The present invention relates to dioxocyclobutene derivatives, processes for their preparation, intermediates in their preparation, their use as therapeutic agents and to pharmaceutical compositions containing them. The compounds of this invention are inhibitors of a calmodulin insensitive cyclic GMP phosphodiesterase and are of use in combating such conditions where such inhibition is thought to be beneficial. They are bronchodilators and are therefore of use in combating chronic reversible obstructive lung diseases such as asthma and bronchitis. Some of the compounds of the present invention have anti-allergic activity and are therefore useful in combating allergic diseases such as allergic asthma, allergic rhinitis, urticaria and gastrointestinal motility disorders such as irritable bowel syndrome. Furthermore the compounds of this invention are vasodilators and are therefore of value in combating angina, hypertension and congestive heart failure. Also the compounds of this invention are smooth muscle relaxants and are therefore of value in treating male sexual dysfunction, e.g. impotence.

Accordingly the present invention provides compounds of the formula (1) :

Formula (1)

and pharmaceutically acceptable salts thereof, wherein

Ar is an optionally substituted aryl or heteroaiyl ring selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, imidazolyl, thienyl, oxazolyl, benzimidazolyl, benzoxazolyl, indolyl or thianaphthenyl, X is CH or N;

Rθ is NR ^J R2 or hydrogen; and R ¹ and R-^ are independently hydrogen or C1.5aU.-yl. Suitably Ar is phenyl.

Suitably Ar is 2- ,3- or 4-pyridyl, 5-pyrimidyl, 2- or 4-imidazolyl, 2- or 3-thienyl, 2-oxazolyl, 2-benzimidazolyl, 2-benzoxazolyl, 2-indolyl or 2-thianaphthenyl. Preferred heteroaryl rings include 3-pyridyl, 2-thiophenyl or 2-indolyl Suitably Ar is unsubstituted or substituted by at least one group selected from Cι_6alkyl, C-^alkoxy or hydroxy.

Suitably Ar is positioned ortho- or meta- to X.

Suitably X is CH. Suitably R° is NR ^Ϊ R ² .

Suitably R* is hydrogen and R ² is hydrogen or Ci.galkyl. Preferably R ¹ and R ² are both hydrogen. Examples of Cι_6alkyl groups include methyl, ethyl, propyl, butyl, pentyl and hexyl, preferably methyl.

Particular compounds of this invention include :

3-amino-4-[4-(3-pyridyl)]a-nilino-3-cyclobutene-l,2-dione ,

3-ammc-4-[3-(4-imidazolyl)anilino]-3-cyclobutene- 1 ,2-dione, 3-methylamino-4- [3-(5-methyl-4-imidazolyl)anilino] -3-cyclobutene- 1 ,2-dione,

3-dimeΛylam o-4-[3-(5-memyl-4- ώdazolyl)anilino]-3-cyclobutene-l,2-dione,

3-amino-4-[3-(3-methyl-4-pyridyl)anilino]-3-cyclobutene- 1 ,2-dione,

3-amino-4-[3-(2-oxazolyl)anilino]-3-cyclobutene-l,2-dione ,

3-amino-4-[3-(4-pyridyl)anilino]-3-cyclobutene-l,2-dione, 3-aιr no-4-[3-(3-pyridyl)anilino]-3-cyclobutene- 1 ,2-dione,

3-amino-4-[3-(2-pyridyl)anilino]-3-cyclobutene-l,2-dione,

3-amino-4-[3-(2-thienyl)anilino]-3-cyclobutene- 1 ,2-dione,

3-a-tmno-4-[3-(3-tMenyl)anilino]-3-cyclobutene-l,2-dione,

3-amino-4-[3-(2-thianaphthene)anilino]-3-cyclobutene-l,2- dione, 3-ammo-4-[3-(5-pyrimidyl)anilino]-3-cyclobutene-l,2-dione,

3-aminc-4-[3-(2-benz»xazoyl)anilino]-3-cyclobutene-l,2-d ione,

3-aιnino-4-[3-(2-benzimidazolyl)anilino]-3-cyclobutene-l ,2-dione,

3-ammo-4-[3-(2-indolyl)anilino]-3-cyclobutene-l,2-dione,

3-amino-4-(3-phenyl)anilino-3-cyclobutene- 1 ,2-dione, 3-amino-4-[3-(2-hydroxyphenyl)anilino]-3-cyclobutene-l,2-dio ne,

