CA2078007A1 - Imidazopyridine paf antagonists - Google Patents

Abstract

2078007 9117162 PCTABS00008 Compounds of formula (I), wherein A is a C1-C8 alkyl, perfluoroalkyl, cycloalkyl, aryl, substituted aryl, heterocyclic or substituted heterocyclic group; B is defined to include a variety of linking groups including straight and branched-chain alkylene and alkenylene groups as well as groups containing an ether, thio-ether, amine or amide group and various substituted and cyclic variations thereof; and R1, R2 and R3 are each H or CH3; are PAF antagonists of value in the treatment of allergic and inflammatory conditions in humans.

Description

~ W091/17162 2 0 7 8 V 0 7 PCT/EP91/00737 IMIDAZOPYRIDINE PAF ANTAGONISTS
.
lhis invention rC1atcC eo imidazopyridines spcci~ic.~ to ccrtain 4-sul)stitutcd-1-(2-met~ liolida.o~4,J-~lp~rid-l-y~ 7cn%et)c derivatives. ~he compoun~s are potenc and sYl~c~iu~ ~nta~onists o~ platelct activa~inl, [ac~or havi[lg clinical u.i~i~y itl t~lC
treacment of al]ergic and infla~macory conditions in numans and animals.
Platelet activatin~ factor (P~;F, i-0-al~ 1-^-ace.yl-sn-glyceryl-3-phosphorylcholine) is an ether phoDholiDid whose structure was first elucidated in 197~. It is ?roduced by, released fro~ and interacts with many pro-lnfl2m~atory cells~
platelets and the kidney. In addition to porent piatelet ;
aggregating activity, PAF exhibits a wide spectru~ of biological activities elicited either directly or via the release of other powerful mediators such as thro~boxane A2 or ehe leukotrienes, which make PAF inhiHitors of potential value in the treat~ent of a variety of conditions including allergic, inflammatory and ~ hypersecretory conditions such as asth~a, arthritis, rhinitis.
',! bronchitis and urticaria, the treatment of circulatory shock, gastric ulceration, psoriasis and cardiovascular conditions.
including an~ina, thrombosis and s~ro'~e.
In our European patent applicaeicn no 0258033 we disclose a ; series of 2-substituted 1,4-dihydropyridine dcrivatives as PAF
antagonists. In our later European patent application no 0310386 we disclose a ~urther series of dihvd~opvridinc P~F antagonisc wherein the 2-posi~ion substituent in~ludes in par;icular a

2-methyl-i~idazo[4,5-c]pyrid-1-yl-?henpl group. ~he present invention provides further PAF antagonists having ~he formula:

SUBS~I~U~E S~EET

W O 91/1716~ 0 7 8 ~ ~ ~ PCT/EP91/00737 j,l A - B ~ `; ~ ~

Rl ~ R3 .... (I) R-and phfi~aceu~ically acceptable sales tbereof, wherein A is a C~-C~ alkyl, perfluoro(Cl-C~)alkyl, C3-C8 cycloai'~yl, arvi or het~rocyclic group, wherein said aryl or heterocyclic group may be unsubstituted or substituted with from one to three substituents each independently chosen from Cl-C4 alkyl, halo, oxo, Co2R4, CoNR5R6, OH, Cl-C4 alkoxy, NH2, N02, CN
and (CH3)3SiCH2;
B is a Cl-C5 alkylene or C2-C5 alXenylene chain which may opeionally be substituted by one or more Cl-C4 alkyl, Cl-C4 alkoxy, perfluoro(Cl-C4)alkyl, C3-C7 cycloalkyl, phenyl, oxo, OH, CN, CoNR5R6 or CO2R groups and wherein up to two carbon atoms in said-chain can intependently be replaced by O, StO)m, -N= or NR , and wherein said chain or part of said chain, may form, or may form part of, a 5-7 membered saturated or mono-unsaturated ring which may contain a nitrogen ato~ or NR7 group, a nitrogen and oxygen atom, or one or two oxygen ato2s, said ring being optionally substicuted with any o the foregoing chain substituents, and, in the case where the group A is an aryl or heterocyclic group, the ring may optionally be fused to said aryl or heterocyclic group;
each of Rl, R2 and R3 is independently H or CH3;

SUBSTITUTE SHEET

:. : ` , ... . .
. .

., 207soo7 W O 91/17162 PCT/EPg1/00737 R is H, Cl-C4 alkyl or ary](Cl-C4~alkyl;
RS and R6 are each independently H or Cl-C4 alkyl, or F~5 is ~1 and R is C3-C& cycloalkyl or aryl, or the two ~roups R5 and R
together with the nitrogen atom to which they are attached, form a piperidino, 4-ketopiperidino, morpholino or piperazinyl group;
R is H, Cl-C4 alkyl, CO2(Cl-C4)alkyl, aryl(Cl-C4?alkyl or heteroaryl(Cl-C4)alkyl;
and m is û, l or 2;
with the proviso that A-B is not C~H5OCOCH2CO- or CH~COCH~CO~CH~-.
In the above definitions, the term aryl includes phenyl, naphthyl, tetrahydronaphthyl and indanyl, each of said groups being optionally substituted as defined in A above; alkyl groups having 3 or more carbon atoms may be straight or branched-chain;
and halo means fluoro, chloro, bromo or iodo. In the definition of A, the term heterocyclic group means a 5 or 6 membered ring containing up to four nitrogen atoms, or one or two nitrogen atoms together with a further oxygen or sulphur atom, or up to two oxygen atoms or a sulphur atom, as heteroatom, and said ring may ' be saturated or unsaturated and substituted with one or more subsitutuents as defined in A above. and may optionally be fused to a phenyl or further 5 or 6 membered heterocyclic ring.
Examples of particular heterocyclic groups include pyridyl, quinolyl, benzimidazolyl, benzthiazolyl, benzdioxolanyl, benzothienyl, triazolyl, imidazolvl, indazolyl, indolinyl, piperidyl and morpholinyl.
The term heteroaryl used in relation to R7 means a 5 or 6 membered aromatic heterocyclic group including, for example, pyridyl, thienyl and imidazolyl.

SUBSTITUTE SHEET

2~7~
W O 91/17162 PCT/EP9t/00737 ~A

As defined ove a variety of linking groups B, are po~sible and as well as simple straight-chain or br~nched alkylcne and alkenylene groups, the invention includes groups cont~ining an ether, thioether, amine or amide group and various cyclic variations thereof:
a) Thus, i~ one particular aspec~ ~f t:~e invencion the linking group, B, is an ether group havin~ an oxygen atom and up to four carbon atoms in the chain lin~ing .;~e gro~3 A t~ p;~enjl r~ ng.
The linking group may optionally have a further oxygen atom in the chain and said chain may optionail~ be substi.uted by hyd~cxy, o~o (to give an ester group), Cl-C4 alkoxy, Cl-C4 alkyl or phenyl. In this embodiment the linking group may also form part of a 5 to 7 membered cyclic ether group containing one or two oxygen atoms in the ring which may optionally be substituted by Cl-C4 alkyl hydroxy, oxo, or Ci C4 alkoxy and which may optionally be fused to a phenyl or tetrahydronaphthalene ring. Thus the ring may be for example, a tetrahydropyranyl, dioxolanvl, dioxanyl or dioxepanyl ring.
In this aspect the group, A, is preferably a phenyl group which may optionally be substituted as defined in A above. Thus parcicular and preferred examples of chis type include compounds of the following formulae-:

~
O~X
~ O ~~O

X ~CO N ~.~ e ¢~f o l x SUBSTITUTE ~IEET

..
. .

~`~` W O 91/17162 2 ~ 7 8 ~ 0 7 PCT/EP91/00737 wherein X is:

\¢~ r~1 e p3 R

R , R and R being preferably H.
Coupounds of this type may be pre?areà Dy â variesv Of methods as will be known to those skilled in the art. In one process the ethers are prepared by reac~ion of ~he corresponding hydroxyalkyl derivative of formula:

HO - D - X

wherein X is as previously defined and D is Cl-C4 alkylene group which may optionally be substituted as defined in B above; by reacting with an appropriate phenol or heteroaryl terivative of formula Ar-OH wherein Ar is an aryl or heteroaryl group which may optionally be substituted as defined for A above. The reaction is performed in an inert organic solvent e.g. tetrahydrofuran, in tha presence of triphenylphosphine~and diethylazodicarboxylate (Mitsunobu reaction). Certain transfor~ation reactions are possible on the products, thus for example when the phenol is substituted by CO2R , wherein R is Cl-C, alkyl, hydrolysis will give the corresponting carboxylic ac~d (wherein R4 is H~. This in eurn may be reacted with a variety of amines of formula R R NH to give the corresponding carboxamide derivatives where the substituent is of formula CoNR5R and R5 and R6 are as previously defined. SUBSTITUTE SHEE~r ~ . , 20780~7 W O 91/17162 ~ PCT/EP91/00737 '' In an alternative process, an oxirane of formula:

~ ~ or ~ CH3 wherein X is as previously defined, may be reacted with a phenolic anion e.g. by heating in dimethylformamide, to give the corresponding compounds of formula(I) wherein the linking group B
is OH OH
-O-~H2-CH- or 2 Cl respectively.
~ Cyclic diethers are readily prepared by reaction of a diol ; with the appropriate aldehyde or ketone. Thus for example reaction of . .
CH

~ ~ HC ~

yields the corresponding 2,4-benzodioxepine derivative. l`his reaction may also be performed bv using the trimethylsilyl derivative of the diol, following the procedure of T. Tsunoda. M.
Suzuki and R. Noyori, Tetrahedron Letters, 1980, 21, 1357.

SUBSTITUTE SHEET

. `
.
.
' ;.~

20780~7 " W O 91/17162 PCT/EP91/00737 Other variants are possible, thus for example reaction of a compound of the formula:
; OH
H(CH2)2CH-X ... (IV) with butyl lithium and chlorotrimethylsilane, followed by reaction with an aldehyd~, gives a 2-aryl-dioxane derivative.
Finallv ester-linked derivatives may be prepared by reaction of the carboxylic acid ot formula H02C-Dl-X with an alkanol of formula A-Dl-OH or by reaction of an alkanol of formula HO-Dl-X
with an acid of formula A-Dl-CO2H wherein A, and X are as previously defined and Dl is as previously defined for D or it may be a direct bond.
Appropriate reagents and conditions for all of the above reactions are given in standard text books and by reference to the experimental examples given hereafter.

b) In a further aspect of the invention, the linking group a contains an a~ide group together with up to three further carbon atoms in the chain linking A to the phenyl ring. The nitrogen atom may optionally be substituted by Cl-C4 alkyl and the chain may optionally be substituted by Cl-C4 alkyl or phenyl, or include a further oxo substituent. In this embodiment the group A may be phenyl, optionally substituted as defined in A above or it may be naphthyl, indanyl, or a heterocyclic group, for example a pyridyl, quinolyl, indazolyl, benzimidazolyl or benzthiazolyl group.

SUBSTITUTE SHE~T

. . ..

W O 91/17162 2 0 7 8 0 ~ 7 PCT/EP91/00737 -~

;

Thus particular and preferred examples of this type include:

~uNHOC 1 X ~ ~ N ~ X Cl ~ ~ X

- Compounds of this tvpe are ~enerally orepared bv reaction of an amine of formula A-D -NHR with an acid o. rormuia H02C-D -~, wherein R is H or Cl-C4 alkyl and A, Dl and ~ are as previously defined. The reaction may conveniently be achieved via the acid chloride which may be prepared by reaction of the acid with, for example, oxalyl chloride in accordance with normal practice. Alternat1vely ~n amine of for~ula Rl9NH_Dl_x ... (VI) may be reacted with a carboxylic acid of for~ula A-D -C02H in an analgous manner.
c) In another aspect of the invention, the linking group contains NR or -N~, together with up to four carbon ato~s in the chain, which may optionally be substituted by oxo or C02(Cl-C4)alkyl. The amino substituent R7 is preferably H, Cl-C4 alkyl, C02tCl-C~)alkyl or aryl(Cl-C )alkyl. The linking group in thls case may optionally be cyclised to form a pyrrolidinyl group or plperidino group, which may option211y be fused to a benzene ring, or it may be an oxazoline ring.
In this aspect the group A is prererably phenyl, optionally substituted as previously defined.

SUBSTITUTE SHEET

. ,` . . . ,: , :.. , ..

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

~780a7 ^ W O 91/17162 PCT/EP91/00737 Thus particular and preferred examples include:

¢~N~X ~ ~) X

~' Compounds of this ty?e maJ be pr2?a ed b: .educ~i:e alk;la.ion of an arylamine or aryi(Cl-C,)alkylamine with an aldehyde of the formula HC0-D -X ... (VII) wherein X and D~are as previously defined.
The reaction is readily achieved via reduction of the Schiff's base using, for example, sodium borohydride or sodium cyanoborohydride. A number of further transformation reactions are possible on the product, as previously described thus, for example, an aryl-nitro group may be reduced to the corresponding amino compound, for example using stannous chloride and, in the case of the 2-aminoanilinomethyl derivative, this may be cyclised by reaction with triethylorthoformate to the corresponding benzlmidazolylmethyl derivative. Further reactions include, for example, reaction of the amine products with n-butyl lithium followed by reaction with a Cl-C4 alkylchloroformate to give the N-alkoxycarbonyl derivatives, or aiky a~ion ~o give the products where R7 is Cl-C4 alkyl, aryl(Cl-C. alkyl) or heteroaryl(Cl-C4)-alkyl.
d) In a further aspect of the ir.~eneion, tne linking group B is a 7 membered saturated or mono-unsaturated ring containing -NR -wherein R7 is as previously defineà. The ring may optionally be SU~STITUTE SHEET

20~8~7 W O 91/17162 ~ PCT/EP91/00737 ~`

substituted as previously defined under B; preferred substituents include oxo and C02R , particularly when R i8 ~ethyl. R iB
preferably H, Cl-C4 alkyl, aryl(Cl-C4)alkyl or heteroaryl(Cl-C4)-alkyl. In this embodiment A is preferably phenyl or substituted phenyl and said phenyl ring is benzofused to the 7-me~bered ring B. Thus particular and preferred compounds of this type include-:

H 0 ~l Cl ~ ~ C02CH3 ~ R-Cl `~' ~ d~l~ ~X

(VIII) (IX) wherein R21 is H, methyl, 4-chlorobenzyl or 2-pyridylmethyl and X
is as previously defined.
The above compounds are prepared by cycllsation of a compound of the formula:

22) ~ 2 C2CH3 <~ C02CH3 X

wherein each R2 is independently H or an aryl group substituent as definet in A above, to give the 3-methoxycarbonyl-tetrahydro-benzazepin-2-one tVIII). Subsequent treatment by heating in pyridine with lithium iodide gives tne tetrahydrobenzazepin-2-one (IX) (R2l~H), whicb may subsequently be alkylated on nitrogen by reaction with a strong base, e~g. socium hydride, followed by reaction with the appropriate alkyl or substituted-alkyl halide to give the l-substituted-tetrahydrobenzazepin-2-ones.

SUBSTITUTE SHEET

. .
: , ..: ..
, . : .

2078~7 ;`1`_~ W O 9t/17162 PCT/EP91/00737 Further particular and preferred compounds of this type include-:

O O
H \\

)3 ~ ~ O IR ~3 ~

X H X

wherein X is as previously defined and R is preferably H.
These compounds are prepared by ring closure of the corresponding open chain compound of formula:
O

22) ~ ~ (R ) ;

respectively by heating under acidic conditions.
e) In a further aspect of the invention the llnXlng group B
contains a S(0) group together with up to four carbon atoms where m is 0-2 . Thus the sulphur atom may be present as a thioether, sulphone or sulphoxide group. The chain may optionally be substltuted by Cl-C4 alkyl or hydroxy. The group A is preferably phenyl optionally substltuted as previously defined in A above.
Particular and preferred examples of this type include:

CONMe~ Cl ~ ,5~ X

SUBSTITUTE S~-IFET

:
:, , `
; :

2~78~7 W O 91/17162 P~/EP91/00737 '~`

Compounds of this type may be prepared by reaction of an aryl or aralkyl thiol of formula A-D -SH with an alcohol of formula HO-Dl-X in the presence of triphenylphosphine and diethylazodicarbo~:ylate to give compounds where the linking group B is -Dl-S-Dl-, where-ln each Dl is as previously defined with the proviso that the number of atoms in the chain linking A to the phenyl ring does not exceed 5.
As be'ore conv2~tiooal ;rans o~_at-o? reac~ions cen be perrormed on the products, for example to give the aryl-carboxamide derivatives ~la nydrolysis OL- ti~e corresponding esters and reaction of the resulting carboxylic acid with an amine.
The sulphones and sulphoxide derivatives (m = l or 2) can be prepared from the thioethers by conventional oxidation, for example using meta-chloroperbenzoic acid.
f) Finally, in a further aspect of the invention, the linking group B is a Cl-C4 alkylene or alkenylene group which may optionally be substituted by one or more OH, oxo, C02R or perfluoroalkyl groups. The group A is preferably phenyl optionally substituted as defined in A above or is heptafluoropropyl. Thus examples of preferred compounds include:

Cl Cl ~ C02Et ~ Cl ; Compounds or this type mav be prepare_ by a number or different methods. In one procedure the aldehyde of formula (VII) may be reacted with dimethylmalonate followed by reaction with the anion derived from 4,5-dichloro-2-nitrotoluene, to provide the compound SU8S'rlTl)TE SHEEl' .' ' '.

- WO 91/17162 Q~r/EP91/OOm of formula (I) wherein the linking group B ls a dimethyl ethylmalonate group of formula:
IH(C~7CH3)2 Alternatively reaction of an arvl aldehyde with a ketoester of formula (~):

O

wherein R4 is C~-C~ alkyl and X is as previously defined, Yields the 3-aryi-2-alko~ycarDonylprop-2-ene-1-one derivative. Reduction gives the 3-aryl-2-alkoxycarbonyl-1-hvdroxypropyl derivative where the linking group is-:

Further possibilities include the reaction of aldehyde (~II) with a benzyl triphenylphosphonium bromide or chloride to give l-aryl ethene derivatives. Finally reac~ion of an ester of formula:
R 02C ~ X
wherein R is Cl-C4 alkyl and ~ and X are as previously defined, by reaction with, for example, a perfluoroalkyl magnesium iodide;
gives the corresponding perfluoroalkyl-carbonyl derivative. The ketone may be further reacted, for example with a further Grignard addition to give further disubstituted-methanol derivatives.

All of the reactions described in a) to f~ above are entirely conveneional and alternative methods and procedures to all of the compounds within the scope of claim ~ will be evident to those skilled in the art. Appropriate reagents and conditions for their performance may be readily established by reference to standard SUBSTITUTE S~EET

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

20~8~
W 0~91/17162 PCT/EP91/00737 text books and to the examples provided hereafter.
The compounds may be purified using conventional methods such as recrystallisation or column chromatography as appropriate, and compounds having acidic or basic centres may be isolated as the free acid or base or in salt form. Compounds having asymmetric centres may be isolated as the racemic mixtures or resolved to give the individual enantiomers. The invention includes all enantiomers whether resolved or not.
The pharmaceutically acceptable acid addition salts of the compounds o~ the formula (~) which form such salts are those formed from acids which form non-toxic acid addition salts, for example the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate, tartrate, metbane-sulphonate, benzenesulphonate and p-toluenesulphonate salts.
; The actlvity 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 rabblt or man into 0.1 vol disodium ethylenedlamine tetraacetic acid buffer and the samples centrifuged for 15 minutes to obtain platelet rich plasma.
~he plasma is further centrifuged to give a platelet pellet which is washed with a buffer solution (4 m~ RH2P04, 6mM Na2HP04, 100 mM
NaCl, O.l~ 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 with stirring for two minutes at 37C in a Paton aggregometer, either with vehicle alone, or with vehicle containing the particular SUBSTITUTE S~tEET

. .
., ` ; .~' 207~0~7 ` ` W O 91/17162 PCT/EP9t/00737 compound under test. PAF ls added at a sufflclent concentration to give a maximum aggregating response ln the abser.ce o~ test compound (lO 8 to lO 9 molar), and the platelet aggregation i~
measured by following the increase in light transmission of ti1e ; 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 maximur.
value is recorded as the IC50 value.
The activity of the compounds of formula (I) is also demonstrated in vivo by their abilitv to protect mice from the lethal effect of an injection of PAF. A mixture of PAF (50 ~glkg~
and DL-propranolol (5 mg/kg) in 0~9/o 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 50X is recorded as the PD50 value.

SUBSTITUTE StlEET

`~` ' ~ ' .'. . `

, 2a~sao7 For therapeutic use the compounds of the formula tI) wlll 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 adminis~ered orally ir. the fon~ of tablets containing such e~cipients as starch or lactose, or in capsules or ovules either alone or in ad~ turP with excipients, or in the form of eli.; rs o. suspens~c..s cGn.alnihO ~ avou.ing or colouring agents.
They may be injected parenterally, for example, intravenously, intramuscularly or suDcutanoousl,. For pa.enteral 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-lO00 mg daily for an average atult patient (70 kg). Thus for a typical adult patient, individual tablets or capsules contain from i to 500 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. ~osages for intravenous atministration would typically ~e within the range l to lO 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 rouee or drug administration. Dose levels by this route would be within the range O.l to 50 mg per single dose as required. In prac~ice 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 SUBSTITUTE SHEET

,`.
~, . . . . .

... . .

particular patient. The above dosages are ex.emplsry of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and such sre within the scope of this invention.
Thus in a further aspect the invencion provides a pharmaceutical composition comprising a compound of the formula (I), without proviso, or a pharmaceuticallv acceptable salt thereor, together with a pharmaceuticallv acceptable diluent or carrier.
The invention aiso inciudes a compound of the formula (I), without proviso, or a pharmaceutically acceptable salt thereof.
for use in medicine, in particular in the treatment of allergic, inflammatory and hypersecretory condltions in a human being.
The preparation of the compounds of the invention is further illustrated by the following Examples.

SUBSTITUTE SltEET

' ' '' .
: .

