GB2202530A - Tricyclic ketones - Google Patents

Description

TRICYCLIC KETONES 1-5 211- 2 5 3 c This invention relates to tricyclic

ketches, to processes for their preparation, to pharmaceutical 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.

Thus for example published UK Patent Specification No.2153821A and published European Patent Specification No. 191562 disclose tetrahyorocarDazolones of the general formula

0 R 4 R 3 1 CH 2\ 0-01 N N # 2 N R 1 R wherein R1 represents a hydrogen atom or a Cl-loalkyl, C3-7cycloalkyl, C3- 7cYclOalkylCl4alkyl, C3-6 alkenyl, C3-10alkynyl, phenyl or pheny1C1- 3alkyl group, and one of the croups represented by R2, R3 and R 4 is a hydrogen atom or a Cl-6alkyl, C3-7cYcloalkyl, C2-6alkenyl or pheny1C1- 3alkyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1-6 alkyl group.

We have now found a novel aroup 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, in one aspect the present invention provides a tricyclic ketone of the general formula M:

4 0 B A c 2) 1H N Im 2 ( I) wherein Im represents an imidazolyl group of the formula / R4 -0 0 i-i N % / NR' 0 1 2 or R 3N N R 2 R 4 R1 represents a hydrogen atom or a group selected from Cl-6alkyl, C3-6 alkenyl, C3-10 alkynyl, C3-7 cycloalkyl, C3-7CYCloalky1C1-4alkyl, phenyl, pheny1C1-3alkyl, -C02R5, -COR5, -CONRSR6 or -S02R5 (wherein RS ano R6, which may oe the same or different, each represents a hydrogen atom, a C16 alkyl or C3-7 cycloalkyl group, or a phenyl or pheny1C1-4alkyl group, in which the phenyl group is optionally suostituted by one or more C1-4 alkyl, C1-4 alkoxy or hydroxy groups or halogen atoms, with the proviso that RS does not represent a hydrogen atom when R1 represents a Qroup C02RS or -SO2R5); one of the groups represe nted by R2, R3 and R4 is a hydrogen atom or a C1-6 alkyl, C3-7 cycloalkyl, C3-6 alkenyl, phenyl or pheny1C1-3alkyl group, ana each of the other two groups, which may be the same or different, represents a hydroqen atom or a C1-6 alkyl aroup; Q represents a hydrogen or a halogen atom, or a hyaroxy, C1-4 alkoxy, pheny1C1-3alkoxy or C1-6 alkyl group or a aroup -NR7R8 or -CONR7R8 wherein R7 and R8, which may oe the same or different, each represents a hydrogen atom or a C1-4 alkyl or C3-4 alkenyl group, or together with the nitrogen atom to which they are attached form a saturated 5 to 7 meMDered ring); n represents 1, 2 or 3; and A-B represents the group CH-CH2 or C=CH; and physiologically acceptable salts and solvates thereof.

1 i 35 SultaDle physiologically acceptable salts of the compounds of general formula (I) include acid addition salts formed with organic or inorganic acids for example, hyarochlorides, hydrODromides, sulphates, alkyl- or arylsulphonates (e.g. methanesulphonates or ptoluenesulphonates), phosphates, acetates, citrates, succinates, tartrates, fumarates and maleates. The solvates may, for example, be hydrates.

It will be appreciated that when A-B represents CH-CH2 the carbon atom A is asymmetric and may exist in the R- or S- confiauration. Furthermore, dependina on the nature of the suostituents A-B, Rl R27 R3 Y R4 and Q, centres of optical and Qeometric isomerism may occur elsewhere in the molecule. All optical isomers of compounds of aeneral formula (I) and their mixtures includinq the racemic mixtures thereof, and all the oeometric isomers of compounds of formula (I), are emoraced by the invention.- Referring to the general formula (I), the alkyl Qroups represented by RI, R2y R3y R4y R5v R6y R7, R8 and n may be straight chain or branched chain alkyl groups, for example, methyl, ethyl, propyl, prop2-yl, butyl, but-2-yl or 2-methylprop-2-yl, and, in the case of RlR6 and Q, pentyl, pent-3-yl or hexyl. An alkenyl group may be, for example, a propenyl or butenyl group. An alkynyl group may be, for example, a prop-2ynyl or oct-2-ynyl group.

It is understood that when R1 or R3 represents a C3-6alkenyl group or R 1 represents a C3-10 alkynyl group, or R7 or R8 represents a C3-4 alkenyl group, the double or triple bond may not be adjacent to the nitrogen atom.

A phenylCl3 alkyl aroup (as such or as part of a pheny1C1-3alkoxy group) may be, for example, a benzyl, phenethyl or 3-phenylpropyl aroup. A cycloalkyl aroup (as such or as part of a cycloalkylalkyl group) may oe, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl qroup. When R1 represents a C3-7 cycloalkyl C1-4 alkyl group, the alkyl moiety may be, for example, a methyl, ethyl, propyl, prop-2-yl or butyl group. When Q represents a C1-4 alkoxy group it may be, for example, a methoxy group. When Q represents a halogen atom it may be, for example, a 4 - 4 fluorine, chlorine or bromine atom. The substituent Q may be at the al b, c or d position of the indole moiety:

a N d 1 A preferred class of compounds of formula (I) is that wherein R1 represents a hydrogen atom or a Cl-j alkyl fke.g. methyl), C3-4 alkenyl (e.g. prop-2-enyl), C3-4 alkynyl (e.q. prop-2ynyl), CS-6cycloalkyl,,e.g. cyclopentyl), CS-6cycloalkylmethyl (e.g. cyclopentylmethyl), pheny1C1-2 alkyl (e.g. benzy0J, C1-3 alkoxycarbonyl (e.q. methoxycarbonyl), N,N-diCl3alkylcarboxamido (e.g. N,Ndimethylcarboxamido) or phenylsulphonyl group. More preferably R' represents a hydrogen atom or a C1-3 alkyl fke.q. methyl), C3-4 alkenyl (e.q. prop-2-enyl), C3-4 alkynyl (e.g. prop-2-ynyl), CS-6cycloalkylmethyl (e.a. cyclopentylmethyl), phenyl C alkyl 1-2 (e.g. benzyl), C1-3 alkoxycarbonyl (e.g. methoxycarbonyl), or N,-diCl3alkylcarboxamido (e.g. N,Ndimethylcarboxamido) aroup. Most preferably R1 represents a hydrogen atom or a C1-3 alkyl (e.a. methyl), C3-4 alkenyl (e. g. prop-2enyl), C3-4alkynyl (e.g. prop-2-ynyl), C5-6 cycloalkylmethyl (e. q. cyclopentylmethyl), pheny1C1-2 alkyl (e.g. benzyl) or N,N-diCl3alkylcarboxamido (e.g. N,N-dimethylcarboxamido) group.

Another preferred class of compounds of formula (I) is that wherein R2 represents a hydrogen atom or a C1-3 alkyl (e.g. methyl) group, more preferably a hydrogen atom.

Another preferred class of compounds of formula (I) is that wherein R3 represents a hydrogen atom or a C1-3 alkyl (e.g. methyl) group, more preferably a hydrogen atom.

A further preferred class of compounds of formula (I) is that wherein R4 represents a hydrogen atom or a C1-3 alkyl (e.g. methyl) group. Most preferably R4 represents a methyl group.

Another preferred class of compounds of formula (I) is that wherein Q represents a hydrogen atom, a halogen (e.g. fluorine) atom Z T Z 1 is or a hydroxy, 8 C1-3 alkoxy (e.a. methoxy) or a C1-3 alkyl (e.g. methyl) group. More preferably Q represents a hydrogen atom, a halonen (e.g. fluorine) atom or a hydroxy croup. Most preferably Q represents a hydrogen or a fluorine atom.

When Q represents a substituent other than a hydrogen atom, Q is preferably at the b- or c- position of the indole moiety.

Another preferred class of compounds of formula (I) is that wherein A-B represent CH-CH2.

A further preferred class of compounds of formula (I) is that wherein n represents 2 or 3, more particularly 2.

A preferred group of compounds of formula (1) is that wherein R1 represents a hydrogen atom or a C1-3 alkyl, C3-4alkenyl, C3-4alkynyl, CS6cYcloalkylmethyl, phenyl C1-2 alkyl, Cl-3alkoxycarbonyl or N,N-diCl3alkylcarboxamido group; R2 and R3 each represent a hydrogen atom; R4 represents a hydrogen atom or a C1-3 alkyl croup; Q represents a hydrogen or a halogen atom or a hydroxy group; A-B represents CH-CH2 or C=CH; and n represents 2 or 3.

A particularly preferred croup of compounds of formula (1) is that wherein R' represents a hydrogen atom or a methyl, prop-2-enyl, prop-2- ynyl, cyclopentylmethyl, benzyl or N,N-dimethylcarboxamido group; R2 and R3 each represent a hydrogen atom; R4 represents a methyl group; Q represents a hydrogen or a fluorine atom; A-B represents CH-CH2; and n represents 2 or 3.

Within the above preferred and particularly preferred aroups of compounds an especially important group of compounds is that in which n represents 2.

Preferred compounds according to the invention are: 6-fluoro-1 2,3,9tetrahydro-9-methyl-3-[ (5-methyl-1H-imidazol-4-yl)methyl]-4H-carbazol-4one; 1,2,3,9-tetrahydro-3-[(5-methyl-1H-imidazol-4-yl)methyll-4H-carbazol 4-one; 9-(cyclopentylmethyl)-1,2,3,9-tetrahydro-3-[(5-methy1-1H-imidazol4yl)methyll-4H-carbazol-4-one; - 6 1,2,3,9-tetrahydro3-[(5-methyl-1H-imidazol-4-yl)methyll-9-(2propynyl)-4Hcarbazol-4-one; a further preferred compound according to the invention is 6p 7 8 9-tetrahydro-5-methyl-9-[(5-methyl-1H-imidazol-4yl)methyllcyclohept[blindol-10(5H)-one; and their physiologically acceptable salts and solvates.

A particularly preferred compound according to the invention is 1,2,3,9tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yljmethyl1-4Hcaroazol-4one and its physiologically acceptable salts and solvates (e.g. hydrates).

Preferred forms of this compound are the hydrochloride and the maleate. A particularly preferred Form is the hydrochloride monohydrate.

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

Compounds of the invention are potent and selective antagonists of 5-HTinduced responses of the rat isolated vagus nerve preparation and thus act as potent and selective antaaonists of the 'neuronal' 5-HT receptor type located on primary afferent nerves. Receptors of this type are now desianated as 5-HT3 receptors. Such receptors are also present in the 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 behavioural syndromes such as mood, psychomotor activity, appetite and memory.

Compounds of formula (I), which antagonise the effect of 5-HT at 5-HT, receptors, are useful in the treatment of conditions such as psychotic disorders (e.g. schizophrenia and mania); anxiety; and nausea and vomiting, particularly that associated with cancer chemotherapy and radiotherapy. Compounds of formula (I) are also useful in the treatment of gastric stasis; symptoms of gastraintestinal dysfunction such as occur with dyspepsia, peptic ulcer, reflux oesophagitis, flatulence and irritable bowel syndrome; migraine; and pain. Compounds of formula (I) may also be used in the treatment of dependency an drugs and substances of abuse, depression and dementia and other cognitive disorders.

9 1 ZI 7 Unlike existing drug treatments for certain of the above conditions, the compounds of the invention, because of their high selectivity for 5-HT3 receptors, would not be expected to produce undesirable side effects. Thus, for example, neuroleptic drugs may exhibit extrapyramioal effects, such as tardive dyskinesia, and oenzooiazepines 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, particularly that associated with cancer chemotherapy and radiotherapy; gastric stasis; symptoms of gastrointestinal dysfunction such as dyspepsia, reflux oesophaqitis, peptic ulcer, flatulence and irritable Dowel synarome; miQraine; or pain, which comprises administering an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.

Accordinqly, the invention also provides a pharmaceutical composition which comprises at least one compound selected from tricyclic ketones derivatives of the aeneral formula (I), their physiologically acceptable salts and solvates (e.c. hydrates) 1 JI 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 physiologically acceptable carriers and/or excipients.

Thus the compounds according to the invention may oe formulated for oral, buccal, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or the 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. pregelatiniseo maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch qlycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in - 8 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 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 j; non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.Q. methyl or propyl-p- hydroxybenzoates or sarbic acid). The preparationS 3y also contain buffer salts, flavouring, colouring and sweetening a,,z;nts as appropriate.

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

ror buccal administration the compositions mav take the form of tablets or lozennes formulated in conventional manner.

The compounds of the invention may be formulated for parenteral administration by injection e.q. by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosaae form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents 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 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, transcutaneously or intramuscularly)- or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable 9 1 polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparinaly 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 nebuliser, with the use of a Suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable nas. In the case of a pressurised aerosol the dosaae unit may be determined oy providina 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 tne invention and a suitaole powder oase such as lactose or starch.

ror intranasal administration, the compounds according to the invention may be formulate-d as solutions for administration via a suitaole metered or unit dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.

The compounds of formula (I) may also be administered in combination with other therapeutic agents. Thus, for example, in the treatment of gastric stasis, symptoms of aastrointestinal dysfunction, and nausea and vomiting, the compounds of formula (I) may be administered in combination with antisecretory auents such as histamine H2-receptor antaaonists (e.a. ranitidine, sufotidine or loxtidine) or H+K+Wase inhibitors (e.a. ameprazole).

A proposed dose of the compounds of the invention for administration to man (of approximately 70ka body weiaht) is 0.001 to 100mq, for example 0. 01 to 50mq, more preferably 0.1 to 20ma of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day. The dose will depend on the route of administration and the condition Deing treated. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated.

