WO2005035528A2 - Nouveaux composes triazoliques, leur procede de preparation et compositions pharmaceutiques les contenant - Google Patents

Nouveaux composes triazoliques, leur procede de preparation et compositions pharmaceutiques les contenant Download PDF

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WO2005035528A2
WO2005035528A2 PCT/IB2004/003360 IB2004003360W WO2005035528A2 WO 2005035528 A2 WO2005035528 A2 WO 2005035528A2 IB 2004003360 W IB2004003360 W IB 2004003360W WO 2005035528 A2 WO2005035528 A2 WO 2005035528A2
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alkyl
optionally substituted
aryl
hydrogen
alkoxy
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PCT/IB2004/003360
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WO2005035528A3 (fr
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Selvakumar Natesan
Jagattaran Das
Mohamed Takhi
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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • C07D403/10—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 aromatic rings

Definitions

  • the present invention relates to novel triazole compounds of formula (I),
  • the present invention also relates to a process for the preparation of the novel compound of the formula (I).
  • Background of the Invention Since the discovery of penicillin, pharmaceutical companies have produced more than one hundred antibacterial agents to combat a wide variety of bacterial infections. In the past several years, there has been rapid emergence of bacterial resistance to several of these antibiotics. The multidrug resistance among these bacterial pathogens may also be due to mutation leading to more virulent clinical isolation; the most disturbing milestone has been the acquisition of resistance to vancomycin, an antibiotic generally regarded as the agent of last resort for serious Gram-positive infections. This growing multidrug resistance has recently rekindled interest in the search for new structural class of antibiotic that inhibit or kill these bacteria possibly by novel mechanisms.
  • MRSA methicillin-resistant Staphylococcus aureas
  • US 6054471 discloses fluorinated triazoles of the formula (ii), 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,
  • novel triazole compound of the present invention is useful for the treatment of various infections Summary of the Invention
  • novel triazole compounds of the general formula (I) as defined above, their prodrugs, their pharmaceutically acceptable salts and their stereoisomers thereof.
  • Another aspect fo the present invention provides a process for the preparation of novel triazole compounds of the formula (I).
  • Yet another aspect of the pesent invention provides the use of novel compounds of formula (I) or its pharmaceutical compositions in the treatment of bacterial infections.
  • the present invention relates to compounds having the general formula (I),
  • R 1 represents halogen, azido, thioalcohol, isothiocyanate, hydroxy, isoindole-l,3-dione, optionally substituted (C ⁇ -C 10 )alkylsulfonyloxy, arylsulfonyloxy, (C]-C 10 )acyloxy group, -SO 2 - (C-C ⁇ o)alkyl, -SO 2 -aryl; NHR 4 wherein R 4 represents (a) hydrogen,
  • R 5 represents (i) hydrogen
  • Optionally substituted groups selected from, ( ⁇ ) alkyl, (iii) cycloalkyl, (iv) alkoxy, (v) cycloalkoxy, (vi) alkenyl, (vii) alkenyloxy, (viii) aryl, (ix) aryloxy, (x) heteroaryl, (xi) heterocyclyl, (xii) heteroaryloxy, (xiii) -S(O) 2 alkyl, (xiv) -S(O) 2 aryl,
  • (xv) -NH-R 6 where R 6 represents hydrogen, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkenyl, aryl, aralkyl, heteroaryl, heteroaralkyl, — C II— R 7 ° 1 ' wherein R 7 is optionally substituted group selected from alkyl, alkoxy, cycloalkyl, alkenyl, alkenyloxy, aryl, aryloxy, aralkyl, aralkoxy, heteroaryl, heteroaryloxy, and Q represents oxygen or sulfur; (xvi) -N-[alkyl] 2 ,
  • R represents hydrogen, optionally substituted groups selected from alkyl, cycloalkyl, aryl or aralkyl;
  • R 6 represents optionally substituted groups selected from (i) alkyl, (ii) cycloalkyl, (iii) alkoxy, (iv) cycloalkoxy, (v) alkenyl, (vi) alkenyloxy, (vii) aryl, (viii) aryloxy, (ix) heteroaryl, (x) heteroaryloxy, (xi) -NH-R , where R represents hydrogen or optionally substituted alkyl, (xii) -N-[alkyl] 2 ;
  • the present invention provides novel triazole compounds that have the general formula (Ila)
  • R 5 represents (i) hydrogen, optionally substituted groups selected from
  • R 2 , and R 3 at each occurrence are the same or different and are selected from hydrogen, halogen or haloalkyl; m represents 0-3, n represents 1-3; Z represents
  • R represents hydrogen, hydroxy, or optionally substituted groups selected from alkyl, alkenyl, cycloalkyl, alkoxy, hydroxyalkyl, dihydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl, carboxyalkyl, alkylsulfonyl, arylsulfonyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, alkylcarbonyloxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino, arylamino, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, carboxylic acid or its derivatives;
  • R 10 and R 11 independently represents hydrogen, alkyl, cycloalyl, alkoxy, aminoalkyl, carboxyalkyl, alkoxyalkyl, aryl, heterocyclyl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl; R 10 and R 11 together form an optionally substituted 3-7 membered ring optionally containing one or more heteroatoms selected from oxygen, nitrogen or sulfur;
  • R 12 represents amino, monoalkylamino, dialkylamino, optionally substituted alkyl where the susbstituents are selected from hydroxyl, alkyl, alkoxy, hydroxyalkyl, CO 2 R 13 where R 13 represents hydrogen or alkyl.
  • the present invention provides novel triazole compounds of formula (Ha), where R 5 represents hydrogen, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, -NH-R 6 where in R 6 represents hydrogen, alkyl or cycloalkyl; R 2 , and R 3 at each occurrence are the same or different and are selected from hydrogen, halogen; Z represents -(CH 2 ) P -NR 10 R 11 , where p represents 1 to 4, R 10 and R independently represents hydrogen, alkyl, cycloalyl, alkoxy, aminoalkyl, carboxyalkyl, alkoxyalkyl, aryl, heterocyclyl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl; R 10 and R 11 together form an optionally substituted 3-7 membered ring optionally containing one or more heteroatoms selected from oxygen, nitrogen or sulfur; 19 1
  • R represents amino, monoalkylamino, dialkylamino, optionally substituted alkyl where the susbstituents are selected from hydroxyl, alkyl, alkoxy, hydroxyalkyl, CO 2 R 12 where R 12 represents hydrogen or alkyl.
