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, psoriasis, inflammatory bowel disease, ulcerative colitis, acne, atherosclerosis, cancer, pruritis or allergic rhinitis. 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, inflammatory bowel disease, ulcerative colitis, acne, atherosclerosis, cancer, pruritis, allergic rhinitis and other inflammatory and/or autoimmune disorders, using the compounds are also provided.
Background of the Invention
Inflammation is a key defence mechanism of the body that is activated as a result of tissue injury. The inflammatory process is self-containing, however, under certain pathophysiological conditions the inflammatory process tends to perpetuate itself, giving rise to chronic inflammatory diseases like bronchial asthma, rheumatoid arthritis etc.
Although the exact cellular and molecular bases of most chronic inflammatory disease remain unclear, it has become apparent that several inflammatory cells act in concert towards initiation and perpertuation of an inflammatory response by releasing a wide range of chemokine. cytokine, proteolytic enzymes and other bioactive molecules. Mast cells primed by hmphocytes interact with environmental allergens and release mediators like histamine, postaglandin. 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 cvtokines (IL-4. IL-5, IL-6, IL-8, IL-13, GM-CSF and TNFalpha), chemokines and proteolytic cn/.ymes (chymase. tryptase) (Cheat 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 c\cle continues. Eosinophils infiltrate inflamed tissue following allergen - mast cell interaction in bronchial asthma and allergic rhinitis. Evidence is emerging that mast cells 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, 1998; Br. J. Pharnuicol. 128, 700. 1999; Br. J. Phurmucol. 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.

347. 1040, 2002; Thorax 57, 649, 2002), inflammatory bowel disease (Gut. 45 Suppl. 116, as well as in rheumatoid arthritis (Science 297, 1626, 2002), pathologies with prominent neutrophilic inflammation, has been proposed.
U.S. Patent 6,329,34481 discloses several monosaccharide derivatives said to be useful as cell adhesion inhibitors. It generally relates to substituted pentose and hexose monosaccharide derivatives, which are said to exhibit cell adhesion inhibitory and anti-inflammatory activities. U.S. Patent 6,590,08581 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 I'uranose and amino furanose compounds reportedly useful for rheumatoid, arthritis, imnumomodulatory diseases inflammatory and proliferative diseases. U.S. Patent 5,298,494 discloses derivatives of monosaccharides, which are said to exhibit anti-proliferative and/or anti-inllammalory activity and are useful for treating mammals having inflammatory disorders and/or autoimmune disorders. U.S Patent 4,996,195 discloses derivatives of oc,D-glucofuranose and u.D-allofuranose described as useful for treating animals and mammals with inflammatory and/or autoimmune disorders.
WO 93/13117 and U.S. Patent 5,360,792 discloses 5- or 6-deoxy hexose monosaccharides having a saturated nitrogen containing heterocycle described as useful as anti-proliferative and anti-inflammatory compounds. WO 94/28910 discloses 5,6-dideoxy-5-amino derivatives of idose and 6-deoxy-6-amino derivatives of glucose, which reportedly exhibit iminmiomodiilatory, anti-inflammatory and anti-proliferative activity. WO 94/11381 discloses derivatives of pentose monosaccharides described as useful as anti-proliferative and anti-inflammatory compounds. U.S. Patent 5,010,058 discloses 3,5,6-disubstituted derivatives of l.2-O-isopropylidene-a,O-glucofuranoside described as useful for treating inflammatory and autoimmune disorders. U.S. Patent 4,849,512 discloses 3-acylamino-3-deoxyallose derivatives. I'.S. Patent 5,367,062 discloses disubstituted and deoxy disubstituted derivatives of ot-D-l\\oluranosides reportedly having anti-inflammatory and anti-proliferative activity. U.S. Patent 5.360.794 discloses disubstituted derivatives of a-D-mannofuranoside reportedly having anti-mllammaiory and anti proliferative activity. WO 03/029263 discloses 3-deoxy-3-amide derivatives of carbohydrates described as useful as inducers of erythroid cell differentiation. FR 2735 130 discloses regiospecific synthesis of new carbamic polyesters.

Summary of the Invention
Monosaccharide derivatives which can be used for the inhibition and prevention of inilummation and associated pathologies, including inflammatory and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, type 1 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, psoriasis, inflammatory bowel disease, ulcerative colitis, acne, atherosclerosis, cancer, pruritis and allergic rhinitis are provided herein.
Other aspects will be set forth in accompanying description which follows and in part \\ ill he apparent from the description or may be learnt by the practice of the invention.
In accordance with one aspect, there are provided compounds having the structure of I formula I.

(Formula Removed)