3-amino-4-[3-(2-methoxyphenyl)anilino]-3-cyclobutene-l,2- dione,

3-amino-4-[3-(3-hydroxy-2-pyridyl)anilino]-3-cyclobutene- l,2-dione,

3-am o-4-[3-(2-imidazolyl)anilino]-3-cyclobutene-l,2-dione,

3-amino-4-[6-(4-pyridyl)-2-pyridylamino]-3-cyclobutene- 1,2-dione, and 3-[3-(4-pyridyl)anilino]-3-cyclobutene-l,2-dione,

or pharmaceutically acceptable salts thereof.

Compounds of the formula (1) may form pharmaceutically acceptable salts with acids such as hydrochloric, hydrobromic, sulphuric and phosphoric acids.

Compounds of the formula (1) may form pharmaceuticaUy acceptable salts with metal ions, such as alkali metals for example sodium and potassium, or with an ammonium ion.

In order to use a compound of the formula (1) or a pharmaceuticaUy acceptable salt thereof for the treatment of humans and other mammals it is normaUy formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Compounds of formula (1) and their pharmaceuticaUy acceptable salts may be administered in standard manner for the treatment of the indicated diseases, for example orally, parenteraUy, transdermally, rectaUy, via inhalation or via buccal administration.

Compounds of formula (1) and their pharmaceutically acceptable salts which are active when given oraUy or via buccal administration can be formulated as Uquids, syrups, tablets, capsules and lozenges. An oral Uquid formulation wiU generally consist of a suspension or solution of the compound or salt in a Uquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include starch, ceUuloses, lactose, sucrose and magnesium stearate. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule sheU. Where the composition is in the form of a soft gelatin sheU capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, ceUuloses, silicates or oUs and are incorporated in a soft gelatin capsule sheU.

Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenteraUy acceptable oil, for example polyethylene glycol, polyvinyl-pyrroUdone, lecithin, arachis oU, or sesame oU. A typical suppository formulation comprises a compound of formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats.

Typical transdermal formulations comprise a conventional aqueous or non- aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.

Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered in the form of an aerosol using a conventional

propeUant such as dichlorodifluoromethane or trichlorofluoromethane, or are in the form of a powder for insufflation.

Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose. Each dosage unit for oral administration contains suitably from 0.001 mg Kg to

30 mg/Kg, and preferably from 0.005 mg Kg to 15 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.001 mg/Kg to 10 mg/Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free base. The daUy dosage regimen for oral administration is suitably about 0.001 mg/Kg to 120 mg/Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free base. The daUy dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, for example about 0.005 mg/Kg to 10 mg/Kg, of a compound of the formula (1) or a pharmaceuticaUy acceptable salt thereof calculated as the free base. The active ingredient may be administered as required for example from 1 to 8 times a day or by infusion. The compositions of the invention are bronchodilators and are useful in chronic reversible obstructive lung disease for example asthma and bronchitis. In addition some of the compositions of the present invention have anti- aUergic activity and are useful in combating allergic diseases such as aUergic asthma, aUergic rhinitis, urticaria and irritable bowel syndrome. The compositions of the present invention also have vasodilator activity and are of use in the treatment of angina, hypertension and congestive heart failure. Such conditions can be treated by administration oraUy, topically, rectally, parenteraUy or by inhalation.

For administration by inhalation dosages are controUed by a valve, are administered as required and for an adult are conveniently in the range 0.1-5.0 mg of a compound of the formula (1) or a pharmaceuticaUy acceptable salt thereof.

The compounds of this invention may be co-administered with other pharmaceuticaUy active compounds, for example in combination, concurrently or sequentiaUy. Conveniently the compounds of this invention and the other active compound or compounds are formulated in a pharmaceutical composition. Examples of compounds which may be included in pharmaceutical compositions with the compounds of the formula (1) are bronchodilators such as sympathomimetic amines for example isoprenaline, isoetharine, sulbutamol, phenylephrine and ephedrine or xanthine derivatives for example theophylline and aminophyUine, anti-aUergic agents for example disodium cromoglycate, histamine Hj-antagonists, vasodilators for example hydralazine, angiotensin converting enzyme inhibitors for example captopril, anti-anginal agents for example isosorbide nitrate, glyceryl trinitrate and pentaerythritol tetranitrate, anti-arrhythmic agents for example quinidine, procainamide and Ugnocaine, calcium antagonists for example

verapamil and nifedipine, diuretics such as thiazides and related compounds for example bendrofluazide, chlorothiazide, chlorothaUdone, hydrochlorothiazide, and other diuretics for example frusemide and triamterene, and sedatives for example nitrazepam, flurazepam and diazepam.

