GB2056439A

GB2056439A - Hexahydroazepine Derivatives

Info

Publication number: GB2056439A
Application number: GB8021911A
Authority: GB
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1979-07-18
Filing date: 1980-07-03
Publication date: 1981-03-18
Also published as: GB2056439B

Abstract

Hexahydroazepines of formula (I> <IMAGE> and their pharmaceutically acceptable acid addition salts, wherein n is 1 to 4, R<1> is hydrogen, lower alkyl, aryl(lower)alkyl, (lower)alkenylmethyl or cycloalkylmethyl, R<2> is hydrogen, lower alkyl or benzyl, R<3> represents hydrogen or a carboxylic acyl group and the lower groups contain up to six carbon atoms possess analgesic activity or are useful as intermediates for compounds possessing such activity. The analgesic compounds are those in which R<2> is hydrogen and R<1> is other than hydrogen. The compounds may be prepared from 2- oxo-3,3-disubstituted- hexahydroazepines of formula (II> <IMAGE> wherein X is CH2OH or a group convertible into a CH2OH group.

Description

SPECIFICATION Hexahydroazepine Derivatives The invention relates to hexahydroazepine derivatives, to processes for their preparation and to pharmaceutical compositions containing them.

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

and their pharmaceutically acceptable acid addition salts, wherein n represents 1 to 4, R1 represents hydrogen, lower alkyl, aryl(lower)alkyl, (lower)alkenyimethyl or cycloalkylmethyl, R2 represents hydrogen, lower alkyl or benzyl and R3 represents hydrogen or a carboxylic acyl group.

The term "lower" as used herein means the radical referred to contains 1 to 6 carbon atoms. The radical preferably contains 1 to 4 carbon atoms. For example when R1 or R2 is a lower alkyl group the radical may be straight or branched chain and may be, for example, methyl, ethyl, propyl or butyl. When R' is aryl(lower)alkyl, the radical is preferably a phenyl(lower)alkyl radical such as phenethyl or benzyl; the phenyl group may be substituted by, for example, one or more substituents such as lower alkyl, halogen, lower alkoxy, trifluoromethyl or other substituents common in medicinal chemistry. When R1 is (lower)alkenylmethyl the radical is preferably allyl. When R' is cycloalkyl-methyl it is cyclopropylmethyl.When R3 is a carboxylic acyl group it is preferably a lower aikanoyl group such as acetyl, propionyl or butyryl. n represents 1, 2, 3 or 4; preferably it represents 2.

The compounds of general formula (I) in which Rç is hydrogen, lower alkyl or aryl(lower)alkyl and R3 represents hydrogen may be prepared by a process in which a compound of general formula (II)

where n and R2 are as defined above, R1 is hydrogen, lower alkyl or aryl(lower)alkyl and X represents -CH2OH or a group convertible into a -CH2OH group, is reduced and, if necessary, where X in the product is a group other than -CH2OH such a group is converted into -CH2OH, and if desired, a base of general formula (I) is converted into a pharmaceutically acceptable acid addition salt thereof.

When X represents a group convertible into a -CH2OH it preferably represents a group that is convertible into -CH2OH by reduction. For example X can represent a carboxyl group or an esterified carboxyl group (such as -COOR4 where R4 is hydrogen or lower alkyl). Reduction of the compound of general formula (II) can then result in both reduction of the amide C=O group to a = CH2 group and also reduction of the carboxyl or esterified carboxyl group X to the group -CH2OH. Alternatively where X represents a group convertible into a -CH2OH group it may be a protected hydroxymethyl group, such as, for example, an etherified hydroxymethyl group.For example, the etherified hydroxymethyl group can be a group such as -CH2OCH3 and the methoxy group can be cleaved to a hydroxy group with, for example, trimethylsilyliodide. A further example of an etherified hydroxymethyl group is tetrahydropyranyloxymethyl; the tetrahydropyranyl group may be removed under acidic conditions.

