WO2005100373A2 - Derives du monosaccharide - Google Patents

Derives du monosaccharide Download PDF

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Publication number
WO2005100373A2
WO2005100373A2 PCT/IB2005/000974 IB2005000974W WO2005100373A2 WO 2005100373 A2 WO2005100373 A2 WO 2005100373A2 IB 2005000974 W IB2005000974 W IB 2005000974W WO 2005100373 A2 WO2005100373 A2 WO 2005100373A2
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WIPO (PCT)
Prior art keywords
aryl
alkyl
compound
heterocyclyl
heteroaryl
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PCT/IB2005/000974
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English (en)
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WO2005100373A3 (fr
Inventor
Viswajanani Jitendra Sattigeri
Sudershan K. Arora
Mohammad Salman
Venkata P. Palle
Abhijit Ray
Raj Kumar Shirumalla
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Ranbaxy Laboratories Limited
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Publication of WO2005100373A2 publication Critical patent/WO2005100373A2/fr
Publication of WO2005100373A3 publication Critical patent/WO2005100373A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/02—Monosaccharides

Definitions

  • the present invention relates to monosaccharide derivatives as anti-inflammatory agents.
  • the compounds provided herein can be useful for inhibition and prevention of inflammation and associated pathologies, including inflammatory and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis, allograft rejection, psoriasis, inflammatory bowel disease, ulcerative colitis, acne, atherosclerosis, cancer, pruritis or allergic rhinitis.
  • Pharmacological compositions containing the compounds of the present invention and the methods of treating bronchial astlima, chronic obstructive pulmonary disease, rheumatoid arthritis, multiple sclerosis, type I diabetes, psoriasis, allograft rejection, inflammatory bowel disease, ulcerative colitis, acne, atherosclerosis, cancer, pruritis or allergic rhinitis and other inflammatory and/or autoimmune disorders, using the compounds are also provided.
  • Background of the Invention Inflammation is a key defense mechanism of the body that is activated as a result of tissue injury.
  • the inflammatory process is self-containing, however, under certain pathophysiological conditions, the inflammatory process tends to perpetuate itself, giving rise to chronic inflammatory diseases like bronchial asthma, rheumatoid arthritis etc.
  • chronic inflammatory diseases like bronchial asthma, rheumatoid arthritis etc.
  • chemokine cytokine
  • proteolytic enzymes and other bioactive molecules.
  • mast cells primed by lymphocytes interact with environmental allergens and release mediators like histamine, prostaglandin, leukotrienes, etc.
  • cytokines IL-4, IL-5, IL-6, IL-8, IL-13, GM-CSF and TNF alpha
  • chemokines and proteolytic enzymes chymase, tryptase
  • Eosinophils infiltrate inflamed tissue following allergen - mast cell interaction in bronchial astlima and allergic rhinitis.
  • U.S. Patent No. 6,329,344B1 discloses several monosaccharide derivatives described as cell adhesion inhibitors. It generally relates to substituted pentose and hexose monosaccharide derivatives, which are said to exhibit cell adhesion inhibitory and anti- inflammatory activities.
  • U.S. Patent No. 6,329,344B1 discloses several monosaccharide derivatives described as cell adhesion inhibitors. It generally relates to substituted pentose and hexose monosaccharide derivatives, which are said to exhibit cell adhesion inhibitory and anti- inflammatory activities.
  • 6,590,085B1 discloses several monosaccharide derivatives described as inhibitors of cell adhesion and cell adhesion mediated pathologies, including inflammatory and autoimmune diseases.
  • U.S. Patent Application US 2002/0173632 Al discloses furanose and ammo furanose compounds said to be useful for rheumatoid, arthritis, immunomodulatory diseases inflammatory and proliferative diseases.
  • U.S. Patent No. 5,298,494 discloses derivatives of monosaccharides, which allegedly exhibit anti-proliferative and/or anti-inflammatory activity and are described as useful for treating mammals having inflammatory disorders and/or autoimmune disorders.
  • 5,367,062 discloses derivatives of disubstituted and deoxydisubstituted ⁇ ,D-lyxofuranosides which reportedly exhibit significant anti-inflammatory and antiproliferative activity and are said to be useful for treating inflammatory and/or autoimmune disorders.
  • U.S. Patent No. 5,360,794 discloses deoxydisubstituted or dideoxy disubstituted derivatives of ⁇ -D-mannomranoside and ⁇ -L-gulofuranosides, which are said to exhibit anti-inflammatory and antiproliferative activity.
  • U.S Patent 4,996,195 discloses derivatives of ⁇ ,D-glucofuranose and ⁇ ,D-allofuranose described as useful for treating animals and mammals with inflammatory and/or autoimmune disorders.
  • U.S. Patent No. 5,010,058 discloses derivatives of 1,2-O-iso-propylidene- ⁇ -D-gluco furanose described as useful for treating animals and mammals with inflammatory and/or autoimmune disorders.
  • WO 93/13117 and U.S. Patent No. 5,360,792 discloses 5- or 6-deoxy hexose monosaccharides having a saturated nitrogen containing heterocycle described as useful as anti-proliferative and anti-inflammatory compounds.
  • WO 94/28910 discloses 5,6- dideoxy-5-amino derivatives of idose and 6-deoxy-6-amino derivatives of glucose, which are said to exhibit immunomodulatory, anti-inflammatory and anti-proliferative activity.
