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WO2017168451A1 - Dérivés d'imidazole et de benzimidazole, leur procédé de préparation et leur utilisation - Google Patents

Dérivés d'imidazole et de benzimidazole, leur procédé de préparation et leur utilisation Download PDF

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WO2017168451A1
WO2017168451A1 PCT/IN2017/050122 IN2017050122W WO2017168451A1 WO 2017168451 A1 WO2017168451 A1 WO 2017168451A1 IN 2017050122 W IN2017050122 W IN 2017050122W WO 2017168451 A1 WO2017168451 A1 WO 2017168451A1
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Prior art keywords
imidazole
mmol
thione
formula
derivatives
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WO2017168451A4 (fr
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Gouriprasanna ROY
Mainak BANERJEE
Ramesh Karri
Ashish CHALANA
Ranajit Das
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Shiv Nadar University
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Shiv Nadar University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/28—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2

Definitions

  • the present invention relates to the field of chemistry, In particular, to the derivatives of imidazole and benzimidazole based thiones and selones. Further the present invention provides the process of preparation of the said derivatives and their use in the degradation of various toxic mercury related compounds and other heavy metals such as lead (Pb), arsenic (As), cadmium (Cd) and copper (Cu).
  • Pb lead
  • As arsenic
  • Cd cadmium
  • Cu copper
  • HgS mercury sulfide
  • HgSe mercury selenide
  • bacteria with broad spectrum mercury resistance encoded by the mer operon, convert MeHg + into volatile Hg(0) by the sequential action of two enzymes, organomercurial lyase (MerB) and mercuric reductase (MerA).
  • MerB cleaves the otherwise inert C-Hg bond of MeHg + to CH 4 and Hg(ll), which is further reduced to volatile Hg(0) by MerA.
  • HgS can be formed by various mechanisms.
  • D. desulfuricans under sulphate-reducing conditions resulted in the precipitation of HgS when the medium is treated with HgCl 2 .
  • HgS hydrogen sulfide
  • Imidazole (1, 3 diazole) is a heterocyclic five-member ring system containing an imino group and a tertiary nitrogen atom with a molecular formula C3H4N2, discovered in the year 1859 by reacting glyoxal and ammonia. It is an aromatic, amphoteric and highly polar compound soluble in water and other polar solvents. Imidazole has numerous application in varied fields including protein purification, pharmaceuticals, fungicides and antifungal, antiprotozoal, and antihypertensive medications, corrosion inhibitor, photography, electronics and forms a part of many biological molecules such as histidine, theophylline molecule etc.
  • Benzimidazole is a heterocyclic aromatic organic compound, bicyclic in nature, containing a benzene ring fused at the 4,5-positions of the imidazole ring.
  • the most prominent benzimidazole compound in nature is N-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12.
  • Imidazole and Benzimidazole derivatives possesses many pharmacological properties in diverse therapeutic applications such as anti-ulcers, anti-hypertensives, anti-bacterial, anti-inflammatory, anti-analgesic, anti-virals, anti-fungals, anti-cancers and anti-histaminics.
  • benzimidazole derivatives are condensed with other heterocycles like pyrazole, thiadiazole, triazole, thiazole, coumarin and 2-azetidinone moieties which have shown diverse pharmacological activities.
  • 583/MUM/2010 provides novel lmidazolidine-2-thione and lmidazole-2-thione derivatives having pharmaceutical or non-pharmaceutical use and also provides synthetic methods for preparation of said compounds.
  • US20000424934 relates to benzimidazole derivatives and their use in medical therapy particularly for the treatment or prophylaxis of virus infections such as those caused by herpes viruses. It also relates to the preparation of the benzimidazole derivatives and pharmaceutical formulations containing them.
  • 2596/DEL/2007 discloses benzimidazole compounds and their use as chromatographic ligands.
  • Solid phase matrix formed by linking certain substituted benzimidazole ligand to a solid phase material, is utilized for the isolation and/or purification of immunoglobulins with high efficiency and with special advantages with respect to the use of little or no salts.
  • the present invention provides the derivatives of imidazole and benzimidazole based thiones and selones and method of preparation thereof. Further the present invention also provides the use of the said derivatives in the degradation of various toxic mercury related compounds and other heavy metals such as lead (Pb), arsenic (As), cadmium (Cd) and copper (Cu).
  • Pb lead
  • As arsenic
  • Cd cadmium
  • Cu copper
  • HgX2 organomercurials
  • Another objective of the present invention is to provide the process of preparation of the said imidazole and benzimidazole-based thione and selone derivatives.
  • Yet another objective of the present invention is to provide the method for detoxification of various heavy metals including mercury, lead (Pb), arsenic (As), cadmium (Cd) and copper (Cu) and salts thereof using the said imidazole and benzimidazole-based thione and selone derivatives .
  • Final objective of the present invention is to use the said imidazole and benzimidazole- based thione and selone derivatives for degrading various other heavy metals such as lead (Pb), arsenic (As), cadmium (Cd) and copper (Cu) and salts thereof.
  • the present invention provides the derivatives of imidazole and benzimidazole based thiones and selones according to formula 1 and formula 2 :
  • Hg + methyl mercury
  • EtHg + ethyl mercury
  • PhHg + phenyl mercury
  • the present invention also provides the process of preparation of the said derivatives of imidazole and benzimidazole based thiones and selones, comprising of : treating the substituted or un-substituted imidazole/benzimidazole with halides (RX) in organic solvents to produce the derived imidazolium/benimidazolium salt; reacting the resulting salt with elemental sulfur or selenium for producing the corresponding thiones or selones, wherein, during the reaction, the deprotonation of imidazolium/benimidazolium salts by the base results in an in situ generation of reactive carbenes, which reacts with elemental sulfur or selenium to form the corresponding thiones or selones.
  • RX halides
  • the present invention provides the method of degradation of various toxic heavy metals including mercury, lead, arsenic, cadmium and copper into a less toxic and stable for, using the said derivatives comprises of: mixing the required amount of the derivative of imidazole/ benzimidazole based thiones/selones with the salt of heavy metal; adding required quantity of solvent; optionally adding required amount of base; and stirring the resulting mixture for predetermined time at suitable temperature for complete degradation of the salts of heavy metals, resulting in a black precipitate.
  • the said derivatives have better degradation activity under physiologically and environmentally relevant conditions as well as greater acceptability in a wide range of bases.
  • the present invention provides derivatives of imidazole and benzimidazole-based thiones and selones according to formula 1 and formula 2
  • heterocyclic hydroxyl, carboxyl, amide, amine, thiol, triphenylphosphonium.
  • R2 is selected from group consisting of hydrogen, alkyl, aryl, alkyl aryl, cycloalkyl, heterocyclic, hydroxyl, carboxyl, amide, amine, thiol.
  • R3 is selected from group consisting of hydrogen, alkyl, aryl, alkyl aryl, cycloalkyl, heterocyclic, hydroxyl, carboxyl, amide, amine, thiol.
