IE910365A1 - Therapeutic agents - Google Patents

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

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 represents hydrogen or together with Rg represents a bond; R2 together with either one of R- and Rg represents a bond; Rg together with either one of Rg and R4 represents a bond; R^ represents hydrogen or together with Rg represents a bond; or when X represents sulphur, and Rg represent a bond, Rg represents methyl and and Rg represent hydrogen? Z represents -CH= or -N= when X represents oxygen; Z represents -CH= when X represents sulphur; Rg represents hydrogen when Rg represents methyl or Rg represents (jH - Rg, when Rg represents a bond together with either one of R2 and R^; Rr represents hydrogen, halo, S (0) Υη , carboxy, 0 n 1 carbamoyl, a carboxylic acyl group, an esterified carboxyl group or CONR-^R^? g, represents hydrogen or methyl; or Rg and Rg, together with the carbon atom to which they are attached represent cyclopropyl; R? represents hydrogen, halo, trifluoromethyl, C1 g alkyl, methoxy or S (0) Y. m 1 / R represents 0 hydrogen, halo or trifluoromethyl; 15 Rg, represents hydrogen, halo or trifluoromethyl; Rg and R^ θ, which may be the same or different, represent halo; or Rg represents hydrogen and R^ θ represents hydrogen, halo, tri fluoromethyl, nitro, C-j_g alkyl, C. , alkoxy, hydroxy or a carboxylic acyloxy 1 — b group; R^2 represents methyl, ethyl or Cg_g cycloalkyl and R.j 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 Cg θ cycloalkyl; or R^g represents phenyl optionally substituted by C_ - alkoxycarbonyl or halo; or 2 and R.j together with the nitrogen to which they are attached represent a 3-8 membered non-aromatic heterocylic group which may be substituted by C2-6 acyloxy (C.j alkyl; Υ-j represents C^_g alkyl; n is 0, 1 or 2 and m is 0 or 1 which have immunmodulatory activity.

In our copending patent applications (patent application nos. IE 2328/89 and IE 2329/89) 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)-3oxo-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 Rg represents a bond; Rg together with either one of and Rg represents a bond; Rg together with either one of Rg and R^ represents a bond; represents hydrogen or together with Rg represents a bond; or when X represents sulphur, and Rg represent a bond, Rg represents methyl and and Rg represent hydrogen; s Z represents -CH= or -N= when X represents oxygen; Z represents -CH= when X represents sulphur; Rg represents hydrogen when Rg represents methyl, or R5 represents CH - Rg, R6 when represents a bond together with either one of R2 and R^; Rg represents hydrogen, halo, S(O)nY^ , carboxy, carbamoyl, a carboxylic acyl group, an esterified carboxyl group or CONR^R-jg? R,, represents hydrogen or methyl; or Rg and Rg, together with the carbon atom to 10 which they are attached represent cyclopropyl; R7 represents hydrogen, halo, trifluoromethyl, C^_g alkyl, methoxy or S(O) Y. m 1 rR8 represents hydrogen, halo or trifluoromethyl; Rg 1 represents hydrogen, halo or trifluoromethyl; Rg and R-jq, which may be the same or different, represent halo; or Rg represents hydrogen and R^θ represents hydrogen, halo, trifluoromethyl, nitro, C^_g alkyl, g alkoxy, hydroxy or a carboxylic acyloxy group; R-_ represents methyl, ethyl or C_ o cycloaikyl 2 J-ο and R._ represents C. c alkyl optionally substituted by I J I “ b cyano, phenyl, a 3-8 membered rfon-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group or C_ o cycloaikyl; or R-, represents phenyl optionally substituted by C_ c alkoxycarbonyl or halo; or 2— O 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 Cg_g acyloxy(C^_g)alkyl; Y^ represents C-j_g alkyl; n is 0, 1 or 2 and m is 0 or 1 provided that: I) when X is oxygen; Z = -CH= and: a) Rg represents cq _g dialkylcarbamoyl, then R^ θ represents a carboxylic acyloxy group other than acetoxy; or b) when Rg represents hydrogen, halo, S(O)nY^, carbamoyl, carboxy, C2_g alkoxycarbonyl, C2_g alkanoyl or when R, and Rr. together with the carbon atom to 0 0 which they are attached form cylopropyl then R^ θ represents a carboxylic acyloxy group other than C2_g alkanoyloxy; or c) when R^ and R2 form a bond, Rg and R4 form a bond, Rg,, Rg, Rg, , Rg and each represent hydrogen, R? represents chloro, then Rg does not represent 4-methoxybenzyloxycarbonyl; II) When X is sulphur and a) Rg represents methyl; or b) Rg represents hydrogen, carboxy, S(O)nY^, C2_g alkoxycarbonyl, carbamoyl or c-|_g dialkylcarbamoyl, then R.j θ represents a carboxy He 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 n-propy1 and isopropyl, and butyl includes n-butyl, sec-butyl, isobutyl and tert-butyl. The term halo includes fluoro, chloro or bromo.

In one class of compounds of formula 1 , R-j and Rg above defined, In another class of compounds of formula I, R^ represents hydrogen, Rg and Rg form a bond and represents hydrogen, as represented by formula III and R, , R,,, R_, Ro, Ro., Rn and Rin are as hereinabove 6 o 7 8 8 9 10 defined.

In another class of compounds of formula I, R^ and Rg form a bond, and R^ and Rg represent hydrogen, as represented by formula IV and Ry, Rg, Rg, , Rg and R^ θ are as herein defined.

Preferred substituents are as given hereinafter. More preferably R? represents halo or trifluoromethyl, Rg represents hydrogen or halo, Rg1 represents hydrogen or halo and R_ represents hydrogen, y In compounds of formula I, preferably Rg' represents hydrogen.

In certain compounds of formula I, the group R, 0 may be an esterified carboxyl group, a carboxylic acyl group or certain tertiary carboxamide groups. These groups may be represented by the formula -C0.r14 in which R^ represents an alkoxy group (for example C.| ; an alkenyloxy group (for example Cg g) ; a cycloalkoxy group (for example Cg ,^θ); 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 Cg_g)' a cycloalkyl group (for Cg_) ; 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 carboxamido 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 Rg may have the formula a) -CO.OR^g b) -CO.Rlg c) -CO.NR^2Ri3 in which R^ represents methyl, ethyl or C3_g cycloaikyl and R13 represents c-,_g alkyl optionally substituted by cyano, phenyl, a 3-8 membered nonaromatic heterocyclic group, a 5 or 6 membered heterocyclic aryl group or R^ represents phenyl optionally substituted by C„ . alkoxvcarbonyl or halo; —o or R^ 2 and R-j 2 together with the nitrogen to which they are attached represent a 3-8 membered non-aromatic heterocyclic group which may be substituted by C2_g acyloxy (C1 g) alkyl; R^ 5 and g represent c-|_g alkyl; C2 g alkenyl; C2-10 cYcloalkyl; a 3-8 membered non-aromatic heterocyclic group, a phenyl group or a 5 or 6 membered heterocyclic aryl group; each of the groups R^, R] g being optionally substituted by Z.

Z represents Z^ , Z2, phenyl, a 3-8 membered non25 aromatic heterocyclic group (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 Z2; Z^ represents halo, trifluoromethyl, hydroxy, carboxy or cyano; Zg represents c-,_g alkyl, C3-io cycloalkyl, SiOjmY^, CONR^gR^g, c-]_g alkoxy, c2-6 alkoxYcar'3Onyl^ C2_g alkanoyl, g alkanoyloxy, phenoxy, NY2Y2,, NHCOY2 or NHSO2Y2 and each may be further substituted by Z .

Y2 and Y2,, which may be the same or different, each represent hydrogen, C^_g alkyl or phenyl; R^ θ and R^ g, which may be the same or different, each represent hydrogen; c alkyl; C. .. cycloalkyl, C_ c alkenyl; a carbocyclic aryl group; a 3-8 membered non-aromatic heterocyclic group; a 5 or 6 membered heterocyclic aryl group; or R.. θ and R. together with io ι y the nitrogen to which they are attached form a 3-8 membered non-aromatic heterocyclic group.

In compounds of formula I, suitable substituents R include the following: hydrogen; halo (fluoro, chloro or bromo), preferably fluoro or chloro, most preferably chloro; carboxy; carbamoyl, S(O)nY1 in which Y^ is preferably C^_4 alkyl and n represents 0, 1 or 2 (for example methylthio, ethylthio, propylthio, methylsulphinyl, ethylsulphinyl, propylsulphonyl) , more preferably Y1 is c-,_2 alkyl, most preferably methyl; suitably n is 0 or 1 and preferably 0. Most preferably Rg represents hydrogen or C„ - alkoxycarbonyl.

In compounds of fonmula I', Rg together with Rg, and the carbon to which they are attached may form cyclopropyl.

Preferably Rg also includes CONR^2R^in which R-| 2 30 represents methyl or ethyl and R^ represents _g 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 g represents phenyl optionally substituted by C2-6 alkoxycarbonyl (for example methoxycarbonyl) or halo (for example chloro); or R1g and R^ g 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 Cg_g acyloxy (C^ _θ) alkyl group (for example propionyloxyethyl).

Preferably Rg also includes a carboxylic ester group, which is preferably represented by the formula -CO.OR15 in which R^5 represents C^_g alkyl; C2-g alkenyl; Cg_^Q 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, C3_g 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.

Preferably Rg also represents a carboxylic acyl group which is preferably represented by the formula -CO.R in which θ represents C-|_g alkyl; alkenyl; ^3-10 cycloaikyl; 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 θ alkyl, C^_g cycloaikyl, 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.

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£ represents the following; C1-6 al^ylz preferably C^_4 alkyl (for example methyl, ethyl or propyl), more preferably methyl or ethyl and most preferably methyl; C^_7 cycloaikyl, preferably cycloaikyl; C^_g alkoxy, preferably C^_4 alkoxy (for example methoxy, ethoxy or propoxy), more preferably methoxy or ethoxy, and most preferably methoxy; S (0) in which Y^ is preferably C^_4 alkyl and m represents 0, 1 or 2, (for example methylthio, ethylthio, propylthio, methylsulphinyl, ethylsulphinyl, propylsulphinyl, methylsulphonyl, ethylsulphonyl, propylsulphonyl) , more preferably Y^ is c-,_2 alkyl, most preferably methyl, suitably m is 0 or 1 and preferably 0; ^2-5 alkoxycarbonyl (for example methoxycarbonyl or ethoxycarbonyl); C2_5 alkanoyl (for example acetyl or propionyl); or C2_g alkanoyloxy (for example acetoxy or propionyloxy); CONR^ gR^ $ in which R^ θ and R^ g preferably represent hydrogen, C._g alkyl, C_ , alkenyl, C. o cycloalkyl, a 3-8 membered z — o J —σ non-aromatic heterocyclic group containing one or two heteroatoms selected from oxygen, sulphur or nitrogen; phenyl, a 5 or 6 membered heterocyclic aryl group containing one to three heteroatoms selected from oxygen, sulphur or nitrogen; or R^g and R^g 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^ θ, R^ being optionally substituted by Z.

In compounds of formula I, particularly preferred substituents Rr include: hydrogen, carboxy or -CO.R^ in which R^4 is as defined above.

Preferred esterified carboxyl groups Rg include: C_ c alkoxycarbonyl (for example methoxycarbonyl, Z“*O ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or pentyloxycarbonyl; C3_8 cycloalkoxycarbonyl (for example cyclobutoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl) or tetrahydro-2H-pyran-4-yloxycarbonyl, each of which groups ''may be substituted by: C.j g alkyl (for example methyl) ; Cg_g cycloalkyl (for example cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl) ; phenyl; a 3-8 membered non-aromatic heterocyclic group containing one or two heteroatoms selected from nitrogen, oxygen or sulphur, (for example tetrahydrofuryl, tetrahydropyranyl, morpholino, 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); C2-6 alkoxycarbonyl (for example ethoxycarbonyl); C2-6 alkanoyl (for example acetyl); Cj_g alkoxy (for example methoxy or ethoxy); S(O)mY1 (for example methylthio); alkanoyloxy (for example acetoxy); cyano, hydroxy, acetamido, trifluoromethyl, halo. The optional Cj_g alkoxy substituent may further be substituted with Cn r alkoxy (for example methoxy) or C_ c alkanoyloxy I —o Z“O (for example acetoxy). The optional phenyl, nonaromatic heterocyclic group or aromatic heterocyclic group substituent may further be substituted by c-,_g alkyl (for example methyl), c-j_g alkoxy (for example methoxy), halo (for example chloro).

In especially preferred compounds Rg represents CO2(CH^)^J in which p is 0-3 and J represents cyano, hydroxy, C3_g cycloalkyl, C2_g alkanoyloxy, C2_6 alkoxycarbonyl, C^_g alkoxy, C]_g alkoxy(C^_θ)alkoxy, C. , 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 _g alkyl, _g alkoxy or halo. Preferably p is 1 or 2.

Particularly preferred substituents Rg also include a carboxylic acyl group which may be C2_g cycloalkylcarbonyl (for example cyclopropylcarbonyl, cyclohexylcarbonyl) ; or ^2_θ alkanoyl (for example acetyl, propionyl, butyryl, pentanoyl, hexanoyl), which may be substituted with phenyl or phenoxy each optionally substituted by halo, C^_4 alkyl, or C^_4 alkoxy; or C2_g alkanoyl may be substituted with C2_g alkoxycarbonyl (for example methoxycarbonyl), C2-6 alkoxy (for example methoxy), C]_4 alkylthio (for example methylthio), C3_g cycloaikyl (for example cyclopentyl).

In especially preferred compounds Rg represents COCH2k in which k represents alkoxy or phenoxy.

Particularly preferred substituents Rg may also include the group CONR^ 2R-| 3 in which 2 represents methyl or ethyl, preferably methyl, and R^includes phenyl or C^_4 alkyl (more preferably methyl or ethyl, and most preferably methyl) substituted with phenyl. Most preferably R^2 represents ethyl and R^ represents phenyl.

Especially preferred substituents Rg include hydrogen; cyclopropylmethoxycarbonyl; 2-methoxybenzyloxycarbony1; 4-chlorobenzyloxycarbonyl; 2-methylbenzyloxycarbonyl; 3-methylbenzyloxycarbonyl; 2- acetamidoethoxycarbonyl; 2-(2-methylpiperidino)ethoxycarbonyl; 3- (2-propionyloxyethyl)-3-azapentamethylenecarbamoyl; methyl (2-methylpheny1) carbamoyl; methyl(3-methylphenyl)carbamoyl; methyl (4-methylpheny1) carbamoyl; methyl(1,3-dioxolan-2-yl-methyl)carbamoyl; chloro; bromo; methylthio; ethylthio; methylsulphinyl; methylsulphonyl; carboxy; methoxycarbonyl; ethoxycarbonyl; propoxycarbonyl; butoxycarbonyl; pentyloxycarbonyl; cyclobutyloxycarbonyl; cyclopentyloxycarbonyl; cyclohexyloxycarbonyl; tetrahydro-2H-pyran-4-yloxycarbonyl; cyclobutylmethoxycarbonyl; tetrahydrofurfuryloxycarbonyl; 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-methoxyethoxy)ethoxycarbonyl; 3- oxobutoxycarbonyl; 2-(2-chlorophenyl)ethoxycarbonyl; 2-(3-methylphenyl)ethoxycarbonyl; 4,4,4-trifluorobutoxycarbonyl; 2-morpholinoethoxycarbonyl; 2-piperidinoethoxycarbonyl; 2- thiomorpholinoethoxycarbonyl; 1-methyl-2-morpholinoethoxycarbonyl; 3- morpholinopropoxycarbonyl; 3-(4-methyl-1-piperazinyl)propoxycarbonyl; 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-(Ν,Ν-dimethylamino)phenyl]ethoxycarbonyl; 2- phenylpropoxycarbonyl; 3-acetoxypropoxycarbonyl; 3- hydroxypropoxycarbony1; 4-chlorophenyl(methyl)carbamoyl; 4-(2-acetoxy-ethyl)piperazinylcarbonyl; 4-(2-propionoxy-ethyl)piperazinylcarbonyl; 4-methoxycarbonylphenyl(methyl)carbamoyl; 2-(4-methoxyphenyl)propionyl; 4-chlorophenoxyacetyl; cyclopentvlacetyl; 2-(3-methylphenyl)propionyl; 2-methylphenoxyacetyl; 2-methylthiopropionyl; methoxyacetyl.

In compounds of formula I, suitable substituents 10 R? include the following: Hydrogen; halo (fluoro, chloro, bromo), preferably fluoro or chloro, more preferably chloro; trifluoromethyl ;C^ θ alkyl, preferably alkyl (for example methyl, ethyl or propyl), more preferably methyl or ethyl, most preferably methyl; methoxy, in which R^ is preferably alkyl and m represents 0 or 1, (for example methylthio, ethylthio, propylthio, methylsulphinyl, ethylsulphinyl, propylsulphinyl.) preferably m is 0, more preferably is _2 alkyl, most preferably methyl.

In preferred compounds of formula I, Rg represents hydrogen, fluoro, chloro or trifluoromethyl, more preferably hydrogen or chloro, and most preferably hydrogen.

In preferred compounds of formula I, Rg ’ represents hydrogen or chloro^ especially hydrogen.

The substituents Rg and R1 θ may be located at any position on the benz ring, namely in position 6-, 7-, 8- and/or 9- of the benz ring. Accordingly each of the substituents R and R specified herein are considered y i u to be named at each of these positions. In one group of compounds R^θ is located at position 6- or 7- of the benz ring, especially position 6-. In a preferred group of compounds is located at position 8- or 9of the benz ring, especially position 8-.

In preferred compounds of formula I, Rg represents 5 hydrogen, fluoro or chloro, more preferably hydrogen or fluoro, most preferably hydrogen.

In certain compounds of formula I, the group R^ θ may represent a carboxylic acyloxy group and may have the formula io - o.co.r17 in which R^ ? represents an alkyl group (e.g. C^_g); an alkenyl group (e.g. C. r) ; a cycloaikyl group (e.g. η) * 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^ 7 represents C^_g alkyl; c2_g alkenyl; C3_1-j cycloaikyl; 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-j_g alkyl, c2_g alkenyl, C3 θ cycloaikyl, 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 7 being optionally substituted by Z^ or Z2· Readily hydrolysable esters are included within the scope of the present invention as well as those which are less readily hydrolysable. Preferably θ represents hydrogen, fluoro, chloro, bromo, trifluoromethyl, hydroxy, nitro, c-]_g alkyl (preferably C^_4 alkyl), C^g alkoxy (preferably _4 alkoxy) or a carboxylic acyloxy group as hereinabove defined. More preferably R^ θ represents hydrogen, halo (preferably fluoro or chloro), hydroxy, C. c alkoxy (for example methoxy), C alkvl (for example methyl) -b or nitro or a carboxylic acyloxy group. Most 5 preferably R^ θ represents hydrogen, fluoro, hydroxy or a carboxylic acyloxy group.

In particularly preferred compounds of formula I, R.J θ includes: hydrogen; hydroxy; Cg cycloalkanoyloxy (for example 10 cycloproylcarbonyl, cyclobutylcarbonyl or adamantylcarbonyloxy); Cg_g alkanoyloxy (for example acetoxy or propionyloxy) or Cg g alkenoyloxy, both of which may be substituted with a substituent selected from Cg_g alkanoyloxy (for example acetoxy), S(O)mY^ (for example methylthio), ci_g alkoxy (for example methoxy), carboxy, chloro, phenyl, di(C^_g)alkylamino or c2-6 alkoxycarbonyl (for example methoxycarbonyl or ethoxycarbonyl) and further optionally substituted by optionally substituted phenyl (for example 4-methoxy20 phenyl, 4-methylphenyl, 4-chlorophenyl); or R^θ represents arylcarbonyloxy in which the aryl group is suitably phenyl, thienyl, furyl, pyridyl [which may themselves by substituted with C. c alkyl (for example I -b methyl), C alkoxy (for example methoxy) or halo (for 1—6 example chloro)].

