1. Patent Search
  2. Details

AMINO SPHINGOGLYCOLIPID ANALOGUES

20170119875 ยท 2017-05-04

    Inventors

    Cpc classification

    International classification

    Abstract

    The invention relates to amino sphingoglycolipid analogues and peptide derivatives thereof, compositions comprising these compounds and methods of treating or preventing diseases or conditions using such compounds, especially diseases or conditions relating to cancer, infection, atopic disorders, autoimmune disease or diabetes.

    Claims

    1. A compound of formula (I): ##STR00084## wherein: A is a self-immolative linker group; D is selected from the group consisting of: ##STR00085## wherein * denotes a point of attachment of group D to group A; R.sup.15 is a side chain of one of the following amino acids: L-lysine, L-citrulline, L-arginine, L-glutamine or L-threonine; R.sup.16 is a side chain of a hydrophobic amino acid; R.sup.19 is an alkylene group; R.sup.32 is an alkylene group or an O-alkylene group wherein the O is attached to the carbonyl group of D2; E is selected from the group consisting of: ##STR00086## ##STR00087## ##STR00088## wherein * denotes a point of attachment of group E to group D; R.sup.20 is H or lower alkyl; R.sup.21 is an alkylene group; g is 0 when R.sup.20 is H or g is 1 when R.sup.20 is lower alkyl; provided that E is E18 only when D is D1, D2 or D3 and provided that E is E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E15, E20, E21, E93, E94 or E96 only when D is D1, D2, D3 or D4; and provided that E is E91, E92 or E95 only when D is D5 and provided that E is E97 only when D is D2; G is absent or G is an amino acid sequence of up to 6 amino acids, attached through its N-terminus to group E and through its C-terminus to group J; J is a peptidic antigen, optionally substituted at its N and/or C-termini with up to 6 amino acids selected from the group of natural flanking residues for the antigen, and optionally terminated with NH.sub.2 at the C-terminus so as to provide a C-terminal amide, and attached to group G through its N-terminus or, wherein G is absent, attached to group E through its N-terminus; R.sup.1 is H or glycosyl, provided that if R.sup.1 is glycosyl then R.sup.2 and R.sup.3 are both OH; R.sup.2 is selected from the group consisting of H, OH, F and OR.sup.10; provided that if R.sup.2 is H, F or OR.sup.10, then R.sup.1 is H and R.sup.3 is OH; R.sup.3 is selected from the group consisting of H, OH, F and OR.sup.10; provided that if R.sup.3 is H, F or OR.sup.10, then R.sup.1 is H and R.sup.2 is OH; R.sup.6 is OH or H; R.sup.7 is OH or H; when R.sup.7 is H, custom-character denotes an optional double bond linking the carbon adjacent to R.sup.7 with the carbon adjacent to R.sup.8; R.sup.8 is H or C.sub.1-C.sub.15 alkyl having a straight or branched carbon chain, wherein the carbon chain optionally incorporates one or more double bonds, one or more triple bonds, one or more oxygen atoms and/or a terminal or non-terminal optionally substituted aryl group; R.sup.10 is glycosyl; R.sup.12 is C.sub.6-C.sub.30 acyl having a straight or branched carbon chain optionally substituted with one or more hydroxy groups at positions 2 and/or 3 of the acyl group and/or an optionally substituted chain terminating aryl group and which optionally incorporates one or more double bonds, one or more triple bonds, and/or one or more optionally substituted arylene groups and wherein the carbon chain is optionally substituted with one or more deuterium atoms; wherein the optional substituents on the aryl and arylene groups may be selected from halogen, cyano, dialkylamino, C.sub.1-C.sub.6 amide, nitro, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 acyloxy and C.sub.1-C.sub.6 thioalkyl; X is O, CH.sub.2 or S; wherein when X is CH.sub.2 then the following must all be true: the stereochemistry of the 6-membered sugar ring in formula (I) is -D-galacto; R.sup.1 is H; R.sup.2 and R.sup.3 are both OH; and: either R.sup.6 is OH and R.sup.7 is OH and the stereochemistry at carbon atoms 2, 3 and 4 is (2S, 3S, 4R), (2S, 3S, 4S), (2R, 3S, 4S), (2R, 3S, 4R) or (2S, 3R, 4S); or R.sup.6 is OH and R.sup.7 is H, and R.sup.8 is C.sub.13H.sub.27 and the stereochemistry at carbon atoms 2 and 3 is (2S, 3S); when X is S then the following must all be true: the stereochemistry of the 6-membered sugar ring in formula (I) is -D-galacto; R.sup.1 is H; R.sup.2 and R.sup.3 are both OH; and: either R.sup.6 is OH and R.sup.7 is OH and the stereochemistry at carbon atoms 2, 3 and 4 is (2S, 3S, 4R); or R.sup.6 is OH and R.sup.7 is H and the stereochemistry at the carbon atoms 2 and 3 is (2S, 3S); n is 1 when X is O or S; or n is 0 or 1 when X is CH.sub.2; or a pharmaceutically acceptable salt thereof.

    2. The compound of claim 1 which is a compound of formula (Ia): ##STR00089## wherein X, R.sup.1, R.sup.2, R.sup.3, R.sup.6, R.sup.7, R.sup.8, R.sup.10, R.sup.12, R.sup.15, R.sup.16, R.sup.19, R.sup.20, R.sup.21, R.sup.32, n, g, A, D, E, G and J are all as defined in claim 1; or a pharmaceutically acceptable salt thereof.

    3. A compound of formula (II): ##STR00090## wherein A, D, X, R.sup.1, R.sup.2, R.sup.3, R.sup.6, R.sup.7, R.sup.8, R.sup.10, R.sup.12, R.sup.15, R.sup.16, R.sup.32, and n are all as defined above for formula (I); Z is selected from the group consisting of: ##STR00091## ##STR00092## wherein * denotes a point of attachment of group Z to group D, except as defined for Z23; R.sup.20 is as defined above for formula (I); R.sup.23 is aryl, aralkyl or optionally substituted alkyl; R.sup.24 is lower alkyl; R.sup.25 is p-C.sub.6H.sub.4L wherein L is H, methoxy, COOH, C(O)NHCH.sub.2COOH or CH.sub.2CH.sub.2NMe.sub.2; R.sup.26 is aralkyl; R.sup.27 is H or lower alkyl; R.sup.28 is alkylene; R.sup.31 is (CH.sub.2CH.sub.2O).sub.k k is an integer from 2 to 100; W is an optionally substituted cyclooctynyl ring; or W is a fused bicyclic or tricyclic ring system comprising an optionally substituted cyclooctynyl ring fused to one or more aryl groups or one or more cycloalkyl groups; wherein the cyclooctynyl ring optionally contains a N atom within the ring, which N atom is optionally substituted with an acyl group; and wherein the cyclooctynyl ring is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxy and aralkyl wherein the aryl part of this group is optionally substituted with a carboxylic acid; and wherein * or one of the optional substituents comprises a point of attachment of Z23 to group D; provided that Z is Z1, Z2, Z3, Z4, Z7, Z8, Z9, Z10, Z11, Z13, Z15, Z16, Z17 or Z18 only when D is DI, D2, D3 or D4 and provided that Z is Z12 only when D is D1, D2 or D3 and provided that Z is Z5 or Z20 only when D is D5, and provided that Z is Z21, Z22 or Z23 only when D is D2; or a pharmaceutically acceptable salt thereof.

    4. The compound of claim 1, wherein A is selected from the group consisting of: ##STR00093## wherein * denotes a point of attachment of group A to group D; each Q.sup.1, the same or different, is independently selected from the group consisting of H, alkyl, alkoxy, halogen, nitro, aryl; or, together with the ring to which it is attached, forms a fused bicyclic aryl group; p is an integer from 1 to 4; Alk.sup.1 is C.sub.1-C.sub.4 straight chain alkyl; and R.sup.29 is H or lower alkyl; provided that A is A1 only when D is D1 and provided that A is A2 only when D is D2, D3 or D5 and provided that A is A3 only when D is D1, D3 or D4 and provided that A is A4 only when D is D2, D3 or D5 and provided that A is A5 only when D is D1, D3 or D4.

