THERAPEUTIC AGENTS

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: IHERAPb I'lC 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 inflaramatory conditions such as asthma and arthritis respectively. Platelet activating factor (PAF) , l-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 13ϊrarriboxane A^ 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 inflaramatory 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 pfevent 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 shewing 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 min 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 SUBSTITUTE SHEET it induces regional shunting and ischaemia. PAF has also been shewn to initiate thrombus formation in a mesentenic artery preparation both when administered exogenously and when released endogenously. Ifore recently PAF has been shewn 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) : (I) wherein A is (CH„) where n is from 2 to 5, or and R is H or a group selected from -C alkyl, hydroxymethyl, (C η -C alkoxy) methyl, C_-C_ cycloalkyl, pyridyl, thienyl, unsubstituted phenyl and phenyl substituted by from one to three substituents each selected from halo, C.-C. alkyl, C -C, alkoxy and CF , and their pharmaceutically acceptable salts. In the definitions given herein the term "halo" means fluoro, chloro, brσmo 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 cxOTpσunds are 4-[4-(2-me1_hyl-i_midazo[4,5-c]pyrid-- : l-yl)phenyl-5,6,7, 8-tetrahydro-imidazo[l,2,3-ij]pyrazolo[3,4-b] [1,4]diazepin-6-one, in which n is 2 and R is phenyl, 2-cyclchexyl-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[l,2-a][l,4]diazep:_n-6-one in which n=4 and R is cyclohexyl, and 2-methyl-4-[4-(2-ιrethyl_uιr dazo- [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 (la) , these forms of the compound being tautαmeric: (la! These compounds and their salts may exist as one tautσmer or a mixture of tautomeric forms, which may be separated by physical methods such as fractional crystallisation or chromatography. The invention includes all the tautσmers whether separated or not. SUBSTITUTE SHEET Cαπpounds 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 iscsners which,may be separated by conventional means. The invention includes all these enantiσmers, 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, irethanesulphonate and dimethanesulphonate, benzenesulphonate and p-toluenesulphonate. The cxjmpσunds of formula (I) may generally be prepared by the following synthesis: (ID (I.< In this synthesis the compound of formula (II) is reacted with 1_riphenylphosphine and diethylazodicarboxylate (DEAD) in a solvent such as tetrahydrofuran and after removal of the solvent the product may be isolated by chrcsnatography. The cαπpσunds of formula (II) may be prepared as follows: OH (III) (IV) (ID ( IIΛ) wherein Q is a leaving group such as C -C alkoxy. 1 4 SUBSTITUTE SHEET In this synthesis aminqpyrazole (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 ccatpound (VI) , for example in the presence of silica gel and a suitable solvent such as toluene, to give the coπpound of formula (II) . In this method a proportion of ccttpound (IIA) is also produced. Alternatively the diaι _nopyrazole 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 tenperature to give cxxπpound (II) . Compounds (II) and (IIA) may be separated by physical methods such as chromatography. In a varient of this synthesis, cσπpσund (IV) is made by the following alternative method: I IV; SUBSTITUTE SHEET In this method tlie appropriate 2-hyd * _-oxyimino acetonitrile derivative is reacted with tlie appropriate