Preferred are those in which R^ θ represents OCO(CH-) L in which p is 0-3 and L represents hydrogen, z p Cg -ii cycloalkyl; di (C^ _galkyl) ainino; Cg_g alkanoyloxy; Cg g alkoxycarbonyl, c-j_g alkylthio; c-|_g alkoxy; adamantyl or phenyl optionally substituted by c-, _g alkyl, C- c alkoxy or halo.

I — b 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; 5 methoxyacetoxy; 4-methoxybenzyloxycarbonylacetoxy; ethoxycarbonylacetoxy; but-2-enoyloxy; 3- ethoxycarbonylpropionyloxy; carboxyacetoxy; adamantylcarbonyloxy; 3-phenylpropionyl; methylthioacetoxy; phenylacetoxy; dimethylaminoacetoxy; thenoyloxy; furoyloxy; 2-methylbenzoyloxy; 2-methoxybenzoyloxy; 4-methoxybenzoyloxy; pyridylcarbonyloxy; eyelopropylcarbonyloxy; cyclobutylcarbonyloxy; 4- methylbenzoyloxy; 3-methylbenzoyloxy.

A more preferred class of compounds of formula I V and R. and preferred mula I i hydrogen, R, in which R, ‘6 ' 7' R8' R9' 10 “““ 14 substituents thereof are as recited in formula I above.

More preferably, Rg1 represents 4 represents 0R15, g NRi2R13 in which Ri2 rePresents methyl or ethyl, R^ represents c-j_g alkyl optionally substituted by cyano, phenyl, a 3-8 membered nonaromatic heterocyclic group containing 1 or 2 hetero25 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 or R.j 2 represents phenyl optionally substituted by C2_g alkoxycarbonyl or halo; or R^ 2 and R^ 2 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 C2-6 acyloxy (C^ _g) alkyl group; and R^ and R-| g , which may be the same or different, represent optionally substituted groups selected from g alkyl; C2_g alkenyl; θ 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; Rg represents hydrogen and R^θ represents hydrogen, hydroxy, halo, g alkoxy or C-j_g alkyl.

A further more preferred class of compounds of formula I are those represented by formula VI in which Rg, , R?, Rg, Rg, R] Q and R1 4 and preferred substituents thereof, are as defined with respect to formula I above. More preferably, Rg' represents hydrogen, R1 represents OR^5, θ or NR^2R^g in which R^ 2 represents methyl or ethyl, R^ g 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^ g represents phenyl optionally substituted by Cg g alkoxycarbonyl or halo? or R^ g and R^ g 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 Cg g acyloxy(C^_g)alkyl group; and R^$ and g, which may be the same or different, represent optionally substituted groups selected from c-|_g alkyl; C2-6 alkenyl; Cg_]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; Rg represents hydrogen and R^ θ 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 Rg, Rg', R?, Rg, and R1 ? and preferred substituents thereof are as defined with respect to formula I above. Preferably the substituent O.CO.R^ is located in the 8-position or 9-position of the ring system, especially the 8-position. More preferably Rg' represents hydrogen and Rg represents hydrogen, Cg_g alkoxycarbonyl or C]_g alkylthio, R-j ? represents optionally substituted groups selected from C^_g alkyl; C2_g alkenyl; C3_-| ·, cycloaikyl; a 3-8 membered nonaromatic 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.

A further more preferred class of compounds of formula I are those represented by formula VIII in which R , Ro and Rn _ and preferred substituents thereof, are as defined with respect for formula I above. More preferably R^represents optionally substituted groups selected from g alkyl; C2-6 alkenyl; cycloaikyl; 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.

A further more preferred class of compounds of /* formula I are those represented by formula IX O in which Rg, Rg,, R^, Rg, Rg,, Rg and R^ θ and preferred substituents thereof, are as defined with respect to formula I above. More preferably Rg' represents hydrogen or methyl; Rg represents hydrogen, halo, C2-g alkanoyl, C_ , alkoxycarbonyl, S(0) ΥΊ , carbamoyl, z-o η ι carboxy or R_ and Rr together with a carbon atom to 5 Ό which they are attached represent cyclopropyl; R? represents hydrogen, halo, trifluoromethyl, methoxy, C1 g alkyl, S(0) Y^; Rg represents hydrogen, halo or trifluoromethyl; Rg’ represents hydrogen, halo or trifluoromethyl; Rg and θ, which may be the same or different, each represent halo; or Rg represents hydrogen and R^ θ represents hydrogen, halo, trifluoromethyl, hydroxy, nitro, Cg_g alkanoyloxy, C-|_g alkyl or θ alkoxy.

In one preferred group of compounds X represents oxygen. In a further preferred group of compounds Rg represents C0R^4, especially COOR^g, X preferably represents oxygen and Z preferably represents -CH=. In a further preferred group of compounds R^θ represents OCOR^7, 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 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 liquid chromatography; selective derivatisation of one enantiomer by reaction with an 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 [ 1]benzothiopyrano20 [4,3-c]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-chlorophenyl)-3-oxo-l,2,3,4tetrahydro[1]benzopyrano[4,3-c]pyrazole-4-acetate. x* When compounds of formula I contain more than one chiral centre, the compounds may exist in diastereoisomeric forms. 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 5 acid addition salts with inorganic or organic acids, for example hydrochloric acid, hydrobromic 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-cJpyrazole 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 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 0.1-90¾ 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 methods, 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 pharmadeutical 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 of formula I are indicated for use as immunomodulatory agents, and are generally immunosuppressants, but some compounds, in certain disease states, may exhibit immunostimulant activity. The compounds according to the invention are useful in the treatment of diseases 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 immunological 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 effect and is generally in the range 0.1 to 2000 mg, preferably 1 to 500 mg.

Accordingly, in another aspect, the present invention also includes a method of treating diseases with an immunological 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.

X* 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 R6 — Cr22R23 in whichR22 represents (OQ)2 andR23 represents OQ or NQ’ 2! OrR22 represents (SQ)2 andR23 represents SQ or NQ’2, orR22 represents =NH andR23 represents OQ or SQ; or R 22 represents = 0 andR23 represents a leaving group for example an optionally substituted 1-imidazolyl group, in which Q and Q' represent a C^_4 alkyl group or a benzyl group, for example by heating at 50-200°C. z Compounds of formula I which are represented by formula II in which Rg, represents hydrogen and Rg represents a carboxylic acyl group may be prepared by reacting compounds of formula X with compounds of formula Xlla Xlla or a tautomer thereof, in which an<^ R25 ma^ same or different, and each represent a C^_g 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 Rg 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 R24 and R2g may be the same or different and each represents a c-,_g alkyl 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 Rr represents a group 0 CONR.J 2R^ or an esterified carboxyl group may be prepared by reacting compounds of formula II' in which θ, represents R^ θ and Ra represents COA, where A represents: a leaving group, for example hydroxyl, halo, c-|“cg alkoxy, aryloxy, arylmethoxy, C-j-Cg acyloxy or g alkoxycarbonyloxy with an amine of formula NHR^or an alcohol, for example of formula R^^OH respectively, for example at 0-250°C, 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 Rg 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 Rig represents a carboxylic acyloxy group may be prepared by acylating compounds of formula II' in which R represents Rr and a o R-j θ, 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^^COCl or an acid anhydride (R^^CO)2θ 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^ ^COOH in the presence of a dehydrating agent, for example dicyclohexylcarbodiimide, preferably in the presence of a base e.g. pyridine. Compounds of formula II' in which θ, represents hydroxy may be prepared by reacting compounds of formula II' in which R^ θ, represents a C]_5 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- and R ' both represent hydrogen b b may be prepared by decarboxylating compounds of formula II in which Rg, represents hydrogen and Rg represents carboxyl, or by hydrolysing compounds of formula II in which Rg' represents hydrogen and Rg represents a group which may be hydrolysed to a carboxyl group such as a C„ c 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 Rg represents a C^_g alkylsulphinyl group or a C-j_g alkylsulphonyl group may be prepared by oxidation of compounds of formula II in which Rg represents a C. c alkylthio group with, for example, 3-chloroperoxybenzoic acid.

Compounds of formula I which are represented by compounds of formula II in which Rg represents a carboxyl group may be prepared from compounds of formula II in which Rg represents 4-methoxybenzyloxycarbonyl 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^θ represents a carboxyalkylcarbonyloxy group for example carboxyacetoxy, may be prepared from compounds of formula II in which R^θ represents 4-methoxybenzyloxycarbonylalkylcarbonyloxy, for example 4-methoxybenzyloxycarbonylacetoxy, 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 XIII XIII in which R„, represents hydrogen, or a tautomer 2 o thereof, or in which R^g represents a group COR^g wherein R„o represents hydrogen, an optionally z substituted C-|_4 alkyl group or a benzyl group and R^ represents COCHRgRg,, 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 are 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 5 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 XIV in which Rg represents hydrogen, R^ represents CHRgRg,, R29 represents COOR3Q or carbamoyl and R3Q represents a C^ alkyl group or a benzyl group with a hydrazine of formula XV 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 be prepared by reacting compounds of formula XIV in which X represents S, R^ represents methyl, R^ represents hydrogen and R^g and R^q 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 compounds of formula XVI reacting in which R^ represents hydrogen, a C^_4 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 θ represents a hydroxyl group may be prepared by reacting compounds of formula X in which R,. represents a C- c alkoxy group 1 U I —b with a Lewis acid, for example aluminium chloride or boron tribromide.

Compounds of formula XI in which Rgg represents (OQ)g and Rgg represents OQ may be prepared for example a) by reacting compounds of formula Rg,RgCH-CXg in which X is halo with a sodium alkoxide of formula NaOQ in which Q is a C^_4 alkyl group or a benzyl group, or b) by reacting compounds of forfhula Rg,RgCH-CN with an alcohol of formula QOH in the presence of an anhydrous acid, for example hydrogen chloride, to give compounds of formula Rg,RgCH-C(=NH)OQ as their acid salts, e.g. hydrochloride salts, which are then reacted with further alcohol of formula QOH. Ε 91365 Compounds of formula XI in which 1^2 represents (SQ)2 and R23 represents SQ may be prepared for example from compounds of formula Rg,RgCH-COCl by reaction with thiols of formula QSH in which Q represents a C^_4 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 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 R2g represents COR2g and R27 represents COCHRgRg, may be prepared by acylation of compounds of formula XIII in which R2g represents COR28 an(^ R27 reFfresents hydrogen, for example by reaction with an acid anhydride of formula (Rg,RgCHCO)2θ or an acid halide e.g. of formula Rr,RCHCOC1. 6 Compounds of formula XIII in which R2g represents COR and R represents hydrogen may be prepared by 2 o 27 the acylation of compounds of formula X for example by reaction with an acid anhydride of formula (R2gCO)20 in the presence of a salt (e.g. the sodium salt) of the corresponding acid.

Compounds of formula XIII in which R^ and R2? are 5 identical and represent COCHRg,Rg, may be prepared by acylation of compounds of formula X for example by using an acid anhydride of formula (Rg,RgCHCO)2O in the presence of a salt (e.g. the sodium salt) of the corresponding acid.

Compounds of formula XIII in which R27 represents COCHR-R,, and represents hydrogen, or tautomers b b zb thereof, may be prepared by reacting a compound of formula XIII in which R2g represents COR2g and R2^ represents COCHRgRg, with a base e.g. piperidine in a suitable solvent e.g. ethanol.

Compounds of formula XIV in which R2g represents COOR30 and Rg represents CHRgRg, may be prepared by heating compounds of formula XX in which R3Q represents a C]-4 alkyl group or a benzyl group, for example with glass powder or glass wool.

Compounds of formula XIV in which R3 represents methyl and Rg represents hydrogen may be prepared by reacting compounds of formula XVIII R 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-Q represents 2 y carbamoyl may be prepared from compounds of formula XIV in which R_o represents cyano by methods known to those 2 y skilled in the art.

Compounds known to those of formula XV may be made by methods skilled in the art.

Compounds of formula XVI in which represents hydrogen may be prepared by reacting compounds of formula XXI r33 'XH XXI in which Rgg 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 Rg^ represents hydrogen may be prepared by reacting compounds of formula XXI in which Rgg represents a group CORg^ in which Rg4 represents a C^_g alkyl group, with a base, for example sodium hydride, followed by treatment with a dialkyl carbonate of formula (QO)gCO in which Q represents a C^_4 alkyl group or a benzyl group, e.g. dimethyl carbonate.

Compounds of formula XVI in which Rg^ represents a 10 c-|_4 alkyl group or a benzyl group may be prepared by base catalysed alkylation or benzylation of compounds of formula XVI in which Rg^ 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 mixture of compounds of formula obtained, these compounds may be separated by virtue of their different solubilities in an organic liquid for example dichloromethane.

In cases where a X and XVII are 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^ θ represents R^OC.O may be prepared by acylation of compounds of formula II in which R^ θ represents a hydroxyl group. During the acylation reaction there may be formed compounds of formula XXII R17OCO XXII 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, 5 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 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 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 in methanol (10 ml) with The solution was cooled to solution of 6-methoxy-4thiochromanone (1.2 g) in methanol (6 ml) was added solution of sodium (0.3 g) warming to aid dissolution, ambient temperature and a dropwise over 15 minutes. ambient temperature for 3 stand for 4 days. The The mixture was stirred at hours and then allowed to solvent was removed under reduced pressure and the residue partitioned between water and toluene. The aqueous layer was basified with ••-*0745 2M sodium hydroxide solution, separated and acidified with 2M hydrochloric acid. The solid formed was collected by filtration and recrystallised from methanol to give methyl 6-methoxy-4-oxo-3-thiochroman5 glyoxylate, m.p. 85-89°C. b) A mixture of methyl 6-methoxy-4-oxo-3-thiochromanglyoxylate (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-thiochromancarboxylate, m.p. 61-65°C. c) A solution of methyl 6-methoxy-4-oxo-3-thiochromancarboxylate (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 then 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 water, dried and evaporated under z 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-methyl-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 160-1 70°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-3in tetrahydrofuran (40 ml) under A 3M solution of methylmagnesium carboxylate (4 g) nitrogen at -78°C. 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-3thiochromancarboxylate 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-l,3dioxane-4,6-dione (20 g) in dichloromethane (220 ml) at Ο °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)-410 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-l,3-dioxane-4,6-dione (XIX) with R^gCOCl (in which R. c is as defined), as summarised in Table 1 1 0 below. z Table r— tn n MO Φ ·—’ +j A Λ o r— 1— 1— r— t— CN kD in 1— 2 — ** '**' 4-1 MO 0 43 — r— H u <— o • 1—1 o 1 σ\ a X — in 1 • »— 00 ε chloro- thane (ml) 1 1 I 1 1 1 00 1 1 tn o o o o o CM ο o o o O 4-) •r4 Φ CN CN CN CN r— CO ο 00 in CM c q ε t— »— r— 1— CN »— CN CN CN CN r— (0 4-) Φ O a td r-4 r-| r—l r—l Φ Ό — ε ε ε ε •r4 tP o o o o r— co in CO o kD 0 J-l • M-l CM CN CM CN kD CN kD co CN CN 0 cm “ ·- - ·“ “ *” r— r— *“ CN *“* tn Γ—1 44 u r—l c o ε o o — kD CM o GO co Γ- O CN r- o MOtp ε t - r— r— Γ“ Γ~ 00 τ— n in i— 00 K T— *” r— »— CN o o o o Γ- ο o o o o 0 X — • H tP o o o o ro ο 1— o o 0 X - Γ“ r— CN ι—1 ι—1 >1 >1 45 43 *—1 4-) 44 Φ ι—1 1—t Φ r—4 43 ε >M >1 ε ^*1 4-) Κ*Ί 45 43 43 Φ X 4-> 44 X 44 C 0 Φ Φ o Φ i—4 Φ S3 C ε c O r-4 43 Φ Φ 1—t Φ •H 43 r—l a 43 43 >1 43 43 44 >1 a >1 a a 44 a 44 Φ X o X 0 r-4 (3 i—H I—1 ε Φ >4 o >4 Φ >< >1 43 43 a 43 ο 43 XX 43 43 X 43 CM 0 0 4-) ι—1 4-> O 44 44 0 Cm O r—1 ι—1 Φ 43 Φ r-1 Φ Φ 43 kD CN CM o o ε Ο ε o ε ε 44 r- 33 W >1 >. 1 1 >1 I Φ ex u u o o Μ* m υ CN CM ε X ο CM CO in w in kD c- 00 r— — — <- mom 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. (5) The crude product was purified by trituration with 10 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 15 as follows: 2,2-dimethyl-5-phenylacetyl-1,3-dioxane-4,6dione 2,2-dimethyl-5-phenoxyacetyl-1,3-dioxane-4,6dione 7 5-cyclohexylcarbonyl-2,2-dimethyl-l,3-dioxane4,6-dione -cyclopropylcarbonyl-2,2-dimethyl-l,3dioxane-4,6-dione 2,2-dimethyl-5-[3-(4-methoxyphenyl)propionyl]-1, 3-dioxane-4,6-dione - (4-chlorophenoxyacetyl)-2,2-dimethyl-l,3dioxane-4,6-dione 2,2-dimethyl-5-[3-(3-methylphenyl)propionyl]1,3-dioxane-4,6-dione -(2-cyclopentyl-l-hydroxyethylidene)-2,2dimethyl-1,3-dioxane-4,6-dione 13 5-[1-hydroxy-2-(2-methylphenoxy)ethylidene]2,2-dimethyl-l,3-dioxane-4,6-dione 2,2-dimethyl-5-(3-methylthiopropionyl)-1,3dioxane-4,6-dione -methoxyacetyl-2,2-dimethyl-l,3-dioxane-4,610 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. (h) 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 (300 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 methylthioacetimidate hydrochloride as a sticky solid. b) A mixture of the methyl methylthioacetimidate hydrochloride and methanol (551 ml) was stirred at -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-6methoxyphenyl)-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 (5fO 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)-230 pyrazolin-5-one, m.p. 197-203°C. b) 1-(4-Chlorophenyl)-3-(2-hydroxy-5-methoxyphenyl)-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)-210 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-trifluoro20 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. z b) A mixture of crude 6-methoxy-4-[2-(4-trifluoromethylphenyl)hydrazino]coumarin (8.5 g), 5M hydro30 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 -(454 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-trifluoromethylphenyl)-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)-2pyrazolin-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 zhours, 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 IE 91365 acid (9:1) as the mobile phase. The appropriate fractions were combined, washed, dried and evaporated to give a solid which was recrystallised from aqueous industrial methylated spirit to give 1 - (4-bromophenyl)5 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-dichlorophenylhydrazine (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-dichlorophenyl) -3-(2-hydroxy-5-methoxyphenyl)-2-pyrazolin-5one, m.p. 210-211°C. b) A stirred mixture of 1 -(3,4-dichlorophenyl)-3-(2hydroxy-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)-2pyrazolin-5-one. ' Example 24 A stirred mixture of 4-hydroxycoumarin (14.3 g) 30 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 91365 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-5one, 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, Rg and Rg^ are hydrogen and R^θ is as defined) with a compound of formula XV (in which Z is -CH=, Rg, is hydrogen and R and Ro are as defined) as summarised in Table 2 7 8 below.

IE 91365 - 57 CN TABLE CO Z M-l —.

