Classifications

• • 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
• • 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
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/18—One oxygen or sulfur atom
  • C07D231/20—One oxygen atom attached in position 3 or 5
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/18—One oxygen or sulfur atom
  • C07D231/20—One oxygen atom attached in position 3 or 5
  • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms

Definitions

• the present invention relates to novel therapeutic agents, and in particular to [1]benzopyrano[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 novel compounds of formula I
• R 1 represents hydrogen, cyano, C 2 -6 alkanoyl, C 2 -6 alkoxycarbonyl, CONH 2 , or R 1 represents C 1 -6 alkyl or C 2 -6 alkenyl both of which may be substituted bv cyano, halo, trifluoromethyl, hydroxy, benzoyl, C 2 -6 alkanoyloxy, C 3 -6 cycloalkoxycarbonyl, a 5-7 membered non-aromatic heterocyclic group containing 2 oxygen heteroatoms, CONR 9 R 9 ,, phenoxy or C 1 -6 alkoxy, in which C 1 -6 alkoxy may be further substituted by halo, hydroxy, C 1 -6 alkoxy or C 2-6 alkanoyloxy;
• R 2 represents hydrogen or chloro
• R 3 represents chloro or trifluoromethyl; or R 2 and R 3 are joined to form a fused benz ring;
• R 4 represents hydrogen, C 1 -6 alkyl, C 1 -6 alkoxy or halo;
• R 9 and R 9 which may be the same or different, represent hydrogen, C 1 -6 alkyl or benzyl, or pharmaceutically acceptable salts thereof.
• 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 represents hydrogen, cyano, carbamoyl, C 2 -4 alkanoyl (for example acetyl), C 2 -4 alkoxycarbonyl (for example methoxycarbonyl or ethoxycarbonyl), or -CH 2 R 10 in which R 10 represents hydrogen, cyano, trifluoro- methyl, halo, hydroxy, C 3-8 cycloalkoxycarbonyl
• R 10 represents C 1 -4 alkyl, (for example methyl, ethyl or propyl, more preferably methyl or ethyl) or C 2 -4 alkenyl (for example vinyl) both optionally substituted with hydroxy, cyano, trifluoromethyl, halo (preferably chloro or bromo), C 1 -6 alkoxy (preferably methoxy or ethoxy), C 1 -6 alkoxy (C 1 - 6 )alkoxy (preferably 2-methoxyethoxy), C 2 -6 alkanoyloxy(
• R. represents (CH 2 ) p J in which J represents hydrogen, C 1 -6 alkoxy, cyano, halo or carbamoyl, and p is 0, 1 or 2, particularly hydrogen, methyl, cyanomethyl, (CH 2 ) 2 -halo, carbamoylmethyl or C 1 -4 alkoxyethyl.
• Preferred substituents R 1 are hydrogen, methyl, ethyl, propyl, butyl, allyl,
• R 1 represents methyl or 2-ethoxyethyl.
• R 2 represents hydrogen.
• R 3 represents chloro or trifluoromethyl, more preferably trifluoromethyl.
• R 4 represents hydrogen, C 1 -4 alkyl, C 1 -4 alkoxy, fluoro, chloro, or bromo. More preferably R 4 represents hydrogen, methyl, methoxy or ethoxy most preferably hydrogen or methoxy.
• R 9 represents hydrogen, methyl or ethyl or benzyl, especially hydrogen or methyl.
• R 9 represents hydrogen or benzyl.
• Particular compounds of formula I are the compounds listed in Table A provided in the specific Examples of the invention, or pharmaceutically acceptable salts thereof.
• 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-liguid 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.
• the following compound may also exist in the R- or S- enantiomeric form: 4-(4-chlorophenyl)-2-(2-ethoxypropyl) [1]- benzopyrano[4,3-c]pyrazol-3(2H)-one.
• 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.
• 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.
• the term "active compound” denotes a [1]benzopyrano[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.
• 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 methods, 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.
• Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil.
• compositions for topical administration are also preferred compositions of the invention.
• the pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel.
• a suitable cream may be prepared by incorporating the active compound in a topical vehicle such as petrolatum and/or light liquid paraffin, dispersed in an aqueous medium using surfactants.
• An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil, petrolatum and/or a wax e.g. paraffin wax or beeswax.
• a gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent e.g. basified Carbomer BP, in the presence of water.
• Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.
• a suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as described above, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol.
• compositions of the invention suitable for rectal administration are known pharmaceutical forms for such administration, for example suppositories with semi-synthetic glycerides or polyethylene glycol bases.