  • the present invention provides novel triazole compounds that have the general formula
  • R 2 , and R 3 at each occurrence are the same or different and are selected from hydrogen, halogen or haloalkyl; m represents 0-3, n represents 1-3; Z represents
  • R b represents hydrogen, hydroxy, or optionally substituted groups selected from alkyl, alkenyl, cycloalkyl, alkoxy, hydroxyalkyl, dihydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl, carboxyalkyl, alkylsulfonyl, arylsulfonyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, alkylcarbonyloxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino, arylamino, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, carboxylic acid or its derivatives;
  • R 10 and R 11 independently represents hydrogen, alkyl, cycloalyl, alkoxy, aminoalkyl, carboxyalkyl, alkoxyalkyl, aryl, heterocyclyl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl; R 13 and R 14 together form an optionally substituted 3-7 membered ring optionally containing one or more heteroatoms selected from oxygen, nitrogen or sulfur; -(CH 2 ) q -O-CO-(CH 2 )r- 12 , where q, r independently represent 0-5, R 12 represents amino, monoalkylamino, dialkylamino, optionally substituted alkyl where the susbstituents are selected from hydroxyl, alkyl, alkoxy, hydroxyalkyl, CO2R 13 where R 13 represents hydrogen or alkyl.
  • the present invention provides novel triazole compounds of formula (lib), where R 5 represents hydrogen, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, -NH-R 6 where in R 6 represents hydrogen, alkyl or cycloalkyl; R 2 , and R 3 at each occurrence are the same or different and are selected from hydrogen, halogen; Z represents -(CH2) P -NR 10 R 11 , where p represents 1 to 4, R 10 and R 11 independently represents hydrogen, alkyl, cycloalyl, alkoxy, aminoalkyl, carboxyalkyl, alkoxyalkyl, aryl, heterocyclyl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl; R 10 and R 11 together form an optionally substituted 3-7 membered ring optionally containing one or more heteroatoms selected from oxygen, nitrogen or sulfur; 19 19
  • R represents amino, monoalkylamino, dialkylamino, optionally substituted alkyl where the susbstituents are selected from hydroxyl, alkyl, alkoxy, hydroxyalkyl, CO 2 R 13 where R 13 represents hydrogen or alkyl.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , Y 2 , Y 3 and Z are described as follows: 'Halogen' is fluorine, chlorine, bromine, or iodine; 'Alkyl' group is a linear or branched (C ⁇ -C ⁇ o)alkyl group.
  • 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 a linear or branched halo(C ⁇ -C ⁇ o)alkyl group.
  • Exemplary alkyl groups include halomethyl, haloethyl, halopropyl, halobutyl, halopentyl, halohexyl, haloheptyl, halooctyl, haloiso-propyl, haloiso-butyl and the like.
  • 'Hydroxyalkyl' group is a linear or branched hydroxy(C ⁇ -C ⁇ o)alkyl group.
  • Exemplary alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, hydroxyheptyl, hydroxyoctyl and the like.
  • 'Alkylcarbonyl' is (C ⁇ -C 10 )alkylcarbonyl, where (C ⁇ -C ⁇ o)alkyl group is as defined above.
  • Exemplary alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl and the like.
  • 'Dihydroxyalkyl' group is a linear or branched dihydroxy(C
  • Exemplary alkyl groups include dihydroxymethyl, dihydroxyethyl, dihydroxypropyl, dihydroxybutyl, dihydroxypentyl, dihydroxyhexyl, dihydroxyheptyl, dihydroxyoctyl and the like.
  • 'Cycloalkyl' group is (C 3 -C 8 )cycloalkyl group.
  • exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Alkoxy' is (C ⁇ -C ⁇ o)alkyl-O-, wherein the (C ⁇ -C ⁇ o)alkyl group is as defined above.
  • Exemplary alkoxy groups include methoxy, ethoxy, propoxy, butoxy, iso-propoxy and the like.
  • 'Cycloalkoxy' is (C 3 -C 8 )cycloalkoxy group.
  • Exemplary cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy and the like.
  • 'Alkenyl' is a ⁇ -C ⁇ alkenyl group.
  • Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.
  • 'Cycloalkenyl' is (C 3 -C 8 )cycloalkenyl group.
  • Exemplary cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.
  • 'Alkoxyalkyl' is (C ⁇ -C ⁇ o)alkoxy(C ⁇ -C ⁇ o)alkyl group, where (C ⁇ -C ⁇ 0 )alkoxy and (C ⁇ -C ⁇ o)alkyl groups are as defined above.
  • Exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, methoxyisopropyl, ethoxyisobutyl and the like.
  • 'Alkoxycarbonyl' is (C ⁇ -C ⁇ o)alkoxycarbonyl, wherein (C ⁇ -C ⁇ o)alkoxy is as defined above.
  • Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl and the like.
  • 'Carboxyalkyl' is carboxy(C ⁇ -C 10 )alkyl, where (C ⁇ -C ⁇ o)alkyl group is as defined above.
  • Exemplary carboxyalkyl groups include carboxymethyl, carboxyethyl and the like.
  • 'Alkylsulfonyl' or '-SO 2 -alkyl' is (C ⁇ -C ⁇ o)alkylsulfonyl or -SO 2 -(C
  • Exemplary alkylsulfonyl or -SO 2 -alkyl group includes methylsulfonyl, ethylsulfonyl and the like.
  • 'Alkylsulfonyloxy' is (C ⁇ -C ⁇ o)alkylsulfonyloxy, where (C ⁇ -C ⁇ o)alkyl group is as defined above.
  • Exemplary alkylsulfonyloxy groups include methylsulfonyloxy, ethylsulfonyloxy and the like.
  • 'Aryl' is monocylic or multicyclic ring system of about 6 to 14 carbon atoms. Exemplary groups include phenyl, naphthyl and the like.
  • 'Arylsulfonyl' or '-SO 2 -aryl' is arylsulfonyl or -SO2-aryl, where aryl group is as defined above.
  • Exemplary arylsulfonyl or -SO 2 -aryl group includes phenylsulfonyl, naphthylsulfonyl and the like.
  • 'Arylsulfonyloxy' is arylsulfonyloxy, where aryl group is as defined above.
  • Exemplary arylsulfonyloxy groups include phenylsulfonyloxy, naphthylsulfonyloxy and the like.
  • 'Alkylcarbonylaminoalkyl' is (C ⁇ -C 10 )alkylcarbonylamino(C ⁇ -C ⁇ o)alkyl, where (Q- C ⁇ o)alkyl group is as defined above.
