WO2004101531A1 - Derives anti-infectieux de 1,2,3-triazole, leur procede de preparation et compositions pharmaceutiques les contenant - Google Patents

Derives anti-infectieux de 1,2,3-triazole, leur procede de preparation et compositions pharmaceutiques les contenant Download PDF

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Publication number
WO2004101531A1
WO2004101531A1 PCT/IB2004/001303 IB2004001303W WO2004101531A1 WO 2004101531 A1 WO2004101531 A1 WO 2004101531A1 IB 2004001303 W IB2004001303 W IB 2004001303W WO 2004101531 A1 WO2004101531 A1 WO 2004101531A1
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alkyl
compound
formula
substituted
unsubstituted
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PCT/IB2004/001303
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English (en)
Inventor
Jagattaran Das
Selvakumar Natesan
Sanjay Trehan
Javed Iqbal
Sitaram Kumar Magadi
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Dr. Reddy's Laboratories Ltd.
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Priority to US10/554,472 priority Critical patent/US20060270628A1/en
Publication of WO2004101531A1 publication Critical patent/WO2004101531A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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),
  • R 1 represents halogen, azido, thioalcohol, isothiocyanate, hydroxy, isoindole-l,3-dione, substituted or unsubstituted (Cl-C20)alkylsulfonyloxy, arylsulfonyloxy, (Cl-C20)acyloxy group, NHR where R 4 represents hydrogen, substituted or unsubstituted groups selected from (Cl-C20)acyl, thio(Cl-C20)acyl, (Cl-C20)alkoxycarbonyl, (C3-C20)cycloalkoxycarbonyl, (C3-C20)cycloalkoxythiocarbonyl, (C2-C20)alkenyloxycarbonyl, ' (C2-C20)alkenylcarbonyl, heteroaryl, aryloxycarbonyl, heteroarylcarbonyl, heteroarylthiocarbonyl, (Cl- C20)alkoxythi
  • MRSA methicillin-resistant Staphylococcus aureas
  • novel triazole compound of the present invention is useful for the treatment of various infections
  • novel triazole compounds of the general formula (I) as defined above their pharmaceutically acceptable salts and their pharmaceutical compositions containing them.
  • Another aspect fo the present invention provides 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, substituted or unsubstituted (Cl-C20)alkylsulfonyloxy, arylsulfonyloxy, (Cl-C20)acyloxy group, NHR 4 where R 4 represents hydrogen, substituted or unsubstituted groups selected from (Cl-C20)acyl, thio(Cl-C20)acyl, (Cl-C20)alkoxycarbonyl, (C3-C20)cycloalkoxycarbonyl, (C3-C20)cycloalkoxythiocarbonyl, (C2-C20)alkenyloxycarbonyl, (C2-C20)alkenylcarbonyl, heteroaryl, aryloxycarbonyl, hetero arylcarbonyl, heteroarylthiocarbonyl, (Cl- C20)alkoxythi
  • a 5 or 6 member heterocycle ring formed by R' & R", containing nitrogen, optionally having one or two additional heteroatoms selected from oxygen, nitrogen or sulfur, is selected from pyrrolidinyl, pyrrolyl, mo ⁇ holinyl, thiomo ⁇ holinyl, benzothiazole, benzoimidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like, the heterocycle may be substituted.
  • Suitable groups represented by R 2 and R 3 may be selected from hydrogen, halogen atom such as fluorine, chlorine or bromine; substituted or unsubstituted (Cl-C20)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, n- hexyl and the like; halo(Cl-C20)alkyl group such as halomethyl, haloethyl, halopropyl, trihalomethyl and the like, wherein the halo group is selected from fluorine, chlorine, bromine or iodine; (Cl-C20)alkoxy group such as methyl, ethyl, propyl and the like; aryl group such as phenyl, naphthyl and the like; heteroaryl groups such as pyridy
  • Suitable substitutents on R a are selected from hydroxy, halogen, nitro, amino, (Cl- C20)alkyl, (Cl-C20)alkoxy, cyano group, or carboxylic acid or its derivatives. These groups are as defined above.
  • Suitable groups represented by Y 1 and Y 2 are selected from hydrogen, cyano, nitro, formyl, hydroxy, amino, halogen such as fluorine, chlorine, bromine or iodine;, substituted or unsubstituted (Cl-C20)alkyl such as methyl, ethyl, n-propyl, isopropyl, n-b tyl, iso-butyl, t-.
  • hydroxy(Cl-C20)alkyl such as hydroxymethyl, ' hydroxyethyl, hydroxypropyl and the like, which may be substituted; dihydroxy(Cl- C20)alkyl such as dihydroxymethyl, dihydroxyethyl, dihydroxypropyl and the like, which , may be substituted; (Cl-C20)alkoxy(Cl-C20) alkyl group such as methoxymethyl, methoxyethyl, ethoxyethyl, ethoxymethyl, methoxypropyl, propoxymethyl, propoxyethyl and the like, which may be substituted; (Cl-C20)alkylcarbonyl group such as methylcarbonyl, ethylcarbonyl and the like, which may be substituted; (Cl-C20)alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl and the like, which may be substituted;
  • the substituents may be selected from hydroxy, nitro, cyano, amino, tert-butyldimethylsilyloxy (TBSO), halogen atom, (Cl-C20)alkyL (Cl-C20)alkoxy, (C3-C20)cycloalkyl, aryl, benzyloxy, acyl or acyloxy group such as formyloxy, acetyloxy and the like, carboxylic acid or its esters.
  • TSO tert-butyldimethylsilyloxy
  • substituents are selected from halogen, hydroxy, nitro, amino, cyano, (Cl-C20)alkyl or (Cl- C20) alkoxy.
  • (C1-C20) alkyl and (C1-C20) alkoxy are as defined above.
  • R 1 represents NHR 4 where R 4 represents (Cl-C20)acyl, Cl-C20)alkoxycarbonyl;
  • R 2 and R 3 may be same or different and independently represent hydrogen, halogen atom, (Cl-C20)alkyl group, halo(Cl-C20)alkyl;
  • Y 1 and Y 2 may be same or different and independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, substituted or unsubstituted groups selected from (Cl- C20)alkyl, hydroxy(Cl-C20)alkyl, dihydroxy(Cl-C20)alkyl, (Cl-C20)alkoxy(Cl-C20)alkyl, aminocarbonyl, (Cl-C20)alkylcarbonyl, (Cl-C20)alkoxycarbonyl, carboxy(Cl-C20)alkyl, (C 1 -C20)alkylsulfonyl, (C 1 -C20)alkylcarbonylamino(C 1 -C20)alkyl, (C 1 -
  • R 1 represents NHR 4 where R 4 represents (Cl-C20)acyl, Cl-C20)alkoxycarbonyl;
  • R 2 and R 3 may be same or different and independently represent hydrogen, halogen atom, halo(Cl-C20)alkyl;
  • the substituents on Y 1 and Y 2 may be selected from hydroxy, cyano, amino, (Cl-C20)alkyl, (Cl-C20)alkoxy, acyl, carboxylic acid or its esters; their pharmaceutically acceptable salts.