  • R4 is selected from group consisting of hydrogen, alkyl, aryl, alkyl aryl, cycloalkyl, heterocyclic, hydroxyl, carboxyl, amide, amine.
  • E is selected from group consisting of sulfur, selenium. n ranges from 0 to 4, and m ranges from 0 to 14.
  • said compound is a derivative of imidazole based thione, wherein said element E is sulfur (S).
  • said compound is a derivative of imidazole based selones, wherein said element E is selenium (Se).
  • said compound is a derivative of benzimidazole based thione, wherein said element E is sulfur (S).
  • the compound is a derivative of benzimidazole based selones, wherein said element E is selenium (Se).
  • the present invention also relates to suitable salts of such compounds.
  • the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers. In addition tautomeric forms of compounds are also encompassed by the present invention.
  • the process of synthesizing the derivatives of formula 1 comprises of : treating the substituted or un-substituted imidazole with halides (RX) in organic solvents to produce the derived imidazolium salt; reacting the resulting imidazolium salt with elemental sulfur or selenium for producing the corresponding thiones or selones, wherein, during the reaction, the deprotonation of imidazolium salts by the base, leads to an in situ generation of reactive carbenes, which reacts with elemental sulfur or selenium to produce the corresponding thiones or selones.
  • RX halides
  • the process of synthesizing the derivatives of formula 2 comprises of : treating the substituted or un-substituted benzimidazole with halides (RX) in organic solvents to produce the derived benzimidazolium salt; reacting the resulting salt with elemental sulfur or selenium for producing the corresponding thiones or selones, wherein, during the reaction, the deprotonation of benzimidazolium salts by the base, leads to an in situ generation of reactive carbenes, which reacts with elemental sulfur or selenium to produce the corresponding thiones or selones.
  • RX halides
  • halides is selected from elements or radicals consisting of halogens such as chlorine, iodine, fluorine and/or bromine.
  • organic solvent is selected from group consisting of, but not limited to, ethyl acetate, tetrahydrofuran, dichloromethane, acetone, ethyl acetate, hexane, acetone, acetonitrile, dimethyl formamide, dimethy sulfoxide, nitromethane, diethyl ether, chloroform, 1 ,4 -dioxane, toluene, trimethylamine combinations and/or mixtures thereof.
  • the compound of formula 1 and formula 2 could be prepared by various schemes as describe below: i) Scheme A for synthesizing the derivatives of the compounds of formula 1 and formula 2 is,
  • HgX2 toxic mercuric compounds
  • HgS mercury sulfide
  • HgSe mercury selenide
  • the compounds of present invention have general formula
  • the derivatives of the present invention are used in degradation of toxic, soluble and volatile mercury and mercury related compounds to stable, insoluble and less toxic mercury sulfide and mercury selenide.
  • the derivatives of the present invention are also used in detoxification of other heavy metals such as lead (Pb), arsenic (As), cadmium (Cd) and copper (Cu).
  • method of degradation of various toxic heavy metals comprises of: mixing the required amount of the derivative of imidazole/ benzimidazole based thiones/selones with the salt of heavy metal; adding required quantity of solvent; optionally adding required amount of base; and stirring the resulting mixture for predetermined time at suitable temperature for complete degradation of the salts of heavy metals, resulting in a black precipitate.
  • said heavy metals includes but not limited to mercury (Hg) particularly organomercurials, lead (Pb), arsenic (As), cadmium (Cd), copper (Cu) and salts thereof.
  • said solvent is selected from group consisting of, but not limited to, water, acetonitrile, phosphate buffer, ethanol, methanol, isopropanol, butanol, ethyl acetate combinations and/or mixtures thereof.
  • said base is a strong base selected from group consisting of, but not limited to, KOH, KOt Bu , NaOMe, NaOH, Ca(OH) 2 , Mg(OH) 2 , Ba(OH) 2 , NaHC03, K2HPO4, imidazole, histidine and combinations and/or mixtures thereof.
  • said black precipitate is a DE
  • said D is selected from mercury, lead, arsenic, cadmium, copper and salts thereof, wherein said E is S or Se.
  • imidazole- based thione and selones when treated with one equivalent of RHgCI in water/acetonitrile at 37°C results in the formation of the corresponding 1 :1 mercury conjugated compounds with chloride ion as a counter anion (as shown in B) and very small amounts of choloro- adducts (4-6%); thiones and selones mediates the protolytic cleavage of Hg-C bond leading to the decomposition of 1 :1 mercury conjugated compounds (B) and the subsequent formation of ketone and the corresponding HgE nanoparticles under alkaline condition, wherein complete degradation of the corresponding 1 :1 mercury conjugated complex is enabled in the presence of the strong base.
  • Step 1 To the solution of 2-bromoethanamine hydrobromide (3 g 14.64 mmol) in THF (100 ml), 3.7 ml of trimethylamine (26.35 mmol) is added and the resulting reaction mixture is stirred for half an hour, then catalytic amount of 2-methylaminopyridine is added to the reaction mixture. Finally, in ice cold condition 4.93 ml of Boc-anhydride is added in a drop wise manner and the reaction mixture is stirred for overnight. Now slowly, the reaction mixture is quenched with ammonium chloride and extracted with ethyl acetate. The combined organic phase is washed with brine and finally dried over anhydrous Na2S0 4 .
  • Step 2 To the solution of 1 -methyl-1 H-imidazole (0.5 g 6.09 mmol) in freshly distilled THF (20 ml), tert-butyl (2-bromoethyl)carbamate, (1.36 g 6.09 mmol) is added at room temperature and the resulting reaction mixture is allowed to reflux at 75°C for 12 hours to produce a brownish solid.
  • reaction progress is monitored by TLC (In ethyl acetate the desired spot is in the baseline). After completion of reaction, the reaction mixture is evaporated to dryness. All the non-polar impurities are washed by using 50 % ethyl acetate/hexane solution then it is dried in vacuum pump and the resulting salt is 3-(2-((tert- butoxycarbonyl)ami no)ethyl)- 1 -methyl-1 H-imidazol-3-ium bromide.
  • Step 3 The imidazolium bromide salt is taken in a 100 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (50 mL), sulfur powder (0.2923g, 9.13 mmol) and anhydrous potassium carbonate (1.26 g, 9.13mmol) under N2 atmosphere. The reaction mixture is allowed for reflux at 75 °C for 20 h. The solution is then filtered through Celite 450.
  • Boc protected product is purified by column chromatography packed with silical 00-200 mesh and ethyl acetate /hexane is used as mobile phase (Rf 0.6 in 70 % ethyl acetate/hexane). The compound is obtained as a brownish solid upon cooling at 4 °C.
  • Step 4 To de-protect the Boc group, the solid compound (500 mg, 1.94 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (48.6 mmol 48.6 ml ) is added portion wise into it and resulting solution is stirred for overnight. After that the reaction mixture is completely dried in vacuum and the crude product is purified by column chromatography packed with silical 00-200 mesh and MeOH/DCM is used as mobile phase (R f 0.2 in 20 % MeOH/DCM). The compound (1-(2-aminoethyl)-3-methyl-1 H-imidazole-2(3H)-thione) (GP001), is obtained as a brownish solid in room temperature.
