WO2005082892A2 - Nouveaux composes de triazole en tant qu'agents antibacteriens et compositions pharmaceutiques en contenant - Google Patents

Nouveaux composes de triazole en tant qu'agents antibacteriens et compositions pharmaceutiques en contenant Download PDF

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WO2005082892A2
WO2005082892A2 PCT/IB2005/000343 IB2005000343W WO2005082892A2 WO 2005082892 A2 WO2005082892 A2 WO 2005082892A2 IB 2005000343 W IB2005000343 W IB 2005000343W WO 2005082892 A2 WO2005082892 A2 WO 2005082892A2
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alkyl
phenyl
mmol
difluoro
compound
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PCT/IB2005/000343
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WO2005082892A3 (fr
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Jagattaran Das
Mohamed Takhi
Selvakumar Natesan
Sanjay Trehan
Javed Iqbal
Sitaram Kumar Magadi
Sreenivas Kandepu
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Dr. Reddy's Laboratories Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic 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
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring 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
    • C07D401/10—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 aromatic rings
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Novel triazole compounds as antibacterial agents and their pharmaceutical compositions containing them
  • the present invention relates to novel triazole compounds of formula (I),
  • the present invention also relates to a process for the preparation of the above said novel compounds.
  • MRSA methicillin-resistant Staphylococcus aureas
  • US 6054471 discloses fluorinated triazoles, which are reported for the treatment of neuropathic pain and associated hyperalgesia, including trigeminal and herpectic neuralgia, diabetic neuropathic pain, migraine, causalgia and deafferentation syndromes such as brachial plexus avulsion,
  • J. Med. Chem., 2843, 1991 discloses compound, which is an anticoccidiostat and also been found to have antiproliferative activity in several disease models and to posses antimetastatic activity in a model of ovarian cancer progression,
  • novel triazole compound ofthe present invention is useful for the treatment of various infections
  • novel triazole compounds ofthe general formula (I) as defined above their pharmaceutically acceptable salts their stereosiomers thereof, their prodrugs, their rotamers, their pharmaceutical compositions containing them.
  • Another aspect of the present invention provides a process for the preparation of novel triazole compounds ofthe formula (I).
  • Yet another aspect ofthe pesent invention provides the use of novel compounds of formula (I) or their pharmaceutical compositions in the treatment of bacterial infections.
  • novel compounds of formula (I) or their pharmaceutical compositions in the treatment of bacterial infections.
  • the present invention relates to compounds having the general formula (I),
  • R 1 is isoindole-l,3-dione, azido, NHR where R represents (a) Hydrogen,
  • Optionally substituted groups selected from, (ii) Alkyl, (iii) Cycloalkyl, (iv) Alkoxy, (v) Cycloalkoxy, (vi) Alkenyl, (vii) Alkenyloxy, (viii) Aryl, (ix) Aryloxy, (x) Heteroaryl, (xi) ⁇ Heterocyclyl, (xii) Heteroaryloxy,
  • R 7 represents hydrogen, optionally substituted groups selected from alkyl, cycloalkyl, hydroxyalkyl, alkoxy, cycloalkoxy, alkenyl, aryl, aralkyl, heteroaryl, heteroaralkyl, — C II — R 8
  • R 8 is optionally substituted group selected from alkyl, alkoxy, cycloalkyl, alkenyl, alkenyloxy, aryl, aryloxy, aralkyl, aralkoxy, heteroaryl, heteroaryloxy, and Q represents oxygen or sulfur;
  • (xvi) -SR 8 wherein R 8 is as defined above, (xv) -S0 2 -alkyl;
  • R 2 and R 3 at each occurrence are the same or different and are (i) Hydrogen, (ii) Halogen, (iii) Cyano, (iv) Nitro, (v) Amino
  • R represents hydrogen or optionally substituted alkyl group
  • R b represents hydrogen or optionally substituted alkyl, alkenyl, cycloalkyl, alkoxy, hydroxyalkyl, alkyl carbonyl, alkoxycarbonyl, alkoxyalkyl, carboxyalkyl, alkylsulfonyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, alkylcarbonyloxyalkyl, amino alkyl, alkylamino, aryl amino;
  • 'Z' represents N, C or CH
  • R 4 represents hydrogen, cyano, alkyl,. cycloalkyl, alkoxy, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylamino, alkylaminoalklyl, acyl, haloacyl, alkylcarbonyl, alkoxycarbonyl,, hydroxyalkylcarbonyl, alkoxyalkyl, alkenyloxy, aryl, aryloxy, arylcarbonyl, aralkyl, aralkylcarbonyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, heteroaralkylcarbonyl, heterocyclylalkyl, heteroaryloxy, cycloalkoxy, heteroarylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, aralkyl, aralkoxyalkyl, aralkoxyalkylcarbonyl, alkenylcarbonyl, aral
  • R 2 , R 3 , R 4 , R 5 , R ⁇ , R 7 and R 8 may take place 1 to 5 times, which may be same or different;
  • One aspect of the present invention provides compound of formula (I), where Z represents 'N', ' ' represents no bond, which is represented by compound of formula
  • Optionally substituted groups selected from, ( ⁇ ) ' Alkyl, (iii) Cycloalkyl, (iv) Alkoxy, (v) Cycloalkoxy, (vi) Alkenyl, (vii) Alkenyloxy,
  • R 2 and R 3 at each occurrence are the same or different and are (i) Hydrogen, (ii) Halogen,
  • R 4 represents hydrogen, cyano, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkylamino, alkylaminoalldyl, acyl, haloacyl, aminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl,, hydroxyalkylcarbonyl, alkoxyalkyl, aryl, aryloxy, arylcarbonyl, . aralkyl, heterocyclyl, heterocyclylalkyl, .
