WO1992004349A1

WO1992004349A1 - Therapeutic agents

Info

Publication number: WO1992004349A1
Application number: PCT/EP1991/001669
Authority: WO
Inventors: Kelvin Cooper; Michael Jonathan Fray
Original assignee: Pfizer Limited; Pfizer Inc.
Priority date: 1990-09-11
Filing date: 1991-09-02
Publication date: 1992-03-19
Also published as: GB9019833D0; IE913167A1; FI931071A0; JPH06500108A; EP0551291A1; PT98902A; FI931071L; CA2088777A1

Abstract

Platelet activating factor antagonists of formula (I), wherein A is -(CH2)n- where n is from 2 to 5, or -CH2CH=CHCH2-, and R is H or a group selected from C1-C6 alkyl, hydroxymethyl, (C1-C4 alkoxy) methyl, C3-C7 cycloalkyl, pyridyl, thienyl, unsubstituted phenyl and phenyl substituted by from one to three substituents independently selected from halo, C1-C4 alkyl, C1-C4 alkoxy and -CF3, or a pharmaceutically acceptable salt thereof.

Description

THERAPEUTlC AGENTS

This invention relates to diazepine derivatives which are potent, orally active antagonists of platelet activating factor and as such have clinical utility for treating allergic and inflammatory conditions such as asthma and arthritis respectively.

Platelet activating factor (PAF), 1-0-alkyl-2-acetyl-sn- glyceryl-3-phosphorylcholine is an ether phospholipid whose structure was first elucidated in 1979. It is produced by, released from and interacts with many pro-inflammatory cells, platelets and the kidney. In addition to potent platelet aggregating activity, PAF exhibits a wide spectrum of biological activities elicited either directly or via the release of other powerful mediators such as thromboxane A₂ or the leukotrienes. In vitro, PAF stimulates the movement and aggregation of neutrophils and the release therefrom of tissue-damaging enzymes and oxygen radicals. These activities contribute to actions of PAF in vivo consistent with it playing a significant role in inflammatory and allergic responses. Thus, intradermal PAF has been shown to induce an inflammatory response, with associated pain,

accumulation of inflammatory cells and increased vascular

permeability, comparable with the allergic skin reaction following exposure to allergen. Similarly, both the acute broncho- constriction and chronic inflammatory reactions elicited by allergens in asthma can be mimicked by intratracheal administration of PAF. Accordingly agents which antagonise the actions of PAF and, consequently also prevent mediator release by PAF, will have clinical utility in the treatment of a variety of allergic and inflammatory conditions such as asthma and arthritis, respectively.

In addition to the above, PAF has been implicated as being involved in a number of other medical conditions. Thus in circulatory shock, which is characterised by systemic hypotension, pulmonary hypertension and increased lung vascular permeability, the symptoms can be mimicked by infusion of PAF. This coupled with evidence showing that circulating PAF levels are increased by endotoxin infusion indicate that PAF is a prime mediator in certain forms of shock. Intravenous infusion of PAF at doses of 20-200 pmol kg^-1 min^-1 into rats results in the formation of extensive haemorrhagic erosions in the gastric mucosa and thus PAF is the most potent gastric ulcerogen yet described whose

endogenous release may underlie or contribute to certain forms of gastric ulceration. Psoriasis is an inflammatory and

proliferative disease characterised by skin lesions. PAF is pro-inflammatory and has been isolated from lesioned scale of psoriatic patients indicating PAF has a role in the disease of psoriasis. And finally, increasing evidence supports a potential pathophysiological role for PAF in cardiovascular disease. Thus recent studies in angina patients show PAF is released during atrial pacing and, in pigs, intracoronary injection of PAF induces a prolonged decrease in coronary flow while in guinea pig hearts it induces regional shunting and ischaemia. PAF has also been shown to initiate thrombus formation in a mesentenic artery preparation both when administered exogenously and when released endogenously. Ifore recently PAF has been shown to play a role in brain ischaemia induced in animal models of stroke.

Thus compounds of the invention, by virtue of their ability to antagonise the actions of PAF, could well be of value in the treatment of any of the above conditions.

