WO1991011448A1 - Agents therapeutiques - Google Patents

Agents therapeutiques Download PDF

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Publication number
WO1991011448A1
WO1991011448A1 PCT/EP1991/000154 EP9100154W WO9111448A1 WO 1991011448 A1 WO1991011448 A1 WO 1991011448A1 EP 9100154 W EP9100154 W EP 9100154W WO 9111448 A1 WO9111448 A1 WO 9111448A1
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WIPO (PCT)
Prior art keywords
group
halo
hydrogen
represents hydrogen
alkyl
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PCT/EP1991/000154
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English (en)
Inventor
Roger Bernard Titman
Michael Henry Hockley
Onkar Singh Gill
Original Assignee
The Boots Company Plc
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Publication date
Priority claimed from GB909002315A external-priority patent/GB9002315D0/en
Priority claimed from GB909002314A external-priority patent/GB9002314D0/en
Priority claimed from GB909002425A external-priority patent/GB9002425D0/en
Application filed by The Boots Company Plc filed Critical The Boots Company Plc
Priority to KR1019920701838A priority Critical patent/KR927003599A/ko
Priority to BR919105984A priority patent/BR9105984A/pt
Publication of WO1991011448A1 publication Critical patent/WO1991011448A1/fr
Priority to FI923486A priority patent/FI923486A0/fi
Priority to NO92923037A priority patent/NO923037L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel therapeutic agents, and in particular to [1]benzopyrano[4,3-c]- pyrazoles or [1]benzothiopyrano[4,3-c]pyrazoles, to processes for their preparation, to pharmaceutical compositions containing them and to their therapeutic activity as immunomodulatory agents.
  • the present invention relates to compounds of formula I
  • R 1 represents hydrogen or together with R 2 represents a bond
  • R 2 together with either one of R 1 and R 3 represents a bond
  • R 3 together with either one of R 2 and R 4 represents a bond
  • R 4 represents hydrogen or together with R 3 represents a bond
  • R 1 and R 2 represent a bond
  • R 6 represents hydrogen, halo, S(O) n Y 1 , carboxy, carbamoyl, a carboxylic acyl group, an esterified carboxyl group or CONR 12 R 13 ;
  • R 6 represents hydrogen or methyl; or R 6 and R 6 , together with the carbon atom to which they are attached represent cyclopropyl;
  • R 7 represents hydrogen, halo, trifluoromethyl, C 1 -6 alkyl, methoxy or S(O) m Y 1 ;
  • R 8 represents hydrogen, halo or trifluoromethyl
  • R 8 represents hydrogen, halo or trifluoromethyl
  • R 9 and R 10 which may be the same or different, represent halo; or R 9 represents hydrogen and R 10 represents hydrogen, halo, trifluoromethyl, nitro, C 1 -6 alkyl, C 1 -6 alkoxy, hydroxy or a carboxylic acyloxy group;
  • R 12 represents methyl, ethyl or C 3 -8 cycloalkyl and R 13 represents C 1 -6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group or C 3 -8 cycloalkyl; or R 13 represents phenyl optionally substituted by C 2 -6 alkoxycarbonyl or halo; or R 12 and R 13 together with the nitrogen to which they are attached represent a 3-8 membered non-aromatic heterocylic group which may be substituted by C 2 -6 acyloxy(C 1 -6 ) alkyl;
  • Y 1 represents C 1 -6 alkyl
  • n 0, 1 or 2 and m is 0 or 1 which have immunmodulatory activity.
  • the first PCT patent application described above also discloses 4-methoxybenzyl 2-(4-chlorophenyl)-3- oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate as an intermediate compound without any therapeutic activity.
  • R 1 represents hydrogen or together with R 2 represents a bond
  • R 2 together with either one of R 1 and R 3 represents a bond
  • R 3 together with either one of R 2 and R 4 represents a bond
  • R 4 represents hydrogen or together with R 3 represents a bond
  • R 1 and R 2 represent a bond
  • R 5 represents hydrogen when R 3 represents methyl. or R 5 represents CH - R 6 '
  • R 6 represents hydrogen, halo, S(O) n Y 1 , carboxy, carbamoyl, a carboxylic acyl group, an esterified carboxyl group or CONR 12 R 13 ;
  • R 6 represents hydrogen or methyl; or R 6 and R 6 , together with the carbon atom to which they are attached represent cyclopropyl;
  • R 7 represents hydrogen, halo, trifluoromethyl, C 1 -6 alkyl, methoxy or S(O) m Y 1 ;
  • R 8 represents hydrogen, halo or trifluoromethyl
  • R 8 represents hydrogen, halo or trifluoromethyl
  • R 9 and R 10 which may be the same or different, represent halo
  • R 9 represents hydrogen and R 10 represents hydrogen, halo, trifluoromethyl, nitro, C 1 -6 alkyl, C 1 -6 alkoxy, hydroxy or a carboxylic acyloxy group;
  • R 12 represents methyl, ethyl or C 3 -8 cycloalkyl and R 13 represents C 1 -6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocylic group, a 5 or 6 membered heterocyclic aryl group or C 3 -8 cycloalkyl; or R 13 represents phenyl optionally substituted by C 2 -6 alkoxycarbonyl or halo; or
  • R 12 and R 13 together with the nitrogen to which they are attached represent a 3-8 membered non-aromatic heterocylic group which may be substituted by C 2-6 acyloxy (C 1 -6 ) alkyl;
  • Y 1 represents C 1 -6 alkyl
  • R 6 represents C 1 -6 dialkylcarbamoyl, then R 10 represents a carboxylic acyloxy group other than acetoxy; or b) when R 6 represents hydrogen, halo, S(O) n Y 1 , carbamoyl, carboxy, C 2-6 alkoxycarbonyl, C 2-6 alkanoyl or when R 6 and R 6 , together with the carbon atom to which they are attached form cylopropyl then R 10 represents a carboxylic acyloxy group other than C 2 -6 alkanoyloxy; or c) when R 1 and R 2 form a bond, R 3 and R 4 form a bond, R 6' , R 8 , R 8 ,, R 9 and R 10 each represent hydrogen, R 7 represents chloro, then R 6 does not represent 4-methoxybenzyloxycarbonyl;
  • R 3 represents methyl; or b) R 6 represents hydrogen, carboxy, S(O) n Y 1 , C 2-6 alkoxycarbonyl, carbamoyl or C 1 -6 dialkylcarbamoyl, then R 10 represents a carboxylic acyloxy group other than acetoxy.
  • R 10 represents a carboxylic acyloxy group other than acetoxy.
  • 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 includes n-butyl, sec-butyl, isobutyl and tert-butyl.
  • halo includes fluoro, chloro or bromo.
  • R 1 and R 2 form a bond and R 3 and R 4 form a bond, as represented by formula II
  • R 6 , R 6 ,, R 7 , R 8 , R 8 ', R 9 and R 10 are as herein- above defined.
  • R 1 represents hydrogen
  • R 2 and R 3 form a bond
  • R 4 represents hydrogen, as represented by formula III
  • R 6 , R 6 ,, R 7 , R 8 , R 8 ,, R 9 and R 10 are as hereinabove defined.