Formula I R i and RT can together form a five-membered acetal, wherein the carbon atom joining the
oxygens can be substituted with R^and Rm [wherein R[,and Rm are independently selected from hulrogen. alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl; or Ri.and Rm can together join to form a 3-8 membered ring, wherein the ring may optionally contain one or more heteroatoms selected from O, N or S, and the ring may be optionally substituted with one or more of alkyl. alkenyl. alkynyl, amino, substituted amino, cycloalkyl, oxo, hydroxy. carboxy, -COQR6 (\\herein Q is O orNH and R(, is selected from alkyl, alkenyl, alkynyl, aryl. aralkyl. and cNcloalkyl), alkoxy, aryloxy, halogen (F,C1, Br, 1), aryl, aralkyl, heteroaryl, heterocyclyl, lieteroarylalkyl. or heterocyclylalkyl; or RL and Rm can together join to form an oxo group].
l<; can be
A) -(CTIi)nG wherein n is an integer from 0-5 and G is selected from I) ORC {wherein Re is selected from
a) acyl (with the proviso that n cannot be 0), and
b) -C(=O)NR(Rq [wherein Rt and RC] can be independently selected from
hydrogen, hydroxy (with the restriction that both Rf and Rq cannot both be hydroxy), alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, and S(O)2Ry (wherein R7 is
selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl,
heterocyclylalkyl, heteroarylalkyl, and optionally substituted amino)]; and Rt and RC1 may also
together join to form a heterocyclyl ring; also, when n is zero, then Rt and Rq cannot be
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl and Rf and Rq together cannot join to form a
heterocyclyl ring};
2) -NRjC(=O)ORs (wherein R, is selected from hydrogen, lower (C|-C6) alkyl, lower
(C'.i-('(,) alkenyl, lower (C2-C&) alkynyl, lower (C3-C6) cycloalkyl, aryl, heteroaryl (with the
proviso that the heteroaryl ring is not linked through a heteroatom), aralkyl (C|-C4),
heteroarylalkyl (Ci-C/t), and heterocyclylalkyl (C|-C4), and Rs is selected from alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heteroarylalkyl);
3) NRjYRLI (wherein Rj is the same as defined above and Y is -C(=O), -C(=S) or SO2
and Ru is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl,
heieroarylalkyl, and heterocyclylalkyl; and when n is 0 then Y cannot be -C(=O));
4) -NRjC(=T)NRtRx (wherein R, is OH or Rx and T is O, S, -N(CN). -N(NO2), -
(.'I UNO:). Rj is the same as defined above and Rx is selected from hydrogen, alkyl, alkenyl,
alkynyl. cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl,
and S(O)2R7 wherein R; is the same as defined above);
5) heterocyclyl;
6) heteroaryl; and
7) -(C=O)NRaRb (wherein Raand Rb are independently selected from hydrogen, and
Ru wherein Ru is same as defined earlier, also, Ra and Rb together with the nitrogen atom
carrying them can be the N-terminus of an amino acid or di-tetrapeptide or Ra and Rb may
together join to form a heterocyclyl ring).
R i can also be
U) -NR,Rm (wherein R, is the same as defined above and Rm is selected from alkyl, cycloalkyl,
an I. aralkyl. heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl);
(.') -O(C1 h)uC| [wherein w is an integer from 1-5 (and G| is selected from ORC (wherein Re is
the same as defined above), -NRjC(=O)ORs (wherein R, and Rs are the same as defined above), -
NRjC(=T)NRiRx (wherein Rj, T, Rt and Rx are the same as defined above), -NRjYRu (wherein
Y. Ru and Rj are the same as defined above), heterocyclyl, and heteroaryl)];
D) -NRjiCTbXvGi (wherein w, R, and GI are the same as defined above);
I:) -CHChbXvG? [wherein w is the same as defined above (and G2 is selected from
-C'(K))NRaRh (wherein Ra and Rh are the same as defined above), and -C(=O)ORk (wherein Rk
is 11 or R,, and R(, is the same as defined above); or
I ) -NR^CTbXvG? (wherein w is as defined above, R, and Ga are the same as defined above))].
Also, when R', is ORC then R2 and Re may together join to form a five membered acetal wherein
the carbon linking the two oxygens is substituted with RL and Rm (wherein RI, and Rm are the
same as defined earlier) (and RI is independently selected from
a) -(CH2)iG| (wherein t is an integer from 2-4 and GI are the same as defined above and
also when GI is heterocyclylalkyl group then the group cannot be 4-(l-pyrrolidinyl) butyl).
b) -(CH2)wG2 (wherein w and G2 are the same as defined above),
c) aryl,
d) aralkyl (with the proviso that aralkyl cannot be phenylpropyl),
e) heteroaryl, and
0 heterocyclyl (wherein the heteroaryl and heterocyclyl rings are not linked through a heieroatom), and cycloalkyl (with the proviso that cycloalkyl cannot be cyclooctyl). R.< and R^ can independently be selected from hydrogen, lower (Ci-QO alkyl, lower (CVCd) aikenyl. lower (CyC6) alkynyl, lower (Ca-Cg) cycloalkyl, aryl, acyl, heterocyclyl, heteroaryl, iovwr (C'i-C_i) heterocyclylalkyl, and lower (C|-C4) heteroarylalkyl; or R4 and R.s may together Kirm a live-membered acetal wherein the carbon linking the two oxygens is substituted with RI and Rm (wherein RI and Rm are the same as defined earlier) with the proviso that when R:, is ORL. then the acetal must be isopropylidene acetal.
The following definitions apply to terms as used herein
The term "alkyl" unless otherwise specified, refers to a monoradical branched or uiibranched 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-he.xyl. n-decyl, tetradecyl. and the like.
Alkyl may further be substituted with one or more substituents selected from alkenyl, alkynyl. alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, a/ido. cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, -COOR6 (wherein R& is the same as ,kTiiK'd earlier), arylthio, thiol, alkylthio, aryloxy, aminosulfonyl. -NRjC(=O)Ru, -NR^. -C r-0)NR;,Rlv -NHC'(=O)NRXR,., -N(OH)C(=O)NRXR,. -C(=O)heteroaryl, C(=0)heterocyclyl, -OIV:O)NR\R| (wherein R,, RB, Rh, Rlh Rx and Rt are the same as defined earlier), nitro, -
S(.(})mR7 (wherein m is an integer from 0-2 and R? 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, -COOR6 (wherein R6 is the same as defined earlier), -NRtRN. -C(=O)NRaRb, -OC(=O)NRXR(, -N(OH)C(=O)NRxRt, -NHC(=O)NRXR( (wherein Ra, Rh R\ and R,are the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and -S(O)mR7 i\\hcre R? and m are the same as defined earlier); or an alkyl group as defined above may also IK- interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur and -NRt. \\hcTi- R, is chosen from hydrogen, alkyi, cycloalkyl, alkenyl, cycloaikenyl, alkynyl, aryl, acyl. uialkyl,-C(=O)OR(,,wherein R& is the same as defined earlier), S(O)2Rv (where RV is same as defined earlier), -C(=O)NRaRb (wherein Ra, Rb, Rx and Rtare as defined earlier).
The term "alkenyl,1' unless otherwise specified, refers to a monoradical of a branched or Linbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms with cis ur trans geometry. In the event that alkenyl is attached to the heteroatom, the double bond cannot be alpha to the heteroatom. Alkenyl groups may further be substituted with one or more substituents selected from alkyl, alkynyl, alkoxy, cycloalkyl, cycloaikenyl, acyl, acylamino, acyloxy, -NRjC(=O)Ru , -NRxRt, -C(=O)NRaRh, -N(OH)C(=O)NRXR,, -NHC(=O)NRXR, . -()C(^C))NRxRi (wherein R,, Ra, Rtl ,Rh, Rx and Rt are the same as defined earlier), Lilkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo. thiocarbonyl, carboxy, -COORfi (wherein Rf, is the same as defined earlier), aryltbio, thiol, alkylthio, aryl. aralkyl, aryloxy, hciomcyclyL heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, alkoxyamino, nitro, and S(O)n,R7 (wherein RI 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, -COOR6 (wherein R6 is the same as defined earlier), hydroxy, alkoxy. halogen, -CF3. cyano, -NRxRt, -C(=O)NRaRb, -OC(=O)NRxRt (wherein Rx ,Ra. Rb and K, are the same as defined earlier) and -S(O)mR7, (where R7 and m are the same as defined curlier)
The lerm "alkynyl," unless otherwise specified, refers to a monoradical of an unsaturated hulrocarbon. preferably having from 2 to 20 carbon atoms. In the event that alkynyl is attached 10 the heteroatom, the triple bond cannot be alpha to the heteroatom. Alkynyl groups may further be substituted with one or more substituents selected from alkyl, alkenyl, alkoxy. cycloalkyl. cycloaikenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy. oxo, thiocarbonyl, carboxy, -COOR6 (wherein R6 is the same as defined earlier), urylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl. nitro, heterocyclyl, heteroaryl. heterocyclyl alkyl, heteroarylalkyl, -NRjC(=O)Ru , -NR,RX, ,-C(=O)NR.,Rh.
N(OH)C(=O)NRXR,, -NHC(=O)NRxRt,, -O-C(=O)NRXR, (wherein Rh Ra, Rb, Ru, Rx and R, are
ihe 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. -COOR6 (wherein R,, is the same as defined earlier), hydroxy, alkoxy, halogen, CF3, NR,RX, -C(-0)NRaR,,. -N(OH)C(=O)NRXR,, -NHC(=0)NRXR< (wherein Ra, Rh, Rx and R, are the same as defined earlier), cyano, and -S(O)mR7 (where R; 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 ulelinic bonds, unless otherwise constrained by the definition. Such cycloalkyl groups include. In way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclooctyl, c>clopentenyl, 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. I'\cloalkyl groups may further be substituted with one or more substituents selected from alkyl, ulkenyl. alkynyl, alkoxy, cycloalkyl, cycloalkenyt, acyl, acylamino, acyloxy, uikoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, -COOR6 h\herein Rh is the same as defined earlier), arylthio. thiol, alkylthio, aryl. aralkyl, aryloxy, ununosutfonyl. -NRjC(=O)Ru, -NR,RK, -C(=0)NRaRb, -N(OH)C(=O)NRXR(, -NHC(=O)NRXRL, -(X'(=O)NRXR1 (wherein Rj, Ra, Rb, RU. R\ and Rt are the same as defined earlier), nitro. heierocyclyl. heteroaryl, heterocyclylalkyl, heteroarylalkyl, and S(O)m-R? (wherein R?and m are ihe 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, -COOR(, i \\ herein R(, is the same as defined earlier), hydroxy, alkoxy, halogen, CF3. -NR,RX, rr-0)NRaRb - -N(OH)C(=O)NRXR,, -NHC(=O)NRxRt,, -C(=O)NRxRy, -NHC(=O)NRXR, . OC'(=O)NRxRy (wherein Ra, Rh, Rx , Rt and Ry are the same as defined earlier), cyano, and S(O),,|R7. (where R7 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 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 carbocyclic aromatic group, for example phenyl, biphenyl or naphthyl ring and the like optionally substituted with 1 to 3 substituents selected from (CH;>)wC(=0)Rg (wherein w is an integer from 1-4 and Rg is hydroxy). -OR/ (wherein R/ is hydrogen, alkyl, aralkyl, heteroaryl alkyl), -NRxRt, -NHORX or -NHOH, halogen (F. Cl, Br, 1). hydroxy. alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy. cyano, nitro,
NR,CX=0)RU, -NRxRt, -C(=O)NRaRb, -N(OH)C(=O)NR,Rt, -NHC(=O)NRXR, , -(SO2}inR7 (wherein R7, Rx, Rt, Ru, Rz and Rt and m are the same as defined earlier), carboxy, -COOR& (wherein R() is the same as defined earlier), heterocyclyl, heteroaryl, heterocyclylalkyl, heieroarylalkyl. The aryl group may optionally be fused with cycloalkyl group wherein the cycloalkyl group may optionally contain heteroatoms selected from the group consisting of O, N. S.
The term "aryloxy" denotes the group O-aryl wherein aryl is the same as defined above.
'f'he 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 heteroatoin(s) independently selected from N, O and S optionally substituted with 1 to 3 iiibstiuient(s) selected from halogen (F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl. carboxy, -COOR(, (wherein R& is the same as defined earlier), aryl, alkoxy, aralkyl, cyano, niiro. -NRxRb ~{CH2)wC(=O)Rg (wherein w is an integer from 1-4 and Rg is hydroxy, OR,, NK.R,, -NHOR, or -NHOH), -C(=O)NRaRb, -N(OH)C(=O)NRxRt, and -NHC(=O)NRXR, , -S(hR.7 and -OC(=O)NRxRt (wherein RV, Rz, Rt, Rx, Ra and Rb 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 can include pyridinyl, pyridazinyt, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, triazinyl, furanyl. benzofuranyl, mdolyl. benzothiazolyl, benzoxazolyl, and the like.
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 the ring are icplaced by heteroatoms selected from O, S or N, and are optionally benzofused or fused hcicroaryl of 5-6 ring members and/or are optionally substituted wherein the substituents are selected from halogen (F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl. acyl, aryl, alkoxy. alkaryl, cyano, nitro, oxo, carboxy, -COORs (wherein R6 is the same as defined earlier), -U=0)NRBRb, SO2R7, -OC(=O)NRxRt, -N(OH)C(=O)NRxRt, -NHC(=O)NRXR,, and -NRxRt (wherein Ra, Rh. R?, Rx and Rt 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 heterocyclyl ring may optionally contain one or more olefinic bond(s). Examples of heterocyclyl groups can include tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyL piperidinyl or piperazinyl.
"Heteroarylalkyl" refers to alkyl-heteroaryl group linked through alkyl portion, wherein ihe alkyl and heteroaryl are the same as defined earlier.
"Heterocyclylalkyl" refers to alkyl-heterocyclyl group linked through alkyl portion, ss herein the alkyl and heterocyclyl are the same as defined earlier.
"Acyl" refers to -C(=O)R" wherein R" is selected from the group alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl.
"Substituted amino," unless otherwise specified, refers to -N(Rk)i wherein each Rk is independently selected from hydrogen (provided that both Rk groups are not hydrogen, defined as "amino"), alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl. heierocyclylalkyl, heteroarylalkyl, acyl, S(0)mR7 (wherein m and R-; is the same as defined above). -C'(=Rv)NRNRt or -NHC(=Rv)NRtRx (wherein Rv is O or S and Rt and Rx are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally he further substituted by 1-3 substituents chosen from alkyl, aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl. carboxy, -COOR&, (wherein R& is the same as defined earlier), hydroxy. alkoxy, halogen. CF3, cyano, -C(=Rv)NRxRt, -O(C=0)NRxRt (wherein Rx, Rt and Rv are the same as defined earlier), -OC(=RV)NRXR1-, and -S(O)mR7, (where Rj is the same as defined above and m isU. 1 Gi-2).
The term "leaving group" generally refers to groups that exhibit the 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 10. halogen (F, Cl, Br, I), Inflates, tosylate, mesylates, alkoxy, thioalkoxy, hydroxy radicals and the like.
The term "activated derivative of a carboxylic acid," can include, for example, protected amino acids, aliphatic acids or aromatic acids converted to their corresponding acyl halides (e.g., acid fluoride, acid chloride and acid bromide), corresponding activated esters (e.g.. nitro phenyl osier, the ester of 1-hydroxybenzotriazole or the ester of hydroxysuccinimide, HOSu) or mixed anhydrides, for example, anhydride with ethyl chloroformate and other derivatives within the skill of the art.
The term "protecting groups" is used herein to refer to moieties which have the property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be left unaffected by the particular chemical modification. Also the term protecting group, unless otherwise specified, may be used with groups such as hydroxy, amino and carboxy. Examples of such groups are found in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2lld Ed., John Wiey and Sons, New York, N.Y. The
species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting jAuip employed are not critical, so long as the derivatised moieties/moiety is/are stable to .-onditions of subsequent reactions and can be removed without disrupting the remainder of the nolecule.
"Amino acid" refers to both natural and unnatural amino acids. The term "natural amino icid." as used hereind, is intended to represent the twenty two naturally-occurring amino acids jjycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, \ rosine. trytophan, cysteine, proline, proline, histidine, aspartic acid, asparagines, glutamic acid, iluiamine. y-carboxyglutamic acid, arginine, ornithine and lysine in their L form. The term •unnatural amino acid," as used herein, is intended to represent the 'D' form of the twenty two luiuraliy-oecurring amino acids described above. It is further understood that the term unnatural imino acid includes homologues of the natural amino acids, and synthetically modified form of lie natural amino acids commonly utilized by those in the peptide chemistry arts when preparing .ynthetic 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 \\o carbon atoms, amino acids comprising optionally substituted aryl groups, and amino acids •omprised 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 amino acids linked through amide inkages. Dipeptide comprises of 2 amino acids, tripeptide refers to a peptide having 3 amino .cids and tetrapeptide refers to one having four amino acids, wherein the term amino acid is as Iclincd earlier. "LDVP" refers to a tetrapeptide leucyl-aspartyl-valyl-prolyl. "DVP" refers to a ripeptide aspartyl-valyl-prolyl. "VP" refers to a dipeptide valyl-prolyl.
Compounds disclosed herein contain one or more asymmetric carbon atoms and thus can \isi as racemates and racemic mixtures, single enantiomers, diastereomieric mixtures and ndividual diastereomers. All such isomeric forms of these compounds are expressly included crcin. Each stereogenic carbon may be of the R or S configuration. Although the specific oinpounds exemplified in this application may be depicted in a particular stereochemical onliguration, compounds having either the opposite stereochemistry at any given chiral center r mixtures thereof are envisioned. Although amino acids and amino acid side chains may be cpicted in a particular configuration, both natural and unnatural forms are envisioned.
Detailed Description of the Invention
Compounds disclosed herein may be prepared by techniques well known in the art and imiliar to a practitioner of ordinary skill in art. In addition, compounds disclosed herein may be prepared by the processes described herein, these processes are not the only means by which ihe compounds described may be synthesised. Further, synthetic steps described herein may be performed in an alternate sequence or order to give the desired compounds.
Compounds of Formula VII can be prepared by Scheme I. Thus, a compound of Formula II (wherein R|. R?, R4 and Rj are the same as defined earlier) can be oxidized to form a compound of Formula 111, which can be reacted with hydroxylamine hydrochloride to form a compound of Formula IV, which can undergo reduction to form a compound of Formula V, \\hich can be reacted with a compound of Formula VI (wherein X is O or S and Rx the same as defined earlier) to furnish a compound of Formula VII.
The oxidation of a compound of Formula II to form a compound of Formula III can be carried out under various conditions. For example, one may use Swern's oxidation utilizing dimethyl sulphoxide and acetic anhydride or oxalyl chloride, optionally in either dimethyl sulphoxide or dichloromethane as solvents. One may also utilize oxidizing agents such as pyridinium chlorochromate, pyridinium dichromate, pyridine-sulfurtrioxide or periodinane in an organic solvent such as dichloromethane, chloroform for the oxidation of a compound of formula II to form a compound of Formula III.
Thus, the oxidation of a compound of Formula II can be carried out utilizing dimethyl sulphoxide and acetic anhydride to furnish a compound of Formula III.
The reaction of a compound of Formula III with hydroxylamine hydrochloride to form a compound of Formula IV can be carried out in an organic solvent such as ethanol, methanol, propanol or isopropyl alcohol, in the presence of an organic base such as pyridine. triethylamine or diisopropylethylamine.
The reduction of a compound of Formula IV to yield a compound of Formula V can be carried out in an organic solvent such as tetrahydrofuran, dimethylformamide, diethylether or dioxane. with a reducing agent such as lithium aluminium hydride or sodium borohydride.
The reaction of a compound of Formula V with an isocyanate or isothiocyanate of I ornuila VI to yield a compound of Formula VII can be carried out in an organic solvent such as ucetonitrile. dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
Alternatively, a compound of Formula VII can also be prepared by reacting a compound of Formula V with an appropriate amine in the presence of reagents such as carbonyldiimidazole (C'L)l) or with carbamates such as phenyl carbamate or p-nitrophenyl carbamate of an amine. Also, optionally thiocarbonyldiimidazole or an isothiocyanate can be used in place of carbonyldiimidazole or isocyanate, respectively in the reaction.
Particular illustrative compounds prepared following Scheme I include:
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-chloro-phenyl)-aminoj-carbonyl]-aniino-a-
D-allofuranoside (Compound No. 1);
l,2;5.6-Di-O-isopropylidene-3-deoxy-3-[{(4-methoxy-phenyl)-amino}-carbonyl]-amino-
u-D-allofuranoside (Compound No. 3);
l,2:5,6-Di-O-isopropylidene-3-deoxy-3-[{phenyl-sulphonylamino}-carbonyl]-amino-a-
D-allofuranoside (Compound No. 5);
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-methyl-phenyl)-sulphonylamino}-
carbonyl]-amino-a-D-allofuranoside (Compound No. 7);
1.2;5.6-Di-0-isopropylidene-3-deoxy-3-[{(4-nitro-phenyl)-amino}-carbonyl]-amino-a-
D-ulloriiranoside (Compound No. 9);
l,2:5,6-Di-O-isopropylidene-3-deoxy-3-[{4-methylphenyl}-amino}-carbonyl]-amino-a-
D-allofuranoside (Compound No. 11);
1.2;5,6-Di-O-isopropy[idene-3-deoxy-3-[{(4-trifluoromethyl-phenyl)-aminoj-carbonyl]-
amino-a-D-allofuranoside (Compound No. 47);
l,2:5,6-Di-O-isopropylidene-3-deoxy-3-{[(2-phenylethyl)-amino]thiocarbonyl}-amino-
u-D-allofuranoside (Compound No. 49);
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-{[(4-fluorophenyl)-amino]thiocarbonylj-aniino-
a-D-allofuranoside (Compound No. 50).
An alternative route for the synthesis of compounds of Formula VII is outlined in
Scheme II below:

(Formula Removed)

Thus, a compound of Formula II (wherein RI, R2, R4 and R? are the same as defined jurlier) can be reacted with a compound of Formula VIII [wherein L is a leaving group such as ios) 1 or mcsyl and hal is a halogen (Cl, Br, I)] to form a compound of Formula IX, which can be reacted with sodium azide to form a compound of Formula X, which can undergo reduction to \ ield a compound of Formula V, which can be reacted with a compound of Formula VI (wherein X is O or S and Rx is the same as defined earlier) to furnish a compound of Formula VII.
A compound of Formula II can be reacted with a compound of Formula VIII to form a compound of Formula IX in the presence of an organic base, such as pyridine, triethylamine or diisopropylethylamine.
Alternatively, the hydroxyl group in a compound of Formula II can also be converted to a irillyl group with triflic anhydride.
A compound of Formula IX can be reacted with sodium azide in an organic solvent such as dimethylformamide, tetrahydrofuran, dioxane or diethyl ether.
Alternatively, one may also use trimethylsilyl azide or lithium azide in place of sodium a/ide. Similarly, one may also use benzyl amine in place of azido moiety, which on dcbcn/.ylation would furnish a compound of Formula V.
A compound of Formula X can be reduced to give a compound of Formula V in an organic solvent such as tetrahydrofuran, dioxane, ethanol or diethyl ether, with a reducing agent such as lithium aluminum hydride or sodium borohydride.
Alternatively, the reduction of a compound of Formula X can also be carried out by hvdrogenation in the presence of catalytic palladium on carbon.
A compound of Formula V can be reacted with a compound of Formula VI to yield a compound of Formula VII in an organic solvent such as acetonitrile, dichloromethane, dichloroethane. chloroform or carbon tetrachloride.
Also, the alternate strategies mentioned in Scheme I are applicable for the syntheses of compounds of Formula VII.
Compounds prepared following Scheme II are:
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-([{4-(2-methoxy-2-oxoethyl)-phenyl}-amino]-
carbonyl)-amino-a-D-glucofuranoside (Compound No. 4);
1.2:5.6-Di-O-isopropylidene-3-deoxy-3-([ {4-(2-hydroxy-2-oxoethyl)-phenyl j -aminoj-
carbonyl)-amino-a-D-glucofuranoside (Compound No. 6);
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-methyl-phenyl)-amino}-carbonyl]-amino-a-D-glucofuranoside (Compound No. 8);
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-chloro-phenyl)-amino}-carbonyl]-amino-a-D- glucofuranoside (Compound No. 10);
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-[phenyl-amino-carbonyl]-amino-a-D-glucofuranoside (Compound No. 12);
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-nitro-phenyl)-aminoj-carbonyl]-amino-a-D-glucofuranoside (Compound No. 14);
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-fluoro-phenyl)-amino}-carbonyl]-amino-a-D-allofuranoside (Compound No. 51).
(Formula Removed)
A compound of Formula XI can be prepared following Scheme III. Thus, a compound of Formula II (wherein R|, Ra, R4 and Rs are the same as defined earlier) can be reacted with a compound of Formula VI (wherein X is O or S and Rx is the same as defined earlier) to form a compound of Formula XI.
A compound of Formula II can be reacted with a compound of Formula VI to furnish a compound of Formula XI in an organic solvent such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
Compounds prepared following Scheme III are:
l,2;5,6-Di-O-isopropylidene-3-O-[(4-fluoro-phenyl)-amino]-carbonyl]-a-D-glucofuranoside (Compound No. 48);
l,2;5,6-Di-O-isopropylidene-3-0-[(4-methyl-phenyl)-amino]-carbonyl]-a-D-glucofuranoside (Compound No. 13);
l,2;5,6-Di-O-isopropylidene-3-O-[(4-methoxy-phenyl)-amino]-carbonyl-a-D-glucofuranoside (Compound No. 15);
l,2;5.6-Di-O-isopropylidene-3-0-[(4-chloro-phenyl)-amino]-carbonyl-ot-D-glucofuranoside (Compound No. 16).

