used herein means that the radical referred to contains up to 6 carbon atoms. The radical preferably contains up to 4 carbon atoms. For example when any of the groups R', R2, R3, R4 and R5 is a lower alkyl group the radical may be, for example, methyl, ethyl propyl or butyl. When R5 is lower alkenyl or lower alkynyl it is to be understood that the alkenyl or alkynyl group does not have an unsaturated bond in the 1-position; suitable groups include, for example, allyl, 2-methyl-2-propenyl, 3-methylbut-2-enyl and propynyl. When R5 is cycloalkylmethyl the group is preferably cyclopropylmethyl or cyclobutylmethyl.When R5 is aryl(lower)alkyl the aryl group can be a phenyl group optionally substituted by substituents common in medicinal chemistry (e.g. halogen, lower alkyl, lower alkoxy); The aryl(lower)alkyl group is preferably benzyl or phenethyl. When R2 is an acyl group it is preferably a lower alkanoyl group such as acetyl, propionyl or butyryl. When R2 is a (lower)alkoxymethyl group it is preferably a methoxymethyl group.

In a preferred group of compounds of general formula I, P1 is an ethyl group, R2 is hydrogen, R3 is methyl or ethyl, R4 is hydrogen and R5 is lower alkyl (e.g. methyl).

The compounds of the invention can be prepared by reduction of a compound of general formula (II)

wherein R', R2, R3, R4 and R5 are as defined above and the groups X and X' represent oxo or

with the proviso that at least one of X and Xz is oxo and if desired converting a free base of general formula (I) into a pharmaceutically acceptable acid addition salt thereof. The compound of general formula (II) can be reduced with, for example, a hydride transfer agent (e.g. lithium aluminium hydride).

Once a compound of general formula (I) has been prepared it may be converted into another compound of general formula (I) by methods known perse. For example, a compound in which R5 is lower alkyl, lower alkenyl, lower alkynyl, aryl(lower)alkyl, 2-tetrahydrofuryl methyl or cycloalkylmethyl may be prepared by "N-alkylating" a compound in which R5 is hydrogen. By "N-alkylating" is meant introducing on to the nitrogen atom of the piperidine ring a lower alkyl, lower alkenyl, lower alkynyl, aryl(lower)alkyl, 2-tetrahydrofurylmethyl or cycloalkylmethyl radical.In one method of carrying out the "N-alkylating" process a compound of general formula I in which R5 is hydrogen is reacted with a halide of general formula R5 - Hal where R5 is lower alkyl, lower alkenyl, lower alkynyl, aryl(lower)alkyl, 2-tetrahydrofurylmethyl or cycloalkylmethyl in the presence of an acid acceptor such as an alkali metal carbonate (e.g. potassium carbonate), preferably in solution in an organic solvent.

Alternatively the compound of general formula (I) in which R5 is hydrogen may be alkylated by reductive alkylation i.e. by treatment with an aldehyde and hydrogen in presence of a hydrogenation catalyst. A preferred method of cycloalkyl-methylating involves reacting the N-unsubstituted compound with a cycloalkylcarbonyl chloride to give an intermediate N-carbonyl cycloalkyl compound which may be reduced with, for example, a hydride transfer agent.

A compound of general formula (I) in which R2 is a hydrogen atom can be obtained from a corresponding compound in which R2 is lower alkyl, lower alkoxymethyl or benzyl by splitting off the ether group in known manner, e.g. by treating the lower alkyl or benzyl ether with hydrogen bromide or boron tribromide, by treating the lower alkyl ether with diisobutylaluminium hydride or by subjecting the benzyl ether to hydrogenolysis or by treating the (lower)alkoxymethyl ether with dilute acid. Similarly a compound of general formula (I) in which R5 is benzyl may be hydrogenolysed to a compound of general formula (I) in which R5 is hydrogen which, if desired may then be "alkylated" as hereinbefore described.Compounds in which R5 is lower alkyl, particularly methyl may also be dealkylated to compounds in which R5 is hydrogen, e.g. by reaction with ethyl-, phenyl-, vinyl- or 2,2,2-trichloroethyl- chloroformate followed by removal of the resulting N-substituent with, for example, dilute acid or zinc and acetic acid or basic conditions as appropriate.

A compound of general formula (I) in which R2 is hydrogen can be acylated (e.g. with acetic anhydride) to give a corresponding compound in which R2 is an acyl group such as a lower alkanoyl radical.