  • Another aspect of the present invention provides compound of the formula (I),JR.' represents NHR 4 where R 4 represents thio(Cl-C20)acyl, (Cl-C20)alkoxythiocarbonyl, R 2 and R 3 may be same or different and independently represent hydrogen, halogen atom, (Cl-C20)alkyl group, halo(Cl-C20)alkyl;
  • Y 1 and Y 2 may be same or different and independently represent hydrogen, halogen, cyano, nitro, formyl, hydroxy, amino, substituted or unsubstituted groups selected from (Cl- C20)alkyl, hydroxy(Cl-C20)alkyl, dihydroxy(Cl-C20)alkyl, (Cl-C20)alkoxy(Cl-C20)alkyl, aminocarbonyl, (Cl-C20)alkylcarbonyl, (Cl-C20)alkoxycarbonyl, carboxy(Cl-C20)alkyl, (C 1 -C20)alkylsulfonyl, (C 1 -C20)alkylcarbonylamino(C 1 -C20)alkyl, (C 1 -
  • _R' represents NHR 4 where R 4 represents thio(Cl-C20)acyl, (Cl-C20)alkoxythiocarbonyl,
  • R and R may be same or different and independently represent hydrogen, halogen atom, halo(Cl-C20)alkyl;
  • the substituents on Y 1 and Y 2 may be selected from hydroxy, cyano, amino, (Cl-C20)alkyl, (Cl-C20)alkoxy, acyl, carboxylic acid or its esters; their pharmaceutically acceptable salts.
  • 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, meglumine, ethylenediamine, N,N'-diphenylethylenediamine, N,N'- dibenzylethylenediamine, N-benzyl phenylethylamine, choline, choline hydroxide
  • cysteine methionine, proline, hydroxy proline, histidine, omithine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids such as D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl such as methyl, ethyl, propyl and the like; alkenyl such as ethenyl, propenyl, butenyl and the like; alkynyl such as ethynyl, propynyl and the like; ammonium or substituted ammonium salts and aluminum salts.
  • Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, halides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, halides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • a preferred compound of the present invention is
  • a preferred compound of the present invention is
  • a preferred compound of the present invention is
  • a preferred compound of the present invention is
  • a preferred compound of the present invention is
  • a preferred compound of the present invention is
  • Yet another aspect of the present invention provides preparation of the the novel compounds of the present invention according to the procedure of the following schemes, using appropriate materials Those skilled in the art will readily understand that l ⁇ iown variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.
  • R c - represents substituted or unsubstituted (Cl-C20)alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like;
  • A, B, D, Y 1 , Y 2 , R 2 and R 3 are as defined earlier, (v) reducing the compound of formula (If), to give a compound of formula (I)
  • R 1 represents hydroxy group
  • A, B, D, Y 1 , Y 2 , R 2 and R 3 are as defined earlier ,
  • R 1 represents azido group and all other symbols are as defined earlier.
  • the compound of formula (lc) may be prepared by reacting a compound of formula (la) with a compound of formula (lb) by using a base such as potassium hydroxide (KOH), sodium hydroxide (NaOH), potassium carbonate (K 2 CO 3 ), sodium carbonate (Na 2 CO 3 ), sodium hydride (NaH), potassium hydride (KH), triethylamine, diisopropylethyl amine and the like.
  • the reaction may be carried out using a solvent such as diemthyl sulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, chloroform, nitrobenzene and the like or mixtures thereof.
  • DMSO diemthyl sulfoxide
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • acetonitrile chloroform, nitrobenzene and the like or mixtures thereof.
  • the reaction may be carried out in inert atmosphere, which may be maintained using inert gases such as N 2 or Ar.
  • the reaction may be carried out at a temperature in the range of 20 to 100°C, preferably at a temperature in the range of ambient- 80°C.
  • the reaction time may range from 1 to 15 h, preferably from 6 to 12 h.
  • the reduction of a compound of formula (lc) to produce a compound of formula (Id) may be carried out in the presence of reducing agents such as 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.
  • the reduction may be carried out in the presence of a solvent such as 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 may be used.
  • the reaction may be carried out at a temperature from 0 to 60°C, preferably at 0 to room temperature.
  • the reaction time ranges from 0.5 to 48 h, preferably in. the range of 0.5 to 5 h.
  • the reduction may also be carried out by employing metal in mineral acids such as Sn/HCl, Fe/HCl, Zn/HCl, Zn/CH 3 CO 2 H and the like.
  • the compound of formula (Id) may be converted to a compound of formula (le) by using sodium nitrite (NaNO 2 ) in the presence of HCl or acetic acid (CH 3 COOH) followed by sodiumazide (NaN 3 ).
  • the temperature of the reaction may be maintained in the range of - 40°C to boiling temperature, preferably in the range of 0°C to room temperature.
  • the duration of the reaction may be in the range of 0.5 to 15 h, preferably in the range of 0.5 to 5 h.
  • the compound of formula (If) may be prepared by heating a compound of formula (le) with (C ⁇ -C 6 )alkyl ester of propiolic acid.
  • the solvent used in the reaction may be selected from benzene, toluene, xylene, acetonitrile, THF, DMF and the like.
  • the temperature of the reaction may be maintained in the range of 10 to 200°C, preferably in the range of room temperature to the boiling temperature of the solvent.
  • the duration of the reaction may be in the range of 1 to 25 h, preferably 5 to 20 h.
  • the conversion of compound of formula (If) to a compound of formula (I), where R 1 represents hydroxy may be carried out by using reducing agents such as LAH, lithiumboronhydride (LiBH 4 ) or sodium tetrahydroborate/iodine (NaBH 4 /I 2 ).
  • the reaction may be carried out in the presence of a solvent such as methanol, ethanol, THF, diethylether (Et 2 O), dioxane and the like, or mixtures thereof.
  • the temperature of the reaction may be in the range of -80 to 100°C, preferably 0°C to boiling temperature of the solvent.
  • the duration of the reaction may be in the range of 0.5 to 10 h.
  • the compound of formula (I) where R 1 represents OH may be converted to compound of foraiula (I) where R 1 represents substituted or unsubstituted (Cl-C20)alkylsulfonyloxy or arylsulfonyloxy group, by treating with alkylsulfonylchloride or arylsulfonylchloride such as methanesulfonyl chloride, p-toluenesulfonyl chloride and the like.
  • the reaction may be carried out in the presence of chloroform, dichloromethane, THF, dioxane and the like or mixtures thereof.
  • the base used in the reaction may be selected from Et 3 N, diisopropyl ethylamine, Na CO 3 , K 2 CO 3 and the like.