According to another aspect of the invention, compounds of qeneral formula (1), and physiologically acceptable salts or solvates thereof, may be prepared by the general methods outlined hereinafter. In the following.description, the groups R1, R2, R3, R4, A, B, Q, n

0 is and Im are as defined for compounds of aeneral formula (I) unless otherwise stated.

According to a first general process (A), a compound of qeneral formula (I) wherein A-B represents the aroup C=CH, may be prepared b dehydratinq a compound of formula (II):

Q 0 OH N (I I) or a protected derivative thereof, followea where necessary by removal of any protecting groups.

The dehydration process may be effected using conventional methods, for example by using an organic or mineral acid (e.g.

ptoluenesulphonic, methanesulphonic, trifluoroacetic or hydrochloric acidy' in a suitable solvent such as an ether (e.g. tetrahvorofuran), an alcohol (e.g. methanol), or alacial acetic acid, at a temperature in the ranue 0 to 1000C.

Accordina to a particular embodiment of this process, a compound of general formula (I), wherein A-B represents the qrouo C=CH, may be prepared directly by the reaction of a compound of formula (III):

Q 0 (CH 2) NI R n (III) or a protected derivative thereof, with a compound of formula (IV):

OHC - Im (IC or a protected derivative thereof, in the presence of a base such as an alkali metal amide (e.g. lithium diisopropylamide) in an inert solvent such as an ether (e.g. tetrahydrofuran). The dehydration is then performed in situ using the appropriate conditions described R 72 above, followed where necessary by deprotection. Compounds of formula (II) may be isolated as intermediates in this particular embodiment of process (A).

According to a further embodiment of this process, a compound of general formula (1), wherein A-B represents the group C=CH, may be prepared oy convertinc the hydroxy Qroup of a compound of formula (II), into a leavinQ qroup such as a hydrocarbylsulphonate (e.c. a mesylate or a trifluoromethanesulphonate) using conventional methods, in the presence of a base (e.a. triethylamine or acueous sodium hydroxide) in a solvent such as an ether (e.o. tetrahvdrofuren. or an alcohol (e.a. methanol).

Accoraina to another general process (B), a compound of general formula (I) may be converted into another compound of formula 'Ill usinQ conventional techniques. Such conventional techniaues include hydrogenation, alkylation, acylation and acid-catalysed cleavage using protection ano ceprotection where necessary.

Thus, according to one emoodiment of the interconversion process f\. B)Icompounds of formula (I) in which A-B represents the qroup CHCH2 and R1 is other than a C3-6 alkenyl or a C3-10 alkynyl oroup, and/or Q is other than a benzyloxy group may be prepared by hydrogenating the corresponding compounds in which A-B represents the group C=CH. Hydrogenation may also be used to convert an alkenyl or an alkynyl substituent into an alkyl substituent or an alkynyl into an alkenyl substituent, or a benzyloxy substituent into a hydroxyl group.

Hydrogenation according to general process (B) may be effected using conventional procedures, for example using hydroaen in the presence of a noble metal catalyst (e.g. palladium, Raney nickel, platinum or rhodium). The catalyst may be supported on, for examole, charcoal, alumina or alternatively a homoneneous 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. methanol or ethanol), an ether (e.g. dioxan), a halogenated hydrocarbon (e.g. dichloromethane) or an ester (e.g. ethyl acetate or mixtures thereof, and at a temperature in the range -20 to +1000C, preferably 0 to 500C.

12 According to another embodiment of the interconversion process (B), a compound of formula (1) in which R1 represents a C1-6 alkyl, C3-7 cycloalkyl, C3-6 alkenyl, C3-10 alkynyl, C3-7 cycloalkylCl4- alkyl or phenyl C1-3 alkyl group, or a compound in which at least one of R 2 and R 3 represents a Cl6 alkyl, C3-7 cycloalkyl, C3-6 alkenyl or phenyl C1-3 alkyl group or a compound in which Q represents a C1-4 alkoxy or a phenyl "1-3 alkoxy group or a compound in which R7 and/or R3 represents a C1-4 alkyl Or C3-4 alkenyl grouO may be prepared by alkylatinc a compound of Formula where one or more of R1, R2 R3 R7 and R8 represent a hydroaen atom, or Q reoresents a hydroxyl group.

The term 'alkylation' accordinQ to ceneral process 13 tnus also includes the introouction of other Qroups such as cycloalkyl, alkenyl or phenalkyl Qroups.

The above alkvlation reactions mav 0e effected usinQ the appropriate alkylating agent selected from compounds of Formula R97 alkyl, cycloalkvl, where R9 represents a C1-6 C3-7 C3-6 alkenyl, C3-10 alkynyl, C3-7 cycloalky1C1-4 alkyl, or phenvIC1-3alkyl group, and Z represents a leaving atom or group such as a halogen atom (e.g.

chlorine, oromine or iodine , an acyloxy group (e.q.

tri'lluoroacetyloxy or acetoxy), or a sulphonyloxy group e.g.

trifluoromethanesulphonyloxy, p-toluenesulphonyloxy or methanesulphonyloxy); or a sulphate of formula (R9)2S04.

The alkylation reaction is conveniently carried out in an inert orQanic solvent such as a substituted amide (e.Q. dimethylformamide, an ether (e.g. tetrahydrofuran) or an aromatic hydrocarbon (e.g.

toluene), preferably in the presence of a base. Suitable bases include, for example, alkali metal hydrides (e.q. sodium hydride), alkali metal amides (e.g. sodium amide or lithium diisopropylamide), alkali 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 at a temperature in the range -80 to +1000C, preferably -80 to +500C.

According to another embodiment of general process (B), a compound of formula (I) wherein R1 represents -C02R5, -COR5, -CONR5R6 or -S02RS may be prepared by acylating a compound of formula (I) 4 - 13 wherein R' represents a hydrogen atom. The acylation reactions may be effected using an appropriate acylating agent according to conventional procedures.

Suitable acylating agents include acyl halides (e.g. an acyl, alkylsulphonyl, or arylsulphonyl chloride, bromide or iodide), mixed and symmetrical anhydrides (e.g. a symmetrical anhydride of formula (R5C0) O 2 J, lowe.- alkvl haloformates (e.q. lower alkyl chloroformates), sulphonates (e.a. hydrocarbylsulphonates such as p-toluenesulphonate), carbamoyl halides (e.q. carbamoyl chlorides of formula R5R6NCOC1, carbonates and isocyanates (e.a. iso-cvanates of fo r.m u 1 a R SNC 0 The reaction may conveniently be effected in the presence of a base such as an alkali metal hvdride (ea. sodium or potassium hydride'., an alkali metal carbonate (e.a. sodium or potassium caroonate), an alkali metal alkoxide (e.g. potassium t-butoxide), butyllithium, lithium diisopropylamide or an organic tertiary amine (e.g. triethylamine or pyridine).

Suitable solvents which may be employed in the acylation of general process (B) include amides (e.g. dimethylformamide or dimethylacetamide), ethers (e.g. tetrehydro Furan or dioxan), halogenated hydrocarbons (e.g. methylene chloride), nitriles (e.g. acetonitrile) and esters (e.g. ethyl acetate). The reaction may conveniently be effected at a temperature of from -10 to +1500C.

According to a yet further embodiment of general process (B), a compound of formula (I) in which Q represents a hydroxyl group may be prepared from the corresponding compound in which Q represents an alkoxy or benzyloxy group by acid-catalysed cleavage. The reaction may be effected using a Lewis acid such as boron tribromide or aluminium trichloride, in a solvent such as a halogenated hydrocarbon (e.q. dichloromethane). The reaction temperature may conveniently be in the range -80 to +1000C.

According to another general process (C), a compound of general formula (I), wherein A-B represents the group CH-CH2, may be prepared by reacting a compound of formula (III) or a protected derivative thereof, with a compound of formula (V):

LCH 2 - IM (V) wherein L represents a leaving atom or group, such as a halogen atom or an acyloxy or Sulphonyloxy group as previously aefineo for Z, or a protected derivative thereof, in the presence of a base, followed where necessarv oy removal of any protectina croups. Suitable oases include alkali metal hydrides \.e.g. sodium or potassium hydride' alkali metal alkoxides e.g. potassium- t-outoxidei or alkali metal amides (e.q. lithium diisoPropylamide). The reaction may conveniently 1 be carried out in an inert solvent such as an ether e.a. tetrahvdrofuran a substituted amide (e.q. dime"hvlformamidei, or an aromatic hydrocarbon e.(j. toluenej' and at a temperature in the ranee -80 to +50'C.

Accordinc to another general process '\D', a compound of ueneral formula fi wherein A-B represents the Qrouo CH-CH2, mav be prepared by oxidisinc a compound of formula f\,vil:

A Im -CH2) N 1 R1 ( ' VI wherein A represents a hydrogen atom or a hydroxyl group, or a salt or protected derivative thereof, followed where necessary by removal of any protecting groups.

The oxidation process may be effected using conventional methods and the reagents and reaction conditions should be chosen such that they do not cause oxidation of the indole moiety or other functional groups. Thus, the oxidation process is preferably effected using a mild oxidising agent.

When oxidising a compound of formula (VI) in which A represents a hydrogen atom, suitable oxidising aqents include quinones in the presence of water (e.g. 2,3-dichloro-5,6-dicyano-1,4-benzoauinone or 2,3,5,6tetrachloro-1,4-benzoquinone), selenium dioxide, cerium (IV) oxidising reagents (e.g. ceric ammonium nitrate) and chromium (VI) 1 51 F oxidising aqents (e.g. a solution of chromic acid in acetone, for example Jones' reagent, or chromium trioxide in pyridine).

When oxidising a compound of formula (VI) in which A represents a hydroxyl group, suitable oxidising agents include quinones in the presence of water ( e.a. 2,3-dichloro-5,6-dicyano-1,4-Denzoauinone or 2,3,5,6-tetrachloro-1,4- oenzoquinone), ketones (e.g. acetone, methyletnylketone or cyclohexanone) in the presence of a base (e.q. aluminium t-outoxiJde, ) chromium (VI) oxidising agents (e.g. a solution of chromic acid in acetone, for example Jones reagent, or chromium t,,ioxide in pyridine',, N-halosuccinimides (e.g. N-chlorosuccinimide or N-oromosuce-'Lnimide',, dialkylsulohoxides (e.Q. dimethvlsulphoxide/ inthe presence of an activating acent such as N,Y d-icvclonexylcaroodiimide or an acyl halide oxalvl chloride or tosvl chlorice',, pyridine-sulphur trioxide complex, and dehvdrocenation cataivsts (e.a. cooper chromite, zinc oxide, copper or silver'/.

Suitable solvents may be selected from ketones (e.q. acetone or butanone ethers (e.a. tetrahydrofuran or dioxan), amides (e.a.

r dimethylformamideil, alcohols (e.g. methanol), hydrocarbons ke.a. benzene or toluene , halogenated hydrocarbons (e.g. dichloromethane) and water or mixtures thereof.

The process is conveniently effected at a temperature of 70 to +500C. It will be understood that the choice of oxidising agent will affect the preferred reaction temperature.

Compounds of formulae (II) and (VI) are novel compounds and constitute a further aspect of the invention.

According to another general process (E), a compound of general formula (I), wherein A-8 represents the group CH-CH2, may be prepared by cyclising a compound of formula (VII):

0 Im (VII) L 0 (CH 2) N__N R H 1 or a salt or protected derivative thereof, followed where necessary by removal of any protectinq groups.

It will be appreciated that the compounds of formula (VII) may exist in the corresponding enol hydrazone tautomeric form.

The cyclisation may be carried out in aqueous or nonaqueous media, in the presence of an acid catalyst. When an aqueous medium is employed this may be water or an aqueous organic solvent such as an aqueous alcohol (e.g. methanol, ethanol or isopropanol) or an aqueous ether (e.c. dioxan or tetrahydrofuran)l as well as mixtures of such solvents and the acid catalyst may be, for example, an inorganic acid such as concentrated hydrochloric or Sulphuric acid. (In some cases the acid catalyst may also act as the reaction solvent). In an anhydrous reaction medium, which may comprise one or more alcohols or ethers f e.Q. as described above), carboxylic acids (e.g. acetic acid) or esters (e.a. ethyl acetate), the acid catalyst will generally oe a Lewis acid such as boron trifluoride, zinc chloride or macnesium chloride. The cyclisation reaction may conveniently be carried out at temperatures of from 20 to 2000C preferably 50 to 1250C.

Alternatively the process may be carried out in the presence of polyphosphate ester in a reaction medium which may comprise one or more oraanic solvents, preferably halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, dichlorodifluoromethane, or mixtures thereof. Polyphosphate ester is a mixture of esters which may be prepared from phosphorus pentoxide, diethylether and chloroform according to the method described in 'Reagents for Organic Synthesis', (Fieser and Fieser, John Wiley and Sons 1967).

According to a particular embodiment of process (E), a compound of general formula (I) may be prepared directly by the reaction of a compound of formula (VIII):

Q 0 0 1 i (VIII) or a salt thereof. with a compound of formula (IX):

0 17 - 0 Im -J CH 2) (ix) or a protected derivative thereof, usinq the appropriate conditions as described aoove, followed where nece-sary by removal of any protecting groups. Compounds of formula (VII) may be isolated as intermediates in this particular emoodiment.

A DfGtected derivative of Formula (IX, may for example nave on-e or octn of the cauDon,,i aroups protecte-- (e.Q. as an enol etne7'. I W111L be aporec-4atei that when a compound of Formula (TEX'; is used in wi-. 2n tne caroonvl Qrouc at the 3position is protected, it mav be to re-,,o,e 'the protecting group in order for reaction to occur witn the compound of formula (VIII). Deprotection may be carried out oy conventional methods, as described hereinafter. If desiLred, deprotection may be effected in situ.