  • WO 94/11381 discloses derivatives of pentose monosaccharides described as antiproliferative and anti inflammatory compound. Summary of the Invention Monosaccharide derivatives, which can be used for the for inhibition and prevention of inflammation and associated pathologies including inflammatory and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis, allograft rejection or psoriasis are provided.
  • inflammatory and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis, allograft rejection, psoriasis, inflammatory bowel disease, ulcerative colitis, acne, atherosclerosis, cancer, pruritis and allergic rhinitis.
  • R j is selected from hydrogen, lower (C ⁇ -C 6 ) alkyl, lower (C 2 -C 6 ) alkenyl, lower (C 2 -C 6 ) alkynyl, lower (C -C 8 ) cycloalkyl, aryl, heteroaryl, lower (C ⁇ -C 6 ) aralkyl, lower (CrC 6 ) heteroarylalkyl, and lower 3-6 ring membered heterocyclylalkyl).
  • R 4 can be hydrogen, or OR c (wherein R c is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl) and, when is OR c , then R 3 and R c may together form an acetal (wherein the acetal is the same as defined earlier) and R 2 can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl.
  • R 5 can be alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocylyl, heteroarylalkyl, or heterocyclylalkyl; except that (1) if R 3 and R c form an isopropylidene radical and R 2 is hydrogen, C 5 -C ⁇ alkyl, n-C 5 -C ⁇ 5 -alkoxy-C 2 -C -alkyl, or phenypropyl and X is NR, where R, is hydrogen and Ri is H and R 5 is alkyl, then this alkyl must be C ⁇ -C alkyl; (2) if either R 2 and R 3 or R 3 and R c form an isopropylidene radical and R c and R 2 are C 5 -C ⁇ 5 alkyl respectively, and Ri is H and X is NR, where R j is H, then R 5 cannot
  • X-R 5 can be aniinoaryl, aminoalkyl, aminoalkaryl, aminoalkyl-oxy - carbonyl-aminoaryl, aminoaryl-urea-aryl, aminoalkyl-carboxyl, aminoheterocyclyl, oxy- alkyl-heterocyclyl, amino-heterocyclyl, or amino acid
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms.
  • This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n- decyl, tetradecyl, and the like.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms with cis or trans geometry. In the event that alkenyl is attached to the heteroatom, the double bond cannot be alpha to the heteroatom.
  • Alkenyl groups may further be substituted with one or more s ⁇ ostituents selected from alkyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms.
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless or otherwise constrained by the definition.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures such as adamantanyl, and bicyclo [2.2.1]heptane, or cyclic alkyl groups to which is fused an aryl group, for example indane, and the like.
  • alkoxy denotes the group O-alkyl wherein alkyl is the same as defined above.
  • aralkyl refers to alkyl-aryl linked through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl portion contains carbon atoms from 1-6 and aryl is as defined below. Examples of aralkyl groups can include benzyl and the like.
  • aryl group may optionally be fused with cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N, S.
  • aryloxy denotes the group O-aryl wherein aryl is the same as defined above.
  • heteroaryl groups can include pyridinyl, pyridazinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like.
  • heterocyclyl substituents are attached to the ring atom, be it carbon or heteroatom.
  • the heterocyclyl ring may optionally contain one or more olefmic bond(s).
  • heterocyclyl groups can include tetrahydro furanyl, dihydrofuranyl, dihydropyridinyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, piperidinyl or piperazinyl.
  • Heteroarylalkyl refers to alkyl-heteroaryl group linked through alkyl portion, wherein the alkyl and heteroaryl are the same as defined earlier.
  • Heterocyclylalkyl refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are the same as defined earlier.
  • leaving group generally refers to groups that exhibit the properties of being labile under the defined synthetic conditions and also, of being readily separated from synthetic products under defined conditions. Examples of such leaving groups include but are not limited to, halogen (F, Cl, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy, hydroxy radicals and the like.
  • activated derivative of a carboxylic acid for example, that of a suitable protected amino acid, aliphatic acid or an aromatic acid refer to the corresponding acyl halide (e.g., acid fluoride, acid chloride and acid bromide), corresponding activated esters (e.g.
  • protecting groups is used herein to refer to moieties which have tfie property of preventing specific chemical reactions at a site on the molecule undergoing chemical modification intended to be left unaffected by the particular chemical modification. Also the term protecting group, unless otherwise specified, may be used with groups such as hydroxy, amino, carboxy and examples of such groups are found in T.W. Greene and P.G.M.
  • natural amino acid is intended to represent the twenty two naturally occurring amino acids glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine , tyrosine, trytophan, cysteine, proline, proline, histidine, aspartic acid, asparagines, glutamic acid, glutamine, ⁇ -carboxyglutamic acid, arginine, ornithine and lysine in their L form.
  • unnatural amino acid is intended to represent the 'D' form of the twenty two naturally occurring amino acids described above.
  • unnatural amino acid includes homologues of the natural amino acids, and synthetically modified form of the natural amino acids commonly utilized by those in the peptide chemistry arts when preparing synthetic analogues of naturally occurring peptides, including D and L forms.
  • the synthetically modified forms include amino acids having alkylene chains shortened or lengthened by up to two carbon atoms, amino acids comprising optionally substituted aryl groups, and amino acids comprised halogenated groups preferably halogenated alkyl and aryl groups.
  • the term "unnatural amino acids,” as used herein, is also intended to represent beta amino acids.
  • peptide refers to a molecule comprising a series of amino acids linked through amide linkages.
  • Dipeptide comprises 2 amino acids, tripeptide refers to a peptide having 3 amino acids and tetrapeptide refers to one having four amino acids, wherein the term amino acid is as defined earlier.
