CONJUGATES OF A PHARMACEUTICAL AGENT AND A MOIETY CAPABLE OF BINDING TO A GLUCOSE SENSING PROTEIN

Abstract

The invention describes novel conjugates of formula (I) of a pharmaceutical agent and a moiety capable of binding to a glucose sensing protein allowing a reversible release of the pharmaceutical agent depending on the glucose concentration.

Claims

1-40. (canceled)

41. A compound of formula (Ia)
R—(O═C)−[L.sub.1].sub.m−[A.sub.1].sub.o−[L.sub.2].sub.p−[A.sub.2].sub.r−[L.sub.3].sub.q−S   (Ia) wherein L.sub.1, L.sub.2, and L.sub.3 are independently a linker having a chain length of 1-20 atoms, A.sub.1 and A.sub.2 are independently: a 5 to 6 membered monocyclic ring, a 9 to 12 membered bicyclic ring, two 5 to 6 membered monocyclic rings connected to each other, two 9 to 12 membered bicyclic rings connected to each other, or a 5 to 6 membered monocyclic ring and a 9 to 12 membered bicyclic ring connected to each other wherein each ring is independently a saturated, unsaturated, or aromatic carbocyclic or heterocyclic ring and wherein each ring is optionally modified with at least one sub stituent, S is a sugar moiety which binds to the insulin independent glucose transporter GluT1, and wherein the sugar moiety S comprises a terminal pyranose Si moiety which is attached via position 2, 4, or 6 to the compound of formula (Ia), m, o, p, r, and q are independently of each other 0 or 1, and wherein at least one of r and o is 1, R is H, halogen, OH, O-alkyl-, an anhydride forming group, an active ester forming group, 4-nitrophenylester, succinate, or N-hydroxy benzotriazol, or a pharmaceutically acceptable salt or solvate thereof.

42. (canceled)

43. The compound of formula (Ia) of claim 41, wherein L.sub.1, L.sub.2, and L.sub.3 are independently of each other (C.sub.1-C.sub.20) alkylene, (C.sub.2-C.sub.20) alkenylene, or (C.sub.2-C.sub.20) alkynylene, wherein one or more C-atoms may be replaced by heteroatoms or heteroatom moieties, particularly by O, NH, N(C.sub.1-4) alkyl, S, SO, SO.sub.2, O—SO.sub.2, O—SO.sub.3, O—PHO.sub.2, or O—PO.sub.3 and/or wherein one or more C-atoms may be substituted with (C.sub.1-4) alkyl, (C.sub.1-4) alkyloxy, oxo, carboxyl, halogen, F, Cl, Br, or I, or a phosphorus-containing group.

44. The compound of formula (Ia) of claim 41, wherein L.sub.3 is (C.sub.1-C.sub.6) alkylene, or (C.sub.1-4) alkylene, wherein one or two C-atoms may be replaced by heteroatoms or heteroatom moieties, particularly by O, NH, N(C.sub.1-4) alkyl, S, SO, SO.sub.2, O—SO.sub.2, O—SO.sub.3, O—PHO.sub.2, or O—PO.sub.3 and/or wherein one or more C-atoms may be substituted with (C.sub.1-4) alkyl, (C.sub.1-4) alkyloxy, oxo, carboxyl, halogen, e.g. F, Cl, Br, or I, or a phosphorus-containing group.

45. The compound of formula (Ia) of claim 41, wherein L.sub.3 is C═O.

46. The compound of formula (Ia) of claim 41, wherein L.sub.2 is selected from —CO—(CH.sub.2).sub.3—, —(CH.sub.2).sub.6—NH—, —(CH.sub.2).sub.2—CO—(CH.sub.2—CH.sub.2—O).sub.2—(CH.sub.2).sub.2—NH— or —CH.sub.2—O—(CH.sub.2—CH.sub.2—O).sub.3—.

47. The compound of formula (Ia) of claim 41, wherein A.sub.1 and A.sub.2 are independently of each other a heterocyclic ring, wherein the ring may carry at least one sub stituent.

48. The compound of formula (Ia) of claim 41, wherein A.sub.1 and A.sub.2 are independently of each other selected from a 5 to 6 membered monocyclic or a 9 to 12 membered bicyclic ring, wherein the ring is heterocyclic with 1 to 4 ring atoms being selected from N, O, and/or S, and wherein the ring may carry at least one substituent.

49. The compound of formula (Ia) of claim 41, wherein A.sub.1 and A.sub.2 are independently of each other a 5 to 6 membered monocyclic ring, wherein the ring is a heteroalkyl ring, particularly selected from pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolidinyl, piperazinyl, piperidinyl, or morpholinyl, wherein the ring may carry at least one substituent, or a 9 to 12 membered bicyclic ring wherein the ring is a heteroalkyl ring with 1 to 4 ring atoms being selected from N, O, and/or S, and wherein the ring may carry at least one substituent.

50. The compound of formula (Ia) of claim 41, wherein A.sub.1 and A.sub.2 are independently of each other 1,2,3-triazolyl.

51. The compound of formula (Ia) of claim 41, wherein A.sub.2 is 1,2,3-triazolyl.

52. The compound of formula (Ia) of claim 41, wherein A.sub.2 is piperazinyl.

53. The compound of formula (Ia) of claim 41, wherein r=1 and A.sub.2 is present and o=0 and A.sub.1 is absent.

54. The compound of formula (Ia) of claim 41, wherein r=1 and A.sub.2 is present and o=1 and A.sub.1 is present.

55. The compound of formula (Ia) of claim 41, wherein (i) m=1, o=0, p=0, and q=0 or 1, or wherein (ii) m=1, o=1, p=1, and q=0 or 1.

56. The compound of formula (Ia) of claim 41, wherein A.sub.2 is piperazinyl, L.sub.2 is absent and A.sub.1 is cyclohexanyl.

57. The compound of formula (Ia) of claim 41, wherein A.sub.2 is piperazinyl, L.sub.2 is absent and A.sub.1 is cyclohexanyl.

58. The compound of formula (Ia) of claim 41, wherein A.sub.2 is piperazinyl, L.sub.2 is —CH.sub.2— and A.sub.1 is cyclohexanyl.

59. The compound of formula (Ia) of claim 41, wherein A.sub.2 is piperazinyl, L.sub.2 is absent and A.sub.1 is phenyl.

60. The compound of formula (Ia) of claim 41, wherein A.sub.2 is1,2,3-triazolyl, L.sub.2 is absent and A.sub.1 is phenyl.

61. The compound of formula (Ia) of claim 41, wherein L3 is —CO—, A.sub.1 is phenyl, L.sub.2 is —O— and A.sub.1 is phenyl wherein each ring may be unsubstituted or carry at least one substituent, for example, 1 to 3 substituents selected from halogen, NO.sub.2, CN, (C.sub.1-4) alkyl, (C.sub.1-4) alkoxy, (C.sub.1-4)alkyl-(C.sub.3-7)cycloalkyl, (C.sub.3-7) cycloalkyl, OH, benzyl, —O-benzyl, carboxyl, carboxyester, carboxamide, or mono (C.sub.1-4) alkyl, or di (C.sub.1-4) alkyl carboxamide.

62. The compound of formula (Ia) of claim 41, wherein the group -A.sub.2-L.sub.3- is selected from the group consisting of: ##STR00179##

63. The compound of formula (Ia) of claim 41, wherein the sugar moiety S comprises a terminal pyranose moiety S1 having a backbone structure of Formula (II) ##STR00180## wherein 1, 2, 3, 4, 5, and 6 denote the positions of the C-atoms in the pyranose moiety; wherein is a single bond and is a single or a double bond; and R1 and R3 are H or a protecting group; which is attached via position 2, 4, or 6 to the compound of formula (Ia).

64. The compound of formula (Ia) of claim 63, wherein the terminal pyranose moiety Si is selected from glucose, galactose, 4-deoxyglucose, or 4,5-dehydroglucose derivatives, wherein the terminal pyranose moiety S1 is attached via position 2, 4, or 6 to the compound of formula (Ia); or S1 is mannose attached via position 6.

65. The compound of formula (Ia) of claim 63, wherein the terminal pyranose moiety S1 is of the Formula (IIIa) or (IIIb): ##STR00181## wherein R1 is H or a protecting group, R2 is OR8, or NHR8 or an attachment site to the compound of formula (Ia), wherein R8 is H or a protecting group, R3 is H or a protecting group, R4 is H, OR8, or NHR8 or an attachment site to the compound of formula (Ia), wherein R8 is H or a protecting group, or R1 and R2 and/or R3 and R4 form together with the pyranose ring atoms to which they are bound a cyclic group, R5 and R6 are H or together with the carbon atom to which they are bound form a carbonyl group, R7 is OR8, or NHR8 or an attachment site to the compound of formula (Ia), wherein R8 is H or a protecting group, and wherein one of R2, R4, and R7 is the attachment site to the compound of formula (Ia).

66. The compound of formula (Ia) of claim 63, wherein R1 and R3 are H.

67. The compound of formula (Ia) of claim 63, wherein R2 is OR8 or an attachment site to the compound of formula (Ia), R4 is H, OR8, or an attachment site to the compound of formula (Ia), and R7 is OR8 or an attachment site to the compound of formula (Ia), and wherein R8 is H or a protecting group.

68. The compound of formula (Ia) of claim 63, wherein position 6 of the pyranose moiety S1 and particularly R7 is the attachment site to the compound of formula (Ia).

69. The compound of formula (Ia) of claim 63, wherein the pyranose moiety S1 is of formula (IVa), (IVb), (IVc), (IVd), or (IVe): ##STR00182## wherein R1, R2, R3, R5, R6, and R7 are defined as in any one of claims 65-68 and wherein R4 is H, a protecting group, or an attachment site to the compound of formula (Ia), or R4a is H, or an attachment site to the compound of formula (Ia).

70. The compound of formula (Ia) of claim 41, wherein the sugar moiety S is of Formula (V):
—[X.sub.2—S.sub.2].sub.s—X.sub.1—S1   (V) wherein X.sub.1 is a bond or O, X.sub.2 is a bond, NH or O, S.sub.2 is a mono- or disaccharide moiety, particularly comprising at least one hexose or pentose moiety, more particularly at least one pyranose or furanose moiety and S1 is a terminal pyranose moiety as defined in any one of claims 63-68, and s is 0 or 1.

71. The compound of formula (Ia) of claim 70, wherein the saccharide moiety S2 is a pyranose moiety, particularly selected from glucose, galactose, 4-deoxyglucose and 4,5-dehydroglucose derivatives, or a furanose moiety, particularly selected from fructose derivatives.

72. The compound of formula (Ia) of claim 70, wherein the saccharide moiety S2 is of Formula (VIa), (VIb), (VIc), (VId), or (VIe): ##STR00183## wherein R11 is a bond to X.sub.1, R12 is OR8 or NHR8 or an attachment site to X.sub.2, wherein R8 is H or a protecting group, R13 is H or a protecting group, R14 is R8 or an attachment site to X.sub.2, wherein R8 is H or a protecting group, R14a is H or an attachment site to X.sub.2, R15 and R16 are H or together with the carbon atom to which they are bound form a carbonyl group, R17 is OR8 or an attachment site to X.sub.2, wherein R8 is H or a protecting group, or R11 and R12 and/or R13 and R14 form together with the ring atoms to which they are bound a cyclic group, and wherein one of R12, R14, and R17 is an attachment site to X.sub.2.

73. The compound of formula (Ia) of claim 41, wherein the sugar moiety S comprises a single terminal saccharide moiety.

Description

EXAMPLE 1

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-methylpiperazine-1-carbonyl)tetrahydropyran-4-yl]acetate

[0147] ##STR00015##

[0148] Example 1 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-methylpiperazine following the procedure described in synthesis method A.

[0149] Purification: MPLC CombiFlash Rf (Teledyne ISCO): column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient:

[0150]

TABLE-US-00001 start % B end % B duration [min] 0 0 2.2 0 4.8 2.8 4.8 4.8 6.0 4.8 10.1 6.0 10.1 10.1 9.1
Yield: 137 mg (0.308 mmol, 55.8%), white solid.
TLC: R.sub.f=0.250 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=445.13 [M+H].sup.+; calculated: 445.44; t.sub.R (λ=220 nm): 0.93 min (LC/MS-method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ =5.96 (d, J=8.3 Hz, 1H, CH), 5.37 (t, J=9.5 Hz, 1H, CH), 5.25 (t, J=9.5 Hz, 1H, CH), 4.97 (m, 2H, 2×CH), 3.63 (m, 1H, NCH.sub.2), 3.55 (m, 1H, CH.sub.2), 3.39 (m, 1H, NCH.sub.2), 3.23 (m, 1H, NCH.sub.2), 2.36 (m, 2H, NCH.sub.2), 2.16 (s, 3H, CH.sub.3), 2.11 (m, 2H, NCH.sub.2), 2.08 (s, 3H, CH.sub.3), 2.02 (s, 3H, CH.sub.3), 1.93 (s, 3H, CH.sub.3), 1.90 (s, 3H, CH.sub.3) ppm.

EXAMPLE 2

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-ethylpiperazine-1-carbonyl)tetrahydropyran-4-yl]acetate

[0151] ##STR00016##

[0152] Example 2 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-ethylpiperazine following the procedure described in synthesis method A.

[0153] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0154]

TABLE-US-00002 Start % B end % B duration [min] 0 0 2.2 0 4.8 2.8 4.8 4.8 6.0 4.8 10.1 6.0 10.1 10.1 9.1
Yield: 201 mg (0.438 mmol, 79.4%), white solid.
TLC: R.sub.f=0.492 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=459.12 [M+H].sup.+; calculated: 459.46; t.sub.R (λ=220 nm): 0.98 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=5.97 (d, J=8.3 Hz, 1H, CH), 5.38 (t, J=9.5 Hz, 1H, CH), 5.25 (t, J=9.5 Hz, 1H, CH), 4.97 (m, 2H, 2×CH), 3.58 (m, 2H, NCH.sub.2), 3.40 (m, 1H, NCH.sub.2), =3.24 (m, 1H, NCH.sub.2), 2.41 (m, 2H, NCH.sub.2), 2.32 (m, 2H, CH.sub.2), 2.16 (m, 2H, NCH.sub.2), 2.08 (s, 3H, CH.sub.3), 2.02 (s, 3H, CH.sub.3), 1.93 (s, 3H, CH.sub.3), 1.89 (s, 3H, CH.sub.3), 0.99 (t, J=7.1 Hz, 3H, CH.sub.3) ppm.

EXAMPLE 3

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-n-propylpiperazine-1-carbonyl)tetrahydropyran-4-yl]acetate (8)

[0155] ##STR00017##

[0156] Example 3 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-n-propylpiperazine following the procedure described in synthesis method A.

[0157] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0158]

TABLE-US-00003 start % B end % B Duration [min] 0 0 1.5 0 5.0 5.0 5.0 5.0 8.0
Yield: 144 mg (0.305 mmol, 55.2%), white solid.
TLC: R.sub.f=0.417 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=473.14 [M+H].sup.+; calculated: 473.89; t.sub.R (λ=220 nm): 1.06 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=5.96 (d, J=8.3 Hz, 1H, CH), 5.38 (t, J=9.5 Hz, 1H, CH), 5.25 (t, J=9.5 Hz, 1H, CH), 4.98 (m, 2H, 2×CH), 3.58 (m, 2H, NCH.sub.2), 3.40 (m, 1H, NCH.sub.2), 3.24 (m, 1H, NCH.sub.2), 2.39 (m, 2H, NCH.sub.2), 2.22 (m, 2H, NCH.sub.2), 2.15 (m, 2H, NCH.sub.2), 2.07 (s, 3H, CH.sub.3), 2.02 (s, 3H, CH.sub.3), 1.93 (s, 3H, CH.sub.3), 1.89 (s, 3H, CH.sub.3), 1.43 (m, 2H, CH.sub.2), 0.85 (t, J=7.3 Hz, 3H, CH.sub.3) ppm.

EXAMPLE 4

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-n-butylpiperazine-1-carbonyl)tetrahydropyran-4-yl]acetate

[0159] ##STR00018##

[0160] Example 4 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-n-butylpiperazine following the procedure described in synthesis method A.

[0161] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0162]

TABLE-US-00004 start % B end % B duration [min] 0 0 1.0 0 10.1 20.0 10.1 10.1 3 10.1 0.0 0.0 0.0 0.0 1.0
Yield: 191 mg (0.393 mmol, 71.1%), white solid.
TLC: R.sub.f=0.458 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=487.19 [M+H].sup.+; calculated: 487.51; t.sub.R (λ=220 nm): 1.14 min (LC/MS-Method 1).

[0163] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ =5.96 (d, J=8.4 Hz, 1H, CH), 5.38 (t, J=9.4 Hz, 1H, CH), 5.25 (t, J=9.4 Hz, 1H, CH), 4.97 (m, 2H, 2×CH), 3.57 (m, 2H, NCH.sub.2), 3.40 (m, 1H, NCH.sub.2), 3.24 (m, 1H, NCH.sub.2), 2.40 (m, 2H, NCH.sub.2), 2.26 (m, 2H, NCH.sub.2), 2.15 (m, 2H, NCH.sub.2), 2.07 (s, 3H, CH.sub.3), 2.02 (s, 3H, CH.sub.3), 1.93 (s, 3H, CH.sub.3), 1.90 (s, 3H, CH.sub.3), 1.39 (m, 2H, CH.sub.2), 1.28 (m, 2H, CH.sub.2), 0.87 (t, J=7.4 Hz, 3H, CH.sub.3) ppm.

EXAMPLE 5

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-n-hexylpiperazine-1-carbonyl)tetrahydropyran-4-yl]acetate

[0164] ##STR00019##

[0165] Example 5 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-n-hexylpiperazine following the procedure described in synthesis method A.

[0166] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0167]

TABLE-US-00005 start % B end % B duration [min] 0 0 1.0 0 20.2 20.0 20.2 20.2 2.9 20.2 0.0 0.0 0.0 0.0 1.0
Yield: 226 mg (0.439 mmol, 79.6%), white solid.
TLC: R.sub.f=0.489 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=515.24 [M+H].sup.+; calculated: 515.57; t.sub.R (λ=220 nm): 1.34 min (LC/MS-Method 1).

[0168] .sup.1H-NMR (400 MHz, 26.9° C., DMSO-d.sub.6): δ=5.96 (d, J=8.3 Hz, 1H, CH), 5.37 (t, J=9.5 Hz, 1H, CH), 5.25 (t, J=9.5 Hz, 1H, CH), 4.97 (m, 2H, CH), 3.57 (m, 2H, NCH.sub.2), 3.40 (m, 1H, CH.sub.2), 3.23 (m, 1H, NCH.sub.2), 2.39 (m, 2H, NCH.sub.2), 2.25 (t, J=7.1 Hz, 2H, NCH.sub.2), 2.15 (m, 2H, NCH.sub.2), 2.16 (s, 3H, CH.sub.3), 2.07 (s, 3H, CH.sub.3), 2.02 (s, 3H, CH.sub.3), 1.93 (s, 3H, CH.sub.3), 1.89 (s, 3H, CH.sub.3), 1.40 (m, 2H, CH.sub.2), 1.26 (m, 6H, 3×CH.sub.2), 0.86 (t, J=6.9 Hz, 2H, CH.sub.3) ppm.

EXAMPLE 6

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-isopropylpiperazine-1-carbonyl)tetrahydropyran-4-yl]acetate

[0169] ##STR00020##

[0170] Example 6 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-isopropylpiperazine following the procedure described in synthesis method A.

[0171] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0172]

TABLE-US-00006 start % B end % B duration [min] 0 0 1.0 0 20.2 20.0 20.2 20.2 2.9 20.2 0.0 0.0 0.0 0.0 1.0
Yield: 129 mg (0.273 mmol, 49.5%), white solid.
TLC: R.sub.f=0.412 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=473.18 [M+H].sup.+; calculated: 473.47; t.sub.R (λ=220 nm): 1.02 min (LC/MS-Method 1).

[0173] .sup.1H-NMR (400 MHz, 26.9° C., DMSO-d.sub.6δ=5.97 (d, J=8.3 Hz, 1H, CH), 5.38 (t, J=9.4 Hz, 1H, CH), 5.25 (t, J=9.4 Hz, 1H, CH), 4.97 (m, 2H, 2×CH), 3.56 (m, 2H, NCH.sub.2), 3.39 (m, 1H, CH.sub.2), 3.24 (m, 1H, NCH.sub.2), 2.66 (m, 1H, CH), 2.43 (m, 2H, NCH.sub.2), 2.27 (m, 2H, NCH.sub.2), 2.08 (s, 3H, CH.sub.3), 2.02 (s, 3H, CH.sub.3), 1.93 (s, 3H, CH.sub.3), 1.90 (s, 3H, CH.sub.3), 0.95 (dd, 6H, CH.sub.3) ppm.

EXAMPLE 7

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-tert-butylpiperazine-1-carbonyl)tetrahydropyran-4-yl]acetate

[0174] ##STR00021##

[0175] Example 7 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-tert-butylpiperazine following the procedure described in synthesis method A.

[0176] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0177]

TABLE-US-00007 start % B end % B duration [min] 0 0 1.0 0 20.2 20.0 20.2 20.2 2.9 20.2 0.0 0.0 0.0 0.0 1.0
Yield: 139 mg (0.286 mmol, 51.8%), white solid.
TLC: R.sub.f=0.464 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=487.20 [M+H].sup.+; calculated: 487.51; t.sub.R: 1.06 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=5.97 (d, J=8.3 Hz, 1H, CH), 5.38 (t, J=9.5 Hz, 1H, CH), 5.25 (t, J=9.5 Hz, 1H, CH), 4.97 (m, 2H, CH), 3.53 (m, 2H, NCH.sub.2), 3.39 (m, 1H, CH.sub.2), 3.26 (m, 1H, NCH.sub.2), 2.67 (m, 2H, NCH.sub.2), 2.32 (m, 2H, NCH.sub.2), 2.07 (s, 3H, CH.sub.3), 2.02 (s, 3H, CH.sub.3), 1.93 (s, 3H, CH.sub.3), 1.90 (s, 3H, CH.sub.3), 0.99 (s, 9H, 3×CH.sub.3) ppm.

EXAMPLE 8

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-allylpiperazine-1-carbonyl)tetrahydropyran-4-yl]acetate

[0178] ##STR00022##

[0179] Example 8 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-allylpiperazine following the procedure described in synthesis method A.

[0180] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0181]

TABLE-US-00008 start % B end % B duration [min] 0 0 1.0 0 9.9 9.9
Yield: 184 mg (0.260 mmol, 70.8%), white solid.
TLC: R.sub.f=0.479 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=471.26 [M+H]+; calculated: 471.19; t.sub.R: 1.02 min (LC/MS-Method
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=5.97 (d, J=8.1 Hz, 1H, CH), 5.81 (m, 1H, H2C═CH), 5.36 (t, J=9.4 Hz, 1H, CH), 5.24 (t, J=9.4 Hz, 1H, CH), 5.17 (m, 2H, HC=CH.sub.2), 4.98 (m, 2H, CH), 3.61 (m, 2H, NCH.sub.2), 3.42 (m, 1H, NCH.sub.2), 3.23 (m, 1H, NCH.sub.2), 2.96 (m, 2H, NCH.sub.2), 2.41 (m, 2H, NCH.sub.2), 2.17 (m, 2H, NCH.sub.2), 2.08 (s, 3H, CH.sub.3), 2.02 (s, 3H, CH.sub.3), 1.94 (s, 3H, CH.sub.3), 1.90 (s, 3H, CH.sub.3) ppm.

EXAMPLE 9

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-cyclohexylpiperazine-1-carbonyl)tetrahydropyran-4-yl]acetate

[0182] ##STR00023##

[0183] Example 9 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-cyclohexylpiperazine following the procedure described in synthesis method A.

[0184] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0185]

TABLE-US-00009 start % B end % B duration [min] 0 0 1.0 0 9.9 9.9
Yield: 227 mg (0.443 mmol, 80.2%), white solid.
TLC: R.sub.f=0.610 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=513.15 [M+H].sup.+; calculated: 513.24; t.sub.R: 1.22 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, 116.9° C., DMSO-d.sub.6): 5.93 (d, J=7.8 Hz, 1H, CH), 5.33 (m, 2H, 2×CH), 4.99 (m, 1H, CH), 4.88 (m, 1H, CH), 3.71 (m, 4H, NCH.sub.2), 3.04 (m, 6H, NCH.sub.2), 3.23 (m, 2H, NCH.sub.2), 2.36 (m, 2H, NCH.sub.2), 2.06 (s, 3H, CH.sub.3), 1.99 (s, 3H, CH.sub.3), 1.93 (s, 3H, CH.sub.3), 1.90 (s, 3H, CH.sub.3), 1.82 (m, 2H, CH.sub.2), 1.63 (m, 1H, CH), 1.30 (m, 8H, CH.sub.2) ppm.

EXAMPLE 10

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(cyclohexylmethyl)piperazine-1-carbonyl]tetrahydropyran-4-yl] acetate

[0186] ##STR00024##

[0187] Example 10 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-cyclohexylmethylpiperazine following the procedure described in synthesis method A.

[0188] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0189]

TABLE-US-00010 start % B end % B duration [min] 0 0 1.0 0 20.0 20.0 20.0 20.0 3 20.0 0.0 0.0 0.0 0.0 1.0
Yield: 178 mg (0.338 mmol, 61.2%), white solid.
TLC: R.sub.f=0.346 (ethylacetate/n-heptan, 2:1).
LC/MS (ES-API): m/z=527.22 [M+H].sup.+; calculated: 527.25; t.sub.R: 1.31 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=5.97 (d, J=8.3 Hz, 1H, CH), 5.39 (t, J=9.4 Hz, 1H, CH), 5.27 (t, J=9.4 Hz, 1H, CH), 4.96 (m, 2H, CH), 3.58 (m, 2H, NCH.sub.2), 3.40 (m, 1H, CH.sub.2), 3.25 (m, 1H, NCH.sub.2), 2.37 (m, 2H, NCH.sub.2), 2.13 (m, 2H, NCH.sub.2), 2.19 (m, 2H, NCH.sub.2), 2.08 (s, 3H, CH.sub.3), 2.02 (s, 3H, CH.sub.3), 1.94 (s, 3H, CH.sub.3), 1.89 (s, 3H, CH.sub.3), 1.69 (m, 4H, 2×CH.sub.2), 1.47 (m, 1H, CH), 1.18 (m, 2H, 2×CH.sub.2), 0.82 (m, 2H, CH.sub.2) ppm.

EXAMPLE 11

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(2-cyclohexylethyl)piperazine-1-carbonyl]tetrahydropyran-4-yl]acetate

[0190] ##STR00025##

[0191] Example 11 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-cyclohexylethylpiperazine following the procedure described in synthesis method A.

[0192] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0193]

TABLE-US-00011 start % B end % B duration [min] 0 0 1.0 0 18.7 18.7
Yield: 183 mg (0.339 mmol, 61.3%), white solid.
TLC: R.sub.f=0.511 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=541.24 [M+H].sup.+; calculated: 541.27; t.sub.R: 1.41 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, 116.9° C., DMSO-d.sub.6): δ=5.93 (d, J=7.8 Hz, 1H, CH), 5.33 (m, 2H, 2×CH), 4.99 (m, 1H, CH), 4.88 (m, 1H, CH), 3.71 (m, 4H, NCH.sub.2), 3.04 (m, 6H, NCH.sub.2), 3.23 (m, 2H, NCH.sub.2), 2.36 (m, 2H, NCH.sub.2), 2.06 (s, 3H, CH.sub.3), 1.99 (s, 3H, CH.sub.3), 1.93 (s, 3H, CH.sub.3), 1.90 (s, 3H, CH.sub.3), 1.71 (m, 1H, CH), 1.61 (m, 6H, CH.sub.2), 1.24 (m, 4H, CH.sub.2), 1.02 (m, 2H, CH.sub.2) ppm.

EXAMPLE 12

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-(4-phenylpiperazine-1-carbonyl)tetrahydropyran-4-yl]acetate

[0194] ##STR00026##

[0195] Example 12 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-phenylpiperazine following the procedure described in synthesis method A.

[0196] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

Yield: 260 mg (0.514 mmol, 62.0%),white solid.
TLC: R.sub.f=0.695 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=507.14 [M+H].sup.+; calculated: 507.19; t.sub.R: 1.70 min (LC/MS-Method 1).

MPLC Gradient

[0197]

TABLE-US-00012 start % B end % B duration [min] 0 0 1.3 0 100.0 13.7 100.0 100.0 3.7 100.0 0.0 0.0 0.0 0.0 1.3
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.24 (t, J=8.2 Hz, 2H, ArH), 6.95 (d, J=8.2 Hz, 2H, ArH), 6.81 (t, J=7.4 Hz, 1H, ArH), 6.00 (d, J=8.4 Hz, 1H, CH), 5.40 (t, J=9.9 Hz, 1H, CH), 5.29 (t, J=9.9 Hz, 1H, CH), 5.05 (d, J=9.6 Hz, 1H, CH), 5.00 (m, 1H, CH), 3.81 (m, 1H, NCH.sub.2), 3.75 (m, 1H, NCH.sub.2), 3.57 (m, 1H, CH.sub.2), 3.39 (m, 1H, NCH.sub.2), 3.24 (m, 2H, NCH.sub.2), 2.82 (m, 2H, NCH.sub.2), 2.07 (s, 3H, CH.sub.3), 2.03 (s, 3H, CH.sub.3), 1.94 (s, 3H, CH.sub.3), 1.91 (s, 3H, CH.sub.3) ppm.

[0198] .sup.13C-NMR (150 MHz, DMSO-d.sub.6): δ=169.64 (s, C), 169.04 (s, C), 169.02 (s, C), 168.43 (s, C), 163.04 (s, C), 150.69 (s, C), 128.99 (s, CH), 119.47 (s, CH), 115.97 (s, CH), 90.94 (s, CH), 72.02 (s, CH), 69.37 (s, CH), 69.15 (s, CH), 68.55 (s, CH), 49.14 (s, CH.sub.2), 48.07 (s, CH.sub.2), 44.78 (s, CH.sub.2), 41.41 (s, CH.sub.3), 20.44 (s, 2 CH.sub.3), 20.30 (s, 2 CH.sub.3) ppm.

EXAMPLE 13

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-[(E)-cinnamyl]piperazine-1-carbonyl]tetrahydropyran-4-yl]acetate

[0199] ##STR00027##

[0200] Example 13 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and trans-1-cinnamylpiperazine following the procedure described in synthesis method A.