(Formula Removed)
A compound of Formula XVI can be prepared by Scheme IV. Thus, a compound of Formula XII (wherein RI, Ra, R4 and R, are the same as defined earlier and r is an integer from 1 hi 3) can be reacted with a compound of Formula VIII [wherein L is a leaving group such as IHOSN I or tosyl and hal is a halogen (Cl, Br, I)] to form a compound of Formula XIII, which can be reacted with sodium azide to form a compound of Formula XIV, which can undergo reduction to give a compound of Formula XV, which can be reacted with a compound of Formula VI to furnish a compound of Formula XVI.
A compound of Formula XII can be reacted with a compound of Formula VIII to form a compound of Formula XIII in the presence of a base such as pyridine, triethylamine or diisopropylethylamine, in an organic solvent selected from the group such as dichloromethane. leirahydrofuran or dimethylformamide. Thus for example, a compound of Formula XII can be reacted with p-toluenesuphonyl chloride to form the tosyl compound, a compound of Formula XIII.
A compound of Formula XIII can be reacted with sodium azide to form a compound of Formula XIV in an organic solvent such as dimethylformamide, tetrahydrofuran, dioxane or diethyl ether.
A compound of Formula XIV can be reduced to yield a compound of Formula XV in an organic solvent such as tetrahydrofuran, dimethylformamide, dioxane or diethyl ether, with a reducing agent such as lithium aluminum hydride, sodium borohydride.
Alternatively, a compound of Formula XV can also be prepared by hydrogenation of a compound of Formula XIV in the presence of palladium on carbon.
A compound of Formula XV can be reacted with a compound of Formula VI in a organic solvent selected from, for example, dichloromethane, dichloroethane, carbon tetrachloride or chloroform.
Alternative methods as provided for the synthesis of a compound of Formula VII in Scheme I, are also applicable for the synthesis of a compound of Formula XVI.
Compounds prepared following Scheme IV are:
l,2;5.6-Di-O-isopropylidene-3-deoxy-3-[2-{3-(4-chloro-phenyl)-ureido!-ethylj-a-D-allofuranoside (Compound No. 2);
1.2;5.6-Di-O-isopropylidene-3-deoxy-3-[2-{3-(4-methyl-phenyl)-ureidoj-ethyl]-a-D-allofuranoside (Compound No. 17);
K2;5,6-Di-O-isopropylidene-3-deoxy-3-{2-[3-(4-methoxy-phenyI)-ureido]-ethyl}-a-D-allofuranoside (Compound No. 18).

(Formula Removed)
Formula XIX can be prepared by PggxiV- Thus, a compound of i-unnula XVII (wherein RI, RS, R4 and RS are the same as defined earlier, r is an integer from 1 Ui 3 and hal is (Cl, Br, I) can be reacted with a compound of Formula XVI]I (wherein 63 is a ik'itTocyelyl ring attached to H through N) to yield a compound of Formula XIX.
A compound of Formula XVII can be reacted with a compound of Formula XVIII to form a compound of Formula XIX in an organic solvent such as dimethylformamide, tetrahydrofuran, dioxane or diethyl ether, In the presence of a base such as potassium carbonate, sodium bicarbonate, triethyl amine, pyridine or diisopropylethylamine.
Compounds prepared following Scheme V are:
2.3;5,6-Di-O-isopropyIidene-l-O-{3-[l-(4-[3-chloro-phenyl]-piperazinyI)]-propyIj-a-D-mannofuranoside (Compound No. 29);
2.3;5,6-Di-O-isopropylidene-l-0-{2-[l-(4-[4-chloro-phenyl]-piperazinyl)]-ethyl}-a-D-mannofuranoside (Compound No. 30);
2.3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-[4-methoxy-phenyl]-piperazinyl)]-ethylS-a-D-mannofuranoside (Compound No. 31);
2,3;5,6-Di-O-isopropylidene-l-0-{2-[l-(4-[2-pyrimidinyl]-piperazinyl)]-ethyl)-a-D-mannofuranoside (Compound No. 32);
2,3;5,6-Di-O-isopropylidene-l-O-{2-[4-morpholinyt]-ethyl}-a-D-mannofuranoside (Compound No. 33):
2.3;5.6-Di-0-isopropylidene-l-O-{2-[l-(4-benzyl-piperazinyl)]-ethyl}-a-D-mannofuranoside (Compound No. 34);
2,3:5.6-Di-O-isopropylidene-l-O-{2-[l-(4-[4-chloro-phenyl-amino-carbonyl]-piperazinyl)]-ethylj-a-D-mannofuranoside (Compound No. 35); 2,3;5.6-Di-O-isopropylidene-l-O-{2-(l-piperazinyl)-ethyl}-a-D-mannofuranoside (Compound No. 36).

(Formula Removed)

Compounds of Formulae XXII, XXIII and XXV can be prepared by Scheme VI. <•'•' A compound of Formula XX (wherein r, R2, Ra, R4, R5 are the same as defined earlier)
can reacted with a compound of Formula XXI (wherein Z is a halogen (Cl, Br, I) or OH, Y and
Ru are the same as defined earlier) to yield a compound of Formula XXII.
I'iiih k: A compound of Formula XX can be reacted with a compound of Formula VI (wherein X
is () or S and RN is the same as defined earlier) to form a compound of Formula XXIII.
I'iiih c: A compound of Formula XX can be reacted with a compound of Formula XXIV
(wherein Rv is alkyl and hal (Cl, Br, I) to form a compound of Formula XXV.
A compound of Formula XX (Path a) can be reacted with a compound of Formula XXI | when Y is -C(=O)j to furnish a compound of Formula XXII an organic solvent such as dichloromethane, dichloroethane, carbon tetrachloride or chloroform, in the presence of an organic base such as triethylamine, pyridine or diisopropylamine.
Alternatively, when Y is -C(=O), a compound of Formula XX may react with "an activated derivative of a carboxylic acid" to furnish a compound of Formula XXII.
A compound of Formula XX (Path b) can be reacted with a compound of Formula VI to \ ield a compound of Formula XXIII in an organic solvent such as dichloromethane, chloroform, carbon tetrachloride or tetrahydrofuran.
Alternative methods as provided for the synthesis of a compound of Formula VII in Scheme 1. are also applicable for the synthesis of a compound of Formula XX1I1.
A compound of Formula XX (Path c) can be reacted with a compound of Formula XXIV io form a compound of Formula XXV in the presence of a base such as potassium carbonate, sodium bicarbonate, triethylamine, pyridine or diisopropylethylamine, in an organic solvent such as dimethylformamide, tetrahydrofuran, dioxane or diethyl ether.
Compounds prepared following Scheme VI, path a are:
2,3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-{4-methyl-phenyl-sulphonyl}-piperazinyl)j-ethylJ-a-D-mannofuranoside (Compound No. 40);
2.3;5.6-Di-O-isopropylidene-l-O-{2-[l-(4-[2-thienyl-methyl-carbonyl]-piperazinyl)|-ethylj-oc-D-mannofuranoside (Compound No. 42);
2,3;5.6-Di-O-isopropylidene-l-O-{2-[l-(4-[4-fluoro-phenyl-carbonylj-piperazinyl)]-eihylj-a-D-mannofuranoside (Compound No. 43); Compounds prepared following Scheme VI, path b are:
2,3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-{(l-naphthyl)-amino-carbonyl}-piperazinyl)J-ethyl { -a-D-mannofuranoside (Compound No. 39);
2,3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-[isopropylamino-thiocarbonyl]-piperazinyl)]-ethylj -a-D-mannofuranoside (Compound No. 38); Compounds prepared following Scheme VI, path c are: 2,3;5,6-Di-O-isopropylidene-l-0-{2-[l-(4-{[3,3']-bithiophenyl-5-ylmethylJ-piperazinyl)]-ethyl}-a-D-mannofuranoside (Compound No. 37); 2.3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-[(2-chloro-3,4-methylenedioxy-phenyl)-methyl]-piperazinyl)]-ethyl}-a-D-mannofuranoside (Compound No. 45).

(Formula Removed)
Compounds of Formula XXVIII and XXX can be prepared by Scheme VII. i'liiludl A compound of Formula XXVI (wherein RI, RS, R4 and Rs are the same as defined earlier and r is an integer from 1 to 3) can reacted with a compound of Formula XXVII (wherein K, and Rm are the same as defined earlier) to form a compound of Formula XXVIII. I'uih h: A compound of Formula XXVI can be reacted with a compound of Formula XXIX (wherein Rs is the same as defined earlier) to give a compound of Formula XXX
A compound of Formula XXVI (path a) can be reacted with a compound of Formula XXVil to form a compound of Formula XXVIII in the presence of a base such as potassium carbonate, sodium bicarbonate, triethylamine, pyridine or diisopropylethylamine in an organic solvent such as dimethylformamide, tetrahydrofuran, diethyl ether, or dioxane.
A compound of Formula XXVI (path b) can be reacted with a compound of Formula XXIX to form a compound of Formula XXX in the presence of a base such as potassium hydroxide, cesium carbonate, potassium carbonate, sodium hydride, potassium tert-butoxide, in an organic solvent such as dimethylformamide, tetrahydrofuran, dioxane and diethyl ether.
Compounds prepared following Scheme VII, path a are
2.3;5.6-Di-O-isopropylidene-l-O-{2-[l-(4-[2-(2,6-dioxo-l-piperidinyl)-acetyl]-piperazinyl)]-ethyl)-a-D-mannofuranoside (Compound No. 41) 2.3;5,6-Di-O-isopropylidene-l-0-{2-[l-(4-{2-(l-[l//-l,2,4-triazolyl])-acetyl{-piperazinyl]-ethyl) -a-D-mannofuranoside (Compound No. 44)
Compounds prepared following Scheme VII, path b are
2.3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-{2-[4-chloro-phenoxy]-acetylj-piperazinyl)J-eihyl! -ct-D-mannofuranoside (Compound No. 46)

(Formula Removed)
A compound of Formula XXXII, can be prepared by Scheme VIII. Thus, a compound of I onnula XXXI (wherein RT, is the same as defined earlier) is hydrolysed to yield a compound of I•ormula XXXII.
A compound of Formula XXXI is hydrolyzed with the reagents, for example aqueous perchloric acid, aqueous acetic acid, aqueous sulphuric acid or Dowex 50W-8X (commercially available) to form a compound of Formula XXXII in an organic solvent such as methanol, leirahydrofuran. dimethylformamide, dioxane or diethyl ether.
Compounds prepared following Scheme VIII are:
1.2-0-Isopropylidene-3-deoxy-3-{[(4-methoxy-phenyl)-amino]-carbonyl}-amino-a-D-allofuranoside (Compound No. 19);
1.2-O-Isopropylidene-3-deoxy-3-{2-[3-(4-methoxy-phenyl)-ureido]-ethyl}-a-D-allofuranoside (Compound No. 20);
L2-O-lsopropylidene-3-O-{(4-chIoro-phenyl)-amino}-carbonyl-a-D-allofuranoside (Compound No. 21);
1.2-O-lsopropyIidene-3-deoxy-3-{[(4-nitro-phenyl)-aniino]-carbonyl}-amino-a-D-allofuranoside (Compound No. 22);
l,2-O-Isopropylidene-3-deoxy-3-{[(4-chloro-phenyl)-amino]-carbonyl}-amino-a-D-alloluranoside (Compound No. 23);
l,2-O-lsopropylidene-3-0-{(4-methyl-phenyl)-amino}-carbonyl-a-D-allofuranoside (Compound No. 24);
l,2-O-lsopropylidene-3-deoxy-3-[2-{3-(4-methyl-phenyl)-ureido}-ethyl]-a-D-allol'uranoside (Compound No. 25);
1.2-O-Isopropylidene-3-deoxy-3-{2-[3-(4-{2-methoxy-2-oxo-ethylj-phenyl)-ureidoj-ethyl}-oc-D-allofuranoside (Compound No. 26);
l,2-O-Isopropylidene-3-deoxy-3-{2-[(4-methyl-phenyl)-amino]-carbonyl}-amino-a-D-allofuranoside (Compound No. 27); L2-O-Isopropylidene-3-deoxy-3-{2-[3-(4-{2-hydroxy-2-oxo-ethyl}-phenyl)-ureidoj-
ethyl] -a-D-allofuranoside (Compound No. 28).
(Formula Removed)
The compounds of the Formula XXXIV and the Formula XXXVI can be prepared by Scheme IX, thus the compound of Formula V (wherein R|, RI, R4 and R.s are the same as defined earlier) can be reacted with a compound of Formula XXXIII (wherein Ru is the same as defined earlier) lo form a compound of Formula XXXIV.
l^UJlJL. the compound of the Formula V can be reacted with a compound of Formula XXXV (wherein L is a leaving group such as halogen) to form a compound of Formula XXXVI.
The compound of Formula V (path a) can be reacted with a compound of Formula XXXI11 lo form a compound XXXIV in an organic solvent such as dichloromethane, carbon icirachloride. tetrahydrofuran or dimethylformamide, in the presence of an organic base such as iricthylamine, pyridine, or diisopropoylethylamiine.
The compound of Formula V (path b) can be reacted with a compound of Formula XXXV in a organic solvent such as acetone, tetrahydrofuran, dimethylformamide, acetonitrile or Jimethylsulphoxide, in the presence of a base such as potassium carbonate, sodium bicarbonate, trieth} lamine or pyridine.
Compounds prepared following Scheme IX, path a are:
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-{[4-fluoro-phenyl]sulphonyl}-amino-a-D-allofuranoside (Compound No. 52);
1.2:5,6-Di-O-isopropylidene-3-deoxy-3-{[4-methyl-phenyl]-sulphonyl}-amino-a-D-allofuranoside (Compound No. 53);
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-}[(4-[2-methoxy-2-oxo-ethyl]-phenyl)-amino]-carbonyl}-methylamino-a-D-allofuranoside (Compound No. 54).
Also, in ail the above representative examples wherever esters are specified, one skilled in the an 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 ihe 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. Esters such as tert-butyl can be hydrolvzed 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, hulrolyzing agents, etc., are mentioned, it is to be understood that other acids, bases, solvents, condensing agents, hydrolyzing agents, etc., may also be used. Similarly, the reaction temperature and duration of the reactions may be adjusted according to the requirements that arise during the process.
i'ariicular compounds being produced by Schemes I through IX are listed in Tables 1, II and 111.
(Table Removed)
Represent the isomer of Compound No. 11 * Represent the isomer of Compound No. 01 '•** Represent the isomer of Compound No. 925