In another aspect the present invention provides a process for the preparation of compounds of the formula (1) or pharmaceutically acceptable salts thereof, which process comprises reacting a compound of the formula (2) :

Formula (2)

with a compound of the formula (3)

Formula (3)

wherein Ar, X and R^ are as hereinbefore defined and L* is a leaving group, and thereafter optionaUy forming a pharmaceuticaUy acceptable salt thereof.

Suitably I-.* is Cι_5alkoxy, halo or Cι_6alkylthio, for examples methoxy, ethoxy, propoxy or n-butoxy. The reaction may be performed in the absence of a solvent or in a solvent such as a Cι_4alkanol (e.g. methanol or ethanol), acetonitrile or pyridine at ambient or elevated temperature such as 30 to 160°C, conveniently at reflux temperature when in the presence of a solvent.

Compounds of the formula (2) are known or may be prepared by standard methods. For example a compound of the formula (2) may be prepared by reacting in the presence of a paUadium catalyst a compound of the formula (4) with a compound of the formula (5) :

Formula (4) Formula (5) wherein one of I-.2 and L.3 is B(OH)2 and the other is a suitable leaving group, Y is amino or a precursor thereof, Arl is a group Ar as hereinbefore defined or a precursor thereof and X is as hereinbefore defined, and thereafter if necessary :

• converting a group Y to amino • converting a group Ar to Ar.

A suitable leaving group for ] or 1? is halo, preferably bromo or trifluoromethanesulphonate. Preferably l_? is B(OH)2- Suitably the reaction of a compound of the formula (4) with a compound of the formula (5) is performed in the presence of a base such as triethylamine, barium hydroxide, sodium carbonate or sodium bicarbonate, and when L-2 or l > is trifluoromethanesulphonate in the presence of Uthium chloride, in a solvent such as dimethoxyethane, tetrahydrofuran, benzene, ethanol, water or mixtures thereof, at elevated temperature (e.g. 30-150°C) preferably at the reflux temperature of the reaction mixture.

An example of a precursor of an amino group is a nitro group which can be reduced to an amino group in conventional manner, e.g. by catalytic hydrogenation. An alternative precursor is a protected amino group such as phthalamido which can be deprotected in conventional manner.

An example of a precursor of the group Ar is when Ar is substituted by an optionaUy substituted benzyloxy group such as 4-methoxybenzyloxy which can be converted to Ar substituted by hydroxy in conventional manner, e.g. by catalytic hydrogenation.

Compounds of the formula (3) are known or can be prepared by standard methods (e.g. as described in UK patent 1563090).

Compounds of the formulae (4) and (5) are known or may be prepared by standard methods.

Pharmaceutically acceptable acid addition salts of the compounds of the formula (1) may be prepared from the corresponding base of the compounds of the formula (1) in conventional manner. For example the base may be reacted with an acid in a Cμ4alkanol, or an ion-exchange resin may be used. The salts of the compounds of the formula (1) may be inter converted using ion-exchange resins. Non-pharmaceuticaUy acceptable salts are therefore of use as they can be converted to pharmaceuticaUy acceptable salts.

Pharmaceutically acceptable base addition salts of the compounds of the formula (1) may be prepared by standard methods, for example by reacting a solution of the compound of the formula (1) with a solution of the base.

The foUowing biological test methods, data and Examples serve to illustrate this invention.

Bronchodilatation - In vivo

Male guinea-pigs of the Dunkin Hartley strain (500 - 600g) are anaesthetised with Sagatal (pentobarbital sodium) (60 mg/kg). Airway resistance is measured using a modification of the classical Konzett-Rossler technique (J. Pharm. Methods, 12.. 309-315, 1985). U46619 (9,1 l-methaneoepoxy-PGH2) is infused i.v. at a rate of 2.5 nmol/min, this produced a steady state of bronchoconstriction (approximately 120% increase from basal airway resistance). The compound under test is administered by i.v. bolus injection, and the subsequent peak inhibition of bronchoconstriction is recorded. The dose of compound required to reduce the U46619-induced broncho¬ constriction by 50% is given as the BD50.

