WO1999001442A1 - Derives de triazine et leur utilisation comme agents antibacteriens - Google Patents

Derives de triazine et leur utilisation comme agents antibacteriens Download PDF

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Publication number
WO1999001442A1
WO1999001442A1 PCT/GB1998/001884 GB9801884W WO9901442A1 WO 1999001442 A1 WO1999001442 A1 WO 1999001442A1 GB 9801884 W GB9801884 W GB 9801884W WO 9901442 A1 WO9901442 A1 WO 9901442A1
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Prior art keywords
triazine
ring
amino
alkyl
optionally substituted
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PCT/GB1998/001884
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English (en)
Inventor
Jeffrey Philip Poyser
Berwick Telford
David Timms
Michael Howard Block
Neil James Hales
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Zeneca Limited
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Priority claimed from GBGB9713908.3A external-priority patent/GB9713908D0/en
Priority claimed from GBGB9720840.9A external-priority patent/GB9720840D0/en
Application filed by Zeneca Limited filed Critical Zeneca Limited
Publication of WO1999001442A1 publication Critical patent/WO1999001442A1/fr

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    • 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
    • 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
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/48—Two nitrogen atoms
    • C07D251/52—Two nitrogen atoms with an oxygen or sulfur atom attached to the third ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • C07D251/70—Other substituted melamines
    • 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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to antibiotic compounds containing a 1,3,5-triazine ring. This invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.
  • DNA Gyrase the enzyme responsible for the process of supercoiling DNA in bacteria, represents an attractive antibacterial target because it is vital to bacteria and has no direct counterpart in mammals. Structurally the enzyme has two discrete subunits (A and B) and it functions as an A 2 B 2 tetramer in which the A subunits are responsible for the binding, breaking and recombination of the DNA and the B subunits which provide the energy for the process by the hydrolysis of ATP.
  • the quinolones bind to the A subunits forming a stable ternary complex between DNA, enzyme and drug, which in turn is responsible for the subsequent cell death.
  • the coumarins typified by the natural product Novobiocin, bind to the B subunit of DNA Gyrase causing inhibition of the ATPase activity.
  • the quinolones have found very widespread use as antibiotics but are gradually being compromised by problems of resistance. They are also limited in that they are not generally approved for use in paediatrics because of cartilage damage in animals.
  • the coumarins have not been used widely because of a combination of problems including the rapid development of resistance, toxicity and poor physical properties.
  • a third class of compounds, which also inhibit DNA Gyrase by competitive binding to the B subunit, are currently under investigation and include the natural product cyclothialidine, a variety of synthetic analogues and the closely related GR122222X.
  • the present inventors have discovered a class of antibiotic compounds containing a 1 ,3,5-triazine ring which has Gyrase inhibitory properties, in particular useful inhibitory activity against the Gyrase enzyme in Gram Positive Bacteria. Accordingly the present invention provides a compound of the formula (I), a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof:
  • R 1 is an optionally substituted aryl ring, optionally substituted heteroaryl ring, or such ring systems fused to an aryl or heteroaryl ring forming a bicyclic ring; or R 1 is carboxy- C, .6 alkyl or imidazolin-2-on-l-ylC,. 6 alkyl; R 2 is an optionally substituted aryl ring or such ring system fused to a heteroaryl ring; R 3 is H, NHR 4 , CHR 5 R 6 , where R 4 , R 5 and R 6 are independently H or optionally substituted C,. 6 alkyl, C 2 . 6 alkenyl or C 2 .
  • 6 alkynyl or R 3 is an optionally substituted aryl ring; wherein optional substituents for aryl, heteroaryl, such ring systems fused to an aryl ring (for example fused to a benzene ring) or fused to a heteroaryl ring, C, .6 alkyl, C 2.6 alkenyl and C 2 . 6 alkynyl are: C,. 6 alkyl, C 2 . 6 alkenyl, C 2 _ 6 alkynyl, C,. 6 alkylC(O)-, C,. 6 alkoxycarbonyl, aryl. aryloxy. heteroaryl.
  • R 3 is H, and X is NH
  • R 1 and R 2 are not both phenyl, 3-halophenyl, 4-halophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4- aminoquinolin-6-yl, 4-amino-2-methylquinolin-6-yl or 4-amino-2,3-dimethylquinolin-6-yl; and 3) excluding:
  • the present invention provides compounds of formula (I) or a pharmaceutically acceptable salt thereof.
  • 'alkyl' includes straight chained, branched structures and ring systems.
  • C,. 6 alkyl includes propyl, isopropyl, /-butyl, cyclopropane and cyclohexane.
  • references to individual alkyl groups such as 'propyl' are specific for the straight chained version only
  • references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only
  • references to the cyclo groups such as cyclohexane are specific to the cyclic groups only.
  • a similar convention applies to other radicals, for example haloC,.
  • 6 alkyl includes 1-bromoethyl and 2-bromoethyl.
  • halo refers to fluoro, chloro, bromo and iodo.
