CA2088777A1 - Therapeutic agents - Google Patents

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

2 0 ~3 ~ ~ 77 ~'0 92/04349 PCT/EP91/(~166'3 ' ~ .

~EER~F~UnIC AGENTS

This invention relates to dia~epine derivatives ~hich are potent, orally active antagonists of platelet act:ivating factor -and as such have clinical utility for treating allergic and inflammatory conditions such as asthma and arthritis respectivel~.
Platelet activating factor tPAF), l-0-aIkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine is an ether phospholipid whose structure was first elucidated in 1979. It is produced by, released frcm and interacts with many pro-inflammatory cells, platelets and the kidney. In addition to potent platelet aggregating activity, PAF exhibits a wide sFe~,rum of biological activities elicited either ~;rec*ly or a the release of other pcwerful mediators such as thromboxane A2 or the leukotrienes. In vitro, PAF stimulates ~he movement and agyregation of neutrophils and the release therefr~m of tissue-damaging enzymes and oxygen . .
radicals. These activities contribute to actions of P~F m 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 increas2d vascular permeability, comparable with the allergic s~ln reaction follcwing -~
exposure to allergen. Similarly, both the acu~e broncho- -constriction and chronic inflammatory reactions elicited by -~
~ ~ .
~ allergens in asthma can be mimicked by intra~rachea : ; . '.' . .
.
' , ~ ~ ~ Sl)BSTITlJTE SHEE~T
:

2~77 ~
9~/04349 PCT/EP91/()16~9 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 treat~ent of a variety of allergic and inflammatory conditions such as asthma and arthritis, respectively.
In addition to the abcve, PAF has been implicated as being involved in a nu~ber of other medical corxlitions. Ihus in circulatory shock, which is characterise~ by syst~mic hypotension, pulmor~ry hypertension and increased lung vascular per~eability, the symptoms can be mimicked by infusion of ppF, This coupled with evidence showi~g that circulating PAF levels are m =}e3~ed by endotoxin infusion indicate that PAF is a prime mediator in certain forms of shoc~. Intravenous infusion of PAF at doses of 20-200 pmol kg 1 mln 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 inflar~matory and proliferative disease characterised by skin lesions. p~F is pro-inflammatory and i~as been isolated from lesioned scale of psoriatic patients indicating PAF has a role in the disease of psoriasis. And finzlly, increasing evidence supports a potential pathophysiological role for PAF in cardiovascular disease. Thus recent studies in angina patients show PAF is released ~uring atrial pac mg and, in pigs, intracoronary injection of PAF induces a prolonged decrease in coronary flc~ while in guinea pig hear s :

' :
.
-Sl)BSTITUTE~ SHEET
.:

7 ~ 7 ~()92/0~3~9 PCT/EP91/(116~') it induces regional shunting and is~haemia. PAF has also beenshcwn to m itiate thrombus formation in a me~entem c artery preparation both ~hen administered exogenously and when released endogenously. More recently PAF has been shcwn to play a role in brain ischaemua induced in animal mcdels of stroke.
~ hus ccmçrunu`s of the invention, by virtue of their abilit~
to antagonise the actions of PAF, cculd well be of value in the treat~ent of any of the above conditions.
According to th~ invention, there are provided ccm~rurrs of formNla (I): `

~ o '` ' wherein A is (CH2)n where n is from 2 ~o ~, or CH2CH=CHCH2, and R
is H or a group selected from Cl-C6 al;~l, hydro~yrleth~l, (Cl-C~
alkoY.y) methyl, C3-C7 c~cloalk~l, p~ridyl, thienyl, unsubstitute~
phenyl and phenyl substituted by fr~m. one to three su~stituents each selected from halo, Cl-C~ alkyl, C -C alko~y an~ CF3 and their p~armaceùtically acceptable salts.

.