Anti-allergic activity

Male Duncan Hartley guinea-pigs (250-300 g) are sensitised to ovalbumen by i.p. injection of 2 ml of 50 mg.ml"! i.p. and 0.2 ml s.c. Three weeks later they are anaesthetised with 60 mg.kg'l sodium pentabarbitone. The trachea is cannulated and the animal respires at a rate of 40 breaths per minute and at an initial tracheal inflation pressure of 16 mmHg. Tracheal inflation pressure is measured by a transducer connected to a side arm of the respiration circuit The carotid artery is cannulated for the measurement of blood pressure and the signal is used to trigger an instantaneous rate meter. A jugular vein is cannulated for the administration of drug and aUergen. After surgery the animals are aUowed to stabilise and the drug is administered i.v. as a bolus. FoUowing this, ovalbumen lmg.kg"! is injected i.v. as the antigen chaUenge either 2, 15 or 30 minutes foUowing drug treatment and the peak bronchoconstrictor response recorded. For the control group ovalbumen only is given. One ovalbumen chaUenge per guinea-pig is used and n = 6 for each time point. The percentage increase in tracheal inflation pressure is calculated.

Phosphodiesterase activity

The activity of the compounds of the present invention as inhibitors of a calmodulin insensitive cycUc GMP phosphodiesterase is measured using the procedure described in European Patent Application No.293063. The concentration of compound

which inhibits the enzyme by 50% is given as the IC50 (μM). The compounds of Examples 2, 5 to 11, 13 to 16, 18, 20 and 23 had IC50 values in the range 6 to 110 μM.

Inhibition of Spontaneous Contraction in Guinea-Pig Colon

Segments of isolated guinea-pig colon (2 cm) are suspended under 2 g tension in standard organ baths containing Krebs solution. The tissues are connected at the free end to isometric transducers which allow recording and display of developed tension on chart recorders. On-line computer capture and analysis are used to quantify the effects of test compounds on spontaneous contractions. Inhibitory responses are calculated as % maximum inhibition of spontaneous contraction distance over 3 consecutive pre and post dose 2 minute readings. The concentration of compound which causes 50% inhibition of the spontaneous contraction is given as the EC50 (μM).

Example 1 3-Amino-4-[4-(3-pyridyl)]anilino-3-cycIobutene-l-2-dione A solution of 3-(4-aminophenyl)pyridine (0.51 g) and 3-amino-4-ethoxy-3-cyclobutene- 1,2-dione (0.42 g) in pyridine (2 ml) was stirred at 80° for 20 hours. The cool mixture was treated with water (15 ml) and the soUd filtered off and washed with water and hot methanol. RecrystaUation from dimethylformamide gave 0.33 g of the title compound, mp 322-4°C dec.

Example 2

3-Amino-4-[3-(4-imidazolyl)aniIino]-3-cyclobutene-l 2-dione

In a manner similar to that of Example 1, 4-(3-aminophenyl)imidazole (0.48 g) and 3- amino-4-ethoxy-3-cyclobutene-l,2-dione (0.42 g) gave 0.40 g of the title compound, mp darkens ca. 300°C (from dimethylformamide/water).

Example 3

3-Methylaπύno-4-[3-(5-methyl-4-imidazolyI)anilino]-3-cy clobutene-l,2-dione

In a manner similar to that of Example 1, 4-(3-ammophenyl)-5-methylimidazole (0.43 g) and 3-ethoxy-4-methylamino-3-cyclobutene-l,2-dione (0.39 g) gave 0.36 g of the title compound, mp >330°C (from dimethylformamide).

Example 4

3-Dimethylamino-4-[3-(5-methyl-4-imidazolyl)aniIino]-3-cy clobutene-l,2-dione

In a manner similar to that of Example 1, 4-(3-aminophenyl)-5-methyl-imidazole (0.57 g) and 3-dimethylamino-4-ethoxy-3-cyclobutene-l,2-dione (0.56 g) gave 0.34 g of the title compound, mp 290-292°C (from methanol).

Example 5

3-Amino-4-[3-(3-methyI-4-pyridyl)aniIino]-3-cyclobutene-l 2-dione

In a manner similar to that of Example 1, 4-(3-aminophenyl)-2-methylpyridine (0.55 g) and 3-amino-4-ethoxy-3-cyclobutene-l ,2-dione (0.42 g) gave 0.28 g of the title compound, mp 205-208°C (from dimemylformamide).

