GB2105326A - Piperidine derivatives - Google Patents

Abstract

Piperidine derivatives of formula <IMAGE> and esters thereof, and pharmaceutically acceptable acid addition salts of the alcohols or esters, wherein R<2> is a phenyl group optionally substituted by one or more specified substituents and R<6> is hydrogen, aryl(lower)alkyl or cycloalkyl(lower)alkyl possess pharmacological activity (e.g. as analgesics, antidepressants or anti-secretary agents) or are intermediates for compounds possessing such activity.

Description

SPECIFICATION Piperidine derivatives This invention relates to piperidine derivatives. More particularly this invention relates to certain novel piperidine derivatives, to the use of such piperidine derivatives and to compositions containing them.

The novel piperidine derivatives of the present invention are those of the general formula

or esters thereof, or pharmaceutically acceptable acid addition salts of the alcohols or esters, wherein R2 is a phenyl group optionally substituted by one or more (lower)alkyl, (lower)alkoxy, halogen, amino, (lower) alkylamino, di(lower)alkylamino or trifluoromethyl substituents and R6 is hydrogen, aryl(lower)alkyl or cycloalkyl(lower)alkyl.

The term "lower" as used herein to qualify a radical means that the radical contains from 1 to 6, preferably from 1 to 4 carbon atoms. When R6 is aryl(lower)alkyl the radical is preferably a phenyl(lower)alkyl group such as phenethyl or more particularly benzyl; the phenyl group may be substituted by, for example, one or more substituents such as halogen, alkoxy, trifluoromethyl or other substituents common in medicinal chemistry. Examples of cycloalkyl(lower)alkyl are cyclopropylmethyl and cyclobutylmethyl.R2 can be an unsubstituted phenyl group or a phenyl group substituted by one or more (lower)alkyl (such as methyl, ethyl, propyl or butyl), hydroxy, (lower)alkoxy (such as methoxy, ethoxy, propoxy or butoxy), halogen (e.g. chlorine or fluorine), amino, lower(alkyl)amino (e.g. methylamino), di(lower)alkylamino (e.g. dimethylamino) or trifluoromethyl groups.

The compounds of the invention may be prepared from dihydropyridine derivatives of general formula

where R2 is as defined above and R5 is aryl(lower)alkyl. For example, a compound of general formula (II) or an acid addition salt thereof may be reduced to a piperidine derivative of general formula (Ill)

where R2 and R5 have the meanings given above, or a pharmaceutically acceptable acid addition salt thereof and if desired, converting a free base of general formula (Ill) into a pharmaceutically acceptable acid addition salt thereof.

The reduction of compounds of general formula (II) or acid addition salts thereof may be effected, for example, by catalytic hydrogenation. Suitable hydrogenation catalysts include, for example, palladium (particularly palladium on charcoal), platinum or nickel. Compound of general formula (II) or acid addition salts thereof may also be reduced by alkali metal (e.g.

lithium or sodium) in liquid ammonia.

Piperidine derivatives of general formula (IV)

where R2 and R5 have the meanings given above, and pharmaceutically acceptable salts thereof may be prepared by reducing a compound of general formula (III) or a pharmaceutically acceptable acid addition salt thereof with a carbonyl reducing agent.

The carbonyl reducing agent may be, for example, a hydride transfer reagent (e.g. sodium borohydride, lithium aluminium hydride, lithium tri-sec-butyl borohydride) or a catalytic reducing agent (hydrogen in the presence of a catalyst such as palladium charcoal or Raney nickel).

Compounds of formula (IV) may be prepared by an alternative process which comprises reducing a compound of general formula (V).

or an acid addition salt thereof, where R2 and R5 have the meanings given above. The compound of formula (IV) may, for example, be reduced by catalytic hydrogenation. The compound of general formula (V) may be prepared by reducing the compound of general formula (II) with, for example, a hydride transfer reagent (e.g. sodium borohydride).