[0201] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0202]

TABLE-US-00013 start % B end % B duration [min] 0 0 1.0 0 9.9 9.9
Yield: 253 mg (0.463 mmol, 83.8%), white solid.
TLC: R.sub.f=0.644 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=547.27 [M+H].sup.+; calculated: 547.22; t.sub.R: 1.34 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.44 (d, J=7.2 Hz, 2H, ArH), 7.32 (t, J=7.2 Hz, 2H, ArH), 7.23 (t, J=7.2 Hz, 2H, ArH), 6.54 (d, J=15.9 Hz, 1H, CH), 6.29 (m, 1H, CH), 5.96 (d, J=8.4 Hz, 1H, CH), 5.37 (t, J=9.5 Hz, 1H, CH), 5.25 (t, J=9.5 Hz, 1H, CH), 4.97 (m, 2H, CH), 3.61 (m, 2H, NCH.sub.2), 3.42 (m, 1H, CH.sub.2), 3.26 (m, 1H, NCH.sub.2), 3.12 (m, 2H, NCH.sub.2), 2.47 (m, 2H, NCH.sub.2), 2.22 (m, 2H, NCH.sub.2), 2.06 (s, 3H, CH.sub.3), 2.02 (s, 3H, CH.sub.3), 1.93 (s, 3H, CH.sub.3), 1.89 (s, 3H, CH.sub.3) ppm.

EXAMPLE 14

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(4-chlorophenyl)piperazine-1-carbonyl]tetrahydropyran-4-yl]acetate

[0203] ##STR00028##

[0204] Example 14 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-(4-chlorophenyl)-piperazine following the procedure described in synthesis method A.

[0205] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0206]

TABLE-US-00014 start % B end % B duration [min] 0 0 2.4 0 5.0 7.9 5.0 5.0 3.7
Yield: 153 mg (0.282 mmol, 51.3%), white solid.
TLC: R.sub.f=0.619 (ethylacetate/n-heptane, 2:1).
LC/MS (ES-API): m/z=541.19 [M+H].sup.+; calculated: 541.15; t.sub.R: 1.80 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.25 (d, J=9.0 Hz, 2H, ArH), 6.96 (d, J=9.0 Hz, 2H, ArH), 6.00 (d, J=8.3 Hz, 1H, CH), 5.40 (t, J=9.5 Hz, 1H, CH), 5.28 (t, J=9.5 Hz, 1H, CH), 5.01 (m, 2H, 2×CH), 3.76 (m, 2H, NCH.sub.2), 3.56 (m, 1H, NCH.sub.2), 3.37 (m, 1H, NCH.sub.2), 3.25 (m, 2H, NCH.sub.2), 2.92 (m, 2H, NCH.sub.2), 2.07 (s, 3H, CH.sub.3), 2.03 (s, 3H, CH.sub.3), 1.94 (s, 3H, CH.sub.3), 1.90 (s, 3H, CH.sub.3) ppm.

EXAMPLE 15

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(2-chlorophenyl)piperazine-1-carbonyl]tetrahydropyran-4-yl]acetate

[0207] ##STR00029##

[0208] Example 15 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-(2-chlorophenyl)-piperazine following the procedure described in synthesis method A.

[0209] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

MPLC Gradient

[0210]

TABLE-US-00015 start % B end % B duration [min] 0 0 1.3 0 100.0 13.7 100.0 100.0 3.7 100.0 0.0 0.0 0.0 0.0 1.3
Yield: 148 mg (0.274 mmol, 49.6%), white solid.
TLC: R.sub.f=0.589 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=541.10 [M+H].sup.+; calculated: 541.15; t.sub.R: 1.80 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.44 (dd, J=1.4 Hz, 2H, ArH), 7.33 (m, 2H, ArH), 7.14 (dd, J=1.4 Hz, 2H, ArH), 7.07 (m, 2H, ArH), 5.98 (d, J=8.3 Hz, 1H, CH), 5.39 (t, J=9.4 Hz, 1H, CH), 5.29 (t, J=9.4 Hz, 1H, CH), 5.01 (m, 2H, 2×CH), 3.84 (m, 1H, NCH.sub.2), 3.76 (m, 1H, NCH.sub.2), 3.57 (m, 1H, CH.sub.2), 3.38 (m, 1H, NCH.sub.2), 3.02 (m, 2H, NCH.sub.2), 2.80 (m, 2H, NCH.sub.2), 2.08 (s, 3H, CH.sub.3), 2.03 (s, 3H, CH.sub.3), 1.94 (s, 3H, CH.sub.3), 1.92 (s, 3H, CH.sub.3) ppm.

EXAMPLE 16

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(4-bromophenyl)piperazine-1-carbonyl]tetrahydropyran-4-yl]acetate

[0211] ##STR00030##

[0212] Example 16 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-(4-bromophenyl)-piperazine following the procedure described in synthesis method A.

[0213] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0214]

TABLE-US-00016 start % B end % B duration [min] 0 0 1.0 0 20.2 20.0 20.2 20.2 2.9 20.2 0.0 0.0 0.0 0.0 1.0
Yield: 168 mg (0.287 mmol, 52.0%), white solid.
TLC: R.sub.f=0.635 (ethylacetate/n-heptane, 2:1).
LC/MS (ES-API): m/z=585.14 [M+H].sup.+; calculated: 585.10; t.sub.R: 1.82 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.37 (d, J=9.0 Hz, 2H, ArH), 6.92 (d, J=9.0 Hz, 2H, ArH), 6.00 (d, J=8.3 Hz, 1H, CH), 5.40 (t, J=9.4 Hz, 1H, CH), 5.28 (t, J=9.4 Hz, 1H, CH), 5.01 (m, 2H, 2×CH), 3.76 (m, 2H, NCH.sub.2), 3.56 (m, 1H, NCH.sub.2), 3.37 (m, 1H, NCH.sub.2), 3.25 (m, 2H, NCH.sub.2), 2.93 (m, 2H, NCH.sub.2), 2.07 (s, 3H, CH.sub.3), 2.03 (s, 3H, CH.sub.3), 1.94 (s, 3H, CH.sub.3), 1.90 (s, 3H, CH.sub.3) ppm.

EXAMPLE 17

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(4-methoxyphenyl)piperazine-1-carbonyl]tetrahydropyran-4-yl]acetate

[0215] ##STR00031##

[0216] Example 17 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-(4-methoxyphenyl)-piperazine following the procedure described in synthesis method A.

[0217] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

MPLC Gradient

[0218]

TABLE-US-00017 start % B end % B duration [min] 0 0 1.0 0 10.0 20.0 10.0 10.0 3.0 10.0 0.0 0.0 0.0 0.0 1.0
Yield: 192 mg (0.320 mmol, 58.0%), white solid.
TLC: R.sub.f=0.508 (ethylacetate/n-heptane, 2:1).
LC/MS (ES-API): m/z=537.14 [M+H].sup.+; calculated: 537.20; t.sub.R: 1.64 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.91 (d, J=9.1 Hz, 2H, ArH), 6.83 (d, J=9.1 Hz, 2H, ArH), 5.99 (d, J=8.0 Hz, 1H, CH), 5.40 (t, J=9.9 Hz, 1H, CH), 5.28 (t, J=9.9 Hz, 1H, CH), 5.00 (m, 2H, 2×CH), 3.77 (m, 2H, NCH.sub.2), 3.69 (s, 3H, OCH.sub.3), 3.56 (m, 1H, CH.sub.2), 3.37 (m, 1H, NCH.sub.2), 3.08 (m, 2H, NCH.sub.2), 2.80 (m, 2H, NCH.sub.2), 2.07 (s, 3H, CH.sub.3), 2.03 (s, 3H, CH.sub.3), 1.94 (s, 3H, CH.sub.3), 1.90 (s, 3H, CH.sub.3) ppm.

EXAMPLE 18

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(3-methoxyphenyl)piperazine-1-carbonyl]tetrahydropyran-4-yl]acetate

[0219] ##STR00032##

[0220] Example 18 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-(3-methoxyphenyl)-piperazine following the procedure described in synthesis method A.

[0221] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

MPLC Gradient

[0222]

TABLE-US-00018 start % B end % B duration [min] 0 0 1.0 0 10.0 20.0 10.0 10.0 3.0 10.0 0.0 0.0 0.0 0.0 1.0
Yield: 120 mg (0.224 mmol, 40.6%), white solid.
TLC: R.sub.f=0.571 (ethylacetate/n-heptane, 2:1).
LC/MS (ES-API): m/z=537.12 [M+H].sup.+; calculated: 537.20; t.sub.R: 1.70 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.12 (d, J=8.2 Hz, 1H, ArH), 6.83 (d, J=8.2 Hz, 1H, ArH), 6.47 (s, 1H, ArH), 6.41 (d, J=8.2 Hz, 1H, ArH), 6.00 (d, J=8.0 Hz, 1H, CH), 5.39 (t, J=9.9 Hz, 1H, CH), 5.28 (t, J=9.9 Hz, 1H, CH), 5.00 (m, 2H, 2×CH), 3.78 (m, 2H, NCH.sub.2), 3.72 (s, 3H, OCH.sub.3), 3.56 (m, 1H, CH.sub.2), 3.37 (m, 1H, NCH.sub.2), 3.24 (m, 2H, NCH.sub.2), 2.92 (m, 2H, NCH.sub.2), 2.08 (s, 3H, CH.sub.3), 2.02 (s, 3H, CH.sub.3), 1.96 (s, 3H, CH.sub.3), 1.90 (s, 3H, CH.sub.3) ppm.

EXAMPLE 19

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(2-methoxyphenyl)piperazine-1-carbonyl]tetrahydropyran-4-yl]acetate

[0223] ##STR00033##

[0224] Example 19 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-(2-methoxyphenyl)-piperazine following the procedure described in synthesis method A.

[0225] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0226]

TABLE-US-00019 start % B end % B duration [min] 0 0 2.5 0 5.0 8.5 5.0 5.0 3.9
Yield: 150 mg (0.280 mmol, 50.6%), white solid.
TLC: R.sub.f=0.492 (ethylacetate/n-heptane, 2:1).
LC/MS (ES-API): m/z=537.14 [M+H].sup.+; calculated: 537.20; t.sub.R: 1.67 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.98 (t, J=4.1 Hz, 1H, ArH), 6.96 (t, J=4.1 Hz, 1H, ArH), 6.89 (d, J=2.2 Hz, 2H, ArH), 6.86 (d, J=2.2 Hz, 2H, ArH), 5.98 (d, J=8.4 Hz, 1H, CH), 5.40 (t, J=9.5 Hz, 1H, CH), 5.29 (t, J=9.5 Hz, 1H, CH), 5.00 (m, 2H, 2×CH), 3.83 (m, 1H, NCH.sub.2), 3.79 (s, 3H, OCH.sub.3), 3.74 (m, 1H, NCH.sub.2), 3.70 (m, 1H, CH.sub.2), 3.54 (m, 1H, NCH.sub.2), 3.03 (m, 2H, NCH.sub.2), 2.74 (m, 2H, NCH.sub.2), 2.07 (s, 3H, CH.sub.3), 2.03 (s, 3H, CH.sub.3), 1.94 (s, 3H, CH.sub.3), 1.91 (s, 3H, CH.sub.3) ppm.

EXAMPLE 20

[(2S,3R,4S,5S,6S)-2,3,5-Triacetoxy-6-[4-(1,3-benzodioxol-5-ylmethyl)piperazine-1-carbonyl]tetrahydropyran-4-yl]acetate

[0227] ##STR00034##

[0228] Example 20 was synthesized from 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid and 1-(1,3-benzodioxol-5-ylmethyl)piperazine following the procedure described in synthesis method A.

[0229] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0230]

TABLE-US-00020 start % B end % B duration [min] 0 0 1.0 0 10.0 20.0 10.0 10.0 3.0 10.0 0.0 0.0 0.0 0.0 1.0
Yield: 221 mg (0.391 mmol, 70.9%), white solid.
TLC: R.sub.f=0.478 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=565.14 [M+H].sup.+; calculated: 565.19; t.sub.R: 1.24 min (LC/MS-Method 1).

[0231] .sup.1H-NMR (400 MHz, DMSO-d6): δ=6.84 (m, 2H, ArH), 6.73 (dd, J=1.4 Hz, 1H, ArH), 5.99 (s, 2H, O—CH.sub.2—O), 5.95 (d, J=8.4 Hz, 1H, CH), 5.36 (t, J=9.5 Hz, 1H, CH), 5.24 (t, J=9.5 Hz, 1H, CH), 4.96 (m, 2H, 2×CH), 3.62 (m, 2H, NCH.sub.2), 3.55 (m, 1H, CH.sub.2), 3.39 (m, 1H, NCH.sub.2), 3.23 (m, 1H, NCH.sub.2), 2.39 (m, 2H, NCH.sub.2), 2.21 (m, 2H, NCH.sub.2), 2.07 (s, 3H, CH.sub.3), 2.02 (s, 3H, CH.sub.3), 1.93 (s, 3H, CH.sub.3), 1.88 (s, 3H, CH.sub.3) ppm.

Method B

Deacetylation of Glucuronic Acid Amides

[0232] 20 mg of [(2,3,5-triacetoxy-6-piperazine-1-carbonyl]tetrahydropyran-4-yl)acetates were dissolved in 2 mL methanol/H.sub.2O/tetrahydrofuran (5:4:1) and cooled to 0° C. 20 μl of a 2 M lithium hydroxide solution in water were added and stirred for 2-12 hours at 0° C. The reaction control was done by TLC and LC/MS. As work-up procedure the reaction mixture was neutralized with 1M HCI, and the organic solvents were evaporated. The residue was diluted with water and lyophilized. The enantiomers were not separated. NMR signals were listed for only one enantiomer.

[0233] sf-4482178

[0234] Example 21

(4-Methylpiperazin-1-yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0235] ##STR00035##

[0236] Example 21 was synthesized from example 1 following the deacteylation procedure described in synthesis method B.

Yield: 11.9 mg (43.07 μmol, 95.7%), colorless oil.
LC/MS (ES-API): m/z=277.15 [M+H].sup.+; calculated: 277.13; t.sub.R (ELSD): 0.21 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.51 (d, J=4.5 Hz, 1H, CH), 5.0-4.3 (m, 4H, 4×OH), 3.5-3.0 (m, 12H, 4×CH.sub.2, 4×CH), 2.21 (m, 3H, CH.sub.3) ppm.

EXAMPLE 22

(4-Ethylpiperazin-1-yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0237] ##STR00036##

[0238] Example 22 was synthesized from example 2 following the deacteylation procedure described in synthesis method B.

Yield: 11.8 mg (40.65 μmol, 93.2%), colorless oil.
LC/MS (ES-API): m/z=291.23 [M+H].sup.+; calculated: 291.15; t.sub.R (ELSD): 0.20 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ =6.48 (d, J=4.6 Hz, 1H, CH), 4.8-4.3 (m, 4H, 4×OH), 3.5-3.0 (m, 12H, 4×CH.sub.2, 4×CH), 2.20 (m, 5H, CH.sub.2CH.sub.3) ppm.

EXAMPLE 23

(4-n-Propylpiperazin-1-yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0239] ##STR00037##

[0240] Example 23 was synthesized from example 3 following the deacteylation procedure described in synthesis method B.

Yield: 12.4 mg (40.74 μmol, 96.3%), colorless oil.
LC/MS (ES-API): m/z=305.21 [M+H].sup.+; calculated: 305.16; t.sub.R (ELSD): 0.19 min (LC/MS-Method 1).

[0241] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.51 (d, J=4.4 Hz, 1H, CH), 4.9-4.1 (m, 4H, 4×OH), 3.6-3.0 (m, 12H, 4×CH.sub.2, 4×CH), 2.32 (m, 2H, NCH.sub.2), 1.49 (m, 2H, CH.sub.2), 0.89 (t, J=7.3 Hz, 3H, CH.sub.3) ppm.

EXAMPLE 24

(4-n-Butylpiperazin-1-yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran -2-yl]methanone

[0242] ##STR00038##

[0243] Example 24 was synthesized from example 4 following the deacteylation procedure described in synthesis method B.

Yield: 12.7 mg (39.89 μmol, 97.0%), colorless oil.
LC/MS (ES-API): m/z=319.21 [M+H].sup.+; calculated: 319.18; t.sub.R (ELSD): 0.23 min (LC/MS-Method 1).

[0244] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.52 (d, J=4.5 Hz, 1H, CH), 4.87 (dd, J=4.2 Hz, 1H, OH), 4.75 (dd, J=4.9 Hz, 1H, OH), 4.29 (d, J=8.9 Hz, 1H, OH), 4.02 (d, J=9.4 Hz, 1H, OH), 3.6-3.15 (m, 12H, 4×CH2, 4×CH), 2.32 (m, 2H, NCH.sub.2), 1.46 (m, 2H, CH.sub.2), 1.29 (m, 2H, CH.sub.2), 0.89 (t, J=7.1 Hz, 3H, CH.sub.3) ppm.

EXAMPLE 25

(4-n -H exylpiperazin-1-yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0245] ##STR00039##

[0246] Example 25 was synthesized from example 5 following the deacteylation procedure described in synthesis method B.

Yield: 12.6 mg (36.37 μmol, 93.6%), white solid.
LC/MS (ES-API): m/z=347.17 [M+H].sup.+; calculated: 347.21; t.sub.R1 (λ=220 nm): 0.50 min; t.sub.R2 (λ=220 nm): 0.53 min (LC/MS-Method 1).

[0247] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.50 (d, J=4.4 Hz, 1H, CH), 4.85 (dd, J=4.4 Hz, 1H, OH), 4.76 (dd, J=4.8 Hz, 1H, OH), 4.27 (d, J=8.8 Hz, 1H, OH), 4.12 (d, J=9.3 Hz, 1H, OH), 3.6-3.1 (m, 12H, 4×CH.sub.2, 4×CH), 2.32 (m, 2H, NCH.sub.2), 1.43 (m, 8H, 4×CH.sub.2), 0.90 (t, J=7.2 Hz, 3H, CH.sub.3) ppm.

EXAMPLE 26

(4-Isopropylpiperazin-1-yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran -2-yl]methanone

[0248] ##STR00040##

[0249] Example 26 was synthesized from example 6 following the deacteylation procedure described in synthesis method B.

Yield: 12.2 mg (40.09 μmol, 94.7%), colorless oil.
LC/MS (ES-API): m/z=305.23 [M+H].sup.+; calculated: 305.16; t.sub.R (ELSD): 0.21 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.48 (d, J=4.6 Hz, 1H, CH), 4.8-4.1 (m, 4H, 4×OH), 3.5-3.1 (m, 12H, 4×CH.sub.2, 4×CH), 2.43 (m, 2H, NCH), 1.01 (m, 6H, 2×CH.sub.3) ppm.

EXAMPLE 27

(4-tert-Butylpiperazin-1-yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0250] ##STR00041##

[0251] Example 27 was synthesized from example 7 following the deacteylation procedure described in synthesis method B.

Yield: 12.5 mg (39.26 μmol, 95.5%), white solid.
LC/MS (ES-API): m/z=319.25 [M+H].sup.+; calculated: 319.18; t.sub.R (ELSD): 0.22 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.49 (d, J=4.9 Hz, 1H, CH), 4.9-4.0 (m, 4H, 4×OH), 3.5-3.1 (m, 12H, 4×CH.sub.2, 4×CH), 1.04 (m, 9H, 3×CH.sub.3) ppm.

EXAMPLE 28

(4-Allylpiperazin-1-yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0252] ##STR00042##

[0253] Example 28 was synthesized from example 8 following the deacteylation procedure described in synthesis method B.

Yield: 12.4 mg (41.02 μmol, 96.5%), colorless oil.
LC/MS (ES-API): m/z=303.22 [M+H].sup.+; calculated: 303.15; t.sub.R (ELSD): 0.21 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.29 (d, J=4.5 Hz, 1H, CH), 4.7-4.0 (m, 4H, 4×OH), 3.4-3.1 (m, 12H, 4×CH.sub.2, 4×CH), 2.41 (m, 5H, 2×CH.sub.2, CH) ppm.

EXAMPLE 29

(4-Cyclohexylpiperazin-1-yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0254] ##STR00043##

[0255] Example 29 was synthesized from example 9 following the deacteylation procedure described in synthesis method B.

Yield: 12.9 mg (37.46 μmol, 96.0%), white solid.
LC/MS (ES-API): m/z=345.25 [M+H].sup.+; calculated: 345.19; t.sub.R1 (ELSD): 0.28 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d6): δ=6.51 (d, J=4.8 Hz, 1H, CH), 4.6-4.0 (m, 4H, 4×OH), 3.4-2.9 (m, 12H, 4×CH.sub.2, 4×CH), 1.71 (m, 4H, 2×CH.sub.2), 1.54 (m, 1H, CH), 1.19 (m, 6H, 3×CH.sub.2) ppm.

EXAMPLE 30

(4-Cyclohexylmethylpiperazin-1-yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0256] ##STR00044##

[0257] Example 30 was synthesized from example 10 following the deacteylation procedure described in synthesis method B.

Yield: 13.1 mg (36.55 μmol, 96.2%), white solid.
LC/MS (ES-API): m/z=359.16 [M+H].sup.+; calculated: 359.21; t.sub.R1 (λ=220 nm): 0.46 min; t.sub.R2 (λ=220 nm): 0.48 min (LC/MS-Method 1).

[0258] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.47 (d, J=4.5 Hz, 1H, CH), 4.9-4.3 (m, 4H, 4×OH), 3.5-2.9 (m, 12H, 4×CH.sub.2, 4×CH), 2.07 (m, 2H, NCH.sub.2), 1.74 (m, 4H, 2×CH.sub.2), 1.52 (m, 1H, CH), 1.21 (m, 4H, 2×CH.sub.2), 0.87 (m, 2H, CH.sub.2) ppm.

EXAMPLE 31

(4-Cyclohexylethylpiperazin-1-yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0259] ##STR00045##

[0260] Example 31 was synthesized from example 11 following the deacteylation procedure described in synthesis method B.

Yield: 12.2 mg (32.76 μmol, 88.5%), white solid.
LC/MS (ES-API): m/z=373.17 [M+H].sup.+; calculated: 373.23; t.sub.R1 (λ=220 nm): 0.81 min; t.sub.R2 (λ=220 nm): 0.84 min (LC/MS-Method 1).

[0261] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.42 (d, J=4.8 Hz, 1H, CH), 4.6-4.1 (m, 4H, 4×OH), 3.6-3.0 (m, 12H, 4×CH.sub.2, 4×CH), 2.05 (m, 2H, NCH.sub.2), 1.72 (m, 4H, 2×CH.sub.2), 1.50 (m, 1H, CH), 1.23 (m, 4H, 2×CH.sub.2), 0.90 (m, 2H, CH.sub.2), 0.87 (m, 2H, CH.sub.2) ppm.

EXAMPLE 32

(4-Phenylpiperazin-1-yl)-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0262] ##STR00046##

[0263] Example 32 was synthesized from example 12 following the deacteylation procedure described in synthesis method B.

Yield: 11.8 mg (34.87 μmol, 88.3%), white solid.
LC/MS (ES-API): m/z=339.13 [M+H].sup.+; calculated: 339.15; t.sub.R1 (λ=220 nm): 0.90 min; t.sub.R2 (λ=220 nm): 0.95 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.23 (t, J=7.9 Hz, 2H, ArH), 6.95 (d, J=7.8 Hz, 2H, ArH), 6.81 (t, J=7.3 Hz, 1H, ArH), 6.66 (d, J=7.0 Hz, 1H, OH), 4.81 (d, J=4.7 Hz, 1H, OH), 4.74 (d, J=5.3 Hz, 1H, OH), 4.62 (d, J=6.4 Hz, 1H, OH), 4.43 (t, J=7.3 Hz, 1H, CH), 4.09 (d, J=9.3 Hz, 1H, CH), 3.70-3.45 (m, 8H, 4×NCH.sub.2), 3.25-3.00 (m, 3H, 3×CH) ppm.
.sup.13C-NMR (150 MHz, DMSO-d.sub.6): δ=166.48 (s, CO), 150.76 (s, C), 129.06 (s, CH), 119.28 (s, CH), 115.78 (s, CH), 93.06 (s, CH), 74.52 (s, CH), 72.71 (s, CH), 71.33 (s, CH), 70.98 (s, CH), 48.93 (s, CH.sub.2), 48.22 (s, CH.sub.2), 44.59 (s, CH.sub.2), 41.15 (s, CH.sub.2) ppm.

EXAMPLE 33

[4-[(E)-Cinnamyl]piperazin-1-yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0264] ##STR00047##

[0265] Example 33 was synthesized from example 13 following the deacteylation procedure described in synthesis method B.

Yield: 12.7 mg (33.56 μmol, 91.7%), white solid.
LC/MS (ES-API): m/z=379.25 [M+H].sup.+; calculated: 379.19; t.sub.R1 (λ=220 nm): 0.56 min; t.sub.R2 (λ=220 nm): 0.60 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.40 (d, J=7.0 Hz, 2H, ArH), 7.33 (t, J=7.0 Hz, 2H, ArH), 7.21 (t, J=7.0 Hz, 2H, ArH), 6.44 (d, J=4.6 Hz, 1H, CH), 4.6-4.1 (m, 4H, 4×OH), 3.65 (m, 2H, NCH.sub.2), 3.51 (m, 2H, 2×CH), 3.4-2.9 (m, 12H, 4×NCH.sub.2, 4×CH) ppm.

EXAMPLE 34

[4-(4-Chlorophenyl)piperazin-1-yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0266] ##STR00048##

[0267] Example 34 was synthesized from example 14 following the deacteylation procedure described in synthesis method B.

Yield: 13.6 mg (36.48 μmol, 98.7%), white solid.
LC/MS (ES-API): m/z=373.16 [M+H].sup.+; calculated: 373.11; t.sub.R1 (λ=220 nm): 1.20 min; t.sub.R2 (λ=220 nm): 1.24 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.40 (d, J=7.8 Hz, 4H, ArH), 6.49 (d, J=4.7 Hz, 1H, CH), 4.9-4.3 (m, 4H, 4×OH), 3.7-3.0 (m, 12H, 4×NCH.sub.2, 4×CH) ppm.

EXAMPLE 35

[4-(2-Chlorophenyl)piperazin-1-yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0268] ##STR00049##

[0269] Example 35 was synthesized from example 15 following the deacteylation procedure described in synthesis method B.

Yield: 13.3 mg (35.68 μmol, 96.5%), white solid.
LC/MS (ES-API): m/z=373.06 [M+H].sup.+; calculated: 373.11; t.sub.R1 (λ=220 nm): 1.23 min; t.sub.R2 (λ=220 nm): 1.26 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.45 (d, J=7.8 Hz, 1H, ArH), 7.31 (t, J=7.8 Hz, 1H, ArH), 7.14 (d, J=7.8 Hz, 1H, ArH), 7.03 (t, J=7.8 Hz, 1H, ArH), 6.52 (d, J=4.7 Hz, 1H, CH), 4.9-4.3 (m, 4H, 4×OH), 3.7-3.0 (m, 12H, 4×NCH.sub.2, 4×CH) ppm.

EXAMPLE 36

[4-(4-Bromophenyl)piperazin-1-yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0270] ##STR00050##

[0271] Example 36 was synthesized from example 16 following the deacteylation procedure described in synthesis method B.

Yield: 12.9 mg (30.92 μmol, 90.5%), white solid.
LC/MS (ES-API): m/z=416.11 [M+H].sup.+; calculated: 416.06; t.sub.R1 (λ=220 nm): 1.25 min; t.sub.R2 (λ=220 nm): 1.28 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.69 (d, J=8.0 Hz, 4H, ArH), 6.52 (d, J=4.9 Hz, 1H, CH), 4.8-4.1 (m, 4H, 4×OH), 3.6-3.1 (m, 12H, 4×NCH.sub.2, 4×CH) ppm.

EXAMPLE 37

[4-(4-Methoxyphenyl)piperazin-1-yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0272] ##STR00051##

[0273] Example 37 was synthesized from example 17 following the deacteylation procedure described in synthesis method B.

Yield: 13.4 mg (36.38 μmol, 97.6%), white solid.
LC/MS (ES-API): m/z=369.11 [M+H].sup.+; calculated: 369.16; t.sub.R1 (λ=220 nm): 0.74 min; t.sub.R2 (λ=220 nm): 0.80 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.91 (d, J=8.2 Hz, 2H, ArH), 6.83 (d, J=8.2 Hz, 2H, ArH), 6.53 (d, J=4.4 Hz, 1H, CH), 4.8-4.1 (m, 4H, 4×OH), 3.69 (s, 3H, OCH.sub.3), 3.6-2.9 (m, 12H, 4×NCH.sub.2, 4×CH) ppm.

EXAMPLE 38

[4-(3-Methoxyphenyl)piperazin-1-yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0274] ##STR00052##

[0275] Example 38 was synthesized from example 18 following the deacteylation procedure described in synthesis method B.

Yield: 13.1 mg (35.56 μmol, 95.4%), white solid.
LC/MS (ES-API): m/z=369.10 [M+H].sup.+; calculated: 369.16; t.sub.R1 (λ=220 nm): 1.01 min; t.sub.R2 (λ=220 nm): 1.04 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.14 (d, J=8.2 Hz, 1H, ArH), 6.84 (d, J=8.2 Hz, 1H, ArH), 6.57 (s, 1H, ArH), 6.51 (d, J=8.2 Hz, 1H, ArH), 6.43 (d, J=4.4 Hz, 1H, CH), 4.8-4.1 (m, 4H, 4×OH), 3.72 (s, 3H, OCH.sub.3), 3.60-3.45 (m, 4H, 4×CH), 3.25-3.00 (m, 8H, 4×NCH.sub.2) ppm.

EXAMPLE 39

[4-(2-Methoxyphenyl)piperazin-1-yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

[0276] ##STR00053##

[0277] Example 39 was synthesized from example 19 following the deacteylation procedure described in synthesis method B.

Yield: 12.8 mg (34.75 μmol, 93.2%), white solid.
LC/MS (ES-API): m/z=369.19 [M+H].sup.+; calculated: 369.16; t.sub.R1 (λ=220 nm): 0.85 min; t.sub.R2 (λ=220 nm): 0.90 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.98 (m, 2H, ArH), 6.87 (d, J=7.2 Hz, 2H, ArH), 6.49 (d, J=4.4 Hz, 1H, CH), 4.8-4.1 (m, 4H, 4×OH), 3.70 (s, 3H, OCH.sub.3), 3.6-3.2 (m, 4H, 4×CH), 3.0-2.8 (m, 8H, 4×NCH.sub.2) ppm.

[0278] sf-4482178

[0279] Example 40 [4-(1,3-Benzodioxol-5-ylmethyl)piperazin-1-yl]-[(2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methanone

##STR00054##

[0280] Example 40 was synthesized from example 20 following the deacteylation procedure described in synthesis method B.

Yield: 12.6 mg (31.79 μmol, 89.7%), white solid.
LC/MS (ES-API): m/z=397.11 [M+H].sup.+; calculated: 397.15; t.sub.R1 (λ=220 nm): 0.95 min; t.sub.R2 (λ=220 nm): 0.99 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.82 (m, 2H, ArH), 6.75 (dd, J=1.4 Hz, 1H, ArH), 6.00 (s, 2H, O—CH.sub.2—O), 6.49 (d, J=4.4 Hz, 1H, CH), 4.8-4.1 (m, 4H, 4×OH), 3.6-3.2 (m, 4H, 4×CH), 3.0-2.8 (m, 8H, 4×NCH.sub.2), 2.41 (m, 2H, NCH.sub.2) ppm.

