NZ240501A - 4- or 5-(2-nitroanilino)thiazole derivatives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £40501 240 50 1 Urtde r iuc prevision lat»n 23 (1) the J3>•:f-jlit; r*\ r {: «* i JI y w * A v^i > Ciuss: (5)..<T..C i.-.b-.S.S. f I 'iw'.l •s PuDiicatio-n Date: s„ .of , Rsc P.(5. Jou1?!af, Mc: ion Filed: ..%.:t.^......wQl 2 6 M« 1992 Specification has been ante-dated to 19 .S?..

NO DRAWINGS DIVIDED OUT OF APPLICATION No.: 230251 Date; 8 August 1989 NEW ZEALAND PATENTS ACT, 1953 .... l COMPLETE SPECIFICATION NITROPHENYL = AMINO THIAZOLE CARBOXYLATE INTERMEDIATES LILLY INDUSTRIES LIMITED, a British company, of Kingsclere Road, Basingstoke, Hampshire RG21 2XA, England, hereby declare the invention for which I / we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by page 1A) -IA- 240 50 1 '-w' ^ NITROPHENYL = AMINO THIAZOLE CARBOXYLATE INTERMEDIATES This invention relates to novel compounds, processes for preparing them and their use as pharmaceuticals.

Various tricyclic compounds with pharmaceutical properties have already been investigated, and for example British Patent 1 533 235 discloses some thieno-benzodiazepine compounds of this type. Such compounds are described as having useful activity on the central nervous system.

New Zealand Patent Specification No. 230251 describes and claims thiazolo- [1,5] -benzodiazeoines of the following formula .5 R O R \ vk A y-R6 (I) H .4 12 3 4 in which R , R , R and R are independently hydrogen, alkyl, C2_^^ alkenyl, halogen, haloalkyl, nitro, alkoxy, ^ haloalkoxy, alkylthio or phenylsulphonyl; in which R^ is a group of the formula 240 50 1 8 N N U\ o where is hydrogen, C-^.g alkyl, cycloalkyl alkyl, benzyl or ZO-Calkyl where Z is hydrogen or an acyl group, g R is hydrogen or alkyl and n is 0 or 1, provided that when is hydrogen n is 0; in which is hydrogen, alkyl, cycloalkyl, cycloalkyl-C^_^ alkyl, haloalkyl, alkoxy or alkylthio; and in which represents a thiazole ring selected from o -N \ or // N and acid addition salts thereof.

Compounds of formula (I) have been found to possess useful biological properties and the invention includes a compound of formula (I) for use as a pharmaceutical, especially for use in treating disorders of the central nervous system.

-""-N 240 50 1 A preferred group of compounds of formula (I) is one 12 3 4 in which R , R , R and R independently represent hydrogen, halogen or haloalkyl, R^ is hydrogen, alkyl, -j cycloalkyl, cycloalkyl alkyl or alkylthio, R^ is g hydrogen or alkyl, R is hydrogen and n is 0, being of the formula: and acid addition salts thereof.

In the above general formula (I), the term alkyl" means a straight or branched chain alkyl group containing 1 to 10 carbon atoms and is especially "C^ ^ alkyl",- for example, methyl, ethyl, isopropyl, propyl, butyl, sec. butyl, isobutyl, tert. butyl, pentyl or hexyl. A preferred alkyl 20 group is "C^ ^ alkyl". The term haloalkyl" means any such alkyl group substituted by one or more, preferably three halogen atoms, and is especially trifluoromethyl. The term "halogen" is preferably bromine, fluorine and chlorine, and especially chlorine and fluorine. The terms alkoxy" and "^1-4 alkylthio" mean any alkyl group attached through an oxygen or sulphur atom to a ring atom and "C^ ^ haloalkoxy" means a alkoxy group substituted by one or more, preferably three halogen atoms and is especially trifluoromethoxy. The i ? i j -A- 240 5 0 1 term "C2-4 alkenyl" refers to groups such as vinyl, allyl and butenyl. "^3-7 Cycloalkyl" means a saturated ring having 3 to 7 carbon atoms in the ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, which can, in the group 5 "^3-7 cycloalkyl alkyl", be attached to the ring via an alkyl chain having 1 to 4 carbon atoms.