Another example of an etherified hydroxy group is a group such as -CH2OCH2C6H5 the benzyl group can be removed by catalytic hydrogenation. The compound of general formula (II) may be reduced to the compound of general formula (I) with, for example, a hydride transfer agent such as lithium aluminium hydride. Once a compound of general formula (I) has been obtained it may be converted into another compound of general formula (I). For example, the present invention also provides a process for preparing a compound of general formula (I) in which R2 is hydrogen, or a pharmaceutically acceptable acid addition salt thereof, which comprises cleaving a compound of general formula (I) in which R2 is lower alkyl or benzyl or a pharmaceutically acceptable salt thereof. The lower alkyl or benzyl group may be split off in known manner.In a preferred method a benzyl ether is cleaved by hydrogenolysis.

Furthermore the invention provides a process for preparing a compound of general formula (I) in which R' is lower alkyl, aryl(lower)alkyl, (lower)alkenylmethyl or cycloalkyl-(lower)alkyl or a pharmaceutically acceptable acid addition salt thereof which comprises (lower)alkylating, aryl(lower)alkylating, (lower)alkenylmethylating or cycloalkyl-methylating compound of general formula (I) in which R1 is hydrogen or a pharmaceutically acceptable acid addition salt thereof.

Methods of "alkylating" [i.e. (lower) alkylating, aryl(lower)alkylating, (loweralkynylating or cylcoalkylmethylating] are known, see for example, our U.K. Patent Specification No. 1,285,025. For example a halide of general formula R1, Hal (where R' has the meaning of R1 other than hydrogen and Hal is a halogen atom) may be reacted with the compound of general formula (I) in which R1 is hydrogen in the presence of an acid acceptor. Alternatively the compound of general formula (I) in which R1 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 Nunsubstituted compound with a cycloalkylcarbonyl chloride to give an intermediate N-carbonyl cycloalkyl compound which may be reduced with, for example, a hydride transfer agent. The invention further provides a process for preparing a compound of general formula (I) in which R3 represents a carboxylic acyl group of a pharmaceutically acceptable acid addition salt thereof which comprises esterifying a compound of general formula (I) in which R3 represents hydrogen or a pharmaceutically acceptable acid addition salt thereof. Methods of esterification are well known and the most suitable method to give the desired product can be used. For example if both R2 and R3 are hydrogen diesterification can occur and it may be necessary to subsequently cleave one ester group.

Alternatively, and preferably, the compound can be monoesterified by means of an ester exchange method.

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.

If in the process 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, methanesuiphonic and p-toluenesulphonic acids.

Since the compounds of the invention possess an asymmetric carbon atom, optical enantiomorphs are possible and the compounds of the invention may be in the form of pure enantiomorphs or mixtures of such enantiomorphs, such as racemates. If, for example, the starting compound of general formula (II) is an optical enantiomorph the compound of the invention will be obtained in the form of an optical enantiomorph, while if the starting compound is a racemate the compound of the invention will also be obtained in the form of a racemate. If required, a racemate may be resolved by methods known in the art.

Starting compounds of general formula (II) in which X is an esterified carboxyl group may be prepared by reacting a compound of general formula (III)

in which R1 represents hydrogen, lower alkyl, aryl(lower) alkyl or cycloalkylmethyl and R2 represents hydrogen, lower alkyl or benzyl, with the proviso that R1 and R2 are not both hydrogen with a haloester of the formula Hal(CH2)n~1 COOR (where Hal is a halogen atom and -COOR is an esterified carboxyl group, e.g.

ethyl chloroformate or ethyl bromoacetate, in presence of a strong base, e.g. sodium hydride or a metal amide such as sodamide or lithium aluminium hydride. The resulting compound of formula (li) in which X is an esterified carboxyl group may be reduced by, for example, lithium aluminium hydride to give a compound of formula (I) in which R3 is hydrogen. Alternatively reduction of the compound of formula (II) with a reducing agent such as lithium borohydride in, for example, tetrahydrofuran gives a compound of formula (II) in which X is -CH2OH which may be further reduced to a compound of formula (I).

The starting compounds of formula (II) in which X -CH2OH can also be prepared by reacting a compound of formula (Ill) with a protected haloalcohol of general formula (IV) Hal(CH2)nY (IV) (where n has the meaning given above, Hal is halogen atom, preferably chlorine and Y is a protected hydroxy group) and then removing the protecting group. Protected hydroxy groups are well known. For example Y can be a methoxy group which can be subsequently cleaved with, for example, trimethyl silyl iodide, a tetrahydropyranyloxy group which may be cleaved under acid conditions or a benzyloxy group which may be cleaved by hydrogenolysis.