• compositions of the invention suitable for parenteral administration are known pharmaceutical forms for such administration, for example sterile suspensions in aqueous and oily media or sterile solutions in a suitable solvent.
• the compounds of the present invention may be beneficial to use 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 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.
• 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.
• the therapeutic activity of compounds of formula I has been demonstrated by means of tests on standard laboratory animals, Such tests include, for example, the oral and parenteral administration of the compounds to BALB/c mice.
• compounds of formula I are useful as immunomodulatory agents.
• a suitable dose for oral administration to mammals 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.
• R 14 represents (OQ) 2 or (SQ) 2 and R 15 represents OQ or SQ or NQ' 2 ;
• Q and Q represent a C 1-4 alkyl group or a benzyl group.
• R 16 represents hydrogen, or a tautomer thereof, or in which R 16 represents a group COR 18 wherein R 18 represents hydrogen, a C 1-4 alkyl group, a benzyl group or a group R 5 and R 17 represents COR 5 in which R 5 represents IlIa
• a base e.g. piperidine in a suitable solvent e.g ethanol.
• Compounds of formula I may be prepared by reacting compounds of formula IV in which R 1 and R 16 represent COR 18 and R 17 represents hydrogen with a carboxylic acid chloride for example a substituted benzoyl chloride in the presence of a base for example triethylamine followed by heating in the presence of a base for example piperidine.
• Compounds of formula I in which R 1 represents an alkyl group or alkenyl group substituted as herein described may be prepared by alkylating corresponding compounds of formula I in which R. represents hydrogen, for example by reaction with a compound of formula R 1 X in which X represents halo in the presence of a base e.g. sodium hydride.
• R 1 represents C 2-6 alkoxycarbonyl
• R. represents hydrogen
• A is a leaving group, for example cyano or halo.
• R 1 represents cyanoalkyl, e.g. cyanomethyl.
• Compounds of formula I in which R 1 represents carbamoyl may be prepared by hydrolysis, for example acid hydrolysis, of corresponding compounds of formula I in which R 1 represents CONHR 30 .
• Compounds of formula I in which R 1 is substituted by a carboxylic amide group may be prepared by reacting corresponding compounds of formula I substituted by a .group -COA where A represents a leaving group for example, hydroxyl, halo, C 1-4 alkoxy, aryloxy, arylmethoxy or C 1-6 acyloxy with a C 1-6 alcohol or amine (HNR 9 R 9 ') respectively, for example at 0-250°C, optionally in the presence of an organic liquid which is preferably a solvent for the reactants and optionally in the presence of a catalyst for the reaction.
• anhydrous acid for example hydrogen chloride
• COR 18 and R 17 represents COR 5 may be prepared by acylation of compounds of formula IV in which R 16 represents COR 18 and R 17 represents hydrogen, for example by reaction with an acid anhydride of formula (R 5 CO) 2 O in the presence of a salt (e.g. the sodium salt) of the corresponding acid or an acid halide e.g. of formula R 5 COCl in the presence of a base e.g. triethylamine.
• a salt e.g. the sodium salt
• R 5 COCl e.g. triethylamine
• Compounds of formula IV in which R 16 represents COR 18 and R 17 represents hydrogen may be prepared by the acylation of compounds of formula II for example by reaction with an acid anhydride of formula (R 18 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 IV in which R 17 represents COR 5 and R 16 represents hydrogen, or tautomers thereof, may be prepared by reacting a compound of formula IV in which R 16 represents COR 18 and R 17 represents COR 5 with a base e.g. piperidine in a suitable solvent e.g. ethanol.
• Compounds of formula IV in which R 1 and R 16 represents COR 18 in which R 18 is as hereinbefore defined, and R 17 represents hydrogen may be prepared by reacting compounds of formula II in which R 1 represents hydrogen with an acid anhydride of formula (R 18 CO) 2 O in the presence of a salt (e.g. the sodium salt) of the corresponding acid.
• R 23 represents hydrogen with malonic acid in the presence of an acid chloride e.g. phosphoryl chloride and a Lewis acid e.g. zinc chloride.
• an acid chloride e.g. phosphoryl chloride and a Lewis acid e.g. zinc chloride.
• Compounds of formula V may be prepared by reacting compounds of formula VI in which R 23 represents an acetyl group with a base, for example sodium hydride, and 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.
• a base for example sodium hydride
• QO 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.
• R. represents C 1-6 alkoxy
• R. represents C 1-6 alkoxy
• R 4 represents halo e.g. fluoro
• R 23 represents an acetyl group with a base for example sodium hydride
• QO 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.
