THERAPEUTIC AGENTS

Abstract: Compounds of formula (I) in which X represents oxygen or sulphur; Z represents -CH= or -N= when X represents oxygen; Z represents -CH= when X represents sulphur; R5 represents hydrogen when R3 represents methyl, or R5 represents (a), when R3 represents a bond together with either one of R2 and R4; R6 represents hydrogen, halo, S(O)nY1, carboxy, carbamoyl, a carboxylic acyl group, an esterified carboxyl group or CONR12R13; R6' represents hydrogen or methyl; or R6 and R6' together with the carbon atom to which they are attached represent cyclopropyl; R9 and R<10>, which may be the same or different, represent halo; or R9 represents hydrogen and R10 represents hydrogen, halo, trifluoromethyl, nitro, C1-6 alkyl, C1-6 alkoxy, hydroxy or a carboxylic acyloxy group; R12 represents methyl, ethyl or C3-8 cycloalkyl and R13 represents C1-6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocyclic group, a 5 or 6 membered heterocyclic aryl group or C3-8 cycloalkyl; or R13 represents phenyl optionally substituted by C2-6 alkoxycarbonyl or halo; or R12 and R13 together with the nitrogen to which they are attached represent a 3-8 membered non-aromatic heterocyclic group which may be substituted by a C2-6 acyloxy(C1-6)alkyl group; Y1 represents C1-6 alkyl; n is 0, 1 or 2, and R1, R2, R4, R7, R8 and R8' are as defined, for use as immunomodulatory agents.

Description: Therapeutic Agents The present invention relates to novel therapeutic agents, and in particular to [1]benzopyrano[4,3-c]- pyrazoles or [1]benzothiopyrano[4,3-c pyrazoles, to processes for their preparation, to pharmaceutical compositions containing them and to their therapeutic activity as immunomodulatory agents. The present invention relates to compounds of formula I in which X represents oxygen or sulphur; when X represents oxygen or sulphur R. represents hydrogen or together with R_ represents a bond; R together with either one of R 1 and R 3 represents . bond; R_ together with either one of R„ and R, represents a bond; R. represents hydrogen or together with R^ represents a bond; or when X represents sulphur, R. and R ? represent a bond, R_ represents methyl and R^ and R represent hydrogen; Z represents -CH= or -N= when X represents oxygen; Z represents -CH= when X represents sulphur; R ς represents hydrogen when R. represents methyl, or R_ represents CH - R g , R 6 when R- represents a bond together with either one of R 2 and R 4 ; R,. represents hydrogen, halo, S(0) Y- , carboxy, carbamoyl, a carboxylic acyl group, an esterified carboxyl group or CONR. - - j 3; R fi , represents hydrogen or methyl; or R fi and R g , together with the carbon atom to which they are attached represent cyclopropyl; R_ represents hydrogen, halo, trifluoromethyl, C- g alkyl, methoxy or S (0) Y. ; R represents hydrogen, halo or trifluoromethyl; o R 0 , represents hydrogen, halo or trifluoromethyl; o R and R, n , which may be the same or different, represent halo; or R q represents hydrogen and R 0 represents hydrogen, halo, trifluoromethyl, nitro, C _ alkyl, C. ,. alkoxy, hydroxy or a carboxylic acyloxy I —D group; R, 2 represents methyl, ethyl or C., _ cycloalkyl and R 13 represents C, g alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group or c - a _ o cycloalkyl; or R. , represents phenyl optionally substituted by C £». —D_ alkoxycarbonyl or halo; or R. and R- 3 together with the nitrogen to which they are attached represent .a 3-8 membered non-aromatic heterocylic group w 'h 'ich may be substituted by C2_— c 0 acyloxy(C._ 6 )alkyl; ' Y represents C, g alkyl; n is 0, 1 or 2 and. m is 0 or 1 which have immunmodulatory activity. In our copendimg patent applications (PCT patent application nos., PCT/GB 89/00859 and PCT/GB 89/00860) there are described certain compounds of formula A and formula B The first PCT patent application described above also discloses 4-methoxybenzyl 2-(4-chlorophenyl)-3- oxo-2,3-dihydro[1]benzopyrano[4,3-c_]pyrazole-4-acetate as an intermediate compound without any therapeutic activity. These compounds are excluded from the scope of the present invention. Accordingly, the present invention provides novel compounds of formula I in which X represents oxygen or sulphur; when X represents oxygen or sulphur represents hydrogen or together with R- represents a bond; R_ together with either one of R. and R_ represents a bond; R together with either one of R and R. represents a bond; R represents hydrogen or together with R_ represents a bond; or when X represents sulphur, R. and R 2 represent a bond, R, represents methyl and R. and R represent hydrogen; Z represents -CH= or -N= when X represents oxygen; Z represents -CH= when X represents sulphur; R_ represents hydrogen when R_ represents methyl. - 5 - or R j . represents CH - R g R 6 when R 3 represents a bond together with either one R g represents hydrogen, halo, S (0) Y. , carboxy, carbamoyl, a carboxylic acyl group, an esterified carboxyl group or CONR. 2 R.,; R,, represents hydrogen or methyl; or R- and R., together with the carbon atom to b b which they are attached represent cyclopropyl; R_ represents hydrogen,_ halo, trifluoromethyl, C, g alkyl, methoxy or S (0) Y., ; R„ represents hydrogen, halo or trifluoromethyl; R R , represents hydrogen, halo or trifluoromethyl; R„ and R._, which may be the same or different, represent halo; or R_ represents hydrogen and R.. _ represents hydrogen, halo, trifluoromethyl, nitro, C, g alkyl, C._ g alkoxy, hydroxy or a carboxylic acyloxy group; R._ represents methyl, ethyl or C - cycloalkyl and R- _ represents C, . alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heteroσyclic aryl group or C, _ cycloalkyl? or R. 3 represents phenyl optionally substituted by C._ g alkoxycarbonyl or halo; or R- 2 and R-_ together with the nitrogen to which they are attached represent a 3-8 membered non-aromatic heterocylic group which may be substituted by C 2 _ g acyloxy(C j^ g)alkyl? Y.. represents C, g alkyl? n is 0, 1 or 2 and is 0 or 1 provided that: I) when X is oxygen; Z = -CH= and: a) R6- represents C,I —,. dialkylcarbamoyl , then R,I 0„ represents a carboxylic acyloxy group other than acetoxy? or b) when R g represents hydrogen, halo, S(0) Y, , carbamoyl, carboxy, C 2 _ g alkoxycarbonyl, C 2 _ g alkanoyl or when R g and R g , together with the carbon atom to which they are attached form cylopropyl then R 1 n represents a carboxylic acyloxy group other than C -_d—6 , alkanoyloxy; or c) when R. and R 2 form a bond, R- and R. form a bond, R gI , R_, Rg,, R g and R 1 Q each represent hydrogen, R ? represents chloro, then R g does not represent 4-methoxybenzyloxycarbonyl? II) When X is sulphur and a) R represents methyl ? or b) R c D represents hydrogen, carboxy, S(0)nY.1 , C2_—6 , alkoxycarbonyl, carbamoyl or C._ g dialkylcarbamoyl, then R. - represents a carboxylic acyloxy group other than acetoxy. It will be understood that a group containing a chain of 3 or more carbon atoms may be straight or branched, for example propyl includes ri-propyl and isopropyl, and butyl includes ri-butyl, sec-butyl, - 7 - isobutyl and tert-butyl. The term "halo" includes fluoro, chloro or bromo. In one class of compounds of formula 1 , R.. and R_ form a bond and R, and R. form a bond, as represented by formula II and R g , R fi , , R_, R g , R_' , R_ and R are as herein- above defined. In another class of compounds of formula I, R. represents hydrogen, R and R form a bond and R. represents hydrogen, as represented by formula III and R g , R g . , R 7 , R g , R g , , Rg and R^ Q are as hereinabove defined. In another class of compounds of formula I, R and R form a bond, and R. and " R represent hydrogen, as represented by formula IV and R.7' "8,' R,8 " R9„ and R.10 are as herein defined. Preferred substituents are as given hereinafter. More preferably R 7 represents halo or trifluoromethyl, R„ represents hydrogen or halo, R g ' represents hydrogen or halo and R q represents hydrogen. In compounds of formula I, preferably R, represents hydrogen. In certain compounds of formula I, the group Ro- may be an esterified carboxyl group, a carboxylic acyl group or certain tertiary carboxamide groups. These- groups may be represented by the formula in which R-. represents an alkoxy group (for example C. ,) ; an alkenyloxy group (for example C_ c ) ; a cycloalkoxy group (for example C, .-); an oxygen atom attached to a non-aromatic heterocyclic group; a carbocyclic aryloxy group; a heterocyclic aryloxy group? an alkyl group (for example C. g ) ; an alkenyl group (for example C 2_6^ ' a cycloalkyl group (for C g _- 0 ); a non-aromatic heterocyclic group; a carbocylic aryl group; or a heterocyclic aryl group each of the groups being optionally substituted. Readily hydrolysable esters and amides as defined herein are included within the scope of the present invention as well as those which are less readily hydrolysable. Also included are certain tertiary carboxa ido groups. Some compounds of formula I may contain a substituted acetyl group in the 4-position of the ring system. In certain preferred compounds of formula I the group R g may have the formula a) " -CO.OR 15 b) - C0 - R 16 c) -CO.NR- 2 - 3 in which R- 2 represents methyl, ethyl or C, g cyclo¬ alkyl and R, 3 > jgjepresents c - j _g alkyl optionally substituted by cyano, phenyl, a 3-8 membered non- aromatic heter cyclic group,- a . . .5 or 6 membered heterocyclic aryl : -group •> ■ :;or R..., represents phenyl optionally substituted by C__ g alkoxycarbonyl or halo; or R, _ and R, , together with the- nitrogen to which they 12 13 are attached represent a 3-8 membered non-aromatic heterocyclic group,.which may be substituted by C 7 _ fi acyloxy(C-,:_g)alkyl|| ' - 5 : and R.. g : , represent ι_g alkyl; C_ - alkejiyife; C_ ,_ cycloalkyl? a 3-8 membered 2—0 J— I U non-aromatic heteroαyclic group, a phenyl group or a 5 or 6 membered heterocyclic aryl group? each of the groups R- tc , £,g " ; being optionally substituted by Z. Z represents Z, , 2 , phenyl, a 3-8 membered non- aromatic heterocyclic groiap (preferably containing one or two heteroatoms selected from oxygen, sulphur or nitrogen), a 5-6 ^membered heterocyclic aryl group (preferably containing one to three heteroatoms selected from oxygen, sulphur or nitrogen) , each group being optionally substituuted by Z. or Z 2 ; Z. represents halo,, -trifluoromethyl, hydroxy, carboxy or cyano;. Z 2 represents c - | _ 6 alkyl, c 3 _ 10 cycloalkyl, SfC mY.,, C0NR ιg R 19 , C^g alkoxy, C 2 _ g alkoxycarbonyl, C 2 _g alkanoyl, C 2-6 & ^ ' i3Ln0 Y 1 - 0x' -Y > phenoxy, NY 2 Y 2 ,, NHCOY 2 or NHS0 2 Y 2 and each may be further substituted by Z. Y 2 and Y.,, which may be the same or different, each represent hydrogen, C. g alkyl or phenyl; R. 8 and R- IQ , which may be the same or different, each represent hydrogen; C- g alkyl; C- .. cycloalkyl, C2_—o,. alkenyl; a carbocyclic aryl group; a 3-8 membered non-aromatic heterocyclic group; a 5 or 6 membered heterocyclic aryl group; or R.._ and R together with the nitrogen to which they are attached form a 3-8 membered non-aromatic heterocyclic group. In compounds of formula I, suitable substituents R c o include the following: hydrogen; halo (fluoro, chloro or bromo) , preferably fluoro or chloro, most preferably chloro; carboxy; carbamoyl, S(0)nY, in which Y, is preferably C, . alkyl and n represents 0, 1 or 2 (for example methylthio, ethylthio, propylthio, methylsulphinyl, ethylsulphinyl, propylsulphonyl) , more preferably Y. is C-_ 2 alkyl, most preferably methyl; suitably n is 0 or 1 and preferably 0. Most preferably R g represents hydrogen or C2_—o_ alkoxycarbonyl. In compounds of formula I, R^ together with R ^ . O 0 and the carbon to which they are attached may form cyclopropyl. Preferably R c also includes CONR,_R,_ in which R,_ o 1 1 J 12 represents methyl or ethyl and R represents C. 1 1—6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocyclic group containing one or two heteroatoms selected from oxygen, sulphur or nitrogen, a 5 or 6 membered heterocyclic aryl group containing one to three heteroatoms selected from oxygen, sulphur or nitrogen; or R, 3 represents phenyl optionally substituted by C 2 -6 alkoxycarbonyl (for example methoxycarbonyl) or halo (for example chloro) ? or R, 2 and R, 3 together with the nitrogen to which they are attached form a 3-8 membered non-aromatic heterocyclic group which may contain a further heteroatom selected from oxygen, sulphur or nitrogen which may be substituted by a C 2 _ g acyloxy(C._ β )alkyl group (for example propionyloxyethyl) . Preferably R g also includes a carboxylic ester group, which is preferably represented by the formula -CO.OR. ς in which R. ,- represents C, g alkyl? C~ g alkenyl?' C, , n cycloalkyl; a 3-8 membered non-aromatic heterocyclic group containing one or two heteroatoms selected from oxygen, sulphur or nitrogen, a carbocyclic aryl group; a 5 or 6 membered heterocyclic aryl group containing one to three heteroatoms selected from oxygen, sulphur or nitrogen, each group being optionally substituted by Z. Preferably R^ _ represents c - ] _g alkyl, C 3_ 8 cycloalkyl, a 5-7 membered non-aromatic heterocyclic group containing one or two Heteroatoms selected from oxygen, sulphur or nitrogen; a phenyl group; a 5 or 6 membered heterocyclic aryl ring containing one or two heteroatoms selected from oxygen, sulphur or nitrogen, each group being optionally substituted by Z. PreferaBIy R g also- represents a carboxylic acyl group which is preferably represented by the formula -CO.R 16 in which R 1 g represents C._g alkyl? C 2 _ g alkenyl ? C 3 cycloalkyl? a 3-8 membered non-aromatic heterocyclic group containing one or two heteroatoms selected from oxygen, sulphur or nitrogen? a carbocyclic aryl group ? a 5 or 6 membered heterocyclic aryl group containing one to three heteroatoms selected from oxygen, sulphur or nitrogen? each group being optionally substituted by Z. Preferably R^ g represents C^g alkyl, C, g cyclo¬ alkyl, a 5-7 membered non-aromatic heterocyclic group containing one or two heteroatoms selected from oxygen, sulphur or nitrogen? a phenyl group? a 5 or 6 membered heterocyclic aryl ring containing one or two hetero¬ atoms selected from oxygen, sulphur or nitrogen, each group being optionally substituted by Z. Preferably Z represents Z or Z . Preferably Z.. represents halo (fluoro, chloro or bromo) , more preferably fluoro or chloro, most preferably chloro? hydroxy or cyano; Preferably Z 2 represents the following: c ι_ c alkyl, preferably C, . alkyl (for example methyl, ethyl or propyl) , more preferably methyl or ethyl and most preferably methyl? C 3 _ 7 cycloalkyl, preferably C-_ j - cycloalkyl? C, g alkoxy, preferably C, . alkoxy (for example methoxy, ethoxy or propoxy) , more preferably methoxy or ethoxy, and most preferably methoxy? S(0) Y in which Y. is preferably C. . alkyl and m represents 0, 1 or 2, (for example methylthio, ethylthio, propylthio, methylsulphinyl, e hylsulphinyl, propylsulphinyl, methylsulphonyl, ethylsulphonyl, propylsulphonyl) , more preferably Y. is C, 2 alkyl, most preferably methyl, suitably m is 0 or 1 and pre-ferably 0? C 2-5 alkoxycarbonyl (for example methoxycarbonyl or ethoxycarbonyl) ? C~ 5 alkanoyl (for example acetyl or propionyl) ? or - e alkanoyloxy (for example acetoxy or propionyloxy) ? CONR- j g R. - in which R. _ and R._ preferably represent hydrogen, C, g alkyl, C- , alkenyl, C_ 0 cycloalkyl, a 3-8 membered 2—0 3—o non-aromatic heterocyclic group containing one or two heteroatoms selected from oxygen, sulphur or nitrogen? phenyl, a 5 or 6 membered heteroσyclic aryl group containing one to three heteroatoms selected from oxygen, sulphur or nitrogen? or R-_ and R._ together with the nitrogen to which they are attached form a 3-8 membered non-aromatic heterocyclic group which may contain a further heteroatom selected from oxygen, sulphur or nitrogen, each of the substituents R, β , R,„ being optionally substituted by Z. In compounds of formula" I, particularly preferred substituents R g include: hydrogen, carboxy or -C0.R-. in which R- . is as defined above. Preferred esterified carboxyl groups R g include: C 2-—o , alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or pentyloxycarbonyl? c _ o cycloalkoxycarbonyl (for example cyclobutoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl) or tetrahydro-2H-pyran-4-yloxy- carbohyl, each of which groups may be substituted by: C j _g alkyl (for example methyl)? C 3 _ g cycloalkyl (for example cyclohexyl, cyclopentyl, cyclobutyl or cyclo¬ propyl) ; phenyl; a 3-8 membered non-aromatic heterocyclic group containing one or two heteroatoms selected frcm nitrogen, oxygen or sulphur, (for example tetrahydrofuryl, tetrahydropyranyl, orpholino, piperidino, thiomorpholino, piperazino) ? a 5 or 6 membered aromatic heterocyclic group containing one to three atoms selected from oxygen, sulphur or nitrogen (for example pyridyl, thiazolyl, thienyl) ? C 2_ alkoxycarbonyl (for example ethoxycarbonyl) ? c 2 _g alkanoyl (for example acetyl) ? C, g alkoxy (for example methoxy or ethoxy)? S{0) Y., (for example methylthio) ? C2_—o c alkanoyloxy (for example acetoxy) ? cyano, hydroxy, acetamido, trifluoromethyl, halo. The optional C. - I —o alkoxy substituent may further be substituted with C.I — c 6 alkoxy (for example methoxy) or C2_— alkanoyloxy (for example acetoxy) . The optional phenyl, non- aromatic heterocyclic group or aromatic heterocyclic group substituent may further be substituted by C. g alkyl (for example methyl) , C, β alkoxy (for example methoxy), halo (for example chloro). In especially preferred compounds R g represents CO-fCH^) J in which p is 0-3 and J represents cyano, hydroxy, C 3_o cycloalkyl, C 2_ alkanoyloxy, c 2 _6 alkoxycarbonyl, C._ g alkoxy, C^g alkoxy(C._g) alkoxy, C.I — c o alkylthio, or J represents a 5 or 6 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms .selected from oxygen, sulphur or nitrogen; a 5 or 6 membered aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen; or a phenyl group, each of which groups is optionally substituted by C- g alkyl, C, g alkoxy or halo. Preferably p is 1 or 2. Particularly preferred substituents R,. also o include a carboxylic acyl group which may be C, „ 3—o cycloalkylcarbonyl (for example cyclopropylcarbonyl, cyclohexylcarbonyl) ; or c 2 - 6 alkanoyl (for example acetyl, propionyl, butyryl, pentanoyl, hexanoyl) , which may be substituted with phenyl or phenoxy each optionally substituted by halo, C, . alkyl, or C, . alkoxy,* or C~ g alkanoyl may be substituted with C~ g - 1 5 - alkoxycarbonyl (for example methoxycarbonyl) , C 2-6 alkoxy (for example mmeetthhooxxyy)) ,, CC j _ 4 alkylthio (for example methylthio) , C 3_ o cycloalkyl (for example cyclopentyl) . In especially preferred compounds R fi represents COCH.k in which k represents C._. alkoxy or phenoxy. > Particularly preferred substituents R may also include the group τ CONR^ 2 13< in which R.. represents methyl or ethyl, preferably methyl, and R. _ includes phenyl or C, . alkyl (more preferably methyl or ethyl, and most preferably methyl) substituted with phenyl. Most preferably R_ ? represents ethyl and R. represents phenyl. T Especially preferred substituents include hydrogen? cyclopropylmethoxycarbony1? 2-methoxybenzyloxycarbonyl? 4-chlorobenzyloxycarbonyl? 2-methylbenzyloxycarbonyl? 3-methylbenzyloxycarbonyl? 2-acetamidoethoxycarbonyl? 2-(2-methylpiperidin®)ethoxycarbonyl? 3-(2-propionyloxyethyl)-3-azapentamethylenecarbamoyl; methyl(2-methylphenyl)carbamoyl; methyl(3-methylphenyl).carbamoyl? methyl(4-meth lphenyl)carbamoyl? methyl(1 ,3-dioxolan-2-yl-methyl)carbamoyl; chloro? bromo? methylthio? ethylthio? methylsulphinyl? methylsulphonyl; carboxy? methoxycarbonyl; ethoxycarbonyl? propoxycarbonyl; butoxycarbonyl? pentyloxycarbonyl? dyclobutyloxycarbonyl? cyclopentyloxycarbonyl? cyclohexyloxycarbonyl ? tetrahydro-2H-pyran-4-yloxycarbonyl; cyclobutylmethoxycarbomyl; tetrahydrofurfuryloxycaxbonyl? benzyloxycarbonyl; 4-methoxybenzyloxycarbonyl; 3-methoxybenzyloxycarbonyl ? 4-methylbenzyloxycarbonyl; 2-chlorobenzyloxycarbonyl; 3-chlorobenzyloxycarbonyl; 2-(phenyl)ethoxycarbonyl ? 2-(4-methoxyphenyl)ethoxycarbonyl? 2-(4-chlorophenyl)ethoxycarbonyl, 2-(2-pyridyl)ethoxycarbonyl, 2-(4-methyl-5-thiazolyl)ethoxycarbonyl ? 2-(2-thienyl)ethoxycarbonyl? 2-cyclohexylethoxycarbonyl; 2-methoxyethoxycarbonyl ? 2-(methylthio)ethoxycarbonyl? 2-hydroxyethoxycarbonyl; 2-acetoxyethoxycarbonyl; 2-cyanoethoxycarbonyl; 2-(ethoxycarbonyl)ethoxycarbonyl; 2-(2-methox ethoxy)ethoxycarbonyl ? 3-oxobutoxycarbonyl? 2-(2-chlorophenyl)ethoxycarbonyl ? 2-(3-methylphenyl)ethoxycarbonyl ? 4,4,4-trifluorobutoxycarbonyl? 2-mσrpholinoethoxycarbonyl? 2-piperidinoethoxycarbonyl? 2-thiomorpholinoethoxycarbonyl? 1-methyl-2-morpholinoethoxycarbonyl? 3-morpholinopropoxycarbonyl? 3-(4-methyl-l-piperazinyDpropoxycarbonyl? 1-methyl-2-piperidylmethoxycarbonyl? acetyl; propionyl ? butyryl? pentanoyl? hexanoyl? cyclopropylcarbonyl? cyclohexylcarbonyl? phenoxyacetyl? phenylacetyl ? 3-methoxycarbonylpropionyl? carbamoyl? 3-oxapentamethylenecarbamoyl? 3-(2-acetoxyethyl)-3-azapentamethylenecarbamoyl ? methyl(2-morpholinoethyl)carbamoyl? benzyl(methyl)carbamoyl; methyl(3-pyridylmethyl)carbamoyl, methyl(2-phenyl)ethylcarbamoyl; 2-cyanoethyl(methyl)carbamoyl; methyl(phenyl)carbamoyl; ethyl(phenyl)carbamoyl? 2-phenoxyethoxycarbonyl? 1-benzylethoxycarbonyl ? 3-(3-pyridyl)propoxycarbonyl; 2-[4-(N,N-dimethylamino)phenyl]ethoxycarbonyl ? 2-phenylpropoxycarbonyl? 3-acetoxypropoxycarbonyl; 3-hydroxypropoxycarbonyl? 4-chlorophenyl(methyl)carbamoyl; 4-(2-acetoxy-ethyl)piperazinylcarbonyl; 4-(2-propionoxy-ethyl)piperazinylcarbonyl; 4-methoxycarbonylphenyl^methyl) carbamoyl; 2-(4-methόxyphenyl)propionyl; 4-chlorophenoxyacetyl; cyclopentylacetyl; 2-(3-πiethylphenyl)propionyl; 2-methylphenoxyacetyfl:? - 2-methylthiopropionyl; methoxyacetyl. In compounds o£ formula I, suitable substituents 7 include the following: Hydrogen; halo (fluoro, chloro, bromo) , preferably fluoro or chloro, more preferably chloro; trifluoro¬ methyl;^ g alkyl, preferably C._. alkyl (for example methyl, ethyl or gtop l) , more preferably methyl or ethyl, most preferably methyl; methoxy, S(0) Y. , in which R. is preferably C. . alkyl and m represents 0 or 1, (for example methylthio, ethylthio, propylthio, methylsulphinyl, e hylsulphinyl, propylsulphinyl) preferably m "is 0, ' -more preferably Y. is C j _ 2 alkyl, most preferably m€tξf l. In preferred cc-mpounds of formula I, R g represents hydrogen, fluoro, i chloro .or trifluoromethyl, more preferably hydrogen or chloro, and most preferably hydrogen. In preferred - compounds ^ of formula I, R g * represents hydrogen or chloro, especially hydrogen. The substituents R_ and R.. may be located at any position on the benz ringf" namely in position 6-, 7-, 8- and/or 9- of the benz ring. Accordingly each of the substituents R a d^R, n specified herein are considered to be named at each of these positions. In one group of compounds- R 1 n is- located at position 6- or 7- of the benz ring, especially position 6-. In a preferred group of compounds R.. 0 is located at position 8- or 9- of the benz ring, especially position 8-. In preferred compounds of formula I, R q represents hydrogen, fluoro or chloro, more preferably hydrogen or fluoro, most preferably hydrogen. In certain compounds of formula I, the group R.. fi may represent a carboxylic acyloxy group and may have the formula - O.CO.R 17 in which R.I_/ represents an alkyl group (e.g. C.I — ,) ; an alkenyl group (e.g. C 2 - 6 ^ ' a cycloalkyl group (e.g. C ..)