According to the invention, there are provided compounds of formula (I):

wherein A is (CH₂)_n where n is from 2 to 5, or CH₂CH=CHCH₂, and R is H or a group selected from C ₁-C₆ alkyl, hydroxymethyl, (C ₁-C₄ alkoxy) methyl, C ₃-C₇ cycloalkyl, pyridyl, thienyl, unsubstituted phenyl and phenyl substituted by from one to three substituents each selected from halo, C ₁-C₄ alkyl, C ₁-C₄ alkoxy and CF₃, and their pharmaceutically acceptable salts. In the definitions given herein the term "halo" means fluoro, chloro, bromo or iodo. Alkyl and alkoxy groups of 3 or more carbon atoms may be straight or branched-chain.

Examples of R are methyl, phenyl and cyclohexyl. Preferred compounds are 4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl-5,6,7, 8-tetrahydro-imidazo[1,2,3-ij]pyrazolo[3,4-b][1,4]diazepin-6-one, in which n is 2 and R is phenyl, 2-cyclohexyl-5,6,7,8,9,10- hexahydro-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]pyrazolo- [4,3,2-fg][l,3]diazepino[1,2-a][1,4]diazepin-6-one in which n=4 and R is cyclohexyl, and 2-methyl-4-[4-(2-methylimidazo- [4,5-c]pyrid-1-yl)phenyl]-5,6,7,8-tetrahydroimidazo[1,2,3-ij]- pyrazolo[3,4-b][1,4]-diazepin-6-one, in which n is 2 and R is methyl.

It will be appreciated that formula (I) may be written alternatively as formula (Ia), these forms of the compound being tautomeric:

These compounds and their salts may exist as one tautomer or a mixture of tautomeric forms, which may be separated by physical methods such as fractional crystallisation or chromatography. The invention includes all the tautomers whether separated or not. Compounds in which R comprises a branched hydrocarbon chain of 4 or more carbon atoms may contain a chiral centre and therefore exist as a pair of isomers which may be separated by conventional means. The invention includes all these enantiomers, whether separated or not.

The pharmaceutically acceptable salts of the compounds of formula (I) are those formed from acids which form non-toxic addition salts, for example the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate, tartrate, methanesulphonate and dimethanesulphonate,

benzenesulphonate and p-toluenesulphonate.

The compounds of formula (I) may generally be prepared by the following synthesis:

In this synthesis the compound of formula (II) is reacted with triphenylphosphine and diethylazodicarboxylate (DEAD) in a solvent such as tetrahydrofuran and after removal of the solvent the product may be isolated by chromatography. The compounds of formula (II) may be prepared as follows:

wherein Q is a leaving group such as C ₁-C₄ alkoxy. In this synthesis aminopyrazole (III) is reacted with a nitrite, for example sodium nitrite in the presence of acetic acid, to yield the nitrosopyrazole (IV) which is then reduced with hydrogen, generally in the presence of a catalyst such as palladium on carbon, to produce the diaminopyrazole (V).

The diaminopyrazole is then reacted with co mpound (VI), for example in the presence of silica gel and a suitable solvent such as toluene, to give the compound of formula (II). In this method a proportion of compound (IIA) is also produced. Alternatively the diaminopyrazole is reacted with compound (VI) in the presence of a catalytic quantity of zinc chloride in ethanol, preferably under reflux for 24 hours, followed by treatment of the cooled solution with sodium hydride at room temperature to give compound (II). Compounds (II) and (IIA) may be separated by physical methods such as chromatography.

In a varient of this synthesis, compound (IV) is made by the following alternative method:

In this method the appropriate 2-hydroxyimino acetonitrile derivative is reacted with the appropriate hydrazino alcohol, generally by heating in the presence of a suitable solvent such as ethanol.

Alternatively, the compounds of formula (I) may be made by the following synthesis:

where X is chloro, bromo, or iodo and Q is a leaving group such as

C₁-C₄ alkoxy. Ih this synthesis the halonitropyrazole (VII) is reacted with the appropriate aminoalcohol, for example by autoclaving the reagents in a solvent such as ethanol, to produce compound (VIII) which is then cyclised by treatment with

trip-henylphosphine and diethyl azodicarboxylate. This compound may then be reduced, for example by treatment with hydrazine and

Raney nickel, to produce amino derivative (X) which is then reacted with ketoester (VI), preferably in the presence of a zinc chloride catalyst followed by treatment with a base such as sodium hydride, to yield the compound of formula (I). This compound may be separated from other reaction products formed by

chromatography.