Two or more of the above mentioned processes for interconverting the compounds of general formula (I) may, if desired, be carried out consecutively. In some instances it may be necessary to protect one or more of the functional groups on the molecule while reaction occurs at another functional group and then subsequently remove the protecting group or groups.

The preferred compound of formula (II) is one in which Xis oxo and X1is

i.e. a compound of general formula (III)

where R', R2, R3, R4 and R5 have the meanings given above. The compound may be prepared by alkylation of a lactam of general formula (IV)

where R1 is as defined above, R5 is lower(alkyl) or aryl(lower)alkyl and R2 is lower alkyl, (lower)alkoxymethyl or benzyl.If desired the R2 group or R5 group in the resulting lactam of general formula (ill) may be converted into another R2 group or R5 group by selection of a suitable method from the methods described above in connection with the interconversion of the R2 group in compound I. The alkylation of the compound (IV) can be carried out by reacting the compound with an alkylating agent such as a (lower)alkyl halide in presence of a strong base such as sodamide or a metal amide MA (where M is sodium, potassium or lithium and A is a secondary amine). The metal amide, such as lithium diisopropylamide, may be formed in situ by reaction of the alkyl metal with a secondary amine. Depending on the proportions of the reagents it is possible to monoalkylate compound (IV) to give compound (III) in which R3 is lower alkyl and R4 is hydrogen or to dialkylate to give a product in which both R3 and R4 are (lower)alkyl. It is also possible to alkylate a compound of formula (III) in which R3 is (lower)alkyl and R4 is hydrogen to give a compound of formula (III) in which both R3 and R4 are (lower)alkyl. The lactams of general formula (IV) are known compounds or can be prepared by methods known for analogous compounds (see, for example, Kugita et al, J.Med.Chem., 1964, 7, 298-301).

The compound of formula (III) in which R3 is (lower)alkyl and R4 is hydrogen can be prepared by an alternative method in which a nitrile-ester of formula (V)

where R1, R and R3 have the meaning given above and one of Y and Y1 is -CN and the other is -COOAlkyl (preferably -COOC2H5) is reduced e.g. by catalytic hydrogenation.

The compound of formula (II) in which both X and X7 are oxo may be prepared by alkylation of a lactam of general formula (Vl)

where R1 and R2 have the meanings given above and R5"' is hydrogen, lower alkyl or aryl(lower)alkyl. The alkylation, and the possible subsequent interconversion of the R2 and R5 groups, may be carried in a manner analogous to that described above in connection with the lactam of formula (IV). Compound (VI) may be prepared in a manner analogous to that known for preparing similar compounds.For example a dinitrile of formula (VII)

(where R1 and R2 have the meanings given above) may be cyclised, e.g. by treatment with concentrated sulphuric acid, or a diester of formula

may be cyclised by reaction with an amine of formula H2NR5 The compound of general formula (II) in which Xis

and X1is oxo may be prepared by reacting an anion of a lactam of general formula

(where R3, R4 and R5 are as defined above and R5 is hydrogen or lower alkyl) with a cyclohexane derivative of general formula (IX)

where 0 is a hydrolysable protecting group such as lower alkoxy, subjecting the product to hydrolysis to give a compound of general formula

where R3, R4, R5 and R6 are as defined above, aromatising (e.g. by treatment with bromine) the compound of general formula (X) and, where RB is hydrogen, alkylating the product in a similar manner to that described above for the alkylation of the lactam IV. The anion of the lactam may be formed in situ e.g. by reaction of the lactam with a compound of formula MlA [where M1 is -MgX (where X is chlorine, bromine or iodine), sodium, potassium or lithium and A is a secondary amine radical]. When M' is sodium, potassium or lithium the compound M1A is a metal amide and is itself preferably formed in situ.

If in any of the processes described above the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base a pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with the conventional procedures for preparing acid addition salts from base compounds.

Examples of acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methane-sulphonic and p-toluenesulphonic acids.

The compounds of the invention possess one or more asymmetric carbon atoms and the compounds may be in the form of the pure enantiomorphs or mixture of such enantiomorphs, such as racemates and diastereoisomers. If, for example, R3 and R4 are different but R5 and R6 are both hydrogen the compounds possess two asymmetric carbon atoms and mixtures of such diastereoisomers may be separated by chromatography (e.g. high pressure liquid chromatography) or fractional crystallisation. The ratio of the diastereoisomers in the mixture may be affected by the choice of reagent used in the process to produce the starting materials or final compounds. Optical isomers may be prepared by resolving a racemic mixture by standard methods described in the literature.The racemate may be prepared by any of the processes outlined above. It is to be understood that the resolution may be carried out on the racemic mixture of the final desired product or it may be carried out on a racemic precursor of the desired compound provided further chemical reaction does not cause racemisation.

