CY1479A - 1,2,3,9-tetrahydro-3-(imidazol-1-ylmethyl)-4h-carbazol-4-one derivatives - Google Patents

Description

1

GB 2 153 821 A

1

SPECIFICATION

Heterocyclic compounds

5 This invention relates to heterocyclic compounds, to processes for their preparation, to pharmaceutical 5

compositions containing them and to their medical use. In particular the invention relates to compounds which act upon certain 5- hydroxytryptamine {5HT) receptors.

5HT, which occurs endogenously in abundance in peripheral nerves and in blood platelets, is known to cause pain in man through a specific action on 5HT receptors situated on terminals of primary afferent 10 nerves. Compounds which antagonise the neuronal effects of 5HThave been shown to possess analgesic 10 activity, for example, to relieve the pain of migraine. 5HT also causes depolarisation of the rat isolated vagus nerve preparation through the same 5HT-receptor mechanism, and inhibition of this effect correlates with an analgesic effect in vivo.

5HT also occurs widely in neuronal pathways in the central nervous system and disturbance of these 5HT 15 containing pathways is known to alter behavioural syndromes, such as mood, psychomotor activity, 15

appetite and memory. Since 'neuronal' 5HT- receptors of the same type as those present on primary afferent terminals are also present in the central nervous system, it is believed that compounds which antagonise the neuronal effects of 5HT will be useful in the treatment of conditions such as schizophrenia, anxiety, obesity and mania.

20 Existing treatments for such conditions sufferfrom a number of disadvantages. Thus, for example, known 20 treatments for migraine include the administration of a vasoconstrictor such as ergotamine, which is non-selective and constricts blood vessels throughout the body. Ergotamine, therefore, possesses undesirable, and potentially dangerous, side effects. Migraine may also be treated by administering an analgesic such as aspirin or paracetamol, usually in combination with an antiemetic such as metaclopra-25 mide, but these treatments are of only limited value. 25

Similarly, existing treatments for psychotic disorders such as schizophrenia exhibit a number of serious side effects such as extrapyramidal side effects.

There is thus need for a safe and effective drug for the treatment of conditions where disturbance of 5HT containing pathways is involved, such as migraine or psychotic disorders such as schizophrenia. It is 30 believed a compound which is a potent and selective antagonist at 'neuronal' 5HT receptors will fulfil such a 30 role.

We have now found a group of3-imidazolylmethyltetrahydrocarbazolones which are potent and selective antagonists at 'neuronal' 5HT receptors.

The present invention provides a tetrahydrocarbazolone of the general formula (I): 35 35

i? rX r (i»

/w\An i H ii i \ //

40 \\ /% /\ /* | 40

N R2

Rl wherein

45 R1 represents a hydrogen atom or a C-mo alkyl, C3.7 cycloalkyl, C3.6 afkenyi, phenyl or phenyl-Ci.3alkyl 45

group, and one of the groups represented by R2, R3 and R4 is a hydrogen atom or a C-|.6 alkyl, C3.7 cycloalkyl, C2-6 alkenyl or phenyl C-|.3alkyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a Ci.6 alkyl group;

and physiologically acceptable salts and solvates, e.g. hydrates, thereof.

50 It will be understood that when R1 represents a C3.e alkenyl group, the double bond may not be adjacent to 50 the nitrogen atom.

Referring to the general formula (I), the alkyl groups represented by R1, R2, R3 and R4 may be straight chain or branched chain alkyl groups, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, methylprop-2-yl, pentyl, pent-3-yl or hexyl.

55 An alkenyl group may be, for example, a propenyl group. 55

A phenyl-Ci.3 alkyl group may be, for example, a benzyl, phenethyl or3-phenylpropyl group.

A cycloalkyl group may be, forexample, a cyclopentyl, cyclohexyl orcycloheptyl group.

It will be appreciated that the carbon atom at the 3- position of the tetrahydrocarbazolone ring is asymmetric and may exist in the R- or S- configuration. The present invention encompasses both the

60 individual isomeric forms of the compounds of formula (I) and all mixtures, including racemic mixtures, 60

thereof.

Suitable physiologically acceptable salts of the indoles of general formula (I) acid addition salts formed with organic or inorganic acids for example, hydrochlorides, hydrobromides, sulphates, phosphates,

citrates, fumarates and maleates. The solvates may, for example, be hydrates.

65 A preferred class of compounds represented by the general formula (I) is that wherein R1 represents a 65

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GB 2 153 821 A

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hydrogen atom or a alkyl, C3.6 cycloalkyl or C3.6 alkenyl group.

Another preferred class of compounds represented by the general formula (I) is that wherein one of the groups represented by R2, R3 and R4 represents a C1.3 alkyl, C3.6 cycloalkyl orC3.6 alkenyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C-i.3 alkyl group.

5 A further preferred class of compounds represented by the general formula (I) is that wherein R1 5

represents a hydrogen atom or a C-,.6 alkyl, C5.6 cycloalkyl or C3.4 alkenyl group, and either R2 represents a hydrogen atom and R3 and/or R4 represents a <^.3 alkyl group or R2 represents a C-|.3 alkyl group and both R3 and R4 represent hydrogen atoms.

A particularly preferred class of compounds according to the invention is that represented by the formula 10 (la): 10

jj R*a R*a

/ w v xn i ii it i \ //

(lA)

15 VVV A* 15

pla

20 (wherein R1a represents a hydrogen atom or a methyl, ethyl, propyl, prop-2-yl, prop-2-enyl or cyclopentyl 20 group; R3a represents a hydrogen atom; and either R2a represents a methyl, ethyl, propyl or prop-2-yl group and R4a represents a hydrogen atom or R2a represents a hydrogen atom and R^3 represents a methyl or ethyl group) and physiologically acceptable salts and solvates (e.g. hydrates) thereof.

Preferred compounds are:-

25 1,2,3,9-tetrahydro-3-[(2-methyl-1W-imidazol-1-yl)methyl]-9-(prop-2-weyl)-4W-carbazol-4-one; 25

9-cyclopentyl-1,2,3,9-tetrahydro-3-[(2-methyl-1W-imidazoI-1-yl)-methylj-4W-carbazol-4-one; and 1,2,3,9-tetrahydro-3-[2-methyl-1W-imidazol-1-yl)methyl]-9-(prop-2-yI)-4//-carbazol-4-one and their physiologically acceptable salts and solvates.

A particularly preferred compound is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methy!-1//-imidazol-1-yl)methyl]-30 4W-carbazol-4-one which may be represented by theformula (lb): 30

(lb)

35

40 and the physiologically acceptable salts and solvates (e.g. hydrates) thereof. A preferred form of this 40

compound is the hydrochloride dihydrate.

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

45 Compounds of the invention are potent and selective antagonists of 5HT-induced responses of the rat 45 isolated vagus nerve preparation and thus act as potent and selective antagonists of the 'neuronal' 5HT receptor type located on primary afferent nerves.

Compounds of the invention are of use as analgesics, for example in the alleviation of pain associated with migraine, headache and many other forms of pain for which 5HT is the endogenous mediator.

50 Experiments in animals have shown that compounds of the invention are also of use in the treatment of 50 schizophrenia and other psychotic disorders. As indicated herein above 5HT occurs widely in the neuronal pathways in the central nen/ous and disturbance of these 5HT containing pathways is known to alter many other behavioural syndromes such as mood, appetite and memory. Since 'neuronal' 5HT receptors of the same type as those present on primary afferent terminals are also present in the central neivous system the 55 compounds of the invention may also be useful in the treatment of conditions such as anxiety, obesity and 55 mania.

In particular, compounds of formula (la) as previously defined have been found to be highly selective and extremely potent in their action. They are well absorbed from the gastro-intestinal tract and are suitable for oral or rectal administration. The compounds of formula (la) do not prolong sleeping time in the 60 pentobarbitone anaesthetised mouse indicating that there is no undesirable interaction with drug 60

metabolising enzymes. Indeed they exhibit no effects on normal behaviour, are non-toxic and exhibit no undesirable effects in mice at doses up to 1 mg/kg intravenously.

As well as exhibiting the outstanting properties of the compounds of formula (la), the compound of formula (lb) when administered to humans showed no untoward effects.

65 According to another aspect, the invention provides a method of treatment of a human or animal subject 65

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35

// \ / \ / \l—1

• > • • N N

1 11 11 1 \ //

• • • • •

w / \ / \ / 1

• N • Me Me

3

suffering from a condition caused by a disturbance of 'neuronal' 5HT function. Thus, for example, the invention provides a method of treatment of a human subject suffering from migraine pain or a psychotic disorder such as schizophrenia.

Accordingly, the invention also provides a pharmaceutical composition which comprises a least one t- compound selected from 3-imidazoly!methyltetrahydrocarbazolone derivatives of the general formula (I), 5

their physiologically acceptable salts and solvates, e.g. hydrates, adapted for use in human or veterinary medicine, and formulated for administration by any convenient route.