  • X is O, NH, CH 2 ;
  • R' is an optionally substituted aryl ring, optionally substituted heteroaryl ring, or such ring systems fused to an aryl or heteroaryl ring forming a bicyclic ring;
  • R 2 is an optionally substituted aryl ring or such ring system fused to a heteroaryl ring;
  • R 3 is H, NHR 4 , CHR 5 R 6 , where R ⁇ R 5 and R 6 are independently H or optionally substituted
  • C,. 6 alkyl, C 2 . 6 alkenyl or C 2 _ 6 alkynyl or R 3 is an optionally substituted aryl ring; wherein optional substituents are as defined above; with the provisos
  • R 3 is H. and X is NH
  • R 1 and R 2 are not both phenyl, 3-halophenyl, 4-halophenyl, 3-methylphenyl, 4-methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4- aminoquinolin-6-yl, 4-amino-2-methylquinolin-6-yl or 4-amino-2,3-dimethylquinolin-6-yl; and
  • X is O, NH, CH 2 preferably O and NH in particular O.
  • R' is an optionally substituted aryl. optionally substituted heteroaryl ring, or such ring systems fused to an aryl or heteroaryl ring forming a bicyclic ring. Suitable aryl and fused aryl rings include phenyl and naphthyl preferably phenyl.
  • Suitable heteroaryl and fused heteroaryl rings include pyridyl, pyrimidyl, triazinyl, imidazolyl, quinolyl, isoquinolyl, benzimidazolyl, coumarinyl, benzofuran-3-onyl preferably pyridyl, imidazolyl, coumarinyl and quinolyl and their N-oxides and N-alkyl derivatives.
  • R' is heteroaryl with only one heteroatom preferably X is meta to the heteroatom.
  • Preferred optional substituents are halo especially fluoro and chloro, R ⁇ S(O)- or R n S(O) 2 - in particular where R" is H, methyl or ethyl, C, .6 C(O)NH- (optionally substituted with di-C ⁇ -6 alkylamino or tri-C ⁇ . 6 alkylamino), carboxy, C ].6 alkylcarbamoyl, carbamoyl, C,. 6 alkyl in particular where C, .6 alkyl is methyl and ethyl, hydroxy, nitro and cyano. Particular values of R !
  • R 2 is an optionally substituted aryl ring. Suitable aryl rings include phenyl and naphthyl preferably phenyl. When R 2 is optionally substituted aryl fused to a heteroaryl ring, suitable ring systems are those listed above with respect to R 1 . Preferred optional substituents for the ring systems of R 2 are halo especially fluoro and chloro, C, .6 alkyl especially methyl and ethyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, R 9 R 10 NC(O)-, cyano, nitro, hydroxy, R n S-, R ⁇ S(O)-, R"S(O) 2 -, carboxy and C,.
  • R 2 Particular values of R 2 are 3 -fluorophenyl, 3,5- difluorophenyl, 3-chlorophenyl, 3,5-dichlorophenyl 3-chloro-5-EtS-phenyl and 3-ethynyl-5- chlorophenyl.
  • R 3 is H, NHR 4 , CHR 5 R 6 , where R 4 , R 5 and R 6 are independently H or optionally substituted C, .6 alkyl, C 2 . 6 alkenyl or C 2 . 6 alkynyl or R 3 is an optionally substituted aryl ring
  • R 3 is H, CR 5 R 6 or an optionally substituted aryl ring.
  • R 3 is CHR 5 R 6 preferable values for R 5 and R 6 are H, C,. 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl optionally substituted with cyano, halo, hydroxy, C,. 6 alkoxy, carboxy, C,.
  • R 12 optionally substituted C,. 6 alkyl, optionally substituted aryl C, .6 alkyl
  • R 5 and R 6 may together form a 3 - 8 membered ring optionally with 1 - 3 heteroatoms (optionally substituted).
  • R 3 is an optionally substituted aryl ring
  • the aryl ring is phenyl and preferable optional substituents are halo in particular fluoro chloro and bromo, C, .6 alkyl in particular methyl and ethyl and C,. 6 alkylS-.
  • R 3 Particular values of R 3 are H, allyl, cyclopropyl, cyanomethyl, 3 -fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-methylphenyl, 3- ethylphenyl, 3-MeS-phenyl and 3-ethynylphenyl.
  • a preferred class of compounds is that of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof wherein: X is O;
  • R 1 is optionally substituted phenyl, 3-pyridyl-N-oxy, 3-quinolyl, 3-quinolyl-N-oxy, or coumarinyl, in particular 3-fluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 3,5-dichlorophenyl, 4-MeS(O)-phenyl, 4-MeS(O) 2 -phenyl, 3-pyridyl, 3-MeC(O)NH-phenyl, 4-MeC(O)NH-phenyl, 3-carboxyphenyl, 4-carboxyphenyl, 3-H 2 NC(O)-phenyl, 4-H 2 NC(O)- phenyl, 6-methyl-3-pyridyl-N-oxy, 4-hydroxycoumarinyl, 3-quinolyl-N-oxy, 8-nitroquinolyl, 8-cyano-quinolyl, 8-tetrazolyl-quinolyl or 8-carboxy quinolyl;
  • R 2 is optionally substituted phenyl. in particular 3 -fluorophenyl. 3,5-difluorophenyl, 3-chlorophenyl, 3,5-dichlorophenyl or 3-ethynyl-5-chlorophenyl; and
  • R 3 is H, CHR 5 R 6 or an optionally substituted aryl ring, in particular H, allyl, cyclopropyl, cyanomethyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-methylphenyl, 3-ethylphenyl, 3-MeS-phenyl or 3-ethynylphenyl.