In any of the above processes the reaction conditions are chosen having regard to the reactivity and stability of the substituents, such that the desired product is obtained.

The novel compounds of the invention possess pharmacological activity, in particular analgesic activity and, or opiate antagonistic activity as indicated by standard pharmacological testing. For example (3R*,5R*)- and (3R*,5S*)-3-(3-ethyl-1,5-dimethyl-3-piperidyl)phenols, representative compounds of the invention, when tested for analgesic activity in a phenylbenzoquinone-induced writhing test (based upon E. Siegmund et al, Proc. Soc. exp. Biol. Med., 1957,95, 729-731) had ED50,s of 5.9 mgíkg s.c. and 0.7 mg/kg s.c.

respectively. The compounds had ED50's of 0.3 mg/kg s.c. and 18.4 mg/kg s.c. respectively in a procedure for opiate antagonistic activity based upon Aceto et al, Brit. J. Pharmac., 1969,36,225-239. Some of the compounds are useful as intermediates for other compounds of the invention by methods described above.

The invention provides a pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical compositions. In such a composition, the carrier may be a solid, liquid or mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, binders ortablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99, preferably 10-80% of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethyl cellulose, a low melting wax, and cocoa butter. The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.

Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredients can be dissolved or suspended in a pharmaceutically acceptable sterile liquid carrier, such as sterile water, sterile organic solvent or a mixture of both. Preferably a liquid carrier is one suitable for parenteral injection. Where the active ingredient is sufficiently soluble it can be dissolved in normal saline as a carrier; if it is too insoluble for this it can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol or polyethylene glycol solutions. Aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable.In other instances other compositions can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance arachis oil. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilised by intramuscular, intraperitoneal or subcutaneous injection. In many instances a compound is orally active and can be administered orally either in liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredients; the unit dosage forms can be packaged compositions, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any of these in package form. The quantity of the active ingredient in a unit dose of composition may be varied or adjusted from 5mg or less to 500mg or more, according to the particular need and the activity of the active ingredient.

The following Examples illustrate the invention.

EXAMPLE 1 5-Eth yl-5-(3-methoxyphen yl]- 1-methyl-2-piperidone A solution of 5-ethyl-5-(3-methoxyphenyl)-2-piperidone (24.79; H.Kugita et al, Chem. Pharm. Bull. Japan, 1963, 11,253) in tetrahydrofuran (250 ml) was added dropwise to a suspension of sodium hydride (5.3g of a 50% dispersion in oil) in THF (50 ml) and stirred at room temperature under argon for 1 hour. Methyl iodide (7 ml) was added and the reaction stirred for a further 0.5 h. After quenching with water the THF was evaporated off and the product extracted into chloroform, dried (Na2SO4) and evaporated to give the title compound as an oil (23.49).

EXAMPLE 2 5-Ethyl-5-(3-methoxyphenyl)- 1, 3-dimethyl-2-piperidone 5-Ethyl-5-(3-methoxyphenyl)-1-methyl-2-piperidone (23.49) in tetrahydrofuran (200 ml) was added to a solution of lithium diisopropylamide (prepared from 56.2 ml of 1.6 M butyl lithium and 12.6 ml isopropylamine) in THF (50 ml) at room temperature and stirred for about 20 minutes. Methyl iodide (63 ml) was added rapidly and the mixture stirred for about 10 minutes. The reaction was poured on to water, the solvent evaporated off and the product extracted into chloroform, dried (Na2SO4) and evaporated to give the title compound as an oil (22.19).

EXAMPLE 3 3-Ethyl-3- (3-meth yloxyph en yl)- 1, 5-dimeth ylpiperidin e 5-Ethyl-5-(3-methoxyphenyl)-1-methyl-2-piperidone (20g) in ether (200 ml) was added to a solution of lithium aluminium hydride (1 2g) in ether (100 ml) at refluxtemperature under argon. After addition was complete the reaction mixture was decomposed by the cautious successive addition of water (12 my),5 M NaOH (12 ml) and water (12 ml). The inorganic material was removed by filtration and the filtrate evaporated to give the title compound as an oil (17.1g).

