This invention relates to substituted carbazole derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine for the reduction of oestrogen and/or androgen levels.

17,20-Lyase activity is responsible for the conversion of 17α- hydroxyprogesterone to androstenedione and of 17α-hydroxypregnenolone to dehydroepiandrosterone. This activity is critical for the biosynthesis of androgens and estrogens, and inhibition of 17,20-lyase by ketoconazole (a known antifungal agent) has been shown to reduce testosterone levels in animals (English, H.F. et al.. Cancer Res. 47, 38-42 (1986) and men (Pont, A. et al., Arch. Intern. Med. 142, 2137-2140 (1982).

High dose ketoconazole has been used in the treatment of prostate cancer (Trachtenberg, J., J. Urol. 132, 61-63 (1984) and Pont, A., et al., Arch. Intern. Med. 145, 1429-1431 (1985)). However, doses of ketoconazole that produce inhibition of testosterone production are significantly more toxic than antifungal doses, and more selective 17,20-lyase inhibitors would be expected to have a much better therapeutic index.

Inhibition of 17,20-lyase, as an approach to inhibition of testosterone biosynthesis, also has the advantage of blocking adrenal as well as testicular derived androgens (English, H.F. et al.. Cancer Res. 46, 38-42 (1986)), and should be a more effective treatment for prostate cancer than that afforded by LHRH agonists.

Thus the present invention provides compounds of general formula (I)

wherein R- _| and R each independently represent a hydrogen atom or a C-j^alkyl group;

each R2 may be the same or different and represents an electron-withdrawing group; each R3 may be the same or different and represents an electron-withdrawing group;

R ₅ is a group of formula

R ₆ is a halogen atom, a C^alkyl group or a C^ alkoxy group; m is zero or an integer 1 to 4; n is zero or an integer 1 to 3; and p is zero, 1 or 2 and pharmaceutically acceptable salts and solvates thereof.

The substituents R2 may each occupy any available position of the 5, 6, 7 or 8 positions. .

The substituents R3 may each occupy any available position of the 1 , 2, 3 or 4 positions, preferably the 1 , 3 or 4 positions.

The group — CHR ₄ R ₅ may occupy any of the 1 , 2, 3 or 4 positions, for example, the 1 , 2 or 3 positions. Preferably the group — CHR ₄ R ₅ will be in the 2 position.

Thus, in one aspect the invention provides compounds of formula (l ^a )

wherein R _{1 t} R ₂ , R3, R4, R5, m and n are as hereinbefore defined.

The substituent RQ may be attached to any carbon atom in the pyridyl ring, but preferably is attached in the 3,4 or 5 positions.

It will be appreciated by those skilled in the art that the numbering of the ring system for individual compounds within the scope of formula (I) will vary according to the nature, number and position of substituents. For convenience the numbering of ring atoms adopted herein is that shown in formula (I) above except where individual compound names are given.

It will be appreciated that the compounds of formula (I) may contain a chiral centre. It is to be understood that formula (I) is intended to encompass all enantiomers and diastereoisomers of the compounds of the invention as well as mixtures thereof, including racemates.

Electron-withdrawing groups are well known to those skilled in the art and any such group may be employed. Such groups include halogen atoms, such as fluorine, chlorine and bromine atoms, nitrile groups, nitro groups, trifluoromethyl groups, aldehydo groups, keto groups and carboxylic acid and ester groups and are preferably selected from fluorine atoms, chlorine atoms and nitrile groups. Particularly preferred as compounds of formula (I) are those wherein each of R2 and R3 represents a fluorine atom.

Suitably R2 represents a fluorine atom and m is an integer 1 to 4.

When m is 1 R2 will preferably be in the 5 or 7 position, especially the 7- position.

C-μ _β alkyl and C-,_ ₆ alkoxy groups may contain straight or branched chain alkyl groups, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, pentyl or hexyl groups, preferably C^alkyl groups. Thus, for example, each of R« _| and R4 may be a hydrogen atom or a methyl, ethyl, propyl or butyl group.

R-l and R4 are each preferably a hydrogen atom or a methyl group.

In one preferred group of compounds of formula (I) R ₅ is a pyridin-3-yl or pyridin-4-yl group.

Suitably R ₆ represents a fluorine atom, a methyl group or a methoxy group.

In a preferred group of compounds of formula (I), R-| and R4 each represent a hydrogen atom or a methyl group, R2 and R3 are fluorine atoms, R ₆ is a fluorine atom, a methyl group or a methoxy group, m is an integer 1 to 4, n is zero or an integer 1 to 3, and p is zero, 1 or 2.

In a particularly preferred group of compounds of formula (I), R., and R ₄ each represent a hydrogen atom, R ₂ and R ₃ are fluorine atoms, R ₆ is a fluorine atom or a methyl or methoxy group and m, n and p each independently represent zero, 1 or 2.

Specific compounds according to the invention include :

2-Fluoro-7-[1 ,2,4]triazol-1 ylmethyl-9H-carbazole

2-Fluoro-7-pyridin-3-ylmethyl-9H-carbazole 2-Fluoro-7-pyridin-4-ylmethyl-9H-carbazole

2-Fluoro-7-(3-fluoropyridin-4-ylmethyl)-9H-carbazole

2-Fluoro-7-(3-methylpyridin-4-ylmethyl)-9H-carbazole

2-Fluoro-7-(3-methoxypyhdin-4-ylmethyl)-9H-carbazole

1 ,7-Difluoro-2-[1 ,2,4]thazol-1 -ylmethyl-9H-carbazole 2,4-Difluoro-7-[1 ,2,4]triazol-1 -ylmethyl-9H-carbazole

1 ,4,7-Trifluoro-2-[1 ,2,4]triazol-1-ylmethyl-9H-carbazole and pharmaceutically acceptable salts and solvates thereof.

Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, phosphates, citrates, tartrates, maleates, fumarates, succinates, p-toluenesulphonates and methanesulphonates. Other suitable salts will be readily apparent to one skilled in the art. Hydrochloride, sulphate and phosphate salts are especially preferred. Salts which are not pharmaceutically acceptable may be useful in the

preparation of compounds of formula (I) and these form a further part of the invention.

Compounds of the invention may be isolated in association with solvent molecules by crystallisation from or evaporation of an appropriate solvent. Such solvates of the compounds of formula (I) are included within the scope of the present invention.

References hereinafter to a compound according to the invention includes both the compounds of formula (I) and their pharmaceutically acceptable salts and solvates.

The compounds according to the invention are potent and selective inhibitors of the enzyme steroidal 17,20-lyase, which is a key enzyme involved in the conversion of C21 -steroids (e.g. pregnenolone) into androgens (e.g. testosterone) and oestrogens (e.g. oestradiol).

The 17,20-lyase-inhibiting activity of the compounds of formula (I) was demonstrated in vitro by their ability to inhibit the conversion of 17α- hydroxypregnenolone into dehydroepiandrosterone by human testicular 17,20- lyase and of 17α-hydroxyprogesterone into androstenedione by rat testicular 17,20-lyase. These assays were conducted according to a method based on that of Ayub and Level, J. Steroid Biochem, 1987, 28, 521.

In in vivo tests the compounds of the invention were tested for their ability to suppress the elevation of testosterone levels produced in male rats when stimulated with human cho onic gonadotrophin (hCG).

