TRIAZOLOPYRIMIDINOL COMPOUNDS AND SALTS THEREOF

Abstract: Isolated 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol and pharmaceutically acceptable salts thereof in the form of individual enantiomers and mixtures thereof including the racemic mixture, pharmaceutical formulations containing this compound and the use of this compound in the treatment of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, head injuries and haemorrhage, are described.

Description: TRIAZOLOPYRIMIDINOL COMPOUNDS AND SALTS THEREOF This invention relates to 7-[1-(4-chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5- a]pyrimidin-5-ol and enantiomers and pharmaceutically acceptable salts thereof and to pharmaceutical compositions containing them, to processes for their preparation and to their use in the treatment of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke brain trauma, head injuries and haemorrhage. Compounds of formula A in which Ri represents H or optionally substituted alkyl, alkoxy or alkanoyl; R and R 3 independently represent H or optionally substituted alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl or sulphonyl; R 4 and R 5 independently represent H, alkyl or together with the carbon atom to which they are attached represent optionally substituted cycloalkylidene; and RQ, R and R 8 independently represent H, halo hydroxy, mercapto, cyano or optionally substituted alkyl, alkanoyl, alkoxy, alkoxycarbonyl, carboxy, alkanoyloxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, sulphamoyl, carbamoyl, alkylcarbamoyl or alkanoylamino; processes for their preparation, and their use in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, head injuries and haemorrhage are described in WO95/10521 (Knoll AG). A process for preparing these compounds is disclosed in WO98/07724 (Knoll AG). One compound of particular interest in WO95/10521 is (R)-7-[1-(4- chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]pyrimidine. In metabolic studies a metabolite of this compound has been identified and surprisingly this metabolite is also active. In particular the present invention provides isolated 7-[1-(4- chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]pyrimidin-5-ol and pharmaceutically acceptable salts thereof in the form of individual enantiomers and mixtures thereof including the racemic mixture. The term isolated is used to indicate that the compound of the invention is in pure form and is not present in a human or an animal either in a free form or in an associated form. 7-[1-(4-Chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]pyrimidin-5-ol may form salts with organic or inorganic acids or bases. Particularly suitable salts of the compound are formed with acids include for example, salts with inorganic acids (such as hydrochloric, hydrobromic, hydriodic, nitric, sulphuric and phosphoric acids), salts with organic acids (such as maleic, acetic, citric, fumaric, tartaric, succinic, benzoic, pamoic, palmitic, methylsulphuric and dodecanoic acids) and salts with acidic amino acids (such as glutamic acid). Preferred compounds of the invention are salts of the compound formed with bases for example the potassium salt , the sodium salt or a salt formed with a basic amino acid. Such salts are prepared by reacting the compound of the invention with a suitable acid or base in a conventional manner. 7-[1-(4-Chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]pyrimidin-5-ol or its salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof. 7-[1-(4-Chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 I 5-a]pyrimidin-5-ol or its salts may also exist in the form of solvates, (such as hydrates) and the present invention includes each solvate and mixtures thereof. The degree of solution may be non- stoichiometric and is preferably in the range 0 to 3, for example a hemihydrate, a monohydrate or a dihydrate. 7-[1-(4-Chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]pyrimidin-5-ol contains a chiral centre and exists in different enantiomeric forms the (+) form and the (-) form. The present invention includes each enantiomer and mixtures thereof. The enantiomers may be obtained by methods known to those skilled in the art. Such methods typically include any of the following: resolution via formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallisation; formation of diastereoisomeric derivatives or complexes which may be separated (for example, by crystallisation, gas-liquid or liquid chromatography), followed by the liberation of the desired enantiomer from the separated derivative; selective derivatisation of one enantiomer by reaction with an enantiomer-specific reagent (for example enzymatic esterification, oxidation or reduction), followed by separation of the modified and unmodified enantiomers; use of gas-liquid or liquid chromatography in a chiral environment (for example on a chiral support such as silica with a bound chiral ligand, or in the presence of a chiral solvent); asymmetric synthesis of a specific enantiomer using optically active reagents, substrates, catalysts, solvents or enzymatic processes; and asymmetric transformation of one enantiomer into the other. It will be appreciated that where the active moiety is transformed by the separation procedures described above, a further step may be required to convert the transformation product back to the active moiety. 