CA2074841A1 - 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 R10, 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

, WO91/11448 PCT/EP91/00154 ~herapeutic A~ents The present invention relates to novel therapeutic agents, and in particular to [l]benzopyrano[4,3-c~-pyrazoles or [l]benzothiopyrano[4,3-c]pyrazoles, to processes for thei; preparation, to pharmaceutical compositions containing them and to their therapeutic activity as immunomodulatory agents.

The present invention relates to compounds of formula I R8' ~ R7 `N N Z R8 R10 ~ 4 in which X represents oxygen or sulphur;

when X represents oxygen or sulphur Rl represents hydrogen or together with R2 represents a bond; R2 together with either one of Rl and R3 represents a bond; R3 together with either one of R2 and R4 represents a bond; R4 represents hydrogen or together with R3 represents a bond;

or when X represents sulphur, Rl and R2 represent a bond, R3 represents methyl and R4 and R5 represent - hydrogen:

20Z represents -CH= or -N= when X represents oxygen;

Z represents -CH= when X represents sulphur;

'-.

WO91/11448 PCT/EP9l/001

2 . ~ k `~
R5 represents hydrogen when R3 represents methyl, or R5 represents ~H - R6, when R3 represents a bond together with ei.her one of R2 and R4;

R6 represents hydrogen, halo, S(O)nYl , carboxy, carbamovl, a carboxylic acyl group, an esterified carboxyl group or CONR12R~3;

R6, represents hydrogen or methyl;

or R6 and R6, togethe_ with the carbon atom to which they are attached represent cyclopropyl;

R7 represents hydrogen, halo, trifluoromethyl, Cl 6 alkyl, methoxy or S()mYl;

R8 represents hydrogen, halo or trifluoromethyl;

R8, represents hydrogen, halo or trifluoromethyl;

Rg and Rlo, which may be the same or different, represent halo; or Rg represents hydrogen and Rlo represents hydrogen, halo, trifluoromethyl, nitro, Cl 6 alkyl, Cl 6 alkoxy, hydroxy or a carboxylic acyloxy group;

R12 represents methyl, ethyl or C3 8 cycloalkyl and R13 represents Cl 6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group or C3 ~ cycloalkyl; or R13 represents phenyl optionally substituted by C2 6 alkoxycarbonyl or halo; or . . .

WO91~11448 PCT/EP91~001 R12 and R13 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(C1 6)alkyl;

Yl represents Cl 6 alkyl;
n is 0, 1 or 2 and m is 0 or l which have immunmodulatory activlty.

In our copending patent applications ~PCT patent appllcation nos. PCT/GB 89/00859 and PCT/GB 89/00860) there are described certain compounds of formula A and formula B
~"R7 R ~

f~o A

~ R 6 ~4 B

The first PCT patent application described above also discloses 4-methoxybenzyl 2-(4-chlorophenyl)-3-oxo- 2, 3-dihydro[l]benzopyrano[4,3-c]pyrazole-4-acetate WO91/11~ PCT/EP91/001 2Y, ~ 4 -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

R10~ R8 in which X represents oxygen or sulphur;

when X represents oxygen or sulphur R1 represents hydrogen or together with R2 represents a bond; R2 together with either one of R1 and R3 represents a bond; R3 together with either one of R2 and R4 represents a bond; R4 represents hydrogen or together with R3 represents a bond;

or when X represents sulphur, R1 and R2 represent a bond, R3 represents methyl and R4 and R5 represent hydrogen;
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 ICH R6, when R3 represents a bond together with either one of R2 and R4;

R6 represents hydrogen, halo, S(O)nYl , carboxy, carbamoyl, a carboxylic acyl group, an esterified carboxvl group or CONR12R13;
R6, represents hydrogen or methyl;

or R6 and R6, together with the carbon atom to which they are at'ached represent cyclopropyl;

R7 represents hydrogen, nalo, .ri'luorome.hyl, Cl 6 alkyl, methoxy or S(O)mYl;
R8 represents hydrogen, halo or trifluoromethyl;
R8, represents hydrogen, halo or trlfluoromethyl;

Rg and R1o, which may be the same or different, represent halo; or Rg represents hydrogen and R1o represents hydrogen, halo, trifluoromethyl, nitro, C1 6 alkyl, Cl 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 heterocylic 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 heterocylic group which may be substituted by C2 6 acyloxy(C1_6)alkyl;

Y1 represents C1 6 alkyl;
n is 0, 1 or 2 and m is 0 or 1 provided that:
I) when X is oxygen; Z = -CH= and:

a) R6 represents C1 6 dialkylcarbamoyl, then R1o represents a carboxylic acyloxy group other than acetoxy; or b) when R6 represents hydrogen, halo, S(O)nY1, carbamoyl, carboxy, C2 6 alkoxycarbonyl, C2 6 alkanoyl or when R6 and R6, together with the carbon atom to which they are attached form cylopropyl then R1o represents a carboxylic acyloxy group other than C2 6 alkanoyloxy; or c) when R1 and R2 form a bond, R3 and R4 form a bond, R6,, R8, R8 " R9 and R1o each represent hydrogen, R7 represents chloro, then R6 does not represent 4-methoxybenzyloxycarbonyl;

II) When X is sulphur and a) R3 represents methyl; or b) R6 represents hydrogen, carboxy, S(O)nY1, C2 6 alkoxycarbonyl, carbamoyl or C1 6 dialkylcarbamoyl, then R1o represents a carboxylic acyloxy group other than acetoxy.

It will be understood that a group containing a chain of 3 or more carbon atoms may be straight or branched, for example propyl includes n-propyl and isopropyl, and butyl incl~des n-butyl, sec-butyl, ~ . , , WO91/11~ ~A~ PCT/EP91/001~

isobutyl and tert-butyl. The term "halo" includes fluoro, chloro or bromo.

In one class of compounds of formula 1, R1 and R2 form a bond and R3 and R4 form a bond, as represented 5 by formula II R8~
~ R7 R 10--~ 11 X CH-R6' 6 6' 7r 8' R8 ~ Rg and R1o are as herein-above defined. In another class of compounds of formula I, R1 represents hydrogen, R2 and R3 form a bond and R4 represents hydrogen, as represented by 10 formula III R8~
~ R7 Il L
H ~ Z~~`R8 J . ._R6 and R6, R6 " R7, R8, R8 " Rg and R1o are as hereinabove defined.

In another class of compounds of formula I, R1 and R2 form a bond, and R4 and R5 represent hydrogen, as represented by formula IV

WO91/11~ PCT/EP91JO~

Rg ~

and R7, R8, R8,, R9 anZ R1o are as herein defined.
Preferred substituents are as given hereinafter. More preferably R7 represents halo or trlfluoromethyl, R8 represents hydrogen or halo, R8' represents hydrogen or S halo and Rg represents hydrogen.

In compounds of formula I, preferably R6' represents hydrogen.

In certain compounds of formula I, the group R6 may be an esterified carboxyl group, a carboxylic acyl group or certain tertiary carboxamide groups. These groups may be represented by the formula -CO.R14 in which R14 represents an alkoxy group (for example C1 6); an alkenyloxy group (for example C2 6); a cycloalkoxy group ~for example C3 10); an oxygen atom attached to a non-aromatic heterocyclic group; a carbocyclic aryloxy group; a heterocyclic aryloxy group; an alkyl group (for example C1 6); an alkenyl group (for example C2 6); a cycloalkyl group (~or C3 10); 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 WO91/11~ ~` PCT/EP91/001~
g well as those which are less readily hvdrolysable.
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 R6 may have the formula a) -CO.OR15 b) -CO.R16 c) -CO.NR12R13 i~ which R12 represents methyl, ethyl or C3_8 cyclo-alkyl and R13 represents C1 6 alkyl optionally substituted by cyano, phenyl, a 3-8 memDered non-aromatic heterocyclic group, a 5 or 6 membered heterocyclic aryl group or R13 represents phenyl optionally subs~ituted by C2 6 alkoxv-arbonyl 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 C2 6 acyloxy(C1 6)alkyl; R15 and Rl6 represent C1 6 alkyl; C2 6 alkenyl; C3 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 R15, R16 being optionally substituted by Z.

Z represents Z1~ Z2' phenyl, a 3-8 membered non-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 Z1 or Z2;

Z1 represents halo, trifluoromethyl, hydroxy, carboxy or cyano;

WO91/l1448 PCT/EP91/OO'.~

2~ 3 ~.~ .~.
Z2 represents C1 6 alkyl~ C3_10 cycloalkyl~
1' 18Rl9, C1_6 alkoxy, C2 6 alkoxycarbonyl C2 6 alkanoyl, C2 6 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, C1 6 alkyl or phenyl;

R18 and R19, which may be the same or different, each represent hydroqen; C1 6 alkyl; C3 10 cycloalkyl, C2 6 alkenyl; a carbocyclic aryl group; a 3-8 membered non-aromatic heterocyclic group; a 5 or 6 membered heterocyclic aryl group or ~18 and R19 together wi~;.
the nitrogen to which they are attached form a 3-8 membered non-aromatic heterocyclic group.

In compounds of formula I, suitable substituents R6 include the following:
hydrogen: halo (fluoro, chloro or bromo), preferably fluoro or chloro, most preferably chloro: carboxy;
carbamoyl, S(O)nY1 in which Y1 is preferably C1 4 alkyl and n represents 0, 1 or 2 (for example methylthio, ethylthio, propylthio, methylsulphinyl, ethylsulphinyl, propylsulphonyl~, more preferably Y1 is C1 2 alkyl, most preferably methyl; suitably n is 0 or 1 and preferably 0. Most preferably R6 represents hydrogen or C2 6 alkoxycarbonyl.

In compounds of formula I, R6 together with R6, and the carbon to which they are attached may form cyclopropyl.

Preferably R6 also includes CONR12R13 in which R12 represents methyl or ethyl and R13 represents C1 6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocyclic group containing one WO91/114~ PCT/EP91/O01~

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 R13 represents phenyl S optionally substituted by C2_6 alkoxycarbonyl (for example methoxycarbonyl) or halo (for example chloro);
or R12 and R13 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 C2 6 acyloxy(Cl 6)alkyl group (for example propionyloxyethyl).

Preferably R6 also includes a carboxyl c ester group, which is preferably represented by the formula -CO.OR15 in which R15 represents Cl_6 alkyl; C2_6 alkenyl; C3 10 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 R15 represents Cl 6 alkyl, C3 8 cycloalkyl, a 5-7 membered non-aromatic heterocyclic group containing one or two heteroatoms selected from oxygen, sulphur or nitrogen; a phenyl group; a 5 or 6 membered heterocyclic aryl ring containing one or two heteroatoms selected from oxygen, sulphur or nitrogen, each group being optionally substituted by Z.

30Preferably R6 also represents a carboxylic acyl group which is preferably represented by the formula -CO.R16 WO91/11448 PCT/EP91/~0~C4 in which R16 represents Cl-6 alkyl; C2 6 alkenyl; C3 1O
cycloalkyl; a 3-8 membered non-aromatic heterocyclic group containing one or two heteroatoms selected from oxygen, sulphur or nitro~en; a carbocyclic aryl group;
a 5 or 6 membered heterocyclic aryl group containing one to three heteroatoms selected from oxygen, sulphu_ or nitrogen; each group being optionally substituted by Z. Preferably R16 represents Cl 6 alkyl, C3 8 cyclo-alkyl, a 5-7 membered non-aromatic heterocyclic grouo containing one or two heteroatoms selected from oxygen, sulphur or nitrogen; a phenyl group; a 5 or 6 membered heterocyclic aryl ring containing one or two hetero~
atoms selected from oxyaen, sulphur o nitrogen, each group being optionallv substituted bv Z.

Preferably Z represents Zl or Z2 Preferably Zl represents halo ~fluoro, chloro or bromo), more preferably f~uoro or chloro, most preferably chloro; hydroxy or cyano;

Preferably Z2 represents the following:

Cl 6 alkyl, preferably C1_4 alkyl (for example methyl, ethyl or propyl), more preferably methyl or ethyl and most preferably methyl; C3 7 cycloalkyl, preferably C3 5 cycloalkyl; Cl 6 alkoxy, preferably Cl 4 alkoxy ~for example methoxy, ethoxy or propoxy), more preferably methoxy or ethoxy, and most preferably methoxy; S()mYl in which Yl is preferably Cl 4 alkyl and m represents 0, 1 or 2, (for example methylthio, ethylthio, propylthio, methylsulphinyl, ethylsulphinyl, propylsulphinyl, methylsulphonyl, ethylsulphonyl, propylsulphonyl), more preferably Yl is Cl 2 alkyl, most preferably methyl, suitably m is 0 or 1 and preferably 0; C2_5 alkoxycarbonyl (for example ~,~?~

methoxycar~onyl or ethoxycarbonyl); C2 5 alkanoyl (for example acetyl or propionylj; o- C2 5 alkanoyloxy tfor example acetoxy or propionyloxy); CONR18R19 in which R18 and R19 preferably represent hydrogen, C1 6 alkyl, 5 C2-6 alkenyl~ C3_8 cycloalkyl, a 3-8 membered non-aromatic heterocyclic group containing one or two heteroatoms selected from oxygen, sulphur or nitrogen;
phenyl, a 5 or 6 membered heterocyclic arvl group containing one to three heteroatoms selected from oxygen, sulphur or nitrogen; or R18 and R19 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 subs~ituents R18, R19 being optionally substituted by Z.

In compounds of formula I, particularly preferred substituents R6 include:

hydrogen, carboxy or -CO.R14 in which R14 is as defined above.
Preferred esterified carboxyl groups R6 include:

C2 6 alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or pentyloxycarbonyl; C3_8 cycloalkoxycarbonyl (for example cyclobutoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl) or tetrahydro-2H-pyran-4-yloxy-carbonyl, each of which groups may be substituted by:
C1 6 alkyl (for example methyl); C3 8 cycloalkyl (for example cyclohexyl, cyclopentyl, cyclobutyl or cyclo-propyl); phenyl; a 3-8 membered non-aromatic heterocyclic group containing one or two heteroatoms selected fr;m nitrogen, oxygen or sulphur, (for example tetrahydrofuryl, tetrahydropyranyl, morpholino, piperidino, thiomorpholino, piperazino); a 5 or 6 WO91/11448 PCT~EP91/OOl~

Z ~
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); C1 6 alkoxy (for example methoxy or ethoxy); 5(0)mYl (for example methyl'hio);
C2 6 alkanoyloxy (Ior example acetoxy); cyano, hydroxy, acetamido, trifluoromethyl, halo. The optional Cl_6 alkoxy substituent mav further be substituted with C1 6 alkoxy (for example methoxy) or C2 6 alkanoyloxy (for example acetoxy). The optional phenyl, non-aromatic heterocyclic group or aromatic heterocyclic group substituent may .urther be substi'uted by Cl 6 alkyl (for example methvl), Cl 6 alkoxy (for example methoxy), halo (for example chloro).

In especially preferred compounds R6 represents CO2(CH2)pJ in which p is 0-3 and J represents cyano, hydroxy, C3 8 cycloalkyl, C2 6 alkanoyloxy, C2 6 alkoxycarbonyl, C1 6 alkoxy, C1_6 alkoxy(Cl 6)alkoxy, C1 6 alkylthio, or J represents a S 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 C1 6 alkyl, C1 6 alkoxy or halo. Preferably p is 1 or 2.

Particularly preferred substituents R6 also include a carboxylic acyl group which may be C3 8 cycloalkylcarbonyl (for example cyclopropylcarbonyl, cyclohexylcarbonyl): or C2 6 alkanoyl (for example acetyl, propionyl, butyryl, pentanoyl, hexanoyl), which may be substituted with phenyl or phenoxy each optionally substituted by halo, Cl 4 alkyl, or C1 4 alkoxy; or C2 6 alkanoyl may be substituted with C2 6 ~ ~ J ~
`WO91/114~ PCT/EP91/001 alkoxycarbonyl (for example methoxycarbonyl), C2_6 alkoxy (for example methoxy), Cl 4 alkylthio (~or example methylthio), C3 8 cycloalkyl [for example cyclopentyl).

S In especially preferred compounds R6 represents COCH2k in which k represents Cl 4 alkoxy or phenoxv.

Particularly preferred substituents R6 may also include the group CONRl 2Rl3 in which Rl 2 represents methyl or ethyl, preferably methyl, and R13 includes phenyl or Cl 4 alkyl ~more preferably methyl or ethyl, and most preferably methyl) substituted with phenyl.
Most preferably Rl 2 represents ethyl and Rl3 representa phenyl.

Especially preferred substituents R6 include hydro~en;
cyclopropylmethoxycarbonyl;
2-methoxybenzyloxycarbonyl; 4-chlorobenzyloxycarbonyi;
2-methylbenzyloxycarbonyl; 3-methylbenzyloxycarbonyl;
2-acetamidoethoxycarbonyl;
2-(2-methylpiperidino)ethoxycarbonyl;

3-~2-propionyloxyethyl)-3-azapentamethylenecarbamoyl;
methyl(2-methylphenyl)carbamoyl;
methyl(3-methylphenyl)carbamoyl;
methyl(4-methylphenyl)carbamoyl;
methyl(l,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;

WO91/11~ PCT/EP9l/OO, 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-(et~oxycarbonyl)ethoxycarbonyl;
2-(2-methoxyethoxy)ethoxycarbonyl;
3-oxobutoxycarbonyl; 2-(2-chlorophenvl)ethoxycarbonyl;
2-(3-methylphenyl)ethoxycarbonyl;
lS 4,4,4-trifluorobutoxycarbonyl;
2-morpho~inoethoxycarbonyl; 2-piperidinoethoxycarbonyl;
2-thiomorpholinoethoxycarbonyl;
l-methyl-2-morpholinoethoxycarbonyl;
3-morpholinopropoxycarbonyl;
3-(4-methyl-1-piperazinyl)propoxycarbonyl;
l-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; l-benzylethoxycarbonyl;
3-(3-pyridyl)propoxycarbonyl;
2-~4-(N,N-dimethylamino)phenyl]ethoxycarbonyl;
2-phenylpropoxycarbonyl; 3-acetoxypropoxycarbonyl;
3-hydroxypropoxycarbonyl;

2r~ 3'~
WO91/11~ PCT/EP91/0~1 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 R7 include the following:

Hydrogen; halo (fluoro, chloro, bromo), preferably fluoro or chloro, more preferably chloro; trifluoro-methyl;C1 6 alkyl, preferably Cl 4 alkyl (for example methyl, ethyl or propyl), more preferably methyl or ethyl, most preferably methyl; methoxy, S()mY1, in which R1 is preferably C1 4 alkyl and m represents 0 or 1, (for example methylthio, ethylthio, propylthio, methylsulphinyl, ethylsulphinyl, propylsulphinyl) preferably m is 0, more preferably Y1 is C1 2 alkyl, most preferably methyl.

In preferred compounds of formula I, R8 represents hydrogen, fluoro, chloro or trifluoromethyl, more preferably hydrogen or chloro, and most preferably hydrogen.

In preferred compounds of formula I, R8' represents hydrogen or chloro, especially hydrogen.

The substituents Rg and R1o may be located at any position on the benz ring, namely in pcsition 6-, 7-, 8- and/or 9- of the benz ring. Accordingly each of the substituents Rg and Rlo specified herein are considered to be named at each of these positions. In one group of compounds Rlo is located at position 6- or 7- of the `

WO91/11 ~ PCT/EP91/oo benz ring, especially position 6-. In a preferred group of compounds R1o is located at position 8- or 9-of the benz ring, especially position 8-.

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

In certain compounds of formula I, the ~roup Rlo may represent a carboxylic acyloxy group and may have the formula - O.CO.R17 in which R17 represents an alkyl group (e.s. Cl 6); ar.
alkenyl group ~e.g. C2 6); a cycloalkyl gr~up (e.g.
C3 11); 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, R17 represents C1 6 alkyl; C2 6 alkenyl; C3 1I cycloalkyl; a 3-8 membered non-aromatic heterocyclic group; a carbocyclic aryl group; or a 5 or 6 membered heterocyclic ary~ group;
each of the groups being optionally substituted by Z.
Preferably R17 represents Cl-6 alkyl, C2 6 alkenyl, C3_10 cycloalkyl, a 5-7 membered non-aromatic heterocyclic group containing one or two heteroatoms selected from oxygen, sulphur or nitrogen; phenyl; a 5 or 6 membered heterocylic aryl group containing one or two heteroatoms selected from oxygen, sulphur or nitrogen, each substituent R17 being optionally substituted by Z1 or Z2 Readily hydrolysable esters are included within the scope of the present invention as well as those which are less readily hydrolysable.
Preferably R1o represents hydrogen, fluoro, chloro, bromo, trifluoromethyl, hydroxy, nitro, C1 6 alkyl (preferably C1 4 alkyl), Cl ~ alkoxy (preferably C1 4 alkoxy) or a carboxylic acyloxy group as hereinabove .

WO9~ 2~ ~ ?~ ~CT/EP91/001~

defined. More preferably Rlo represents hydrogen, halo (preferably fluoro or chloro), hydroxy, Cl 6 alkoxy (for example methoxy), Cl 6 alkvl (for example methyl) or nitro or a carboxylic acyloxy group. Most preferably Rlo represents hydrogen, fluoro, hydroxy or a carboxylic acyloxy group.

In particularly preferred compounds of formula I, Rlo includes:
hydrogen; hydroxy; C3 1O cycloalkanoyloxy (for example cycloproylcarbonyl, cyclobutylcarbonyl or adamantyl-carbonyloxy); C2_6 alkanoyloxy (for example acetoxy or propionyloxy) or C2_6 alkenoyloxy, both of which may be substituted with a substituent selected from C2 6 alkanoyloxy (for example acetoxy), S()mYl (for example methylthio), Cl_6 alkoxy (for example methoxy), carboxy, chloro, phenyl, di(Cl 6)alkylamino or C2 6 alkoxycarbonyl (for example methoxycarbonyl or ethoxycarbonyl) and further optionally substituted by optionally substituted phenyl (for example 4-methoxy-phenyl, 4-methylphenyl, 4-chlorophenyl); or Rl o represents arylcarbonyloxy in which the aryl group is suitably phenyl, thienyl, furyl, pyridyl [which may themselves by substituted with Cl 6 alkyl (for example methyl), C~ 6 alkoxy (for example methoxy) or halo (for example chloro)].

Preferred are those in which R1o represents OCO(CH2)pL in which p is 0-3 and L represents hydrogen, C3 1l cycloalkyl; di(Cl_6alkyl)amino; C2 6 alkanoyloxy;
C2 6 alkoxycarbonyl, C1_6 alkylthio; C1 6 alkoxy;
adamantyl or phenyl optionally substituted by Cl 6 alkyl, Cl 6 alkoxy or halo.