  • Step 1 To the 3-(2-((tert-butoxycarbonyl)amino)ethyl)-1 -methyl-1 H-imidazol-3-ium bromide salt, dry methanol (50 mL), selenium powder (0.720 g, 9.13 mmol) and anhydrous potassium carbonate (1.26 g, 9.13 mmol) were added. The reaction mixture is allowed to reflux for 20 h under inert atmosphere. The solution is then filtered in hot condition through Celite 450. Filtrate is evaporated under reduced pressure to yield crude product of 9 which is purified by column chromatography packed with silica, and ethyl acetate/hexane is used as mobile phase.
  • Step 2 To de-protect the Boc group, the solid compound (500 mg, 1.64 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (41 mmol 41 ml ) is added portion wise into it and resulting solution is stirred for overnight. After that the reaction mixture is completely dried in vacuum and the crude product is purified by column chromatography packed with silical 00-200 mesh and MeOH/DCM is used as mobile phase (R f 0.2 in 20 % MeOH/DCM). The compound 1 -(2-aminoethyl)-3-methyl-1 H-imidazole-2(3H)-selenone (GP002), is obtained as a yellow solid in room temperature. Yield: 0.33 g.
  • Step 1 NaH (1.76 g, 44.05 mmol) is taken in 250 mL two necked round bottom flask and dispersed in dry THF (50 mL) in the nitrogen atmosphere. Imidazole (2 g, 29.37 mmol) is dissolved dry THF (50 mL) and added to the NaH dispersed solution drop by drop at 0 °C then mixture brought to room temperature and stirred for half an hour. After half an hour of stirring, addition of Ethyl bromide (4.16 g, 2.84 ml, 38.19 mmol,) is done drop by drop to this mixture at 0 °C and stirred for 6 h.
  • the product 1 -ethyl-1 H-imidazole is extracted using 150 mL ethylacetate. Product is purified through column chromatography in ethylacetate/hexane as mobile phase (0.4 %). The product 1 -ethyl-1 H-imidazole is obtained as a white solid (50) and used for further step.
  • Step 2 Now to a solution of 1 -ethyl-1 H-imidazole (1 g, 10.40 mmol) in freshly distilled THF (20 ml) Boc-protected ethylamine, tert-butyl (2-bromoethyl)carbamate (2.33 g 10.40 mmol), is added at room temperature and the resulting reaction mixture is allowed to reflux at 75°C for 12 hours to produce a brownish solid. The reaction progress is monitored by TLC (In ethyl acetate the desired spot is in the baseline). After completion of reaction, the reaction mixture is evaporated to dryness.
  • Step 3 The salt, 3-(2-((tert-butoxycarbonyl)amino)ethyl)-1-ethyl-1 H-imidazol-3-ium bromide, is taken in a 250 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (150mL), sulfur powder (0.0.499g, 15.60 mmol) and anhydrous potassium carbonate (2.15 g, 15.60mmol) under N2 atmosphere. The reaction mixture is allowed for reflux at 75 °C for 20 h. The solution is then filtered through Celite 450.
  • Step 3 To de-protect the Boc group, the solid compound (500 mg, 1.64 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (41 mmol 41 ml ) is added portion wise into it and resulting solution is stirred for overnight.
  • Step 1 The salt, 3-(2-((tert-butoxycarbonyl)amino)ethyl)-1-ethyl-1 H-imidazol-3-ium bromide is taken in a 250 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (100 mL), selenium powder (1.23 g, 15.6 mmol) and anhydrous potassium carbonate (2.15 g, 15.6 mmol) were added. The reaction mixture is allowed to reflux for 20 h under inert atmosphere. The solution is then filtered in hot condition through Celite 450.
  • Step 2 The Boc group is removed using the following procedure mentioned in the synthesis procedure of GP001.
  • Step 1 NaH is taken in 250 mL two necked round bottom flask (1.0 g, 44.0 mmol) and dispersed in dry THF (50 mL) in the nitrogen atmosphere. Imidazole (2 g, 29.37 mmol) is dissolved dry THF (50 mL) and added to the NaH dispersed solution drop by drop at 0 °C then mixture brought to room temperature and stirred for half an hours. After half an hour of stirring, addition of benzyl bromide (6.13 g, 4.26 ml, 35.25 mmol,) is done drop by drop to this mixture at 0 °C and stirred for 6 h. The desired product is extracted using ethyacetate.
  • Step 2 To a solution of 1 -benzyl-1 H-imidazole (1 g, 6.32 mmol) in freshly distilled THF (20 ml) tert-butyl (2-bromoethyl)carbamate (2.33 g 10.40 mmol), is added at room temperature and the resulting reaction mixture is allowed to reflux at 75°C for 12 hours to produce a brownish solid. The reaction progress is monitored by TLC (In ethyl acetate the desired spot is in the baseline).
  • reaction mixture is evaporated to dryness. All the non-polar impurities are is washed by using 50 % ethyl acetate/hexane solution then it is dry in vacuum pump and the resulting salt is 1 -benzyl-3-(2-((tert- butoxycarbonyl)amino)ethyl)-1 H-imidazol-3-ium bromide.
  • Step 3 The resulting salt 1 -benzyl-3-(2-((tert-butoxycarbonyl)amino)ethyl)-1 H-imidazol-3- ium bromide is taken in a 250 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (150mL), sulfur powder (0.0.499g, 15.60 mmol) and anhydrous potassium carbonate (2.15 g, 15.60mmol) under N2 atmosphere. The reaction mixture is allowed for reflux at 75 °C for 20 h. The solution is then filtered through Celite 450.
  • Step 4 To de-protect the Boc group, the solid compound (500 mg, 1.64 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (41 mmol 41 ml ) is added portion wise into it and resulting solution is stirred for overnight. After that the reaction mixture is completely dried in vacuum and the crude product is purified by column chromatography packed with silical 00-200 mesh and MeOH/DCM is used as mobile phase (R f 0.2 in 20 % MeOH/DCM).. The compound 1 -(2-aminoethyl)-3-benzyl-1 H-imidazole-2(3H)-thione (GP005), is obtained as a brownish solid in room temperature. Yield: 0.3g (86%).
  • Example 6 Synthesis of 1 -(2-aminoethyl)-3-benzyl-1 H-imidazole-2(3H)-selenone (GP006)
  • Step 1 The resulting salt 1 -benzyl-3-(2-((tert-butoxycarbonyl)amino)ethyl)-1 H-imidazol-3- ium bromide is taken in a 250 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (100 mL), selenium powder (1.23 g, 15.6 mmol) and anhydrous potassium carbonate (2.15 g, 15.6 mmol) were added. The reaction mixture is allowed to reflux for 20 h under inert atmosphere. The solution is then filtered in hot condition through Celite 450. Filtrate is evaporated under reduced pressure to yield Boc- protected crude product which is purified by column chromatography packed with silica, ethyl acetate/hexane as mobile phase (70%).The desired product is obtained as a white crystalline solid.
