NZ232598A - Imidazolylmethyl tetracyclic lactam derivatives and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £32598 232 59 No.-Date: Priority Datc(s):.

Corrvpicte Specification Filed: ...i— Class: (5)..,:.

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Publication Data: .... P.O. Journal, No: v. 28 JUL tfflK NO DR W.'!?,'OS NEW ZEALAND PATENTS ACT. 1953 COMPLETE SPECIFICATION I.

LACTAM DERIVATIVES ¥^We, GLAXO GROUP LIMITED, a British company, of Clarges House, 6/12 Clarges Street, London, W1Y 8DH, England hereby declare the invention for which J?! we pray that a patent may be granted to ro2/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by page 1A) - \A- l ACTAM ULR1VAT IVI'5 232 5 This invention relates to lactam derivatives, to proconr.es for their preparation, to pharmaceutical composi Lions containing them and to their medical use.

In particular tin* invention relates to compounds which ore potent and selective antagonists of 5-hydro\y LrypLuinine (5-411) ot 5-HT receptors of the type located on terminals of primary afferent nerves. Receptors of this type are now designated ns 5-HT3 receptors and 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 having antagonist activity at 5-HT3 receptors have been described previously.

Thus for example German Offenlegungsschrift No. 3740352 discloses 2^ compounds which may be represented by the general formula: 0 !i • • 8 // \ / \ / \ • •—-• A Im Q-4- !i 1! 1 v V /—<CH,) \ / \ / n .V ft 1 wherein Im represents an itnidazolyl group of the formula: R4 R4 / / I I , or J 'I N \!R3 R N / \ • R2 R* represents a hydrogen atom or a group selected from Cj_6alkyl, C 3_ ball<enyl, C3_ 10alkynyl, C 3_ -;Oycloalkyl, C 3_ yCydoalkylC j^alkyl-, phenyl, phenylC _ ,alkyl-, -CO R'j, -CORb, -C0\R=Roor -S0-R5 (wherein i j c Rs and Rg, which may be the same or different, each represents a hydrogen atom, a C^^alkyl or C 3_ yCycloalkyl group, or a phenyl or 9 232 5 98 phenylC ,(nIky 1- group, in which the phenyl qroup is opt Loiuil 1 y substituted by unu or mure C^^nlkyl, Cj_l(nlkoxy or hydroxy groups or halogen atoms, with tlie proviso that does not represent n hydrogen ntotn when R1 represents a group -C0.,RJ or -50-J?J); one of the groups represented by R RJ and R1' is u h>drogen ntom or a Ci_balkyl, C 3_ ;cycloalkyl, C j_ bnlkeny 1, phenyl or phenylC j_ ^nlky 1-group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a Ci_oalkyl group; Q represents q hydrogen or a halogen utoin, or a hydroxy, Ci_Halkoxy, phenylC j_ 3alkoxy- or C^alkyl group or a group -NR7R° or -CONR'R8 (wherein R7 and RB, which may be the same or different, each represents a hydrogen ntom or a Cj.^olkyl or Cj.^alkenyl 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 ttie group CH-CH, or C=CH; and physiologically acceptable salts ond solvates thereof.

We have now found a novel group of compounds which differ in structure from those described previously, and which are potent antagonists of the effect of 5 —HT at 5-HT3 receptors.

The present invention provides a tetracyclic lactam of the general formula (I): 0 A A A I a * f Im (l) • • •—(CH-,) \\ / \ / ^ n N V wherein n represents 2 or 3; Im represents an imidazolyl group of the formula: R3 R3 / / N iVR2 R 2N N \ / or \ !! R1 ^ fj*- ntm 4 W ^ 232 5 wherein one of the group:; represented by R , K *■ nnd K is a hydrogen atom or a Ci_balkyl, C 3_ /cycl on Iky 1, C3_0alkenyl, phenyl or phenylC jtilkyl- group, nnd each of the other two groups, which mtiy be the .same or different, represents n hydrogen ntom or o L'.^nlky] r group; V represents n group —(CM2^m~» wherein m represents 2, 5 or A; or V represents n group -X(C!lj)p-, wherein p represents 2 or 3, \ represents on oxygen or o sulphur atom or n group NR"1, where R"1 is a Cj-^alkyl group, and X is attached to the benzene ring moiety of the molecule; and physiologically acceptable salts and solvates thereof.

