CA1202309A - Aurore derivatives - Google Patents

Abstract

AURONE DERIVAT IVES
ABSTRACT OF THE INVENTION

Substituted aurones ot formula (I) :

(I) wherein R1, R2, R3, R4, R5 and R6 are the same or different and can each represent hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, optionally substituted phenyl, Cl 6 haloalkyl, amido, amino, cyano, hydroxy, nitro, C2-4 alkenyl, carboxyl, tetrazol-5-yl and -CH_CHCOOH; or wherein R1 and R2 taken together can represent a group of formula -CH-CH-CH-CH- provided that at least ono of R17 R2, R3, R4, R5 and R6 is carboxyl, tetrazol-5-yl or -CH=CICOOH;
or a pharmaceutically-acceptable salt or ester thereof, are effective in the prophylactic chemotherapy of allergic conditions such as bronchial asthma.

Description

?2~09 ~h~ invention relates to novel aurone derivatives possessing va1uab1e pharmacological activity, a process for their production and their use as ph~maceuticQls.
In recent years, extensive ef~orts have been made to discover new compounds use~ulin the ~ eviation of allergi~ disea~es and there is, in particolar, a need for therapeutic agents which aPe effective in treating im~ediate hypersensitivity conditions such as a thma.
We have discovered certain aurone derivatives po~sessing the following basi~ skeleton, which have such useful ac~ivity.

' 6~$~ ~

According to t~e pres~ntinvention there is provided ~ substituted aurone o~ formula I

R~ Cll ~6 in which R~ 2, R3, R4, R5 and R6 are the s~lme or different and can each represent hydrogen. halogen, Cl_~ alkyl, Cl~ alkoxy, C3-8 cyclonlkyl, 30~

optianally substituted phenyl, Cl_6 halo~l, amido, amino, cyano, hydroxy, nitro~C2~ kenyl, carboxyl, tetra~ol-5-yl or ~ HCOO~; or in which R1 ~nd R~ talcen together represent ~ group of formula ~I=CH-CEI=CH-; provld~d 'chat at least oneof Rl, R2~ R3~ R4, R5 ~nd R6 is carboxyl, te~a~ol.-5-yl or ~H=CHCOOH, or a pharmaceuti~ally-acceptable salt or ester thereof.
The compound~ of formula I may ea~ist in the (E)- or (Z)- form, the (Z~-form being prefer~ed.
A more particular group OI compound3 is one of formul~ ~I) in which R], R2, R3, R4, R5 and R6 have the values defined above provided that when Rl, R2 and R3 are all hydrogen at least one of R4, R5 ~nd R6 is tetrazol-5-yl or -CH-CHCC)OH. It is preferred that the benzofuranone ring be substituted and thus a preferred group is one of f~mula (I) in which at leRst one of R] ? :R2 and R3 is other th n hydrogen.
A further particular group of ~ompounds is one oi~ ~ormula ~ n wh~ch ~, R2, ~3, R4, R5 ~nd R~ havQ the values defined above provided that when one ofR], R2 and R3 is carboxyl at least one of R4, R5 And R6 is halogen, C3_8 cyclo~lkyl, optianally substituted phenyl, C]_6 hal~ mido, cyano, ni~¢o, ~arhoxyl, tetraz~l-5-yl or -CH=CHCC)OEI. It i~ frequently preferTed that at lea~t one of the substituents on the free benzene ring is one such substituent and thus a preferred group is one o~ f~rmul~ (I) in which ~t least one of R4, R5 ~nd ~6 is halo~n, C3 8 cyclo~lkyl, opticnalIy substituted phengl, C]_6 haloalkyl, amido, cyas~o, nitro,carboxyl,te~azol-5~yl or -C H-C H C 0.0 H.

~.-' :,i ~gr~3o~3 --3~

An espeeially preferred group of compounds is one of formula tI) in whichat least one of R] ~ R2 and R3 is other than hydrogen and at l.east one of R4, R-~ and R is halogen, C3_8 cycloalkyl3 optionally substituted phenyl, C]_6 haloalkyl, amido, cyano7 nitro, carboxyl, tetrazol-5-yl or-CH=CECOOH.
The term "halogen" means especially chlorine, bromine and fluorine. The term 7T Cl_6 a~l" includes, for example, methyl9 ethyl, propyl, isopropyl, butyl, tert butyl, pentyl and hexyl, being prePerably methyl~ ethyl or tert-butyl. The term "Cl_6 aL'coxy'1 includes, for example~ methoxy, ethoxy, propoxy, buto2y and is preferablv metho~. The term "C3_8 cycloal~l" is preferably cyclohexyl. The term "optiondlly substitu~ed phenyl" includes, for example, phenyl optionally substituted with 1 to 3 substituents selected from methyl, methoxy, halogen and nitro.The term "Cl_8 haloalkyl" can be, for example, any of the group~ listed for ITCl_6 alkylT' substituted with OnQ to three halo atoms such as iluorine or chlorine and 1~ especially tr~uoromethyl. The term "C2_4 alkenyln i9 preferably Rllyl. It 19 pre~erred thflt Rl, ~2, R3, R4, ~5 and P~ be s~lected from hydrogen, halogen, Cl_4 alkyl, Cl_4 ~Ikoxy, cyclohexyl, trifluoromethyl, N-isopropylcarboxamido, acetarnido, dimethylamino, hy~oxy, carboxyl, tetrazol-5-yl or -CH=CHCOOH, ~r 11l and R2 together represent -CE=CH~H=CH-.
Other prefe~red compounds falling within the scope of the aurones or^
formula (I) ~re th~e compounds having one or more of the following characteristics:

ta) Rl i9 Cl_~ alkyl such ~s methyl (b) Rl is Cl_4 alkoxy such as metho3cy (c) Rl is halogen such as chlorine O~9 ~d) Rlis C3_8 cycloalkylsuch ~s cyclohexyl !e~ R~lis am~no (f) Rlis carboxyl (g) Rlis a 5- or 6- subs~ituent (h) Rl ~ hydrox91 (i) R2 is hydrogen (j) R3 ~ hydrogen ~k) R4 is carboxyl (1) R4 ~ tetrazol-5-yl (m) R4 ~ -CH=C H C O O~I
(n) R5 i3 hydrogen (o) R6 is hydrogen A p~ti~ularly preferred group of compounds is one in which Rl is Cl_4 alcyl~ carbo~ or halogen~ ~2 and R3 are hydrogen, R4 is c~rboxy1 or -C~I~CHCOOEI
and ~l5 ~nd R6 ~re hydrogen. O~ this group, the compounds in which Rl is slky~ or carboxyl, R2 and R3 are hydrogen, R4 is carboxyl or -CH=CHCOOH and R5 and R~
are hydrogen ~re most preferred.
The compounds OI formul~ 1 can also be in the form OI their pharmaceutically-acceptable saltg or esters. Such derivatives sre encountered, for example, when one ~r mcre of the substituents Rl, R2, ~3, R4, R5 and R6 are the acid funetion, carboxyl or -C~aC~COOH. Suitnble salt~ 1nclude ~or example those of mineral bases suoh as ah'culi metal hydroxides, especiaIly the potassium or sodium salts, or aLcaline earth metal hydroxides, especially the calcium s~lts, or o~ organic bases such as amines. Pre~erred esters are those derived from Cl_4 alkanols, for example, the methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxyethyl or ethoxyethyl esters.