Preferred substituents Rlo include chloroacetoxy;
4-chlorobenzoyloxy; cyclopentylcarbonyloxy;
cyclohexylcarbonyloxy; hydrogen; fluoro; chloro;

WO91~11448 PCT/EP91/001 ~`1~ - 20 -F~o :~, ~ A ~
hydroxy; acetoxy; propionyloxy; butyryloxy;
pentanoyloxy; methoxycarbonylacetoxy;
3-methoxycarbonylpropionyloxy;
acetoxyacetoxy; 3-~methylthio)propionyloxy; benzoyloxy;
methoxyacetoxy; 4-methoxybenzyloxycarbonylacetoxv;
ethoxycarbonylacetoxy; but-2-enoyloxy;
3-ethoxycarbonylpropionyloxy; carboxyacetoxy;
adamantylcarbonyloxy; 3-phenylpropionyl;
methylthioacetoxy; phenylacetoxy; dlmethylaminoacetoxy;
thenoyloxy; furoyloxy; 2-methylbenzoyloxy;
2-methoxybenzoyloxy; 4-methoxvbenzoyloxy;
pyridylcarbonyloxy; cyclopropylcarbonyloxy;
cyclobutylcarbonyloxy;
4-methylbenzoyloxy;
3-methylbenzoyloxy.

A more preferred class of compounds of formula I
are those represented by formula V R

R

Fl 9~C H--R 6 ' C =O

in which R6', R7, R8, Rg, Rlo and R14 and preferred substituents thereof are as recited in formula I above.
More preferably, R6' represents hydrogen, R14 represents OR15~ R16 or NR12Rl3 in which R12 represents methyl or ethyl, R13 represents Cl 6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 hetero-atoms selected from oxygen, sulphur or nitrogen, a 5 or6 membered heterocyclic aryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur or nitrogen - 21 - .~ J ~

or R~3 represents phenyl optionally substituted by C2 6 alkoxycarbonyl or halo; or R12 and R~3 together with nitrogen to which they are attached form a 3-8 membered non-aromatic heterocyclic ring which may contain a further heteroatom selected from oxygen, sulphur or nitrogen which may be substituted by a C2_6 acvloxy(C1 6)alkyl group; and R15 and Rl6, whioh mav be the same or different, represent optionally substituted groups selected from Cl 6 alkyl; C2 6 alkenyl; C3 10 cycloalkyl; a 3-8 membered non-aromatic heterocvclic group con~aining 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen; phenyl; a ; or 6 membered heterocyclic aryl group containing 1 to 3 heteroa_oms selected from oxygen, sulphur o- nit-ogen; Rg represents hydrogen and R1o represents hydrogen, hydroxy, halo, C1 6 alkoxy or Cl 6 alkyl.

A further more preferred class of compounds of formula I are those represented by formula VI

N--N ~ V I

R~~C R6' in which R6 " R7, R8, Rg, R1o and R14 and preferred substituents thereof, are as defined with respect to formula I above. More preferably, R6' represents hydrogen, R14 represents OR15, R16 or NR12R13 in which R12 represents methyl or ethyl, R13 represents C1 6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen, a 5 or 6 membered heterocyclic aryl group 2 ~7-~ 22 ~
containing 1 to 3 heteroatoms selected from oxygen, sulphur or nitrogen or R13 r~presents phenyl optionally substituted by C2 6 alkoxycarbonyl or halo; or R12 and R13 together with nitrogen to which they are a~tached 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~Cl 6)alkyl group; and R15 and R16, which may be the same or different, represent optionally substituted groups selected from Cl 6 alkyl; C2 6 alkenyl; C3 1O cycloalkyl; a 3-~ membered non-aromatic heterocyclic qroup containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen; phenyl; a 5 or 6 membered heterocyclic aryl group containins 1 to 3 heteroatoms selected from oxygen, sulphur or nitrogen;
Rg represents hydrogen and Rlo represents hydrogen, hydrox~, halo, Cl 6 alkoxy or Cl 6 alkyl.

A further more preferred class of compounds of formula I are those represented by formula VII

N - N R~
R 1 7t:)CO--~ Vl I

X CH--R6' in which R6, R6', R7, R8, and R17 and preferred substituents thereof are as defined with respect to formula I above. Preferably the substituent O.CO.R17 is located in the 8-position or 9-position of the ring system, especially the ~-position. More preferably R6' represents hydrogen and R6 represents hydrogen, C2 6 alkoxycarbonyl or Cl 6 alkylthio, R17 represents optionally substituted groups selected from Cl 6 alkyl;

..W091/11448 PCT/EP91/001 - 23 - ~ ~ q~.;.~

C2 6 alkenyl; C3 11 cycloalkyl; a 3-8 membered non-aromatic heterocyclic group containing l or 2 hetero-atoms selected from oxygen, sulphur or nitrogen;
phenyl; a 5 or 6 membered heterocyclic aryl group S 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

/~ R 8 ~ o Vlll R170Co ~ S CH3 in which R7, R8 and R17 and preferred substituents thereof, are as defined with respect for formula I
above, More preferably R17 represents optionally substituted groups selected from Cl 6 alkyl; C2_6 alkenyl; C3 1l cycloalkyl; a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen; phenyl; a 5 or 6 membered heterocyclic aryl group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen.

A further more preferred ,class of compounds of formula I are those represented by formula IX

I! ~ ' R 1 0 ~C H--R 6 WO91~ 24 - PCT/EPgl/001~

6~ 6~ R7, R8, R8,, Rg and Rlo and preferred substituents thereof, are as defined with respect to formula I above. More preferably R6' represents hydrogen or methyl; R6 represents hydrogen, halo, C2 6 alkanoyl, C2 6 alkoxycarbonyl, StO)nY1, carbamoyl, carboxy or R5 and R6 together with a carbon atom to which they are attached represent cyclopropyl; R7 represents hydrogen, halo, trifluoromethyl, methoxy, C1 6 alkyl, S()mY1; R8 represents hydrogen, halo or trifluoromethyl; R8' represents hydrogen, halo or trifluoromethyl; R9 and R1o, which may be the same or different, each represent halo; or R9 represents hydrogen and R1o represents hydrogen, halo, trifluoromethyl, hydroxy, nitro, C2 6 alkanoyloxy, C1 6 alkyl or C1 6 alkoxy.

In one preferred group of compounds X represents oxygen. In a further preferred group of compounds R6 represents COR14, especially COOR15, X preferably represents oxygen and Z preferably represents -CH=. In a further preferred group of compounds R1o represents OCOR17, and X preferablv 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.

Campounds 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 .
... ~. ,`

WO91/11 ~ PCT/EP91/001 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 S derivatives which may ~e separated, for example, by crystallisation, gas-liquid or liquid chromatography;
selective derivatisation of one enantlomer 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 t5 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 ~1jbenzothiopyrano-[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-1,2,3,4-tetrahydro~1]benzopyrano~4,3-c]pyrazole-4-acetate.

When compounds of formula ~ 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 s~illed in the art, for example by crystallisation or li~uid chromatography.

,:.'' ,, :.

O 91/11448 PCr/F,P91/00'C4 - Certain compounds of formula I may exist in different tautomeric forms or as different geometric isomers.

Some compounds o- formula I are bases and may form 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 2 conventional manner.

Certain compounds of formula I may exist in more than one crystal form and the present invention includes each crvstal 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 ~erm "active compound"
denotes a [1]benzopyrano[4,3-c]pyrazole or a [1]benzothiopyrano[4,3-c~pyrazole of formula I. In therapeutic use, the active compound may be administered orally, rectally, parenterally or topically, preferably orally or topically. Thus the therapeutic compositions of the present invention take the form of any of the known pharmaceutical WO91/114~ PCT/EP91/001 - 27 - ~J ~

compositions for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The compositions of the invention may contain 0.1-90% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. The excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.

Compositions for oral administration are preferred compositions of the invention and these are known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oily suspensions. Tablets may be prepared by mixing the active compound with an inert diluent such as lactose or calcium phosphate in the presence of disintegrating agents, for example maize starch, and lubricating agents, for example magnesium stearate, and tableting the mixture by known methods. The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Such tablets may, if desired, be provided with enteric coatings by known method , for example by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known ma~ner. 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 WO91/114~ - 28 - PCT/EPgl/oo ~3~J~
present invention in a suitable vegetable oil, for example arachis oil.

Compositions for topical administration are also preferred compositions of the inventior. The pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel. A
suitable cream may be prepared by incorpora_ing the active compound in a topical vehicle such as petrolatum and/or light liquid paraffin, dispersed in an aaueous 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.a.
paraffin wax or beeswax. A gel may be prepared bv mixing the active compound with a topical vehicle comprising a gelling agent e.g. basified Carbomer BP, in the presence of water. Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. A suitable transdermal composition may be~ prepared by mixing the pharmaceutically active compound with a topical vehicle, such as described above, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol.

Compositions of the invention suitable for rectal administration are known pharmaceutical forms for such administration, for example suppositories with semi-synthetic glycerides or polyethylene glycol bases.

Compositions of the invention suitable for parenteral administration are known pharmaceutical forms for such administration, for example sterile - 29 - ~r~f ~

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 fhe 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, ir 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 ~ill 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 WO91/114~ PCT/EP91/001 2~ ~ q ~
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 standar~
laboratory animals. Such tests include, for example, the oral and parenteral administration of the compoun~s to BAL~/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 condi~ion and the past medica history and always lies within the sound discretion o' 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-q.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 o the present invention.

Compounds of formula I which are represented by formula II may be prepared by oxidising compounds of formula I which are represented by formula III, for example by reaction with chloranil.

. .
.. . .

.WO91/114~ PCT/EPg1/001~

Compounds of formula I which are represented by formula II may be prepared by reacting compounds of formula x, RB' ~R7 R 10--~ X

or a tautomer thereof, with compounds of formula XI

R 6 '--CH--CR 22R 23 X I

J
in which R22 represents (Q)2 and R23 represents OQ or NQ'2; or R22 represents (SQ)2 and R23 represents SQ or NQ'2; or R22 represents =NH and R23 represents OQ or SQ; or R22 represents =O and R23 represents a leaving group for example an optionally substituted 1-imidazolyl group, in which Q and Q' represent a C1 4 alkyl group or a benzyl group, for example by heating at 50-200C.

Compounds of formula I which are represented by formula II in which R6, represents hydrogen and R6 represents a carboxylic acyl group may be prepared by reacting compounds of formula X with compounds of formula XIIa WO 91/11448 PCl/EP91/OOt~4 ~r~

~0 R 24 \\ X Xlla ~0 R25 or a tautomer thereof, in which R24 and R25 may be the same or different, and each represent a Cl 6 alkyl group or a benzyl group, for example by heating in an organic liquid for example xylene at a temperature between 50-200C.

Compounds of formula I which are represented by compounds of formula II in which R6 represents a carboxylic acyl group may be prepared by reacting compounds of formula X with compounds of formula XIIb o o R 1 6--C~,~ O~/R 24 R6' ~0 R25 Xllb o or a tautomer thereof, in which R24 and R25 may be the same or different and each represents a C1 6 alkyl group or a benzyl group, for e~ample by heating in an organic liquid, for example xylene at a temperature between 50 and 250C.

Compounds of formula I which are represented by compounds of formula II in which R6 represents a group CONR12Rl3 or an esterified carboxyl group may be prepared by reacting compounds of formula II' WO91tl1~ PCT/EP91/001 ~R7 )~ZJ~ R 8 R10 ~ CH R6 il' in which R1ol represents R1o and Ra represents COA, where A represents a leaving group, for example hydroxyl, halo, C1-C6 alkoxy, aryloxy, arylmethoxy, C1-C6 acyloxy or C1 6 alkoxycarbonyloxy with an amine of formula NHR12R13 or an alcohol, for example of formula R15OH respectively, for example at 0-250C, 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 R6 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 R6 represents a group which is substituted by a h~droxyl group may be prepared from corresponding compounds of formula 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 R1o represents a carboxylic acyloxy group may be prepared by acylating WO91/11~ PCT/EP91/001~
2~ J ? ~
compounds of formula II' in which Ra represents R6 and Rlo, 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. R1~COC1 or an acid anhydride (R17CO)2O
in the presence of a base at a temperature in the range -10C to 40C. The acylation reaction may also be carried out by reacting the compound o' formula II' with a carboxylic acid R17COO~ in the presence of a dehydrating agent, for example dicyclohexylcarbodii-mide, preferably in the presence of a base e.g.
pyridine. Compounds of .ormula II' in which R1o, represents hydroxy may be prepared by reacting compounds of formula II' in which R1o, represents a C1 6 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 R6 and R6' both represent hydrogen may be prepared by decarboxylating compounds of formula II in which R6, represents hydrogen and R6 represents carboxyl, or by hydrolysing compounds of formula II in which R6' represents hydrogen and R6 represents a group which may be hydrolysed to a carboxyl group such as a C2 6 alkoxycarbonyl group or carbamoyl, for example by reaction with sulphuric acid, followed by decarboxylation.

Compounds of formula I which are represented by formula II in which R6 represent's a Cl 6 alkylsulphinyl group or a Cl_6 alkylsulphonyl group may be prepared by oxidation of compounds of formula II in which R6 represents a Cl 6 alkylthio group with, for example, 3-chloroperoxybenzoic acid.

Compounds of formula I which are represented by compounds of formula II in which R6 represents a WO91/114~ PCT/EP91/001 - 35 - ~ ~"~

carboxyl group may be prepared from compounds of formula II in which R6 represents 4-methoxybenzyloxy-carbonyl for example by treatment with trifluoroacetic acid and anisole in a solvent, for example dichloromethane.

Compounds of formula I which are represented by compounds of formula II in which Rlo represents a carboxyalkylcarbonyloXy group for example carboxy-acetoxy, may be prepared from compounds of formula II
in which R1o represents 4-methoxybenzyloxycarbonyl-alkylcarbonyloxy, for example 4-methoxybenzyloxy-carbonylacetoxy, by treatment with trifluoroacetic acid and anisole in a so1vent, for example dichloromethane.

Compounds of formula I which are represented by formula II may be prepared by reacting compounds of formula XIII RB~

Z ~ R8 ~ ~ R26 R10' ~XR27 in which R26 represents hydrogen, or a tautomer thereof, or in which R26 represents a group COR28 wherein R28 represents hydrogen, an optionally substituted C1 4 alkyl group or a benzyl group and R27 represents COC~R6R6 " 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.

WO91/11~ PCT/EPgl~00 2 ' J ~
Compounds of formula I which are represented by formula III or IV may be prepared from the corresponding compounds of formula I' R8 ~
~[~R7 N ~ Z R8 R 10'~

in a similar manner as compounds of formula II are prepared from compounds of formula II'.

Compounds of formula I which are represented by formula III may be prepared by reacting compounds of formula XIV

R 1 o ~ R 3 X I V

in which R3 represents hydrogen, R5 represents C~R6R6,, R29 represents COOR30 or carbamoyl and R30 represents a Cl 4 alkyl group or a benzyl group with a hydrazine of formula XV

WO91/114~ PCT/EP91/001 R8~

H2N-N~R8 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 bv formula IV may be prepared bv reacting compounds of formula XIV in which X represents S, R3 represents methyl, R5 represents hydrogen and R29 and R30 are as defined, with compounds of formula XV in which Z
represents -CH=.

Compounds o' formula I which are represented by formulae V to IX may be prepared as described with reference to the preparation of compounds of formulae II to IV above.

Compounds of formula X may be prepared by reacting compounds of formula XVI

Rlo ~ X\/l in which R31 represents hydrogen, a C1 4 alkyl group or a benzyl group with a hydrazine of formula XV, for example by heating at 50-200C in an organic liquid for example toluene. Preferably the compound of formula XVI is used in excess of the stoichiometric amount.

WO91/11448 - 38 - PCT/EP9]/On'-~

`~- ~-' Compounds of formula X may be prepared by reacting compounds of formula XVII

~ R7 HN--NH ~ R8 R 1 c--~ X V I I

wi~h an acid, for example hydrochloric acid, or with a base, for example a solution of sodium hydroxide.

Compounds of formula X in which R1o represents a hydroxyl group may be prepared by reactin~ compounds of formula X in which R1o represents a Cl-6 alkoxy group with a Lewis acid, for example aluminium chloride or boron tribromide.

1 a Compounds of formula XI in which R22 represents ~Q)2 and R23 represents OQ may be prepared for example a) by reacting compounds of formula R6,R6CH-CX3 in which X is halo with a sodium alkoxide of formula NaOQ
in which Q is a Cl 4 alkyl group or a benzyl group, or b) by reacting compounds of formula R6,R6CH-CN with an alcohol of formula QOH in the presence of an anhydrous acid, for example hydrogen chloride, to give compounds of formula R6,R6CH-C(=NH)OQ as their acid salts, e.g.
hydrochloride salts, which are then reacted with further alcohol of formula QOH.

WO91tll448 PCT/EP91/001~
- 39 - f~` ' f ~ - '1 Compounds of formula XI in which R22 represents (SQ)2 and R23 represents SQ may be prepared for example from compounds of formula R6,R6CH-COCl by reaction with thiols of formula QSH in which Q represents a C1 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 bv methods known to those s~illed in the art.

Compounds of formula XIIb or tautomers thereof mav be prepared by the acylation of compounds of formula XIX

R6 ~ X XIX

o by reaction with an acyl chloride R16-COCl, for example in the presence of pyridine in an inert solvent at a temperature in the range -10C to 50C.

Compounds of formula XIII in which R26 represents COR28 and R27 represents COCHR6R6, may be prepared by acylation of compounds of formula XIII in which R26 represents COR28 and R27 represents hydrogen, for example by reaction with an acid anhydride of formula (R6,R6C~CO)2O or an acid halide e.g. of formula R6 R6cRcocl .

Compounds of formula XIII in which R26 represents COR28 and R27 represents hydrogen may be prepared by the acylation of compounds of formula X for example by WO91/114~ PCT/EP91/001

5 ~
reaction with an acid anhydride of formula (R28CO)2O in the presence of a salt (e.g. the sodium salt) of the corresponding acid.

Compounds of formula XIII in which R26 and R27 are identical and represent COCHR6,R6, may be prepared by acylation of compounds of formula X for example by using an acid anhydride of formula (R6,R6CHCO)2O in the presence of a salt (e.g. the sodium salt) o' the corresponding acid.

Compounds o. formula XIII in which R27 represen~s COCHR6R6, and R26 represents hydrogen, or tautomers thereof, may be prepared bv reacting a compound of formula XIII in which R26 represents COR28 and R27 represents COCHR6R6, with a base e.g. piperidine in a suitable solvent e.g. ethanol.

Compounds o' formula XIV in which R29 represents COOR30 and R5 represents CHR6R6, may be prepared by heating compounds of formula XX

R 9~XC O C O O R 3 0 in which R30 represents a Cl_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 R5 represents hvdrogen may be prepared by reacting compounds of formula XVIII

, . .

- 4l -R 1 o ~ X V l l i 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 R29 represents carbamoyl may be prepared from compounds OL formula XIV
in which R29 represents cyano by methods known to those skilled in the art.

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

Compounds of formula X~I in which 231 represents hydrogen may be prepared by reacting compounds of formula XXI

R10 ~ XH

in which R33 represents hydrogen with malonic acid in the presence of an acid chloride e.g. phosphoryl chloride and a Lewis acid e.g. zinc chloride.

WO9l~l1448 PCT/EP91/001 Compounds of formula XVI in which R3~ represents hydrogen may be prepared by reacting compounds of for~ula XXI in which R33 represents a group COR34 in which R34 represents a Cl 5 alkyl group, with a base, for example sodium hydride, followed by treatment with a dialkyl carbonate of formula (QO)2CO in which Q
represents a Cl 4 alkyl group or a benzyl srou2, e.g.
dimethyl carbonate.

Compounds of formula XVI in which R31 represents a Cl 4 alkyl group or a benzyl group may be prepared by base catalysed alkylation or benzylation of compounds of formula XVI in which R31 represents hydrogen for example by reaction with an alkyl halide o- 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 50-200C in a suitable solvent for example toluene. In cases where a mixture of compounds of formula X and XVII are obtained, these compounds may be separated by virtue of their different solubilities in an organic liquid for example dichloromethane.

Compounds of formula XVIII to XXI may be prepared by methods known to those skilled in the art.

Compounds of formula I which are represented by formula II in which Rlo représents R17OC.O may be prepared by acylation of compounds of formula II in which Rlo represents a hydroxyl group. During the acylation reaction there may be formed compounds of formula XXII

W091/11448 PCT/EP91/00]~

~ R7 N N ~ Z R8 R170CO - ~ C~6~6' X Xll which may be hydrolysed, for example on exposure to atmospheric moisture to the desired compounds of formula II mentioned above.

Certain intermediate compounds or formulae X, XI, XII a) and b), XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, and XXII are believed to be novel compounds.
All novel compounds herein are claimed as a further aspect of the invention.

The invention 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.

WO91/114~ PCT/EPsl/OO~

r1'~.J "'~
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 S 20 minutes to a stirred suspension o 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 fo_ 4 hours. Or. cooling, the reac-ion 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 SM hydrochloric acid. The solid obtained was collected by filtration, washed with water and dried to give 6-fluoro-4-hydroxycoumarin, m.p. 250-251C.

Preparation of Novel Com~ounds of Formula XIV

Example 2 a) Dimethyl oxalate (1.4 g) was added to a stirred solution of sodium (0.3 g) in methanol (10 ml) with warming to aid dissolution. The' solution was cooled to ambient temperature and a solution of 6-methoxy-4-thiochromanone (1.2 g) in methanol (6 ml) was added dropwise over 15 minutes. The mixture was stirred at ambient temperature for 3 hours and then allowed to stand for 4 days. The solvent was removed under reduced pressure and the residue partitioned between water and toluene. The aqueous layer was basified with WO91/11~ PCT/EP91/001~
2 J ~
2M sodium hy~roxide solution, separated and acidified with 2M hyd_~chloric acid. The solid formed was collected by filtration and recrystallised from methanol to give methyl 6-methoxv-4-oxo-3-thiochroman-glyoxylate, m.p. 85-89C.

b) A mixture of methyl 6-methoxy-4-oxo-3-thiochroman-glyoxylate (6.2 g) and glass powder (2.8 g) was heated with stirring at 180C for 30 minutes. The mixture was cooled to ambient temperature, extracted with boiling acetone and filtered. The filtrate was evaporated and the residue was taken up in hot propan-2-ol then hot filtered from some tar. The filtrate was cooled and filtered to give methyl 6-methoxy-4-oxo-3-thiochroman-carboxylate, m.p. 61-65C.

c) A solution of methyl 6-methoxy-4-oxo-3-thio-chromancarboxylate (1.0 g) in toluene (10 ml) was added to a solution of sodium (0.4 g) in dry methanol (15 ml) with stirring. The mixture was boiled under reflux for 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 u~er reduced pressure. The residue'was separated by flash chromatography on silica using ethyl acetate/petroleum ether (b.p. 60-80C, 1:4) as the mobile phase. The solid obtained was recrystallised from ethyl acetate/petroleum ether (b.p. 60-80C) to give methyl

6-methoxy-3-methyl-4-oxo-3-thiochromancarboxylate, m.p.
66-73C.