In a further method for preparing the compounds of general formula (Il) in which n is 2 and X is CH2OH a compound of general formula (III) may be reacted with ethylene oxide in presence of a base.

If a starting compound of general formula (oil) is required in which both R' and R2 are hydrogen then a compound of general formula (Ill) should be used in any of the processes referred to above in which at least one of R1 and R2 is other than hydrogen and this group subsequently removed. For example in the compound of formula (III) R1 can be hydrogen and R2 can be benzyl and the benzyl group can be subsequently removed by hydrogenolysis.

Compounds of general formula (II) in which X is a group convertable into a --CH,OH group may be prepared from compounds of formula II in which X is-CH2OH by known methods.

The compounds of general formula (III) are described in European Patent Application No.

78300753.7 (Publication Number 0003 253) or may be prepared by procedures analogous to those described therein.

The novel compounds of general formula (I) possess pharmacological activity or are intermediates for other compounds of the invention possessing such activity. The compounds in which R1 is hydrogen and the compounds in which R2 is lower alkyl or aryl(lower)alkyl are primarily of use as intermediates and they map be converted into other compounds of general formula (I) by the methods described above.The compounds of general formula (I), and their acid addition salts, in which n and R3 have the meanings given above, R1 represents lower alkyl, aryl(lower)alkyl, (lower)alkenylmethyl or cycloalkyl-methyl and R2 represents hydrogen possess pharmacological activity, in particular analgesic activity as indicated by standard pharmacological testing procedures such as a rat tail flick method (based upon D'Amour and Smith, J. Pharmacol., 1941, 72, 74) or a phenylbenzoquinone-induced writhing test (based upon E. Siegmund et al, Proc.Soc. exp. Biol. Med., 1957,95, 729-731). For example, m-[3-(2-acetoxyethyi)-hexahydro- 1 -methyl-2H-azepin-3-yl] phenol, a representative compound of the invention produced analgesic in 10 out of 10 mice at a subcutaneous dosage of 25 mg/kg in the writhing test. Some of the compounds also possess morphine antagonistic activity or can be used in treatment of psychotic disturbances.

The invention provides a pharmaceutical composition comprising a compound of general formula (I) wherein n and R3 have the meanings given above, R1 represents lower alkyl, aryl(lower)alkyl (lower)alkenylmethyl or cycloalkyl(lower)alkyl and R2 represents hydrogen 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 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 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 1080% of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, iactose, 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 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 ingredient; 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 carried or adjusted from 5mg. or less to 500mg. or more, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of the carrier where the compounds are in unit dosage form.

The following Examples illustrate the invention.

Example 1 Hexahydro-3-(2-hydroxyethyl)-3-(3-methoxyphenyl)-1 -methyl-2H-azepin-2-one Diisopropylamine (8.4ml) was added dropwise to a stirred solution of butyl lithium in hexane (42.9mI, O.O6moles, 1 .4M) at-I O0C. After the addition, 3-(3-methoxyphenyl)-1 methylhexahydroazepin-2-one (1 1.7g) in dry T.H.F. (50ml) was added, also at -lO0C. The reaction mixture was cooled to -500C and ethylene oxide (5ml) was added in one portion. After stirring for 16 hours at room temperature under nitrogen, the reaction was cooled and decomposed by the addition of 2M HCI (aq) (100ml).The organic phase was separated and the aqueous phase was extracted with dichloromethane (3 x 1 O0ml). Combined organic extracts were dried (MgSO4) and evaporated to an oil under reduced pressure. The oil crystallised over 24 hours with light petroleum (B.p 60 80 ) affording 10.41 g product, 95% pure by glc. The product was recrystallised from cyclohexane yielding 5.6g of the pure title compound, m.p. 780-790C. Analysis found: C:69.29, H:8.36, N:5.05.