? a non-aromatic heterocyclic group? a carbocyclic aryl group or a heterocyclic aryl group? each of the groups being optionally substituted. In preferred compounds of formula I, R._ represents C. β alkyl? C_~ c Ό alkenyl? C3_—.1.I cycloalkyl? a 3-8 membered non-aromatic heterocyclic group? a carbocyclic aryl group? or a 5 or 6 membered heterocyclic aryl group? each of the groups being optionally substituted by Z. Preferably R, 7 represents C, g alkyl, C 2< _ g alkenyl, C 3 _, n cycloalkyl, a 5-7 membered non-aromatic heterocyclic group containing one or two heteroatoms selected from oxygen, sulphur or nitrogen? phenyl; a 5 or 6 membered heterocylic aryl group containing one or two heteroatoms selected from oxygen, sulphur or nitrogen, each substituent R- 7 being optionally substituted by Z. -or Z 2 . Readily hydrolysable esters are included within the scope of the present invention as well as those which are less readily hydrolysable. Preferably R. Q represents hydrogen, fluoro, chloro, bromo, trifluoromethyl, hydroxy, nitro, C, g alkyl (preferably C^_ alkyl), C, g alkoxy (preferably -C. alkoxy) or a carboxylic acyloxy group as hereinabove defined. More preferably R 1 . represents hydrogen, halo (preferably fluoro or chloro) , nydroxy, C alkoxy (for example methoxy), C . alkyl (for example methyl) or nitro ' or a carboxylic acyloxy group. Most preferably R. Q represents hydrogen, fluoro, hydroxy or a carboxylic acyloxy group. In particularly preferred compounds of formula I, R. Q includes: hydrogen? hydroxy? C_ - n cycloalkanoyloxy (for example cycloproylcarbonyl, cyclobutylcarbonyl or adamantyl- carbonylbxy) ? 2 _ g alkanoyloxy (for example acetoxy or propionyloxy) or C 2 _ g alkenoyloxy, both of which may be substituted with a substituent selected from C 2_— c alkanoyloxy (for example acetoxy), S(O) Y. (for example methylthio), c ι _g alkoxy (for example methoxy), carboxy, chloro, phenyl, di(C, g )alkylamino or C 2 _ g alkoxycarbonyl (for example methoxycarbonyl or ethoxycarbonyl) and further optionally substituted by optionally substituted phenyl (for example 4-methoxy- phenyl, 4-methylphenyl, 4-chlorophenyl) ? or R.. represents arylcarbonyloxy in which the aryl group is suitably phenyl, thienyl, furyl, pyridyl [which may themselves by substituted with C alkyl (for example methyl) , C. alkoxy (for example methoxy) or halo (for 1—o example chloro) ] . Preferred are those in which R. - represents OCO(CH 2 ) L in which p is 0-3 and L represents hydrogen, C 3 , , cycloalkyl? di(C._ g alkyl)amino? C 2 _ g alkanoyloxy ? C 2 _g alkoxycarbonyl, c - | _g alkylthio? c ι _ 6 alkoxy? adamantyl or phenyl optionally substituted by C- c 1 — alkyl, C._ g alkoxy or halo. Preferred substituents R.._ include chloroacetoxy ? 4-chlorobenzoyloxy? cyclopentylcarbonyloxy ? cyclohexylcarbonyloxy? hydrogen? fluoro ? chloro ? hydroxy? acetoxy? propionyloxy? butyryloxy ? pentanoyloxy? methoxycarbonylacetoxy; 3-methoxycarbonylpropionyloxy; acetoxyacetoxy; 3-(methylthio)propionyloxy; benzoyloxy; methoxyacetox ; 4-methoxybenzyloxycarbonylacetoxy; ethoxycarbonylacetoxy; but-2-enoylox ; 3-ethoxycarbonylpropionyloxy; carboxyacetoxy; adamantylcarbonyloxy? 3-phenylpropionyl? methylthioacetoxy? phenylacetoxy? dimethylaminoacetoxy ? thenoyloxy? furoyloxy; 2-methylbenzoyloxy; 2-methoxybenzoyloxy; 4-methoxybenzoyloxy; pyridylcarbonyloxy; cyclopropylcarbonyloxy; cyclobutylcarboπyloxy; 4-methylbenzoyloxy? 3-methylbenzoyloxy. A more preferred class of compounds of formula I are those represented by formula V in which preferred substituents thereof are as recited in formula I above, More preferably. represents hydrogen. represents OR. 5 , R. g or NR.. 2 R 13 in which R. - represents methyl or ethyl, R. 3 represents C, g alkyl optionally substituted by cyano, phenyl, a 3-8 membered non- aromatic heterocyclic group containing 1 or 2 hetero¬ atoms selected from oxygen, sulphur or nitrogen, a 5 or 6 membered heterocyclic aryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur or nitrogen - 21 - or R 13 represents phenyl optionally substituted by C 2 _ g alkoxycarbonyl or halo; or R. 2 and R, 3 together with nitrogen to which they are attached form a 3-8 membered non-aromatic heterocyclic ring which may contain a further heteroatom selected from oxygen, sulphur or nitrogen which may be substituted by a C 2-g acyloxy(C, fi )alkyl group; and R. 5 and R.,, which may be the same or different, represent optionally substituted groups selected from C- g alkyl; C 2 _ g alkenyl; C, .- cycloalkyl; a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen? phenyl? a 5 or 6 membered heterocyclic aryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur or nitrogen? R_ represents hydrogen and ^ 10 represents hydrogen, hydroxy, halo, C, g alkoxy or _ alkyl. A further more preferred class of compounds of formula I are those represented by formula VI in which R erred substituents thereof, are as defined with respect to formula I above. More preferably, represents hydrogen, R... represents OR.,.. R.g or NR.. 2 R. 3 in which R- _ represents methyl or ethyl, R. 3 represents C 1-6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen, a 5 or 6 membered heterocyclic aryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur or nitrogen or R 13 represents phenyl optionally substituted by C_ g alkoxycarbonyl or halo? or R. 2 and R together with nitrogen to which they are attached form a 3-8 membered non-aromatic heterocyclic ring which may contain a further heteroatom selected from oxygen, sulphur or nitrogen which may be substituted by a C 2 _ g acyloxy(C^g)alkyl group? and R 15 and R. g , which may be the same or different, represent optionally substituted groups selected from C | _ g - alkyl? ~ g alkenyl ? C., , 0 cycloalkyl? a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen? phenyl ? a 5 or 6 membered heterocyclic aryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur or nitrogen; R q represents hydrogen and R.. 0 represents hydrogen, hydroxy, halo, C.. g alkoxy or C, g alkyl. A further more preferred class of compounds of formula I are those represented by formula VII in which Re ' and 7 and prefer nts the Vreo' "1 R. 1_ red substitue f are as defined with respect to formula I above. Preferably the substituent 0.CO.R 17 is located in the 8-position or 9-position of the ring system, especially the 8-position. More preferably R g ' represents hydrogen and R g represents hyi ' ΪS "' ^ 2-6 alkoxycarbonyl or c ι _g alkylthio, R. η represents optionally substituted groups selected from C. c alkyl; 1 — 6 - 23 - C 2_—o, alkenyl; C3_—.1.1 cyclpalky_,l; a 3-8 membered non- aromatic heterocyclic group containing 1 or 2 hetero¬ atoms selected from oxygen, sulphur or nitrogen; phenyl; a 5 or 6 membered heterocyclic aryl group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitroge . t * > i A further more preferred class of compounds of formula I are tihose, represented by formula VIII in which R 7 , R8_ „and R.1_7 and p c referred substituents thereof, are as defined with respect for formula I above. More preferably R._ represents optionally substituted groups selected from C. I —b c alkyl; C_. — b_ alkenyl; C_ .. cycloalkyl?, a 3-8 membered non-aromatic heterocyclic group;.- containing 1 or 2 heteroatoms selected from oxygen, sulp ur or nitrogen; phenyl; a 5 or 6 membered heteroicyclic aryJL group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen. A further more preferred class of compounds of formula I are those-represented by formula IX IX in which R g , R gt , R 7 , R g , R gw R 9 and R 1 Q and preferred substituents thereof, are as defined with respect to formula I above. More preferably R g ' represents hydrogen or methyl; R g represents hydrogen, halo, C 2 _ g alkanoyl, c 2 _g alkoxycarbonyl, S(0) Y 1 , carbamoyl, carboxy or R g . and R g together with a carbon atom to which they are attached represent cyclopropyl; R represents hydrogen, halo, trifluoromethyl, methoxy, C, g alkyl, S(0) Y. ; R g represents hydrogen, halo or trifluoromethyl; R g * represents hydrogen, halo or trifluoromethyl; R- and R-, 0 , which may be the same or different, each represent halo; or R q represents hydrogen and R. Q represents hydrogen, halo, trifluoromethyl, hydroxy, nitro, C 2_—b- alkanoyloxy, C.I —b , alkyl orC._ g alkoxy. In one preferred group of compounds X represents oxygen. In a further preferred group of compounds R g represents COR-., especially C00R. 5 , X preferably represents oxygen and Z preferably represents -CH=. In a further preferred group of compounds R. fi represents OCOR._, and X preferably represents oxygen and Z preferably represents -CH=. Particular compounds of formula I are the compounds listed in Table A and pharmaceutically acceptable salts thereof provided in the specific Examples of the invention, including the free bases of compounds which have been exemplified as salts, hydrates or solvates. -» Compounds of formula I may contain one or more chiral centres and exist in different optically active forms. When compounds of formula I contain one chiral centre the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers. The enantiomers may be - 25 - resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallisation? formation of diastereoisomeric derivatives which may be separated, for example, by crystallisation, gas-liquid or f liquid chromatography ? selective derivatisation of,.one enantiomer by reaction with a enantiomer-specific .reagent, for example enzymatic oxidation or reduction? or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral ^ support, for example silica with a bound chiral ligand * or in the presence- of a chiral solvent. Alternatively, specific enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation. For example, all compounds of formula IV have a chiral centre. In particular each [I benzothiopyrano- [4,3-£]pyrazole having a 3a-methyl substituent listed in Table A (hereinafter) is hereby named as the R- or S- enantiomer. In addition the following named compound " may also exist in the R- or S- enantiomeric form: 2-morpholinoethyl 2-(4-chlorophenyi)-3-oxo-l ,2,3,4- tetrahydro[1]benzopyrano[4,3-c pyrazole-4-acetate. When compounds of formula -I contain more than one chiral centre, the compounds may exist in diastereoisomeric-.. forms. s The present invention includes each . diastereoisomer and mixtures of the diastereoisomers. The diastereoisomers may be separated by methods known to those skilled in the art, for example by crystallisation or liquid chromatography. Certain compounds of formula I may exist in different tautomeric forms or as different geometric isomers. Some compounds of formula I are bases and may form acid addition salts with inorganic or organic acids, for example hydrochloric acid, hydrobro ic acid, fumaric acid, tartaric acid and citric acid. It will be appreciated that such salts, provided they are pharmaceutically acceptable, may be used in therapy in place of the corresponding compounds of formula I. Such salts may be prepared for example by reacting the compound of formula I with a suitable acid in a conventional manner. Certain compounds of formula I may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof. Certain compounds of formula I may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof. The present invention also includes pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I together with a pharmaceutically acceptable diluent or carrier. As used hereinafter, the -term "active compound" denotes a . [1]benzopyrano[4,3-c_]pyrazole or a [1]benzothiopyrano[4,3-c pyrazole of formula I. In therapeutic use, the active compound may be administered orally, rectally, parenterally or topically, preferably orally or topically. Thus the therapeutic compositions of the present invention take the form of any of the known pharmaceutical - 27 - compositions for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The compositions of the invention may contain 0.1-90% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. The. excipients used in the preparation of these compositions are the excipients known in the pharmacist's art. Compositions for oral administration are preferred compositions of the invention and these are known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oily suspensions. Tablets may be prepared by mixing the active compound with an inert diluent such as lactose or calcium phosphate in the presence of disintegrating agents, for example maize starch, and lubricating agents, for example magnesium stearate, and tableting the mixture by known methods. The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Such tablets may, if desired, be provided with enteric coatings by known method--, for example by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by conventional means and, .if desired, provided with enteric coatings in a known manner. The tablets and capsules may conveniently each contain 0.1 to 500 mg of the active compound. Other compositions for oral administration include, for example, aqueous suspensions containing the- active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil. Compositions for topical administration are also preferred compositions of the invention. The pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel. A suitable cream may be prepared by incorporating the active compound in a topical vehicle such as petrolatum and/or light liquid paraffin, dispersed in an aqueous ^ medium using surfactants. An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil, petrolatum and/or a wax e.g. paraffin wax or beeswax. A gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent e.g. basified Carbomer BP, in the presence of water. Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are ' -dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. A suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as described above, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol. Compositions of the invention suitable for rectal administration are known pharmaceutical forms for such administration, for example suppositories with semi-synthetic glycerides or polyethylene glycol bases. Compositions of the invention suitable for parenteral administration are known pharmaceutical forms for such administration, for example sterile suspensions in aqueous and oily media or sterile solutions in a suitable solvent. In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling. In the compositions of the present invention the active compound may, if desired, be associated with other compatible pharmacologically active ingredients. The compounds . j of formula I are indicated for use as immunomodulatory agents, and are generally immunosuppressants, but some compounds, in certain disease states, ay exhibit immunostimulant activity. The compounds according to the invention are useful in the treatment of dr Iseases resulting from an aberrant immune reaction. Thus the pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I may be used to treat diseases with an immunologioal association for example tissue rejection, such as kidney rejection? autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus? cutaneous disorders, such as contact sensitivity, eczema and psoriasis? and neoplasia, such as melanoma. In such treatment the amount of the compound of formula I administered per day will be such as to give a therapeutic e fect and is generally in the range 0.1 to 2000 mg, preferably 1 to 500 mg. Accordingly, in another aspect, the present invention also inc jl,udes a method of treating diseases with an immunol gical association, comprising the administration of a therapeutically effective amount of a compound of formula I. The therapeutic activity of compounds of formula I has been demonstrated by means of tests on standard laboratory animals. Such tests include, for example, the oral and parenteral administration of the compounds to BALB/c mice. Thus, compounds of formula I are useful as immunomodulatory agents. Whilst the precise amount of active compound administered will depend on a number of factors, for example the age of the patient, the severity of the condition and the past medical history and always lies within the sound discretion of the administering physician, a suitable dose for oral administration to mammals, including humans, is generally within the range 0.01-40 mg/kg/day, more usually 0.2-25 mg/kg/day given in single or divided doses. For parenteral administration, a suitable dose is generally within the range 0.001-4.0 mg/kg/day, more usually 0.005-1 mg/kg/day given in single or divided doses or by continuous infusion. A suitable preparation for topical administration generally contains the active ingredient within the range 0.01-20% by weight, more usually 0.05-5% by weight. Oral administration is preferred. Processes for the preparation of compounds of formula I will now be described. These processes form a further aspect of the present invention. Compounds of formula I which are represented by formula II may be prepared by oxidising compounds of formula I which are represented by formula III, for example by reaction with chloranil. Compounds of formula I which are represented by formula II may be prepared by reacting compounds of formula X, or a tautomer thereof, with compounds of formula XI R 6 '—CH—CR22R23 XI in which R_ represents (OQ) _ and R-, represents OQ or NQ' ; or R 22 represents (SQ) 2 and R 23 represents SQ or NQ' ? or R 2 _ represents =NH and R 23 represents OQ or SQ? or R 22 represents =0 and R 23 represents a leaving group for example an optionally substituted 1-imidazolyl group, in which Q and Q' represent a C, . alkyl group or • a benzyl group, for example by heating at 50-200°C. Compounds of formula I which are represented by formula II in which R g , represents hydrogen and R g represents a carboxylic acyl group may be prepared by reacting compounds of formula X with compounds of formula Xlla or a tautomer thereof, in which R~ 4 and R 25 may be the same or different, and each represent a C. I — , alkyl group or a benzyl group, for example by heating in an organic liquid for example xylene at a temperature between 50-200°C. Compounds of formula I which are represented by compounds of formula II in which R fi represents a carboxylic acyl group may be prepared by reacting compounds of formula X with compounds of formula Xllb or a tautomer thereof, in which R 24 and R 2 _ may be the same or different and each represents a C. c alkyl I— group or a benzyl group, for example by heating in an organic liquid, for example xylene at a temperature between 50 and 250°C. Compounds of formula I which are represented by compounds of formula II in which R- represents a group CONR R or an esterified carboxyl group may be prepared by reacting compounds of formula II' - 33 - in which R- . , represents R- _ and R represents COA, where A represents a leaving group, for example hydroxyl , halo, c ι ~ c g alkoxy, aryloxy, arylmethoxy, C.-C 8 acyloxy or C, g alkoxycarbonyloxy with an amine of formula NHR. R , or an alcohol, for example of formula R. _OH respectively, for example at 0-250°C, 15 optionally in the presence of an organic liquid which is preferably a solvent for the reactants and optionally in the presence of a catalyst for the reaction. Compounds of- formula I which are represented by compounds of formula II in which R g represents a group which is substituted by a carboxylic acyloxy group may be prepared by acylation of corresponding compounds of formula II substituted by a hydroxy group, for example by reaction with an acyl halide. Compounds of formula I which are represented by compounds of formula II in which R- represents a group which is substituted by a hydroxyl group may be prepared from corresponding compounds of formula I substituted with a carboxylic acyloxy group, for example acetoxy, by hydrolysis. Compounds of formula I which are represented by compounds of formula II in which R. _ represents a carboxylic acyloxy-group may be prepared by acylating compounds of formula II* in which R represents R- and a 6 R , represents a hydroxy group by reaction with an acylating agent. The acylation reaction may be carried out by reacting the compound of formula II' with an acyl halide e.g. R, 7 C0C1 or an acid anhydride (R 17 CO) 2 0 in the presence of a base at a temperature in the range -10°C to 40°C. The acylation reaction may also be carried out by reacting the compound of formula II' with a carboxylic acid R, 7 COOH in the presence of a dehydrating agent, for example dicyclohexylcarbodii- _mide, preferably in the presence of a base e.g. pyridine. Compounds of formula II' in which R, n f represents hydroxy may be prepared by reacting compounds of formula II* in which R, Q , represents a c ι„c alkoxy group with a Lewis acid, for example aluminium chloride or boron tribromide. Compounds of formula I which are represented by formula II in which R g and R * both represent hydrogen may be prepared by decarboxylating compounds of formula II in which R g , represents hydrogen and R g represents carboxyl, or by hydrolysing compounds of formula II in which Rb..' represents hydrogen and Rb- represents a group which may be hydrolysed to a carboxyl group such as a C ? _ 6 alkoxycarbonyl group or carbamoyl, for example by reaction with sulphuric acid, followed by decarboxylation. Compounds of formula I which are represented by formula II in which R g represents a C, fi alkylsulphinyl group or a C, g alkylsulphonyl group may be prepared by oxidation of compounds of formula II in which R,. b represents a C- alkylthio group with, for example, 3-chloroperoxybenzoic acid. Compounds of formula I which are represented by compounds of formula II in which R- represents a 6 - 35 - carboxyl group may be prepared from compounds of formula II in which R g represents 4-methoxybenzyloxy- carbonyl for example by treatment with trifluoroacetic acid and anisole in a solvent, for example dichloromethane. Compounds of formula I which are represented by compounds of formula II in which R- Q represents a carboxyalkylcarbonyloxy group for example carboxy- acetoxy, may be prepared from compounds of formula II in which R- - represents 4-methσxybenzyloxycarbonyl- alkylcarbonyloxy, for example 4-methoxybenzyloxy- carbonylacetoxy, by treatment with trifluoroacetic acid and anisole in a solvent, for example dichloromethane. Compounds of formula I which are represented by formula II may-be prepared by reacting compounds of formula X-II-I in which represents hydrogen. 