WO1998009969A1 - Novel aryl-pyridazines - Google Patents

Novel aryl-pyridazines Download PDF

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Publication number
WO1998009969A1
WO1998009969A1 PCT/SE1997/001359 SE9701359W WO9809969A1 WO 1998009969 A1 WO1998009969 A1 WO 1998009969A1 SE 9701359 W SE9701359 W SE 9701359W WO 9809969 A1 WO9809969 A1 WO 9809969A1
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WIPO (PCT)
Prior art keywords
chlorophenyl
tetrahydro
represent
pyrazole
benzopyrano
Prior art date
Application number
PCT/SE1997/001359
Other languages
French (fr)
Inventor
John Bantick
Simon Hirst
Matthew Perry
Eifion Phillips
Original Assignee
Astra Pharmaceuticals Ltd.
Astra Aktiebolag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9618487.4A external-priority patent/GB9618487D0/en
Priority claimed from GBGB9619122.6A external-priority patent/GB9619122D0/en
Priority claimed from GBGB9619642.3A external-priority patent/GB9619642D0/en
Application filed by Astra Pharmaceuticals Ltd., Astra Aktiebolag filed Critical Astra Pharmaceuticals Ltd.
Priority to AU38736/97A priority Critical patent/AU711539B2/en
Priority to CA002263586A priority patent/CA2263586A1/en
Priority to JP10512539A priority patent/JP2001501180A/en
Publication of WO1998009969A1 publication Critical patent/WO1998009969A1/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/36—Benzo-cinnolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • 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
    • C07D491/12—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 three hetero rings
    • C07D491/14—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
    • C07D495/12—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 three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • This invention relates to pharmaceutically useful pyrazole and pyridazine derivatives, their use as medicaments and pharmaceutical compositions containing them.
  • A, A 1 , A 2 and A 3 are all CH or CR 4 or one of A, A 1 , A 2 or A 3 is nitrogen and the others are all CH or CR 4 ;
  • X is or CH 2 , 0 or S(O) m where m is 0, 1 or 2;
  • Z is a single bond or CH 2 ;
  • R 1 is hydrogen, C
  • R 2 is hydrogen and R 3 is hydrogen or C ⁇ . alkyl or R 2 together with R 3 forms a bond;
  • R 4 groups are independently OH, halogen, nitro, cyano, phenyl, amidoxime, CO 2 R 7 , NR 8 R 9 , SO 2 NR 8 R 9 , NR IO C(O)R", methoxy (optionally substituted by CO 2 R 12 ), C,. 6 alkyl or
  • p is O, 1, 2, 3 or 4;
  • R 7 , R 10 and R 11 are independently hydrogen or C ⁇ . 6 alkyl or R 11 is Ar 2 ;
  • R 8 and R 9 are independently hydrogen, C ⁇ . 6 alkyl or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl or piperidinyl ring;
  • Ar 1 and Ar 2 are independently phenyl, pyridyl, benzothiazolyl, quinolyl or quinoxalinyl all of which are optionally substituted by one or more substituents selected from CO 2 H,
  • compositions of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulfonic acids.
  • acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulfonic acids.
  • the compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
  • the compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. All diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various optical isomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under condi- tions which will not cause racemisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica) followed by regeneration of the compounds of the invention from the chiral derivative by appropriate means well known to those skilled in the art. All stereoisomers are included within the scope of the invention.
  • Alkyl groups whether alone or as part of another group, can be linear or branched, saturated or unsaturated and may optionally be interrupted by oxygen.
  • A, A 1 , A 2 and A 3 are all CH or CR 4 or one of A, A 1 , A 2 or A 3 is nitrogen and the others are all CH or CR 4 thus forming a phenyl or pyridyl ring, preferably A, A 1 , A 2 and A 3 are all CH or one of A, A 1 or A 2 is nitrogen and the others are CH. More preferably A, A 1 , A 2 and A 3 are all CH forming a phenyl ring.
  • X is or CH , 0 or S(O) m where m is 0, 1 or 2, preferably X is O or S.
  • Z is a single bond or CH 2 .
  • Z is a single bond fo ⁇ ning a 5-membered ring.
  • R 1 is hydrogen, C ⁇ - 6 alkyl or - ⁇ alkoxy, preferably R 1 is hydrogen.
  • R 2 is hydrogen and R 3 is hydrogen or Cj- alkyl or R 2 together with R 3 forms a bond, preferably R 2 and R 3 are hydrogen or R 2 together with R 3 forms a bond. More preferably R " and R 3 are both hydrogen.
  • R 4 groups are independently OH, halogen, nitro, cyano, phenyl, amidoxime, CO 2 R 7 , NR 8 R 9 , SO 2 NR 8 R 9 ,NR 10 C(O)R", methoxy (optionally substituted by CO 2 R 12 ), C,. 6 alkyl or C 2 _ 6 alkoxy which latter two groups are optionally substituted by one or more substituents selected from NH 2 , hydroxy or CO 2 R 12 where R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are as defined above and p is 0, 1, 2, 3 or 4.
  • R 4 groups can be attached to any suitable position on the ring A.
  • p is 0 or 1.
  • R 4 groups include fluoro, NHCOMe, nitro, amino, NMe 2 , NHEt, hydroxy, methoxy, OCH 2 CO 2 Me, OCH 2 CO 2 H, and C(NH)NHOH.
  • Ar 1 and Ar 2 are independently phenyl, pyridyl, benzothiazolyl, quinolyl or quinoxalinyl all of which are optionally substituted by one or more substituents selected from CO 2 H, CO 2 C].
  • Ar 1 is phenyl optionally substituted in the 4-position, more preferably substituted by fluorine, chlorine, bromine, C ⁇ - 6 alkoxy substituted by fluorine or C
  • Particularly preferred compounds of the invention include: 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c] ⁇ yrazole, 2-(4-Chlorophenyl)-3,3a,4,5-tetrahydro-2H-benz[g]indazoIe, 2-(4-Chlorophenyl)-2,4-dihydro[ 1 ]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)[l]benzothiopyrano[4,3-c]pyrazoI-4(2 ⁇ )-one,
  • Ar 1 does not represent unsubstituted phenyl, 3-bromo-, 3-methoxy- or
  • Ar 1 does not represent unsubstituted phenyl, 3-bromo- or 3-methylphenyl;
  • R 1 and R 3 represent H, then Ar 1 does not represent 4-chloro- or 4-methylphenyl;
  • R 1 is methyl, then A 2 is not CR 4 where R 4 is chloro or methyl; and (ii) R 1 is ethyl, then A 2 is not CR 4 where R 4 is H; (n) when X and Y both represent CH 2 , Z is a single bond, A 2 is CR 4 where R 4 is H and:- (i) R 1 , R 2 and R 3 represent H, then Ar 1 does not represent unsubstituted phenyl or 3-chlorophenyl;
  • R 1 is H or methyl and R 2 and R 3 together represent a bond, then Ar 1 does not represent unsubstituted phenyl;
  • a sub-class of compounds of formula (I) are compounds of formula (LA):
  • X represents O, S(O) m or CH 2 ;
  • Y represents a single bond, C(R 3 )R 4 or (CH 2 ) n ; m represents 0, 1 or 2; n represents 1 or 2; R represents one or more substituents selected from H, hydroxy, halogen, nitro, cyano, phenyl, CO 2 R 5 , NR 6 R 7 , NR 8 C(O)R 9 , methoxy (optionally substituted by CO 2 R 10 ), C,_ ⁇ alkyl or C _ 6 alkoxy (which latter two groups are optionally substituted by one or more substituents selected from NH , hydroxy or CO 2 R ! ');
  • R 1 and R 2 both represent H or together represent a bond
  • R 3 and R 4 independently represent C ⁇ _$ alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidyl ring;
  • R 6 represents H, C
  • R 7 represents H, C ⁇ - f , alkyl, CH 2 Ar 2 or, together with R 6 and the nitrogen atom to which it is attached, forms a pyrrolidinyl or piperidyl ring;
  • R 9 represents H, C 1 -. 5 alkyl or Ar 3 ;
  • R 5 , R 8 , R 10 and R 1 ' independently represent H or C
  • Ar 1 represents pyridyl, benzothiazolyl, quinolyl or quinoxalinyl all of which are optionally substituted by one or more substituents selected from halogen, hydroxy, methoxy (optionally substituted by halogen), phenoxy, C _fj alkoxy and Cj_ 6 alkyl (which latter three groups are optionally substituted by one or more substituents selected from halogen, hydroxy or C ⁇ _ 6 alkyl);
  • Ar and Ar independently represent phenyl optionally substituted by one or more substituents selected from halogen, hydroxy, methoxy (optionally substituted by halogen), phenoxy, C _ ⁇ 5 alkoxy and Cj_fj alkyl (which latter three groups are optionally substituted by one or more substituents selected from halogen, hydroxy or C
  • Ar 2 or Ar 3 are substituted by C _ ⁇ 5 alkoxy substituted by hydroxy, then the hydroxy or NH 2 substituent as appropriate is not attached to the carbon atom which is ⁇ to the oxygen; and further provided that:
  • a further sub-class of compounds of formula (I) are compounds of formula (IB):
  • X represents O or S
  • Y represents CH 2 or (CH 2 ) 2 ;
  • R" represents H, C,. 6 alkyl or CH 2 OR l3 ;
  • R 2 represents H, C ⁇ - 6 alkyl, or together with R 3 forms a bond
  • R 3 represents H, or together with R 2 forms a bond
  • R 13 represents H or C ⁇ . 6 alkyl
  • Ar 1 represents phenyl optionally substituted by one or more substituents selected from halogen, methyl and trifluoromethyl; or a pharmaceutically acceptable derivative thereof.
  • A, A 1 , A 2 and A 3 are all CH, then Ar 1 does not represent unsubstituted phenyl, 3-bromo-, 3-methoxy- or 3-methylphenyl; and (ii) A, A 1 and A 3 are all CH and A 2 is CR 4 where R 4 is nitro or bromo, then Ar 1 does not represent unsubstituted phenyl, 3-bromo- or 3-methylphenyl; or a pharmaceutically acceptable derivative thereof for use as a pharmaceutical.
  • X a is S, O or CH 2
  • Y a is a single bond or (CH 2 ) n and p
  • A, A 1 , A 2 , A 3 , Ar 1 , n, R 1 , R 2 , R 3 and R 4 are as hereinbefore defined, for example by heating (eg to around 140°C) in the presence of a suitable organic solvent (eg xylene).
  • a suitable organic solvent eg xylene
  • X b is S or O
  • p, A, A 1 , A 2 , A 3 , Ar 1 , R 1 and R 4 are as hereinbefore defined, for example by heating (eg to around 140°C) in the presence of a suitable organic solvent (eg xylene).
  • a suitable organic solvent eg xylene
  • X a , Y a , p, A, A 1 , A 2 , A 3 , Ar 1 , R 1 , R 2 , R 3 and R 4 are as hereinbefore defined, for example at reflux in the presence of N-chlorosuccinimide and a base (eg triethylamine) and an appropriate organic solvent (eg tetrahydrofuran); or at 0°C in the presence of sodium hypochlorite followed by addition of appropriate base (eg triethylamine) and a suitable organic solvent (eg dichloromethane).
  • a base eg triethylamine
  • an appropriate organic solvent eg tetrahydrofuran
  • Y b is (CH 2 ) discipline and n, A, A 1 , A 2 , A 3 , X a , p, Ar 1 , R 1 , R 2 , R 3 and R 4 are as hereinbefore defined, for example by heating under reflux in the presence of a suitable organic solvent (eg xylene).
  • a suitable organic solvent eg xylene
  • R 8 and R 9 are independently C ⁇ - 6 alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidinyl ring, Z is a single bond, R 1 , R" and R 3 represent H and n is as hereinbefore defined by reaction of a compound of formula VI:
  • R is N(CH 3 ) 2 or N + (CH 3 ) 3 I ⁇ Y° is a single bond
  • (CH 2 ) n or C(R 8c )R 9c , R 8c and R 9c are independently C
  • A, A 1 , A 2 , A 3 , X a , n, p and R 4 are as hereinbefore defined, or, when R is N(CH 3 ) 2 or an acid addition salt thereof, with a compound of formula VQ:
  • Ar 1 is as hereinbefore defined, or an acid addition salt thereof, for example by heating to 70°C in the presence of a suitable base (eg triethylamine) and an appropriate organic solvent (eg ethanol or n-propanol).
  • a suitable base eg triethylamine
  • an appropriate organic solvent eg ethanol or n-propanol
  • A, A 1 , A 2 , A 3 , X a , Y c , p and R 4 are as hereinbefore defined, with a compound of formula VII as hereinbefore defined, or an acid addition salt thereof, for example by heating to reflux in the presence of an suitable organic solvent (eg glacial acetic acid).
  • an organic solvent eg glacial acetic acid
  • R 3a is H or C ⁇ alkyl and A, A 1 , A 2 , A 3 , X, Y c , p, Ar 1 , R 1 and R 4 are as hereinbefore defined, for example at or below room temperature in the presence of a suitable reducing agent (eg borane) and an appropriate organic solvent (eg tetrahydrofuran).
  • a suitable reducing agent eg borane
  • an appropriate organic solvent eg tetrahydrofuran
  • Y d is a single bond
  • (CH 2 ) n or C(R 8d )R 9d and R 8d and R 9d are independently C ⁇ - 6 alkyl
  • a suitable reducing agent eg borane
  • an appropriate organic solvent eg tetrahydrofuran
  • R 11 is C ⁇ _ 6 alkyl and Hal is Cl, Br or I, for example at room temperature in the presence of a suitable base (eg potassium carbonate) and an appropriate organic solvent (eg dimethylformamide).
  • a suitable base eg potassium carbonate
  • an appropriate organic solvent eg dimethylformamide
  • R 11 is as hereinbefore defined, for example at room temperature in the presence of an appropriate peptide synthesis agent (eg dicyclohexylcarbodiimide and catalytic 4-dimethylaminopyridine) and a suitable organic solvent (eg dichloromethane or dimethyl- formamide).
  • an appropriate peptide synthesis agent eg dicyclohexylcarbodiimide and catalytic 4-dimethylaminopyridine
  • a suitable organic solvent eg dichloromethane or dimethyl- formamide
  • R is C
  • a suitable reducing agent eg sodium cyanoborohydride
  • zinc chloride and appropriate organic solvent eg methanol
  • R' is C ⁇ _ 6 alkyl and Hal is as hereinbefore defined, for example at room temperature in the presence of base (eg sodium hydride) and an appropriate organic solvent (eg dimethylformamide).
  • base eg sodium hydride
  • organic solvent eg dimethylformamide
  • R" is ⁇ alkyl and R' is as hereinbefore defined, for example by heating up to reflux temperature in the presence of a suitable catalyst system (eg palladium on activated carbon, triphenylphosphine and either dichIoro-(triphenylphosphine)palladium or lithium chloride and 2,6-di- rt-butyl-4-methylphenol) and an appropriate organic solvent (eg dimethylformamide or dioxane).
  • a suitable catalyst system eg palladium on activated carbon, triphenylphosphine and either dichIoro-(triphenylphosphine)palladium or lithium chloride and 2,6-di- rt-butyl-4-methylphenol
  • an appropriate organic solvent eg dimethylformamide or dioxane
  • the OH group may be activated with the use of an appropriate activating agent (eg trifluoromethanesulphonic anhydride).
  • A is C 2 . 6 alkylene and R " and Hal are as hereinbefore defined, for example at room temperature in the presence of a suitable base (eg potassium carbonate) and an appropriate organic solvent (eg dimethylformamide).
  • Alkylene groups which A 5 may represent may be linear.
  • R 8 and R 9 are as hereinbefore defined, for example at room temperature in the presence of a suitable organic solvent (eg acetone or a mixture of acetone and tetrahydrofuran).
  • a suitable organic solvent eg acetone or a mixture of acetone and tetrahydrofuran.
  • Compounds of formula XVUI may be prepared by reaction of a corresponding compound of formula I, wherein R 4 is H with chlorosulfonic acid, for example at or below room temperature
  • Ar is phenyl or phenyl substituted in the 4-pos ⁇ t ⁇ on with, for example, methyl, methoxy, chloro or nitro
  • A, A 1 , A 2 , A 3 , X J , Y a , R 1 , R 2 , R 3 and R 4 are as hereinbefore defined, with a diazonium salt of formula XXI-
  • R 1 is C ⁇ . 6 alkyl
  • R 3 is H or C ⁇ . 6 alkyl
  • A, A 1 , A 2 , A 3 , X b , p, Ar 1 , R 1 and R 4 are as hereinbefore defined using a suitable dehydrating agent.
  • suitable agents which may be used include methyltriphenoxyphosphonium iodide, for example at room temperature in the presence of a suitable organic solvent (eg dimethylformamide) followed by the addition of strong base (eg sodium hydroxide) to liberate the alkene.
  • a suitable organic solvent eg dimethylformamide
  • strong base eg sodium hydroxide
  • R 1 is as hereinbefore defined for example at room temperature in the presence of a suitable base (eg triethylamine) and an appropriate organic solvent (eg dichloromethane).
  • a suitable base eg triethylamine
  • an appropriate organic solvent eg dichloromethane
  • A, A 1 , A", A , 3', v X- a , v Ya a , p, R 1 , R 2 , R 3 and R 4 are as hereinbefore defined, with a compound of formula VO as hereinbefore defined, for example between 0 and 80°C, in the presence of suitable organic solvent (eg methanol or ethanol).
  • suitable organic solvent eg methanol or ethanol.
  • Compounds of formula V and acid addition salts thereof may be prepared by reaction of a compound of formula XXV, wherein Y a is (CH 2 ) n and n is as hereinbefore defined with a compound of formula VE, or an acid addition salt thereof, for example between room temperature and reflux temperature in the presence of hydrogen chloride and a suitable organic solvent (eg diethyl ether).
  • a suitable organic solvent eg diethyl ether
  • A, A 1 , A 2 , A 3 , X a , Y c , p, and R 4 are as hereinbefore defined, with formaldehyde and dimethylamine or acid addition salts thereof, for example by heating under reflux in the presence of acid and a suitable organic solvent (eg ethanol) followed by liberation of the free base if necessary.
  • a suitable organic solvent eg ethanol
  • compounds of formula VI, wherein R is N(CH 3 ) may be prepared by the reaction of a compound of formula XXVI, as hereinbefore defined with N,N-dimethylmethylenearnmonium chloride, for example by heating under reflux in the presence of a suitable organic solvent (eg acetonitrile).
  • Compounds of formula VIE may be prepared by reaction of a compound of formula XXVI as hereinbefore defined with methyl formate, for example at room temperature in the presence of a suitable base (eg sodium methoxide) and an appropriate organic solvent (eg ethanol).
  • a suitable base eg sodium methoxide
  • an appropriate organic solvent eg ethanol
  • . 6 alkyl may be prepared analogously to the method described in Example 2 of European Patent Application No. 181 145.
  • Compounds of formula IX wherein R 3a is H are known from Yaku. Zass. 110, 561 (1990) or ibid. 110, 573 (1990), or may be prepared analogously to the syntheses described therein.
  • A, A 1 , A 2 , A 3 , X, Y c , p and R 4 are as hereinbefore defined, with a compound of formula VE as hereinbefore defined, for example by heating to around 140°C in the presence of a suitable organic solvent (eg xylene).
  • a suitable organic solvent eg xylene
  • Ar is as hereinbefore defined, for example between 0 and 80°C in the presence of an appropriate organic solvent (eg ethanol).
  • an appropriate organic solvent eg ethanol
  • A, A 1 , A 2 , A 3 , X b , p, Ar 2 and R 4 are as hereinbefore defined with a diazonium salt of formula XXI as hereinbefore defined, for example between -20° and -10°C in the presence of pyridine.
  • A, A 1 , A 2 , A 3 , X a , Y a , p, R 1 , R 2 , R 3 and R 4 are as hereinbefore defined with manganese dioxide, for example at room temperature in the presence of an suitable organic solvent (eg dichloromethane).
  • an organic solvent eg dichloromethane
  • Y b , R 1 , R 2 and R 3 are as hereinbefore defined, for example at room temperature in the presence of a suitable base (eg lithium hydroxide) and an appropriate organic solvent (eg dimethylformamide).
  • a suitable base eg lithium hydroxide
  • an appropriate organic solvent eg dimethylformamide
  • Hal, Y b , R 1 , R 2 and R 3 are as hereinbefore defined, for example at reflux in the presence of potassium fluoride and a suitable organic solvent (eg acetone).
  • a suitable organic solvent eg acetone
  • A, A 1 , A 2 and A 3 are CH or CR 4 and n, p and R 4 are as hereinbefore defined, in the presence of a suitable dehydrating agent (eg polyphosphoric acid) under appropriate reaction conditions (eg at 80°C).
  • a suitable dehydrating agent eg polyphosphoric acid
  • Y e O (XXXVET) wherein Y is C(R 8e )R 9e and R 8e and R 9e are independently C ⁇ . 6 alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidinyl ring, for example by refluxing in the presence of base (eg pyrrolidine) and a suitable organic solvent (eg toluene).
  • base eg pyrrolidine
  • a suitable organic solvent eg toluene
  • A, A 1 , A 2 , A 3 , X b , R la , R 3c , p and R 4 are as hereinbefore defined with a compound of formula XXVEI as hereinbefore defined, for example by refluxing in the presence of a suitable organic solvent (eg ethanol).
  • a suitable organic solvent eg ethanol
  • A, A 1 , A 2 , A 3 , X b , p and R 4 are as hereinbefore defined with a compound of formula XXVTE as hereinbefore defined, for example by heating to reflux in the presence of acid (eg hydrochloric acid) and a suitable organic solvent (eg ethanol).
  • acid eg hydrochloric acid
  • suitable organic solvent eg ethanol
  • A, A 1 , A 2 , A , X , p and R are as hereinbefore defined with a compound of formula XLEI: wherein Hal, Y a , R 1 , R 2 and R 3 are as hereinbefore defined, for example at room temperature in the presence of a base (eg potassium carbonate) and an appropriate organic solvent (eg dimethylformamide).
  • a base eg potassium carbonate
  • an appropriate organic solvent eg dimethylformamide
  • R R 1 , R 2 and R 3 are as hereinbefore defined, for example by heating to 100°C in the presence of a suitable catalyst system (eg tetrakis(triphenylphosphine)palladium) and an appropriate organic solvent (eg toluene).