  • LDNP refers to a tetrapeptide leucyl-aspartyl- valyl-prolyl.
  • DVP refers to a tripeptide aspartyl-valyl-prolyl.
  • NP refers to a dipeptide valyl-prolyl.
  • the compounds disclosed herein generally contain one or more asymmetric carbon atoms and thus can occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
  • Each stereo genie carbon may be of the R or S configuration.
  • the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are envisioned.
  • amino acids and amino acid side chains may be depicted in a particular configuration, both natural and unnatural forms are envisioned.
  • Detailed Description of the Invention Compounds disclosed herein may be prepared by techniques well known in the art and familiar to synthetic organic chemist of ordinary skill, addition, the compounds of the present invention may be prepared by following the reaction scheme as depicted below.
  • Path a The compound of Formula IN can be reacted with (R d CO) 2 O, for example, acetic anhydride, to form a compound of Formula N (wherein R ⁇ j, Ri, R 2 , R 3 & R- t are same as defined earlier).
  • Path b The compound of Formula IV can be reacted with a compound of Formula VI (wherein hal is halogen and R 6 is as defined earlier) to yield a compound of Formula VII (wherein R 6 , Ri, R 2 , R 3 and Rj are same as defined earlier).
  • Path c The compound of Formula IV can be reacted with a compound of Formula VIII to form a compound of Formula IX.
  • R d , Ri, R , R 3 and i are same as defined earlier.
  • the compound of Formula II can be reacted with -nitrofluorobenzene to form a compound of Formula III in an organic solvent, for example, acetonitrile, dimethylsulphoxide or ethyl acetate, in the presence of a organic base, for example, diisopropylethylamine, pyridine or triethylamine.
  • the catalytic hydro genation of compound of Formula III can be carried out to fonn a compound of Fonnula IV in an organic solvent, for example, methanol, ethanol, propanol, isopropyl alcohol, tefrahydrofuran or ethyl acetate, under hydrogen atmosphere utilizing, for example, catalytic palladium on carbon.
  • an organic solvent for example, methanol, ethanol, propanol, isopropyl alcohol, tefrahydrofuran or ethyl acetate
  • a person skilled in the art of this invention can utilize a palladium-catalyzed coupling reaction of an amine with aryl halides (which are exemplified by reactions known as Buchwald-Hartwig coupling reactions) for the synthesis of analogous compounds of Formula III, V, VII or EX with various aryl subsitutents.
  • reaction of compound of Formula IV with an anhydride (Path a), for example, acetic anhydride to form a compound of Formula V can be carried out in an organic solvent, for example, dichloromethane, dichloro ethane, chlorofonn or carbon tetrachloride, in the presence of a organic base triethylamine, diisopropylethylamme or pyridine.
  • organic solvent for example, dichloromethane, dichloro ethane, chlorofonn or carbon tetrachloride
  • compounds of Formula IV can react with an acid halide to provide compounds of Formula V in the presence of abase, such as triethylamine, diisopropylethylamme, pyridine, or with an activated derivative of a carboxylic acid, as defined earlier.
  • abase such as triethylamine, diisopropylethylamme, pyridine
  • reaction of compound of Formula IV with a compound of Formula VI to fonn a compound of Formula VII can be carried out in an organic solvent, such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride, and in the presence of a base, such as triethylamine, diisopropylethylamme or pyridine.
  • a base such as triethylamine, diisopropylethylamme or pyridine.
  • reaction of compounds of Formula IV with a compound of Formula VIII to yield a compound of Formula IX can be carried out in an organic solvent, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
  • a compound of Formula IV may react with an amine in the presence of carbonyldiimidazole (CDI) to yield a compound of Formula IX or may react with a carbamate such as phenyl or p-nitrophenyl carbamate of an amine to yield a compound of Formula IX.
  • CDI carbonyldiimidazole
  • Path a l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ 4-amino-phenyl ⁇ -amino- ⁇ -L- gulofuranoside (Compound No. 2)
  • Path b l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ [4-(4-methyl-phenyl-sulphonyl)- an ino]-phenyl ⁇ -amino- ⁇ -L-gulofuranoside (Compound No. 3)
  • Formula XIII Formula XV
  • the compounds of Formula XI, XIII and XV can be prepared following Scheme II. Path a: A compound of Formula II can be reacted with a compound of Formula X to form a compound of Formula XI (wherein Ri, R 2 , R 3 , R t and R is same as defined earlier).
  • Path b The compound of Formula II can be reacted with compound of Formula XII (wherein hal is a halogen and R is same as defined earlier) to yield a compound of Formula XIII (wherein Ri, R 2 , R 3 , R t & j are as described before).
  • Path c The compound of Formula II can be reacted with a compound of Formula XIV (wherein hal is a halogen and Hy is heterocyclyl or heteroaryl) to yield a compound of Formula XV.
  • the compound of Formula II can be reacted with compound of Formula X to yield a compound of Formula XI in an organic solvent, for example, methanol or ethanol, using a reducing agent, for example, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, borane in pyridine or H 2 /Pd catalyst, and when desired, the reaction can be carried out in the presence of catalytic amount of an acid, for example, acetic acid or propionic acid.
  • an organic solvent for example, methanol or ethanol
  • a reducing agent for example, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, borane in pyridine or H 2 /Pd catalyst, and when desired, the reaction can be
  • the compound of Formula ⁇ can be reacted with a compound of Formula XII to provide a compound of Formula XIII and the reaction can be carried out in an organic solvent, for example, acetone, acetonitrile, tefrahydrofuran or dimethylformamide, in the presence of a base, for example, potassium carbonate, sodium carbonate, triethylamine or pyridine.