  • the temperature of the reaction may be maintained in the range of 0 to 50°C, preferably in the range of 0 to room temperature.
  • the duration of the reaction may be in the range of 1 to 12 h, preferably in the range of 1 to 4 h.
  • the compound of foraiula (I) where R 1 represents substituted or unsubstituted (Cl- C20)alkylsulfonyloxy or arylsulfonyloxy group may be converted to compound of formula (I) wherein R 1 represents azido group, by treating with NaN 3 .
  • the solvent used in the reaction may be selected from DMF, DMSO, acetonitrile, nitromethane and the like.
  • the tempearature of the reaction may be maintained in the range of room temperature to 120 °C, preferably room temperature to 80 °C.
  • the duration of the reaction may be in the range of 1 to 12 h, preferably 1 to 4 h.
  • the compound of formula (I) wherein R 1 represents hydroxy can be converted to a compound of formula (I) wherein R 1 represents azido group without isolating and characterizing the alkylsulfonyl or arylsulfonyl intermediate formed.
  • Another embodiment of the present invention provides an alternative process for the preparation of the compound of foraiula (I) where R 1 represents azido and all other symbols are as defined earlier, which comprises: (i) converting the compound of formula (le)
  • R 1 represents hydroxy
  • A, B, D, Y 1 , Y 2 , R 2 and R 3 are as defined earlier and (ii) reacting the compound of formula (I) where R 1 represents hydroxy group, with MsCl, triethylamine and sodium azide to give a compound of formula (I) where R 1 represents azido group and all other symbols are as defined above
  • the compound of formula (le) may be converted to a compound of foraiula (I), where R 1 represents hydroxy group, by treating with propargyl alcohol.
  • the solvent used in the reaction may be selected from benzene, toluene, xylene, acetonitrile, THF and the like.
  • the temperature of the reaction may be maintained in the range of 10 to 200°C, preferably room temperature to the boiling temperature of the solvent.
  • the duration of the reaction may be in the range of 1 to 25 h, preferably in the range of 5 to 20 h.
  • step (1) the compound of fo ⁇ nula (I) where R 1 represents OH is converted to compound of formula (I) where R represents leaving group such as halogen atom, by treating with CBr 4 /PPh 3 , PBr 3 , thionylchloride (SOCl 2 ) and the like.
  • the reaction may be carried out in the' presence of chloroform, dichloromethane, THF, dioxane and the like or mixtures thereof.
  • the temperature of the reaction may be maintained in the range of 0 to 80°C, preferably in the range of 0 to 50°C.
  • the duration of the reaction may be in the range of l-12h, preferably in the range of l-4h.
  • step (2) the compound of formula (I) where R 1 represents halogen atom may be converted to compound of foraiula (I) where R 1 represents azido group by treating with NaN 3 , LiN 3 , trialkylsilylazide and the like.
  • the solvent used in the reaction may be selected from acetone, THF, DMF, dimethyl sulfoxide (DMSO), acetonitrile and the like.
  • the temperature of the reaction may be maintained in the range of room temperature to 120°C, preferably room temperature to 80°C.
  • the duration of the reaction may be in the range of 1 to 12 h, preferably 1 to 4 h.
  • Yet another embodiment of the present invention provides an alternative process for the preparation of compound of formula (I), where R 1 represents azido group, which comprises: (i) converting the compound of formula (le)
  • R 1 represents halogen atom such as chlorine, bromine and the like, and all other symbols are as defined earlier and
  • the compound of formula (I), where R 1 represents halogen atom such as chlorine, bromine and the like, may be prepared from a compound of formula (le) by using propargyl halide such as propargylchloride or propargyl bromide.
  • the solvent used in the reaction may be selected from benzene, toluene, xylene, acetonitrile, THF and the like.
  • the temperature of the reaction may be maintained in the range of 10 to 200°C, preferably room temperature to the boiling temperature of the solvent.
  • the duration of the reaction may be in the range of 1 to 25 h, preferably in the range of 5 to' 20 h.
  • the conversion of a compound of formula (I) where R 1 represents halogen atom such as chlorine, bromine and the like, to a compound of formula (I) where R 1 represents azido group may be carried out in the presence of one or more equivalents of metal azide such as LiN 3 , NaN 3 or trialkyl silylazide.
  • the reaction may be carried out in the presence of solvent such as THF, acetone, DMF, DMSO and the like or mixtures thereof.
  • the reaction may be carried out in inert atmosphere, which may be maintained using N 2 or Ar.
  • the reaction may be carried out at a temperature in the range of ambient temperature to reflux temperature of the solvent, preferably at a temperature in the range of 50 to 80°C.
  • the reaction time may be in the range from 0.5 to 18 h, preferably 1 to 4 h.
  • Another embodiment of the present invention provides a process for the preparation of compound of foraiula (I) where R 1 represents NHR 4 wherein R 4 represents hydrogen atom, which comprises: (i) converting the compound of formula (If)
  • R c represents substituted or unsubstituted (Cl-C20)alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like;
  • A, B, D, Y 1 , Y 2 , R 2 and R 3 are as defined earlier, to a compound of formula (Ig)
  • R 1 represents NHR wherein R represents hydrogen atom and all other symbols are as defined earlier.
  • the conversion of compound of formula (If) to a compound of foraiula (Ig) may be carried out in the presence of ammonia solution in water or alcohol.
  • the temperature of the reaction may be in the range of -40 to 50°C, preferably of 0°C to room temperature.
  • the duration of the reaction may be in the range of 0.5 to 12 h, preferably 0.5 to 4 h.
  • the reduction of compound of foraiula (Ig) to a compound of formula (I), where R 1 represents NHR 4 wherein R 4 represents hydrogen atom may be carried out by using borane complex in THF, diethylether, SMe 2 or amine.
  • the solvent used in the reaction may be selected from THF, diethylether, dioxane and the like.
  • the temperature of the reaction may be in the range of -20 to 70°C, preferably 0 to boiling temperature of the solvent.
  • the duration of the reaction may be in the range of 1 to 15 h, preferably 1 to 6 h.
  • Yet another embodiment of the present invention provides an alternative process for the preparation of compound of formula (I) where R 1 represents NHR 4 wherein R 4 represents hydrogen atom, which comprises:
  • R 1 represents NHR 4 wherein R 4 represents hydrogen atom
  • A, B, D, Y 1 , Y 2 , R 2 and R 3 are as defined earlier.
  • the reduction of a compound of formula (I) where R 1 represents azido group, to produce a compound of foraiula (I) where R 1 represents NHR 4 wherein R 4 represents hydrogen atom may be carried out in the presence of 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 may be carried out in the presence of a solvent such as 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 may be used.
  • the reaction may be carried out at a temperature in the range of 25 to 60°C, preferably at room temperature.
  • the duration of the reaction may be in the range of 2 to 48 h.