Example 6

3-Amino-4-[3-(2-oxazolyl)anilino]-3-cyclobutene-l,2-dione In a manner similar to that of Example 1, 2-(3-aminophenyl)oxazole (0.50 g) and 3- amino-4-ethoxy-3-cyclobutene-l,2-dione (0.44 g) gave 0.56 g of the title compound, mp 312-314°C (from dimethylformamide).

Example 7 3-Amino-4-[3-(4-pyridyI)anilino]-3-cyclobutene-l-2-dione

(a) A stirred mixture of 3-nitrophenylboronic acid (2.00 g), 4-bromopyridine hydrochloride (1.56 g), bis(diphenylphosphino)butanepaUadium(II) chloride (0.48 g), sodium bicarbonate (2.69 g), water (30 ml) and 1,2-dimethoxyethane (100 ml) was heated under reflux for 3 hours. The cool mixture was added to water (300 ml) and extracted with chloroform (3 x 150 ml), and the combined organic extracts washed with water and brine, dried (MgSO4), charcoaled and filtered. The solvent was evaporated to give a residue which was purified by flash chromatography (siUca, ether) to give 1.19 g of 4-(3- nitrophenyl)pyridine, mp 109-110.5°C (from acetone hexane).

(b) A solution of the above nitre compound (1.18 g) in ethanol (30 ml) was shaken with 10% paUadium on carbon (0.2 g) under hydrogen (50 psi) for 2.5 hours.

Evaporation of the filtered solution gave a soUd residue which was recrystaUised from ethanol/40-60° Pet ether to give 0.81 g of 4-(3-aminophenyl)pyridine, mp 167.5-168°C.

(c) In a manner similar to that of Example 1 , the above amino compound (0.50 g) and 3-amino-4-n-butoxy-3-cyclobutene-l,2-dione (0.50 g) gave 0.50 g of the title compound, mp 297-300°C dec. (from dimethylformamide).

Example 8 3-Aιnino-4-[3-(3-pyridyl)anilino]-3-cyclobutene-l,2-dione

(a) In a manner similar to that of Example 7(a), 3-nitrophenylboronic acid (2.00 g) and 3-bromopyridine (1.26 g) gave 1.22 g of 3-(3-nitrophenyl)pyridine, mp 98.5- 101°C (from acetone/hexane).

(b) A stirred mixture of the above nitro compound (1.22 g), stannous chloride dihydrate (6.5 g), cone, hydrochloric acid (6.5 ml) and ethanol (12.5 ml) was heated under reflux for 3.5 hours. Most of the ethanol was evaporated under reduced pressure and the residue made alkaline with 40% sodium hydroxide solution. The mixture was extracted with toluene (3 x 20 ml) and the combined organic extracts washed with water, dried (MgSO4) and evaporated to give a residue which was recrystaUised from chloroform/40-60 ^o Pet ether to give 0.92 g of 3-(3-aminophenyl)pyridine, mp 75-76°C.

(c) In a manner simUar to that of Example 1, the above amino compound (0.51 g) and 3-amino-4-ethoxy-3-cyclobutene-l,2-dione (0.42 g) gave 0.45 g of the title compound, mp 256-258°C (from methanol).

Example 9 3-Amino-4-[3-(2-pyridyl)anilino]-3-cyclobutene-l,2-dione (a) In a manner simUar to that of Example 7(a), 3-nitrophenylboronic acid

(1.45 g), 2-bromopyridine (1.26 g) and tetrakis(triphenylphosphine)paUadium(0) (0.50 g) gave 0.92 g of 2-(3-nitrophenyl)pyridine, mp 71.5-73°C (from ethanol).

(b) In a manner simUar to that of Example 7(b), the above nitro compound (0.92 g) gave 2-(3-aminophenyl)pyridine (0.50 g) as a colourless oU. (c) In a manner simUar to that of Example 1, the above amino compound

(0.50 g) and 3-amino-4-n-butoxy-3-cyclobutene-l,2-dione (0.50 g) gave 0.50 g of the title compound, mp 300-303°C dec. (from dimethylformamide/water).