  • an organic solvent for example, acetone, acetonitrile, tefrahydrofuran or dimethylformamide
  • a base for example, potassium carbonate, sodium carbonate, triethylamine or pyridine.
  • the compound of Formula II can be reacted with a compound of Formula XIV to form a compound of Formula XV and the reaction can be carried out in an organic solvent, for example, tefrahydrofuran or dimethylformamide, in the presence of a base, for example, pyridine, triethylamine or diisopropylethylamme.
  • an organic solvent for example, tefrahydrofuran or dimethylformamide
  • a base for example, pyridine, triethylamine or diisopropylethylamme.
  • Scheme IN an alternative synthetic route to produce compounds of Formula XV is presented in Scheme IN.
  • the compound of Formula XXI can be prepared following Scheme III.
  • a compound of Formula XVI can be reacted with a compound of Formula XVII (wherein m is an integer from 1-3 and hal is halogen) to yield a compound of Formula XVIII, the hydroxy group of which can be converted to a leaving group in a compound of Formula XIX (wherein LG is a leaving group and R ls R , R 3 , R 4 are same as defined earlier), which on further reaction with a compound of Formula XX can form a compound of Formula XXI (wherein m, R R l5 R 2 , R 3 , R t are same as defined before).
  • the compound of Formula XVI can be reacted with 3-chloropropanol to form a compound of Formula XVHI in the presence of a base, for example, sodium hydroxide, potassium hydroxide, sodium hydride or potassium tert-butoxide.
  • the hydroxy group in compound of Formula XVIII can be converted to a leaving group, for example,, tosyl, mesyl or triflyl.
  • Fonnula XVIII can be tosylated with p-tosyl chloride to form a compound of Formula XIX in the presence of a base, for example, pyridine, triethylamine or diisopropylethylamine.
  • reaction of compound of Formula XIX with a compound of Formula XX to provide a compound of Formula XXI can be facilitated in the presence of a base, such as triethylamine, diisopropylethylamine or pyridine, in a solvent such as acetone, acetonitrile, tefrahydrofuran or dimethylformamide.
  • a base such as triethylamine, diisopropylethylamine or pyridine
  • a solvent such as acetone, acetonitrile, tefrahydrofuran or dimethylformamide.
  • Formula XV FormulaXXIV
  • the compounds of Formula XXIV and XV can be prepared according to Scheme IV.
  • a compound of Formula XVI can be reacted with a leaving group to form a compound of Formula XXII.
  • a compound of Formula XXII on reaction with aminoalkylalcohol, such as 3- aminopropanol can form a compound of Formula XXHI (wherein n is an integer 0-2), which on reaction with a compound of Formula NIII can form a compound of Formula XXIN (wherein n, R , Ri, R 2 , R 3 , P are same as described earlier).
  • Path b The compound of Formula XXII on reaction with a compound of Fonnula XXN can yield a compound of Formula XV (wherein Hy is heterocyclyl or heteroaryl and Ri, R 2 , R 3 , t are same as described earlier).
  • the hydroxy group in compound of Formula XVI can be converted to a leaving group, for example tosyl, mesyl or triflyl.
  • Formula XVI can be tosylated with p-tosyl chloride to form a compound of Formula XXII in the presence of a base, for example, pyridine, triethylamine or diisopropylethylamine.
  • reaction of compound of Formula XXIII with a compound of Formula VIII to give a compound of Formula XXIV can be carried out in the presence of a solvent, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
  • a solvent for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
  • the reaction of compound of Formula XXII with a compound of Formula XXN to yield a compound of Formula XV can be carried out in an organic solvent, for example, tefrahydrofuran or dimethylformamide in the presence of a base, for example, sodium hydride or potassium tert-butoxide.
  • FormulaXXVIII A compound of Formula XXVIII can be prepared following either Path a or Path b of Scheme V.
  • Path a A compound of Formula XVI can be reacted with a compound of Formula XXVII to yield a compound of Formula XXVIII (wherein R f, R q , Ri, R 2 , R 3 and R are same as defined earlier).
  • a compound of Formula XVI can be reacted with a compound of Formula XXIX (wherein R is alkyl or aralkyl), for example, ester of chloroacetic acid to fonn a compound of Formula XXX, which on hydrolysis can yield a compound of Formula XXXI.
  • the compound of Formula XXXI on reaction with a compound of Formula XXXII can yield a compound of Formula XXVIII (wherein R f, R q , Ri, R 2 , R 3 and t are same as defined earlier).
  • a compound of Formula XVII with a compound of Formula XXVII to yield a compound of Formula XXVIII can be facilitated in an organic solvent such as tefrahydrofuran or dimethylformamide, in the presence of a base, for example, sodium hydride or potassium tert-butoxide.
  • a base for example, sodium hydride or potassium tert-butoxide.
  • a compound of Formula XXVIII may also be formed by following Path b.
  • reaction of a compound of Formula XVI with a compound of Formula XXIX to form a compound of Formula XXX can be facilitated in an organic solvent, for example, tefrahydrofuran or dimethylfonnamide, in the presence of a base, for example, sodium hydride or potassium tert-butoxide.
  • Hydrolysis of a compound of Formula XXX to yield a compound of Formula XXXI can be carried out in a solvent, for example, methanol in water, ethanol, propanol, tetral ydrofuran or isopropyl alcohol, in the presence of a base, for example, sodium hydroxide, lithium hydroxide or potassium hydroxide.