2~88~t7 ~ -~()92/0~3~9 PC~T/~P()I/~

4 ~
In the definitions given herein the term "halo" ~eans 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 cyclohe~l. Preferre~
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],~ diazepin-6-or,~
in which n is 2 ar~ R is phenyl, 2-cyclohex~1-5,6,7,8,9,10-hexahydro-4-[4-(2-~,ethylimidazo[4,5-c]pyrid-1-yljphenyl]pyrazolo- :
[4,3,2-fg][1,3]diazepino[1,2-a][1,4]diazepin-6-one in ~-hich n--ar~ R is cycloheY.yl, and 2-methyl-4-[4-(2-r.le_hyiir.ldazc-[4,5-c]pyrid-1-yl)phenyl]-5,6,7,8-te~rahyc~oi~idazo~1,2,3-ijj- :
pyrazolo[3,4-b][1,4~- diazepin-6-one, in ~hicn n is 2 and R is methyl.
It will be appreciated that formula (I) r2y be ~.~itten alternatively as formula (Ia), these forms of the cor~pound bein~
tautomeric:

~. ~ ~) :
"~

'' i ) . '~ :

~nese co~pounds and their salts r2~ is- as one ~auiomer c- . :
a ~ux31re of lautomeric for~s, ~niGh .~ sep2~a~ed ~; pnysica: .
meuhocs sucn as fractional crystallisa_ic~ r~r.~-~g~a~
inven~icn in~ludes all tr.e tautor.~s ;,~r-~r._-- se~ no .

~ , SUBST!TI~JT~ SHE;~T
:: :

2 ~ ~ ~ 7 1 7 0 92/~4349 PCT/EP91/()16h() Ccmpounds in which R comprises a brarx~hed hydrocarbon chain of 4 or more carbon atcms may contain a chiral centre and therefore exist as a pair of iscmers which may be separated by corTventional mean_. The invention include_ all these enantiomers, whether se~arated or not.
The pn3rmaceutically acceptable salts of the c~mpourdLc of formula (I) are those formed from acids which form non-toxic addition salts, for ex~mple the hydro~hloride, hydrobromide, sulphate or bisulphate, phosphate or acid pho~phate, acetate, citrate, fumarate, gluconate, lactate, rnaleate, sucOLnate, tartrate, r~ethanesulphonate an~ dimethansulphonate, benzenesulphonate and g-toluenesNlphonate.
The compounds of formula (I) may ge~erally be prepared by the ~'ollowing synthesis:

(IL) In this synthesis the com~ound of formNla (II) is rea ted ~ith triphenylphosphine and diethylazodicar~o~ late (DE~D) in a soiverll_ such a_ te_rahydrofuran and after re ~v-a: of th~ -cl~
product m,~ be isolated b~ chrcmatcgraDh..

.

SUE~STITUTE SHEET

~0 92/W 349 2 ~ ~ 8 7 ~ ~ PCT/E1'91/(~166') -The ccD~x~unds of formula (II) may be prepared a~ follows:

' .

()11 __ o~j :

i\o I ' > ';\0~ ~ "~ ,', R R
(III) (I~! , /0~
,~ CO -~ C~ . ..
Z ~ OJ~/~

(V) (Vl) 0: ~ ' '; ' n . i . :
ro~

(Il) /'' 1 ''`' .
. :
: ~
: : wnerein Q is a leavLng group su~n as c.-r~ alko~.~. .
, 1 '~:
; ' :,..
~: :
~ SlJ8ST3TUTE SI~EET
.

.,.. .; .. ~, .. ; .,.. ; . ...... ... ........ , , . .. , . ;.. .... ; .. ~ . .- ,.. ,,.. .. ~, . , -. . . . .. .

.. .... ,. ... .. .. , . ........ ... .. , . .. ,. , .,.. ~, ....... .. . . - . . ...... . . .
... .. . . . .,~ ~ . `. . . .. .. .... . . . ... .. . . . . . . . . .. .. ..

0 92/0~3~9 ~ 777 PCT/EP91/1)1~6' In this synthesis aminopyrazole (III) is reacted with a nitrite, for example s~dium nitrite in the presence of acetic acid, to yield the nitrosopyrazole (rV) which is then reduced with hydrogen, generally in the presence of a caLalyst such as palladium on carbon, to produce the dia~urc~yrazole (V).
Ih.e diaminopyrazole is then reacted wi~ c~pound (~), for e~ample in the presence of silica gel and a suitable solvent sucn as toluene, to give the compound of forrmlla (II). In this method a proportion of ccm~c~md (IIA) is also pro~lced. Alternatively the diaminopyrazole is reacted with compc~rd (VI) in the presence of a catalytic quar.tity 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 co~pound (II). Co~pounds (II) and (IIA) may be separated by physical methods such as c~x~matography.
In a varient of this synthesis, com~o~nd (IV) is made bv the following alternative method: -:-- Oi~
H~; 'L-01!