Suitable physiologically acceptable salts of the compounds of general formula (1) include acid addition salts formed with organic or inorganic acids for example, hydrochlorides, hydrobromides, sulphates, 25 alkyl or aryl sulphonates (e.g. methanesulphonates or £-toluenesulphonates), phosphates, citrates, succinates, tartrates, acetates, fumarotes and maleates. The solvates may, for example, be hydrates.

All optical isomers of compounds of general formula (I) and their 20 mixtures including the racemic mixtures thereof, and all the geometric isomers of compounds of formula (I), are embraced by the invention.

Referring to the general formula (1), an alkyl group may be a straight chain or branched chain alkyl group, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, 2-methylprop-2-yl, pentyl, 25 pent-3-yl or hexyl. A C3_6alkenyl group may be, for example, a propenyl or butenyl group. 'When RJ represents a C3_balkenyl group, the double bond may not be adjacent to the nitrogen atom. A phenylC3alkyl- group may be, for example, a benzyl, phenethyl or 3-phenylpropyl group. A C 3_ -/cyclonlkyl group may be, for example, a 30 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

A preferred class of compounds of formula (I) is that in which R1, R2 and R3 each independently represent a hydrogen atom or a C]_4alkyl (e.g. methyl) group. A further preferred class of compounds 23 2 5 4 - in thai wherein R1 aiul Reach represent a hydrogen atom, nnd RJ is a Cj.jHlkyl (e.g. methyl) group.

Another preferred cIush of compounds of formula (I) its that in which Y represents the group -(Ufl?)2-, -(CH;,)j- or —11 (CM ^, more preferably -(CH2);.- or -(CH^),-.

Preferred compounds according to the invention are: 5,6,9,10-tctrahydro-1 □—[ (5-methyl-lH-imidazol-4-y l)methyl]-4H-pyrido[31 ,4':4,5] pyrrolo[3,2,l-ij]quinolin-11 (8H_)-one; 4, 5, 7, 8-tetrahydro-9-[ (5-methyl-lH-imidnzul-4-yl )methyl]pvrido-[4,3-b]pyrrol o[3,2 ,l-hi]indol- 10(9jO-one; 4,5,7,8,9,10-hcxahydro-10-[ (5-methyl-lH-imidazol-4-yl)methy 1]-11H- azepino[4,3-b]pvrrolo[3,2,l-hi]indo L-ll-one; and their physiologically acceptable salts and solvates.

The potent and selective antagonism of 5-HT at 5 —HT 3 receptors by the compounds of the invention may be demonstrated by their ability to inhibit 3-(5-methyl-lH-imidazol-4-yl)-l-[l-(methyl-tj)-lH-indol-3-yl]-l-propanone binding in rot entorhinal cortex homogenates (following the general procedure described by G. Kilpatrick jjt _el. in Nature, 1987, 330, 746), and/or by their ability to inhibit the 5-HT-induced depolarisation of the rat isolated vagus nerve preparation.

Compounds of formula (I), which antagonise the effect of 5-HT at 5-HT3 receptors, are useful in the treatment of conditions such as psychotic disorders (e.g. schizophrenia and mania); 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 gastrointestinal dysfunction such as occur with dyspepsia, peptic ulcer, reflux oesophagitis, flatuLence and irritable bowel syndrome; migraine; obesity and conditions such as bulimia; and pain. Compounds of formula (1) may also be used in the treatment of dependency on drugs and substances of abuse, depression, and dementia and other cognitive disorders.

According to another aspect, the invention provides a method of treatment of a hunan or animal subject suffering from a psychotic 232 5 98 disorder such us schi /nphrenia nr mania; or from anxiety; nausea or vomiting; gastric stasis; symptoms of gastrointestinal dysfunction ouch us dyspepsia, reflux oesuphag itis, peptic ulcer, flatulence and irritable bowel syndrome; itiiqraino; obesity and conditions sucli us 5 bulimia; pain; dependency on drugs or substances of abuse; depression; or dementia or another cognitive disorder, which comprises administering an effective amount of a compound of formula (1) or a physiologically acceptable salt or solvate thereof.

Accordingly, the invention also provides a pharmaceutical 10 composition which comprises at least one compound selected from compounds of the general formula (I), and their physiologically acceptable salts and solvates (e.g. hydrates), for use in himan 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 be formulated for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose). for oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with phormaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or 25 hydroxylpropyl methylcellulose); fillers (e.g. lactose, raicrocrystalline cellulose or calciun hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrates (e.g. potato starch or sariiun starch glvcollate); or wetting agents (e.g. sodiun lauryl sulphate). The tablets may be coated by methods well known in 30 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 35 as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or 232 5 9 ncncia); non-aqueous vehi cle:; (i?. y. almond nil, oily ester:;, ethyl alcohol or fractionated veget iibl c oil;;); nnd preservot ives (e.g. methyl or propyl-jj-hydrovyben/oates or sorbic acid). Itu: preparations may olso contain buffer salts, flavouring, colouring and sweetening 5 agents a:; appropriate.