  • a suitable catalyst system eg tetrakis(triphenylphosphine)palladium
  • organic solvent eg toluene
  • A, A 1 , A 2 , A 3 , p and are as hereinbefore defined with a compound of formula XLVE: CH 2 CH(CH 2 ) p CO 2 H (XLVE) wherein p is 0 or 1 , for example at 65°C in the presence of a suitable base (eg pyrrolidine) and an appropriate organic solvent (eg dimethylformamide).
  • a suitable base eg pyrrolidine
  • an appropriate organic solvent eg dimethylformamide
  • XLVEI X b , R la and R 3c are as hereinbefore defined, for example between 75° and 150°C in the presence of a suitable base (eg potassium carbonate) and an appropriate organic solvent (eg dimethylformamide).
  • a suitable base eg potassium carbonate
  • an appropriate organic solvent eg dimethylformamide
  • R la and R 3c are as hereinbefore defined for example at 95°C in the presence of a suitable base (eg potassium carbonate).
  • a suitable base eg potassium carbonate.
  • - 6 alkyl or Cj- 6 alkoxy may alternatively be prepared according to the methods described in steps (a) to (t) above from appropriate corresponding intermediates of same
  • Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid.
  • Suitable protecting groups for hydroxy include trialkylsilyl groups (eg rer -butyldimethylsilyl, rr-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl.
  • Suitable protecting groups for amino include t ⁇ rt-butyloxycarbonyl or benzyloxy carbonyl.
  • Suitable protecting groups for carboxylic acid include C ⁇ - 6 alkyl or benzyl esters.
  • the protection and deprotection of functional groups may take place before or after a reaction step.
  • the compounds of the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals.
  • the compounds of the invention possess antiallergic and anti-inflammatory activity, for example as shown in the tests described below.
  • the compounds of the invention are thus indicated for use in the treatment of allergic and inflammatory diseases of the airways such as asthma (e.g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (e.g. late asthma and airway hyper-responsiveness), bronchitis and the like.
  • asthma e.g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma
  • chronic or inveterate asthma e.g. late asthma and airway hyper-responsiveness
  • bronchitis e.g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma
  • chronic or inveterate asthma e.g. late asthma and airway hyper-responsiveness
  • the compounds of the invention are indicated in the treatment of diseases including inflammations/allergies such as rhinitis, including all conditions characterised by inflammation of the nasal mucus membrane, such as acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta and rhinitis sicca, rhinitis medicamentosa, membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis, scrofoulous rhinitis, seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis.
  • diseases including inflammations/allergies such as rhinitis, including all conditions characterised by inflammation of the nasal mucus membrane, such as acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic
  • the compounds of the invention are also indicated for use in the treatment of chronic allergic disorders, atopic dermatitis, cutaneous eosinophilias, eosinophilic fascitis, hyper IgE syndrome, vernal conjunctivitis, systemic lupus erythematosis, thyroiditis, lepromatous leprosy, sezary syndrome, chronic graft versus host disease, myasthenia gravis, idiopathic thromocytopenia pupura and the like.
  • the compounds of the invention may also have activity in both the prophylactic and therapeutic treatment of acquired immunodeficiency syndrome (AIDS), the prevention of chronic rejection of allografts mediated by humoral immunity, and in the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
  • AIDS acquired immunodeficiency syndrome
  • autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
  • a method of treatment of an allergic or an inflammatory disorder in particular asthma, which comprises administration of a therapeutically effective amount of a compound of formula I as defined above, or a pharmaceutically acceptable derivative thereof, to a person suffering from, or susceptible to such a disease.
  • Administration of the compounds of the invention may be topical (for example by inhalation to the lung).
  • the compounds of the invention may be inhaled as a dry powder which may be pressurized or non-pressurized.
  • the active ingredient in finely divided form may be used in admixture with a larger sized pharmaceutically acceptable inert carrier
  • the composition may alternatively be pressurized and contain a compressed gas, eg nitrogen, or a liquefied gas propellant.
  • a compressed gas eg nitrogen
  • a liquefied gas propellant e.g., a liquefied gas propellant
  • the active ingredient is preferably finely divided.
  • the pressurized composition may also contain a surface active agent.
  • the pressurized compositions may be made by conventional methods.
  • the compounds of the invention may be administered systemically (for example by oral administration to the gastrointestinal tract).
  • the active ingredient may be formulated together with known adjuvants, diluents or carriers using conventional techniques to produce tablets or capsules for oral administration to the gastrointestinal tract.
  • Suitable adjuvants, diluents or carriers for oral administration in the form of tablets, capsules and dragees include microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin.
  • a pharmaceutical composition comprising a compound of formula I as hereinbefore defined or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant diluent or carrier.
  • Suitable doses for administration topically or orally are in the range 0.01 to 30 mg kg "1 day “1 , for example 0.3 mg kg '1 day “1 .
  • Example 1 The invention is illustrated by the following examples.
  • Example 1 The invention is illustrated by the following examples.
  • Example 1(b) Prepared according to the method of Example 1(b) from l -(l-oxo-2,3,4,5-tetrahydronaptha- lene)-N,N,N-trimethyl-l-methanaminium iodide (1.6 g; from step (a) above) and 4-chloro- 35 phenylhydrazine (0.7 g). Recrystallisation from ethanol afforded the title compound as a solid (0.7 g). mp 129-130°C MS(EI) 282,284 (M + )
  • N NMMRR ((336600 MMIHz; d6-DMSO) ⁇ 3.47(1H) 4.01(2H) 4.14(1H) 4.53(1H) 7.18(2H) 7.36(2H)
  • Example 1(b) Prepared according to the method of Example 1(b) from 3-[(dimethylamino)methyl]-2,3-di- hydro-2,2-dimethyl-4H-[l]benzothiopyran-4-one (0.1 g; from step (a) above) and 4-chloro- phenylhydrazine hydrochloride (0.1 g). Recrystallisation from ethanol gave the title compound as yellow needles (0.03 g). mp 176-177°C MS(EI) 328,330 (M + )
  • Example 12 2-(4-Chlorophenyl)-6-fluoro-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole Prepared according to the method described in Example 1 using 8-fluoro-2,3-dihydro- -4H-l-benzopyran-4-one (J. Med. Chem., 1988, 31, 230) as starting material, mp 184°C MS(EI) 302,304 (M + )
  • N-(2,3-Dihydro-4-oxo-2H-l-benzopyran-7-yl)acetamide (International Patent Application WO 89/07594; 1.0 g) was dissolved in ethanol (10 ml) and concentrated hydrochloric acid (10 ml) and heated at reflux under a nitrogen atmosphere for 30 minutes. The reaction mixture was allowed to cool to room temperature then basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (thrice). The combined organic phase was washed with brine and dried over sodium sulphate. Filtration and evaporation gave a brown oil which was triturated with diethyl ether to give the subtitle compound as a beige solid (0.68 g). (b) 7-Fluoro-2,3-dihydro-4H-l-benzopyran-4-one.
  • a solution containing p-chlorobenzenediazonium chloride was prepared by the dropwise addition of aqueous sodium nitrite (7.70 g in 100 ml) to a solution of p-chloroaniline ( 12.75 g) in a 1 : 1 mixture of 2M aqueous hydrochloric acid and tetrahydrofuran ( 100 ml), maintaining the temperature below 5°C. Following the addition, stirring was continued at 0°C (bath temperature) for 10 minutes.
  • Example 15(a) Prepared according to the method of Example 15(a) from o-vanillin (7.95 g), potassium fluoride ( 11.3 g), and allyl bromide (6.5 ml). The crude product was used without further purification.
  • Example 17 8-Chloro-2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole Prep-ared according to the methods described in Example 15, using 5-chloro-2-hydroxybenz- aldehyde as starting material, mp 165°C
  • Example 20 6,8-DichIoro-2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole Prepared according to the methods described in Example 15, using 3,5-dichloro-2-hydroxybenzaldehyde as starting material. mp 213-214°C MS(EI) 352,354,356,358 (M + )
  • Example 21 2-(4-Chlorophenyl)-3-methyl-2,3,3a,4-tetrahydro[l]benzopyrano[4,3- ]pyrazole
  • Example 22 2-(3-Bromo-4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole Prepared according to the methods described in Example 15, using 2-hydroxybenzaldehyde as starting material.
  • the diazonium salt was prepared from 3-bromo-4-chloroaniIine, the latter being prepared by the reduction of commercially available 1 -bromo-2-chloro-4-nitro- benzene. mp 1 18°C MS(EI) 364 (M + )
  • Example 1(b) Prepatred according to the methods described in Example 1(b), from 3-[(N,N-dimethyl)amino- methyl]thiochroman-4-one (from Example 1 (a) above) and phenylhydrazine. mp 79-80°C MS(APCI) 351 ((M+H) + )
  • Example 24 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-7-methoxy[l]be ⁇ zopyra ⁇ o[4,3-c]pyrazole. Prepared according to the methods described in Example 15, using 4-methoxy-2-hydroxy- benzaldehyde as starting material, mp 147-148°C MS(EI) 314,316 (M + )
  • N-(2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-yl)acetamide (0.46 g; from Example 28 above) was suspended in concentrated hydrochloric acid (5 ml) and ethanol (5 ml) and heated at reflux under a nitrogen atmosphere for 4 hours. The reaction mixture was allowed to cool to room temperature and the title compound as the hydrochloride salt was filtered off (0.42 g). 0.18 g of this was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate (thrice). The combined organic phase was washed with brine and dried over sodium sulphate.
  • Aluminium tribromide (7.8 g) was dissolved in ethanethiol ( 14 ml) and cooled in an ice bath under a nitrogen atmosphere.
  • 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-7-methoxy[l]benzo- pyrano[4,3-c]pyrazole 1.85 g; from Example 24 above
  • Methanol was added carefully then diluted with water and acidified with dilute hydrochloric acid solution.
  • the aqueous phase was extracted with dichloromethane (thrice).
  • the combined organic phase was washed with brine and dried over sodium sulphate.
  • Methyl bromoacetate (0.16 ml) was added to a stirred mixture of 2-(4-chlorophenyl)- -2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-ol (0.5 g; from Example 31 above) and potassium carbonate (0.28 g) in dry dimethylformamide (15 ml) under a nitrogen atmosphere.
  • Example 37 2-(4-Chlorophenyl)-3,4,4a,5-tetrahydro-2 ⁇ -[l]benzothiopyrano[4,3-c]pyridazine Prepared according to the method described in Example 36, from 2-(4-chlorophenyl)- -3,4,4a,5-tetrahydro-3H-benzothiopyrano[4,3-c]pyridazine-3-one (Yaku. Zass. 110, 573 (1990)). mp 133°C MS(EI) 314,316 (M + )
  • step (b) 3-(2,3,3a,4-Tetrahydro[l]benzothiopyrano[4,3-cjpyrazol-2-yl)quinoIine 3-(N,N-dimethylaminomethyl)[ 1 ]benzothiopyran-4-one hydrochloride (51 mg; prepared by reacting the intermediate of step (a) above with ethereal hydrogen chloride) and 3-hydr- azinoquinoline dihydrochloride (510 mg) were dissolved in a solution of ethanol (10 ml) containing triethylamine (0.335 ml). The mixture was heated to reflux under nitrogen for 5.5 hours then allowed to cool.
  • Triethylamine 300 mg was added to a solution of 2-hydrazinobenzothiazole (385 mg) and 3-(N,N-dimethylaminomethyl)[l]benzothiopyran-4-one hydrochloride (600 mg; prepared by reacting the intermediate of Example 1(a) above with ethereal hydrogen chloride) in ethanol (50 ml) and refluxed under nitrogen. After 105 minutes the reaction mixture was concen- trated and the residue dissolved in ethyl acetate and successively washed once with water, twice with dilute hydrochloric acid, twice with saturated sodium bicarbonate solution and once with brine, dried over magnesium sulphate, filtered and concentrated.
  • 3-Chloroperoxybenzoicacid 35mg was added at 25C to a solution of 2-(4-Chlorophenyl)- 2,3,4,4a,5,6-hexahydropyridino[2,3-h]cinnoline (example 64) (25mg) in dichloromethane (5ml). After 4 hours sodium metabisulfite was added until the reaction mixture tested negative to starch/KI. The reaction mixture was diluted with dichloromethane and extracted with sodium hydrogen carbonate soln., dried and evaporated. Purification by chromatography eluting ethyl acetate/methanol (4: 1 ) gave the title compound ( 17mg).
  • Example 66 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydro-9-oxidopyridino[4,3-h]cinnoline 3-Chloroperoxybenzoicacid (35mg) was added at 25C to a solution of 2-(4-Chlorophenyl)- 2,3,4,4a,5,6-hexahydropyridino[4,3-h]cinnoline (example 68) (25mg) in dichloromethane (5ml). After 4 hours sodium metabisulfite was added until the reaction mixture tested negative to starch/KI. The reaction mixture was diluted with dichloromethane and extracted with sodium hydrogen carbonate soln., dried and evaporated. Purification by chromatography eluting ethyl acetate/methanol (4: 1) gave the title compound ( 19mg). MS (APCI) 314/316 M+H mp 216 C dec
  • Test A Chronic graft-versus-host test
  • Pharmacological activity of the compounds of the invention may be demonstrated using the method of M Doutrelepont et al ([Gin Exp Immunol, 1991, vol 83, 133-6; Inhibition of chronic graft-versus-host (c-GVH) disease in the mouse].
  • Test compound was administered to mice subcutaneously as a suspension in saline with TWEEN-80 every day for 21 days.
  • mice Male Balb/c mice were sensitised to ovalbumin/Al(OH) 3 mixture. Fourteen days after sensitisation dosing with compound commenced. Compound was administered daily either orally or subcutaneously as a suspension or solution (depending on dose and compound solubility) in 5% Tween 80.
  • mice 17 days after sensitisation and one hour after the fourth dose of compound, the mice were placed in perspex chambers into which a solution of ovalbumin (2%w/v) was nebulised, The mice were allowed to inhale the ovalbumin for a period of 30-40 min. This challenge was repeated daily at the same time for a further 3 or 7 days.
  • Certain compounds of the invention show activities in the chronic graft versus host test and the inhibition of eosinophilia test with ED 5 o's in the range of 0.1 - 10 mg/kg.

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Abstract

Use of a compound of formula (I) wherein, A, A?1, A2 and A3¿ are all CH or CR4 or one of A, A?1, A2 or A3¿ is nitrogen and the others are all CH or CR?4; Ar1 and Ar2¿ are independently phenyl, pyridyl, benzothiazolyl, quinolyl or quinoxalinyl all of which are optionally substituted by one or more substituents, X, Y, Z, R?1, R2, R3, R4¿ are as described in the specification or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the treatment of an allergic or an inflammatory condition.

Description

NOVEL ARYL-PYRIDAZINES
This invention relates to pharmaceutically useful pyrazole and pyridazine derivatives, their use as medicaments and pharmaceutical compositions containing them.
The antiarrhythmic and anti-inflammatory activity of certain 2-arylbenz[g]indazole and 2-arylindenopyrazole derivatives has been reported in J. Heterocycl. Chem. (1976) 13, 545.
Certain 2-aryl-3-methyl[l]benzopyrano[4,3-c]pyrazol-4-one derivatives are known from J.Pharm. Sci. (1991 ) 80, 276 and J. Med. Chem. (1988) 31, 1 ; certain 2-aryl[l]benzo- pyrano[4,3-<--]pyridazine derivatives from Indian J. Chem., Sect. B, (1990) 29B, 685; and 3,3a,4,5-tetrahydro-2-pheny]-2H-l-benzothiepino[5,4-c]pyrazole from J. Chem. Soc. C (1971) 12, 4825. In all cases, the reported compounds' use in the treatment of allergy and inflammation is not suggested.
Similar compounds have also been reported for use in non -pharmaceutical applications. For example various 2-aryl[l]benzopyrano[4,3-c]pyrazoles are known from Ηelv. Chim. Acta
(1985) 68, 1283, Bull. Chem. Soc. Jpn (1984) 57, 134, Tetrahedron Lett. (1981) 1333, Ηelv. Chim. Acta (1977) 60, 3035, Tetrahedron (1987) 43, 5873, Chimia (1980) 34, 506,
Tetrahedron Lett. (1979) 3877 and J. Org. Chem. (1978) 43, 1664;
2-arylbenzoxepino[4,3-c]pyrazoles from Ηelv. Chim. Acta (1985) 68, 1283;
2-aryl[l]benzopyrano[4,3-c]pyrazol-4-ones from Tetrahedron Lett. (1983) 381 ;
2-arylbenz[g]indazoles from UK Patent N° GB 1 154608, Chem. Ber. (1968) 101, 839, Ganguang Kexue Yu Kuang Ηuaxue (1993) 11, 69, J. Photochem. Photobiol. A (1992) 66,
69, Dutch Patent N° 651 1492, J. Chem Soc. (1964) 4825, J. Prakt. Chem. (2) (1932),
134(82), 94 and US Patent N° 3,447,943; and 2-aryl[l]benzothieno[3,2-c]pyrazoles from J.
Chem. Soc. (1973) 129. In all cases, the reported compounds' use as pharmaceuticals is not suggested.
It has now surprisingly been found that a series of pyrazole and pyridazine derivatives are of potential use in the treatment of allergy and inflammation. According to the invention there is provided the use of a compound of formula I:
Figure imgf000004_0001
(D wherein: A, A1, A2 and A3 are all CH or CR4 or one of A, A1, A2 or A3 is nitrogen and the others are all CH or CR4;
X is or CH2, 0 or S(O)m where m is 0, 1 or 2;
Y is a single bond, (CH2)n where n is 1 or 2, C=O or CR5R6 where R5 and R6 are C,.6 alkyl or together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidinyl ring;
Z is a single bond or CH2;
R1 is hydrogen, C|-6 alkyl or Cι-6 alkoxy;
R2 is hydrogen and R3 is hydrogen or Cι. alkyl or R2 together with R3 forms a bond;
R4 groups are independently OH, halogen, nitro, cyano, phenyl, amidoxime, CO2R7, NR8R9, SO2NR8R9, NRIOC(O)R", methoxy (optionally substituted by CO2R12), C,.6 alkyl or
C2.6 alkoxy which latter two groups are optionally substituted by one or more substituents
1 selected from NH2, hydroxy or CO2R ; p is O, 1, 2, 3 or 4;
R7, R10 and R11 are independently hydrogen or Cι.6 alkyl or R11 is Ar2; R8 and R9 are independently hydrogen, Cι.6 alkyl or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl or piperidinyl ring;
Ar1 and Ar2 are independently phenyl, pyridyl, benzothiazolyl, quinolyl or quinoxalinyl all of which are optionally substituted by one or more substituents selected from CO2H,
CO2Cι.6 alkyl, halogen, hydroxy, methoxy, phenoxy, C2-6 alkoxy and Cι.6 alkyl (optionally interrupted by oxygen), which latter four groups are optionally substituted by one or more substituents selected from halogen, hydroxy or Cι_6 alkyl; or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the treatment of an allergic or an inflammatory condition, provided that: • when A, A1, A2 and A3 form a phenyl ring:
(a) when Z is CH2 or when X is CH2, SO or SO2, then Y is not C=O; (b) when R5 and R6, together with the carbon atom to which they are attached, form a cyclopentyl, cyclohexyl or 4-piperidinyl ring, then X is O;
(c) when X is S(0)m or O, and Y and Z both represent single bonds, then R3 does not represent Cι.6 alkyl; (d) R1 is C|.6 alkoxy only when Z is a single bond and R2 and R3 together represent a bond; (e) when X is CH2, Z is a single bond, R2 and R3 together represent a bond, R1 represents hydrogen, and:-
(i) Y is CH2 and A1 is CR4 where R4 is hydrogen or methoxy, then Ar1 does not represent 4-fluorophenyl; (ii) Y is CH2 and A1 is CR4 where R4 is chloro, then Ar1 does not represent
3-methylphenyl or 4-carboxyphenyl; (iii) Y is CH2 and A1 is CR4 where R4 is methoxy, then Ar1 does not represent 2-methyl- phenyl; and ( (iivv)) YY iiss aa ssingle bond and A1 is CR4 where R4 is hydrogen, then Ar1 does not represent 4-fluorophenyl;
(f) when X represents O, Y represents CH2 and R1, R2, R3 and R4 all represent H, then Ar1 does not represent 2-pyridyl; and
(g) when X and Y both represent CH2, and R1, R2, R3 and R4 all represent H, then Ar1 does not represent benzothiazoI-2-yl.
Pharmaceutically acceptable derivatives includes solvates and salts. For example the compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulfonic acids.
The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. All diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various optical isomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under condi- tions which will not cause racemisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica) followed by regeneration of the compounds of the invention from the chiral derivative by appropriate means well known to those skilled in the art. All stereoisomers are included within the scope of the invention.
Alkyl groups, whether alone or as part of another group, can be be linear or branched, saturated or unsaturated and may optionally be interrupted by oxygen.
Suitably A, A1, A2 and A3 are all CH or CR4 or one of A, A1, A2 or A3 is nitrogen and the others are all CH or CR4 thus forming a phenyl or pyridyl ring, preferably A, A1, A2 and A3 are all CH or one of A, A1 or A2 is nitrogen and the others are CH. More preferably A, A1, A2 and A3 are all CH forming a phenyl ring.
Suitably X is or CH , 0 or S(O)m where m is 0, 1 or 2, preferably X is O or S.
Suitably Y is a single bond, (CH2)n where n is 1 or 2, C=O or CR5R6 where R5 and R6 are C|.6 alkyl or together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidinyl ring. Preferably Y is a single bond, CH2, C=O or CR5R6 where R5 and R6 are both Cι.6 alkyl, in particular methyl. More preferably Y is CH2.
Suitably Z is a single bond or CH2. Preferably Z is a single bond foπning a 5-membered ring.
Suitably R1 is hydrogen, Cι-6 alkyl or -β alkoxy, preferably R1 is hydrogen.
Suitably R2 is hydrogen and R3 is hydrogen or Cj- alkyl or R2 together with R3 forms a bond, preferably R2 and R3 are hydrogen or R2 together with R3 forms a bond. More preferably R" and R3 are both hydrogen.