It should be appreciated that in the above transformations it mav be necessarv or desiraole to protect anv sensitive aroups in the molecule of the comoound in auestion to avoid undesirable side reactions. For example, it may be necessary to protect the keto group, for example, as a ketal or a thioketal or as an enol ether. It may also be necessary to protect the carbazolone and/or imidazole nitroaen atoms, for example with an arylmethyl (e.g. benzyl or trityl), alkyl (e.g. t-Dutyl), alkoxymethyl (e. g. methoxymethyl), acyl (e.g. benzyloxycaroonyl) or a sulphonyl (e.g. N,N- dimethylaminosulphonyl or p-toluenesulphonyl) group. When Q represents a hydroxyl group it may be necessary to protect the hydroxyl group, for example with an arylmethyl (e.g. benzyl or trityl) group.

Thus according to another general process (F), a compound of general formula (I) may be prepared by the removal of any protecting groups from a protected form of a compound of formula (I). Deprotection may be effected using conventional techniques such as 1 18 those described in 'Protective Groups in Organic Synthesis' by Theodora W. Greene (John Wiley and Sons, 1981).

For example a ketal Such as an alkv1eneketal Qroun may be removed by treatment with a mineral acid such as hydrochloric acid. A thioketal group may be cleaved by treatment with a mercuric salt, (e.ci. mercuric chloride), in a suitable solvent, such as ethanol. An enol ether mav De hydrolvsed in the presence of an acueous aci-- (e.- dilute sulphuric or hydrochloric acid',. An arvlmetnvI N-protectina aroup may be cleaved ov hvcroqenolys-is in the presence of ke.j. palladium on charcoal-: anc a trity! croup aisc D'v aCid e.Q. usino Gi-:ute nvcir,:cnlor--.3r 2ce Qrou:D,nav ne re,cveci us--r.c a- 'Le,.j-Js ac-c scn as 2cr3r.

triDro,T,.e. An acyll QroLp mav be removed ov un2e: ac-ljzL2 4 or oasic conditions (e.q. usinc nvci:.)ce.9:)r sncJun sul,ncry.:'_ crou..c may be renovec --v al<al;ne hvcri.vs-:s. Ar, arVi. meLnvl OH-protectinq CrOUD M3V be cle3vea uncer acidic concitions e.c. with dilute acetic acid, h,,croorom-ic acid or oor3n triorom-ide; or ov hydrogenolysis in the presence of a catai,.,st' (e.a. pallaclum on charcoal).

Compounds of formula (II) mav be prepared bv condensinQ a compound of formula (III,', or a protected derivative thereof, with compound of formula fIV), or a protected derivative therof, in the presence of a base such as an alkali metal amide (e.a. lithium diisopropylamide) in an inert solvent such as an ether fe.a. tetrahydrofuran).

Compounds of formula (III) may be prepared, for example, by the method or methods analogous to that described by Oikawa and Yonemitsu in J. 0122Chem., 1977, 42, 1213.

Compounds of formula (IV) may be prepared, for example, by oxidation of the corresponding hydroxymetnylimidazole of formula (XI):

a C3talyst ce Clea,,eo HOCH2-IM (n) or a protected derivative thereof, with an oxidising agent such as manganese dioxide.

Compounds of formula (V) in which L represents a halogen atom may be obtained by reacting a compound of formula (M), or a protected 1 R J! 19 derivative thereof, with a halogenating agent such as thionyl chloride or a phosphorus trihalide (e.g. phosphorus trichloride). Compounds of formula (V) in which L represents an acyloxy group.or a sulphonyloxy group may be prepared by reacting a compound of formula (M) with an appropriate acylating or sulphonylating agent such as.an anhydride or a sulphonyl halide (e.g. methanesulphonyl chloride), optionally in the presence of a base (e.g. triethylamine or pyridine).

Compounds of formula fVI) may be prepared, for example, by reacting a compound of formula (I) with an appropriate reducina agent. Thus a compound of formula (VI) wherein A represents a hydroQen atom may be prepared by reactina a compound of Formula (I) with a hydride reduc-nQ acent such as di;sooutylalum-inium hydride, or socium orohvt--.ride. When diisobt,.tv-lalumin-ium hydride is used, it may be necessarv to fol-low the reaction with an additional hydroaenation s::ep.

Hyarooenation may be effected usina conventional procedures, for example, as described in process (B). A compound of formula (VI) whe."---4n A reoresents a hydroxyl group may be prepared, for example, by reacting a compound of tormula (I) with an alkali metal hydride (e.g. lithium hydride).

Compounds of formula (VII) may be prepared, for example, by the reaction of a compound of formula (VIII) or a salt thereof, with a compound of formula (IX), or a protected derivative thereof, in a suitable solvent such as an alcohol, and at a temperature of, for example, from 20 to 1000C. V Compounds of formula (IX) may be prepared by reacting a compound of formula (V), or a protected derivative thereof, with the appropriate 1,3- diketone, or a protected derivative thereof, under the conditions referred to in process (C) above.

Compounds of formulae (VIII) and (XI) are either known or may be prepared from known compounds by conventional procedures.

Where it is desired to isolate a compound of the invention as a salt, for example a physiologically acceptable salt, this may be achieved by reacting the compound of formula (I) in the form of the free base with an appropriate acid, preferably with an equivalent amount, in a suitable solvent such as an alcohol (e.g. ethanol or methanol), an aqueous alcohol (e.g. aqueous ethanol), an ester (e.g. ethyl acetate) or an ether (e.g. tetrahydrofuran).

Physiologically acceptable salts may also be prepared from other salts, including other physiologically acceptable salts, of the compound of formula (I) using conventional methods.

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 (Mc'Uraw Hill 1962) and 'Tables of Resolving Agents' bv 5. H. Wilen.

Examples of oPtically active resolvinc acids tnat may be used to orm salts witn the racemic comcounds include tne and (S; Forms oiF ornanic carboxylic and SUlnhonic acLds such as tartaric acid. dic, toluoyltartartic acid, camphorsu!Qhon-ic acid and lactic acid. The -esultinQ mixture of isomeric salts mav ne seoarated, IF-ir examole, Ov fractional crysxallisatLon into the diasll--reoisomers and if desirecj, the recuired optically active isomer may be converted into the free base.

The methods indicated above for preparing the compounds of the invention can be used as the last main step in the preparative seQuence. The same Qeneral 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 in the molecule which are desired in the final product.

The invention is further illustrated by the following Examples. All temperatures are in OC. Thin layer chromatography (t.l.c.) was carried out on silica, and flash column chromatography (FCC) and 1 lc n-Butyllithium (1.57M; 1.08mft) was added at -780 under nitroqen with stirring to a solution of diisopropylamine (0.24m.Q in dry THF (7mt) and stirred at 00 for 30 min. The solution was cooled to -780 and added via a cannula to 1,2,3,9-tetrahydro-9- methyl-4H-carbazol-4-one (282mg) at -780 under nitrogen with stirring. After 1h at -780, followed by 1h at 00, the mixture was cooled to -780 and treated with Intermediate 2 (500ma) in THF (6m.C. After 4h at -780 1, the mixture was allowed to warm to 230 and stirred for 14h. The resultant solid (the reaction mixture had evaporated) was cooled to -780 treated with THF (10M1), followed by acetic acid flml',, war-ned to 00, and poured in't--o aciueous saturated sodium bicarbonate (50m)C. The mixture was extracted with dichlorome--nane fg-x6,nmZ', and tne comoinec, oroanic extracts were evaGorated. The residue was Dv EPCC elutina with System A (96-1:3"-,:--) to nive the 'Lit-le 14111LL7'-.

Intermediate 41, 3-'3-FluoroDnenvlhldrazonc,-1-CVCI-Ohexan-l-ol 3-Fluorophenylhvoraz-4ne hvdroch'Laride f9.35a, in water '100m1' was treated with 2N aqueous sodium hydroxide anc tne resultant solution was adoed over 2h to a stirred solution of cyclohexan-1 3-cjione (6.65ci) in water (10OWC under nitroaen. This mixture was stirred for 18h and the resultant precipitate was filtered off and then stirred with water (150mY1). The solid was again filtered off, washed with water (50m. C and dried to give a powder (9.90Q). This was washed with hexane (2 x 200m1) and the solid was collected to give the title compound (5.3g), m.p. 142-1440.

Intermediate 5 1 7-Fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one A mixture of glacial acetic acid (25m1), 3-(3-fluorophenylhydrazono)-1cyclohexen-l-ol (1.1q) and fused zinc chloride (1.0g) was heated at 1000 for 20h. The cooled reaction mixture was poured into water (35m.C and extracted with dichlaromethane (2 x 30m1). The combined, dried organic extracts were evaporated to give an oil which was purified by SPCC eluting with ethyl POOP, GUALITY 1 - 21 short-path column chromatography (SPCC) on silica (Merck 9385 and Merck 7747 respectively). Solvent System A as used for chromatography denotes dichloromethane:ethanol:0.88 ammonia solution. 1H-N.m.r.

spectra were obtained at 250 MHz (integration, multiplicity); multiplicity legend: s = singlet, d = doublet, t = triplet, m multiplet, Dr = broad. Organic extracts were dried over magnesium sulphate or sodium. sulphate. The following aonre\,iations are used: THF iG nen,,i-'Lileti, -IH-imidazole-4carboxalde'ivde - teftlranvdrofuran: DNIF - ainietnvl loo rrp.am ide:!IMS - industrial TethvlatL L 3 1 resultine sol-i A35 acet-one to give tne title como3unc A mixture oF "--nenlvi-l-\'tz-L.ohenyimethyl'1-1H-imigazol---4-methanol S nc, "aC'--iva'-d'40ci" and dioxan t225m1', was 1-,, fflancanese dJoxice 1 1 L-, %. j st-Lrp-d at room tenpeL-a'Lure overniaht. The suspension was filtered and the solid was washed with hot chloroform (U). The combined filtrates were evaporated in vacuo to leave a solid (4.0g) which was purified by FCC elutina with chloroform to give a solid which was triturated with hexane 1, k-a. 50m1) to give the title compound (2.99g), m.p. 184-1880 decomp.,.

Intermediate 3 1,2,3,9-Tetrahydro-3-[hydroxy[5-methyl-l-(triphenylmethyl)-1H-imidazol4-yllmethyll-9-methyl-4H-carbazol-4-one POOR GUALITY 1 -) r 3U acetate:hexane (3:2) to give the title compound-(0.15g) as a powder,. m.p. 231-2330 Intermediate 6 7-Fluoro-l,'?,3,9-tetranydro9-methyl-4H-carDazol-4-one A solution of 7-fluoro-1,2,3,9-tetrahvdro-4H-carnazol-4-one (1.0a-'/ in drv DH1r was added dropwise to a stirred, ice-cooled sus-pension of pre-, 4ashe.--i-'\.hexine: 21 x 10m1), sodium hydride (78% dispersion in oil; 175ma,' in 0-rv DMF,5m-li undep nitrogen and stirring was continued at for 1. 5n The solution was cooled to 0'37 =---2ed and was con"--;,-iue,2L;C ar.-L.eok-,s in r-,7v W;F a of j -,,.!",1h-cacl)azol--11-one f3,', en.

n in d rv DMF \35ri---. under nitrog stirrine '1cr 4h the mixture,ias poured into water 300m1) ano extracted witn The comoined extracts were washed with wa:ec oried and evaDorated to give an oil (ca. 9q) which was purified ny FCC eluting with System-A (200:10:1) to give the title co-moound 'k-h.57ai as a foam, t.l.c. (System A 200:10:1) Rf 0.32'.

Intermediate 8 4-(ChloromethVl)-5-methyl-l--triphenylmethvl)-1H-imidazole A solution of thionyl chloride (1.3m.Q in dry dichloromethane (10m1) was added over 5 min. to a stir-red suspension of 5-methyl1(triphenylmethyl)-1H-imidazole-4-methanol (5.0Q) in a mixture of dichloromethane (10OmY.) and dry DMF (2m.C at 00. The mixture was stirred at 00 for 30 min. and washed consecutively with 8% sodium 0 bicarbonate (2 x 50m1), water (50mY), dried and evaporated in vacuo below 400-to dive an oil (5a). This was dissolved in ether (100m.Q and the resulting solution was filtered through a pad of silica which was further eluted with ether (2 x 100m1). The Combined filtrates were evaporated below 400 to give a foam which was triturated witn cold hexane and filtered to give the title compound (4.2g) as a solid, m.p..33-1350.

ntermeciate 9 3-.'--thoxy-6- F, [5 -met h v l-! -t-r-inhen v Imeth v -i a z c v 1.me th, v! l-,? cvc-lohexen-lcne ',8'., in ne.,<-ne: 21 1', was acced at -75 unCer n..cocen to a stIrred solj'--;jn of in -,2v l-) THF 75m) and '-.ne SolUt;nn.laS st;r-e: at 03 f-Gr -i- Mn. T'e 43S cool--d to -781 anc. adoe"_, to a so-lution oF one in dry THF_ at -78'3 undec n-i17-r7jc.---n witn sz-i--rJne.