  • the reduction may also be carried out by employing PPh 3 in water.
  • Another embodiment of the present invention provides a process for the preparation of compound of foraiula (I) where R 1 represents hydroxy group, which comprises: (i) converting the compound of foraiula (le),
  • A, B, D, Y 1 , Y 2 , R 2 and R 3 are as defined earlier, to a compound of formula (I), where R , 1 represents substituted or unsubstituted (Cl-C20)acyloxy group, and all other symbols are as defined earlier and
  • the conversion of compound of formula (le) to a compound of formula (I) where R ! represents (Cl-C20)acyloxy group may be carried out in the presence of esters ((Cl- C20)alkyl or aryl)of propargyl alcohol.
  • the solvent used in the reaction may be selected from benzene, toluene,, xylene, acetonitrile, THF and the like.
  • the temperature of the reaction may be maintained in the range of 10 to 200°C, preferably room temperature to the boiling temperature of the solvent.
  • the duration of the reaction may be in the range of 1 to 25 h, preferably in the range of 5 to 20 h.
  • the present invention also relates to a process for the preparation of the compound of formula (I) where R represents azido and all other symbols are as defined earlier, which comprises:
  • R 1 represents NHR ,4 4
  • R z and R J are as defined earlier
  • R 1 is as defined above, R 2 and R 3 are as defined earlier,
  • R 1 is as defined above; R 2 and R 3 are as defined earlier,
  • the compound of formula (Im) may be prepared by reacting a compound of formula (la) with a compound of formula (II).
  • the reaction may be carried out using a solvent such as DMSO, DMF, THF, acetonitrile, chloroform, nitrobenzene and the like or mixtures thereof
  • the reaction may be carried out in inert atmosphere, which may be maintained using inert gases such as N 2 or argon (Ar).
  • the reaction may be carried out at a temperature in the range of 20 to 100°C, preferably at a temperature in the range of ambient to 80 °C.
  • the reaction time may range from 1 to 15 h, preferably from 6 to 12 h.
  • the reduction of a compound of formula (Im) to produce a compound of formula (In) may be carried out in the presence of reducing agents such as NiCl 2 /NaBH 4 , lithium aluminium hydride (LAH), gaseous hydrogen and a catalyst such as Ru, Pd, Rli, Pt, Ni on- solid beads such as charcoal, alumina, asbestos and the like.
  • reducing agents such as NiCl 2 /NaBH 4 , lithium aluminium hydride (LAH), gaseous hydrogen and a catalyst such as Ru, Pd, Rli, Pt, Ni on- solid beads such as charcoal, alumina, asbestos and the like.
  • the reduction may be earned out* in the presence of a solvent such as 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 may be used.
  • the reaction may be carried out at a temperature from 0 to 60°C, preferably at 0 to room temperature.
  • the reaction time ranges from 0.5 to 48 h, preferably in the range of 0.5 to 5 h.
  • the reduction may also be carried out by employing metal in mineral acids such Sn/HCl, Fe/HCl, Zn/HCl, Zn/CH 3 CO 2 H and the like.
  • the compound of formula (In) may be converted to a compound of formula (Io) by using NaNO 2 in the presence of HCl or CH 3 COOH followed by NaN 3 .
  • the temperature of the reaction may be maintained in the range of -40 °C to boiling temperature, preferably in the range of 0 °C to room temperature.
  • the duration of the reaction may be in the range of 0.5 to 15 h, preferably in the range of 0.5 to 5 h.
  • the compound of formula (In) is converted to a compound of formula (Io) by using alkylnitrite such as t-butylnitrite and the like along with alkali metal azide such as sodium azide, potassium azide and the like.
  • the solvent used in the reaction is selected from benzene, toluene, DMF, alcohol such as methanol, ethanol, propanol, isopropanol, butanol, tertiary butanol and the like.
  • the temperature of the reaction may be maintained in the range of -40 °C to boiling temperature, preferably in the range of 0 °C to room temperature.
  • the duration of the reaction may be in the range of 0.5 to 15 h, preferably in the range of 0.5 to 5 h.
  • the compound of formula (Io) is reacted with compound of formula (Ip), to obtain a compound of formula (Iq) by using Cu(I) halide in the presence or absence of a base such as DMAP, pyridine, triethylamine, diisopropylethylamine, lutidine and the like.
  • a base such as DMAP, pyridine, triethylamine, diisopropylethylamine, lutidine and the like.
  • the solvent used in the reaction may be selected from DMF, DMSO, THF, ether, dioxane, acetonitrile and the like.
  • the compound of formula (Iq) is converted to a compound of formula (Ir) by using hydrazine hydrate or an amine such as methylamine, ethylamine, ethylene diamine etc.
  • the solvent used in the reaction is selected from methanol, ethanol, propanol, isopropanol and the like or mixtures thereof.
  • the compound of formula (Ir) is converted to a compound of formula (I), by treating with 2,5-dimethoxytetrahydrofuran or 2,5-dimethoxytetrahydrofuran-3-carboxaldehyde.
  • the solvent used in the reaction is selected from acetic acid, propanoic acid and the like.
  • the temperature of the reaction is maintained in the range of -20 °C to boiling temperature of the solvent used.
  • the duration of the reaction is in the range of 0.5 to 15 h, preferably 0.5 to 10 h.
  • Another embodiment of the present invention provides a process for the preparation of compound of formula (I), where R 1 represents azido group, which comprises: (i) converting the compound of formula (Io)
  • R 2 and R 3 are as defined earlier.
  • the compound of fo ⁇ nula (Io) is converted to a compound of foraiula (Is) by using hydrazine hydrate or an amine such as methylamine, ethylamine, ethylene diamine etc.
  • the solvent used in the reaction is selected from methanol, ethanol, propanol, isopropanol and the like or mixtures thereof.
  • the compound of fo ⁇ nula (Is) is converted to a compound of foraiula (le), by treating with 2,5-dihydroxymethoxytetrahydrof ⁇ xran or 2,5-dimethoxytetrahydro-3-carboxaldehyde.
  • the solvent used in the reaction is selected from acetic acid, propanoic acid and the like.
  • the temperature of the reaction is maintained in the range of -20 °C to boiling temperature of the solvent used.
  • the duration of the reaction is in the range of 0.5 to 15 h, preferably 0.5 to 10 h.
  • the compound of formula (le) is reacted with compound of formula (Ip), to obtain a compound of formula (I) by using Cu(I) halide.
  • the solvent used in the reaction may be selected from DMF, DMSO, THF, ether, dioxane, acetonitrile and the like.
  • Another embodiment of the present invention provides an alternate process for the preparation of compound of foraiula (Ir), which comprises: (i) converting the compound of formula (Iu)
  • the compound of formula (Iu) may be converted to a compound of foraiula (Iv) by using NaNO 2 in the presence of HCl or CH 3 COOH followed by NaN 3 .