2 ~ ~ ~ P,Q.62 ! ' PCT/EP91/00737 Methyl 2-~4-(2-me~hylimidazo~4,5-c]pyrid-l-yl~benzyloxylben%oa~e A mixture of 4-(2-methylimidazo[4,5-c]pyrid-1-yl)benz~l alcohol (2.39 g, 10 m~ol), methyl salicylate (1.67 g, 11 m~ol~>
- triphenylphosphine (2.88 g, 11 ~mol) and dry tetrahydrofuran (50 ml) was stirred at room temperature under nitroge~.
Diethylazodicarboxylate (2.09 g, 12 mmol) was added dropwise over five minutes. The resulting solution was stirred at roo~
temperature for 1 hour and the solvent then removed under reduced pressure. The residue was purified by chromatography os silica eluting with a mixture of dichloromethane and methanol (97:3).
The product containing fractions were combined and evaporated to dryness. The resitue was crystallised from diethyl ether to yield the title product (3.42 g, 92%), m.p. 126-128C.
Found: C,70.92; H,S.ll; N,11.17. C22HlgN303 requires C,70.78;
H,5.09; N,11.26X.
i EXAMPLES 2-8 The following compounds were made following the procedure of Example 1 using the appropriate phenol as starting material.

RlO

~8 ~ ~ _ C8 SUBSTITUTE S~EET

.
.
~ ' ' ' ' , ` ., . ~ . . ` .. . .

~u7sao7 - "~WO 91/17162 PCI/EP91/00737 ~ _ _ ~ U~ ~ ~ C`l ~
,_ Z ~ o~ ~ X ~ ~, ~ ~_ O O O O O G C O

~: `D~ u~~ ~ 1_~
~ 5 ~_ ~ u~ ~ ~ ~r ~
111 U~, L~ Ul ~ ~ ~ ~

O ~ ~ ~1 ~ ~J ~ ~ I

__ ~

O O . O r O
: . . ___ _......................... .g _ :Z ~ , SUBSTITUTE SHEE

20i80~7 WO-91/17162 PCr/EP91/00737 ' .. _. ... ~

o ~`, oo ~' ~ ,_ ,_ Z ~ ~ ~ _i ~C ~_, _,~ ~
~: ~ ~ ._ ~ o~ ~ ,_ _ = ~:~ L^, U~ ~D ~ ~

C) r~ U) ~ 0 0 r 0~ r~ 1~ 0 0 ,~ ~n ~ ~ ~

~ ~_~

I~Oy = _ ._ E o r~ c SUBSTITUTE SHEE~

, ': W O 91/17162 PCT/EP91/00737 2-[4-(2-MethYlimidazo[4,5-clpvrid-1-yl)benævloxv~benzoic acid Meth~l 2-[4-(2-methyli~idazo[4,5-c]p~.~rld-1-yl)benzyloxy]-be~zoate (3.73 g, 10 m~ol) was dissolved in ethanol (100 ml), 2N
sodium hydro~ide (20 ml) added and the solution stirred at room temperature for 2 hours. The solvent volu~e was reduced to 30 ml under reduced pressure and the residue poured into water (100 ml).
The aqueous pnase was washed wi.h d~chloromethane (2 x 50 ml) and acidified with glacial acetic acid. The ecid mixture was then e~tracted witll dichloromethanP (3 ~ 75 ml) and the combined acid extracts dried over Na2S04, filtered and the solvent evaporated under reduced pressure to yield a white solid. Trituration with diethyl ether gave the pure title product (2.03 g 57%). m.p.
217-219C. Found: C,68.48; H,4.89; N,11.41. C21H17N3O3 0.5 H20 requires C,68.65; H,4.73; N,11.21%.

The followlng compounds were prepared in a si~ilar ~anner from the appropriate benzoate of Examples 2-5.

R8~_ 0CH

SUBSTITUTE SHEET

"

, w~ a~ 7 i PCl tEP91/00737 .

Z X O~ C _ .
. ~ .

v r,o ~ ~ r- c~J r~ r~ r~
a~o ~a = ~ ~ _ ~ C ~ CJ _ ;~
~ ~rl Irl U~ 1\1 . U~ ~:1 ~ ~-- I

~ O --~ E ~J r~ E rr~ ~ ~ ~

I I ~
~ o I~ _ . U _ :', __ _._ ... _._ _ .
CO~ :~ _~ _ ~ .

~1 _ SUBSTITUTE SHEET

.
' :., , 2~78~07;
. ~ ~

; 23 N,N-Dimethyl 2-[4-(2-methvlimidazo[4,5-c]pyrid-1-Yl)benzYlO~Y
benzamide 2-~4-(2-Methylimidazo[4,5-c]pyrid-1-yl)benzylo~y]benzoic acid (359 mg, 1 mmol) was stirred in dichloromethane (15 ml) and 3 drops of N,N-dimethylformamide were added. Oxalyl chloride (25 mg, 2 mmol) was added dropwise over 1 minute. The resulting solution was stirred at room temperature for 30 ~inutes tnen evaporated to dryness. The residue was redissolved in drv dichloromethane (5 ml) and added dropwise to an ice-cold solution of dimethylamine (1 ml) in ethanol (9 ml) over a five minute perlod. The mixture was stirred at 0C for 30 minutes and the solvent tben evaporatet to dryness. The residue was stirred in ethyl acetate (100 ml), the solution washed with water (2 x 50 i ml), driet over Na2S04, filtered and evaporated to dryness. The residue was further purified by chromatography on silica eluting with a mixture of dichloromethane and ~ethanol (96:4) and the ` product containing fraction were combined and evaporated to dryness. The crude product was crystallised from diethyl ether (258 mg, 67%) m.p. 148-I50C. Found: C,71.12; H,5.78; N,14.29.
C23H22N402 requires C,71.50; H,5.70; N,14.51%.

The ~ollowing compounds were prepared from the corresponding benzoic acid following the above procedure.

coRll R8~0CH~ ~ ~K

SUBSTITUTE SHEET

, . .

~ 20~o`~ ~ -WO 91/17162 PCI'/EP91/00737 _._ ~ jvv; ~
~ `JU~ ~;r `J`~ ~t~

u~ :: r- ~ O Cl~ ~ _ ~ O O o~
. - ~ ~ - ~ ~ U~ ~

~ r ~ ~1 ~ D ~ ;~ ~ L^~ ~ Lr~ C~
~ ' `D~OO ~0~0~ ~_~ `D`D

__ _l _~ Z æ

E o "~

SUBSTITUTE SHEET

;, 2~780~7 .~.. WO 91/17162 PCI'/EP91/00737 . ~. _ _ .._ ~ ~ ~

û. Z I` o ~ ~D O Cl:1C~ O

~ ~o C ~ ~J ~ ~ ~ ~ ~`J ~
V~ ~ ~ X - ~ ~ O' ~ X
. X ~ ~ ~ ~o o~ _~ o .C o ~J ~ ~ ,,~ _ G _ C "~ _ ~ . ~ ~J ~ _ ~S ,~, .
~ O ~ C ~`5 ~ _ ~O C
_ __ ._ .; e ~ ~ ~ o _, N Cl~ O ~

.~ ~ _, .

~ _~ Z Z

_ t~ .
. __ . .. __ ... ... _._ .. -e Z c~ . _ -SUBSTlTlJT6 SI~EEF

....... ..

, " 20780~ l W O 91/17162 PCT/EP91/00737 ~3 The following compounds were prepared using the procedure of Example 1, starting with 2-methyl-2-[4-(2-methylimidazo~4,5-c~-pyrid-l-yl) phenyl]propan-l-ol and reacting with the appropriate phenol, followed by conversion to the corresponding acid or a~.ide following the procedures of Examples 9 and 14 as appropriate.

E~8~ 2 CH ~3-- Cr.

SUBSTITUTE SHEET

~78~7 ~W O 91/17162 P~r/EP91/00737 I T~-U~ _ G. C' .-a~ O _ ,~ ~ O ~ C G ~ -~ ~ --. G 1` G
,~ ~ r r ~n -I
. 0,~,~, .

..

SUBSTITUTE SHEET

2078a'37 WO 91/17162 PCI/EP91/00737 ,,".~

U c ~ ~ A ~ A

_1 X c~

__.

SUBSTITUTE S~IEEl-'207~D~7 Wo 91/17162 PCI/EP91 737 , ~, .

EXAMPLE 3_ 1-(4-~2-chlorophenoxvethvlDheny-~])-2-methylimidazo[4~5-c]pyridine 2-Chlorophenol (0.87 mmol, 112 mg), 1-~4-(2-hydroxyethyl-phenyl)]-2-methylimidazo[4,5-c]pyridine (0.87 mmol, 220 mg) and triphenylphosphine (0.87 mmol, 228 mg) were dissolved in dry tetrahydrofuran (10 ml). Diethylazodicarboxylate (0.87 mmol, 151 mg) was added dropwise and the solution stirred for 24 hours, then eYaporated to drynesc~ The residue was purified by column chro~atographq on si]i~ el~tir.~, w'~.. ' chloL~e~nane an~ methanol (97:3), and the 2roduct-containing fractions evaporated to dryness to give an oil (0.23 g, 73~) which crystallised on standing. M.p.
111-113C. Found: C,68.78; H,4.96; N,11.47. C21H18ClN30 0.25 H20 requlres C,68.48; H,5.06; N,11.41%.

SUBSTIT.UT~!::~EET

7 ~ ~ PCT/EP9l/00737 _ EXf~PLE 31 1_(2_Chlorophenoxy)-2-[4-(2-methylimidazo~4,5-clpyrid-1-yl~-phenyl]propan-2-ol A mixture of 2-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl~-2-methyloxirane (133 mg, 0.5 mmol), 2-chlorophenol (129 mg, 1 mmol) and potassium carbonate (138 mg, 1 mmol) ~as stir ed in N,N-dimethylformamide (5 ml) at 90C under nitrogen for 10 hours.
The cooled mi~ture was poured into brine (;0 ml) ,her e~.~~ac~e~
with dichloromethane (3 x ~n ml), Thc com~ neu ~rganic extracts were dried over Na2S04, filtered and evaporated to drynPss. The residue was further purified by column chromatography on silica ' eluting with dichloromethane/methanol (97:3). The product-containing fractions were evaporated to dryness and the crude ~ product crystallised from diethyl ether. (119 mg, 61X). m.p.
; 225-227C. Fount: C,66.95; H,S.24; N,10.36. C22~20ClN302 requires C,67.09; H,5.08; N.10.67X.

The following compounts were prepared as described above using the appropriate oxirane and phenol as starting materials:

R8 ~ OCH? I ~ CH3 ~' SUBSrITUTE S~EET

2~7~007 `: WO 91/17162 PCI/EP91/00737 ~ ~ 1 1 ~ ~ ~ '~

_ . _ SUBSTITUTE SHEET

.

W O 91/17162 PCT/EP91/00737 ,.

2 - r 4 - ( 2 -~l2 t hv-Li~ida~ c ~ ~ ~ 5-c i p~ rid~ v ~ 3-benzo [ e ]
dio~eDane p-Toluenesulphonic acid hydrate (0.23 g, 1.2 mmol) was added in small portions to a boilillg solution of 4-(2-methyimidazo~4.5-c]pyrid l-yl)-benzaldehyde (0.23 g, 1 ~mol) and 1,2-bis-hydroxy-methyl-benzene (0.16 g, 1.2 mmol) in dichloromethane (6 ml). This mixture W25 refluxed through a scxl~let thimble containing 4 Angstrom ~olecular sieves for 2 h~llrs, then pa.. ;iol-~d be~ween dichloromethane and satz~rat2d aqueous sodium bicarbonate. The organic layer was separated, dried over magnesium sulphate and the solvent evaporated to yield a foam which was crystallised from et~yl acetate/diethyl ether (0.3 g, 822). m.p. 142-144C. Found:
C,73.29; H,5.38; N,11.32. C22H19N302 requires C,73.93; H.5.36;
N,11.76Z.

The Examples in tbe follouing Tables were prepared following the above proceture reacting 4-(2-methylimidazo[4,5-c]pyrid~l-yl)-benzaldehyde with the appropriate diol or with butanol.

A ~

SUBSTITUTE SHEET

.'' ,~

20780~7 W O 91tl7162 PCT/EP91/00737 . _ _._ .. _ Example A-B- m.p, Analysis %
C(Theoretical in brackets) C H N

33 _ 0 foam72.33 5.36 11.25 . ~ol (72.51 4.98 11.53) ; ¦ (0.25 mole CH3C02C2H5) ~ _ ._ - I 39 ~lass70.40 5.66 10.26 ! ~ H2 ~ 0 ~ (70.39 5.55 10.63) (0.25 ~ole CH3C02C2H5) ~- _ .

73.22 5.62 11.18 (72.82 5.58 11.07) (0.5 ~ole CH3C02C2H
_ . _ _ _ _ _ 41 1 0 ~51-53 73.68 5.59 11.33 (73.93 5.36 11.76) __; ~ .
42 ~ ~88-8 76.60 5.47 9.34 (76.40 5.53 9.22) ~" 0 (0.25 mole CH3CO~C,H5) _ . . . -43 ~ foam ! 73.02 5.72 10.36 (73.05 5.89 9.86) (0-5 mole CH3CO2c2H5) . _ SUBSTITUTE StlE~T-- - - . ~ . . - .

~. :
'`,, .. , s ~: ~v~(~uu ~
W O 91/17162 . ~ . PCl/EP91/00737 ~.

Examplel A-B-¦ ~.p.l Analysis /, No I ¦ c ~ eorecical in br~7ckets) ¦ I ~ H 1 , I ! - - __ I
44 CH3(CH2)30 oil 70.9~ 8.02 10.79

3(CH2)30 (70.61 7.96 10.95 . 0.25 moie CH3CO~C H ) i 45 ~ _ . ~
. /~ 0 ~ 1;4-o 1 /4.02 ~.7010.95 ; ~ I (74.37 5.7011.31) ~ ._ - , - .
46 ~== \ r 0 148-501 74.37 5.8011.40 ) ~ (74,37 5.7011.31) 47 157-9 ' 72.26 5.3911.41 ~ ~72 11 5 5011.47) SUEIST~TUTE SHEET

'. ' : ` , 2~730~7 2-~4-(2-Methylimidazo~4,5-c]pvrid-1-yl)phenyl]-2-me~hyl-4 phenYl-1,3-dioxolane Neat 1,2-bis(trimethylsilyloxy)-1-phenylethane (0.17 g, 0.6 mmol) was added to a cold (-78C), stirred solution of trimethylsilyl trifluoromethanesulphonate (0.1 ml) in dichloromethane (1 ml). After 5 minutes, a solution of

4-(2-methylimidazo[4,5-c]pyrid-1-yl)acP~ophenone ~0.13 g, 0.5 mmol) in dichloromethan~ fl ml) 'as aducu. lh~ resultant solution was war~ed to 20C during 2 hours, then stirred for 72 hours before partitiouing between dichloromethane and saturated sodium blcarbonate solution. The organic layer was washed with brine, dried over magnesium sulphate and evaporaeed to a yellow oil.
Silica gel chro~atography uslDg 10~ methanol iD ethyl acetate as eluant afforded a colourless foam (0.1 g, 48%). The product was a 1:3 mixture of cis/trans isomers. m.p. less than 40C. Found:
C,72.56; H,5.85; N,10.53. C23H21N302.~H20 requires C,72.61;
H,5.ô3; N,11.04Z.

2-(2-Chloro~henyl)-4 14-~2-~ethYlimidazo~4,5-c]p~rid-1-~l)phen l~-1,3-dioxane ~ utyllithium (1.6M in hexane; 0.91 ml, 1.46 mmol) was added in trops to a stirred suspension of l-[~-tl,3-dihydroxypropyl)-phenyl]-2-methylimidazo~4,5-c]pyridine (0~2 g, 0.7 mmol) in anhydrous tetrahydrofuran. The ~ixture was heated to re~lux ~o-30 minutes, then cooled ant treated with chlorotrimethylsilane SUBS~ E SH~E~

2~780~7 W O 91/17162 PCrJEP91/00~37 (0.22 ml, 1.7 mmol). After stirring for 16 hours, the golvent was evaporated and the residue partitioned between dichloromethane and saturated aqueous sodlum bicarbonate. The organic laver was drled over magnesium sulphate and concentrated to an oil. To a solution of this oil in anhydrous dichloromethane (5 ml) at 0C were added sequentially a solution of trimethylsilyl trifluoromethane-sulphonate (0.18 ml, 0.92 mmol) in dichloromethane (1 ml) followed by 2-chlorobenzaldehyde (0.1 g, 0.7 mmol). The mixture was stirred at a~bi2nt temperatllr~ for 24 h^u.s, and .hel~ par~irioned between dichlorsm2than2 and saturated, aqueous sodium bicarbonate.
The organic layer was dried over magnesium sulphate and evaporated to an oil. Silica-gel chromatography eluting with 10% methanol in etbyl acetate and trlturation with diethyl ether afforded a white solid (0.15 g, 52Z), m.p. 161-164C. Found: C,67.81; H,5.02;

N~10-14. C23H20ClN302 requlres C,68.06; H,4.97; N,10.35X

AMP~E 50 4-~4-(2-Methylimidazo~4,5-c3p2rid-1-yl)~henyl]-2-(3,4,5-tr methox~phenvl)-1,3-dioxane The procedure of Example 49 was followed but replacing 2-chlorobenzaldehyde with 3,4,5-trimethoxybenzaldehye in the second stage of the process to yield the title product as a white solid in 28~ yield. M.p. 135C. Found: C,66.95; H,5.97; N,8.8~.
C2~H27N305. 0.25 H~0 requires C,67.01; H,5.95; ~,9.02X.

, W O 91/17162 2 0 7 8 0 Q 7 PCT/EP91/00737 2-~4-(2-Methvlimidazo~4,5-c]pyrid-~ )phenyl]-4-pheny~ 3 dioxolane _ 1,2-Bistrimethylsilyloxy-l-phenylethane (from Preparation 6) (0.34 g, 1.2 mmol) was added to a cold (-70C), stirred solution of trimethylsilyl trifluoromethane-sulphonate (0.23 ml, 1.2 mmol) in dry dichloromeehane (2 ml). After 5 minutes, a solution of 4-(2-methylimidazo~4,5-c]-pyrid-1-yl)benzaldehyde (0.24 g, 1 mmol) in 2 mi or dichloromethane w~s added. The m 2;ur~ was alloweb to warm to 22-24C then stirred at this temperature for 22 hours.
The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and dichloromethane, the organic layer was dried (MgSO4) and evaporated to a residue which was purifled by sllica-gel chromatography (5X methanol in ethyl acetate as eluant) to afford the title compound as a foam (0.031g, 8%). Found:
C,71.37; H,5.39; N,10.83. C22~19N302. 0.75 H20 requires C,71.24;
H,5.57; N,11.27~.

SUBSTITUTE S~IEET

.
, 20780~7 W O 91/17162 ' PCT/EP91/00737 -2-Chlorobenzvl 4-(2-methylimidaæo~4,5-c]pyrid-1-Yl)benzoa~e Oxalyl chloride (0.7 ml, 8 mmol) and dime~hylfor~a~'c'e (1 drop) were added to a stirred suspension of 4-(2-methylimidazo-[4,5-c]pyrid-1-yl)benzoic acid (0.51 g, 2 mmol~ in dichlorometnane (10 ml) at 0~ under nitrogen. After 1 hour, the solvenr ~as evaporated and the residue dissolved in dichloro~ethane (lu ml~ tG
which was added 2-chlorobenzyl alcohol (0.86 g, 6 ~mol) and 4-dimethylamino-pyridine ('7~3 c rr-s~als~ ~irer 1~ hours, he mixture was diluted with dichloromethane and ~ashed with aqueo~s sodium carbonate. The organic layer was dried (MgS04) and evaporated to an oil. Flash chromatography, eluting with 15%
methanol ~n ethyl acetate left a residue which solidified on trituration with diethyl ether (0.255g, 33%). M.p. 147-149C.
Found: C~66.86; H,4.32; N,11.15. C21H16C12N302 requires C,66.76;
H,4.27; N,11.12;;.

EXA~fPLE 53 ~4-(2-Methylimidazo~4,5-c]pyrid-1-yl)benzvlo~ldi henylmethane hydrochloride 4-(2-Methylimidazo[4,5-c]pyrid-1-yl)benzyl alcohol ~1 mmoi, 253 mg), and benzhydrol (1 mmol, 184 mg) were dissolved ir.
dichloromethane (5 ml). ~'rifluoroacecic acid (0.5 ~1~ was added dropwise and the mixture stirred ror 15 minutes. The solution ~as poured into 2~; sodium hYdroxide and che aaueous phase e~racted with dichloromethane (3 x 4~ ml). The co~bined organic extractC
were dried over MgS~,, filtered and evaporated to dryness. The residue was further purified by column chromatography on silica SUBSTITUTE SHEET

. .
..

W O 91/17162 2 0 7 ~ ~ ~ 7 PCT/EP91/00737 gel eluting with dichloromethane/methanol (95:5). The product containing fractions were evaporated to drvness, dissolved ln ether and treated with ethanolic hvdroges chloride. ~he resulti solid was recrystallised from eth~l ace~a~e/methanol, (6A~ mg, 14%). M.p.235-237C. Found: C,7~.,3; H,5.5~ 5~
C27H23N3O.HCl. 0.25 H20 requires C,72.65; H,5.49; `~,C.42,' ~ A.~PLE ~4 ~4-(2-Methylimidazor4.~-e!nvrid~ bc".vlo-~ -chloro~ne~
methane hvdrochloride 4-(2-Methylimidazo[4,5-c]pyrid-1-yl)benzyl alcohol (1 mmol, 253 mg) was dissolved in dimethylformamide (10 ml) and sodium hydride (60X in oil, 1.15 mmol, 46 mg) was added and the mixture stirred at room temperature for 1 hour. Freshly distilled chlorobenzyl chloride (1.1 mmol, 177 mg) was added and the mixture stirred for 4 hours at room temperature. The reaction was quenched with lN hydrochloric acid (1 ml) then basified with 5X
sodium carbonate solution and the aqueous phase extracted with dichloromethane (3 x 50 ml). The organic extracts were dried over MgS04, filtered and evaporated to dryness. The residue was purified by column chromatography on silica elucing with dichloromethane/methanol (97:3) and the produce containing fractions evaporated to dryness. The oil was redissolved in diethyl ether and ~reated with ethereal hvdrogen chloride. lhe solid precipitate was recrvstallised tro- eth~l aceta;e/methanol to give the title product, (67 mg, 177,). ~.p. 218-A~20C. Found:

C,62.44; H,..75; N,10.34. C21H18Cl,;~O.H~i. 0.25 H~0 requires C,62.31; H,4.86; 10.387 SUBSTITUTE S~IEET
. .

