WO2005092907A2 - Monosaccharide derivatives as anti-cancer and anti-inflammatory agents - Google Patents

Monosaccharide derivatives as anti-cancer and anti-inflammatory agents Download PDF

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Publication number
WO2005092907A2
WO2005092907A2 PCT/IB2005/000803 IB2005000803W WO2005092907A2 WO 2005092907 A2 WO2005092907 A2 WO 2005092907A2 IB 2005000803 W IB2005000803 W IB 2005000803W WO 2005092907 A2 WO2005092907 A2 WO 2005092907A2
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compound
amino
isopropylidene
carbonyl
phenyl
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PCT/IB2005/000803
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French (fr)
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WO2005092907B1 (en
WO2005092907A3 (en
Inventor
Viswajanani Jitendra Sattigeri
Sudershan K. Arora
Mohammad Salman
Venkata P. Palle
Gyan Chand Yadav
Madan Pal Tanwar
Ashis Mukherjee
Ramamurthy Narayanan
Abdul Rehaman Abdul Rauf
Keshav Prabhakar Naik
Ajay Soni
Abhijit Ray
Raj Kumar Shirumalla
Kasim Abbas Mookhtiar
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Ranbaxy Laboratories Limited
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Publication of WO2005092907B1 publication Critical patent/WO2005092907B1/en

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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
    • 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 disclosed 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 or psoriasis.
  • Pharmacological compositions containing compounds disclosed herein and the methods of treating bronchial asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, multiple sclerosis, type I diabetes, psoriasis, allograft rejection, and other inflammatory and/or autoimmune disorders, using the compounds are also provided.
  • Inflammation is a key defense mechanism of the body that is switched on as a result of tissue injury.
  • the inflammatory process is self-containing, however, under certain pathophysiological conditions 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.
  • chemokines cytokines
  • proteolytic enzymes and other bioactive molecules.
  • Mast cells primed by lymphocytes can interact with environmental allergens and release mediators like histamine, prostaglandin, leukotrienes, etc. (Clin. Exp. Allergy, 32, 1682, 2002) to initiate an early inflammatory response. This is followed by a delayed inflammatory response due to release of cytokines (for example IL-4, IL-5, IL-6, IL-8, IL-13, GM-CSF and TNFalpha), chemokines and proteolytic enzymes (for example chymase, tryptase) (Chest 112, 523, (1997); Lancet 350, 59, (1997)) that not only bring about tissue damage, but attract other inflammatory cells and initiate tissue fibrosis, and the cycle continues.
  • cytokines for example IL-4, IL-5, IL-6, IL-8, IL-13, GM-CSF and TNFalpha
  • chemokines and proteolytic enzymes for example chymase, tryptas
  • U.S. Patent 6,329,344 Bl discloses several monosaccharide derivatives said to be useful as cell adhesion inhibitors. It generally relates to a group of substituted pentose and hexose monosaccharide derivatives, which are described exhibiting as cell adhesion inhibitory and anti-inflammatory activities.
  • U.S. Patent 6,590,085 Bl discloses several monosaccharide derivatives, described as inhibitors of cell adhesion and cell adhesion mediated pathologies, including inflammatory and autoimmune diseases.
  • Patent Application US 2002/0173632 Al discloses furanose and amino furanose compounds said to be useful for treatment of rheumatoid, arthritis, immunomodulatory diseases, inflammatory and proliferative diseases.
  • U.S. Patent 5,298,494 discloses derivatives of monosaccharides, which reportedly exhibit anti-proliferative and/or anti-inflammatory activity, and are described as useful for treating mammals having inflammatory disorders and/or autoimmune disorders.
  • U.S. Patent 5,367,062 discloses derivatives of disubstituted and deoxydisubstituted ,D-lyxofuranosides which reportedly exhibit significant anti-inflammatory and antiproliferative activity, and are described as useful for treating inflammatory and/or autoimmune disorders.
  • Patent 5,360,794 discloses deoxydisubstituted or dideoxy disubstituted derivatives of ⁇ -D- mannofuranoside and ⁇ -L-gulofuranosides, which are described as exhibiting anti- inflammatory and antiproliferative activity.
  • U.S Patent 4,996,195 discloses derivatives of ⁇ ,D-glucofuranose and ⁇ ,D-allofuranose said to be useful for treating animals and mammals with inflammatory and/or autoimmune disorders.
  • U.S. 5,010,058 discloses derivatives of 1,2- O-iso-propylidene- ⁇ -D-glucofuranose said to be useful for treating animals and mammals with inflammatory and/or autoimmune disorders.
  • Patent 5,360,792 disclose 5- or 6-deoxy hexose monosaccharides having a saturated nitrogen containing heterocycle said to be useful as antiproliferative 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 described as exhibiting immunomodulatory, anti-inflammatory and anti-proliferative activity.
  • WO 94/11381 discloses derivatives of pentose monosaccharides said to be useful as antiproliferative and anti-inflammatory compounds.
  • Monosaccharide derivatives which can be used for the 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 herein.
  • Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides of these compounds having the same type of activity are also provided.
  • compositions containing the compounds, and which may also contain pharmaceutically acceptable carriers or diluents, which may be used for the treatment of inflammatory and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis, allograft rejection or psoriasis are provided herein.
  • inflammatory and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis, allograft rejection or psoriasis.
  • alkyl is optionally substituted with hydroxyl, cycloalkyl, aryl, -OCONR p R q , -NR p R q
  • R p and R q are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyjl or R p and R q may together join to form a cyclic ring (3-8 membered), which may be optionally benzofused, containing 0-4 heteroatoms (selected from O, S, and N) [wherein the ring may be substituted with one or more of alkyl, alkenyl, alkynyl, hydroxyl, - NH 2 , substituted amino, cycloalkyl, -COOR 7 (wherein R is selected from alkyl, alkenyl, alkynyl, hydroxyl,
  • R 2 and R 3 together can form a five-membered acetal wherein the carbon joining the oxygens is substituted with Ri b and R m wherein
  • R L and R m are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and aralkyl;
  • R L and R m together can join to form a cyclic ring (3-8 membered), wherein the ring may optionally contain one or more heteroatoms selected from O, N or S, and the ring may be substituted with one or more of alkyl, alkenyl, alkynyl, -NH 2 , substituted amino, cycloalkyl, COOR 7 (wherein R 7 is the same as defined above), carboxy, oxo, hydroxyl, alkoxy, aryloxy, halogen (F,C1, Br, I), aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl; or
  • R L and R m together can join to form an oxo group.
  • R can be
  • Rc is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl.
  • R 4 when R 4 is ORc then R 3 and Rc together can form an acetal (wherein acetal is the same as defined earlier) and R 2 can be selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl.
  • R x and R y are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, S(O) 2 R 6 [wherein R 6 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, -NR p Rq (wherein R p and R q are the same as defined earlier), aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, or heteroarylalkyl], heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, or cycloalkyl ⁇ , or R x and R y may also together join to form a heterocyclyl or heteroaryl ring;
  • R s is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, and heteroarylalkyl; and Rj is selected from hydrogen, lower (Ci- C 4 ) alkyl, lower (C 3 -C 6 ) alkenyl, lower (C 3 -C 6 ) alkynyl, lower (C 2 -C 6 ) cycloalkyl, lower (Ci- C 3 ) aralkyl, aryl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl;
  • Rj is the same as defined above and R u is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl;
  • R j is the same as defined above and R t is OH or R x and T is O, S, -N(CN), -N(NO 2 ), -CH(NO 2 ) and R x is the same as defined earlier (with the proviso that when T is O, Ri is H or CH 3 , R t is H and R x is S(O) 2 R 6 (where R 6 is aryl) or aryl, then the aryl cannot be substituted at its para position with Cl, NO 2 , OCH 3 , CH 2 COOH, CH 2 COOCH 3 , CH 2 COLDVP, CH 2 CODVP or CH 2 COVP).
  • heterocyclyl and also, wherein the said heterocyclic ring, which may or may not be benzofused, is always substituted when Ri is H, CH 3 or alkyl substituted with -NR p R q
  • R p and Rq are hydrogen, alkyl, aralkyl or together joins to form a cyclic ring as defined earlier).
  • Ri and R 5 may also together join form a heterocyclyl ring with the proviso that Ri and R 5 together do not form an isopropylidene ring.
  • R 5 can be, for example, amino carbonyl alkylheterocyclyl amino sulfonyl aryl (-
  • Het-NH-SO 2 -alkyl with n from 0 to 6, and where Het and alkyl can be substituted as indicated above
  • oxo carbonyl amino aryl (-O-CONH-Ar, where Ar can be substituted as indicated above)
  • oxo carbonyl amino alkylaryl (O-CONH-(CH 2 ) n -Ar, with n from 0 to 6, and where Ar can be substituted as indicated above)
  • oxo carbonyl amino sulfonyl heterocyclyl - O-CONH-SO 2 -Het, where Het can be substituted as indicated above
  • oxo carbonyl amino sulfonyl aryl (-O-CONH-SO 2 -Ar, where Het can be substituted as indicated above)
  • alkyl amino carbonyl aryl ((CH 2 ) n -NHCO-Ar, with n from 0 to 6, and where Ar can be substituted as indicated
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term is 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.
  • alkynyl unless and otherwise specified 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 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.
  • alkyl groups 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.
  • the substituents are attached to the ring atom, be it carbon or heteroatom.
  • heteroaryl groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like as well as non-fused systems such as bipyrimidinyl, and other such analogues.
  • heterocyclyl ring may optionally contain one or more olefinic bond(s).
  • heterocyclyl groups are tetrahydro furanyl, dihydrofuranyl, dihydropyridinyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, piperidinyl or piperazinyl.
  • Heteroarylalkyl refers to alkyl-heteroaryl group linked tlirough 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.
  • R p is the same as defined earlier.
  • Substituted amino unless otherwise specified refers to a group -N(R k ) wherein each
  • leaving group generally refers to groups that exhibit the desirable properties of being labile under the defined synthetic conditions and also, of being easily 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 refers to, for example, protected amino acids, aliphatic acids or aromatic acids, for example their corresponding acyl halide (e.g.
  • protecting groups is used herein to refer to known moieties which have the desirable property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be 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.
  • natural amino acid represents 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' forms 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 of 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.
  • DNP refers to a tripeptide aspartyl-valyl-prolyl.
  • NP refers to a dipeptide valyl-prolyl.
  • Compounds described herein generally contain one or more asymmetric carbon atoms and thus can occur as racemates and racemic mixtures, single enantiomers, diastereomieric mixtures and individual diastereomers.
  • each stereogenic 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.
  • the compounds disclosed herein may be prepared by techniques well known in the art and familiar to a practitioner skilled in art of this invention.
  • the compounds disclosed herein may be prepared by the processes described herein, although these processes are not the only means by which the compounds described may be synthesised. Further, some of the various synthetic steps described herein may be performed in an alternate sequence or order to give the desired compounds.
  • the compound of Formula IN can be prepared following Scheme I.
  • a compound of Formula II (wherein W is -OH or - ⁇ H 2 , R t is H or CH > R 2 , R 3 and R 4 are the same as defined earlier) is reacted with a compound of Formula III (wherein R x is the same as defined earlier) to give a compound of Formula IN (wherein T is -O or - ⁇ H)
  • the compound of Formula II can be reacted with a compound of Formula III to give a compound of Formula IN in an organic solvent, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride in the presence of an organic base for example pyridine, triethylamine or diisopropylethylamine.
  • a compound of an organic solvent for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride in the presence of an organic base for example pyridine, triethylamine or
  • Formula II can be reacted with a phenyl or p-nitrophenylcarbamate of an amine (R X ⁇ H 2 ) to give a compound of FormulalN in a solvent for example tetrahydrofuran, dimethylformamide or dimethyl sulfoxide optionally in the presence of bases such as triethylamine, pyridine or diisopropylethylamine.
  • a solvent for example tetrahydrofuran, dimethylformamide or dimethyl sulfoxide
  • bases such as triethylamine, pyridine or diisopropylethylamine.
  • Tris salt of l,2-O-isopropylidene-3-O-dodecyl-6-deoxy-6-( ⁇ [4-(2-hydroxy-2-oxo-ethyl)- phenyl]-amino-carbonyl)-amino- ⁇ -D-glucofuranoside (Compound No.196 ).
  • the compounds of Formula VIII can be prepared by Scheme II.
  • a compound of Formula V (wherein R 2 , R 3 and R 4 are the same as defined earlier) is reacted with a compound of Formula VI (wherein X can be -CH-, -O-, or -NH- and k is 1-2) to give a compound of Formula Nil, which is finally reacted with a compound of Formula III (wherein R x is the same as defined earlier) to give a compound of Formula NHL
  • the compound of Formula Nil can be reacted with a compound of Formula III to give a compound of Formula NIII in an organic solvent, for example, dichloromethane, dichloroethane, carbon tetrachloride or chloroform.
  • Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O- ⁇ (4-methoxy-phenyl)-amino ⁇ - carbonyl-6-deoxy-6-(l-pyrrolidinyl)- ⁇ -D-mannofuranoside (Compound No. 52) Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O- ⁇ (4-methyl-phenyl)-amino ⁇ - carbonyl-6-deoxy-6-(l-pyrrolidinyl)- ⁇ -D-mannofuranoside (Compound No.
  • Hydrochloride salt of 1 -O-Heptyl-2,3 -O-isopropylidene-5-O- ⁇ [4-methyl- ⁇ henyl] -amino ⁇ - carbonyl-6-deoxy-6-(l-azepanyl)- ⁇ -D-mannofuranoside (Compound No. 56)
  • Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O- ⁇ (4-methoxy-phenyl)-amino ⁇ - carbonyl-6-deoxy-6-(l-azepanyl)- ⁇ -D-mannofuranoside Compound No.
  • 6-deoxy-6-(l-azepanyl)- ⁇ -D-glucofuranoside (Compound No. 67) l,2-O-Isopropylidene-3-O-decyl-5-O- ⁇ [4-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino ⁇ -carbonyl-
  • 6-deoxy-6-(l-azepanyl)- ⁇ -D-glucofuranoside (Compound No. 68) l,2-O-Isopropylidene-3-O-decyl-5-O-(4-methoxy-phenyl)-amino ⁇ -carbonyl-6-deoxy-6-(l- azepanyl)- ⁇ -D-glucofuranoside (Compound No. 69) l,2-O-Isopropylidene-3-O-decyl-5-O-(phenylamino)-carbonyl-6-deoxy-6-(l-azepanyl)- ⁇ -D- glucofuranoside (Compound No.
  • 6-(4-morpholinyl)- ⁇ -D-mannofuranoside Compound No. 95
  • l-O-Heptyl-2,3-O-isopropylidene-5-O- ⁇ (4-methyl-phenyl)-amino ⁇ -carbonyl-6-deoxy-6-(4- mo holinyl)- ⁇ -D-mannofuranoside Compound No. 96
  • l-O-Heptyl-2,3-O-isopropylidene-5-O- ⁇ (4-chloro-phenyl)-amino ⁇ -carbonyl-6-deoxy-6-(4- morpholinyl)- ⁇ -D-mannofuranoside Compound No.
  • Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O- ⁇ (4-chloro-phenyl)- sulfonylamino ⁇ -carbonyl-6-deoxy-6-(l -pynolidinyl)- ⁇ -D-glucofuranoside (Compound No. 102)
  • Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-(phenyl-sulfonylamino)-carbonyl- 6-deoxy-6-(l-pyrrolidinyl)- ⁇ -D-glucofuranoside Compound No.
  • Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-(phenyl-sulfonylamino)- carbonyl-6-deoxy-6-(l-piperidinyl)- ⁇ -D-glucofuranoside (Compound No. 106) Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O- ⁇ 4-chloro-phenyl)- sulfonylamino ⁇ -carbonyl-6-deoxy-6-(l-piperidinyl)- ⁇ -D-glucofuranoside (Compound No.
  • Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O- ⁇ (phenylsulfonylamino)- carbonyl ⁇ -6-deoxy-6-(l-pyrrolidinyl)- ⁇ -D-glucofuranoside (Compound No.l 14 ) Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O- ⁇ [(4-methyl-phenyl)-amino]- carbonyl ⁇ -6-deoxy-6-(l-azepanyl)- ⁇ -D-glucofuranoside (Compound No.
  • Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O- ⁇ [4-methyl-phenyl)- sulfonylamino ⁇ -carbonyl-6-deoxy-6-(l-pyrrolidinyl)- ⁇ -D-allofuranoside (Compound No. 129)
  • Hydrochloride salt of l,2-O-isopropylidene-3-0-heptyl-5-O-[(4-methyl-phenyl)- sulfonylamino]-carbonyl-6-deoxy-6-(4-morpholinyl)- ⁇ -D-allofuranoside Compound No.
  • Tris salt of l,2-O-isopropylidene-3-0-dodecyl-5-O- ⁇ [4-(2-hydroxy-2-oxo-ethyl)-phenyl]- amino ⁇ -carbonyl-6-deoxy-6-(4-morpholinyl)- ⁇ -D-glucofuranoside (Compound o. 132)
  • Formula IX (wherein Ri is H, -OH, -CH 3 or -Oalkaryl) is reacted with a compound of Formula X (wherein R u is the same as defined earlier, L is a leaving group such as OH (activated in situ, as is obvious to a skilled practitioner) or halogen (F, Cl, Br, I) and Y is -
  • reaction of a compound of Formula IX with a compound of Formula X can be carried in an organic solvent for example, tetrahydrofuran or dimethylformamide or dioxane with a condensing agent, for example, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in the presence of organic base, for example, N-methylmorpholine, diisopropylamine or triethylamine.
  • organic solvent for example, tetrahydrofuran or dimethylformamide or dioxane
  • a condensing agent for example, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in the presence of organic base, for example, N-methylmorpholine, diisopropylamine or triethylamine.
  • the compounds of Formula XNI and XNIII can be prepared following Scheme IN.
  • a compound of Formula XII (wherein Ri, R 2 , R 3 and R 4 are the same as defined earlier)
  • a compound of Formula XIII wherein P is protecting group such as aralkyl or acyl
  • P is protecting group such as aralkyl or acyl
  • Path a The compound of Formula XN is reacted with a compound of Formula III (wherein R x is the same as defined earlier) to give a compound of Formula XNI.
  • Path b The compound of Formula XN is reacted with a compound of Formula XNII (wherein hal is halogen (F, Cl, Br, I) to give a compound of Formula XNIII.
  • the compound of Formula XIN can be deprotected (when P is aralkyl, for example, benzyl) to give a compound of Formula XN in an organic solvent, for example, methanol, ethanol, propanol, isopropylalcohol, tefrahydrofuran or ethyl acetate, under deprotection, conditions, for example, hydrogenatically utilizing palladium on carbon or, for example, under catalytic transfer hydrogenation conditions of ammonium formate and palladium on carbon.
  • reaction of a compound of Formula XN with a compound of Formula III (Path a) to give a compound of Formula XNI can be carried out carried out in an organic solvent, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
  • reaction of a compound of Formula XN with a compound of Formula XNII (Path b) to give a compound of Formula XNIII can be carried out in an organic solvent, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride, tetrahydrofuran or dimethylformamide in the presence of a base, for example, pyridine, triethylamine or diisopropylethylamine.
  • an organic solvent for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride, tetrahydrofuran or dimethylformamide
  • a base for example, pyridine, triethylamine or diisopropylethylamine.
  • l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- ⁇ l-[4- ⁇ [4-(2-methoxy-2-oxo-ethyl)-phenyl]- amino ⁇ -carbonyl]-piperazinyl ⁇ - ⁇ -D-lyxofuranoside Compound No. 159
  • l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- ⁇ l-[4-(4-chloro-phenylamino)-carbonyl]- piperazinyl ⁇ - ⁇ -D-lyxofuranoside Compound No.
  • the compound of Formula XXIV can be prepared by Scheme V.
  • a compound of Formula XIX (wherein R 2 , R 3 and R 4 are the same as defined earlier) is reacted with a compound of Formula XX (wherein R p , Ri is the same as defined earlier) to give a compound of Formula XXI, which is N-protected to give a compound of Formula XXII (wherein P is protecting group such as aralkyl or acyl), which is reacted with a compound of Formula III (wherein R x is same as defined earlier) to give a compound of Formula XXIII, which is deprotected to give a compound of Formula XXIV.
  • XXII can be carried out in an organic solvent, for example, tetrahydrofuran, dioxane or diethyl ether with the protecting agent for example benzyl chloroformate, di-tert-butyl dicarbonate, acetic anhydride, benzyl chloride, benzyl bromide, benzyl iodide or sulphonyl halide in the presence of a base, for example, triethylamine, diisopropylethylamine or pyridine.
  • organic solvent for example, tetrahydrofuran, dioxane or diethyl ether
  • the protecting agent for example benzyl chloroformate, di-tert-butyl dicarbonate, acetic anhydride, benzyl chloride, benzyl bromide, benzyl iodide or sulphonyl halide in the presence of a base, for example, triethylamine,
  • reaction of a compound of Formula XXII with a compound of Formula III to give a compound of Formula XXIII can be carried out in an organic solvent, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
  • organic solvent for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
  • XXIII to give a compound of Formula XXIV can be carried out in an organic solvent, for example, methanol, ethanol, propanol, isopropylalcohol or ethyl acetate under conditions of deprotection, for example, hydrogenatically utilizing palladium on carbon under catalytic transfer hydrogenation conditions of ammonium formate and palladium on carbon.
  • an organic solvent for example, methanol, ethanol, propanol, isopropylalcohol or ethyl acetate
  • deprotection for example, hydrogenatically utilizing palladium on carbon under catalytic transfer hydrogenation conditions of ammonium formate and palladium on carbon.
  • the compound of Formula XXVII can be prepared by Scheme VI.
  • a compound of Formula XXV wherein Xi is OH or halogen (F, Cl, Br, I) and R 2 , R 3 , and R 4 are the same as defined earlier
  • a compound of Formula XXNI wherein R x and R y are the same as defined earlier
  • reaction of a compound of Formula XXN with a compound of Formula XXNI to give a compound of Formula XXNII can be carried out in an organic solvent, for example, tetrahydrofuran or dimethylformamide with the condensing agent, for example, l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide in the presence of an organic base, for example, ⁇ -methylmorpholine, diisopropylethylamine or triethylamine.
  • an organic solvent for example, tetrahydrofuran or dimethylformamide
  • the condensing agent for example, l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide in the presence of an organic base, for example, ⁇ -methylmorpholine, diisopropylethylamine or
  • Formula XXNI to give a compound of Formula XXNII can be carried out in an organic solvent, for example, tetrahydrofuran or dimethylformamide in the presence of carbonyldiimidazole and a base such as triethylamine, ⁇ -ethyldiisopropylamine or pyridine.
  • organic solvent for example, tetrahydrofuran or dimethylformamide
  • carbonyldiimidazole and a base such as triethylamine, ⁇ -ethyldiisopropylamine or pyridine.
  • the compounds of Formula XXIX, XXX and XXXII can be prepared by Scheme NIL Thus Path a: The compound of Formula XXNIII (wherein R 2 , R 3 and R ⁇ are the same as defined earlier) is reacted with a compound of Formula XXNI (wherein R x and R y are the same as defined earlier) and carbonyldiimidazole to give a compound of Formula XXIX (wherein X 2 is O or S).
  • Path b The compound of Formula XXNIII is reacted with a compound of Formula XXVI and phenyl chloroformate to give a compound of Formula XXX (wherein R x , R 3 and t are the same as defined earlier).
  • carbonyldi- 1,2,3- benzotriazole or carbonyldi- 1,2,4-triazole can also be used in place of carbonyldiimidazole.
  • phenyl chloroformate to give a compound of Formula XXX can be carried out in an organic solvent, for example, tetrahydrofuran, dimethylformamide, diethylether or dioxane.
  • organic solvent for example, tetrahydrofuran, dimethylformamide, diethylether or dioxane.
  • chloroformates for example p- nitrophenyl chloroformate can also be used in place of phenyl chloroformate.
  • reaction of a compound of Formula XXNIII with a compound of Formula XXXI (Path c) to give a compound of Formula XXXII can be carried out in a solvent, for example, dichloromethane, dichloroethane, carbon tetrachloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide or dimethylsulphoxide.
  • a solvent for example, dichloromethane, dichloroethane, carbon tetrachloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide or dimethylsulphoxide.
  • Formula XU Formula XLIl
  • the compound of Formula XLII can be prepared by Scheme VIII.
  • a compound of Formula XXXIII (wherein R 2 , R 3 and j are the same as defined above) is reacted with a cyanating agent, for example, sodium cyanide, to give a compound of Formula XXXIN, which undergoes -OH activation to give a compound of Formula XXXV (Pi is, for example, mesyl, tosyl or triflyl), which is reacted with a compound of Formula XXXVI (P is protecting group such as aralkyl or acyl) to give a compound of Formula XXXVII, which is hydrolyzed to give a compound of Formula XXXVIII, which is further esterified to give a compound of
  • a cyanating agent for example, sodium cyanide
  • the -OH activation of a compound of Formula XXXIN to give a compound of Formula XXXN can be carried out in an organic solvent, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride with OH activating reagents, for example, methanesulphonyl chloride, toluenesulphonyl chloride or triflic anhydride.
  • organic solvent for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride with OH activating reagents, for example, methanesulphonyl chloride, toluenesulphonyl chloride or triflic anhydride.
  • the hydrolysis of a compound of Formula XXXNII to give a compound of Formula XXXNIII can be carried out an organic solvent, for example, ethanol, methanol, propanol, tetrahydrofuran or isopropylalcohol in the presence of a base, for example, sodium hydroxide, potassium hydroxide or lithium hydroxide.
  • a base for example, sodium hydroxide, potassium hydroxide or lithium hydroxide.
  • the hydrolysis can also be carried out in the presence of acid, for example, trifluoroacetic acid and hydrochloric acid.
  • the compound of Formula XXXVIII can be esterified to give a compound of Formula XXXIX in an organic solvent, for example, dichloromethane or dichloroethane with a halogenating agent, for example, oxalyl chloride, or thionyl chloride, followed by reaction with an alcohol for example, ethanol, methanol, tert-butanol or benzyl alcohol in the presence of base, for example, pyridine, triethylamine, or diisopropylethyl amine.
  • an organic solvent for example, dichloromethane or dichloroethane with a halogenating agent, for example, oxalyl chloride, or thionyl chloride
  • an alcohol for example, ethanol, methanol, tert-butanol or benzyl alcohol in the presence of base, for example, pyridine, triethylamine, or diisopropylethyl amine.
  • the compound of Formula XXXVIII can also be an esterified compound of Formula XXXIX with the condensing agent being, for example, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide, and in the presence of an organic base for example dimethylaminopyridine and an alcohol, for example, ethanol, methanol, propanol or isopropyl alcohol, benzyl alcohol, or tertbutanol.
  • the condensing agent being, for example, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide
  • an organic base for example dimethylaminopyridine
  • an alcohol for example, ethanol, methanol, propanol or isopropyl alcohol, benzyl alcohol, or tertbutanol.
  • the ⁇ -deprotection of a compound of Formula XXXIX to give a compound of Formula XL can be carried out in an organic solvent, for example, methanol, ethanol, ethyl acetate, tetrahydrofuran, propanol or isopropylalcohol, under deprotection conditions, for example, hydrogenatically utilizing palladium on carbon under catalytic transfer hydrogenation conditions of ammonium formate and palladium on carbon.
  • an organic solvent for example, methanol, ethanol, ethyl acetate, tetrahydrofuran, propanol or isopropylalcohol
  • reaction of a compound of Formula XL with a compound of Formula III to give a compound of Formula XLI can be carried out in the presence of an organic solvent, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
  • an organic solvent for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
  • a compound of Formula XL can be converted to a compound of Formula XLI by utilizing
  • Formula XLVII The compound of Formula XLVII can be prepared by Scheme IX.
  • a compound of Formula XXVIII (wherein R 2 , R 3 and R-j are the same as defined earlier) is reacted with a compound of Formula XLIII (wherein P is a protecting group such as arallcyl or acyl), to give compound of Formula XLIV, which is deprotected to give a compound of Formula XLV.
  • Path a The compound of Formula XLV is reacted with a compound of Formula XXVI and carbonyldiimidazole to give a compound of Formula XL VI.
  • Pathb The compound of Formula XLV is reacted with a compound of Formula R x --hal
  • hal is a halogen (F, Cl, Br, I) and R x is the same as defined earlier
  • the reaction of a compound of Formula XXVIII with a compound of Formula XLIII to give a compound of Formula XLIN can be carried in an organic solvent, for example, tetrahydrofuran or dimethylformamide with the condensing agent, for example, l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in the base, for example, ⁇ -methylmorpholine, diisopropylamine or triethylamine.
  • an organic solvent for example, tetrahydrofuran or dimethylformamide
  • the condensing agent for example, l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in the base, for example, ⁇
  • the deprotection of a compound of Formula XLIN (when P is tert-butoxycarbonyl group) to give a compound of Formula XLN can be carried in an organic solvent for example dichloromethane or dichloroethane in the presence of acid, for example, trifluoroacetic acid or hydrochloric acid.
  • an organic solvent for example dichloromethane or dichloroethane in the presence of acid, for example, trifluoroacetic acid or hydrochloric acid.
  • (Path a) and carbonyldiimidazole to give a compound of Formula XLNI can be carried out in an organic solvent, for example, tetrahydrofuran, dimethylformamide, diethylether or dioxane.
  • organic solvent for example, tetrahydrofuran, dimethylformamide, diethylether or dioxane.
  • carbonyldi-l,2,3-benzotriazole or carbonyldi- 1,2,4-triazole can also be used in place of carbonyldiimidazole.
  • Formula XLNI could be used, as would be evident to a skilled person in the art of this invention.
  • the compound of Formula XLN is reacted with a compound of Formula R x --hal
  • (Path b) to give a compound of Formula XLNII can be carried out in an organic solvent, for example, dimethylformamide, tetrahydrofuran, dioxane, acetone or diethyl ether in the presence of an organic base, for example, sodium hydride, potassium hydride, potassium tert- butoxide or potassium carbonate.
  • organic solvent for example, dimethylformamide, tetrahydrofuran, dioxane, acetone or diethyl ether
  • an organic base for example, sodium hydride, potassium hydride, potassium tert- butoxide or potassium carbonate.
  • the compound of Formula LI can be prepared by Scheme X.
  • a compound of Formula XLVIII (wherein R 2 , R 3 and R 4 are same as defined earlier) is reacted with a compound of Formula XLIX [wherein hal is halogen (F, Cl, Br, I)] to give a compound of Formula L (wherein ki is an integer ranging from 1-6), which is reacted with a compound of formula XXVI (wherein R x and R y are the same as defined earlier) to give a compound of Formula LI.
  • the reaction of a compound of Formula XLVIII with a compound of Formula XLIX to give a compound of Formula L can be carried out in an organic solvent, for example, di-n butyl ether, diethylether or tetrahydrofuran in the presence of a base, for example, triethylamine, pyridine or potassium carbonate.
  • a base for example, triethylamine, pyridine or potassium carbonate.
  • the reaction of a compound of Formula L with a compound of Formula XXVI to give a compound of Formula LI can carried out in an organic solvent, for example, acetone or tetrahydrofuran in the presence of a base, for example, potassium carbonate or sodium hydride.
  • the compounds of Formula LIV and Formula LV can be prepared by Scheme XI.
  • Path a The compound of Formula LII (wherein Ri, R 2 , R 3 and 4 are the same as defined earlier) is reacted with a compound of Formula LIII (wherein hal is halogen (F, Cl, Br, I) and Y & R u are the same as defined earlier) to give a compound of formula LIV.
  • Path b The compound of Formula LII is reacted with a compound of Formula III (wherein R x is the same as defined earlier) to give a compound of Formula LV.
  • the reaction of a compound of Formula LII (Path a) with a compound of Formula LIII to give a compound of Formula LIV can be carried out in the presence of an organic base selected from, for example, triethylamine, diisopropylethylamine or pyridine in an organic solvent selected from, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
  • an organic base selected from, for example, triethylamine, diisopropylethylamine or pyridine
  • an organic solvent selected from, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
  • the reaction of a compound of Formula LII (Path b) with a compound of Formula III to give a compound of Formula LV can be carried out in an organic solvent selected from, for example, dichloromethane, dichloromethane, chloroform or carbon tetrachloride.
  • LVIV Formula LVIV
  • reaction of a compound of Formula LV with a compound of Formula LVI to give a compound of Formula LVII can be carried out in the presence of a base selected from diisopropylethylamine, triethylamine, N-methylmorpholine or pyridine in an organic solvent selected from, dimethylsulphoxide, dimethylformamide, tetrahydrofuran, diethyl ether or dioxane.
  • a base selected from diisopropylethylamine, triethylamine, N-methylmorpholine or pyridine
  • organic solvent selected from, dimethylsulphoxide, dimethylformamide, tetrahydrofuran, diethyl ether or dioxane.
  • an isocyanate would give a compound of Formula LVII.
  • reaction of a compound of Formula LVII (when U is OH, path a) with a compound of Formula III to give a compound of Formula LVIII can be carried out in the presence of a base selected from triethylamine, diisopropylethylamine, N-methylmorpholine or pyridine in an organic solvent selected from, dichloromethane, dichloroethane, carbon tetrachloride or chloroform.
  • a base selected from triethylamine, diisopropylethylamine, N-methylmorpholine or pyridine
  • organic solvent selected from, dichloromethane, dichloroethane, carbon tetrachloride or chloroform.
  • the reacton of a compound of Formula LVII with a compound of Formual LVIV to give a compound of Formula LW can be carried out in the presence of a base selected from triethylamine, diisopropylethylamine, N-methylmorpholine or pyridine in an organic solvent selected from, dichloromethane, dichloroethane, tetrahydrofuran or dioxane.
  • a base selected from triethylamine, diisopropylethylamine, N-methylmorpholine or pyridine
  • organic solvent selected from, dichloromethane, dichloroethane, tetrahydrofuran or dioxane.
  • Cyclization of a compound of Formula LW to give a compound of Formula LVVI can be carried out in the presence of a base selected from, sodium hydride, potassium tert-butoxide or pyridine in an organic solvent selected from, dimethylformamide, tetrahydrofuran, diethyl ether or dioxane.
  • a base selected from, sodium hydride, potassium tert-butoxide or pyridine
  • organic solvent selected from, dimethylformamide, tetrahydrofuran, diethyl ether or dioxane.
  • Compound prepared following scheme XII are: l-0-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5,6- ⁇ [(methylamino)carbonyl]azanediyl ⁇ - ⁇ - L-gulofuranoside (Compound No.
  • Formula LVXIV Formula LVXII I
  • the compounds of Formulae LVXI and LVXIV can be prepared by following the procedure as depicted in scheme XIII.
  • a compound of Formula LVVII is reacted with a compound of Formula NHR X P (wherein R x and P are the same as defined earlier) to give a compound of Formula LWIII, which undergoes deprotection to give a compound of Formula LNIX, which is reacted with Path a: phenyl carbamate to give a compound of Formula LNX, which undergoes cyclization to give a compound of Formula LNXI Path b: compound of Formula III (wherein R x is the same as defined earlier) to give a compound of Formula LVXII, which is reacted with a compound of Formula L 2 -hal (wherein
  • LVIX can be carried out in an organic solvent selected from, methanol, ethanol, propanol or isopropylalcohol with deprotecting agent selected from, hydrogenatically utilizing palladium on carbon or under catalytic transfer hydrogenation conditions of ammonium formate and palladium on carbon.
  • deprotecting agent selected from, hydrogenatically utilizing palladium on carbon or under catalytic transfer hydrogenation conditions of ammonium formate and palladium on carbon.
  • the reaction of a compound of Formula LVIX with phenyl chloroformate (path a) to give a compound of Formula LVX can be carried out in an organic solvent selected from tetrahydrofuran, dimethylformamide, diethyl ether or dioxane in the peresence of a base selected from, triethyl amine, ⁇ -methylmorpholine, diisopropylethylamine or pyridine.
  • LVXI can be carried out in an organic solvent selected from dimethylsulphoxide, tetrahydrofuran, dimethylformamide, diethyl ether or dioxane in the peresence of a base selected from, triethyl amine, ⁇ -methylmorpholine, diisopropylethylamine or pyridine.
  • the reaction of a compound of Formula LVIX with a compound of Fornmula III (path b) to give a compound of Formula LVXII can be carried out in an organic solvent selected from, dichloromethane, dichloroethane, carbon tetrachloride or chloroform.
  • reaction of a compound of Formula LVXII with a compound of Formula L 2 -hal to give a compound of Formula LVXIII can be carried out in an organic solvent selected from, dichloromethane, dichloroethane, carbon tetrachloride or chloroform in the presence of a base selected from, triethylamine, ⁇ -methylmorpholine, diisopropylethylamine or pyridine.
  • the cyclisation of a compound of Formula LVXIII to give a compound of Formula LVXIV can be carried out in an organic solvent selected from, tetrahydrofuran, dimethylformamide, diethyl ether or dioxane in the presence of a base for example, potassium tert-butoxide, sodium ethoxide or sodium hydride.
  • a base for example, potassium tert-butoxide, sodium ethoxide or sodium hydride.
  • the compound prepared following scheme XIII, path a are: l-O-Dodecyl-2,3-O-isopropylidene-6-deoxy-6-amino-5-O,6-N-(carbonyl)-oc-D- mannofuranoside (Compound No.
  • the reaction of a compound of Formula LWIII with a compound of Formula LVXV to give a compound of Formula LVXI can be carried out in an organic solvent selected from, dichloromethane, dichloroethane, carbon tetrachloride or chloroform in the presence of a base selected from, triethylamine, N-methylmorpholine, diisopropylethylamine or pyridine.
  • a base selected from, triethylamine, N-methylmorpholine, diisopropylethylamine or pyridine.
  • the reaction of a compound of Formula LVXVI with a compound of Formula NH 2 P to give a compound of Formula LVXVII is carried out using NH 2 P as a solvent.
  • the deprotection of a compound of Formula LVXVII to give a compound of Formula LVXVIII can be carried out in an organic solvent selected from, methanol, ethanol, n- propanol or isopropylalcohol with deprotecting agent selected from, hydrogenatically utilizing palladium on carbon or under catalytic transfer hydrogenation conditions of ammonium formate and palladium on carbon.
  • the cyclisation of a compound of Formula LVXVIII to give a compound of Formula LVXIX can be carried out with carbonylating agent selected from, triphosgene, phosgene, diphosgene orcarbonyldiimidazole in an organic solvent selected from, dichloromethane, dichloroethane, carbon tetrachloride or terahydrofuran in the presence of a base selected from diisopropylethylamine, triethylamine, N-methylmorpholine or pyridine.
  • carbonylating agent selected from, triphosgene, phosgene, diphosgene orcarbonyldiimidazole
  • organic solvent selected from, dichloromethane, dichloroethane, carbon tetrachloride or terahydrofuran
  • a base selected from diisopropylethylamine, triethylamine, N-methylmorpholine or pyridine.
  • the N-derivatization of a compound of Formula LVXIX with a compound of Formula R x -hal to give a compound of Formula LVXIV can be carried out an organic solvent selected from tetrahydrofuran, dioxin, ether, ethanol, t-butanol in the presence of a base selected from sodium hydride, potassium tert-butoxide, sodium ethoxide or sodium methoxide.
  • reaction of a compound of Formula LVXX with a compound of Formula LXXXI to give a compound of Formula LXXXII can be carried out in an organic solvent selected from, dichloromethane, dichloroethane, carbontetrachloride or chloroform in the presence of a base selected from diisopropylethylamine, triethylamine, pyridine or ⁇ -methylmorpholine.
  • reaction of a compound of Formula LXXXII with a compound of Formula L 2 -hal to give a compound of Formula LXXXIII can be carried out in an organic solvent selected form, dichloromethane, dichloroethane, carbontetrachloride or chloroform in the presence of a base selected from triethylamine, diisopropylethylamine, pyridine or ⁇ -methylmorpholine.
  • cyclization of a compound of Formula LXXXIII to give a compound of Formula LXXXIV can be carried out out in an organic solvent selected from, dichloromethane, dichloroethane, carbon tetrachloride or chloroform in the presence of a base selected from, diazabicycloundecene, diazabicyclooctane, diazabicyclononene or diisopropylethylamine.
  • Compounds prepared following scheme XV are: l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- ⁇ [4-fluorobenzoyl]amino ⁇ - ⁇ -L-gulofuranoside
  • LXXXVI to give a compound of Formula LXXXVII which undergoes cyclisation to give a compound of Formula LXXXVIII.
  • the reaction of a compound of Formula LXXXV with a compound of Formula LXXXVI to give a compound of Formula LXXXVII can be carried out in an organic solvent selected from tetrahydrofuran, dimethylformamide, diethyl ether or dioxane in the presence of a base selected from, diisopropylethylamine, triethylamine, N-methylmorpholine or pyridine.
  • LXXXVIII can be carried out in an organic solvent selected from, acetonitrile, dichloromethane or dichloroethane with coupling agent selected from, dicyclohexylcarbodiimide or l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride.
  • esters are specified, one skilled in the art could optionally hydrolyze them to their respective acids.
  • hydrolysis of alkyl esters such as ethyl, methyl or benzyl ester
  • hydrolysis of benzyl ester can be carried out hydrogenatically using catalysts, for example, palladium on carbon or platinum on carbon.
  • the esters such as tert- butyl can be hydrolyzed to their corresponding acids in the presence of acid, for example, trifluoroacetic acid or hydrochloric acid.
  • Example 1 Synthesis of l-O-dodecyl-2.3-O-isopropylidene-5.6-dideoxy-5-(4-amino- phenyl)-amino- ⁇ -L-gulofuranoside
  • Step a Synthesis of l-O-dodecyl-2,3-O-isopropyIidene-5,6-dideoxy-5-(4-nitro-phenyl)- amino- ⁇ -L-guIofuranoside.
  • Step b Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(4-amino-phenyl)- amino- ⁇ -L-gulofuranoside.
  • Step a Synthesis of l-O-dodecyl ⁇ 2,3-O-isopropylidene-5,6-dideoxy-5-O-methane sulphonyl- ⁇ ,D-mannofuranoside
  • the compound 1 -O-dodecyl-2,3 -O-isopropylidene-6-deoxy- ⁇ -D-mannofuranoside (synthesised following the procedure as per described in U.S. Patent No. 6,329,344) (11.5g) in dichloromethane (50 ml) was cooled at -5°C. To the reaction mixture was added triethylamine (3.75g) followed by slow addition of methanesulphonyl chloride (4.25g) over a period of 30 minutes with stirring. The reaction mixture was diluted with water. The layers were separated and aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water, brine and dried over anhydrous sodium sulphate. The solvent was evaporated off under vacuum to obtain the title compound (12g).
  • Step b Synthesis of 2,3-O-isopropylidene-l-O-dodecyl-5,6-dideoxy-5-benzylamino- ⁇ -L- gulofuranoside
  • benzylamine (30 ml)
  • Benzylamine 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 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-dodecyl-2,3-O-isopropylidene-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).
  • Step a Synthesis of 1,2; 5,6-Di-O-isopropylidene-3-O-benzyl- -D-gIucofuranoside
  • sodium hydride 60% in oil, 1.308 g, 32.68 mmol
  • tetrabutyl ammonium iodide (1.206 g, 3.268 mmol) in dry tetrahydrofuran (115 ml) was added diacetoneglucose (5 g, 19.23 mmol) in dry tetrahydrofuran (10 ml) slowly at 0°C.
  • the reaction mixture was stirred for 20 minutes at same temperature and then for 30 minutes at room temperature.
  • the reaction mixture was cooled to 0°C, which was further treated benzyl bromide (2.52 ml, 21.15 mmol) in dry tetrahydrofuran (5 ml), followed by stirring it at room temperature for 20 hours.
  • the reaction mixture was quenched with excess amount of water.
  • the reaction mixture was evaporated off under reduced pressure and . the residue thus obtained was taken in ethyl acetate and washed with brine.
  • the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the crude product was purified by column chromatography using 5% ethyl acetate in hexane as eluent to furnish the title compound (6.59g).
  • Step b Synthesis of l,2-O-isopropylidene-3-O-benzyl- ⁇ -D-glucofuranoside
  • a solution of the compound obtained from step a above (3.36 g) in tetrahydrofuran was stirred at 0°C in an ice bath followed by the addition of 30% perchloric acid solution (4 ml) slowly over a period of 30 minutes.
  • the mixture was st red at 0°C for 2 hours.
  • the reaction mixture was neutralized with dilute aqueous sodium hydroxide solution, the solvent was evaporated off under reduced pressure and the product was extracted with ethyl acetate.
  • Step c Synthesis of l,2-O-isopropylidene-3-O-benzyI-6-O-benzoyI- ⁇ -D-glucofuranoside
  • pyridine 0.6 ml
  • benzoyl chloride 0.86 ml, 4.419 mmol
  • the reaction mixture was slowly warmed to room temperature and stirred for 24 hours.
  • the reaction mixture was washed with water and the organic layer was separated followed by washing with brine and dried (anhydrous sodium sulphate).
  • the crude product was purified by column chromatography to furnish the title compound (2g).
  • Step d Synthesis of l,2-O-isopropylidene-3,5-di-O-benzyl-6-O-benzoyl- ⁇ -D- glucofuranoside
  • sodium hydride 50% in oil, 0.3 g, 7.75 mmol
  • tetrabutyl ammonium bromide 0.29 g, 0.792 mmol
  • Step f Synthesis of l,2-O-isopropylidene-3,5-di-O-benzyl-6-O-methylsulphonyl- ⁇ -D- glucofuranoside To the compound obtained from step e above (9.8 g), was added pyridine (25ml) and the reaction mixture was stirred at 0°C for 15 minutes.
  • Methanesulphonyl chloride (3.44 ml) was added to the reaction mixture and stirred until completion (TLC). Pyridine was evaporated off and the residue thus obtained was dissolved in ethyl acetate. The organic layer was washed with water, brine and dried (anhydrous sodium sulphate). The solvents were evaporated off under reduced pressure to furnish the title compound (9 g).
  • Step g Synthesis of l,2-O-isopropylidene-3,5-di-O-benzyl-6-deoxy-6-azido- ⁇ -D- glucofuranoside
  • sodium azide 8g
  • TLC time-dependent liquid phase
  • Step h Synthesis of l,2-O-isopropy!idine-3-O-benzyI-5-O-benzyI-6-deoxy-6-amino- ⁇ -D- glucofuranoside
  • lithium aluminium hydride 0.605g
  • the reaction mixture was stirred at 0°C for 5 hours.
  • Dilute solution of sodium hydroxide and ethyl acetate was added dropwise to the reaction mixture at 0°C to quench the reaction.
  • the insolubles were filtered off, the filterate was concentrated under reduced pressure, which was taken in ethyl acetate and was washed with brine.
  • the organic layer was dried and concentrated under reduced pressure to obtain the title compound (1.5g).
  • Example 4 Synthesis of 3-ethoxy-5-(l-methyl-7-oxo-3-propyl-6.7-dihydro-lH-pyrazalor4,3- d] pyrimidin-4-yl)-benzenesulphonyl chloride
  • the compound l-methyl-5-(2-methoxy-phenyl)-3-propyl-l,6-dihydro-pyrazolo [4,3- d]pyrimidin-7-one was added in small portions to a cooled solution of chlorosulphonic acid.
  • the temperature of the reaction mixture was maintained at the 10- 15°C and stirred for 5-6 hours followed by the addition of thionyl chloride slowly.
  • the reaction mixture was stirred for another 20 hours.
  • Example 5 Synthesis of l,2-O-cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-amino- ⁇ -L- idofuranoside
  • Step a Synthesis of l,2;5,6-di-O-cyclohexylidene- ⁇ -D-glucofuranoside
  • sulphuric acid 27.7 ml
  • D-glucose 200 g
  • reaction mixture was allowed to stand at room temperature for overnight, followed by the addition of 750 ml of hexane.
  • the reaction mixture was refluxed for few minutes. Decanted the upper layer and repeated the same procedure for 2-3 times.
  • the combined hexane extract was cooled in refrigerator. Filtered the crystalline material and recrystallised from hexane as eluent using decolorizing charcoal to obtain the title compound (182g).
  • Step b Synthesis of l,2;5,6-di-O-cyclohexylidene-3-O-nonyl- ⁇ -D-glucofuranoside
  • a mixture of the compound obtained form step a above (50 g), bromononane (35.5 g) and sodium hydroxide (17.6 g) was stirred at 110-120°C for 24 hours.
  • the product was ' extracted with ethyl acetate followed by washing with sodium carbonate solution, water, brine ' and dried over sodium sulphate.
  • the crude product obtained was purified by column chromatography using 15% ethyl acetate in hexane as eluent to furnish the title compound (55g).
  • Step c Synthesis of l,2-O-cyclohexylidene-3-O-nonyl- ⁇ -D-glucofuranoside
  • aqueous acetic acid 250ml, 75% v/v
  • the solvent was evaporated off under reduced pressure and to the residue thus obtained was added 50 ml of hot water and sodium bicarbonate to neutralize the remaining acetic acid.
  • the product was then extracted with ethyl acetate followed by washing with water, brine and dried sodium sulphate.
  • the crude product was purified by column chromatography using 30% ethyl acetate in hexane as eluent to furnish a title compound (18g).
  • Step d Synthesis of l,2-O-cyclohexy!idene-3-O-nonyl-6-O-p-toluenesuIphonyl- ⁇ -D- glucofuranoside To a solution of a compound obtained from step c above (18g) in pyridine (30ml) at 0-
  • Step e Synthesis of l,2-O-cyclohexyIidene-3-O-nonyl-6-deoxy- ⁇ -D-glucofuranoside
  • a solution of lithium aluminium hydride (5 g) taken in dry tetrahydrofuran (30 ml) at 0°C
  • solution of the compound obtained from step d above (18.0g) in dry tetrahydrofuran (30 ml) with continuous stirring.
  • the reaction was allowed to proceed at room temperature.
  • After 12 hour added 30 ml of ethyl acetate, 5 ml of water, 5 ml of 15% sodium hydroxide solution at -5°C.
  • the solids obtained were filtered.
  • Step f Synthesis of l,2-O-cyclohexylidene-3-O-nonyl ⁇ 5-O-p-toluene-sulphonyl-6-deoxy- ⁇ -D-glucofuranoside
  • p-toluenesulphonyl chloride 5.0 g
  • Step g Synthesis of l,2-O-cyclohexylidene-3-O-nonyI-5,6-dideoxy-5-azido- ⁇ -L- idofuranoside
  • sodium azide 3.2 g
  • Step h Synthesis of l,2-O-cyclohexylidene-3-O-nonyI-5,6-dideoxy-5-amino- ⁇ -L- idofuranoside To a solution of lithium aluminium hydride (3 g) in dry tetrahydrofuran (20 ml) at
  • Example 6 Synthesis of 1.2-O-isopropylidene-3-O-dodecyl-6-deoxy-6-amino- -D- glucofuranoside.
  • Step a Synthesis of l,2-O-isopropy!idene-3-O-dodecyl-6-deoxy-6-azido- ⁇ -D- glucofuranoside To a solution of l,2-O-isopropylidene-3-O-dodecyl-6-O-tosyl- ⁇ -D-gluco-furanoside
  • Step b Synthesis of l,2-O-isopropylidene-3-O-dodecyl-6-deoxy-6-amino- ⁇ -D- glucofuranoside To a solution of the compound (l.Og) obtained form step a above in tetrahydrofuran
  • Example 9 Synthesis of 1.2-O-isopropylidene-3-O-dodecyl-5-O-[ ⁇ 4-r2-methoxy-2-oxo- ethyl)-phenyl ⁇ -amino1-carbonyl-6-deoxy- ⁇ -D-glucofuranoside (Compound No. 1) To a solution of l,2-isopropylidene-3-O-dodecyl-6-deoxy- ⁇ -D-glucofuranoside (synthesised following the procedure as per reported in U.S. Patent No.
  • Example 10 Synthesis of l-O-dodecyl-2.3-O-isopro ⁇ ylidene-5-O-(r2-methylphenylamino]- carbonyl ⁇ -6-deoxy- ⁇ -D-mannofuranoside (Compound No. 13 * ) To a solution of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy- ⁇ -O-mannofuranoside
  • Step a Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-O-(tert-butyldimethylsilyl)- ⁇ - D-mannofuranoside To a solution of the compound l-O-dodecyl-2,3-O-isopropylidene- ⁇ -D-mannofuranoside
  • Step b Syntheis of l-O-dodecyl-2,3-O-isopropylidene-5-O-methanesulphonyl-6-O-(tert- butyldimethylsilyl)- ⁇ -D-mannofuranoside
  • Step c Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-O-methanesulphonyl- -D- mannofuranoside
  • tetra-n-butylammonium fluoride 22ml of IM solution in tetrahydrofuran
  • the resulting reaction milcxture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulphate and concemtrated under reduced pressure.
  • Step d Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-benzy!amino- ⁇ -L- gulofuranoside
  • Step e Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-amino- ⁇ -L- gulofuranoside
  • Step f Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-( ⁇ [(4- [methoxycarbonylmethyl]phenyl)amino] carbonyl ⁇ -amino)- ⁇ -L-gulofuranoside
  • methyl ⁇ 4-[(phenoxycarbonyl)amino]phenyl ⁇ acetate prepared by the reaction of phenyl chloroformate with methyl 4-aminophenylacetate
  • diisopropylethylamine 67mg, 0.51mmol
  • Step g Synthesis of l-O-dodecyl-2,3-O-isopropyIidene-5-deoxy-5-( ⁇ [(4- [carboxymethyl]phenyl)amino] carbonyl ⁇ -amino)- ⁇ -L-gulofuranoside (Co mpound No. 251)
  • Step a Synthesis of l,2-O-CycIohexylidene-3-O-nonyl-5,6-dideoxy-5- ⁇ ([4-(2-methoxy-2- oxo-ethyl)-phenyl]-amino)-carbonyl ⁇ -amino- ⁇ -L-idofuranoside (Compound No.
  • Step b Synthesis of l,2-O-Cyclohexylidene-3-O-nonyI-5,6-dideoxy-5- ⁇ [(4-(2-hydroxy-2- oxo-ethyl)-phenyl)-amino]-carbonyI ⁇ -amino- ⁇ -L-idofuranoside
  • sodium hydroxide IN, 20 ml
  • Methanol was removed under reduced pressure and the aqueous layer was neutralized with hydrochloric acid.
  • Analogues of 1 ,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5- ⁇ [(4-(2-hydroxy-2- oxo-ethyl)-phenyl)-amino]-carbonyl ⁇ -amino-y5-L-idofuranoside (Compound No. 27) described below were prepared by replacing the appropriate isocyanate in place of methyl 4- isocyanatophenylacetato and by replacing appropriate sugar moiety in place of 1,2- cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-amino-/?-L-idofuranoside respectively, as applicable in each case.
  • Tris salt of l,2-O-isopropylidene-3-O-dodecyl-6-deoxy-6-( ⁇ [4-(2-hydroxy-2-oxo-ethyl)- phenyl]-amino-carbonyl)-amino- ⁇ -D-glucofuranoside (Compound No. 196).
  • l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ [l-((3,4-methylenedioxy-phenyl)-3- hydroxy-3-oxo-propyl)-amino]-carbonyl]-amino- ⁇ -L-gulofuranoside (Compound No. 233) Scheme II
  • Step a Synthesis of l-O-heptyl-2,3-O-isopropylidene-6-hexamethyleneimine- ⁇ -D- mannofuranoside
  • 1 -O-heptyl-2,3 -O-isopropylidene-6-tosyl- ⁇ -O-mannofuranoside (synthesised following the procedure as described in U.S. Patent No. 6,329,344) (6.0 g), was added azepane (6 ml) and the reaction mixture was heated at 60-70°C for 5-6 hours. Excess azepane was evaporated off under reduced pressure and the reaction mixture was triturated with ether.