EXAMPLE 41

[(2S,3R,4S)-2,3-Diacetoxy-6-(4-butylpiperazine-1-carbonyl)-3,4-di hydro-2H -pyran-4-yl]acetate

[0281] ##STR00055##

[0282] Step 1: (2S,3R,4S)-2,3,4-triacetoxy-3,4-dihydro-2H-pyran-6-carboxylic acid

##STR00056##

[0283] A solution of 2 g (5.52 mmol) 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid in 6 mL (63.59 mmol) acetic acid anhydride and 3 mL (22.08 mmol; 4 eq.) triethylamine was stirred at room temperature for 8 hours. The reaction mixture was diluted with water and lyophillized.

Yield: 1.6 g (5.38 mmol, 95.8%), colorless oil.
LC/MS (ES-API): not detectable. .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=7.99 (s, 1H, COOH), 6.33 (s, 1H, CH), 6.27 (m, 1H, CH), 5.19 (m, 1H, CH), 5.10 (m, 1H, CH), 2.05 (s, 3H, CH.sub.3), 2.04 (s, 3H, CH.sub.3), 2.03 (s, 3H, CH.sub.3) ppm.

Method C

[0284] Amide coupling with (2S,3R,4S)-2,3,4-triacetoxy-3,4-dihydro-2H-pyran-6-carboxylic acid (example 41, step 1)

[0285] To a solution of 0.66 mmol (2S,3R,4S)-2,3,4-triacetoxy-3,4-dihydro-2H-pyran-6-carboxylic acid (example 41, step 1) in 2 mL dimethylformamide were added 1.2 eq. (0.79 mmol) HATU and 1.4 eq. (0.93 mmol) amine. The reaction mixture was stirred at room temperature for 2 hours. The reaction was controlled by TLC and LC/MS. After completion the reaction mixture was extracted with 5-10 mL dichloromethane. The organic phase was washed with 1 M aqueous HCl, water, saturated aqueous NaHCO.sub.3 solution, and water. The organic phase was dried with Na.sub.2SO.sub.4, filtered, and evaporated. The crude material was purified by MPLC.

[0286] Step 2: [(2S,3R,4S)-2,3-diacetoxy-6-(4-butylpiperazine-1-carbonyl)-3,4-dihydro-2H-pyran-4-yl]acetate

[0287] Example 41 was synthesized from example 41, step 1 and 1-n-butylpiperazine following the amide coupling procedure described in synthesis method C.

[0288] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0289]

TABLE-US-00021 start % B end % B duration [min] 0 0 2.2 0 4.8 2.8 4.8 4.8 6.0 4.810.0 10.1 6.0 10.1 10.1 9.1
Yield: 141 mg (0.331 mmol, 50.8%), orange oil.
LC/MS (ES-API): m/z=427.20 [M+H].sup.+; calculated: 427.20; t.sub.R (λ=220 nm): 0.57 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, CDCl.sub.3): δ=6.28 (d, J=3.6 Hz, 1H, C=CH), 5.67 (d, J=3.8 Hz, 1H, CH), 5.25 (m, 1H, CH), 5.19 (m, 1H, CH), 3.73 (m, 4H, 2×NCH.sub.2), 2.60 (m, 4H, 2×NCH.sub.2), 2.15 (s, 3H, CH.sub.3), 2.13 (s, 3H, CH.sub.3), 2.10 (s, 3H, CH.sub.3) ppm.

EXAMPLE 42

[(2S,3R,4S)-2,3-Diacetoxy-6-(4-tert-butylpiperazine-1-carbonyl)-3,4-dihydro-2H-pyran-4-yl]acetate

[0290] ##STR00057##

[0291] Example 42 was synthesized from example 41, step 1 and 1-tert-butylpiperazine following the amide coupling procedure described in synthesis method C.

[0292] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0293]

TABLE-US-00022 start % B end % B duration [min] 0 0 2.2 0 4.8 2.8 4.8 4.8 6.0 4.810.0 10.1 6.0 10.1 10.1 9.1
Yield: 81 mg (0.190 mmol,28.7%), orange oil.
LC/MS (ES-API): m/z=427.15 [M+H].sup.+; calculated: 427.20; t.sub.R (λ=220 nm): 0.53 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, CDCl.sub.3): δ=6.29 (d, J=3.6 Hz, 1H, C═CH), 5.69 (d, J=3.8 Hz, 1H, CH), 5.24 (m, 1H, CH), 5.20 (m, 1H, CH), 3.75 (m, 4H, 2×NCH.sub.2), 2.62 (m, 4H, 2×NCH.sub.2), 2.16 (s, 3H, CH.sub.3), 2.13 (s, 3H, CH.sub.3), 2.10 (s, 3H, CH.sub.3), 1.27 (s, 9H, 3×CH.sub.3) ppm.

EXAMPLE 43

[(2S,3R,4S)-2,3-Diacetoxy-6-[4-(cyclohexylmethyl)piperazine-1-carbonyl]-3,4-dihydro-2H-pyran-4-yl]acetate

[0294] ##STR00058##

[0295] Example 43 was synthesized from example 41, step 1 and 1-cyclohexylmethylpiperazine following the amide coupling procedure described in synthesis method C.

[0296] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0297]

TABLE-US-00023 start % B end % B duration [min] 0 0 2.2 0 4.8 2.8 4.8 4.8 6.0 4.810.0 10.1 6.0 10.1 10.1 9.1
Yield: 145 mg (0.311 mmol, 47.0%), orange oil.
LC/MS (ES-API): m/z=467.20 [M+H].sup.+; calculated: 467.23; t.sub.R (λ=220 nm): 0.64 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, CDCl.sub.3): δ=6.29 (d, J=3.2 Hz, 1H, C═CH), 5.63 (d, J=3.2 Hz, 1H, CH), 5.24 (m, 1H, CH), 5.19 (m, 1H, CH), 3.75 (m, 4H, 2×NCH.sub.2), 2.62 (m, 4H, 2×NCH.sub.2), 2.16 (s, 3H, CH.sub.3), 2.13 (s, 3H, CH.sub.3), 2.11 (s, 3H, CH.sub.3), 1.73 (m, 1H, CH), 1.62 (m, 4H, 2×CH.sub.2), 1.13 (m, 4H, 2×CH.sub.2), 0.92 (m, 2H, CH.sub.2) ppm.

EXAMPLE 44

[(2S,3R,4S)-2,3-Diacetoxy-6-(4-phenylpiperazine-1-carbonyl)-3,4-dihydro-2H-pyran-4-yl]acetate

[0298] ##STR00059##

[0299] Example 44 was synthesized from example 41, step 1 and 1-phenylpiperazine following the amide coupling procedure described in synthesis method C.

[0300] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0301]

TABLE-US-00024 start % B end % B duration [min] 0 0 2.2 0 4.8 2.8 4.8 4.8 6.0 4.810.0 10.1 6.0 10.1 10.1 9.1
Yield: 135 mg (0.303 mmol, 45.5%), orange oil.
LC/MS (ES-API): m/z=447.13 [M+H].sup.+; calculated: 447.17; t.sub.R (λ=220 nm): 0.81 min (LC/MS-Method 1).

[0302] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=7.31 (t, J=7.9 Hz, 2H, ArH), 7.00 (m, 3H, ArH), 6.32 (dd, J=0.9 Hz, 1H, C═CH), 5.67 (dd, J=0.8 Hz, 1H, CH), 5.27 (m, 1H, CH), 5.21 (m, 1H, CH), 3.76 (m, 4H, 2×NCH.sub.2), 3.22 (m, 4H, 2×NCH.sub.2), 2.15 (s, 3H, CH.sub.3), 2.13 (s, 3H, CH.sub.3), 2.10 (s, 3H, CH.sub.3) ppm.

EXAMPLE 45

[(2S,3R,4S)-2,3-Diacetoxy-6-[(4-phenylpiperazin-1-yl)methyI]-3,4-dihydro-2H-pyran-4-yl]acetate

[0303] ##STR00060##

[0304] Step 1: [(2S,3R,4S)-2,3-diacetoxy-6-formyl-3,4-dihydro-2H-pyran-4-yl]acetate

##STR00061##

[0305] A solution of 2.87 mL dry DMSO (40.31 mmol; 2.6 eq.) in 3 mL dry dichloromethane was dropped slowly to a solution of 1.61 mL oxalylchloride (18.60 mmol; 1.2eq.) in 4 mL dry dichloromethane at −70° C. After stirring the reaction mixture at −70° C. for 30 minutes, a solution of 5.4 g 1,2,3,4-tetra-O-acetyl-β-D-glucopyranose in 20 mL dry dichloromethane was added. After stirring the reaction mixture at −70° C. for 30 minutes, 11 mL triethylamine were added slowly. The reaction mixture was warmed to room temperature and diluted with 20 mL water. After stirring for 10 minutes at room temperature, the aqueous phase was separated and extracted with dichloromethane. The combined organic phases were dried with Na2SO4, filtered, and evaporated.

Yield: 3.13 g (10.94 mmol, 70.5%), colorless oil.
TLC: R.sub.f=0.509 (ethylacetate/n-heptane, 2:1).
LC/MS (ES-API): m/z=304.05 [M+H.sub.2O]; calculated: 287.07; t.sub.R (λ=254 nm): 0.63 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.28 (s, 1H, CHO), 5.19 (d, J=4.2 Hz, 1H, CH), 5.10 (m, 2H, 2×CH), 2.08 (s, 3H, CH.sub.3), 2.07 (s, 3H, CH.sub.3), 2.04 (s, 3H, CH.sub.3) ppm.

Method D

Reductive amination with [(2S,3R,4S)-2,3-diacetoxy-6-formyl-3,4-dihydro-2H-pyran-4-yl]acetate (example 45, step 1)

[0306] To a solution of 0.52 mmol [(25,3R,45)-2,3-diacetoxy-6-formyl-3,4-dihydro-2H-pyran-4-yl] acetate (example 45, step 1) in 10 mL dichloroethane were added 0.57 mmol (1.1 eq.) amine and 0.74 mmol (1.41 eq.) sodiumtriacetoxyboronhydride. The reaction mixture was stirred at room temperature over night. The reaction was controlled by TLC and LC/MS. The reaction mixture was filtered and evaporated. The crude material was purified by MPLC.

Step 2: [(2S,3R,4S)-2,3-diacetoxy-6-[(4-phenylpiperazin-1-yl)methyl]-3,4-dihydro-2H-pyran-4-yl]acetate

[0307] Example 45 was synthesized from example 45, step 1 and 1-phenylpiperazine following the reductive amidation procedure described in synthesis method D.

[0308] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

Yield: 154 mg (0.356 mmol, 68.0%), yellow oil.
TLC: R.sub.f=0.639 (ethylacetate/n-heptane, 2:1).
LC/MS (ES-API): m/z=433.20 [M+H].sup.+; calculated: 433.19; t.sub.R (λ=220 nm): 1.26 min (LC/MS-Method 1).

MPLC Gradient

[0309]

TABLE-US-00025 start % B end % B duration [min] 0.0 0.0 1.6 0.0 70.2 28.0
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.20 (t, J=8.0 Hz, 2H, ArH), 6.92 (d, J=8.0 Hz, 2H, ArH), 6.76 (d, J=7.2 Hz, 1H, ArH), 5.96 (dd, J=3.6 Hz, J=1.0 Hz 1H, CH), 5.12 (d, J=4.2 Hz, 1H, CH), 5.04 (m, 2H, 2×CH), 3.12 (m, 4H, 2×NCH.sub.2), 3.02 (AB-system, q, J=14.3 Hz, 2H, CH.sub.2), 2.50 (m, 4H, 2×NCH.sub.2), 2.08 (s, 3H, CH.sub.3), 2.07 (s, 3H, CH.sub.3), 2.04 (s, 3H, CH.sub.3) ppm.
.sup.13C-NMR (150 MHz, DMSO-d.sub.6): δ=169.83 (s, C), 168.62 (s, C), 168.40 (s, C), 151.31 (s,2× C), 129.16 (s, CH), 118.98 (s, CH), 115.23 (s, CH), 97.54 (s, CH), 93.66 (s, C), 88.92 (s, CH), 66.82 (s, CH), 64.19 (s, CH), 52.04 (s, 2×CH), 47.96 (s,2× CH), 21.13 (s, CH.sub.3), 20.85 (s, CH.sub.3), 20.74 (s, CH.sub.3) ppm.

EXAMPLE 46

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-[(E)-cinnamyl]piperazin-1-yl]methyl]-3,4-dihydro-2H-pyran-4-yl]acetate

[0310] ##STR00062##

[0311] Example 46 was synthesized from example 45, step 1 and trans-1-cinnamylpiperazine following the reductive amidation procedure described in synthesis method D.

[0312] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

Yield: 194 mg (0.411 mmol, 78.3%), yellow oil.
TLC: R.sub.f=0.136 (ethylacetate/n-heptane, 2:1).
LC/MS (ES-API): m/z=473.23 [M+H].sup.+; calculated: 473.22; t.sub.R (λ=220 nm): 1.32 min (LC/MS-Method 1).

MPLC Gradient

[0313]

TABLE-US-00026 start % B end % B duration [min] 0.0 0.0 1.3 0.0 13.3 15.1
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.42 (d, J=7.3 Hz, 2H, ArH), 7.31 (t, J=7.3 Hz, 2H, ArH), 7.23 (t, J=7.3 Hz, 1H, ArH), 6.52 (d, J=15.9 Hz, 1H, CH), 6.27 (m, 1H, CH), 6.18 (dd, J=1.2 Hz, 1H, CH), 5.08 (d, J=4.1 Hz, 1H, CH), 5.03 (m, 2H, 2×CH), 3.33 (m, 6H, 3×NCH.sub.2), 2.96 (q, J=14.2 Hz, 2H, CH.sub.2), 2.41 (m, 4H, 2×NCH.sub.2), 2.08 (s, 3H, CH.sub.3), 2.07 (s, 3H, CH.sub.3), 2.04 (s, 3H, CH.sub.3) ppm.

EXAMPLE 47

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]methyl]-3,4-dihydro-2H-pyran-4-yl]acetate

[0314] ##STR00063##

[0315] Example 47 was synthesized from example 45, step 1 and 1-(1,3-benzodioxol-5-ylmethyl)piperazine following the reductive amidation procedure described in synthesis method D.

[0316] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

Yield: 249 mg (0.508 mmol, 96.9%), yellow oil.
TLC: R.sub.f=0.242 (ethylacetate/n-heptane, 2:1).
LC/MS (ES-API): m/z=491.24 [M+H].sup.+; calculated: 491.19; t.sub.R (λ=220 nm): 1.19 min (LC/MS-Method 1).

MPLC Gradient

[0317]

TABLE-US-00027 start % B end % B duration [min] 0.0 0.0 1.9 0.0 10.1 13.1
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.84 (m, 2H, ArH), 6.73 (dd, J=1.4 Hz, 1H, ArH), 6.28 (dd, J=1.0 Hz, 1H, CH), 5.97 (s, 2H, O—CH.sub.2—O), 5.08 (d, J=4.2 Hz, 1H, CH), 5.04 (m, 2H, 2×CH), 3.31 (m, 4H, 2×NCH.sub.2), 2.94 (q, J=14.4 Hz, 2H, CH.sub.2), 2.38 (m, 4H, 2×NCH.sub.2), 2.08 (s, 3H, CH.sub.3), 2.07 (s, 3H, CH.sub.3), 2.03 (s, 3H, CH.sub.3) ppm.

EXAMPLE 48

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-3,4-dihydro-2H-pyran-4-yl]acetate

[0318] ##STR00064##

[0319] Example 48 was synthesized from example 45, step 1 and 1-(4-chlorophenyl)piperazine following the reductive amidation procedure described in synthesis method D.

[0320] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

Yield: 131 mg (0.281 mmol, 53.5%), yellow oil.
TLC: R.sub.f=0.636 (ethylacetate/n-heptane, 2:1).
LC/MS (ES-API): m/z=467.16 [M+H].sup.+; calculated: 467.91; t.sub.R (λ=220 nm): 1.40 min (LC/MS-Method 1).

MPLC Gradient

[0321]

TABLE-US-00028 start % B end % B duration [min] 0.0 0.0 2.0 0.0 10.1 23.0
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.21 (d, J=9.1 Hz, 2H, ArH), 6.93 (d, J=9.1 Hz, 2H, ArH), 6.20 (dd, J=1.1 Hz, 1H, CH), 5.12 (d, J=4.4 Hz, 1H, CH), 5.04 (m, 2H, 2×CH), 3.12 (m, 4H, 2×NCH.sub.2), 3.02 (q, J=14.1 Hz, 2H, CH.sub.2), 2.51 (m, 4H, 2×NCH.sub.2), 2.07 (s, 3H, CH.sub.3), 2.06 (s, 3H, CH.sub.3), 2.04 (s, 3H, CH.sub.3) ppm.

EXAMPLE 49

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-(2-chlorophenyl)piperazin-1-yl]methyl]-3,4-dihydro-2H-pyran-4-yl]acetate

[0322] ##STR00065##

[0323] Example 49 was synthesized from example 45, step 1 and 1-(2-chlorophenyl)piperazine following the reductive amidation procedure described in synthesis method D.

[0324] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

Yield: 144 mg (0.308 mmol, 58.9%), yellow oil.
TLC: R.sub.f=0.621 (ethylacetate/n-heptane, 2:1).
LC/MS (ES-API): m/z=467.16 [M+H].sup.+; calculated: 467.91; t.sub.R (λ=220 nm): 1.38 min (LC/MS-Method 1).

MPLC Gradient

[0325]

TABLE-US-00029 start % B end % B duration [min] 0.0 0.0 1.6 0.0 70.2 23.0
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.39 (d, J=7.9 Hz, 1H, ArH), 7.28 (t, J=7.7 Hz, 1H, ArH), 7.17 (d, J=8.1 Hz, 1H, ArH), 7.03 (t, J=7.6 Hz, 1H, ArH), 6.21 (dd, J=1.2 Hz, 1H, CH), 5.13 (d, J=4.1 Hz, 1H, CH), 5.04 (m, 2H, 2×CH), 3.07 (q, J=14.4 Hz, 2H, CH.sub.2), 2.98 (m, 4H, 2×NCH.sub.2), 2.59 (m, 4H, 2×NCH.sub.2), 2.08 (s, 3H, CH.sub.3), 2.07 (s, 3H, CH.sub.3), 2.03 (s, 3H, CH.sub.3) ppm.

EXAMPLE 50

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-(4-methoxyphenyl)piperazin-1-yl]methyl]-3,4-dihydro-2H-pyran-4-yl]acetate

[0326] ##STR00066##

[0327] Example 50 was synthesized from example 45, step 1 and 1-(4-methoxyphenyl)piperazine following the reductive amidation procedure described in synthesis method D.

[0328] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

Yield: 151 mg (0.326 mmol, 62.3%), yellow oil.
TLC: R.sub.f=0.530 (ethylacetate/n-heptane, 2:1).
LC/MS (ES-API): m/z=463.19 [M+H].sup.+; calculated: 463.20; t.sub.R (λ=220 nm): 1.25 min (LC/MS-Method 1).

MPLC Gradient

[0329]

TABLE-US-00030 start % B end % B duration [min] 0.0 0.0 1.3 0.0 100.0 13.7 100.0 100.0 3.6
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.88 (d, J=9.1 Hz, 2H, ArH), 6.80 (d, J=9.1 Hz, 2H, ArH), 6.20 (dd, J=1.0 Hz, 1H, CH), 5.12 (d, J=4.1 Hz, 1H, CH), 5.04 (m, 2H, 2×CH), 3.69 (s, 3H, OCH.sub.3), 3.00 (m, 6H, CH.sub.2+NCH.sub.2), 2.52 (m, 4H, NCH.sub.2), 2.08 (s, 3H, CH.sub.3), 2.07 (s, 3H, CH.sub.3), 2.04 (s, 3H, CH.sub.3) ppm.

EXAMPLE 51

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-(3-methoxyphenyl)piperazin-1-yl]methyl]-3,4-dihydro-2H-pyran-4-yl]acetate

[0330] ##STR00067##

[0331] Example 51 was synthesized from example 45, step 1 and 1-(3-methoxyphenyl)piperazine following the reductive amidation procedure described in synthesis method D.

[0332] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

Yield: 135 mg (0.292 mmol, 55.7%), yellow oil.
TLC: R.sub.f=0.591 (ethylacetate/n-heptane, 2:1).
LC/MS (ES-API): m/z=463.24 [M+H].sup.+; calculated: 463.20; t.sub.R (λ=220 nm): 1.28 min (LC/MS-Method 1).

MPLC Gradient

[0333]

TABLE-US-00031 start % B end % B duration [min] 0.0 0.0 1.3 0.0 100.0 13.7 100.0 100.0 3.6
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ =7.09 (t, J=8.2 Hz, 1H, ArH), 6.51 (d, J=8.2 Hz, 1H, ArH), 6.43 (s, 1H, ArH), 6.35 (dd, J=1.1 Hz, 1H, CH), 5.12 (d, J=4.3 Hz, 1H, CH), 5.04 (m, 1H, CH), 3.71 (s, 3H, OCH.sub.3), 3.11 (m, 4H, 2×NCH.sub.2), 3.01 (q, J=14.3 Hz, 2H, CH.sub.2), 2.52 (m, 4H, 2×NCH.sub.2), 2.08 (s, 3H, CH.sub.3), 2.07 (s, 3H, CH.sub.3), 2.04 (s, 3H, CH.sub.3) ppm.

EXAMPLE 52

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]-3,4-dihydro-2H-pyran-4-yl]acetate

[0334] ##STR00068##

[0335] Example 52 was synthesized from example 45, step 1 and 1-(2-methoxyphenyl)piperazine following the reductive amidation procedure described in synthesis method D.

[0336] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

Yield: 167 mg (0.361 mmol, 68.9%), yellow oil.
TLC: R.sub.f=0.533 (ethylacetate/n-heptane, 2:1).
LC/MS (ES-API): m/z=463.24 [M+H].sup.+; calculated: 463.20; t.sub.R (λ=220 nm): 1.26 min (LC/MS-Method 1).

MPLC Gradient

[0337]

TABLE-US-00032 start % B end % B duration [min] 0.0 0.0 1.3 0.0 100.0 13.7 100.0 100.0 3.6

[0338] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.90 (m, 4H, ArH), 6.21 (dd, J=1.0 Hz, 1H, CH), 5.12 (d, J=4.4 Hz, 1H, CH), 5.03 (m, 1H, CH), 3.68 (s, 3H, OCH.sub.3), 3.04 (q, J=14.3 Hz, 2H, CH.sub.2), 2.96 (m, 4H, 2×NCH.sub.2), 2.54 (m, 4H, 2×NCH.sub.2), 2.10 (s, 3H, CH.sub.3), 2.09 (s, 3H, CH.sub.3), 2.05 (s, 3H, CH.sub.3) ppm.

EXAMPLE 53

[(2S,3R,4S)-2,3-Diacetoxy-6-[[4-(4-bromophenyl)piperazin-1-yl]methyl]-3,4-dihydro-2H-pyran-4-yl]acetate

[0339] ##STR00069##

[0340] Example 53 was synthesized from example 45, step 1 and 1-(4-bromophenyl)piperazine following the reductive amidation procedure described in synthesis method D.

[0341] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 12 g; flow rate: 30 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

Yield: 248 mg (0.485 mmol, 92.5%), yellow oil.
TLC: R.sub.f=0.644 (ethylacetate/n-heptane, 2:1).
LC/MS (ES-API): m/z=511.14 [M+H].sup.+; calculated: 511.10; t.sub.R (λ=220 nm): 1.42 min (LC/MS-Method 1).

MPLC Gradient

[0342]

TABLE-US-00033 start % B end % B duration [min] 0.0 0.0 1.3 0.0 100.0 13.7 100.0 100.0 3.6
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.33 (d, J=9.0 Hz, 2H, ArH), 6.88 (d, J=9.0 Hz, 2H, ArH), 6.20 (dd, J=1.2 Hz, 1H, CH), 5.12 (d, J=4.3 Hz, 1H, CH), 5.04 (m, 2H, 2×CH), 3.12 (m, 4H, 2×NCH.sub.2), 3.03 (q, J=14.2 Hz, 2H, CH.sub.2), 2.52 (m, 4H, 2×NCH.sub.2), 2.09 (s, 3H, CH.sub.3), 2.08 (s, 3H, CH.sub.3), 2.05 (s, 3H, CH.sub.3) ppm.

[0343] Example 54

5-(Dimethylamino)-N-[[1-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-3-yl]triazol-4-yl]methyl]naphthalene-1-sulfonamide

[0344] ##STR00070##

Step 1: 5-(dimethylamino)-N-prop-2-ynyl-naphthalene-1-sulfonamide

[0345] ##STR00071##

[0346] To a solution of 405 mg (1.5 mmol) dansylchloride in 4 mL dimethylformamide were added 91 mg (1.65 mmol) propargylamine and 530 μl (3 mmol, 2 eq.) N,N-diisopropylethylamine. The reaction mixture was stirred at 100° C. in the microwave for 45 minutes. The reaction mixture was filtered and evaporated.

[0347] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 24 g Gold; flow rate: 40 mL/min; wavelength for detection: 254 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0348]

TABLE-US-00034 start % B end % B duration [min] 0.0 0.0 2.0 0.0 50.0 33.0
Yield: 92 mg (0.319 mmol, 21.5%), yellow oil.
TLC: R.sub.f=0.510 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=289.13 [M+H].sup.+; calculated: 289.09; t.sub.R (λ=220 nm): 1.62 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.48 (d, J=8.6 Hz, 1H, ArH), 8.40 (s, 1H, SO.sub.2NH), 8.25 (d, J=8.6 Hz, 1H, ArH), 8.13 (dd, J=1.1 Hz, 1H, ArH), 7.60 (m, 2H, ArH), 7.26 (d, J=7.4 Hz, 1H, ArH), 3.71 (s, 2H, NCH.sub.2), 2.91 (s, 1H, CH), 2.84 (s, 6H, 2×NCH.sub.3) ppm.

Method E

[0349] Copper-Catalyzed Azide-Alkyne-Cycloaddition (CuAAC) with Azidodeoxyglucose

[0350] To a solution of 146 μmol azidodeoxyglucose (1-azido-1-deoxyglucose, 2-azido-2-deoxyglucose, or 6-azido-6-deoxyglucose) in 0.5 mL water 1.1 eq. alkyne were added. If needed dimethylformamide was added until the reaction mixture was a clear solution. A mixture of 0.1 eq. CuSO.sub.4*5 H.sub.2O (0.1 M in water), 0.25 eq. sodium ascorbate (1 M in water), and 0.4 eq. THPTA (0.5 M in water) was added. The reaction mixture was stirred at room temperature for 2-6 hours. The reaction was controlled by TLC and LC/MS. The reaction mixture was evaporated and purified by HPLC. Alpha/beta isomers were not separated, NMR data belong to only one isomer.

[0351] Purification: Agilent 1200 preparative HPLC; column: Agilent Prep-C.sub.18 column (10 μm, 21.5×150 mm); flow rate: 40 mL/min; wavelength for detection: 220 nm; 254 nm; 324 nm; eluent: (A) water, (B) acetonitrile.

HPLC-Gradient

[0352]

TABLE-US-00035 start % B end % B duration [min] 3.0 3.0 5.0 3.0 90.0 7.5 90.0 90.0 2.5 90.0 10.0 0.5 10.0 10.0 2.0

Step 2: 5-(dimethylamino)-N-[[1-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)-tetrahydropyran-3-yl]triazol-4-yl]methyl]naphthalene-1-sulfonamide

[0353] Example 54 was synthesized from 2-azido-2-deoxyglucose and example 45, step 1 following the CuAAC procedure described in synthesis method E.

Yield: 33 mg (67 μmol, 46.7%), yellow oil.
TLC: R.sub.f=0.032 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=494.19 [M+H].sup.+; calculated: 494.16; t.sub.R1 (λ=220 nm): 1.17 min; t.sub.R2 (λ=220 nm): 1.20 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.47 (d, J=8.6 Hz, 2H, ArH), 8.40 (s, 1H, SNH), 8.13 (d, J=7.3 Hz, 1H, ArH), 7.84 (s, 1H, NCH), 7.61 (m, 2H, ArH), 7.27 (d, J=7.4 Hz, 1H, ArH), 6.95 (d, J=6.4Hz, 1H, OH), 5.17 (d, J=6.2 Hz, 1H, OH), 5.09 (d, J=6.2 Hz, 1H, OH), 4.89 (dd, J=6.4 Hz, 1H, CH), 4.61 (dd, J=6.4 Hz, 1H, OH), 4.07 (s, 2H, NCH.sub.2), 4.01 (m, 1H, CH), 3.85 (m, 1H, CH), 3.74 (m, 1H, CH), 3.53 (m, 2H, CH.sub.2), 3.22 (m, 1H, CH.sub.2), 2.84 (s, 6H, 2×NCH.sub.3) ppm.

EXAMPLE 55

(3R,4R,5S,6R)-6-(Hydroxymethyl)-3-(4-phenyltriazol-1-yl)tetrahydropyran-2,4,5-triol

[0354] ##STR00072##

[0355] Example 55 was synthesized from 2-azido-2-deoxyglucose and ethynylbenzene following the CuAAC procedure described in synthesis method E.

Yield: 15 mg (49 μmol, 33.4%), white solid.
TLC: R.sub.f=0.333 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=308.10 [M+H].sup.+; calculated: 308.12; t.sub.R1 (λ=220 nm): 0.81 min; t.sub.R2 (λ=220 nm): 0.85 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.61 (s, 1H, NCH), 7.86 (dd, J=1.3 Hz, 2H, ArH), 7.45 (m, 2H, ArH), 7.40 (m, 1H, ArH), 7.10 (d, J=6.2 Hz, 1H, OH), 5.48 (d, J=6.2 Hz, 1H, OH), 5.25 (d, J=6.6 Hz, 1H, OH), 5.25 (t, J=4.2 Hz, 1H, CH), 4.65 (t, J=6.1 Hz, 1H, OH), 4.65 (dd, J=10.8 Hz, J=3.1 Hz, 1H, CH), 4.08 (m, 1H, CH), 3.96 (m, 1H, OH), 3.76 (m, 1H, CH.sub.2), 3.52 (m, 1H, CH.sub.2), 3.36 (m, 1H, CH), 3.29 (m, 1H, CH) ppm.
.sup.13C-NMR (150 MHz, DMSO-d.sub.6): δ=145.70 (s, C), 131.00 (s, C), 128.90 (s, CH), 127.64 (s, CH), 125.05 (s, CH), 120.64 (s, CH), 90.80 (s, CH), 72.42 (s, CH), 70.93 (s, CH), 69.72 (s, CH), 65.24 (s, CH), 60.86 (s, CH.sub.2) ppm.

EXAMPLE 56

(3R,4R,5S,6R)-6-(Hydroxymethyl)-3-[4-(p-tolyl)triazol-1-yl]tetrahydropyran-2,4,5-triol

[0356] ##STR00073##

[0357] Example 56 was synthesized from 2-azido-2-deoxyglucose and 1-ethynyl-4-methylbenzene following the CuAAC procedure described in synthesis method E.