EXAMPLE 4 3-r3-Ethyl- 1, 5-dimethyl-3-piperidyl)phen ol 3-Ethyl-3-(3-methoxyphenyl)-1,5-dimethylpiperidine (179) in 48% aqueous HBr (35 ml) was heated under argon for about 24 hours. The reaction mixture was poured on to ice and conc. aqueous ammonia, extracted into chloroform, dried ( Na25;O4) and evaporated to give the title compound as an oil (14.2g), shown by n.m.r.

to be a 50:50 mixture of diastereoisomers. The diastereoisomers were separated by column chromatography (using diisopropyl ether on basic alumina) and converted to their hydrochlorides yielding: (a) (3R*,5R*)-3-(3-ethyl-1,5-dimethyl-3-piperidyl)phenol hydrochloride, m.p. 253-255"C.

Analysis Found: C,66.6; H,9.1; N,4.9% C15H23NO.HCl requires: C,66.8; H,8.9; N,5.2% (b) (3R*, SS*)-3-(3-ethyl-1 ,S-dimethyl-3-piperidyl)phenol hydrochloride semihydrate, m.p. 247-250"C.

Analysis Found: C,64.9; H.9.1; N,4.9% C15H23NO.HCl.1/2H2O requires: C, 64.6; H, 9.0; N, 5.0 EXAMPLE 5 5-Ethyl-SF3-methoxyphenyl)- 1-meth yl-3-prop yl-2-pip eridon e 5-EthYI-5-(3-methoxyphenyl)-1-methyl-2-piperidone (7.39) in THF (70 ml) was added dropwise to a solution of lithium diisopropylamide (prepared from 19 ml of 1.6 M butyl lithium and 4.3 ml isopropylamine) in THF (50 ml) at room temperature and stirred for 20 minutes. Propyl iodide (10 ml) was added rapidly and the reaction stirred for 10 minutes. After quenching with water the THF was evaporated off and the residue extracted into chloroform, dried (Na2SO4) and evaporated to give the title compound as an oil (6.2g).

EXAMPLE 6 3-Eth yl-3-(3-meth oxyph en yl)- 1-meth yl-5-prop ylpiperidine 5-Ethyl-5-(3-methoxyphenyl)-1-methyl-3-propyl-2-piperidone (5.5 g) in ether (50 ml) was added dropwise to a solution of lithium aluminium hydride (49) in ether under argon and the mixture allowed to reach reflux temperature. Immediately after the addition TLC showed the reaction to be complete. The reaction mixture was decomposed by the successive addition of water (4 ml) 4 M NaOH (4 ml) and water (4 ml). The inorganic material was removed by filtration and the filtrate evaporated to give the title compound as an oil (5g).

EXAMPLE 7 3- (3-Ethyl- 1-methyl-5-propyl-3-piperidyl)phenol 3-Ethyl-3-(3-methoxyphenyl)-1-methyl-5-propyl-piperidine (5g) in 48% aqueous HBr (16 ml) was heated at reflux under argon for 24 hours. Aqueous ammonia was added and the mixture extracted into chloroform, dried (Na2SO4) and evaporated to give the title compound as an oil (3.2g), shown by nmrto be a 50:50 mixture of diastereoisomers. The diastereoisomers were separated by column chromatography (using diisopropyl ether on basic alumina) and converted to their salts yielding: (a) (3R*,5R*)-3-(3-ethyl-1-methyl-5-propyl-3-piperidyl) phenol hydrochloride, m.p. 206-8"C.

Analysis Found: C,68.2; H,9.85; N, 4.5% C17H27NO.HCl requires: C, 68.6; H, 9.4: N, 4.7% (b) (3R*, SS*)-3-(3-ethyl-1 -methyl-S-propyl-3-piperidyl) phenol tosylate, m.p. 224-6"C.

Analysis Found: C, 66.7; H, 8.5: N, 3.1% C17H27NO.CH3C6H4SO3H requires: C, 66.5; H, 8.1; N, 3.2% EXAMPLE 8 3-Ethyl-i-rn eth yl-3- (3-h ydroxyphen yl)-5, 5-di-( 1-prop yl) pip eridine (a) 5-Ethyl-5-(3-methoxyphenyl)-1-methyi-2-piperidone (2.49) in tetrahydrofuran was added dropwise to a solution of lithium diisopropylamide (prepared from 7.3 ml of 1.6M butyl lithium and 1.6 ml diisopropylamine) in THF (10 ml) and stored at room temperature for about 20 minutes. n-Propylbromide (3.5 ml) was added and the reaction stirred for a further 10 minutes.The reaction was poured on to water, the THF evaporated off and the product extracted into chloroform, dried(Na2SO4) and evaporated to give S-ethyl-I-methyl-S-(methoxyphenyl)-3,3-di-(1 -propyl )-2-piperidone as an oil (1.2 g).