Theinvention a~oincludes a methoclofpreparing aurones o~formula(I) which ~ompr;ses r~.ctin~ a ~nzaldehvde ofform u~a(D~

~HC _ ~ III

:`
with(a)~ benzofuranone of~ormulatIV) !~

R2 ~ IV

R~

or(b) ~n~ubstituted ~cetophenone offormulatV~

R2 ~C~2~( V

in which X ~ a lea~ng group;optiona~y fo~owed when ~ne or more o~ Rl, R2~ ~3, R4, R5 or R6 ~ cyano by re~tiQn ~ith en Qæide to give the corresponding tetrazol-5-yl compound; and where desired, forming a pharmaceutically accepkable salt or ester of the c~mpound of formula (I) so prepared.

P~`30~

As indicated above9 aurones of formula (~ may be prepared by conden$ing an al~propriatelv sul~stituted benzal~ehvde ~m~ w7th a ben~ofuranone derivative (IV) as schematically depicted below:

RZ~> ~ OHC

(IV) (I) ~ uit~blo solvents ~or thi~ r~nction inalude ethero~l ~olvents su¢h a~
dloxRn ~nd te~rahydrofuran and l~quid Qlkanols suoh a~ ethanol. ln general, temperature is not critical and is only determin~tive ~ the reaction rate. The reaction wDl proceed a~ all temperatures between ambient and the re~lux temperature of the reacffon mixture, ~or example, between 25 and 15ûC. The reaction is pre~erably acid or base c~talysed. Suitable acid catalysts include mineral acids such a~ hydrochloric acid &nd strong organic acids such as p-toluene sulphonic acids, whereas suit~ble inorganic or org~nic base catalysts include alkalies such ~s caustic soda, c~ustic pot~sh, sodium carbonate or triethylamine. This type of conder~7~tion reaction is well known and those slcilled fn the art will well appreciate the n~ture o~ the reaction conditions And reagents necessary to produce a particular aurone of formula (I~, 3V~

An alte~native process for preparing compounds of formul~ (I) involves the reaction of anh~suhst~tuted acetophenonet~` with an appropriate benz~dehyde (m) as depicted schematically belowo R1 o R4 R2 _~ + OHC ~RR~;

R (V) ~ (III) (I) where X is a leaving group, such a~ i'or example h~log~2, e9pecial1y chloride orbromide, or the tosyl group. Suitable 901vent9 Include ethereal Yolvents such asdioxu~ and tetrahydrofuran and llq~d alkanols such as ethanol. ln this instance the re~tion is preferably base catalysed using a catalyst such as caustic soda, caustic p~tash or sodium car~onate. Temperatures from 0 to 15aC c~n be u3ed to e~ect the re~ction. The reactant~; oi~ formula (m), (IV) and (V) are in the main known~ompounds and can be prep~red by well cnown routes described in the literature.
~ ad~ition, compounds OI formulA (I) in which one oi~ the R groups i9 tetrazol~5-yl can be derivecl by preparing the corresponding nitrile and forming the tetrazole therefrom utili.Ying a preferably non-nucleophilic azide, eor example trimethylsilyl azide, in ~ high boiling solvent such as dimethylformamide at temperatures sb~ve 10~C.

w8 ~

These re~ctions ~vi31 produce the (Z)- 1somer which, if desired, can be conve~te~ to the co~respo~ding l~isomer b~ phct.-~!yffc m~t1~s wh;~.~h are ~e?l h~n ~ the art.
The aurones of ioPmul~ (I) have ~een ~hown to be useI7l1 in the prophylacti~ treatment of asthma in mammals. I~ ctivity has been demonstrated in guinea pigs using either the "Herxheimel~" test descPibed in the Journal of }Ig~l~v ~L~L;L~ 2Sl 9S2) or the "guine~-pig ~hopped lung test" described by Mo~gar and Schild in the Jourllal OI Phy~ ~London) ~ 3], 207 (1956) or Brocklehurst Journa of Ph~iolo~ (London) ~52, 414 (1960). Compounds are also ective in the "rat p~ritoneal anaphylaxis tes~" based on an allergic re~ction in the peritoneal cavity of the rat, ~9 degcribed by Orange, Stechschulte and Austen in~ed.Proc. 2~ 1~10 ( I ~û9).
The "Her~h~ime~" test i~ bQsed on an ~Jlergic broncha~pasm induced in gulne~ pigs which closely re~emble~ an asthmatic attack in m~ medi~tors causing the bronchosp~sm are very similar to tho e releAsed when sens~tised human 11mg tissue is challenged with ~n antigen. Compounds of the invention h~ve e~hibited a~ff~rib in the ~Her~heimer" test at dosages ranging irom 2~ mg/kg to 200 mglkg.
Th2 compo~ds of fo~mul~ (I) may be ~dministered by v~ious route3 ~nd ~or thi~ purpose mQ~T be l~ormulQte~ in ~ v~riety Oe ~orrn~, although it is Q spe~i~
feQture o~ the compounds oi~ th~ invention that they are effective when administered orally. Thus the compounds OI the invent~on may be administerecl by the oral andrectal routes, topically, pflrenternlly, e.g. by inje~tion, in the form of, for example, t~blets, lozenges, sub-1ingu~l tablets, sachets, cachets, eli2Qrs, suspen~ions, aerosols, ointments, faP example, containing up to 1096 by weight o~ the aetive compound in a suitable base~ soft ~nd h~r~ gelatin c~psules, '~,' .3~)g _9_ suppositories, injectian solutions and suspellsions in physiologically acceptable m~ia, an~ st~rile packeg~l po~ud~!s adsorh~ onto ~ sv~pot~t matePial fOl' ~e~
injection solutions. The nature of the various excipie~ts and aclditives required to produce such formulations will be well-l~nown to those skilled in the art.
llowever, some examples of excipients which may be employed in the pharmaceutical formulati~ns of the present invention are lactose, dextrose, sucrose, sorbitol, msnnitol, propyIene gly~ol, ~iquid p~raIfin~ white soft para:Efin, kaolin, ~umed silicon dioxide, microcrystalline cellulose, calcium silicate, silica, polyvinylpyrrolidone, cetostearyl alcohol, starch, modified starches, gum a~acia, calcium phosphate, cocoa butter, ethoxylated esters, oil OI theobronna, arachis oil, alginQtes, tragacanth, gelatîn, syrup lB.P., methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxyben~oate, sorbit~ trioleate, sorbit~n sesquioleate and oleyl alcohol and propellants ~u~h as trichlommono~luorometh8ne, dichlorodiiluoromethane and dlchlorote~ra~luoroethane. In the ca~e oi~ tabletY, a lubricant may be incorporated to prevent sticking and bindln~ of the powdered ingredlents in the dies nnd on the p-mch oi~ the tabletting machine. For such purpose there may be ernployed Por instancealuminium, mQgnesium or calcium stearates, talc or mineral o~l.
The invention also include~ a ph~rmaceuticsl i~ormulation which comp~ises as an active ingredient a compound OI formul~ (I) or a pharmaceutically-ac~eptable s~lt or ester thereoL77 associated with a pharmaceutic~lly-a¢ceptable carrier therel70r~ Pharmaceutical formulations can be provided in dosage unit foPm, each dosage unit preferably ~, o~ ~

