GB2192885A

GB2192885A - Heterocyclic compounds

Info

Publication number: GB2192885A
Application number: GB08717353A
Authority: GB
Inventors: Ian Harold Coates; William Leonard Mitchell; David Cedric Humber; James Angus Bell; George Blanch Ewan
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1986-07-23
Filing date: 1987-07-22
Publication date: 1988-01-27
Anticipated expiration: 2007-07-22
Also published as: IT1211667B; CH674008A5; NL8701728A; JPS6335570A; FR2601951A1; GB2192885B; BE1000730A5; GB8617994D0; DE3724322A1; IT8748207A0; GB8717353D0; FR2601951B1

Description

1 GB2192885A 1

SPECIFICATION

Heterocyclic compounds This invention relates to heterocyclic compounds, to processes for their preparation, to pharma- 5 ceutical compositions containing them and to their medical use. In particular the invention relates to compounds which act upon 5-hydroxytryptamine (5-HT) receptors of the type located on terminals of primary afferent nerves.

Compounds having antagonist activity at 'neuronal' 5-HT receptors of the type located on primary afferent nerves have been described previously. 10 Thus for example published UK patent specification No 2153821A discloses tetrahydrocarba zolones of the general formula 0 R4 ' ---C" R3 15 ::#", CH2.r _1 1 1 1 H- 'M cl:N& V 1 R2 20 R 1 wherein R' represents a hydrogen atom or a C,_loalky], C,_,cycloalky], C,- , alkenyl, phenyl or phenyl C,_,alkyl group, and one of the groups represented by R 2, R 3 and R4 is a hydrogen atom or a Cl,alky], C3-7CYCloalky], C2_.alkenyl or phenVIC,_,alkyl group and each of the other two 25 groups, which may be the same or different, represents a hydrogen atom or a C,, alkyl group.

We have now found a novel group of compounds which differ in structure from those described previously, and which are potent antagonists of the effect of 5- HT at 5-HT 'neuronal' reCeptors.

Thus the present invention provides a tetrahydrocarbazolone of the general formula (1): 30 0 R4 R3 R5 N T_ N 35 R2 R 40 wherein R' represents a hydrogen atom or a group selected from C,_,0alky], C3-7CYCloalky], C3-7 cycloalkylCl-4 alkyl, C,-, alkenyl, C,_,o alkynyi, phenyl or phenylC,3alkyl, COR6, -COR6, -CONR6R7 or -S02R6 (wherein R6 and R7, which may be the same or different each represents a hydrogen atom, a Cl6 alkyl or C3-7 cycloalkyl group, or a phenyl or phenyl C 1-4 alkyl group, in which the phenyl group is optionally substituted by one or more C,-, alky], C 1-4 alkoxy or hydroxy groups 45 or halogen atoms, with the proviso that R6 does not represent a hydrogen atom when R' represents a group -C02R6 or -SO,R6); one of the groups represented by R2, R3 and R4 is a hydrogen atom or a C, _,alkyl, C3-7cycloal kyl, C2-6alkenyl or phenyiC,-,aikyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C,, alkyl group; and 1 50 R5 represents a C,_c, alkyl group; and physiologically acceptable salts and solvates thereof.

It will be appreciated that the carbon atom at the 3-position of the tetrahydrocarbazolone ring is asymmetric and may exist in the R- or Sconfiguration. All optical isomers of compounds of general formula (1) and their mixtures including the racemic mixtures thereof, and all the geomet55 ric isomers of compounds of formula (1), are embraced by the invention.

Referring to the general formula (1), the alkyl. groups represented by R1, R2,R 3 134 R5,136 and R7 may be straight chain or branched chain alkyl 'groups for example, methyl, ethyl, propyl, prop-2 yi, butyl, -but-2-yi, 2-methylprop-2-yi, pentyl, pent-3-yl or hexyl groups.

A C3-6 alkenyl group may be, for example, a propenyl or butenyl group. A C3-10 alkynyl group, 60 may be, for example, a prop-2-ynyl or oct-2-ynyl group. It will be appreciated that when R' represents a C3-6alkenyl or C3-1. alkynyl group, the double or triple bond respectively may not be adjacent to the nitrogen atom. A phenVIC1-3alkyl group may be, for example, a benzyi, phenethyl or 3-phenylpropyl group. A C3-,cycloalkyl group, either alone or as part of a C3-7CYCloalky1C1-,a]- kyl group, may be, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl 65 2 GB2192885A 2 group.