Example 10 3-Amino-4-[3-(2-thienyl)anilino]-3-cyclobutene-l _y 2-dione

(a) In a manner simUar to that of Example 7(a), 3-nitrophenylboronic acid (2.00 g) and 2-bromothiophene (1.30 g) gave 0.69 g of 2-(3-nitrophenyl)thiophene, mp 70-72°C (from ether).

(b) In a manner simUar to that of Example 8(b), the above nitro compound (0.69 g) and stannous chloride dihydrate (3.6 g) gave 0.43 g of 2-(3-aminophenyl)- thiophene, mp 30.5-32°C.

(c) In a manner similar to that of Example 1, the above amino compound

(0.42 g) and 3-amino-4-ethoxy-3-cyclobutene-l,2-dione (0.34 g) gave 0.35 g of the title compound, mp 297-299°C dec. (from dimethylforrnamide/water).

Example 11

3-Amino-4-[3-(3-thienyl)anilino]-3-cyclobutene-l,2-dione

(a) In a manner simUar to that of Example 7(a), 3-nitrophenylboronic acid

(1.45 g), 3-bromothiophene (1.30 g) and tetrakis(triphenylphosphine)paUadium(0) (0.50 g) gave 1.46 g of 3-(3-nitrophenyl)thiophene, mp 70.5-72.5°C (from ether hexane). (b) In a manner simUar to that of Example 8(b), the above nitro compound

(0.72 g) and stannous chloride dihydrate (3.75 g) gave 0.38 g of 3-(3- aminophenyl)thiophene, mp 86-88°C.

(c) In a manner similar to that of Example 1, the above amino compound (0.37 g) and 3-amino-4-n-butoxy-3-cyclobutene-l,2-dione (0.36 g) gave 0.37 g of the title compound, mp 304-307°C dec. (from dmethylformamide/water).

Example 12 3-Amino-4-[3-(2-thianaphthenyl)anilino]-3-cyclobutene-l _f 2-dione

(a) In a manner simUar to that of Example 7(a), 3-nitrophenylboronic acid (2.20 g), 2-bromothianaphthene (2.81 g) and tetrakis(triphenylphosphine)paUadium(0)

(0.25 g) gave 1.19 g of 2-(3-nitrophenyl)thianaphthene, mp 158-159°C (from acetone).

(b) In a manner simUar to that of Example 8(b), the above nitro compound (1.18 g) and stannous chloride dihydrate (5.0 g) gave 0.45 g of 2-(3- aminophenyl)thianaphthene, mp 146-147°C. (c) In a manner simUar to that of Example 1, the above amino compound

(0.44 g) and 3- amino-4-ethoxy-3-cyclobutene-l,2-dione (0.33 g) gave 0.37 g of the title compound, mp 318-321°C dec. (from dimethylformamide/water).

Example 13 3-Amino-4-[3-(5-pyrimidyl)anilino]-3-cyclobutene-l,2-dione

(a) In a manner similar to that of Example 7(a), 3-nitrophenylboronic acid (2.00 g) and 5-bromopyrimidine (1.27 g) gave 1.16 g of 5-(3-nitrophenyl)pyrimidine, mp 159-160.5°C (from acetone).

(b) In a manner simUar to that of Example 7(b), the above nitro compound (0.91 g) gave 0.65 g of 5-(3-aminophenyl)pyrimidine, mp 165-167.5°C (from acetone/hexane).

(c) In a manner similar to that of Example 1, the above amino compound

(0.51 g) and 3-amino-4-ethoxy-3-cyclobutene-l,2-dione (0.42 g) gave 0.51 g of the tide compound, mp 288-290°C dec. (from dimethylformamide/water).

Example 14

3-Amino-4-[3-(2-benzoxazoyl)aniIino]-3-cyclobutene-l-2-di one

In a manner simUar to that of Example 1, 2-(3-aminophenyl)benzoxazole (0.49 g) and 3- amino-4-ethoxy-3-cyclobutene-l,2-dione (0.33 g) gave 0.25 g of the tide compound, mp 330-332°C dec. (from dimeΛytformamide/water).

Example 15

3-Amino-4-[3-(2-benzimidazolyl)aniIino]-3-cyclobutene-l,2 -dione

In a manner simUar to tiiat of Example 1, 2-(3-aminophenyl)benzimidazole (0.52 g) and 3- amino-4-ethoxy-3-cyclobutene-l,2-dione (0.36 g) gave 0.35 g of the tide compound, mp >320°C (from dimethylformamide/water).