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

For buccal administration the compositions may take the form of tablets or lo/enijes formulated in conventional manner. 10 The compound:; of the invention may be formulated for parenteral administration by bolus injection or continuous infusion.

Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or 15 emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may tie 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 25 compounds of the invention may also be formulated as depot preparations- Such long acting formulations may be administered by implantation (for example subcutaneouslv or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic 30 materials (Tor example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

For administration by inhalation the compounds according to the invention are conveniently delivered in ttie form of an aerosol spray 35 presentation from pressurised packs or a ncbuliser, with the use of a suitable propellent, e.g. dichlorodifluoromcthane, 2 3 2 5 9 8 triehlorofluoromethane, dichlorutet rufl iniroetluine, cnrhon dioxide ur other suitable gas. In tho cnst: of n pressurised aerosol t hi- douage unit may be determined by providing a valve to deliver a metered amount. Capsules und cartridge:; uf e.g. gelatin for use in an inhaler 5 or insufflator may be formulated containing a powder mix of a compound of the invention ami a suitable powder base such a:; lactone or starch.

Tor intranasal administration, the compounds according to the invention may lie formulated as solution:; for administration via a 10 suitable 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 15 treatment of gastric stasis, symptoms of gastrointestinal dysfunction and nausea and vomiting, the compounds of formula (I) may be administered in combination with antisecretory agents such as histamine H .,-receptor antagonists (e.g. ranitidine, sufotidine, ciinetidine, famotidine, nizatidine or roxntidine) or H+K+ATPase 20 inhibitors (e.g. omeprazole). In the treatment of nausea and vomiting, compounds of formula (I) may also be administered in combination with dexernethasone or a cycl o-o\ygenase inhibitor such as piroxicam.

A proposed dose of the compounds of the invention far 25 administration to man (of approximately 70kg body weight) is 0.Q01 to lOOmg, preferably 0.0.1 to 50mg, of the active ingredient per unit dose expressed as the weight of free base, which could he administered, for example, 1 to A times per day. It will be appreciated that it may be 30 necessary to make routine variations to the dosage, depending on the age and condition of the patient. The dosage will also depend on the route of administration.

Compounds of general formula (I) and physiologically acceptable 35 salts or solvates thereof may be prepared by the general methods outlined hereinafter. In the following description, the groups R* to RJ, n, Y and Im are as defined for compounds of general formula (I) unless otherwise stated. 23 2 5 9 According to n fir.st general process (A) a compound of general formula (I) may lie prepured by alkvlat iny n r; ompoutid of" formula (II): 0 il /A A • • • Mli I II il I N (ID • • • (CHp) \\ / \ / 2 n • N Ly J with a compound of formula (111): LCH,-Im (III) or o protected derivative thereof, wherein L represents a leaving atom or group, such as a halogen atom (e.g. chlorine, bromine or iodine), or on acyloxy group (e.g. trifluoroacetyloxy or acetoxy), or a 15 sulphonyloxy group (e.g. trifluoromethanesulphonyloxy, £-toluenesulphonyloxy or methanesulphonyloxy); followed where necessary by removal of any protecting groups. L is preferably a halogen atom (e.g. o chlorine atom).

The reaction may be carried out in an inert solvent such as on 20 ether (e.g. dimethoxyethane, diglyne or tetrohydrofuran), a substituted amide (e.g. dimethylforrnamide or _N-methylpyrrol idone), an aromatic hydrocarbon (e.g. toluene), a ketone (e.g. acetone), or dimethyl sulphoxide, at a temperature between ambient and 1Q0UC, in the presence of a base. Suitable bases include alkali metal hydrides 25 (e.g. sodium hydride), alkali metal carbonates (e.g. sodium carbonate), alkali metal amides (e.g. sodiuft amide), alkali metal alkoxides (e.g. potassium _t-butoxide) or alkali metal hydroxides (e.g. sodium or potassium hydroxide).

According to another general process (B), a compound of general formula (I) may be converted into another compound of formula (I) using conventional techniques. Such conventional techniques include hydrogenation and alkylation using protection and deprotection where necessary.