  • R 2 form a bond
  • R 4 and R 5 represent hydrogen, as represented by formula IV and R 7 , R 8 , R 8 ,, R 9 and R 10 are as herein defined. Preferred substituents are as given hereinafter. More preferably R 7 represents halo or trifluoromethyl, R 8 represents hydrogen or halo, R 8 ' represents hydrogen or halo and R 9 represents hydrogen.
  • R 6 ' represents hydrogen
  • the group R 6 may be an esterified carboxyl group, a carboxylic acyl group or certain tertiary carboxamide groups. These groups may be represented by the formula
  • R 14 represents an alkoxy group (for example C 1 -6 ); an alkenyloxy group (for example C 2 -6 ); a cycloalkoxy group (for example C 3-10 ); an oxygen atom attached to a non-aromatic heterocyclic group; a carbocyclic aryloxy group; a heterocyclic aryloxy group; an alkyl group (for example C 1 -6 ); an alkenyl group (for example C 2 -6 ); a cycloalkyl group (for C 3-10 ); a non-aromatic heterocyclic group; a carbocylic aryl group; or a heterocyclic aryl group each of the groups being optionally substituted.
  • R 14 represents an alkoxy group (for example C 1 -6 ); an alkenyloxy group (for example C 2 -6 ); a cycloalkoxy group (for example C 3-10 ); an oxygen atom attached to a non-aromatic heterocyclic group; a carbocycl
  • esters and amides as defined herein are included within the scope of the present invention as well as those which are less readily hydrolysable. Also included are certain tertiary carboxamido groups. Some compounds of formula I may contain a substituted acetyl group in the 4-position of the ring system. In certain preferred compounds of formula I the group R 6 may have the formula a) -CO.OR 15
  • R 12 represents methyl, ethyl or C 3 -8 cycloalkyl and R 13 represents C 1 -6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non- aromatic heterocyclic group, a 5 or 6 membered heterocyclic aryl group or R 13 represents phenyl optionally substituted by C 2 -6 alkoxycarbonyl or halo; or R 12 and R 13 together with the nitrogen to which they are attached represent a 3-8 membered non-aromatic heterocyclic group which may be substituted by C 2-6 acyloxy (C 1 -6 )alkyl; R 15 and R 16 represent C 1 -6 alkyl; C 2 -6 alkenyl; C 3 -10 cycloalkyl; a 3-8 membered non-aromatic hetero ⁇ yclic group, a phenyl group or a 5 or 6 membered heterocyclic aryl group; each of the groups
  • Z represents Z 1 , Z 2 , phenyl, a 3-8 membered non- aromatic heterocyclic groiap (preferably containing one or two heteroatoms selected from oxygen, sulphur or nitrogen), a 5-6 membered heterocyclic aryl group (preferably containing one to three heteroatoms selected from oxygen, sulphur or nitrogen), each group being optionally substituuted by Z 1 or Z 2 ;
  • Z 1 represents halo, trifluoromethyl, hydroxy, carboxy or cyano;.
  • Z 2 represents C 1 -6 alkyl, C 3-10 cycloalkyl,
  • NHCOY 2 or NHSO 2 Y 2 and each may be further substituted by Z.
  • Y 2 and Y 2 which may be the same or different, each represent hydrogen, C 1 -6 alkyl or phenyl;
  • R 18 and R 19 which may be the same or different, each represent hydrogen; C 1 -6 alkyl; C 3-10 cycloalkyl, C 2 -6 alkenyl; a carbocyclic aryl group; a 3-8 membered non-aromatic heterocyclic group; a 5 or 6 membered heterocyclic aryl group; or R 18 and R 19 together with the nitrogen to which they are attached form a 3-8 membered non-aromatic heterocyclic group.
  • suitable substituents in compounds of formula I, suitable substituents
  • R 6 include the following:
  • Y 1 is preferably C 1 -4 alkyl and n represents 0, 1 or 2 (for example methylthio, ethylthio, propylthio, methylsulphinyl, ethylsulphinyl, propylsulphonyl), more preferably Y 1 is C 1 -2 alkyl, most preferably methyl; suitably n is 0 or 1 and preferably 0.
  • R 6 represents hydrogen or C 2 -6 alkoxycarbonyl.
  • R 6 together with R 6 , and the carbon to which they are attached may form cyclopropyl.
  • R 6 also includes CONR 12 R 13 in which R 12 represents methyl or ethyl and R 13 represents C 1 -6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocyclic group containing one or two heteroatoms selected from oxygen, sulphur or nitrogen, a 5 or 6 membered heterocyclic aryl group containing one to three heteroatoms selected from oxygen, sulphur or nitrogen; or R 13 represents phenyl optionally substituted by C 2-6 alkoxycarbonyl (for example methoxycarbonyl) or halo (for example chloro); or R 12 and R 13 together with the nitrogen to which they are attached form a 3-8 membered non-aromatic heterocyclic group which may contain a further heteroatom selected from oxygen, sulphur or nitrogen which may be substituted by a C 2-6 acyloxy (C 1 -6 ) alkyl group (for example propionyloxyethyl).
  • R 12 represents methyl
  • R 6 also includes a carboxylic ester group, which is preferably represented by the formula -CO.
  • R 15 represents C 1 -6 alkyl; C 2 -6 alkenyl;' C 3-10 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.
  • R 15 represents C 1 -6 alkyl, C 3-8 cycloalkyl, a 5-7 membered non-aromatic heterocyclic group containing one or two Heteroatoms selected from oxygen, sulphur or nitrogen; a phenyl group; a 5 or 6 membered heterocyclic aryl ring containing one or two heteroatoms selected from oxygen, sulphur or nitrogen, each group being optionally substituted by Z.
  • PreferabIy R 6 also represents a carboxylic acyl group which is preferably represented by the formula
  • R 16 represents C 1 -6 alkyl; C 2-6 alkenyl; C 3-10 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.
  • R 16 represents C 1 -6 alkyl, C 3 -8 cycloalkyl, a 5-7 membered non-aromatic heterocyclic group containing one or two heteroatoms selected from oxygen, sulphur or nitrogen; a phenyl group; a 5 or 6 membered heterocyclic aryl ring containing one or two heteroatoms selected from oxygen, sulphur or nitrogen, each group being optionally substituted by Z.
  • Z represents Z 1 or Z 2 .
  • Z 1 represents halo (fluoro, chloro or bromo), more preferably fluoro or chloro, most preferably chloro; hydroxy or cyano;
  • Z 2 represents the following: C 1 -6 alkyl, preferably C 1 -4 alkyl (for example methyl, ethyl or propyl), more preferably methyl or ethyl and most preferably methyl; C 3-7 cycloalkyl, preferably
  • Y 1 is preferably C 1 -4 alkyl and m represents 0, 1 or 2, (for example methylthio, ethylthio, propylthio, methylsulphinyl, ethylsulphinyl, propylsulphinyl, methylsulphonyl, ethylsulphonyl, propylsulphonyl), more preferably Y 1 is C 1 -2 alkyl, most preferably methyl, suitably m is 0 or 1 and pre-ferably 0; C 2-5 alkoxycarbonyl (for example methoxycarbonyl or ethoxycarbonyl); C 2 -5 alkanoyl (for example acetyl or propionyl); or C 2 -5 alkanoyloxy (for example acetoxy or propionyl); or C 2 -5 alkanoyloxy (for example acetoxy or propionyl);
  • R 6 include: hydrogen, carboxy or -CO.R 14 in which R 1 4 is as defined above.