Yield: 34 mg (106 μmol, 72.4%), white solid.
TLC: R.sub.f=0.349 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=322.19 [M+H].sup.+; calculated: 322.13; t.sub.R1 (λ=220 nm): 1.07 min; t.sub.R2 (λ=220 nm): 1.11 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.47 (s, 1H, NCH), 7.76 (d, J=8.1 Hz, 2H, ArH), 7.24 (d, J=8.1 Hz, 2H, ArH), 6.93 (d, J=4.4 Hz, 1H, OH), 5.29 (d, J=5.4 Hz, 1H, OH), 5.20 (d, J=5.4 Hz, 1H, OH), 5.00 (dd, J=8.0 Hz, 1H, CH), 4.56 (dd, J=3.2 Hz, 1H, OH), δ=4.09 (m, 1H, CH), 3.96 (m, 1H, CH), 3.76 (m, 1H, CH.sub.2), 3.53 (m, 1H, CH.sub.2), 3.36 (m, 1H, CH), 3.28 (m, 1H, CH), 2.35 (s, 3H, CH.sub.3) ppm.

Example 57

(3R,4R,5S,6R)-6-(Hydroxymethyl)-3-[4-(3-phenylpropyl)triazol-1-yl]tetrahydropyran-2,4,5-triol

[0358] ##STR00074##

[0359] Example 57 was synthesized from 2-azido-2-deoxyglucose and pent-4-yn-1-ylbenzene following the CuAAC procedure described in synthesis method E.

Yield: 40 mg (114 μmol, 78.3%), white solid.
TLC: R.sub.f=0.406 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=350.19 [M+H].sup.+; calculated: 350.16; t.sub.R1 (λ=220 nm): 1.24 min; t.sub.R2 (λ=220 nm): 1.26 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.78 (s, 1H, NCH), 7.75 (m, 5H, ArH), 6.81 (d, J=5.0 Hz, 1H, OH), 5.22 (d, J=5.7 Hz, 1H, OH), 5.12 (d, J=5.7 Hz, 1H, OH), 4.92 (dd, J=6.7 Hz, 1H, CH), 4.52 (dd, J=5.5 Hz, 1H, OH), 4.09 (m, 1H, CH), 3.95 (m, 1H, CH), 3.76 (m, 1H, CH.sub.2), 3.53 (m, 1H, CH.sub.2), 3.36 (m, 1H, CH), 3.28 (m, 1H, CH), 2.61 (m, 4H, CH.sub.2), 1.90 (m, 2H, CH.sub.2) ppm.

EXAMPLE 58

Methyl 4-[1-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-3-yl]triazol-4-yl]benzoate

[0360] ##STR00075##

[0361] Example 58 was synthesized from 2-azido-2-deoxyglucose and 4-ethynylmethylbenzoate following the CuAAC procedure described in synthesis method E.

Yield: 31 mg (85 μmol, 58.0%), white solid.
TLC: R.sub.f=0.429 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=366.12 [M+H].sup.+; calculated: 366.12; t.sub.R1 (λ=220 nm): 0.97 min; t.sub.R2 (λ=220 nm): 1.00 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.80 (s, 1H, NCH), 8.05 (d, J=8.2 Hz, 2H, ArH), 8.00 (d, J=8.2 Hz, 2H, ArH), 7.09 (d, J=6.4 Hz, 1H, OH), 5.49 (d, J=6.3 Hz, 1H, OH), 5.25 (d, J=5.7 Hz, 1H, OH), 5.00 (dd, J=8.0 Hz, 1H, CH), 4.65 (dd, J=5.2 Hz, 1H, OH), 4.09 (m, 1H, CH), 3.95 (m, 1H, CH), 3.87 (s, 3H, OCH.sub.3), 3.76 (m, 1H, CH.sub.2), 3.53 (m, 1H, CH.sub.2), 3.36 (m, 1H, CH), 3.28 (m, 1H, CH) ppm.

EXAMPLE 59

(3R,4R,5S,6R)-3-[4-[[Benzyl(methyl)amino]methyl]triazol-1-yl]-6-(hydroxymethyl)tetrahydropyran-2,4,5-triol

[0362] ##STR00076##

[0363] Example 59 was synthesized from 2-azido-2-deoxyglucose and N-benzyl-N-methylprop-2-yn-1-amine following the CuAAC procedure described in synthesis method E.

Yield: 32 mg (88 μmol, 60.1%), white solid.
TLC: R.sub.f=0.064 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=365.20 [M+H].sup.+; calculated: 365.17; t.sub.R (ELSD): 0.34 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.00 (s, 1H, NCH), 7.71 (m, 5H, ArH), 6.82 (d, J=6.0 Hz, 1H, OH), 5.25 (d, J=5.8 Hz, 1H, OH), 5.14 (d, J=5.8 Hz, 1H, OH), 4.93 (dd, J=5.7 Hz, 1H, CH), 4.49 (dd, J=5.2 Hz, 1H, OH), 4.08 (m, 1H, CH), 3.95 (m, 1H, CH), 3.76 (m, 2H, CH.sub.2), 3.62 (s, 3H, NCH.sub.3), 3.36 (m, 1H, CH), 3.28 (m, 1H, CH), 2.13 (m, 4H, 2×NCH.sub.2) ppm.

EXAMPLE 60

(3R,4R,5S,6R)-6-(Hydroxymethyl)-3-[4-(6-methoxy-2-naphthyl)triazol-1-yl]tetrahydropyran-2,4,5-triol

[0364] ##STR00077##

[0365] Example 60 was synthesized from 2-azido-2-deoxyglucose and 2-ethynyl-6-methoxynaphthalene following the CuAAC procedure described in synthesis method E.

Yield: 28 mg (72 μmol, 49.4%), white solid.
TLC: R.sub.f=0.461 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=388.16 [M+H].sup.+; calculated: 388.14; t.sub.R1 (λ=220 nm): 1.27 min; t.sub.R2 (λ=220 nm): 1.29 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.64 (s, 1H, NCH), 7.88 (m, 4H, ArH), 7.34 (s, 1H, ArH), 7.07 (d, J=6.5 Hz, 1H, OH), 5.47 (d, J=6.4 Hz, 1H, OH), 5.23 (d, J=6.4 Hz, 1H, OH), 5.00 (dd, J=6.6 Hz, 1H, CH), 4.49 (dd, J=5.2 Hz, 1H, OH), 4.11 (m, 1H, CH), 3.98 (m, 1H, CH), 3.89 (s, 3H, OCH.sub.3), 3.77 (m, 1H, CH.sub.2), 3.53 (m, 1H, CH.sub.2), 3.46 (m, 1H, CH), 3.38 (m, 1H, CH) ppm.

EXAMPLE 61

(3R,4R,5S,6R)-3-[4-[4-Chloro-6-methyl-2-(p-tolyl)pyrimidin-5-yl]triazol-1-yl]-6-(hydroxymethyl)tetrahydropyran-2,4,5-triol

[0366] ##STR00078##

[0367] Example 61 was synthesized from 2-azido-2-deoxyglucose and 4-chloro-5-ethynyl-6-methyl-2-(p-tolyl)pyrimidine following the CuAAC procedure described in synthesis method E.

Yield: 51 mg (110 μmol, 75.5%), white solid.
TLC: R.sub.f=0.556 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=462.22 [M+H].sup.+; calculated: 462.15; t.sub.R1 (λ=220 nm): 1.51 min; t.sub.R2 (λ=220 nm): 1.52 min (LC/MS-Method 1).

[0368] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.19 (d, J=8.2 Hz, 2H, ArH), 7.89 (s, 1H, NCH), 7.71 (d, J=8.2 Hz, 2H, ArH), 6.93 (d, J=6.6 Hz, 1H, OH), 5.21 (d, J=6.1 Hz, 1H, OH), 5.14 (d, J=6.1 Hz, 1H, OH), 4.91 (dd, J=6.7 Hz, 1H, CH), 4.50 (dd, J=5.5 Hz, 1H, OH), 4.21 (s, 3H, CH.sub.3), 4.05 (m, 1H, CH), 3.97 (m, 1H, CH), 3.85 (m, 2H, CH.sub.2), 3.71 (m, 1H, CH), 3.50 (m, 1H, CH), 2.62 (s, 3H, CH.sub.3) ppm.

EXAMPLE 62

Ethyl-2-diethoxyphosphoryl-3-[1-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)-tetrahydropyran-3-yl]priazol-4-yl]propanoate

[0369] ##STR00079##

[0370] Example 62 was synthesized from 2-azido-2-deoxyglucose and ethyl 2-diethoxyphosphorylpent-4-ynoate following the CuAAC procedure described in synthesis method E.

Yield: 30 mg (64 μmol, 43.9%), white solid.
TLC: R.sub.f=0.389 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=468.17 [M+H].sup.+; calculated: 468.17; t.sub.R1 (λ=220 nm): 0.99 min; t.sub.R2 (λ=220 nm): 1.01 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.89 (s, 1H, NCH), 6.90 (d, J=6.6 Hz, 1H, OH), 5.17 (d, J=6.0 Hz, 1H, OH), 5.10 (d, J=6.0 Hz, 1H, OH), 4.86 (dd, J=6.5 Hz, 1H, CH), 4.61 (dd, J=5.5 Hz, 1H, OH), 4.01 (m, 1H, CH), 3.88 (m, 1H, CH), 3.61 (m, 1H, CH), 3.50 (m, 1H, CH.sub.2), 3.22 (m, 1H, CH.sub.2), 3.01 (m, 1H, CH), 1.29 (m, 9H, CH.sub.3), 1.14 (m, 6H, CH.sub.2) ppm.

EXAMPLE 63

(3R,4R,5S,6R)-6-(Hydroxymethyl)-3-[4-[[(4-nitro-2,1,3-benzoxadiazol-7-yl)amino]methyl]triazol-1-yl]tetrahydropyran-2,4,5-triol

[0371] ##STR00080##

Step 1: 4-nitro-N-prop-2-ynyl-2,1,3-benzoxadiazol-7-amine

[0372] ##STR00081##

[0373] To a solution of 450 mg (2.23 mmol) 4-chloro-7-nitro-2,1,3-benzoxadiazole in 4 mL dry dimethylformamide were added 135 mg (2.46 mmol) propargylamine and 395 μl (2.23 mmol) N,N-diisopropylethylamine. The reaction mixture was stirred at 100° C. in the microwave for 45 minutes and evaporated.

[0374] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 40 g; flow rate: 40 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

MPLC Gradient

[0375]

TABLE-US-00036 start % B end % B duration [min] 0.0 0.0 1.6 0.0 27.7 16.6 27.7 79.8 19.9 79.8 0.0 0.0 0.0 0.0 2.9
Yield: 98 mg (0.449 mmol, 20.1%), orange solid.
TLC: R.sub.f=0.664 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=219.01 [M+H].sup.+; calculated: 219.04; t.sub.R (λ=220 nm): 1.32 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.62 (s, 1H, NH), 8.62 (d, J=8.7 Hz, 1H, ArH), 6.48 (d, J=8.7 Hz, 1H, ArH), 4.34 (s, 2H, NCH.sub.2), 3.37 (s, 1H, CH) ppm.

Step 2: (3R,4R,5S,6R)-6-(hydroxymethyl)-3-[4-[[(4-nitro-2,1,3-benzoxadiazol-7-yl)amino]methyl]triazol-1-yl]tetrahydropyran-2,4,5-triol

[0376] Example 63 was synthesized from 2-azido-2-deoxyglucose and example 63, step 1 following the CuAAC procedure described in synthesis method E.

Yield: 43 mg (101 μmol, 69.5%), orange solid.
TLC: R.sub.f=0.294 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=424.10 [M+H].sup.+; calculated: 424.16; t.sub.R1 (λ=220 nm): 0.77 min; t.sub.R2 (λ=220 nm): 0.81 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.83 (s, 1H, NH) 8.62 (d, J=8.7 Hz, 1H, ArH), 8.04 (s, 1H, NCH), 6.93 (d, J=6.4Hz, 1H, OH), 6.51 (d, J=8.7 Hz, 1H, ArH), 5.21 (d, J=6.2 Hz, 1H, OH), 5.14 (d, J=6.2 Hz, 1H, OH), 4.92 (dd, J=6.4 Hz, 1H, CH), 4.67 (s, 2H, NCH.sub.2), 4.61 (dd, J=6.4 Hz, 1H, OH), 4.06 (m, 1H, CH), 3.90 (m, 1H, CH), 3.64 (m, 1H, CH), 3.52 (m, 2H, CH.sub.2), 3.22 (m, 1H, CH.sub.2), 3.01 (m, 1H, CH) ppm.

EXAMPLE 64

(3R,4R,5S,6R)-3-[4-(Cyclohexylmethyl)triazol-1-yl]-6-(hydroxymethyl)tetrahydropyran-2,4,5-triol

[0377] ##STR00082##

[0378] Example 64 was synthesized from 2-azido-2-deoxyglucose and prop-2-yn-1-ylcyclohexane following the CuAAC procedure described in synthesis method E.

Yield: 23 mg (70 μmol, 48.0%), white solid.
TLC: R.sub.f=0.437 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=328.24 [M+H].sup.+; calculated: 328.18; t.sub.R1 (λ=220 nm): 1.23 min; t.sub.R2 (λ=220 nm): 1.26 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.67 (s, 1H, NCH), 6.78 (d, J=6.5 Hz, 1H, OH), 5.19 (d, J=6.3 Hz, 1H, OH), 5.14 (d, J=5.7 Hz, 1H, OH), 4.90 (dd, J=8.0 Hz, 1H, CH), 4.52 (dd, J=6.2 Hz, 1H, OH), 4.41 (dd, J=4.2 Hz, 1H, OH), 4.07 (m, 1H, CH), 3.76 (m, 2H, CH.sub.2), 3.56 (m, 2H, 2×CH), 3.20 (m, 1H, CH), 1.60 (m, 6H, CH.sub.2), 1.55 (m, 1H, CH), 1.21 (m, 4H, CH.sub.2), 0.93 (m, 2H, CH.sub.2) ppm.

EXAMPLE 65

(3R,4R,5S,6R)-6-(Hydroxymethyl)-3-(4-pentyltriazol-1-yl)tetrahydropyran-2,4,5-triol

[0379] ##STR00083##

[0380] Example 65 was synthesized from 2-azido-2-deoxyglucose and hept-1-yne following the CuAAC procedure described in synthesis method E.

Yield: 19 mg (63 μmol, 43.1%), white solid.
TLC: R.sub.f=0.405 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=302.22 [M+H].sup.+; calculated: 302.16; t.sub.R1 (λ=220 nm): 1.08 min; t.sub.R2 (λ=220 nm): 1.12 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ =7.73 (s, 1H, NCH), 6.81 (d, J=4.5 Hz, 1H, OH), 5.21 (d, J=5.7 Hz, 1H, OH), 5.16 (d, J=5.6 Hz, 1H, OH), 4.91 (dd, J=6.7 Hz, 1H, CH), 4.52 (dd, J=5.9 Hz, 1H, OH), 4.39 (dd, J=3.2 Hz, 1H, OH), 4.04 (m, 1H, CH), 3.71 (m, 2H, CH.sub.2), 3.52 (m, 2H, 2×CH), 3.20 (m, 1H, CH), 2.59 (m, 2H, CH.sub.2), 1.59 (m, 2H, CH.sub.2), 1.31 (m, 4H, CH.sub.2), 0.93 (m, 3H, CH.sub.3) ppm.

EXAMPLE 66

(3R,4R,5S,6R)-3-[4-(3-Chloropropyl)triazol-1-yl]-6-(hydroxymethyl)tetrahydropyran-2,4,5-triol

[0381] ##STR00084##

[0382] Example 66 was synthesized from 2-azido-2-deoxyglucose and 5-chloro-pent-1-yne following the CuAAC procedure described in synthesis method E.

Yield: 36 mg (117 μmol, 80.0%), white solid.
TLC: R.sub.f=0.286 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=308.21 [M+H].sup.+; calculated: 308.09; t.sub.R1 (λ=220 nm): 0.72 min; t.sub.R2 (λ=220 nm): 0.74 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d6): δ=7.75 (s, 1H, NCH), 6.32 (d, J=4.4 Hz, 1H, OH), 5.24 (d, J=5.6 Hz, 1H, OH), 4.91 (dd, J=4.1 Hz, 1H, CH), 4.79 (d, J=5.0 Hz, 1H, OH), 4.63 (dd, J=5.9 Hz, 1H, OH), 4.32 (dd, J=8.2 Hz, 1H, OH), 3.92 (m, 1H, CH), 3.68 (t, J=6.5 Hz, 2H, CH.sub.2), 3.43 (m, 3H, 3×CH), 3.10 (m, 1H, CH.sub.2), 2.91 (m, 1H, CH.sub.2), 2.00 (m, 4H, 2×CH.sub.2) ppm.

EXAMPLE 67

(3R,4R,5S,6R)-6-(Hydroxymethyl)-3-[4-[7-(4-nitro-2,1,3-benzoxadiazol-7-yl)heptyl]triazol-1-yl]tetrahydropyran-2,4,5-triol

[0383] ##STR00085##

Step 1: 4-nitro-N-oct-7-ynyl-2,1,3-benzoxadiazol-7-amine

[0384] ##STR00086##

[0385] To a solution of 300 mg (1.49 mmol) 4-chloro-7-nitrobenzofurazane in 4 mL dry dimethylformamide was added 216 mg (1.64 mmol) 7-octyn-1-amine and 527 μl (2.98 mmol) N,N-diisopropylethylamine. The reaction mixture was stirred at room temperature for 2 days and evaporated.

[0386] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 40 g; flow rate: 40 mL/min; wavelength for detection: 254 nm; eluent: (A) n-heptane, (B) ethylacetate.

MPLC Gradient

[0387]

TABLE-US-00037 start % B end % B duration [min] 0.0 0.0 1.6 0.0 27.7 16.6 27.7 79.8 19.9 79.8 0.0 0.0 0.0 0.0 2.9
Yield: 96 mg (0.333 mmol, 22.4%), orange solid.
TLC: R.sub.f=0.689 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=289.10 [M+H].sup.+; calculated: 289.30; t.sub.R (λ=220 nm): 1.25 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.53 (s, 1H, NH), 8.51 (d, J=8.8 Hz, 2H, ArH), 6.41 (d, J=8.9 Hz, 1H, OH), 5.23 (d, J=5.7 Hz, 1H, OH), 4.87 (dd, J=4.2 Hz, 1H, CH), 4.56 (d, J=6.7 Hz, 1H, OH), 4.63 (dd, J=5.9 Hz, 1H, OH), 4.32 (dd, J=8.2 Hz, 1H, OH), 3.71 (m, 2H, 2×CH), 3.45 (m, 3H, 3×CH), 3.31 (m, 1H, CH.sub.2), 3.20 (m, 1H, CH.sub.2), 2.59 (m, 2H, CH.sub.2), 1.65 (m, 6H, 3×CH.sub.2), 1.36 (m, 4H, 2×CH.sub.2) ppm.

Step 2: (3R,4R,5S,6R)-6-(hydroxymethyl)-3-[4-[7-(4-nitro-2,1,3-benzoxadiazol-7-yl)heptyl]triazol-1-yl]tetrahydropyran-2,4,5-triol

[0388] Example 67 was synthesized from 2-azido-2-deoxyglucose and example 67, step 1 following the CuAAC procedure described in synthesis method E.

Yield: 32 mg (64 μmol, 44.3%), orange solid.
TLC: R.sub.f=0.833 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=494.24 [M+H].sup.+; calculated: 494.19; t.sub.R1 (λ=220 nm): 1.33 min; t.sub.R2 (λ=220 nm): 1.35 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.53 (s, 1H, NH), 8.51 (d, J=8.8 Hz, 2H, ArH), 8.00 (s, 1H, NCH), 6.41 (d, J=8.9 Hz, 1H, OH), 5.23 (d, J=5.7 Hz, 1H, OH), 4.87 (dd, J=4.2 Hz, 1H, CH), 4.56 (d, J=6.7 Hz, 1H, OH), 4.63 (dd, J=5.9 Hz, 1H, OH), 4.32 (dd, J=8.2 Hz, 1H, OH), 3.71 (m, 2H, 2×CH), 3.45 (m, 3H, 3×CH), 3.31 (m, 1H, CH.sub.2), 3.20 (m, 1H, CH.sub.2), 2.59 (m, 2H, CH.sub.2), 1.65 (m, 6H, 3×CH.sub.2), 1.36 (m, 4H, 2×CH.sub.2) ppm.

EXAMPLE 68

5-(Dimethylamino)-N-[[1-[[(2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methyl]triazol-4-yl]methyl]naphthalene-1-sulfonamide

[0389] ##STR00087##

[0390] Example 68 was synthesized from 6-azido-6-deoxyglucose and example 54, step 1 following the CuAAC procedure described in synthesis method E.

Yield: 18 mg (36.47 μmol, 49.9%), white-yellow solid.
TLC: R.sub.f=0.045 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=494.25 [M+H].sup.+; calculated: 494.16; t.sub.R1 (λ=220 nm): 1.18 min; t.sub.R2 (λ=220 nm): 1.20 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.46 (d, J=8.4 Hz, 2H, ArH), 8.13 (d, J=7.0 Hz, 1H, ArH), 7.84 (s, 1H, NCH), 7.67 (s, 1H, SNH), 7.57 (m, 2H, ArH), 7.25 (d, J=7.2 Hz, 1H, ArH), 6.31 (d, J=6.4Hz, 1H, OH), 5.23 (d, J=6.3 Hz, 1H, OH), 4.92 (d, J=6.2 Hz, 1H, OH), 4.85 (dd, J=6.4 Hz, 1H, CH), 4.58 (d, J=6.0 Hz, 1H, OH), δ=4.21 (m, 1H, CH.sub.2), 4.07 (s, 2H, NCH.sub.2), 3.89 (m, 1H, CH.sub.2), 3.47 (m, 1H, CH), 3.14 (m, 1H, CH), 2.96 (m, 1H, CH), 2.81 (s, 6H, 2×NCH.sub.3) ppm.

EXAMPLE 69

(3R,4S,5S,6R)-6-[(4-Phenyltriazol-1-yl)methyl]tetrahydropyran-2,3,4,5-tetrol

[0391] ##STR00088##

[0392] Example 69 was synthesized from 6-azido-6-deoxyglucose and ethynylbenzene following the CuAAC procedure described in synthesis method E.

Yield: 36 mg (117 μmol, 80.1%), white solid.
TLC: R.sub.f=0.242 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=308.16 [M+H].sup.+; calculated: 308.12; t.sub.R1 (λ=220 nm): 0.90 min; t.sub.R2 (λ=220 nm): 0.97 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.49 (s, 1H, NCH), 7.86 (dd, J=1.3 Hz, 2H, ArH), 7.46 (m, 2H, ArH), 7.42 (m, 1H, ArH), 6.36 (d, J=6.0 Hz, 1H, OH), 5.31 (d, J=5.8 Hz, 1H, OH), 4.96 (t, J=5.7 Hz, 1H, CH), 4.90 (d, J=4.2 Hz, 1H, OH), 4.65 (d, J=6.1 Hz, 1H, OH), 4.41 (m, 2H, CH.sub.2), 3.99 (m, 1H, CH), 3.49 (m, 1H, CH), 3.22 (m, 1H, CH), 3.00 (m, 1H, CH) ppm.
.sup.13C-NMR (150 MHz, DMSO-d.sub.6): δ=146.03 (s, C), 130.84 (s, C), 128.85 (s, CH), 127.75 (s, CH), 125.09 (s, CH), 122.25 (s, CH), 92.35 (s, CH), 72.69 (s, CH), 72.07 (s, CH), 71.89 (s, CH), 69.97 (s, CH), 61.26 (s, CH.sub.2) ppm.

EXAMPLE 70

(3R,4S,5S,6R)-6-[[4-(p-Tolyl)triazol-1-yl]methyl]tetrahydropyran-2,3,4,5-tetrol

[0393] ##STR00089##

[0394] Example 70 was synthesized from 6-azido-6-deoxyglucose and 1-ethynyl-4-methyl-benzene following the CuAAC procedure described in synthesis method E.

Yield: 32 mg (100 μmol, 68.1%), white solid.
TLC: R.sub.f=0.250 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=322.19 [M+H].sup.+; calculated: 322.13; t.sub.R1 (λ=220 nm): 1.12 min; t.sub.R2 (λ=220 nm): 1.16 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.49 (s, 1H, NCH), 7.72 (d, J=8.0 Hz, 2H, ArH), 7.21 (d, J=8.0 Hz, 2H, ArH), 6.43 (d, J=4.4 Hz, 1H, OH), 5.30 (d, J=5.4 Hz, 1H, OH), 4.94 (d, J=5.4 Hz, 1H, OH), 4.90 (dd, J=4.2 Hz, 1H, CH), 4.58 (d, J=5.3 Hz, 1H, OH), 4.40 (m, 1H, CH.sub.2), 4.00 (m, 1H, CH.sub.2), 3.49 (m, 1H, CH), 3.17 (m, 1H, CH), 3.06 (m, 1H, CH), 2.94 (m, 1H, CH), 2.36 (s, 3H, CH.sub.3) ppm.

EXAMPLE 71

(3R,4S,5S,6R)-6-[[4-(3-Phenylpropyl)triazol-1-yl]methyl]tetrahydropyran-2,3,4,5-tetrol

[0395] ##STR00090##

[0396] Example 71 was synthesized from 6-azido-6-deoxyglucose and pent-4-yn-1-ylbenzene following the CuAAC procedure described in synthesis method E.

Yield: 43 mg (123 μmol, 84.2%), white solid.
TLC: R.sub.f=0.273 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=350.18 [M+H].sup.+; calculated: 350.16; t.sub.R1 (λ=220 nm): 1.29 min; t.sub.R2 (λ=220 nm): 1.35 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.72 (s, 1H, NCH), 7.25 (m, 2H, ArH), 7.20 (m, 3H, ArH), 6.31 (d, J=5.0 Hz, 1H, OH), 5.23 (d, J=5.6 Hz, 1H, OH), 4.89 (d, J=6.5 Hz, 1H, CH), 4.80 (d, J=5.0 Hz, 1H, OH), 4.55 (dd, J=5.5 Hz, 1H, OH), 4.31 (m, 1H, CH.sub.2), 3.93 (m, 1H, CH.sub.2), 3.49 (m, 2H, 2×CH), 3.11 (m, 1H, CH), 2.97 (m, 1H, CH), 2.63 (m, 4H, CH.sub.2), 1.90 (m, 2H, CH.sub.2) ppm.

EXAMPLE 72

Methyl-4-[1-[[(2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methyl]triazol-4-yl]-benzoate

[0397] ##STR00091##

[0398] Example 72 was synthesized from 6-azido-6-deoxyglucose and 4-ethynylmethylbenzoate following the CuAAC procedure described in synthesis method E.

Yield: 34 mg (93 μmol, 63.6%), white solid.
TLC: R.sub.f=0.258 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=366.23 [M+H].sup.+; calculated: 366.12; t.sub.R1 (λ=220 nm): 1.05 min; t.sub.R2 (λ=220 nm): 1.08 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.59 (s, 1H, NCH), 8.01 (m, 4H, ArH), 6.37 (d, J=5.0 Hz, 1H, OH), 5.31 (d, J=5.6 Hz, 1H, OH), 4.94 (d, J=4.8 Hz, 1H, OH), 4.89 (dd, J=4.3 Hz, 1H, CH), 4.61 (d, J=5.1 Hz, 1H, OH), 4.44 (m, 1H, CH.sub.2), 4.02 (m, 1H, CH.sub.2), 3.90 (s, 3H, OCH.sub.3), 3.51 (m, 1H, CH), 3.19 (m, 1H, CH), 3.08 (m, 1H, CH), 2.91 (m, 1H, CH) ppm.

EXAMPLE 73

(3R,4S,5S,6R)-6-[[4-[[Benzyl(methyl)amino]methyl]triazol-1-yl]methyl]tetrahydropyran-2,3,4,5-tetrol

[0399] ##STR00092##

[0400] Example 73 was synthesized from 6-azido-6-deoxyglucose and N-benzyl-N-methylprop-2-yn-1-amine following the CuAAC procedure described in synthesis method E.

Yield: 36 mg (99 μmol, 67.6%), white solid.
TLC: R.sub.f=0.053 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=365.20 [M+H].sup.+; calculated: 365.18; t.sub.R (ELSD): 0.37 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.85 (s, 1H, NCH), 7.31 (m, 5H, ArH), 6.33 (d, J=6.1 Hz, 1H, OH), 5.24 (d, J=5.8 Hz, 1H, OH), 4.90 (d, J=5.6 Hz, 1H, OH), 4.87 (dd, J=6.0 Hz, 1H, CH), 4.58 (d, J=5.0 Hz, 1H, OH), 4.41 (m, 1H, CH.sub.2), 3.97 (m, 1H, CH.sub.2), 3.62 (s, 3H, NCH.sub.3), 3.50 (m, 2H, 2×CH), 3.15 (m, 1H, CH), 2.96 (m, 1H, CH), 2.10 (m, 4H, 2×NCH.sub.2) ppm.

EXAMPLE 74

(3R,4S,5S,6R)-6-[[4-(6-Methoxy-2-naphthyl)triazol-1-yl]methyl]tetrahydropyran-2,3,4,5-tetrol

[0401] ##STR00093##

[0402] Example 74 was synthesized from 6-azido-6-deoxyglucose and 2-ethynyl-6-methoxynaphthalene following the CuAAC procedure described in synthesis method E.

Yield: 43 mg (111 μmol, 75.9%), white solid.
TLC: R.sub.f=0.288 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=388.20 [M+H].sup.+; calculated: 388.14; t.sub.R1 (λ=220 nm): 1.30 min; t.sub.R2 (λ=220 nm): 1.33 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.51 (s, 1H, NCH), 7.86 (m, 4H, ArH), 7.34 (s, 2H, ArH), 6.39 (d, J=5.8 Hz, 1H, OH), 5.41 (d, J=6.1 Hz, 1H, OH), 4.94 (d, J=6.0 Hz, 1H, OH), 4.90 (dd, J=6.3 Hz, 1H, CH), 4.58 (d, J=5.2 Hz, 1H, OH), 4.42 (m, 1H, CH.sub.2), 4.01 (m, 1H, CH.sub.2), 3.90 (s, 3H, OCH.sub.3), 3.51 (m, 1H, CH), 3.19 (m, 1H, CH), 3.06 (m, 1H, CH), 2.97 (m, 1H, CH) ppm.

EXAMPLE 75

(3R,4S,5S,6R)-6-[[4-[[(4-Nitro-2,1,3-benzoxadiazol-7-yl)amino]methyl]triazol-1-yl]methyl]tetrahydropyran-2,3,4,5-tetrol

[0403] ##STR00094##

[0404] Example 75 was synthesized from 6-azido-6-deoxyglucose and example 63, step 1 following the CuAAC procedure described in synthesis method E.

Yield: 56 mg (132 μmol, 90.5%), orange solid.
TLC: R.sub.f=0.121 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=424.16 [M+H].sup.+; calculated: 424.11; t.sub.R1 (λ=220 nm): 0.83 min; t.sub.R2 (λ=220 nm): 0.87 min (LC/MS-Method 1).