When is ZO-C^ g alkyl, Z is hydrogen or an acyl group. Preferably when Z is an acyl group, the group is of the formula RCO- where R is ^.20 alkyl, for example, 10 alkyl. Preferred examples of R^ of this type are hydroxyethyl or hydroxypropyl of the formula -(C^) OH where m is 2 or 3.

The and groups are preferably alkyl, for 14 8 example methyl or ethyl. Preferably also R , R and R are hydrogen, and n is 0, and X is A particular group of compounds is one of the following formula •w' N-r s * 240 5 0 1 2 3 in which R and R independently represent hydrogen or halogen, R^ is alkyl and R^ is alkyl.

Examples of the compounds of the invention of NZ Patent Specification No. 230251 are as follows: 8-Fluoro-2-methyl-4- (4-methyl- 1-piperazinyl) - lOH-thiazolo [5,4-b ] [1,5]benzodiazepine 2-Methyl-4-(4-methyl-1-piperazinyl)-lOH-thiazolo[5,4-b][1,5]benzodiazepine 7-Fluoro-2-methyl-4-(4-methyl-1-piperazinyl)-lOH-thiazolo [5,4-b] [1,5]benzodiazepine 7-Chloro-2-methyl-4- (4-methyl- 1-piperazinyl) -lOH-thiazolo [5,4-b] [1,5]benzodiazepine 7 ,8-Difluoro-2-methyl-4-(4-methyl-1-piperazinyl)-10H-thiazolo- [5,4-b][1,5]benzodiazepine 2-Ethyl-4-(4-methyl- 1-piperazinyl)-lOH-thiazolo[5,4-b] [1 ^benzodiazepine 2-Ethyl-8-fluoro-4-(4-methyl-1-piperazinyl)-lOH-thiazolo[5,4-b] [1,5]benzodiazepine 2-Ethyl-7-fluoro-4-(4-methyl-l-piperazinyl)-10H-thiazolo[5,4-b] [1,5]benzodiazepine 7-Chloro-2-ethyl-4-(4-methyl-1-piperazinyl)-lOH-thiazolo[5,4-b] [1,5]benzodiazepine 4-(8-Fluoro~2-methyl-lOH-thiazolo[5,4-b][1,5]benzodiazepin-4-yl)- 1-methyl piperazine-l-oxide 4-(2-Methyl-lOH-thiazolo [5,4-b](1,5]benzodiazepin-4-yl)-l-methyl piperazine-l-oxide 4-(7-Fluoro-2-methyl-lOH-thiazolo[5,4-b][1,5]benzodiazepin-4-yl)-1-methyl piperazine-l-oxide n 240 5 0 1 n 4- (7-Fluoro-2-methyl-10H-thiazolo[5,4-b][1,5]ben2odiazepin-4-yl)~ piperazine-l-ethanol 4-(7-Chloro-2-methyl-lOH-thiazolo[5,4-b][1,5]benzodiazepin-4-yl)-1-methyl piperazine-l-oxide 5 8-Fluoro-2-methyl-10-(4-methyl-1-piperazinyl)-4H-thiazolo[4,5-b] [1,5]benzodiazepine 2-Methyl-10-(4-methyl-1-piperazinyl)-4H-thiazolo[4,5-b] [ 1 ^benzodiazepine 7-Fluoro-2-methyl-10-(4-methyl-1-piperazinyl)-4H-thiazolo[4,5-b] 10 [ 1,5 benzodiazepine 7-Chloro-2-methy1-10-(4-methyl-1-piperazinyl)-4H-thiazolo[4,5-b] [1,5]benzodiazepine; and acid addition salts thereof.