containing from 5 to 500 mg. (from 5.0 to 50 mg. in the case of parenteral ~dmin-stration, from 5.0 to sn n!~. ~n the case o~ r~alat;on anc~ f~om ~ to ~OQ mg.
in the case of oral or rectal administration) o~ a compound of formula (1). The term "unit dosage form", as used in the spe~ification and cIaims, refers to physi~ally dis~rete units suitable as unit~ry dosages for hwnan subjects and animals, each unit containing a predetermined quantity of acffve material calculated to produce thedesired therapeutic effect in association with the required pharmaceutical diluent, ca~Tier or vehicle.
Dosages of from 0.5 to 200 mg/kg per day, preferably 1 to 20 mg/kg of active ingredient may be administered, although it will, of course, be understood that the ~mount of the aurone OI ~ormula ~1~ actually administered will be determined by a physician, in the light of the relevant circum~t~nces incIuding the condltial to be treateci, the ohoice o~ compound to be administered and the cho~en o~ route o~ adminlstration and therefore the above preferrecl dosage range is not intended to limit the scope of the present invention in any way.
The ~ollowing 33xamples illustrate the invention.

EgAMPLE ]
(Z)~'-C~rbox~1-2-benzyliden~5-methylbenzofuran-3(2H~-one ~J~hloro-2-hydroxy-5-methylacetophenone t8.73g,û.05 mole)rChem.Ber 41, 4271,(1908)] and 4-carboxybenzaldehyde (7.S~, 0.05 mole) were dis~olved in ethanol (100 ml) and tha mixture heated to 60C. Sodium hydroxide (4g, 0.1 mole) in w~ter (20 ml) was then slowly added to the stirred mi~ture which turned deep red. After I
hour at 60C a pale yellow precipitate formed which was then reflu2~ed for a further hour.

~PZ.3V5~

The suspensicn so formed was then cooled to 0C and acidified with hydrochloric acid ~5n~. The result~nt psle ye11Ow solicl was filtered o~, wasllecl with water, ~ie~' unde~ reduced pressure ~nd recrystallised from dioxan to yield the title compound ~s pale yellow nee;lle~, m.p. 288-290C(decomp.

The following eompo~d3 were similarly prep~red u~ing the appropriate benz~ldehyde ~nd chloroacetophenone.
(Z)-2'~arboxyl-a~enzyliden~S-methylbenzofur~n-3(2H)~ne m.p. 187~C.
(Z)-2'~C~rboxyl-2-benzylidene-6-methylbenzofuran-3(2H)-one, m~p. lg6-198C. (de~omp.) (Z)-2'{~rbo~ a- benzylidenenaphtho (2, l-b) ~uran-3 (2H) ~ne, m.p. 207-208C.
(Z)~'-<;'flrboxyl-2-be~zylidene-5-isopropylb~nzo~ 3~2}~)-one, m.p. 262-ZB3C.

(Z)-3-C~1-2~enzylidene-5-metho~ybenzofuran-~(2H)-one 5-Metho2cybenzofuran-3(2~)-one (6.0g, 0.036 mole) ~Ann en ~ 281, n914)] ~nd 3~carboxyb~zQldehydQ (5.4g, 0.036 mole) ~J.Chem 8OC. 4778 (1952)1 were dissolvedin dio~an (50 ml) ~nd concentrated hydrochloric acid (10 ml) added. The resultant yellow solutian was then heated under re~ fcr 2 hours. On cooling Md addition ofwater (20 ml) a yellow precipitate formed. Thi9 materiRl on recrystallization from acetic acid ylelded the title compound as yellow needles, m.p. 252-254C.

.~
s }-_LEB 7 O 3 6 The followin~ cs>rnpo~ds were prepare~ u~;r~ a Dl~ocess simil~r to that o~ m~e vYith appropriate v~riation QI the berlzofuranDne and benz~ldehyde.
(Z)-2'-~arboxyl-2~e~lzylidene 6-methoxyb~zofur~n-3(2EI) one, m.p. 217-220C (decomp.) (Z~-3'~bo~ 2-benzylidene~6-metho~be~azofilr~n 3(2El)-one, m.p. 258~60C [de~or~lp~) C~rbo~1-2~enzyliderl~6~ etho~ybenzofuran-3(2H)~rle~
m~p. 273-275C (decomp.3 (Z)-3~-Carbo~yl-2-benzylidene-5~methylbe~lzofuPan-3(2~)-one~
m.p. 264-265C.
(Z)-3'-C~rboxy1-2 benxylidene 6-m~thylbenzofur~n-312H)-o~e~
m~p~ 283 2~i4Co (Z)~/-Carbos~rl-2-b enzylidene-6-methylbenzo~uran-3(2~ one9 m.p. 288-~8gC.
(Z)-3'-C~bo~l~'~ydroxy-~-ben~:lidene-6-methylbenzoIuran~3(2H)~one m.pD 290~291C.
~Z)-3'-Carbo~yl~'-hydro~:y-2-benz5tlidenebel1zofuran-3(21I)-one, m.p. 268-270C.
(2;)~'~C~rbo~yl-2~en~ylidenebenzofuran-3(2H)-one, m.p. 274-275C
(Z)-3'-CQrbog~ be;lzylidene-6~~ oben~ofllran-3(2~ one, m.p. 278-280C.
(Z)-2'~arb~ 2-benzylidene-~hlorobenzofuran-3t2~I)~e, m~p. 20S-206C.
(Z)-3'-C~rbo~rl-2~zyl1dene-6 chlo~obel~ofuran-3~2H)~ne, m~p. 286-288C~ ~
(Z)-4'-Car~xyl-2~nzylidene~5~hloroben~o~ 3(2~ one, m.pO.~ 300C.