Suitably R4 groups are independently OH, halogen, nitro, cyano, phenyl, amidoxime, CO2R7, NR8R9, SO2NR8R9,NR10C(O)R", methoxy (optionally substituted by CO2R12), C,.6 alkyl or C2_6 alkoxy which latter two groups are optionally substituted by one or more substituents selected from NH2, hydroxy or CO2R12 where R7, R8, R9, R10, R11 and R12 are as defined above and p is 0, 1, 2, 3 or 4. R4 groups can be attached to any suitable position on the ring A. Preferably p is 0 or 1. Preferably R4 groups include fluoro, NHCOMe, nitro, amino, NMe2, NHEt, hydroxy, methoxy, OCH2CO2Me, OCH2CO2H, and C(NH)NHOH. Suitably Ar1 and Ar2 are independently phenyl, pyridyl, benzothiazolyl, quinolyl or quinoxalinyl all of which are optionally substituted by one or more substituents selected from CO2H, CO2C].6 alkyl, halogen, hydroxy, methoxy, phenoxy, C2.6 alkoxy and Cι- alkyl (optionally interrupted by oxygen), which latter four groups are optionally substituted by one or more substituents selected from halogen, hydroxy or .6 alkyl.
Preferably Ar1 is phenyl optionally substituted in the 4-position, more preferably substituted by fluorine, chlorine, bromine, Cι-6 alkoxy substituted by fluorine or C|.6alkyl substituted by fluorine. Most preferably Ar1 is phenyl substituted in the 4-position by chloro.
Particularly preferred compounds of the invention include: 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]ρyrazole, 2-(4-Chlorophenyl)-3,3a,4,5-tetrahydro-2H-benz[g]indazoIe, 2-(4-Chlorophenyl)-2,4-dihydro[ 1 ]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)[l]benzothiopyrano[4,3-c]pyrazoI-4(2Η)-one,
2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,4-dihydro[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-3a-methyl[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-4,4-dimethyl[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,4-dihydro[l]benzothiopyrano[4,3-c]pyrazoIe,
N-(2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazol-8-yl)acetamide, 2-(4-Chlorophenyl)-6-fluoro-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-7-fluoro-2,3,3a,4-tetrahydro[l]benzopyraπo[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-7-nitro[l]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-6-nitro[l]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-6-methoxy[l]benzopyrano[4,3-c]pyrazole, 8-Chloro-2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole, 2-(4-Bromophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-8-methoxy-2,3,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazole, 6,8-Dichloro-2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazoIe, 2-(4-Chlorophenyl)-3-methyl-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole, 2-(3-Bromo-4-chlorophenyI)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole, 2-(4-Trifluoromethoxyphenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-ChlorophenyI)-2,3,3a,4-tetrahydro-7-methoxy[l]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l ]benzothiopyrano[4,3-c]pyrazol-8-amine, 2-(4-ChIoro-2,6-dinitrophenyl)-2,3,3a,4-tetrahydro-5-oxide[l]benzothiopyrano[4,3-c]pyr- azole,
2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[ l]benzopyrano[4,3-c]pyrazol-6-ol, N-(2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-yl)acetamide, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazol-7-amine,
2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-N,N-dimethyl[l]benzopyrano[4,3-c]pyrazol-7-amine, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-ol, Methyl {2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]- pyrazol-7-yl Joxyacetate, {2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-yl }oxyacetic acid, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazol-6-amine, 2-(4-Chlorophenyl)-2,3,3a,4-NN-dimethyl-tetrahydro[l]benzopyrano[4,3-c]pyrazol-6-amine, 2-(4-Chlorophenyl)-3,4,4a,5-tetrahydro-2H-indeno[l,2-c]pyridazine, 2-(4-Chlorophenyl)-3,4,4a,5-tetrahydro-2Η-[l]benzothiopyrano[4,3-c]pyridazine, 2-(4-Chlorophenyl)-3,4,4a,5-tetrahydro-4a-methyl-2H-indeno[ 1 ,2-c]pyridazine, 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydrobenzo[h]cinnoline, 2-(4-Chlorophenyl)-3,4,4a,5-tetrahydro-2H-[l]benzopyrano[4,3-c]pyridazin-8-amine, 2-(4-Chlorophenyl)-N-ethyl-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-amine, 7-Chloro-2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-8-fluoro-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole,
8-Chloro-2-(4-trifluoromethylphenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole, 2,3,3a,4-Tetrahydro-2-phenyl-[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydroindeno[ 1 ,2-c]pyrazole, 2-(4-Chlorophenyl)-2,4-dihydro-6-nitro[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-8-methoxy-[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-8-hydroxy-[l]benzothiopyrano[4,3-c]pyrazole, 2,3,3a,4-Tetrahydro-2-(4-methylphenyl)[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole-6-carbonitrile, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-6-amidoxime, 3-(2,3,3a,4-Tetrahydro[l]benzothiopyrano[4,3-c]pyrazol-2-yl)quinoline,
2-(2,3,3a,4-Tetrahydro[l]benzothiopyrano[4,3-c]pyrazol-2-yl)benzothiazole, 2-(2,3,3a,4-Tetrahydro[l]benzopyrano[4,3-c]pyrazol-2-yl)benzothiazole, 2-(2,4-Dihydro[ 1 ]benzopyrano[4,3-c]pyrazol-2-yl)benzothiazole, 3-(2,3,3a,4-Tetrahydro[l]benzopyrano[4,3-c]pyrazol-2-yl)quinoline, 2,3,3a,4-Tetrahydro-2-(3-pyridyl)[ 1 ]benzopyrano[4,3-c]pyrazole,
2-(2-Chloropyridin-5-yl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole, 2-(2-Chloropyridin-5-yl)-2,4-dihydro[l]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydropyrazolo[3',4':4,5]thiopyrano[2,3-b]pyridine, l-(4-Chlorophenyl-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-3-yl) methanol, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine, 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydropyridino[2,3-h]cinnoIine,
2-(4-ChIorophenyl)-2,3,4,4a,5,6-hexahydro-7-oxidopyridino[2,3-h]cinnoline, 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydro-9-oxidopyridino[4,3-h]cinnoline, 2, 3, 4, 4a, 5, 6-Hexahydro-2-(4-methylphenyl)pyrido[3,4-h]cinnoIine, 2-(4-Chlorophenyl)-2, 3, 4, 4a, 5, 6-hexahydro-pyrido[4,3-h]cinnoline, and pharmaceutically acceptable salts or N-oxides thereof.
Certain compounds of formula I are novel. Accordingly there is also provided a compound of formula I, as hereinbefore defined, with the additional provisos that: • when A, A1, A2 and A3 form a phenyl ring (h) when X is S, Y is (CH2)2, Z is a single bond and R1, R2, R3 and R4 represent H, then Ar1 does not represent unsubstituted phenyl;
(i) when X is O, Y and Z both represent CH2, R1, R2 and R3 are hydrogen, A, A1 and A3 are CH and A2 is CR4 where R4 is OH or methoxy, then Ar1 does not represent unsubstituted phenyl; (j) when X is O, Y is C =O, Z is a single bond, R1 is methyl, R2 and R3 together represent a bond then:
(i) when R4 is H Ar1 does not represent unsubstituted phenyl, 3-bromo-, 3-methoxy- or
3-methylphenyl; and
(ii) when A2 is CR4 where R4 is nitro or bromo, then Ar1 does not represent unsubstituted phenyl, 3-bromo- or 3-methylphenyl;
(k) when X is O, Y is CH2 or (CH )2, Z is a single bond, R2 and R3 both represent H or together represent a bond, and R1 and R4 represent H, then Ar1 does not represent unsubstituted phenyl;
(1) when X is O, Y is CH2, Z is a single bond, R2 and R4 represent H, and:- (i) R1 is H and R3 is methyl, then Ar1 does not represent unsubstituted phenyl;
(ii) R1 and R3 represent H, then Ar1 does not represent 4-chloro- or 4-methylphenyl;
(iii) R1 is methyl and R3 is H, then Ar1 does not represent unsubstituted phenyl, 4-chloro- or 4-methylphenyl; (m) when X is O, Y is C =O, Z is a single bond, R2 and R3 together represent a bond and Ar1 is unsubstituted phenyl and:-
(i) R1 is methyl, then A2 is not CR4 where R4 is chloro or methyl; and (ii) R1 is ethyl, then A2 is not CR4 where R4 is H; (n) when X and Y both represent CH2, Z is a single bond, A2 is CR4 where R4 is H and:- (i) R1, R2 and R3 represent H, then Ar1 does not represent unsubstituted phenyl or 3-chlorophenyl;
(ii) R1 is H or methyl and R2 and R3 together represent a bond, then Ar1 does not represent unsubstituted phenyl;
(o) when X is S, Y and Z both represent single bonds, R2 and R3 together represent a bond and R1 and R4 represent H, then Ar1 does not represent unsubstituted phenyl, 3-chloro- or 4-methoxyphenyl; or a pharmaceutically acceptable derivative thereof.
A sub-class of compounds of formula (I) are compounds of formula (LA):
Figure imgf000010_0001
wherein
X represents O, S(O)m or CH2;
Y represents a single bond, C(R3)R4 or (CH2)n; m represents 0, 1 or 2; n represents 1 or 2; R represents one or more substituents selected from H, hydroxy, halogen, nitro, cyano, phenyl, CO2R5, NR6R7, NR8C(O)R9, methoxy (optionally substituted by CO2R10), C,_^ alkyl or C _6 alkoxy (which latter two groups are optionally substituted by one or more substituents selected from NH , hydroxy or CO2R! ');
R1 and R2 both represent H or together represent a bond; R3 and R4 independently represent Cι_$ alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidyl ring;
R6 represents H, C|_6 alkyl or, together with R7 and the nitrogen atom to which it is attached, forms a pyrrolidinyl or piperidyl ring;
R7 represents H, C\-f, alkyl, CH2Ar2 or, together with R6 and the nitrogen atom to which it is attached, forms a pyrrolidinyl or piperidyl ring;
R9 represents H, C1-.5 alkyl or Ar3; R5, R8, R10 and R1 ' independently represent H or C|_r3 alkyl; and
Ar1 represents pyridyl, benzothiazolyl, quinolyl or quinoxalinyl all of which are optionally substituted by one or more substituents selected from halogen, hydroxy, methoxy (optionally substituted by halogen), phenoxy, C _fj alkoxy and Cj_6 alkyl (which latter three groups are optionally substituted by one or more substituents selected from halogen, hydroxy or Cι_6 alkyl);
Ar and Ar independently represent phenyl optionally substituted by one or more substituents selected from halogen, hydroxy, methoxy (optionally substituted by halogen), phenoxy, C _<5 alkoxy and Cj_fj alkyl (which latter three groups are optionally substituted by one or more substituents selected from halogen, hydroxy or C|_6 alkyl); provided that when A represents C2_δ alkoxy substituted by hydroxy or NH2, or when Ar1,
Ar2 or Ar3 are substituted by C _<5 alkoxy substituted by hydroxy, then the hydroxy or NH2 substituent as appropriate is not attached to the carbon atom which is α to the oxygen; and further provided that:
(a) when X represents O, Y represents CH2 and A, R1 and R2 all represent H, then Ar1 does not represent 2-pyridyl; and
(b) when X and Y both represent CH , and A, R1 and R~ all represent H, then Ar1 does not represent benzothiazol-2-yl; or a pharmaceutically-acceptable derivative thereof
A further sub-class of compounds of formula (I) are compounds of formula (IB):
Figure imgf000011_0001
wherein
X represents O or S;
Y represents CH2 or (CH2)2;
R" represents H, C,.6 alkyl or CH2ORl3;
R2 represents H, Cι-6 alkyl, or together with R3 forms a bond;
R3 represents H, or together with R2 forms a bond;
R13 represents H or Cι.6 alkyl; and
Ar1 represents phenyl optionally substituted by one or more substituents selected from halogen, methyl and trifluoromethyl; or a pharmaceutically acceptable derivative thereof.
Certain compounds of formula I are known in the prior art in non-pharmaceutical indications.
According to a further aspect of the invention there is provided a compound of formula I, as hereinbefore defined, with the additional provisos that: • when A, A1, A2 and A3 form a phenyl ring:
(h) when X is S, Y is (CH2)2, Z is a single bond and R1, and R2, R3 and R4, represent H, then Ar1 does not represent unsubstituted phenyl;
(j) when X is O, Y and Z both represent CH2, R1, R2 and R3 represent H, and A2 is CR4 where R4 is OH or methoxy, then Ar1 does not represent unsubstituted phenyl;
(k) when X is O, Y is C =O, Z is a single bond, R1 is methyl, R2 and R3 together represent a bond, and:-
(i) A, A1, A2 and A3 are all CH, then Ar1 does not represent unsubstituted phenyl, 3-bromo-, 3-methoxy- or 3-methylphenyl; and (ii) A, A1 and A3 are all CH and A2 is CR4 where R4 is nitro or bromo, then Ar1 does not represent unsubstituted phenyl, 3-bromo- or 3-methylphenyl; or a pharmaceutically acceptable derivative thereof for use as a pharmaceutical.
According to the invention there is also provided a process for the preparation of compounds of formula I which comprises:
(a) Preparation of a compound of formula I, wherein X is S, O or CH2, Y is a single bond or (CH2)n, Z is a single bond and n is as hereinbefore defined, by cyclisation of a compound of formula II:
Figure imgf000012_0001
wherein Xa is S, O or CH2, Ya is a single bond or (CH2)n and p, A, A1, A2, A3, Ar1, n, R1, R2, R3 and R4 are as hereinbefore defined, for example by heating (eg to around 140°C) in the presence of a suitable organic solvent (eg xylene). I I
(b) Preparation of a compound of formula I, wherein X is S or O, Y is C=O, Z is a single bbooind and R2 and R3 together represent a bond by, by cyclisation of a compound of formula
IH:
Figure imgf000013_0001
wherein Xb is S or O, and p, A, A1, A2, A3, Ar1, R1 and R4 are as hereinbefore defined, for example by heating (eg to around 140°C) in the presence of a suitable organic solvent (eg xylene).
(c) Preparation of a compound of formula I, wherein X represent S, O or CH2, Y is a single bond or (CH2)n, Z is a single bond and n is as hereinbefore defined, by cyclisation of a compound of formula IV:
Figure imgf000013_0002
wherein Xa, Ya, p, A, A1, A2, A3, Ar1, R1, R2, R3 and R4 are as hereinbefore defined, for example at reflux in the presence of N-chlorosuccinimide and a base (eg triethylamine) and an appropriate organic solvent (eg tetrahydrofuran); or at 0°C in the presence of sodium hypochlorite followed by addition of appropriate base (eg triethylamine) and a suitable organic solvent (eg dichloromethane).
(d) Preparation of a compound of formula I, wherein X is S, O or CH2, Y is (CH )n, Z is a single bond and n is as hereinbefore defined, by oxidation of a compound of formula V:
Figure imgf000014_0001
or an acid addition salt thereof, wherein Yb is (CH2)„ and n, A, A1, A2, A3, Xa, p, Ar1, R1, R2, R3 and R4 are as hereinbefore defined, for example by heating under reflux in the presence of a suitable organic solvent (eg xylene).
(e) Preparation of a compound of formula I, wherein X is S, O or CH2, Y is a single bond,
(CH2)n or C(R8)R9, R8 and R9 are independently Cι-6 alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidinyl ring, Z is a single bond, R1, R" and R3 represent H and n is as hereinbefore defined by reaction of a compound of formula VI:
Figure imgf000014_0002
wherein R is N(CH3)2 or N+(CH3)3I\ Y° is a single bond, (CH2)n or C(R8c)R9c, R8c and R9c are independently C|.6 alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidinyl ring, and A, A1, A2, A3, Xa, n, p and R4are as hereinbefore defined, or, when R is N(CH3)2 or an acid addition salt thereof, with a compound of formula VQ:
Ar'NHNH2 (VII) wherein Ar1 is as hereinbefore defined, or an acid addition salt thereof, for example by heating to 70°C in the presence of a suitable base (eg triethylamine) and an appropriate organic solvent (eg ethanol or n-propanol).
(f) Preparation of a compound of formula I, wherein X is S, O or CH2, Y is a single bond, (CH2)n or C(R8)R9, R8 and R9 are independently Ci-β alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidinyl ring, Z is a single bond, R , 11 : is. H, R2 and R3 together represent a bond and n is as hereinbefore defined by reaction of a compound of formula VILI:
Figure imgf000015_0001
wherein A, A1, A2, A3, Xa, Yc, p and R4 are as hereinbefore defined, with a compound of formula VII as hereinbefore defined, or an acid addition salt thereof, for example by heating to reflux in the presence of an suitable organic solvent (eg glacial acetic acid).
(g) Preparation of a compound of formula I, wherein Y is a single bond, (CH2)n or C(R8)R9 aanndd RR88 aanndd RR99 aarree iinnddeeppeennddeennttllyy CCιι__66 aallkkyyll,, ZZ iiss CCHH ,, RR22 iiss HH,, R3 is H or Cι-6 alkyl and n is as hereinbefore defined, by reducing a compound of formula IX:
Figure imgf000015_0002
wherein R3a is H or C^ alkyl and A, A1, A2, A3, X, Yc, p, Ar1, R1 and R4 are as hereinbefore defined, for example at or below room temperature in the presence of a suitable reducing agent (eg borane) and an appropriate organic solvent (eg tetrahydrofuran).
(h) Preparation of a compound of formula I, wherein X is O or S, Y is a single bond, (CH2)n or C(R8)R9 and R8 and R9 are independently Cι-6 alkyl, Z is a single bond, R1 and R2 both represent H, R3 is Cι.6 alkyl and n is as hereinbefore defined, by reducing a compound of formula X:
Figure imgf000015_0003
wherein Yd is a single bond, (CH2)n or C(R8d)R9d and R8d and R9d are independently Cι-6 alkyl, R3b is d.6 alkyl and A, A1, A2, A3, Xb, n, p, Ar1, R4, R5, R6 and R7 are as hereinbefore defined, for example at or below room temperature in the presence of a suitable reducing agent (eg borane) and an appropriate organic solvent (eg tetrahydrofuran). and optionally thereafter any of the above processes:
• removing any protecting groups
• converting the compound of formula (I) into a further compound of formula (I)
• forming a pharmaceutically acceptable derivative.
Compounds of formula (I) can be converted into a further compound of formula (I) using procedures known in the art, for example:
(a) Preparation of a compound of formula I, wherein R4 represents NRIOC(O)R' ' and R10 is C[.6 alkyl, by reaction of a corresponding compound of formula I, wherein R10 is H with a compound of formula XI:
Rl lHal (XI)
wherein R11 is Cι_6 alkyl and Hal is Cl, Br or I, for example at room temperature in the presence of a suitable base (eg potassium carbonate) and an appropriate organic solvent (eg dimethylformamide).
(b) Preparation of a compound of formula I, wherein R4 represents NR10C(O)R11 and R10 and R1 ' are as hereinbefore defined, by reaction of a corresponding compound of formula I, wherein R4 represents NHR10 wherein R10 is H or Cι.6 alkyl with a compound of formula XII: Rl lC(O)OH (XH)
wherein R11 is as hereinbefore defined, for example at room temperature in the presence of an appropriate peptide synthesis agent (eg dicyclohexylcarbodiimide and catalytic 4-dimethylaminopyridine) and a suitable organic solvent (eg dichloromethane or dimethyl- formamide).
(c) Preparation of a compound of formula I, wherein R4 represents NR8R9, R8 is H or
C|.6 alkyl and R9 is CH2(Cι.5 alkyl), by reduction of a corresponding compound of formula I, wherein R4 represents NR10C(O)R", wherein R10 and R11 are as hereinbefore defined and R10 and R8 correspond, for example at room temperature in the presence of a suitable reducing agent (eg borane) and an appropriate organic solvent (eg tetrahydrofuran). (d) Preparation of a compound of formula I, wherein R represents NHR8 and R8 is H or C|.6 alkyl, by hydrolysis of a corresponding compound of formula I, wherein R4 represents NR10C(O)CH3 and R10 is as hereinbefore defined and corresponds with R8, for example at reflux in the presence of aqueous acid (eg hydrochloric acid).
(e) Preparation of a compound of formula I, wherein R4 represents NR8R9 and R8 and R9 represent Cμ6 alkyl or, together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidyl ring, by reaction of a corresponding compound of formula I, wherein R4 represent NH , with a compound of formula XHI:
RxCHO (xm)
wherein R is C|.5 alkyl or HC(O)A\ wherein Ax is C2.3 alkylene, and a suitable reducing agent (eg sodium cyanoborohydride) for example at room temperature in the presence of zinc chloride and appropriate organic solvent (eg methanol).
(f) Preparation of a compound of formula I wherein R4 represents cyano by reaction of a corresponding compound of formula I wherein R4 represents bromine with copper (I) cyanide, for example at reflux in the presence of N-methylpyrrolidone.
(g) Preparation of a compound of formula I wherein R represents amidoxime by reaction of a corresponding compound of formula I wherein R4 represents cyano with hydroxylamine, for example at reflux in the presence of a suitable base (eg potassium carbonate) and an appropriate organic solvent (eg methanol).
(h) Preparation of a compound of formula I wherein R4 groups represent fluorine by reaction of a compound of formula IV via decomposition of the appropriate diazonium salt with sodium tetrafluoroborate, for example by heating to 170°C in the presence of a suitable organic solvent (eg 1 ,2-dichlorobenzene). Alternatively, when the counter ion is tetrafluoroborate, compounds of formula I may be prepared by heating the diazonium salt to 170°C, in the presence of a suitable organic solvent (eg 1 ,2-dichlorobenzene).
(i) Preparation of a compound of formula I wherein R4 represents nitro by reaction of a diazonium salt of formula TV, as hereinbefore defined with sodium nitrite, for example at room temperature in the presence of copper powder and an appropriate solvent (eg water). (j) Preparation of a compound of formula I wherein R4 represents chlorine by reaction of a diazonium salt of formula IV, as hereinbefore defined with copper (I) chloride, for example by warming in a suitable solvent (eg aqueous ethanol).
(k) Preparation of a compound of formula I wherein R4 represents bromine by reaction of a diazonium salt of formula IV, as hereinbefore defined with copper (I) bromide, for example by warming in a suitable solvent (eg aqueous ethanol).
(1) Preparation of a compound of formula I wherein R4 represents iodine by reaction of a diazonium salt of formula IV, as hereinbefore defined with potassium iodide, for example by warming in a suitable solvent (eg aqueous ethanol).
(m) Preparation of a compound of formula I wherein R4 represents NH2 by reduction of a corresponding compound of formula I, wherein R4 represents nitro in the presence of a suitable reducing agent (eg iron and ammonium chloride) for example by heating to reflux in the presence of a suitable solvent (eg aqueous ethanol).
(n) Preparation of a compound of formula I wherein R4 represents CO2H by hydrolysis of a corresponding compound of formula I, wherein R represents cyano under appropriate conditions for example by refluxing in the presence of 50% sulphuric acid.