According to one aspect, the invention provides compounds of formula (1) in which R1 repre sents a hydrogen atom, or a Cl-10 alkyl, C3-7 CYCloalkyl, C3_6 alkenyl, phenyl or phenylCl-3alkyl group, and R2, R3, R4 and R5 are as defined in formula (1).

A preferred class of compounds represented by the general formula (1) is that wherein R1 5 represents a hydrogen atom or a C1-3 alkyl (e.g. methyl), C,-6 cycloalkyl or C3_6 alkenyl group.

Another preferred class of compounds represented by the general formula (1) is that wherein one of the groups represented by R2, R3 and R4 represents a C,-3 alkyl, C3-6 cycloalkyl or C3-6 alkenyl group and each of the other two groups, whch may be the same or different, represents a hydrogen atom or a C1-3 alkyl group. When -R2 represents a hydrogen atom, R3 and/or R4 10 preferably represents a C1-3 alkyl (e.g. methyl) group. When R2 represents a C,-3alkyl (e.g.

methyl) group R3 and R4 both preferably represent hydrogen atoms.

Yet another preferred class of compounds of formula (1) are those in which R5 represents a v C1-3 alkyl (e.g. methyl) group.

A particularly preferred group of compounds of formula(l) are those in which R1 represents a 15 methyl group, R 2 represents a methyl group, R3 represents a hydrogen atom, R4 represents a hydrogen atom and RI represents a Cl-,alkyl group.

A particular compound of the invention is 1,2,3,9-tetrahydro-3,9-dimethyl3-[(2-methyl-lH-imi- dazol-1-yl)methyl]-4H-carbazol-4-one and its physiologically acceptable salts and solvates.

Suitable physiologically acceptable salts of the compounds of general formula (1) include acid 20 addition salts formed with organic or inorganic acids for example, hydrochlorides, hydrobrom ides, sulphates, phosphates, citrates, succinatps, tartrates, furnarates, maleates and p-toluenesul phonates. The solvates may, for example, be hydrates.

It will be appreciated that the invention extends to other physiologically acceptable equivalents of the compounds according to the invention, i.e. physiologically acceptable compounds which 25 are converted in vivo into the parent compound of formula (1).

Compounds of the invention are potent and selective antagonists of 5-HTinduced depolarisa tion of the rat isolated vagus nerve preparation and thus act as potent and selective antagonists of the 'neuronal' 5-HT receptor type located on primary afferent nerves. Receptors of this type are now designated as 5-HT, receptors. Such receptors are also believed to be present in the 30 central nervous system. 5-HT occurs widely in the neuronal pathways in the central nervous system and disturbance of these 5-HT containing pathways is known to alter aspects of behaviour such as mood, psychornotor activity, appetite and memory.

Compounds of formula (1), which antagonise the effect of 5-HT at 5-HT3 receptors, are useful in the treatment of conditions such as psychotic disorders (e.g. schizophrenia and mania); 35 anxiety; and nausea and vomiting. Compounds of formula (1) are also useful in the treatment of gastric stasis; symptoms of gastrointestinal dysfunction such as occur with dyspepsia, peptic ulcer, reflux oesophagitis, flatulence and irritable bowel syndrome; migraine; and pain.

Unlike existing drug treatments for these conditions, the compounds of the invention, because of their high selectivity for 5-HT, receptors, would not be expected to produce undesirable side 40 effects. Thus, for example, neuroleptic drugs may exhibit extrapyramidal effects, such as tardive dyskinesia, and berzodiazepines may cause dependence.

According to another aspect, the invention provides a method of treatment of a human or animal subject suffering from a psychotic disorder such as schizophrenia or mania; or from anxiety; nausea or vomiting; gastric statis; symptoms of gastrointestinal dysfunction such as 45 dyspepsia, reflux oesophagitis, peptic ulcer, flatulence and irritable bowel syndrome; migraine; or pain, which comprises administering an effective amount of a compound of formula (1) or a physiologically acceptable salt or solvate thereof.