As indicated above, the compounds of the invention of NZ Patent 15 Specification No. 230251 are useful both in their free base and acid addition salt forms. The acid addition salts are preferably the pharmaceutically acceptable, non-toxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydro-bromic, nitric, sulphuric or phosphoric acids, or with organic 20 acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric or lactic acid, or organic sulphonic acids for example methane sul-phonic, ethane sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic or naphthalene-2-sulphonic acid. Apart from pharma-25 ceutically acceptable acid addition salts, other salts are also included within the scope of acid addition salts such as, for example, those with picric or oxalic acid, since they may serve as intermediates in the purification of the compounds or in the preparation of other, for example, pharmaceutically acceptable, 24 0 5 0i acid addition salts, or are useful for identification, characterization or purification of the bases.

According to a further aspect of the invention of NZ Patent Specification No. 230251 there is provided a process for producing a compound of formula (1) or an acid addition salt thereof, which comprises (a) ring-closing a compound of formula (II) >2 6 (II) in which to R^ and X have the values defined above, optionally followed when is hydrogen by alkylation to give a compound in which R^ is alkyl, £3.7 cycloalkyl alkyl, benzyl or Z0-C^_g alkyl where Z is hydrogen or an acyl group, (b) rea formula (III) (b) reacting an amine of formula R~*H with a compound of R I6 (III) H in which R^ to R^ and X have the values defined above and Q represents a radical capable of being split off with the hydro-25 gen atom of the amine R^H, optionally followed when R'' is hydrogen by alkylation to give a compound in which is alkyl, cycloalkyl alkyl, benzyl or ZO-C^ g alkyl where Z is hydrogen or an acyl group, or 240 5 0 1 (c) oxidising a compound of formula (I) in which is C^_g alkyl, cycloalkyl ^1-4 alkyl, benzyl or ZO-C2_g alkyl where Z is an acyl group and n is 0, to give a compound in which n is 1.

The above processes are of a general type previously described in the literature and appropriate reaction conditions, and suitable Q radicals can be readily chosen.

In reaction (a), compounds of formula (II) may be ring-closed by employing, for example, as catalyst titanium tetrachloride and as solvent anisole, and preferably at a temperature of 100°C to 250°C, for example from 150°C to 200°C. The compounds of formula (II) are preferably prepared in situ without isolation, as described below.

It may be mentioned, for example, that in reaction (b) the radical Q can be an amino group or a mono- or dialkyl-substituted amino group (each alkyl substituent containing 1 to 4 carbon atoms), hydroxyl, thiol, or an alkoxy, alkylthio or alkylsulphonyl group containing 1 to 4 carbon atoms, for example a methoxy or methylthio group, or a halogen atom, especially a chlorine atom. Preferably, Q is amino (NH^), hydroxyl or thiol, and amino is most preferred. The reaction is preferably carried out at a temperature of from 50°C to 200°C.

When Q is amino the intermediates of formula (III) may also exist in the imino form: NH II NH— C / \ A 0 5 0 1 and when Q is hydroxyl or thiol, the intermediates of formula (III) may exist in their amide and thioamide forms: O s fi 11 NH c ra — C / \ / \ The amidines of formula (III) (Q is NH^) , can be in a salt form for example as the hydrochloride, and they can be reacted with amines of formula R^H, optionally diluted with a 10 solvent such as anisole, toluene, dimethylformamide or dimethyl-sulphoxide, and at a temperature range of 100 to 150°C. Alternatively the amidine can be converted into the corresponding amide of formula (III) (Q is OH) by alkaline hydrolysis.

When Q is hydroxyl, reaction (b) can be accomplished 15 in the presence of titanium tetrachloride which has the ability to react with the amine of formula R^H to form a metal amine complex. Other metal chlorides such as those of zirconium, hafnium or vanadium may also be employed. The reaction can be carried out in the presence of an acid binding agent such as a 20 tertiary amine, for example, triethylamine.

Alternatively, the reaction can be carried out using > J excess of the amine of formula R^H to act as an acid-binding 'u agent. A suitable organic solvent such as toluene or chloro-benzene can be used as a reaction medium, although it has been 25 found that the use of anisole is particularly desirable, at least as a co-solvent, in view of its ability to form a soluble complex with TiCl^.

O 240 5 0 1 If desired, elevated temperatures, for example up to 200°C, can be used to expedite the reaction and a preferred temperature range for carrying out the reaction is from 80°C to 120°C.