[0405] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.85 (s, 1H, NH) 8.53 (d, J=8.4 Hz, 1H, ArH), 8.01 (s, 1H, NCH), 6.51 (d, J=8.4 Hz, 1H, ArH), 6.33 (d, J=6.0 Hz, 1H, OH), 5.24 (d, J=6.1 Hz, 1H, OH), 4.94 (d, J=6.2 Hz, 1H, OH), 4.86 (dd, J=5.8 Hz, 1H, CH), 4.65 (s, 2H, NCH.sub.2), 4.57 (dd, J=6.0 Hz, 1H, OH), 4.37 (m, 1H, CH.sub.2), 3.91 (m, 1H, CH.sub.2), 3.49 (m, 1H, CH), 3.14 (m, 1H, CH), 2.95 (m, 1H, CH) ppm.

EXAMPLE 76

(3R,4S,5S,6R)-6-[[4-(Cyclohexylmethyl)triazol-1-yl]methyl]tetrahydropyran-2,3,4,5-tetrol

[0406] ##STR00095##

[0407] Example 76 was synthesized from 6-azido-6-deoxyglucose and prop-2-yn-1-ylcyclohexane following the CuAAC procedure described in synthesis method E.

Yield: 33 mg (101 μmol, 68.9%), white-yellow solid.
TLC: R.sub.f=0.220 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=328.24 [M+H].sup.+; calculated: 328.18; t.sub.R1 (λ=220 nm): 1.23 min; t.sub.R2 (λ=220 nm): 1.29 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.68 (s, 1H, NCH), 6.33 (d, J=5.0 Hz, 1H, OH), 5.22 (d, J=5.5 Hz, 1H, OH), 4.87 (dd, J=4.3 Hz, 1H, CH), 4.78 (d, J=5.0 Hz, 1H, OH), 4.59 (dd, J=2.3 Hz, 1H, OH), 4.55 (d, J=6.7 Hz, 1H, OH), 4.36 (m, 1H, CH.sub.2), 3.92 (m, 1H, CH.sub.2), 3.44 (m, 1H, CH), 3.12 (m, 1H, CH), 2.90 (m, 1H, CH), 2.49 (m, 2H, CH.sub.2), 1.64 (m, 6H, 3×CH.sub.2), 1.53(m, 1H, CH), 1.17 (m, 4H, 2×CH.sub.2), 0.95 (m, 2H, CH.sub.2) ppm.

EXAMPLE 77

(3R,4S,5S,6R)-6-[(4-Pentyltriazol-1-yl)methyl]tetrahydropyran-2,3,4,5-tetrol

[0408] ##STR00096##

[0409] Example 77 was synthesized from 6-azido-6-deoxyglucose and hept-1-yne following the CuAAC procedure described in synthesis method E.

Yield: 7 mg (23 μmol, 15.9%), white-yellow solid.
TLC: R.sub.f=0.235 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=302.25 [M+H].sup.+; calculated: 302.16; t.sub.R1 (λ=220 nm): 1.12 min; t.sub.R2 (λ=220 nm): 1.17 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): ϵ=7.70 (s, 1H, NCH), 6.33 (d, J=4.8 Hz, 1H, OH), 5.23 (d, J=5.7 Hz, 1H, OH), 4.87 (dd, J=4.0 Hz, 1H, CH), 4.78 (d, J=4.9 Hz, 1H, OH), 4.60 (dd, J=2.3 Hz, 1H, OH), 4.55 (d, J=6.6 Hz, 1H, OH), 4.31 (m, 1H, CH.sub.2), 3.92 (m, 1H, CH.sub.2), 3.52 (m, 1H, CH), 3.12 (m, 1H, CH), 2.94 (m, 1H, CH), 2.58 (t, J=7.5 Hz, 2H, CH.sub.2), 1.58 (m, 2H, CH.sub.2), 1.30 (m, 4H, CH.sub.2), 0.87 (m, 3H, CH.sub.3) ppm.

EXAMPLE 78

(3R,4S,5S,6R)-6-[[4-(3-Chloropropyl)triazol-1-yl]methyl]tetrahydropyran-2,3,4,5-tetrol

[0410] ##STR00097##

[0411] Example 78 was synthesized from 6-azido-6-deoxyglucose and 5-chloro-pent-1-yne following the CuAAC procedure described in synthesis method E.

Yield: 24 mg (78 μmol, 53.3%), white-yellow solid.
TLC: R.sub.f=0.182 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=308.17 [M+H].sup.+; calculated: 308.09; t.sub.R1 (λ=220 nm): 0.70 min; t.sub.R2 (λ=220 nm): 0.72 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.78 (s, 1H, NCH), 6.33 (d, J=5.0 Hz, 1H, OH), 5.24 (d, J=5.7 Hz, 1H, OH), 4.89 (dd, J=4.9 Hz, 1H, CH), 4.79 (d, J=5.3 Hz, 1H, OH), 4.61 (dd, J=2.2 Hz, 1H, OH), 4.55 (d, J=6.6 Hz, 1H, OH), 4.34 (m, 1H, CH.sub.2), 3.93 (m, 1H, CH.sub.2), 3.68 (t, J=6.6 Hz, 2H, CH.sub.2), 3.44 (m, 2H, 2×CH), 3.15 (m, 1H, CH), 2.91 (m, 1H, CH), 2.07 (m, 4H, 2×CH.sub.2) ppm.

EXAMPLE 79

(3R,4S,5S,6R)-6-[[4-[6-[(4-Nitro-2,1,3-benzoxadiazol-7-yl)amino]hexyl]triazol-1-yl]methyl]tetrahydropyran-2,3,4,5-tetrol

[0412] ##STR00098##

[0413] Example 79 was synthesized from 6-azido-6-deoxyglucose and example 67, step 1 following the CuAAC procedure described in synthesis method E.

Yield: 20 mg (40.53 μmol, 55.4%), orange oil.
TLC: R.sub.f=0.222 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=494.23 [M+H].sup.+; calculated: 494.19; t.sub.R1 (λ=220 nm): 1.33 min; t.sub.R2 (λ=220 nm): 1.35 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.50 (s, 1H, NH), 8.49 (d, J=8.8 Hz, 2H, ArH), 769 (s, 1H, NCH), 6.41 (d, J=5.9 Hz, 1H, OH), 5.23 (d, J=5.7 Hz, 1H, OH), 4.91 (d, J=6.7 Hz, 1H, OH), 4.87 (dd, J=4.0 Hz, 1H, CH), 4.63 (dd, J=5.9 Hz, 1H, OH), 4.56 (d, J=6.2 Hz, 1H, OH), 4.30 (m, 1H, CH.sub.2), 3.91 (m, 1H, CH.sub.2), 3.49 (m, 2H, 2×CH), 3.17 (m, 1H, CH), 2.94 (m, 1H, CH), 2.58 (m, 2H, CH.sub.2), 1.65 (m, 4H, 2×CH.sub.2), 1.40 (m, 6H, 3×CH.sub.2) ppm.

EXAMPLE 80

5-(Dimethylamino)-N-[[1-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]triazol-4-yl]methyl]naphthalene-1-sulfonamide

[0414] ##STR00099##

[0415] Example 80 was synthesized from 1-azido-1-deoxyglucose and example 54, step 1 following the CuAAC procedure described in synthesis method E.

Yield: 46 mg (94 μmol, 63.7%), white-yellow solid.
TLC: R.sub.f=0.129 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=494.26 [M+H].sup.+; calculated: 494.16; t.sub.R (λ=220 nm): 1.20 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.48 (d, J=8.4 Hz, 1H, ArH), 8.32 (d, J=8.6 Hz, 1H, ArH), 8.14 (dd, J=1.1 Hz, 1H, ArH), 8.02 (s, 1H, NCH), 7.62 (m, 2H, ArH), 7.27 (d, J=7.6 Hz, 1H, ArH), 5.49 (d, J=9.2 Hz, 1H, OH), 5.31 (d, J=6.2 Hz, 1H, OH), 5.23 (d, J=4.9 Hz, 1H, OH), 5.13 (d, J=5.4 Hz, 1H, CH), 4.62 (dd, J=5.4 Hz, 1H, OH), 4.08 (d, J=5.1 Hz, 1H, NCH.sub.2), 3.68 (m, 2H, CH.sub.2), 3.43 (m, 2H, 2×CH), 3.19 (m, 1H, CH), 2.84 (s, 6H, 2×NCH.sub.3) ppm.

EXAMPLE 81

(2R,3S,4S,5R,6R)-2-(Hydroxymethyl)-6-(4-phenyltriazol-1-yl)tetrahydropyran-3,4,5-triol

[0416] ##STR00100##

[0417] Example 81 was synthesized from 1-azido-1-deoxyglucose and ethynylbenzene following the CuAAC procedure described in synthesis method E.

Yield: 40 mg (130 μmol, 89.0%), white solid.
TLC: R.sub.f=0.295 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=308.14 [M+H].sup.+; calculated: 308.12; t.sub.R (λ=220 nm): 0.92 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.81 (s, 1H, NCH), 7.88 (d, J=8.0 Hz, 2H, ArH), 7.46 (t, J=7.5 Hz, 2H, ArH), 7.34 (d, J=7.5 Hz, 1H, ArH), 5.57 (d, J=9.2 Hz, 1H, CH), 5.42 (d, J=5.8 Hz, 1H, OH), 5.31 (d, J=4.9 Hz, 1H, OH), 5.16 (d, J=5.5 Hz, 1H, OH), 4.62 (dd, J=5.6 Hz, 1H, OH), 3.81 (m, 1H, CH.sub.2), 3.73 (m, 1H, CH.sub.2), 3.49 (m, 2H, 2×CH), 3.17 (m, 1H, CH) ppm.
.sup.13C-NMR (150 MHz, DMSO-d.sub.6): δ=146.31 (s, C), 130.62 (s, C), 128.91 (s, CH), 127.92 (s, CH), 125.15 (s, CH), 120.47 (s, CH), 87.68 (s, CH), 79.95 (s, CH), 76.85 (s, CH), 72.19 (s, CH), 69.60 (s, CH), 60.76 (s, CH.sub.2) ppm.

EXAMPLE 82

(2R,3S,4S,5R,6R)-2-(Hydroxymethyl)-6-[4-(p-tolyl)triazol-1-yl]petrahydropyran-3,4,5-triol

[0418] ##STR00101##

[0419] Example 82 was synthesized from 1-azido-1-deoxyglucose and 1-ethynyl-4-methylbenzene following the CuAAC procedure described in synthesis method E.

Yield: 39 mg (121 μmol, 83.0%), white solid.
TLC: R.sub.f=0.326 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=322.20 [M+H].sup.+; calculated: 322.13; t.sub.R (λ=220 nm): 1.14 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.76 (s, 1H, NCH), 7.77 (d, J=8.3 Hz, 2H, ArH), 7.27 (d, J=8.3 Hz, 2H, ArH), 5.55 (d, J=9.1 Hz, 1H, OH), 5.41 (d, J=5.9 Hz, 1H, OH), 5.30 (d, J=5.1 Hz, 1H, OH), 5.15 (d, J=5.5 Hz, 1H, CH), 4.61 (dd, J=5.5 Hz, 1H, OH), 3.80 (m, 1H, CH.sub.2), 3.72 (m, 1H, CH.sub.2), 3.45 (m, 2H, 2×CH), 3.26 (m, 1H, CH), 2.34 (s, 3H, CH.sub.3) ppm.

EXAMPLE 83

(2R,3S,4S,5R,6R)-2-(Hydroxymethyl)-6-[4-(3-phenylpropyl)triazol-1-yl]tetrahydropyran-3,4,5-triol

[0420] ##STR00102##

[0421] Example 83 was synthesized from 1-azido-1-deoxyglucose and pent-4yn-1ylbenzene following the CuAAC procedure described in synthesis method E.

Yield: 50 mg (143 μmol, 97.9%), white solid.
TLC: R.sub.f=0.356 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=350.21 [M+H].sup.+; calculated: 350.16; t.sub.R (λ=220 nm): 1.27 min (LC/MS-Method 1).

[0422] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.07 (s, 1H, NCH), 7.25 (m, 5H, ArH), 5.46 (d, J=9.2 Hz, 1H, OH), 5.31 (d, J=5.9 Hz, 1H, OH), 5.24 (d, J=5.0 Hz, 1H, OH), 5.12 (d, J=5.5 Hz, 1H, CH), 4.59 (dd, J=5.0 Hz, 1H, OH), 3.72 (m, 2H, CH.sub.2), 3.42 (m, 2H, 2×CH), 3.21 (m, 1H, CH), 2.63 (m, 4H, 2×CH.sub.2), 1.90 (m, 2H, CH.sub.2) ppm.

EXAMPLE 84

Methyl-4-[1-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]triazol-4-yl]benzoate

[0423] ##STR00103##

[0424] Example 84 was synthesized from 1-azido-1-deoxyglucose and 4-ethynylmethylbenzoate following the CuAAC procedure described in synthesis method E.

Yield: 44 mg (120 μmol, 82.4%), white solid.
TLC: R.sub.f=0.062 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=366.12 [M+H].sup.+; calculated: 366.12; t.sub.R1 (λ=220 nm): 0.97 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.00 (s, 1H, NCH), 8.05 (s, 4H, ArH), 5.60 (d, J=9.3 Hz, 1H, OH), 5.44 (d, J=5.9 Hz, 1H, OH), 5.32 (d, J=4.8 Hz, 1H, OH), 5.17 (d, J=5.5 Hz, 1H, CH), 4.62 (dd, J=5.8 Hz, 1H, OH), 3.87 (s, 3H, OCH.sub.3), 3.87 (m, 1H, CH.sub.2), 3.80 (m, 1H, CH.sub.2), 3.49 (m, 1H, CH), 3.43 (m, 1H, CH), 3.27 (m, 1H, CH) ppm.

EXAMPLE 85

(2R,3R,4S,5S,6R)-2-[4-[[Benzyl(methyl)amino]methyl]triazol-1-yl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

[0425] ##STR00104##

[0426] Example 85 was synthesized from 1-azido-1-deoxyglucose and N-benzyl-N-methylprop-2-yn-1-amine following the CuAAC procedure described in synthesis method E.

Yield: 51 mg (140 μmol, 95.7%), white solid.
TLC: R.sub.f=0.091 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=365.20 [M+H].sup.+; calculated: 365.17; t.sub.R (ELSD): 0.34 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.19 (s, 1H, NCH), 7.33 (m, 4H, ArH), 7.25 (m, 1H, ArH), 5.50 (d, J=9.4 Hz, 1H, OH), 5.34 (d, J=6.1 Hz, 1H, OH), 5.24 (d, J=5.0 Hz, 1H, OH), 5.12 (d, J=5.7 Hz, 1H, CH), 4.60 (dd, J=5.6 Hz, 1H, OH), 3.77 (m, 1H, CH.sub.2), 3.70 (m, 1H, CH.sub.2), 3.62 (s, 2H, NCH.sub.2), 3.52 (s, 2H, NCH.sub.2), 3.43 (m, 1H, CH), 3.38 (m, 1H, CH), 3.24 (m, 1H, CH) 2.11 (s, 3H, NCH.sub.3) ppm.

EXAMPLE 86

(2R,3S,4S,5R,6R)-2-(Hydroxymethyl)-6-[4-(6-methoxy-2-naphthyl)triazol-1-yl]tetrahydropyran-3,4,5-triol

[0427] ##STR00105##

[0428] Example 86 was synthesized from 1-azido-1-deoxyglucose and 2-ethynyl-6-methoxynaphthalene following the CuAAC procedure described in synthesis method E.

Yield: 42 mg (108 μmol, 74.1%), white solid.
TLC: R.sub.f=0.318 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=388.10 [M+H].sup.+; calculated: 388.14; t.sub.R (λ=220 nm): 0.95 min (LC/MS-Method 1).

[0429] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.51 (s, 1H, NCH), 7.86 (m, 4H, ArH), 7.34 (s, 2H, ArH), 6.39 (d, J=5.8 Hz, 1H, OH), 5.41 (d, J=6.1 Hz, 1H, OH), 4.94 (d, J=6.0 Hz, 1H, OH), 4.90 (dd, J=6.3 Hz, 1H, CH), 4.58 (d, J=5.2 Hz, 1H, OH), 4.42 (m, 1H, CH.sub.2), 4.01 (m, 1H, CH.sub.2), 3.90 (s, 3H, OCH.sub.3), 3.51 (m, 1H, CH), 3.19 (m, 1H, CH), 3.06 (m, 1H, CH), 2.97 (m, 1H, CH) ppm.

EXAMPLE 87

Ethyl-2-diethoxyphosphoryl-3-[1-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-pyran-2-yl]triazol-4-yl]propanoate

[0430] ##STR00106##

[0431] Example 87 was synthesized from 1-azido-1-deoxyglucose and 2-(diethoxyphosphoryl)ethylpent-4-ynoate following the CuAAC procedure described in synthesis method E.

Yield: 48 mg (103 μmol, 70.2%), white solid.
TLC: R.sub.f=0.258 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=468.26 [M+H].sup.+; calculated: 468.17; t.sub.R (λ=220 nm): 1.04 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.05 (s, 1H, NCH), 5.46 (d, J=9.1 Hz, 1H, OH), 5.30 (d, J=6.3 Hz, 1H, OH), 5.24 (d, J=4.7 Hz, 1H, OH), 5.12 (d, J=5.5 Hz, 1H, CH), 4.59 (dd, J=5.3 Hz, 1H, OH), 4.08 (m, 2H, CH.sub.2), 3.70 (m, 2H, CH.sub.2), 3.43 (m, 4H, 4×CH), 3.00 (m, 1H, CH), 1.25 (m, 6H, 3×CH.sub.2), 1.13 (s, 9H, 3×CH.sub.3) ppm.

EXAMPLE 88

(2R,3S,4S,5R,6R)-2-(Hydroxymethyl)-6-[4-[[(4-nitro-2,1,3-benzoxadiazol-7-yl)amino]methy]triazol-1-yl]petrahydropyran-3,4,5-triol

[0432] ##STR00107##

[0433] Example 88 was synthesized from 1-azido-1-deoxyglucose and example 63, step 1 following the CuAAC procedure described in synthesis method E.

Yield: 58 mg (138 μmol, 93.7%).
TLC: R.sub.f=0.152 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=424.13 [M+H].sup.+; calculated: 424.16; t.sub.R1 (λ=220 nm): 0.84 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.87 (s, 1H, NH), 8.51 (d, J=8.9 Hz, 1H, ArH), 8.35 (s, 1H, NCH), 6.55 (d, J=8.9 Hz, 1H, ArH), 5.50 (d, J=9.3 Hz, 1H, OH), 5.32 (d, J=6.0 Hz, 1H, OH), 5.25 (d, J=4.9 Hz, 1H, OH), 5.12 (d, J=5.5 Hz, 1H, CH), 4.80 (s, 2H, NCH.sub.2), 4.60 (dd, J=5.5 Hz, 1H, OH), 3.70 (m, 2H, CH.sub.2), 3.43 (m, 2H, 2×CH), 3.19 (m, 1H, CH) ppm.

EXAMPLE 89

(2R,3R,4S,5S,6R)-2-[4-(Cyclohexylmethyl)triazol-1-yl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

[0434] ##STR00108##

[0435] Example 89 was synthesized from 1-azido-1-deoxyglucose and prop-2-yn-1-ylcyclohexane following the CuAAC procedure described in synthesis method E.

Yield: 35 mg (107 μmol, 73.1%), white solid.
TLC: R.sub.f=0.258 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=328.26 [M+H].sup.+; calculated: 328.18; t.sub.R (λ=220 nm): 1.27 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.99 (s, 1H, NCH), 5.45 (d, J=9.3 Hz, 1H, OH), 5.30 (d, J=6.0 Hz, 1H, OH), 5.23 (d, J=5.0 Hz, 1H, OH), 5.11 (d, J=5.3 Hz, 1H, CH), 4.59 (dd, J=5.5 Hz, 1H, OH), 3.71 (m, 2H, CH.sub.2), 3.42 (m, 2H, 2×CH), 3.22 (m, 2H, 2×CH), 1.66 (m, 6H, 3×CH.sub.2), 1.54 (m, 1H, CH), 1.17 (m, 4H, 2×CH.sub.2), 0.95 (m, 2H, CH.sub.2) ppm.

EXAMPLE 90

(2R,3R,4S,5S,6R)-2[4-(3-Chloropropyl)triazol-1-yl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

[0436] ##STR00109##

[0437] Example 90 was synthesized from 1-azido-1-deoxyglucose and 5-chloro-pent-1-yne following the CuAAC procedure described in synthesis method E.

Yield: 17 mg (55 μmol, 37.8%), white solid.
TLC: R.sub.f=0.288 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=308.12 [M+H].sup.+; calculated: 308.09; t.sub.R1 (λ=220 nm): 0.62 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.09 (s, 1H, NCH), 5.46 (d, J=9.1 Hz, 1H, OH), 5.31 (d, J=6.0 Hz, 1H, OH), 5.25 (d, J=4.7 Hz, 1H, OH), 5.12 (d, J=5.8 Hz, 1H, CH), 4.60 (dd, J=5.2 Hz, 1H, OH), 3.74 (m, 2H, CH.sub.2), 3.70 (m, 2H, CH.sub.2), 3.39 (m, 2H, 2×CH), 3.22 (m, 2H, 2×CH), 2.77 (m, 2H, CH.sub.2), 2.06 (m, 2H, CH.sub.2) ppm.

EXAMPLE 91

[6-(Diethylamino)-9-[2-[[1-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]triazol-4-yl]methylcarbamoyl]phenyl]xanthen-3-ylidene]diethyl-ammonium chloride

[0438] ##STR00110##

Step 1: [6-(diethylamino)-9-[2-(prop-2-ynylcarbamoyl)phenyl]xanthen-3-ylidene]-diethyl-ammonium chloride

[0439] ##STR00111##

[0440] To a solution of 500 mg (244 μmol) Rhodamin B in 5 mL dimethylformamide were added 78 mg (1.39 mmol; 1.4 eq.) propargylamine, 554 mg (1.98 mmol; 2 eq.) 2-bromo-1-ethylpyridinium tetrafluoroborate, and 348 μl (1.98 mmol; 2 eq.) N,N-diisopropylethylamine. The reaction mixture was stirred at room temperature for 4 hours and evaporated.

[0441] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 24 g Gold; flow rate: 40 mL/min; wavelength for detection: 254 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0442]

TABLE-US-00038 start % B end % B duration [min] 0.0 0.0 5.0 0.0 100.0 45.0
Yield: 223 mg (0.432 mmol, 43.6%), light pink solid.
TLC: R.sub.f=0.622 (dichloromethane/ethanol, 19:1).
LC/MS (ES-API): m/z=480.28 [M+H].sup.+; calculated: 480.27; t.sub.R (λ=220 nm): 2.08 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.80 (m, 1H, ArH), 7.51 (m, 1H, ArH), 7.03 (m, 1H, ArH), 6.35 (m, 6H, ArH), 3.79 (d, J=6.9 Hz, 2H, NCH.sub.2), 3.31 (m, 8H, H), 2.65 (m, 8H, CH.sub.2), 1.08 (t, J=6.9 Hz, 12H, CH.sub.3) ppm.

Step 2: [6-(diethylamino)-9-[2-[[1-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]triazol-4-yl]methylcarbamoyl]phenyl]xanthen-3-ylidene]-diethyl-ammonium chloride

[0443] Example 91 was synthesized from 1-azido-1-deoxyglucose and example 91, step 1 following the CuAAC procedure described in synthesis method E.

Yield: 33 mg (67 μmol, 46.7%), white-yellow solid.
TLC: R.sub.f=0.485 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=686.38 [M+H].sup.+; calculated: 686.33; t.sub.R (λ=220 nm): 1.67 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.09 (s, 1H, NCH), 7.82 (m, 1H, ArH), 7.51 (m, 1H, ArH), 7.08 (m, 1H, ArH), 6.33 (m, 6H, ArH), 5.40 (d, J=9.1 Hz, 1H, OH), 5.24 (d, J=6.0 Hz, 1H, OH), 5.19 (d, J=4.7 Hz, 1H, OH), 5.08 (d, J=5.6 Hz, 1H, CH), 4.63 (dd, J=5.0 Hz, 1H, OH), 3.82 (d, J=6.9 Hz, 2H, NCH.sub.2), 3.77 (m, 2H, CH.sub.2), 3.69 (m, 2H, CH.sub.2), 3.42 (m, 2H, 2×CH), 3.29 (m, 8H, H), 3.18 (m, 2H, 2×CH), 2.73 (m, 2H, CH.sub.2), 2.60 (m, 8H, CH.sub.2), 2.03 (m, 2H, CH.sub.2), 1.05 (t, J=6.9 Hz, 12H, CH.sub.3) ppm.

EXAMPLE 92

(2R,3S,4S,5R,6R)-2-(Hydroxymethyl)-6-[4-[6-[(4-nitro-2,1,3-benzoxadiazol-7-yl)amino]hexyl]triazol-1-yl]tetrahydropyran-3,4,5-triol

[0444] ##STR00112##

[0445] Example 92 was synthesized from 1-azido-1-deoxyglucose and example 67, step 1 following the CuAAC procedure described in synthesis method E.

Yield: 24 mg (48 μmol, 66.6%), orange solid.
TLC: R.sub.f=0.310 (dichloromethane/ethanol, 4:1).
LC/MS (ES-API): m/z=494.25 [M+H].sup.+; calculated: 494.19; t.sub.R (λ=220 nm): 1.34 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): 67 =8.48 (d, J=8.6 Hz, 1H, ArH), 8.00 (s, 1H, NCH), 8.14 (d, J=8.6 Hz, 1H, ArH), 5.45 (d, J=9.3 Hz, 1H, OH), 5.29 (d, J=6.1 Hz, 1H, OH), 5.24 (d, J=4.9 Hz, 1H, OH), 5.11 (d, J=5.6 Hz, 1H, CH), 4.58 (dd, J=5.5 Hz, 1H, OH), 3.93 (s, 1H, NCH.sub.2), 3.72 (m, 2H, CH.sub.2), 3.41 (m, 3H, 3×CH), 3.20 (m, 1H, CH), 1.66 (m, 6H, 3×CH.sub.2), 1.41 (m, 4H, 2×CH.sub.2) ppm.

EXAMPLE 93

[(2S,3R,4S,6S)-2,3-Diacetoxy-6-(4-phenylpiperazine-1-carbonyl)tetrahydropyran-4-yl]acetate

[0446] ##STR00113##

[0447] A suspension of 7 mg (0.1 eq.) Pd/C (10%) in 3 mL dry methanol (argon atmosphere) was overlayed with hydrogen and stirred at room temperature for 30 minutes. A solution of 30 mg example 41, step 1 in 2 mL dry methanol was added. The reaction mixture was stirred at room temperature for 3 hours and filtered over celite.

[0448] Purification: MPLC CombiFlash Rf (Teledyne ISCO); column: RediSep Silica 4 g; flow rate: 12 mL/min; wavelength for detection: 220 nm; eluent: (A) dichloromethane, (B) ethanol.

MPLC Gradient

[0449]

TABLE-US-00039 start % B end % B duration [min] 0 0 4.0 0 5.0 3.0 5.0 5.0 10.0
Yield: 19 mg (42.37 μmol, 63.0%), orange oil.
LC/MS (ES-API): m/z=449.10 [M+H].sup.+; calculated: 449.18; t.sub.R (λ=220 nm): 0.79 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, CDCl.sub.3): δ=7.28 (m, 2H, ArH), 6.92 (m, 3H, ArH), 5.55 (d, J=7.9 Hz, 1H, CH), 5.13 (d, J=5.2 Hz, 1H, CH), 5.08 (d, J=7.7 Hz, 1H, CH), 4.36 (dd, J=1.7 Hz, J=11.6 Hz 1H, CH), 3.99 (m, 1H, NCH.sub.2), 3.82 (m, 1H, NCH.sub.2), 3.54 (m, 2H, NCH.sub.2), 3.28 (m, 2H, NCH.sub.2), 3.03 (m, 2H, NCH.sub.2), 2.32 (ddd, J=2.4 Hz, 1H, CH.sub.2), 2.17 (pseudo-q, J=11.6 Hz, 1H, CH.sub.2), 2.11 (s, 3H, CH.sub.3), 2.06 (s, 6H, 2×CH.sub.3) ppm.

EXAMPLE 94

(4-Phenylpiperazin-1-yl)-[(2S,4S,5R)-4,5,6-tri hydroxytetrahydropyran-2-yl]methanone

[0450] ##STR00114##

[0451] To a solution of 10 mg example 93 in 1 mL methanol 4 μl of a 5.4 M aqueous sodium methoxide solution were added. The reaction mixture was agitated at room temperature for 10 minutes and controlled by TLC and LC/MS. The reaction mixture was quenched and evaporated

Yield: 4 mg (12.41 μmol, 55.6%), orange oil.
LC/MS (ES-API): m/z=323.05 [M+H].sup.+; calculated: 323.15; t.sub.R (ELSD): 0.11 min (LC/MS-Method 1).
.sup.1H-NMR (400 MHz, MeOD): δ =7.14 (t, J=8.0 Hz, 2H, ArH), 6.88 (d, J=8.0 Hz, 2H, ArH), 6.76 (t, J=7.0 Hz, 1H, ArH), 5.12 (d, J=3.6 Hz, 1H, OH), 4.78 (dd, J=2.0 Hz, 1H, OH), 4.42 (d, J=7.6 Hz, 1H, OH), 4.33 (dd, J=2.0 Hz, 1H, OH), 3.6-4.0 (m, 4H, 4×CH), 3.4-3.0 (m, 8H, 4×NCH.sub.2), 1.94 (dd, J=4.7 Hz, 1H, CH.sub.2), 1.91 (qi, J=12.2 Hz, 1H, CH.sub.2) ppm.

EXAMPLE 95

1-[[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-Tetramethyl-5,5a,8a,8b-tetrahydro-3aH-di[1,3]dioxolo[4,5-a:4′,5′-c]pyran-5-yl]methyl]-4-(4-benzyloxyphenyl)piperazine

[0452] ##STR00115##

[0453] To a solution of (3aR,5S,5aR,8aS,8bR)-2,2,7,7-tetramethyl-5,5a,8a,8b-tetrahydro-3aH-di[1,3]dioxolo[4,5-a:4′,5′-c]pyran-5-carbaldehyde (300 mg, 1.16 mmol, 1 eq.), 1-(4-(benzyloxy)phenyl)piperazine (374mg, 1.39 mmol, 1.2 eq.), and acetic acid (132 μl, 2.32 mmol, 2 eq.) in methanol was added sodium boronhydride (147 mg, 2.32 mmol, 2 eq.). The reaction mixture was agitated overnight at room temperature and evaporated. The residue was separated between ethylacetate and a saturated solution of NaHCO.sub.3. The aqueous phase was extracted twice with ethylacetate. The organic phase was dried with MgSO.sub.4, evaporated in vacuo, and purified by flash chromatography on silica gel (100% heptane till 100% ethylacetate in 40 minutes).