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

1J Thus the compounds of the invention may be formulated for oral, buccal, parenteral or rectal 10

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 15 agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers 15

I j.g lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be 20 presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid 20

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 jgents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid). 25 The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate. 25 Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

For buccal administration the compositions may take the form of tablets or lozenges formulated in :onventional manner.

20 The compounds of the invention may be formulated for parenteral administration by injection. 30

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 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 35 suitable vehicle, e.g. sterile pyrogen-free water, before use. 35

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 a depot preparation. Such long acting formulations may be administered by implantation (for 40 example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the 40

compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

For administration by inhalation the compounds according to the invention are conveniently delivered in 45 the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable 45 propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base 50 such as lactose or starch. 50

A proposed dose of the compounds of the invention for administration in man (of approximately 70 kg body weight) is 0.05 to 20mg, preferably 0.1 to 10mg of the active ingredient per unit dose which could be administered, for example, 1 to 4times per day. The dose will depend on the route of administration and the body weight of the patient. It will be appreciated that it may be necessary to make routine variations to the 55 dosage depending on the age and weight of the patient as well as the severity of the condition to be treated. 55 For oral administration a unit dose will preferably contain from 0.5 to 10mg of the active ingredient. A unit dose for parenteral administration will contain 0.1 to 10mg of the active ingredient.

Aerosol formulations are preferably arranged so that each metered dose or 'puff' delivered from a pressurised aerosol contains 0.2 to 2mg, of a compound of the invention, and, each dose administered via 60 capsules and cartridges in an insufflator or an inhaler contains 0.2 to 20 mg of a compound of the invention. 60 The overall daily dose by inhalation will be within the range 0.4 to 80mg. Administration may be several times daily, for example from 2 to 8 times, giving for example 1,2 or 3 doses each time.

The compounds of the invention may, if desired, be administered in combination with one or more other therapeutic agents, such as anti-nauseants.

BNSDOCID: <GB 2153821 A_J_>

4 GB 2 153 821 A

4

According to another aspect of the invention, compounds of general formula (I) and physiologically acceptable salts or solvates or physiologically acceptable equivalents thereof may be prepared by the general methods outlined hereinafter.

According to a first general process (A), a compound of general formula (I) or a physiologically acceptable 5 salt or solvate or a physiologically acceptable equivalent thereof may be prepared by reacting a compound 5 of general formula (II):

io A_/vY 10

I II II I

• • 4 •

/ \ / \ /

• H •

R1

15 15

(wherein Ft1 is as defined previously and Y represents a reactive substituent) or a protected derivative thereof with an imidazole of general formula (111):

/3 (III)

20 *—• 20

HN N \ //

25 25

(wherein R2, R3 and R4 are as defined previously) or a salt thereof.

Examples of compounds of formula (II) employed as starting materials in the process (A) include compounds wherein Y represents a group selected from an alkenyl group=CH2 or a group of formula CH2Z where Z represents a readily displaceable atom or group such as a halogen atom, e.g. chlorine or bromine; 30 an acyloxy group such asacetoxy,trifluoromethanesulphonyloxy,p-toluenesulphonyloxy or methanesul- 30 phonyloxy; a group - NR5R6R7X~, where R5, Reand R7, which may be the same or different each represents lower alkyl e.g. methyl, aryl e.g. phenyl oraralkyl e.g. benzyl, or Rs and R6 together with the nitrogen atom to which they are attached may form a 5- to 6-membered ring e.g. a pyrrolidine ring, and X represents an anion such as a halide ion e.g. chloride, bromide or iodide; or a group -NR5R6 where R5and R6are as defined 35 above, for example-IM(CH3)2. 35

When Y represents the group =CH2, the process may conveniently be carried out in a suitable solvent,

examples of which include water; esters, e.g. ethyl acetate; ketones, e.g. acetone; or methylisobutylketone; amides, e.g. dimethylformamide; alcohols, e.g. ethanol; and ethers e.g. dioxan ortetrahydrofuran; or mixtures thereof. The process may be effected at a temperature of, for example, 20 to 100°C.

40 When Y represents the group CH2Z, where Z is a halogen atom or an acyloxy group, the process may 40

conveniently be carried out in a suitable solvent such as an amide, e.g. dimethylformamide; an alcohol, e.g. methanol or industrial methylated spirit; or a haloalkane, e.g. dichloromethane, and at a temperature of from —10 to 150°C, e.g. +20 to +100°C.

Jhe reaction of a copound of formula (II) where Y represents the group CH2Z where Z is the group 45 -NR5R6R7X", may conveniently be carried out in a suitable solvent such as water, an amide, e.g. 45

dimethylformamide; a ketone, e.g. acetone; oran ether,e.g. dioxan,and atemperature of from 20 to 150°C.

The reaction including a compound of formula (!1) where Y represents the group -CH2Z, where Z is the group —NRST6, may conveniently be carried out in a suitable solvent such as water or an alcohol, e.g.

methanol, or mixtures thereof, and at a temperature of from 20 to 150°C.

50 According to another general process (B) a compound of formula (I) may be prepared by oxidising a 50

compound of formula (IV):

(IV)

55 • I 55

60 60

(wherein A represents a hydrogen atom or a hydroxyl group and R1, R2, R3 and R4 are as previously defined) or a salt or a protected derivative thereof.

The oxidation process may be effected using conventional methods and the reagents and reaction conditions should be chosen such thatthey do not cause oxidation of the indole group. Thus, the oxidation 65 process is preferably effected using a mild oxidising agent. 65

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GB 2 153 821 A

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When oxidising a compound of formula (IV) in which A represents a hydrogen atom, suitable oxidising agents include quinones in the presence of water, e.g. 2,3-dich!oro-5,6-dicyano-,1,4-benzoquinoneor 2,3,5,6-tetrachloro-1,4-benzoquinone; selenium dioxide; a cerium (IV) oxidising reagent such as eerie ammonium nitrate or a chromium (VI) oxidising agent, e.g. a solution of chromic acid in acetone (for 5 example Jones'reagent) or chromium trioxide in pyridine. 5

When oxidising a compound of formula (IV) in which A represents a hydroxyl group, suitable oxidising agents include quinones in the presence of water, e.g. 2,3-dichloro-5,6-ducyano-1,4-benzoquinone or 2,3,5,6-tetrachloro-1,4-benzoquinone; ketones, e.g. acetone, methylethylketone orcyclohexanone, in the presence of a base e.g. aluminium t-butoxide; a chromium (VI) oxidising agent, e.g. a solution of chromic 10 acid in acetone (for example Jones reagent) or chromium trioxide in pyridine; an N-halosuccinimide, e.g. io N-chlorosuccinimide or N-bromosuccinimide; a dialkylsulphoxide e.g. dimethylsulphoxide, in the presence of an activating agent such as N,N'-dicyclohexylcarbodiimide or an acyl halide, e.g. oxalyl chloride ortosyl chloride; pyridine-sulphur trioxide complex; or a dehydrogenation catalyst such as copper chromite, zinc oxide, copper or silver.

15 Suitable solvents may be selectedfrom ketones, e.g. acetone or butanone; ethers e.g. tetrahydrofuran or 15 dioxan; amides, e.g. dimethylformamide; alcohols, e.g. methanol; hydrocarbons, e.g. benzene ortoluene; halogenated hydrocarbons, e.g. dichloromethane; and water or mixtures thereof.

The process is conveniently effected at a temperature of -70 to +50°C. It will be understood that the choice of oxidising agent will affect the preferred reaction temperature.

20 According to another general process (C), a compound of formula (I) according to the invention or a salt or 20 protected derivative thereof may be converted into another compound of formula (I) using conventional techniques. Such conventional techniques include alkylation, which may be effected at any position in a compound of formula (I) where one or more of R1 and R2 represents a hydrogen atom, and hydrogenation,

which may, for example, be used to convert an alkenyl substituent into an alkyl substituent. The term 25 "alkylation" includes the introduction of other groups such as cycloalkyl or alkenyl groups. Thus, for 25

example, a compound of formula (!) in which R1 represents a hydrogen atom may be converted into the corresponding compound in which R1 represents a Ci.l0 alkyl, C3.7 cycloalkyl, C3.6 alkenyl or phenyl-C^ alkyl group.

The above alkylation reactions may be effected using the appropriate alkylating agent selected from 30 compounds of formula RaXa where Ra represents a Cn.10 alkyl. C3.7 cycloalkyl, C3.6alkenyl or phenyl- C-,.3 30 alkyl group, and Xa represents a leaving group such as a halide or an acyloxy group as previously defined for Y, or sulphate of formula (Ra)2S04.

The alkylation reaction is conveniently carried out in an inert organic solvent such as an emide, e.g. dimethylformamide; an ether, e.g. tetrahydrofuran; or an aromatic hydrocarbon, e.g. toluene, preferably in 35 the presence of a base. Suitable bases include, for example, metal hydrides such as sodium hydride, alkali 35 metal amides such as sodium amide, alkali metal carbonates such as sodium carbonate or an alkali metal alkoxide such as sodium or potassium methoxide, ethoxide ort-butoxide. The reaction may conveniently be effected at a temperature in the range -20 to +1003C, preferably 0 to 5CTC.