Thioamides of formula (III) (Q is SH), iminothioethers , iminoethers or iminohalides, or other derivatives containing active Q radicals as specified above, tend to be more reactive towards the amine R H and can usually be reacted without the necessity for the presence of TiCl^, but otherwise employing the 10 same conditions of temperature and solvent.

When it is desired to prepare a compound in which R^ is other than hydrogen, it is preferred to start with the react-ants of formula (II) or amine of formula R^H, in which R^ has the required value, and then to perform reaction (a) or (b). 15 However, as an alternative, the corresponding compound of formula (I) in which R^ is hydrogen may first be prepared and this then reacted with a suitable alkylating agent of formula -r-\ R^X by conventional methods employing an inert solvent and base, X being a leaving group such as for example chlorine, bromine 20 or iodine, or a group such as tosyl or mesyl.

As mentioned above, in reaction (c), compounds of formula (I) in which R^ is other than hydrogen and n is 1, can be made by oxidation of the corresponding compounds in which n is 0. Suitable oxidising agents include for example m-chloro-25 perbenzoic acid and the reaction is preferably carried out in an inert solvent such as for example dichloromethane, at a temperature of from -20°C to +20°C for example from -10°C to +10°C. 240 50 1 The compounds of formula (I) produced by the above processes may be isolated per .se or may be converted to their corresponding acid addition salts using conventional methods.

Intermediate compounds of formula (II) in process (a) described above, are preferably prepared in situ without isolation by reacting a compound of formula x )—r6 (IV) R3 14 6 9 in which R to R and R have the values defined above and R is an ester group, preferably alkyl, with an amine of formula R^H, such as by heating to a temperature between 30°C and 120°C, for example about 100°C, in a suitable solvent such as for example anisole, and employing TiCl^ as catalyst.

Compounds of formula (IV) can be prepared from the corresponding nitro compounds of formula R R"''- " ' - > ,6 <v, R 3' , if convenient, without isolation, for directly reacting with amine R^H. The present invention provides novel intermediate ccmpounds of formula (V) and processes for producing those intermediates. In 2 4 0 5 0 1 particular, ccmpounds of formula (V) can be made by condensation of a thiazole compound of formula (VI) with an ortho-halonitrobenzene of formula O (VII) where Y is a halogen, preferably fluorine, bromine or chlorine, 15 in the presence of a base, for example, sodium hydride, in a solvent such as for example tetrahydrofuran and at a temperature of from -20°C to 30°C, or anhydrous potassium carbonate in a solvent such as dimethylsulphoxide at a temperature of from 90°C to 120°C.

As disclosed in NZ Patent Specification No. 230251 cannpounds of formula (V) are converted to the ccmpounds of formula (IV) by reduction, for example catalytically, employing for instance, hydrogen and palladium/carbon or chemically, enploying for example, stannous chloride and hydrogen chloride in aqueous ethanol, or ammonium 25 polysulphide.

An illustration of the preparation of representative compounds of the invention in NZ Patent Specification No. 230251 (4-(4-alkyl-l-piperazinyl)-lOH-thiazolo[5,4-b][1,5] benzodiazepines) by this route is given in the reaction scheme below: 240501 R The intermediate amidines of formula (III) (Q is Nl^), employed in process (b), can be prepared by condensation 20 of a thiazole of formula nc h2n .V1 or nc h2n (VIII) with an ortho-halonitrobenzene of formula (VII) above, in the presence of a base for example, sodium hydride in a solvent such as tetrahydrofuran or n-butyl lithium in tetrahydrofuran, or 240 5 0 1 potassium carbonate in dimethylsulphoxide or with a tetraalkyl-ammonium salt in a two-phase system, to form a nitronitrile of formula: which can be simultaneously reduced and ring-closed to the amidine of formula (III) employing for example, stannous chloride and hydrogen chloride in aqueous ethanol or, alternatively by reduction with hydrogen and palladium/carbon or ammonium polysulphide followed by acid-catalysed ring closure.