Example 16

3-Amino-4-[3-(2-indolyl)aniIino]-3-cyclobutene-l,2-dione

In a manner simUar to diat of Example 1, 2-(3-aminophenyl)indole (0.48 g) and 3-amino- 4-ethoxy-3-cyclobutene-l ,2-dione (0.33 g) gave 0.22 g of die tide compound, mp ca, 335° C dec. (from dimemylformamide/water).

Example 17

3-Amino-4-(3-phenyl)anilino-3-cyclobutene-l,2-dione (a) In a manner similar to that of Example 7(b), 3-nitrobiphenyl (2.48 g) gave 1.77 g of 3-aminobiphenyl, mp 27.5-28.5°C.

(b) In a manner simUar to that of Example 1, 3-aminobiphenyl (0.51 g) and 3-am o-4-ethoxy-3-cyclobutene-l ,2-dione (0.42 g) gave 0.33 g of the tide compound, mp 300-301°C (from dimethylformamide/water).

Example 18

3-Amino-4-[3-(2-hydroxyphenyI)anilino]-3-cycIobutene-l-2- dione

(a) A stirred mixture of 2-bromophenol (5.19 g), 4-methoxybenzyl chloride (4.70 g), potassium carbonate (4.15 g) and acetone (30 ml) was heated under reflux for 8

hours. The cool mixture was evajxwated under reduced pressure and die residue was mixed witii water (60 ml) and etiier (60 ml) and shaken. The aqueous layer was extracted with ether (2 x 60 ml) and die combined extracts washed witii 2M sodium hydroxide solution (20 ml) and water (20 ml), dried (MgSO4) and evaporated to give a soUd residue which was recrystaUised from ethanol to give 6.18 g of l-bromo-2-(4-methoxybenzyloxy)- benzene, mp 87-90°C.

(b) In a manner simUar to tiiat of Example 7(a), 3-nitrophenylboronic acid (1.09 g), l-bromo-2-(4-methoxybenzyloxy)benzene (1.76 g) and tetrakis(triphenyl- phosphine)palladium(O) (0,20 g) gave 1.34 g of 2-(4-methoxybenzyloxy)-3'-nitrobiphenyl, mp 99.5- 100.5°C (from acetone/ether).

(c) In a manner similar to that of Example 7(b), the above nitro compound (0.86 g) gave 0.29 g of 2-hydroxy-3'-aminobiphenyl, mp 158-161°C.

N.B.: It is possible to terminate tiiis reaction after adsorption of 3 moles of hydrogen to give 2-(4-methoxybenzyloxy)-3'-aminobiphenyl, mp 68-70°C (from ether/hexane). (d) In a manner simUar to mat of Example 1, 2-hydroxy-3'-aminobiphenyl

(0.28 g) and 3-amino-4-n-butoxy-3-cyclobutene-l,2-dione (0.26 g) gave 0.19 g of the tide compound, mp 294-297°C dec. (from dimethylformamide/water).

Example 19 3-Amino-4-[3-(2-methoxyphenyI)anilino]-3-cyclobutene-l,2-dio ne

(a) In a manner simUar to mat of Example 7(a), 3-nitrophenylboronic acid, (1.45 g), 2-bromoanisole (1.50 g) and tetrakis(triphenylphosphine)paUadium(0) (0.25 g) gave 0.39 g of 2-methoxy-3'-nitrobiphenyl, mp 67-8°C.

(b) In a manner simUar to that of Example 7(b), the above nitro compound (0.39 g) gave 174 mg of 2-metiιoxy-3'-aminobiphenyl as an oU.

(c) In a manner similar to mat of Example 1, d e above amino compound (174 mg) and 3-amino-4-n-butoxy-3-cyclobutene-l^-dione (148 mg) gave 146 mg of the tide compound, mp 294-296°C (from dimediylformamide/water).

Example 20

3-Amino-4-[3-(3-hydroxy-2-pyridyl)anilino]-3-cyclobutene- l,2-dione

(a) A stirred mixture of 2,6-dibromopyridine (3.55 g), benzyl alcohol

(1.63 g), potassium hydroxide (1.68 g), 18-Crown-6 (0.20 g) and toluene (25 ml) was heated under reflux for 30 minutes. The cool solution was washed widi water and brine, dried (MgSO4) and evaporated to give an oU which was vacuum-distiUed (Kugelrohr) to give 3.85 g of 2-benzyloxy-6-bromopyridine, bp 220-225°C / 1.0 mm.