Hydrogenation according to general process (C) may be effected using conventional procedures, for 40 example by using hydrogen in the presence of a noble metal catalyst e.g. palladium, Raney nickel, platinum, 40 platinum oxide or rhodium. The catalyst may be supported on for example charcoal or a homogeneous catalyst such astris(triphenylphosphine) rhodium chloride may be used. The hydrogenation will generally be effected in a solvent such as an alcohol, e.g. ethanol; an amide, e.g. dimethylformamide; an ether, e.g.

dioxan; or an ester, e.g. ethyl acetate, and at a temperature in the range -20 to 100°C, preferably 0 to 50°C. 45 It should be appreciated that in some of the above transformations it may be necessary or desirable to 45 protect any sensitive groups in the compound to avoid undesirable side reactions. The protecting groups used in the preparation of compounds of formula (I) are desirably groups which may be readily split off at a suitable stage in the reaction sequence, conveniently at the last stage. For example, during any of the reaction sequences described above, it may be necessary to protect the keto group, for example, as ketal or a 50 thioketal. 50

Compounds of general formula (I) may thus be prepared according to another general process (D), which comprises 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 Chemistry' Ed. J.F.W McOmie (Plenum Press, 1973). Thus, a ketal such as an alkyleneketal group 55 may be removed by treatment with a mineral acid such as hydrochloric acid. The thioketal group may be 55 cleaved by treatment with a mercuric salt, e.g. mercuric chloride, in a suitable solvent, such as ethanol.

The compounds of formula (I) may be converted into their physiologically acceptable salts according to conventional methods. Thus, for example, the free base of general formula (I) may be treated with an appropriate acid, preferably with an equivalent amount in a suitable solvent (e.g. aqueous ethanol). 60 Physiologically acceptable equivalents of a compound of formula (I) may be prepared according to 60

conventional methods.

Individual enantiomers of the compounds of the invention maybe 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.EIiel (McGraw Hill 1962) and 'Tables of 65. Resolving Agents' by S. H. Wilen. 65

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Examples of optically active resolving acids that may be used to form salts with the racemic compounds include the (R) and (S) forms of organic carboxylicand sulphonic acids such as tartaric acid,

di-p-toluoyltartartic, camphorsulphonic acid and lactic acid. The resulting mixture of isomeric salts may be separated, for example, by fractional crystallisation, into the diastereoisomers and if desired, the required 5 optically active isomer may be converted into the free base. 5

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 general methods can be used for the introduction of the desired groups at an intermediate stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different ways in such multi-stage processes.

10 The sequence of the reactions in multi-stage processes should of course be chosen so that the reaction 10

conditions used do not affect groups in the molecule which are desired in thefinal product.

The starting materials of formula (II) wherein Y represents the group =CH2 may be prepared from compounds of formula (II) where Y represents the group CH2N5R6R7X~ by reaction with a base in a suitable solvent. Examples of bases include alkali metal hydroxides, e.g. potassium hydroxide or alkali metal

15 carbonates or hydrogen carbonates e.g. sodium hydrogen carbonate. 15

The quaternary salts may be formed from the corresponding tertiary amine by reaction with an alkylating agent such as methyl iodide or dimethyl sulphate, if preferred in a suitable solvent, e.g. dimethylformamide. The tertiary amine may be prepared by reaction of a tetrahydrocarbazolone of general formula (V):

20 0 (V) 20

/ \ A • •——♦ •

I II II I • • • •

\\ / \ / \ /

25 . N . 25

R1

with formaldehyde and the corresponding secondary amine, if desired in a suitable solvent such as an alcohol, e.g. ethanol.

30 Compounds of general formula (V) maybe prepared for example, by the method described by H. lida eta!., 30 in J.Org.Chem. (1980) Vol 45, No. 15, pages 2938-2942.

The starting materials of general formula (II) where Y represents —CH2Z where Z is a halogen atom or an acyloxy group may be prepared from the corresponding hydroxymethyl derivative of general formula (VI):

35 0 (VI) 35

A A /ctl2°H

i II III

*\\ A A /'

40 • N • 40

f}1

which may be obtained by reacting the tetrahydrocarbazolone of general formula (V) with formaldehyde, preferably in a suitable solvent such as an alcohol, e.g. ethanol, and preferably in the presence of a base.

45 Thus, the compounds where Z is a halogen atom may be obtained by reacting a compound of formula (VI) 45 with a halogenating agent such as a phosphorus trihalide, e.g. phosphorus trichloride.

The compounds where Z is an acyloxy group may be prepared by reacting a compound of formula (VI)

with an appropriate acylating agent such as an anhydride or a sulphonyl halide such as sulphonyl chloride. Compounds of formula (II) where Y represents —CHzZ where Z is a halogen atom may also be prepared by

50 reacting a compound of formula (II) where Y represents the group =CH2 with the appropriate hydrogen 50

halide, e.g. hydrogen chloride, conveniently in a suitable solvent such as an ether, e.g. diethyl ether.

Compounds of genera! formula (IV) maybe prepared by reacting a compound of formula (VII):

(VII)

55 / \ jCHjZ1 55

\/\/\/

• N •

60 R1 ' 60

(wherein R1 and A are as defined previously andZ1 is a readily displaceable atom or group such as a halogen atom, an acyloxy group or the group -NR5R6R7X~ as previously defined for Z1) with an imidazole of formula (III) according to the method of process (A) described herein.

65 Compounds of formula (VII) may be prepared by reducing compounds of formula (II) using for example 65

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lithium aluminium hydride or sodium borohydride.

Compounds of formula (VII) wherein A represents a hydrogen atom may also be prepared by reacting a compound of formula (VII) wherein A represents a hydroxyl group with a tosyl halide (e.g. tosyl chloride) and then reducing the resulting tosylate with lithium aluminium hydride.

5 Compounds of formula (IV) are novel compounds, and as such provide afurtherfeature of the invention. The following examples illustrate the invention. Temperatures are in °C. Where indicated, solutions were dried over Na2S04 and solids were dried in vacuo over P205 at 50° overnight. Chromatography was carried out using the technique described by W.C. Still eta! (J. Org. Chem., 1978,43,2923-2925), on kieselgel 9385.

10 PREPARATION 1

2,3,4,9-Tetrahydro-N,N,N-trimethyl-4-oxo-1H-carbazoie-3-methanaminium iodide

A solution of 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-4//-carbazol-4-one (0.53g) in iodomethane (15ml) was heated under reflux for 5h and evaporated to dryness, giving the title compound as a white solid (0.84g)m.p. 202-205°.

15

PREPARATION 2

2,3,4,9-Tetrahydro-N,N,Nr9-tetramethyt-4-oxo- 1H-carbazoie-3-methanaminium iodide

A suspension of 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4W-carbazol-4-one (3.80g) in iodomethane (100ml) was stirred at reflux for 57h. The resulting suspension was concentrated in vacuo to 20 give the title methanaminium iodide as a solid (5.72g) m.p. 192°-195°.

PREPARATION 3

7, 2,3,9-Te tra hydro -9-meth yi-3-meth yiene-4H-carbazoi-4-one A solution of the product from Preparation 2 (5.0g) in water (20ml) was treated with 2N sodium carbonate 25 (6.55ml) and warmed at 35° for 45 min. The resulting slurry was cooled to 0° and the solid was filtered off, washed with water and dried to give the title compound (2.8g) m.p. 127-9°.

PREPARATION 4

2,3,4,9-Tetrahydro-9-methyl-3-f(2-methyl-1H-imidazol- 1-yi)methy!]- JH-carbazole maleate 30 Sodium borohydride (90mg) was added under nitrogen to a stirred solution of the productfrom Example 7 (500mg) in a mixture of methanol (3ml) and chloroform (3ml). Stirring was continued for 48h (further sodium borohydride (250mg) was added after 17.75h and 42h), and then the suspension was partitioned between 2N hydrochloric acid (15ml) and chloroform (3x10ml). The aqueous layer was basified with solid sodium carbonate, extracted with chloroform (3x10ml), and the combined extracts washed with water (2x 10ml) and 35 brine (10ml), dried and concentrated in vacuo. Column chromatography of the residual foam (557mg) eluting with a mixture of duchloromethane, ethanol and 0.88 aqueous ammonia (300:10:1) afforded a solid (200mg). This material was dissolved in refluxing absolute ethanol (3ml) and a solution of maleic acid (80mg) in refluxing absolute ethanol (1ml) was added. The hot solution was filtered, stirred, and diluted with dry ether (40ml) to give the title compound (240mg) m.p. 138.5°-140°.