Inhibitors of 17,20-lyase reduce circulating and local levels of androgens and oestrogens. The compounds of the invention can thus be used in the treatment of androgen- and/or oestrogen-dependant diseases such as malignant and benign diseases of the breast, endometrium, ovary, prostate and pancreas. These diseases include cancer of the prostate, breast and endometrium, prostatic hypertrophy and hyperplasia, fibrocystic breast disease, endomet osis and polycystic ovarian disease. The compounds of formula (I) are also useful in the treatment of Cushing's syndrome, gynecomastia, premature labour, precocious puberty, female hirsutism, premenstrual syndrome, male pattern

baldness and acne. The compounds of the invention will be particularly useful in the treatment of prostate cancer.

The invention thus further provides compounds of formula (I) and their pharmaceutically acceptable salts and solvates for use as active therapeutic agents in particular for the treatment of conditions whose underlying aetiology is associated with elevated androgen and/or oestrogen levels in animals (especially humans).

In a particular aspect of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of prostate cancer.

In a further or alternative aspect there is provided a method for the lowering of the levels of androgens and/or oestrogens in a mammal including a human comprising administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

There is also provided in a further or alternative aspect use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the lowering of levels of androgens and/or oestrogens.

It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established symptoms.

While it is possible that, for use in therapy, a compound of the invention may be administered to a patient as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation.

The invention accordingly provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof together with one or more pharmaceutically acceptable carriers or excipients and, optionally, other therapeutic and/or prophylactic ingredients. The carriers must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical, implant or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium 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 presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl-g-hydroxybenzoates or sorbic acid).

For topical administration in the mouth, the pharmaceutical compositions may take the form of buccal or sub-lingual tablets, drops or lozenges formulated in conventional manner.

For topical administration to the epidermis the compounds of the invention may be formulated as creams, gels, ointments or lotions or as transdermal patches.

Such compositions may, for example, be formulated with an aqueous or oily

base with the addition of suitable thickening, gelling, emulsifying, stabilising, dispersing, suspending, and/or colouring agents.

The compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds 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.

The compounds of the invention may be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous 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 emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

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

For intranasal administration the compounds of the invention may be used, for example, as a liquid spray, as a powder or in the form of drops.

For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1 ,1 ,2-tetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an

inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.

Any of the pharmaceutical compositions described above may be presented in a conventional manner associated with controlled release forms.

Preferably the pharmaceutical compositions according to the invention are suitable for oral, rectal or topical administration.

A convenient unit dose formulation contains the active ingredient in an amount of from 0.1 to 200mg.

It will be appreciated that the amount of a compound of formula (I) required for use in treatment will vary not only with the particular compound selected, but also with the route of administration, the nature of the condition being treated and the age, weight and condition of the patient and will ultimately be at the discretion of the attendant physician or veterinarian. In general, however, a suitable dose will be in the range of from about 1 to about 500mg per day, preferably in the range of 20 to 200mg per day, most preferably in the range of 50 to 120mg per day.

A suitable daily dose for use in prophylaxis will generally be in the range of 0.1 mg to 50mg.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day. The compound is conveniently administered in unit dosage form.

The compounds of the present invention may also be used in combination with other therapeutic agents, for example, other androgen and/or oestrogen lowering agents, or anticancer agents. In particular the compounds of the invention may be employed together with known anticancer agents.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) as defined herein together with another therapeutically active agent, in particular an anticancer agent.

The combination referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier therefor comprise a further aspect of the invention.

When compounds of formula (I) are used in combination with a second therapeutic agent, the compounds may be administered either sequentially or simultaneously by any of the routes described above.

Suitable therapeutic agents for use in the combinations defined above include, for example cyproterone acetate, flutamide and anandron.

When compounds of formula (I) are used in combination with a second therapeutic agent effective to reduce levels of androgens and/or oestrogens in a mammal including a human the dose of each compound may vary from that when the compound is used alone. Thus when compounds of formula (I) are used together with a second therapeutic agent the dose of each compound may be the same or different to that employed when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

The compounds according to the invention may be prepared by any process known in the art for the preparation of compounds of analogous structure. In the following description R-| , R2, R3, R4, R5, R ₆ , m, n and p are as defined for general formula (I) unless otherwise specified.

In one general process (A), a compound of general formula (I) wherein R-| represents a hydrogen atom may be prepared from an intermediate of formula

by cyclisation. The reaction is conveniently effected in the presence of a suitable solvent, such as a hydrocarbon solvent, for example dodecane, or a

halogenated solvent, such as dichlorobenzene, preferably at elevated temperature, for example 100 to 300°C, preferably 150 to 220°C. General process (A) is particularly useful for the preparation of compounds of formula (I) wherein R ₅ is a triazole group.

Intermediates of formula (II) may be prepared from the corresponding amines of formula (III)

by treatment with sodium nitrite in the presence of a mineral acid, e.g. sulphuric acid, followed by sodium azide. The reaction is conveniently effected in aqueous solution.

Compounds of formula (III) may be prepared from the corresponding nitro compounds of formula (IV)

by reduction using hydrogen or a hydrogen-donor, e.g. ammonium formate, in the presence of a catalyst, such as a noble metal catalyst, e.g. platinum, palladium, platinum oxide or rhodium, which may be supported, e.g. on charcoal. The reduction may be carried out in a solvent such as an alcohol e.g. methanol or ethanol (which may be aqueous), acetic acid, aqueous acetic acid, an ether e.g. dioxan, an ester e.g. ethyl acetate or an amide e.g. dimethylformamide, and conveniently at a temperature of from '10 to +5θOC, preferably 20 to 30°C.

Compounds of formula (IV) may be prepared from compounds of formula (V)

by treatment with a compound of formula HR ₅ or the sodium salt thereof. The reaction is conveniently effected in a suitable solvent, e.g dimethylformamide.

Intermediates of formula (V) may be prepared from compounds of formula (VI)

by free radical bromination, for example using N-bromosuccinimide in the presence of an initiator, such as a peroxide and/or ultra-violet light. The reaction is conveniently effected in a non-polar solvent, such as a halogenated solvent, e.g. chloroform or tetrachloromethane, at a temperature of 20 to βO^C.

Compounds of formula (VI) may be prepared from compounds of formula (VII)

(wherein L represents a readily displaceable atom or group) by reaction with a compound of formula (VIII)

in the presence of a suitable palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base, e.g. sodium carbonate, in a suitable aqueous solvent such as an alcohol, e.g. ethanol, an aromatic hydrocarbon, e.g. benzene, or an ether, e.g. dimethoxyethane, or an aqueous mixture of solvents. Suitable atoms or groups represented by L include halogen atoms, e.g. bromine or iodine atoms, or a triflate group.

In another general process (B), a compound of formula (I) may be prepared from a compound of formula (IX)

by deoxygenation. The deoxygenation reaction is effected using a suitable reducing agent such as hydrogen in the presence of a catalyst, such as a noble metal catalyst, e.g. platinum, palladium, platinum oxide or rhodium, which may be supported, e.g. on charcoal. The reaction may conveniently be carried out in a solvent such as an alcohol, e.g. methanol or ethanol, which may be aqueous, in the presence of an acid, e.g. hydrochloric acid, preferably at elevated temperature, e.g. at the reflux temperature of the solvent or at elevated pressure. General process (B) is particularly useful for the preparation of compounds of formula (I) wherein R ₅ is a pyridyl group.