O U X o Cu ε X co 3 +) c (C +J o <0 cu 4J c O ε cu C x-K φ rd s ε rH o Eh > &> X ~ I-1 -> 01 X ~ r-~ ω ι—( Cb ε (0 X ω P“ CN r— r~ cn in in *3* in o cn 00 CO r* r·— CM co o 00 σι r-~ co cn 00 ’SP CM r— >- CN r“ r— 1 1 o LD o CN cn O kO σι 00 σι r- cn Γ- cn 00 V r~ CM *“ m in CN CN o o o o o Ti* CN CN CM CM CM V o o cn o in o o o Γ- o in in I—· o o m Γ“ in GO 00 Γ o C σ> GO Γ' o »— r— cn r— *“ CN *“ CN CN CN o kO o o r“ o r-~ IO in Γ' CN cn cn in CM rH rH u S3 S3 S3 SS S3 SB S3 u cn cn S3 cn rH rH M rH fa u S3 υ u « Cm u U o U ffi cu Pm 2 SS kO SS SS kO S3 S3 S3 S3 X ID in in id rCN CN CN co σι CN CN cn -OH Cl H 10.0 10.0 200 4.5 268-271 cn m «31 cn cn cn in co in 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. as The compounds prepared in the above Examples were follows :- 25 1-(3,4-dichlorophenyl)-3-(2-hydroxyphenyl)-2- pyrazolin-5-one 26 1 -(4-chlorophenyl)-3-(5-fluoro-2-hydroxyphenyl)- 20 2-pyrazolin-5-one 27 1 - (4-bromophenyl) -3- (2-hydrzoxyphenyl) -2- pyrazolin-5-one 28 1 -(4-fluorophenyl)-3-(2-hydroxyphenyl)-2pyrazolin-5-one 25 29 1 -(4-chlorophenyl)-3-(2-hydroxy-5-methylphenyl)-2pyrazolin-5-one 3-(2-hydroxyphenyl)-1-(4-trifluoromethylphenyl)2-pyrazolin-5-one 3-(2-hydroxyphenyl)-1 -(4-methoxyphenyl)-2pyrazolin-5-one 32 3-(2-hydroxyphenyl)-1 -(4-methylphenyl)-2pyrazolin-5-one 1-(3-chlorophenyl)-3-(2-hydroxyphenyl)-2pyrazolin-5-one 1 -(4-chlorophenyl)-3-(2 ,6-dihydroxyphenyl)-210 pyrazolin-5-one Examples 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, Rg and R^ are hydrogen and R^θ is as defined) with a compound of formula XV (in which Z is -N= and R^, Rg and Rg, are as defined) as summarised in Table 3 below. z Table cn m MO φ *—* 4-> κ 0 CM in CN 00 2 *—* *—* M-l 00 σ> tn ro kD o o ro 0 σι [ σ r— o σ CN σ u f— r— r— CN CN 1— CN f— • X o 1 1 1 1 1 1 1 1 a kD «3* co ro <— o co co r— • ο o I— o 00 r— σ» ε r—· CN *— CN CN f—' CN r— X cn b ω )4 i—4 ε b in ro in in 4-1 •r4 0 MO • • kD • • Φ Η 43 r— CN in r— CN CN CN « o o MO in cn •**s» o o o 44 x ε o O o o o in in in σ\ c b b — kO σ> ro in CN CN I— fd r-4 ·Η H +4 44 ό ε o id Ό u 43 T3 Ό Ό 0 ω φ — r— r— r—· f—- r- p— r— nJ ex ε ·*-* *-«* Φ ex © o o o in o 00 o 00 4-1 0 > CP co in r- ro in X — r— r— -P β b r— I— r— r· o N< o o o Η —κ ε > CP ro ro ro in CN CN in o < X — r— co ι—1 ex S3 a a a u a a a a ro 00 t—1 Pm i—4 > ex B cj a CJ a CJ a a a X ro cn co r-· Cm i—4 Pm )4 »—1 t-l ex U a cj a a CJ a CJ CJ a H o o Cm > f- z ι 1 X ex a a a a a a a in MO φ r-4 a ε (0 X LD kD r- 00 σ o r~ CN co ω m n co co co m ο in 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 20 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 evaporated to dryness, dichloromethane, hot the toluene liquors were The residue was boiled with 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:- 3-(2-hydroxyphenyl)-1 -(5-trifluoromethyl-2pyridyl)-2-pyrazolin-5-one 10 36 1 -(6-chloro-2-pyridyl)-3-(2-hydroxyphenyl)-2pyrazolin-5-one 37 1 -(5-chloro-2-pyridyl)-3-(2-hydroxyphenyl)-2pyrazolin-5-one 38 3-(2-hydroxyphenyl)-1 -(6-trifluoromethyl-2- 15 pyridyl)-2-pyrazolin-5-one 39 1 -(4-chloro-2-pyridyl)-3-(2-hydroxyphenyl)-2pyrazolin-5-one 40 1 - (6-chloro-5-trifluoromethyl-2-pyridyl)-3(2-hydroxyphenyl)-2-pyrazolin-5-one 20 41 1 -(5-bromo-2-pyridyl)-3-(2-hydroxyphenyl, -2pyrazolin-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- 25 2-pyridyl)-2-pyrazolin-5-one Example 44 z 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 at ambient temperature for 18 hours. The filtrate was evaporated, the solid residue dissolved in dichloromethane and the solution washed with water, dried and concentrated and the solid obtained washed with dichloromethane to give 3-(2-mercaptophenyl)-1 -(4trifluoromethylphenyl)-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-(2hydroxyphenyl)-2-pyrazolin-5-one (2.9 g) and tripropyl ortho(propoxycarbonyl)acetate (8.7 g) was heated at 145-150°C for 40 minutes. 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[1Jbenzopyrano[4,3-c]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-pyrazolin5-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-chl'orophenyl) -8-hydroxy-325 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-(2hydroxyphenyl)-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[1J 5 benzopyrano[4,3-c]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 Rg, is hydrogen and R is COOC-H,.) was prepared.by reacting a compound of formula X (in which Z is -CH=, Rg’ and Rg represent hydrogen and X, R?, Rg and R^ θ are as defined) with triethyl ortho(ethoxycarbonyl,acetate (XI) as summarised in Table 4 below: z % <* Table W (U +J Ο z M-l O - — H U Cb l-H o e cp c — -r4 Q) cn 4J ε c (Ό Ή ·Η M-l cn 4-) cn 4-) £ <0 £ 4-1 < 05 H tP X — CP X o r— r* X cu rH cu ε λ X fa CN <— t— CQ »— o^f- -ο—» O CN r- CN V in kD I— kO co in in in in r* in in Γ- o CN *- Y r— <— I t— r— I p— I I 1 CN | I 1 r* 1 o 1 CQ 1 o 1 CN Λ 1 CQ 1 o 1 CQ 1 CN 1 in 1 cn co in n- in in in r* <3* in in o v CN I— I— j— i— 1— I— r— 1— r— CN t— in o in o o o o o -- r— i— ID CN in in in tn in o 00 σ> -- ΟΛ σ\ σ\ 00 ID -- r* cn C- ID n- 00 cn Γ' Γ' Γ r— r- CP CN Γ— 00 p— 00 CN CN ID 00 in in ,- ,- in CQ CN CQ *3* -- CQ CQ o o CQ -- CQ CQ a a a a u O fa u o o in in in a a a kD a a a a ID a r-H rH a B a u a a a a a a u a a CQ cn a CQ CQ rH rH rH ι—1 bl rH fa u a rH Pm u u u u a fa u u o u a u u o o o o o o o o o o o o cn CP •cr >* o ·— CN in tn in cn 'J' in in in ιο rm in in co CN 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-2,315 dihydro[1]benzopyrano[4, 3-c]pyrazole-4-acetate; ethyl 2-(4-chlorophenyl)-8-fluoro-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate; ethyl 2-(4-chlorophenyl)-8-methyl-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate; 51 ethyl 2-(3,4-dichlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate; ethyl 2-(4-bromophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate; ethyl 2- (4-fluorophenyl)-3-oxo-2,3-dihydro(1]25 benzopyrano [ 4,3-c] pyrazole-^-acetate; ethyl 2-(4-chlorophenyl)-9-hydroxy-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate; ethyl 3-oxo-2-(4-trifluoromethylphenyl)-2,3dihydro[1]benzopyrano[4,3-c]-pyrazole-4-acetate; 56 ethyl 2-(4-methoxyphenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate; ethyl 2-(4-methylphenyl)-3-oxo-2,3-dihydro[ 1 ] benzopyrano[4,3-c]pyrazole-4-acetate; ethyl 2-(3-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate; 59 ethyl 2-(4-chlorophenyl)-9-methoxy-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate; ethyl 3-oxo-2-(4-trifluoromethylphenyl)-2,3dihydro[1]benzothiopyrano[4,3-c]pyrazole-4acetate 0 Examples 61-65 In a similar manner to that described in Example 47, a compound of formula II’ (in which R^ and Rg, are hydrogen) was prepared by reacting a compound of formula X (in which X is oxygen, Z is -CH=; Rg’ and Rg represent hydrogen and R?, Rg and R^ θ are as defined) with triethyl orthoacetate (XI) as summarised in Table 5 below: in Table cn tu -P z iw - — H tj . Η o G — •h tu cn Ρ ε G cd ·π -h +) G (0 -P Ο (β tu OS m o -P G m Cn X — Cn X o eT PS t· PS tu ι—I G. ε to X w o cn in ro ί- o r- CM σο cn CM 1 I * 1 1 'X) ID o cn CM CM τ- kO o r* CM γο CM cn CM in ο o in in cm n i— i— i—l i—l ε ε σι ω (Ί co Γ' ι— in οο ι— ο cn I— M· LD CM • · • • » r- o cn S3 U S3 S3 B3 03 O I O I O | O I O I 1 in 1 in in in ffi ffi r-H o ffi tc rH I—f rH P CO Ph u u u S3 U ι— cm η in vo vo vo vo vo G •H -P Ή tn O. ε o o tu Ό II in o Notes (1) Heating temperature = 140-150°C.

The compounds prepared in the above Examples were:5 61 2-(4-chlorophenyl)-9-methoxy-4-methyl[1]benzopyrano [ 4,3-c ]pyrazol-3(2H)-one; 2-(4-chlorophenyl)-8-hydroxy-4-methyl[1Jbenzopyrano[4,3-c]pyrazol-3(2H)-one; 2-(3,4-dichlorophenyl)-8-hydroxy-4-methyl[1]benzo10 pyrano[4,3-c]pyrazol-3(2H)-one; 2-(4-bromophenyl)-8-hydroxy-4-methyl[1]benzopyrano [4,3-c]pyrazol-3(2H)-one; 8-hydroxy-4-methyl-2-(4-trifluoromethylphenyl) [1]benzopyrano[4,3-c]pyrazol-3(2H)-one; Example 66 A mixture of 2-(4-chlorophenyl)-9-methoxy-4methyl[1]benzopyrano[4,3-c]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[1Jbenzopyrano[4,3-c] pyrazol-3 (2H)-one, m.p. 2Ί3-215°Ο.

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,410 dihydro[1]benzothiopyrano[4,3-c]-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 R1 θ, 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 Rg/ represents hydrogen and R? and Rg are as defined) , as summarised in Table 6 below. In each case 0.4 g p-toluenesulphonic acid was used in the reaction. z KO Table ca CD 4-> Z M-l • - u CbH o • **** £ X cn 3 CD P i-4 £ 3 M4 •rl 0 CD Eh -£ 05 ω 4-) C (0 4ϋ CO CD P5 CD £ ~ CD ΪΗ' X mh > tn O x — ω -Ρ C > — H tp X — > iX 05 tPO £ £ M-l -r4 3 Ο -P 0 > P CbH • « £ X X 4-· 0 w cn u td CN CN CN cn t— ·*-* fd fd XI td td X2 r·— t— r— r— ’d’ *** ”** **** '*** CO kD cn •3* cn σ* r— I r- I Γ— | r— 1 Γ 1 1 *3* 1 o Λ *3* -3* r* cn σ\ r— r— T“ r— r- co ID KD CN o o o o o o o o o o CN CN CN CN Hj* I— KO oo in o o m CN • • • • • in in in in kD ffi tc a ffi C“ rH o cn Pm rH m Cm rH O u fa U u CN cn cn m co σ\ o «— kD kD Γ r* z CQ td in o in 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 : 10 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-c]pyrazol-3(2H)-one 69 2-(4-chlorophenyl)-8-methoxy-3a-methyl-3a,4dihydro[1]benzothiopyrano[4,3-c]pyrazol-3(2H)one 2-(4-fluorophenyl)-8-methoxy-3a-methyl-3a,4dihydro [1 ]benzothiopyrano [4*, 3-c] pyrazol-3 (2H) 25 one 8-methoxy-4-methyl-2-(4-trifluoromethylphenyl)(1]benzothiopyrano[4,3-c]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,4dihydro[1]benzothiopyrano[4,3-c]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-(4trifluoromethylphenyl)-3a,4-dihydro[1]benzothiopyrano15 [4,3-c]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 1' (in which X is sulphur, Z is -CH=, Rg is hydrogen and θr is 8-hydroxy) was prepared from a compound of formula 1' (in which R.j θ1 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.

Table Notes Γ— co CN cn 44 44 00 kD CM r- 0 0 υ 00 i— r— «*- 3 ο Τ- CM CM CN co • Τ3 — SX 0 Ι ιη 00 1 m CM • L - 00 I— O r* i— ε α η CM CM CN CO eaction Time (hours) kD kD 00 kD PS CM 1“ CN φ β nJ Λ 4) to Φ -μ ε ~ β 0 Ή in O O in in nJ μ ε r—· kD ι- r— +) ο - Ο j—1 (0 43 Φ Ο PS •Η Ο 44 0 (0 m o ΟΝ kD cn 44 <*>— • • • • • • β β ι-Ι CM CM CO in CM t— 3 m ε »— CM 0 m ε < Ο CM o o O - tr> • • • « • Η r- CM *3* tnO β β 44 -ι4 3 Ο 44 Ο nJ μ £χ- • nJ ε Η r* O »—rO> X 44 0 ω w υ kD kD Γ- r- r< φ r-4 Οι ε id X co *3* in kD kD W r* r* r* C* r- in ο in IE 91335 - 75 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 silica 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^ (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 15 as follows :73 2-(3,4-dichlorophenyl)-8-hydroxy-3a-methyl-3a,4dihydro[1]benzothiopyrano[4,3-c]pyrazol-3(2H)-one? 2-(4-chlorophenyl)-8-hydroxy-3a-methyl-3a,4dihydro[1]benzothiopyrano[4,3-c]pyrazol-320 (2H)-one; 2-(4-fluorophenyl)-8-hydroxy-3a-methyl-3a,4dihydro[1]benzothiopyrano[4,3-c]pyrazol-3(2H)-one? 8-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)z [1]benzothiopyrano[4,3-c]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=, Rg is hydrogen, and R?, Rg, Rg, and θ are as defined) with triethyl orthoacetate (XI) as summarised in Table 8 below: οο Table Notes CN Γ“ co r— M-l r- Ό ΟΊ m σ» co 0 CM 00 00 00 CO m <Χ> CM «— 1— CM CM CN CM CM • U OjHI 0 1 in CM 1 1 r— I CO 1 co 1 in 1 CN • CM co r- co 00 co in kO © ε CM CM CN r— CM CN CN CM CM C — •rl φ 0! +i ε c in in in o o o O o © in (0 ·Η ·»Η T— I— T— in vo p—- © Ϊ— T— »— k ~ 00 co -4· © o © CM M-l H r-l 0 ω x ε co «5Γ o in cn © o O n~ ounts actant p— r— '___ Γ- o CO o N· © o o ,- o ε X CP < 04 «— CM CM r— CM o CM S3 o O t Eh Cm r— ί 04 tc SB S3 S3 S3 S3 S3 © in in 00 r-l 04 B S3 S3 S3 t_> SB S3 S3 S3 BB X CO 00 rH Cm rH 04 S3 S3 u U S3 u S3 S3 S3 S3 CO cn cn Γ- Eh «—1 Eh Ϊ4 rH (h rH 04 u u S3 SB SB o CQ υ u u <13 rH Cb ε Λ3 X Γ 00 o r— CM CO TJ* in kO W r* r- r- 00 00 CO co 00 00 00 in o in IE 91365 Φ78 Notes (1) Heating temperature = 1 40-1 50°C (2) Recrystallised from ethanol/dichloromethane (3) The crude product was purified by flash 5 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-(2hydroxyphenyl)-2-pyrazolin-5-one (1.4 g) and trimethyl ortho(methylthio)acetate (2.5 ml) was heated at 1 40-1 45°C for 10 minutes, then cooled and triturated with industrial methylated spirit, to give 2-(5chloro-2-pyridyl)-4-methylthiomethyl[1]benzopyrano[4,3-c]pyrazol-3(2H)-one, m.p. 217-219°C. z Example 88 In a similar manner to that described in Example 47, a stirred mixture of 1 -(5-chloro-2-pyridyl)-3-(2hydroxyphenyl)-2-pyrazolin-5-one (3.0 g) and triethyl ortho(ethoxycarbonyl)acetate (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]benzopyrano [4 , 3-c] pyrazole-4-acetate , m.p. 152-154°C.

Example 89 Acetyl chloride (0.5 ml) was added dropwise to a 10 stirred mixture of 2-(5-chloro-2-pyridyl)-9-hydroxy-4methyl[1]benzopyrano[4,3-c]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-c]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-4acetate (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 z washed with ether to give eyelobutylmethyl 2-(5-chloro2-pyridyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 157-160°C.

Example 91 A mixture of propyl 2-(4-chlorophenyl)-3-oxo2,3-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 210 piperidinoethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]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. z - 81 Table tn tu r- CM CO +j - 0 z 4-t © Γ- o co KD 00 o 0 Ό r— o r— o cn tj CM 1— cn 1— © CM © r- • M 0 1 1 Γ- 1 1 1 1 1 a o co © 1 in OT ro H- • o 1— © co OT t— o 00 ε CM CM r— H- r— CM CM cn tu G in £ •r| o © o © © © © o •rl £ © r— r— r—· CM T— CM r— © Eh hol ) cp 0 H 00 O O CM in © ο ε « 4-i tn ι—1 '**’ © kd KO © © H- © 0 +> < G -P (0 G -P P 3 U © 0 (0 Ρ H tP H- σι o OT r- © © o £ CO HI — • < « W * CM r—r” r— CM CM 1 EC r—l O >1 CM G SB EG EC EC EC EC EC EC •rf O O O CJ O O O O N CM CM CM CM CM © CM CM to EC eb EG EC EC EC EC EC P CJ cj CJ CJ CJ CJ CJ CJ tu CN CN CN CM © © © © a EG EC EC EC EC EG EC EG •rl CJ CJ CJ CJ CJ CJ CJ CJ a 1 _- EC 0 0 0 0 0 0 0 0 1 o G G G G G G G G r—1 CM •r| •iH •H •r| •r| •r| •rl •r| EG rH rH rH rH rH r-H i-H rH r-1 jG U 0 0 0 0 0 0 0 0 0 P CN £! Λ Λ Λ 4G £ Λ Λ ri tu EG a a a a a a a a 0 ε CJ P P P P P P P P o 1 © 0 0 0 0 0 0 0 0 rH EC ε ε ε ε ε ε ε ε CJ *** Cn hi G Hl 4-1 -H Ο -Ρ P P tu © 1— OT r- CM CO OT • 3 -P X -P tn WWW in M4 in in in tu rH G> CM © © KD r-~ 00 OT © ε cn cn OT cn cn cn o to r— X w ο decomposition 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-2,3dihydro[1]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-c]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 w^s prepared by reacting ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro-[1]benzopyrano[4,3-c]pyrazole-4-acetate (II1) with the appropriate alcohol, as summarized in Table 10 below.