  • Step 2 To de-protect the Boc group, the solid compound (500 mg, 1.64 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (41 mmol 41 ml ) is added portion wise into it and resulting solution is stirred for overnight. After that the reaction mixture is completely dried in vacuum and the crude product is purified by column chromatography packed with silical 00-200 mesh and MeOH/DCM is used as mobile phase (R f 0.2 in 20 % MeOH/DCM). The compound 1 -(2-aminoethyl)-3-benzyl-1 H-imidazole-2(3H)-selenone (GP006), is obtained as a yellow solid in room temperature. Yield: 0.32 g (89 %).
  • Example 7 Synthesis of 1 -(3-aminopropyl)-3-methyl-1 H-imidazole-2(3H)-thione (GP011)
  • Step 1 In a solution of 3-bromopropan-1 -amine hydrobromide (1.00 g, 0.46 mmol) in THF (40ml) trimethylamine (1 ml, 0.58 mmol) is added and the resulting reaction mixture is stirred for half an hour, then catalytic amount of 2-methylaminopyridine is added into the reaction mixture. Finally, in ice cold condition 1.23 ml of Boc anhydride is also added into it, in a dropwise manner and the reaction mixture is stirred for overnight. Now slowly, the reaction mixture is quenched with ammonium chloride and extracted with ethyl acetate. The combined organic phase is washed with brine and finally dried over anhydrous Na2S0 4 .
  • the crude product is further purified by flash chromatography by using 60-120 mesh silica gel and ethyl acetate/hexane as mobile phase.
  • the product tert-butyl (3- bromopropyl)carbamate is obtained as a yellowish solid upon cooling at 4 °C (Yield: 0.9 g (83%))
  • Step 2 To a solution of 1 -methyl-1 H-imidazole (0.5 g, 6.1 mmol) in freshly distilled THF (50 ml) tert-butyl (3-bromopropyl)carbamate (1.45 g, 6.1 mmol) is added at room temperature and the resulting reaction mixture is allowed to reflux at 75°C for 12 hours to produce a brownish solid. The reaction progress is monitored by TLC (In ethyl acetate the desired spot is in the baseline). After completion of reaction, the reaction mixture is evaporated to dryness.
  • Step 3 The resulting salt, 3-(3-((tert-butoxycarbonyl)amino)propyl)-1 -methyl-1 H-imidazol- 3-ium bromide, is taken in a 100 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (25 mL), sulfur powder (0.29 g, 9.13 mmol) and anhydrous potassium carbonate (1.26 g, 9.1 mmol) under N2 atmosphere. The reaction mixture is allowed for reflux at 75 °C for 20 h. The solution is then filtered through Celite 450.
  • Step 4 To remove Boc group, the solid Boc-protected compound (500 mg, 1.57 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (39.3 mmol 39.3 ml ) is added portion wise into it and resulting solution is stirred for overnight. After that the reaction mixture is completely dried in vacuum and the crude product is purified by column chromatography packed with silical 00-200 mesh and MeOH/DCM is used as mobile phase (R f 0.2 in 20 % MeOH/DCM). The product 1 -(3-aminopropyl)-3-methyl-1 H-imidazole-2(3H)-thione (GP01 1 ), is obtained as a brownish solid in room temperature. Yield: 0.34 g.
  • Example 8 Synthesis of 1 -(3-aminopropyl)-3-methyl-1 H-imidazole-2(3H)-selenone (GP012)
  • Step 1 The resulting salt, 3-(3-((tert-butoxycarbonyl)amino)propyl)-1 -methyl-1 H-imidazol- 3-ium bromide, is taken in a 100 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (20 mL), selenium powder (0.72 g, 9.13 mmol) and anhydrous potassium carbonate (1.26 g, 9.13 mmol) were added. The reaction mixture is allowed to reflux for 20 h. The solution is then filtered in hot condition through Celite.
  • Step 2 To de-protect the Boc group, the solid compound (500 mg, 1.64 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (41 mmol 41 ml ) is added portion wise into it and resulting solution is stirred for overnight.
  • Step 1 Now to a solution of 1 -ethyl-1 H-imidazole (1 g, 10.40 mmol) in freshly distilled THF (50 ml) tert-butyl (3-bromopropyl)carbamate (1.45 g, 6.09 mmol) is added at room temperature and the resulting reaction mixture is allowed to reflux at 75°C for 12 hours to produce a brownish solid. The reaction progress is monitored by TLC (In ethyl acetate the desired spot is in the baseline). After completion of reaction, the reaction mixture is evaporated to dryness.
  • Step 2 The resulting salt, 3-(3-((tert-butoxycarbonyl)amino)propyl)-1 -ethyl-1 H-imidazol-3- ium bromide, is taken in a 100 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (25 mL), sulfur powder (0.292 g, 9.13 mmol) and anhydrous potassium carbonate (1.26 g, 9.13mmol) under N2 atmosphere. The reaction mixture is allowed for reflux at 75 °C for 20 h. The solution is then filtered through Celite 450.
  • Step 3 To de-protect the Boc group, the solid compound (500 mg, 1.64 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (41 mmol 41 ml ) is added portion wise into it and resulting solution is stirred for overnight.
  • Step 1 The resulting salt, 3-(3-((tert-butoxycarbonyl)amino)propyl)-1-ethyl-1 H-imidazol-3- ium bromide, is taken in a 100 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (20 mL), selenium powder (0.720 g, 9.13 mmol) and anhydrous potassium carbonate (1.26 g, 9.13 mmol) were added. The reaction mixture is allowed to reflux for 20 h. The solution is then filtered in hot condition through Celite.
  • Step 2 To de-protect the Boc group, the solid compound (500 mg, 1.64 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (41 mmol 41 ml ) is added portion wise into it and resulting solution is stirred for overnight. After that the reaction mixture is completely dried in vacuum and the crude product is purified by column chromatography packed with silical 00-200 mesh and MeOH/DCM is used as mobile phase (R f 0.2 in 20 % MeOH/DCM). The product 1 -(3-aminopropyl)-3-ethyl-1 H-imidazole-2(3H)-selenone (GP014), is obtained as a yellow solid in room temperature. Yield: 0.33 g.
  • Step 1 In a 250 ml two necked round bottom flask NaH (1.76 g, 35.25 mmol) is taken and dispersed in dry THF (40 mL) at 0 °C under nitrogen atmosphere. Imidazole (2 g, 29.37 mmol) dissolved in dry THF (40mL) is added to in drop wise manner at 0 °C and the resulting mixture is left to stir for half an hour, tert-butyl (2-bromoethyl)carbamate (8.39 g, 35.25 mmol) is added drop by drop to this mixture at 0 °C and stirred for 8 h. TLC of reaction mixture confirms complete consumption of starting material.
  • Step 2 To a solution tert-butyl (2-(1 H-imidazol-1 -yl)ethyl)carbamate (1 g, 4.73 mmol) in freshly distilled THF (20 ml) tert-butyl (2-bromoethyl)carbamate (1.15 g 4.73 mmol) is added at room temperature and the resulting reaction mixture is allowed to reflux at 75°C for 12 hours to produce a brownish solid. The reaction progress is monitored by TLC. After completion of the reaction, the reaction mixture is evaporated to dryness.