Accordingly, the invention also provides a pharmaceutical composition which comprises at least one compound selected from compounds of the general formula (1), and their physiologi- 50 cally acceptable salts and solvates e.g. hydrates, adapted for use in human or veterinary medicine, and formulated for administration by any convenient route.

Such compositions may be formulated in conventional manner using one or more physiologi cally acceptable carriers or excipients.

Thus the compounds according to the invention may be formulated for oral, buccal, parenteral 55 or rectal administration or in a-form suitable for administration by inhalation or insufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such 'as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxylpropyl 60 methyleellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, tale or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agens (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for 65 3 GB2192885A 3 constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyi-p- hydroxybenzoates or sor- 5 bic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

For buccal administration the compositions may take the form of tablets or lozenges formu- 10 lated in conventional manner.

The compounds of the invention may be formulated for parenteral administration by injection. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multidose containers, with an added preservative. The compositions may take such forms as suspen- sions, solutions or emulsions in oily or aqueous vehicles. and may contain formulatory agents 15 such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa 20 butter or other glycerides.

In addition to the formulations described previously, the compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or 25 hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs or a nubuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlo30 rotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch. 35 A proposed dose of the compounds of the invention for administration to man (of approxi mately 70kg body weight) is 0,05 to 10Orng, preferably 0.1 to 5Orng of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition 9f the patient. The dosage will also depend on the route of administration. 40 According to another aspect of the invention, compounds of general formula (1) and physiologi cally acceptable salts or solvates thereof may be prepared by the general methods outlined hereinafter. In the following description, the groups R' to R' are as defined for compounds of general formula (1) unless otherwise stated.

According to a fifst general process (A), a compound of formula (1) may be prepared by 45 alkylating a compound of formula (11) 0 R4 R5 50 CH21 C:) 1 W T_ H R2 (11) 1 R' - 55 or a salt or a protected derivative thereof, using an alkylating agent, followed where necessary by rerpoval of any protecting groups.

Alkylating agents which may be used in the above process according to the invention include 60 compounds of formula R5Z, where Z represents' a leaving atom or group such as a halogen atom (e.g. chlorine, bromine or iodine), an acyloxy group (e.g. trifluoroacetyloxy or acetoxy), or a sulphonyloxy group (e.g. trifluoromethanesulphonyloxy, ptoluenesulphonyloxy or methanesulpho nyloxy); or a sulphate of formula (R1)2SO, The alkylation reaction is conveniently carried out in an inert organic solvent such as a 65 4 GB2192885A 4 substituted amide (e.g. dimethylformamide), an ether (e.g. tetrahydrofuran) or an aromatic hydro carbon (e.g. toluene), and in the presence of a base. Suitable bases include, for example, alkali metal hydrides (e.g. sodium hydride), alkali metal amides (e.g. sodium amide or lithium diisopro pylamide), and alkali metal alkoxides (e.g. sodium or potassium methoxide, ethoxide or t-butox ide). The reaction may conveniently be effected a temperature in the range -80 to +100'C, 5 preferably -80 to +25'C.

It will be appreciated that when it is desired to prepare a compound of formula (1) in which R' represents a hydrogen atom by the above process (A), it will be necessary to protect the carbazolone nitrogen atom in order to prevent it from being alkylated by the alkylating agent.

The protecting group may be a conventional protecting group such as those described in 10 -Protective Groups in Organic Synthesis- by Theodora W. Greene (John Wiley and Sons 1981), referred to hereinafter.

The compounds of formula (11) may be prepared by the methods described in UK patent specification no. 2153821A and methods analogous to those described therein.

According to another general process (B), a compound of general formula (1), or a salt or 15 protected derivative thereof, may be converted into another compound of formula (1) using conventional techniques. Such conventional techniques include hydrogenation, alkylation and acylation.