  • the coupling of compound of Formula XXXI with a compound of Formula XXXII to yield a compound of Formula XXVIII can be carried out in a solvent, for example, dimethylformamide or tefrahydrofuran, in the presence of a condensing agent, for example, 1-ethyl- (3-dimethylamino propyl)-3-carbodimide, in the presence of 1- hydroxybenzotriazole and a base, for example, N-methylmorpholine or alternatively, through a mixed anhydride by reaction of Formula XXXI with a chlorofonnate, for example, ethyl chloroformate or isobutyl chloroformate.
  • a solvent for example, dimethylformamide or tefrahydrofuran
  • a condensing agent for example, 1-ethyl- (3-dimethylamino propyl)-3-carbodimide
  • esters are specified one skilled in the art could optionally hydrolyze them to their respective acids, for example, hydrolysis of alkyl esters (such as ethyl, methyl or benzyl ester) to their corresponding acids can be carried out in the presence of a base for example lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • a base for example lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • hydrolysis of benzyl ester can be carried out hydrogenatically using catalysts for example palladium on carbon or platinum on carbon.
  • Esters such as tert-butyl can be hydrolyzed to their corresponding acids in the presence of acid for example trifluoroacetic acid or hydrochloric acid.
  • acid for example trifluoroacetic acid or hydrochloric acid.
  • Example A Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5.6-dideoxy-5-amino- ⁇ -L- gulofuranoside
  • Step a Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-O-methane sulphonyl-cx ,D-mannofuranoside
  • a solution of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy- ⁇ -Z5-mannofuranoside (synthesized following the procedure as described in United States Patent No. 6,329,344) (11.5g) in dichloromethane (50 ml) was cooled at -5°C.
  • Step b Synthesis of 2,3-O-isopropylidene-l-O-dodecyl-5,6-dideoxy-5-benzyIammo- ⁇ - L-gulofuraiioside
  • benzyl amine (30 ml)
  • Benzyl amine was removed by distillation under vacuum and the reaction mixture was diluted with water and stirred for 30-40 minutes.
  • the aqueous layer was extracted with ethyl acetate.
  • the combined hexane layer was washed with water.
  • the combined organic layer was washed with brine and dried over anhydrous sodium sulphate.
  • the solvent was evaporated off and the residue was purified by column chromatography to obtain the title compound (9.2g).
  • Step c Synthesis of l-O-dodecyI-2,3-O-isopropy!idene-5,6-dideoxy-5-amino- ⁇ -L- gulofuranoside
  • methanol 200 ml
  • 10% palladium on carbon 4g
  • the reaction mixture was shaken for 7 hours under hydrogen atmosphere at 55 psi.
  • the reaction mixture was filtered through celite pad.
  • the filtrate was concentrated under reduced pressure.
  • the residue was purified by column chromatography using 2% triethylamine in ethyl acetate as eluent to furnish the title compound (5.7 g).
  • Example B Synthesis of methyl ⁇ 4-r(piperazin-1-yl-carbo ⁇ yl)-a ⁇ nino1-i3he ⁇ yl)-acetate
  • Step a Synthesis of methyl (4- ⁇ [(4-benzylpiperazin-1-yl)-carbonyl]-amino ⁇ -phenyl)-acetate
  • 1-benzylpiperazine 0.5g
  • dry tefrahydrofuran 10ml
  • triethylamine 0.47ml
  • methyl ⁇ 4-[(phenoxycarbonyl)-amino]- ⁇ henyl ⁇ -acetate obtained by t ie reaction of methyl 4-aminophenylacetate and phenyl chloroformate
  • Step b Synthesis of methyl ⁇ 4-[(piperazin-1-yI-carbonyI)-amino]-phenyl ⁇ -acetate
  • methanol 15ml
  • 10% palladium carbon 0.5g
  • dry ammonium formate 0.338g
  • Reaction mixture was refluxed at 70°C for about 3 hr.
  • Reaction mixture was filtered through celite and filtrate was concentrated. Residue was taken in water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulphate. The solvents were evaporated under reduced pressure to obtain the title compound (0.06g).
  • Example 1 Synthesis of l-O-Dodecyl ⁇ .S-O-isopropylidene-S. ⁇ -dideoxy-S- -nitro- phenyll-amino- ⁇ -L-guloftiranoside (Compound No. 1) To a solution of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-amino- ⁇ -L- gulofuranoside ( from Example A 1 gm) in acetonitrile (5ml) was added 4-nitro-fluoro- benzene (0.37gm) and diisopropylethylamine (0.52 ml) and the reaction mixture refluxed overnight.
  • Step a Synthesis of l-O-DodecyI-2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ 4-amino- phenyl ⁇ -amino- ⁇ -L-gulofuranoside
  • methanol 20 ml
  • 50 mg of 10% Pd/C was added to a solution of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ 4-nitro- phenyl ⁇ -amino- ⁇ -L-gulofuranoside (0.43 gm) taken in methanol (20 ml) was added 50 mg of 10% Pd/C and the reaction mixture was shaken under hydrogen atmosphere at 5O- 55 psi using a Parr shaker for 4 hours. The insoluble were filtered through a bed of celite and the filtrate concentrated, the crude product was purified using column chromatography to furnish the title compound (230 mg)
  • Step b Synthesis of l-O-Dodecyl-2,3-O-isopropyIidene-5,6-dideoxy-5- ⁇ 4-acetamido- phenyl ⁇ -amino- ⁇ -L-gulofuranoside (Compound No.