  • substitutions on the possible groups represented by R 4 may take place 1 to 5 times, which may be same or different;
  • R 6 represents alkyl or alkoxy group
  • R and R which may be same or different, independently represent hydrogen or halogen
  • R represents
  • R e OH, OCH 3 , CH 3 , NH 2
  • R 2 and R 3 which may be same or different, independently represent hydrogen or halogen
  • R 4 represents
  • R' represents hydrogen or alkyl grou'p n represents 0-6;
  • R y represents alkyl or aryl Another embodiment of compound of formula (la), where Ri represents , wherein R represents alkyl or alkoxy group; R 2 and R 3 , which may be same or different, independently represent hydrogen or halogen; R represents cyano,
  • Another aspect of the present invention provides compound of formula (I), where
  • R 6 represents
  • R 2 and R 3 at each occurrence are the same or different and are (i) Hydrogen, (ii) Halogen,
  • R 4 represents hydrogen, cyano, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkylamino, alkylammoalklyl, acyl, haloacyl, ammocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl,, hydroxyalkylcarbonyl, alkoxyalkyl, aryl, aryloxy, arylcarbonyl, aralkyl, heterocyclyl, heterocyclylalkyl,- heteroaryl, heteroaralkyl, heteroaralkylcarbonyl, heteroaryloxy, cycloalkoxy, heteroarylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcaarbonyl, tert-butoxycarbonyl (BOC), alkenylcarbonyl, aralkyl, aralkyl
  • substitutions on the possible groups represented by R 4 may take place 1 to 5 times, which may be same or different; which is represented by compound of formula (Ia); their pharmaceutically acceptable salts their stereosiomers thereof, pharmaceutical compositions containing them
  • R 6 represents alkyl or alkoxy group
  • R 2 and R 3 which may be same or different, independently represent hydrogen or halogen
  • R represents
  • n 0-6;
  • R e OH, QCH 3 , CH 3 , NH 2
  • R y represents alkyl or aryl
  • R 6 represents alkyl or alkoxy group
  • R 2 -and R 3 which may be same or different, independently represent hydrogen or halogen
  • R represents alkyl or alkoxy group
  • R 2 and R 3 which may be same or different, independently represent hydrogen or halogen
  • R 4 represents
  • n 0-6;
  • R y represents alkyl or ' aryl
  • R represents alkyl or alkoxy group
  • R 2 and R 3 which may be same or different, independently represent hydrogen or halogen
  • R 4 represents cyano
  • 'Halogen' is fluorine, chlorine, bromine, or iodine
  • 'Alkyl' group is optionally substituted linear or branched ( -C 10 ) alkyl group.
  • exemplary alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t- butyl, n-pentyl, iso-pentyl, hexyl, heptyl, octyl and the like.
  • 'Haloalkyl' group is optionally substituted linear or branched monohalo(C
  • Exemplary alkyl groups include monohalomethyl, dihalomethyl, trihalomethyl, monohaloethyl, dihaloethylm trihaloehtylm tetrahaloethylm pentahaloethyl and the like.
  • 'Hydroxyalkyl' group is linear or branched hydroxy (Q-C ⁇ o)alkyl group.
  • exemplary alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, hydroxyheptyl, hydroxyoctyl and the like.
  • 'Hydroxyalkylamino' group is linear or branched hydroxy(C ⁇ -C ⁇ o)alkylamino group.
  • exemplary hydroxyalkylamino groups include hydroxymethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxypentylamino, hydroxyhexylamino, hydroxyheptyl amino, hydroxyoctylamino and the like.
  • 'Cycloalkyl' group is (C 3 -C 8 ) cycloalkyl group.
  • exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • 'Alkylamino' group represents monoalkylamino or dialkylamino group.
  • 'Monoalkylamino' is (C ⁇ -C ⁇ o)alkylamino, where (C ⁇ -C ⁇ o)alkyl is as defined above.
  • Exemplary monoalkylamino groups include methylamino, ethylamino, propylamino, isoporpylamino and the like.
  • 'Dialkylamino' is di(C ⁇ -C 2 o)alkylamino, where (C1-C10) alkyl is as defined above.
  • Exemplary dialkylamino groups include dimethylamino, diethylamino, ethylmethylamino and the like.
  • Alkoxy' is ( -Cio) alkyl-O-, wherein the ( -C 1 0) alkyl group is as defined above.
  • Exemplary alkyl groups include methoxy, ethoxy, propoxy, butoxy, iso-propoxy and the like.
  • 'Cycloalkoxy' is (C3-C10) cycloalkoxy group.
  • exemplary cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy and the like.
  • alkenyl' is (C 2 -C ⁇ o) alkenyl group.
  • alkenyl groups include ethenyl, propenyl, but-1-enyl, pentenyl, hexenyl and the like.
  • 'Cycloalkenyl' is (C 3 -C ⁇ o)cycloalkenyl group.
  • exemplary cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.
  • alkylaminoalkyl' is (C ⁇ -C ⁇ o)alkylamino(C ⁇ -C ⁇ o)alkyl group, where alkyl group is as defined above.
  • alkylaminoalkyl groups include methylaminomethyl, methylaminoethyl, methylaminopropyl, methylaminobutyl, ethylaminomethyl, ethylaminoethyl, ethylaminopropyl, ethylaminobutyl, propylaminoethyl, propylaminobutyl, butylaminopropyl, butylaminobutyl, propylaminomethyl, butylaminomethyl, ethylaminobutyl, propylaminopropyl and the like.
  • alkylcarbonyl' is (C ⁇ -C ⁇ o)alkylcarbonyl group.
  • alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isoporpynylcarbonyl, butylcarbonyl and the like.
  • alkenylcarbonyl' is (C 2 -C ⁇ o)alkenyl-CO, wherein (C 2 -C ⁇ 0 ) alkoxy is as defined above.
  • alkenycarbonyl groups include ethenylcarbonyl, propenylcarbonyl, butenylcarbonyl, but-1-enylcarbonyl and the like.
