Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • 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
  • A61P37/08—Antiallergic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• • 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 novel triazole derivatives, their use as medicaments, pharmaceutical formulations including them and methods for their preparation.
• each group R , 1 independently represents a halogen atom or a d-C 6 alkyl, -C 6 alkoxy,
• each group R 2 , R 3 and R 4 independently represents a hydrogen atom or a -C 6 alkyl or
• n O, 1, 2, 3 or 4;
• X is N or CR 5 where R 5 represents a hydrogen or halogen atom, or a nitro, carboxyl, sulphonic acid (SO 2 H), C ⁇ -C 6 alkyl, C 3 -C 7 cycloalkyl, -C 6 alkoxy,
• R 7 and R 8 each independently represent a hydrogen atom, a C 3 -C 7 cycloalkyl group, an optionally substituted phenyl-, pyridinyl- or imidazolyl-sulphonyl group, or an optionally substituted
• C C 6 alkyl(sulphonyl) group or together with the nitrogen atom to which they are attached form an optionally substituted 3- to 7-membered heterocyclic ring optionally containing a fu irrtthheerr hheetteerrooaattoomm sseelleecctteedd f frroomm nniittrrooggeenn,, o oxxyyggeenn oorr ssuullpphhuurr;; Y iiss N N oorr CCRR 6 wwhheerree R Ft" represents a hydrogen or halogen atom, or aNR R , C ⁇ -C 6 alkoxy, C 33 --CC 7 ccyyccllooaallkkyyll oorr a ann optionally substituted Q-C 6 alkyl group where R 7 and R 8 are as here :i hingentb,e ⁇ f.co
• Ar 1 represents a phenyl, pyridinyl, pyrimidinyl, benzothiazolyl, quinolyl or quinoxalinyl group, each of which may be optionally substituted; or a pharmaceutically acceptable salt or solvate thereof.
• an alkyl group whether alone or part of another group, can be straight or branched chain and a 'heterocyclic ring' is saturated.
• Each group R independently represents a halogen atom (e.g. fluorine, chlorine or bromine) or a C ⁇ -C 6 , preferably -C 4 , more preferably -C2, alkyl, C t -C 6 , preferably -C 4 , more preferably -C 2 , alkoxy, C 3 -C 7 , preferably C 4 -C 6 , cycloalkyl, hydroxyl, nitro, cyano, CO 2 R 2 , NR 3 R 4 , CONR 3 R 4 , SO 2 NR 3 R 4 or NR 3 SO 2 R 4 group.
• a halogen atom e.g. fluorine, chlorine or bromine
• Preferred R 1 groups include halogen atoms, in particular fluorine atoms.
• Each group R 2 , R 3 and R 4 independently represents a hydrogen atom or a -C 6 alkyl or C 3 -C cycloalkyl group.
• each group R 2 , R 3 and R 4 independently represents a hydrogen atom or a C ⁇ -C 3 alkyl or cycloalkyl group.
• n is 0, 1 or 2.
• Particularly advantageous compounds of formula (I) are those in which n is 0.
• the group X is N or CR 5 where R 5 represents a hydrogen or halogen atom (e.g. fluorine, chlorine or bromine), or a nitro, carboxyl, sulphonic acid, preferably -C , alkyl, C -C cycloalkyl, C ⁇ -C 6 , preferably -C , alkoxy, C ⁇ .-C 6 alkoxycarbonyl, preferably C ⁇ -C 4 alkoxycarbonyl, C 3 -C cycloalkoxycarbonyl, -C 6 alkylsulphonyl, preferably C C 4 alkylsulphonyl, C 3 -C 7 cycloalkylsulphonyl, NR 7 R 8 , CONR 7 R 8 or SO 2 NR 7 R 8 group where R 7 and R 8 each independently represent a hydrogen atom, a C 3 -C 7 cycloalkyl group, an optionally substituted (e.g.
• X represents N or CR 5 where R 5 represents a hydrogen or halogen atom, or a nitro, C ⁇ -C 6 alkyl, Q-C 6 alkoxy, NR 7 R 8 or SO 2 NR 7 R 8 group where R 7 and R 8 each independently represent a hydrogen atom, an optionally substituted imidazolylsulphonyl group or an optionally substituted CrC 6 alkyl(sulphonyl) group, or together with the nitrogen atom to which they are attached form an optionally substituted 3- to 7-membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen and oxygen.
