CA2091057A1 - Substituted 6,7-dihydroimidazo(1,5,4-ef) (1,5) benzodiazepin-6-ones, their preparation and pharmaceutical compositions - Google Patents

Abstract

Platelet activating factor antagonists of formula (I), wherein R1 is H or C1-C4 alkyl optionally substituted by a substituent selected from phenyl, halophenyl, pyridyl, (C1-C4 alkoxy) carbonyl and di-(C1-C4 alkyl) amino, or is C2-C4 alkyl substituted by hydroxyl or by one ore two C1-C4 alkoxy groups or is (CH2)nCONR7R8 where n is an integer from 1 to 4 and R7 and R8 are each independently H or C1-C4 alkyl, R2 is selected from H, OH and C1-C4 alkyl, R3 is selected from halo and C1-C4 alkyl, R4 is methyl, and p is an integer from 0 to 3 and m is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof.

Description

W ~ 92/04354 PCT/EP91/01671 2 ~ 7 .

SUBSTITUTED 6;7-DIHYDROIMIDAZO(1,5,4-EF)t1,5) BENZODIA~EPIN-6-ONES, THEIR PREPARATION AND
PHARMACEUTICAL COMPOSITIONS
.
Ihis ir~ention relates to diazepine derivatives which are potent, orally active antagonists of platelet activating factor and as such have clini~l utility for treating allergic and inflam~atory conditicns such as asthma and arthritis r~spectively.
Platelet activating factor (PAF, 1-0-aLky1-2-a oetyl-sn-glyceIyl-3-phosphorylcholine) is an ether phospholipid whose structure was first elucidated in 1979. It is produced by, released from ar~ interacts with ~any pro-inflammatory cells, platelets ar~ the kidney. In addition ~o 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 thrcmboKane A~ or the leukotrienes. In vitro, PAF stimLlates the n~v~ment and ag~regation of neutrcphils ~`1 .
~l and the release therefrom of ti~le-damaging enzymes and oxygen 5j ~ radicals. Thcsc activities contribute to actions of PAF n v o ,: .. .
~ consistent with it playing a significant role in inflammatory and ,. . . .
allergic responses. Thus, intradermal PAF has been shc~n to .~ , i~ ino~ce an inflamm~tcry resFonse, with associated pain, ~ accumulation of inflammatory cells and incsr3sed vasc~lar ;.......................................................................... .
~ permeability, comparable with the allergic skin reaction follcwing .~ , i~ exposure to allergen. Slmilarly, both the acute broncho-c~nstriction and chronic inflam~atory reactions elicited by allergens in asthma can be mumiched by intratracheal , ;~
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administzation of PAF. Accor~ingly agenks 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 mvolved in a number of other medical ccn~itions. Thus in circulatory shock, wkich is characterised by systemic hypotension, pulmonary hypertension and Lncre3sed lung vascular permeability, the symptcms can be ~;m;cked by infusion of PAF. This coupled with evidence showing that circulating PAF levels are Lncreased 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 l min l into rats results in the formation of extensive haemorrhagic erosions in the gastric mucosa and thus PAF
is the ~st pckent gastric ulcerogen yet described whoee endogenous rele~se may underlie or contribute to certain forms of gastric ulceration. Psoriasis is an inflammatory and ~ -proliferative disease characteriised by skin lesions. PAF is ~' pro-inflammatory and has been isolated fram lesioned scale of ' ' ;:
psoriatic patients indicating PAF has a role in the disease of ~ -psoriasis. And finally, increasing evidence supports a pote~tial I pathophysiological role for PAF in cardiovascular disease. Thus -i; recent studies in angLna patients shcw PAF is released dUrLng atrial pacing and, in pigs, mtracoronary injection of PAF induces a prolonyed decrease in coronary flow while in guinea pig hearts ., ~ .
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it induces regional shunting and ischaemia. PAF has also been shown to initiate thrombus formation in a mesentenic artery preparation both when administered exogencusly and when released endogenously. More recently PAF has been shown to play a role in brain ischaemia induced m anim21 mcdels of stroke.
Thus cnnFx~nds of the invention, by vir~ e of their ability to antagoni æ the actions of PAF, could well be of value in the treatment of any of the above conditions.
` In Eurcpean Patent Application No. 0258033 we disclose a series of 2-substituted 1,4-dihydr3pyridine derivatives as PAF
antagonists. In European Patent Application 03lO386 we disclose a further series of dihydrcpyridine PAF antagonists in which the - 2-position substituent may be a 2-methyl-imidazo~4~5-c]
pyrid-l-phenyl group.
According to the present m vention, there are provided ~
nompcurds of formula (I): -, i -.
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,,~ 1 ( R ) p~ N ~ ~ I ) G ~ R ) m~