• Example 1 a) 2'-Fluoro-6'-hydroxyacetophenone (30 g) was added dr ⁇ pwise over 30 minutes to a stirred suspension of sodium hydride (17.1 g, 60% dispersion in mineral oil) in dry toluene (400 ml) which was boiling under reflux under nitrogen. After boiling for a further 20 minutes heating was continued while diethyl carbonate (50.8 g) was added dropwise over 10 minutes. The resulting mixture was stirred and heated under reflux for 20 hours. The reaction mixture was cooled to ambient temperature and water (150 ml) added dropwise. After separation, the aqueous phase was washed with ether and then acidified with concentrated hydrochloric acid. The precipitate was collected by filtration and washed with water to give, after drying and recrystallisation from ethyl acetate, 5-ethoxy-4-hydroxycoumarin, m.p. 110-111°C.
• Example 2 2'-Fluoro-6'-hydroxyacetophenone
• Examples 4 to 6 In a similar manner to that described in Example 3, a compound of formula II was prepared by reacting a compound of formula V, with a hydrazine of formula H 2 NNHR 1 , as summarized in Table A below in which substituents R 4 and R 1 are given.
• Example 9 a A mixture of 5-ethoxy-4-hydroxycoumarin (5.0 g) (Example 1) and methylhydrazine (2.2 g) in industrial methylated spirit (60 ml) was heated under reflux for 20 hours. On cooling, the solvent was evaporated off under reduced pressure to give the crude product. Methanol (50 ml) and concentrated hydrochloric acid (20 ml) were added to this crude product and the solution obtained was heated under reflux for 2 hours. After evaporating off the solvents under reduced pressure, the residue was triturated with water and the solid obtained collected by filtration and dried to give 3-(2-hydroxy-6-ethoxyphenyl)-1-methyl-2-pyrazolin- 5-one.
• Example 11 a A mixture of 3-(2-hydroxyphenyl)-1-methyl-2- pyrazolin-5-one (3.8 g), prepared as in Example 4, anhydrous sodium acetate (1.64 g) and acetic anhydride (30 ml) was stirred at ambient temperature for 1.5 hours. The reaction mixture was added to water (10 volumes) and extracted with ethyl acetate. The combined organic extracts were washed with water, dried and evaporated. The semi-crystalline residue was triturated with petroleum ether (b.p. 60-80°C) and the solid collected by filtration and dried to give 3-(2-hydroxyphenyl)-1-methyl-5-pyrazolyl acetate, m.p. 113-116°C.
• Example 12 a A solution of 3-(2-hydr ⁇ xyphenyl)-1-methyl-5- pyrazolyl acetate (2.32 g), prepared as in Example 11a, in dry tetrahydrofuran (50 ml) was treated successively with triethylamine (1.5 ml) and 2-naphthoyl chloride
• stage (a) Part of the crude solid of stage (a) (2.43 g) and piperidine (0.63 ml) were boiled under reflux in absolute ethanol (19 ml) for 30 minutes. On cooling, the mixture was filtered to give 2-(1-methyl-5-oxo- 4,5-dihydro-3- ⁇ yrazolyl)phenyl 2-naphthoate, m.p. 207-210°C. c) The filtrate was boiled under reflux for a further hour. The mixture was concentrated and then cooled. The solid formed was collected by filtration to give 2-methyl-4-(2-naphthyl) [1]benzopyrano[4,3-c]pyrazol- 3(2H)-one, m.p. 159-161 °C.
• a compound of formula I was prepared by reacting a compound of formula II with a compound of formula III as summarized in Table B below in which substituents R 1 and R 4 in compound II are given.
• the compounds of formula III used were of the type R 5 C (OQ) 3 in which R 2 represents hydrogen and R 3 and Q are as given in Table B.
• Examples 27 to 41 In a similar manner to Example 26, compounds of formula I were prepared by reacting 4-(4-chloro- phenyl)[1]benzopyrano[4,3-c]pyrazol-3(2H)-one (A) (Example 13) with compounds of formula R,X, in which X is halo as summarized in Table C below.
• reaction mixture was added to water and acidified with 5M hydrochloric acid. The solid was collected by filtration and recrystallised from N,N-dimethylformamide. (11) The reaction mixture was added to water. The solid obtained was collected by filtration and recrystallised from propan-2-ol.