Yield: 394 mg (771 μmol,66%), oil.
LC/MS (ES-API): m/z=511.2 [M+H].sup.+; calculated: 511.6 ; t.sub.R (λ=220 nm): 0.77 min (LC/MS-Method 2).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.44-7.28 (m, 5H), 6.86 (s, 4H), 5.45 (d, 1H, J=5.1 Hz), 5.01 (s, 2H), 4.57 (dd, 1H, J=7.9, 2.2 Hz), 4.31 (dd, 1H, J=5.1, 2.34 Hz), 4.21 (dd, 1H, J=7.9, 1.6 Hz), 2.98 (t, 4H, J=4.9 Hz), 2.65-2.57 (m, 3H), 2.42 (dd, 1H, J=12.7, 7.0 Hz), 1.45 (m, 3H), 1.35 (m, 1H), 1.28 (m, 1H) ppm.

EXAMPLE 96

(3R,4S,5R,6R)-6-[[4-(4-Benzyloxyphenyl)piperazin-1-yl]methyl]tetrahydropyran-2,3,4,5-tetrol

[0454] ##STR00116##

Method F

[0455] A solution of isopropylidene compounds (1 eq.) in trifluoroacetic acid/water (4/1, v/v) was agitated at room temperature for 2 hours, evaporated under vacuo, and lyophilised.

[0456] Example 96 was obtained from example 95 following the isopropylidene deprotection described in synthesis method F.

Yield: 21 mg (38.4 μmol, quant.).
LC/MS (ES-API): m/z=431.1 [M+H].sup.+; calculated: 431.2 ; t.sub.R (λ=220 nm): 0.620 min (LC/MS-Method 2).
.sup.1H-NMR (400 MHz, MeOD): δ=7.33 (s, 1H), 7.31 (s, 1H), 7.26 (t, 2H, J=7.1 Hz), 7.22-7.17 (m, 1H), 6.87 (q, 4H, J=6.87 Hz), 5.13 (d, 0.9 H), 4.93 (s, 3H), 4.43 (d, 0.5 H, J=6.6 Hz), 4.37 (d, 0.5 H, J=9.6 Hz), 3.95 (d, 0.7 H, J=8.4 Hz), 3.76 (s, 1H), 3.74-3.66 (m, 2H), 3.56-3.38 (m, 4H), 3.31 (s, 1H), 3.28 (s, 1H), 3.26 (s, 1H), 3.22 (s, 2H) ppm. Mixture of diastereoisomers.

EXAMPLE 97

4-[4-[[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-Tetramethyl-5,5a,8a,8b-tetrahydro-3aH-di[1,3]dioxolo[4,5-a:4′,5′-c]pyran-5-yl]methyl]piperazin-1-yl]phenol

[0457] ##STR00117##

[0458] To a solution of example 95 (395 mg, 77 μmol, 1 eq.) in methanol (3 mL) under argon was added Pd/C (8.3 mg, 77 μmol, 0.1 eq.). The reaction mixture was purged with a flux of hydrogen. The reaction mixture was agitated at room temperature for 1 hour. The reaction mixture was filtrated on celite, rince with methanol, and evaporated in vacuo.

Yield: 366 mg (870 μmol, quant.).
LC/MS (ES-API): m/z=421.1 [M+H]+; calculated: 421.5 ; t.sub.R (λ=220 nm): 0.60 min (LC/MS-Method 2).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.72 (d, 2H, J=8.7 Hz), 6.62 (d, 2H, J=8.7 Hz), 5.42 (d, 1H, J=5.1 Hz), 4.53 (dd, 1H, J=7.8, 2.3 Hz), 4.26-4.18 (m, 2H), 3.93-3.86 (m, 1H), 2.94 (t, 4H, J=5.0 Hz), 2.69-2.49 (m, 4H), 1.50 (s, 3H), 1.35 (s, 3H), 1.28 (s, 6H) ppm.

EXAMPLE 98

(2S,3R,4S,5R,6R)-6-[4-(4-Hydroxyphenyl)piperazin-1-yl]methylpetrahydropyran-2,3,4,5-tetrol

[0459] ##STR00118##

[0460] Example 98 was obtained from example 97 following the isopropylidene deprotection described in synthesis method F.

Yield: 31 mg (55 μmol, 93%), oil.
LC/MS (ES-API): m/z=341.2 [M+H].sup.+; calculated: 341.2 ; t.sub.R=0.07 min (LC/MS-Method 2).
.sup.1H-NMR (400 MHz, MeOD): ϵ=6.8 (d, 2H, J=9.0 Hz), 6.64 (d, 2H, J=9.0 Hz), 5.12 (d, 1H, J=3.6 Hz), 4.40 (dd, 1 H, J=5.8, 1.3 Hz), 4.35 (dd, 1H, J=10.0, 2.5 Hz), 3.95-3.90 (m, 1H), 3.77-3.69 (m, 4H), 3.56-3.46 (m, 4H), 3.43-3.40 (m, 2H), 3.31-3.23 (m, 3H) ppm. Mixture of diastereoisomers.

EXAMPLE 99

1-[[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-Tetramethyl-5,5a,8a,8b-tetrahydro-3aH-di[1,3]dioxolo[4,5-a:4′,5′-c]pyran-5-yl]methyl]-4-[4-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]phenyl]piperazine

[0461] ##STR00119##

Step 1: 2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethyl 4-methyl benzenesulfonate

[0462] ##STR00120##

[0463] To a solution of 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethanol (50 mg, 266 μmol, 1 eq.) in pyridine (2 mL) were added N,N,N′,N′-tetramethyl-1,6-diaminohexane (5.8 μl, 27 μmol, 0.1 eq.) and 4-methylbenzene-1-sulfonyl chloride (76 mg, 398 μmol, 1.5 eq.). The reaction mixture was agitated at room temperature for 2 hours. The reaction mixture was evaporated in vacuo.

[0464] Purification: flash chromatography on silica gel (100% heptane till 100% ethylacetate in 30 minutes).

Yield: 62 mg (181 μmol, 68%).
LC/MS (ES-API): m/z=343.1 [M+H].sup.+; calculated: 343.4 ; t.sub.R (λ=220 nm): 0.804 min (LC/MS-Method 2).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.78 (d, 2H, J=8.5 Hz), 7.48 (d, 2H, J=8.5 Hz), 4.15-4.08 (m, 4H), 3.61-3.47 (m, 10H), 3.41 (t, 1H, J=2.5 Hz), 2.42 (s, 3H) ppm.

Step 2: 1-[[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-Tetramethyl-5,5a,8a,8b-tetrahydro-3aH-di[1,3]dioxolo[4,5-a:4′,5′-c]pyran-5-yl]methyl]-4-[4-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]phenyl]piperazine

[0465] A solution of example 99, step 1 (41 mg, 120 μmol, 1.2 eq.), example 97 (42 mg, 100 μmol, 1 eq.), and Cs.sub.2CO.sub.3 (130 mg, 400 μmol, 4 eq.) in dimethylformamide (1 mL) under argon was irradiated in the microwave for 10 minutes at 70° C. and 40 minutes at 80° C. The crude mixture was diluted with ethylacetate. The organic phase was washed with a saturated solution of NaHCO.sub.3, water, dried with MgSO.sub.4, and evaporated in vacuo.

[0466] Purification:flash chromatography on silica gel (dichloromethane till dichloromethane/methanol 9/1 in 30 minutes).

Yield: 16 mg (27 μmol, 27%).
LC/MS (ES-API): m/z=591.3 [M+H].sup.+; calculated: 591.3 ; t.sub.R (λ=220 nm): 0.70 min (LC/MS-Method 2).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.89-6.81 (m, 4H), 5.57 (d, 1H, J=5.1 Hz), 4.60 (dd, 1H, J=7.8, 2.3 Hz), 4.31 (dd, 1H, J=5.1, 2.3 Hz), 4.25-4.19 (m, 4H), 4.07 (t, 2H, J=5.1 Hz), 4.02-3.96 (m, 1H), 3.82 (t, 2H, J=5.1 Hz), 3.75-3.66 (m, 10H), 3.11 (t, 4 H, J=4.5 Hz), 2.80-2.58 (m, 6H), 2.43-2.40 (m, 1H), 2.08 (s, 1H), 1.73 (s, 1H), 1.54 (s, 3H), 1.46 (s, 3H), 1.34 (s, 3H), 1.33 (s, 3H) ppm.

EXAMPLE 100

(3R,4S,5R,6R)-6-[[4-[4-[2-[2-(2-Prop-2-ynoxyethoxy)ethoxy]ethoxy]phenyl]piperazin-1-yl]methyl]tetrahydropyran-2,3,4,5-tetrol

[0467] ##STR00121##

[0468] Example 100 was obtained from example 99 following the isopropylidene deprotection described in synthesis method F.

Yield: 18 mg (28 μmol, quant).
LC/MS (ES-API): m/z=511.2 [M+H].sup.+; calculated: 511.3 ; t.sub.R (λ=220 nm): 0.552 min (LC/MS-Method 2).

[0469] .sup.1H-NMR (400 MHz, MeOD): δ=6. 99 (d, 2H, J=8.9 Hz), 6.91 (d, 2H, J=8.78 Hz), 5.23 (d, 0.6H, J=3.5 Hz), 4.52 (d, 0.5 H, J=6.0 Hz), 4.47 (d, 0.6H, J=10.0 Hz), 4.23-4.16 (m, 3.2H), 4.11-4.02 (m, 2H), 3.88-3.75 (m, 5H), 3.73-3.59 (m, 15H), 3.57-3.49 (m, 1.4H), 3.08 (s1, 2H), 2.84 (s, 1.2H) ppm. Mixture of diastereoisomers.

EXAMPLE 101

1-[[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-Tetramethyl-5,5a,8a,8b-tetrahydro-3aH-di[1,3]dioxolo[4,5-a:4′,5′-c]pyran-5-yl]methyl]-4-(4-chlorophenyl)piperazine

[0470] ##STR00122##

[0471] To a solution of (3aR,5S,5aR,8aS,8bR)-2,2,7,7-tetramethyl-5,5a,8a,8b-tetrahydro-3aH-di[1,3]dioxolo[4,5-a:4′,5′-c]pyran-5-carbaldehyde (50 mg, 194 μmol, 1 eq.), 1-(4-chlorophenyl)piperazine (114 mg, 581 μmol, 3 eq.), and acetic acid (22 μl, 387 μmol, 2 eq.) in methanol was added sodium cyanoboronhydride (25 mg, 387 μmol, 2 eq.). The reaction mixture was agitated overnight at room temperature and evaporated in vacuo. The crude mixture was separated between ethylacetate and a saturated solution of NaHCO3. The aqueous phase was extracted twice with ethylacetate. The organic phase was dried with MgSO.sub.4 and evaporated.

[0472] Purification: flash chromatography on silica gel (100% heptane till 100% ethylacetate in 40 minutes).

Yield: 63 mg (144 μmol, 74%), oil.
LC/MS (ES-API): m/z=439.2 [M+H].sup.+; calculated: 439.9; t.sub.R (λ=220 nm): 0.713 min (LC/MS-Method 2).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.21 (d, 2H, J=8.9 Hz), 6.93 (d, 2H, J=8.9 Hz), 5,45 (d, 1H, J=5.1 Hz), 4.58 (dd, 1H, J=7.9, 2.4 Hz), 4.32 (dd, 1H, J=5.2, 2.3 Hz), 4.21 (dd, 1H, J=7.9, 1.7 Hz), 3.90-3.85 (m, 1H), 3.10 (t, 4H, J=4.9 Hz), 2.65-2.57 (m, 4H), 2.43 (dd, 2H, J=13.0, 7.1 Hz), 1.45 (s, 3H), 1.35 (s, 3H), 1.28 (s, 6H) ppm.

EXAMPLE 102

(3R,4S,5R,6R)-6-[[4-(4-Chlorophenyl)piperazin-1-yl]methyl]tetrahydropyran-2,3,4,5-tetrol

[0473] ##STR00123##

[0474] Example 102 was obtained from example 101 following the isopropylidene deprotection described in synthesis method F.

Yiels: 78 mg (133 μmol, 95%).
LC/MS (ES-API): m/z=359.1 [M+H].sup.+; calculated: 359.1 ; t.sub.R (λ=220 nm): 0.493 min (LC/MS-Method 2).
.sup.1H-NMR (400 MHz, MeOD): δ=7.27 (d, 2H, J=8.5 Hz), 7.01 (d, 2H, J=8.5 Hz). 5.24 (d, 0.5 H, J=3.0 Hz), 4.55 (d, 0.5 H, J=6.7 Hz), 4.48 (d, 0.5 H, J=9.8 Hz), 4.07 (d, 0.5 H, J=9.2 Hz), 3.90-3.76 (m, 2H), 3.66-3.30 (m, 9H) ppm. Mixture of diastereoisomers.

EXAMPLE 103

N-[2-[2-[2-[[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-Tetramethyl-5,5a,8a,8b-tetrahydro-3aH-di[1,3]dioxolo[4,5-a:4′,5′-c]pyran -5-yl]methylamino]ethoxy]ethoxy]ethyl]pent-4-ynamide

[0475] ##STR00124##

Step 1: tert-butyl N-[2-[2-[2-(pent-4-ynoylamino)ethoxy]ethoxy]ethyl]carbamate

[0476] ##STR00125##

[0477] To a solution of pent-4-ynoic acid (43.5 mg, 442 μmol, 1.1 eq.) and tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (100 mg, 402 μmol, 1 eq.) in dimethylformamide (3 mL) was added N,N-diisopropylethylamine (77 μl, 443 μmol, 1.1 eq.), HOBt (67.8 mg, 443 μmol, 1.1 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (84.9 mg, 443 μmol, 1.1 eq.). The reaction mixture was agitated overnight at room temperature. The crude mixture was diluted with ethylacetate, washed with 0.5 N aqueous HCl, a saturated solution of NaHCO.sub.3, and brine, dried with MgSO.sub.4, and concentrated in vacuo.

[0478] Purification: flash chromatography on silica gel (100% heptane till 100% ethylacetate in 20 minutes, 100% ethylacetate for 10 minutes)

Yield: 99 mg (301 μmol, 75%).
LC/MS (ES-API): m/z=351.2 [M+Na].sup.+; calculated: 351.4; t.sub.R: 0.675 min (LC/MS-Method 2).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=3.49 (s, 4H), 3.41-3.34 (m, 4H), 3.19 (q, 2H, J=5.8 Hz), 3.05 (q, 2H, J=5.8 Hz), 2.89 (s, 2H), 2.73 (s, 2H), 2.37-2.31 (m, 2H), 2.28-2.24 (m, 2H), 1.90 (s, 1H), 1.37 (s, 9H) ppm.

Step 2: N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]pent-4-ynamide

[0479] ##STR00126##

[0480] A solution of example 103, step 1 (98 mg, 298 μmol, 1 eq.) in trifluoroacetic acid/dichloromethane (1/1, v/v, 1 mL) was agitated at room temperature for 30 minutes. The reaction mixture was evaporated under vacuo and lyophilised.

Yield: 108 mg (315 μmol, quant).
LC/MS (ES-API): m/z=229.2 [M+H].sup.+; calculated: 229.1; t.sub.R: 0.123 min (LC/MS-Method 2).

.SUP.1.H-NMR (400 MHz, MeOD): δ=3.72 (t, 2H, J=4.9 Hz), 3.67 (s, 4H), 3.58 (t, 2H, J=5.5 Hz), 3.40 (t, 2H, J=5.5 Hz), 3.15 (t, 2H, J=4.8 Hz), 2.51-2.45 (m, 2H), 4.44-2.39 (m, 2H), 2.28 (s, 1H) ppm.

Step 3: N-[2-[2-[2-[[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyl-5,5a,8a,8b-tetrahydro-3aH-di[1,3]dioxolo[4,5-a:4′,5′-c]pyran-5-yl]methylamino]ethoxy]ethoxy]ethyl]pent-4-ynamide

[0481] A solution of (3aR,5S,5aR,8aS,8bR)-2,2,7,7-tetramethyl-5,5a,8a,8b-tetrahydro-3aH-di[1,3]dioxolo[4,5-a:4′,5′-c]pyran-5-carbaldehyde (41.5 mg, 160 μmol, 1 eq.), example 103, step 2 (55 mg, 160 μmol, 1 eq.), and triethylamine (44.8 μl, 321 μmol, 2 eq.) in methanol (3 mL) containing 4 Å molecular sieves was agitated overnight at room temperature. Sodium boronhydride (12 mg, 321 μmol, 2 eq.) was added to the reaction mixture. The reaction mixture was agitated at room temperature for 2 hours. A 1 N aqueous solution of sodium hydride was added. The reaction mixture was extracted with ether (three times). The organic phase was dried with MgSO.sub.4 and evaporated in vacuo.

[0482] Purification: flash chromatography on silica gel (dichloromethane till dichloromethane/methanol 9/1 in 30 minutes).

Yield: 21.4 mg (45.5 μmol, 28%), oil.
LC/MS (ES-API): m/z=471.2 [M+H].sup.+; calculated: 471.5; t.sub.R (λ=220 nm): 0.615 min (LC/MS-Method 2).
.sup.1H-NMR (400 MHz, MeOD): δ=6.70 (t, 1H, J=5.2 Hz), 6.21 (s, 1H), 5.72 (d, 1H, J=7.9 Hz), 5.31 (t, 1H, J=9.3 Hz), 5.20 (t, 1H, J=9.3 Hz), 5.11 (t, 1H, J=8.5 Hz), 4.07 (d, 1H, J=9.8 Hz), 3.62 (s, 5H), 3.59-3.53 (m, 5H), 3.52-3.46 (m, 4H), 3.40-3.31 (m, 1H) ppm.

EXAMPLE 104

N-[2-[2-[2-[[(3R,4S,5R)-3,4,5,6-Tetrahydroxytetrahydropyran-2-yl]methylamino]ethoxy]ethoxy]ethyl]pent-4-ynamide

[0483] ##STR00127##

[0484] Example 104 was obtained from example 103 following the isopropylidene deprotection described in synthesis method F.

Yield: 17.3 mg (44 μmol, quant).
LC/MS (ES-API): m/z=391.1 [M/5+H].sup.+; calculated: 391.4; t.sub.R (λ=220 nm): 0.07 min (LC/MS-Method 2).

EXAMPLE 105

[(2S,3R,4S,5S)-2,3,5-Triacetoxy-6-[2-[2-[2-(pent-4-ynoylamino)ethoxy]ethoxy]ethylcarbamoyl]tetrahydropyran-4-yl]acetate

[0485] ##STR00128##

[0486] To a solution of (2R,3S,4S,5R)-2,3,4,5-tetraacetoxycyclohexanecarboxylic acid (101 mg, 280 μmol, 1.2 eq.) in dimethylformamide (3 mL) was added HATU (106.7 mg, 280 μmol, 1.2 eq.) and 4 Å molecular sieves. After 5 minutes example 103, step 2 (80 mg, 233 μmol, 1 eq.) was added. The reaction mixture was agitated at room temperature for 72 hours. The reaction mixture was diluted with ethylacetate. The organic phase was washed with 1N aqueous HCl, saturated NaHCO.sub.3, and brine, dried with MgSO.sub.4, filtered, and evaporated in vacuo.

[0487] Purification: flash chromatography on silica gel (dichloromethane till dichloromethane/methanol 9/1 in 30 minutes)

Yield: 74.45 mg (130 μmol, 56%), oil.
LC/MS (ES-API): m/z=513.2 [M-OAc].sup.+; calculated: 513.6; t.sub.R (λ=220 nm): 0.652 min (LC/MS-Method 2).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.15 (t, 1H, J=5.6 Hz), 7.93 (t, 1H, J=5.6 Hz), 5.96 (d, 1H, J=8.3 Hz), 5.43 (t, 1H, J=9.8 Hz), 5.08 (t, 1H, J=9.8 hz), 4.98 (dd, 1H, J=9.8, 8.4 Hz), 4.30 (s, 1H, J=9.8 Hz), 3.49 (s, 4H), 3.38 (q, 4H, J=6.0 Hz), 3.24-3.13 (m, 4H), 2.73 (t. 1H, J=2.6 Hz), 2.37-2.31 (m, 2H), 2.30-2.24 (m, 2H), 2.07 (s, 3H), 2.00 (s, 3H), 1.95 (s, 3H), 1.93 (s, 3H) ppm.

EXAMPLE 106

(3S,4S,5R)-3,4,5,6-Tetrahydroxy-N-[2-[2-[2-(pent-4-ynoylamino)ethoxy]ethoxy]ethyl]tetrahydropyran-2-carboxamide

[0488] ##STR00129##

Method G

[0489] To a solution of the tetraacetate derivative (1 eq.) in methanol/water/THF (5/4/1, v/v/v) at 0° C. was added a solution of an aqueous 1 N lithium hydroxyde solution (1 eq.). The reaction mixture was agitated 15 minutes at 0° C., quenched with a 1 N aqueous solution of HCl, evaporated, and lyophilised.

[0490] Example 106 was obtained from example 105 using acetyl deprotection method G.

Yield: 62.2 mg (153 μmol, quant).
LC/MS (ES-API): m/z=405.2 [M+H].sup.+; calculated: 404.4; t.sub.R (λ=324 nm): 0.087 min (LC/MS-Method 2).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.77 (d, 0.5H, J=6.7 Hz), 6.47 (d, 0.5H, J=4.6 Hz), 4.98-4.92 (m, 2H), 4.90 (d, 0.5H, J=4.3 Hz), 4.77 (d, 0.5H, J=4.9 Hz), 4.57 (d, 0.5H, J=6.3 Hz), 4.32 (t, 0.5 H, J=7.4 Hz), 3.95 (t, 0.5H, J=10 Hz), 3.50 (d, 4H, J=2.7 Hz), 3.49-3.37 (m, 4H), 3.26-3.09 (m, 6H), 2.98-2.91 (m, 0.5 H), 2.74 (t, 1H, J=2.6 Hz), 2.37-2.32 (m, 2H), 2.99-2.45 (m, 2H) ppm. Mixture of diastereoismers.

EXAMPLE 107

[0491] N-[[(3aR,5aS,8aS,8bR)-2,2,7,7-Tetramethyl-5,5a,8a,8b-tetrahydro-3aH-di[1,3]dioxolo[4,5-a:4′,5′-c]pyran-5-yl]methyl]oct-7-yn-1-amine

##STR00130##

[0492] A solution of (3aR,5S,5aR,8aS,8bR)-2,2,7,7-tetramethyl-5,5a,8a,8b-tetrahydro-3aH-di[1,3]dioxolo[4,5-a:4′,5′-c]pyran-5-carbaldehyde (50 mg, 174 μmol, 1 eq.), oct-7-yn-1-amine hydrochloride (31 mg, 192 μmol, 1.1 eq.), and triethylamine (27 μl, 192 μmol, 1.1 eq.) in methanol (1 mL) was agitated at room temperature for 3 hours. The reaction mixture was cooled to 0° C. and sodium boronhydride (13 mg, 348 μmol, 2 eq.) was added. The reaction mixture was agitated at 0° C. for one hour. A 1 N aqueous solution of sodium hydroxide was added. The aqueous phase was extracted with ether (three times), dried over MgSO.sub.4, filtered, and evaporated in vacuo.

[0493] Purification: flash chromatography on silica gel (dichloromethane till dichloromethane/methanol 9/1 in 30 min).

Yield: 29 mg (79 μmol, 45%), oil.
LC/MS (ES-API): m/z=368.4 [M+H].sup.+; calculated: 368.5; t.sub.R: 0.684 min (LC/MS-Method 2).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=5.43 (d, 1H, J=5.2 Hz), 4.55 (dd, 1H, J=7.7, 2.3 Hz), 4.44-4.39 (m, 0.3 H), 4.30 (dd, 1H, J=5.1, 2.3 Hz), 4.20 (dd, 1H, J=7,7, 1.7 Hz), 3.74 (td, 1H, J=6.5, 1.5 Hz), 3.40-3.37 (m, 0.7 H), 2.72 (t, 0.6 H, J=2.8 Hz), 2.68-2.65 (m, 0.3H), 2.63-2.58 (m, 0.9 H), 1.7 (t, 0.8 H, J=2.5 Hz), 1.48-1.22 (m, 20.6 H) ppm.

EXAMPLE 108

(3R,4S,5R)-6-[(Oct-7-ynylamino)methyl]tetrahydropyran-2,3,4,5-tetrol

[0494] ##STR00131##

[0495] Example 108 was obtained from example 107 following the isopropylidene deprotection described in synthesis method F.

Yield: 32 mg (80 μmol, quant).
LC/MS (ES-API): m/z=288.2 [M+H].sup.+; calculated: 288.2; t.sub.R=0.648 min (LC/MS-Method 3).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=6.71 (d, 0.5H, J=7.5 Hz), 6.38 (d, 0.5H, J=4.6 Hz), 5.00 (t, 0.5H, J=4.0 Hz), 4.91-4.79 (m, 2H), 4.71 (s, 0.5H), 4.51 (s, 0.5H), 4.29 (t, 0.5H, J=6.8 Hz), 4.12-4.07 (m, 0.5H), 3.70-3.65 (m, 1H), 3.63-3.51 (m, 1.5H), 3.19-3.00 (m, 2H), 2.95-2.83 (m, 2H), 2.75 (t, 0.5H, J=2.6 Hz), 2.19-2.07 (m, 2H), 1.72 (t, 1H, J=2.6 Hz), 1.64-1.52 (m, 2H), 1.48-1.52 (m, 6H) ppm. Mixture of diastereoisomers.

EXAMPLE 109

[(2S,3R,4S,5S)-2,3,5-Triacetoxy-6-(oct-7-ynylcarbamoyl)tetrahydropyran-4-yl]acetate

[0496] ##STR00132##

[0497] To a solution of (2R,3S,4S,5R)-2,3,4,5-tetraacetoxycyclohexanecarboxylic acid (20 mg, 55 μmol, 1 eq.) in dimethylformamide (2 mL) with 4 Å molecular sieves was added HATU (29.4 mg, 77 μmol, 1.4 eq.) followed by oct-7-yn-1-amine hydrochloride (26.8 mg, 166 μmol, 3 eq.) in 0.5 mL dimethylformamide. The reaction mixture was agitated overnight at room temperature and evaporated in vacuo.

[0498] Purification: flash chromatography on silica gel, (heptane till ethyl acetate in 20 min, 100% ethyl acetate for 20 min).

Yield: 25.5 mg (54 μmol, 98%), white solid.
LC/MS (ES-API): m/z=492.1 [M+H].sup.+; calculated: 492.5; t.sub.R=0.851 min (LC/MS-Method 2).
.sup.1H-NMR (400 MHz, CDCl.sub.3): δ=6.29 (t, 1H, J=4.9 Hz), 5.76 (d, 1H, J=8.0 Hz), 5.30 (t, 1H, J=9.4 Hz), 5.19 (t, 1H J=9.4Hz), 5.11 (td, 1H, J=8.0, 1.5 Hz), 4.05 (d, 1H, J=9.4 Hz), 3.30-3.13 (m, 2H), 2.28 (td, 1H, J=7.0, 2.6 Hz), 2.14 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 1.95 (t, 1H, J=2.6 Hz), 1.78 (t, 1H, J=2.3 Hz) , 1.58-1.22 (m, 8H) ppm.

EXAMPLE 110

(3S,4S,5R)-3,4,5,6-Tetrahydroxy-N-oct-7-ynyl-tetrahydropyran-2-carboxamide

[0499] ##STR00133##

[0500] Example 110 was obtained from example 109 using acetyl deprotection method G.

Yield: 17 mg (49 μmol, 91%), orange oil.
LC/MS (ES-API): m/z=302.1 [M+H].sup.+; calculated: 302.1; t.sub.R (λ=220 nm): 0.831 min (LC/MS-Method 3).
.sup.1H-NMR (400 MHz, MeOD): δ=5,19 (s, 0.5H), 4.55 (d, 0.5H, J=7.5 Hz), 4.17 (d, 0.7H, J=9.9 Hz), 3.71 (t, 1H, J=9.0 H), 3.58 (s, 0.3H), 3.51-3.39 (m, 1.7H), 3.27-3.18 (m, 3H), 2.18 (s, 3H), 2.12 (s, 1.1H), 1.92 (s, 0.9H), 1.74 (s, 1.4H), 1.59-1.29 (m, 6H) ppm. Mixture of diastereoisomers.

EXAMPLE 111

N-[6-[1-(4-(Human Insulin-B29Lys-amino)-4-oxo-butyl)triazol-4-yl]hexyl]-(3S,4S,5R)-3,4,5,6-tetrahydroxy-tetrahydropyran-2-carboxamide

[0501] ##STR00134##

Step 1: 4-azido-butan-(human Insulin-B29Lys)-amide

[0502] ##STR00135##

[0503] To a solution of human insulin (300 mg, 51 μmol, 1 eq.) in dimethylformamide/water (½, v/v, 9 mL) was added triethylamine (144 μl, 1.03 mmol, 20 eq.) to get to pH=10. The reaction mixture was cooled to 0° C. A solution of 2,5-dioxopyrrolidin-1-yl 4-azidobutanoate (12.9 mg, 56 μmol, 1.1 eq.) in dimethylformamide (1 mL) was added dropwise to the reaction mixture at 0° C. over 10 minutes. The reaction mixture was agitated 2 hours, quenched with 1 N aqueous HCl till pH=3, and lyophilized.

[0504] Purification: AEKTA avant 25 (GE Healthcare), HPLC; column: Kinetex Prep-C18 column (5 μm, 250×21.1 mm, Phenomenex, volume 87 mL); wavelength for detection: 280 nm; eluent: (A) water+0.5% acetic acid, (B) 60/40 acetonitrile/water+0.5% acetic acid.

HPLC Gradient:

[0505]

TABLE-US-00040 Flow rate Flow rate Column start % B end % B [cm/h] [mL/min] volume 0 0 80 4.7 2.0 0 100 105 6.2 14.0 100 100 105 6.2 2.0
Yield: 146.5 mg (24.75 μmol, 48%), white powder.
LC/MS (ES-API): m/z=1184.6 [M/5+H].sup.+; calculated: 1184.7; t.sub.R (λ=215 nm): 4.30 min (LC/MS-Method 4).

Step 2: N-[6-[1-(4-(human Insulin-B29Lys-amino)-4-oxo-butyl)triazol-4-yl]hexyl]-3,4,5,6-tetrahydroxy-tetrahydropyran-2-carboxamide

Method H

[0506] To a solution of the alkynes (1.2 eq.) and example 111, step 1 (1 eq.) in dimethylformamide and water was added a mixture of the click reagents premixed in this order: CuSO.sub.4*5H.sub.2O (0.5 eq.), THPTA (0.8 eq.), and sodium ascorbate (1 eq.). The reaction mixture was agitated at room temperature for 2 hours. The reaction mixture was lyophilised. Purification was done on reverse phase chromatography.

[0507] Example 111, step 2 was obtained from example 111, step 1 and example 110 following the click chemistry procedure described in synthesis method H.

[0508] Purification and HPLC gradient like in example 111, step 1.