  • alkoxyalkyl' is (C
  • alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxypropyl, ethoxybutyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, propoxyethyl, isopropoxyethyl, butoxyethyl, isobutoxyethyl and the like.
  • alkoxycarbonyl' is (C.-C 10 ) alkoxycarbonyl, wherein ( -C 1 0) alkoxy is as defined above.
  • alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl and the like.
  • Carboxy alkyl' is carboxy (C ⁇ -C . o)alkyl, where ( -C ⁇ o)alkyl group is as defined above.
  • Exemplary carboxyalkyl groups include carboxymethyl, carboxyethyl and the like.
  • alkylsulfonyl is (C ⁇ -C ⁇ o)alkylsulfonyl, where (C ⁇ -C ⁇ o)alkyl group is as defined above.
  • alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl and the like
  • alkylsulfmyl is (C ⁇ -C ⁇ o)alkylsulfinyl, where (C ⁇ -C ⁇ o)alkyl group is as defined above.
  • alkylsulfmyl groups include methylsulfinyl, ethylsulfinyl and the like
  • 'Alkylsulfanyl' is (C ⁇ -C ⁇ o)alkylsulfanyl, where ( -C ⁇ o)alkyl group is as defined above.
  • Exemplary alkylsulfanyl groups include methylsulfanyl, ethylsulfanyl and the like
  • 'Alkylsulfonyloxy' is (C 1 -C 1 0) alkylsulfonyloxy, where (C ⁇ -C ⁇ o)alkyl group is as defined above.
  • Exemplary alkylsulfonyloxy groups include methylsulfonyloxy, ethylsulfonyloxy and the like.
  • 'Aryl' is monocylic or polycyclic ring system of about 6 to 14 carbon atoms.
  • exemplary groups include phenyl, naphthyl and the like.
  • 'Arylcarbonyl' is aryl-carbonyl group, where aryl group is as defined above.
  • arylcarbonyl groups include phenylcarbonyl, naphthylcarbonyl and the like.
  • 'Arylsulfonyl' is aryl-sulfonyl, where aryl group is as defined above.
  • Exemplary arylsulfonyl groups include phenylsulfonyl, naphthylsulfonyl and the like.
  • 'Arylsulfanyl' is aryl-sulfanyl, where aryl group is as defined above.
  • Exemplary arylsulfanyl groups include phenylsulfanyl, naphthylsulfanyl and the like.
  • 'Arylsulfinyl' is aryl-sulfinyl, where aryl group is as defined above.
  • arylsulf ⁇ nyl groups include phenylsulfinyl, naphthylsulfinyl and the like.
  • alkylcarbonylaminoalkyl is (C ⁇ -C ⁇ o)alkylcarbonylamino(C ⁇ -C ⁇ o)alkyl, where (Q- C ⁇ o)alkyl group is as defined above.
  • alkylcarbonylaminoalkyl groups include methylcarbonylaminomethyl, methylcarbonylaminoethyl and the like.
  • 'Arylcarbonylaminoalkyl' is arylcarbonylamino (C ⁇ -C ⁇ o)alkyl, where aryl and (Q- C ⁇ o)alkyl group are as defined above.
  • exemplary arylcarbonylaminoalkyl include phenylcarbonylaminomethyl, phenylcarbonylaminoethyl and the like.
  • alkyl carbonyloxyalkyl' is (C
  • exemplary alkylcarbonyloxyalkyl groups include methylcarbonyloxymethyl, ethylcarbonyloxymethyl and the like.
  • 'Hydroxyalkylcarbonyl' is hydroxyl-(C]-C ⁇ o)alkylcarbonyl, where (C ⁇ -C ⁇ o)alkyl group is as defined above.
  • exemplary hydroxyalkylcarbonyl groups include hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl and the like.
  • 'Aminoalkyl' is amino (C ⁇ -C ⁇ o)alkyl, where (C ⁇ -C ⁇ o)alkyl is as defined above.
  • exemplary amino alkyl groups include amino methyl, amino ethyl and the like.
  • aryl group is as defined above.
  • aryl amino groups include phenyl amino, naphthylamino and the like.
  • alkenyloxy' is (C3-C 1 0) alkenyl-O-, where the (C 2 -C ⁇ ) alkenyl group is as defined above.
  • alkenyl groups include ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy and the like.
  • 'Acyl' is H-CO or (C ⁇ -C 20 ) alkyl-CO- group, where (C ⁇ -C 2 o)alkyl is as defined above.
  • exemplary acyl groups include acetyl, propionyl, wo-propionyl, tert-butionyl and the like.
  • Haloacyl' is Halogen-(C ⁇ -C ⁇ o) alkyl-CO- group, where (C ⁇ -C ⁇ o)alkyl is as defined above.
  • exemplary haloacyl groups include haloacetyl, halopropionyl and the like.
  • 'Acyloxy' is (C1-C10) acyl-O-, where acyl group is defined as H-CO- or (C 1 -C 10 ) alkyl-CO-, where (C1-C10) alkyl group is as defined above.
  • acyl groups include acetyl, propionyl, and the like.
  • acyloxy groups include acetyloxy, propionyloxy, t_. ⁇ -propionyloxy, tert-butionyloxyand the like.
  • 'Aryloxy' is optionally substituted aryl-O- group, where the aryl group is as defined above.
  • aryloxy groups include phenoxy, naphthyloxy and the like.
  • 'Aralkyl' is aryl-(C ⁇ -C ⁇ o) alkyl group, wherein aryl and (C1-C10) alkyl groups are as defined above.
  • Exemplary aralkyl groups include benzyl, 2-phenylethyl and the like.
  • 'Aralkylcarbonyl' is aralkyl-carbonyl group, wherein aralkyl group is as defined above.
  • exemplary aralkylcarbonyl groups include benzylcarbonyl, 2-phenylethylcarbonyl and the like.
  • 'Aralkoxy' is aralkyl-O- group, wherein the aralkyl group as defined above.