    5. The compound as of claim 4, wherein A is A1 or A2.

    6. The compound of claim 5, wherein A is A1 wherein R.sup.28 is H, or wherein A is A2 wherein Q.sup.1 is H.

    7. The compound of claim 1, wherein D is D1.

    8. The compound of claim 1, wherein D is D2.

    9. The compound of claim 1, wherein D is D5.

    10. The compound of claim 1, wherein R.sup.15 is selected from the group consisting of: ##STR00094##

    11. The compound of claim 1, wherein R.sup.16 is selected from the group consisting of: ##STR00095##

    12. The compound of claim 1, wherein J is selected from the group consisting of: TABLE-US-00004 (SEQ ID NO: 1) AMLGTHTMEV, (SEQ ID NO: 2) MLGTHTMEV, (SEQ ID NO: 3) EAAGIGILTV, (SEQ ID NO: 4) AAGIGILTV, (SEQ ID NO: 5) AADHRQLQLSISSCLQQL, (SEQ ID NO: 6) AAGIGILTVILGVL, (SEQ ID NO: 7) AARAVFLAL, (SEQ ID NO: 8) ACDPHSGHFV, (SEQ ID NO: 9) ACYEFLWGPRALVETS, (SEQ ID NO: 10) ADHRQLQLSISSCLQQL, (SEQ ID NO: 11) AEEAAGIGILT, (SEQ ID NO: 12) AEEAAGIGIL, (SEQ ID NO: 13) AELVHFLLL, (SEQ ID NO: 14) AELVHFLLLKYRAR, (SEQ ID NO: 15) AEPINIQTW, (SEQ ID NO: 16) AFLPWHRLF, (SEQ ID NO: 17) AGATGGRGPRGAGA, (SEQ ID NO: 18) ALCRWGLLL, (SEQ ID NO: 19) ALDVYNGLL, (SEQ ID NO: 20) ALFDIESKV, (SEQ ID NO: 21) ALGGHPLLGV, (SEQ ID NO: 22) ALIHHNTHL, (SEQ ID NO: 23) ALKDVEERV, (SEQ ID NO: 24) ALLAVGATK, (SEQ ID NO: 25) ALLEIASCL, (SEQ ID NO: 26) ALNFPGSQK, (SEQ ID NO: 27) ALPYWNFATG, (SEQ ID NO: 28) ALSVMGVYV, (SEQ ID NO: 29) ALWPWLLMAT, (SEQ ID NO: 30) ALWPWLLMA, (SEQ ID NO: 31) ALYVDSLFFL, (SEQ ID NO: 32) ANDPIFVVL, (SEQ ID NO: 33) APPAYEKLSAEQ, (SEQ ID NO: 34) APRGPHGGAASGL, (SEQ ID NO: 35) APRGVRMAV, (SEQ ID NO: 36) ARGPESRLL, (SEQ ID NO: 37) ASGPGGGAPR, (SEQ ID NO: 38) ATGFKQSSKALQRPVAS, (SEQ ID NO: 39) AVCPWTWLR, (SEQ ID NO: 40) AWISKPPGV, (SEQ ID NO: 41) AYVCGIQNSVSANRS, (SEQ ID NO: 42) CATWKVICKSCISQTPG, (SEQ ID NO: 43) CEFHACWPAFTVLGE, (SEQ ID NO: 44) CLSRRPWKRSWSAGSCPGMPHL, (SEQ ID NO: 45) CMTWNQMNL, (SEQ ID NO: 46) CQWGRLWQL, (SEQ ID NO: 47) CTACRWKKACQR, (SEQ ID NO: 48) DPARYEFLW, (SEQ ID NO: 49) DTGFYTLHVIKSDLVNEEATGQFRV, (SEQ ID NO: 50) DVTFNIICKKCG, (SEQ ID NO: 51) EAAGIGILTV, (SEQ ID NO: 52) EADPTGHSY, (SEQ ID NO: 53) EAFIQPITR, (SEQ ID NO: 54) EDLTVKIGDFGLATEKSRWSGSHQFEQLS, (SEQ ID NO: 55) EEAAGIGILTVI, (SEQ ID NO: 56) EEKLIVVLF, (SEQ ID NO: 57) EFYLAMPFATPM, (SEQ ID NO: 58) EGDCAPEEK, (SEQ ID NO: 59) EIIYPNASLLIQN, (SEQ ID NO: 60) EKIQKAFDDIAKYFSK, (SEQ ID NO: 61) ELTLGEFLKL, (SEQ ID NO: 62) ELVRRILSR, (SEQ ID NO: 63) ESRLLEFYLAMPF, (SEQ ID NO: 64) ETVSEQSNV, (SEQ ID NO: 65) EVDPASNTY, (SEQ ID NO: 66) EVDPIGHLY, (SEQ ID NO: 67) EVDPIGHVY, (SEQ ID NO: 68) EVISCKLIKR, (SEQ ID NO: 69) EVYDGREHSA, (SEQ ID NO: 70) EYLQLVFGI, (SEQ ID NO: 71) EYLSLSDKI, (SEQ ID NO: 72) EYSKECLKEF, (SEQ ID NO: 73) EYVIKVSARVRF, (SEQ ID NO: 74) FIASNGVKLV, (SEQ ID NO: 75) FINDEIFVEL, (SEQ ID NO: 76) FLDEFMEGV, (SEQ ID NO: 77) FLEGNEVGKTY, (SEQ ID NO: 78) FLFLLFFWL, (SEQ ID NO: 79) FLIIWQNTM, (SEQ ID NO: 80) FLLHHAFVDSIFEQWLQRHRP, (SEQ ID NO: 81) FLLLKYRAREPVTKAE, (SEQ ID NO: 82) FLTPKKLQCV, (SEQ ID NO: 83) FLWGPRALV, (SEQ ID NO: 84) FMNKFIYEI, (SEQ ID NO: 85) FMVEDETVL, (SEQ ID NO: 86) FPSDSWCYF, (SEQ ID NO: 87) FRSGLDSYV, (SEQ ID NO: 88) FSWAMDLDPKGA, (SEQ ID NO: 89) GARGPESRLLEFYLAMPFATPMEAELARRSLAQDAPPL, (SEQ ID NO: 90) GDNQIMPKAGLLIIV, (SEQ ID NO: 91) GELIGILNAAKVPAD, (SEQ ID NO: 92) GFKQSSKAL, (SEQ ID NO: 93) GLASFKSFLK, (SEQ ID NO: 94) GLCTLVAML, (SEQ ID NO: 95) GLPPDVQRV, (SEQ ID NO: 96) GLYDGMEHLI, (SEQ ID NO: 97) GRAMLGTHTMEVTVY, (SEQ ID NO: 98) GVALQTMKQ, (SEQ ID NO: 99) GVGSPYVSRLLGICL, (SEQ ID NO: 100) AKFVAAWTLKAAA, (SEQ ID NO: 101) GVLLKEFTVSGNILTIRLT, (SEQ ID NO: 102) GVLVGVALI, (SEQ ID NO: 103) GVYDGREHTV, (SEQ ID NO: 104) HLFGYSWYK, (SEQ ID NO: 105) HLIRVEGNLRVE, (SEQ ID NO: 106) HLSTAFARV, (SEQ ID NO: 107) HLYQGCQVV, (SEQ ID NO: 108) HQQYFYKIPILVINK, (SEQ ID NO: 109) HTMEVTVYHR, (SEQ ID NO: 110) IALNFPGSQK, (SEQ ID NO: 111) IGRIAECILGMNPSR, (SEQ ID NO: 112) IISAVVGIL, (SEQ ID NO: 113) ILAKFLHWL, (SEQ ID NO: 114) ILDSSEEDK, (SEQ ID NO: 115) ILDTAGREEY, (SEQ ID NO: 116) ILHNGAYSL, (SEQ ID NO: 117) ILSRDAAPLPRPG, (SEQ ID NO: 118) ILTVILGVL, (SEQ ID NO: 119) IMDQVPFFS, (SEQ ID NO: 120) IMDQVPFSV, (SEQ ID NO: 121) IMIGVLVGV, (SEQ ID NO: 122) INKTSGPKRGKHAWTHRLRE, (SEQ ID NO: 123) ISGGPRISY, (SEQ ID NO: 124) ISPNSVFSQWRVVCDSLEDYD, (SEQ ID NO: 125) ISQAVHAAHAEINEAGR, (SEQ ID NO: 126) ITDQVPFSV, (SEQ ID NO: 127) ITKKVADLVGF, (SEQ ID NO: 128) KASEKIFYV, (SEQ ID NO: 129) KAVYNFATM, (SEQ ID NO: 130) KCDICTDEY, (SEQ ID NO: 131) KEFTVSGNILT, (SEQ ID NO: 132) KEFTVSGNILTI, (SEQ ID NO: 133) KELEGILLL, (SEQ ID NO: 134) KHAWTHRLRERKQLVVYEEI, (SEQ ID NO: 135) KIFGSLAFL, (SEQ ID NO: 136) KIFSEVTLK, (SEQ ID NO: 137) KIFYVYMKRKYEAM, (SEQ ID NO: 138) KIFYVYMKRKYEAMT, (SEQ ID NO: 139) KILDAVVAQK, (SEQ ID NO: 140) KINKNPKYK, (SEQ ID NO: 141) KISQAVHAAHAEINEAGRESIINFEKLTEWT, (SEQ ID NO: 142) KKLLTQHFVQENYLEY, (SEQ ID NO: 143) KMDAEHPEL, (SEQ ID NO: 144) KNCEPVVPNAPPAYEKLSAE, (SEQ ID NO: 145) KRYFKLSHLQMHSRKH, (SEQ ID NO: 146) KSSEKIVYVYMKLNYEVMTK, (SEQ ID NO: 147) KTWGQYWQV, (SEQ ID NO: 148) KVAELVHFL, (SEQ ID NO: 149) KVHPVIWSL, (SEQ ID NO: 150) KVLEYVIKV, (SEQ ID NO: 151) KYDCFLHPF, (SEQ ID NO: 152) KYVGIEREM, (SEQ ID NO: 153) LAALPHSCL, (SEQ ID NO: 154) LAAQERRVPR, (SEQ ID NO: 155) LAGIGILTV, (SEQ ID NO: 156) LAMPFATPM, (SEQ ID NO: 157) LGFKVTLPPFMRSKRAADFH, (SEQ ID NO: 158) LGPGRPYR, (SEQ ID NO: 159) LHHAFVDSIF, (SEQ ID NO: 160) LIYRRRLMK, (SEQ ID NO: 161) LKEFTVSGNILTIRL, (SEQ ID NO: 162) LKLSGVVRL, (SEQ ID NO: 163) LLANGRMPTVLQCVN, (SEQ ID NO: 164) LLDGTATLRL, (SEQ ID NO: 165) LLEFYLAMPFATPM, (SEQ ID NO: 166) LLEFYLAMPFATPMEAELARRSLAQ, (SEQ ID NO: 167) LLFGLALIEV, (SEQ ID NO: 168) LLGATCMFV, (SEQ ID NO: 169) LLGPGRPYR, (SEQ ID NO: 170) LLGRNSFEV, (SEQ ID NO: 171) LLKYRAREPVTKAE, (SEQ ID NO: 172) LLLDDLLVSI, (SEQ ID NO: 173) LLLLTVLTV, (SEQ ID NO: 174) LLWSFQTSA, (SEQ ID NO: 175) LLYKLADLI, (SEQ ID NO: 176) LMLQNALTTM, (SEQ ID NO: 177) LPAVVGLSPGEQEY, (SEQ ID NO: 178) LPHSSSHWL, (SEQ ID NO: 179) LPRWPPPQL, (SEQ ID NO: 180) LPSSADVEF, (SEQ ID NO: 181) LSHLQMHSRKH, (SEQ ID NO: 182) LSRLSNRLL, (SEQ ID NO: 183) LTDLQPYMRQFVAHL, (SEQ ID NO: 184) LWWVNNQSLPVSP, (SEQ ID NO: 185) LYATVIHDI, (SEQ ID NO: 186) LYSACFWWL, (SEQ ID NO: 187) LYVDSLFFL, (SEQ ID NO: 188) MEVDPIGHLY, (SEQ ID NO: 189) MIAVFLPIV, (SEQ ID NO: 190) MIFEKHGFRRTTPP, (SEQ ID NO: 191) MKLNYEVMTKLGFKVTLPPF, (SEQ ID NO: 192) MLAVISCAV, (SEQ ID NO: 193) MLLAVLYCL, (SEQ ID NO: 194) MLMAQEALAFL, (SEQ ID NO: 195) MPFATPMEA, (SEQ ID NO: 196) MPREDAHFIYGYPKKGHGHS, (SEQ ID NO: 197) MSLQRQFLR, (SEQ ID NO: 198) MVKISGGPR, (SEQ ID NO: 199) NLVPMVATV, (SEQ ID NO: 200) NPPSMVAAGSVVAAV, (SEQ ID NO: 