Similarly, the intermediates amides of formula (III) (0 is OH), employed in process (b), can be derived from compounds of formula (IV) above, by ring closure employing for example sodium methylsulphinyl methanide in a suitable solvent such as dimethylsulphoxide can give an amide of formula (III) (Q is OH). Alternatively, these amides can be prepared by ring closure of an amino-acid, employing for example dicyclo-hexylcarbodiimide (DCC) in a suitable solvent such as tetrahydrofuran. These amino-acids can be obtained for example from the esters of formula (IV) by basic hydrolysis using for example sodium hydroxide in ethanol: Thioamides of formula (III) (Q is SH) can be prepared by treating a solution of the corresponding amide in an anhydrous basic solvent such as for example pyridine with phosphorus penta-sulphide. Similarly, the amides can be converted to iminothio- 24 0 5 0 1 •aw^ ethers, iminoethers or iminohalides, or other derivatives containing active Q radicals, by treatment with conventional reagents such as for example in the case of an iminochloride, phosphorus pentachloride.

Thiazole starting materials of formulae (VI) and (IX), used in the processes described above, are either known compounds, see for example Chem. & Ind. (1970) 1470; J.Chem.Soc. (1947) 1594, 1598; (1948) 2028; (1959) 4040; J.Prakt.Chem. (1967) 35 70; Arch.Pharm. (Weinheim) (1970) 303 625; Tetrahedron Lett. 10 (1981) 22 2285; Monatsch.Chem. (1981) 112 1393; Bull.Chem.Soc.

Japan (1983) 56 3851; J.Prakt. Chem. (1985) 327 604; Liebigs Ann.Chem. (1986) 780; or can be prepared by conventional techniques from known compounds. The ortho-halonitrobenzene intermediates are either commercially available or can be 15 simply prepared from commercially available substances.

As mentioned above, the compounds of the invention of NZ Patent Specification No. 230251 have useful central nervous system activity.

This activity has been demonstrated in animal models using well-established procedures. In behavioural studies in mice, for instance, the 20 compounds of the invention described in the following Examples were observed to produce activity decrease at a dose range of 1.6 to 200 mg/kg p.o. In addition compounds have been found to be active in the spiroperidol binding test described by P.

Seeman et al., in Nature 261, 717-719 (1976) and for example" have an value (the concentration of the compound required to reduce the binding of spiroperidol by 50 per cent) of less than 1 pM. Thus the compounds are potent centrally acting agents with neuroleptic, sedative or relaxant, anxiolytic or 240 5 0 1 anti-emetic properties. These properties, coupled with their high therapeutic index, render them useful in the treatment of certain kinds of psychotic conditions such as schizophrenia and acute mania and of mild anxiety states.

The compounds are effective over a wide dosage range, the actual dose administered being dependent on such factors as the particular compound being used, the condition being treated and the type and size of mammal being treated. However, the dosage required will normally fall 10 within the range of 0.01 to 2 mg/kg per day, for example in the treatment of adult humans, dosages of from 0.5 to 100 mg per day may be used.

The compounds will normally be admin istered orally or by injection and, for this purpose, the com-15 pounds will usually be utilised in the form of a pharmaceutical composition. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

Accordingly the invention of NZ Patent Specification No. 230251 20 includes a pharmaceutical composition comprising as active ingredient a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable carrier.

In making the compositions of the invention, the active ingredient will usually be mixed with a carrier, or diluted by a 25 carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium >40501 for the active ingredient. Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propyl-hydroxybenzoate, talc, magnesium stearate or mineral oil. The compositions may, if desired, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.

Depending on the route of administration, the fore-10 going compositions may be formulated as tablets, capsules or suspensions for oral use and injection solutions for parenteral use or as suppositories. A preferred formulation is an injection especially a sustained release formulation for intramuscular injection. Preferably the compositions are formulated 15 in a dosage unit form, each dosage containing from 0.5 to 100 mg, more usually 1 to 100 mg, of the active ingredient.