• X represents N or CR 5 where R 5 represents a hydrogen, chlorine or bromine atom, or a nitro, C ⁇ -C 3 alkyl (especially isopropyl), Ci-C 3 alkoxy (especially methoxy), NR 7 R 8 or SO 2 NR 7 R 8 group where R 7 and R 8 each independently represent a hydrogen atom, a methyl-substituted imidazolylsulphonyl group, or an optionally substituted C C 3 alkyl(sulphonyl) group, or together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen and oxygen (e.g. an azetidine, morpholine, piperidine, pyrrolidine or piperazine ring).
• R 5 represents a hydrogen, chlorine or bromine atom, or a nitro, C ⁇ -C 3 alkyl (especially isopropyl), Ci-C 3 alkoxy (especially methoxy),
• R 7 or R 8 represents an optionally substituted alkyl or alkylsulphonyl group
• examples of the one or more (e.g. 1 , 2 or 3) optional substituents that may be present in the alkyl moiety include hydroxyl, amino and Q-C 6 alkoxy (particularly methoxy) groups.
• the group Y is N or CR 6 where R 6 represents a hydrogen or halogen (e.g. fluorine, chlorine or bromine) atom, or a NR 7 R 8 , -C ⁇ , preferably -C , alkoxy, C 3 -C 7 cycloalkyl or an optionally substituted CrC 6 , preferably -C 4 , alkyl group where R 7 and R 8 are as previously defined.
• R 6 represents a hydrogen or halogen (e.g. fluorine, chlorine or bromine) atom, or a NR 7 R 8 , -C ⁇ , preferably -C , alkoxy, C 3 -C 7 cycloalkyl or an optionally substituted CrC 6 , preferably -C 4 , alkyl group where R 7 and R 8 are as previously defined.
• R 6 represents a hydrogen or halogen (e.g. fluorine, chlorine or bromine) atom, or a NR 7 R 8 , -C ⁇
• Y is N or CR 6 where R 6 represents a hydrogen atom, aNR 7 R 8 group where R 7 and R are as previously defined (particularly an azetidine or morpholine ring) or an optionally substituted C C 4 alkyl (e.g. methyl, ethyl, propyl, isopropyl or butyl) group.
• R 6 represents a hydrogen atom, aNR 7 R 8 group where R 7 and R are as previously defined (particularly an azetidine or morpholine ring) or an optionally substituted C C 4 alkyl (e.g. methyl, ethyl, propyl, isopropyl or butyl) group.
• R represents an optionally substituted alkyl group
• the one or more (e.g. 1, 2 or 3) optional substituents may be selected from the group including halogen atoms (e.g. fluorine, chlorine or bromine) and NR'R' where each R' independently represents a hydrogen atom, or a -Co alkyl or C 3 -C 7 cycloalkyl group, or the groups R' may together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulphur (e.g.
• halogen atoms e.g. fluorine, chlorine or bromine
• NR'R' where each R' independently represents a hydrogen atom, or a -Co alkyl or C 3 -C 7 cycloalkyl group, or the groups R' may together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring optionally
• R' may together with the nitrogen atom to which they are attached from an imidazole, pyrazole or pyrrole ring optionally substituted by one or more (e.g. one or two) substituents selected from -C 6 alkyl and C 3 -C 7 cycloalkyl groups.
• R 9 represents a hydrogen atom, or a C 3 -C 7 cycloalkyl or an optionally substituted C ⁇ -C 6 , preferably -C 4 , alkyl group (e.g. methyl, ethyl, propyl or isopropyl)
• R 9 represents an optionally substituted alkyl group
• examples of the one or more (e.g. 1, 2 or 3) optional substituents that may be present in the alkyl group include halogen atoms (e.g. fluorine, chlorine or bromine), C ⁇ -C 6 alkoxy and NR"R" where each R" independently represents a hydrogen atom, or a -C 6 alkyl or C 3 -C 7 cycloalkyl group, or the groups R" may together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulphur (e.g. morpholinyl or piperazinyl).