201) NSIVKSITVSASG, (SEQ ID NO: 202) NSNHVASGAGEAAIETQSSSSEEIV, (SEQ ID NO: 203) NSQPVWLCL, (SEQ ID NO: 204) NTYASPRFK, (SEQ ID NO: 205) NYARTEDFF, (SEQ ID NO: 206) NYKRCFPVI, (SEQ ID NO: 207) NYNNFYRFL, (SEQ ID NO: 208) PDTRPAPGSTAPPAHGVTSA, (SEQ ID NO: 209) PFATPMEAELARR, (SEQ ID NO: 210) PGSTAPPAHGVT, (SEQ ID NO: 211) PGTRVRAMAIYKQ, (SEQ ID NO: 212) PGVLLKEFTVSGNILTIRLTAADHR, (SEQ ID NO: 213) PLLENVISK, (SEQ ID NO: 214) PLPPARNGGL, (SEQ ID NO: 215) PLQPEQLQV, (SEQ ID NO: 216) PLTSIISAV, (SEQ ID NO: 217) PRALAETSYVKVLEY, (SEQ ID NO: 218) PVTWRRAPA, (SEQ ID NO: 219) PYYFAAELPPRNLPEP, (SEQ ID NO: 220) QCSGNFMGF, (SEQ ID NO: 221) QCTEVRADTRPWSGP, (SEQ ID NO: 222) QGAMLAAQERRVPRAAEVPR, (SEQ ID NO: 223) QGQHFLQKV, (SEQ ID NO: 224) QLAVSVILRV, (SEQ ID NO: 225) QNILLSNAPLGPQFP, (SEQ ID NO: 226) QQITKTEV, (SEQ ID NO: 227) QRPYGYDQIM, (SEQ ID NO: 228) QYSWFVNGTF, (SEQ ID NO: 229) RAGLQVRKNK, (SEQ ID NO: 230) REPFTKAEMLGSVIR, (SEQ ID NO: 231) REPVTKAEML, (SEQ ID NO: 232) RIAECILGM, (SEQ ID NO: 233) RKVAELVHFLLLKYR, (SEQ ID NO: 234) RKVAELVHFLLLKYRA, (SEQ ID NO: 235) RLLEFYLAMPFA, (SEQ ID NO: 236) RLLQETELV, (SEQ ID NO: 237) RLMKQDFSV, (SEQ ID NO: 238) RLPRIFCSC, (SEQ ID NO: 239) RLSSCVPVA, (SEQ ID NO: 240) RLVDDFLLV, (SEQ ID NO: 241) RMPEAAPPV, (SEQ ID NO: 242) RMPTVLQCVNVSVVS, (SEQ ID NO: 243) RNGYRALMDKS, (SEQ ID NO: 244) RNGYRALMDKSLHVGTQCALTRR, (SEQ ID NO: 245) RPGLLGASVLGLDDI, (SEQ ID NO: 246) RPHVPESAF, (SEQ ID NO: 247) RQKRILVNL, (SEQ ID NO: 248) RSDSGQQARY, (SEQ ID NO: 249) RTKQLYPEW, (SEQ ID NO: 250) RVIKNSIRLTL, (SEQ ID NO: 251) RVRFFFPSL, (SEQ ID NO: 252) RYQLDPKFI, (SEQ ID NO: 253) SAFPTTINF, (SEQ ID NO: 254) SAWISKPPGV, (SEQ ID NO: 255) SAYGEPRKL, (SEQ ID NO: 256) SEIWRDIDF, (SEQ ID NO: 257) SELFRSGLDSY, (SEQ ID NO: 258) SESIKKKVL, (SEQ ID NO: 259) SESLKMIF, (SEQ ID NO: 260) SFSYTLLSL, (SEQ ID NO: 261) SHETVIIEL, (SEQ ID NO: 262) SIINFEKL, (SEQ ID NO: 263) SLADTNSLAV, (SEQ ID NO: 264) SLFEGIDIYT, (SEQ ID NO: 265) SLFPNSPKWTSK, (SEQ ID NO: 266) SLFRAVITK, (SEQ ID NO: 267) SLGWLFLLL, (SEQ ID NO: 268) SLLMWITQC, (SEQ ID NO: 269) SLLMWITQCFLPVF, (SEQ ID NO: 270) SLLQHLIGL, (SEQ ID NO: 271) SLPYWNFATG, (SEQ ID NO: 272) SLSKILDTV, (SEQ ID NO: 273) SLYKFSPFPL, (SEQ ID NO: 274) SLYSFPEPEA, (SEQ ID NO: 275) SNDGPTLI, (SEQ ID NO: 276) SPRWWPTCL, (SEQ ID NO: 277) SPSSNRIRNT, (SEQ ID NO: 278) SQKTYQGSY, (SEQ ID NO: 279) SRFGGAVVR, (SEQ ID NO: 280) SSALLSIFQSSPE, (SEQ ID NO: 281) SSDYVIPIGTY, (SEQ ID NO: 282) SSKALQRPV, (SEQ ID NO: 283) SSPGCQPPA, (SEQ ID NO: 284) STAPPVHNV, (SEQ ID NO: 285) SVASTITGV, (SEQ ID NO: 286) SVDYFFVWL, (SEQ ID NO: 287) SVSESDTIRSISIAS, (SEQ ID NO: 288) SVYDFFVWL, (SEQ ID NO: 289) SYLDSGIHF, (SEQ ID NO: 290) SYLQDSDPDSFQD, (SEQ ID NO: 291) TFPDLESEF, (SEQ ID NO: 292) TGRAMLGTHTMEVTVYH, (SEQ ID NO: 293) TLDSQVMSL, (SEQ ID NO: 294) TLDWLLQTPK, (SEQ ID NO: 295) TLEEITGYL, (SEQ ID NO: 296) ZTLMSAMTNL, (SEQ ID NO: 297) TLNDECWPA, (SEQ ID NO: 298) TLPGYPPHV, (SEQ ID NO: 299) TLYQDDTLTLQAAG, (SEQ ID NO: 300) TMKQICKKEIRRLHQY, (SEQ ID NO: 301) TMNGSKSPV, (SEQ ID NO: 302) TPRLPSSADVEF, (SEQ ID NO: 303) TSCILESLFRAVITK, (SEQ ID NO: 304) TSEKRPFMCAY, (SEQ ID NO: 305) TSYVKVLHHMVKISG, (SEQ ID NO: 306) TTEWVETTARELPIPEPE, (SEQ ID NO: 307) TVSGNILTIR, (SEQ ID NO: 308) TYACFVSNL, (SEQ ID NO: 309) TYLPTNASL, (SEQ ID NO: 310) TYYRPGVNLSLSC, (SEQ ID NO: 311) VAELVHFLL, (SEQ ID NO: 312) VFGIELMEVDPIGHL, (SEQ ID NO: 313) VGQDVSVLFRVTGALQ, (SEQ ID NO: 314) VIFSKASSSLQL, (SEQ ID NO: 315) VISNDVCAQV, (SEQ ID NO: 316) VLDGLDVLL, (SEQ ID NO: 317) VLFYLGQY, (SEQ ID NO: 318) VLHWDPETV, (SEQ ID NO: 319) VLLKEFTVSG, (SEQ ID NO: 320) VLLQAGSLHA, (SEQ ID NO: 321) VLPDVFIRCV, (SEQ ID NO: 322) VLPDVFIRC, (SEQ ID NO: 323) VLRENTSPK, (SEQ ID NO: 324) VLYRYGSFSV, (SEQ ID NO: 325) VPGVLLKEFTVSGNILTIRLTAADHR, (SEQ ID NO: 326) VPLDCVLYRY, (SEQ ID NO: 327) VRIGHLYIL, (SEQ ID NO: 328) VSSFFSYTL, (SEQ ID NO: 329) VVLGVVFGI, (SEQ ID NO: 330) VVPCEPPEV, (SEQ ID NO: 331) VVVGAVGVG, (SEQ ID NO: 332) VYFFLPDHL, (SEQ ID NO: 333) WEKMKASEKIFYVYMKRK, (SEQ ID NO: 334) WLPFGFILI, (SEQ ID NO: 335) WNRQLYPEWTEAQRLD, (SEQ ID NO: 336) WQYFFPVIF, (SEQ ID NO: 337) WRRAPAPGA, (SEQ ID NO: 338) YACFVSNLATGRNNS, (SEQ ID NO: 339) YFSKKEWEKMKSSEKIVYVY, (SEQ ID NO: 340) YLEPGPVTA, (SEQ ID NO: 341) YLEPGPVTV, (SEQ ID NO: 342) YLNDHLEPWI, (SEQ ID NO: 343) YLQLVFGIEV, (SEQ ID NO: 344) YLSGANLNL, (SEQ ID NO: 345) YLVPQQGFFC, (SEQ ID NO: 346) YMDGTMSQV, (SEQ ID NO: 347) YMIMVKCWMI, (SEQ ID NO: 348) YRPRPRRY, (SEQ ID NO: 349) YSVYFNLPADTIYTN, (SEQ ID NO: 350) YSWRINGIPQQHTQV, (SEQ ID NO: 351) YVDFREYEYY, (SEQ ID NO: 352) YYWPRPRRY, (SEQ ID NO: 353) IMDQVPFFS, (SEQ ID NO: 354) SVDYFFVWL, (SEQ ID NO: 355) ALFDIESKV, (SEQ ID NO: 356) NLVPMVATV and (SEQ ID NO: 357) GLCTLVAML, (SEQ ID NO: 358) SVASTITGV, (SEQ ID NO: 359) VMAGDIYSV, (SEQ ID NO: 360) ALADGVQKV, (SEQ ID NO: 361) LLGATCMFV, (SEQ ID NO: 362) SVFAGVVGV, (SEQ ID NO: 363) ALFDGDPHL, (SEQ ID NO: 364) YVDPVITSI, (SEQ ID NO: 365) STAPPVHNV, (SEQ ID NO: 366) LAALPHSCL, (SEQ ID NO: 367) SQDDIKGIQKLYGKRS, (SEQ ID NO: 368) FLPSDFFPSV (SEQ ID NO: 369) FLPSDFFPSV, (SEQ ID NO: 370) TLGEFLKLDRERAKN, (SEQ ID NO: 371) TFSYVDPVITSISPKYGMET, (SEQ ID NO: 372) AMTQLLAGV, (SEQ ID NO: 373) KVFAGIPTV, (SEQ ID NO: 374) AIIDGVESV, (SEQ ID NO: 375) GLWHHQTEV, (SEQ ID NO: 376) NLDTLMTYV, (SEQ ID NO: 377) KIQEILTQV, (SEQ ID NO: 378) LTFGDVVAV, (SEQ ID NO: 379) TMLARLASA, (SEQ ID NO: 380) IMDQVPFSV, (SEQ ID NO: 381) MHQKRTAMFQDPQERPRKLPQLCTELQTTIHD, (SEQ ID NO: 382) LPQLCTELQTTI, (SEQ ID NO: 383) HDIILECVYCKQQLLRREVY, (SEQ ID NO: 384) KQQLLRREVYDFAFRDLCIVYRDGN, (SEQ ID NO: 385) RDLCIVYRDGNPYAVCDKCLKFYSKI, (SEQ ID NO: 386) DKCLKFYSKISEYRHYCYSLYGTTL, (SEQ ID NO: 387) HYCYSLYGTTLEQQYNKPLCDLLIR, (SEQ ID NO: 388) YGTTLEQQYNKPLCDLLIRCINCQKPLCPEEK, (SEQ ID NO: 389) RCINCQKPLCPEEKQRHLDKKQRFHNIRGRWT, (SEQ ID NO: 390) DKKQRFHNIRGRWTGRCMSCCRSSRTRRETQL, (SEQ ID NO: 391) MHGDTPTLHEYMLDLQPETTDLYCYEQLNDSSEEE, (SEQ ID NO: 392) LYCYEQLNDSSEEEDEIDGPAGQAEPDRAHYNIVT, (SEQ ID NO: 393) GQAEPDRAHYNIVTFCCKCDSTLRLCVQSTHVDIR, (SEQ ID NO: 394) TLRLCVQSTHVDIRTLEDLLMGTLGIVCPICSQKP, (SEQ ID NO: 395) ALPFGFILV, (SEQ ID NO: 396) TLADFDPRV, (SEQ ID NO: 397) IMDQVPFSV, (SEQ ID NO: 398) SIMTYDFHGA, (SEQ ID NO: 399) AQYIKANSKFIGITEL, (SEQ ID NO: 400) FLYDDNQRV, (SEQ ID NO: 401) YLIELIDRV, (SEQ ID NO: 402) NLMEQPIKV, (SEQ ID NO: 403) FLAEDALNTV, (SEQ ID NO: 404) ALMEQQHYV, (SEQ ID NO: 405) ILDDIGHGV, (SEQ ID NO: 406) KLDVGNAEV, (SEQ ID NO: 407) TFEFTSFFY, (SEQ ID NO: 408) SWPDGAELPF, (SEQ ID NO: 409) GILGFVFTL, (SEQ ID NO: 410) ILRGSVAHK (SEQ ID NO: 411) SVYDFFVWLKFFHRTCKCTGNFA, (SEQ ID NO: 412) DLAQMFFCFKELEGW, (SEQ ID NO: 413) AVGALEGPRNQDWLGVPRQL and (SEQ ID NO: 414) RAHYNIVTF.