  • the temperature of the • reaction may be maintained in the range of -40°C to boiling temperature, preferably in the range of 0°C to room temperature.
  • the duration of the reaction may be in the range of 0.5 to 15 h, preferably in the range of 0.5 to 5 h.
  • the compound of formula (Iu) is converted to a compound of formula (Iv) by using alkylnitrite such as t-butylnitrite and the like along with alkali metal azide such as sodium azide, potassium azide and the ' like.
  • the solvent used in the reaction is selected from benzene, toluene, DMF, alcohol such as methanol, ethanol, propanol, isopropanol, butanol, tertiary butanol and the like.
  • the temperature of the reaction may be maintained in the range of -40 °C to boiling temperature, preferably in the range of 0 °C to room temperature.
  • the duration of the reaction may be in the range of 0.5 to 15 h, preferably in the range of 0.5 to 5 h.
  • the compound of formula (Iv) is reacted with compound of foraiula (Ip), to obtain a compound of formula (Iw) by using Cu(I) halide in the presence or absence of a base such as 4-(dimethylammo)pyridine (DMAP), pyridine, triethylamine, diisopropylethylamine, lutidine and the like.
  • a base such as 4-(dimethylammo)pyridine (DMAP), pyridine, triethylamine, diisopropylethylamine, lutidine and the like.
  • the solvent used in the reaction may be selected from DMF, DMSO, THF, ether, dioxane, acetonitrile and the like.
  • the reduction of a compound of foraiula (Iw) to produce a compound of foraiula (Ir) may be carried out in the presence of reducing agent such as NiCl 2 /NaBH , lithium aluminimn 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.
  • reducing agent such as NiCl 2 /NaBH , lithium aluminimn 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 may be ca ⁇ ied out in the presence of a solvent such as 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 may be used.
  • the reaction may be carried out at a temperature from 0 to 60°C, preferably at 0 to room temperature.
  • the reaction time ranges from 0.5 to 48 h, preferably in the range of 0.5 to 5 h.
  • the reduction may also be carried out by employing metal in mineral acids such Sn/HCl, Fe/HCl, Zn/HCl, Zn/CH 3 CO 2 H, Fe/NH 4 C1 and the like.
  • 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 substituted or unsubstituted acetyl group and all other symbols are as defined earlier, from a compound of formula (I) where R 1 represents azido group,
  • A, B, D, Y 1 , Y 2 , R 2 and R 3 are as defined earlier.
  • the compound of formula (I), where R 1 represents NHR 4 , wherein R 4 represents substituted or unsubstituted acetyl group may be prepared from compound of foraiula (I), where R 1 represents azido group may be ca ⁇ ied out by using thiolacetic acid with or without using solvent such as THF, DMF, toluene and the like.
  • the reaction may be carried out at a temperature in the range of 25 to 40 °C, preferably at room temperature.
  • the duration of the reaction may be in the range from 3 to. 24 h, preferably from 4 to 12 h.
  • R 1 represents azido group; and all other symbols are as defined earlier, with triphenylphosphine/water or H 2 -Pd/C, to produce a compound of formula (I), where R 1 represents NHR 4 , wherein R 4 represents hydrogen atom and all other symbols are as defined earlier,
  • the conversion of compound of formula (I), where R 1 represents azido to a compound of formula (I), where R 1 represents NHR 4 , wherein R 4 represents hydrogen atom may be ca ⁇ ied out in the presence of 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 may be conducted in the presence of a solvent such as dioxane, acetic acid, ethyl acetate, THF, alcohol such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof.
  • a pressure between atmospheric pressure to 60 psi may be used.
  • the reaction may be earned out at a temperature in the range of 25 to 60°C, preferably in the range of room temperature to 80°C.
  • the duration of the reaction may be in the range of 2 to 48 h, preferably in the range of 5 to 15 h.
  • the reduction may also be canied out by employing PPh 3 and water.
  • the compound of formula (I), where R represents NHR 4 , wherein R 4 represents hydrogen atom may be converted to a compound of fo ⁇ nula (I) where R 1 represents isothiocyanate group, by using thiophosgene or carbon disulfide and chloromethylfomiate in the presence of a base such as Et 3 N, K 2 CO 3 , NaOH and the like.
  • the reaction may be earned out in the presence of a solvent such as dichloromethane (CH 2 C1 2 ), acetonitrile, chloroform (CHCI 3 ), DMF, THF and the like.
  • the reaction may be carried at a temperature in the range of 0 to 60°C, preferably at 0°C.
  • the reaction may be carried out in an inert atmosphere using argon or any other inert gas.
  • the duration of the reaction may be in the range of 1 to 24 h, preferably 2 to 10 h.
  • the reaction may be canied out in the presence of a solvent such as THF, toluene, DMF and the like.
  • the reaction may be carried out at a temperature in the range of room temperature to 130°C, preferably at reflux temperature of the solvent used.
  • the duration of the reaction may be in the range of 6 to 24 h.
  • R 1 represents NHR 4
  • the reaction may be carried out at a . temperature in the range of -10 °C to room temperature, preferably at -10 °C.
  • the duration of the reaction may be in the range from 20 min to 4 h, preferably 30 min.
  • the reaction may be carried out in the presence of alkyl halide such as methyliodide, ethylbromide, propylbromide and the like.
  • the solvent used in the reaction may be selected from ethanol, methanol, isopropanol, THF, diethylether, acetonitrile and the like, or mixtures thereof.
  • the reaction may be earned out at a temperature in the range of room temperature to 60°C, preferably at room temperature.
  • the duration of the reaction may be in the range of 6 to 24 h.
  • the solvent used in the reaction may be selected from acetone, ethanol, methanol, isopropanol, THF, diethylether, acetonitrile and the like.
  • the temperature of the reaction may be maintained in the range of 0 to 80°C, preferably in the range of room temperature to 60 °C.
  • the duration of the reaction may be in the range of 1 to 20 h, preferably in the range of 1 to 10 h.
  • the reaction may also be carried out by using corresponding heteroaryl acid and dicyclohexylcarbodiimide (DCC) in the presence of DMAP.
  • the solvent used in the reaction may be selected from acetonitrile, THF, acetonitrile, Et 2 O and the like.
  • the temperature of the reaction may be maintained in the range of -5 to 100°C, preferably in the range of 0 to 80°C.
  • the duration of the reaction may be in the range of 1 to 15 h, preferably in the range of 2 to 12 h.
  • acid halide such as acetyl chloride, propionyl chloride and the like
  • alkylchloro formate like methylchloroforaiate, ethylchloroformate and the like
  • the reaction may be carried out in the presence of a solvent such as CH C1 2 , CHC1 3 , toluene, THF and the like or mixtures thereof.