J A '~
Example 3 a) A stirred mixture of 4-methoxythiophenol (20 g), diethyl ethoxymethylene malonate t29.3 ml) and potassium hydrogen sulphate (0.4 g) was heated at 160-170~C for 2 hours. Polyphosphoric acid (152 g) was added to the reaction mixture with heating at 80-90C
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. 60-80C) to give ethyl 6-methoxy-4-oxo-4-H-thiochromene-3~carboxylate, m.p.
102-104C.

b) Copper chloride (150 mg) was added to a stirred mlxture of ethyl 6-methoxy-4-oxo-4-H-thiochromene-3-carboxylate (4 g) in tetrahydrofuran (40 ml) under nltrogen at -78C. A 3M solution of methylmagnesium bromide in ether (5 ml) was added slowly maintaining the temperature below -65C and then the reaction mixture was allowed to warm to ambient temperature.
The reaction mixture was poured into ether/2M
hydrochloric acid, the aqueous layer extracted with ether, and the combined ether layers dried to give the crude product. Purification by flash chromatography over silica using 1% methanol/dichloromethane as the mobile phase gave ethyl 6-methoxy-2-methyl-4-oxo-3-thiochromancarboxylate as an oil.
Preparation of Novel Compounds of Formula XIIb Example 4 Pyridine (12 g) was added dropwise over 3-S
minutes to a stirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (20 g) in dichloromethane (220 ml) at 0C. The resulting solution was stirred at 0C for 10 minutes and then while the temperature was maintained at 0-2C 3-methoxycarbonylpropionyl chloride (22.8 g) was added dropwise. After the addition the mixture was S stirred at 0C for 60 minutes, then allowed to warm up to ambient temperature and kept at this temperature for 18 hours. The mix'ure was washed with lM hydrochloric acid, then water, dried and e~aporated to give methyl 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-4-oxobutyrate as a ~iscous oil.

Examples 5-15 In a simila_ manner to that described in Example 4, a compound of formula XIIb was prepared by reacting 2,2-dimethyl-1,3-dioxane-4,6-dione (XIX) with R16COCl (in which R16 is as defined), as summarised in Table l below, WC~91/11448 - 48 - PCr/EP91/001~4 ~C '., ~ ,... ...
~! ~- ~-O ~
Z
o o 3 _ . ~ O I a~
~ X- U~ , e l ,,,,, _,, ~,, ~ a) o C--c~ e tn ~ O O O OO ~ O O O O O
o a~
0 c~ E _ _ _ _ ~ _ ~ ~ ~ ~ _ t~ C
0 ~ ~
~: .,1 ~ o O E - - E
L~--o o o~ _ _ _ _ _ _ _ _ _ ~ _ _ U~ ~
o c o E
_1 ~ C~-- ~ ~ O ~ ~ o~ r o ~ _ o ~ . . . . . . . . .
0 E . _ _ _ I` a: _ r~ ~ u~ _ co E~ ,~;: ~ _ _ _ _ _ ~
O O O O 1` 0 0 0 0 0 O
X_ ~ cr o o o o ~ o ~r _ o o o X- ---------~-~ e ~. ~. e ~
Q~ X ~ ~ X
C O Q~ ~ O ~ --c c E C o ~ c ~
x o x o _I c --I --I E
Cl. '' O ,C '~,C .~ X
o o ~ _~ v o ~ ~ o P~ o --I --I 0 c 0 --~D~ ~ U U E u E u E E
_~ ~ :~. ~ I I I ~ I 1 0 P:~ O U U ~ 'r ~ U ~ ~1 E

Xo -- r~
~o 1` ~ ~ _ _ _ _ _ _ U~o ~

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

Notes (1) Product was a viscous oil.

(2) After washing with hydroch~oric acid and water, the solid product was collected by filtration.

(3) The reaction was car-ied out unde- nitrogen.

(4) The crude product was purified by flash chromato~raphy using dichloromethane as the mobile phase.

(5) The crude product was purified by trituration with hot industrial methylated spirit and the solid product collected by evaporation.

(6) After washing with hydrochloric acid and water the solvent was removed to leave a dark solid.

The compounds prepared in the above Examples were as follows:

2,2-dimethyl-5-phenylacetyl-1,3-dioxane-4,6-dione 6 2,2-dimethyl-5-phenoxyacetyl-1,3-dioxane-4,6-dione

7 5-cyclohexylcarbonyl-2,2-dimethyl-1,3-dioxane-4,6-dione

8 5-cyclopropylcarbonyl-2,2-'dimethyl-1,3-dioxane-4,6-dione

9 2,2-dimethyl-5-~3-(4-methoxyphenyl)propionyl]-1, 3-dioxane-4,6-dione 5-(4-chlorophenoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione ~, .

., WO91/11448 PCT/EP91/001~
-- 50 -- .

~r~, A.~J''~ ~ 11 2r2-dimethyl-5-[3-(3-methylphenyl)propion 1,3-dioxane-4,6-dione 12 5-(2-cyclopentyl-1-hydroxyethvlidene)-2,2-dimethyl-1,3-dioxane-4,6-dione S 13 5-[1-hydroxy-2-(2-methylphenoxy)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione 14 2,2-dimethyl-5-(3-methylthiopropionyl)-1,3-dioxane-4,6-dione 5-methoxyacetyl-2,2-dimethyl-1,3-dioxane-4,6-dione Preparation of Novel Compounds of Formula XI

Exam~le 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 0-5C. 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 45-50C 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.
165-175C (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 0-5C. 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.

, ~

WO91/11448 PCTtEP91/00154 (b) A mixture of methyl isopropoxycarbonylacetimidate hydrochloride (17 g) and dry methanol ~52.7 ml) was stirred for 30 minutes. Dry ether (2gO ml) was added and the mixture stirred and heated under reflux for 18 hours. The reaction mixture was cooled to 0C, 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 0-5C. The mixture was allowed to warm to ambient temperature during 16 hours.
The resulting solid product was collected by filtration, washed and dried to give methyl methylthio-acetimidate hydrochloride as a sticky solid.

b) A mixture of the methyl methylthioacetimidate hydrochloride and methanol (SSl ml) was stirred at 35-45C 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. 96-104C (5 mm Hg).

WO91/11~ PCT/EP91/OQ

2r ~ Preparation of Novel Compounds of Formula X
Example 19 a) A stirred mixture o 4-hydroxy-5-methoxy-coumarin (6.5 g), 4-chlorophenylhydrazine (7.3 g) and drv toluene (66 ml) was heated under reflux with removal o the water formed in the reaction. On coolins, the solid obtained was collected by filtration to give 4-[2-(4-chlorophenyl)hydrazino]-5-methoxy-coumarin, m.p. 206-209C.

b) A mixture of 4-[2-(4-chlorophe~yl)hydrazino]-5-methoxycoumarin (1.6 g), 5M aqueous sodium hydroxide (I ml) and industrial methylated spirit (100 ml) was boiled under reflux for 4 hours. On cooling, the mixture was filtered. The filtrate was evaporated to dryness and the residue was partitioned between dichloromethane and water. The dichloromethane layer was separated off, dried and concentrated to give after filtration, 1-(4-chlorophenyl)-3-(2-hydroxy-6-methoxyphenyl)-2-pyrazolin-5-one, m.p. 185-188C.
_ am~le 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 (5'0 g) was added and the mixture heated under reflux for a further 2 hours. The mixture was allowed to cool to ambient temperature and the solid formed collected by filtration to give 1-(4-chlorophenyl)-3-(2-hydroxy-5-methoxyphenyl)-2-pyrazolin-5-one, m.p. 197-203C.

O91/114~ PCT/EP91/00154 - 53 - ~ ~ ~.~

b) 1-(4-Chlorophenyl)-3-(2-hydroxy-5-methoxy-phenyl)-2-pyrazolin-S-one (5.S g), aluminium chloride (9.35 g) and dry xylene (66 ml) were stirred and heated at 100C for 1 hour. On cooling, the xylene was S decanted off and a mixture of 2M hydrochloric acid (90 ml) and ice (200 g) added to the residue. After trituration the solid formez was collected by filtration, dried and then recrystallised from methanol to give 1-(4-chlorophenyl)-3-(2,5-dihydroxyphenyl)-2-

10 pyrazolin-S-one, m.p. 220-225C ~with decomposition).
Example 21 a) A stirred mixture of 4-hydroxy-6-methoxycoumarin (10.0 g), 4-trifluoromethylphenylhydrazine (22.9 g), dry toluene (375 ml) and p-toluenesulphonic acid (0.2 g) was refluxed for a total of 25 hours (with intermittent storage at ambient temperature for a total of 130 hours) during which a further portion of p-toluenesulphonic acid ~0.2 g) was added after refluxing for 7.5 hours, and then further 4-trifluoro-methylphenylhydrazine (5 g) and p-toluenesulphonic acid (0.2 g) added after refluxing for 13 hours. After cooling to ambient temperature, the reaction mixture was filtered and the solid recrystallised from acetonitrile with hot filtration. The solid collected was boiled with dichloromethane and hot filtered to give crude 6-methoxy-4-~2-(4-trifluoromethylphenyl)-hydrazino] coumarin.

b) A mixture of crude 6-methoxy-4-[2-(4-trifluoro-methylphenyl)hydrazino]coumarin (8.5 g), 5M hydro-chloric acid (8.5 ml) and industrial methylated spirit(82 ml) was stirred and boiled under reflux for 29 hours. On cooling, the solid obtained was collected by filtration to give 3-(2-hydroxy-5-methoxyphenyl)-1-(4-- ' "

WO91/11~ P~T/EP91/001 ~r ~ h`~'_~, trifluoromethylphenyl)-2-pyrazolin-5-one, m.p.
212-216C.

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 a~ueous industrial methylated spirit to give 1-(4-trifluoro-methylphenyl)-3-(2,5-dihydroxyphenyl)-2-pyrazolinone, 10 m.p. 253-257C.
Example 22 a) A stirred mixture of 4-hydroxy-6-methoxy coumarin t17.1 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 àdded and re~luxing was continued for a further 3 hours. The reaction mixture was cooled to ambient temperature and the solid collected after filtration digested with boiling dichloromethane and then hot filtered. The filtrate was concentrated, cooled and filtered to give 1-(4-bromophenyl)-3-(2-hydroxy-5-methoxyphenyl)-2-pyrazolin-S-one, m.p. 197-200C.

b) A stirred mixture of 1-(4-bromophenyl)-3-(2-hydroxy-5-methoxyphenyl)-2-pyrazolin-5-one (5.4 g), aluminium chloride (8.2 g) and dry xylene (60 ml) was heated on a steam bath for 5'hours, then cooled to ambient temperature and kept at this temperature for 18 hours. The xylene was decanted away to leave a gum which was treated with dilute hydrochloric acid (117 ml) and ice. The solidified gum was collected by filtration and washed with water and petroleum ether (b.p. 60-80C). The crude product was purified by flash chromotography on silica using toluene/acetic WO 91/11448 55 P~/EP91/001~4 _~?~! q 5;~
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)-3-~2,5-dihydroxyphenyl)-2-pyrazolin-5-one, m.p.
237-239C.
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-dichloro-phenyl)-3-(2-hydroxy-5-methoxyphenyl)-2-pyrazolin-5-one, m.p. 210-211C.

b) A stirred mixture of 1-~3,4-dichlorophenyl)-3-~2-hydroxy-5-methoxyphenyl)-2-pyrazolin-5-one ~20 g) aluminium chloride ~34 g), and xylene ~280 ml) were heated on a steam bath for 6 hours. The xylene was decanted off and the remaining mixture poured into a mixture of ice and lM hydrochloric acid with stirring.
The mixture was stirred for an hour, stored at ambient temperature for a 18 hours, and filtered to give 1-(3,4-dichlorophenyl)-3-~2,5-dihydroxyphenyl)-2-pyrazolin-5-one.
Example 24 A stirred mixture of 4-hydroxycoumarin ~14.3 g) and 4-chlorophenylhydrazine (18.9 g) in dry toluene (150 ml) was heated under reflux for 2.5 hours with removal of the water produced in the reaction. The WO91/114~ PCT/EP91/00154 ~r~
mixture was al~owed to cool to ambient temperature,then filtered and the solid product collected to give 1-(4-chlorophenyl)-3-(2-hydroxyphenyl)-2-pyrazolin-5-one, m.p. 183-185C.

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 R31 are hydrogen and R1o is as defined) with a compound of formula XV (in which Z is -CH=, R8, is hydrogen and R7 and R8 are as defined) as summarised in Table 2 below.

-- WO 91/11448 _ 57 _ PCr/EP91/00154 U~ _ ~ _ _ _~________ O ~
Z __________ o ~ ~ ~ er 1`
O
~_ ~___~____~
o ~ l l l l l l l l l l X O ~D O U O ~ ~ ~ O ~D CO
E -- -- -- -- ~ -- -- -- --X Ul U7 ~ ~ o o o o o Ul .,1 o D~ ~ .C

u~S:-- ~r o o ~ o ~ o o o o :~ E ~` ~o o u~ ~n _ o o u~ o ~ E~
~ s; _ CO ~ o t~ o m ~ ~ ~ CD ,~ o ~ _ ~ o ~ o X- _ ~ ~ o ~ o ~o o _ ~r o o E _ ~ o X-- _ _ _ _ ~ _ _ CO
~X
O O C~ O o o - o aJ
~ l o ~ -c- l X u~ o r~

o WO 91tll44~ PCr/EP91/001~4 2~ ~

(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 drvness.

(4) The reaction solution was allowed to cool and the solid o~tained followin~ evaporation was heated with dichloromethane.

~5) ~ecrystallisation from acetonitrile.

(6) The solid collected on filtration was boiled with industrial methylated spirit/water (3:1), cooled and the solid product collected by filtration.

The compounds prepared in the above Examples were as follows:-1-(3,4-dichlorophenyl)-3-(2-hydroxyphenyl)-2-pyrazolin-5-one 26 1-(4-chlorophenyl)-3-(5-fluoro-2-hydroxyphenyl)-2-pyrazolin-5-one 27 1-(4-bromophenyl)-3-(2-hydffoxyphenyl)-2-pyrazolin-5-one 28 1-(4-fluorophenyl)-3-(2-hydroxyphenyl)-2-pyrazolin-5-one 29 1-(4-chlorophenyl)-3-(2-hydroxy-5-methylphenyl)-2-pyrazolin-5-one W091/11448 ~ _ , PCT/EP91/001 -- 5 9 -- o~

3-(2-hydroxyphenyl)-1-(4-trifluoromethylphenyl)-2-pyrazolin-5-one 31 3-(2-hydroxyphenyl)-1-(4-methoxyphenyl)-2-pyrazolin-5-one 32 3-(2-hydroxyphenyl)-1-~4-methylphenyl)-2-pyrazolin-5-one 33 1-(3-chlorophenyl)-3-(2-hydroxyphenyl)-2-pyrazolin-5 one 34 1-(4-chlorophenyl)-3-(2,6-dihydroxyphenyl)-2-pyrazolin-5-one Exam~les 35-43 -In a similar manner to that des~ribed in Exam?le 24, a compound of formula X was prepared by reacting a compound of formula XVI (in which X is oxygen, Rg and R31 are hydrogen and Rlo is as defined) with a compound of formula XV (in which Z is -N= and R7, R8 and R8, are as defined) as summarised in Table 3 below.

WO 91/11448 - 6 n - PCI~/EP91/00154 2?~
l_ _ _ ~D
~ _ _ _ _ _ O ~ ~r ~ ~ a~
Z _ _ _ _ c~ D O O
O _ a~ o a~
~ _ _ _t'~lN ; t~ _ X l l lll l l l -- ~ ~ CO ~ -- O 1 W _ . ~ o 1--a~ _ o w _ e _ ~

-~ e ~ u~
~-r/ O
G) E~ r _ ~u~ er _ t~l t~
_ O O
0 ~ O O O
~ x e O O O O O u~
~ ~ _ ~D a~ ~ ~ er ~ ~ _ _ ~ ~ / ~ _ _ _ _ _ ~
~ ~ ~ E
o ~ _ _ _ _ _ _ _ _ _ ~: E _ _ _ _ _ _ _ _ _ o o o o u~ o w o w ~ ~ .........
~ O ~ ~ w ~
--I x-- _ _ ~:
E~ o ~_ o~ _ _ _ r o ~r o o E ~ ~ ~ ~ ~ ~ u~ o x~ __ w _, _ _ _ _ O _ _ _ _ _ O ~ o l~ ~ ~
c:~ C~ - U ~ ~ m U U

~ I _ , O
x ~ _ _ ~ ~ -- -- ~ u-, ~
a) E
X n ~D 1` ~ ~ O --U~ o U~

WO91/114~ PCT/EP91/001 Notes (1) Reactants refluxed in a) ethyl acetate b) xylene i c) toluene/ethyl acetate d) toluene (2) ~thyl acetate (50-100% of ~olume of toluene) added to refluxin~ mixture after 20 minutes.

(3) Recrystallised from ethanol.

(4) The reaction mixture was cooled and evaporated.
The solid obtained was digested with ethyl acetate and hot filtered. The filtrate was evaporated and the oil obtained purified by flash chromatography on silica using 2~ methanol/dichloromethane as the mobile phase.
The fractions were combined and evaporated to give a solid which was recrystallised from ethyl acetate.

(5) The crude product was boiled with ethanol and filtered twice.

(6) A further portion of the hydrazine (2.0 g) was added after 3 hours.

(7) The hot reaction mixture was decanted off, concentrated and filtered. The solid collected was suspended in diethyl ether (300 ml) and extracted with 2.5M sodium hydroxide solution. The extracts were combined, washed with diethyl ether and then acidified with concentrated hydrochloric acid. The solid product was collected by filtration, washed with water and dried.

., , ~,.

-WO91/114~ PCT/EP91/OOI'~

~J ~ ~. (8) After refluxing the toluene liquors were evaporated to dryness. The residue was boiled with dichloromethane, hot filtered, and the filtrate concentrated. Cooling and scratching gave the solid product which was collected by filtration.

The compounds prepared in the above Examples were as follows:-3-(2-hydroxyphenyl)-1-(5-trifluoromethyl-2-pyridyl)-2-pyrazolin-5-one 36 1-(6-chloro-2-pyridyl)-3-(2-hydroxyphenyl)-2-pyrazolin-5-one 37 1-(5-chloro-2-pyridyl)-3-(2-hydroxyphenyl)-2-pyrazolin-5-one 38 3-(2-hydroxyphenyl)-1-(6-tri'luoromethyl-2-pyridyl)-2-pyrazolin-5-one 39 1-(4-chloro-2-pyridyl)-3-(2-hydroxyphenyl)-2-pyrazolin-5-one l-(6-chloro-5-trifluoromethyl-2-pyridyl)-3-(2-hydroxyphenyl)-2-pvrazolin-5-one 41 1-(5-bromo-2-pvridyl)-3-(2-hydroxyphenyl)-2-pyrazolin-5-one 42 1-(5-chloro-2-pyridyl)-3-(2,6-dihydroxyphenyl)-2-pyrazolin-5-one 43 3-(5-fluoro-2-hydroxyphenyl)-1-(5-trifluoromethyl-2-pyridyl)-2-pyrazolin-5-one Example 44 A stirred mixture of 4-hydroxythiocoumarin (4.5 g) and 4-trifluoromethylphenylhydrazine (7.0 g) in dry toluene (47 ml) was heated under reflux for 4.5 hours 3~ under nitrogen, adding more of the hydrazine (l.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 ~ 5 ,~
at ambient temperature for 18 hours. The filtrate was evaporated, the solid residue dissolved in dichloro-methane and the solution washed with water, dried and concentrated and the solid obtained washed with dichloromethane to give 3-(2-~ercaptophenyl)-1-(4-trifluoromethylphenyl)-2-py_azolin-5-one, m.p.
161-164C.

Preparation of Novel Compounds of Formula II' ~xam~le 45 A stirred mixtu;e of 1-(4-chlorophenvl)-3-(2-hvdroxyphenyl)-2-pyrazolin-5-one (2.9 g) and trlpropyl ortho(propoxycarbonyl)acetate (8.7 g) was heated at 14S-150C for 40 minutes. The mixture was cooled below 100C and diluted with industrial methylated spirit.
The solid produced was collected by filtration to give propyl 2-~4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzo-pyrano[4,3-c]pyrazole-4-acetate, m.p. 138-140C.

Example 46 In a similar manner to Example 45, a mixture of 1-(4-chlorophenyl)-3-(2,5-dihydroxyphenyl)-2-pyrazolin-5-one (6.6 g) and trimethyl ortho(isopropoxycarbonyl)-acetate (21.9 g) was heated at 140C for 2 hours, then cooled, filtered and the solid product washed with ether to give isopropyl 2-(4-chrorophenyl)-8-hydroxy-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c~pyrazole-4-acetate, m.p. 224-225C.

Example 47 A stirred mixture of 1-(4-chlorophenyl)-3-(2-hydroxyphenyl)-2-pyrazolin-5-one (2.9 g) and triethyl WO91~11448 PCT/EP91/001 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-2t3-dihydro[
benzopyrano[4,3-c]pyrazole-4-aCetate, t59-161C.

Examples 48-60 In a similar manner to that described in Example 47, a compound of formula II' (in which R6, is hydrogen and Ra is COOC2H5) was prepared by reacting a compound of formula X (in which Z is -CH=, R8' and Rg represent hydrogen and X, R7, R8 and R1o are as defined) with t-iethyl ortho(ethoxycarbonyl)acetate (XI) as summarised in Table 4 below:

WO 91/11448 - 65 - PCI'/EP91/00154 r~
u~ Utr~ o ~
~U ~ _ _ _ _ _ _ _ _ _ _ ~ _ o l l l l l l l l l l l l l H U r` O ~ ~ O ~t-l ~ O ~ ~J Ll~
C~ H o t~l _ _ . _ _erU~ U~ I` O

a.l u~
E ~: u~ o u~ o o o o o u~ ~ o ~ E~ E _ _ _ _ _ _ ~o ~ _ _ _ _ _ _ _ o cz~ ~ _ c~ a~ a~ co ~o _ r O ~ ~ ~ I~ r r~
Ul C:X--lJ
C ~
_I O ~ _ CO ~ _ C:~ ~ ~ ~ ~D CO U~ U~ _ _ ~ E ~ ~
E~ ~ x - u~ o o ~ _ o ~ U o y C~ U~

X
t-7~~
~_ ~ ~ u ~ ~ m ~ o X o o o o o o o o o o o o U~

X ~ a~ o ~ O

U~ O U~ O
t~l WO91/114~ - 66 - PCT/EP91/001~
2 ~? ~
Notes on Table 4 (1) Heating temperature = 140-150C

(2) After dilution with ether and filtration the solid product was stirred with dichloromethane and filtered. The fil'rate was evaporated an~ the solid obtained triturated with ether.