The activity of the compounds of the invention is shown by their ability to inhibit the platelet aggregating activity of PAF in vitro. Testing is performed as follows:

Blood samples are taken from either rabbit or man into 0.1 vol disodium ethylenediamine tetraacetic acid buffer and the samples centrifuged for 15 minutes to obtain platelet rich plasma.

The plasma is further centrifuged to give a platelet pellet which is washed with a buffer solution (4 mM KH₂PO₄, 6mM Na₂HPO₄, 100 mM

NaCl, 0.1% glucose and 0.1% bovine serum albumin, pH 7.25) and finally resuspended in buffer solution to a concentration of 2 x 10⁸ platelets/ml. A sample (0.5 ml) is pre-incubated for two minutes at 37°C in a Paton aggregαmeter with stirring, either with vehicle alone, or with vehicle containing the particular compound under test. PAF is added at a sufficient concentration to give a maximum aggregating response in the absence of test compound (10^-8 to 10^-9 molar), and the platelet aggregation is measured by following the increase in light transmission of the solution. The experiment is repeated in the presence of test compound at a range of concentrations and the concentration of compound required to reduce the response to 50% of its maximum value is recorded as the

IC₅₀ value.

The activity of the compounds of formula (I) is also demonstrated in vivo by their ability to protect mice from the lethal effect of an injection of PAF. A mixture of PAF (50 μg/kg) and DL-propranolol (5 mg/kg) in 0.9% w/v sodium chloride is injected (0.2 ml) via a tail vein into mice. The compounds under test are either injected into the tail vein immediately prior to the PAF/propranolol injection or administered orally by gavage two hours earlier. The compounds are tested at several doses in groups of 5 mice and the dose which reduces mortality to 50% is recorded as the PD₅₀ value.

For therapeutic use the compounds of the formula (I) will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of

administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.

For administration to man in the curative or prophylactic treatment of allergic bronchial conditions and arthritis, oral dosages of the compounds will generally be in the range of from 2-1000 mg daily for an average adult patient (70 kg). Thus for a typical adult patient, individual tablets or capsules contain from 1 to 500 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous

administration would typically be within the range 1 to 10 mg per single dose as required. For the treatment of allergic and bronchial hyper-reactive conditions, inhalation via a nebuliser or aerosol may be the preferred route of drug administration. Dose levels by this route would be within the range 0.1 to 50 mg per single dose as required. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

Thus in a further aspect the invention provides a

pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier. The invention also includes a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use in medicine, in particular in the treatment of allergic and inflammatory conditions in a human being.

The preparation of the compounds of the invention is further illustrated by the following Examples.

EXAMPLE 1

2-Methyl-4-[4-(2-methyli-midazo[4,5-c]pyrid-1-yl)phenyl]- 5,6,7,8-tetrahydroimidazo[1,2,3-ij]pyrazolo[3,4-b][1,4]- diazepin-6-one

(a) A solution of sodium nitrite (800 mg, 11.6 mmol) in water

(4 ml) was added dropwise over 30 min to a solution of 5-amino-1-(2-hydroxyethyl)-3-methylpyrazole (1.41g, 10 mmol) (Bull. Soc. Chim. Fr., (1975), 255) in glacial acetic acid (14 ml) and water (10 ml) with ice cooling. The mixture was stirred at 0°C for 1h, and the red precipitate was filtered off and dried in vacuo to give 5-amino-1-(2-hydroxyethyl)-3- methyl-4-nitrosopyrazole (1.2g, 71%).

¹ H NMR (300MHz, dmso-d ₆) δ = 2.51 (3H, s), 3.30 (2H, br s), 3.62 (2H, t, J = 4Hz), 3.85 (2H, t, J = 4Hz) p.p.m.