After stirrina for Ith a- -7.3'3 and 30 min. 'at 03 solt-,t--or,.4as cooled 41-o -780 and a solution of -',-!cnloromethvl' ltri-pheny',-neIL-.ny'L,-1H4mi-dazcl--- (11Oe', in dry THF 100ml'/, was added dropwis-e with stirzinc under nit-rocen. The solution was stl--iz7ed at -780 fo:. 3n and at 0'3 for 30 min., 8% aqueous sc,!-iijm DiCarDonate and ext-nacle( er--iv-i acetaL Le f'-x300m.Z,'. Tne comoined, dried ornanic extracts were evaporated to give an oil (ca. 13g) which was purified Dv SPC'IC elutina with System A f0,6'i:30:3j to give the title comoound (3.28g/ m.p. 145 Intermediate 10 1,2,379-Tetrahydro-3-[[5-methvl-l-ftriphenvlmethvl''-1H- imidazol 4-yllmethyll-9-(phenylmethyl)-4H-caroazol-4-one A solution of 1 2,3,9-tetrahydro-3-[[5-methvl-l(triphenylmethyl)-1Himidazol-4-yl]methyl]-4H-carbazol4-one (500mq) in dry DMF (3m1) was added dropwise to a stirred suspension of sodium hydride (73% dispersion in oil; 38ma) in dry DMF (lml) under nitrogen. After 20 min. benzyl bromide (0. 14mY-) was added and the mixture was stirred for 3h. Water (50m.C was added and the suspension was extracted with dichloromethane (3 x 25m1). The combined, dried organic extracts were evaporated to give an oil (ca. 850mq) which was I S I- purified by FCC (column made up in ethyl acetate:hexane:triethylamine 79:20:1) eluting with ethyl acetate: hexane (4:1) to give the title comoound (265ma) as a solid, m.p. 78-800.

IntermedOte 11 9CvcloDentyllmethvlll-1,2,3,9-tetrahvdro-3-[[5-methvi-l"tri-Dhenv'L- Meti i v2 1 H- imI, cj a zol-1-1 - v 1 Imeth. v 11 -11H c art) a zo one Us I nn tne proceoures aescrioed aoo, e for iiite,-.r.e.:: late 121, 1.2 triDnen v I rnetn v' -ine '500nc, was treated witn 3 l.',-- s is c e r S I j n in G i l: an--, Yj as t h en s 'L i C 2 -- c w L tn C v::a; O 1 me c al-) a zol- e 11 5 0 Ome ',' and po ijl-!, c SE n on at, e 2"ne.

ne rp.,<'u:,e was s'irred unce- ni F;3:.

j. L 0 - 138'n aG,.2.ei and tne sr 24n ana tnen at rel..jx for 6n.

a t e 2!' S J ',..

x'raced,-ii n!- sc,:,,ed e,.- ne s-13n was e, - - Z_ --- X mJ,. ine comcnec. jried ol,canic extracts were evapora'edJ to ave a was ourified oy FCf-' (column made up in ethyll 80:19:11' eluting with ethyl acetate:

to nive the title compound '95mg) as a foam, t.l.c. on hexane ",- ' k Et-,' Impresnated SiO (ethyl acetate:hexane 4:1) RF 0.30. 2 \ Intermeciate 13!.?-,3.9Tell.ranvdro9-,,nethyl-3-[(5-methyl-1H-imidazol-4- yl)methyl3 4H-caroazole maleate A suspension of 1,2.,,3,9-tetrahydro-3-[(5-methyl-1H-imidazol-4-yl) metnyll-9-methyl4H-carbazol-4-one (0.5g) in dry dichloromethane f 150m.%,' at -570 under nitroaen was treated with a solution of diisobutylaluminium hydride (1.0M in cyclohexane; 6m.C and the mixture OOR QU 1 1 - 1 D was stirred for 4h while warming to 5 0. Methanol '\5mt) was added and the mixture was stirred for a further 1h and was then filtered. The gelatinous precipitate was further washed with dichloromethane \50m., and the combined filtrates were evaporated in vacuo. The residual oil (ca.. 0.55o', was purified oy FCC elutinci with System A (95:5:0.5) to give a Solid k198mgl. A mixture of this solid (175mQ) in ethanol 15n atrriosplieric pressure )'.. was nydricenated at room t'emoe:ature and over a stirred suspension oF pf-e-reouced 10% nalladium on ca:,Oon '50% acueous paste; 2-0me, in etnanol "1'Uml' For The mixtire Yas evaporated in va-uo, and tne residual cum was partitioned De-1ween acill and Tme acioic -1a,,e2 was Dasil---=!.- cn-"or-j'icr:..n These s-e dr.e- and ejac;3:,at-ea in vacuo to!e-m,,e Qum ""(;c; sso-llvec -n 5, and a c ma'-4c acc, 6c5mc" n C in -2,-;o to c-,. =nd di 1 i:i:-\i ether a 'I d i t OX C C, c- n C 6 m o "' a s a sc, L _ cj m. 3 cec oj-iic Tn'Le7med-;P---e 11 1 2. '1.9 --, et- _r c ro-9- m-= th v 1-3-,' F 5--,.e4---n v-',--', - t r in-heny -v] '-A H i,-n j. h v 1 ' 1 cazo-l-i-vllmeL.'J-Lu--ar-Dazol-4-one A solutlon of triphenylchloromethare 'n dry DtAF 'Oml ' was added droow-ise to a stirfed solution of 1,2,3,9-tet-rahvdro9-m--thvl-3[15-x.ethvl-']H-imidazol-L,.-yl)methvill-l,Hcarbazol--on-- (292mci, and triethylamine (101ma) in dry DW (20mY_) and the resultinq solution was stirred at room temperature under nitrogen for 3.5h. The reaction mixture was then poured into water and t.ie resultant suspension was extracted with dichloromet-nane k3x50m1'.. Tne COMDined, dried organic extracts were adsoroed onto FCC silica Ahich was then applied to a column and FCC eluting with System A (150:3:1) gave a solid which was further purified by crystallisation from dichlorometh.ane:hexane (2:1) to qive the title compound (304ma), M.D. 193-1950.

f, rry i 1 1 r 13 2.0 27 Intermediate 15 N,N,5-Trimethyl4-[(2,3,4,9-tetrahydro-9-methyl-4-oxo-1HcarlDazol-3yl)methyl]-JH-imidazole-l-sulphonamide A solution of dimethylsulphamoyl chloride (0.16mY-J in dry dicnloromethane was added to a stirred solution of 1,2,3,9 tetrahydro-9-me'Lhyl-3[1\5-methvl-1H-imidazo.'L-4-vl'lmethvll4H- caroazol- 4-one fk438.m-,', and triethylamine 0.25mY. in dry dichloromethane f30mY and the mixture was heated at re'llux for 18h. AFter cooling the reaction mixture was adsorbed onto FCC silica which was then apQlied tc a column and FCC elutinQ with Svs11-em A '150.8:1 cave an oil solidified to a powder on triturattion with Cry hexane T-iS po,qae,n,,;as 'Emen further purified oy in jrv and, crystailisa4--.-4on ov aodition of dry hexane 10,n.,',' to give tne title cor7,,oounj '122-12)40.

TnLecT,e-- late 16 2.3.9 [1 -"met oxvmet- h v"'. v L i-r. c; a Z-1-_'- v' L m L and 1 2 J.9-t=-tLr-mnvcro-7-F, .metifoxvmel--hvl-4-methvl-1H-;mida701-5-vllmethvll-9-me'nvl-I,H. L carn; zol-'-one (4:1) A solution of chloromethv! methyl ether '0 in f\,10m.Z was added to a stirred solution of 112739 te+1.rahydro-3-[\5-methyl-1Himidazol-4-yl)meLhvll-Ql-m--thyl-LH-carnaz oI and triethylamine (0.5m1) in chloroform I'30m.C under nitroQen. The resulting solution was stirred at 200 for 2h and partitioned between chloroform (25mk) and 2N sodium bicarbonate solution (2x3Oml). The dried organic extract was evaporated and the residue (0.45g) was purified by FCC eluting with System A (200:8:1) to give the title compounds (0.25g) as a gum, t.l.c. (System A 75:8:1) Rf 0.5. N.m.r. (CDC1 3) showed the title compounds to Oe in the ratio of 4:1.

Intermediate 17 Phenylmethyl 5-methyl-4-[(2,3,4,9-tetrahydro-9-methyl-4oxo-1Hcarbazol-3-yl)methyl]-1H-imidazole-l-carboxylate and.phenylmethyl 28 4-methyl-5.-["2,3,4,9-tetrahv(ro-9methvl-4-oxo-1H-caroazol-3-vlmetnyll-1 H- 'Lr-iiciazole-1 -carboxvl ate (97:3 A solution of carooDenzoxy chloride 0.26m-Z,' in chlor.o:7or;,,, was added to a stirred solution of 1,2,3,9-tetrahdro 3-[(5jnethvi-l..,',\'0.'+ .4c]',, anc t.:4Pnylain-;ne 0.25,n) in ch-',,jro';c--.T, under n.41-roQen. The L was stirred at 200 -,7 2h and Eaftitioned let,.,ieen L L- -5 7 - en,.j--o'l.3r-n and 2N sodium Dicarnonate so'Lution (200m311. Th e o 7 --, an ic _= x 7_ f Ec t dr Le,-. a-nd ev apo r ats d to le av e a ourr.. 0. sq ' -01-, W 9S D C.r i ' JLe.',.3y F C e 1 u t A (200:8: 1) 'L o a iv e a sol i 'U otlnom '3rp,.Z" to t.,-,e W2s o 17:3.

N' m. P. ( Cum: - - 1 so I S G et -mi a7 n en v lm t.

c J I a c 1 2 c e t 1. 2 a c 1,1 d w a s 'L r e a t -- d w i t h -,c-nesu-",:ncr.. ic sc -i, ri-,onc.-i,icir ate j. EGO o' and the s t ir r eed sol ut ion at The cool, oark liquId was evaDorated, treall-ed sidium o-Lcar-nonat- f-95CmJ.. and extracted into et._1V1 acetate \'hx25-Uml,'. The combined, dried ornanic extracts were ev ed ? and pc-- --f ied 0y SIP CLIC. E1ution with System A (978:20:2 945:50:5' af100:.de(j-l the free Dase of the title compound as a liQht yellow-nzo,4n solid (.!L88mc,. A hot solution of the free oase (87mQ) in etnanol 16m1) was treated with a hor solution of maleic acid -he precipitate was collected in etnanoj- 1,1.n.', and on cooling 1 to give ".'ne -t-4'--le co.n.oounC m.p. 205-209'.

Analysis Foune: C,055.1; H,5.2;N,10.2; C18H,7N O.C H 0 requires C,64.9; H,5.2; N,10.3%'. 3 4 4 4 Ex2mole 2 \fE',,-1,2,3,9-Te'Lrahvdro-3-['5-methyl-1H-imidazol-4-yl)methylenel-4HcarDazol4-one i 29 Lithium moi-iol-L.etrah,,.,jroFurai-t) fl.5?1;in to a c,31.-,] lk' 710.

in drv THF undec v,,he-euco,-, e so u-- -:j n.' wa s s r ed at T nterT.ed-Lat,-e 'I was added and the mixture was allo,.,,!e-lj to reach -com --nioec.-Gre ove 3-n.

I t -,-/as t!h- n c o 2 1 ed tO 1-10 and a c e t i c a! c n., 7, 1 t we -4 n,l 1-, - P- t. j -l uenes u -1.5non Lc a c -i,-1,'. 5 1 we 2 e a.d Th e res U-1 t inc su, lut lin wGs neate-- az Fof 2U'L-i t-)e sol,,e'---t was rernolel--! in, 1/2CUIG. i.-,e:,es-,,Llu.e was wit-n 8% socium. n.;cart)c. na---- an,-j ext-rac---=-- witn d.Lc-1-;nromethane \,3xl).i.The cL),r.bn-1, g r'.

cj:,-ie- organ,c we:--e to c.ive a Qum U. --;C], w2S eel DV C M c C1 1-, r. c 3 c 1 1 0 -, r, e-'u,-Jne w;tn to c-,.e -e t4.-!= 3 1 tOC:

3 -7v, 71 ' 5,Teth! l-, u- mi 2zo 1 ---o - -.T.,;= 0 e:, a." e 3. 3 rn 2'..,4 c- s a d f,:,'e d d 7 o i s e o,i 0,-,1 in. at under n E.

a stirred' suspension i-fluoco-1,2,3,9-etrahydro-9 capbazol-4-one 975mo in drv THF (30m1) After 1.5n a suscension of intermedilate 2 (1 in drv THF f.10m.Z," was added and t:-ie suspension was Stirred at -100 For 2n. The resultant solution was cooled to -700 and acetic acid 112ml') was added., Tne solution was then allowecl 1Co warm to -100 and p-toluenesulphonic acid monohydrate (5.8g) was accec anc tne sollution was stirred at reflux for 20h. It was then cooled and evaporated and the residue was partitioned between Wa'!:1queous sodium bicarbonate (100m).) and dichloromethane (70m1). The suspension was filtered and the resultant solid (1.02g) was crystallised from methanol (100m.Z) to give the title compound (366mg), m.p. 290-21950 -,: 'I - A n a s- s c ', -zll, m 13 Fotir;: C, 69. 9: 1. 5. 2 13. 2.

requJLres '',9.9; H,5.2, ExsmDle 4 -Z I it-nium 'l.39-'1 in hexane: 5.0m-1 was adced Gfopwise ti a CO- ',-7Cli stir-T-ed solution of d4-soorooviam-ine fkO.96.ni in drv THF 1 0m un d e -r n i t r o ri en. Tne so lution was st i2.-e,., at 0 3 for 30 min cooIed to -700 and adGed dropwise to a cold. 70 st ir-red soLut. ion 0 1 ? 1 ' - 3 h v d. G - -4 r:.-, e --: G x,,. - 9 a z 1 - o r, e C r-. c -:r. r -,,2 c e! r d tL.! e s ij a n sa, u. j n w. 2- a. '.jsed n c- e z -1 i a s t.- e n co, c. I ed 7 0) a r, c a s u sn s 1.0.7. c I(D e f e c,, ec: I n v ---c,-, c an c tne -7 es L c ue 'L re a t _e c -,4 - -- - C: -".9 8 ,U anc ine Di-,ec c::ieG orcanic ext,---m--ts were to Give a cun ca. 2,, win PLr 1: Fied ov F'2C e -1-, t inc A' 1 tO:;-ive -the as a sc I -i d m 13 -3 -131 Ir. t.i.c. (System A 20C:10:1 Rf 0.24.