  • Example 5 Synthesis of l-O-Dodecyl-2.3-O-isopropylidene-5,6-dideoxy-5- ⁇ 2-methyl- butyl ⁇ -amino- ⁇ -L-gulofuranoside (Compound No. 5)
  • a solution of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-amino- ⁇ -L- gulofuranoside 500 mg
  • acetic acid 0.5 ml
  • 2- methylbutyraldehyde 0.15 ml, 1.35 mmol
  • Example 6 Synthesis of l-O-dodecyl-2, 3-O-isopropylidene-5, 6-dideoxy-5-dibenzyl- amino- ⁇ -L-gulofuranoside (Compound No. 11
  • benzyl bromide 0.32 ml
  • potassium carbonate 0.46 gm
  • Example 7 Synthesis of l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(benzoxazol- 2-yl ' )-amino- ⁇ -L-gulofuranoside (Compound No. 12)
  • l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-amino- ⁇ -L- gulofuranoside 500 mg
  • 2-chlorobenzoxazole (0.15 ml) and pyridine (0.3 ml).
  • reaction mixture was refluxed for 3 hour cooled, poured into water (20 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous sodium sulphate. The solvent was evaporated followed by purification of the residue over a silica gel column using 2.5% methanol-dichloromethane as eluent to furnish the title compound. (220 mg).
  • Example 8 Synthesis of 1.2-O-Isopropylidene-3-O-decyl-5-O- ⁇ 3-[l -(4- ⁇ 4- methoxyphenyl ⁇ Vpiperazinyl]-propyl
  • Step a Synthesis of l,2-O-Isopropylidene-3-O-decyl-5-O- ⁇ 3-hydroxypropyI ⁇ - ⁇ -D- xylofuranoside
  • a mixture of l,2-O-isopropylidene-3-O-decyl- ⁇ -D-xylofuranoside (3.5 gm) prepared following the procedure described in U.S.Patent 6,329,344).
  • 3-chloropropanol (1.202 g) and sodium hydroxide (1.27 g) in dimethyl sulphoxide (20 ml) was stirred at 110-120°C for 24 hours.
  • Step b - Synthesis of l,2-O-Isopropylidene-3-O-decyl-5-O-[3-(p-toluenesulphonyl)- oxypropyl] - -D-xylofur anoside
  • a solution of p- tosyl chloride (l.Og) in pyridine (10ml) was added dropwise with continuous stirring at 0-5°C. After 5 hours, water was added to the reaction mixture and then the solvents were removed at reduced pressure. The product was extracted with ethyl acetate followed by washing with water and brine and dried over anhydrous sodium sulphate.
  • Step c Synthesis of l,2-O-Isopropylidene-3-O-decyI-5-O- ⁇ 3-[l-(4- ⁇ 4- methoxyphenyI ⁇ )-piperazinyl]-propyl ⁇ - ⁇ -D-xylofuranoside (Compound No. 13) To a solution of the compound (0.25 g) obtained from step b in dimethylformamide (5 ml) was added l-(4-methoxy-phenyl)-piperazine (0.11 g) and the reaction mixture was stirred at 60-70°C for 8 hours.
  • Example 8a Synthesis of l,2-O-Isopropylidene-3-O-dodecyl-5-O- ⁇ 3-[4-( ⁇ [4-(2-methoxy- 2-oxoethyl phenyl1amino ⁇ carbonyD-piperazinyl]-propyll- ⁇ -D-xylofuranoside (Compound No. 27)
  • Step a Synthesis of l,2-O-Isopropy!idene-3-O-dodecyI-5-O- ⁇ 3-hydroxypropyl ⁇ - ⁇ -D- x xylofuranoside
  • l,2-O-isopropylidene-3-O-dodecyl- ⁇ -D-xylofuranoside 0.5g
  • 5-ml dry dimethylsulphoxide
  • 3-chloropropanol (0.160g) and sodium hydroxide(0.167g) stirred at 110°C - 120°C for overnight.
  • reaction mixture was quenched with dilute sodium hydrogen sulphate solution and extracted with ethyl acetate, the organic layer was washed with water and brine and dried over anhydrous sodium sulphate and the solvent was evaporated, residue was purified by silica gel column using 15% ethyl acetate -hexane as eluent to get the title compound (0.170g).
  • Step b - Synthesis of l,2-O-IsopropyIidene-3-O-dodecyI-5-O-[3-(p-methylsulphonyl) -oxypropyl] - ⁇ -D-xylofuranoside
  • dichloromethane 5ml
  • triethylamine 0.85ml
  • reaction mixture was stirred for 15 minutes followed by the addition of methansulphonyl chloride (0.047ml) and further stirred for 2hrs from 0°C to room temperature.
  • the reaction mixture was taken in distilled water and extracted with dichloromethane, the organic layer was washed with water and brine and dried over anhydrous sodium sulphate and the solvent was evaporated to get the title compound (250g).
  • Step c - Synthesis of l,2-O-Isopropylidene-3-O-dodecyl-5-O- ⁇ 3-[4-( ⁇ [4-(2-methoxy-2- oxoethyl)phenyl]amino ⁇ carbonyl)-piperazinyl]-propyI ⁇ - ⁇ -D-xylofuranoside To a solution of methyl ⁇ 4-[(piperazin-l-yl-carbonyl)-amino]-phenyl ⁇ -acetate
  • reaction mixture (0.26g) in dry dimethylformamide (5ml) was added dry potassium carbonate (0.209g) at 0°C and reaction mixture was stirred for 15 minutes followed by the addition of solution of compound obtained from the step b above (0.25g) in dry dimethylformamide (2ml) and further stirred for overnight at room temperature.