  • Step b Synthesis of l-O-heptyl-2,3-O-isopropylidene-5-O- ⁇ (4-chloro-phenyl)-amino ⁇ - carbonyl-6-deoxy-6-(l-azepanyl)- ⁇ -D-mannofuranoside
  • dichloromethane 10ml
  • p-chlorophenyl isocyanate 200mg, 1.3mmol
  • Step c Synthesis of hydrochloride salt of l-O-heptyI-2,3-O-isopropylidene-5-O- ⁇ (4- chloro-phenyl)-amino ⁇ -carbonyl-6-deoxy-6-(l-azepanyl)- ⁇ -D-mannofuranoside
  • ether 5ml
  • Analogues of l-O-heptyl-2,3-O-isopropylidene-5-O- ⁇ (4-chloro-phenyl)-amino ⁇ - carbonyl-6-deoxy-6-(l-azepanyl)- ⁇ -D-mannofuranoside (Compound No. 44) described below were prepared by replacing appropriate amine in place of azepane and by replacing appropriate sugar moiety in place of l-O-heptyl-2,3-O-isopropylidene-6-tosyl- ⁇ -D- mannofuranoside, respectively.
  • Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O- ⁇ (4-nifro-phenyl)-amino ⁇ - carbonyl-6-deoxy-6-(l-pyrrolidinyl)- ⁇ -D-mannofuranoside (Compound No. 55)
  • Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O- ⁇ [4-methyl-phenyl]-amino ⁇ - carbonyl-6-deoxy-6-(l-azepanyl)- ⁇ -D-mannofuranoside Compound No.
  • Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5-O- ⁇ (4-methoxy-phenyl)-amino ⁇ - carbonyl-6-deoxy-6-(l-piperidinyl)- ⁇ -D-mannofuranoside (Compound No. 78) Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5-O- ⁇ (4-methyl-phenyl)-amino ⁇ - carbonyl-6-deoxy-6-(l-piperidinyl)- ⁇ -D-mannofuranoside (Compound No.
  • 6-(l-piperidinyl)- ⁇ -D-mannofuranoside Compound No. 94) l-O-Heptyl-2,3-O-isopropylidene-5-O-[(4-methyl-phenyl)-sulfonylamino ⁇ -carbonyl-6-deoxy- 6-(4-morpholinyl)- ⁇ -D-mannofuranoside (Compound No. 95) l-O-Heptyl-2,3-O-isopropylidene-5-O- ⁇ (4-methyl-phenyl)-amino ⁇ -carbonyl-6-deoxy-6-(4- morpholinyl)- ⁇ -D-mannofuranoside (Compound No.
  • Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O- ⁇ (4-methyl-phenyl)- sulfonylamino ⁇ -carbonyl-6-deoxy-6-(l-piperidinyl)- ⁇ -D-glucofuranoside (Compound No. 105)
  • Hydrochloride salt of 1 ,2-O-isopropylidene-3 -O-dodecyl-5-O- ⁇ henyl-sulfonylamino)- carbonyl-6-deoxy-6-(l-piperidinyl)- ⁇ -D-glucofuranoside Compound No.
  • Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-(phenylsulfonylamino)-carbonyl- 6-deoxy-6-(4-morpholinyl)- ⁇ -D-glucofuranoside (Compound No. 112)
  • Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O- ⁇ [(4-chloro-phenyl)- sulfonylamino]-carbonyl ⁇ -6-deoxy-6-(l-pyrrolidinyl)- ⁇ -D-glucofuranoside Compound No. 113
  • Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O- ⁇ [(4-methyl-phenyl)-amino]- carbonyl ⁇ -6-deoxy-6-(l-azepanyl)- ⁇ -D-glucofuranoside (Compound No. 115) Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O- ⁇ [(4-chloro-phenyl)- sulfonylamino] -carbonyl ⁇ -6-deoxy-6-(4-morpholinyl)- ⁇ -D-glucofuranoside (Compound No. 116)
  • Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O- ⁇ (phenylsulfonylamino)- carbonyl ⁇ -6-deoxy-6-(4-morpholinyl)- ⁇ -D-glucofuranoside (Compound No. 119) Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O- ⁇ (4-methyl-phenyl sulfonylamino)-carbonyl ⁇ -6-deoxy-6-(4-morpholinyl)- ⁇ -D-glucofuranoside (Compound No. 120)
  • Step a Synthesis of l,2,5,6-di-O-isopropylidine-3-O- ⁇ (methylthio)-thio-carbonyl ⁇ - ⁇ -D- glucofuranoside
  • sodium hydride over a period of 10 minutes.
  • the reaction mixture was stirred at room temperature for 30 minutes followed by cooling it to 0°C.
  • carbon disulphide (2.28g) and methyl iodide and stirred for 30 minutes at room temperature.
  • the reaction mixture was diluted with acetic acid (2 ml) and cold water
  • Step b Synthesis of l,2,5,6-di-O-isopropylidene-3-deoxy- ⁇ -D-glucofuranoside
  • a mixture of the compound obtained from step a above (300 mg, 0.97 mmol) and tri butyl tin hydride (291.01mg, 0.97 mmol) was refluxed for 3-4 hours in toluene (20ml) and the reaction mixture was stirred till completion (TLC). The solvent was evaporated off under reduced pressure and the residue was taken in ethyl acetate (20 ml), washed with water, dried over anhydrous sodium sulphate and concentrated.
  • Step c Synthesis of l,2-O-isopropylidene-3 ⁇ deoxy- ⁇ -D-glucofuranoside
  • perchloric acid (30%, 12 ml)
  • Step d Synthesis of l,2-O ⁇ isopropyliene-3-deoxy-5-O-(4-toluenesulfonyl)- ⁇ -D- glucofuranoside
  • a solution of the compound obtained from step c above (7g, 0.034mol) in pyridine (50 ml) was added a solution of p-toluenesulphonyl chloride (7.2g, 0.0377 mmol) in pyridine (10ml).
  • the reaction mixture was st rred for 7-8 hours at 0-5°C.
  • the solvent was evaporated off under reduced pressure and the residue was extracted with dichloromethane (40 ml), washed with water and dried over anhydrous sodium sulphate and concentrated.
  • the crude compound was purified by column chromatography using 10-20% ethyl acetate as eluent to furnish the title compound (8g).
  • Step e Synthesis of l,2-O-isopropylidene-3,6-dideoxy-6-(l-piperidiny ⁇ )- ⁇ -D- glucofuranoside
  • a mixture of the compound obtained from step d above (500mg, 1.39 mmol) and piperidine (0.5 ml, 4.4 mmol)) was stirred at 90°C for 7-8 hours. Excess of piperidine was removed under reduced pressure and the residue was triturated with ether. The solid thus obtained was filtered and the filterate was washed with water, sodium bicarbonate and brine. The organic layer was concenfrated to furnish the title compound (440mg).
  • Step f Synthesis of l,2-O-isopropylidene-3,6-dideoxy-5-O- ⁇ [4-(2-methoxy-2-oxo-ethyl)- phenyl]-carbonyl ⁇ -6-(l-piperidinyl)- ⁇ -D-glucofuranoside
  • dichloromethane 10ml
  • 4-isocyanatophenylacetic acid methyl ester 4 mmol
  • Step g Synthesis of l,2-O-isopropylidene-5-O- ⁇ [4-(2-hydroxy-2-oxo-ethyl)-phenyl]- amino ⁇ -carbonyl-6-deoxy-6-[l-piperidinyl]- ⁇ -D-glucofuranoside
  • lithium hydroxide (2 ml, IN)
  • Step h Synthesis of Tris salt of l,2-0 ⁇ isopropylidene-5-O- ⁇ [4-(2-hydroxy-2-oxo-ethyl)- phenyl]-amino ⁇ -carbonyl-6-deoxy-6-[l-piperidinyI]- ⁇ -D-glucofuranoside (Compound No. 124).
  • Example 16 Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5.6-dideoxy-5-(2-r4- ⁇ 3-(2- methyl-phenyl)-ureido-phenyl]-acetyl
  • reaction mixture was stirred for about 15- 20 minutes followed by the addition of l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.58mg, 0.3 mmol).
  • the reaction mixture was stirred at the same temperature for about 30 minutes before allowing it to gradually warm at room temperature.
  • the reaction mixture was stirred at room temperature for overnight.
  • the reaction mixture was diluted with ethyl acetate and washed thoroughly with water.
  • the aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine and dried over anhydrous sodium sulphate.
  • the solvents were evaporated off and the residue thus obtained was purified by column chromatography using 20-60% ethyl acetate in hexane as eluent to yield the title compound (174 mg).
  • the reaction mixture was stirred at 0°C in an ice bath followed by the addition of triethylamine (0.447 ml, 1.1 mmol), hydroxybenzotriazole (0.536 g, 3.5 mmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.616g, 3.21mmol).
  • the reaction mixture was stirred at 0°C for 3 hours and at room temperature for 33 hours.
  • the organic layer was washed with hydrochloric acid solution (10%), water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the crude organic compound thus obtained was purified by column chromatography to furnish the title compound (0.725 g).
  • Example 18 Synthesis of 1 ,2-O-isopropylidene-3 -O-benzyl-5-O-benzyl-6-deoxy-6- ⁇ [3 A- dimethoxy-phenyll-carbonyl-amino- ⁇ -D-glucofuranoside (Compound No. 148) To a solution of l,2-O-isopropylidene-3-O-benzyl-6-deoxy-6-amino- ⁇ -D- glucofuranoside (0.482g, 2.65 mmole) in ethyl acetate (25 ml), was added 3,4-dimethoxy benzoic acid (0.482 g, 2.65 mmole).
  • reaction mixture was stirred at 0°C followed by the addition of triethylamine (0.5 ml), hydroxybenzotriazole (3.18 mole) and l-(3-dimethylamino propyl)-3-ethylcarbodiimide (0.599g, 2.915 mole).
  • the reaction mixture was stirred at 0°C for 3 hours followed by stirring at room temperature for 33 hours.
  • the organic layer was washed with hydrochloric acid solution (10%), water, saturated sodium bicarbonate and finally with brine. The organic layer was dried over anhydrous sodium sulphate and then concentrated under reduced pressure.
  • Analogues of l,2-O-isopropylidene-3-O-heptyl-5-deoxy-5- ⁇ (4-methyl-phenyl)- sulfonylamino ⁇ - ⁇ -D-xylofuranoside (Compound No. 155) described below can be prepared by replacing appropriate sulphonyl halide group in place of p-toluene sulphonyl chloride and appropriate sugar moiety in place of l,2-O-isopropylidene-3-O-heptyl-5-amino xylofuranoside, respectively.
  • Example 20 Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ 4-methyl- phenyl ⁇ -sulphonyl
  • Analogues of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ 4-methyl-phenyl ⁇ - sulphonyl ⁇ -amino- ⁇ -L-gulofuranoside (Compound No. 188) described below can be prepared by replacing appropriate sulphonyl halide in place of p-toluene sulphonyl chloride and appropriate sugar moiety in place of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- amino- ⁇ -L-gulofuranoside, respectively, as applicable in each case.
  • Analogues of 1 -O-dodecyl-2,3 -O-isopropylidene-5,6-dideoxy-5- ⁇ (3,4,5 -trimethoxy- phenyl)-carbonyl ⁇ amino- ⁇ -L-gulofuranoside (Compound No. 192) described below were prepared by replacing appropriate acyl halide in place of 3,4,5 -trimethoxy benzoyl chloride and appropriate sugar moiety in place l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- amino- ⁇ -L-gulofuranoside, respectively.
  • Example 22 Synthesis of l-O-dodecyl-2.3-O-isopropylidene-5.6-dideoxy-5- ⁇ [3-(3.4- methylenedioxy-phenyl)-propionyll-amino- ⁇ -L-gulofuranoside (Compound No.
  • reaction mixture was stirred at 0°C for 20 minutes followed by the addition of l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (113 mg, 0.59 mmol).
  • the reaction mixture was gradually allowed to warm for room temperature and stirred for overnight.
  • the reaction mixture was diluted with water and the compound was extracted with ethyl acetate.
  • the combined organic extracts were washed with brine and dried over anhydrous sodium sulphate.
  • the solvents were evaporated off and the residue thus obtained was purified by column chromatography using 30% ethyl acetate in hexane as eluent to obatin the title compound (250 mg).
  • Analogues of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ [3-(3,4- methylenedioxy-phenyl)-propionyl-amino- ⁇ -L-gulofuranoside (Compound No. 197) described below were prepared by replacing appropriate acid in place of 3,4- methylenedioxyphenylpropionic acid and appropriate sugar moiety in place of 1-O-dodecyl- 2,3-O-isopropylidene-5,6-dideoxy-5-amino- ⁇ -L-gulofuranoside, respectively, as applicable in each case.
  • Example 23 Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5- ⁇ l-r4-ir4-(2- methoxy-2-oxo-ethyl)-phenyl]-aminol-carbonyl1-piperazmyl
  • Step a Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-tosyl- ⁇ -D-lyxofuranoside
  • the mixture of a compound l-0-dodecyl-2,3-O-isopropylidene-5-tosyl- ⁇ ,D- lyxofuranoside (synthesised following the procedure as descried in U.S. Patent No.
  • Step b Synthesis of l-O-dodecyl-2,3-0-isopropylidene-5-deoxy-5-piperazinyl- ⁇ -D- lyxofuranoside
  • palladium on carbon 6 g, 50% by wt.
  • ammonium formate 3 g
  • the reaction mixture was refluxed for 30 minutes.
  • the reaction mixture was filtered over celite pad and the filtrate was concentrated.
  • the residue thus obtained was washed in dichloromethane and washed with water and brine.
  • the dichloromethane layer was dried over sodium sulphate and concentrated to furnish the desired product (8g).
  • Step c Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5- ⁇ l-[4- ⁇ [4-(2-methoxy-
  • Example 24 Synthesis of hydrochloride salt of 1.2-O-dodecyl-3.4-O-isopropylidene-5.6- dideoxy-5- ⁇ l-(4-[(4-methyl-phenyl)-amino]-carbonyl)-piperazinyl
  • Step a Synthesis of l,2-O-dodecyI ⁇ 3,4-0-isopropylidene-5,6-dideoxy-5- ⁇ l-(4-[(4-methyl- phenyl)-amino]-carbonyl)-piperazinyl ⁇ - ⁇ -L-gulofuranoside
  • the title compound was prepared following the procedure as described for the synthesis of Compound No.
  • Step b Synthesis of hydrochloride salt of l,2-O-dodecyl-3,4-O-isopropylidene- 5,6-dideoxy-5- ⁇ l-(4-[(4-methyI-phenyl)-amino]-carbonyl)-piperazinyl ⁇ - ⁇ -L- gulofuranoside
  • the title compound was prepared following the procedure described in step c of
  • Example 12 by using compound of step a in place of l-O-heptyl-2,3-O-isopropylidene-5-O-
  • Tris salt of l-O-dodecyl-3,4-O-isopropylidene-5,6-dideoxy-5- ⁇ l-(4-[(4- ⁇ 2-hydroxy-2-oxo- ethyl ⁇ -phenyl)-amino]-carbonyl)-piperazinyl ⁇ - ⁇ -L-gulofuranoside (Compound No. 168)
  • Hydrochloride salt of l-O-dodecyl-3,4-O-isopropylidene-5,6-dideoxy-5- ⁇ l-(4-[(phenyl sulfonylamino)-carbonyl])-piperazinyl ⁇ - ⁇ -L-gulofuranoside Compound No. 169)
  • Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ l-[4- ⁇ (4-methoxy- phenyl)-amino ⁇ -carbonyl]-piperazinyl ⁇ - ⁇ -L-gulofuranoside (Compound No. 170)
  • Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ l-(4-benzyl)- piperazinyl ⁇ - ⁇ -L-gulofuranoside Compound No.
  • Step a Synthesis of l,2-O-isopropylidene-3-O-pentyl-5-deoxy-5-piperazinyl- ⁇ -D- xylofuranoside The title compound was prepared following the procedure described in step a of
  • Example 20 by using l,2-O-isopropylidene-3-O-pentyl-5-tosyl- ⁇ -D-xylofuranoside (lOg) in place of l-O-dodecyl-2,3-O-isopropylidene-5-tosyl- ⁇ -D-lyxofuranoside to furnish the desired product (520mg).
  • lOg l,2-O-isopropylidene-3-O-pentyl-5-tosyl- ⁇ -D-xylofuranoside
  • Step b Synthesis of l,2-O-isopropylidene-3-O-pentyl ⁇ 5-deoxy ⁇ 5-[l-(4- benzyl)piperazinyl- ⁇ -D-xylofuranoside The title compound was synthesised following the procedure described in step b of
  • Example 20 by using the compound obtained from step a above in place of 1 -O-dodecyl-2,3 - O-isopropylidene-5-tosyl- ⁇ -D-lyxofuranoside (12g) to furnish the title compound (200mg).
  • Step c Synthesis of l,2-O-Isopropylidene-3-O-pentyl-5-deoxy-5-[l-(4-[4-methoxy-3- ⁇ 5-
  • Example 26 Synthesis of l,2-O-isopropylidene-3-O-heptyl-5-O- ⁇ [3-(2-hydroxy-2-oxo- ethyl)-phenyl]-amino
  • Step a Synthesis of l,2-O-isopropylidene-3-O-heptyl-6-deoxy- ⁇ (l-piperidinyl)-ethyl ⁇ - amino - ⁇ -D-glucofuranoside
  • the mixture of l,2-O-isopropylidene-3-O-heptyl-6-tosyl- ⁇ -D-glucofuranoside (1.26 g, 2.66 mmole) (synthesised following the procedure described in U.S. Patent No. 6,329,344) and 2-piperidin-l-yl-ethyl amine (1.3 ml, 9.155 mmol) was heated at 60-70°C stirred for 3 hours with continuous stirring.
  • Step b Synthesis of l,2-O-isopropylidene ⁇ 3-O-heptyl ⁇ 6-deoxy-6-(benzyl-oxycarbonyl)- ([l-piperidinyI]-ethyl)-amino- ⁇ -D-glucofuranoside
  • benzyl chloroformate (1.27 g, 3.27 mmol) followed by the addition of triethylamine (excess).
  • the reaction mixture was stined for overnight.
  • the reaction mixture was evaporated off to dryness and the compound was extracted with ether.
  • the organic layer was washed with water and brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the crude product was purified by column chromatography to furnish the title compound (1.045g).
  • Step c Synthesis of 1,2-O-isopropylidene -3-O-heptyl5-O- ⁇ (4-[2-methoxy-2-oxo-ethyl]- phenyl)-amino ⁇ -carbonyl-6-deoxy-6-(benzyloxycarbonyl)-([l-piperidinyl]-ethyl)-amino- ⁇ -D-glucofuranoside ⁇
  • the reaction mixture was evaporated to dryness and then triturated with ether. It was concentrated under reduced pressure.
  • the resulting compound was taken in methanol (7 ml) followed by the addition of aqueous sodium hydroxide (IN, 4ml). After the completion of the reaction, methanol was evaporated off and the reaction mixture was acidified and the product was extracted with dichloromethane. The organic layer was washed with brine and dried over sodium sulphate. It was concentrated under reduced pressure to obtain the title compound (0.493 g).
  • Step d Synthesis of l,2-O-isopropylidene-3-O-heptyl-5-O- ⁇ (4-[2-methoxy-2-oxo-ethyl]- phenyl)-amino ⁇ -carbonyl-6-deoxy-6-)-([l-piperidinyl]-ethyl)-amino- ⁇ -D-gIucofuranoside
  • methanol methanol
  • Step e Synthesis of l,2-O-isopropylidene-3-O-heptyl-5-O- ⁇ [3-(2-hydroxy-2-oxo-ethyl)- phenyl]-amino ⁇ -carbonyl-6-deoxy-6- ⁇ (l-piperidinyI)-ethyl ⁇ -amino- ⁇ -D-glucofuranoside
  • the compound obtained from step d above (0.4188 g) was hydrolyzed with lithium hydroxide (6.5 mg, 0.15 mmole) in water-tefrahydrofuran following the general conditions to furnish the title compound (0.38g).
  • Example 27 Synthesis of l-O-Dodecyl-2.3-O-isopropylidene-5.6-dideoxy-5-( ⁇ [4- ⁇ 2-[2S-2- il-methoxy-4-methyl-l-oxo]-pentyl
  • L-gulofuranoside (Compound No. 178) described below were prepared by replacing appropriate ester in place of leucine methyl ester and appropriate sugar in place of l-O- dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[4-(2-hydroxy-2-oxoethyl)- phenyl]- aminocarbonylamino ⁇ - ⁇ -L-gulofuranoside, respectively.
  • Example 28 Synthesis of l-O-dodecyl-2.3-O-isopropylidene-5.6-dideoxy-5- ⁇ (r4-(2-(l- azepanyl)-2-oxo-ethyl-phenyl]-amino)-carbonyl ⁇ -amino- ⁇ -L- ulofuranoside (Compound No.
  • Patent 6,329,344 (1 g, 1.82 mmole) was added followed by the addition of hexamethyleneimine. After 24 hours, the reaction mixture was diluted with water and the product was extracted with dichloromethane. The crude product was washed with water, brine and dried over anhydrous sodium sulphate. The events were evaporated off under reduced pressure and the residue thus obtained was purified by column chromatography to obtain the title compound (lg).
  • Example 29 Synthesis of l-O-Dodecyl-2.3-O-isopropylidene-5.6-dideoxy-5- ⁇ [4-((2-[2-(lH- imidazol-4-yl)ethyll-amino-2-oxo-ethyl)-phenyl
  • Step a Synthesis of l-O-dodecyI-2,3-0-isopropylidene-5,6-dideoxy-5- ⁇ [(2S)-2-(l- methoxy-4-methyl-l-oxo-pentyl ⁇ -amino]-carboxyl ⁇ -amino- ⁇ -L-guIofuranoside
  • l-O-dodecyl-2,3-O-isopropylidene-5-amino- ⁇ -L-gulofuranoside 100 mg, 0.2 mmole
  • dry tefrahydrofuran (2 ml) at 0°C was added carbonyldiimidazole (52 mg, 0.32 mmole) and diisopropylethylamine (41 mg, 0.32 mmole).
  • reaction mixture was stined for 30 minutes followed by the addition of hydrochloride salt of leucine methyl ester (5.8 mg, 0.32 mmole).
  • the reaction mixture was stined at room temperature for 16 hours.
  • the reaction mixture was diluted with water and the product was exfracted with ethyl acetate.
  • the combined organic extracts were washed with water brine and dried over anhydrous sodium sulphate.
  • the solvents were evaporated off and the residue thus obtained was purified by coloumn chromatography using 20% ethyl acetate in hexane as eluent to furnish the title compound (118mg).
  • Step b Synthesis of l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ [(2S)-2-(l- hydroxy-4-methyl-l-oxo-pentyl)-amino]-carbonyl ⁇ -amino- ⁇ -L-gulofuranoside
  • aqueous lithium hydroxide 14mg, 0.33 mmol
  • Example 31 Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5.6-dideoxy-5- ⁇ [3-(2-(4- methylphenyl)-5-tert-butyl-2H-pyrazolyl)-amino1-carbonyl ⁇ -amino- ⁇ -L-gulofuranoside (Compound No.
  • Example 34 Synthesis of l-O-Dodecyl-2.3-0-isopropylidene-5,6-dideoxy-5- ⁇ (r4-(2- hydroxy-2-oxo-ethyl)-phenyl]-amino)- thiocarbonyl ⁇ -amino- ⁇ -L-gulofuranoside (Compound No. 208)
  • Step a Synthesis of l-O-DodecyI-2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ ([4-(2-methoxy-2- oxo-ethyl)-phenyI] -amino)- thiocarbonyl ⁇ -amino- ⁇ -L-gulofuranoside
  • 4-aminophenylacetic acid methyl ester 500mg, 3.3 mmol
  • tefrahydrofuran 10ml
  • reaction mixture was stirred for overnight followed by the addition of 1 -O-dodecyl-2,3 -O- isopropylidene-5,6-dideoxy-5-amino- ⁇ -L-gulofuranoside (1.12g, 3mmol)).
  • the reaction mixture was stirred for 2 hours at room temperature followed by refluxing at 80°C for 3 hours.
  • the reaction mixture was diluted with distilled water and exfracted with ethyl acetate.
  • the organic extract of was washed with brine and dreid over anhydrous sodium sulphate and concentrated.
  • the crude compound was purified by column chromatography using 20% ethyl acetate in hexane as eluent to obtain the title compound (1.2g).
  • Step b Synthesis of l-O-Dodecyl ⁇ 2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ ([4-(2-hydroxy-2- oxo-ethyl)-phenyl] -amino)- thiocarbonyl ⁇ -amino- ⁇ -L-gulofuranoside
  • a solution of the compound obtained from step a above (970 mg, 1.6 mmol) in tefrahydrofuran-methanol- water (2ml)
  • lithium hydroxide monohydrate (1:1, 77mg, 1.8 mmol
  • Example 35 Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5--iT(4-chloro- phenyl)-amino]-carbonyl
  • Step a Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6-cyano- ⁇ -D- mannofuranoside
  • l-O-dodecyl-2,3-isopropylidene-6-O-tosyl- ⁇ ,D- gulofuranoside 8 g, 14.7 mmole
  • sodium cyanide 8.64 g, 17.6 mmol
  • Step b Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-O-methanesulphonyI-6-deoxy- 6-cyano- ⁇ -D-mannofuranoside
  • methanesulphonyl chloride 1.73 g, 15 mmol
  • Step c Synthesis of a mixture of l-O-dodecyl-2,3-O-isopropy!idene-5,6-dideoxy-5- benzyIamino-6-cyano- ⁇ -L-gulofuranoside and isomeric ⁇ -D-mannofuranoside derivative
  • benzyl amine (20 ml) and heated at 115°C for 5 hours.
  • the reaction mixture was concentrated under reduced pressure and the residue thus obtained was taken in ether.
  • the solid was separated out and filtered followed by washing with ether.
  • Step d Synthesis of mixture of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- benzylamino-6-carboxy- ⁇ -L-gulofuranoside and isomeric ⁇ -D-mannofuranoside derivative
  • ethanol 5 ml
  • the reaction mixture was concenfrated and taken into water.
  • the compound was extracted with ethyl acetate.
  • the aqueous layer was acidified and then exfracted with ethyl acetate,
  • the organic extracts were washed with brine and dried. Over anhydrous sodium sulphate and concentrated to obtain the title compound (1.4 g).
  • Step e Synthesis of a mixture of l-O-dodecyI-2,3-O-isopropylidene-5,6-dideoxy-5- benzylamino-6-carboxy- ⁇ -L-gulofuranoside and isomeric ⁇ -D-mannofuranoside derivative
  • oxalyl chloride 0.5 g, 3.9 mmole
  • Step f Synthesis of a mixture of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- amino-6-cyano- ⁇ -L-gulofuranoside and isomeric ⁇ -D-mannofuranoside derivative
  • methanol 20 ml
  • 10% palladium hydroxide 50% wet
  • the reaction mixture was shaken under hydrogen atmosphere (50psi).
  • the reaction mixture was filtered and the filtrate was concentrated and the residue thus obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluent to obtain the title compound (350 mg).
  • Step g Synthesis of l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[ ⁇ (4-chloro- phenyI)-amino ⁇ -carbonyl]-amino-6-ethoxycarbonyl- ⁇ -L-gulofuranoside (Compound No. 221) and l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[ ⁇ (4-chIoro-phenyl)-amino ⁇ - carbonyl]-amino-6-ethoxycarbonyl- ⁇ -D-mannofuranoside (Compound No.
  • Step h Synthesis of l-O-dodecyl-2,3-isopropyIidene-5,6-dideoxy-5- ⁇ [(4-chloro-phenyl)- amino]-carbonyl ⁇ -amino-6-carboxy- ⁇ -L-gulofuranoside (Compound No. 218) / l-O- dodecyl-2,3-isopropylidene-5,6-dideoxy-5- ⁇ [(4-chloro-phenyl)-amino]-carbonyl ⁇ -amino-
  • Example 36 Synthesis of l-O-dodecyl-2.3-O-isopropylidene-5.6-dideoxy-5-[ ⁇ (2S)-2-[3-(4- (2-hvdroxy-2-oxo-ethyl)-phenyl)-ureido1-4-methyl ⁇ pentanoyl]-amino- ⁇ -L- gulofuranoside (Compound No.
  • Step a Synthesis of l-O-dodecyl-2,3 ⁇ 0-isopropylidene-5,6-dideoxy-5- ⁇ [(4-methyI-2-tert- butoxycarbony!amino)-pentanoyl]-amino- ⁇ -L-gulofuranoside
  • N-tert-butoxycarbonyl-L-leucine 122 mg, 0.54 mmol
  • N-methylmo ⁇ holine 60 mg, 0.64 mmol
  • hydroxy benzotriazole 80 mg, 0.58 mmol
  • reaction mixture was stined for 20 minutes followed by the addition of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.58 mmol).
  • the reaction mixture was gradually warmed to room temperature and stined for 16 hours.
  • the reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate.
  • the combined organic extracts were washed with brine and dried over anhydrous sodium sulphate.
  • the solvents were evaporated off and the residue thus obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluent to furnish the title compound (210 mg).
  • Step b Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ (2S)-[2-amino-4- methyl]-pentanoyl ⁇ -amino- ⁇ -L-gulofuranoside (Compound No .232)
  • Step c Synthesis of l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[ ⁇ (2S)-2-[3-(4-[2- methoxy-2-oxo-ethyl]-phenyl)-ureido]-4-methyl ⁇ -pentanoyl]-amino- ⁇ -L-gulofuranoside
  • Step d Synthesis of l-O-dodecyl-2,3-O-is,opropyIidene-5,6-dideoxy-5-[ ⁇ (2S)-2-[3-(4-(2- hydroxy-2-oxo-ethyl)-phenyl)-ureido]-4-methyl ⁇ pentanoyl]-amino- ⁇ -L-gulofuranoside
  • the compound obtained from step c above 70 mg, 0.1 mmole
  • Example 37 Synthesis of l-O-(3,4-methylenedioxy-benzyl)-2.3-O-isopropylidene-5.6- dideoxy-5- ⁇ [l-(2-tert-butoxycarbonylamino-4-methyl-pentyl)-oxo -amino ⁇ - ⁇ -L- gulofuranoside (Compound No. 234)
  • Step a Synthesis of 2,3;5,6-di-O-isopropylidene- ⁇ -D-mannofuranoside To the solution of D-mannose (50g, 0.277 mole) in acetone cooled at 0°C, was added sulphuric acid (9ml, 0.16 mole) dropwise maintaining temperature of the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 30 minutes and then at 20°C for 30 minutes followed by heating it at 40°C for 5 hours. The reaction mixture was concentrated to get sticky mass, which was then stirred, with water for 15 min. The aqueous layer was exfracted with ethyl acetate and the organic layer was washed with water and brine. The organic layer was dried and concenfrated followed by washing with hexane as eluent to furnish the title compound (47 g).
  • Step b Synthesis of l-O-(3,4-methylenedioxybenzyl)-2,3;5,6-di-O-isopropylidene- ⁇ -D- mannofuranoside
  • dimethylsulphoxide 150 ml
  • potassium hydroxide 7.75g, 0.138mol
  • methane sulphonic acid benzo [l,3]dioxol-5-methyl ester (17.59g, 0.076mol) and stined at room temperature for 30 minutes.
  • the reaction mixture was heated to 45 °C for 3 hours.
  • the reaction was quenched with ice-cold water and neutralized with hydrochloric acid.
  • the product was exfracted with ethyl acetate, which was washed with water, and brine.
  • the organic layer was dried over anhydrous sodium sulphate and concenfrated.
  • the crude compound was purified by column chromatography using 20% ethyl acetate in hexane as eluent to furnish the title compound (14.6g).
  • Step c Synthesis of l-O-(3,4-methylenedioxybenzyl)-2,3-O-isopropy!idene- ⁇ -D- mannofuranoside
  • perchloric acid 8.98g, 0.0872 mol
  • Reaction mixture was neutralized with aqueous sodium hydroxide and exfracted with ethyl acetate.
  • the organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concenfrated.
  • the crude product was purified by column chromatography using 20% ethyl acetate in hexane as eluent to furnish the title compound (9. Ig).
  • Step d Synthesis of l-O-(3,4-methylenedioxybenzy ⁇ )-2,3-O-isopropylidene-6-O-p- toluene-sulphonyl- ⁇ -D-mannofuranoside
  • triethylamine (13.6 ml, 0.1347mol)
  • p- toluenesulphonyl chloride (6.16g, 0.0323 mole) slowly maintaining temperature at 0°C.
  • the reaction mixture was stined at same temperature for 4 hours.
  • the compound was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulphate and concenfrated to get crude compound. The crude compound was purified by column chromatography using 30% ethyl acetate in hexane as eluent to obtain the title compound (12. Ig).
  • Step e Synthesis of l-O-(3,4-methylenedioxybenzyI)-2,3-O-isopropylidene-6-deoxy- ⁇ -D- mannofuranoside
  • tetrahydrofuran 150 ml
  • lithium aluminium hydride 1.735g, 0.045 mol
  • the reaction mixture was washed by quenching lithium alluminium hydride carefully with few drops of IN aqueous sodium hydroxide and ethyl acetate.
  • reaction mixture was filtered through sintered funnel and the filterate thus obtained was concenfrated under reduced pressure. Residue thus obtained was taken in dichloromethane and washed with water and brine. The organic layer was dried and concenfrated to furnish the title compound (5.7g).
  • Step f Synthesis of l-O-(3,4-methylene-dioxybenzyl)-2,3-O-isopropyIidene-5-O- methanesulphonyI-6-deoxy- ⁇ -D-mannofuranoside
  • dichloromethane 50ml
  • triethylamine 2.04g
  • methanesulphonyl chloride 2.32g, 0.0202 mol
  • Step g Synthesis of l-O-(3,4-methylenedioxybenzyl)-2,3-O-isopropylidene-5,6-dideoxy- S-azido- ⁇ -L-gulofuranoside
  • sodium azide 3.12g, 48 mmol
  • tefrabutyl ammonium bromide 0.18g, 19.2 mmol
  • Step h Synthesis of l-O-(3,4-methylenedioxybenzyl)-2,3-O-isopropylidene-5- ⁇ (2S)-(4- methyl-2-tert-butoxycarbonyl-amino)-pentanoyl ⁇ -amino-5,6-dideoxy-5-amino- ⁇ -L- gulofuranoside
  • Example 38 Synthesis of l-O-Dodecyl-2.3-O-isopropylidene-5,6-dideoxy-5-r((2S)-2- r ⁇ (carboxymethyl)-aminol-4-methyl ⁇ -pentanoyll - ⁇ -L-gulofuranoside (Compound No. 23)
  • Step a Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ (2S)-2-
  • Step b Synthesis of l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[ ⁇ (2S)-2- ⁇ (carboxymethyl)-amino]-4-methyl ⁇ -pentanoyl] - ⁇ -L-gulofuranoside
  • Example 39 Synthesis of l,2-O-Isopropylidene-3-O-benzyl-5-deoxy-5-r6-(l- ⁇ 2-rcarboxy- piperidinyl ⁇ )-hexanoyl]-amino-alpha-D-xylofuranoside (Compound No. 237)
  • Step a Synthesis of l,2-O-Isopropylidene-3-O-benzyl-5-deoxy-5-(6-bromohexanoyl)- amino- ⁇ -D-xylofuranoside To a suspension of sodium hydride (0.275g) in di-n butyl ether (20ml), was added 1,2-
  • Step b Synthesis of l,2-O ⁇ Isopropylidene-3-O-benzyl-5-deoxy-5-[6-(l- ⁇ 2- ethoxycarbonyl-piperidinyl ⁇ )-hexanoyI]-amino-o;-D-xylofuranoside (Compound No.
  • Step c Synthesis of l,2-O-Isopropylidene-3-O-benzyl-5-deoxy-5-[6-(l- ⁇ 2-carboxy- piperidinyl ⁇ )-hexanoyl]-amino-e.-D-xylofuranoside
  • sodium hydroxide solution 25 ml, IN
  • Methanol was removed under reduced pressure and acidified.
  • the product was exfracted with ethyl acetate (50 ml), washed with water, brine and dried over sodium sulphate.
  • Example 41 Synthesis of l-O-dodecyl-2.3-O-isopro ⁇ ylidene-5.6-dideoxy-5- ⁇ (2- methylphenyl-amino)-carbonyl ⁇ - ⁇ 4-r2-(2-methylphenyl)-ureido1-phenyl ⁇ -amino- ⁇ -L- gulofuranoside (Compound No.
  • Step b Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-( ⁇ [(4- [methoxycarbonylmethyI]phenyl)amino] carbonyl ⁇ -amino)- ⁇ -L-gulofuranoside
  • Step d Synthesis of l-O-dodecyI-2,3-O-isopropylidene-5-deoxy-5-( ⁇ [(4- carboxymethylphenyI)amino]carbonyI ⁇ amino)-6-O- ⁇ [(4- benzoylphenyl)amino]carbonyl ⁇ - ⁇ -L-guIofuranoside (Compound No.
  • Example 43 Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5,6- ⁇ r(methylamino)carbonyl]azanediyl ⁇ - ⁇ -L-gulofuranoside (Compound No. 271)
  • Step a Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6- ⁇ [(methylamino)carbonyl]amino ⁇ - ⁇ -D-mannofuranoside
  • Step b Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-O- methanesulphonyl-6- ⁇ [(methy!amino)carbonyI]amino ⁇ - ⁇ -D-mannofuranoside
  • the title compound was prepared by following the procedure as described in Example 38, step b, by using the compound obtained from step a above in place of using 1 -O-dodecyl-2,3 - O-isopropylidene-6-O- (tert-butyldimethylsilyl)- ⁇ -D-mannofuranoside. Yield: 0.5g.
  • Step c Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5,6- ⁇ [(methylamino)carbonyl]azanediyl ⁇ - ⁇ -L-gulofuranoside (Compound No. 271)
  • sodium hydride 70 mg
  • stined the reaction mixture at 60-70°C for 3 hours.
  • the reaction mixture was cooled and diluted with water exfracted with ethyl acetate.
  • the combined organic extracts were washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound. Yield: 150mg.
  • Step a Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6-benzylamino- ⁇ -D- mannofuranoside
  • l,2-O-isopropylidene-3-O-dodecyl-6-O-tosyl- ⁇ -D-gluco- furanoside (2g) in benzylamine (5ml) and refluxed the reaction mixture for 2 hours at 100-110°C.
  • Step b Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6-amino- ⁇ -D- mannofuranoside
  • Step c Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6- ⁇ [(phenoxy)-carbonyI]- amino ⁇ - ⁇ -D-mannofuranoside
  • Step d Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6-amino-5-O-,6-N- (carbonyl)-oc-D-mannofuranoside (Compound No. 248)
  • methylamine hydrochloride (0.17g)
  • triethylamine (0.68ml)
  • the rection mixture was diluted with water and exfracted with ethyl acetate.
  • Example 45 Synthesis of 1 -O-dodecyl-2,3 -O-isopropylidene-5,6-dideoxy-5- ⁇ (4- fluorophenyDamino ⁇ -6-(methylamino)-5,6-N-carbonyl- ⁇ -L-gulofuranoside (Compound No. 249)
  • Step a Synthesis of l ⁇ O-dodecyl-2,3-O-isopropylidene-6-deoxy-6-(methylamino)- ⁇ -D- mannofuranoside
  • Step b Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6-[ ⁇ [4- fluorophenyl)amino]carbonyl ⁇ (methylamino)]- ⁇ -D-mannofuranoside
  • Step c Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-O-methanesulphonyI-6-deoxy-
  • Step d Synthesis of l-O-dodecyl-2,3-0-isopropylidene-5,6-dideoxy-5- ⁇ (4- fluorophenyl)amino ⁇ -6-(methylamino)-5,6-N-carbonyl- ⁇ -L-gulofuranoside (Compound No. 249)
  • Example 46 Synthesis of l-O-dodecyl-2.3-O-isopropylidene-5,6-dideoxy-5-amino-6- (methylamino)-5.6-N-carbonyl- ⁇ -L-gulofuranoside (Compound No.
  • Step a Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-O-methanesulphonyI-6-deoxy- 6-benzyl(methyl)amino- ⁇ -D-mannofuranoside
  • methanesulphonyl chloride 2g, 17.4mmol
  • triethylamine 8g, 79.4mmol
  • Step b Synthesis of l-O-dodecyI-2,3-O-isopropyIidene-5,6-dideoxy-5-benzylamino-6- benzyl(methyl)amino- ⁇ -L-gulofuranoside
  • benzylamine 20ml
  • Step c Synthesis of l-O-dodecyl-2,3 ⁇ O-isopropylidene-5,6-dideoxy-5-amino-6- methylamino- ⁇ -L-guIofuranoside
  • Step d Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-amino-6- (methylamino)-5,6-N-carbonyl- ⁇ -L-gu!ofuranoside
  • Example 48 Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5- ⁇ r4- fluorobenzoyl]amino ⁇ - ⁇ -L-gulofuranoside (Compound No. 264)
  • dichloromethane 5ml
  • 4-fluorobenzoyl chloride 204mg, 1.29mmol
  • Example 49 Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-amino-5-N,6-O- ⁇ (4- fluorobenzylylidenel - ⁇ -L-gulofuranoside (Compound No. 267)
  • Step a Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-[(4- fluoro)benzovIlamino-6-O-methanesuIphonyl- ⁇ -L-gulofuranoside
  • dichloromethane (10ml) a solution of the Compound No. 264 (347mg, 0.68mmol) in dichloromethane (10ml) at 0°C was added triethylamine (75mg, 0.74mmol) and methanesulphonyl chloride (78mg, 0.68mmol) and stirred at 0°C for lhour.
  • Step b Synthesis of l-O-dodecyl-2,3-O-isopropyIidene-5-deoxy-5-amino-5-N,6-O- ⁇ (4- fluorobenzylylidene ⁇ - ⁇ -L-gulofuranoside (Compound No. 267)
  • Example 50 Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-( ⁇ [(4- carboxymethylphenyl)amino]thiocarbonyl ⁇ -ammo)- ⁇ -L-gulofuranoside (Compound No.
  • Step a Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-( ⁇ ([4- (methoxycarbonylmethyl)-phenyllamino)thiocarbonyl ⁇ -amino)- ⁇ -L-gulofuranoside
  • diisopropylethylamine 332mg, 2.58mmol
  • thiocarbonyl diimidazole (229mg, 1.29mmol) and stined for lhour at room temperature.
  • Step b Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-( ⁇ [4- carboxymethylphenyl)amino]thiocarbonyl ⁇ -amino)- ⁇ -L-gulofuranoside (Compound No. 270)
  • tefrahydrofuran methanol: water (3:1:1) ml
  • Example 51 Synthesis of l-O-dodecyI-2,3-O-isopropylidene-5-deoxy-5-amino-5-N,6-O-
  • Step a Synthesis of l-O-dodecyI-2,3-O-isopropylidene-5-deoxy-5-amino-5-N,6-O- ⁇ ([4- methoxycarbonylphenyl]amino)methylylidene ⁇ - ⁇ -L-gulofuranoside
  • step a 150mg, 0.25mmol
  • acetonitrile 5ml
  • dicyclohexylcarbodiimide 78mg, 0.37mmol
  • Step b Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5 ⁇ deoxy-5-amino-5-N,6-O- ⁇ ([4- carboxymethylphenyl]amino)methylylidene ⁇ - ⁇ -L-gulofuranoside
  • Example 52 Pharmacological activity
  • the compounds of the present invention were tested in one or more of the assays described herein. Standard assays were used to evaluate activity of compounds in present invention on inflammatory cells. Attenuation of agonist-induced release of lipid mediator of neutrophil chemotaxis, leukotriene B4 (LTB4), is used to evaluate inhibitory effect on neutrophils.
  • LTB4 leukotriene B4
  • 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 4 release using LTB ELISA kits (Assay Design Inc., USA). The amount of LTB 4 released was quantified and percent inhibition of LTB 4 release was calculated with respect to the difference between the A23187 stimulated and negative control cells, to compute IC 50 values.
  • IC 50 values of compounds of from about 30 ⁇ M to about 1.2 ⁇ M for example, from about 20 ⁇ M to about 1.2 ⁇ M, or from about 10 ⁇ M to about 1.2 ⁇ M, or from about 8.2 ⁇ M to about 1.2 ⁇ M, or from about 2.5 ⁇ M to about 1.2 ⁇ M.
  • Assay for 5-Lipoxygenase Activity In a 96 well UN-plate, 100 ⁇ l of phosphate buffer saline (PBS) containing DTT (200 ⁇ M), ATP (100 ⁇ M) and calcium chloride (100 ⁇ M) was added.
  • PBS phosphate buffer saline
  • 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 ImM freshly prepared arachidonic acid and increase in absorbance was monitored at 236 mn 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 confrol values, to compute IC 50 values.
  • Compound numbers 218, 220, 228, 277, 281, 282, 283, 284, 287, 288, and 289 were tested in this way, providing activities, as measured by IC 50 values, of between about 9.5 ⁇ M and about 0.1 ⁇ M, for example between about 6.7 ⁇ M and about 0.1 ⁇ M., or for example, between about 4.5 ⁇ M and about 0.1 ⁇ M, or for example, between about 2.8 ⁇ M and about 0.1 ⁇ M, or for example, between about 0.5 and about 0.1 ⁇ M.

Abstract

The present invention relates to monosaccharide derivatives as anti-inflammatory agents. The compounds disorder 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 or psoriasis. Pharmacological compositions containing compounds disclosed herein and the methods of treating bronchial asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, multiple sclerosis, type I diabetes, psoriasis, allograft rejection, and other inflammatory and/or autoimmune disorders, using the compounds are also provided.

Description

MONOSACCHARIDE DERIVATIVES Field of The Invention The present invention relates to monosaccharide derivatives as anti-inflammatory agents. The compounds disclosed 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 or psoriasis. Pharmacological compositions containing compounds disclosed herein and the methods of treating bronchial asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, multiple sclerosis, type I diabetes, psoriasis, allograft rejection, 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 switched on as a result of tissue injury. The inflammatory process is self-containing, however, under certain pathophysiological conditions inflammatory process tends to perpetuate itself giving rise to chronic inflammatory diseases like bronchial asthma, rheumatoid arthritis, etc. Although the exact cellular and molecular bases of most chronic inflammatory diseases remain unclear, it has become apparent that inflammatory cells can act in concert towards initiation and perpertuation of an inflammatory response by releasing a wide range of chemokines, cytokines, proteolytic enzymes and other bioactive molecules. Mast cells primed by lymphocytes can interact with environmental allergens and release mediators like histamine, prostaglandin, leukotrienes, etc. (Clin. Exp. Allergy, 32, 1682, 2002) to initiate an early inflammatory response. This is followed by a delayed inflammatory response due to release of cytokines (for example IL-4, IL-5, IL-6, IL-8, IL-13, GM-CSF and TNFalpha), chemokines and proteolytic enzymes (for example chymase, tryptase) (Chest 112, 523, (1997); Lancet 350, 59, (1997)) that not only bring about tissue damage, but attract other inflammatory cells and initiate tissue fibrosis, and the cycle continues. Eosinophils infiltrate inflamed tissue following allergen-mast cell interaction in bronchial asthma and allergic rhinitis. Evidence is emerging that mast cells can also interact with bacterial endotoxins leading to generation of cytokines like TNFalpha, that encourage neutrophil influx into the site of inflammation (Br. J. Pharmacol, 123, 31; Br. J. Pharmacol, 128, 700, (1999); Br. J. Pharmacol, 136, 111, (2002); J. Clin. Invest., 109, 1351, (2002)). Involvement of mast cells in the inflammatory response of chronic obstructive pulmonary disease (New. Eng. J. Med
347, 1040, (2002); Thorax, 57, 649, (2002)), inflammatory bowel disease (Gut., 45 Suppl 116,
(1999)) as well as rheumatoid arthritis (Science, 297, 1626, (2002)), pathologies with prominent neutrophilic inflammation, has been proposed. U.S. Patent 6,329,344 Bl discloses several monosaccharide derivatives said to be useful as cell adhesion inhibitors. It generally relates to a group of substituted pentose and hexose monosaccharide derivatives, which are described exhibiting as cell adhesion inhibitory and anti-inflammatory activities. U.S. Patent 6,590,085 Bl 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 amino furanose compounds said to be useful for treatment of rheumatoid, arthritis, immunomodulatory diseases, inflammatory and proliferative diseases. U.S. Patent 5,298,494 discloses derivatives of monosaccharides, which reportedly exhibit anti-proliferative and/or anti-inflammatory activity, and are described as useful for treating mammals having inflammatory disorders and/or autoimmune disorders. U.S. Patent 5,367,062 discloses derivatives of disubstituted and deoxydisubstituted ,D-lyxofuranosides which reportedly exhibit significant anti-inflammatory and antiproliferative activity, and are described as useful for treating inflammatory and/or autoimmune disorders. U.S. Patent 5,360,794 discloses deoxydisubstituted or dideoxy disubstituted derivatives of α-D- mannofuranoside and β-L-gulofuranosides, which are described as exhibiting anti- inflammatory and antiproliferative activity. U.S Patent 4,996,195 discloses derivatives of α,D-glucofuranose and α,D-allofuranose said to be useful for treating animals and mammals with inflammatory and/or autoimmune disorders. U.S. 5,010,058 discloses derivatives of 1,2- O-iso-propylidene-α-D-glucofuranose said to be useful for treating animals and mammals with inflammatory and/or autoimmune disorders. WO 93/13117 and U.S. Patent 5,360,792 disclose 5- or 6-deoxy hexose monosaccharides having a saturated nitrogen containing heterocycle said to be useful as antiproliferative 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 described as exhibiting immunomodulatory, anti-inflammatory and anti-proliferative activity. WO 94/11381 discloses derivatives of pentose monosaccharides said to be useful as antiproliferative and anti-inflammatory compounds. Summary of the Invention Monosaccharide derivatives which can be used for the 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 herein. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides of these compounds having the same type of activity are also provided. Pharmaceutical compositions containing the compounds, and which may also contain pharmaceutically acceptable carriers or diluents, which may be used for the treatment of inflammatory and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis, allograft rejection or psoriasis are provided herein. Other aspects will be set forth in accompanying description which follows and in part will be apparent from the description or may be learnt by the practice of the invention. In accordance with one aspect, there is provided a compound having the structure of Formula I
Figure imgf000004_0001
Ri can be Formula I
A) hydrogen,
B) lower (Cι-C6) alkyl {wherein alkyl is optionally substituted with hydroxyl, cycloalkyl, aryl, -OCONRpRq, -NRpRq [wherein Rp and Rq are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyjl or Rp and Rq may together join to form a cyclic ring (3-8 membered), which may be optionally benzofused, containing 0-4 heteroatoms (selected from O, S, and N) [wherein the ring may be substituted with one or more of alkyl, alkenyl, alkynyl, hydroxyl, - NH2, substituted amino, cycloalkyl, -COOR7 (wherein R is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, or cycloalkyl), carboxy, oxo, alkoxy, aryloxy, halogen (F, Cl, Br, I), aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl]], -ORp (where Rp is as defined above), -C(= )QRz (wherein Q is O or NH and Rz is selected from hydrogen, alkyl, aralkyl, aryl, or heteroarylalkyl), heteroaryl, or heterocyclyl},
C) lower (C2-C6) alkenyl,
D) lower (C2-C6) alkynyl, E) aryl,
F) heterocyclyl (see proviso immediately below),
G) heteroaryl (with the proviso that when R5 (defined below) is a derivative of a heteroatom such as O or N then the heterocyclyl or heteroaryl cannot be linked through a heteroatom), H) -ORp wherein Rpis the same as defined earlier (with the proviso that when Rs (defined below) is a derivative of a heteroatom such as O or N then Ri cannot be — ORp), or I) -C(=O)QRz (wherein Q and Rz is the same as defined above).
R2 and R3 together can form a five-membered acetal wherein the carbon joining the oxygens is substituted with Riband Rm wherein
A) RL and Rm are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and aralkyl;
B) RL and Rm together can join to form a cyclic ring (3-8 membered), wherein the ring may optionally contain one or more heteroatoms selected from O, N or S, and the ring may be substituted with one or more of alkyl, alkenyl, alkynyl, -NH2, substituted amino, cycloalkyl, COOR7 (wherein R7 is the same as defined above), carboxy, oxo, hydroxyl, alkoxy, aryloxy, halogen (F,C1, Br, I), aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl; or
C) RL and Rm together can join to form an oxo group. R can be
A) hydrogen, or B) ORc wherein Rc is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl.
Also, when R4 is ORc then R3 and Rc together can form an acetal (wherein acetal is the same as defined earlier) and R2 can be selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl. Also, R2 and R3 instead of forming an acetal as defined earlier may optionally and independently be selected from lower (Cι-C4)alkyl, (CH2)g-aryl (wherein g is an integer from 1-4), -C(=Ry)NHRx (wherein Ry is O or S and Rxis the same as defined below) and acyl; with
R4 as defined earlier.
Also, R3 and Rc (when R4=ORc) instead of forming an acetal as defined earlier may optionally and independently be selected from lower (Cι-C4)alkyl, (CH2)g-aryl (wherein g is an integer from 1-4), -C(=Ry)NHRx (wherein Ry is O or S and Rx is the same as defined below), and acyl; with R2 is as defined earlier.
Rs can be
A) -OC(=O)NRxRy {wherein Rx and Ry are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, S(O)2R6 [wherein R6 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, -NRpRq (wherein Rp and Rq are the same as defined earlier), aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, or heteroarylalkyl], heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, or cycloalkyl}, or Rx and Ry may also together join to form a heterocyclyl or heteroaryl ring;
B) -NRjC(:=O)ORs wherein Rs is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, and heteroarylalkyl; and Rj is selected from hydrogen, lower (Ci- C4) alkyl, lower (C3-C6) alkenyl, lower (C3-C6) alkynyl, lower (C2-C6) cycloalkyl, lower (Ci- C3) aralkyl, aryl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl;
C) -(CH2)o-ιNRjYRu (wherein Y is -C(=O), -C(=S) or SO2 , Rj is the same as defined above and Ru is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl;
D) -NRjC(=T)NRtRx wherein Rj is the same as defined above and Rt is OH or Rx and T is O, S, -N(CN), -N(NO2), -CH(NO2) and Rxis the same as defined earlier (with the proviso that when T is O, Ri is H or CH3, Rt is H and Rx is S(O)2R6 (where R6 is aryl) or aryl, then the aryl cannot be substituted at its para position with Cl, NO2, OCH3, CH2COOH, CH2COOCH3, CH2COLDVP, CH2CODVP or CH2COVP). Also, when R2 and R3 together join to form a five membered acetal (wherein acetal is the same as defined above) and R5 is NRjC(=O)NRtRx or NRjC(=O)Ru then Rc cannot be Cι-C alkyl or (CH2)0.4-aryl and Rj cannot be (Cι-C4)alkyl, (CH2)0.2cycloalkyl, (C2-C6)alkenyl, (CH2)ι-4aryl, (CH2)0-4-heterocyclyl, (CH )ι- heteroaryl, or (CH2)ι-2-O-aryl; E) heteroaryl; or
F) heterocyclyl and also, wherein the said heterocyclic ring, which may or may not be benzofused, is always substituted when Ri is H, CH3 or alkyl substituted with -NRpRq
(wherein Rp and Rq are hydrogen, alkyl, aralkyl or together joins to form a cyclic ring as defined earlier).