Thus, for example, hydrogenation may be used to convert an alkenyl or an alkynyl substituent into an alkyl substituent, or an alkynyl into an alkenyl substituent. 20 Hydrogenation according to general process (B) may be effected using conventional proce dures, for example using hydrogen in the presence of a noble metal catalyst (e.g. palladium, Raney nickel, platinum or rhodium). The catalyst may be supported on, for example, charcoal, or alternatively a homogeneous catalyst such as tris(triphenylphosphine)rhodium chloride may be used. The hydrogenation will generally be effected in a solvent such as an alcohol (e.g. ethanol), 25 an ether (e.g. dioxan), or an ester (e.g. ethyl acetate), and at a temperature in the range -20 to + 1 00'C, preferably 0 to 50'C.

Alkylation according to general process (B) may be effected for example on a compound of formula (1) where one or both of R' and R2 represent a hydrogen atom.

The term 'alkylation' also includes the introduction of other groups such as cycloalkyl or 30 alkenyl groups. Thus, for example, a compound of formula (1) in which R' represents a hydrogen atom may be converted into the corresponding compound in which R, represents a Cl-10 alkyl, C3-, cycloalky], C,-, alkeny], C,-, alkynyi, C3-7CYCI0alky1C1-,alkyl or pheny1C1-3alkyl group.

The above alkylation reactions may be effected using the appropriate alkylating agent selected from compounds of formula R8Z where R8 represents a C,10 alky], C3-, cycloalky], C3-, alkeny], 35 C3-, alkynyi, C3-7 cycloalky[C,-,alkyl or pheny1C1-,alkyl group, and Z represents a leaving atom or group such as a halogen atom or an acyloxy or sulphonyloxy group as previously defined for Z; or a sulphate of formula (F18),SO, The alkylation reaction is conveniently carried out in an inert organic solvent such as a substituted amide (e.g. dimethylformamide), an ether (e.g. tetrahydrofuran) or an aromatic hydro- 40 carbon (e.g. 1 toluene), preferably in the presence of a base. Suitable bases include, for example, alkali metal hydrides (e.g. sodium hydride), alkali metal amides (e.g. sodium amide or lithium diisopropylamide), qikaii metal carbonates (e.g. sodium carbonate) or an alkali metal alkoxide (e.g.

sodium or potassium methoxide, ethoxide or t-butoxide). The reaction may conveniently be effected a temperature in the range -20 to +10M, preferably 0 to 5M. 45 Acylation according to general process (B) may be used to prepare compounqs of formula (1) wherein R' represents -C02R6, -COR6, -CONR6R7 or -S02R6, from a compound of formula (1) wherein R' represents a hydrogen atom. The acylation reactions may be effected according to conventional procedures using an appropriate acylating agent.

It should be appreciated that in the above transformations it may be necessary or desirable to 50 protect any sensitive groups in the molecule of the compound in question to avoid undesirable side reactions. For example, it may be necessary to protect the keto group, for'example, as a ketal or a thioketal. It may also be necessary to protect the carbazolone nitrogen atom, for example with an aryimethyl (e.g. benzyl or trityl) group.

Thus according to another general process (C), a compound of formula (1) may be prepared by 55 the removal of any protecting groups from a protected form of a compound of formula (1).

Deprotection may be effected using conventional techniques such as those described in 'Protec tive Groups in Organic Synthesis' by Theodora W. Greene (John Wiley and Sons, 1981).

For example a ketal such as an alkyleneketal group may be removed by treatment with a mineral acid such as hydrochloric acid. A thioketal group may be cleaved by treatment with a 60 mercuric salt, (e.g. mercuric chloride), in a suitable solvent, such as ethanol. An aryimethyl N protecting group may be cleaved by hydrogenolysis in the presence of a catalyst (e.g. palladium on charcoal) and a trityl group may also be cleaved by acid hydrolysis (e. g. using dilute hydrochloric or acetic acid).

Where it is desired to isolate a compound of the invention as a salt, for example a physiologi- 65 GB2192885A 5 cally acceptable salt, this may be achieved by treating the free base of general formula (1) with an appropriate acid, preferably with an equivalent amount, in a suitable solvent such as an alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetate) or an ether (e.g. tetrahydrofuran).

Physiologically acceptable equivalents of a compound of formula (1) may be prepared according to conventional methods. 5 Individual enantiomers of the compounds of the invention may be obtained by resolution of a mixture of enantiomers (e.g. a racemic mixture) using conventional means, such as an optically active resolving acid; see for example 'Stereochemistry of Carbon Compounds' by E.L.Eliel (MeGraw Hill 1962) and 'Tables of Resolving Agents' by S. H. Wilen.