...

, . . .
, . ~ . .

20780~7 ; 40

5~(2-Chlorophenvl~-2-[4-(2-methylimidazo~4~5-c~pvrid-l-vl~phen delta~-oxazoline 2-t2-chlorophenyl)-2-hydroxyethyl]-4-(2-methylimidazo[4~5-c]
pvrid-l-vl) benzamide (0.5 mmol, 200 mg) and triphenylphosphine (0.6 ~ol, 157 mg) were dissolved in tetrahydrofuran (5 ml) at room te~perature. Diethvlazodicarboxylate (0.6 mmol, 104 mg) was ad~d d opwis2 and the mi~ure stlrred for 12 hours then poured into ether 150 ml~ and ex~-acted ~ith 0.5 N :,vurochioric aci~ ~ x 25 ml). The combined aqueous eY.tracts where basified with 2~
sodium hydroxide then re-extracted with dichloromethane (3 x 50 ml), dried over NaS04, filtered and evaporated to dryness. The residue was partially purified by column chromatography eluting with ethyl acetate/diethylamine (97:3), the product-containing fractions were evaporated and the residue further purified by preparative thin-layer chromatography in dichloromethane/methanol (95:5) to give the title product (25 mg, 13%), m.p. 127-130C.
Found: C,67.68; H,4.67; N,13.79. C22H17ClN40 requires C.67-95;
H,4.38; N,14.41Z.

SUBSTITUTE SHEET

.

. .

~ . WO 91/17162 2 0 7 8 0 ~ 7 PCT/EP91/00737 ~,N-Diethvl-~4-(q-methylimidazo[4,S-clpyrid-l-yl)phenYl~-propionamide a) Methyl 3-[4-(2-methvlimidazo]4,5-c1pyrid-l-yl)phenyl]-propanoate (3.56 mmol, 1.05 g) was dissolved in ethanol t25 ml) and 2.~ sodium hvdro.:ide (10 ml) added. The solution was stirred at roo~ temperature for 1 hour then poured into water and acid- fied with glac al ac-tic acid. TAe soiution was extracted with dichioromethane t3 x 50 ml! i an.d ~ hc cO~L-llêd eX~L~LS were dried o~er ~gS04, rilterêd and evaporated to ~ield 3-[4-(2-methyl-imidazo[4,5-c]pyrid-1-yl)phenyl]propanoic acid.
b) ~4-(2-Methylimidazo[4,5-c] pyrid-l-yl)phenyl]propanoic acid (1 mmol, 281 mg) was stirred in dichloromethane (10 ml) and one drop of dimethylformamide adted. Oxalyl chloride (2 mmol, 254 mg) was added dropwise and the resulting solution stirred at room temperature for 30 minutes then evaporated to dryness. The residue was redissolved in dichloro~ethane tlO ml) and diethylamine (3 mmol, 219 mg) were added and the solution stirred for 30 minutes at room temperature. The reaction mixture was poured into water and extracted with dichloromethane (3 x 25 The combined extracts were dried over ~a2S04, filtered and evaporated to dr~ness and the residue was purified b~ column chromatography on silica eluting with cichloromethane/methanol (9;:3). ~he product containing fracticns were evaporated to dryness and the oil crystallised from dieth~l ether/he~ane to give the title compound ~194 mg, 58%), m.D. lq3-lq5C. Found: C,71.1q;
H,7.22; ~;,16.84. C20H2 ~ 0 requires C, 1.43; H,7.1~; ~;,16.67,~.

SUE~STITUTE S! IEET

, -, ` ... ..
. .
. , ,~, . . .. ; . ~. 1.".. ,. ; ., ,' ... ` . .
' .. . ' ::. ' ` ' 207~0Q7 W O 91/17162 ~ ` PCT/EP91/00737 ,.
, The following compounds were prepared as described in Example 56(b) above using t~e appropriate a~ine instead Oc dieth:'a~irc.

; C~13 R CO(CH~

Exa~ple R13 Im.p. Analysis %
(Theorecic~l in brackets) 57 . 237-67.35 5.13 18.59 239(67.37 5.15 18.49) NH- (0-25 mole CH2C12) 58 ~ 1171-70.93 7.25 16.33 (CH3)3cNH- ¦173 (70.8Q 7.26 16.52) II (0.17 ~ole a~o) . ~
59 ~190-65.21 5.95 13.01 CH~H- 194~65.02 5.8 13.19 (HCl, H~0) . . . _ .
~ 155- 68.~4 6.5~ 3 ~ 157 (68.57 6.~9 16.00) SUBSTITUTE SHEET

, .. ~ . . . .: . .
. ~ .' . ....
~,. ..

.O W O 91/17162 2 o 7 8 ~ ~ 7 PCT/EP91/00737 EXAMPLES 6l-64 Ethyl 2-[4-(2-methylimidazo~4,5-c]pvrid-1-yl)phenyl]propanoate (Preparation ~T) was hydrolysed following the procedure of E;:am~lc 56 (a) and reacted with appropriate amines following the procedure of Example 56(b~ to give the following co~po~nd~s:

Ch3 ICr~

\~

Example R13 m.p. Analysis %
C (Theorec~ical in brack 61 (C~3)3cNH- 165- 71.45 7.22 16.95 167 (71.43 7.14 16.67) 62 ~ ~ 100- 1 70.34 5.50 20.25 NH- 104 (70.59 5.32 19.61) . . , _ __ . _ (C2H5)~N- !151- 71.14 7.26 16.33 161 (71.~3 7.1~ 16.67!

T
64 ~ 1123- 7~.10 ,.03 16.5 ~ ¦1 5 t7_.41 6.90 16.0 . . _ .

SUBSTITUTE StlEET

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

wo 91il7162 2 0 7 8 ~ 0 7 PCT/EP91/00737,~

~ -(2,4-Difluorobenzvlamin~methYl)Dhenyl~-2-methylimldazo~4,5-c]pvridine a) A suspension o} 4-(2-methylimldazo[4,5-c]pYrid-l-yl)-benzaldehyde (750 mg, 3.16 mmol). 2,4-difluorobenzyl-amine (500 mg, 3.5 mmol) and silica gel (230-400 mesh) (1 g) in anhydrous dichlorome~hane (20 ml) was stirred for 16 hours at embient temperature. The suspension was f.ltered, the filtrate evaporat~d to dryness and th~ resid-_al gum ;ri-u~ea wi~n anhydrous diethyl ether to af~ord the Schiff's base as white solid (700 mg, 61%).
b) Sodium borohydride (57 mg, 1.5 mmol) was added to a stirred solution of the above product (500 mg, 1.4 mmol) in anbydrous methanol (10 ml) at 0C. The stirred solution was warmed to 20C
over 1 hour, then the solution concentrated, the residue acitified to pH 1 with 2M hydrochloric acid, water (20 ml) added ant sodium bicarbonate added to pH 8. The solution was extracted with ethyl acetate (50 ml). The ethyl acetate extract was wasbed with water, dried over ma~nesium sulphate and concentrated to dryness.
The residual gum was triturated with anhydrous diethyl ether to give the title co~pound as a white solid. tO.l g, 20~), m,p.
108-110C. Found: C,69.06, H,5.00; ~,15.48. C~IHl8F2Nl requires C,69.22; H,4.98; N,15.37~.

SUBSTITUTE SHEET

-, .
. , :
.. , ", .
. ' .

~ ; ~
W O 91/17162 2 0 i8 0 ~ 7 PCT/EP91/00737 ' 45 lhe abo~e procedure was followed using the appropriate amlne in step (a) to yield the following products ~ -CH~ ~ t~ t~

E~a~ple R14 m.p. I Analysis No ¦ (Theoreeical in brackets) 66 ~ CH2NH- 88-69.73 5.28 15.58 1 90(69.51 5.28 15.44) 67 131- ! 77.51 5.97 16.20 t~' - 1321 (77.62 5.92 16.40) ¦ tO.25 mole H20) , 1 _ 104-69.26 5.76 1~.79 I I ~ ( 2)2NH 106(69.28 5.68 14.69) . _ . _ .
64 ~ ~ roa~74.5,6.43 14.10 t/4.5~ 6.78 l~.jO) ¦ (hydrate!

.. . .

SUBSTITUTE SHEET

' W O 91/17162 2 0 7 8 0 0 7 PCT/EP9t/00737 ~

1-[4-(1,2,3,4-Tetrahydroisoquinolir.-1-vl-~eth~l)phenyll-2-~ethvl-imidazo[4,5-c]pyridine Glacial acetic acid was added ~o a stirred solution o.
1,2,3,4-tetrahydroisoquinoline (3.5~ g, ~6.~ mmol) in anhyd.ous methanol (15 ml) until the pH was ,. 4-(2-Methyl midazo[4,~c7-pyrid-1-yl)benzaldehyde (1.56 g, 6.6 mmoi) was then added and the reactants stirred at ambient ;emDP~a~ure ,~r ~0 ~ nutes Derore adding sodium cyanoborohydride (0.63 b~ 10 ~vl)~ lh~ reaC~all~C
were stirred at ambient tempera~u~e ~or ~0 minu~es, then ~a~er (sC
ml) added. 2M Hydrochloric acid was added to pH 2, followed b~
sodium bicarbonate to pH 8 and the aqueous solution was ehen extracted with dichloromethane (100 ml). The organic exeract was washed with water (50 ml), drled over magnesium sulphate and concentrated under vacuum.
The residual gum was chromatographed on silica (230-400 mesh), eluting with 5% diethylamine in ethyl acetate. Appropriate fractions were combined and concentrated and the residual gum triturated with diethyl ether to give the title compound as a white solid (450 mg, 20~). tl.p. 110 -112C. Found: C,77.73;

H,6-21; N,15,76- ~13H22N4 requires C,7/.94; H,6.26; N,lj.817O.

SUBSTITUTE SHEET

' ^; W O 91/17162 2 0 7 8 ~ 0 7 PCT/EP91/00737 1he following co~pounds were prepared by the above procedure usin~ the appropriaee amine ins~ead cf t~rr2~ droiso~uinol.irc ~, -C~
'~

_ Example Rl~ m.~. ! Analysis /~
No. ~ IC ¦ (Theoretical in brackets) __ _ j C H

71 1 ~ 140- 77.83 6.22 16.11 l I _ 142 (77.94 6.26 15.81) 7~ ¦ 102CH3 gu~ I characterised b~ N~P~( ) ¦ ~ CH2-CH-NH- l l 2 _ 269- 1 66.67 4.8~ 19.14 ~H- l273 1 (66.84 4.7/ 19.49 .
(1) ~ (C~C13): 2.58(3H,s!, 3.01(1H,dd -11.6Hz~ 3.10(1H,dd J=li, 6Hz), 3.60(1H,~ J~6Hz), 3.74(3H,s), 3.,8 and 3.98(each lH,c J=15Hz), 7.08(1H,d J=4.5Hz)t 7.~-. .4( H,~, 7.~7¢3'r.,d J=c~
8.41(1H,d J=4.5Hz) and 9.08(1H,s!.

SUBSTITUTE S~IEET

;' ' , . ., " . ' . .
~. ' . . ,~

W O 91/17162 2 0 7 8 0 a 7 PCT/EP91/00737 1-(4-~-Phthalimidomethylphenyl)-2-methvlimidazo[4,5-c]pvridlne To a stirred suspension of 4-(2-methylimidazo~4,5-c]pyrid-1-yl)benzyl alcohol (431 mg, 1.8 mmol) in anhydrous teerahydrofuran (10 ml) under nitrogen were added in turn, phthalimide (26~ mg, 1.8 mmol), triphenylphosphine (471 mg, 1.8 mmol) and diethylazodicarboxylate (6.283 ml, 1.8 mmol). The solution was stirred ae ambient tempera~ure for 16 hours then evaporated to ~rvnP99 anA ~hc rcs-Jual ~uul cilLu~L~rapned on silica (~30-4uu mesh), eluting with 10% - 20% methanol in ethyl acetate.
Appropriate fractions were combined, concentrated and the residual gum triturated with ethyl acetate to ~ive the title compound as a white solid (200 mg, 30X), m.p. 222-224C. Found: C,71.44;
H~4-42; N~15-22- C22H16N402 requires C,71.73; H,4.38; N,ls.21%.

1-~4-~N-(2-Amino~henyl~sminomethAYl]ohen-1~-2-methVlimidazo~4.5-C ! -pvridine Stannous chloride dihydrate (280 2g, 1.25 mmol~ was added to a s~irred solution of 2-methyl-1~4-~N-(2-nitrophen)~l)amino-methyl]phenyl~-2-methylimidazol'4,5-c]p~ridine (from Example 73) (90 mg, 0.25 mmol) in 2M hydrochloric acid (0.5 ml), ethanol (1 ml) and wacer (1 ml). The solution was stirred under reflu~: for hours then cooled to ambient temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbona e The or~anic e~tract was washed with water~ dried over magnesium sulphate and concentrated to drvness. The residual gum was chromatographed on silica (230-400 mesh), eluting with 2Z-10,.

SUBSTITUTE StlEET

wo 9l/17162 2 0 7 8 0 G 7 PCT/EP9l/00737 ' diethylamine in ethyl acetate. Appropriate fractions were combined, concentrated and the residual ~um triturated with dieth~l ether to give the title compound as an o~-white solid (~7 mg, 27%), m.p. 190-195C. Found: C,71.99; H,5.88; ~,20.28.
C20HI9~5. 0.l25 CH3C02C2H5 requires C,72.33; H,5-92; ~20.57~o-EXAMP~E 76l-r4-Benzi~idazol-l-ylmeth,~l)phenyl~-2-~ethvlimidazo[4~5-c]

nV r ~ ' n O
A solution of 1-~4-[N-(2-aminophen~l)a~inomethyl]phenY~ -2-methyl-imidazo[4,5-c]pyridine (300 mg, 0.91 mmol) and triethyl-orthoformate (5 ml, 30 mmol) in formic acid (0.5 ml) was stirred under reflux for 1 hour, then cooled to ambient temperature, diluted with water (S0 ml) aod stirred at ambient temperature for 16 hours. The solution was concentrated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate (pH 8). The organic extract was separated, washed with water, dried over magnesium sulphate and concentrated to drvness. The residual gum was chromatographed on silica (230-400 mesh), eluting with 20Z methanol in eth~l acetate. Appropriate fractions were combined and concentrated under high vacuum to give the title compound as a foa~ (150 mg, ~9Z). Found: C,73.57;
H,5-06; ~,20-16- C21H17~5. 1/4 H~0 recuires C,73.34; H,5.13;
0.36%.

SUBSTITUTE SHEET

' ': ' ' `' ', '' . ' : . ', ~ ` ' -. , ' ' , . ', `, 2~78~
W O 91~17162 PCT/EP91/00737,~.

1-~4-(N-(2-Ch_.~robenzyl)-N-ethoxvcarbonylamino)phenYll-~-methYI-imidazo~ 4, 5-c]pvridine n-~utyl lithium (1.6M in hexane) (1.19 ml, 1.9 mmol) was added dropwise to a stirred solution o~ -(2-chiorobenz~
; aminomethyl)phenyl~-2-methylimidazo~,5-clp~ridine (0.61 ~, 1.7 mmol) in anhydrous tetrahydrofuran1 under ~t.ogen, at -30~.
After stirrin~ for 20 minutes at _30C~, et:~l chlororor~ace (C.2~
ml. 2.? ~m^'~ as ad ~ ' ald .~ irred rea_.lon ~;~;ur~ wa~ed tc ambient temperature over 16 hours. Saturated aqueous sodium bicarbonate solution was added to the stirred reaction mixture and the product extracted into ethyl acetate. The organic extract was washed with water, dried over magnesium sulphate and concentrated to an oil (700 mg). Chromatography on silica elut~ng with 5Z
methanol in ethyl acetate gave the title co~pound as a solid (90 mg, llX), m.p. 118-122C. Found: C,65.32; H,5.30; N,12~51.
C24H?3C1~40?.~H2O requires C,64 93; H,5.45; ~ 12 62,' 1-~4-~N-Benz~ e~hoxv~rbonvlamino)ehenvl]-~-meth~l-imidazo~4,5--c]pvridine This compound was prepared as described in the previous Example starting with the corresponding ~-ben~.laminometh~l derivative to give the title ~-benz~l compound as a solid (37~).

~I.p. 1~9-132C. Found: C~71~7~J; H,j.~2-; `:.13.S5.
requires C,71.98; H,6.04; ~13.9g~o.

SUBSTITUTE StlEET

~e W O 91/17162 2 0 7 8 0 ~ 7 PCT/EP91/00737 E,YAMPLE 79 N-(2-Chlorophenvlacetvl)-4-(2-methylimidazo~4,5-c]pYrid-l-vl)benzvlamine . .
a) Raney nickel (0.25 g) was added to a solution of 4-(2-methylimidazo~4,5-c]pyrid-1-yl)benzonitrile (2.3~ g, 0.G7 mmol) in acetic anhydride (15 ml) and the reaction m :ture hydrogenated at 50C and 50 p.s.i. (3.45 bar) ror 1 nour. The reaction mixture was filtered, the filtrate dilu~ea ~ith water (5 ml~ dnU aonc~n~ra~ed hyd-ochlorlc 2C' ~ ) ar.d t~e sol~tio~.
stirred at 100~C for 16 hours. On cooling to ambient temperature.
2~1 sodium hydroxide was added to pH 9 and the product extracted with ethyl acetate. The organic extract was washed with water~
dried over magnesium sulphate and concentrated under reduced pressure. Chromatography on sllica, eluting with ethylacetate:
methanol:diethylamine (90:5:5) gave 4-(2-methylimidazo~4,5-c]-pyrid-l-yl)benzylamine. (0.6g, 252).
b) Oxalyl chloride (0.7 ml, 8 mmol) was added to a stirred solution of 2-chlorophenylacetic acid (340 mg, 2 mmol) in anhydrous dichloromethane (6 ml) under nitrogen. Anhydrous ; dimethylformamide (2 drops) was added and the solution stirred aè
ambient temperature for 2 hours. The solution was concentrated under high vacuum, then re-dissolved in dichloromethane (10 ml) and a solution of 4-(2-methylimidazo[~,5-c~-pyrià-1-yl)benzylamine (0.6 g, 2.5 mmol) in anhydrous dichloromethane (10 ml) added over 5 ninutes. lhe solucion was stirred a~ ambien~ temperature for 16 hours, then washed with saturated aqueous sodium carbonate (pH 9), dried over magnesium sulphate and concentrated under vacuum SUBSTITU~E StlEET

. . ' '`' W O 91/17162 2 0 7 8 0 a 7 PCT/EP91/00737, r-Chromatograph on silica, eluting with 10% methanol in ethyl acetate ~ve the title compound as a foam (350 mg, 45%). Found ~,66.08; H.4.95; N,13.75. C22HIgClN O.~H~0 requires C.66.08:
~,5.04; N,14.01%.

EXAMP~E 80 ~-(3',4'-DichlorobenzoYl~amino-4-(2-methvlimidazo~4,5-c~pvrid-1-yl acetophenone ..~Eeh~ 2~ e;hyii-uiu;~ pyrid-i-vl~-2-oximlnoben.o~,laceta.e A solution ol sodium nitrite (3.3 g, 47 mmol) in water (40 ml) was added in drops to a solution of ethyl 4'-(2-methyl-imidazo[4,5-c]pyrid-1-yl~benzoylacetate (12.6 g, 39 mmol) in glacial acetic acid (45 ml) at 5C. After 1.5 hours the ~ixture was partitioned between tichloromethane and brine. The organic layer was washed again with brine and then with saturated aqueous sodium bicarbonate, dried (MgSO4) and evaporated to an oil which rapidly crystallised on addition of ether (9.61 g, 707~), (2:1 mixture of syn/anti isomers). M.p. 168-170C.
b) Ethyl 2-acetamido-4'-(2-methYlimidazo~4,5-c]p~rid-1-ylbenzoyl-acetate A solution of ehe product from al above (6 g, 17 mmol) in acetic acid (33 ml) and acetic anhydride (9 ml~ was hydrogenated over 5~ palladium on carbon (1 g) at 50 p.s.i. (3.45 bar! at 30C

ror 2 hours. The mi~tute was filtered ehrough a filter pad, washing the ca~e with methanol and the filtrate was evaporated.
The residue was chromatographed eluting with methanol and then 10, methanol in ethyl acetate to afford 2 colourless foam (6.1 g, 94X). M.p. 71-73C.

SUBSTITUTE SHEET

.`
' ~ wo gl/17162 2 0 7 8 0 ~ 7 PCT/EP91/00737 c) 2-Amino-4'-(2-methvlimidazo~4,5~clpYrid dihvdrochloride A solution of the product from b) above (1.2 g, 3.2 mmol~ in 2M hydrochloric acid (30 ml) was heated at reflux for 3 hours.
The solution was evaporated to dryness to vield the amine hydrochloride salt as a colourless foam (1.35 g), which was stored under vacuum.
d) N-(3',4'-Dichlorobenzoyl)amino-4-(2-methylimidazo~4,5-c]p~rid-i-yi ace~oinenone N-~ethylmorpholine (1.6 ml, 16 mmol) was added to a stirred suspension of the product from c) above (0.7 g, 1.8 mmol), l-hydroxybenzotriazole (0.34 g, 2.4 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (0.89 g, 4.7 mmol) and 3,4-dichlorobenzoic acid (0.42 g, 2.2 mmol) in dichloromethane (25 ml). After 26 hours, the mixture was evaporated and partitioned between water and ethyl acetate. The organic layer was dried (MgS04) and evaporated to an orange gum t0.69 g~-Chromatography, eluting with 15X methanol in ethyl acetate, afforded a foam which solidified upon tri~uration with dieth~l ether, (0.3 g, 38%), m.p. 108-110C. Found: C,58.78; H,3.76;
~'~12-20%- C22H16C12N402.~H20 requires C,58-93; H,3-83; ~12-50~-SUBSTITUTE SHEET

.
.