hydrazino alcohol, generally by heating in tlie presence of a suitable solvent such as etlianol. Alternatively, the compounds of formula (I) may be made by tle following synthesis: KH (IX) ( (VI SUBSTITUTE SHEET where X is chloro, bromo, or iodo and Q is a leaving group such as C -C alkoxy. Ih this synthesis the halonitropyrazole (VII) is reacted with the appropriate aminoaloohol, for example by autoclaving the reagents in a solvent such * as ethanol, to produce coπpαund (VIII) which is then cyclised by treatment with trip-henylphosphine and diethyl azodicarboxylate. This corrpσund may then be reduced, for example by treatment with hydrazϊne 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 ccstpound 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 dissodium ethylenediamine tetraacetic acid buffer and the samples ceπtrifuged 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 m KH»P0., 6mM Na ^ HPO. , 100 mM v 2 4 2 4' 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 10 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 conteining the particular ccαrpound under test. PAF is added at a sufficient concentration to give a maximum aggregating response in the absence of test coπpound (lc -ε -9 to 10 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 IC,_ n 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 c rpounds 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 PD,__ value. For therapeutic use the ccatpour s of the formula (I) will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of admini_5tration and standard harmaceutical practice. For example, they may be adnunistered 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. SUBSTITUTE SHEET They may be injected parenterally, for example, intravenously, i-ntramuscularly or subcutaneously. For parenteral acύnistration, they are best used in the form of a sterile aqueous solution whic 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 ccsipounds 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 adriiinistration would typically be within the range 1 to 10 irg per single dose as required. For the treatment of allergic and bronchial hyper-reaσtive 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 coirprising a cαrtpou d of the formula (I) , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier. The invention also includes a ccaxpound of the formula (I) , or a pha_πnaceutically acceptable salt thereof, for tase 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. — SUBSTITUTE SHEET EXAMPLE 1 2-***Metoyl-4-r4-(2-methyl_*-midazor4 , 5-c lpyrid-1-yl) phenyl ] - 5,6.7.8-tetrahvdro_ui-iidazori.2.3-ii]pyrazolor3,4-b]ri.41- diazepin-6-one SUBSTITUTE SHEET (a) A solution of sodium nitrite (800 mg, 11.6 mmol) in water (4 ml) was added drαpwise over 30 ittin to a solution of 5-amir_o-l-(2-hydro^ethyl)-3-methylpyrazole (1.41g, 10 mmol) (Bull. Soc. C_him. Fr. , (1975) , 255) in glacial acetic acid (14 ml) and water (10 ml) with ice cooling. The mixture was stirred at 0°C.for lh, and the red precipitate was filtered off and dried in vacuo to give 5-amino-l-(2-hydroxyethyl)-3- ιretoyl-4-nitrosopyrazole (1.2g, 71%). ~~l NMR (300MHz, dmso-d ) 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-l-(2-hydro_-yetoyl)-3-metoyl-4-nitroso pyrazole (902 mg, 5.3 mmol) in ethanol/dichlorcmethane = 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-l- (2-hydrox ethyl)-3-methylpyrazole (800 rog, 97%) as a brown gum. ~Η. NMR (300 MHz, CDC1 3 ) δ = 2.15 (3H, s) , 2.25 (4H, br s) , 3.96 (2H, m) , 4.03 (2H, m) p.p.m. SUBSTITUTE SHEET (c) A mixture of 4 , 5-<_ amino-l-(2-hydroxyethyl) -3-methylpyrazole (800 irg, 5.12 mmol) , ethyl 4 • -(2-metoylimidazo[4 , 5-c]pyrid- l-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/diciilorcsnethane = 1: 3 (200 ml) . The solvents were removed under reduced pressure and the residue was purified by flash chrcstatography (gradient elution with ethyl acetote/methanol/diei^ylamine) . 