  • the reaction may also be carried out in the presence of a base like Et 3 N, diisopropyl ethylamine, pyridine, K 2 CO 3 , NaH, potassium tert-butoxide (t-BuOK) and the like.
  • the temperature of the reaction may be maintained in the range of -20 to 60°C, preferably in the range of 0 to room temperature.
  • the duration of the reaction may be in the range of 1 to 12 h, preferably from 1 to 4 h.
  • the temperature of the reaction may be in the range of 0 to 120°C, preferably in the range of 0 to 90°C.
  • the duration of the reaction may be in the range of 0.2 to 15 h, preferably in the range of 0.5 to 10 h.
  • the second step the compound obtained in the first step may be reacted with trifluoroacetic acid in the presence of a solvent such as dichloromethane, chloroform, THF and the like.
  • the temperature of the reaction may be in the range of 0 to 110°C, preferably in the range of 0 to 90°C.
  • the duration of the reaction may be in the range of 0.5 to 60 h, preferably in the range of 0.5 to 54 h.
  • the solvent used in the reaction may be seleceted from t-butyl alcohol.
  • the base used in the reaction may be selected from NaH, KH, sodium hexamethyldisilazide (NaHMDS) and the like.
  • the temperature of the reaction may be in the range of 0°C to boiling temperature of the solvent used.
  • the duration of the reaction may be in the range of 1 to 30 h, preferably in the range of 1 to 24 h.
  • the base used in the reaction may be selected from NaH, KH, Na-HMDS and the like.
  • the temperature of the reaction may be in the range of 0 to boiling temperature of the solvent.
  • the duration of the reaction may be in the range of 0.5 to 14 h, preferably in the range of 0.5 to 10 h.
  • the reaction may be carried out in the presence of a solvent such as DMF, THF, chloroform, dichloromethane and the like.
  • the base used in the reaction may be selected from triethylamine, diisopropylethylamine, pyridine and the like.
  • the temperature of the reaction may be in the range of 0 to 120°C, preferably in the range of 0 to 90°C.
  • the duration of the reaction may be in the-range of 0.5 to 24 h, preferably in the range of 0.5 to 20 h.
  • the compound obtained in the first step may be reacted with trifluoiOacetic acid in the presence of a solvent such as dichloromethane, chloroform, THF and the like.
  • the temperature of the reaction may be in the range of 0 to 110°C, preferably in the range of 0 to 90°C.
  • the duration of the reaction may be in the range of 0.5 to 60 h, preferably in the range of 0.5 to 54 h.
  • Another embodiment of the present invention provides 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 1 represents hydroxy group may be carried out by treating with SOCl 2 , PC1 5 , PBr 3 , tetrahalomethane group such as CBr 4 , CC1 4 and the like, in the presence of PPh 3 , P(alkyl) 3 and the like.
  • the reaction may be carried out in the presence of a solvent such as dry dichloromethane, chloroform, tetrachloromethane, benzene, DMF, DMSO, THF and the like.
  • the temperature of the reaction may be maintained in the range of 0 to 60°C, preferably at room temperature.
  • the duration of the reaction may be in the range of 0.5 to 24 hours, preferably 1 to 13h.
  • Still another embodiment of the present invention provides a process for the preparation of a compound of formula (I) where R 1 represents 'SH',
  • the compound of foraiula (Ii) is prepared from compound of foraiula (I) where R 1 represents halogen atom may be prepared by using thiolacetic acid in the presence of a base such as triethylamine, di-isopropylamine, di-isopropylethylamine, pyridine, piperidine, DMAP, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lithium diisopropylamide (LDA), potassium bis-(trimethyl silyl)amide, BuLi, Na 2 CO 3 , K 2 CO 3 , NaOH, KOH, NaOMe, NaOEt, NaOiPr, t-BuOK, NaH, KH and the like.
  • a base such as triethylamine, di-isopropylamine, di-isopropylethylamine, pyridine, piperidine, DMAP, l,8-diazabicyclo[5.4.0
  • the solvent used in the reaction may be seleceted from THF, benzene, dioxane and the like.
  • the temperature of the reaction may be maintained in the range of room temperature to reflux temperature, preferably at reflux temperature.
  • the duration of the reaction may be in the range of 2 to 24 hours, preferably 6 hours.
  • the compound of formula (I), where R represents 'SH' group may be prepared from a compound of formula (Ii) by reacting with a base such as K 2 CO 3 , NaOH, KOH, BuLi and . the like.
  • the reaction may be carried out at a temperature in the range of room temperature to reflux temprature.
  • the duration of the reaction may be in the range of 1 to 24 hours.
  • Still yet another embodiment of the present invention provides a process for the preparation of compound of formula (I), where R 1 represent NHR wherein R 4 represents substituted or unsubstituted -S(O) 2 (Cl-C20)alkyl or -S(O) 2 aryl group, from a compound of formula (I) where R 1 represents NHR 4 where R 4 represents hydrogen atom, (i) reacting the compound of fo ⁇ nula (I),
  • R 1 represents NHR 4 where R 4 represents hydrogen atom and all other symbols are as defined in the description, to a compound of formula (I), where R 1 represents NHR 4 , wherein R 4 represents substituted or unsubstituted group selected from -S(O) 2 -(Cl-C20)alkyl or - S(O) 2 -aryl group and all other symbols are as defined in the description, to a compound of fo ⁇ nula (I).
  • the solvent used may be selected from dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and the like.
  • the temperature of the reaction may be in the range of 0 to 50°C, for a duration of 1 to 6 hours.
  • Another embodiment of the present invention provides a novel intermediate of the fo ⁇ nula (le),
  • A, B, D, Y 1 , Y , R and R J are as defined earlier.
  • Yet another embodiment of the present invention provides a process for the preparation of novel intermediate of formula (le), which comprises: (i) reacting the compound of formula (la)
  • the compound of fo ⁇ nula (lc) may be prepared by reacting a compound of foraiula (la) with a compound of foraiula (lb) by using a base such as KOH, NaOH, K 2 CO 3 , Na 2 CO 3 , NaH, KH, triethylamine, dusopropylethyl amine and the like.
  • the reaction may be earned out using a solvent such as DMSO, DMF, THF, acetonitrile, chloroform, nitrobenzene and the like or mixtures thereof.
  • the reaction may be canied out in inert atmosphere, which may be maintained using inert gases such as N 2 or Ar.
  • the reaction may be canied out at a temperature in the range of 20 to 100°C, preferably at a temperature in the range of ambient - 80°C.
  • the reaction time may range from 1 to 15 hours, preferably from 6 to 12 hours.
  • the reduction of a compoimd of formula (lc) to produce a compound of foraiula (Id) may be canied out in the presence of reducing agents such as NiCl 2 /NaBH , 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 may be canied out in the presence of a solvent such as 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 may be used.
  • the reaction may be canied out at a temperature from 0 to 60°C, preferably at 0 to room temperature.