.

WO 91/17162 2 0 ( 8 a o 7 PCI'/EP91/00737 _ EXAMPLES 8l-83 . _ lhe following compounds were pre~ared as described in the previous E~ample using the a~propri~te acid in S~eD d):

oCH3 R 15 -COl;iH-CH ., -C

~xample I pl5 I ~-?~ ~ ^nalysis '~
No C l(Theoretical in brackees)¦
¦ C H

81 148- ; 67.82 4.88 17.57 150 (67.78 4.98 17.96) H3C (0.25 mole H20) ._ 82 ~ 2 Z q - charac~erised b~ :~MR ( 1) 83 ', ~ CH2Si(CH3)3 197- characterised by NMR (2j (1) ,S (DMS0-d6) 2.56(3H,s), 5.16(2H.d J=SHz) 7.28(1H,d J=5.;H7), 7.38(1H,t J-8Hz), 7.80t3H,m), 7.91(1H,d J=7Hz~, 8.31(3H,m)~ 8.5j and 8.94(each lH,s), 10.43 (lH.t J=5Hz)~ and 13.0~3 (lH,s).
(2) (CDC13) 0.05(9H,s), 2.56(2H,s), 2.nl(3n,5~ 5.04(2H,d, J=5Hz), 6.90 br(lH,t), 7.15(3H,~), ,.38(1H,t, J=7Hz), 7.54(1H,d, J~7Hz), 7.60(2H,dJ-9Hz), 8.32(2H,d J-9Hz!, 8.45(1H,d J=5H~ and 9.12(1H,s). SUBSTITUTE SHEET

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

wo gl/~7162 2 0 7 8 ~ ~ 7 Pcr/EP9l/0073~

~-(2-Meth~l~ benzovl)amino-4-(2-methylimidazo~4,5-c]pvrid-1-vl)-aceto~henone Sodium methoxide (284 mg, 5.26 mmol) was added to a stirred solution of N-(2-trimethylsilylmethYlbenzoyl)-4-(2-meehYl-imidazo~4,5-c]pyrid- l-yl)aminoacetophenone (from Ex2mple 83 above) (1.2 g, 2.63 ~mol) in anhydrous c_~etnyl~orm22ide (10 ml) under nitro~en. The solution was seirred a. lOO~C for 30 minutes.
tn~n concen~rated to dryness. The rasidue was dlssolved in ethyl acetate (50 ml), washed with water (3 x 50 ml), dried over magnesium sulphate and concentrated under reduced pressure.
Chromatography on silica (230-400 mesh), eluting with 15% methanol in ethyl acetate, and trlturation with diethyl ether gave the title compound as a hygroscopic white solid (200 mg, 20Z). lH NMR
(CDC13): 2.56(3H,s); 2.64(3H,s); 5.04(2H,d, J-5Hz);

6.90(1H,broad); 7.17tlH,d,J=5Hz); 7.28(3H,m); 7.58(1H,d,J=7Hz);

7.60(2H,d,J=9Hz); 8.32(2H,d,J=9Hz); 8.4;(1H,d,J=5Hz); 9.12(1P,s).

4-(2-Methylimidazo[ ~ -~l)-N-~3-quinolin~l)benzamide Oxalyl chloride (508 mg, 40 mmol) was added dropwise to a stirred suspension of 4-(2-methylimidazo~4,5-c]pyrid-1-yl~benzoic acid (253 mg, 1.0 mmol) in dry dichloro-ethane (4 ~.1) at 0c unde~
nitrogen. After the addltion was complere, the suspension was sonicaced at room temperature for 1 ho_- ~he solvent wzs ~he~
evaporated under reduced pressure ~o ~i~e an o r-white solid, which was resuspended in dry dichlorome:hane (4 ml) and a solution SUBSTITUTE SHEET
" ' ` .
-` .. . ~.`: . .
` -, : "''` . `' , : `: ` , . ,.. ~`

WO 91/17162 PCI/EP91/00737- ...
2078~7 of 3-amino-quinoline (288 mg, 2.0 mmol) and triethylamine (505 mg, 5.0 mmol) in dr~ dichloromethane (7 ml) was added dropwlse. The resulting ~i~ture was sonicated for 1 hour at roo~ temperature, and then treated with saturated aqueous sodium bicarbonate (20 mi). The mixture was extracted with dichloromethane (3 ~ 30 ml) and the combined extracts were dried (Na2S04) and concentrated under reduced pressure. The residue was purified b~ flash chromatographv eluting with dichloromethane/methanol. Fractions CUllL~ining produc~ were comblned, concentrated and triturated with a little ether to give the title compound, as a white solid, m.p.
259-261C. Found: C,72.56; H,5.45; N,18.13. C23H17N50 requires C,72.80; H,4.52; N,18.46%.
The following compounds shown in the Table were prepared by a similar method substituting the corresponding amine for 3-aminoquinoline.

c~3 NH-CO ~IN ~\' SUBSTITUTE SHEET

, ~ .

- `~.WO 91/17162 PCI-/EP91/00737 2078i~o7 _, ¦Example R16 m.p.Analy8is ~
No C(Theoretical in brackets' C H
I
86 1 ~ l221_223 1 68.86 4.58 21.01 (69.28 4.59 21.27) 7 1 ~ ,i~ 9 1 74.99 5.57 15.40 I
~74.98 5.47 15.21) .

88 ~ 218-220 75.02 5.36 15.12 (74.98 5.47 15.21) 89 5C202C ~ 193-195 68.92 5.07 13.80 (68.98 5.03 13.99) ... ._ ~ C2CH3 ~220-222 ¦68.35 4.72 14.40 ¦
(68.38 4.70 14.50) . _. _ I
91 ¦ ¦309-31~ 1 63.47 4.04 17.80 !
' '(63.45 4.14 17.62) S tO.67 mole 820) _ 92 1 269-271 6l.63 4.3, ~2.83 (67.64 4.46 ~.54) H (0.25 mole H20) , SUBSTITUTE SHEET

.
.
. ; ,, ` . ..
- .
' ~ . ~ .. . .

W O 91/17162 2 0 7 8 0 0 7 PCT/EP91/00737,-J

. ~
j. , .
.~

... . _ .
~xample R16 I m.p. ~ Analysls No ~ (Theoretical in bracke~s) . I
I C H ~:

93 / l280-~83 ~ 60,86 4.33 21.96 h I (66.33 4.54 ~.27) H , (0.5 mole H?0) 94 ~ C02CY.3 19 -196 characterised bv h~lR (1) ~ 213-215 ~ 76.02 5.36 13.07 C~- I (76.39 5.38 13.20) I ~ ! ~ 33 mole H20) t 96 1 ~ Cl 1 94-q/ 66.55 4.88 14.88 I ~ CH~- ' (66.93 4.55 14.87) -97 ' 153-15566.21 4.58 1~38 C0 (66.30 4.77 18.41~ -(0.5 mole H20) (1) ~ (300MHz,CUC13) 2.64(3H,s), 4.11(3r.,s), 7.20(1H,d~J=5Hz), 7.48(1H,e,J~7Hz), 7.60(2H,d,J=8Hz). .65(1H,t,J=7Hz), 7.92(1H,d,J-8Hz), 7.95(1H,d,i=8Hz), 8.38(2H,d,J=8Hz)~

8.46(1H,d,J=5Hz), 8.79(1H,s), 9.13(1H,s), 9.44(1H,s).

SUBSTITUTE SHEET

~ W O 91/17162 PCT/EP91/00737 2l3780V7 ' 4-(2-Methylimida~o[4,5-c]p~rid-1-vl.)benzovlbenzo[c]pYrrollne Sodium hvdride (60~ oil dispersion, 0.~ ~, 5 rmol? wes added to a stirred solution of 4-t2-methylimidazo[4,5-c]pvrid-l-Yl)-benzamide (0.5 g, 2 mmol) in tetrahvdrofuran (5 mlj and dimethylformamide (5 ml). After warr,ing a~ aO~C for 20 minu~es, 1,2-bis-bromomethylbenzene (0.53 g, 2 mmol) was added. After ~
hours at 25C, the solvents were evaporated and the residue was par;L;iu~ be~ween aqueous sodlu~ b ca-~ona~e and ethyl ace~ate.
The organic layer was dried (~gS04) and evaporated to a residue which was purified by flash chromatography, eluting with 5,~
diethylamioe in ethyl acetate, to afford a white solid (0.038 g, 7%), m.p. 226-229C. Found: C,72.79; H,5.14; N.15.12.
C22H18N4O.~H2O requires C,72.71; H,5.27; N,15.41%.

EXAMP~E 99 N,N-~is(~-Chlorobenzyl)-4-(2-meth~limidazo~4,5-c]pyrid-1-~1)-benzamide Sodium hydride (60% dispersion in ~ineral oil), (44 mg, 1.1 mmol) was added to a stirred solution of ~-(2-methylimida2O-[4,5-c]-pyrid-1-yl)-benzamide (252 mg, 1 mmol), in anhvdrous tetrahydrofuran (1 ml) and anhydrous dimethyl~ormamide (1 ml).
The solution was stirred at 50C for an additional 20 minutes before addlng a solution of ~-chloroben~ylchloride (1l, ~g, 1.1 mmol) in anhvdrous tetrah~drofu a-. 1 rl~. The reactio..
mixture was stirred ae ambient te~pera~ure for 16 hours~ then diluted with water, 2~ hydrochloric ac~c added to pH 1, followec by sodium bicarbonate to give pR 8 and ~he product was extractec SUBSTITUTE SHEET

.

. .

W O 91/t7162 PCT/EP91/00737.~, 20780jO7 ;; i~ .
with ethvl acetate. The organic extract was washed wlth water, dried over magnesium sulphate and concentrated under reduced pressure. The residual gum was chromatographed on silica elutin with 15% methanol in ethyl acetate. The faster running (less polar) of the two ensuing fractions was concentrated and the residual gum crYstallised with ether in an ultrasonic bath to give the title compound as a white solid (8 mg, 2%), m.p. 176-180C.
Found C~66-36; H,4-42; N,ll.10. C28H22C12N 0. 0 33 H 0 recuire~ ~ ~s ~a; U,4./.G; ~ ,9~,o Methyl-2-[4-(2-methylimidazo~4,5-c]pyrid-1-yl)benzylthio]benzoate 4-(2-Methylimidazol4,5-c3pyrid-1-yl)benzyl alcohol (7.78 mmol, 1.86 g), methyl thiosalicylate (8.56 ~mol, 1.44 g~ and triphenylphosphine (18.56 mmol, 2.24 g) were dissolved in dry tetrahydrofuran (30 ml). Diethylazodicarboxylate (9.34 mmol, 1.95 g) was added dropwise and the mixture stirred for 2 hours at roo~
temperature then evaporated to dryness. The residue was purified by column chromatography on silica eluting with tichloro~ethane/
methanol (97:3). l`he oily product was dissolved in dichloromethane and treated with anhvdrous HCl. The hydrochloride crystallised on standing (1.66 g, 507,) M.p. 249-253C. Found:
C,60.1?: H,4.67; N,9.57. C22HIa~3o~s~ HC1:0.75 H~0 requires C,60.14; H~4.90; ~9.57Z.

'~ W O 91/17162 PCT/EP91/00737 20780~

Methyl 4-chloro-2-~4-(2-methvlimidazo~4,5-clpyrid-l-yl)ben thiol benzoate 4-(2-~ethylimidazo[4,5-c]pyrid-l-yl)benzyl alcohol (7.4 mmol, 1.76 g) was dissolved in 48% hydrobromic acid (25 ml) and heated under reflux for 15 minutes then evaporated to dryness under vacuum. The residue was dissolved in methanol (100 ml) and methyl -chloro-thiosalic~late (10 mmol, 2.03 g) added. Sodiu~ hydrogen carbonate (~ mmnl, 2.10 g~ ~-as adu~d por~ionwlse and the mixture stirred overnight. The resulting suspension was poured into ethyl acetate and washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was chromatographed on silica eluting with methanol, dichloromethane (97:3) to give the pure protuct. l'his was redissolved in dichloromethane and treated with ethanolic hydrogen chloride. The solution was evaporated to dryness and the residue recrystallised from ethyl acetate/methanol to give the hydrochloride salt (3.69 g, 95X), m.p. 233-255C. Found: C,56.82; H,4.39; N,8.87. C22H18ClN302S.
HClØ25 H20 requires C,56.84; H,4.20; N,9.04%.

1-~4-(2-Chloro~hen~lthiometh~l)ohen,~1]-7-methyl-imidazo~4,j-c]-p,~ridine The above compound ~as made follo~ing the procedure o.
Example 101 using 2-chloro-~enzenethiol as starting ma~eria_.
~!.p. 278-280C. Found: C,58.75; H,4.31; N,10.38.
C20H16ClN3S.HCl. 0.25 H20 requires ~,59.04; H,4.31; N,10.33',.

SUBSTITUTE SHEET
, ' . ~ ' `
.. . .
. . . .
, . . . ; . .
.;, . - .. , ., . ,, - ; . ,~, ..

2078~
W O 91/17162 PCT/~P91/00737,~`?

2-[4-(2-Methvlimidazo[4,5-c]pyrid-]-vl)benzvlthiolbenzoic acid Methvl 2-~4-(2-methylimidazo~4,5-c!p~rid-1-yl)benzvlthiolbe~.zoate (7.5 mmol, 1 g) was dissolved in ethanol (20 ml) and 2N sodiu~
hydroxide (1~ ml) was added. The mixture was stirred overnight then poured onto water and washed with dicnlorometnane. ~he aqueous phase was acidified with acetic acid and re-e~tracted with dichloromethane (3 ~ 75 ml). I`he CG~3i ned e.~cracts ~ere dried over NA ~n~, fi~e-eA a-nd e-vavu--d,~d ~o cr~rness. lhe resultin~
white solid was washed with ether. (0.~1 ~, 86%). ~I.p. 251-254~. -Found C 65-95; ~,4.68; N,10.71. C21H17N302S 0 5 ~2 q C,65.63; H,4.69; N,10.94Z.

4-Chloro-2-~4-(2-methylimitazol4,5-c]pvrid-1-yl)benzvlthio]benzoic acid The above E~ample was followed using the co~pound of Example 101 to give the title product in 78% yield. M.p. 264-267C.
Found: C,61.31; H,3.95; ~,10.11. C21P.16N3C102S requires C,61.54;
H,3.91; N,10.26%.

EX~IPLE 105 N-Methvl-2-~4-(2-meth~limidazo~4,5-c`~rid~ l)ben-vlthiol-benzamide 2-~4-(2-Meth~limidazo~4,5-c]7~rià-:-~l)be~~~7:hio]benzoic acid (1 mmol, 375 mg) was stirred e d chlûrome~hane (10 ml) anc drop of dimethylformamide was added. C~:al~l chloride (2 m~.ol, 25-mg) was added and the mixture stirred ^or 90 minutes under SUBSTITUTE SHEET

,- W O 91/17162 2 D 7 8 Q O 7 PCT/EP91/00737 nitrogen. l'he solvent was removed under vacuum and the residue dissolved in dichloromeehane (10 ml) and added dropwise to an lce cold solution of meth~lamine (33,' sclution in ethanol 10 ~ . lhe mixture was stirred at 0C for 30 minutes then poured into water and extracted with dichloromethane (3 x 50 ml). Tne combined extracts were d.ied over NaAS0 , filtered and evaporated to dryness. Purification was effected b~ column ch omatog.ap, on silica eluting with dichloromethane,iQ-rhanol (97:3). The product cont~ining fr ^ti^r.s wer2 2V2Vu~ d ~0 cr~ness and cr~sta'lised on trituration with ether. (0.28 g, 73%). M.p. 172-174C. Found:
C,67.26; H,5.25; N,13.92. C22H20N40S. 0.25 H20 requires C,67.26;
H,5.22; N,14.27%.

SU~STITUTE SHEET

. - , , ' ' . '` ,; "~ ' . ~ ..

W O 91/17162.~ 2 ~ 7 8 0 a 7 PCT/EP91/00737 lhe following compounds were prepared as described in the previous Example using the appropriate acid and reactin~ with dimethylamine.

; R18 CH3 ~SC~

R17 ~ ~
Example R17 R18 m.p. Analysis %
No C (Theoretical in brackets~

106 H -CON(CH3)2 178- 1 68.17 5.53 13.60 180 1(67.90 5.54 13.78 ¦ ,(0.25 mole H20) . .~
107 ¦ Cl ~-CON(CH3)2 ll36- ' 58.38 5.08 10.82 139 (58.03 5.03 10.83) ` (HCl, 0.5 mole C4H80~) .

SUBSTITUTE SHEET

,~ .... ~ . .

wo 9"".62 2 0 7 8 0 ~ 7 PCT/EP91/00737 : 65 Methvl 2-~v-(2-methylimidazo[4,5-c]pyrid-l-yl)benzxlthlolbenzoate S-oxide Methyl 2-[4-(2-methylimidazol4,5-c]pyrid-l-yl)benzylchio]-benzoate (1 mmol, 389 mg) was dissolved in dichloromethane (15 ml) and cooled in an ice bath, m-chloroperbenzoic acid (85~ 1 mmol, 203 mg) was added and the solution stirred for 2 hours then poured into dilute sodium hydrogen carbonate solution and extracted with ~; rhloromerh.a"c ~3 A 50 ml) . The combined organic extracts were dried over Na2S04, filtered and evaporated to dryness, the residue being purified by column chromatography on silica eluting with dichloromethane/methanol (97:3). The product-containing fractions were evaporated to dryness and the residue re-crystallised from dichloromethane. (0.33 g, 81X). M.p. 146-148C. Found: C,64.79;
H~4-74; N,10.24. C22H19N303S requires C,65.19; H,4.69; N,10.37X.

SUBSTITUTE SHEET

. `

.

WO 91~17162 2 G 7 8 0 0 7 PCr/EP91/00737 ~

Oxidation o~ the appropriate thio compound of Examples 102-107 with met2-chloroperbenznic acid as descrived in ~he previous example gave the foll~ wing sulphoxides:

~1~ c~,-3 ~ SCH., Example R17 R18 I m p Analysis %
llo ¦ ~ ¦ (Thcore~ical n brackets 109 U -CONHCH3 1 205- 64.46 5.11 13.46 . j 207 (64.39 5.04 13.66) ' (O.33 =~le U 0) 110 I H -CONtcH3)2 ! 183- 66.01 5.58 13.2_ ~ 185 (66.03 5.26 13.40)`

. ._ .
111 H Cl ` 120- 62.67 4.18 10.86 i 1^' (6^.9' 4.19 11.01!
--- . I
-C0N(CH3~A I l'C- 60.9~ ~.66 1'.^3 I 1~, (50.99 ~.6~i 1^.38) .

~ WO gl/l7l62 2 0 7 8 o ~ 7 PCT/EP9l/00737 EXAMPL~ I 13 N-Methyl-2-~4-(2-~ethvl.i~idazo-~4,5-c~p~rid-1-Ylbenzt~lthiolbenza-mide-S,S-dioxide N-Methyl-2-~4-(2-methvlimidazo~4,5-c~pyrid-1-yl)benzylthio]-benzamide-S-oxide (0.25 mmol, 101 mg) was dissolved in dichloromethane (10 ml~ an~ cooled in ar. ice bath. ~oncentrated hydrochloric acid (; drops) waa adaed followed b~-m-chloroperbenzoic acid (85%, 0.25 mmoi, 5i mg) and the mi.~:ture s....eu d~ VC ror ^~ nours ~Hen at room ~em?erarure ~cr ? hcurs.
The mixture was basified with S~O scdium carbonate sclution and extracted with dichloromethane (3 x 50 ml). The combined extracts were dried over Na2S04, filtered and evaporated to dryness with the residue being purified by column chromatography on silica eluting with dichloromethane/~ethanol (96:4). Evaporation of the product-containing fractions gave an oil which crYstallised on trituration with ether, (14 mg, 13X). M.p. 241-243C. Found:
C,61.91; H,4.75; N.12.79. C2?H20N403S. 0.33 H?~ requires C,61.97;
H,4.85; N,13.14%.

EXAMPLE l14 N,N-Dimethyl-4-chloro- -~4-(2-metht~limidazo~4,5-c]p~rid~
benzvlthio]ben _mide-S,S-dioxide 1he above procedure was rollowed s-arting wit~. the corresponding ~-chloro-derivative to git.e the title product. ~I.p.
193-194C; Found: C.57.81; ~i,4.4&; ~ '0. C?~U.~.u~ S. 0.; H~O
requires C,57.80; H,4.61; ~,11.~3..

SUBST~TUTE SHEET

.
:.'.

2078~07 EXAMPLE l15 l-~t~-Dimethylaminocarbonyl)phenylsulphinyl~ 4-(~-methYl-imidazo[4,5-c]pyrid-1-yl?phenvl]methanol N,N-Dimethyl-2-[4-(2-methylimidazo[4;5-c]pyrid-1-yl)benz,l-thio]benzamide-S-oxide (0.3 mmol, 125 mg~ was dissolved in dry dichloromethane (110 ml) and anhydrous hydrogen chloride added.
m-Chloroperbenzoic acid (85X, 0.3 mmol, 61 mg~ was added and the mixture s~irred at room temperature for 2 hours then poured into ," suuiu~ carbona~e solutlon and extracted with dichloromethare (3 x 50 ml). The combined organic extracts were dried over Na~S04, filtered and evaporated to dryness. The residue was purified by high pressure liquid chromatography and the product crystallised from diethyl ether (17 mg, 13X). M.p. 174-176C. Found:
C,60.90; H,4.70; N,12.14. C23H22~4O3S. H20 requires C,61.06;
H,5.30; N,12.39~.