(b) In a manner simUar to that of Example 7(a), 3-nitrophenylboronic acid

(1.09 g), 2-benzyloxy-6-bromopyridine (1.58 g) and tetrakis(triphenylphosphine)- paUadium(O) (0.40 g) gave 0.95 g of 2-benzyloxy-6-(3-nitrophenyl)pyridine, mp 82.5-83.5 °C (from ether). (c) In a manner simUar to that of Example 7(b), the above nitro compound

(0.94 g) gave 0.37 g of 2-(3-aminophenyl)-6-hydroxypyridine, mp 237-239°C (from methanol).

(d) In a manner similar to that of Example 1 , die above amino compound (0.36 g) and 3- amino-4-n-butoxy-3-cyclobutene-l,2-dione (0.32 g) gave 0.46 g of the tide compound, mp 320-322°C dec. (from dimethylformamide).

Example 21 3-Amino-4-[3-(2-imidazolyl)anilino]-3-cyclobutene-l,2-dione

(a) A stirred solution of methyl 3-nitrobenzimidate (7.57 g) and aminoacetaldehyde dimethylacetal (5.57 g) in methanol (20 ml) was heated under reflux for 24 hours. The cool solution was eva ^* porated and die residue treated witii water (9.5 ml) and cone, hydrochloric acid (21 ml). The mixture was heated (steam batii) for 15 minutes and evaporated under reduced pressure. Water (50 ml) was added to the residue and the insoluble soUd filtered and washed with water. The filtrate was neutraUzed with -potassium carbonate solution and die precipitated soUd filtered and washed witii water. The combined soUds were charcoaled and recrystaUised from ethanol to give 3.87 g of 2-(3- nitrophenyl)imidazole, mp 193-194.5°C.

(b) In a manner simUar to that of Example 8(b), die above nitro compound (0.72 g) and stannous chloride dihydrate (4.25 g) gave 0.39 g of 2-(3-aminophenyl)- imidazole, mp 134-135.5°C.

(c) In a manner simUar to mat of Example 1, the above amino compound (0.38 g) and 3-amino-4-n-butoxy-3-cyclobutene-l,2-dione (0.40 g) gave 0.34 g of the tide compound, mp >340°C (from dimediylformamide).

Example 22

3-Amino-4-[6-(4-pyridyl)-2-pyridylamino]-3-cyclobutene-l^ -dione

A stirred solution of 2-amino-6-(4-pyridyl)pyridine (0.34 g) and 3-amino-4-n-butoxy-3- cyclobutene-1 ,2-dione (0.34 g) in pyridine (2 ml) was heated under reflux for 8 hours. The cool mixture was treated with water (15 ml) and die mixture stirred for 1 hour. The soUd was filtered, washed with water, ethanol and ether, charcoaled and recrystaUised from dimethylformamide to give 73 mg of me title compound, mp >340°C.

Example 23

3-[3-(4-Pyridyl)anilino]-3-cyclobutene-l,2-dione

A solution of 4-(3-aminophenyl)pyridine (0.81 g) and 3-n-butoxy-3-cyclobutene-l ,2-dione (0.73 g) in ethanol (20 ml) was stirred at ambient temperature for 15 hours. The resultant precipitated soUd was washed witii methanol and edier and recrystaUised from dimediylformamide to give 0.91 g of the tide compound, mp 252-255.5°C.

Example 24 Pharmaceutical compositions for oral administration are prepared by combining the foUowing :

% w/w 3-Amino-4-[4-(3-pyridyl)]anUino- 3-cyclobutene- 1,2-dione 0.5 3.0 7.14

2% w/w Soya lecithin in soya bean oU 90.45 88.2 84.41

Hydrogenated vegetable shortening and beeswax 9.05 8.8 8.45 The formulations are then filled into individual soft gelatin capsules.

Example 25

A pharmaceutical composition for parenteral administration is prepared by dissolving die title compound of Example 2 (0.02 g) in polyethylene glycol 300 (25 ml) with heating. This solution is then dUuted with water for injections Ph. Eur. (to 100 ml). The solution is tiien sterilised by filtration through a 0.22 micron membrane filter and sealed in sterile containers.