Examole Ir.

fZ'),-6.7,8,9-'letrahvdro-5-methvl-9rL f5-.-nethvi-l.n-4Lmi-(lazol-4-vl-I methylene] cycloheotE bl indol-1 0 (5W -one maleate A solution of lithium diisopropylamide (1.5M in cyclohexane; 3.2m111 was added to a cold (-700',' stipred suscension of 5methyl-6,7,8, 9'Letrahvdrocyclone;DtrLh-llindol--'i01"5H:-one 1(0.96c; in dry THF fk3Gml,' under nitrocen. The result-nQ solution was stirred at -700 for 15 min. and then at 200 for 30 min., cooled to 700 and treated with a solution of Intermediat-- 2 (1.6a) in THF (30m111. The reaction mixture was then stirred at -700 for 30 min., at 200 for 1h, cooled to -700.and treated with acetic acid (25m.Q. The resulting solution was heated on a steam Dath for 1h and concentrated in vacuo to 1 -Z ' 11 I'- cl f.3t- S C:, 1.:

-p! 1 1 -i 5-n 1 17- -:-) r', L,2 r"(7 7--, -- -1 t _ 1 n -1 t z c s a nd. pa:7 t i t io n e c 3 e e t n v 1 ac a _ e\ 3 X 9J;-n 1,1 an-, sa ine comc;ne,, criej ae--e -=v aPL- cated to lea,, e a ca 2-.in was P:-:L:- t C c i X, e a cu, 7 t,2. Wn C-.S o a 7 e e e e n h,, d r c -- h -1 o a c i 'd \' 3 3 m. 1, a n c e t c e t a -11 1 an VC ro-5- met h v 1-9- E (5-.,netin y l -l H -i m Jxj a z c blindol-10 '5H'l-one,T,e-nv-'enejcvclch--ct,.Z 1 uz4j c 'ne col u,-on o 1x amp e 5 al so Qav e a semi- soa i n - - lL- - whicri was crystallised From aosolute ethanol (25m1) to give the 1:z L i t -' -- c c. c. c c. n d '10. 3 Y m. p. 230-2320.

1 Ana. ysis Found: C,74.3;H,6.3; N,13.6; (l i ' resuires C,74.7; H,6.3; N,13.8%.

30) Examole 7 1,2,11,9-Te±rahvdro-9-methyl-3-[(1H-imidazol-4-yl)methylenel-4HlarDazol-4-one A solution of diisopropylamine (1.54mY) in dry THF (20m.C at -780 was treated dropwise with n-butyllithium (1.32M in hexane; 8.3my).

The mixture was allowed to warm to 00 and was recooled to -780. It was 3 2 ID tnen ac-oei o,er 3 i,-in, to a stiirei susoension of metny I- li-e ar,)azc)-1 ' -one.0c, in dr,, 80mZ" at --5 'n resultan'. susoension was Inen s'.--1rrec az Fcr 2n ar...,i was treated with 1 - ( tr i p[-,env Imeth vE -1 H- im icia zol e-4..z ar-rjo x a The mixture was stirred for a Further 2h, whilse it WES SLOW1... a! LOWe to warm to room tenperature and was C-nen cooied to -7,30 anc. ntjenc,,e., ' witn acetic acJLa Tne -esu-ILEant solution was to war.11 t,' room tempezazure and was poured into 8% acueous socium n--,'carDor,,at.e '60OmI The i-n-Lx'.u--e was ext-racted with '1,3x15ijm.Z' and -'-e GrqanIc evar-orated to fcavn.

c, tnis foam _mr.d a -,i-ixtL,-e oF acetic acid and, drv :,ef.Lux F3r 5M. The anc was n was hea'-e a-c a u, t 'D U S 1,1 t j 3 a c I-J e U S 3 5 0 T h e.G m b) -,',n c-: 2 q c j a n c e X a r_ t S e e J: D o L Z_ wni:-- was zv -C e,L--nc win o cve a solit-3 j-:ve zne --i4r--!e --2%itcounc X; Analys-is clo L, n c. C 7 3 32 3 P 7 C E; C U i e s C 7 3 6 5 5 1 carDazol-4-one maleate A solution oF imidazol-4-ylIrnethvlenel-4H-caroazol-4-one f3.50ain DMF f85my' anethanol (50m.C was added to a prereduced suspension of 10% palladium oxide on carbon '3.4Q/ in ethanol and hv(irocenated at room temperature and atmospheric pressure until uptake ceased!k?-70m.Z. The catalyst was filtered off and the evacoratec. The residue was adsorbed from methanol (.170m1) onto 5PCC silica and aciDlied to an F-C-C column. Gradient elution with System A Q,67:30:3-A,12:80:8'1 afforded the free base of the title compound as a solid A portion of this solid (500mq) in hot ethanol (15m1) was treated with a hot solution of maleic acid (224mall in ethanol (2mI, and on coolina, the _z 1 of' 7- a z;i, 1 L In e t n en -C -3 I'D e h 1 a F0Efr. was i F --- e -l o i s s o!,,, e:i o a n c.:

a- --.) -3 t a o e r e s U1 t. an '-- w - _it -, 3. n.,,--":s ---- -1 L anc r_ne -"es!2un'.31.1 was tri-itr:z-ec etnez 1 5 -)o metnyl-1 '- im i--' azo, 11 -y 1 met- v i -3.2 2-- =_ ' "C.-nc:' z - --. -11 aczc;--= ethanol was af-.c pressure over a stirrec sus--e-ns-Loi-i 2' 1,22% Paliaclum Dxi:je or, CSr3On catalvst (50% aaueous past=: in -3bs---!.-jte e'nano' Tne mixture was filtere-- anj eva.era"L-ec was purified oy FCC elu-l-ln(-compound '154..nL,, as a s.iiicl, RF 0.26.

D v 7 5 1 -z 1 1 W.., - % ---IL = 'I = -j -- "::. 1 G e m T'n i s x to qve a solid was c IsscIved in ho', methanol '5,m.Z and &-nvI acetate 17 -,-:zs a--ce-- ine- solution was concentrated to a volume of 10m) a l, tv e:l L C C 0 o!h 'Ene precipitated solid was collected to zne tit -1e comocund 'I31 4mo',, m. P. 160-1620.

Foi _inG, 0.36 w.'w=1.06-.nol H20.

C,63.3: [1,5.3; N,10.2; 3C -es C,63.6; H,5A; '.,10.6" c,l. c e nu i :-xanc)-,e Ii Iuoro-1,2,3,11-tetrahvdro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl)maleate --, L, "inh P;-- e C C -2.

1,3 - D 1 - _U -1 0 3^5 A. o, in eth a no 50m,.;as -,in-e,,i:=- e,' a roorn t= m, 3 Lr -3 a! 3-<1",-e onn. Caf'),j..

Tne was F ilter ec of asne.,;esh-ec wi tn a -,e- T OF ='na i Ine were -nc no -- 1. - - - - 1 - _= _; LJ wn icr. was nuc i 7, led D. FE- II L: t S 2 C 0: 3-1 o a _; v e a, n o i i 0. 32 cf' Tnis was in etnanol anc; treatec with a ': m, 7 ' o' P-C-,j s'.-A-cne in e,Inar,.o.- jet- e.,e C--- e n a ai c ospher,-c Dcessure an' room f-mce 3n cnarcoa,: catalyst "50'0'" acueous paste; 130,nci'. A F t e r L L c a. 110 m 1.- a D --ec i D i t ate c rm e a and. THF ( c a. 30m)."' A@ s ad c, e,, t- o 1- ec Is s o ' v e m e p recipi t_ ate X, 2 The mixture was stir2ed for a fu-z:ne.- -4n and was tl)en Filtered. The filtrate was treated with maleic acid 5-- 1 ion was evaporated to giv-- a solid wh4c.n ano the resultant solu- -I was recrvstailised from a mixture of methanol and etnyl acetate- to ni,,e t Lne title compound k' Anallysis 1.35q), m.p. 175-1770.

Found: C,64.2; H,5.5; N,10.6; C,7H17N3M4H 40. recuires C,63.8; H,5.4; N,10.6%.

EXP-7,31-2 1A 1 c 11. 5 3-m c in -j:7,, Dt. IF T,,: w as a c c ec ex-r2-ec: wiin '3<'5,,r.' e\-ra-cr-S.qeze- to an D--' - G -)5 me- Gre.

sulDhonvl;L,H-caroazoi-hone ma-le=;- Inter.meciate -1 ',,50Onie, was -eactec oenzene su-l.--non,jl cnior:ce (0.15mY, to give tne title n-or..-,oounc Analysis Fo umi: C, 6 0. 3: ':-', _. 7:: '-.., -. S..

c 2 3H,) IN H c e cj u ir e s C, -60. 6: H 7 303S.C4 404 Example 16

MethvI 1.2 3.4-tetrahvdro-3- [(5 -methyl -1 H- -.m. Jeazo vmetnv 1 1_;,OX0- 9H-carDazole-9-acetate maleate 1 'i 3; l l MJ 1,e a CL ec, w l t i me h I c n l cc, for. l l a ---mo c i, e '1.11,e c or. c f-P b 7 L i.D TntLe,-,ned-'a-le- 7.0', in. du. DIMF was a(i.,-ej a S-L-","-reCI susoert-slon o-. sof-,-.jm nvId.n;Loe "713')tl oil 71 -rocen and tle rescitine susoension was rD:r.c. G unce: nit Gt -70G.M te!7i3e-ratire ror 30 min, then a solution oF ally].

G r wa s a--lcej and tne -- esu 1 t ino so I A inn 1 f- i 3 3-15 Tn-Zea:-7-Or-: r- was tnen J_ L 7 e,-- --- n E 9 A e-- 5.1 c C an c ex ac t: e c w i th c i c o 7 o fE --- tn a n e 4. x j 0 o m T-,e 2C.-"0 W ext we:e A Itn 31 x25-,n 1,, c-- ie..-- n c c 2 n c -.n z i a e D c v 9 an wri w -m s c-1 -4 s so 1,j e d i n a m i X t -; r _= o f F T neateL, an ace. c acan- a t c e F --- u x 'o 1- 1. 5 r,.

= i tne sc) Ijti._n,.ias nasi: --=: wItn 2',i sod-icn carocna--- - ' -:-,. t -l - - - -. - -.. - - - ' 7 x 5 Cm 'n e arl --" r-n .iere concentrated to nive an ail l." to Qive the free mc, as a so 1 id T..'i-s was dsso' Ivei in ime was aded and the resultino on a steam, Oatn for 10 min. The solution was then and was adde-j to PPeciPitate the title comDound 17 p. G An a! y S S Fo un c LC, 65 IF11,6.0; N,9.3; r L4 renui-res C,66.1; H,5.8; N,9.65%.

2 T' 21 '3 4;'4- 4 c 1.213 -meth,,.L-1 H- -imicazol-4-vl J1 methyl 1-9evel.ocentvl';--H-carnazol--/,-one maleate A so-lutLon of Intermediate 7 (750mg', in dry DMF (30mY) was added to a stir-rec suspensLon of sodium h dride (73% oil dispersion; 50mg in ory DMF under nitrogen and the resulting mixture was stirred 38 at roo!r:, te'noepail-ure for 301 A solution of e in drv DiMF e.'ji-l-d anj the riitt-n, en, -1 f:ni 1-en;z_---; J r 10 3 -1 J C..

3 13 n C.

L G -- L L -",-I eT 1 - was C-2 an d tne zes,-i'L;i-- -inci suspens -I,:) n was e,(-rac ted vii 'i me- ane 3 x 10 0 rnV, i'le CG-noined extracts were wp-she.d r,'r:ec anl concentrate- 1- L - to cive an oil 4nich ) e-4 onto FrUC s-lica. FrCE elutine Svs-1-_n Free Dasr- of the compound as an oil Th _ s a s d i s sc I v e,-i J n Ti-3t',)anol Offil'., male --- ac il "26i-.9c." was and t, le Cesul t.In,- so I ution was heaten, on a steam fo-r 1 pin Th e s o 11 -j t i D,-, -, a, 3 coD!I-o and ettier was aCced to or-ec_i, L-,e tne 'itle C' M.3.11 3: I j a z 0 1 - o ni e i n a I e a t e C0-, c 'AE, a 2 a r 3 o n a t e 7 0 2n d e x t r ac e i. n 2 romi e an e 3 x 2 5. m. n e - nW noinec, d-ried o7.n-anic ex--pacts we,-e 2;,,e a.3 j-j;c.h was c.issz.-'ved in -r., 33 D M L a: r, c -- z e a z e sol-lium hvd-ri--e f 73% d-isp-zrsi.in in r., 5 5. ri c' T h e m ---' x t r e S E 2 ec at 5' For 20 min. and was -1reated wi-n m e t, i v i o d J 5 e solution was stirred for a furthe-- 1h and was treaed with 3;-z2f-,eous socium bicarbonate \'10m2J.. The sus-.ension waS ,120.n)., and extracted with dichloromethane '3x',0.-nl'.. e onn o i n e c dried orQanic extracts were evaporated to aive a sollid wnich was purified Dy FCC. Gradient elution with Svstem A 100:10:1) nave a wax "432m(iy' which was puriFied bv Pilch Ge.-7ic-niarce liQuid chromatography fkh.p.l.c.) fkSpher.soro 5 sw c.31up.,,-. eluting with chloro Form: liexane:methatol: wat-e c 200:810:15:1 at 20m---1 mingiving, as the First eluted u.v. active component, an oil.1,1!0ma,'. A solution of this oil and maleic acid (44mg) in ethanol (15m.Z, was evaporated to dryness to give the title compound 1k154..-ng as a so-ii-,, m.p. 1381410, t.l.c. (System A 100:10:1) RF 0.4.

o 1, 1) Examnle 20 9- lletral-ivGro-9-metnvl-'-FL L- - the -2- F 3 SC 1 1,-l 0k., A sli-lu-- ion c tn is s--L _Js anc -'e ic acid in e:,'-ano was tj C1:v.ness to civ e t-.ne ' it,' e c- n 7 0 io n -0 n -5 3 0, t S v S t em., A 1 C 0 J R 0 Bo n t- ic. 0m e 1 il,! in o i c m 1.3 rom e t h an e1. 4 m J_ via s ad d ed d r o ovii se c. G3, t ah,, o-C") - -n e t h o x v -9 - 1 7 -2 d SC I C in o 2 -oazol ---or OMc:"

TI e n p- z c v c a E e n r v G c n D r j m e t: n a n e und.es Afte-- ',h -r.. e t h an c VaS GUIC-el, sc Ine reS-LdGe 1)v 83 c: s 7: r-, C.,1 -1 5 V.2 7 =19 0.2 IJI e G SO j m c iw a -=C:' 'W1 !::m. 0 n1' t so ut on o Tia 1---c anc f-c.r-,n-cLrc M.3.