  • a further preferred class of compounds is that of Examples 1 - 43 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
  • Suitable pharmaceutically acceptable salts include acid addition salts such as methanesulphonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid.
  • suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine.
  • a preferred pharmaceutically acceptable salt is the sodium salt.
  • an ⁇ -oxide refers to the ⁇ -oxides which may be formed on an available nitrogen atom on the R 1 ring where R' is heteroaryl or a heteroaryl fused to an aryl ring, for example where R ! is pyridyl or quinolyl.
  • R 2 is an aryl ring fused to a heteroaryl ring which contains an available nitrogen atom, for example a quinolyl.
  • N-oxides may also be formed here.
  • An N-oxide may be optionally in the form of a pharmaceutically acceptable salt.
  • N-alkylation refers to an N-alkyl derivative that may be formed on R 1 where it is heteroaryl or a heteroaryl fused to an aryl ring, for example where R' is pyridyl or quinolyl.
  • R 2 is an aryl ring fused to a heteroaryl ring which contains an available nitrogen atom, for example a quinolyl
  • N-alkyl derivatives may also be formed here.
  • An N-alkyl derivative may be optionally in the form of a pharmaceutically acceptable salt.
  • Preferred N-alkyl derivatives are N-methyl and N-ethyl derivatives, especially N-methyl derivatives.
  • the invention relates to all tautomeric forms of the compounds of formula (I) that possess Gyrase inhibitory activity. It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess Gyrase inhibitory activity.
  • the compounds of the formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the formula (I).
  • pro-drugs include in vivo hydrolysable esters of a compound of the formula (I).
  • An in vivo hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include C, .6 alkoxymethyl esters for example methoxymethyl, C,.
  • 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 . 8 cycloalkoxycarbonyloxyC,.
  • 6 alkyl esters for example 1-cyclohexylcarbonyloxyethyl
  • l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3- dioxolen-2-onylmethyl
  • C,. 6 alkoxycarbonyloxy ethyl esters for example 1 -methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
  • An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof which process comprises of: a) reacting a compound of formula (II):
  • R ⁇ HA (V) where R 1 and X are as defined for formula (I), L is a leaving group, A is as defined above and R x is R 2 and R y is R 3 ; or R is R 3 and R y is R 2 ;
  • R'A (IX) where R 1 is as defined for formula (I), and A is as defined above; and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.
  • aqueous inorganic base such as sodium or potassium carbonate or sodium bicarbonate or a tertiary organic base such as diisopropylamine or triethylamine or excess (V)
  • inert solvent such as acetone or 1,4-dioxane at a temperature range of 10° C to 40° C, normally in the range 18 to 30 °C.
  • R 2 NHA (XII) Compounds of formula (XI) and (XII) may be reacted together in the presence of a base, either an aqueous inorganic base such as sodium or potassium carbonate or sodium bicarbonate or an organic base such as diisopropylamine or triethylamine, in an inert solvent such as acetone or chloroform at a temperature range of -10° C to ambient temperature, normally in the range -5 to 5 ° C.
  • a base either an aqueous inorganic base such as sodium or potassium carbonate or sodium bicarbonate or an organic base such as diisopropylamine or triethylamine
  • Compounds of formula (IV) are prepared by reacting compounds of formula (X) with compounds of formula (III). These may be reacted together in the presence of a base, either aqueous inorganic base such as sodium or potassium carbonate or sodium hydroxide or a tertiary organic base such as diisopropylamine or triethylamine or excess (III), in an inert solvent such as acetone or 1 ,4-dioxane at a temperature range of 10 to 40 ° C, normally in the range 18 to 30 °C.
  • a base either aqueous inorganic base such as sodium or potassium carbonate or sodium hydroxide or a tertiary organic base such as diisopropylamine or triethylamine or excess (III)
  • an inert solvent such as acetone or 1 ,4-dioxane at a temperature range of 10 to 40 ° C, normally in the range 18 to 30 °C.
  • Compounds of formula (VI) and (VII) may be condensed together in the presence of a base, typically a tertiary organic base such as diisopropylamine or triethylamine in an inert solvent such as N,N-dimethylformamide at a temperature range of ambient temperature to 150 °C. normally in the range 85- 105 ° C.
  • a base typically a tertiary organic base such as diisopropylamine or triethylamine
  • an inert solvent such as N,N-dimethylformamide
  • A is a group capable of forming a cation, usually A is H or Na.
