WO1998009969A1 - Nouveaux aryle-pyridazines - Google Patents

Nouveaux aryle-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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Prior art keywords
chlorophenyl
tetrahydro
represent
pyrazole
benzopyrano
Prior art date
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PCT/SE1997/001359
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English (en)
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.)
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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/fr
Priority to JP10512539A priority patent/JP2001501180A/ja
Publication of WO1998009969A1 publication Critical patent/WO1998009969A1/fr

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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

L'invention concerne un composé selon la formle (I). Dans cette dernière, A, A?1, A2 et A3¿ sont tous CH ou CR4 ou un élément parmi A, A?1, A2 ou A3¿ est de l'azone et les autres sont tous CH ou CR?4. Ar1 et Ar2¿ représentent, indépendamment, phényle, pyridyle, benzothiazolyle, quinolyle ou quinoxalinyle, tous éventuellement substitués par un ou plusieurs substituents. X, Y, Z, R?1, R2, R3, R4¿ sont tels que définis dans le descriptif, ou un dérivé pharmaceutiquement acceptable de ce dernier dans la fabrication d'un médicament pour le traitement des allergies ou des inflammations.
PCT/SE1997/001359 1996-09-05 1997-08-19 Nouveaux aryle-pyridazines WO1998009969A1 (fr)

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WO2008053300A1 (fr) * 2006-10-31 2008-05-08 Pfizer Products Inc. Composés de pyrazoline en tant qu'antagonistes des récepteurs minéralocorticoïdes
US7999107B2 (en) 2007-01-31 2011-08-16 Merck Sharp & Dohme Corp. Substituted pyrano[2,3-B]pyridine derivatives as cannabinoid-1 receptor modulators
WO2012022121A1 (fr) * 2010-08-18 2012-02-23 山东轩竹医药科技有限公司 Composé cyclique fusionné utilisé comme antagoniste des récepteurs des minéralocorticoïdes
WO2014094664A1 (fr) * 2012-12-22 2014-06-26 山东亨利医药科技有限责任公司 Forme cristalline d'un composé utilisé comme antagoniste des récepteurs des minéralocorticoïdes et son procédé de préparation

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EP0351435A1 (fr) * 1987-11-02 1990-01-24 Yoshitomi Pharmaceutical Industries, Ltd. Composes de pyridazine fusionnes et leurs utilisations medicales
EP0354694A1 (fr) * 1988-08-09 1990-02-14 The Boots Company PLC [1]Benzothiopyrano[4,3-c]pyrazoles thérapeutiques
WO1991011448A1 (fr) * 1990-02-02 1991-08-08 The Boots Company Plc Agents therapeutiques

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AP2527A (en) * 2006-10-31 2012-12-06 Pfizer Prod Inc Pyrazoline compounds as mineralocorticoid receptorantagonists
JP2010508257A (ja) * 2006-10-31 2010-03-18 ファイザー・プロダクツ・インク 鉱質コルチコイド受容体拮抗薬としてのピラゾリン化合物
US7781428B2 (en) 2006-10-31 2010-08-24 Pfizer Inc. Pyrazoline compounds
KR101107800B1 (ko) * 2006-10-31 2012-01-25 화이자 프로덕츠 인코포레이티드 무기질코르티코이드 수용체 길항제로서의 피라졸린 화합물
WO2008053300A1 (fr) * 2006-10-31 2008-05-08 Pfizer Products Inc. Composés de pyrazoline en tant qu'antagonistes des récepteurs minéralocorticoïdes
EA016370B1 (ru) * 2006-10-31 2012-04-30 Пфайзер Продактс Инк. Пиразолиновые соединения в качестве антагонистов минералокортикоидных рецепторов
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 (fr) * 2010-08-18 2013-06-26 KBP Biosciences Co., Ltd. Composé cyclique fusionné utilisé comme antagoniste des récepteurs des minéralocorticoïdes
WO2012022121A1 (fr) * 2010-08-18 2012-02-23 山东轩竹医药科技有限公司 Composé cyclique fusionné utilisé comme antagoniste des récepteurs des minéralocorticoïdes
EP2607363A4 (fr) * 2010-08-18 2014-01-22 Kbp Biosciences Co Ltd Composé cyclique fusionné utilisé comme antagoniste des récepteurs des minéralocorticoïdes
CN103547577A (zh) * 2010-08-18 2014-01-29 山东亨利医药科技有限责任公司 作为盐皮质激素受体拮抗剂的并环类化合物
US8946279B2 (en) 2010-08-18 2015-02-03 Kbp Biosciences Co., Ltd. Fused ring compound for use as mineralocorticoid receptor antagonist
CN103547577B (zh) * 2010-08-18 2015-09-09 山东亨利医药科技有限责任公司 作为盐皮质激素受体拮抗剂的并环类化合物
US9468635B2 (en) 2010-08-18 2016-10-18 Kbp Biosciences Co., Ltd. Fused ring compound for use as mineralocorticoid receptor antagonist
WO2014094664A1 (fr) * 2012-12-22 2014-06-26 山东亨利医药科技有限责任公司 Forme cristalline d'un composé utilisé comme antagoniste des récepteurs des minéralocorticoïdes et son procédé de préparation
CN105026391A (zh) * 2012-12-22 2015-11-04 山东亨利医药科技有限责任公司 作为盐皮质激素受体拮抗剂的化合物的晶型及其制备方法
KR101737883B1 (ko) 2012-12-22 2017-05-19 케이비피 바이오사이언시즈 씨오., 엘티디. 미네랄코르티코이드 수용체 길항제로서 사용된 화합물의 결정형 및 이의 제조방법
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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