Dimethyl 2-(4,5-dichloro-2-nitrophenyl)-1-~4-(2-methylimidazo~4,5-! c]p~rid-l-yl)phenyl]et lonate a) Following the method of W. Lehrest, Tetrahedron 1973, 29, ! 635, titanium tetrachloride (4.40 ml, 40 mmol) was added at 5-lO
to dry tetrahytrofuran (80 ml) under nitrogen. Dimethvl malonate (2.6~ g, 20 mmol) was added by syringe, followed b a solution c-4-(2-methylimidazo[4,5-c]pyrid-1-yl)ben-aldehyde ~4.7~ g, 20 mmol) SUBSTITUTE SHEET

`- ~. Wo 91/17t62 PCl/EP91/00737 2o78o~7 in dry tetrahydrofuran (80 ml). Finally dry pyridine (4.85 ml, 60 mmol) ~as added dropwise and the resulting sugpension was stlrred at roo~ temperature for 24 hours. Methanol (30 ~1) was added, anc the resulting white suspension was poured into a mixture of dichloromethane (100 ml), ice, and saturated aqueous sodium bicarbonate (500 ml). The titaniu~ salts were removed b~
filtration, and washed with dichloromethane. The filtrate layers were separated, and the aqueous laver extracted with dichLu~u~etnane t2 x lûû mij. ~l~ne combined organic extracts were dried (MgSû4) and concentrated to give a yellow oil. On the addition of diethyl ether (50 ml), the product crystallised, and was filtered off and dried, to afford dimethyl 4'(2-methylimidazo-~4,5-c]pyrid-1-yl)benzylidene malonate, as a white solid, 5.1 g 73X). A portion was recrystallised from hot ethyl acetate. M.p.
155-156C. Found: C,64.79; H,4.95; N,11.87. ClgH17N3O requires C,64.95 N,/~.85 N,11.96X.

SUBSTITUTE SHEET

.. ~, . .

wo 91/17162 2 0 7 8 ~ ~ 7 PCT/EP91/00737,i-, , (b) A solueion of 4,5-dichloro-2-nitrotoluene (2.472 g, 12.~
mmol) in dry dimethylfor~amide (5 ml) was added over 2 mlnutes by s~rin~e to a suspension of sodium hydride t600 mg, 60/~ dispersion in oil, 15.0 mmol) and dimethyl 4'-(2-mèthylimidazo[4,5-c]pyrid-l-yl)benzylidene malona~e (from part a) in dry dimethylformamide (40 ml) whilst maint2ining the te~perature below 15C. The resulting bro~n solution ~as s;irrod at 20C for 3 hours, and glacial a.ecic ~cid (2 ml) was added. The mixture was pOULCu - Lli~ ~n~i aceraee ~4~Ju ml) and the solution rendered basic by the addition of saturaeed a~ueous sodium bicarbonate. The organic layer was washed with water (3 x 100 ml), brine (100 ml), dried (MgS04) and concentrated under reduced pressure. The crude product was purified by chromatography, eluting with a gradient of ethyl acetate/methanol, to glve the title compound as a white solid, (3.119 g, S6~). m.p. 94-96C (methanol). Found: C,53.18;
26H22C12N406. 1-5 H20 requlres C,53.43; H,4 31;
N,9.59X.

Dimethyl 2-(2-amino-4,5-dichloro~henyl)-1-14-(2-methvlimidazo~4.5-c]pyrid-l-yl~phen~l]ethvlmalonate A solution of 25X aqueous eitanium trichloride (4 ml, 6.5 mmol) was added dropwise to a solution of dimethyl 2-t4,5-dichloro-2-nitro-phenyl)-1-[4-t~-meth~limidazo~,5-c]pyrid-l-yl)phenyl]eeh~lmalona~e (557 mg, l.C cmo') in de~assed me~hanol (15 ml) under nitrooen at room tempera;ur-. The solu~ion was stirred for 1 hour, poured into dichloro~ethane (50 ml! and rendered basic by the atdition of saturated aqueous sodium SUBSTITUTE SHEET

2Q780~7 ; ~ W O 91/17162 PCT/EP91/00737 bicarbonate. The precipi~ated salts were filtered off and washed with dichloromethane (150 ml). The filtrate was separated, dried (MgS0 ) and concentrated tlrder reduced pressure to tne ~ e tne title compound as a whi~e solid, (45~ mg, 86%), m.p. 186-188C
(methanol~. H ~R (300 MHz, CD~13) : ~.52(3H,s~, ~.59(1H,d,J
12Hz), 3.15(1H,dd,J 1~ and 2H7), '7.55!3H,s), 3.70(1~.,dc, J 1~ and 2Hz), 3.91(3H,s), 3.95(7~.,d,J 1~ (2H,br s), 6.'5(1~,s), 6.78(1H,s), 7.03(1H,d, J 6'.~7), ,.29 (~H,s), 8.39(1H,d,J 6Hz), .û/ (;n,s) -EXAMPLE 11~
3-t2-ChloroPhenyl)-2-ethoxycarbonyl-1-~4-(2-methylimidazo~4,5-c]-' pyrid-l-vl)phenyl]prop-2-ene-1-one ` A mixture of 2-chlorobeozaldehyde (2.8 g, 19.9 mmol)~ethyl 4'-(2-methylimidazo~4,5-c~pyrid-1-yl~benzoyl acetate (6.4 g, 19~9 mmol) and piperidine (100 microlitres) were stirred at room temperature for 48 hours in acetonitrile (30 m7). The mixture was evaporated eo dryness and the residue chromatographed on silica eluting wi~h ethyl-acetate/meehanol (5:1). The fractions containing product were combined and evaporated to give the title compound (5.3 g, 60~). lH N~R (CDC13) 1.35(3H, t,J 8Hz), 2.53(3H, s), 4.27(2H, q,J 8H2), 7-9.1~1~H, m).

UBsTlTuTE SltEET

.: . .

.

` 2Q78~U ~

EXAMPLES ll9-120 The following compounds were made by the method o~
E~ample 118 using the appropriate aro~atic aldehyde as s~artin~
~aterial.

C2CH2CH~ c~-3 R -CH=C-C ~ ~
~/>

Exa~ple R20 N.M.R data No (CDC13) ._ _ . . .
119 < 01.38(3H,t,J=8); 2.6(3H,s);
0 ~4.32(2H,q,J=8); 6.02(2H,s);
6.7-9.1(llH,~) 120 ¦ I1.31(3H,t,J-8); 2.58(3H,s~;
.28(2H,q,J~8);

9.1(13H,~.).

__ . .

SUBSTITUTE SHEET

-` ` W O 91~17162 2 0 7 8 0 0 7 PCT/EPgl/00737 Ethyl 2-(2-chlorophenylmethyl)-3-hvdroxv-3-~4-(2-methvlimidazo-~4,rl-c~vrid-l-yl?phenyl]propanoate Sodium borohydride (0.012 g) was added in a single portion to a solution of 3-(2-chlorophenyl~-2-ethox~carbonyl-1-~4-(2-meth~
imidazo~4,5-c]pyrid-1-yl)phenyl]prop-2-ene-1-one (0.13 g, 0.3 mmol) in ethanol (2 ml) at 20C. After 1 hour~ the mixture was partitioned between ethyl acetate and brine. The organic layer w~ dried ~-~g~u4j and evaporated ~o a gum. Purification bv chromatography on silica afforded a colourless gum (0.12 g, 91%!.
Found: C,61.79; H,5.41; N,8.93. C25H24ClN3O3.2 H2O requires C,61.79; H,5.81; N,8.65%.

EXA~PLE 122 2-Chlorobenzyl 2-(2-chlorophenylmethylidene)-3-~4-(2-methyl-i imidazo[4,5-c]pyrid-1-yl)phenyl]-3-oxopropanoate a) 2-Chlorobenzyl 4'-(2-methylimidazo~4,5-c]pyrid-1-vl~-benzo~l-acetate A solution of ethyl 4'-(2-methylimidazo[4,5-c]pyrid-1-yl)-benzoylacetate (1 g, 3 m~ol) and 2-chlorobenzyl alcohol (1.4 g, 10 mmol) in toluene (15 ml) was heated at reflux for 20 hours, then cooled and evaporated. l`he residue was purified b~ chromatography to artord a colourless roam (1.23g. C57;), Found: C,64.15; H,4.38; ~,9.55. C~3HI~C1~30~. 0.5 H~0 requires:
C,64.~1; H,4.47; ~,9.80,o.
b) Piperidine (0.02 ml~ was added ~o a stirred solution Ot the product from a) (0.7 g, 1.67 mmol) ar.d 2-chlorobenzaldehyde (0.28 g, 2 mmol) in acetonitrile (8 ml) a~ 2C. The mixture was allowed SUBSTITUTE SHEET

2~78007 W O 9I/17162 YCT/EP9t/00737 to stand for 6~ hours. then evaporated and purified by chromatography to give the title compound ag a colourless foam (Q.39 g, 43"), ~.5. ~-51~. Found: C,65.5~; H,4.10; ~,7.40, C30H21Cl~N303. 0.5 H~0 requires C,65.35; H,4.02; ~',7.62%.

E~AMPLE I23 3-(2-Chloroohenvl)-l-r.~ 2-~ethyli idazo[~',5-c]pyrid-1-Yl)-.
phenvl]-l-o~c-2-pro~ene Soliu suuiu~ nydrc~ide (O.u4 ~, 1 m~ol) was added to a stirred solution of 2-chlorobenzaldehvde (û.194 g, 1.~ ~mol) and 4~-(2-methyli~idazo[4,5-c]pyrid-1-yl~acetophenone (0.35 g, 1.4 mmol) in methanol at 25C. Water (2-3 drops) was added to aid dissolution. After 2 hours, the pH was adjusted to 8 by addition of 2M hydrochloric acid followed by sodium bicarbonate solution, then the mixture was extracted with ethyl acetate. The or~anic layer was dried over MgS04 and evaporated to a gum. Flash chromatography, eluting with lû% methanol in ethvl acetate, afforded a solid which was recrystallised rrom methanol to give the title compound (û.û8 g, 16%), m.p. 155-157C. Found:
C,70.67; H,4.22; ~,11.12. C22H16ClN30 requires: C,70.68; H,4.31;

~,11.24Z.

EXAMPL~ I2-E and Z-l-Phen~ 4'-(~-meth~limidazo~4,~-clpvrid~ l)Phen~
ethene ~ =:
Sotium methoxide (û.ll g, 2 mmo;` was added to a stirrec solution of 4'-(2-meth)~limidaæo~4,~-cj?yrid-1-vl~benzaldehyde (0.24 g, 1 mmol) and benzyltriphenylphosphonium chloride (0.43 ~, SUBSTITUTE SHEET

~ W O 91/17162 2 ~ 7 ~ O 0 7 PCT/EPg1/00737 1.1 mmol) in anhydrous dimethylformamide (5 ml). After 18 hours at 23C the solvent was evaporated and the residue was particioned between ethvl acetate and water. The or~anic extract was washed three times with wa~er, dried (~SgS04) and evaporated to a gum.
Flash chromztography elutin~ with 5,~ methanol in ethyl acetate, afforded an amorphous solid (0.13 g, 44%). (Ratio of E/Z isomers was approximately 9:1) lH N~R (CDC13): 2.57(3J.,s) 6.58 and 6.81 (each lH,d J=14Hz), 7.13(1H.d J=4.5H7~; ?.23(2U,d J-~H,c~, 7.34~n,brsi, 7.4Y~
J=8~z), 8.42(1H,d J=4.5Hz) and 9.07(1H,s).

1-~4-(2-Methylimidazo~4,5-c]pyrid-1-yl)phenyl]-2-pyrid-2-yl ethanol Sodium methoxide (0.33 g, 6 mmol) was added to a stirred solution of 2-(trimethylsilylmethyl)pyritine (0.55 g, 3.3 mmol) and 4'-(2-methylimidazo[4,5-clpyrid-1-yl-benzaldehyde (0.71 g, 3 mmol) in dry dimethylfor~amide (10 ml) under nitrogen. After 30 minutes, most of the solvent was removed and the residue partitioned between eth~l acetate and water. The organic layer was washed several times with water then dried (MgS04) and evaporated to an oil. Purification by flash chromatograph~, eluting with 20X methanol in ethyl acetate, followed b~
~rituration with ether, gave a white solid (0.1 ~ ). M.p.
160-16`'~C. Found: C,72.23; H,5.46; ~,16.6~ h'l~`.;,0. 0.1~5 H~0 requires C,7~.~1; H,5.53; ~,18.8~.

SUBSTlTlJTE SHEET

W 0 91/17162 2 ~ 7 8 0 0 7 PCT/EP91/00737 ~
; ' ;, EXAMPLE I~6 E and Z-1-(2-~yanophenyl?-2-[4'-(2-methylimidazo~4,;-c~pyrid-1-vl)-~henyl]ethane Sodium methoxide (4.32 g, 80 mmol) was added to a stirred suspension of 2-chlorobenzyltriphenylphosphoniu~ bromide (20.~ g, 44 m~ol) and 4'-(2-methylimidazo[4,5-c]pyrid-l-yl)benzaldehYde (9.5 g, 40 mmol) in dimethylformamide (210 ml). The mixture was heated to 100C for 3 hours then evaporated and the residue ~-2s partitioned between ethvl 2e~tal e and water. Tll~ organic layer was dried (MgS04) and evaporated co a gum (20 g) which was :. .
chromatographed on silica eluting with a gradient of from 5% to 25% methanol in ethyl acetate, to afford two products:

a) E-isomer, colourless foam (0.5 g, 4%).

H NMR (CD3SOCD3): 2.46(3H,s), 6.91 and 7.05 (each lH,d J=15Hz), 7.15(1H,d J-5Hz) 7.33(2H,d J=7.5Hz), 7.49(4H,m), 7.66(1H,t J=7.5Hz), 7.90 (lH,t J=7.5Hz), 8.28(1H,d J=5Hz) and 8.89tlH,s).

b) Z-isomer, recrystallised from toluene (7 g, 522). M.p.

213-215C.

H NMR (CD3SOCD3): 2.51(3H,s), 7.25(1~,d J=5Hz), 7.50(2H,m), 7.67(3H,~), 7.75(1H,t J=7.5Hz), 7.91 (3H,m), 8.07(1H,d J=7.5Hz), 8.30(1H,d J~5Hz) and 8.92 (lH,s).

EXAMP~E 127 1-~4-(7-Methvlimidazo~4,5-c]pYrid-l-Yl)~henYl]-l-oxo-?,~,3,3,4,4,4-heptafluoro~utane To a solution of heptafluoropropyliodide (60 mmol, 1 .76 ~!
in ether (200 ml) was added phenylmagnesium bromide (55 mmol 18.33 ml) (3M in ether) whilst keeping the internal temperature below -60C. The m~xture was then stirred at -70C for 15 minutes Sl)!?~STITUTE StlEET

.: . . .. ' . . . .. . : .

wo gl/17162 2 ~ 7 8 0 o 7 pcr/Ep9l/oo737 . ~ , , followed by the dropwise a'ddition of ethyl ~4-(2-methyllmldazo-~4,5-c]pyrid-1-yl)benzoate (25 mmol, 7.05 g) in tetrahydrofuran (40 ~1) again keeping the temperature below -60C. l'he ~ilxture was allowed to warm to 0C very slowly over a 5 hour period then quenched with ammonium chloride solution. After pouring the mixture into water the product was extracted into ethyl acetate (~
x 300 ml) and the combined organic e~tracts dried over MgSO,, filtered and evaporated to dryness. The residue was purified Dy column chrnm3tQ~ arh~, ^r si' .a elu~ing with dlchloromethane/
methanol (95:5) then recrystallised from ethyl acetate/hexane.
(5.41 g, 53Z). M.p. 138-141C. Found: C,41.10; H,2.74; N,10.01.
HloF7N30 0.5 H20 requires C,49.29; H,2.68; N,10.14~.

1-[4-(2-MetbYlimidazo~4,5-c]pyrid-1-yl)phenyl]-2,2,3,3,4,4,4-he~tafluoro-1-~4-fluorophenyl]butanol 1-14-(2-Methylimidazo[4,5-c]pyrid-1-yl)phenyl~ oxo-2,2,3,3,4,4,4-heptafluorobutane (1 mmol, 405 mg) was dissolved in tetrahydrofuran (10 ml) and cooled to -40C. 4-Fluorophenyl-~agnesium bromide (5 mmol, 5 ~1, lM in teerahydrofuran~ was added dropwise and the solution allowed to warm to room temperature over 1 hour and then stirred for a further ~ hours at room te~perature.
The reaction was quenched with ammonium chloride solution and poured into water tlOO ml) then extracted with ethylacetate (3 50 ~1). l'he combined organic extracts were dried over MgSCI , filtered and evaporated to dryness. The residue was purified b~
chromatography on silica eluting with ethyl acetate/dietbylamine SUBSTITUTE SHEET

. . . . . .. ... ~ ... . . . ... .. .

W O 91/~7162 2 0 7 8 0 O ~ PCT/EP9t/00737 ~

(98:2), the product containing fractions were evaporated to dryness and the residue recrystallised fram ether (134 m~, ~;70), M.p. 192-194C. Found C,54.77; H,3.31; `;,~.37 C~3,~1 r~-;
requires C,55.09; H,2.99; N,8.38~.

EXAMPLE l29 4-~4-(2-Methylimidazo~ -c]~vrid~ .l?~henvll-tetrado~a-~uc-o-heptan-4-ol The above w~s pre?o-od a..al~Oo-uslv Lo [he ?re~;lous ~et'.:Gd using heptafluoropropyl magnesium bromide as the Grignard rea~ent and was obtained in 5% yield. M.p. 221-223C. Found: C,41.74;

H~l-91; N~7-30- C20HllF14N30 requireS C,41.44; H,2.11; N,7.30%.

4-1- [4-(2-methylimidazo[4,5-c]pyrid-l-yl)phenyl]-l~ 2~2~3~3 heptafluoropentan-2-ol The above was prepared analogousl to the previous method using methylmagnesium bromide as the Grignard reagent to give the produce in 56Z yield. M.p. 233-235C. Found: C,51.15; H,3.31;
N,9.82. C8H14F7~3Q requires C,51.31; h,3.33; N,9.98X-EXA~LE l31 3-HePtafluoro~ropvl-3-hvdroxv-~-~4-t~-~sth~ ida-o~4.5-cl~rid-l-yl)phenYl~propionamide 8is(trimethylsilvl)acetamide (5 mm31, i.~ ml) was cissolved in tetrahydrofuran (15 ~1) and cooled :a -7S~ in a CQ~/ace~one bath. Butyllithium (2.2M, in hexane, ; Fmol, 2.27 ml) was addec dropwise over 5 minutes and the solution stirred at -78C for a SUBSTITUTE StlEET

.
., ~

.: . .

j W O 91/17162 2 0 7 8 0 0 7 PCT/EP91/00737 7~
rurther 15 ~inutes. A solution of 1-~4-(2-methylimidazo[4~5-cl-p~rid-l-yl)phenylJ-l-oxo-2,2,3,3,4,4,4-heptafluorobutane (1 m~ol 40O mg) fresh]~ dried by evaporation of a toluene solution w2.c dissolved in tetrahydrofuran (15 ml) and added dropwise to the anion solution over 20 ~inutes. lhe mixture was stirred at -7~CC
for 1'~ hours then the cooling bath removed and the mixture ~uenched with ammonium chloride solution. The reaction ~ix~urs was poured in water (lnO ml) and extracted with ethyl acstate (3 A
50 ml). The ~mhined o ga.. c eAtrac;~ were dried over MgS~' , filtered and evaporated to dryness. Chromatography on silica followed by recrystallisation from ethyl acetate/ether gave the title product (145 mg, 31%), m.p. 233-239C dec. Found: C,48.93;

ClgH15F7~4o2 requires C,49.14; H,3.23; N,12.07%

l-Heptafluoropropy~ 4-(2-m~hy~dazor4~5-c]pyrid~ l)phen 2-~1?2,4-triazol-1-yllethanol a) l-Heptafluoropropyl-1-~4-(2-methyli~idazo~4,5-c]pyrid-1-yl)-ph ~ oxirane 1-14-(2-Methylimidazo~4,5-c]pyrid-1-)~l)phenyl]-1-oxo-2,2,3,3,4,4,4-heptafluorobutane (6 ~mol. 2.43 g) was dissolved in teerahydrofuran (30 ml) and cooled in an ice bath.
~imethylsulphoxonium methylide (0.~ `' in tetrahydroruran, lC! m~ol, 16.7 ml) was added dropwise and the solution stirred at ~C for ~G
minute~. lhe reaction mixture was then poured into brine ar.^
ex~rac~ed with ethvl acetate (3 x 5G ml). The combined organic extracts were dried over MgS04, filtered and evaporated to SUBSTITUTE SHEET

: ` :

W O 91/17162 2 0 7 8 0 0 7 PCT/EP91/00737 ~, dryness. The residue was purifled by column chromatograph-~ on silica eluting with dichloromethane/methanol (97:3) to glve the oxirane a~ an unstable oil which was u~e~ immPdiatel.~.
b) l-Heptafluoropropyl-1-[4-t2-methylimidazo[4,5-c]pyrid-]-yl) phenylo~irane (0.6 m~ol, ~0 mg) and sodium triazole (1 mmol, 93 mg) were stirred in dimeth~lformamide (5 ml) for 40 minu~es at room temperature. The reac~ion mixturC was ?cu.~d in~o brine anG
extracted with ethyl aceta~e (3 ~ 50 ml). The comDined e~erac~s were dri~d oVcr Mgc~ , f'l;e-Leu ar.r eva~orated to dr~ness. The residue was purified by column chromatograph~ eluting with dichloromethaneJmethanol (94:6). The product containing fractions were evaporated to dryness and triturated with ether to give the title product (80 mg, 27X), ~.p. 211-213C. Found: C,48.39;

C20al5F7N6' 0.1 (C2H5)2O, 0.5 H20 requires C,48.53; H,3.37; N,16.65%.