  • Step 3 The resulting ,3-bis(2-((tert-butoxycarbonyl)amino)ethyl)-1 H-imidazol-3-ium bromide salt is taken in a 100 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (50 mL), sulfur powder (0.227 g, 7.10 mmol) and anhydrous potassium carbonate (0.981 g, 7.10mmol) under N2 atmosphere. The reaction mixture is allowed for reflux at 75 °C for 20 h. The solution is then filtered through Celite 450.
  • Step 4 To de-protect the Boc group, the solid compound (500 mg, 1.64 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (41 mmol 41 ml ) is added portion wise into it and resulting solution is stirred for overnight.
  • Step 1 The resulting 1 ,3-bis(2-((tert-butoxycarbonyl)amino)ethyl)-1 H-imidazol-3-ium bromide salt is taken in a 100 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (60 mL), selenium powder (0.560 g, 7.10 mmol) and anhydrous potassium carbonate (981 g, 7.10 mmol) were added. The reaction mixture is allowed to reflux for 20 h. The solution is then filtered in hot condition through Celite 450.
  • Example 13 Synthesis of -(2-aminoethyl)-3-methyl-1 H-benzo[d]imidazole-2(3H)- thione (GP049) Step 1 : To a solution of methyl benzoimidazole (1 -methyl-1 H-benzo[d]imidazole, 0.5 gm 3.78 mmol) in freshly distilled THF (10 ml) tert-butyl (2-bromoethyl)carbamate (0.795 g, 3.78 mmol) is added at room temperature and the resulting reaction mixture is allowed to reflux at 75°C for 12 hours to produce a brownish solid. After completion of reaction, the reaction mixture is evaporated to dryness.
  • Step 2 The resulting salt 3-(2-((tert-butoxycarbonyl)amino)ethyl)-1-methyl-1 H- benzo[d]imidazol-3-ium bromide is taken in a 100 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (25 mL), sulfur powder (0.181 g, 5.67 mmol) and anhydrous potassium carbonate (0.78 g, 5.67mmol) under N2 atmosphere. The reaction mixture is allowed for reflux at 75 °C for 20 h. The solution is then filtered through Celite 450.
  • Step 3 To de-protect the Boc group, the solid compound (500 mg, 1.64 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (41 mmol 41 ml ) is added portion wise into it and resulting solution is stirred for overnight. After that the reaction mixture is completely dried in vacuum and the crude product is purified by column chromatography packed with silical 00-200 mesh and MeOH/DCM is used as mobile phase (R f 0.2 in 20 % MeOH/DCM). The product 1 -(2-aminoethyl)-3-methyl-1 H-benzo[d]imidazole-2(3H)-thione (GP049), is obtained in yield: 0.24g (-89%).
  • Example 14 Synthesis of 1 -(2-aminoethyl)-3-methyl-1 H-benzo[d]imidazole-2(3H)- selenone (GP050)
  • Step 1 The resulting salt 3-(2-((tert-butoxycarbonyl)amino)ethyl)-1 -methyl-1 H- benzo[d]imidazol-3-ium bromide is taken in a 100 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (60 mL), selenium powder (0.454 g, 5.73 mmol) and anhydrous potassium carbonate (0.79 g, 5.73 mmol) were added. The reaction mixture is allowed to reflux for 20 h. The solution is then filtered in hot condition through Celite 450.
  • Step 2 To de-protect the Boc group, the solid compound (500 mg, 1.64 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (41 mmol 41 ml ) is added portion wise into it and resulting solution is stirred for overnight. After that the reaction mixture is completely dried in vacuum and the crude product is purified by column chromatography packed with silical 00-200 mesh and MeOH/DCM is used as mobile phase (R f 0.2 in 20 % MeOH/DCM). The product 1 -(2-aminoethyl)-3-methyl-1 H-benzo[d]imidazole-2(3H)- selenone (GP050), is obtained in yield (0.340g, 94%).
  • Example 15 Synthesis of 1 -(3-aminopropyl)-3-ethyl-1 H-benzo[d]imidazole-2(3H)- thione (GP061)
  • Step 1 To a solution of 1 -ethyl-1 H-benzo[d]imidazole (0.5 g, 3.78 mmol) in freshly distilled THF (10 ml) tert-butyl (3-bromopropyl)carbamate (0.9 g, 3.78 mmol) is added at room temperature and the resulting reaction mixture is allowed to reflux at 75°C for 12 hours to produce a brownish solid. The reaction progress is monitored by TLC (In ethyl acetate the desired spot is in the baseline). After completion of reaction, the reaction mixture is evaporated to dryness.
  • Step 2 The resulting salt obtained in the previous step is taken in a 100 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (-20 mL), sulfur powder (0.181 g, 5.67 mmol) and anhydrous potassium carbonate (0.78 g, 5.67mmol) under N2 atmosphere.
  • the reaction mixture is allowed for reflux at 75 °C for 20 h.
  • the solution is then filtered through Celite 450. Filtrate is evaporated under reduced pressure to yield crude product 20 which is purified by column chromatography packed with Silical 00-200 mesh and Ethyl Acetate / Hexane as mobile phase (R f 0.6 in 70 % EA- Hexane).
  • Step 3 To remove Boc group, the solid compound (500 mg, 1.55 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (38.88 mM 38.88 ml) is added portion wise into it and resulting solution is stirred for overnight. After that the reaction mixture is completely dried in vacuum and the crude product is purified by column chromatography packed with Silical 00-200 mesh and MeOH / DCM as mobile phase (R f 0.2 in 20 % MeOH-DCM).
  • Step 1 The resulting salt, 3-(3-((tert-butoxycarbonyl)amino)propyl)-1 -methyl-1 H- benzo[d]imidazol-3-ium bromide is taken in a 100 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (50 mL), selenium powder (0.447 g, 5.67 mmol) and anhydrous potassium carbonate (0.78 g, 5.67 mmol) were added. The reaction mixture is allowed to reflux for 20 h. The solution is then filtered in hot condition through Celite 450.
  • Step 2 To remove Boc group, the solid compound (500 mg, 1.55 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (38.88 mM 38.88 ml) is added portion wise into it and resulting solution is stirred for overnight. After that the reaction mixture is completely dried in vacuum and the crude product is purified by column chromatography packed with Silical 00-200 mesh and MeOH / DCM as mobile phase (R f 0.2 in 20 % MeOH-DCM). The product 1-(3-aminopropyl)-3-ethyl-1 H-benzo[d]imidazole-2(3H)-selenone (GP062), is obtained as a yellow solid in room temperature. Yield: 0.34 g (94%).