~.~9~?;~
~13-tZ)-3'~rbo~ 2~nzyliden~-5~ethylb~zofuran--3(2H)~ne9 rn.~. ~5?C.
(Z~-3'~arboxyl-2 benzy:lideneben~of~n~3(2F~)~ne9 m.p. 259-26DC.
(Z)-4'~[(E)-C~rbo~yvinyl]~ nzylidene-5-methylb~z~ 3(20 one, m.p~, 2~5~276C.
(~;)-3'~arbo~ 2 b~zylidene-5~y~1~he2~ylbenzo:furan-3(2EI)~ne7 rn~pO 252-253C~
~Z)~ Carboxyl-2-benzylidene-& chlorobeDzoîuFan-3~2H)-one, m.p.~ 300C.
(Z) 2'-C~rboxyl-2~en~1idene-6-~hlorobenzoIuran-3(2~I)~ne7 m.p. 1~4C.
(Z)-4'{(E3-2-C~boxyvinyl]-2-ben~yliderl~-6-hyclroxyb~llzoPuran 3(2H~-on~, m.p.~300C (de~omp.) ) 3'~nrbo~1-~-ben~ 3en~6 hydroxybenzDfurun-3~2~ ne~
m.p. 323C (decomp.) (Z)-2'~rboxyl 2-be~ ides~ hyd~xsrbenzofur~n-3(2H~ne, m.p. 282-283C.
(Z)~-[(E)-2~arbo:~vinyl~-2~enzyli~ene-5,7~iehlorobenzofuPan 3(2~ on~, m.pO~ 300C.
t~)-3'~(E)-2~ rbo~;yvinyl]-2~erl~ylidene 5,7~i~hlorobenzo:~ur~ 2~)ffne m.p. 300C
t~ 3'~(E~2 C:~Lrboxyvlnyll-2 benzylldene~-hydwxyben~o~urQn-3~2H)~ne, m.p.~30ûC
(Z)-3'~(ie)-2~arboxyvinyl~ -2~enzylidene~5-metho:~b~zo~urall-3-(2H~ne~
m.p~ 242co (Z)-3'~Qrboxyl-2~en~ylldenenaptho(1,2~)furan-3(21~)~ne9 n~.p. 276-278C.

14~

(Z3-3'-r~E~-2~arboxyvinyl)] -2-benzylidenenaphtho~1,2-b)furan-3(2H)~ne7 m.p. ~n~.
~Z)-3'~arbo~yl-2-benzylidene-4~ydroxybenzofur~)-3(2H3~ne7 m.p~285-287C.
(Z)-2'-Carboxyl-2-berizylidene-5,7~ibrom~4-hydroxybenzofuran-3(2H)~ne, m.p~258-260~

E2~A~aPLE 37 _____ 4{~y~nobenzaldehyde (13.1g, 01 mole), ethylesle glycol (6.2g 0.1 mole) and toluene -4~ulphonic acid (19.0 mg, 0.1 m. mole) were refluxed in benzene ~la0 ml~ for 8 hours using ~ Dean and Stsrk apparatus. I'he b~nzene was then evaporated to dryness to give 4 cyano-(2-1,3 dioxaldne) benz~ne ~Q9 a W~l~y colourless solid (m.p. 44~5C~
which wa~ u9etl without ~rther puri:~ication4 The above dioxalane (lY.l~, 0.1 mole), sodlum azide (fi.5g, 0.1 mole) and lithium chloride (~.5g, 0.15 mole) were refluxed in 2-met~oxyeth~nol (100 ml) for 8 hours. The suspensiall was then poured into ice and hydrochlori~ a~id (5M). On standing, this solution deposited white crystals of 4~5-tetrazolyl)-benzaldhyde, mOp.
~OOC.
Ihi~ benzaldhyde and 5~hlorobenzofuran -3(2E:I)-one[AIulalen 2924 405 34~] were reacted togethel~ using ~he procedure o~ Example 6 to yield the title compound which was recrystallised from dlmethylformamide, m.p. 260C (decomp!.

!

~AMPLE~_38 T0 4~
~e ~ol7owing comp~7f's ~el e sim~ y prepared using the a~ropr ~te cyanob~nzaldehyde a~d benzofuranone.
(Z)-3'~5 Tetr~zolyl)~2~benzylidene-5-methoxyben~ofur~n-3(2}I~ e, m.p. 278-280C (decomp.) ~Z)-4t-(5-Te~azolyl)-2-benzylidene-6 hy~oxybenzl3~uran-3(2H)~ne, m.p. 300~ (decomp~) (Z)-4'~5-Tetrazolyl)-2~enzylidene-5-methoxyb~a:o~uran-3~H)~ e, m.p. 268-270C (de~mp.) (Z)-3r~5-Tetraz~lyl)-2~e~zylidene-5,7 dichlorobenzoiuran-3(2~)-one, m.p~ 283-285C ~decomp) E~AMPLE 42 . . _ ~Tetr~z~.v~ne-5-eth~rl:~n 3(2H)-one 5-Ethylbenzo~ur~n-3(2H)~ne (3.4g, 0~02 mole) rJ. Indinn Chem.So~ 20 (19B5)1 ~nd 3-cyanoberlzaldehyde (2.~2g, 0.02 mole) were dissolved in dioxan (lO0 ml) and concentrated hydPo~ ric acid (5 ml) added. The result~nt yellow solution w~s heQted un~er refl~ i~or 2 hours. t)n cooling, yellow needles oP
cy~o-2-b~n~ylidenebenzo:t`ur1n-3(2EI)~ne mOp. 162C ~rmed ~nd were r~moved by ~iltration. The aurone (0.5g, 0.0018 mole) ~nd trim~thyl silyl azide (l~, 0.086 mole) were rePluxed together in dimethyl~ormamid~ for B hvurs. The cooled qolution w~s poured into lce ond hydrochloric a~id. The suspension WR~ then heated to 70C ~or 30 minutes ~d after coolin~ the precipitate Wa9 ~iltered o~. ~his ye11Ow oily solid, rl~ter chromatogr~phy, yielded the title compound, m.p. 242-243C.