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~ . :

:

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W O 92/043~ 7 P ~ /EP91/01671 wherein Rl is either H or Cl-C4 alkyl optionally substituted by a substituent selected frc~ phenyl, halophenyl, pyridyl, ( 1 4 alkoxy) carbonyl and di-(Cl-~4 c~lkyl) c~mm o, or C2-C4 iLkyl substituted by hydroxyl or by one or two C~-C4 aIkoxy grcups or is (CH2)nCCNR7R where n is an `~ integer from 1 to 4 and R7 and R8 are each independently ~.
H or Cl-C4 al~yl, and R is selec~ frcm H, OH c~nd ~: Cl-C4 alkyl; R is selected from h~o or Cl-C4 c~lkyl; R4 is methyl; p is 0-3 and m is 0-3; and their pharmaceutically ac~ptable salts.

Examples of R1 are H, ~ and ethoxy~arbo~ylmethyl. R2 may be sele~ted fram H, ~;~1 and ~ . Particularly preferred compcunds are 7-methyl-4-[4-~2-methyllmidazo~4,5-c]pyrid-1-yl)phe~y~]-6,7-dihydroimiP~zo[1,5,4_ef][1,5]benz~Jdiazepinr6-one, in which Rl -.
is '~ and R2 is H an~ m and p are 0; and 4-[4-(2-~ thylimidaæo-[4,5-c]pyrid-}-yl)phenyl]-7-e~Dc-v~bcnvl~e~yl-6,7-droimidazo[l,5,4-ef][l,5] ken20diazepin-6-one, in which Rl is ethoxycarbon~l methyl and R2 is H and m and p are 0.
.~ When R2 is O~I formula (I) may alternatively be wrltten as for~la (Ia), these forms of the can~ound be~ng taut~meric.
R I O

(R ~1~ N~N (I' )1~ 3 ~ ~;

)m~) (R )m~
. ~:
( 1 ) ( I a ) ,s~

; W ~ 92/04354 % ~ 7 PCT/EP91/01671 . ,,, -.

Such ccmpcu=ds and their salts may exist as one tautcmer or as a mix*Nre of tautLmers, which may generally be sPparated by physical means such as fractional crystallisation or chromatography. The invention includes all tautcmers whether separated or not.
When at least one of Rl, R or R ccmprises a branched alkyl or alkoxy group having 4 carbon atcms the ccmpcund may contain a chiral oe ntre and exist as a pair of isomers which may be s~parated by conventional means. The invention includes all such enantiomRrs, whether separated or not.

.

~ he pharmaoe utically accepkable salts of ~he CC~FXDGdS of formula (I) are those formed f mm acids which form non-toxic : addition salts, for example the hydrochloride, hydr~bm mide, sul p ate or bisulphate, phosphate or acid p osphate, acetate, . citrate, fu~arate, gluconate, lactate, maleate, succinate, ~i tartrate, metlun,rsulphonate and di~eth~nY-sulphonate, benzenesulphonate and E-toluenesulphonate.
l 2 hen R is H and R is H or Cl-C4 aIkyl the C1 mpounds of formula (I) may be made by the following method.
. : .
; ,~
.~
H