  • Preferred esterified carboxyl groups R 6 include:
  • C 2-6 alkoxycarbonyl for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or pentyloxycarbonyl
  • C 3 -8 cycloalkoxycarbonyl for example cyclobutoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl
  • tetrahydro-2H-pyran-4-yloxy- carbohyl each of which groups may be substituted by: C 1 -6 alkyl (for example methyl); C 3-8 cycloalkyl (for example cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl); phenyl; a 3-8 membered non-aromatic heterocyclic group containing one or two heteroatoms selected from nitrogen, oxygen or sulphur, (for example tetrahydrofuryl, tetrahydropyranyl, morpholino, piperidino
  • C 2-6 alkanoyloxy for example acetoxy
  • cyano, hydroxy, acetamido, trifluoromethyl, halo The optional C 1 -6 alkoxy substituent may further be substituted with C 1 -6 alkoxy (for example methoxy) or C 2 -6 alkanoyloxy
  • the optional phenyl, non- aromatic heterocyclic group or aromatic heterocyclic group substituent may further be substituted by C 1 -6 alkyl (for example methyl), C 1 -6 alkoxy (for example methoxy), halo (for example chloro).
  • p is 1 or 2.
  • Particularly preferred substituents R 6 also include a carboxylic acyl group which may be C 3 -8 cycloalkylcarbonyl (for example cyclopropylcarbonyl, cyclohexylcarbonyl); or C 2 -6 alkanoyl (for example acetyl, propionyl, butyryl, pentanoyl, hexanoyl), which may be substituted with phenyl or phenoxy each optionally substituted by halo, C 1 -4 alkyl, or C 1 -4 alkoxy; or C 2 -6 alkanoyl may be substituted with C 2 -6 4lkoxycarbonyl (for example methoxycarbonyl), C 2-6 alkoxy (for example methoxy), C 1-4 alkylthio (for example methylthio), C 3-8 cycloalkyl (for example cyclopentyl).
  • C 3 -8 cycloalkylcarbonyl for example cyclopropylcarbonyl,
  • R 6 represents COCH 2 k in which k represents C 1-4 alkoxy or phenoxy.
  • R 6 may also include the group CONR 12 R 13 in which R 12 represents methyl or ethyl, preferably methyl, and R 13 includes phenyl or C 1 -4 alkyl (more preferably methyl or ethyl, and most preferably methyl) substituted with phenyl. Most preferably R 12 represents ethyl and R 13 represents phenyl.
  • Especially preferred substituents include hydrogen;
  • R 7 include the following:
  • R 8 represents hydrogen, fluoro, chloro or trifluoromethyl, more preferably hydrogen or chloro, and most preferably hydrogen.
  • R 8 ' represents hydrogen or chloro, especially hydrogen.
  • the substituents R 9 and R 10 may be located at any position on the benz ring, namely in position 6-, 7-, 8- and/or 9- of the benz ring. Accordingly each of the substituents R 9 and R 10 specified herein are considered to be named at each of these positions.
  • one group of compounds R 10 is located at position 6- or 7- of the benz ring, especially position 6-.
  • In a preferred group of compounds R 10 is located at position 8- or 9- of the benz ring, especially position 8-.
  • R 9 represents hydrogen, fluoro or chloro, more preferably hydrogen or fluoro, most preferably hydrogen.
  • the group R 10 may represent a carboxylic acyloxy group and may have the formula
  • R 17 represents an alkyl group (e.g. C 1 -6 ) ; an alkenyl group (e.g. C 2 -6 ) ; a cycloalkyl group (e.g. C 3-11 ); a non-aromatic heterocyclic group; a carbocyclic aryl group or a heterocyclic aryl group; each of the groups being optionally substituted.
  • R 17 represents an alkyl group (e.g. C 1 -6 ) ; an alkenyl group (e.g. C 2 -6 ) ; a cycloalkyl group (e.g. C 3-11 ); a non-aromatic heterocyclic group; a carbocyclic aryl group or a heterocyclic aryl group; each of the groups being optionally substituted.
  • R 17 represents C 1 -6 alkyl; C 2 -6 alkenyl; C 3-11 cycloalkyl; a 3-8 membered non-aromatic heterocyclic group; a carbocyclic aryl group; or a 5 or 6 membered heterocyclic aryl group; each of the groups being optionally substituted by Z.
  • R 17 represents C 1 -6 alkyl, C 2 -6 alkenyl, C 3-10 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 R 17 being optionally substituted by Z 1 or Z 2 .
  • Hydrolysable esters are included within the scope of the present invention as well as those which are less readily hydrolysable.
  • R 10 represents hydrogen, fluoro, chloro, bromo, trifluoromethyl, hydroxy, nitro, C 1 -6 alkyl (preferably C 1 -4 alkyl), C 1 -6 alkoxy (preferablyC 1 -4 alkoxy) or a carboxylic acyloxy group as hereinabove defined. More preferably R 10 represents hydrogen, halo (preferably fluoro or chloro), nydroxy, C 1 -6 alkoxy (for example methoxy), C 1 -6 alkyl (for example methyl) or nitro or a carboxylic acyloxy group. Most preferably R 10 represents hydrogen, fluoro, hydroxy or a carboxylic acyloxy group.
  • R 10 includes:
  • R 10 represents arylcarbonyloxy (for example cycloproylcarbonyl, cyclobutylcarbonyl or adamantyl- carbonylbxy); C 2-6 alkanoyloxy (for example acetoxy or propionyloxy) or C 2-6 alkenoyloxy, both of which may be substituted with a substituent selected from C 2 -6 alkanoyloxy (for example acetoxy), S(O) m Y 1 (for example methylthio), C 1 -6 alkoxy (for example methoxy), carboxy, chloro, phenyl, di (C 1 -6 ) alkylamino or C 2-6 alkoxycarbonyl (for example methoxycarbonyl or ethoxycarbonyl) and further optionally substituted by optionally substituted phenyl (for example 4-methoxy- phenyl, 4-methylphenyl, 4-chlorophenyl); or R 10 represents arylcarbonyloxy
  • Preferred substituents R 10 include chloroacetoxy; 4-chlorobenzoyloxy; cyclopentylcarbonyloxy; cyclohexylcarbonyloxy; hydrogen; fluoro; chloro; hydroxy; acetoxy; propionyloxy; butyryloxy; pentanoyloxy; methoxycarbonylacetoxy;
  • a more preferred class of compounds of formula I are those represented by formula V
  • More preferably. represents hydrogen.