40

PREPARATION 5

2,3,4,9-Tetrahydro-9-methyl-3-[(2-methyl-1 H-imidazol-1-yl)methyl]-1 H-carbazoi-4-ol

The product from Example 7 (30.0g) was added, under nitrogen, to a stirred suspension of lithium hydride (7.75g) in dry tetrahydrofuran (750ml). The mixture was stirred under reflux for 1h and then cooled in ice. The 45 suspension was cautiously diluted with aqueous tetrahydrofuran (15% H20; 100ml) and water (100ml), concentrated in vacuo and the residual solid extracted with dichloromethane (2 x500ml). The organic extracts were concentrated in vacuo and the residual solid (16.4g) purified by short path column chromatography on silica {Kieselgel 60; Merck (RTM) 7747; 500g) eluted with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (150:10:1) to give the title compound as a foam (13.4g). T.l.c. Silica, 50 dichloromethane/ethanol/0.88 ammonia (150:10:1) Rf 0.34 and 0.36 (two pairs of diastereoisomers),

detection u.v. and iodoplatinic acid.

N.m.r. 5[CDCI3 + CD3OD (1 drop)] 1.6-2.3 and2.6-3.0(5H,m), 2.32 and 2.40 (3H,s+s, Me in two different isomers), 3.32 (3H,s,NMe), 3.65 -4.3(2H,m,CHCH2N), 4.75-4.85(1 H,m,CW-OH),6.8-7.8 (CH,m,aromatic).

55 EXAMPLE 1a

1,2,3,9Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazoi-1-yl}methyl]-4H-carbazol-4-one hydrochloride

Asolution of the product of Preparation 2 (2.0g) and 2-methylimidazole (5.0g) in dry dimethylformamide (30ml) was stirred, under nitrogen, at 95° for 16.75h and then allowed to cool. The solid that crystallised was filtered off, washed with ice-cold, dry dimethylformamide (3x2ml) and dry ether (2x 10ml) and then dried. 60 The resulting solid (0.60g) was suspended in a mixture of absolute ethanol (30ml) andethanolic hydrogen chloride (1ml), and warmed gently to obtain a solution, which was filtered whilst warm. The filtrate was then diluted with dry ether to deposit a solid (0.6g) which was recrystallised from absolute ethanol to give the title compound as a solid (0.27g) m.p. 186-187°.

Analysis Found: C,61.9;H,6.4;N,11.8.

65 C^H^NsO.HCI.HaO requires C,62.3;H,6.1 ;N, 12.1%,

BNSDOCID: <GB 2153821A_I_>

5

10

15

20

25

30

35

40

45

50

55

60

65

8

GB 2 153 821 A

The following compounds were prepared by a similar procedure as detailed in Table I:-

8

Q.

£

1

LO

c

LO

d d

x—

CM

CO

Oi o

LO

LO

r*.

x—

CM

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ID IT)

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o x o

<d a)

BNSDOCID: <GB 2153821 A_L>

9

GB 2 153 821 A

9

Analysis (%)

Molecular Found Requires

C H N C H N 5 5

c17h17n30.

62.05 5.5 12.7 61.8 5.9 12.7

HCI.0.8H20

10 10

C19H21N30. C4H4O4.0.2H2O

64.6 6.0 9.8 64.7 6.0 9.8

15 C20H23N3O. 15

64.9 6.9 11.2 65.5 6.9 11.45

HCI.0.5H20 C24H23N3O.

20 69.1 6.1 9.9 69.5 6.1 10.1 20

HCI. 0.5H20

C24H23N3O.

25 72.8 6.2 10.5 72.7 6.6 10.6 25

1.5 H20

C23H27N3O.

68.5 7.55 10.4 68.4 7.15 10.4 30 HCI. 0.3H20 30

* 2,3,4,9-Tetrahydro-9,N,N,N-tetramethyl-4-oxo-1A/-carbazol-3-methanaminium methosulphate used as starting material. In the Table, £ represents cyclohexyl.

BNSDOCID: <GB 2153821 A_J_>

10

GB 2 153 821 A

10

NOTE 1

Compounds 1e and 1f were prepared in the same experiment and the isomers separated by short path chromatography (D.F. Taber, J. Org. Chem., 1982,47,1351) eluting with dichloromethane/ethanol/0.88 ammonia (300:10:1). The following 'H n.m.r. data was obtained.

a

10

15

1« ! 2 .

YY'

I II 11 I, ,1 l„,

A\ A /*\ /* !>/ *\ _

. V V ir r3

d - doublet dd =■ doublet of doublets s = singlet

8 ^1 1

'H NMR SPECTRA {obtained at 250 MHz) Selected Proton Chemical Shifts {?> ppm] and multiplicities

10

15

Solvent

Carbazolone Protons

20

25

30

35

1e

Aromatic H-5,6,7,8

7.2-8.05

d6-DMS0

If CDCI3 7.15-8.05 - DMSO

1g 7.2-8.05

d6-DMS0

Aliphatic CH2-1 and CH2-2 H-3

2.6-3.05 1.75-2.1

interalia 2.9-3.3 1.6-2.2

tmidazolyi Imidazone Protone Methylene

Protons H-2' H-4' and/or H-5'

4.47 (dd) 2.91-3.25 1.75-2.3 and

4.64(dd)

4.02(dd) and

4.63(dd)

4.42(dd) and

4.73(dd)

9.20s 7.55s

8.17s 6.93s

7.61 d and

7.70d

20

25

30

35

EXAMPLE 2

40 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol- 1-y/JmethylJ-4H-carbazol-4-one ma/eate 40

1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyiimidazol-1-yl)methyl-4/y-carbazol-4-one (300mg) was suspended in hot ethanol (5ml) and treated with maieicacid (116mg). The solution was cooled and the white crystalline solid was filtered off and dried to give the title compound (300mg) m.p. 132.3°.

45 EXAMPLE 3a 45

1,2,3,9- Tetrahydro-3-( iH-imidazoi- 1-ylmethyl)-4H-carbazol-4-one

A solution of the product of Preparation 1 (0.84g) and imidazole (0.90g) in dimethylformamide (25ml) was heated at 105= for 6h, cooled, added to water (200ml) and extracted six times with ethyl acetate. The combined extract was washed, dried and evaporated to give a solid which was purified on a silica column

50 (Merck 7734) eluting with ethyl acetate/methanol (4:1). Recrystallisation twice from ethyl acetate/methanol 50 gave the title compound (0.095g) as a crystalline solid m.p. 220-220°.

BNSDOCID: <GB 2153821A_L>

11 GB 2 153 821 A

11

T.l.c. Silica, dichloromethane/ethanol/0.88 ammonia (100:8:1) Rf 0.33, detection u.v. and iodoplatinic acid. The following compounds were prepared by a similar procedure as detailed in Table II. Salt formation was carried out as described in Example 2.

5 TABLE II 5

FORMULA (!) Wtof

Ex. appropr- Vol Reaction

Ato. Wt iate Sol- TimelTemp. Salt Wt.

10 R' ff Ft3 F? S.M. Imidazole vent (hl°C) Formed Product m.p. 10

(9) (9) (ml) (g)

155-

3b H CH3 H H 6.60 17.00 75 17.25/100 Maleate 0.40

15 156° 15

154.5-

3c H CH2CH3 H H 7.00 10.50 75 18/85 Maleate 0.48

156°

20 20

100.5-

3d H CH3Ph H H 3.00 3.10 25 24/100 Maleate 0.61

102°

25 144- 25

3e H H CH3 H Maleate 0.16

145.5°

30 1.00 2.2 5 18/95 143- 30

3f H H H CH3 Maleate 0.09

144°

142-

35 3g H 7 H H 1.80 1.0 20 20/100 HCI 0.11 35

146°

•HNMR SPECTRA (obtained at 250 MHz in dg-DMSO)

■■ <GB 2153821 A_l_>

12

GB 2 153 821 A

12

Selected Proton Chemical Shifts (b ppm) and multiplicities

Carbazolone

Imidazolyl Imidazole Methylene

Aromatic Aliphatic H-5,6,7,8 CHZ-1 and CH2-2 H-3

10

4.29(dd}

7.1-8.05 3.0-3.25 1.9-2.2 and

4.69(dd)

H-2' H-4'

and/or H-5'

7.57d and

7.67d

10

15 4.32(dd)

7.15-8.05 3.0-3.25 1.9-2.2 and

4.72{dd)

7.61 d and

7.69d

15

4.28(dd)

20 7.15-8.05 2.85-3.1 1.8-2.05 and

4.71 (dd)

7.59d and 7.71 d

20

25

4.48(dd)

7.15-8.05 3.0-3.20 1.75-2.25 and

4.62(dd)

8.97s 7.46s

25

4.29(dd)

7.15-8.05 3.0-3.20 1.90-2.20 and

4.74(dd)

30

6.32(dd)

7.1-8.0 2.9-3.2 1.75-2.1 and

6.70(dd)

8.93s 7.41s

7.75d and

7.83d

30

35

NOTE 1

35

40

Compounds 3e and 3f were prepared in the same experiment and the isomers separated by preparative h.p.l.c. on Zorbax-sil eluting with hexane/ethyl acetate/ethanol/0.88 ammonia (400:100:100:0.6).