  • exemplary alkylcarbonylaminoalkyl groups include methylcarbonylaminomethyl, methylcarbonylaminoethyl and the like.
  • 'Arylcarbonylaminoalkyl' is arylcarbonylamino(C ⁇ -C ⁇ 0 )alkyl, where aryl and (C ⁇ -C ⁇ o)alkyl group are as defined above.
  • Exemplary arylcarbonylaminoalkyl include phenylcarbonylaminomethyl, phenylcarbonylaminoethyl and the like.
  • 'AlkylcarbonyloxyalkyF is (C ⁇ -C 1 o)alkylcarbonylamino(C ⁇ -C ⁇ 0 )alkyl, where (C ⁇ -C ⁇ o)alkyl group is as defined above.
  • Exemplary alkylcarbonyloxyalkyl groups include methylcarbonyloxymethyl, ethylcarbonyloxymethyl and the like.
  • 'Aminoalkyl' is amino(C ⁇ -C ⁇ 0 )alkyl, where (C ⁇ -C] 0 )alkyl is as defined above.
  • Exemplary aminoalkyl groups include aminomethyl, aminoethyl and the like.
  • 'Monoalkylamino' is 'mono(C ⁇ -C 1 o)alkylamino' where (C ⁇ -C ⁇ o)alkyl is as defined above.
  • Exemplary monoalkylamino groups include methylamino, ethylamino, propylamino, isopropylamino and the like.
  • 'Dialkylamino' is 'di(C
  • Exemplary dialkylamino groups include dimethylamino, diethylamino and the like.
  • aryl group is as defined above.
  • arylamino groups include phenylamino, naphthylamino and the like.
  • 'Alkenyloxy' is (C 2 -C 10 )alkenyl-O-, where the (C 2 -C 6 )alkenyl group is as defined above.
  • alkenyl groups include ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy and the like.
  • 'Acyloxy' is (C ⁇ -C ⁇ o)acyl-O-, where acyl group is defined as H-CO- or (C ⁇ -C ⁇ o)alkyl-CO-, where (C ⁇ -C ⁇ o)alkyl group is as defined above.
  • acyl groups include acetyl, propionyl, and the like.
  • acyloxy groups include acetyloxy, propionyloxy, and the like.
  • 'Aryloxy' is aryl-O- group, where the aryl group is as defined above.
  • Exemplary aryloxy groups include phenoxy, naphthyloxy and the like.
  • 'Aralkyl' is aryl-(C ⁇ -C 10 )alkyl group, wherein aryl and (C ⁇ -C ⁇ o)alkyl groups are as defined above.
  • Exemplary aralkyl groups include benzyl, 2-phenylethyl 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.
  • '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.
  • heterocyclyl groups include aziridinyl, pyrrolidinyl, piperidinyl, piperazinyl, mo ⁇ holinyl, thiomo ⁇ holinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl and the like.
  • 'Heterocyclylalkyl' is heterocyclyl(C ⁇ -C ⁇ o)alkyl.
  • heterocyclylalkyl groups include aziridinylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinylmethyl, piperazinylmethyl, mo ⁇ holinylmethyl, mo ⁇ holinylethyl, thiomo ⁇ holinylmethyl, , thiazolidinylmethyl, 1,3-dioxolanylmethyl, 1,3-dioxolanylethyl, 1,4-dioxanylmethyl and the like.
  • 'Heteroaryl' is aromatic monocyclic or multicyclic ring system of about 5 to about 10 carbon atoms, having at least one heteroatom selected from O, S or N.
  • heteroaryl groups include as pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyridazinyl, thienopyrimidyl, furyl, indolyl, isoindolyl, 1,3-benzodioxole, 1,3-benzoxathiole, quinazolinyl, pyridyl, thiophenyl and the like.
  • 'Heteroaralkyl' is heteroaryl-(C ⁇ -C ⁇ 0 )alkyl group, wherein the heteroaryl and (C ⁇ -C ⁇ o)alkyl groups are as defined above.
  • heteroaralkyl groups include thienylmethyl, pyridylmethyl, imidazolylmethyl and the like.
  • '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.
  • the cyclic rings formed by R' and R" selected from pyrrolidine, piperidine, piperazine, mo ⁇ holine, thiomo ⁇ holine, piperazin-2-one and the like.
  • the cyclic rings formed by R 10 and R 11 selected from pyrrolidine, piperidine, piperazine, mo ⁇ holine, thiomo ⁇ holine, piperazin-2-one and the like.
  • the optional substitutions on the above defined groups, cyclic rings formed by R' and R" & R 10 and R 11 may take place on 1-4 times at suitable sites.
  • salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases such as N,N'- diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N- ethylmo ⁇ holine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, mo ⁇ holine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine
  • Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, halides, acetates, tartrates, maleates, citrates, succinates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Representative compounds in accordance with the present invention are presented in the below table. This table is not intended to be exclusive of the compounds of the present invention, but rather exemplary of the compounds that are encompassed by this invention or their pharmaceut cally acceptable salts thereof.
  • the present invention also relates to a process for the preparation of the compound of formul aa ((II)) wwhheerree RR 11 rreepprreesseennttss N NHHRR 44 wwhheerreeiinn RR 44 rreepprreesseennttss 1 hydrogen atom and all other symbols are as defined earlier, the process is as shown in the Scheme-I: where all other symbols are as defined earlier.
  • the compound of formula (Ic) is prepared by reacting a compound of formula (la), wherein X represents halogen atom, with a compound of formula (lb) by using a base, which can be selected from potassium hydroxide (KOH), sodium hydroxide (NaOH), potassium carbonate (K 2 CO 3 ), sodium carbonate (Na 2 CO 3 ), sodiumhydride (NaH), potassiumhydride (KH), triethylamine, diisopropylethyl amine and the like.
  • a base which can be selected from potassium hydroxide (KOH), sodium hydroxide (NaOH), potassium carbonate (K 2 CO 3 ), sodium carbonate (Na 2 CO 3 ), sodiumhydride (NaH), potassiumhydride (KH), triethylamine, diisopropylethyl amine and the like.
  • the reaction is carried out using a solvent, which can be diemthylsulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, chloroform, nitrobenzene and the like or mixtures thereof.
  • a solvent which can be diemthylsulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, chloroform, nitrobenzene and the like or mixtures thereof.
  • the reaction is carried out in inert atmosphere, which can be maintained using inert gases such as N 2 or Ar.
  • the reaction can be carried out at a temperature in the range of about 20 to 100°C, preferably in the range of about 20 to 80 °C.