    13. The compound of claim 1, wherein the stereochemistry of the 6-membered sugar ring of formula (I) or formula (II) is -D-galacto.

    14. The compound of claim 1, wherein X is O.

    15. The compound of claim 1, wherein n is 1, the stereochemistry of the 6-membered sugar ring of formula (I) or formula (II) is -D-galacto, R.sup.6 is OH and R.sup.7 is OH.

    16. The compound of claim 1 which is selected from the group consisting of: ##STR00096## ##STR00097## or a pharmaceutically acceptable salt thereof.

    17. The compound of claim 3 which is selected from the group consisting of: ##STR00098## ##STR00099## or a pharmaceutically acceptable salt thereof.

    18. A pharmaceutical composition, comprising the compound of claim 1 or CN168 ##STR00100## and a pharmaceutically acceptable exipient.

    19. (canceled)

    20. A vaccine, comprising (i) the compound of claim 1 and a pharmaceutically acceptable diluent, or (ii) the compound of claim 1, a pharmaceutically acceptable diluent, and an antigen.

    21. A method of treating or preventing an infectious disease, an atopic disorder, an autoimmune disease, diabetes or cancer comprising administering a pharmaceutically effective amount of the compound of claim 1 to a patient requiring treatment.

    22. (canceled)

    Description

    BRIEF DESCRIPTION OF THE FIGURES

    [0303] FIG. 1 shows CD86 expression on B cells in the peripheral blood as a readout of NKT cell activity in response to injection of compounds of the invention. Groups of C57BL/6 mice (n=3) are injected intravenously with 0.23 nmol of the indicated glycolipid compounds and then the blood samples collected 20 h later for the analysis of CD86 expression on CD45 (B220)+B cells by antibody labelling and flow cytometry. Mean fluorescence index (MFI)SEM are presented, *P<0.05, *P<0.01, ***P<0.001. The data show that injection of the conjugate CN169 induces activation of NKT cells resulting in levels of CD86 expression on B cells that are similar to injection of admixed -GalCer and SIINFEKL, or admixed -GalCer and CN159, an N-terminal extended peptide derivative that is a presumed in vivo breakdown product of CN169.

    [0304] FIG. 2 shows enumeration of T cells with specificity for the peptide antigen SIINFEKL following intravenous administration of compounds of the invention as vaccines into mice. The compounds are injected to give the equivalent molar dose of SIINFEKL peptide in each case. To increase sensitivity of the assay, all mice are initially donated a cohort of 10,000 SIINFEKL-specific T cells from a transgenic mouse encoding a T cell receptor for this antigen (OT-1 mice) by intravenous injection of the cells one day before the vaccines are administered. To discriminate the donated T cells from those of the host, the donated cells exhibit congenic expression of the CD45.1 variant of the CD45 molecule. It is therefore possible to enumerate SIINFEKL-specific T cells in blood by flow cytometry using antibodies for CD45.1 together with antibodies for the transgenic T cell receptor (V2). Control animals (nave) are injected with the diluent phosphate-buffered saline (PBS). The data show that injection of the conjugate CN169 induces a larger population of SIINFEKL-specific T cells than injection of admixed components -GalCer and SIINFEKL, or admixed -GalCer and CN159. Each dot represents a different animal; mean per treatment groupSEM are presented. *P<0.05, *P<0.01, ***P<0.001

    [0305] FIG. 3 shows CD86 expression on dendritic cells. The data show that injection of compounds of the invention induces activation of iNKT cells and subsequent maturation of dendritic cells, as indicated by up-regulation of expression of the activation marker CD86. Groups of C57BL/6 mice (n=3) are injected intravenously with 0.571 nmol of the indicated compounds and then the spleens removed 20 h later for the analysis of CD86 expression on CD11c.sup.+ dendritic cells by antibody labelling and flow cytometry. Mean fluorescence index (MFI)SEM are presented. *P<0.05, *P<0.01, ***P<0.001

    [0306] FIG. 4 shows the cytotoxic capacity of T cells with specificity for the peptide antigen SIINFEKL following intravenous administration of compounds of the invention as vaccines into wild type mice. The compounds are injected to give the equivalent molar dose of SIINFEKL peptide, in each case of 0.571 nmol. Flow cytometry is used to assess the killing of target cells comprised of syngeneic splenocytes loaded ex vivo with 5 M SIINFEKL injected intravenously 7 days after vaccination. To discriminate the targets from host tissue, the injected cells are labelled with the fluorescent dye carboxyfluorescein succinimidyl ester (CFSE). A cohort syngeneic splenocytes (without peptide) labelled with the fluorescent dye cell tracker orange are also injected to serve as controls. Killing is defined as the percentage of peptide-loaded targets killed relative to control cells. Each treatment group contained 5 animals. Control animals are injected with the diluent phosphate-buffered saline (PBS). The data show that injection of CI-017 induces greater SIINFEKL-specific cytotoxicity compared to injection of PBS, or injection of -GalCer mixed with CN159, which is an N-terminal extended SIINFEKL peptide (including the protease cleavage sequence FFRK) that is used in manufacture of the conjugate. Mean percentage of killing per groupSEM are shown. ***p<0.001

    [0307] FIG. 5 shows the antitumour effect of vaccination with conjugate vaccine CI-017 (0.571 nmol) compared to vaccination with peptide CN159 (0.571 nmol) mixed with -GalCer (0.571 nmol). Progression of subcutaneous B16.OVA tumours is monitored in animals treated five days after tumour challenge with intravenous CI-017 or CN159 peptide and -GalCer or with PBS. The mean tumour sizes per group (n=5)SEM are shown. These data show that vaccination with CI-017 results in superior anti-tumour activity as compared to the control groups.

    ABBREVIATIONS

    [0308] NMR Nuclear magnetic resonance spectrometry

    [0309] HRMS High resolution mass spectrometry

    [0310] ESI Electrospray ionisation

    [0311] RT Room temperature

    [0312] THF Tetrahydrofuran

    [0313] PBS Phosphate-buffered saline

    [0314] HPLC High performance liquid chromatography

    [0315] FCS Fetal calf serum

    [0316] MS Mass spectrometry

    [0317] LC-MS Liquid chromatography-mass spectrometry

    [0318] TFA Trifluoroacetic acid

    [0319] TLC Thin layer chromatography

    [0320] DMF Dimethylformamide

    [0321] DMSO Dimethylsulfoxide

    [0322] DCM Dichloromethane

    [0323] NMP N-methyl-2-pyrrolidone

    [0324] DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

    [0325] PMB p-Methoxybenzyl

    [0326] DMAP 4-Dimethylaminopyridine

    [0327] TMS Trimethylsilyl

    [0328] DCC N,N-dicyclohexylcarbodiimide

    [0329] DIPEA N,N-diisopropylethylamine

    [0330] TBDPS tert-Butyldiphenylsilyl

    [0331] TBAF Tetra-n-butylammonium fluoride

    [0332] THP Tetrahydropyranyl

    [0333] EDCI 1-Ethyl-3--dimethylaminopropyl)carbodiimide

    [0334] CAN Ceric ammonium nitrate

    [0335] Tbeoc-Thz N-(2-(tert-Butyldisulfanyl)ethoxycarbonyl)-L-thiazolidine-4-carboxylic acid

    [0336] HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate.

    [0337] TCEP Tris(2-carboxyethyl)phosphine)

    [0338] TBTA Tris(benzyltriazolylmethyl)amine

    [0339] THPTA Tris(3-hydroxypropyltriazolylmethyl)amine

    [0340] Bim(Py).sub.2 ((2-Benzimidazolyl)methyl)-bis-((2-pyridyl)methyl)amine

    [0341] EDTA Ethylenediaminetetraacetic acid

    EXAMPLES

    [0342] The examples described herein are for purposes of illustrating embodiments of the invention. Other embodiments, methods, and types of analyses are within the capabilities of persons of ordinary skill in the art and need not be described in detail herein. Other embodiments within the scope of the art are considered to be part of this invention.

    [0343] Anhydrous solvents are obtained commercially. Air sensitive reactions are carried out under Ar. Thin layer chromatography (TLC) is performed on aluminium sheets coated with 60 F.sub.254 silica. Flash column chromatography is performed on Merck or SiliCycle silica gel (40-63 m) or SiliCycle reversed phase (C18) silica gel (40-63 m). NMR spectra are recorded on a Bruker 500 MHz spectrometer. .sup.1H NMR spectra are referenced to tetramethylsilane at 0 ppm (internal standard) or to residual solvent peak (CHCl.sub.3 7.26 ppm, CHD.sub.2OD 3.31 ppm, CHD.sub.2S(O)CD.sub.3 2.50 ppm). .sup.13C NMR spectra are referenced to tetramethylsilane at 0 ppm (internal standard) or to the deuterated solvent peak (CDCl.sub.3 77.0 ppm, CD.sub.3OD 49.0 ppm, CD.sub.3S(O)CD.sub.3 39.52 ppm). CDCl.sub.3-CD.sub.3OD solvent mixtures are always referenced to the methanol peak. High resolution electrospray ionization mass spectra are recorded on a Q-Tof Premier mass spectrometer.

    Example 1Synthesis of (2S,3S,4R)-1-O--6-Amino-6-deoxy-D-Galactopyranosyl-4-hexacosanoyl-2-((4-oxopentanoyloxy)methoxycarbonylamino) octadecane-1,3,4-triol (CN300)

    [0344] ##STR00072##

    Example 1.1(4-Nitrophenoxy)carbonyloxymethyl 4-oxopentanoate (41)

    [0345] ##STR00073##

    [0346] The silver salt of levulinic acid is prepared by adding a solution of AgNO.sub.3 (700 mg, 4.1 mmol) in water (10 mL) to the sodium salt of levulinic acid (4.3 mmol in 10 mL water, prepared by basification of levulinic acid with 1 M aq NaOH to pH 7-8). After 30 min, the resultant precipitate is isolated by filtration and washed with cold water followed by Et.sub.2O. The product is dried under vacuum to afford the silver salt as a white solid (636 mg, 69%). A mixture of iodomethyl 4-nitrophenyl carbonate (Gangwar, Pauletti et al. 1997) (105 mg, 0.325 mmol, dried by azeotropic distillation with toluene), 4 molecular sieves (250 mg) and silver levulinate (89 mg, 0.40 mmol) in dry toluene (1.5 mL) is protected from light and stirred at 40 C. After 4 h, the mixture is diluted with Et.sub.2O, filtered through celite, and concentrated under reduced pressure. The crude residue is purified by silica gel chromatography (30% to 40% EtOAc/petroleum ether) to afford the title compound (41) (85 mg, 84%) as a colourless oil. .sup.1H NMR (500 MHz, CDCl.sub.3) 2.20 (s, 3H), 2.67-2.70 (m, 2H), 2.80-2.83 (m, 2H), 5.88 (s, 2H), 7.38-7.48 (m, 2H), 8.24-8.34 (m, 2H); .sup.13C NMR (126 MHz, CDCl.sub.3) 27.7, 29.7, 37.6, 82.5, 121.8, 125.4, 145.7, 151.5, 155.1, 171.2, 206.0; HRMS (ESI): m/z calcd for C.sub.13H.sub.13NO.sub.8Na [M+Na].sup.+ 334.0539, found 334.0544.

    Example 1.2(2S,3S,4R)-1-(2,3-Di-O-benzyl-6-O-(4-toluenesulfonyl)--D-galactopyranosyloxy)-3,4-di(benzyloxy)-2-hexacosanoylamino-octadeca-6-ene (CN301)

    [0347] ##STR00074##

    [0348] Tosyl chloride (0.091 g, 0.476 mmol) is added to diol 1 (0.276 g, 0.227 mmol) (which is prepared as described in Lee, A., K. J. Farrand, et al. (2006) Novel synthesis of alpha-galactosyl-ceramides and confirmation of their powerful NKT cell agonist activity. Carbohydr Res 341(17): 2785-2798.) stirring in pyridine (2.76 ml, 34.1 mmol) at 0 C. and the mixture left to warm to r.t. over 18 h. Over the following 8 h, the reaction mixture is warmed to 35 C. and more tosyl chloride added in aliquots (total added: 0.300 g, 1.57 mmol) until the starting material has disappeared by TLC. Once cool, the solution is diluted with EtOAc, H.sub.2O is added and allowed to stir for 30 mins. The layers are then separated, the organic layer dried (MgSO.sub.4) and the solvent removed. Purification of the resulting residue by silica gel chromatography (10% EtOAc/petroleum ether changing to 20% EtOAc/petroleum ether) gave the mono-tosylated material CN301 (0.246 g, 0.179 mmol, 79%) as a colourless oil. [].sub.D.sup.20=+16.4 (c 0.005, CHCl.sub.3); .sup.1H NMR (500 MHz, CDCl.sub.3) 0.88 (t, J=6.8 Hz, 6H), 1.22-1.32 (m, 62H), 1.47-1.51 (m, 2H), 1.86-1.95 (m, 2H), 2.02-2.06 (m, 2H), 2.40 (s, 3H), 2.43-2.53 (m, 2H), 3.60-3.63 (m, 1H), 3.74-3.77 (m, 4H), 3.80 (dd, J=9.7, 3.2 Hz, 1H), 3.93-3.94 (m, 1H), 3.97-3.99 (m, 1H), 4.09-4.17 (m, 2H), 4.33-4.38 (m, 1H), 4.51-4.54 (m, 2H), 4.58 (d, J=11.7 Hz, 1H), 4.60 (d, J=11.6 Hz, 1H), 4.66 (d, J=11.6 Hz, 1H), 4.70 (d, J=11.7 Hz, 2H), 4.74 (d, J=11.5 Hz, 1H), 4.77 (d, J=3.4 Hz, 1H), 5.43-5.52 (m, 2H), 5.68-5.72 (m, 1H), 7.22-7.32 (m, 22H), 7.74 (d, J=8.3 Hz, 2H); .sup.13C NMR (125 MHz, CDCl.sub.3) 14.1, 22.7, 25.6, 27.6, 27.8, 29.3, 29.4, 29.6, 29.7, 31.9), 36.7, 49.8, 67.1, 67.9, 68.5, 68.9, 71.5, 72.7, 73.3, 75.7, 77.0, 79.29, 79.31, 98.5, 125.4, 127.5, 127.6, 127.68, 127.72, 127.76, 127.8, 128.0, 128.3, 128.4, 128.5, 129.8, 132.1, 137.8, 138.2, 138.5, 138.6, 144.8, 172.8; HRMS (ESI): m/z calcd for C.sub.85H.sub.127NO.sub.11SNa [M+Na].sup.+ 1392.9028, found 1392.9031.