(b) A solution of 5-amino-1-(2-hydroxyetoyl)-3-metoyl-4-nitroso pyrazole (902 mg, 5.3 mmol) in ethanol/dichloromethane = 1:1 (80 ml) was hydrogenated over 10% palladium on charcoal (100 mg) at 20 p.s.i. and 20°C for 2h. The catalyst was filtered off losing Arbocel filter aid, and the filtrate was concentrated under reduced pressure to give 4,5-diamino-1- (2-hydroxvethyl)-3-methylpyrazole (800 mg, 97%) as a brown gum.

¹Η NMR (300 MHz, CDCl₃) δ = 2.15 (3H, s), 2.25 (4H, br s), 3.96 (2H, m), 4.03 (2H, m) p.p.m. (c) A mixture of 4,5- damino-1-(2-hydroxyethyl)-3-methylpyrazole (800 mg, 5.12 mmol), ethyl 4'-(2-metoylimidazo[4,5-c]pyrid- 1-yl)benzoylacetate (1.60 g, 5.6 mmol), silica gel (40-60μ, 0.5 g) and toluene (25 ml) was heated under reflux for 16h. The toluene was removed under reduced pressure and the product extracted into methanol/dichloromethane = 1:3 (200 ml). The solvents were removed under reduced pressure and the residue was purified by flash chromatography

(gradient elution with ethyl acetote/methanol/dieithylamine). The fractions containing the product with Rf = 0.17 (ethyl acetate/methanol = 3:1) were combined and concentrated, and the residue was recrystallised from methanol to give

1-(2-hydroxyethyl)-3-metoyl-5-[4-(2-methylimidazo[4,5-c] pyrid-1-yl)phenyl]-1,6,7,8-tetrahydropyrazolo[3,4-b][1,4] diazepin-7-one (480 mg, 23%) as a yellow solid, m.p.

238-240°C.

Analysis %:-

Found C, 61.56; H, 5.37; N, 22.83

C₂₂H₂₁N₇O₂.3//4H₂O requires C, 61.58; H, 5.28; N, 22.85

(d) A mixture of 1-(2-hydroxyethyl)-3-methyl-5-[4-(2-methyl

imidazo[4,5-c]pyrid-1-yl)phenyl]-1,6,7,8-tetrahydropyrazolo [3,4-b][1,4] diazepin-7-one (510mg, 1.23 mmol),

triphenylphosphine (386 mg, 1.47 mmol) and diethyl

azodicarboxylate (257 mg, 1.47 mmol) in dry tetrahydrofuran (25ml) was stirred at room temperature under nitrogen for 16h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with ethyl acetate/methanol/diethylamine = 94:3:3. The title product was isolated as a white solid (60 mg, 12%), m.p. 282-284°C (from methanol).

Analysis %:-

Found C, 66.33; H, 4.88; N, 24.54

C₂₂H₁₉N₇O recquires C, 66.49; H, 4.82; N, 24.67

EXAMPLE 2

4-[4-(2-Methylimidazo[4,5-c]pyrid-1-yl)phenyl]-2-phenyl- 5,6,7,8-tetrahydro-imidazo[1,2,3-ij]pyrazolo[3,4-b][1,4] diazepin-6-one

(a) 2-Hydroxyethylhydrazine (760 mg, 10 mmol) was added to a solution of 2-hydroxyimino-benzoylacetonitrile (1.74 g,

10 mmol) (Ger. Offen. 2,722,416 (1978)) in ethanol (15 ml) and the resulting solution was heated at reflux for 16h. The mixture was concentrated under reduced pressure to about 5 ml, and the red solid product was filtered off and washed with methanol (10 ml) to give 5-amino-1-(2-hydroxyethyl)- 4-nitroso-3-phenylpyrazole (740 mg, 32%), m.p. 193-197°C.

Analysis %:-

Found C, 56.88; H, 5.17; N, 23.90

requires

C₁₁H₁₂N₄O₂ C, 56-89; H, 5.21; N, 24.12

(b) By the method of Example 1(b), 5-amino-1-(2-hydroxyethyl)- 4-nitroso-3-phenylpyrazole was reduced to give 4,5-diamino- 1-(2-hydroxyethyl)-3-phenylpyrazole (98% yield) as a buff solid.