Thus, according to one embodiment of the interconversion process 35 (B), hydrogenation may he used to convert an alkenvl substituent into an alkyl substituent. Hydrogenation according to general process (B) 232 5 may be effected using convent inmil procedures, for examplu, using hydrogen in the presence of n catalyst, na described in published European Patent specification No. 242973.

Ihe term 'nlkylation' according to general process (B) includes the introduction of groups such as cyclonlkyl, nlkenyl or phonalky] groups.

Thus, for example, n compound of formula (1) in which R2 represents a C,_0nlkyl, C /:ycloolkyl, C^_oalkenyl or phenylC 3al kyl- group inoy be prepared by alkylating the corresponding compound of formula (1) in which R2 represents a hydrogen atom, using conventional procedures, for example as described in published European Patent specification No. 242973. Thus the reactions may be effected using an appropriate alkylating agent of formula R^Z (where Rb is the group to be introduced and Z is a leaving atom or group), preferably in the presence of a base.

It should be appreciated that in the above transformations it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in question to avoid undesirable side reactions, for example, it may he necessary to protect the imidazole nitrogen atom, for example with on arylmethyl (e.g. trityl), alkyl (e.g. _t-butyl), alkoxymethyl (e.g. methoxwiethyl) , acyl (e.g. benzyloxycarbonyl) or a sulphonyl, (e.g. jN,\-dimethylamir>osulphonyl or £-tolucnesulphenyl) group.

Thus according to another general process (C), 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 those described in 'Protective Groups in Organic Synthesis' by T. W. Greene (John Wiley and Sons, 1981). for example, a trityl group may be cleaved by acid hydrolysis (e.g. using dilute hydrochloric or acetic acid). An alkoxyalkyl group may be removed using a mineral acid (e.g. dilute hydrochloric acid). An acyl group may be removed by hydrolysis under acidic or basic conditions (e.g. using hydrogen bromide or sodium hydroxide). A sulphonyl group may be removed by alkaline hydrolysis.

- ID - Compounds of formula (II) may be prepared, for example, hy cyclisiny a compound of formula (IV): 0 II //\ /\ 232598 <JH • • «—(CH i) \\ / \ / N N (IV) V or a salt thereof. The cyclisation may be carried out in aqueous or non-aqueous media, optionally in the presence of an acid catalyst.

When on acid catalyst is used, this may be, for example, an inorganic acid such as concentrated sulphuric or hydrochloric acid. The acid catalyst may also act as the reaction solvent. In an anhydrous 25 reaction medium, the acid catalyst may alternatively be a Lewis acid such as zinc chloride. The cyclisation reaction may conveniently be carried out at a temperature in the range of 20 to 200°C. When no acid catalyst is used, the cyclisation may be effected thermally, by heating in a high boiling organic solvent, such as diethylene glycol, 2o conveniently at a temperature in the range 100 to 200°C.

Compounds of formula (IV) may be prepared, for example, by the reaction of a compound of formula (V): (V) // \ • • f » • • V v V ~ or a salt thereof, with a compound of formula (VI): 0 it /\ (VI) . m I ,i ^ •—(CH ,) U n 0 V»fc * " V ^ L J 23 or it protected derivative thereof, in u suitable solvent such as on alcohol (e.g. ethanol), ami at. n temperature of, fur example, from 20 to 100°C.

Alternatively, compound;; of formula (II) may be prepared directly r by t.bo reaction of a compound of formula (V), or a sail thereof, with a compound of formula (VI), or a protected derivative thereof, using the appropriate condition;; us described above. Compounds of formula (IV) may be isolated u:» intermediates in the above reaction.

Compounds of formula (III) and protected derivatives thereof, are either known, or may he prepared, for example, by the methods described in German Offenlegungsschrift No. .5740352- Compounds of formulae (V) and (VI) 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), a halogenated hydrocarbon (e.g. dichloromethane), 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 ot- compound of formula (I) using conventional methods- Individual cnantiomers of the compounds of the invention may be obtained by resolution of a mixture of cnantiomers using conventional means, such as an optically active resolving acid; see for example 'Stereochemistry of Carbon Compounds' by C.t.Qiel (McGraw Hill, 1962) and 'Tables of Resolving Agents' by 5. H. Wilen.