  • exemplary aralkoxy groups include bezyloxy, 2-phenethyloxy and the like.
  • 'Aralkoxyalkylcarbonyl' is aralkyl-0-(C ⁇ -C ⁇ o)alkyl-CO group, where aralkyl and (C ⁇ -C ⁇ o)alkyl groups are as defined above.
  • exemplary aralkoxyalkylcarbonyl groups include benzyloxymethylcarbonyl, benzyloxyethylcarbonyl, benzyloxypropylcarbonyl and the like.
  • Heterocyclyl' is non-aromatic saturated monocyclic or polycyclic ring system of about 5 to about 10 carbon atoms, having at least one hetero atom selected from O, S or N.
  • exemplary heterocyclyl groups include aziridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, oxazolidinyl, azepanyl, [1,3]- dioxanyl, 1,3-dioxolanyl, 1 ,4-dioxolanyl and the like.
  • Heterocyclylcarbonyl' is heterocyclylcarbonyl, where heterocyclyl is as defined above.
  • exemplary heterocyclylcarbonyl groups include aziridinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, thiazolidinylcarbonyl, oxazolidmylcarbonyl, azepanylcarbonyl, [l,3]-dioxanylcarbonylcarbonyl, 1,3-dioxolanylcarbonyl, 1 ,4-dioxolanylcarbonyl and the like.
  • Heterocyclylalkyl' is non-aromatic saturated monocyclic or polycyclic ring system of about 5 to about 10 carbon atoms, having at least one hetero atom selected from O, S or N.
  • exemplary heterocyclylalkyl groups include 4-ethylmorpholinyl, 4- propylmorpholinyl, 4-butylmorpholinyl, 4-pentylmo ⁇ holinyl, 4-ethyl-[l ,3]dioxolanyl, 4- propyl-[l,3]dioxolanyl, 4-butyl-[l,3]dioxolanyl, 4-pentyl-[l,3]dioxolanyl, 5-ethyl- oxazolidinyl, 5-propyl-oxazolidinyl, 5-butyl-oxazolidinyl, 5-pentyl-oxazolidinyl, 1-ethyl- pyrrolidine, 1-prop
  • Heteroaryl' is aromatic monocyclic or polycyclic ring system of about 5 to about 10 carbon atoms, having at least one heteroatom selected from O, S or N.
  • exemplary heteroaryl groups include as pyrazinyl, isothiazolyl, oxazolyl, isoxazolyl, lH-pyrazolyl, pyrrolyl, pyridazinyl, thienopyrimidyl, furanyl, lH-indolyl, isoindolyl, 1,3-benzodioxole, 1 ,3-benzoxathiole, quinazolinyl, pyridyl, thiophenyl and the like.
  • Heteroarylcarbonyl' is heteroarylcarbonyl.
  • exemplary heteroarylcarbonyl groups include as pyrazinylcarbonyl, isothiazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, lH-pyrazolylcarbonyl, pyrrolylcarbonyl, pyridazinylcarbonyl, thienopyrimidylcarbonyl, furanylcarbonyl, 1 H-indolylcarbonyl, isoindolylcarbonyl, 1,3 -benzodioxolecarbonyl, 1,3- benzoxathiolecarbonyl, quinazolinylcarbonyl, pyridylcarbonyl, thiophenylcarbonyl and the like.
  • Heteroaralkyl' is heteroaryl-(C ⁇ -C ⁇ o) alkyl group, wherein the heteroaryl and (C ⁇ - Cio) alkyl groups are as defined above.
  • Exemplary heteroaralkyl groups include 1-ethyl- 1 H-pyrazolyl, 1 -propyl- lH-pyrazolyl, 1 -butyl- 1 H-pyrazolyl, 1 -pentyl- 1 H-pyrazolyl, 1- ethyl-lH-imidazolyl, 1 -propyl- 1 H-imidazolyl, 1-butyl-lH-imidazolyl, 1-pentyl-lH- imidazolyl, 4-ethylpyridinyl, 4-propylpyridinyl, 4-butylpyridinyl, 4-pentylpyridinyl, 3- ethylpyridinyl, 3-propylpyridinyl, 3-butylpyridinyl
  • Heteroaryloxy' is heteroaryl-O-, wherein the heteroaryl group is as defined above.
  • exemplary heteroaryloxy groups include pyrazinyloxy, isothiazolyloxy, oxazolyloxy, pyrazolyloxy, phthalazinyloxy, indolyloxy, quinazolinyloxy, pyridyloxy, thienyloxy and the like.
  • Heteroaralkylcarbonyl' is heteroaralkyl-CO-group, where heteroaralkyl group is as defined above.
  • exemplary heteroaralkylcarbonyl groups include 1-ethyl-lH- pyrazolylcarbonyl, 1 -propyl- lH-pyrazolylcarbonyl, 1 -butyl- 1 H-pyrazolylcarbonyl, 1- pentyl- 1 H-pyrazolylcarbonyl, 1 -ethyl- 1 H-imidazolylcarbonyl, 1 -propyl- 1 H- imidazolylcarbonyl, 1 -butyl- 1 H-imidazolylcarbonyl, 1 -pentyl- 1 H-imidazolylcarbonyl, 4- ethylpyridinylcarbonyl, 4-propylpyridinylcarbonyl, 4-butylpyridinylcarbonyl, 4- pentylpyridinylcarbonyl, 3-e
  • Heterocyclylalkylcarbonyl' is heterocyclyl-CO-group, where heterocyclylalkyl group is as defined above.