The following Examples illustrate the invention of NZ Patent Specification No. 230251: EXAMPLE 1 Ethyl 5-(5-fluoro-2-nitrophenylamino)-2-methylthiazole-4-carboxylate Ethyl 5-amino-2-methylthiazole-4-carboxylate (Chem.St Ind. (1970) 1470) (3.72 g) 2,4-difluoronitrobenzene (3.2 g) and potassium carbonate (5.6 g) were stirred under a nitrogen 25 atmosphere in dimethylsulphoxide (80 ml) at 110°C for 50 minutes. The mixture was poured onto a mixture of crushed ice and 2M hydrochloric acid (100 ml) and extracted into dichloromethane. 240 50 1 The extract was washed with water, dried with magnesium sulphate and the solvent removed to leave the product, which was purified by chromatography on a column of silica and recrystallisation from ethanol, m.p. 179-182°C.

Similarly prepared were:- Ethyl 5-(4-fluoro-2-nitrophenylamino)-2-methylthiazole-4- carboxylate, m.p. 170-174°C Ethyl 5-(4-chloro-2-nitrophenylamino)-2-methylthiazole-4-carboxylate, m.p. 175-181°C 10 Ethyl 5-(2-nitrophenylamino)-2-methylthiazole-4-carboxylate, m.p. 133-134°C.

EXAMPLE 2 Ethyl 5-(2-nitrophenylamino)-2-methylthiazole-4-carboxylate To sodium hydride (50% oil dispersion, 1.44 g) in dry tetrahydrofuran (25 ml) under a nitrogen atmosphere was added ethyl 5-amino-2-methylthiazole-4-carboxylate (2.78 g) and ■ ;N o-fluoronitrobenzene (2.82 g) in tetrahydrofuran (100 ml). •w' The mixture was stirred at 25°C for 20 hours and carefully 20 poured onto excess crushed ice. The mixture was acidified with 2M hydrochloric acid and the precipitate filtered, washed with water and dried. The crude product was recrystallised from ethanol, m.p. 133-134°C.

Ethyl 5-(4-fluoro-2-nitrophenylamino)-2-methylthiazole-4-carboxylate, m.p. 170-174°C, was similarly prepared. £40501 EXAMPLE 3 8-Fluoro-2-methy1-4-(4-methyl-1-piperazinyl)-lOH-thiazolo [5 ,4-b]-[1,5]benzodiazepine Ethyl 5-(5-fluoro-2-nitrophenylamino)-2-methylthiazole-5 4-carboxylate (2.85 g) was hydrogenated at 60 p.s.i. in ethanol (100 ml) with 10% palladium on charcoal (0.35 g) . The catalyst was removed by filtration and the solvent removed under reduced pressure to leave the diaminoester which was used without further purification in the next stage.

This diaminoester was stirred in a mixture of N-methyl- piperazine (17.65 ml) and anisole (40 ml) under a nitrogen atmosphere. A solution of titanium tetrachloride (2.9 ml) in anisole (15 ml) was added over 5 minutes and the stirred mixture heated at 100°C for 1 hour and then at 160-180°C, under reflux, for 48 15 hours. After cooling the stirred mixture to about 70°C, a mixture of 20M ammonia solution (5 ml) and 2-propanol (5 ml) was cautiously added. The stirred suspension was allowed to slowly cool to 25°C over 1 hour to precipitate the titanium salts which were then removed by filtration through a pad of celite, washing 20 with ethyl acetate (100 ml). The combined filtrate and washings were extracted twice with 2N hydrochloric acid and the extracts washed with ethyl acetate. The acid solution was basified with 20M ammonia solution and extracted into dichloromethane. After washing with water and drying with magnesium sulphate'the solvent 25 was removed under reduced pressure to leave the crude product which was purified by chromatography on a column of magnesium silicate followed by crystallisation from acetonitrile, m.p. 234-237°C. 240 5 0 1 , "S w Similarly prepared were:-2-Methyl-4-(4-methyl-1-piperazinyl)-lOH-thiazolo[5,4-b][1,5] benzodiazepine, m.p. 258-263°C (acetonitrile) 7-Fluoro-2-methyl-4-(4-methyl-1-piperazinyl)-10H-thiazolo-[5,4-b][1,5]benzodiazepine, m.p. 253-255°C (acetonitrile) 7-Chloro-2-methyl-4-(4-methyl-1-piperazinyl)-10H-thiazolo-[5,4-b][1,5] benzodiazepine, m.p. 256-264°C (acetonitrile) EXAMPLE 4 Tablets each containing 10 mg of active ingredient are made up as follows Active ingredient 10 mg Starch 160 mg Microcrystalline cellulose 100 mg Polyvinylpyrrolidone (as 10% solution in water) 13 mg Sodium carboxymethyl starch 14 mg Magnesium stearate 3 mg Total 300 mg The active ingredient, starch and cellulose are mixed" 25 thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders and passed through a sieve. The granules so produced are dried and re-passed through a sieve. 240 50 1 The sodium carboxymethyl starch and magnesium stearate are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 300 mg.