(Table Removed)
wherein R? & Re (when RB is OR^) and R4& Rj together form isopropylidene groups)

Compound No.
29

Rl

Compound
No.
30

Rl

\ _ /
32

33

34



35

36



37

38

/— s JL
"''



39

40



41

42



43

44



45

46

l:\amples set forth general synthetic procedures for the preparation of representative compounds. The examples are provided to illustrate particular aspect of the disclosure and do noi be limit the scope of the present invention.
EXAMPLES 1 xample A: Synthesis of l,2;5.6-Di-Q-isopropylidene-3-deoxy-3-amino-oc-D-allofuranoside
Step a: Synthesis of l,2;5,6-di-O-isopropyIidene-3-oxo-oc-D-glucofuranoside
To diacetoneglucose (25g) (commercially available) was added dimethyl sulphoxide i 100ml) and acetic anhydride (50ml), The reaction mixture was stirred at 50-60°C for 24 hours. Dimethyl sulphoxide was evaporated under reduced pressure and water (2.5ml) was added with vigorous stirring followed by the addition of ether (10ml) and hexane. The mixture was kept in Ldrigc-roior for overnight. The solid thus separated was filtered to obtain the title compound
Step b: Synthesis of l,2;5,6-di-O-isopropylidene-3-deoxy-3-hydroxyimino-a-D-Ulucofuranoside
To a compound from step a above (12g), was added hydroxylamine hydrochloride (2.5g) pyridine ( 100ml) and anhydrous ethanol (100ml) at room temperature. The reaction mixture was stirred for half an hour The temperature of the reaction was raised to 75(IC and the reaction mixture was stirred for 24 hours, The solvents were evaporated off under reduced pressure and the residue thus obtained was poured into ice cold water. The organic product was extracted with eihyi acetate followed by washing with water, brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography using 25% ethyl acetate in hexane as eluent to furnish the title compound iX.5g). Step c: Synthesis of l,2;5,6-Di-O-isopropylidene-3-deoxy-3-amino-oc-D-allofuranoside
To a suspension of lithium aluminum hydride (8.4g) in tetrahydrofuran (50 ml) at 0°C, \\iis Lidded the compound obtained from step b above (8.5g in 50ml tetrahydrofuran) with constant stirring. After complete addition, the reaction mixture was allowed to attain room temperature and stirred for 8 hours. The excess of lithium aluminum hydride was decomposed by addition of ethyl acetate (100 ml) followed by the addition of water and sodium hydroxide solution (2ml. 15%) dropwise at 0°C .The reaction mixture was filtered off, washed with warm ethyl acetate and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the crude compound was purified by column chromatography using 50% iiieihanol in ethyl acetate as eluent to furnish the title compound (7.0g)
I \ ample _ B\ _ Synthesis of L2;5.6-Di-Q-lsopropvlidene-3-deoxy-3-hydroxvethyl-gc-D allofuranoside Sit-p a: Synthesis of l,2;5,6-di-O-isopropylidene-3-oxo-a-D-glucofuranoside
To diacetone glucose (25g) (commercially available) was added dimethyl sulphoxide ( 100 ml) and acetic anhydride (50ml) .The reaction mixture was stirred at 50-60°C for 24 hours. Dimethyl sulphoxide was evaporated under reduced pressure and water was added with constant sin-ring followed by the addition of ether (10ml) and hexane. The mixture was kept in refrigerator for overnight and the solid thus separated was filtered to obtain the title compound.
Step b: Synthesis of l,2;5,6-di-O-isopropylidene-3-deoxy-3-(methoxycarbonyl-methylene)-
a-l)-glucofuranoside
The ice-cold solution of trimethyl phosphonoacetate (34ml) in dimethylformamide i .54ml). was added potassium tert-butoxide (8.5g) and the reaction mixture was stirred at room temperature for 10 minutes. To it was added a solution of the compound (17g) obtained from the wr/; u above in dimethyl formamide (34ml) and the reaction mixture was stirred for 1 hour at 0-loV. The solvent was evaporated under reduced pressure and the residue was taken in water and extracted with ether followed by washing with water and brine. The mixture was dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure. The crude compound thus obtained was taken in hexane and the mixture was kept in refrigerator for u\ernight. After trituration, the solid was separated out which was filtered and dried. The compound was purified by column chromatography using to furnish the title compound (11 g). Step c: Synthesis of l,2;5,6-di-O-isopropylidene-3-deoxy-3-(methoxycarbonyl-methyl)-a-D-allot'uranoside
To a solution of a compound obtained from step b above (1 Ig) in methanol (100ml) at 0-5V. was added sodium borohydride (2.5g) in small portion with continuous stirring. The reuction mixture was stirred for one hour. The reaction mixture was allowed to come to room temperature followed by stirring for 24 hours. Acetone (10ml) was added to the reaction mixture u> decompose excess of sodium borohydride. Methanol was removed under reduced pressure. I he organic product was extracted with chloroform followed by washing with water, and brine. The reaction mixture was dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the syrup thus obtained was taken in hexane, which on scratching gave solid product, which was filtered and dried. The crude compound was purified by column chromatography using 10% ethyl acetate in hexane as eluent (9g). Sti-p d: Synthesis of l,2;5,6-di-O-isopropylidene-3-(2-hydroxyethyl)-a-D-allofuranoside
To a suspension of lithium aluminum hydride (5.7g) in tetrahydrofuran (50ml) at 0°C, \\as added a solution of the compound (16g) obtained from step c above in tetrahydrofuran (50ml) dropwise with constant stirring. After complete addition the reaction mixture was alkmed to attain room temperature and stirred for 8 hours. The excess of lithium aluminum hulride was decomposed by adding ethyl acetate (100ml) followed by the addition of water and aqueous sodium hydroxide solution (2ml, 15%) at 0°C. The reaction mixture was filtered washed with warm ethyl acetate and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography using 20% methanol in ethyl acetate as eluent to furnish the title compound
hxainple C: Synthesis of 1,2;5,6-di-O-isopropylidene-3-deoxv-3-ethylamino-a-D-
allot'uranoside
Step a: Synthesis of l,2;5,6-di-O-isopropylidene-3-deoxy-3-|2-(4-methyl-phenyI-
Milphonyloxy)-ethyl|-a-D-allofuranoside
To a solution of l,2;5,6-Di-0-isopropylidene-3-hydroxyethyl-8(lH.m). 4.29(lH,m), 4.13(2H,m), 4.01(lH,m), 3.89(lH,m), 1.55(3H,s), 1.45(3H,s), 1.35(6H.s).
Analogues of 1,2;5,6-Di-0-isopropylidene-3-deoxy-3-[{(4-trifluoromethyl-phenyl)-Liinino!-carbonyl]-amino-a-D-allofuranoside (Compound No.47) can be prepared by replacing appropriate isocyanate, respectively, as applicable in each case.
1.2:5.6-Di-O-isopropylidene-3-deoxy-3-[{(4-chloro-phenyl)-amino}-carbonylJ-amino-a-D-allofuranoside (Compound No. 1)
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-methoxy-phenyl)-aminoj-carbonyl]-amino-a-D-allofuranoside (Compound No. 3)
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-[{phenyl-sulphonylamino}-carbonyl]-amino-a-D-atlofuranoside (Compound No. 5)
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-methyl-phenyl)-sulphonylamino]-carbonyl]-amino-a-D-allofuranoside (Compound No. 7)
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-nitro-phenyl)-aminoj-carbonyl]-amino-a-D-allofuranoside (Compound No. 9) l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-methyI-phenyl)-amino}-carbonyl]-amino-
u-D-allofuranoside (Compound No. 11)
i:\ample 2: Synthesis of l,2;5.6-Di-O-isopropvlidene-3-deoxy-3-i[(2-phenvlethyl)-
aminojthiocarbonyl} -amino-q-D-allofuranoside (Compound No. 49)
To a solution of the compound l,2;5,6-Di-isopropylidene-3-deoxy--a-D-allofuranoside i lOOmg) in dichloromethane (5ml), was added triethylamine (0.06 ml) and 2-phenyl isocyanate (43mg) at room temperature. The reaction mixture was stirred for 4 hours at 55° C. Solvent was evaporated under reduced pressure. The crude compound thus obtained was purified with 50% ethyl acetate in hexane as eluent to furnish the title compound (lOOmg).
II NMR (CDCI3) (300 MHz):5 7.35-7.21(5H,m), 6.13(lH,bs), 5.92(lH,bs), 5.82(lH.d, 3.6Hz), 4.68(1 H.t, 8.7Hz), 4.52(lH,bs), 4.27(lH,q, 10.5 Hz), 4.16(lH,t, 6.6Hz), 4.00-3.88(2H,m), 3.60-V80(2H.m),2.92(2H,t,5.7Hz), 1.55(3H,s), 1.41(3H,s), 1.33(6H,s)
Analogues of 1,2;5,6-Di-O-isopropylidene-3-deoxy-3-{[(2-phenylethyl)-amino]-thio-carbonyl j-amino-a-D-allofuranoside (Compound No. 49) described below, can be prepared by replacing appropriate isothiocyanate group in place of 2-phenyl isocyanate, respectively, as applicable in each case
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-{[(4-fluorophenyl)-amino]-thio-carbonylj-
amino-a-D-allofuranoside (Compound No. 50) Scheme II
1;sample 3: Synthesis of l,2;5,6-Di-O-isopropvlidene-3-deoxv-3-([i4-(2-methoxv-2-oxo-ethyl)-phenvl !-amino]-carbonyl)-amino-q-D-glucofuranoside (Compound No. 4) Step a: Synthesis of l,2;5,6-Di-O-isopropylidene-3-O-tosyl-a-D-glucofuranoside
To a solution of diacetoneglucose (8 g) (commercially available) in pyridine (20 ml) was added a solution of p-toluenesulphonyl chloride (4 g) in pyridine (20 ml) at 0°C.The reaction mixture was stirred for 8-10 hours. The solvent was evaporated under reduced pressure and the residue thus obtained was washed with hexane to obtain the title compound (8g). Siep h: Synthesis of l,2;5,6-Di-O-isopropylidene-3-deoxy-3-azido-a-D-g!ucot'uranoside
To a solution of a compound obtained from step a above (8 g) in dimethylformamide (5()ml) was added sodium azide (1.5g). The reaction mixture was heated at 130°C for 10 hours, extracted with ethyl acetate followed by washing with water, brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography using 30% ethyl acetate in hexane as eluent to furnish the title compound (4 g). Step c: Synthesis of l,2;5,6-Di-O-isopropylidene-3-deoxy-3-amino-a-D-glucofuranoside
To a solution of lithium aluminum hydride (1.1 g) in tetrahydrofuran (20ml) at 0°C, was added the compound obtained from step b (3.5 g) in tetrahydrofuran (10ml). The reaction mixture was stirred at this temperature for 15 minutes, and then was allowed to attain at room temperature and stirred for 10 hours. The reaction mixture was extracted with ethyl acetate followed by washing with aqueous sodium bicarbonate, water and brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the crude residue was purified by column chromatography using 30% ethyl acetate in hexane as an eluent to furnish the title compound (2 g).
Step d: Synthesis of l,2;5,6-D-O-isopropylidene-3-deoxy-3-([{4-(2-methoxy-2-oxoethyl)-phenyl}-amino|-carbonyl)-amino-a,D-glucofuranoside
To a solution of the compound (1 g) obtained from step c above in dichloromethane (10 ml) at 0°C was added methyl 4-isocyanatophenyl acetate (0.71 g). The reaction mixture was stirred lor 15 minutes at the same temperature. The reaction mixture was allowed to attain room temperature and stirred for 24 hours. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography using 15% ethyl acetate in hexane as duent furnish the title compound (1.3 g).
il NMR (CDCb) (300 MHz}:5 7.35(lH,s), 7.60-7.14(4H,m), 5.95(lH,d,7.5Hz), 5.81(lH,d, 3.3H/), 4.60(1 H,d,3.48Hz), 4.3-4.23(2H,m), 4.16-4.07(2H,m), 3.96(lH,m), 3.68(3H.s), 3.56(2H.s). 1.51(3H,s), 1.4(3H,s), 1.32(3H,s), 1.27(3H,s),
Analogues of 1,2; 5,6-Di-0-isopropylidene-3-deoxy-3-([{4-(2-methoxy-2-oxo-ethyl)-phenyl}-amino]-carbonyl)-amino-a-D-glucofuranoside (Compound No. 4) can be prepared by using appropriate isocyanate in place of methyl-4-isocyanatophenyl acetate
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-methyl-phenyl)-amino}-carbonyl]-amino-
a-D-glucofuranoside (Compound No. 8)
1.2:5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-chloro-phenyl)-amino}-carbonyl]-amino-a-
D-glucofuranoside (Compound No. 10}
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-[phenyl-amino-carbonyl]-amino-a-D-
glucofuranoside (Compound No. 12)
1.2;5,6-Di-0-isopropylidene-3-deoxy-3-[i(4-nitro-phenyl)-amino}-carbonyl|-amino-a-
D-glucofuranoside (Compound No. 14)
l,2;5.6-Di-O-isopropylidene-3-deoxy-3-{[(4-fluoro-phenyl)-aminoJ-carbonyl}-amino-a-
D-allofuranoside (Compound No. 51)
1:xample 4: Synthesis of l,2:5,6-Di-O-isopropylidene-3-deoxy-3-([{4-(2-hydroxy-2-oxo-ethyl)-phenyl i -amino|-carbonyl)-amino-a-D-glucofuranoside (Compound No. 6)
To a solution of the compound No. 4 (1 g, Example 2) in methanol (100 ml), was added sodium hydroxide (20 ml, IN). The reaction mixture was stirred for 6 hour at 50°C. The solvent was evaporated under reduced pressure. The aqueous layer was neutralized with dilute hydrochloric acid. The solid thus obtained was extracted with ethyl acetate followed by washing with water, brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the crude compound was purified by column chromatography using 10% ethyl acetate in hexane as eluent to furnish the title compound (500mg).
'I! NMR (CDCb) (300 MHz):5 7.57(lH,s). 7.17(3H,s), 6.08(lH,bs), 5.85(lH,d, 3.3Hz), 4.03(1 H,d, 3.24Hz), 4.24(2H,m), 4.l4(3H,m), 4.10(lH,m), 3.56(2H,s), l.51(3H,s), 1.40(3H.s), !.33(3II,s), 1.29(3H,s).
Example 5: Synthesis of l,2;5,6-Di-O-isopropvlidene-3-O-[(4-fluoro-phenvl)-amino]-
carbonyl |-a-D-glucofuranoside (Compound No. 48)
To a solution of diacetoneglucose (260mg) in dichloromethane (10ml) at 0°C, was added 4-lluorophenyl isocyanate (105mg) and triethylamine (40mg) and then stirred at room temperature for 3-4hours, followed by refluxing for 3 hours. The volatiles were evaporated under reduced pressure and the crude residue was purified by column chromatography using 20% ethyl acetate in hexane as eluent to furnish the title compound (170mg). 'II NMR (CDC13) (300mHz): 8 7.35(2H,bs), 7.02(2H,t, 8.4Hz), 6.65(1H,N//), 5.89(1 H,d, 3.3H/.), 5.25(1 H,s), 4.65(1 H,d, 3.6Hz), 4.20-4.25(2H,m), 4.03-4.12(2H,m), 1.53(3H,s), i 43(31 l.s). 1.33(3H,s)and 1.32(3H,s).
Analogues of 1,2; 5,6-Di-O-isopropylidene-3-0-[(4-fluoro-phenyl)-amino]-carbonyl]-a-l)-allofuranoside (Compound No. 13) can be prepared by using appropriate isocyanate in place of 4-fluoro-phenyl isocyanate respectively, as applicable in each
case.
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-chloro-phenyl)-amino|-carbonyl]-amino-a-
D-allofuranoside (Compound No. 1) 1.2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-methoxy-phenyl)-aminoj-carbonyl]-amino-
u-D-allofuranoside (Compound No. 3)
1.2;5,6-Di-0-isopropylidene-3-deoxy-3-[{phenyl-sulphonylamino{-carbonyl]-amino-a-D-allofuranoside (Compound No. 5)
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-methyl-phenyl)-sulphonylaminoJ-carbonyl]-amino-a-D-allofuranoside (Compound No. 7)
l,2:5.6-Di-O-isopropylidene-3-deoxy-3-[{(4-nitro-phenyl)-aminoj-carbonyl]-amino-a-D-allofuranoside (Compound No. 9) l,2;5.6-Di-0-isopropylidene-3-deoxy-3-[{(4-methyl-phenyl)-aminoj-carbonyl]-amino-
cx-D-allofuranoside (Compound No. 11)
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-{[(4-fluorophenyl)-amino]-thio-carbonylj-
amino-cc-D-allofuranoside (Compound No. 50)
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-methyl-phenyl)-aminoj-carbonyl]-amino-
ot-D-glucofuranoside (Compound No. 8)
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-chloro-phenyl)-amino}-carbonyl]-amino-a-D-glucofuranoside (Compound No. 10)
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[phenyl-amino-carbonylJ-amino-a-D-glucofuranoside (Compound No. 12)
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-nitro-phenyl)-aminoj-carbonylJ-amino-a-D-glucofuranoside (Compound No. 14)
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-{[(4-fluoro-phenyl)-amino]-carbonylj-amino-a-D-allofuranoside (Compound No. 51)
1.2;5.6-Di-O-isopropylidene-3-O-[(4-methyl-phenyl)-amino]-carbonyl]-a-D-glucofuranoside (Compound No. 13)
l,2;5,6-Di-O-isopropylidene-3-O-[(4-methoxy-phenyl)-aminoJ-carbonyl-a-D-glucofuranoside (Compound No. 15)
l,2;5.6-Di-O-isopropylidene-3-O-[(4-chloro-phenyl)-amino]-carbonyl-a-D-glucofuranoside (Compound No. 16) Scheme IV
i xample 6: Synthesis of l,2;5,6-Di-O-isopropvlidene-3-deoxy-3-[2-!3-(4-chloro-phenyl)-LIividoi-ethyl]-a-D-allofuranoside (Compound No. 2)
To a solution of the compound l,2;5,6-di-O-isopropylidene-3-deoxy-3-ethylamino-cc-D-alloluranoside (200 mg) in dichloromethane (20 ml) at 0-5°C, was added a solution of p-dilorophenyl isocyanate (0.12 g) in dichloromethane (10 ml) with constant stirring and the reaction mixture was stirred for 15 minutes. The reaction mixture was allowed to attain room temperature and stirred for 8 hours. The solvent was evaporated under reduced pressure and the (.•rude product was purified by column chromatography using 50% ethyl acetate as eluent to I'urnish the title compound (150 mg).
'II NMR (CDC13) (300 MHz):8 7.74(lH,s), 7.35(2H,m), 7.20(2H,m), 7.35(lH,d, 3Hz), 7.20(2H,m). 5.73(1 H,d, 3Hz), 5.59(lH,d, 4.8Hz), 4.72(lH,t. 3.93Hz), 4.07-3.92(3H,m), .V75(lH.t. 7.4Hz), 3.42-3.3(2H,m), 1.90(3H,m), 1.49(3H,s), 1.4(3H,s), 1.33(3H,s). &1.30(3H,s).
Analogues of l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[2-{3-(4-chloro-phenyl)-ureidoj-eth\ Ij-u-D-allofuranoside (Compound No. 2) can be prepared by using appropriate isocyanate in place of p-chlorophenyl isocyanate, respectively, as applicable in each case
1.2;5.6-Di-O-isopropylidene-3-deoxy-3-[2-{3-(4-methyl-phenyl)-ureidoJ-ethyl]-a-D-allofuranoside (Compound No. 17)
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-{2-[3-(4-methoxy-phenyl)-ureido]-ethyl}-a-D-allofuranoside (Compound No. 18) Scheme V
hxample 7: Synthesis of 2.3;5,6-Di-O-isopropylidene-l-Q-{2-(l-piperazinyl)-ethyl}-a-D-
mannoiliranoside (Compound No. 36)
Step a: Synthesis of l-O-(2-chloroethyl)-2,3;5,6-di-O-isopropylidene-a-D-mannofuranoside
A suspension of mannose (500 mg) in anhydrous acetone (20ml) was cooled to 0°C followed by the addition of sulphuric acid (0.05 ml) and chloroethanol (558 ing). The reaction mixture was refluxed till the reaction showed completion (TLC). The reaction mixture was neutralized with triethylamine and excess of acetone was evaporated under reduced pressure. The residue thus obtained was dissolved in ethyl acetate followed by washing with aqueous sodium bicarbonate and dried over anhydrous sodium sulphate. The solvent was evaporated