When R5 in the compound of general formula (IV) is benzyl or a substituted benzyl such as alkyl- or alkoxy-benzyl this may be removed by, for example, catalytic hydrogenation to give a compound of general formula (VI)

or a pharmaceutically acceptable acid addition salt thereof. The compounds of general formula (VI) are particularly important intermediates since they can be alkylated to give compounds having the formula (I) given above in which R2 is as defined above and in which R6 is cycloalkyl(lower)alkyl, e.g. cyclopropyl methyl and cyclobutyl methyl.In a preferred method of alkylation the compound of general formula (VI) is treated with an acyl halide (e.g. a cycloalkane carboxylic acid halide such as cyclopropane carboxylic acid chloride) and the resulting Nalkanoyl-3-acyloxy-piperidine compound reduced (e.g. with a hydride transfer reagent).

The esters of the compounds of the invention may be prepared by esterifying the corresponding free alcohol or its acid addition salt.

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 although, as mentioned above, if the product of any of the processes 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 conventional procedures for preparing acid addition salts from base compounds. Example of acid addition salts are those formed from inorganic and organic acids such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic and p-toluenesulphonic acids.

The piperidine alcohols of the invention and their esters possess two asymmetric carbon atoms and hence the compounds can exist in various stereochemical forms all of which are provided by the invention. The proportions of the cis and trans isomers in the alcohol depend on the reducing agent used in its method of preparation.

Processes for preparing the starting materials of general formula (II) are described in our UK Patent Application No. 8027891 (Publication Number 2,060,61 7A), from which the present application is divided.

The compounds of the invention possess pharmacological activity or are intermediates for other compounds having pharmacological activity. The compounds of the invention in which R6 is cycloalkyl(lower)alkyl are particularly useful because they possess analgesic and antidepressant activity, as indicated by testing in standard pharmacological test procedures.

The compounds of the invention in which R6 is hydrogen are anti-ulcer agents which possess anti-secretory activity in the standard test of H. Shay et al Gastroenterlogy, 1954, 26, 906-913. In addition the compounds can be N-alkylated, as mentioned above, to the compounds of the invention in which R6 is cycloalkyl(lower)alkyl. The compounds can also be Nalkylated to give alcohols cor?esponding to those of general formula (I) in which R6 is (lower)alkyl. Such alcohols are described in our Specification No. 1,578,444. In a preferred method of carrying out the alkylation the compound is treated with a lower a lower alkanoyl halide such as acetyl chloride and the resulting N-alkanoyl-3-acyloxy-piperidine reduced (e.g.

with a hydride transfer reagent). In an alternative method of alkylation the compound of formula I in which R6 is hydrogen is treated with an aldehyde and a reducing agent such as sodium cyanoborohydride. The alkylation can also be effected by a lower alkyl halide in presence of an acid acceptor.

The invention further provides a pharmaceutical composition which comprises a compound of the invention in which RS is cycloalkyl(lower)alkyl or hydrogen in association with a pharmaceutically acceptable carrier. The active ingredients of the compositions should, of course, be chosen so that they are stable in the particular composition employed. In the compositions of the invention the carrier may be a solid, liquid or mixture of a solid and 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, solubiliser, suspending agents, binders, or tablet 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 ingredients.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, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, 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 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 ingredient 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 be dissolved in a suitable organic solvent, for instance aqueous propylene glycol containing from 10-75% of the glycol by weight is generally suitable.

In other instances 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 utilized 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. In such form, the composition is sub-divided in unit doses containing appropriate quantities of active ingredient; the unit dosage form can be a packaged composition, the package containing specific quantities of compositions, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any of these in packaged form. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from about 5 mg. to 500 mg., according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.The daily dose of compound will vary depending upon the route of administration, the particular compound employed and the particular animal involved.