  • a further more preferred class of compounds of formula I are those represented by formula VI
  • R 6 , , R 7 , R 8 , R 9 , R 10 and R 14 and prreferred substituents thereof, are as defined with respect to formula I above. More preferably, R 6 ' represents hydrogen, R 14 represents OR 15 , R 16 or NR 12 R 13 in which
  • R 12 represents methyl or ethyl
  • R 13 represents C 1-6 alkyl optionally substituted by cyano, phenyl, a 3-8 membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen, a 5 or 6 membered heterocyclic aryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur or nitrogen or
  • R 13 represents phenyl optionally substituted by C 2 -6 alkoxycarbonyl or halo; or R 12 and
  • R 13 together with nitrogen to which they are attached form a 3-8 membered non-aromatic heterocyclic ring which may contain a further heteroatom selected from oxygen, sulphur or nitrogen which may be substituted by a C 2-6 acyloxy(C 1 -6 ) alkyl group; and R 15 and R 16 , which may be the same or different, represent optionally substituted groups selected from C 1 -6 alkyl; C 2 -6 alkenyl; C 3-10 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; R 9 represents hydrogen and R 10 represents hydrogen, hydroxy, halo, C 1 -6 alkoxy or C 1 -6 alkyl.
  • a further more preferred class of compounds of formula I are those represented by formula VII.
  • R 6' R 6 ', R 7 , R 8 , and R 17 aannd preferred substituents thereoff are as defined with respect to formula I above.
  • the substituent 0.CO.R 17 is located in the 8-position or 9-position of the ring system, especially the 8-position.
  • R 6 ' represents hydrogen and R 6 represents hydrogen, C 2 -6 alkoxycarbonyl or C 1 -6 alkylthio
  • R 17 represents optionally substituted groups selected from C 1 -6 alkyl; C 2-6 alkenyl; C 3-1 1 cyclpalkyl; 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 tihose, represented by formula VIII
  • R 7 , R 8 and R 17 and preferred substituents thereof are as defined with respect for formula I above. More preferably R 17 represents optionally substituted groups selected from C 1 -6 alkyl; C 2 -6 alkenyl; C 3-11 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 heteroicyclic 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
  • R 6 , R 6' , R 7 , R 8 , R 8 ,, R 9 and R 10 and preferred substituents thereof, are as defined with respect to formula I above. More preferably R 6 ' represents hydrogen or methyl; R 6 represents hydrogen, halo, C 2-6 alkanoyl , C 2 -6 alkoxycarbonyl , S (O) n Y 1 , carbamoyl, carboxy or R 5 and R 6 together with a carbon atom to which they are attached represent cyclopropyl; R 7 represents hydrogen, halo, trifluoromethyl, methoxy, C 1 -6 alkyl, S(O) m Y 1 ; R 8 represents hydrogen, halo or trifluoromethyl; R 8 ' represents hydrogen, halo or trifluoromethyl; R 9 and R 10 , which may be the same or different, each represent halo; or R 9 represents hydrogen and R 10 represents hydrogen, halo, trifluoromethyl, hydroxy, nitro, C 2
  • X represents oxygen.
  • R 6 represents COR 14 , especially COOR 15
  • R 10 represents OCOR 17
  • Particular compounds of formula I are the compounds listed in Table A and pharmaceutically acceptable salts thereof provided in the specific Examples of the invention, including the free bases of compounds which have been exemplified as salts, hydrates or solvates.
  • Compounds of formula I may contain one or more chiral centres and exist in different optically active forms. When compounds of formula I contain one chiral centre the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers.
  • the enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallisation; formation of diastereoisomeric derivatives which may be separated, for example, by crystallisation, gas-liquid or liquid chromatography; selective derivatisation of one enantiomer by reaction with an enantiomer-specific reagent, for example enzymatic oxidation or reduction; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • specific enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • each [1]benzothiopyrano- [4,3-c]pyrazole having a 3a-methyl substituent listed in Table A is hereby named as the R- or S- enantiomer.
  • 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.
  • compounds of formula I When compounds of formula I contain more than one chiral centre, the compounds may exist in diastereoisomeric forms.
  • the present invention includes each diastereoisomer and mixtures of the diastereoisomers.
  • the diastereoisomers may be separated by methods known to those skilled in the art, for example by crystallisation or liquid chromatography.
  • Certain compounds of formula I may exist in different tautomeric forms or as different geometric isomers.
  • Some compounds of formula I are bases and may form acid addition salts with inorganic or organic acids, for example hydrochloric acid, hydrobromic acid, fumaric acid, tartaric acid and citric acid. It will be appreciated that such salts, provided they are pharmaceutically acceptable, may be used in therapy in place of the corresponding compounds of formula I. Such salts may be prepared for example by reacting the compound of formula I with a suitable acid in a conventional manner.
  • Certain compounds of formula I may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.
  • Certain compounds of formula I may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
  • the present invention also includes pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I together with a pharmaceutically acceptable diluent or carrier.
  • active compound denotes a [1]benzopyrano[4,3-c]pyrazole or a [1]benzothiopyrano [4,3-c]pyrazole of formula I.
  • the active compound may be administered orally, rectally, parenterally or topically, preferably orally or topically.
  • the therapeutic compositions of the present invention take the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration.
  • Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy.
  • 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.
  • capsules for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner.
  • the tablets and capsules may conveniently each contain 0.1 to 500 mg of the active compound.
  • compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil.
  • a non-toxic suspending agent such as sodium carboxymethylcellulose
  • oily suspensions containing a compound of the present invention in a suitable vegetable oil for example arachis oil.
  • compositions for topical administration are also preferred compositions of the invention.
  • the pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel.
  • a suitable cream may be prepared by incorporating the active compound in a topical vehicle such as petrolatum and/or light liquid paraffin, dispersed in an aqueousmedium using surfactants.
  • An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil, petrolatum and/or a wax e.g. paraffin wax or beeswax.
  • a gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent e.g. basified Carbomer BP, in the presence of water.
  • Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.
  • a suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as described above, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol.
  • compositions of the invention suitable for rectal administration are known pharmaceutical forms for such administration, for example suppositories with semi-synthetic glycerides or polyethylene glycol bases.
  • compositions of the invention suitable for parenteral administration are known pharmaceutical forms for such administration, for example sterile suspensions in aqueous and oily media or sterile solutions in a suitable solvent.
  • the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
  • the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
  • the compounds of formula I are indicated for use as immunomodulatory agents, and are generally immunosuppressants, but some compounds, in certain disease states, may exhibit immunostimulant activity.
  • compositions containing a therapeutically effective amount of a compound of formula I may be used to treat diseases with an immunologioal association for example tissue rejection, such as kidney rejection; autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus; cutaneous disorders, such as contact sensitivity, eczema and psoriasis; and neoplasia, such as melanoma.
  • 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
  • neoplasia such as melanoma.
  • the present invention also includes a method of treating diseases with an immunological association, comprising the administration of a therapeutically effective amount of a compound of formula I.
  • compounds of formula I are useful as immunomodulatory agents. Whilst the precise amount of active compound administered will depend on a number of factors, for example the age of the patient, the severity of the condition and the past medical history and always lies within the sound discretion of the administering physician, a suitable dose for oral administration to mammals, including humans, is generally within the range 0.01-40 mg/kg/day, more usually 0.2-25 mg/kg/day given in single or divided doses.
  • a suitable dose is generally within the range 0.001-4.0 mg/kg/day, more usually 0.005-1 mg/kg/day given in single or divided doses or by continuous infusion.