Table 1 Ο (B n X^k nJ nJ nJ CN 31 3* tn *—· *»* a) —«k x-k x-k x-^ X»k x-k . +J nJ ns nJ nJ nJ 0 nJ 0 0 1— I— 3* in 31 3* t— r— Z **** M-l kO KO CN KO cn σ\ r- 0 kO kD 0 k0 0 KD in r- CN CN CQ CN in 0 CQ CP CQ u Γ— r— I— r- «— i— i— I— r~ t— <” r~ • H o 1 1 1 1 1 1 1 1 1 1 1 1 Cb in CQ σι in CN 00 3« 00 31 CQ σ> 3 • κο in KD CN CN CQ CN 3* 0 cn 00 cn me m ins) r~ r— r- r— o o o O O o in in in 0 o 0 £ r* 00 oo KD κο CN I— 0 0 in 0 r— El m *“ I— r— CQ CN rH o — 43 r-l tp 0 £ CP CP CN a — «— V 00 o o o 0 CN 0 CN M-ι tn rH • • O -P 00 vo 3* Oh in kO 3< kD in r* io £ -P nJ C -P P 3 O 0) O nJ -P tPH o o o o o o o r— 0 0 0 0 £ CD cn ·~ h • CN < 05 w CQ CN CN CN CN CN CN CN CN CN CN a 0 CN a u CN a a 0 a 0 CN O X. a X-k r—l u rH >1 a a a >1 rH o o 0 rH £ 0 cn a CN CN >H nJ N a o a x»k P P nJ a u CN u CN 3 >t •r| o cn a cn a a M-l Cb 23 a U a 0 0 0 0 -P rH a <_> x-^ u x-k ·»—’ P P 1 >1 o rH x^. rH 0 Ό Ό in a P CN r-l >. £ >« CN >1 >1 1 o £ a -P -P χ-κ 2C 2C r-l CN CD u £ 3 Ό 3 CN nJ 3 >, sc x^ Cb CN CD 23 •Η 23 a P P Xt 0 o CN 0 a ••H O P 0 u -P •P -P 43 cn a rH u 43 rH ΪΡ rH T” CD CD CD O a o o o -P o Cb 0 0 -P P £ υ u >1 cn 1 >1 1 >1 cn 1 1 I rH 43 43 O a CN o CN υ a CN 3* V Cb Ob CJ *·* 0 CN cn T in KO Γ— 00 CTi 0 CN CQ X o o o o o o o 0 I— 1— 1— *— w r~ p— r— r- r- Γ“ in o CN in nj n· ra Φ +> O O Φ ε Ή E4 1-4 O ra C Ή ε id CD s n id kD id kD >—< XI X 42 id 42 rt rt rt rt J3 Ό Γ0 cn n r— MO <3* kD kD kD n w 'e” w *—* ·*»»* *-** o in MO r-~ CM in 00 00 cn o m 00 04 r- 04 CO ro 04 r- I— V >— I r— I σι I I r— I I Ύ t I I 1 r- 1 04 1 CO 1 1 N· 1 O 1 04 MO 1 MO 1 o 00 04 00 CM OA 04 cn co 04 r- r— ro 1— 1- (— t— T“' l— T— r— r— ο ο ο ο ο σι σι ιο ιη ιη η ο ο ο 04 MD ο ο ιη μο Table 10 cont ’ d m 0 +» G (C β 44 ο — 43 Ή ο ε υ — r-i < tP tP in tP Cn kD b> o o o <- o o σ> n MO c* cn cn cn in in fO 04 μ <υ — 44 ©Η ra —1-4 w OOJOOOON’N'OOO 04 ι— ι— ι— 04 ι— ι— 04 ι— ι— rd ο Ο υ ι—I ιη a o a o 04 a u a o a o 04 a u a o 04 a u a o a r-H 04 04 04 04 04 o a >1 a a a a a o a u u u u u rH 44 a —-. >4 (Ή Φ i-4 r4 o r4 r4 r4 r—1 N >4 fl >1 >1 04 >4 a >4 o fl N Φ fl fl a fl fl o fl •rl Φ fl a Φ Φ u Φ Φ Φ Ό 42 Φ a a a 04 a a |—1 a Φ >1 42 >, a a a a a >4 a fl X r-1 X 0 o u 0 r—f X o IC 0 >» o )4 )4 μ Φ )4 a a a a 0 0 r-4 0 a a 0 0 44 44 44 r—l r-4 >4 i-4 4) 0 ι—1 μ φ Φ φ a a a a Φ i—l a a ε ε ε υ o φ o ε Q □ 1 1 1 1 1 1 o 1 1 >1 1 ro ro N Ν’ Ν’ 04 (0 04 ro υ ro *» —- —·’ Ν’ in MO O' 00 O CM ro ’’T r— r— r— 1— r— t— 04 04 CM 04 CM 1— r— t— r— i— 1— |— r— I— r— ο © 43 I— ω Φ -P z M-l Φ ε ••H Eh tn G •H ε 3 3 S' © Π3 KD 3 r— 3 © Λ Π3 (0 flj 43 Λ Π3 © KD r- KD KD © CO r- © *»» *3* O> r- KO 00 co in | o © I © r- 1 r* σ> r— I CO τ- ι CM CM 1 CO 1 σ> 1 00 1 r— 1 in 1 1 o CM 00 > KD f— r- r— r— T— ι— i— r— i— r— © in o © o © o in o KD r— *3· 00 © r— 00 r- o t— t— CM r- © o o © Table 10 Cont'd μη ω -P G io -P o (0 Φ « o o u P Φ - — -P ι-n cn 01 H'W M4 © © CP © CP © tp © cn KD r- r- M4 © co co co ro co © CO ^3* CM in r— 1— o © in o 1— r- T— r· r- r- r— © o © SB O © EC υ © EC CJ r-l G Φ S3 a o ο © G S3 •P cj ε © ns S3 rH CJ Eh 43 >1 P r-l X Φ 0 0 ε 43 G •P o Φ Ό O 43 1 ι—1 a P· < © © X © © w r— r— S3 S3 S3 SB SB O S3 O O O O O © © © © © © SB S3 S3 S3 EC SB CJ CJ CJ CJ CJ CJ © S3 © rH S3 o S3 rH rH rH Eh CJ — CJ Eh Eh Eh G © © C G G Φ S3 S3 3 Φ Φ Φ 43 CJ CJ G 43 43 43 a •H a a Eh ι—1 S3 ε rH rH 3 X EH CJ (0 Eh Eh P 0 T3 — rH 43 43 0 43 -P rH Eh -P -P ι—1 -P P Eh -P Φ Φ rC Φ Eh N Φ ε ε υ ε a G O 1 1 1 1 Φ (0 © © *3* © © 43 — **** r- 00 OT © © © © © © ' CO © © © r— r— ,— »— r— ,— T— 134 (cyclopropyl)CH90H 2.0 4.0 90 162-165 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 a) b) c) d) reaction mixture was heated at:120°C; 150-160°C; 180°C; 214°C. (4) The crude product was purified by flash chromotography on silica using, as a mobile phase:a) toluene/acetic acid (9:1); b) toluene; , c) ethyl acetate/acetic acid (9:1).

The fractions obtained were evaporated and triturated with ether to give the product. (5) The cooled reaction mixture was dissolved in 30 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. z ω Φ X Z M-l • w Cb •rl Eh cn fi H ε CP V κο CN 00 CM Γ- m ρ- 3 CO KO r— r— r— Ο 1— τ- 1— 1 1 I 1 ι 1 co cn 00 1 3 o κο CM r- CN σ> 3 co κο T” r— σ\ f— r— r— o o o o I I sxqej, MH X fi O ε to X α (0 4-) υ iC Φ K in P Φ - — X Η tP cn i-H — w Xi U tp fi ΜΗ -H Ο X P Ρ Φ .

WWW Cb ε CO X w in σ\ 3 0* 3 ο·* CT\ co cn CM cn CM Γ— in cm in o o Γ- o P- 1— t— <— CN co CN S3 S3 S3 S3 X X O O o o o o o CM CM CM CM CM CM CM S3 S3 S3 S3 X X X U U U U u u u X-k X-k x-k X-k x-k x-k Φ Φ Φ Φ Φ Φ Φ c fi fi fi fi fi c (0 CO (0 (0 (0 ¢0 fO X X X X X X X 3 3 3 3 3 3 3 X X X X X X X 0 0 o 0 o 0 0 rH rH rH rH rH rH rH Φ 0 o o □ u υ >1 >1 >. >1 >1 o υ Φ o O Φ o m ο κο rin in in in in κο r- oo cn cn co n Notes (1) Cycle included 26 hours refluxing and 140 hours storage at ambient temperature. A further portion of the alcohol (2 g) was added after 13 hours refluxing.

Examples 142 and 143 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo2.3- dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate (2.0 g), 1,2-ethanediol acetate (2.0 ml, ca 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 the 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-c]pyrazole-4-acetate (Example 142 m.p. 136— 139°C, and 2-hydroxyethyl 2-(4-chlorophenyl)-3-oxo2.3- dihydro[11benzopyrano[4,3-c]pyrazole-4-acetate (Example 143), m.p. 161-162°C.

Example 144 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate (2.0 g), 4-(2-hydroxyethyl)thiomorpholine (1 g) , dry xylene (20 ml) and N-methylmorpholine λ(0.6 ml) containing 4A molecular sieves was stirred and heated at 150°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-oxo2.3- dihydro [ 1 ] benzopyrano [4,3-c] pyrazole-4-aceta.te 5 hydrochloride, m.p. 223-226°C.

Example 145 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo2.3- dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate (2.00 g), 2-methylthioethanol (0.5 ml), N-methyl10 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-(4chlorophenyl)-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-2,3dihydro[1]benzopyrano[4,3-c]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-2,3dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 114-115°C.

Example 147 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo2,3-dihydro[1]benzopyrano[4,3-c]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 dichloromethane 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-oxo2,3-dihydro[1]benzopyrano[4,3-c]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]benzopyrano [4,3-c]pyrazole-4-acetate (2.0 g), ethyl 320 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-oxo25 2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 126-129°C. z Example 149 In a similar manner to Example 145, a mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzo30 pyrano[4,3-c]pyrazole-4-acetate (1.1 g) , 2-phenyl-1propanol (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-1-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 β-methylphenethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro5 [1]benzopyano[4,3-c]pyrazole-4-acetate, m.p. 86-90°C.

Example 150 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate (2.0 g), cyclohexylethanol (0.7 ml), N-methylmorpholine (0.6ml) 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-chlorophenyl) -3-OXO-2,3-dihydro[1]-benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 149-151 °C.

Example 151 A solution of ethyl 2-(4-chlorophenyl)-3-oxo20 2,3-dihydro[1]benzopyrano[4,3-c]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-225 morpholinoethanol (0.8 ml) was, added and heating/distilling continued for 7 hours. More 1-methyl-2morpholinoethanol (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-oxo2,3-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]benzopyrano [4,3-c]pyrazole-4-acetate (1.0 g) , (1-methyl-25 piperidyl)methanol (0.7 ml) and toluene (15 ml) gave, after flash chromatography, 1-methyl-2-piperidylmethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 159-163°C.

Example 153 A stirred suspension of 2-morpholinoethyl 2-(4chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]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-1,2,3,4tetrahydro[1]-benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 125-128°C.

Example 154 z 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-c]-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-c]pyrazole-4-acetate, m.p. 29-131 °C.

Example 155 A stirred mixture of ethyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]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-chlorophenyl) -N-methyl-3-oxo-2,3-dihydro[1]benzopyrano20 [4,3-cJpyrazole-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 estqr is provided) with the appropriate amine as summarised in Table 12 below. - 95 ω φ -μ Ο Oj ra φ μ ε ο •Η Ο Ε-» 43 ΜΟ CN ,— tn 00 Ν' tn CM CM r- ο Γ- 00 Γ- Ο Γ'- σ> ιη ΜΟ <“ - I (Ν I ι I Γ“ | I ι 1 00 ι ο I ιη 1 1 CN 1 00 1 σ> I σν < ΜΟ kO 00 Γ- ο Γ- ΓΩ 00 ιη 1“ CN γ— ιη Ν> ιη ιη ο ιο ιη Γ- CM ιη CN • • « Γ— ιη tn Table 12 ra φ +) c — c Φ .-Η ra ή ε -μ Ο X ra φ 03 φ . C — ιμ •μ tr 0 ε ~ +) C 3 μ Ο 0) ε +j tr> < ra — w ο tn CN co m ιη ο ο ι— in η r- o m m o i— i— σ, ο o • · · 1 £5 -μ Φ cn o ac cn in tn mo in in ε ε ε ε m cn in in n* tn oo in r- cn cn Ο ι— r— »— γ- m 0 Κ SC tn tn tn 33 SC C CJ CN 33 33 SC 2 Φ υ •Η —. CJ CJ CJ tJ — (3 sc rH -4 33 33 33- 33 i-4 μ 2 0 >4 2 2 2 2 3-4 ε £5 Ό —. —. —. 43 μ Oj μ r4 1-4 r4 1—1 -μ >1 μ μ Si >4 S-ι >4 Φ Ν 0 co 3-4 C N N N (3 <3 Ε 33 Oj Φ c c C Φ Φ ι U 1 43 Φ Φ Φ 43 Λ (Ν 33 cn Oj 42 42 42 Oj -- 2 — - Π 33 u tn 33 33 2 y — r-d >1 43 -μ Φ 0 £3 4 u I tP Η C H γ—I *Η Οι -μ μ βμ μ φ ra ο ra -μ χ -μ ra W ra φ ιη r~ r-~ Ν’ Ν’ Γ- ΓΝ' Ν' CN ι— ιη ιη σι r~ r-~ Ν* Ν' Ν' ΜΟ Γ' ιη ιη co ο ιη ιη ο ΜΟ ιη r- (Ν ΜΟ ΜΟ tn ν· ΜΟ ΜΟ 165 47 morpholine 3.0 1.4ml 50 4 246-247 ο CN Table 12 cont' in -P G (0 +J υ <ΰ φ os μη Ο Ρ G Ο I - 96 ω φ -Ρ ο ζ (X ε (0 Φ Ρ ε g •ρ ο ΕΗ Β Φ G φ rH «ρ ε Εη — X φ G — •Ρ ζρ ε ~ ιη ΚΟ 00 Ο ιη ΚΟ Γ*· τ— <— ί- Ι CM ι CM 1 ^3* 1 KD 1 00 ιη κο Γ- ©r~ CM ο κο ιη Ο © CM • CM © ιη r- ο r— © © r~~ οο ο ο © © ιη © ο ,— ο ο Φ ~ σ\ © o CM -ρ σ> • • • • ιη — γ— r~ © r— W rH 1 >1 © 1 rH Β © Eh Ο 1 G Β G Φ Ζ nJ B rH Cb r-H 0 rH Εη X Eh C © o G φ B P 0 φ Β U T3 B G Cb B 1 P •Η 0 Z © (0 ε Ρ a 0 rH ,— Eh rH Eh X Β N © 0 © U G B B B 1 Φ U •P U n Λ B Φ B -r ·— Z ε Z © 1 B N* tP Μ U z G Η ‘Ρ •Ρ Ρ P- © P' Γ— Ρ Φ N* © Ν' N ω φ Cb ε μη (β Ο (0 -Ρ X -Ρ ιη νο νο Γ' 00 OT VO VO νο © ο 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°C. z Example 170 a) A mixture of propyl 2-(4-chlorophenyl)-3-oxo-2,3dihydro[1Jbenzopyrano[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,M-[3-(2hydroxyethyl)-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-(2hydroxyethyl)-3-azapentamethylene]-3-oxo-2,3-dihydro [1]benzopyrano[4,3-c]pyrazole-4-acetamide hydrochloride (0.7 g) in dichloromethane (28 ml) was cooled to 0°C 20 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 25 overnight. The mixture was washed with water, then dried and evaporated under reduced pressure. The solid obtained was triturated with eth,er and the solid formed collected by filtration and dried to give 2-^4-(2-(4chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]30 pyrazole-4-acetyl]piperazin-1-yl)ethyl acetate, 162-166°C. m.p.

Example 171 A stirred mixture of 2-(4-chlorophenyl)-N,N[3-(2-hydroxyethyl)-3-azapentamethylene]-3-oxo-2,3dihydro[1]benzopyrano[4, 3-£]pyrazole-4-acetamide hydrochloride (0.8 g) (Example 170a) and dichloromethane (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 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-(4chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetyl]piperazine-1-yl)ethyl propionate, m.p. 173-175°C.

Example 172 A stirred a mixture of ethyl 3-oxo-2-(4-trifluoromethylphenyl)-2,3-dihydro[1]benzothiopyrano[4,3-c]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-(3oxapentamethylene)-3-oxo-2-(4-trifluoromethylphenyl)2,3-dihydro[1]benzothio-pyrano[4,3-c]pyrazole-430 acetamide, m.p. 210-212°C.

Example 173 A stirred mixture of ethyl 3-oxo-2-(4-tri- 100 fluoromethylphenyl)-2,3-dihydro[1]benzothiopyrano[4,3-c]pyrazol-4-acetate (0.6 g) , (Example 60) N-ethylaniline (0.4 ml) and dry xylene (2.4 ml) was heated under reflux for 4 hours. A further portion of N5 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-ethylaniline (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-trifluoromethylphenyl)-2,3-dihydro[1Jbenzothiopyrano[4,3-c]pyrazol-4-acetamide, m.p. 179-181 °C.