  • the reaction time can be in the range of about 1 to 15 hours, preferably about 6 to 12 hours.
  • the compound of formula (Ic) is converted to a compound of formula (Id).
  • the reaction can be carried out in the presence of reducing agents such as nickel chloride/tetrahydridoborate (NiCl 2 /NaBH 4 ), lithium aluminium hydride (LAH), gaseous hydrogen and a catalyst such as Ru, Pd, Rh, Pt, Ni on solid beads such as charcoal, alumina, asbestos and the like, in presence of a solvent, which can be selected from dioxane, acetic acid, ethyl acetate, tetrahydrofuran (THF), alcohol such as methanol, ethanol and the like or mixtures thereof.
  • reducing agents such as nickel chloride/tetrahydridoborate (NiCl 2 /NaBH 4 ), lithium aluminium hydride (LAH), gaseous hydrogen and a catalyst such as Ru, Pd, Rh, Pt, Ni on solid beads such as charcoal, alumina, asbestos and the like
  • a solvent which can be selected from dioxane, acetic acid, eth
  • the reaction can be carried out at a temperature about 0 to 60 °C, preferably about 0 to 40 °C.
  • the reaction period can be in the range of about 0.5 to 48 hours, preferably in the range of about 0.5 to 5 hours.
  • the reduction is carried out by employing metal in mineral acids, which can be selected from Sn/HCl, Fe/HCl, Zn/HCl, Z11/CH 3 CO 2 H and the like.
  • the compound obtained is further treated with NaNO 2 in the presence of HCl or acetic acid (CH 3 COOH) followed by sodium azide (NaN 3 ).
  • the temperature of the reaction can be in the range of about -40 °C to boiling temperature of the solvent used, preferably in the range of about 0 to 35 °C.
  • the duration of the reaction can be in the range of about 0.5 to 15 hours, preferably about 0.5 to 5 hours.
  • the compound of formula (Id) is converted to a compound of formula (Ie) by using a reagent (BOC) 2 ⁇ .
  • the base used in the reaction can be selected from 4-(dimethylamino)pyridine (DMAP), pyridine, ethylamine, NaH, KH, diisopropyl ethylamine or triethylamine (Et 3 N) and the like.
  • the temperature and duration of the reaction can be 0 to 100 °C, preferably about 0 to 30 °C, and about 1 to 24 hours, preferably about 1 to 12 hours, respectively.
  • the compound of formula (Ie) is converted to a compound of formula (If), where R 1 represents hydroxy group and Z represent NR wherein R represents hydrogen atom, by treating with propargyl alcohol in the presence of a reagent, which can be selected from copper(I)iodide (Cul), copper sulfate (CuSO 4 ) and the like.
  • a reagent which can be selected from copper(I)iodide (Cul), copper sulfate (CuSO 4 ) and the like.
  • the reaction can be carried out in the presence of amine selected from diisopropylethylamine, Et 3 N, 2,6-lutidine and the like.
  • the solvent used in the reaction can be selected from benzene, toluene, xylene, acetonitrile, THF, dioxane, DMF and the like.
  • the temperature of the reaction can be maintained in the range of about 10 to 200 °C, preferably 20 °C to the boiling temperature of the solvent.
  • the duration of the reaction can be in the range of about 2 to 48 hours, preferably about 12 to 24 hours.
  • the compound of formula (If), where R 1 represents hydroxy group is converted to a compound of formula (If), where R 1 represents azido group and Z represent NR b wherein R b represents hydrogen atom, is carried out by treating with alkylsulfonylchloride or arylsulfonylchloride such as methanesulfonyl chloride, p-toluenesulfonyl chloride and the like.
  • the reaction solvent used in the reaction can be selected from chloroform, dichloromethane, THF, dioxane and the like.
  • the base used in the reaction can be selected from Et 3 N, diisopropyl ethylamine, Na 2 CO 3 , K. 2 CO and the like.
  • the temperature of the reaction can be maintained in the range of about 0 to 50 °C, preferably in the range of about 0 to 35 °C.
  • the duration of the reaction can be in the range of about 1 to 12 hours, preferably in the range of about 1 to 4 hours.
  • the resultant compound is converted to a compound of formula (I) wherein R 1 represents azido group, by treating with NaN 3 .
  • the solvent used in the reaction can be selected from dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, nitromethane and the like.
  • the tempearature of the reaction can be maintained in the range of about 20 to 120 °C, preferably about 20 to 80 °C.
  • the duration of the reaction can be in the range of about 1 to 12 hours, preferably about 2 to 5 hours.
  • the compound of formula (If), where R 1 represents azido group is converted to a compound of formula (I), where R 1 represents azido group can be carried out in the presence of trifluroaceticacid (TFA), hydrochloric acid (HCl), p-toluene sulfonic acid (PTSA) and the other related reagents.
  • TFA trifluroaceticacid
  • HCl hydrochloric acid
  • PTSA p-toluene sulfonic acid
  • the solvent used in the reaction can be selected from dichloromethane, chloroform and the like.
  • the temperature and duration of the reaction can be in the range of about 0 to 100 °C, preferably about 20 to 60 °C.
  • the duration of the reaction can be maintained in the range of about 2 to 24 hours, preferably about 2 to 12 hours.
  • the compound of formula (I), where R 1 represents azido group is converted to a compound of formula (I) where R 1 represents NHR 4 wherein R 4 represents hydrogen atom, by using triphenyl phosphine, in the presence of a solvent, which can be selected from THF, DMF, toluene and the like, along with water.
  • the above conversion can also be accomplished by using hydrogenation conditions used in the conversion of compound of formula (Ic) to (Id).
  • the reaction can be carried out at a temperature in the range of about 25 to 40 °C, preferably 20 to 35 °C.
  • the duration of the reaction can be in the range from about 3 to 24 hours, preferably about 4 to 12 hours.
  • the present invention also provides a process for the preparation of the compound of formula (I) where R 1 represents NHR 4 wherein R 4 represents various groups as defined earlier; the process is as shown in the Scheme-II:
  • Process (a): The compound of formula (I), where R 1 represents NHR 4 wherein R 4 represents hydrogen atom is converted to a compound of formula (I), where R 1 represents NHR 4 , where R 4 represents-C( O)-R 4a wherein R 4a represents optionally substituted (C ⁇ -C ⁇ o)alkyl, (C ⁇ -C ⁇ o)alkoxy, (C 2 -C ⁇ 0 )alkenyl, halo(C ⁇ -C ⁇ 0 )alkyl, aryl, aryloxy, heteroaryl, (C 2 -C ⁇ 0 )alkenyloxy, (Ci- C ⁇ o)alkylcarbonyl, arylcarbonyl, aryloxycarbonyl, (C ⁇ -C ⁇ o)alkoxycarbonyl, (Ci- C ⁇ o)alkylthiocarbonyl or (C 1 -C] 0 )arylthiocarbonyl, by treating with appropriate acid halide, which can be selected from ace
  • the reaction is carried out in the presence of a solvent, which can be selected from dichloromethane (CH2CI2), chloroform (CHC1 3 ), toluene, THF and the like or mixtures thereof.