  • a suitable preparation for topical administration generally contains the active ingredient within the range 0.01-20% by weight, more usually 0.05-5% by weight. Oral administration is preferred. Processes for the preparation of compounds of formula I will now be described. These processes form a further aspect of the present invention.
  • Compounds of formula I which are represented by formula II in which R 6 , represents hydrogen and R 6 represents a carboxylic acyl group may be prepared by reacting compounds of formula X with compounds of formula Xlla or a tautomer thereof, in which R 24 and R 25 may be the same or different, and each represent a C 1 -6 alkyl group or a benzyl group, for example by heating in an organic liquid for example xylene at a temperature between 50-200°C.
  • R 24 and R 25 may be the same or different and each represents a C 1 -6 alkyl group or a benzyl group, for example by heating in an organic liquid, for example xylene at a temperature between 50 and 250°C.
  • Compounds of formula I which are represented by compounds of formula II in which R 6 represents a group CONR 12 R 13 or an esterified carboxyl group may be prepared by reacting compounds of formula II'
  • R 10 represents R 10 and R a represents COA
  • A represents a leaving group, for example hydroxyl , halo, C 1 -C 6 alkoxy, aryloxy, arylmethoxy,
  • R 10 represents a hydroxy group by reaction with an acylating agent.
  • the acylation reaction may be carried out by reacting the compound of formula II' with an acyl halide e.g. R 17 COCl or an acid anhydride (R 17 CO) 2 O in the presence of a base at a temperature in the range -10°C to 40°C.
  • the acylation reaction may also be carried out by reacting the compound of formula II' with a carboxylic acid R 17 COOH in the presence of a dehydrating agent, for example dicyclohexylcarbodii ⁇ mide, preferably in the presence of a base e.g. pyridine.
  • R 10' represents hydroxy
  • R 10 represents a C 1 -6 alkoxy group
  • a Lewis acid for example aluminium chloride or boron tribromide
  • Compounds of formula I which are represented by formula II in which R 6 and R 6 ' both represent hydrogen may be prepared by decarboxylating compounds of formula II in which R 6 , represents hydrogen and R 6 represents carboxyl, or by hydrolysing compounds of formula II in which R 6 ' represents hydrogen and R 6 represents a group which may be hydrolysed to a carboxyl group such as a C 2-6 alkoxycarbonyl group or carbamoyl, for example by reaction with sulphuric acid, followed by decarboxylation.
  • Compounds of formula I which are represented by compounds of formula II in which R 10 represents a carboxyalkylcarbonyloxy group for example carboxyacetoxy may be prepared from compounds of formula II in which R 10 represents 4-methoxybenzyloxycarbonyl- alkylcarbonyloxy, for example 4-methoxybenzyloxy- carbonylacetoxy, by treatment with trifluoroacetic acid and anisole in a solvent, for example dichloromethane.
  • R 26 represents hydrogen. or a tautomer thereof, or in which R 26 represents a group COR 28 wherein R 28 represents hydrogen, an optionally substituted C 1-4 alkyl group or a benzyl group and R 27 represents COCHR 6 R 6'' with a base e.g. piperidine in a suitable solvent e.g ethanol.
  • R 3 represents hydrogen
  • R 5 represents CHR 6 R 6'
  • R 29 represents COOR 30 or carbamoyl and R 30 represents a C 1 -4 alkyl group or a benzyl group with a hydrazine of formula XV
  • R 31 represents hydrogen, a C 1 -4 alkyl group or a benzyl group with a hydrazine of formula XV, for example by heating at 50-200°C in an organic liquid for example toluene.
  • the compound of formula XVI is used in excess of the stoichiometric amount.
  • Compounds of formula X may be prepared by reacting compounds of formula XVII
  • (SQ) 2 and R 23 represents SQ may be prepared for example from compounds of formula R 6' R 6 CH-COCl by reaction with thiols of formula QSH in which Q represents a C 1 -4 alkyl group or a benzyl group in the presence of a
  • Lewis acid for example zinc chloride.
  • COR 28 and R 27 represents COCHR 6 R 6
  • COR 28 and R 27 represents hydrogen may be prepared by the acylation of compounds of formula X for example by reaction with an acid anhydride of formula (R 28 CO) 2 O in the presence of a salt (e.g. the sodium salt) of the corresponding acid.
  • a salt e.g. the sodium salt
  • Compounds of formula XIII in which R 26 and R 27 are identical and represent COCHR 6' R 6 may be prepared by acylation of compounds of formula X for example by using an acid anhydride of formula (R 6' R 6 CHCO) 2 O in the presence of a salt (e.g. the sodium salt) of the corresponding acid.
  • a salt e.g. the sodium salt
  • COO R 30 and R 5 represents CHR 6 R 6 , may be prepared by heating compounds of formula XX
  • R 30 represents a C 1 -4 alkyl group or a benzyl group, for example with glass powder or glass wool.
  • 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.
  • a base for example a sodium alkoxide e.g. sodium methoxide.
  • R 33 represents hydrogen with malonic acid in the presence of an acid chloride e.g. phosphoryl chloride and a Lewis acid e.g. zinc chloride.
  • Compounds of formula XVI in which R 31 represents hydrogen may be prepared by reacting compounds of formula XXI in which R 33 represents a group COR 34 in which R 34 represents a C 1 -5 alkyl group, with a base, for example sodium hydride, followed by treatment with a dialkyl carbonate of formula (QO) 2 CO in which Q represents a C 1 -4 alkyl group or a benzyl group, e.g. dimethyl carbonate.
  • Compounds of formula XVI in which R 31 represents a C 1 -4 alkyl group or a benzyl group may be prepared by base catalysed alkylation or benzylation of compounds of formula XVI in which R 31 represents hydrogen for example by reaction with an alkyl halide or a benzyl halide.
  • Compounds of formula XVII may be prepared by reacting compounds of formula XVI with a hydrazine of formula XV for example by heating at 50-200°C in a suitable solvent for example toluene. In cases where a mixture of compounds of formula X and XVII are obtained, these compounds may be separated by virtue of their different solubilities in an organic liquid for example dichloromethane.
  • Compounds of formula XVIII to XXI may be prepared by methods known to those skilled in the art.
  • Compounds of formula I which are represented by formula II in which R 10 represents R 17 OC.O may be prepared by acylation of compounds of formula II in which R 10 represents a hydroxyl group. During the acylation reaction there may be formed compounds of formula XXII
  • 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.
  • Example 2 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 2M sodium hydroxide solution, separated and acidified with 2M hydrochloric acid.
  • Example 3 a A stirred mixture of 4-methoxythiophenol (20 g), diethyl ethoxymethylene malonate (29.3 ml) and potassium hydrogen sulphate (0.4 g) was heated at 160-170°C for 2 hours. Polyphosphoric acid (152 g) was added to the reaction mixture with heating at 80-90°C for 1 hour. The reaction mixture was poured into water, extracted with ether and the ether extracts combined and dried. Following removal of the solvent the solid obtained was recrystallised from ethyl acetate/petroleum ether (b.p.