  • exemplary heterocyclylalkylcarbonyl groups include 4- ethylmorpholinylcarbonyl, 4-propylmorpholinylcarbonyl, 4-butylmorpholinylcarbonyl, 4- pentylmo ⁇ holinylcarbonyl, 4-ethyl-[l,3]dioxolanylcarbonyl, 4-propyl-
  • Heteroarylsulfonyl' is heteroaryl-sulfonyl group
  • Exemplary heteroarylsulfonyl groups include pyrazinylsulfonyl, isothiazolylsulfonyl, oxazolylsulfonyl, pyrazolylsulfonyl, pyrrolylsulfonyl, pyridazinylsulfonyl, thienopyrimidylsulfonyl, furylsulfonyl, indolylsulfonyl, isoindolylsulfonyl, quinazolinylsulfonyl, pyridylsulfonyl, thiophenylsulfonyl and the like.
  • Carboxylic acid or its derivatives' may be amides or esters.
  • Exemplary carboxylic acid groups include CONH 2 , CONHMe, CONMe 2 , CONHEt, CONEt 2 , CONHPh, COOCH 3 , COOC 2 H 5 or COOC 3 H 7 .
  • 'Phosphoric acid or its derivates' include PO(OCH 3 ) 2 , PO(OC 2 H 5 ) 2 and the like.
  • Another embodiment of the present invention provides a process for the preparation of compound of formula (I), Where R represents R or R 4 , wherein R represents protecting group such as 't-butoxy carbonyl group (protecting group) and R 4 is as defined in description of compound of formula (I).
  • the compound of formula (2) represents compound of formula (I), when R 1 represents NHR 5 , R b represents R 4 and all other symbols are as defined in the description of compound of formula (I).
  • the compound of formula (2) represents compound of formula (I), when R 1 represents represents isoindole-l,3-dione, R b represents R 4 and all other symbols are as defined in the description of compound of formula (I).
  • the compound of formula (2) represents compound of formula (I), when R 1 represents NHR 5 wherein R 5 represents hydrogen atom, R b represents R 4 and all other symbols are as defined in the description of compound of formula (I), which comprises:
  • the compound of formula (2a) and and piperazine were stirred in a suitable solvent selected from tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, acetonitrile and the like.
  • a suitable solvent selected from tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, acetonitrile and the like.
  • the temperature of the reaction was maintained in the range of 20 °C to boiling temperature of the solvent used in the reaction.
  • the mixture was poured into cold water, and the mixture was cooled to ice temperature.
  • the material was filtered and dried or can be extracted from aqueous layer with a solvent such as ethyl acetate, DCM, chloroform and the like.
  • the above compound of formula (2b) was converted to a compound of formula (2c) by using a solvent such as DMF, THF, 1,4-dioxane and the like, and t- butoxycarbonylanhydride [(Boc) 2 0] in the presence of a base such as sodiumhydroxide (NaOH), potassiumhydroxide (KOH) and the like.
  • a base such as sodiumhydroxide (NaOH), potassiumhydroxide (KOH) and the like.
  • the temperature of the reaction was maintained in the range of 0 to 50 °C, and the duration ofthe reaction is in the range of 0.5 to 5 hours.
  • the resultant product was poured into water to obtain (t-butoxycarbonyl)'Boc' protected compound.
  • the compound of formula 2(c) was reduced to a compound of formula 2(d), by using a reducing agent such as palladium/carbon (Pd/C) or Platinum and hydrogen (H 2 ), sodium borohydrate/niclechloride (NaBE NiC ⁇ ) and the like.
  • a reducing agent such as palladium/carbon (Pd/C) or Platinum and hydrogen (H 2 ), sodium borohydrate/niclechloride (NaBE NiC ⁇ ) and the like.
  • the solvent used in the reaction was selected from methanol, ethanol, propanol, isopropanol, ethyl acetate and the like.
  • the compound of formula (2d) was converted to a compound of formula (2e) by using sodium nitrite (NaN0 2 ) in the presence of hydrochloride (HCI) or acetic acid (CH 3 COOH) followed by sodiumazide (NaN 3 ).
  • the temperature of the reaction may be maintained in the range of about -40 °C to boiling temperature of the solvent used, preferably in the range of 0 °C to boiling temperature.
  • the duration of the reaction may be in the range of about 0.5 to 15 hours, preferably in the range of about 0.5 to 5 hours
  • the compound of formula (2g) is reacted with a compound of formula (2h), to obtain a compound of formula (2i), when X represents halogen atom, by using (C 1 -C 10 ) alkyllithium such as methyllithium (MeLi), n-butyllithium (n-BuLi), secondary butyllithium (sec.BuLi), tertiary butyllithium (ter.BuLi) and the like, and the like.
  • the compound of formula (Ic), where X represents hydrogen atom is obtained by treating with CsF.
  • the solvent used in the reaction may be selected from tetrahydrofuran (THF), hexamethylphosphoramide (HMPA), diethylether and the like.
  • the temperature and duration of the reaction can be maintained in the range of about -78 to about 100 °C and about 30 min to about 1.5 h respectively.
  • the compound of formula (2i) is reacted with a compound of formula (2j), by using a reagent (Ci-Cio) alkyllithium such as methyllithium (MeLi), n-butyllithium (n- BuLi), secondary butyllithium (sec.BuLi), tertiary butyllithium (ter.BuLi) and the like.
  • a reagent (Ci-Cio) alkyllithium such as methyllithium (MeLi), n-butyllithium (n- BuLi), secondary butyllithium (sec.BuLi), tertiary butyllithium (ter.BuLi) and the like.
  • the solvent used in the reaction may be selected from THF, hexametaphosphoric (HMPA), diethyl ether, 1 ,4-dioxane and the like.
  • the temperature and duration of the reaction can be maintained in the range of about -78 to about 50
  • the resultant compound was treated with any of the reagents selected from cone HCI, p-toluene sulfonic acid (p-TSA), mesyl chloride & triethylamine, 1,2- diazabicyclo[5,4,0]undec-7-ene (DBU), phosphorous oxychloride (POCl 3 ),
  • the solvent used in the reaction is selected from pyridine, dichloromethane, acetonitrile, toluene and the like.
  • the temperature and duration of the reaction can be maintained in the range of about 0 to about 150 °C and about 30 min to about 24 h respectively.