(3) After storage for 18 hours a further portion of the ortho ester (5 g) was added and the mixture heated for a further 60 minutes. The mixture was triturated with ether and the solid product collected by filtration.

The compounds prepared in the above Examples were:-48 ethyl 2-(4-chlorophenyl)-8-hydroxy-3-oxo-2,3-dihydro[l]benzopyrano[4,3-c]pyrazole-4-acetate;
49 ethyl 2-(4-chlorophenyl)-a-fluoro-3-oxo-2,3-dihydro[t]benzopyrano[4,3-c]pyrazole-4-acetate;
ethyl 2-(4-chlorophenyl)-8-methyl-3-oxo-2,3-dihydro[l]benzopyrano[4,3-c]pyrazole-4-acetate;
51 ethyl 2-(3,4-dichlorophenyl)-3-oxo-2,3-dihydro-[l]benzopyrano[4,3-c]pyrazole-4-acetate;
52 ethyl 2-(4-bromophenyl)-3-oxo-2,3-dihydro[l]-benzopyrano[4,3-c]pyrazole-4-acetate;
53 ethyl 2-(4-fluorophenyl)-3-oxo-2,3-dihydro[l]-benzopyrano[4,3-c]pyrazole:4-acetate;
54 ethyl 2-(4-chlorophenyl)-9-hydroxy-3-oxo-2,3-dihydro[l]benzopyrano[4,3-c]pyrazole-4-acetate;
ethyl 3-oxo-2-~4-trifluoromethylphenyl)-2,3-dihydro[l]benzopyrano[4,3-c]-pyrazole-4-acetate;
56 ethyl 2-(4-methoxyphenyl)-3-oxo-2,3-dihydrotl]-benzopyrano[4,3-c]pyrazole-4-acetate;

W091/11448 PCT/EPg1/00 - 67 - ~ r~

57 ethyl 2-(4-methylphenyl)-3-oxo-2,3-dihydro[l]-benzopyrano[4,3-c]pyrazole-4-acetate;
58 ethyl 2-(3-chlorophenyl)-3-oxo-2,3-dihydro[l]-benzopyrano[4,3-c]pyrazole-4-acetate;
59 ethyl 2-(4-chlorophenyl)-9-methoxy-3-oxo-2,3-dihydro[1~benzopyrano[4,3-c]pyrazole-4-acetate;
ethyl 3-oxo-2-(4-trifluoromethylphenyl)-2,3-dihydro[1]benzothiopyrano[4,3-c]pyrazole-4-acetate Examples 61-65 In a similar manner to that described in Example 47, a compound of formula II' (in which Ra and R6, are hydrogen) was prepared by reacting a compound of formula X (in which X is oxygen, Z is -CH=; R8' and Rg represent hydrogen and R7, R8 and R1o are as defined) with triethyl orthoacetate (XI) as summarised in Table S below:

WO 91/11448 PCT~/EP91/0015"

o.O ' ~ ,..~:..

o c~
o- _ ~_ o ~`
r~
. ~ o -- ~ O r~ N
. ~ 5 o r~
C t~ 1'1 N ~ ~I

C L~l o o Ll~ Il') OE-~ ~
._ V a~ COI` 'V

U~ ~ _ . . . . . C
a) ~ ~ _ u~ ~ _ O

E~ v x-- ~ E
~ ~ _ ~
_ r~_o ~~
~ 3~
o ooooo ., X ~; ~

~; u ~ c~ m o X ~ N 1"7 ~ L0 ~ ~ O

U~ O

,"

Notes (1) Heating temperature = 140-150C.

The compounds prepared in the above ~xamples were:-; 61 2-(4-chlorophenyl)-9-methoxy-4-methyl[l~benzo-pyrano[4,3-c]pyrazol-3(2H)-one;
62 2-(4-chlorophenyl)-8-hydroxy-4-methyl[1]benzo-pyrano[4,3-c]pyrazol-3(2H)-one;
63 2-(3,4-dichlorophenyl)-8-hydroxy-4-methyl[1]benzo-pyrano[4,3-c]pyrazol-3(2H)-one;
64 2-(4-bromophenyl)-8-hydroxy-4-methyl[l]benzo-pyrano[4,3-c~pyrazol-3(2H)-one;
6~ 8-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-[1]benzopyrano[4,3-c]pyrazol-3~2H)-one;

ExamDle 66 A mixture of 2-(4-chlorophenyl)-9-methoxy-4-methyl[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 100-110C for 35 minutes. On cooling, 2M hydrochloric acid (10 ml) and ice were added to the reaction mixture. The yellow solid obtained was collected by filtration to give 2-(4-chlorophenyl)-9-hydroxy-4-methyl[1]benzopyrano-[4,3-c]pyrazol-3(2H)-one, m.p. 213-215C

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

;~t; ~
(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 chromatoaraphy on silica using firstly dichloromethane as the mobile phase and then dichloromethane/pet~oleum ether (b.p. 40-60C, 1:1).
The oil obtained was cr-~stallised from propan-2-ol to give 2-(3,4-dichlorophenyl)-8-methoxy-3a-methyl-3a,4-dihydro[1]benzothiopyrano[4,3-c] pyrazol-3~2H)-one, m.p~ 73-76C.

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=, R9 is hydrogen and R1ol is 8-methoxy) was prepared by reacting a compound of formula XIV
(preparative example of starting compound provided) with a compound of formula XV ~in which R
represents hydrogen and R7 and R8 are as defined), as summarised in Table 6 below. In each case 0.4 g p-toluenesulphonic acid was used in the reaction.

--.

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

____ ~
~ ~ ~ r~ ;
0 _ _ _ _ _ a) _ _ _ _ _ _ O ~
Z _ _ _ _ _ _ C~
O
_ _ _ _ . r ~1-~ 0 t` 1~ ~r O ~I
. _ ~

C~
~D
a~ 0 c ~
,~ ~ a) ,~ o o o o o C _~ ~ O O O O O
3 X - ~
C~: ~ ~ _ o u~
~ ~ ~ I` ~ ~D U~ CO
X -V
~ ~ ~ u~ o o r~ ~
X_ U~
CO _, ~; ~ V
:~ ~` ~ --I h X ~; t) ~
tn~a O ~ 0:~ ~ ~ ~ ~ ~
~ ~ e x XJJ O
X o ~ a~ o _ _ U~ O U~

2~ ~ 72 No~es (1) Single flash chromatographic purification process using as the mobile phase:-a) dichloromethane b) dichloromethane/methanol ~99.5:0.5) (2) Recrystallised from isopropyl alcohol.

(3) 0.2 g p-toluenesulphonic acid used.

(4) The reaction mixture was filtered and the filtrate was:-a) concentrated to give a soliZ 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[l]benzothiopyrano[4,3-clpyrazol-3-(2H)-one 69 2-(4-chlorophenyl)-8-methoxy-3a-methyl-3a,4-dihydro[l]benzothiopyrano[4,3-c]pyrazol-3~2H)-one 2-(4-fluorophenyl)-8-methoxy-3a-methyl-3a,4-dihydro[l]benzothiopyrano~4',3-c]pyrazol-3(2H)-one 71 8-methoxy-4-methyl-2-(4-trifluoromethylphenyl)-[l]benzothiopyrano[4,3-c]pyrazol-3(2H)-one Example 72 ~oron tribromide (21.4 ml), (lM solution in . . .

.

dichloromethane) was added dropwise to a mixture of 8-methoxy-3a-methyl-2-(4-trifluoromethylphenyl)-3a,4-dihydro[t]benzothiopyrano[4,3-C~pyrazol-3(2H)-one (4.2 g) in dry dichloromethane (80 ml) at -70C 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. 40-60C) to give 8-hydroxy-3a-methyl-2-(4-trifluoromethylphenyl)-3a,4-dihydro[1~benzothiopyrano-~4,3-c]pyrazol-3-(2H)-one, m.p. 211-213C, Examples 73-76 In a similar manner to that described in Example 72, a compound of formula I' (in which X is sulphur, Z
is -CH=, Rg is hydrogen and R1ol is 8-hydroxy) was prepared from a compound of formula I' (in which R1ol 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 -70C, as shown in the Table.

WO 91/11448 PCl/EP91/001~4 ~ s~
ut ~ _ _ ~
O _ N ~
Z _ _ _ ~I J,J _ a~ ~D N 1--O t) ~ CO _ ~ _ N N N 1 .~_ l l l l l O u~ ~coLn N
h- ~ Or-- _ E ~ ~--I _ N N N ~) O U~
~,1 aJ h :~
t~ O
~ -- u~
Ct~ N _ _ _ N

~` o~_l U~ O O U~ U~
~1 ~ ~ E~ --E~ V O-1/~ Itl Or~ N D 1 J- ~
~ h _I N N ~u~ N _ :~ ~ _ N
E m--_ O N O O O
_ ~ _ N~r 4.,.~
0~ 0 h ~-~ E ~ I~ O~ O -- _ X ~ O ~ r X
~ I~

u~ o ul Notes (1~ A further portio~ of BBr3 ~5.5 ml) was added after 18 hours. The residlle 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. 40-60C).

(2) A further portion o. BBr3 (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 ~ive the product.

The compounds prepared in the above Examples were as follows:-73 2-(3,4-dichlorophenyl~-8-hydroxy-3a-methyl-3a,4-dihydro[l]benzothiopyranot4,3-c]pyrazol-3~2H)-one;
74 2-(4-chlorophenyl)-8-hydroxy-3a-methyl-3a,4-dihydro[l]benzothiopyrano[4,3-c]pyrazol-3-(2H)-one;
2-(4-fluorophenyl)-8-hydroxy-3a-methyl-3a,4-dihydro[1~benzothiopyrano[4,3-c]pyrazol-3-(2H)-one;
76 8-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-~l~benzothiopyrano[4,3-c~pyrazol-3(2H)-one;

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

W091tl1448 - 76 - PCT/EP91/001 Preparation of Novel Compounds of Formula I

~xamDles 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 R7, R8, R8, and R1o are as defined) with triethyl orthoacetate (XI) as summarised in ~able 8 below:

- WO 91/11448 - 77 - PCI`/EP91/00154 Pff , . ~ XJ~

_ _ _ _ Z _ =_ == ~ ~r O N ~ CO ~ ~1111 ~ N _ ~ N ~`J N N ~J
. ~ l l l l l l l l ~1_1 o L~ O _trl CO ~ 11~ N
. _ t~l ~.'')t`CO 0 ~11~') ~D ~
E N ~`J ~ _ _ N t~ N N N

~-1 a) u, ~ E ~: ul u~ ~ o o o o o o ~
~ ~-,/ , _ ~
a) E~ E~
--a~ r o ~ o _ O u~X ~ er ~ ~r o u~ ~ ~ o o r~
U) ~
~ o ~~ I~ o ~ o ~ o o o - o _~ E ~ x cr 2 ~ r._ _ N _ N ~ C r~l O O
~ ~ ~

C~ ~
X
C~
1~; _ ~ ~_) U ~ ~ ''~
r ~; c) C) ~ m ~

x r~ ~ o~ o ~
~ r~ r- I~ c~ CD ~ ~ CO ~ CO

Ul O U~

O 91/11448 PCI/EP9ltO01~4 Notes

11) Heating temperature = 140-150C

(2) Recrystallised from ethanol/dichloromethane (3) The crude product was purified bv flash chromatorgraphy on silica using a 4~ solution of methanol in dichloromethane. The extracts were combined, triturated with dichloromethane/petroleum ether (b.p. 40-60C) and then acetone and then dried ~nder 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.

Exam~le 87 In a similar manner to that described in Example 47, a stirred mixture of 1-(5-chloro-2-pyridyl)-3-(2-hydroxyphenyl)-2-pyrazolin-5-one (1.4 g) and trimethyl ortho(methy7thio)acetate (2.5 ml) was heated at 140-145C for 10 minutes, then cooled and triturated with industrial methylated spirit, to give 2-(5-chloro-2-pyridyl)-4-methylthiomethyl[1]benzopyrano-[4,3-c~pyrazol-3(2H)-one, m.p. 217-219C.

Example 88 In a similar manner to that described in Example 47, a stirred mixture of 1-(5-chloro-2-pyridyl)-3-(2-hydroxyphenyl)-2-pyrazolin-5-one (3.0 g) and triethyl ortho(ethoxycarbonyl)acetate (7.3 g) was stirred at 140-145C for 45 minutes, adding further portions of the ortho ester (2 x 3.7 g), after 15 and 30 minutes.

- 79 - ~ , '~ ~

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-dihycro[l]benzo-pyrano[4,3-c]pyrazole-4-acetate, m.p. 152-154C.

Example 89 Acetyl chloride (0.5 ml) was added dropwise to a stirred mixture OL 2-(;-chloro-2-pyridyl)-9-hydroxy-4-methyl[l]benzopyrano[4,3-c~pyrazol-3(2H)-one (2.0 g), dry tetrahydrofuran (30 ml) and triethvlamine (1.0 ml) at 0C. 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~l]-benzopyrano[4,3-c~pyrazol-9-yl acetate, m.p. 252-255C.

Example 90 A stirred mixture of ethyl 2-(5-chloro-2-pyridyl)-3-oxo-2,3-dihydro[l]benzopyrano[4,3-c]pyrazole-4-acetate (1.4 g) and cyclobutylmethanol (3.5 ml) was heated at 150C for 1 hour. The reaction mixture was allowed to cool to ambient temperature, triturated with ether and the solid product collected by filtration and washed with ether to give cyclob~tylmethyl 2-(5-chloro-2-pyridyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]-pyrazole-4-acetate, m.p. 157-160C.

Example 91 A mixture of propyl 2-(4-chlorophenyl)-3-oxo-2,3~dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate WO91/11448 - 80 - PCTtEP91/001~4 (1.9 g) and 2-piperidinoethanol (6.4 ml) was stirred at 150C 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 S combined organic extracts were washed well with water, dried and evaporated. The residual oil was dissolved in absolute ethanol and treated with ethanolic hydrogen chloride. The solid formed on cooling and scratching was collected by filtration and dried giving 2-piperidinoethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro-[1]benzopyrano[4,3-c]pyrazole-4-acetate hydrochloride, m.p. 193-197C (with decomposition).

~xamples 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.

01 _ _ ~ _ _ _ Z
~ ~ U~ ~ o ~ ~ ~ o o ~ U ~ ~
_ o ~ u~
o . ~:r U) ~ ~ ~ o o:
E ~ ~ . ~` . .~ ~ _ a) c ~J o u~ C u~O n E ~ , .- _ ~ .~ ~ ~
~o ~
o-- co O o a~ o --o c ~
c~ ~ c E ~ ~ -- ~ o co ~~ o m o ~ l ~
a,~ _ o o E~ C _S~~~
N t~ ~I r~l ~ ~1 s :~: -- _ s ~1 ~,) U CJ U U U U U
----S--_--~_, ~ ~ -U U U ~) -U U U
I _ _ _ _ _ _ _ _ I O C C C C 1:: C C
_/ r U O O O O O O O O
O ~1 ~.C .C .~: ~ .C _ .C .C:
,, al -- ~ 3 CL C~J tl ~ 3 o E U L~
-- u _ E E E E E E E

.
O ~ ~ ~ ~~ . ~ r- ~ r~ o~
.
X J- U~
a~
_~ ~ ~ ~ In ~ o E ~ ~ o~ o U~ o U~ o r . :,.

WOgl/114~ - 82 - PCT/EP91/001~

~ 17 ~ NOte5 (1) Product converted inlo its free-base using triethylamine and purified bv flash chromatography on silica using dichloromethane/methanol (9:1) as the mobile phase.

(2) After heating at 150C for lS 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 55C.

ExamDle 101 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[l~benzopyrano[4,3-clpyrazol~-4-acetate (3.0 g) and 4-methoxybenzyl alcohol (9.6 ml) was stirred at lS 150C 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-[l]benzopyrano-~4,3-c]pyrazole-4-acetate, m.p. 152-155C.

Examples 102-134 In a similar manner to that described in Example 101, a compound of formula I was prepared by reacting ethyl 2-(4-chlorophenyl~-3-oxo-2,3-dihydro-[1]-benzopyrano[4,3-c]pyrazole-4-acetate (II') with the appropriate alcohol, as summarized in Table 10 below.

WO gl/11448 PCI/EP91/00154 a)l _ _ _ O _ _ ~ U~ ~ ~ ~ ~ .
Z _ _ _ _ _ _ _ _ _ 4~ ~ ~ o ~ D O ~O
O ~ ~ I` ~ ~ ~ ~ ~ O ~ ~ r~
C~ _ _ _ _ . _ _ _ _ _ . ~o l l l l l l l l l l l l C _ u~ ~ cr~ u~ ~ ~ ~ cr ~ ~ c~ ~r E _ _ ~D ~ ~ /~ ~ ~ o r ~

E c o o o o o o u~ o o o .~ ~ 1~O O m o r~
E~ ~
~0-O E ~ c~t~
~~ _ ~r ~ o o o o ~ o ~ o1 ~ . o . .
O O ~
al ~ S~_-O ~ ~ o-~ o o o o o o o _ o o o o n~ E ~ ~7--H
E~ ~:

O - ~
~ O

0~ ~ O O --/ C O
-- o ~
o ~~ ~_ ~ ~
-- 5 C) ~ O C~ O O JJ
h ~ O _ ~ I O '~1 ~ U'l _ O C S C >~ --_~~: _ CL ~ 0 .a OO ~ O ~ ~ O ~1 0 0 .~: ~
o ~ o u O ~ u C~ u O ~ ~ E
U O ~
_I S . ~ l U ~ U ~ ~ ~ ~r ~ ~ ~ u~ ~ o X o o o o o o o o . _ _ _ ~ ____________ In O U~ O

WO 91/11448 PCI/EP91/001~i4 f~ ~' J ' 5;~
_ _ _ _ _ ~ 0 0 ~
_ _ _ _ _ n 3 ~
O ~ ~ ~ ~ o Z _ _ _ _ _ _ _ _ _ _ _ ~ O U~ ~D 1` ~ Ul ~ ~ ~ O
O _ ~ c~, ~ ~ ~ ~ ~ ~ I_,-- ~r ~) _ . ~o _ ~r ~ o ~ ~D ~D O Cl~
E ~ co ~ a~ ~ ~ ~ ~ I` _, E .,., o o o o o u7 o o o o o .~ ~ co a~

o _ _ cr.
. O ~ ~ c~
-- ~ o C~ I~ ~ C o o -- o C ~ D~ ~ . . . .. .. . . . .
O O ~ ~ ~D 1` ~ ~ ~ ~r ~r ~ U~ r~ ~
C~ J~ C
o c ~ h O ~ ~ ~ o ~ o o o o ~r ~r o o o O E aJ m--~
_~ ~ ~

O ~
_ C~ o U U O
_ o s U U U U
N :~ C ~ ~ O
N a~ C C ~ C C O C~
c s a, ~ s ~.c s X ~ X 0~ 0~ o~ C
O :~ O L~ h ~
_I ~: .C ,c O O _I o ~O o O ~ ~ ~ ~ ~ I ~ O
s aJ a~ a~ s s O E Ei E u u o uE o u U I I I I I U I I ~ I
_~ r~
: _ _ _ ~ U~ ~D 1~ CO a~ o _ _ _ _ _ _ _ _ _ _ _ U~ o U~ o WO 91tl 1448 PCl'/EP91/00154 ~ _ ____ _ ~
I ~ ~ ~â 0 ~ Q R R 0 O ~ ~
Z; _ _ _ _ _ _ _ _ _ O r O ~ ~ C~
C) _ _ _ _ _ _ _ _ _ . ~o ~:L _ ~ ~ ~ a~ o t~

Ei .,, o ~r\ o o o o o L'l O O O
E~ ~ ~ _ o o c~
-01 ~
~ 0 ~ Dl ~
C ~ u~ U -- ~ 0 0 O O J- ~ ~r ~ ~ r~ ~ r~ ~ Ln r~ ~ ~
O ~ ~
_ ~ u a)- --O ~ ~ ~ ~ ~ O o Y~ o o ~_ _ r~

S~
U~

,,~ _ _ ~ ~ _ - S O O
r; S ~ ~ S
O O ~-- ~ ~ O
S ~ O ~ ~ ~ C~ ~ --~ ~ O ~ aCJ ~ S~ a u S ~ C S S S ~ _ ~ s E ~ o x :~ c) o ~ IJ 0 ~ :~ ~ O ~ -- h _, x a~ _1 ,C S O .. C ~-1 ~ Q.
o o E ~ ~ o S C ~ 1 O C ~1~ N _l o ~ E E u E3Q. c u u s I u I I I II a~ ~, ~ U

Ul ~D 1` ~ ~ O
X ~ ~ ~ ~ ~ ~ ~ ~ ~ r~
_ _ _ _ _ _ _ _ _ _ In O U~ O

~
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 bv filtration.

(2) The product was recrystallised from:-a) acetonitrile;
b) ethyl acetate.

(3) The reaction mixture was heated at:-a) 120C:
b) 150-160C;
c) 180C;
d) 214C.

(4) The crude product was purified by flash chromo-tography on silica using, as a mobile phase:-a) toluene/acetic acid (9:1);
b) toluene;
c) ethyl acetate/acetic acid (9:1).
The fractions obtained were evaporated and triturated with ether to give the product.

(5) The cooled reaction mixture was dissolved in dichloromethane and washed with water. After dryingand concentration, the mixture was purified on a W091tll448 PCT/EP91/00154 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 90C then diluted with:-a) industrial methylated spirit;
b) absolute ethanol.
The product was collected by fil,-ation.

Exam~les 135-141 _ _ In a similar manner to that described in Example 101, a compound o' 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.

WO 91/11448 - 88 - PCr/EP91/001~4 a~
O

o ~ ~ ~ _ o . ~ ~, o : r~ co I ~ o ~o . _ ~ 1-- ~ ~ C C; ~ ~D
E _ . _ cr~ _ _ .

E .~ o o o o o D o .,~ E a~ ~ o ~ ~D
_ _~-1 _~
O
C E ~ 1~
~ -- Ul ~ ~ ~ ~ ~ CO

_ C~ ¢ r~ r _ ~ ~ ~_ _ O ~ ~ ~ ~ U~ ~ ~ o o 1` o O E aJ u) ~--2 ~ ~ ____~
_ _ _ ~ _ _ --_~
_ _ U ~ U ~ ~J
_~ _ _ _ _ _ _ _ O C C C C C C C
.c O ~ ~ J
o .a ~
~C O O O
t~ ~ o u o t~ o Dl 4,, .c o~ ~
~ ~- h~ O ~D 1` CO ~r Cl~
Ia ~ ~ U~
X ~ Ul H

E u~ o _ ~ _______ Ul o U~

f~ ', 'I~' ~ 9 Notes (1) Cycle included 26 hours refluxing and 140 hours storage at ambient temperature. A further portion o' the alcohol (2 g) was added after 13 hours reCluxing.