NOTE 1 to TABLE II continued In the Table, the positions of the protons are numbered with reference to the formula below,

40

45

50

n R2

« , I,

* • • 1 *, 21

// \ / \3/ \ / *

I

N N3'

!« .Ul-

♦ • • <■ c ■ • • ^•

7 / \ / \ / 5/

• N • ^ n

8 A1 1

45

50

The symbols in Table II have the following meanings d = doublet, dd = doublet of doublets, s = singlet 7 represents the group ,—T

55 1 V

55

EXAMPLE 4

1,2,3,9-TetrahYdro-9-methyl-3-[{2-methyl-1H-imidazoI-1-yl}methyl]-4H-carbazol-4-one 60 Asolution of 1,2,3,9-tetrahydro-3-[(2-methyl-1W-imidazol-1-yl) methyl]-4//-carbazol-4-one (1.0g) in dry 60 dimethylformamide (10ml) was added dropwise under nitrogen to a stirred, ice-cooled suspension of sodium hydride (80% in oil; 0.11 g> in dry dimethylformamide (5ml). After 0.5h dimethylsulphate (0.34ml) was added, and the solution stirred at room temperature for 4h. The resultant solid was filtered off, washed with ice-cold dry dimethylformamide (2x5ml) and dry ether (3x15ml) and dried to give the title compound 65 as a solid (0.25g) m.p. 223-224° (dec). 65

BNSDOCID: <GB 2153821A l_>

13

GB 2 153 821 A 13

T.l.c. Silica, chloroform/methanol (93:7) Rf 0.27 detection u.v. and iodoplatinic acid, identical to the product from Example la. The following compounds were prepared by a similar procedure using the appropriate alkylating agent as detailed in Table ill.

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BNSDOCID: <GB 2153821 A_L>

14

GB 2 153 821 A

14

Molecular Formula

5 C19H?1N30. HCI.05H20

C24H23N3O. C4H4O4

Analysis (%)

Found Requires

C H N C H N

64.7 6.5 11.8 64.7 6.6 11.9

69.355.5 8.5 69.3 5.6 8.65

10

10

Ct9H2IN3O.C4H4O4 65.156.1 9.85 65.255.95 9.9

C24H23N3O.C4H4O4 69.1 5.65 8.55 69.3 5.6 8.65

15

C23H29N30.C4H404 67.4 6.9 8.7 67.6 6.9 8.8

15

20 C26H27N30. 69.5 5.9 8.0 69.7 6.1 8.1

C4H4O4.o.2h2o

C27H37N3O.C2H2O4

25 .0.3H20

C22H27N3O.HCL

1.1 h2o

66.7 7.8 7.8 66.6 7.8 8.0

65.8 7.9 10.3 65.4 7.5 10.4

30

NOTE 1

The following 'H.n.m.r. data was obtained.

35

40

0 R2

5 * >2,

6/\_a3a /v l II II l . I—L

'\\ /'\ /'\ /*2 b/ \

• N • R* 1

8 1

R3

d = doublet dd = doublet of doublets s = singlet

20

25

30

35

40

45

50

55

■H NMR SPECTRA (obtained at 250 MHz)

Selected Proton Chemical Shifts (b ppm) and multiplicities

Solvent

4g

60 4h d6-DMS0

d6-DMS0

Carbazoione Protons

Aromatic Aliphatic

H-5,5,7,8 CH2-1 and CHz-2

H-3

7.15-8.1 2.9-3.2 1.9-2.2

7.2-8.1 2.9-3.3 1.8-2.2

Jmidazolyl Methylene Protons

6.29{dd) and

6.68(dd)

6.26(dd) and

6.65(dd)

Imidazole Protons

H-2' H-4' andlor H-5'

7.55d and

7.65d

7.42d and

7.57d

45

50

55

60

BNSDOCID: <GB 2163821A_i_>

15

GB 2 153 821 A

15

EXAMPLE 5

9-Cyclopentyl- 1,2,3,9-tetrahydro-3-{(2-methyi- 7H-imidazol- 1-yl)methyl]-4H-carbazol-4-one maleate

Asolution of 1,2,3r9-tetrahydro-3-[(2-methyl-1/T,-imidazol-1-yl)methyl]-4//-carbazol-4-one (1.20g) in dry dimethylformamide (9ml) was added to a stirred, ice-cooled, suspension of sodium hydride (80% in oil; 5 0.14g) in dry dimethylformamide (2ml) under nitrogen, and stirring continued for0.25h. Bromocyclopentane (0.51 ml) was added and the stirred solution heated at 100° for 18.5h. The solution was allowed to cool and then partitioned between water (100ml) and ethyl acetate (3x70ml). The combined organic extracts were washed with 2N sodium carbonate (2x50ml), water (2x50ml) and brine (50ml), dried, evaporated to dryness and purified by chromatography eluting with a mixture of dichloromethane, ethanol, 0.88 ammonia 10 (150:10:1) to give an oil (0.27g). This oil was dissolved in refluxing absolute ethanol (7ml) and a solution of maleic acid (0.1 Og) in refluxing absolute ethanol (0.5ml) was added. The hot solution was filtered, stirred and diluted with dry ether (20ml). The resultant yellow gum was washed with dry ether (7 x 25ml), and the combined mother-liquors and washings left to stand. The solid that crystallised from the solution was filtered off, washed with dry ether (3x5ml) and dried to give the title salt as a white crystalline solid (0.058g), 15 m.p. 104-5°-106°

Analysis Found:C,65;95;H,6.4;N,8.6.

C22]H25N3O.C4H404.0.6H20 requires C,65.8;H,6.4;N,8.9%.

EXAMPLE 6

20 1,2,3,9-Tetrahydro-3-[2-methyl- 1H-imidazol- 1-y/)methyiJ-9-(2-propenyl)-4H-carbazol-4-one maleate

Asolution of 1,2,3,9-tetrahydro-3-[(2-methyl-1/T,-imidazol -1-yl)methyl]-4//-carbazol-4-one (1.0g) in dry dimethylformamide (6ml) was added to a stirred, ice-cooled suspension of sodium hydride (80% in oil; 0.12g) in dry dimethylformamide (2ml). After 0.25h allyl bromide was added, the solution stirred at 0° for 0.25h, and at room temperature for 20h before partitioning between water (75ml) and ethyl acetate 25 (3x50ml). The combined organic extracts were washed with water (2 x50ml), brine (50ml), dried, and concentrated in vacuo and purified by chromatography eluting with a mixture of dichloromethane, ethanol, and 0.88 aqueous ammonia (200:10:1)to afford a solid (0.43g). This solid was dissolved in refluxing absolute ethanol (2ml) and a solution of maleic acid (0.18g) in refluxing absolute ethanol (1 ml) was added. The hot solution was filtered, diluted with dry ether (4ml) and the crystallised solid was filtered off, washed with dry 30 ether (3x5ml) and dried to give the title compound as a white solid (0.48g), m.p. 150.5°-151°

Analysis Found: C,66.3;H,5.75;N,9.6.

C20H21N3O.C4H4O4 requires C,66.2;H,5.8;N,9.65%.

EXAMPLE 7

35 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yllmethyl]-4H-carbazol-4-one

Asolution of 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4/V-carbazol-4- one hydrochloride (1.7g) in water (17ml) was treated with 2-methylimidazole (1.4g) and then heated under reflux for 20h. The cooled mixture was filtered and the residue washed with water (3x15ml) to give crude product (1.7g) m.p. 221-221.5°. This material was recrystallised from methanol to give the title compound (1.4g) m.p. 231-232°, 40 identical by tl.cwith product from Example 4.

EXAMPLE 8

1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yi)methyl]-4H-carbazol-4-one A suspension of the product from Preparation 3 (0.5g) and 2-methylimidazole (0.4g) in water (5ml) was 45 heated under reflux for 20h. The cooled reaction mixture was filtered and the residue washed with water (3x10ml), dried and recrystallized from methanol (18ml) to give the title compounds (0.3g) m.p. 232-234° (dec), identical by t.l.c. with the product from Example 4.

EXAMPLE 9

50 7,2r3,9-Tetrahydro-9-l7-methylethyl)-3-[(2-methyl-7H-imidazol-7-yl)methyl]-4H-carbazol-4-one hydroch-loride

Sodium hydride (80% dispersion in oil 0.208g) was added to a stirred solution of 1,2,3,9-tetrahydro-3-[(2-methyl-1//-imidazol-1-yl)methyl]-4//-carbazol-4-one (1.93g) at 0°C in DMF (35ml) and the resultant suspension stirred at 0°C for 0.25h. 2-Bromopropane (0.78ml) was then added and stirring continued at room 55 temperature overnight, followed by 4h at 40°C.

The reaction mixture was partitioned between sodium carbonate (2N; 200ml) and ethyl acetate (2x150ml). The combined organic extracts were washed with water (3x75ml), dried, and evaporated in vacuo and the product purified by chromatography eluting with dichloromethane:ethanol:ammonia (100:8:1) togive an oil. This oil was dissolved in ethanol (3ml), acidified with ethereal hydrogen chloride and diluted with dry ether 60 to deposit the title compound as a white solid (0.13g) m.p. 230-232°.

Analysis Found: C,65.3;H,6.6;N,11.1%.