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 l-(2-hydroxyetoyl) -3-metoyl-5-[4-(2-methyl_lmidazo[4 , 5-cl 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 C 22 H 21 N 7 0 2 ' 3 4H 2 0 rec 3 uireΞ C ' 61 - 58 *- H, 5.28 ; N, 22.85 (d) A mixture of l-(2-hydroxyethyl) -3-methyl-5-[4- (2-methyl imidazo[4,5-c]pyrid-1-yl)phenyl]-1,6,7,8-tøtrahydropyrazolo [3,4-b] [1,4] diazepin-7-one (510 mg, 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 chroπatography eluting with ethyl acetate/iretharol/diethylamine = 94:3:3. The title product was isolated as a white solid (SO g, 12%) , m.p. 282-284°C (front methanol) . Analysis %:- Found C, 66.33; H, 4.88; N, 24.54 C 22 H 19 N 7° rec 3 ui es c ' 66 - 4 9' " H, 4.82; N, 24.67 SUBSTITUTE SHEET EXAMPLE 2 4-T4- f2-Methylimidazor4,5-c]pyrid-l-yl) phenyl 1-2-phenyl- 5,6,7, 8-tetrahydro-imidazo \ 1 , 2 , 3-ij ] pyrazqlo \ 3 , 4-b] \ 1 , 41 diazepin-6-one (a) 2-Hydroxyet_hy_Lhyd_t^ine (760 mg, 10 mmol) was added to a solution of 2-hydroxyi_mi-no-ber_zoylacetonitrile (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, artd the red solid product was filtered off and washed with methanol (10 ml) to give 5-amino-l-(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 C 11 H 12 N 4°2 ***^'3 u * ires C ' 56 - 89 ' * H - 5. 1; N, 24.12 (b) Ey the method of Example 1(b) , 5-amino-l-(2-hyά_roxyethyl)- 4-nitroso-3-phenylpyrazole was reduced to give 4,5-diamino- l-(2-hydroxyethyl)-3-phenylpyrazole (98% yield) as a buff solid. ~ ~ i NMR (dmso-d δ = 3.40 (2H, br s) , 3.65 (2H, m) , 3.92 (2H, b t, J = 5Hz), 4.58 (2H, s) 4.92 (1H, t, J = 4Hz) , 7.17 (_LH, 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-l- (2-hydroxyethyl)-3-phenylpyrazole was condensed with ethyl 4'-(2-methylimidazo[4,5-c]pyrid-1-yl)benzoylacetate to give SUBSTITUTE SHEET 1- (2-hydroxyethyl) -5- [4- (2-methylimidazo[4 , 5-c]pyrid-l-yl) - phenyl] -3-pheπyl-l , 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 C j ^ N 7 0 2 .K^O requires C, 65.42 ; H, 5.08 ; N, 19.78 (d) By the method of Exairple 1(d) , l-(2-hydroxyethyl) -5- [ 4- ( 2-rι_ethylimidazo [ 4 , 5-c] pyrid-1-yl ) phenyl ] -3-phenyl- l, 6,7, 8-tetrahydropyrazolo[3,4-b] [l,4]ά_iazepin-7-one was treated with triphenylphosphine and diethyl azodicarboxylate in dry tetrahydrofuiran to give the title compound (34% yield) , m.p. 277 °C (from methanol) . Analysis %:- Found C, 69.75 ; H, 4.44 ; N, 21.06 C L N 1/4 O requires C, 69.88 ; H, 4.66; N, 21.13 EXAMPIE 3 2-Cvclchexyl-5,6,7,8.9.lO-hexahydro-4-[4-(2-methylimidazo- [4,5****c]pyrid-l-yl)phenyllpyrazolor4.3.2-fαl ri,31diazepinof1,2-a]- [1,4]diazepin-6-one __, (a) 5-<3 loro-3-cyclohe^l-4-rat_π -_lH-pyrazole (U.S. Pat. 4,025,530 (1977)) (3.44g, 15 mmol) and 4-aminobutan-l-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 (lOg, 60-200μ) was added, and the ethanol was removed under reduced pressure. The residue was applied to the top of a c_hromatography column (silica gel 40-60μ) and the product was eluted with ethyl acetate: ethanol (gradient elution) . The product, 3-cyclcΛexyl-5-(4-hydroxybutylamino)- 4-nitro-lH-pyrazole, was obtained as a yellow solid, 2.17g (51%) m.p. 192°C (from ethyl acetate/hexane) . ~ Ε NMR (500 MHz, CDC1 ) δ * = 1.2-2.1 (14H, cαrrplex) , 3.30 (IH, m), 3.50 (2H, ), 3.85 (2H, t, J = 6Hz) , 6.84 (IH, br s) . (b) A mixture of 3* yclohexyl-5-(4-hydroxybutyla_i