  • Example 4 Pyridine (12 g) was added dropwise over 3-5 minutes to a stirred solution of 2,2-dimethyl-1,3- dioxane-4,6-dione (20 g) in dichloromethane (220 ml) at 0°C. The resulting solution was stirred at 0°C for 10 minutes and then while the temperature was maintained at 0-2°C 3-methoxycarbonylpropionyl chloride (22.8 g) was added dropwise. After the addition the mixture was stirred at 0°C for 60 minutes, then allowed to warm up to ambient temperature and kept at this temperature for 18 hours.
  • Product was a viscous oil.
  • reaction mixture was cooled to 0°C, filtered and the filtrate washed with 10% sodium carbonate solution (300 ml) saturated sodium carbonate solution (50 ml), dried and evaporated under reduced pressure to give trimethyl ortho (isopropoxycarbonyl) acetate as an oil.
  • Example 18 a) A solution of methylthioacetonitrile (100 g) and methanol (47 ml) in dry ether (644 ml) was saturated with hydrogen chloride at 0-5°C. The mixture was allowed to warm to ambient temperature during 16 hours. The resulting solid product was collected by filtration, washed and dried to give methyl methylthio- acetimidate hydrochloride as a sticky solid. b) A mixture of the methyl methylthioacetimidate hydrochloride and methanol (551 ml) was stirred at
  • Example 19 A stirred mixture of 4-hydroxy-5-methoxy-coumarin (6.5 g), 4-chlorophenylhydrazine (7.3 g) and dry toluene (66 ml) was heated under reflux with removal of the water formed in the reaction. On cooling, the solid obtained was collected by filtration to give 4-[2-(4-chlorophenyl)hydrazino]-5-methoxy-coumarin, m.p. 206-209°C. b) A mixture of 4-[2-(4-chlorophenyl)hydrazino]-
  • Example 22 a A stirred mixture of 4-hydroxy-6-methoxy coumarin (17.1 g), 4-bromophenylhydrazine (25.0 g) and dry toluene (160 ml) was refluxed for 3 hours. A further portion of the hydrazine (25.0 g) was added and refluxing was continued for a further 3 hours. The reaction mixture was cooled to ambient temperature and the solid collected after filtration digested with boiling dichloromethane and then hot filtered. The filtrate was concentrated, cooled and filtered to give 1 -(4-bromophenyl)-3-(2-hydroxy-5-methoxyphenyl)-2- pyrazolin-5-one, m.p. 197-200°C.
  • R 7 and R 8 are as defined) as summarised in Table 2 below.
  • Example 45 A stirred mixture of 1-(4-chlorophenyl)-3-(2- hydroxyphenyl)-2-pyrazolin-5-one (2.9 g) and tripropyl ortho (propoxycarbonyl) acetate (8.7 g) was heated at 145-150°C for 40 minutes. The mixture was cooled below 100°C and diluted with industrial methylated spirit. The solid produced was collected by filtration to give propyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro [1]benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 138-140°C.
  • Example 45 In a similar manner to Example 45, a mixture of 1-(4-chlorophenyl)-3-(2,5-dihydroxyphenyl)-2-pyrazolin- 5-one (6.6 g) and trimethyl ortho (isopropoxycarbonyl)- acetate (21.9 g) was heated at 140°C for 2 hours, then cooled, filtered and the solid product washed with ether to give isopropyl 2-(4-chlorophenyl)-8-hydroxy-3- oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 224-225°C.
  • Heating temperature 140-150°C.
  • Heating temperature 140-150°C.
  • Example 76a a further portion of boron tribromide was added to the reaction mixture cooled to -70°C, as shown in the Table.
  • Heating temperature 140-150°C
  • Example 87 In a similar manner to that described in Example 47, a stirred mixture of 1-(5-chloro-2-pyridyl)-3-(2- hydroxyphenyl)-2-pyrazolin-5-one (1.4 g) and trimethyl ortho (methylthio) acetate (2.5 ml) was heated at 140-145°C for 10 minutes, then cooled and triturated with industrial methylated spirit, to give 2-(5- chloro-2-pyridyl)-4-methylthiomethyl [1]benzopyrano- [4,3-c]pyrazol-3 (2H)-one, m.p. 217-219°C.
  • Acetyl chloride (0.5 ml) was added dropwise to a stirred mixture of 2-(5-chloro-2-pyridyl)-9-hydroxy-4- methyl[1]benzopyrano,[4,3-c]pyrazol-3 (2H)-one (2.0 g), dry tetrahydrofuran (30 ml) and triethylamine (1.0 ml) at 0°C. The mixture was allowed to warm to ambient temperature and then stirred for 2,5 hours.
  • Example 90 A stirred mixture of ethyl 2-(5-chloro-2-pyridyl)- 3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4- acetate (1.4 g) and cyclobutylmethanol (3.5 ml) was heated at 150°C for 1 hour. The reaction mixture was allowed to cool to ambient temperature, triturated with ether and the solid product collected by filtration and washed with ether to give cyclobutylmethyl 2-(5-chloro- 2-pyridyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]- pyrazole-4-acetate, m.p. 157-160°C.
  • Example 91 A mixture of propyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate (1.9 g) and 2-piperidinoethanol (6.4 ml) was stirred at
  • 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.
  • a compound of formula I was prepared by reacting a compound of formula II' (the Example for the preparation of the starting ester is provided) with the appropriate alcohol as summarized in Table 11 below.
  • Cycle included 26 hours refluxing and 140 hours storage at ambient temperature. A further portion of the alcohol (2 g) was added after 13 hours refluxing. Examples 142 and 143
  • Example 147 A mixture of ethyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate (2.0 g), 2-cyanoethanol (0.4 ml), N-methylmorpholine (0.6 ml) and molecular sieves (20 pieces) was stirred in dry xylene (40 ml) at 170°C for 5 hours. More 2-cyanoethanol (0.4 ml) was added and the mixture was stirred at 170°C for 18 hours. The mixture was evaporated under reduced pressure and the residual oil purified on a short Florisil column using dichloromethane as the mobile phase.
  • the material obtained was separated using flash chromatography on a silica column using toluene/acetic acid (9:1) as the mobile phase.
  • the material obtained after removal of the solvent was triturated with petroleum ether (b.p. 60-80°C) and filtered to give 2-cyanoethyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 120-122°C.
  • Example 145 In a similar manner to Example 145, a mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate (2.0 g), ethyl 3- hydroxypropionate (1.2 ml), N-methylmorpholine (0.6 ml) and dry xylene (40 ml) was heated at 170°C for six hours to give, after flash chromatography on silica using toluene/acetic acid (9:1) as the mobile phase, 2-ethoxycarbonylethyl 2-(4-chlorophenyl)-3-oxo- 2,3-dihydro[1]benzopyrano[4,3-c]pyrazole-4-acetate, m.p. 126-129°C.
  • Example 145 In a similar manner to Example 145, a mixture of ethyl 2-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzo- pyrano[4,3-c]pyrazole-4-acetate (1.1 g), 2-phenyl-1- propanol (0.4 ml) and N-methylmorpholine (0.3 g) in dry xylene (3 ml) was stirred and boiled under reflux for 15 hours, adding more 2-phenyl-1-propanol (0.2 ml) and N-methylmorpholine (0.2 ml) after 14 hours.