Intermediates of formula (IX) may be prepared from compounds of formula (X)

by reaction with compounds of formula (XI)

Hal - R ₅ (XI)

in the presence of a suitable base, such as an alkyllithium, e.g. n-butyllithium. The reaction is conveniently effected in the presence of a suitable solvent such as an ether, e.g. diethyl ether, dimethoxyethane or tetrahydrofuran, or a mixture of solvents, suitably at low temperature, e.g. -90 to - 50^, preferably about -70°C.

Compounds of formula (X) may be prepared from compounds of formula (XII)

by oxidation. Suitable oxidising agents will be readily apparent to one skilled in the art and include pyridinium chlorochromate, potassium dichromate in sulphuric acid and barium manganate. The reaction may conveniently be effected in the presence of a solvent, e.g. a halogenated solvent such as dichloromethane.

Compounds of formula (XII) may be prepared from compounds of formula (XIII)

by cyclisation. The reaction is conveniently effected in the presence of a suitable solvent, such as a hydrocarbon solvent, e.g. dodecane, or a halogenated solvent, e.g. dichloromethane, preferably at elevated temperature, e.g. 100 to 300°C, preferably 150 to 22θOC.

Compounds of formula (XIII) may be prepared from compounds of formula (XIV)

by treatment with sodium nitrite in the presence of a mineral acid, e.g. sulphuric acid, followed by sodium azide. The reaction is conveniently effected in aqueous solution.

Compounds of formula (XIV) may be prepared from compounds of formula (XV)

(wherein G represents a hydroxy protecting group) by reduction using- hydrogen or a hydrogen-donor, e.g. ammonium formate, in the presence of a catalyst, such as a noble metal catalyst, e.g. platinum, palladium, platinum oxide or rhodium, which may be supported, e.g. on charcoal and subsequent removal of the protecting group G. The reduction may conveniently be carried out in a solvent such as an alcohol, e.g. methanol or ethanol, which may be aqueous, optionally in the presence of an acid, e.g. hydrochloric acid. Suitable hydroxy protecting groups are described hereinafter.

Compounds of formula (XV) may be prepared from compounds of formula (XVI)

(wherein L represents a readily displaceable atom or group) by reaction with a compound of formula (XVII)

in the presence of a suitable palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base, e.g. sodium carbonate, in a suitable aqueous solvent such as an alcohol, e.g. ethanol, an aromatic hydrocarbon, e.g. benzene, or an ether, e.g. dimethoxyethane, or an aqueous mixture of solvents preferably at elevated temperature. Suitable atoms or groups represented by L include a halogen atom, e.g. a bromine or iodine atom, and a triflate group.

Alternative synthetic routes to the intermediates of formula (X) will be readily apparent to those skilled in the art.

In another general process (C) a compound of formula (I) according to the invention may be converted into another compound of the invention using conventional procedures.

According to one embodiment of general process (C) a compound of formula (I) wherein R- represents a hydrogen atom may be alkylated using conventional techniques. The reaction may be effected using a suitable al ylating agent such as an alkyl halide, alkyl tosylate or dialkylsulphate. The reaction may conveniently be carried out in an inert organic solvent such as an amide, e.g. dimethylformamide, or an ether, e.g. tetrahydrofuran, preferably in the presence of a base. Suitable bases include, for example, alkali metal hydrides, e.g. sodium hydride, alkali metal carbonates, e.g. sodium carbonate, or alkali metal alkoxides, e.g. sodium or potassium, methoxide, ethoxide or t-butoxide. The alkylation reaction is conveniently effected at a temperature of 25 to lOO^C.

According to another general process (D), a compound of formula (I) according to the invention, or a salt thereof may be prepared by subjecting a protected derivative of formula (I) or a salt thereof to reaction to remove the protecting group or groups. Thus, at an earlier stage in the preparation of a compound of formula (I) or a salt thereof it may have been necessary and/or desirable to

protect one or more sensitive groups in the molecule to prevent undesirable side reactions. Such protection may be effected in conventional manner, for example as described in 'Protective Groups in Organic Chemistry' Ed.J.F.W. McOmie (Plenum Press 1973) or 'Protective Groups in Organic Synthesis' by T W Greene (John Wiley and Sons 1981 ).

In compounds of formula (I) wherein R ^« | represents hydrogen the group NR-| may be protected for example with a conventional amino protecting group. Such groups may include for example aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl groups such as tosyl, N- benzyloxycarbonyl or t-butoxycarbonyl.

Removal of any amino protecting groups present may be achieved by conventional procedures. Thus an aralkyl group such as benzyl, may be cleaved by hydrogenolysis in the presence of a catalyst (e.g. palladium on charcoal); an acyl group such as t-butoxycarbonyl may be removed by cleavage with, for example, hydrogen chloride in dioxan or sodium methoxide in methanol.

As will be appreciated, in some of the general processes (A) to (C) described above it may be necessary or desired to protect any sensitive groups in the molecule as just described. Thus, a reaction step involving deprotection of a protected derivative of general formula (I) or a salt thereof may be carried out subsequent to any of the above described processes (A) to (C).

Where it is desired to isolate a compound of the invention as a salt, for example as an acid addition salt, this may be achieved by treating the free base of general formula (I) with an appropriate acid, preferably with an equivalent amount. Solvates of the compounds of the invention may be prepared by crystallisation from or evaporation of an appropriate solvent solution of the compounds of formula (I). Separation of enantiomers of formula (I) may be carried out in conventional manner, for example by resolution of racemic mixtures e.g. using chiral HPLC techniques or by stereospecific synthesis from isome cally pure starting material or any convenient intermediate, for example as described in Stereochemistry of Carbon Compounds by E.L. Eliel (McGraw Hill, 1962) and Tables of Resolving Agents by S.H. Wilen.

Thus, according to a further aspect of the invention, the following reactions may, if necessary and/or desired be carried out in any appropriate sequence subsequent to any of the processes (A) to (C):

(i) removal of any protecting groups;

(ii) conversion of a compound of formula (I) or a salt or solvate thereof into a pharmaceutically acceptable salt or solvate (for example, hydrate) thereof;

(iii) separation of a racemic mixture into individual enantiomers of formula (I).

As well as being employed as the last main step in the preparative sequence, the general methods indicated above for the preparation of the compounds of the invention may also be used for the introduction of the desired groups at an intermediate stage in the preparation of the required compound. It should therefore be appreciated that in such multi-stage processes, the sequence of reactions should be chosen in order that the reaction conditions do not affect groups present in the molecule which are desired in the final product.

As indicated above the compounds of the invention are useful as 17,20-lyase inhibitors. 17,20-Lyase inhibition may be demonstrated by the following tests:

ACTIVITY in vitro

Biological activity in vitro was determined by measuring the inhibition of 17,20- lyase activity in a microsomal preparation from human testes. A range of concentrations of each compound was incubated with the microsomal preparation and 17-oc-hydroxy (21- ¹ C) pregnenolone as substrate for 60 mins at 37 ^C C. Radioactive product was assayed and enzyme inhibition determined by comparison with uninhibited control samples.