  • the compound of formula (2k) in dil. HCI is reacted with NaN0 2 and NaN 3 or t- Butyl nitrile and NaN 3 , to obtain a compound of formula (21),
  • the temperature and duration of the reaction can be maintained in the range of about 0 to about 150 °C and about 30 min to about 24 h respectively.
  • the compound of formula (2f) and/or (21) was subjected to 1,3-dipolar cycloaddition with the corresponding acetylene derivative to obtain a compound of formula (2).
  • the solvent used in the reaction was selected from DMF, acetonitrile, THF, toluene and the like.
  • the reaction may be carried out in the presence of a catalyst such as Cul.
  • the temperature of the reaction was maintained in the range of 0 to 90 °C.
  • the duration of he reaction was maintained in the range of 0.5 to 6 hours.
  • the compound of formula (2f) and/or (2k) was converted to a compound of formula (2) by adopting the similar procedure as described above.
  • the compound of formula (3) was converted to a compound of formula (4) by using reagents such as hydrazine, dialkylamine, ethylenediamine and the like.
  • the solvents used in the reaction may be selected from methanol, ethanol, propanol, isopropanol and the like.
  • the temperature was maintained in the range of 20 °C to the boiling temperature of the solvent used in the reaction.
  • the duration of the reaction is in the range of 1 to 12 h.
  • the compound of formula (4) was converted to amide (where R 5 represents COR) by using the corresponding acid chloride and triethylamine or acid anhydride and base such as triethylamine, pyridine and the like.
  • the resultant amide can be further converted to thioamide by using sulfur transfer reagent such as La wesson's reagent or the amine can be converted to thiocyanate (NCS) by treating with thiophosgene and triethylamine, followed by refluxing in alcohol such as methanol, ethanol, propanol, isopropanol and the like.
  • the compound of formula (2f) and/or (21), where R represents 'Boc' was first deprotected with chloroethylchloroformate, dil. HCI or trifluoroacetic acid in a suitable solvent such as dichloromethane, 1 ,2-dichloroethane, THF, 1,4-dioxane, chloroform and the like.
  • a suitable solvent such as dichloromethane, 1 ,2-dichloroethane, THF, 1,4-dioxane, chloroform and the like.
  • the temperature of the reaction may be in the range of 0 to 40 °C.
  • the duration of the reaction may be in the range of 0.5 to 12 hours.
  • the resultant mixture was neutralized by sodium carbonate, sodium bicarbonate and the like, followed by extraction with a solvent such as ethylacetate, dichloromethane, chloroform and the like to obtain a free amine.
  • the free amine can be converted to
  • the deprotection can be carried out by using H 2 /Pd-C,
  • the solvent used may be selected from ethylacetate, methanol, ethanol, propanol and the like.
  • the temperature of the reaction may be in the range of 0 to 40 °C.
  • the duration of the reaction may be in the range of 0.5 to 12 hours.
  • the compound of formula 2(p) was converted to a compound of formulae or (5), by using the procedure as defined for the conversion of 2(f) and/or 2(1) to the compound of formulae (2) or (5).
  • Another aspect of the present invention provides an intermediate of formula (2f)
  • Another aspect ofthe present invention provides an intermediate of formula (21)
  • any reactive group in the substrate molecule may be protected according to conventional chemical practice.
  • Suitable protecting groups in any of the above mentioned reactions are tertiarybutyldimethylsilyl, methoxymethyl, triphenyl methyl, benzyloxycarbonyl, tetrahydropyran(THP) etc, to protect hydroxyl or phenolic hydroxy group; N-tert- butoxycarbonyl (N-Boc), N-benzyloxycarbonyl (N-Cbz), N-9-fluorenyl methoxy carbonyl (-N-FMOC), benzophenoneimine, propargyloxy carbonyl (POC) etc, for protection of amino or anilino group, acetal protection for aldehyde, ketal protection for ketone and the like.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • a method of treating or preventing an bacterial infections in a subject is provided by administering an therapeutically effective amount of compound of formula (I).
  • terapéuticaally effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or patient that is being sought.
  • the pharmaceutically acceptable salts are prepared by reacting the compounds of formula (I) wherever applicable with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in the presence of a solvent like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used.
  • Organic bases like lysine, arginine, diethanolamine, choline, tromethamine, guanidine and their derivatives etc. may also be used.
  • acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in the presence of a solvent like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvent may also be used.
  • the salts of amino acid groups and other groups may be prepared by reacting the compounds of formula (I) with the respective groups in the presence of a solvent like alcohols, ketones, ether etc. Mixture of solvents may be used.
  • the present invention also provides pharmaceutical compositions, containing compounds of the general formula (I), their pharmaceutically acceptable salts
  • the pharmaceutical compositions according to this invention can be used for the treatment of bacterial infections. They can also be used for the treatment of bacterial infections associated with multidrug resistance.
  • the pharmaceutical compositions according to this invention can also be administered prophylatically for the prevention of bacterial infections in a patient at risk of developing a bacterial infection.
  • prodrugs comprise functional derivatives of the claimed compounds which are capable of being enzymatically activated or converted into the more active parent form.
  • administering encompasses the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs (1985). See also, Wihnan, 14 Biochem. Soc. Trans. 375-82 (1986); Stella et al., Prodrugs: A Chemical Approach to Targeted Drug Delivery in Directed Drug Delivery 241-61 (1985).
  • the regioisomers of compound of formula (I) may be prepared by modifying the reaction conditions, use of reagents like acid to base or base to acid or by reaction with free base hydrazine instead of its salt with diketone.
  • the molar proportion also can change the regioisomer formation.
  • the stereoisomers of the present invention include enatiomers such as (R), (S), a mixture of (R), (S), and mixture of (R) and (S).
  • the individual optical isomers or required isomers may be obtained by using reagents in such a way to obtain single isomeric form in the process wherever applicable or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form.