¹ H NMR (dmso-d₆) δ = 3.40 (2H, br s), 3.65 (2H, m), 3.92 (2H, t, J = 5Hz), 4.58 (2H, s) 4.92 (1H, t, J = 4Hz) , 7.17 (1H, t, J = 5Hz), 7.31 (2H, t, J = 5Hz), 7.82 (2H, d, J = 5Hz) p.p.m.

(c) By the method of Example 1(c), 4,5-diamino-1- (2-hydroxyethyl)-3-phenylpyrazole was condensed with ethyl 4'-(2-methylimidazo[4,5-c]pyrid-1-yl)benzoylacetate to give 1-(2-hydroxyethyl)-5-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)- phenyl]-3-phenyl-1,6,7,8-tetrahydropyrazolo[3,4-b][1,4]- diazepin-7-one (39% yield), m.p. 185-190°C (from methanol).

Analysis %:-

Found C, 65.29; H, 4.90; N, 19.53

C₂₇H₂₃N₇O₂.H₂O requires C, 65.42; H, 5.08; N, 19.78

(d) By the method of Example 1(d), 1-(2-hydroxyethyl)-5- [4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-3-phenyl- 1,6,7,8-tetrahydropyrazolo[3,4-b][1,4]diazepin-7-one was treated with triphenylphosphine and diethyl azodicarboxylate in dry tetrahydrofuran to give the title compound (34% yield), m.p. 277°C (from methanol).

Analysis %:-

Found C, 69.75; H, 4.44; N, 21.06

C₂₇H₂₁N₇1/4H₂O requires C, 69.88; H, 4.66; N, 21.13

EXAMPLE 3

2-Cyclohexyl-5,6,7,8,9,10-hexahydro-4-[4-(2-methylimidazo- [4 ,5-c]pyrid-1-yl)phenyl]pyrazolo[4,3,2-fg][1,3]diazepino[1,2-a]- [1,4]diazepin-6-one

(a) 5-Ch loro-3-cyclohexyl-4-nitro -1H-pyrazole (U.S. Pat.

4,025,530 (1977)) (3.44g, 15 mmol) and 4-aminobutan-1-ol (6.90 ml, 75 mmol) were dissolved in ethanol and then heated in an autoclave at 100°C for 8h. The mixture was cooled, silica gel (10g, 60-200μ) was added, and the ethanol was removed under reduced pressure. The residue was applied to the top of a chromatography column (silica gel 40-60μ) and the product was eluted with ethyl acetate:methanol (gradient elution). The product, 3-cyclohexyl-5-(4-hydroxybutylamino)- 4-nitro-1H-pyrazole, was obtained as a yellow solid, 2.17g (51%) m.p. 192°C (from ethyl acetate/hexane).

¹H NMR (500 MHz, CDCl₃) δ = 1.2-2.1 (14H, complex), 3.30 (1H, m), 3.50 (2H, m), 3.85 (2H, t, J = 6Hz), 6.84 (1H, br s).

(b) A mixture of 3-cyclohexyl-5-(4-hydroxybutylamino)-4-nitro- 1H-pyrazole (2.17g, 7.7 mmol), diethyl azodicarboxylate (1.70 ml, 10.8 mmol) and triphenylphosphine (2.85g,

10.8 mmol) in dry tetrahydrofuran (50 ml) was stirred under nitrogen at room temperature for 2h. The solvent was removed under reduced pressure and the residue purified by flash chromatography (gradient elution with hexane/ethyl acetate). The product, 2-cyclohexyl-3-nitro-5,6,7,8-tetrahydro-4H- pyrazolo[2,3-a][1,3]diazepine was obtained as a yellow solid, 0.85g (42%), m.p. 147-149°C. ¹H NMR (300 MHz, CDCl₃) δ = 1.10-2.00 (14H, m), 3.10 (1H, m), 3.20 (2H, m), 4.05 (2H, m), 7.15 (1H, br s).