(o) Preparation of a compound of formula I wherein R4 represents CO2R7 and R7 is Cι_6 alkyl, by esterification of a corresponding compound of formula I, wherein R4 represents CO2H, in the presence of a compound of formula XIV:
C,.6 alkyl-OH (XIV) and a suitable acid or base catalyst or activating agent (eg thionyl chloride).
(p) Preparation of a compound of formula I wherein R4 represents OH by hydrolysis of a corresponding compound of formula I wherein R4 represents Cι_6 alkoxy, for example at -78°C in the presence of a suitable Lewis acid (eg boron tribromide or aluminium tribromide in ethanethiol) and an appropriate organic solvent (eg dichloromethane). (q) Preparation of a compound of formula I wherein R4 represents C|.6 alkoxy, by reaction of a corresponding compound of formula I wherein R4 represents OH with a compound of formula XV:
RΗal (XV)
wherein R' is Cι_6 alkyl and Hal is as hereinbefore defined, for example at room temperature in the presence of base (eg sodium hydride) and an appropriate organic solvent (eg dimethylformamide).
(r) Preparation of a compound of formula I wherein R4 represents -g alkyl, by reaction of a corresponding compound of formula I wherein R4 represents OH with a compound of formula XVI:
R'(R")3Sn (XVI)
wherein R" is ^ alkyl and R' is as hereinbefore defined, for example by heating up to reflux temperature in the presence of a suitable catalyst system (eg palladium on activated carbon, triphenylphosphine and either dichIoro-(triphenylphosphine)palladium or lithium chloride and 2,6-di- rt-butyl-4-methylphenol) and an appropriate organic solvent (eg dimethylformamide or dioxane). Alternatively the OH group may be activated with the use of an appropriate activating agent (eg trifluoromethanesulphonic anhydride).
(s) Preparation of a compound of formula I wherein R4 represents phenyl, by reaction of a corresponding compound of formula I wherein R4 represents bromine with phenylboric acid, for example by refluxing in the presence of cesium fluoride and tetrakis- (triphenylphosphine)palladium and an appropriate organic solvent (eg dimethoxyethane).
(t) Preparation of a compound of formula I wherein R represents C .6 alkoxy substituted by CO2R12 where R12 is Cι.6 alkyl, by reaction of a corresponding compound of formula I wherein R4 represents OH with a compound of formula XVII:
R12OC(O)AΗal (XVTJ)
wherein A is C2.6 alkylene and R " and Hal are as hereinbefore defined, for example at room temperature in the presence of a suitable base (eg potassium carbonate) and an appropriate organic solvent (eg dimethylformamide). Alkylene groups which A5 may represent may be linear. (u) Preparation of a compound of formula I wherein R4 represents Cj.6 alkoxy substituted by CO2H, by hydrolysis of a corresponding compound of formula I wherein represents Cι-6 alkoxy substituted by CO2R15 and R15 is Cι-6 alkyl, for example at room temperature in the presence of a suitable hydrolytic agent (eg lithium hydroxide) and an appropriate organic/aqueous solvent system (eg tetrahydrofuran/water).
(v) Preparation of a compound of formula I wherein R4 is S02NR8R9, by reaction of a compound of formula XVHI:
Figure imgf000020_0001
wherein A, A1, A2, A3, X, Y, Z, R1, R2, R3 and Ar1 are as hereinbefore defined with a compound of formula XIX:
HNR8R9 (XLX)
wherein R8 and R9 are as hereinbefore defined, for example at room temperature in the presence of a suitable organic solvent (eg acetone or a mixture of acetone and tetrahydrofuran).
(w) Preparation of a compound of formula I, wherein X is S(O)m, and m is 1 or 2, by oxidation of a corresponding compound of formula I, wherein X is S, for example at room temperature in the presence of an appropriate quantity of a suitable oxidising agent (eg 3-chloroperoxybenzoic acid) and organic solvent (eg dichloromethane).
(x) Preparation of a compound of formula I, wherein R" and R together represent a bond, by
7 ^ oxidation of a corresponding compound of formula I, wherein R and R represent H, for example at room temperature in the presence of a suitable oxidising agent (eg manganese dioxide) and an appropriate organic solvent (eg dichloromethane).
(y) Preparation of a compound of formula I, wherein X is S, Y is C=O, Z is a single bond and R2 and R3 together represent a bond, by oxidation of a corresponding compound of formula I, wherein Y is CH2 and R2 and R3 represent H, in the presence of a suitable oxidising agent (eg manganese dioxide) and an appropriate organic solvent (eg dichloromethane)
Compounds of formula XVUI may be prepared by reaction of a corresponding compound of formula I, wherein R4 is H with chlorosulfonic acid, for example at or below room temperature
Compounds of formula II may be prepared by reaction of a compound of formula XX
Figure imgf000021_0001
wherein Ar is phenyl or phenyl substituted in the 4-posιtιon with, for example, methyl, methoxy, chloro or nitro, and A, A1, A2, A3, XJ, Ya, R1, R2, R3 and R4 are as hereinbefore defined, with a diazonium salt of formula XXI-
Ar'N2 + (XXI)
wherein Ar is as hereinbefore defined, for example between -20° and -10°C in the presence of pyndine
Compounds of formula II wherein Xa is O or S, Ya is a single bond, R1 is 6 alkyl, R2 is H and R is H or Ci alkyl, may be prepared by dehydration of a compound of formula XXJT
Figure imgf000021_0002
(xxπ) wherein R1 is Cι.6 alkyl, R3 is H or Cι.6 alkyl and A, A1, A2, A3, Xb, p, Ar1, R1 and R4 are as hereinbefore defined using a suitable dehydrating agent. Suitable agents which may be used include methyltriphenoxyphosphonium iodide, for example at room temperature in the presence of a suitable organic solvent (eg dimethylformamide) followed by the addition of strong base (eg sodium hydroxide) to liberate the alkene.
Compounds of formula r-Q may be prepared by reaction of a compound of formula XXUI:
Figure imgf000022_0001
wherein A, A', A A 2, A Λ i3, X vb°, p, Ar and R are as hereinbefore defined with a compound of formula XXIV
Figure imgf000022_0002
wherein R1 is as hereinbefore defined for example at room temperature in the presence of a suitable base (eg triethylamine) and an appropriate organic solvent (eg dichloromethane).
Compounds of formula IV may be prepared by reaction of a compound of formula XXV:
Figure imgf000022_0003
wherein A, A1, A", A , 3', v X-a, v Yaa, p, R1, R2, R3 and R4 are as hereinbefore defined, with a compound of formula VO as hereinbefore defined, for example between 0 and 80°C, in the presence of suitable organic solvent (eg methanol or ethanol). Compounds of formula V and acid addition salts thereof may be prepared by reaction of a compound of formula XXV, wherein Ya is (CH2)n and n is as hereinbefore defined with a compound of formula VE, or an acid addition salt thereof, for example between room temperature and reflux temperature in the presence of hydrogen chloride and a suitable organic solvent (eg diethyl ether).
Compounds of formula VI, wherein R is N(CH3)2 and acid addition salts thereof may be prepared by the Mannich reaction of a compound of formula XXVI:
Figure imgf000023_0001
wherein A, A1, A2, A3, Xa, Yc, p, and R4 are as hereinbefore defined, with formaldehyde and dimethylamine or acid addition salts thereof, for example by heating under reflux in the presence of acid and a suitable organic solvent (eg ethanol) followed by liberation of the free base if necessary. Alternatively, compounds of formula VI, wherein R is N(CH3) , may be prepared by the reaction of a compound of formula XXVI, as hereinbefore defined with N,N-dimethylmethylenearnmonium chloride, for example by heating under reflux in the presence of a suitable organic solvent (eg acetonitrile).
Compounds of formula VI, wherein R is Ν+(CH3)3I', may be prepared by reacting a corresponding compound of formula VI, wherein R is N(CH )2, with methyl iodide at room temperature in the presence of an appropriate organic solvent (eg acetonitrile).
Compounds of formula VIE may be prepared by reaction of a compound of formula XXVI as hereinbefore defined with methyl formate, for example at room temperature in the presence of a suitable base (eg sodium methoxide) and an appropriate organic solvent (eg ethanol).
Compounds of formula LX, wherein R3a is C|.6 alkyl may be prepared analogously to the method described in Example 2 of European Patent Application No. 181 145. Compounds of formula IX wherein R3a is H are known from Yaku. Zass. 110, 561 (1990) or ibid. 110, 573 (1990), or may be prepared analogously to the syntheses described therein.
Compounds of formula IX wherein R1 and R3a represent H may be prepared by reaction of a compound of formula XXVE:
Figure imgf000024_0001
wherein A, A1, A2, A3, X, Yc, p and R4 are as hereinbefore defined, with a compound of formula VE as hereinbefore defined, for example by heating to around 140°C in the presence of a suitable organic solvent (eg xylene).
Compounds of formula X are known from inter alia European patent application 0 354 694 or may be prepared analogously to the methods described therein.
Compounds of formula XX may be prepared by reaction of a compound of formula XXV as hereinbefore defined with a compound of formula XXV-E:
Figure imgf000024_0002
(XXV T)
wherein Ar" is as hereinbefore defined, for example between 0 and 80°C in the presence of an appropriate organic solvent (eg ethanol).
Compounds of formula XXE may be prepared by reaction of a compound of formula XXIX:
Figure imgf000024_0003
(XXIX) wherein A, A1, A2, A3, Xb, p, Ar2, Rl , R3c and R4 are as hereinbefore defined with a diazonium salt of formula XXI as hereinbefore defined, for example between -20° and -10°C in the presence of pyridine.
Compounds of formula XXEI may be prepared by reaction of a compound of formula XXX,
Figure imgf000025_0001
wherein A, A1, A2, A3, Xb, p, Ar2 and R4 are as hereinbefore defined with a diazonium salt of formula XXI as hereinbefore defined, for example between -20° and -10°C in the presence of pyridine.
Compounds of formula XXV may be prepared by oxidation of a compound of formula XXXI:
Figure imgf000025_0002
wherein A, A1, A2, A3, Xa, Ya, p, R1, R2, R3 and R4 are as hereinbefore defined with manganese dioxide, for example at room temperature in the presence of an suitable organic solvent (eg dichloromethane).
Compounds of formula XXV wherein Xa is S and Ya is (CH2)n and n, is as hereinbefore defined may alternatively be prepared by reaction of a compound of formula XXXE:
Figure imgf000025_0003
wherein A, A1, A2, A3, R4 and p are as hereinbefore defined with a compound of formula XXXEI:
Figure imgf000026_0001
wherein Yb, R1, R2 and R3 are as hereinbefore defined, for example at room temperature in the presence of a suitable base (eg lithium hydroxide) and an appropriate organic solvent (eg dimethylformamide).
Compounds of formula XXV wherein Xa is O and Yb is (CH2)n may be prepared by reaction of a compound of formula XXXIV:
Figure imgf000026_0002
wherein A, A1, A2, A3, R4 and p are as hereinbefore defined with a compound of formula
XXXV:
Figure imgf000026_0003
wherein Hal, Yb, R1, R2 and R3 are as hereinbefore defined, for example at reflux in the presence of potassium fluoride and a suitable organic solvent (eg acetone).
Compounds of formula XXVI wherein Yc is a single bond, (CH2)n or C(R8c)R c, R8c and R9c are independently C|.6 alkyl and n is as hereinbefore defined are known in the literature or can be prepared conveniently using known techniques. For example compounds of formula XXVI wherein Xa is S and Yc is (CH2)n and n is as hereinbefore defined may be prepared by dehydrative cyclisation of a compound of formula XXXVI:
Figure imgf000027_0001
(XXXVI)
wherein A, A1, A2 and A3 are CH or CR4 and n, p and R4 are as hereinbefore defined, in the presence of a suitable dehydrating agent (eg polyphosphoric acid) under appropriate reaction conditions (eg at 80°C).
Compounds of formula XXVI, wherein Xa is O and Yc is C(R8c)R9c, wherein R8c and R9c are independently d-6 alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidinyl ring may be prepared by reaction of a compound XXXVE:
Figure imgf000027_0002
(XXXVE)
wherein A, A , A , A , p and R are as hereinbefore defined with a compound of formula XXX VEI:
Ye =O (XXXVET) wherein Y is C(R8e)R9e and R8e and R9e are independently Cι.6 alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidinyl ring, for example by refluxing in the presence of base (eg pyrrolidine) and a suitable organic solvent (eg toluene).
Compounds of formula XXVE may be prepared by hydrolysis of a corresponding compound of formula XXXIX:
Figure imgf000027_0003
(XXXLX) wherein A, A1, A2, A3, X, Yc, p and R4 are as hereinbefore defined for example at reflux in the presence of a suitable hydrolytic agent (eg hydrochloric acid).
Compounds of formula XXIX may be prepared by reaction of a compound of formula XL:
Figure imgf000028_0001
wherein A, A1, A2, A3, Xb, Rla, R3c, p and R4 are as hereinbefore defined with a compound of formula XXVEI as hereinbefore defined, for example by refluxing in the presence of a suitable organic solvent (eg ethanol).
Compounds of formula XXX may be prepared by reaction of a compound of formula XLI:
Figure imgf000028_0002
wherein A, A1, A2, A3, Xb, p and R4 are as hereinbefore defined with a compound of formula XXVTE as hereinbefore defined, for example by heating to reflux in the presence of acid (eg hydrochloric acid) and a suitable organic solvent (eg ethanol).
Compounds of formula XXXI wherein Xa is O or S may be prepared by reaction of a compound of formula XLE:
Figure imgf000028_0003
wherein A, A1, A2, A , X , p and R are as hereinbefore defined with a compound of formula XLEI:
Figure imgf000029_0001
wherein Hal, Ya, R1, R2 and R3 are as hereinbefore defined, for example at room temperature in the presence of a base (eg potassium carbonate) and an appropriate organic solvent (eg dimethylformamide).
Compounds of formula XXXI wherein Xa is CH2 may be prepared by reaction of a compound of formula XLIV:
Figure imgf000029_0002
wherein A, A1, A2, A3, p and R4 are as hereinbefore defined with a compound of formula XLV:
Figure imgf000029_0003
wherein R", R1, R2 and R3 are as hereinbefore defined, for example by heating to 100°C in the presence of a suitable catalyst system (eg tetrakis(triphenylphosphine)palladium) and an appropriate organic solvent (eg toluene).
Compounds of formula XXXVI may be prepared by reaction of a compound of formula XLVI:
Figure imgf000029_0004
wherein A, A1, A2, A3, p and are as hereinbefore defined with a compound of formula XLVE: CH2=CH(CH2)pCO2H (XLVE) wherein p is 0 or 1 , for example at 65°C in the presence of a suitable base (eg pyrrolidine) and an appropriate organic solvent (eg dimethylformamide).
Compounds of formula XXXIX wherein X is SO or SO2 may be prepared by oxidation of a corresponding compound of formula XXXIX wherein X is S for example under appropriate reaction conditions in the presence of a suitable oxidising agent (eg 3-chloroperoxybenzoic acid) and an appropriate organic solvent (eg dichloromethane).
Compounds of formula XXXIX wherein X is O, S or CH may be prepared by reaction of a corresponding compound of formula XV wherein R is N+(CH3)3I" with sodium cyanide for example at room temperature in the presence of a suitable organic solvent (eg wet dimethylformamide).
Compounds for formula XL may be prepared by reaction of a compound of formula XXXE as hereinbefore defined with a compound of formula XLVEI:
Figure imgf000030_0001
(XLVEI) wherein Xb, Rla and R3c are as hereinbefore defined, for example between 75° and 150°C in the presence of a suitable base (eg potassium carbonate) and an appropriate organic solvent (eg dimethylformamide).
Compounds of formula XL wherein Xb is O may alternatively be prepared by reaction of a compound of formula XLI wherein Xb is O with a compound of formula XLEX:
Figure imgf000030_0002
wherein Rla and R3c are as hereinbefore defined for example at 95°C in the presence of a suitable base (eg potassium carbonate). Compounds of formula XVIE, XX, XXE, XXffl, XXV, XXVI, XXVE, XXIX, XXX, XXXI, XXXE, XXXIV, XXXVI, XXXVE, XXXIX, XL, XLI, XLE, XLIV and XLVI wherein one or more R4 groups represent OH, halogen, nitro, cyano, phenyl, CO2R7, NR8R9, NRI0C(O)R' ', C|-6 alkyl or Cj-6 alkoxy may alternatively be prepared according to the methods described in steps (a) to (t) above from appropriate corresponding intermediates of same general formulae. All novel intemediates form a further aspect of the invention.
Compounds V, VI, VE, VIE, X, XI, XE, XIE, XIV, XV, XVI, XVE, XIX, XXI, XXIV, xxvi, xxvm, XXXE, xxxm, xxxrv, xxxv, XXXVE, xxxvm, XLI, XLE, XLEI, XLIV, XLV, XLVI, XLVE, XLVEI and XLIX are either commercially available, are well known in the literature or may be prepared conveniently using known techniques.
It will be appreciated by those skilled in the art that in the process described above the functional groups of intermediate compounds may need to be protected by protecting groups.
Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl groups (eg rer -butyldimethylsilyl, rr-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable protecting groups for amino include tørt-butyloxycarbonyl or benzyloxy carbonyl. Suitable protecting groups for carboxylic acid include Cι-6 alkyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after a reaction step.
The use of protecting groups is fully described in "Protective Groups in Organic Chemistry', edited by J W F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis', 2nd edition, T W Greene & P G M Wutz, Wiley-Interscience (1991).
The compounds of the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals. In particular, the compounds of the invention possess antiallergic and anti-inflammatory activity, for example as shown in the tests described below.
The compounds of the invention are thus indicated for use in the treatment of allergic and inflammatory diseases of the airways such as asthma (e.g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (e.g. late asthma and airway hyper-responsiveness), bronchitis and the like.
Further, the compounds of the invention are indicated in the treatment of diseases including inflammations/allergies such as rhinitis, including all conditions characterised by inflammation of the nasal mucus membrane, such as acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta and rhinitis sicca, rhinitis medicamentosa, membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis, scrofoulous rhinitis, seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis.
The compounds of the invention are also indicated for use in the treatment of chronic allergic disorders, atopic dermatitis, cutaneous eosinophilias, eosinophilic fascitis, hyper IgE syndrome, vernal conjunctivitis, systemic lupus erythematosis, thyroiditis, lepromatous leprosy, sezary syndrome, chronic graft versus host disease, myasthenia gravis, idiopathic thromocytopenia pupura and the like.
The compounds of the invention may also have activity in both the prophylactic and therapeutic treatment of acquired immunodeficiency syndrome (AIDS), the prevention of chronic rejection of allografts mediated by humoral immunity, and in the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
Of particular interest amongst the above indications are the use of the compounds of the invention in asthma, especially the prophylaxis of asthma, and in rhinitis, most particularly allergic rhinitis and seasonal rhinitis including rhinitis nervosa (hay fever).
According to a further aspect of the present invention, there is provided a method of treatment of an allergic or an inflammatory disorder, in particular asthma, which comprises administration of a therapeutically effective amount of a compound of formula I as defined above, or a pharmaceutically acceptable derivative thereof, to a person suffering from, or susceptible to such a disease.
Administration of the compounds of the invention may be topical (for example by inhalation to the lung). The compounds of the invention may be inhaled as a dry powder which may be pressurized or non-pressurized. In non-pressurized powder compositions, the active ingredient in finely divided form may be used in admixture with a larger sized pharmaceutically acceptable inert carrier
The composition may alternatively be pressurized and contain a compressed gas, eg nitrogen, or a liquefied gas propellant. In such pressurized compositions, the active ingredient is preferably finely divided. The pressurized composition may also contain a surface active agent. The pressurized compositions may be made by conventional methods.
The compounds of the invention may be administered systemically (for example by oral administration to the gastrointestinal tract). The active ingredient may be formulated together with known adjuvants, diluents or carriers using conventional techniques to produce tablets or capsules for oral administration to the gastrointestinal tract.
Examples of suitable adjuvants, diluents or carriers for oral administration in the form of tablets, capsules and dragees include microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin.
According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula I as hereinbefore defined or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant diluent or carrier.
Suitable doses for administration topically or orally are in the range 0.01 to 30 mg kg"1 day"1, for example 0.3 mg kg'1 day"1.
It will be understood by those skilled in the art that certain functional groups in the compounds of the invention may be protected using appropriate protecting groups as hereinbefore described to form "protected derivatives" of compounds of the invention. It will also be appreciated that, although such protected derivatives may not possess pharmacological activity as such, they may be administered and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All protected derivatives and prodrugs of compounds of formula I are included within the scope of the invention.
The invention is illustrated by the following examples. Example 1
2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazoIe
(a) 3-[(N^V-dimethyI)aminomethyl]thiochroman-4-one
5 A solution of thiochroman-4-one (5.58 g) paraformaldehyde (0.99 g, 0.031 mol) dimethyl- a ine hydrochloride (3.47 g, 0.043 mol) and concentrated hydrochloric acid (0.9 ml) in ethanol (20 ml) was heated at reflux for 24 hours. The reaction mixture was then poured into water, basified with 2M sodium hydroxide and extracted with ether. The extracts were dried over anhydrous sodium sulphate and the solvent was removed in vacuo, yielding 7.10 g of the lo subtitle product as a yellow oil. GC/MS 222 (M+)
NMR Η (d6-DMSO) 52.17(6H) 2.55(1 H) 3.17(1H) 3.34(2H) 3.45(1 H) 7.22(1 H) 7.32(1 H) 7.46(1H) 7.93(1H)
!5 (b) 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole
A solution of 3-[(N,N-dimethyl)aminomethyI]thiochrornan-4-one (from step (a) above) and 4-chlorophenylhydrazine (8.84 g) in n-propanol (50 ml) was heated at reflux for 2 hours. A yellow solid precipitated, and was collected by filtration. This material was triturated with hot ethanol, collected by filtration and dried in vαcuo, to yield 5.16 g of title product as a yellow
20 solid. mp 152-153°C
MS 300,302 (M+)
ΝMR Η (d6-DMSO) δ 3.31(2H) 3.41(1H) 3.86(1H) 4.35(1H) 7.08(2H) 7.13(1H) 7.24(2H)
7.30(2H) 7.93(1 H)
25
Example 2
2-(4-Chlorophenyl)-3,3a,4,5-tetrahydro-2H-benz[g]indazole
(a) l-(l-oxo-2^,4,5-tetrahydronapthalene)-V^V; V-trimethyl-l-methanaminium iodide
Prep.ared according to the method of Example 1(a) from 1-tetralone, formaldehyde and 30 dimethylamine, followed by reaction of the resultant amine with methyl iodide.