• Example 26 In a similar manner to Example 26, a mixture of sodium hydride (0.74 g, 60% dispersion in mineral oil), dry N,N-dimethylformamide (180 ml), 4-(4-chlorophenyl) [1]benzo ⁇ yrano[4,3-c]pyrazol-3(2H)-one
• Example 13 In a similar manner to Example 26, a mixture of sodium hydride (0.44 g, 60% dispersion in mineral oil), dry N,N-dimethylformamide (100 ml), 4-(4-chloro- phenyl)[1]benzopyrano[4,3-c]pyrazol-3(2H)-one (3.0 g) (Example 13 ) and 1-bromo-2-ethoxypropane (2.9 g) was stirred at ambient temperature for 16 hours. The mixture was warmed at about 60°C for 1.5 hours then cooled to ambient temperature. The mixture was added to water and the product extracted into ether. The combined ether extracts were dried and evaporated.
• Example 26 In a similar manner to Example 26, a mixture of sodium hydride (1.82 g, 60% dispersion in mineral oil), dry N,N-dimethylformamide (450 ml), 4-(4- trifluoromethylphenyl)[1]benzopyrano[4,3-c]pyrazol- 3(2H)-one (15.0 g) (Example 20) and 2-bromoethyl acetate (7.62 g) was stirred at ambient temperature for 48 hours. The mixture was added to water. The solid formed was filtered off and dissolved in ethyl acetate which was washed with water.
• Example 26 In a similar manner to Example 26, a mixture of sodium hydride (0.74 g, 60% dispersion in mineral oil), dry N,N-dimethylformamide (150 ml), 4-(4-chloro- phenyl)[1]benzopyrano[4,3-c]pyrazol-3(2H)-one (5.0 g) and 2-(2-bromoethyl)-1,3-dioxane (2.52 ml) was stirred at ambient temperature for 42 hours. The reaction mixture was added to water. The product was extracted into ether and the extracts washed with water.
• Example 46 A mixture of 2-[3-oxo-4-(4-trifluoromethylphenyl)- 2,3-dihydro[1]benzopyrano[4,3-c]pyrazol-2-yl]ethyl acetate (17.93 g) (Example 44), 2M hydrochloric acid (22 ml) and industrial methylated spirit (750 ml) was stirred and boiled under reflux for 18 hours . The mixture was cooled to 0°C and the solid formed collected by filtration to give 2-(2-hydroxyethyl)- 4-(4-trifluoromethylphenyl)[1]benzopyrano[4,3-c]- pyrazol-3(2H)-one, m.p. 199-201 °C.
• Example 47 Dilute hydrochloric acid (2 ml) was added to a stirred suspension of 2-[4-(4-chlorophenyl)-3-oxo-2,3- dihydro[1]benzopyrano[4,3-c]pyrazol-2-yl]ethyl acetate
• Example 48 A mixture of 3-[4-(4-chlorophenyl)-3-oxo-2,3- dihydro[1]benzopyrano[4,3-c]pyrazol-2-yl]propyl acetate (1.5 g) (Example 41), 2M hydrochloric acid (1.9 ml) and industrial methylated spirit (75 ml) was boiled under reflux for 5 hours. The mixture was cooled to room temperature and the solid formed collected by filtration to give 4-(4-chlorophenyl)-2-(3-hydroxy- propyl)[1]benzopyrano[4,3-c]pyrazol-3(2H)-one, m.p. 166-168°C.
• Example 49 A mixture of 2-(2-[4-(4-chlorophenyl)-3-oxo-2,3- dihydrofl]benzopyrano[4,3-c]pyrazol-2-yl]ethoxyj ethyl acetate (11 g) (Example 39), 5M hydrochloric acid (100 ml) and water (100 ml) was stirred and boiled under reflux for 24 hours.
• Example 32 and concentrated sulphuric acid (10 ml) was heated at 120-125 °C for 15 minutes to give, after recrystallisation from industrial methylated spirit, 4-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano-
• Example 53 In a similar manner to Example 52(a) 4-(4-chlorophenyl)-3-oxo-2,3-dihydro[1]benzopyrano
• [4,3-c]pyrazole-2-acetic acid (1.87 g) was converted into the acid chloride (1.89 g) and then suspended in dry tetrahydrofuran (172 ml) at 0-5°C.
• Aqueous methylamine (0.69 ml, 25/30% w/v) was added dropwise and the mixture stirred in a melting ice bath for. 2.5 hours.
• the solid was filtered off, washed with water and then ether to give 4-(4-chlorophenyl)-N- methyl-3-oxo-2,3-dihydro[1]benzopyrano[4,3-c]pyrazole- 2-acetamide, m.p. 244-250°C.