under reduced pressure and the crude product was purified by column chromatography using 10% ethyl acetate as eluent to furnish the title compound (200mg).
Step b: Synthesis of 2,3;5,6-Di-O-isopropylidene-l-O-{2-(l-piperazinyl)-ethyl}-a-D-mannofuranoside (Compound No. 36)
To the compound obtained from the above step a (100 mg) was added a solution of potassium iodide (52mg) in dimethylformamide (5ml). The reaction mixture was stirred at 80°C for one hour followed by the addition of piperazine (133mg) and potassium carbonate (86mg). .After completion of reaction (TLC) the reaction mixture was poured in cold water and extracted \\ith ethyl acetate .The organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The crude residue was purified by column chromatography using 10% methanol in ethyl acetate as eluent to furnish the title compound (60 mg).
jll NMR (CDC13, 300MHz):5 4.99(1H, s), 4.78-4.75(lH, m), 4.60(1 H, m), 4.39(1 H, m). 4.09-4.03(2H, m), 4.95-4.92(1 H, m), 3.74(1H, m), 3.55-3.53(lH, m), 2.91(3H, t, 4.89Hz), 2.56(2H, t, 5.XII/), 2.26(6H, bs), 1.45(6H, s), 1.37(3H, s), 1.31(3H, s).
Analogues of 2,3;5,6-Di-O-isopropylidene-l-O-{2-(l-piperazinyl)-ethylj-a-D-mannofuranoside (Compound No. 36) can be prepared by replacing appropriate amine in place ol pipera/.ine and appropriate sugar moiety respectively, as applicable in each case.
2.3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-[4-methoxy-phenyl]-piperazinyl)J-ethylj-a-D-rnannofuranoside (Compound No. 31)
2.3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-[2-pyrimidinyl]-piperazinyl)]-ethylj-a-D-mannofuranoside (Compound No. 32)
2,3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-benzyl-piperazinyl)]-ethyl}-a-D-mannofuranoside (Compound No. 34)
2.3;5.6-Di-O-isopropylidene-l-0-{2-[4-morpholinyl]-ethyl}-a-D-mannofuranoside (C'ompound No. 33)
2.3:5,6-Di-O-isopropylidene-l-O-{2-[l-(4-[{4-chloro-phenylj-aminocarbonylj-piperazinyl)J-ethylj-a-D-mannofuranoside (Compound No. 35)
2,3;5.6-Di-O-isopropylidene-l-0-{3-[l-(4-[3-chloro-phenyl]-piperazinyl)]-propylj-a-D-mannofuranoside (Compound No. 29)
2,3;5,6-Di-O-isopropylidene-l-0-{2-[l-(4-[4-chloro-phenyl]-piperazinyl)]-ethylJ-a-D-mannofuranoside (Compound No. 30)
Scheme VI, (path a)
Example 8: Synthesis of 2.3;5,6-Di-Q-isopropylidene-l-Q-i2-[l-(4-[2-thienyl-methyl-carhonylJ-piperazinvl)]-ethyl{-a-D-mannofuranoside (Compound No. 42)
To a solution of the compound No. 36 (200 mg) in dichloromethane (10ml) cooled at 0"X'. was added triethylamine (82mg) and chloroacetylthiophene (104 mg) slowly. The reaction mixture was stirred till the reaction showed completion (TLC). The reaction mixture was poured
into ice-cold water and the product was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure. Hie crude product was purified by column chromatography using 90% ethyl acetate in hexane as eluent to furnish the title compound (90 mg).
'II NMR (CDCb) (300 MHz):8 7.21(lH,d, 4.5Hz), 6.96(lH,dd, 4.5Hz), 6.91 (lH,d, 3Hz), 4.99(1 H,s), 4.77(lH,t, 4Hz), 4.60(1 H,d, 5.8Hz), 4.4 (lH,m), 4.1 l-4.03(2H,m), 3.95(3H,m), 3.73(1 H,tn), 3.67(2H,bs), 3.53(3H,bs), 2.57(2H,bs), 2.47-2.39(4H,m), 1.48(3H,s), 1.46(3H,s), 1.39(3H,s), 1.33(3H,s).
Analogues of 2,3;5,6-Di-0-isopropylidene-l-O-{2-[l-(4-[2-thienyl-methyl-carbonyl]-pipcra/inyl)J-ethyl}-a-D-mannofuranoside (Compound No. 42) can be prepared by using appropriate acyl halide group in place of chloroacetylthiophene, respectively, as applicable in each case.
2,3;5,6-Di-O-isopropylidene-l-0-{2-[l-(4-[4-fluoro-phenyl-carbonyl]-piperazinyl)]-
ethyl]-a-D-mannofuranoside (Compound No. 43)
l-xample 9: Synthesis of 2,3;5,6-Di-0-isopropylidene-l-O-{2-[l-(4--{4-methyl-phenyl-sulphonyl !-piperazinyl)]-ethyl}-a-D-mannofuranoside (Compound No. 40)
To a solution of the Compound No.36 (200 mg) in pyridine (5ml). was added p-loluenesulphonyl chloride (122 mg) the reaction mixture was stirred for 2 hours. The reaction mixture was poured into cold water and was extracted with ethyl acetate followed by washing with water, brine and dried over anhydrous sodium sulphate. The solvent was evaporated 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 (130 mg).
'II NMR (CDCb) (300 MHz):8 7.64(2H,d, 8Hz), 7.32(2H,d), 4.94(1 H,s), 4.74 (IH.t, 3.4Hz), 4.56(1 H.d. 5.9Hz), 4.38(1 H,m), 4.06(lH,m), 3.99 (lH,m), 3.89(lH,m), 3.87(1 H,m), 3.69(1 H,m), U8(lH,m). 3.02(4H, s), 2.55(6H,s), 2.43(3H,s), 1.44(3H,s), 1.42(3H,s), 1.3(3H,s). 1.26(3H,s). Scheme VI, (path b)
I'xample 10: Synthesis of 2,3;5,6-Di-O-isopropvlidene-l-Q-{2-[l-(4-!(l-naphthyl)-amino-earbonyli-piperazinvl)]-ethvl}-a-D-mannofuranoside (Compound No. 39)
To a solution of the Compound No. 36 (200 mg) in acetonitrile (5ml) was added iniphthyl isocyanate (109mg). The reaction mixture was stirred at room temperature till the reaction shown completion (TLC). The solvent was evaporated under reduced pressure. The crude product was purified by column chromatography using 90% ethyl acetate in hexane as eluenl to furnish the title compound (100 mg).
'H NMR (CDCb) (300 MHz):S 7.88(2H,m), 7.68(2H,m), 7.54-7.47(3H,m), 6.67(lH,s), 5.04(1 H.s), 4.80(1 H,t, 2.3IHz), 4.64(lH,d, 5.8Hz), 4.40(lH,m), 4.13-4.08(2H,m) 4.00(1 H,m), i.80(1 H,m). 3.60(5H,t), 2.66(2H,m), 2.57(4H,t), 1.49(3H,s), 1.48(3H,s), 1.40(3H,s), 1.35(3H,s).