~3) ~ ~ (n )1~ Cl!~

R2CO 11 (R )m~ /

W O 92/043 ~ 7 PCT/EP91/01671 In this method 6-amlnc-4-[4-(2-~ethylimiclazo[4,5-c]pyrid-l-yl)phenyl][1,5]benzodiazepin-4-one (soe Preparation), or the derivative thereof containing the appropriate substituQnts R3 and R4 (compound II) reacts with an orthoester of the appropriate carboxylic acid in the presence of that acicl and compound (I) may be isolated by conventional means. :
The compcund (I) in which R2 is OH may be ~ade fr~m compound (II) by reaction of the latter with trichloromethyl chloroformate in 1,2-dichlor~ethane as a solvent.
Ccmpcunds of formLla (I) in which Rl is cpkionally substituted aIkyl may be prepared from the corresponc~i~g compcunds in which Rl .is H by reaction of the latter with co~pound Rl-X when X is chloro, br~.~ or iodo. The r~actiQn is generally conducted in the prei~ence of a base such as sodium hydride.
~ Ihe activity of the compourds of the inven~ion i5 shown by - their ability to inhibit the platelet aggregating activity of PAF
i,, .
; in vitro. Testing is performed-as follcws:
~!i Blcod samples are taken frcm either rabbit or man mto o.l vol disodium ethylenediaminei tetraa oe tic acid buffer and the samples centrifuged for 15 minutes to obtain platelet rich plasma.
The plasma is further oentrlf~ged to give a platelet pellet which .is wa~hed with a buffer solution (4 mM KH2PO4, 6mM Na2HP04, l00 mM
. NaCl, 0.l~ glucose and-0.l~ bovine serum al~umin, pH 7.25) and finally resusperded in buffer solution to a concentration of 2 x l08 platelets/ml. A sa~ple (0.5 ml) is pre-incubated for two ~ mdnLtes at 37 C in a Paton aggregometer with stirring, either with `-! vehicle alone, or with vehicle containing the parti~1ar compclnd ,.i , :

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W ~ 92/04354 ~ ,5 7 PCT/EP91/01671 :`

under test. PAF is added at a sufficient concentration to give a maximum aggregatLng response in the absence of test compound (lO 8 to lO 9 molar), and the platelet aggregation is measured by following the increase in light transmussion of the solution. The experLm2nt is repeated in the presence of tes~ ccmpound at a range of concentrations and the concentration of ~x~und required to ; reduce the response to 50% of its maxImum value is recorded as the IC50 v2lue.
The activity of the ccmpoun~s of formLla (I~ is also - demonstrated in vivo by their ability to protect mice from the lethal effect of an injecti~n of PAF. A mixture of PAF (50 ~g/kg) and DLrpropranolol (5 mg/kg) in 0.9~ w/v sodium chloride is -; injected (0.2 ml) via a tail vein into mioe. The crmpounds under ,; , .
s~ test are either injected into the tail vein immediately prior to ; the PAF/propranolol injection or adm misterel orally by gavage two hours earlier. Ihe o~pcunos are tested at several doses in gro~ps of 5 mice andi the dose which reduces mortality bo S0% is recorded as the PD50 value.
For therapeutic use the o~ pcunds of the formNla (I) will generally be administered in admixture with a pharmaceutical carrier selected with regard bo the intended route of admu m stration 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 flavour mg or colouring agents.

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2 ~ 5 7 m ey may be injected parenterally, for example, intravenously, intramLscularly or subcutaneclsly. For pare~teral administration, they are best used in the form of a sterile aqueous solution which may contain other substan~s, for example, encugh salts or glucose to make the solution isotonic with blood.
For administration to man in the curative or pr3phylactic treat = t of allergic bronchial conditions and arthritis, oral dosages of the ccmpcunds will generally be in the range of fr~m 2-lO00 mg daily for an average adult patient (70 kg). Thus for a typical adult patient, individual tablets or capsules contain fram 1 to 500 mg of active ccmpeund, in a suitable phar~aceutically acceptable vehicle or carrier. Dosages for intravenous ad=inlstr~tion 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 nekuliser or aerosol may be the preferred ~ e of drug administration. Dose levels by this route w~uld be within the range O.l to S0 mg per s m gle dose as required. In practice the physician will determine ;
the actual dosage which will be most sultable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of thè
; .
average case but there can, of course, be indi~idual instances where higher or lower dosage ranges are ~erited, and such are . ~
~ within the scope of this invention.
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W ~ 92/04354 ~ ~3~ 7 PCT/EP91/01671 Thus in a further aspect the inYention provides a pharmaoeutical cxa~position ~rising a ccmpound of the formLla (I) or a pharma oeutically acceptable salt thereof, together with a pharmaceutically acx~eptable diluent or carrier.
The invention also incl~des a co~pound of the formula tI) or a pharmaoeutically ac oeptable salt thereof, for use in medic me, in partic~lar in the treat~ent of allergic and 1~5, inflammatory conditions in a human being.
The preparation of the ccmpiuncs of the invention is further illustrated by the follc~ing Examples.