ACTIVITY in vivo Biological activity in vivo was determined in a rat model of testosterone biosynthesis. Compounds were administered p.o. at a dose of 3mg/kg. One hour later the rats were given human chorionic gonadotrophin (hCG) s.c. to stimulate testosterone synthesis and two hours after hCG administration, blood was taken and serum testosterone concentrations measured. Inhibitory activity was determined by comparison to values from rats receiving vehicle only.

The results of the in vitro and in vivo assays for the compounds of the following examples are shown in Table 1. The results for the known 17,20-lyase inhibitor ketoconazole are included for comparison.

Table 1

Example In vitro assav In vivo assav IC ₅₀ concentration (nM) % Inhibition of serum testosterone

Ketoconazole 85 56 ^*

1 97 50

2 6 84

3 5 74

4 8 40

5 5 78

6 19 71

7 41 14

8 12 36

9 25 5

* The dose of ketoconazole was 30mg/kg.

Acute toxicity studies indicate that single doses of 3mg/kg p.o. of the compound of Example 2 are well tolerated in rats and no overt toxicity was observed.

The invention is further illustrated by the following non-limiting examples. All temperatures are in ^C. Chromatography was performed on silica gel. Dried means dried over anhydrous magnesium sulphate. DMSO means dimethyl sulphoxide. DMF means dimethylformamide. THF means tetrahydrofuran. DME means dimethoxyethane. IPE means isopropyl ether.

Intermediate 1

4-(t-Butyldimethylsilyloxymethyl.phenylboronic acid π. 4-ft-Butyldimethylsilyloxymethyl.-bromobenzene

A solution of t-butyldimethylsilyl chloride (21.1g) in DMF (25ml) was treated dropwise with a solution of 4-bromo-benzyl alcohol (25g) and imidazole (18.2g) in DMF (100ml). Resulting solution was left standing at room temperature for

72h. Reaction mixture was added to ethyl acetate (2000ml) and organic layer was washed with 2N HCI (2 x 250ml), water (4 x 250ml), brine (250ml), dried and evaporated to give a yellow oil. Chromatography on silica gel (1 kg), eluting with cyclohexane/ethyl acetate (10:1 v/v) gave the product as a pale yellow oil.

(ii) 4(t-Butyldimethylsilyloxymethv0phenylboronic acid

A solution of (i) (32.37g) in dry tetrahydrofuran (250ml) was cooled to -70° under N2. n-Butyllithium (70ml of a 1.6M solution in hexane) was added dropwise over 15 minutes maintaining temperature below -65°C. Resulting yellow solution was stirred below -70°C for 2h, then triisopropyl borate (75ml) was added dropwise, maintaining temperature below -65°. When addition was complete, the reaction was allowed to warm to room temperature, then quenched with water (550ml) and then ether (250ml).

The organic layer was separated off and the aqueous phase extracted with ether (2 x 500ml). The combined organic layers were washed with brine (200ml), dried and evaporated to give the product as a pale yellow crystalline solid.

For the avoidance of doubt, in the compounds of Examples 1 to 7 and 9, R ₂ is in the 7-position of formula (I), in Example 8 R ₂ is in the 5 and 7 positions, in Example 7 R ₃ is in the 1 -position and in Example 9 R ₃ is in the 1 and 4 positions of formula (I). Individual compound names are in accordance with IUPAC nomenclature.

Example 1 2-Fluoro-7-f 1.2.4ltriazol-1 -ylmethyl-9H-carbazole 1 (i) 4-Fluoro-4'-methyl-2-nitro-biphenyl

A solution of 2-bromo-5-fluoronitrobenzene(15g) in benzene (60ml) was rapidly stirred under N ₂ , and treated with tetrakistriphenylphosphine palladium (0) (1.13g), aq. 2M sodium carbonate (35.7ml) and a solution of p-tolylboronic acid (10.2g) in 95% ethanol (25ml). Mixture was heated at 95°C and rapidly stirred under N ₂ for 16h. Reaction mixture was extracted with ethyl acetate (400ml) then (2x 100ml). The combined extracts were washed with water (100ml), brine (100ml), dried (MgS0 ₄ ) and evaporated to give a brown oil. Chromatography

on silica gel (500g), eluting with cyclohexane/ethyl acetate (25:1v/v) gave the title compound.

1 (ii) 4'-Bromomethyl-4-fluoro-2-nitro-biphenyl

A solution of 1 i) (2.04g) in carbon tetrachloride (40ml) was treated with a trace of benzoyl peroxide, and N-bromosuccinimide (1.81g). Mixture was refluxed over a 150W bulb for 1h, then the precipitate of succinimide was filtered off, and washed with CCI ₄ (2 x 5ml). The filtrate and washings were evaporated to give the title compound as a yellow oil.

Kiii) 1-(4'-Fluoro-2'-nitro-biphenyl-4-ylmethyl)-1 H-f1. 2. 41triazole A solution of 1 ,2,4-triazole (0.613g) in DMF (5ml) was treated with sodium hydride (0.266g of an 80% dispersion, in oil). After 5 minutes when all effervescence had ceased, mixture was treated with a solution of 1 ii) (3.1g) in DMF(3ml). Resulting pale brown solution was stirred at room temperature for 20h. Mixture was added to ethyl acetate (500ml) and the organic phase was washed with water (4 x 50ml) then extracted with 2N HCI (6 x 80ml), then washed with brine (100ml), dried (MgS0 ₄ ) and evaporated. The residue was purified by chromatography on silica gel (150g) eluting with CHCI ₃ to give a yellow crystalline solid. Elution with CHCI ₃ /MeOH (19:1 v/v) gave the title compound as a yellow gum.

1 (iv) 4-Fluoro-4'-H ,2,4ltriazol-1 -ylmethyl-biphenyl-2-ylamine

A solution of 1 iii) (1.20g) in acetic acid (5ml) was treated with 10% Pd/C catalyst (400 mg) and stirred under H ₂ for 3h. The catalyst was filtered off through a Kieselguhr pad, and washed with acetic acid (2 x 5 ml), then the filtrate and washings were evaporated to a yellow gum. This was dissolved in dichloromethane (100ml) and was carefully washed with sat. aq. NaHC0 ₃ (100ml), then the organic layer was dried (MgS0 ₄ ) and evaporated to give the title compound as a brownish crystalline solid.

1 (v) 1 -(2'-Azido-4'-fluoro-biphenyl-4-ylmethyl)-1 H-M .2.41triazole A solution of 1 iv) (970mg) in water (9ml) and cone, sulphuric acid (0.75ml) was cooled in an ice-bath. A solution of sodium nitrite (261 mg) in water (3ml) was added dropwise. Resulting yellow solution was stirred at ice-bath temperature

for 30 minutes. A solution of sodium azide (243mg) in water (6ml) was added dropwise. Rapid effervescence of N ₂ gas was observed. After 30 minutes the mixture was neutralized with sat. aq. NaHC0 ₃ , then extracted with dichloromethane (4 x 50ml). The combined extracts were dried (MgS0 ₄ ), and evaporated to give the title compound as a pale brown crystalline solid.