(c) A mixture of 2-cyclohexyl-3-nitro-5,6,7,8-tetrahydro-4H- pyrazolo[2, 3-a]diazepine (0.66g, 2.5 mmol), hydrazine hydrate (1ml) and Raney nickel (200 mg) in ethanol (20 ml) was heated at 50°C under nitrogen for 2h. The mixture was cooled and filtered through Arbocel filter aid under a nitrogen atmosphere. The filtrate was concentrated under reduced pressure to give an unstable brown gum, which was immediately dissolved in fresh ethanol (20 ml). Ethyl

4'-(2-methylimidazo[4,5-c]pyrid-1-yl)benzoylacetate (840 mg, 2.6 mmol) and anhydrous zinc chloride (136 mg, 1.0 mmol) were added, and the mixture was heated at reflux under nitrogen for 17h. The mixture was cooled and sodium hydride (217 mg, 60% dispersion in oil, 5.4 mmol) was added and the mixture was stirred for 3h at room temperature. The ethanol was removed under reduced pressure and the residue was dissolved in dichloromethane (150 ml), washed with brine (30 ml) and dried (MgSO₄). The dichloromethane solution was concentrated under reduced pressure and the residue was purified by flash chromatography (gradient elution with dichloromethane/ methanol) to give the title compound as a white solid, 806 mg (65%), m.p. 206-207°C (from dichloromethane/methanol).

Analysis %:-

Found C, 68.63; H, 6.24; N, 18.76

C₂₉H₃₁N₇O.3/ 4H₂O requires C, 68.69 ; H, 6.46; N, 19.33

Claims

CLAIMS 1. A compound of formula (I)

wherein A is -(G-L) - where n is from 2 to 5, or

-CH₂CH-CHCH₂-, and R is H or a group selected from C₁-C₆ alkyl, hydroxymethyl, (C₁-C₄ alkoxy) methyl, C₃-C₇

cycloalkyl, pyridyl, thienyl, unsubstituted phenyl and phenyl substituted by from one to three substituents independently selected from halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and -CF3, or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, in which R is methyl, phenyl or cyclohexyl.

3. 4-[4-(2-Methylimidazo[4,5-c]pyrid-1-yl)phenyl-5,6,7,8- tetrahydro-imidazo[1,2,3-ij]pyrazolo[3,4-b][1,4]diazepin-

6-one.

4. 2-Cyclohexyl-5,6,7,8,9,10-hexahydro-4-[4-(2-methyl imidazo

[4,5-c]pyrid-1-yl)phenyl]pyrazolo[4,3,2-fg][1,3]diazepino

[1,2-a][1,4]diazepin-6-one.

5. 2-Methyl-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-

5,6,7,8-tetrahydroimidazo[1,2,3-ij]pyrazolo[3,4-b][1,4]- diazepin-6-one.

6. A composition comprising a compound according to any preceding claim or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier or excipient.

7. A compound according to any one of claims 1 to 5 or a

pharmaceutically acceptable salt thereof, for use in medicine.

8. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for making a medicament for antagonising platelet activating factor.

9. A method for making a compound of formula (I):

wherein A is -(CH₂)_n- where n is from 2 to 5, or

-CH₂CH=CHCH₂-, and R is H or a group selected from C₁-C₆ alkyl, hydroxymethyl, (C₁-C₄ alkoxy) methyl, C₃-C₇

cycloalkyl, pyridyl, thienyl, unsubstituted phenyl and phenyl substituted by from one to three substituents independently selected from halo, C₁-C₄alkyl, C₁-C₄ alkoxy and -CF3, or a pharmaceutically acceptable salt thereof which comprises cyclising a compound of formula (II):

wherein A and R are as defined for formula (I) and if necessary forming a salt thereof.

10. A method according to claim 9, in which the compound of

formula (II) is cyclised by reaction with triphenylphosphine and diethylazodicarboxylate.

11. A method according to claim 9 or 10, in which the compound of formula (II) is made by reaction of compounds (V) and (VI):

wherein A and R are as defined for formula (I) and Q is a leaving group.

12. A method of making a compound of formula (I) as defined in claim 9, or a pharmaceutically acceptable salt thereof, which comprises allowing compounds (X) and (VI) to react together:

wherein A and R are as defined for formula (I) and Q is a leaving group, and if necessary forming a salt thereof.

13. A method according to claim 12, in which the compound of

formula (X) is made by cyclising a compound of formula (VIII) to form a compound of formula (IX) and reducing the compound of formula (IX)

R and A being as defined for formula (I) .