  • Some of the preferred methods of resolution of racemic compounds include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like. Commonly used methods are compiled by Jaques et al in “Enantiomers, Racemates and Resolution” (Wiley Interscience, 1981).
  • the compounds of formula (I) may be resolved by treating with chiral amines, aminoacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula (I) may be prepared by hydrolyzing the pure diastereomeric amide.
  • compositions may be in the forms normally employed, such as tablets, capsules, powders, dispersible granules, cachets, suppositories, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • Such compositions typically contain from 0.5 to 90 % by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active compounds will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the compounds can be combined with a suitable solid, liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
  • the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds.
  • the injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the compounds of the formula (I) or pharmaceutical compositions thereof as defined above are clinically administered to mammals, including human beings, via oral, parenteral and/or topical routes. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication, or abso ⁇ tion following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally.
  • the dosage is in the range of about 0.1 mg/kg to about 150 mg / kg, morepreferably about 3.0 mg/kg to about 100 mg/kg of body weight of the subject per day administered singly or as a divided dose.
  • the optimum dosage whether for prevention or treatment for the individual subject being treated will be determined by the person responsible for treatment, Initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administering, e.g. 2-6 times per day. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of the bacterial infection being treated, and the particular compound being used.
  • a topical treatment an effective amount of compound of formula (I) is admixed in a pharmaceutically acceptable gel or cream vehicle that can be applied to the patient's skin at the area of treatment.
  • Such creams and gels can be prepared by the procedures available in the literature and can include penetration enhancers.
  • N-Butyllithium (62 mL, 1.6M in hexane) was added drop wise to a solution of 3- fluoroaniline (5 grams, 45.1 mmol) in dry THF (100 mL) at -78 °C under nitrogen atmosphere and stirred for 30 minutes.
  • a solution of 1,2 -bis (chlorodimethylsilyl)-ethane (10.65 grams, 49.54 mmol) in dry THF (100 mL) was then added.
  • the reaction mixture was stirred at the same temperamre for 45 minutes and then warmed to 25-35 °C.
  • the reaction mixture was quenched with water (60 mL) and then extracted with diethyl ether. The combined organic layers were dried over sodium sulphate.
  • the title compound was prepared from 4-[(4-azido-2-fluoro-phenyl)-piperazine-l- carboxylic acid tert-butyl ester and 5-nitro-furoyl chloride, obtained in preparation 17, following the same procedure as described for the preparation of [4-(4-azido-2,6-difluoro- phenyl)-piperazin-l-yl]-(5-nitro-furan-2-yl)-methanone (Preparation 19).
  • IR (KBr, cm “1 ): 3118, 2928, 2822, 2323, 2203, 2117, 1746, 1648, 1572, 1505, 1430, 1356, 1281, 1237, 1196, 1152, 1027, 980.
  • CI-MS (m/z): 335 (M + +l), 306, 225, 151, 96, 90.
  • IR (KBr, cm “1 ): 3405, 2930, 2856, 1667, 1524, 1470, 1256, 11 19, 1045, 938, 859, 805, 779, 670, 605, 564.
  • CI-MS (m/z): 412 (M + +l), 383, 354, 326, 307, 231, 193, 144, 105, 91.
  • the title compound was prepared from 4-(l -Benzyl- 1, 2, 3, 6-tetrahydro-pyridin- 4-yl)-3, 5-difluoro-phenylamine (6 grams, 20 mmol), obtained from preparation 13, following the same procedure as described for the preparation of l-[4-(4-azido-2-fluoro - phenyl)-piperazin-l-yl] -ethanone (Preparation 7), in 62% yield.
  • aqueous layer was then extracted with ethyl acetate (50 mL x 4) and the combined organic layers were washed with water and brine and dried over sodium sulfate. Removal of volatiles left 1.6 grams (97%) of the title acid, which was used directly for the next step.
  • the desired product (600 mg) was obtained from 4-(4-azido-2, 6-difluoro-phenyl)- 1 , 2, 3, 6-tetrahydro-pyridine (687 mg, 2.91 mmol), obtained in preparation 27, by the same procedure as described for the preparation of [4-(4-azido-2-fluoro-phenyl)-3,6- dihydro-2H— pyridin-l-yl]-(2,2-dimethyl-[l,3]dioxolan-4-yl)-methanone (Preparation 30).
  • the title compound was prepared from was synthesized from l-(4-Azido-2,6- difluoro-phenyl)-piperazine, obtained in the process of preparation 19, and 2-amino-3- hydroxy-propionic acid methyl ester using the same procedure as described for synthesis of 3-[4-(4-Azido-2, 6-difluoro-phenyl)- piperazin-l-yl]-N-methyl-3-oxo-propionamide (preparation 36).
  • the title compound (250 mg, 53 %) was synthesized from (3-Hydroxy-phenyl)- acetic acid (191 mg, 1.25 mmol) and l-(4-Azido-2,6-difluoro-phenyl)-piperazine, obtained in the process of preparation 19, using the same procedure as described in example 27.
  • the title compound (490 mg, 58 %) was synthesized from (4-Nitro-phenyl)-acetic acid (379 mg, 2.09 mmol) and l-(4-Azido-2,6-difluoro-phenyl)-piperazine, obtained in the process of preparation 19, using the same described in example 27.
  • the title compound (87 mg, 1 1 %) was synthesized from hydroxyl phenyl-acetic acid (344 mg, 2.26 mmol) and l-(4-Azido-2-fluoro-phenyl)-piperazine obtained in the process of preparation 20, applying the same procedure as described in example 27.
  • the title compound (700 mg, 29 %) was synthesized from 3-Chloromethyl- benzoyl chloride (1.78 mL, 12.6 mmol) and l-(4-Azido-2,6-difluoro-phenyl)-piperazine, obtained in the process of preparation 19, using the same procedure as described in preparation 34.