1 ''' '~' ':; .
:

SUBSTITUTE SHEET

2 ~
-U'O 92/04349 PC-r/EI'9~ 6~) ~ .

In this m~i-od ti~ ~ a~ -opriat:~ 2-hydro~ imil rJ ;~ o d~-~L~ t iV~ lCt~ --i Ul til~ ro;~L-iat~ à~
gel~L-a].ly ~ eatiJ~3 i:~ ti~ r~ o~~ c~ t~; s `r~l .
.~lt~rr~t ively, t:h~ cc~ldsi o~ l:or~ r.
t-~ .`oll~ 3 ~

!, O l i : .
.~l l~-A--N~2 ;

(~'II j ( ~' T ~

j: ! ~ .. .
: ~ ' ' ,..

~ ' ' '.,'',- ' ', ` : . ' ' ~:
~` ~ "' ' .

~3~ 7 .~O 92/043~9 PCT/EP91/01hh') where X is chloro, bromo, or iodo and Q is a leaving group such as Cl-C4 alkoxy. In this synthesis the halonit~opyrazole (VII) is react~ed with the appropriate amincalcchol, for example by autoclaving the reagents in a solvent such as ethanol, to produce compound (VIII) which is then cyclised by treatrxent with ~ ~ -trip~enylpnosphine and diethyl azodicarboxylate. T~is compound may then be reduced, for example by treatmRnt w:ith hydrazine ana Ra~ey nicXel, to produce amino derivative (X) whiGh is then reacted with ketoester (VI), preferably in the presence of a z~
chloride catalyst follcwed b~ treatr~n~ with a base such as sodium~
hydride, to yield the compound of formula (I). This compc~nd r~-be separated from other reaction products formed by chromatography The activity of the compounds of the invention is shohn by their ability to inhibit the platelet aggregating activity of P~F
m vitro. I`esting is Ferîormed as follows:
Blo~d samples are taken f mm either rabbit or ran into G.l vol discdium ethylenediamine tetraacetic acid buffer and tne samples centrifuged for 15 munutes to obtain platelet riGh plasr~.
The plasma is further centrifuged to give a platelet pellet ~icl~
is washed with a buffer solution (4 rM KH21~, 6rM Na2HPO4, lO0 r~i NaCl, 0.1% glucose and 0.1% bovine serum albumin, pH 7.25) an~
finally resuspended in buffer solution to a conc ntration of 2 x lO~ platelets/ml. A sample (0.5 ml) is pre-incubated for two m mutes at 37C in a Paton ag~regometer with stirring, either with vehicle alone, or with vehicle containlng the particllar co~poun~ :
under tes~. PAF is added at a suffici~nt concentration to gi~e a ma~ir~ aggregating response in the absence o tf~ co~our,- ;' :, : ..

SUBSTITUTE SH EET

~088 i 7 ~
~O 92/04349 PC~ P91/01h~') to 10 9 molar), and the platelet aggregation is m~easured by foll~awing the incr~aase in light transmission of the solution. The experiment is repeated in the presence of test oompound at a range of concentrations and the concentration of compound required to reduce the response to 50% of its m2ximNm value is recorded as the IC50 value-The activity of the ccmpc~nds of formula (I) is alsodemonstrated in vivo by their ability to protect mice from the lethal effect of an irljection of PAF. A muxture of PAF (50 ~ig~g) and DLrpropranolol (5 mg/kg) in 0.9% w/v sodium chloride is injected (0.2 ml) via a tail vein into mice. rne comDounds unde~
test are either injected into the tail vein immediately prior to the PAF/propranolol injection or admunistered orally by gavage two hours earlier. 'rhe c~mpoun/ s are tested at several do~es in ~roups of 5 mice and the dose Which reduces ~ortality to 50% is recorded as the PD50 vzlue.
For therapeutic u~e the compounds of the formula (I) will generally be administerei in admixture with a pharmaceu~ical carrier selected with r~ard to the inten~ed route of a~mlnistration and st~ndard pharmaceutical practice. For exampie, they may be ad~inistered orally in the form of tablets containlng such excipients as starch or lacto~e, or in capsules or cNules either alone or in admixture with e~cipients, or in tne form of elixir or _ spension ~ ntainirg flavouri g or colo ri g ag n-~.