  • a solvent which can be selected from dichloromethane (CH2CI2), chloroform (CHC1 3 ), toluene, THF and the like or mixtures thereof.
  • the reaction can also be carried out in the presence of a base like Et 3 N, diisopropyl ethylamine, pyridine, K 2 CO3, NaH, potassium tert-butoxide (t-BuOK) and the like.
  • the temperature of the reaction can be maintained in the range of about -20 to 60 °C, preferably in the range of about 0 to 35 °C.
  • the duration of the reaction can be in the range of about 1 to 12 hours, preferably about 1 to 4 hours.
  • a base which can be selected from Et 3 N, K 2 CO 3 , NaOH and the like.
  • the reaction is carried out in the presence of a solvent, which can be selected from CH 2 CI 2 , acetonitrile (CH 3 CN), CHCI 3 , DMF, THF and the like.
  • the reaction can be carried at a temperature in the range of 0 to 60 °C, preferably at 0 °C.
  • the reaction is carried out in an inert atmosphere, which can be maintained by using argon or any other inert gas.
  • the duration of the reaction is in the range of 1 to 24 hours, preferably 2 to 10 hours.
  • the reaction is carried out in the absence or presence of a solvent, which can be selected from THF, toluene, DMF and the like.
  • a solvent which can be selected from THF, toluene, DMF and the like.
  • the reaction can be carried out at a temperature in the range of about 20 to 130 °C, preferably at reflux temperature of the solvent used.
  • the duration of the reaction can be in the range of about 6 to 24 hours.
  • Process (c): The compound of fomula (I), where R 1 represents NHR 4 , wherein R 4 represents optionally substituted -C( S)-SR 4c , wherein R 4c is as defined above, is prepared from compound of formula (I), where R 1 represents NHR 4 , wherein R 4 represents hydrogen atom, by using carbondisulfide (CS 2 ) in the presence of a base, which can be selected from Et 3 N, diisopropyl ethylamine, K 2 CO 3 , NaH, t-BuOK and the like. The reaction is carried out in the presence of alkyl halide, which can be selected from methyliodide, ethylbromide, propylbromide and the like.
  • the solvent used in the reaction can be selected from benzene, THF, diethylether, acetonitrile and the like, or mixtures thereof.
  • the reaction temperature can be, in the range of about 20 to 60 °C, preferably at 20 to 35 °C.
  • the duration of the reaction is can be in the range of about 6 to 24 hours.
  • Process (d): The compound of fomula (I), where R 1 represents NHR 4 , wherein R 4 represents optionally substituted -C( S)-NH-R 4d wherein R 4d is as defined above, may be prepared from compound of formula (I), where R 1 represents NHR 4 , wherein R 4 represents hydrogen atom by using benzoylisothiocyanate.
  • the solvent used in the reaction can be selected from acetone, ethanol, methanol, isopropanol, THF, diethylether, acetonitrile and the like.
  • the temperature of the reaction can be maintained in the range of about 0 to 80 °C, preferably in the range of about 20 to 60 °C.
  • the duration of the reaction can be in the range of about 1 to 20 hours, preferably in the range of about 1 to 10 hours.
  • Process (e): The compound of fomula (I), where R 1 represents NHR 4 , wherein R 4 represents optionally substituted -C( O)-heteroaryl, is prepared from compound of formula (I), where R 1 represents NHR 4 , wherein R 4 represents hydrogen atom by treating with corresponding heteroaroyl acid chloride and a base, which can be selected from pyridine, triethylamine or diisopropylamine.
  • a base which can be selected from pyridine, triethylamine or diisopropylamine.
  • the reaction can be carried out by using corresponding heteroaryl acid and dicyclohexylcarbodiimide (DCC) in the presence of DMAP.
  • DCC dicyclohexylcarbodiimide
  • the solvent used in the reaction can be selected from acetonitrile, THF, Et2 ⁇ and the like.
  • the temperature of the reaction can be maintained in the range of about -5 to 100 °C, preferably in the range of about 0 to 80°C.
  • the duration of the reaction can be in the range of about 1 to 15 hours, preferably in the range of about 2 to 12 hours.
  • a solvent which can be selected from DMF, acetone, THF, dichloromethane and the like.
  • the base used in the reaction can be selected from triethylamine, diisopropylethylamine, pyridine and the like.
  • the temperature of the reaction can be in the range of 0 to 120°C, preferably in the range of about 0 to 90°C.
  • the duration of the reaction can be in the range of about 0.2 to 15 hours, preferably in the range of about 0.5 to 10 hours.
  • the compound obtained in the first step is reacted with trifluoroacetic acid in the presence of a solvent, which can be selected from dichloromethane, chloroform, THF and the like.
  • the temperature of the reaction can be in the range of about 0 to 110 °C, preferably in the range of about 0 to 90 °C.
  • the duration of the reaction can be in the range of about 0.5 to 60 hours, preferably in the range of about 0.5 to 54 hours.
  • the solvent used can be selected from dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and the like.
  • the temperature of the reaction can be in the range of about 0 to 50 °C, for duration of about 1 to 6 hours.
  • the present invention also provides an alternate process for the preparation of the compound of formula (I) where all symbols are as defined earlier, which is shown in the following Scheme-Ill
  • the compound of formula (Ic) is prepared by reacting a compound of formula (la) with a compound of formula (lb) by using a base such as KOH, NaOH, K 2 CO 3 , Na 2 CO 3 , NaH, KH, triethylamine, diisopropylethyl amine and the like.
  • a base such as KOH, NaOH, K 2 CO 3 , Na 2 CO 3 , NaH, KH, triethylamine, diisopropylethyl amine and the like.
  • the reaction is carried out using a solvent, which can be selected from DMSO, DMF, THF, acetonitrile, chloroform, nitrobenzene and the like or mixtures thereof.
  • the reaction is carried out in inert atmosphere, which can be maintained using inert gases such as N2 or Ar.