1 (vO 2-Fluoro-7-H .2.41triazol-1-ylmethyl-9H-carbazole

A solution of 1v) (200mg) in 1 ,2-dichlorobenzene (5ml) was heated at 170°C for

4h. The reaction mixture was diluted with ethyl acetate (200ml) and extracted with 2N HCI (3 x 60ml). The organic layer was then washed with brine (50ml), dried (MgS0 ) and evaporated to give the impure product plus dichlorobenzene. Impure product was added to cyclohexane (100ml) and the solid filtered off and dried to give crystals of the title compound. NMR δ (DMSO-d6) 5.57 s (2H), 6.99 t (1 H), 7.12 d (1 H), 7.25 dd (1 H), 7.38 s (1 H), 8.00 s (1 H), 8.05 d (1 H), 8.10 dd (1 H), 8.70 s (1 H), 11.42 s (1 H).

Example 2

2-Fluoro-7-pyridin-3-ylmethyl-9H-carbazole

2(0 4-t-Butyldimethylsilyloxymethyl-4'-fluoro-2'-nitrodiphenyl A solution of 4-(t-butyldimethylsilyloxymethyl)-phenylboronic acid (Intermediate 1 ) (25g) and 2-bromo-5-fluoro-nitrobenzene (15.5g) in dry dimethoxyethane (120ml) was treated with tetrakistriphenylphosphine palladium (O) (1.1g) and 2M aq sodium carbonate (40ml). Resulting mixture was refluxed under N ₂ for 16h. Reaction mixture was diluted with ethyl acetate (600ml) and washed with water (2 x 100ml), brine (100ml), dried (MgS0 ₄ ) and evaporated to give a brown oil. Chromatography on silica gel (750g), eluting with cyclohexane -> cyclohexane/ethyl acetate (15:1 ) gave the title compound as a yellow oil.

2(ii 2-Amino-4'-t-butyldimethylsilyloxymethyl-4-fluorodiphenyl A solution of 2(i) (21 g) in methanol (300ml) was treated with 10% Pd/C catalyst. (3.4g) and dry ammonium formate (16.48g). Mixture was stirred under N ₂ at room temperature for 24h. The catalyst was filtered off, washed with methanol (2 x 25ml), under a blanket of N ₂ , then the filtrate and washings evaporated to give a brownish residue. This was dissolved in water (200ml) and extracted

with dichloromethane (3 x 200ml). Combined extracts were dried (MgS0 ) and evaporated to give the title compound as a brown oil.

2(ii0 (2'-Azido-4'-fluoro-biphenyl-4-vO-methanol A solution of 2(ii) (18.408g) in dioxan (200ml) and water (200ml) was treated with conc.sulphuric acid (11.47ml) then cooled to 5°C. A solution of sodium nitrite (4.00g) in water (15ml) was added dropwise. The resulting orange solution was stirred at 5°C for 30 minutes, then a solution of sodium azide (3.75g) in water (20ml) was added carefully, avoiding over-effervescence of N ₂ gas. When addition was complete, reaction was stirred at 5°C for 30 minutes, then carefully treated with sat. aq NaHC0 ₃ solution until neutral. Mixture was extracted with dichloromethane (5 x 200ml) and the extracts were dried (MgS0 ₄ ), and evaporated to give the title compound as a brown oil.

2(iv) (7-Fluoro-9H-carbazol-2-yl.-methanol

A solution of 2(iii) (13.9g) in 1 ,2-dichlorobenzene (200ml) was refluxed under N ₂ for 3h. Mixture was allowed to cool, and then was added to cyclohexane (100ml). Solid material was filtered off, and washed with cyclohexane (2 x 100ml), then dried in vacuo to give the title compound as a pale brown solid.

2(v) 2-Fluoro-7-formyl-carbazole-9-carboxylic acid tert-butyl ester A solution of 2(iv) (7.18g) in dichloromethane (1500ml) was treated with barium manganate (54.5g) and stirred under N ₂ for 5h. The solid was filtered off and washed with dichloromethane (4 x 100ml). Filtrate and washings were evaporated to give a green-brown solid. This was suspended in dichloromethane (100ml) and treated with 4-dimethylaminopyridine (3.78g) and dMbutyldicarbonate (7.43g). Resulting brown solution was stood at room temperature for 30 minutes, then diluted with ethyl acetate. Organic solution was washed with 2N HCI (2 x 400ml), water (200ml), brine (2 x 200ml) then dried (MgS0 ₄ ) and evaporated to give impure product. This was purified by chromatography, on silica gel (500g), eluting with cyclohexane/ethyl acetate (15:1 v/v) to give the title compound as a pale cream solid.

2(vi.2-Fluoro-7-(hvdroxy-pyridin-3-yl-methvO-carbazole-9- carboxylic acid tert- butyl ester

A solution of 3-bromopyridine (0.306ml) in ether (10ml) was cooled to -45°C under N ₂ . A solution of "butyllithium (2ml of 1.6M sol. in hexane) was added dropwise. Resulting brownish suspension was warmed to 0°C, then cooled again to -45°C and left for 15 minutes. A sol. of 2(v) (0.5g) in dry THF (10ml) was added. Mixture was stirred at -40°C for 1 h, then quenched with ammonium chloride solution (20ml). Mixture was extracted with ethyl acetate (3 x 30ml) and the combined extracts were washed with brine (200ml), dried (MgS0 ₄ ) and evaporated to give the title compound as a yellow foam.

2(vi0 2-Fluoro-7-Pyridin-3-ylmethyl-9H-carbazole

A solution of 2(vi) (670mg) in methanol (20ml) was treated under N ₂ with palladium black catalyst (300mg) and cone. HCI (0.8ml). Mixture was stirred under H ₂ for 3h at 50°C, then a further 300mg of catalyst was added and reaction continued for 3h. Catalyst was filtered off, and washed with methanol (2 x 10ml), then the filtrate and washings were evaporated to give a sticky yellow foam. Chromatography on silica gel (100g), eluting with CHCI ₃ /IPE (50:1 → 20:1 v/v) gave the title compound.

NMR δ (DMSO-d6) 4.12 s (2H), 6.97 t (1 H), 7.08 d (1 H), 7.22 d (1 H), 7.32 m (1 H), 7.68 d (1 H), 8.05 m (2H), 8.41 d (1 H), 8.58 s (1 H), 11.31 s (1 H).

