Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • 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
  • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
• • 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
• • 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
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• This invention relates to pharmaceutically useful compounds, methods for their preparation, their use as medicaments, and pharmaceutical formulations including them.
• Certain pyrazolo[4,3-c]isoquinolin-3-ones are known from J. Chem. Soc. 599 (1959) (Hinton et ai). Their use as pharmaceuticals is not suggested. The synthesis and ability of certain pyrazolo[4,3-c]isoquinolin-3-ols to inhibit radioligand binding to benzodiazepine receptors has been detailed in f. Med. Chem. 35, 368 ( 1992) (Allen et ai).
• the invention therefore provides a compound of formula I or a pharmaceutically acceptable derivative thereof for use as a pharmaceutical:
• B, D, E and G each represent CH, CA or N provided that no more than one of B, D, E and G represents CA and no more than one of B, D, E and G represents N;
• R 1 represents OH or C
• R 2 represents H, C ⁇ _ 6 alkyl (optionally substituted by phenyl, COOR 9 , NR 10 R n , OR 12 or F) or C3_7 cycloalkyl, or with either R 1 , R 3 or R 4 forms a bond;
• R 3 represents H or a bond with R 2 ;
• R 4 represents C]_ 6 alkyl or a bond with R : ; • R represents a bond with R 1 or R ;
• R 6 represents H, C ⁇ _6 alkyl (optionally substituted by phenyl), C 3 _ 7 cycloalkyl, phenyl, halogen, C
• R 7 represents C ⁇ _ 6 alkyl (optionally substituted by phenyl) or C 3 _ 7 cycloalkyl, either of which may be optionally substituted by halogen, hydroxy, C ⁇ _ 6 alkoxy, C ⁇ _6 alkylthio, C,- 6 alkylsulfinyl, NR 16 R 17 , COOH, COO(C,_ 6 alkyl) or cyano;
• R 6 and R 7 together represent C 3 _ alkylene, X and Y thereby forming a ring of 5-7 members; • R 8 represents H, C ⁇ _ 6 alkyl or a bond with R 5 ;
• R 9 , R 10 , R n , R 12 , R 15 , R 16 , R 17 and R 18 independently represent C ⁇ _ 6 alkyl or H;
• R 13 and R 14 are independently C
• Ar 1 represents phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2- or 3-quinolyl or 2-quinoxalinyl, all of which are optionally substituted by one or more substituents selected from halo, nitro, cyano, phenyl, phenylsulfonyl, C ⁇ alkyl, C ⁇ _ 6 alkoxy, C ⁇ _ 6 alkylthio, C ⁇ _ 6 alkylsulfinyl, COOH, COO(d_ 6 alkyl).
• A represents halo, cyano, amino, nitro, C
• R 1 when R 1 represents alkyl, then R 5 represents a bond with R 8 , Y represents N, R 2 does not represent a bond, and X does not represent NR 4 ; (vn) when R 1 represents a bond with R 2 , then R 5 and R 8 form a bond, and if X represents
• R 4 represents alkyl, (vi ⁇ ) when R 6 represents aryl, halogen, alkoxy, thioalkyl, then R 2 and R 3 form a bond, (ix) when Y represents N or N + R 7 and R 2 is substituted by any of NR I0 R' ⁇ OR 12 or F, then the substituent and the ⁇ ng nitrogen of Y may not be attached to the same carbon atom of R 2 , (x) when R 7 is substituted by any of NR l6 R 17 , OR 12 or halogen then the substituent and the ⁇ ng nitrogen of Y may not be attached to the same carbon atom of R 7 , (xi) when one of B, D, E and G represents N, then X does not represent NR 4 , (xn) when Y represents CR 18 , then X represents CR 3 R 6 , with the further proviso that