  • the reaction mixture was taken in water, extracted with ethyl acetate and the organic layer was washed with distilled water and brine and dried over anhydrous sodium sulphate, the solvent was evaporated and residue was purified by silica gel column using 70% ethyl acetate - hexane as eluent to furnish the title compound (0.035g).
  • Step a Synthesis of l-O-Methyl-2,3-O-isopropy!idene-5-deoxy-5-[3-hydroxypropyl]- aniino- ⁇ -D-Iyxofuranoside
  • a mixture of l-O-methyl-2,3-O-isopropylidene-5-tosyl- ⁇ -D-lyxofuranoside (prepared as described in U.S. Patent No. 6,329,344) (5.0gm) and 3-aminopropanol (2.0gm) were heated up to 60-70°C for 16 hours. Reaction mixture was diluted with hexane (100ml), the solid obtained was filtered off and the compound extracted with ethyl acetate.
  • Step b Synthesis of l-O-Methyl-2,3-O-isopropylidene-5-deoxy-5-[ ⁇ 3-[(4- ⁇ 2-methoxy- 2-oxo-ethyl ⁇ -phenyl)-amino]-carbonyloxy ⁇ -propyl]-amino- ⁇ -D-lyxofuranoside
  • dichloromethane (2ml) cooled to 0°C was added methyl 4-isocynatophenyl acetate (84 mg) and stirred for one hour.
  • Step c Synthesis of l-O-Methyl-2,3-O-isopropyIidene-5-deoxy-5-[ ⁇ 3-[(4- ⁇ 2-hydroxy- 2-oxo-ethyl ⁇ -phenyI)-amino]-carbonyIoxy ⁇ -propyl]-amino- ⁇ -D-lyxofuranoside
  • methanol 3 ml
  • the reaction mixture was heated upto 50- 60°C for 3 hours.
  • the reaction mixture was cooled and acidified with 10% HC1 solution.
  • the aqueous layer was extracted with ethyl acetate and the organic extracts washed with water and brine and dried over anhydrous sodium sulphate and concentrated.
  • the crude product was purified by column chromatography to furnish the title compound. (110 mg).
  • Step d Synthesis of Tris salt of l-O-Methyl-2,3-O-isopropylidene-5-deoxy-5-[ ⁇ 3-[(4- ⁇ 2-hydroxy-2-oxo-ethyI ⁇ -phenyI)-amino]-carbonyIoxy ⁇ -propyl]-amino- ⁇ -D- lyxofuranoside (Compound No. 16)
  • the compound obtained in step c (lOOmg) was dissolved is ethanol (1 ml) and equivalent amount of tris (hydroxymethyl) aminomethane (27.65mg) was added to it.
  • the reaction mixture stirred for 2 hours and the solvent was removed to get yellowish semi- solid as the title compound. (80 mg)
  • Step a Synthesis of l,2-O-IsopropyIidene-3-O-decyl-5-deoxy-5-bromo- ⁇ -D- xylofuranoside
  • Lithium bromide (1.25 g) was added to a solution of l,2-O-Isopropylidene-3-O- decyl-5-tosyl- ⁇ -D-xylofuranoside (2.5 g), in dry dimethylformamide (25 ml) at room temperature with stirring. After complete addition, the temperature of the reaction mixture was raised up to 70-80°C and stirred for 36 hours.
  • dimethylformamide was removed at reduced pressure and extracted with ethyl acetate followed by washing with saturated sodium bicarbonate, water and brine and then dried over anhydrous sodium sulphate. Evaporated the solvent under reduced pressure to obtain crude residue, which was then purified by column chromatography to furnish the title compound. (500 mg)
  • Step b Synthesis of l,2-O-Isopropylidene-3-O-decyl-5-deoxy-5-[2-(4-phenyl- thiazoIyl)-amino]- ⁇ -D ⁇ xylofuranoside
  • sodium hydride 1.0 gm
  • dry tefrahydrofuran 10 ml
  • 4-phenyl-thiazolyl-amine 166 mg
  • step a the compound (200 mg) obtained from step a in dry tetrahydrofuran (5 ml) was added through a dropping funnel and allowed the reaction to proceed at 70-80°C.
  • the solvent was evaporated under reduced pressure and extracted with ethyl acetate followed by washing with water, sodium carbonate and brine and dried over anhydrous sodium sulphate. Evaporated the solvent and the crude residue thus obtained was purified by column chromatography using hexane as eluent to furnish the title compound.
  • Example 10a Synthesis 1.2-O-Isopropylidene-3-O-dodecyl-5-deoxy-5-[(4-methyl- 1,3- thiazolyl)-amino]- ⁇ -D-xylofuranoside (Compound No. 28)
  • Step a Synthesis of l,2-O-Isopropylidene-3-O-dodecyl-5-O-methanesuIfonyI- ⁇ -D- xylofuranoside
  • triethylamine 0.13ml triethylamine 0.13ml
  • methansulphonyl chloride 0.074ml
  • Step b Synthesis of l,2-O-IsopropyIidene-3-O-dodecyl-5-deoxy-5-[(4-methyl-l,3- thiazolyl)-amino]- ⁇ -D-xylofuranoside
  • sodium hydride 0.057g 50%
  • 2-amino-4-methyl thiazole 0.136g
  • dry dimethylformamide (2ml) stirred for 3 firs at room temperature and then at 60°C for overnight followed by heating to 100°C for about 4hrs.