Example 3

2-Fluoro-7-pyhdin-4-ylmethyl-9H-carbazole i) 2-Fluoro-7-(hvdroxy-pyridin-4-yl-methvO-carbazole-9-carboxyl ic acid, tert butyl ester

A solution of 4-bromopyridine (253mg) in ether (10ml) was cooled to -75° under N ₂ . A solution of "butyllithium (1 ml of 1.6M sol. in hexane) was added. After stirring for 10 minutes at -75° a solution of 2(v) (0.5g) in dry THF (5ml) was added. After stirring the reaction at -70° for 1h, a further mixture of 4- bromopyridine (506mg) and 2ml of "butyllithium (2ml of 1.6M sol.) in ether (10ml) was added (premixed at -70°). After a further 1h at -70°, aqueous ammonium chloride (10ml) was added. The mixture was extracted with ether (4 x 30ml). The combined ether extracts were then extracted with 2N HCI (3 x 30ml). These combined acid extracts were treated with 40% aqueous sodium hydroxide to pH 11 , then extracted with dichloromethane (4 x 40ml), then the

combined extracts were dried (MgS0 ₄ ) and evaporated to give a yellow solid. Preparative t.l.c. gave the title compound as a yellow solid.

ii) 2-Fluoro-7-pyridin-4-ylmethyl-9H-carbazole

A solution of 3i) (164mg) in methanol (5ml) was treated under N ₂ with palladium black catalyst (40mg) and cone. HCI (0.2ml). Mixture was stirred under H ₂ for 1.5h at 50°, then a further charge of catalyst (80mg) was added and then the reaction stirred under H ₂ at 50° for 3h. The catalyst was filtered off , washed with methanol (2 x 5ml) then the filtrate and washings evaporated to a gum. This was dissolved in 4M HCI in dioxan (5ml) for 30 minutes then evaporated to give a yellow gum. This was dissolved in water (10ml), treated with 40% aqueous sodium hydroxide to pH 11 then the mixture was extracted with dichloromethane (4 x 20ml). The combined extracts were dried (MgS0 ) and evaporated to give a yellow solid. Preparative t.l.c. gave the title compound as a yellow solid. NMR (DMSOdδ). 4.12δ s (2H), 6.97δ t (1 H), 7.06δ d (1 H), 7.2-7.45 m (4H), 8.0-

8.1δ m (2H), 8.46δ d (1 H), 11.335 s (1 H ).

Example 4

2-Fluoro-7-(3-fluoropyridin-4-yl-methyl)-9H-carbazole i) 2-Fluoro-7-(hvdroxy-(3-fluoropyridin-4-yl)-methyl)-carbazole -9-carboxylic acid, tert butyl ester

A solution of N,N,N',N'-tetramethylethylenediamine (0.48ml) in dry THF (5ml) was cooled to -70° under N ₂ . A solution of "butyllithium (2ml of 1.6M sol. in hexane) was added. The resulting solution was stirred at -20° for 1h then cooled to -70°. A solution of 3-fluoropyridine (0.273ml) in dry THF (3ml) was added. The resulting suspension was stirred at -40° for 1 h, then a solution of 2(v) (500mg) in dry THF (10ml) was added, over 2 minutes. The reaction was stirred at -70° for 1h then quenched with aqueous ammonium chloride (20ml). The mixture was extracted with ethyl acetate (3 x 30ml), then the combined extracts were washed with water (4 x 10ml ) and brine (10ml), then dried (MgS0 ₄ ) and evaporated to give a yellow solid. Chromatography on silica gel (100g), eluting with chloroform/isopropanol (50:1 -> 20:1 v/v) gave the title compound as a white solid.

ii) 2-Fluoro-7-(3-fluoropyridin-4-yl-methyl)-9H-carbazole

A solution of 4i) (328mg) in methanol (10ml) was treated with palladium black catalyst (320mg) and cone. HCI (0.4ml). Mixture was stirred under H ₂ for 6h at 50°. The catalyst was filtered off and washed with methanol (3 x 5ml). The filtrate and washings were evaporated to give a yellow solid. This was dissolved in water (20ml) and treated with 40% aqueous sodium hydroxide to pH 11. The mixture was extracted with dichloromethane (4 x 30ml), then the combined extracts were dried (MgS0 ₄ ) and evaporated to give a cream solid. Chromatography on silica gel (50g), eluting with chloroform: isopropanol (50:1 → 20:1 v/v) gave the title compound as a white solid. NMR (DMSOd6). 4.195 s (2H), 6.97δ t (1 H), 7.07δ d (1 H), 7.23δ d (1 H), 7.40δ m (2H), 8.05δ m (2H), 8.355 d (1 H), 8.525 s (1 H), 11.325 s (1 H).

Example 5 2-Fluoro-7-(3-methylpyridin-4-yl-methyl)-9H-carbazole i) 2-Fluoro-7-(hvdroxy-(3-methylpyridin-4-vO-methyl)-carbazole- 9-carboxylic acid, tert butyl ester

A solution of 4-bromo-3-methylpyridine (549mg) in ether (10ml) was cooled to -70° under N ₂ . A solution of "butyllithium (3.2ml of 1.6M sol. in hexane) was added. The resulting suspension was stirred at -70° for 30 minutes, then a solution of 2(v) (500mg)in dry THF (10ml) was added. The solution was stirred at -70° for 1 h then quenched with aqueous ammonium chloride (20ml). The mixture was extracted with ethyl acetate (3 x 30ml) then the combined extracts were washed with brine (10ml), dried (MgS0 ₄ ) and evaporated to give a yellow gum. Chromatography on silica gel (90g), eluting with chloroform: isopropanol (50:1 -» 20:1 v/v) gave the title compound as a pale yellow foam.

i0 2-Fluoro-7-(3-methylpyridin-4-yl-methvπ-9H-carbazole

A solution of 5i) (267mg) in methanol (5ml) was treated with palladium black catalyst (100mg) and cone. HCI (0.25ml). Mixture was stirred under H ₂ for 14h with periodic additions of further batches of catalyst. The catalyst was filtered off and washed with methanol (3 x 2ml) and acetic acid (2 x 1ml). The filtrate and washings were evaporated to give a pale yellow gum. This was dissolved in water (10ml) and treated with 40% aqueous sodium hydroxide to pH 11. The mixture was extracted with dichloromethane (4 x 15ml), then the combined extracts were dried (MgS0 ₄ ) and evaporated to give a pale cream foam.

Chromatography on silica gel (50g), eluting with chloroform: isopropanol (50:1 → 20:1 v/v) gave the title compound as a white solid.

NMR (DMSOd6). 2.255 s (3H), 4.145 s (2H), 6.97δ t (1 H), 7.01δ d (1 H), 7.135 d (1 h), 7.235 m (2H), 8.0-8.15 m (2H), 8.335 m (2H), 11.275 s (1 H).

Example 6

2-Fluoro-7-(3-methoxypyridin-4-yl-methvO-9H-carbazole

0 2-Fluoro-7-(hydroxy-(3-methoxypyridin-4-yl)-methyl)-carbazol e-9-carboxylic acid, tert butyl ester A solution of 4-bromo-3-methoxypyridine (530mg) in ether (10ml) was cooled to -70° under N ₂ . A solution of "butyllithium (1.76ml of 1.6M sol. in hexane) was added. The resulting suspension was stirred at -70° for 30 minutes, then a solution of 2(v) (442mg)in dry THF (10ml) was added. The solution was stirred at -70° for 1h then quenched with aqueous ammonium chloride (20ml). The mixture was extracted with ethyl acetate (3 x 50ml) then the combined extracts were washed with water (30ml), brine (30ml), dried (MgS0 ₄ ) and evaporated to give a yellow solid. Chromatography on silica gel (90g), eluting with chloroform: isopropanol (50:1 → 20:1 v/v) gave the title compound as a white solid.

i0 2-Fluoro-7-(3-methoxypyridin-4-yl-methyl.-9H-carbazole A solution of 6i) (200mg) in methanol (5ml) was treated under N ₂ with palladium black catalyst (100mg) and cone. HCI (0.25ml). Mixture was stirred under H ₂ for 8h at 50°. The catalyst was filtered off , washed with methanol and acetic acid then the filtrate and washings evaporated to a white solid. This was dissolved in 4M HCI in dioxan (15ml) and dichloromethane (50ml) and stirred at room temperature for 6h then evaporated to give a gum. This was dissolved in water (10ml), treated with 40% aqueous sodium hydroxide to pH 11 then the mixture was extracted with dichloromethane (4 x 20ml). The combined extracts were dried (MgS0 ₄ ) and evaporated to give a yellow solid. Chromatography on silica gel (50g), eluting with chloroform: isopropanol (50:1 -> 20:1 v/v) gave the title compound as a white solid.