  • L and Z are leaving groups. Preferable values for L and Z are halo for example chloro and aryloxy for example phenoxy.
  • These compounds of formula (I) produced by the above routes may optionally be further manipulated by processes known in the art such as oxidation e.g. of nitrogen or sulphur, removal of a protecting group e.g. an ester or quaternization e.g. of a nitrogen, forming a pharmaceutically acceptable salt or in vivo hydrolysable ester or other processes to give further compounds of formula (I).
  • N-oxides of compounds of the formula (I) may be prepared directly from a compound of formula (I) (see example 21) or a compound of the formula (XII) (see example 9) using techniques well known to the ordinary skilled organic chemist, such as, for example, using a peracid (such as m-chloroperoxybenzoic acid) or perphthalic acid in a suitable solvent (such as 1 ,4-dioxane or a mixture of water and tetrahydrofuran) at a suitable temperature (such as ambient temperature).
  • a peracid such as m-chloroperoxybenzoic acid
  • perphthalic acid such as 1 ,4-dioxane or a mixture of water and tetrahydrofuran
  • N-alkyl derivatives of compounds of the formula (I) may be prepared directly from a compound of formula (I) or a compound of the formula (XII) using techniques well known to the ordinary skilled organic chemist, such as, for example, using a methylating agent (such as iodomethane) in a suitable solvent (such as 1 ,4-dioxane or dichloromethane) at a suitable temperature (such as ambient temperature).
  • a methylating agent such as iodomethane
  • suitable solvent such as 1 ,4-dioxane or dichloromethane
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or /-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a r-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifiuoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is. for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a /-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifiuoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a /-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifiuoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art. It will also be appreciated that certain of the various optional substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acylhalide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • a pharmaceutically-acceptable salt of a compound of the formula (I) When a pharmaceutically-acceptable salt of a compound of the formula (I) is required, it may be obtained, for example, by reaction of said compound with the appropriate acid (which affords a physiologically acceptable anion), or with the appropriate base (which affords a physiologically acceptable cation), or by any other conventional salt formation procedure.
  • an optically active form of a compound of the formula (I) When an optically active form of a compound of the formula (I) is required, it may be obtained, for example, by carrying out one of the aforesaid procedures using an optically active starting material or by resolution of a racemic form of said compound using a conventional procedure.
  • a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for the therapeutic treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • X is O, NH, CH 2 ;
  • R 1 is an optionally substituted aryl ring, optionally substituted heteroaryl ring, or such ring systems fused to an aryl or heteroaryl ring forming a bicyclic ring; or
  • R 1 is carboxy- C, .6 alkyl or imidazolin-2-on-l-ylC,. 6 alkyl;
  • R 2 is an optionally substituted aryl ring or such ring system fused to a heteroaryl ring
  • R 3 is H, NHR 4 , CHR 5 R 6 , where R 4 , R 5 and R 6 are independently H or optionally substituted C,. 6 alkyl, C 2 . 6 alkenyl or C 2 . 6 alkynyl or R 3 is an optionally substituted aryl ring; wherein optional substituents for aryl, heteroaryl, such ring systems fused to an aryl ring (for example fused to a benzene ring) or fused to a heteroaryl ring, C, .6 alkyl, C 2.6 alkenyl and C 2 .
  • 6 alkynyl are: C,. 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C,. 6 alkylC(O)-, C,. 6 alkoxycarbonyl, aryl, aryloxy, heteroaryl, halo, cyano, nitro, hydroxy, carboxy, amino, C,. 6 alkoxy, (C,. 6 alkoxy) 2 CH-, carboxy C). 6 alkyl, hydroxyC ⁇ - 6 alkyl, C,.
  • R 7 R 8 amino including quaternary derivatives thereof such as R7R8R7N-
  • R 9 R 10 NC(O)- (where R 9 is OR 10 , NHR 10 or R 10 and R 10 is H, C,. 6 alkyl, aryl, arylC,.
  • heteroalkyl rings and aryl groups referred to may themselves be optionally substituted as defined above; where any nitrogen containing heteroaryl ring in R 1 or R 2 may optionally be N oxidised or N alkylated; with the provisos
  • R 3 is H, and X is NH, R 1 and R 2 are not both 4-aminoquinolin-6-yl or 4-amino-2- methylquinolin-6-yl;
  • a method for producing an antibacterial effect, and in particular a Gyrase mediated antibacterial effect in a warm blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (IA), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • the invention also provides a compound of the formula (IA), or a pharmaceutically acceptable salt, N-oxide or in vivo hydrolysable ester thereof, for use as a medicament.