(b) 2-(4-Chlorophenyl)-3,3a,4,5-tetrahydro-2H-benz[g]indazole
Prepared according to the method of Example 1(b) from l -(l-oxo-2,3,4,5-tetrahydronaptha- lene)-N,N,N-trimethyl-l-methanaminium iodide (1.6 g; from step (a) above) and 4-chloro- 35 phenylhydrazine (0.7 g). Recrystallisation from ethanol afforded the title compound as a solid (0.7 g). mp 129-130°C MS(EI) 282,284 (M+)
Example 3 2-(4-Chlorophenyl)-2,4-dihydro[l]benzopyrano[4,3-c]pyrazole.
A slurry of 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole (Bull. Chem. Soc. Jpn. (1984) 57, 134; 0.18 g) and manganese dioxide (0.90 g) in dichloromethane (40 ml) was stirred at room temperature for 24 hours. The solution was then filtered through celite and the filtrate evaporated to afford the title compound as a solid (0.09 g). mp 131-132°C.
MS(ESI) 283 (M+H+)
Example 4 2-(4-ChlorophenyI)[l]benzothiopyrano[4,3-c]pyrazoI-4(2H)-one. A slurry of 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole (0.6 g; from Example 1 above) and manganese dioxide (3.0 g) in dichloromethane (50 ml) was stirred at room temperature for 24 hours. The solution was filtered through celite and the filtrate evaporated. The product was then repeatedly recrystallised from aqueous ethanol to afford the title compound as a solid (0.09 g). mp 253-254°C
MS(EI) 312,314 (M+) I max 1743 cm"'
Example 5 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l ]benzothiopyrano[4,3-c]py razole, 5-oxide
To a solution of 2-(4-chlorophenyI)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole (1 g; from Example 1 above) in dichloromethane (40 ml) was added 3-chloroperoxybenzoic acid (70%; 0.82 g). After five minutes at room temperature the reaction mixture was poured into aqueous sodium hydrogen carbonate and extracted with dichloromethane. The extracts were washed with water and brine, then dried over anhydrous sodium sulphate. The solvent was removed in vacuo to afford a yellow foam. Column chromatography on silica gel, eluting with 1 : 1 ethyl acetate:isohexane followed by neat ethyl acetate, gave the two diastereomers of the title compound as yellow solids. The less polar diastereomer was recrystallised from ethanol to afford yellow needles (0.120 g). mp 238-239°C MS 316,318 (M+)
NMR 1H (d6-DMSO) δ 3.40(2H) 3.93(2H) 4.51(1H) 7.13(2H) 7.33(2H) 7.59(2H) 7.76(1H)
8.03(1H)
The more polar diastereomer was recrystallised twice from ethanol to afford yellow needles
(0.36 g). mp 193-194°C
MS 317,319 ((M+H)+)
NMR !H (d6-DMSO) δ 3.27(1H) 3.44(1H) 3.67(1H) 4.26(1H) 4.56(1H) 7.17(2H) 7.35(2H)
7.57(1H) 7.68(1H) 7.87(1H) 8.17(1H)
Example 6 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole, 5,5-dioxide
To a solution of 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole
(0.52 g; from Example 1 above) in dichloromethane (20 ml) was added 3-chloroper- oxybenzoic acid (50%; 1.8 g). The reaction mixture was stirred at room temperature for 1 hour, poured into aqueous sodium hydrogen carbonate and extracted with dichloromethane.
The extracts were washed with water and brine, then dried over sodium sulphate. The solvent was removed in vacuo to give a gold foam which was recrystallised from methanol, yielding the title compound as yellow needles (0.11 g). MS 332,334 (M+)
N NMMRR ΗΗ ((336600 MMIHz; d6-DMSO) δ 3.47(1H) 4.01(2H) 4.14(1H) 4.53(1H) 7.18(2H) 7.36(2H)
7.63(1H) 7.73(1H) 7.89 (IH) 8.13(1H)
Example 7 2-(4-ChlorophenyI)-2,4-dihydro[l]benzothiopyrano[4,3- ]pyrazole, 5,5-dioxide
A slurry of 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro-5,5-dioxide[ 1 ]benzothiopyrano[4,3-c]- pyrazole (0.12 g; from Example 6 above) and manganese dioxide (0.6 g) in dimethyl sul- phoxide w.as heated at 100°C for 200 hours. The reaction mixture was filtered, poured into water and extracted with ethyl acetate. The extracts were washed with water and brine then dried over sodium sulphate. Removal of the solvent in vacuo yielded an orange solid. Purification of this solid by column chromatography on silica gel, eluting with 1 :3 ethyl acetate:isohexane gave the title compound as a yellow solid (0.023 g). mp 241-2°C MS 331,333 ((M+H)+) NMR IH (d6-DMSO) δ 4.88 (2H) 7.44 (2H) 7.68 (IH) 7.83 (IH) 7.97 (3H) 8.12 (IH) 8.67 (IH) Example 8 2-(4-ChlorophenyI)-2,3,3a,4-tetrahydro-3a-methyI[l]benzothiopyrano[4,3-c]pyrazole
2-(4-ChlorophenyI)-3a,4-dihydro-3a-methyl[l]benzothiopyrano[4,3-c]pyrazol-3(2H)-one (0.197 g; from European Patent Application 0354 694) was cooled to 0°C and to this was added borane-tetrahydrofuran complex (1M solution in tetrahydrofuran; 3 ml). The reaction mixture was allowed to warm to room temperature and stirred for 3.5 days. Methanol was added carefully, then water and the mixture extracted with ethyl acetate. The extracts were washed with aqueous sodium hydrogen carbonate and brine then dried over anhydrous sodium sulphate. Removal of the solvent in vacuo yielded a yellow solid which on recrystallisation from ethanol gave the title compound as yellow crystals (0.08 g). mp 139-140°C MS 314,316 (M+) NMR IH (d6-DMSO) δ 1.42(3H) 3.16(1H) 3.55(2H) 4.12(1H) 7.09 - 7.32(7H) 7.91(1H)
Example 9
2-(4-ChlorophenyI)-2,3,3a,4-tetrahydro-4,4-dimethyl[l]benzothiopyrano[4,3-c]pyrazole
(a) 3-[(Dimethylamino)methyl]-2,3-dihydro-2,2-dimethyl-4H-[l]benzothiopyran-4-one-
2,3-Dihydro-2,2-dimethyl-4H-[l]benzothiopyran-4-one (0.25 g) and -V,N-dimethylmethylene- ammonium chloride (0.12 g) were suspended in acetonitrile (5 ml) and stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was then heated at reflux for 30 minutes in order to force the reaction to completion. The reaction mixture was allowed to cool to room temperature and poured onto dilute hydrochloric acid solution and washed with ethyl acetate (thrice). The aqueous phase was basified with dilute sodium hydroxide solution and extracted with ethyl acetate (thrice). The combined organic phase was then washed with brine and dried over sodium sulphate. Filtration and evaporation gave the subtitle compound as a yellow oil (0.1 1 g). MS(EI) 249 (M+)
(b) 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-4,4-dimethyl[l]benzothio- pyrano[4,3-c]pyrazole
Prepared according to the method of Example 1(b) from 3-[(dimethylamino)methyl]-2,3-di- hydro-2,2-dimethyl-4H-[l]benzothiopyran-4-one (0.1 g; from step (a) above) and 4-chloro- phenylhydrazine hydrochloride (0.1 g). Recrystallisation from ethanol gave the title compound as yellow needles (0.03 g). mp 176-177°C MS(EI) 328,330 (M+)
Example 10 2-(4-Chlorophenyl)-2,4-dihydro[l]benzothiopyrano[4,3-c]pyrazole 2-(Hydroxymethylene)thiochroman-4-one (2.17 g; J. Med. Chem. 1977, 20, 847) was dissolved in glacial acetic acid. 4-Chlorophenylhydrazine hydrochloride (2.24 g) was added and the temperature raised to reflux and then cooled. The reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were evaporated and the crude product purified by column chromatography on silica gel, eluting with 5% ethyl acetate in isohexane. Recrystallisation from ethanol yielded the title compound as a solid (0.41 g). mp 161-162°C MS(EI) 298,300 (M+)
Example 11 N-(2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3- ]- pyrazol-8-yl)acetamide (a) 3-{[4-(acetylamino)phenyl]thio}propanoic acid
4-Acetamidothiophenol (13.06 g) was dissolved in 1,4-dioxane (250 ml). Pyrrolidine (0.65 ml) was added followed by acrylic acid (5.35 ml). After stirring at room temperature for 24 hours, the resulting solid was filtered, washed with ether and dried in vacuo to afford the subtitle compound as a solid (16.84 g). MS(EI) 239 (M+) NMR lH (d6-DMSO); δ 10.0(1H); 7.5-7.3(4H); 3.0(2H); 2.5(2H); 2.0(3H)
(b) N-(2,3-dihydro-4-oxo-4H-[l]benzothiopyran-6-yl)acetamide
A mixture of 3-{[4-(acetylamino)phenyl]thio}propanoic acid (5 g; from step (a) above) and polyphosphoric acid (20.53 g) was heated at 80°C, with stirring, for 2 hours. The mixture was poured into ice water, made basic with 10% sodium hydroxide and extracted with ethyl acetate. The combined extracts were evaporated and the crude product purified by column chromatography on silica gel, eluting with 50-100% ethyl acetate in isohexane, to yield the subtitle compound as a solid (3.63 g) MS(EI) 221 (M+) NMR Η (d6-DMSO); δ 10.0(1H); 8.2-7.3(3H); 3.3(2H); 2.9(2H); 2.0(3H) (c) N-(2,3-Dihydro-3[(dimethylamino)methyl]-4-oxo-4H-[l]benzothiopyran-6-yl) acetamide
Prepared according to the method of Example 9(a) from N-(2,3-dihydro-4-oxo-4H-benzothio- pyr∑ιn-6-yl)acetamide (8 g; from step (b) above) and N^/V-dimethyl-methyleneammonium chloride (2.61 g) to yield the subtitle compound as a solid (6.96 g). MS(ESI+loop) 279 ((M+Η)+) ΝMR Η (d6-DMSO); δ 10.3(1H); 10.0(1H); 8.3-7.3(3H); 2.8(6H); 2.0(3H)
(d) N-(2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]- pyrazol-8-yl)-acetamide
Prepared according to the method of Example 1(b) from N-(2,3-dihydro-3-[(dimethylamino)- methyl]-4-oxo-4H-[l]benzothiopyran-6-yl)acetamide (6.96 g; from step (c) above) and 4-chlorophenylhydrazine (3.15 g). Recrystallisation from ethanol yielded the title compound as a solid (0.054 g) mp 231-232°C
MS(EI) 357,359 (M+)
Example 12 2-(4-Chlorophenyl)-6-fluoro-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole Prepared according to the method described in Example 1 using 8-fluoro-2,3-dihydro- -4H-l-benzopyran-4-one (J. Med. Chem., 1988, 31, 230) as starting material, mp 184°C MS(EI) 302,304 (M+)
Example 13
2-(4-Chlorophenyl)-7-fluoro-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole. (a) 7-Amino-2,3-dihydro-4H-l-benzopyran-4-one.
N-(2,3-Dihydro-4-oxo-2H-l-benzopyran-7-yl)acetamide (International Patent Application WO 89/07594; 1.0 g) was dissolved in ethanol (10 ml) and concentrated hydrochloric acid (10 ml) and heated at reflux under a nitrogen atmosphere for 30 minutes. The reaction mixture was allowed to cool to room temperature then basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (thrice). The combined organic phase was washed with brine and dried over sodium sulphate. Filtration and evaporation gave a brown oil which was triturated with diethyl ether to give the subtitle compound as a beige solid (0.68 g). (b) 7-Fluoro-2,3-dihydro-4H-l-benzopyran-4-one.
7-Amino-2,3-dihydro-4H-l-benzopyran-4-one (0.4 g; from step (a) above) was added portionwise to a cooled suspension of nitrosonium tetrafluoroborate (0.32 g) in dry dichloromethane (5 ml) under a nitrogen atmosphere. A dark precipitate formed which was stirred cold for 1 hour. 1,2-Dichlorobenzene (10 ml) was then added and the temperature was raised to 170°C for 1 hour. The crude mixture was purified by column chromatography (SiO2; isohexane then 20% ethyl acetate: isohexane) to give the subtitle compound as a yellow solid (0.21 g). mp 56-59°C MS(EI) 166 (M+)
(c) 2-(4-Chlorophenyl)-7-fluoro-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole.
Prepared according to the method of Example 9 using 7-fluoro-2,3-dihydro-4H-l-benzo- pyran-4-one (from step (b) above) as starting material. mp 155-156°C
MS(EI) 302,304 (M+)
Example 14 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-7-nitro[l]benzopyrano[4,3-c]pyrazole. (a) 7-Nitro-2,3-dihydro-4H-l-benzopyran-4-one.
7-Amino-2,3-dihydro-4H-l-benzopyran-4-one (50 mg) was added portionwise to a cold stirred suspension of nitrosonium tetrafluoroborate (40 mg) in dry dichloromethane (1 ml). The dark suspension was stirred cold for 1.5 hours before the solvent was removed. The residue was then suspended in water (1 ml) and added to a mixture of sodium nitrite (250 mg) and copper powder (50 mg) in water (2 ml). After stirring at room temperature for 15 minutes the mixture was diluted with water and extracted with ethyl acetate (thrice). The combined organic phase was washed with dilute hydrochloric acid and brine and dried over sodium sulphate. Filtration and evaporation gave a solid which was purified by column chromatography (SiO2:20% ethyl acetate/isohexane) to give the subtitle compound as an orange foam (20 mg). mp 133-135°C MS(EI) 193 (M+)
(b) 2-(4-Chlorophenyl)-2 3,3a,4-tetrahydro-7-nitro[l]benzopyrano[4,3-c]pyrazole. Prepared according to the method of Example 9 using 7-nitro-2,3-dihydro-4H- 1 -benzopyran- -4-one (from step (a) above) as starting material. mp 260-262°C MS(EI) 329,331 (M+)
Example 15 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-6-nitro[l]benzopyrano[4,3-c]pyrazole (a) 3-Nitro-2-(2-propenyloxy)benzaldehyde
A solution containing 2-hydroxy-3-nitrobenzaldehyde (9.13 g), potassium fluoride (15.8 g), and allyl bromide (7.0 ml) in acetone (50 ml) was stirred under reflux for 22 hours. The mixture was allowed to cool then filtered and evaporated leaving a pale solid (2.37 g). The crude product was used in the next step without further purification. MS(FAB) 208 ((M+H)+)
(b) 4-MethyIbenzenesulphonic acid {[3-nitro-2-(2-propenyloxy)phenyI]- methy lene } hydrazide A solution containing 3-nitro-2-propenyloxybenzaldehyde (2.32 g; crude from step (a) above), p-toluenesulphonyl hydr-azide (2.30 g) and concentrated hydrochloric acid (1 ml) in ethanol (40 ml) was heated to reflux temperature then allowed to cool. The subtitle compound (3.27 g) precipitated from the solution and was collected by filtration, p 148°C MS(FAB) 376 ((M+H)+)
(c) 2-(4-Chlorophenyl)-5-[3-nitro-2-(2-propenyloxy)phenyl]-2H-tetrazole
A solution containing p-chlorobenzenediazonium chloride was prepared by the dropwise addition of aqueous sodium nitrite (7.70 g in 100 ml) to a solution of p-chloroaniline ( 12.75 g) in a 1 : 1 mixture of 2M aqueous hydrochloric acid and tetrahydrofuran ( 100 ml), maintaining the temperature below 5°C. Following the addition, stirring was continued at 0°C (bath temperature) for 10 minutes. Of the resulting solution 25 ml was added to a solution of 4-methylbenzenesulphonic acid { [3-nitro-2-(2-propenyloxy)phenyl]- methylene} hydr-azide (1.96 g; from step (b) above) in pyridine (50 ml) whilst the temperature was maintained below -10°C. Following the addition, the reaction mixture was stirred overnight, being allowed to warm gradually to room temperature. The solution was then evaporated. The residue was partitioned between dilute aqueous hydrochloric acid and dichloromethane, and the organic layer was then dried (magnesium sulphate), filtered and evaporated. Filtration of the residue through a silica column, eluting with ether: isohexane mixtures then dichloromethane, evaporation of the solvent, followed by recrystallisation from ethanol gave the subtitle compound (1.24 g). mp 157-158°C MS(EI) 329 ((M-N2)+)
(d) 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-6-nitro[l]benzopyrano[4,3-c]pyrazole A solution of 2-(4-chlorophenyl)-5-[3-nitro-2-(2-propenyloxy)phenyl]-2H-tetrazole (0.92 g; from step (c) above) in xylene (50 ml) was heated under reflux for 18 hours. Evaporation followed by column chromatography using ether: isohexane: dichloromethane mixtures as the eluant gave the title compound (0.70 g) as an orange solid.
A sample of the material (0.1 g) was further purified by recrystallisation from dichloro- methane:isohexane, followed by dichloromethane:ethanol. mp 268-269°C
MS(EI) 329,331 (M+)
Example 16 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-6-methoxy[l]benzopyrano[4,3-c]pyrazole
(a) 3-Methoxy-2-(2-p ropen Ioxy )benzaldehyde
Prepared according to the method of Example 15(a) from o-vanillin (7.95 g), potassium fluoride ( 11.3 g), and allyl bromide (6.5 ml). The crude product was used without further purification.
(b) 4-MethyIbenzenesulphonic acid {[3-methoxy-2-(2-propenyloxy)phenyl]methylene}- hydrazide
Prepared according to the method of Example 15(b) from 3-methoxy-2-propenyloxybenz- aldehyde (10.07 g; crude from step (a) above) and p-toluenesulphonyl hydrazide (9.94 g) to give the subtitle compound as a colourless solid (10.91 g). mp 107°C MS(FAB) 361 ((M-Η)+)
(c) 2-(4-Chlorophenyl)-5-[3-methoxy-2-(2-propenyIoxy)phenyl]-2H-tetrazole Prepared according to the method of Example 15(c) from p-chloroaniline (4.68 g) and
4-methylbenzenesulphonic acid { [3-methoxy-2-(2-propenyloxy)- phenyl]methylene} -hydrazide (2.1 1 g; from step (b) above) to give the subtitle compound as a pale solid (1.24 g). mp 85-86°C MS(EI) 343,345 (M+) (d) 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-6-methoxy[l]benzopyrano[4,3-c]pyrazole
Prepared according to the method of Example 15(d) from 2-(4-chlorophenyl)-5-[3-methoxy- -2-(2-propenyloxy)phenyl]-2H-tetrazole (0.50 g; from step (c) above) to give the title compound (0.38 g) as a yellow solid. mp 183-184°C
MS(EI) 314,316 (M+)
Example 17 8-Chloro-2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole Prep-ared according to the methods described in Example 15, using 5-chloro-2-hydroxybenz- aldehyde as starting material, mp 165°C
MS(EI) 318,320 (M+)
Example 18
2-(4-Bromophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole
Prepared according to the methods described in Example 15, using 2-hydroxybenzaldehyde as starting material. The diazonium salt was prepared from 4-bromoaniline. mp 150-152°C MS(EI) 344,346 (M+)
Example 19 2-(4-Chlorophenyl)-8-methoxy-2,3,3a,4-tetrahydro[l]benzopyrano[4,3- ]pyrazole
Prepared according to the methods described in Example 15, using 5-methoxy-2-hydroxy- benzaldehyde as starting material, mp 136-137°C MS(EI) 314,316 (M+)
Example 20 6,8-DichIoro-2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole Prepared according to the methods described in Example 15, using 3,5-dichloro-2-hydroxybenzaldehyde as starting material. mp 213-214°C MS(EI) 352,354,356,358 (M+) Example 21 2-(4-Chlorophenyl)-3-methyl-2,3,3a,4-tetrahydro[l]benzopyrano[4,3- ]pyrazole
Prepared according to the methods described in Example 15, using 2-hydroxybenzaldehyde and crotyl bromide as starting materials. p 1 18-120°C
MS(GCMS) 298,300 (M+)
Example 22 2-(3-Bromo-4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole Prepared according to the methods described in Example 15, using 2-hydroxybenzaldehyde as starting material. The diazonium salt was prepared from 3-bromo-4-chloroaniIine, the latter being prepared by the reduction of commercially available 1 -bromo-2-chloro-4-nitro- benzene. mp 1 18°C MS(EI) 364 (M+)
Example 23 2-(4-Trifluoromethoxyphenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyr.azole
Prepatred according to the methods described in Example 1(b), from 3-[(N,N-dimethyl)amino- methyl]thiochroman-4-one (from Example 1 (a) above) and phenylhydrazine. mp 79-80°C MS(APCI) 351 ((M+H)+)
Example 24 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-7-methoxy[l]beπzopyraπo[4,3-c]pyrazole. Prepared according to the methods described in Example 15, using 4-methoxy-2-hydroxy- benzaldehyde as starting material, mp 147-148°C MS(EI) 314,316 (M+)
Example 25 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazoI-8-amine
A solution of N-(2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazol-8- -yl)acetamide (0.53 g; from Example 1 1 above) and concentrated hydrochloric acid ( 1 ml) in ethanol (15 ml) was heated at reflux for 5 hours. The reaction mixture was allowed to cool and the resulting solid filtered and washed with ethanol. The solid was stirred in saturated sodium bicarbonate and extracted thrice with ethyl acetate. The combined extracts were evaporated and the crude product purified by column chromatography on silica gel, eluting with 20% ethyl acetate in isohexane. Recrystallisation from ethanol yielded the title compound as a solid. mp 158-159°C
MS(EI) 315,317 (M+)
Example 26 2-(4-Chloro-2,6-dinitrophenyl)-2,3,3a,4-tetrahydro-5-oxide[l]benzothio- pyraπo[4,3-c]pyrazole.