Yield: 2.9 mg (0.46 μmol, 18%), white powder.
LC/MS (ES-API): m/z=1244.9 [M/5+H].sup.+; calculated: 1245.0; t.sub.R (λ=215 nm): 3.95 min (LC/MS-Method 4).

EXAMPLE 112

4-[4-[3-Oxo-3-[1-[2-[2-[[(3R,4S,5R)-3,4,5,6-tetrahydroxytetrahydropyran-2-yl]methylamino]ethoxy]ethoxy]ethylamino]propyl]triazol-1-yl]butan-(human Insulin-B29Lys)-amide

[0509] ##STR00136##

[0510] Example 112 was obtained from example 111, step 1 and example 114 following the click chemistry procedure described in synthesis method H.

[0511] Purification and HPLC gradient like in example 111, step 1.

Yield: 1.37 mg (0.22 μmol, 11%), white powder.
LC/MS (ES-API): m/z=1262.7 [M/5+H].sup.+; calculated: 1262.8; t.sub.R (λ=215 nm): 3.75 min (LC/MS-Method 4).

EXAMPLE 113

4-[4-[6-[[(3R,4S,5R)-3,4,5,6-Tetrahydroxytetrahydropyran-2-yl]methylamino]hexyl]triazol-1-yl]butan-(human Insulin-B29Lys)-amide

[0512] ##STR00137##

[0513] Example 113 was obtained from example 111, step 1 and example 108 following the click chemistry procedure described in synthesis method H.

[0514] Purification and HPLC gradient like in example 111, step 1.

Yield: 4.36 mg (0.70 μmol, 35%), white powder.
LC/MS (ES-API): m/z=1242.0 [M/5+H].sup.+; calculated: 1242.2; t.sub.R (λ=215 nm): 3.77 min (LC/MS-Method 4).

EXAMPLE 114

(3S,4S,5R)-N-[2-[2-[2-[3-[1-(4-(Humannsulin-B29Lys)-4-oxo-butyl)triazol-4-yl]propanoylamino]ethoxy]ethoxy]ethyl]-3,4,5,6-tetrahydroxy-tetrahydropyran-2-carboxamide

[0515] ##STR00138##

[0516] Example 114 was obtained from example 111, step 1 and example 106 following the click chemistry procedure described in synthesis method H.

[0517] Purification and HPLC gradient like in example 111, step 1.

Yield: 3.74 mg (0.59 μmol, 29%), white powder.
LC/MS (ES-API): m/z=1265.4[M/5+H].sup.+; calculated: 1265.6; t.sub.R (λ=215 nm): 3.87 min (LC/MS-Method 4).

Example 115

4-[4-[2-[2-[2-[4-[4-[[(3R,4S,5R)-3,4,5,6-Tetrahydroxytetrahydropyran-2-yl]methyl]piperazin-1-yl]phenoxy]ethoxy]ethoxy]ethoxymethyl]triazol-1-yl]butan-(human Insulin-B29Lys)-amide

[0518] ##STR00139##

[0519] Example 115 was obtained from example 111, step 1 and example 100 following the click chemistry procedure described in synthesis method H.

[0520] Purification and HPLC gradient like in example 111, step 1.

Yield: 15.2 mg (2.36 μmol, 28%), white powder.
LC/MS (ES-API): m/z=1072.3 [M/6+H].sup.+; calculated: 1072.5; t.sub.R (λ=215 nm): 3.81 min.

EXAMPLE 116

Methy-6-O-p-toluolsulfonyl-β-D-glucopyranoside

[0521] ##STR00140##

[0522] To a solution of methyl-β-D-glucopyranoside (15 g, 77.3 mmol) in pyridine (50 mL) a solution of toluenesulfonylchloride (19.1 g, 100.5 mmol) in CH.sub.2Cl.sub.2 (50 mL) was added dropwise at 0° C. The mixture was then left for 16 h at 8° C. Methanol (200 mL) was added to the reaction and the solvens evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (10:1 CH.sub.2Cl.sub.2/MeOH) to give the product as a white solid

Yield: 13.1g (49%).

[0523] LC-Mass Method: Mobile phase: A=2.5 mM TFA/H2O, B=2.5 mM TFA/MeCN; Gradient: B=10%-95% in 1 min; Flow rate: 1.5 mL/min; Column: Xbridge-C18, 30×4.6 mm, 2.5 um.). LC purity: 92% (214 nm);
Mass: find peak 370.8 (M+Na)+ at 1.60 min.
.sup.1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.0Hz, 2H), 5.23 (d, J=5.6 Hz 1H), 5.13 (d, J=5.2 Hz, 1H), 5.00 (d, J=5.2 Hz, 1H), 4.20 (dd, J=10.4 Hz, 2.0 Hz, 1H), 4.06-4.02 (m, 2H), 3.36-3.34 (m, 1H), 3.30 (s, 3H), 3.12-3.07 (m, 1H), 3.01-2.95 (m, 1H), 2.93-2.87 (m, 1H), 2.43 (s, 3H).

EXAMPLE 117

Methyl-6-O-(3-phenoxyphenylcarbonyl)-β-D-glucopyranoside

[0524] ##STR00141##

[0525] Sodium hydride (17,22 mg, 430,58 μmol) was added to a solution of 3-phenoxybenzoic acid (92.24 mg, 430.58 μmol) in DMF (4 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred for about 30 min and methyl-6-O-p-toluensulfonyl-β-D-glucopyranoside 116 (100 mg, 287.05 μmol) was added and the reaction stirred for 16 h at 80° C. The solvens was evaporated under reduced pressure in vacuo and the residue extracted with CH.sub.2Cl.sub.2/H.sub.2O (3×). The organic layer was dried, the solvens evaporated and the product purified by HPLC.

Yield: 53 mg (47%)

[0526] LC/MS (ES-API): m/z=435.20 [M−H+formic acid]-; calculated: 435.16, tR (λ=220 nm): 1.6 min (LC/MS-Method 2)
.sup.1H NMR (400.23 MHz, DMSO-d6) d ppm 7.72 (d, J=7.48 Hz, 1 H), 7.56 (t,J=7.95, 7.95 Hz, 1H),7.44 (m, 3H), 7.33 (ddd, J=8.19, 2.57, 0.86 Hz, 1H), 7.21 (t, J=7.18, 7.18 Hz, 1H), 7.08 (d, J=7.84 Hz, 2H), 5.15 (br s, 1H), 4.55 (dd, J=11.68, 2.02 Hz, 1H), 4.26 (dd, J=11.74, 6.48 Hz, 1H), 4.08 (d, J=7.82 Hz, 1H), 3.46 (br s, 2H), 3.43 (u), 3.29 (s, 5H), 3.17 (m, 3H), 2.97 (m, 1H).

EXAMPLE 118

Methyl-6-O-(4-phenoxyphenylcarbonyl)-β-D-glucopyranoside

[0527] ##STR00142##

[0528] Methyl-6-O-(4-phenoxyphenylcarbonyl)-β-D-glucopyranoside was synthesized as described for example 117 from Methyl-6-O-p-toluolsulfonyl-β-D-glucopyranoside (116)

(100 mg, 287.05 μmol) and 4-phenoxybenzoic acid (92.24 mg, 430.58 μmol).

Yield: 49 mg (43.7%)

[0529] LC/MS (ES-API): m/z=435.22 [M−H+formic acid]-; calculated: 435.16, tR (λ=220 nm): 1.6 min (LC/MS-Method 2)
.sup.1H NMR (400.23 MHz, DMSO-d6) d ppm 7.97 (m(para), 2 H), 7.46 (t, J=7.56, 7.56 Hz, 2 H), 7.25 (m, 1H), 7.13 (d, J=7.83 Hz, 2H), 7.08 (m(para), 2H), 4.54 (dd, J=11.80, 1.90 Hz, 1H), 4.29 (dd, J=11.80, 6.17 Hz, 1H), 4.11 (d, J=7.82 Hz, 1H), 3.47 (m, 4H), 3.20 (m, 6H), 2.99 (m, 2H), 2.50 (u), 2.33 (m, 1H)

EXAMPLE 119

Methyl-6-O-(2-Methyl-4-phenoxyphenylcarbonyl)-β-D-glucopyranoside

[0530] ##STR00143##

[0531] Methyl-6-O-(2-Methyl-4-phenoxyphenylcarbonyl)-β-D-glucopyranoside was synthesized as described for example 117 from Methyl-6-O-p-toluolsulfonyl-β-D-glucopyranoside (116; 100 mg, 287.05 μmol) and 2-Methyl-4-phenoxybenzoic acid (98.28 mg, 430.58 μmol)

Yield: 46 mg (39.6%)

[0532] LC/MS (ES-API): m/z=499.17 [M−H+formic acid].sup.−; calculated: 449.18, tR (λ=220 nm): 1.63 min (LC/MS-Method 2)

EXAMPLE 120

Methyl-6-O-(3-chloro-3′-methoxy-4-phenoxyphenylcarbonyl)-β-D-glucopyranoside

[0533] ##STR00144##

[0534] Methyl-6-O-(3-chloro-3′-methoxy-4-phenoxyphenylcarbonyl)-β-D-glucopyranoside was synthesized as described for example 117 from Methyl-6-O-p-toluolsulfonyl-β-D-glucopyranoside (116; 100 mg, 287.05 μmol) and 3-Chloro-3′-methoxy-4-phenoxybenzoic acid (120 mg, 430.58 μmol).

Yield: 43 mg (32.9%)

[0535] LC/MS (ES-API): m/z=499.17 [M−H+formic acid].sup.−; calculated: 499.13, tR (λ=220 nm): 1.64 min (LC/MS-Method 2)

EXAMPLE 121

Methyl-6-O-(3-methoxy-4-phenoxyphenylcarbonyl)-β-D-glucopyranoside

[0536] ##STR00145##

[0537] Methyl-6-O-(3-methoxy-4-phenoxyphenylcarbonyl)-β-D-glucopyranoside was synthesized as described for example 117 from Methyl-6-O-p-toluolsulfonyl-β-D-glucopyranoside (116; 100 mg, 287.05 μmol) and 3-Methoxy-4-phenoxybenzoic acid (105.17 mg, 430.58 mmol).

Yield: 58 mg (48.1%)

[0538] LC/MS (ES-API): m/z=465.14 [M−H+formic acid].sup.−; calculated: 465.17, tR (λ=220 nm): 1.53 min (LC/MS-Method 2)
.sup.1H NMR (400.23 MHz, DMSO-d6) d ppm 7.64 (d, J=1.96 Hz, 1 H), 7.59 (dd, J=8.31, 1.96 Hz, 1H), 7.37 (t, J=7.64, 7.64 Hz, 2H), 7.13 (t, J=7.13, 7.13 Hz, 1H), 7.04 (d, J=8.44 Hz, 1H), 6.96 (d, J=7.84 Hz, 2H), 5.24 (d, J=5.01 Hz, 1H), 5.11 (d, J=4.89 Hz, 1H), 5.05 (d, J=4.03 Hz, 1H), 4.59 (dd, J=11.74, 1.96 Hz, 1H), 4.29 (dd, J=11.74, 6.48 Hz, 1H), 4.12 (d, J=7.70 Hz, 1H), 3.83 (s, 3H), 3.47 (u), 3.20 (m, 3H), 3.00 (m, 1H).

EXAMPLE 122

Methyl-6-O-(1-benzyl-3-bromo-2-oxo-1,2-dihydropyridinyl-4-carbonyl)-β-D-glucopyranoside

[0539] ##STR00146##

[0540] Methyl-6-O-(1-benzyl-3-bromo-2-oxo-1,2-dihydropyridinyl-4-carbonyl)-β-D-glucopyranoside was synthesized as described for example 117 from Methyl-6-O-p-toluolsulfonyl-β-D-glucopyranoside (116; 100 mg, 287.05 μmol) and 1-benzyl-3-bromo-2-oxo-1,2-dihydropyridine-4-carboxylate (400 mg, 649.07 μmol).

Yield: 8 mg

[0541] LC/MS (ES-API): m/z=484.09 [M+H].sup.+; calculated: 484.06, tR (λ=220 nm): 1.33 min (LC/MS-Method 2)

EXAMPLE 123

Methyl-2-O-(3-methoxy-4-phenoxyphenylcarbonyl)-α-D-glucopyranoside

[0542] ##STR00147##

[0543] Methyl-2-O-(3-methoxy-4-phenoxyphenylcarbonyl)-α-D-glucopyranoside was synthesized according to a method described by Muramatsu and Takemoto from Methyl-α-D-glucopyranoside and 3-Methoxy-4-phenoxybenzoic acid.

[0544] 3-Methoxy-4-phenoxybenzoic acid (182.27 mg, 669.47 μmol) is suspended in CH.sub.2Cl.sub.2 (3 mL) under Argon atmosphere. 1-Chloro-N,N,2-trimethylpropenylamine (88.57 μl, 669.47 μmol) is added and the reaction mixture stirred for 20 min at 20° C. to yield the corresponding carboxylic acid chloride.

[0545] A solution of Methyl-α-D-glucopyranoside (97.05 mg, 257.49 μmol) and Dibutyltinndichloride (16.47 mg, 51.50 μmol) in THF (3 mL) is stirred for 15 min. Tetrabutylammonium iodide (97.05 mg, 257.49 μmol) and Diisopropylethylammine (DIPEA; 113.85 μl, 669.47 μmol) are added. Subsequently the solution of 3-Methoxy-4-phenoxybenzoic acid chloride in CH.sub.2Cl.sub.2 is added, the reaction mixture stirred for 2 h and left for 18 h at 20° C.

[0546] The reaction is quenched with NH4Cl-solution and the product extracted with EtOAc (3×5 mL). The product is finally purified by HPLC and freece dried.

Yield: 55 mg (25.4%)

[0547] LC/MS (ES-API): m/z=465.0 [M−H+formic acid].sup.−[M+H t.sub.R (λ=220 nm): 1.73 min (LC/MS-Method 2)
.sup.1H NMR (400.23 MHz, DMSO-d6) d ppm 7.66 (m, 1H), 7.62 (d, J=1.83 Hz, 1H), 7.37 (m, 2H), 7.13 (m, 1H), 7.06 (d, J=8.46 Hz, 1H), 6.95 (d, J=7.82 Hz, 2H), 4.88 (d, J=3.67 Hz, 1H), 4.64 (dd, J=9.96, 3.61 Hz, 1H), 3.84 (s, 3H), 3.78 (m, 1H), 3.69 (br d, J=10.15 Hz, 1H), 3.52 (br dd, J=11.80, 5.56 Hz, 2H), 3.44 (u), 3.28 (s, 5H), 3.25 (m, 1H), 2.50 (u), 2.33 (s, 1H)

EXAMPLE 124

Methyl-2-O-(3-chloro-3′-methoxy-4-phenoxyphenylcarbonyl)-α-D-glucopyranoside

[0548] ##STR00148##

[0549] Methyl-2-O-(3-chloro-3′-methoxy-4-phenoxyphenylcarbonyl)-α-D-glucopyranoside was synthesized as described for example 123 from Methyl-α-D-glucopyranoside (100 mg, 514.98 μmol) and 3-Chloro-3′-methoxy-4-phenoxybenzoic acid (124.24 mg, 669.47 μmol).

Yield: 124 mg (50%)

[0550] LC/MS (ES-API): m/z=499.0 [M−H+formic acid].sup.−t.sub.R (λ=220 nm): 1.94 min (LC/MS-Method 2)
.sup.1H NMR (400.23 MHz, DMSO-d6) d ppm 7.80 (d, J=1.83 Hz, 1H), 7.67 (d, J=1.71 Hz, 1H), 7.31 (t, J=8.01, 8.01 Hz, 2H), 7.05 (t, J=7.40, 7.40 Hz, 1H), 6.82 (d, J=7.95 Hz, 2H), 5.42 (br s, 1H), 5.22 (br s, 1H), 4.91 (d, J=3.55 Hz, 1H), 4.63 (m, 1H), 3.82 (s, 3H), 3.79 (m, 1H), 3.69 (br d, J=10.27 Hz, 1H), 3.53 (dd, J=11.80, 5.56 Hz, 1H), 3.44 (u), 3.29 (s, 5H), 3.27 (m, 1H), 3.20 (br s, 1H), 2.33 (s, 1H)

Synthesis of Allyl-6-O-toluenesulfonyl-β-D-glucopyranoside

[0551] ##STR00149##

[0552] Allyl-6-O-toluenesulfonyl-β-D-glucopyranoside was synthesized according to a published procedure [R. Brisco et al,. Carb. Res. 348 (2012), 27-32] starting from commercially available allyl-β-D-glucopyranoside.

[0553] To a solution of allyl-β-D-glucopyranoside (1 g, 4.54 mmol) in pyridine (30 mL) was added p-toluensulfonylchloride ((1.47 g, 7.72 mmol) at 0° C. The reaction mixture was stirred for 30 min and then stored at 0° C. for 16 h. The reaction was controlled by TLC (9:1, CH.sub.2Cl.sub.2/MeOH) proving consumption of starting material. The reaction mixture was quenched with MeOH and the solvents were removed under reduced pressure. The Product was purified by flash chromatography (EtOAc/MeOH, 9:1).

Yield: 850 mg (51%)

EXAMPLE 125

[0554] Allyl-6-O-(3-phenoxyphenylcarbonyl)-β-D-glucopyranoside

##STR00150##

[0555] Allyl-6-O-(3-phenoxyphenylcarbonyl)-β-D-glucopyranoside was synthesized from allyl-6-O-toluenesulfonyl-β-D-glucopyranoside (200 mg, 534.18 μmol) and 3-phenoxyphenylcarboxylic acid (171.65 mg, 801.27 μmol) as described for example 117.

Yield: 113 mg (50.8%)

[0556] LC/MS (ES-API): m/z=461.25 [M−H+formic acid].sup.−; calculated: 461.18 t.sub.R (λ=220 nm): 1.69 min (LC/MS-Method 2)
.sup.1H NMR (400.23 MHz, DMSO-d6) d ppm 7.73 (d, J=7.44 Hz, 1 H), 7.57 (t, J=7.95, 7.95 Hz, 1H), 7.48 (s, 1H), 7.43 (t, J=7.27, 7.27 Hz, 2H), 7.33 (ddd, J=8.19, 2.57, 0.98 Hz, 1H), 7.20 (m, 1H), 7.07 (d, J=7.78 Hz, 2H), 5.85 (m, 1 H), 5.23 (m, 2H), 5.09 (m, 3H), 4.54 (dd, J=11.74, 1.96 Hz, 1H), 4.28 (dd, J=11.74, 6.60 Hz, 1H), 4.16 (m, 2H), 3.98 (m, 1H), 3.44 (u), 3.17 (m, 2H), 3.01 (td, J=8.34, 8.34, 4.95 Hz, 1H).

EXAMPLE 126

Allyl-6-O-(4-phenoxyphenylcarbonyl)-β-D-glucopyranoside

[0557] ##STR00151##

[0558] Allyl-6-O-(4-phenoxyphenylcarbonyl)-β-D-glucopyranoside was synthesized from allyl-6-O-toluenesulfonyl-β-D-glucopyranoside (200 mg, 534.18 μmol) and 3-phenoxyphenylcarboxylic acid (171.65 mg, 801.27 μmol) as described for example 117.

Yield: 116 mg (52.1%)

[0559] LC/MS (ES-API): m/z=461.20 [M−H+formic acid].sup.−; calculated: 461.18 t.sub.R (λ=220 nm): 1.70 min (LC/MS-Method 2)
.sup.1H NMR (400.23 MHz, DMSO-d6) d ppm 7.98 (m(para), 2 H), 7.46 (t, J=7.26, 7.26 Hz, 2H), 7.25 (t, J=7.47, 7.47 Hz, 1H), 7.13 (d, J=7.84 Hz, 2H), 7.08 (m(para), 2 H), 5.87 (m, 1H), 5.26 (m, 2H), 5.09 (br dd, J=10.39, 1.83 Hz, 2H), 4.53 (dd, J=11.74, 1.96 Hz, 1H), 4.22 (m, 3H), 4.02 (m, 1H), 3.46 (u), 3.20 (m, 4 H), 3.03 (m, 1H).

Synthesis of Trimethylsilyethoxy-6-O-tosyl-β-D-glucopyranoside LCMS Conditions

LCMS-Condition 01: Method:— LCMS_X-Select (Formic Acid)

[0560] Column: X-Select CSH C18 (4.6*50) mm 2.5u, Mobile Phase: A.0.1% Formic acid in water B. 0.1% Formic acid in Acetonitrile Inj Volume; 5.0 μL, Flow Rate: 1.0 mL/minute, Gradient program: 2% B to 98% B in 2.8 minute, Hold till 4.8 min, At 5.0 min B conc is 2% up to 7.0 min.

ELSD Conditions:

ELSD-Condition 01: Method:-LCMS_X-Bridge (NH.SUB.3.)

[0561] Column :X-Bridge C18 (4.6*50)mm 3.5 μ; Mobile Phase: A. 0.05% NH3 in water. B: 0.05% NH3 in Acetonitrile Inj Volume; 0.2 μL, Flow Rate: 1.200 mL/minute; Gradient program: 2% B to 100% B in 3.5 minute, Hold till 4.5 min, At 4.7 min B conc is 2% up to 6.0 min.

Step-1: Synthesis of (2R,3R,4S,5R,6R)-6-(acetoxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate (2)

[0562] ##STR00152##

[0563] To (2S, 3R,4S,5S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol 1 (50 g, 277.7 mmol) in pyridine (500 mL) at 0° C. was added DMAP (339 mg, 2.777 mmol) and acetic anhydride (500 mL). The reaction mixture was further stirred at room temperature for 20 h. After completion of the reaction, the pyridine was evaporated under reduced pressure and the residue was diluted with water and extracted with CH.sub.2Cl.sub.2 (thrice). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude compound was purified by trituration with n-hexane to afford 100 g (92% yield) of compound 2 as off white solid.

ELSD-Condition-1: [M+H].sup.+=408.00; R.sub.t=2.88 min
.sup.1H NMR (400 MHz, CDCl.sub.3) δ: 6.33 (d, J=3.91 Hz, 1H), 5.47 (t, J=10.03 Hz, 1H), 5.07-5.17 (m, 2H), 4.24-4.29 (m, 1H), 4.08-4.15 (m, 2H), 2.18 (s, 3H), 2.09 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H).

Step-2: Synthesis of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5-triyl triacetate (3)

[0564] ##STR00153##

[0565] To (2R,3R,4S,5R,6R)-6-(acetoxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate 1 (25 g, 64.04 mmol) in CH.sub.2Cl.sub.2 (500 mL) at 0° C. was added 33% solution of HBr in acetic acid (250 mL) and stirred for 4 h. After completion of the reaction, the reaction mixture was poured over ice and the organic layer was separated and washed with water (400 mL) followed by saturated NaHCO.sub.3 (200 mL×2). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography eluting with 0-50% ethyl acetate in n-hexane to afford 24 g (89% yield) of compound 3 as off white solid.

.sup.1H NMR (400 MHz, CDCl.sub.3): 6.61 (d, J=3.91 Hz, 1 H), 5.56 (t, J=9.54 Hz, 1 H), 5.17 (t, J=9.78 Hz, 1H), 4.84 (dd, J=3.91, 10.27 Hz, 1H), 4.28-4.36 (m, 2H), 4.10-4.16 (m, 1H), 2.10 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H).

Step-3: Synthesis of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(2-(trimethylsilyl)ethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (4)

[0566] ##STR00154##

[0567] To a stirred solution of HgO (12.1 g, 55.93 mmol), HgBr.sub.2 (700 mg catalytic), CaSO.sub.4 (15.2 g, 111.86 mmol) and 2-(trimethylsilyl)ethan-1-ol (9.9 g, 83.90 mmol) in CHCl.sub.3 (184 mL) was added (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5-triyltriacetate 3 (23 g, 55.93 mmol) and stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and washed with CH.sub.2Cl.sub.2 and washed with saturated NaHCO.sub.3 solution. The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography eluting with 0-30% ethyl acetate in n-hexane to afford 20 g (83% yield) of compound 4 as colorless oil.

.sup.1H NMR (400 MHz, CDCl.sub.3): 5.19 (dd, J=8.07, 9.54 Hz, 1 H), 5.08 (dd, J=8.07, 9.54 Hz, 1H), 4.97 (dd, J=8.07, 9.54 Hz, 1H), 4.51 (d, J=8.31 Hz, 1H), 4.23-4.29 (m, 1H), 4.09-4.16 (m, 2H), 3.97 (dt, J=5.87, 10.03 Hz, 1H), 3.66-3.76 (m, 2 H), 3.52-3.60 (m, 1H), 2.08 (s, 2H), 2.03-2.04 (m, 3H), 2.02 (s, 3 H), 2.00 (s, 3H), 1.25 (t, J=7.09 Hz, 1H), 0.85-0.98 (m, 3H), 0.02 (s, 3H), 0.00 (s, 6H).

Step-4: Synthesis of (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(2-(trimethylsilyl)ethoxy)tetrahydro-2H-pyran-3,4,5-triol (5)

[0568] ##STR00155##

[0569] To (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(2-(trimethylsilyl)ethoxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate 4 (10 g, 22.32 mmol) in methanol (100 mL) was added solution of sodium methoxide (100 mg sodium in 7.5 mL methanol) and stirred at room temperature for 12 h. After completion of the reaction, the pyridine was evaporated under reduced pressure and the residue was stirred in diethyl ether. The solid precipitated out was filtered and dried to afford 4.2 g (67% yield) of 5 as off white solid.

.sup.1H NMR (400 MHz, D.sub.2O) δ: 4.34 (d, J=7.83 Hz, 1H), 3.87-3.96 (m, 1H), 3.78 (d, J=11.74 Hz, 1H), 3.55-3.68 (m, 2H), 3.22-3.38 (m, 4H), 3.11 (t, J=8.56 Hz, 1H), 0.80-1.00 (m, 2H), −0.10 (s, 9H).

Step-5: Synthesis of ((2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6-(2-(trimethylsilyl)ethoxy)tetrahydro-2H-pyran -2-yl)methyl 4-methyl benzenesulfonate (2016-00144)

[0570] ##STR00156##

[0571] To (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(2-(trimethylsilyl)ethoxy)tetrahydro-2H-pyran-3,4,5-triol 5 (9.5 g, 33.92 mmol) in pyridine (95 mL) was added DMAP (413 mg, 3.392 mmol) and tosyl chloride (7.1 g, 37.32 mmol) stirred at room temperature for 12 h. After completion of the reaction, the pyridine was evaporated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography eluting with 0-10% methanol in CH.sub.2Cl.sub.2 to afford 10.2 g (69% yield) of 2016-00144 as off white solid.

LCMS-Condition-1: [M+18].sup.+=452.15; R.sub.t=1.78 min
.sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 7.76 (d, J=8.31 Hz, 2H), 7.47 (d, J=8.31 Hz, 2H), 5.16 (d, J=5.38 Hz, 1H), 4.99 (dd, J=4.89, 9.29 Hz, 2H), 4.21 (d, J=10.27 Hz, 1H), 4.12 (d, J=7.83 Hz, 1H), 4.02 (dd, J=6.60, 10.03 Hz, 1H), 3.69-3.79 (m, 1H), 3.43-3.52 (m, 1H), 3.35 (br. s, 1H), 3.05-3.13 (m, 1H), 2.95-3.03 (m, 1H), 2.84-2.92 (m, 1H), 2.42 (s, 3H), 0.82-0.95 (m, 2H), 0.00 (s, 9H).

EXAMPLE 127

Trimethylsilyethyl-6-O-(2-methyl-3-phenoxyphenylcarbonyl)-β-D-glucopyranoside

[0572] ##STR00157##

[0573] Trimethylsilyethyl-6-O-(2-methyl-3-phenoxyphenylcarbonyl)-β-D-glucopyranoside was syntzhesized as described for example 117 from trimethylsilyethoxy-6-O-tosyl-β-D-glucopyranoside (100 mg, 230.11 μmol) and 2-methyl-3-phenoxybenzoic acid (78.78 mg (345.16 μmol).

Yield: 63 mg (55.8%)

[0574] LC/MS (ES-API): m/z=535.23 (M−H+formic acid].sup.−; calculated: 535.23; tR (λ=220 nm): 1.94 min (LC/MS-Method 2)
.sup.1H NMR (400.23 MHz, DMSO-d6) d ppm 7.95 (d, J=8.68 Hz, 1 H), 7.52 (t, J=7.23, 7.23 Hz, 2H), 7.31 (t, J=7.14, 7.14 Hz, 1H), 7.17 (d, J=7.82 Hz, 2H), 7.00 (d, J=2.32 Hz, 1H), 6.89 (dd, J=8.68, 2.45 Hz, 1H), 5.28 (br s, 1H), 5.07 (br s, 2H), 4.60 (dd, J=11.68, 2.02 Hz, 1H), 4.33 (dd, J=11.68, 7.15 Hz, 1H), 4.27 (d, J=7.82 Hz, 1H), 3.84 (ddd, J=11.06, 9.78, 6.05 Hz, 1H), 3.55 (m, 2H), 3.24 (quin, J=8.71, 8.71, 8.71, 8.71 Hz, 2H), 3.05 (t, J=8.19, 8.19 Hz, 1H), 2.58 (m, 10H), 2.50 (u), 0.95 (m, 2H).

EXAMPLE 128

Trimethylsilyethyl-6-O-(3-chloro-3′-methoxy-4-phenoxyphenylcarbonyl)-β-D-glucopyranoside

[0575] ##STR00158##

[0576] trimethylsilyethyl-6-O-(3-chloro-3′-methoxy-4-phenoxyphenylcarbonyl)-β-D-glucopyranoside was synthesized as described for example 117 from trimethylsilyethoxy-6-O-tosyl-β-D-glucopyranoside (100 mg, 230.11 μmol) and 2-methyl-3-phenoxybenzoic acid (78.78 mg, 345.16 μmol).

Yield: 64 mg (51.4%)

[0577] LC/MS (ES-API): m/z=585.15 [M−H+formic acid].sup.−; calculated: 585.19 t.sub.R (λ=220 nm): 1.92 min (LC/MS-Method 2)
.sup.1H NMR (400.23 MHz, DMSO-d6) d ppm 7.79 (d, J=1.83 Hz, 1H), 7.72 (d, J=1.83 Hz, 1H), 7.39 (t, J=7.24, 7.24 Hz, 2H), 7.13 (t, J=7.34, 7.34 Hz, 1H), 6.88 (d, J=7.82 Hz, 2H), 5.34 (br s, 1H), 5.10 (br s, 1H), 4.66 (dd, J=11.62, 1.96 Hz, 1H), 4.45 (dd, J=11.68, 7.15 Hz, 1H), 4.30 (d, J=7.82 Hz, 1H), 3.89 (s, 3H), 3.84 (m, 1 H), 3.60 (m, 2H), 3.56 (s, 1H), 3.26 (m, 2H), 3.07 (br t, J=8.13, 8.13 Hz, 1H), 2.58 (dt, J=3.61, 1.74, 1.74 Hz, 16H), 2.50 (u), 0.95 (m, 2H), 0.08 (s, 1H)

EXAMPLE 129

Trimethylsilyethyl-6-O-(3-methoxy-4-phenoxyphenylcarbonyl)-β-D-glucopyranoside

[0578] ##STR00159##

[0579] Trimethylsilyethyl-6-O-(3-methoxy-4-phenoxyphenylcarbonyl)-β-D-glucopyranoside was synthesized as described for example 117 from trimethylsilyethoxy-6-O-toluenesulfonyl-β-D-glucopyranoside (100 mg, 230.11 μmol) and 2-methyl-3-phenoxybenzoic acid (84.31 mg, 345.16 μmol).