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SUBSTiTUTE SHEtT ~:
:

, ,, j , , ` ; . `; . . . . - . . .

0 92/0~3i9 2 0 8 S ~ 7 7 PCT/EP91/(1166~

They may be injected parenterally, for example, intraventausly, intlanuscularly or subcDtanecusly. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other sub~stances, for example, enou~h salts or glucose to r~ke the solution isotonic with blood.
For ad~inistration to m~n in the curative or prophylactic treatment of allergic bronchial conditions and art~xitis, oral dosages of the compc~nds will generally be in the range of fram 2-lOOO rg daily for an average adult patient (70 kg). Thus for a typical adlllt patient, individual tablets or capsules contain frc 1 to 500 rg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. D~sages for intravenous admunistration would typically be within the range l to lO mg per single dose as required. For the treatment of allergic and bronchial hyper-reactive conditions, inhalation vla a nebuliser or aerc,sol rzy be the preferred route of drug administration. Dcse levels by this route would be within the range O.l to 50 mg per single dose as require~. In practice the physician -~ill decer~in~
the ac~ual dosage which will be r~st suitable for a.' indi~idu~' ;
patient and it will vary with the age, ~eight and response o~ th~
particular patient. The abo~e dosages are exemplari of the average case but there can, of cc ~ se, ~e individual instances where higher or lower dosage ranges are .~rited, and SUG; ar_ within the scope of this invention.
Thus in a further aspeA~ the inven_lon provides a charmaceutical ccmpcsi~ion ccmprisina a cc~x~d o tne cr. ~la (I), or a ~narmaceutically acceptable sa't thereo~, toae-,n~- wit`
a ~nar~aceu~ically ac,ce~able diluen~ c- ca ~e~

' 2 0 3 8 7 7 ~ pcr/Ep9~ 1669 The invention also includes a compound of the formLla (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 pre~aration of the ccmçouods of the inven~ion is further illustrated by the follcwing Examples.

,. ..

SUBSTITuT~ FT

... ... , . ... ... .. , . .. - . . , ., ,, . . .. . - . . . , - . ~ , . .

2~77i,~l :
~O 92/0~3~19 PC~/EP91/1)16h') E~AMPLE 1 2 ~ ethvl-4-r4-(2-methylimidazor4,5 ~ 1pYrid-l-vl)phenyl]
5~6~7~8-tetrahvdroimidazorl~2~3-iilpyrazolor3~4-blrl,41-diazepin-6-one O ! ~ O i 1, 0~ HOAC ` 0 ?~f'~ `~1~ ' C'.-.~ CH3 C!i ~oluene S iQ 2 0 i .

O~ ,.,.'- ' ,/ :
~ ' ' ~r~
1 ' ! ' : ~ ` ol '. :'' SUBSTlTV-rt SHt.FT

~) n o r r ~O 92/0~3~19 ~r U O ~ 7 PC~r/EP()1/~)16 (a) A solution of sradium nitrite (800 mg, 11.6 mmol) in water (4 ml) was added dropwise r~ver 30 min to a solution of 5~amino-1-(2-hydroxyethyl)-3-methylpyrazole (1.4lg, io mmol) (Eull. Soc. Chim. Fr., (1975), 255) in glacial acetic acid (14 ml) and water (10 ml) with ice ~ooling. The mi~ure was stirred at 0C for lh, and the red precipitate was filtered off and dried m vacuo to give 5-amin~-1-(2-hydL-oxye~hyl)-3-methyl-4-nitr~asopyrazole (1.2g, 71%).

~ N~ (300MHz, dmsotd6) ~ = 2.51 (3H, s), 3.30 (2H, br s), 3.62 (2H, t, J = 4Hz), 3.8~ (2H, t, J = 4Hz) p.p.m.