To a solution of 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole (0.20 g; from Example 1 above) in acetic acid (10 ml) was added dropwise 70% nitric acid (0.3 ml). The solution was warmed to 40°C for 5 minutes and then diluted with water and extracted with ethyl acetate. The extracts were evaporated and purified by column chromatography on silica gel, eluting with 1 : 1 ethyl acetate/isohexane. The solid obtained was then recrystallised from methanol to afford the title compound as a solid, mp 237-239°C (dec.) MS(EI) 406,408 (M+)
Example 27
2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-6-oI
Boron tribromide (1M in dichloromethane; 2 ml) was added dropwise to a solution of 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro-6-methoxy[l]benzopyrano[4,3-c]pyrazole (138 mg; from Example 16 above) in dichloromethane (5 ml) stirred at -78°C. After 2 hours, the solution was allowed to warm to room temperature, and after 15 minutes the reaction mixture was added to aqueous sodium bicarbonate. The mixture was extracted with dichloromethane and the organic solution was dried (magnesium sulphate), filtered, and evaporated. Chromatography of the residue using ether: isohexane and ethyl acetate: isohexane mixtures as the eluants gave a yellow solid which was recrystallised from ethyl acetate:isohexane to give the title compound (54 mg). mp 177-178°C MS(EI) 300,302 (M+) Example 28 N-(2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-yI)acetamide
Prepared according to the method of Example 1(b) from N-[3-[(Dimethylamino)methyl]-3,4- -dihydro-4-oxo-2H-[l]benzopyran-7-yl]acetamide hydrochloride (2.80 g; from International Patent Application WO 89/07594) and 4-chlorophenylhydrazine (2.0 g) to yield the title compound as yellow crystals (0.13 g). mp 258-161 °C MS(EI) 341,343 (M+)
Example 29
2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-amine
N-(2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-yl)acetamide (0.46 g; from Example 28 above) was suspended in concentrated hydrochloric acid (5 ml) and ethanol (5 ml) and heated at reflux under a nitrogen atmosphere for 4 hours. The reaction mixture was allowed to cool to room temperature and the title compound as the hydrochloride salt was filtered off (0.42 g). 0.18 g of this was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate (thrice). The combined organic phase was washed with brine and dried over sodium sulphate. Filtration and evaporation followed by column chromatography (SiO2; 20% ethyl acetate: isohexane) and recrystallisation from ethanol gave the title compound as yellow crystals (0.07 g). mp 173-176°C MS(EI) 299,301 (M+)
Example 30 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-N^-dimethyI[l]benzopyrano- [4,3-c]pyrazoI-7-amine
Sodium cyanoborohydride (105 mg) and zinc chloride (1 10 mg) were dissolved in dry methanol (5 ml) and stirred at room temperature under a nitrogen atmosphere for 1 hour to give a colourless solution. 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]- pyrazol-7-amine (45 mg; from Example 29 above) was dissolved in dry methanol (0.5 ml), 37% aqueous formaldehyde solution (0.034 ml) and an aliquot of the sodium cyanoborohydride solution (0.9 ml) were added and the resulting mixture was stirred at room temperature for 5 hours. The solution was then poured onto 2M sodium hydroxide solution and extracted with ethyl acetate (thrice). The combined organic phase was washed with brine, dried over sodium sulphate then filtered and evaporated. Purification by column chromato- graphy (SiO2:20% ethyl acetate/isohexane) and recrystallisation from ethanol gave the title compound as a yellow solid (7 mg). mp 211-212°C MS(EI) 327,329 (M+)
Example 31 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-ol
Aluminium tribromide (7.8 g) was dissolved in ethanethiol ( 14 ml) and cooled in an ice bath under a nitrogen atmosphere. 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-7-methoxy[l]benzo- pyrano[4,3-c]pyrazole ( 1.85 g; from Example 24 above) was added portionwise and the mixture was stirred cold for 2 hours. Methanol was added carefully then diluted with water and acidified with dilute hydrochloric acid solution. The aqueous phase was extracted with dichloromethane (thrice). The combined organic phase was washed with brine and dried over sodium sulphate. After filtration and evaporation the residue was purified by column chromatography (SiO2: 1 % ethyl acetate/dichloromethane) to give the title compound as a solid (1.61 g). A small portion (0.1 g) was recrystallised from tert-butyl methyl ether/isohexane to give the title compound as a yellow solid (0.08 g). mp 180-182°C MS(EI) 300,302 (M+)
Example 32
Methyl {2-(4-chIorophenyI)-2,3,3a,4-tetrahydro[l]beπzopyrano[4,3-c]- py razol-7- I }oxy acetate
Methyl bromoacetate (0.16 ml) was added to a stirred mixture of 2-(4-chlorophenyl)- -2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-ol (0.5 g; from Example 31 above) and potassium carbonate (0.28 g) in dry dimethylformamide (15 ml) under a nitrogen atmosphere.
The mixture was stirred at room temperature for 16 hours then diluted with water and extracted with ethyl acetate (thrice). The combined organic phase was washed with dilute hydrochloric acid solution, sodium bicarbonate solution and brine and dried over sodium sulphate. Filtration and evaporation yielded a solid which was recrystallised from ethanol:ethyl acetate to give the title compound as a yellow solid (0.36 g). mp 171-173°C
MS(EI) 372,374 (M+) Example 33
{2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-yl}oxyacetic acid.
Methyl 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazol-7-yloxyacetate (0.12 g; from Example 32 above) and lithium hydroxide monohydrate (0.04 g) were suspended in 4: 1 tetrahydrofuran: water and stirred at room temperature under a nitrogen atmosphere for 16 hours. The resulting solution was poured onto dilute hydrochloric acid solution and extracted with ethyl acetate (thrice). The combined organic phase was washed with brine and dried over sodium sulphate. Filtration and evaporation yielded a solid which was recrystallised from tert-butyl methyl ether: isohexane to give the title compound as a pale yellow solid (0.047 g). mp 192-195°C MS(APCI) 359,361 (M+)
Example 34
2-(4-ChlorophenyI)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazol-6-amine (a) 2-(4-Chlorophenyl)-5-[3-amino-2-(2-propenyloxy)phenyl]-2H-tetrazole
2-(4-Chlorophenyl)-5-[3-nitro-2-(2-propenyloxy)phenyl]-2H-tetrazole (0.23 g; from Example 15(c) above), iron powder (0.98 g), ammonium chloride (0.98 g) were combined in 1: 1 ethano water (30 ml) and heated under reflux for 2 hours. The solution was filtered through celite, the celite was washed with dichloromethane and the combined organic phases concentrated. The residue was partitioned between water and dichloromethane, the organic phases were dried, filtered and concentrated. The crude product was chromatographed on silica (eluant 1:3 to 1 : 1 etheπisohexane) and crystallised from ethanol to give the subtitle compound (0.056 g). mp 107°C MS(EI) 327,329 (M+)
(b) 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazoI-6-amine Prepared according to the method of Example 15(d) from 2-(4-chlorophenyl)-5-[3-amino- -2-(2-propenyloxy)phenyl]-2H-tetrazole (from step (a) above) with a trace of butylated hydroxytoluene in the reaction mixture as an antioxidant. mp 130-131°C MS(APCI) 300,302 ((M+Η)+) Example 35
2-(4-Chlorophenyl)-2,3,3a,4-N^-dimethyl-tetrahydro[l]beπzopyrano-
[4,3-c]pyrazol-6-amine
Prepared according to the method described in Example 30 from 2-(4-chlorophenyl)- -2,3,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazol-6-amine ( 18.2 mg; from Example 34 above) to yield the title compound as a yellow solid, mp 175°C MS(EI) 327,329 (M+)
Example 36
2-(4-ChIorophenyl)-3,4,4a,5-tetrahydro-2H-indeno[l,2-c]pyridazine
2-(4-Chlorophenyl)-3,4,4a,5-tetrahydro-3H-indeno[l ,2-c]pyridazine-3-one (Yaku. Zass. 110, 561 (1990)) (165 mg) was placed in a flask under nitrogen. Borane tetrahydrofuran complex (1M; 5 ml) was added and the solution heated under reflux for 3 hours. The solution was cooled and methanol (5 ml) added. The solvents were evaporated and the resulting solid dissolved in ethyl acetate (10 ml). The solution was washed with water, hydrochloric acid (2.5 M; twice), sodium hydrogen carbonate (saturated solution; twice), and brine then dried over magnesium sulphate, filtered and concentrated to give a pale yellow solid. Recrystallisation from ethanol gave the title compound (84 mg). mp 164°C
MS(EI) 282,284 (M+)
Example 37 2-(4-Chlorophenyl)-3,4,4a,5-tetrahydro-2Η-[l]benzothiopyrano[4,3-c]pyridazine Prepared according to the method described in Example 36, from 2-(4-chlorophenyl)- -3,4,4a,5-tetrahydro-3H-benzothiopyrano[4,3-c]pyridazine-3-one (Yaku. Zass. 110, 573 (1990)). mp 133°C MS(EI) 314,316 (M+)
Example 38 2-(4-Chlorophenyl)-3,4,4a,5-tetrahydro-4a-methyl-2H-indeno[l,2-c]pyridazine
Prep.ared according to the method described in Example 36 from 2-(4-chlorophenyl)- -3,4,4a,5-tetrahydro-4a-methyl-3H-indeno[l,2-c]pyridazine-3-one (which was in turn prepared analogously to the method described in Example 2 of European Patent Application No. 181 145). mp 120-I21 °C MS(EI) 297,299 (M+)
Example 39 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydrobenzo[h]cinnoline
Prepared according to the method described in Example 36 from 2-(4-chlorophenyl)- -2,3,4,4a,5,6-hexahydrobenzo[h]cinnolin-3-one (Yaku. Zass. 110, 561 (1990)) mp 160-162°C MS(EI) 296,298 (M+)
Example 40
2-(4-ChlorophenyI)-3,4,4a,5-tetrahydro-2H-[l]benzopyrano[4,3-c]pyridazin-8-amine (a) 7-Amino-3,4-dihydro-4-oxo-2H-[l]benzopyran-3-acetic acid
N-[3-(Cyanomethyl)-3,4-dihydro-4-oxo-2H-l-benzopyran-7-yl]acetamide (0.49 g; International Patent Application WO 89/07594) was dissolved in concentrated hydrochloric acid (2 ml) and water (2 ml) and heated at reflux for 4 hours. On cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate (thrice). The combined organic phase was washed with brine and dried over sodium sulphate. Filtration and evaporation gave an oil which was triturated with diethyl ether to give the subtitle compound as a beige solid (0.2 g). MS(EI) 221 (M+)
(b) 8-Amino-2-(4-chIorophenyl)-4a,5-dihydro-2H-[l]benzopyrano[4,3-c]- pyridazin-3(4Η)-one 7-Amino-3,4-dihydro-4-oxo-2H-[l]benzopyran-3-acetic acid (0.25 g; from step (a) above), 4-chlorophenylhydrazine (0.18 g) and 4-chlorophenylhydrazine hydrochloride (0.06 g) were heated at reflux in xylene (10 ml) for 3 hours. A further portion of 4-chlorophenylhydrazine (0.05 g) was added and reflux continued for a further hour. The product was absorbed onto silica and chromatographed eluting with 3:2 isohexane:ethyl acetate. The product was triturated with ether then recrystallised from ethanol to give the subtitle compound (0.16 g). mp 208-209°C MS(EI) 327,329 (M+) (c) 2-(4-Chlorophenyl)-3,4,4a,5-tetrahydro-2H-[l]benzopyrano[4,3-c]pyridazin-8-amine
Prepared according to the method described in Example 36 from 8-amino-
-2-(4-chlorophenyl)-4a,5-dihydro-2H-[I]benzopyrano[4,3-c]pyridazin-3(4H)-one (from step (b) above). mp 223-224°C
MS(EI) 313,315 (M+)
Example 41 2-(4-Chlorophenyl)-N-ethyl-2,3,3a»4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-amine 1.0 M Borane-tetrahydrofuran complex in tetrahydrofuran (2.6 ml) was added dropwise to N-(2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[ l]benzopyrano[4,3-c]pyrazol-7-yl)- acetamide (from Example 28 above) cooled in ice under a nitrogen atmosphere. After allowing the mixture to warm to room temperature over 3 hours methanol was carefully added and the solvent was removed. Methanol (5 ml) and concentrated hydrochloric acid (0.5 ml) were then added and the mixture was warmed to 60°C for 10 minutes. On cooling to room temperature saturated sodium bicarbonate solution was added and the aqueous phase was extracted with ethyl acetate (thrice). The combined organic phase was washed with brine and dried over sodium sulphate then filtered and evaporated. Purification by column chromatography (SiO2:10% ethyl acetate:isohexane) and recrystallisation from ethanol gave the title compound as yellow needles (0.06 g). mp l62-163°C MS(EI) 327,329 (M+)
Example 42 7-Chloro-2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole
2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazol-7-amine hydrochloride (0.1 g; derived from Example 29 above) was suspended in concentrated hydrochloric acid (0.4 ml) and water (2 ml) and cooled in an ice bath to 0°C. A solution of sodium nitrite (0.022 g) in water (0.4 ml) was added dropwise maintaining the temperature below 5°C. The solution was stirred at 0°C for 15 minutes prior to dropwise addition to a cooled solution of copper (I) chloride (0.038 g) dissolved in concentrated hydrochloric acid (0.2 ml). The reaction mixture was allowed to warm to room temperature over 16 hours then briefly heated at reflux and diluted with water. The aqueous phase was extracted with ethyl acetate (thrice). The combined organic phase was washed with dilute hydrochloric acid solution, saturated sodium bicarbonate solution and brine then dried over sodium sulphate. Filtration and evaporation gave a solid which was purified by preparative HPLC (eluting with 5% ethyl acetate/isohexane) and recrystallised from ethanol to give the title compound as yellow crystals (0.02 g). mp 150-151°C
MS(EI) 318,320,322 (M+)
Example 43 2-(4-Chlorophenyl)-8-fluoro-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-cjpyrazole
Prepared according to the method of Example 1 using 6-fluorochromanone and 4-chloro- phenyl hydrazine. mp 154-155°C
MS(EI) 302,304 (M+)
Example 44
8-Chloro-2-(4-trifluoromethyIphenyl)-2,3,3a,4-tetrahydro[l]benzothio- pyrano[4,3-c]pyrazole
Prepared according to the method of Example 1 using 6-chlorothiochromanone and 4-trifluoromethylphenyl hydrazine. mp 174-6°C MS(EI) 368,370 (M+)
Example 45 2,3,3a,4-Tetrahydro-2-phenyl-[l]benzothiopyrano[4,3-c]pyrazole
Prepared according to the method of Example 1 using thiochromanone and phenyl hydrazine. mp 144-5°C MS(EI) 266 (M+)
Example 46
2-(4-ChIoropheπyl)-2,3,3a,4-tetrahydroindeno[l,2-c]pyrazole (a) 2-(N^-Dimethylanιinomethyl)-l-indanone Prepared according to the method of Example 2 from 1 -indanone and 4-chlorophenylhydrazine hydrochloride (0.70 g). mp l83-184°C (dec.) MS(EI) 268 (M+) Example 47 2-(4-Chlorophenyl)-2,4-dihydro-6-nitro[l]benzothiopyrano[4,3-c]pyrazole
Prepared according to the method of Example 3 from 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro- -6-nitro[l]benzopyrano[4,3-c]pyrazole (from Example 15 above). mp 237-239°C
MS(EI) 327,329 (M+)
Example 48 2-(4-ChIoropheπyl)-2,3,3a,4-tetrahydro-8-methoxy-[l]benzothiopyrano[4,3-c]pyrazoIe (a) 3-(4-Methoxyphenylthio)propionic acid
To a solution of 4-methoxythiophenol (24.2 g) in 1 ,4-dioxane (200 ml) was added pyrrolidine (1.4 ml), and acrylic acid (14.2 ml) and the reaction stirred at ambient temperature for 24 hours. A further portion of acrylic acid was added (7.1 ml) and again added (7.1 ml) after another 24 hours. The reaction was then poured into 2N hydrochloric acid and extracted with ethyl acetate three times. The extracts were then dried and evaporated. The solid obtained was triturated with isohexane and the subtitle compound was collected by filtration. MS(EI) 212 (M+)
(b) 6-Methoxythiochroman-4-one A slurry of 3-(4-methoxyphenylthio)propionic acid (1.09 g) in polyphosphoric acid (4.2 g) was heated at 80°C for 1 hour. The reaction mixture was then poured into ice:water and basified with sodium hydroxide, before extracting with ethyl acetate. The extracts were dried and evaporated and the crude product was purified by column chromatography on silica gel, eluting with 1 : 1 ethyl acetate: isohexane to afford the subtitle compound as an oil. MS(EI) 194 (M+)
NMR IH (salient features) CDC13 δ 2.97 (2H, t, CH2CO), 3.22 (2H, t, SCH2), 3.82 (3H, s, MeO), 7.62 (lH, s, ArH)
(c) 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-8-methoxy-[l]benzothiopyrano- [4,3-c]pyrazoIe
Prepared according to the method described in Example 1 from 6-methoxy-thiochroman- -4-one (from step (b) above), mp 89-90°C MS(EI) 330,332 (M+) Example 49 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-8-hydroxy-[l]benzothiopyrano[4,3-c]pyrazole
Prepared analogously to the method described in Example 27 from 2-(4-chlorophenyl)- -2,3,3a,4-tetrahydro-8-methoxy[l]benzothiopyrano[4,3-c]pyrazole (from Example 48 above). mp 104-106°C
MS(EI) 316,318 (M+)
Example 50
2,3,3a,4-Tetrahydro-2-(4-methylphenyl)[l]benzothiopyrano[4,3-c]pyrazole (a) 2-(2-Propenylthio)benzaldehyde
2-Nitrobenzaldehyde (15.1 g), potassium carbonate (15.0 g) and 2-propenethiol ( 14.0 ml) were suspended in dimethylformamide ( 150 ml) and heated to 65°C for 10 hours. The reaction mixture was poured into water and extracted five times with ether. The organic phases were combined, washed with brine twice, dried, filtered and concentrated. The product was chromatographed eluting with 23:2 isohexane:ethyl acetate to give the subtitle compound as a yellow oil (5.6 g). MS(EI) 178 (M+)
(b) l,2,3,3a,4,9b-Hexahydro-2-(4-methyIphenyl)[l]benzothiopyrano[4,3-c]pyrazole hydrochloride
2-(2-Propenylthio)benzaldehyde (0.250 g; from step (a) above), 4-methylphenylhydrazine hydrochloride (0.225 g) and ethereal HCl (1.0 M; 2 ml) were heated to reflux for 2 hours. The solvent was removed and the residue triturated with toluene. The resultant solid was collected by filtration to give the subtitle compound (0.215 g). MS(EI) 282 (free base; M+)
(c) 2,3,3a,4-Tetrahydro-2-(4-methylphenyl)[l]benzothiopyrano[4,3-c]pyrazole l,2,3,3a,4,9b-Hexahydro-2-(4-methylphenyl)[l]benzothiopyrano[4,3-c]pyrazole hydrochloride (0.205 g; from step (b) above) and triethylamine (0.10 ml) were stirred in dichloromethane (40 ml) for 30 minutes. The reaction mixture was washed with water and brine, dried, filtered and concentrated. The product was dissolved in xylene (10 ml) and heated to reflux for 2 hours. The solvent was removed and the product absorbed onto silica and chromatographed eluting with 19: 1 isohexane:ethyl acetate to give a solid that was recrystallised from ethanol to give the title compound (0.016 g). mp 161-162°C MS(EI) 280 (M+) Example 51
2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole-6-carbonitriIe
(a) 3-(2-Bromophenoxy)propanonitriIe
A solution containing 2-bromophenoI (17.3 g), aqueous benzyltrimethylammonium hydroxide (40%; 2 ml) and acrylonitrile was heated under reflux for 72 hours. The mixture was diluted with ether then washed with aqueous sodium hydroxide, and brine. Drying (magnesium sulphate) followed by evaporation gave the subtitle compound (1 1.98 g). mp 51-52°C (from ether: isohexane) MS(EI) 225, 227 (M+) 1H NMR (CDC13) 2.91 (2H, t), 4.26 (2H, t), 6.92 (2H, m), 7.28 (IH, t) 7.56 (IH, d)
(b) 3"(2-Bromophenoxy)propanoic acid
A solution containing 3-(2-bromophenoxy)propanonitrile (34.3 g; used crude from step (a) above), concentrated hydrochloric acid (50 ml) and acetic acid (200 ml) was heated under reflux overnight. The solution was allowed to cool, and then diluted with water. The subtitle compound (33.5 g) precipitated and was collected by filtration. mp 1 11°C (from ether: isohexane)
MS(GCMS) 244, 246
Η NMR (CDCI3) 2.94 (2H, t), 4.32 (2H, t), 6.86 (IH, t), 6.93 (IH, d), 7.26 (IH, m), 7.53 (lH, d)
(c) 8-Bromo-2,3-dihydro-4H-l-benzopyran-4-one
3-(2-Bromophenoxy)propanoic acid (20.1 g; crude from step (c) above), and polyphosphoric acid (200 g) were heated at 90°C for 4 hours, then poured onto ice. The product was extracted with ethyl acetate thrice, the extracts washed with brine, dried and evaporated. The residue was purified by chromatography (1 :9 etheπisohexane) to give the subtitle compound as a solid (15.3 g). mp 57-65°C (from ethanol)
MS(GCMS) 226, 228 Η NMR (CDCb) 2.86 (2H, t), 4.66 (2H, t), 6.92 (IH, t), 7.73 (IH, m), 7.87 (IH, m)
(d) 6-Bromo-2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole
8-Bromo-2,3-dihydro-4H-l-benzopyran-4-one (4.21 g; from step (c) above), and N-N-ώ- methyl- ethyleneammonium chloride (2.08 g) in acetonitrile (100 ml) were heated under reflux for 4 hours then evaporated. The residue, 4-chlorophenylhydrazine hydrochloride (4.97 g), triethylamine (15 ml), 4-t-butyl-2,6-dimethylphenol (a few crystals) and ethanol (200 ml) were heated under reflux for 3 hours and then evaporated. The residue was triturated with ethanol, and the remaining solid was recrystallised from ethanol to give the subtitle compound as a yellow solid (1.52 g). mp 182°C (from ethanol) MS(EI) 362, 364, 366 (M+)
Η NMR (DMSO-d6) 3.35 (IH, m), 3.88 (IH, m), 4.28 (2H, m), 4.86 (IH, dd), 6.96 (IH, t), 7.10 (2H, d) 7.31 (2H, d), 7.60 (IH, dd), 7.73 (IH, dd)
(e) 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole-6-carbonitrile A solution containing 6-bromo-2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]- pyrazole (348 mg), cuprous cyanide (0.26 g) and N-methyl-2-pyrrolidinone (6 ml) was heated under reflux for 1 hours. The reaction mixture was partitioned between dichloromethane and water, the organic layer was dried (magnesium sulphate) and evaporated to a residue which was redissolved in ethyl acetate and washed twice with water, then dried and concentrated. Chromatography ( 1 :1 to 3: 1 dichloromethane: isohexane) gave the title compound as a yellow solid (268 mg). mp 244-246°C (from ethanol) MS(EI) 309, 31 1 Η ΝMR (DMSO-d6) 3.39 (IH, dd), 3.96 (IH, m), 4.33 (IH, t), 4.36 (IH, t), 4.93 (IH, dd) 7.1 1 (2H, d), 7.17 (IH, t), 7.33 (2H, d), 7.77 (IH, d), 8.00 (IH, d)
Example 52 2-(4-Chlorophenyl)-2,3>3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-6-amidoxime
A solution containing 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole- -6-carbonitrile (47 mg; from Example 51 above), hydroxylamine hydrochloride (0.25 g), potassium carbonate (0.21 g) and methanol (10 ml) was heated under reflux overnight.