Example 11: Synthesis of 2,3;5,6-Di-0-isopropylidene-l-Q-{2-[l-(4-[isopropylamino-ihiocarbonylj-piperazinyl)]-ethvl}-g-D-mannofuranoside (Compound No. 38)
To a solution of the Compound No.36 (200 mg) in acetonitrile (5ml) was added p-chlorophenyl isothiocyanate (65mg). The reaction mixture was stirred at room temperature till the reaction showed completion (TLC). The solvent was evaporated under reduced pressure. The crude product was purified by column chromatography using 50% ethyl acetate in hexane as eluenl to furnish the title compound (140 mg).
'11 NMR (CDC13) (300 MHz):5 5.23-5.20(lH,bs), 4.99(lH,s), 4.78-4.75(lH,m). 4.60-4.59(2H.m), 4.41-4.39(1 H,m), 4.09-4.03(2H,m), 3.95-3.92(lH,m), 3.80-3.74(5H,m), 3.57-3.55(lH,m),2.61-2.51(6H,m), 1.46(6H,s), 1.37(3H,s), 1.32(3H,s), 1.25(3H,s), 1.24(3H,s).
Scheme VI, (path c)
I Example 12: Synthesis of 2.3;5.6-Di-0-isopropvlidene-l-O-|2-[l-(4-f [3,3']-bithiophenyl-5-yl-inethvl!-piperazinyl)]-ethyl}-a-D-mannofuranoside (Compound No. 37)
To a solution of 5-chloromethyl-[3,3']-bithiophenyl (200 mg) in dimethylformamide (5ml) and potassium carbonate (11 Img) was slowly added the Compound No. 36 (138mg). The reaction mixture was stirred for 3 hours at room temperature and then the reaction mixture was poured into ice-cold water and the product was extracted with ethyl acetate. The organic layer \\as dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude product was purified by column chromatography to furnish the title compound (90 mg).
'II NMR (CDC'b) (300 MHz): 5 7.34-7.26(4H,m), 7.15(lH,s), 4.99(lH,s), 4.76(1 H,t. 5.61Hz). 4.60(1 H,d, 5.8Hz), 4.40 (lH,m), 4.10-3.92 (3H,m), 3.78-3.72 (3H,m), 3.56 (IH.m), 2.58 (1 ()H,bs). 2.04 (1H, s). 1.46(3H,s), 1.45 (3H,s), 1.37 (3H,s), 1.32 (3H,s).
Analogues of 2,3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-{[3,3']-bithiophenyl-5-yl-methyl}-piperazinyl)]-ethyl}-a-D-mannofuranoside (Compound No. 37) can be prepared by replacing appropriate alkyl halide group in place of 5-chloromethyl-[3, 3']-bithiophenyl, respectively, as applicable in each case.
2,3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-[(2-chloro-3,4-methylenedioxy-phenyl)-methyl]-piperazinyl)]-ethyl}-a-D-mannofuranoside (Compound No. 45)
Scheme VII, (path a)
I: xample 13: Synthesis of 2,3;5,6-Di-O-isopropylidene-l-Q-{2-[l-(4-f2-(l-[lH-l,2,4-
iiia/.c)lylJ)-acetyl!-piperazinyl]-ethyli-a-D-mannofuranoside (Compound No. 44)
Step a: Synthesis of 2,3;5,6-Di-O-isopropylidene-l-O-{2-(l-[4-chloroacetyl]-piperazinyl)-
ethyl}-a-D-mannofuranoside

To a solution of the Compound No. 36 (2 g) in dichloromethane (35 ml) cooled at 0°C, as added triethylamine (1.13 gm) and chloroacetyl chloride (0.51 ml). The reaction mixture v\as poured into ice-cold water and the product was extracted with dichloromethane. The solvent was evaporated under reduced pressure. The crude product was purified by column chromatography using 50% ethyl acetate in hexane as eluent to furnish the title compound (1.6
y)-
Stop b: Synthesis of 2.3:5.6-Di-O-isopropvlidene-l-Q-{2-ri-(4-i2-(l-flH-1.2.4-i r i a/olyl])acetyli-piperazinvl]-ethvli-a-D-mannofuranoside
To a solution of the compound obtained from step a above (200 mg) in diinethyllbrmamide (5ml), was added l//-[l,2,4]-triazole (37 mg) and cesium carbonate (I45mg). The reaction mixture was stirred at room temperature till the reaction showed completion (TLC). The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and filtered. The solvent uas evaporated under reduced pressure. The crude compound was purified by column chromatography using 90% ethyl acetate in hexane as eluent to furnish the title compound (12mg).
'11 NMR (CDC13) (300 MHz):5 8.26(lH,s), 7.98(lH,s), 5.06(2H,s), 5.01(lH,s), 4.79(lH.t, 3.211/), 4.62(1 H,d,5.9Hz), 4.40(lH,m), 4.12-4.06(2H,m), 3.97(lH,m), 3.80(lH,m), 3.68(2H,bs), 3.57(3H,bs). 2.64-2.60(2H,m), 2.56-2.50(4H,m), 1.49(3H,s), 1.48(3H,s), 1.48(3H,s), 1.40(3H,s), 1.34(3H.s).
Analogues of 2,3;5,6-Di-O-isopropylidene-l-O-{[l-(4-(2-(l-[lH-l,2,4-triazolyl])-vicci\l!-piperazinyl]-ethyl}-a-D-mannofuranoside (Compound No. 44) can be prepared by replacing appropriate amine group in place of l//-[l,2,4]-triazole, respectively, as applicable in each case.
2,3;5.6-Di-O-isopropylidene-l-O-{2-[l-(4-[2-(2,6-dioxo-l-piperidinyl)-acetyl]-
piperazinyl)]-ethyl}-a-D-mannofuranoside (Compound No. 41)
Scheme VII, (path b)
Exaxample 14: Synthesis of 2.3;5.6-Di-Q-isopropvlidene-l-O-l2-fl-(4-f2-f4-chloro-phenoxv|-acetyli-piperazinyl)]-ethvl}-q-D-mannofuranoside (Compound No. 46)
To a solution of a compound obtained from step a of Example 12 above (200 mg) in dimethylformamide (5 ml), was added cesium carbonate (145 mg) and 4-chlorophenol (69mg). The reaction mixture was stirred at 60°C till the reaction completion (TLC). The solvent was cuiporated 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 (160
nig).
'11 NMR (CDC13) (300 MHz):5 7.27(2H,d, 9Hz), 6.90(2H,d, 9Hz), 5.01(1 H,s), 4.78(lH,m), 4.68(2H.s), 4.61(lH,d, 5.8Hz), 4.43 (lH,m), 4.12-4.08(2H,m) 3.97(lH,m), 3.75-3.65(lH,m), 3.59-3.54(5H,m), 2.59(2H,t, 5.8Hz), 2.48(4H,bs), 1.49(3H,s), 1.47(3H,s), 1.40(3H,s), l.34(3H,s). Scheme VIII
lixample 15: Synthesis of l,2-O-isopropylidene-3-deoxy-3-{2-[3-(4-{2-methoxy-2-oxoethyl}-phenyl)-ureido]-ethyl}-a-D-allofuranoside (Compound No. 26)
To a solution of the compound No. 4 (prepared following Scheme II) (4.0 g) in icirahydrofuran (4 ml) was added aqueous perchloric acid (30%, 4.0 ml) at 0°C and stirred the reaction mixture at this temperature for 6 hours. The solvent was evaporated under reduced pressure and the crude compound was purified by column chromatography using 70% ethyl acetate in hexane as eluent to furnish the title compound (2.0 g).
Vvlk (ClX'h. 300 MHz):8 7.27(2H.d, 7.59Hz), 7.17 (3H.d. 7.62II/.). 5.71(lH.d. 3.121!/). •: K 11 l.si. 4.()2(lll.d. 3.4Hz), 3.72(8H.m). 3.57(2H.s). 3.36(311,m). 1.99(111. m). 1.78(211.hs). ..••i 'll.si. 1.26(311.s).
Analogues of l,2-O-Isopropylidene-3-deoxy-3-{2-[3-(4-{2-methoxy-2-oxoethyl)-ureido|-ethylJ-a-O-allofuranoside (Compound No. 26) can be prepared by using appropriate sugar derivative in place of compound No. 4, respectively as applicable in each case.
l,2-O-Isopropylidene-3-0-[(4-methoxy-phenyl)-amino]-carbonyl-a-D-allofuranoside (Compound No. 19)
l,2-O-Isopropylidene-3-deoxy-3-{2-[3-(4-methoxy-phenyl)-ureido]-ethyl}-a-D-glucofuranoside (Compound No. 20)
l,2-O-Isopropylidene-3-O-{(4-chloro-phenyl)-amino}-carbonyl-a-D-glucofuranoside (C'ompound No. 21)
1.2-O-Isopropylidene-3-deoxy-3-{[(4-nitro-phenyl)-amino]-carbonylj-amino-a-D-allofuranoside (Compound No. 22)
l,2-O-Isopropylidene-3-deoxy-3-{[(4-chloro-phenyl)-amino]-carbonyl}-amino-a-D-allofuranoside (Compound No. 23)
1.2-O-Isopropylidene-3-O-{(4-methyl-phenyl)-amino}-carbonyl-a-D-glucofuranoside (Compound No. 24)
l,2-O-Isopropylidene-3-deoxy-3-[2-{3-(4-methyl-phenyl)-ureido)-ethyl]-a-D-allofuranoside (Compound No. 25)
1.2-O-Isopropylidene-3-deoxy-3-{[(4-methyl-phenyl)-amino]-carbonylj-amino-a-D-allofuranoside (Compound No. 27)
l,2-O-lsopropylidene-3-deoxy-3-{2-[3-(4-{2-hydroxy-2-oxo-ethylj-phenyl)-ureido]-ethylJ-a-D-allofuranoside (Compound No. 28).
Scheme IX, (path a)
Example 16: Synthesis of l,2;5,6-Di-Q-isopropylidene-3-deoxy-3-{[4-fluoro-phenyl]-sulphonyl j -amino-a -D -allofuranoside (Compound No. 52)
To a solution of l,2;5,6-Di-O-isopropylidene-3-deoxy-3-amino-a-D-allofuranoside (K)Omg) in dichloromethane (5ml), was added 4-fluorobenzenesulphonyl chloride (75mg) at 0"C and stirred the reaction mixture for 2 hours. Solvent was evaporated under reduced pressure. The reaction mixture was taken into water, extracted with ethyl acetate, and the combined organic extracts were washed with brine and dried over anhydrous sodium sulphate. Solvent was euiporated under reduced pressure and the residue thus obtained was purified with 40% ethyl acetate in hexane as eluent to furnish the title compound (77mg).
\V1U iCDCk 300 MH/):6 7.92-7.97(2H.m). 7.23-7.18(3 11. m). 5.72(1 II. d. 311/). 5,15(1 .!. 9j|/). 4.23-4.17(2 IT. m). 3.98-3.95(2 H. m). 3.84-3.88(1 II. in). ".56-3.20(1 II. m). :,;||.M. !.42(3 II. s). 1.32(3 11. s). 1.25(3 II. s).
Analogues of l,2:5,6-Di-O-isopropylidene-3-deoxy-3-{[4-fluoro-phenyl]-sulphonyl}-amino-a-I )-allofuranoside (compound no. 52) described below can be prepared by replacing appropriate sulphonyl group in place of 4-fluoro-benzenesulphonyl chloride , respectively, as applicable in each case.
1,2 ;5,6-Di-O-isopropylidene-3-deoxy-3- {[4-methyl-phenyl]-sulphonyl} -amino-a-D-
allofuranoside (Compound No. 53).
Scheme IX, (path b)
I xaniple 17: Synthesis of l,2;5,6-Di-0-isopropylidene-3-deoxy-3-i[(4-methoxy-2-oxo-cihyDaminoJ-carbonyl!-methyl amino-a-D-allofuranoside (Compound No. 54)
To a solution of l,2;5,6-Di-O-isopropylidene-3-deoxy-3-amino-oc-D-allofuranoside (IQOmg) in dry acetone (10ml), at room temperature, was added potassium carbonate (172mg) followed by the addition of 4-(2-chloro-acetyl amino)-phenyl acetic acid methyl ester (lOOmg) utter 5-10 minutes. The reaction mixture was stirred for 3 hours at room temperature followed by retluxing for overnight. Solvent was evaporated under reduced pressure .The reaction mixture \\as taken into water and extracted with ethyl acetate. The combined organic layer was washed with water, brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the residue thus obtained was purified by column chromatography using 60% ethyl acetate in hexane to furnish the title compound (46 mg).
,-v In l=. 31XIMH/): o y.61(lH.s). 7.6l(2H.d, 9H/.). 7.26-7.22(41 Lm). 5.77(lll.s). 4.64(11 l.d. ; i.N-.;,HI( I2ll.ni). 1-57(3 II. s). 1.46(3 11. s). 1.25(6Il.s).
Pharmacological activity
The compounds of the present invention were tested in one or both 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 ncutrophil chemotaxis, leukotriene B4 (LTB4), was used to evaluate inhibitory effect on nculrophils. 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 licoll separation (Eur J Biochem. 169, 175, 1987). 180 ul of the of neutrophil suspension (0.2x106 cells/ml) was taken and added 19uL of Hank's Buffer salt solution along with luL of ihc lest drug (200 times concentrated) in a 24 well plate and incubated at 37°C for Ihour. 3 minutes before the end of test compound incubation, 0.25 mM Ca++/Mg++were added. Then. 0.3 My/mi A23187 (Sigma Chem, USA) was added and incubated for further 10 min at 37°C. The reaction was stopped by adding 80 uL of cold methanol and centrifuged to remove cell debris (J Pharmacol Exp Ther. 297:267, 2001). The samples were analysed for LTB4 release using LTB4 1:1.ISA 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 IC^o values.

Compound Nos. 49, 50 and 52-54 were investigated and they exhibited IC\o of from about 30 uM to about 14 uM.
Assay for 5-Lipoxygenase Activity
In a 96 well UV-plate, 100 ul of phosphate buffer saline (PBS) containing DTT (200 uM). ATP (100 uM) and calcium chloride (100 uJVl) is added. To each well 0.5 ul of test drug (200 times concentrated) or vehicle is added, followed by 4 ul of recombinant 5-Lox (3 units/ul) and is incubated at 37°C for 5 min. The reaction was initiated by adding 1 u,l of ImM freshly prepared arachidonic acid and increase in absorbance is monitored at 236 nm for 10 min. (./ Biol. ('lie/n. 261:11512, 1986) A plot of absorbance verses time curve is prepared and area under curve (AUC) is computed for each well. Percent inhibition of AUC for different treatments is calculated with respect to the difference between the Arachidonic acid stimulated and negative control values, to compute ICjo values.