NMR (DMSOd6). 3.935 s (3H), 4.075 s (2H), 6.965 t (1H), 7.045 d (1H), 7.135 d (1 H), 7.215 d (1 H), 7.295 s (1 H), 7.95-8.155 m (3H), 8.335 s (1 H), 11.285 s (1 H).

Examples 7 to 9

The following compounds were prepared by methods analogous to those described in Examples 1 to 6:

7. 1.7-Difluoro-2-π .2.41triazol-1 -ylmethyl-9H-carbazole NMR 5 (DMSO-d6) 5.63 s (2H), 7.10 m (2H), 7.26 dd (1 H), 7.92 d (1 H), 7.98 s (1 H), 8.15 dd (1 H), 8.69 s (1 H), 11.90 s (1 H).

8. 2.4-Difluoro-7-H ,2.4ltriazol-1 -ylmethyl-9H-carbazole

NMR δ (DMSO-d6) 5.59 s (2H), 6.96 1 (1 H), 7.19 m (2H), 7.44 s (1 H), 7.99 m (2H), 8.72 s (1 H).

9. 1.4.7-Trifluoro-2-π ,2,4ltriazol-1-ylmethyl-9H-carbazole.

NMR 5 (DMSO-d6) 5.62 s (2H), 6.96 dd (1 H), 7.11 t (1 H), 7.31 dd (1 H), 8.02 m (2H), 8.72 s (1 H), 12.25 s (1 H).

Example 10

0 4-Fluorophenyl boronic acid A solution of 1-bromo-4-fluorobenzene (318.2g) in THF (3000ml) was cooled to -52° under N ₂ . "Butyllithium (2.5M in hexane, 800ml) was added by cannula over 5 minutes, temperature rising to — 44°. After addition was complete, the reaction was allowed to store at -52° for 15 minutes, then tri-isopropyl borate (1240ml) was added over 10 minutes. Cooling was removed and the reaction allowed to warm to -15°. It was quenched by adding water (2000ml). The mixture was then partitioned between a further 2000ml of water, and ethyl acetate (2000ml). The gelatinous white material remaining in the flask was discarded.

The aqueous phase was further extracted with ethyl acetate (2000ml), then the combined ethyl acetate layers were washed with brine (1500ml), dried (MgS0 ₄ ) and evaporated to give a pale cream solid, (228.12g). The solid was crystallized from boiling water (1100ml) to give the title compound (152.18g).

ii. m-Nitro-p-bromobenzaldehvde

Cone, sulphuric acid (3125ml) and cone, nitric acid (1250ml) were mixed together (cone, nitric acid added in ~100ml portions) and subsequently cooled

to 5°C, in an ice/salt bath. p-Bromobenzaldehyde (500g) was then added portion-wise, maintaining the temperature below 10°C. Once the addition was complete, the resulting mixture was stored at room temperature for -3 hrs (until all p-bromobenzaldehyde dissolved), then carefully poured over ice. The precipitate formed was collected by filtration and washed thoroughly with water, until washings ~pH6, then dried in vacuo at 40°C to give the title compound as white powder (607.63g).

iii) 4'-Fluoro-2-nitrobiphenyl-4-carbaldehvde A mixture of 10i) (300g), 10ii) (448g), tetratristriphenyl phosphine palladium (0) (15g) and aq. 2M sodium carbonate (1.07L) in DME (3.2L) was refluxed under N ₂ for 16h. After cooling, the reaction mixture was extracted with ethyl acetate (2 x 2000ml). The combined extracts were washed with brine (1000ml), dried (MgS0 ₄ ) and evaporated. Before complete evaporation, the product crystallized. The crystals were filtered off, washed with IPE, then dried to give the title compound (244.3g).

The washings and mother liquors were concentrated. The residue crystallized and was triturated with ether, then the solid filtered and dried to give a further crop of the title compound (120g).

iv) 2-(4'-Fluoro-2-nitrobiphenyl-4-ylH1 ,31-dioxolane

A solution of 10iii) (357.4g) in isopropyl acetate (4000ml) was treated with p- toluene sulphonic acid, monohydrate (27g) and ethylene glycol (750ml). The mixture was refluxed with a Dean-Stark trap for 2 hours. After cooling, the solution was washed with water (2000ml, sat aq. NaHC0 ₃ (2000ml), water (2 x 2000ml), brine (1000ml), then dried (MgS0 ₄ ) and evaporated to give the title compound as a yellowish syrup (520.96g).

Toluene has also been found to be a suitable solvent for this reaction.

v) 2-M .31-Dioxolan-2-yl-7-fluoro-9H-carbazole

Xylene (1250ml) and triethylphosphite (1250ml) were mechanically stirred under

N ₂ and heated to reflux (~142°). A solution of 10iv) (514.76g) in xylene (3750ml) was added over 2h, maintaining reflux. Reflux was continued for a

further δVsfo, and then further triethylphosphite (500ml) was added dropwise. Reflux was continued for VA , then reaction was left to cool to room temperature overnight. After cooling in ice/water for 30 minutes, crystals were filtered off, washed with xylene and cyclohexane, then dried in vacuo at 40° to give the title compound (171.75α..

Further crops were obtained from the cyclohexane washes and the rest of the mother liquors.

Neat triethylphosphite has also been found to be a suitable solvent for this reaction.

vO 7-Fluoro-9H-carbazole-2-carbaldehvde

A suspension of 10v) (209.626g) in acetone (5000ml) was treated with 2N HCI (1250ml) and the resulting yellow brine solution was stored for 30 minutes. The acetone was evaporated off, and the aqueous layer and solid was extracted with ethyl acetate (7000ml). The organic solution was washed with water (1000ml), dried (MgS0 ) and evaporated to give the title compound as a pale apricot/mango solid (171.59g).

vii) 2-Fluoro-7-formyl-carbazole-9-carboxylic acid tert-butyl ester A suspension of 10vi) (168.25g) in ethyl acetate (300ml) was stirred with 4- dimethylaminopyridine (96.41 g) at room temperature under N ₂ . A solution of di- butyldicarbonate (172.2g) in ethyl acetate (1000ml) was added over 30 minutes, so C0 ₂ effervescence was only at a slow rate and then further BOC anhydride (25g) was added to complete reaction. A white solid crystallized out. After stirring for ~30 minutes, this was filtered off, washed with 2N HCI (2 x 500ml), then water until neutral, then dried in vacuo to give the title compound (187.44g).