  • Step 1 In a 250 ml two necked round bottom flask NaH (1.52 g, 38.08 mmol) is taken and dispersed in dry THF (35 mL) at 0 °C under nitrogen atmosphere. Benzimidazole 5 (3 g, 25.39 mmol) dissolved in dry THF (35mL) is added to in drop wise manner at 0 °C and the resulting mixture is left to stir for half an hour, tert-butyl (2-bromoethyl)carbamate (6.82 g, 30.47 mmol) is added drop by drop to this mixture at 0 °C and stirred for 8 h. TLC of reaction mixture confirms complete consumption of starting material.
  • Step 2 To a solution of tert-butyl (2-(1 H-benzo[d]imidazol-1-yl)ethyl)carbamate (1 g, 3.8 mmol) in freshly distilled THF (10 ml) tert-butyl (2-bromoethyl)carbamate (0.86 g, 3.8 mmol) is added at room temperature and the resulting reaction mixture is allowed to reflux at 75°C for 12 hours to produce a brownish solid. The reaction progress is monitored by TLC (In ethyl acetate the desired spot is in the baseline). After completion of reaction the reaction mixture is evaporated to dryness.
  • Step 3 To the resulting salt, 1,3-bis(2-((tert-butoxycarbonyl)amino)ethyl)-1 H- benzo[d]imidazol-3-ium bromide is taken in a 100 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (50 mL), sulfur powder (0.183 g, 5.73 mmol) and anhydrous potassium carbonate (0.79 g, 5.73mmol) under N2 atmosphere. The reaction mixture is allowed for reflux at 75 °C for 20 h. The solution is then filtered through Celite 450.
  • Step 4 To remove Boc groups, the solid compound (500 mg, 1.14 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (57.14 mM 57.14 ml) is added portion wise into it and resulting solution is stirred for overnight. After that the reaction mixture is completely dried in vacuum and the crude product is purified by column chromatography packed with silical 00-200 mesh and MeOH/DCM as mobile phase (R f 0.2 in 40 % MeOH/DCM). The 1 ,3-bis(2-aminoethyl)-1 H-benzo[d]imidazole-2(3H)-thione (GP067), is obtained in a quantitative yield (0.330g).
  • Example 18 Synthesis of 1,3-bis(2-aminoethyl)-1 H-benzo[d]imidazole-2(3H)- selenone (GP068)
  • Step 1 To the resulting salt, 1,3-bis(2-((tert-butoxycarbonyl)amino)ethyl)-1 H- benzo[d]imidazol-3-ium bromide is taken in a 100 mL two-neck round bottom flask fitted with a reflux condenser and treated with dry methanol (60 mL), selenium powder (0.45 g, 5.7 mmol) and anhydrous potassium carbonate (0.79 g, 5.73 mmol) were added. The reaction mixture is allowed to reflux for 20 h. The solution is then filtered in hot condition through Celite 450.
  • Step 2 To remove Boc groups, the solid compound (500 mg, 1.14 mmol) is dissolved in 100 ml MeOH and 1 (M) HCI (57.14 mM 57.14 ml) is added portion wise into it and resulting solution is stirred for overnight. After that the reaction mixture is completely dried in vacuum and the crude product is purified by column chromatography packed with silical 00-200 mesh and MeOH/DCM as mobile phase (R f 0.2 in 40 % MeOH/DCM). The product 1 ,3-bis(2-aminoethyl)-1 H-benzo[d]imidazole-2(3H)-selenone (GP068), is obtained in good yield (90%).
  • a mixture of 1 -methylbenzimidazole (0.5 g, 3.75 mmol) and chloroethanol (0.3 g, 3.75 mmol) is heated at 90 °C for 4 days without any solvent in 100 ml round bottom flask. After 4 days of stirring, white precipitated is isolated and is washed with ethylacetate (twice with 25 mL) and dried in high vacuum. The obtained white salt (0.66 g) is taken in methanol (50 mL) and treated with elemental sulphur (0.18 g, 5.63 mmol), anhydrous potassium carbonate (0.780 g, 5.63 mmol). The reaction mixture is allowed to reflux for 20 h. The solution is then filtered in hot condition through Celite.
  • Example 20 Synthesis of 1 -(2-hydroxyethyl)-3-methyl-1 H-benzo[d]imidazole-2(3H)- selenone (GP074)
  • a mixture of 1-methylbenzimidazole (0.5 g, 3.75 mmol) and Chloroethanol (0.3 g, 3.75 mmol) is heated at 90 °C for 4 days without any solvent in 100 ml round bottom flask. After 4 days of stirring, white precipitated is isolated and washed with ethylacetate (twice with 25 mL) and dried in high vacuum.
  • Step 1 NaH is taken in 50 mL two necked round bottom flask (0.25 g, 6.3 mmol) and dispersed in dry THF (25 mL) in the nitrogen atmosphere.
  • 1 H-benzo[d]imidazole 0.5 g, 4.2 mmol
  • 1 H-benzo[d]imidazole 0.5 g, 4.2 mmol
  • benzyl chloride 0.8 g, 730 ul, 6.34 mmol, is done drop by drop to this mixture at 0 °C and stired for 6 h.
  • the desired product is extracted using 50 mL ethyacetate/10 mL water.
  • Product is purified through column chromatography in ethylacetate/hexane as mobile phase (0.2 %).
  • the product 1 -benzyl-1 H-benzo[d]imidazole is obtained as a white solid and used for further step.
  • Step 2 A mixture of 1-benzyl-1 H-benzo[d]imidazole (0.4 g, 1.9 mmol) and chloroethanol (0.67 mL, 2.9 mmol) is heated at 90 degree C for 4 days without any solvent in 100 ml round bottom flask. After 4 days of stirring, white precipitated is isolated and washed with ethylacetate (2*10 mL) and dried in high vacuum. The above white precipitate (0.3 g, 1.2 mmol) is taken in methanol (20 mL) and treated with elemental sulphur (0.06 g, 1.77 mmol), anhydrous potassium carbonate (0.24 g , 1.77 mmol). The reaction mixture is allowed to reflux for 20 h.
  • Step 1 A mixture of 1-benzyl-1 H-benzo[d]imidazole (0.4g, 1.9mmol) and chloroethanol (0.670 mL, 2.88 mmol) is heated at 90 degree C for 4 days without any solvent in 100 ml round bottom flask. After 4 days of stirring, white precipitated is isolated and is washed with ethylacetate (2*10 mL) and dried in high vacuum.
  • a mixture of 1-benzylbenzimidazole (0.400g, 1.9 mmol) and chloropropanol (0.18 g, 1.9 mmol) is heated at 90 °C for 4 days without any solvent in 100 ml round bottom flask. After 4 days of stirring, white precipitated is isolated and washed with ethyl acetate (twice with 25 mL) and dried in high vacuum. Now to the solid crude is taken in methanol (50 mL) and treated with elemental sulphur (0.09 g, 2.8 mmol), anhydrous potassium carbonate (0.395 g, 2.85 mmol). The reaction mixture is allowed to reflux for 20 h. The solution is then filtered in hot condition through celite.