• B, D, E and G each represent CH, CA or N provided that no more than one of B, D, E and G represents CA and no more than one of B, D, E and G represents N,
• R 1 represents OH or C
• R 2 represents H, _6 alkyl (optionally substituted by phenyl, COOR 9 , NR' ', OR 12 or F) or C 3 _ 7 cycloalkyl, or with either R 1 , R 3 or R 4 forms a bond, • R 3 represents H or a bond with R 2 ,
• R 4 represents Cj_ 6 alkyl or a bond with R 2 ,
• R 5 represents a bond with R 1 or R 8
• R 6 represents H, C ⁇ _ 6 alkyl (optionally substituted by phenyl), C 3 _ 7 cycloalkyl, phenyl, halogen, C
• R 7 represents C ⁇ _ 6 alkyl (optionally substituted by phenyl) or C 3 _ 7 cycloalkyl, either of which may be optionally substituted by halogen, hydroxy, C]_ 6 alkoxy,
• R 6 and R 7 together represent C 3 _ 5 alkylene, X and Y thereby forming a ring of 5-7 members;
• R 8 represents H, C
• R 13 and R 14 are independently C
• 2-quinoxalinyl all of which are optionally substituted by one or more substituents selected from halo, nitro, cyano, phenyl, phenylsulfonyl, C ⁇ _ 6 alkyl, C,_ 6 alkoxy, C ⁇ _ alkylthio, C,_ 6 alkylsulfinyl, COOH, COO(C,_ 6 alkyl), C,_ 6 alkyl substituted by phenyl, or phenyl, in which any alkyl, alkoxy, alkylthio and alkylsulfinyl groups may optionally be substituted by fluoro; and
• Ar 1 represents phenyl or pyridyl, most preferably phenyl.
• the phenyl group Ar 1 preferably has a substituent in th para position, more preferably a Cl, Br, CF 3 , C 2 F 5 , OCF 3 or SCH 3 substituent in the para position especially a CF 3 , C 3 F 5 , OCF 3 or SCH 3 substituent in the para position.
• Y represents N + R 7
• X represents CR 3 R 6 in which R 3 forms a bond with R 2 and R 6 represents alkyl.
• R 6 preferably represents branched alkyl.
• X may represent NR 4 in which R 4 represents a bond with R 2 and Y represent
• B represents CA.
• A preferably represents F.
• one of B, D, E and G represents N, preferably it is D or G that represents
• R 1 represents a bond with R 2 or R 5 .
• R 1 preferably represents a bond with R 5 .
• Particularly preferred compounds of the invention include those exemplified herein including the free form and all salts and solvates thereof.
• compositions includes solvates and salts.
• Particular salts which may be mentioned include hydrochloride, hydrobromide, benzenesulfonate, tosylate and methanesulf onate.
• the compounds of formula I may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
• the compounds of formula I 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, for example chromatography or fractional crystallisation.
• the various optical isomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, for example fractional crystallisation or HPLC, techniques.
• the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (for example HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.
• Alkyl groups which R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R n , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R t8 may represent or which may be substituted on one or more of the aromatic rings forming part of Ar 1 may be saturated or unsaturated, and straight chain or branched.
• _ 6 alkylsulfinyl, COO(d_ 6 alkyl) and C 3 _ 5 alkylene are to be inte ⁇ reted accordingly.