5 Exam~les 142 and 143 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-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) 10 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 15 2-(4-chlorophenyl)-3-oxo-2,3-dihydro-[1~benzopyrano ~4,3-c~pyrazole-4-acetate (Example 142 m.p. 136-139C, and 2-hydroxyethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[l~benzopyrano[4,3-c]pyrazole-4-acetate (Example 143), m.p. 161-162C.

20 Example 144 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate (2.0 g), 4-(2-hydroxyethyl)thiomorpholine (1 g), dry xylene (20 ml) and N-methylmorpholine (0.6 ml) containing 4A
25 molecular sieves was stirred ana heated at 150C 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 30 molecular sieves, the solution was washed with water, dried and evaporated under reduced pressure. The residual gum was dissolved in ethanol, treated with WO9l/l1448 PCT/EP91/oO~t -- 90 -- ;

ethanolic hydrogen chloride and then cooled to 0C.
The solid formed was collected by filtration and dried to give 2-thiomorpholinoethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate hydrochloride, m.p. 223-226C.

Example 145 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate (2.00 g), 2-methylthioethanol (0.5 ml), N-methyl-morpholine (0 6 ml) and dry xylene (40 ml) was stirred at 170C for 5 hours. The mixture was evaporated unde~
reduced pressure and the residue recrystallised twice _rom acetonit_lle to give 2-metnyl.hioethyl 2-l~-chlorophenyl)-3-oxo-2,3-dihydro-[l]benzopyrano[4,3-c~
pyrazole-4-acetate, m.p. 113-114C.

Example 146 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[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-2,3-dihydro[l~benzopyranor4,3-c]pyrazole-4-acetate, m.p. 114-115C.

Example 147 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate ~ . , .

WO91/11448 PCT/EP91/001~

(2.0 g), 2-cyanoethanol (0.4 ml), N-methylmorpholine (0.6 ml) and molecular sieves (20 pie es) was stirred in dry xylene (40 ml) at 170C for 5 hours. More 2-cyano~thanol (0.4 ml) was added and the mixture was stirred at 170C for 18 hours. The mixture was evaporated under reduced pressure and the residual oil purlfied on a sho~t Florisil column using dichloro-methane as the mobile phase. The mate-ial 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. 60-80C) and filtered to give 2-cyanoethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[l]benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 120-122C.

Example 148 In a similar manner to Example 14;, a mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[l]benzo-pyrano[4,3-c]pyrazole-4-acetate (2.0 g), ethyl 3-hydroxypropionate (1.2 ml), N-methylmorpholine ~0.6 ml) and dry xylene ~40 ml) was heated at 170C for six hours to give, after flash chromatosraphy on silica using toluene/acetic acid t9:1) as the mobile phase, 2-ethoxycarbonylethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro~l]benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 126-129C.

ExamPle 149 In a similar manner to Example 145, a mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[l~benzo-pyrano[4,3-c]pyrazole-4-acetate (1.1 g), 2-phenyl-t-propanol (0.4 ml) and N-methylmorpholine (0.3 g) in dry xylene (3 ml) was stirred and boiled under reflux for 15 hours, adding more 2-phenyl-1-propanol (0.2 ml) and -WO91/11~ PCT/EP91/001 N-methylmorpholine (0.2 ml) after 14 hours. The reaction mixture was cooled, the solid collected by filtration and recrystallised from acetonitrile to give ~-methylphenethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro-[1]benzopyano[4,3-c]pyrazole-4-acetate, m.p. 86-90C.

Example 150 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano~4,3-c1pyrazole-4-acetate (2.0 g), cyclohexylethanol (0.7 ml), N-methylmorpholine (0.6 ml) and xylene ~40 ml) was heated under reflux 'or 6 hours.
A further portion of cvclohexylethanol (0.7 ml) was added and the mixture heated under reflux for a further 3 hours. The mixture was evaporated unde- reduced pressure and the residue recrystallised twice from acetonitrile to give 2-cyclohexylethyl 2-(4-chloro-phenyl)-3-oxo-2,3-dihydro[1]-benzopyrano[4,3-c]-pyrazole-4-acetate, m.p. 149-151C.

Example 151 A solution of ethyl 2-(4-chlorophenyl)-3-oxo-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-2-morpholinoethanol (0.8 ml) was added and heating/-distilling continued for 7 ho~rs. More l-methyl-2-morpholinoethanol (0.8 ml) was added and the mixture heated for a further 5 hours. The reaction mixture was cooled to 0C and the solid obtained collected by filtration, washed with ether and dried to give 1-methyl-2-morpholinoethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 176-179C.

Example 152 In a similar manner to Example 151, a mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzo-pvrano[4,3-c]pyrazole-4-acetate (1.0 g), (1-methyl-2-piperidyl)methanol (0.7 ml) and toluene (15 ml) gave,after flash chromatography, l-methyl-2-piperidylmethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro~1]benzopyrano-[4,3-c]pyrazole-4-acetate, m.p. 159-163C.

Example 153 A stirred suspension of 2-morpholinoethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]-pyrazole-4-acetate hyd-ochlo-ide (1.; g) in absolute ethanol (50 ml) at 0-5C was treated portionwise with sodium borohydride (O.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 0-5C 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-1,2,3,4-tetrahydro[1]-benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 125-128C.

Example 154 Acetyl chloride (2.3 ml) and triethylamine (1.1 ml) were added to a solution of 3-hydroxypropyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano-[4,3-c]-pyrazole-4-acetate in dichloromethane (75 ml) ~Example 124) at 0C. The reation mixture was stirred at room temperature for 18 hours, then washed, dried, filtered and the filtrate evaporated. The residual O91~11~ PCT/EP91/O01 h '~ ' mixture was passed down a Florisilv column usingdichloromethane as the mobile phase. The re~uired fractions were combined anc evaporated. The crude product was purifled 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]pyrazoie-4-acetate, m.?.
129-l31oc~

Example 155 A stirred mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c)pyrazole-4-acetate (1.9 g) (~xample 47), ~-methvlanlline (0.~ g) an~
xylene (15 ml) was heated under reflux for 22 hours.
More N-methylaniline (0.3 g) was added and the mixture heated under reflux for a further 5 hours. The mixture was cooled and scratched. The solid formed was collected by filtration and dried to give 2-(4-chloro-phenyl)-N-methyl-3-oxo-2,3-dihydro~1]benzopyrano-[4,3-c]pyrazole-4-acetanilide, m.p. 200-202C.

Examples 156-170 In a similar manner to that described in Example 155, a compound of formula I was prepared by reacting a compound of formula II' ~the Example for the preparation of the starting ester is p-ovided) with the appropriate amine as summariséd in Table 12 below.

_ _ _ _ O
Z
_ ~ co ~r ~ ~ ~ _ c 1`
I` ~ I` o ~ D
. _ _ _ ~ _ _ _ _ _ ~ l l l l l l l l l l . ~ 1~ o U~
~ ~ `

r~ O U~ o u E~ _ ~ ~ ~
U~ ~
C~ O U~ O O ~ ~D 1` ~ In o J~ ~ E
X
~; ~ E E E3 E E
C ^ t~l1~ 0 r~ t N Ulu~ G`' ~er ~r~ ~
O E~-- _ o _ _ _ _ o o o o o _ _ 3 ~ ~ o~ o o CD u~ o ~ ~ ~ ~ o_~
' ~ ~
, _ ~ U

a) ~ O ~ 5: ~ ~ r~ _ -- C U ~ -- -- -- Z
U ~-~ -- U U U U -- ,C
~:: _ ~
,.. Z ~a Z Z Z Z ,c o ~1 ,~1 ~ ~ h ~ , C ,-1 N O ~ :'~ C N N N C :~ S
C E -- ~ aJ C CC O t) a~ ~ U I c ~ ~ ~ o _ _ z ~ -- -- -- E

Cl. ~J h E 4~ h ,a o 1~ ~
X ~ ~q ~ O --X u~
~ _ _ _ _ _ _ _ _ _ _ In O ~ O
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f~ ''7'.?JL _ ~
O
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~;
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.a ~ ~ ,~
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C~ o C
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.,~ o Z
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1~ 1~
~I h ~1 ~ u7 ~ ~r ~ O ~
X ~ 0 ~ 0 a~

X
~ _ _ _ _ In O

, ~ ' ' '' '' :-- WO91/lt448 PCT~EP91/001 Notes (1) The solid was recrystallised from acetonitrile.

(2) The reaction mixture was evaporated under reduced pressure and the residue recrystallised from dichloromethane/industrlal 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 filt_ation.

(4) The solid was recrystallised from acetone.

(5) The reaction mixture was evaporated and the residue was recrystallised from acetonitrile.

(6) Softened at 158C.

WO91/11~ 98 PCT/EPsl/001 Example 170 f~ ., :~ I.'J ;.
a) A mixture of propyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[l]benzopvrano[4,3-c]pyrazole-4-acetate (1.9 g) (Example 45) and l-piperazineethanol (5.9 ml) was stirred and heated at 150C for 1.5 hours. The mixture was cooled to ambient temperature, diluted with water and extracted with dichloromethane. The combined organic extracts were washed with water, dried and evaporated. The residue was dissolved in ethanol and treated with ethanolic hydrogen chloride. The solid formed on cooling and scratching was collected by filtration to give 2-(4-chlorophenyl)-N,N-[3-(2-hydroxyethyl)-3-azapentamethylene]-3-oxo-2,3-dihydro-[l]benzopvrano[4,3-c]py~azole-4-acetamide hydrochloride, 200-205~C (with decomposition).

b) A solution of 2-(4-chlorophenyl~-N,N-[3-(2-hydroxyethyl)-3-azapentamethylene]-3-oxo-Z,3-dihydro [l~benzopyrano[4,3-c]pyrazole-4-acetamide hydrochloride (0.7 g) in dichloromethane (28 ml) was cooled to 0C
with stirrinq 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 0C for a further 30 minutes then left at 0C
overnight. The mixture was washed with water, then dried and evaporated under reduced pressure. The solid obtained was triturated with ether and the solid formed collected by filtration and dr~ed to give 2-~4-[2-(4-chlorophenyl)-3-oxo-2,3-dihydro[l]benzopyrano~4,3-c]-pyrazole-4-acetyl]piperazin-1-yl 3 ethyl acetate, m.p.
162-166C.

!~WO91/11~ PCTtEP91/OOl~

Example 171 A stlrred mixture of 2-(4-chlorophenyl)-N,N-[3-~2-hydroxyethyl)-3-azapentamethylene]-3-oxo-2,3-dihydro[l]benzopyrano[4,3-c]pyrazole-4-acetamide hydrochloride (0.8 g) (Example 170a) and dichloro-methane ~45 ml) was treated with triethylamine (0.5 ml) followed by propionyl chloride (0.3 ml) at 0C. 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-(4-chlorophenyl)-3-oxo-2,3-dihydro~l~benzopyrano[4,3-c]-pyrazole-4-acetyl~piperazine-l -yl3 ethyl propionate, m.p. 173-175C.

Example 172 A stirred a mixture of ethyl 3-oxo-2-(4-tri-fluoromethylphenyl)-2,3-dihydro[l]benzothiopyrano-~ 4,3-~]pyrazol-4-acetate (0.9 g) ~Example 60), morpholine (0.4 ml) and dry xylene (3.5 ml) was heated under reflux for 2.3 hours. The reaction mixture was allowed to cool to ambient temperature and the solid collected by filtration was washed with xylene and ether and then dissolved in dichloromethane. The solution was washed with water, dried, evaporated and triturated with ether with scratching. The solid product was collected by filtration to give N,N-~3-oxapentamethylene)-3-oxo-2-(4-trifluoromethylphenyl)-2,3-dihydro[l]benzothio-pyrano[4,3-c~pyrazole-4-acetamide, m.p. 210-212C.

Exam le 173 p A stirred mixture of ethyl 3-oxo-2-(4-tri-WO 91/11448 PCr/EP91/001'`4 - l oo -fluoromethylphenyl)-2,3-dihydro[1]benzothiopyrano-[4,3-c]pvrazol-4-acetate (0.6 g), (Example 60) N-ethyl-aniline (0.4 ml) and dry xylene (2.4 ml) was heated under reflux for 4 hours. A further por.ion of N-ethylaniline (0.1 ml) was added and the reactionmixture refluxed for a further 2 hours. The reaction mixture was stored at ambient temperature for 72 hours and a furthe_ portion N-ethylaniline (0.2 ml) added with refluxing for a further 3 hours. The solid product wzs collected by filtration, washed with xylene and ether to give N-ethyl-3-oxo-N-phenyl-2-(4-tri-fluoromethylphenyl)-2,3-dihydro[1]benzothiopyrano-[4,3-c]pyrazol-4-acetamide, m.p. 179-181C

Example 174 A mixture of 1-(4-chlorophenyl)-3-(2-hydroxy-phenyl)-2-pyrazolin-5-one ~17.0 g) and methyl 4-(2,2-dimethyl-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-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-cl-pyrazol-4-yl]-4-oxopentanoate, m.p. 142-143C.

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 R8' and Rg are hydrogen, and R7, R8 and R1o are as defined) with a compound of formula XIIb (the Example for the preparation of the starting compound XIIb is provided) as summarised in Table 13 below:

WO 91/11'148 PCI'/EP91/00154 ~ 101 p~ ~ ~ r u~
______ _~____ O _ _ ~ ~ r~
Z _ _ _ _ _ _ _ _ _ _ _ ~ r ~ ~ ~ ~r ~ co _ a~ co r.~ _ O _ c~ _____, ______ .~ o I ~ I I I I I I I I I I
CL _ ~O O ~D _ ~ CD ~O a~ ~ u~ ~ G~
.
~ ______ ______ ~ _ a u~ u~
E~ .C ~D ~O 10 ~D ~D ~O ~ ~r _ ~ _ ~ ~o ~:
u~
o o o o o o o o o o u~ o _~ ~ ~ o ~ ~ u~ O u~ ~
o ~,_ _ _ _ _ ~ _ ~:
D u~ O ~ O _ ~ co co r H _ ~ O ~ _ ~
_ V
8 _ r o r~ co o u~ o o u~ o o o E~ X

_ _ I~
U ~ U ~J U U C~

4~ ~ ~
O ~ X
u~ o ~
. ~ _ _ _ _ _ X ~ C~.
~U~ U
a~

u~ ~.D 1` co o~ o _ ~ ~ ~ u~ ~D
X I` r 1` 1` ~ co ~ co c~ ~ co co 1~ _______ _____ U-~ o ~ o WO91/11448 PCT/EP91/00~4 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 ~ecrystallised f-om propan-2-ol.

(2) Recrystallised from industrial methylated spirit.

(3) Recrystallised from methanol.

(4) On cooling the reaction mixture the soll~ product was filtered off.

(5) Solid triturated with ether, fi1tered, washed and dried to give product.

(6) On evaporation of the reaction mixture and scratching a solid was produced which was triturated with hot industrial methylated spirit, washed and dried to give the product.

(7) Solid product obtained on filtration after cooling the reaction mixture to room temperature.

(8) Reaction mixture allowed to cool to ambient temperature and kept at this te~perature 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.

~091/11448 PCT/EP91~001 Example 187 A stirred mixture of 2-(4-chlorophenyl)-9-hydroxy-4-methyl[1]benzopyrano[4,3-c]pyrazol-3(2H)-one (2.0 g) ~Example 66), triethylamine (1.4 g~ and dichloromethane (20 ml) was cooled in an ice bath while methyl malonyl chloride (1.5 ml) was added. More dichloromethane (20 ml) was added and the mixture allowed to warm up to ambient temperature over 18 hours. The mixture was filtered and the residue washed with dichloromethane and then water. This residue was recrystallised from acetonitrile to give 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihvdro[1]benzopyrano[4,3-c]pyrazol-9-yl methyl malonate, m.p. 204-206C.

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[l~benzopyrano-[4,3-c]pvrazol-3(2H)-one ~Example 62) with the appropriate acyl chloride (R17COCl) as summarised in Table 14 below.

WO 91/11448 PCI`/EP91/00154 ~A ,~q ~ ,~ ~ ~ 0 4 ., ~ .~ . .. .

U) ~
_ _ _ _ _ _ ~ _ _ _ O _ _ r~
Z ~_ _ _ _ _ _ _ _ _ _ _ D O ~ Ir~ ~ O N 1` ~ ~
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.-- l l l l l l l l l l l l l l l . . ~ C~ ~ N ~ O ~D
. _ ~ ~ t~ O _ ~ O ~ C U-l O _ E 1~ _ . ~ ~ _ _ ~ ~ ~ ~ ~ ~ .

._ o 1~ D ~ O O
JJ E
~-- ~ _ _ _ _ _ ~ ~ ~ ~ ~ ~ _ .

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~ ~ ~ ~ - o ~ - - - - - - - - -~r ~ 1) _ OE
~ ~ ~ ~ ~ o o ~ u~ o o o o o o o Ll ~_~_ ~ ~ ~
~.

C :~ ~. C :~
c) a~ c c ,c ~ ~ Q. C ,C ' ~ ,C
C~ O ~ X ~O ~ X --U ~ h IJ C O --1 C ~ I C~ O :~
o ~ ~ c ~ ~ .a .c o 11 _ o u o ~ o JJ --Ir~ O --~ E C N a~ :~ C ~
r~ ~ ~~ aJ c E ~ LJ ~ e u ~ E E
~~ ~, ~a ~ ~, I I I ~. I I _ In ~ ~ o _ ~
CD a ~ a~ o o o ~ _ _ _ U~ o U o U~

WO 91/11448 PCI/EPgl/001~4 2 . ~
_ _ JJ ~ _ _ O ~

a~ ~ _ co o_ o ~ ~
. ~, ~
G-- CO O CD ~D
. 0 ~
E ~ ~ ~ ~ ~

~ In U~

~ ~ ~ .
~ O u~ ~
Ul C ~: _ _ _ _ V ~: lY - _ U~

Q) C
C~ .c ~ la c~ _~
:: X -~ ~
~ s s o o _I _I a ~` U U
~: U U~

E ~ er X o o o o i!l~ N t`~ ~I N

l~ O

WO91/11~ PCT/EP91/00154 2 ~ J ,~ 0 6 Notes t1) 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 isop-opanol 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 (R17COCl) as summarised in Table 15 below.

WO 91/114~8 PCI/EP9ltO0154 f~ ., J `~

a~
JJ ~ _ ~ ~ _ _ O
Z _ _ _ _ _ _ _ _ _ _ _ 4~ o ~ u~
O In ~ ~ C~ ~ ~ O ~ C~
~ _ _ _ _ .- ~ ~ ~ _ . O l l l l l l l l l p~-l ~~ O
. _ ~ ~ O ~ c~
E _ _ æ~
~ - . _ ~ o O o o o o v I~E ~ ' ~
~a . ~ ~ ~ _ o o o o _ :: ~ ~ . o o U
- _ u~ ~ O ~r co co o co u~
NOO 'O_ ,~
r ~ ,C r .C a) S 1~1 JJ O V ~
E x E ~ E ~ x ~ o ~ ~ ~ ~ :~ o -I X ,C X X X _1 X C
~. o ~ o o o ~ o ~
N .C ~U J,l V ,C .C J~ O
r~ c JJ e ~ ~ ~ V ~ e E ~ ~ t~ F. e 0~ E ~~ ~ a:~ u~
a~ la ~ X4 ~o E o o o_ -- ~ ~

In o u~ o - - ~

:

WO gl/l 1448 PCI/EP91/001:~4 2 ~i ~ 1 0 8 -U~
_ _ o _ o CO C~
Z _ _ _ _ _ ~o ~ ~ ~ ~
O ~ ~D _ ~D CO
I--~ o ~r o ~ _ N
. _ ~1 ~D; ~ CO
_ _ _ . _ - G~
~- _ O O _ -_~
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~n O--O ~
1~ l~ - O O _ _ V ~ _ _ O U~ ~ O O
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V J- ~ V ~
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X ~ n o ul o ~n :
WO91/11~ PCT/EPgl/001~

2 ; ~ .
Notes (1) Th~ reaction mixture was evaporated to dryness and the solid triturated with ethyl acetate and filtered.
The solid collected was recrystallised from industrial methylated spirit.

(2) The reaction mixture was washed with water and evaporated to dryness.

(3) The product obtained was triturated with ether.

(4) Further portions of acyl chloride (0.2 ml) and triethylamine (0.3 ml)were added after twelve hours and the reaction mixture stirred for a further three hours at ambient temperature. The reaction mixture was washed, dried and concentrated to give a solid.

(5) The solid was purified by flash chromatography on silica using dichloromethane as the mobile phase. The product was recrystallised from ethyl acetate, (6) The solid was washed with aqueous triethylamine and filtered and washed with water, isopropyl alcohol and ether.

(7) The solid product was recrystallised from ethyl acetate.

(81 The reaction mixture was filtered and the product was recrystallised from dioxan .

(9) The reaction mixture was added to ether, filtered and the filtrate evaporated to dryness and recrystallised from industrial methylated spirit.

W~91/11448 PCT~EP91/ool~

(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 129C.

Example 221 A solution of 2-(4-chlorophenyl)-8-hydroxy-4-methyl[l]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 disso~ved in dichloromethane and loaded on to a dry-packed Florisil~ column. The column was eluted with dichloromethane/acetone (99:1).
The required fractions were evaporated and the residue was triturated with ether to give 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihydro[l]benzopyrano[4,3-c]pyrazol-8-yl methyl succinate, m.p. 152-153C.

~091/114~ PCT/EP91/001~
1 1 1 _ Examples 222-225 In a similar manner to that described in Example 221 a compound of formula I was prepared by reacting 2-(4-chlorophenyl)-8-hydroxy-4-methyl[l]benzopyrano-[4,3-c]-pyrazol-3(2H)-one (II') (Example 62) with the appropriate acid chloride, R17COCl, as summarised ln 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.

wo 91/11448 pcr/Epglto~ ~

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A stirred mixture of 2-(4-chlorophenyl)-9-hydroxy-4-methyl[1]benzop~rano[4,3-C]pyrazol-3t2H)-one (2 g) ~Example 66) and pyridine (20 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-chloro-phenyl)-4-methyl-3-oxo-2,3-dihydro[l]benzopyrano-[4,3-c]pyrazol-9-yl benzoate, m.p. 218-222C.