2-C~ano-l-heptafluorooropvl-1-[4-(2-methvlimidazor4,5-c]pvrid-1-yl)phenyl~ethanol The above was prepared in a similar manner to the previous example, but reacting the oxirane with sodium cyanide to give the tltle product m.p. 290-29lC dec. Found: C,51.12; H,3.05;
N,12.48. ClgHI3F7N40 requires C,51.12; H,2.91; ~,12.5~%.

EYAMPLE 13~
N-~2-t2-Chlorophen~ -hvcro~eth~ ~-meth~ idazor~i~;-c]-p,vrid~ benzamide 2-(2-Chlorophenyl)-2-hydroxyethylamine (^.5~ mmol, 440 mg) and triethylamine ~3.15 m~mol, 318 mg) were dissolved in SUBSTITUTE SHEET

, .. ' ! WO 91~17162 2 0 7 8 0 0 7 PCT/EP91/00737 .

~ 81 ;dichloromethane (20 ml) and the solution cooled ln an lce bath A
suspension of 4-(2-methyl-imidazo[4,5-c~pyrid-1-yl)ben~oylchloride (1.57 m~ol 426 ~g) in dichloromethane (20 ml) was added and the mixture stirred at 0~ for 15 minutes then at room temperature for 45 minutes. The mixture was poured into lN hydrochlor~c acid an~
the organic phase separated. The aqueous phase was basified wi~:~
2N sodium hydroxide then evtracted with dichloromethane (3 x 100 ml). The co~bined organic extracts were dried over ~aAS04, filt~red ar.d ev-~ora.ed ;o d-L-y!l~ss. rurirication was effec;ed b~
column chromatography on silica eluting with dichloromethane/
methanol/ ammonia 94:6:0.1 and the product-containing fractions evaporated to dryness. The resulting oil was dissolved in a little dichloromethane and the product precipitated with cold ether, (0.24 g, 37X). M.p. 126-128C. Pound: C,63.52; H,4.61;
N,13.19. C22HlgClN402. 0.5 H20 requires C,63.54; H,4.81; N,13.47%.

3RS,4SR-7,8-Dichloro-3-methoxycarbonyl-4-14-(2-methvlimidazo[4,5-c]pyrld-l-yl)phenyl-2~3~4~5-tetrahydro-lH-l-benzazepin-2-one Sotium metal (846 mg, 36.8 mmol) was dlssolved in dry methanol (250 ml) under nitro~en. Di~ethyl 2-(2-amino-4,5-dichlorophenyl)-1-~4-(2-methylimidazo~4,5-c]pyrid-1-yl)phenyl]-ethyl-~alonate (from Example 117, 16.15 g, 30.16 ~mol) was added and the mixture was heated at reflux for 4.5 hours, cooled and poured into 15 ml of 4N hydrochloric acid and ice. The pH was ad~usted to 7 by the addition of saturated aqueous sodiu~

bicarbonate and the product was extracted into dichloromethane (4 ;x 150 ml). The combined extracts were dried (MgS04) and SUBSTITUTE SHEET

~ ~ . .. ..... ...... .... .. .. .

. ' ~" "'. '.
:

207~37 W O 91~17162 PCT/EP91/00737 ~~

concentrated under reduced pressure to give a white ~ol~d (14.6~
g, 96%). A portion, recrystallised fro~ methanol/dichloromethane had m.p. 221-223C. lhe stereoche~istr; or ~he produc~ ~a~
assigned fro~ the H3-H4 coupling constant (9 Hz). Found: C,60.29;

25 20 2 43 requires C,60.62; H,4.07;
~,11.317~.
-EXAM~LE 136 7,8-Dichlorn-6~ o~ r/.c-~llv-yïlu-~-v~ne~ 3 4,5-tetrahydro-lH-l-benzazepin-2-one A mixture of 7,8-dichloro-3-methoxycarbonyl-4-~4-(2-methyl-imidazo[4,5-c]pyrid-1-yl)phenyl]-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one (14.42 g, 29.1 mmol) and lithium iodide (19.36 g, 145.5 mmol) in try pyrldlne (200 ml) was heated at reflux under nitrogen for 2 hours. The mixture was concentrated under reduced pressure, and purified by flash chromatography (gradient elution with ethyl acetate/methanol) to give the title compound (9.52 g, 75%), m.p. 314-316C (after recrystallisation from methanol/
dichloromet~ane). Found: C,62.14; H,4.24; N,12.23. C~3HI~Cl2N40.
0.5 H~0 requires C,61.89; H,4.29; N,12.557~.

7,8-Dichloro-l-methyl-4-~4-(2-meth~limidazo~4,j-cjD~rid~
phenvl]-2.3,4,5-tetrahvdro-lH-benzazepin-2-one A mi~ture of 7,8-dichloro-'-t~-(2-met~ylimidazot4,;-cjpyrid-l-yl)phenyl]-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one (1.093 g, 2.5 mmol) and sodium hydride (150 m~. 60% dispersion in oii, 3.75 mmol), in dry dimethylformamite (10 ml) under nitrogen at room SUBSTITUTE SHEET

.. ~ , . .

.
W O 91/17162 2 0 7 8 0 ~ ~ PCT/EP91/00737 temperature was sonicated for 5 minutes then stirre~ for a rurther 1 hour. ~ethyl iodide (171 microlitres, 2.75 mmol) was added tn the light brown solution and the mixture was stirred fo~
hours , then poured into excess ice cold dilute hydrochloric acid.
The solution was reDdered basic by the addition of saturated aqueous sodium bicarbonate and the product was extracted Wit;~
dichloromethane (4 x 125 m]!. The combined extracts were drie~
(MgS04) and concentrated under reduced pressure. The residue ~as ,ur~fiod b; f'ash chLumatu~L~hv eiu~ir.g with ethyi ace.e~e methanol (9:1) to give a white solid (848 mg, 75%), m.p. 259-261 (after recrystallisation from ethyl acetate). Found: C,63.33;

24 20Cl2N4 0-25 CH3C2C2H5 requires C,63.43;
H,4.68; N,11.84%.

The following compounds were prepared from 7,8-dichloro-4-~4-(2-methylimidazû~4,5-c]pyrid-l-yl)phenyl~-2,3,4,5-tetrahydro-ln-l-benzazepin-2-one by the method of Example 137, using 2-picolyl chloride and 4-chlorobenzyl chloride instead of methyl iodide.

Cl~O
~ C'' SUBSTITUTE SHEET

6 ~ PCT/EP91/00737 Example R21 ¦ m.p. I Analysls/. I

! No I O~ ¦(theoretical in brac'~ets~

C H

138 ~ l135-13765.024.39 13.1C

~ CH2- (6~.814.50 13.03) .' , ~39 j ~ 208~ 63.974.05 9.86 j 1 2 ~ (64.124.13 9.97) ~ Calculated for hemihydrate .

EXA _ LE 140 6-~4'-(2-Meth,vlimidazol4,5-c~p~lrid-1-yl)Dhenyl]-5-cyano-2H-1~7-dih~dro~3,4]benzazePin-2-one A solution of hexane-washed sodium hydride in dimethyl-sulphoxide (4 mg in 0.5 ml) was added to a stirred solution of 2-(2-cyano~ethylbenzylamido)-4'-(2-methylimidazo~4,5-c]pyrid-1-yl)acetophenone (0.05 g, 0.12 mmol) in dimethylsulphoxide (1 ml).
The solution was stirred at ambient temperature for 16 hours, then partitioned between ethyl acetate and ~rine. ~he organic lave was washed with brine, dried ~M~S0 ) and the solvent eVaporateG .c give a yellow solid (0.028 g). Flash chromatography, eluting witri 5 then 15X methanol in ethyl acetate, afforded the title product as a yellow solid (0.011 g, 23~), m.p. above 320C. lH NMR

SUBSTITUTE SHEET

`
:. ,~ .. . `
:. :
- , ., . . , .. ` , wo 91/17162 2 0 7 ~ o ~ 7 PCT/EP9l/00737 ~' (CDC13): 2.62(3H,s), 4.58(2H,s), 7.17(1H,d Jn5.7Hz) 7.45(2H,d J=8.5Hz), 7.60(2H,m), 7.76(1H, t J=7.5Hz), 8.13(2H,d J=8.5Hz), : 8.17(1H,s), 8.43(2H,m) and 9.08(1H,s).

,~
; EXAMPLE 141 Ethyl 4'-(2-methylimidazo~4.5-c]~ -l-yl)-2-(2~-nitro~hen acetYl) -2-benz~e Hexane-washed sodium hydride (0.053 g, 2.2 mmol) was added to a sti..e' sulutiuu ~i e~hyi 4T-~2-methylimidazol4~5-c~pyrid-l-yl) benzoylacetate (0.65 g, 2 mmol) in dry tetrahydrofuran (8 ml).
After 0.5 hours, solid 2-nitrophenacyl bromide was added in ; portions and the resultant brown solution was stirred for 1 hour.
The mixture was partitioned between ethyl acetate and water, buffering the aqueous phase to pH 7 with lM hydrochloric acid.
The organic layer was dried (MgSO4) and evaporated to dryness.
Flash chromatography eluting with 5% methanol in ethyl acetate afforded the title product as a foam (0.61 g, 63~). lH NMR
(CDC13): 1.29 (3H,t J=7.5Hz), 2.67(3H,s), 3.68(1H,dd J-16,5Hz~, 3.79(1H,dd J=16,8Hz), 4.28(2H,q, J=7.5Hz), 5.23(1H,dd J=8,5Hz), 7.19(1H,d J25.3Hz), 7.60~2H,d J=8.5Hz), 7.69(2H,m), 7.83~1H, t J~5.5Hz), 8.18(1H, d J-9Hz), 8.40(2H,d J-8.5Hz), 8.50(1H,d J~5.4Hz), 9.12(1H,s).

.
(2-Methvlimidazol4.5-c]pvrid-l-yl~henyl~ -(2~-nitr phenvl)butane-1,4-dione A solution of ethyl 4'-(2-meehylimidazo[4,5-c]pyrid-1-yl)-2-(2'-nitrophenylacetyl)-2-benzoylacetate (0.6 g, 1.23 mmol) in 2M

.
: ' ' ' 20780~7 hydrochloric acid (12 ml) was heated at 100C for 5 hours then cooled and basified with solid sodium hydrogen carbonate and partitioned between ethyl acetate and ~ater. The aq~eous la~e~
was re-extracted with ethyl acetate and the combined organic layers were dried (MgS04) and the solvent evaporated. Flash chromatography, eluting with 3~0 methanol in ethvl acetate ~ffor~ed the title compound as a yellow solid (0.186 g, 37~ H ~
(CDC13): 2.62(3H,s), 3.37 and 3.62 (each 2H, t J=5.9Hz), 7.15(1H.,c ~=5~T~, 7..J~d,u ô.~az~, 7.7û(2-~ ), 7.~0(1~3~), 8.18(1H,d,J=8.2~z), 8.31(2H,d J=8.4Hz), 8.44tlH,d J=5.5'zi and 9.10(1H,s).

1-(2'-Aminophenyl)-4-~4'-(2-methylimidazo~4,5-c]pyrid-1-yl)-phenyl]butane-1,4-dione A solution of 1-~4'-(2-methylimidazo~4,5-c]pyrid-1-yl)-phenyl]-4-(2'-nitrophenyl)butane-1,4-dione (û.18 g, û.43 mmol) ie ethanol (8 ml) was hydrogenated over 5X palladium on carbon (0.3 g) at 30 p.s.i. (2.1 bar) and 22C for 2 hours. ~he catalyst was flltered off and the filtrate was evaporated to vield a pale-yellow foam (0.166 g, lOû~). H NMR (CDC13): 2.63t3P.,s), 3.45 and 3.54 (each 2H,t J~7Hz), 6.25 br (2H,s), 6.70(2H,m), 7.27t2H,m), 7.52(2H,d J=8.5Hz), 7.90(2~';,d J=9.5H~), 8.32( n,d J-8.5Hz) 8.46(1H,d J-4.5Hz) and 9.û8(1n,s).

SUBSTITUTE SHEET

: ..
. ,, . ' W O 91/17162 2 0 7 8 ~ ~ 7 PCT/EP91/00737 ~7 F,XAMPLE 146 7-~4'-(2-Methylimidazor4,5-c]pyrid-1 ~l)phenyl]-lH-4,5-d_hvdro-~2,3~-benzazepin-4-one A solution of 1-(2'-aminophenyl)-4-~4'-(2-methylimidazo~4,5-c]pyrid-l-yl)phenyl]butane-1,4-dione (0.166 g, 0.43 mmol) in toluene (16 ~1) and acetic acid (2 ml) was heated at reflux for 5 hours, then evaporated to dryness. Flash chromatography, eluting with 5% methanol in ethyl acetate afforded a foam whic~ was crystaliised ~rom ethyl acetate to give the title 4,5-dihYdro~2.
3~benzazepin-4-one (0.036 g, 23%), M.p. 223-227C. lH ~MR
(CDC13): 2.60(3H,s), 3.35(2H,d J=7.5~z), 5.36~1H,t J=7.5Hz), 6.59br(1H,s), 7.10(3H,m), 7.43(2H,d J=9Hz), 7.53(2H,d J=9H~), 7.72t2H,d J~8.5Hz), 8.11(1H,d J=8Hz), 8.42(1H,d, J-4.5Hz), 9.10(1H,s).
:;

3-(7-Carboxyphenyl)-2-r6-(2-methylimidazo~4,5-c]pyrid-l-,vl~-phenyl]propenenitrile (a) A mixture of 4-aminobenzyl cyanide (29.2 g, 0.22 ~mol) and 4-chloro-3-nitropyridine (42.0 g, 0.27 mmol) in ethanol t550 ml) was stirred at room temperature overnight. The solid which had precipitated was dissolved in water (1 litre) and neutralised with saturated aqueous sodium bicarbonate. The product was extracteG
into dichloromethane (1 x 100 ml and 2 ~ 500 ml), and the combined extracts were dried (MgS06) and concentrated under reduced pressure to give a 4-(4-cyanomethylphenvl)amino-3-nitropvridine (55.5 g, 99Z) as a bright yellow solid.
(b) A solution of the nitropyridine (10.0 g, 39.4 mmol) prepared SUBSTITUTE SHEET

;.
.. . ~ .

W O 91/17162 2 0 7 8 0 a ~ PCl/EP91/00737 in (a~ above in ethanol:dichloro~ethane (2:1, 300 ml) was hvdrogenated over 10% palladium on carbon (1.0 ~) at 20 p.s.l.
(1.4 bar) and at room temperature for 2 hours. lne ca~al~
filtered off and the solvent removed under reduced pressur~ tO
give 3-amino-4-(4-cyano~ethylphenvl)aminopyridine (8.5 g, 6"~, which was used directlv for the next reactio~,.
(c) A mixture of the diaminopyridine (8.5 ~, 37.5 mmo') (preDar2c in (b) above), acetic acid (25 ml) and ace~ic annydride (2~ ml) was heated at reflux for 16 hours. Arter bein~ cooled~ ~he e.cess reagents were removed under reduced pressure and the residue W2S
dissolved in water (150 ml). This solution was rendered basic bv the additioD of concentrated aqueous ammonia solution and the product was extracted into dichloromethane (3 x 100 ml). The combined extracts were dried (MgS04) and concentrated under reduced pressure. The residue was purified by flash cbromatography, eluting wlth ethyl acetate/methanol (9:1) to give l-(cyanomethyl)-4-(2-methylimidazo[4,5-c]pyrid-1-yl~benzene (7.43 g, 79Z), as a brown solit.
(d) l-(Cyanomethyl)-4-(2-methylimidazo[~,5-c]pyrid-1-yl)benzene (272 mg, 1.1 mmol~ in dry methanol (1 ml) was treated with a solution of sodium methoxide (250 microlltres, 5.4M in methanol, 1.1 mmol) at room temperature under nitrogen. After the mixture had been stlrred for 20 minutes, 2-carboxybenzaldehvde (ljO m~, 1.0 mmol) was added, and the mixture was heated at reflux for 2 hours. The mixture was cooled, neutra ~sed wit;n acetic acid, anc concentrated under reduced pressure to ~ive the title compound (417 mg) which was used directly for E~:ample 146 without rurther purlfication. I~ NMR (CD30D): 2.65t3H,s), 7.38(1H,d,J 5Hz), gU~STlTUTE SHEET

,.. ~, . . , . :, .,;
-, , : -: . . :, `

wo gl/17162 2 0 7 8 0 ~ 7 PCT/EP91/00737 ~ s-.~ ; :. `.; .;

7.54(2H,m), 7.69(2H,d,J 8Hz), 7.89(1H,m), 8.0~(1H,m), 8.07(2H,d, J

8~z), 8.39(1H,d,J 5Hz), 8.65(lH~s?~ 8.94(1H,s~.

4-~4-(2-Methvlimidazo!4,5-c]pyrid-1-yl2 ~ envll-2,3-dihvdro-lH-2-benzaze~in-1~3-dione A mixture of 3-(2-carboxyphenyl)-2-[4-(2-methylimidazor4,5-cjpyrid-l-vl)phenyl]propenenitrile (410 mg, 1.08 mmol) and polypnosphoric acid (5 ml~ was heated at 100C for 2.5 hours, cooled and treated with ice water (20 ml). The resulting solution was neutralised with dilute aqueous ammonia and the product was extracted into dichloromethane. The extracts were dried (MgSO4) and concentrated under reduced pressure, and the residue W25 purified by flash chromatography, eluting with ethyl acetate/
methanol (4:1) followed by recrystallisation from hot ethanol to give the title 2,3-dihydro-lH-2-benzazepin-1,3-dione (49 mg, 12~) m.p. 273-276C. Found: C,71.64; ~,4.34; N,14.37. C23H16~4O2.
0.25 H20 requires C,71.76; H,4.32; N,14.56%.

2-Methvl-l-r4-(3-py _ dYloxvmethv1)phenvl]-imidazo~4,5-c]PYridine fumarate 4-( -Methylimidazol4,5-c]pyrid-1-yl)benz~l alcohol (0.48 g, ~
mmol) was treated with 48% hydrobromic acid (8 ml~ as described in Example 101. The crude benzylic bromide was dissolved in dimethylsulphoxide (2 ml) and added to a mixture of 3-hydrox.v pvridine (0.38 g, 4 mmol~ and flake po~assium hydroxide (0.68 g, 12 mmol) in dimethylsulphoxide (8 ml) at room temperature. After SUBSTITUTE SHEET

" ' ' ~ ~ ' .... ~

. . . ~

wo gl/17162 2 0 7 8 0 0 7 PCT/EP91/00737,-, ... ... ..
9~
being stirred for 16 hour.s, the mixture was poured onto ice, neutralised with diluee hvdrochloric acid, and extrac~ed with dichloromethane (3 x 50 ml). The comb ned extracts wer~ ~ ed (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatographv (gradient elution witb dichloromethane/methanol). Fractions containing the produc: were combined, concentrated under reduced pressure, and treeted ~ith fumaric acid (60 mg) in methanol. The methanol was re~oved unae-red--cd prassu.e, tll~ residue was dissolved in water ar.c' f-ee7e-dried, to give a pale ye11Ow powder, ~145 mg, 15%), m.p. 84C.
Found C,61.59; H,4-68; N,11.37. ClgH16N4O. 1.5 C4H404 re~uires C,61.22; H,4.52; N,11.42~.

Examples 148-151 were prepared by the method of Example 1 using 4-(2-methylimidazor4,5-c]pyrid-1-yl)benzyl alcohol and the appropriate phenol. Example 152 was prepared similarl~ using the procedure of Example 147 but isolating the product as the rree base.

~10 CH3 R8 ~ 0 _ CH~

SUBSTITUTE StlEET

~ , .
. . ~' . ~ ` ` ' ,` ' , ,. ' ' ' ' W 0 91/17162 2 0 78 ~ o 7 PCT/~P91/00737 _ _ Example i R8 R10 m.p. Analvsls ~' _ _ C( c he ore t lc.! l L ~ b r.c Ke ~ s ) 148 ~ Br 151-60.59 4.16 10.42 L 152(60.93 4.09 10.66) 1 6 G r 1 -- C~`' ~ 5 ) ,~ ; 7-- D ~ . o h 1 1 . 4 4 60(65.56 5.72 12.23) (hemihydrate) ., _ _ _ _._ 150 Cl -CO-N ~ 0 119- 63.34 5.31 11.26 120(63.35 5.11 11.37 (hydrate~

~151 Cl-CO-~ ~ 0 17564.-24 5.10 11.92 ~, (64.86 5.01 12.10) ._ _ 152 Cl-CO-N ~ 159-67.36 5.39 12.08 162(67.75 5.47 12.15) l_ .

`E.YAMPLE lS3 1-(2-Hvdroxv-~ ethvlDhenvl~-3-~4-t~-methvlimidazo[4~5-c]D~rid-l-v])Dhen,vl]-2-proDen-l-one A mixture of 4-(2-methylimidazo~4 "-c]pyrid-1-yl)benzaldehvde SUBSl lTUTE SHEET

, . ~ ~ ' -.

W O 91/17162 ~ ~ 2 ~ q ~ ~ O ~ 7 PCT/EP91/00737~

,. ~
.

(Preparation 13) (3.555 g, 15 mmol), 2-hydroxy-5-methyl-acetophenone (2.225 g, 15 mmol) and lithium hydroxide hydrate (3.720 g, 75 mmol) in ethanol/water (96:4) (100 ml) was stirred under nitrogen at room temperature for 18 hours. The red suspension was concentrated under reduced pressure, and the residue was dissolved in excess dilute hydrochloric acid. The solution was poured into a mixture of excess saturated aqueous sodium bicarbonate and dichloromethane (100 ml). The orvanic iajel w~ ~epara~ed and the aqueous laver was extracted ~-ith dichloromethane (2 x 200 ml). The combined organic solutions were dried (MgS04) and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate/dichloromethane to give orange prisms (2.42S g, 44%), m.p. 229-230C. Found:
C,73.99; H,5.28; N,11.30. C23HlgN3O2. 0.25 H2O requires C,73.88;
H,5.26; N,11.24%.