Example 174 A mixture of 1-(4-chlorophenyl)-3-(2-hydroxyphenyl) -2-pyrazolin-5-one (17.0 g) and methyl 4-(2,2dimethyl-4,6-dioxo-1,3-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-(4chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c] 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 Rg ’ and Rg are hydrogen, and R^, Rg and R^ θ are as 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: - 101 ω φ X Ο Ζ X ο • Η £Χ X-k X-k X-k. x-k X-k x-k Χ-». X*. J— r— CN CN CQ 3 in kD Γ* *—* -Χ» ’*** *—» **** CN Γ* co 3 cn 00 cn 3 kD r- in in 00 3 kD t— r— t *— | Ύ I | I r_ I B kD 1 o 1 kD I CN 1 00 1 kD 1 00 3 kD Γ* in in 00 3 in σ> r— j— r— r- »— r— r— m Table 13 C Ο •Η Q) χ ε υ ·η (0 Εη Φ (0 X fi (0 X υ φ φ χ Ο ω χ C Ο ω b| Ο χ kDkOkDkOkOkOCQ3t— CN ιη φ fi —~ φ χ •χ ε Sh — X Λ H — Η Οϊ X ~ X ο οΓ &> o o o o o o o o o o CM o CM CN in in in co in o *“ *“ CN in CM σι Γ- o co O r- m 00 r- CM CN CM cn Γ- kD 1— 3 LD CQ r— r— CN Γ- o Γ- 00 o in O O in O in in in kD 3 CN n CN CN CN ffi ffi X ffi ffl W E ffiffi K W ffi ffi ® ffi ffi S3 ffiffiffl χ uuuouuo u u o CP23 fi Η X ·Η H Ο X X Sh • (0 Ό xx a w ω u in id r- oo σ\ o CN ΓΟ 3 φ Γ—I ε X ω ιη in kD r- r* rΓΟΟ CN CQ 00 00 185 6 Cl Cl H 3.0 6.8 55 3.5 192-193 (9) 186 15 Cl Η. H 5.0 9.1 120 6 139-141 (1) in o CN 02 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 15 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. 103 Example 187 A stirred mixture of 2-(4-chlorophenyl,-9-hydroxy4-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-chlorophenyl)-4-methyl-3-oxo2,3-dihydro[1]benzopyrano[4,3-c]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 (R17COC1) as summarised in Table 14 below. 104 tn Φ 4J M-l ~. O U o ex g H kD © in 00 00 00 00 CN o CM r— r- r— in c* cn o (— Ν' r— CM r- r-· CM I CM r— CM I CN I CN CM I CM I 1 1 00 1 in 1 CM Λ 1 in 1 uo 1 1- 00 1 00 1 kD ,— in cn o T~ m © CN r— r— CM CM 1— r— CM CN CN CM CN — m-l +> g W — ο Γ- in in in in n· Ν' Ν’ MD Ν' mi— ι— ι— r— r-mmmi— m Table 14 M-l tn +> tn fl +) ra fl +J fl o o ra g φ < os in r—l cj o — CJ r-l r-g ex h Cn ex ε rt X w Or— σι o in in co r- cn mo Ν' CN CN ooininininooooo CN CN CN CN tN CN CN Φ fl >4 fl Φ 4fl Φ r—l >4 fl Φ CN ra ex c 43 EC ex Γ—Ι r—1 >1 ι-1 ra ex u 0 >1 >4 X >4 +) r—l υ CN μ +) 43 o r-l fl a >4 o EG ex fl +> ι—1 43 S>4 Φ 43 43 o CJ 0 ra Φ S>4 X» μ •H Ο P m o ι—1 H C N Φ fl 43 r—1 Φ EC m o ra Φ fl g M4 +J o g cn EG >4 Ό 43 Φ 1 1 I >4 1 CJ U o ra ex 43 CN CN CM o CN oo 199 4-chlorophenyl 2.0 1.6 2.0 244-247 200 CH3CH=CH 2.0 1.2 2.0 159-162 (1)(3) 201 4-methoxyphenyl 1.4 1.5 1.2 200-202 (5)(6) 202 4-methylphenyl 1.4 1.2 1.2 216-218 (3)(6) in o CM in CM 105 ω ro © Φ M-l s. 0 CM CM z Uh O — υ • o a — ε* h γ- I— CO © ΓΟ *3* co CM CM CM CM I 00 © 1 00 1 KO © co CO co CM CM CM CM z — m-i •ρ ε w — Table 14 Cont' M-l Ο ω -P ω c M-l 3 G M-i 3 U O 3 ε φ < 04 U O — U --1 ι^ε oP~ i-m cn h — Cn © Ν' © vo >1 Φ G G Φ φ 3 G B -P 3 IX i—l G X rH Eh φ Φ Eh Ό (X B B •rl O O -P Em rH rH Φ ϊ>1 0 υ ε a Eh 1 υ υ © Ν’ © ^31 in vo O © o o © CM CM © © o 06 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 was 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. r - 1Θ7 η φ -Ρ Ο ζ Μ-Ι Ο • U IX Η Ο Ζ —©-Μ χ» ε ω — M-l Ο -Ρ G Ο σι Ρ G Μ-* Ο Φ r-ε Η tp «mt © CO © KD © KD © © r— © © 1— r— © Ν’ H- © © *—* o © © © © Ν’ © © 00 σ'» © o © r— r— y r— CM CM © 1 r- o 1 CM Ν’ σ> σ» 1— © Ν’ © Ν’ 00 00 r- o © T— 1— r— © CM © CM © KD r- KD OT VO -- r— -- © o o O o tP tP KD vo © OT © CM OT © • • • • • 0 • • τ— o o o o o in in © •3* OD co © 00 r- r— © © o o I- o Table 15 Εη Β Μ-Ι Φ ι-Η α φ r-H • ΙΧΗΙ ιχ ε hi Φ 3 ρ χ μ-ι Λ W Ο IX ε X W 0 Eh i-H B i-H i-H i-H B i-H P Eh Eh -P Eh B 3 B B B Φ B -P O P P •Ρ 0 M-l Φ Eh Φ Φ Φ H Φ ε X ε ε ε B ε Eh o EH Eh Eh M-l Eh i-H X B X X X ι—1 X Eh o -P 0 0 0 EH 0 N B Φ P -P B B -P G +i ε Φ Φ P -P Φ Φ Φ □ υ Φ Φ υ Λ ε © 3 3 ε ε 3 ΟΟ ΟΟ 00 *3* *3* <3* ιη *3· co KD KO © co co KD KD Γ*· 00 cn © I— CM CO © o © I- f—’ Γ“ r— r— CM © CM CM CM CM CM CM ιη 215 63 2-methoxycarbonylethyl 1.5 1.1 0.9g 182-184 (2)(7) © CM 108 Table 15 cont’d ω co Φ X X-k x^. o I— o 00 CM 1— 1— z **** *—* X kD CN κο co o CN kD r— KD co X-k t— I— 1— I— • L> 1 1 1 1 1 Cb H ° 3 o ’sr I— CM • kW CN kD ,— KD CO ε *“ r- z in fX σ\ co Oi in OK χ ε • • • • • w — r- o o *“ ι—1 x in o ~ O X O X CN CQ CM KD C t-ε • • • • • X (fl i —· r— o o I— «— fi X 05 3 a O ε φ < 05 - O in CO O o X CP • • » • • H — CN o *- CM CM X >1 23 X Φ X Sh fi O ι—1 X X X 23 SH Sh SH SH 23 23 23 23 (fl X X X X O Φ Φ Φ Φ Sh ε ε ε ε X >1 SH SH Sh O >5 X X 23 o O O 0 X 23 X X X Φ r- X Φ Φ Φ ε I- Φ □ o υ 1 05 ε (fl (0 (0 CM (1) I-1 » • CbH cb ε h KD o r_ κο κο φ φ KD 3 V KO b XX ι- ί- Cb W 0 Φ «Η Cb c (fl KD ι^ σο σκ o X ,— 1- ι- r— CM ω CM cm ΟΝ CN CM m o m 109 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 10 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 15 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 25 and the filtrate evaporated to dryness and recrystallised from industrial methylated spirit. no (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-415 methyl[1]benzopyrano[4,3-c]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)^4methyl-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazol-830 yl methyl succinate, m.p. 152-153°C.

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[1]benzopyrano5 [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. 112 9L X C φ X ϋ φ φ X Ο X S3 Ο ω χ ο ζ χ Ο ~ υ • ο Cb — ε η Sh Φ 3 ε ο X 23 Εη — Φ S3 Ή χ-. Ό γΗ χ ε ο — SH Cb l-H CP Η — u ο ο ~ IX φ X Λ ε φ χ ω ιη X-k x-k X-k CN f— ro «-Χ ·— in CN KD 1— ok kO in tn | r— γ CN f 1 ro 1 1 00 ok in in 3 1— r— 1— CN οο οο Μ* CM 00 CM ι— CM r— οο in in o KD KD KD KD in in in O CN CN CN o « • • • CN CN CN CN oo Γ ok in CM CM CM CM CM ® CM U S3 CM u SB o CM U CM o O o ω in ro ro SB S3 S3 CM U CJ U CN ro 3 m CN CN CN CN CN CN CN CN o in X Φ X S3 Sh Φ Φ 23 X X Φ Sh ε ό 23 c • 01 Φ Ό Sh X Φ 23 23 Φ X Οι X fi ϋ nJ Φ Φ Sh Ό 23 X CP fi X X Ο Φ Φ 0 X ε □ ns Φ 0 ε fi Sh οι 0 Φ O Φ >Η 23 X & 23 X 23 ϋ Φ ϋ Φ ε χ bi X ο Ό 3 3 Sh X 0 0 23 X 23 X X X X 23 X ε χ Ο £ .5 •Η Sh Ό Ό Φ Sh • Φ X X Φ S3 X Φ X fi X 3 £ ϋ Φ rH φ 23 φ φ Φ Μ X γΗ X X Φ 23 οι Φ Γ3 ε fi Φ X 0 χ 5 φ X SH 0 Ο ϋ O 01 S3 Φ 3 ι—1 fi εΓ0 23 X fi ιΗ 0 ϋ X Sh Μ X οι 0 23 Cb Ό Φ ϋ X £ Φ Φ 23 φ •fi X X 23 • Φ X X U Εη r— 23 3 ·· X Φ Ό <η > Ό 0 · <η S3 X Φ Sh C X CP X Cb Ο 3 X Φ Φ Ο X Φ X fi X X Φ Ό Φ 0 23 3 Sh X 3 Ό 01 Sh X φ X φ Φ ϋ X Ο 0 X 5 ‘Η φ οι Sh φ X ''k S3 Ό S3 23 φ X ε X >ι S3 'Ό 3 23 φ X S3 rH X 23 Φ Φ 0 0 Ό X X ϋ Φ Φ >Η S3 Φ > ε Φ 0 Φ ε ο ο X X 23 ο ε SH Φ X EH σι φ Ο S φ Sh rH Sh 23 X ^k ^k 01 U . rH |- CM Φ •Η CO ·Η — - ΪΦ o CM 3 Example 226 ϊ ί ι A stirred mixture of 2-(4-bhlorophenyl)-9-hydroxy4-methyl[1]benzopyrano[4,3-c]pyrazol-3(2H)-one (2 g) (Example 66) and pyridine (2’0 ml) was treated with 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 from toluene to give 2-(4-chlorophenyl) -4-methyl-3-oxo-2,3-dihydro[1]benzopyrano10 [4,3-c] pyrazol-9-yl benzoate, m{.p. 21 8-222°C.

Example 227 ξ § r A solution of 2- (4-chlorophenyl)-8-hydroxy-4methyl[1]benzopyrano[4,3-c]pyra^ol-3(2H)-one (Example 62) (1.5 g) and nicotinoyl ichloride hydrochloride (1.6 g) in a mixture of 5 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--chloro20 phenyl)-4-methyl-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazol-8-yl nicotinate,· m.p. 230-235°C.

Example 228 A mixture of 2-(4-chlorophenyl)-8-hydroxy-4methyl[1]benzopyrano[4,3-c]pyrazol-3(2H)-one (Example 62) (1.8 g)and 4-methoxybenzyl hydrogen malonate (2.0 g) in dry pyridine (18 ml) was stirred in a cold ί 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 poured on to water. This mixture was extracted with ethyl acetate and the combined]organic extracts washed 114 with water, dried and evaporated. The residue was triturated with ether and 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]benzopyrano [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-c]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-oxo2,3-dihydro[1]benzopyrano[4,3-c]pyrazol-8-y1 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[1Jbenzopyrano[4,3-cJpyrazol-3(2H)-one (Example 62) (1.5 g), N,Ndimethylglycine (0.78 g) and dry pyridine (15 ml) was stirred at ambient temperature. 1,3-dicyclohexylcarbodiimide (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-£] pyrazol-8-yl dimethylaminoacetate, m.p. 174-176°C.

Example 231 In a similar manner to Example 227, a stirred 5 mixture of 2-(4-chlorophenyl)-8-hydroxy-4-methyl[1]benzopyrano[4,3-c]pyrazol-3-(2H)-one (Example 62) (1.5 g) , methylthioacetic acid (0.6 ml) and dry pyridine (15 ml) was treated with 1 ,3-dicyclohexylcarbodiimide (1.35 g) at ambient temperature. The mixture was stirred at ambient temperature for 2 days to give, after chromatography, 2-(4-chlorophenyl)-4methyl-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazol8-yl methylthioacetate, m.p. 163-166°C.

Example 232 A mixture of ethyl 2-(4-chlorophenyl)-8-hydroxy3- oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4acetate (2.0 g) (Example 48) in dry dichloromethane (60 ml) was stirred at 0°C while triethylamine (1.6 ml) was added followed by 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(acetoxyacetoxy)-2-(4-chlorophenyl)-2,4-dihydro[1]benzopyrano25 [4,3-c]pyrazol-4-ylideneacetate which on standing in air hydrolysed to ethyl 8-acetoxyacetoxy-2-(4-chlorophenyl) -3-OXO-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole4- acetate hemihydrate containing one mole of acetoxyacetic acid, m.p. 157-160°C.

‘Jtjj - 116 Example 233 A stirred mixture of 2-(3,4-dichlorophenyl)-8hydroxy-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-tetra15 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 1' (preparatives Example of starting compound provided) with an acyl chloride ^COCl as summarised in Table 17 below. In each case dichloromethane (30 ml) was used. - 117 23 Table 17 ra φ X ο ζ X ο CbH ε C Ο •Η X ϋ Φ Ε-ι Φ cn X S3 O cn X C Φ X u Φ Φ ω $Η Ο ro X W Cn Z — u o — U X r-ε tP Γ— 05~ Cn c •H X H Cl Φ Ό X X Cb W enu tn η aJ γ- ΓΝ 3 3 r— s Φ3 ω 7? 7) u r— Ο r— in CN σ\ kD t—' m CN kD c— kD CN CN ro co ro KD CN o r— r- Γ- in T | I 7 I y Γ- Ι I σ> 1 τ- γ- Ι 1 Ι 1 σ» ro I σ\ 1 γ- 1 00 m CN in ΟΝ m kD r- CN γο 00 ro kD CN cn O τ— I— r—’ Γ— r— r— 1— r— t— ** t— ιη CMCMCMCMCMt— CMOr- «— >— CM inKocDKoininroro’^inx'^r·^’ ^' oooooooooooooo 'a,inooininrocMcocoro'a’'3,CMCM ··········*··* oooooooooooooo minroincni— οοοοσκ,— οοοοσκοο r— t— “ r— r— o o o o o o Γ—i r-H 23 Sm X 23 Φ X ε Φ r—1 ε Sh I—1 ι—1 r-H S3 X ι—1 r-l ι—1 Sh X >1 Sm 0 Sh Sh Sm Sm S3 Sm 23 23 23 φ 23 23 23 23 o 23 X X bc S3 X X X X Λ X Φ Φ Φ Φ Φ Φ Φ Φ be Φ ε O ι—1 ε ε ε ε Φ ε >1 Sh Sh >1 Sh Sh Sh Sh ϋ Sm X X ι—1 i—1 X Cb X X X X Sh X 0 0 Sh Sh o o ι—1 0 O O 0 X o 23 X CM (3 23 be Sm X X 23 X 0 23 X Φ S3 Φ X Cb 23 Φ Φ X Φ 23 X Φ υ Φ 23 Φ 1 X ϋ υ Φ u X Φ ε φ 23 (3i ε T— Φ Φ φ ε Φ Φ ε CO co ro ro ro ro ro (ϋ kO CN in in CN r* r* r- r* r- r* r- r* m kD Γ- CO σ> o r— CN ro sr in kD ro cn ro ΓΗ ro ro CN CM CN CM CN CN CN CN CN CN CN CN CN 247 75 methoxymethyl O in o |— r— CN 118 Table 17 Cont'd Mm φ 0) p— ι— φ ^-k. —-* MJ υ υ Ο p— m © 1— Ζ —-' ΜΜ in OT Γ- 0 CO r- r— N U τ- σ» © I— CbH ο Ι 1 1 1 • *—< o in 00 vo ε co σ» r— Ν' 1— © G Ο ω •γΜ φ Εμ in ρ ε 3 • υ -η 0 1— r— © Ν’ 3 Ε-Ι Β φ 04 © MJ — in xr © VO W Cn • • • • ζ ~ o o o o ΜΜ ι—1 Ο ω ο MJ ο — ro G U rH co co © in mJ 3 r-ε » • • • G MJ o o o o 3 υ 04 Ο 3 ε φ <2 04 00 r- σ\ - tn • • • • Η — o o o rH EH 1—1 B Eh MJ B Φ MJ ε Φ i-H ε 1—1 EH 1—1 f—1 Eh G Eh Eh r- B 0 B G r— MJ B P 0 04 Φ Em Φ B ε 3 ε El Eh 0 EH 3 X Eh X υ o X O rH mJ o MJ >1 Φ B Φ xi υ MJ U -P 3 Φ 3 ω Cn G ‘rH “ mm J h Ν’ © vo KD O Em r— r— r~~ 3 Ό X MJ Cb W W U 00 OT o X N* Ν' © m w © © © CM Φ G •H ε i-H B MJ Φ •H Em MJ II © P ω z tx ε X ω © ο © 119 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 10 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) Ν,Ν-dimethyl formamide (2 ml) was added to the reaction mixture initially. A further portion of triethylamine (0.3 ml) and acetoxyacetyl 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 5 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. 0 Example 254 Tablets are prepared from the following ingredients .

Parts by weight Active compound 10 Lactose 1 90 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 starch. machine with magnesium The mixture is to give tablets a) 1 0 mg b) 100 mg c) 500 mg of active compound. 21 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 intc ι 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 1 0 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. 22 Female BALB/c mice, weight range 16-24 g, were used in groups of eight. The abdomen of each mouse was shaved and 20 μΐ 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 μΐ) . 100 μΐ of the same suspension was injected likewise every 2 4 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 μΐ 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 0 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 immunomodulatory agent. The compounds were considered to be active at a particular dose if a 23 % 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 50 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.