• Specific examples of optionally substituted alkyl groups include methyl, ethyl, propyl, isopropyl, 2-aminoethyl and 2,2,2-trifluoroethyl.
• R 10 represents a hydrogen atom or a -C 4 alkyl, especially methyl, group.
• the group Ar 1 represents a phenyl, pyridinyl, pyrimidinyl, benzothiazolyl (e.g. 2-benzothiazolyl), quinolyl (e.g. 2-, 3- or 6-quinolyl) or quinoxalinyl (e.g. 2-quinoxalinyl) group, each of which may be optionally substituted, e.g. by one or more, preferably one to four, more preferably one or two, substituents selected from halogen atoms (e.g.
• methoxy or ethoxy groups which latter four groups may, in turn, be optionally substituted by one or more, e.g. one, two, three, four, five or six, substituents selected from halogen atoms (e.g. fluorine, chlorine or bromine), hydroxyl and amino groups, e.g. trifluoromethyl, trifluoromethylthio or trifluoromethoxy.
• halogen atoms e.g. fluorine, chlorine or bromine
• hydroxyl and amino groups e.g. trifluoromethyl, trifluoromethylthio or trifluoromethoxy.
• Ar 1 represents a phenyl, pyridinyl, 3-quinolyl or 6-quinolyl group, each of which may be optionally substituted by one or more substituents selected from halogen atoms, C 3 -C 7 cycloalkyl, -C 6 alkylthio, C]-C 6 alkyl, C ⁇ -C 6 alkoxy, trifluoromethyl, trifluoromethylthio and trifluoromethoxy.
• Particularly preferred compounds of the invention include:
• Compounds of the invention can form pharmaceutically acceptable solvates and salts.
• 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, oxalic, mandelic, tartaric and methanesulphonic acids.
• Certain compounds of formula (I) are capable of existing in stereoisomeric forms including enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
• the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
• the invention also extends to any tautomeric forms and mixtures thereof. According to the invention there is also provided a process for the preparation of a compound of formula (I) which comprises (i) reacting a compound of formula (II):
• nitronium tetrafluoroborate e.g. in a solvent such as dichloromethane, optionally followed by hydrogenation, e.g. over a palladium on charcoal catalyst; or
• n, R 1 and Ar 1 are as defined in formula (I), with diphenylphosphorylazide or with a chloroformate in the presence of a source of azide, e.g. sodium azide, and, if required, cyclising the compound obtained, optionally in the presence of an acid chloride (e.g. phosgene) or a sulphonyl chloride (e.g. sulphuryl chloride); or
• the reaction of compounds of formula (II) and (IE) can be carried out using standard conditions.
• the diazonium salt of formula (III) can be prepared from the corresponding aniline and sodium nitrite in water at reduced temperature, for example at about 0 - 5°C.
• the resulting triazine intermediate can then be cyclised and dehydrated, for example by treating with pyridine and acetic anhydride.
• Compounds of formula (II) where A is X'-Y' and X' is CH 2 and Y' is CHR 10 can be prepared from compounds of formula (VII):
• R 11 is an ester forming group, by hydrogenation followed by ester hydrolysis.
• the group R 11 can be any ester forming group such as a C C 6 alkyl group, for example methyl.
• Hydrogenation of compounds of formula (VII) can be carried out under conventional conditions, for example using 5% platinum on carbon (Pt/C) in ethanol.
• Ester hydrolysis can be carried out under conventional conditions, for example using sodium hydroxide.
• n, R 1 , R' ⁇ and R" are as defined in formula (VII) by reaction with a suitable chlorinating agent, such as phosphorus oxychloride, POCl 3 , at reflux.
• a suitable chlorinating agent such as phosphorus oxychloride, POCl 3
• n, R 1 , R 10 and R 11 are as defined in formula (VII) and R 12 is an ester forming group.
• Cyclisation can be carried out in diphenyl ether at elevated temperature, for example at about 250°C.
• R 11 and R 12 are the same and are both methyl or ethyl.