1-(5-Fluoro-2-h~droxyphenyl)-3-~4-t2-methylimidazo~4,5-c]pvrid-1-yl)phenyl]-2-propen-1-one The tltle compound was prepared by the method of Example 15i, using the appropriate 2-hydroxyacetophenone and 4-(2-methyl-imidazo~4,5-c]pyrid-1-yl)benzaldehyde. The product was obtained as a bright orange solid. lH NMR (300 ~.H , CDC13): 2.60(3H,s~, ; 7.02(1H,m), 7.13tlH,d,J 4Hz), 7.30(1H,m~, 7.48(2H,d,J 8Hz!~
7.61(1H,m), 7.64(1H,d,J 18Hz), 7.92(2H,d,J 6Hz~, 8.00tlH,d,J
18Hz), 8.41(1H,d,J 4Hz), 9.08(1H,s~, 12.'2(1H,s).

SUBSTITUTE SHEET

.

- W O 91/17162 2 0 7 8 0 ~ 7 PCT/EP91/00737 1-(4,5-Dimechyl-2-hydrox~phenx1?-3-~4-!2-methylimidazo~4,5-C]-p~rid~ Dherv]~-2-propen-1-one The title compound was prepared by the method of Example 153,and was obtained as a bright yellow solid. lH NMR (300 MHz, CDC13) 2.28(3H,s), 2.31(3H,s), 2.60(3H,s), 6.86(1H,s), 7.13(1H,d,J
5Hz), 7.'5(2Y.,d,J 8Hz), 7.64(1H,S!, 7.73tlH,d,J 14Hz), 7.91(2H,d,J
8Hz), 7.9,(l~.,d,J 14Hz), 8.41(1H,d,J 5Hz), 9.07(1H,s), ~.JO~in~s l .

2RS-6-Methyl-2-~4-(2-~o~4,5-c~pyrid-l--yl-)phenyl]-2~3 dihytro-4H-benzolb]pyran-4-one ~' A mixture of 1-(2-hydroxy-5-methylphenyl)-3-~4-t2-methyl-, imidazo~4,5-c]pyrid-1-yl)phenyl]-2-propen-1-one (400 mg, 1.08 mmol) and anhydrous potassium fluoride t50% on Celite, 200 mg) in dry methanol (20 ml~ was heated under reflux for 48 hours, then cooled and filtered. The filtrate was concentrated under reduced pressure, and purified by flash chromatography on silica gel, eluting with dichlorometbane/isopropanol t20-10:1). Fractions containing the product were combined. concentrated and recrvstallised twice from ethanol ~o give a creamy-coloured solid (42 m~ ), m.p. 202-203C. Found: C,73.72; H,5.10: ~,11.08.
C 3H19r~3C~. 0.33 H~0 requires C,73.59; Y.,5.29; ~;,11.19,~,.

SUBSTITUTE Sl IEET

W O 9t/17162 2 0 7 8 0 0 7 PCr/EP91/00737 A~

2RS,4RS-4-Hvdroxy-6-methyl-2-~4-(2-me~hylimidazor4~5-c~pvrid l?phenyl~-2,3-dihydro-4H-benzo~b,lpYran The product from Example 153 (2.43 g, 6.54 mmol) was dissolved in a mixture or methanol (60 ml), water (40 ml) and aqueous sodium hydroxide (lM, 3.2/ ml, 3.27 mmol~ at roo~
temperature with stirring, and then sodium borohydride (7jb mg, 6.54 mmol) was added. The mixture was stirred for 18 hours at room. t~mr''.~ .r~ CrlJ ;he-ll y.lL;itioned be~ween dichloromethane (i x 50 ml) and O.lM aqueous sodium hydroxide (200 ml). The organic ` solutions were dried (MgS04) and concentrated under reduced pressure, and the residue was purified by flash chromatography, eluting with ethyl acetate:methanol:diethylamine (90:5:5~ to give a white solid tl.57 g, 65X), m.p. 238-241C (after trituration with methanoliethyl acetate). Fount: C,73.73; H,5.62; N,11.38.
C23H21N3O2. 0.2 H20 requires C,73.66; H,5.75; N,11.20~.
The stereochemistry of the product was assigned from the coupling constants in the lH NMR spectrum (300 MHz, CDC13) as follows: H-2 (dd, J 1 ant 11.6Hz) and H-4 (dd, J 6 and 10.5Hz), hence both hydrogens are axial.

2RS,4RS-6-Fluoro-4-hvdrox -2-~4-(7-methvlimidazol4,5-c]~rid-l-yl)~henyl]-2.3-dih,~dro-4H-benzo~blpvran The product o~ example 154 was cyclised following ~he me~hod :

SU~STITUTE SHEET

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

.; ~ - ' ` ~ ,~

W O 91/17162 2 0 7 ~ O ~ 7 PCT/EP91/D0737 ;~;t ~

of Example 157 to give the title compound, m.p. 219-220C (from methanol~. Found: C,70.50; H,4.73; N,11.21- C22Hl8FN307 requires C,70.38; H.4.83; N,ll.l9~',.

2RS, 4RS-6,7-Dimethyl-L-hvdroxv-2-~4-(2-methYlimidazo~4,5-c~P~rid-l-~l)phenyl~-2,3-dihYdro-4H-benzu[b] yran The procuc~ of E~ample 155 was cyclised following the method OT E~mrl_ 15~ U ~ive sne t~tle comDound. m.p. 243-246C (~ror.

: me~hanol/dichloromethane). Found: C,74.94; H,6.05; N,10.90.
C24H23N303 requires C,74.78; H,6.01; N,10.90%.

.i 2RS 4RS-4-Methoxy-6-methvl-2-~4-(2-methylimidazo[4,5-c]P~rid-l-yl~ph ~ ,3-dihydro-4H-benzolb]pyran The compound from Example 157 (371 mg, 1.0 mmol) was dissolved in dry dimethylformamide t8 ml) and sodium hydride (48 mg, 60~ dispersion, 1.2 mmol) was added at room temperature.
After 45 minutes methyl iodide t68 ~1, 1.1 mmol) was added and the mixture was stirred for a further 1 hour. The mixture was concentrated unter reduced pressure, dissolved in ethyl acetate (20 ml), washed with water tlO ml), dried (MgS04) and concentrated under reduced pressure. The residue was purified by flash chromato~raphy, eluting with dichloromethane:methanol (16:1), followed by recrystallisation from diethy: ether to give a white solid (200 mg, 52~), m.p. 151-153C. Found: C,74.74; H,6.03;

~10-91- C~4H23N302 requires C,74.78; H,6.01; N,10.90~.

SUBSTlTUtE SHEET

W O 91/17162 2 0 7 8 0 q 7 . PCT/EPg1/00737 --1 2RS,4RS-4-(4-Fluorophenyl)-2-~4-(2-methylimidazo~4,5-c~pvrid-1-l)phenvll-',3-dioxane The method of Example 37 was followed using 4-fluoro-(1,3-dihydroxypropyl)benzene to give the title compound, m.p. 70C.
Found C,69.48; H,5.29; N,9.99. C23H20FN302. 0.5 H 0 requires C,69.33; H,5.31; N,10.55~.

~XAMPLE 162 .
2-Methyl~ 4-(rhenYlmethyl)phenyl]-imidazo~4,5-c]~vridine a~ A mixture of 4-chloroimidazor4,5-c]pyridine (670 mg, 4.0 mmol), p-fluorobenzophenone (880 mg, 4.4 mmol) ant anhydrous potassium carbonate (607 mg, 4.4 mmol) in dry dimethylformamide (8 ml) was stirred at reflux for 3 hours. The mixture was then concentrated under reduced pressure, dissolved in dichloromethane (75 ml) and washed with water. The organic solution was dried (MgS04~ and concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with ethyl acetate/
dichloromethane (3:2~ to give 1-(4-benzoyl)phenyl-2-methyl-imidazo~4,5-c]pyridine, (1.14 g, 82X~, m.p. 205-207C (from ethyl acetate~.
b) The compound from (a) above (612 mg, 1.94 mmol) was hydrogenated over 30Z palladium on carbon (500 mg) in a mi~ure o-ethanol t60 ml~ and dichloromethane (15 ml~ in the presence of magnesium o~ide (61? mg~ at 60 p.s.i. (4.1 bar) and 40C fo-hours. The mixture was cooled, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with dichloromethane/methanol SUBSTITUTE SI~IEET

., . . - . ` : : :, . .

` ;.

~ wo gl/17162 2 0 7 8 0 ~ 7 PCT/EP91/00737 (16:1) to give 2-meth~ 4-(hydroxy(phenyl~methyl~pheny]l-imidazo!4,5-c]pyridine (430 mg, 77%), m.p. 232-234C (from me~hanol".
(c~ The product from s~ep (b) above, (240 mg, 0.76 mmol) was added co a mixture or trifluoroacetic acid (8 ml) and triethyl-silane (14s ~1, 0.91 m~ol), and the mixture was stirred at 50C
for 1 hour. The m-:iture was concentrated under reduced pressure, and the residue W2S dissolved in dichloromethane (20 ml) and Pn,~Pre~ ~7S' C ~-,.' ~hc a'~Ui;LV~I ~f salura~ea aqueous sodium bicarbonate. The aqueous layer was separated, extracted with dichloromethane (2 x 15 ml), and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica, eluting with ethyl acetate/methanol (6:1) to give the title compound t205 mg, 90%), which was further purified by reverse-phase h.p.l.c.
(C18 silanized silica, eluting with methanol/water, 85:15) to give a white solid, m.p. 131-132C (from aqueous methanol). Found:
C~80-79; H~5-75; N~13.70- C20~17N3 requires C,80.24; H,5.72;
N,14.04%.

SUBSTITUTE S~IEET
.

.
.
.

W O 91/17162 PCT/EP91/00737 ~
2 0 7 ~ . ~

PREPARATION I
Ethvl ~4-(2-methylimidazor4,5-c]pvrid-1-yl)phenvl~acetate a) Ethvl 4-aminophenvlacetate (17.7 g, 0.1 mole) and sodium bicarbonate (8.4 g, 0.1 mole) were stirred in ethanol (200 ml).
4-Chloro-3-nitropyridir.e (15.9 g, 0.1 mole) was added as A
solution in ethanol (50 ml) and the whole stirred at roo~
temperature ror 3 hours. The mixture was then evaporated to low bulk and poured into ethyl acetate (500 ml) and washed with water (~00 ~ij. Tne organic phase was then extracted with 0.5~
hydrochloric acid and the combined aqueous extracts basiried with 2N sodium hydroxide and extracted with dichloromethane. The combined organic extracts were dried over Na2S04, filtered and evaporated to dryness. rhe residue was recrystallised from aqueous ethanol to give ethyl 4-(3-nitro-pyrid-4-ylamino)phenyl acetate (7.32 g), m.p. 124-126C. A further 8.56 g was recovered from the mother liquors.
b) The above product (15.7 g) was hydrogenated at 60 p.s.i. (4.1 bar) over 5% palladium on charcoal for 3 hours at room temperature. Filt tion and evaporation of the solvent gave ethyl 4-t3-amino-pYrid-4-Ylamino)PhenYl acetate (14.1 g).
c) Ethyl 4-(3-amino-pyrid-4-yla~ino)phenyl acetate (14.1 g, 52 mmol), glacial acetic acid (100 ml) and acetic anhytride tlOO ml) were mixed and heated at reflux under nitrogen for 1~ haurs. The coolet solution was evaporated to dryness and basified with lOX
aqueous sodium carbonate solution then e~:;racted with dichloromethane (3 .~: 100 ml!. The combir.ed organic extracts were evaporated to dryness and purified by chromatography on silica elutlng with dichloromethane/eehanol to give ethyl ~4-t~-methyl-SUBSTITUTE S1~EET

, .

.

;- W O 91/17162 ~ ~ 7 8 G ~ 7 PCT/EP91/00737 imidazo~4,5-c]pyrid-l-yl!phenyl~acecate (13.6 g~.

PREPAF;ATION 7 Ethy1 2-[4-(2-methvlimidazo[4,5-c]pvrid-l-yl)phenyl~proDanoate Ethyl ~4-(2-methyl-imidazo~4,5-c]pyrid-l-yl)phenyl~acetate (7.4 g, 25 mmol) was dissolved in tecrahydrofuran (lO0 ml) and the solution cooied tO -/0C. Lithium diisopropylamide (1.5M, 18.4 ml, 27.5 mmol! was added under nitrogon ard the resultir.g susye~1~ion sz-rrer ror 15 m nu.es. Methyl iodide (3.91 c, 27.5 mmol) was added and the mixture allowed to come to room temperature over 2~2 hours. The reaction was then quenched with hydrochloric acid (25 ml, lN) and evaporated to low bulk, the solution was basified with sodium carbonate solution and extracted wlth dichloromethane (3 x lOO ml). The organic extracts were dried, filtered and evaporatet to tryness. The resitue was purifiet by column chro~atography on silic2 to yielt ethyl 2-t4-(2-methylimidazo~4,5-c]pyrid-l-yl~-phenyl]propanoate (4.5 g, 58X), m.p. 78-80C.

2-Me~ y ~ -methylimitazor4,5-c~pyrid-l-yl)phenyl]propan Ethyl 2-[4-(2-methylimidazot4,5-c]pyrid-l-yl)-phenyl]propanoate (~.94 g, 9.5 mmol) was dissolved in tetrahydrofuran ~50 ml) and cooled in an ice bath under nitrogen.
Lithium aluminium hydride (0.19 g, 5 ~ol) was added portionwise over 2 minutes~ The mixture was stirred at 0C for l0 minutes then at room temperature for 3 hours. Fu.ther lithium aluminiu~

hydride (0.l9 g) was added and after l; minutes water was added cautiously. The mixture was acidified with N hydrochloric acid (15 SUBSTITUTE Sl~EET

, .
.

W O 91/17162 PCT/EP9t/00737~
2 0 7 8 ~3~

ml~ then basified with sodium carbonate solution and extracted with dichloromethane (2 x 100 m]). The combined organic extracts were dried over ~a~S04, ~iltered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with 10% methanol in dichloromethane to give the title product (2.3 g). Found: C,71.78; H,6.45; ~,15.56. C16H17N3O requires C,71.91; H,6.37; ~,io.73%.

'-~bl-n--r-l- ,3-Dro~aneaioi A solution of ethyl 3-phenyl-3-hvdroxy-propanoate (4.7 g, 26 mmol) in anhydrous ether (20 ml) was added dropwise to a cold (0C), stirred suspension of lithium aluminiu~ hydride in diethyl ether (50 ml). A vigourous reaction ensued during the addition.
The resultant mixture was stirred at 18C for 15 hours, then cautiously treated with water (1.1 ml), 15% aqueous sodium hydroxide (1.1 ml) and water (3.1 ml). The mixture was filtered through a filter pad and evaporated to a pale-yellow oil. Silica-gel chromatography afforded the title diol as a colourless, viscous oil (3.27g, 91%).

PREPARATIO~' 5 2-Phenvl-1,3-propanediol A solution of tropic acid (3 ~, 18 mmol~ in tetrahydroruran (20 ml) was added dropwise to a cold (0C), stirred suspension of lithium aluminium hydride in tetra~yd-oruran (40 ml~. Af~er ~
hours, the mixture was cautiously hydrolysed by addition or water (0.8 ml), 15Yo aqueous sodium hydroxide (0.8 ml) and water (2.5 ml). The mixture was filtered through a filter pad and evaporated SUBSTITUTE SHEET

:`. . `.

` ~ . . . : .
.

- .- wo 9l/17162 2 0 7 8 ~ ~ 7 PCT/EP91/00737 to a pale-yellow oil. Ch~omatographv on silica elutin& wlth diethyl ether afforded the title diol as a colourless oil which crs~stallised on standing. M.p. 41-~5~C.

, .

1,2-Bis(trimethylsil~lo ~ hen~-lethane Butyllithium (1.6H in hexane; 19 ml, 30 mmol) was added drop~ise to a cold (-20C), stirred solution of phen~lethanediol ~ L/.~ iJ in ~e~ranydro~uran (80 ml). A}ter iO minutes~
neat chlorotrimethyl-silane (4.5 ml, 3j mmol) was added. After 3C
minutes, all volatiles were removed under vacuum and the residue was partitioned between hexane and saturated sodium bicarbonate solution. The hexane layer was dried over magnesium sulphate and evaporated to give the title product as a pale-yellow oil (4g, 97%).

.,~

PREPARATIO~ 7 ., .
2-~4-(2-Meth~limidazol4,5 ~ ~y ~d-l-~l)phenyl]-~-methyl-oxirane 4-(2-Methylimidazo~4,5-c]pyrid-1-yl)acetophenone (430 mg 1~7 mmol) was dissolved in tetrahydrofuran and cooled in an ice bath under nitrogen. Dimethylsulphoxonium methylide (0.6M in tetrahydrofuran, 5 ml, 3 m~ol) was added and the solution stirred at room temperature for 4 davs. The solvent ~as remo~ed under vacuum and the residue purified by column chromatographY on silica eluting with dichloromethane/methanol (9~:~). The title comround crystallised on removal of the solver.~ under vacuum (416 mp, 92,~'.
lH NMR CDC13: 9.08(1H,s), 8.40(1H,d J~6Hz?~ 7.57(2H,d,J=
9Hz), 7.38(2H,d,J~9Hz), 7.10~1H,s), 4.02(1H,t~, 3.28(1H,m), .
.
. . '~, ~: '`': ' W O 91/17162 2 0 7 8 0 0 ~ PCT/EP91/00737 ~-2.90(1H,~), 2.63(3H,s~.

PREPAR~TTO~' 8 2-~4-(2-Methylimidazo~4,5-c]pvrid-l-vl)~7henvl~oxirane 4-(2-Methvlimidazo[4,5-c]pyrid-1-y])benzaldehyde !1.19 g, 5mmol~
waS dissolved in tetrahydroruran (20 ml) and the solution cooled in an ice bash. Dimethyl-sulphoxonium methylide (0.6M in tetrahydrofuran; 15ml, 9 rmol) was added and the resulting white suspenslon stirred at O~C for 1 hour then at room temperature for 1 hour. The mi~ture as evaporated to 5 ml, poured into brine and extracted with dichloromethane (3 x 50 ml). The combined extracts were dried (MgS04), filtered and evaporated to dryness. The residue was further purified by column chromatography on silica eluting with dichloromethane/methanol (97:3) to give the title oxirane as a clear, unstable oil which turned red on standing (362 mg, 29g).

4-(2-Methylimidazo[4,5-c]pvrid-l-yl)acetophenone (a) -(4-Acetylph~v~ n~-]-nitropyridine hvdrochloride A solution of 4-chloro-3-nitropyridine hydrocbloride (9,75 g, 50 mmol) in ethanol (40 ml) was added to a slurry of p-aminoaceto-phenone (6~76 g, 50 mmol) in ethanol (2j ml), and the mixture was stirred at room temperature overnight. The mixture was chilled in ice, and the yellow solid fil~ered o~f and dried (10.] g, 69%).
m.p. 197-200~C.
b) 4- ~ henyl)amino-3-aminorvridine 4-(4-Acetylphenyl)amino-3-nitropyridine hydrochloride (2.0 g, SUBSTITUTE S'rlEET

. . - , ,' , ~

. W O 91/17162 2 ~ 7 ~ O '~ 7 PCT/EP91/00737 78.8 mmol) was partitioned between aqueous sodlum hydro~ide and dichloromethane (3 x 20 ml). The combined organic phases were washed with water (20 ml) and concentrated under reduced pressurr to give a solid. Ethanol (20 ml~ was added, and the solution was hydrogenated over 5% palladium on carbon (0.2 g) at 50 p.s.i. (3.4 bar) for 3.5 hours. The catalyst was filtered of-, and the solvent removed under reduced pressure tO give a brown solid.
(l.8 g, ca 100%) which was used directly for the nexr stage wirhou~ purification.
(c) 4-2(-Methylimidazo[4,5-c]pvrid-l-yl)aceto~henone A solution of 4-(4-acetylphenyl)amino-3-aminopyridine (68.0 g, 0.3 mmol) in acetic acid (204 ml) and acetic anhydride (204 ml) :~
was heated ~t 95C for 1.5 hours then cooled and concentrated under reducet pressure. The residue was dissolved in water (500 ml) and rendered basic by the addition of saturated aqueous ammonia. The product was filtered off, washed with water (2 x lOO
ml) and dried under vacuum to give the title compound, (61.0 g, 81%) as a brown solid, m.p. 155-156C tfrom water).

PREPARATION lO
Ethyl 4-(2-methylimidazo[4,5-c]pyrid-l-yl)benzoYlacetate A solution of 4-(2-methylimidazo~4,5-c]pyrid-l-yl-acetophenone~l7.5 ~, 69.7 mmol) in drv tetrahydroruran (175 ml~
was added to a slurry of sodium hydride (3.68 g, 153 mmol~ in a mix~ture of drv tetrahydrofuran (35 r'~ and dieth.l carbonate (^~., g, 209 mmol) at reflux wich stirring over 45 minutes~ After a further l hour, the mixture was cooled, hexane (200 ml) was added, ` ant the resulting precipitate was fileered off and washed with SUE~STITUTE Sl-IEET

,, ` , .

, W O 91/17162 PCT/EP91/00737 ~
20780~':

, hexane (2 x 100 ml). The solid was suspended in ethyl acets~e (200 ml) and acetic acid (10.2 g) was added. After stirring for 15 minutes, water !200 ml) was added, and the orranic laver was separated. The aqueous phase was eY.tracted with ethyl acetate (100 ml) and the combined organic solutions were washed with w~ter (200 ml), dried (MgS04~ and concentrated to give the title product as a gum (17.3 g, 77"). Further purification by flash chromatography (eluting wi.h ethyl acetate/methanol (7:1) gave the ;iLi~ co~pound as a white solid. m.p. 16;-166 C.