26 or a tautomer thereof, or in which R 26 represents a group COR 2g wherein R_ 0 represents hydrogen, an optionally substituted C 1-4 alkyl group or'a benzyl group and R represents COCHR g R gl % with a base e.g. piperidine in a suitable solvent e.g ethanol. Compounds -.of formula I which are represented by formula III may be prepared by reducing compounds of formula I which arse* represented by formula II, for example by reaction with sodium borohydride. Compounds of formula I which are represented by formula III or IV may be prepared from the corresponding compounds of formula I* in a similar manner as compounds of formula II are prepared from compounds of formula II*. Compounds of formula I which are represented by formula III may be prepared by reacting compounds of formula XIV in which R3_ represents hydrogen, R D_ represents CHR6..R6,. f , R 29 represents COOR 3 _ or carbamoyl and R 3Q represents a C, 4 alkyl group or a benzyl group with a hydrazine of formula XV for example, by heating at 50-250%, for example in acetate acid or in an inert organic liquid containing an acid catalyst, e.g. xylene containing p-toluene sulphonic acid. Compounds of formula I which are represented by formula IV may befprepared by reacting compounds of formula XIV in which X represents S, R, represents methyl, R ς represents hydrogen" and R_ g and R 3 _ are as defined, with compounds of formula XV in which Z represents -CH=. Compounds of formula I which are represented by formulae V to IX may be " prepared as described with reference to the preparation of compounds of formulae II to IV above. Compounds of formula X may be prepared by reacting compounds of formula XVI in which R_ represents hydrogen, a C, . alkyl group or a benzyl group with a hydrazine of formula XV, for example by heating at 50-200°C in an organic liquid for example toluene. Preferably the compound of formula XVI is used in excess of the stoichiometric amount. Compounds of formula X may be prepared by reacting compounds of formula XVII with an acid, for example hydrochloric acid, or with a base, for example a solution of sodium hydroxide. Compounds of formula X in which R. _ represents a hydroxyl group may be prepared by reacting compounds of formula X in which R. I U. represents a C.I— , alkoxy group with a Lewis acid, for example aluminium chloride or boron tribromide. Compounds of formula XI in which R_ represents (OQ) 2 and R 23 represents OQ may be prepared for example a) by reacting compounds of formula R R CH-CX. in which X is halo with a sodium alkoxide of formula NaOQ in which Q is a C, . alkyl group or a benzyl group, or b) by reacting compounds of formula R gl R g CH-CN with an alcohol of formula QOH in the presence of an anhydrous acid, for example hydrogen chloride, to give compounds of formula R gl R g CH-C(=NH)OQ as their acid salts, e.g. hydrochloride salts, which are then reacted with further alcohol of formula QOH. - 39 - Compounds of formula XI in which R represents (SQ) 2 and R 23 represents SQ may be prepared for example from compounds of formula R gI R g CH-COCl by reaction with thiols of formula QSH in which Q represents a C. alkyl group or a benzyl group in the presence of a Lewis acid, for example zinc chloride. Other compounds^ of formula XI may be prepared by methods known to those skilled in the art. Compounds of formula Xllb or tautomers thereof may be prepared by the acylation of compounds of formula XIX by reaction with an acyl chloride R.. g -COCl, for example in the presence of pyridine in an inert solvent at a temperature in the range -10°C to 50°C. Compounds of formula XIII in which R 2g represents COR 2R and R_ 7 represents COCHR g R g , may be prepared by acylation of compounds of formula XIII in which R 2b_ represents COR^ o and R 27 represents hydrogen, for example by reaction with an acid anhydride of formula (R gl R g CHCO) 2 0 or an acid halide e.g. of formula Compounds of formula XIII in which n . represents 26 COR 2R and R 27 represents hydrogen may be prepared by the acylation of compounds of formula X for example by reaction with an acid anhydride of formula (R 2g C0) 2 0 in the presence of a salt (e.g. the sodium salt) of the corresponding acid. Compounds of formula XIII in which R_ ^ and R _ are b 27 identical and represent COCHR gf R g , may be prepared by acylation of compounds of formula X for example by using an acid anhydride of formula (R gt R g CHCO) 2 0 in the presence of a salt (e.g. the sodium salt) of the corresponding acid. Compounds of formula XIII in which R 27 represents C0CHR g R g , and R 2g represents hydrogen, or tautomers thereof, may be prepared by reacting a compound of formula XIII in which R 2g represents COR 2g and R 27 represents COCHR g R g , with a base e.g. piperidine in a suitable solvent e.g. ethanol. Compounds of formula XIV in which R_ represents COOR and R represents CHR g R , may be prepared by 30 heating compounds of formula XX in which R 3Q represents a C. . alkyl group or a benzyl group, for example with glass powder or glass wool. Compounds of formula XIV in which R_ represents methyl and R_ represents hydrogen may be prepared by reacting compounds of formula XVIII XVIII with a methylating agent for example a methyl halide, for example methyl iodide in the presence of a base, for example a sodium alkoxide e.g. sodium methoxide. Compounds of formula XIV in which R represents carbamoyl may be prepared from compounds of formula XIV iinn wwhhiicchh RR 22Qg rreepprreessients cyano by methods known to those skilled in the art. Compounds of formula XV may be made by methods known to those skilled in the art. Compounds of formula XVI in which R-.. represents hydrogen may be prepared by reacting compounds of formula XXI in which R represents hydrogen with malonic acid in the presence of an acid chloride e.g. phosphoryl chloride and a Lewis acid e.g. zinc chloride. Compounds of formula XVI in which 31 represents hydrogen may be prepared by reacting compounds of formula XXI in which R 33 represents a group C0R- 4 in which R 34 represents a C. _ alkyl group, with a base, for example sodium hydride, followed by treatment with a dialkyl carbonate of formula (QO) 2 C0 in which Q represents a C, . alkyl group or a benzyl group, e.g. dimethyl carbonate. Compounds of formula XVI in which R.,, represents a C, 4 alkyl group -or- a benzyl group may be prepared by base catalysed alkylation or benzylation of compounds of formula XVI in which 31 represents hydrogen for example by reaction with an alkyl halide or a benzyl halide. Compounds of formula XVII may be prepared by reacting compounds of formula XVI with a hydrazine of formula XV for example by heating at 50-200°C in a suitable solvent for example toluene. In cases where a mixture of compounds of formula X and XVII are obtained, these compounds may be separated by virtue of their different solubilities in an organic liquid for example dichloromethane. Compounds of formula XVIII to XXI may be prepared by methods known to those skilled in the art. Compounds of formula I which are represented by formula II in which R.. n represents R.-OC.O may be prepared by acylation of compounds of formula II in which R. n represents a hydroxyl group. During the acylation reaction there may be formed compounds of formula XXII - 43 - which may be hydrolysed, for example on exposure to atmospheric moisture to the desired compounds of formula II mentioned above. Certain intermediate compounds of formulae X, XI, XII a) and b) , XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, and XXII are believed to be novel compounds. All novel compounds ^ herein are claimed as a further aspect of the invention. The invention e is illustrated by the following non-limitative Examples. In the Examples parts and percentages are by weight and compositions of mixed solvents are given by volume. Characterisation was by elemental analysis and one or more of the following spectroscopic techniques: nuclear magnetic resonance, infra-red and mass spectroscopy. Preparation of Novel Compounds of Formula XVI Example 1 A mixture of 5'-fluoro-2'-hydroxyacetophenone (10 g) in dry toluene (130 ml) was added dropwise over 20 minutes to a stirred suspension of sodium hydride (6.2 g ? 60% dispersion in mineral oil) in dry toluene (130 ml) which was boiling under reflux under nitrogen. After boiling for a further 10 minutes heating was continued while a solution of diethyl carbonate (15.7 ml) in dry toluene (130 ml) was added dropwise over 25 minutes. This mixture was stirred and heated under reflux for 4 hours. On cooling, the reaction mixture was poured on to iced 2M hydrochloric acid (700 ml) . The solid obtained was collected by filtration and then dissolved in 4M aqueous sodium hydroxide (325 ml) . This solution was washed with ether and then acidified with 5M hydrochloric acid. The solid obtained was collected by filtration, washed with water and dried to give 6-fluoro-4-hydroxycoumarin, m.p. 250-251 °C. Preparation of Novel Compounds of Formula XIV Example 2 a) Dimethyl oxalate (1.4 g) was added to a stirred solution of sodium (0.3 g) in methanol (10 ml) with warming to aid dissolution. The' solution was cooled to ambient temperature and a solution of 6-methoxy-4- thiochromanone (1.2 g) in methanol (6 ml) was added dropwise over 15 minutes. The mixture was stirred at ambient temperature for 3 hours and then allowed to stand for 4 days. The solvent was removed under reduced pressure and the residue partitioned between water and toluene. The aqueous layer was basified with - 45 - 2M sodium hydroxide solution, separated and acidified with 2M hydrochloric acid. The solid formed was collected , by filtration and reσrystallised from methanol to give methyl 6-methoxy-4-oxo-3-thiochroman- glyoxylate, m.p. 85-89°C. b) A mixture of methyl 6-methoxy-4-oxo-3-thiochroman- glyoxylate (6.2 g) and glass powder (2.8 g) was heated with stirring at 180°'C for 30 minutes. The mixture was cooled to ambient temperature, extracted with boiling acetone and filtered. The filtrate was evaporated and the residue was taken up in hot propan-2-ol then hot filtered from some. tar. • The filtrate was cooled and filtered to give methyl 6-methoxy-4-oxo-3—thiochroman- carboxylate, m.p. 61-65°C. c) A solution of methyl 6-methoxy-4-oxo-3-thio- chromancarboxylate (1.0 g) in toluene (10 ml) was added to a solution of sodium (0.4 g) in dry methanol (15 ml) with stirring. The mixture was boiled under reflux for 10 minutes then cooled to ambient temperature and methyl iodide (1 ml) added. The mixture was boiled under reflux, with stirring, for 3 hours then left at ambient temperature for 18 hours. The mixture was neutralised with glacial acetic acid them evaporated under reduced pressure. The residue was added to water and extracted with toluene. The combined toluene extracts were washed with saturated sodium bicarbonate solution, then wate.r, dried . and evaporated urder reduced pressure. The residue -'was separated by flash chromatography on silica using ethyl acetate/petroleum ether (b.p. 60-80°C, 1:4) as the mobile phase. The solid obtained was recrystallised from ethyl acetate/petroleum ether (b.p. 60-80°C) to give methyl 6-methoxy-3-n3ethyl-'4-oxo-3-thiochromancarboxylate, m.p. 66-73°C. Example 3 a) A stirred mixture of 4-methoxythiophenol (20 g) , diethyl ethoxymethylene malonate (29.3 ml) and potassium hydrogen sulphate (0.4 g) was heated at 160-170°C for 2 hours. Polyphosphoric acid (152 g) was added to the reaction mixture with heating at 80-90°C for 1 hour. The reaction mixture was poured into water, extracted with ether and the ether extracts combined and dried. Following removal of the solvent the solid obtained was recrystallised from ethyl acetate/petroleum ether (b.p. 60-80°C) to give ethyl 6-methoxy-4-oxo-4-H-thiochromene-3-carboxylate, m.p. 102-104°C. b) Copper chloride (150 mg) was added to a stirred mixture of ethyl 6-methoxy-4-oxo-4-H-thiochromene-3- carboxylate (4 g) in tetrahydrofuran (40 ml) under nitrogen at -78°C. A 3M solution of methylmagnesium bromide in ether (5 ml) was added slowly maintaining the temperature below -65°C and then the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was poured into ether/2M hydrochloric acid, the aqueous layer extracted with ether, and the combined ether layers dried to give the crude product. Purification by flash chromatography over silica using 1% methanol/dichloromethane as the mobile phase gave ethyl 6-methoxy-2-methyl-4-oxo-3- thiochromancarboxylate as an oil. Preparation of Novel Compounds of Formula Xllb Example 4 Pyridine (12 g) was added dropwise^ over 3-5 minutes to a stirred solution of 2,2-dimethyl-1 ,3- dioxane-4,6-dione (20 g) in dichloromethane (220 ml) at 0°C. The resulting solution was stirred at 0°C for 10 minutes and then while the temperature was maintained at 0-2°C 3-methoxycarbonylpropionyl chloride (22.8 g) was added dropwise. After the addition the mixture was stirred at 0°C for 60 minutes, then allowed to warm up to ambient temperature and kept at this temperature for 18 hours. The mixture was washed with 1M hydrochloric acid, then water, dried and evaporated to give methyl 4-(2,2-dimethyl-4,6.-dioxo-l ,3-dioxan-5-yl)-4- oxobutyrate as a viscous oil. Examples 5-15 In a similar manner to that described in Example 4, a compound of formula Xllb was prepared by reacting 2,2-dimethyl-1 ,3-dioxane-4,6-dione (XIX) with R. I,b-COCl (in which R. I b. is as defined), as summarised in Table 1 below. Table 1 Amounts of Reactants π p_. of Notes E R 16 XIX R C0C1 Pyridine Dichloro- Xllb (g) (g) (g) methane (°C) (ml) 5 6 10 7 8 9 ( ) 10 115-116 (2) 11 (6) 15 12 (4) (3) (1) 13 88-90 (5) 14 (1) (6) 15 Notes (1) Product was a ;viscous oil. (2) After washing " with hydrochloric acid and water, the solid product was collected by filtration. (3) The reaction was ' ,carried out under nitrogen. (4) The crude product was purified by flash chromatography using dichloromethane as the mobile phase. - ~ l (5) The crude product was purified by trituration with hot industrial methylated spirit and the solid product collected by evaporation. (6) After washing with hydrochloric acid and water the solvent was removed to leave a dark solid. The compounds prepared in the above Examples were as follows: 5 2,2-dimethyl-5-phenylacetyl-l ,3-dioxane-4,6- dione 6 2,2-dimethyl-5-phenoxyacetyl-l ,3-dioxane-4,6- dione 7 5-cyclohexylcarbonyi-2, 2-dimethyl-l ,3-dioxane- 4,6-dione 8 5-cyclopropylcarbonyl-2,2- * dimethyl-l ,3- dioxane-4,6-dione 9 2 ,2-dimethyl-5-[3- (4-methoxyphenyl)propionyl]-1 , 3-dιoxaήe-4,6-dιone 10 5- (4-chlorophenoxyacetyl) -2,2-dimethyl-l ,3- dioxane-4,6-dione - so ¬ li 2,2-dimethyl-5-[3-(3-meth lphenyl)propionyl]- 1 ,3-dioxane-4,6-dione 12 5-(2-cyclopentyl-l-hydroxyethylidene)-2,2- dimethyl-1 ,3-dioxane-4,6-dione 13 5-[1-hydroxy-2-(2-methylphenoxy)ethylidene]- 2,2-dimethyl-1 ,3-dioxane-4,6-dione 14 2,2-dimethyl-5-(3-methylthiopropionyl)-1 ,3- dioxane-4,6-dione 15 5-methoxyacetyl-2,2-dimethyl-1 ,3-dioxane-4,6- dione Preparation of Novel Compounds of Formula XI Example 16 A stirred mixture of propyl cyanoacetate (30.5 g) , dry propanol (18.5 g) and dry ether (134 ml) was saturated with hydrogen chloride at 0-5°C. The mixture was allowed to warm to ambient temperature and kept at this temperature for 66 hours. After evaporation under reduced pressure, the residual oil obtained was stirred and heated at 45-50°C in dry propanol (180 ml) for 24 hours. After cooling to ambient temperature, dry ether (200 ml) was added and the mixture filtered. The filtrate was evaporated under reduced pressure to give an oil which was distilled under reduced pressure to give tripropyl ortho(propoxycarbonyl)acetate, b.p. 165-175°C (5 mm Hg) . Example 17 (a) A stirred mixture of isopropyl cyanoacetate (15.0 g) and dry methanol (4.2 g) was saturated with hydrogen chloride at 0-5°C. Dry ether (70 ml) was added to the reaction mixture and the solid product collected by filtration and washed with ether., to give methyl isopropoxycarbonylacetimidate hydrochloride. - 1 - (b) A mixture of methyl isopropoxycarbonylacetimidate hydrochloride (17 g) and dry methanol (52.7 ml) was stirred for 30 minutes. Dry ether (290 ml) was added and the mixture stirred and heated under reflux for 18 hours. The reaction mixture was cooled to 0°C, filtered and the filtrate washed with 10% sodium carbonate solution (3O0 ml) saturated sodium carbonate solution (50 ml) , dried and evaporated under reduced pressure to give trimethyl ortho (isopropoxycarbonyl) acetate as an oil. Example 18 a) A solution of methylthioacetonitrile (100 g) and methanol (47 ml) in dry ether (644 ml) was saturated with hydrogen chloride at 0-5°C. The mixture was allowed to warm to ambient temperature during 16 hours. The resulting solid product was collected by filtration, washed and dried to give methyl methylthio- acetimidate hydrochloride as a sticky solid. b) A mixture of the methyl methylthioacetimidate hydrochloride and methanol (551 ml) was stirred at 35-45°C for three hours and then left at ambient temperature for 72 hours. The mixture was then filtered and the filtrate evaporated to give an oil containing a little solid which was removed by filtration through cotton wool giving trimethyl ortho(methylthio) acetate as an oil, b.p. 96-104°C (5 mm Hg) . Preparation of Novel Compounds of Formula X Example 19 a) A stirred mixture of 4-hydroxy-5-methoxy-coumarin (6.5 g) , 4-chlorophenylhydrazine (7.3 g) and dry toluene (66 ml) was heated under reflux with removal of the water formed in the reaction. On cooling, the solid obtained was collected by filtration to give 4-[2-(4-chlorophenyl)hydrazino]-5-methoxy-coumarin, m.p. 206-209°C. b) A mixture of 4-[2-(4-chlorophenyl)hydrazino]- 5-methoxycoumarin (1.6 g), 5M aqueous sodium hydroxide (1 ml) and industrial methylated spirit (100 ml) was boiled under reflux for 4 hours. On cooling, the mixture was filtered. The filtrate was evaporated to dryness and the residue was partitioned between dichloromethane and water. The dichloromethane layer was separated off, dried and concentrated to give after filtration, 1-(4-chlorophenyl)-3-(2-hydroxy-6- methoxyphenyl)-2-pyrazolin-5-one, m.p. 185-188°C. Example 20 a) A stirred mixture of 4-hydroxy-6-methoxy-coumarin (9.2 g) and 4-chlorophenylhydrazine (10.2 g) in dry toluene (82 ml) was heated under reflux -for 5.5 hours with removal of the water produced in the reaction. More 4-chlorophenylhydrazine (5ϊO g) was added and the mixture heated under reflux for a further 2 hours. The mixture was allowed to cool to ambient temperature and the solid formed collected by filtration to give 1-(4-chlorophenyl)-3-(2-hydroxy-5-methoxyphenyl)-2- pyrazolin-5-one, m.p. 197-203°C. b) 1- (4-Chlorophenyl)-3- (2-hydroxy-5-methoxy- phenyl) -2-pyrazolin-5-one (5.5 g) , aluminium chloride (9.35 g) and dry xylene (66 ml) were stirred and heated at 100°C for 1 hour. On cooling, the xylene was decanted off and a mixture of 2M hydrochloric acid (90 ml) and ice (200 g) added to the residue. After trituration the solid formed was collected by filtration, dried and then recrystallised from methanol to give 1- (4-chlorophenyl) -3- (2,5-dihydroxyphenyl) -2- pyrazolin-5-one, m.p. 220-225°C (with decomposition) . Example 21 a) A stirred mixture of 4-hydroxy-6-methoxycoumarin (10.0 g) , 4-trifluoromethylphenylhydrazine (22.9 g) , dry toluene (375 ml) and p-toluenesulphonic acid (0.2 g) was refluxed for a total of 25 hours (with intermittent storage at ambient temperature for a total of 130 hours) during which a further portion of p-toluenesulphonic acid (0.2 g) was added after refluxing for 7.5 hours, and then further 4-trifluoro- methylphenylhydrazine (5 g) and p-toluenesulphonic acid (0.2 g) added after refluxing for 13 hours. After cooling to ambient temperature, the reaction mixture was filtered and _ the solid recrystallised from acetonitrile with hot filtration. The solid collected was boiled with dichloromethane and hot filtered to give crude 6-methoxy-4- [2- (4-trifluoromethylphenyl) - hydrazino] coumarin. b) A mixture of crude 6-methoxy-4- [2- (4-trifluoro- methylphenyl)hydrazino]coumarin (8.5 g) , 5M hydro- chloric acid (8.5 ml) and industrial methylated spirit (82 ml) was stirred and boiled under reflux for 29 hours. On cooling, the solid obtained was collected by filtration to give 3- (2-hydroxy-5-methoxyphenyl) -1- (4- trifluoromethylphenyl)-2-pyrazolin-5-one, m.p. 212-216°C. c) A stirred mixture of 3- (2-hydroxy-5-methoxyphenyl) -1-(trifluoromethylphenyl) -2-pyrazolin-5-one (2.0 g) and aqueous hydrobromic acid (48%, 200 ml) was refluxed for two hours. The reaction mixture was hot filtered and the solid collected recrystallised from aqueous industrial methylated spirit to give 1- (4-trifluoro- methylphenyl) -3- (2,5-dihydroxyphenyl)-2-pyrazolinone, m.p. 253-257°C. Example 22 a) A stirred mixture of 4-hydroxy-6-methoxy coumarin (17.1 g) , 4-bromophenylhydrazine (25.0 g) and dry toluene (160 ml) was refluxed for 3 hours. A further portion of the hydrazine (25.0 g) was added and refluxing was continued for a further 3 hours. The reaction mixture was cooled to ambient temperature and the solid collected after filtration digested with boiling dichloromethane and then hot filtered. The filtrate was concentrated, cooled and filtered to give 1-(4-bromophenyl) -3- (2-hydroxy-5-methoxyphenyl) -2- pyrazolin-5-one, m.p. 197-200°C. b) A stirred mixture of 1- (4-bromophenyl)-3- (2-hydroxy-5-methoxyphenyl)-2-pyrazolin-5-one (5.4 g) , aluminium chloride (8.2 g) and dry xylene (60 ml) was heated on a steam bath for 5 'hours, then cooled to ambient temperature and kept at this temperature for 18 hours. The xylene was decanted away to leave a gum which was treated with dilute hydrochloric acid (117 ml) and ice. The solidified gum was collected by filtration and washed with water and petroleum ether (b.p. 60-80°C) . The crude product was purified by flash chromotography on silica using toluene/acetic — 33 — acid (9:1) as appropriate fractions were evaporated to give a solid which was recrystallised from aqueous industrial methylated spirit to give 1-(4-bromophenyl) - 3-(2,5-dihydroxyphenyl)-2-pyrazolin-5-one, m.p. 237-239°C. Example 23 a) A stirred mixture of 4-hydroxy-6-methoxycoumarin (15 g) , 3,4-dichlorόphenylhydrazine (23.8 g) and dry toluene (200 ml) was. refluxed for 5 hours. A further portion of the hydrazine (12.4 g) was added and refluxing continued for a further 3 hours. The reaction mixture was cooled to ambient temperature and the solid collected by filtration digested with dichloromethane and then dried to give 1- (3,4-dichloro- phenyl) -3- (2-hydroxy-5-methoxyphenyl) -2-pyrazolin-5- one, m.p. 210-211°C. b) A stirred mixture of 1- (3,4-dichlorophenyl) -3- (2- hydroxy-5-methoxyphenyl)-2-pyrazolin-5-one (20 g) aluminium chloride (34 g) , and xylene (280 ml) were heated on a steam bath for 6^ hours. The xylene was decanted off and the remaining mixture poured into a mixture of ice and 1M hydrochloric acid with stirring. The mixture was stirred for an hour, stored at ambient temperature for 'a 18 hours, and filtered to give 1- (3,4-dichlorophenyl) -3- (2,5-dihydroxyphenyl) -2- pyrazolin-5-one. Example 24 A stirred mixture of 4-hydroxycoumarin (14.3 g) and 4-chlorophenylhydrazine (18.9 g) in dry toluene (150 ml) was heated under reflux for 2.5 hours with removal of the water produced in the reaction. The mixture was allowed to cool to ambient temperature, then filtered and the solid product collected to give 1-(4-chlorophenyl)-3-(2-hydroxyphenyl)-2-pyrazolin-5- one, m.p. 183-185°C. Examples 25-34 In a similar manner to that described in Example 24, a compound of formula X was prepared by reacting a compound of formula XVI (in which X is oxygen, R g and -R-. are hydrogen and R.. - is as defined) with a compound of formula XV (in which Z is -CH=, R g , is hydrogen and R_ and R_ are as defined) as summarised in Table 2 7 o below. 