EXAMPLE 5 Capsules each containing 20 mg of medicament are made as follows Active ingredient 20 mg Dried starch 178 mg Magnesium stearate 2 mg Total 200 mg The active ingredient, starch and magnesium stearate 15 are passed through a sieve and filled into hard gelatin capsules in 200 mg quantities.

EXAMPLE 6 A freeze dried formulation for reconstitution into 20 an aqueous injection is prepared from the following ingredients Active ingredient 15 mg 0.1M Hydrochloric acid 0.48 ml Mannitol 100 mg Water to 2 ml The active ingredient is suspended in water, acidified with hydrochloric acid and mannitol added, and adjusted to pH5. Water is added to 2 ml and the mixture filled into vials and then freeze dried. 240 50 1 EXAMPLE 7 A sustained release formulation for intra-muscular injection is prepared from the following ingredients Active ingredient 20 mg Aluminium stearate 2 mg Soya bean oil to 2 ml 240 5 0 1 - 23

Claims (11)

WHAT WE CLAIM IS:

1. A compound of the formula R R ■R 6 V R 4 in which r*. r^, r3, r4, are independently hydrogen, Cj_4 alkyl, C2_4 alkenyl, halogen, Ci_4 haloalkyl, nitro, C^_4 alkoxy, C^_4 haloalkoxy, Ci_4 alkylthio or phenylsulphonyl; R^ is hydrogen, Ci_io alkyl, C3_7 cycloalkyl, C3-7 cycloalkyl-C;i__4 alkyl, Ci_4 haloalkyl, Ci_4 alkoxy or C^_4 alkylthio; represents a thiazole ring selected from or and R9 is an ester group.

2. A compound as claimed in claim 1 wherein R^ is C^_4 alkyl. 240 50 1 - 24

3. A process for producing a compound of formula V as defined in claim 1, which comprises condensing a thiazole compound of formula (VI) wherein R6, R9 and with an ortho-halonitrobenzene of formula are as defined in claim 1, (VII) wherein R1, R2, R3 and R4 are as defined in claim 1 and Y is a halogen, in the presence of a base, in a solvent.

4. A process as claimed in claim 3 wherein Y is selected from the group flourine, bromine and chlorine.

5. A process as claimed in claim 3 or claim 4 wherein the base is selected from sodium hydride and anhydrous potassium carbonate- - 25 -

6. A process as claimed in claim 3 or claim 4 wherein the solvent is selected from tetrahydrofuran and dimethylsulphoxide.

7. A process as claimed in claim 3 or claim 4 wherein the base is sodium hydride, the solvent is tetrahydrofuran and the condensation process is carried out at a temperature of from -20 °C to 30°C.

8. A process as claimed in claim 3 or claim 4 wherein the base is anhydrous potassium chloride, the solvent is dimethylsulphoxide and the condensation process is carried out at a temperature of from 90°C to 120°C.

9. A compound as defined in claim 1 substantially as herein described with reference to any example thereof.

10. A process as defined in claim 3 substantially as herein described with reference to any example thereof.

11. A compound as defined in claim 1 when produced by the process as claimed in any one of claims 3 to 8 or 10. ^ By Mis/Their authorised Agent A.J. PARK & SON