Ex Compound Name 124 Table A Minimum Effective Dose (mg/kg) 4-methyl-2-(5-trifluoromethyl-2pyridyl) [1J benzopyrano[4,3-c]pyrazol3(2H)-one 3 78 2-(5-chloro-2-pyridyl)-4-methyl[1]benzopyrano[4,3-c]pyrazol-3(2H)-one 3 2-(6-chloro-2-pyridyl)-4-methyl [1]benzopyrano[4, 3-c]pyrazol-3(2H)-one 50 80 4-methyl-2-(6-trifluoromethyl-2-pyridyl)[1]benzopyrano[4,3-c]pyrazol-3(2H)-one 50 2-(4-chloro-2-pyridyl)-4-methyl[1]- $3 benzopyrano[4,3-c]pyrazol-3(2H)-one 2-(6-chloro-5-trifluoromethyl-2- 3 pyridyl)-4-methyl[1]benzopyrano[4,3c]pyrazol-3(2H)-one 2-(5-bromo-2-pyridyl)-4-methyl[1]- 50 benzopyrano[4,3-c]pyrazol-3(2H)-one 2-(5-chloro-2-pyridyl)-9-hydroxy- 50 4-methyl[1]benzopyrano[4,3-c]pyrazol-3(2H)-one 8-fluoro-4-methyl-2-(5-trifluoro- ^50 methyl-2-pyridyl)[1Jbenzopyrano[4,3cj pyrazol-3(2H)-one 125 Ex Compound Name 86 2-(5-chloro-2-pyridyl)-8-fluoro-4methyl[1]benzopyrano[4,3-c]pyrazol3(2H)-one 2-(5-chloro-2-pyridyl)-4-methylthiomethy1[1]benzopyrano[4,3-c]pyrazol10 3(2H)-one ethyl 2-(5-chloro-2-pyridyl)-3-oxo2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 2-(5-chloro-2-pyridyl)-4-methyl-31 5 oxo-2,3-dihydro[1]benzopyrano[4,3£] pyrazol—9—yl acetate 2-(5-chloro-2-pyridyl)-3-oxo-2,3dihydro[1]benzopyrano[4,3-£]pyrazole4-acetate Minimum Effective Dose (mg/kg) s<3(a) <:3 (a) 126 Ex Compound Name Minimum Effective Dose (mg/kg) 5 91 2- piperidinoethyl 2-(4-chlorophenyl)- 3- oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate hydrochloride 0.4 hydrate 50 10 92 3-(4-methyl-l-piperazinyl)propyl 2-(4chlorophenyl)-3-oxo-2,3-dihydro(1]benzopyrano[4,3-c]pyrazole-4-acetate 2.5 hydrochloride dihydrate 50 1 5 93 2-morpholinoethyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate hydrochloride hemihydrate $3 94 2-morpholinoethyl 2-(3,4-dichlorophenyl) -3-OXO-2,3-dihydro[1]benzopyrano [4 , 3-c]pyrazole-4-acetate <550 20 95 2-morpholinoethyl 2-(4-chlorophenyl)8-hydroxy-3-oxo-2,3-dihydro[1]benzopyrano [4,3-c]pyrazole-4-acetate 50 25 96 3-morpholinopropyl 2-(4-chlorophenyl)3-oxo-2,3-dihydro[11benzopyrano[4,3-c]pyrazole-4-acetate hydrochloride monohydrate <3 30 97 2-morpholinoethyl 2-(4-bromophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate hydrochloride hemihydrate ^50 127 Ex Compound Name Minimum Ef fecti1 Dose (mg/kg) 5 98 2- morpholinoethyl 2-(4-fluorophenyl)- 3- oxo-2,3-dihydro[1]benzopyrano[4,3c]pyrazole-4-acetate hydrochloride «50 1 0 99 2-morpholinoethyl 2-(4-chlorophenyl)8-fluoro-3-oxo-2,3-dihydro[1Jbenzopyrano [4,3-c]pyrazole-4-acetate hydrochloride 0.4 hydrate $50 15 100 2-morpholinoethyl 2-(4-chlorophenyl)9-methoxy-3-oxo-2,3-dihydro[1]benzopyrano [4,3-c]pyrazole-4-acetate hydrochloride 50 101 4-methoxybenzyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-cJ pyrazole-4-acetate x 20 1 02 benzyl 2-(4-chlorophenyl)-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazole- 4-acetate «3 1 03 phenethyl 2-(4-chlorophenyl,-3-oxo-2,3dihydro[1]benzopyrano[4, 3-c]pyrazole- 4-acetate x<3 25 104 cyclopentyl 2-(4-chlorophenyl)-3-oxo2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate v<3 28 Ex Compound Name Minimum Effective Dose (mg/kg) 105 2-methoxyethyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 106 2-(2-thienyl)ethyl 2-(4-chlorophenyl)- ^3 3-oxo-2, 3-dihydro[1]benzopyrano[4,3-c]10 pyrazole-4-acetate 107 cyclobutyImethyl 2-(4-chlorophenyl)-3- 3 oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 108 2-(2-pyridyl)ethyl 2-(4-chlorophenyl)- 50 3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 109 cyclobutyl 2-(4-chlorophenyl)-3-oxo- ^3 2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 110 2-(2-methoxyethoxy)ethyl 2-(4-chloro- ^3 phenyl)-3-oxo-2,3-dihydro[1]benzopyrano [4,3-c]pyrazole-4-acetate 111 tetrahydrofurfuryl 2-(4-chlorophenyl)- ^3 3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]25 pyrazole-4-acetate 112 tetrahydro-2H-pyran-4-yl 2-(4-chloro- x<3 phenyl)-3-oxo-2,3-dihydro[ 1 ]benzopyrano [4,3-c]pyrazole-4-acetate 29 Ex Compound Name 113 2-(4-methyl-5-thiazolyl)ethyl 2-(4chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 114 3-methoxybenzyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]10 pyrazole-4-acetate 115 4-methylbenzyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 116 4-methoxyphenethyl 2-(4-chlorophenyl)15 3-oxo-2,3-dihydro[1]benzopyrano[4,3-c] pyrazole-4-acetate 117 4-chlorophenethyl 2-(4-chlorophenyl)3-oxo-2,3-dihydro[1]benzopyrano[4,3-c] pyrazole-4-acetate 118 2-chlorobenzyl 2-(4-chlorophenyl)3-oxo-2,3-dihydro[1]benzopyrano[4,3-c] pyrazole-4-acetate 119 3-oxobutyl 2-(4-chlorophenyl)-3-oxo2,3-dihydro[1]benzopyrano[4,3-c]25 pyrazole-4-acetate 120 2-chlorophenethyl 2-(4-chlorophenyl)3-oxo-2,3-dihydro[1]benzopyrano[4,3-c] pyrazole-4-acetate Minimum Effective Dose (mg/kg) «3 x<3 $3 $50 $50 $50 Ex Compound Name 121 3-methylphenethyl 2-(4-chlorophenyl)3-oxo-2,3-dihydro[1]benzopyrano[4,3-c] pyrazole-4-acetate 122 cyclohexyl 2-(4-chlorophenyl)-3-oxo2,3-dihydro[1]benzopyrano[4,3-c]10 pyrazole-4-acetate 123 3-chlorobenzyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 124 3-hydroxypropyl 2-(4-chlorophenyl)-315 oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 2-phenoxyethyl 2-(4-chlorophenyl)3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 126 4-dimethylaminophenethyl 2-(4-chlorophenyl) -3-OXO-2,3-dihydro[1]benzopyrano [4,3-c]pyrazole-4-acetate 127 2-acetamidoethyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]25 pyrazole-4-acetate 128 3-methylbenzyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate Minimum Effective Dose (mg/kg) $50 ¢50 $50 $50 $50 $50 $50 131 Ex Compound Name 129 2-methylbenzyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 130 4-chlorobenzyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]10 pyrazole-4-acetate 131 2-methoxybenzyl 2-(4-chlorophenyl)3-oxo-2,3-dihydro[1]benzopyrano[4,3— c]pyrazole-4-acetate 132 3-(3-pyridyl)propyl 2-(4-chlorophenyl)15 3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 133 α-methylphenethyl 2-(4-chlorophenyl)3-oxo-2,3-dihydro[1]benzopyrano[4,3c]pyrazole-4-acetate 134 cyclopropyImethyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 135 cyclobutyImethyl 3-oxo-2-(4-trifluoromethy lphenyl, -2,3-dihydro[1]benzopyrano [4,3-c]pyrazole-4-acetate 136 cyclobutyImethyl 2-(4-chlorophenyl)-8methyl-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate Minimum Effective Dose (mg/kg) «50 «50 «50 «50 «50 «3 «50 $50 ( 132 Ex Compound Name 137 cyclobutylmethyl 2-(4-methoxyphenyl)3-oxo-2,3-dihydro[1]benzopyrano [4,3-c]pyrazole-4-acetate 138 cyclobutylmethyl 2-(4-methylphenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]10 pyrazole-4-acetate 139 cyclobutylmethyl 2-(3-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 140 cyclobutylmethyl 2-(4-chlorophenyl)-915 hydroxy-3-oxo-2, 3-dihydro[1]benzopyrano [4,3-cJ pyrazole-4-acetate 142 2-acetoxyethyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano [4,3-c]pyrazole-4-acetate 143 2-hydroxyethyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 144 2-thiomorpholinoethyl 2-(4-chlorophenyl) -3-ΟΧΟ-2, 3-dihydro[1]benzo25 pyrano[4,3-c]pyrazole-4-acetate hydrochloride 145 2-methylthioethyl 2-(4-chlorophenyl)3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate Minimum Effective Dose (mg/kg) $50 $50 ,$50 $:50 «3 «3 33 Ex Compound Name 146 4,4,4-trifluorobutyl 2-(4-chlorophenyl) -3-OXO-2,3-dihydro[1]benzopyrano [4,3-c]pyrazole-4-acetate 147 2-cyanoethyl 2-(4-chlorophenyl)-3-oxo2 ,3-dihydro[1]benzopyrano[4,3-c]10 pyrazole-4-acetate 148 2-ethoxycarbonylethyl 2-(4-chlorophenyl) -3-OXO-2,3-dihydro[1]benzopyrano [4,3-c]pyrazole-4-acetate 149 β-methylphenethyl 2-(4-chlorophenyl)15 3-oxo-2,3-dihydro[1]benzopyrano[4,3c]pyrazole-4-acetate 150 2-cyclohexylethyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 151 1-methyl-2-morpholinoethyl 2-(4-chlorophenyl) -3-oxo-2,3-dihydro[1]benzopyrano [4,3-c]pyrazole-4-acetate 152 1-methyl-2-piperidyImethyl 2-(4chlorophenyl)-3-oxo-2,3-dihydro[1]25 benzopyrano[4,3-c]pyrazole-4-acetate 153 2-morpholinoethyl 2-(4-chlorophenyl)3-oxo-l,2,3,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole-4-acetate Minimum Effective Dose (mg/kg) «3 «50 «3 134 Ex Compound Name Minimum Effecti’ Dose (mg/kg) 5 1 54 3-acetoxypropyl 2-(4-chlorophenyl)-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate $50 1 0 155 2-(4-chlorophenyl)-N-methyl-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazole-4- acetanilide 50 1 56 N-benzyl-2-(4-chlorophenyl)-N-methy1-3oxo-2,3-dihydro[1]benzopyrano [4,3-c]pyrazole-4-acetamide 50 15 1 57 2-(4-chlorophenyl)-N-methyl-N-(2morpholinoethyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetamide 50 20 158 2-(4-chlorophenyl)-N-methyl-3-oxo-N(3-pyridylmethyl)-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4- acetamide 50 1 59 2-(4-chlorophenyl)-N-ethyl-3-oxo-Nphenyl-2,3-dihydro[1Jbenzopyrano[4,3-c]pyrazole-4-acetamide 3 25 1 60 N-benzyl-2-(4-bromophenyl)-N-methyl3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetamide 50 135 Ex Compound Name 161 N-benzyl-2-(3,4-dichlorophenyl)-Nmethyl-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetamide 162 N-benzyl-2-(4-chlorophenyl)-8-fluoroN-methyl-3-oxo-2,3-dihydro[ 1 ]benzo10 pyrano[4,3-c]pyrazole-4-acetamide 63 2-(4-chlorophenyl)-N-methyl-3-oxo-Nphenethyl-2,3-dihydro[1]benzopyrano[ 4,3-c]pyrazole-4-acetamide 164 2-(4-chlorophenyl)-N-(2-cyanoethyl)-N15 methyl-3-oxo-2,3-dihydro[1]benzopyrano [ 4,3-c]pyrazole-4-acetamide 165 2-(4-chlorophenyl)-N,N-(3-oxapentamethylene)-3-oxo-2,3-dihydro[ 1]benzopyrano [ 4,3-c]pyrazole-4-acetamide 166 4’-chloro-2-(4-chlorophenyl)-N-methyl3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetanilide 167 N-benzyl-2-(4-fluorophenyl)-N-methyl3-oxo-2,3-dihydro[1]benzopyrano[4,325 c]pyrazole-4-acetamide 68 2- (4-chlorophenyl,-N-(1,3-dioxolan-2ylmethyl)-N-methyl-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4acetamide Minimum Effective Dose (mg/kg) 36 Ex Compound Name 169 methyl 4-[2-(4-chlorophenyl)-N-methyl3-oxo-2,3-dihydro[1]benzopyrano[4,3-c ] pyrazole-4-acetamido]benzoate 70 71 2-|4-[2-(4-chlorophenyl)-3-oxo-2,3dihydro[1]benzopyrano[4,3-c ]pyrazole4-acetyl]piperazin-1-ylJ ethyl acetate 2-^4-[2-(4-chlorophenyl)-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazole4-acetyl]piperazin-1-yl)ethyl propionate Minimum Effective Dose (mg/kg) 172 N,N-(3-oxapentamethylene)-3-oxo-2(4-trifluoromethylphenyl)-2,3dihydro[1]benzothiopyrano[4,3-c]pyrazole-4-acetamide 173 N-ethyl-3-oxo-N-phenyl-2-(4-tri20 fluoromethylphenyl)-2,3-dihydro[1] benzothiopyrano[4,3-c]pyrazole-4acetamide «50 $:50 174 methyl 5-[2-(4-chlorophenyl)-3-oxo2,3-dihydro[1]benzopyrano[4,3-c]pyrazol-4-yl]-4-oxopentanoate 175 2-(4-chlorophenyl)-4-(2-oxo-3-phenylpropyl)[1]benzopyrano[4,3-c]pyrazol3(2H)-one 137 - Ex Compound Name Minimum Effecti1 Dose (mg/kg) 5 1 76 2-(4-chlorophenyl)-4-(2-oxo-3-phenoxypropyl)[1]benzopyrano[4,3tc]pyrazol3(2H)-one 3 1 0 177 2-(4-chlorophenyl)-4-(2-cyclohexyl-2oxoethyl)[1]benzopyrano[4,3-c]pyrazol- 3(2H)-one 50 1 78 2-(4-chlorophenyl)-4-(2-cyclopropyl-2oxoethyl)[1]benzopyrano[4,3-c]pyrazol- 3(2H)-one 50 15 1 79 2-(4-chlorophenyl)-4-[4-(4-methoxyphenyl) -2-oxobutyl] [ 1]benzopyrano[4,3 — c]pyrazol-3(2H)-one : $50 1 80 4-[3-(4-chlorophenoxy)-2-oxopropyl]2-(4-chlorophenyl)[1]benzopyrano[4,3c]pyrazol-3(2H)-one $3 20 1 81 2-(4-chlorophenyl)-4-[4-(^-methylphenyl) -2-oxobutyl][1Jbenzopyrano[4,3-c]pyrazol-3(2H)-one j $50 25 1 82 2-(4-chlorophenyl)-4-(3-cyclopentyl2-oxopropyl)[1]benzopyrano[4,3-c]pyrazol-3(2H)-one f $50 1 83 2-(4-chlorophenyl)-4-[3-(2-methylphenoxy)-2-oxopropyl][1Jbenzopyrano[4,3-c]pyrazol-3(2H)-one I $50 138 Ex Compound Name 184 2-(4-chlorophenyl)-4-(4-methylthio-2oxobutyl)[1]benzopyrano[4,3-c]pyrazol3(2H)-one 185 2-(3,4-dichlorophenyl)-4-(2-oxo-3phenoxypropyl)[1]benzopyrano[4,3-c]10 pyrazol-3(2H)-one 186 2-(4-chlorophenyl)-4-(3-methoxy-2-oxopropyl) [ 1 ]benzopyrano[4,3-c]pyrazol-3(2H)-one 187 2-(4-chlorophenyl)-4-methyl-3-oxo-2,315 dihydro[1]benzopyrano[4,3-c]pyrazol-9yl methyl malonate 188 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazol-8yl ethyl malonate 1 89 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazol-8yl methoxyacetate 90 2- (4-chlorophenyl)-4-methyl-3-oxo-2,3dihydro[1]benzopyrano[4, 3-c]pyrazol-825 yl cyclopropanecarboxylate 191 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazol-8yl 1-adamantanecarboxylate Minimum Effective Dose (mg/kg) $50 $50 $3 (a) $3 «1 $3(a) x<3 39 Ex Compound Name j 192 2-(4-chlorophenyl)-4-methyl-3-oxo-2,2 dihydro[1]benzopyrano[4,3-c ]pyrazol-i yl 3-phenylpropionate i 193 2-(4-chlorophenyl)-4-methyl-3-oxo-2,: dihydro[1]benzopyrano[4,3-c]pyrazol-i yl phenylacetate J £ 94 2-( 4-chlorophenyl) -4-methysl-3-oxo-2 ,: dihydro[1]benzopyrano[4,3-b]pyrazol-i Ϊ yl 2-methoxybenzoate ί i 95 2- (4-chlorophenyl) -4-methy-l-3-oxo-2,: dihydro[1]benzopyrano[4,3-^]pyrazol-l yl 2-furoate ; i ί 96 2- (4-chlorophenyl) -4-methy>l-3-oxo-2 , dihydro[1]benzopyrano[4,3-c]pyrazol-i yl 2-thenoate Ί 197 2-(4-chlorophenyl)-4-methyl-3-oxo-2, ( dihydro[1]benzopyrano[4,3-c]pyrazolyl cyclobutanecarboxylate 5 ? s 198 2-(4-chlorophenyl)-4-methyl-3-oxo-2, dihydro[1]benzopyrano[4,3-c]pyrazol25 yl 2-methylbenzoate J i 99 2- (4-chlorophenyl) -4-methyp.-3-oxo-2, dihydro [ 1 ] benzopyrano [ 4,3-jc] pyrazolyl 4-chlorobenzoate I Minimum Effective Dose (mg/kg) «3 «50 3- «50 . I 140 Ex Compound Name Minimum Effective Dose (mg/kg) 200 2-(4-chlorophenyl)-4-methyl-3-oxo- 50 2,3-dihydro[1]benzopyrano[4,3-c]pyrazol-8-yl crotonate 201 2-(4-chlorophenyl)-4-methyl-3-oxo- $50 2,3-dihydro[1]benzopyrano[4,3-c]10 pyrazol-8-yl 4-methoxybenzoate 202 2-(4-chlorophenyl)-4-methyl-3-oxo- $50 2,3-dihydro[1]benzopyrano[4,3-c]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-c]pyrazol-8-yl cyclohexanecarboxylate 205 2-(4-chlorophenyl)-4-methyl-3-oxo- 50 2.3- dihydro[1]benzopyrano[4,3-c]pyrazol8-yl 3-methylbenzoate 206 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- ,$50 dihydro[1]benzopyrano[4,3-c]pyrazol-825 yl isonicotinate 207 Ethyl 2-(4-chlorophenyl)-3-ΟΧΟ-8- 50 phenylacetoxy-2,3-dihydro[1]benzopyrano [ 4,3—cjpyrazole-4-acetate I 141 Ex Compound Name 208 Ethyl 2-(4-chlorophenyl)-8-methoxyacetoxy-3-oxo-2,3-dihydro [ 1 ] benzopyrano[4,3-c]pyrazole-4-acetate 0.3 methoxyacetic acid solvate 209 2-(4-chlorophenyl)-4-ethoxycarbonyl10 methyl-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazol-8-yl methyl succinate 210 4-methyl-3-oxo-2-(4-trifluoromethylphenyl) -2,3-dihydro[1]benzopyrano[4,3-c]pyrazol-8-yl acetoxyacetate 211 2-(4-bromophenyl)-4-methyl-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazol-8yl acetoxyacetate 212 2-(3,4-dichlorophenyl)-4-methyl-3oxo-2,3-dihydro[1]benzopyrano[4,3— cjpyrazol-8-yl methoxyacetate 213 2-(3,4-dichlorophenyl)-4-methyl-3oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazol-8-yl 3-(methylthio)propionate 214 2-(3,4-dichlorophenyl)-4-methyl-325 oxo-2,3-dihydro[1Jbenzopyrano[4,3-c]pyrazol-8-yl acetoxyacetate 215 2-(3,4-dichlorophenyl)-4-methyl-3oxo-2,3-dihydro[1]benzopyrano[4,3-cJ pyrazol-8-yl methyl succinate Minimum Effective Dose (mg/kg) $50 $50 $50 $50 K<50 42 Ex Compound Name 21 6 2- (4-chlorophenyl)-4-methyl-3-oxo2,3-dihydro[1]benzopyrano[4,3-c]pyrazol-9-yl methoxyacetate 217 cyclobutylmethyl 9-acetoxyacetoxy-2(4-chlorophenyl)-3-oxo-2,3-dihydro[1]10 benzopyrano[4,3-c]pyrazole-4-acetate 218 cyclobutylmethyl 8-acetoxyacetoxy-2(4-chlorophenyl)-3-oxo-2,3-dihydro[1 ] benzopyrano[4,3-c]pyrazole-4-acetate 0.5 hydrate, 0.35 acetoxyacetic acid solvate 219 Isopropyl 8-acetoxyacetoxy-2-(4chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 0.2 hydrate, 0.5 acetoxyacetic acid solvate 220 2-(4-chlorophenyl)-4-methyl-3-oxo-,2,3 dihydro[1]benzopyrano(4,3-c]pyrazol-9yl methyl succinate 221 2-(4-chlorophenyl)-4-methyl-3-oxo-2,325 dihydro[1]benzopyrano[4,3-c]pyrazol-8yl methyl succinate 222 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazol-8yl acetoxyacetate Minimum Effective Dose (mg/kg) <50 >$50 $50 «1 43 Ex Compound Name Minimum Effective Dose (mg/kg) 223 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 3 dihydro[1]benzopyrano[4,3-c ]pyrazol-8yl 3-(methylthio)propionate 224 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[1]benzopyrano[4,3-c]pyrazol-810 yl ethyl succinate 225 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 3 dihydro[1]benzopyrano[4,3-c]pyrazol-8yl benzoate 226 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[1]benzopyrano[4,3-c]pyrazol-9yl benzoate 227 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[1]benzopyrano[4,3-c]pyrazol-8yl nicotinate 228 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[1]benzopyrano[4,3-cJpyrazol-8yl 4-methoxybenzyl malonate 229 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[1]benzopyrano[4,3-c]pyrazol-825 yl hydrogen malonate 230 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- «3 dihydro[1]benzopyrano[4,3-c]pyrazol-8yl dimethylaminoacetate 144 Ex Compound Name Minimum Effective Dose (mg/kg) 231 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[1]benzopyrano[4,3-c]pyrazol-8yl (methylthio)acetate 232 ethyl 8-acetoxyacetoxy-2-(4-chloro- 3 phenyl)-3-oxo-2,3-dihydro[1]benzo10 pyrano[4,3-c]pyrazole-4-acetate hemihydrate acetoxyacetic acid solvate 233 2-(3,4-dichlorophenyl)-3a-methyl-3- $3 oxo-2,3,3a,4-tetrahydro[1]benzothiopyrano [4,3-c]pyrazol-8-yl ethyl malonate 234 2-(3,4-dichlorophenyl)-3a-methyl-3- $3 oxo-2,3,3a,4-tetrahydro[1]benzothiopyrano [4,3-c]pyrazol-8-yl methoxyacetate 235 2-(3,4-dichlorophenyl)-3a-methyl-3- $3 oxo-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazol-8-yl acetoxyacetate 236 2-(3,4-dichlorophenyl)-3a-methyl-3- $3 oxo-2,3,3a,4-tetrahydro[1]benzothio25 pyrano[4,3-c]pyrazol-8-yl phenylacetate 237 2-(3,4-dichlorophenyl)-3a-methyl-3- $1 oxo-2,3,3a,4-tetrahydro[1]benzothiopyrano [4 , 3-c]pyrazol-8-yl benzoate j 45 Ex Compound Name Minimum Effective Dose (mg/kg) 238 2-(3,4-dichlorophenyl)-3a-methyl-3- $1 oxo-2,3,3a,4-tetrahydro[1]benzothiopyrano [4,3-c]pyrazol-8-yl methyl succinate 239 2-(3,4-dichlorophenyl)-3a-methyl-3- $50 oxo-2,3,3a,4-tetrahydro[1]benzothiopyrano [4,3-c]pyrazol-8-yl crotonate 240 2-(3,4-dichlorophenyl)-3a-methyl-3- $50 oxo-2,3,3a,4-tetrahydro[1]benzothiopyrano [4 , 3-c]pyrazol-8-yl propionate 241 2-(3,4-dichlorophenyl)-4-methyl-3- 50 oxo-2,3-dihydro[1]benzothiopyrano[4,3-c]pyrazol-8-yl acetoxyacetate 242 3a-methyl-3-oxo-2-(4-trifluoromethyl- $50 phenyl)-2,3,3a,4-tetrahydro[1Jbenzo20 thiopyrano[4,3-c]pyrazol-8-yl acetoxyacetate 243 2-(4-chlorophenyl)-3a-methyl-3-oxo- $50 2,3,3a,4-tetrahydro[1]benzothiopyrano[4,3-c]pyrazol-8-yl methoxyacetate 244 2-(4-fluorophenyl)-3a-methyl-3-oxo-2,3, $50 3a,4-tetrahydro[1]benzothiopyrano[4,3-c]pyrazol-8-yl acetoxyacetate 146 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-c]pyrazol-8-yl malonate 246 3a-methyl-3-oxo-2-(4-trifluoromethyl- $3 phenyl)-2,3,3a,4-tetrahydro[1]benzothio10 pyrano[4,3-c]pyrazol-8-yl methoxyacetate 247 2-(4-fluorophenyl)-3a-methyl-3-oxo- 50 2,3,3a,4-tetrahydro[1]benzothiopyrano[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-c]pyrazol-8-yl acetoxyacetate 249 Ethyl 3a-methyl-3-oxo-2-(4-trifluoro- $50 methylphenyl)-2,3,3a,4-tetrahydro[1]20 benzothiopyrano[4,3-c]pyrazol-8-yl malonate 250 4-Methyl-3-oxo-2-(4-trifluoromethyl- $50 phenyl)-2,3-dihydro[1]benzothiopyrano[4,3-c]pyrazol-8-yl acetoxyacetate 251 Ethyl 4-methyl-3-oxo-2-(4-trifluoro- $50 methylphenyl)-2,3-dihydro[1 ]benzothiopyrano [4,3-c]pyrazol-8-yl malonate Notes : (a) Active in each of two tests at 3 mg/kg 147 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 the 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 inununity 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 administration at 50 mg/kg. be active, if at a dose test after parenteral A compound was deemed to 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. (Tp 25 O.D.(C1) - O.D.(Cg) where O.D.icp is the optical density of the control serum at a dilution of 1/128 O.D. (Cg) 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 1/128 148 The control and test sera were diluted phosphate buffered saline (pH 7.3) containing v/v Tween 20 (trade name).