The following Examples illustrate the invention EXAMPLE 1 cis- I-Benzyl-3-hydroxy-5-phenylpiperidine A solution of 1-benzyl-1,6-dihydro-5phenyl-3-[2H] pyridone hydrochloride hydrate (25 g) in 50% aqueous methanol (500 ml) was treated with sodium bicarbonate (6.9 g) followed by sodium borohydride (6 g) in portions over 2 hours. The solvents were removed under reduced pressure and the residue partitioned between water (250 ml) and ether (250 ml). The organic phase was dried and the solvent removed under reduced pressure to yield an oil.

A solution of the above oil in ethanol (200 ml) was hydrogenated over 10% Pd/charcoal at atmosphere and room temperature. After the theoretical uptake of hydrogen had occurred (c.3h) the catalyst was removed by filtration and the solvent removed under reduced pressure. The resulting oil was dissolved in ether (500 ml) and treated with an excess of a solution of hydrogen chloride in ether. Removal of the resulting precipitate by filtration and recrystallisation from IPA gave the title compound as the hydrochloride quarter hydrate (18 g) m.p. 231-4" Analysis Found: C, 70.4; H, 7.6; N, 4.4% C8H21N0.HCl.-41H20 requires C, 70.1; H, 7.5; N, 4.5%.

EXAMPLE 2 cis-3-Hydroxy-5-phen ylpiperidine e A solution of cis-1-benzyl-3-hydroxy-5-phenylpiperidine hydrochloride (6.16 g) in methanol (100 ml) was hydrogenated over 10% Pd/charcoal in a Parr apparatus at 50 psi (about 3.5 x 104 kg/sq.m.) and room temperature. After the theorectical uptake of hydrogen had occurred (about 7 hours) the catalyst was removed by filtration and the solvent evaporated under reduced pressure. Recrystallisation of the residue from IPA gave the title compound as the hydrochloride (3.1 g) m.p. 200-4'C.

Analysis Found: C, 61.85; H, 7.9; N, 6.3%.

C"H,5NO.HCI requires: C, 61.8; H, 7.6; N, 6.6%.

EXAMPLE 3 cis- 1-Cyclopropylmethyl-3-hydroxy-5-phenylpiperidine A solution of cis-3-hydroxy-5-phenyl-piperidine hydrochloride (3.6 g) in dichloromethane (50 ml) was treated with cyclopropane carboxylic acid chloride (10 ml) followed by triethylamine (10 ml). After 24 hours the reaction mixture was partitioned between water (200 ml) and methylene chloride (100 ml). The organic phase was washed with 2N HCI, 2N NaOH and water, dried and the solvents removed under reduced pressure. The residue was dissolved in THF (25 ml) and added to a solution of lithium aluminium hydride (1.3 g) in THF (25 ml). After 24 hours a saturated solution of Rochelle salt (50 ml) was added and the layers separated. The aqueous layer was extracted with chloroform (2 x 100 ml).The combined organic layers were washed with brine, dried and the solvents removed under reduced pressure. The residue was dissolved in ether (100 ml), filtered and treated with an excess of an ethereal solution of hydrogen chloride. Removal of the resultant precipitate by filtration, followed by recrystallisation from IPA gave the title compound as the hydrochloride (1.2 g) m.p. 194-5 Analysis Found: C, 66.8; H, 8.6; N, 4.7% C,5H2,NO.HCI requires C, 67.3; H, 8.3; N, 5.2%.

EXAMPLE 4 cis- I-Ethyl-3-hydroxy-5-phenylpiperidine (a) A solution of cis-3-hydroxy-5-phenyl-piperidine hydrochloride (3.6 g) in a mixture of dichloromethane (50 ml) and acetyl chloride (5 ml) was treated with triethylamine (10 ml). After 24 hours the reaction mixture was partitioned between water (200 ml) and dichloromethane (100 ml). The organic phase was washed with 2N HC1,2N NaOH and water, dried and the solvents removed under reduced pressure. The residue was dissolved in THF (25 ml) and added to a solution of lithium aluminium hydride (1.3 9) in THF (25 ml). After 24 hours a saturated solution of Rochelle salt (50 ml) was added and the layers separated. The aqueous layer was extracted with chloroform (2 X 100 ml) and the combined extracts washed with brine, dried and the solvents removed under reduced pressure.Chromatography of the residue on Grade Ill silica, using 3% methanol in chloroform as eluant, evaporation of the appropriate fractions, conversion to the hydrochloride and recrystallisation from IPA gave the title compound as the hydrochloride (1.0 g) m.p. 182-4".