ExamPle 227 A solution of 2-(4-chlorophenyl)-8-hydroxy-4-methyl~l]benzopyrano[4,3-c]pyrazol-3(2H)-one (Example 62) ~1.5 g) and nicotinoyl chloride hydrochloride (1.6 g) in a mixture of pyridine (45 ml) and triethylamine (2.55 ml) was stirred at ambient temperature for 18 hours. The mixture was le~t standing at ambient temperature for 48 hours then added to water and this mixture filtered to give 2-(4-chloro-phenyl)-4-methyl-3-oxo-2,3-dihydro[l]benzapyrano-[4,3-c]pyrazol-8-yl nicotinate, m.p. 230-235C.

Exam~le 228 A mixture of 2-(4-chlorophenyl)-8-hydroxy-4-methyl[l]benzopyrano[4,3-c]pyraz,ol-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 water-bath. l,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 WO91/11~ PCT/EP9l/001 ~r~
J ,. .
with water, dried and evaporated. The residue was triturated with ether ana the solid collected by filtration then stirred with dichloromethane. After removing some insoluble material by filtration the dichloromethane solutior. 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[l]benzo-pyrano[4,3-c~pyrazol-8-yl 4-methoxybenzyl malonate, 10 m.p. 162-163C.

Example 229 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihydro~
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 0C for 2.5 hours then washed with water whereupon a solid separated. The solid was collected by filtration, washed with dichloromethane and dried to give 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihydro~l]benzopyrano[4,3-c]pyrazol-8-yl hydrogen malonate, m.p. 166C.

ExamDle 230 , In a similar manner to Example 227, a mixture of 2-(4-chlorophenyl)-8-hydroxy-4-methyl[l]benzopyrano-[4,3-c]pyrazol-3(2H)-one (Example 62) (1.5 g), N,N-dimethylglycine (0.78 g) and dry pyridine (15 ml) was $tirred at ambient temperature. 1,3-dicyclohexyl-carbodiimide (1.35 g) was added a~d 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)-~ .

- 115 - ~ ~ ~

4-methyl-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]
pyrazol-8-yl dimethylaminoacetate, m.p. 174-176C.

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

Example 232 A mixture of ethyl ~-(4-chlorophenyl)-8-hydroxy-3-oxo-2,3-dihydro[1]benzopyrano~4,3-c]pyrazole-4-acetate (2.0 g) (Example 48) in dry dichloromethane (60 ml) was stirred at 0C 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(acetoxy-acetoxy)-2-(4-chlorophenyl)-2,4-,dihydro[1]benzopyrano-[4,3-c]pyrazol-4-ylideneacetate which on standing in air hydrolysed to ethyl 8-acetoxyacetoxy-2-(4-chloro-phenyl)-3-oxo-2,3-dihydro[1lbenzopyrano[4,3-c]pyrazole-4-acetate hemihydrate containing one mole of acetoxy-acetic acid, m.p. 157-160C.

. ~ x~ _~ ~ 116 -Example 233 A stirred mlxture of 2-(3,4-dichlorophenyl)-8-hydroxy-3a-methyl-3a,4-dihydro[1]benzothiopyrano[4,3-c]
pyrazol-3l2H)-one ~1.50 g), (Example 73) triethylamine (0.61 ml) and dichloromethane (30 ml) was treated dropwise with ethyl malonyl chloride (0.56 ml). The mixture was stirred at ambient temperature for 2 hours and then evaporated under reduced pressure. The residue was partitioned between ether (50 ml) and water (50 ml). The organic layer was separated and the aqueous layer extracted with ether. The combined ether extracts were dried and evaporated to give a solid which was recrystallised from ethyl acetate to give 2-(3,4-dichlorophenyl)-3a-methyl-3-oxo-2,3,3a,4-tetra-15 hydro[11benzothiopyrano[4,3-c]pyrazol-8-yl ethyl malonate, m.p. 139-141C.

Examples 234-251 In a similar manner to that described in Example 233, a compound of formula I was prepared by reacting a compound of formula I' (preparative Example of starting compound provided) with an acyl chloride R17COCl as summarised in Table 17 below. In each case dichloromethane (30 ml) was used.

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WO91/11448 PCT/EP91/001~
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Notes ~1) Recrystallisation from:-a) ether b) ethanol c) ethyl acetate/petroleum ether (b.p. 60-80C) d) methanol e) ethyl acetate f) isopropanol (2) The ether extracts were evaporated and then water added to the residue. Extraction with ethyl acetate followed by 2 recrystallisations from ethyl acetate gavs the product.

(3) A further equivalent portion of triethylamine and acyl chloride was added after 1 hour.

lS (4) N,N-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 weightof active compound and 240 parts by weight of lactose are de-aggregated and blended. The mixture is filled WO91~114~ PCTlEP91/OO

into hard gelatin capsules, each capsule containing 10 mg active compound.

Example 253 In the preparation of capsules, S0 parts bv weight of active compound, 300 parts by weight of lactose and 3 parts by weight of magnesium stearate are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule contianing 50 mg of active ingredient.

ExamDle 254 _ Tablets are prepared from the following ingredients.

Parts by weight Active compound lo 15 Lactose 190 Maize starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3 The active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture is granulated with a solution of the polyvinylpyrrolidone in ethanol. The dry granulate is blended with magnesium stearat,e and the rest of the starch. The mixture is then compressed in a tableting machine to give tablets containing:

a) 10 mg b) 100 mg c) 500 mg of active compound.

'. ~ '' ~ , , -. . .
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14~ PCT/EP9ltOOl~

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% dlethyl 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.

Exam~le 257 In the preparation of ointments the active compound is incorporated into the base by thorough homoqenization until the drug is evenly distributed.
The ointment is packed into 10 g amber jars with screw-capped lined lids.

Active compound 0.1 g White soft paraffin to 10 g The compounds of the invention are immuno-modulatory agents, especial~y 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.

WO9ltl1~ PCT/EP91/001~
~r,~ 122 -Female BALB/c mice, weight range 16-24 g, were used in groups of eight. The abdomen of each mouse was shaved and 20 ~l of a solution of a sensitising agent, 5~ w/v 4-ethoxymethylene-2-phenyl-2-oxazolin-;-one S (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 10name Tween 80, in sterile water (100 ~l). 100 ~l of the same suspension was injected likewise every 24 hours for a further 7 days. The dosages used were selected from the following values: 50, 30, 10, 3, 1, 0.3, 0.1, 0.03 or 0.01 mg/kg.

15Two 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 ul of a solution of 1% w/v oxazolone in acetone: olive oil (3:1 by volume) was applied to one ear (the challenged ear) of each of the test mice and the control mice. (A more potent challenge dose of 1.5% w/v oxazolone in acetone:olive oil was employed in a few cases). After 24 hours the thickness of the challenged ear and the thickness of the non-challenged ear of the same animal were measured with an engineer's screw gauge micrometer. The difference in thickness between the challenged ear and the non-challenged ear in each animal is a measure of the response of that animal to oxazolone. A comparison between the response of mice treated with the test compound and mice treated with the control indicates the effectiveness of the test compound as an immunomodulatory agent. The compounds were considered to be active at a particular dose if a WO 91tll4~ PCT/EPg1~001 - ~ 23 20% or greater reduction in ear swelling, which was statistically significant (p <0.05) according to Dunnett's test, between treated and control groups was obtained in at least two out of three CH tests, (or, where more than three tests have been carried out, a majority of the tests) at that dose (see for example Int. Arch. Allergy, 38, p246-259 (1970)).

Each of the compounds of formula I illustrated in Table A below was active at 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) numbe~ or numbers listed adjacent to each compound indicates the process or processes illustrating the preparation of that compound in the Examples.

WQ91/11448 PCT/EP91/O01~
2 ~ 124 -Table A

_ Compound Name Minimum Effective Dose (mq/kg) 77 4-methyl-2-(5-trifluoromethyl-2-pyridyl)[l]benzopyrano[4,3-c]pyrazol-3(2H)-one 3 -1078 2-(5-chloro-2-pyridyl)-4-methyl[1]-benzopyrano~4,3-c]pyrazol-3(2H)-one 3 79 2-(6-chloro-2-pyridyl)-4-methyl[l]-benzopyrano[4,3-c]pyrazol-3(2H)-one 50 4-methyl-2-~6-trifluoromethyl-2-pyridyl)-[l]benzopyrano[4,3-clpyrazol-3(2H)-one S0 81 2-(4-chloro-2-pyridyl)-4-methyl~l]- ~3 benzopyrano[4,3-c]pyrazol-3(2H)-one 82 2-(6-chloro-5-trifluoromethyl-2- 3 pyridyl)-4-methyl[l]benzopyrano[4,3-c]pyrazol-3(2H)-one 83 2-(5-bromo-2-pyridyl)-4-methyl[1]- 50 benzopyrano[4,3-c]pyrazol-~(2H)-one 84 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)[l]benzopyrano[4,3-c]pyrazol-3(2H)-one WO91/1lM8 PCT/EP9ltO0154 - 12; -_ Compound Name Minimum Effective Dose (m~/kq) 86 2-(S-chloro-2-pyridyl)-8-fluoro-4- 50 methyl[l]benzopyrano[4,3-c]pyrazol-3(2H)-one 87 2-(5-chloro-2-pyridyl)-4-methylthio- 50 methyl[ 11 benzopyrano[4,3-c]pyrazol-3(2H)-one 88 ethyl 2-(;-chloro-2-pyridyl)-3-oxo-2,3-dihvdro[l]benzopyrano[4,3-c]-pyrazole-4-acetate ~3(a) 89 2-(5-chloro-2-pyridyl)-4-methyl-3- ~3(a) oxo-2,3-dihydro[l]benzopyrano~4,3-c~pyrazol-9-yl acetate 90 2-(5-chloro-2-pyridyl)-3-oxo-2,3- 50 dihydro[l]benzopyrano[4,3-c]pyrazole-4-acetate WO91~11448 PCT/EP91/001 f~ ~c ~ 'I ~ ~ ~
_ Compound Name Minimum Effective Dose (mg/kq) 91 2-piperidinoethyl 2-(4-chlorophenyl)- 50 3-oxo-2,3-dihydro~l]benzopyrano[4,3-c~-py~azole-4-acetate hydrochloride 0.4 hydrate 92 3-(4-methyi-1-piperazinyl)propyl 2-(4- 50 chlorophenyl)-3-oxo-2,3-dihydro[l]-benzopyranol4,3-c]pyrazole-4-acetate 2.5 hy~-ochloride dihydrate 93 2-morpholinoethyl 2-(4-chlorophenyl)-3- ~3 oxo-2,3-dihydro[l]benzopyrano[4,3-c]-pyrazole-4-acetate hydrochloride hemihydrate 94 2-morpholinoethyl 2-(3,4-dichloro- ~<S0 phenyl)-3-oxo-2,3-dihydro[1]benzo-pyrano[4,3-c]pyrazole-4-acetate 95 2-morpholinoethyl 2-(4-chlorophenyl)- ;0 8-hydroxy-3-oxo-2,3-dihydro[l]benzo-pyrano[4,3-c]pyrazole-4-acetate 96 3-morpholinopropyl 2-(4-ch~orophenyl)- ~3 3-oxo-2,3-dihydro[1]benzopyrano[4,3-cl-pyrazole-4-acetate hydrochloride monohydrate 97 2-morpholinoethyl 2-(4-bromophenyl)-3- ~50 oxo-2,3-dihydro[l]benzopyrano[4,3-c]-pyrazole-4-acetate hydrochloride hemi-hydrate WO91/114~ PCT/EPgl/00154 - 127 - F~ .., . .. `~. _ 1.

_ Compound Name Minimum Effective Dose (mq/kg) 98 2-morpholinoethyl 2-(4-fluorophenyl)- ~50 3-oxo-2,3-dihydro[l]benzopyrano[4,3-c]pyrazole-4-acetate hydrochloride 99 2-morpholinoethyl 2-(4-chlorophenyl)- ~50 8-fluoro-3-oxo-2,3-dihydro[11benzo-pyrano[4,3-c3pyrazole-4-acetate hydrochloride 0.4 hydrate 100 2-morpholinoethyl 2-~4-chlorophenyl)- 50 9-methoxy-3-oxo-2,3-dihydro[l]benzo-pyrano[4,3-c]pyrazole-4-acetate hydrochloride 101 4-methoxybenzyl 2-(4-chlorophenyl)-3- ~1 oxo-2,3-dihydro[l]benzopyrano[4,3-c]-pyrazole-4-acetate 102 benzyl 2-(4-chlorophenyl)-3-oxo-2,3- ~3 dihydro[l]benzopyrano[4,3-c]pyrazole-4-acetate 103 phenethyl 2-(4-chlorophenyl)-3-oxo-2,3- ~3 dihydro[l]benzopyrano[4,3-c1pyrazole-4-acetate 104 cyclopentvl 2-(4-chlorophenyl)-3-oxo- ~3 2,3-dihydro[l]benzopyrano[4,3-c]-pyrazole-4-acetate _ Compound N2me Minim~m Effective Dos e (mg~kq) 105 2-methoxyethyl 2-(4-chlorophenyl)-3- ~3 oxo-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[l]benzopyrano[4,3-cl-pyrazole-4-acetate 107 cyclobutylmethyl 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 lS 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[l]benzo-pyrano[4,3-c]pyrazole-4-ace~tate 111 tetrahydrofurfuryl 2-(4-chlorophenyl)- ~3 3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]-pyrazole-4-acetate 112 tetrahydro-2H-pyran-4-yl 2-(4-chloro- ~<3 phenyl)-3-oxo-2,3-dihydro[l]benzo-pyrano[4,3-c]pyrazole-4-acetate --WO91/114~ PCT/EP91/001 Ex Compound Name Minimum Ef f ective Dose (mq/kq) 113 2-(4-methyl-5-thiazolyl)ethyl 2-(4- ~3 chlorophenyl)-3-oxo-2,3-dihydro~l]-benzopyrano~4,3-c]pyrazole-4-acetate 114 3-methoxybenzyl 2-(4-chlorophenyl)-3- ~3 oxo-2,3-dihydro[1~benzopyrano[4,3-cl-pyrazole-4-acetate 11; 4-methylbenzyl 2-(4-chlorophenyl)-3- ~3 oxo-2,3-dihydro[l]benzopyrano[4,3-cl-pyrazole-4-acetate 116 4-methoxyphenethyl 2-(4-chlorophenyl)- ~3 3-oxo-2,3-dihydro[1]benzopyrano[4,3-c~-pyrazole-4-acetate 117 4-chlorophenethyl 2-(4-chlorophenyl)- ~3 3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]-pyrazole-4-acetate 118 2-chlorobenzyl 2-(4-chlorophenyl)- ~S0 3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]-pyrazole-4-acetate 119 3-oxobutyl 2-(4-chlorophenyl)-3-oxo- ~S0 2,3-dihydro[l]benzopyrano[4,3-c]-pyrazole-4-acetate 120 2-chlorophenethyl 2-(4-chlorophenyl)- ~50 3-oxo-2,3-dihydro[l]benzopyrano[4,3-c]-pyrazole-4-acetate WO gl/11448 PCr/EP91/01''154 _ Compound Name Minimum Effective Dose (mq/kq) t21 3-methylphenethyl 2-(4-chlorophenyl)- ~50 3-oxo-2,3-dihydro[1]benzopyrano~4,3-c7-pyrazole-4-acetate 122 cyclohexyl 2-(4-chlorophenyl)-3-oxo- ~50 2,3-dihydro~1~benzopyrano~4,3-c~-pyrazole-4~acetate 123 3-chlorobenzyl 2-(4-chlorophenyl)-3- ~;o oxo-2,3-dihydro~l~benzopyrano~4,3-c]-pyrazole-4-acetate 124 3-hydroxypropyl 2-(4-chlorophenyl)-3- 50 oxo-2,3-dihydrott]benzopyranot4,3-c]-pyrazole-4-acetate 125 2-phenoxyethyl 2-(4-chlorophenyl)- ~<50 3-oxo-2,3-dihydrotl]benzopyrano-[4,3-c]pyrazole-4-acetate 126 4-dimethylaminophenethyl 2-(4-chloro- ~50 phenyl)-3-oxo-2,3-dihydrotl]benzo-pyranot4,3-c]pyrazole-4-acetate 127 2-acetamidoethyl 2-(4-chlorophenyl)-3- ~S0 oxo-2,3-dihydro~l]benzopyrano[4,3-c]-pyrazole-4-acetate 128 3-methylbenzyl 2-(4-chlorophenyl)-3- ~50 oxo-2,3-dihydrotl]benzopyrano~4,3-c]-pyrazole-4-acetate WO91/11~ PCT/EP91/001 ,~ 7 - 131 - : ~

Ex Com~ound Name Minimum -Effective Dose ~mq/kq) 129 2-methylbenzyl 2-(4-chlorophenyl)-3- ~50 axo-2,3-dihydro[l]benzopvrano~4,3-c]-pyrazole-4-acetate 130 4-chlorobenzyl 2-(4-chlorophenyl)-3- ~S0 oxo-2,3-dihydro[l]benzopyrano[4,3-c]-pyrazole-4-acetate 131 2-methoxybenzyl 2-(4-chlorophenyl)- ~50 3-oxo-2,3-dihydro[l]benzopyrano[4,3-c]pyrazole-4-acetate 132 3-(3-pyridyl)propyl 2-(4-chlorophenyl)- ~50 3-oxo-2,3-dihydro[llbenzopyrano[4,3-c]-pyrazole-4-acetate 133 a-methylphenethyl 2-(4-chlorophenyl)- ~50 3-oxo-2,3-dihydro[l]benzopyrano[4,3-c~pyrazole-4-acetate 134 cyclopropylmethyl 2-(4-chlorophenyl)-3- ~3 oxo-2,3-dihydro[l]benzopyrano[4,3-c]-pyrazole-4-acetate 135 cyclobutylmethyl 3-oxo-2-(4-trifluoro- ~50 methylphenyl)-2,3-dihydro[l]benzopyrano-14,3-c]pyrazole-4-acetate 136 cyclobutylmethyl 2-(4-chlorophenyl)-8- ~S0 methyl-3-oxo-2,3-dihydro[l~benzopyrano-[4,3-c]pyrazole-4-acetate : ' ' :

WO 91/11448 PCr/l:Pgl/00154 ~ . . , , _ .~, Ex Compound Name Minimum Effective Dose (mg/kg) 5 137 cyclobutylmethyl 2-(4-methoxyphenyl)- ~50 3-oxo-2,3-dihydro[l]benzopyrano[4,3-c]-pyrazole-4-acetate 138 cyclobutylmethyl 2-(4-methylphenyl)-3- ~50 oxo-2,3-dihydro[l]benzopyrano[4,3-c]-pyrazole-4-acetate 139 cyclobutylmethyl 2-(3-chlorophenyl)-3- ~50 oxo-2,3-dihydro[1]benzopyrano[4,3-c]-pyrazole-4-acetate 140 cyclobutylmethyl 2-~4-chlorophenyl)-9- ~50 hydroxy-3-oxo-2,3-dihydro[l]benzopyrano-[4,3-c]pyrazole-4-acetate 142 2-acetoxyethyl 2-(4-chlorophenyl)-3- ~3 oxo-2,3-dihydro[l]benzopyrano[4,3-c]-pyrazole-4-acetate 143 2-hydroxyethyl 2-(4-chlorophenyl)-3- ~3 oxo-2,3-dihydro[l]benzopyrano[4,3-c]-pyrazole-4-acetate 144 2-thiomorpholinoethyl 2- (4-chloro- ~3 phenyl)-3-oxo-2,3-dihydro[l]benzo-pyrano[4,3-c]pyrazole-4-acetate hydrochloride 145 2-methylthioethyl 2-(4-chlorophenyl)- ~c3 3-oxo-2,3-dihydro[l]benzopyrano[4,3-c]-pyrazole-4-acetate WO91/11448 PCT/EP91/001;4 - 133 - ~ ~ A `~

_ Compound Name Minimum Effective Dose (mg/kq) 146 4,4,4-trifluorobutyl 2-(4-chloro- 50 phenyl)-3-oxo-2,3-dihydro[1]benzo-pyrano[4,3-c]pyrazole-4-acetate 147 2-cyanoethyl 2-(4-chlorophenyl)-3-oxo- ~3 2,3-dihydro[1]benzopyrano[4,3-c]-pyrazole-4-acetate l48 2-ethoxycarbonylethyl 2-(4-chloro- 50 phenyl)-3-oxo-2,3-dihydro[1]benzo-pyrano[4,3-c]pyrazole-4-acetate 149 B-methylphenethyl 2-(4-chlorophenyl)- ~50 3-oxo-2,3-dihydro[1]benzopyrano~4,3-c]pyrazole-4-acetate 150 2-cyclohexylethyl 2-(4-chlorophenyl)-3- ~3 oxo-2,3-dihydro[1]benzopyrano[4,3-c]-pyrazole-4-acetate 151 1-methyl-2-morpholinoethyl 2-(4-chloro- 50 phenyl)-3-oxo-2,3-dihydro[1]benzo-pyrano[4,3-c]pyrazole-4-acetate 152 1-methyl-2-piperidylmethyl 2-(4- So chlorophenyl)-3-oxo-2,3-dihydro[1]-benzopyrano[4,3-c]pyrazole-4-acetate 153 2-morpholinoethyl 2-(4-chlorophenyl)- 50 3-oxo-l,2,3,4-tetrahydro[1]benzopyrano-[4,3-c]pyrazole-4-acetate - ,.
,. . .