Compounds active in above test: Examples 77-79, 81-137, 139-140, 142-159, 161, 166-7, 169-197, 199-240, 242-251. with 0.05% 164, 49 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 5 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-c]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-c]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-c]pyrazol-8-yl nicotinate 262 2-(3,4-dichlorophenyl)-3a-methyl-3-oxo- 132-135 2,3,3a,4-tetrahydro[1]benzothiopyrano20 [4,3-c]pyrazol-8-yl 3-methylbenzoate 263 ethyl 2-(5-chloro-2-pyridyl)-8-hydroxy- 258-265 3-oxo-2,3-dihydro[1]benzopyrano[4, 3-c]- (dec) pyrazole-4-acetate - 150 Ex Compound Name Melting Point(°C) 264 2-(2-methylpiperidino)ethyl 2-(4-chloro- 210-213 phenyl)-3-oxo-2,3-dihydro[1]benzopyrano5 [4,3-c]pyrazole-4-acetate hydrochloride 265 2-[4,5-bis(trifluoromethyl)-2-pyridyl]- 235-238 4-methyl[1]benzopyrano[4,3-c]pyrazol3(2H)-one 266 2-(5-chloro-2-pyridyl)-N-ethy1-3-oxo- 181-184 N-phenyl-2,3-dihydro[1]benzopyrano[4, 3c]pyrazole-4-acetamide 267 cyclobutylmethyl 2-(5-chloro-2-pyridyl)- 157-160 3-oxo-2,3-dihydro[1]benzopyrano[4, 3-c]pyrazole-4-acetate 268 4-[3-(3-chlorophenoxy)-2-oxopropyl]-2(4-chlorophenyl)[1]benzopyrano[4,3-c]pyrazol-3(2H)-one 193-195 269 4-[3-(2-chlorophenoxy)-2-oxopropyl]-2- 215-217 (4-chlorophenyl)[1]benzopyrano[4,3-c]20 pyrazol-3(2H)-one 270 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 153-156 dihydro[1]benzopyrano[4,3-c]pyrazol-8yl 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-c]pyrazole-4-acetate 151 Ex Compound Name Melting Point(°C) 272 2-acetoxyacetoxyethyl 2-(4-chlorophenyl) -3-ΟΧΟ-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 131 273 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazol-8yl 4-diethylaminomethylbenzoate 147-151 274 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 305-310 10 dihydro[1]benzopyrano[4,3-c]pyrazol-8yl glycinate (0.9) hydrochloride (dec) 275 4-(2-oxo-3-phenylpropyl)-2-(4-trifluoromethylphenyl) [1]benzothiopyrano[4,3-c]pyrazol-3(2H)-one 173-175 15 276 4-methoxybenzyl 3-oxo-2-(4-trifluoromethy lphenyl) -2,3-dihydro[1]benzothiopyrano [4,3-c]pyrazole-4-acetate 137-138 20 277 2-(5-chloro-2-pyridyl)-9-methoxy-4methy1[1]benzopyrano[4,3-c]pyrazol- 3(2H)-one 254-256 278 2-(4-chlorophenyl)-4-(4-methylsulphonyl-2-oxobutyl)[1]benzopyrano[4,3-c]pyrazol-3(2H)-one 221-223 25 279 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazol-8yl tert-butoxycarboxamidoacetate 192-193 152 Ex Compound Names 280 4-[3-(4-methoxyphenyl)-2-oxopropyl]2-(4-trifluoromethylphenyl)[1]5 benzothiopyrano[4,3-c]pyrazol-3(2H)one 281 2-(4-chlorophenyl)-4-[3-(4-methoxyphenyl) -2-oxopropyl] [1]benzopyrano[4,3-c]pyrazol-3(2H)-one 282 2-(3,4-dichlorophenyl)-3a-methyl-3oxo-2,3,3a,4-tetrahydro[1]benzothiopyrano [4 , 3-c] pyrazol-8-yl 4-methoxybenzoate 283 2-(3,4-dichlorophenyl,-3a-methyl-31 5 oxo-2,3,3a,4-tetrahydro[1]benzothiopyrano [4,3-c]pyrazol-8-yl 2-furoate 284 2-(3,4-dichlorophenyl)-3a-methyl-3oxo-2,3,3a,4-tetrahydro[1]benzothiopyrano [4,3-c]pyrazol-8-yl 4-chloro20 benzoate 285 2-(3,4-dichlorophenyl)-3a-methyl-3oxo-2,3,3a,4-tetrahydro[1]benzothiopyrano [4 , 3-c]pyrazol-8-yl 3-(methylthio) propionate 286 2-(2-thienyl)ethyl 3-oxo-2-(4-trifluoro methylphenyl)-2,3-dihydro[1]benzothiopyrano [ 4,3-c]pyrazole-4-acetate Melting Point ( °C) 184-187 178-180 141-142 189-190 170-173 97-99 144-146 Ex Compound Name Melting Point(°C) 5 288 4-(2-oxo-3-phenoxypropyl)-2-(4trifluoromethylphenyl)[1]benzothiopyrano [4,3-c]pyrazol-3(2H)-one 205-208 289 2-methoxyethyl 3-oxo-2-(4-trifluoromethylphenyl) -2,3-dihydro[1]benzothiopyrano [4,3-c]pyrazole-4-acetate 134-137 10 290 2-morpholinoethyl 3-oxo-2-(4-trifluoromethylphenyl)-2,3-dihydro[ 1 ] — benzothiopyrano[4,3-c]pyrazole-4-acetate 154-156 291 4-(3-methoxy-2-oxopropyl)-2-(4-trifluoromethylphenyl)[1]benzothiopyrano[4,3-c]pyrazol-3(2H)-one 148-150 15 292 4-[2-ΟΧΟ-3-(2-thienyl)propyl]-2-(4trifluoromethylphenyl)[1]benzothiopyrano [4,3-c]pyrazol-3(2H)-one 169-179 20 293 Tetrahydro-2H-pyran-4-yl 3-oxo-2-(4trifluoromethylphenyl)-2,3-dihydro[1]benzothiopyrano[4,3-c]pyrazole-4-acetate 172-175 294 2-(3,4-dichlorophenyl)-3a-methyl-3oxo-2,3,3a,4-tetrahydro[1]benzothiopyrano [4,3-c]pyrazol-6-y1 propionate 123-126 25 295 2-(3,4-dichlorophenyl)-3a-methyl-3oxo-2,3,3a,4-tetrahydro[1]benzothiopyrano [4,3-c]pyrazol-6-y1 acetoxyacetate 113 - 154 Ex Compound Name Melting Point(°C) 296 2-(4-chlorophenyl)-4-[2-OXO-3-(2- 135-138 thienyl) propyl] [1]benzopyrano[4,3-c]5 pyrazol-3(2H)-one 297 2-(4-chlorophenyl)-N-cyclopropyl-N- 160-162 cyclopropylmethyl-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 298 2-(4-chlorophenyl)-4-[4-(2-chloro- 166-168 phenyl)-2-oxobutyl][Ijbenzopyrano[4,3-c]pyrazol-3(2H)-one 299 CyclobutyImethyl 2-(4-chlorophenyl)6-methoxy-3-oxo-2,3-dihydro[1]benzopyrano [4,3-c]pyrazole-4-acetate 164-166 300 N-Benzyl-2-(4-chlorophenyl)-N-cyclopentyl-3-oxo-2,3-dihydro[1]benzopyrano [4,3-c]pyrazole-4-acetamide 197-199 301 2-(5-Chloro-2-pyridyl)-6,8-difluoro- 218-223 4-methyl[1]benzopyrano[4,3-c]pyrazol20 3(2H)-one 302 Ethyl 4-methyl-3-oxo-2-(4-trifluoromethylphenyl) -2,3-dihydro[1]benzothiopyrano [4,3-c[pyrazol-8-yl malonate 146-147 -.4 w 155

Claims (16)

Claims

1 . A compound of formula 1 when X represents oxygen or sulphur represents 5 hydrogen or together with Rg represents a bond; R ? together with either one of R. ) and Rg represents a bond; R 3 together with either one of R 2 and R 4 represents a bond; R 4 represents hydrogen or together with Rg represents a bond; 10 or when X represents sulphur, R and R 2 represent a bond, Rg represents methyl and R 4 and Rg represent hydrogen; S represents -CH= or -N= when X represents oxygen; 15 z represents -CH= when X represents sulphur; Rg represents hydrogen when Rg represents methyl, or Rg represents CH - Rg, *6 when Rg represents a bond together with either one 20 of R 2 and R 4 ; 156 Rg represents hydrogen, halo, S(O) n Y 1 , carboxy, carbamoyl, a carboxylic acyl group, an esterified carboxyl group or CONR^R^; R represents hydrogen or methyl; 5 or R, and R,, together with the carbon atom to 6 u which they are attached represent cyclopropyl; R 7 represents g alkyl, methoxy hydrogen, or S(O) Y, m 1 halo, / trifluoromethyl, R represents o hydrogen, halo or trifluoromethyl; 1 0 R„, represents o hydrogen, halo or trifluoromethyl; R q and R-,Qf which may be the same or different, represent halo; cr R o represents hydrogen and R ] θ represents hydrogen, halo, trifluoromethyl, nitro, C^g alkvl, C n , alkoxy, hydroxv or a carboxylic acyloxy 15 group; R „ reoresents methvl, ethyl or C- cycloalkyl 12 -j-g and represents C^g alkyl optionally substituted by cyano, phenvl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group or 20 C_ cycloalkyl; or R represents phenyl optionally substituted by C alkoxycarbonyl or halo; or Z *” o » R and R 13 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 25 acyloxy (C^g) alkyl group; Yl represents C^_g alkyl; n is 0, 1 or 2 and m is 0 or 1; 157 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-, θ 5 represents a carboxylic acyloxy group other than acetoxy? or b) when Rg represents hydrogen, halo, S(O) n Y.j, carbamoyl, carboxy, C 2 _ g alkoxycarbonyl, C 2 _g alkanovl or when R r and R, together with the carbon atom to 6 6 10 which they are attached form cylopropyl then R ] θ represents a carboxylic acyloxy group other than C 2 -6 alkanoyloxy? or c) when R ] and P 2 form a bond, Rg and R 4 form a bond, Rg,, R g , R gI , R 9 and R ] θ each represent hydrogen, R ? 15 represents chloro, then Rg does not represent 4-methoxybenzyloxycarbonyl? or II) When X is sulphur and a) Rg represents methyl? or b) Rg represents hydrogen, carboxy, S (0)^.,, c 2_g alkoxycarbonyl, carbamoyl, or c -,_ g dialkvlcarbamoyl, 2. C then R ]Q represents a carboxylic acyloxy group other than acetoxy.