Analysis Found: C, 64.3; H, 8.15; N, 5.9% C13H,9NO.HCI requires C, 64.6; H, 8.3; N, 5.8%.

(b) 5-Phenyl-3-piperidinol (5.2 g), tetramethylpiperidine (8.3 ml) and iodoethane (1.97 ml) was stirred at room temperature in methanol (100 ml) for 48 hours. The methanol was removed under reduced pressure and excess 2M NaOH added. The oil was extracted with ether and washed with brine. After drying (MgSO4) the ether was removed and the product crystallised affording, after recrystallisation from cyclohexane, 3.2 g of pure title compound which could be converted to the hydrochloride salt, m.p. 182-4"C.

EXAMPLE 5 1 -Benzyl-5-hydroxy 1,2,5, 6tetrah ydro- 3(p-trifluorom eth ylph en yl)p yridin e A solution of 1-benzyl-1,6-dihydro-5-(p-trifluoromethylphenyl)-3-(2H)pyridone hydrochloride hydrate (11.6 g) in ethanol (250 ml) was treated with sodium bicarbonate (2 g) followed by sodium borohydride (1.5 g). After 2 hours the solvents were removed under reduced pressure and the residue partitioned between water (100 ml) and ether (400 ml). The organic phase was dried and the solvent removed under reduced pressure. Recrystallisation of the residue from cyclohexane gave the title compound (7.3 g), m.p. 88-90".

Analysis Found: C, 68.05; H, 5.3; N, 3.95% C,9H18F3NO requires C, 68.1; H,5.5; N, 4.2%.

EXAMPLE 6 cis-3-Hydroxy-5-(p-trifluoromethylphen ypiperidine A solution of 1 -benzyl-5-hydroxy-1 ,2,5,6-tetrahydro-3-(p-trifluoromethylphenyl)pyridine (5.9 g) in methanol (200 ml) was hydrogenated over 10% palladium on carbon (500 mg) in a Parr apparatus at 30 psi (about 2.11 X 104 kg/sq.m) and room temperature. After the theoretical uptake of hydrogen had occurred (about 3 hours), the catalyst was removed by filtration and the solvent evaporated under reduced pressure. Recrystallisation of the residue from toluene gave the title compound as the free base (4 g). The free base was dissolved in a small volume of IPA and treated with an excess of ethereal hydrogen chloride.On cooling crystals of the title compound hydrochloride separated, m.p. 189-92" Analysis Found: C, 51.0; H, 5.7; N, 4.7% C,2H,4F3NO.HCI. requires C, 51.2; H, 5.4; N, 5.0%.

EXAMPLE 7 cis-3-Hydroxy- 1 -meth yl-5-(p-trifluoromethylphen yl)piperidine A solution of cia3-hydroxy-5-(p-trifluoromethylphenyl)piperidine (2.1 g) in a mixture of acetonitrile (25 ml) and 40% aqueous formaldehyde (3.5 ml) was treated with sodium cyanoborohydride (900 mg). After 1 5 min. acetic acid was added to adjust the mixture to pH6 to 7. The pH was maintained in this range by further additions of acetic acid over 45 min. and the solvents removed under reduced pressure. The residue was partitioned between 2N aqueous sodium hydroxide (20 ml) and ether (50 ml). The ether layer was extracted with 2N hydrochloric acid (20 ml), the acid solution basified to pH9 with sodium carbonate and extracted with ether (2 x 50 ml). The organic phase was dried and the solvent removed under reduced pressure to give an oil which was converted to the hydrochloride and recrystallised from isopropanol/ether to give the title compound as the hydrochloride (1.2 g), sublimes 210 .