  • This invention further provides the use of a compound of the formula (IB):
  • R 1 is an optionally substituted aryl ring, optionally substituted heteroaryl ring, or such ring systems fused to an aryl or heteroaryl ring forming a bicyclic ring; or R 1 is carboxy- C, .6 alkyl or imidazolin-2-on-l-ylC,. 6 alkyl;
  • R 2 is an optionally substituted aryl ring or such ring system fused to a heteroaryl ring;
  • R 3 is H, NHR 4 , CHR 5 R 6 , where R 4 , R 5 and R 6 are independently H or optionally substituted
  • C,. 6 alkyl, C 2 . 6 alkenyl or C 2 . 6 alkynyl or R 3 is an optionally substituted aryl ring; wherein optional substituents for aryl, heteroaryl, such ring systems fused to an aryl ring (for example fused to a benzene ring) or fused to a heteroaryl ring, C,. 6 alkyl, C 2.6 alkenyl and C 2 . 6 alkynyl are:
  • R 7 R 8 amino including quaternary derivatives thereof such as R7R8R7N-
  • heteroalkyl rings and aryl groups referred to may themselves be optionally substituted as defined above; where any nitrogen containing heteroaryl ring in R 1 or R 2 may optionally be N oxidised or N alkylated; with the proviso that on any optionally substituted phenyl or naphthyl ring the two positions on the ring ortho to the NH or X group linking to the 1,3,5-triazine ring must both be unsubstituted; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof in the manufacture of a novel medicament for use in the production of an antibiotic effect, and in particular a Gyrase mediated antibacterial effect in a warm blooded animal, such as man.
  • compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • the pharmaceutical composition of this invention may also contain or be co-administered with one or more known drugs selected from other clinically useful antibacterial agents (for example ⁇ -lactams or aminoglycosides). These may include penicillins, for example oxacillin or flucloxacillin and carbapenems, for example meropenem or imipenem, to broaden the therapeutic effectiveness against methicillin-resistant staphylococci.
  • drugs of this invention may also contain or be co-administered with bactericidal/permeability-increasing protein product (BPI) or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.
  • BPI bactericidal/permeability-increasing protein product
  • efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.
  • a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between lOOmg and lg of the compound of this invention.
  • a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
  • Each patient may receive, for example, a daily intravenous, subcutaneous or intramuscular dose of 5 rngkg " ' to 20 mgkg " ' of the compound of this invention, the composition being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Altematively the intravenous dose may be given by continuous infusion over a period of time.
  • each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • Synthetic products were tested for gyrase inhibitory activity in a standard supercoiling assay (M. Gellert, K. Mizuuchi, M. H. O'Dea and H. A. Nash, Proc. Natl. Acad. Sci. USA, 1976, 73, 3872-76) and for antibacterial activity in a standard antimicrobial susceptibility assays (National Committee for Clinical Laboratory Standards,. (1993) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - 3rd ed; approved standard. Document M7-A3 13 (25), Villanova, PA.). Antibacterial Activity.
  • the following results were obtained on a standard in vitro test system.
  • the activity is described in terms of the minimum inhibitory concentration (MIC) determined by the agar- dilution technique with an inoculum size of 10 4 CFU/spot. Staphylococci were tested on agar, using an inoculum of 10 4 CFU/spot and an incubation temperature of 37 °C for 24 hours - standard test conditions for the expression of methicillin resistance.
  • MIC minimum inhibitory concentration
  • Streptococci and enterococci were tested on agar supplemented with 5% defibrinated horse blood, an inoculum of 10 4 CFU/spot and an incubation temperature of 37 °C in an atmosphere of 5% carbon dioxide for 48 hours - blood is required for the growth of some of the test organisms.
  • Organism MIC (ug mn
  • DNA gyrase subunits A and B quantities are adjusted such that 50% of relaxed pUC 18 is supercoiled in 20min. Volumes vary depending upon the activity of a particular preparation.
  • reaction is stopped by the addition of 4 ⁇ l loading buffer (0.25% bromophenol blue, 0.25% xylene cymol, 15% Ficol tybe 400, 2% SDS).
  • 4 ⁇ l loading buffer 0.25% bromophenol blue, 0.25% xylene cymol, 15% Ficol tybe 400, 2% SDS.
  • the separation of relaxed from supercoiled pUC18 is by 0.7% agarose gel submarine electrophoresis visualised by ethidium bromide staining and UV illumination.
  • the supercoiled plasmid having higher mobility than the relaxed.
  • the IC 50 value is the concentration of compound which reduces the control 50% supercoiling by 50% and can be assessed visually or by densitometry. A typical dose response would exhibit the full range from total inhibition i.e. only relaxed plasmid visible, to no effect ie supercoiled and relaxed bands present at equal intensity.
  • Standard inhibitors of gyrase include Norfloxacin IC 50 1.O ⁇ g/rnl and novobiocin IC 50 0.075 ⁇ g/ml.
  • Typical active gyrase inhibitors have an IC 50 ⁇ 10.
  • IC 50 for Example 31 0.55.
  • the filtrate was diluted with ethyl acetate/methanol; 3:1 and filtered through a column of silica.