Aqueous work up followed by chromatography using ether then 9: 1 ether: dichloromethane then ethyl acetate as eluant followed by HPLC (2:3 ethyl acetate: dichloromethane) gave the title compound as a yellow solid (42 mg). mp 204-209°C (decomp.)
MS(FAB) 343, 345
Η ΝMR (DMSO-d6) 3.30 (IH, m), 3.86 (IH, m), 4.18 (IH, t), 4.29 (IH, t), 4.78 (IH, dd),
5.69 (2H, s), 7.01 (IH, t), 7.10 (2H, d), 7.31 (2H, d), 7.39 (IH, d), 7.76 ( IH, d), 9.46 (IH, s) Example 53
3-(2,3,3a,4-Tetrahydro[l]benzothiopyrano[4,3-c]pyrazol-2-yI)quinoIine
(a) 3-(N^V-Dimethylaminomethyl)[l]benzothiopyran-4-one
A solution of thiochroman-4-one (5.58 g), paraformaldehyde (0.99 g, 0.031 mol) dimethyl- amine hydrochloride (3.47 g, 0.043 mol) and concentrated hydrochloric acid (0.9 ml) in ethanol (20 ml) was heated at reflux for 24 hours. The reaction mixture was then poured into water, basified with 2M sodium hydroxide and extracted with ether. The extracts were dried over anhydrous sodium sulphate and the solvent was removed in vacuo, yielding 7.10 g of the subtitle product as a yellow oil. GC/MS 222 (M+)
NMR Η (de-DMSO) δ 2.17(6H) 2.55(1 H) 3.17(1H) 3.34(2H) 3.45(1 H) 7.22(1 H) 7.32(1 H)
7.46(1 H) 7.93(1 H)
(b) 3-(2,3,3a,4-Tetrahydro[l]benzothiopyrano[4,3-cjpyrazol-2-yl)quinoIine 3-(N,N-dimethylaminomethyl)[ 1 ]benzothiopyran-4-one hydrochloride (51 mg; prepared by reacting the intermediate of step (a) above with ethereal hydrogen chloride) and 3-hydr- azinoquinoline dihydrochloride (510 mg) were dissolved in a solution of ethanol (10 ml) containing triethylamine (0.335 ml). The mixture was heated to reflux under nitrogen for 5.5 hours then allowed to cool. The volatiles were removed on a rotary evaporator and the residues diluted with water and extracted with ethyl acetate (thrice). The combined organic extracts were washed with saturated brine, dried over magnesium sulphate and concentrated to a brown oil (500 mg) which was chromatographed on silica gel eluting with ethyl acetate:isohexane (1: 1) to produce an orange oil (130 mg). Recrystallisation from ethanol yielded the title compound as a brown solid (23 mg). mp 160-161°C MS(EI) 317 (M+)
NMR Η (ds-DMSO) δ 3.40 (2H; m), 3.60 (IH; dd), 3.95 (IH; ), 4.50 (IH; dd), 7.20 (IH; m), 7.30 (2H; d), 7.50 (2H; m), 7.60 (IH; d), 7.85 (IH; d), 7.95 (IH; d), 8.05 (IH; d), 9.10 (lH; d)
Example 54 2-(2,3,3a,4-Tetrahydro[l]benzothiopyrano[4,3-c]pyrazoI-2-yl)benzothiazoIe
Triethylamine (300 mg) was added to a solution of 2-hydrazinobenzothiazole (385 mg) and 3-(N,N-dimethylaminomethyl)[l]benzothiopyran-4-one hydrochloride (600 mg; prepared by reacting the intermediate of Example 1(a) above with ethereal hydrogen chloride) in ethanol (50 ml) and refluxed under nitrogen. After 105 minutes the reaction mixture was concen- trated and the residue dissolved in ethyl acetate and successively washed once with water, twice with dilute hydrochloric acid, twice with saturated sodium bicarbonate solution and once with brine, dried over magnesium sulphate, filtered and concentrated. Purification by chromatography eluting with isohexane:ethyl acetate (2: 1 ; 1 : 1 ; 1 :2) and recrystallisation from ethanol gave the title product (50 mg). mp 246°C MS(EI) 323 (M+)
NMR Η (d6-DMSO) δ 3.31 (IH; t), 3.45 (IH; t), 3.86 (IH; t), 3.98 (IH; dq), 4.56 (IH; t), 7.15 (IH; t), 7.20 (IH; t), 7.30 (3H; m), 7.58 (IH; d), 7.83 (IH; d), 7.90 (IH; d)
Example 55
2-(2,3,3a,4-Tetrahydro[l]benzopyrano[4,3-c]pyrazol-2-yl)benzothiazole
(a) 2,3-Dihydro-3-(dimethylaminomethyI)[l]benzopyran-4-one hydrochloride
Chroman-4-one (30 g), paraformaldehyde (12 g), dimethylamine hydrochloride (40 g) and concentrated hydrochloric acid (10 ml) were suspended in dry ethanol (150 ml) and heated under reflux overnight. The resultant solution was allowed to cool to ambient temperature and the solid that formed was collected, washed with ethanol and dried in vacuo to give the subtitle compound (40 g).
MS(EI) 206 (M+) NMR H (d^-DMSO) δ 2.81 (6H; br s), 3.1 (IH; dd), 3.6 (2H; m), 4.38 (IH; t), 4.90 (IH; dd),
7.10 (2H; m) 7.61 (IH; t), 7.79 (IH; d) and 10.7 (IH; br s)
(b) 2-(2,3,3a,4-Tetrahydro[l]benzopyrano[4,3-c]pyrazol-2-yl)benzothiazole
Prepared according to the method of Example 2 from 2-hydrazinobenzothiazole and 2,3-dihydro-3-(dimethylaminornethyl)[l]benzopyran-4-one hydrochloride (from step (a) above). mp >250°C
MS(EI) 307 (M+)
NMR Η (ds-DMSO) δ 3.77 (IH; t), 4.00 (IH; m), 4.25 (IH; t), 4.48 ( IH; t), 4.75 (IH; dd), 7.01 (IH; d), 7.07 (IH; t), 7.15 (IH; t), 7.33 (IH; t), 7.40 (IH; t), 7.58 (IH; d), 7.73 (IH; d),
7.83 (lH; d)
Example 56 2-(2,4-Dihydro[l]benzopyrano[4,3-c]pyrazoI-2-yl)benzothiazole o-Chloranil (360 mg) was added to a suspension of 2-(2,3,3a,4-tetrahydro[ 1 ]benzopyrano- [4,3-c]pyrazol-2-yl)benzothiazole (133 mg; from Example 3 above) in dimethyl sulphoxide (7 ml) and heated at 140°C for 2.5 hours. On cooling the reaction mixture was poured onto sodium hydroxide solution (2.5M) and extracted with dichloromethane (twice). The organic phases were washed once with sodium hydroxide solution (2.5M) and once with brine, dried, filtered and concentrated. Purification by chromatography eluting with isohexane.ethyl acetate (4: 1) and recrystallisation from ethyl acetate gave the title compound (22 mg). mp 206 - 209°C MS(EI) 305 (M+)
NMR Η (c-6-DMSO) δ 5.36 (2H; s), 7.00 (IH; d), 7.10 (IH; t), 7.33 (IH; t), 7.41 (IH; t), 7.50 (IH; t), 7.79 (IH; d), 7.88 (IH; d), 8.00 (IH; d), 8.49 (IH; s)
Example 57
3-(2,3,3a,4-Tetrahydro[l]benzopyrano[4,3-c]pyrazol-2-yl)quinoline
(a) 3-(5-(2-Propenyloxyphenyl)-2H-tetrazol-2-yl)quinoline
To a solution of 3-aminoquinoline in tetrahydrofuran (25 ml) and 2M hydrochloric acid ( 12 ml) was added a solution of sodium nitrite (240 mg) in water ( 12 ml) dropwise maintaining the reaction temperature below 5°C. The diazonium salt solution thus formed was added to a solution of 4-methylbenzenesulphonic acid [(2-propenyloxy-phenyl)methylene] hydrazide (Bull. Chem. Soc. lapan, 1980, 53, 429; 1.00 g) in pyridine (25 ml) maintaining the reaction temperature below -5°C. The reaction was allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was then poured into water and extracted with ethyl acetate thrice. The combined organic layers were washed with brine, dried over magnesium sulphate and evaporated. The residues were chromatographed on silica gel using ethyl acetate: isohexane (1:4) to give a pale yellow solid (600 mg) which was recrystallised from ethyl acetate to give the subtitle compound (575 mg) as a pale yellow solid. MS (APCI+loop) 302 ((M+H-N2)+)
NMR lH (d6-DMSO) δ 4.75(2H; d), 4.85 (IH; d), 5.20 (IH; d), 6.1-6.2 (IH; m), 7.1-7.2 (2H; m), 7.50 (IH; t), 7.70 (IH; t), 7.85 (IH; t), 8.00 (IH; d), 8.15 (IH; d), 8.25 (IH; d), 8.95 (IH; s), 9.70 (lH; s)
(b) 3-(2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-2-yl)quinoline
A solution of 3-(5-(2-propenyloxyphenyl)-2H-tetrazol-2-yl)quinoline (530 mg; from step (a) above) in xylene (50 ml) was heated to 150°C under nitrogen for 3 hours. The solution was then evaporated and the residue recrystallised from ethanol. Further purification using preparative HPLC (ethyl acetate:dichloromethane 3:47) gave the title compound (95 mg) as a bright yellow solid. MS(EI) 301 (M+) NMR Η (de-DMSO) δ 3.45 (IH; dd), 3.95 (IH; m), 4.20 (IH; t), 4.40 ( IH; t), 4.80 (IH; dd), 7.00 ( IH; d), 7.05 (IH; t), 7.35 (IH; t), 7.50 (2H; m), 7.60 (IH; d), 7.70 (2H; t), 7.90 (IH; d), 9.10 (lH; d)
Example 58
2,3,3a,4-Tetrahydro-2-(3-pyridyI)[l]benzopyrano[4,3-c]pyrazoIe
Prepared according to the method described in Example 5, starting with 3-aminopyridine. mp 134-5°C MS(EI) 251 M+ Η NMR (DMSO-d6) 3.30 (IH, m), 3.85 ( IH, m), 4.15 (IH, t), 4.30 (IH, t), 4.75 (IH, dd), 6.95 (IH, d), 7.05 (IH, t), 7.30 (2H, m), 7.45 (IH, d), 7.75 ( IH, d), 8.10 (IH, bs), 8.40 (IH, s)
Example 59 2-(2-Chloropyridin-5-yI)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole Prepared according to the method described in Example 5, starting with
5-amino-2-chloropyridine.
Figure imgf000060_0001
MS(EI) 285/287 (M+)
Η NMR (DMSO-de) 3.40 (IH, m), 3.90 (IH, m), 4.20 (IH, t), 4.35 (IH, t), 4.75 (IH, dd), 7.00 (IH, d), 7.05 (IH, t), 7.35 (IH, t), 7.40 (IH, d), 7.55 (IH, dd), 7.75 (IH, d), 8.20 (IH, d)
Example 60 2-(2-Chloropyridin-5-yl)-2,4-dihydro[l]benzopyrano[4,3-c]pyrazole
This compound was also isolated from the reaction mixture of Example 7. mp 188-90°C
MS(EI) 283/285 (M+)
Η NMR (DMSO-d6) 5.35 (2H, s), 7.00 (IH, d), 7.05 (IH, t), 7.30 (IH, t), 7.70 (IH, d), 7.75
(IH, d), 8.35 (IH, dd), 8.50 (IH, s), 9.00 (IH, s)
Example 61
2-(4-Chlorophenyl)-2,3,3a,4-tetrahydropyrazoIo[3',4,:4,5]thiopyrano[2,3-b]pyridine (a) 2-Chloro-3-(2-(4-chlorophenyl)-2H-tetrazoI-5-yl)-pyridine
Sodium nitrite (0.26 g) in water (2 ml) was added slowly to a solution of 4-chloroaniline in aqueous ethanol (1: 1; 20 ml) containing concentrated hydrochloric acid (2.5 ml) at 0-5°C. After 10 minutes the solution was transferred to a dropping funnel and added dropwise to a solution of 2-chloropyridine-3-carboxaldehyde tosylhydrazone (prepared from 2-chloro- pyridine-3-carboxaldehyde, the latter being prepared according to the method of Queguiner (J. Chem. Soc, (1990) Perkin Trans I, 2409)) in pyridine (25 ml) at 0°C. After 2.5 h the reaction mixture was diluted with ethyl acetate and water, and the layers separated. The aqueous phase was extracted once with ethyl acetate and then the combined ethyl acetate 5 layers were washed once with water, once with brine then dried over magnesium sulphate, filtered and concentrated to give a dark oil. Purification by chromatography, eluting with isohexane: ethyl acetate (3: 1) gave the subtitle product (0.47 g). MS(FAB) 292,294,296 ((M+H)+)
l o (b) 2-Propenylthio-3-(2-(4-chloropheny I)-2H-tetrazol-5-yI)-pyridine
Allyl mercaptan (1.2 ml) and potassium carbonate (0.9 g) were added to a solution of 2-chloro-3-(2-(4-chlorophenyl)-2H-tetrazol-5-yl)-pyridine (0.3 g; from step (a) above) in dimethylacetamide (15 ml) and heated at 50°C under nitrogen. After 2 hours heating was ceased and the reaction mixture allowed to stand at room temperature overnight. The dark 15 solution was diluted with ethyl acetate and water, acidified with hydrochloric acid (2.5 M) and the layers separated. The ethyl acetate layer was washed once with hydrochloric acid (2.5 M), twice with sodium hydroxide (2.5 M), once with brine then dried over magnesium sulphate, filtered and concentrated to give the partially purified subtitle product (1.0 g). MS(ESI) 330,332 ((M+H)+) 0
(c) 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydropyrazoIo[3',4':4,5]thiopyrano[2,3-b]pyridine
Partially purified 2-propenylthio-3-(2-(4-chlorophenyl)-2H-tetrazole-5-yl)- pyridine (1.0 g; from step (b) above) was dissolved in xylene (100 ml) and heated to reflux under nitrogen. After 1.75 hours the solvent was evaporated and the resultant residue 5 purified by chromatography, eluting isohexane:isopropyl alcohol (19: 1). Recrystallisation from ethanol gave the title product (0.092 g). mp 179-18TC MS(ESI) 302,304 ((M+H)+)
0 Example 62 l-(4-ChlorophenyI-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-3-yl) methanol (a) Dimethyl l-(4-chlorophenyl)-3-(2-chloropyridin-3-yI)-lH-pyrazole-4,5-dicarboxylate
2-ChIoro-3-(2-(4-chlorophenyl)-2H-tetrazol-5-yl)-pyridine (0.58 g; from Example 1(a) above) and dimethyl acetylenedicarboxylate (2.5 ml) were dissolved in xylene (20 ml) and 5 refluxed under nitrogen. After 19 hours the solvent was evaporated and the resultant residue purified by chromatography. Eluting isohexane:ethyl acetate (4: 1) gave the subtitle product
(0.51 g).
MS(ESI) 406,408,410 ((M+H)+)
(b) (l-(4-Chlorophenyl)-3-(2-chloropyridin-3-yl)-5-hydroxymethylpyrazoI-4-yI) methanol
Lithium aluminium hydride (1M in tetrahydrofuran; 2.25 ml) was added at -78°C to a solution of dimethyl l-(4-chlorophenyl)-3-(2-chloropyridin-3-yl)-lH-pyrazole-4,5- dicarboxylate (0.4 g; from step (a) above) in tetrahydrofuran (10 ml). After 17 hours and warming to ambient temperature, water was carefully added and the solution was basified with sodium hydrogen carbonate and then saturated with sodium chloride. The reaction mixture was extracted thrice with ethyl acetate and the pooled organic fractions dried over magnesium sulphate, filtered and concentrated. Purification by chromatography, eluting ethyl acetate:methanol (19: 1) gave the subtitle product (0.125 g). MS(ESI) 350,352,354 ((M+H)+)
(c) l-(4-Chlorophenyl-2,4-dihydropyrazoIo[3',4':4,5]pyrano[2,3-b]pyridin-3-yl) methanol
Sodium hydride (60% in oil; 0.03 g) was added at ambient temperature to a solution of (l-(4-Chlorophenyl)-3-(2-chloropyridin-3-yl)-5-hydroxymethylpyrazol-4-yl) methanol (0.1 15 g; from step (b) above) in dimethyl acetamide (5 ml). The reaction was kept at ambient temperature for 24 hours, then 80°C for 24 hours and then at 125°C for 58 hours. The cooled reaction mixture was partitioned between ethyl acetate and saturated bicarbonate solution and the organic phase washed once with saturate bicarbonate solution, once with brine, dried over magnesium sulphate, filtered and concentrated. Purification by chromatography eluting hexane:ethyl acetate (2:1/1:1/0:1) and recrystallisation from ethanol gave the title product (0.013 g). mp 257°C (decomp.) MS(EI) 313,315 (M+)
Example 63
2-(4-Chlorophenyl)-2,3,3a,4-tetrahydropyrazolo[3*,4':4,5]pyrano[2,3-b]pyridine
(a) 2-Prop-2-enyloxy-3-(2-(4-chlorophenyl)-2H-tetrazoI-5-yl)-pyridine
Allyl alcohol (0.1 ml), 60% sodium hydride (50 mg) and 15-crown-5 (0.25 ml) were added to a solution of 2-chloro-3-(2-(4-chlorophenyl)-2H-tetrazol-5-yl)-pyridine (0.3 g; from Example 1(a) above) in dimethylformamide (5 ml) under nitrogen at ambient temperature. After 4 hours further portions of allyl alcohol (2 drops), 60% sodium hydride (20 mg) and 15-crown-5 (0.1 ml) were added. After 18 hours, the magenta solution was diluted with ethyl acetate and water and the layers separated. The aqueous layer was extracted once more with ethyl acetate and the pooled ethyl acetate layers washed twice with saturated sodium bicarbonate solution, once with brine then dried over magnesium sulphate, filtered and concentrated. Purification by chromatography, eluting hexane:ethyl acetate (4: 1 ) gave the subtitle product (0.25 g). MS(ESI) 314,316 ((M+H)+)
(b) 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydropyrazoIo[3',4':4,5]pyrano[2,3-b]pyridine Prepared according to the method of Example 1(c) from 2-prop-2-enyloxy-3- (2-(4-chlorophenyl)-2H-tetrazole-5-yl)-pyridine (0.25 g; from step (a) above). MS(ESI) 286,288 ((M+H)+)
Example 64
2-(4-ChIorophenyl)-2,3,4,4a,5,6-hexahydropyridino[2,3-h]cinnoIine
1M Borane solution in tetrahydrofuran (lOml) was added at 25C to 2-(4-chlorophenyl)-
4,4a,5,6-tetrahydropyrido[2,3-h]cinnoIin-3(2H)-one (290mg), under nitrogen. After 2.5h methanol (10ml) and concentrated hydrochloric acid (0.1ml) were added and the resultant mixture heated to reflux for 30 minutes, then cooled and evaporated. The resultant residue was dissolved in ethyl acetate and extracted with sodium hydrogen carbonate soln. twice, once with brine, dried and evaporated. Recrystalisation from ethanol/water mixture gave the title compound (216mg).
MS (El) 297/299 mp 142-3C
IH NMR (DMSO) δ 1.55 ( IH, dq), 1.65(1H, dq), 2.20 (IH, br), 2.30 ( IH, br), 2.50 (IH, br), 2.95 (2H, br s), 3.40 (IH, dt), 4.07 (IH, br d), 7.24 (IH, dd), 7.30 (4H, q), 8.33 (IH, d),
8.38 (lH, d).
Example 65
2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydro-7-oxidopyridino[2,3-h]cinnoline
3-Chloroperoxybenzoicacid (35mg) was added at 25C to a solution of 2-(4-Chlorophenyl)- 2,3,4,4a,5,6-hexahydropyridino[2,3-h]cinnoline (example 64) (25mg) in dichloromethane (5ml). After 4 hours sodium metabisulfite was added until the reaction mixture tested negative to starch/KI. The reaction mixture was diluted with dichloromethane and extracted with sodium hydrogen carbonate soln., dried and evaporated. Purification by chromatography eluting ethyl acetate/methanol (4: 1 ) gave the title compound ( 17mg). MS (APCI) 314/316 M+H mp 202 C dec IH NMR (DMSO) δ 1.44 (IH, dq), 1.64 (IH, dq), 2.20 (2H, br), 2.59 (2H, br), 3.30 (lH. br s), 3.41 (IH, dt), 4.08 (IH, dt), 7.29 (IH, t), 7.34 (4H, q), 7.89 (IH, d), 8.21 ( IH, d).
Example 66 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydro-9-oxidopyridino[4,3-h]cinnoline 3-Chloroperoxybenzoicacid (35mg) was added at 25C to a solution of 2-(4-Chlorophenyl)- 2,3,4,4a,5,6-hexahydropyridino[4,3-h]cinnoline (example 68) (25mg) in dichloromethane (5ml). After 4 hours sodium metabisulfite was added until the reaction mixture tested negative to starch/KI. The reaction mixture was diluted with dichloromethane and extracted with sodium hydrogen carbonate soln., dried and evaporated. Purification by chromatography eluting ethyl acetate/methanol (4: 1) gave the title compound ( 19mg). MS (APCI) 314/316 M+H mp 216 C dec
IH NMR (DMSO) δ 1.42 (IH, dq), 1.63 ( IH, dq), 2.12 (IH, br d), 2.24 (IH, br d), 2.7-2.9 (3H, br m), 3.45 (IH, dt), 4.08 (IH, dd), 7.24 (IH, d), 7.35 (4H, s), 7.99 (IH, d), 8.55 (IH, S).