Analysis Found: C, 52.5; H, 5.9; N, 4.6% C,3H,6F3NO.HCI requires C, 52.8; H, 5.8; N, 4.7%.

EXAMPLE 8 7 -Benzyl-5h ydroxy- 1,2,5, 6-tetrah ydro-3-(p-tolyl)pyridine A solution of 1 -benzyl-1 , 6-d ihydro-5-(p-tolyl)-3-[2 H]-pyridone hydrochloride hydrate (4.7 g) in ethanol (100 ml) was treated with sodium bicarbonate (1.2 g), followed by sodium borohydride (1 g). After 1 hour the solvents were removed under reduced pressure and the residue partitioned between water (50 ml) and ether (200 ml). The ether layer was dried and the solvent removed under reduced pressure to give the title compound as an oil (3.5 g).

EXAMPLE 9 cis- 1 -Benzyl-3hydroxy-5-(p-tolyl)piperidine and cis-3-Hydroxy-5-(p-tolyl)piperidine A solution of the crude product of Example 8(3.5 g) in ethanol (100 ml) was hydrogenated over 10% palladium on carbon (500 mg) at atmospheric pressure and room temperature.

Uptake ceased after 0.6 molar equivalents of hydrogen had been consumed, hence further catalyst (500 mg) was added. Uptake ceased again after the consumption of 1.5 molar equivalents of hydrogen. The catalyst was removed by filtration, the filtrate treated with an excess of ethereal hydrogen chloride and the solvents removed under reduced pressure.

Fractional crystallisation of the residue from isopropanol/ether gave cisl-benzyl-3-hydroxy-5-(p- tolyl)piperidine hydrochloride quarter hydrate (500 mg) m.p. 238-242' Analysis Found: C, 70.6; H, 7.8; N, 4.1% C,9H23NO HCI-H2O requires C, 70.8; H, 7.7; N, 4.3% and cis-3-hydroxy-5-(p-tolyl)piperidine hydrochloride three quarters hydrate (900 mg) m.p.

200-211 Analysis Found: C, 59.95; H, 8.0; N, 5.4% C12H,7NO.HCL4H2O requires C, 59.8; H, 8.1; N, 5.8% EXAMPLE 10 1 -Benzyl- 1. 6-dihydro-5-(p-chlorophenyl-3[2H]-pyridone A solution of p-chlorophenyl magnesium bromide (0.1 7 M) in ether (100 ml) was treated with a solution of 1-benzyl-1,6-dihydro-5-methoxy-3-[2H]pyridone (32.5 g, 0.25 M) in THF (150 ml). The reaction was stirred 1 hour, poured onto cold 2N hydrochloric acid (250 ml) and stirred 30 min. Removal of the resulting precipitate by filtration, followed by air-drying and recrystallisation from methanol gave the title compound as the hydrochloride hydrate (24.1 9) m.p.

166-8" Analysis Found: C, 61.7; H, 5.0; N, 3.7% C,8H16CINO.HCl H2O requires C, 61.3; H, 5.4; N, 4.0 /O.

EXAMPLE 11 5-Hydroxy- 1 -methyl-3-(4-methylphen yl)- 1,2,5, 6-tetrah ydropyridine A solution of 1,6-dihydro-5-(4-methylphenyl)-1 methyl-3[2H]pyridone hydrochloride (189) in 50% aqueous ethanol (500 ml) was treated with sodium bicarbonate (6.4 g) followed by sodium borohydride (4 g) in portions. After 2 hours, the solvent was removed under reduced pressure and the residue extracted with ether (2 X 250 ml). Drying (MgSO4) followed by removal of the solvent under vacuum gave an oil which crystallised and was recrystallised from pentane to give the title compound (9 g) m.p. 67-69" Analysis Found: C, 77.1; H, 8.4; N, 6.7%.

C13H,7NO requires: C, 76.8; H, 8.4; N, 6.9%.