The methods described above for preparing the compounds of the invention may be used for the introduction of the desired groups at any stage in the stepwise formation of the required compounds, and it will be appreciated that these methods can be combined in different ways in such multi-stage processes. The sequence of the reactions in multi-stage processes should of course he chosen so that the reaction conditions used do not affect groups in the molecule which are desired in the final product. 232598 Itu' invention i :> further i 1 1 ustrat «:d hy the following Intermediates and fxiunpl es. -Ml t empor at ures are in ^C. Thin layer chroma t ocjrnphy (t.l.c.* was carried out on silica, and flash nolimn chromatography (i CI') was i:a r r i t'i 1 out on silica (Merck 9 5 B!»). Solvent 5 System A as used for chromatography denotes dichloromethane: e t haanl : 0. 88 nrmnonin solution. Organic extracts were dried, where indicated, over magneniuu sulphate.

Intermediate 1 5.6,9,10-Tetrahydro-4H-pyrido[ 3' ,4' :4 ,5 1 pyrrol ol_3,2,]-ij]-quinolin-.ll(8H)-one A solution of 2-amino-l, 2, 3,4-tetrahydroquinol ine hemisulphate (500mg) and 2,4-dioxopiperidine (287mg) in absolute ethanol (20ml) was kept under nitrogen for 20h. The solvent was removed in vacuo to leave a 15 gum (700mg) which was treated with concentrated sulphuric acid (7ml) for 15 min. The resulting solution was neutralised with 8S> sodium bicarbonate solution (200ml) and extracted with dichloromethane (3x100ml). The combined, dried organic extracts were evaporated to give a solid (47Qmg) which was purified by TCC eluting with System A 20 (400:10:1) to give the title compound (230mg) as a solid, m.p. 254-256°.

Intermediate 2 4,5,7,8-T ctrahydropyrido[4,3-b]pyrrolo[3.2,l-hi]indol-10(9H)-one 25 A solution of 1-amino-indoline hydrochloride (l.Og) and 2,4-dioxopiperidine (663mg) in ebsolute ethanol (40mX) was stirred under nitrogen for 48h. The solvent was removed in vacuo and the residue was dissolved in diethylcne glycol (30ml) and heated at 200° for 2h. The solution was allowed to cool, poured into water (200ml) 30 and extracted with dichloromethane (3xl00m£). The combined, dried organic extracts were evaporated to give an oil (ca.2.5g) which was purified by short path column chromatography on silica gel (Merck 7729) eluting with System A (400:10:1) to give the title compound (330mg) as a solid, m.p. 265—2670- 23 2 5 9 Intermediate 3 3 ,4-Dihydro-2H-l ,4-beii/oxo?in-4-amine A cold (0U) solution of sodium nitrite (2.6g) in water (12.5mA) wns added dropwisu to a cold (l) °) stirred solution of 3, 4-dihydro-2M_-l, 4-^ benzoxa/ine (4.9g) in water (27.'>mA) and concentrated hydrochlori c acid (9.5mA). The mixture war. stirred at 0-5 u for 1. , then extracted with ether (3x60mt)- The combined, dried organic extracts were evaporated to give a solid which was dissolved in a mixture of acetic acid (11mA), water (11 m.5.) und ethanol (17in?.) and added dropwise jq to o vigorously stirred suspension of zinc powder (25y) in ethanol (32mA) at 40-50°. After 30min the mixture was cooled and filtered, and the filtrate was evaporated to dryness. The residue was treated with 5N sodiun hydroxide solution (300mA) and extracted with ether (3x100mA). The combined, dried organic extracts were evaporated to give an oil (_ca_.5.3g) which was purified by TCC eluting with hexane:ethyl acetate (4:1) to give the title compound (3.2q) as an oil, t.l.c. (hexane:ethyl acetate, 4:1) Rf 0.25.

Intermediate 4 9q 1,2 ,9 ,10-TetrahydropyridoL' 3' ,4 ': 4 ,5Jpyrrolo[l ,2 ,3-de][l ,4 ] benzoxa2in-7(8H)-one A solution of 4-amino-3,4-dihydro-2H-l,4-benzoxazine (l.Og) and 2,4-dioxopiperidine (753mg) in absolute ethanol (40mA) was stirred under nitrogen for 1.5h. The solvent was removed in vacuo and the residue was dissolved in diethylene glycol (30mA) and heated at 100^ for Ih, then at 150° for 2h. The solution was allowed to cool, poured into water (200mA) and extracted with dichloromethane (3x100mA). The combined, dried organic extracts were evaporated to give a semi-solid (ca.3g) which was purified by TCC eluting with System A (400:10:1) to 30 give the title compound (740mg) ns a solid, m.p. 298-300°.