Example 67
2, 3, 4, 4a, 5, 6-Hexahydro-2-(4-methylphenyl)pyrido[3,4-h]cinnoline
A 1.0 M solution of borane tetrahydrofuran complex in tetrahydrofuran (2.4 ml) was added to the cooled 4, 4a, 5, 6-tetrahydro-2-(4-methylphenyl)pyrido[3,4-h]cinnolin-3(2H)-one (0.14 g). After addition, the mixture was allowed to warm to room temperature for 4 h before being carefully quenched with methanol followed by water. The aqueous phase was extracted with ethyl acetate (thrice). The combined organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulphate, filtered and evaporated to dryness. Purification by flash chromatography (3: 10 ethyl acetate/hexane then ethyl acetate) followed by recrystallisation from ethyl acetate/hexane gave the title compound as a yellow solid (30 mg). m.p. 158-159°C MS (El) 277 (M+, 100%) Η NMR (CDCI3) δ 1.55 (IH, td), 1.75 (IH, m), 2.20 (2H, ), 2.30 (3H, s), 2.45 (IH, m), 2.90 (2H, m), 3.50 (IH, td), 4.05 (IH, ), 7.15 (2H, d), 7.25 (2H, d), 7.90 (I H, d), 8.37 (2H, d).
Example 68
2-(4-Chlorophenyl)-2, 3, 4, 4a, 5, 6-hexahydro-pyrido[4,3-h]cinnoline A 1.0 M solution of borane tetrahydrofuran complex in tetrahydrofuran (5.6 ml) was added to the cooled 2-(4-chlorophenyl)-4, 4a, 5, 6-tetrahydropyrido[4,3-h]cinnolin-3(2H)-one (0.35 g). After addition, the mixture was allowed to warm to room temperature for 2 h before being carefully quenched with methanol. The solvent was removed in vacuo then methanol (10 ml) and concentrated hydrochloric acid (1 ml) were added and the resulting suspension was heated under reflux for 30 mins. On cooling to room temperature the solvent was removed and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous phase was extracted with ethyl acetate (thrice). The combined organic phase was washed with brine, dried over sodium sulphate, filtered and evaporated. Recrystallisation from isopropanol gave the title compound as yellow needles (0.15 g). m.p. 170-172°C MS (El) 297/299 (M+), 297 (100%) Η NMR (CDCI3) δ 1.55 (IH, m), 1.80 (IH, m), 2.20 (IH, m), 2.25 (IH, m), 2.45 (IH, m), 2.90 (2H, m), 3.50 (IH, m), 4.00 (IH, m), 7.00 ( IH, d), 7.26 (4H, br, s), 8.30 (IH, d), 9.30 (lH, s).
Pharmacological Data
Test A - Chronic graft-versus-host test
Pharmacological activity of the compounds of the invention may be demonstrated using the method of M Doutrelepont et al ([Gin Exp Immunol, 1991, vol 83, 133-6; Inhibition of chronic graft-versus-host (c-GVH) disease in the mouse]. Test compound was administered to mice subcutaneously as a suspension in saline with TWEEN-80 every day for 21 days.
2-(4-Chlorophenyl)-4,4a,5,6-tetrahydropyrido[4,3-h]cinnoIin-3(2H)-one was found to inhibit IgE production by 45% at a single dose of lOmgkg" 1.
2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydropyrido[2,3-h]cinnoline was found to inhibit IgE production by 58% at a single dose of lOmgkg"1. Test B - Inhibition of Eosinophilia
The effects of the compounds of the invention on inflammatory cells in mouse lungs was assessed by the following method, adapted from Brusselle et al , Clin. Exp. Allergy 1994, 24, 73-80. The measurement of eosinophil peroxidase as a marker for eosinophil numbers was adapted from Cheng et al, J. Pharmacol Exp. Ther. 1993, 264, 922-929.
Male Balb/c mice were sensitised to ovalbumin/Al(OH)3 mixture. Fourteen days after sensitisation dosing with compound commenced. Compound was administered daily either orally or subcutaneously as a suspension or solution (depending on dose and compound solubility) in 5% Tween 80.
17 days after sensitisation and one hour after the fourth dose of compound, the mice were placed in perspex chambers into which a solution of ovalbumin (2%w/v) was nebulised, The mice were allowed to inhale the ovalbumin for a period of 30-40 min. This challenge was repeated daily at the same time for a further 3 or 7 days.
In the case of the 4 day challenge, on the final day of dosing an additional challenge with ovalbumin was given 4 hours after the first.
The following day the animals were sacrificed and inhibition of the following parameters was measured by comparison to control animals:
( 1 ) Increase in the numbers of inflammatory cells in the bronchioalveolar lavage, in particular eosinophils (after the 4 day dosing). (2) Accumulation of eosinophils within lung tissue, as measured by the increase in eosinophil peroxidase activity in homogenised lung tissue (after the 8 day dosing).
(3) Increase in antibody titres (IgE, IgGl and IgG2a) present in the serum obtained from whole blood (after the 8 day dosing).
Certain compounds of the invention show activities in the chronic graft versus host test and the inhibition of eosinophilia test with ED5o's in the range of 0.1 - 10 mg/kg.

Claims

1. Use of a compound of formula (I):
Figure imgf000067_0001
wherein:
A, A , A and A are all CH or CR or one of A, A , A" or A" is nitrogen and the others are all CH or CR4;
X is or CH2, 0 or S(O)m where m is 0, 1 or 2;
Y is a single bond, (CH2)n where n is 1 or 2, C=O or CR5R6 where R5 and R6 are Cι-6 alkyl or together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or
4-piperidinyl ring;
Z is a single bond or CH ;
R1 is hydrogen, Cι-6 alkyl or Cι-6 alkoxy;
R2 is hydrogen and R3 is hydrogen or Cι.6 alkyl or R2 together with R3 forms a bond; R4 groups are independently OH, halogen, nitro, cyano, phenyl, amidoxime, CO R7, NR8R9,
SO2NR8R9,NR10C(O)R", methoxy (optionally substituted by CO2R12), C,.6 alkyl or
C2_6 alkoxy which latter two groups are optionally substituted by one or more substituents selected from NH2, hydroxy or CO2R12; p is O, 1, 2, 3 or 4; R7, R10 and R1 ' are independently hydrogen or C|.6 alkyl or R1 ' is Ar2;
R and R are independently hydrogen, Cι-6 alkyl or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl or piperidinyl ring;
Ar and Ar are independently phenyl, pyridyl, benzothiazolyl, quinolyl or quinoxalinyl all of which are optionally substituted by one or more substituents selected from CO2H, CO2Ci_6 alkyl, halogen, hydroxy, methoxy, phenoxy, C2.6 alkoxy and
Ci.6 alkyl (optionally interrupted by oxygen), which latter four groups are optionally substituted by one or more substituents selected from halogen, hydroxy or Cι-6 alkyl; or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the treatment of an allergic or an inflammatory condition, provided that:
• when A, A1, A2 and A3 form a phenyl ring: (a) when Z is CH2 or when X is CH2, SO or SO2, then Y is not C=O;
(b) when R5 and R6, together with the carbon atom to which they are attached, form a cyclopentyl, cyclohexyl or 4-piperidinyl ring, then X is O;
(c) when X is S(O)m or O, and Y and Z both represent single bonds, then R3 does not represent C i .6 alkyl ;
(d) R1 is Cμ6 alkoxy only when Z is a single bond and R2 and R3 together represent a bond;
(e) when X is CH2, Z is a single bond, R2 and R3 together represent a bond, R1 represents hydrogen, and
(i) Y is CH2 and A1 is CR4 where R4 is hydrogen or methoxy, then Ar1 does not represent 4-fluorophenyl;
(ii) Y is CH2 and A1 is CR4 where R4 is chloro, then Ar1 does not represent
3-methylphenyl or 4-carboxyphenyl;
(iii) Y is CH and A1 is CR4 where R4 is methoxy, then Ar1 does not represent 2-methyl- phenyl; and (iv) Y is a single bond and A1 is CR4 where R4 is hydrogen, then Ar1 does not represent
4-fluorophenyl;
(f) when X represents O, Y represents CH2 and R1, R2, R3 and R4 all represent H, then Ar1 does not represent 2-pyridyl; and
(g) when X and Y both represent CH2, and R1, R2, R3 and R4 all represent H, then Ar1 does not represent benzothiazol-2-yl.
2. Use according to claim 1 where A, A1, A2 and A3 are all CH or one of A, A1 or A2 is
4 nitrogen and the others are CH or CR
3. Use according to claim 1 or 2 where Ar1 is phenyl optionally substituted in the 4-position.
4. Use according to any one of claims 1 to 3 where Y is CH .
5. Use according to any one of claims 1 to 4 where Z is a single bond.
6. Use according to any one of claims 1 to 5 where R1, R2 and R3 are all hydrogen.
7. Use according to any one of claims 1 to 6 where R4 is NHCOMe, nitro, amino, NMe2, NHEt, hydroxy, methoxy, OCH2CO2Me, OCH2CO2H, or C(NH)NHOH.
8. Use according to claim 1 where the compound ccording to claim 1 is: 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole 2-(4-Chlorophenyl)-3,3a,4,5-tetrahydro-2H-benz[g]indazole 2-(4-Chlorophenyl)-2,4-dihydro[ 1 ]benzopyrano[4,3-c]pyrazole. 2-(4-Chlorophenyl)[l]benzothiopyrano[4,3-c]pyrazoI-4(2Η)-one. 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l ]benzothiopyrano[4,3-c]pyrazole, 5-oxide 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazoIe, 5,5-dioxide 2-(4-Chlorophenyl)-2,4-dihydro[l]benzothiopyrano[4,3-c]pyrazole, 5,5-dioxide 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-3a-methyl[l]benzothiopyrano[4,3-c]pyrazole 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-4,4-dimethyI[I]benzothiopyrano[4,3-c]pyrazole 2-(4-Chlorophenyl)-2,4-dihydro[ 1 ]benzothiopyrano[4,3-c]pyrazole
N-(2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazol-8-yl)acetamide 2-(4-Chlorophenyl)-6-fluoro-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-7-fluoro-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-7-nitro[l]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-6-nitro[l]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-6-methoxy[l]benzopyrano[4,3-c]pyrazole, 8-Chloro-2-(4-chIorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole, 2-(4-Bromophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-8-methoxy-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole, 6,8-Dichloro-2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-3-methyl-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole, 2-(3-Bromo-4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole, 2-(4-Trifluoromethoxyphenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-7-methoxy[l]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazol-8-amine,
2-(4-Chloro-2,6-dinitrophenyl)-2,3,3a,4-tetrahydro-5-oxide[l]benzothiopyrano[4,3-c]pyr- azole,
2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-6-ol,
N-(2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-yl)acetamide, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazol-7-amine,
2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-N,N-dimethyI[l]benzopyrano[4,3-c]pyrazol-7-amine, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-ol, Methyl (2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]- pyrazol-7-yl } oxyacetate, {2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazol-7-yl }oxyacetic acid, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzothiopyrano[4,3-c]pyrazol-6-amine, 2-(4-Chlorophenyl)-2,3,3a,4-N,N-dimethyl-tetrahydro[l]benzopyrano[4,3-c]pyrazol-6-amine, 2-(4-Chlorophenyl)-3,4,4a,5-tetrahydro-2H-indeno[ l,2-c]pyridazine, 2-(4-Chlorophenyl)-3,4,4a,5-tetrahydro-2Η-[l]benzothiopyrano[4,3-c]pyridazine, 2-(4-Chlorophenyl)-3,4,4a,5-tetrahydro-4a-methyl-2H-indeno[l ,2-c]pyridazine, 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydrobenzo[h]cinnoline,
2-(4-Chlorophenyl)-3,4,4a,5-tetrahydro-2H-[l]benzopyrano[4,3-c]pyridazin-8-amine, 2-(4-Chlorophenyl)-N-ethyl-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-7-amine, 7-Chloro-2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-8-fluoro-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole, 8-Chloro-2-(4-trifluoromethylphenyl)-2,3,3a,4-tetrahydro[ 1 ]benzothiopyrano[4,3-c]pyrazole, 2,3,3a,4-Tetrahydro-2-phenyl-[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydroindeno[ 1 ,2-c jpyrazole, 2-(4-Chlorophenyl)-2,4-dihydro-6-nitro[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-8-methoxy-[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-8-hydroxy-[l]benzothiopyrano[4,3-c]pyrazole, 2,3,3a,4-Tetrahydro-2-(4-methylphenyl)[l]benzothiopyrano[4,3-c]pyrazole, 2-(4-chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazole-6-carbonitrile, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydro[l]benzopyrano[4,3-c]pyrazol-6-amidoxime, 3-(2,3,3a,4-Tetrahydro[l]benzothiopyrano[4,3-c]pyrazol-2-yl)quinoline, 2-(2,3,3a,4-Tetrahydro[l]benzothiopyrano[4,3-c]pyrazol-2-yl)benzothiazole, 2-(2,3,3a,4-Tetrahydro[l]benzopyrano[4,3-c]pyrazol-2-yl)benzothiazole, 2-(2,4-Dihydro[l]benzopyrano[4,3-c]pyrazol-2-yl)benzothiazole, 3-(2,3,3a,4-Tetrahydro[l]benzopyrano[4,3-c]pyrazol-2-yl)quinoline, 2,3,3a,4-Tetrahydro-2-(3-pyridyl)[ 1 ]benzopyrano[4,3-c]pyrazole, 2-(2-Chloropyridin-5-yl)-2,3,3a,4-tetrahydro[ 1 ]benzopyrano[4,3-c]pyrazole, 2-(2-Chloropyridin-5-yl)-2,4-dihydro[l]benzopyrano[4,3-c]pyrazole, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydropyrazolo[3',4':4,5]thiopyrano[2,3-b]pyridine, l-(4-Chlorophenyl-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-3-yl) methanol, 2-(4-Chlorophenyl)-2,3,3a,4-tetrahydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine, 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydropyridino[2,3-h]cinnoline,
2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydro-7-oxidopyridino[2,3-h]cinnoline, 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydro-9-oxidopyridino[4,3-h]cinnoline, 2, 3, 4, 4a, 5, 6-Ηexahydro-2-(4-methylphenyl)pyrido[3,4-h]cinnoline, 2-(4-Chlorophenyl)-2, 3, 4, 4a, 5, 6-hexahydro-pyrido[4,3-h]cinnoline, or a pharmaceutically acceptable salt thereof.
9. Use according to any one of claims 1 to 9 where the condition is asthma.
10. A compound of formula (I) as defined in claim 1 with the additional provisos that: • when A, A1, A2 and A3 form a phenyl ring (h) when X is S, Y is (CH2)2, Z is a single bond and R1, R2, R3 and R4 represent H, then Ar1 does not represent unsubstituted phenyl;
(i) when X is O, Y and Z both represent CH , R1, R2 and R3 are hydrogen, A, A1 and A3 are
CH and A2 is CR4 where R4 is OH or methoxy, then Ar1 does not represent unsubstituted phenyl; (j) when X is O, Y is C =O, Z is a single bond, R1 is methyl, R2 and R3 together represent a bond then:
(i) when R4 is H Ar1 does not represent unsubstituted phenyl, 3-bromo-, 3-methoxy- or 3-methylphenyl; and
(ii) when A2 is CR4 where R4 is nitro or bromo, then Ar1 does not represent unsubstituted phenyl, 3-bromo- or 3-methylphenyl;
(k) when X is O, Y is CH2 or (CH2)2, Z is a single bond, R2 and R3 both represent H or together represent a bond, and R1 and R4 represent H, then Ar1 does not represent unsubstituted phenyl;
(1) when X is O, Y is CH2, Z is a single bond, R2 and R4 represent H, and:- (i) R1 is H and R3 is methyl, then Ar1 does not represent unsubstituted phenyl;
I I I
(ii) R and R represent H, then Ar does not represent 4-chloro- or 4-methylphenyl;
(iii) R1 is methyl and R3 is H, then Ar1 does not represent unsubstituted phenyl, 4-chloro- or 4-methylphenyl; (m) when X is O, Y is C =O, Z is a single bond, R2 and R3 together represent a bond and Ar1 is unsubstituted phenyl and:-
(i) R1 is methyl, then A2 is not CR4 where R4 is chloro or methyl; and
(ii) R1 is ethyl, then A2 is not CR4 where R4 is H; (n) when X and Y both represent CH2, Z is a single bond, A2 is CR4 where R4 is H and:- (i) R1, R2 and R3 represent H, then Ar1 does not represent unsubstituted phenyl or 3-chlorophenyl;
(ii) R1 is H or methyl and R2 and R3 together represent a bond, then Ar1 does not represent unsubstituted phenyl;
(o) when X is S, Y and Z both represent single bonds, R2 and R3 together represent a bond and R1 and R4 represent H, then Ar1 does not represent unsubstituted phenyl, 3-chloro- or 4-methoxyphenyl; or a pharmaceutically acceptable derivative thereof.
1 1. A compound of formula (I) as defined in claim 7.
12. A compound of formula (IA) :
Figure imgf000072_0001
wherein
X represents O, S(O)m or CH2;
Y represents a single bond, C(R3)R4 or (CH2)n; m represents 0, 1 or 2; n represents 1 or 2;
R represents one or more substituents selected from H, hydroxy, halogen, nitro, cyano, phenyl, CO2R5, NR6R7, NR8C(O)R9, methoxy (optionally substituted by CO2R10), C,_6 alkyl or C2-& alkoxy (which latter two groups are optionally substituted by one or more substituents selected from NH2, hydroxy or CO2R' '); R1 and R2 both represent H or together represent a bond;
R3 and R4 independently represent Cι- alkyl or, together with the carbon atom to which they are attached form a cyclopentyl, cyclohexyl or 4-piperidyl ring;
R6 represents H, Cι_6 alkyl or, together with R7 and the nitrogen atom to which it is attached, forms a pyrrolidinyl or piperidyl ring; R7 represents H, d_6 alkyl, CH2Ar2 or, together with R6 and the nitrogen atom to which it is attached, forms a pyrrolidinyl or piperidyl ring;
R9 represents H, C|_5 alkyl or Ar3;
R5, R8, R10 and R11 independently represent H or Cι_6 alkyl; and
Ar1 represents pyridyl, benzothiazolyl, quinolyl or quinoxalinyl all of which are optionally substituted by one or more substituents selected from halogen, hydroxy, methoxy (optionally substituted by halogen), phenoxy, C2-6 alkoxy and Cι_6 alkyl (which latter three groups are optionally substituted by one or more substituents selected from halogen, hydroxy or Cι_5 alkyl);
Ar2 and Ar3 independently represent phenyl optionally substituted by one or more substituents selected from halogen, hydroxy, methoxy (optionally substituted by halogen), phenoxy, C2_ό alkoxy and C|-6 alkyl (which latter three groups are optionally substituted by one or more substituents selected from halogen, hydroxy or C|_6 alkyl); provided that when A represents C2_^ alkoxy substituted by hydroxy or NH2, or when Ar1, Ar2 or Ar3 are substituted by C2_6 alkoxy substituted by hydroxy, then the hydroxy or NH2 substituent as appropriate is not attached to the carbon atom which is α to the oxygen; and further provided that:
(a) when X represents O, Y represents CH2 and A, R1 and R2 all represent H, then Ar1 does not represent 2-pyridyl; and
(b) when X and Y both represent CH2, and A, R1 and R2 all represent H, then Ar1 does not represent benzothiazol-2-yl; or a pharmaceutically-acceptable derivative thereof
13. A compound of formula (D3):
Figure imgf000073_0001
wherein
X represents O or S;
Y represents CH2 or (CH2)2;
R1 represents H, C,.6 alkyl or CH2OR13;
R2 represents H, Cι-6 alkyl, or together with R3 forms a bond; R3 represents H, or together with R2 forms a bond;
R13 represents H or C1-0 alkyl; and
Ar1 represents phenyl optionally substituted by one or more substituents selected from halogen, methyl and trifluoromethyl; or a pharmaceutically acceptable derivative thereof.
14. A compound of formula (IA) or (IB) for use in therapy.
15. A pharmaceutical composition comprising a compound of formula (IA) or (BB) in association with a pharmaceutically acceptable carrier or diluent.
PCT/SE1997/001359 1996-09-05 1997-08-19 Novel aryl-pyridazines WO1998009969A1 (en)

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AP2527A (en) * 2006-10-31 2012-12-06 Pfizer Prod Inc Pyrazoline compounds as mineralocorticoid receptorantagonists
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KR101107800B1 (en) * 2006-10-31 2012-01-25 화이자 프로덕츠 인코포레이티드 Pyrazoline compounds as mineralocorticoid receptor antagonists
WO2008053300A1 (en) * 2006-10-31 2008-05-08 Pfizer Products Inc. Pyrazoline compounds as mineralocorticoid receptor antagonists
EA016370B1 (en) * 2006-10-31 2012-04-30 Пфайзер Продактс Инк. Pyrazoline compounds as mineralocorticoid receptor antagonists
US7999107B2 (en) 2007-01-31 2011-08-16 Merck Sharp & Dohme Corp. Substituted pyrano[2,3-B]pyridine derivatives as cannabinoid-1 receptor modulators
EP2607363A1 (en) * 2010-08-18 2013-06-26 KBP Biosciences Co., Ltd. Fused ring compound for use as mineralocorticoid receptor antagonist
WO2012022121A1 (en) * 2010-08-18 2012-02-23 山东轩竹医药科技有限公司 Fused ring compound for use as mineralocorticoid receptor antagonist
EP2607363A4 (en) * 2010-08-18 2014-01-22 Kbp Biosciences Co Ltd Fused ring compound for use as mineralocorticoid receptor antagonist
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US8946279B2 (en) 2010-08-18 2015-02-03 Kbp Biosciences Co., Ltd. Fused ring compound for use as mineralocorticoid receptor antagonist
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US9468635B2 (en) 2010-08-18 2016-10-18 Kbp Biosciences Co., Ltd. Fused ring compound for use as mineralocorticoid receptor antagonist
WO2014094664A1 (en) * 2012-12-22 2014-06-26 山东亨利医药科技有限责任公司 Crystal form of compound used as mineralocorticoid receptor antagonist and preparation method therefor
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KR101737883B1 (en) 2012-12-22 2017-05-19 케이비피 바이오사이언시즈 씨오., 엘티디. Crystal form of compound used as mineralocorticoid receptor antagonist and preparation method therefor
US9809589B2 (en) 2012-12-22 2017-11-07 Kbp Biosciences Co., Ltd. Crystal form of compound used as mineralocorticoid receptor antagonist and preparation method therefor

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