7-[1-(4-Chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]pyrimidin-5-ol may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and/or geometric isomer and mixtures thereof. 7-[1-(4-Chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]pyrimidin-5-ol may exist in zwitterionic form and the present invention includes each zwitterionic form and mixtures thereof. The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of isolated 7-[1-(4-chlorophenoxy)ethyl]-1 ,2,4- triazolo[1 ,5-a]pyrimidin-5-ol together with a pharmaceutically acceptable diluent or carrier. Such pharmaceutical compositions may be used for the treatment of seizures and/or neurological disorders such as epilepsy and/or as neuroprotective agents to protect against conditions such as stroke. As used hereinafter, the term "active compound" denotes isolated 7-[1-(4- chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]pyrimidin-5-ol. In therapeutic use, the active compound may be administered orally, rectally or parenterally. Thus the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art, to give a controlled release, for example rapid release or sustained release, of the active compound. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The compositions may contain from about 0.1% to about 99% by weight of active compound and are generally prepared in unit dosage form. Preferably the unit dosage of active ingredient is from about 1 mg to about 500 mg. The excipients used in the preparation of these compositions are the excipients known in the pharmacist's art. Preferably the compositions of the invention are administered orally in the known pharmaceutical forms for such administration. Dosage forms suitable for oral administration may comprise tablets, pills, capsules, caplets, multiparticulates including: granules, beads, pellets and micro-encapsulated particles; powders, elixirs, syrups, solutions and aqueous or oily suspensions. Solid oral dosage forms, for example tablets, may be prepared by mixing the active compound with one or more of the following ingredients or mixtures thereof: inert diluents, for example calcium carbonate, calcium sulphate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactose, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc and tribasic calcium phosphate disintegrating agents, for example alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch; including maize starch and agar; lubricating agents, for example calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoat sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc and zinc stearate; binders, for example acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, magnesium aluminium silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, starch including maize starch, zein, sugars (such as sucrose, molasses and lactose), and natural and synthetic gums (such as extract of Irish moss, polyethylene glycol, waxes, microcrystalline cellulose and polyvinylpyrrolidone); colouring agents, for example conventional pharmaceutically acceptable dyes; sweetening and flavouring agents; preservatives; one or more pharmaceutically acceptable couple or couples (such as those comprising an acid and a carbonate or bicarbonate salt), which effervesces to aid dissolution when the solid dosage form is added to water; and other optional ingredients known in the art to permit production of oral dosage forms by known methods such as tabletting. Solid oral dosage forms may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Film coated, solid oral dosage forms comprising compositions of the invention may be advantageous, depending on the nature of the active compound. Various materials, for example shellac and/or sugar, may be present as coatings, or to otherwise modify the physical form of the oral dosage form. For example tablets or pills may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate and/or hydroxy propyl methylcellulose phthalate. Capsules or caplets (for example hard or soft gelatin capsules) comprising the active compound (with or without added excipients such as a fatty oil), may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner. The contents of the capsule or caplet may be formulated using known methods to give sustained release of the active compound. Liquid oral dosage forms comprising compositions of the invention may be an elixir, suspension or syrup, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent (such as sodium carboxymethylcellulose), or oily suspensions containing the active compound in a suitable vegetable oil (such as arachis oil or sunflower oil). Liquid oral dosage forms may also comprise one or more sweetening agent, flavouring agent, preservatives and mixtures thereof. The active compound may be formulated into granules or powders with or without additional excipients. The granules or powders may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example water) before ingestion. The granules or powders may contain disintegrants (for example a pharmaceutically acceptable effervescent couple formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium. Preferably each of the above oral dosage forms may contain from about 1 mg to about 500 mg (for example 10 mg, 50 mg, 100 mg, 200 mg, or 400 mg) of the active compound. Compositions of the invention may be administered rectally in the known pharmaceutical forms for such administration, for example, suppositories with hard fat, semi-synthetic glyceride, cocoa butter or polyethylene glycol bases. Compositions of the invention may also be administered parenterally, for example by intravenous injection, in the known pharmaceutical forms for such administration, for example sterile suspensions in aqueous or oily media, or sterile solutions in a suitable solvent. The active compound may also be administered by continuous infusion either from an external source (for example by intravenous infusion) or from a source of the compound placed within the body. Internal sources include implanted reservoirs containing the compound to be infused which is continuously released (for example by osmosis) or implants. Implants may be liquid such as a suspension or solution in a pharmaceutically acceptable oil of the compound to be infused (for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or ester). Implants may also be solid in the form of an implanted support (forexample a synthetic resin or waxy material) for the compound to be infused. The support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered. The amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time. In some formulations it may be beneficial to use the active compound, or pharmaceutical compositions containing them, in the form of particles of very small size, for example as obtained by fluid energy milling. In the above compositions the active compound may, if desired, be associated with other compatible pharmacologically active ingredients. Isolated 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1 ,5-a]pyrimidin-5-ol is indicated for use as neuroprotective agents to protect against conditions such as stroke, and for the treatment of seizures and neurological disorders such as epilepsy. The therapeutic activity of the compound has been demonstrated by means of various in vivo pharmacological tests in standard laboratory animals. Such tests include those tests of convulsant activity in mice described below. Accordingly, a further aspect of the present invention provides a method of treating seizures and/or neurological disorders such as epilepsy and/or a method of neuroprotection to protect against conditions such as stroke, in animals including human beings, which comprises the administration to a patient in need thereof a therapeutically effective amount of the active compound and/or a pharmaceutical composition or compositions containing a therapeutically effective amount of the active compound. Thus isolated 7-[1-(4-chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5- a]pyhmidin-5-ol is useful for the inhibition of seizures and/or neurological disorders such as epilepsy and/or as neuroprotective agents to protect against conditions such as stroke, in animals including human beings. Whilst the precise amount of the active compound administered in the treatments outlined above will depend on a number of factors, for example the severity of the condition, the age and past medical history of the patient, and always lies within the sound discretion of the administering pharmacist, physician or veterinary a suitable daily dose of the active compound for administration to human beings, is generally from about 1 mg to about 5000 mg, more usually from about 5 mg to about 1000 mg, given in a single dose or in divided doses at one or more times during the day. Oral administration is preferred. The active compounds may be used in adjunctive therapy with one or more other compound or compounds having activity in the treatment of seizures and/or neurological disorders such as epilepsy and/or as neuroprotective agents to protect against conditions such as stroke, in animals including human beings. It will be appreciated that the term therapy as used herein includes prophylactic use of the active compound and pharmaceutical composition or compositions comprising a therapeutically effective amount of the active compound, for example to prevent the onset of neurological disorders such as epileptic seizures, or as neuroprotective agents to protect against conditions such as stroke, in animals including human beings. The active compound and/or a pharmaceutical composition or compositions comprising a therapeutically effective amount of the active compound may be used to provide a local and/or systemic therapeutic effect. A still further aspect of the present invention provides use of the active compound in the preparation of a medicament for the treatment of seizures and/or neurological disorders such as epilepsy and/or for neuroprotection to protect against conditions such as stroke, in animals including human beings. Processes for the preparation of the above compound are part of the present invention. 