    Example 1.2(2S,3S,4R)-2-Hexacosanoylamino-1-(6-O-(4-toluenesulfonyl)--D-galactopyranosyloxy)-3,4-octadecandiol (CN302)

    [0349] ##STR00075##

    [0350] Pd(OH).sub.2/C (20% Pd; 5 mg) is added to protected tosylate CN301 (0.040 g, 0.029 mmol) stirring in anhydrous CH.sub.2Cl.sub.2:MeOH (4 mL; 1:1). The reaction vessel is evacuated and flushed with hydrogen and stirred at r.t. for 24 h. The product mixture is filtered through celite, washed repeatedly with CHCl.sub.3:MeOH (3:1) and then concentrated. Purification by silica gel chromatography (100% CHCl.sub.3 changing to 10% MeOH/CHC.sub.3) gives the target CN302 (23 mg, 0.023 mmol, 79%) as a white solid. .sup.1H NMR (500 MHz, CDCl.sub.3/CD.sub.3OD 3:1) 0.88 (t, J=6.9 Hz, 6H), 1.23-1.42 (m, 68H), 1.52-1.68 (m, 4H), 2.16-2.26 (m, 2H), 2.46 (s, 3H), 3.35-3.36 (m, 1H), 3.52-3.58 (m, 2H), 3.64 (dd, J=10.7, 4.0 Hz, 1H), 3.70-3.76 (m, 2H), 3.83-3.87 (m, 2H), 4.03-4.06 (m, 1H), 4.13-4.23 (m, 2H), 4.85 (d, J=3.4 Hz, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.79 (d, J=8.1 Hz, 2H); .sup.13C NMR (125 MHz, CDCl.sub.3/CD.sub.3OD 3:1) 14.2, 21.7, 22.9, 26.1, 29.59, 29.63, 29.7, 29.8, 29.92, 29.95, 30.04, 32.2, 32.8, 36.8, 50.4, 68.1, 68.9, 69.2, 69.6, 70.1, 72.4, 74.9, 77.8, 99.9, 128.2, 130.2, 132.8, 145.5, 174.6; HRMS (ESI): m/z calcd for C57H.sub.105NO.sub.11SNa [M+Na].sup.+ 1034.7306, found 1034.7317.

    Example 1.3(2S,3S,4R)-2-Hexacosanoylamino-1-(2,3,4-tri-O-acetyl-6-O-(4-toluenesulfonyl)--D-galactopyranosyloxy)-3,4-di(acetyloxy)octadecane (CN303)

    [0351] ##STR00076##

    [0352] Tosylate CN302 (10 mg, 9.9 mol) is dissolved in pyridine (0.10 mL, 1.2 mmol) and cooled to 0 C. Acetic anhydride (0.10 mL, 1.0 mmol) and 4-(dimethylamino)pyridine (1.0 mg, 8.1 mol) are then added and stirred at r.t. for 5 h. The product mixture is diluted with CH.sub.2Cl.sub.2, and is washed with 1M HCl, saturated NaHCO.sub.3, brine, dried (MgSO.sub.4) and the solvent removed in vacuo. Purification by silica gel chromatography (20% EtOAc/petroleum ether changing to 30% EtOAc/petroleum ether) affords the acetylated compound CN303 (10 mg, 8.2 mol, 83%) as a colourless oil. .sup.1H NMR (500 MHz, CDCl.sub.3) 0.88 (t, J=6.9 Hz, 6H), 1.22-1.33 (m, 68H), 1.62-1.75 (m, 4H), 1.97 (s, 3H), 1.99 (s, 3H), 2.05 (s, 3H), 2.07 (s, 3H), 2.08 (s, 3H), 2.23-2.29 (m, 2H), 2.45 (s, 3H), 3.37 (dd, J=10.8, 2.7 Hz, 1H), 3.62 (dd, J=10.8, 2.9 Hz, 1H), 3.98 (dd, J.sub.A,B=10.3, J.sub.A,X=5.9 Hz, 1H), 4.04 (dd, J.sub.B,A=10.2, J.sub.B,X=6.7 Hz, 1H), 4.16 (t, J=6.9 Hz, 1H), 4.36 (tt, J=9.7, 2.7 Hz, 1H), 4.87-4.90 (m, 2H), 5.10 (dd, J=10.9, 3.6 Hz, 1H), 5.23 (dd, J=9.8, 2.5 Hz, 1H), 5.29 (dd, J=10.9, 3.4 Hz, 1H), 5.41 (br d, J=2.8 Hz, 1H), 6.24 (d, J=9.7 Hz, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.75 (d, J=8.2 Hz, 2H); HRMS (ESI): m/z calcd for C.sub.67H.sub.115NO.sub.16SNa [M+Na].sup.+ 1244.7834, found 1244.7844.

    Example 1.4(2S,3S,4R)-1-(6-Deoxy-6-azido--D-galactopyranosyloxy)-2-hexacosanoylamino-3,4-octadecandiol (CN304)

    [0353] ##STR00077##

    [0354] To a stirred solution of the tosylate CN303 (140 mg, 0.115 mmol) in DMF (5 mL) is added sodium azide (150 mg, 2.28 mmol) and 15-crown-5 ether (20 mg, 0.089 mol). The mixture is heated to 90 C. for 18 hr at which time further sodium azide (50 mg, 0.041 mmol) is added and heating continued at 100 C. for 2 hrs. After cooling, the mixture is diluted with DCM (50 mL) and water (50 mL). The aqueous phase is re-extracted with ethyl acetate (250 mL) and the combined organic extract is dried over MgSO.sub.4 and filtered. The solvent is removed via reduced pressure and the crude residue is purified by silica gel chromatography (0% to 20% to 40% to 100% EtOAc/toluene) to afford the azide (115 mg, 96%). The azide is dissolved in DCM/MeOH (3:3 mL) to which 30% NaOMe in MeOH (3 drops) is added and is stirred for 3 hrs. The solvents are removed via reduced pressure and the crude solid is purified by chromatography eluting with MeOH/CHCl.sub.3 (0% to 20% to 40%) to afford the title compound CN304 (80 mg, 86%) as a thin film. .sup.1H NMR (500 MHz, CDCl.sub.3) 0.88 (t, J=7.0 Hz, 6H), 1.22-1.41 (m, 68H), 1.50-1.69 (m, 4H), 2.18-2.22 (m, 2H), 3.30-3.38 (m, 2H), 3.50-3.52 (m, 3H), 3.70-3.78 (m, 2H), 3.79-3.84 (m, 1H), 3.85 (brs, 1H), 3.90 (m, 1H), 4.19-4.23 (m, 1H), 4.92 (d, J=3.4 Hz, 1H); .sup.13C NMR (126 MHz, CDCl.sub.3) 15.3, 24.0, 27.2, 30.6, 30.7, 30.9, 31.0, 33.3, 33.9, 37.9, 51.4, 52.6, 69.2, 70.1, 71.0, 71.3, 71.4, 73.5, 76.1, 101.0, 175.6; HRMS (ESI): m/z calcd for C.sub.50H.sub.99N.sub.4O.sub.8 [M+H].sup.+ 883.7463, found 883.7465.

    Example 1.5(2S,3S,4R)-1-(6-Deoxy-6-(4-(oxopentanoyloxy)methoxycarbonylamino)--D-galactopyranosyloxy)-2-hexacosanoylamino-3,4-octadecandiol (CN300)

    [0355] ##STR00078##

    [0356] To a solution of the azide CN304 (18 mg, 0.020 mmol) in DCM/MeOH (1:2, 2 mL) is added 20% Pd(OH).sub.2 (20 mg) and the mixture is stirred under hydrogen for 2 hrs. After the hydrogen is removed, the mixture is filtered through celite, and washed CHCl.sub.3/MeOH/H.sub.2O (30 mL) and hot ethanol (30 mL). The volatiles are concentrated under reduced pressure and pyridine (2 mL) is added followed by a solution of the pNP-carbonate 41 (9.8 mg, 0.032 mmol) in DCM (200 L) followed by the further addition of triethylamine (1 mL). After stirring at 30 C. for 1 hr, the mixture is diluted with chloroform and the volatiles are removed under reduced pressure. The crude residue is purified by silica gel chromatography (1.5:40:60 to 1.5:45:55 MeOH/dioxane/CHCl.sub.3) to afford the title compound CN300 (3 mg, 0.0029 mmol, 15%) as a thin film. .sup.1H NMR (500 MHz, 1:1 CDCl.sub.3/CD.sub.3OD) 0.88-0.90 (m, 6H), 1.24-1.34 (m, 68H), 1.55-1.72 (m, 4H), 2.20 (s, 3H), 2.17-2.24 (m, 2H), 2.59-2.63 (m, 2H), 2.79-2.83 (m, 2H), 3.30-3.83 (m, 11H), 4.90-4.93 (m, 1H), 5.69-5.75 (m, 2H); .sup.13C NMR (126 MHz, 1:1 CDCl.sub.3/CD.sub.3OD) 14.2, 22.8, 26.1, 28.1, 29.5, 29.9, 32.1, 33.0, 36.7, 37.8, 41.4, 50.6, 67.5, 69.1, 69.6, 70.4, 72.4, 75.1, 80.4, 99.9, 156.1, 172.3, 174.7, 208.0; HRMS (ESI): m/z calcd for C57H.sub.108N.sub.2O.sub.13Na [M+Na].sup.+ 1051.7749, found 1051.7750.

    Example 1.6(2S,3S,4R)-1-(6-Deoxy-6-amino)--D-galactopyranosyloxy)-2-hexacosanoylamino-3,4-octadecandiol (CN168)

    [0357] ##STR00079##

    [0358] To a solution of the azide CN304 (18 mg, 0.020 mmol) in DCM/MeOH (1:2, 2 mL) is added 20% Pd(OH).sub.2 (20 mg) and the mixture is stirred under hydrogen for 2 hrs. After the hydrogen is removed, the mixture is filtered through celite, and washed with CHCl.sub.3/MeOH (30 mL) and hot ethanol (30 mL). The volatiles are concentrated under reduced pressure to afford the title compound CN168 (Zhou, Forestier et al. 2002) (13 mg, 0.015 mmol, 74%) as a white solid. .sup.1H NMR (500 MHz, 3:1 CDCl.sub.3/CD.sub.3OD) 0.82-0.85 (m, 6H), 1.18-1.328 (m, 68H), 1.43-1.67 (m, 4H), 2.13-2.20 (m, 2H), 3.07 (dd J=3.8, 13.3 Hz, 1H), 3.20-3.24 (m, 1H), 3.46-3.52 (m, 2H), 3.58-3.62 (m, 1H), 3.68-3.76 (m, 4H), 3.85-3.89 (m, 1H), 3.99-4.02 (m, 1H), 4.92 (d, J=3.5 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H); HRMS (ESI): m/z calcd for C.sub.50H.sub.101N.sub.2O.sub.8 [M+H].sup.+ 857.758, found 857.7559.