C20H23N3O.HCLO.5H2O requires C,65.4;H,6.9;N,11.45%.

5

10

15

20

25

30

35

40

45

50

55

60

BNSDOCID: <GB 2153821 A_J_>

16 GB 2 153 821 A

16

EXAMPLE 10

1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl- 1H-imidazol- 1-yl)methyl]-4H-carbazol-4-one hydrochloride dihy-drate

1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-lW-imidazol-1-yl)methyll-4W-carbazol-4-one (18.3g) in a hot mix-5 ture of isopropanol (90ml) and water (18.3ml) was treated with concentrated hydrochloric acid (6.25ml). The hot mixture was filtered and the filtrate diluted with isopropanol (90ml) and stirred at room temperature for 17h, cooled to 2" and the solid filtered off (21.6g). A sample (6g) was recrystallized from a mixture of water (6ml)and isopropanol (10ml)togivethef/f/ecompoi/A?cfasawhite crystalline solid (6g) m.p. 178.5-179.5'. Analysis Found:C,59.45; H,6.45; N.11.5.

10 C12H19N3O.HCI.2HzO requires C,59.1; H,6.6; N,11.5%.

Water assay Found: 10.23%.

C1SH19N30.HCI.2H20 requires 9.85%.

EXAMPLE 11

15 1,2,3,9-Tetrahydro-3-[(2-methyl- 1H-imidazoi- 1-yt)methyl]-9-phenyl-4H-carbazoi~4-one maleate i) 3-[(Dimethylamino)methylJ- 1,2,3,9-tetrahydro-9-phenyl-4H-carbazol-4-one hydrochloride Asolution of 1,2,3,9-tetrahydro-9-phenyl-4W-carbazol-4-one (3.90g) dimethylamine hydrochloride(1.50g)

and paraformaldehyde (0.60g) in glacial acetic acid was stirred at reflux under nitrogen for 42h, allowed to cool and concentrated in vacuo. The residual brown gum was stirred with water (50ml),ethyl acetate (50ml) 20 and brine (20ml) for 0.25h, and the resultant solid filtered off, washed with dry ether (4x30mI) and dried to give the title compound (4.2g). A portion of this solid (1.0g) was recrystallised twice from absolute ethanol (10ml) to give the title compound as a fawn powder (0.39g) m.p. 193°-194° (dec).

ii) 1,2,3,9-Tetrahydro-3-[2-methyl-1H~imidazol- 1-yl)methyl]-9-phenyl-4H-carbazol-4-one maleate 25 2-Methyl-1W-imidazole (1.4g) was added, under nitrogen, to a stirred suspension of 3-

[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-phenyl-4W-carbazol-4-one hydrochloride (2.0g) in water (20ml). The mixture was heated at 90° for 43h and the solvent decanted from the fawn solid. Chloroform was added to the solid, the suspension was filtered through hyflo (RTM), the filtrate dried and concentrated in vacuo. Chromatography of the residual fawn foam (2.04g) eluting with a mixture of dichloromethane, 30 ethanol and 0.88 aqueous ammonia (200:10:1) afforded a white foam (1.1g). Asolution of this foam in ethanol (3ml) was treated with maleic acid (0.4g) in ethanol (1 ml) followed by dry ether (40ml) and the resultant gum triturated with dry ether (2x40m!)to afford the title compound as a cream solid (1.37g), m.p. 165-166° (dec).

Analysis Found: C,68.65; N,5.5; N,8.7.

35 C23H2iN30.CilH404 requires C,68.8; N,5.3; N,8.9%.

EXAMPLE 12

1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one phosphate (1:1) 1,2,3,9-Tetrahydro-9-methy!-3-|(2-methyl-1W-imidazol-1-yl)methy!]-4W-carbazol-4-one (0.61g)was dis-40 solved in a hot mixture of phosphoric acid (90%, 0.13ml) and water (10ml), filtered through Hyflo and allowed to crystallize to give the title compound (0.5g) m.p. 225°

Analysis Found: C,55,1;H,5.6;N,10.55.

C18Hi9N30.H3P04 requires C,55.2;H,5.7;N,10.7%.

45 EXAMPLE 13

l,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl- IH-imidazol- 1-yl)methy/J-4H-carbazoi-4-one citrate (2:1)

1,2,3,9-Tetrahydro-9-methyl-3-K2-methyl-1W-imidazol-1-yl)methyl]-4W-carbazol-4-one (0.89g) was dissolved in a hot solution of citric acid <0.58g) in ethanol (20ml) and allowed to crystallize. The resulting crystalline solid was recrystallized by dissolving in acetone/water (2:1,2ml) and diluting with acetone (20ml) 50 to give the title compound (0.6g) m.p. 162°.

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EXAMPLE 14

1,2,3,9-Tetrahydro-3[f2-propyl-IH-imidazol-f-yllmethylJ-4H-carbazol-4-one hydrochloride

Iodomethane (0.75ml) was added to a stirred solution of 3-[(dimethy! amino)methylj-1,2,3,9-tetrahydro-4W-carbazol-4-one (2.9g) in dry DMF(30ml) and the solution stirred at room temperature for 30 min. A 5 solution of 2-propyl-1/Y-imidazole (2g) in DMF (5ml) was added, and the solution stirred at 100°C for 2 days, 5 cooled and partitioned between sodium carbonate (2N, 150m!) and ethyl acetate (2x 100ml). The combined extracts were washed with water (100ml), dried and evaporated in vacuo. The residue was purified by column, chromatography eluting with dichloromethaneiethanohammonia (400:30:3) to give the free base asa solid (1.2g). Asample (0.2g) was dissolved in absolute ethanol (5ml), acidified with ethereal hydrogen 10 chloride and diluted with dry ether (ca 200ml) to give an oil. On scratching, the oil crystallised to give a solid 10 (0.15g). The salt was crystallised from a mixture of methanol and isopropyl acetate to give the title compound (0.08g) m.p. 206-208°C Analysis Found: C,65.6;H,6.8;N,12.0.

C19H21N3O.HCI 0.2H20 requires C,65.7;H,6.5;N,12.1%.

15 N.m.r. S(CD3SOCD3) 0.94(3H,t,CH3), 1.77(2H,sextet,CH2Ctf2CH3),1.9-2.15 and 2.95-3.2 (7H,m), 4.32 and 4.71 15 (2H, ABX, CHCH2H), 7.1-8.0(6H, aromatic)

EXAMPLE 15

1,2,3,9-Tetrahydro-3-[(2-propyl- IH-imidazoi- l-yllmethylj-4H-carbazol-4-one hydrochloride 20 Asolution of the product from Example 3g (0.03g) in methanol (15ml) was hydrogenated at room 20

temperature and pressure over 10% palladium oxide on charcoal (50% aq. paste, 0.03g) for 4h (H2 uptake, 5ml). The catalyst was filtered off, and the filtrate evaporated in vacuo to give an oil. Trituration with ether gave the title compound as a white solid (0.03g) m.p. 199,>-203°C.

This material was identical by t.l.c. and n.m.r. to the product from Example 14. 25 25

EXAMPLE 16

1,2,3,9-Tetrahydro-9-propyl-3-[(2-propyl-1H-imidazol-1-yl)methylj-4H-carbazol-4-one hydrochloride

Sodium hydride (80%disp. in oil) was added, under nitrogen, to a stirred solution of the product from Example 14 (1.0g) in dry DMF (20ml) and the suspension stirred at room temperature for 30 30 min.1-Bromopropane (0.35ml) was added, and the solution stirred at 40"Cfor20h. The solution was 30

partitioned between sodium carbonate (2N, 150ml) and ethyl acetate (2x100ml).The combined extracts were washed with water (100ml), dried and evaporated in vacuo to give an oil. The oil was purified by column chromatography eluting with dichloromethane:ethanol:ammonia (100:8:1) to give pure free base as an oil. The oil was dissolved in absolute ethanol (5ml), acidified with ethereal hydrogen chloride, and diluted 35 with dry ether (200ml). The ether was decanted off the resulting oil and replaced with more dry ether (200ml). 35 On storage at 0°C overnight the oil crystallised to give the title compound {0.53g) m.p. 144°-147°C N.m.e. 8(CD3SOCD3) 0.90 and 0.93(6H,t + t, 2xMe), 1.65-2.2 and 2.9-3.25 (10H,m) 4.19(2H,t,CH2CT/2N), 4.32 and 4.71 (2H.ABX, CH2CW2N), 7.15-8.1 (6H,m, aromatic)

Analysis Found: C,66.6;H,7.7;N,10.0.

40 C22H27N3O.HCI.0.7H20 requires C,66.3;H,7.4;N, 10.5%. 40

EXAMPLE 17

7,2,3,9-Tetrahydro-3-f(2-methyl-1H-imidazo/-1-yl)methylJ-9-propyl-4H-carbazol-4-one maleate A solution of the product from Example 6 (0.86g) in a mixture of absolute ethanol (20ml) and dry 45 dimethylformamide (5ml) was hydrogenated at room temperature and pressure over 5% platinum on carbon 45 [(0,1 g, pre-reduced in absolute ethanol (10ml) for 1h. (H2 uptake = 70ml). The catalyst was filtered off,

washed with ethanol, and the filtrate concentrated in vacuo to ca 15ml. The residual solution was stirred,

diluted with water (50ml) and the precipitated solid filtered off, washed with water (3x15mI) and dried to give a powder (0.73g).