2. A compound according to claim 1 represented by formula II ch-r 6 · 158 in which R 'represents hydrogen.

3. A compound according to either one of claims 1 and 2 wherein Rg represents COg(CHg)pJ in which p is 0-3 and J represents cyano, hydroxy, Cg_g cycloalkyl, Cg_g 5 alkanoyloxy, c 2_g alkoxycarbonyl, c -j_g alkoxy, C ]_g alkoxy (C^g) alkoxy, _ 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 10 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, 15 4. A compound according to either one of claims 1 and 2 wherein Rg represents COgNR^gR^g in which R^ 2 represents ethyl and R^g represents phenyl. 5. A compound according to either one of claims 1 and 2 wherein R_ represents COCH.K in which K represents o 20 C.j alkoxy or phenoxy. 6. A compound according to any one of claims 1 to 5 in which R^q represents hydrogen, hydroxy, halo, C^_g alkoxy or C^_g alkyl. 7. A compound according to any one of the preceding 25 claims in which R^ θ represents OCO(CHg)pL in which p is 0-3 and L represents hydrogen, Cg_^ 1 cycloalkyl; di(C.j_g alkyl) amino; C 2 _g alkanoyloxy; c 2_g alkoxycarbonyl, C-j_g alkylthio; C-| _g alkoxy; adamantyl or phenyl optionally substituted by c ^_g alkyl, C ]_g 30 alkoxy or halo. 8. A compound according to claim 7 in which R^ θ is substituted in the 8- or 9- position. 159 9. A compound according to either one of claims 7 and 8 in which Rg represents hydrogen or C 2-6 alkoxycarbonyl and Rg' represents hydrogen. 10. A compound according to claim formula IV represented by in which R ? represents halo or trifluoromethyl, R g represents hydrogen or halo, R g , represents hydrogen or halo and R Q represents hydrogen. 1 1 . A compound according to claim 1 represented by formula V V in which Rg' represents hydrogen, 4 represents OR ]5 , p. or NR 1O R 19 in which R. 9 represents methyl or ethyl, 16 12 1 J · _______ _ alkyl optionally substituted by 13 1 -6 2 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 represents C. 160 selected from oxygen, sulphur or nitrogen or represents phenyl optionally substituted by C 2 _g alkoxycarbonyl or halo; or R 12 and R-, 3 together with nitrogen to which they are attached form a 3-8 membered 5 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 Ί θ) alkyl group; and R 1 5 and R^, which may be the same or different, represent optionally substituted 10 groups selected from C^_g alkyl; C 2-6 a lkenyl; C 3_-| 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 15 selected from oxygen, sulphur or nitrogen; R g represents hydrogen and θ represents hydrogen, hydroxy, halo, C-,_g alkoxy or alkyl. 12. A compound according to claim formula VI '14 1 represented by VI in which R,' 0 represents hydrogen, R^ 4 represents OR.^, R or NR R , in which R represents methyl or ethyl, R represents θ 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 3 161 represents phenyl optionally substituted by Cg_ g alkoxycarbonyl or halo; or g and g together with nitrogen to which they are attached form a 3-8 membered non-aromatic heterocyclic ring which may contain a 5 further heteroatom selected from oxygen, sulphur or nitrogen which may be substituted by a Cg_g acyloxy (C ] _ 6 ) alkyl group; and R^ 5 and R-jg, which may be the same or different, represent optionally substituted groups selected from C^g alkyl; Cg_g alkenyl; Cg_ 10 10 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; Rg 15 represents hydrogen and θ represents hydrogen, hydroxy, halo, C^g alkoxy or C^g alkyl. represented by 13. A compound according to claim formula VII in which Rg' represents hydrogen and Rg represents 20 hydrogen, Cg_ 6 alkoxycarbonyl or C^g alkylthio, R ] ? represents optionally substituted groups selected from C, r alkvl; C„ c alkenyl; C_ .. cycloalkyl; a 3-8 1-6 z-o J- ι ι membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or 25 nitrogen; phenyl; a 5 or 6 membered heterocyclic aryl group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen. 162 14. A compound according to claim 1 represented by formula VIII r 17 oco VIII in which selected alkvl, a R^ represents optionally substituted groups from C 1 alkyl, C^_ 6 alkenyl, C 3 _ 10 cyclo3-8 membered non-aromatic heterocyclic group selected from oxygen, a 5 or 6 membered containing 1 or 2 heteroatoms sulphur or nitrogen; phenyl; heterocyclic aryl group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen. 1 0 IX represents hydrogen or methyl; C_ , alkanoyl, C , i Z“D carbamoyl, carboxy or R_ and R, in which R^, represents hydrogen, halo, C 2 -6 alkanoyl, C 2 _ g alkoxycarbonyl, SlOl^Y^ together with a carbon atom to which they are attached represent cyclopropyl; R ? represents hydrogen, halo, trifluoromethyl, methoxy, c -|_ g alkyl, S(O)__Y,; R represents hydrogen, halo or trifluoromethyl; R g 163 represents hydrogen, halo or trifluoromethyl; R g and R^, which may be the same or different, each represent halo; or R g represents hydrogen and θ represents hydrogen, halo, trifluoromethyl, hydroxy, nitro, C 2-6 5 alkanoyloxy, C^_g alkyl or C^_g alkoxy. 16. A compound selected from:cyclobutylmethyl 2-(4-chlorophenyl)-3-oxo-2,3dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 2-hydroxyethyl 2-(4-chlorophenyl)-3-oxo-2,31 0 dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 2-thiomorpholinoethyl 2-(4-chlorophenyl)-3-oxo2,3-dihydro[ 1 ]benzopyrano[4,3-c]pyrazole-4-acetate 2-(4-chlorophenyl)-4-(2-oxo-3-phenoxypropyl)[1]benzopyrano[4,3-c]pyrazol-3(2H)-one 15 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazol-8-yl (3-methylthio)propionate 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihydro[1Jbenzopyrano[4,3-c]pyrazol-8-yl dimethylamino 20 acetate Ethyl 8-acetoxyacetoxy-2- (4-chlorophenyl)-3X oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazol4-acetate 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihydro[1]25 benzopyrano[4,3-c]pyrazol-8-yl ethyl malonate 2-(3,4-dichlorophenyl)-3a-methyl-3-oxo-2,3,3a,4164 tetrahydro[1]benzothiopyrano[4,3-c]pyrazol-8-yl methoxy acetate. 17. of A pharmaceutical composition comprising a compound formula I R a' 1 8 Λ z R 7 R 1 Λ A 1 % N — z z — N >8 R 9 R 2j ASrS R 10 I 1 fR? 0 1 X ^“ R 4 R 5 in which X represents oxygen or sulphur; when X represents oxygen or sulphur represents hydrogen or together with Rg represents a bond; Rg together with either one of and Rg represents a bond; Rg together with either one of Rg and R^ 10 represents a bond; R^ represents hydrogen or together with Rg represents a bond; or when X represents sulphur, and Rg represent a bond, Rg represents methyl and R 4 and Rg represent hydrogen; 15 Z represents -CH= or -N= when X represents oxygen; Z represents -CH= when X represents sulphur; Rg represents hydrogen when Rg represents methyl, or R r represents CH - R,, 5 ι o R 6 when Rg represents a bond together with either one of Rg and R^; 165 Κθ represents hydrogen, halo, S(0) n Y 1 , carboxy, carbamoyl, carboxylic acyl group, an esterified carboxyl group or CONR·^^^ R represents hydrogen or methyl; 5 or R, and R , together with the carbon atom to 6 v which they are attached represent cyclopropyl? R? represents C, c alkyl, methoxv 1—0 hydrogen, halo, or SIO^Y; trifluoromethyl, *8 represents hydrogen, halo or trifluoromethyl; 1 0 *c, represents hydrogen, halo or trifluoromethvl? R q and which may be the same or different, represent halo? or R g represents hydrogen and R ]Q represents hydrogen, halo, trifluoromethyl, nitro, c -,_ g alkvl, g alkoxy, hydroxy or a carboxylic acyloxy 15 group; R represents methyl, or ethyl or C 3 _ 5 cycloaikyl and R 1n 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 20 C, θ cycloaikyl, or R . represents phenyl optionally substituted by C 9 _ g alkoxycarbonyl or halo? or R and R 1 g together with the nitrogen with to which they are attached represent a 3-8 membered non-aromatic heterocylic group which may be substituted 25 by a C 9 _ 6 acyloxy(C 1 _ g )alkyl group; Y^ represents C^_g alkyl? n is 0, 1 or 2 and m is 0 or 1 166 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 1 θ 5 represents a carboxylic acyloxy group other than acetoxy; or b) when R g represents hydrogen, halo, S (0)^, carbamoyl, carboxy, c 2-6 a l kox ycarbonyl, C 2 _ g alkanoyl or when R, and R , together with the carbon atom to 6 o 10 which they are attached form cylopropyl then R 1 θ represents a carboxylic acyloxy group other than Cg_g alkanoyloxy; II) When X is sulphur, Z is -CH=, and a) Rg represents methyl; or b) R g represents hydrogen, carboxy, S(0), 15 C 2 6 alkoxvcarbonyl, carbamoyl or C 1-6 dialkylcarbamoyl, then R^θ represents a carboxylic acyloxy group other than acetoxy. 18. A pharmaceutical composition according to claim 17 in unit dosage form. 20 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. 25 20. A compound of formula 1 as defined in claim 17 for use as an immunomodulatory agent. 21. A compound of formula X 167 as defined in 22. A compound of formula XIV XIV in which R n , R_ and R. are as defined in claim 1 and 3 5 9 5 R ] represents a carboxylic acyloxy group, R 2g represents carbamoyl or COOR^g and R^g represents C^_ 4 alkyl or benzyl. 168 together with R 2 represents a bond; R g together with R^ represents a bond; Z represents -CH= or -N= when X represents oxygen; 5 Z represents -CH= when X represents sulphur; R 5 represents CH - R g , Xr 6 R^ represents hydrogen, halo, S(0) Υ η , carboxy, ο η ι carbamoyl, a carboxylic acyl group, an esterified 10 carboxyl group or CONR^R^; R represents hydrogen or methyl; 6 r or R, and R,, together with the carbon atom to 6 6 which they are attached represent cyclopropyl; R„ represents ί hydrogen, halo, trifluoromethyl, 1 5 C, r alkvl, methoxy 1—0 or S(O) Y m ι « R represents 8 hydrogen, halo or trifluoromethvl; R o , represents 8 hydrogen, halo or trifluoromethyl? R g and R^, which may be the same or different, represent halo; or Rg represents hydrogen and R ] θ 20 represents hydrogen, halo, trifluoromethvl, nitro, C^g alkvl, C, . alkoxy, hydroxy or a carboxylic acyloxy group; R represents methyl, ethyl or C 3 _ g cycloaikyl and R,, represents C- c alkyl optionally substituted by 13 l-b 25 cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group or C, o cycloaikyl or R represents phenyl optionally substituted by C_ , alkoxycarbonyl or halo; or ζ — Ό 169 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 2 _g acyloxy(C 1 _g)alkyl group; 5 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: x) when X is oxygen, Z is -CH= and: 10 a) Rg represents c -,_g dialkylcarbamoyl, then R 1 θ represents a carboxylic acyloxy group other than acetoxy; or b) when R, represents hydrogen, halo, S(O) Y, , b Π I carbamoyl, carboxy, C 2 _g alkoxycarbonyl, C 2 _g alkanoyl 15 or when Rg and Rg, together with the carbon atom to which they are attached form cylopropyl then R 1 θ represents a carboxylic acyloxy group other than C 2 _g alkanoyloxy; or c) when R 1 and R 2 form a bond, R g and R 4 form a bond, 20 Rg,, R g , R gI , R g and R ] θ each represent hydrogen, R ? represents chloro, then Rg does not represent

4. -methoxybenzyloxvcarbonyl; or Ii) when X is sulphur and R g represents hydrogen, carboxy, S (0)^, c 2-6 ^loxycarbonyl, carbamoyl, or 25 C, c dialkylcarbamoyl, then R represents a carboxylic 1—6 ’ v acyloxy group other than acetoxy:a) comprising oxidising a compound of formula I in which R ] represents hydrogen, R 2 and R g represent a bond and R 4 represents hydrogen and X, Z, Rg, R ? , R g , 30 R ’, R q and R-_ are as herein defined; 8 9 I U 170 b) comprising reacting a.compound of formula X or a tautomer thereof, with a compound of formula XI R 6 '“CH — CR 22 R 23 R 6 XI in which Rgg represents (OQ) 2 and Rgg represents OQ or NQ\; or R^g represents (SO) g and Rgg represents SQ or

5. NQ' ; or R__ represents =NH and R o represents OQ or /// d SQ; or Rgg represents =0 and Rgg represents a leaving group and Q and Q' represent a C alkyl group or a benzyl group; c) in which R, is selected from a carboxylic acyl 6 10 group comprising reacting a compound of formula X XH 171 with a compound of formula Xlla 0. V 24 0 R 25 Xlla or a tautomer thereof, or a compound of formula XIlb Xllb or a tautomer thereof, in which θ represents an optionally substituted group selected from C^g alkyl, 5 C 2 _ 6 alkenyl, c 3_i 0 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„ r which may be the same or different, 24 25 represent a alkyl group or a benzyl group; 10 d) comprising reacting a compound of formula XIII XIII 172 represents hydrogen or a tautomer thereof, Rgg represents a group CORgg in which Rgg hydrogen, an optionally substituted _ 4 or benzyl and Rg 7 represents COCHRgRg,, in which Rgg or in which represents alkyl group with a base. 24. A process to prepare a compound of formula 1 in which λ represents oxygen or sulphur; P represents hydrogen; Rg together with R g represents a bond; represents hydrogen; 10 Z represents -CH= or -N= when X represents oxygen; Z represents -CH= when X represents sulphur; Rg represents CH - Rg, R, represents hydrogen, halo, S (Ο) Y.. ο π I carbamoyl, a carboxylic acyl group, an carboxyl group or CONR^R^; , carboxy, esterified R c , represents hydrogen or methyl; 0 173 or Rg and Rg, together with the carbon atom to which they are attached represent cyclopropyl; R ? represents C, , alkvl, methoxy hydrogen , or S(O) Y. m ι halo, t trifluoromethyl, 5 R o represents o hydrogen, halo or trifluoromethyl; R o , represents o hydrogen, halo or trifluoromethyl; R and R , which may be the same or different, y ι u represent halo; or Rg represents hydrogen and R^ θ represents hydrogen, halo, trifluoromethyl, nitro, C-|_ g 10 alkvl, C, , alkoxv, nvdroxy or a carboxylic acyloxy :—o group; R. 9 represents methyl, ethvl or C 3 _ g cycloaikyl and R 1 3 represents C^g alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic 15 group, a 5 or 6 membered heterocyclic aryl group or C 3 8 cycloaikyl, or 3 represents phenyl optionally substituted bv C_ , alkoxycarbonyl or halo; or 2-6 R and R. - together with the nitrogen to which I 2. 13 they are attached represent a 3-8 membered non-aromatic 20 heterocylic group which may be substituted by a C 2 -6 acyloxyiC. ,)alkyl group; J —fc Y. represents C, r alkvl; 1 I — Ό n is 0, 1 or 2 and m is 0 or 1; or a pharmaceutically acceptable salt thereof; 25 provided that: I) when X is oxygen, Z is -CH= and: 174 a) R. represents CL r dialkylcarbamoyl, then R6 1— 6 IU represents a carboxylic acyloxy group other than acetoxy; or b) when Rg represents hydrogen, halo, S(O) n Y 1 , 5 carbamoyl, carboxy, Cg_g alkoxycarbonyl, Cg_ 6 alkanoyl or when R g and R g , together with the carbon atom to which they are attached form cylopropyl then R 1 θ represents a carboxylic acyloxy group other than Cg_g alkanoyloxy; or ΊΟ II) When X is sulphur and R g represents hydrogen, carboxy, S (0) Y ] , Cg_g alkox y carbon Y- L ' carbamoyl, or C. , dialkylcarbamoyl, then R. represents a carboxylic 1—6 * u acyloxy group other than acetoxy:a) comprising reducing a compound of formula I 15 wherein R ] and Rg represents a bond; Rg and R 4 represent a bond; and R_, R^, Rg, Rg, , Rg and R^ θ are as herein defined; or b) comprising reacting a compound formula XIV XIV in which Rg represents hydrogen, Rg represents CHRgRg', 20 Rgg represents COORg 0 or carbamoyl and Rg Q represents a 4 alkyl group or a benzyl group with a compound of formula XV XV 25. A process to prepare a compound of formula I in which X represents sulphur, and R 2 represent a bond, Rg represents methyl and and Rg represent hydrogen; Z represents -CH=; R ? represents hydrogen, halo, θ alkvl, methoxy or SiO^Y^; R represents hvdrogen, halo or 8 R represents hydrogen, halo or 8 trifluoromethyl, trifluoromethyl; trifluoromethyl; 10 R and R , which may be the same or different, y ι u represent halo; or R g represents hydrogen and R ] θ represents hydrogen, halo, trifluoromethyl, nitro, alkyl, C. c alkoxy, hydroxy or a carboxylic acyloxy I -6 group ? 176 R-] 2 represents methyl, ethyl or Cg_ Q cycloalkyl and R^g 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 5 Cg θ cycloalkyl or R ] g represents phenyl optionally substituted by C__, alkoxycarbonvl or halo; or R 1 g and R^ g together with the nitrogen to which they are attached represent a 3-8 membered non-aromatic heterocylic group which may be substituted by a Cg_g 10 acyloxy(C ] _ g )alkyl group; 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 1Ci represents a carboxylic group other than 15 acetoxy, comprising reacting a compound of formula XIV in which Rg represents methyl, X represents S, Rg represents hydrogen Rg g represents COORg Q or carbamoyl and Rg 0 represents a C ]-4 alkyl group or a benzyl group 20 with a compound of formula XV R 7 h 2 n-nh XV 177 in which Z represents -CH=. 26. A process to prepare a compound of formula I when X represents oxygen or sulphur represents 5 hydrogen or together with R 2 represents a bond; R 2 together with either one of R 1 and Rg represents a bond; R 3 together with either one of R 2 and R 4 represents a bond; R 4 represents hydrogen or together with Rg represents a bond; 10 or when X represents sulphur, R^ and R ? represent a bond, R 3 represents methyl and R 4 and Rg represent hydrogen; Z represents -CH= or -N= when X represents oxygen; 15 z represents -CH= when X represents sulphur; Rg represents hydrogen when Rg represents methyl, or Rg represents CH - Rg, *6 when Rg represents a bond together with either one of Rg and R 4 ; 178 R g represents hydrogen, halo, S(O) n Y 1 , carboxy, carbamoyl, a carboxylic acyl group, an esterified carboxyl group or CONR^ 2 R^ 2 ; Rg, represents hydrogen or methyl; 5 or R^ and R^. together with the carbon atom to

6. C which they are attached represent cyclopropyl; R^ represents C, r alkyl, methoxy I — c hydrogen, or S(O) Y. m 1 halo , t trifluoromethyl, *8 represents hydrogen, halo or trifluoromethyl; 1 0 Rg , represents hydrogen , halo or trifluoromethvl; F and R n , which may be the same or different, y ι υ represent halo; or Rg represents hydrogen and R ] θ represents hydrogen, halo, trifluoromethyl, nitro, C-|_g alkvl, c n r alkoxy, hydroxy or a carboxylic acyloxy 15 group; R represents methyl, ethyl or c 3_ g cycloaikyl and R ]3 represents g alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group or 20 C. o cycloaikyl; or R represents phenyl optionally substituted bv C„ c alkoxvcarbonyl or halo; or R-j 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 2 _g 25 acyloxy(C^_g)alkyl group; Y.j represents C-|_g alkyl; n is 0, 1 or 2 and m is 0 or 1; 179 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^ θ 5 represents a carboxylic acyloxy group other than acetoxy; or b) when Rg represents hydrogen, halo, S(O) n Y^, carbamoyl, carboxy, Cg_g alkoxycarbonyl, C 2 ~6 a l kan °Yl or when Rg and Rg, together with the carbon atom to

7. 10 which they are attached form cylopropyl then θ represents a carboxylic acyloxy group other than Cg_g alkanoyloxy; or c) when and Rg form a bond, Rg and R 4 form a bond, Rg, , R g , Rg, , Rg and R^ θ each represent hydrogen, R?

8. 15 represents chloro, then R, does not represent 0 4-methoxybenzyloxycarbonyl; or II) When X is sulphur and a) Rg represents methyl; or b) R. represents hydrogen, carboxy, S(0) Y , C . ο η ι z—o alkoxycarbonyl, carbamoyl, or c -,_g dialkylcarbamoyl,

9. 20 then R^ θ represents a carboxylic acyloxy group other than acetoxyla) in which Rg represents -CHRgRg’ and Rg is selected from CONR^gR^g or an esterified carboxyl group, comprising reacting a compound of formula 1’ 180 in which R lo' represents R^ Q , r 5 represents -CHR a Rg,, represents COA and A represents a leaving group, with an amine of formula NHR^R^g or an alcohol of formula R-| 5 OH in which R^g represents an optionally 5 substituted group selected from _g alkyl, ^2-6 alkenyl, Cg 1Q 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 ] θ is selected from a carboxylic acyloxy 10 group comprising reacting a compound of formula I’ X 181 in which R r represents -CHR R r ,, R represents R,. and 5 a o a o R-| θ' represents hydroxy with an acylating agent. 27. A compound of formula 1 in which X represents oxygen or sulphur; 5 when X represents oxygen or sulphur R^ represents hydrogen or together with Rg represents a bond; Rg together with either one of R^ and Rg represents a bond; Rg together with either one of Rg and R^ represents a bond; R^ represents hydrogen or together 10 with Rg represents a bond; or when X represents sulphur, R^ and Rg represent a bond, Rg represents methyl apd R^ and Rg represent hydrogen; Z represents -CH=; R$ represents hydrogen when Rg represents methyl, 182 or Rg represents CH - Rg, *6 when Rg represents a bond together with either one of Rg and R^? 5 R, represents hvdrogen, halo, S(0) Y.. , carboxy, carbamoyl, a carboxylic acyl group, an esterified carboxyl group or CONR^R^g,· Rg, represents hydrogen or methyl; or R- and R,, together with the carbon atom to 6 6 10 which they are attached represent cyclopropyl; R_, represents hydrogen, halo , trifluoromethyl, alkyl, methoxv 6 or S(0) Ym 1 z R o represents o hydrogen, halo or trifluoromethyl; Rg , represents hydrogen, halo or trifluoromethvl; 15 R o and R. n , which may be the same or different, represent halo; or R g represents hydrogen and R^ θ represents hydrogen, halo, trifluoromethyl, nitro, C^_ 6 alkvl, C 1 , alkoxv, hvdroxy or a carboxylic acyloxy 1-6 group; 20 R ]2 represents methyl or ethyl and R 1 g represents r . alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group; or R 1 g represents phenyl optionally substituted by C 2 _ g alkoxycarbonyl or 25 halo; or R ]2 and R^ g together with the nitrogen to which they are attached represent a 3-8 membered non-aromatic 183 . heterocylic group which may be substituted by a C 2 _g acyloxy (C^g) alkyl group; Y 1 represents C^_g alkyl; n is 0, 1 or 2 and m is 0 or 1; 5 or a pharmaceutically acceptable salt thereof; provided that: I) when X is oxygen and: a) Rg represents C ]_g dialkylcarbamoyl, then R 1Q represents a carboxylic acyloxy group other than 10 acetoxy; or b) when R, represents hydrogen, halo, S(O)_Y , b *· * carbamoyl, carboxy, C 2 _ g alkoxycarbonyl, C 2 _ g alkanoyl or when R, and R,, together with the carbon atom to 6 o which they are attached form cyclopropyl then R^g 15 represents a carboxylic acyloxy group other than C 2 _ g alkanoyloxy; or c) when R 1 and R 2 form a bond, Rg and R 4 form a bond, Rg,, Rg, Rg,, R g and Q each represent hydrogen, R ? represents chloro, then Rg does not represent 20 4-methoxybenzyloxycarbonyl; or II) When X is sulphur and a) Rg represents methyl; or b) Rg represents hydrogen, carboxy, S (0)^, C 2 _ g alkoxycarbonyl, carbamoyl, or C] _g dialkylcarbamoyl, then R-j θ represents a carboxylic acyloxy group other

10. 25 than acetoxy. 184

11. 28. A compound according to claim 1, substantially as hereinbefore described and exemplified.

12. 29. A process for preparing a compound according to claim 1, substantially as hereinbefore described and exemplified.

13. 30. A compound according to claim 1, whenever prepared by a process claimed in a preceding claim.

14. 31. A pharmaceutical composition according to claim 17, substantially as hereinbefore described.

15. 32. A compound according to claim 21, substantially as hereinbefore described and exemplified.

16. 33. A compound according to claim 22, substantially as hereinbefore described and exemplified.