  • a mixture of 1-benzylbenzimidazole (0.4g, 1.9 mmol) and chloropropanol (0.18 g, 1.9 mmol) is heated at 90 °C for 4 days without any solvent in 100 ml round bottom flask. After 4 days of stirring, white precipitated is isolated and washed with ethyl acetate (twice with 25 mL) and dried in high vacuum. Now the solid crude is taken in methanol (50 mL) and treated with elemental selenium (2.8 mmol), anhydrous potassium carbonate (0.4 g, 2.8 mmol). The reaction mixture is allowed to reflux for 20 h. The solution is then filtered in hot condition through celite.
  • a mixture of benzimidazole (1.0g, 8.5 mmol) and 2-chloroethanol (1.35 g, 16.9 mmol) is heated at 80 °C for 4 days without any solvent in 100 ml round bottom flask. After 4 days of stirring, white precipitated is isolated and washed with ethyl acetate (2*10 mL) and dried in high vacuum. Obtained white solid is taken in methanol (50 mL) and treated with elemental sulphur (0.4 g, 12.6 mmol), anhydrous potassium carbonate (1.8 g, 12.6 mmol). The reaction mixture is allowed to reflux for 20 h. The solution is then filtered in hot condition through celite.
  • Example 28 Synthesis of 1 -(2-methoxyethyl)-3-methyl-1 H-benzo[d]imidazole-2(3H)- thione (GP155)
  • a mixture of 1-methylbenzimidazole (0.5 g, 3.75 mmol) and 2-chloroethylmethylether (0.35 g, 3.75 mmol) is heated at 90 °C for 4 days without any solvent in 100 ml round bottom flask. After 4 days of stirring, white precipitated is isolated and washed with ethylacetate (twice with 25 mL) and dried in high vacuum.
  • a mixture of 1-methylbenzimidazole (0.5 g, 3.75 mmol) and 2-chloroethylmethylether (0.35 g, 3.75 mmol) is heated at 90 °C for 4 days without any solvent in 100 ml round bottom flask. After 4 days of stirring, white precipitated is isolated and washed with ethylacetate (twice with 25 mL) and dried in high vacuum. The so obtained white salt (0.665 g) is taken in methanol (50 mL) and treated with selenium powder (5.63 mmol), anhydrous potassium carbonate (0.78 g, 5.63 mmol). The reaction mixture is allowed to reflux for 20 h. The solution is then filtered in hot condition through celite.
  • a mixture of benzimidazole (1.0g, 8.5 mmol) and 2-Chloroethylmethylether (1.6 g, 16.94 mmol) is heated at 90 °C for 4 days without any solvent in 100 ml round bottom flask. After 4 days of stirring, white precipitated is isolated and washed with ethyl acetate (2*10 mL) and dried in high vacuum. Obtained white solid is taken in methanol (50 mL) and treated with elemental sulphur (0.4 g, 12.6 mmol), anhydrous potassium carbonate (1.8 g, 12.6 mmol). The reaction mixture is allowed to reflux for 20 h. The solution is then filtered in hot condition through celite.
  • Example 33 Synthesis of 1,3-bis(2-methoxyethyl)-1 H-benzo[d]imidazole-2(3H)- selenone (GP170)
  • GP170 A mixture of benzimidazole (1.00g, 8.47 mmol) and 2-Chloroethylmethylether (1.59 g, 16.4 mmol) is heated at 90 °C for 4 days without any solvent in 100 ml round bottom flask. After 4 days of stirring, white precipitated is isolated and is washed with ethyl acetate (2*10 mL) and dried in high vacuum.
  • Step 1 1,4-dibromo butane and triphenyl phosphine is heated in 5:1 equivalent ratio at 80°C to yield (4-bromobutyl)triphenylphosphonium bromide as a light yellow crude which is washed with cold diethyl ether several times and vacuum dried to produce a white solid which was used for further step.
  • Step2 NaH is taken in 250 mL two necked round bottom flask (1.0 g, 44.0 mmol) and dispersed in dry THF (50 mL) in the nitrogen atmosphere. Imidazole (2 g, 29.37 mmol) is dissolved dry THF (50 mL) and added to the NaH dispersed solution drop by drop at 0 °C then mixture brought to room temperature and stirred for half an hours. After half an hour of stirring, addition of 1.5 equivalents either of 2-chloroethanol or 1 -chloro-2- methoxyethane is done drop by drop to this mixture at 0 °C and stirred for 6 h.
  • the desired product 2-(1 H-imidazol-1 -yl)ethanol or 1 -(2-methoxyethyl)-1 H-imidazole is extracted using ethyacetate.
  • Product is purified through column chromatography in ethylacetate/hexane as mobile phase (0.3 %). The desired obtained as a brown liquid and used for further step.
  • Step3 A 1 :1 equivalent mixture of 1 -methyl imidazole or 2-(1 H-imidazol-1 -yl)ethanol or 1- (2-methoxyethyl)-1 H-imidazole and (4-bromobutyl)triphenylphosphonium bromide is refluxed in ACN/THF (1 :1) mixture for 12h to yield a brown oily crude which is washed with hexane and dried to give a foamy solid.
  • the substituted imidazolium salt is dissolved in dry methanol. Now anhydrous potassium carbonate and sulfur or selenium is added into the mixture and refluxed for 20 hours to afford (GP177-182) which were purified by column chromatography from the reaction crude.
  • Example 37 General Synthetic procedure for mitochondria targeted benzimidazole thiones and selones (GP183-188).
  • Step 1 1,4-dibromo butane and triphenyl phosphine is heated in 5:1 equivalent ratio at 80°C to yield (4-bromobutyl)triphenylphosphonium bromide as a light yellow crude which is washed with cold diethyl ether several times and vacuum dried to produce a white solid which was used for further step.
  • Step2 NaH is taken in 250 mL two necked round bottom flask (1.0 g, 44.0 mmol) and dispersed in dry THF (50 mL) in the nitrogen atmosphere.
  • Imidazole (2 g, 29.37 mmol) is dissolved dry THF (50 mL) and added to the NaH dispersed solution drop by drop at 0 °C then mixture brought to room temperature and stirred for half an hours. After half an hour of stirring, addition of 1.5 equivalents either of methyl iodide or 2-chloroethanol or 1-chloro- 2-methoxyethane is done drop by drop to this mixture at 0 °C and stirred for 6 h.
  • the desired product 2-(1 H-benzo[d]imidazol-1-yl)ethanol or 1-(2-methoxyethyl)-1 H- benzo[d]imidazole is extracted using ethyacetate. Product is purified through column chromatography in ethylacetate/hexane as mobile phase (0.3 %).The desired obtained as a brown liquid and used for further step.
  • Step3 A 1 :1 equivalent mixture of 1 -methyl benzimidazole, 2-(1 H-benzo[d]imidazol-1- yl)ethanol or 1-(2-methoxyethyl)-1 H-benzo[d]imidazole and (4- bromobutyl)triphenylphosphonium bromide is refluxed in ACN/THF (1 :1) mixture for 12h to yield a brown oily crude which is washed with hexane and dried to give a foamy solid.
  • the substituted benzimidazolium salt is dissolved in dry methanol. Now anhydrous potassium carbonate and sulfur or selenium is added into the mixture and refluxed for 20 hours to afford (GP183-188) which were purified by column chromatography from the reaction crude.