We claim:
1. The compound of Formula I
(Formula Removed)
wherein R1 and R2 together form a five-membered acetal, wherein the carbon atom joining the oxygens can be substituted with RL and Rm [wherein RL and Rm are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl; or RL and Rm can together join to form a 3-8 membered ring, wherein the ring may optionally contain one or more heteroatoms selected from O, N or S, and the ring may be optionally substituted with one or more of alkyl, alkenyl. alkynyl, amino, substituted amino, cycloalkyl, oxo, hydroxy, carboxy, -COQR6 (wherein Q is O or NH and R6 is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl), alkoxy, aryloxy, halogen (F,C1, Br, I), aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl; or RL and Rm can together join to form an oxo group]; R3 is selected from A) -(CH2)nG wherein n is an integer from 0-5 and G is selected from 1) ORc (wherein Re is selected from
a) acyl (with the proviso that n cannot be 0), and
b) -C(-O)NRfRq [wherein Rf and Rq can be independently selected from
hytrogen, hydroxy (with the restriction that both Rf and Rq cannot both be hydroxy), alkyl,
alkenyl. alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, and S(O)2R7 (wherein R; is
selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl,
heterocyclylalkyl, heteroarylalkyl, and optionally substituted amino)]; and Rr and Rq may also
together join to form a heterocyclyl ring; also, when n is zero, then Rf and Rq cannot be
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl and Rf and Rq together cannot join to form a
heterocyclyl ring};
2) -NRfC(=O)ORs (wherein Rj is selected from hydrogen, lower (C1-C6) alkyl, lower (C2-C6) alkenyl, lower (C2-C6) alkynyl, lower (C3-C6) cycloalkyl, aryl, heteroaryl (with the proviso that the heteroaryl ring is not linked through a heteroatom), aralkyl (C1-C4), heteroarylalkyl (C1-C4), and heterocyclylalkyl (C1-C4), and Rs is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heteroarylalkyl);
3) NR|YRL, (wherein Rj is the same as defined above and Y is -C(=O), -C(=S) or SO? and Ru is selected from alkyl, alkenyi, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl; and when n is 0 then Y cannot be -C(=O)); \) -NR,C(-T)NR,RX (wherein Rt is OH or R, and T is O, S, -N(CN), -N(NO2), -CH(NO2), R, is the same as defined above and Rx is selected from hydrogen, alkyl, alkenyi, alkynyl, cycloalkyl, aryl. aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, and S(O)2R7 wherein R? is the same as defined above);
5) heterocyclyl;
6) heteroaryl; and
7) -(C=O)NRaRh(wherein Raand Rb are independently selected from hydrogen, and Ru wherein
R,, is same as defined earlier, also, Ra and Rb together with the nitrogen atom carrying them can
be the N-terminus of an amino acid or di-tetrapeptide or Ra and Rb may together join to form a
heterocyclyl ring);
R: is alternately selected from
B) -NRjR,,, (wherein R, is the same as defined above and Rm is selected from alkyl, cycloalkyl,
aryl. aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl);
( i -OtrHiKvGi [wherein w is an integer from 1-5 (and G| is selected from ORC (wherein Rc is
i he same as defined above), -NRJC(:=0)ORS (wherein Rj and Rs are the same as defined above). -
NRjC^.'ONRtRx (wherein RJ? T, Rt and Rx are the same as defined above), -NRjYRu (wherein
Y. Ru and Rj are the same as defined above), heterocyclyl, and heteroaryl)];
I)) -NR/CHiXvGi (wherein w, R1 and GI are the same as defined above);
10 -O(CH2)wG2 [wherein w is the same as defined above (and Ga is selected from
-(. V-())NR;iRh (wherein Ru and Rb are the same as defined above), and -C(=O)ORk (wherein Rk
is H or R() and R(, is the same as defined above); or
I ) -NR,(CH2K\G2 (wherein w is as defined above, R, and 62 are the same as defined above))];
further, when R_^ is ORe then R2 and Re may together join to form a five membered acetal
wherein the carbon linking the two oxygens is substituted with RI, and Rnl (wherein RL and Rm
are the same as defined earlier, and RI is independently selected from
a) -(CH?)iGi (wherein t is an integer from 2-4 and GI are the same as defined above and
alst: when GI is heterocyclylalkyl group then the group cannot be 4-(l-pyrrolidinyl) butyl),
b) -(CHiXvGi (wherein w and 62 are the same as defined above),
c) aryl,
d) aralkyl (with the proviso that aralkyl cannot be phenylpropyl),
e) heteroaryl, and 0 heterocyclyl (wherein the heteroaryl and heterocyclyl rings are not linked through a heteroatom), and cycloalkyl (with the proviso that cycloalkyl cannot be cyclooctyl); and R4 and R.s are independently selected from hydrogen, lower (C\-C(,) alkyl, lower (C2-C6) alkenyl, lower (CVCh) alkynyl, lower (Cs-Cg) cycloalkyl, aryl, acyl, heterocyclyl, heteroaryl, lower (Ci-C,) heierocyclylalkyl, and lower (C|-C4) heteroarylalkyl; or R4 and RS may together form a five-membered acetal wherein the carbon linking the two oxygens is substituted with RL and Rm (wherein RI and Rn, are the same as defined earlier) with the proviso that when R} is ORL. then ihe acetal must be isopropylidene acetal. 2. A compound selected from:
! .2;5,6-Di-O-isopropylidene-3-deoxy-3-[ {(4-chloro-phenyl)-amino} -carbonyl]-amino-a-D-allofuranoside (Compound No. 1),
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[2-{3-(4-chloro-phenyl)-ureido}-ethyl]-a-D-allofuranoside (Compound No. 2),
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-methoxy-phenyl)-amino}-carbonyl]-amino-a-D-allofuranoside (Compound No. 3).
1,2; 5,6-Di-O-isopropylidene-3-deoxy-3-([{4-(2-methoxy-2-oxo-ethyl)-phenyl}-amino]-carbonyl)-amino-a-D-glucofuranoside (Compound No. 4),
l,2;5.6-Di-O-isopropylidene-3-deoxy-3-[{phenyl-sulphonylamino}-carbonyl]-amino-a-D-allofuranoside (Compound No. 5),
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-([{4-(2-hydroxy-2-oxo-ethyl)-phenyl]-amino]-carbonyl)-amino-a-D-glucofuranoside (Compound No. 6),
1.2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-methyl-phenyl)-sulphonylamino}-carbonyl]-amino-a-D-allofuranoside (Compound No. 7),
l,2:5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-methyl-phenyl)-amino}-carbonyl]-amino-u-D-glucofuranoside (Compound No. 8),
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-nitro-phenyl)-amino}-carbonyl]-amino-a-D-allofuranoside (Compound No. 9),
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-chloro-phenyl)-amino}-carbonyl]-amino-a-D-glucofuranoside (Compound No. 10),
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[{(4-methyl-phenyl)-amino}-carbonyl]-amino-a-D-ailofuranoside (Compound No. 11),
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[phenyl-amino-carbonyl]-amino-a-D-glucofuranoside (Compound No. 12),
l,2;5,6-Di-O-isopropylidene-3-O-[(4-methyl-phenyl)-amino]-carbonyl]-a-D-glucofuranoside (Compound No. 13),
1.2;5.6-Di-O-isopropylidene-3-deoxy-3-[{(4-nitro-phenyl)-aminoj-carbonyl]-amino-a-D-glucofuranoside (Compound No. 14),
l,2;5,6-Di-O-isopropylidene-3-O-[(4-methoxy-phenyl)-amino]-carbonyl-a-D-glucofuranoside (Compound No. 15),
l,2;5,6-Di-0-isopropylidene-3-0-[(4-chloro-phenyl)-amino]-carbonyl-a-D-glucofuranoside (Compound No. 16),
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-[2-{3-(4-methyl-phenyl)-ureido}-ethyl]-a-D-allofuranoside (Compound No. 17),
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-{2-[3-(4-methoxy-phenyl)-ureido]-ethylj-a-D-allofuranoside (Compound No. 18),
l,2-O-lsopropylidene-3-O-[(4-methoxy-phenyl)-amino]-carbonyl-a-D-allofuranoside (Compound No. 19),
1.2-O-Isopropylidene-3-deoxy-3-{2-[3-(4-methoxy-phenyl)-ureido]-ethyl}-a-D-glucofuranoside (Compound No. 20),
l,2-O-Isopropylidene-3-O-{(4-chloro-phenyl)-amino}-carbonyl-a-D-glucofuranoside (Compound No. 21),
1.2-O-Isopropylidene-3-deoxy-3-{[(4-nitro-phenyl)-amino]-carbonyl}-amino-a-D-allofuranoside (Compound No. 22),
l,2-O-Isopropylidene-3-deoxy-3-{[(4-chloro-phenyl)-amino]-carbonyl}-amino-a-D-allofuranoside (Compound No. 23),
1,2-O-lsopropylidene-3-O-{(4-methyl-phenyl)-amino}-carbonyl-a-D-glucofuranoside (Compound No. 24),
l,2-O-Isopropylidene-3-deoxy-3-[2-{3-(4-methyl-phenyl)-ureido}-ethyl]-a-D-allofuranoside (Compound No. 25),
K2-O-isopropylidene-3-deoxy-3-{2-[3-(4-{2-methoxy-2-oxoethyl}-phenyl)-ureido]-ethyl {-a-D-allofuranoside (Compound No. 26),
l,2-O-Isopropylidene-3-deoxy-3-{[(4-methyl-phenyl)-amino]-carbonyl}-amino-a-D-ullotliranoside (Compound No. 27),
1.2-O-lsopropylidene-3-deoxy-3-{2-[3-(4-{2-hydroxy-2-oxo-ethyl}-phenyl)-ureido]-ethyl}-a-D-allofuranoside (Compound No. 28),
2,3 ;5,6-Di-O-isopropylidene-1 -O- {3-[ 1 -(4-[3-chloro-phenyl]-piperazinyl)]-propyl J -a-D-mannofuranoside (Compound No. 29),
2,3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-[4-chloro-phenyl]-piperazinyl)]-ethylj-a-D-mannofuranoside (Compound No. 30),
2.3 ;5,6-Di-O-isopropylidene-1 -O- {2-[ 1 -(4-[4-methoxy-phenyl]-piperaziny l)]-ethyl} -a-D-mannofuranoside (Compound No. 31),
2,3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-[2-pyrimidinyl]-piperazinyl)]-ethylj-a-D-mannofuranoside (Compound No. 32),
2,3;5,6-Di-O-isopropylidene-l-O-{2-[4-morpholinyl]-ethyl}-a-D-mannofuranoside (Compound No. 33),
2,3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-benzyl-piperazinyl)]-ethyl}-a-D-mannofuranoside (Compound No. 34),
2,3;5.6-Di-O-isopropylidene-l-O-{2-[l-(4-[{4-chloro-phenylJ-aminocarbonyl]-piperazinyl)]-ethyl}-a-D-mannofuranoside (Compound No. 35), 2,3;5,6-Di-O-isopropylidene-l-O-{2-(l-piperazinyl)-ethyl}-a-D-mannofuranoside (Compound No. 36),
2,3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-{[3,3']-bithiophenyl-5-yl-methyl}-piperazinyl)]-ethyl}-a-D-mannofuranoside (Compound No. 37),
2,3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-[isopropylamino-thiocarbonyl]-piperazinyl)]-ethylJ-a-D-mannofuranoside (Compound No. 38),
2,3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-{(l-naphthyL)-amino-carbonyl}-piperazinyl)]-ethyl | -a-D-mannofuranoside (Compound No. 39),
2.3:5,6-Di-O-isopropylidene-l-O-{2-[l-(4-{4-methyl-phenyl-sulphonylj-piperazinyl)]-ethylj -a-D-mannofuranoside (Compound No. 40),
2,3;5,6-Di-O-tsopropylidene-l-O-{2-[l-(4-[2-(2,6-dioxo-l-piperidinyl)-acetyl]-piperazinyDJ-ethyI}-a-D-mannofuranoside (Compound No. 41),
2.3;5,6-Di-0-isopropylidene-l-0-{2-[l-(4-[2-thienyJ-methyl-carbonyl]-piperazinyl)]-ethyl} -a-D-mannofuranoside (Compound No. 42),
2,3;5,6-Di-0-isopropylidene-l-0-{2-[l-(4-[4-fluoro-phenyl-carbonyl]-piperazinyl)]-ethyl}-a-D-mannofuranoside (Compound No. 43),
2.3 ;5,6-Di-O-isopropylidene-1 -O- {2-[ 1 -(4- {2-( 1 -[ 1H-1,2,4-triazolyI] )-acety 1} -piperazinyl]-ethyl}-a-D-mannofuranoside (Compound No. 44),
2,3;5,6-Di-O-isopropylidene-l-O-{2-[l-(4-[(2-chloro-3,4-methylenedioxy-phenyl)-methyl]-piperazinyi)]-ethyl}-a-D-mannofuranoside (Compound No. 45).
2.3;5,6-Di-O-isopropylidene-l-0-{2-[l-(4-{2-[4-chloro-phenoxy]-acetyl]-piperazinyl)]-ethylj -a-D-mannofuranoside (Compound No. 46),
1.2; 5.6-Di -O-isopropy lidene-3 -deoxy-3 -[ {(4-trifhioromethy l-pheny l)-amino} -carbony \] -amino-a-D-allofuranoside (Compound No. 47),
!.2;5,6-Di-O-isopropylidene-3-O-[(4-fluoro-phenyl)-amino]-carbonyl]-a-D-glucofuranoside (Compound No. 48),
l.2;5,6-Di-O-isopropylidene-3-deoxy-3-{[(2-phenylethyl)-amino]thiocarbonyl}-amino-a-D-aJlofuranoside (Compound No. 49),
l,2;5,6-Di-O-isopropylidene-3-deoxy-3-{[(4-fluorophenyl)-amino]-thio-carbonyl}-amino-a-D-allofuranoside (Compound No. 50),
l.2;5.6-Di-0-isopropylidene-3-deoxy-3-{[(4-fluoro-phenyl>amino]-carbonyl}-amino-a-D-allofuranoside (Compound No. 51),
1,2;5,6-Di-O-isopropylidene-3-deoxy-3-{ [4-fluoro-phenyl]-sulphonyl} -amino-a -D -allofuranoside (Compound No. 52),
1.2;5,6-Di-0-isopropylidene-3-deoxy-3-{[4-methyl-phenyl]-sulphonyl} -amino-a-D-allofuranoside (Compound No. 53),
l,2;5.6-Di-O-isopropylidene-3-deoxy-3-{[(4-methoxy-2-oxo-ethyl)amino]-carbonylj-meihyl amino-a-D-allofuranoside (Compound No. 54).
3. A method of making compounds of Formula VII
(Formula Removed)
wherein
RI and R2 together form a five-membered acetal, wherein the carbon atom joining the oxygens can be substituted with RL and Rm [wherein RL and Rm are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl; or RL and Rm can together join to form a 3-8 membered ring, wherein the ring may optionally contain one or more heteroatoms selected from 0, N or S, and the ring may be optionally substituted with one or more of alkyl, alkenyl, alkynyl, amino, substituted amino, cycloalkyl, oxo, hydroxy, carboxy, -COQR6 (wherein Q is O or NH and Re is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl), alkoxy, aryloxy, halogen (F,C1, Br, I), aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl; or RL and Rni can together join to form an oxo group]; and R4 and Rs are independently selected from hydrogen, lower (C|-C6) alkyl, lower (Ca-Ce) alkenyl, lower (CVC\,) alkynyl, lower (Cj-Cs) cycloalkyl, aryl, acyl, heterocyclyl, heteroaryl, lower (C|-('4) heterocyclylalkyl, and lower (C|-C4) heteroarylalkyl; or R4 and R, may together form a five-membered acetal wherein the carbon linking the two oxygens is substituted with RI. and Rm (wherein RL and Rm are the same as defined earlier), ihc method comprising
oxidizing a compound of Formula II to give a compound of Formula III;
reacting the compound of Formula III with hydroxylamine hydrochloride to form a compound of Formula IV;
reducing the compound of Formula IV to form a compound of Formula V; and reacting the compound of Formula V with a compound of Formula VI (wherein X is S or O, and Ks is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl. heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, and S(O)2Ry wherein R? is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, hcieroarylalkyl, and optionally substituted amino) to give a compound of Formula VII.
Wherein K1 and R2 together form a five-membered acetal, wherein the carbon atom joining the oxygens can he substituted with RL and Rm [wherein RL and Rm are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl; or Ri_and Rm can together join to lorm a 3-8 membered ring, wherein the ring may optionally contain one or more heteroatoms selected from O, N or S, and the ring may be optionally substituted with one or more of alkyl, alkenyl, alkynyl, amino, substituted amino, cycloalkyl, oxo, hydroxy, carboxy, -COQR6 (wherein Q is O or NH and R& is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl), alkoxy, aryloxy, halogen (F,C1, Br, I), aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl; or RL and Rm can together join to form an oxo group]; and RI and R> are independently selected from hydrogen, lower (C\-C(>) alkyl, lower (C2-C<,) alkenyl, lower (CVC(,) alkynyl, lower (C3-Cs) cycloalkyl, aryl, acyl, heterocyclyl, heteroaryl, lower (Ci-(.' i) heterocyclylalkyl, and lower (C|-C4) heteroarylalkyl; or R4 and R? may together form a five-membered acetal wherein the carbon linking the two oxygens is substituted with RI, and Rm (wherein RL and Rm are the same as defined earlier), ihe method comprising
reacting a compound of Formula II with a compound of Formula VIII (wherein L is a leaving group and hal is halogen) to form a compound of Formula IX;
reacting the compound of Formula IX with sodium azide to form a compound of Formula X; reducing the compound of Formula X to form a compound of Formula V, and reacting the compound of Formula V with a compound of Formula VI (wherein X is S or O, and R\ is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, and S(O)2R7 wherein Ry is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, and optionally substituted amino) to give a compound of Formula VII.
5. A method of making a compound of Formula XI
(Formula Removed)
wherein
RI and R2 together form a five-membered acetal, wherein the carbon atom joining the oxygens can be substituted with RL and Rm [wherein RL and Rm are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl; or RL and Rm can together join to 1 brni a 3-8 membered ring, wherein the ring may optionally contain one or more heteroatoms selected from O, N or S, and the ring may be optionally substituted with one or more of alkyl, alkenyl, alkynyl, amino, substituted amino, cycloalkyl, oxo, hydroxy, carboxy, -COQR(, (wherein Q is O or NH and R& is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl. and cvcloalkyl). alkoxy, aryloxy, halogen (F,C1, Br, I), aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl; or RL and Rm can together join to form an oxo group]; and RI and Rs are independently selected from hydrogen, lower (Ci-C&) alkyl, lower (Ci-Cfi) alkenyl, lower (CyC(,) alkynyl, lower (Cs-Cg) cycloalkyl, aryl, acyl, heterocyclyl, heteroaryl, lower (C|-C'-O heterocyclylalkyl, and lower (Ci-C4) heteroarylalkyl; or R4 and R? may together form a five-membered acetal wherein the carbon linking the two oxygens is substituted with RL and Rm (wherein RL and Rm are the same as defined earlier),
the method comprising reacting a compound of Formula II with a compound of Formula VI VI (wherein X is S or O, and Rx is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl. heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, and S(O)2R? (wherein Ry is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, and optionally substituted amino) to give a compound of Formula XI. 6. A method of making a compound of Formula XVI.
wherein
Ri and R2 together form a five-membered acetal, wherein the carbon atom joining the oxygens can be substituted with RL and Rm [wherein RL and Rm are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl; or RL and Rm can together join to Ibrm a 3-8 membered ring, wherein the ring may optionally contain one or more heteroatoms selected from O, N or S, and the ring may be optionally substituted with one or more of alkyl, aikenyl, alkynyl. amino, substituted amino, cycloalkyl, oxo, hydroxy, carboxy. -COQR(, (\\herein Q is O or NH and R& is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl), alkoxy, aryloxy, halogen (F,C1, Br, I), aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl; or RL and Rm can together join to form an oxo group]; and R4 and Rs are independently selected from hydrogen, lower (Ci-Q) alkyl, lower (C2-Q) alkenyl, lower (CyCt1) alkynyl, lower (Ca-Cg) cycloalkyl, aryl, acyl, heterocyclyl, heteroaryl, lower (C|-Cj) heterocyclylalkyl, and lower (Ci-C4) heteroarylalkyl; or R4 and RS may together form a five-membered acetal wherein the carbon linking the two oxygens is substituted with RL and Rm I wherein RI and Rm are the same as defined earlier),
the method comprising reacting a compound of Formula XI with a compound of Formula VIII (wherein L is a leaving group and hal is halogen) to form a compound of Formula XIII; reacting the compound of Formula XIII with sodium azide to form a compound of Formula XIV:
reducing the compound of Formula XIV to form a compound of Formula XV; and reacting the compound of Formula XV with a compound of Formula VI (wherein X is S or O. and Rx is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, araJkyl. heteroaryl, heterocyclyl. heteroarylalkyl, heterocyclyl alky L and S(O)2R7 (wherein R7 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, and optionally substituted amino) to give a compound of Formula XVI.
7. A method of making a compound of Formula XIX