(b) The lactam from part (a) (1.2 g) in diethylether (20 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (0.75 g) in diethylether (10 ml) and stirred at reflux for about 20 minutes. The reaction mixture was decomposed by the addition of water (0.75 ml). The precipitate was filtered off, washed with ether and the combined filtrates evaporated under reduced pressure to give 3-ethyl-1-methyl-3-(3methoxyphenyl)-5,5-di-(1 -propyl )piperidine.

(c) The methyletherfrom part (b) (800 mg) was heated at reflux in 48% aqueous HBr (2 ml) under argon for 24 hours. The reaction mixture was decomposed by addition of aqueous ammonia, extracted into chloroform, dried (Na2SO4) and evaporated to an oil. The oil was converted to the HBr salt yielding the title compound as the hydrobromide 1/4 hydrate.

Analysis Found: C, 61.7; H, 9.2; N, 3.5% C20H33NO.HBr.H2O requires C, 62.0; H, 9.0; N, 3.6%.

Claims

1. A piperidine derivative of the general formula (I)

or a pharmaceutically acceptable acid addition salt thereof wherein R1 represents lower alkyl; R2 represents hydrogen, lower alkyl, benzyl, (lower)alkoxymethyl or an acyl group; R3 represents lower alkyl; R4 represents hydrogen or lower alkyl and R5 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl (lower)alkyl, 2-tetrahydrofuryl methyl or cycloalkylmethyl.

2. A compound as claimed in Claim 1 wherein R5 is lower alkyl.

3. A compound as claimed in Claim 1 or 2 wherein R2 is hydrogen.

4. A compound as claimed in any one of Claims 1 to 3 wherein R' is ethyl.

5. (3R*,5R*)-3-(3-Ethyl-1,5-dimethyl-3-piperidyl)phenol or a pharmaceutically acceptable acid addition salt thereof.

6. (3R*,5S*)-3-(3-Ethyl-1,5-dimethyl-3-piperidyl)phenol or a pharmaceutically acceptable acid addition salt thereof.

7. (3R*,5R*)-3-(3-Ethyl-1-methyl-5-propyl-3-piperidyl)phenol or a pharmaceutically acceptable acid addition salt thereof.

8. (3R*,SS*)-3-(3-Ethyl-1 -methyl-S-propyl-3-piperidyl)phenol or a pharmaceutically acceptable acid addition salt thereof.

9. A process for preparing a compound claimed in Claim 1 which comprises (a) reducing a compound of general formula (II)

wherein R1, R2, R3, R4 and R5 are as defined in Claim 1 and the groups X and X repesent oxo or

with the proviso that at least one of X and X' is oxo; or (b) N-alkylating a compound claimed in Claim 1 in which R5 is hydrogen to give a compound claimed in Claim 1 which is lower alkyl, lower alkenyl, lower alkynyl, aryl(lower)alkyl, 2-tetrahydrofurylmethyl or cycloalkylmethyl; or (c) de-etherifying a compound claimed in Claim 1 in which R2 is lower alkyl, lower alkoxymethyl or benzyl to give a compound in which R2 is hydrogen; or (d) hydrogenolysing a compound claimed in Claim 1 in which R5 is benzyl or dealkylating a compound claimed in Claim 1 in which R5 is lower alkyl to give a compound in which R5 is hydrogen; or (e) acylating a compound claimed in Claim 1 in which R2 is hydrogen to give a compound in which R2 is an acyl group; and, if desired, separating isomers of the product or converting a free base of general formula (I) into a pharmaceutically acceptable acid addition salt thereof.

10. A process for preparing a compound as claimed in Claim 1 substantially as hereinbefore described with reference to any one of Examples 4(a), 4(b), 7(a), 7(b) and 8(c).

11. A compound as claimed in Claim 1 when prepared by the process claimed in Claim 9 or 10.

12. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 8 and 11 in association with a pharmaceutically acceptable carrier.

13. A compound as claimed in any one of Claims 1 to 8 and 11 for use as an analgesic and'our opiate antagonist.