• [4,3-c]pyrazol-3(2H)-one (Example 13) (3.0 g) and potassium carbonate (2.79 g) in AR acetone (20 ml) at ambient temperature. The mixture was stirred at ambient temperature for 42 hours. More potassium carbonate (6.98 g) was added followed by more acetyl chloride (3.6 ml) in AR acetone (15 ml). The mixture was stirred at ambient temperature for 18 hours. Morepotassium carbonate (2.79 g) and acetyl chloride
• Example 57 A stirred mixture of 4-(4-chlorophenyl)[1]benzopyrano[4,3-c]pyrazol-3(2H)-one (Example 13) (20 g) and ethyl chloroformate (200 ml) was boiled under reflux for 5 hours. More ethyl chloroformate (50 ml) was added and the mixture was stirred and boiled under reflux for 4 hours. The reaction mixture was cooled to ambient temperature and the solid was collected by filtration and recrystallised from acetonitrile. The crude product obtained was purified by flash column chromatography on silica using dichloromethane/methanol (9:1) as the mobile phase.
• Example 63 a In a similar manner to Example 60, 4-(4-trifluoromethylphenyl)[1]benzopyrano[4,3-c]pyrazol-3(2H)-one (5 g), sodium hydride (0.7 g, 60% dispersion in mineral oil), ethyl 4-bromobutyrate (2.4 ml) and dry N,N- dimethylformamide (230 ml) were mixed and stirred at ambient temperature for 24 hours. The reaction mixture was added to water (2.3 1) and petrol (b.p.
• capsules 10 parts by weight of active compound and 240 parts by weight of lactose are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing
• Tablets are prepared from the following ingredients.
• Magnesium stearate 3 The active compound, the lactose and some of the. starch are de-aggregated, blended and the resulting mixture is granulated with a solution of the polyvinylpyrrolidone in ethanol. The dry granulate is blended with magnesium stearate and the rest of the starch. The mixture is then compressed in a tableting machine to give tablets containing a) 10 mg, b) 100 mg and c) 500 mg of active compound.
• Tablets are prepared by the method of Example 67.
• the tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and
• 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 screwcapped lined lids.
• the compounds of the invention are immunomodulatory 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.
• CH test cutaneous hypersensitivity test
• mice 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,
• test compound in one of the dosages listed below was injected intraperitoneally as a suspension in 1.5% v/v sorbitan esters, under the trade name Tween 80, in sterile water (100 ⁇ 1). 100 ⁇ l of the same suspension was injected likewise every 24 hours for a further 7 days.
• the dosages used weee selected from the following values: 50, 30, 10, 3, 1, 0.3, 0.1, 0.03 or 0.01 mg/kg.
• mice 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 50 mg/kg in at least two out of three tests at 50 mg/kg unless indicated otherwise (see Notes following the Table).
• the minimum effective dose for each compound is given in Table A.
• the Example (Ex) number or numbers listed adjacent to each compound indicates the process or processes illustrating the preparation of that compound in the Examples.
• the compounds of the present invention also show activity in a variety of other in-vivo screens, which show the utility of the compounds as immunomodulants, particularly in suppressing the immune response.
• ELISA 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
• 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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• 1990
  • 1990-02-06 GB GB909002423A patent/GB9002423D0/en active Pending
• 1991
  • 1991-01-24 IN IN51/MAS/91A patent/IN172129B/en unknown
  • 1991-01-26 KR KR1019920701870A patent/KR927003600A/ko not_active Withdrawn
  • 1991-01-26 WO PCT/EP1991/000153 patent/WO1991012255A1/en active Application Filing
  • 1991-01-26 JP JP3503424A patent/JPH05504141A/ja active Pending
  • 1991-01-26 HU HU922540A patent/HUT63848A/hu unknown
  • 1991-01-26 FI FI923528A patent/FI923528A0/fi not_active Application Discontinuation
  • 1991-01-26 AU AU71877/91A patent/AU7187791A/en not_active Abandoned
  • 1991-01-26 BR BR919105990A patent/BR9105990A/pt unknown
  • 1991-01-26 CA CA002074816A patent/CA2074816A1/en not_active Abandoned
  • 1991-01-28 IE IE028791A patent/IE910287A1/en unknown
  • 1991-01-31 IL IL97109A patent/IL97109A0/xx unknown
  • 1991-02-04 MX MX2440791A patent/MX24407A/es unknown
  • 1991-02-05 ZA ZA91833A patent/ZA91833B/xx unknown
  • 1991-02-06 PT PT96687A patent/PT96687A/pt unknown
• 1992
  • 1992-08-05 NO NO923082A patent/NO923082D0/no unknown

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