    Example 2(2S,3S,4R)-1-(6-Deoxy-6-(4-((2-(FFRKSIINFEKL)-2-(oxo)ethoxyimino)pentanoyloxy)methoxycarbonylamino)--D-galactopyranosyloxy)-2-hexacosanoylamino-3,4-octadecandiol (CN169)

    [0359] ##STR00080##

    [0360] Peptide 2-(aminooxy)acetyl-FFRKSIINFEKL (12.2 mg, 7.55 mmol) and ketone CN300 (4.20 mg, 4.08 mol) are stirred together in a mixture of THF (0.71 mL), MeOH (0.35 mL) and water/aniline/TFA (200:6:3, 0.4 mL) at 30-40 C. for 48 h. The solvent is removed and the crude product purified by preparative HPLC (Phenomenex Luna C18(2), 5 m, 25030 mm, 35 C., 50 mL/min; Mobile phase A=20:80:0.05 water/MeOH/TFA; Mobile phase B=100:0.05 MeOH/TFA; 0-10 min: 100% A-100% B; 10-15 min: 100% B; 15-16 min: 100% B-100% A; 16-17 min: 100% A) to give the title compound CN169 (5.6 mg, 52%). .sup.1H NMR (500 MHz, d.sub.6-DMSO) 0.69-0.96 (m, 24H), 1.00-1.45 (m, 74H), 1.70-1.50 (m, 27H), 1.79 (s, 3H), 1.90-2.13 (m, 6H), 2.20-2.30 (m, 2H), 2.35-2.49 (m, 6H), 2.72-2.89 (m, 7H), 2.92-2.98 (m, 1H), 3.03-3.21 (m, 8H), 3.53-3.73 (m, 6H), 3.93-4.00 (m, 2H), 4.12-4.47 (m, 13H), 4.48-4.64 (m, 6H), 4.72 (s, 1H), 5.35 (t, J=4.8 Hz, 1H), 5.61-5.66 (m, 2H), 6.95 (s, 1H); 7.12-7.30 (m, 15H), 7.35-8.22 (m, 22H); HRMS (ESI): m/z calcd for C.sub.134H.sub.227N.sub.21O.sub.31 [(M+2H)/2].sup.+ 1313.3416, found 1313.3412.

    Example 2.1 (2S,3S,4R)-1-(6-Deoxy-6-(N-(6-azidohexanoyl)-Val-Cit-4-aminobenzyloxycarbonylamino)--D-galactopyranosyloxy)-2-hexacosanoylamino-3,4-octadecandiol (CI1022)

    [0361] ##STR00081##

    [0362] To a mixture of CN168 (20 mg, 0.023 mmol) and pNP-carbonate 92 (20 mg, 0.029 mmol) in anhydrous pyridine (600 L) under Ar is added Et.sub.3N (20 L, 0.28 mmol) and the mixture is stirred at rt. After 26 h, the mixture is concentrated to dryness under high vacuum, and the crude residue is purified by column chromatography on silica gel (MeOH/CHCl.sub.3=0:1 to 1:1) to afford the title compound CI1022 as a white solid (20 mg, 61%). .sup.1H NMR (500 MHz, d6-DMSO) 0.82-0.87 (m, 12H), 1.21-1.32 (m, 70H), 1.40-1.56 (m, 10H), 1.57-1.63 (m, 1H), 1.66-1.75 (m, 1H), 1.95-2.01 (m, 1H), 2.04-2.10 (m, 2H), 2.12-2.24 (m, 2H), 2.90-2.97 (m, 1H), 2.97-3.03 (m, 1H), 3.11-3.16 (m, 2H), 3.20-3.46 (m, 5H), 3.46-3.73 (m, 7H), 3.97 (br s, 1H), 4.17-4.27 (m, 2H), 4.33-4.61 (m, 4H), 4.69 (s, 1H), 4.90-4.95 (m, 2H), 5.39 (s, 2H), 5.97-6.01 (m, 1H), 7.03-7.08 (m, 1H), 7.26 (d, J=8.3 Hz, 2H), 7.55-7.61 (m, 3H), 7.81 (d, J=8.4 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 9.96 (s, 1H); HRMS-ESI [M+Na].sup.+ calcd for C.sub.75H.sub.136N.sub.10NaO.sub.14: 1424.0135; found 1424.0134.

    Example 2.2(2S,3S,4R)-1-(6-Deoxy-6-(4--(FFRKSIINFEKL)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)hexanoyl)-(N-Val-Cit-4-aminobenzyloxycarbonylamino)-1-(-D-galactopyranosyloxy))-2-hexacosanoylamino-3,4-octadecandiol (CI-017)

    [0363] ##STR00082##

    [0364] To a stirred solution of peptide 4-pentynoyl-FFRKSIINFEKL (4.2 mg, 2.6 mol), CI1022 (1.3 mg, 0.93 mol) and TBTA (0.35 mg, 0.66 mol) in DMSO (280 L) is added CHCl.sub.3 (280 L) and MeOH (280 L) followed by a small amount of copper foil (5 mm2 mm) and the reaction mixture is stirred at 20 C. for 15 h then at 30 C. for 24 h. The volatiles are removed under reduced pressure to give a residue which is centrifuged with an aqueous solution of 0.05 M EDTA (pH 11) (210 mL), water (210 mL) and the remaining pellet is dried under high vacuum. The crude product is purified by preparative HPLC (Phenomenex Luna C18(1), 5 m, 25010 mm, 40 C., 3.0 mL/min; Mobile phase A=100:0.05 water/TFA; Mobile phase B=100:0.0.05 MeOH/TFA; 0-5 min: 80-100% B; 5-12 min: 100% B; 12-13 min: 100-80% B; 13-15 min: 80% B) to give the title compound CI017 (1.30 mg, 46%, 97% pure by HPLC); HRMS-ESI m/z calcd for C.sub.155H.sub.258N.sub.28O.sub.32 [M+2H].sup.2+ 1511.9633, found 1511.9722.

    Example 34-((2-(FFRKSIINFEKL)-2-oxoethoxy)imino)pentanoic acid (CN159)

    [0365] ##STR00083##

    [0366] Peptide 2-(aminooxy)acetyl-FFRKSIINFEKL (6.0 mg, 3.72 mmol) is dissolved in THF/MeOH (2:1, 600 L) and added to an aqueous mixture of water/aniline/TFA (200:6:4, 300 L, pH 4.3). A solution of levulinic acid (100 mg, 0.86 mmol) dissolved in MeOH (200 L) is added and the reaction mixture stirred at 25 C. for 48 h. The solvent is removed and the crude product purified by preparative HPLC (Phenomenex Luna C18(1), 5 m, 25010 mm, 40 C., 1.4 mL/min; Mobile phase A=100:0.1 water/TFA; Mobile phase B=100:0.1 MeOH/TFA; 0-10 min: 50-100% B; 10-15 min: 100% B; 15-16 min: 100-50% B; 16-20 min: 50% B) to give the title compound CN159 (3.9 mg, 62%, 96% pure by HPLC). .sup.1H NMR (500 MHz, d6-DMSO) 0.70-0.88 (m, 18H), 0.99-1.11 (m, 2H), 1.24-1.43 (m, 7H), 1.44-1.60 (m, 12H), 1.60-1.577 (m, 8H), 1.79 (s, 2H), 1.91 (s, 1H), 2.17-2.30 (m, 2H), 2.31-2.40 m, 3H), 2.67-2.96 (m, 9H), 2.98-3.16 (m, 4H), 3.54-3.62 (m, 4H), 4.11-4.62 (m, 15H), 5.00 (br s, 1H), 6.92 (s, 1H), 7.11-7.29 (m, 17H), 7.36 (d, J=7.9 Hz, 1H), 7.41 (s, 1H), 7.45-7.53 (m, 1H), 7.57-7.87 (m, 8H), 7.91-8.21 (m, 8H); HRMS (ESI): m/z calcd for C.sub.82H.sub.126N.sub.19O.sub.21 [M+H].sup.+ 1712.9376, found 1712.9366.

    Example 4Formulating Compounds of the Invention for Intravenous Injection

    [0367] Compounds of the invention are formulated analogously to reported methods for -GalCer. Briefly, solubilisation is based on excipient proportions described by Giaccone et al (Giaccone, Punt et al. 2002). Thus, 100 L of a 10 mg/mL solution of -GalCer or a compound of the invention in 9:1 THF/MeOH is added to 1.78 mL of an aqueous solution of Tween 20 (15.9 mg), sucrose (177 mg) and L-histidine (23.8 mg). This homogeneous mixture is freeze dried and the resulting foam is stored under Ar at 18 C. This material is reconstituted with 1.0 mL of PBS or water prior to serial dilutions in PBS to achieve final injectable solutions of -GalCer or compounds of the invention.

    Example 5Biological Studies

    [0368] Mice:

    [0369] C57BL/6 are from breeding pairs originally obtained from Jackson Laboratories, Bar Harbor, Me., and used according to institutional guidelines with approval from the Victoria University of Wellington Animal Ethics Committee.

    [0370] Administration of Compounds of the Invention:

    [0371] Each compound of the invention is supplied as formulated product (see example 3), and diluted in phosphate-buffered saline (PBS) for injection (0.23 nmol/mouse) by intravenous injection into the lateral tail vein. In humans the expected therapeutic dose lies in the 50-4800 (g/m.sup.2) range (Giaccone, Punt et al. 2002). Note, 0.23 nmol in a mouse is a human equivalent dose of 30 g/m.sup.2 for -GalCer. All antibody labelling is performed on ice in FACS buffer (PBS supplemented with 1% FCS, 0.05% sodium azide, and 2 mM EDTA). Non-specific FcR-mediated antibody staining is blocked by incubation for 10 min with anti-CD16/32 Ab (24G2, prepared in-house from hybridoma supernatant). Flow cytometry is performed on a BD Biosciences FACSCalibur or BD LSRII SORP flow cytometer with data analysis using FlowJo software (Tree Star, Inc., OR, USA).

    [0372] Phenotyping B Cells from Peripheral Blood:

    [0373] Antibody staining and flow cytometry are used to examine the expression of the maturation markers CD86 on peripheral blood B cells following injection of compounds of the invention. Blood was collected from the lateral tail vein, followed by lysis of red blood cells with RBC lysis buffer (Puregene, Gentra Systems, Minneapolis, Minn., USA). Antibody staining is performed in PBS 2% fetal bovine serum and 0.01% sodium azide. The anti-FcgRII monoclonal antibody 2.4G2 is used at 10 mg/ml to inhibit non-specific staining. Monoclonal antibodies (all BD Biosciences Pharmingen, San Jose, Calif., USA) are used to examine expression of CD86 on gated CD45 (B220)+B cells.

    [0374] Analysis of Peptide-Specific T Cell Proliferation In Vivo:

    [0375] Pooled lymph node cell suspensions are prepared from animals of a cross between OT-1 mice, which express a transgenic T cell receptor (TCR) specific for the ovalbumin epitope SIINFEKL in the context of H-2K.sup.b molecules, and B6.SJL-Ptprc.sup.a Pepc.sup.b/BoyJ mice, which are congenic with C57BL/6 mice for the CD45.1.sup.+ marker. The samples are enriched for CD8.sup.+ cells using antibody coated magnetic beads (Miltenyi), and then transferred into C57BL/6 mice (110.sup.4 per mouse). Groups of recipient animals (n=5) are immunized with compounds of the invention one day later. Doses are chosen to provide equivalent molar values of SIINFEKL peptide. Control animals received PBS. After seven days, blood samples are collected from the lateral tail vein and stained directly ex vivo with antibodies for TCR V2, CD45.1 and CD8 to detect the SIINFEKL-specific CD8.sup.+ T cells by flow cytometry.