  • the purified filtrate was evaporated to dryness, taken into a small volume of methanol, filtered, diluted with ethyl acetate (3 volumes), and concentrated to give a purified product that was collected by filtration. Yield 0.027 g (16%); Mp 241-243 °C; NMR ⁇ 5.03 (s, 2H), 6.90 (s, IH), 7.10 (t, IH), 7.17 (s, IH), 7.32 (br. s, 2H), 7.66 (s, IH), 7.82 (br. s, 2H), 9.82 (br. s, IH); MS (ES + ) w/z 336 [MH] + .
  • Example 22 Yield 80 mg (35%); mp 203-205 °C; NMR ⁇ 3.78 (s, 3H), 6.80 (m, 2H), 7.2-7.85 (m, 6H), 7.50 (d, 2H), 7.78 (d, IH), 10.05 (s, 2H); MS (ES + ) m/z 454 ([Mrl] * , 100%).
  • Example 26 2-Amino-4-(3'-fluoroanilino)-6-(3"-pyridyloxy)-l,3,5-triazine.
  • 2-Chloro-4-(3'-fluoroanilino-6-(3"-pyridyloxy)-l ,3,5-triazine 80 mg, 0.25 mM was dissolved in acetone (10 ml) and cone, ammonia (1 ml) was added. After 30 mins., the solution was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was washed with brine (30 ml), dried, filtered and concentrated and the residue was chromatographed over silica and eluted with ethyl acetate to give Example 26 as a white solid.
  • Example 29 2-Amino-4-(3'-carboxamidophenoxy)-6-(3"-fluoroanilino)-l,3,5-triazine.
  • Example 29 had precipitated and was collected by filtration.
  • Example 30 The following compound wherein X, R 1 , R 2 and R 3 are as shown in formula (I), were prepared using the appropriate starting materials, by a similar process to that described in Example 29:
  • Example 31 2-Amino-4-(3'-chloroanilino)-6-(l"-N-oxy-6"-methyl-3"pyridyloxy)-l,3,5-triazine.
  • 2-amino-4-(3'chloroanilino)-6-(6"-methyl-3"-pyridyloxy)-l,3,5-triazine (0.5 g, 1.5 mM) was dissolved in acetone (10 ml) and m-chloroperoxybenzoic acid (50% aqu.. 584 mg. 1.7 mM) was added. The mixture was stirred for 1 h. and a further portion of m- chloroperoxybenzoic acid (300 mg) was added and stirring continued for 2 h. The mixture was concentrated and slurried with acetone (5 ml) and diethyl ether (5 ml) and the product was filtered off as a white solid.
  • Example 32 The following compound wherein X, R'. R 2 and R 3 are as shown in formula (I), were prepared using the appropriate starting materials, by a similar process to that described in Example 31 :
  • Example 34 2-Amino-4-(3'-fluoroanilino)-6-(4"-hydroxy-7"-coumarinyloxy)-l,3,5-triazine.
  • Example 37 as a white solid. Yield 600 mg (25%); Mp 245-248 °C; NMR ⁇ 6.95 (d, IH), 7.10 (s, IH), 7.20 (s, 2H), 7.40 (s,lH), 7.70 (s, IH), 7.82 (t, IH), 8.31 (d, IH), 8.45 (d, IH). 8.60 (d, IH), 9.15 (d, IH), 9.75 (s, IH); MS (ES " ) m/z 407 [M-H]-.
  • Example 41 Diethyl-2-(bis-4,6-(3-fluoroanilino)-l,3,5-triazin-2-yl)hydrazino)methylenemalonate.
  • Example 43 2- Amino-4-(3 ' ,5 ' -dichloroanilino)-6-(5 "-(3 " ' -carboxy ethyl)- 1 ' ' -N-oxypy rid-3 ' '-yloxy)- 1,3,5-triazine.
  • Cyanuric chloride (7.36 g, 40 mM) was dissolved in the minimum volume of acetone and added dropwise to rapidly stirred crushed ice to give a finely divided solid.
  • 3- Fluoroaniline (8.89 g, 80 mM) was added dropwise, followed by sodium hydroxide (3.2 g, 80 mM) in water (50 ml) at a rate which maintained pH between 7 and 10.
  • sodium hydroxide 3.2 g, 80 mM
  • the reaction mixture was heated at 45-50 °C for 10 mins., cooled and filtered. The solid was washed with water, a small volume of ethanol and dried.
  • the salt was suspended in dichloromethane (150 ml) and ammonia (5M in methanol, 10 ml) was added, followed by methanol (50 ml) and water (100 ml). The aqueous phase was separated, adjusted to pH6 with 2M HCl, the solid filtered off and washed with water. Yield 5.3 g (87%); Mp 324-326 °C; NMR as for the trifiuoroacetic acid salt except ⁇ 7.15 (s, IH).
  • the pentafluorophenyl ester (309 mg, 0.5 mM) and N,N-dimethylethylenediamine (44 mg, 55 ⁇ l, 0.5 mM) were stirred in THF (3 ml) for 2 h. After distribution between ethyl acetate and water, the organic phase was separated and washed with aqueous sodium hydrogen carbonate solution and water, evaporated and chromatographed on an Isoelute column (5 g), eluting with ethyl acetate/methanol/triethylamine; 9:1 :0, then 18:1 : 1 to give a white solid.