50 This material was dissolved in refluxing absolute ethanol (7ml), filtered, and a solution of maleic acid (0.25g) 50 in refluxing absolute ethanol (1ml) was added. The stirred solution was diluted with dry ether (50ml) to give the title compound (0.84g), m.p. 150°-151°

Analysis Found: C,65.8;H,6.1;N,9.3;

C20H23N3O.C4H4O4 requires C,65.9;H,6.2;N,9.6% 55 55

EXAMPLE 18

1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl- IH-imidazol- 1-yl\methyl}-4H-carbazol-4-one (i) 3-(Chloromethyl)-7,2,3,9-tetrahydro-9-methyI-4H-carbazol-4-one Ethereal hydrogen chloride (3.0ml) was added to a stirred, ice-cooled solution of the product from 60 Preparation 3 (1.90g) in chloroform (15ml), and the resultant suspension was stirred in a sealed vessel at 60 room temperature for 16.5h, concentrated in i/acwoandthe residual solid (2.27g) purified by column chromatography eluting with chloroform to give the title compound (1.75g) m.p. 109-110.5 'An attempt to crystallise a portion of this material from ethyl acetate resulted in partial decomposition.

<GB_

.2153821A l_>

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GB 2 153 821 A

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(ii) 1,2,3,9- Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol- 1-yl)methyl]-4H-carbazol-4-one

Asolution of 3-(chloromethyl)-1,2,3,9-tetrahydro-9-methyl-4/y-carbazol-4-one (0.50g) and 2 methyl-IW-imidazole (1.60g) in dry DMF was stirred under nitrogen at 90° for3.75h, and then poured onto water (25ml). The suspension was stirred for 1h, and the solid filtered off, washed with water (3 x30ml) and dried in vacuo 5 at 50°. Column chromatography of this solid (0.53g) eluting with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (150:10:1) afforded the title compound (0.45g) m.p. 228-229°. This material was identical to the product from Example 7 by t.l.c. and n.m.r.

EXAMPLE 19

10 l,2,3,9-tetrahydro-9-methyl-3-[(methyl-W-imidazol-1-yl)methyl}-4H-carbazol-4-one

Asolution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (170mg) in dry tetrahydrofuran (1.5ml) was added dropwise under nitrogen to a stirred, ice-cooled suspension of the product from Preparation 4 (lOOmg) in a mixture of tetrahydrofuran (3.5ml) and water (0.4ml). The resultant blue solution was stirred for 1.5h, and then concentrated in vacuo. Column chromatography of the residual solid eluting with a mixture of 15 dichloromethane, ethanol and 0.88 ammonia (150:10:1) afforded the title compound (45mg) m.p.

227°-228.5°. This material was identical to the product from Example 7 by t.l.c. and n.m.r.

EXAMPLE 20

1,2,3,9-Tetrahydro-9-methyi-3-[(2-methyl-1H-imidazol-1-yl)methylJ-4H-carbazol-4-one 20 Asolution of 2,3-dich!oro-5,6-dicyano-1,4-benzoquinone (80mg) in dry tetrahydrofuran (1.5ml) was added dropwise under nitrogen to a stirred, ice-cooled suspension of the product from Preparation 5 (100mg) in a mixture of tetrahydrofuran (3.5ml) and water (0.4ml). The resultant blue solution was stirred for 1,5h, and then the red suspension was concentrated in vacuo.

Column chromatography of the residual solid eluting with a mixture of dichloromethane, ethanol and 0.88 25 ammonia (150:10:1) afforded the title compound as a white solid (0.47g) m.p. 227.5°-229°. This material was identical to the product from Example 7 by t.l.c. and n.m.r.

EXAMPLE 21

3S-1,2,3r9-Tetrahydro-3[(2-methylimidazol-1-yl)metfiylJ-9-methyl-4H-carbazol-4-one maleate 30 Asolution of the product from Example 7(0.5g) was dissolved in hot methanol (30mt) and treated with a hot solution of (+)-di-p-toluoyl -D-tartaric acid monohydrate (0.7g) in methanol (10mt)and the resulting solution allowed to crystallise overnight to give the desired salt (0.68g). This salt was dissolved in hot dimethylformamide (DMF, 20ml) diluted with hot water(IOml) and allowed to crystallise overnight. The product was filtered off, and dried in vacuo to give ca 90% enantiomerically pure (as shown by n.m.r.) 35 (+)-di-p-toluoyl-D-tartaric acid salt (0.23g) m.p. 231-233°. A sample of the salt (0.15g) was partitioned between 8% sodium bicarbonate (25ml) and chloroform (2x25ml). The combined extracts were dried and evaporated in vacuo to give pure free base (0.07g). The base was dissolved in methanol (5ml) acidified with maleic acid (0.03g) and the salt precipitated by adding excess dry ether (80ml) to give the title compound (0.062g) m.p. 142-145°

40 T.l.c. Silica, dichloromethane/ethanol/0.88 ammonia (100:8:1) Rf 0.3 detection u.v. and iodoplatinic acid, identical to the product from Example 7. The enantiomer ratio, determined by 'H n.m.r. was 93:7 (S:R). A sample of the maleate salt showed no significant optical rotation in methanol. The free base, regenerated from the maleate salt gave [<x]d5 - 14° (c 0.19, MeOH).

45 EXAMPLE 22

3R-1,2,3,9-Tetrahydro-9-methyl-3-l(2-methyi-1H-imidazol-1-yl)methyf]-4H-carbazol-4-one maleate

Asolution of the product from Example 7 (0.5g) was dissolved in hot methanol (30ml) and treated with a hot solution of (—) di-p-toluoyl -L-tartaric acid monohydrate (0.7g) in methanol (10ml) and the resulting solution allowed to crystallise overnight to give the desired salt (0.8g).This salt was dissolved in hot 50 dimethylformamide (DMF, 20ml), diluted w i hot water (10ml) and allowed to crystallise for3 days. The product was filtered off, and dried in vacuo to give ca 95% enantiomerically pure (as shown by n.m.r.) (-)-di-p-toluoyl-L-tartaric salt (0.26g) m.p. 170°-172°. A sample of the salt (0.2g) was partitioned between 8% sodium bicarbonate (25ml) and chloroform (2x25ml). The combined extracts were dried and evaporated in vacuo to give pure free base (0.12g). The base was dissolved in methanol (5ml) acidified with maleic acid 55 (0.045g) and the salt precipitated by adding excess dry ether (80ml) to give the title compound (0.08g) m.p. 142-145°

T.l.c. Silica, dichloromethane/ethanol/0.88 ammonia (100:8:1) Rf 0.3 detection u.v. and iodoplatinic acid, identical to the product from Example 7. The enantiomer ratio, determined by 'H n.m.r. was 95:5. A sample of the maleate salt showed no significant optical rotation in methanol. The free base, regenerated from the 60 maleate salt, gave [a]o4 + 16° (c 0.34, MeOH).

The following examples illustrate pharmaceutical formulations according to the invention, containing 1,2,3,9-tetrahydro-9-methy!-3-[(2-methyl-1/y-imidazol-1-yl)methyl]-4W-carbazol-4-one hydrochloride dihy-drateas the active ingredient (1.25g of the hydrochloride dihydrate contains 1.00g of the free base). Other compounds of the invention may be formulated in a similar manner.

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GB 2 153 821 A 19

TABLETS FOR ORAL ADMINISTRATION Tablets may be prepared by the normal methods such as direct compression or wet granulation. The tablets may be film coated with suitable film forming materials, such as hydroxypropyl methylcellu-lose, using standard techniques. Alternatively the tablets may be sugar coated.

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Direct compression

Tablet mgltabiet

1C Active Ingredient 4.688 28.125

Calcium Hydrogen Phosphate BP* 83.06 87.75

Croscarmellose Sodium NF 1.8 1.8

Magnesium Stearate BP 0.45 0.45

Compression weight 90.0 118;0

15

* of a grade suitable for direct compression.

The active ingredient was passed through a 60 mesh sieve, blended with the calcium hydrogen phosphate, croscarmellose sodium and magnesium stearate. The resultant mix was compressed into tablets using a 20 Manesty (RTM) F3 tablet machine fitted with 5.5mm, flat bevelled edge punches.

Sub-Linguai Tablet mgltabiet

Active Ingredient 2.5

25 Compressive Sugar NF 62.5

Magnesium Stearate BP 0.5

Compression Weight 65.0

30 The active ingredient is sieved through a suitable sieve, blended with the excipients and compressed using suitable punches. Tablets of other strengths may be prepared by altering eitherthe ratio of active ingredient to excipients or the compression weight and using punches to suit.