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W O 92t04354 ~ 7 PCT/EP91/01671 ~E 1 4-r4-(2-Methvlimidazor4.5-Clpyrid-l-yl~p~enyll-6,7 ~ih~7dro .`- midazorl,5,4 ~ fl-C1.5~-b ~zodiazepin-6-one H

:, :

.:

9-Pmino-4-[4-(2-methylimidazo[4,5ic]pyrid-1-yl)phenyl~-" ~,5~benzodiazepin-4-one (0.765g, 2mmol) was suspended in ;~ triethylor~hoformate (10ml,.60mmol) and formic acid (3ml, ~mmol)added to give a clear solution which was stirred at rocm :~
; temperature for two hours and under reflux for one hour.
' On cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and aqueGus sodium hydrogen :
i carhonate such that the aqueous phase had pH8. The organic .. : extract was washed withiwater, dried over]magnesium sul~hate and., ` . .
:i the drying agent filteredi off.
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W O 92/04354 ~ PCT/EP~1/01671 Pre-adsorption silica (Kieselgel 60, 70-230 mesh, lg) was added to the filtrate which wasi concentrated to dryness under reduced pressure. The residue was purified ~y fli~sh chr~matography (Kies21gel 60, 230-400 mesh) eluting with 5%
- diethylamln2 m ethyl acetate.
Product-containing ~ractions were combined, concentrated under reduc~d pressure and the residue triturated with methanol to give the title c~pcund (25mg, 3%). M.Pt. > 300C.

. .
Analysis %~

Found C, 68.37; H, 3.99; N, 20.33 C23H16N60. 3/4 H20 requlre C, 68.05; H, 4.34; N, 20.70 , . , .
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2 ~ 12 EX~MPIE 2 2-Methyl-4- r 4-t2-methvlimidazo- r 4,5-clpvrid-1-vl2~henvl1- ;
~: 6,7-dihydroimidazo[1,5.4-eflrl.51benzodiazepin-6-one .' ' ' O
`~ 0 H

~ ~ ~ CH3C02H

,, '~ .

, .. . .
, ~ . ...
Ihis co~pound was prepared by the method of Example 1 .
: su~stituting t~ y k~'Y~ t~e and a oetic acid for : :
~, triethylorthoformate and formlc acid resFectively, to yield the title co~pound, (9Omg, 26%) M.Pt. > 300C
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Analvsis %:-Found C, 69.37; H, 4.43;~ N, 19.87 . . . .
C24H18N60. 1/2 H20 requlres C, 69.38; H, 4.61; N, 20023 ~ . . .
~;~ .. ..

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.., W O 92/04354 ~ PCT/EP9l/01671 .~ .
2-HvdroxY-4-r4-(2-methylimidaZor4,5-Clpvrid-l-yl)phenVll-6,7 dihydr~midazorl.5.a-eflrl.51benzodiazePin-6 ~ne :.

: O
: ~ O

3 ~ N~ 3 ~ I N OH )~
: NH N CH2Cl ~)>

~ N
.~,. .

~.~
Trichloromethylchloroformate (O.lg, 0.5mmo1) was added to a `.~ stirred suspension of 9-amino-4-[4-(2-methylimidazo[4,5-c]-,.;
~, pyrid-l-yl)phenyl][1,5]benzodiazepin-4-one (O.lg, 0.26m~o1) in anhydrous 1,2-dichloroet ~ (5ml) under a nitrogen atmosphere and the reaction mlxture stirred under reflux for 16 hours.
Methanol (5ml) was added to give a clear solution, followed , . , by pre-adsorption silica (Kieselgel 60, 70-230 nesh, lg) and the ~` solution evaporated to dryness under reduced pressure. The residue was purified by flash chromatography ~Kieselgel 60, 230-400 mesh) eluting with 25% methanol in ethyl acetate.
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~, . , %~ 57 : 14 Product-containing fractions were ccmbir~d, evaporated to dryness under reduced pre5sure and the residhle triturated with methanol to give the hygr2scopic title comçx~Yl (55mg, 50%).
M.Pt. > 300C

Analysis %:- -Found C, 64.52; H, 3.99; N, 19.3 C23H16N602.~ 0 requires C, 64.78, H, 4.25; N, 19.7 . .