  • Example 153 A stirred suspension of 2-morpholinoethyl 2-(4- chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]- pyrazole-4-acetate hydrochloride (1.5 g) in absolute ethanol (50 ml) at 0-5°C was treated portionwise with sodium borohydride (0.6 g). The reaction mixture was stirred for 4 hours at this temperature with 3 further portions of sodium borohydride (0.28 g, 0.28 g, 0.14 g) added after 1 hour, 3 hours and 3.5 hours respectively. The reaction mixture was poured onto water, cooled to 0-5°C and neutralised with glacial acetic acid.
  • a compound of formula I was prepared by reacting a compound of formula II' (the Example for the preparation of the starting ester is provided) with the appropriate amine as summarised in Table 12 below.
  • [1]benzopyrano[4,3-c]pyrazole-4-acetamide hydrochloride (0.7 g) in dichloromethane (28 ml) was cooled to 0°C with stirring and treated with triethylamine (0.42 ml) followed by acetyl chloride (0.14 ml). The mixture was stirred in an ice-bath for 2 hours. More acetyl chloride (0.07 ml) was added and the mixture stirred at 0°C for a further 30 minutes then left at 0°C overnight. The mixture was washed with water, then dried and evaporated under reduced pressure.
  • 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
  • Example 4 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-c]- pyrazol-4-yl]-4-oxopentanoate, m.p. 142-143°C. Examples 175-186
  • Examples 188-206 In a similar manner to that described in Example 187, a compound of formula I was prepared by reacting 2-(4-chlorophenyl)-8-hydroxy-4-methyl[1]benzopyrano- [4,3-c]pyrazol-3(2H)-one (Example 62) with the appropriate acyl chloride (R 17 COCl) as summarised in Table 14 below.
  • Examples 207-220 In a similar manner to that described in Example 187 a compound of formula I was ⁇ prepared by reacting a compound of formula II' (the Example for the preparation of the starting ester is provided) with the appropriate acyl chloride (R 17 COCl) as summarised in Table 15 below.
  • Example 62 In a similar manner to that described in Example 221 a compound of formula I was prepared by reacting 2-(4-chlorophenyl)-8-hydroxy-4-methyl[1]benzopyrano- [4,3-c]-pyrazol-3(2H)-one (II') (Example 62) with the appropriate acid chloride, R 17 COCl, as summarised in Table 16. In Examples 223, 224 and 225 more acid chloride was added and the mixture stirred for an additional period of time as shown.
  • Example 232 A mixture of ethyl 2-(4-chlorophenyl)-8-hydroxy-
  • a compound of formula I was prepared by reacting a compound of formula I' (preparative Example of starting compound provided) with an acyl chloride R 17 COCl as summarised in Table 17 below. In each case dichloromethane (30 ml) was used.
  • Tablets are prepared from the following ingredients.
  • the active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture is granulated with a solution of the polyvinylpyrrolidone in ethanol.
  • the dry granulate is blended with magnesium stearate and the rest of the starch.
  • the mixture is then compressed in a tableting machine to give tablets containing: a) 1 0 mg
  • Tablets are prepared by the method of Example 254.
  • the tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol:dichloromethane (1:1).
  • 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.
  • the active compound is incorporated into the base by thorough homogenization until the drug is evenly distributed.
  • the ointment is packed into 10 g amber jars with screw-capped lined lids.
  • the compounds of the invention are immuno- modulatory agents, especially immunosuppressants and may show therapeutic activity at a dose of 200 mg/kg or lower. Preferred compounds of the invention show activity at 50 mg/kg or lower.
  • the therapeutic activity of the preferred compounds of the present invention has been demonstrated by a cutaneous hypersensitivity test (CH test) in which the compounds are administered parenterally to BALB/c mice. This test was carried out in the following way. Female BALB/c mice, weight range 16-24 g, were used in groups of eight.
  • the dosages used were selected from the following values: 50, 30, 10, 3, 1, 0.3, 0.1, 0.03 or 0.01 mg/kg.
  • Two groups of at least eight BALB/c mice were used as a control simultaneously with each test in a similar manner to that described above except that no test compound was included in the daily injections.
  • mice treated with the test compound were considered to be active at a particular dose if a 20% or greater reduction in ear swelling, which was statistically significant (p ⁇ 0.05) according to Dunnett's test, between treated and control groups was obtained in at least two out of three CH tests, (or, where more than three tests have been carried out, a majority of the tests) at that dose (see for example Int. Arch. Allergy, 38, p246-259 (1970)).
  • each of the compounds of formula I illustrated in Table A below was active at 5-0 mg/kg in at least two out of three tests at 50 mg/kg unless indicated otherwise (see Notes following the Table).
  • the minimum effective dose for 'each compound is given in Table A.
  • the Example (Ex) number or numbers listed adjacent to each compound indicates the process or processes illustrating the preparation of that compound in the Examples.
  • hydrochloride 101 4-methoxybenzyl 2-(4-chlorophenyl)-3- ⁇ 1 oxo-2,3-dihydro[1]benzopyrano[4,3-c]- pyrazole-4-acetate 102 benzyl 2-(4-chlorophenyl)-3-oxo-2,3- ⁇ 3 dihydro[1]benzopyrano[4,3-c]pyrazole- 4-acetate 103 phenethyl 2-(4-chlorophenyl)-3-oxo-2,3- ⁇ 3 dihydro[1]benzopyrano[4,3-c]pyrazole- 4-acetate 104 cyclopentyl 2-(4-chlorophenyl)-3-oxo- ⁇ 3 2,3-dihydro[1]benzopyrano[4,3-c]- pyrazole-4-acetate
  • the compounds prepared in the following Examples were also found to be active in the above-described antibody test after parenteral administration at 50 mg/kg.
  • a compound was deemed to be active, if at a dose of 50 mg/kg it caused a decrease in the relative serum anti-oxazolone antibody concentration determined by an enzyme linked immunosorbent assay (ELISA) by a factor of 0.5 or greater calculated by the following formula:-
  • ELISA enzyme linked immunosorbent assay
  • O.D. (C 1 ) is the optical density of the control serum at a dilution of 1/128
  • O.D. (C 2 ) is the optical density of the control serum at a dilution of 1/256
  • O.D. (T 1 ) is the optical density of the test serum at a dilution of 1/128
  • the control and test sera were diluted with phosphate buffered saline (pH 7.3) containing 0.05% v/v Tween 20 (trade name).