  • Phenyl 3-pyridineacetate' 8 (2.812 g, 13.2 mmol), 3-chloroperoxybenzoic acid (50% strength, 4.83 g, 14 mmol), and acetone (30 ml) were stirred at room temperature for 50 mins.. An additional portion of 3-chloroperoxybenzoic acid (50% strength, 0.23 g, 0.667 mmol) was added and the mixture was stirred for a further 10 mins.. The mixture was evaporated to dryness and the oily residue was triturated with diethyl ether (50 ml) until crystallisation occurred. The mixture was diluted with isohexane (50 ml) and filtered.
  • the resulting solid was washed with isohexane/ether (1 :1, 100 ml) and then dissolved in dichloromethane (200 ml). The solution was washed with saturated aqueous sodium bicarbonate (3 x 15 ml), dried, and evaporated to leave an oil that crystallised when triturated with diethyl ether/isohexane (1 :1). The solid was collected by filtration and washed with diethyl ether/isohexane (1 :1).
  • Example 9 Using the appropriate starting materials and a procedure similar to that of Example 9 the following compounds were prepared: E) 2,4-(&w-3'-fluoroanilino)-6-(4"-methylmercaptophenoxy)-l,3,5-triazine; El) Methyl 2-amino-4-(3'-carboxyphenoxy)-6-(3"-fluoroanilino)-l,3,5-triazine; E2) 2-amino-4-(3'chloroanilino)-6-(6"-methyl-3"-pyridyloxy)-l,3.5-triazine; E3) 19 4-carboxyphenoxy- ⁇ w-m-fluoroanilino-l,3,5-triazine.
  • Cyanuric chloride (36.8 g, 0.2 M) was dissolved in chloroform (500 ml) and cooled in an ice bath.
  • m-Fluoroaniline 38.4 ml, 44.4 g, 0.4 M
  • chloroform 100 ml
  • the mixture was allowed to warm to room temperature and then filtered to give 2,4-dichloro-6-(3'-fluoroanilino)-l,3,5-triazine (30 g).
  • a portion of this material (2.64 g, 10 mM) was dissolved in ethanol (20 ml) and ammonia (2M in ethanol, 10.5 ml, 21 mM) was added.
  • Methyl 5-hydroxynicotinate 20 (2.5 g, 16.3 mM) was dissolved in DMSO (25 ml) and added to a cooled solution of sodium methoxide in methanol (375 mg sodium, 5 ml methanol). Benzyl bromide (2.79 g, 16.3 mM) was added dropwise and after 30 min the reaction was concentrated under vacuum and partitioned between ethyl acetate and water. The organic layer was dried, filtered and concentrated and the residue chromatographed on silica using 30% ethyl acetate in hexane as eluent to give methyl 5-benzyloxypyridine-3-carboxylate (1.5 g).
  • 2,4-Dichloro-6-(3'-fluoroanilino)-l,3,5-triazine (1.0 g, 3.8 mM) was dissolved in acetone (30 ml) and cooled to 5-10 °C. 3 -Hydroxypyridine (0.37 g, 3.8 mM) was added followed by aqueous sodium hydroxide (IM, 3.8 ml, 3.8 mM). The solution was stirred for 1.5 h. and then partitioned between ethyl acetate (100 ml) and water (100 ml).
  • 3-bromo-5-chloronitrobenzene (31.5 g, 133 mM) was dissolved in DMF (500 ml) under argon and bis-(triphenylphosphine)-palladium(II) chloride (1.87 g, 2.66 mM), EtMe 2 N (40 ml), copper(I) iodide (1.01 g, 5.32 mM) and trimethylsilylacetylene (36.8 g. 266 mM) were added. The reaction mixture was stirred at 40 °C for 16 h.
  • the nitro compound (9.1 g, 50 mM) and iron powder (18.2 g, 0.33 g Atom) were refluxed in 1 : 6 acetic acid/ethanol (350 ml) for 1 h., allowed to cool, poured into water (1 1). This was extracted with ethyl acetate (2 x 750 ml) and the organic phase was separated and washed with water (750 ml), NaHCO 3 (3 x 500 ml), brine (500 ml), dried and evaporated. The brown oil (7.05 g) was chromatographed on silica by MPLC.
  • 5-benzyloxy-3-bromopyridine 24 (3.5 g, 13.3 mM), t-butyl acrylate (3.4 g, 26.7 mM), tetramethylethylenediamme (1.55 g, 13.3 mM), palladium acetate (0.12 g, 0.5 mM) and tri-o- tolylphosphine (0.324 mg, 1.06 mM) were stirred at 125 °C under argon for 48 h. After leaving at room temperature for 24 h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried, filtered and concentrated.