C,6H23NO3 requires: C:69.01, H:8.57, N:5.03% Example 2 3-(2-Hydroxyethyl)-3-(3-methoxyphenyl)-1 -methylhexahydrn-2H-azepine Hexahydro-3-(2-hydroxyethyl)-3-(3-methoxyphenyl)-2H-azepin-2-one (4.1 6g, 0.01 Smole) was added dropwise in dryTHF (50ml), to a refluxing stirred suspension of lithium aluminium hydride (1.2g) in dry THF (50ml). The reaction was refluxed and stirred for 8 hours and then allowed to cool. The excess lithium aluminium hydride was destroyed with water and 15% aqueous sodium hydroxide solution. The alumina was filtered off and washed with THF.The filtrate was then evaporated to an oil under reduced pressure and distilled at 142-1 460C at 0.08mm/Hg affording 2.659 of title compound as an extremely viscous clear liquid. Analysis: found C:73.28, H:9.99, N:5.07. C16H25NO2 requires: C:72.96, H:9.57, N:5.32% Example 3 Ethyl-[3-(3-methoxyphenyl)-1 -methylhexahydro-2-oxo-2H-axepin]-3-carboxylate 3-(3-Methoxyphenyl-1-methylhexahydroazepin-2-one (23.339,) in THF (1 00ml) was added dropwise to a stirred solution of lithium diisopropylamide [0.101 moles, from (72ml) 1.4M butyl lithium in hexane and diisopropylamine (14.1 ml)] under an atmosphere of dry nitrogen. After 10 minutes, ethyl chloroformate (9.55ml) was added dropwise with cooling. After stirring for 2 hours aqueous HCI was added (200ml,2M) with cooling.The phases were separated and the aqueous was extracted (3x 1 50ml) with dichloromethane. Organic extracts were dried (MgSO4) and evaporated to an oil under reduced pressure. This afforded 2 crops of colourless crystals from ethyl acetate/400--600 petroleum spirit, totaling 23.249 of title compound, m.p. 85--6"C. Analysis found: C;66.50, H:8.1 0, N:4.44.

C17H23NO4 requires C:66.86, H:7.59, N:4.59% Example 4 [Hexahydro-l -methyl-3-(3-methoxyphenyl)-l H-azepin-3-yl]-methanol Ethyl-[3-(3-methoxyphenyl)-1 -methylhexahydro-2-oxo-2H-azepin]-3-carboxylate (6.1 3g) in 80ml of dry THF was added to a refluxing solution of 2g of lithium aluminium hydride in 40ml of dry THF under an atmosphere of dry nitrogen. After heating under reflux for 3 hours the reaction mixture was cooled and the complex decomposed with 250ml of saturated aqueous potassium sodium tartrate. The phases were separated and the aqueous phase extracted with ether (3x250ml).

Combined organic phases were dried (MgSO4) and evaporated to an oil which was distilled at 1 220C at 0.1 mm/Hg to afford the title compound as a glass.

Analysis found: C:71 .91, H:9.7, N:5.06. CXsH23NO2 requires C:72.25, H:9.3, N:5.62 Example 5 Ethyl [3-(3-hydroxyphenyl)-1 -methylhexahydro-2-oxo-2H-azepin]-acetat 3-(Hexahydro-l -methyl-2-oxo-2H-azepin-3-yl)phenol (10.96g) in dry THF (400 ml) was added to a stirred solution of lithium diisopropylamine (0.1 mole) in THF (50ml) and hexane (72ml) with cooling under nitrogen. The reaction mixture was heated under reflux for 45 minutes, cooled and ethyl bromoacetate (5.57ml) in THF (25ml) added. After stirring at room temperature for 3 hours a further portion of ethyl bromoacetate was added. After leaving overnight 2M hydrochloric acid (100ml) was added dropwise. The organic phase separated and the aqueous phase was extracted with dichloromethane (3 x 1 50ml) and the combined organic extracts dried (MgSO4) and evaporated to dryness under reduced pressure. The product crystallised from ethyl acetate affording a total of 10.439 of title compound m.p. 1 62-50C.

Analysis found C:67.1 5, H:7.82, N:4.38. C17H23NO4 requires C:66.86, H:7.59, N:4.59%.