The methods indicated above for preparing the compounds of the invention can be used as 10 the last main step in the preparative sequence. The same general methods can be used for the introduction of the desired groups at an intermediate stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different ways in such multi-stage processes. The sequence of the reactions in multi-stage processes should of course be chosen so that the reaction conditions used do not affect groups 15 in the molecule which are desired in the final product.

The following Example illustrates the invention. All temperatures are in 'C.

Example 1

1,2,3,9-Tetrahydro-3,9-dimethyl-3[(2-methyl-1H-imidazol-l-yl)methyll-4Hcar bazol-4-one 4-methyl- 20 benzenesulphonate n-Butyllithium (1.37mi of a 1.53M solution in hexane) was added dropwise at -78', under nitrogen, with stirring, to a solution of diisopropylamine (0.30m1) in dry tetrahydrofuran (5mi) and the solution stirred at -5 to 0' for 30 min. The solution was cooled to - 78' and added via a cannula to 1,2,3,9-tetrahydro-9-methyi-3-[(2-methyi-1H-imidazol-lyl)methyll-4H-carbazo l-4-one 25 (500m9) at -78' under nitrogen with stirring. After 5.5h at -78' iodomethane (0.13mi) was added and stirring at -78' continued for 2h, then at room temperature for 13h. The mixture was treated with saturated aqueous ammonium chloride (30mi), extracted with chloroform (5x30mi), and the combined, dried (Na2S04) organic extracts were evaporated. The residue was combined with the residues obtained from three other identical reactions and crystallised from 30 ethyl acetate. The precipitate was filtered off and discarded, and the mother liquors were evaporated. The residual foam was purified by HPLC (using a 170 x 8mm column of 5 urn Spherisorb silica gel and a Gilson Autoprep machine), eluting with hexane- chloroform-ethanol 0.880 ammonia (476:476:48 1: 1) to give the free base of the title compound (1 72m9). A hot solution of 4-methylbenzenesulphonic acid monohydrate (104mg, 0.55mmol) in ethanol (2m]) was 35 added and on cooling the title compound crystallised as fine white needles (180mg), m.p.

115-120'.

Analysis Found: C,63.8; H,6.7; N,8.0. Cl,H,1N,O.CH,O,S.O.84 C21-1,0.0.181120 requires C,63.75; H,6.65;N,8.1%. Water Assay Found: 0.62% w/w20.18mol H20.

The following examples illustrate pharmaceutical formulations according to the invention. The 40 term---activeingredient- is used herein to represent a compound of formula (1).

TABLETS FOR ORAL ADMINISTRATION Tablets may be prepared by the normal methods such as direct compression or wet granulation.

The tablets may be film coated with suitable film forming materials, such as hydroxypropyl 45 methylcellu lose, using standard techniques. Alternatively the tablets may be sugar coated.

Direct Compression Tablet mgItablet 50 Active Ingredient 5.00 Calcium Hydrogen Phosphate BP 82.75 Croscarmellose Sodium NF 1.8 Magnesium Stearate BP 0.45 Compression weight 90.0 55 of a grade suitable for direct compression.

The active ingredient is passed through a 60 mesh sieve, blended with the calcium hydrogen phosphate, croscarmellose sodium and magnesium stearate. The resultant mix is compressed 60 into tablets using a Manesty F3 tablet machine fitted with 5.5mm, flat bevelled edge punches.

Tablets of other strengths may be prepared by altering the ratio of active ingredient to excipients or the compression weight and using punches to suit.