WO91/11448 PCTJEP9l/00~4 - ~34 -Ex Co~Dound Name Minimum ~f f ective Dose (mg/kg) 154 3-acetoxypropyl 2-(4-chlorophenyl)-3- ~50 oxo-2,3-dihydro[13benzopyrano[4,3-c]-pyrazole-4-acetate lSS 2-~4-chlorophenyl)-N-methyl-3-oxo-2,3- 50 dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetanilide l56 N-benzyl-2-(4-chlorophenyl)-N-methyl-3- 50 oxo-2,3-dihydro[llbenzopyrano[4,3-c]-pyrazole-4-acetamide 157 2-(4-chlorophenyl)-N-methyl-N-~2- S0 lS morpholinoethyl)-3-oxo-2,3-dihydro[tl-benzopyrano(4,3-clpyrazole-4-acetamide 158 2-(4-chlorophenyl)-N-methyl-3-oxo-N- 50 (3-pyridylmethyl)-2~3-dihydro[l]-benzopyrano~4,3-c]pyrazole-4-acetamide lS9 2-(4-chlorophenyl)-N-ethyl-3-oxo-N- 3 phenyl-2,3-dihydro[l~benzopyrano-[4,3-c]pyrazole-4-acetamid~

160 N-benzyl-2-(4-bromophenyl)-N-methyl- 50 3-oxo-2,3-dihydro[l]benzopyrano[4,3-c~-pyrazole-4-acetamide ~_ WO 91/11448 PCI/EP9l/00154 - 135 - ~ ~

Ex ComDound Name Minimum .
Effective Dose (mq/kg) 161 N-benzyl-2-(3,4-dichlorophenyl)-N- 50 methyl-3-oxo-2,3-~ihydro[1]benzopyrano-[4,3-c]pyrazole-4-acetamide 162 N-benzyl-2-(4-chlorophenyl)-8-fluoro- 50 N-methyl-3-oxo-2,3-dihydro[l]benzo-pyrano[4,3-c]pyrazole-4-acetamide 163 2-t4-chlorophenyl)-N-methyl-3-oxo-N- 50 phenethyl-2,3-dihydro[1]benzopyrano-[4,3-c]pyrazole-4-acetamide 164 2-(4-chlorophenyl)-N-(2-cyanoethyl)-N- 50 methyl-3-oxo-2,3-dihydro[1]benzo-pyrano[4,3-c]pyrazole-4-acetamide 165 2-(4-chlorophenyl)-N,N-(3-oxapenta- 50 methylene)-3-oxo-2,3-dihydro[l]benzo-pyrano[4,3-c]pyrazole-4-acetamide 166 4'-chloro-2-(4-chlorophenyl)-N-methyl- 50 3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]-pyrazole-4-acetanilide 167 N-benzyl-2-(4-fluorophenyl)-N-methyl- 50 3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetamide 168 2-(4-chlorophenyl)-N-(1,3-dioxolan-2- 50 ylmethyl)-N-methyl-3-oxo-2,3-dihydro-[l]benzopyrano[4,3-c]pyrazole-4-acetamide Ex Compound Name Minlmum Ef f ective Dose (mq/kg) 169 methyl 4-[2-(4-chlorophenyl)-N-methyl- 50 3-oxo-2,3-dihydro[l]benzopyrano~4,3-c]-pyrazole-4-acetamido]benzoate 170 2-1~-t2-(4-chlorophenyl)-3-oxo-2,3- 50 dihydro[l]benzopyrano[4,3-c]pyrazole-4-acetyl]piperazin-1 -yl3 ethyl acetate 171 2-14-[2-t4-chlorophenyl)-3-oxo-2,3- 50 dihydro[l]benzopyrano[4,3-c]pyrazole-4-acetyl]piperazin-1-yl~ethyl propionate 172 N , N- ( 3-oxapentamethylene)-3-oxo-2- ~50 (4-trifluoromethylphenyl)-2,3-dihydro[1]benzothiopyrano[4,3-c~-pyrazole-4-acetamide 173 N-ethyl-3-oxo-N-phenyl-2-(4-tri- ~50 fluoromethylphenyl)-2,3-dihydro[l]-benzothiopyrano[4,3-c]pyrazole-4-acetamide 174 methyl 5-[2-(4-chlorophenyl) -3-oxo- S0 2,3-dihydro[l]benzopyrano[4,3-c]-pyrazol-4-yl]-4-oxopentanoate 175 2-(4-chlorophenyl)-4-(2-oxo-3-phenyl- 50 propyl)[l]benzopyrano[4,3-c]pyrazol-3t2H)-one . .

.
..

. WO91/11448 PCT/EP91/001 - ~37 -_ Compound Name Minimum Effective Dose Img/kq) 176 2-(4-chlorophenyl)-4-(2-oxo-3-phenoxy- 3 propyl)[l1benzopyrano[4,3-c]pyrazol-3(2H~-one l77 2-(4-chlorophenyl)-4-(2-cyclohexyl-2- 50 oxoethyl)[l]benzopyrano[4,3-c]pyrazol-3(2H)-one 178 2-(4-chlorophenyl)-4-~2-cyclopropyl-2- S0 oxoethyl)[l]benzopyrano[4,3-c]pyrazol-3(2H)-one 179 2-(4-chlorophenyl)-4-[4-(4-methoxv- ~50 lS phenyl)-2-oxobutyl][l]benzopyrano[4,3-c]pyrazol-3~2H)-one 180 4-I3-(4-chlorophenoxy)-2-oxopropyl]- ~3 2-(4-chlorophenyl)[l]benzopyrano[4,3-c]pyrazol-3(2H)-one 181 2-(4-chlorophenyl)-4-[4-(3-methyl- ~So phenyl)-2-oxobutyl][l]benzopyrano-[4,3-c]pyrazol-3(2H)-one l82 2-(4-chlorophenyl)-4-(3-cyclopentyl- ~50 2-oxopropyl)[l]benzopyrano[4,3-c~-pyrazol-3(2H)-one 183 2-(4-chlorophenyl)-4-[3-(2-methyl- ~50 phenoxy)-2-oxopropyl][l]benzopyrano-[4,3-c]pyrazol-3(2H)-one , .

, WO91/114~ PCT/EP91/00]~
%r.~ ~".~ - 138 -Ex Compound Name Minimum Effective Dose (mq/kg) 184 2-(4-chlorophenyl)-4-(4-methylthio-2- ~50 oxobutyl)El]benzopyrano[4,3-c~pyrazol-3(2H)-one -185 2-(3,4-dichlorophenyl)-4-(2-oxo-3- ~so phenoxypropyl)[llbenzopyrano[4,3-c]-pyrazol-3(2H)-one 186 2-(4-chlorophenyl)-4-(3-methoxy-2-oxo- ~3(a) propyl)[1lbenzopyrano[4,3-c]pyrazol-3-(2H)-one 187 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- ~3 dihydro[l]benzopyrano[4,3-c]pyrazol-9-yl methyl malonate 188 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- ~1 dihydro~1]benzopyrano[4,3-c]pyrazol-8-yl ethyl malonate 189 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- ~3(a) dihydro[l]benzopyrano[4,3-c]pyrazol-8-yl methoxyacetate 190 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[1]benzopyrano[4,3-c]pyrazol-8-yl cyclopropanecarboxylate 191 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- ~C3 dihydro[1]benzopyrano[4,3-c]pyrazol-8-yl l-adamantanecarboxylate .

- 139 ~

Ex Compound_Name Minimum Effective Dose (mg/kq) 192 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[l]benzopyrano[4,3-c~pyrazol-8-yl 3-phenylpropionate 193 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[l]benzopyrano[4,3-clpyrazol-8-yl phenylacetate 194 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[1]benzopyrano[4,3-c]pyrazol-8-yl 2-methoxybenzoate 195 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[1]benzopyrano[4,3-c]pyrazol-8-yl 2-furoate l96 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- S0 dihydro~1]benzopyrano[4,3-c]pyrazol-8-yl 2-thenoate 197 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- ~3 dihydro[l]benzopyrano[4,3-c]pyrazol-8-yl cyclobutanecarboxylate 198 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- ~S0 dihydro[1]benzopyrano[4,3-c]pyrazol-8-yl 2-methylbenzoate 199 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- ~<50 dihydro[1]benzopyrano[4,3-c]pyrazol-8-yl 4-chlorobenzoate WO91/11448 PCT/EP91/0~-~
2~ o Ex ComDound Name Minimum Effective Dose (mg/kq) 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[l]benzopyrano[4,3-c]-pyrazol-8-yl 4-methoxybenzoate 202 2-(4-chlorophenyl)-4-methyl-3-oxo- ~S0 2,3-dihydro[1]benzopyrano[4,3-c]-pyrazol-8-yl 4-methylbenzoate 203 2-(4-chlorophenyl)-4-methyl 3-oxo- S0 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]pyrazol-8-yl 3-methylbenzoate 206 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- ~50 dihydro[1]benzopyrano[4,3-c]pyrazol-8-yl isonicotinate 207 Ethyl 2-(4-chlorophenyl)-3-oxo-8- 50 phenylacetoxy-2,3-dihydro[l]benzo-pyrano~4,3-c]pyrazole-4-acetate . Wo 91/ll448 PCI`~EP91/00154 ~x Compound Name Minimum Effective Dose (mg/kg) 208 Ethyl 2-(4-chlorophenyl)-8-methoxy- 50 acetoxy-3-oxo-2,3-dihydro[1]-benzopyrano[4,3-c]pyrazole-4-acetate 0.3 methoxyacetic acid solvate 209 2-(4-chlorophenyl)-4-ethoxycarbonyl- 50 methyl-3-oxo-2,3-dihydro~l]benzopyrano-[4,3-c]pyrazol-8-yl methyl succinate 210 4-methyl-3-oxo-2-(4-trifluoromethyl- ~50 phenyl)-2,3-dihydro[1]benzopyrano-[4,3-clpyrazol-8-yl acetoxyacetate 211 2-(4-bromophenyl)-4-methyl-3-oxo-2,3- ~<50 dihydro[l]benzopyrano[4,3-c]pyrazol-a-yl acetoxyacetate 212 2-(3,4-dichlorophenyl)-4-methyl-3- ~So oxo-2,3-dihydroll]benzopyrano[4,3-c~pyrazol-8-yl methoxyacetate 213 2-(3,4-dichlorophenyl)-4-methyl-3- ~S0 oxo-2,3-dihydro[1]benzopyrano[4,3-c]-pyrazol-8-yl 3-(methylthio)propionate 214 2-(3,4-dichlorophenyl)-4-methyl-3- 50 oxo-2,3-dihydro[llbenzopyrano[4,3-c]-pyrazol-8-yl acetoxyacetate 215 2-(3,4-dichlorophenyl)-4-methyl-3- ~<50 oxo-2,3-dihydro[1]benzopyrano[4,3-c]-pyrazol-8-yl methyl succinate WO 91/11448 PCl'/EP91/001~4 f~i~ ,A~ ~,"7 ~
Ex Compound Name Minimum Effective Dose (mq/k~) 216 2-(4-chlorophenyl)-4-methyl-3-oxo- 50 2,3-dihydro[l]benzopyrano[4,3-c]-pyrazol-9-yl methoxyacetate 217 cyclobutylmethyl 9-acetoxyacetoxy-2- ~50 (4-chlorophenyl)-3-oxo-2,3-dihydro[l]-benzopyrano~4,3-c]pyrazole-4-acetate 218 cyclobutylmethyl 8-acetoxyacetoxy-2- ~50 (4-chlorophenyl)-3-oxo-2,3-dihydro[l]-benzopyrano[4,3-c]pyrazole-4-acetate 0.5 hydrate, 0.35 acetoxyacetic acid solvate 219 Isopropyl 8-acetoxyacetoxy-2-(4- ~50 chlorophenyl)-3-oxo-2,3-dihydro[l]-benzopyrano[4,3-clpyrazole-4-acetate 0.2 hydrate, 0.5 acetoxyacetic acid solvate 220 2-(4-chlorophenyl)-4-methyl-3-oxo-,2,3- ~3 dihydro[llbenzopyrano[4,3-c]pyrazol-9-yl methyl succinate 221 2-~4-chlorophenyl)-4-methyl-3-oxo-2,3- ~1 dihydro~l]benzopyrano[4,3-c]pyrazol-8-yl methyl succinate 222 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- ~1 dihydro[l]benzopyrano[4,3-c]pyrazol-8-yl acetoxyacetate WOsltl1448 PCT/EP91/001 P;-J
Ex Compound Name Minimum Effective Dose (mq/kq) 223 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 3 dihydro[l]benzopyrano[4,3-c]pyrazol-8-yl 3-(methylthio)propionate 224 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[l]benzopyrano[4,3-c]pyrazol-8-yl ethyl succinate 225 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 3 dihydrol1]benzopyrano[4,3-c]pyrazol-8-yl benzoate 226 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- So dihydro[1]benzopyrano[4,3-c]pyrazol-9-yl benzoate 227 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[l]benzopyrano[4,3-c]pyrazol-8-yl nicotinate 228 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[l]benzopyrano[4,3-c]pyrazol-8-. yl 4-methoxybenzyl malonate 229 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[l]benzopyrano[4,3-c]pyrazol-8-yl hydrogen malonate 230 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- ~3 dihydro[l]benzopyrano[4,3-c]pyrazol-8-yl dimethylaminoacetate WO91/11448 PCT/EP91/001'~

o~ .. , ~ ...... ....
~x Compound Name Minimum Effective Dose ~mq/kg) 231 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 50 dihydro[l]benzopyrano[4,3-c]pyrazol-8-yl (methylthio)acetate 232 ethyl 8-acetoxyacetoxy-2-(4-chloro- 3 phenyl)-3-oxo-2,3-dihydro[l]benzo-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[l]benzothio-pyrano[4,3-c]pyrazol-8-yl ethyl malonate 234 2-(3,4-dichlorophenyl)-3a-methyl-3- ~3 oxo-2,3,3a,4-tetrahydro[l]benzothio-pyrano[4,3-c]pyrazol-8-yl methoxyacetate 235 2-(3,4-dichlorophenyl)-3a-methyl-3- ~3 oxo-2,3,3a,4-tetrahydro[l]benzothio-pyrano[4,3-c]pyrazol-8-yl acetoxy-acetate 236 2-(3,4-dichlorophenyl)-3a-methyl-3- ~3 oxo-2,3,3a,4-tetrahydro~l]benzothio-pyrano~4,3-clpyrazol-8-yl phenyl-acetate 237 2-~3,4-dichlorophenyl)-3a-methyl-3- ~1 oxo-2,3,3a,4-tetrahydro[l]benzothio-pyrano[4,3-c]pyrazol-8-yl benzoate ,--WO91/11448 PCT/EP91/O01 - 145 ~

_ Compound Name Minimum Effective Dose (mq/kg) 238 2-(3,4-dichlorophenyl)-3a-methyl-3- ~1 oxo-2,3,3a,4-tetrahydro[l]benzothlo-pyrano[4,3-c]pyrazol-8-yl methyl succinate 239 2-(3,4-dichlorophenyl)-3a-methyl-3- ~50 oxo-2,3,3a,4-tetrahydro[1lbenzothio-pyrano[4,3-c]pyrazol-8-yl crotonate 240 2-(3,4-dichlorophenyl)-3a-methyl-3- ~50 oxo-2,3,3a,4-tetrahydro[1]benzothio-pyrano[4,3-c]pyrazol-8-yl propionate 241 2-(3,4-dichlorophenyl)-4-methyl-3- S0 oxo-2,3-dihydro[l]benzothiopyrano-[4,3-c]pyrazol-8-yl acetoxyacetate 242 3a-methyl-3-oxo-2-(4-trifluoromethyl- ~50 phenyl)-2,3,3a,4-tetrahydro[l]benzo-thiopyrano[4,3-c]pyrazol-8-yl acetoxy-acetate 243 2-(4-chlorophenyl)-3a-methyl-3-oxo- ~50 2,3,3a,4-tetrahydro[l]benzothiopyrano-~4,3-c]pyrazol-8-yl methoxyacetate 244 2-~4-fluorophenyl)-3a-methyl-3-oxo-2,3, ~50 3a,4-tetrahydro[1]benzot..iopyrano[4,3-c]-pyrazol-8-yl acetoxyacetate WO91/114~ PCT/EPsl~oo~

_ Compound Name Minimum Ef f ective Dose (mq/kq) 245 Ethyl 2-(4-fluorophenyl)-3a-methyl-3- ~50 oxo-2,3,3a,4-tetrahydro[l]benzothiopyrano-[4,3-c]pyrazol-8-yl malonate 246 3a-methyl-3-oxo-2-(4-trifluoromethyl- ~3 phenyl)-2,3,3a,4-tetrahydro[l~benzothio-pyrano[4,3-c~pyrazol-8-yl methoxy-acetate 247 2-(4-fluorophenyl)-3a-methyl-3-oxo- 50 2,3,3a,4-tetrahydro[l]benzothiopyrano-[4,3-c]pyrazol-8-yl methoxyacetate 248 2-(4-chlorophenyl)-3a-methyl-3-oxo- ~S0 2,3,3a,4-tetrahydro[l]benzothiopyrano-[4,3-c]pyrazol-8-yl acetoxyacetate 249 Ethyl 3a-methyl-3-oxo-2-(4-trifluoro- ~50 methylphenyl)-2,3,3a,4-tetrahydro[l]-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[l]benzothio-pyrano[4,3-c]pyrazol-8-yl malonate Notes:
(a) Active in each of two tests at 3 mg/kg O91/11~ PCT/EP91/00154 _ 147 -The compounds of the present invention also showactivity 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 immunity by assaying the sera collected at the end of the oxazolone induced cutaneous hypersensitivity test desc~ibed above (cu test) for changes in the amount of anti-oxazolone antibody produced, and a Graft versus Host tes. similar to that used by Smith S R, Terminelli C, Klpilman C T and Smith Y,, J. Immunopharmacology 1981;3(2),133-17Q.

For example, the compounds prepared in the following E~amples were also found to be active in the above-described antibody test after parenteral administration at 50 mgtkg. A compound was deemed to be active, if at a dose of 50 mg/kg it caused a decrease in the relative se~um 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.(Cl) - O.D.(Tl) O.D.(Cl) - O.D.~C2) where O.D.(Cl) is the optical density of the control serum at a dilution of 1~128 O.D.(C2) is the optical density of the control serum at a dilution of l/256 O.D.(Tl) is the optical density of the test serum at a dilution of 1/128 , ~J ~ 148 -The control and test sera were diluted with phosphate buffered saline (pH 7.3) containing 0.05%
v/v Tween 20 (trade name).

Compounds active in above test:

Examples 77-79, 81-137, 139-140, 142-159, 161, 164, 166-7, 169-197, 199-240, 242-251, - ~ WO91/11~ PCT/EP91/001 - 149 ~

The following compounds were active at or below 50 mg/kg as defined herein and were prepared in an analogous manner to those described herein:

Ex Compound Name Melting Point(C) 258 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 115-188 dihydro[1]benzopyrano[4,3-c]pyrazol-~- (dec) yl 4-morpholinomethylbenzoate 259 methyl 5-[3-oxo-2-(4-trifluoromethyl- 140-143 phenyl)-2,3-dihydro[l~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]benzothiopyrano-[4,3-c]pyrazol-8-yl 3-methylbenzoate 263 ethyl 2-(5-chloro-2-pyridyl)-8-hydroxy- 258-265 3-oxo-2,3-dihydro f 1 ] benzopyrano[4,3-c]- (dec) pyrazole-4-acetate WO 91/11448 PCI~/EP91~001 `~
2 ~ 150 -Ex Compound Name Melting Point ( C) 264 2-~2-methylpiperidino)ethyl 2-(4-chloro- 210-213 phenyl)-3-oxo-2,3-dihydro[1]benzopyrano-[4,3-c]pyrazole-4-acetate hydrochloride 265 2-[4,5-bis(trifluoromethyl)-2-pyridyl]- 235-238 4-methyl[1~benzopyrano[4,3-c]pyrazol-3(2H)-one 266 2-(5-chloro-2-pyridyl)-N-ethyl-3-oxo- 181-184 N-phenyl-2,3-dihydro[1]benzopyrano[4,3-c~pyrazole-4-acetamide 267 cyclobutylmethyl 2-(5-chloro-2-pyridyl)- 157-160 3-oxo-2,3-dihydro~l]benzopyrano[4,3-c]-pyrazole-4-acetate 268 4-[3-~3-chlorophenoxy)-2-oxopropyl]-2- 193-195 ~4-chlorophenyl)[1]benzopyrano[4,3-c]-pyrazol-3(2H)-one 269 4-[3-~2-chlorophenoxy)-2-oxopropyl]-2- 215-217 (4-chlorophenyl)[1]benzopyrano[4,3-c]-pyrazol-3(2H)-one 270 2-(4-chlorophenyl)-4-methyl- 3-oxo- 2,3- 153-156 dihydro[l]benzopyrano[4,3-c]pyrazol-8-yl 4-(4-methylpiperazin-1-ylmethyl)-benzoate hydrochloride hydrate 271 4-methoxybenzyl 2-(3,4-dichlorophenyl)- 188-190 3-oxo-2,3-dihydro[l]benzothiopyrano-~4,3-c~pyrazole-4-acetate WO 91/11448 PCI'/EP91/00154 Ex Compound Name Melting Point(C) 272 2-acetoxyacetoxyethyl 2-(4-chloro- 131 phenyl)-3-oxo-2,3-dihydro[1]benzopyrano-[4,3-c~pyr~zole-4-acetate 273 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 147-151 dihydro[1]benzopyrano[4,3-c]pyrazol-8-yl 4-diethylaminomethylbenzoate 274 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 305-310 dihydro[l]benzopyrano[4,3-c]pyrazol-8- (dec) yl glycinate (0.9) hydrochloride 275 4-(2-oxo-3-phenylpropyl)-2-(4-trifluoro- 173-175 methylphenyl)[l]benzothiopyrano[4,3-c]-pyrazol-3(2H)-one 276 4-methoxybenzyl 3-oxo-2-(4-trifluoro- 137-138 methylphenyl)-2,3-dihydro[l]benzothio-pyrano[4,3-c]pyrazole-4-acetate 277 2-(5-chloro-2-pyridyl)-9-methoxy-4- 254-256 methyl[1]benzopyrano[4,3-c]pyrazol-3(2H)-one 278 2-(4-chlorophenyl)-4-(4-methyl- 221-223 sulphonyl-2-oxobutyl)[1]benzopyrano-[4,3-c]pyrazol-3(2H)-one 279 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3- 192-193 Zihydro[l]benzopyrano[4,3-c]pyrazol-8-yl tert-butoxycarboxamidoacetate . .

WO91/1l448 pcT/Epsl/
~,?~ - 152 -Ex Compound Names Melting Point ( C) 280 4-[3-(4-methoxyphenyl)-2-oxopropyl]- 184-187 2-(4-trifluoromethylphenyl)[l]-benzothiopyrano~4,3-c]pyrazol-3(2H)-one 281 2-(4-chlorophenyl)-4-[3-(4-methoxy- 17B-180 phenyl)-2-oxopropyl][l]benzopyrano-[4,3-c]pyrazol-3t2H)-one 282 2-(3,4-dichlorophenyl)-3a-methyl-3- 141-142 oxo-2,3,3a,4-tetrahydro[1]benzothio-pyrano~4,3-c]pyrazol-8-yl 4-methoxy-benzoate 283 2-(3,4-dichlorophenyl)-3a-methyl-3- 189-190 oxo-2,3,3a,4-tetrahydro(l]benzothio-pyrano[4,3-c~pyrazol-8-yl 2-furoate 284 2-(3,4-dichlorophenyl)-3a-methyl-3- 170-173 oxo-2,3,3a,4-tetrahydro[l]benzothio-pyrano[4,3-c]pyrazol-8-yl 4-chloro-: 20 benzoate 285 2-(3,4-dichlorophenyl)-3a-methyl-3- 97-99 oxo-2,3,3a,4-tetrahydro[l]benzothio-pyrano[4,3-c]pyrazol-8-yl 3-(methyl-thio)propionate 286 2-(2-thienyl)ethyl 3-oxo-2-(4-trifluoro- 144-146 methylphenyl)-2,3-dihydro[l]benzothio-pyrano~4,3-c]pyrazole-4-acetate \

-WO91/114~ PCT/EPgl/001 _ 153 - ~ ~ ~ ~ r -~

Ex Compound Name Melting Point(C) 288 4-(2-oxo-3-phenoxypropyl)-2-(4- 205-208 trifluoromethylphenyl)[l]benzothio-pyrano[4,3~c]pyrazol-3(2~)-one 289 2-methoxyethyl 3-oxo-2-(4-trifluoro- 134-137 methylphenyl)-2,3-dihydro[l]benzothio-pyrano[4,3-c]pyrazole-4-acetate 290 2-morpholinoethyl 3-oxo-2-(4-tri- 154-156 fluoromethylphenyl)-2,3-dihydro[l]-benzothiopyrano[4,3-c]pyrazole-4-acetate 291 4-(3-methoxy-2-oxopropyl)-2-(4-tri- 148-150 fluoromethylphenyl)[l~benzothiopyrano-[4,3-c]pyrazol-3(2H)-one 292 4-[2-oxo-3-t2-thienyl)propyl]-2-(4- 169-179 trifluoromethylphenyl)~l]benzothio-pyrano[4,3-c]pyrazol-3(2H)-one 293 Tetrahydro-2H-pyran-4-yl 3-oxo-2-(4- 172-175 trifluoromethylphenyl)-2,3-dihydro[l]-benzothiopyrano[4,3-c]pyrazole-4-acetate 294 2-(3,4-dichlorophenyl)-3a-methyl-3- 123-126 oxo-2,3,3a,4-tetrahydro[l]benzothio-pyrano[4,3-c]pyrazol-6-yl propionate 295 2-(3,4-dichlorophenyl)-3a-methyl-3- 113 oxo-2,3,3a,4-tetrahydro[l]benzothio-pyrano[4,3-c]pyrazol-6-yl acetoxyacetate :.