3-Hydroxy-3-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl)propanol Sodium borohydride (0.38 g, 10 mmol) was added to a stirred suspension of ethyl 4-(2-methylimitazot4,5-c~pyrid-1-yl]-benzoyl acetate (2.4 g, 7.4 mmol) in isopropanol (20 ml) and the mixture stirred at ambient temperature for one wee~. The solution was concentrated and partitioned between water and dichloromethane. The organic layer was dried over magnesium sulphate and evaporated to an oil. Chromatography on silica eluting with methanol in ethyl aceeate afforded a colourless foam which crystallised from dichloromethane (0.25 g, 12,',). M.p.
148-50~C. Found: C,66.80; H,6.04; ~,14.57. C16H17~3O~Ø25 H~0 requires C,66.76; H,6.13; ~,14.60~;.

PREPAR~T-~O~ 12 4-(2-Methvlimidazo~4.5-cjpvrid-1--})benzonicrile a~ 4-Cyanoaniline (6.894 g, 58.4 mmol) was added to a solution of 4-chloro-3-nitropyridine (9.26 g, ;8.4 mmol) in ethanol (200 S~IBSTITUTE StlEET

. ` .. ~ ; ........
:
. .
' - . .~ . ~

-~ W O 91/17162 2 ~ 7 8 0 0 7 PCT/EP91/00737 ml) and the mixture was stirred at room te~perature for 18 hours.
The resulting yellow suspension was poured into 500 ml of ice-cold dilute ammonia and filtered. The solid was treated with 150 ' o' boiling ethanol, cooled in ice, and filtered to give ~-(4-cyano-phenyl)-4-amino-3-nitropyridine, 12.15 g, as a bright yellow powder, m.p. 210-211C.
b) According to a modification of the method of Phar~. Hel~.
Acta, 1975, 50, 188., tin dichloride dihydrate (56.4 g, ~50 mnol) was dUU~U to a suspension o~ ~-(4-cyanophenyl)-4-ami~o-3-nitropyridine (12.0 g, 50 mmol) in 2N aqueous hydrochloric acid (35 ml), water (150 ml) and ethanol (75 ml) and the resulting mixture was heated to reflux for 10 minutes under nitrogen. The mixture was cooled in ice, poured into ice-cold 2N aqueous sodium hydroxide (400 ml) and filtered. The creamy coloured solid was washed with 2N aqueous sodium hydroxide and ~ater, and then dried in a vacuum tesiccator. The product, 3-amino-4-(4'-cvanophenyl)-aminopyridine, 9.31 g, gradually turned reddish brown on exposure to light and air.
c) A mixture of 3-amino-4-(4'-cyanophenyl)aminopyridine (9.31 g, 44.3 mmol)~ triethyl-orthoacetate (40 ml) and acetic anhydride (30 ml) was heated at reflux for 2 hours ~nder nitrogen, cooled, then concentrated under reduced pressure. The brown residue was dissolved in lM hydrochloric acid and washed with ethyl acetate ~200 ~1). The aqueous layer was rendered basic with saturated aqueous ammonia and extracted with dichloromethane (3 x 200 ml).
The combined extracts were washed with water, dried (MgS04) and concentrated to give the title product as a brown solid (6.j g).
H NMR (CDC13): 2.61t3H,s), 7.13(1H,d, J 6Hz), 7.58(2H,d,J 9Hz~, S~JBSTITUTE S'.IEET

`
.

W O 91/17162 2 0 7 8 O ~ 7 PCT/EP91/00737 --.

7.98(2H,d,J 9Hz~, 8.45(1H,d,J 6hz~, 9.11(1H,s).

PREPARATIO~l l3 4-(2-Methvlimid2zor4,5-c~l~vrid-l-vl?benzaldehvd~
Nickel-aluminium alloy (1 g) was added to a stirred solution of 4-(2-methylimidazo~4,5-c]pyrid-1-yl)benzonitrile (1 g, 4.3 m~ol) in 90% formic acid (13 ml) and weter (3 ml). The mixture was heated to 120C when an e~:othP~i~ r~2ction .n~t_ated, ;hen heated under reflux for an additional 1 hour. The solution was ~led and ril~ered usir.~ a filter aid, was:~ing the rilter cake with methanol. The filtrate was concentrated and partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (100 ml). The organic layer was separated, dried over magnesium sulphate and evaporated to dryness. Trituration with ethyl acetate, followed by recrystallisation from isopropanol afforded the aldehyde as a colourless solid tO.2 g, 20X), m.p.
158-160C. Found: C,70.31; H,4.63; N,17.38. C14HllN3O requires C,70.87; H,4.67; N,17.71~.

PREP~RATION 14 Methyll4-(2-methylimidazo~4,5-c]pyrid-1-yl)~henyl]pro~anoate The procedure described under Preparation 9 was followed but .i using p-aminophenylpropanoate in place of p-~minoacetophenone to give the title compound (65X) m.p. 88-91C. Found: C,67.16;
i H,5.84; N,13.55. C17H17N302. 0.5 H~0 requires C,67.11; H,5.92;
N,13.82~.

, SUBSTlTUTEi Sl IEET

, .
:, ' ' : :.

-~ W O 91/17162 2 0 7 8 0 ~ 7 PCT/EP91/00737 4-(2-~lethylimidazo[4,5-c]pyrid-1-Yl~benzyl alcohol The procedure described under Preparation 9 was follo~e~ bu~
using 4-aminobenzyl alcohol instead of 4-aminoacetophenone to give the title product (83%) m.p. 154-156C. Found: C,70.10; H"5._2;
~17-89- C14H13N30 requires C,70.29; H,5.44; N,17.577O.

. .
2-'~varoxyetnvl~henyij~ -methvlimidazol4~5-c]~yridine ;; The procedure described under Preparation 9 was foliowed but ; using 4-aminophenethyl alcohol instead of 4-aminoacetophenone to give the title product (67%) m.p. 196-198C. Found: C,70.99;
H,6-16; N,16.50- C15H15N3O requires C,71.15; N,5.93; N,16.60%.

PREPARATION 1?
4-(2-Methylimidazo~4,5-c]pyrid-1-yl)benzoic acid A mixture of 4-(2-methylimidazo~4,5-c]pyrid-1-yl?benzonitrile (12.0 g, 51.3 mmol) and sodium hydroxide (22.0 g, 0.55 mmol) in a mixture of ethanol (55 ml) and water (55 ml) was heated under nitrogen at refluY. for 1~ hours, cooled ant concentratet under reduced pressure. The brown resitue was tissolved in iced water and glacial acetic acid (33 ml) was added, at which pcint a bufr-coloured solid precipitated. The solid was washed with ~ater and dried under vacuum at 70C to gi~e the title compound, (9.139 &, 70%). H ~R (DMSO-d6), 2.50(3H,s!, 7.25(1H,d,J=5Hz~, 7.72(2H,d,J=8Hz), 8.16(2H.d,J=8Hz), 8.30~1H,d,J=5Hz), 3.9^(1'n.s~.

SUBSTlTU~E St~EET

:
, . . .

WO 91/17162 ` 2 0 7 ~3 o ~ '7 PCI/EP91/00737 ,~

].08 PUEPARATIo~ 1 8 4-(2-Methylimidazor4,5-cl ~ rid-1-vl)benzar!~.ide A mixture of 4-(2-meth!~limida7O[4,5-cjp~.~ri~ cer.2onrril^-(4.69 g, 20 mmol) and concentrated sulphuric acid (50 ml~ was heated at 110C with stirring for one hour, then slowlv poured onto crushed ice (200 g~. The pH of the mi~ture was adjusted to c .. by addition of aqueous sodium hydroxide and the soiution e~tractec with ethyl ace~ate. The organic pnase was dried (MgSOL~ and evaporated to a yellow solid (5 g) which was re^rystalll.sed r^ro...
isopropanol to give the title product (2.19 g, 44"), m.p.
194-195C- Found C~65-46; H~6-35; N,18.40. C14N12N4O, (CH3)2CHo,L
requires C.65.36; H,6.45; N,17.94%.

SURSTITUTE SltEE~

.. ,, . :
~; " . . ..
. .
.. . ` . ..
. . ~ . . .
,,. ; ` ~, ' `` ` : ~

Claims (22)

109

1. A compound having the general formula:

.... (I) or a pharmaceutically acceptable salt thereof, wherein A is a C1-C8 alkyl, perfluoro(C1-C8)alkyl, C3-C8 cycloalkyl, aryl or heterocyclic group, wherein said aryl or heterocyclic group may be unsubstituted or substituted with from one to three substituents each independently chosen from C1-C4 alkyl, halo, oxo, CO2R4, CONR5R6, OH, C1-C4 alkoxy, NH2, NO2, CN
and (CH3)3SiCH2;
B is a C1-C5 alkylene or C2-C5 alkenylene chain which may optionally be substltuted by one or more C1-C4 alkyl, C1-C4 alkoxy, perfluoro(C1-C4)alkyl, C3-C7 cycloalkyl, phenyl, oxo, OH, CN, CONR5R6 or CO2R4 groups and wherein up to two carbon atoms in said chain can independently be replaced by O, S(O)m, -N= or NR7, and wherein said chain or part of said chain, may form, or may form part of, a 5-7 membered saturated or mono-unsaturated ring which may contain a nitrogen atom or NR7 group, a nitrogen and oxygen atom, or one or two oxygen atoms, said ring being optionally substituted with any of the foregoing chain substituents, and, in the case where the group A is an aryl or heterocyclic group, the ring may optionally be fused to said aryl or heterocyclic group;
each of R1, R2 and R3 is independently H or CH3;
R4 is H, C1-C4 alkyl or aryl(C1-C4)alkyl;
R5 and R6 are each independently H or C1-C4 alkyl, or R5 is H and R6 is C3-C8 cycloalkyl or aryl, or the two groups R5 and R6 together with the nitrogen atom to which they are attached, form a piperidin? 4-ketopiperidino, morpholino or piperazinyl group;
R7 is H, C1-C4 alkyl, CO2(C1-C4)alkyl, aryl(C1-C4)alkyl or heteroaryl(C1-C4)alkyl;
and m is 0, 1 or 2;
with the proviso that A-B is not C2H5OCOCH2CO- or CH3COCH2CO2CH2-.

2. A compound according to claim 1 wherein the linking group B, is an ether group having an oxygen atom and up to four carbon atoms in the chain linking the group A to the phenyl ring, and wherein said linking group may optionally have a further oxygen atom in the chain and said chain may optionally be substituted by hydroxy, oxo, C1-C4 alkoxy, C1-C4 alkyl or phenyl, or wherein the linking group may also form part of a 5 to 7 membered cyclic ether group containing one or two oxygen atoms in the ring which may optionally be substituted by C1-C4 alkyl hydroxy, oxo, or C1-C4 alkoxy and which may optionally be used to a phenyl or tetrahydronaphthalene ring.

3. A compound as claimed in claim 2 having the formula:
wherein X is:

4. A compound according to claim 1 wherein the linking group B
contains an amide group together with up to three further carbon atoms in the chain linking A to the phenyl ring. The nitrogen atom may optionally be substituted by C1-C4 alkyl and the chain may optionally be substituted by C1-C4 alkyl or phenyl, or include a further oxo substituent.

W O 91~17162 PCT/EP91/00737

5. A compound as claimed in claim 4 having the formula:

wherein X is as previously defined in claim 3.

6. A compound according to claim 1 wherein the linking group B
contains NR7 or -N=, together with up to four carbon atoms in the chain linking A to the phenyl group,which may optionally be substituted by oxo or CO2(C1-C4)-alkyl, wherein R7 is H, C1-C4 alkyl, CO2(C1-C4)alkyl or aryl(C1-C4)alkyl; and wherein said linking group may optionally be cyclised to form a pyrrolidinyl group or piperidino group, which may optionally be fused to a benzene ring, or it may be an oxazoline ring.

7. A compound as claimed in claim 6 having the formula:

wherein X is as previously defined in claim 3.

WO 91/17162 PCT/EP91/00737 R. A compound according to claim 1 wherein the linking group B
is a 7-membered saturated or mono-unsaturated ring containing -NR7- wherein R7 is as previously defined in claim 6, and wherein said ring may optionally be substituted with oxo or CO2CH3.

9. A compound as claimed in claim 8 having the formula:
wherein R21 is H, methyl, 4-chlorobenzyl or 2-pyridylmethyl and X
is as previously defined in claim 3.

10. A compound according to claim 1 wherein the linking group B
contains a S(O)m group together with up to four carbon atoms in the chain linking A to the phenyl ring, where m is 0-2, and wherein the chain may optionally be substituted by C1-C4 alkyl or hydroxy.

11. A compound as claimed in claim 10 having the formula:

wherein X is as previously defined in claim 3.

12. A compound according to claim 1 wherein the linking group B
is a C1-C4 alkylene or C2-C4 alkenylene group which may optionally be substituted by one or more OH, oxo, CO2R4 or perfluoroalkyl groups, wherein R4 is as previously defined in claim 1.

13. A compound as claimed in claim 12 having the formula:
wherein X is as previously defined in claim 3.

14. A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 13, together with a pharmaceutically acceptable diluent or carrier.

15. A compound of the formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 13 for use in medicine, in particular for use in the treatment of allergic, inflammatory and hypersecretory conditions in humans.

PROCESS CLAIMS

16. A process for preparing a compound having the formula:

....(I) and pharmaceutically acceptable salts thereof, wherein A id a C1-C8 alkyl, perfluoro(C1-C8)alkyl, C3-C8 cycloalkyl, aryl or heterocyclic group, wherein said aryl or heterocyclic group may be unsubstituted or substituted with from one to three substituents each independently chosen from C1-C4 alkyl, halo, oxo, CO2R4, CONR5R6, OH, C1-C4 alkoxy, NH2, NO2, CN
and (CH3)3SiCH2;
B is a C1-C5 alkylene or C2-C5 alkenylene chain which may optionally be substituted by one or more C1-C4 alkyl, C1-C4 alkoxy, perfluoro(C1-C4)alkyl, C3-C7 cycloalkyl, phenyl, oxo, OH, CN, CONR5R6 or CO2R4 groups and wherein up to two carbon atoms in said chain can independently be replaced by O, S(O)m, -N= or NR7, and wherein said chain or part of said chain, may form, or may form part of, a 5-7 membered saeurated or mono-unsaturated ring which may contain a nitrogen atom or NR7 group, a nitrogen and oxygen atom, or one or two oxygen atoms, said ring being optionally substituted with any of the foregoing chain substituents, and, in the case where the group A is an aryl or heterocyclic group, the ring may optionally be fused to said aryl or heterocyclic group;
each of R1, R2 and R3 is independently H or CH3;
R4 is H, C1-C4 alkyl or aryl(C1-C4)alkyl;
R5 and R6 are each independently H or C1-C4 alkyl, or R5 is H and R6 is C3-C8 cycloalkyl or aryl, or the two groups R5 and R6 together with the nitrogen atom to which they are attached, form a piperidino, 4-ketopiperidino, morpholino or piperazinyl group;
R7 is H, C1-C4 alkyl, CO2(C1-C4)alkyl, aryl(C1-C4)alkyl or heteroaryl(C1-C4)alkyl;
and m is 0, 1 or 2;
which process comprises one of the following-:
a) for compounds of the formula (I) wherein A is Ar and Ar is an aryl or heteroaryl group which may optionally be subsituted as defined in A above and the linking group B is an ether group having an oxygen atom and up to four carbon atoms in the chain linking A to the phenyl ring, said compounds having the formula:
Ar-O-D-X
wherein D is a C1-C4 alkylene group which may optionally be substituted as defined in B above and X is:
wherein R1, R2 and R3 are as previously defined;
by reaction of a compound of the formula Ar-OH either with a hydroxyalkyl derivative of formula HO-D-X in the presence of triphenyl phosphine snd diethylazodicarboxylate or with a halo alkyl derivative of formula hal-D-X. wherein hal is chloro or bromo, in the presence of an acid acceptor, wherein Ar, D and X
are as previously defined; and optionally using a chemical transformation reaction to obtain compounds wherein Ar is substituted by -CO2R4 and R4 is H or wherein the substituent is CONR5R6 and R5 and R6 are as defined above, or is NH2; or b) for compounds of the formula:
wherein Ar is an aryl group which may optionally be substituted as defined in A above and R12 is H or CH3; by reacting an oxirane of formula wherein Y and R12 are as previously defined above, with a phenolic anion of formula Ar-O?; or c) for compounds of the formula (I) wherein B forms a 5-7 membered cyclic diether group, by reaction of an aldehyde of formula HCO-X wherein X is as previously defined in a) above, either wich a diol of formula wherein each D2 is independently a direct bond or C1-C2 alkylene group with the proviso that the total number of carbon atoms in both together does not exceed 2, to give compounds wherein A is a phenyl group benzofused to said cyclic diether group; or by reaction of the aldehyde with a diol of formula A-B1-OH. wherein A
is as previously defined and B is a C2-C4 alkylene group optionally substituted by phenyl or with a further oxygen atom in the chain and containing a further OH group separated by from 2 to 4 carbon atoms from the terminal OH group; or by reaction of an aryl aldehyde of formula:
Ar-CHO
wherein Ar is as previously defined in b) above with a diol of formula:

wherein B1 and X are as previously defined; or d) for compounds of formula (I) wherein B contain a -O-CO-(ester) group and up to three further carbon atoms in the chain linking A to the phenyl group, either by reaction of an acid of formula HO2C-D1-X with an alcohol of formula A-D1OH, or by reaction of an alkanol of formula HO-D1-X with an acid of formula A-D1-CO2H, wherein A, and X are as previously defined and D1 is as previously defined for D or it may be a direct bond, with the proviso that the number of atoms in the chain linking A to the phenyl ring does not exceed 5; or e) for compounds of the formula (I) wherein B contain a -NR19CO-(amide) group and up to three further carbon atoms in the chain linking A to the phenyl group, either by reaction of an amine of formula A-D1-NHR19 with an acid of formula HO2C-D1-X, or by reaction of an acid of formula A-D1-CO2H with an amine of formula R19NH-D1-X, wherein A, D1 and X are as previously defined and R19 is H or C1-C4 alkyl, with the proviso the the number of atoms in the chain linking A to the phenyl ring in X does not exceed 5; or f) for compounds or formula (I) wherein A is a saturated nitrogen-containing heterocyclic group and B contains a carbonyl group together with up to four further carbon atoms in the chain linking A to the phenyl group, by reaction of the heterocyclic compound with a carboxylic acid of formula HO2C-D1-X, wherein D1 and X are as previously defined; or g) for compounds of the formula (I) wherein B contains -N= or -NR7- (amines) together with up to four carbon atoms in the chain linking A to the phenyl group and R7 is as defined above, by reaction of an aldehyde of formula HCO-D1-X with an amine of formula A-D1-NH2 to give the schiff's base, followed by reduction to give the amine (R7=H), followed, if desired, by alkylation or acylation to give the compounds wherein R7 is C1-C4 alkyl, CO2(C1-C4)alkyl, aryl(C1-C4)alkyl or heteroaryl(C1-C4)alkyl;
wherein D1 and X are as previously defined with the proviso that the number of carbon atoms in the chain linking A to the phenyl ring in X does not exceed 5; or h) for compounds wherein B is a 7-membered saturated or mono unsaturated ring containing NR7 having the formula wherein R7 and X are as previously defined and each R22 is independently H or an aryl group substituent as defined in A
above, by cyclising a compound of the formula to give the product where R7 is H, and if desired subsequently treating with lithium iodide in pyridine to give compounds having the formula .

wherein R7 is H; or for compounds having the formulae or by ring closure of the corresponding open chain compound of formulae or wherein R22 and X are as previously defined, by heating under acidic conditions to give the products wherein R7 is H: and, if desired alkylating or acylating any of the above products where R7 is H by reaction with a strong base followed by a C1-C4 alkyl halide, aryl(C1-C4)alkyl halide or heteroaryl(C1-C4)alkyl halide or (C1-C4 alkyl) chloroformate to give compounds wherein R7 is C1-C4 alkyl, aryl(C1-C4)alkyl, heteroaryl(C1-C4)aklyl or CO2(C1-C4)alkyl; or i) for compounds of the formula (I) wherein the linking group B
contains S(O)m together with up to four carbon atoms in the chain linking A to the phenyl group, and m is 0, 1 or 2; by reaction of a thiol of formula A-D1-SH with an alcohol of formula HO-D1-X
wherein A, D1 and X are as previously defined, in the presence of triphenylphosphine and diethylazodicarboxylate to give the thioethers where m is 0 and optionally oxidising to give the sulphone or sulphoxide derivatives where m is 1 or 2, with the proviso that the number of atoms in the chain does not exceed 5:
or j) for compounds of the formula (I) wherein the linking group is a C1-C5 alkylene or C2-C5 alkenylene chain which may optionally be substituted by one or more OH, oxo, CO2R4 or perfluoroalkyl groups, either by reaction of an aldehyde of formula:
HCO-X
with dimethylmalonate followed by reaction with an aryl anion to give compounds of the formula:
wherein Ar and X are as previously defined, or by reaction of an aryl aldehyde with a ketoester of formula:
to yield compounds of the formula wherein R4, Ar and X are as previously defined, followed, if desired, by reduction to give compounds of the formula:

17. A process as claimed in claim 16 wherein said compound of formula I has the formula:
wherein X is:

18. A process as claimed in claim 16 wherein said compound of formula I has the formula:
or wherein X is as previously defined in claim 17.

19. A process as claimed in claim 16 wherein said compound of formula I has the formula:
or wherein X is as previously defined in claim 17.

20. A process as claimed in claim 16 wherein said compound of formula (I) has the formula:

wherein R21 is H, methyl, 4-chlorobenzyl or 2-pyridylmethyl and X

is as previously defined in claim 17.

21. A process as claimed in claim 16 wherein said compound of formula (I) has the formula:

or wherein X is as previously defined in claim 2.

22. A process as claimed in claim 16 wherein said compound of formula (I) has the formula:

wherein X is as previously defined in claim 17.