100:10:"," R' 0.33.

L.

ngo maleate anc he.mi,,na -leate Qen-- -ol! A so I.ut o,-, o ith ium di de ( 1.5iM in cvclohexane 6m was addet t-,-) a cold stir-ed susQension o' 3,4-,-.i-hvdro-4m--tliv'--cycloQenL-FLni-l?H"-one '1.5a in dry THF -ion was stirred at -700 for 90mi) under ni'rocien. The resulinci solut min.;:-nc. at 203 F1r 30 rnin. The solution was then recooled to -700 and ".-eated "-,-,..cniorone.-,i\,!,'i-t--i.ohenvlmethyl,-1H-imidazole 3.0c.,. The mixture was stirced at -700 for 2h and then at 200 for 2h and ouencned with acetic acid (30m.C and water (30mY). The resultinq mixture was left overniaht and then heated on a steam bath for 1h, cooled and partitioned between ethyl acetate (200mY,; discarded) and 2N hydrochloric acid (2x10OmI,'. The acidic aaueous layer was basified (to - pH 911' witn potassium cal.)onp-te and extracted with a mixture of eth,'I acetate:ethanol (.20:1; 3x150r,-,.Z,. The ewi,1)ine(,, oried orQanIc extracts -ej --"h.ancl 5mJ,' Tnis solid cissolver, in ho', absolute ethanol \2Fin.Z,' and treated witn a solition 3-j -p.a-'e-c ac;- in etnanol 5mI, The resulltino solution was c,Dnce.n-ca.eci to ca. 5t-,,.2. and ailuted witn drv ether ',10m '2.1 to a so.'.id wh-icn was r-=crys-la.ilised from a mix-jce c etnvl acetaLe:t,,etnenol (15:1; ca. 15mC' to (ii,e the title cornDo.-.nc:

he,n.imaleat--: 0.2c\, m.D. 207- 20,80.

Wate2 Analvs-is round 0.211 'a' w;lw _= 0.0_ mol H20.

rou ri d 6 7. 1 1. 5.

fl L.' r, 0 OLl'-' n reoulires C 6 -1. 5 L 4 5. 7. 2.

2- 2 5 9', e a roam, ca. 2a, wnien was puc-Liei o,. FU2 "150:8:1, to o14,,e a s e c o n c c -. o ri o h e t e c o m c c- J n d j 1 a 1 e a t e s a 1-, t: 0. 3 c:.

3ic:50 OCZa;F.;C, M.Q. t.l.c. (5,,,s',en A RF '.26.

1 X Sm. c I e 2 3 0 -1.2.3 9 -en,,i H-ca2Dazol-L, -one maleate A solution of -,-niazol -4-vll,,neInvll--?-cyclohexen-gone!1.2g'-, in a:1..ixzj-re 0 15n.Z' ana 2'' n\,drochicric acid f2.7m,',' was stizrea unciec 12 n. l-l.e'Lnv-1-1-"'4-fluoroplienyl)hydrazine '378mg' was acced and tne susoension was stirred at reflux unoer nitrogen for -2h. The cooled mixtu---- was poured into 8% aqueous sodium bicarbonate anc extracted with ethyl acetate (2x5Omft-y. The combined, dried ornanic extracts were evaporated to give an oil (ca. 1.2n) which was QuriFied by SPCC elutina with System A (923:70:7) to aive the free base oF the title compound \'?-40mnj as a powder. This was dIssolved in hot e--nanol (15mY,), a solution of maleic acid (99ma'y,in warm ethano'L ', 2m 2.',- was added and the resultant solution was evaporated. The solid residue was crystallised from ethanol 'k6mY.) to give the title comiDound '175mu,, m.p. 148-1500.

j -, 1.

W3ter Anal.,sis Found 2.17'f).j..w 11 0.53 m01 1-120.

An a l ysis Found: C,60.5: H,5.2. N1,9_':., 1 ---0.531H 0 reauires H,5.3: ',9 CISH18F1,30.C4' 4P1 2 -. -1 ExEir-cle 2', T-,, e t h v 1, 2 3. 9 T e t r a h. y c o - 6, 9 th y 1 - 3 - In a s -,.n 11 -n manner to tha t cesc r:l_o ec in Ex sm pie 23, 6 r ', - 1 r- 1 -3 h e n v!.-,i -- t 1 im a Z -, 1 1'1 m e t n v 1 Cv c 10 h e x n - 1 -one 1 1 _ c was r-eacted wiltn 1 -.Tie tInv! -1 - L-met.n, lphenyl hy Q r azine 3 5 0 m c Pul r 1.0 i --ai-Jon cy SPCC e-'ur--in, witn System the Free Oase oF thie 'Lltle comcound!350mc' as a solid. Ma 1.2 a t e -ne t 52 csive An a 1 v S i s P-o u n a 9 7 rec.ulles C,65.2: H. 15 Evamcle 25 et nhpn,,.

n, tr 1m -i-- a z o me n v 1 h e,,j m e ' n H - c a r 3 a z o -L -o n e 2 n in R- mixture L,.- acid anc TH.F "7-9-', was neated at re;0_UX 2n. Tne:Tl-lxEure waS -!.-.to n cicnicrof,,ei-.,-iane 'x20m).

anc eX7Z=Cleo.,j4 t - 1 1.

The comc-ine, 2rieO o2-an-4c extPac-_s wece evaporated to giv- a S3lid 19 .56t-.ici,' onicli was ed 0,,.. SO'-C e with Svstem A '-2CO: 10:1 'Y, to -s was 2issolved in e±!'lanol 3,n., and treated cive a solis Iccmc Th w-,tn a soLution d.' rnaleJLc acid (33mo,' in etnanol,.1m.C The solvent was removed in vacuo and the residue was triturated with dry ether to L Cive the tit-le comcounc m.o. 1 ". 2 - 1 n Water Ana.lvs-'s P-clunc 0.27% w/w =_ 0.07.mol H.),- Anal vs is Found: C,68.7; H,5.6; Ni.,8.5; c H N O.C H 0 0 recuires ',69.1; H,5.05; N,8.6 24 23 3 4 4 40.07H '0.

1 2 Examples 26 and 27 were prepared in a similar manner to Example 25 from the appropriate protected intermediate.

j 42 lz; n r.

93 Exe-ole 26 9- "--vcloDent--vlrpeti-vi)-1.2.3 9-tetrahvdro-3-E 1"5.,nethv - 1-1 maleate Tne C. 2i 3neny!,Tie 11 -1 H- im 4 dazol-4 -v riet.' vi--''A- -0a 0 C2, z ?55, gave the Free- oase of the title compoun(i 1 2-i"nq" -,ne l- mo ki':aleate Formation a-3ve tne title comDouna,144mciy', m.). 173-180. 'Aazer Ana-1 ysis n. G 1 S --- S Founa:

Founo: 0.3-7 '0' w/ - ,i""3.lmol H20 C,67.3; H,6.2; N,M; C, H N O.C H 0 0.

3 227 3 4 4 4.0.1H20 requires C,67.7. H,6A: N,B.E ExamQ1e 27 3 9- Tet '5--neth v!-! H iT.Ic a.zo!--!v 1 me±- y! 1-9- p.aleale 1,2,3,9-,---,-rahvdro-3-"5-meth.v'--1- 1 H- MidaZO1-4 -vl ",,ne t.n,j'L 1-9- v! le and purification by FCC cave the Free base oF the t, l-ine m c L formation -"1a,e the tit-le comcourd 01m c.

c.3 i-.,.o o u n M.Z.

a A'n a 1 S s Found: c 05.0; H,5_ C 0. C H --. 0 20.0.125C2H50Hrecuires C,65.4: H,5.5 4.0.3L.H Pound 1.4% A.."w E_ 0.34mol HgO.

X alMID e 'E,1,?-,3,9-Tetrahvdro-9Methvl-3-E'5-methv-L-1H-imiciazol-4-vl. ir.et--,nvlenz-,1 - 4 H-carDazol-4 -one methanesulphonate Litnium ciisopropylai-,iide (from n-Dutyllithium, 1.55M in hexane, -,.3m). and diisopropylamine (11.64m1) in THF (45m111) was ad e cropwisle over 15 min. at -50 under nitrogen to a stirred suspension of 1,2,3,9'Letrahydro-9-methyl-4H-carbazol-4-one (15g) in THF (510m.Z.". AtLe-min., Intermediate 2 (26.5g) was added in one portion and the resultant solution was stirred at -5 to +50 for 1.75h. The solution was treated with acetic acid at below 200 and stirred for 1h. Methanesulphonic acid (34m1) was added and th,e mixture was stirred and heated under reflux for 16n. The resultant suspension was cooled to - 43 P', stirred at oelow 5 0 for lli an1 the solid was Fil tereo off. The Product was wasned with THF '2x51im). and iried in at 533 to Clive a soii-,, (28.5c was recr.,s'all,s-c Ir-in t3 c-ve ne t t 1 e -.oTDo.-.n(i 3 Analysis Found C,54.5; H1,5.3; ';,9.'15; C13H ', 1. 4 CH requices C,5_'.7: H,5.35; N,9.9%3.

17 113 403S Ex3in.ol.- ?9 1 2 3. 9 - T et r a 9 v d _ro-9 m e t h,, 1- 3 5 - me tn v 1 - 1 H_ imi cj a zo 1- 4- v 1',Me l. h v 11 -L..H - soLution of f,"-'"-1.2,3,9-tetrc-hvdro-gm--tnvl.-3-rl'5-,-nethv'--!H- in, in iret.-..harol "1,5nuMI".

an o tr, ie tn a m ine 3 6,.!' jv-=s rocen a 'L ei at roo in 'L e-.,-nre c a L, ur e a nd at,nosphen.-ie presc-..-;,-e ove-c a suspenslon oft pre-re.juced 10% palladium ox ice on c a c non c a t a a cue,,, us pas --e: 1 Q', in me t,nanoli,1 Orri.(",' 'the mixture was then ux. WateC -was n -1 1 L 9_ D 30- c o nc en t: r a t ed t c -- 2 10 0,9 and ns ea t ed, t o aodec and was cooLes ts 00.

Tn e su I t a n t s o -L -4 d w p- s D..4 a r a -1 ,jaL- anc OrLei Lri vacuo at r.:D Cj,,,e -:ne --iz:le corr.jct-,n2: 3..Cci" The anc t.l.c. oF,,4ecA- consistent witn those oo'Lain-nz F01r tne pc3duct IF Exam.ple 8.

5-m---ny'L-1H-imi-dazo.'L-4-vl-)me-hvil-9-,p.etr)vl-4H- carDazol-4-one hvdrochlori--'-e monohvdr:ge A susoensi_.n oF 1.2,3,9- rahvd.-o3 L,, -methvl-1H-i.,nidazol-', Y1)metnyl] 9 metnv 1-4H-caroazol--,, -one in IMS "?-00ml',, was heated to ooilina and 2' hvdrich'Loric acd 150m.2,' was added. The r--sul'LinQ solution was allowed to cool to 200. the resultant suscension was 0 stirred for 1h and then cooled aL 0 r 2.1. The or,)auc'-was filtered off and dried in vacuo at 5-50 Ci- the title comoound M.P. 2900,cecomp.).

Analysis Found: C,614.1; H,6.25; N,12.05; C1,9.85; C18H19N3O.HC,z.H20 recui.---s C,62.5; H,6.4; N,12.15; C),10.25%].