  • Example 44 degradation of mercuric acetate A mixture of compound 1 -(2-hydroxyethyl)-3-methyl-1 H-benzo[d]imidazole-2(3H)-thione (GP073) (9.4 mg, 0.045 mmol) and mercuric acetate (14.3 mg, 0.045 mmol) is stirred in 3 mL of water/acetonitrile mixture (1 :1) for 12 hours at 35°C. After 12 hours of stirring, the black precipitate of HgS is isolated by centrifugation and washed intensively with water and acetonitrile mixture. After washing HgS powder were dried completely over vacuum and characterized thoroughly by various techniques such as SEM, TEM and EDX analysis. Yield: 9 mg.
  • Example 46 degradation of PhHgCI A mixture of compound 1 -(2-hydroxyethyl)-3-methyl-1 H-benzo[d]imidazole-2(3H)-thione (GP073) (9.4 mg, 0.045 mmol) and PhHgCI (14.1 mg, 0.045 mmol) is stirred in 3 mL of water/acetonitrile mixture (1 :1 ) for 2 hours at 35°C. After 2 hours of stirring, NaHC0 3 (5.7 mg, 0.0675 mmol) is added and left to stir for 10 h and after 10 hours the black precipitate of HgS is isolated by centrifugation and washed intensively with water and acetonitrile mixture. After washing HgS powder were dried completely over vacuum and characterized thoroughly by various techniques such as SEM, TEM and EDX analysis. Yield: 9 mg.
  • Example 50 degradation of Cu(ll) compounds A mixture of 1-(2-hydroxyethyl)-3-methyl-1 H-benzo[d]imidazole-2(3H)-selenone (GP074) (10 mg, 0.04 mmol) and copper(ll) acetate (7.76 mg, 0.04 mmol) is stirred in 4 mL of water/acetonitrile mixture (1 :1) for 9 hours at 37°C to ensure complete degradation. After stirring, the black precipitate of CuSe is isolated by centrifugation and washed intensively with water and acetonitrile mixture. After washing CuSe powder were dried completely over vacuum and characterized thoroughly by various techniques such as SEM, TEM and EDX analysis. Yield: 20mg
  • Example 54 degradation of ArHgCys by GP073 and synthesis of water-soluble HgS nanoparticles Synthesis of ArHgCys To a solution of L-cysteine. HCI (100 mg, 0.56 mmol) in 10 ml of water/acetonitrile mixture (1 :1), 4-(Hydroxymercuri)benzoic acid sodium salt (203.4 mg, 0.56 mmol) was added and stirred overnight at 37°C. After stirring for 10 h white precipitate was obtained, which was washed thoroughly with water and acetonitrile mixture to yield white solid powder ArHgCys. Degradation of ArHgCys by GP073
  • the compound GP073 (37.5 mg, 0.18 mmol) was added and dissolved in a mixture of ArHgSG (56.4 mg, 0.09 mmol) in 3 mL of either water/acetonitrile mixture (1 :1) or phosphate buffer (pH 9.5) and stirred at 37°C.
  • water/acetonitrile mixture 2 equivalents of weak base NaHC03 or K2HPO4 was added after 1 h of stirring.
  • the black precipitate of HgS was isolated by centrifugation and washed intensively with water and acetonitrile mixture and characterized thoroughly by various techniques such as SEM, TEM and EDX analysis. Yield: 12 mg.
  • MeHgCys To a solution of L-cysteine. (100 mg, 0.82 mmol) in 5 ml of water/acetonitrile mixture (1 :1), methylmercury chloride (207.2 mg, 0.82 mmol) was added and stirred overnight at 37°. After stirring for 10 h white precipitate is formed and washed thoroughly with water and acetonitrile mixture and dried in air to yield white solid powder MeHgCys. Degradation of MeHgCys by GP073
  • the compound GP073 (37.5 mg, 0.18 mmol) was added and dissolved in a mixture of MeHgCys (30.2 mg, 0.09 mmol) in 3 mL of either water/acetonitrile mixture (1 :1) or phosphate buffer (pH 9) and stirred at 37°C.
  • 2 equivalents of weak base NaHC03 or K2HPO4 was added after 1 h of stirring.
  • the black precipitate of HgS was isolated by centrifugation and washed intensively with water and acetonitrile mixture and characterized thoroughly by various techniques such as SEM, TEM and EDX analysis. Yield: 7 mg.
  • MeHgSG To a solution of glutathione (100 mg, 0.32 mmol) in 5 ml of water/acetonitrile mixture (1 :1), methylmercury chloride (80.3 mg, 0.32 mmol) was added and stirred overnight at 37°. After stirring for 10 h white precipitate was formed, which was then washed thoroughly with water and acetonitrile mixture and dried in air to yield white solid powder MeHgSG.
  • the compound GP073 (37.5 mg, 0.18 mmol) was added and dissolved in a mixture of MeHgSG (46.8 mg, 0.09 mmol) in 3 mL of either water/acetonitrile mixture (1 :1) or phosphate buffer (pH 9.5) and stirred at 37°C.
  • 2 equivalents of weak base NaHC0 3 or K2HPO4 was added after 1 h of stirring.
  • the black precipitate of HgS was isolated by centrifugation and washed intensively with water and acetonitrile mixture and characterized thoroughly by various techniques such as SEM, TEM and EDX analysis. Yield: 11 mg.
  • Example 59 degradation of MeHgCys by GP074 and synthesis of water-soluble Hg(SSe) nanoparticles The compound GP074 (22.9 mg, 0.09 mmol) was added and dissolved in a mixture of MeHgCys (30.2 mg, 0.09 mmol) in 3 mL of either water/acetonitrile mixture (1 :1) or phosphate buffer (pH 9) and stirred at 37°C. In case of water/acetonitrile mixture 2 equivalents of weak base NaHC0 3 or K2HPO4 was added after 1 h of stirring. The reaction mixture was continued to stir for another 6 h.

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Abstract

La présente invention concerne des dérivés de thiones et de sélones à base d'imidazole et de benzimidazole utilisés pour dégrader divers métaux lourds toxiques et leurs sels en une forme moins toxique, stable et insoluble. La présente invention concerne également le procédé de préparation desdits dérivés de thiones et de sélones à base d'imidazole et de benzimidazole et un procédé de détoxification et de dégradation de divers métaux lourds, y compris le mercure, en particulier les composé organo-mercuriels, le plomb, l'arsenic, le cadmium, le cuivre et leurs sels à l'aide desdits dérivés de thiones et de sélones à base d'imidazole et de benzimidazole. Lesdits dérivés présentent une meilleure activité de dégradation dans des conditions physiologiques et environnementales appropriées, ainsi qu'une plus grande acceptabilité dans un grand nombre de bases.
PCT/IN2017/050122 2016-03-31 2017-03-31 Dérivés d'imidazole et de benzimidazole, leur procédé de préparation et leur utilisation Ceased WO2017168451A1 (fr)

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