~ 160 E:gAMPLE 43 ____ ~Z~-2'-~arbo~n~2-~enzv7iden~5~arbomethogv~-aminobenzofuran-3~?F!`~ne The methyl 3 acetyl~-hydro~y-6~minobenzo~Lte ~8.0g, 0.038 mole~ in diehlo~ometh~e (250 mlj was added to trifluoroaeeti~ anhydride (16g, U.076 mole?and the solution stirred at room temperature of 15 minutes. On evElporation, thepale yellow solutian y~elded methyl 3-acetyl-4-aceto~y 6-~iflu~roa~etamidobenzoate, m.p. 130-131Co CoppeP (Il)bromide (17~0gg DoO76 mole) was suspended in ethyl acetate (300 ml) by rapid stir~ing. To this suspension wss added the benzoate produ~ed above (11.5 g, 0.038 mole) as a solution in ethyl acetate (200 ml) and the result~nt mi~ture was stirred and heated under relux ~or 3 hours. The pale gre~n ~uprous bromi~ so formed was removed, after coolLng, by filtration and the ~;olution evAporated to eiv~ a pale yellow sol~d whi~h wa~ re~ryst~.llised from ether/petroleurn ett~r (4ll-60C) yielding methyl 3-bromoac~etyl-4-acetoxy-6~tri~1uoro~cetamiàobenzoate as white c~ystals, m .p260-:161C3 This compolmd (1.9g,0 0û5 mole) and 2~carboxybenzaldehyde (0.75g, .005 mole) in metltanol ~100 ml) were then heated to 60C. Sodium hydroxide (0.6~, 00015 m ole) un water (20 ml) was slowly added to the stirred solution. The resllltant red solution w~s he~ted u~der re~uLY for 3 hour3 nnd then poured on to ice ancl hyclro~hlnric acid (5~j. The ye~ow solid 90 form ed wns ~iltered o~ and dissolved in aqueous sodium bi~rbone~te soluti~n (10%) at 50C. The pll OI this solution was adjusted to 7 ~n~ ~mberlite Res~n DRA-401111 the hydro~yl fOrM added. The res~n w~s then ~lltered o~f and washed, ;~ilstly with wate~ and then with glacial acetic ~cid. On ~oncentraffon the aceti~ a~id washings yieIded the title compound &s bright yellow prisms, m.p. 280C (de~omp.) * Trademark ~17 EgA~PLE 44 ~Z~-3'~arbox~1-2~enzvlidene-5 7~ihromo~lvc~o~rbenæofur~-~?~'-one Finely ground ~opper ~ bPomisle (88g9 0.4: mole3 w~s suspeslded in a 50 sa mixture of ethyl ace~ate and ~hloroform (200 ml~. 296-Dihydro~y~cetophellone (lOg, 0.0657 mole~ in chloroform (20 ml) was add~ to the abovle suspeDsi~n whi~h w~s stirred mlder re~l~g fcP 8 hou~, hyd~g~ bromide being e~olv~d~ Afte~ cool~ng the ~opp~
(I~ bromide formled in the above rea~ff~n w~s ~iltered of~ and the so1ution evaporated to dryn~ss to give 3,5-dibroms~2,6-dihydro~_~brs)moa~etophenone, m p. 150C.
The6~romoacetophenone ~3.2g, U.21 mole) and s~ium Qcetate (20 g~ were re~luxed in 90% eth~nol (100 ml) f~ 15 minutes~ On cooling and following the additi~ o w~ter (100 ml), the yellow solution deposited a greenisl1 solid which ~ras recrystallised irom ethQnol/water to glYe 5,7~ibrom~4 hydroxyb~zo~urQn-3~2H)-one? m.p~ 185~C (decomp.~
The benzo~uran-3(2H)-one wa~ then reac~ed with 3-~arboxylbenzaldehyde using ~he procedur~ des~rlbed in :Elc~mpl~ ~ to ylel~ the title compound, m.p.~300C

(decompO) EgAMPLES 45 AND 46 The ~ollowing aompo~ds were prepared by fl m~hod simil~r ~o E2~ample 44 using the appropriate benzaldehyde.
~Z) 4'-C~rbos:yl-2-benzyli~ene-5,7-~3ibrom~4~hydro~benzo~uran--3(2:~ne, m~p.
300~C.(de~omp) (~)-2'CRrboxyl~2-benzylidene-5,7~1ibromo 4~ydroxybellzofutan-3~2~ne, m.p. 258-26~C
E:~AMPLE 47 (Z)~ (E)-2~arbox~rinyl1-2~enzyliderle-6-amino-5~yanob~zofuran-3(2 one .`3~)~

~18-4~ 5~yQno-2~droxyacetophenone (3.C.S.P~k~ I 1979 3 677~ ~s cor~v~Pted i~to .~t~luo~o~eetami~5~r~v-2~yd~1~ tophenone~m~p- ~14~C) IlSing the pro~edure de~cribed ila ~ample 43.
This ace~oph~orle was then brominat~d lE;ing ~p~er ~3I) bromid~ b~ the method desc~ibed in E~ample 44 to yield 4~ 1uol~cetamido~yano-2~ydro~y-~romo~cetophenone m.p. 202~C, The~romoacetophenone (3.8g 0.011 mole~ w~s dissolved in eth~nol 50 ml ~nd e:~cess sodium acet~te (lOg) added ~g with w~ter (10 mI). The m~ture was ~en re1u~ed fcr 23 minutes md Q~2 cooling depo~ited ~n ~rRnge solid whidl was recrysWli~ed from e~han~ water to yield orange p~tes o~
6~mi~5 cganobenzofuran-3(2~one, m.p. ~70C ~decomp) This ben20:1uranon~ w~s ~en re~cte~ with (E) 4-~rmylcintlarllic a~id u~ing the proce~ur~ cribed in P~EImple 6~ the title compolmd being obtAined Q8 oranKe cry3t~s, m.p.9 3000C.
MPLE: 48 ycl~ ~
4-Cyclohe~ulphenol ~8~g, ~,5 md~ d a~ l chloride (39g, O.S mol~) were heated togeth~r at 170C for 3 hou~s. The cle~r liq~d ~o ~ormed WQ~ then ~oled to 100C. and ~luminium c~l~rlde (133g, l.Omole) 1dded ~lowly, '~e brown st~cky o;l wn~ then he~ted to 130~C f~ 5 ho~ . A~ter cooling, ice and hydrochloric acid ~re added and the phenol e~tracted w~th chloroitorDI. llus e:~ract w~s thRnetr~porlted to dryness snd tl~ residue ste~m dist~lled to give

2~cety1~ cydohe~lphenol as a cle~r oiL Th~s phenoI was then re!QCte~5 ~ith copper (II) bromid~ u~ng ~ p~cedw deseribed in E~ample 43. Thi$ reacffan ~ielding ~rorn~acet~ clohexylphenol ~s ~ ye~low o~ This On ~æ ~issolv~d Ln eth~nol noo ml~, snd sodium aceeate ~44g) nnd ~ter ~20 ml~ added.