(Formula Removed)


R} and R; form an acetal, wherein the carbon linking the two oxygens is substituted with RI. and Knl (wherein R| and Rm are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl; or RL and Rm can together join to form a 3-8 membered ring, u herein the ring may optionally contain one or more heteroatoms selected from O, N or S, and ihe ring may be optionally substituted with one or more of alkyl, alkenyl, alkynyl, amino, substituted amino, cycloalkyl, oxo, hydroxy, carboxy, -COQR& (wherein Q is O or NH and R6 is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl), alkoxy, aryloxy, halogen (I'.Cl. Br, 1), aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl; or RI. and Rm can together join to form an oxo group);
R} is -(CH2)pG wherein n is an integer from 0-5 and G is ORe (wherein Re is selected from
a i acyl (with the proviso that n cannot be 0), and
b) -C'(=<))NRtRt| [wherein Rt and Rq can be independently selected from hydrogen, hydroxy (with the restriction that both Rf and R^ cannot both be hydroxy), alkyl, alkenyl, alkynyl, cycloaikyl. aryl, aralkyl, heteroaryl, heterocyclyl, and S(O)2R7 (wherein R? is selected from alkyl. alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, and optionally substituted amino)]; and Rt and Rqmay also together join to form a heterocyclyl ring; also, when n is zero, then Rf and Rq cannot be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl and Rrand Rq together cannot join to form a heterocyclyl ring}; and R4 and R; are independently selected from hydrogen, lower (C\-C(,) alkyl, lower (C2-C&) alkenyl, lower (tyCf,) alkynyl, lower (CVCs) cycioalkyl, aryl, acyl, heterocyclyl, heteroaryl, lower (C|-C4) heierocyclylalkyl, and lower (Ci-C4) heteroarylalkyl; or R4 and R> may together form isopropylidene acetal,
i he method comprising reacting a compound of Formula XVII (wherein r is an integer from 1-3 aiki hal is halogen) with a compound of Formula XVIII (wherein GT, is a heterocyclyl ring attached to H through N) to form a compound of Formula XIX.
(Formula Removed)

wherein
Ri and R.i form an acetal, wherein the carbon linking the two oxygens is substituted with RI. and Rm (wherein RI, and Rm are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl; or RL and Rm can together join to form a 3-8 membered ring, wherein the ring may optionally contain one or more heteroatoms selected from O, N or S, and the ring may be optionally substituted with one or more of alkyl, alkenyl. alkynyl, amino. substituted amino, cycloalkyl, oxo, hydroxy, carboxy, -COQR6 (wherein Q is O or NH and R(, is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl), alkoxy, aryloxy, halogen (I'.('I. Bi. I), aryl. aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl; or R[, and Rm can together join to form an oxo group);
R< is -(CH2)nG wherein n is an integer from 0-5 and G is ORe {wherein Rc is selected from
a) acyl (with the proviso that n cannot be 0). and
h) -C'(=O)NRt-Rq [wherein Rf and Rq can be independently selected from hydrogen, hydroxy (with the restriction that both Rf and Rq cannot both be hydroxy), alkyl. alkenyl, alkynyl, cycloalkyl. aryl, aralkyl, heteroaryl, heterocyclyl, and S(O)2R? (wherein R? is selected from alkyl. alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, heieroarylalkyl, and optionally substituted amino)]; and Rf and Rqmay also together join to form a heterocyclyl ring; also, when n is zero, then Rf and Rq cannot be hydrogen, alkyl, alkenyl, alkynyl. cycloalkyl and Rf and Rq together cannot join to form a heterocyclyl ring); and R4 and R, are independently selected from hydrogen, lower (C\-C(,) alkyl, lower (C2-Q,) alkenyl, lower (C2-t'<,) alkynyl, lower (Cs-Cs) cycloalkyl, aryl, acyl, heterocyclyl, heteroaryl, lower (€(-€4) heterocyclylalkyl, and lower (Ci-C4) heteroarylalkyl; or R4 and R, may together form isopropylidene acetal.
the method comprising
a. reacting a compound of Formula XX with a compound of Formula XXI (wherein Z is
halogen or OH; -C(=O), -Q^S) or SOz and Ru is selected from alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl;
and when n is 0 then Y cannot be -C(=O)) to give a compound of Formula XXII.
b. reacting a compound of Formula XX with a compound of Formula VI (wherein X is S or
O. and Rx is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl,
heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, and S(O)2Rv wherein Ry is
alkyl. alkenyl. alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl,
heterocyclylalkyl, heteroarylalkyl, and optionally substituted amino) to give a compound
of Formula XXIII.
c. reacting a compound of Formula XX with a compound of Formula XXIV (wherein Ry is
alkyl and hal is halogen) to form a compound of Formula XXV.
(Formula Removed)
wherein
Rj and R.5 form an acetal, wherein the carbon linking the two oxygens is substituted with RL and Rm (wherein RL and Rm are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl; or RL and Rm can together join to form a 3-8 membered ring, wherein the ring may optionally contain one or more heteroatoms selected from O, N or S, and the ring may be optionally substituted with one or more of alkyl, alkenyl, alkynyl, amino, substituted amino, cycloalkyl, oxo, hydroxy, carboxy, -COQR6 (wherein Q is O or NH and R<, is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl), alkoxy, aryloxy, halogen (I\C1. Br, I), aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl; or RL imd Rm can together join to form an oxo group); R i is -(CH2)nG wherein n is an integer from 0-5 and G is ORe (wherein Re is selected from
a) acyl (with the proviso that n cannot be 0), and
b) -C(=O)NRfRt| [wherein Rf and R-, can be independently selected from hydrogen,
hydroxy (with the restriction that both Rf and Rq cannot both be hydroxy), alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, and S(O)2R? (wherein R; is selected
from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl,
heteroarylalkyl, and optionally substituted amino)]; and Rf and R^ may also together join to form
a heterocyclyl ring; also, when n is zero, then Rf and Rq cannot be hydrogen, alkyl, alkenyl,
alkynyl. cycloalkyl and Rf and Rq together cannot join to form a heterocyclyl ring}; and
R-j and R> are independently selected from hydrogen, lower (C1-C6) alkyl, lower (C2-C6) alkenyt, lower (CVCft) alkynyl, lower (Ca-Cg) cycloalkyl, aryl, acyl, heterocyclyl, heteroaryl, lower (C|-C4) heterocyclylalkyl, and lower (C1-C4) heteroarylalkyl; or Rj and R? may together form isopropylidene acetal, the method comprising
a. reacting a compound of Formula XXVI (wherein r is an integer from 1-3) with a
compound of Formula XXVII (wherein R, is selected from hydrogen, lower (C1-C6)
alkyl. lower (C2-C6) alkenyl, tower (C2-C6) alkynyl, lower (C3-C6) cycloatkyl. aryl,
heteroaryl (with the proviso that the heteroaryl ring is not linked through a heteroatom),
aralkyl (C1-C4), heteroarylalkyl (C1-C4), and heterocyclylalkyl (C1-C4) and Rm is as
defined above) to give a compound of Formula XXV111.
b. reacting a compound of Formula XXVI (wherein r is an integer from 1-3) with a
compound of Formula XXIX (wherein Rs is selected from alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heteroarylalkyl) to form a compound of
Formula XXX.
i 0. A method of making a compound of Formula XXXII

(Formula Removed)
wherein R7 is -(CH2)nG wherein n is an integer from 0-5 and G is from
a) acyl (with the proviso that n cannot be 0), and
b) -C(=O)NRfRq [wherein Rf and Rq can be independently selected from hydrogen,
hydroxy (with the restriction that both Rf and Rq cannot both be hydroxy), alkyl, alkenyl,
alkynyl. cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, and S(O)2R7 (wherein R7 is selected
from alkyl. alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl,
lleteroarylalkyl. and optionally substituted amino)]; and Rf and Rq may also together join to form
a heterocyclyl ring; also, when n is zero, then Rf and Rq cannot be hydrogen, alkyl, alkenyl,
alkynyl, cycloalkyl and Rf and Rq together cannot join to form a heterocyclyl ring); the method
comprising
hydrolysing a compound of Formula XXXI with aqueous perchloric acid, aqueous acetic acid, aqueous sulphuric acid or Dowex 50W-8X to give a compound of Formula XXX11. 11. A method of making a compound of Formula XXXIV and XXXVI
(Formula Removed)
wherein
R1 and R2 together form a five-membered acetal, wherein the carbon atom joining the oxygens
can be substituted with RL and Rm [wherein RL and Rm are independently selected from
hydrogen, alkyl, alkenyl, cycloalkyl, aryl, or aralkyl; or RL and Rm can together join to form a 3-8 membered ring, wherein the ring may optionally contain one or more heteroatoms selected from O, N or S, and the ring may be optionally substituted with one or more of alkyl, alkenyl, alkynyl, amino, substituted amino, cycloalkyl, oxo, hydroxy, carboxy, -COQR6 (wherein Q is O or NH and R& is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl), alkoxy, aryloxy, halogen (F,C1, Br, I), aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl; or RL and Rm can together join to form an oxo group]; and R4 and R are independently selected from hydrogen, lower (C1-C6) alkyl, lower (C2-C6) alkenyl, lower (C2-C6) alkynyl, lower (C3-C8) cycloalkyl, aryl, acyl, heterocyclyl, heteroaryl, lower (C1-C4) heterocyclylalkyl, and lower (C1-C4) heteroarylalkyl; or R4 and R5 may together form a five-membered acetal wherein the carbon linking the two oxygens is substituted with RL, and Rm (wherein R1. and Rm are the same as defined earlier)
the method comprising
a. reacting a compound of Formula V with a compound of Formula XXXIII (wherein Ru is
selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl,
heteroarylalkyl, and heterocyclylalkyl) to form a compound of Formula XXXIV.
b. reacting a compound of Formula V with a compound of Formula XXXV (wherein L is a
leaving group, and Ra and Rb together with the nitrogen atom carrying them are the N-
terminus of an amino acid or di-tetrapeptide or Ra and Rb together join to form a
heterocyclyl ring) to form a compound of Formula XXXVI.
12. A pharmaceutical composition comprising a compound of claim 1 and at least one
pharmaceutically acceptable excipient.
13. Use of a compound for the manufacture of a medicament for inhibiting or preventing
inflammation or autoimmune diseses, comprising administering the pharmaceutical composition
of claim 12 to a patient in need thereof.
14. Hie method of claim 13, wherein inflammation or autoimmune disease are bronchial
asthma, chronic obstructive pulmonary diseses, rheumatoid arthritis, type I diabetes, multiple
sclerosis, allograft rejection, psoriasis, inflammatory bowel disease, ulcerative colitis, acne,
atherosclerosis, cancer, pruriris or allergic rhinitis.