EXAMPLE 12 cis-3-Hydroxy- 1-methyl-5-(4-methylphenyl)piperidine A solution of 5-hydroxy-l -methyl-3-(4-methylphenyl)-1,2,5,6-tetrahydropyridine (5.1 9, 25 mM) in methanol (200 ml) was hydrogenated in a Parr apparatus at 50 psi (about 3.51 x 104 kg/sq.m) and room temperature over 10% palladiurn-on-charcoa! (1g). After the theoretical uptake of hydrogen had occurred (about 3 hours) the catalyst was removed by filtration and the solvent removed under vacuum. Recrystallisation from cyclohexane gave the title compound (4 g). A portion was converted to the hydrochloride and recrystallised from methanol/ether to give the title compound hydrochioride, m.p. 218-9'.

Analysis Found: r 64.4; \rl, 3 75; N, 6 0% C13H1N0.HCl requires: C. 64.6; H, 8.3; N, 5.8%.

Claims (14)

1. An alcohol of general formula

or an ester thereof, or a pharmaceutically acceptable acid addition salt of the alcohol or ester, wherein R2 is a phenyl group optionally substituted by one or more (lower)alkyl, (lower)alkoxy, halogen, amino, (lower)alkylamino, di(lower)alkylamino or trifluoromethyl substituents and Re is hydrogen, aryl(lower) alkyl or cycloalkyl(lower)alkyl.

2. cisl -Benzyl-3-hydroxy-5-phenylpiperidine or a pharmaceutically acceptable acid addition salt thereof.

3. ciS1-Cyclopropylmethyl-3-hydroxy-5-phenylpiperidine or a pharmaceutically acceptable acid addition salt thereof.

4. cis1-Benzyl-3-hydroxy-5-(p-tolyl)piperidine or a pharmaceutically acceptable acid addition salt thereof.

5. cis3-Hydrnxy-5-phenylpiperidine or a pharmaceutically acceptable acid addition salt thereof.

6. cis-3-Hydroxy-5-(p-trifiuoromethylphenyl)piperidine or a pharmaceutically acceptable acid addition salt thereof.

7. A process for preparing an alcohol or a pharmaceutically acceptable acid addition salt thereof as claimed in Claim 1 in which R6 is aryl(lower)alkyl which comprises reducing a compound of general formula (IV)

wherein R2 is as defined in Claim 1 and R5 is aryl (lower)alkyl or a pharmaceutically acceptable acid addition salt thereof, with a carbonyl reducing agent.

8. A process for preparing an alcohol or a pharmaceutically acceptable acid addition salt thereof as claimed in Claim 1 in which R6 is aryl(lower)alkyl which comprises reducing a compound of general formula (V)

wherein R2 is as defined in Claim 1 and R5 is aryl(lower)alkyl, or an acid addition salt thereof.

9. A process for preparing an alcohol or a pharmaceutically acceptable acid addition salt thereof as claimed in Claim 1 in which R6 is hydrogen which comprises subjecting an alcohol as claimed in Claim 1 in which R6 is benzyl or substituted benzyl to catalytic hydrogenation.

10. A process for preparing an alcohol or a pharmaceutically acceptable acid addition salt thereof as claimed in Claim 1 in which Rs is cycloalkyl(lower)alkyl which comprises alkylating an alcohol as claimed in Claim 1 in which R6 is hydrogen.

11. A process for preparing a compound claimed in Claim 1 substantially as hereinbefore described with reference to any one of Examples 1,2,3,6 and 9.

1 2. A piperidine derivative whenever prepared by the process claimed in any one of Claims 7 to 11.

1 3. A pharmaceutical composition comprising a compound as claimed in Claim 1 wherein R6 is hydrogen or cycloalkyl(lower)alkyl in association with a pharmaceutically acceptable carrier.

14. A compound as claimed in Claim 1 in which R6 is cycloalkyl(lower)alkyl for use as an analgesic or antidepressant.

1 5. A compound as claimed in Claim 1 in which R6 is hydrogen for use as an anti-ulcer agent.