10 15 Notes (1) The solid collected on filtration was heated with dichloromethane, hot filtered and the solid product was deposited on cooling. (2) Filtrate concentrated under reduced pressure until crystallisation occurred. (3) Dichloromethane extracts evaporated to dryness. (4) The reaction solution was allowed to cool and the solid obtained following evaporation was heated with dichloromethane. (5) Recrystallisation from acetonitrile. (6) The solid collected- on filtration was boiled with industrial methylated spirit/water (3:1), cooled and the solid product collected by filtration. The compounds prepared in the above Examples were as follows:- 25 1-(3,4-dichlorophenyl)-3-(2-hydroxyphenyl)-2- pyrazolin-5-one 26 1-(4-chlorophenyl)-3-(5-fluoro-2-hydroxyphenyl)- 2-pyrazolin-5-one 27 1-(4-bromophenyl)-3-(2-hydroxyphenyl)-2- pyrazolin-5-one 28 1-(4-fluorophenyl)-3-(2-hydroxyphenyl)-2- pyrazolin-5-one 29 l-(4-chlorophenyl)-3-(2-hydroxy-5-methylphenyl)-2- pyrazolin-5-one - 59 - 30 3-(2-hydroxyphenyl)-1-(4-trifluoromethylphenyl)- 2-pyrazolin-5-one 31 3-(2-hydroxyphenyl) -1-(4-me hoxyphenyl)-2- pyrazolin-5-one 32 3-(2-hydroxyphenyl)-1-(4-methylphenyl)-2- pyrazolin-5-one 33 1-(3-chlorophenyl)-3-(2-hydroxyphenyl)-2- pyrazolin-5-one 34 1-(4-chlorophenyl)-3- (2,6-dihydroxyphenyl)-2- pyrazolin-5-one Examp -les 35-43 In a similar manner to that described in Example 24, a compound of formula X was prepared by reacting a compound of formula XVI (in which X is oxygen, R- and R 3 - are hydrogen and R» 0 is as defined) with a compound of formula XV (in which Z is -N= and R 7 , R„ and R fi , are as defined) as summarised in Table 3 below. 10 15 Notes (1) Reactants refluxed in a) ethyl acetate b) xylene c) toluene/ethyl acetate d) toluene (2) Ethyl acetate (50-100% of volume of toluene) added to refluxing mixture after 20 minutes. (3) Recrystallised from ethanol. (4) The reaction mixture was cooled and evaporated. The solid obtained was digested with ethyl acetate and hot filtered. The filtrate was evaporated and the oil obtained purified by flash chromatography on silica using 2% methanol/dichloromethane as the mobile phase. The fractions were combined and evaporated to give a solid which was recrystallised from ethyl acetate. (5) The crude product was boiled with ethanol and filtered twice. (6) A further portion of the hydrazine (2.0 g) was added after 3 hours. (7) The hot reaction mixture was decanted off, concentrated and filtered. The solid collected was suspended in diethyl ether (300 ' 'ml) and extracted with 2.5M sodium hydroxide solution. The extracts were combined, washed with diethyl ether and then acidified' with concentrated hydrochloric acid. The solid product was collected by filtration, washed with water and dried. (8) After refluxing the toluene liquors were evaporated to dryness. The residue was boiled with dichloromethane, hot filtered, and the filtrate concentrated. Cooling and scratching gave the solid product which was collected by filtration. The compounds prepared in the above Examples were as follows:- 35 3-(2-hydroxyphenyl)-1-(5-trifluoromethyl-2- pyridyl)-2-pyrazolin-5-one 36 l-(6-chloro-2-pyridyl)-3-(2-hydroxyphenyl)-2- pyrazolin-5-one 37 1-(5-chloro-2-pyridyl)-3-(2-hydroxyphenyl)-2- pyrazolin-5-one 38 3-(2-hydroxyphenyl)-1-(6-trifluoromethyl-2- pyridyl)-2-pyrazolin-5-one 39 1-(4-chloro-2-pyridyl)-3-(2-hydroxyphenyl)-2- pyrazolin-5-one 40 1-(6-chloro-5-trifluoromethyl-2-pyridyl)-3- (2-hydroxyphenyl)-2-pyrazolin-5-one 41 l-(5-bromo-2-pyridyl)-3-(2-hydroxyphenyl)-2- pyrazolin-5-one 42 1-(5-chloro-2-pyridyl)-3-(2,6-dihydroxyphenyl)- 2-pyrazolin-5-one 43 3-(5-fluoro-2-hydroxyphenyl)-1-(5-trifluoromethyl- 2-pyridyl)-2-pyrazolin-5-one Example 44 A stirred mixture of 4-hydroxythiocoumarin (4.5 g) and 4-trifluoromethylphenylhydrazine (7.0 g) in dry toluene (47 ml) was heated under reflux for 4.5 hours under nitrogen, adding more of the hydrazine (1.5 g) after 2 hours, with removal of the water produced in the reaction. The mixture was allowed to cool to ambient temperature, filtered and the filtrate stored - 63 - at ambient temp'erature for 18 hours. The filtrate was evaporated, the' solid residue dissolved in dichloro¬ methane and the solution washed with water, dried and concentrated and the solid obtained washed with dichloromethane to give 3-(2-mercaptophenyl)-1-(4- trifluoromethylphenyl)-2-pyrazolin-5-one, m.p. 161-164°C. Preparation of ..Novel Compounds of Formula II' Example 45 A stirred mixture of 1-(4-chlorophenyl)-3-(2- hydroxyphenyl)-2-pyrazt>lin-5 '« -one (2.9 g) and tripropyl ortho(propoxycarbonyl)acetate (8.7 g) was heated at 145-150°C for 40 minuses. The mixture was cooled below 100°C and diluted with industrial methylated spirit. The solid produced was collected by filtration to give propyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzo- pyrano[4,3-£]pyrazole-4-acetate, m.p. 138-140°C. Example 46 In a similar manner to Example 45, a mixture of 1-(4-chlorophenyl -3-(2,5-dihydroxyphenyl)-2-pyrazolin- 5-one (6.6 g) and trimethyl ortho(isopropoxycarbonyl)- acetate (21.9 g) was heated at 140°C for 2 hours, then cooled, filtered and the solid product washed with ether to give isopropyl 2-(4-chϊOrophenyl)-8-hydroxy-3- oxo-2,3-dihydro[1 ]benzopyrano[4,3-c_]pyrazole-4-acetate, m.p. 224-225°C. Example 47 A stirred mixture of 1-(4-chlorophenyl)-3-(2- hydroxyphenyl)-2-pyrazolin-5-one (2.9 g) and triethyl ortho(ethoxycarbonyl)acetate (7.0 g) was heated at 130-135°C for 10 minutes, then cooled and diluted with ether. The solid produced was collected by filtration to give ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1 ]- benzopyrano[4,3-£]pyrazole-4-acetate, 159-161 °C. Examples 48-60 In a similar manner to that described in Example 47, a compound of formula II' (in which R g , is hydrogen and R is COOC-H..) was prepared by reacting a compound of formula X (in which Z is -CH=, R ' and R g represent hydrogen and X, R 7 , R g and R, Q are as defined) with triethyl ortho(ethoxycarbonyl)acetate (XI) as summarised in Table 4 below: Table 4 X Amounts of Reactants Heating mp of Notes Time II' (mins) (°C) Example X R_ R Q R. _ X XI 7 8 10 (g) (g) 10 48 0 Cl H 5-OH 5.8 13.5 15 49 0 Cl H 5-F 3.4 7.4 10 50 0 Cl H 5_ H 3 2* 1 6 -° 15 51 0 Cl Cl H 3.8 7.8 10 52 O Br H H . 4.2 8.9 10 15 53 O F H H 1.2 3.1 * 10 54 0 Cl H 6-OH 3.4 7.9 60 55 O CF- H H 3.6 7.9 20 * 56 0 OCH H H 4.8 7.9 15 57 0 CH H H 0.5 1.8 15 20 58 O H Cl H 0.5 1.6 15 59 0 Cl H 6-OCH-, 3.1 9.1 15 3 60 S CF- H H 1.1 2.7 10 Notes on Table 4 (1) Heating temperature = 140-150°C. (2) After dilution with ether and filtration the solid product was stirred with dichloromethane and filtered. The filtrate was evaporated and the solid obtained triturated with ether. (3) After storage for 18 hours a further portion of the ortho ester (5 g) was added and the mixture heated for a further 60 minutes. The mixture was triturated with ether and the solid product collected by filtration. The compounds prepared in the above Examples were:- 48 ethyl 2- (4-chlorophenyl) -8-hydroxy-3-oxo-2,3- dihydro[1 ]benzopyrano[4,3-£]pyrazole-4-acetate; 49 ethyl 2- (4-chlorophenyl) -8-fluoro-3-oxo-2,3- dihydro [1 ]benzopyrano [4,3-£]pyrazole-4-acetate; 50 ethyl 2- (4-chlorophenyl) -8-methyl-3-oxo-2,3- dihydro [1 ]benzopyrano [4,3-£]pyrazole-4-acetate; 51 ethyl 2- (3,4-dichlorophenyl) -3-oxo-2,3-dihydro- [1 ]benzopyrano [4,3-£]pyrazole-4-acetate; 52 ethyl 2- (4-bromophenyl) -3-oxo-2,3-dihydro [1 ]- benzopyrano [4,3-£]pyrazole-4-acetate; 53 ethyl 2- (4-fluorophenyl) -3-oxo-2,3-dihydro[l ]- benzopyrano [4,3-c]pyrazole- * 4-acetate; 54 ethyl 2- (4-chlorophenyl) -9-hydroxy-3-oxo-2,3- dihydro [1 ]benzopyrano [4,3-£]pyrazole-4-acetate; 55 ethyl 3-oxo-2- (4-trifluoromethylphenyl) -2,3- dihydro [1 ]benzopyrano [4,3-cj-pyrazole-4-acetate; 56 ethyl 2- (4-methoxyphenyl) -3-oxo-2,3-dihydro [1 ]- benzopyrano [4,3-£]pyrazole-4-acetate; 57 ethyl 2-(4-methylphenyl)-3-oxo-2,3-dihydro[1 ]- benzopyrano[4,3-£]pyrazole-4-acetate; 58 ethyl 2-(3-chlorophenyl)-3-oxo-2,3-dihydro[1]- benzopyrano[4,3-£]pyrazole-4-acetate; 59 ethyl 2-(4-chlofophenyl)-9-methoxy-3-oxo-2,3- dihydro[T] " benzopyrano[4,3-£]pyrazole-4-acetate; 60 ethyl 3-oxo-2-(4-trifluoromethylphenyl)-2,3- dihydro[1 ]benzothiopyrano[4,3-c]pyrazole-4- acetate Examples 61-65 In a similar manner to that described in Example 47, a compound of formula II' (in which R and R are hydrogen) was prepared by reacting a compound of formula X (in which X is oxygen, Z is -CH=; Ro' and R.y represent hydrogen and R 7 , R_ and R. _ are as defined) with triethyl orthoacetate (XI) as summarised in Table 5 below: 10 (d) = decomposition Notes (1) Heating temperature = 140-150°C. The compounds prepared in the above Examples were:- 61 2-(4-chlorophenyl)-9-methoxy-4-methyl[1]benzo¬ pyrano[4,3-£]pyrazol-3(2H)-one; 62 2-(4-chlorophenyl)-8-hydroxy-4-methyl[1 ]benzo¬ pyrano[4,3-c]pyrazol-3 (2H)-one; * 63 2-(3,4-dichlorophenyl)-8-hydroxy-4-methyl[1 ]benzo- pyrano[4,3'-c]pyrazol-3(2H_)-one; 64 2-(4-bromophenyl)-8-hydroxy-4-methyl[1 ]benzo¬ pyrano[4,3.-£]pyrazQ.l-3 (2H)-one; 65 8-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)- [1 ]benzopyrano[4,3-£]pyrazol-3 (2H)-one; Example 66 A mixture of 2.-.(4-chlorophenyl)-9-methoxy-4- methyl[1 ]benzopyrano[4,3-£]pyrazol-3 (2H)-one (0.5 g) and aluminium chloride (0.78 g)in dry xylene (4.8 ml) was placed in a preheated oil bath at 100-110°C for 35 minutes. On cooling, 2M hydrochloric acid (10 ml) and ice were added to the reaction mixture. The yellow solid obtained was collected by filtration to give 2-(4-chlorophenyl)-9-hydroxy-4-methyl[1 ]benzopyrano- [4,3-£]pyrazol-3(2H)-one, m.p. 2 * 13-215°C. Example 67 A solution of 3,4-dichlorophenylhydrazine (3.2 g) in xylene (75 ml) was added to a mixture of methyl 6-methoxy-3-methyl-4-oxo-3-thiochromancarboxylate (2.0 g) and p-toluenesulphonic acid (0.4 g) in xylene (50 ml) . The mixture was boiled under reflux for 22 hours, under nitrogen, with removal of the water formed in the reaction. The mixture was cooled and evaporated under reduced pressure. The residue was separated twice by flash chromatography on silica using firstly dichloromethane as the mobile phase and then dichloromethane/petroleum ether (b.p. 40-60°C, 1:1). The oil obtained was crystallised from propan-2-ol to give 2-(3,4-dichlorophenyl)-8-methoxy-3a-methyl-3a,4- dihydro.1]benzothiopyrano[4,3-£]-pyrazol-3 (2H)-one, m.p. 73-76°C. Examples 68-71 In a similar method to that described in Example 67, a compound of formula I' (in which X is sulphur, Z is -CH=, Rg is hydrogen and R 1QI is 8-methoxy) was prepared by reacting a compound of formula XIV (preparative example of starting compound provided) with a compound of formula XV (in which R 0 o > represents hydrogen and 7 and R are as defined) , as summarised in Table 6 below. In each case 0.4 g p-toluenesulphonic acid was used in the reaction. of Notes Ex Ex. of XV Starting R_ R, Compound XIV 10 68 147-148 (la) (2) 69 147-149 (1a) (2) 70 174-176 (1b) (2) 71 190-191 (la) (3) 15 (4a) 71a 192-193 (4b) (la) Notes (1) Single flash chromatographic purification process using as the mobile phase:- a) dichloromethane b) dichloromethane/methanol (99.5:0.5) (2) Recrystallised from isopropyl alcohol. (3) 0.2 g p-toluenesulphonic acid used. (4) The reaction mixture was filtered and the filtrate was:- a) concentrated to give a solid which was crystallised from methanol; or b) evaporated to give a solid which was crystallised from methanol followed by flash chromatography. The compounds prepared in the above Examples were as follows:- 68 8-methoxy-3a-methyl-2-(4-trifluoromethylphenyl)- 3a,4-dihydro[1]benzothiopyrano[4,3-£]pyrazol-3- (2H)-one 69 2-(4-chlorophenyl)-8-methoxy-3a-methyl-3a,4- dihydrofl]benzothiopyrano[4,3-£]pyrazol-3 (2H)- one 70 2-(4-fluorophenyl)-8-methoxy-3a-methyl-3a,4- dihydro[1]benzothiopyrano[ %3-£]pyrazol-3 (2H)- one 71 8-methoxy-4-methyl-2-(4-trifluoromethylphenyl)- [1]benzothiopyrano[4,3-£]pyrazol-3 (2H)-one Example 72 Boron tribromide (21.4 ml), (1M solution in dichloromethane) was added dropwise to a mixture of 8-methoxy-3a-methyl-2-(4-trifluoromethylphenyl)-3a,4- dihydro[1 ]benzothiopyrano[4,3-£]pyrazol-3 (2H)-one (4.2 g) in dry dichloromethane (80 ml) at -70°C with stirring • under nitrogen. The mixture was stirred at ambient temperature for 1 hour. The reaction mixture was poured onto methanol (800 ml) followed by evaporation under reduced pressure. The oil obtained was dissolved in ethyl acetate, washed with water and then aqueous sodium bicarbonate solution (10%), and the ethyl acetate layer dried and evaporated. The solid was recrystallised from ethyl acetate/petroleum ether (b.p. 40-60°C) to give 8-hydroxy-3a-methyl-2-(4- trifluoromethylphenyl)-3a,4-dihydro[1]benzothiopyrano- [4,3-£]pyrazol-3-(2H)-one, m.p. 211-213°C. Examples 73-76 In a similar manner to that described in Example 72, a compound of formula I' (in which X is sulphur, Z is -CH=, Rg is hydrogen and R-. Q 1 is 8-hydroxy) was prepared from a compound of formula I' (in which R. _' is 8-methoxy- preparative example of starting compound provided) as summarised in Table 7 below. In Example 76a a further portion of boron tribromide was added to the reaction mixture cooled to -70°C, as shown in the Table. 10 15 Notes (1) A further portion of BBr. (5.5 ml) was added after 18 hours. The residue obtained after treatment with methanol and recrystallisation from ethyl acetate and sodium bicarbonate was separated by flash chromatography on * s*ilica using dichloromethane as the mobile phase to give a solid which was recrystallised from ether/petroleum ether (b.p. 40-60°C) . (2) A further portion of BBr 3 (5.2 ml) was added after 2 hours . (3) The solid produced on pouring the reaction mixture on to methanol was filtered and dried to give the product. The compounds prepared in the above Examples were as follows:- 73 2- (3,4-dichlorophenyl) -8-hydroxy-3a-methyl-3a, 4- dihydro[1 ]benzothiopyrano [4,3-£]pyrazol-3 (2H) -one; 74 2- (4-chlorophenyl) -8-hydroxy-3a-methyl-3a,4- dihydro [1 ]benzothiopyrano [4,3-c]pyrazol-3- (2H)-one; 75 2- (4-fluorophenyl) -8-hydroxy-3a-methyl-3a,4- dihydro[l ]benzothiopyrano [4,3-c]pyrazol-3- (2H)-one; 76 8-hydroxy-4-methyl-2- (4-trifluoromethylphenyl) - [1 ]benzothiopyrano [4,3-£]pyrazol-3 (2H)-one; Preparation of Novel Compounds of Formula I Examples 77-90 In a similar manner to that described in Example 47, a compound of formula I was prepared by reacting a compound of formula X (in which X is oxygen, Z is -N=, R q is hydrogen, and R 7 , R g , R g , and R. _ are as defined) with triethyl orthoacetate (XI) as summarised in Table 8 below: Notes (1) Heating temperature = 140-150°C (2) Recrystallised from ethanol/dichloromethane (3) The crude product was purified by flash chromatorgraphy on silica using a 4% solution of methanol in dichloromethane. The extracts were combined, triturated with dichloromethane/petroleum ether (b.p. 40-60°C) and then acetone and then dried under reduced pressure to give the product. (4) A further portion of the orthoacetate (7.2 ml) was added after 5 minutes. The solid produced from the reaction mixture was triturated with industrial methylated spirit. Example 87 In a similar manner to that described in Example 47, a stirred mixture of 1- (5-chloro-2-pyridyl) -3- (2- hydroxyphenyl)-2-pyrazolin-5-one (1.4 g) and trimethyl ortho(methylthio) acetate (2.5 ml) was heated at 140-145°C for 10 minutes, then cooled and triturated with industrial methylated spirit, to give 2- (5- chloro-2-pyridyl)-4-methylthiomethyl [1 ]benzopyrano- [4,3-£]pyrazol-3 (2H)-one, m.p. 217-219°C. Example 88 In a similar manner to that described in Example 47, a stirred mixture of 1- (5-chloro-2-pyridyl)-3- (2- hydroxyphenyl)-2-pyrazolin-5-one (3.0 g) and triethyl ortho(ethoxycarbonyl) cetate (7.3 g) was stirred at 140-145°C for 45 minutes, adding further portions of the ortho ester (2 x 3.7 g) , after 15 and 30 minutes. The reaction mixture was cooled and triturated with ether. The solid obtained was dissolved in methylene chloride and passed down a Florisil® column eluting with methylene chloride . " The eluant was evaporated and the residue triturated with ether to give ethyl 2-(5-chloro-2-pyridyl)-3-oxo-2,3-dihydro[1 ]benzo¬ pyrano[4,3-c]pyrazol#-4-acetate, m.p. 152-154°C. Example 89 Acetyl chloride (0.5 ml) was added dropwise to a stirred mixture of 2-(5-chloro-2-pyridyl)-9-hydroxy-4- methyl[1]benzopyrano,[4,3-£]pyrazol-3(2H)-one (2.0 g) , dry tetrahydrofuran (30 ml) and triethylamine (1.0 ml) at 0°C. The mixture was allowed to warm to ambient temperature and then stirred for 2,5 hours. A solid was collected on filtration which was washed with water and triturated with hot ethanol then dried to give 2-(5-chloro-2-pyridyl)-4-methyl-3-oxo-2,3-dihydro[1]- benzopyrano[4,3-£]pyrazol-9-yl acetate, m.p. 252-255°C. Example 90 A stirred mixture of ethyl 2-(5-chloro-2-pyridyl)- 3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4- acetate (1.4 g) and cyclobutylmethanol (3.5 ml) was heated at 150°C for 1 hour. The reaction mixture was allowed to cool to ambient temperature, triturated with ether and the solid product collected by filtration and washed with ether to give cyclobutylmethyl 2-(5-chloro- 2-pyridyl)-3-oxo-2,3-dihydro[1 ]benzopyrano[4,3-£]- pyrazole-4-acetate, m.p. 157-160°C. Example 91 A mixture of propyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate (1.9 g) and 2-piperidinoethanol (6.4 ml) was stirred at 150°C for 1 hour. The reaction mixture was cooled to room temperature and poured on to water (30 ml) . This mixture was extracted with dichloromethane and the combined organic extracts were washed well with water, dried and evaporated. The residual oil was dissolved in absolute ethanol and treated with ethanolic hydrogen chloride. The solid formed on cooling and scratching was collected by filtration and dried giving 2- piperidinoethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro- [1 ]benzopyrano[4,3-£]pyrazole-4-acetate hydrochloride, m.p. 193-197°C (with decomposition). Examples 92-100 In a similar manner to that described in Example 91, a compound of formula I was prepared by reacting a compound of formula II' (the Example for the preparation of the starting ester is provided) with the appropriate alcohol as summarised in Table 9 below. 