  • the reaction time ranges from 0.5 to 48 hours, preferably in the range of 0.5 to 5 hours.
  • the reduction may also be canied out by employing metal in mineral acids such Sn/HCl, Fe/HCl, Zn/HCl, Zn/CH 3 CO 2 H and the like.
  • the compound of foraiula (Id) may be converted to a compound of formula (le) by using NaNO 2 in the presence of HCl or CH 3 COOH followed by NaN 3 .
  • the solvent used in the reaction may be selected from methanol, ethanol, ethylacetate, THF, ether, dioxan and the like.
  • the temperature of the reaction may be maintained in the range of -40°C to boiling temperature, preferably in the range of 0°C to room temperature.
  • the duration of the reaction may be in the range of 0.5 to 15 hours, preferably in the range of 0.5 to 5 hours.
  • Another embodiment of the present invention provides a novel intermediate of the foraiula (If),
  • R c represents substituted or unsubstituted (Cl-C20)alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like;
  • A, B, D, Y 1 , Y 2 , R 2 and R 3 are as defined earlier.
  • Yet another embodiment of the present invention provides a process for the preparation of novel intermediate of formula (If), which comprises: (i) reacting the compound of foraiula (la)
  • R c represents substituted or unsubstituted (Cl-C20)alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like;
  • A, B, D, Y 1 , Y 2 , R 2 and R 3 are as defined earlier.
  • the compound of formula (lc) may be prepared by reacting a compound of foraiula (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, dusopropylethyl amine and the like.
  • the reaction may be canied out using a solvent such as DMSO, DMF, THF, acetonitrile, chloroform, nitrobenzene and the like or mixtures thereof.
  • the reaction may be canied out in inert atmosphere, which may be maintained using inert gases such as N 2 or Ar.
  • the reaction may be canied out at a temperature in the range of 20 to 100°C, preferably at a temperature in the range of ambient - 80°C.
  • the reaction time may range from 1 to 15 hours, preferably from 6 to 12 hours.
  • the reduction of a compound of formula (lc) to produce a compound of foraiula (Id) may be canied out in the presence of reducing agents such as 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.
  • reducing agents such as 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.
  • the reduction may be canied out in the presence of a solvent such as 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 may be used.
  • the reaction may be canied out at a temperature from 0 to 60°C, preferably at 0 to room temperature.
  • the reaction time ranges from 0.5 to 48 hours, preferably in the range of 0.5 to 5 hours.
  • the reduction may also be canied out by employing metal in mineral acids such Sn/HCl, Fe/HCl, Zn/HCl, Zn/CH 3 CO 2 H and the like.
  • the compound of foraiula (Id) may be converted to a compound of formula (le) by using NaNO 2 in the presence of HCl or CH 3 COOH followed by NaN 3 .
  • the solvent used in the reaction may be selected from methanol, ethanol, ethylacetate, THF, ether, dioxan and the like.
  • the temperature of the reaction may be maintained in the range of -40°C to boiling temperature, preferably in the range of 0°C to room temperature.
  • the duration of the reaction may be in the range of 0.5 to 15 hours, preferably in the range of 0.5 to 5 hours.
  • the compound of formula (If) may be prepared by heating a compound of formula (le) with esters ((Cl-C20)alkyl or aryl).
  • the solvent used in the reaction may be selected from benzene, toluene, xylene, acetonitrile, THF and the like.
  • the temperature of the reaction may be maintained in the range of 0 to 200°C, preferably in the range of room temperature to boiling temperature of the solvent.
  • the duration of the reaction may be in the range of 2 to 25 ' hours, preferably 3 to 15 hours.
  • Another embodiment of the present invention provides a novel intermediate of the formula (Ig),
  • Yet another embodiment of the present invention provides a process for the preparation of novel intermediate of foraiula (Ig), which comprises: (i) converting the compound of formula (If) where R c represents substituted or unsubstituted (Cl-C20)alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like; A, B, D, Y 1 , Y 2 , R 2 and R 3 are as defined earlier, to a compound of formula (Ig)
  • the conversion of compound of formula (If) to a compound of formula (Ig) may be canied out in the presence of ammonia solution in water or alcohol.
  • the temperature of the reaction may be in the range of -40 to 50°C, preferably of 0°C to room temperature.
  • the duration of the reaction may be in the range of 0.5 to 12 hours, preferably 0.5 to 4 hours.
  • Another embodiment of the present invention provides a novel intermediate of the fo ⁇ nula (Ij),
  • Still yet another embodiment of the present invention provides a process for the preparation of novel intennediate of foraiula (Ij), which comprises: (i) converting the compound of foraiula (le), where Z, Y 1 , Y 2 , Y 3 , R 2 and R 3 are as defined earlier, with
  • the compound of formula (Ij) may be prepared by reacting the compound of formula (le) with a compound of formula (H ), in the presence of a base such as triethylamine, ethyldiisopropylamine, DABCO and the like.
  • a base such as triethylamine, ethyldiisopropylamine, DABCO and the like.
  • the reaction may be canied out in the presence of a solvent such as dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile and the like.
  • the reaction may be canied out in the presence ofCu (I)I.
  • 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 pharaiaceutical 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 foraiula (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
  • 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.
  • compositions may be in the forms no ⁇ nally employed, such as tablets, capsules, powders, dispersib ' le granules, cachets, suppositories, syraps, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid caniers 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 pharaiaceutically acceptable carriers, diluents or solvents.
  • Suitable pharmaceutically acceptable caniers 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, syraps, 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 fonn 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 pha ⁇ naceutically-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 fo ⁇ nula (I) or pharaiaceutical 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 prefened, being more convenient and avoiding the possible pain and initation of injection. However, in circumstances where the patient cannot swallow the medication, or absorption 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.
  • a pharmaceutically acceptable gel or cream vehicle 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.
  • reaction mixture was diluted with cold water (100 mL) and extracted with ethyl acetate (100 mL x ' 3). The combined ethyl acetate extracts were washed with water followed by brine and dried over sodium sulfate. Evaporation of volatiles on rotavapor yielded the title compounds (mixture of regioisomers) as yellow oil (10 g, 76%).
  • reaction mixture was then poured onto crushed ice and the resulting solid was filtered.
  • Triethyl amine (1.24 grains, 12.20 mmol) was added to a solution of [l-(3-fluoro-4- pyrazol-l-ylphenyl)-lH-[l,2,3]triazol-4-yl]-methanol & [l-(3-fluoro-4-pyrazol-l-ylphenyi)- lH-[l,2,3]triazol-5-yl]-methanol (1.60 grams, 6.17 mmol), obtained in preparation 32, in dichoromethane (30 mL) followed by the addition of methanesulfonyl chloride (1.05 grams, 9.20 mmol) at 0 °C and stined for 1 hours.
  • This compound was prepared by following the procedure as described in prepration
  • This compound was prepared by following the procedure as described in prepration
  • This compound was prepared by following the procedure as described in prepration 41.