Wet Granulation

35

Conventional Tablet mgltabiet

Active Ingredient 2.5

Lactose BP 151.5

40 Starch BP 30.0

Pregelatinised Maize Starch BP 15.0

Magnesium Stearate BP 1.5

Compression Weight 200.0

45

The active ingredient is sieved through a suitable sieve and blended with lactose, starch and pregelatinised maize starch. Suitable volumes of purified water are added and the powders are granulated.

50 After drying, the granules are screened and blended with the magnesium stearate. The granules are then compressed into tablets using 7mm diameter punches.

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

55 Sub-Lingual Tablet mgltabiet

Active Ingredient 2.5

Mannitol BP 56.5 Hydroxypropylmethylcellulose 5.0 60 Magnesium Stearate BP 1.5

Compression Weight 65.5

BNSDOCID: <GB 2153821A_L>

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GB 2 153 821 A

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The active ingredient is sieved through a suitable sieve and blended with the mannitol and hydroxypropylmethylcellulose. Suitable volumes of purified water are added and the powders are granulated. After drying, the granules are screened and blended into tablets using suitable punches.

Tablets of other strengths maybe prepared by altering the ratio of active ingredient to mannitol or the compression weight and punches to suit.

CAPSULES

mgltabiet

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Active Ingredient *Starch 1500 Magnesium Stearate BP

Fill Weight

2.5 97.0 1.0

100.0

.0

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* a form of directly compressible starch.

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The active ingredient is sieved and blended with the excipients. The mix is filled into size No. 2 hard gelatin capsules using suitable machinery. Other doses may be prepared by altering the fill weight and if necessary 20 changing the capsule size to suit.

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SYRUP

This may be either a sucrose or sucrose free presentation. 25 A. Sucrose Syrup mg/Sml dose

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Active Ingredient Sucrose BP Glycerine BP Buffer ) Flavour ) Colour ) Preservative) Purified Water BP

to

2.5 2750.0 500.0

as required 5.0ml

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The active ingredient, 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.

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B. Sucrose-Free Active Ingredient

Hydroxypropylmethylcellulose USP

(viscosity type 4000)

Buffer )

Flavour )

Colour )

Preservative)

Sweetener )

mg!5ml dose 2.5 22.5

as required

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Purified Water BP

to

5.0ml

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solution containing the active ingredient and the other components of the formulation. The resultant solution is adjusted to volume and mixed. The syrup is clarified by filtration.

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GB 2 153 821 A 21

INJECTION

The injection may be administered by the intravenous or subcutaneous route.

Injection

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Active Ingredient 50 800

Dilute Hydrochloric Acid BPtopH 3.5 topH3.5

Sodium Chloride Injection BPto 1ml to 1ml

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The active ingredient was dissolved in a suitable volume of Sodium Chloride Injection BP, the pH of the resultant solution was adjusted to pH3.5 with dilute hydrochloric acid BP then the solution was made to volume with sodium chloride injection BP and thoroughly mixed. The solution was filled into Type 1 clear glass 5ml ampoules which were sealed under a headspace of air, by fusion of the glass then sterilised by 15 autoclaving at 120°for not lessthan 15 minutes. 15

HEAT DOSE PRESSURISED AEROSOL

Suspension Aerosol mg!metered dose Per can 20 20

Active Ingredient micronised 0.250 66mg

Oleic Acid BP 0.020 5.28mg

Trichlorofluoromethane BP 23.64 5.67g

Dichlorodifluoromethane BP 61.25 14.70g 25 25

The active ingredient is micronised in a fluid energy mill to a fine particle size range. The Oleic Acid is mixed with theTrichlorofluoromethane at a temperature of 10-15°C and the micronised drug is mixed into the solution with a high shear mixer. The suspension is metered into aluminium aerosol cans and suitable 30 metering valves, delivering 85mg of suspension are crimped onto the cans and the Dichlorodifluoromethane 30 is pressure filled into the cans through the valves.

Solution Aerosol

35 mg/metered dose Per can 35

Active Ingredient 0.25 30.0mg

Ethanol BP 7.500 1.80g

Trichlorofluoromethane BP 18.875 4.35g

40 Dichlorodofluoromethane BP 48.525 11.65g 40

Oleic Acid BP, on a suitable surfactant e.g. Span (RTM) 85 (sorbitan trioleate) may be also included).

The active ingredient is dissolved in the ethanol together with the Oleic Acid or surfactant if used. The alcoholic solution is metered into suitable aerosol containers followed by the trichlorofluoromethane.

45 Suitable metering valves are crimped onto the containers and dichlorodifluoromethane is pressure filled into 45 them through the valves.

Inhalation Cartridges

50 mg/cartridge 50

Active Ingredient (micronised) 0.5

Lactose BP to 25.00

55 The active ingredient is micronised in a fluid energy mill to a fine particle size range priorto blending with 55 norma! tabletting grade lactose in a high energy mixer. The powder blend is filled into No. 3 hard gelatin capsules on a suitable encapsulating machine. The contents of the cartridges are administered using a powder inhaler.

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Claims (11)

1. A compound of the general formula (I)

3 (I)

10 Ii r2 10

wherein

R1 represents a hydrogen atom or a C^io alkyl, C3.7 cycloalkyl, C3.6 alkenyl, phenyl or phenyl-Cn.3 alkyl

15 group, and one of the groups represented by R2, R3 and R4 is a hydrogen atom or a Ci_6 alkyl, C3.7 cycloalkyl, 15 C2-6 alkenyl or phenyl-Ci.3 alkyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C^ alkyl group;

and physiologically acceptable salts and solvates thereof.

2. Acompound according to claim 1 in which R1 represents a hydrogen atom or a C-,.6 alkyl, C3.6

20 cycloalkyl or C3.6 alkenyl group. 20

3. A compound according to claim 1 or 2 in which one of the groups represented by R2, R3 and R4 representsa C-, 3 alkyl, C3.6 cycloalkyl or C3.6 alkenyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a Cn.3 alkyl group.

4. Acompound according to claim 1 in which R1 represents a hydrogen atom or a C^ alkyl, C5.6

25 cycloalkyl or C3.4alkenyl group and either R2 represents a hydrogen atom and R3 and /or R4 represents a ^.3 25 alkyl group orR2 represents a C].3 alkyl group and both R3and R4 represent hydrogen atoms.

5. Acompound of the general formula (la)

(la)

30 30

35 35

wherein

Rla represents a hydrogen atom or a methyl, ethyl, propyl, prop-2-yl, prop-2-enyl or cyclopentyl group; R3a represents a hydrogen atom; and either R2a represents a methyl, ethyl, propyl or prop-2-yl group and R4a represents a hydrogen atom or R2a represents a hydrogen atom and R4a represents a methyl or ethyl group; 40 and physiologically acceptable salts and solvates thereof. 40

6. 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyi-1A/-imidazal-1y!)methyl]-4/y-carbazol-4-one and physiologically acceptable salts and solvates thereof.

7. 1,2,3,9-Tetrahydro-3-[(2-methyl-1//-imidazol-1-y!)methyl]-9-(prop-2-enyl)-4A/-carbazol-4-one; 9-Cyclopentyl-1,2,3,9-tetrahydro-3-[(2-methyl-1W-imidazol-yl)methyl]-4W-carbazol-4-one;

45 1,2,3,9-Tetrrahydro-3-[2-methyl-1Mmidazol-1-yl)methyl]-9-(prop-2-yl)-4/y-carbazol-4-one 45

and physiologically acceptable salts and solvates thereof.

8. A process for the preparation of a compound of general formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof, which process comprises:

(A) reacting a compound of genera! formula (II) 50 0 50

(II)

55 ^ 55

(in which R1 is as defined in claim 1 and Y represents a reactive substituent) or a protected derivative thereof with an imidazole of general formula (III)

^4 „3

(III)

w

HN H

,2

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GB 2 153 821 A

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(in which R', R3 and R4 are as defined in claim 1) or a salt thereof; or (B) oxidising a compound of formula (IV)

5

(IV)

5

10

10

(in which A represents a hydrogen atom or a hydroxyl group and R\ R2, R3 and R4 are as defined in claim 1) or a salt or a protected derivative thereof; or

(C) converting a compound of formula (I) or a salt or a protected derivative thereof into another compound of

(D) removing a protecting group or groups from a protected form of a compound of formula (I);

and when a 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

9. A process as claimed in claim 8(A) in which Y represents an alkenyl group -CH2 or a group of formula CH2Z where Z represents a readily displaceable atom or group.

10. A process as claimed in claim 8(C) in which a compound of formula (I) or a salt or a protected derivative thereof is converted into another compound of formula (I) by alkylation or hydrogenation.

25

11. A pharmaceutical composition comprising at least one compound of general formula (I) as defined in 25 claim 1 ora physiologically acceptable salt orsolvate thereof together with at least one physiologically acceptable carrier or excipient.

15 formula (I); or

15

20 into a salt.

20

Printed in the UK for HMSO, D8318935. 7 86. 7102.

Published by The Patent Office, 25 Southampton Buifdings, London, WC2A 1AY, from which copies may be obtained.

BNSDOCID: <GB 2153821A__L>