Further crops were obtained from the mother liquors.

vii0 2-Fluoro-7-(hvdroxy-pyridin-3-ylmethvO-9H-carbazole A solution of 3-bromopyridine (16.6ml) in THF (500ml) was cooled to -70°C under N ₂ . This solution was added dropwise over 10 minutes to a solution of n-

butyllithium (220ml of a 1.6M solution in hexanes) that was cooled to -70°C. After 10 minutes, a solution of 10vii) (27g) in THF (700ml) that was cooled to -70°C was added dropwise over 20 minutes. The mixture was stirred at -70°C for 40 minutes, then quenched with ammonium chloride solution (300ml). The mixture was extracted with ethyl acetate (2 x 500ml), and the combined organic layers washed with brine (500ml), dried (MgS0 ) and evaporated to give a mixture of 2-fluoro-7-(hydroxy-pyhdin-3-ylmethyl)-carbazole-9-carboxyli c acid tert-butyl ester and 2-fluoro-7-(hydroxy-pyridin-3-ylmethyl)-9H-carbazole as an amber oil.

This oil was dissolved in methanol (500ml) and treated with sodium methoxide (37g of a 25% solution in methanol). After stirring for 24 hours, the reaction was concentrated to 50ml, then water (250ml) was added and the mixture was extracted with ethyl acetate (3 x 250ml). The combined organic layers were extracted with HCI (20% aqueous solution, 3 x 250ml). The combined HCI layers were washed with ethyl acetate (250ml). The aqueous layer was then neutralized to pH10 with NaOH pellets, then was extracted with methylene chloride (2 x 500ml). The combined methylene chloride layers were washed with brine (500ml), dried (MgS0 ), and evaporated to 100ml. Toluene (250ml) was added, and the suspension concentrated to 150ml. Collection of the resulting precipitate afforded, upon drying, the title compound as an off white powder.

ix) 2-Fluoro-7-pyridin-3-ylmethyl-9H-carbazole A solution of 10viii) in 50% methanol/THF (200ml) was treated with concentrated HCI (5ml) and palladium on carbon catalyst (10% active catalyst, 50% water wet). The suspension was placed in a Parr hydrogenation bottle and treated with hydrogen gas at 10 PSI, 25°C for 3 hours. The catalyst was filtered off, the catalyst cake was washed with HCI (10%, 100ml), water (100ml), and 10% NaOH (100ml). The filtrate was concentrated to 200ml, then neutralized with NaOH pellets to pH9. The solution was then extracted with ethyl acetate (2 x 250ml), and the combined organic layers washed with brine (250ml), dried (Na ₂ S0 ₄ ) and concentrated to give a white solid. The crude product was dissolved in methanol (400ml) and treated dropwise with water (200ml). The

resulting precipitate was collected and dried to give the title compound as a white crystalline solid.

Melting point: 196-197°C.

Mass Spectrum (FAB+): 277

Elemental analysis:

% C H N

Calculated: 78.24 4.74 10.13 Found: 78.25 4.80 10.18

The following examples illustrate pharmaceutical formulations according to the invention containing 2-fluoro-7-pyridin-3-ylmethyl-9H-carbazole as the active ingredient. Other compounds of the invention may be formulated in a similar manner.

Tablets for oral administration a) Direct Compression Tablet

Component Composition (%)

Active ingredient 20.0

Microcrystalline cellulose 50.0

Spray dried lactose 24.2

Sodium starch glycolate 5.0

Colloidal silicon dioxide 0.3

Magnesium stearate 0.5

All materials except magnesium stearate are blended until sufficiently mixed. Magnesium stearate is screened and added to the mixture which is blended thoroughly. The resultant mix is compressed to predetermined tablet size and weight.

b) Wet Granulation Tablet

Component Composition (%)

Active ingredient 30.0

Microcrystalline cellulose 55.2

Starch 1500 6.0

Sodium starch glycolate 5.0

10% polyvinylpyrrolidone 3.0 in water

Magnesium stearate 0.5

Colloidal silicon dioxide 0.3

All of the ingredients except for the polyvinylpyrrolidone solution and magnesium stearate are blended in a fluidized air bed. Polyvinylpyrrolidone solution is added to the blended powders with constant mixing until uniformly moist. After drying, the granules are milled to reduce particle size and increase size uniformity and blended with the magnesium stearate. The granules are then compressed to predetermined tablet size and weight.

Tablets of other strengths may be prepared by altering the ratio of active ingredient e.g. to lactose or altering the compression weight.

The tablets may be film-coated with suitable film-forming materials such as hydroxypropyl methylcellulose using standard techniques. Alternatively the tablets may be sugar coated or enteric coated.

Syrup for oral administration

Component Composition (%)

Active ingredient, micronized 5.00 Magnesium aluminum silicate 0.50 Sodium carboxymethylcellulose 0.80

Component Composition (%)

Sodium lauryl sulphate 0.01

Sorbitol solution, USP 26.0

Methylparaben 0.20

Propylparaben 0.04

Flavour 0.50

Purified water 66.95

The sodium carboxymethylcellulose and magnesium aluminium silicate is hydrated in a solution of sodium lauryl sulphate in water for 24 hours. Active ingredient is suspended in the vehicle with the aid of a mixer. The preservatives are dissolved in the remaining water by heating and after cooling to room temperature, the sorbitol solution is added. The solution is added to the suspension, flavour mixed in and the pH adjusted as needed. The final suspension is mixed in a homogenizer.

Soft gelatin capsules for oral administration

Component Composition (%)

Active ingredient, micronized 5.0 Polyethylene glycol 47.5 Propylene glycol 47.5

The glycols are blended with warming until homogeneous. Active ingredient is added and the mixture homogenised and filled into an appropriate gelatin mass to give soft gelatin capsules containing the appropriate fill weight.

Suppository for rectal administration

Component Composition (%)

Active ingredient, micronized 2 Witepsol W32, hard fat 98

A slurry of the active ingredient in a portion of molten Witepsol (approximately 36°C) is prepared using a high speed mixer and is then evenly dispersed in the

remaining molten hard fat. The suspension is filled, using suitable machinery, into 1 or 2g size suppository moulds and allowed to cool.

Transdermal system

Component Composition (%)

Active ingredient 5 Silicone fluid 90 Colloidal silicon dioxide 5

The silicone fluid and active ingredient are mixed together and the colloidal silicon dioxide is added to increase viscosity. The material is then dosed into a subsequently heat sealed polymeric laminate comprised of the following: polyester release liner, skin contact adhesive composed of silicone or acrylic polymers, a control membrane which is a polyolefin (e.g. polyethylene or polyvinyl acetate) or polyurethane, and an impermeable backing membrane made of a polyester multilaminate. The laminated sheet is then cut into patches.

Formulations for parenteral administration

a) Intravenous solution

Component Composition (%)

Active ingredient 5.0

Sodium chloride USP 0.9

Phosphate buffer (monobasic 7.0 and dibasic potassium phosphate)

Water for Injection USP 87.1

Active ingredient is dissolved in the water with the remaining components and sterile filtered (0.22μm filter). The solution is filled into glass vials, stoppered and sealed before autoclaving.

b) Lyophilised product

Component Composition (%)

Active ingredient 2.5

Mannitol 5.0

Phosphate buffer (monobasic 7.0 and dibasic potassium phosphate)

Water for Injection USP 85.5

Active ingredient is dissolved in the water with the remaining components and sterile filtered (0.22μm filter). The solution is filled into glass vials, stoppered and lyophilised before sealing. The lyophilised product is reconstituted with saline prior to administration.