7-[1-(4-Chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]pyrimidin-5-ol may be prepared by cyclising a compound of formula II optionally in the presence of an acid. Preferably the process is carried out at a temperature in the range 0° -250°C, more preferably in the range 50° -150°C. Preferably the acid is polyphosphoric acid. The anticonvulsant activity of 7-[1-(4-chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5- a]pyrimidin-5-ol was demonstrated by the following pharmacological test. The anticonvulsant activity involved observing the ability of a test compound to inhibit seizures in mice induced by a maximal electroshock. Hereinafter, this test is referred to as 'MESM'. In the MESM experiments, groups of male mice in the weight range 25 to 30 grammes had free access to food and water until the start of the experiment. The mice were divided into two groups, a control group and a test group to which the test compound would be administered. The control group received an oral dose of 10 ml/kg of a vehicle of 1% aqueous methyl cellulose solution. The test group received orally, suspended in the same dose of the methylcellulose vehicle, the test compound at a dose of either 100 mg/kg for initial testing or, if enough compound was available, at a range of doses to determine an ED 50 (see below). One hour after administration of all drugs an electroshock of duration 1.0 second was administered to all the mice in both groups through ear clip electrodes moistened with saline. The electroshock had an intensity of 99 mA, frequency of 50 Hz and pulse width of 0.4 ms. Such a shock would generally be expected to induce a seizure in the mice. During the following two minutes the mice in each group were observed, the number of mice in each group exhibiting tonic hind limb extension was recorded and thus the percentage of mice in which seizures had been inhibited was determined. The greater the anticonvulsant activity of the test compound, the higher was the percentage recorded in the MESM test. If results at more than one dose were available, then a value for the dose inhibiting seizures in 50% of the mice (ED 50 ) was calculated from the regression straight line plot of the percentage of mice in which seizures were inhibited against the dose of the test compound administered. 7-[1-(4-Chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]pyrimidin-5-ol was administered at a dose of 100 mg/kg 60 min before tests either by the intraperitoneal (i.p.) or oral (p.o.) route. The test compound increased significantly the threshold for maximal electroshock-induced seizures following both i.p. (77% increase) and p.o. (22% increase) administration. The invention will now be illustrated by the following non-limiting examples. The final product of each example was characterised using one or more of the following techniques: elemental analysis; infra-red spectroscopy; nuclear magnetic resonance spectroscopy; gas-liquid chromatography; and liquid chromatography. Temperatures are given in degrees Celsius. Example 1 1 a) A mixture of 2-(4-chlorophenoxy)propionic acid (30.0 g) in toluene (300 ml) was added to a solution of thionyl chloride (22.0 ml) and dimethylformamide (2 ml) in toluene (150 ml) at 60-70°C with stirring. The mixture was stirred for 18 hours at 70-80°C and then evaporated under reduced pressure to give the acid chloride. A solution of Meldrum's acid (23.5 g) in dichloromethane (90 ml) was cooled to 0-5°C under nitrogen and pyridine (33 ml) was added at 0-5°C. To this mixture was added a solution of the acid chloride prepared above in dichloromethane (90 ml) dropwise keeping the temperature below 5°C. The mixture was stirred for 1 hour at 0-5°C and then at ambient temperature for 18 hours. The mixture was diluted with dichloromethane (150 ml) and washed with 2M hydrochloric acid (2 x 100 ml) and then with saturated sodium bicarbonate solution (100 ml) and then water (100 ml). The bicarbonate washes were acidified with 5M hydrochloric acid and extracted into dichloromethane (2 x 50 ml). These dichloromethane extracts were combined with the original dichloromethane solution and dried over magnesium sulphate and evaporated to give the crude intermediate Meldrum's acid derivative. This derivative was boiled under reflux with methanol (400 ml) and methanolic hydrogen chloride solution (10 ml) for 6 hours and then left to stand at ambient temperature for 66 hours. The mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The ethyl acetate layer was separated, washed with sodium bicarbonate solution (0.5M, 100 ml), brine and then dried over magnesium sulphate and evaporated under reduced pressure to give an oil which was distilled under high vacuum. The distillate was purified by flash column chromatography on silica gel using petroleum ether, b.p. 60-80°C / ethyl acetate 20:1 as the mobile phase to give methyl 4-(4-chlorophenoxy)-3-oxopentanoate as an oil. Guanidine hydrochloride (1.87 g) was added with stirring to a solution of sodium (0.41 g) in ethanol (15 ml). The mixture was stirred for 15 minutes and then to this mixture was added a solution of methyl 4-(4-chlorophenoxy)- 3-oxopentanoate (5.0 g) in ethanol (15 ml). The mixture was stirred and boiled under reflux for 16 hours. The mixture was cooled and then evaporated to dryness under reduced pressure to give a solid. The solid was triturated with water (10 ml) containing