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Abstract

L'invention concerne des composés antibactériens efficaces de la formule (I), des sels pharmaceutiquement acceptables ou des esters hydrolysables in vivo desdits composés. Dans ladite formule, X est O, NH, CH2; R1 est un noyau aryle éventuellement substitué, un noyau hétéroaryle éventuellement substitué ou des systèmes cycliques fusionnés à un noyau aryle ou hétéroaryle pour former un noyau bicyclique, ou R1 est carboxy-C¿1-6?alkyle ou imidazoline-2-one-1-yleC1-6alkyle; R?2¿ est un noyau aryle éventuellement substitué ou un système cyclique fusionnés à un noyau hétéroaryle; R3 est H, NHR?4, CHR5R6 (R4, R5 et R6¿ étant, indépendamment, H ou C¿1-6?alkyle éventuellement substitué, C2-6alcényle ou C2-6alkynyle, ou R?3¿ étant un noyau aryle éventuellement substitué). Les éventuels noyaux hétéroaryles contenant de l'azote compris dans R1 ou R2 peuvent être éventuellement N-oxydés ou N-alkylés. L'invention concerne en outre des compositions pharmaceutiques, des méthodes et de procédés de préparation de composés de la formule (I).
PCT/GB1998/001884 1997-07-02 1998-06-26 Derives de triazine et leur utilisation comme agents antibacteriens WO1999001442A1 (fr)

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EP1409463A1 (fr) * 2001-06-26 2004-04-21 Bristol-Myers Squibb Company Inhibiteurs n-heterocycliques de l'expression de tnf-alpha
WO2004054989A1 (fr) * 2002-12-17 2004-07-01 Hamari Chemicals, Ltd. Nouveau derive de 2,4-diamino-1,3,5-triazine
WO2004089947A2 (fr) * 2003-04-08 2004-10-21 Morphochem Ag Nouveaux composes a activite antibacterienne
US6906067B2 (en) 1999-12-28 2005-06-14 Bristol-Myers Squibb Company N-heterocyclic inhibitors of TNF-α expression
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CN104396965A (zh) * 2014-11-11 2015-03-11 张家港互益染整有限公司 一种反应型卤胺抗菌剂及其制备方法和应用
CN110606831A (zh) * 2018-06-14 2019-12-24 上海度德医药科技有限公司 一种Iclaprim的新中间体及其制备方法和应用
US10675274B2 (en) 2018-09-19 2020-06-09 Forma Therapeutics, Inc. Activating pyruvate kinase R
US10836771B2 (en) 2017-03-20 2020-11-17 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
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WO2001047897A1 (fr) * 1999-12-28 2001-07-05 Pharmacopeia, Inc. Inhibiteurs de la cytokine, en particulier de tnf-alpha
JP2003519130A (ja) * 1999-12-28 2003-06-17 ファーマコペイア， インコーポレイテッド Ｎ−ヘテロ環ＴＮＦ−α発現阻害剤
JP4794793B2 (ja) * 1999-12-28 2011-10-19 ファーマコペイア， インコーポレイテッド Ｎ−ヘテロ環ＴＮＦ−α発現阻害剤
US7479495B2 (en) 1999-12-28 2009-01-20 Pharmacopeia, Inc. N-heterocyclic inhibitors of TNF-α expression
US6906067B2 (en) 1999-12-28 2005-06-14 Bristol-Myers Squibb Company N-heterocyclic inhibitors of TNF-α expression
EP1409463A4 (fr) * 2001-06-26 2004-11-17 Bristol Myers Squibb Co Inhibiteurs n-heterocycliques de l'expression de tnf-alpha
EP1409463A1 (fr) * 2001-06-26 2004-04-21 Bristol-Myers Squibb Company Inhibiteurs n-heterocycliques de l'expression de tnf-alpha
US7375222B2 (en) 2002-02-05 2008-05-20 Astellas Pharma Inc. 2,4,6-Triamino-1,3,5-triazine derivative
JPWO2003066099A1 (ja) * 2002-02-05 2005-05-26 山之内製薬株式会社 ２，４，６−トリアミノ−１，３，５−トリアジン誘導体
WO2003066099A1 (fr) * 2002-02-05 2003-08-14 Yamanouchi Pharmaceutical Co., Ltd. Derives de 2,4,6-triamino-1,3,5-triazine
US7622469B2 (en) 2002-12-17 2009-11-24 Hamari Chemicals, Ltd. 2,4-diamino-1,3,5-triazine derivatives
WO2004054989A1 (fr) * 2002-12-17 2004-07-01 Hamari Chemicals, Ltd. Nouveau derive de 2,4-diamino-1,3,5-triazine
WO2004089947A2 (fr) * 2003-04-08 2004-10-21 Morphochem Ag Nouveaux composes a activite antibacterienne
WO2004089947A3 (fr) * 2003-04-08 2005-01-06 Morphochem Ag Nouveaux composes a activite antibacterienne
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US10675274B2 (en) 2018-09-19 2020-06-09 Forma Therapeutics, Inc. Activating pyruvate kinase R
US11844787B2 (en) 2018-09-19 2023-12-19 Novo Nordisk Health Care Ag Activating pyruvate kinase R
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