Example 6 Hexahydro-3-(3-hydroxyphenyl) -1-methyl-i H-azepin-3-ethanol acetate (ester) Hexahydro-3-(3-hydroxyphenyl)-1 -methyl-2-oxo-lH-azepine-3-acetic acid ethyl ester (1 2.26g) in dry THF was added to a stirred, refluxing suspension of lithium aluminium hydride (3.049) in THF under nitrogen. After 2 hours the reaction was cooled and sodium potassium tartrate (250ml of a saturated aqueous solution) added. The mixture was extracted with ether (2x500ml) and after drying MgS04) the ether removed under reduced pressure. The resulting oil was dissolved in ethyl acetate and made acid with ethereal hydrogen chloride.After heating under reflux the hydrochloride of the title product crystallised and recrystallised from ethyl acetate/ethanol affording 5.98 g, m.p. 1 75-60C.

Analysis found; C:62.29, H:8.12, N:4.1 1. C17H25NO3HCI requires: C:62.32, H:7.94, N:4.27%.

Example 7 Hexahydro-3-(3-hydrophenyl)-l -methyl-l H-azepine-3-ethanol Ethyl [3(3-hydroxyphenyl)-1 -methylhexahydro-2-oxo-2H-azepine] acetate (22.129) was added to a refluxing solution of lithium aluminium hydride (5.59) in dry THF under an atmosphere of dry nitrogen. After 2 hours the reaction was cooled to 200C and saturated aqueous sodium potassium tartrate (500ml) was added. The phases were separated and the aqeuous phase was extracted with ether (3x300ml). All organic phases were combined and dried (MgSO4) and evaporated to an oil under reduced pressure. This afforded 2 crops of colourless needies from ethanol, totaliing 6.99g. The fumarate salt of the title compound was then made using a stoichiometric quantity of fumaric acid and free base.The acid and base were dissolved in IPA and the salt crystallised over 3 days as colourless crystals, m.p. 1 61--1 62 OC. Analysis found: C:62.44, H:7.56, N:3.49. C19H27O6 requires C:62.45, H:7.45, N:3.83%.

Example 8 Hexahydro-3-(2-hydroxyethyl)-3-(3-methoxyphenyl)-2H-azepin-2-one Lithium diisopropylamide was prepared at -200C by adding 1 5% butyl lithium in hexane (86ml) to diisopropylamine (17.2ml) in dry THF (250ml) under nitrogen. After 10 minutes a solution of 3-(3methoxyphenyl)hexahydroazepin-2-one (11 .0g) was added and after a further 15 minutes, neat oxiran (3.0ml) by syringe. After stirring at ambient temperature overnight the reaction was quenched with 5N HCI (200ml).The THF layer was combined with several chloroform extracts from the aqueous and evaporated to give an oil that crystallised from toluene-cyclohexane to give the title compound (5.399, m.p. 82--70C).

Analysis found C:68.7, H:8.3, N:5.0%. C15H21NO3 requires C:68.42, H:8.04, N:5.32%.

Example 9 3-(2-Hydroxyethyl)-3-(3-methoxyphenyl) hexahydroazepine Hexahydro-3-(2-hydroxyethyl)-3-(3-methoxyphenyl)-2H-azepin-2-one (7.49) was heated under reflux with stirring with lithium aluminium hydride (6.8g) in dry tetrahydrofuran (300ml) for four hours.

The cooled suspension was treated slowly with a solution of potassium sodium tartrate (919) in water (200ml). The THF layer was combined with two THF extracts from the aqueous layer (2x300ml), and the combined extracts washed with water (100ml) and dried (MgSO4). Evaporation of the solvent left 6.79 of the title compound as an oil.

Claims

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

or a pharmaceuticaily acceptable acid addition salt thereof, wherein n represents 1 to 4, R1 represents hydrogen, lower alkylaryl(lower)alkyl, (lower)alkenylmethyl or cycloalkylmethyl, R2 represents hydrogen, lower alkyl or benzyl and R3 represents hydrogen or a carboxylic acid group.

2. A compound as claimed in claim 1 wherein n is 2.

3. A compound as claimed in claim 1 or 2 wherein R3 is hydrogen.

4. A compound as claimed in claim 1 or where R3 is lower alkanoyl.

5. A compound as claimed in any one of claims 1 to 4 wherein R1 is lower alkyl.

6. A compound as claimed in any one of claims 1 to 5 wherein R2 is hydrogen.

7. 3-(2-Hydroxyethyl)-3-(3-methoxyphenyl)-1 -methylhexahydro-2H-azepine.