Ri and R5 may also together join form a heterocyclyl ring with the proviso that Ri and R5 together do not form an isopropylidene ring. R5 can be, for example, amino carbonyl alkylheterocyclyl amino sulfonyl aryl (-
NHCO-(CH2)n-Het-NH-SO2-Ar, with n from 0 to 6, and where Het and Ar can be substituted as indicated above), amino carbonyl alkylheterocyclyl amino alkylsulfonyl (-NHCO-(CH2)n-
Het-NH-SO2-alkyl, with n from 0 to 6, and where Het and alkyl can be substituted as indicated above), oxo carbonyl amino aryl (-O-CONH-Ar, where Ar can be substituted as indicated above), oxo carbonyl amino alkylaryl (O-CONH-(CH2)n-Ar, with n from 0 to 6, and where Ar can be substituted as indicated above), oxo carbonyl amino sulfonyl heterocyclyl (- O-CONH-SO2-Het, where Het can be substituted as indicated above), oxo carbonyl amino sulfonyl aryl (-O-CONH-SO2-Ar, where Het can be substituted as indicated above), alkyl amino carbonyl aryl ((CH2)n-NHCO-Ar, with n from 0 to 6, and where Ar can be substituted as indicated above), and amino sulfonyl aryl (NH-SO2-Ar, where Ar can be substituted as indicated above). The following definitions apply to terms as used herein: The term "alkyl" unless otherwise specified refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term is 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. Alkyl may further be substituted with one or more substituents selected alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, allcylthio, aryloxy, aminosulfonyl, aminocarbonylamino, -COORs (wherein Rs is the same as defined earlier), - NHC(-O)Rx, -NRxRy, -C(=O)NRxRy, -NHC(=O)NRxRt, -N(OH)C(=O)NRxRt, - C(=:O)heteroaryl, C(=O)heterocyclyl, -O-C(=O)NRxRy wherein Rx and Ry are the same as defined earlier, nitro, -S(O)mR6 (wherein m is an integer from 0-2 and R6 is the same as defined earlier). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, carboxy, -NRxRy, -C(=O)NRxRy, - O-C(=O)NRxRy, -NHC(=O)NRxRy wherein Rx and Ry are the same as defined earlier, hydroxy, alkoxy, halogen, CF3, cyano, and -S(O)mRδ, where R6 and m are the same as defined earlier; or an alkyl group as defined above may also be interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur and -NRa-, [where Ra is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl,-C(=O)ORs
(wherein Rsis the same as defined earlier), S(O)2R6 (where R6is as defined earlier), or -
C(=O)NRxRy (wherein Rx and Ry are as defined earlier)]. Unless otherwise constrained by the definition, all substituents maybe further substituted by 1-3 substituents chosen from alkyl, carboxy, -NRxRy, -C(=O)NRxRy, -O-C(=O)NRxRy wherein Rx and Ry are the same as defined earlier hydroxy, alkoxy, halogen, CF3, cyano, and -S(O)raR6, (where m and R6 are the same as defined earlier); or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above. The term "alkenyl" unless otherwise specified 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 may further be substituted with one or more substituents selected from alkyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, -COORs (wherein Rs is the same as defined earlier), -NHC(=O)Rx, -NRxRy, -C(=O)NRxRy, -NHC(=O)NRxRt, - N(OH)C(=O)NRxRt, -O-C(=O)NRxRy (wherein Rx and Ry are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, aminocarbonylarnino, alkoxyamino, nitro, or S(O)mR6 (wherein R6 and m are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, hydroxy, alkoxy, halogen,-CF3, cyano, -NRxRy, -C(=O)NRxRy, -O-C(=O)NRxRy (wherein Rx and Ry are the same as defined earlier) and -S(O)mR6, (where R6 and m are the same as defined earlier). The term "alkynyl" unless and otherwise specified refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms. In the event that alkynyl is attached to the heteroatom, the triple bond cannot be alpha to the heteroatom. Alkenyl may further be substituted with one or more substituents selected from alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, allcylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, nitro, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroarylalkyl, -COORs (wherein Rs is the same as defined earlier), - NHC(=O)Rx -NRxRy, -NHC(=O)NRxRt, -N(OH)C(=O)NRxRt, -C(=O)NRxRy, -O- C(= )NRxRy (wherein Rx and Ry are the same as defined earlier), -S(O)mR6 (wherein R6 and m are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF3, -NRxRy, -C(=O)NRxRy, -
NHC(=O)NRxRt , -C(=O)NRxRy wherein Rx and Ry are the same as defined earlier cyano, and -S(O)mR6, where R6 and m are the same as defined earlier; The term "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 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. Cycloalkyl may further be substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, -COORs (wherein Rs is the same as defined earlier), -NRxRy, - NHC(=O)NRxRt, -N(OH)C(=O)NRxRt, -NHC(=O)Rx -C(=O)NRxRy, -O-C(-O)NRxRy (wherein Rx and Ry are the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, or S(O)m-R6 (wherein R6 and m are the same as defined earlier and wherein the carbon joining the oxygus is substituted with Re. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, hydroxy, alkoxy, halogen, CF3, -NRxRy, - C(=O)NRxRy, -NHC(=O)NRxRt, -O-C(-O)NRxRy wherein Rx and Ry are the same as defined earlier cyano, and -S(O)mR,5, where R6 and m are the same as defined earlier. The term "alkoxy" denotes the group O-alkyl wherein alkyl is the same as defined above. The term "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 include benzyl and the like. The term "aryl" herein refers to a carbacyclic aromatic group, for example phenyl, biphenyl or naphthyl ring and the like optionally substituted with 1 to 3 substituents selected from -(CH2)wC(=O)Rg wherein w is an integer from 1-4 and Rg is hydroxy, ORz, NRxRy, - NHORz or -NHOH, halogen (F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, cyano, nitro, -COORs (wherein Rs is the same as defined earlier), NHC(=O)Rx, -NRxRy, -C(=O)NRxRy, -NHC(=O)NRxRt, -N(OH)C(=O)NRxRt, -O- C(=O)NRxRy (wherein Rx and Ry are the same as defined earlier); -(SO2)mR6 (wherein R6 and m are the same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino. The aryl group may optionally be fused with cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N, S. The term "aryloxy" denotes the group O-aryl wherein aryl is the same as defined above. The term "carboxy" as defined herein refers to -C(=O)OH. The term "heteroaryl" unless otherwise specified refers to an aromatic ring structure containing 5 or 6 atoms, or a bicyclic aromatic group having 8 to 10 atoms, with one or more heteroatom(s) independently selected from N, O and S the balance being carbon atoms optionally substituted with 1 to 3 substituent(s) selected from halogen (F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, amino carbonyl amino, -COORs (wherein Rs is the same as defined earlier), -NRxRy, - (CH2)wC(=O)Rg wherein w is an integer from 1-4 and Rg is hydroxy, ORz, NRxRy, -NHORz or -NHOH, -C(=O)NRxRy and-NHC(=O)NRxRt, -N(OH)C(=O)NRxRt, -SO2R6, -O- C(=O)NRxRy wherein Rx and Ry are the same as defined earlier. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, be it carbon or heteroatom. Examples of heteroaryl groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like as well as non-fused systems such as bipyrimidinyl, and other such analogues. The term 'heterocyclyl" unless otherwise specified refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms in which 1 to 3 carbon atoms in a ring are replaced by heteroatoms selected from the group comprising of O, S or N, and are optionally benzofused or fused heteroaryl of 5-6 ring members and/or are optionally substituted wherein the substituents are selected from the group consisting of halogen (F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy, aminocarbonylamino, -COORs (wherein Rs is the same as defined earlier), - C(=O)NRxRy, SO2R6, -O-C(=O) NRxRy, -N(OH)C(=O)NRxRt, -NHC(=O)NRxRt, or -NRxRy (wherein Rx and Ry are the same as defined earlier). Unless otherwise constrained by the definition, the substituents are attached to the ring atom, be it carbon or heteroatom. Also unless otherwise constrained by the definition the said heterocyclyl ring may optionally contain one or more olefinic bond(s). Examples of heterocyclyl groups are tetrahydro furanyl, dihydrofuranyl, dihydropyridinyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, piperidinyl or piperazinyl. "Heteroarylalkyl" refers to alkyl-heteroaryl group linked tlirough 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. "Acyl" refers to -C(=O)R" wherein R" is selected from alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl. "Acyl" refers to -CORp (wherein Rp is the same as defined earlier). "Substituted amino" unless otherwise specified refers to a group -N(Rk) wherein each
Rkis independently selected from hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, acyl, S(O)mR6 (wherein m and R6 is the same as defined above), -C(=Rv)NRxRy wherein Rv, Rx and Ry are the same as defined earlier) or NHC(=Rv)NRtRx (wherein Rv, Rt and Rx are the same as defined earlier) provided that both Rk groups are not hydrogen (defined as "amino"). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF3, cyano, -C(=Rv)NRxRy, -O(C=O)NRxRy (wherein Rx, Ry and Rv are the same as defined earlier) and -OC(=Rv)NRxRy,, -S(O)mRδ, (where R6 is the same as defined above and m is 0, 1 or 2). The term "leaving group" generally refers to groups that exhibit the desirable properties of being labile under the defined synthetic conditions and also, of being easily 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. The term "activated derivative of a carboxylic acid" refers to, for example, protected amino acids, aliphatic acids or aromatic acids, for example their corresponding acyl halide (e.g. acid fluoride, acid chloride and acid bromide), corresponding activated esters (e.g., nitro phenyl ester, the ester of 1- hydroxybenzotriazole or the ester of hydroxysuccinimide, HOSu) or a mixed anhydride, for example anhydride, with ethyl chloroformate and other conventional derivatives known to those of ordinary skill in the art. The term "protecting groups" is used herein to refer to known moieties which have the desirable property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be 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. Wuts, "Protective Groups in Organic Synthesis", 2nd ED, John Wiley and Sons, New York, N.Y., which is incorporated herein by reference. The particular carboxylic protecting groups, amino protecting groups or hydroxy protecting group employed are not critical, so long as the derivatised moieties are stable to the conditions of subsequent reactions and can be removed at an appropriate point without disrupting the remainder of the molecule. "Amino acid" refers to both natural and unnatural amino acids. The term "natural amino acid," as used herein, represents 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, γ-carboxyglutamic acid, arginine, ornithine and lysine in their L form. The term "unnatural amino acid," as used herein, is intended to represent the 'D' forms of the twenty-two naturally-occurring amino acids described above. It is futher understood that the term 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. The term "peptide" refers to a molecule comprising a series of amino acids linked through amide linkages. Dipeptide comprises of 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. "DNP" refers to a tripeptide aspartyl-valyl-prolyl. "NP" refers to a dipeptide valyl-prolyl. Compounds described herein generally contain one or more asymmetric carbon atoms and thus can occur as racemates and racemic mixtures, single enantiomers, diastereomieric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included herein. Each stereogenic carbon may be of the R or S configuration. Although 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. Although 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 The compounds disclosed herein may be prepared by techniques well known in the art and familiar to a practitioner skilled in art of this invention. In addition, the compounds disclosed herein may be prepared by the processes described herein, although these processes are not the only means by which the compounds described may be synthesised. Further, some of the various synthetic steps described herein may be performed in an alternate sequence or order to give the desired compounds. Scheme
Figure imgf000014_0001
Formula II Formula IV The compound of Formula IN can be prepared following Scheme I. Thus a compound of Formula II (wherein W is -OH or -ΝH2, Rt is H or CH > R2, R3 and R4 are the same as defined earlier) is reacted with a compound of Formula III (wherein Rx is the same as defined earlier) to give a compound of Formula IN (wherein T is -O or -ΝH) The compound of Formula II can be reacted with a compound of Formula III to give a compound of Formula IN in an organic solvent, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride in the presence of an organic base for example pyridine, triethylamine or diisopropylethylamine. Alternatively, a compound of
Formula II can be reacted with a phenyl or p-nitrophenylcarbamate of an amine (RXΝH2) to give a compound of FormulalN in a solvent for example tetrahydrofuran, dimethylformamide or dimethyl sulfoxide optionally in the presence of bases such as triethylamine, pyridine or diisopropylethylamine. Exemplary compounds which are prepared through Scheme I are listed below:
1 ,2-O-Isopropylidene-3 -O-dodecyl-5 -O- [ {4-(2-methoxy-2-oxo-ethyl)-phenyl} -amino] - carbonyl-6-deoxy-α-D-glucofuranoside (Compound No. 1) l,2-O-Isopropylidene-3-O-dodecyl-5-O-{[(4-morpholinyl)-sulphonylamino]-carbonyl}-α-D- xylofuranoside (Compound No. 2) 1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [(4-azepanyl)-sulphonylamino]-carbonyl} - -D- xylofuranoside (Compound No. 3)
1 ,2-O-Isopropylidene-3-O-dodecyl-5-O- { [(1 -piperidinyl)-sulphonylamino]-carbonyl} -α-D- xylofuranoside (Compound No. 4) l,2-O-Isopropylidene-3-O-decyl-5-O-{[(l-piperidinyl)-sulphonylamino]-carbonyl}- -D- xylofuranoside (Compound No. 5) l,2-O-Isopropylidene-3-O-dodecyl-5-O-{[(l-azepanyl)-sulphonylamino]-carbonyl}-α-D- xylofuranoside (Compound No. 6) 1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [(4-morpholinyl)-sulphonylamino]-carbonyl} -α-D- xylofuranoside (Compound No. 7) l,2-O-Isopropylidene-3-O-decyl-5-O-{[(l-pyrrolidinyl)-sulphonylamino]-carbonyl}-α-D- xylofuranoside (Compound No. 8) l,2-O-Isopropylidene-3-O-heptyl-5-O-{[(l-piperidinyl)-sulfonylamino]-carbonyl}-α-D- xylofuranoside (Compound No. 9)
1 ,2-O-Isopropylidene-3 -O-hexadecyl-5-O-[ { ( 1 -piperidinyl)-sulfonylamino } -carbonyl]-α-D- xylofuranoside (Compound No. 10) l,2-O-Isopropylidene-3-O-decyl-5-O-[{4-(2-methoxy-2-oxo-ethyl)-phenyl}-amino]-carbonyl-
6-deoxy-α-D-glucofuranoside (Compound No. 11) 1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [4-(2-hydroxy-2-oxoethyl)-phenyl]-amino} -carbonyl-
6-deoxy-α-D-glucofuranoside (Compound No. 12)
1 -O-Dodecyl-2,3-O-isopropylidene-5-O- { [2-methyl-phenylamino]-carbonyl} -6-deoxy- -D- mannofuranoside (Compound No.13 ) l-O-Heptyl-2,3-O-isopropylidene-5-O-{[(2-methyl-phenyl)-sulphonylamino]-carbonyl}-6- deoxy- -D-mannofuranoside (Compound No. 14)
1 -O-Heptyl-2,3 -O-isopropylidene-5-O-[ {2-(4-[2-methoxy-2-oxo-ethyl]-thiazolyl)-amino} - sulfonyl-amino]-carbonyl-6-deoxy-α-D-mannofuranoside (Compound No. 15)
1 -O-Heptyl-2,3 -O-isopropylidene-5-O- {(1 -azepanyl)-sulfonylamino} -carbonyl-6-deoxy-α-D- mannofuranoside (Compound No. 16) l-O-Heptyl-2,3-O-isopropylidene-5-O-{(l-pyrrolidinyl)-sulfonylamino}-carbonyl-6-deoxy- -D-mannofuranoside (Compound No. 17) l-O-(3-Undecyloxy-propyl)-2,3-O-isopropylidene-5-O-{[(l-pyrrolidinyl)-sulphonylamino]- carbonyl}-β-D-lyxofuranoside (Compound No. 18) l-O-(3-Undecyloxy-propyl)-2,3-O-isopropylidene-5-O-{[(l-piperidinyl)-sulfonylamino]- carbonyl} -β-D-lyxofuranoside (Compound No. 19) l-O-(3-Undecyloxy-propyl)-2,3-O-isopropylidene-5-O-{[(l-azepanyl)-sulphonylamino] carbonyl} -β-D-lyxofuranoside (Compound No. 20) l-O-(3-Undecyloxy-propyl)-2,3-O-isopropylidene-5-O-[{(4-morpholinyl)-sulphonylamino}- carbonyl]-β-D-lyxofuranoside (Compound No. 21) l-O-(3-Undecyloxy-propyl)-2,3-O-isopropylidene-5-O-[(phenylamino)carbonyl]-β-D- lyxofuranoside (Compound No. 22)
1 -O-Dodecyl-2,3-O-isopropylidene-5-O- { [4-(2-methoxy-2-oxo-ethyl)-phenyl]-amino} - carbonyl-6-deoxy-α-D-mannofuranoside (Compound No. 23) l-O-Dodecyl-2,3-O-isopropylidene-5-O-[{4-methyl-phenyl-amino}-carbonyl]-6-deoxy-α-L- mannofuranoside (Compound No. 24)
1 -O-Dodecyl-2,3-O-isopropylidene-5-O- { [3-chloro-phenyl-amino]-carbonyl} -6-deoxy-α-D- mannofuranoside (Compound No. 25)
1 -O-Dodecyl-2,3-O-isopropylidene-5-O- { [4-chloro-phenyl amino] -carbonyl} -6-deoxy-α-D- mannofuranoside (Compound No. 26) 1 ,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-( { [4-(2-hydroxy-2-oxo-ethyl)-phenyl]- amino}-carbonyl)-amino-β-L-idofuranoside (Compound No. 27) l,2-O-Cyclohexylidene-3-O-decyl-5-deoxy-5-[{(4-[2-hydroxy-2-oxo-ethyl]-phenyl)-amino}- carbonyl]-amino- -D-xylofuranoside (Compound No. 28) l,2-O-Cyclohexylidene-3-O-decyl-5-deoxy-5-{[(4-methoxy-phenyl)-amino]-carbonyl}- amino-α-D-xylofuranoside (Compound No. 29)
1 ,2-O-Cyclohexylidene-3 -O-decyl-5-deoxy-5- { [(4-methyl-phenyl)-amino] -carbonyl} -amino- α-D-xylofuranoside (Compound No. 30)
1 ,2~O-Cyclohexylidene-3-O-decyl-5-deoxy-5- { [(4-chlorophenyl)-amino]-carbonyl} -amino-α- D-xylofuranoside (Compound No. 31) l,2-O-Cyclohexylidene-3-O-decyl-5-deoxy-5-{(phenylamino)-carbonyl}-amino-α-D- xylofuranoside (Compound No. 32) l,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-{([4-(2-methoxy-2-oxo-ethyl)-phenyl]- amino)-carbonyl}-amino-β-L-idofuranoside (Compound No. 33) l,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-({[4-methoxy-phenyl]-amino}-carbonyl)- amino-β-L-idofuranoside (Compound No. 34) l,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5-{[(4-methoxy-phenyl)-amino]-carbonyl}- amino-β-L-idofuranoside (Compound No. 35) l,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-{[(4-methyl-phenyl)-amino]-carbonyl}- amino-β-L-idofuranoside (Compound No. 36) 1 ,2-O-Cyclohexylidene-3 -O-nonyl- 5 , 6-dideoxy-5 - { [(4-nitro-phenyl)-amino] -carbonyl } - amino-β-L-idofuranoside (Compound No. 37)
1 ,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5- { [(4-chloro-phenyl)-amino]-carbonyl} - amino-β-L-idofuranoside (Compound No. 38)
1 ,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5- { [(4-methyl-phenyl)-amino]-carbonyl} - amino-β-L-idofuranoside (Compound No. 39) l,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5-{([4-(2-methoxy-2-oxoethyl)-phenyl]- amino)-carbonyl} -amino-β-L-idofuranoside (Compound No. 40)
1 ,2-O-Cyclohexylidene-3 -O-heptyl-5 ,6-dideoxy-5-( { [4-(2-hydroxy-2-oxo-ethyl)-phenyl] - amino}-carbonyl)-amino-β-L-idofuranoside (Compound No. 41) 1 ,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5- { [(4-chloro-phenyl)-amino]-carbonyl} - amino-β-L-idofuranoside (Compound No. 42) l,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5-{[(4-nitro-phenyl)-amino]-carbonyl}- amino-β-L-idofuranoside (Compound No. 43)
1 ,2-O-Cyclopentylidene-3-O-decyl-5-deoxy-5- {[4-nitro-phenyl-amino] -carbonyl} -amino-α- D-xylofuranoside (Compound No. 236)
Tris salt of l,2-O-isopropylidene-3-O-dodecyl-6-deoxy-6-({[4-(2-hydroxy-2-oxo-ethyl)- phenyl]-amino-carbonyl)-amino-α-D-glucofuranoside (Compound No.196 ).
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [ 1 -((3 ,4-methylenedioxy-phenyl)-3 - hydroxy-3-oxo-propyl)-amino]-carbonyl]-amino-β-L-gulofuranoside (Compound No. 233) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-azidophenyl)amino] carbonyl} amino)-β-L-gulofuranoside (Compound No. 246) l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-({[(4-[carboxymethyl]phenyl)amino] carbonyl} -amino)-β-L-gulofuranoside (Compound No. 251)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [(amino)carbonyl]amino} -β-L- gulofuranoside (Compound No. 263) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [(phenylamino)carbonyl] amino } -β-L- gulofuranoside (Compound No. 265)
1 ,2-O-Isopropylidene-3-O-dodecyl-5,6-dideoxy-5-[( { [(4-carboxymethyl)- 1 ,3-thiazol-2- yl]amino}-carbonyl)amino]-β-L-talofuranose (Compound No. 273) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[({(2-[2-carboxybenzoyl] phenyl)amino}carbonyl)-amino]-β-L-gulofuranoside (Compound No. 274) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[({(4-carbonylmethyl-2-iodo- phenyl)amino}-carbonyl)amino]-β-L-gulofuranoside (Compound No. 275) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(3- carboxymethylphenyl)amino]carbonyl} -amino)-β-L-gulofuranoside (Compound No. 276) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(2- carboxymethylphenyl)amino]carbonyl}-amino)-β-L-gulofuranoside (Compoun No. 277) l-O-(2,4-Dodecadienyl)-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-carboxymethyl-2,6-di- iodophenyl)amino]carbonyl}amino)-β-L-gulofuranoside (Compound No. 278) l-O-(2,4-Dodecadienyl)-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-carboxymethyl-2- iodophenyl)-amino]carbonyl}amino)-β-L-gulofuranoside (Compound No. 279) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(2,6-diiodophenyl)amino] carbonyl} amino)-β-L-gulofuranoside (Compound No. 280)
1 -O-Dodecyl-2,3-O-isopropylidene-6-deoxy-5-O- { [(phenylsulfonyl)amino]carbonyl} -α-D- mannofuranoside (Compound No. 281)
1 -O-Dodecyl-2,3-O-isopropylidene-6-deoxy-5-O- { [(2-tolylsulfonyl)amino]carbonyl} -α-D- mannofuranoside (Compound No. 282) l-O-Dodecyl-2,3-O-isopropylidene-6-deoxy-5-O-{[(4- chlorophenylsulfonyl)amino]carbonyl}-α-D-mannofuranoside (Compound No. 283) 1 -O-Dodecyl-2,3-O-isopropylidene-6-deoxy-5-O- { [(4-tolylsulfonyl)amino]carbonyl} -α-D- mannofuranoside (Compound No. 284)
1 -O-Dodecyl-2,3-O-isopropylidene-6-deoxy-5-O- { [(benzyl)amino]carbonyl} -α-D- mannofuranoside (Compound No. 285) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4- tolylsulfonyl)amino]carbonyl}amino)-β-L-gulofuranoside (Compound No. 286) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(2- tolylsulfonyl)amino]carbonyl}amino)-β-L-gulofuranoside (Compound No. 287) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4- chlorosulfonyl)amino]carbonyl}amino)-β-L-gulofuranoside (Compound No. 288) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(phenylsulfonyl) amino] carbonyl} amino)- β-L-gulofuranoside (Compound No. 289).
Figure imgf000019_0002
Formula VI Formula V
Figure imgf000019_0001
The compounds of Formula VIII can be prepared by Scheme II. Thus a compound of Formula V (wherein R2, R3 and R4 are the same as defined earlier) is reacted with a compound of Formula VI (wherein X can be -CH-, -O-, or -NH- and k is 1-2) to give a compound of Formula Nil, which is finally reacted with a compound of Formula III (wherein Rx is the same as defined earlier) to give a compound of Formula NHL The compound of Formula Nil can be reacted with a compound of Formula III to give a compound of Formula NIII in an organic solvent, for example, dichloromethane, dichloroethane, carbon tetrachloride or chloroform. Exemplary compounds which are prepared following Scheme II are listed below: 1 -O-Heptyl-2,3 -O-isopropylidene-5-O- {(4-chloro-phenyl)-amino} -carbonyl-6-deoxy-6-( 1 - azepanyl)-α-D-mannofuranoside (Compound No. 44) l-O-Dodecyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}-carbonyl-6-deoxy-6-(l- azepanyl)-α-D-mannofuranoside (Compound No. 45) 1 -O-Dodecyl-2,3-O-isopropylidene-5-O- {(4-methyl-phenyl)~amino} -carbonyl-6-deoxy-6-(l - azepanyl)-α-D-mannofuranoside (Compound No. 46)
Hydrochloride salt of l,2-0-isopropylidene-3-O-decyl-5-O-(phenylsulfonyl-amino)-carbonyl-
6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 47) 1 ,2-O-Isopropylidene-3 -O-decyl-5-O- { [4-methyl-phenyl]-amino} -carbonyl-6-deoxy-6-( 1 - piperidinyl)-α-D-glucofuranoside (Compound No. 48)
1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [4-chloro-phenyl]-amino} -carbonyl-6-deoxy-6-(l - piperidinyl)-α-D-glucofuranoside (Compound No. 49) l,2-O-Isopropylidene-3-O-decyl-5-O-{[4-methoxy-phenyl]-amino}-carbonyl-6-deoxy-6-(l- piperidinyl)-α-D-glucofuranoside (Compound No. 50) l,2-O-Cyclohexylidene-3-O-decyl-5-O-{(4-methyl-phenyl)-amino}-carbonyl-6-deoxy-6-(l- pyrrolidinyl)-α-D-allofuranoside (Compound No. 51)
Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-methoxy-phenyl)-amino}- carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-mannofuranoside (Compound No. 52) Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-amino}- carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-mannofuranoside (Compound No. 53) Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}- carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-mannofuranoside (Compound No. 54) Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-nitro-phenyl)-amino}- carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-mannofuranoside (Compound No. 55)
Hydrochloride salt of 1 -O-Heptyl-2,3 -O-isopropylidene-5-O-{[4-methyl-ρhenyl] -amino} - carbonyl-6-deoxy-6-(l-azepanyl)-α-D-mannofuranoside (Compound No. 56) Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-methoxy-phenyl)-amino}- carbonyl-6-deoxy-6-(l-azepanyl)-α-D-mannofuranoside (Compound No. 57) Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}- carbonyl-6-deoxy-6-( 1 -azepanyl)-α-D-mannofuranoside(Compound No. 58) Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{4-nitro-phenyl)-amino}- carbonyl-6-deoxy-6-(l-azapenyl)-α-D-mannofuranoside (Compound No. 59) 1 ,2-O-Isopropylidene-3-O-dodecyl-5-O- { [4-methyl-phenyl]-amino} -carbonyl-6-deoxy-6-(l - azepanyl)-α-D-glucofuranoside (Compound No. 60) l,2-O-Isopropylidene-3-O-dodecyl-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino}- carbonyl-6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 61) l,2-O-Isopropylidene-3-O-dodecyl-5-O-{(4-methoxy-phenyl)-amino}-carbonyl-6-deoxy-6-
(l-azepanyl)-α-D-glucofuranoside (Compound No. 62) l,2-O-Cyclohexylidene-3-O-decyl-5-O-{(4-nitro-phenyl)-amino}-carbonyl-6-deoxy-6-(l- azepanyl)-α-D-glucofuranoside (Compound No. 63) l,2-O-Cyclohexylidene-3-O-decyl-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino}- carbonyl-6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 64) l,2-O-Cyclohexylidene-3-O-decyl-5-O-{(4-methyl-phenyl)-amino}-carbonyl-6-deoxy-6-(l- azepanyl)-α-D-glucofuranoside (Compound No. 65) l,2-O-Cyclohexylidene-3-O-decyl-5-O-[(4-chloro-phenyl)-amino]-carbonyl-6-deoxy-6-(l- azepanyl)-α-D-glucofuranoside (Compound No. 66)
1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [4-(2-methoxy-2-oxo-ethyl)-phenyl]-amino} -carbonyl-
6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 67) l,2-O-Isopropylidene-3-O-decyl-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino}-carbonyl-
6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 68) l,2-O-Isopropylidene-3-O-decyl-5-O-(4-methoxy-phenyl)-amino}-carbonyl-6-deoxy-6-(l- azepanyl)-α-D-glucofuranoside (Compound No. 69) l,2-O-Isopropylidene-3-O-decyl-5-O-(phenylamino)-carbonyl-6-deoxy-6-(l-azepanyl)-α-D- glucofuranoside (Compound No. 70) l,2-O-Cyclohexlidene-3-O-decyl-5-O-{(4-methoxy-phenyl)-amino}-carbonyl-6-deoxy-6-(l- pyrrolidinyl)-α-D-glucofuranoside (Compound No. 71) l,2-O-Cyclohexylidene-3-O-decyl-5-O-{(4-chloro-phenyl)-amino}-carbonyl-6-deoxy-6-(l- pyrrolidinyl)-α-D-glucofuranoside (Compound No. 72) 1 ,2-O-Cyclohexylidene-3-O-decyl-5-O- {(4-nitro-phenyl)amino}-carbonyl-6-deoxy-6-(l- pynolidinyl)-α-D-glucofuranoside (Compound No. 73) l,2-O-Cyclohexylidene-3-O-decyl-5-O-{[4-(2-methoxy-2-oxo-ethyl)-phenyl]-amino}- carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 74)
1 ,2-O-Cyclohexylidene-3-O-decyl-5-O-[(4- {2-hydroxy-2-oxo-ethyl} -phenyl)-amino]- carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 75) l,2-O-Cyclohexylidene-3-O- decyl-5-O-(phenylamino) -carbonyl -6-deoxy-6-(l -pyrrolidinyl)
-α-D-glucofuranoside (Compound No. 76)
Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5-O-{(4-nitro-phenyl)-amino}- carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 77) Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5-O-{(4-methoxy-phenyl)-amino}- carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 78)
Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-amino}- carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 79)
Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}- carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 80)
Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-{(4-methyl-phenyl)- sulphonylamino]-carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No.
81)
Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{(4-methyl-phenyl)- sulphonylamino}-carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No.
82)
Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{(4-methyl-phenyl)- sulphonylamino} -carbonyl-6-deoxy-6-(4-morpholinyl)-α-D-glucofuranoside (Compound No.
83) Hydrochloride salt of 1 ,2-O-isopropylidene-3-O-heptyl-5-O- {(4-methyl-phenyl)- sulphonylamino}-carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No.
84)
1 -O-Dodecyl-2,3-O-isopropylidene-5-O- {(4-methyl-phenyl)-amino} -carbonyl-6-deoxy-6-(4- morpholinyl)-α-D-mannofuranoside (Compound No. 85) 1 -O-Dodecyl-2,3-O-isopropylidene-5-O- {(4-methoxy-phenyl)-amino} -carbonyl-6-deoxy-6-
(4-morpholinyl)-α-D-mannofuranoside (Compound No. 86)
1 -O-Dodecyl-2,3-O-isopropylidene-5-O- {(4-chloro-phenyl)-amino} -carbonyl-6-deoxy-6-(4- morpholinyl)-α-D-mannofuranoside (Compound No. 87) l-O-Dodecyl-2,3-O-isopropylidene-5-O-{(4-nitro-phenyl)-amino}-carbonyl-6-deoxy-6-(4- morpholinyl)-α-D-mannofuranoside (Compound No. 88) 1 -O-Heptyl-2,3 -O-isopropylidene-5-O- {(4-chloro-phenyl)-amino} -carbonyl-6-deoxy-6-( 1 - piperidinyl)-α-D-mannofuranoside (Compound No. 89) l-O-Heptyl-2,3-O-isopropylidene-5-O-{(4-methoxy-phenyl)-amino}-carbonyl-6-deoxy-6-(l- piperidinyl)-α-D-mannofuranoside (Compound No. 90) l-O-Heptyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-amino}-carbonyl-6-deoxy-6-(l- piperidinyl)-α-D-mannofuranoside (Compound No. 91) l-O-Heptyl-2,3-O-isopropylidene-5-O-{(4-nitro-phenyl)-amino}-carbonyl-6-deoxy-6-(l- ρiperidinyl)-α-D-mannofuranoside (Compound No. 92)
1 -O-Dodecyl-2,3-O-isopropylidene-5-O- {(4-methyl-phenyl)-sulfonylamino} -carbonyl-6- deoxy-6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 93) l-O-Heptyl-2,3-O-isopropylidene-5-O-[(4-methyl-phenyl)-sulfonylamino]-carbonyl-6-deoxy-
6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 94) l-O-Heptyl-2,3-O-isopropylidene-5-O-[(4-methyl-phenyl)-sulfonylamino}-carbonyl-6-deoxy-
6-(4-morpholinyl)-α-D-mannofuranoside (Compound No. 95) l-O-Heptyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-amino}-carbonyl-6-deoxy-6-(4- mo holinyl)-α-D-mannofuranoside (Compound No. 96) l-O-Heptyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}-carbonyl-6-deoxy-6-(4- morpholinyl)-α-D-mannofuranoside (Compound No. 97) l-O-Heptyl-2,3-O-isopropylidene-5-O-{(4-nitro-phenyl)-amino)-carbonyl-6-deoxy-6-(4- morpholinyl)-α-D-mannofuranoside (Compound No. 98) l-O-Decyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}-carbonyl-6-deoxy-6-(l- piperidinyl)-α-D-mannofuranoside (Compound No. 99) l-O-Heptyl-2,3-O-isopropylidene-5-O-[(4-methoxy-phenyl)-amino]-carbonyl-6-deoxy-6-(4- morpholinyl)-α-D-mannofuranoside (Compound No. 100) Hydrochloride salt of 1 ,2-O-isopropylidene-3-O-decyl-5-O- {(4-methyl-phenyl)- sulfonylamino}-carbonyl-6-deoxy-6-(l-pynolidinyl)-α-D-glucofuranoside (Compound No.
101)
Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-{(4-chloro-phenyl)- sulfonylamino} -carbonyl-6-deoxy-6-(l -pynolidinyl)-α-D-glucofuranoside (Compound No. 102) Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-(phenyl-sulfonylamino)-carbonyl- 6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 103) Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{(4-methyl-phenyl)- sulfonylamino}-carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 104)
Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{(4-methyl-phenyl)- sulfonylamino}-carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No.
105)
Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-(phenyl-sulfonylamino)- carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No. 106) Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-{4-chloro-phenyl)- sulfonylamino}-carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No. 107) Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-[(4-chloro-phenyl)- sulfonylamino}-carbonyl-6-deoxy-(l-azepanyl)-α-D-glucofuranoside (Compound No. 108) Hydrochloride salt of l,2-O-isopropylidene-3-0-heptyl-5-O-(4-methyl-phenyl)- sulfonylamino}-carbonyl-6-deoxy-(l-azepanyl)-α-D-glucofuranoside (Compound No. 109) Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-(phenylsulfonylamino)-carbonyl- 6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 110) Hydrochloride salt of 1 ,2-O-isopropylidene-3-O-decyl-5-O-(phenylsulfonylamino)-carbonyl- 6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No. Ill) Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-(phenyl sulfonylamino)- carbonyl-6-deoxy-6-(4-morpholinyl)-α-D-glucofuranoside (Compound No. 112) Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{[(4-chloro-phenyl)- sulfonylamino]-carbonyl} -6-deoxy-6-(l -pyrrolidinyl)-α-D-glucofuranoside (Compound No. 113)
Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{(phenylsulfonylamino)- carbonyl}-6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No.l 14 ) Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{[(4-methyl-phenyl)-amino]- carbonyl} -6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 115) Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-{[(4-chloro-phenyl)- sulfonylamino]-carbonyl}-6-deoxy-6-(4-mo holinyl)-α-D-glucofuranoside (Compound No.
116)
Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{[(4-chloro-phenyl)- sulfonylamino] -carbonyl} -6-deoxy-6-(4-morpholinyl)-α-D-glucofuranoside (Compound No.
117)
Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{[(4-chloro-phenyl)- sulfonylamino]-carbonyl}-6-deoxy-6-(4-morpholinyl)-α-D-glucofuranoside (Compound No.
118) Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-{(phenylsulfonylamino)- carbonyl}-6-deoxy-6-(4-morpholinyl)-α-D-glucofuranoside (Compound No. 119) Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-{(4-methyl-phenyl sulfonylamino)-carbonyl}-6-deoxy-6-(4-moφholinyl)-α-D-glucofuranoside (Compound No. 120) Hydrochloride salt of 1 ,2-O-isopropylidene-3-O-decyl-5-O-(phenyl-sulfonylamino)-carbonyl- 6-deoxy-6-(4-morpholinyl)-α-D-glucofuranoside (Compound No. 121) Tris salt of l,2-O-isopropylidene-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino}-carbonyl- 6-deoxy-6-[l-piperidinyl]-α-D-glucofuranoside (Compound No. 124) 1 ,2-O-Isopropylidene-5-O- { [4-(2-hydroxy-2-oxo-ethyl)-phenyl] -amino} -carbonyl-6-deoxy-6- [ 1 -azepanyl] -α-D-glucofuranoside (Compound No. 125) l,2-O-Isopropylidene-3-O-dodecyl-5-O-{(4-nitro-phenyl)-amino}-carbonyl-6-deoxy-6-(l- azepanyl)-α-D-glucofuranoside (Compound No. 126) l,2-O-Isopropylidene-3-O-dodecyl-5-O-{[4-(2-methoxy-2- oxo-ethyl)-phenyl)-amino}- carbonyl-6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 127) l,2-O-Isopropylidene-3-O-dodecyl-5-O-(phenyl-amino)-carbonyl-6-deoxy-6-(l-azepanyl)-α- D-glucofuranoside (Compound No. 128)
Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{[4-methyl-phenyl)- sulfonylamino}-carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-allofuranoside (Compound No. 129) Hydrochloride salt of l,2-O-isopropylidene-3-0-heptyl-5-O-[(4-methyl-phenyl)- sulfonylamino]-carbonyl-6-deoxy-6-(4-morpholinyl)-α-D-allofuranoside (Compound No.
130)
Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-[(4-methyl-phenyl)- sulfonylamino]-carbonyl-6-deoxy-6-(l -piperidinyl)-α-D-allofuranoside (Compound No. 131)
Tris salt of l,2-O-isopropylidene-3-0-dodecyl-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]- amino}-carbonyl-6-deoxy-6-(4-morpholinyl)-α-D-glucofuranoside (Compound o. 132)
Tris salt of l,2-O-isopropylidene-3-0-dodecyl-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]- amino}-carbonyl-6-deoxy-6-[l-piperidinyl]-α-D-glucofuranoside (Compound No. 133)
Tris salt of l,2-O-isopropylidene-3-0-dodecyl-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]- amino}-carbonyl-6-deoxy-6-(l-pynolidinyl)-α-D-glucofuranoside (Compound No.134 )
Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{(phenyl-sulfonylamino)- carbonyl}-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No. 135)
Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O- {(phenyl sulfonylamino)- carbonyl}-6-deoxy-6-(l-pynolidinyl)-α-D-glucofuranoside (Compound No. 136) l-O-Dodecyl-2,3-O-isopropylidene-5-0-{(4-methyl-phenyl)-sulfonylamino}-carbonyl-6- deoxy-6-(4-morpholinyl)-α-D-mannofuranoside (Compound No. 203)
Scheme
Figure imgf000026_0001
Formula IX Formula XI
The compound of Formula XI, can be prepared by Scheme III. Thus a compound of
Formula IX (wherein Ri is H, -OH, -CH3 or -Oalkaryl) is reacted with a compound of Formula X (wherein Ru is the same as defined earlier, L is a leaving group such as OH (activated in situ, as is obvious to a skilled practitioner) or halogen (F, Cl, Br, I) and Y is -
C(=O) or C(=S)) to give a compound of Formula XL
The reaction of a compound of Formula IX with a compound of Formula X (when Y is C(=O) and L is OH) to give a compound of Formula XI can be carried in an organic solvent for example, tetrahydrofuran or dimethylformamide or dioxane with a condensing agent, for example, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in the presence of organic base, for example, N-methylmorpholine, diisopropylamine or triethylamine. Exemplary compounds which were prepared following Scheme III are listed below: l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{2-[4-{3-(2-methyl-phenyl)-ureido}- phenyl]-acetyl}-amino-β-L-gulofuranoside (Compound No. 137)
1 ,2-O-Isopropylidine-3 -O-benzyl-5-deoxy-5- {2-[(4- {2-(4-methyl-phenyl-sulfonylamino)- thiazolyl}-acetyl]-amino-α-D-xylofuranoside (Compound No. 138) l,2-O-Isopropylidene-3-O-[3-phenyl-propyl]-5-deoxy-5-{2-[4-(2-phenylsulfonylamino)- thiazolyl] -acetyl} -amino-α-D-xylofuranoside (Compound No. 139) l,2-O-Isopropylidene-3-O-benzyl-5-deoxy-5-{2-[4-(2-phenylsulfonylamino)-thiazolyl]- acetyl}-amino-α-D-xylofuranoside (Compound No. 140) l,2-O-Isopropylidene-3-O-(3-phenyl-propyl)-5-deoxy-{2-[4-(2-methylsulfonylamino)- thiazolyl]-acetyl}-amino-α-D-xylofuranoside (Compound No. 141) 1 ,2-O-Isopropylidene-3-O-benzyl-5-deoxy- {2-[4-(2-methylsulfonylamino)-thiazolyl]-acetyl} - amino-α-D-xylofuranoside (Compound No. 142) l,2-O-Isopropylidene-3-O-(3-phenyl-propyl)-5-deoxy-5-{2-[4-(2-[4-methyl-phenyl]- sulfonylamino)-thiazolyl]-acetyl} -amino-α-D-xylofuranoside (Compound No. 143) l,2-O-Isopropylidene-3-O-benzyl-6-deoxy-6-[(3,4-dimethoxy-phenyl)-carbonyl]-amino-α-D- glucofuranoside (Compound No. 144) l,2-O-Isopropylidene-3-O-benzyl-6-deoxy-6-{[(4-chloro-phenyl)-carbonyl]-amino}-α-D- glucofuranoside (Compound No. 145) l,2-O-Isopropylidene-3-O-(3-phenyl-propyl)-6-deoxy-6-{(3,4-dimethoxy-phenyl)-carbonyl}- amino-α-D-glucofuranoside (Compound No. 146) 1 ,2-O-Isopropylidene-3-O-[3-phenyl-propyl]-6-deoxy-6- {(4-chloro-phenyl)-carbonyl} - amino-α-D-glucofuranoside (Compound No. 147) l,2-O-Isopropylidene-3-O-benzyl-5-O-benzyl-6-deoxy-6-{[3,4-dimethoxy-phenyl]- carbonyl}-amino-α-D-glucofuranoside (Compound No. 148) l,2-O-Isopropylidene-3-O-benzyl-5-O-benzyl-6-deoxy-6-{[(4-chloro-phenyl)-carbonyl]- amino}-α-D-glucofuranoside (Compound No. 149) l,2-O-Isopropylidene-3-O-[3-phenyl-propyl]-5-O-benzyl-6-deoxy-6-{(4-chloro-phenyl)- carbonyl} -amino-α-D-glucofuranoside (Compound No. 150) l,2-O-Isopropylidene-3,5-bis-O-(3-phenyl-propyl)-6-deoxy-6-[(4-chloro-phenyl)-carbonyl]- amino-α-D-glucofuranoside (Compound No. 151) l,2-O-Isopropylidene-3-O-(3-phenyl-propyl)-5-O-benzyl-6-deoxy-6-[(3,4-dimethoxy- phenyl)-carbonyl]-amino-α-D-glucofuranoside (Compound No. 152) l,2-O-Isopropylidene-3,5-bis-O-(3-phenyl-propyl)-6-deoxy-6-[(3,4-dimethoxy-phenyl)- carbonyl]-amino-α-D-glucofuranoside (Compound No. 153) l,2-O-Isopropylidene-3-O-benzyl-5-O-(3-phenyl-propyl)-6-deoxy-6-[(3,4-dimethoxy- phenyl)-carbonyl]-amino-α-D-glucofuranoside (Compound No. 154) l,2-O-Isopropylidene-3-O-heptyl-5-deoxy-5-{(4-methyl-phenyl)-sulfonylamino}-α-D- xylofuranoside (Compound No.155) l,2-O-Isopropylidene-3-O-heptyl-5-deoxy-5-{(4-tert-butyl-phenyl)-sulfonylamino}-α-D- xylofuranoside (Compound No.156) l,2-O-Isopropylidene-3-O-pentyl-5-deoxy-5-{[{4-methoxy-3-(5-{l-methyl-3-ρropyl-7-oxo-
1 ,6-dihydro-pyrazolo[4,3 -d]pyrimidinyl} -phenyl)} -sulfonyl]-amino} -α-D-xylofuranoside
(Compound No. 157)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {4-methyl-phenyl} -sulfonyl} -amino-β-L- gulofuranoside (Compound No. 188) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{ethylsulfonyl}-amino-β-L-gulofuranoside
(Compound No. 189)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {4-fluoro-phenyl)-sulfonyl} -amino-β-L- gulofuranoside (Compound No. 190) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {(4-acetamido)-phenyl]-sulfonyl} -amino- β-L-gulofuranoside (Compound No. 191) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(3,4,5-trimethoxy-phenyl)- carbonyl}amino-β-L-gulofuranoside (Compound No. 192) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(2-fluorophenyl)-carbonyl}-amino-β-L- gulofuranoside (Compound No. 193)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {4-ethoxy-4-oxo-butanoyl} -amino-β-L- gulofuranoside (Compound No. 194) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{4-hydroxy-4-oxo-butanoyl}-amino-β-L- gulofuranoside (Compound No. 195)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [3-(3,4-methylenedioxy-phenyl)- propionyl}-amino-β-L-gulofuranoside (Compound No. 197) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{2-phenyl-ethenyl)-carbonyl}-amino-β-L- gulofuranoside (Compound No. 198) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{2-(3,4-methylenedioxy-phenyl)-acetyl}- amino-β-L-gulofuranoside (Compound No. 199)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {(4-fluoro-benzyl)-carbonyl} -amino-β-L- gulofuranoside (Compound No. 200) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{2-(3,4-methylenedioxy-phenyl)ethenyl}- carbonyl} amino-β-L-gulofuranoside (Compound No. 201)
Scheme IV
Figure imgf000029_0002
Formula XII
Figure imgf000029_0001
hal — S02Rx Formula XVII
Figure imgf000029_0003
The compounds of Formula XNI and XNIII can be prepared following Scheme IN. Thus a compound of Formula XII (wherein Ri, R2, R3 and R4 are the same as defined earlier), is reacted with a compound of Formula XIII (wherein P is protecting group such as aralkyl or acyl) to give a compound of Formula XIN, which is deprotected to give a compound of Formula XN.
Path a: The compound of Formula XN is reacted with a compound of Formula III (wherein Rx is the same as defined earlier) to give a compound of Formula XNI.
Path b: The compound of Formula XN is reacted with a compound of Formula XNII (wherein hal is halogen (F, Cl, Br, I) to give a compound of Formula XNIII. The compound of Formula XIN can be deprotected (when P is aralkyl, for example, benzyl) to give a compound of Formula XN in an organic solvent, for example, methanol, ethanol, propanol, isopropylalcohol, tefrahydrofuran or ethyl acetate, under deprotection, conditions, for example, hydrogenatically utilizing palladium on carbon or, for example, under catalytic transfer hydrogenation conditions of ammonium formate and palladium on carbon. The reaction of a compound of Formula XN with a compound of Formula III (Path a) to give a compound of Formula XNI can be carried out carried out in an organic solvent, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride. The reaction of a compound of Formula XN with a compound of Formula XNII (Path b) to give a compound of Formula XNIII can be carried out in an organic solvent, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride, tetrahydrofuran or dimethylformamide in the presence of a base, for example, pyridine, triethylamine or diisopropylethylamine. Exemplary compounds which are prepared following Scheme IN, path a are listed below: l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-{l-[4-{[4-(2-methoxy-2-oxo-ethyl)-phenyl]- amino}-carbonyl]-piperazinyl}-α-D-lyxofuranoside (Compound No. 159) l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-{l-[4-(4-chloro-phenylamino)-carbonyl]- piperazinyl}-α-D-lyxofuranoside (Compound No. 160) l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-{l-[4-{(4-methyl-phenyl)-amino}-carbonyl]- piperazinyl}-α-D-lyxofuranoside (Compound No. 161) 1 -O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- { 1 -[4- {(4-methoxy-phenyl)-amino} -carbonyl]- piperazinyl}-α-D-lyxofuranoside (Compound No. 162) l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-{l-[4-{(4-nitro-phenyl)-amino}-carbonyl]- piperazinyl}-α-D-lyxofuranoside (Compound No. 163)
1 -O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- { l-[4- {(4-chloro-phenyl)-sulfonylamino} - carbonyl]-piperazinyl}-α-D-lyxofuranoside (Compound No. 164)
1 -O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- { 1 -[4- {[4-(2-hydroxy-2-oxo-ethyl)-ρhenyl]- amino}-carbonyl]-piperazinyl}-α-D-lyxofuranoside (Compound No. 165) l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-{l-[4-(4-tolylsulfonylamino)-carbonyl]- ρiperazinyl}-α-D-lyxofuranoside (Compound No. 166) Hydrochloride salt of l,2-O-dodecyl-3,4-O-isopropylidene-5,6-dideoxy-5-{l-(4-[(4-methyl- phenyl)-amino]-carbonyl)-piperazinyl}-β-L-gulofuranoside (Compound No. 167)
Tris salt of l-O-dodecyl-3,4-O-isopropylidene-5,6-dideoxy-5-{l-(4-[(4-{2-hydroxy-2-oxo- ethyl}-phenyl)-amino]-carbonyl)-piperazinyl}-β-L-gulofuranoside (Compound No. 168)
Hydrochloride salt of l-O-dodecyl-3,4-0-isopropylidene-5,6-dideoxy-5-{l-(4-[(phenyl sulfonylamino)-carbonyl])-piperazinyl}-β-L-gulofuranoside (Compound No. 169)
Hydrochloride salt of l-O-dodecyl-2,3-0-isopropylidene-5,6-dideoxy-5-{l-[4-{(4-methoxy- phenyl)-amino}-carbonyl]-piperazinyl}-β-L-gulofuranoside (Compound No. 170)
Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{l-(4-benzyl)- piperazinyl}-β-L-gulofuranoside (Compound No. 171) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{l-(4-[(4-chloro-phenyl)-amino]- carbonyl)-piperazinyl}-β-L-gulofuranoside (Compound No. 172) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[l-(4-{(4-nitro-phenyl)-amino}-carbonyl)- piperazinyl]-β-L-gulofuranoside (Compound No. 173) Examplary compounds which were prepared following Scheme IN, path b are listed below: l,2-O-Isopropylidene-3-O-pentyl-5-deoxy-5-[l-(4-{4-methoxy-3-(5-[l-methyl-3-propyl-
7oxo- 1 ,6-dihydro-pyrazolo[4,3-d]pyrimidinyl])-phenyl} -sulphonyl)-piperazinyl])-α-D- xylofuranoside (Compound No. 174) Scheme V
Figure imgf000032_0001
Formula XXI Fomnula XXII
Figure imgf000032_0002
The compound of Formula XXIV can be prepared by Scheme V. Thus a compound of Formula XIX (wherein R2, R3 and R4 are the same as defined earlier) is reacted with a compound of Formula XX (wherein Rp, Ri is the same as defined earlier) to give a compound of Formula XXI, which is N-protected to give a compound of Formula XXII (wherein P is protecting group such as aralkyl or acyl), which is reacted with a compound of Formula III (wherein Rx is same as defined earlier) to give a compound of Formula XXIII, which is deprotected to give a compound of Formula XXIV. The N-protection of a compound of Formula XXI to give a compound of formula
XXII can be carried out in an organic solvent, for example, tetrahydrofuran, dioxane or diethyl ether with the protecting agent for example benzyl chloroformate, di-tert-butyl dicarbonate, acetic anhydride, benzyl chloride, benzyl bromide, benzyl iodide or sulphonyl halide in the presence of a base, for example, triethylamine, diisopropylethylamine or pyridine. The reaction of a compound of Formula XXII with a compound of Formula III to give a compound of Formula XXIII can be carried out in an organic solvent, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride. The deprotection (when P is aralkyl for example benzyl) of a compound of Formula
XXIII to give a compound of Formula XXIV can be carried out in an organic solvent, for example, methanol, ethanol, propanol, isopropylalcohol or ethyl acetate under conditions of deprotection, for example, hydrogenatically utilizing palladium on carbon under catalytic transfer hydrogenation conditions of ammonium formate and palladium on carbon. Examplary compounds which were prepared following Scheme N are listed below:
1 ,2-O-Isopropylidene-3-O-heptyl-5-O- { [3-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino} - carbonyl-6-deoxy-6- {(1 -piperidinyl)-ethyl} -amino-α-D-glucofuranoside (Compound No.
175) l,2-O-Isopropylidene-3-O-heptyl-5-O-{[3-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino}- carbonyl-6-deoxy-6- {(1 -pyrrolidinyl)- ethyl] -amino-α-D-glucofuranoside (Compound No.
176) l,2-O-Isopropylidene-3-O-heptyl-5-O-{[3-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino}- carbonyl-6-deoxy-6- {(4-morpholinyl)-ethyl} -amino} -α-D-glucofuranoside (Compound No.
177) Scheme VI
Figure imgf000033_0001
The compound of Formula XXVII can be prepared by Scheme VI. Thus a compound of Formula XXV (wherein Xi is OH or halogen (F, Cl, Br, I) and R2, R3, and R4 are the same as defined earlier) is reacted with a compound of Formula XXNI (wherein Rx and Ry are the same as defined earlier) to give a compound of Formula XXNII. The reaction of a compound of Formula XXN with a compound of Formula XXNI to give a compound of Formula XXNII can be carried out in an organic solvent, for example, tetrahydrofuran or dimethylformamide with the condensing agent, for example, l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide in the presence of an organic base, for example, Ν-methylmorpholine, diisopropylethylamine or triethylamine. Alternatively, the reaction of a compound of Formula XXN with a compound of
Formula XXNI to give a compound of Formula XXNII can be carried out in an organic solvent, for example, tetrahydrofuran or dimethylformamide in the presence of carbonyldiimidazole and a base such as triethylamine, Ν-ethyldiisopropylamine or pyridine. Exemplary compounds which were prepared following Scheme VI are listed below:
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-( { [4- {2-[2S-2- { 1 -methoxy-4-methyl- 1- oxo]-pentyl}-amino]-2-oxo-ethyl}-phenyl]-amino}-carbonyl)-amino-β-L-gulofuranoside
(Compound No. 178) l-O-Dodecyl-2,3-0-isopropylidene-5,6-dideoxy-5-{(4-[2-(bis-[2-thienylmethyl] -amino)-2-oxo-ethyl]-phenyl)-amino}-carbonyl-β-L-gulofuranoside (Compound No. 179) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(4-[2-(benzyl-[2-thienylmethyl]-amino)- 2-oxo-ethyl]-phenyl)-amino}-carbonyl-β-L-gulofuranoside (Compound No. 180) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[4-(2-oxo-2-( benzyl -α-methylbenzyl- amino)-ethyl)-phenyl]-amino}-carbonyl)-amino-β-L-gulofuranoside (Compound No. 181) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-(2-benzyloxyamino-2-oxo-ethyl)- phenyl)-amino]-carbonyl}-amino-β-L-gulofuranoside (Compound No. 182) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-[2-hydroxyamino-2-oxo-ethyl]- phenyl)-amino]-carbonyl}-amino-β-L-gulofuranoside (Compound No. 183) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{([4-(2-(l-azepanyl)-2-oxo-ethyl)- phenyl]-amino)-carbonyl}-amino-β-L-gulofuranoside (Compound No. 184) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[4-(2-oxo-2-(l-pyrrolidinyl)-ethyl)- phenyl]-amino}-carbonyl)-amino-β-L-gulofuranoside (Compound No. 185) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[4-(2-oxo-2-(l-piperidinyl)-ethyl)- phenyl]-amino}-carbonyl)-amino-β-L-gulofuranoside (Compound No. 186) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [4- {(2-amino-2-oxo-ethyl)-phenyl} - amino]-carbonyl}-amino-β-L-gulofuranoside (Compound No. 187) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-( { [(4- {2-[(4-benzoylphenyl)amino]-2- oxoethyl}-phenyl)amino} carbonyl} amino)-β-L-gulofuranoside (Compound No. 243) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-{2-[(4-azidophenyl)amino]-2- oxoethyl}-phenyl)amino]carbonyl}amino)-β-L-gulofuranoside (Compoun No. 244) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[4-{(2-[2-(lH-imidazol-4-yl)ethyl]- amino-2-oxo-ethyl)-phenyl} -amino]-carbonyl} -amino-β-L-gulofuranoside (Compound No.
245) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-{2-[(5-carboxypentyl)amino]-2- oxoethyl}-phenyl)amino}carbonyl}amino)-β-L-gulofuranoside (Compound No. 247) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-[{[(3,4- dimethoxybenzyl)amino]carbonyl}methyl]-phenyl)-amino]carbonyl}amino)-β-L- gulofuranoside (Compound No. 290). Scheme VII
Figure imgf000035_0001
Formula XXXII Formula XXVIII Formula XXIX 1. phenyl chloroformate 2. HNRxRy Pat b Formula XXVI ,
Figure imgf000035_0002
Formula XXX
The compounds of Formula XXIX, XXX and XXXII can be prepared by Scheme NIL Thus Path a: The compound of Formula XXNIII (wherein R2, R3 and R^ are the same as defined earlier) is reacted with a compound of Formula XXNI (wherein Rx and Ry are the same as defined earlier) and carbonyldiimidazole to give a compound of Formula XXIX (wherein X2 is O or S).
Path b: The compound of Formula XXNIII is reacted with a compound of Formula XXVI and phenyl chloroformate to give a compound of Formula XXX (wherein Rx, R3 and t are the same as defined earlier).
Path c: The compound of Formula XXNIII is reacted with a compound of Formula XXXI (wherein Z is C(=O) or C(=S)) to give a compound of Formula XXXII. The reaction of a compound of Formula XXNIII with a compound of Formula XXNI (Path a) and carbonyldiimidazole or thiocarbonyldiimidazole to give a compound of Formula XXIX wherein X=O/S, can be carried out in an organic solvent, for example, tetrahydrofuran, diethylether, dimethylformamide or dioxane in the presence of a base, for example, diisopropylethylamine, triethylamine or pyridine. Alternatively, carbonyldi- 1,2,3- benzotriazole or carbonyldi- 1,2,4-triazole can also be used in place of carbonyldiimidazole. The reaction of a compound of Formula XXNIII with a compound of Formula XXNI
(Path b) and phenyl chloroformate to give a compound of Formula XXX can be carried out in an organic solvent, for example, tetrahydrofuran, dimethylformamide, diethylether or dioxane. Alternatively, other chloroformates for example p- nitrophenyl chloroformate can also be used in place of phenyl chloroformate. The reaction of a compound of Formula XXNIII with a compound of Formula XXXI (Path c) to give a compound of Formula XXXII can be carried out in a solvent, for example, dichloromethane, dichloroethane, carbon tetrachloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide or dimethylsulphoxide. An exemplary compound which was prepared following Scheme Nil, path a is listed below: l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{((2S)-2-(l-hydroxy-4-methyl-l-oxo- pentyl-amino)-carbonyl} -amino-β-L-gulofuranoside (Compound No. 202) Examplary compounds prepared following Scheme Nil, path b are: l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[3-(2-(4-methylphenyl)-5-tert-butyl-2H- pyrazolyl)-amino]-carbonyl}-amino-β-L-gulofuranoside (Compound No. 209) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [3-(5-tert-butyl-2H-pyrazolyl)-amino]- carbonyl} -amino-β-L-gulofuranoside (Compound No. 210) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[3-(lH-l,2,4-triazolyl)-amino]- carbonyl}-amino-β-L-gulofuranoside (Compound No. 211)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [2-(5-methyl- 1 ,3 ,4-thiadiazolyl)-amino]- carbonyl} -amino-β-L-gulofuranoside (Compound No. 212)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [2- {4-(2-hydroxy-2-oxo -ethyl)- thiazolyl}-amino]-carbonyl} -amino-β-L-gulofuranoside (Compound No. 213) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[3-(2-benzyl-5-tert-butyl-2H-pyrazolyl)- amino] -carbonyl} -amino-β-L-gulofuranoside (Compound No. 214) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{2-[3-(l,3,4-thiadiazolyl)-amino]- carbonyl} -amino-β-L-gulofuranoside (Compound No. 215) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(2-[4-(2-ethoxy-2-oxo-ethyl)-thiazolyl]- amino)- carbonyl}-amino-β-L-gulofuranoside (Compound No. 217) Examplary compounds prepared following scheme Nil, path c are: l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[butylamino]-carbonyl}-amino-β-L- gulofuranoside (Compound No. 204)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {(2-phenyl-ethyl)-amino]-thiocarbonyl} - amino-β-L-gulofuranoside (Compound No. 205)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {(tert-butyl-amino)-thiocarbonyl} -amino- β-L-gulofuranoside (Compound No. 206)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [(4-fluorophenyl)-amino]-thiocarbonyl} - amino-β-L-gulofuranoside (Compound No. 207) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{([4-(2-hydroxy-2-oxo-ethyl)-phenyl]- amino)- thiocarbonyl} -amino-β-L-gulofuranoside (Compound No. 208) Scheme VIII
Figure imgf000038_0001
Formula XXXIII Formula XXXtV Formula XXXV Formula XXXVII hydrolysis
N — deprotection esterification
Figure imgf000038_0002
1. halogenating
Figure imgf000038_0003
2. alcohol Formula XL
Figure imgf000038_0004
Formula XXXIX Formula XXXVIII O=C=N-RX
Figure imgf000038_0005
Formula XU Formula XLIl The compound of Formula XLII can be prepared by Scheme VIII. Thus a compound of Formula XXXIII (wherein R2, R3 and j are the same as defined above) is reacted with a cyanating agent, for example, sodium cyanide, to give a compound of Formula XXXIN, which undergoes -OH activation to give a compound of Formula XXXV (Pi is, for example, mesyl, tosyl or triflyl), which is reacted with a compound of Formula XXXVI (P is protecting group such as aralkyl or acyl) to give a compound of Formula XXXVII, which is hydrolyzed to give a compound of Formula XXXVIII, which is further esterified to give a compound of
Formula XXXIX, which undergoes N-deprotection to give a compound of Formula XL, which is reacted with a compound of Formula III to give a compound of Formula XLI, which is hydrolyzed to give a compound of Formula XLII. The reaction of a compound of Formula XXXIII with cyanating agent to give a compound of Formula XXXIV can be carried out in solvent for example ethanol, methanol, propanol, isopropylalcohol or water. The -OH activation of a compound of Formula XXXIN to give a compound of Formula XXXN can be carried out in an organic solvent, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride with OH activating reagents, for example, methanesulphonyl chloride, toluenesulphonyl chloride or triflic anhydride. The hydrolysis of a compound of Formula XXXNII to give a compound of Formula XXXNIII can be carried out an organic solvent, for example, ethanol, methanol, propanol, tetrahydrofuran or isopropylalcohol in the presence of a base, for example, sodium hydroxide, potassium hydroxide or lithium hydroxide. Alternatively the hydrolysis can also be carried out in the presence of acid, for example, trifluoroacetic acid and hydrochloric acid. The compound of Formula XXXVIII can be esterified to give a compound of Formula XXXIX in an organic solvent, for example, dichloromethane or dichloroethane with a halogenating agent, for example, oxalyl chloride, or thionyl chloride, followed by reaction with an alcohol for example, ethanol, methanol, tert-butanol or benzyl alcohol in the presence of base, for example, pyridine, triethylamine, or diisopropylethyl amine. Alternatively, the compound of Formula XXXVIII can also be an esterified compound of Formula XXXIX with the condensing agent being, for example, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide, and in the presence of an organic base for example dimethylaminopyridine and an alcohol, for example, ethanol, methanol, propanol or isopropyl alcohol, benzyl alcohol, or tertbutanol. The Ν-deprotection of a compound of Formula XXXIX to give a compound of Formula XL (when P aralkyl for example benzyl) can be carried out in an organic solvent, for example, methanol, ethanol, ethyl acetate, tetrahydrofuran, propanol or isopropylalcohol, under deprotection conditions, for example, hydrogenatically utilizing palladium on carbon under catalytic transfer hydrogenation conditions of ammonium formate and palladium on carbon. The reaction of a compound of Formula XL with a compound of Formula III to give a compound of Formula XLI can be carried out in the presence of an organic solvent, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride. Alternatively, a compound of Formula XL can be converted to a compound of Formula XLI by utilizing
CDI or chloroformates as previously mentioned in Scheme VII. The hydrolysis of a compound of Formula XLI to give a compound of Formula XLII can be carried out in solvent, for example, ethanol, dimethylformamide, tetrahydrofuran, dimethyl sulphoxide, dioxane in water or methanol in water, in the presence of a base, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide. Examplary compounds which were prepared following Scheme NIII are listed below: l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-chloro-phenyl)-amino]-carbonyl}- amino-6-carboxy-α-D-mannofuranoside. (Compound No. 216) l-O-Dodecyl-2,3-isopropylidene-5,6-dideoxy-5-{[(4-chloro-phenyl)-amino]-carbonyl}- amino-6-carboxy-β-L-gulofuranoside (Compound No. 218) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-methyl-phenyl)-amino]-carbonyl}- amino-6-ethoxycarbonyl-β-L-gulofuranoside (Compound No. 219)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [(4-methyl-phenyl)-amino] -carbonyl } - amino-6-carboxy-β-L-gulofuranoside (Compound No. 220) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[{(4-chloro-phenyl)-amino}-carbonyl]- amino-6-ethoxycarbonyl-β-L-gulofuranoside (Compound No. 221) l-O-Dodecyl-2,3-isopropylidene-5,6-dideoxy-5-{[(4-[2-methoxy-2-oxo-ethyl]-phenyl)- amino]-carbonyl}-amino-6-ethoxycarbonyl-β-L-gulofuranoside (Compound No. 222) l-O-Dodecyl-2,3-isopropylidene-5,6-dideoxy-5-{[(4-{2-hydroxy-2-oxo-ethyl]-phenyl)- , amino]-carbonyl}-amino-6-carboxy-β-L-gulofuranoside (Compound No. 223) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-[2-hydroxy-2-oxo-ethyl]-phenyl)- amino]-carbonyl}-amino-6-carboxy-α-D-mannofuranoside (Compound No. 224) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-methyl-phenyl)-amino]-carbonyl}- amino-6-carboxy-α-D-mannofuranoside (Compound No. 225) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [((2S)-2-[l -oxo- 1 - {(2-thienylmethyl)- benzyl)-amino}]-4-methyl-pentyl)-amino]-carbonyl}-amino-6-carboxy-β-L-gulofuranoside (Compound No. 226) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [((2S)-2-[l -oxo- 1 -(bis-[2-thienylmethyl]- amino)]-4-methyl-pentyl)-amino]-carbonyl}-amino-6-carboxy-β-L-gulofuranoside (Compound No. 227) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [(2-methyl-phenyl)-amino]-carbonyl} - amino-6-carboxy-α-D-mannofuranoside (Compound No. 228) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(2-methyl-phenyl)-amino]-carbonyl}- amino-6-carboxy-β-L-gulofuranoside (Compound No. 229) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[{(4-chloro-phenyl)-amino}-carbonyl]- amino-6-ethoxycarbonyl-α-D-mannofuranoside (Compound No. 239)
Scheme IX
Figure imgf000041_0001
Formula XLV Path b Rx— al
Figure imgf000041_0002
Formula XLVII The compound of Formula XLVII can be prepared by Scheme IX. Thus a compound of Formula XXVIII (wherein R2, R3 and R-j are the same as defined earlier) is reacted with a compound of Formula XLIII (wherein P is a protecting group such as arallcyl or acyl), to give compound of Formula XLIV, which is deprotected to give a compound of Formula XLV. Path a: The compound of Formula XLV is reacted with a compound of Formula XXVI and carbonyldiimidazole to give a compound of Formula XL VI. Pathb: The compound of Formula XLV is reacted with a compound of Formula Rx--hal
(wherein hal is a halogen (F, Cl, Br, I) and Rx is the same as defined earlier) to give a compound of Formula XLVII. The reaction of a compound of Formula XXVIII with a compound of Formula XLIII to give a compound of Formula XLIN can be carried in an organic solvent, for example, tetrahydrofuran or dimethylformamide with the condensing agent, for example, l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in the base, for example, Ν-methylmorpholine, diisopropylamine or triethylamine. The deprotection of a compound of Formula XLIN (when P is tert-butoxycarbonyl group) to give a compound of Formula XLN can be carried in an organic solvent for example dichloromethane or dichloroethane in the presence of acid, for example, trifluoroacetic acid or hydrochloric acid. The reaction of a compound of Formula XLN with a compound of Formula XXNI
(Path a) and carbonyldiimidazole to give a compound of Formula XLNI can be carried out in an organic solvent, for example, tetrahydrofuran, dimethylformamide, diethylether or dioxane. Alternatively, carbonyldi-l,2,3-benzotriazole or carbonyldi- 1,2,4-triazole can also be used in place of carbonyldiimidazole. Also, as described in Scheme Nil, the alternate strategies to functionalize XLN to
Formula XLNI could be used, as would be evident to a skilled person in the art of this invention. The compound of Formula XLN is reacted with a compound of Formula Rx--hal
(Path b) to give a compound of Formula XLNII can be carried out in an organic solvent, for example, dimethylformamide, tetrahydrofuran, dioxane, acetone or diethyl ether in the presence of an organic base, for example, sodium hydride, potassium hydride, potassium tert- butoxide or potassium carbonate. Exemplary compounds which were prepared following Scheme IX, path a are listed below: l-O-Dodecyl-2,3-O-isoρropylidene-5,6-dideoxy-5-[{(2S)-2-[3-(4-(2-hydroxy-2-oxo-ethyl)- phenyl)-ureido]-4-methyl}pentanoyl]-amino-β-L-gulofuranoside (Compound No. 230) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[{(2S)-2-[3-(4-[2-methoxy-2-oxo-ethyl]- phenyl)-ureido]-4-methyl} -pentanoyl]-amino-β-L-gulofuranoside (Compound No. 231) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(2S)-[2-amino-4-methyl]-pentanoyl}- amino-β-L-gulofuranoside (Compound No. 232)
1 -O-(3 ,4-Methylenedioxy-benzyl)-2,3 -O-isopropylidene-5,6-dideoxy-5- { [ 1 -(2-tert- butoxycarbonylamino-4-methyl-pentyl)-oxo]-amino} -β-L-gulofuranoside (Compound No.
234) Exemplary compounds which were prepared following Scheme IX, path b are listed below: l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[{(2S)-2-[(carboxymethyl)-amino]-4- methyl}-pentanoyl]-β-L-gulofuranoside (Compound No. 235) SCHEME X
Figure imgf000043_0001
Formula XLVIII Fnrm..ia i Formula LI
The compound of Formula LI can be prepared by Scheme X. Thus a compound of Formula XLVIII (wherein R2, R3 and R4 are same as defined earlier) is reacted with a compound of Formula XLIX [wherein hal is halogen (F, Cl, Br, I)] to give a compound of Formula L (wherein ki is an integer ranging from 1-6), which is reacted with a compound of formula XXVI (wherein Rx and Ry are the same as defined earlier) to give a compound of Formula LI. The reaction of a compound of Formula XLVIII with a compound of Formula XLIX to give a compound of Formula L can be carried out in an organic solvent, for example, di-n butyl ether, diethylether or tetrahydrofuran in the presence of a base, for example, triethylamine, pyridine or potassium carbonate. The reaction of a compound of Formula L with a compound of Formula XXVI to give a compound of Formula LI can carried out in an organic solvent, for example, acetone or tetrahydrofuran in the presence of a base, for example, potassium carbonate or sodium hydride. Examplary compounds which were prepared following Scheme X are listed below: l,2-O-Isopropylidene-3-O-benzyl-5-deoxy-5-[6-(l-{2-carboxy-piperidinyl})-hexanoyl]- amino-α-D-xylofuranoside (Compound No. 237) l,2-O-Isopropylidene-3-O-benzyl-5-deoxy-5-[6-(l-{2-ethoxycarbonyl-piperidinyl})- hexanoyl] -amino- -D-xylofuranoside (Compound No. 238) Scheme XI
Figure imgf000044_0001
Formula LV Formula Lll Formula LIV
The compounds of Formula LIV and Formula LV can be prepared by Scheme XI. Path a: The compound of Formula LII (wherein Ri, R2, R3 and 4 are the same as defined earlier) is reacted with a compound of Formula LIII (wherein hal is halogen (F, Cl, Br, I) and Y & Ru are the same as defined earlier) to give a compound of formula LIV. Path b: The compound of Formula LII is reacted with a compound of Formula III (wherein Rx is the same as defined earlier) to give a compound of Formula LV. The reaction of a compound of Formula LII (Path a) with a compound of Formula LIII to give a compound of Formula LIV can be carried out in the presence of an organic base selected from, for example, triethylamine, diisopropylethylamine or pyridine in an organic solvent selected from, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride. The reaction of a compound of Formula LII (Path b) with a compound of Formula III to give a compound of Formula LV can be carried out in an organic solvent selected from, for example, dichloromethane, dichloromethane, chloroform or carbon tetrachloride. Exemplary compounds which were prepared following Scheme XI, path a are listed below: l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(4-acetamido-phenyl)-(acetyl)-amino-β-L- gulofuranoside (Compound No. 242) Exemplary compounds which were prepared following Scheme XI, path b are listed below: l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(2-methylphenyl-amino)-carbonyl}-{4-[2-
(2-methylphenyl)-ureido] -phenyl} -amino-β-L-gulofuranoside (Compound No. 240) l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(2-methoxyphenyl)-amino]-carbonyl}- {4-[3-(2-methoxy phenyl)-ureido]-phenyl}-amino-β-L-gulofuranoside (Compound No. 241) Scheme XII
+ — C — NRXRY «-
Figure imgf000045_0002
Formula LVI
Figure imgf000045_0001
Formula LV Formula LVII Formula LVIII -hal Pat b Formula LVIV /(when lJ is 0H)
Figure imgf000045_0003
Formula LW
Figure imgf000045_0004
Formula LWI Compounds of Formulae LNII, LNIII and LNVI can be prepared by following the procedure as depicted in Scheme XII. Thus a compound of Formula LV (wherein Ji and J are integer selected from 0 or 1 and U is -OH or H) is reacted with a compound of Formula LVI (wherein Li is -Oaryl, Rx and Ry are the same as defined earlier) to give a compound of Formula LVII, which, Path a: when U = OH, can be reacted with a compound of Formula III (wherein Rx is the same as defined earlier) to give a compound of Formula LVIII.
Path b: when U =OH, can be reacted with a compound of Formula LVIV (wherein L2 is - Otosyl, -Omesyl or -Otriflyl and hal is the same as defined earlier) to give a compound of Formula LW which undergoes ring cyclisation to give a compound of Formula LVVI.
The reaction of a compound of Formula LV with a compound of Formula LVI to give a compound of Formula LVII can be carried out in the presence of a base selected from diisopropylethylamine, triethylamine, N-methylmorpholine or pyridine in an organic solvent selected from, dimethylsulphoxide, dimethylformamide, tetrahydrofuran, diethyl ether or dioxane. Alternatively, the reaction of a compound of Formula LV with an isocyanate would give a compound of Formula LVII.
The reaction of a compound of Formula LVII (when U is OH, path a) with a compound of Formula III to give a compound of Formula LVIII can be carried out in the presence of a base selected from triethylamine, diisopropylethylamine, N-methylmorpholine or pyridine in an organic solvent selected from, dichloromethane, dichloroethane, carbon tetrachloride or chloroform.
The reacton of a compound of Formula LVII with a compound of Formual LVIV to give a compound of Formula LW can be carried out in the presence of a base selected from triethylamine, diisopropylethylamine, N-methylmorpholine or pyridine in an organic solvent selected from, dichloromethane, dichloroethane, tetrahydrofuran or dioxane.
Cyclization of a compound of Formula LW to give a compound of Formula LVVI can be carried out in the presence of a base selected from, sodium hydride, potassium tert-butoxide or pyridine in an organic solvent selected from, dimethylformamide, tetrahydrofuran, diethyl ether or dioxane. Compound prepared following scheme XII are: l-0-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5,6-{[(methylamino)carbonyl]azanediyl}-β- L-gulofuranoside (Compound No. 271) l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-({[(4- carboxymethylphenyl)amino]carbonyl}amino)-6-O-{[(4-benzoylphenyl)amino]carbonyl}-β- L-gulofuranoside (Compound No. 272).
Scheme XIII
Figure imgf000047_0001
Formula LVX
Figure imgf000047_0002
Figure imgf000047_0003
Formula LVXI Formula LVXII
L, — hal
Figure imgf000047_0004
Formula LVXIV Formula LVXII I The compounds of Formulae LVXI and LVXIV can be prepared by following the procedure as depicted in scheme XIII. Thus a compound of Formula LVVII is reacted with a compound of Formula NHRXP (wherein Rx and P are the same as defined earlier) to give a compound of Formula LWIII, which undergoes deprotection to give a compound of Formula LNIX, which is reacted with Path a: phenyl carbamate to give a compound of Formula LNX, which undergoes cyclization to give a compound of Formula LNXI Path b: compound of Formula III (wherein Rxis the same as defined earlier) to give a compound of Formula LVXII, which is reacted with a compound of Formula L2-hal (wherein
L2 and hal are the same as defined earlier) to give a compound of Formula LVXIII, which undergoes cyclization to give a compound of Formula LVXIV. The reaction of a compound of Formula LWII with a compound of Formula NHRXP to give a compund of Formula L III can be carried out using NHRXP as a solvent. The deprotection of a compound of Formula LVNIII to give a compound of Formula
LVIX can be carried out in an organic solvent selected from, methanol, ethanol, propanol or isopropylalcohol with deprotecting agent selected from, hydrogenatically utilizing palladium on carbon or under catalytic transfer hydrogenation conditions of ammonium formate and palladium on carbon. The reaction of a compound of Formula LVIX with phenyl chloroformate (path a) to give a compound of Formula LVX can be carried out in an organic solvent selected from tetrahydrofuran, dimethylformamide, diethyl ether or dioxane in the peresence of a base selected from, triethyl amine, Ν-methylmorpholine, diisopropylethylamine or pyridine.
Alternatively, other chloroformates for example p- nitrophenyl chloroformate can also be used in place of phenyl chloroformate. The cyclisation of a compound of Formula LVX to give a compound of Formula
LVXI can be carried out in an organic solvent selected from dimethylsulphoxide, tetrahydrofuran, dimethylformamide, diethyl ether or dioxane in the peresence of a base selected from, triethyl amine, Ν-methylmorpholine, diisopropylethylamine or pyridine. The reaction of a compound of Formula LVIX with a compound of Fornmula III (path b) to give a compound of Formula LVXII can be carried out in an organic solvent selected from, dichloromethane, dichloroethane, carbon tetrachloride or chloroform. The reaction of a compound of Formula LVXII with a compound of Formula L2-hal to give a compound of Formula LVXIII can be carried out in an organic solvent selected from, dichloromethane, dichloroethane, carbon tetrachloride or chloroform in the presence of a base selected from, triethylamine, Ν-methylmorpholine, diisopropylethylamine or pyridine. The cyclisation of a compound of Formula LVXIII to give a compound of Formula LVXIV can be carried out in an organic solvent selected from, tetrahydrofuran, dimethylformamide, diethyl ether or dioxane in the presence of a base for example, potassium tert-butoxide, sodium ethoxide or sodium hydride. The compound prepared following scheme XIII, path a are: l-O-Dodecyl-2,3-O-isopropylidene-6-deoxy-6-amino-5-O,6-N-(carbonyl)-oc-D- mannofuranoside (Compound No. 248), The compound prepared following scheme XIII, path b are: l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[4-fluorophenyl]amino]-6-(methylamino)- 5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 249) l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[4-carboxymethylphenyl]amino]-6- (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 253) Scheme XIV
Figure imgf000049_0001
Formula LVXVI Formula LVXVI I deprotection
cyclization
Figure imgf000049_0002
Figure imgf000049_0003
Formula LVXIV Formula LVXIX Formula LVXVIII
Compounds of Formulae LVXIX and LVXIV can be prepared by following the procedure as depicted in Scheme XIV. Thus a compound of Formula LWII (wherein R2, R3, R4, RX and P are the same as defined earlier) is reacted with a compound of Formula LVXV (wherein L2 and hal are the same as defined earlier) to give a compound of Formula LVXVI, which is reacted with a compound of Formula NH2P (wherein P is the same as defined earlier) to give a compound of Formula LVXII, which undergoes deprotection to give a compound of Formula LVXVIII, which undergoes ring cyclisation to give a compound of Formula LVXIX, which undergoes N-derivatization with a compound of Formula Rx-hal (wherein Rx and hal are the same as defined earlier) to give a compound of Formula LVXIV. The reaction of a compound of Formula LWIII with a compound of Formula LVXV to give a compound of Formula LVXI can be carried out in an organic solvent selected from, dichloromethane, dichloroethane, carbon tetrachloride or chloroform in the presence of a base selected from, triethylamine, N-methylmorpholine, diisopropylethylamine or pyridine. The reaction of a compound of Formula LVXVI with a compound of Formula NH2P to give a compound of Formula LVXVII is carried out using NH2P as a solvent. The deprotection of a compound of Formula LVXVII to give a compound of Formula LVXVIII can be carried out in an organic solvent selected from, methanol, ethanol, n- propanol or isopropylalcohol with deprotecting agent selected from, hydrogenatically utilizing palladium on carbon or under catalytic transfer hydrogenation conditions of ammonium formate and palladium on carbon. The cyclisation of a compound of Formula LVXVIII to give a compound of Formula LVXIX can be carried out with carbonylating agent selected from, triphosgene, phosgene, diphosgene orcarbonyldiimidazole in an organic solvent selected from, dichloromethane, dichloroethane, carbon tetrachloride or terahydrofuran in the presence of a base selected from diisopropylethylamine, triethylamine, N-methylmorpholine or pyridine. The N-derivatization of a compound of Formula LVXIX with a compound of Formula Rx-hal to give a compound of Formula LVXIV can be carried out an organic solvent selected from tetrahydrofuran, dioxin, ether, ethanol, t-butanol in the presence of a base selected from sodium hydride, potassium tert-butoxide, sodium ethoxide or sodium methoxide. Compounds prepared following scheme XIV is: ( l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(n-butylamino)-6-(methylamino)-5,6-N- carbonyl-β-L-gulofuranoside (Compound No. 250) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[2,4-difluorobenzyl]amino}-6- (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 252) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[4-trifluoromethylbenzyl]amino}-6- (methylamino)-5„6-N-carbonyl-β-L-gulofuranoside (Compound No. 254) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[2,6-dichlorobenzyl]amino}-6-
(methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 255) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(benzylamino)-6-(methylamino)-5,6-N- carbonyl-β-L-gulofuranoside (Compound No. 256) l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(propargylamino)-6-(methylamino)-5,6-N- carbonyl-β-L-gulofuranoside (Compound No. 257) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(cyclopropylmethylamino)-6- (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 258) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [2-ethoxycarbonylethyl]amino} -6- (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 259) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(n-propylamino)-6-(methylamino)-5,6-N- carbonyl-β-L-gulofuranoside (Compound No. 260)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {(3-phenylρroρyl)amino} -6- (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 261) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {(4-chlorobenzyl)amino} -6- (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 262) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-amino-6-(methylamino)-556-N-carbonyl-β- L-gulofuranoside (Compound No. 268)
Scheme XV
Figure imgf000052_0001
Formula LVXX Formula LXXXII Formula LXXXII)
Formula LXXXIV
Compounds of Formulae LXXXII, LXXXIII and LXXXIV can be prepared by following the procedure as depicted in scheme XV. Thus a compound of Formula LNXX (wherein R2, R3 and R4 are the same as defined earlier) can be reacted with a compound of Formula LXXXI (wherein hal and Rx are the same as defined earlier) to give a compound of LXXXII, which can be reacted with a compound of Formula L2-hal (wherein L2 and hal are the same as defined earlier) to give a compound of Formula LXXXIII, which undergoes cyclization to give a compound of Formula LXXXIV. The reaction of a compound of Formula LVXX with a compound of Formula LXXXI to give a compound of Formula LXXXII can be carried out in an organic solvent selected from, dichloromethane, dichloroethane, carbontetrachloride or chloroform in the presence of a base selected from diisopropylethylamine, triethylamine, pyridine or Ν-methylmorpholine. The reaction of a compound of Formula LXXXII with a compound of Formula L2-hal to give a compound of Formula LXXXIII can be carried out in an organic solvent selected form, dichloromethane, dichloroethane, carbontetrachloride or chloroform in the presence of a base selected from triethylamine, diisopropylethylamine, pyridine or Ν-methylmorpholine. The cyclization of a compound of Formula LXXXIII to give a compound of Formula LXXXIV can be carried out out in an organic solvent selected from, dichloromethane, dichloroethane, carbon tetrachloride or chloroform in the presence of a base selected from, diazabicycloundecene, diazabicyclooctane, diazabicyclononene or diisopropylethylamine. Compounds prepared following scheme XV are: l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-{[4-fluorobenzoyl]amino}-β-L-gulofuranoside
(Compound No. 264) l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-amino-5-N,6-O-{[(4- fluorophenyl)amino]methylylidene}-β-L-gulofuranoside (Compound No. 266)
1 -O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-amino-5-N,6-O- {(4-fluorobenzylylidene} -β-
L-gulofuranoside (Compound No. 267). Scheme XVI
cyclization H,N
Figure imgf000053_0001
Formula
Figure imgf000053_0002
Formula LXXXV
Figure imgf000053_0003
Formula LXXXVII Formula LXXXVIII
Compounds of Formulae LXXXVII and LVXXXVIII can be prepared by following the procedure as depicted in Scheme XVI. Thus a compound of Formula LXXXV (wherein Rx,
R , R3 and R are the same as defined earlier) is reacted with a compound of Formula
LXXXVI to give a compound of Formula LXXXVII, which undergoes cyclisation to give a compound of Formula LXXXVIII. The reaction of a compound of Formula LXXXV with a compound of Formula LXXXVI to give a compound of Formula LXXXVII can be carried out in an organic solvent selected from tetrahydrofuran, dimethylformamide, diethyl ether or dioxane in the presence of a base selected from, diisopropylethylamine, triethylamine, N-methylmorpholine or pyridine. The cyclisation of a compound of Formula LXXXVII to give a compound of Formula
LXXXVIII can be carried out in an organic solvent selected from, acetonitrile, dichloromethane or dichloroethane with coupling agent selected from, dicyclohexylcarbodiimide or l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride.
Compounds prepared following scheme XVI are: l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-amino-5-N,6-O-{([4-carboxy methylphenyl]amino)methylylidene} -β-L-gulofuranoside (Compound No. 269) l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-({[4-carboxymethylphenyl)amino] thiocarbonyl} -amino)-β-L-gulofuranoside (Compound No. 270).
Also, in all the above representative examples, wherever 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. Alternatively, hydrolysis of benzyl ester can be carried out hydrogenatically using catalysts, for example, palladium on carbon or platinum on carbon. The esters such as tert- butyl can be hydrolyzed to their corresponding acids in the presence of acid, for example, trifluoroacetic acid or hydrochloric acid. In the above schemes, where specific bases, acids, solvents, condensing agents, hydrolyzmg agents, etc., are mentioned, it is to be understood that other acids, bases, solvents, condensing agents, hydrolyzmg agents, etc., known to those skilled in the art may also be used. Similarly, the reaction temperature and duration of the reactions may be adjusted as desired. Particular compounds desired herein, having been produced by Schemes I or II are listed below in Table I, Table II and Table III and Table IN.
TABLE I
Figure imgf000055_0001
Formula I (Wherein R2 and R3 together form isopropylidene)
Figure imgf000055_0002
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
* represents hydrochloride salt ** represents tris salts.
TABLE II
Figure imgf000059_0001
Formula I (Wherein R3 and R4 (when R4 is ORc) together form isopropylidene)
Figure imgf000059_0002
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000063_0002
Figure imgf000064_0001
Figure imgf000065_0002
Figure imgf000065_0001
**tris salt *** isomer of compound no. 228 $ is a diastereomer of Compound No. 218 $$ is a diastereomer of Compound No. 223 $$$ is a diastereomer of Compound No. 229 $$$$ is a diastereomer of Compound No. 221
TABLE III
Figure imgf000066_0001
Formula I 15 (Wherein R2 and R3 together form cyclohexylidene acetal)
Figure imgf000066_0002
Figure imgf000067_0002
TABLE IN
Figure imgf000067_0001
Formula I 15 (Wherein R2 and R3 together forms cyclopentylidene acetal)
Figure imgf000067_0003
TABLE N
Figure imgf000068_0001
Formula I (Wherein R3 and R4 (when * is ORc) together form isopropylidene)
Figure imgf000068_0002
Figure imgf000069_0001
Examples set forth below demonstrate the general synthetic procedure for the preparation of representative compounds. The examples are provided to illustrate particular aspect of the disclosure and do not limit the scope of the present invention. Examples Example 1: Synthesis of l-O-dodecyl-2.3-O-isopropylidene-5.6-dideoxy-5-(4-amino- phenyl)-amino-β-L-gulofuranoside
Step a: Synthesis of l-O-dodecyl-2,3-O-isopropyIidene-5,6-dideoxy-5-(4-nitro-phenyl)- amino-β-L-guIofuranoside.
To a solution of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-amino-β-L- gulofuranoside (lg, 2.69 mmole) in acetonitrile (5 ml), was added 4-nitrofluorobenzene (0.37g, 2.69 mmol) and diisopropylethylamine (0.52 ml, 2.96 mmol). The reaction mixture was refluxed for overnight. The reaction mixture was cooled and poured into water, extracted with ethyl acetate. The combined organic extract was washed with water, brine and dried over anhydrous sodium sulphate. The solvent was evaporated off under reduced pressure and the residue thus obtained was purified by column chromatography using 7.5% ethylacetate in hexane as eluent to furnish the title compound (0.43g).
Step b: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(4-amino-phenyl)- amino-β-L-gulofuranoside. To a solution of the compound obtained from step a above (0.43 g) in methanol
(20ml), was added 10% Palladium on carbon (50mg) and the reaction mixture was shaken under hydrogen atmosphere at 50-55 psi for 4 hours. The reaction mixture was filtered through celite pad. The filtrate was concentrated under reduced pressure to furnish the title compound (230mg).
Example 2: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-amino-β-L- gulofuranoside
Step a: Synthesis of l-O-dodecyl~2,3-O-isopropylidene-5,6-dideoxy-5-O-methane sulphonyl-α ,D-mannofuranoside
The compound 1 -O-dodecyl-2,3 -O-isopropylidene-6-deoxy- α-D-mannofuranoside (synthesised following the procedure as per described in U.S. Patent No. 6,329,344) (11.5g) in dichloromethane (50 ml) was cooled at -5°C. To the reaction mixture was added triethylamine (3.75g) followed by slow addition of methanesulphonyl chloride (4.25g) over a period of 30 minutes with stirring. The reaction mixture was diluted with water. The layers were separated and aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water, brine and dried over anhydrous sodium sulphate. The solvent was evaporated off under vacuum to obtain the title compound (12g).
Step b: Synthesis of 2,3-O-isopropylidene-l-O-dodecyl-5,6-dideoxy-5-benzylamino-β-L- gulofuranoside To a compound obtained from step a above (10. Ig), was added benzylamine (30 ml), and the mixture was stirred at 120°C for 5-6 hours. Benzylamine 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 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-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-amino-β-L- gulofuranoside To a solution of the compound obtained from step b above (9.2 g) in methanol (200 ml), was added 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 3: Synthesis of 1.2-O-isopropylidene-3.5-di-O-benzyl-6-deoxy-6-amino-α-D- giucofuranoside
Step a: Synthesis of 1,2; 5,6-Di-O-isopropylidene-3-O-benzyl- -D-gIucofuranoside To a suspension of sodium hydride (60% in oil, 1.308 g, 32.68 mmol) and tetrabutyl ammonium iodide (1.206 g, 3.268 mmol) in dry tetrahydrofuran (115 ml) was added diacetoneglucose (5 g, 19.23 mmol) in dry tetrahydrofuran (10 ml) slowly at 0°C. The reaction mixture was stirred for 20 minutes at same temperature and then for 30 minutes at room temperature. The reaction mixture was cooled to 0°C, which was further treated benzyl bromide (2.52 ml, 21.15 mmol) in dry tetrahydrofuran (5 ml), followed by stirring it at room temperature for 20 hours. The reaction mixture was quenched with excess amount of water. The reaction mixture was evaporated off under reduced pressure and . the residue thus obtained was taken in ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography using 5% ethyl acetate in hexane as eluent to furnish the title compound (6.59g).
Step b: Synthesis of l,2-O-isopropylidene-3-O-benzyl-α-D-glucofuranoside The a solution of the compound obtained from step a above (3.36 g) in tetrahydrofuran was stirred at 0°C in an ice bath followed by the addition of 30% perchloric acid solution (4 ml) slowly over a period of 30 minutes. The mixture was st red at 0°C for 2 hours. The reaction mixture was neutralized with dilute aqueous sodium hydroxide solution, the solvent was evaporated off under reduced pressure and the product was extracted with ethyl acetate.
The organic layer was washed with water, brine and dried over anhydrous sodium sulphate.
The solvents were evaporated off to obtain title compound (2.3g).
Step c: Synthesis of l,2-O-isopropylidene-3-O-benzyI-6-O-benzoyI-α-D-glucofuranoside The solution of the compound obtained from step b above (2.3 g, 7.42 mmol) in of dry dichloromethane (20 ml) was stirred at 0°C in an ice bath. To this solution was added pyridine (0.6 ml) followed by the addition of benzoyl chloride (0.86 ml, 4.419 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 24 hours. The reaction mixture was washed with water and the organic layer was separated followed by washing with brine and dried (anhydrous sodium sulphate). The crude product was purified by column chromatography to furnish the title compound (2g).
Step d: Synthesis of l,2-O-isopropylidene-3,5-di-O-benzyl-6-O-benzoyl-α-D- glucofuranoside To a suspension of sodium hydride (60% in oil, 0.3 g, 7.75 mmol) and tetrabutyl ammonium bromide (0.29 g, 0.792 mmol), in dry tetrahydrofuran (65 ml) at 0°C, was added a compound obtained from step c above (1.8 g, 4.66 mmol) in dry tetrahydrofuran (6 ml) and the mixture was stirred at the same temperature for 10 minutes followed by stirring at room temperature for 30 min. The reaction mixture was again cooled to 0°C and treated with benzyl bromide (0.554 ml, 4.66 mmol) in dry tetrahydrofuran (4 ml) then stirred at room temperature for 48 hours. The reaction mixture was quenched and concentrated under reduced pressure. The residue thus obtained was dissolved in ethyl acetate, washed with brine and dried over anhydrous sodium sulphate. The solvents were evaporated off to obtain crude title compound (1.12g). Step e: Synthesis of l,2-O-isopropylidene-3,5-di-O-benzyI-α-D-glucofuranoside The compound (1.12) obtained from step d above was dissolved in sodium hydroxide
(0.5 g) in methanol and water. The reaction mixture was stirred till the reaction was completed. The reaction mixture was diluted with excess amount of ethyl acetate and washed with brine. The organic layer was dried (anhydrous sodium sulphate), concentrated under reduced pressure to obtain title compound (0.65g). Step f: Synthesis of l,2-O-isopropylidene-3,5-di-O-benzyl-6-O-methylsulphonyl-α-D- glucofuranoside To the compound obtained from step e above (9.8 g), was added pyridine (25ml) and the reaction mixture was stirred at 0°C for 15 minutes. Methanesulphonyl chloride (3.44 ml) was added to the reaction mixture and stirred until completion (TLC). Pyridine was evaporated off and the residue thus obtained was dissolved in ethyl acetate. The organic layer was washed with water, brine and dried (anhydrous sodium sulphate). The solvents were evaporated off under reduced pressure to furnish the title compound (9 g). Step g: Synthesis of l,2-O-isopropylidene-3,5-di-O-benzyl-6-deoxy-6-azido-α-D- glucofuranoside To a solution of the compound obtained from step/above (12g) in dimethylformamide (30ml), was added sodium azide (8g) and stirred at 100°C until completion (TLC). The solid thus obtained from the reaction mixture was filtered off, the filtrate was evaporated. The residue thus obtained was dissolved in ethyl acetate, washed with brine, and dried (anhydrous sodium sulphate). Solvent was evaporated off under reduced pressure to obtain the title compound (9.8g).
Step h: Synthesis of l,2-O-isopropy!idine-3-O-benzyI-5-O-benzyI-6-deoxy-6-amino-α-D- glucofuranoside To a solution of the compound obtained from step g above (2.26g) in dry tetrahydrofuran (25ml) at 0°C, was added lithium aluminium hydride (0.605g). The reaction mixture was stirred at 0°C for 5 hours. Dilute solution of sodium hydroxide and ethyl acetate was added dropwise to the reaction mixture at 0°C to quench the reaction. The insolubles were filtered off, the filterate was concentrated under reduced pressure, which was taken in ethyl acetate and was washed with brine. The organic layer was dried and concentrated under reduced pressure to obtain the title compound (1.5g).
Example 4: Synthesis of 3-ethoxy-5-(l-methyl-7-oxo-3-propyl-6.7-dihydro-lH-pyrazalor4,3- d] pyrimidin-4-yl)-benzenesulphonyl chloride The compound l-methyl-5-(2-methoxy-phenyl)-3-propyl-l,6-dihydro-pyrazolo [4,3- d]pyrimidin-7-one was added in small portions to a cooled solution of chlorosulphonic acid. The temperature of the reaction mixture was maintained at the 10- 15°C and stirred for 5-6 hours followed by the addition of thionyl chloride slowly. The reaction mixture was stirred for another 20 hours. Reaction mixture was poured onto crushed ice followed by the addition of dichloromethane (approx. 50 ml) and stirred for 15 minutes. The reaction mixture was filtered through celite pad. The organic layer was collected and the solvent was evaporated off. The solvent was dried over anhydrous sodium sulphate. The residue thus obtained was triturated with hexane and filtered to obtain the title compound (10.5 g.). Example 5: Synthesis of l,2-O-cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-amino-β-L- idofuranoside Step a: Synthesis of l,2;5,6-di-O-cyclohexylidene-α-D-glucofuranoside To cyclohexanone (466.6 ml) cooled at 0°C, was added sulphuric acid (27.7 ml) dropwise at 0°C followed by the addition of dried D-glucose (200 g) portionwise with constant stirring. The reaction mixture was allowed to attain room temperature and continuous stirring over a period of 8 hours till the crystalline mass separated out. The reaction mixture was allowed to stand at room temperature for overnight, followed by the addition of 750 ml of hexane. The reaction mixture was refluxed for few minutes. Decanted the upper layer and repeated the same procedure for 2-3 times. The combined hexane extract was cooled in refrigerator. Filtered the crystalline material and recrystallised from hexane as eluent using decolorizing charcoal to obtain the title compound (182g). Step b: Synthesis of l,2;5,6-di-O-cyclohexylidene-3-O-nonyl-α-D-glucofuranoside A mixture of the compound obtained form step a above (50 g), bromononane (35.5 g) and sodium hydroxide (17.6 g) was stirred at 110-120°C for 24 hours. The product was ' extracted with ethyl acetate followed by washing with sodium carbonate solution, water, brine ' and dried over sodium sulphate. The crude product obtained was purified by column chromatography using 15% ethyl acetate in hexane as eluent to furnish the title compound (55g). Step c: Synthesis of l,2-O-cyclohexylidene-3-O-nonyl-α-D-glucofuranoside To a solution of the compound obtained from step b (50 g) above in aqueous acetic acid (250ml, 75% v/v) was heated at 70-80°C with continuous stirring. After 16 hours, the solvent was evaporated off under reduced pressure and to the residue thus obtained was added 50 ml of hot water and sodium bicarbonate to neutralize the remaining acetic acid. The product was then extracted with ethyl acetate followed by washing with water, brine and dried sodium sulphate. The crude product was purified by column chromatography using 30% ethyl acetate in hexane as eluent to furnish a title compound (18g).
Step d: Synthesis of l,2-O-cyclohexy!idene-3-O-nonyl-6-O-p-toluenesuIphonyl-α-D- glucofuranoside To a solution of a compound obtained from step c above (18g) in pyridine (30ml) at 0-
5°C, was added p-toluene sulphonyl chloride (9g) in pyridine (20 ml) dropwise. The reaction mixture was stirred for 6 hours. The reaction mixture was diluted with water, solvents were evaporated under reduced pressure. The compound was extracted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine and dried over anhydrous sodium sulphate.
The crude product was purified by column chromatography using 50% ethyl acetate in hexane as eluent to furnish the title compound (18g).
Step e: Synthesis of l,2-O-cyclohexyIidene-3-O-nonyl-6-deoxy-α-D-glucofuranoside To a solution of lithium aluminium hydride (5 g) taken in dry tetrahydrofuran (30 ml) at 0°C, was added solution of the compound obtained from step d above (18.0g) in dry tetrahydrofuran (30 ml) with continuous stirring. After complete addition, the reaction was allowed to proceed at room temperature. After 12 hour, added 30 ml of ethyl acetate, 5 ml of water, 5 ml of 15% sodium hydroxide solution at -5°C. The solids obtained were filtered. The filtrate dried over anhydrous sodium sulphate. The solvent was evaporated off under reduced pressure and the crude product thus obtained was purified by column chromatography using 50% ethyl acetate in hexane as eluent to furnish the title compound
(Hg)-
Step f: Synthesis of l,2-O-cyclohexylidene-3-O-nonyl~5-O-p-toluene-sulphonyl-6-deoxy- α-D-glucofuranoside To a solution of the compound obtained from step e above (11.0 g) in pyridine (20 ml) at 0-5°C, was added p-toluenesulphonyl chloride (5.0 g) in pyridine with continuous stirring. After complete addition the temperature of the reaction mixture was raised to 50°C. After 8 hour, the reaction mixture was diluted with water, followed by the removal of the solvent under pressure. The compound was extracted with ethyl acetate, followed by washing with water, saturated sodium bicarbonate solution, brine and dried over anhydrous sodium sulphate. The solvent was evaporated off and the crude product was purified by column chromatography using 50% ethyl acetate in hexane as eluent to obtain the title compound
(10g).
Step g: Synthesis of l,2-O-cyclohexylidene-3-O-nonyI-5,6-dideoxy-5-azido-β-L- idofuranoside To a solution of the compound obtained from step/above (10.0 g) in dry dimethylformamide (50ml), was added of sodium azide (3.2 g) and the reaction mixture was allowed'to stirr for 14 hours. Dimethylformamide was evaporated off under reduced pressure.
The residue was extracted with ethyl acetate followed by washing with water, brine. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane 10% ethyl acetate in hexane as eluent to furnish the title compound (6g).
Step h: Synthesis of l,2-O-cyclohexylidene-3-O-nonyI-5,6-dideoxy-5-amino-β-L- idofuranoside To a solution of lithium aluminium hydride (3 g) in dry tetrahydrofuran (20 ml) at
0°C, was added the compound obtained from step g above (6 g) in dry tetrahydrofuran dropwise with continuous stirring. After complete addition the reaction mixture was allowed to attain room temperature and stirred for 10 hour. The reaction mixture was quenched with sodium hydroxide in water(15%, 3ml) and ethyl acetate (25 ml). The solid thus separated was filtered off and the filterate was dried over anhydrous sodium sulphate. The crude product was purified with column chromatography to furnish the title compound (3.5 g).
Example 6: Synthesis of 1.2-O-isopropylidene-3-O-dodecyl-6-deoxy-6-amino- -D- glucofuranoside.
Step a: Synthesis of l,2-O-isopropy!idene-3-O-dodecyl-6-deoxy-6-azido-α-D- glucofuranoside To a solution of l,2-O-isopropylidene-3-O-dodecyl-6-O-tosyl-α-D-gluco-furanoside
(synthesised following the procedure described in U.S. Patent No. 6,329,344) (5.5 g,) in dimethylformamide (40ml), was added sodium azide (3.3g). The reaction mixture was heated upto 70-80°C for 4 hours. The solid thus obtained was filtered and dimethyl formamide was evaporated off under reduced pressure. Residue thus obtained was dissolved in ethyl acetate, washed with water, brine and dried over sodium sulphate. The solvents were evaporated off and concentrated under reduced pressure to furnish the title compound (lg).
Step b: Synthesis of l,2-O-isopropylidene-3-O-dodecyl-6-deoxy-6-amino-α-D- glucofuranoside To a solution of the compound (l.Og) obtained form step a above in tetrahydrofuran
(15ml) at 0°C, was added lithium aluminum hydride (287mg). Reaction mixture was allowed to come at room temperature. The reaction mixture was filtered through celite pad and ethyl acetate (100 ml) was added to it. It was washed with water, brine, dried over celite pad and concentrated under reduced pressure to furnish the title compound (700mg). Example 7: Synthesis of 2-benzyl-5-tert-butyl-2H-pyrazol-3-ylamine To a solution of pivolyl acetonitrile (2g) in ethyl alcohol (75ml), was added benzyl hydrazine dihydrochloride (3.43g) at room temperature. The reaction mixture was refluxed for overnight at 80°C. The reaction mixture was concentrated and treated with water, then basified by using IN aqueous sodium hydroxide solution. The compound was extracted with ethyl acetate (25x3 ml). The ethyl acetate extract was washed with brine and concentrated to yield the title compound (3.8g). Example 8: Synthesis of 2-p-tolyl-5-tert-butyl-2H-pyrazol-3-ylamine The title compound can be prepared following the same procedure as described for the synthesis of 2-benzyl-5-tert-butyl-2H-pyrazol-3-ylamine by using p-tolyl hydrazine hydrochloride in place of benzylhydrazine dihydrochloride. Scheme I
Example 9: Synthesis of 1.2-O-isopropylidene-3-O-dodecyl-5-O-[{4-r2-methoxy-2-oxo- ethyl)-phenyl}-amino1-carbonyl-6-deoxy-α-D-glucofuranoside (Compound No. 1) To a solution of l,2-isopropylidene-3-O-dodecyl-6-deoxy-α-D-glucofuranoside (synthesised following the procedure as per reported in U.S. Patent No. 6,329,344) (1.0 g) in dichloromethane (30 ml) at 0-5°C, was added pyridine and 4-isocyanatophenylacetic acid methyl ester (0.6 g) under constant stirring. The reaction mixture was allowed to attain room temperature and stirred for 5 hours. The reaction mixture was diluted with water followed by the removal of the solvent under reduced pressure. The residue was extracted with dichloromethane, which on concentration furnished a crude compound. The crude compound was purified by column chromatography using 10% ethyl acetate in hexane as eluent to obtain the title compound (1.10 gm).
1H NMR (CDCI3, 300 MHz):δ 7.33 (2H, d, 8.2Hz), 7.29-7.19 (2H, m), 6.57 (IH, bs, NH),
5.91 (IH, d, 3.6Hz), 5.15 (IH, t, 6.7Hz), 4.53 (IH, m), 4.15 (IH, m), 3.83 (IH, d, 3.1Hz), 3.68 (3H, s), 3.59-3.32 (4H, m), 1.61-1.20 (29H, m), 0.87 (3H, t, 6.5Hz). Analogues of l,2-O-isopropylidene-3-O-dodecyl-5-O-[{4-(2-methoxy-2-oxo-ethyl)- phenyl}-amino]-carbonyl-6-deoxy-α-D-glucofuranoside (Compound No. 1) described below were prepared by replacing the appropriate isocyanate in place of 4-isocyanato phenyl acetic acid methyl ester and appropriate sugar moiety in place of l,2-isopropylidene-3-O-dodecyl-6- deoxy-α-D-glucofuranoside, respectively, as applicable in each case.
1 ,2-O-Isopropylidene-3-O-dodecyl-5-O- { [(4-morpholinyl)-sulphonylamino]-carbonyl} -α-D- xylofuranoside (Compound No. 2)
1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [(4-azepanyl)-sulphonylamino]-carbonyl} - -D- xylofuranoside (Compound No. 3) 1 ,2-O-Isopropylidene-3-O-dodecyl-5 -O- { [( 1 -piperidinyl)-sulphonylamino] -carbonyl} -α-D- xylofuranoside (Compound No. 4)
1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [(1 -piperidinyl)-sulphonylamino]-carbonyl} -α-D- xylofuranoside (Compound No. 5)
1 ,2-O-Isopropylidene-3-O-dodecyl-5-O- { [(1 -azepanyl)-sulphonylamino]-carbonyl} -α-D- xylofuranoside (Compound No. 6) l,2-O-Isopropylidene-3-O-decyl-5-O-{[(4-morpholinyl)-sulphonylamino]-carbonyl}-α-D- xylofuranoside (Compound No. 7)
1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [(1 -pyrrolidinyl)-sulphonylamino]-carbonyl} -α-D- xylofuranoside (Compound No. 8) l,2-O-Isopropylidene-3-O-heptyl-5-O-{[(l-piperidinyl)-sulfonylamino]-carbonyl}-α-D- xylofuranoside (Compound No. 9) l,2-O-IsopiOpylidene-3-O-hexadecyl-5-O-[{(l-piperidinyl)-sulfonylamino}-carbonyl]-α-D- xylofuranoside (Compound No. 10)
1 ,2-O-Isopropylidene-3-O-decyl-5-O-[ {4-(2-methoxy-2-oxo-ethyl)-phenyl} -amino] -carbonyl- 6-deoxy-α-D-glucofuranoside (Compound No. 11) l,2-O-Isopropylidene-3-O-decyl-5-O-{[4-(2-hydroxy-2-oxoethyl)-phenyl]-amino}-carbonyl-
6-deoxy- -D-glucofuranoside (Compound No. 12)
Example 10: Synthesis of l-O-dodecyl-2.3-O-isoproρylidene-5-O-(r2-methylphenylamino]- carbonyl}-6-deoxy-α-D-mannofuranoside (Compound No. 13*) To a solution of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-α-O-mannofuranoside
(synthesised following the procedure as per reported in U.S. Patent No. 6,329,344) (100 mg,
0.27 mmole) in dichloroethane (3 ml), was added O-tolyl isocyanate (35 mg, 0.27 mmole) and pyridine (a drop). The reaction mixture was refluxed for 7 hours, cooled and washed with water. The organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvents were evaporated off and the residue thus obtained was purified by column chromatography using 5% ethyl acetate in hexane as eluent to furnish the title compound (30 mg).