~b) A solution of 5-aminc-1-(2-hydroxyethyl)-3-methyl-4-ni,roso pyrazole (902 ~g, 5.3 mmol) in ethanol/dichloromethane = 1:1 (80 ml) was hydrogenate~ over 10% palladium on charcoal (100 mg) at 20 p.s.i. and 20C for 2h. The catalyst was filtered off using Arbocel filter aid, and the filtrate was concentrated under re~uced pressure to give ~;,5-diam~nc-1-(2-hydroxyethyl)~3-methylp~azole (800 mg, 97%) as a brc~.n ,~. . :.

~ N~ (300 MHz, CDC13) ~ = 2.1~ (3H, s), 2.2~ (~H, ~- s~, 3.96 (2H, m), 4.03 (2H, m) p.p.m.

.

: ~ : SUBSTITUTÇ~ SH~ET

~ 2/()~9 2 ~ ~ ~ 7 7 ~ PCT/EP9~

(c) A mixture of 4,5-dia~ino-1-(2-hydroxyethyl)-3-methylpyrazole ~800 ~g, 5.12 mmol), ethyl 4'-(2-methylimidazo[4,5-c]pyrid-l-yl)benzoylacetate (1.60 g, 5.6 mmol), silica gel (40-60~, 0.5 g) and toluene (25 ml) was heated under reflux fQr 16h.
The toluene was removed under reduced pres~sure and the proauct extracted into methanol/dichloromethane = 1:, (200 ml). The solvents were removed under reauced pr~ssure and the residue was purifled by flash chrsmatography (gradient elution with ethyl acetate/methanol/diethyla~ m e).
The fractions containing the product with RI^ = 0.17 (eth~
acetate/methanol = 3:1) were c~bined and concentrated, and the residue was recrystallised from methanol to give 1-(2-hydroxyethyl)-3-methyl-5-[4-(2-methylimidazo[4,5-c;
pyrid-1-yl)phenyl]-1,6,7,8-tetrahydr~pyrazolo[3,4-b][1,4]
diazepin-7-one (480 mg, 23%) as a yellow solid, m.p.
238-240C.

Analvsis %:-FOUA~d C, 61.56; H, 5.37; N, 22.E_ C22H21~702.3/4H20 re~uires C, 61.58; H, 5.2~ , 22.8 (d~ A mixture of 1-(2-hydroxyeth~1)-3-r~thyl-~-[~-(2-methyl imidazo[4,5-c]pyrid-1-yl)phenyl]-1,6,7,8-tetrahydropira~olc [3,4-b][1,4] diazepin~7-one (510 mg, 1.23 mmol), triphenylphospni~e (386 mg, 1.~7 m~ol) and diethyl ~zodicarto~ylate (257 ~g, 1.~7 mmol) m ory ter~h~~c~lran SU13STITUTE SHEE~T

~a~sr~J7 :il W O 92/0~349 PCT/EP91/01669 (25ml) was stirred at room temperature under nitxogen for 16h. The solvent was remcved under reduced press~re and the residue was purified by flash chr~matography elutin~ with ethyl acetate/methanoVdiethyla~ine = 94:3:3. The title prcduct was isolated as a white solid (60 m~, 12~), m.p. :
282-284~C (frcm methanol).

Analysis ~:-Found C, 66.33; H, 4.88; N, 24.54 22 19 7 e~ulres C, 66.49; H, 4.82; N, 24.67 " ~;

;U~;T~U~ ~;HE~
, ~O 92/043~9 ~ ~ 8 ~ 7 7 ~ P Cl/EP9l/~

E~MPLE 2 4-r4-(2-Methvlimidazo r 4,5-clpvrid-1-yl)~henvll-~-~hen~

5,6,7,8-tetrahYdro-imidazorl,2,3-iilPvrazolor3~4-b~ 4 diaze~in-6-one ~> ~ Eto~
i;.,. 1 toLuen~
s ~O ~ >

~!112 o ~ ~ C

)~``~, : ' .