Yield: 73 mg (52.6%)

[0580] LC/MS (ES-API): m/z=551.16 [M−H+formic acid].sup.−; calculated: 551.23 tR (λ=220 nm): 1.84 min (LC/MS-Method 2)

EXAMPLE 130

6-O-(3-phenoxyphenylcarbonyl)-D-glucopyranose

[0581] ##STR00160##

[0582] To a solution of allyl-6-O-(3-phenoxyphenylcarbonyl)-β-D-glucopyranoside (Example 125; 110 mg, 264.15 μmol) in MeOH (2 mL) Pd (II)chloride (9.37 mg, 52.83 μmol) was added. After 3 h at 25° C. the reaction was controlled by LC/MS. A product with the desired mass could be detected. MeOH was added (4 mL) and the product was purified by HPLC.

Yield: 51 mg (53%, mixture of anomers)
LC/MS (ES-API): m/z=375.14 [M−H+formic acid].sup.−; calculated: 375.12 tR (λ=220 nm): 1.45/1.43 min (Mixtuure of anomers, LC/MS-Method 2)
.sup.1H NMR (400.23 MHz, DMSO-d6) d ppm 7.72 (m,1 H), 7.48 (m, 4 H), 7.31(ddd, J=8.10, 2.54, 0.86Hz, 1H), 7.21 (m, 1H),7.08 (m, 2H), 4.91 (d,J=3.55 Hz, 1H), 4.52 (dd,J=11.74, 1.83 Hz, 1H),4.47 (dd, J=11.68, 1.90 Hz, 1H), 4.31 (m, 2H), 3.88 (m, 1H), 3.48 (br s, 4H), 3.16 (m, 4H).

EXAMPLE 131

6-O-(4-Phenoxyphenylcarbonyl)-D-glucopyranose

[0583] ##STR00161##

[0584] 6-O-(4-phenoxyphenylcarbonyl)-D-glucopyranose was syntzhesized as described for example 129 from Allyl-6-O-(4-phenoxyphenylcarbonyl)-β-D-glucopyranoside (Example 126; 110 mg, 264.15 mg) as described for Example 129.

Yield: 46 mg (46.3%, mixture of anomers)
LC/MS (ES-API): m/z=375.09 [M−H].sup.−; calculated: 375.12 tR (λ=220 nm): 1.46/1.44 min (Mixture of anomers, LC/MS-Method 2)

EXAMPLE 132

6-O-(2-Methyl-4-phenoxyphenylcarbonyl)-D-glucopyranose

[0585] ##STR00162##

[0586] To a solution of Trimethylsilyethyl-6-O-(2-methyl-3-phenoxyphenylcarbonyl)-β-D-glucopyranoside (Example 127, 60 mg, 122.29 μmol) in CH.sub.2Cl.sub.2 (1. 8 mL) TFA (200 μl, 2.60 mmol) was added under Argon atmosphere wurde. After 5 h LC/MS analysis showed consumption of starting material and one new peak could be detected. The reaction mixture was diluted with Water and freeze dried. The product was purified by HPLC.

Yield: 42 mg (88%mixture of anomers)
LC/MS (ES-API): m/z=389.16 [M−H].sup.−; calculated: 389.13 tR (λ=220 nm): 1.53/1.51 min (Mixture of anomers, LC/MS-Method 2)

EXAMPLE 133

6-O-(3-Chloro-3′methyloxy-4-phenoxyphenylcarbonyl)-D-glucopyranose

[0587] ##STR00163##

[0588] 6-O-(3-Chloro-3′methyloxy-4-phenoxyphenylcarbonyl)-D-glucopyranose was synthesized from trimethylsilyethyl-6-O-(3-chloro-3′-methoxy-4-phenoxyphenylcarbonyl)-β-D-glucopyranoside (128; 60 mg, 110.89 μmol) as described for example 131

Yield: 42 mg (85.9%, mixture of anomers)
LC/MS (ES-API): m/z=485.1/487.0 [M−H+formic acid].sup.−; calculated: 485.12 tR (λ=220 nm): 1.55/1.53 min (Mixture of anomers, LC/MS-Method 2)

EXAMPLE 134

6-O-(4-Hydroxy-2-methyl-phenylcarbonyl)-D-glucopyranose

[0589] ##STR00164##

[0590] 6-O-(3-Chloro-3′methyloxy-4-phenoxyphenylcarbonyl)-D-glucopyranose was synthesized from trimethylsilyethyl-6-O-(4-hydroxy-2-methylphenyl)carbonyl-β-D-glucopyranoside (21 mg, 50.66 μmol) as described for example 131

Yield: 16 mg (quantitative, mixture of anomers)
LC/MS (ES-API): m/z=313.06 [M−H].sup.−; calculated: 313.10 tR (λ=220 nm): 0.72/0.64 min (Mixture of anomers, LC/MS-Method 2)
.sup.1H NMR (400.23 MHz, DMSO-d6) d ppm 10.11 (d, J=4.77 Hz, 1 H), 7.75 (d, J=7.58 Hz, 1H), 6.67 (m, 2H), 6.32 (br d, J=3.55 Hz, 1H), 5.14 (br s, 1H), 5.08 (br s, 1H), 4.92 (br s, 1H), 4.74 (br s, 1H), 4.50 (br s, 1H), 4.43 (ddd, J=17.76, 11.71, 1.71 Hz, 1H), 4.33 (br s, 1H), 4.20 (m, 1H), 3.87 (m, 1H), 3.48 (u), 3.16 (m, 3H), 2.92 (br t, J=8.19, 8.19 Hz, 1H).

EXAMPLE 135

6-O-(3-Methyloxy-4-phenoxyphenylcarbonyl)-D-glucopyranose

[0591] ##STR00165##

[0592] 6-O-(3-Methyloxy-4-phenoxyphenylcarbonyl)-D-glucopyranose was synthesized from trimethylsilyethyl-6-O-(3-chloro-3′-methoxy-4-phenoxyphenylcarbonyl)-β-D-glucopyranoside (128; 60 mg, 110.89 μmol) as described for example 131

Yield: 42 mg (85.9%, mixture of anomers)
LC/MS (ES-API): m/z=405.09 [M−H].sup.−; calculated: 405.13 tR (λ=220 nm): 1.43/1.41 min (Mixture of anomers, LC/MS-Method 2)
.sup.1H NMR (400.23 MHz, DMSO-d6) d ppm 7.64 (m, 1H), 7.58 (d, J=8.60 Hz, 1H), 7.37 (t, J=7.64, 7.64 Hz, 2H), 7.13 (t, J=7.04, 7.04 Hz, 1H), 7.06 (d, J=8.58 Hz, 1H), 6.95 (d, J=8.44 Hz, 2H), 4.93 (d, J=3.42 Hz, 1H), 4.51 (m, 1H), 4.32 (m, 1H), 3.91 (br dd, J=9.90, 3.91 Hz, 1H), 3.84 (s, 3H), 3.49 (br s, 2H), 3.46 (br d, J=9.17 Hz, 3H), 3.18 (m, 5H), 2.93 (br t, J=8.19, 8.19 Hz, 1H), 2.50 (u), 2.33 (br s, 1H)

EXAMPLE 136

1,2:3,4-Diisopropyliden-6-O-(3-Methoxy-4-phenoxy)-phenylcarbonyl-D-glucopyranose

[0593] ##STR00166##

Lit: Angew. Chem. Int. Ed. 2008, 47, 8264 -8267

[0594] A solution of 3-Methoxy-4-phenoxybenzoic acid (93,84 mg, 384, 19 μmol) in CH2Cl2 (1,5 ml) was stirred under argon atmosphere at 0° C. Consecutively a solution of 1,2:3,4-Di-O-isopropyliden-D-galactose (100 mg, 384.19 μmol) in DMF (1 mL), DMAP (9.39 mg, 76.84 μmol) and finally DCC (79.27 mg, 384.19 μmol) where added and the reaction was kept at 0° C. for 10 min. The reaction mixture was left at 25° C. for 16 h. The desired mass could be detected by LC/MS. The reaction mixture was diluted with MeOH (2 mL) filtrated and the product finally purified by HPLC,

Yield: 154 mg (82.4%)

[0595] LC/MS (ES-API): m/z=487.20 [M−H].sup.−; calculated: 487.19 tR (λ=220 nm): 2.72 min (LC/MS-Method 2)
.sup.1H NMR (400.23 MHz, DMSO-d6) d ppm 7.63 (d, J=1.71 Hz, 1H), 7.57 (dd, J=8.38, 0.90 Hz, 1H), 7.38 (t, J=7.95, 7.95 Hz, 2H), 7.14 (t, J=7.16, 7.16 Hz, 1H), 7.00 (m, 3H), 0.48 (d, J=5.01 Hz, 1H), 4.65 (dd, J=7.95, 2.32 Hz, 1H), 4.36 (m, 4H), 4.12 (m, 1H), 3.83 (s, 3H), 3.46 (u), 2.50 (u), 1.44 (s, 3H), 1.39 (s, 3H), 1.31 (s, 3H), 1.28 (s, 3H)

EXAMPLE 137

6-O-(3-Methoxy-4-phenoxyphenylcarbonyl)-D-glucopyranose

[0596] ##STR00167##

[0597] 1,2:3,4-Diisopropyliden-6-O-(3-methoxy-4-phenoxyphenylcarbonyl)-D-glucopyranose (154 mg, 316.54 pmol) was dissolved in acetonitril. Under argon atmosphere HCl (2.37 ml, 4.75 mmol) was added and the Reaction mixture was stirred at 40° C. for 16 h.

[0598] Water was added and the product was freeze dried. The product was finally purified by HPLC.

Yield: 51 mg (39.6%) (Mixture of Anomers)

[0599] LC/MS (ES-API): m/z=389.1 [M+H−H.sub.2O]+; calculated: 389.11 tR (λ=220 nm): 1.58/1.60 min (LC/MS-Method 2)

EXAMPLE 138

6-O-(3-Chloro-3′Methoxy-4-phenoxyphenylcarbonyl)-D-glucopyranose

[0600] ##STR00168##

[0601] 6-O-(3-Chloro-3′Methoxy-4-phenoxyphenylcarbonyl)-D-glucopyranose was synthesized as described for example 136 from 1,2:3,4-Diisopropyliden-6-O-(3-chloro-3′methoxy-4-phenoxy)phenylcarbonyl-D-glucopyranose (150 mg, 287.93 μmol).

Yield: 93 mg (73. 3%).

[0602] LC/MS (ES-API): m/z=423.1/425.1 [M+H—H.sub.2)].sup.+; calculated: 423.07 tR (λ=220 nm): 1.76/1.78 min (LC/MS-Method 2)

EXAMPLE 139

Step 1: Amide Coupling

4-(2,4-Dichlorophenyl)piperazin-1yl-(1,2:3,4-diisopropyliden)-D-galacturonic acid amide

[0603] ##STR00169##

[0604] A solution of 1,2:3,4-Diisopropyliden-D-galacturonic acid (150 mg, 546.91 μmol) in DMF (5 ml) under argon atmosphere was treated with HATU (291.14 mg, 765.67 μmol) and the reaction mixture stirred for 5 min. 1-(2,4-dichlorophenyl)piperazine (176.96 mg, 765.67 μmol) was added and the reaction mixture was stirred at 25° C. The reaction was monitored by LCMS. After 24 h starting material could be detected, DIPEA (2,2 equivalents) was added and the reaction mixture left for another 24 h at 25° C. CH2Cl2 (1×10 ml) and water were added and the product extracted. The organic layer was dried, the solvens evaporated and the product purified by HPLC.

Yield: 163 mg (61.2%)

EXAMPLE 140

Step 2: Deprotection

4-(2,4-Dichlorophenyl)piperazin-1-yl-D-galacturonic acid amide

[0605] ##STR00170##

[0606] A suspension of 4-(2,4-Dichlorophenyl)piperazin-1yl-(1,2:3,4-Diisopropyliden)-D-galacturonic acid amide (163 mg, 334.45 μmol) was treated with aqueous HCl (2.51 ml, 5.02 mmol) under argon atmosphere and left for 16 h at 25° C. The reaction was monitored by LC/MS, starting material could still be detected. The reaction mixture was dissolved in MeOH and again treated with HCl (2.5 mL) and left at 25° C. for 16 h. Methanol was evaporated, the residue diluted with water and freeze dried. The product was purified by HPLC.

Yield: 46 mg (28. 3%)

[0607] LC/MS (ES-API): m/z=407.1/409.0/411. [M+H]+; calculated: 407.24 tR (λ=220 nm): 1.46/1.48 min (LC/MS-Method 2)

EXAMPLE 140

Step 1: Preparation of Substituted Amine

(R)-2-((benzyloxy)methyl)-4-chloro-piperazine

[0608] ##STR00171##

Lit.: ACS Med. Chem. Lett., 2015, 6 (10), pp 1041-1046

[0609] A solution of tert-butyl (R)-2-((benzyloxy)methyl)piperazine-1-carboxylate (333.98 mg, 1.09 mmol), 1-bromo-4-chlorobenzene (227.46 mg, 1.19 mmol) and BINAP (40.72 mg, 65.40 μmol) in toluene (5 ml) was treated with Pd(II)acetate(9.79 mg, 43.60 μmol) under argon atmosphere. KoTBu (183.47 mg, 1.64 mmol) was added and the reaction mixture was irradiated in the microwave for 30 min at 130° C.

[0610] EtOAc and H.sub.2O where added, the reaction mixture filtered, and the filtrate washed with brine. The solvens was evaporated and the residue purified by HPLC.

Yield; 142 mg (41%)

Step 2: Reductive amination

6-Desoxy-6-((R)-2-((benzyloxy)methyl)-4-chlorophenyl)-piperazin-1-yl-(1,2:3,4-diisopropyliden)-D-galactopyranose

[0611] ##STR00172##

[0612] To a solution of (3aR,5S,5aR,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4′,5′-d]pyran-5-carbaldehyde (125.54 mg, 486.07 μmol) in methanol (2 ml), (R)-3-((benzyloxy)methyl)-1-(4-chlorophenyl)piperazine (140 mg, 441.88 μmol), acetic acid (50.59 μl, 883.76 μmol) and sodiumcyanoborhydride (58.46 mg, 883.76 μmol) are added. The reaction mixture was left for 16 h at 25° C. LCMS showed consumption of starting material. The reaction mixture was evaporated and the product purified by HPLC.

Yield: 105 mg (40%)

Step 3: Deprotection

Methyl-6-desoxy-6-((R)-2-((benzyloxy)methyl)-4-chlorophenyl)-piperazin-1-yl-D-galactopyranoside

[0613] ##STR00173##

[0614] A suspension of 6-desoxy- 6-(4-chlorophenyl)piperazino-(1,2:3,4-diisopropyliden)-D-galactopyranose (103 mg, 172,95 μmol) in MeOH (2 mL) is treated with mit HCl (1.73 ml, 3.46 mmol) and stirred for 2 h and left for 16 h at 25° C.

Yield: 13 mg (12.4%)

[0615] LC/MS (ES-API): m/z=479.3/481.3. [M+H]+; calculated: 478.20 tR (λ=220 nm): 1.37 (LC/MS-Method 2)
1H NMR (400.23 MHz, DMSO-d6) d ppm 9.62 (br s, 1H), 7.35 (m, 8 H), 7.02 (br d, J=8.80 Hz, 2H), 5.05 (br s, 1H), 4.93 (br s, 1H), 4.58 (m, 3H), 4.38 (br d, J=5.50 Hz, 1H), 4.28 (br d, J=10.03 Hz, 1H), 3.95 (br s, 1H), 3.89 (br d, J=10.64 Hz, 2H), 3.77 (m, 4H), 3.64 (br d, J=6.85 Hz, 1H), 3.57 (m, 4H), 3.17 (br s, 1H), 3.01 (m, 2H), 2.50 (u) 1H NMR (250.13 MHz, DMSO-d6) d ppm 7.29 (m, 6H), 6.92 (m, 2H), 5.02 (m, 1H), 4.55 (s, 2H), 3.80 (m, 4H), 3.63 (m, 1H), 3.52 (br s, 2H), 3.18 (m, 7H), 2.93 (br s, 97H), 2.75 (br s, 4H), 2.50 (u).

SYNTHESIS OF EXAMPLE 141

Step 1: Reductive Amination

6-Desoxy- 6-(3-hydroxyphenyl)-piperazin-1-yl-(1,2:3,4-diisopropyliden)-D-galactopyranose

[0616] ##STR00174##

[0617] (3aR,5S,5aR,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4′,5′-d]pyran-5-carbaldehyde (239.09 mg, 925.74 μmol) was dissolved in MeOH (3 ml). 3-(piperazin-1-yl)phenol (150 mg, 841.59 μmol), acetic acid, (96.36 μl, 1.68 mmol) and NaCNBH3 (111.34 mg, 1.68 mmol) where added and the reaction mixture stirred for 3 h and left for 16 h at 25° C. The reaction was monitored by LCMS. Starting material was consumed. The solvens was evaoporated, the resuidue taken up in EtOAc/H2O and the product extracted with EtOAc and finally purified by HPLC.

Yield: 280 mg (72.8%)

Step 2: Activation of Spacer

Undec-10-yn-1-yl 4-methylbenzenesulfonate

[0618] ##STR00175##

Lit.: Tetrahedron 56 (2000) p1233-1245

[0619] Undec-10-yn-1-ol (343.17 μl, 2.97 mmol) was dissolved in CH.sub.2Cl.sub.2 (10 ml) under argon atmosphere. 4-Methylbenzenesulfonyl chloride (810.01 mg, 4.25 mmol) was added and the reaction mixture cooled to 0° C. Pyridine (355.67 μl, 4.40 mmol) was added dropwise over 5 min and the reaction mixture was stirred for 3 h at 0° C. The ice bath was removed and the solution was left for 16 h at 25° C. The reaction was monitored by LCMS. 1 N HCl was added and the product extracted with CH.sub.2Cl.sub.2. The solvens was removed in vacuo and the product purified by HPLC

Yield: 1.57 g (29.3%)

Step 3: Ether Coupling

6-Desoxy- 6-(3-undecenyloxyphenyl)-4-piperazin-1-yl-(1,2:3,4-diisopropyliden)-D-galactopyranose

[0620] ##STR00176##

[0621] A mixture of 6-desoxy- 6-(3-hydroxyphenyl)-piperazin-1-yl-(1,2:3,4-diisopropyliden)-D-galactopyranose Hydrochlorid (275 mg, 601.80 μmol) and undec-10-yn-1-yl 4-methylbenzenesulfonate (445.78 mg, 842.52 μmol) was treated with Cesiumcarbonat (980.39 mg, 3.01 mmol). DMF (2mL) was added and the reaction mixture was iiradiated in the microwave at 80° C. for 1 h. LCMS showed the expected mass. The product was extracted with EtOAc/H.sub.2O, the organic layer washed with aqueous NaCL solution (10%) and dried. The solvens was evaporated in vacuo and the product purified by HPLC.

Yield: 105 mg (28.7%)

Step 3: Deprotection

EXAMPLE 141

6-Desoxy- 6-(3-undecenyloxypheny)-4-piperazin-1-yl-D-galactopyranose

[0622] ##STR00177##

[0623] 6-Desoxy- 6-(3-undecenyloxyphenyl)-4-piperazin-1-yl-(1,2:3,4-diisopropyliden)-D-galactopyranose (101 mg, 166,33 pmol) was treated with 2 n HCl (1.66 ml, 3.33 mmol) and then heated for 2 h at 80° C. LCMS showed consumption of starting material, the reaction mixture was diluted with H.sub.2O and freeze dried.

Yield; 18 mg (20.5%)

SYNTHESIS OF EXAMPLE 142

6-Desoxy- 6-(1-(4-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)piperazin-1yl-D-galactopyranose

[0624] ##STR00178##

[0625] The synthesis of example 142 was following the procedure described for example 141 starting from 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethan-1-ol (500 mg, 2.66 mmol) and 4-methylbenzenesulfonyl chloride (759.63 mg, 3.98 mmol) to yield the activated spacer (2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl 4-methyl-benzenesulfonate, yield: 420 mg, 46.2%).

[0626] In parallel 6-Desoxy- 6-(4-hydroxyphenyl)-piperazin-1-yl-(1,2:3,4-diisopropyliden)-D-galactopyranose (269 mg, 639.71 pmol) was prepared and then coupled with (2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl 4-methyl-benzenesulfonate (262.85 mg, 767.65 μmol) to yield. 6-desoxy- 6-(1-(4-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)piperazin-1yl-(1,2:3,4-diisopropyliden)-D-galactopyranose (180 mg, 47.6%), which was then deprotected with aqueous HCl.

Yield: 130 mg (69.5%)

[0627] LC/MS (ES-API): m/z=511.38 [M+H]+; calculated: 510.25 tR (λ=220 nm): 0.98 (LC/MS-Method 2)

EXAMPLE 143

Biological Assays

1. HepG2 Assay:

Procedure

[0628] For measurement of .sup.14C 2-deoxy-D-glucose transport into HepG2 cells, cells were seeded in collagen treated 96-well plates (Cytostar-T Plates Perkin Elmer, 40.000 cells/200p/well) in medium complete (MEM W/GLUT-I, EARLES (Gibco #41090)/NEAA/PS/10% FCS) and grown for 48 hours. After starvation for 2 hours with MEM W/GLUT-I,EARLES (Gibco #41090)/NEAA/no serum 100 μl/well and washing twice with 200 μL KRB buffer, cells were stimulated in a dose dependent manner by adding 20 μL of test compound dilution 0-750 μM (7.5 times higher concentration than final) or 20 μL of 188 μM Cytochalasin B solution as negative control, to 80 μL KRB buffer and incubated for 30 minutes. After compound stimulation, the transport of .sup.14C 2-deoxy-D-glucose was started by adding of 50 μL .sup.14C 2-deoxy-D-glucose solution (250 μM 2-deoxy-D-glucose cold and 15 μM .sup.14C 2-deoxy-D-glucose 0.13 μCi/well) for 20 minutes. Transport was stopped by adding 50 μL/well 40 μM Cytochalasin B solution. Plates were measured in a 96-well Wallac Microbeta device. The cpm (counts per minute) values were used to determine the % inhibition values for the test compounds within each experiment, which then are averaged over the number of experiments performed.

TABLE-US-00041 Table of results: % inhibition of .sup.14C-2-deoxy-glucose Example transport [100 μM] SD 1 6.32 6.32 ± 3.81 2 6.50 6.50 ± 4.16 6 7.75 7.75 ± 3.28 7 6.99 6.99 ± 2.52 8 7.67 7.67 ± 5.12 9 5.11 5.11 ± 3.56 12 5.43 5.43 ± 6.31 14 5.67 5.67 ± 5.11 19 6.89 6.89 ± 6.28 21 7.53 7.53 ± 3.59 22 11.40 11.40 ± 3.95  27 13.06 13.06 ± 1.96  28 9.95 9.95 ± 1.83 29 18.44 18.44 ± 3.80  34 20.47 20.47 ± 3.07  36 20.63 20.63 ± 3.24  37 6.88 6.88 ± 1.71 38 12.70 12.70 ± 1.51  39 10.99 10.99 ± 4.75  40 10.08 10.08 ± 7.98  45 29.31 29.31 ± 4.46  46 8.76 8.76 ± 2.67 47 13.82 13.82 ± 5.23  48 28.82 28.82 ± 4.82  49 19.91 19.91 ± 3.87  50 13.84 13.84 ± 1.91  51 17.86 17.86 ± 6.82  52 14.55 14.55 ± 3.95  53 23.89 23.89 ± 5.32  54 10.48 10.48 ± 8.16  55 12.39 12.39 ± 2.89  56 21.08 21.08 ± 2.76  57 24.14 24.14 ± 5.94  58 19.98 19.98 ± 5.00  59 7.56 7.56 ± 4.50 60 14.75 14.75 ± 4.72  61 9.42 9.42 ± 6.75 63 37.62 37.62 ± 4.09  64 8.86 8.86 ± 3.67 65 7.79 7.79 ± 2.92 66 5.12 5.12 ± 6.07 67 25.77 25.77 ± 3.88  69 6.14 6.14 ± 6.61 75 31.19 31.19 ± 6.64  79 25.54 25.54 ± 3.49  88 31.37 31.37 ± 1.75  92 23.10 23.10 4.60

2. Glucose Displacement Assay (ATP Measurement)

[0629]

TABLE-US-00042 Reagent Provider Catalogue n. CellTiter-Glo ® Luminescence Promega G-7571 Cell Viability Assay A2780 Human Carcinoma Cell ECACC 93112519 line 96-well LIA plate, white Greiner Bio-one 655073 RPMI 1640 medium GlutaMAX Thermo Fisher 61870 Scientitic RPMI 1640 medium (no glucose) Thermo Fisher 11879 Scientific Fetal Bovine Serum Pan Biotech P-30-3305 D-(+)-Glucose solution Sigma Aldrich G-8644 PBS buffer Life Technologies 14190 KRB buffer PAN P05-32500* DMSO Sigma D-2650 Rotenone Sigma R-8875 *Customer Formulation, sterile filtered: 1.7 mM CaCl.sub.2 × 2H.sub.2O; 1.2 mM KH.sub.2PO.sub.4; 4.8 mM KCl; 1.2 mM MgSO.sub.4 × 7H.sub.2O; 120 mM NaCl; 26 mM NaHCO.sub.3

[0630] 30.000 A2780 Human Carcinoma Cells are seeded per well in a Greiner 96-well plate. Cells are expanded and cultured in RPMI 1640 medium+GlutaMAX® with 10% FCS and 11 mM glucose, at 37° C. with 5% CO2. After 44 h, culture media is changed and washed once with PBS to starvation media consisting of RPMI 1640 medium with 1% FCS without glucose for 2 hours. Cells are then washed with KRB buffer, followed incubation for 20 min at 37° C. of the treatment mix consisting of: 60 μL KRB buffer/well with 10 μL of compound or DMSO 10×. 10 μl of rotenone is added to the mix to a final concentration of 0.5 μM. Cell plates are left for 2 min at room temperature. 20 μL of different glucose concentrations are added to the mix—typically 0.1 to 20 mM range—. Cells are incubated for another 15 min at 37° C., before measuring ATP with the CellTiter-Glo® Assay, under manufacturer's guidance, but without the equilibration step at room temperature for 30 min. In brief, 100 μl of Cell-Titer-Glo® Reagent is added to the wells containing already 100 μl of the previous reaction mix. Plates are mixed for 2 min at 800 rpm, followed by incubation at room temperature for 10 min to stabilize the luminescent signal. Luminescence is then recorded with the Tekan Ultra Evolution reader.

EXAMPLE 140: IC.SUB.50 .67.9 μM

EXAMPLE 141: IC.SUB.50 .84.8 μM

EXAMPLE 138: IC.SUB.50 .8.37 μM (>100 μM@10 mM Gluc)

EXAMPLE 124: IC.SUB.50 .33.2 μM (>100 μM@10 mM Gluc)

3. Erythrocyte Dialysis Assay

[0631] 6-NBD Glc (6-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-6-Deoxyglucose) is a small fluorescent glucose derivative, which has been shown to bind to GluT-1 in astrocytes (L. F. Barros et al., JOURNAL OF NEUROCHEMISTRY 109 (2009) 94-100). Here 6-NBD-Glc or alternatively 2-NBD-Glc was used in dialysis based competition experiments.

[0632] Freshly isolated heparinized rat blood samples were immideately diluted (1:5) in PBS buffer to generate a stable stock solution. This stock solution was further diluted (1:1 or 1:3) for the following dialysis experiments in Rapid Equilibrium Dialysis (RED) devices (Thermo Scientific Pierce).

[0633] The aforementioned stock solution was further diluted (1:1 or 1:3 respectively) and added to the dialysis compartiment of a RED device. In parallel stock solution was diluted (1:1) with buffer containing 6 NBD Glc (25 μM).

[0634] Dialyses was started by addition of 6 NBD Glc (25 μM) in PBS Buffer (k.sup.on) or pure PBS buffer (k.sup.off) respectively into the buffer compartiment. Aliquots (20 μl) were taken after defined time intervals from the buffer compartiment and fluorescence was measured in a UV plate reader (Thermovarioskan, Thermo).

[0635] As a control, free diffusion of 6-NBD-Glc (25 μM) in PBS buffer vs pure buffer was measured.

Data are Given in the Following Table:

[0636]

TABLE-US-00043 Time 1:1 Dilution 1:1 Dilution Diffusion (min) k.sup.on k.sup.off (Control) 0 55 0 0 30 50.6 3.4 3.7 60 45.1 6.5 7.5 90 33 12 9.2 120 34 16.1 10
Graphical evaluation of the different slopes gave a K.sub.D=0.68 for 6-NBD-Glc. K.sup.on=0.199; K.sup.off=0.136; K.sub.D=0.136/0.199; K.sub.D=0.68: 68% free.

[0637] FIG. 1: Fluorescence intensity [AU] is plotted vs time [min].

[0638] Squares: Decreasing fluorescence intensity measured in buffer compartiment, due to binding to eyrothrocytes.

[0639] Triangles: Increasing fluorescence intensity measured in buffer compartiment, due to release from erythrocytes.

[0640] K.sub.D was calculated from the slopes: K.sub.D=0.68 for 6-NBD-Glc.

[0641] Glucose dependency was determined following the protocol described above, comparing the following solutions: 6 NBD-Glc (100 μM), 6 NBD-Glucose (100 μM)+Glucose 20 mM. Data are shown in the next table

TABLE-US-00044 Time 6-NBD-Glc NBD-Glc [50 μM] + (min) [50 μM] Glc [10 mM] 0 0 0 15 7.5 7.2 30 10.6 11.9 60 11.1 17 90 14.9 18.5 120 15.8 20.3 180 16 22.5
Free concentration of 6-NBD-Glc is increased in presence of Glc [10 mM].

[0642] FIG. 2: Fluorescence intensity [AU] is plotted vs time [min].

[0643] Increase of fluorescence in buffer compartiment in presence (squares) or absence of glucose (rhombus).

[0644] Example 102 was investigated in a competition experiment following the same protocol using a 6-NBD-Glc solution (100 μM) in comparison to 6 NBD-Glucose (100 μM)+Example 102 (50 μM). The results are shown in the following table

TABLE-US-00045 Time Example 102 (min) [25 μM] Control 0 0 0 15 4.9 0.9 30 11.1 2.2 60 12.5 3.3 90 19.3 3.8 120 25.1 8 180 32.1 10.1

[0645] FIG. 3: Fluorescence intensity [AU] is plotted vs time [min].

[0646] In presence of the Example 102 a clear increase in the slope (rhombus) is seen in comparison to control (squares) indicating the competition with 6-NBD-Glc.