1H NMR (CDC13, 300 MHz):δ 7.79 (IH, bs), 7.22-7.14 (2H, m), 7.02 (IH, m), 6.33 (IH, bs),
5.16 (IH, m), 5.0 (IH, s), 4.73 (IH, bs), 4.56 (IH, d, 5.7Hz), 3.94 (IH, bs), 3.60 (IH, bs), 3.41 (IH, m), 2.25 (3H, s), 1.45 (6H, s), 1.27 (23H, bs), 0.87 (3H, bs). Analogues of l-O-dodecyl-2,3-O-isopropylidene-5-O-{[2-methyl-phenylamino]- carbonyl} -6-deoxy-α-D-mannofuranoside (Compound No. 13) described below were prepared by replacing appropriate isocyanate in place of O-tolyl isocyanate, and appropriate sugar moiety in place of 2,3-O-isopropylidene-l-O-dodecyl-6-deoxy- -O-mannofuranoside, respectively as applicable in each case. l-O-Heptyl-2,3-O-isopropylidene-5-O-{[(2-methyl-phenyl)-sulphonylamino]-carbonyl}-6- deoxy-α-D-mannofuranoside (Compound No. 14) l-O-Heptyl-2,3-O-isopropylidene-5-O-[{2-(4-[2-methoxy-2-oxo-ethyl]-thiazolyl)-amino}- sulfonyl-amino]-carbonyl-6-deoxy-α-D-mannofuranoside (Compound No. 15) 1 -O-Heptyl-2,3 -O-isopropylidene-5-O- {(1 -azepanyl)-sulfonylamino} -carbonyl-6-deoxy-α-D- mannofuranoside (Compound No. 16) l-O-Heptyl-2,3-O-isopropylidene-5-O-{(l-pyrrolidinyl)-sulfonylamino}-carbonyl-6-deoxy- α-D-mannofuranoside (Compound No. 17) l-O-(3-Undecyloxy-propyl)-2,3-O-isopropylidene-5-O-{[(l-pyrrolidinyl)-sulphonylamino]- carbonyl} -β-D-lyxofuranoside (Compound No. 18) l-O-(3-Undecyloxy-propyl)-2,3-O-isopropylidene-5-O-{[(l-piperidinyl)-sulfonylamino]- carbonyl}-β-D-lyxofuranoside (Compound No. 19) l-O-(3-Undecyloxy-propyl)-2,3-O-isopropylidene-5-O-{[(l-azepanyl)-sulphonylamino]- carbonyl}-β-D-lyxofuranoside (Compound No. 20) 1 -O-(3-Undecyloxy-propyl)-2,3-O-isopropylidene-5-O-[ {(4-morpholinyl)-sulphonylamino} - carbonyl]-β-D-lyxofuranoside (Compound No. 21) l-O-(3-Undecyloxy-propyl)-2,3-O-isopropylidene-5-O-[(phenylamino)carbonyl]-β-D- lyxofuranoside (Compound No. 22)
1 -O-Dodecyl-2,3-O-isopropylidene-5-O- { [4-(2-methoxy-2-oxo-ethyl)-phenyl]-amino} - carbonyl-6-deoxy-α-D-mannofuranoside (Compound No. 23) l-O-Dodecyl-2,3-O-isopropylidene-5-O-[{4-methyl-phenyl-amino}-carbonyl]-6-deoxy-α-L- mannofuranoside (Compound No. 24) l-O-Dodecyl-2,3-O-isopropylidene-5-O-{[3-chloro-phenyl-amino]-carbonyl}-6-deoxy-α-D- mannofuranoside (Compound No. 25) 1 -O-Dodecyl-2,3-O-isopropylidene-5- { [4-chlorophenylamino] -carbonyl} -6-deoxy-α-D- mannofuranoside (Compound No. 26) ι l-O-Dodecyl-2,3-O-isopropylidene-6-deoxy-5-O-{[(phenylsulfonyl)amino]carbonyl}-α-D- mannofuranoside (Compound No. 281)
1 -O-Dodecyl-2,3-O-isopropylidene-6-deoxy-5-O- { [(2-tolylsulfonyl)amino]carbonyl} -α-D- mannofuranoside (Compound No. 282) l-O-Dodecyl-2,3-O-isopropylidene-6-deoxy-5-O-{[(4- chlorophenylsulfonyl)amino]carbonyl}-α-D-mannofuranoside (Compound No. 283)
1 -O-Dodecyl-2,3-O-isopropylidene-6-deoxy-5-O- { [(4-tolylsulfonyl)amino]carbonyl} -α-D- mannofuranoside (Compound No. 284) l-O-Dodecyl-2,3-O-isopropylidene-6-deoxy-5-O-{[(benzyl)amino]carbonyl}-α-D- mannofuranoside (Compound No. 285)
Example 11: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-({r(4-
[carboxymethyl]phenyl amino] carbonyl} -aminoVβ-L-gulofuranoside (Compound No. 251)
Step a: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-O-(tert-butyldimethylsilyl)-α- D-mannofuranoside To a solution of the compound l-O-dodecyl-2,3-O-isopropylidene-α-D-mannofuranoside
(lOg, 25mmol) in dichloromethane (200ml) were added tert-butyldimethylsilylchloride (4.2 g,
2.8 mmol) and triethylamine (3.9g, 3.8mmol) at 0°C followed by the addition of dimethylaminopyridine (610mg, 5mmol). The reaction mixture was stirred for 1 hour at the same temperature and then at room temperature for overnight. The resulting rection mixture was diluted with dichloromethane, washed with water and brine. The organic layer was dried and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography to furnish the title compound. Yield: 10.7g.
Step b: Syntheis of l-O-dodecyl-2,3-O-isopropylidene-5-O-methanesulphonyl-6-O-(tert- butyldimethylsilyl)-α-D-mannofuranoside
To a solution of the compound obtained from step a above (7.57g, 15mmol) in dichloromethane (100ml) at 0°C was added triethylamine (7.6g, 75 mmol) and methane sulphonyl chloride (2.58g, 22mmol) and sthred the reaction mixture at the same temperature for 30 minutes. The reaction mixture was diluted with dichloromethane (100ml) and washed the organic layer with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced prssure to furnish the title compound. Yield: 8.9 g. Step c: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-O-methanesulphonyl- -D- mannofuranoside To the compound obtained from step b above (8.5g) was added tetra-n-butylammonium fluoride (22ml of IM solution in tetrahydrofuran) and stirred the reaction mixture at room temperature for thirty minutes. The resulting reaction milcxture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulphate and concemtrated under reduced pressure. The residue thus obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluent to furnish the title compound. Yield: 5.2g. Step d: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-benzy!amino-β-L- gulofuranoside
To the compound obtained from step c above (4.3 g) was added benzylamine (10ml) and stirred the reaction mixture at 140°C for five hours. Excess of benzyl amine was removed under reduced pressure and the residue thus obtained was purified by column chromatography to furnish the title compound. Yield: 3.5g. Step e: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-amino-β-L- gulofuranoside
To a solution of the compound obtained from step d above (3.2g) in methanol (30 ml) was added palladium on carbon (10%, lg) and stirred the reaction mixture for 8 hours at a pressure of 50 psi. The resulting reaction mixture was filtered through celite pad and the filterate aws concentrated under reduced pressure to furnish the title compound. Yield: 820mg. Step f: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-({[(4- [methoxycarbonylmethyl]phenyl)amino] carbonyl}-amino)-β-L-gulofuranoside To a solution of the compound obtained from step e above (lOOmg, 0.25mmol) in dimethylsulphoxide (2ml) was added methyl {4-[(phenoxycarbonyl)amino]phenyl}acetate (prepared by the reaction of phenyl chloroformate with methyl 4-aminophenylacetate) (81mg, 0.28mmol) and diisopropylethylamine (67mg, 0.51mmol) and stirred the reaction mixture for 5 hours. The resulting reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 1% methanol in dichloromethane to furnish the title compound. Yield: 80 mg.
Step g: Synthesis of l-O-dodecyl-2,3-O-isopropyIidene-5-deoxy-5-({[(4- [carboxymethyl]phenyl)amino] carbonyl}-amino)-β-L-gulofuranoside (Co mpound No. 251)
To a solution of the compound obtained from step/above (90mg, 0.155mmol) in tetrahydrofuran: methanol: water (3:1:1) ml was added lithium hydroxide monohydrate (7. lmg, 0.17mmol) and stirred the reaction mixture for 4 hours. The resulting mixture was concentrated under reduced pressure and the residue thus obtained was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with sodium bisulphate and extraceted with ethyl acetate. The combined organic extract was washed with aqueous sodium bisulphate and brine. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to furnish the title compound. Yield: 70 mg. 1H NMR (CDCl3):δ 7.29-7.06 (4H, m), 5.0 (IH, s), 4.73-4.75 (IH, m), 4.59-4.61 (IH, m),
4.15-4.25 (2H, m), 3.91-3.95 (IH, m), 3.77-3.79 (IH, m), 3.58-3.62 (3H, m), 3.33-3.36 (2H, m), 1.43-1.51 (5H, m), 1.25-1.31 (21H, m), 0.83-0.9 (3H, m).
LCMS (m/z): 565.2 (M++1). Example 12: Synthesis of l-O-dodecyl-2.3-O-isopropylidene-5.6-dideoxy-5-
Figure imgf000083_0001
To a solution of the compound l-O-dodecyl-2,3-O-isopropylidene-5,6-deoxy-5-amino-β-L- gulofuranoside (240 mg, 0.6469mmol) in tefrahydrofuran (10ml) at room temperature was added triethylamine (0.1 ml, 0.9703 mmol) and phenyl carbamate (132mg, 0.9703 mmol) and refluxed the reaction mixture at 60°C for 6 hours. The solvent was evaporated under reduced pressure and then subsequently poured into water. The mixture was extracted with ethyl acetate and and the combined organic layers were washed with water and brine. The solvent was evaporated under reduced pressure. The residue thus obtained was purified by column chromatography using 5% methanol in dichloromethane as elunt to furnish the title compound. Yield: 250 mg.
1H NMR (CDC13, 300 MHz):δ 4.99 (s, IH), 4.67-4.64 (t, IH), 4.56 (d, IH), 3.89-3.75 (m,
2H), 3.62-3.34 (m, 2H), 1.52 (m, 5H), 1.29-1.26 (m, 24H), 0.88 (t, 3H).
LCMS (m/z): 415 (M÷+l), 437 (M÷+Na).
Analogous of 1 -O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [(amino)carbonyl]amino} - β-L-gulofuranoside (Compound No. 263), described below were prepared similarily, 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-( { [(4-azidophenyl)amino] carbonyl} amino)-β-L-gulofuranoside (Compound No. 246)
1 -0-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [(phenylamino)carbonyl]amino} -β-L- gulofuranoside (Compound No. 265) l,2-O-Isopropylidene-3-O-dodecyl-5,6-dideoxy-5-[({[(4-carboxymethyl)-l,3-thiazol-2- yl]amino}-carbonyl)amino]-β-L-talofuranose (Compound No. 273) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[({(2-[2-carboxybenzoyl] phenyl)amino}carbonyl)-amino]-β-L-gulofuranoside (Compound No. 274) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[({(4-carbonylmethyl-2-iodo- phenyl)amino}-carbonyl)amino] -β-L-gulofuranoside (Compound No. 275) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(3- carboxymethylphenyl)amino]carbonyl}-amino)-β-L-gulofuranoside (Compound No. 276) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(2- carboxymethylphenyl)amino]carbonyl}-amino)-β-L-gulofuranoside (Compound No. 277) 1 -O-(2,4-Dodecadienyl)-2,3-O-isopropylidene-5,6-dideoxy-5-( { [(4-carboxymethyl-2,6-di- iodophenyl)amino]carbonyl}amino)-β-L-gulofuranoside (Compound No. 278) l-O-(2,4-Dodecadienyl)-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-carboxymethyl-2- iodophenyl)-amino]carbonyl}amino)-β-L-gulofuranoside (Compound No. 279) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(2,6-diiodophenyl)amino] carbonyl} amino)-β-L-gulofuranoside (Compound No. 280) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4- tolylsulfonyl)amino]carbonyl}amino)-β-L-gulofuranoside (Compound No. 286) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(2- tolylsulfonyl)amino]carbonyl}amino)-β-L-gulofuranoside (Compound No. 287) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4- chlorosulfonyl)amino]carbonyl}amino)-β-L-gulofuranoside (Compound No. 288) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(phenylsulfonyl) amino]carbonyl}amino)-β-L-gulofuranoside (Compound No. 289).
Example 13: Synthesis of 2-O-Cyclohexylidene-3-O-nonyl-5.6-dideoxy-5-{ (4-(2-hydiOxy- 2-oxo-ethyl)-phenyl -amino1-carbonyl} -amino-β-L-idofuranoside (Compound No. 27)
Step a: Synthesis of l,2-O-CycIohexylidene-3-O-nonyl-5,6-dideoxy-5-{([4-(2-methoxy-2- oxo-ethyl)-phenyl]-amino)-carbonyl}-amino-β-L-idofuranoside (Compound No. 33 ) To a solution of the compound l,2-O-cyclohexylidene-3-O-nonyl-5,6-dideoxy-5- amino-/?-L-idofuranoside (lg) in dichloromethane (20 ml) at 0°C, was added methyl 4- isocyanatophenylacetate (0.90 g) in dichloromethane (10 ml) dropwise with constant stirring. After 15 minutes the reaction mixture was allowed to attain the room temperature. After 8 hours, dichloromethane was evaporated off under reduced pressure and the residue thus obtained was purified by coloumn chromatography using 30% ethyl acetate in hexane and ethyl acetate as eluent to furnish the title compound (0.8g). Step b: Synthesis of l,2-O-Cyclohexylidene-3-O-nonyI-5,6-dideoxy-5-{[(4-(2-hydroxy-2- oxo-ethyl)-phenyl)-amino]-carbonyI}-amino-β-L-idofuranoside To a solution of the compound obtained from step a above (0.8g) in methanol (20ml) aqueous was added sodium hydroxide (IN, 20 ml) and the reaction mixture was stirred at 50°C for 6 hours. Methanol was removed under reduced pressure and the aqueous layer was neutralized with hydrochloric acid. The solid thus obtained was extracted with ethyl acetate followed by washing with water and brine. The crude product thus obtained was purified by column chromatography using 30% ethyl acetate in hexane and ethyl acetate in methanol to obtain the title compound (0.45g). 1H NMR (DMSO-d6, 300 MHz): δ 12.16 (IH, bs), 8.39 (2H, s), 7.31 (2H, d, 8.2Hz), 7.09 (2H, d, 8.2Hz), 6.08 (IH, bs), 5.83 (IH, m), 4.64 (IH, bs), 3.97 (3H, m), 3.72 (IH, s), 3.63 (2H, m), 1.99 (IH, s), 1.61-1.49 (11H, m), 1.25 (15H, bs), 1.06 (3H, d, 5.4Hz), 0.88 (3H, t, 6.7Hz). Analogues of 1 ,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5- { [(4-(2-hydroxy-2- oxo-ethyl)-phenyl)-amino]-carbonyl}-amino-y5-L-idofuranoside (Compound No. 27) described below were prepared by replacing the appropriate isocyanate in place of methyl 4- isocyanatophenylacetato and by replacing appropriate sugar moiety in place of 1,2- cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-amino-/?-L-idofuranoside respectively, as applicable in each case. l,2-O-Cyclohexylidene-3-O-decyl-5-deoxy-5-[{(4-[2-hydroxy-2-oxo-ethyl]-phenyl)-amino}- carbonyl]-amino-α-D-xylofuranoside (Compound No. 28) l,2-O-Cyclohexylidene-3-O-decyl-5-deoxy-5-{[(4-methoxy-phenyl)-amino]-carbonyl}- amino-α-D-xylofuranoside (Compound No. 29) l,2-O-Cyclohexylidene-3-O-decyl-5-deoxy-5-{[(4-methyl-phenyl)-amino]-carbonyl}-amino- α-D-xylofuranoside (Compound No. 30) 1 ,2-O-Cyclohexylidene-3-O-decyl-5-deoxy-5- { [(4-chlorophenyl)-amino]-carbonyl} -amino-α- D-xylofuranoside (Compound No. 31) l,2-O-Cyclohexylidene-3-O-decyl-5-deoxy-5-{(phenylamino)-carbonyl}-amino-α-D- xylofuranoside (Compound No. 32) l,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-({[4-methoxy-phenyl]-amino}-carbonyl)- amino-β-L-idofuranoside (Compound No. 34) l,2-O-Cyclohexylidene-3-O-dodecyl-5,6-dideoxy-5-({[4-(2-hydroxy-2-oxo-ethyl)-phenyl]- amino}-carbonyl)-amino-β-L-idofuranoside (Compound No. 35) l,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-{[(4-methyl-phenyl)-amino]-carbonyl}- amino-β-L-idofuranoside (Compound No. 36) l,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-{[(4-nitro-phenyl)-amino]-carbonyl}- amino-β-L-idofuranoside (Compound No. 37) l,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-{[(4-chloro-phenyl)-amino]-carbonyl}- amino-β-L-idofuranoside (Compound No. 3 )
1 ,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5- { [(4-methyl-phenyl)-amino] -carbonyl } - amino-β-L-idofuranoside (Compound No. 39) l,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5-{([4-(2-methoxy-2-oxoethyl)- phenyl]- amino)-carbonyl} -amino-β-L-idofuranoside (Compound No. 40) l,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5-({[4-(2-hydroxy-2-oxo-ethyl)-phenyl]- amino}-carbonyl)-amino-β-L-idofuranoside (Compound No. 41) 1 ,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5- { [(4-chloro-phenyl)-amino]-carbonyl} - amino-β-L-idofuranoside (Compound No. 42) l,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5-{[(4-nitro-phenyl)-amino]-carbonyl}- amino-β-L-idofuranoside (Compound No. 43)
1 ,2-O-Cyclopentylidene-3 -O-decyl-5-deoxy-5- { [4-nitro-phenyl-amino] -carbonyl} -amino-α- D-xylofuranoside (Compound No. 236)
Tris salt of l,2-O-isopropylidene-3-O-dodecyl-6-deoxy-6-({[4-(2-hydroxy-2-oxo-ethyl)- phenyl]-amino-carbonyl)-amino-α-D-glucofuranoside (Compound No. 196). l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[l-((3,4-methylenedioxy-phenyl)-3- hydroxy-3-oxo-propyl)-amino]-carbonyl]-amino-β-L-gulofuranoside (Compound No. 233) Scheme II
Example 14: Synthesis of hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4- chloro-phenylVamino}-carbonyl-6-deoxy-6-(l-azepanyl -α-D-mannofuranoside (Compound
No. 44) Step a: Synthesis of l-O-heptyl-2,3-O-isopropylidene-6-hexamethyleneimine-α-D- mannofuranoside To 1 -O-heptyl-2,3 -O-isopropylidene-6-tosyl-α-O-mannofuranoside (synthesised following the procedure as described in U.S. Patent No. 6,329,344) (6.0 g), was added azepane (6 ml) and the reaction mixture was heated at 60-70°C for 5-6 hours. Excess azepane was evaporated off under reduced pressure and the reaction mixture was triturated with ether. It was filtered and the filtrate thus obtained was washed with water, aqueous sodium bicarbonate and finally dried over anhydrous sodium sulphate. The organic layer was further concentrated and the crude product was purified by column chromato raphy to furnish the title compound (9.8g).
Step b: Synthesis of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}- carbonyl-6-deoxy-6-(l-azepanyl)-α-D-mannofuranoside To a solution of the compound obtained form step a above (500 mg, 1.2mmol) in dichloromethane (10ml), was added p-chlorophenyl isocyanate (200mg, 1.3mmol) at room temperature. The reaction mixture was stirred at room temperature for 3-4 hours. The reaction mixture was diluted with water and washed with sodium bicarbonate solution, brine, dried over anhydrous sodium sulphate and finally concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to obtain the title compound (590 mg). Step c: Synthesis of hydrochloride salt of l-O-heptyI-2,3-O-isopropylidene-5-O-{(4- chloro-phenyl)-amino}-carbonyl-6-deoxy-6-(l-azepanyl)-α-D-mannofuranoside To a solution of a compound obtained from step b above (175mg) in ether (5ml), was added an ethereal solution of hydrochloric acid (2ml). The reaction mixture was stirred for 30 minutes. The solvent was evaporated off under reduced pressure and the residue was dried over high vacuum for l-2hours, followed by triturating it with hexane. The solid thus obtained was filtered and dried to obtain the title compound (175mg).
1H NMR (CDC13, 300 MHz):δ 7.35 (2H, d, 8.7Hz), 7.25 (2H, d, 8.7Hz), 7.14 (IH, bs), 5.19 (IH, bs), 5.00 (IH, s), 4.79 (IH, dd, 3.8Hz, & 1.8Hz), 4.57 (IH, d, 5.8Hz), 4.20 (IH, bs), 3.62 (IH, m), 3.40 (IH, m), 3.11 (IH, d, 14Hz), 2.88-2.74 (5H, m), 1.60-1.56 (8H, m), 1.48 (3H, s), 1.30 (13H, bs), 0.88 (3H, t, 7Hz). Analogues of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}- carbonyl-6-deoxy-6-(l-azepanyl)-α-D-mannofuranoside (Compound No. 44) described below were prepared by replacing appropriate amine in place of azepane and by replacing appropriate sugar moiety in place of l-O-heptyl-2,3-O-isopropylidene-6-tosyl-α-D- mannofuranoside, respectively. l-O-Dodecyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}-carbonyl-6-deoxy-6-(l- azepanyl)-α-D-mannofuranoside (Compound No. 45)
1 -O-Dodecyl-2,3-O-isopropylidene-5-O- {(4-methyl-phenyl)-amino} -carbonyl-6-deoxy-6-(l - azepanyl)-α-D-mannofuranoside (Compound No. 46) Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-(phenylsulfonyl-amino)-carbonyl- 6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 47) 1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [4-methyl-phenyl] -amino} -carbonyl-6-deoxy-6-(l - piperidinyl)-α-D-glucofuranoside (Compound No. 48) 1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [4-chloro-phenyl]-amino} -carbonyl-6-deoxy-6-(l - piperidmyl)-α-D-glucofuranoside (Compound No. 49)
1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [4-methoxy-phenyl]-amino} -carbonyl-6-deoxy-6-(l - piperidinyl)-α-D-glucofuranoside (Compound No. 50)
1 ,2-O-Cyclohexylidene-3 -O-decyl-5-O- {(4-methyl-phenyl)-amino} -carbonyl-6-deoxy-6-( 1 - pynolidinyl)-α-D-allofuranoside (Compound No. 51) Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-methoxy-phenyl)-amino}- carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-mannofuranoside (Compound No. 52) Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-amino}- carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-mannofuranoside (Compound No. 53) Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}- carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-mannofuranoside (Compound No. 54)
Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-nifro-phenyl)-amino}- carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-mannofuranoside (Compound No. 55) Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{[4-methyl-phenyl]-amino}- carbonyl-6-deoxy-6-(l-azepanyl)-α-D-mannofuranoside (Compound No. 56) Hydrochloride salt of l-0-heptyl-2,3-O-isopropylidene-5-O-{(4-methoxy-phenyl)-amino}- carbonyl-6-deoxy-6-(l-azepanyl)-α-D-mannofuranoside (Compound No. 57)
Hydrochloride salt of l-0-heptyl-2,3-O-isopropylidene-5-O-{4-nitro-phenyl)-amino}- carbonyl-6-deoxy-6-(l-azapenyl)-α-D-mannofuranoside (Compound No. 59) 1 ,2-O-Isopropylidene-3-O-dodecyl-5-O- { [4-methyl-phenyl] -amino} -carbonyl-6-deoxy-6-(l - azepanyl)-α-D-glucofuranoside (Compound No. 60)
1 ,2-O-Isopropylidene-3-O-dodecyl-5-O- { [4-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino} - carbonyl-6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 61)
1 ,2-O-Isopropylidene-3-O-dodecyl-5-O- {(4-methoxy-phenyl)-amino} -carbonyl-6-deoxy-6- (1 -azepanyl)-α-D-glucofuranoside (Compound No. 62) l-2-O-Cyclohexylidene-3-O-decyl-5-O-{(4-nitro-phenyl)-amino}-carbonyl-6-deoxy-6-(l- azepanyl)-α-D-glucofuranoside (Compound No. 63) l,2-O-Cyclohexylidene-3-O-decyl-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino}- carbonyl-6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 64) l,2-O-Cyclohexylidene-3-O-decyl-5-O-{(4-methyl-phenyl)-amino}-carbonyl-6-deoxy-6-(l- azepanyl)-α-D-glucofuranoside (Compound No. 65) l,2-O-Cyclohexylidene-3-O-decyl-5-O-[(4-chloro-phenyl)-amino]-carbonyl-6-deoxy-6-(l- azepanyl)-α-D-glucofuranoside (Compound No. 66)
1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [4-(2-methoxy-2-oxo-ethyl)-phenyl]-amino} -carbonyl- 6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 67) l,2-O-Isopropylidene-3-O-decyl-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino}-carbonyl-
6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 68)
1 ,2-O-Isopropylidene-3 -O-decyl-5-O-(4-methoxy-phenyl)-amino } -carbonyl-6-deoxy-6-( 1 - azepanyl)-α-D-glucofuranoside (Compound No. 69) l,2-O-Isopropylidene-3-O-decyl-5-O-(phenylamino)-carbonyl-6-deoxy-6-(l-azepanyl)-α-D- glucofuranoside (Compound No. 70) l,2-O-Cyclohexlidene-3-O-decyl-5-O-{(4-methoxy-phenyl)-amino}-carbonyl-6-deoxy-6-(l- pynolidinyl)-α-D-glucofuranoside (Compound No. 71) l,2-O-Cyclohexylidene-3-O-decyl-5-O-{(4-chloro-phenyl)-amino}-carbonyl-6-deoxy-6-(l- pyrrolidinyl)-α-D-glucofuranoside (Compound No. 72) 1 ,2-O-Cyclohexylidene-3 -O-decyl-5-O- {(4-nifro-phenyl)amino} -carbonyl-6-deoxy-6-( 1 - pyrrolidinyl)-α-D-glucofuranoside (Compound No. 73)
1 ,2-O-Cyclohexylidene-3-O-decyl-5-O- { [4-(2-methoxy-2-oxo-ethyl)-phenyl]-amino} - carbonyl-6-deoxy-6-(l-pynolidinyl)-α-D-glucofuranoside (Compound No. 74) l,2-O-Cyclohexylidene-3-O-decyl-5-O-[(4-{2-hydroxy-2-oxo-ethyl}-phenyl)-amino]- carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 75) l,2-O-Cyclohexylidene-3-O-decyl-5-O-(phenylamino) -carbonyl -6-deoxy-6-(l -pyrrolidinyl)
-α-D-glucofuranoside (Compound No. 76)
Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5-O-{(4-nitro-phenyl)-amino}- carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 77)
Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5-O-{(4-methoxy-phenyl)-amino}- carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 78) Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-amino}- carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 79) Hydrochloride salt of 1 -O-dodecyl-2,3 -O-isopropylidene-5-O- { (4-chloro-phenyl)-amino } - carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 80) Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-{(4-methyl-phenyl)- sulphonylamino]-carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No.
81) Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{(4-methyl-phenyl)- sulphonylamino}-carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No.
82)
Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{(4-methyl-phenyl)- sulphonylamino} -carbonyl-6-deoxy-6-(4-morpholinyl)-α-D-glucofuranoside (Compound No. 83)
Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{(4-methyl-phenyl)- sulphonylamino}-carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No.
84) l-O-Dodecyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-amino}-carbonyl-6-deoxy-6-(4- morpholinyl)-α-D-mannofuranoside (Compound No. 85) l-O-Dodecyl-2,3-O-isopropylidene-5-O-{(4-methoxy-phenyl)-amino}-carbonyl-6-deoxy-6-
(4-morpholinyl)-α-D-mannofuranoside (Compound No. 86)
1 -O-Dodecyl-2,3-O-isopropylidene-5-O- {(4-chloro-phenyl)-amino} -carbonyl-6-deoxy-6-(4- morpholinyl)-α-D-mannofuranoside (Compound No. 87) 1 -O-Dodecyl-2,3-O-isopropylidene-5-O- {(4-nitro-phenyl)-amino} -carbonyl-6-deoxy-6-(4- morpholinyl)-α-D-mannofuranoside (Compound No. 88)
1 -O-Heptyl-2,3 -O-isopropylidene-5-O- {(4-chloro-phenyl)-amino} -carbonyl-6-deoxy-6-( 1 - piperidinyl)-α-D-mannofuranoside (Compound No. 89) l-O-Heptyl-2,3-O-isopropylidene-5-O-{(4-methoxy-phenyl)-amino}-carbonyl-6-deoxy-6-(l- piperidinyl)-α-D-mannofuranoside (Compound No. 90) l-O-Heptyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-amino}-carbonyl-6-deoxy-6-(l- piperidinyl)-α-D-mannofuranoside (Compound No. 91)
1 -O-Heptyl-2,3 -O-isopropylidene-5-O- {(4-nitro-phenyl)-amino} -carbonyl-6-deoxy-6-( 1 - piperidinyl)-α-D-mannofuranoside (Compound No. 92) l-O-Dodecyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-sulfonylamino}-carbonyl-6- deoxy-6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 93) l-O-Heptyl-2,3-O-isopropylidene-5-O-[(4-methyl-phenyl)-sulfonylamino]-carbonyl-6-deoxy-
6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 94) l-O-Heptyl-2,3-O-isopropylidene-5-O-[(4-methyl-phenyl)-sulfonylamino}-carbonyl-6-deoxy- 6-(4-morpholinyl)-α-D-mannofuranoside (Compound No. 95) l-O-Heptyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-amino}-carbonyl-6-deoxy-6-(4- morpholinyl)-α-D-mannofuranoside (Compound No. 96) l-O-Heptyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}-carbonyl-6-deoxy-6-(4- mo holinyl)-α-D-mannofuranoside (Compound No. 97) l-O-Heptyl-2,3-O-isopropylidene-5-O-{(4-nitro-phenyl)-amino)-carbonyl-6-deoxy-6-(4- moφholinyl)-α-D-mannofuranoside (Compound No. 98)
1 -O-Decyl-2,3-O-isopropylidene-5-O- {(4-chloro-phenyl)-amino} -carbonyl-6-deoxy-6-( 1- piperidinyl)-α-D-mannofuranoside (Compound No. 99) l-O-Heptyl-2,3-O-isopropylidene-5-O-[(4-methoxy-phenyl)-amino]-carbonyl-6-deoxy-6-(4- morpholinyl)-α-D-mannofuranoside (Compound No. 100) Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-{(4-methyl-phenyl)- sulfonylamino}-carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No.
101)
Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-{(4-chloro-phenyl)- sulfonylamino}-carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No.
102)
Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-(phenyl-sulfonylamino)-carbonyl-
6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 103)
Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{(4-methyl-phenyl)- sulfonylamino}-carbonyl-6-deoxy-6-(l-pynolidinyl)-α-D-glucofuranoside (Compound No.104)
Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{(4-methyl-phenyl)- sulfonylamino}-carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No. 105) Hydrochloride salt of 1 ,2-O-isopropylidene-3 -O-dodecyl-5-O-φhenyl-sulfonylamino)- carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No. 106) Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-{4-chloro-phenyl)- sulfonylamino}-carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No. 107) Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-[(4-chloro-phenyl)- sulfonylamino}-carbonyl-6-deoxy-(l-azepanyl)-α-D-glucofuranoside (Compound No. 108) Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-(4-methyl-phenyl)- sulfonylamino}-carbonyl-6-deoxy-(l-azepanyl)-α-D-glucofuranoside (Compound No. 109) Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-(phenylsulfonylamino)-carbonyl- 6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 110)
Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-(phenylsulfonylamino)-carbonyl- 6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No. I l l)
Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-(phenylsulfonylamino)-carbonyl- 6-deoxy-6-(4-morpholinyl)-α-D-glucofuranoside (Compound No. 112) Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{ [(4-chloro-phenyl)- sulfonylamino]-carbonyl} -6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 113)
Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O- {(phenyl sulfonylamino)- carbonyl} -6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 114)
Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{[(4-methyl-phenyl)-amino]- carbonyl}-6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 115) Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-{[(4-chloro-phenyl)- sulfonylamino] -carbonyl} -6-deoxy-6-(4-morpholinyl)-α-D-glucofuranoside (Compound No. 116)
Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{[(4-chloro-phenyl)- sulfonylamino]-carbonyl} -6-deoxy-6-(4-morpholinyl)-α-D-glucofuranoside (Compound No.
117)
Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{[(4-chloro-phenyl)- sulfonylamino]-carbonyl} -6-deoxy-6-(4-morpholinyl)-α-D-glucofuranoside (Compound No. 118)
Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-{(phenylsulfonylamino)- carbonyl}-6-deoxy-6-(4-morpholinyl)-α-D-glucofuranoside (Compound No. 119) Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O- {(4-methyl-phenyl sulfonylamino)-carbonyl} -6-deoxy-6-(4-morpholinyl)-α-D-glucofuranoside (Compound No. 120)
Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-(phenyl-sulfonylamino)-carbonyl- 6-deoxy-6-(4-moφholinyl)-α-D-glucofuranoside (Compound No. 121) 1 ,2-O-Isopropylidene-5-O- { [4-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino} -carbonyl-6-deoxy-6- [l-azepanyl]-α-D-glucofuranoside (Compound No. 125)
1 ,2-O-Isopropylidene-3-O-dodecyl-5-O- {(4-nitro-phenyl)-amino} -carbonyl-6-deoxy-6-(l - azepanyl)-α-D-glucofuranoside (Compound No. 126)
1 ,2-O-Isopropylidene-3-O-dodecyl-5-O- { [4-(2-methoxy-2-oxo-ethyl)-phenyl)-amino} - carbonyl-6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 127) l,2-O-Isopropylidene-3-O-dodecyl-5-O-(phenyl-amino)-carbonyl-6-deoxy-6-(l-azepanyl)-α-
D-glucofuranoside (Compound No. 128)
Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{[4-methyl-phenyl)- sulfonylamino}-carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-allofuranoside (Compound No. 129)
Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-[(4-methyl-phenyl)- sulfonylamino]-carbonyl-6-deoxy-6-(4-moφholinyl)-α-D-allofuranoside (Compound No.
130)
Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-[(4-methyl-phenyl)- sulfonylamino]-carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-allofuranoside (Compound No. 131) Tris salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]- amino}-carbonyl-6-deoxy-6-(4-moφholinyl)-α-D-glucofuranoside (Compound No. 132) Tris salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]- amino}-carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No. 133) Tris salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]- amino}-carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 134) Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{(phenyl-sulfonylamino)- carbonyl}-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No. 135) Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{(phenyl sulfonylamino)- carbonyl} -6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 136)
1 -O-Dodecyl-2,3-O-isopropylidene-5-O- {(4-methyl-phenyl)-sulfonylamino} -carbonyl-6- deoxy-6-(4-moφholinyl)-α-D-mannofuranoside (Compound No. 203). Example 15: Synthesis of Tris salt of 1.2-O-isopropylidene-5-O-|[4-(2-hydroxy-2-oxo- ethyl)-phenyl1-amino}-carbonyl-6-deoxy-6-ri-piperidinyl]-α-D-glucofuranoside (Compound No. 12)
Step a: Synthesis of l,2,5,6-di-O-isopropylidine-3-O-{(methylthio)-thio-carbonyl}-α-D- glucofuranoside To a solution of diacetoneglucose (2.6g) and imidazole (lOmg) in tetrahydrofuran (50ml), was added sodium hydride over a period of 10 minutes. The reaction mixture was stirred at room temperature for 30 minutes followed by cooling it to 0°C. To the reaction mixture was added carbon disulphide (2.28g) and methyl iodide and stirred for 30 minutes at room temperature. The reaction mixture was diluted with acetic acid (2 ml) and cold water
(5ml). Solvents were evaporated off under reduced pressure. The residue thus obtained was taken in ethyl acetate, washed with water, dried over anhydrous sodium sulphate and concentrated. The crude compound was purified by column chromatography using 10% ethyl acetate in hexane as eluent to obtain the title compound (1.5g).
Step b: Synthesis of l,2,5,6-di-O-isopropylidene-3-deoxy-α-D-glucofuranoside A mixture of the compound obtained from step a above (300 mg, 0.97 mmol) and tri butyl tin hydride (291.01mg, 0.97 mmol) was refluxed for 3-4 hours in toluene (20ml) and the reaction mixture was stirred till completion (TLC). The solvent was evaporated off under reduced pressure and the residue was taken in ethyl acetate (20 ml), washed with water, dried over anhydrous sodium sulphate and concentrated. The crude compound was purified by column chromatography using 10-20% ethyl acetate in hexane as eluent to obtain the title compound (180 mg). Step c: Synthesis of l,2-O-isopropylidene-3~deoxy-α-D-glucofuranoside To a cooled solution of the compound obtained from step b above (12g) in tetrahydrofuran, was slowly added perchloric acid (30%, 12 ml) and the reaction mixture was stirred for 7-8 hours at 0-5°C. The reaction mixture was neutralized using saturated solution of potassium carbonate and filtered. The filterate thus obtained was concenfrated under reduced pressure and the residue was exfracted with ethyl acetate (50 ml), washed with water, dried over anhydrous sodium sulphate and concentrated to furnish the title compound (7g). Step d: Synthesis of l,2-O~isopropyliene-3-deoxy-5-O-(4-toluenesulfonyl)-α-D- glucofuranoside To a solution of the compound obtained from step c above (7g, 0.034mol) in pyridine (50 ml), was added a solution of p-toluenesulphonyl chloride (7.2g, 0.0377 mmol) in pyridine (10ml). The reaction mixture was st rred for 7-8 hours at 0-5°C. The solvent was evaporated off under reduced pressure and the residue was extracted with dichloromethane (40 ml), washed with water and dried over anhydrous sodium sulphate and concentrated. The crude compound was purified by column chromatography using 10-20% ethyl acetate as eluent to furnish the title compound (8g). Step e: Synthesis of l,2-O-isopropylidene-3,6-dideoxy-6-(l-piperidinyι)-α-D- glucofuranoside A mixture of the compound obtained from step d above (500mg, 1.39 mmol) and piperidine (0.5 ml, 4.4 mmol)) was stirred at 90°C for 7-8 hours. Excess of piperidine was removed under reduced pressure and the residue was triturated with ether. The solid thus obtained was filtered and the filterate was washed with water, sodium bicarbonate and brine. The organic layer was concenfrated to furnish the title compound (440mg). Step f: Synthesis of l,2-O-isopropylidene-3,6-dideoxy-5-O-{[4-(2-methoxy-2-oxo-ethyl)- phenyl]-carbonyl}-6-(l-piperidinyl)-α-D-glucofuranoside To a cooled solution of the compound obtained from step e above (1.4 mmol) in dichloromethane (10ml), was added 4-isocyanatophenylacetic acid methyl ester (1.4 mmol) and stirred for 15 minutes. The organic layer was washed with sodium bicarbonate solution (2x3 ml), water and then dried over sodium sulphate. The organic layer was concentrated to obtain the title compound (400 mg). Step g: Synthesis of l,2-O-isopropylidene-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]- amino}-carbonyl-6-deoxy-6-[l-piperidinyl]-α-D-glucofuranoside To a solution of the compound obtained from step /"above (320 mg, 6.9 mmol) in methanol (10 ml), was added lithium hydroxide (2 ml, IN) and stirred for overnight at room temperature. The solvent was evaporated off under reduced pressure and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and concentrated. The residue thus obtained was triturated with hexane to furnish the title compound (200 mg).
Step h: Synthesis of Tris salt of l,2-0~isopropylidene-5-O-{[4-(2-hydroxy-2-oxo-ethyl)- phenyl]-amino}-carbonyl-6-deoxy-6-[l-piperidinyI]-α-D-glucofuranoside (Compound No. 124). To a solution of the compound obtained from step g above (280 mg, 6 mmol) in ethanol (10 ml), was added tris(hydroxymethyl)aminomethane (73 mg, 6 mmol) and few drops of water. The reaction mixture was stirred for 30-40 minutes. The solvents were evaporated off and the residue was dried under reduced pressure to furnish the title compound (180 mg). 1HNMR (DMSO, 300 MHz):δ 9.46 (IH, bs), 7.32 (2H, d, 8Hz), 7.10 (2H, d, 8Hz), 5,.73
(IH, bs), 5.05 (IH, bs), 4.72 (IH, bs), 4.20 (2H, m), 3.27 (10H, s), 2.48-2.32 (6H, m), 2.07
(2H, s), 1.98-1.8 (2H m), 1.42-1.15 (11H, m), 0.82 (lH, bs). Analogues of Tris salt of l,2-O-isopropylidene-5-O-{[4-(2-hydroxy-2-oxo-ethyl)- phenyl]-amino}-carbonyl-6-deoxy-6-[l-piperidinyl]-α-D-glucofuranoside (Compound
No.124) described below were prepared by using appropriate amine in place of piperidine, respectively as applicable in each case.
Tris salt of l,2-O-isopropylidene-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino}-carbonyl-
6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 122) Tris salt of 1 ,2-O-isopropylidene-5-O- { [4-(2-hydroxy-2-oxo-ethyl)-phenyl] -amino} -carbonyl- 6-deoxy-6-[4-moφholinyl]-α-D-glucofuranoside (Compound No. 123). Scheme III
Example 16: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5.6-dideoxy-5-(2-r4-{3-(2- methyl-phenyl)-ureido-phenyl]-acetyl| -amino-β-L-gulofuranoside (Compound No. 137) To a solution of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-amino-α-L- gulofuranoside (100 mg, 0.27 mmol) in dimethylformamide at 0°C, was added N-methyl moφholine (33 mg, 0.32 mmol), hydroxybenzotriazole (41 mg, 0.3 mmole) and 4-(3-phenyl- ureido)-phenyl acetic acid (77mg, 0.32mmol). The reaction mixture was stirred for about 15- 20 minutes followed by the addition of l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.58mg, 0.3 mmol). The reaction mixture was stirred at the same temperature for about 30 minutes before allowing it to gradually warm at room temperature. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was diluted with ethyl acetate and washed thoroughly with water. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvents were evaporated off and the residue thus obtained was purified by column chromatography using 20-60% ethyl acetate in hexane as eluent to yield the title compound (174 mg).
1H NMR (CDC13, 300 MHz):δ 7.55 (IH, d, 7.7Hz), 7.26-7.10 (7H, m), 6.81 (IH, bs, NH), 6.50 (IH, bs), 5.75 (IH, bs, NH), 4.93 (IH, s), 4.61 (IH, bs), 4.52 (IH, d, 5.9Hz), 4.30 (IH, m), 3.74 (IH, dd, 3.4 & 5.8Hz), 3.48 (3H, bs), 3.32 (IH, m), 2.28 (3H, s), 1.41 (3H, s), 1.25
(26H, bs), 0.87 (3H, t, 6.5Hz). Analogues of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{2-[4-{3-(2-methyl- phenyl)-ureido}-phenyl]-acetyl-amino-β-L-gulofuranoside (Compound o. 137) described below were prepared by replacing the appropriate acid in place of 4-(3 -phenyl ureido)-phenyl) acetic acid, respectively and appropriate sugar moiety in place of 1 -O-dodecyl-2,3 -O- isoproplidene-5,6-dideoxy-5-amino-β-L-gulofuranoside.
1 ,2-O-Isopropylidine-3 -O-benzyl-5-deoxy-5- {2-[(4- {2-(4-methyl-phenyl-sulfonylamino)- thiazolyl}-acetyl]-amino-α-D-xylofuranoside (Compound 138) l,2-O-Isopropylidene-3-O-[3-phenyl-propyl]-5-deoxy-5-{2-[4-(2-phenylsulfonylamino)- thiazolyl]-acetyl}-amino-α-D-xylofuranoside (Compound 139) l,2-O-Isopropylidene-3-O-benzyl-5-deoxy-5-{2-[4-(2-phenylsulfonylamino)-thiazolyl]- acetyl} -amino-α-D-xylofuranoside (Compound 140) l,2-O-Isopropylidene-3-O-(3-phenyl-propyl)-5-deoxy-{2-[4-(2-methylsulfonylamino)- thiazolyl]-acetyl} -amino-α-D-xylofuranoside (Compound No .141) l,2-O-Isopropylidene-3-O-benzyl-5-deoxy-{2-[4-(2-methylsulfonylamino)-thiazolyl]-acetyl}- amino-α-D-xylofuranoside (Compound No . 142) l,2-O-Isopropylidene-3-O-(3-phenyl-propyl)-5-deoxy-5-{2-[4-(2-[4-methyl-phenyl]- sulfonylamino)-thiazolyl]-acetyl} -amino-α-D-xylofuranoside (Compound No. 143). Example 17: Synthesis of 1.2-O-Isopropylidene-3-O-benzyl-6-deoxy-6-[(3,4-dimethoxy- phenyl)-carbonyl]-amino-α-D-glucofuranoside (Compound No. 144) To a compound l,2-O-isopropylidene-3-O-benzyl-6-deoxy-6-amino-α-D- glucofuranoside (1.25 g, 2.92 mmol) in ethyl acetate (25 ml), was added 3,4-dimethoxy benzoic acid (0.531 g, 1 mmol). The reaction mixture was stirred at 0°C in an ice bath followed by the addition of triethylamine (0.447 ml, 1.1 mmol), hydroxybenzotriazole (0.536 g, 3.5 mmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.616g, 3.21mmol). The reaction mixture was stirred at 0°C for 3 hours and at room temperature for 33 hours. The organic layer was washed with hydrochloric acid solution (10%), water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude organic compound thus obtained was purified by column chromatography to furnish the title compound (0.725 g).
1H NMR (CDC13, 300 MHz):δ 7.41-7.26 (7H, m), 6.87 (IH, d, 8.3Hz), 6.66 (IH, bs), 5.93
(IH, d, 3.63Hz), 4.69-4.60 (3H, m), 4.24 (IH, bs), 4.13 (3H, m), 3.93 (7H, s), 3.76 (IH, m), 1.42 (3H, s), 1.31 (3H, s). Analogues of l,2-O-Isopropylidene-3-O-benzyl-6-deoxy-6-[(3,4-dimethoxy-phenyl)- carbonyl]-amino-α-D-glucofuranoside (Compound No. 144) described below were prepared by replacing appropriate acid in place of 3,4-dimethoxybenzoic acid and appropriate sugar moiety in place of l,2-O-isopropylidene-3-O-benzyl-6-deoxy-6-amino-α-D-glucofuranoside, respectively, as applicable in each case.
1 ,2-O-Isopropylidene-3-O-benzyl-6-deoxy-6- { [(4-chloro-phenyl)-carbonyl]-amino} -α-D- glucofuranoside (Compound No. 145) l,2-O-Isopropylidene-3-O-(3-phenyl-propyl)-6-deoxy-6-{(3,4-dimethoxy-phenyl)-carbonyl}- amino-α-D-glucofuranoside (Compound No. 146) l,2-O-Isopropylidene-3-O-[3-phenyl-propyl]-6-deoxy-6-{(4-chloro-phenyl)-carbonyl}- amino-α-D-glucofuranoside (Compound No. 147).
Example 18 : Synthesis of 1 ,2-O-isopropylidene-3 -O-benzyl-5-O-benzyl-6-deoxy-6- { [3 A- dimethoxy-phenyll-carbonyl-amino-α-D-glucofuranoside (Compound No. 148) To a solution of l,2-O-isopropylidene-3-O-benzyl-6-deoxy-6-amino-α-D- glucofuranoside (0.482g, 2.65 mmole) in ethyl acetate (25 ml), was added 3,4-dimethoxy benzoic acid (0.482 g, 2.65 mmole). The reaction mixture was stirred at 0°C followed by the addition of triethylamine (0.5 ml), hydroxybenzotriazole (3.18 mole) and l-(3-dimethylamino propyl)-3-ethylcarbodiimide (0.599g, 2.915 mole). The reaction mixture was stirred at 0°C for 3 hours followed by stirring at room temperature for 33 hours. The organic layer was washed with hydrochloric acid solution (10%), water, saturated sodium bicarbonate and finally with brine. The organic layer was dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 30% ethyl acetate in hexane as eluent to obtainthe title compound (0.9 g). 1H NMR (CDC13, 300 MHz):δ 7.26 (12H, s), 6.83 (IH, d, 8.4Hz), 6.66 (IH, bs), 5.96 (IH, d,
3.7Hz), 4.77 (IH, d, 11.2Hz), 4.64 (2H, d, 11.3Hz), 4.48 (IH, d, 10.9Hz), 4.25 (IH, d, 3Hz),
4.12 (lH,d, 3Hz), 3.98 (2H, m), 3.92 (6H, s), 3.76 (IH, m), 1.49 (3H, s), 1.26 (3H, s). Analogues of l,2-O-isopropylidene-3-O-benzyl-5-O-benzyl-6-deoxy-6-{[3,4- dimethoxy-phenyl]-carbonyl}-amino-α-D-glucofuranoside (Compound No. 148) described below can be prepared by replacing appropriate acid in place of 3,4-dimethoxy benzoic acid and appropriate sugar moiety in place of l,2-O-isopropylidene-3-O-benzyl-6-deoxy-6-amino- α-D-glucofuranoside, respectively.
1 ,2-O-Isopropylidene-3-O-benzyl-5-O-benzyl-6-deoxy-6- { [(4-chloro-phenyl)-carbonyl]- amino} -α-D-glucofuranoside (Compound No. 149) l,2-O-Isopropylidene-3-O-[3-phenyl-propyl]-5-O-benzyl-6-deoxy-6-{(4-chloro-phenyl)- carbonyl} -amino-α-D-glucofuranoside (Compound No. 150) l,2-O-Isopropylidene-3,5-bis-O-(3-phenyl-propyl)-6-deoxy-6-[(4-chloro-phenyl)-carbonyl]- amino-α-D-glucofuranoside (Compound No. 151) l,2-O-Isopropylidene-3-O-(3-phenyl-propyl)-5-O-benzyl-6-deoxy-6-[(3,4-dimethoxy- phenyl)-carbonyl]-amino-α-D-glucofuranoside (Compound No. 152) l,2-O-Isopropylidene-3,5-bis-O-(3-phenyl-propyl)-6-deoxy-6-[(3,4-dimethoxy-phenyl)- carbonyl]-amino-α-D-glucofuranoside (Compound No. 153) l,2-O-Isopropylidene-3-O-benzyl-5-O-(3-phenyl-propyl)-6-deoxy-6-[(3,4-dimethoxy- phenyl)-carbonyl]-amino-α-D-glucofuranoside (Compound No. 154).
Example 19: Synthesis of 2-O-isopropylidene-3-O-heptyl-5-deoxy-5-((4-methyl-phenyl)- sulfonylamino}-α-D-xylofuranoside (Compound No. 155) To a solution of l,2-O-isopropylidene-3-O-heptyl-5-amino-α-D-xylofuranoside (1 g) in pyridine (5 ml) at 0-5°C, was added tert-butyl-benzenesulphonyl chloride (0.82 g) in small fraction with continuous stirring. The reaction mixture was allowed to attain room temperature. After 8 hours, the reaction mixture was diluted with water and the solvents were evaporated off under reduced pressure. The crude product was purified by column chromatography using 15% ethyl acetate in hexane as eluent to obtain the title compound
(350 mg). Analogues of l,2-O-isopropylidene-3-O-heptyl-5-deoxy-5- {(4-methyl-phenyl)- sulfonylamino}-α-D-xylofuranoside (Compound No. 155) described below can be prepared by replacing appropriate sulphonyl halide group in place of p-toluene sulphonyl chloride and appropriate sugar moiety in place of l,2-O-isopropylidene-3-O-heptyl-5-amino xylofuranoside, respectively.
1 ,2-O-Isopropylidene-3-O-heptyl-5-deoxy-5- {(4-tert-butyl-phenyl)-sulfonylamino} -α-D- xylofuranoside (Compound No. 156)
1 ,2-O-Isopropylidene-3-O-pentyl-5-deoxy-5- { [ {4-methoxy-3 -(5- { 1 -methyl-3 -propyl-7-oxo-
1 ,6-dihydro-pyrazolo[4,3 -d]pyrimidinyl} -phenyl)} -sulfonyl]-amino} -α-D-xylofuranoside (Compound No. 157).
Example 20: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{4-methyl- phenyl}-sulphonyl|-amino-β-L-gulofuranoside (Compound No. 188) To a solution of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-amino-α-L- gulofuranoside (200 mg, 0.54 mmol) in dry dichloromethane (3 ml) at 0°C, was added of p- toluenesulphonyl chloride (103mg, 0.54 mmole) and triethylamine (0.08 ml, 0.59 mmole). The reaction mixture was gradually warmed to room temperature for 2 hours. The reaction mixture was diluted with water (approx. 10 ml) and exfracted with dichloromethane. The combined organic extracts were washed with brine and dried over anhydrous sodium sulphate. The solvents were evaporated off and the residue thus obtained was purified by column chromatography using 15% ethyl acetate in hexane as eluent to furnish the title compound (280 mg).
1H NMR (CDC13, 300 MHz):δ 7.78 (2H, d, J=8.2Hz) & 7.28 (2H, d, J=7.6Hz) [aromatic], 4.90 (IH, bs, NH), 4.81 (1Η, s, Η-l), 4.60 (IH, dd, J=5.76 and 3.5Hz, H-3), 4.50 (IH, d, J=5.9Hz, H-2), 3.68 (IH, dd, J=3.48Hz, H-4), 3.52 (2H, m) & 3.30 (IH, m) [OCH2 and CH- N], 2.41 (3Η, s, Ar-CH3), 1.48 (2Η, m, OCH2CH2), 1.26 (bs), 1.23 (s) & 1.20 (s) [27Η, CH3CH, CCH3x2 and CH2x9] and 0.88 (3Η, t, J=6.3Hz, terminal CH3). Analogues of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{4-methyl-phenyl}- sulphonyl}-amino-β-L-gulofuranoside (Compound No. 188) described below can be prepared by replacing appropriate sulphonyl halide in place of p-toluene sulphonyl chloride and appropriate sugar moiety in place of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- amino-β-L-gulofuranoside, respectively, as applicable in each case. l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{ethylsulphonyl}-amino-β-L- gulofuranoside (Compound No. 189) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {4-fluoro-phenyl)-sulphonyl} -amino-β-L- gulofuranoside (Compound No. 190) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(4-acetamido)-phenyl]-sulphonyl}- amino-β-L-gulofuranoside (Compound No. 191). Example 21: Synthesis of l-O-dodecyl-2,3-O-isopropyridene-5,6-dideoxy-5- 1(3.4,5- trimethoxy-phenvD-carbonylj amino-β-L-gulofuranoside (Compound No. 192) To a solution of the compound l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- amino-α-L-gulofuranoside (200mg, 0.54 mmole) in dichloromethane (4 ml) at 0°C, was added 3,4,5-trimethoxybenzoyl chloride (137 mg, 0.54 mmole) and triethylamine (0.08 ml, 0.59 mmole). The reaction mixture was stirred at 0°C for 3 hours. The reaction was quenched with water and the product was extracted with dichloromethane. The combined organic extracts were washed with brine and dried over anhydrous sodium sulphate. The solvents were evaporated and the residue thus obtained was purified by column chromatography using (40%) ethyl acetate in hexane as eluent to obtain the title compound (200 mg). 1H NMR (CDC13, 300 MHz):δ 7.00 (2H, s, aromatic), 6.38 (IH, d, NH), 5.03 (1Η, s, Η-l), 4.73 (IH, dd, J=6.6 and 3.6Hz, H-3), 4.59 (IH, d, J=5.7Hz, H-2), 4.49 (IH, q, J=6.6Hz, CH- N), 3.99 (IH, dd, J=6 & 3.3Hz, H-4), 3.90 (s) & 3.88 (s) [9H OCH3x3], 3.61 (1Η, dt, J=9.6 and 2.7Ηz), & 3.41 (IH, dt, J=6.6 and 3Hz) [OCH2], 1.55 (2Η, t, JM6H, OCH2CH2), 1.41 (3Η, d, J=6.6Hz, CH3CH), 1.38 (3H, s, CCH3), 1.29 (bs) & 1.25 (bs) [21Η, CH2x4 and CCH3] and 0.88 (3Η, t, J=6Hz, terminal CH3). Analogues of 1 -O-dodecyl-2,3 -O-isopropylidene-5,6-dideoxy-5- { (3,4,5 -trimethoxy- phenyl)-carbonyl}amino-α-L-gulofuranoside (Compound No. 192) described below were prepared by replacing appropriate acyl halide in place of 3,4,5 -trimethoxy benzoyl chloride and appropriate sugar moiety in place l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- amino-α-L-gulofuranoside, respectively. 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {(2-fluoro-phenyl)-carbonyl} -amino-β-L- gulofuranoside (Compound No. 193)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {4-ethoxy-4-oxo-butanoyl} -amino-β-L- gulofuranoside l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{4-hydroxy-4-oxo-butanoyl}-amino-β-L- gulofuranoside (Compound No. 195).