  • Example 11 Pharmacological activity The compounds disclosed herein were tested in one or both of the assays described herein. Standard assays were used to evaluate activity of compounds on inflammatory cells. Attenuation of agonist induced release of lipid mediators ofneutrophil chemotaxis, leukotriene B4 (LTB4), was used to evaluate inhibitory effect on neutrophils ⁇
  • Venous blood was collected from healthy human donors using heparin as an anticoagulant.
  • Neutrophils were isolated from freshly drawn blood after dextran sedimentation and ficoll separation (Eur J Biochem. 169, 175, 1987). 180 ⁇ l of the ofneutrophil suspension (0.2xl0 6 cells/ml) was taken and added 19 ⁇ L of Hank's Buffer salt solution along with l ⁇ L of the test drug (200 times concentrated) in a 24 well plate and incubated at 37°C for Ihour. 3 minutes before the end of test compound incubation, 0.25 mM Ca ⁇ / g** were added. Then, 0.3 ⁇ g/ml A23187 (Sigma Chem, USA) was added and incubated for further 10 min at 37°C.
  • the reaction was stopped by adding 80 ⁇ L of cold methanol and centrifuged to remove cell debris (J Pharmacol Exp Ther. 297:267, 2001).
  • the samples were analysed for LTB release using LTB ELISA kits (Assay Design Inc., USA). The amount of LTB 4 released was quantified and percent inhibition of LTB release was calculated with respect to the difference between the A23187 stimulated and negative control cells, to compute IC 50 values.
  • test drug 200 times concentrated or vehicle was added, followed by 4 ⁇ l of recombinant 5-Lox (3 units/ ⁇ l) and was incubated at 37°C for 5 min.
  • the reaction was initiated by adding 1 ⁇ l of lmM freshly prepared arachidonic acid and increase in absorbance was monitored at 236 nm for 10 min.
  • a plot of absorbance verses time curve was prepared and area under curve (AUC) was computed for each well. Percent inhibition of AUC for different treatments was calculated with respect to the difference between the Arachidonic acid stimulated and negative control values, to compute IC 50 values.
  • Particular compound numbers 1, 8, 10, 16, and 27 were examined, showing activity from about 1.9 ⁇ M to about 8 ⁇ M, or from about 1.9 ⁇ M to about 3 ⁇ M.

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Abstract

L'invention concerne des dérivés du monosaccharide en tant qu'agents anti-inflammatoires. Les composés de l'invention peuvent servir à inhiber et à prévenir une inflammation et des pathologies associées, y compris des maladies inflammatoires et auto-immunes telles que l'asthme, la polyarthrite rhumatoïde, le diabète de type I, la sclérose en plaques, le rejet de greffe allogénique, le psoriasis, les maladies entériques inflammatoires, la colite ulcéreuse, l'acné, l'athérosclérose, le cancer, la prurit ou la rhinite allergique. La présente invention porte également sur des compositions pharmaceutiques contenant les composés de l'invention et sur des méthodes pour traiter l'asthme, les maladies respiratoires obstructives, la polyarthrite rhumatoïde, le diabète de type I, la sclérose en plaques, le rejet de greffe allogénique, le psoriasis, les maladies entériques inflammatoires, la colite ulcéreuse, l'acné, l'athérosclérose, le cancer, la prurit ou la rhinite allergique, ainsi que d'autres troubles inflammatoires et/ou auto-immunes, au moyen des composés de l'invention.
PCT/IB2005/000974 2004-04-13 2005-04-13 Derives du monosaccharide WO2005100373A2 (fr)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
JP2014528482A (ja) * 2011-10-14 2014-10-27 アムビト ビオスシエンセス コルポラチオン Ｉｉｉ型受容体チロシンキナーゼの調節因子としての複素環式化合物及びその使用
KR20210158277A (ko) * 2020-06-23 2021-12-30 (주)바이오메트릭스 테크놀로지 항암 활성 그리고 항바이러스 활성을 갖는 신규한 벤지미다졸-탄수화물 결합체 화합물(Benzimidazole carbohydrate conjugate compound) 및 이의 제조 방법
US12043644B2 (en) 2020-06-23 2024-07-23 Biometrix Technology Inc Benzimidazole derivatives, preparation method thereof and use thereof as anti-cancer agent or anti-virus agent comprising the same

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014528482A (ja) * 2011-10-14 2014-10-27 アムビト ビオスシエンセス コルポラチオン Ｉｉｉ型受容体チロシンキナーゼの調節因子としての複素環式化合物及びその使用
KR20210158277A (ko) * 2020-06-23 2021-12-30 (주)바이오메트릭스 테크놀로지 항암 활성 그리고 항바이러스 활성을 갖는 신규한 벤지미다졸-탄수화물 결합체 화합물(Benzimidazole carbohydrate conjugate compound) 및 이의 제조 방법
KR102449266B1 (ko) * 2020-06-23 2022-09-30 (주)바이오메트릭스 테크놀로지 항암 활성 그리고 항바이러스 활성을 갖는 신규한 벤지미다졸-탄수화물 결합체 화합물(Benzimidazole carbohydrate conjugate compound) 및 이의 제조 방법
US12043644B2 (en) 2020-06-23 2024-07-23 Biometrix Technology Inc Benzimidazole derivatives, preparation method thereof and use thereof as anti-cancer agent or anti-virus agent comprising the same

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