glacial acetic acid (2 ml) and dichloromethane (20 ml) for 1 hour and then filtered. The residue obtained was washed with water (20 ml) and then with dichloromethane (20 ml) and dried in vacuo to give 2-amino-4-[1-(4-chlorophenoxy)ethyl]-6- hydroxypyrimidine, m.p. 125°C. c) A mixture of 2-amino-4-[1-(4-chlorophenoxy)ethyl]-6-hydroxypyrimidine (0.5 g), dimethylformamide dimethyl acetal (0.5 ml) and toluene (5 ml) was stirred and boiled under reflux for 8 hours. The mixture was allowed to stand at ambient temperature for 24 hours and then evaporated to dryness under reduced pressure to give a solid which was triturated with diethyl ether (2 x5ml) and filtered to give N-{4-[1-(4-Chlorophenoxy)ethyl]-6- hydroxypyrimidin-2-yl}- 'N'-dimethylformamidine, m.p. 190°C. d) Sodium hydride (62 mg of a 60% dispersion in mineral oil from which the mineral oil had been removed by washing with petrol) was dissolved in methanol (10 ml) and hydroxylamine hydrochloride (0.12 g) was added. The mixture was stirred for 5 minutes and then theformamidine (0.5 g) obtained in c) was added. The mixture was stirred at ambient temperature for 72 hours and then evaporated under reduced pressure to give a residue which was washed with water (2 x 5ml) and dried in vacuo to give N-{4-[1-(4- chlorophenoxy)ethyl]-6-hydroxypyrimidin-2-yl}formamide oxime, m.p. 120°C. e) The product from d) (5.0 g) and polyphosphoric acid (100 g) were stirred and heated on a steam bath for 4 hours. The mixture was allowed to cool to ambient temperature and then ice (100 g) and ethyl acetate (100 ml) were added. A solution of potassium carbonate (110 g) in water (total volume 100 ml) was added dropwise over 15 minutes to neutralise the mixture. The mixture was separated and the aqueous layer was extracted with ethyl acetate (100ml). The combined ethyl acetate layers were dried over magnesium sulphate and evaporated under reduced pressure to give a solid which was purified by flash column chromatography on silica gel using dichloromethane / methanol (75:3) as the mobile phase to give 7-[1-(4- chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]pyrimidin-5-ol, m.p. 190°C. Example A The use of compounds of the present invention in the manufacture of pharmaceutical compositions is illustrated by the following description. In this description the term "active compound" denotes any compound of the invention but particularly any compound which is the final product of one of the preceding Examples. a) Capsules In the preparation of capsules, 10 parts by weight of active compound and 240 parts by weight of lactose are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of active compound. b) Tablets Tablets are prepared from the following ingredients. Parts by weight Active compound 10 Lactose 190 Maize starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3 The active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture is granulated with a solution of the polyvinylpyrrolidone in ethanol. The dry granulate is blended with the magnesium stearate and the rest of the starch. The mixture is then compressed in atabletting machine to give tablets each containing a unit dose or a part of a unit dose of active compound. c) Enteric coated tablets Tablets are prepared by the method described in (b) above. The tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol:dichloromethane (1 :1). d) Suppositories In the preparation of suppositories, 100 parts by weight of active compound is incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient.

Claims: CLAIMS 1. Isolated 7-[1-(4-chlorophenoxy)ethyl]-1 ,2,4-triazolo[1 ,5-a]pyrimidin-5-ol and pharmaceutically acceptable salts thereof in the form of individual enantiomers and mixtures thereof including the racemic mixture. 2. Pharmaceutical compositions for the treatment of seizures and/or neurological disorders such as epilepsy, and/or for use as neuroprotective agents to protect against conditions such as stroke, comprising a therapeutically effective amount of a compound according to claim 1. 3. Use of a compound as claimed in claim 1 in the preparation of a medicament for the treatment of seizures and/or neurological disorders such as epilepsy, and/or for neuroprotection to protect against conditions such as stroke, in animals including human beings. 4.. A method of treating seizures and/or neurological disorders such as epilepsy and/or of neuroprotection to protect against conditions such as stroke, in animals including human beings, which comprises the administration of a therapeutically effective amount of a compound as claimed in claim 1. 5. A process for the preparation of the compound as claimed in claim 1 comprising cyclising a compound of formula II optionally in the presence of an acid.

Inventors: BARNES HILARY JANE, HARAN GERRARD, HOLMAN NICHOLAS JOHN, VOWLES DAVID THOMAS, BARNES, HILARY, JANE, HARAN, GERRARD, HOLMAN, NICHOLAS, JOHN, VOWLES, DAVID, THOMAS
Applicants: BARNES HILARY JANE, HARAN GERRARD, HOLMAN NICHOLAS JOHN, KNOLL AG, VOWLES DAVID THOMAS, BARNES, HILARY, JANE, HARAN, GERRARD, HOLMAN, NICHOLAS, JOHN, KNOLL AKTIENGESELLSCHAFT, VOWLES, DAVID, THOMAS
Application year: 2000
Main classification: C07D487
IPC codes: A61K31, A61P9, A61P25, C07B61, C07D487