Example 22: Synthesis of l-O-dodecyl-2.3-O-isopropylidene-5.6-dideoxy-5-{[3-(3.4- methylenedioxy-phenyl)-propionyll-amino-β-L-gulofuranoside (Compound No. 197) To a solution of l-0-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-amino-α-L- gulofuranoside (200 mg, 0.54 mmole) in dimethylformamide (6 ml) at 0°C, were added 3,4- methylenedioxy phenylpropionic acid (105 mg, 0.54 mmol), 1 -hydroxybenzotriazole (80 mg, 0.59 mmol) and N-methylmoφholine (0.15 ml, 1.35 mmole). The reaction mixture was stirred at 0°C for 20 minutes followed by the addition of l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (113 mg, 0.59 mmol). The reaction mixture was gradually allowed to warm for room temperature and stirred for overnight. The reaction mixture was diluted with water and the compound was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous sodium sulphate. The solvents were evaporated off and the residue thus obtained was purified by column chromatography using 30% ethyl acetate in hexane as eluent to obatin the title compound (250 mg). 1H NMR (CDC13, 300 MHz):δ 6.60-6.75 (3H, m, aromatic), 5.91 (2H, s), OCH2O), 5.62 (1Η, d, NH), 4.97 (1Η, s, Η-l), 4.61 (IH, t, J=3Hz, H-3), 4.54 (IH, d, J=6Hz, H-2), 4.30 (IH, q, J=6H, CH-N), 3.80 (IH, dd, J=6 and 3Hz, H-4), 3.56 (IH, q, J=9Hz) & 3.37 (IH, q, J=9Hz) [OCH2], 2.89 (2Η, t, J=9Hz, CH2CO), 2.41 (2Η, m, CH2Ar), 1.51 (2Η, t, J=6Hz, OCH2CH2), 1.43 (3Η, s, CCH3), 1.28 (s), 1.25 (bs) &1.23 (s) [24Η, CH2x9, CH2CΗ and CCH3] and 0.88 (3Η, t, J=6Hz, terminal CH3). Analogues of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[3-(3,4- methylenedioxy-phenyl)-propionyl-amino-β-L-gulofuranoside (Compound No. 197) described below were prepared by replacing appropriate acid in place of 3,4- methylenedioxyphenylpropionic acid and appropriate sugar moiety in place of 1-O-dodecyl- 2,3-O-isopropylidene-5,6-dideoxy-5-amino-β-L-gulofuranoside, respectively, as applicable in each case.
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {2-phenyl-ethenyl)-carbonyl} -amino-β-L- gulofuranoside (Compound No. 198) 1 -O-Dodecyl-2,3 -O-isopropylidene-5,6-dideoxy-5- {2-(3 ,4-methylenedioxy-phenyl)-acetyl} - amino-β-L-gulofuranoside (Compound No. 199) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(4-fluoro-benzyl)-carbonyl}-amino-β-L- gulofuranoside (Compound No. 200) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{2-(3,4-methylenedioxy-phenyl)ethenyl}- carbonyl}amino-β-L-gulofuranoside (Compound No. 201).
Scheme IN, Path a
Example 23: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-{l-r4-ir4-(2- methoxy-2-oxo-ethyl)-phenyl]-aminol-carbonyl1-piperazmyl|-α-D-lyxofuranoside
(Compound No. 159) Step a: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-tosyl-α-D-lyxofuranoside The mixture of a compound l-0-dodecyl-2,3-O-isopropylidene-5-tosyl-α,D- lyxofuranoside (synthesised following the procedure as descried in U.S. Patent No.
5,367,062) (10 g) and N-benzylpiperazine (10ml) was' heated at 80-90°C for 7-8 hours. The reaction mixture was triturated with ether and filtered. The filtrate was washed with water, and brine. The ethanol layer was dried over anhydrous sodium sulphate and finally concentrated to obtain the title compound (12g).
Step b: Synthesis of l-O-dodecyl-2,3-0-isopropylidene-5-deoxy-5-piperazinyl-α-D- lyxofuranoside To a solution of the compound obtained from step a above (12 g) in methanol (60 ml), was added palladium on carbon (6 g, 50% by wt.) and ammonium formate (3 g). The reaction mixture was refluxed for 30 minutes. The reaction mixture was filtered over celite pad and the filtrate was concentrated. The residue thus obtained was washed in dichloromethane and washed with water and brine. The dichloromethane layer was dried over sodium sulphate and concentrated to furnish the desired product (8g). Step c: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-{l-[4-{[4-(2-methoxy-
2-oxo-ethyl)-phenyl]-amino}-carbonyl]-piperazinyl}-α-D-lyxofuranoside To a cooled solution of the compound obtained from step b above (7.5 g, 3.52xl0"3 mol) in dichloromethane (20 ml), was slowly added a solution of 4-isocyanato phenyl acetic acid methyl ester (732 mg, 3.87mmol) and stirred for 30 minutes. The reaction mixture was washed with water and brine and dried over anhydrous sodium sulphate. The dichloromethane layer was concenfrated and the residue thus obtained was purified by column chromatography to obtain a title compound (3g).
1H NMR (CDCI3) 300 MHz.δ: 8.7 (4H, m), 6.29 (IH, s, NH), 5.0 (IH, s), 4.68 (IH, d, J=3Hz), 4.5 (1, d, J=3Hz), 4.13 (IH, d, J=3Hz), 3.68 (3H, s), 3.62-3.52 (8H, ), 2.77-2.56
(6H, m), 1.56 (2H, s), 1.45 (3H, s), 1.31-1.26 (21, m), 0.87 (3H, t, J=6Hz)
Mass (M/Z): 618.7 (M++1). Analogues of l-O-dodecyl-2,3-0-isopropylidene-5-deoxy-5-{l-[4-{[4-(2-methoxy-2- oxo-ethyl)-phenyl]-amino}-carbonyl]-piperazinyl}-α-D-lyxofuranoside (Compound No. 159) described below were prepared by replacing appropriate isocyanate group in place of 4- isocyanato phenyl acetic acid methyl ester and appropriate sugar moiety in place of l-O- dodecyl-2,3-O-isopropylidene-5-tosyl-α,D-lyxofuranoside. l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-{l-[4-(4-chloro-phenylamino)-carbonyl]- piperazinyl}-α-D-lyxofuranoside (Compound No. 160) 1 -O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- { 1 -[4- {(4-methylphenyl)-amino} -carbonyl]- piperazinyl}-α-D-lyxofuranoside (Compound No. 161)
1 -O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- { 1 -[4- {(4-methoxy-phenyl)-amino} -carbonyl]- piperazinyl}-α-D-lyxofuranoside (Compound No. 162) l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- { 1 -[4- {(4-nitrophenyl)-amino} -carbonyl]- piperazinyl}-α-D-lyxofuranoside (Compound No. 163)
1 -O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- { 1 -[4- {(4-chlorophenyl)-sulfonylamino} - carbonyl]-piperazinyl}-α-D-lyxofuranoside (Compound No. 164) l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-{l-[4-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]- amino}-carbonyl]-piperazinyl}-α-D-lyxofuranoside (Compound No. 165) 1 -0-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- { 1 -[4-(4-tolylsulfonylamino)-carbonyl]- piperazinyl}-α-D-lyxofuranoside (Compound No. 166)
Example 24: Synthesis of hydrochloride salt of 1.2-O-dodecyl-3.4-O-isopropylidene-5.6- dideoxy-5-{l-(4-[(4-methyl-phenyl)-amino]-carbonyl)-piperazinyl|-β-L-gulofuranoside (Compound No. 167)
Step a: Synthesis of l,2-O-dodecyI~3,4-0-isopropylidene-5,6-dideoxy-5-{l-(4-[(4-methyl- phenyl)-amino]-carbonyl)-piperazinyl}-β-L-gulofuranoside The title compound was prepared following the procedure as described for the synthesis of Compound No. 159 by using l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- piperaziny-α-L-gulofuranoside (300mg, 0.68mmole) in place of 1 -O-dodecyl-2,3 -O- isopropylidene-5-deoxy-5-piperazinyl-α,D-lyxofuranoside and using p-tolyl isocyanate
(99mg, 0.75mmol) in place of 4-isocyanatophenylacetic acid methyl ester to furnish the title compound (150mg). Step b: Synthesis of hydrochloride salt of l,2-O-dodecyl-3,4-O-isopropylidene- 5,6-dideoxy-5-{l-(4-[(4-methyI-phenyl)-amino]-carbonyl)-piperazinyl}-β-L- gulofuranoside The title compound was prepared following the procedure described in step c of
Example 12, by using compound of step a in place of l-O-heptyl-2,3-O-isopropylidene-5-O-
{(4-chloro-phenyl)-amino}-carbonyl-6-deoxy-6-(l-azepanyl)-α-D-mannofuranoside. 1HNMR (DMSO, 300 MHz):δ 8.71 (IH, bs), 7.32 (2H, d, 8.3Hz), 7.04 (2H, d, 8.3Hz), 5.06
(IH, bs), 4.85 (IH, bs), 4.58 (IH, d, 5.5Hz), 4.25 (2H, bs), 4.11 (2H, bs), 3.64-3.39 (6H, m),
3.25 (2H, bs), 2.22 (3H, s), 1.46-1.22 (29H, m), 0.85 (3H, t, 6.7Hz). Analogues of hydrochloride salt of l,2-O-dodecyl-3,4-O-isopropylidene-5,6-dideoxy-
5- { 1 -(4-[(4-methyl-phenyl)-amino]-carbonyl)-piperazinyl} -β-L-gulofuranoside (Compound No. 167) described below were prepared by replacing appropriate isocyanate in place of p- tolyl isocyanate and appropriate sugar moiety in place of 1 -O-dodecyl-2,3 -O-isopropylidene-
5-toxyl-6-deoxy-β-L-gulofuranoside, respectively.
Tris salt of l-O-dodecyl-3,4-O-isopropylidene-5,6-dideoxy-5-{l-(4-[(4-{2-hydroxy-2-oxo- ethyl}-phenyl)-amino]-carbonyl)-piperazinyl} -β-L-gulofuranoside (Compound No. 168) Hydrochloride salt of l-O-dodecyl-3,4-O-isopropylidene-5,6-dideoxy-5-{l-(4-[(phenyl sulfonylamino)-carbonyl])-piperazinyl}-β-L-gulofuranoside (Compound No. 169)
Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{l-[4-{(4-methoxy- phenyl)-amino}-carbonyl]-piperazinyl}-β-L-gulofuranoside (Compound No. 170) Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{ l-(4-benzyl)- piperazinyl} -β-L-gulofuranoside (Compound No. 171) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{l-(4-[(4-chloro-phenyl)-amino]- carbonyl)-piperazinyl} -β-L-gulofuranoside (Compound No. 172)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[ 1 -(4- {(4-nifro-phenyl)-amino} -carbonyl)- piperazinyl] -β-L-gulofuranoside (Compound No. 174).
Scheme IV. Path b
Example 25: Synthesis of 2-O-Isopropylidene-3-O-pentyl-5-deoxy-5-[l-(4-[4-methoxy-3-
{5-[l-methyl-3-propyl-7-oxo- 6-dihvdro-pyrazolo[4,3-dlpyrimidmyl1}-phenyll-sulphonyl)l- piperazinyl]-α-D-xylofuranoside (Compound No. 174) Step a: Synthesis of l,2-O-isopropylidene-3-O-pentyl-5-deoxy-5-piperazinyl-α-D- xylofuranoside The title compound was prepared following the procedure described in step a of
Example 20, by using l,2-O-isopropylidene-3-O-pentyl-5-tosyl-α-D-xylofuranoside (lOg) in place of l-O-dodecyl-2,3-O-isopropylidene-5-tosyl-α-D-lyxofuranoside to furnish the desired product (520mg).
Step b: Synthesis of l,2-O-isopropylidene-3-O-pentyl~5-deoxy~5-[l-(4- benzyl)piperazinyl-α-D-xylofuranoside The title compound was synthesised following the procedure described in step b of
Example 20, by using the compound obtained from step a above in place of 1 -O-dodecyl-2,3 - O-isopropylidene-5-tosyl-α-D-lyxofuranoside (12g) to furnish the title compound (200mg).
Step c: Synthesis of l,2-O-Isopropylidene-3-O-pentyl-5-deoxy-5-[l-(4-[4-methoxy-3-{5-
[l-methyl-3-propyl-7-oxo-l,6-dihydro-pyrazolo[4,3-d]pyrimidinyl]}-phenyl]-sulphonyl)l- piperazinyl]-α-D-xylofuranoside To a solution of the compound obtained from step b above (400 mg) in dichloromethane and pyridine (5.1 ml), was slowly added 3-methoxy-[5-(l-methyl-7-oxo-3- propyl-6,7-dihydro-lH-pyrazalo[4,3-d] pyrimidin-4-yl)]-benzenesulphonyl chloride (400 mg) at a temperature of 0-5°C. The reaction mixture was then brought to room temperature and stirred for another 1-2 hours. The solvents were evaporated off under reduced pressure and the residue thus obtained was washed with sodium bicarbonate and water. The dichloromethane layer was then dried over sodium sulphate. Dichloromethane was evaporated off and the residue thus obtained was purified by column chromatography to obtain the title compound (400mg).
1H NMR (CDCI3, 300 MHz):δ 10.82 (IH, s), 8.82 (IH, s), 7.83 (2H, dd, 2.22Hz), 7.14 (IH, d,
8.7Hz), 5.85 (d, 3.7Hz), 4.48 (IH, d, 3.8Hz), 4.38 (2H, d, 7Hz), 4.27 (6H, m), 1.85 (3H, m), 1.02 (3H, t, J=7Hz), 0.88 (3H, t, J=6.6Hz). Scheme V
Example 26: Synthesis of l,2-O-isopropylidene-3-O-heptyl-5-O-{[3-(2-hydroxy-2-oxo- ethyl)-phenyl]-amino|-carbonyl-6-deoxy-6-{(l-piperidinyl)-ethyl|-amino-α-D- glucofuranoside (Compound No. 175) Step a: Synthesis of l,2-O-isopropylidene-3-O-heptyl-6-deoxy-{(l-piperidinyl)-ethyl}- amino -α-D-glucofuranoside The mixture of l,2-O-isopropylidene-3-O-heptyl-6-tosyl-α-D-glucofuranoside (1.26 g, 2.66 mmole) (synthesised following the procedure described in U.S. Patent No. 6,329,344) and 2-piperidin-l-yl-ethyl amine (1.3 ml, 9.155 mmol) was heated at 60-70°C stirred for 3 hours with continuous stirring. The reaction mixture was diluted with ether (approx 200 ml) and the organic layer was washed with water, brine and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure to furnish the title compound (1.3296 g). Step b: Synthesis of l,2-O-isopropylidene~3-O-heptyl~6-deoxy-6-(benzyl-oxycarbonyl)- ([l-piperidinyI]-ethyl)-amino-α-D-glucofuranoside To a solution of the compound obtained from step a above (1.32 g, 3.10 mmol) in tetrahydrofuran was added a solution of benzyl chloroformate (1.27 g, 3.27 mmol) followed by the addition of triethylamine (excess). The reaction mixture was stined for overnight. The reaction mixture was evaporated off to dryness and the compound was extracted with ether. The organic layer was washed with water and brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography to furnish the title compound (1.045g).
Step c: Synthesis of 1,2-O-isopropylidene -3-O-heptyl5-O-{(4-[2-methoxy-2-oxo-ethyl]- phenyl)-amino}-carbonyl-6-deoxy-6-(benzyloxycarbonyl)-([l-piperidinyl]-ethyl)-amino- α-D-glucofuranoside \ To a solution of the compound obtained from step b above (1.046g, 1.86 mmol) in dichloromethane (10 ml) was added 4-isocyanatophenylacetic acid methyl ester (0.426 g, 2.23 mmol) and stined till the completion of the reaction (TLC). The reaction mixture was evaporated to dryness and then triturated with ether. It was concentrated under reduced pressure. The resulting compound was taken in methanol (7 ml) followed by the addition of aqueous sodium hydroxide (IN, 4ml). After the completion of the reaction, methanol was evaporated off and the reaction mixture was acidified and the product was extracted with dichloromethane. The organic layer was washed with brine and dried over sodium sulphate. It was concentrated under reduced pressure to obtain the title compound (0.493 g). Step d: Synthesis of l,2-O-isopropylidene-3-O-heptyl-5-O-{(4-[2-methoxy-2-oxo-ethyl]- phenyl)-amino}-carbonyl-6-deoxy-6-)-([l-piperidinyl]-ethyl)-amino-α-D-gIucofuranoside To a solution of the compound obtained from step c above (0.493 g, 0.668 mmole) in methanol (10 ml) was added palladium on carbon (50mg). The reaction mixture was stined for overnight under an atmosphere of hydrogen. The reaction mixture was filtered through celite pad. The filtrate was evaporated to dryness to obtain the title compound (0.4188 g). Step e: Synthesis of l,2-O-isopropylidene-3-O-heptyl-5-O-{[3-(2-hydroxy-2-oxo-ethyl)- phenyl]-amino}-carbonyl-6-deoxy-6-{(l-piperidinyI)-ethyl}-amino-α-D-glucofuranoside The compound obtained from step d above (0.4188 g) was hydrolyzed with lithium hydroxide (6.5 mg, 0.15 mmole) in water-tefrahydrofuran following the general conditions to furnish the title compound (0.38g).
1H NMR (CDC13, 300MHz):δ 8.66 (IH, bs), 7.32-7.28 (3H, m), 7.14 (IH, bs), 5.95 (IH, bs), 5.29 (IH, bs), 4.80 (4H, bs), 4.60-4.49 (2H, m), 3.99 (IH, bs), 3.68-3.47 (4H, m), 3.30-3.25 (5H, m), 3.03-2.93 (3H, bs), 1.78 (3H, bs), 1.58-1.43 (7H, m), 1.33-1.27 (12H, m), 0.87 (3H, t, 6.2Hz). Analogous of l,2-O-isopropylidene-3-O-heptyl-5-O-{[3-(2-hydroxy-2-oxo-ethyl)- phenyl] -amino} -carbonyl-6-deoxy-6- {(1 -piperidinyl)-ethyl} -amino-α-D-glucofuranoside
(Compound No. 175) described below were prepared by replacing appropriate amine in place of 2-(l-piperidin)-ethyl amine and appropriate isocyanate group in place of 4- isocyanatophenylacetic acid methyl ester, respectively, as applicable in each case. l,2-O-Isopropylidene-3-O-heptyl-5-O-{[3-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino}- carbonyl-6-deoxy-6- {(1 -pyrrolidinyl)-ethyl]-amino-α-D-glucofuranoside (Compound No.
176)
1 ,2-O-Isopropylidene-3-O-heptyl-5-O- { [3-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino} - carbonyl-6-deoxy-6-{(4-moφholinyl)-ethyl}-amino}-α-D-glucofuranoside (Compound No. 177).
Scheme Nl
Example 27: Synthesis of l-O-Dodecyl-2.3-O-isopropylidene-5.6-dideoxy-5-({[4-{2-[2S-2- il-methoxy-4-methyl-l-oxo]-pentyl|-amino1-2-oxo-ethyl|-phenyl]-amino|-carbonyl)-amino- β-L-gulofuranoside (Compound No. 178) To a suspension of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.42 g) and hydroxybenzotriazole (0.25 g) in dimethylformamide (20 ml) at room temperature, was added triethylamine (0.75 ml) and the reaction mixture was stined for 30 minutes. Hydrochloride salt of leucine methyl ester (0.33 g) was added followed by the addition of 1 -O-dodecyl-2,3 - 0-isopropylidene-5,6-dideoxy-5- { [4-(2-hydroxy-2-oxo-ethyl)-phenyl]- aminocarbonylamino}-α, L-gulofuranoside (prepared following the procedure described in 6,329,344). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with water and the product was exfracted with dichloromethane, washed with water, brine and dried over anhydrous sodium sulphate. Solvents were removed off under reduced pressure and the residue thus obtained was purified by column chromatography to furnish the title compound (1.20 g).
1H NMR (CDC13, 300MHz):δ 7.50 (IH, bs, NH), 7.30 (2H, d, 8.3Hz), 7.15 (2H, d, 8.3Hz), 4.68 (IH, bs), 4.59 (IH, bs), 4.12 (IH, q, 7Hz), 3.84 (IH, dd, 3.3 & 4.5Hz), 3.69 (3H, s), 3.60 (IH, bd), 3.52 (2H, s), 3.35 (IH, m), 2.96 (IH, s), 2.88 (IH, s), 1.61-1.25 (31H, m), 0.87 (9H, bs). Analogues of l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[4-{2-[2S-2-{l- methoxy-4-methyl-l-oxo]-pentyl}-amino]-2-oxo-ethyl}-phenyl]-amino}-carbonyl)-amino-β-
L-gulofuranoside (Compound No. 178) described below were prepared by replacing appropriate ester in place of leucine methyl ester and appropriate sugar in place of l-O- dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[4-(2-hydroxy-2-oxoethyl)- phenyl]- aminocarbonylamino} -β-L-gulofuranoside, respectively. l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(4-[2-(bis-[2-thienylmethyl]
-amino)-2-oxo-ethyl]-phenyl)-amino} -carbonylamino-β-L-gulofuranoside (Compound No.
179) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(4-[2-(benzyl-[2-thienylmethyl]-amino)- 2-oxo-ethyl]-phenyl)-amino}-carbonylamino-β-L-gulofuranoside (Compound No. 180) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[4-(2-oxo-2-( benzyl -α-methylbenzyl- amino)-ethyl)-phenyl]-amino}-carbonyl)-amino-β-L-gulofuranoside (Compound No. 181) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-(2-benzyloxyamino-2-oxo-ethyl)- phenyl)-amino]-carbonyl} -amino-β-L-gulofuranoside (Compound No. 182) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-[2-hydroxyamino-2-oxo-ethyl]- phenyl)-amino]-carbonyl} -amino-β-L-gulofuranoside (Compound No. 183) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-[{[(3,4- dimethoxybenzyl)amino]carbonyl}methyl]-phenyl)-amino]carbonyl}amino)-β-L- gulofuranoside (Compound No. 290).
Example 28: Synthesis of l-O-dodecyl-2.3-O-isopropylidene-5.6-dideoxy-5-{(r4-(2-(l- azepanyl)-2-oxo-ethyl-phenyl]-amino)-carbonyl}-amino-β-L- ulofuranoside (Compound No. 184) To a suspension of the compound l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.42 g) and hydroxybenzotriazole (0.25 g) in dimethylformamide (20 ml) at room temperature, was added triethylamine (0.75 ml) and the reaction mixture was stined for 30 minutes. To it l-O-dodecyl-2,3-isopropylidene-5,6-dideoxy-5-{[4-(2-hydroxy-2-oxo-ethyl ) phenyl]-aminocarbonylamino}-α,L-gulofuranoside (prepared following the procedure described in U.S. Patent 6,329,344) (1 g, 1.82 mmole) was added followed by the addition of hexamethyleneimine. After 24 hours, the reaction mixture was diluted with water and the product was extracted with dichloromethane. The crude product was washed with water, brine and dried over anhydrous sodium sulphate. The events were evaporated off under reduced pressure and the residue thus obtained was purified by column chromatography to obtain the title compound (lg). 1H NMR (CDCI3, 300MHz):δ 7.26 (2H, bs), 7.15 (2H, d, 8.1Hz), 5.02 (IH, s), 4.67 (IH, bs),
4.57 (IH, d, 5.2Hz), 4.1 (IH, bs), 3.82 (IH, bs), 4.57 (IH, d, 5.2Hz), 4.1 (IH, bs), 3.82 (IH, bs), 3.64-3.34 (6H, m), 2.95 (2H, s), 1.89-1.25 (37H, m), 0.86 (3H, bs). Analogues of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{([4-(2-(l-azepanyl)-
2-oxo-ethyl-phenyl]-amino)-carbonyl}-amino-β-L-gulofuranoside (Compound No. 184) described below were prepared by replacing appropriate amine in place of hexamethyleneimine, respectively as applicable in each case. l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[4-(2-oxo-2-(l-pynolidinyl)-ethyl)- phenyl] -amino} -carbonyl)-amino-β-L-gulofuranoside (Compound No. 185) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[4-(2-oxo-2-(l-piperidinyl)-ethyl)- , phenyl]-amino}-carbonyl)-amino-β-L-gulofuranoside (Compound No. 186)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [4- {(2-amino-2-oxo-ethyl)-phenyl} - amino] -carbonyl} -amino-β-L-gulofuranoside (Compound No. 187) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-( { [(4- {2-[(4-benzoylphenyl)amino]-2- oxoethyl}-phenyl)amino} carbonyl} amino)-β-L-gulofuranoside (Compound No. 243) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-{2-[(4-azidophenyl)amino]-2- oxoethyl}-phenyl)amino]carbonyl}amino)-β-L-gulofuranoside (Compoun No. 244) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-( { [(4- {2-[(5-carboxypentyl)amino]-2- oxoethyl}-phenyl)amino}carbonyl}amino)-β-L-gulofuranoside (Compound No. 247). Example 29: Synthesis of l-O-Dodecyl-2.3-O-isopropylidene-5.6-dideoxy-5-{[4-((2-[2-(lH- imidazol-4-yl)ethyll-amino-2-oxo-ethyl)-phenyl|-amino]-carbonyl}-amino-β-L- gulofuranoside (Compound No. 245)
To a solution of the compound l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- ({[(4carboxymethylphenyl)amino]carbonyl}amino)-β-L-gulofuranoside (200mg, 0.3649mmol)in tetrahydrofuran (10ml) at room temperature was added triethyl amine (0.1ml, 0.9124) and 1,1, carbonyldiimidazole (76mg, 0.4744mmol) and stined at the same temperature for 1 hour. To the resulting reaction mixture was added histamine dihydrochloride (67mg,
0.3649mmol) and stirred the mixture at the same temperature for 3 days. The solvent was evaporated under reduced pressure and poured the residue in water. The mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulpahte. The solvent was evaporated under reduced pressure and the residue thus obtained was pirifϊed by column chromatography using 10% methanol in dichloromethane as eluent to furnish the title compound. Yield: 90 mg.
1HNMR (CDC13, 300MHz): 7.32(s, IH), 7.26 (s, IH), 7.14 (dd, 2H, 6Hz), 7.00 (dd, 2H, 6Hz,
6.18 (s, IH, NH), 5.03 (s, IH), 4.71 (dd, IH, 3Hz), 4.61 (d, IH, 3Hz), 4.16 (m, IH), 3.87 (m, IH), 3.62 (m, 2H), 3.42-3.34 (m, 6H), 2.66 (s, 2H), 1.53-1.45 (m, 5H), 1.35-1.25 (m, 24H), 0.88 (m, 3H).
LCMS(M/Z): 642 (M'+l). Scheme NIL Path a Example 30: Synthesis of l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5--iT(2S)-2-(l- hydroxy-4-methyl-l-oxo-pentyl)-amino1-carbonyl}-amino-β-L-gulofuranoside (Compound No. 202)
Step a: Synthesis of l-O-dodecyI-2,3-0-isopropylidene-5,6-dideoxy-5-{[(2S)-2-(l- methoxy-4-methyl-l-oxo-pentyl}-amino]-carboxyl}-amino-β-L-guIofuranoside To a solution of l-O-dodecyl-2,3-O-isopropylidene-5-amino-α-L-gulofuranoside (100 mg, 0.2 mmole) in dry tefrahydrofuran (2 ml) at 0°C was added carbonyldiimidazole (52 mg, 0.32 mmole) and diisopropylethylamine (41 mg, 0.32 mmole). The reaction mixture was stined for 30 minutes followed by the addition of hydrochloride salt of leucine methyl ester (5.8 mg, 0.32 mmole). The reaction mixture was stined at room temperature for 16 hours. The reaction mixture was diluted with water and the product was exfracted with ethyl acetate. The combined organic extracts were washed with water brine and dried over anhydrous sodium sulphate. The solvents were evaporated off and the residue thus obtained was purified by coloumn chromatography using 20% ethyl acetate in hexane as eluent to furnish the title compound (118mg). Step b: Synthesis of l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(2S)-2-(l- hydroxy-4-methyl-l-oxo-pentyl)-amino]-carbonyl}-amino-β-L-gulofuranoside To a solution of the compound obtained from step a above (118mg, 0.2mmol) in tetrahydrofuran , water and methanol (2:1:1), was added aqueous lithium hydroxide (14mg, 0.33 mmol) and stirred for 2 hours. The solvents were evaporated off and residue was taken into water and given a ethyl acetate wash, acidified with concentrated hydrochloric acid and exfracted with ethyl acetate (2x10ml). The organic extracts were washed with brine and dreid over anhydrous sodium sulphate. Evaporation of the solvent furnished the title compound (40mg). H1 NMR (CDC13, 300MHz):δ 5.34-3.49 (9H, m), 1.57-1.25 (32H, m), 0.96-0.85 (9H, m). Scheme VII, Path b
Example 31: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5.6-dideoxy-5-{[3-(2-(4- methylphenyl)-5-tert-butyl-2H-pyrazolyl)-amino1-carbonyl}-amino-β-L-gulofuranoside (Compound No. 209) To a solution of 5-tert-butyl -2-p-tolyl-2H-pyrazol-3-ylamine (200 mg, 0.87 mmol) in dry tetrahydrofuran (10 ml), was added phenyl chloroformate (0.11 ml, 0.87 mmol) and triethylamine (0.18 ml, 1.31 mmol). The reaction mixture was stirred at room temperature for 3 hours followed by the addition of l-O-dodecyl-2,3-isopropylidene-5,6-dideoxy-5-amino-α- L-gulofuranoside (323 mg, 0.87 mmol). The reaction mixture was stined at room temperature for 16 hours. The reaction mixture was diluted with water and the product was exfracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvents were evaporated off and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 30%) ethyl acetate in hexane as eluent to furnish the title compound (250 mg). 1H NMR (CDC13, 300MHz):δ 7.34 (2H, d, J=8. IHz) & 7.23 (2H, d, J=8. IHz) [aromatic], 6.35 (IH, s, NH), 5.30 (1Η, bs, NH), 4.76 (1Η, s, Η-l), 4.60 (IH, t, J=5.4Hz, H-3), 4.50 (IH, d, J=5.7Hz, H-2), 3.99 (IH, , CH-N), 3.75 (IH, dd, J=7.8 and 3.3Hz, H-4), 3.49 (IH, q, J=9Hz) & 3.24 (IH, q, J=9.3Hz) [OCH2], 2.37 (3Η, s, ArCH3), 1.46 (2Η, bs, OCH2CH2), 1.37 (s), 1.34 (s) & 1.26 (bs) [36Η, CH2x9, CH3CΗ, CCH3x2 and CH3x3] and 0.88 (3Η, t, J=6Hz, terminal CH3). Analogues of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[3-(2-(4- methylphenyl)-5-tert-butyl-2H-pyrazolyl)-amino]-carbonyl}-amino-β-L-gulofuranoside
(Compound No. 209) as described below were prepared by replacing appropriate amine in place of 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine and appropriate sugar moiety in place of l-O-dodecyl-2,3-isopropylidene-5,6-dideoxy-5-amino-β-L-gulofuranoside, respectively. l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[3-(5-tert-butyl-2H-pyrazolyl)-amino]- carbonyl} -amino-β-L-gulofuranoside (Compound No. 210)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [3-( IH- 1 ,2,4-triazolyl)-amino]- carbonyl}-amino-β-L-gulofuranoside (Compound No. 211) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [2-(5-methyl- 1 ,3,4-thiadiazolyl)-amino]- carbonyl}-amino-β-L-gulofuranoside (Compound No. 212)
1 -O-dodecyl-2,3 -O-isopropylidene-5,6-dideoxy-5- { [2- {4-(2-hydroxy-2-oxo -ethyl)- thiazolyl}-amino]-carbonyl} -amino-β-L-gulofuranoside (Compound No. 213) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[3-(2-benzyl-5-tert-butyl-2H-pyrazolyl)- amino]-carbonyl}-amino-β-L-gulofuranoside (Compound No. 214) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{2-[3-(l,3,4-thiadiazolyl)-amino]- carbonyl}-amino-β-L-gulofuranoside (Compound No. 215)
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [(4-chloro-phenyl)-amino]-carbonyl} - amino-6-carboxy-α-D-mannofuranoside (Compound No. 216) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(2-[4-(2-ethoxy-2-oxo-ethyl)-thiazolyl]- amino)- carbonyl} -amino-β-L-gulofuranoside (Compound No. 217) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[ {(4-chloro-phenyl)-amino} -carbonyl]- amino-6-ethoxycarbonyl-α-D-mannofuranoside (Compound No. 237) Scheme VII, Path c Example 32: Synthesis of l-O-dodecyl-2,3-O-isopiOpylidene-5,6-dideoxy-5-{[butylamino1- carbonyll -amino-β-L-gulofuranoside (Compound No. 204) To a solution of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-amino-α-L- gulofuranoside (synthesised following the procedure as described in U.S. Patent 6,329,344) (0.2 g, 0.54 mmol) at 0°C in dry dichloromethane (10 ml), was added n-butyl isocyanate (53 mg,0.54 mmol) The reaction mixture was stined for 2 hours. Solvents were evaporated off and the residue thus obtained was purified by column chromatography using 20% ethyl acetate in hexane to obtain the title compound (219 mg).
1H NMR (CDCI3, 300MHz):δ 5.04 (IH, s, NH), 4.97 1Η, s, Η-l), 4.65 (IH, bs, H-3), 5.56
(IH, d, J=6Hz, H-2), 4.29 (IH, d, NH), 3.87 (1Η, m, CH-N), 376 (1Η, d, J=9Ηz, H-4), 3.59 (IH, q, J=9Hz) & 3.35 (IH, q, J=9Hz) [OCH2], 3.17 (2Η, m, NCH2), 1.50 (2Η, t, J=6Hz,
OCH2CH2), 1.46 (3Η, s, CCH3), 1.18-1.30 (m), 1.30 (s) & 1.26 (bs) [2.8Η, CH2xl l, CCH3 and CH3CN), 0.94 (3Η, t, J=6Hz, 1.26 (bs) [2.8H, CH2xl l, CCH3 and CH3CΗ), 0.94 (3H, t,
J=6Hz) and 0.88 (3H, t, J=6Hz, terminal CH Exampie 33: Synthesis of l-O-dodecyl-2.3-O- isoprop ylidene-5 , 6-dideoxy-5 - { (2-phenyl-ethyl)-amino"| -thiocarbonyl} -amino- β-L- gulofuranoside (Compound No. 205) To a solution of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-amino-α-L- gulofuranoside (200 mg, 0.54 mmol) in dichloromethane (5 ml), was added phenethyl isothiocyanate (85 mg,0.54 mmole) The reaction mixture was refluxed for 2 hours, cooled and washed with water. The aqueous layer was extracted with dichloromethane (2x5 ml) and the combined organic extract was washed with brine and dried over anhydrous sodium sulphate. The solvents were evaporated off and the residue thus obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluent to furnish the title compound (240 mg). 1H NMR (CDC13, 300MΗz):δ 7.20-7.35 (5H, m, aromatic, 6.89 (IH, bs, NH), 5.85 (1Η, d, NH), 4.66 (1Η, s, Η-l), 4.59 (1Η, dd, J=6 and Ηz, Η-3), 4.49 (IH, d, J=6Hz, H-2), 3.87 (3, m, CH-N and NCH2), 3.69 (1Η, dd, J=9.3Ηz, H-4), 3.45 (IH, dt, J=6Hz and 3Hz) & 3.16 (IH, dt, J=9 and 6Hz), [OCH2], 2.93 (2Η, t, J=6Hz, CH2Ar), 1.45 (2Η, t, OCH2CH2), 1.43 (3Η, s, CCH3), 1.30 (bs) & 1.27 (bs) [24Η, CH2x9, CH3CΗ and CCH3] and 0.88 (3Η, t, J=6Hz, terminal CH3). Analogues of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(2-phenyl-ethyl)- amino] -thiocarbonyl} -amino-β-L-gulofuranoside (Compound No. 205) described below were prepared by replacing appropriate isothiocyanate in place of phenethyl isothiocyanate, respectively. l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(tert-butyl-amino)-thiocarbonyl}-amino- β-L-gulofuranoside (Compound No. 206) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [(4-fluorophenyl)-amino]-thiocarbonyl} - amino-β-L-gulofuranoside (Compound No. 207)
Example 34: Synthesis of l-O-Dodecyl-2.3-0-isopropylidene-5,6-dideoxy-5-{(r4-(2- hydroxy-2-oxo-ethyl)-phenyl]-amino)- thiocarbonyl} -amino-β-L-gulofuranoside (Compound No. 208)
Step a: Synthesis of l-O-DodecyI-2,3-O-isopropylidene-5,6-dideoxy-5-{([4-(2-methoxy-2- oxo-ethyl)-phenyI] -amino)- thiocarbonyl}-amino-β-L-gulofuranoside To a solution of the compound 4-aminophenylacetic acid methyl ester (500mg, 3.3 mmol) in tefrahydrofuran (10ml), was added thiocarbonyldiimidazole (500mg, 3.3mmol). The reaction mixture was stirred for overnight followed by the addition of 1 -O-dodecyl-2,3 -O- isopropylidene-5,6-dideoxy-5-amino-β-L-gulofuranoside (1.12g, 3mmol)). The reaction mixture was stirred for 2 hours at room temperature followed by refluxing at 80°C for 3 hours. The reaction mixture was diluted with distilled water and exfracted with ethyl acetate. The organic extract of was washed with brine and dreid over anhydrous sodium sulphate and concentrated. The crude compound was purified by column chromatography using 20% ethyl acetate in hexane as eluent to obtain the title compound (1.2g).
Step b: Synthesis of l-O-Dodecyl~2,3-O-isopropylidene-5,6-dideoxy-5-{([4-(2-hydroxy-2- oxo-ethyl)-phenyl] -amino)- thiocarbonyl}-amino-β-L-gulofuranoside To a solution of the compound obtained from step a above (970 mg, 1.6 mmol) in tefrahydrofuran-methanol- water (2ml), was added lithium hydroxide monohydrate (1:1, 77mg, 1.8 mmol). The reaction mixture was stirred at room temperature for 3 hours, concentrated and residue was treated with water and washed with ethyl acetate. The aqueous was acidified by sodium hydrogen sulphate solution followed by extracting with ethyl acetate. The organic extract was washed with brine and dried over anhydrous sodium sulphate and concentrated to furnish the title compound (800mg). Scheme VIII
Example 35: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5--iT(4-chloro- phenyl)-amino]-carbonyl|-amino-6-carboxy-β-L-gulofuranoside (Compound No. 218) / l-O- dodecyl-2.3-O-isopropylidene-5,6-dideoxy-5-{r(4-chloro-phenyl)-amino1-carbonyl}-amino-6- carboxy-α-D-mannofuranoside. (Compound No. 216) Step a: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6-cyano-α-D- mannofuranoside To a solution of the compound l-O-dodecyl-2,3-isopropylidene-6-O-tosyl-α,D- gulofuranoside (8 g, 14.7 mmole) (synthesised following the procedure described in U.S. Patent No. 6,329,344) in ethanol (50 ml) was added sodium cyanide (8.64 g, 17.6 mmol) in water (10 ml) and refluxed for 8 hours. The solvents were evaporated off and the residue thus obtained was taken in water and the aqueous layer was exfracted with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous sodium sulphate. The solvents were evaporated off and the residue thus obtained was purified by column chromatography using 30% ethyl acetate in hexane as eluent to obtain the title compound (5.6g).
Step b: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-O-methanesulphonyI-6-deoxy- 6-cyano-α-D-mannofuranoside To a solution of the compound obtained from step a above (5 g, 12 mmol) in dry dichloromethane (50 ml) at 0°C, was added methanesulphonyl chloride (1.73 g, 15 mmol) and stirred for 3 hours at room temperature. It was washed with water, brine and dried over anhydrous sodium sulphate. The solvents were evaporated off to obtain the title compound (5-4 g).
Step c: Synthesis of a mixture of l-O-dodecyl-2,3-O-isopropy!idene-5,6-dideoxy-5- benzyIamino-6-cyano-β-L-gulofuranoside and isomeric α-D-mannofuranoside derivative To the compound obtained from step b above (3 g, 6.3 mmol) was added benzyl amine (20 ml) and heated at 115°C for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was taken in ether. The solid was separated out and filtered followed by washing with ether. The filtrate was concentrated and the crude residue was purified by column chromatography using 15% ethyl acetate in hexane to obtain the title compound (2.1 g). Step d: Synthesis of mixture of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- benzylamino-6-carboxy-β-L-gulofuranoside and isomeric α-D-mannofuranoside derivative To a solution of the compound obtained from step c above (2 g, 4.2 mmol) in ethanol (5 ml) was added a solution of sodium hydroxide (170 mg in 2 ml water) and refluxed for 10 hours. The reaction mixture was concenfrated and taken into water. The compound was extracted with ethyl acetate. The aqueous layer was acidified and then exfracted with ethyl acetate, The organic extracts were washed with brine and dried. Over anhydrous sodium sulphate and concentrated to obtain the title compound (1.4 g). Step e: Synthesis of a mixture of l-O-dodecyI-2,3-O-isopropylidene-5,6-dideoxy-5- benzylamino-6-carboxy-β-L-gulofuranoside and isomeric α-D-mannofuranoside derivative To a solution of the compound obtained from step d above (1.9 g, 3.86 mmol) in dry dichloromethane (10 ml) at about 15°C, was added oxalyl chloride (0.5 g, 3.9 mmole) and the reaction mixture was warmed to room temperature. It was stined for 5 hours. The solvents were evaporated off and the residue was taken in ethanol (10 ml) and stirred for 3 hours. The solvent was evaporated off and the residue thus obtained was taken in water (10 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous sodium sulphate. The solvents were evaporated off and the residue was purified by column chromatography using 20% ethyl acetate in hexane as eluent to obtain the title compound (760 mg).
Step f: Synthesis of a mixture of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- amino-6-cyano-β-L-gulofuranoside and isomeric α-D-mannofuranoside derivative To a solution of the compound obtained from step e above (650 mg) in methanol (20 ml), was added 10% palladium hydroxide (50% wet). The reaction mixture was shaken under hydrogen atmosphere (50psi). The reaction mixture was filtered and the filtrate was concentrated and the residue thus obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluent to obtain the title compound (350 mg). Step g: Synthesis of l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[{(4-chloro- phenyI)-amino}-carbonyl]-amino-6-ethoxycarbonyl-β-L-gulofuranoside (Compound No. 221) and l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[{(4-chIoro-phenyl)-amino}- carbonyl]-amino-6-ethoxycarbonyl-α-D-mannofuranoside (Compound No. 239) To the solution of the compound obtained from step/above (200 mg, 0.45 mmol) in dichloromethane (1 ml) at 0°C was added 4-chlorophenyl isocyanate (82 mg, 0.54 mmol) and stirred for 30 minutes. The solvents were evaporated off under reduced pressure and the residue thus obtained was purified by column chromatography using 40% ethyl acetate in hexane as eluent to obtain the title compound as a separable pair of diastereomers
(diastereomer I (HOmg) and diastereomer II (80mg)).
Step h: Synthesis of l-O-dodecyl-2,3-isopropyIidene-5,6-dideoxy-5-{[(4-chloro-phenyl)- amino]-carbonyl}-amino-6-carboxy-β-L-gulofuranoside (Compound No. 218) / l-O- dodecyl-2,3-isopropylidene-5,6-dideoxy-5-{[(4-chloro-phenyl)-amino]-carbonyl}-amino-
6-carboxy-α-D-mannofuranoside (Compound No. 216) The diastereomer I (120 mg, 0.2 mmole) obtained from step g above was subjected to general hydrolysis using lithium hydroxide (13 mg, 0.3 mmole) to furnish the title compound (HO mg).
1H NMR (CDCI3, 300MHz):δ 8.21(lH,bs, NH). 7.52 (2H,d, 8.8Hz), 7.22 (2H, d, 8.8Hz), 5.97
(IH, bs, NH), 4.93 (IH, s), 4.80 (lH,bs), 4.56 (IH, d, 5.9Hz), 4.45 (lH,bs), 4.28 (lH,m), 3.60
(IH, m), 3.36 (lH,m), 2.75 (2H, m), 1.52 (2H, bs), 1.42 (3H, s), 1.28 (2H, s), 0.87 (3H, t,
6.7Hz). The analogues of l-O-dodecyl-2,3-isopropylidene-5,6-dideoxy-5- { [(4-chloro-phenyl)- amino] -carbonyl} -amino-6-carboxy-β-L-gulofuranoside (Compound No. 218) described below were prepared similarly.
1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [(4-methyl-phenyl)-amino]-carbonyl} - amino-6-ethoxycarbonyl- β-L-gulofuranoside (Compound No. 219) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-methyl-phenyl)-amino]-carbonyl}- amino-6-carboxy-β-L-gulofuranoside (Compound No. 220)
1 -O-Dodecyl-2,3-isopropylidene-5,6-dideoxy-5- { [(4-[2-methoxy-2-oxo-ethyl]-phenyl)- amino]-carbonyl}-ammo-6-ethoxycarbonyl-β-L-gulofuranoside (Compound No. 222) l-O-Dodecyl-2,3-isopropylidene-5,6-dideoxy-5-{[(4-{2-hydroxy-2-oxo-ethyl]-phenyl)- amino] -carbonyl} -amino-6-carboxy-β-L-gulofuranoside (Compound No. 223) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-[2-hydroxy-2-oxo-ethyl]-phenyl)- amino] -carbonyl} -amino-6-carboxy-α-D-mannofuranoside (Compound No. 224) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-methyl-phenyl)-amino]-carbonyl}- amino-6-carboxy-α-D-mannofuranoside (Compound No. 225) 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [((2S)-2-[ 1-oxo- 1 - {(2-thienylmethyl)- benzyl)-amino}]-4-methyl-pentyl)-amino]-carbonyl}-amino-6-carboxy-β-L-gulofuranoside
(Compound No. 226) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [((2S)-2-[ 1 -oxo- 1 -(bis- [2-thienylmethyl] - amino)]-4-methyl-pentyl)-amino]-carbonyl}-amino-6-carboxy-β-L-gulofuranoside (Compound No. 227) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(2-methyl-phenyl)-amino]-carbonyl}- amino-6-carboxy-α-D-mannofuranoside (Compound No. 228) l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(2-methyl-phenyl)-amino]-carbonyl}- amino-6-carboxy-β-L-gulofuranoside (Compound No. 229). Scheme IX, path a
Example 36: Synthesis of l-O-dodecyl-2.3-O-isopropylidene-5.6-dideoxy-5-[{(2S)-2-[3-(4- (2-hvdroxy-2-oxo-ethyl)-phenyl)-ureido1-4-methyl}pentanoyl]-amino-β-L- gulofuranoside (Compound No. 230) Step a: Synthesis of l-O-dodecyl-2,3~0-isopropylidene-5,6-dideoxy-5-{[(4-methyI-2-tert- butoxycarbony!amino)-pentanoyl]-amino-β-L-gulofuranoside To a solution of the compound l-O-dodecyl-2,3-isopropylidene-5,6-dideoxy-5-amino- α-L-gulofuranoside (200 mg, 0.5 mmol) in dry dimethylformamide (2 ml) at 0°C, was added N-tert-butoxycarbonyl-L-leucine (122 mg, 0.54 mmol), N-methylmoφholine (60 mg, 0.64 mmol) and hydroxy benzotriazole (80 mg, 0.58 mmol). The reaction mixture was stined for 20 minutes followed by the addition of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.58 mmol). The reaction mixture was gradually warmed to room temperature and stined for 16 hours. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous sodium sulphate. The solvents were evaporated off and the residue thus obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluent to furnish the title compound (210 mg).
Step b: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(2S)-[2-amino-4- methyl]-pentanoyl}-amino-β-L-gulofuranoside (Compound No .232) To a solution of the compound obtained from step a above (200 mg, 0.34 mmole) in dry dichloromethane (5 ml) was added trifluoroacetic acid (1 ml) and stirred for 2 hours. The reaction mixture was neutralized with potassium carbonate. The solid thus separated was filtered off and the filtrate was concentrated to obtain the title compound (160 mg).
Step c: Synthesis of l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[{(2S)-2-[3-(4-[2- methoxy-2-oxo-ethyl]-phenyl)-ureido]-4-methyl}-pentanoyl]-amino-β-L-gulofuranoside
(Compound No .231) To a solution of the compound obtained from step b above (150 ml, 0.31 mmol) in dry tefrahydrofuran (2 ml) at 0°C, was added carbonyldiimidazole (60 mg, 0.37 mmol) followed by the addition of 4-aminophenylacetic acid methyl ester (61 mg, 0.37 mmol) and the reaction mixture was stined for overnight. It was poured into water (10 ml) and exfracted with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous sodium sulphate. The solvents were evaporated off and the residue thus obtained was purified by coloumn chromatography using 30% ethyl acetate in hexane as eluent to obtain the title compound (85 mg). Step d: Synthesis of l-O-dodecyl-2,3-O-is,opropyIidene-5,6-dideoxy-5-[{(2S)-2-[3-(4-(2- hydroxy-2-oxo-ethyl)-phenyl)-ureido]-4-methyl}pentanoyl]-amino-β-L-gulofuranoside The compound obtained from step c above (70 mg, 0.1 mmole) was hydrolyzed with lithium hydroxide (6.5 mg, 0.15 mmole) in water-tefrahydrofuran following the general conditions to furnish the title compound (30 mg). 1H NMR (CDC13, 300MHz):δ 6.95 (4H, bs, aromatic), 4.97 (lh, s), 4.58 (2H, m), 4.35 (2H, m), 3.88 (2H, m), 3.59 (IH, m), 3.48 (3H, m), 3.35 (IH, bs), 1.54-1.44 (9H, m), 1.27 (23H, bs), 1.0-0.87 (9H, m). Example 37: Synthesis of l-O-(3,4-methylenedioxy-benzyl)-2.3-O-isopropylidene-5.6- dideoxy-5-{[l-(2-tert-butoxycarbonylamino-4-methyl-pentyl)-oxo -amino}-β-L- gulofuranoside (Compound No. 234)
Step a: Synthesis of 2,3;5,6-di-O-isopropylidene-α-D-mannofuranoside To the solution of D-mannose (50g, 0.277 mole) in acetone cooled at 0°C, was added sulphuric acid (9ml, 0.16 mole) dropwise maintaining temperature of the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 30 minutes and then at 20°C for 30 minutes followed by heating it at 40°C for 5 hours. The reaction mixture was concentrated to get sticky mass, which was then stirred, with water for 15 min. The aqueous layer was exfracted with ethyl acetate and the organic layer was washed with water and brine. The organic layer was dried and concenfrated followed by washing with hexane as eluent to furnish the title compound (47 g).
Step b: Synthesis of l-O-(3,4-methylenedioxybenzyl)-2,3;5,6-di-O-isopropylidene-α-D- mannofuranoside To the compound obtained from step a above (18g, 0.0692 mol) in dimethylsulphoxide (150 ml) cooled at 0°C, was added potassium hydroxide (7.75g, 0.138mol) and methane sulphonic acid benzo [l,3]dioxol-5-methyl ester (17.59g, 0.076mol) and stined at room temperature for 30 minutes. The reaction mixture was heated to 45 °C for 3 hours. The reaction was quenched with ice-cold water and neutralized with hydrochloric acid. The product was exfracted with ethyl acetate, which was washed with water, and brine. The organic layer was dried over anhydrous sodium sulphate and concenfrated. The crude compound was purified by column chromatography using 20% ethyl acetate in hexane as eluent to furnish the title compound (14.6g). Step c: Synthesis of l-O-(3,4-methylenedioxybenzyl)-2,3-O-isopropy!idene-α-D- mannofuranoside To the compound obtained from step b above (16g, 0.042 mole) in tetrahydrofuran (200 ml) at 0°C, was added perchloric acid (8.98g, 0.0872 mol) and stirred the reaction mixture at 0°C for 5 hour. Reaction mixture was neutralized with aqueous sodium hydroxide and exfracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concenfrated. The crude product was purified by column chromatography using 20% ethyl acetate in hexane as eluent to furnish the title compound (9. Ig).
Step d: Synthesis of l-O-(3,4-methylenedioxybenzyι)-2,3-O-isopropylidene-6-O-p- toluene-sulphonyl-α-D-mannofuranoside To the compound obtained form step c above (9g, 0.0269 mol) in dichloromethane cooled at 0°C, was added triethylamine (13.6 ml, 0.1347mol) followed by the addition of p- toluenesulphonyl chloride (6.16g, 0.0323 mole) slowly maintaining temperature at 0°C. The reaction mixture was stined at same temperature for 4 hours. The reaction mixture with water and neutralized with hydrochloric acid. The compound was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulphate and concenfrated to get crude compound. The crude compound was purified by column chromatography using 30% ethyl acetate in hexane as eluent to obtain the title compound (12. Ig).
Step e: Synthesis of l-O-(3,4-methylenedioxybenzyI)-2,3-O-isopropylidene-6-deoxy-α-D- mannofuranoside To a solution of the compound obtained form step d above (11.2g, 0.0228 mol) in tetrahydrofuran (150 ml), was added lithium aluminium hydride (1.735g, 0.045 mol) slowly and stirred at 0°C for 2 hours followed by stirring at room temperature for 5 hours. The reaction mixture was washed by quenching lithium alluminium hydride carefully with few drops of IN aqueous sodium hydroxide and ethyl acetate. The reaction mixture was filtered through sintered funnel and the filterate thus obtained was concenfrated under reduced pressure. Residue thus obtained was taken in dichloromethane and washed with water and brine. The organic layer was dried and concenfrated to furnish the title compound (5.7g). Step f: Synthesis of l-O-(3,4-methylene-dioxybenzyl)-2,3-O-isopropyIidene-5-O- methanesulphonyI-6-deoxy-α-D-mannofuranoside To a solution of the compound obtained from step e above (5.7g, 0.0169 mol) in dichloromethane (50ml) cooled 0°C, was added triethylamine (2.04g) followed by the addition of methanesulphonyl chloride (2.32g, 0.0202 mol) slowly. Reaction mixture was then stined at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane followed by washing with water and brine. The organic layer was dried over anhydrous sodium sulphate and concenfrated to give the title product (7.6g). Step g: Synthesis of l-O-(3,4-methylenedioxybenzyl)-2,3-O-isopropylidene-5,6-dideoxy- S-azido-β-L-gulofuranoside To a solution of the compound obtained from step/above (4g, 9.6 mmol) in dimethylformamide (50ml), was added sodium azide (3.12g, 48 mmol) and tefrabutyl ammonium bromide (0.618g, 19.2 mmol). The reaction mixture was heated at 120°C for 12 hours. The reaction mixture was concenfrated under reduced pressure. The residue thus obtained was dissolved in ethyl acetate and washed with water. The organic layer was separated, dried over anhydrous sodium sulphate and finally concenfrated to get crude compound, which was purified by column chromatography using 10% ethyl acetate in hexane as eluent to furnish the title compound (2.5 g).