  • the reaction can be carried out at a temperature in the range of about 20 to 100 °C, preferably at a temperature in the range of about 20 to 80 °C.
  • the reaction time can be in the range of about 1 to 15 hours, preferably from about 6 to 12 hours.
  • the reduction of a compound of formula (Ic) to produce a compound of formula (Id) is carried out in the presence of a reducing agent selected from Ni ⁇ 2 /NaBH 4 , lithium aluminium hydride (LAH), gaseous hydrogen and a catalyst such as Ru, Pd, Rh, Pt, Ni on solid beads such as charcoal, alumina, asbestos and the like.
  • a reducing agent selected from Ni ⁇ 2 /NaBH 4 , lithium aluminium hydride (LAH), gaseous hydrogen and a catalyst such as Ru, Pd, Rh, Pt, Ni on solid beads such as charcoal, alumina, asbestos and the like.
  • the reduction can be carried out in the presence of a solvent, which can be selected from dioxane, acetic acid, ethyl acetate, THF, alcohol such as methanol, ethanol and the like or mixtures thereof.
  • a pressure between atmospheric pressure to 60 psi can be maintained.
  • the reaction can be carried out at a temperature from about 0 to 60 °C, preferably about 0 to 45 °C.
  • the reaction time ranges from about 0.5 to 48 hours, preferably in the range of about 0.5 to 5 hours.
  • the reduction may also be carried out by employing metal in mineral acids, which can be selected from Sn/HCl, Fe HCl, Zn/HCl, Zn/CH 3 CO 2 H and the like, or Zn/NH 4 C1..
  • the compound of formula (Id) is converted to a compound of formula (Ie) by using sodium nitrite in the presence of HCl or CH COOH followed by NaN 3 .
  • the temperature of the reaction can 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 can be in the range of about 0.5 to 15 hours, preferably in the range of about 0.5 to 5 hours.
  • the conversion can also be carried out by (C ⁇ -C 6 )alkylnitrites such as isoamylnitrite,. t-butylnitrite and the like, in the presence of inorganic azides such as NaN 3 and the like.
  • the solvent used in the reaction can be selected from acetonitrile, CHC1 , THF, DMF, DMSO, (Cj-C 8 )alcohols such as methanol, ethanol, propanol, iso-propanol, t-butylalcohol and the like.
  • the temperature of the reaction can be in the range of about 0 °C to boiling temperature of the solvent used.
  • the duration of the reaction can be maintained in the range of about 15 minutes to 18 hours, preferably about 0.5 to 10 hours.
  • the compound of formula (Ie) is converted to a compound of formula (Ie') by treating with hydroxylamine hydrochloride.
  • the solvent used in the reaction can be selected from CHCI 3 , THF, acetonitrile, (C ⁇ -C 8 )alcohol such as methanol, ethanol, propanol, iso-propanol, t-butylalcohol and the like.
  • the reaction can be carried out in the presence of a base selected from triethylamine, pyridine, DMAP, sodium methoxide, sodium ehthoxide and the like.
  • the temperature and duration of the reaction can be maintained in the range of about 0 °C to boiling temperature of the solvent used and about 0.5 to 8 hours respectively.
  • the compound of formula (Ie') is converted to a compound of formula (Ie") by Beckmann Rearragement reaction conditions.
  • the compound of formulae (d), (e), (e') or (e") is reacted with compound of formula (Ig), to obtain a compound of formula (I) by using Cu(I) halide in the presence or absence of a base, which can be selected from DMAP, pyridine, friethylamine, diisopropylethylamine, 2,6-lutidine and the like.
  • a base which can be selected from DMAP, pyridine, friethylamine, diisopropylethylamine, 2,6-lutidine and the like.
  • the solvent used in the reaction can be selected from DMF, DMSO, THF, ether, dioxane, acetonitrile and the like.
  • the temperature and duration of the reaction can be maintained in the range of about 0 °C to boiling temperature of the solvent used and about 0.5 to 5 hours respectively.
  • Yet another embodiment of the present invention provides a process for the preparation of compound of formula (I), where R 1 represents NHR 4 , wherein R 4 represents acetyl group and all other symbols are as defined earlier, from a compound of formula (I) where R 1 represents azido group,
  • the compound of formula (I), where R 1 represents NHR 4 , wherein R 4 represents optionally substituted acetyl group is prepared from compound of formula (I), where R 1 represents azido group by using thiolacetic acid with or without using a solvent, which can be selected from THF, DMF, toluene and the like.
  • a solvent which can be selected from THF, DMF, toluene and the like.
  • the reaction can be carried out at a temperature in the range of about 25 to 40 °C, preferably 20 to 40 °C.
  • the duration of the reaction can be in the range from about 3 to 24 hours, preferably about 4 to 12 hours.
  • the reaction can be carried out at a temperature in the range of about 20 to 130 °C, preferably about 55 to 90 °C.
  • the duration of the reaction can be in the range of about 3 to 24 hours, preferably about 3 to 10 hours
  • R 1 represents NHR 4
  • the reaction can be carried out at a temperature in the range of about -10 to 35 °C, preferably about -10 to 20 °C.
  • the duration of the reaction can be in the range from about 20 minutes to 4 hours, preferably about 30 minutes.
  • the solvent used in the reaction can be seleceted from t-butyl alcohol, DMF and the like.
  • the base used in the reaction can be selected from NaH, KH, sodium hexamethyldisilazide (Na-HMDS) and the like.
  • the temperature of the reaction can be in the range of about 0 °C to boiling temperature of the solvent used.
  • the duration of the reaction can be in the range of about 1 to 30 hours, preferably in the range of about 1 to 24 hours.
  • the solvents used in the reaction may be selected from THF, ether, dioxane, toluene, benzene, DMF, DMSO, methylcyanide and the like.
  • the temperature of the reaction can be in the range of about - 20 to 150 °C, preferably in the range of about -10 to 100 °C.
  • the duration of the reaction can be in the range of about 0.2 to 64 hours, preferably in the range of about 1 to 48 hours.
  • a base which can be selected
  • the solvent used in the reaction can be selected from DMF, DMSO, THF, dioxane, benzene, toluene and the like.
  • the temperature of the reaction can be maintained in the range of about -5 to 150 °C, preferably in the range of about 0 °C to reflux temperature of the solvent used.
  • the duraion of the reaction can be in the range of about 0.2 to 48 hours, preferably in the range of about 0.5 to 24 hours.