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4 ~ j r~ PCI-/EP91/01671 EX~MPLE 4 4-r4-(2-MethyllmidazoL~5-clpyrid-l-yl)phen~yll-7 ethoxycarbonYlmethyl-6,7-dih~Ydroimidazo~1,5.4-efl~1,5]
kenzodiaze~in-6-one . . .
,- O . , CH3 EtO ~.~N
laF/DMF ~

.X`
,~ .
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Sodium hydride (60% dispersion in ndn~lal oil, 60mg, 1.5mmol) was added to a stirred y ion of the t~tle product from Example 1 (0.51g, 1.3mmol) in anhydrous dimethylformamide (lOml) i under nitrogen. After being stirred under reflux for 1 hour, the Pi reaction mixture was cooled to room ~ ture, whereupon ethyl bromoacetate (0.166ml, 1.5mmo1) was added and the solution ~ stirred for an additional 36 hours at rocm temperature.
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W O 92/04354 PCT/EP91~01671 2 ~ 7 16 The dimethylformamide was evaporated off under reduced pressure. The residue was diluted with water, hydrochloric acid (2M) added to give pH1, followed k~ sodium hydrcgen carbonate to .; give pH3 and product extracted with ethyl aa~tate. The organic extract was washed t~ree tImes with wat~r, ~ried ov~r magn2sium sulphate and the drying agent filtered off. Pre-adsorption silica (Xieselgel 60,70-230 ~esh, 2g) was added to the filtrate which W25 evaporated to dryness under reduced pr~ssure.
Ihe residue was purified by flash chrcmatLgraphy (Xiei~elgel .. . .
60, 230-400 mesh) eluting with 2% ~ethanol m chloroform. Product contalning fractions ~ere cG~bined, evaporated to dryness under reduced pressure and the res.idue triturated with ether to gi~e the yellow title corpcund t30mg, 5~).
M.Pt. 237-239 C

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Analysis%:-i. Found C, 66.08; H, 4.65; N, 16.91 ~; C27H22N603-3/4 H20 requlreS C, 65.91; H, 4.81; N, 17.08 ~ .

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W O 92/04354 2 $ ~ 7 PCT/EP91/~1671 EX~MPIE 5 7 ~ethyl-4-~4-~2-methylimidazo~4,5-c1pyrid-1-yl)p~enY11-6,7~
dihydroimldazo[1.5.4-ef][1 5]benzodiazepin-6-one .'~ ,.
, : :
0 C~H3 ., .
--The proce*ure~of Example 4 was followed, using methyl iodide - .
. instead of ethyl bromoacetate, to yield the title compound, (30mg, 13%). N.Pt. 320~-323C
. ~
... . .
-~ AnalYsis%:-Found C, 69.32; H, 4.50; N, 20.25 C24H18N60. V2 ~ O requires C, 69.38; H, 4.61; N, 20.23 I,'~ ' .~ ' ':

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6'3 ~ 5 7 ~ 18 PREPARP$1CN
6-Amin~2 .3~h~4-r4-~2-methYlimidazor4~5~1~rid-1-Yl)-~henvll-lH-rl.51b~nzodiazepin-2-one !, .
H o 3 . ~ ~ N ~ .. .

.. NH2 ~() :;

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~,., ~a) 2,3-DihYdro-4-~4-~2-methvlimidazo~4,5-clPvrid-l-vl)~hen 6-nitro-IH-rl,_~berzodiazepin-2-one .~ .
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W O 92~04354 ~ 9 ~ ~3 ~ 7 PCT/EP91/01671 A mixture of 3-nitro-1,2-phenylenediamine t5g, 33mmol) and ethyl 4'-(2-methylimidazo[4,5-c]-pyrid-1-yl)kenzoylacetate (9.7g, lOmmol) in 100 ml of toluene was heated at reflux for . 16 hours. After ccoling, ~he red/orange precipitate (12g) was filtered and washed with ether.