Step h: Synthesis of l-O-(3,4-methylenedioxybenzyl)-2,3-O-isopropylidene-5-{(2S)-(4- methyl-2-tert-butoxycarbonyl-amino)-pentanoyl}-amino-5,6-dideoxy-5-amino-β-L- gulofuranoside To a solution of the compound (2.5g, 6.8mmol) obtained form step g above in dry tefrahydrofuran at 0°C, was added lithium aluminium hydride (0.387g, 10.3 mmol) and stined at same temperature for 30 minutes followed by stirring at room temperature for 18 hours. The reaction mixture was filtered tlirough sintered funnel and the filtrate thus obtained was concentrated to get crude compound, which was purified using column chromatography. using 3% methanol in chloroform to furnish the title compound (1.2g). Step i: Synthesis of l-O-(3,4-methylenedioxy-benzyl)-2,3-O-isopropylidene-5,6-dideoxy-
5-{[l-(2-tert-butoxycarbonylamino-4-methyl-pentyl)-oxo]-amino}-β-L-gulofuranoside To the solution of the compound obtained form step h above (250 mg, 74 mmol) in dimethylformamide (5ml), was added N-tert-butoxycarbonyl leucine (188 mg, 0.82 mmol), hydroxybenzotriazole (95mg, 0.81 mmol), N-methylmoφholine (82mg, 0.81 mmol) at 0°C and stined the reaction mixture for 15 minutes at same temperature. l-(3- dimethylaminopropyl)-3 -ethyl carbodiimide (156mg, 8.16 mmole) was added to the reaction mixture and stirred for overnight. The reaction mixture was diluted with water and extracted the product with ethyl acetate. The organic layer was dried and concenfrated. The crude compound was concentrated and purified by column chromatography using 20% ethyl acetate in hexane to furnish the title compound (280 mg). 1H NMR (CDC1 ) 300MHz):δ 6.80 (3H, m), 6.17 (IH, bs), 5.95 (2H, s), 5.05 (IH, s), 4.87
(IH, bs), 4.67 (IH, bs), 4.61 (IH, d, 5.9Hz), 4.52 (IH, d, 11.5Hz), 4.36 (IH, d, 11.5 Hz), 4.15
(IH, bs), 3.90 (IH, bs), 1.74-1.60 (2H, bs), 1.48 (IH, s), 1.44 (12H, bs), 1.28 6H, d, 7.1Hz),
0.95 (6H, bs). Scheme IX, Path b
Example 38: Synthesis of l-O-Dodecyl-2.3-O-isopropylidene-5,6-dideoxy-5-r((2S)-2- r{(carboxymethyl)-aminol-4-methyl}-pentanoyll -β-L-gulofuranoside (Compound No. 23)
Step a: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(2S)-2-
{(ethoxycarbonylmethyl)}-4-methyl]-pentanoyl}-amino-β-L-gulofuranoside To a compound obtained from step b of Example 31 (500 mg, 1.1 mmol) was added sodium hydride (31 mg, 1.3 mmole) and dimethylformamide. The reaction mixture was cooled at 0°C followed by the addition of ethyl bromoacetate. The reaction mixture was stirred for overnight and excess of sodium hydride was carefully quenched by the addition of water. The product was extracted with ethyl acetate followed by washing it with water and dried over anhydrous sodium sulphate. The solvents were evaporated off and the residue thus obtained was purified by column chromatography using 15% ethyl acetate in hexane as eluent to furnish the title compound (200mg).
Step b: Synthesis of l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[{(2S)-2- {(carboxymethyl)-amino]-4-methyl}-pentanoyl] -β-L-gulofuranoside To a solution of the compound obtained from step a above (200 mg, 0.35 mmol) in tefrahydrofuran and water mixture (3:1 ml), was added methanol (2ml) and lithium hydroxide in water (30mg, 0.7 mmol). The reaction mixture was stirred for 45 minutes. Solvents were evaporated off under reduced pressure and the aqueous extract was washed with ether. It was acidified with IN hydrochloric acid followed by extraction with ethyl acetate. The combined organic extracts were washed with water and dried over anhydrous sodium sulphate. The solvents were evaporated off under reduced pressure to furnish the title compound (120 mg). 1H NMR (DMSO, 300 MHz):δ 8.65 (IH, bs, NH), 4.84 (IH, s), 4.71 (IH, bs), 4.50 (IH, d, 5.8Hz), 4.2 (IH, m), 3.78-3.21 (6H, m), 1.60 (3H, m), 1.46 (2H, bs), 1.37 (3H, s), 1.23 (21H, bs), 1.13 (3H, d, 6.6Hz), 0.90-0.83 (9H, m). Scheme X
Example 39: Synthesis of l,2-O-Isopropylidene-3-O-benzyl-5-deoxy-5-r6-(l-{2-rcarboxy- piperidinyl})-hexanoyl]-amino-alpha-D-xylofuranoside (Compound No. 237)
Step a: Synthesis of l,2-O-Isopropylidene-3-O-benzyl-5-deoxy-5-(6-bromohexanoyl)- amino-α-D-xylofuranoside To a suspension of sodium hydride (0.275g) in di-n butyl ether (20ml), was added 1,2-
O-isopropylidene-3-O-benzyl-5-deoxy-5-amino-α-D-glucofuranoside (1.6g, 5.73mmol). The reaction mixture was stined at 60°C for 1 hour followed by the addition of 6-bromo-hexanoyl chloride (1.22g). The reaction mixture was again stirred for 2 hours followed by diluting it with water. The product was exfracted with ethyl acetate, washed water, brine and dried over sodium sulphate. The solvent was evaporated off under reduced pressure and the crude product was purified by column chromatography using 50% ethyl acetate in hexane as eluent to furnish the title compound (1.4g) Step b: Synthesis of l,2-O~Isopropylidene-3-O-benzyl-5-deoxy-5-[6-(l-{2- ethoxycarbonyl-piperidinyl})-hexanoyI]-amino-o;-D-xylofuranoside (Compound No. 238) To a solution of the compound obtained from step a above (1.2g, 2.63 mmol) in acetone (30 ml;), was added potassium carbonate (0.47g), piperidine-2-carboxylic acid methyl ester and the reaction mixture was refluxed for 6 hours followed by stirring it at room temperature for 48 hours. The reaction mixture was filtered off and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to furnish the title compound (1.32g)
Step c: Synthesis of l,2-O-Isopropylidene-3-O-benzyl-5-deoxy-5-[6-(l-{2-carboxy- piperidinyl})-hexanoyl]-amino-e.-D-xylofuranoside To a solution of the compound obtained from step b above (lg, 1.93 mmol) in methanol (20ml), was added sodium hydroxide solution (25 ml, IN) and stined the reaction mixture for 3 hours at 60°C. Methanol was removed under reduced pressure and acidified. The product was exfracted with ethyl acetate (50 ml), washed with water, brine and dried over sodium sulphate. The organic layer was separated and concenfrated to give the crude product, which was purified by column chromatography to furnish the title compound (0.74g). 1H NMR (DMSO, 300 MHz):δ 7.37-7.22(5H,m), 5.94 (IH, d, 3.5 Hz), 5.73 (IH, bs, NH),
4.63 (3H,m), 4.46 (IH, m), 4.2 (IH, bs), 3.92 (2H, bs), 3.7 (2H, bs), 3.53-3.38 (5H, m), 2.08-
0.85 (18H, m).
Scheme XI, Path a Example 40: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(4-acetamido- phenyl)-(acetyl)-L-gulofuranoside (Compound No. 242) To a solution of the compound l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(4- amino-phenyl)-amino-β-L-gulofuranoside (150mg, 0.32 mmole) in dichloromethane (10 ml) at 0°C was added triethylamine (0.113 ml, 0.97 mmol) and acetyl chloride (0.03 g, 0.32 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was poured into water, exfracted with dichloromethane. The combined organic extract was washed with brine and dried over anhydrous sodium sulphate. The solvent was evaporated off and the residue thus obtained was purified by coloumn chromatography using 20% hexane in ethyl acetate as eluent to furnish the title compound (162 mg).
1H NMR (CDC13, 300MHz):δ 7.54 (2H, d, J=6Hz), 7.23 (2H) [aromatic], 5.10 (IH, bs, NH), 5.02 (IH, s, H-l), 4.54 (2H, s, H-2 and H-3), 3.60-3.70 (2H, m, H-4 and CH-N), 3.35-3.50 (2H, m, OCH2), 2.20 (3H, s, COCH3), 1.76 (3H, s, COCH3), 1.52 (2H, bs, OCH2CH2), 1.30 (3H, s, CCH3), 1.26 (s), 1.20 (bs) [21H, CH2x9 and CCH3), 1.13 (3H, d, J=9Hz, CH3CH) and 0.88 (3H, t, J=6Hz, terminal CH3). Scheme XI, Path b
Example 41 : Synthesis of l-O-dodecyl-2.3-O-isoproρylidene-5.6-dideoxy-5-{(2- methylphenyl-amino)-carbonyl}-{4-r2-(2-methylphenyl)-ureido1-phenyl}-amino-β-L- gulofuranoside (Compound No. 240) To a solution of the compound l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(4- amino-phenyl)amino-β-L-gulofuranoside (0.15 g, 0.32 mmol) in dichloromethane (5 ml), was added O-tolyl isocyanate (0.043 g, 0.32 mmol) and stined for 1 hour. The reaction mixture was concenfrated and the residue thus obtained was purified by coloumn chromatography using 20% ethyl acetate in hexane to furnish the title compound (95 mg) 1H NMR (CDCL3, 300 MHz):δ 8.01 (IH, bs, NH), 7.72 (IH, d, J=6hz), 7.57 (IH, d, J=6H),
7.42 (2H, bs, NH), 6.95-7.26 (9H, m), 6.88 (IH, t, J=6Hz) [aromatic], 4.97 (IH, bs, CH-N),
4.90 (IH, s, H-l), 4.53 (2H, s, H-2 and H-3), 3.80 (IH, bs, H-4), 3.65 (IH, dt, J=6 and 3Hz) &
3.35 (IH, dt, J=6hz) [OCH2], 2.14 (3H, s, ArCH3), 1.92 (3H, s, ArCH3), 1.49 (2H, t, J=6Hz, OCH2CH2), 1.44 (3H, s, CCH3), 1.26 (24H, bs, CCH3, CH3CH and CH2x9) and 0.87 (3H, t,
J=6Hz, terminal CH3).
LCMS (m/e): 729.4 (M+1 , 100%) The analogue of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(2-methylphenyl- amino)-carbonyl} - {4-[2-(2-methylphenyl)-ureido]-phenyl} -amino-β-L-gulofuranoside (Compound No. 240) as described below was prepared by replacing appropriate isocyanate in place of O-tolyl isocyanate respectively as applicable in each case. l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(2-methoxyphenyl)-amino]-carbonyl}-
{4-[3-(2-methoxy phenyl)-ureido] -phenyl} -amino-β-L-gulofuranoside (Compound No. 241)
Scheme XII, path a: Example 42: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-({[(4- carboxymethylphenyl)amino]carbonyl} amino)-6-O- { [(4-benzoylphenyl)aminolcarbonyl} -β-
L-gulofuranoside (Compound No. 272)
Step a: Synthesis of (4-isocyanatophenyl)(phenyl)methanone
To a solution of the compound 4-aminobenzophenone (lOOmg, 0.51 mmol) (Commercially available) in dichloromethane (10 ml) at 0°C was added triethyl amine (0.1ml, 0.56mmol) and triphosgene (136mg, 0.51 mmol). The reaction mixture was stirred for 1 hour at the same temperature. The solvent was evaporated under reduced pressure to furnish the title compound. Yield: lOOmg.
Step b: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-({[(4- [methoxycarbonylmethyI]phenyl)amino] carbonyl}-amino)-β-L-gulofuranoside
To a solution of the compound l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-amino-β-L- gulofuranoside (lg, 2.583 mmol) in tetrahydrofuran (10ml) at room temperature was added triethylamine (0.5 ml, 3.8758 mmol) and methyl {4-[(phenoxycarbonyl)amino]phenyl}acetate
(0.736 g, 2.5839mmol) and stirred the reaction mixture at 80°C for 3 hours. The solvent was evaporated under reduced pressure and the reaction mixture was poured into water. The mixture was exfracted with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the residue thus obtaine was purified by column chromatography using 30% ethyl acetate in hexane as eluent to furnish the title compound. Yield: 750mg. Step c: Synthesis of l-O-dodecyI-2,3-O-isopropylidene-5-deoxy-5-({[(4-
[methoxycarbonylmethyl]phenyl)amino] carbonyI}-amino)-6-O-{[(4- benzoy!phenyl)amino]carbonyl}-β-L-gulofuranoside
To a solution of the compound obtained from step b above (259mg, 0.4484 mmol) in dichloromethane (5ml) at 0°C was added triethylamine (0.1ml, 0.6726mmol) and stined the reaction mixture for 10 minutes at the same temperature followed by the adition of the solution of the compound obtained from step a (lOOmg, 0.4484mmol) in dichlomethane (5ml). The resulting reaction mixture was again stireed for 2 hours at the same temperature, which was subsequently poured into water and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 10% methanol in dichloromethane to furnish the title compound. Yield: 200mg. Step d: Synthesis of l-O-dodecyI-2,3-O-isopropylidene-5-deoxy-5-({[(4- carboxymethylphenyI)amino]carbonyI}amino)-6-O-{[(4- benzoylphenyl)amino]carbonyl}-β-L-guIofuranoside (Compound No. 272) The title compound was preperaed following the procedure as described in Example 38, step g, by using the compound obtained from step c above in place of using the compound l-O- dodecyl-2,3-O-isopropylidene-5-deoxy-5-({[(4-[carboxymethyl]phenyl)amino]carbonyl}- amino)-β-L-gulofuranoside. 1H NMR (DMSO, 300 MHz):δ 8.65 (s, IH), 7.70-7.52 (m, 9H), 7.09-6.99 (m, 5H), 4.95 (s, IH), 4.80 (s, IH), 4.53 (d, IH, 6Hz), 4.30-4.01 (m, 4H), 3.38-3.17 (bm, 4H), 1.40 (m, 5H), 1.37-1.13 (bm, 24H), 0.83 (t, 3H). Scheme XII, path b:
Example 43: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5,6- {r(methylamino)carbonyl]azanediyl} -β-L-gulofuranoside (Compound No. 271) Step a: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6- {[(methylamino)carbonyl]amino}-α-D-mannofuranoside
To a solution of the compoundl-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6-amino-α-D- mannofuranoside (synthesised following the procedure as per reported in U.S. Patent No. 6,329,344 by using benzylamine followed by deprotection of the benzyl group) (0.75g) in dimethylsulphoxide (4ml) was added triethylamine (0.54ml) at room temperature followed by the addition phenyl methylcarbamate (0.26g) and stined the reaction mixture at 65-70°C for 2 hours. The mixture was cooled and diluted with water followed by extracting it with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtaine was purified by column chromatography using 3% methanol in dichloromethane as eluent to furnish the title compound. Yield: 0.35g.
Step b: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-O- methanesulphonyl-6-{[(methy!amino)carbonyI]amino}-α-D-mannofuranoside The title compound was prepared by following the procedure as described in Example 38, step b, by using the compound obtained from step a above in place of using 1 -O-dodecyl-2,3 - O-isopropylidene-6-O- (tert-butyldimethylsilyl)-α-D-mannofuranoside. Yield: 0.5g. Step c: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5,6- {[(methylamino)carbonyl]azanediyl}-β-L-gulofuranoside (Compound No. 271) To a solution of the compound obtained from step b above (0.5g) in dimethylformamide (3ml) was added sodium hydride (70 mg) and stined the reaction mixture at 60-70°C for 3 hours. The reaction mixture was cooled and diluted with water exfracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound. Yield: 150mg.
1H NMR (CDCI3, 300 MHz):δ 5.75 (IH, d, 4.2Hz), 5.04 (IH, s), 4.74 (IH, m), 4.6 (IH, d, 6Hz), 3.71 (IH, m), 3.60 (IH, m), 3.36 (IH, m), 2.80 (3H, d, 5.1Hz), 2.56 (IH, m), 2.47 (IH, d, 6.6Hz), 2.025 (IH, 4Hz), 1.59-1.25 (26H, m), 0.88 (3H, m). LCMS (m/e): 427 (M++l). Scheme XIII, path a: Example 44: Synthesis of l-O-dodecyl-2.3-O-isopropylidene-6-deoxy-6-amino-5-O-.6-N-
(carbonyl)-oc-D-mannofuranoside (Compound No. 248)
Step a: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6-benzylamino-α-D- mannofuranoside To a solution of the compound l,2-O-isopropylidene-3-O-dodecyl-6-O-tosyl-α-D-gluco- furanoside (synthesised following the procedure as per reported in U.S. Patent No. 6,329,344) (2g) in benzylamine (5ml) and refluxed the reaction mixture for 2 hours at 100-110°C. Excess of benzylamine was removed under reduced pressure and the residue thus obtained was purified by column chromatography using 3% ethyl acetate in hexane as an eluent to furnish the title compund. Yield: 1.85g.
Step b: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6-amino-α-D- mannofuranoside
To a solution of the compound obtained from step a above (1.85g) in methanol (20ml) was added palladium on carbon (40%w/w) and hydrogenated on Pan apparatus for 20 hours. The reaction mixture was filtered over celite pad and the filterated was concentrated under reduced pressure to furnish the title compound. Yield: l.lg.
Step c: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6-{[(phenoxy)-carbonyI]- amino}-α-D-mannofuranoside To a solution of the compound obtained step b above (l.lg) in tetrahydrofuran (15ml) at 0°C was added triethylamine (0.44ml) and stined the reaction mixture for 10 minutes. To the resulting teaction mixture was added phenyl chloroformate (0.37ml) and stined for 2 hours at room temperature. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulphate and concenfrated under reduced pressure. The residue thus obtained was purified by column chromatography using 3% methanol in dichloromethane as eluent to furnish the title compound. Yield: 0.91g.
Step d: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6-amino-5-O-,6-N- (carbonyl)-oc-D-mannofuranoside (Compound No. 248) To a solution of the compound obtained from step c above (0.25g) in dimethyl sulphoxide (5ml) was added methylamine hydrochloride (0.17g) and triethylamine (0.68ml) at room temperature and stined the reaction mixture for 4 hours at room temperature. The rection mixture was diluted with water and exfracted with ethyl acetate. The combined organic extracts were washed with water and brine, died over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 40% ethyl acetate in hexane as eluent to furnish the title compound.
Yield: 0.12g.
1H NMR (CDC13, 300 MHz):δ 5.11 (IH, s), 5.03 (IH, s), 4.94 (IH, m), 4.78 (IH, m), 4.59
(IH, d, 6Hz), 4.21 (IH, m), 3.73-3.61 (3H, m), 3.38 (IH, m), 1.57-1.26 (26H, m), 0.88 (3H, m). LCMS (m/e): 414 (Mf'+l). Scheme XIII, path b:
Example 45: Synthesis of 1 -O-dodecyl-2,3 -O-isopropylidene-5,6-dideoxy-5-{ (4- fluorophenyDamino} -6-(methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 249) Step a: Synthesis of l~O-dodecyl-2,3-O-isopropylidene-6-deoxy-6-(methylamino)-α-D- mannofuranoside
To a solution of the compound l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6- (benzyl(methyl)amino)-β-L-gulofuranoside (prepared following procedure as depicted in step a in Example 44 wherein instead of benzylamine, commercial benzylmethylamine was used) (lg) in methanol (20ml) was added palladium on carbon (10%, 500mg) and stined the reaction mixture at 50 psi under hydrogen atmosphere for 8 hours. The reaction mixture was filtered through celite pad and filterate was concenfrated under reduced pressure to furnishthe title compound. Yield: 700mg. Step b: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-6-[{[4- fluorophenyl)amino]carbonyl}(methylamino)]-α-D-mannofuranoside
To a solution of the compound obtained from step a above (700mg, O.lδmmol) in dichloromethane at 0°C was added 4-fluorophenylisocyanate (commercially available) (247mg. 0.18mmol) and stined the mixture at the same temperature for 1 hour. The mixture was diluted dichloromethane and washed the organic layer with water and brine. The organic layer was dried and concentrated under reduced pressure to furnish the title compound. Yield:
920mg.
Step c: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-O-methanesulphonyI-6-deoxy-
6-[{[4-flurophenyl)amino]carbonyl}(methyl)amino]-α-D-mannofuranoside The title compound was prepared following the procedure described in Example 38, step g by using the compound obtained from step b above in place of using the l-O-dodecyl-2,3-O- isopropylidene-6-deoxy-α-D-mannofuranoside.
Step d: Synthesis of l-O-dodecyl-2,3-0-isopropylidene-5,6-dideoxy-5-{(4- fluorophenyl)amino}-6-(methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 249)
To a solution of the compound obtained form step c above (210mg) in tefrahydrofuran (10ml) was added potassium tert-butoxide (85mg, 0.76mmol) and stirred for overnight at room temperature. The reaction mixture was quenched with water, exfracted with ethyl acetate, dried over anhydrous sodium sulphate and concenfrated under reduced pressure. The residue thus obtained was purified by column chromatography using 15% ethylacetate in hexane as eluent to furnish the title compound. Yield: 90mg.
1H NMR (CDCl3):δ 7.27-7.36 (2H, m), 6.95-7.02 (2H, m), 5.03 (IH, s), 4.81-4.83 (IH, m), 4.46-4.47 (2H, m), 3.69-3.82 (3H, m), 3.60-3.62 (IH, m), 3.30-3.33 (IH, m), 3.11-3.15 (3H, m), 2.87 (3H, s), 1.45 (3H, s), 1.49 (2H, bs), 1.25-1.28 (21H, m), 0.86-0.90 (3H, m). LCMS (m/z): 521.24 (M++l).
Analogs of 1 -O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {(4-fluorophenyl)amino} -6- (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 249) described below were prepared similarily, l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[4-carboxymethylphenyl]amino]-6- (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 253) Scheme XIV, procedure:
Example 46: Synthesis of l-O-dodecyl-2.3-O-isopropylidene-5,6-dideoxy-5-amino-6- (methylamino)-5.6-N-carbonyl-β-L-gulofuranoside (Compound No. 268) Step a: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-O-methanesulphonyI-6-deoxy- 6-benzyl(methyl)amino-α-D-mannofuranoside To a solution of the compound l-O-dodecyl-2,3-O-isoρropylidene-6-deoxy-6- benzyl(methyl)amino-α-D-mannofuranoside (7.8g, 15.8mmol) in dichloromethane at 0°C was added methanesulphonyl chloride (2g, 17.4mmol) and triethylamine (8g, 79.4mmol) and stirred the reaction mixture for 30 minutes at the same temperature and then at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulphate and concenfrated under reduced pressure to furnish the title compound. Yield: 8.8g
Step b: Synthesis of l-O-dodecyI-2,3-O-isopropyIidene-5,6-dideoxy-5-benzylamino-6- benzyl(methyl)amino-β-L-gulofuranoside To the compound obtained from step a bove (8.8g) was added benzylamine (20ml) at 140°C and stirred the reaction mixture for 4 hours. Excess of benzylamine was removed under reduced pressure. The residue thus obtained was purified by column chromatography to furnish the title compound. Yield: 5.5g. Step c: Synthesis of l-O-dodecyl-2,3~O-isopropylidene-5,6-dideoxy-5-amino-6- methylamino-β-L-guIofuranoside
To a solution of the compound obtained from step b above (5.5g) in methanol (50 ml) was added palladium on carbon (4g, 10%) and stined the reaction mixture under hydrogen atmosphere at 50 psi for 8 hours. The reaction mixture was filtered tlirough celit pad and the filterate was concenfrated under reduced pressure to furnish the title compound. Yield: 2.8g. Step d: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-amino-6- (methylamino)-5,6-N-carbonyl-β-L-gu!ofuranoside
To a solution of the compound obtained from step c above (2.4g) and triphosgene (588 mg, 1.98mmol) in dichloromethane (20ml) was added diisopropylethylamine (7.74g) at 0°C and stirred the reaction mixture at room temperature for 1 hour. The reaction mixture was diluted with dichlomethane, washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 2% methano in dichloromethane as eluent to furnish the title compound. Yield: 1.8g. 1H NMR (DMSOd6):δ 4.98 (IH, s), 4.79-4.80 (IH, m), 4.47 (IH, d, J=6Hz), 3.79-3.8 (IH, m), 3.48-3.57 (2H, m), 3.01-3.04 (IH, m), 2.68 (3H, s), 1.21-1.46 (26H, m), 0.81-0.83 (3H, m). LCMS (m/z): 427.37 (M++l).
Example 47: Synthesis of l-O-dodecyl-2.3-O-isopropylidene-5,6-dideoxy-5-(n-butylamino)-
6-(methylamino)-5.6-N-carbonyl-β-L-gulofuranoside (Compound No. 250)
To a solution of the Compound No. 268, (lOOmg, 0.23mmol) and n-butylamine (64mg, 0.46mmol) in tetrahydrofuran (5ml) at 0°C was added potassium-tertbutoxide (52mg,
0.46mmol) and stirred at the same temperature for 30 minutes followed by stirring at room temperature for overnight. The resulting reaction mixture was heated at 60°C for 1 hour followed by quenching with water and brine. The mixture was exatracetd with ethylacetate, dried over anhydrous sodium sulphate and concenfrated under reduced pressure. The residue thus obtained was purified by column chromatography using 20% ethylacetate in hexane as eluent to furnish the title compound. Yield: 95mg.
1H NMR (CDCl3):δ 5.04 (IH, s), 4.71-4.72 (IH, m), 4.54-4.56 (IH, m), 3.90-3.91 (IH, m), 3.54-3.66 (3H, m), 3.33-3.43 (2H, m), 3.11-3.23 (IH, m), 2.97-3.00 (IH, m), 2.90 (3H, s), 1.44-1.58 (5H, m), 1.25-1.28 (23H, m), 0.86-0.95 (6H, m). LCMS (m/z): 483.3 (M++1).
Following compounds were prepared similarily, l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[2,4-difluorobenzyl]amino}-6- (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 252) l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[4-trifluoromethylbenzyl]amino}-6- (methylamino)-5„6-N-carbonyl-β-L-gulofuranoside (Compound No. 254)
1 -O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [2,6-dichlorobenzyl]amino} -6- (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 255) l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(benzylamino)-6-(methylamino)-5,6-N- carbonyl-β-L-gulofuranoside (Compound No. 256) l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(propargylamino)-6-(methylamino)-5,6-N- carbonyl-β-L-gulofuranoside (Compound No. 257) l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(cyclopropylmethyl)-6-(methylamino)-5,6- N-carbonyl-β-L-gulofuranoside (Compound No. 258) l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[2-ethoxycarbonylethyl]amino}-6- (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 259) l-O-dode,cyl-2,3-O-isopropylidene-5,6-dideoxy-5-(n-propylamino)-6-(methylamino)-5,6-N- carbonyl-β-L-gulofuranoside (Compound No. 260) l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(3-phenylpropyl)amino}-6-
(methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 261) l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(4-chlorobenzyl)amino}-6-
(methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 262) Scheme XV, procedure:
Example 48: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-{r4- fluorobenzoyl]amino}-β-L-gulofuranoside (Compound No. 264) To a solution of the compound l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-amino-β-L- gulofuranoside (500mg, 1.29mmol) in dichloromethane (5ml) was added 4-fluorobenzoyl chloride (204mg, 1.29mmol) and stirred the reaction mixture at 0°C for 40 minutes. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound. Yield: 650mg.
1H NMR (CDCl3):δ 7.78-7.83 (2H, m), 7.08-7.26 (2H, m), 6.84-6.86 (IH, m), 5.02 (IH, s), 4.76-4.796 (IH, m), 4.59-4.61 (IH, m), 4.30-4.38 (2H, m), 3.86-3.98 (2H, m), 3.57-3.61 (IH, m), 3.37-3.40 (IH, m), 1.51-1.53 (2H, m), 1.38 (3H, s), 1.25-1.29 (21H, m), 0.85-0.89 (3H, m). LCMS (m/z): 510.3 (M++1).
Example 49: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-amino-5-N,6-O-{(4- fluorobenzylylidenel -β-L-gulofuranoside (Compound No. 267)
Step a: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-[(4- fluoro)benzovIlamino-6-O-methanesuIphonyl-β-L-gulofuranoside To a solution of the Compound No. 264 (347mg, 0.68mmol) in dichloromethane (10ml) at 0°C was added triethylamine (75mg, 0.74mmol) and methanesulphonyl chloride (78mg, 0.68mmol) and stirred at 0°C for lhour. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried dried over anhydrous sodium sulphate and concenfrated under reduced pressure to furnish the title compound. Yield: 340mg. Step b: Synthesis of l-O-dodecyl-2,3-O-isopropyIidene-5-deoxy-5-amino-5-N,6-O-{(4- fluorobenzylylidene}-β-L-gulofuranoside (Compound No. 267)
To a solution of the compound obtained from step a above (340mg) in dichloromethane (5ml) was added diazabicycloundecene (155mg, l.Ommol) and refluxed for 2 hours. The reaction mixture was diluted with dichloromethane, washed water and brine, dried dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 10% ethylacetate in hexane as eluent to furnish the title compound. Yield: 320mg. 1H NMR (CDCl3):δ 7.98-8.0 (2H, m), 7.01-7.10 (2H, m), 5.11 (IH, s), 4.70-4.73 (IH, m), 4.54-4.61 (3H, m), 4.60-4.61 (IH, m), 3.94-3.97 (IH, m), 3.68-3.71 (IH, m), 3.41-3.44 (IH, m), 1.47-1.54 (5H, m), 1.21-1.30 (21H, m), 0.87 (3H, t, J=6Hz). LCMS (m/z): 492.4 (M++l).
1 -O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-amino-5-N,6-O- { [(4- fluorophenyl)amino]methylylidene} -β-L-gulofuranoside (Compound No. 266) Scheme XVI, procedure:
Example 50: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-({[(4- carboxymethylphenyl)amino]thiocarbonyl}-ammo)-β-L-gulofuranoside (Compound No. 270) Step a: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-({([4- (methoxycarbonylmethyl)-phenyllamino)thiocarbonyl}-amino)-β-L-gulofuranoside To a solution of the compound methyl (4-aminophenyl)acetate (208mg, 1.29mmol) in tetrahydrofuran (5ml) was added diisopropylethylamine (332mg, 2.58mmol) and thiocarbonyl diimidazole (229mg, 1.29mmol) and stined for lhour at room temperature. To the resulting reaction mixture was added 1 -O-dodecyl-2,3 -O-isopropylidene-5-deoxy-5-amino-β-L- gulofuranoside (500mg, 1.29mmol) and stirred for overnight. The reaction mixture was diluted with ethyl acetate, washed water and brine, dried dried over anhydrous sodium sulphate and concenfrated under reduced pressure. The residue thus obtained was purified by column chromatography using to furnish the title compound. Yield: 350mg. Step b: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-({[4- carboxymethylphenyl)amino]thiocarbonyl}-amino)-β-L-gulofuranoside (Compound No. 270) To a solution of the compound obtained from step a above (lOOmg, 0.16mmol) in tefrahydrofuran: methanol: water (3:1:1) ml, was added lithium hydroxide monohydrate (7mg,
O.lδmmol) and stirred for 3 hours. The resulting reaction mixture was concenfrated under reduced pressure and subsequently acidified with sodium bisulphate. The mixture was extracted with ethyl acetate, washed water and brine, dried dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound. Yild: 80 mg.
1H NMR (CDCl3):δ 7.16-7.26 (4H, m), 4.99 (IH, s), 4.68-4.69 (IH, m), 4.58-4.60 (IH, m),
4.38 (IH, bs), 3.97-4.00 (IH, m), 3.82-3.87 (IH, m), 3.56-3.65 (3H, m), 3.33-3.50 (IH, m),
1.51-1.52 (2H, m), 1.41 (3H, s), 1.25-1.29 (21H, m), 0.86-0.88 (3H, m). LCMS (m/z): 581.37 (M++1).
Example 51: Synthesis of l-O-dodecyI-2,3-O-isopropylidene-5-deoxy-5-amino-5-N,6-O-
{( [4-carboxymethylphenyll amino)methylylidenel-β-L-gulofuranoside (Compound No.
269)
Step a: Synthesis of l-O-dodecyI-2,3-O-isopropylidene-5-deoxy-5-amino-5-N,6-O-{([4- methoxycarbonylphenyl]amino)methylylidene}-β-L-gulofuranoside
To a solution of the compound obtained from Exmple 46, step a (150mg, 0.25mmol) in acetonitrile (5ml) was added dicyclohexylcarbodiimide (78mg, 0.37mmol) and refluxed for 5 hours. The resulting reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by column chromatography to furnish the title compound. Yield: 85mg.
Step b: Synthesis of l-O-dodecyl-2,3-O-isopropylidene-5~deoxy-5-amino-5-N,6-O-{([4- carboxymethylphenyl]amino)methylylidene}-β-L-gulofuranoside
To a solution of the compound obtained from step a above (85mg, 0.15mmol) in tefrahydrofuran: methanol: water (3:1:1) ml, was added lithium hydroxide monohydrate (9.5mg, 0.22mmol) and stirre for 3 hours. The resulting reaction mixture was concentrated under reduced pressure and subsequently acidified with sodium bisulphate. The mixture was exfracted with ethyl acetate, washed water and brine, dried dried over anhydrous sodium sulphate and concenfrated under reduced pressure to furnish the title compound. Yield: 63 mg. 1H NMR (DMSOd6):δ 7.43-7.45 (2H, m), 7.08-7.11 (2H, m), 4.99 (IH, s), 4.78-4.79 (IH, m),
4.51-4.53 (IH, m), 4.21-4.30 (3H, m), 3.77-3.78 (IH, m), 3.33-3.53 (4H, m), 1.48 (2H, bs),
1.37 (3H, s), 1.02-1.23 (21H, m), 0.83-0.85 (3H, m).
LCMS (m/z): 547.36 (M++l). Example 52: Pharmacological activity The compounds of the present invention were tested in one or more of the assays described herein. Standard assays were used to evaluate activity of compounds in present invention on inflammatory cells. Attenuation of agonist-induced release of lipid mediator of neutrophil chemotaxis, leukotriene B4 (LTB4), is used to evaluate inhibitory effect on neutrophils.
A23187 induced LTB4 release 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 μl of the of neutrophil suspension (0.2x10 cells/ml) was taken and added 19μL of Hank's Buffer salt solution along with lμL of the test drug (200 times concentrated) in a 24 well plate and incubated at 37°C for lhour. 3 minutes before the end of test compound incubation, 0.25 mM Ca^/Mg"1" " were added. Then, 0.3 μg/ml A23187 (Sigma Chem, USA) was added and incubated for further 10 min at 37°C. The reaction was stopped by adding 80 μL of cold methanol and centrifuged to remove cell debris (J Pharmacol Exp Ther. 297:267, 2001). The samples were analysed for LTB4 release using LTB ELISA kits (Assay Design Inc., USA). The amount of LTB4 released was quantified and percent inhibition of LTB4 release was calculated with respect to the difference between the A23187 stimulated and negative control cells, to compute IC50 values. In vitro data on the following compounds were obtained: compound numbers 24, 64, 75, 81, 83-84, 94-95, 102, 104, 107-109, 111-114, 117-121, 129-135, 164, 166, 168, 189-196, 199-202, 205- 208, 210-211, 213-215, 217-218, 220, 223-225, 228-230, 233, 235, 237, 243-244, 246, 251- 254, 256-271, 274-277, and 281-289. The results showed IC50 values of compounds of from about 30 μM to about 1.2 μM, for example, from about 20 μM to about 1.2 μM, or from about 10 μM to about 1.2 μM, or from about 8.2 μM to about 1.2 μM, or from about 2.5 μM to about 1.2 μM. Assay for 5-Lipoxygenase Activity In a 96 well UN-plate, 100 μl of phosphate buffer saline (PBS) containing DTT (200 μM), ATP (100 μM) and calcium chloride (100 μM) was added. To each well 0.5 μl of test drug (200 times concentrated) or vehicle was added, followed by 4 μl of recombinant 5-Lox (3 units/μl) and was incubated at 37°C for 5 min. The reaction was initiated by adding 1 μl of ImM freshly prepared arachidonic acid and increase in absorbance was monitored at 236 mn for 10 min. (JBiol Chem. 261:11512, 1986) 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 confrol values, to compute IC50 values. Compound numbers 218, 220, 228, 277, 281, 282, 283, 284, 287, 288, and 289 were tested in this way, providing activities, as measured by IC50 values, of between about 9.5 μM and about 0.1 μM, for example between about 6.7 μM and about 0.1 μM., or for example, between about 4.5 μM and about 0.1 μM, or for example, between about 2.8 μM and about 0.1 μM, or for example, between about 0.5 and about 0.1 μM.

Claims

We Claim: 1. A compound of Formula I
Figure imgf000142_0001
Formula I and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-oxides, metabolites, polymoφhs, or pharmaceutically acceptable solvates
wherein
A) hydrogen, B) lower (Cι-C6) alkyl {wherein alkyl is optionally substituted with hydroxyl, cycloalkyl, aryl, -OCONRpRq, -NRpRq [wherein Rp and Rq are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalky]l or Rp and Rq may together join to form a cyclic ring (3-8 membered), which may be optionally benzofused, containing 0-4 heteroatoms (selected from O, S, and N) [wherein the ring may be substituted with one or more of alkyl, alkenyl, alkynyl, hydroxyl, - NH2, substituted amino, cycloalkyl, -COOR (wherein R7 is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, or cycloalkyl), carboxy, oxo, alkoxy, aryloxy, halogen (F, Cl, Br, I), aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl]], -ORp (where Rp is as defined above), -C(=O)QR2 (wherein Q is O or NH and Rz is selected from hydrogen, alkyl, aralkyl, aryl, or heteroarylalkyl), heteroaryl, or heterocyclyl}, C) lower (C2-C6) alkenyl, D) lower (C2-C6) alkynyl, E) aryl, F) heterocyclyl (see proviso immediately below), G) heteroaryl (with the proviso that when R5 (defined below) is a derivative of a heteroatom such as O or N then the heterocyclyl or heteroaryl cannot be linked through a heteroatom), H) -ORp wherein Rp is the same as defined earlier (with the proviso that when R5 (defined below) is a derivative of a heteroatom such as O or N then Ri cannot be -ORp), or I) -C(=O)QRz (wherein Q and Rz is the same as defined above). R2 and R3 together can form a five-membered acetal wherein the carbon joining the oxygens is substituted with RL and Rm wherein A) RL and Rm are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and aralkyl; B) RL and Rm together can join to form a cyclic ring (3-8 membered), wherein the ring may optionally contain one or more heteroatoms selected from O, N or S, and the ring may be substituted with one or more of alkyl, alkenyl, alkynyl, — H2, substituted amino, cycloalkyl, COOR (wherein R7 is the same as defined above), carboxy, oxo, hydroxyl, alkoxy, aryloxy, halogen (F,C1, Br, I), aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl; or C) RL and Rm together can join to form an oxo group.
A) hydrogen, or B) ORc wherein Rc is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl.
Also, when Rt is ORc then R3 and Rc together can form an acetal (wherein acetal is the same as defined earlier) and R2 can be selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl.
Also, R2 and R3 instead of forming an acetal as defined earlier may optionally and independently be selected from lower (Cι-C4)alkyl, (CH2)g -aryl (wherein g is an integer from 1-4), -C(=Ry)NHRx (wherein Ry is O or S and Rxis the same as defined below) and acyl; with R as defined earlier. Also, R3 and Rc (when R4=OR0) instead of forming an acetal as defined earlier may optionally and independently be selected from lower (Cι-C )alkyl, (CH2)g -aryl (wherein g is an integer from 1-4), -C(=Ry)NHRx (wherein Ry is O or S and Rxis the same as defined below), and acyl; with R2 is as defined earlier. R5 can be A) -OC(=O)NRχRy {wherein Rx and Ry are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, S(O)2Re [wherein R6 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, -NRpRq (wherein Rp and Rq are the same as defined earlier), aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, or heteroarylalkyl], heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, or cycloalkyl}, or Rx and Ry may also together join to form a heterocyclyl or heteroaryl ring; B) -NRjC(=O)ORs wherein Rs is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, and heteroarylalkyl; and Rj is selected from hydrogen, lower ( - C4) alkyl, lower (C3-C6) alkenyl, lower (C3-C6) alkynyl, lower (C2-C6) cycloalkyl, lower (Ci- C3) aralkyl, aryl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl; C) -(CH2)0-ιNRjYRu (wherein Y is -C(=O), -C(=S) or SO2 , Rj is the same as defined above and Ru is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl; D) -NRjC(=T)NRtRx wherein Rj is the same as defined above and Rt is OH or Rx and T is O, S, -N(CN), -N(NO2), -CH(NO2) and Rx is the same as defined earlier (with the proviso that when T is O, Ri is H or CH3, Rt is H and Rx is S(O)2R6 (where R6 is aryl) or aryl, then the aryl cannot be substituted at its para position with Cl, NO2, OCH3, CH2COOH, CH2COOCH3, CH2COLDNP, CH2CODNP or CH2CONP). Also, when R2 and R3 together join to form a five membered acetal (wherein acetal is the same as defined above) and R5 is ΝRjC(=O)ΝRtRx or NRjC(=O)Ru then R0 cannot be C1-C4 alkyl or (CH2)o-4-aryl and Rj cannot be (Cι-C4)alkyl, (CH2)0-2cycloalkyl, (C2-C6)alkenyl, (CH2)ι-4aryl, (CH2)0- -heterocyclyl, (CH2)ι.4heteroaryl, or (CH2)ι-2-O-aryl; E) heteroaryl; or F) heterocyclyl and also, wherein the said heterocyclic ring, which may or may not be benzofused, is always substituted when Ri is H, CH3 or alkyl substituted with -NRpRq (wherein Rp and Rq are hydrogen, alkyl, aralkyl or together joins to form a cyclic ring as defined earlier). Ri and R5 may also together join to form a heterocyclyl ring with the proviso that Ri and R5 together do not form an isopropylidene ring.
2. The compound according to claim 1, wherein Ri is selected from hydrogen, hydroxy, lower alkyl, lower alkylcarboxyl, lower alkyl heterocyclyl and -Oaralkyl; R2 and R3 together form isopropylidene; and R4 is selected from hydrogen, -Oaralkyl and C6.ι alkoxy.
3. The compound according to claim 2, wherein R5 is selected from Λθγ Λθ-
Figure imgf000145_0001
Figure imgf000145_0002
- irfO - *
Figure imgf000145_0003
Figure imgf000145_0004
4. The compound according to claim 1, wherein Ri is selected from hydrogen, hydroxy, lower alkyl, lower alkylcarboxyl, lower alkyl heterocyclyl, and -Oaralkyl; R2 is selected from hydrogen, -Oaralkyl, and C6-ι6 alkoxy, and Cι-3 alkoxyl C6-i6 alkoxy; and R3 and R (as -ORo) together form isopropylidene.
5. The compound of claim 4, wherein R5 is selected from,
Figure imgf000145_0005
.SA -°-V- _Λ HJ II-
Figure imgf000146_0001
Figure imgf000146_0002
Figure imgf000147_0001
Figure imgf000147_0002
6. The compound of claim 1, wherein Ri is selected from hydrogen, hydroxy, lower alkyl, lower alkylcarboxyl, lower alkyl heterocyclyl and -Oaralkyl; R2 and R3 together form a cyclohexylidene acetal; R4 is selected from hydrogen, -Oaralkyl and C6-ι6 alkoxy, and Cι-3 alkoxyl C6-ι6 alkoxy.
7. The compound of claim 6 wherein R5 is selected from
Figure imgf000148_0001
Λ-ø -Λ-CH -Ao * Ao^ -°Λιrθα ϋ^A
Figure imgf000148_0002
8. The compound of claim 1, wherein Ri is selected from hydrogen, hydroxy, lower alkyl, lower alkylcarboxyl, lower alkyl- heterocyclyl and -Oaralkyl; R2 and R3 together form a cyclopentylidene acetal; and Ri is selected from hydrogen, -Oralkyl, and C6-i6 alkoxy, and .3 alkoxyl C6-ι6 alkoxy. ( o
9. The compound of claim 8, wherein R5 is ~w N \=/ N°2
10. The compound according to claim 1, wherein R2 is selected from hydrogen, C1.3 alkoxy aryl, and C6.ι6 alkoxy, and Cι-3 alkoxyl C6-ι6 alkoxy; and R3 and R4 (as -ORc) together form isopropylidene.
11. The compound of claim 10, wherein Ri and R5 together joins to form
Figure imgf000149_0001
12. The compounds selected from 1 ,2-O-Isopropylidene-3-O-dodecyl-5-O-[ {4-(2-methoxy-2-oxo-ethyl)-phenyl} -amino]- carbonyl-6-deoxy-α-D-glucofuranoside (Compound No. 1) 1 ,2-O-Isopropylidene-3-O-dodecyl-5-O- { [(4-morpholinyl)-sulphonylamino]-carbonyl} -α-D- xylofuranoside (Compound No. 2) 1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [(4-azepanyl)-sulphonylamino]-carbonyl} -α-D- xylofuranoside (Compound No. 3) l,2-O-Isopropylidene-3-O-dodecyl-5-0-{[(l-piperidinyl)-sulphonylamino]-carbonyl}-α-D- xylofuranoside (Compound No. 4) l,2-O-Isopropylidene-3-O-decyl-5-O-{[(l-piperidinyl)-sulphonylamino]-carbonyl}-α-D- xylofuranoside (Compound No. 5) 1 ,2-O-Isopropylidene-3-O-dodecyl-5-O- { [(1 -azepanyl)-sulphonylamino]-carbonyl} -α-D- xylofuranoside (Compound No. 6) 1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [(4-moφholinyl)-sulphonylamino]-carbonyl} -α-D- xylofuranoside (Compound No. 7) l,2-O-Isopropylidene-3-O-decyl-5-O-{[(l-pyrrolidinyl)-sulphonylamino]-carbonyl}-α-D- xylofuranoside (Compound No. 8) l,2-O-Isopropylidene-3-O-heptyl-5-O-{[(l-piperidinyl)-sulfonylamino]-carbonyl}-α-D- xylofuranoside (Compound No. 9) l,2-O-Isopropylidene-3-O-hexadecyl-5-O-[{(l-piperidinyl)-sulfonylamino}-carbonyl]-α-D- xylofuranoside (Compound No. 10) 1 ,2-O-Isopropylidene-3-O-decyl-5-O-[ {4-(2-methoxy-2-oxo-ethyl)-phenyl} -amino] -carbonyl- 6-deoxy-α-D-glucofuranoside (Compound No. 11) 1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [4-(2-hydroxy-2-oxoethyl)-phenyl]-amino} -carbonyl- 6-deoxy-α-D-glucofuranoside (Compound No. 12) 1 -O-Dodecyl-2,3-0-isopropylidene-5-O- { [2-methyl-phenylamino]-carbonyl} -6-deoxy-α-D- mannofuranoside (Compound No.13 ) l-O-Heptyl-2,3-0-isopropylidene-5-O-{[(2-methyl-phenyl)-sulphonylamino]-carbonyl}-6- deoxy-α-D-mannofuranoside (Compound No. 14) l-O-Heptyl-2,3-O-isopropylidene-5-O-[{2-(4-[2-methoxy-2-oxo-ethyl]-thiazolyl)-amino}- sulfonyl-amino]-carbonyl-6-deoxy-α-D-mannofuranoside (Compound No. 15) l-O-Heptyl-2,3-0-isopropylidene-5-O-{(l-a-?epanyl)-sulfonylamino}-carbonyl-6-deoxy-α-D- mannofuranoside (Compound No. 16) l-O-Heptyl-2,3-0-isopropylidene-5-O-{(l-pyrrolidinyl)-sulfonylamino}-carbonyl-6-deoxy- α-D-mannofuranoside (Compound No. 17) l-O-(3 -Undecyloxy-propyl)-2, 3 -O-isopropylidene-5 -O- { [( 1 -pyrrolidinyl)-sulphonylamino] - carbonyl} -β-D-lyxofuranoside (Compound No. 18) 1 -O-(3 -Undecyloxy-propyl)-2,3 -O-isopropylidene-5-O- { [( 1 -piperidinyl)-sulfonylamino] - carbonyl} -β-D-lyxofuranoside (Compound No. 19) 1 -O-(3-Undecyloxy-propyl)-2,3-O-isopropylidene-5-O- {[(l-azepanyl)-sulphonylamino] - carbonyl} -β-D-lyxofuranoside (Compound No. 20) l-O-(3-Undecyloxy-propyl)-2,3-O-isopropylidene-5-O-[{(4-moφholinyl)-sulphonylamino}- carbonyl]-β-D-lyxofuranoside (Compound No. 21 ) l-O-(3-Undecyloxy-propyl)-2,3-O-isopropylidene-5-O-[(phenylamino)carbonyl]-β-D- lyxofuranoside (Compound No. 22) 1 -O-Dodecyl-2,3-O-isopropylidene-5-O- { [4-(2-methoxy-2-oxo-ethyl)-phenyl]-amino} - carbonyl-6-deoxy-α-D-mannofuranoside (Compound No. 23) l-O-Dodecyl-2,3-O-isopropylidene-5-O-[{4-methyl-phenyl-amino}-carbonyl]-6-deoxy-α-L- mannofuranoside (Compound No. 24) l-O-Dodecyl-2,3-O-isopropylidene-5-O-{[3-chloro-phenyl-amino]-carbonyl}-6-deoxy-α-D- mannofuranoside (Compound No. 25) l-O-Dodecyl-2,3-O-isopropylidene-5-O-{[4-chloro-phenyl amino]-carbonyl}-6-deoxy-α-D- mannofuranoside (Compound No. 26) l,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-({[4-(2-hydroxy-2-oxo-ethyl)-phenyl]- amino} -carbonyl)-amino-β-L-idofuranoside (Compound No. 27) 1 ,2-O-Cyclohexylidene-3-O-decyl-5-deoxy-5-[ {(4-[2-hydroxy-2-oxo-ethyl]-phenyl)-amino} - carbonyl]-amino-α-D-xylofuranoside (Compound No. 28) 1 ,2-O-Cyclohexylidene-3-O-decyl-5-deoxy-5- { [(4-methoxy-phenyl)-amino]-carbonyl} - amino-α-D-xylofuranoside (Compound No. 29) l,2-O-Cyclohexylidene-3-O-decyl-5-deoxy-5-{[(4-methyl-phenyl)-amino]-carbonyl}-amino- α-D-xylofuranoside (Compound No. 30) 1 ,2-O-Cyclohexylidene-3-O-decyl-5-deoxy-5- { [(4-chlorophenyl)-amino]-carbonyl} -amino-α- D-xylofuranoside (Compound No. 31) 1 ,2-O-Cyclohexylidene-3-O-decyl-5-deoxy-5- {(phenylamino)-carbonyl} -amino-α-D- xylofuranoside (Compound No. 32) 1 ,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5- {([4-(2-methoxy-2-oxo-ethyl)-phenyl]- amino)-carbonyl} -amino-β-L-idofuranoside (Compound No. 33) l,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-({[4-methoxy-ρhenyl]-amino}-carbonyl)- amino-β-L-idofuranoside (Compound No. 34) l,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5-{[(4-methoxy-phenyl)-amino]-carbonyl}- amino-β-L-idofuranoside (Compound No. 35) l,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-{[(4-methyl-phenyl)-amino]-carbonyl}- amino-β-L-idofuranoside (Compound No. 36) l,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-{[(4-nifro-phenyl)-amino]-carbonyl}- amino-β-L-idofuranoside (Compound No. 37) l,2-O-Cyclohexylidene-3-O-nonyl-5,6-dideoxy-5-{[(4-chloro-phenyl)-amino]-carbonyl}- amino-β-L-idofuranoside (Compound No. 38) 78 l,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5-{[(4-methyl-phenyl)-amino]-carbonyl}- 79 amino-β-L-idofuranoside (Compound No. 39) 80 l,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5-{([4-(2-methoxy-2-oxoethyl)-phenyl]- 81 amino)-carbonyl} -amino-β-L-idofuranoside (Compound No. 40) 82 l,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5-({[4-(2-hydroxy-2-oxo-ethyl)-phenyl]- 83 amino}-carbonyl)-amino-β-L-idofuranoside (Compound No. 41) 84 l,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5-{[(4-chloro-phenyl)-amino]-carbonyl}- 85 amino-β-L-idofuranoside (Compound No. 42) 86 l,2-O-Cyclohexylidene-3-O-heptyl-5,6-dideoxy-5-{[(4-nifro-phenyl)-amino]-carbonyl}- 87 amino-β-L-idofuranoside (Compound No. 43) 88 1 -O-Heptyl-2,3 -O-isopropylidene-5-O- {(4-chloro-phenyl)-amino} -carbonyl-6-deoxy-6-( 1- 89 azepanyl)-α-D-mannofuranoside (Compound No. 44) 90 1 -O-Dodecyl-2,3-O-isopropylidene-5-O- {(4-chloro-phenyl)-amino} -carbonyl-6-deoxy-6-(l - 91 azepanyl)-α-D-mannofuranoside (Compound No. 45) 92 l-O-Dodecyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-amino}-carbonyl-6-deoxy-6-(l- 93 azepanyl)-α-D-mannofuranoside (Compound No. 46) 94 Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-(phenylsulfonyl-amino)-carbonyl- 95 6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 47) 96 1 ,2-O-Isopropylidene-3 -O-decyl-5-O- { [4-methyl-phenyl] -amino} -carbonyl-6-deoxy-6-( 1 - 97 piperidinyl)-α-D-glucofuranoside (Compound No. 48) 98 l,2-O-Isopropylidene-3-O-decyl-5-O-{[4-chloro-phenyl]-amino}-carbonyl-6-deoxy-6-(l- 99- piperidinyl)-α-D-glucofuranoside (Compound No. 49)
100 1 ,2-O-Isopropylidene-3-O-decyl-5-O- { [4-methoxy-phenyl] -amino} -carbonyl-6-deoxy-6-(l -
101 piperidinyl)-α-D-glucofuranoside (Compound No. 50)
102 1 ,2-O-Cyclohexylidene-3-O-decyl-5-0- {(4-methyl-phenyl)-amino} -carbonyl-6-deoxy-6-(l -
103 pynolidinyl)-α-D-allofuranoside (Compound No. 51)
104 Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-methoxy-phenyl)-amino}-
105 carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-mannofuranoside (Compound No. 52)
106 Hydrochloride salt of l-O-heptyl-2,3-0-isopropylidene-5-O-{(4-methyl-phenyl)-amino}-
107 carbonyl-6-deoxy-6-(l-pynolidinyl)-α-D-mannofuranoside (Compound No. 53) 108 Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}-
109 carbonyl-6-deoxy-6-( 1 -pyrrolidinyl)-α-D-mannofuranoside (Compound No. 54)
110 Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-nifro-phenyl)-amino}-
111 carbonyl-6-deoxy-6-( 1 -pynolidinyl)-α-D-mannofuranoside (Compound No . 55)
112 Hydrochloride salt of l-O-Heptyl-2,3-O-isopropylidene-5-O-{[4-methyl-phenyl]-amino}-
113 carbonyl-6-deoxy-6-(l-azepanyl)-α-D-mannofuranoside (Compound No. 56)
114 Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-methoxy-phenyl)-amino}-
115 carbonyl-6-deoxy-6-(l-azepanyl)-α-D-mannofuranoside (Compound No. 57)
116 Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}-
117 carbonyl-6-deoxy-6-( 1 -azepanyl)-α-D-mannofuranoside(Compound No. 58)
118 Hydrochloride salt of l-O-heptyl-2,3-O-isopropylidene-5-O-{4-nifro-phenyl)-amino}-
119 carbonyl-6-deoxy-6-( 1 -azapenyl)-α-D-mannofuranoside (Compound No . 59)
120 l,2-O-Isopropylidene-3-O-dodecyl-5-O-{[4-methyl-phenyl]-amino}-carbonyl-6-deoxy-6-(l-
121 azepanyl)-α-D-glucofuranoside (Compound No. 60)
122 l,2-O-Isopropylidene-3-O-dodecyl-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino}-
123 carbonyl-6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 61)
124 l,2-O-Isopropylidene-3-O-dodecyl-5-O-{(4-methoxy-phenyl)-amino}-carbonyl-6-deoxy-6-
125 (l-azepanyl)-α-D-glucofuranoside (Compound No. 62)
126 l,2-O-Cyclohexylidene-3-O-decyl-5-O-{(4-nifro-phenyl)-amino}-carbonyl-6-deoxy-6-(l-
127 azepanyl)-α-D-glucofuranoside (Compound No. 63)
128 1 ,2-O-Cyclohexylidene-3 -O-decyl-5-O- { [4-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino } -
129 carbonyl-6-deoxy-6-( 1 -azepanyl)-α-D-glucofuranoside (Compound No. 64)
130 l,2-O-Cyclohexylidene-3-O-decyl-5-O-{(4-methyl-phenyl)-amino}-carbonyl-6-deoxy-6-(l-
131 azepanyl)-α-D-glucofuranoside (Compound No. 65)
132 l,2-O-Cyclohexylidene-3-O-decyl-5-O-[(4-chloro-phenyl)-amino]-carbonyl-6-deoxy-6-(l-
133 azepanyl)-α-D-glucofuranoside (Compound No. 66)
134 l,2-O-Isopropylidene-3-O-decyl-5-O-{[4-(2-methoxy-2-oxo-ethyl)-phenyl]-amino}-carbonyl-
135 6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 67)
136 l,2-O-Isopropylidene-3-O-decyl-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino}-carbonyl-
137 6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 68) 138 l,2-O-Isopropylidene-3-O-decyl-5-O-(4-methoxy-phenyl)-amino}-carbonyl-6-deoxy-6-(l-
139 azepanyl)-α-D-glucofuranoside (Compound No. 69)
140 l,2-O-Isopropylidene-3-O-decyl-5-O-(phenylamino)-carbonyl-6-deoxy-6-(l-azepanyl)-α-D-
141 glucofuranoside (Compound No. 70)
142 l,2-O-Cyclohexlidene-3-O-decyl-5-O-{(4-methoxy-phenyl)-amino}-carbonyl-6-deoxy-6-(l-
143 pyrrolidinyl)-α-D-glucofuranoside (Compound No. 71)
144 1 ,2-O-Cyclohexylidene-3-O-decyl-5-O- {(4-chloro-phenyl)-amino} -carbonyl-6-deoxy-6-(l-
145 pyrrolidinyl)-α-D-glucofuranoside (Compound No. 72)
146 l,2-O-Cyclohexylidene-3-O-decyl-5-O-{(4-nifro-phenyl)amino}-carbonyl-6-deoxy-6-(l-
147 pyrrolidinyl)-α-D-glucofuranoside (Compound No. 73)
148 l,2-O-Cyclohexylidene-3-O-decyl-5-O-{[4-(2-methoxy-2-oxo-ethyl)-phenyl]-amino}-
149 carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 74)
150 l,2-O-Cyclohexylidene-3-O-decyl-5-O-[(4-{2-hydroxy-2-oxo-ethyl}-phenyl)-amino]-
151 carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 75)
152 l,2-O-Cyclohexylidene-3-O- decyl-5-O-(phenylamino) -carbonyl -6-deoxy-6-(l-pynolidinyl)
153 -α-D-glucofuranoside (Compound No. 76)
154 Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5-O-{(4-nitro-phenyl)-amino}-
155 carbonyl-6-deoxy-6-( 1 -piperidinyl)-α-D-mannofuranoside (Compound No . 77)
156 Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5-O-{(4-methoxy-phenyl)-amino}-
157 carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 78)
158 Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-amino}-
159 I carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 79)
160 Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}-
161 carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 80)
162 Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-{(4-methyl-phenyl)-
163 sulphonylamino]-carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No.