  • This compound was prepared by following the procedure as described in prepration
  • This compound was prepared by following the procedure as described in prepration
  • This compound was prepared by following the procedure as described in prepration
  • reaction mixture was then diluted with ethyl acetate (50 mL) and aqueous layer was separated. The organic layer was washed with water followed by brine and dried over sodium sulfate. Evaporation of volatiles on rotavapor and purification of the resulting residue through silica gel column (ethyl acetate/ pet ether, 1 :2) yielded the title compound as light brown solid (34 mg, 25%).
  • aqueous layer was then extracted with ethyl acetate (50 mL x 2) and the combined extracts were washed with water followed by brine. After drying over sodium sulfate, ethyl acetate was removed on rotavapor and the resulting residue was purified through a silica gel column (ethyl acetate/pet ether: 2:1) to yield the title compound as light brown solid (79 mg, 50%).
  • aqueous layer was then extracted with ethyl acetate (50 mL x 2) and the combined extracts were washed with water followed by brine. After drying over sodium sulfate, ethyl acetate was removed on rotavapor and the resulting residue was purified by passing through a silica gel column (ethyl acetate/pet ether: 1 :1) to yield the title compound as light brown solid (169 mg, 81%).
  • the blue colour solution was diluted with ethyl acetate (100 mL) and aqueous layer was separated. The organic layer was washed with water followed by brine and dried over sodium sulfate, Evaporation of volatiles on rotavapor and purification of the residue by silica gel column chromatography yielded the pink color compound (245 mg, 30 %).
  • reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined extracts were washed with water followed by brine and dried over sodium sulfate. Evaporation of volatiles and purification of the resulting residue by column chromatography yielded the required regioisomer as pale yellow solid (800 mg, 55%).
  • Example 1 l-[3-Fluoro-4-pyrazol-l-yl-phenyl]-lH-[l,2,3]triazol-4-yl-methylamino-hydrazino methanethione:
  • reaction mixture was then diluted with ethyl acetate (100 mL) and the aqueous layer was separated. The organic phase was washed with water followed by brine and dried over sodium sulfate. Evaporation of volatiles and purification of the resulting residue through a silica gel column yielded the title compound as white powder (105 mg, 28%). Mp. 223 °C.
  • the blue colour solution was diluted with ethyl acetate (100 mL) and aqueous layer was separated. The organic layer was washed with water followed by brine and dried over sodium sulfate. Evaporation of volatiles on rotavapor and purification of the resulting residue through silica gel column yielded the white color compound (300 mg, 40 %). Mp.
  • Example 29 ⁇ l-[4-(4-Cyano-imidazoI-l-yl)-3-fluoro-phenyl]-lH-[l,2,3]triazol-4-ylmethyl ⁇ - thiocarbamic acid O-methyl ester
  • the title compound was prepared from l-(4-azido-2-fluoro-phenyl)-lH-imidazole-4- carbonitrile (230 mg, 1.0 mmol) following the procedure described in example 10 (yield, 150 mg, 40%).
  • This compound was prepared by following the procedure as described in Example 10.
  • MICs Minimum Inhibiton Concentrations
  • 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 ⁇ 01
  • 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 8 CFU/ml. The stock was further diluted in sterile broth to obtain 1-2 X IO 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.

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Abstract

La présente invention concerne de nouveaux composés de triazole de formule (I), leurs sels pharmaceutiquement acceptables et leurs compositions pharmaceutiques. Dans ladite formule, tous les symboles ont les significations définies dans la description. Ces composés s'utilisent dans le traitement des infections bactériennes.
PCT/IB2004/001303 2003-04-29 2004-04-29 Derives anti-infectieux de 1,2,3-triazole, leur procede de preparation et compositions pharmaceutiques les contenant WO2004101531A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
ITMI20131180A1 (it) * 2013-07-15 2015-01-16 Fond Istituto Italiano Di Tecnologia O-alchil triazolil carbammati come inibitori di idrolasi delle ammidi degli acidi grassi (faah)
US9073875B2 (en) 2012-11-20 2015-07-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
US9221756B2 (en) 2011-12-05 2015-12-29 University Of Leicester Pyrrole derivatives
US20160083356A1 (en) * 2009-03-11 2016-03-24 Isp Investments Inc. Functionalized 4- and 5-vinyl substituted regioisomers of 1, 2, 3-triazoles via 1, 3- dipolar cycloaddition and polymers thereof
US9540351B2 (en) 2013-09-18 2017-01-10 Axikin Pharmaceuticals, Inc. Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors
US9546163B2 (en) 2014-12-23 2017-01-17 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors

Citations (1)

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Publication number Priority date Publication date Assignee Title
GB1044145A (en) * 1963-03-14 1966-09-28 Ciba Ltd New sulphonamides and process for preparing same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1044145A (en) * 1963-03-14 1966-09-28 Ciba Ltd New sulphonamides and process for preparing same

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7696352B2 (en) 2004-06-18 2010-04-13 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US8153670B2 (en) 2004-06-18 2012-04-10 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US8377974B2 (en) 2004-06-18 2013-02-19 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US7521470B2 (en) 2004-06-18 2009-04-21 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US7763608B2 (en) 2006-05-05 2010-07-27 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US7767697B2 (en) 2006-05-05 2010-08-03 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US8063077B2 (en) 2006-05-05 2011-11-22 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
US8349873B2 (en) 2006-05-05 2013-01-08 Millennium Pharmaceuticals, Inc. Factor XA inhibitors
US20160083356A1 (en) * 2009-03-11 2016-03-24 Isp Investments Inc. Functionalized 4- and 5-vinyl substituted regioisomers of 1, 2, 3-triazoles via 1, 3- dipolar cycloaddition and polymers thereof
US10093633B2 (en) * 2009-03-11 2018-10-09 Isp Investments Llc Functionalized 4- and 5-vinyl substituted regioisomers of 1, 2, 3-triazoles via 1, 3-dipolar cycloaddition and polymers thereof
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
US9221756B2 (en) 2011-12-05 2015-12-29 University Of Leicester Pyrrole derivatives
US9073875B2 (en) 2012-11-20 2015-07-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
US9499497B2 (en) 2012-11-20 2016-11-22 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
ITMI20131180A1 (it) * 2013-07-15 2015-01-16 Fond Istituto Italiano Di Tecnologia O-alchil triazolil carbammati come inibitori di idrolasi delle ammidi degli acidi grassi (faah)
US9540351B2 (en) 2013-09-18 2017-01-10 Axikin Pharmaceuticals, Inc. Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors
US9546163B2 (en) 2014-12-23 2017-01-17 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
US9730914B2 (en) 2014-12-23 2017-08-15 Axikin Pharmaceuticals 3,5-diaminopyrazole kinase inhibitors

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