1 CI 44 Exa.mDle 71 ' I- - -r.ethvi]- 9-Te'rahvdro-9-,-nethvi-3-E "5-.-nethvl-l H-ir-ntidazol-4-v 1 A solution o', i,nilazol-Lvl'jmet-nyll-4H-carbazol-4-one (500me) in warm methanol 30m-1 was treated with a solution of '+,--2,3-Dis-,FE"4- methvlpnenvi" MeL C3C,-)0n,.illoxvl acid 690ma. in Lhanol (10m.C and the s3i,jton was allowed to stand at 00 for 3 ciavs. It was then filtel-en ti 1--a,j-- a solic which was recrvstallised from methanol to give tne cesi-red salt;'1195mq,', m.p. 146-1480. A portion oF this salt was suspended in water 10m.Z'/ and potassium caroonate solution l(i in watec. was added and the mixture was extracted wit-'n Tne comD4Lried, cried orqanic extracts weDe in vacuo to leave the -t-- 4tle COMD0und 7Q,.2mQ,' as a solid, m 230-2320 r 29-.70 c.= 0.4100' CHCl -49 11 1 3 E xam- l e-3 2 -hvdro-9-meti-.,, 2i oazo'i -4-3ne solution of '±.,-1Y2,319-tetrahydro-9-m--"-hyl-3-rL'5- tr.ethvl-1Hin---azol -t.,-vl-,..-nethvll-4H-carbazol-4-one (500mc) in warm methanol.'.3jfn.),' was treate,' with a solution of \.-1273-nis- rL[fk4--.ieL-hv'Lpnenvi-j 2a-3cnv-l-l.--x,;!, oi,,.aneu-ioic acid 'C')90mQ in methanol f10m,' and tne so-!ijui-on was allowed to stand at 00 for 3 days. It was tme-n Filtered ti leave a solid which wa.s recrystallised from methanol to give the jesifed salt '162mQ',, m.p. 147- 1490. This was suspended in water,15m) and potassium caroonate solution (. 1g in 1OmI water) was added, and tne mixture was extracted with dichloromethane 'k2x3OmY-11. The. comoined, dried organic extracts were evaporated in vacuo to leave the title compound (72.5ma) as a solid, m.p. 230-2320, [a] 20_48.40 (c.= D 0.4L.O.', CH.Cl 31- Example 33 1,2,3,9-Tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4yl)methyll-4Hcaroazol-4-one 35 1 b ir so,' ution of I nl--rn. edi ate.19 G rri,:i' in dpv DM-- 1 m. W 3 S alde:i dropwise to a stirred suspension of sDdiu-.i h\,,9Eicle in oil: 20r,-ia.' in dry DKIF unce-, nitrocen. 15 iodomethane f0.02-1-nJ, w3s aded an;! the -nixtjr-e was Water 1\.1Ornl, was adjed anc. susDensi.:)n was extracted dichloromethane (3x110m), The combined, dried o7natic extracts were e,vapora'L--d to nive an oil ca. 300.,rci'. W-lich was In, a of THF acetic acid and water and heated at reflux for 1.5h. Tne mixture was Poure.d inta r(3,,ass-;um cc-rb.,Dnate solution "20,-n.Z, and extractecl with dicnlozomel-nane. T h. e corr,Dined, dried oroanic extracts we.-e e,,aoo.-ated to ci,,e a se:-,-;so-li- ca. 255.nc',' w-ic.h was ptjri--e,, Dy SPICC elj----i-ic witn Svz-zel D 1, material wep-= consi stenz -;nose oocla-,,-.ec F3r e;D:'sc.-c: if pie Lxamo-Le 3 1n, M -V 4 3 9 e:i carcazo-!--',-one n-Bu.L-yll itnium (1,. -'15M in hexane, 2.', -,m-" was to a irv coici (-700'1 stirred solution of ci-;-lsoDroovia-,i-ine THF unde7 nitrocen. TMe sollution qas a-'-',Dwe-,) ti reac'l 0 o\ie.

3.0 min, cooled to -700 and added t-3 a c-old s:c7ec sclution o.

1 2,3,9t--trahvoro-9-me-nvl-'-",-'-cacna--7 3 In --c,, T;iF 1Ori.,Z under nitrocen. Hexametnyl,nhosohorami;je was added and tne mixture was allowed to r--acn 00 over 1h. The so-'.,,jt-icn was cooled to -700 and a suspension of h-'--n!3rometnvl, -1H-imidazole f930'mc', in ory THF "15m.Z, was a,-4ced anc tne mixture was allowed to reach ca. 200 o,er 2.5n. It was sticre- For a further 18h, poured into W6 sodium bicarnonate so'lution (100m),' anG extracted wii dienloromethane '3x50m).,. The cr,,noit-ieij, IP-Lec)rn-anLc extracts were evaporated to give a semisolld.4hicn was treated wit' a mixture of acetic acid (10m.Zi, water (10mI, and THF \'.10m),,' anc heated at relolux for 1.5h. The solution was poured into saturated potassium carbonate solution (10OmmY) and extracted with dicnloromet,-iane 3x50m,,. The combined, dried organic extracts were evaporated to Qive a solid (ca. 1.8g) which was purified by SPCC, eluting with System A '200:10 :1 1, 1 7m Tne to nve the title cor--)c)unci c, H L -n.m.r. anG of t!lls were consistent with tnose oDtailel fro;,i the Product Of 1 2 3 9-Tetrahvcro-9-meL1-,,v-IL-3-[ f,5-.,r.e'Lhvl-1H-irr.laazcl4-vl', methvll- 1 3, 9-T---rar-,vj ro-9-meth, 1-3 -FL '15 -.-9e4I-hvl- 1 H- irn idazo 1- 4 -vl'), met.hyl -1, L '37.

a-!-j a z -j 1 e. P, a ' e a a -nci' was Qartitioned Detween 2', bicaroonate and %3x15r.i.Z". The combined, dried orclanic layers we.-e evaporated to cive tne free base which was dissolved in 10% aci-;e2us at -100 uncie.- nitroqen. To this stirred solution, a s3,jt-;on cl 2,--,-.,-icnior,---5,0'-ci2vano-1,4-oenzo?juinone in tiry was accec cjr,3.owise and the reaction mixture was allowei to U ove2 3n. Tne soiutijn was evaporated in vacuo and purified to "'-C e-j-L.'L.ne S,,sten, A \,9-".5:5:0.51 ti alve the 'Llt-le comoou-d as a soi-a.;me 1-nn.m.r. and t.l.c. of tn--Ls material were witn tincse obtained for tne p,-ojuct of 315 3 k-',-,netnvl-1H-imidazol-14-vl.methv 3-.le:ncxv---FI.15-m--th\,'.-1-',triQhenvlmethvli-1H-irnidazol-'-,-vl' \.203,TiQ, was treated with a mixture of water '5m,,',. and -2\ nvirochloric acid '0.45m.Z,' and the resultant solution was s-.iced at room temPerature under nitrogen for 18h. 1-Methyl -1DnenvIhvdrazine!0.05m. Z, was added dropwise and stirrinn was continued lir 7h. Further 1-methy11-phenylhydrazine (0.05mtj was added and stirr-inQ was continued at room temperature for 5 days. The suspension was poured into 8%) acueous sodium bicarbonate fklOmZ", and extracted with ac e t a t 3 x 15 j The combined, dried orqanic extracts were evaporated to give an oil 'ca. 240mn) which was purified by FCC eluting k_ wit'i System A (189:10:1) to aive a solid (55mQ). A portion of this solid (40ma) was heated at 850 with fused zinc chloride (450ma) in glacial acetic acid f\.3m) for 5h. The mixture was cooled, poured into 9- N aqueous sodium hydroxide (20m.Q and extracted with ethyl acetate 3 x l 5rr,1', Ine comoinen, oried orqanic extracts were e,,aporat.--j to aie an oil 'ca. 20mQ', which was purified D, FCC elutina with S,,sten A ir.q: The 114-n..n.2. anc t.l.c.

(89:10:1/ to Give the title corrc)un, L of this material were consistent those 0,')t3-iiied for the Example 8.

Example 37

1 2 3 9-T-tra.hvdro-9-,net,.ivl-3-F 5-methvl-l ---- - - H- i.Ti c a zo 1 ',ne tz n v -4H-carDazol-4-one A solution of 172,3,9-tetrahvdro-9--,..-thvl-3-F1[5metnvitriphenvlmef-hvl"-1'A-imidazol-4-vlljmetnvll--artDazo'--'-I -one in a mixture of Glacial acetic acid "5mz,, THF 5,n.Z, and water '5m)-', was heated at 100-1100 fir 8n. Afteu ccolinc, 2' Sod:jm i,drcx-' e '50r mI, was a--(jec anc tne result-Ing suseensii-n was ext-racted w--,-i dienlorometnane (2x50m1';. T IMe comD-Jnee. Crcanic extracts weze concentrated ti Q1ve a foam wh-i,,n was -,!ri7ed v F-= ei!jtlno wit,) Systern A to give the 'Lit-.e as a so!-;rj. Tne H-n.m.r. and t.l.c. o th-Js mateEia! were consistenz wi,-.-, t,,ose obtaineil- for tne PrOduct oF Examc-le 8.

-)o Examole 38 1 2.3 9-Te'rah, C. ro-c- me thvi-3- F -4Hcaroazol-4-one A solution of oxo-1Hcarc)azol3-vl'lmet,-iv']-1Li-imi-,-laz-jle-i-suipnonamide'400mc', in 2N L hydrochloric acid (30mY.',. anc aosoltite ethanol was heated at 100-1100 for 8h. Work up and FCC as oes=ioed in 32- jave the title compound (261ma) as a solid. The!H-n.,,n.r. and t.l.c. of this material were consistent with those oDtained for the product of ExamD,'-8.

Example 39 1,2,3,9-Tetrahvdro-3-[(5-meknvl-1H-imidazol-L-vl "me"i'lvl'-qmeth,,1-!4Hcarbazol-4-one A solution of the products from Inter.fleciate 16 \'0.2a" 1 in 49% hydrobromic acid (3m1) was stirred at 200 for 30 min.The mixture was 48 - 13 -)5 tnen heated on a steam natn For 30 min. and refluxed cienLJ,, (at ca.

fo:. 1. 5n Tne mixtire vas diluted with water (.20,92.' and wasec-1 sitn et.,ivl acezate ci.s2arieG, The acidic a-,L:ejus pnase was nasi-,ed ',to witn potLasslj7,. carbonate and extracted witn aceL-ate:ethanol (20:1; 2x30m.Z'Y,. The combined, dried organic extracts 4ece evaporate-, to leav-- a solid which was tritursted with any ether 5xl' to aive tne title compound fO.09cj' as a solid. The 1!i-n.m,.r. and t.l.c. of this material were consistent with those ootained for the orocuct of Example 8.

Examc-le 40 1.2.3 A solution o tne oroducts from intermediate 171 (0.5o' in a mixture of absolute ethanol 1'20m-',, and 21.M hydrochloric acid.,ias es:ed on a steam oath for 1n. The resultinu solution was concentrated in vacuo to ca. 20m 1 diluted with water and washed with etnvl ancetate f,-gx.,0m,.4 ciscaEdeLti The acidic acueous layer was basified fto o,i 9, witn potassium caroonate and- extracted with et-ivl acel- ate:etnancl 1,7 L - -9:1; 2x50m1_ The como'ned, oriei organic extracts were evaporate- zo nive the title ccmDounc kO.3-'g' as a solid. The 'H-n.,m.r. and I- 1 1 - 1 1 - - c. o' t.n;s mal-erial were consistent with those obtained for the,:3cuct of Example 8.

The fol!3w.nci examples illustrate pharmaceutical formulations acc,3Piina to the invention, containing 1,2,3,9tetrahvdro-9-m--thyl-3metnvl1Hiinidazol-l-vljmet.,yll-4H-carbazo l-4-one as the active incredient. Physioloqically acceptable salts and/or solvates of this comoound, and other compounds of formula I, and their physiolooical1v acceotable salts and.lor solvates may be formulated in a similar manner.

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

- 49 Tne tablets inav be film coated with suitaPle Film Forininj materials, such as hvdroxvpllopyl metnvlcellulose. usiric stan-,@,-d teChnicues. Alternativelv the taolets may ne stica,- coatej.

Direct Compression TaDlet Active Ingrezjient Calcium Hydrogen Phosphate BP Croscarmellose Sodium NF 1Macnesium Stearate BP 1 Lom3cess-ilon 4e-ont oF a aracde suitaole for direct comocession.

0. 50 8 -17. 2- 5 1.80 0 5 9C.00 The active incredient- was Passed thpot,,cn a 6.0;Ties.i sieve, blended witn the -calcium hyoricen QhosDhate. crtDscac.-nell:)se sodium and macinesium stearate. Tine resultant was coir.ocessei i.nzo taolets using a F3 tablet- machine Fitted witn 5.5mm, iFlat oevelled edce punches.

Sun-Linouall TaDlet Active Inaredient Compressible Sugar NF MaQnesium Stearate BP Compression W--ign'L mc, taclet 0.5 61.5 0.5 65.0 The active ingredient is sieved throuch a suitable sieve, blended with the excipients and compressed usLnQ suitable punches. Taolets of other strengths may oe prepared by alterinc either the ratio of active ingredient to excipients or the compression wei4aht and usino Punches to suit.

,.,'et Granulation 1 Conventional Tan.le Active In:resie.nt LactoSe BP Starch BP Prenelatinisec Maize Starc.n BP amnesium Stearate 1:P L Compression Weiqnt ? 0 ? 5 mQ/taDlet 0.5 153.5 30.0 15.0 1.5 200.0 The active inaredient is sieved throuch a suitable sieve and witn lactise, starh and precelatinised maize starch. Suit an' e o' purified water a.-e acided and the powders a7e cranulated.

irvinQ, the Qranules are screened and blended with the mannesium s--arate. The -,ranuies are then compressed into tablets usina. 7mm c,3-i-tez Qunches. TaDlets of other strenaths mav be preoared ov alterina the ratio j active incredlent to!aCtose or the compression weiQht and usina ouncnes t3 suit.

Tanlet.Acti.ve Ingrejient Mannitol BP Hyjrox,ioroovlmethylcellulose MaQnesium Stearat-e BP LOMpression Weight ma/taolet 0.5 58.5 5.0 1.0 65.0 The active inQredient. is sieved throuqh a Suitable sieve and Diended witn the mannitol and hydroxvoropylmethylcellulose. Suitable volumes ofpurified water are added and the powders are Qranulated. After dryinq, the granules are screened and blended into tablets usinq suitable punches.

'1 faDlets of other strenqths mav be prepared D,. alteriti,,- tne of active inQredient to mannitol or the compression weicint and pun-ches to suit.

CAPSULES Active Incireoient Starch 1500 MaQnesium Stearate BP Fill Weight 0.5 98.5 1.0 100.0 a form of directly compressiDle Tne active incredient is sieved and nle-Cec tne The mix is filled into size N.o. 2 hard qelgl---4ln caosules usinc suitanle machinery. Other coses may nePreoafec Dy -mi-euina tne fill weicht and if necessarv chanainn the capsule size to suit.