164 81)
165 Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{(4-methyl-phenyι)-
166 sulphonylamino}-carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No.
167 82) 168- Hydrochloride salt of 1 ,2-O-isopropylidene-3 -O-heptyl-5-O- {(4-methyl-phenyl)-
169 sulphonylamino}-carbonyl-6-deoxy-6-(4-morpholinyl)-α-D-glucofuranoside (Compound No.
170 83)
171 Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{(4-methyl-phenyl)-
172 sulphonylamino}-carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No.
173 84)
174 l-O-Dodecyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-amino}-carbonyl-6-deoxy-6-(4-
175 moφholinyl)-α-D-mannofuranoside (Compound No. 85)
176 l-O-Dodecyl-2,3-O-isopropylidene-5-O-{(4-methoxy-phenyl)-amino}-carbonyl-6-deoxy-6-
177 (4-moφholinyl)-α-D-mannofuranoside (Compound No. 86)
178 l-O-Dodecyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}-carbonyl-6-deoxy-6-(4-
179 moφholinyl)-α-D-mannofuranoside (Compound No. 87)
180 1 -O-Dodecyl-2,3-O-isopropylidene-5-O- {(4-nitro-phenyl)-amino} -carbonyl-6-deoxy-6-(4-
181 moφholinyl)-α-D-mannofuranoside (Compound No. 88)
182 1 -O-Heptyl-2,3 -O-isopropylidene-5-O- {(4-chloro-phenyl)-amino} -carbonyl-6-deoxy-6-( 1 -
183 piperidinyl)-α-D-mannofuranoside (Compound No. 89)
184 1 -O-Heptyl-2,3 -O-isopropylidene-5-O- {(4-methoxy-phenyl)-amino} -carbonyl-6-deoxy-6-( 1 -
185 piperidinyl)-α-D-mannofuranoside (Compound No. 90)
186 1 -O-Heptyl-2,3 -O-isopropylidene-5-O- {(4-methyl-phenyl)-amino} -carbonyl-6-deoxy-6-( 1 -
187 piperidinyl)-α-D-mannofuranoside (Compound No . 91)
188 1 -O-Heptyl-2,3 -O-isopropylidene-5-O- {(4-nifro-phenyl)-amino} -carbonyl-6-deoxy-6-(l -
189 piperidinyl)-α-D-mannofuranoside (Compound No. 92)
190 l-O-Dodecyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-sulfonylamino}-carbonyl-6-
191 deoxy-6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 93)
192 l-O-Heptyl-2,3-O-isopropylidene-5-O-[(4-methyl-phenyl)-sulfonylamino]-carbonyl-6-deoχy-
193 6-(l-piperidinyl)-α-D-mannofuranoside (Compound No. 94)
194 l-O-Heptyl-2,3-O-isopropylidene-5-O-[(4-methyl-phenyl)-sulfonylamino}-carbonyl-6-deoxy-
195 6-(4-moφholinyl)-α-D-mannofuranoside (Compound No. 95)
196 l-O-Heptyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-amino}-carbonyl-6-deoxy-6-(4-
197 moφholinyl)-α-D-mannofuranoside (Compound No. 96) 198 l-O-Heptyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}-carbonyl-6-deoxy-6-(4-
199 moφholinyl)-α-D-mannofuranoside (Compound No. 97)
200 1 -O-Heptyl-2,3 -O-isopropylidene-5-O- {(4-nitro-phenyl)-amino)-carbonyl-6-deoxy-6-(4-
201 moφholinyl)-α-D-mannofuranoside (Compound No. 98)
202 l-O-Decyl-2,3-O-isopropylidene-5-O-{(4-chloro-phenyl)-amino}-carbonyl-6-deoxy-6-(l-
203 piperidinyl)-α-D-mannofuranoside (Compound No. 99)
204 l-O-Heptyl-2,3-O-isopropylidene-5-O-[(4-methoxy-phenyl)-amino]-carbonyl-6-deoxy-6-(4-
205 moφholinyl)-α-D-mannofuranoside (Compound No. 100)
206 Hydrochloride salt of 1 ,2-O-isopropylidene-3 -O-decyl-5-O- {(4-methyl-phenyl)-
207 sulfonylamino}-carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No.
208 101) l
209 Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-{(4-chloro-phenyl)-
210 sulfonylamino}-carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No.
211 102)
212 Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-(phenyl-sulfonylamino)-carbonyl-
213 6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 103)
214 Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{(4-methyl-phenyl)-
215 sulfonylamino}-carbonyl-6-deoxy-6-(l-pynolidinyl)-α-D-glucofuranoside (Compound No.
216 104)
217 Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{(4-methyl-phenyl)-
218 sulfonylamino}-carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No.
219 105)
220 Hydrochloride salt of 1 ,2-O-isopropylidene-3-O-dodecyl-5-O-(phenyl-sulfonylamino)-
221 carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No. 106)
222 Hydrochloride salt of 1 ,2-O-isopropylidene-3-O-decyl-5-O- {4-chloro-phenyl)-
223 sulfonylamino}-carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No.
224 107)
225 Hydrochloride salt of 1 ,2-O-isopropylidene-3-O-heptyl-5-O-[(4-chloro-ρhenyl)-
226 sulfonylamino}-carbonyl-6-deoxy-(l-azepanyl)-α-D-glucofuranoside (Compound No. 108) 227 Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-(4-methyl-phenyl)-
228 sulfonylamino}-carbonyl-6-deoxy-(l-azepanyl)-α-D-glucofuranoside (Compound No. 109)
229 Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-(phenylsulfonylamino)-carbonyl-
230 6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 110)
231 Hydrochloride salt of 1 ,2-O-isopropylidene-3-O-decyl-5-O-(phenylsulfonylamino)-carbonyl-
232 6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No. I l l)
233 Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-(phenyl sulfonylamino)-
234 carbonyl-6-deoxy-6-(4-moφholinyl)-α-D-glucofuranoside (Compound No. 112)
235 Hydrochloride salt of 1 ,2-O-isopropylidene-3-O-heptyl-5-O- { [(4-chloro-phenyl)-
236 sulfonylamino]-carbonyl} -6-deoxy-6-(l -pyrrolidinyl)-α-D-glucofuranoside (Compound No.
237 113)
238 Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{(phenylsulfonylamino)-
239 carbonyl} -6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No.114 )
240 Hydrochloride salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{[(4-methyl-phenyl)-amino]-
241 carbonyl} -6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 115)
242 Hydrochloride salt of 1 ,2-O-isopropylidene-3 -O-decyl-5-O- { [(4-chloro-phenyι)-
243 sulfonylamino]-carbonyl}-6-deoxy-6-(4-moφholinyl)-α-D-glucofuranoside (Compound No.
244 116)
245 Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-{[(4-chloro-phenyl)-
246 sulfonylamino]-carbonyl}-6-deoxy-6-(4-moφholinyl)-α-D-glucofuranoside (Compound No.
247 117)
248 Hydrochloride salt of 1 ,2-O-isopropylidene-3-O-dodecyl-5-O- { [(4-chloro-phenyl)-
249 sulfonylamino] -carbonyl} -6-deoxy-6-(4-moφholinyl)-α-D-glucofuranoside (Compound No.
250 118)
251 Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-{(phenylsulfonylamino)-
252 carbonyl}-6-deoxy-6-(4-moφholinyl)-α-D-glucofuranoside (Compound No. 119)
253 Hydrochloride salt of 1 ,2-O-isopropylidene-3-O-decyl-5-O- {(4-methyl-phenyl
254 sulfonylamino)-carbonyl}-6-deoxy-6-(4-moφholinyl)-α-D-glucofuranoside (Compound No.
255 120) 256 Hydrochloride salt of l,2-O-isopropylidene-3-O-decyl-5-O-(phenyl-sulfonylamino)-carbonyl-
257 6-deoxy-6-(4-moφholinyl)-α-D-glucofuranoside (Compound No. 121)
258 Tris salt of l,2-O-isopropylidene-5-O- {[4-(2 -hydroxy-2-oxo-ethyl)-phenyl] -amino} -carbonyl-
259 6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 122)
260 Tris salt of 1 ,2-O-isopropylidene-5-O- { [4-(2-hydroxy-2-oxo-ethyl)-phenyl] -amino} -carbonyl-
261 6-deoxy-6-[4-moφholinyl]-α-D-glucofuranoside (Compound No. 123)
262 Tris salt of 1 ,2-O-isopropylidene-5-O- { [4-(2-hydroxy-2-oxo-ethyl)-phenyl] -amino} -carbonyl -
263 6-deoxy-6-[l-piperidinyl]-α-D-glucofuranoside (Compound No. 124)
264 l,2-O-Isopropylidene-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino}-carbonyl-6-deoxy-6-
265 [l-azepanyl]-α-D-glucofuranoside (Compound No. 125)
266 l,2-O-Isopropylidene-3-O-dodecyl-5-O-{(4-nitro-phenyl)-amino}-carbonyl-6-deoxy-6-(l-
267 azepanyl)-α-D-glucofuranoside (Compound No. 126)
268 1 ,2-O-Isopropylidene-3-O-dodecyl-5-O- { [4-(2-methoxy-2- oxo-ethyl)-phenyl)-amino} -
269 carbonyl-6-deoxy-6-(l-azepanyl)-α-D-glucofuranoside (Compound No. 127)
270 1 ,2-O-Isopropylidene-3 -O-dodecyl-5-O-(phenyl-amino)-carbonyl-6-deoxy-6-( 1 -azepanyl)-α-
271 D-glucofuranoside (Compound No. 128)
272 Hydrochloride salt of 1 ,2-O-isopropylidene-3 -O-heptyl-5-O- { [4-methyl-phenyl)-
273 sulfonylamino}-carbonyl-6-deoxy-6-(l-pyrrolidinyl)-α-D-allofuranoside (Compound No.
274 129) I
275 Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-[(4-methyl-phenyl)-
276 sulfonylamino]-carbonyl-6-deoxy-6-(4-moφholinyl)-α-D-allofuranoside (Compound No.
277 130)
278 Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O-[(4-methyl-phenyl)-
279 sulfonylamino]-carbonyl-6-deoxy-6-(l-piperidinyl)-α-D-allofuranoside (Compound No. 131)
280 Tris salt of 1 ,2-O-isopropylidene-3-O-dodecyl-5-O- { [4-(2-hydroxy-2-oxo-ethyl)-phenyl]-
281 amino}-carbonyl-6-deoxy-6-(4-moφholinyl)-α-D-glucofuranoside (Compound No. 132)
282 Tris salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]-
283 amino}-carbonyl-6-deoxy-6-[l-piperidinyl]-α-D-glucofuranoside (Compound No. 133)
284 Tris salt of l,2-O-isopropylidene-3-O-dodecyl-5-O-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]-
285 amino }-carbonyl-6-deoxy-6-(l-pynolidinyl)-α-D-glucofuranoside (Compound No.134 ) 286 Hydrochloride salt of 1 ,2-O-isopropylidene-3 -O-heptyl-5-O- {(phenyl-sulfonylamino)-
287 carbonyl} -6-deoxy-6-(l-piperidinyl)-α-D-glucofuranoside (Compound No. 135)
288 Hydrochloride salt of l,2-O-isopropylidene-3-O-heptyl-5-O- {(phenyl sulfonylamino)-
289 carbonyl} -6-deoxy-6-(l-pyrrolidinyl)-α-D-glucofuranoside (Compound No. 136)
290 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {2-[4- {3-(2-methyl-phenyl)-ureido} -
291 phenyl] -acetyl} -amino-β-L-gulofuranoside (Compound No. 137)
292 l,2-O-Isopropylidine-3-O-benzyl-5-deoxy-5-{2-[(4-{2-(4-methyl-phenyl-sulfonylamino)-
293 thiazolyl} -acetyl] -amino-α-D-xylofuranoside (CompoundNo. 138) I
294 1 ,2-O-Isopropylidene-3-O-[3-phenyl-propyl]-5-deoxy-5- {2-[4-(2-phenylsulfonylamino)-
295 thiazolyl]-acetyl} -amino-α-D-xylofuranoside (Compound No. 139)
296 1 ,2-O-Isopropylidene-3-O-benzyl-5-deoxy-5- {2-[4-(2-phenylsulfonylamino)-thiazolyl]-
297 acetyl} -amino-α-D-xylofuranoside (Compound No. 140)
298 1 ,2-O-Isopropylidene-3-O-(3-phenyl-propyl)-5-deoxy- {2-[4-(2-methylsulfonylamino)-
299 thiazolyl]-acetyl} -amino-α-D-xylofuranoside (Compound No. 141)
300 1 ,2-O-Isopropylidene-3-O-benzyl-5-deoxy- {2-[4-(2-methylsulfonylamino)-thiazolyl]-acetyl} -
301 amino-α-D-xylofuranoside (Compound No. 142)
302 1 ,2-O-Isopropylidene-3-O-(3-phenyl-propyl)-5-deoxy-5- {2-[4-(2-[4-methyl-phenyl]-
303 sulfonylamino)-thiazolyl]-acetyl} -amino-α-D-xylofuranoside (Compound No. 143)
304 l,2-O-Isopropylidene-3-O-benzyl-6-deoxy-6-[(3,4-dimethoxy-phenyl)-carbonyl]-amino-α-D-
305 glucofuranoside (Compound No. 144)
306 l,2-O-Isopropylidene-3-O-benzyl-6-deoxy-6-{[(4-chloro-phenyl)-carbonyl]-amino}-α-D-
307 glucofuranoside (Compound No. 145)
308 l,2-O-Isopropylidene-3-O-(3-phenyl-propyl)-6-deoxy-6-{(3,4-dimethoxy-phenyl)-carbonyl}-
309 amino-α-D-glucofuranoside (Compound No. 146)
310 l,2-O-Isopropylidene-3-O-[3-phenyl-propyl]-6-deoxy-6-{(4-chloro-phenyl)-carbonyl}-
311 amino-α-D-glucofuranoside (Compound No. 147)
312 l,2-O-Isopropylidene-3-O-benzyl-5-O-benzyl-6-deoxy-6-{[3,4-dimethoxy-phenyl]-
313 carbonyl} -amino-α-D-glucofuranoside (Compound No. 148)
314 l,2-O-Isopropylidene-3-O-benzyl-5-O-benzyl-6-deoxy-6-{[(4-chloro-phenyl)-carbonyl]-
315 amino} -α-D-glucofuranoside (Compound No. 149) 316 1 ,2-O-Isopropylidene-3-O-[3-phenyl-propyl]-5-O-benzyl-6-deoxy-6- {(4-chloro-phenyl)-
317 carbonyl} -amino-α-D-glucofuranoside (Compound No. 150)
318 1 ,2-O-Isopropylidene-3,5-bis-O-(3-phenyl-propyl)-6-deoxy-6-[(4-chloro-phenyl)-carbonyl]-
319 amino-α-D-glucofuranoside (Compound No . 151)
320 l,2-O-Isopropylidene-3-O-(3-phenyl-propyl)-5-O-benzyl-6-deoxy-6-[(3,4-dimethoxy-
321 phenyl)-carbonyl]-amino-α-D-glucofuranoside (Compound No. 152)
322 l,2-O-Isopropylidene-3,5-bis-O-(3-phenyl-propyl)-6-deoxy-6-[(3,4-dimethoxy-phenyl)-
323 carbonyl]-ammo-α-D-glucofuranoside (Compound No. 153)
324 l,2-O-Isopropylidene-3-O-benzyl-5-O-(3-phenyl-propyl)-6-deoxy-6-[(3,4-dimethoxy-
325 phenyl)-carbonyl]-amino-α-D-glucofuranoside (Compound No. 154)
326 1 ,2-O-Isopropylidene-3-O-heptyl-5-deoxy-5- {(4-methyl-phenyl)-sulfonylamino} -α-D-
327 xylofuranoside (Compound No.155)
328 1 ,2-O-Isopropylidene-3-O-heptyl-5-deoxy-5- {(4-tert-butyl-phenyl)-sulfonylamino} -α-D-
329 xylofuranoside (Compound No.156)
330 l,2-O-Isopropylidene-3-O-pentyl-5-deoxy-5-{[{4-methoxy-3-(5-{l-methyl-3-propyl-7-oxo-
331 1 ,6-dihydro-pyrazolo[4,3 -d]pyrimidinyl} -phenyl)} -sulfonyl]-amino} -α-D-xylofuranoside
332 (Compound No. 157)
333 l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-{l-[4-{[4-(2-methoxy-2-oxo-ethyl)-phenyl]-
334 amino}-carbonyl]-piperazinyl}-α-D-lyxofuranoside (CompoundNo. 159)
335 1 -O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- { 1 -[4-(4-chloro-phenylamino)-carbonyl]-
336 piperazinyl}-α-D-lyxofuranoside (Compound No. 160)
337 1 -O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- { 1 -[4- {(4-methyl-phenyl)-amino} -carbonyl]-
338 piperazinyl}-α-D-lyxofuranoside (Compound No. 161)
339 1 -O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- { 1 -[4- {(4-methoxy-phenyl)-amino} -carbonyl]-
340 piperazinyl}-α-D-lyxofuranoside (Compound No. 162)
341 l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-{l-[4-{(4-nitro-phenyl)-amino}-carbonyl]-
342 piperazinyl}-α-D-lyxofuranoside (Compound No. 163)
343 1 -O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- { 1 -[4- {(4-chloro-phenyl)-sulfonylamino} -
344 carbonyl]-piperazinyl}-α-D-lyxofuranoside (Compound No. 164) 345 l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-{l-[4-{[4-(2-hydroxy-2-oxo-ethyl)-phenyl]-
346 amino} -carbonylj-piperazinyl} -α-D-lyxofuranoside (Compound No. 165)
347 l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-{l-[4-(4-tolylsulfonylamino)-carbonyl]-
348 piperazinyl} -α-D-lyxofuranoside (CompoundNo. 166)
349 Hydrochloride salt of l,2-O-dodecyl-3,4-O-isopropylidene-5,6-dideoxy-5-{ l-(4-[(4-methyl-
350 phenyl)-amino]-carbonyl)-piperazinyl} -β-L-gulofuranoside (CompoundNo. 167)
351 Tris salt of l-O-dodecyl-3,4-O-isopropylidene-5,6-dideoxy-5-{l-(4-[(4-{2-hydroxy-2-oxo-
352 ethyl}-phenyl)-amino]-carbonyl)-piperazinyl}-β-L-gulofuranoside (CompoundNo. 168)
353 Hydrochloride salt of l-O-dodecyl-3,4-O-isopropylidene-5,6-dideoxy-5-{l-(4-[(phenyl
354 sulfonylamino)-carbonyl])-piperazinyl}-β-L-gulofuranoside (CompoundNo. 169)
355 Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{l-[4-{(4-methoxy-
356 phenyl)-amino} -carbonylj-piperazinyl} -β-L-gulofuranoside (Compound No. 170)
357 Hydrochloride salt of l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{l-(4-benzyl)-
358 piperazinyl} -β-L-gulofuranoside (CompoundNo. 171)
359 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{l-(4-[(4-chloro-phenyl)-amino]-
360 carbonyl)-piperazinyl} -β-L-gulofuranoside (CompoundNo. 172)
361 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[l-(4-{(4-nifro-phenyl)-amino}-carbonyl)-
362 piperazinyl]-β-L-gulofuranoside (Compound No. 173)
363 l,2-O-Isopropylidene-3-O-pentyl-5-deoxy-5-[l-(4-{4-methoxy-3-(5-[l-methyl-3-propyl-
364 7oxo- 1 ,6-dihydro-pyrazolo[4,3-d]pyrimidinyl])-phenyl} -sulphonyl)-piperazinyl])-α-D-
365 xylofuranoside (CompoundNo. 174)
366 1 ,2-O-Isopropylidene-3-O-heptyl-5-O- { [3-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino} -
367 carbonyl-6-deoxy-6- {(l-piperidinyl)-ethyl} -amino-α-D-glucofuranoside (Compound No.
368 175)
369 1 ,2-O-Isopropylidene-3-O-heptyl-5-O- { [3-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino} -
370 carbonyl-6-deoxy-6- {(l-pyrrolidinyl)-ethyl]-amino-α-D-glucofuranoside (Compound No.
371 176)
372 1 ,2-O-Isopropylidene-3-O-heptyl-5-O- { [3-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino} -
373 carbonyl-6-deoxy-6- {(4-moφholinyl)-ethyl} -amino} -α-D-glucofuranoside (Compound No.
374 177) 375 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[4-{2-[2S-2-{l-methoxy-4-methyl-l-
376 oxo]-pentyl} -amino]-2-oxo-ethyl} -phenyl]-amino} -carbonyl)-amino-β-L-gulofuranoside
377 (Compound No. 178)
378 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(4-[2-(bis-[2-thienylmethyl]
379 -amino)-2-oxo-ethyl]-phenyl)-amino}-carbonyl-β-L-gulofuranoside (Compound No. 179)
380 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(4-[2-(benzyl-[2-thienylmethyl]-amino)-
381 2-oxo-ethyl]-phenyl)-amino}-carbonyl-β-L-gulofuranoside (Compound No. 180)
382 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[4-(2-oxo-2-( benzyl -α-methylbenzyl-
383 amino)-ethyl)-phenyl]-amino}-carbonyl)-amino-β-L-gulofuranoside (Compound No. 181)
384 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-(2-benzyloxyamino-2-oxo-ethyl)-
385 phenyl)-amino]-carbonyl}-amino-β-L-gulofuranoside (Compound No. 182)
386 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-[2-hydroxyamino-2-oxo-ethyl]-
387 phenyl)-amino]-carbonyl}-amino-β-L-gulofuranoside (Compound No. 183)
388 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{([4-(2-(l-azepanyl)-2-oxo-ethyl)-
389 phenyl]-amino)-carbonyl}-amino-β-L-gulofuranoside (Compound No. 184)
390 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[4-(2-oxo-2-(l-pyrrolidinyl)-ethyl)-
391 phenyl]-amino}-carbonyl)-amino-β-L-gulofuranoside (Compound No. 185)
392 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[4-(2-oxo-2-(l-piperidinyl)-ethyl)-
393 phenyl]-amino}-carbonyl)-amino-β-L-gulofuranoside (Compound No. 186)
394 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[4-{(2-amino-2-oxo-ethyl)-phenyl}-
395 amino]-carbonyl} -amino-β-L-gulofuranoside (Compound No. 187)
396 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{4-methyl-phenyl}-sulfonyl}-amino-β-L-
397 gulofuranoside (Compound No. 188)
398 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {ethylsulfonyl} -amino-β-L-gulofuranoside
399 (Compound No. 189)
400 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {4-fluoro-phenyl)-sulfonyl} -amino-β-L-
401 gulofuranoside (Compound No. 190)
402 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {(4-acetamido)-phenyl]-sulfonyl} -amino-
403 β-L-gulofuranoside (CompoundNo. 191) 404 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(3,4,5-frimethoxy-phenyl)-
405 carbonyl} amino-β-L-gulofuranoside (Compound No. 192)
406 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(2-fluorophenyl)-carbonyl}-amino-β-L-
407 gulofuranoside (CompoundNo. 193)
408 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {4-ethoxy-4-oxo-butanoyl} -amino-β-L-
409 gulofuranoside (Compound No. 194)
410 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{4-hydroxy-4-oxo-butanoyl}-amino-β-L-
411 gulofuranoside (Compound No. 195)
412 Tris salt of l,2-O-isopropylidene-3-O-dodecyl-6-deoxy-6-({[4-(2-hydroxy-2-oxo-ethyl)-
413 phenyl]-amino-carbonyl)-amino-α-D-glucofuranoside (Compound No.196 )
414 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [3-(3,4-methylenedioxy-phenyι)~
415 propionyl} -amino-β-L-gulofuranoside (Compound No. 197)
416 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{2-phenyl-ethenyl)-carbonyl}-amino-β-L-
417 gulofuranoside (Compound No. 198)
418 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{2-(3,4-methylenedioxy-phenyl)-acetyl}-
419 amino-β-L-gulofuranoside (Compound No. 199)
420 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(4-fluoro-benzyl)-carbonyl}-amino-β-L-
421 gulofuranoside (Compound No! 200)
422 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{2-(3,4-methylenedioxy-phenyl)ethenyl}-
423 carbonyl}amino-β-L-gulofuranoside (Compound No. 201)
424 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {((2S)-2-(l -hydroxy-4-methyl- 1 -oxo-
425 pentyl-amino)-carbonyl} -amino-β-L-gulofuranoside (Compound No. 202)
426 l-O-Dodecyl-2,3-O-isopropylidene-5-O-{(4-methyl-phenyl)-sulfonylamino}-carbonyl-6-
427 deoxy-6-(4-moφholinyl)-α-D-mannofuranoside (Compound No. 203)
428 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[butylamino]-carbonyl}-amino-β-L-
429 gulofuranoside (Compound No. 204)
430 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {(2-phenyl-ethyl)-amino]-thiocarbonyl} -
431 amino-β-L-gulofuranoside (Compound No. 205)
432 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {(tert-butyl-amino)-thiocarbonyl} -amino-
433 β-L-gulofuranoside (CompoundNo. 206) 434 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-fluorophenyl)-amino]-thiocarbonyl}-
435 amino-β-L-gulofuranoside (Compound No. 207)
436 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{([4-(2-hydroxy-2-oxo-ethyl)-phenyl]-
437 amino)- thiocarbonyl} -amino-β-L-gulofuranoside (Compound No. 208)
438 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[3-(2-(4-methylphenyl)-5-tert-butyl-2H-
439 pyrazolyl)-amino]-carbonyl} -amino-β-L-gulofuranoside (Compound No. 209)
440 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [3-(5-tert-butyl-2H-pyrazolyl)-amino]-
441 carbonyl}-amino-β-L-gulofuranoside (Compound No. 210)
442 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [3-(lH- 1 ,2,4-triazolyl)-amino]-
443 carbonyl} -amino-β-L-gulofuranoside (Compound No. 211)
444 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [2-(5-methyl- 1 ,3 ,4-thiadiazolyl)-amino]-
445 carbonyl} -amino-β-L-gulofuranoside (Compound No. 212)
446 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [2- {4-(2-hydroxy-2-oxo -ethyl)-
447 thiazolyl} -amino]-carbonyl} -amino-β-L-gulofuranoside (Compound No. 213)
448 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[3-(2-benzyl-5-tert-butyl-2H-pyrazolyl)-
449 amino]-carbonyl} -amino-β-L-gulofuranoside (Compound No. 214)
450 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{2-[3-(l,3,4-thiadiazolyl)-amino]-
451 carbonyl}-amino-β-L-gulofuranoside (Compound No. 215)
452 l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-chloro-phenyl)-amino]-carbonyl}-
453 amino-6-carboxy-α-D-mannofuranoside. (Compound No. 216)
454 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {(2-[4-(2-ethoxy-2-oxo-ethyl)-thiazolyl]-
455 amino)- carbonyl} -amino-β-L-gulofuranoside (Compound No. 217)
456 l-O-Dodecyl-2,3-isopropylidene-5,6-dideoxy-5-{[(4-chloro-phenyl)-amino]-carbonyl}-
457 amino-6-carboxy-β-L-gulofuranoside (Compound No. 218)
458 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-methyl-phenyl)-amino]-carbonyl}-
459 amino-6-ethoxycarbonyl-β-L-gulofuranoside (Compound No. 219)
460 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [(4-methyl-phenyl)-amino] -carbonyl } -
461 amino-6-carboxy-β-L-gulofuranoside (Compound No. 220)
462 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[{(4-chloro-phenyl)-amino}-carbonyl]-
463 ammo-6-ethoxycarbonyl-β-L-gulofuranoside (Compound No. 221) 464 l-O-Dodecyl-2,3-isopropylidene-5,6-dideoxy-5-{[(4-[2-methoxy-2-oxo-ethyl]-phenyl)-
465 amino]-carbonyl} -amino-6-ethoxycarbonyl-β-L-gulofuranoside (Compound No. 222)
466 1 -O-Dodecyl-2,3-isopropylidene-5,6-dideoxy-5- {[(4- {2-hydroxy-2-oxo-ethyl]-phenyl)-
467 amino]-carbonyl} -amino-6-carboxy-β-L-gulofuranoside (Compound No. 223)
468 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(4-[2-hydroxy-2-oxo-ethyl]-phenyl)-
469 amino]-carbonyl}-amino-6-carboxy-α-D-mannofuranoside (Compound No. 224)
470 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [(4-methyl-phenyl)-amino]-carbonyl} -
471 amino-6-carboxy-α-D-mannofuranoside (CompoundNo. 225)
472 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {[((2S)-2-[ 1 -oxo- 1 - {(2-thienylmethyl)-
473 benzyl)-amino}]-4-methyl-pentyl)-amino]-carbonyl}-amino-6-carboxy-β-L-gulofuranoside
474 (CompoundNo. 226)
475 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [((2S)-2-[l -oxo- 1 -(bis-[2-thienylmethyl]-
476 amino)]-4-methyl-pentyl)-amino]-carbonyl}-amino-6-carboxy-β-L-gulofuranoside
477 (CompoundNo. 227)
478 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [(2-methyl-phenyl)-amino]-carbonyl} -
479 amino-6-carboxy-α-D-mannofuranoside (CompoundNo. 228)
480 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(2-methyl-phenyl)-amino]-carbonyl}-
481 amino-6-carboxy-β-L-gulofuranoside (CompoundNo. 229)
482 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[{(2S)-2-[3-(4-(2-hydroxy-2-oxo-ethyl)-
483 phenyl)-ureido]-4-methyl}pentanoyl]-amino-β-L-gulofuranoside (Compound No. 230)
484 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[{(2S)-2-[3-(4-[2-methoxy-2-oxo-ethyl]-
485 phenyl)-ureido]-4-methyl}-pentanoyl]-amino-β-L-gulofuranoside (Compound No. 231)
486 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {(2S)-[2-amino-4-methyl]-pentanoyl} -
487 amino-β-L-gulofuranoside (Compound No. 232)
488 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[l-((3,4-methylenedioxy-phenyl)-3-
489 hydroxy-3-oxo-propyl)-amino]-carbonyl]-amino-β-L-gulofuranoside (CompoundNo. 233)
490 1 -O-(3,4-Methylenedioxy-benzyl)-2,3 -O-isopropylidene-5,6-dideoxy-5- { [ 1 -(2-tert-
491 butoxycarbonylamino-4-methyl-pentyl)-oxo]-amino} -β-L-gulofuranoside (Compound No.
492 234) 493 1 -0-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[ {(2S)-2-[(carboxymethyl)-amino]-4-
494 methyl} -pentanoyl]-β-L-gulofuranoside (Compound No. 235)
495 l,2-O-Cyclopentylidene-3-O-decyl-5-deoxy-5-{[4-nitro-phenyl-amino]-carbonyl}-amino-α-
496 D-xylofuranoside (Compound No. 236)
497 l,2-O-Isopropylidene-3-O-benzyl-5-deoxy-5-[6-(l-{2-carboxy-piperidinyl})-hexanoyl]-
498 amino-α-D-xylofuranoside (Compound No. 237)
499 l,2-O-Isopropylidene-3-O-benzyl-5-deoxy-5-[6-(l-{2-ethoxycarbonyl-piperidinyl})-
500 hexanoyl] -amino- -D-xylofuranoside (Compound No. 238)
501 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[{(4-chloro-phenyl)-amino}-carbonyl]-
502 amino-6-ethoxycarbonyl-α-D-mannofuranoside (Compound No. 239)
503 l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(2-methylphenyl-amino)-carbonyl}-{4-[2-
504 (2-methylphenyl)-ureido]-phenyl} -amino-β-L-gulofuranoside (Compound No. 240)
505 1 -O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [(2-methoxyphenyl)-amino]-carbonyl} -
506 {4-[3-(2-methoxy phenyl)-ureido]-phenyl} -amino-β-L-gulofuranoside (Compound No. 241)
507 l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(4-acetamido-phenyl)-(acetyl)-amino-β-L-
508 gulofuranoside (Compound No. 242)
509 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-{2-[(4-benzoylphenyl)amino]-2-
510 oxoethyl}-phenyl)amino}carbonyl}amino)-β-L-gulofuranoside (CompoundNo. 243)
511 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-{2-[(4-azidophenyl)amino]-2-
512 oxoethyl} -phenyl)amino]carbonyl} amino)-β-L-gulofuranoside (Compoun No. 244)
513 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[4-{(2-[2-(lH-imidazol-4-yl)ethyl]-
514 amino-2-oxo-ethyl)-phenyl}-amino]-carbonyl}-amino-β-L-gulofuranoside (Compound No.
515 245)
516 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-azidophenyl)amino]
517 carbonyl} amino)-β-L-gulofuranoside (Compound No. 246)
518 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-{2-[(5-carboxypentyl)amino]-2-
519 oxoethyl}-phenyl)amino}carbonyl}amino)-β-L-gulofuranoside (Compound No. 247)
520 l-O-Dodecyl-2,3-O-isopropylidene-6-deoxy-6-amino-5-O,6-N-(carbonyl)-oc-D-
521 mannofuranoside (Compound No. 248) 522 l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[4-fluorophenyl]amino]-6-(methylamino)-
523 5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 249)
524 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(n-butylamino)-6-(methylamino)-5,6-N-
525 carbonyl-β-L-gulofuranoside (Compound No. 250)
526 l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-({[(4-[carboxymethyl]phenyl)amino]
527 carbonyl} -amino)-β-L-gulofuranoside (Compound No. 251)
528 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[2,4-difluorobenzyl]amino}-6-
529 (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (CompoundNo. 252)
530 1 -O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [4-carboxymethylphenyl]amino]-6-
531 (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 253)
532 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [4-trifluoromethylbenzyl] amino} -6-
533 (methylamino)-5„6-N-carbonyl-β-L-gulofuranoside (Compound No. 254)
534 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[2,6-dichlorobenzyl]amino}-6-
535 (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 255)
536 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(benzylamino)-6-(methylamino)-5,6-N-
537 carbonyl-β-L-gulofuranoside (CompoundNo. 256)
538 l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(propargylamino)-6-(methylamino)-5,6-N-
539 carbonyl-β-L-gulofuranoside (Compound No. 257)
540 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(cyclopropylmethylamino)-6-
541 (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 258)
542 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- { [2-ethoxycarbonylethyl]amino} -6-
543 (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 259)
544 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-(n-propylamino)-6-(methylamino)-5,6-N-
545 carbonyl-β-L-gulofuranoside (Compound No. 260)
546 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{(3-phenylpropyl)amino}-6-
547 (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (Compound No. 261)
548 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- {(4-chlorobenzyl)amino} -6-
549 (methylamino)-5,6-N-carbonyl-β-L-gulofuranoside (CompoundNo. 262)
550 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(amino)carbonyl]amino}-β-L-
551 gulofuranoside (CompoundNo. 263) 552 1 -O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5- { [4-fluorobenzoyl]amino} -β-L-gulofuranoside
553 (Compound No. 264)
554 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-{[(phenylamino)carbonyl]amino}-β-L-
555 gulofuranoside (Compound No. 265)
556 1 -0-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-amino-5-N,6-O- { [(4-
557 fluorophenyl)amino]methylylidene}-β-L-gulofuranoside (Compound No. 266)
558 l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-amino-5-N,6-O-{(4-fluorobenzylylidene}-β-
559 L-gulofuranoside (Compound No. 267)
560 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-amino-6-(methylamino)-5,6-N-carbonyl-β-
561 L-gulofuranoside (CompoundNo. 268)
562 l-O-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-amino-5-N,6-O-{([4-carboxy
563 methylphenyl]amino)methylylidene}-β-L-gulofuranoside (Compound No. 269)
564 l-0-Dodecyl-2,3-O-isopropylidene-5-deoxy-5-({[4-carboxymethylphenyl)amino]
565 thiocarbonyl} -amino)-β-L-gulofuranoside (Compound No. 270)
566 l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5,6-{[(methylamino)carbonyl]azanediyl}-β- '
567 L-gulofuranoside (Compound No. 271)
568 l-O-dodecyl-2,3-O-isopropylidene-5-deoxy-5-({[(4-
569 carboxymethylphenyl)amino]carbonyl}amino)-6-O-{[(4-benzoylphenyl)amino]carbonyl}-β-
570 L-gulofuranoside (Compound No. 272)
571 l,2-O-Isopropylidene-3-O-dodecyl-5,6-dideoxy-5-[({[(4-carboxymethyl)-l,3-thiazol-2-
572 yljamino} -carbonyl)amino]-β-L-talofuranose (Compound No. 273)
573 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[({(2-[2-carboxybenzoyl]
574 phenyl)amino}carbonyl)-amino]-β-L-gulofuranoside (Compound No. 274)
575 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-[({(4-carbonylmethyl-2-iodo-
576 phenyl)amino}-carbonyl)amino]-β-L-gulofuranoside (Compound No. 275)
577 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(3-
578 carboxymethylphenyl)amino]carbonyl}-amino)-β-L-gulofuranoside (Compound No. 276)
579 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(2-
580 carboxymethylphenyl)amino]carbonyl}-amino)-β-L-gulofuranoside (CompounNo. 277) 581 l-O-(2,4-Dodecadienyl)-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-carboxymethyl-2,6-di-
582 iodophenyl)amino]carbonyl}amino)-β-L-gulofuranoside (CompoundNo. 278)
583 l-O-(2,4-Dodecadienyl)-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-carboxymethyl-2-
584 iodophenyl)-amino]carbonyl}amino)-β-L-gulofuranoside (CompoundNo. 279)
585 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(2,6-diiodophenyl)amino]
586 carbonyl} amino)-β-L-gulofuranoside (Compound No. 280)
587 1 -O-Dodecyl-2,3-O-isopropylidene-6-deoxy-5-O- { [(phenylsulfonyl)amino]carbonyl} -α-D-
588 mannofuranoside (Compound No. 281)
589 1 -O-Dodecyl-2,3-O-isopropylidene-6-deoxy-5-O- { [(2-tolylsulfonyl)amino]carbonyl} -α-D-
590 mannofuranoside (Compound No. 282)
591 l-O-Dodecyl-2,3-O-isopropylidene-6-deoxy-5-O-{[(4-
592 chlorophenylsulfonyl)amino]carbonyl} -α-D-mannofuranoside (Compound No. 283)
593 l-O-Dodecyl-2,3-O-isopropylidene-6-deoxy-5-O-{[(4-tolylsulfonyl)amino]carbonyl}-α-D-
594 mannofuranoside (CompoundNo. 284)
595 l-O-Dodecyl-2,3-O-isopropylidene-6-deoxy-5-O-{[(benzyl)amino]carbonyl}-α-D-
596 mannofuranoside (Compound No. 285)
597 1 -O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-( { [(4-
598 tolylsulfonyl)amino]carbonyl}amino)-β-L-gulofuranoside (Compound No. 286)
599 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(2-
600 tolylsulfonyl)amino]carbonyl}amino)-β-L-gulofuranoside (CompoundNo. 287)
601 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(4-
602 chlorosulfonyl)amino]carbonyl}amino)-β-L-gulofuranoside (CompoundNo. 288)
603 l-O-Dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5-({[(phenylsulfonyl)
604 amino]carbonyl} amino)-β-L-gulofuranoside (Compound No. 289)
605 l-O-Dodecyl-2,3-O-isoproρylidene-5,6-dideoxy-5-({[(4-[{[(3,4-
606 dimethoxybenzyl)amino]carbonyl}methyl]-phenyl)-amino]carbonyl}amino)-β-L-
607 gulofuranoside (Compound No. 290).
608 13. A method of making a compound of Formula IN Scheme I
Figure imgf000170_0001
609
610 wherein
611 R2, R3, R4 and Rx are the same as defined in claim 1.
612 the method comprising:
613 reacting a compound of Formula II (wherein W is -OH or -NH2 and Rr is H or CH3) with a
614 compound of Formula III to give a compound of Formula IN (wherein T is -O or -ΝH). 1 14. A method of making a compound of Formula NIII
Scheme II
Figure imgf000170_0002
Formula VIII 2 3 wherein 4 R2, R3, R-i and Rx are the same as defined in claim 1 5 the method comprising: 6 reacting a compound of Formula V with a compound of Formula VI (wherein X is -CH-, - 7 NH- or -O and k is 1-2) to give a compound of Formula Nil; and 8 reacting the compound of Formula Nil with a compound of Formula III to give a compound 9 of Formula NIII. 1 15. A method of making a compound of Formula XI Scheme
Figure imgf000171_0001
Formula IX Formula XI
wherein
Ri, R2, R3 and 4 are the same as defined in claim 1 the method comprising: reacting a compound of Formula IX with a compound of Formula X (wherein Ruis selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, and heteroarylalkyl; L is a leaving group such as OH (activated in situ, as is obvious to a sldlled practitioner) or halogen (F, Cl, Br, I) and Y is -C(=O) or C(=S)) to give a compound of Formula XI.
16. A method of making a compound of Formula XVI
Scheme IV
deprotection
Figure imgf000172_0001
FormiJq XII Formula XIV
Figure imgf000172_0002
wherein Ri, R2, R3, R-< and Rx are the same as defined in claim 1 the method comprising: reacting a compound of Formula XII with a compound of Formula XIII (wherein P is a protecting group) to give a compound of Formula XIV; deprotecting the comound of Formula XIV to give a compound of Formula XV; reacting the compound of Formula XV with a compound of Formula III to give a compound of Formula XVI.
17. A method of making a compound of Formula XNIII
Scheme IV
Figure imgf000173_0001
XII Foπnula XIV
Figure imgf000173_0002
Formula XV hal— S02Rx Path b Formula XVII
Figure imgf000173_0003
Formula XVIII wherein
Ri, R2, R3, R and Rx are the same as defined in claim 1 the method comprising: reacting a compound of Formula XII with a compound of Formula XIII (wherein P is a protecting group) to give a compound of Formula XIN; deprotecting the comound of Formula XIN to give a compound of Formula XN; reacting the compound of Formula XN with a compound of Formula XNII [wherein hal is halogen (F, Cl, Br, I)] to give a compound of Formula XNIII.
18. A method of making a compound of Formula XXIN
Scheme V
Figure imgf000173_0004
Formula XXI Formula XXII wherein R2, R3, R4, Rp and Rx are the same as defined in claim 1 the method comprising reacting a compound of Formula XIX with a compound of Formula XX to give a compound of Formula XXI; N-protecting the compound of Formula XXI to give a compound of Formula XXII (wherein P is a protecting group); reacting a compound of Formula XXII with a compound of Formula III to give a comound of I Formula XXIII; and deprotecting the compound of Formula XXIII to give a compound of Formula XXIN.
19. A method of making a compound of Formula XXNII Scheme VI
Figure imgf000174_0001
Formula XXV Formula XXVII wherein
R2, R3, R4, Rx and Ry are the same as defined in claim 1 the method comprising
reacting a compound of Formula XXV (wherein Xi is OH or halogen) with a compound of Formula XXNI to give a compound of Formula XXNII.
20. A method of maiding a compound of Formula XXIX Scheme VII
I CDIorTCD I
Figure imgf000175_0002
Figure imgf000175_0001
Formula XXVIII Formula XXIX wherein R2, R3, R , Rx and Ry are the same as defined in claim 1 the method comprising
reacting a compound of Formula XXNIII is reacted with a compound of Formula XXNI to give a compound of Formula XXIX (wherein X2 is O or S).
21. A method of making a compound of Formula XXX Scheme VII
Figure imgf000175_0003
Formula XXVIII 1. phenyl chloroformate 2. HΝRxRy Path b Formula XXVI . '
Figure imgf000175_0004
FOΓTΠL la XXX wherein
R , R3, R4, Rx and Ry are the same as defined in claim 1 the method comprising reacting a compound of Formula XXNIII is reacted with a compound of Formula XXNI and phenyl chlorformate to give a compound of Formula XXX.
22. A method for making a compound of Formula XXXII Scheme VII
Figure imgf000176_0001
Formula XXXII Formula XXVIII wherein
R2, R3, R and Rx are the same as defined in claim 1 the method comprising reacting a compound of Formula XXNIII with a compound of Formula XXXI (wherein Z is 0=0 or C=S) to give a compound of Formula XXXII.
23. A method for making a compound of Formula XLII
3 4
Figure imgf000176_0002
wherein
R2, R3, R4 and Rx are the same as defined in claim 1 the method comprising reacting a compound of Formula XXNIII with a compound of Formula XLIII (wherein P is a protecting group) to give a compound of Formula XLIN; deprotecting the compound of Formula XLIN to give a compound of Formula XLN; and reacting the compound of Formula XLN with a compound of Formula XXNI and carbonyldiimidazole to give a compound of Formula XLNI.
24. A method of making a compound of Formula XLNII Scheme IX
Figure imgf000177_0001
Formula XLV Pat b Rx— hal
Figure imgf000177_0002
Formula XLVII wherein
R2, R3, R4 and Rx are the same as defined in claim 1 the method comprising reacting a compound of Formula XXNIII with a compound of Formula XLIII (wherein P is a protecting group) to give a compound of Formula XLIN; deprotecting the compound of Formula XLIN to give a compound of Formula XLN; and reacting the compound of Formula XLN with a compound of Formula Rx-hal (wherein hal is halogen and Rx is as defined earlier) to give a compound of Formula XLNII.
25. A method of making a compound of Formula LI SCHEME X
Figure imgf000178_0001
Formula XLVIII Formula L Formula LI
wherein
R2, R3, R4, Rx and Ry are the same as defined in claim 1 the method comprising reacting a compound of Formula XLVIII with a compound of Formula XLVIII (wherein hal is halogen) to give a compound of Formula L (wherein ki is an integer ranging from 1-6); and reacting the compound of Formula L with a compound of Formula XXNI to give a compound of Formula LI.
26. A method of making a compound of Formula LIN Scheme XI
Figure imgf000178_0002
Formula LII Formula LIV wherein R^ R2, R3 and R4 are the same as defined in claim 1 the method comprising reacting a compound of Formula LII with a compound of Formula LIII (wherein hal is halogen and Y and Ru are as defined earlier) to give a compound of Formula LIN.
27. A method of making a compound of Formula LN Scheme X!
Figure imgf000179_0001
Formula LV Formula LII wherein Ri, R2, R3, R4 and Rx are the same as defined in claim 1
the method comprising
reacting a compound of Formula LII with a compound of Formula III (wherein Rx is as defined earlier) to give a compound of Formula LN.
28. A method of preparing a compound of Formula LNIII Scheme XII
Figure imgf000179_0002
Formula LV Formula LVII Formula LVIII
wherein
R2, R3, Rit, Rx and Ry are the same as defined in claim 1 the method comprising a compound of Formula LN (wherein Ji and J are integer selected from 0 or 1 and U is -OH or H) is reacted with a compound of Formula LNI (wherein Li is -Oaryl) to give a compound of Formula LNII, which, when U = OH, can be reacted with a compound of Formula Illto give a compound of Formula LNIII.
29. A method of preparing a compound of Formula LWI
Scheme XII
Figure imgf000180_0001
Formula LV Formula LVII L2— hal Path Formula LVIV (when U is OH)
Figure imgf000180_0002
Formula LW
(when J1=l and J is O) Cyclization
Figure imgf000180_0003
Formula LWI
wherein
hal, R2, R3, R}, Rx and Ry are the same as defined in claim 1 the method comprising a compound of Formula LN (wherein Ji and J are integer selected from 0 or 1 and U is -OH or H) is reacted with a compound of Formula LNI (wherein Lj is -Oaryl) to give a compound of Formula LNII, when U =OH, can be reacted with a compound of Formula LNIN (wherein L2 is -Otosyl, -Omesyl or -Otriflyl) to give a compound of Formula LNN which undergoes cyclisation to give a compound of Formula LNNI.
30. A method of preparing a compound of Formula LVXI Scheme XIII
Figure imgf000181_0001
Formula LWII Formula LWIII Formula LVIX Formula LVX
Figure imgf000181_0002
Formula LVXI
wherein
P, R2, R3, R4 and Rx are the same as defined in claim 1 the method comprising reacting a compound of Formula LVVII with a compound of Formula NHRXP to give a compound of Formula LWIII, which undergoes deprotection to give a compound of Formula LNIX, which is reacted with phenyl carbamate to give a compound of Formula LNX, which undergoes cyclization to give a compound of Formula LNXI
31. A method of preparing a compound of Formula LNXIN Scheme XIII
deprotection
Figure imgf000182_0001
Figure imgf000182_0002
Formula LWII Formula LWIII Formula LVIX 0=C=NHRx Path b Formula III
Figure imgf000182_0003
Formula LVXII
Figure imgf000182_0004
wherein
P, R2, R3, R-i and RX are the same as defined in claim 1 the method comprising reacting a compound of Formula LVVII with a compound of Formula NHRXP to give a compound of Formula LWIII, which undergoes deprotection to give a compound of Formula LVIX, which is reacted with a compound of Formula III to give a compound of Formula LVXII, which is reacted with a compound of Formula L2-hal (wherein L2 and hal are the same as defined earlier) to give a compound of Formula LVXIII, which undergoes cyclization to give a compound of Formula LVXIV.
32. A method of preparing compounds of Formulae LVXIX and LVXIV
Figure imgf000183_0001
Formula LVXIV
wherein P, R2, R3, R-i and Rx are the same as defined in claim 1 the method comprising reacting a compound of Formula LVVII is reacted with a compound of Formula LVXV to give a compound of Formula LVXVI, which is reacted with a compound of Formula NH2P to give a compound of Formula LVXII, which undergoes deprotection to*give a compound of Formula LVXVIII, which undergoes cyclisation to give a compound of Formula LVXIX, which undergoes N-derivatization with a compound of Formula Rx-hal (wherein hal are as defined earlier) to give a compound of Formula LVXIV.
33. A method of preparing compounds of Formula LXXXIV
Figure imgf000183_0002
wherein R2, R3, R4 and Rx are the same as defined in claim 1 the method comprising reacting a compound of Formula LVXX can be reacted with a compound of Formula LXXXI (wherein hal is the same as defined earlier) to give a compound of LXXXII, which can be reacted with a compound of Formula L2-hal (wherein L2 is the same as defined earlier) to give a compound of Formula LXXXIII, which undergoes cyclisation to give a compound of Formula LXXXIV.
34. A method of preparing compounds of Formula LXXXVIII Scheme XVI
Figure imgf000184_0001
wherein R2, R3, t and Rx are the same as defined in claim 1 the method comprising reacting a compound of Formula LXXXV (wherein R , R3 and R4 are the same as defined earlier) with a compound of Formula LXXXVI to give a compound of Formula LXXXVII, which undergoes cyclisation to give a compound of Formula LXXXVIII.
35. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , and at least one pharmaceutically acceptable excipient.
36. A method of inhibiting or preventing inflammation, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof.
37. A method of inhibiting or preventing autoimmune disease, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof.
38. A method of treating bronchial asthma, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof.
39. A method of treating chronic obstructive pulmonary disorder, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof. .
40. A method of treating rheumatoid arthritis, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof.
41. A method of treating type I diabetes, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof.
42. A method of treating multiple sclerosis, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof.
43. A method of treating allograft rej ection, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof.
44. A method of treating psoriasis, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof.
45. A method of treating inflammatory bowel disease, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof.
46. A method of treating Ulcerative colitis, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof.
47. A method of treating acne, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof 48. A method of treating atherosclerosis, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof. 49. A method of treating cancer, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof. 50. A method of treating pruritis, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof. 51. A method of treating allergic rhinitis, comprising administering the pharmaceutical composition of claim 35 to a patient in need thereof.
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US20210347776A1 (en) * 2019-08-12 2021-11-11 Cadila Healthcare Limited Process for preparation of grapiprant

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