3 ~3 ~
-19~

This solution was the~ reflu~ed for 10 milrlUlteS7 cooled ~nd wat~ adde~ to deposit a hroYIm oil ~hich waS e~trac~ed wit,'l chlo~oform. On evaporation to ~ryness the chloro~orm 2xtract yi~lded the S~yclohe~ylbenzof.urQn 3(2~ne ~hich was then re~et~d with 3-carboxybenzaldehyde using the procedure of EXample 6 to yield the title comE~ound as ye11Ow cryst~ls, rn.p. 252-253C~
E~EAMPLE 49 (a) Methyl~-Qceto~ybenæoate (126g, 0.65 rnole~ and alwninium chloride (220g, L63 mole) were intim~tely rnixed, stilred and reacted ~t 16ûC by the method o~ G. l:~ora et al., ~ur.J. Med.Chem 1978 ~ 33. The crude solid procluct obtained afte~ ~cid keQtment WQS stirred with saturated sodium bicnrbon~te soluticn an~ the mixture filtered. Tha :~iltrnte WR9 cnrei~lty acidi~ied to give 3-~cetyl~hydroxy~ oic ~id~ which wa~ ~ltered o~, water wa~hed ant1 dried, m.p. 232C.
The Insoluble solicl ~rom the above bicarbonRte e~traction was dissolved in dilute ~odium hydroxide (2N) solution an~ careiully acidi~ied with dilute hydrochl~ic ncid ~5M~ solution to give methyî 3^~cetyl~-hydroxyben~oate, which n~ter filtratiorll water washing and drying, had m.p. 90 92C.
(b) 3-Acetyl~ hydroxyben~oic acid (24.0g. 0.133 mole) wns di~solved in dioxane (400 ml) at ~0C ~d bromine (7.2 ml, 014 mole) aclded ~opwise with stirring. Tha colour soon ~ded and ~lter 45 minutes the cle~r supernatQnt was dec~nted ~rom some insoluble m~erinl and evnporQted to give Q llght straw coloured solid~ 3~romoQc2tyl 4-hyclroxyben2.oic ~cid, m~p. 226C7 ?~
`~..} ?

20~

(c) The product from (b) was dissolved in ethanol/water (35~/70 ml\, sodium acetate '30g' added and the solution stirred at 60t~ for '0 minutes. 'rhe deep orange red solution was cooled to 10C, stirred, and carefu31y acidified with 5N hydroehloric acid solution. The resultant bright yellow solution was diluted with an equal volume of w~ter ~nd storecl in a refrigerat~r overnight~ The yellow crystal~ine solid was filtered o~, washed with cold water and dried to give 5~arboxybenzofuran-3~2H)one, with m.p. 204C (decomp.) (d) 5-Carbo2~ybenzofuran-3~2H)one(3.56g., 0.02 mole) and 3,4,5-trimetho~
benzaldehyde (3.92g., 0.02 mole) were d:issolved in warm dio~Ane (50 ml.), concentrated hydrochloric acid (10 ml) added and the mixture stirred and gently heated in a steam bath for 15 minutes. After cooling and the additiMI of an equal volume OI water the yellow crystalline solid was filtered ofi, washed with water and driedJ Recryatal1isation from glacial acetic ~cid gQVe~ th2 t~tle compound, m.p.
290C.
qP:LES 50 TO 60 The following compounds were prepared by a method similar to that described in Example 49:
(Z)-2-Ben~ylidene 5~arbox:ybenzo:~uran-3~2H)one7 m.p. 280C.
(Z) 4' Chloro-2~enzylidine~5~arbo~{gbenzoIuran-3~2H)one, m .p.~ 300C.

(Z)-2' Chloro-4'~imethylamino-2-be~rlzylidine~5-carboxybenzo.~urall-3~2H)one.
m.p. 275C (decomp) (Z~-4'~13utyl-2-bellzylidene-5~arboacybenzo:Fursn-3~ 2H)one, m.p. 252C.
(Z)-~'-Dim ethylamino-2~enzylidene-S~arboxybenzofurall-3~2El~on~, m.pO 295C.

-21 ~

(Z~-4'-Methoxy-2-benzylldene~carboxybenzofuran-3~2H)one, m.p~300C.
(Z~-4'-[~E~2~arboxyvinyll-2-benzylidene~5 carbo.xybenzofulan3~2H~one, m~p.>300C~
(Z)-3'-C~rbo~yl~'-hydroxy-2~enzylidene-5~arboxybenzofuran-3~2H~one9 m.p.~ 300C.

(Z)-4'-Acet~mido-2-ben ~rlidene-5 ~ arbo2~ybenzoIuran-3~2~I)ones m.p.~ 300C
(Z)-3'-Trinuorom e~hyl-2-ben~ylidene-S~arbo~ybe~zofuran-3~2H)one, m.p. 264C.
(Z)-3'-(N-Isopropylcarboxamido)-2~enzylidene-5-cQrboxy benzofuran 3-(2H)one, m.p. 300C.

5-( ~!~Y~I~n -~(~ 5-Acetyl-2,4-dlmetho2~yben~oic acid (Ber. 41~ lffO7, 1908~ (21.1g, 0.094 mole) was stirPed in dioxane (200 ml.) at room temperature and brornine (5 ml., ca 0.1 mole) was added dropwise. The brornine colour gradu~ly disappeared o~er 30 minutes and tlle mixture WAS then gently w~rmed in a steambath for 30 minutes, cooled ~nd the dioxane removed in vacuo. The solid product was treated with boiling __ _ ethyl acetate, ~iltered hot and the ~gltr~te evaporate{l to gi~e 5-bromo~cetyl-2~-dimethoxyben:~oic acid, m.p. 236C.
(b) The product from (a) (21.6g., 0.0~1 mole) W19 stirred in dichloromethane (~50 ml), eooled In M~ ice ba~h and boron tribrornide (25 ml) added dropwise. The solution was the~ heated under reflux (water bath) for 4 hours. The mixture was cooled and poured onto ice tl kg.3. After removal OI dichlorometllane, the result~nt pinlc solid was filtered off, wRter washed, sucked dr~ ~nd dissolved in ethaT201/water no/~o 11~

31`3'~3 -2~-Sodium acetate t25g) was added and the solution warmed at 6~S~ for 30 minutes.
A~ter coolin~ and the removal of etb~nol in ~ ~urthf~ t~ 5 ~dded. The solution was cooled iJI an ice bath ~nd hydrochloric acid solution r5~) added dropwise with stirring to pH2. After overni~ht storage in a refrigeratur the pale yellow crystalline solid was filtered o~, vv~ter washed and dried to give the title benzofuranone9 m.pn 216C.