.: ~
"~

WO91~114~ PCT/EP91/OO
~"r~ 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]-pyrazol-3 (2H) -one 297 2-(4-chlorophenyl)-N-cyclopropyl-N- 160-l62 cyclopropylmethyl-3-oxo-2,3-dihydro-~1]benzopyrano[4,3-c]pyrazole-4-acetate 298 2-(4-chlorophenyl)-4-[4-(2-chloro- 166-l68 phenyl)-2-oxobutyl][l]benzopyrano-[4,3-c]pyrazol-3(2H)-one 299 Cyclobutylmethyl 2-(4-chlorophenyl)- l64-l66 6-methoxy-3-oxo-2,3-dihydro[llbenzo-pyrano[4,3-c]pyrazole-4-acetate lS 300 N-Benzyl-2-(4-chlorophenyl)-N-cyclo- l97-199 pentyl-3-oxo-2,3-dihydro[l]benzo-pyrano[4,3-c]pyrazole-4-acetamide 301 2-(5-Chloro-2-pyridyl)-6,8-difluoro- 218-223 4-methyl[1]benzopyrano[4,3-c]pyrazol-3(2H)-one 302 Ethyl 4-methyl-3-oxo-2-(4-trifluoro- 146-147 methylphenyl)-2,3-dihydro[l]benzo-thiopyrano[4,3-c[pyrazol-8-yl malonate

Claims (27)

Claims

1. A compound of formula 1 I

in which X represents oxygen, or sulphur;

when X represents oxygen or sulphur R1 represents hydrogen or together with R2 represents a bond; R2 together with either one of R1 and R3 represents a bond; R3 together with either one of R2 and R4 represents a bond; R4 represents hydrogen or together with R3 represents a bond;

or when X represents sulphur, R1 and R2 represent a bond, R3 represents methyl and R4 and R5 represent hydrogen;
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 - R6, 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:

R7 represents hydrogen, halo, trifluoromethyl, C1-6 alkyl, methoxy or S(O)mY1;

R8 represents hydrogen, halo or trifluoromethyl;

R8, represents hydrogen, halo or trifluoromethyl;

R9 and R10, 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 heterocylic 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 heterocylic 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 m is 0 or 1;

or a pharmaceutically acceptable salt thereof;
provided that:

I) when X is oxygen, Z is -CH= and:

a) R6 represents C1-6 dialkylcarbamoyl, then R10 represents a carboxylic acyloxy group other than acetoxy; or b) when R6 represents hydrogen, halo, S(O)nY1, carbamoyl, carboxy, C2-6 alkoxycarbonyl, C2-6 alkanoyl or when R6 and R6, together with the carbon atom to which they are attached form cylopropyl then R10 represents a carboxylic acyloxy group other than C2-6 alkanoyloxy; or c) when R1 and R2 form a bond, R3 and R4 form a bond, R6', R8, R8', R9 and R10 each represent hydrogen, R7 represents chloro, then R6 does not represent 4-methoxybenzyloxycarbonyl; or II) When X is sulphur and a) R3 represents methyl; or b) R6 represents hydrogen, carboxy, S(O)nY1, C2-6 alkoxycarbonyl, carbamoyl, or C1-6 dialkylcarbamoyl, then R10 represents a carboxylic acyloxy group other than acetoxy.

2. A compound according to claim 1 represented by formula II

II

in which R6'represents hydrogen.

3. A compound according to either one of claims 1 and 2 wherein R6 represents CO2(CH2)pJ in which p is 0-3 and J represents cyano, hydroxy, C3-8 cycloalkyl, C2-6 alkanoyloxy, C2-6 alkoxycarbonyl, C1-6 alkoxy, C1-6 alkoxy(C1-6)alkoxy, C1-6 alkylthio, or J represents a 5 or 6 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen; a 5 or 6 membered aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen or a carbocyclic aryl group, each of which groups is optionally substituted by C1-6 alkyl, C1-6 alkoxy or halo.

4. A compound according to either one of claims 1 and 2 wherein R6 represents CO2NR12R13 in which R12 represents ethyl and R13 represents phenyl.

5. A compound according to either one of claims 1 and 2 wherein R6 represents COCH2K in which K represents C1-4 alkoxy or phenoxy.

6. A compound according to any one of claims 1 to 5 in which R10 represents hydrogen, hydroxy, halo, C1-6 alkoxy or C1-6 alkyl.

7. A compound according to any one of the preceding claims in which R10 represents OCO(CH2)pL in which p is 0-3 and L represents hydrogen, C3-11 cycloalkyl;
di(C1-6 alkyl)amino; C2-6 alkanoyloxy; C2-6 alkoxy-carbonyl, C1-6 alkylthio; C1-6 alkoxy; adamantyl or phenyl optionally substituted by C1-6 alkyl, C1-6 alkoxy or halo.

8. A compound according to claim 7 in which R10 is substituted in the 8- or 9- position.

9. A compound according to either one of claims 7 and 8 in which R6 represents hydrogen or C2-6 alkoxycarbonyl and R6' represents hydrogen.

10. A compound according to claim 1 represented by formula IV

IV

in which R7 represents halo or trifluoromethyl, R8 represents hydrogen or halo, R8, represents hydrogen or halo and R9 represents hydrogen.

11. A compound according to claim 1 represented by formula V

V

in which R6' represents hydrogen, R14 represents OR15, R16 or NR12R13 in which R12 represents methyl or ethyl, R13 represents C1-6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen, a 5 or 6 membered heterocyclic aryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur or nitrogen or R13 represents phenyl optionally substituted by C2-6 alkoxycarbonyl or halo; or R12 and R13 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 C2-6 acyloxy(C1-6)alkyl group; and R15 and R16, which may be the same or different, represent optionally substituted groups selected from C1-6 alkyl; C2-6 alkenyl; C3-10 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; R9 represents hydrogen and R10 represents hydrogen, hydroxy, halo, C1-6 alkoxy or C1-6 alkyl.

12. A compound according to claim 1 represented by formula VI

VI

in which R6' represents hydrogen, R14 represents OR15, R16 or NR12R13 in which R12 represents methyl or ethyl, R13 represents C1-6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen, a 5 or 6 membered heterocyclic aryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur or nitrogen or R13 represents phenyl optionally substituted by C2-6 alkoxycarbonyl or halo, or R1- and R13 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(C1-6)alkyl group; and R15 and R16, which may be the same or different, represent optionally substituted groups selected from C1-6 alkyl; C2-6 alkenyl; C3-10 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; R9 represents hydrogen. and R10 represents hydrogen, hydroxy, halo, C1-6 alkoxy or C1-6 alkyl.

13. A compound according to claim 1 represented by formula VII

VII

in which R6' represents hydrogen and R6 represents hydrogen, C2-6 alkoxycarbonyl or C1-6 alkylthio, R17 represents optionally substituted groups selected from C1-6 alkyl: C2-6 alkenyl; C3-11 cycloalkyl; a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen; phenyl; a 5 or 6 membered heterocyclic aryl group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen.

14. A compound according to claim 1 represented by formula VIII

VIII

in which R17 represents optionally substituted groups selected from C1-6 alkyl, C2-6 alkenyl, C3-10 cyclo-alkyl, a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen; phenyl; a 5 or 6 membered heterocyclic aryl group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen.

15. A compound according to any one of claims 1-6 represented by formula IX

IX

in which R6, represents hydrogen or methyl; R6 represents hydrogen, halo, C2-6 alkanoyl, C2-6 alkoxy-carbonyl, S(O)nY1, carbamoyl, carboxy or R5 and R6 together with a carbon atom to which they are attached represent cyclopropyl; R7 represents hydrogen, halo, trifluoromethyl, methoxy, C1-6 alkyl, S(O)mY1; R8 represents hydrogen, halo or trifluoromethyl; R8, represents hydrogen, halo or trifluoromethyl; R9 and R10, which may be the same or different, each represent halo; or R9 represents hydrogen and R10 represents hydrogen, halo, trifluoromethyl, hydroxy, nitro, C2 6 alkanoyloxy, C1-6 alkyl or C1-6 alkoxy.

16. A compound selected from:-cyclobutylmethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 2-hydroxyethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate 2-thiomorpholinoethyl 2-(4-chlorophenyl)-3-oxo-2,3-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 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[1]-benzopyrano[4,3-c]pyrazol-8-yl dimethylamino acetate Ethyl 8-acetoxyacetoxy-2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazol-4-acetate 2-(4-chlorophenyl)-4-methyl-3-oxo-2,3-dihydro[1]-benzopyrano[4,3-c]pyrazol-8-yl ethyl malonate 2-(3,4-dichlorophenyl)-3a-methyl-3-oxo-2,3,3a,4-tetrahydro[1]benzothiopyrano[4,3-c]pyrazol-8-yl methoxy acetate.

17. A pharmaceutical composition comprising a compound of formula I

I

in which X represents oxygen or sulphur;

when X represents oxygen or sulphur R1 represents hydrogen or together with R2 represents a bond; R2 together with either one of R1 and R3 represents a bond; R3 together with either one of R2 and R4 represents a bond; R4 represents hydrogen or together with R3 represents a bond;

or when X represents sulphur, R1 and R2 represent a bond, R3 represents methyl and R4 and R5 represent hydrogen;

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 when R3 represents a bond together with either one of R2 and R4;

R6 represents hydrogen, halo, S(O)nY1 , carboxy, carbamoyl, 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;

R7 represents hydrogen, halo, trifluoromethyl, C1-6 alkyl, methoxy or S(O)mY;

R8 represents hydrogen, halo or trifluoromethyl;

R8' represents hydrogen, halo or trifluoromethyl;

R9 and R10, 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, or ethyl or C3-8 cycloalkyl and R13 represents C1-6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic 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 with to which they are attached represent a 3-8 membered non-aromatic heterocylic 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 m is 0 or 1 or a pharmaceutically acceptable salt thereof, provided that:

I) when X is oxygen, Z is -CH= and:

a) R6 represents C1-6 dialkylcarbamoyl, then R10 represents a carboxylic acyloxy group other than acetoxy; or b) when R6 represents hydrogen, halo, S(O)nY1, carbamoyl, carboxy, C2-6 alkoxycarbonyl, C2-6 alkanoyl or when R6 and R6, together with the carbon atom to which they are attached form cylopropyl then R10 represents a carboxylic acyloxy group other than C2-6 alkanoyloxy;

II) When X is sulphur, Z is -CH=, and a) R3 represents methyl: or b) R6 represents hydrogen, carboxy, S(O)nY1, C2-6 alkoxycarbonyl, carbamoyl or C1-6 dialkylcarbamoyl, then R10 represents a carboxylic acyloxy group other than acetoxy.

18. A pharmaceutical composition according to claim 17 in unit dosage form.

19. A method of treating diseases with an immunological association in a mammal in need of such treatment comprising the administration of a therapeutically effective amount of a compound of formula I as defined in claim 17.

20. A compound of formula 1 as defined in claim 17 for use as an immunomodulatory agent.

21. A compound of formula X

in which R7, R8, R8', R9 and R10 are as defined in claim 1 and Z is nitrogen.

22. A compound of formula XIV

XIV

in which R3, R5 and R9 are as defined in claim 1 and R10 represents a carboxylic acyloxy group, R29 represents carbamoyl or COOR30 and R30 represents C1-4 alkyl or benzyl.

23. A process to prepare a compound of formula 1 I

in which X represents oxygen or sulphur;

R1 together with R2 represents a bond; R3 together with R4 represents a bond;

Z represents -CH= or -N= when X represents oxygen;

Z represents -CH= when X represents sulphur;

R5 represents , 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;

R7 represents hydrogen, halo, trifluoromethyl, C1 6 alkyl, methoxy or S(O)mY1, R8 represents hydrogen, halo or trifluoromethyl;

R8, represents hydrogen, halo or trifluoromethyl;

R9 and R10, 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 heterocylic 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 heterocylic 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 m is 0 or 1;
or a pharmaceutically acceptable salt thereof;
provided that:

I) when X is oxygen, Z is -CH= and:

a) R6 represents C1-6 dialkylcarbamoyl, then R10 represents a carboxylic acyloxy group other than acetoxy; or b) when R6 represents hydrogen, halo, S(O)nY1, carbamoyl, carboxy, C2-6 alkoxycarbonyl, C2-6 alkanoyl or when R6 and R6, together with the carbon atom to which they are attached form cylopropyl then R10 represents a carboxylic acyloxy group other than C2-6 alkanoyloxy; or c) when R1 and R2 form a bond, R3 and R4 form a bond, R6 " R8, R8 " R9 and R10 each represent hydrogen, R7 represents chloro, then R6 does not represent 4-methoxybenzyloxycarbonyl; or II) When X is sulphur and R6 represents hydrogen, carboxy, S(O)nY1, C2-6 alkoxycarbonyl, carbamoyl, or C1-6 dialkylcarbamoyl, then R10 represents a carboxylic acyloxy group other than acetoxy:-a) comprising oxidising a compound of formula I in which R1 represents hydrogen, R2 and R3 represent a bond and R4 represents hydrogen and X, Z, R5, R7, R8, R8', R9 and R10 are as herein defined;

b) comprising reacting a compound of formula X

or a tautomer thereof, with a compound of formula XI

XI

in which R22 represents (OQ)2 and R23 represents OQ or NQ'2; or R22 represents (SQ)2 and R23 represents SQ or NQ'2; or R22 represents =NH and R23 represents OQ or SQ; or R22 represents =0 and R23 represents a leaving group and Q and Q' represent a C1-4 alkyl group or a benzyl group;

c) in which R6 is selected from a carboxylic acyl group comprising reacting a compound of formula X

X

with a compound of formula XIIa XIIa or a tautomer thereof, or a compound of formula XIIb XIIb or a tautomer thereof, in which R16 represents an optionally substituted group selected from C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, a 3-8 membered non-aromatic heterocyclic group, a carbocyclic aryl group or a S or 6 membered heterocyclic aryl group and R24 and R25 which may be the same or different, represent a C1-6 alkyl group or a benzyl group;

d) comprising reacting a compound of formula XIII

XIII

in which R26 represents hydrogen or a tautomer thereof, or in which R26 represents a group COR28 in which R28 represents hydrogen, an optionally substituted C1-4 alkyl group or benzyl and R27 represents COCHR6R6., with a base.

24. A process to prepare a compound of formula 1 I

in which X represents oxygen or sulphur;

R1 represents hydrogen; R2 together with R3 represents a bond; R4 represents hydrogen;

Z represents -CH= or -N= when X represents oxygen;

Z represents -CH= when X represents sulphur;

R5 represents , 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;

R7 represents hydrogen, halo, trifluoromethyl, C1-6 alkyl, methoxy or S(O)mY1;

R8 represents hydrogen, halo or trifluoromethyl;

R8' represents hydrogen, halo or trifluoromethyl;

R9 and R10, 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 heterocylic 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 heterocylic 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 m is 0 or 1;
or a pharmaceutically acceptable salt thereof;
provided that:

I) when X is oxygen, Z is -CH= and:

a) R6 represents C1-6 dialkylcarbamoyl, then R10 represents a carboxylic acyloxy group other than acetoxy; or b) when R6 represents hydrogen, halo, S(O)nY1, carbamoyl, carboxy, C2-6 alkoxycarbonyl, C2-6 alkanoyl or when R6 and R6' together with the carbon atom to which they are attached form cylopropyl then R10 represents a carboxylic acyloxy group other than C2-6 alkanoyloxy; or II) When X is sulphur and R6 represents hydrogen, carboxy, S(O)nY1, C2-6 alkoxycarbonyl, carbamoyl, or C1-6 dialkylcarbamoyl, then R10 represents a carboxylic acyloxy group other than acetoxy:-a) comprising reducing a compound of formula wherein R7 and R2 represents a bond; R3 and R4 represent a bond; and R5, R7, R8, R8', R9 and R10 are as herein defined; or b) comprising reacting a compound formula XIV

XIV

in which R3 represents hydrogen, R5 represents CHR6R6', R29 represents COOR30 or carbamoyl and R30 represents a C1-4 alkyl group or a benzyl group with a compound of formula XV

XV

25. A process to prepare a compound of formula I

I

in which X represents sulphur, R1 and R2 represent a bond, R3 represents methyl and R4 and R5 represent hydrogen;

Z represents -CH=;

R7 represents hydrogen, halo, trifluoromethyl, C1-6 alkyl, methoxy or S(O)mY1;

R8 represents hydrogen, halo or trifluoromethyl;

R8, represents hydrogen, halo or trifluoromethyl;

R9 and R10, 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 heterocylic 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 heterocylic 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 m is 0 or 1;
or a pharmaceutically acceptable salt thereof, provided that R10 represents a carboxylic group other than acetoxy, comprising reacting a compound of formula XIV

XIV

in which R3 represents methyl, X represents S, R5 represents hydrogen R29 represents COOR30 or carbamoyl and R30 represents a C1-4 alkyl group or a benzyl group with a compound of formula XV

XV

n which Z represents -CH=.

26. A process to prepare a compound of formula I

I

in which X represents oxygen or sulphur;
when X represents oxygen or sulphur R1 represents hydrogen or together with R2 represents a bond; R2 together with either one of R1 and R3 represents a bond; R3 together with either one of R2 and R4 represents a bond; R4 represents hydrogen or together with R3 represents a bond;

or when X represents sulphur, R1 and R2 represent a bond, R3 represents methyl and R4 and R5 represent hydrogen;
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 , 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;

R7 represents hydrogen, halo, trifluoromethyl, C1-6 alkyl, methoxy or S(O)mY1;

R8 represents hydrogen, halo or trifluoromethyl;

R8, represents hydrogen, halo or trifluoromethyl, R9 and R10, 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 heterocylic 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 heterocylic 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 m is 0 or 1;

or a pharmaceutically acceptable salt thereof;
provided that:

I) when X is oxygen, Z is -CH= and:

a) R6 represents C1-6 dialkylcarbamoyl, then R10 represents a carboxylic acyloxy group other than acetoxy; or b) when R6 represents hydrogen, halo, S(O)nY1, carbamoyl, carboxy, C2-6 alkoxycarbonyl, C2-6 alkanoyl or when R6 and R6' together with the carbon atom to which they are attached form cylopropyl then R10 represents a carboxylic acyloxy group other than C2-6 alkanoyloxy; or c) when R1 and R2 form a bond, R3 and R4 form a bond, R6', R8, R8', R9 and R10 each represent hydrogen, R7 represents chloro, then R6 does not represent 4-methoxybenzyloxycarbonyl; or II) When X is sulphur and a) R3 represents methyl; or b) R6 represents hydrogen, carboxy, S(O)nY1, C2-6 alkoxycarbonyl, carbamoyl, or C1-6 dialkylcarbamoyl, then R10 represents a carboxylic acyloxy group other than acetoxy:-a) in which R5 represents -CHR6R6' and R6 is selected from CONR12R13 or an esterified carboxyl group, comprising reacting a compound of formula I' I' in which R10' represents R10, R5 represents -CHRaR6,, Ra represents COA and A represents a leaving group, with an amine of formula NHR12R13 or an alcohol of formula R150H in which R15 represents an optionally substituted group selected from C1-6 alkyl, C2-6 alkenyl, C3-10 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 R10 is selected from a carboxylic acyloxy group comprising reacting a compound of formula I' I' or R5 represents , 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;

R7 represents hydrogen, halo, trifluoromethyl, C1-6 alkyl, methoxy or S(O)mY1;

R8 represents hydrogen, halo or trifluoromethyl;

R8, represents hydrogen, halo or trifluoromethyl;

R9 and R10, 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 or ethyl and R13 represents C1-6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group; 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 in which R5 represents -CHRaR6,, Ra represents R6 and R10' represents hydroxy with an acylating agent.

27. A compound of formula 1 I

in which X represents oxygen or sulphur;

when X represents oxygen or sulphur R1 represents hydrogen or together with R2 represents a bond; R2 together with either one of R1 and R3 represents a bond; R3 together with either one of R2 and R4 represents a bond; R4 represents hydrogen or together with R3 represents a bond;

or when X represents sulphur, R1 and R2 represent a bond, R3 represents methyl and R4 and R5 represent hydrogen;

Z represents -CH=;

R5 represents hydrogen when R3 represents methyl, heterocylic 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 m is O or l;
or a pharmaceutically acceptable salt thereof;
provided that:

I) when X is oxygen and:

a) R6 represents C1-6 dialkylcarbamoyl, then R10 represents a carboxylic acyloxy group other than acetoxy; or b) when R6 represents hydrogen, halo, S(O)nY1, carbamoyl, carboxy, C2-6 alkoxycarbonyl, C2-6 alkanoyl or when R6 and R6, together with the carbon atom to which they are attached form cyclopropyl then R10 represents a carboxylic acyloxy group other than C2 6 alkanoyloxy; or c) when R1 and R2 form a bond, R3 and R4 form a bond, R6 " R8, R8,, R9 and R10 each represent hydrogen, R7 represents chloro, then R6 does not represent 4-methoxybenzyloxycarbonyl; or II) When X is sulphur and a) R3 represents methyl; or b) R6 represents hydrogen, carboxy, S(O)nY1, C2-6 alkoxycarbonyl, carbamoyl, or C1-6 dialkylcarbamoyl, then R10 represents a carboxylic acyloxy group other than acetoxy.