  • Another embodiment of the present invention there is provided a process for the preparation of a compound of formula (I) where R 1 represents halogen, from compound of formula (I) where R 1 represents hydroxy group,
  • the compound of formula (I) where R represents halogen is prepared from compound of formula (I) where R represents hydroxy group is carried out by treating with tetrahalomethane group such as CBr 4 , CC1 and the like, in the presence of triphnyl phosphine (PPh 3 ), P(alkyl) 3 and the like.
  • the reaction is carried out in the presence of a solvent, which is selected from dichloromethane, chloroform, tetrachloromethane, benzene, DMF, DMSO, THF and the like.
  • the temperature of the reaction is maintained in the range of about 0 to 60 °C, preferably about 20 to 40 °C.
  • the duration of the reaction can be in the range of about 2 to 24 hours, preferably about 8 to 13 hours.
  • the compounds of above formula (I) may be prepared by treating the compound of formula (I), where R 1 represents isothiocyanate group with heterocycles such as mo ⁇ holine, piperidine, pyrrolidine and the like in the presence or absence of a solvent.
  • the temperature of the reaction can be maintained in the range of about 0 °C to reflux temperature of the solvent used, preferably about 20 to 35 °C.
  • the duration of the reaction can be maintained in the range of about 1 to 24 hours, preferably about 1 to 12 hours.
  • Still yet another embodiment of the present invention provides a process for the preparation of novel compound of formula (Ii), which comprises: (i) converting the compound of formula (Id),
  • the compound of formula (Ii) is prepared by reacting the compound of formula (Id) with a compound of formula (Ij), in the presence of a base, which is selected from triethylamine, ethyldiisopropylamine, 1 ,4-diazabicyclo [2.2.2]octane
  • reaction can be carried out in the presence of a solvent such as dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile and the like.
  • a solvent such as dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile and the like.
  • the reaction is carried out in the presence of Cu (1)1.
  • 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.
  • 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).
  • therapeutically 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.
  • 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,
  • 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.
  • the prodrugs such as esters and amides of the compounds of formula (I) can be prepared by conventional methods.
  • 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.
  • the pharmaceutical 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.
  • 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.
  • injectable solutions or suspensions For example, 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 prefened 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 100 mg / kg, morepreferably about 3.0 mg/kg to about 50 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. 2-4 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.
  • the manner in which the compounds of this invention can be prepared is illustrated in the following examples, which demonstrate the preparation of typical species of the invention. In these examples, the identities of compounds, intermediates and final, were confirmed by infrared, nuclear magnetic spectral analyses as necessary. The examples are for the pu ⁇ ose of illustration only and should not be regarded as limiting the invention in any way.
  • Preparation 1 Prop-2-ynyl-thiocarbamic acid 0-methyl ester To an ice cooled solution of propargyl amine (10 g, 182 mmol) and triethyl amine (38 mL,
  • Preparation 8 has been prepared according to the procedure as described in preparation 7 by taking appropriate starting material.
  • reaction mixture was extracted with ethyl acetate (2 x 250 ml). The combined extract was washed with water followed by brine and dried over sodium sulfate. Evaporation of volatiles on rotavapor yielded the title compound as viscous liquid (4.00 grams, 63%).
  • Preparation 11 has been prepared according to the procedure as described in preparation 10 by taking appropriate starting material.
  • Preparations 13-17 have been prepared according to the procedure as described in preparation 12 by taking appropriate starting materials.
  • the title compound can be prepared by taking sodium azide (860 mg, 13.3 mmol), moist with water (670 ⁇ L), was suspended in t-BuOH (4.5 mL) into which l-(4-amino-2,6- difluorophenyl)-4-piperidinone (1.0 grams, 4.42 mmol), was added followed by the addition of t-
  • Reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (75 mL x
  • Preparation 19 has been prepared according to the procedure as described in preparation 18 by taking appropriate starting material.
  • the compound of preparation 19 can be prepared by taking sodium azide (860 mg, 13.3 mmol), moist with water (670 ⁇ L), was suspended in t-BuOH (4.5 mL) into which l-(4-amino-2-fluorophenyl)-4-piperidinone (920 mg, 4.42 mmol) was added followed by the addition of t-BuONO ( 10.5 mL, 53 mmol) and the reaction mixture was stirred at 25-30 °C for 6 to 8 hours. Reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (75 mL x 2).
  • Preparations 21 and 22 have been prepared according to the procedure as described in preparation 20 by taking appropriate starting material.
  • Preparation 24 has been prepared according to the procedure as described in preparation 14 by taking appropriate starting material.
  • Preparation 26 has been prepared according to the procedure as described in preparation 25 by taking appropriate starting material.
  • Preparations 28-30 have been prepared according to the procedure as described in preparation 27 by taking appropriate starting materials.
  • the compounds given in the below table have been prepared according to the procedure as described in preparation 27 by taking appropriate starting materials.
  • Preparation 32 has been prepared according to the procedure as described in preparation 31 by taking appropriate starting materials.
  • reaction mixture was diluted with ethyl acetate (100 mL), washed successively with water (20 mL) and brine (20 mL). The solvent was dried over sodium sulfate and evaporated on a rotavapor.
  • the crude material was purified by silica gel column chromatography (ethyl acetate/pet ether; 1 :1) to obtain the title compound (100 mg, 30%).
  • Preparations 37 and 38 have been prepared according to the procedure as described in preparation 36 by taking appropriate starting materials.
  • Preparations 40 and 41 have been prepared according to the procedure as described in preparation 39 by taking appropriate starting materials.
  • Example 1 4-[4-(4-Azidomethyl-[l,2,3]triazoI-l-yl)-2-fluoro-phenyl]-piperazin-2-one
  • Examples 2 and 3 have been prepared according to the procedure as described in Example 1 by taking appropriate starting materials.
  • Triphenyl phosphine (1.49 grams, 5.7 mmol) was added portion wise to a solution of the azide compound (1.5 grams, 4.74 mmol), obtained in example 1, in THF and the resultant mixture was stined at 25-30 °C for 5 hours. Water (1 mL) was added and the reaction mixture was heated to 60 °C for 12 hours. The solvent was evaporated and the residue was passed through a column of silica gel to afford the title compound (1.2 grams, 93%).