no)-4-nitro-- IH-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 tenperature 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-cyclchexyl-3-nitro-5,6,7,8-tetrahydro-4H- pyrazolo[2,3-a] [l,3]diazepine was obtained as a yellow solid, 0.85g (42%), m.p. 147-149°C. hi NMR (300 MHz, CDC1 3 ) δ = 1.10-2.00 (14H, m) , 3.10 (IH, m) , 3.20 (2H, m), 4.05 (2H, m) , 7.15 (IH, 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 mmoi) , ' 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-ιtethyl_i_midazo[4,5-c]pyrid-l-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 tenperature. The ethanol was removed under reduced pressure and the residue was issolved in dichloromethane (150 ml) , washed with brine (30 ml) and dried (MgSO.) . The dichloromethane solution was concentrated under reduced pressure and the residue was purified by flash chrcmatography (gradient elution with dichloromethane/ methanol) to give the title coπpound 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 C 29 H 31 N 7°* 3 4H 2° r** ^3 uires C ' 68 - 69 ' " H, 6 - 46 ' " N * 19 - 33 SUBSTITUTE SHEET

Claims: CIAIM5 A cσπpound of formula (I) (I) wherein A is -(G-L) - where n is from 2 to 5, or • ■■■ CH^CH HCH -, and R is H or a group selected from C -C alkyl, hydroxymethyl, (C -C alkoxy) methyl, ~ —C cycloalkyl, pyridyl, thienyl, unsubstituted phenyl and phenyl substituted by from one to three substituents independently selected from halo, C.-C. alkyl, C.-C. alkoxy and -CF3, or a pharmaceutically acceptable salt thereof. A coirpound according to claim 1, in which R is methyl, phenyl or cyclohexyl. 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. 2-Cyclohexyl-5,6,7,8,9,lO-hexahydro-4-[4-(2-methyl imidazo [4,5-c]pyrid-l-yl)phenyl]pyrazolo[4,3,2-fg] [1,3]diazepino [1,2-a] [l,4]diazepin-6-one. 2-Methyl-4-[4-(2-methylimidazo[4,5-c]pyrid-l-yl)phenyl]- 5,6,7,8-tetxahydroimidazo[l,2,3-ij]pyrazolo[3,4-b] [1,4]- diazepin-6-one. 6. A composition coπprising a coitpound according to any preceding claim or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier or excipient. A cσrrpound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, for use in medicine. Use of a coitpound 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 coitpound of formula (I) : (i) wherein A is -(C3_L) - where n is from 2 to 5, or -CH_CH=CHCH_-, and R is H or a group selected from C.-C, zi. -L 6 alkyl, hydroxymethyl, (C.-C. alkoxy) methyl, C -C cycloalkyl, pyridyl, thienyl, unsubstituted phenyl and phenyl substituted by from one to three substituents independently .selected from halo, C -C alkyl, C -C alkoxy and -CF3, or a pharmaceutically acceptable salt thereof which comprises cyclising a coitpound of formula (II) : (I D 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 coitpound of formula (II) is cyclised by reaction with triphenylphosphine and diethylazodicarboxylate. 11. A method according to claim 9 or 10, in which the coitpound 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, v iich comprises allowing compounds (X) and (VI) to react together: wherein A.and R are as defined for formula (I) and is a leaving group, and if necessary forming a salt thereof. 13. A method according to claim 12, in which the coitpound of formula (X) is made by cyclising a cσπpound of formula (VIII) to form a cαtpound of formula (IX) and reducing the cαmpσund of formula (IX) R and A being as defined for formula (I)

Inventors: COOPER KELVIN, FRAY MICHAEL JONATHAN, COOPER, KELVIN, FRAY, MICHAEL, JONATHAN
Applicants: PFIZER, PFIZER LTD, PFIZER INC., PFIZER LIMITED
Application year: 1991
Main classification: C07D487
IPC codes: A61K31, A61P7, C07D519