SYRUP This mav-be either a sucrose or sucrose free)resentation.

A. Sucrose Syrup Active Ingreolent Sucrose BP GIycerine BP Buffer Flavour Colour Preservative Purified Water BP mc,'5m! close 0.5 2-1,50.0 500. 0 as recu-i----d to 5. Ornl The active inQredient, buffer, flavour, colour and preservative are dissolved in some of the water and 'the glycerine is added. The remainder of the water is heated to dissolve the sucrose and is then cooled. The two solutions are combined, adjusted to volume and mixed. The syrup is clarified by filtration.

2 B Sucrose-Free Active Inqredient HyciroxvQropyl,net,liylcellulose USP,\.viscosity type 4000; 1 -0 mo.5rr-'. cose 0.5 22.5 BuFer Flavour Co iour Preservative Sweetener PuriFiec War-er BP to 5.Omi The myoroxypropylmethylcellulose is dispersed in hot water, cooled ana tnen mixed with an aQueous solution con'taininQ the active ingre(,'ient and the other components of the formulation. The resultant so-]-jt-,on is adjusted to volume and mixed. The syrup is clarified Oy iltea--ion.

!',-7i-'TTON FOR INTRAVENOUS ADMI\TSTRATION 1 - Active incredient Socium Chloride BP 'YVate:, for Injection BP to as recuired MC1/M.z 0.05 as reouired 1.0my 0.5 as recuired 1.0M2 Sodium chloride may bee added to adjust the tonicity of the sjl.-;tion and the pH may be adjusted, using acid or alkali, to that of o,,D't-i- nutTi staoilitv and/or facilitate solution of the active inQredient. Aiternatively, suitaole Duffer salts may be used.

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 cvcles. 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.

53 METERED DOSE PRESSURISED AEROSOL SusDension Aerosol mc.i 1 metered dose Active InQredient micronised 0.050 1 2.Oinq Oleic Acid BP 0.020 4. SOMC Trichlorofluoromethane BP 23.0'-', 5.6(i DiJchlorodi'iluoro,methane BP 611.25 14.70o The active ingredient is micronised in a fluid energy imill to a fine particle size ranee. The Oleic Acid is mixea w-itM the TriChlorofluoromethane at a temperature of 10-15'3C and the micronised drug is mixed into the solution witn a high shear mixer. The suspension is meterec into aluminium aerosol cans and suitaole metezinci,alves, delivering 85mg of suspension are crimped onti the cans and tne DichlorodiFluoromethane is pressure filled into the cans throuQh the valves.

Solution Aer--sol M0,11- tered dose Per can me L Active Ingredient 0.05 1 2. 0 m cl Ethanol BP 7.500 1.80Q Trichlor3Fluorometnane BP 18.8715 4.539 Dichlorodifluoromethane BP 48.525 11.65o Oleic Acid 1-10, on a suitaDle surfac-ant e.Q. Span 85 ( soriDitan trioleate) may also Oe included".

The active inQredient is dissolved in the ethanol toQether with the Oleic Acia or surfactant if used. The alcoholic Solution is metered into SuitaOle aerosol containers followed ov the trichlorofluoro-methane. Suitaole metering valves are crimped onto the containers and dichlorodifluorometnane is pressure Filled into tnem through the valves.

54 Inalation Cartridaes is ma/cartridoe Active Ingredient (micronised) Lactose BP 0.05 to 25.00 The active inqredient is micronised in a fluid energy mill to a Fine particle size range prior to blendina with normal taolettina arade lactose in a hinh energy mixer. The powder blend is filled into No. 3 mari aelatin capsules on a suitable encapsulatinQ machine. The contents of the cartridges are administered using a powder inhaler.

SUPPOSITORY Active Ingredient Witepsol H15 to 0.5mg 1.0a Witepsol H15 is a proprietary grade of Adeps Solidus Ph. Eur. A susoension of tne active inaredient is preoared in the molten Witepsol and filled, using suitable machinery, into lq size suppository moulds.

Claims (29)

CLAIMS:

1.

Compounds of the general formula (I):

Q 0 !I A Im B CH2) n R' (I) wherein Im represents an imidazolyl group of the formula:

R4 R4 N NR3 1 R2 or 1 p3N R _ N R1 represents a hydrogen atom or a group selected from Cl-6alkyl, C3- 6alkenyl, C3-10alkynyl, C3-7cycloalkyl, C3-7cycloalkylCl-4alkyl, phenyl, pheny1C1-3alkyl, -C02R5, -CORS, -CONR5R6 or -S02R5; R5 and R6, which may be the same or different, each represents a hydrogen atom, a Cl-6alkyl Or C3-7cycloalkyl group, or a phenyl or pheny1C1-4alkyl group, in which the phenyl group is optionally substituted by one or more Cl-4 alkyl, Cl-4alkoxy or hydroxy groups or halogen atoms, with the proviso that R5 does not represent a hydrogen atom when Rl rep resents a group -C02R5 or -S02R5; one of the groups represented by R2, R3 and R4 is a hydrogen atom or a Cl- 6alkyl, C3-7cycloalkyl, C3-6alkenyl, 56 phenyl or pheny1C1-3alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a Cl-6alkyl group; Q represents a hydrogen or a halogen atom, or a hydroxy, Cl-4alkoxy, pheny1C1-3alkoxy or Cl-6alkyl group or a group - NR7R8 or -CONR7R8; R7 and R8, which may be the same or different, each represents a hydrogen atom or a Cl-4alkyl or C3-4alkenyl group, or together with the nitrogen atom to which they are attached form a saturated 5 to 7 membered ring; n represents 1, 2 or 3; and A-B represents the group CH-CH2 or C=CH; and physiologically acceptable salts and solvates thereof.

2. Compounds as claimed in claim 1 in which Rl represents a hydrogen atom or a Cl-3alkyl, C3-4alkenyl, C3-4alkynyl, C5-6cycloalkyl, CS-6cycloalkylinethyl, phenylCl-2alkyl, Cl- 3alkoxycarbonyl, N,N-diCl-3alkylcarboxamido or phenylsulphonyl group.

3. Compounds as claimed in claim 1 or 2 in which R2 represents a hydrogen atom or a Cl-3alkyl group.

4. Compounds as claimed in any of claims 1 to 3 in which R3 represents a hydrogen atom or a Cl-3alkyl group.

5. Compounds as claimed in any of claims 1 to 4 in which R4 represents a hydrogen atom or a Cl-3alkyl group.

6. Compounds as claimed in claim 1 or 2 in which R2 and R3 each represent a hydrogen atom and R4 represents a methyl group.

7. Compounds as claimed in any of claims 1 to 6 in which 57 Q represents a hydrogen atom, a halogen atom or a hydroxy, Cl-3alkoxy or Cl-3alkyl group.

8. Compounds as claimed in any of claims 1 to 7 in which A-B represent CHCH2.

9. Compounds as claimed in any of claims 1 to 8 in which n represents 2 or 3.

10. Compounds as claimed in claim 1 in which R1 represents a hydrogen atom or a Cl-3alkyl, C3-4alkenyl, C3-4alkynyl, CS-6cycloalkylmethyl, pheny1C1-2alkyl, Cl-3- alkoxycarbonyl or -N,-N-diCl-3alkylcarboxamido group; R2 and R3 each represent a hydrogen atom; R4 represents a Cl-3alkyl group; Q represents a hydrogen or a halogen atom or a hydroxyl group; A-B represents CH-CH2 or C=CH; and n represents 2 or 3.

11. Compounds as claimed in claim 1 in which R1 represents a hydrogen atom or a methyl, prop-2-enyl, prop-2ynyl, cyclopentylmethyl, benzyl or N, N-dimethylcarboxamido group; R2 and R3 each represent a hydrogen atom; Rld represents a methyl group; Q represents a hydrogen or a fluorine atom; A-B represents CH-CH2; and n represents 2 or 3.

12. Compounds as claimed in claim 10 or 11 in which n represents 2.

13. 1,2,3,9-Tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol4-yl)methyl]-4Hcarbazol-4-one and physiologically acceptable salts and solvates thereof.

14. The compound of claim 13 in the form of a hydrochloride salt.

is 58

15. 1,2,3,9-Tetrahyclro-9-methyl-3-[(5-nethyl-1H-imidazol4-yl)methyl]-4Hcarbazo1-4-one hydrochloride monohydrate.

16. 6-Fluoro-1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1Himidazol-4-yl)methyl]-4H-carbazol-4-one; 1, 2, 3, g -tetrahydro-3-[ (5 -methyl1H-imidazol-4-yl)inethyl]- 4Hcarbazol-4-one; 9-(cyclopentylmethyl)-1,2,3,9-tetrahydro-3-[(5-methyl-1Himidazol-4yl)methylj-4H-carbazol-4-one; 1, 2, 3,9-tetrahydro-3-[ (5-methyl-1H-imidazol-4-yl) methyl] -9 10 (2- propynyl)-4H-carbazol-4-one; 6,7,8,9-tetrahydro-5-methyl-9-[(5-methyl-1H-imidazol-4yl)methyl]cyclohept[b]indol-10(5H)-one; and physiologically acceptable salts and solvates thereof.

17. A process for the production of a compound of general formula (I) as defined in any of claims 1 to 16 or a physiologically acceptable salt or solvate thereof, which comprises:

(A) for the preparation of a compound of formula (I) in which A-B represents the group C=CH, dehydrating a 20 compound of formula (II) Q 0 OH (CH2) n N 1 Rl Im (II) or a protected derivative thereof, followed if necessary by removal of any protecting groups present; or 59 (B) converting a compound of formula (I) into another compound of formula (I) using conventional techniques; or (C) for the preparation of a compound of formula (I) in which A-B represents the group CH-CH2, reacting a compound of formula (III) Q 0 N (CH2) n 1 R1 or a protected derivative thereof, with a compound of formula (V) is LCH2-IM (V) wherein L represents a leaving atom or group, or a protected derivative thereof, in the presence of a base, followed if necessary by removal of any protecting groups present; or (D) for the preparation of a compound of formula (I) 0 in which A-B represents the group CH-CH2, oxidising compound of formula (V1) Q (III) 2 A CH2) n N 1 Rl Im (VI) wherein A represents a hydrogen atom or a hydroxyl group, or a salt or protected derivative thereof followed if necessary 30 by removal of any protecting groups present; or (E) for the preparation of a compound of formula (I) in which A-B represents the group CH-CH2, cyclising a compound of formula (VII) Q 1 1 "", N- N R1 H or a salt or protected derivative thereof, followed if necessary by removal of any protecting groups present; or (F) removing protecting group(s) from a protected form of a compound of formula (1); and when the compound of formula (I) is obtained as a mixture of enantiomers, optionally resolving the mixture to obtain the desired enantiomer; and/or where the compound of formula (I) is in the form of a free base, optionally converting the free base into a salt.

18. A pharmaceutical composition comprising at least one compound of general formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof together with at least one physiologically acceptable carrier or excipient.

19. Compounds of the general formula (II) Q 0 OH CH2)n Im W 1 Rl 0 1 Im (VII) (CH2) n (II) 61 in which Im, RI, Q and n are as defined- in any of claims 1 to 11.

20. Compounds of the general formula (VI) Q A (CH2) n Rl Im (VI) in which A represents a hydrogen atom or a hydroxyl group and Im, Rl, Q and n are as defined in any of claims 1 to 11.

21. compounds of the general formula (I) as def ined in any of claims 1 to 16 and physiologically acceptable salts and solvates thereof for use in the treatment of a condition caused by disturbance of 1Ineuronall' 5HT function.

22. Compounds of the general formula (I) as defined in any of claims 1 to 16 and physiologically acceptable salts and solvates thereof for use in the treatment of anxiety.

23. Compounds of the general formula (I) as defined in any of claims 1 to and solvates thereof 16 and physiologically acceptable salts for use in the treatment of a psychotic disorder.

24. A pharmaceutical composition for the treatment of a condition caused by disturbance of 1Ineuronall' 5HT function which comprises as active ingredient at least one compound of the general formula (1) as defined in any of claims 1 to 16 or a physiologically acceptable salt or solvate thereof. -

25. A pharmaceutical composition for the treatment of anxiety which comprises as active ingredient at least one 62 compound of the general formula (I) as defined in any of claims 1 to 16 or a physiologically acceptable salt or solvate thereof.

26. A pharmaceutical composition for the treatment of a 5 psychotic disorder which comprises as active ingredient at least one compound of the general formula (I) as defined in any of claims 1 to 16 or a physiologically acceptable salt or solvate thereof.

27. A therapeutic agent for the treatment of a condition 10 caused by disturbance of 1Ineuronall' 5HT function which comprises as active ingredient at least one compound of the general formula (I) as defined in any of claims 1 to 16 or a physiologically acceptable salt or solvate thereof.

28. A therapeutic agent for the treatment of anxiety which comprises as active ingredient at least one compound of the general formula (I) as def ined in any of claims 1 to 16 or a physiologically acceptable salt or solvate thereof.

29. A therapeutic agent for the treatment of a psychoti-c disorder which comprises as active ingredient at least one compound of the general formula (I) as defined in any of claims 1 to 16 or a physiologically acceptable salt or solvate thereof.

Published 1988 at The Patent Office, State House, 66,171 High Holborn, London WC1R 4TP. Further copies maybe obtained from The Patent Office, Sales Branch, St Maxy Cray, Orpington, Kent BRS 3RD. Printed by Multiplex techniques ltd, St Mary Cray, Kent. Con. 1187. Sales Branch. St Maxv Crav. OrDbioWn. Kent 13ktb 6.K.U. k=wo by mulLipiex rec=ques itzL, bT, mary uray, AenL. uui:L itov.

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