    [0376] Phenotyping DC from Spleen:

    [0377] Antibody staining and flow cytometry is used to examine the expression of maturation markers on dendritic cells in the spleen following injection of compounds of the invention (0.23 nmol). Splenocyte preparations are prepared by gentle teasing of splenic tissue through gauze in Iscove's Modified Dulbecco's Medium with 2 mM glutamine, 1% penicillin-streptomycin, 510-5 M 2-mercapto-ethanol and 5% fetal bovine serum (all Invitrogen, Auckland, New Zealand), followed by lysis of red blood cells with RBC lysis buffer (Puregene, Gentra Systems, Minneapolis, Minn., USA). Antibody staining is performed in PBS 2% fetal bovine serum and 0.01% sodium azide. The anti-FcgRII monoclonal antibody 2.4G2 is used at 10 mg/ml to inhibit non-specific staining. Monoclonal antibodies (all BD Biosciences Pharmingen, San Jose, Calif., USA) are used to examine expression of the maturation markers CD40, CD80 and CD86 on CD11c+ dendritic cells.

    [0378] Analysis of Peptide-Specific T Cell-Mediated Cytotoxicity In Vivo:

    [0379] The cytotoxic capacity of induced CD8.sup.+ T cell responses is measured by VITAL assay (Hermans, Silk et al. 2004). Mice are immunized with the compounds of the invention, or PBS, and then injected intravenously seven days later with two populations of syngeneic splenocytes; those loaded with 500 nM, SIINFEKL-peptide and labelled with 1.65 nM carboxyfluorescein succinimidyl ester (CFSE), or those loaded with peptide and labelled with 10 M cell tracker orange (CTO). Specific lysis of the peptide-loaded targets is monitored by flow cytometry of blood or spleen samples 24 h later. Mean percent survival of peptide-pulsed (CFSE+) targets is calculated relative to that of the control population (CTO+), and cytotoxic activity is expressed as percent specific lysis (100mean percent survival of peptide-pulsed targets).

    [0380] Analysis of Anti-Tumour Activity:

    [0381] Groups of C57BL/6 mice (n=5) receive a subcutaneous injection into the flank of 110.sup.5 B16.OVA melanoma cells, which express a cDNA encoding the chicken ovalbumin (OVA) sequence. The different groups are treated five days later by intravenous injection of one of the following; CI-017 (0.571 nmol), peptide CN159 (0.571 nmol) mixed with -GalCer (0.571 nmol), or PBS. Mice are monitored for tumour growth every 3-4 days, and tumour size for each group calculated as the mean of the products of bisecting diameters (SEM). Measurements are terminated for each group when the first animal develops a tumour exceeding 200 mm.sup.2.

    [0382] Where the foregoing description reference has been made to integers having known equivalents thereof, those equivalents are herein incorporated as if individually set forth.

    [0383] Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments.

    [0384] It is appreciated that further modifications may be made to the invention as described herein without departing from the spirit and scope of the invention.

    [0385] The examples described herein are for purposes of illustrating embodiments of the invention. Other embodiments, methods, and types of analyses are within the capabilities of persons of ordinary skill in the art and need not be described in detail herein. Other embodiments within the scope of the art are considered to be part of this invention.

    [0386] Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments.

    [0387] It is appreciated that further modifications may be made to the invention as described herein without departing from the spirit and scope of the invention.

    INDUSTRIAL APPLICABILITY

    [0388] The invention relates to sphingoglycolipid analogues and peptide derivatives thereof, which are useful in treating or preventing diseases or such as those relating to infection, atopic disorders, autoimmune diseases or cancer.