10 15 20 Notes (1) Product converted into its free-base using triethylamine and purified by flash chromatography on silica using dichloromethane/methanol (9:1) as the mobile phase. (2) After heating at 150°C for 15 minutes, the reaction mixture was diluted with dichloromethane (100 ml) and washed with water. The solid product which separated was collected by filtration. (3) Product softens at 55°C. Example 101 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3- dihydrofl]benzopyrano[4,3-c]pyrazole-4-acetate (3.0 g) and 4-methoxybenzyl alcohol (9.6 ml) was stirred at 150°C for 50 minutes. The reaction mixture was cooled to ambient temperature, diluted with ether and the product collected by filtration to give 4-methoxybenzyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro-[1 ]benzopyrano- [4,3-£]pyrazole-4-acetate, m.p. 152-155°C. Examples 102-134 In a similar manner to that described in Example 101, a compound of formula I was prepared by reacting ethyl 2-(4-chlorophenylH3-oxo-2,3-dihydro-[1]- benzopyrano[4,3-£]pyrazole-4-acetate (II') with the appropriate alcohol, as summarized in Table 10 below. Table 10 Ex Alcohol Amount of Reactants Time m -P- of Notes Ester Alcohol (mins) I (g) (ml) (°C) II' 102 PhCH 2 OH 0 8.1 70 165 ■ 166 10 103 Ph(CH_) _OH p 6.4g 80 153 ■ 156 104 (cyclopentyl)OH 0' 4..8 - 80 169 ■ 172 105 CH 3 OCH 2 CH 2 OH 0 40 60 125 ■ 126 (la) 106 (2-thienyl)CH 2 $H 2 OH 0 t 9.0g 360 122 • 123 (la) (2a) (3a) 107 (cyclobutyl)CH 2 OH 0 5.0 120 138 ■ 139 (4a) IS. 10*8 (2-pyridyl)CH 2 CH 2 OH 0 " 6.0 15 124 •127 (5) 109 (cyclobutyl)OH 1 4.0g 105 148 ■ 150 (4a) 110 CH 3 0(CH 2 ) 2 0(CH 2 ) 2 OH 0 6.2 105 104 ■ 106 (4a) 111 (2-tetrahydrofuryl)CH 2 OH 0 5.0 150 133 • 136 (1c) (4a) 112 (4-tetrahydropyranyl) OH 0 7.2 300 189 • 190 (4a) 20 113 (4-methyl-5-thiazolyl)CH 2 CH 2 OH 0 6.2 270 134 • 136 (1c) (4a) Table 10 cont'd Ex Alcohol Amount of Reactants Time m.p. of Notes Ester Alcohol (mins) I ( g ) (ml) <°C) II' 3-methoxybenzy1)OH 10 4-methylbenzyl)OH 4-methoxyphenethyl)OH 4-chlorophenyl)CH 2 CH 2 OH 2-chlorophenyl)CH 2 OH acetyl)CH 2 CH 2 OH 15 2-chlorophenyl)CH 2 CH 2 OH 3-methylpheny1)CH 2 CH 2 OH cyclohexyl)OH 3-chlorophenyl)CH 2 OH ,3-propanediol 20 Table 10 Cont'd Ex Alcohol Amount of Reactants Time 5^ of Notes Ester Alcohol (mins) I II' (°C) (g) (ml) 125 (phenoxy)CH 2 CJH 2 OH 1.4 4.4 60, 122 (2b) (1e) 10 126 (4-dimethylaminophenyl)CH CH 2 0H 1.2 2.5 15 192-194 (6a) 127 (acetylamino)CH 2 CH 2 OH 1.5 3.6 40 183-186 (Id) (4c) 128 (3-methylphenyl)CH 2 OH 1.1 3.5g 180 149-153 (6a) 129 (2-methylphenyl)CH 2 OH 1.1 3.5g 150 148-150 (6a) 130 (4-chlo * ophenyl)CH 2 OH 1.0 3.7g 210 171-173 (3b) (7b) 15 131 (2-methoxyphenyl)CH 2 OH 1.0 3.6g 180 165-167 (3b) (6a) 132 (3-pyridyl)CH 2 CH 2 CH 2 OH 1.5 5.1 15 117-119 (lb) (lb) (12) 133 (benzyl)CH(CH 3 ) OH 2.0 3.7 600 110-113 (2a) (3c) (4b) 2.0 300 134 (cyclopropyl) CH 2 OH 2.0 4.0 90 162-165 20 Notes (1) The cooled reaction mixture:- a) yielded a solid which was collected by filtration; b) yielded a solid which was triturated with toluene and ether; c) was dissolved in dichloromethane, washed with water, dried and evaporated; d) was dissolved in dichloromethane, washed with water, dried and evaporated and the resulting gum triturated with ether; e) was poured into water, the solid collected by filtration. (2) The product was recrystallised from:- a) acetonitrile; b) ethyl acetate. (3) The reaction mixture was heated at:- a) 120°C; b) 150-160°C; c) 180°C; d) 214°C. (4) The crude product was purified by flash chromo- tography on silica using, as a mobile phase:- a) toluene/acetic acid (9:1); b) toluene; c) ethyl acetate/acetic acrid (9:1). The fractions obtained were evaporated and triturated with ether to give the product. (5) The cooled reaction mixture was dissolved in dichloromethane and washed with water. After drying and concentration, the mixture was purified on a Florisil® column using dichloromethane containing increasing amounts of acetone (from 1 to 10%) as the mobile phase. The material obtained was triturated with ether to give the product. (6) The reaction mixture was cooled to about 90°C then diluted with:- a) industrial methylated spirit; b) absolute ethanol. The product was collected by filtration. Examples 135-141 In a similar manner to that described in Example 101, a compound of formula I was prepared by reacting a compound of formula II' (the Example for the preparation of the starting ester is provided) with the appropriate alcohol as summarized in Table 11 below. Table 11 Amount of Time m.p. of Notes Reactants I Example Ex. of Alcohol Ester Alcohol (mins) (°C) Starting II' Ester ( g ) (ml) II' 10 135 00 CO 136 137 138 15 139 140 (1) 141 - 89 - Notes (1) Cycle included 6 hours refluxing and 140 hours storage at ambient temperature. A further portion of the alcohol (2 g) wajs added after 13 hours refluxing. Examples 142 and 143 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1]benzopyrano[4,3-£]pyrazole-4-acetate (2.0 g) , 1 ,2-ethanedrol acetate (2.0 ml, c_a 1:1 mixture of the mono and diacetate) , N-methylmorpholine (0.6 ml) and dry xylene (20 ml) was heated under reflux for 6 hours. The mixture was evaporated under reduced pressure - and " tne residue separated by flash chromatography on * silica using toluene/acetic acid (9:1) as the mobile phase. This gave 2-acetoxyethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro-[1 ]benzopyrano [4,3-£]pyrazole-4-acetate (Example 142 m.p. 136- 139°C, and 2-hydroxyethyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1]benzopyrano[4,3-£]pyrazole-4-acetate (Example 143), m.p. T61-l£Z β C. - . >*tt Example 144 : A mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3- dihydro[1 ]benzopyrano[4,3-£]pyrazole-4-acetate (2.0 g) , 4-(2-hydroxyethyl)thiomorpholine (1 g) , dry xylene (20 ml) and N-methy morpholine (0.6 ml) containing 4A molecular sieves was stirred and heated at 15.0°C for 3 hours. More 4-(2-Hydroxyethyl)thiomorpholine (1.0 g) was added and heating was continued for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate. After decanting from the molecular sieves, the solution was washed with water, dried and evaporated under reduced pressure. The residual gum was dissolved in ethanol, treated with ethanolic hydrogen chloride and then cooled to 0°C. The solid formed was collected by filtration and dried to give 2-thiomorpholinoethyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1 ]benzopyrano[4,3-£]pyrazole-4-acetate hydrochloride, m.p. 223-226°C. Example 145 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1]benzopyrano[4,3-£]pyrazole-4-acetate (2.00 g) , 2-methylthioethanol (0.5 ml), N-methyl- morpholine (0.6 ml) and dry xylene (40 ml) was stirred at 170°C for 5 hours. The mixture was evaporated under reduced pressure and the residue recrystallised twice from acetonitrile to give 2-methylthioethyl 2-(4- chlorophenyl)-3-oxo-2,3-dihydro-[1]benzopyrano[4,3-c] pyrazole-4-acetate, m.p. 113-114°C. Example 146 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3- dihydrojH ]benzopyrano[4,3-£]pyrazole-4-acetate (2.0 g) , 4,4,4-trifluorobutanol (1.3 g) , N-methyl-morpholine (0.6 ml) and dry xylene (40 ml) was stirred and boiled under reflux or 5 hours. More xylene (10 ml) and more 4,4,4-trifluorobutanol (1.5 g) were added. The mixture was boiled under reflux for a further 2 hours and then evaporated under reduced pressure. The solid residue was recrystallised twice from acetonitrile to give 4,4,4-trifluorobutyl 2-(4-chlorophenyl)-3-oxo-2,3- dihydro[1]benzopyrano[4,3-£]pyrazole-4-acetate, m.p. 114-115°C. Example 1 7 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1]benzopyrano[4,3-£]pyrazole-4-acetate (2.0 g) , 2-cyanoethanol (0.4 ml), N-methylmorpholine (0.6 ml) and molecular sieves (20 pieces) was stirred in dry xylene (40 ml) at 170°C for 5 hours. More 2-cyanoethanol (0.4 ml) was added and the mixture was stirred at 170°C for 18 hours. The mixture was evaporated under reduced pressure and the residual oil purified on a short Florisil column using dichloro¬ methane as the mobile phase. The material obtained was separated using flash chromatography on a- silica column using toluene/acetic acid (9:1) as the mobile phase. The material obtained after removal of the solvent was triturated with petroleum ether (b.p. 60-80°C) and filtered to give 2-cyanoethyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1]benzopyrano[4,3-£]pyrazole-4-acetate, m.p. 120-122°C. Example 148 In a similar manner to Example 145, a mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzo¬ pyrano[4,3-£]pyrazole-4-acetate (2.0 g) , ethyl 3- hydroxypropionate (1.2 ml), N-methylmorpholine (0.6 ml) and dry xylene (40 ml) was heated at 170°C for six hours to give, after flash chromatography on silica using toluene/acetic acid (9:1) as the mobile phase, 2-ethoxycarbonylethyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1]benzopyrano[4,3-£]pyrazole-4-acetate, m.p. 126-129°C. Example 149 In a similar manner to- Example 145, a mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzo- pyrano[4,3-£]pyrazole-4-acetate (1.1 g) , 2-phenyl-1- propanol (0.4 ml) and N-methylmorpholine (0.3 g) in dry xylene (3 ml) was stirred and boiled under reflux for 15 hours, adding more 2-phenyl-l-propanol (0.2 ml) and N-methylmorpholine (0.2 ml) after 14 hours. The reaction mixture was cooled, the solid collected by filtration and recrystallised from acetonitrile to give 8-methylphenethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro- [1]benzopyano[4,3-£]pyrazole-4-acetate, m.p. 86-90°C. Example 150 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3- dihydro[l]benzopyrano[4,3-£]pyrazole-4-acetate (2.0 g) , cyclohexylethanol (0.7 ml), N-methylmorpholine (0.6 ml) and xylene (40 ml) was heated under reflux for.6 hours. A further portion of cyclohexylethanol (0.7 ml) was added and the mixture heated under reflux for a further 3 hours. The mixture was evaporated under reduced pressure and the residue recrystallised twice from acetonitrile to give 2-cyclohexylethyl 2-(4-chloro- phenyl)-3-oxo-2,3-dihydro[1]-benzopyrano[4,3-£]- pyrazole-4-acetate, m.p. 149-151 °C. Example 151 A solution of ethyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1]benzopyrano[4,3-£]pyrazole-4-acetate (1.0 g) , 1-methyl-2-morpholinoethanol (0.8 ml) and dry toluene (10 ml) was stirred and heated under continuous distillation for 9 hours with addition of fresh toluene to maintain the initial volume. More 1-methyl-2- morpholinoethanol (0.8 ml) was added and heating/- distilling continued for 7 hours. More l-methyl-2- morpholinoethanol (0.8 ml) was added and the mixture heated for a further 5 hours. The reaction mixture was cooled to 0°C and the solid obtained collected by filtration, washed with ether and dried to give 1-methyl-2-morpholinoethyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 176-179°C. Example 152 In a similar manner to Example 151, a mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzo¬ pyrano[4,3-£]pyrazole-4-acetate (1.0 g) , (1-methyl-2- piperidyl)methanol (0.7 ml) and toluene (15 ml) gave, after flash chromat graphy, 1-methyl-2-piperidylmethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1 ]benzopyrano- [4,3-£]pyrazole-4-acetate, m.p. 159-163°C. Example 153 A stirred suspension of 2-morpholinoethyl 2-(4- chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-£]- pyrazole-4-acetate hydrochloride (1.5 g) in absolute ethanol (50 ml) at 0-5°C was treated portionwise with sodium borohydride (0.6 g) . The reaction mixture was stirred for 4 hours at this temperature with 3 further portions of sodium borohydride (0.28 g, 0.28 g, 0.14 g) added after 1 hour, 3 hours and 3.5 hours respectively. The reaction mixture was poured onto water, cooled to 0-5°C and neutralised with glacial acetic acid. The aqueous layer was extracted with dichloromethane. The extracts were washed, dried and evaporated to give 2-morpholino-ethyl 2-(4-chlorophenyl)-3-oxo-l ,2,3,4- tetrahydro[1 ]-benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 125-128°C. Example 154 Acetyl chloride (2.3 ml) and triethylamine (1.1 ml) were added to a solution of 3-hydroxypropyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano- [4,3-£]-pyrazole-4-acetate in dichloromethane (75 ml) (Example 124) at 0°C. The reation mixture was stirred at room temperature for 18 hours, then washed, dried, filtered and the filtrate evaporated. The residual mixture was passed down a Florisil® column using dichloromethane as the mobile phase. The required fractions were combined and evaporated. The crude product was purified by flash chromatography on silica using ethyl acetate as the mobile phase. The product was, recrystallised from ethyl acetate to give 3-acetoxypropyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro- [1]benzopyrano[4,3-£]pyrazole-4-acetate, m.p. 129-131°C. Example 155 A stirred mixture of ethyl 2-(4-chlorophenyl)-3- oxo-2,3-dihydro[1]benzopyrano[4,3-£]pyrazole-4-acetate (1.9 g) (Example 47), N-methylaniline (0.5 g) and xylene (15 ml) was heated under reflux for 22 hours. More N-methylaniline .(0.3 g) was added and the mixture heated under reflux for a further 5 hours. The mixture was cooled and scratched. The solid formed was collected by filtration and dried to give 2-(4-chloro- phenyl)-N-methyl-3-oxo-2,3-dihydro[1]benzopyrano- [4,3-£]pyrazole-4-acetanilide, m.p. 200-202°C. Examples 156-170 In a similar manner to. that described in Example 155, a compound of formula I was prepared by reacting a compound of formula II* (the Example for the preparation of the starting ester is provided) with the appropriate amine as summarised in Table 12 below. Table 12 10 15 20 Table 12 cont'd Example Amount of Reactants of Ex starting Amine Ester Amine Xylene Time m.p. Notes ester II' (g) (g) (ml) (hours) 166 47 (4-chlorophenyl)NHCH. 1.9 10 167 53 (benzyl)NHCH 3 1.5 168 47 CH NHCH (1 ,3-dioxolan-2-yl 2.0 (5) 169 47 (4-methoxycarbonylphenyl)- 1.2 NHCH., - 97 - Notes (1) The solid was recrystallised from acetonitrile. (2) The reaction " mixture was evaporated under reduced pressure and • the residue recrystallised from dichloromethane/industrial methylated spirit (33:1). (3) The solid obtained was collected by filtration then dissolved" ' in dichloromethane, filtered and industrial- methylated spirit added to the filtrate. The' solution was concentrated under reduced pressure cooled and the solid collected by filtration. (4) The solid was recrystallised from acetone. #,, (5) The reaction mixture was evaporated and the residue was recrystallised from acetonitrile. (6) Softened at 158°G. ft f Example 170 a) A mixture of propyl 2-(4-chlorophenyl)-3-oxo-2,3- dihydro[l]benzopyrano[4,3-c]pyrazole-4-acetate (1.9 g) (Example 45) and 1-piperazineethanol (5.9 ml) was stirred and heated at 150°C for 1.5 hours. The mixture was cooled to ambient temperature, diluted with water and extracted with dichloromethane. The combined organic extracts were washed with water, dried and evaporated. The residue was dissolved in ethanol and treated with ethanolic hydrogen chloride. The solid formed on cooling and scratching was collected by filtration to give 2-(4-chlorophenyl)-N,N-[3-(2- hydroxyethyl)-3-azapentamethylene]-3-oxo-2,3-dihydro- [1 ]benzopyrano[4,3-c]pyrazole-4-acetamide hydrochloride, 200-205°C (with decomposition) . b) A solution of 2-(4-chlorophenyl)-N,N-[3-(2- hydroxyethyl)-3-azapentamethylene]-3-oxo-2,3-dihydro [1 ]benzopyrano[4,3-£]pyrazole-4-acetamide hydrochloride (0.7 g) in dichloromethane (28 ml) was cooled to 0°C with stirring and treated with triethylamine (0.42 ml) followed by acetyl chloride (0.14 ml). The mixture was stirred in an ice-bath for 2 hours. More acetyl chloride (0.07 ml) was added and the mixture stirred at 0°C for a further 30 minutes then left at 0°C overnight. The mixture was washed with water, then dried and evaporated under reduced pressure. The solid obtained was triturated with ether and the solid formed collected by filtration and dried to give 2-[4-[2-(4- chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-£]- pyrazole-4-acetyl]piperazin-l-yljethyl acetate, m.p. 162-166°C. - - Example 1 7 A stirred mixture of 2-(4-chlorophenyl)-N,N- [3-(2-hydroxyethyl)-3-azapentamethylene]-3-oxo-2,3- dihydro[1 ]benzopyrano[4,3-£]pyrazole-4-acetamide hydrochloride (0.8 g) (Example 170a) and dichloro¬ methane (45 ml) was treated with triethylamine (0.5 ml) followed by propionyl chloride (0.3 ml) at 0°C. The reaction mixture was stirred at this temperature for 3.5 hours. The mi-xture was washed with water then dried and evaporated under reduced pressure. The solid obtained was triturated with ether and the solid formed collected by filtration and dried to give 2-(4-[2-(4- chlorophenyl) ,3-dihydro[1]benzopyrano[4,3-£]- pyrazole-4-acetyl]piperazine-l-yl)ethyl propionate, m.p. 173-175°C. Example 172 A stirred a mixture of ethyl 3-oxo-2-(4-tri- fluoromethylphenyl) - ,3-dihydro[1]benzothiopyrano- [4,3-£]pyrazol-4-acetate (0.9 g) (Example 60), morpholine (0.4 ml) and dry xylene (3.5 ml) was heated under reflux for 2.3 hours. The reaction mixture was allowed to cool to ambient temperature and the solid collected by filtration was washed with xylene and ether and then dissolved in dichloromethane. The solution was washed with water, dried, evaporated and triturated with ether with scratching. The solid product was collected by filtration to give N,N-(3- oxapentamethylene)-3-oxo-2-(4-trifluoromethylphenyl)- 2,3-dihydro[1 ]benzothio-pyrano[4,3-£]pyrazole-4- acetamide, m.p. 210,-212°C. Example 173 A stirred mixture of ethyl 3-oxo-2-(4-tri- fluoromethylphenyl)-2,3-dihydro[1]benzothiopyrano- [4,3-£]pyrazol-4-acetate (0.6 g) , (Example 60) N-ethyl- aniline (0.4 ml) and dry xylene (2.4 ml) was heated under reflux for 4 hours. A further portion of N- ethylaniline (0.1 ml) was added and the reaction mixture refluxed for a further 2 hours. The reaction mixture was stored at ambient temperature for 72 hours and a further portion N-ethy1aniline (0.2 ml) added with refluxing for a further 3 hours. The solid product was collected by filtration, washed with xylene and ether to give N-ethyl-3-oxo-N-phenyl-2-(4-tri- fluoromethylphenyl)-2,3-dihydro[1]benzothiopyrano- [4,3-£]pyrazol-4-acetamide, m.p. 179-181 °C. Example 174 A mixture of l-(4-chlorophenyl)-3-(2-hydroxy- phenyl)-2-pyrazolin-5-one (17.0 g) and methyl 4-(2,2- dimethyl-4,6-dioxo-l ,3-dioxan-5-yl)-4-oxobutyrate (30.0 g) (Example 4) was stirred and heated under reflux in xylene (200 ml) under nitrogen for 6 hours. The mixture was cooled to ambient temperature, the solvent evaporated and the resulting solid recrystallised from propan-2-ol to give methyl 5-[2-(4- chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-£]- pyrazol-4-yl]-4-oxopentanoate, m.p. 142-143°C. Examples 175-186 In a similar manner to that described in Example 174 a compound of formula I was prepared by reacting a compound of formula X (in which X is oxygen, Z is -CH= and R 0 ' and R Q are hydrogen, and R_, R. and R.. are as o y 7 o 10 defined) with a compound of formula Xllb (the Example for the preparation of the starting compound Xllb is provided) as summarised in Table 13 below: Table 13 X Amounts of Reactants Reaction m.p. of Time I Notes 10 15 20 Notes (1) After removal of the solvent, the resultant oil was taken up in propan-2-ol. The solution was treated with charcoal, hot filtered and the filtrate concentrated. The resulting solid was collected by filtration, washed with ether and recrystallised from propan-2-ol. (2) Recrystallised from industrial methylated spirit. (3) Recrystallised from methanol. (4) On cooling the reaction mixture the solid product was filtered off. (5) Solid triturated with ether, filtered, washed and dried to give product. (6) On evaporation of the reaction mixture and scratching a solid was produced which was triturated with hot industrial methylated spirit, washed and dried to give the product. (7) Solid product obtained on filtration after cooling the reaction mixture to room temperature. (8) Reaction mixture allowed to cool to ambient temperature and kept at this temperature for 18 hours. After decanting off the solution, cooling and scratching gave the solid product. (9) Allowed to cool to ambient temperature over 18 hours. The solid collected by filtration was" recrystallised from ethyl acetate with hot filtration. Example 187 A stirred mixture of 2-(4-chlorophenyl)-9-hydroxy- 4-methyl [1 ]benzopyrano[4,3-c]pyrazol-3 (2H)-one (2.0 g) (Example 66), triethylamine (1 . 4 g) and dichloromethane (20 ml) was cooled in an ice bath while methyl malonyl chloride (1.5 ml) was„. added. More dichloromethane (20 ml) was added and the mixture allowed to warm up to ambient temperature over 18 hours. The mixture was filtered and the residue washed with dichloromethane and then water. This residue -was recrystallised from acetonitrile to give 2-(4-chl ' orophenyl)-4-methyl-3-oxo- 2,3-dihvdro[1 ]benzopyrano[4,3-£]pyrazol-9-yl methyl malonate, m.p. 204-206°C. Examples 188-206 In a similar manner to "that described in Example 187, a compound of formula I was prepared by reacting 2-(4-chlorophenyl)-8-hydroxy-4-methyl[1 ]benzopyrano- [4,3-c]pyrazol-3 (2H)-one (Example 62) with the appropriate acyl chloride (R.-COC1) as summarised in Table 14 below. Table 14 Cont'd Amounts of Reactants Example R 17 f Notes 203 cyclopentane 1.5 1.3g 1.5 208-209 (2) (3) 10 204 cyclohexane 1.5 1.4 1,5 230-231 (2) (3) 205 3-methylphenyl 1.5 1.3 1.5 238-241 206 4-pyridyl 1.5 1.6 1.3 236-238 (4) Notes (1) Filtrate evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed and dried and then loaded on to a Florisil® column. The product was obtained on elution with dichloromethane. (2) Reaction mixture washed, dried and evaporated. (3) Residue washed, triturated with ether and filtered to give the solid product. (4) Pyridine (0.4 ml) was included with the starting materials in the reaction mixture. On filtration, the solid collected was triturated with triethylamine/water (1:6), filtered and washed with isopropanol and ether to give the product. (5) The product obtained on evaporating off the solvent, was heated in boiling ethyl acetate. (6) The solid collected after filtration was triturated with water/triethylamine (6:1) , then filtered to give the product. Examples 207-220 In a similar manner to that described in Example 187 a compound of formula I as^prepared by reacting a compound of formula II' (the Example for the preparation of the starting ester is provided) with the appropriate acyl chloride (R.-COCl) as summarised in Table 15 below. Table 15 Amount of Reactants 10 C - 15 20 Table 15 cont'd Amount of Reactants Example of Notes 10 15 Notes (1) The reaction mixture Was evaporated to dryness and the solid triturated with ethyl acetate and filtered. The solid collected was recrystallised from industrial methylated spirit. (2) The reaction mixture was washed with water and evaporated to dryness * . (3) The product obtained was triturated with ether. (4) Further portions of acyl chloride (0.2 ml) and triethylamine (0.3 ml)were added after twelve hours and the reaction mixture stirred' for a further three hours at ambient temperature. The reaction mixture was washed, dried and concentrated to give a solid. (5) The solid 'was purified by flash chromatography on silica using dichloromethane as the mobile phase. The product was recrystallised "from ethyl acetate. (6) The solid was washed with aqueous triethylamine and filtered and washed with water, isopropyl alcohol and ether. (7) The solid product was recrystallised from ethyl acetate. ' * » (8) The reaction mixture was filtered and the product was recrystallised from dioxan . (9) The reaction mixture was added to ether, filtered and the filtrate evaporated to dryness and recrystallised from industrial methylated spirit. (10) The reaction mixture was washed with dilute hydrochloric acid, water, then dried and evaporated. The solid obtained was recrystallised from propan-2-ol. (11) Recrystallised from acetonitrile. (12) Further portions of acyl chloride (0.6 ml) and triethylamine (0.6 ml) were added after 20 hours. An oil obtained on evaporating off the solvent was dissolved in dichloromethane, washed with dilute hydrochloric acid and water, dried and evaporated to give a gum which yielded the product on trituration with ether. (13) Compound softens at 129°C. Example 221 A solution of 2-(4-chlorophenyl)-8-hydroxy-4- methyl[1]benzopyrano[4,3-£]pyrazol-3 (2H)-one (1.95 g) (Example 62) in dry pyridine (58 ml) was stirred in an ice-bath and treated with methyl succinyl chloride (1.6 ml). The reaction mixture was allowed to warm up to ambient temperature over 18 hours and then stirred at ambient temperature for a further 24 hours. The reaction mixture was added to water and extracted with ethyl acetate. The combined organic extracts were washed with water, dried and evaporated under reduced pressure. The residue was dissolved in dichloromethane and loaded on to a dry-packed Florisil® column. The column was eluted with dichloromethane/acetone (99:1). The required fractions were evaporated and the residue was triturated with ether to give 2-(4-chlorophenyl)-4- methyl-3-oxo-2,3-dihydro[1 ]benzopyrano[4,3-£]pyrazol-8- yl methyl succinate, m.p. 152-153°C. • - m - Examples 222-225 In a similar manner to that described in Example 221 a compound of formula I was prepared by reacting 2-(4-chlorophenyl)-8-hydroxy-4-methyl[l ]benzopyrano- [4,3-c]-pyrazol-3(2H)-one (II') (Example 62) with the appropriate acid chloride, R^-COCl, as summarised in Table 16. In Examples 223, 224 and 225 more acid chloride was added and the mixture stirred for an additional period of time as shown. 