( ~ I .
"~?- ' ~ ` c,`~
! 0~
(~ ?,`
" (~

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::

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SlJ8ST~TUT~ SHEET
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~O 9~/0~3~9 2 ~ ~ g 7 7 7 PCT/EP91/lll66() (a) 2-Hydroxyethylhydrazine (760 mg, 10 mmol) was added to a solution of 2-hydroxyimuno-benzoyla~etonitrile (1.74 g, 10 mmol) (Ger. Offen. 2,722,416 (1978)) in ethanol (lS ml) and the resulting solution was heated at reflux for 16h. rne mixture was concentrated under reduced pressure to ahout 5 ml, and t~e red solid pr~duct was filtered off and washed with methanol (10 ml) to give 5-aminotl-(2-hydroxyethyl)-4-nitroso-3-phenylpyrazole (740 mg, 32%), m.p. 193-197C.

Analvsis %:-Found C, 56.i38; H, 5.1~ , 23.90 CllH12N~2 requires C, 56.89; H, 5.21; ~, 2~.12 (b) By the method of Example l(b), 5-amuno-1-~2-hydroxyethyl)-4-nitro6O-3-phenylpyrazole was reduced to give 4,5-diamino-1-(2-hydroxyethyl)-3-phenylpyrazole (98% yield) as a buff solid.

-H ~ ~ (dmsc-d6) o = 3.40 (2H, br s), 3.6~ (2H, m), 3.92 (2r., t, J = 5Hz), 4.58 (2H, s) 4.92 (lH, t, J = 4Hz), 7.1 (LH, ~, J = 5Hz), 7.31 (2H, t, J = 5Hz), 7.82 (2H, d, J = 5Hz) p.p.m.

(c) B~ tne method of E~ample l(c), ~,o-~iam1no-l-(2-hydroxyethyl)-3-phenylpyrazole w~s condensed witn etnyl ~'-(2-methylimidazo[4,5-c]pyrid-1-;l)benzoylacetate to gi~e :.

:

SU~3STITUTE SHEET
...... ";~ ... ".... "", ,.. ", ,,~ , ,."" ", , "

; ', .. . ' ' . ' ~ .~ , . , . . , . ' , ' , ' ~ O 9Z/(~4349 2 ~ ~ ~ r/ 7 ~ PCT/EP91/01669 1-(2-hydroxyethyl)-5-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)-phenyl]-3-phenyl-1,6,7,8-tetrahydr~pyrazolo[3,4-b~[1,4j-diazepin-7-one (39% yield), m.p. 185-190C (frc~ methanol).

Analvsis ~:-Found C, 65.29; H, 4.90; r;, 19.53 C27~ 3N702.H20 re~uires C, 6~.42; H, 5.08; ';, 19.7 (d) By the method of EXample l(d), 1-(2-hydro~yeth~1)-5-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl3-3-phenyl-1,6,7,8-tetrahydropyrazolo[3,4-b][1,4]diazepin-7-one was treated with triphenylphosphine and dieth~l azodicarboxylate in dry tetrahydrofuran to give the title co~pound (34 yield), m.p. 277C (from methanol).

Analysis %:-Found C, 69.75; H, 4.4~ , 21.06 C27H21N7 V4H20 reou1res C, 69.88, H, 4.66; rl, 21.13 ' ~

:
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SUBSTITUTE SHEET

O 92/0~349 2 0 ~ ~ 7 ~ I PCT/EP91/01669 EX~MPL~ 3 2-CYclohexyl-5 . 6,7.8,9,10-hexahvdro-4- r 4- ( 2-methYl imidazo-r 4, 5-C 1 pYrid-l-vl~Phenyllpyrazolo r 4,3, 2 -fa 1 r 1,31diazepino r 1 2 -al-r 1 . 41 diazepin-6-one ~ .
I' ~J .,:
Cl liO(C1i7)~,i;ii7 ~o~; DL ~

Tli!~

O ~'~
H Rane~
O7 ~2~1~2 ~/~`;~
EtO~

', ' :"' i3 ZnCl7, cat.
I.~Oi; ~ ~.
U ~'~i Cli~

~ .