...IrfMny 1'* 232 5 9 Intermediate 5 3-(2,3-Dihydro-lH-inriol-l-yl)-2-cyclohexon-l-ono A mixture of indolinc ( 3.39ij) und cyclohevane-l,3-dione (^.U7cj) was hented at ca. J50u for 7h. After cooling, the mixture was purified by 5 rCC eluting with ethyl ncetote: methanol (It): 1) to cjive u solid (7.30g) which was recrystal 1 ised from ethyl ncetate: ether (_cn. 4:1) to give the title compound (5.08tj), m.p. 83-86°.

Intermediate 6 4,5,8 ,9-Tetrahydropyrrolo[3,2,1-jk]corbozol-10(7H)-one A mixture of 3-(2,3-dihydro-lH-indol-l-yl)-2-cyclohexen-L-one (2.515g), cupric acetate (4.71g) and palladium (II) acetate (0.20g) in dry dimethylformamide (40ml) was heated at 135° under nitrogen for 4h. The solvent was then removed under reduced pressure and the residue 15 was suspended in methanol and then filtered. Hie filtrate was evaporated under reduced pressure and the resultant residue was purified by FCC eluting with ethyl acetate to give the title compound C0.36g) as a solid. A sample (20mg) was recrystal1ised from ethyl acetate to give the title compound (I5mg), m.p. 208-210°.

Intermediate 7 4 ,5 ,8 ,9-Tetrahydropyrrolo[3,2,l-jk]carbaZQl~10(7H)-one oxime A mixture of 4, 5, 8,9-tetrahydropyrrol o[ 3, 2,.l-jk]carbazol-10(7lO-one (364mg) and hydro.xylamine hydrochloride (479mg) in pyridine (50ml) was 25 heated to 50° for 60h, and was then poured into 2N hydrochloric acid (100ml). The resultant precipitate was filtered off, washed with water (50ml), and dried in vacuo at 50° for 6h to give the title compound (l40tny). Filtration of the precipitate that formed subsequently in the filtrate gave a further crop of the title compound 30 (104mg), m.p. 271-272°. 1 5 232 u Intermedinte 8 A ,5 ,7,8,9,10-Hexnhydro-l 1 H-azcpi no[ 4 ,3-b]pyrroIo[ 3.2,1— tii] indol-11-one 4.5.8.9-1 etrahydropyrrol o[ 3,2, 1 - jk] corbu/ol-10(7j_[)-one oxime (2Afimq) was added to polvphosphoric acid (20inl) at 120°, and the mixture was stirred at 120° for lh. After cooling, the mixture was poured into water (150ml) und extracted with dichloronethonr;: ethunol (10:1; 4 x 100ml). The combined, dried onjunic extracts were evaporated under reduced pressure to give n solid (150mg) which was purified by FCC eluting with 5ystem A (100:10:1) to give the title compound (92mcj) , t.l.c. (System A, 100:10:1) Rf 0.47.

Example 1 .6.9.10-Tetrahydro-10-[(5-methyl-lH-imidnzol-4-yl)methyl]-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]guinolin-11(8H)-one maleate Sodium hydride (60% dispersion in oil; 57mg) was added to a stirred suspension of 5,6,9,10-tetrahydro-4H-pyrido[3',4 1:4,5]pyrrol o~ [3,2, l-ij]quinol in-ll(8jO-one (270ing) in dimethoxyethane (15ml) and the mixture was heated at 50° for 6h. The mixture was then treated with 4-(chloramethyl)-5-methyl-l-(triphenylmethyl)-lH-imidazole (522mg) und stirring was continued at 50° for 18h. Water (3ml) and acetic acid (3ml) were added and the solution was heated at reflux for 3h. The mixture was poured into 8« sodiun bicarbonate solution (60ml) and extracted with dichloromethane (3x30ml). The combined, dried organic extracts were evaporated to give a solid (310mg) which was purified by FCC eluting with System A (200:10:1) to give a solid (324mg). This material was dissolved in dichloroiiethane/absolute ethanol (3ml) and treated with a solution of roaleic acid (117mg) in absolute ethanol (lml). The solvent was removed in vacuo and the residue was triturated with dry ether (3x5ml) to give the title compound (415mg) , m.p. 146-148°.

Water Analysis Found 0.565o w/w = 0-13mol H20.