This material was used directly without further purification m Step (b) belcw, m.p. 200C (broad).
.

H-NMR (300MHz, ~MSO-d6) 2.52 (3H, s), 4.30 (2H, s), 6.68 (lH, s), 7.27 (IH, d, J 5 Hz), 7.82 and 8.29 (each 2H, d, J 8 Hz), 8.33 (IH, d, J 5 Hz), 8.92 (lH, s) and 9.70 (IH brs).
~ ' .
Ethyl 4'-(2-methylimidazo[4,5-c]-pyrid-1-yl)benzoylacetate may be prepared as des~ribed in Eur~pean Patent Application :~ .
No. 0310386A.
.. :

(b) A solution of the product fro~ Step (a) (10.3g, 25mmol), and stannous chloride dihydrate (28g, }25mmol) in 2M HCl (20ml~, ethanol (40ml) and water (75ml) was heated at reflux for 20 minutes, then stood at ambient temperature overnight (16 hours). Precipitated solids were fi}tered o~f, then the filtrate was adjusted to pH 6 by addition of saturated aqueous sodium bicarhonate and extracted with dichloro~ethane. The organic layer was dried (magnesium :, .
sulphate) and evaporated to a solid (3g). ;

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. : . . . . ... , ~ . , - , . , , . ; . . -W O 92/04354 PCTtEP91/01671 G~ 7 20 Two crude batches, obtained as descrih0d above, were chromatographed on silica gel, eluti~g using a gradient of 2-10% of diethylamine in ethyl acetate to afford the title ccmpound as a yellow solid (3.7g, 20%), m.p. 259-263C.

Analysis %:-' FGund C, 67.63; H, 4.86; N, 21.56%
C22~ 8N6- V2 ~ 0 requlres: C, 67.51; H, 4.89; N, 21.47%, . .

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Claims (9)

1. A compound of formula (I):

(I) wherein R1 is H or C1-C4 alkyl optionally substituted by a substituent selected from phenyl, halophenyl, pyridyl, (C1-C4 alkoxy) carbonyl and di-(C1-C4 alkyl) amino, or is C2-C4 alkyl substituted by hydroxyl or by one or two C1-C4 alkoxy groups or is (CH2)nCONR7R8 where n is an integer from 1 to 4 and R7 and R8 are each independently H or C1-C4 alkyl, R2 is selected from H, OH and C1-C4 alkyl, R3 is selected from halo and C1-C4 alkyl, R4 is methyl, and p is an integer from 0 to 3 and m is an integer from 0 to 3;
or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, in which R1 is H, CH3 or ethoxycarbonylmethyl.

3. A compound according to claim 1 or 2, in which R is H, OH or CH3.

4. 7-Methyl-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-6,7-dihydroimidazo[1,5,4-ef][1,5]benzodiazepin-6-one.

5. 4-[4-(2-Methylimidazo[4,5-c]pyrid-1-yl)phenyl]-7-ethoxycarbonylmethyl-6,7-dihydroimidazo[1,5,4-ef][1,5]
benzodiazepin-6-one.

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

7. A compound according to any one of claims 1 to 5 for use in medicine.

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

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

(I) wherein R1 is H or C1-C4 alkyl optionally substituted by a substituent selected from phenyl, halophenyl, pyridyl, (C1-C4 alkoxy) carbonyl and di-(C1-C4 alkyl) amino, or is C2-C4 alkyl substituted by hydroxyl or by one or two C1-C4 alkoxy groups or is (CH2)nCONR7R8 where n is an integer from 1 to 4 and R7 and R8 are each independently H or C1-C4 alkyl, R2 is selected from H, OH and C1-C4 alkyl, R3 is selected from halo and C1-C4 alkyl, R4 is methyl, and p is an integer from 0 to 3 and m is an integer from 0 to 3;
or a pharmaceutically acceptable salt thereof which comprises allowing a compound of formula (II):

(II) wherein R3, R4, p and m are as defined for formula (I), to react either with an acid of formula R2CO2H and an orthoester thereof, where R2 is as defined for formula (I), or with trichloroethyl chloroformate, if necessary allowing the product to react with a compound of formula R1X wherein R1 is an optionally substituted alkyl group as defined for formula (I) and X is Cl, Br or I, and if necessary forming a salt of the product.