• N + R 7 , Z represents O " , R 3 and R 2 form a bond, R 1 and R 5 form a bond and R 6 represents alkylthio by displacement reaction of a corresponding compound of formula I, where X represents CR 3 R 6 wherein R 6 represents methylthio or halogen and B, D, E. G, Y, Z, Ar', R 1 , R 2 , R 3 and R 5 are as hereinbefore defined, with a compound of formula II:
• R H (II) wherein R 6a represents C
• N + R 7 , Z represents O " , R 3 and R 2 form a bond, R 1 and R 5 form a bond and R 6 represents alkoxy by displacement reaction of a corresponding compound of formula I, where X represents CR 3 R 6 wherein R 6 represents methylthio or halogen and B, D, E, G, Y, Z, Ar 1 , R l , R 2 , R 3 and R 5 are as hereinbefore defined, with a compound of formula UI: R 6a/ ⁇ H
• R 13 and R 14 are as hereinbefore defined, in the presence of a base, for example sodium hydrogen carbonate, in an appropriate solvent, for example, DMF at 100 °C;
• a base for example sodium hydrogen carbonate
• an appropriate solvent for example, DMF at 100 °C;
• R 6 is as hereinbefore defined and Hal represents halogen, for example in the presence of a copper salt, for example copper(I) bromide in an appropriate solvent, for example dimethoxyethane, for example at reflux; (1) preparation of compounds of formula I where X represents CR 3 R 6 , Y represents
• N + R 7 , Z represents O " , R 3 and R 2 form a bond, R 1 and R 5 form a bond and R 6 represents alkyl by reaction of a corresponding compound of formula I, where X represents CR 3 R 6 wherein R 6 represents H and B, D, E, G, Y, Z, Ar 1 , R 1 , R 2 , and R 5 are as hereinbefore defined, with a nucleophilic alkylating reagent, for example a compound of formula V as hereinbefore defined in an appropriate solvent, for example
• THF for example at 0 °C
• R 8 and Hal are as hereinbefore defined, for example in the presence of a base, for example sodium hydride, in an appropriate solvent, for example DMF;
• a base for example sodium hydride
• an appropriate solvent for example DMF
• (n) preparation of compounds of formula I where R 1 represents OH, X represents C 0, Y represents N, Z represents OR 8 and R 5 represents a bond with R 8 by reaction of a corresponding compound of formula I, where Z represents O " , R 1 and R 5 form a bond and B, D, E, G, X, Y, Ar 1 and R 2 are as hereinbefore defined, by treatment with an oxidising agent, for example eerie ammonium nitrate, in an appropriate solvent, for example acetonitrile, for example at ambient temperature;
• an oxidising agent for example eerie ammonium nitrate
• an appropriate solvent for example acetonitrile
• R 7 and Hal are as hereinbefore defined and a base, for example sodium hydride, in an appropriate solvent, for example DMF, for example at ambient temperature;
• a and Ar 1 are as hereinbefore defined, with a base, for example sodium hydride, and a compound of formula EX as hereinbefore defined, in an appropriate solvent, for example DMF, for example at ambient temperature; (r) preparation of compounds of formula I where B, D, E and G represent CH or CA, X represents NR 4 , Y represents N, Z represents OR 8 , R 2 and R 1 form a bond and R 5 and R 8 form a bond by reaction of a compound of formula VIII as hereinbefore defined with a base, for example sodium hydride, and a compound of formula X: R"Hal (X)
• R 4 and Hal are as hereinbefore defined, in an appropriate solvent, for example DMF, for example at ambient temperature;
• R' is as hereinbefore defined, in the presence of a base, for example potassium carbonate, for example in acetone at 50 °C.
• a base for example potassium carbonate, for example in acetone at 50 °C.
• the functional groups of intermediate compounds may need to be protected by protecting groups.
• the protection of functional groups may take place before any the process steps hereinbefore described.
• the nitrogen atom of compounds of formula XI, XHI and XVI may be protected before further reaction using a suitable protecting group, for example a benzyl group or preferably a 4-methoxyphenylmethyl group.
• a suitable protecting group for example a benzyl group or preferably a 4-methoxyphenylmethyl group.
• Protecting groups may be removed following a reaction step or at the end of the reaction process using techniques which are well known to those skilled in the art (for example acid hydrolysis).
• the compounds of the invention are useful possess pharmacological activity and are therefore indicated as pharmaceuticals useful in therapy.
• 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 i5 of the airways such as asthma (for example bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (for example late asthma and airway hyper-responsiveness), bronchitis and the like.
• 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.
• acute rhinitis such as acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta and rhinitis sicca, rhinitis medicamentosa, membranous rhinit
• 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 3o thrombocytopenia 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 35 autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
• AIDS acquired immunodeficiency syndrome
• rhinitis most particularly allergic rhinitis and seasonal rhinitis including rhinitis nervosa (hay fever).
• a method of treatment or prophylaxis of an allergic or an inflammatory disorder which method com ⁇ prises administration of a therapeutically effective amount of a compound of formula I as defined above, but without provisos (b) or (c), 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 pressurised or non-pressurised.
• 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 pressurised and contain a compressed gas, for example nitrogen, or a liquefied gas propellant.
• the active ingredient is preferably finely divided.
• the pressurised composition may also contain a surface active agent.
• the pressurised 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 mantel, talc, stearic acid, starch, sodium bicarbonate and/or gelatine.