10 15 (1) The column was eluted with dichloromethane. (2) Some of the crude product was insoluble in dichloromethane and this material was removed by filtration. The column was eluted with dichloromethane and then dichloromethane/acetone, 99:1. 20 (3) Material insoluble in the ethyl acetate/water mixture was collected by filtration and dried to give the product directly without chromatography. - 113 - Example 226 A stirred mixture of 2-(4-chlorophenyl)-9-hydroxy- 4-methyl[1]benzopyrano[4,3-c]pyrazol-3 (2H)-one (2 g) (Example 66) and pyridine (20 ml) was treated with 5 benzoyl chloride (0.8 ml) and stirred for 48 hours at ambient temperature. The reaction mixture was poured into water and filtered. The solid obtained was recrystallised frtom toluene to give 2-(4-chloro- phenyl)-4-methyl-3-oxo-2,3-dihydro[1]benzopyrano- 10 [4,3-£]pyrazol-9-yl benzoate, m.p. 218-222°C. Example 227 A solution of 2-(4-chlorophenyl)-8-hydroxy-4- methyiπ ]benzopyrano[4,3-£]pyrazol-3 (2H)-one (Example 62) (1.5 g) and nicotinoyl chloride hydrochloride 15 (1.6 g) in a mixture of pyridine (45 ml) and triethylamine (2.55 ml) was stirred at ambient temperature for 18 hours. The mixture was left standing at ambient temperature for 48 hours then added to water and this mixture filtered to give 2-(4-chloro- 20 phenyl)-4-methyl-3-oxo-2,3-dihydro[1 ]benzopyrano- [4,3-£]pyrazol-8-yl nicotinate, m.p. 230-235°C. Example 228 A mixture of 2-(4-chlorophenyl)-8-hydroxy-4- ethyl[1 ]benzopyrano[4,3-£]pyrazpl-3 (2H)-one (Example 25 62) (1.8 g)and 4-methoxybenzyl hydrogen malonate (2.0 g) in dry pyridine (18 ml) was stirred in a cold water-bath. 1 ,3-dicyclohexylcarbodiimide (1.6 g) was added in portions over 5 minutes. The mixture was stirred at ambient temperature for 18 hours and then 30 poured on to water. This mixture was extracted with ethyl acetate and the combined organic extracts washed with water, dried and evaporated. The residue was triturated with ether ana the solid collected by filtration then stirred with dichloromethane. After removing some insoluble material by filtration the dichloromethane solution was added to a Florisil® column. Elution with dichloromethane gave a solid which was triturated with ether and filtered to give 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihydro[1]benzo¬ pyrano[4,3-c]pyrazol-8-yl 4-methoxybenzyl malonate, m.p. 162-163°C. Example 229 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihydro[1 ]- benzopyrano[4,3-£]pyrazol-8-yl 4-methoxybenzyl malonate (Example 228) (0.7 g) was stirred with dichloromethane (3 ml) in an ice-bath and treated with anisole (0.14 ml) and trifluoroacetic- acid (1.54 ml). The solution was stirred at 0°C for 2.5 hours then washed with water whereupon a solid separated. The solid was collected by filtration, washed with dichloromethane and dried to give 2-(4-chlorophenyl)-4-methyl-3-oxo- 2,3-dihydro[1]benzopyrano[4,3-£]pyrazol-8-yl hydrogen malonate, m.p. 166°C. Example 230 In a similar manner to Example 227, a mixture of 2-(4-chlorophenyl)-8-hydroxy-4-methyl[1]benzopyrano- [4,3-£]pyrazol-3(2H)-one (Example 62) (1.5 g) , N,N- dimethylglycine (0.78 g) and dry pyridine (15 ml) was stirred at ambient temperature. 1 ,3-dicyclohexyl- carbodiimide (1.35 g) was added and the reaction mixture stirred at ambient temperature for 2 days to give, after chromatography -using dichloromethane/ acetone (99:1) as the mobile phase, 2-(4-chlorophenyl)- 4-methyl-3-oxo-2,3-dihydro[1 ]benzopyrano[4,3-c] pyrazol-8-yl dimethylaminoacetate, m.p. 174-176°C. Example 231 In a similar manner tp Example 227, a stirred mixture of 2-( -chlorophenyl)-8-hydroxy-4-methyl[1 ]- benzopyrano[4,3-c]pyra,zol-3-(2H)-one (Example 62) (1.5 g) , methylthioacetic acid (0.6 ml) and dry pyridine (15 ml)- was treated with 1 ,3-dicyclohexyl- carbodiimide (1.35 g) at ambient temperature. The mixture was s/tirred,„at ambient temperature for 2 days to give, after chromatography, 2-(4-chlorophenyl)-4- methyl-3-oxo-2,3-dihydro[1 ]benzopyrano[4,3-c]pyrazol- 8-yl methylthioace-tate, m.p. 163-166°C. Example 232 A mixture of ethyl 2-(4-chlorophenyl)-8-hydroxy- 3-OXP-2,3-dihydro[1]benzopyrano[4,3-£]pyrazole-4- acetate (2.0 g) (Example 48) in dry dichloromethane (60 0°C while triethylamine (1.6 ml) was d d f ll d b acetoxyacetyl chloride (1.2 ml) . The mixture was allowed to warm up to ambient temperature during 30 minutes then washed with water, dried and evaporated. The solid residue was triturated with ether and filtered to give ethyl 3,8-di(acetoxy- acetoxy)-2-(4-chlorophenyl)-2,4-dihydro[1 ]benzopyrano- [4,3-£]pyrazol-4-ylideneacetate which on standing in air hydrolysed to ethyl 8-acetoxyacetoxy-2-(4-chloro- phenyl)-3-oxo-2,3-dihydro[1 ]benzopyrano[4,3-£]pyrazole- 4-acetate hemihydrate containing one mole of acetoxy- acetic acid, m.p. 157-160°C. Example 233 A stirred mixture of 2-(3,4-dichlorophenyl)-8- hydroxy-3a-methyl-3a,4-dihydro[1]benzothiopyrano[4,3-c] pyrazol-3 (2H)-one (1.50 g) , (Example 73) triethylamine (0.61 ml) and dichloromethane (30 ml) was treated dropwise with ethyl malonyl chloride (0.56 ml). The mixture was stirred at ambient temperature for 2 hours and then evaporated - under reduced pressure. The residue was partitioned between ether (50 ml) and water (50 ml) . The organic layer was separated and the aqueous layer extracted with ether. The combined ether extracts were dried and evaporated to give a solid which was recrystallised from ethyl acetate to give 2-(3,4-dichlorophenyl)-3a-methyl-3-oxo-2,3,3a,4-tetra- hydro[1]benzothiopyrano[4,3-c]pyrazol-8-yl ethyl malonate, m.p. 139-141 °C. Examples 234-251 In a similar manner to that described in Example 233, a compound of formula I was prepared by reacting a compound of formula I' (preparative Example of starting compound provided) with an acyl chloride R.-COC1 as summarised in Table 17 below. In each case dichloromethane (30 ml) was -used.- - 117 - Table 1 7 Cont ' d Amounts of Reaction m.p.of Notes Reactants Time I Ex Ex of R R-_C0C1 NEt, Starting 17 ( g ) Ml) (g) J (hours) (°C) Cpd I' 10 248 74 acetoxymethyl 249 73 ethoxycarbonylmethyl 250 76 acetoxymethyl 251 76 ethylcarbonylmethyl 15 Ex = Example; NEt- = triethylamine Notes (1) Recrystallisation from:- a) ether b) ethanol c) ethyl acetate/petroleum ether (b.p. 60-80°C) d) methanol e) ethyl acetate f) isopropanol ; (2) The ether extracts were evaporated and then water added to the residue. Extraction with ethyl acetate followed by 2 recrystallisations from ethyl acetate gave the product. (3) A further equivalent portion of triethylamine and acyl chloride was added after 1 hour. (4) N,N-dimethyl formamide (2 ml) was added to the reaction mixture initially. A further portion of triethylamine (0.3 ml) and acetoxy cetyl chloride (0.3 ml) was added after 16 hours. (5) Purification of crude product by flash chromatography on silica using dichloromethane as the mobile phase. The following compounds have a chiral carbon atom and may exist in R- and S- enantiomeric forms:- Examples 111, 133, 149, 151, 152, 153 Example 252 In the preparation of capsules, 10 parts by weight of active compound .and 240 parts by weight of lactose are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing 10 mg active compound. Example 253 In the preparation of capsules, 50 parts by weight of active compound, 300 parts by weight of lactose and 3 parts by weight of magnesium stearate are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule contianing 50 mg of active ingredient. Example 254 Tablets are prepared from the following ingredients. Parts by weight Active compound 10 Lactose 190 Maize starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3 The active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture is granulated with a solution of the polyvinylpyrrolidone in ethanol. The dry granulate is blended with magnesium stearate and the rest of the starch. The mixture is then compressed in a tableting machine to give tablets containing: of active compound. - 121 - Example 255 Tablets are prepared by the method of Example 254. The tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol:dichloromethane (1:1). Example 256 In the preparation of suppositories, 100 parts by weight of active compound is incorporated in 1300 parts by weight of semi-synthetic glycerides as the suppostiroy base and the mixture formed into suppositories each containing 100 mg of active ingredient. Example 257 In the preparation of ointments the active compound is incorporated into the base by thorough homogenization until the drug is evenly distributed. The ointment is packed into 10 g amber jars with screw-capped lined lids. Active compound 0.1 g White soft paraffin to 10 g The compounds of the invention are immuno- modulatory agents, especially immunosuppressants and may show therapeutic activity at a dose of 200 mg/kg or lower. Preferred compounds of the invention show activity at 50 mg/kg or lower. The therapeutic activity of the preferred compounds of the present invention has been demonstrated by a cutaneous hypersensitivity test (CH test) in which the compounds are administered parenterally to BALB/c mice. This test was carried out in the following way. Female BALB/c mice, weight range 16-24 g, were used in groups of eight. The abdomen of each mouse was shaved and 20 μl of a solution of a sensitising agent, 5% w/v 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (oxazolone) in acetone:ethanol (1:1 by volume), was applied to the shaved area. Immediately after sensitisation, the test compound in one of the dosages listed below was injected intraperitoneally as a suspension in 1.5% v/v sorbitan esters, under the trade name Tween 80, in sterile water (100 μl) . 100 μl of the same suspension was injected likewise every 24 hours for a further 7 days. The dosages used were selected from the following values: 50, 30, 10, 3, 1, 0.3, 0.1, 0.03 or 0.01 mg/kg. Two groups of at least eight BALB/c mice were used as a control simultaneously with each test in a similar manner to that described above except that no test compound was included in the daily injections. On the seventh day after sensitisation, 10 μl of a solution of 1% w/v oxazolone in acetone: olive oil (3:1 by volume) was applied to one ear (the challenged ear) of each of the test mice and the control mice. (A more potent challenge dose of 1.5% w/v oxazolone in acetone:olive oil was employed in a few cases) . After 24 hours the thickness of the challenged ear and the thickness of the non-challenged ear of the same animal were measured with an engineer's screw gauge micrometer. The difference in thickness between the challenged ear and the non-challenged ear in each animal is a measure of the response of that animal to oxazolone. A comparison between the response of mice treated with the test compound and mice treated with the control indicates the effectiveness of the test compound as an immunomodula or agent. The compounds were considered to be active at a particular dose if a 20% or greater ' reduction in ear swelling, which was statistically significant (p <0.05) according to Dunnett's test, between treated and control groups was obtained in at least two out of three CH tests, (or, where more than three tests have been carried out, a majority of the tests) at that dose (see for example Int. Arch. Allergy, 38, p246-259 (1970)). Each of the compounds of formula I illustrated in Table A below was active at 5-0 mg/kg in at least two out of three tests at 50 mg/kg unless indicated otherwise (see Notes following the Table) . The minimum effective dose for 'each compound is given in Table A. The Example (Ex) number or numbers listed adjacent to each compound indicates the process or processes illustrating the preparation of that compound in the Examples. r ,V1 Table A Ex Compound Name Minimum Effective Dose (mg/kg) 77 4-methyl-2-(5-trifluoromethyl-2- pyridyl) [1]benzopyrano[4,3-c]pyrazol- 3(2H)-one 78 2-(5-chloro-2-pyridyl)-4-methyl[1]- benzopyrano[4,3-£]pyrazol-3 (2H)-one 79 2-(6-chloro-2-pyridyl)-4-me hyl[1]- benzopyrano[4,3-c]pyrazol-3(2H)-one 50 80 4-methyl-2-(6-trifluoromethyl-2-pyridyl) [1]benzopyrano[4,3-£]pyrazol-3(2H)-one 50 81 2-(4-chloro-2-pyridyl)-4-methyl[1 ]- $3 benzopyrano[4,3-c]pyrazol-3(2H)-one 82 2-(6-chloro-5-trifluoromethyl-2- pyridyl) -4-methyl [1 ] benzopyrano [4 , 3- £] pyrazol-3 (2H) -one 3 2-(5-bromo-2-pyridyl)-4-methyl[1 ]- 50 benzopyrano[4,3-£]pyrazol-3'(2H)-one 4 2-(5-chloro-2-pyridyl)-9-hydroxy- 50 4-meth l[1]benzopyrano[4,3-£]- pyrazol-3(2H)-one 5 8-f luoro-4-methyl-2- (5-trifluoro- ^50 methy 1-2-pyridy 1) [ 1 ] benzopyrano [4 , 3- £] pyrazol-3 ( 2H) -one - 1 25 - Ex Compound Name Minimum Effective Dose (mg/kg) 86 2- (5-chloro-2-pyridyl)-8-fluoro-4- 50 methyl [1 ]benzopyrano [4,3-c]pyrazol- 3(2H)-one 87 2- (5-chloro-2-pyridyl) -4-methylthio- 50 methyl [1 ]benzopyrano[4,3-c]pyrazol- 3(2H)-one 88 ethyl 2- (5-chloro-2-pyridyl) -3-oxo- 2,3-dihydro [1 ]benzopyrano[4,3-£] - pyrazσle-4-acetate 3 (a) 89 2- (5-chloro-2-pyridyl) -4-methyl-3- $3 (a) oxo-2,3-dihydro[1 ]benzopyrano[4,3- £]pyrazol-9-yl acetate 90 2- (5-chloro-2-pyridyl) -3-oxo-2,3- 50 dihydro[1 ]benzopyrano[4,3-£] yrazole- 4-acetate Ex Compound Name Minimum Effective Dose (mg/kg) 91 2-piperidinoethyl 2-(4-chlorophenyl)- 50 3-OXO-2,3-dihydro[1 ]benzopyrano[4,3-c]- pyrazole-4-acetate hydrochloride 0.4 hydrate 92 3-(4-methyl-l-piperazinyl)propyl 2-(4- 50 chlorophenyl)-3-oxo-2,3-dihydro[1 ]- benzopyrano[4,3-£]pyrazole-4-acetate 2.5 hydrochloride dihydrate 93 2-morpholinoethyl 2-(4-chlorophenyl)-3- $3 oxo-2,3-dihydro[1]benzopyrano[4,3-£]- pyrazole-4-acetate hydrochloride hemihydrate 94 2-morpholinoethyl 2-(3,4-dichloro- <C50 phenyl)-3-oxo-2,3-dihydro[1 ]benzo¬ pyrano[4,3-£]pyrazole-4-acetate 95 2-morpholinoethyl 2-(4-chlorophenyl)- 50 8-hydroxy-3-oxo-2,3-dihydro[1]benzo¬ pyrano[4,3-£]pyrazole-4-acetate 96 3-morpholinopropyl 2-(4-chlrorophenyl)- ^3 3-oxo-2,3-dihydro[l]benzopyrano[4,3-£]- pyrazole-4-acetate hydrochloride monohydrate 97 2-morpholinoethyl 2-(4-bromophenyl)-3- ^50 oxo-2,3-dihydro[1]benzop rano[4,3-£]- pyrazole-4-acetate hydrochloride hemi- hydrate 1 27 - Ex Compound Name Minimum Effective Dose (mg/kg) 98 2-morpholinoethyl 2- (4-fluorophenyl) - <50 3-oxo-2,3-dihydro [1 ]benzopyrano[4,3- £]pyrazole-4-acetate hydrochloride 99 2-morpholinoethyl 2- (4-chlorophenyl) N <50 8-fluoro-3-oxo-2,3-dihydro [1 ]benzo¬ pyrano[4,3-£]pyrazole-4-acetate hydrochloride 0.4 hydrate 00 2-morpholinoethyl 2- (4-chlorophenyl) - 50 9-methoxy-3-oxo-2,3-dihydro[1 ]benzo¬ pyrano[4,3-£]pyrazole-4-acetate hydrochloride 01 4-methoxybenzyl 2- (4-chlorophenyl) -3- xl oxo-2,3-dihydro [1 ]benzopyrano [4,3-£]- pyrazole-4-acetate 02 benzyl 2- (4-chlorophenyl) -3-oxo-2,3- $3 dihydro [1 ]benzopyrano[4,3-c]pyrazole- 4-acetate 3 phenethyl 2-(4-chlorophenyl)-3-oxo-2,3- x<3 dihydro [1 ]benzopyrano[4,3-c * ]pyrazole- 4-acetate 4 cyclopentyl 2-(4-chlorophenyl) -3-oxo- v< 3 2,3-dihydro[1 ]benzopyrano [4,3-£] - pyrazole-4-acetate Ex Compound Name Minimum Effective Dose (mg/kg) 105 2-methoxyethyl 2-(4-chlorophenyl)-3- x<3 oxo-2,3-dihydro[1]benzopyrano[4,3-£]- pyrazole-4-acetate 106 2- (2-thienyl) ethyl 2- (4-chlorophenyl) - v<3 3-OXO-2 , 3-dihydro [1 ] benzopyrano [4 , 3-£] - pyrazole-4-acetate 107 cyclobutylmethyl 2-(4-chlorophenyl)-3- oxo-2,3-dihydro[13benzopyrano[4,3-£]- pyrazole-4-acetate 108 2-(2-pyridyl)ethyl 2-(4-chlorophenyl)- 50 3-oxo-2,3-dihydro[l ]benzopyrano[4,3-£]- pyrazole-4-acetate 109 cyclobutyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1]benzopyrano[4,3-£]- pyrazole-4-acetate 110 2-(2-methoxyethoxy)ethyl 2.-(4-chloro- < phenyl)-3-oxo-2,3-dihydro[1]benzo¬ pyrano[4,.3-c]pyrazole-4-acetate 111 tetrahydrofurfuryl 2-(4-chlorophenyl)- ^3 3-OXO-2,3-dihydro[1 ]benzopyrano[4,3-£]- pyrazole-4-acetate 112 tetrahydro-2H-pyran-4-yl 2-(4-chloro- N<3 phenyl)-3-OXO-2,3-dihydro[l]benzo¬ pyrano[4,3-£]pyrazole-4-acetate Ex Compound Name Minimum Effective Dose (mg/kg) 113 2-(4-methyl 5-thiazolyl)ethyl 2-(4- <3 chlorophenyl)-3-oxo-2,3-dihydro[1 ]- benzopyrano[4,3-£]-pyraz.ole-4-acetate 114 3-methoxybenzyl * 2-(4-chlorophenyl)-3- « oxo-2,3-dihydro[1 ]benzopyrano[4,3-£]• pyrazole-4-acetate 115 4-methylbenzyl 2-(4-chlorophenyl)-3- v<3 oxo-2,3-dihydro[1]benzopyrano[4,3-£]- pyrazole-4-acetate 116 4-methoxyphenethyl 2-(4-ehlorophenyl)- «3 3-oxo-2,3-dihyd-Sθ[l ]benzopyrano[4,3-c]- pyrazole-4-acetate 117 4-chlorophen thyl 2-(4-chlorophenyl)- 3 3-OXO-2,3-dihydro[1]benzopyrano[4,3-c] pyrazole-4-acetajte 118 2-chlorobenzyl 2-(4-chlorophenyl)- 50 3-OXO-2,3-dihydro[1]benzopyrano[4,3-£] pyrazole-4-acetaifee 119 3-oxobutyl 2-(4-chlorophenyl)-3-oxo- ^50 2,3-dihydro[1 ]benzopyrano[4,3-£]- pyrazole-4-acetate 120 2-chlorophenethyl 2-(4-chlorophenyl)- ^50 3-oxo-2,3-dihydκo[1 ]benzopyrano[4,3-c] pyrazole-4-acetate Ex Compound Name Minimum Effective Dose (mg/kg) 121 3-methylphenethyl 2- (4-chlorophenyl) - ^50 3-OXO-2,3-dihydro[1]benzopyrano[4,3-£]- pyrazole-4-acetate 122 cyclohexyl 2- (4-chlorophenyl) -3-oxo- 50 2,3-dihydro[1 ]benzopyrano[ ,3-£]- pyrazole-4-acetate 123 3-chlorobenzyl 2- (4-chlorophenyl) -3- ^50 oxo-2,3-dihydro[1]benzopyrano[4,3-c]- pyrazole-4-acetate 124 3-hydroxypropyl 2- (4-chlorophenyl)-3- 50 oxo-2,3-dihydro[1 ]benzopyrano[4,3-£]- pyrazole-4-acetate 125 2-phenoxyethyl 2-(4-chlorophenyl) - N <50 3-oxo-2,3-dihydro[1 ]benzopyrano- [4,3-£]pyrazole-4-acetate 126 4-dimethylaminophenethyl 2-(4-chloro- $50 phenyl) -3-oxo-2,3-dihydro[1 ]benzo¬ pyrano[4,3-£]pyrazole-4-acetate 127 2-acetamidoethyl 2- (4-chlorophenyl) -3- 50 oxo-2,3-dihydro[1 ]benzopyrano[4,3-£]- pyrazole-4-acetate 28 3-methylbenzyl 2- (4-chlorophenyl) -3- ^50 oxo-2,3-dihydro [1 ]benzopyrano[4,3-£]- pyrazole-4-acetate Ex Compound Name Minimum Effective Dose (mg/kg) 129 2-methylbenzyl 2- (4-chlorophenyl) -3- 50 oxo-2,3-dihydro [1 ]benzopyrano [4,3-£] ■ pyrazole-4-acetate 130 4-ch orobenzyl 2-(4-chlorophenyl) -3- <50 oxo-2,3-dihydro [1 ]benzopyrano[4,3-c] - pyrazole-4-acetate 131 2-methoxybenzyl 2- (4-chlorophenyl) - ^50 3-OXO-2,3-dihydr'o[1 ]benzopyrano[4,3- £]pyrazole-4-acetate 132 3- (3-pyridyl)propyl 2- (4-chlorophenyl) ^50 3-OXO-2,3-dihydro[1 ]benzopyrano [4,3-£] pyrazole-4-acetate 133 α-methylphenethyl 2- (4-chlorophenyl) - 50 3-oxo-2,3-dihydro [1 ]benzopyrano [4,3- £]pyrazole-4-acetate 134 cyclopropylmethyl 2—(4-->chlorophenyl) -3- < oxo-2,3-dihydro [1 ]benzopyrano[4',3-£]- pyrazole-4-acetate 135 cyclobutylmethyl 3-oxo-2- (4-trifluoro¬ £50 methylphenyl) -2,3-dihydro[1 ]benzopyrano- [4,3-£]pyrazole—4-acetate 136 cyclobutylmethyl 2- (4-chlorophenyl) -8- $50 methyl-3-oxo-2,3-dihydro[1 ]benzopyrano- [4,3-c]pyrazole-4-acetate Ex Compound Name Minimum Effective Dose (mg/kg) 137 cyclobutylmethyl 2-(4-methoxyphenyl)- $50 3-OXO-2,3-dihydro[1 ]benzopyrano[4,3-£]- pyrazole-4-acetate 138 cyclobutylmethyl 2-(4-methylphenyl)-3- $50 oxo-2,3-dihydro[1]benzopyrano[4,3-c]- pyrazole-4-acetate 139 cyclobutylmethyl 2-(3-chlorophenyl)-3- ^50 oxo-2,3-dihydro[l]benzopyrano[4,3-£]- pyrazole-4-acetate 140 cyclobutylmethyl 2-(4-chlorophenyl)-9- ^50 hydroxy-3-oxo-2,3-dihydro[1]benzopyrano- [4,3-£]pyrazole-4-acetate 142 2-acetoxyethyl 2-(4-chlorophenyl)-3- $3 oxo-2,3-dihydro[1]benzopyrano[4,3-£]- pyrazole-4-acetate 143 2-hydroxyethyl 2-(4-chlorophenyl)-3- <3 oxo-2,3-dihydro[1]benzopyrano[4,3-£]- pyrazole-4-acetate 144 2-thiomorpholinoethyl 2-( -chloro- «3 phenyl)-3-oxo-2,3-dihydro[1 ]benzo¬ pyrano[4,3-£]pyrazole-4-acetate hydrochloride 145 2-methylthioethyl 2-(4-chlorophenyl)- 3 3-OXO-2,3-dihydro[1]benzopyrano[4,3-c] pyrazole-4-acetate Ex Compound Name Minimum Effective Dose (mg/kg) 1 46 4 , 4 , 4-trifluorobutyl 2- (4-chloro- 50 pheny 1) -3-oxo-2 , 3-dihydro [ T] benzo¬ pyrano [4 , 3-£] pyrazole-4-acetate 147 2-cyanoethyl 2-(4-chlorophenyl)-3-oxo- $3 2,3-dihydro[1 ]benzopyrano[4,3-c]- pyrazole-4-acetate 148 2-ethoxycarbony3.*ethyl 2-(4-chloro- 50 phenyl)-3-oxo-2,3-dihydro[1]benzo¬ pyrano[4,3-£]pyrazole-4-acetate 149 6-methylpheneth l 2-(4-chlorophenyl)- £50 3-OXO-2,3-dihydro[1]benzopyrano[4,3- £]pyrazole-4-acetate 150 2-cyclohexylethyl 2-(4-chlorophenyl)-3- $3 oxo-2,3-dihydro[1]benzopyrano[4,3-£]- pyrazole-4-acetate- 151 l-methyl-2-morpholinoethyl 2-(4-chloro- 50 phenyl)-3-oxo'-Z,3-dih.ydr.o[1]benzo¬ pyrano[4,3'-£]pyrazole-4-acetate 152 1-methyl-2-piperidylmethyl 2-(4- 50 chlorophenyl)-3-oxo-2 3-dihydro[l]- benzopyrano[4,3-£]pyrazole-4-acetate 153 2-morpholinoethyl 2-(4-chlorophenyl)- 50 3-oxo-l ,2,3,4-tetrahydro[1 ]benzopyrano- [4,3-£]pyrazole-4-acetate Ex Compound Name Minimum Effective Dose (mg/kg) 154 3-acetoxypropyl 2-(4-chlorophenyl)-3- $50 oxo-2,3-dihydro[1]benzopyrano[4,3-£]■ pyrazole-4-acetate 155 2-(4-chlorophenyl)-N-methyl-3-oxo-2,3- 50 dihydro[1]benzopyrano[4,3-£]pyrazole-4- acetanilide 156 N-benzyl-2- (4-chlorophenyl) -N-methyl-3- 50 oxo-2 , 3-dihydro [ 1 ] benzopyrano [ 4 , 3-£] - pyrazole-4-acetamide 57 2-(4-chlorophenyl)-N-methyl-N-(2- 50 morpholinoethyl)-3-oxo-2,3-dihydro[1]- benzopyrano[4,3-£]pyrazole-4-acetamide 58 2-(4-chlorophenyl)-N-methyl-3-oxo-N- 50 (3-pyridylmethyl)-2,3-dihydro[1]- benzopyrano[4,3-£]pyrazole-4- acetamide 59 2-(4-chlorophenyl)-N-ethyl-3-oxo-N- phenyl-2,3-dihydro[1 ]benzopyrano- [4,3-£]pyrazole-4-acetamide. 