8. [Hexahydro-1 -methyl-3-(3-methoxyphenyl)-1 H-azepin-3-yl]-methanol.

9. Hexahydro-3-(3-hydroxyphenyl)-l -methyl-l H-azepin3-ethanol acetate or a pharmaceutically acceptable acid addition salt thereof.

10. Hexahydro-3-(3-hydroxylphenyl)-1 -methyl-1 H-azepine-3-ethanol or a pharmaceutically acceptable acid addition salt thereof.

11. 3-(2-hydroxyethyl)-3-(3-methoxyphenyl) hexahydroazepine.

12. A hexahydroazepine derivative of general formula (II)

wherein n and R2 are as defined in claim 1, R1 is hydrogen, lower alkyl or aryl(lower)alkyl and X represents -CH2OH or a group convertible into a -CH2OH group.

13. A compound as claimed in claim 1 2 wherein X is -CH2OH, a carboxyl group, an esterified carboxyl group or an etherified hydroxymethyt group.

14. Hexahydro-3-(2-hydroxyethyl)-3-(3-methoxyphenyl)-1 -methyl-2H-azepin-2-one.

15. Ethyl [3-(3-methoxyphenyl)-1 -methylhexahydro-2-oxo-2 H-azepi n]-3-carboxylate.

1 6. Ethyl [3-(3-hydroxyphenyl)-1 -methyl hexahydro-2-oxo-2 H-azepin]-acetate.

17. Hexahydro-3-(2-hydroxyethyl)-3-(3-methoxyphenyl)-2 H-azepin-2-one.

1 8. A process for preparing a compound claimed in claim 1 in which R1 is hydrogen, lower alkyl or aryl(lower)alkyl and R3 is hydrogen which comprises reducing a compound claimed in claim 12 and, if necessary, where X is the product is other than -CH2OH converting such a group into -CH2OH and, if desired, converting a base of general formula (I) into a pharmaceutically acceptable acid addition salt thereof.

19. A process as claimed in claim 18 wherein X in the compound of formula (II) is -CH2OH, a carboxyl group or an esterified carboxyl group.

20. A process as claimed in claim 18 wherein X in the compound of formula II is an etherified hydroxymethyl group and the etherified hydroxymethyl group in the reduction product is cleaved to a hydroxymethyl group.

21. A process for preparing a compound claimed in claim 1 in which R2 is hydrogen which comprises cleaving a compound as claimed in claim 1 in which R2 is lower alkyl or benzyl and, if desired, converting a base of general formula I into a pharmaceutically acceptable acid addition salt thereof.

22. A process for preparing a compound claimed in claim 1 in which R1 is lower alkyl, aryl(lower)alkyl,(lower)alkenymethyl or cycloalkyl(lower)methyl which comprises (lower) alkylating, aryl(lower)alkylating,(lower)alkenylating or cycloalkylmethylating a compound claimed in claim 1 in which R1 is hydrogen and, if desired, converting a base of general formula I into a pharmaceutically acceptable acid addition salt thereof.

23. A process for preparing a compound claimed in claim 1 in which R3 is a carboxylic acyl group which comprises esterifying a compound claimed in claim 1 in which R3 is hydrogen and, if desired, converting a base of general formula I into a pharmaceutically acceptable acid addition salt thereof.

24. A process for preparing a compound claimed in claim 1 substantially as hereinbefore described with reference to any one of Examples 2, 4, 6, 7 and 9.

25. A process for preparing a compound claimed in claim 12 substantially as hereinbefore described with reference to any one of Examples 1, 3, 5 and 8.

26. A compound claimed in claim 1 whenever prepared by the process claimed in any one of claims 18 to 24.

27. A compound claimed in claim 1 2 whenever prepared by the process claimed in claim 25.

28. A pharmaceutical composition comprising a compound claimed in claim 1 in which R1 is lower alkyl, aryl(lower)alkyl,(iower)alkenylmethyl or cycloalkylmethyl and R2 is hydrogen in association with a pharmaceutically acceptable carrier.

29. A hexahydroazepine derivative as claimed in claim 1 wherein R1 is lower alkyl, aryl(lower)alkyl, (lower)alkenylmethyl or cycloalkylmethyl for use as an analgesic.