Analysis round: C ,62.8; H,5.5; N',12.55; C1^20,S\0-C')H^°n-0-13H20 requires C,62.9; H.5.5; N,12.8«. 232 5 98 - i rt - 1 xmnple 2 A ,'? ,7 ,6-1 etrahydro-9-[ (b-^tjA' 1 -111- imidain 1 -4-y 1)meLby 1 ]py rido-[ 4, 3-b] py rrul ol 3,2 ,1-hi ] i ndol-10(9H)-one mn leu to Sodium hydride (fiOo dispersion in oil; 60mtj) was added to u stirred solution of 4, 5,7,8-tet rnhydrupyr ido[4,3-bjpvrrol o[ 5,2.,1 -h i J-indol-10{9H)-ono (^OOmy) in dry dimethoxyethane (I5m0 under nitrogen, and the mixture was heated nt 60'1 for 6b. 1 be mixture was then treated with 4-(chlororneth> 1 )-5-mot hy 1- 1 — (t r iphen vine thy])- ljl- ini da/ol e (65';,ng) and stirring was continued for 2Gb. Water (3nu) nnd acetic 10 ncid (3mX) were added and the solution was heated at reflux for Ah.

The mixture was poured into sodium bicarbonate solution (6flmf.) and extracted with dichloromethane (3\30mA). I tie combined, dried organic extracts were evaporated to give n solid (935mg) which was purified by FCC eluting with System A (200:10:1) to give a solid (510mg). This 15 material was dissolved in absolute ethanol (5mX) and treated with a solution of maleic acid (llSmg) in absolute ethanol (2mi). The solvent was removed in vacuo and the residue was triturated with dry ether (3x10ml) to give the title compound (413mg), m.p.125-128°.

Water Analysis Found: l-79^w/w =Q.43mal H^O.

Analysis Found: C,6.1.3; H,5.4; Nf, 12-9; C^i^O-C^O,.0.4311,0 requires 0,61.4; H,5.4; N,13.0$.

Fxomple 3 1,2,9,lO-Tetrahydro-8-[(5-methyl-I)l-inndazol-4-yl)methyl]pyrido-25 [3' ,4' :4,5]pyrrolQ[l,2,3-de][1,4lbenzoxazin-7(8H)-one maleate 1,2,9,10-tetrahydropyridot3' ,41:4,5]pyrrolo[1,2,3-de][1,4]benzoxazin-7(8Hp-one (350mg) and 4-(chloromethyl)-5-iticlhyl-l-(triphenyltnethyl)-lH-imidazole (686mg) were treated according to the method of l.xample 2 to give the title compound (565tng) as a solid, m.p. 149-151 . 30 Analysis Found: C,60-0; H,5.1; \',12.6; ClsHiSN\°2-C^U0^ requires C ,60.3 ; H,5.1; 17 232 09 11 xom(i le A A ,5 ,7,8 ,9 , lQ-Hexnhydro-10-[ (3-niethyl-lH-imidayol-A-yl )methyl ]-llH-azcpino[ A , 3-b]pvrrolo[ 3 ,2 ,1-hi] indol-.ll-une maleate A, 5, 7, 8, 9,10-Hoxahydro-llH-uzupinol A, 3-b] pyrrol o[ 3,2, 1-hi ] indol-^ 11-one (A3ing) and A-(chloromethy 1 )-5-ini;thy 1—1 — (tri ptieny lmethy 1 )-lM-imidazolc (.1 59mg) were treated accordinij to the method of Example 2, except that the FCC eluant wus System A (100:15:1), to give the title compound (57rng) as a solid, m.p. 175-176 °.

Analysis Found: C,63.A; H,5.8; N,12.B; ^ 2 3H 2 lil-) 5 requires C,65.3; H, 5.5; 12.8V The following examples illustrate pharmaceutical formulations according to the invention. The term "active ingredient" is used herein to represent a compound of formula (I).

TABLET5 FOR ORAL ADMINISTRATION' Tablets may be prepared by the normal methods such as direct compression or wet granulation.

The tablets may be film coated with suitable film forming 2o materials, such as hydroxypropvl methylcellulose, using standard techniques. Alternatively the tablets may be sugar coated.

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

Direct Compression Tablet mq/tablet Active Ingredient Calcium Hydrogen Phosphate BP+ Croscarmellose Sodiim NF Magnesium Stearate BP 0.50 87.25 1.80 0.A5 Compression weight 90.00 * of a grade suitable for direct compression.