60 N-benzyl-2-(4-bromophenyl)-N-methyl- 50 3-oxo-2,3-dihydro[l ]benzopyrano[4,3-c] pyrazole-4-acetamide - 1 35 - Ex Compound Name Minimum Effective Dose (mg/kg) 161 N-benzyl-2-(3,4-dichlorophenyl)-ti¬ 50 methy1-3-oxo-2,3-dihydro [1 ]benzopyrano- [4,3-c]pyrazole-4-acetamide *« 162 N-benzyl-2-(4-c lorophenyl ' )-8-fluoro- 50 N-methyl-3-oxo-2,3-dihydro[1]benzo¬ pyrano[4,3-£]pyrazole-4-acetamide 163 2-(4-chlorophenyi)-N-methyl-3-oxo-N- 50 phenethyl-2,3-dihydro[1 ]benzόpyrano- [4,3-c]pyrazole-4-acetamide 164 2-(4-chlorophenyl)-N-(2-cyanoethyl)-N- 50 methyl-3-oxo-2,3-dihydrό[1]benzo¬ pyrano[4,3-£]pyrazole-4-acetamide 165 2-(4-chlorophenyl)-N,N-(3-oxapenta- 50 methylene)-3-oxo-2,3-dihydro[1 ]benzo- t pyrano[4,3-£]pyrazole-4-acetamide 166 4'-chloro-2-(4-chlorophenyl)-N-methyl- 50 % < ~~ 3-OXO-2,3-dihydrδ[1 ]benzopyrano[4,3-£]- pyrazole-4-acetanilide 167 N-benzyl-2-(4-fluorophenyl)-N-methyl- 50 3-OXO-2,3-dihydro[1 ]benzopyrano[4,3- c]pyrazole-4-acetamide 168 2-(4-chlorophenyl)-N-(1 ,3-dioxolan-2- 50 ylmethyl)-N-methyl-3-oxo-2 ' ,3-dihydro- [1 ]benzopyrano[4,3-£]pyrazole-4- acetamide Ex Compound Name Minimum Effective Dose (mg/kg) 169 methyl 4- [2- (4-chlorophenyl) -N-methyl- 50 3-OXO-2,3-dihydro[1 ]benzopyrano[4,3-£]- pyrazole-4-acetamido]benzoate 170 2-(4-[2-(4-chlorophenyl)-3-oxo-2,3- 50 dihydro[1 ]benzopyrano[4,3-£]pyrazole- 4-acetyl]piperazin-1-yl)ethyl acetate 171 2- - [2- (4-chlorophenyl) -3-oxo-2,3- 50 dihydro [1 ]benzopyrano [4,3-£]pyrazole- 4-acetyl]piperazin-1-yljethyl propionate 172 N,N-(3-oxapentamethylene)-3-oxo-2- $50 (4-trifluoromethylphenyl) -2,3- dihydro [1 ]benzothiopyrano[4,3-£]- pyrazole-4-acetamide 173 N-ethyl-3-oxo-N-phenyl-2-(4-tri- ,<50 luoromethylphenyl) -2,3-dihydro [1 ]- benzothiopyrano[4,3-£]pyrazole-4- acetamide 74 methyl 5- [2- (4-chlorophenyl)-3-oxo- 50 2 ,3-dihydro[1 ]benzopyrano[4,3-£]- pyrazol-4-yl]-4-oxopentanoate 75 2-(4-chlorophenyl)-4-(2-oxo-3-phenyl- 50 propyl) [1 ]benzopyrano[4,3-£]pyrazol- 3(2H)-one - 1 37 - Ex Compound Name Minimum Effective Dose (mg/kg) 176 2-(4-chlorophenyl)-4-(2-oxo-3-phenoxy- propyl) [1 ]benzopyrano[4,3-c]pyrazol- 3(2H)-one 177 2-(4-chlorophenyl)-4-(2-cyclohexyl-2- 50 oxoethyl) [1 ]benzopyrano[4,3-£]pyrazol- 3(2H)-one 1 78 2- (4-chlorophenyl) -4- ( 2-cyclopropyl-2- 50 oxoethyl) [1 ] benzopyrano [4 , 3-c] pyrazol- 3 (2H) -one 179 2-(4-chloropheήyl)-4-[4-(4-methoxy- $50 phenyl)-2-oxobutyl] [1]benzopyrano[4,3- £]pyrazol-3 (2H)-one 180 4-[3-(4-chloropHιenoxy)-2-oxppropyl]- $3 2-(4-chlorophenyi) [1 ]benzopyrano[4,3- £]pyrazol-3 (2Η)-one ' , 181 2-(4-chlo^ophenyl)-4-[4-(3-methyl- £50 phenyl)-2τ-oxobu,tyl] [1 ]benzopyrano- [4,3-c]pyrazol-3 (2H)-one 182 2-(4-chlorophenyl)-4-(3-cyclopentyl- $50 2-oxopropyl) [11benzopyrano[4,3-£]- pyrazol-3(2H)-one 1 83 2- ( 4-chlorophenyl) -4- [3- (2-methyl- $50 phenoxy) -2-oxopropyl] [1 ] benzopyrano- [4 , 3-£] pyrazol-3 (2H) -one Ex Compound Name Minimum Effective Dose (mg/kg) 184 2-(4-chlorophenyl)-4-(4-methylthio-2- $50 oxobutyl) [1]benzopyrano[4,3-£]pyrazol- 3(2H)-one 185 2-(3,4-dichlorophenyl)-4-(2-oxo-3- $50 phenoxypropyl) [1]benzopyrano[4,3-£]- pyrazol-3 (2H)-one 186 2-(4-chlorophenyl)-4-(3-methoxy-2-oxo- £3 (a) propyl) [1 ]benzopyrano[4,3-£]pyrazol-3- (2H)-one 187 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- ,$3 dihydro[1]benzopyrano[4,3-c]pyrazol-9- yl methyl malonate 188 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- .$1 dihydro[1]benzopyrano[4,3-c]pyrazol-8- yl ethyl malonate 189 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- ^3(a) dihydro[1]benzopyrano[4,3-£]pyrazol-8- yl methoxyacetate 190 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[1]benzopyrano[4,3-£]pyrazol-8- yl cyclopropanecarboxylate 191 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- dihydro[1 ]benzopyrano[4,3-£]pyrazol-8- yl 1-adamantanecarboxylate Ex Compound Name Minimum Effective Dose (mg/kg) 92 2- ( 4-chlorophenyl) -4-methyl-3-oxo-2 , 3- 50 dihydro f l ] benzopyrano [4 , 3-£] pyrazol-8- yl 3-phenylpropionate 93 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[1 ]benzopyrano[4,3-£]pyrazol-8- yl phenylacetate 94 2- (4-chlorophenyl) -4-methyl-3-oxo-2,3- 50 dihydro [1 ]benzopyrano [4,3-£]pyrazol-8- yl 2-methoxybenzoate 95 2- (4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro [1 ]benzopyrano[4,3-£]pyrazol-8- yl 2-furoate 6 2- (4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[1 ]benzopyrano[4,3-£]pyrazol-8- yl 2-thenoate 7 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- $3 dihydro [1 ]benzopyrano[4,3-£]pyrazol-8- yl cyclobutanecarboxylate 8 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- .$50 dihydro [1 ]benzopyrano [4,3-£]pyrazol-8- yl 2-methylbenzoate 9 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- x <50 dihydro[1 ]benzopyrano[4,3-c]pyrazol-8- yl 4-chlorobenzoate Ex Compound Name Minimum Effective Dose (mg/kg) 200 2-(4-chlorophenyl)-4-methyl-3-oxo- 50 2,3-dihydro[1]benzopyrano[4,3-£]- pyrazol-8-yl crotonate 201 2-(4-chlorophenyl)-4-methyl-3-oxo- £50 2,3-dihydro[1]benzopyrano[ ,3-£]- pyrazol-8-yl 4-methoxybenzoate 202 2- (4-chlorophenyl) -4-methyl-3-oxo- $50 2 , 3-dihydro [ 1 ] benzopyrano [4 , 3-£] - pyrazol-8-yl 4-methylbenzoate 203 2-(4-chlorophenyl)-4-methyl-3-oxo- 50 2,3-dihydro[1]benzopyrano[4,3 -c] - pyrazol-8-yl cyclopentanecarboxylate 204 2-(4-chlorophenyl)-4-methyl-3-oxo- 50 2,3-dihydro[1]benzopyrano[4,3-£]- pyrazol-8-yl cyclohexanecarboxylate 205 2-(4-chlorophenyl)-4-methyl-3-oxo- 50 2,3-dihydro[1]benzopyrano[4,3-£]pyrazol- 8-yl 3-methylbenzoate 206 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- ,<50 dihydro[1]benzopyrano[4,3-£]pyrazol-8- yl isonicotinate 207 Ethyl 2-(4-chlorophenyl)-3-oxo-8- 50 phenylacetoxy-2,3-dihydro[1]benzo¬ pyrano[4,3-£]pyrazole-4-acetate Ex Compound Name Minimum Effective Dose (mg/kg) 208 Ethyl 2- (4-chlo'r " ophenyl) ' -8-methoxy- 50 acetoxy-3-oxo-2,3-dihydro [1 ]- benzopyrano [4,3-£]pyrazole-4-acetate 0.3 methoxyacetic acid solvate 209 2- (4-chlorophenyl) -4-ethoxycarbonyl- 50 methyl-3-oxo-2,3-dihydro[1 ]benzopyrano- [4,3-£]pyrazol-8-yl methyl succinate 210 4-methyl-3-oxo-2-(4-trifluoromethyl¬ £50 phenyl) -2,3-dihydro [1 ]benzopyrano- [4,3-£]pyrazol-8-yl acetoxyacetate 211 2-(4-bromophenyl)-4-methyl-3-oxo-2,3- ,<50 dihydro [1 ]benzopyrano [4,3-£]pyrazol-8- yl acetoxyacetate 212 2- (3,4-dichlorophenyl)-4-methyl-3- £50 oxo-2,3-dihydrόt1 ]benzopyrano[4,3- £]pyrazol-8-yl methoxyacetate 213 2- (3,4-dichlorophenyl) -4-methyl-3- £50 oxo-2,3-dihydro[1 ]benzopyrano[4,3-£]- pyrazol-8-yl 3-(methylthio)propionate 214 2- (3,4-dichlorophenyl) -4-methyl-3- 50 oxo-2,3-dihydro[1 ]benzopyrano[4,3-£]- pyrazol-8-yl acetoxyacetate 215 2- (3,4-dichlorophenyl) -4-mefchyl-3- _<50 oxo-2,3-dihydro[1 ]benzopyrano[4,3-£]- pyrazol-8-yl methyl succinate Ex Compound Name Minimum Effective Dose (mg/kg) 216 2-(4-chlorophenyl)-4-methyl-3-oxo- 50 2,3-dihydro[1]benzopyrano[4,3-£]- pyrazol-9-yl methoxyaσetate 217 cyclobutylmethyl 9-acetoxyacetoxy-2- £50 (4-chlorophenyl)-3-oxo-2,3-dihydro[l ] benzopyrano[4,3-£]pyrazole-4-acetate 218 cyclobutylmethyl 8-acetoxyacetoxy-2- £50 (4-chlorophenyl)-3-oxo-2,3-dihydro[1] benzopyrano[4,3-£]pyrazole-4-acetate 0.5 hydrate, 0.35 acetoxyacetic acid solvate 19 Isopropyl 8-acetoxyacetoxy-2-(4- £50 chlorophenyl)-3-oxo-2,3-dihydro[l]- benzopyrano[4,3-£]pyrazole-4-acetate 0.2 hydrate, 0.5 acetoxyacetic acid solvate 20 2-(4-chlorophenyl)-4-methyl-3-oxo-,2,3- 3 dihydro[1]benzopyrano[4,3-£]pyrazol-9- yl methyl succinate 21 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- £1 dihydro[1]benzopyrano[4,3-£]pyrazol-8- yl methyl succinate 22 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- dihydro[1]benzopyrano[4,3-£]pyrazol-8- yl acetoxyacetate - 1 43 - Ex Compound Name Minimum Effective Dose (mg/kg) 223 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- dihydro[1]benzopyrano[4,3-£]pyrazol-8- yl 3-(methylthio) t propionate 224 2-(4-chlorophen|l).-4-methyl-3-oxo-2,3- 50 dihydro[1]benzopyrano[4,3-£]pyrazol-8- yl ethyl,succinate 225 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- dihydro[1-]benzopyrano[ ,3-£]pyrazol-8- yl benzoate 226 2-(4-chlorophenyl)-4-methyl- -oxo-2,3- 50 dihydro[1 ]benzopyrano[4,3-£]pyrazol-9- yl benzoate 227 2-(4-chlorophenyl)-4-methyl-.3-oxo-2,3- 50 dihydro[1]benzopyrano[4,3-£]pyrazol-8- yl nicotinate 228 2- (4-chlorophenyd) -4-methyl-3-oxo-2 , 3- 50 dihydro [1 ] benzopyrano [4 , 3-c] pyrazol-8- yl 4-methoxybenzyl- malonate 229 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[1 ]benzopyrano[4,3-£]pyrazol-8- yl hydrogen malonate 230 2- (4-chloropheny]i) -4-methy l-3-oxo-2 , 3- S dihydro [1 ] benzopy rano [4 , 3-?c] pyrazol-8- yl dimethylamiaoacetate Ex Compound Name Minimum Effective Dose (mg/kg) 231 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[1 ]benzopyrano[4,3-£]pyrazol-8- yl (methylthio)acetate 232 ethyl 8-acetoxyacetoxy-2-(4-chloro- phenyl)-3-oxo-2,3-dihydro[1]benzo¬ pyrano[4,3-£]pyrazole-4-acetate hemihydrate acetoxyacetic acid solvate 233 2-(3,4-dichlorophenyl)-3a-methyl-3- $3 oxo-2,3,3a,4-tetrahydro[1]benzothio¬ pyrano[4,3-£]pyrazol-8-yl ethyl malonate 234 2-(3,4-dichlorophenyl)-3a-methyl-3- £3 oxo-2,3,3a,4-tetrahydro[1 ]benzothio¬ pyrano[4,3-£]pyrazol-8-yl methoxyacetate 35 2-(3,4-dichlorophenyl)-3a-methyl-3- S3 oxo-2,3,3a,4-tetrahydro[1]benzothio¬ pyrano[4,3-£]pyrazol-8-yl acetoxy¬ acetate 36 2- (3 , 4-dichlorophenyl) -Ja-methyl-3- $3 oxo- 2 , 3 , 3a, 4- tetr ahydr o [ 1 ] benzothio¬ pyrano [4 , 3-£] pyrazol-8-yl phenyl- acetate 37 2-(3,4-dichlorophenyl)-3a-methyl-3- $1 oxo-2,3,3a,4-tetrahydro[1]benzothio¬ pyrano[4,3-£]pyrazol-8-yl benzoate Ex Compound Name Minimum Effective Dose (mg/kg) 238 2- (3 , 4-dichlorophenyl) -3a-methyl-3- oxo-2 , 3 , 3a , 4-tel4rahydro [ 1 ] benzothio¬ pyrano [4 , 3-£] pyrazol-8-yl methyl succinate 239 2- (3 ,4-dάchlorophenyl) -3a-methyl-3- ^50 oxo-2,3,3a,4-tetrahydro [1 ]benzothio¬ pyrano[4,3-c]pyrazol-8-yl crotonate 240 2- (3,4-dichlorophenyl) -3a-methyl-3- .$50 oxo-2,3,3a,4-tetrahydro[1 ]benzothio¬ pyrano[4,3-£]pyrazol-8-yl propionate 241 2-(3,4-dichlorophenyl)-4-methyl-3- 50 oxo-2,3-dihydro[1 ]benzothiopyrano- [4,3-£]pyrazol-8-yl acetoxyacetate 242 3a-methyl-3-oxo-2- (4-trifluoromethyl- s £?50 phe-nyl)-2,3,3a r 4-tetrahydxo[1 ]benzo¬ thiopyrano [4,3-c]pyrazol-8-yl acetoxy¬ acetate 243 2- (4-chlorophenyl) -3a-methyl-3-oxo- $50 2,3,3a,4-tetrahydro[1 ]benzothiopyrano- [4,3-£]pyrazol-8-yl methoxyacetate 244 2-(4-fluorophenyl)-3 -methyl-3-σxσ-2,3, $50 3a,4-tetrahydro[1 ]benzothiopyrano[4,3-£] pyrazol-8-yl acetoxyacetate Ex Compound Name Minimum Effective Dose (mg/kg) 245 Ethyl 2-(4-fluorophenyl)-3a-methyl-3- £50 oxo-2,3,3a,4-tetrahydro[1 ]benzothiopyrano- [4,3-£]pyrazol-8-yl malonate 246 3a-methyl-3-oxo-2-(4-trifluoromethyl- ,$3 phenyl)-2,3,3a,4-tetrahydro[l]benzothio- pyrano[4,3-£]pyrazol-8-yl methoxy¬ acetate 247 2-(4-fluorophenyl)-3a-methyl-3-oxo- 50 2,3,3a,4-tetrahydro[1]benzot iopyrano- [4,3-c]pyrazol-8-yl methoxyacetate 248 2-(4-chlorophenyl)-3a-methyl-3-oxo- ,$50 2, 3,3a,4-tetrahydro[1]benzothiopyrano- [4,3-£]pyrazol-8-yl acetoxyacetate 249 Ethyl 3a-methyl-3-oxo-2-(4-trifluoro- £50 methylphenyl)-2,3,3a,4-tetrahydro[1 ]- benzothiopyrano[4,3-£]pyrazol-8-yl malonate 250 -Methyl-3-oxo-2-(4-trifluoromethyl- ,$50 phenyl)-2,3-dihydro[1Jbenzothiopyrano- [4,3-£]pyrazol-8-yl acetoxyacetate 251 Ethyl 4-methyl-3-oxo-2-(4-trifluoro- <50 methylphenyl)-2,3-dihydro[1]benzothio¬ pyrano[4,3-£]pyrazol-8-yl malonate Notes: (a) Active in each of two tests at 3 mg/kg - 1 47 - The compounds of the present invention also show activity in a variety of other in-vivo screens, which show the utility of the compounds as immunomodulants, particularly in suppressing the immune response. Administration of ;he compounds has been carried out orally or parenterally. Some compounds have been found to be active in a test which determines their effects on humoral immunity by assaying the sera collected at the end of the oxazolone induced cutaneous hypersensitivity test described above (CH test) for changes- in the amount- of anti-oxazolone antibody produced, and a Graft versus Host test similar to that used by Smith S R, Terminelli C, Kipilman C T and Smith Y., J. Immunopharmacology 1981 ;3 (2) ,133-170. For example, the compounds prepared in the following Examples were also found to be active in the above-described antibody test after parenteral administration at 50 mg/kg. A compound was deemed to be active, if at a dose of 50 mg/kg it caused a decrease in the relative serum anti-oxazolone antibody concentration determined by an enzyme linked immunosorbent assay (ELISA) by a factor of 0.5 or greater calculated by the following formula:- O.D. (C ) - O.D. (T. j ) O.D. (C.) - O.D. (C 2 ) where O.D.(C-) is the optical density of the control serum at a dilution of 1/128 O.D. (C-) is the optical density of the control serum at a dilution of 1/256 O.D.(T-) is the optical density of the test serum at a dilution of 1/128 The control and test sera were diluted with phosphate buffered saline (pH 7.3) containing 0.05% v/v Tween 20 (trade name) . Compounds active in above test: Examples 77-79, 81-137, 139-140, 142-159, 161, 164, 166-7, 169-197, 199-240, 242-251. The following compounds were active at or below 50 mg/kg as defined herein and were prepared in an analogous manner to those described herein: Ex Compound Name Melting Point(°C) 258 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 115-188 dihydro[1 ]benzopyrano[4,3-c]pyrazol-8- (dec) yl 4-morpholinomethylbenzoate 259 methyl 5-[3-oxo-2-(4-trifluoromethyl- 140-143 phenyl)-2,3-dihydro[1 ]benzothiopyrano- [4,3-£]pyrazol-4-yl]-4-oxopentanoate 260 2-(3,4-dichlorophenyl)-3a-methyl-3-oxo- 191-193 2,3,3a,4-tetrahydro[1 ]benzothiopyrano- [4,3-£]pyrazol-8-yl 2-thenoate 261 2- (3,4-dichlorophenyl)-3a-methyl-3-oxo- 149-150 2,3,3a,4-tetrahydro[1 ]benzothiopyrano- [4,3-£]pyrazol-8'^yl nicotinate 262 2-(3,4-dichlorophenyl)-3a-methyl-3-oxo- 132-135 2,3,3a,4-tetrahydro[1 ]beήzothiopyrano- [4,3-£]pyrazol-8-yl 3-methylbenzoate 263 ethyl 2-(5-chloro-2-pyridyl)-8-hydroxy- 258-265 3-oxo-2,3- * dihydro[l ]benzopyrano[4,3-c]- (dec) pyrazole-4-acetate Ex Compound Name Melting Point(°C) 264 2-(2-methylpiperidino)ethyl 2-(4-chloro- 210-213 phenyl)-3-oxo-2,3-dihydro[1]benzopyrano- [4,3-£]pyrazole-4-acetate hydrochloride 265 2-[4,5-bis (trifluoromethyl)-2-pyridyl]- 235-238 4-methyl[1]benzopyrano[4,3-£]pyrazol- 3(2H)-one 266 2- (5-chloro-2-pyridyl) -N-ethyl-3-oxo- 1 81 -1 84 N-phenyl-2 , 3-dihydro [ l ] benzopyrano [4 , 3- ]pyrazole-4-acetamide 267 cyclobutylmethyl 2-(5-chloro-2-pyridyl)- 157-160 3-OXO-2,3-dihydro[1]benzopyrano[4,3-£]- pyrazole-4-acetate 268 4-[3-(3-chlorophenoxy)-2-oxopropyl]-2- 193-195 (4-chlorophenyl) [1]benzopyrano[4,3-c]- pyrazol-3(2H)-one 269 4-[3-(2-chlorophenoxy)-2-oxopropyl]-2- 215-217 (4-chlorophenyl) [1]benzopyrano[4,3-£]- pyrazol-3 (2H)-one 270 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 153-156 dihydro[1 ]benzopyrano[4,3-£]pyrazol-8- yl 4-(4-methylpiperazin-1-ylmethyl)- benzoate hydrochloride hydrate 271 4-methoxybenzyl 2-(3,4-dichlorophenyl)- 188-190 3-oxo-2,3-dihydro[1]benzothiopyrano- [4,3-£]pyrazole-4-acetate - 151 - Ex Compound Name Melting Point(°C) 272 2-acetoxyacetoxyethyl 2-(4~chloro- 131 phenyl)-3-oxo-2,3-dihydro[1]benzopyrano- [4,3-£]pyrazole-4-acetate 273 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 147-151 dihydro[1]benzopyrano[ ,3-£]pyrazol-8- yl 4-diethylaminomethylbenzoate 274 2- (4-chlorophenyl) -4-methyl-3-oxo-2 , 3- 305-31 0 dihydro [ 1 ] benzopyrano [4 , 3-£] pyrazol-8- (dec) yl glycinate (0.9) hydrochloride 275 4-(2-oxo-3-phenylpropyl)-2-(4-trifluoro- 173-175 methylphenyl) [1]benzothiopyrano[4,3-£]- pyrazol-3 (2H)-one 276 4-methoxybenzyl 3-oxo-2-(4-trifluoro- 137-138 methylphenyl)-2,3-dihydro[1]benzothio¬ pyrano[4,3-£]pyrazole-4-acetate 277 2-(5-chloro-2-pyridyl)-9-methoxy-4- 254-256 methyl[1 ]benzopyrano[4,3-£]pyrazol- 3(2H)-one 278 2-(4-chlorophenyl)-4-(4-methyl- 221-223 sulphonyl-2-oxobuτ*yl) [1 ]benzopyrano- [4,3-£]pyrazol-3 (2H)-one 279 2-(4-chlorophenyl').-4-methyl-3-oxo-2,3- 192-193 dihydro[1 ]benzopyrano[4,3-£]pyrazol-8- yl tert-butoxycaLrboxamidoacetate Ex Compound Names Melting PointCC) 280 4-[3-(4-methoxyphenyl)-2-oxopropyl]■ 184-187 2-(4-trifluoromethylphenyl) [1]- benzothiopyrano[4,3-£]pyrazol-3(2H)■ one 281 2-(4-chlorophenyl)-4-[3-(4-methoxy- 178-180 phenyl)-2-oxopropyl] [1]benzopyrano- [4,3-£]pyrazol-3(2H)-one 282 2-(3,4-dichlorophenyl)-3a-methyl-3- 141-142 oxo-2,3,3a,4-tetrahydro[1 ]benzothio¬ pyrano[4,3-£]pyrazol-8-yl 4-methoxy- benzoate 283 2-(3,4-dichlorophenyl)-3a-methyl-3- 189-190 oxo-2,3,3a,4-tetrahydro[1]benzothio¬ pyrano[4,3-£]pyrazol-8-yl 2-furoate 284 2-(3,4-dichlorophenyl)-3a-methyl-3- 170-173 oxo-2,3,3a,4-tetrahydro[1 ]benzothio¬ pyrano[4,3-£]pyrazol-8-yl 4-chloro- benzoate 285 2-(3,4-dichlorophenyl)-3a-methyl-3- 97-99 oxo-2,3,3a,4-tetrahydro[1]benzothio¬ pyrano[4,3-£]pyrazol-8-yl 3-(methyl¬ thio)propionate 286 2-(2-thienyl)ethyl 3-oxo-2-(4-trifluoro¬ 144-146 methylphenyl)-2,3-dihydro[1]benzothio¬ pyrano[4,3-£]pyrazole-4-acetate Ex Compound Name Melting Point(°C) 288 4-(2-oxo-3-phenoxypropyl)-2-(4- 205-208 trifluoromethylphenyl) [1]benzothio¬ pyrano[4,3»-£]pyrazol-3(2H)-one 289 2-methoxyethyl 3-oxo-2-(4-trifluoro¬ 134-137 methylphenyl)-2,3-dihydro[1]benzothio¬ pyrano[4,3-£]pyrazole-4-acetate 290 2-morpholinoethyl 3-oxo-2-(4-tri- 154-156 fluoromethylphenyl)-2,3-dihydro[1 ]- benzothiopyrano[4,3-c]pyrazole-4-acetate 291 4-(3-methoxy-2-oxopropyl)-2-(4-tri- 148-150 fluoromethylphenyl) [1 ]benzothiopyrano- [4,3-£]pyrazol-3(2H)-one 292 4-[2-oxo-3-(2-thienyl)propyl]-2-(4- 169-179 trifluoromethylphenyl) II]benzothio¬ pyrano[4,3-£] yrazol-3(2H)-one 293 Tetrahydro-2H-pyran-4-yl 3-oxo-2-(4- 172-175 trifluoromethylphenyl)-2,3-dihydro[1 ]- benzothiopyrano[4,3-£]pyrazole-4-acetate 294 2-(3,4-dichlorophenyl)-3a-methyl-3- 123-126 oxo-2,3,3a,4-tetrahydro[1 ]benzothio¬ pyrano[4,3-c]pyrazol-6-yl propionate 295 2-(3, -dichlorophenyl)-3a-methyl-3- 113 oxo-2,3,3a,4-tetrahydro[1]benzothio¬ pyrano[4,3-£]pyrazol-6-yl acetoxyacetate Ex Compound Name Melting Point(°C) 296 2-(4-chlorophenyl)-4-[2-oxo-3-(2- 135-138 thienyl)propyl] [1]benzopyrano[4,3-£]- pyrazol-3(2H)-one 297 2-(4-chlorophenyl)-N-cyclopropyl-N- 160-162 cyclopropylmethyl-3-oxo-2,3-dihydro- [l]benzopyrano[4,3-£]pyrazole-4-acetate 298 2-(4-chlorophenyl)-4-[4-(2-chloro- 166-168 phenyl)-2-oxobutyl] [1]benzopyrano- [4,3-£]pyrazol-3(2H)-one 299 Cyclobutylmethyl 2-(4-chlorophenyl)- 164-166 6-methoxy-3-oxo-2,3-dihydro[1 ]benzo¬ pyrano[4,3-£]pyrazole-4-acetate 300 N-Benzyl-2-(4-chlorophenyl)-N-cyclo- 197-199 pentyl-3-oxo-2,3-dihydro[1 ]benzo¬ pyrano[4,3-£]pyrazole-4-acetamide 301 2-(5-Chloro-2-pyridyl)-6,8-difluoro- 218-223 4-methyl[1Jbenzopyrano[4,3-£]pyrazol- 3(2H)-one 302 Ethyl 4-methyl-3-oxo-2-(4-trifluoro- - 146-147 methylphenyl)-2,3-dihydrop]benzo¬ thiopyrano[4,3-£[pyrazol-8-yl malonate

Claims: Claims 1 . A compound of formula 1 in which X represents oxygen or sulphur; when X represents oxygen or sulphur R. represents hydrogen or together with R represents a bond; R_ together with either one of R ' and R. represents a bond; R, together with 'either one of R 2 and R. represents a bond; R. represents hydrogen or together with R, represents a bond; or when X represents sulphur, R. and R„ represent a bond, R represents methyl and R and R represent hydrogen; Z represents --OH or -N= when X represents oxygen; -i « Z represents -CH= when X represents sulphur; R e represents hydrogen when R- represents methyl, or R D c represents CIH - Rb., R 6 when R- represents a bond together with either one of R„ and R 4 ' Rg represents hydrogen, halo, S(0) Y. , carboxy, carbamoyl, a carboxylic acyl group, an esterified carboxyl group or CONR. 2 R.. 3 ; R,,, represents hydrogen or methyl; 6 or R fi and R g , together with the carbon atom to which they are attached represent cyclopropyl; R_ represents hydrogen, halo, trifluoromethyl, C-1 —o. alkyl, methoxy or S (0)mYi ; Ro_ represents hydrogen, halo or trifluoromethyl; R„, represents hydrogen, halo or trifluoromethyl; R g and Rig' which ma Y b e the same or different, represent halo; or R g represents hydrogen and R. n represents hydrogen, halo, trifluoromethyl, nitro, C._ fi alkyl, C. .. alkoxy, hydroxy or a carboxylic acyloxy group; R 1 _ represents methyl, ethyl or C___ cycloalkyl and R. ^ represents C, g alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group or C- „ cycloalkyl; or R represents phenyl optionally j—b I J substituted by C, . alkoxycarbonyl or halo; or R._ and R.. 3 together with the nitrogen to which they are attached represent a 3-8 membered non-aromatic heterocylic group which may be substituted by a C_ 2—6 acyloxy(C, g )alkyl group; Y. represents C, g alkyl; n is 0, 1 or 2 and m is 0 or 1 /I5 or a pharmaceutically acceptable salt thereof; provided that: I) when X is oxygen, Z is -CH= and: a) Rg represents c ι_g " dialkylcarbamoyl, then R, „ represents a carb xylic acyloxy group other than acetoxy; or b) when R, represents hydrogen, halo, S (0) Y. , b ., n i carbamoyl, carboxy, * C 2 _ g alkoxycarbonyl, C- fi alkanoyl or when R,. and R- , together with the carbon atom to b b , which they are attached form cylopropyl then R represents a carboxylic acyloxy group other than C„ c 2—6 alkanoyloxy; or c) when R. and R 2 form a bond, R- and R. form a bond, Rg t , R g , R_ , , R g and R. _ each represent hydrogen, R_ represents chloro, then R g does not represent 4-methoxybenzyloxycarbonyl; or II) When X is sulphur and a) R 3 represents methyl; or b) R, represents hydrogen, carboxy, S (0) Y. , C_ , alkoxycarbonyl, carbamoyl, or C.__ g dialkylcarbamoyl, then R.. _ represents a carboxylic acyloxy group other than acetoxy. 2. A compound according to claim 1 represented by formula II in which Rb'represents hydrogen, 3. A compound according to either one of claims 1 and 2 wherein g represents C0 2 (CH 2 ) J in which p is 0-3 and J represents cyano, hydroxy, C_ cycloalkyl, C_ - o—o 2—6 alkanoyloxy, C 2 -6 alkoxvcar bonyl, C, . alkoxy, C. alkoxy(C._ g ) alkoxy, C j _ g alkylthio, or J represents a 5 or 6 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen; a 5 or 6 membered aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen or a carbocyclic aryl group, each of which groups is optionally substituted by C, g alkyl, C, g alkoxy or halo. 4. A compound according to either one of claims 1 and 2 wherein R g represents C0 2 NR. 2 R.- in which R.. ? represents ethyl and R. 3 represents phenyl. 5. A compound according to either one of claims 1 and 2 wherein R g represents COCH-K in which K represents C alkoxy or phenoxy. 6. A compound according to any one of claims 1 to 5 iinn wwhhiicchh RR.... 0Q rreepprreesssents hydrogen, hydroxy, halo, C. alkoxy or C, g alkyl, 7. A compound according to any one of the preceding claims in which R^ Q represents dCO(CH 2 ) L in which p is 0-3 and L represents hydrogen, C_ .. cycloalkyl; di(C._ 6 alkyl)amino; C 2 _ g alkanoyloxy; C 2 _ g alkoxy¬ carbonyl, C,_ g alkylthio; C.__ g alkoxy; adamantyl or phenyl optionally substituted by C. - alkyl, C, I— 1—6 alkoxy or halo. 8. A compound according to claim 7 in which R is substituted in the 8- or 9- position. Sβ 9. A compound according to either one of claims 7 and 8 in which represents hydrogen or C 2-6 alkoxycarbonyl and R g ' represents hydrogen. 10. A compound according to claim 1 represented by formula IV in which R 7 represents halo or trifluoromethyl, R_ represents hydrogen or halo, R gl represents hydrogen or halo and R q represents hydrogen. 11. A compound according to claim 1 represented by formula in which R g ' represents hydrogen, R.. represents OR..