• a pharmaceutical composition comprising a compound of formula I as hereinbefore defined, but without proviso (c), or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant diluent or carrier.
• Suitable doses for administration topical or orally are in the range 0.01 to 30 mg kg ' day ', for example 0.3 mg kg " day
• the mixture was heated under reflux for 16 hours and allowed to cool to room temperature. Water was added and the organic phase was separated. The aqueous phase was then extracted with ethyl acetate (thrice). The combined organic phase was washed with brine and dried over sodium sulfate.
• Methyl 2-[((l-methoxycarbonyl)ethyl)methylamino]methylbenzoate (2 g) in dry toluene (10 ml) was added dropwise to a refluxing suspension of oil free sodium hydride (from 0.42 g of 60% dispersion) in dry toluene (30 ml) and 2-methyl-2-propanol (5 drops) under a nitrogen atmosphere. After being heated at reflux for 45 minutes the solution was cooled in ice and poured into saturated ammonium chloride solution which was extracted with ethyl acetate (thrice). The organic phase was washed with brine and dried over sodium sulfate.
• Methyl l,2,3,4-tetrahydro-2,3-dimethyl-4-oxo-3-isoquinolinecarboxylate (0.84 g), 4-chlorophenylhydrazine ( 1.54 g) and 4-toluenesulfonic acid (20 mg) were fused together at 150 °C for 10 minutes under a nitrogen atmosphere.
• Xylene (10 ml) was then added and the mixture was heated at 150 °C a further 6 hours. After cooling to room temperature the solvent was removed and the residue was dissolved in dichloromethane/methanol. The solution was washed with 2M hydrochloric acid and brine, then dried over sodium sulfate.
• Methyl l,2,3,4-tetrahydro-2,3-dimethyl-l,4-dioxo-3-isoquinoIinecarboxylate (0.53 g)
• 4-chlorophenylhydrazine (0.92 g)
• 4-toluenesulfonic acid (10 mg) were fused together at 150 °C under a nitrogen atmosphere for 10 minutes.
• Xylene (5 ml) was then added and the mixture was heated at 150 °C for 10 hours. After cooling to room temperature the solvent was removed and the residue dissolved in dichloromethane/methanol, was washed with 2M hydrochloric acid, sodium bicarbonate solution and brine. The solution was dried over sodium sulfate, filtered and evaporated.
• the sub-title compound was prepared according to the method described in Example 1(c) using [l , r-biphenyl)-4-ylhydrazine (see J. Chem. Soc, Perkin Trans. I, (1975) 1280).
• Example 15 2-(4-Bromophenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol
• the title compound (0.053 g) was prepared according to the method described in Example
• the sub-title compound was prepared according to the method described in Example 1(c) using 4-[(l ,l-dimethylethyl)phenyI]hydrazine and was used without further purification in the proceeding step.
• Trifluoroacetic acid (4 ml) was added to 2,4-dihydro-3-hydroxy-4-(methoxyphenylmethyl)- -2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one (example 66) (425 mg) and the mixture was heated at reflux for 12 hours. After cooling to room temperature the solvent was removed and the resultant residue was recrystallised from methanol/water to give a yellow solid, which was further purified by trituration with isohexane to give the title compound (150 mg). m.p. >200 °C. MS (APCI) 346 ((M+ ⁇ f).
• Example 116 4,5-Dihydro-2-(5-methyI-2-pyridinyl)-2H-benz[g]indazol-3-ol l-Oxotetrahydronaphthalene-2-carboxylic acid methyl ester (2.18g) and 2-hydrazino-5- methylpyridine (2.85g) were heated together in xylene (15ml) under reflux for 6h. The reaction was allowed to cool and then the product was filtered and dried. Recrystallisation from diethyl ether/isohexane gave the title compound as pale brown needles (0.69g). m.p. 1 12°C.
• Test A Chronic graft-versus-host test Pharmacological activity of the compounds of the invention may be demonstrated using the method of J. M. Doutrelepont et ai ([Clin. 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.
• Test B • Inhibition of Eosinophilia
• 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 EDso's m the range of 0 1 - 10 mg/kg

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