(Z)-3'~~b~8g~1-S~ydro~7b n2:ofuran-3~.H~one 5-carbo~-6-hydroxyben2oIuran-3-t2H)one (5.82g9 0.03 mole) wa~ dissolved in dio~ane (75 ml~, 3-carboxybenzaldehyde t4.50gO, 0.03 mole) added, followed by concentrated hydrochloric ~cid ~15 ml). The soluti~n was gently hented on a steam bath fo~ 30 minutes with occasion~l stirring. '~le solid mixture was cooled, diluted with ~n equal volume of water and stored in a refrigerator ~or 1 hour. The product was fllt~red of~ water wn~hed nnd dried~ ~lecl~tallisation ~rorn dimethylPormamide gave the de~ired compouncl with m.p. 335C (decomp).
EgAMPLE5 63 AND 64 The fo~lowing compounds were prep~red by a simil~r method to that describe~ in Example 62.
(Z~ 3'-Carbo~ hydroxy-2-benzylidene-5~Qrboxyl-6-hydrOxy ben~.ofuran-3~2H~one, m.p. 332C (decomp.~
(Z)-4'~Te~razol-5-yl)-~-benzylidene-S-cQrboxyl-6-hydro2~y benzo~uran-3-~2H)one.
m.p. 3~7-28C (decomp.~

E:~AMPLE 65 Methyl-3-acetyl-4-hydroxy benzoate (5.39g 0.028 mole~ was stirred in dioxan (200 ml~ at ~0C and bromine (1.5 ml~ adc3ed drops~liseO After 45 minute~ the colourless solution was evaporated to g~ve a straw coloured oil which was dissolved in ethanol/wateP (75/15 ml.). ~odium acetate (6.0g) was added and the solution stirred at room temperature for 5 rninutesO The red solul:ion was poured on to ice ~lOOg) and extracted via chloroform. Evaporation of the chloroform extract gave 5-methoxycarbonylbenzoîuran-3~2H) one as an orange red oil( 659~ pure by ~MR).
ThLs product was imrnediately dissolved in dioxane (50 ml.~, ~
3-carboxybenzaldehyde (4.5g., O.û3 mole) added, followed by concentrated hydro~hloric acid (10 ml) and the solution heated on a steam bath for 15 minutes.
Worlc up wa~ as Example 49 with recry~talllsRtion ~rom dimethyl~orrnnmide to give tha desired aur~ne~ m.p. 281)C.
E~AMPLE 61i (a) 3-Aminophenol (54.5g., O.S mole) and acetic anhydride (200 ml) were stirred and heated on a steam bath ~or 2 hoursO The straw coloured liquid was ev~pol~Qted in vacuo to give a vLscous oil which was heated to 110-120C aluminium chloride ~170g. 1~27 mole) being added gradually with stirring. A~ter 30 minutes the solid product was cooled somewhat and care~ully decomposecl with ice/water ~CR
SOOg.) ~ol1owed by concentr~Lted hydrochloric ncid (200 ml.), stirred well nnd wQrmed slightly on steam bath. On cooling, the crystalline solid was filtered off, water washed and dried to give the clesired compound 2-hyclroxy-4-acetamidoacetophenone, m.p. ] 40C.

2 ~

(b) The product :erom (a) (14.0g û.072 mole) was dissolvecl in ethyl acetate ~300 ml! and added to a stirred suspension of eo~per~` bromide/32g. 0.1~ m ole`;n ethyl acetate (lOO m ole). The mixture was heated under re~ux for 4 hours,then Pilterecl hot ~nd the ~trate evaporated in vacuo to give an oil which crysta~ised.
This solid was converted to the ben~ofuranone ~d reacted with 3-cQrboxybenzaldehyde (as ~cample ~5~. :EIowever, during this reaction the product was partia~y d~acylated and it was urther reQcted with acetic ~nhydride (20 ml) under re~ux to c~nvert to the f ~ y acehy1ated compoundO This reaction mixtura was poured onto i~e (10~ g~ and the e~cess acetic anhydride hydrolysed. The resultant solid was filtered off and recrystallised from glacial acetic acid/water (50% v/v) to give (Z3 3'~arboxyl-~enzylidene-6-acetalllidobenzofuran-3~2H~one, m.p. 31D5C (decomp.!
EX~MPLE 67 . .
( Z;)~'-Chloro-2-benz~dene-5-n bu ox~arbon~l bel~ofuran-3-(2~I)one Z~'~hloro-2~enzyliden~5~arboxybenzo~uran-3-(2:EI)olle (3.0g. 0.01 mole) wa~
suspended in n-butanol (5a ml), concentrated sulphuric acid (1.5 rnl) added dropwise with sffrring and the mixture heated ImdeP re:flux for 5 hours. The resultant ye110w soluffon on c~ling deposited yellolN ~lu:i~y needle crystals OI the desired n~utyl este~. The cryst~ls were f~tered of~, washed with cold n-butanol, then diethylether ~d dried, m.p. l54C.

(E)~'-Chlo~ benzo;Furan 3~2~I)one (Z)-4~ hlor~2~enzylidene-5-n-butoxycarbonyll:~enzofuran 3~2H)one ~l.Og~ ~was dissolved in b~zene (800 ml) and irradi~ted in a 1 litre Hanovia photo~hemi~al reactor for 15 hours. The solution was e~aporated in vaeuo to give l.~g of solid with m.p. ca 13D and having an E/Z isomer ratio of r5/25 (based on NMR and H.PLC3.

~ ~5--" ,. *
500 mg o:~ this solid wa~ chroma~graphed on a Sor~sil silicQ gel colwnn !?OOg.~ using be~zene ~s the developing svlvent and the fractions containing the faster moving (E)-isorner collected. These fractions were buLked and evaporated to give a yellow cry~ta~ine solid; yield 35~ mg. o~ mp 142C and having an E/Z isomer raltio of 88tl2~
200 mg. this solid w~ recrystallised from dichloromethanet40~0C
petroleum ether (lt3 ~/v) to give 130 mg. of ~rystalline solid o~ m.p. 142C and l~virlg an ~/2; isorlle~ raffo oP ga.~/7.5.
The ~ollowing foE mulati~s were prepared using as A~tiVe ingredient the compound (Z)-3'-~arboxyl-2~enzyliden~5-~hla~obenzofur~n-3-(2~ e, and simil~r formul~tions c~n be prepared with other solid compounds of the invention.
E~AMPLE ~9 ,__ ~3:nrd gelntin capsules were prepared l~ing the Iollowing in~redients:

Aetive ~ompound ~SO
~ dried 200 Magnesium s~enrate 10 The above indredients we~e mi~ nd fiUed into hard gelatin cap~sule~s A tablet fo~mula w~s prepared using the ingredients below:

Active compound 250 Ce~ulo6e miero~rystalline 400 Silicon clioxide ~umed 10 Stearic acid 5 , ~ ~
* Trademark P~3~
.~ .