-, R- g or NR- 2 R. 3 in which R. 2 represents methyl or ethyl, R- _ ' represents -_g_ alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen, a 5 or 6 membered heterocyclic aryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur or nitrogen or "13 represents phenyl optionally substituted by C2-6 alkoxycarbonyl or halo; or R- j 2 and R- 3 together with nitrogen to which they are attached form a 3-8 membered non-aromatic heterocyclic ring which may contain a further heteroatom selected from oxygen, sulphur or nitrogen which may be substituted by a c - β acyloxy(C._ g )alkyl group; and R. 5 and R-ig, which may be the same or different, represent optionally substituted groups selected from C. j _ g alkyl; C 2 _ g alkenyl; C- .- cycloalkyl; a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen; phenyl; a 5 or 6 membered heterocyclic aryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur or nitrogen; R_ represents hydrogen and w 10 represents hydrogen, hydroxy, halo, C, g alkoxy or C._ g alkyl, 12. A compound according to claim 1 represented by formula VI in which R fi ' represents hydrogen, R.. represents OR , R or NR R. - in which R. represents methyl or ethyl, R- 3 represents C, g alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen, a 5 or 6 membered heterocyclic aryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur or nitrogen or R.- represents phenyl optionally substituted by C 2-6 alkoxycarbonyl or halo; or R^ and R. 3 together with nitrogen to which they are attached form a 3-8 membered non-aromatic heterocyclic ring which may contain a further heteroatom selected from oxygen, sulphur or nitrogen which may be substituted by a c n-6 acyloxy(C, g )alkyl group; and R. 5 and 16 , which may be the same or different, represent optionally substituted groups selected from C- j _ g alkyl; C 2 __ g alkenyl; C- - Q cycloalkyl; a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen; phenyl; a 5 or 6 membered heterocyclic aryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur or nitrogen; R Q represents hydrogen and R 10 represents hydrogen, hydroxy, halo, C g alkoxy or C, alkyl. 13. A compound according to claim 1 represented by formula VII in which R fi ' represents hydrogen and R fi represents hydrogen, C 2 _ g alkoxycarbonyl ©r C, g alkylthio, R.._ represents optionally substituted groups selected from C._ 6 alkyl; C alkenyl; C.^.. cycloalkyl; a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen; phenyl; a " 5 or- 6 membered heterocyclic aryl group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen. 14. A compound according to claim 1 represented by formula VIII in which R. represents optionally substituted groups selected from C. - alkyl, C- ,. alkenyl, C- , . cyclo- I — 2—b — 0 alkyl, a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen; phenyl; a 5 or 6 membered heterocyclic aryl group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen. 15. A compound according to any one of claims 1-6 represented by in which g . r_e_p r resents h ..y j drog-,e_n.. o„r m.. 1 e_thy Jr l..; / . g represents hydrogen, halo, C «,..—b alkanoyl, C2„—6_ alkoxy- carbonyl, S(0) Y , carbamoyl, carboxy or R_ and R ^ n I 5 6 together with a carbon atom to which they are attached represent cyclopropyl; R ? represents hydrogen, halo, trifluoromethyL, methoxy, C n I—_ alkyl, ' 1-6 m i represents hydrogen, halo or trifluoromethyl; v 8 represents hydrogen, halo or trifluoromethyl; R g and R„ Λ , which mav be the same o-r.1 different, each represent 10 " , ' halo; or R q represents hydrogen and R. Q represents hydrogen, halo, trifluoromethyl, hydroxy, nitro, C_ g alkanoyloxy, C 1-6 alkyl or C._ g alkoxy. 16. A compound selected from:- cyclobutylmethyl 2-(4-chlorophenyl)-3-oxo-2,3- dihydro[1 ]benzςpyrano[4,3-£]pyrazole-4-acetate 2-hydroxyethyl 2-(4-chlorophenyl)-3-oxo-2,3- dihydro[1]benzopyrano[4,3-£]pyrazole-4-acetate 2-thiomorpholinoethyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1 ]benzopyrano>[ ,3-£]pyrazole-4-acetate 2-(4-chlorophenyl)-4-(2-oxo-3-phenoxypropyl) [1]- benzopyrano[,4,3-c]pyrazol-3(2H)-one 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihydro[l ]- benzopyrano'[4,3-£]pyrazol-8-yl (3-methylthio)- propionate 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihydro[1 ]- benzopyrano[4,3-£]pyrazol-8-yl dimethyla ino acetate- * Ethyl 8-acetoxyaceto.xy-2-(4,-chlorophenyl)-3- oxo-2,3-dihydro[1]benzopyrano[4,3-£]pyrazol- 4-acetate 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihydro[1]- benzopyrano[4,3-c]pyrazol-8-yl ethyl malonate 2-(3,4-dichlorophenyl)-3a < -methyl-?3-oxo-2,3,3a,4- - / 6V- tetrahydro[1]benzothiopyrano[4,3-£]pyrazol-8-yl methoxy acetate. 17. A pharmaceutical composition comprising a compound of formula I in which X represents oxygen or sulphur; when X represents oxygen or sulphur R. represents hydrogen or together with - represents a bond; R_ together with either one of R. and - represents a bond; R3- together with either one of R2„ and R4. represents a bond; R represents hydrogen or together with R, represents a bond; or when X represents sulphur, R. and R_ represent a bond, R 3 represents methyl and R. and R.. represent hydrogen; Z represents -CH= or -N= when X represents oxygen; Z represents -CH= when X represents sulphur; R_ represents hydrogen when R 3 represents methyl, or R_ represents CH - R_. 3 when R 3 represents a bond together with either one of R„ and R.; 2 4 /I 65 * R g represents hydrogen, halo, S (0) Y. , carboxy, carbamoyl, carboxylic acyl group, an esterified carboxyl group or CONR.. 2 R 13 ; R -( represents hydrogen or methyl; o or R, and R,, together with the carbon atom to 6 b which they are attached represent cyclopropyl; R_ represents hydrogen, halo, trifluoromethyl, C._ 6 alkyl, methoxy or S(0) m Y; R_ represents hydrogen, halo or trifluoromethvl; Ro 0 , represents hydrogen, halo or trifluoromethyl; R_ and R ln , which may be the same or different, represent halo; or ^R- represents hydrogen and R. Q represents hydrogen, halo, trifluoromethyl, nitro, C. fi alkyl, C. fi alkoxy, hydroxy or a carboxylic acyloxy group; R. _ represents methyl, or ethyl or C, - cycloalkyl 12 J—o and R. _ represents C. _ alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 " or 6 membered heterocyclic aryl group or C, 0 cycloalkyl, or R._ represents phenyl optionally J—0 I -5 substituted by C 2 _ g alkoxycarbonyl or halo; or R and R. 3 together with the nitrogen with to which they are attached represent a 3-8 membered non-aromatic heterocylic group which may be substituted by a 2 _ g acyloxy(C. ^ g)alkyl group; Y. represents C, g alkyl; n is 0, 1 or 2 and is 0 or 1 A &£> or a pharmaceutically acceptable salt thereof, provided that: I) when X is oxygen, Z is -CH= and: a) Rg represents c - ι _g dialkylcarbamoyl, then R.. _ represents a carboxylic acyloxy group other than acetoxy; or b) when R g -represents hydrogen, halo, S (0) Y. , carbamoyl, carboxy, C_ c alkoxycarbonyl, C, c alkanoyl 2— — b or when R,. and R- , together with the carbon atom to b b which they are attached form cylopropyl then R represents a .carboxylic acyloxy group other than C_ , 2—6 alkanoyloxy; II) When X is sulphur, Z is -CH=, and a) R 3 represents methyl; or b) R g represents hydrogen, carboxy, S (0) Y. , C_ , alkoxycarbonyl, carbamoyl or C. c 2—b I —b dialkylcarbamoyl, then R. fi represents a carboxylic acyloxy group other than acetoxy. 18. A pharmaceutical composition according to claim 17 in unit dosage form. 19. A method of treating diseases with an immunological association in a mammal in need of such treatment comprising the administration of a therapeutically effective amount of a compound of formula I as defined in claim 17. 20. A compound of formula 1 as defined in claim 17 for use as an immunomodulatory agent. 22. A compound of formula X λ (o in which R_, R g , R g ' , R ~ g and R η 1 n 0 are as defined in claim 1 and Z is nitrogen . 22. A compound of fαrmula XIV in which R_, R_ and R are as defined in claim 1 and 3 D y R represents a carboxylic acyloxy group, R Io y represents carbamoyl or COOR n and R represents C alkyl or benzyl. 23. A pr formula 1 in which X represents oxygen or su p ur; A ' ' i R- together with R 2 represents a bond; R 3 together with R. represents a bond; Z represents -CH= or -N= when X represents oxygen; Z represents -CH= when X represents sulphur; R5_ represents CH \ - R c b, R 6 R g represents hydrogen, halo, S(0) Y. , carboxy, carbamoyl, a carboxylic acyl group, an esterified carboxyl group or C0NR--R.._; R , represents hydrogen or methyl; or Rb- and b,, together with the carbon atom to which they are attached represent cyclopropyl; R_ represents hydrogen, halo, trifluoromethyl, c ι _ 6 alkyl, methoxy or S(0) Y_; R R represents hydrogen, halo or trifluoromethyl; R g t represents hydrogen, halo or trifluoromethyl; R g and R- I Q , which may be the same or different, represent halo; or R represents hydrogen and R.._ represents hydrogen, halo, trifluoromethyl, nitro, C. c l—o alkyl, C, fi alkoxy, hydroxy or a carboxylic acyloxy group; R 12 represents methyl, ethyl or C. . cycloalkyl and R- 3 represents C alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group or C- 8 cycloalkyl or R. represents phenyl optionally substituted by C 2 _ β alkoxycarbonyl or halo; or A h5 R 12 and R. 3 together with the nitrogen to which they are attached represent a 3-8 membered non-aromatic heterocylic group which may be substituted by a C 2 _ g acyloxy(C._ g )alkyl group; Y, represents C, g alkyl; n is 0, 1 or 2 and m is 0 or 1 ; or a pharmaceutically acceptable salt thereof; provided that: I) when X is oxygen, Z is -CH= and: a) Rb, represents C.I — c dialkylcarbamoyl, then R,I 0. represents a carboxylic acyloxy group other than acetoxy; or b) when R g represents hydrogen, halo, S (0) Y. , carbamoyl, carboxy, C 2 _ g alkoxycarbonyl, C_ g alkanoyl or when R g and R gI ' together with the carbon atom to which they are attached form cylopropyl then R. „ represents a carboxylic acyloxy group other than C~_ g alkanoyloxy; or c) when R. and R 2 form a bond, 3 and R, form a bond, R g , , R , R g , , R« and R- Q each represent hydrogen, R_ represents chloro, then R g does not represent 4-methoxybenzyloxycarbonyl; or II) When X is sulphur and R c represents hydrogen, carboxy, S (0)nY.I , C2_—b_ alkoxycarbonyl, carbamoyl, or c - ι _ 6 dialkylcarbamoyl, then R. represents a carboxylic acyloxy group other than acetoxy:- a) comprising oxidising a compound of formula I in which R.. represents hydrogen, R 2 and R 3 represent a bond and R. represents hydrogen -and X, Z, R_, R_, R 0 , ^ 5 7 8 Rg 1 , Rg and R.. are as herein defined; 'rO b) comprising reacting a compound of formula X or a tautomer thereof, with " a compound of formula XI 6 '-CH-CR 2 2 23 XI R 6 in which R 22 represents (0Q) 2 and R represents OQ or NQ' ; or R 22 represents (SQ) 2 and R 3 represents SQ or NQ' ; or R 22 represents =NH and R represents OQ or SQ; or R__ represents =0 and R 23 represents a leaving group and Q and Q' represent a C alkyl group or a benzyl group; c) in which R g is selected from a carboxylic acyl group comprising reacting a compound of formula X - 1 7 | - with a compound of 'formula XI I a or a tautomer thereof, or a compound of formula Xllb or a tautomer thereof, in which R, g represents an optionally substituted group selected from C, g alkyl, C2,— c b alkenyl, CJ.—.I U. cycloalkyl, a 3-8 membered non-aromatic heterocyclic group, a carbocyclic aryl group or a 5 or 6 membered heterocyclic aryl group and R_. and R„_ which may be the same or different, 24 25 represent a C.I —b , alkyl group or a benzyl group; d) comprising reacting a compound of formula XIII XIII in which R 2g represents hydrogen or a tautomer thereof, or in which R 2g represents a group COR 2g in which R 2g represents hydrogen, an optionally substituted C. alkyl group or benzyl and 27 represents COCHR fi R g , , with a base. 24. A process to prepare a compound of formula 1 in which X represents oxygen or sulphur; R represents hydrogen; R together with R, represents a bond; R. represents hydrogen; Z represents -CH= or -N= when X represents oxygen; Z represents -CH= when X represents sulphur; R g represents CH - R g , " R 6 Rg represents hydrogen, halo, S(0) Y 1 , carboxy, carbamoyl, a carboxylic acyl group, an esterified carboxyl group or CONR. 2 R._; R g , represents hydrogen or methyl; /1*3 or Rg and R g , together with the carbon atom to which they are attached represent cyclopropyl; R_ represents hydrogen, halo, trifluoromethyl, C, 6 alkyl, methoxy or S(0) m Y-; R D represents hydrogen, halo or trifluoromethyl; o R gl represents hydrogen, halo or trifluoromethyl; R and R , which may be the same or different, represent halo; or R represents- hydrogen and R. represents hydrogen, halo, trifluoromethyl, nitro, C, _ 1 —b alkvl, C-I —b,. alkoxy, hydroxy or a carboxylic acyloxy group; R. I 2 r. represents methyl, ethvl or Cj_—o_ cycloalkyl and R., represents C, g alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group or C 3 -8 cycioaiky 1 ' or R i3 represents phenyl optionally substituted by C~ g -alkoxycarbonyl or halo; or R.. 2 and R. 3 together with the nitrogen to which they are attached represent a 3-8 membered non-aromatic heterocylic group which may be substituted by a C__ fi acyloxy(C. .)alkyl group; I—b Y,1 represents C,I — c b alkyl; • n is 0, 1 or 2 and m is 0 or 1 ; or a pharmaceutically acceptable salt thereof; provided that: I) when X is oxygen, Z is -CH= and: a) R b- represents C. I — ,. dialkylcarbamoyl , then R. I n U represents a carboxylic acyloxy. group other than acetoxy; or b) when R, represents hydrogen, halo, S (0) Y. , b n l carbamoyl, carboxy, C -6 alkoxycarbonyl, C 2 -6 alkanoyl or when R.. and R,, together with the carbon atom to b b which they are attached form cylopropyl then R.. - represents a carboxylic acyloxy group other than C 2 _ g alkanoyloxy; or II) When X is sulphur and R g represents hydrogen, carboxy, S(0) Y, , c 2 _g alkoxycarbonyl, carbamoyl, or C, g dialkylcarbamoyl, then R. Q represents a carboxylic acyloxy group other than acetoxy:- a) comprising reducing a compound of formula I wherein R.. and R 2 represents a bond; R 3 and R. represent a bond; and R g , R_, R g , R g , , R g and R.. are as herein defined; or b) comprising reacting a compound formula XIV in which R 3 represents hydrogen, R g represents CHRgRg', R 2q represents COOR 3Q or carbamoyl and R 3Q represents a C. . alkyl group or a benzyl group with a compound of formula XV /ITS ' 25. A proces's to prepare a compound of formula I in which X represents sulphur, R.. and R 2 represent a bond, R 3 represents methyl and R. and R g represent hydrogen; Z represents -CH=; R_ represents hydrogen, halo, trifluoromethyl, C, g alkyl, methoxy or S (0) Y^ ; R g represents hydrogen, 'halo or trifluoromethyl; R , represents hydrogen, halo or trifluoromethyl; o "1 R and R ιn , which may be the same or different, represent halo; or R. represents hydrogen and R. n represents hydrogen, halo, trifluoromethyl, nitro, C, fi alkyl, C, g alkoxy, hydroxy or a carboxylic acyloxy group; - Λ T6 R, 2 represents methyl, ethyl or C 3 _ g cycloalkyl and R, 3 represents C._ g alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group or C 3_ B cycloalkyl or R^ 3 represents phenyl optionally substituted by C 2 _ g alkoxycarbonyl or halo; or l 12 and R, 3 together with the nitrogen to which they are attached represent a 3-8 membered non-aromatic heterocylic group which may be substituted by a C_ 2—6 acyloxy(C g )alkyl group; Y. represents C._ g alkyl; n is 0, 1 or 2 and m is 0 or 1 ; or a pharmaceutically acceptable salt thereof, provided that R 1Q represents a carboxylic group other than acetoxy, comprising reacting a compound of formula XIV in which R 3_ r ~e~p r resents me—th-y,l-,, - r*ep r r*es-en„ts » S,, R « 5c represents hydrogen R y represen * ts COOR j_ o. or carbamoyl and R 30 represents a C, . alkyl group or a benzyl group with a compound of formula XV H 2 N- /n-T in which Z represents -CH=. 26. A process to prepare a compound of formula I in which X represents oxygen or sulphur; when X represents oxygen or sulphur R. represents hydrogen oτ together with 2 represents a bond; 2 together with either one of "R. and R_ represents a bond; R together ' ""with either one of R- and R. represents a bond; R. represents hydrogen or together with R represents a bond; or when X -repr sents sulphur, R. and R represent a bond, R, represents methyl and R. and R_ represent hydrogen; Z represents -CH= or -N= when X represents oxygen; Z represents -CH= when X represents sulphur; R 5 represents hydrogen" hen R 3 represents methyl, or R5 c represents C>H - Rb-, R, when R, represents a bond together with either one of R„ and R. A T-S R g represents hydrogen, halo, S(0) n Y. j , carboxy, carbamoyl, a carboxylic acyl group, an esterified carboxyl group or CONR- 2 R. j3 ; g , represents hydrogen or methyl; or Rb, and R c b , together with the carbon atom to which they are attached represent cyclopropyl; R_ represents hydrogen, halo, trifluoromethyl, C, g alkyl, methoxy or SfOJ^Y- j ; R 8 represents hydrogen, halo or trifluoromethyl; Ro 0 , represents hydrogen, halo or trifluoromethyl; R and R lπ , which may be the same or different, represent halo; or R g represents hydrogen and R.. fi represents hydrogen, halo, trifluoromethyl, nitro, C, g alkyl, C-_ g alkoxy, hydroxy or a carboxylic acyloxy group; R- 12_ represents methyl, ethyl or CJ_—o_ cycloalkyl and R _ represents C._ fi alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group or C- R cycloalkyl; or R. 3 represents phenyl optionally substituted by C_ 2—b- alkoxycarbonyl or halo; or R and R. 3 together with the nitrogen to which they are attached represent a 3-8 membered non-aromatic heterocylic group which may be substituted by a C_ 2—6 acyloxy(C, β )alkyl group; Y- represents C, g alkyl; n is 0, 1 or 2 and m is 0 or 1 ; yl 3 or a pharmaceutically acceptable salt thereof; provided that: I) when X is oxygen, Z is -CH= and: a) Rg represents C- | _ g dialkylcarbamoyl, then R.. Q represents a carboxylic acyloxy group other than acetoxy; or b) when R- represents hydrogen, halo, S(0) Y, , b n i carbamoyl, carboxy, C 2 _ g alkoxycarbonyl, C 2 _ g alkanoyl or when R fi and R g , together with the carbon atom to which they are attached form cylopropyl then R - represents a carboxylic acyloxy group other than C. , 2— alkanoyloxy; or c) when R. and 2 form a bond, R 3 and R 4 form a bond, R gI , R g , R gl , R g and ' R 1Q each represent hydrogen, R 7 represents chloro, then R g does not represent 4-methoxybenzyloxycarbonyl; or II) When X is sulphur and a) R, represents methyl; or b) R, represents hydrogen, carboxy, S (0) Y. , C_ c b n I 2— alkoxycarbonyl, carbamoyl, or C, fi dialkylcarbamoyl, then R. π represents a carboxylic acyloxy group other than acetoxy:- a) in which R_ represents -CHR.R ' and R- is selected 5 'b b 6 from CONR R or an esterified carboxyl group, comprising reacting a--compound- of formula I' $0 in which R..' represents R. Q , R_ represents -CHR R., , R represents COA and A represents a leaving group, with an amine of formula NHR R or an alcohol of formula R....OH in which R... represents an optionally substituted group selected from C 1-6 alkyl, C 2-6 alkenyl, C, - Q cycloalkyl, a 3-8 membered non-aromatic heterocyclic group, a carbocyclic aryl group or a 5 or 6 membered heterocyclic aryl group respectively; b) in which R, n is selected from a carboxylic acyloxy group comprising reacting a compound of formula I* R 1 AS I in which R_ represents -CHR R g , , R represents R β and R- ' represents hydroxy with an acylating agent. 27, A compound of formula 1 in which X represents oxygen or sulphur; when X represents oxygen or sulphur R. represents hydrogen or together with R 2 represents a bond; R_ together with either one of R. and R 3 represents a bond; R, together with either one of R 2 and R. represents a bond; R. represents hydrogen or together with R 3 represents a bond; or when X represents sulphur, R.. and 2 represent a bond, R, represents methyl and R. and R_ represent hydrogen; Z represents -CH=; R e represents hydrogen when R_ represents methyl, or R g represents CH - R g , when R 3 represents a bond together with either one of R 2 and R.; R g represents hydrogen, halo, S (0) Y.. , carboxy, carbamoyl, a carboxylic acyl group, an esterified carboxyl group or CONR. 2 R.. 3 ; R g , represents hydrogen or methyl; or Rg and R g , together with the carbon atom to which they are attached represent cyclopropyl; R represents hydrogen, halo, trifluoromethyl, C. g alkyl, methoxy or S (0) Y. ; R g represents hydrogen, halo or trifluoromethyl; R gl represents hydrogen, halo or trifluoromethyl; R g and R, n , which may be the same or different, represent halo; or R g represents hydrogen and R._ represents hydrogen, halo, trifluoromethyl, nitro, C. c I —b alkyl, C. β alkoxy, hydroxy or a carboxylic acyloxy group; R_ 2 represents methyl or ethyl and R. 3 represents C. g alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group; or R._ represents phenyl optionally substituted by C alkoxycarbonyl or 2—6 halo; or R 12 and R.- 3 together with the nitrogen to which they are attached represent a 3-8 membered non-aromatic I S 3 heterocylic group which may be substituted by a C 2-6 acyloxy(C, g ) alkyl group; Y. represents C, g alkyl; n is 0, 1 or 2 and m is 0 or 1 ; or a pharmaceutically acceptable salt thereof; provided that: I) when X is oxygen and: a) R g represents " C, g dialkylcarbamoyl, then R 10 represents a carboxylic acyloxy group other than acetoxy; or b) when R r represents hydrogen, halo, S (0) Y. , b n i carbamoyl, carboxy, C alkoxycarbonyl, C_ _ alkanoyl 2—b Z~ b or when R,. and R-., together with the carbon atom to b b which they are attached form cyclopropyl then R.. represents a carboxylic acyloxy group other than C__ g alkanoyloxy; or c) when R- and R 2 form a bond, R 3 and R. form a bond, Rg,, R g , Rg , , Rg and R.. Q each represent hydrogen, R_ represents chloro, then R β does not represent 4-methoxybenzyloxycarbonyl; or II) When X is sulphur and a) R 3 represents methyl; or b) R-. represents hydrogen, carboxy, S (O) Y. , C- c n i 2— alkoxycarbonyl, carbamoyl, or ≠ C. _ g dialkylcarbamoyl, then R- n represents a carboxylic acyloxy group other than acetoxy.

Inventors: GILL ONKAR SINGH, HOCKLEY MICHAEL HENRY, TITMAN ROGER BERNARD, GILL, ONKAR, SINGH, HOCKLEY, MICHAEL, HENRY, TITMAN, ROGER, BERNARD
Applicants: BOOTS CO PLC, THE BOOTS COMPANY PLC
Application year: 1991
Main classification: C07D405
IPC codes: A61K31, A61P37, C07D311, C07D335, C07D401, C07D491, C07D495