• n, R 1 and R 12 are as hereinbefore defined, with a compound of formula (XV), Ar'-NH 2 , in which Ar 1 is as hereinbefore defined, in the presence of sodium nitrite to form an intermediate that can be cyclised and dehydrated, for example by treating with pyridine and acetic anhydride, followed by ester hydrolysis.
• Compounds of formula (V) can be prepared by reacting a compound of formula (VI) as ddeeffiinneedd aabboo ⁇ ve with a compound of formula (XVI), R 6 COCl, in which R 6 is as defined in formula (I).
• An alternative, preferred method for preparing the compounds of formula (V) involves reacting a compound of formula (XVII) or a salt thereof (e.g. a lithium salt):
• R 13 both represent a hydrogen or oxygen atom and n, R 1 and R are as hereinbefore defined, with a compound of formula (IX) as specified above under an atmosphere of hydrogen and in the presence of a catalyst such as palladium on charcoal.
• Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures.
• Pd/C DMA dimethylacetamide
• MnO 2 /CHCl 3 manganese dioxide in trichloromethane
• DDQ/toluene 2,3-dichloro-5,6-di
• Ar 1 is as defined in formula (I) with an amine HNR 7 R 8 in the presence of a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0), a base such as sodium ferr-butoxide and a phosphine ligand such as bis(diphenylphosphino)-l,l-binaphthyl in an organic solvent such as toluene, for example at reflux.
• a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0)
• a base such as sodium ferr-butoxide
• a phosphine ligand such as bis(diphenylphosphino)-l,l-binaphthyl in an organic solvent such as toluene, for example at reflux.
• Compounds of formula (XX) can be prepared by reaction of a compound of formula (I) where X is CH and Y is CH with bromine in an appropriate solvent such as dichloromethane and in the presence of a base, for example pyridine.
• Ar 1 is as defined in formula (I) with an amine HNR 7 R 8 , for example with heating.
• Functional groups which it is desirable to protect include hydroxyl, amino and carboxylic acid.
• Suitable protecting groups for hydroxyl include organosilyl groups (e.g. -butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetr ⁇ hydro- pyranyl.
• Suitable protecting groups for amino include tert-butoxycarbonyl or benzyloxy carbonyl.
• Suitable protecting groups for carboxylic acid include Q-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 for use in therapy 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/disorders 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) and bronchitis.
• 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/disorders 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/disorders including inflammations/allergies such as rhinitis, including all conditions characterised by inflammation of the nasal mucus membrane, such as acute rhinitis, allergic rhinitis, a
• 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 and idiopathic thrombocytopenia pupura.
• 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) and oestrogen- dependent cancers (e.g. breast cancer).
• AIDS acquired immunodeficiency syndrome
• autoimmune diseases such as multiple sclerosis and rheumatoid arthritis
• oestrogen- dependent cancers e.g. breast cancer
• oestrogen- dependent cancers e.g. breast cancer.
• a method of treatment or prophylaxis of an allergic or an inflammatory disorder comprises administration of a therapeutically effective amount of a compound of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt or solvate thereof, to a person suffering from, or susceptible to such a disorder.
• the invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of the above disorders, in particular asthma and rhinitis.
• 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, e.g. nitrogen, or a liquefied gas propellant.
• a compressed gas e.g. nitrogen
• a liquefied gas propellant e.g. 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, stark acid, starch, sodium bicarbonate and/or gelatine.
• a pharmaceutical composition comprising a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
• Suitable doses for administration topical or orally are in the range 0.01 to SOmgkg ⁇ day “1 , for example 0.3mgkg '1 day “1 .
• Example 1 lc 8-fluoro- 1,2,3, 4-tetrahydroquinoline-2- carboxylic acid (Example 1 lc) (4.9g) and 5-amino-2-chloropyridine (3.2 lg) to give the title compound (1.7g) as a pale orange solid.
• Example 18 Prepared by the route of Example 9 using 4,5-dihydro-3-hydroxy-4-methyl-2-[4- (trifluoromethyl)phenyl]-[l,2,3]triazolo[l,5-a]quinolinium hydroxide, inner salt (Example 18) (1.1 g) to give the title compound (0.745g) as a yellow solid.