6 GB2192885A 6 INJECTION FOR INTRAVENOUS ADMINISTRATION Mg1M1 Active Ingredient 0.5 Sodium Chloride BP as required 5 Water for Injection BP to 1.0m] Sodium chloride maybe added to adjust the tonicity of the solution and the pH may be adjusted, using acid or alkali, to that of optimum stability and/or facilitate solution of the active ingredient. Alternatively suitable buffer salts may be used. 10 The solution is prepared, clarified and filled into appropriate size ampoules sealed by fusion of the glass. The injection is sterilised by heating in an autoclave using one of the acceptable cycles. Alternatively the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen or other suitable gas. 15

Claims

1. Compounds of the general formula (I):

0 R4 R3 20 R5 N N N R2 M 25 1, R wherein R' represents a hydrogen atom or a group selected from Cl-, alkyl, C3-7 cycloalkyl, C3-7 30 cycloalky]C,-,aikyi, C3-, alkenyl, C3-1, alkynyi, phenyl, pheny1C1-3alkyl, -C02R6, -COR6, -CONR6R1 or -SO,R6 (wherein R6 and R7, which may be the same or different, each represents a hydrogen atom, a C,-, alkyl or C3-7 cycloalkyl group, or a phenyl or phenyl C1-4 alkyl group, in which the phenyl group is optionally substituted by one or more Cl-, alky], Cl-, alkoxy or hydroxy groups or halogen atoms, with the proviso that R6 does not represent a hydrogen atom when R' 35 represents a group -CO,R6 or -S02R6); one of the groups represented by R2, R3 and R4 is a hydrogen atom or a C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl or phenylC,- 3alkyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C,-, alkyl group; and R5 represents a Cl-, alkyl group; and physiologically acceptable salts and solvates thereof. 40

2. Compounds according to claim 1, wherein in the general formula (1), R' represents a hydrogen atom or a C1-3 alkyl, C3-, cycloalkyl or C3-6 alkenyl group.

3. Compounds according to claim 1, wherein in the general formula (1), one of the groups represented by R 2, P3 and R4 represents a C,_, alky], C3-6 cycloalkyl or C3-6 alkenyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom 45 or a C1-3 alkyl group.

4. Compounds according to claim 1 or 3, wherein in the general formula (1), R2 represents a Cl, alkyl group and R3 and R4 both represent hydrogen atoms.

5. Compounds according to claim 1, wherein in the general formula (1), R5 represents a C1-3 alkyl group. 50

6. Compounds according to claim 1, wherein in the general formula (1), R, represents a methyl group, R2 represents a methyl group, R3 represents a hydrogen atom, R4 represents a hydrogen atom and R 5 represents a Cl-, alkyl group.

7. 1,2,3,9-Tetrahydro-3,9-dimethyi-3[(2-methyi-1H-imidazol-l-yi)methyll4H-carb azol-4-one and physiologically acceptable salts and solvates thereof. 55

8. A pharmaceutical composition which comprises at least one compound selected from compounds of the general formula (1) as defined in claim 1, and their physiologically acceptable salts and solvates, together with one or more physiologically dcceptable carriers or excipients.

9. A process for the preparation of a compound of general formula (1) as defined in claim 1 or a salt thereof which comprises 60 (A) alkylating a compound of general formula (II):

7 GB2192885A 7 R4 R5 _N 5;- 1 1 "", H 5 R2 (II) 10 (wherein W, R2, R3 and R4 are as defined in claim 1), or a salt or a protected derivative thereof; or (B) subjecting one compound of general formula (1) as defined in claim 1, or a salt or protected derivative thereof to a conventional interconversion reaction to form another compound 15 of general formula (1) as defined in claim 1, or a salt or protected derivative thereof; or (C) subjecting a protected derivative of a compound of general formula (1) or a salt thereof to reaction to remove the protecting group or groups; and if necessary and/or desired subjecting the compound obtained from step (A), (B) or (C) to one or more further reactions comprising (1) removing any protecting group or groups; 20 (2) converting the resulting compound of general formula (1) or a salt thereof into a physiolog ically acceptable salt or solvate thereof; and (3) where the compound of general formula (1) is obtained as a mixture of enantiomers, optionally resolving the mixture to obtain the desired enantiomer.

10. Compounds according to claim 1, wherein in the general formula (1), R' represents a 25 hydrogen atom, or a C,,o alky], C,-, cycloalky], C,-, alkeny], phenyl or pheny1C1-,alkyl group, and R2, F13, R 4 and R5 are as defined in claim 1.

Published 1988 at The Patent Office, State House, 66/71 High Holborn, London WC 1 R 4TP. Further copies may be obtained from The Patent Office, Sales Branch, St Mary Cray, Orpington, Kent BIRS 3RD. Printed by Burgess & Son (Abingdon) Ltd. Con. 1/87.