  • Preparation 56 l-[4-(4-Azido-2,6 -fluoro-phenyl)- piperazin-l-yl]-2-imidazoI-l-yI-ethanone
  • the title compound 400 mg, 55%o was synthesized from l-[4-(4-Azido-2,6- fluorb-phenyl)-piperazin-l-yl]-2-bromo-ethanone (750 mg, 2.08 mmol) obtained in preparation 47, and imidazole using the same procedure employed in preparation 45.
  • the title compound (630 mg, 50 %) was synthesized from acryloyl chloride (1.25 grams, 13.8 mmol) and l-(4-Azido-2-fluoro-phenyl)-piperazine, obtained in the process of preparation 20, following the same procedure as described in preparation 34.
  • n-Butyl lithium 0.41 mL, 1.6 M in hexane was added to a solution of tert-butyl hydroperoxide (TBHP). ( 0.2 mL, 4M in toluene) in THF ( 5 mL ) at -78 °C . The mixmre was stirred for 5 minutes. A solution of (l-[4-(4-Azido-2-fluoro-phenyl)-piperazin-l-yl]- propenone (150 mg, 0.54 mmol) obtained in preparation 63, in dry THF (5 mL) was added to the reaction mixmre and stirred for 9 to 13 hours.
  • TBHP tert-butyl hydroperoxide
  • the title compound (100 mg, 50 %>) was synthesized from 2-Phenyl-[l,3]dioxane- 5-carboxylic acid (92 mg, 0.47 mmol) (Ref: J.Org.Chem., 62, 4029 - 4035, 1997) and 4- (4-azido-2,6-difluorophenyl)-l,2,3,6-tetrahydro-pyridine employing the procedure as described in example 27.
  • the title compound (1.3 grams, 69 %) was synthesized from pyrrolidine- 1 ,2- dicarboxylic acid 1 -tert-butyl ester (1 gram, 4.65 mmol) and l-(4-Azido-2-fluoro-phenyl)- piperazine, obtained in the process of preparation 20, following the same procedure as described in example 27.
  • the title compound (395 mg, 46 %) was synthesized from 1 -(4-Azido-2, fluoro- phenyl)-piperazine, obtained in the process of preparation 20, (720 mg, 3.26 mmol) applying the procedure as described in preparation 38.
  • the title compound (350 mg, 58 %) was synthesized from 4-pyridyl acetic acid (348 mg, 2 mmol) and l-(4-Azido-2,6-difluoro-phenyl)-piperazine, obtained in the process of preparation 19, using the same procedure as described in example 27.
  • Example 1 ⁇ l-[4-(4-Acetyl-piperazin-l-yl)-3-fluoro-phenyI]-l_?7-[l,2,3]triazol-4-ylmethyl ⁇ - thiocarbamic acid ⁇ ?-methyl ester
  • Example 8 ⁇ l-[3,5-Difluoro-4-(4-methanesulfonyl-piperazin-l-yl)-phenyl]-l_f7-[l,2,3]triazoI-4- ylmethylj-thiocarbamic acid O-methyl ester:
  • IR (KBr, cm “1 ): 3336, 3141 , 2920, 2855, 2361, 1747, 1520, 1451, 1408, 1322, 1268, 1207, 1 144, 1024, 958, 840, 783, 666, 517.
  • CI-MS (m/z): 447 (M+l), 415, 328.
  • IR (KBr, cm “1 ): 3404, 2930, 1590, 1518, 1454, 1393, 1355, 1233, 1143, 1023, 858, 811, 613.
  • CI-MS (m/z): 494 (M + +l), 462, 369, 337, 165, 158, 121.
  • reaction mixmre was washed with water followed by brine. Evaporation of volatiles left a residue, which was passed through a silica gel column (60-120 mesh; eluent: ethyl acetate: pet. ether) to produce the title compound (2.0 grams, 44%).
  • reaction mixmre was diluted with ethyl acetate (50 mL) followed by the addition of triethylamine (0.5 mL). Usual washings with water and brine and evaporation of the volatiles produced the title compound (550 mg, 73%).
  • the title compound was prepared from 4-(4-azido-2,6-difluoro-phenyl)- piperazine-1 -carboxylic acid tert-butyl ester, obtained from preparation 18, and propargyl phthalimide following the same procedure as described for the preparation of 4- ⁇ 4-[4- (l,3-dioxo-l,3-dihydro-isoindol-2-ylmethyl)-[l,2,3]triazol-l-yl]-2-fluoro-phenyl ⁇ - piperazine-1 -carboxylic acid tert-butyl ester (Example 15).
  • IR (KBr, cm '1 ): 3416, 1718, 1637, 1519, 1467, 1396, 1279, 1232, 1211, 1027, 939, 855, 715,530.
  • CI-MS (m/z): 513 (M + +l), 483, 425, 315, 287, 229, 163, 91.
  • IR (KBr, cm “1 ): 3262, 3012, 2947, 2858, 1635, 1519, 1457, 1389, 1334, 1278, 1231, 1149, 1118, 1096, 1029, 857, 756.
  • CI-MS (m/z): 457 (M + +l), 425, 369, 320, 295, 245, 207, 183, 157, 128, 91.
  • reaction mixmre was diluted with water (30 mL) and then cooled to
  • reaction mixmre was diluted with dichloromethane (50 mL) washed with water followed by brine and dried over anhydrous sodium sulphate. The volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography

Abstract

La présente invention a trait à de nouveaux composés de triazole de formule (I), dans laquelle tous les symboles sont tels que définis dans la description, leurs sels pharmaceutiquement acceptables, leurs stéréoisomères, leurs prodrogues, leurs rotamères, les compositions pharmaceutiques les contenant. La présente invention a également trait à un procédé pour la préparation de desdits nouveaux composés.
PCT/IB2005/000343 2004-02-17 2005-02-11 Nouveaux composes de triazole en tant qu'agents antibacteriens et compositions pharmaceutiques en contenant WO2005082892A2 (fr)

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