The components were blended and compre~ed to form tablets.
A~flPLE 71 An &erosol solutir~ wns prepOEed containing the following components:

W~%
Active ingredient0.25 ~th~Dol 29.75 " Propellant 22 " *70 ( Chlorodi~luorom ethQzle) ll~e active compo~d was mixed with ethanol and the mixture added to thç
propell~nt 22, cooled to -30C and ~an~ferred to a filling deYiceO The required amount was then ~ed to a stainles~ steel containe~ and diluted further with a metered amount of propellant. The valve uni~ were then fitted to the container.
EXAMPL~. 72 A suppository formula wa~ prepared containing 200 mg OI t~ compound usinK the ~ollowing ingredients:
Acti-.re eompound 200 mg Polyethylene glycol 1000 750 mg Polyethylene gly~ol 4000 250 mg The activ~ compound was mi~:ed in ~he molten glycol base~ and then the mixt~re was poured intn apl?ropriate suppository moulds~ to give the active f~l weight.
E~A~qPL13 73 An ointm~t w~s made to the i~ollowing fo~mula:
Active compound 1% by wei~ht White soft p~rafin up to 1û0%
The activ~ compound wa~ added to tlle mol~en paraffin Qnd th~n the mixtur~ was a310~ed to co~l.

* Trademark

Claims (12)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the formula (I) in which R1, R2 and R3 are the same or different and can each represent hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, phenyl optionally substituted with from 1 to 3 substituents selected from methyl, methoxy, halogen and nitro, C1-6 haloalkyl, amido, amino, cyano, hydroxy, nitro, C2-4 alkenyl, carboxyl, tetrazol-5-yl or CH=CHCOOH; or in which R1 and R2 taken together represent a group of formula -CH=CH-CH=CH-; and wherein R4, R5 and R6 are the same or different and can each represent hydrogen, halogen, C3-8 cycloalkyl, phenyl optionally substituted with from one to three substituents selected from methyl, methoxy, halogen and nitro, C1-6 haloalkyl, amido, cyano, nitro, carboxyl, tetrazol-5-yl, or -CH=CHCOOH; or a pharmaceutically acceptable salt or ester thereof; provided that at least one of R1, R2, R3, R4, R5 and R6 is carboxyl, tetrazol-5-yl or -CH=CHCOOH;

and with the proviso that compounds of the formula wherein R1 is hydrogen, C1-6 alkyl or C2-C4 alkenyl and each of R4, R5 and R6 is independently selected from hydrogen, C1-C6 alkoxy or C1-C6 alkyl, as well as pharmaceutically acceptable salts thereof, are excluded;
which comprises reacting a benzaldehyde of formula with a reactant selected from (a) a benzofuranone of formula or (b) an .omega.-substituted acetophenone of formula wherein R1, R2, R3, R4, R5 and R6 are as previously defined herein and in which X is a leaving group, optionally followed, when one or more of R4, R5 and R6 is cyano, by reaction with an azide to give the corresponding tetrazol-5-yl compound; and where desired, forming a pharmaceutically acceptable salt or ester of said compound of formula (I) so prepared.

2. A process according to claim 1, wherein at least one of R1, R2 and R3 is other than hydrogen.

3. A process according to claim 2 in which R1 is C1-4 alkyl, carboxyl or halogen, R2 and R3 are hydrogen, R4 is carboxyl or -CH=CHCOOH, and R5 and R6 are hydrogen.

4. A process according to claim 2 in which R1 is C1-4 alkyl or carboxyl, R2 and R3 are hydrogen, R4 is carboxyl or -CH=CHCOOH, and R5 and R6 are hydrogen.

5. A process according to claim 1 wherein at least one of R4, R5 and R6 is halogen, C3-8 cycloalkyl, phenyl optionally substituted with from 1 to 3 substituents selected from methyl, methoxy, halogen and nitro, C1-6 haloalkyl, amido, cyano, nitro, carboxyl, tetrazol-5-yl or -CH=CHCOOH.

6. A process according to claim 5 in which at least one of R1, R2 and R3 is other than hydrogen.

7. A compound of formula (I) <IMAGE<

in which R1, R2 and R3 are the same or different and can each represent hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, phenyl optionally substituted with from 1 to 3 substituents selected from methyl, methoxy, halogen and nitro, C1-6 haloalkyl, amido, amino, cyano, hydroxy, nitro, C2-4 alkenyl, carboxyl, tetrazol-5-yl or CH=CHCOOH, or in which R1 and R2 taken together represent a group o formula -CH=CH-CH=CH-; and wherein R4, R5 and R6 are the same or different and can each represent hydrogen, halogen, C3-8 cycloalkyl, phenyl optionally substituted with from one to three substituents selected from methyl, methoxy, halogen and nitro, C1-6 haloalkyl, amido, cyano, nitro, carboxyl, tetrazol-5-yl, or -CH=CHCOOH; or a pharmaceutically acceptable salt or ester thereof; provided that at least one of R1, R2, R3, R4, R5 and R6 is carboxyl, tetrazol-5-yl or -CH=CHCOOH;
and with the proviso that compounds of the formula wherein R1 is hydrogen, C1-6 alkyl or C2-C4 alkenyl and each of R4, R5 and R6 is independently selected from hydrogen, C1-C6 alkoxy or C1-C6 alkyl, as well as pharmaceutically acceptable salts thereof, are excluded;
whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

8. A compound according to claim 7 wherein at least one of R1, R2 and R3 is other than hydrogen, whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.

9. A compound according to claim 7 in which R1 is C1-4 alkyl, carboxyl or halogen, R2 and R3 are hydrogen, R4 is carboxyl or -CH=CHCOOH, and R5 and R6 are hydrogen, when prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

10. A compound according to claim 7 in which R1 is C1-4 alkyl or carboxyl, R2 and R3 are hydrogen, R4 is carboxyl or -CH=CHCOOH, and R5 and R6 are hydrogen, when prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

11. A compound according to claim 7 wherein at least one of R4, R5 and R6 is halogen, C3-8 cycloalkyl, phenyl optionally substituted with from 1 to 3 substituents selected from methyl, methoxy, halogen and nitro , C1-6 haloalkyl, amido, cyano, nitro, carboxyl, tetrazol-5-yl or -CH=CHCOOH, when prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

12. A compound according to claim 7 wherein at least one of R1, R2 and R3 is other than hydrogen and wherein at least one of R4, R5 and R6 is halogen, C3-8 cycloalkyl, phenyl optionally substituted with from 1 to 3 substituents selected from methyl, methoxy, halogen and nitro, C1-6 haloalkyl, amido, cyano, nitro, carboxyl, tetrazol-5-yl or -CH=CHCOOH, when prepared by the process of claim 6 or by an obvious chemical equivalent thereof.