• Example 22 Prepared by the route of Example 13 using 4,5-dihydro-3-hydroxy-5-oxo-2-[4- (trifluoromethoxy)phenyl]-[l,2,3]triazolo[l,5-a]quinazolinium hydroxide, inner salt (Example 22) (0.45g) to give the title compound (0.26g) as a yellow solid.
• Example 23b 8-fluoro-3-methyl- 1,2,3, 4-tetrahydroquinoline-2- carboxylic acid (Example 23b) (5g) and 5-amino-2-chloropyridine (2.67g) to give the title compound (1.2g) as a yellow solid.
• Example 31 Prepared by the route of Example 9 using 4,5-dihydro-3-hydroxy-2-(4-methylphenyl)- [l,2,3]triazolo[l,5-a]quinolinium hydroxide, inner salt (Example 31) (1.3g) to give the title compound (0.74g) as a yellow solid.
• Example 35 Prepared by the route of Example 9 using 4,5-dihydro-3-hydroxy-2-[4- (trifluoromethoxy)phenyl)-[l,2,3]triazolo[l,5-a]quinolinium hydroxide, inner salt (Example 35) (5g) to give the title compound (4.3g) as a yellow solid.
• Example 4 Prepared by the route of Example 20 using 4,5-dihydro-2-(4-chlorophenyl)-3-hydroxy- [l,2,3]triazolo[l,5-a]quinolinium hydroxide, inner salt (Example 4) (12.7g) to give the title compound (4.8g) as a yellow solid.
• Example 48 Prepared as for Example 48 employing 4-chloroaniline and methyl 2- (carboxymethylamino)benzoate to give the title compound as a colourless solid.
• Example 33 2-(4-fluorophenyl)-3-hydroxy- [l,2,3]triazolo[l,5-a]quinolinium hydroxide, inner salt (Example 33) (1.7g) to give, after recrystallization from ethyl acetate, the title compound (1.58g) as an orange solid.
• Example 3 Prepared by the route of Example 3 using 8-fluoro-l,2,3,4-tetrahydroquinoline-2- carboxylic acid (Example 1 lc) (2.2g) and 5-amino-2-methylpyridine (l.Og) to give the title compound (0.23g) as a beige solid.
• Example 66 9-fluoro-4,5-dihydro-3-hydroxy-2-(6-methyl-3- pyridinyl)-[l,2,3]triazolo[l,5-a]quinolinium hydroxide, inner salt (Example 66) (0.68g) to give the title compound (0.16g) as a yellow solid. m.p. 205°C
• Example 68 Prepared by the route of Example 20 using 9-fluoro-4,5-dihydro-3-hydroxy-4-methyl-2-(6- methyl-3-pyridinyl)-[l,2,3]triazolo[l,5-a]quinolinium hydroxide, inner salt (Example 68) (0.5g) to give the title compound (0.15g) as a yellow solid.
• Example 18c 3-methyl- 1,2,3, 4-tetrahydroquinoline-2- carboxylic acid hydrochloride (Example 18c) (5.1g) and 4-fluoroaniline (2.12ml) to give the subtitle compound (0.4g) as a yellow solid.
• Example 18c 3-methyl-l,2,3,4-tetrahydroquinoline-2- carboxylic acid hydrochloride (7.48g) and 5-amino-2-methylpyridine (4.2g) to give the subtitle compound (1.21g) as a yellow solid.
• Example 78 Prepared by the route of Example 51 using 3-hydroxy-4-methyl-2-(6-methyl-3-pyridinyl)- [l,2,3]triazolo[l,5-a]quinolinium hydroxide, inner salt (Example 78) (0.3g) to give the title compound (0.4g) as an orange solid.
• Chlorotrimethylsilane (0.56ml) was added to a stirred suspension of 2-(3-fluorophenyl)- 4,5-dihydro-3-hydroxy-4-oxo-[l,2,3]triazolo[l,5-a]quinoxalinium hydroxide, inner salt (Example 76) (l.Og) and triethylamine (0.61ml) in toluene (30ml) and the mixture was warmed to 40°C for 4h. The reaction mixture was then cooled in an ice bath and a solution of isopropylmagnesium chloride (2M in diethyl ether, 5.1ml) was added dropwise then this mixture was allowed to warm to room temperature slowly over 16h.