    REFERENCES

    [0389] Alexander, J., R. Cargill, et al. (1988). (Acyloxy)alkyl carbamates as novel bioreversible prodrugs for amines: increased permeation through biological membranes. J Med Chem 31(2): 318-322. [0390] Alexander, J., J Sidney, et al. (1994) Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides. Immunity 1 (9), 751-61. [0391] Amblard, M., J. A. Fehrentz, et al. (2006). Methods and protocols of modern solid phase Peptide synthesis. Mol Biotechnol 33(3): 239-254. [0392] Amsberry, K. L. and R. T. Borchardt (1991). Amine prodrugs which utilize hydroxy amide lactonization. I. A potential redox-sensitive amide prodrug. Pharm Res 8(3): 323-330. [0393] Amsberry, K. L., A. E. Gerstenberger, et al. (1991). Amine prodrugs which utilize hydroxy amide lactonization. II. A potential esterase-sensitive amide prodrug. Pharm Res 8(4): 455-461. [0394] Atherton, E., H. Fox, et al. (1978). A mild procedure for solid phase peptide synthesis: use of fluorenylmethoxycarbonylamino-acids. Journal of the Chemical Society, Chemical Communications (13): 537-539. [0395] Atwell, G. J., B. M. Sykes, et al. (1994). Relationships between structure and kinetics of cyclization of 2-aminoaryl amides: potential prodrugs of cyclization-activated aromatic mustards. J Med Chem 37(3): 371-380. [0396] Baek, D. J., J.-H. Seo, et al. (2011). The 3-Deoxy Analogue of -GalCer: Disclosing the Role of the 4-Hydroxyl Group for CD1d-Mediated NKT Cell Activation. ACS Medicinal Chemistry Letters 2(7): 544-548. [0397] Banchet-Cadeddu, A., E. Henon, et al. (2011). The stimulating adventure of KRN 7000. Org Biomol Chem 9(9): 3080-3104. [0398] Bendelac, A., P. B. Savage, et al. (2007). The biology of NKT cells. Annu Rev Immunol 25: 297-336. [0399] Berinstein, N. L., M. Karkada, et al. (2012). First-in-man application of a novel therapeutic cancer vaccine formulation with the capacity to induce multi-functional T cell responses in ovarian, breast and prostate cancer patients. Journal of translational medicine 10, 156. [0400] Bettinotti, M. P., C. J. Kim, et al. (1998). Stringent allele/epitope requirements for MART-1/Melan A immunodominance: implications for peptide-based immunotherapy. J Immunol 161(2): 877-889. [0401] Borg, N. A., K. S. Wun, et al. (2007). CDld-lipid-antigen recognition by the semi-invariant NKT T-cell receptor. Nature 448(7149): 44-49. [0402] Brossart, P., K. S. Heinrich, et al. (1999). Identification of HLA-A2-restricted T-cell epitopes derived from the MUC1 tumor antigen for broadly applicable vaccine therapies. Blood 93(12): 4309-4317. [0403] Cai, H., Z. H. Huang, et al. (2011). Towards a fully synthetic MUC1-based anticancer vaccine: efficient conjugation of glycopeptides with mono-, di-, and tetravalent lipopeptides using click chemistry. Chemistry 17(23): 6396-6406. [0404] Campos, L. M., K. L. Killops, et al. (2008). Development of Thermal and Photochemical Strategies for Thiol-Ene Click Polymer Functionalization. Macromolecules 41(19): 7063-7070. [0405] Carpino, L. A., S. A. Triolo, et al. (1989). Reductive lactonization of strategically methylated quinone propionic acid esters and amides. The Journal of Orqanic Chemistry 54(14): 3303-3310. [0406] Chang, J. (2006). Efficient amplification of melanoma-specific CD8+ T cells using artificial antigen presenting complex. Exp Mol Med 38(6): 591-598. [0407] Chaudhary, A., M. Girgis, et al. (2003). Using mixed anhydrides from amino acids and isobutyl chloroformate in N-acylations: a case study on the elucidation of mechanism of urethane formation and starting amino acid liberation using carbon dioxide as the probe. Tetrahedron Lett 44(29): 5543-5546. [0408] Chen, G., J. Schmieg, et al. (2004). Efficient synthesis of alpha-C-galactosyl ceramide immunostimulants: use of ethylene-promoted olefin cross-metathesis. Org Lett 6(22): 4077-4080. [0409] Choi, J. K., D. C. Ha, et al. (1989). .alpha.-acylamino radical cyclizations: application to the synthesis of a tetracyclic substructure of gelsemine. The Journal of Orqanic Chemistry 54(2): 279-290. [0410] Ciesielski, M. J., D. Kozbor, et al. (2008). Therapeutic effect of a T helper cell supported CTL response induced by a survivin peptide vaccine against murine cerebral glioma. Cancer Immunol Immunother 57(12): 1827-1835. [0411] Davidson, E. J., R. L. Faulkner, et al. (2004). Effect of TA-CIN (HPV 16 L2E6E7) booster immunisation in vulval intraepithelial neoplasia patients previously vaccinated with TA-HPV (vaccinia virus encoding HPV 16/18 E6E7). Vaccine 22(21-22): 2722-2729. [0412] de Araujo, A. D., J. M. Palomo, et al. (2006). Diels-Alder ligation of peptides and proteins. Chemistry 12(23): 6095-6109. [0413] Deng, S., J. Mattner, et al. (2011). Impact of sugar stereochemistry on natural killer T cell stimulation by bacterial glycolipids. Org Biomol Chem 9(22): 7659-7662. [0414] Dere, R. T. and X. Zhu (2008). The first synthesis of a thioglycoside analogue of the immunostimulant KRN7000. Org Lett 10(20): 4641-4644. [0415] Dirksen, A., T. M. Hackeng, et al. (2006). Nucleophilic catalysis of oxime ligation. Angew Chem Int Ed Engl 45(45): 7581-7584. [0416] Dondoni, A. (2008). The emergence of thiol-ene coupling as a click process for materials and bioorganic chemistry. Anqew Chem Int Ed 47: 8995-8997 [0417] Du, W., S. S. Kulkarni, et al. (2007). Efficient, one-pot syntheses of biologically active alpha-linked glycolipids. Chem Commun (Camb)(23): 2336-2338. [0418] Dubowchik, G. M., R. A. Firestone, et al. (2002). Cathepsin B-labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: model studies of enzymatic drug release and antigen-specific in vitro anticancer activity. Bioconjug Chem 13(4): 855-869. [0419] Ebensen, T., C. Link, et al. (2007). A pegylated derivative of alpha-galactosylceramide exhibits improved biological properties. J Immunol 179(4): 2065-2073. [0420] Fang, G. M., J. X. Wang, et al. (2012). Convergent chemical synthesis of proteins by ligation of Peptide hydrazides. Anqew Chem Int Ed Engl 51(41): 10347-10350. [0421] Fields, G. B. and R. L. Noble (1990). Solid phase peptide synthesis utilizing 9-fluorenylmethoxycarbonyl amino acids. Int J Pept Protein Res 35(3): 161-214. [0422] Friedrichs, B., S. Siegel, et al. (2006). Survivin-derived peptide epitopes and their role for induction of antitumor immunity in hematological malignancies. Leuk Lymphoma 47(6): 978-985. [0423] Fujii, S., K. Shimizu, et al. (2003). Activation of natural killer T cells by alpha-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein. J Exp Med 198(2): 267-279. [0424] Gangwar, S., G. M. Pauletti, et al. (1997). Synthesis of a Novel Esterase-Sensitive Cyclic Prodrug of a Hexapeptide Using an (Acyloxy)alkoxy Promoiety. The Journal of Organic Chemistry 62(5): 1356-1362. [0425] Geoghegan, K. F. and J. G. Stroh (1992). Site-directed conjugation of nonpeptide groups to peptides and proteins via periodate oxidation of a 2-amino alcohol. Application to modification at N-terminal serine. Bioconjug Chem 3(2): 138-146. [0426] Giaccone, G., C. J. Punt, et al. (2002). A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res 8(12): 3702-3709. [0427] Greenwald, R. B., Y. H. Choe, et al. (2000). Drug delivery systems based on trimethyl lock lactonization: poly(ethylene glycol) prodrugs of amino-containing compounds. J Med Chem 43(3): 475-487. [0428] Greenwald, R. B., A. Pendri, et al. (1999). Drug delivery systems employing 1,4- or 1,6-elimination: poly(ethylene glycol) prodrugs of amine-containing compounds. J Med Chem 42(18): 3657-3667. [0429] Hackenberger, C. P. and D. Schwarzer (2008). Chemoselective ligation and modification strategies for peptides and proteins. Anqew Chem Int Ed Engl 47(52): 10030-10074. [0430] Hatakeyama, T., N. Nakagawa, et al. (2009). lIron-Catalyzed Negishi Coupling Toward an Effective Olefin Synthesis. Orqanic letters 11(20): 4496-4499. [0431] Hermans, I. F., J. D. Silk, et al. (2003). NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J Immunol 171(10): 5140-5147. [0432] Hong, S., M. T. Wilson, et al. (2001). The natural killer T-cell ligand alpha-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice. Nat Med 7(9): 1052-1056. [0433] Howell, A. R., R. C. So, et al. (2004). Approaches to the preparation of sphinganines. Tetrahedron 60(50): 11327-11347. [0434] Huarte, E., P. Sarobe, et al. (2002). Enhancing immunogenicity of a CTL epitope from carcinoembryonic antigen by selective amino acid replacements. Clin Cancer Res 8(7): 2336-2344. [0435] Hudlicky, T., F. F. Koszyk, et al. (1980). Cyclopentene annulation via intramolecular addition of diazoketones to 1,3-dienes. Applications to the synthesis of cyclopentanoid terpenes. The Journal of Orqanic Chemistry 45(25): 5020-5027. [0436] Iha, R. K., B. A. van Horn, et al. (2010). Complex, degradable polyester materials via ketoxime ether-based functionalization: Amphiphilic, multifunctional graft copolymers and their resulting solution-state aggregates. Journal of Polymer Science Part A: Polymer Chemistry 48(16): 3553-3563. [0437] Isidro-Llobet, A., M. Alvarez, et al. (2009). Amino acid-protecting groups. Chem Rev 109(6): 2455-2504. [0438] Jager, E., H. Hohn, et al. (2002). Peptide-specific CD8+ T-cell evolution in vivo: response to peptide vaccination with Melan-A/MART-1. Int J Cancer 98(3): 376-388. [0439] Jervis, P. J., L. R. Cox, et al. (2011). Synthesis of a Versatile Building Block for the Preparation of 6-N-Derivatized -Galactosyl Ceramides: Rapid Access to Biologically Active Glycolipids. J. Or. Chem. 76, 320-323. [0440] Karbach, J., S. Gnjatic, et al. (2010). Tumor-reactive CD8+ T-cell responses after vaccination with NY-ESO-1 peptide, CpG 7909 and Montanide ISA-51: association with survival. Int J Cancer 126(4): 909-918. [0441] Kawano, T., J. Cui, et al. (1997). CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science 278(5343): 1626-1629. [0442] Kiick, K. L., E. Saxon, et al. (2002). Incorporation of azides into recombinant proteins for chemoselective modification by the Staudinger ligation. Proc Natl Acad Sci USA 99(1): 19-24. [0443] Kinjo, Y., P. Illarionov, et al. (2011). lInvariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria. Nature Immunology: 1-10. [0444] Kreiter, S., Vormehr, M., et al. (2015). Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 7549: 692-696. [0445] Lee, A., K. J. Farrand, et al. (2006). Novel synthesis of alpha-galactosyl-ceramides and confirmation of their powerful NKT cell agonist activity. Carbohydr Res 341(17): 2785-2798. [0446] Lennerz, V.; Fatho, M.; et al. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. P.N.A.S., 102 (44), 16013-8. [0447] Levy, A., J. Pitcovski, et al. (2007). A melanoma multiepitope polypeptide induces specific CD8+ T-cell response. Cell Immunol 250(1-2): 24-30. [0448] Li, Y., E. Girardi, et al. (2010). The V14 invariant natural killer T cell TCR forces microbial glycolipids and CD1d into a conserved binding mode. Journal of Experimental Medicine 207(11): 2383-2393. [0449] Li, X., Fujio, M. et al. (2010). Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant. PNAS 107(29): 13010-13015. [0450] Li, Z., Y. Oka, et al. (2008). Identification of a WT1 protein-derived peptide, WT1, as a HLA-A 0206-restricted, WT1-specific CTL epitope. Microbiol Immunol 52(11): 551-558. [0451] Liu, Y., S. Deng, et al. (2008). Synthesis of diglycosylceramides and evaluation of their iNKT cell stimulatory properties. Bioorg Med Chem Lett 18(10): 3052-3055. [0452] Liu, C.-F., C. Rao, et al. (1996). Orthogonal Ligation of Unprotected Peptide Segments through Pseudoproline Formation for the Synthesis of HIV-1 Protease Analogs. Journal of the American Chemical Society 118(2): 307-312. [0453] Liu, C.-F. and J. P. Tam (1994). Chemical Ligation Approach To Form a Peptide Bond between Unprotected Peptide Segments. Concept and Model Study. Journal of the American Chemical Society 116(10): 4149-4153. [0454] Lu, X.-L., Z.-H. Liang, et al. (2006). Induction of the Epstein-Barr Virus Latent Membrane Protein 2 Antigen-specific Cytotoxic T Lymphocytes Using Human Leukocyte Antigen Tetramer-based Artificial Antigen-presenting Cells. Acta Biochimica et Biophysica Sinica 38(3): 157-163. [0455] Majireck, M. M. and S. M. Weinreb (2006). A study of the scope and regioselectivity of the ruthenium-catalyzed [3+2]-cycloaddition of azides with internal alkynes. J Or Chem 71(22): 8680-8683. [0456] Morita, M., K. Motoki, et al. (1995). Structure-activity relationship of alpha-galactosylceramides against B16-bearing mice. J Med Chem 38(12): 2176-2187. [0457] Motoki, K., M. Morita, et al. (1995). lImmunostimulatory and antitumor activities of monoglycosylceramides having various sugar moieties. Biol Pharm Bull 18(11): 1487-1491. [0458] Nicolaou, M. G., C.-S. Yuan, et al. (1996). Phosphate Prodrugs for Amines Utilizing a Fast Intramolecular Hydroxy Amide Lactonization. The Journal of Orqanic Chemistry 61(24): 8636-8641. [0459] Noppen, C., F. Levy, et al. (2000). Naturally processed and concealed HLA-A2.1-restricted epitopes from tumor-associated antigen tyrosinase-related protein-2. Int J Cancer 87(2): 241-246. [0460] O'Reilly, C. and P. V. Murphy (2011). Synthesis of alpha-S-glycosphingolipids based on uronic acids. Org Lett 13(19): 5168-5171. [0461] Parekh, V. V., M. T. Wilson, et al. (2005). Glycolipid antigen induces long-term natural killer T cell anergy in mice. J Clin Invest 115(9): 2572-2583. [0462] Park, J. J., J. H. Lee, et al. (2008). Synthesis of all stereoisomers of KRN7000, the CD1d-binding NKT cell ligand. Bioorg Med Chem Lett 18(14): 3906-3909. [0463] Pauwels, N., S. Aspeslagh, et al. (2012). Synthesis of 6-triazole-substituted alpha-GalCer analogues as potent iNKT cell stimulating ligands. Bioorg Med Chem 20(24): 7149-7154. [0464] Petersen, T. R., D. Sika-Paotonu, et al. (2010). Potent anti-tumor responses to immunization with dendritic cells loaded with tumor tissue and an NKT cell ligand. Immunol Cell Biol 88(5): 596-604. [0465] Plettenburg, O., V. Bodmer-Narkevitch, et al. (2002). Synthesis of alpha-galactosyl ceramide, a potent immunostimulatory agent. J Org Chem 67(13): 4559-4564. [0466] Presolski, S. I.; Hong, V. et al. (2010). Tailored ligand acceleration of the Cu-catalyzed azide-alkyne cycloaddition reaction: practical and mechanistic implications. J Am Chem Soc 132: 14570-14576. [0467] Raju, R., B. F. Castillo, et al. (2009). Synthesis and evaluation of 3- and 4-deoxy and -fluoro analogs of the immunostimulatory glycolipid, KRN7000. Bioorg Med Chem Lett 19(15): 4122-4125. [0468] Rostovtsev, V. V., L. G. Green, et al. (2002). A stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective ligation of azides and terminal alkynes. Anqew Chem Int Ed Engl 41(14): 2596-2599. [0469] Saxon, E. and C. R. Bertozzi (2000). Cell surface engineering by a modified Staudinger reaction. Science 287(5460): 2007-2010. [0470] Schmitz, M., P. Diestelkoetter, et al. (2000). Generation of survivin-specific CD8+ T effector cells by dendritic cells pulsed with protein or selected peptides. Cancer Res 60(17): 4845-4849. [0471] Semmling, V., V. Lukacs-Kornek, et al. (2010). Alternative cross-priming through CCL17-CCR4-mediated attraction of CTLs toward NKT cell-licensed DCs. Nat Immunol 11(4): 313-320. [0472] Silk, J. D., I. F. Hermans, et al. (2004). Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell-mediated immunotherapy. J Clin Invest 114(12): 1800-1811. [0473] Soellner, M. B., A. Tam, et al. (2006). Staudinger ligation of peptides at non-glycyl residues. J Org Chem 71(26): 9824-9830. [0474] Speiser, D. E. and P. Romero (2010). Molecularly defined vaccines for cancer immunotherapy, and protective T cell immunity. Semin Immunol 22(3): 144-154. [0475] Tam, A., M. B. Soellner, et al. (2007). Water-soluble phosphinothiols for traceless staudinger ligation and integration with expressed protein ligation. J Am Chem Soc 129(37): 11421-11430. [0476] Trappeniers, M., K. Van Beneden, et al. (2008). 6-derivatised alpha-GalCer analogues capable of inducing strong CD1d-mediated Th1-biased NKT cell responses in mice. J Am Chem Soc 130(49): 16468-16469. [0477] Trappeniers, M., S. Goormans, et al. (2008). Synthesis and in vitro evaluation of alpha-GalCer epimers. ChemMedChem 3(7): 1061-1070. [0478] Tupin, E., A. Nicoletti, et al. (2004). CDld-dependent activation of NKT cells aggravates atherosclerosis. J Exp Med 199(3): 417-422. [0479] Veerapen, N., M. Brigl, et al. (2009). Synthesis and biological activity of alpha-galactosyl ceramide KRN7000 and galactosyl (alpha1-->2) galactosyl ceramide. Bioorg Med Chem Lett 19(15): 4288-4291. [0480] Widdison, W. C., S. D. Wilhelm, et al. (2006). Semisynthetic maytansine analogues for the targeted treatment of cancer. J Med Chem 49(14): 4392-4408. [0481] Wingender, G., P. Rogers, et al. (2011). lInvariant NKT cells are required for airway inflammation induced by environmental antigens. J Exp Med 208(6): 1151-1162. [0482] Wu, T.-N., K.-H. Lin, et al. (2011). Avidity of CD1d-ligand-receptor ternary complex contributes to T-helper 1 (Th1) polarization and anticancer efficacy. Proc Natl Acad Sci USA 108(42): 17275-17280. [0483] Zeng, D., Y. Liu, et al. (2003). Activation of natural killer T cells in NZB/W mice induces Th1-type immune responses exacerbating lupus. J Clin Invest 112(8): 1211-1222. [0484] Zhang, L., X. Chen, et al. (2005). Ruthenium-catalyzed cycloaddition of alkynes and organic azides. J Am Chem Soc 127(46): 15998-15999. [0485] Zhou, X. T., C. Forestier, et al. (2002). Synthesis and NKT cell stimulating properties of fluorophore- and biotin-appended 6-amino-6-deoxy-galactosylceramides. Org Lett 4(8): 1267-1270.