:
:: .

cllR~;TlT~TE Sti~ET

2~3~7 17 (~9~/~13~9 PCT/EP91/01669 (a) 5-Chloro-3-{~rcloheYyl-4-nitro-lH-pyra2ole (U.S. Pat.
4,025,530 ~1977)) (3.44g, 15 mmol) and 4-aminKbutan-l-ol (6.90 ml, 75 mmol) were dissolved in Qthanol and then heated in an autoclave at 100C for 8h. The mLXture was cooled, silica gel (lOg, 60-200~) was added, and the ethanol was removed under reduced pressure. The residue was applied to the top of a chrc~atography column (silica gel 40-60~) and the product was eluted with ethyl ace~ate:methanol (gradient elution). Th2 prcduct, 3-cyclohexyl-~-(4-hydro~utylamlno)-4-nitro-lH-pyrazole, ~s ob~ained as a yellow solid, 2.17g (51%) m.p. 192C (from ethyl acetate/hexane).

lH NMR (500 MHz, CDC13) ~ = 1.2-2.1 (14H, complex), 3.3C (lH, m), 3.50 (2H, m), 3.85 (2H, t, J = 6Hz), 6.84 (lH, br s).

:
(b) A mixbure of 3-c~rclohexyl-5-(4-hydrox~rbut~rlammo)-4-nitrc-IH-pyrazole (2.17g, 7.7 mmol), diethyl azodi~arbox~rlate ~-(1.70 ml, 10.8 mmol) and triphenylphos~ mne (2.85g, 10.8 mmol) Ln dx~r tetrahydrofuran (50 ml) was slirred under nitrogen at rocm temperature for 2h. The solvent was removed under redu oed pressure and the residue purified by flash chrcmatography (gradient elution with heY2ne/ethyl acetate).
The product, 2-c~clohe~1-3-nitrc-5,6,7,8-tetrahydro-4H-pyrazolo[2,3-a][1,3]diazepir~ ~s ob~aln~ as a yell~.~ solid, 0.8 7 (4Z9~), m.F. 1~7-149'C.

. . "
' '"

SUBSTITUT~ SHt~:T
. . . .

~O 92/0~3~9 ~ ~ ~ 3 ~ 7 ~ PCT/EP9l/()166~) lH NMR (300 MHz, CDC13) ~ = 1.10-2.00 (14H, m), 3.10 (lH, m), 3.20 (2H, m), 4.05 (2H, m), 7.15 (lH, br s).

(c) A mixture of 2-cyclohexyl-3-nitro-5,6,7,t3-tetrahydro-4H-pyrazolo[2,3-a]diazepine (0.66g, 2.5 m~ol), hydrazine hydrate (lml) and Raney nickel (200 rg) in ethano (20 r~) was heated at 50C under nitrogen for 2h. The mixture was cooled and filtered thro~gh Arbocel filter aid under a nitrogen atmosphere. The filtrate was concentrated under reduced pressure to give an unstable brown gum, which W25 im~diatel~
dissolved in fresh ethanol (20 r~). Ethyl 4'-(2-methylimidazo[4,5-c]pyrid-1-yl)benzoylacetate (8~0 mg, 2.6 mmol) and anhydrous zinc chloride (136 mg, 1.0 r~ol) were added, and the mixture was heated at reflux under nitrogen for 17h. 'Ihe nixture was cooled an~ sodium hydride (217 m~, 60% dispersion in oil, 5.4 mmol) was added and the mlxture was stirred for 3h at room temperature. The ethanol was removed under reduced pressure and the residue was oissolved in dichloromethane (150 r~), washed with brine (30 r`) and dried (MgSO4). The dichloromethane solution was concen rate~
under reduced pressure and the residue was purified by flash chrcmatography (gradient elution with dichloro~ethane/
methanol) to give the title com~ound as a white solid, ~06 rg (65~), r,.p. 206-207C (frGm dichlorcmethane/rlethanol).
:
Analysis ~
Found C, 6~.6~: H, 6.2; ; 1G .76 C29H31N70.3~H2O requires ~, 63.~3; ~, 6.~

SUBSTITUTE SHEE~
.

. . . ... . . . . .

. .
. .

Claims (13)

1. A compound of formula (I):

(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.

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):

(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 which comprises cyclising a compound of formula (II):

(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):

(V) (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:

(X) (VI) 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) (VIII) (IX) R and A being as defined for formula (I).