  • Example 18 has been prepared according to the procedure as described in Example 17 by taking appropriate starting material
  • Examples 35-60 have been prepared according to the procedure as described in Example 34 by taking appropriate starting materials
  • Example 61 ⁇ l-[3-Fluoro-4-(3-oxo-piperazin-l-yl)-phenyl]-4H-[l,2,3]triazol-4-ylmethyl ⁇ -thiourea
  • step (i) of example 19 A solution of isothiocyanate (100 mg, 0.3 mmol), obtained in step (i) of example 19, and aqueous ammonia (5 mL) was stined at 20-35°C for 2 hours. The residue obtained upon evaporation of the volatiles was passed through a column of silica gel to afford the product (60 mg,
  • Morpholine-4-carbothioic acid ⁇ l-[3-fluoro-4-(3-oxo-piperazin-l-yl)-phenyI]-4H-
  • Example 63 has been prepared according to the procedure as described in Example 62 by taking appropriate starting material
  • Examples 67 has been prepared according to the procedure as described in Example 66 by taking appropriate starting materials
  • MICs In vitro Data Minimum Inhibiton Concentrations (MICs) were determined by broth microdilution technique as per the guidelines prescribed in the fifth edition of Approved Standards, NCCLS document M7-A5 Vol 20 - No 2, 2000 Villinova, PA. Initial stock solution of the test compound was prepared in DMSO. Subsequent two fold dilutions were carried out in sterile Mueller Hinton Broth (Difco) (MHB). Frozen cultures stocks were inoculated into 50 ml sterile MHB in 250 ml Erlyn Meyer flasks.
  • Composition of MHB is as follows: Beef Extract Powder - 2.0 grams/litre Acid Digest of Casein - 17.5 grams/ litre Soluble Starch - 1.5 grams/litre Final pH 7.3 ⁇ 0.1 Flasks were incubated for 4 to 5 hours at 35 °C on a rotary shaker at 150 rpm. Inoculum was prepared by diluting the culture in sterile MHB to obtain a turbidity of 0.5 McFarland standard. This conesponds to 1-2 x 10 CFU/ml. The stock was further diluted in sterile broth to obtain 1-2 X 10 6 CFU/ml. 50 ⁇ l of the above diluted inoculum was added from 1-10 wells. The plates were incubated overnight at 37 °C. MIC is read as the lowest concentration of the compound that completely inhibits growth of the organism in the microdilution wells as detected by the unaided eye.
  • mice Systemic Infection S.aureus ATCC 29213 and other tested strains were grown overnight on Columbia Blood agar (DIFCO).
  • the inoculum was prepared by suspending the culture in 0.9% saline and adjusted to 100 x LD 50 dose in 10% Hog Gastric Mucin (DIFCO).
  • DIFCO Hog Gastric Mucin
  • Test compounds were solubilised in suitable formulation and 0.25ml was administered intra venously or orally or sub-cutaneously at 1 hour and 5 hours post infection by BID or TID or single dose protocol • The animals were observed for 5-7 days and the survival was noted.
  • • ED 0 was calculated by probit analysis.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à de nouveaux composés triazoliques répondant à la formule (I), leurs précurseurs de médicament, leurs sels pharmaceutiquement acceptables, et leurs stéréoisomères. La présente invention se rapporte également à un procédé de préparation des nouveaux composés répondant à la formule (I).
PCT/IB2004/003360 2003-10-14 2004-10-14 Nouveaux composes triazoliques, leur procede de preparation et compositions pharmaceutiques les contenant WO2005035528A2 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1931460A2 (fr) * 2005-08-31 2008-06-18 The Scripps Research Institute Stabilisation d'organogels et d'hydrogels par cycloaddition d'azide-alcyneý2+3¨
US7521470B2 (en) 2004-06-18 2009-04-21 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US7696352B2 (en) 2004-06-18 2010-04-13 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US7763608B2 (en) 2006-05-05 2010-07-27 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
WO2011051960A3 (fr) * 2009-09-25 2011-06-23 Cadila Healthcare Limited Procédé de préparation de dérivés de rapamycine
US8530501B2 (en) 2009-12-17 2013-09-10 Millennium Pharmaceuticals, Inc. Salts and crystalline forms of a factor Xa inhibitor
US8742120B2 (en) 2009-12-17 2014-06-03 Millennium Pharmaceuticals, Inc. Methods of preparing factor xa inhibitors and salts thereof

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Publication number Priority date Publication date Assignee Title
WO2002051819A2 (fr) * 2000-12-26 2002-07-04 Dr. Reddy's Laboratories Ltd. Composés hétérocycliques antibactériens, mode d'élaboration et compositions pharmaceutiques ainsi obtenues
WO2003059894A1 (fr) * 2002-01-18 2003-07-24 Dr.Reddy's Laboratories Ltd. Nouveaux composes antibacteriens, procede pour leur preparation et compositions pharmaceutiques contenant de tels composes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002051819A2 (fr) * 2000-12-26 2002-07-04 Dr. Reddy's Laboratories Ltd. Composés hétérocycliques antibactériens, mode d'élaboration et compositions pharmaceutiques ainsi obtenues
WO2003059894A1 (fr) * 2002-01-18 2003-07-24 Dr.Reddy's Laboratories Ltd. Nouveaux composes antibacteriens, procede pour leur preparation et compositions pharmaceutiques contenant de tels composes

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8153670B2 (en) 2004-06-18 2012-04-10 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US7521470B2 (en) 2004-06-18 2009-04-21 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US7696352B2 (en) 2004-06-18 2010-04-13 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US8377974B2 (en) 2004-06-18 2013-02-19 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
EP1931460A4 (fr) * 2005-08-31 2010-06-02 Scripps Research Inst Stabilisation d'organogels et d'hydrogels par cycloaddition d'azide-alcyneý2+3¨
EP1931460A2 (fr) * 2005-08-31 2008-06-18 The Scripps Research Institute Stabilisation d'organogels et d'hydrogels par cycloaddition d'azide-alcyneý2+3¨
US8349873B2 (en) 2006-05-05 2013-01-08 Millennium Pharmaceuticals, Inc. Factor XA inhibitors
US8063077B2 (en) 2006-05-05 2011-11-22 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US7767697B2 (en) 2006-05-05 2010-08-03 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US7763608B2 (en) 2006-05-05 2010-07-27 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
WO2011051960A3 (fr) * 2009-09-25 2011-06-23 Cadila Healthcare Limited Procédé de préparation de dérivés de rapamycine
US8754207B2 (en) 2009-09-25 2014-06-17 Cadila Healthcare Limited Process for the preparation of rapamycin derivatives
US8530501B2 (en) 2009-12-17 2013-09-10 Millennium Pharmaceuticals, Inc. Salts and crystalline forms of a factor Xa inhibitor
US8742120B2 (en) 2009-12-17 2014-06-03 Millennium Pharmaceuticals, Inc. Methods of preparing factor xa inhibitors and salts thereof

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