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  • Steroid Compounds (AREA)

Abstract

Composés de formule (I) dans laquelle X représente oxygène ou soufre ; Z représente -CH= ou -N= quand X représente oxygène ; Z représente -CH= quand X représente soufre ; R5 représente hydrogène quand R3 représente méthyle, ou R5 représente (a) quand R3 représente une liaison avec soit R2 sit R4 ; R6 représente hydrogène, halo, S(0)nY1, carboxy, carbamoyle, un groupe acyle carboxylique, un groupe carboxyle estérifié ou CONR12R13 ; R6' représente hydrogène ou méthyle ; ou R6 et R6' avec l'atome de carbone auquel ils sont reliés représentent cyclopropyle ; R9 et R10 qui peuvent être similaires ou différents, représentent halo ; ou R9 représente hydrogène et R10 représente hydrogène, halo, trifluorométhyle, nitro, alkyle C1-6, alcoxy C1-6, hydroxy ou un groupe acyloxy carboxylique ; R12 représente méthyle, éthyle ou cycloalkyle C3-8 et R13 représente alkyle C1-6 éventuellement substitué par cyano, phényle, un groupe hétérocyclique non aromatique de 3 à 8 éléments, un groupe aryle hétérocyclique de 5 ou 6 éléments ou cycloalkyle C3-8 ; ou R13 représente phényle éventuellement substitué par alcoxycarbonyle C2-6 ou halo ; ou R12 et R13 avec l'azote auquel ils sont reliés représentent un groupe hétérocyclique non aromatique de 3 à 8 éléments qui peut être substitué par un groupe alkyle (C1-6) acyloxy (C2-6) ; Y1 représente alkyle C1-6 ; n est 0, 1 ou 2 et R1, R2, R4, R7, R8 et R8' sont définis dans le descriptif. Ces composés s'utilisent en tant qu'agents immunomodulateurs.
PCT/EP1991/000154 1990-02-02 1991-01-26 Agents therapeutiques WO1991011448A1 (fr)

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KR1019920701838A KR927003599A (ko) 1990-02-02 1991-01-26 치료제
BR919105984A BR9105984A (pt) 1990-02-02 1991-01-26 Processo de preparacao de derivados do pirazol e de composicoes farmaceuticas que contem os mesmos
FI923486A FI923486A0 (fi) 1990-02-02 1992-07-31 Terapeutiska aemnen.
NO92923037A NO923037L (no) 1990-02-02 1992-07-31 Terapeutiske midler

Applications Claiming Priority (6)

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GB9002315.1 1990-02-02
GB909002315A GB9002315D0 (en) 1990-02-02 1990-02-02 Therapeutic agents
GB9002314.4 1990-02-02
GB909002314A GB9002314D0 (en) 1990-02-02 1990-02-02 Therapeutic agents
GB9002425.8 1990-02-06
GB909002425A GB9002425D0 (en) 1990-02-06 1990-02-06 Therapeutic agents

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CA (1) CA2074841A1 (fr)
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IE (1) IE910365A1 (fr)
IL (1) IL97114A0 (fr)
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993003036A1 (fr) * 1991-07-27 1993-02-18 The Boots Company Plc BENZOPYRANO[4,3-c]PYRAZOLES, LEUR PREPARATION ET LEUR UTILISATION COMME IMMUNOMODULATEURS
WO1998009969A1 (fr) * 1996-09-05 1998-03-12 Astra Pharmaceuticals Ltd. Nouveaux aryle-pyridazines
WO2003004495A1 (fr) * 2001-07-04 2003-01-16 Active Biotech Ab Nouveaux composes immunomodulateurs
US6642249B2 (en) 2001-07-04 2003-11-04 Active Biotech Ab Immunomodulating compounds
WO2004048378A1 (fr) * 2002-11-22 2004-06-10 Active Biotech Ab Pyrazoloquinolines a activite immunomodulatrice
WO2004055014A1 (fr) * 2002-12-16 2004-07-01 Active Biotech Ab Composes immunomodulateurs tetracycliques
CN103626787A (zh) * 2013-12-10 2014-03-12 沈阳药科大学 噻吩并硫杂类化合物及其应用

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US4268516A (en) * 1978-10-11 1981-05-19 Pfizer Inc. [1]Benzothiopyrano[4,3-c]pyrazoles as immunoregulatory agents

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US4268516A (en) * 1978-10-11 1981-05-19 Pfizer Inc. [1]Benzothiopyrano[4,3-c]pyrazoles as immunoregulatory agents

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Chemical Abstracts, Volume 106, no. 15, issued 1987, April 13 (13.04.87) (Columbus, Ohio, USA) Ghosh, C.K. et al. "Benzopyrans. Part XX. 4-Oxo- 4H-(1)benzopyran-3-carboni- trile/carboxylic acid: change of their reaction courses by a methyl substi- tuent at the 2-position". *
Chemical Abstracts, Volume 111, no. 9, issued 1989, August 28 (28.08.89) (Columbus, Ohio, USA) Colotta, V. et al. "Tricyclic heteroarometic systems: synthesis, (3H) flunitrazepam brain membrane binding inhibition, and structure-activity relation- ships of 2,3-dihydro-2-aryl- 4-R- (1)benzopyrano(4,3-c) pyrazol-3-ones". *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993003036A1 (fr) * 1991-07-27 1993-02-18 The Boots Company Plc BENZOPYRANO[4,3-c]PYRAZOLES, LEUR PREPARATION ET LEUR UTILISATION COMME IMMUNOMODULATEURS
WO1998009969A1 (fr) * 1996-09-05 1998-03-12 Astra Pharmaceuticals Ltd. Nouveaux aryle-pyridazines
WO2003004495A1 (fr) * 2001-07-04 2003-01-16 Active Biotech Ab Nouveaux composes immunomodulateurs
US6642249B2 (en) 2001-07-04 2003-11-04 Active Biotech Ab Immunomodulating compounds
HRP20031055B1 (en) * 2001-07-04 2008-01-31 Active Biotech Ab Novel immunomodulating compounds
US7081456B2 (en) 2002-11-22 2006-07-25 Active Biotech Ab Immunomodulatory compounds
EP1813616A3 (fr) * 2002-11-22 2007-08-08 Active Biotech AB Pyrazoloquinolines avec activité immunomodulatrice
US7291612B2 (en) 2002-11-22 2007-11-06 Active Biotech A.B. Immunomodulatory compounds
CN100347173C (zh) * 2002-11-22 2007-11-07 活跃生物技术股份公司 具有免疫调制活性的吡唑并喹啉
WO2004048378A1 (fr) * 2002-11-22 2004-06-10 Active Biotech Ab Pyrazoloquinolines a activite immunomodulatrice
WO2004055014A1 (fr) * 2002-12-16 2004-07-01 Active Biotech Ab Composes immunomodulateurs tetracycliques
US7674906B2 (en) * 2002-12-16 2010-03-09 Active Biotech Ab Tetracyclic immunomodulatory compounds
CN103626787A (zh) * 2013-12-10 2014-03-12 沈阳药科大学 噻吩并硫杂类化合物及其应用
CN103626787B (zh) * 2013-12-10 2016-06-15 沈阳药科大学 噻吩并硫杂类化合物及其应用

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BR9105984A (pt) 1992-11-10
KR927003599A (ko) 1992-12-18
HU9202510D0 (en) 1992-10-28
FI923486A (fi) 1992-07-31
FI923486A0 (fi) 1992-07-31
AU7220991A (en) 1991-08-21
IE910365A1 (en) 1991-08-14
IL97114A0 (en) 1992-03-29
JPH05505180A (ja) 1993-08-05
EP0539372A1 (fr) 1993-05-05
PT96656A (pt) 1991-10-31
CA2074841A1 (fr) 1991-08-03
CS23891A2 (en) 1991-09-15

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