Claims (11)

232 5 9 - IB - The uctivo ingredient is par.sed through q 60 mesh sieve, blended with the calcium hydrogen phor.phute, croscormel 1 oae sodium nnd moyne.'iiijn stenrate. Hie resultant mix is compressed into tablets using u Manesty \"!> tablet machine fitted with 5.5mm, flat bevelled 5 edge punches. INJECTION' TOR INTRAVENOUS ADMINISTRATION Active ingredient Sodium Chloride BP Water for Injection BP to mq/m£ 0.05 1.0 as required as required 1. 0m A .1. 0m £ 15 Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted, using acid or alkali, to that of optimum stability and/or facilitate solution of the active ingredient. Alternatively, suitable buffer salts may be used. The solution is prepared, clarified and filled into appropriate 20 si2e ampoules sealed by fusion of the glass- The injection is sterilised by heating in an autoclave using one of the acceptable cycles. Alternatively, the solution may be sterilised by filtration end filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen or other 25 suitable gas. 30 19 2.3-25^ % WHAT^WE CLAIM IS:

1. Compounds of the general formula (I) N Im -('cH 2) n (I) N i 0 wherein n represents 2 or 3; Im represents an imidazolyl group of the formula : 15 R3 R3 / 20 N^^^NR2 or R2N R1 R1 wherein one of the groups represented by R1, R2 and R3 is a hydrogen atom or a C1_6alkyl, C3_7cycloalkyi, C3_galkenyl, phenyl or phenylC]__3alkyl group, and each of the other two groups, which may be the same of different, represents a ..5 hydrogen atom or a C]__6alkyl group; and Y represents a group wherein m represents 2, 3 or 4; or Y represents a group -X(CK2)D-, wherein p represents 2 or 3, and X represents an oxygen or a sulphur atom or a group NR4, where R4 is a C^galkyl group, and X is attached to 0 the benzene ring moiety of the molecule; and physiologically acceptable salts and solvates thereof.

2. Compounds as claimed in claim 1 in which R1, R2 and R3 each independently represent a hydrogen atom or a 35 C]__4alkyl group. •v c i'* 7 u*% 6269/1 74 '(*28 JAN 1992 " ) " C f s 20

3. Compounds as claimed in claim 1 in which R1 and R2 each represent a hydrogen atom, and R-3 is a Cj^alkyl group.

4. Compounds as claimed in any one of claims 1 to 3 in which Y represents the group -(CH2)2- or ~(CH2)3~-

5. 5,6,9,10-Tetrahydro-10-[(5-methyl-lH-imidazol-4-yl)methyl]-4H-pyrido[3 1 ,4' :4, 5] pyrrolo [ 3,2,l-ij]quinolin-11 (8H)-one; 4 , 5 , 7 , 8-tetrahydro-9 - [ (5-methyl-l H_- imidazol-4 -yl)methyl]pyrido[4,3-b]pyrrolo[3,2,1-hi]indol-10(9H)-one; Q? 4 , 5 , 7', 8 , 9 , 10-hexahydro-10-[ ( 5-methyl-lH-imidazol-4-yl) methyl ]-llH-azepino[4,3-bjpyrrolo[3,2,l-hi] indol -11-one ; and physiologically acceptable salts and solvates thereof.

6. A process for the preparation of compounds of general formula (I) as defined in any one of claims 1 to 5 or physiologically acceptable salts and solvates thereof, which comprises : (A) alkylating a compound of formula (II) 0 wherein Y and n are as defined in claim 1 with a compound of formula (III) LCH2 - Im (III) or a protected derivative thereof, wherein L is a leaving atom or group and Im is as defined in claim 1, followed if necessary by removal of any protecting groups present; or •. i- ' 'X • J "28 J AN 1992 21 23"2-Sc:\'S. (B) converting a compound of general formula (I) into another compound of formula (I) using conventional techniques; or (C) removing protecting group(s) from a protected form 3 of a compound of formula (I); 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 "0 a free base, optionally converting the free base into a salt.

7. A pharmaceutical composition comprising at least one compound of general formula (I) as defined in claim 1 15 or a physiologically acceptable salt or solvate thereof together with at least one physiologically acceptable carrier or excipient.

8. A compound of formula (I) as defined in any one of 20 claims 1 to 5 or a physiologically acceptable salt or solvate thereof for use as an active therapeutic agent.

9. Compounds of the general formula (I) as defined in claim 1 and physiologically acceptable salts and solvates thereof substantially as herein described with reference to any example thereof.

10. A process as defined in claim 6 for the preparation of compounds of general formula (1) or physiologically acceptable salts and solvates thereof substantially as herein described with reference to any example thereof.

11. A pharmaceutical composition as defined in claim 7 substantially as herein described with reference to any example thereof. OATSDTHIS ?-3'"daTOP lc,'" 'i ■■ ^ I*"' 'L • ;•>. A. J. PARK ft SON -"'to. ' / ,r H PER i i( .UL j r ] AGENTS fJO)' THE APPt takit? ^7 8 JANW# ■ ■ ?c p v