• 2-(3-fluorophenyl)- 4,5-dihydro-3-hydroxy-4-oxo-[l,2,3]triazolo[l,5-a]quinoxalinium hydroxide, inner salt (Example 76
• Chlorotrimethylsilane (0.37ml) was added to a stirred suspension of 2-(3-fluorophenyl)- 4,5-dihydro-3-hydroxy-4-oxo-[l,2,3]triazolo[l,5-a]quinoxalinium hydroxide, inner salt (Example 76) (0.66g) and triethylamine (0.4ml) in toluene (20ml) and the mixture was warmed to 40°C for 4h. The reaction mixture was then cooled in an ice bath and a solution of methylmagnesium chloride (3M in tetrahydrofuran, 2.2ml) was added dropwise before warming to 40°C for 3h.
• methylmagnesium chloride (3M in tetrahydrofuran, 2.2ml
• Example 63a Prepared as for Example 63a employing 4-toluidine (lOg) and [2-(acetylamino)- phenyl]amino acetic acid, lithium salt (Example 63a, 20g) to give the subtitle compound (5.3 lg) as a beige solid.
• Example 63b Prepared as for Example 63b employing l-(2-acetylamino)phenyl-4-hydroxy-3-(4- methylphenylH 1 ,2,3]triazolium hydroxide, inner salt (4.8 lg) to give the title compound (0.445g) as a yellow solid. m.p. 192-193°C
• Example 63a Prepared as for Example 63a employing 5-amino-2-methoxypyridine (11.6g) and [2- (acetylamino)phenyl] amino acetic acid, lithium salt (Example 63a, 20g) to give the subtitle compound (7.29g) as an orange solid.
• Example 63b Prepared as for Example 63b employing l-(2-acetylamino)phenyl-4-hydroxy-3-(6- methoxy-3-pyridinyl)-[l,2,3]triazolium hydroxide, inner salt (6.67g) to give the title compound as a yellow solid.
• Example 87 2-(6-chloro-3-pyridinyl)-3-hydroxy-4-methyl- [l,2,3]triazolo[l,5-a]quinolinium hydroxide, inner salt (Example 87) (lg) to give, after recrystallization from ethyl acetate, the title compound (0.39g).
• 2-(4-Chlorophenyl)-3-hydroxy-5-nitro-[l,2,3]triazolo[l,5-a]quinolinium hydroxide, inner salt 2-(4-Chlorophenyl)-3-hydroxy-[l,2,3]triazolo[l,5-a]quinolinium hydroxide, inner salt (Example 46) (l.OOg) was dissolved in dichloromethane (75 ml) and nitronium tetrafluoroborate (0.5M solution in sulfolane) was added dropwise until there was no starting material left by thin layer chromatography (ca. 12 ml). The mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution.
• Example 42 2-(6-chloro-3-pyridinyl)-4,5-dihydro-3- hydroxy-[l,2,3]triazolo[l,5-a]quinolinium hydroxide, inner salt (Example 42) (l.Og) to give the subtitle compound (0.93 g) as a yellow solid. Used crude for the next step.
• Example 63b Prepared as for Example 63b employing 4-ethylaniline (6.05g) and [2-(acetylamino)- phenyljamino acetic acid, lithium salt (10.7g) to give the subtitle compound (4.3g) as a beige solid.
• Example 63c Prepared as for Example 63c employing l-(2-acetylamino)phenyl-3-(4-ethylphenyl) -4- hydroxy-[l,2,3]triazolium hydroxide, inner salt (4.0g) to give the title compound (1.265g) as a yellow solid.
• Example 63b Prepared as for Example 63b employing 3-chloroaniline (2.98g) and [2-(acetylamino)- phenyljamino acetic acid, lithium salt (5.0g) to give the subtitle compound (3.52g) as a beige solid.
• Example 63c Prepared as for Example 63c employing l-(2-acetylamino)phenyl-3-(3-chlorophenyl)-4- hydroxy-[l,2,3]triazolium hydroxide, inner salt (3.32g) to give the title compound (1.265g) as an orange solid.

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