FURANEOL GLYCOSIDE COMPOUND, PHARMACEUTICAL COMPOSITION THEREOF, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF

Abstract

Disclosed are a furaneol glycoside compound, a pharmaceutical composition thereof, a preparation method therefor, and an application thereof. Specifically disclosed are a compound as represented by formula A-1, a pharmaceutically acceptable salt thereof or a crystal form thereof. Also disclosed is a pharmaceutical composition, which comprises the compound as represented by formula A-1, the pharmaceutically acceptable salt thereof, and a pharmaceutical adjuvant. Also disclosed is an application of the compound as represented by formula A-1, the pharmaceutically acceptable salt thereof, the crystal form thereof, or the pharmaceutical composition in the preparation of drugs. The drugs are drugs for treating inflammatory bowel diseases. The furaneol glycoside compound has a good effect of treating inflammatory bowel diseases, particularly ulcerative colitis.

##STR00001##

Claims

1. A compound represented by formula A-1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a crystal form thereof, ##STR00062## wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen, C.sub.1-4 alkyl, benzyl, —C(═O)R, or —C(═O)—O—R′, and R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are not simultaneously hydrogen; each R.sup.1 is independently C.sub.1-4 alkyl; each R is independently C.sub.1-4 alkyl or phenyl; R.sup.5 and R.sup.6 are independently hydrogen, or R.sup.5 and R.sup.6 are taken together to form ═O; R.sup.8 and R.sup.9 are independently C.sub.1-4 alkyl; alternatively, R.sup.8 and R.sup.9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 3- to 7-membered cycloalkyl substituted with one or a plurality of R.sup.a, or 3- to 7-membered heterocycloalkyl substituted with one or a plurality of R.sup.b; in the 3- to 7-membered heterocycloalkyl and the 3- to 7-membered heterocycloalkyl substituted with one or a plurality of R.sup.b, the heteroatoms in the 3- to 7-membered heterocycloalkyl are independently selected from N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; R.sup.a and R.sup.b are independently C.sub.1-4 alkyl, —C(═O)R″; each R″ is independently C.sub.1-4 alkyl; carbon atoms marked with “*” indicate that when the carbon atoms are chiral, the carbon atoms are in the R-configuration, S-configuration, or a mixture of R-configuration and S-configuration.

2. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvate thereof, or the crystal form thereof as claimed in claim 1, wherein the structure of the compound represented by formula A-1 is as follows: ##STR00063## wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen, C.sub.1-4 alkyl, benzyl or —C(═O)R, and R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are not simultaneously hydrogen; each R is independently C.sub.1-4 alkyl or phenyl.

3. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvent thereof, or the crystal form thereof as claimed in claim 1, wherein when R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently C.sub.1-4 alkyl, then the C.sub.1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; or, each R.sup.1 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; or, when each R is independently C.sub.1-4 alkyl, then the C.sub.1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; or, when R.sup.8 and R.sup.9 are independently C.sub.1-4 alkyl, then the C.sub.1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; or, when R.sup.8 and R.sup.9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered cycloalkyl or 3- to 7-membered cycloalkyl substituted with one or a plurality of R.sup.a, then the 3- to 7-membered cycloalkyl is a 5- to 6-membered cycloalkyl; or, when R.sup.8 and R.sup.9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered heterocycloalkyl or 3- to 7-membered heterocycloalkyl substituted with one or a plurality of R.sup.b, in the 3- to 7-membered heterocycloalkyl, the heteroatoms are independently selected from N and O, and the number of heteroatoms is independently 1; or, when R.sup.8 and R.sup.9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered heterocycloalkyl or 3- to 7-membered heterocycloalkyl substituted with one or a plurality of R.sup.b, then the 3- to 7-membered heterocycloalkyl is a 5- to 6-membered heterocycloalkyl; or, when R.sup.a and R.sup.b are independently C.sub.1-4 alkyl, then the C.sub.1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; or, each R″ is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

4. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvent thereof, or the crystal form thereof as claimed in claim 3, wherein when R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently C.sub.1-4 alkyl, then the C.sub.1-4 alkyl is methyl; or, each R.sup.1 is independently ethyl; or, when each R is independently C.sub.1-4 alkyl, then the C.sub.1-4 alkyl is methyl or tert-butyl; or, when R.sup.8 and R.sup.9 are independently C.sub.1-4 alkyl, then the C.sub.1-4 alkyl is methyl; or, when R.sup.8 and R.sup.9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered heterocycloalkyl, then ##STR00064## is ##STR00065## or, each R″ is independently methyl; or, when R.sup.8 and R.sup.9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered heterocycloalkyl substituted with one or a plurality of R.sup.b, then ##STR00066## is ##STR00067##

5. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvent thereof, or the crystal form thereof as claimed in claim 1, wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen, C.sub.1-4 alkyl, —C(═O)R, or —C(═O)—O—R′; or, each R is independently C.sub.1-4 alkyl; or, R.sup.a and R.sup.b are independently —C(═O)R″; or, R.sup.8 and R.sup.9 are independently C.sub.1-4 alkyl, or, R.sup.8 and R.sup.9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, or 3- to 7-membered heterocycloalkyl substituted with one or a plurality of R.sup.b; or ##STR00068## is ##STR00069##

6. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvate thereof, or the crystal form thereof as claimed in claim 5, wherein R.sup.1 is C.sub.1-4 alkyl, —C(═O)R, or —C(═O)—O—R′; or, when R.sup.5 and R.sup.6 are independently hydrogen, then R.sup.1 is —C(═O)R or —C(═O)—O—R′; when R.sup.5 and R.sup.6 are taken together to form =0, then R.sup.1 is C.sub.1-4 alkyl; or, R.sup.2 and R.sup.3 and R.sup.4 are independently hydrogen or —C(═O)R; or, each R is independently methyl or tert-butyl; or, R.sup.a and R.sup.b are independently ##STR00070## or, R.sup.8 and R.sup.9 are independently C.sub.1-4 alkyl, or, R.sup.8 and R.sup.9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl; ##STR00071## is ##STR00072##

7. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvate thereof, or the crystal form thereof as claimed in claim 5, wherein R.sup.1 is methyl, ##STR00073## or, R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen, ##STR00074## or, R.sup.2, R.sup.3, and R.sup.4 are the same group; or, ##STR00075## is ##STR00076##

8. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvate thereof, or the crystal form thereof as claimed in claim 2, wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen or —C(═O)R; or, each R is independently C.sub.1-4 alkyl.

9. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvate thereof, or the crystal form thereof as claimed in claim 2, wherein when R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently C.sub.1-4 alkyl, then the C.sub.1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; or, each R is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or phenyl; or, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are the same group; or, the structure of the said compound represented by formula A is as follows: ##STR00077## or a mixture of ##STR00078## in a molar ratio of 1:1

10. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvent thereof, or the crystal form thereof as claimed in claim 1, wherein the compound represented by formula A-1 is any of the following compounds, ##STR00079## ##STR00080## ##STR00081##

11. A pharmaceutical composition comprising a compound as represented by formula A-1, a pharmaceutically acceptable salt thereof, and a pharmaceutical adjuvant; ##STR00082## wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen, C.sub.1-4 alkyl, benzyl, —C(═O)R, or —C(═O)—O—R; R, R′, *, R.sup.5, R.sup.6, R.sup.8, and R.sup.9 are defined as claimed in claim 1.

12. The pharmaceutical composition as claimed in claim 11, wherein the structure of the compound represented by formula A-1 is as follows: ##STR00083## wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen, C.sub.1-4 alkyl, benzyl, —C(═O)R; R is defined as above.

13. The pharmaceutical composition as claimed in claim 11, wherein the pharmaceutical composition is a pharmaceutical composition for treating inflammatory bowel disease; or, when R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently C.sub.1-4 alkyl, then the C.sub.1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; or, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen, —C(═O)R, or —C(═O)—O—R′; or, R.sup.2, R.sup.3, and R.sup.4 are the same group; or, ##STR00084## is ##STR00085## or, the structure of the compound represented by formula A is as follows: ##STR00086## or a mixture of ##STR00087## in a molar ratio of 1:1.

14. The pharmaceutical composition as claimed in claim 11, wherein R.sup.1 is C.sub.1-4 alkyl, C(═O)R, or —C(═O)—O—R′; or, R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen or —C(═O)R; or, when R.sup.5 and R.sup.6 are independently hydrogen, then R.sup.1 is —C(═O)R or —C(═O)—O—R′; when R.sup.5 and R.sup.6 are taken together to form ═O, then R.sup.1 is C.sub.1-4 alkyl; or, ##STR00088## is ##STR00089## or, the structure of the compound represented by formula A is as follows: ##STR00090##

15. The pharmaceutical composition as claimed in claim 11, wherein R.sup.1 is methyl, ##STR00091## or, R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen, ##STR00092##

16. The pharmaceutical composition as claimed in claim 11, wherein the structure of the compound represented by formula A-1 is any of the following compounds: ##STR00093## ##STR00094## ##STR00095##

17-18. (canceled)

19. A crystal form of a compound represented by formula I-2, ##STR00096## the unit cell parameters of the compound represented by formula I-2 are: a=10.5391(3) Å, α=90°; b=14.2167(4) Å, β=90°; c=15.9116(5) Å, γ=90°; space group P2.sub.12.sub.12.sub.1; preferably: TABLE-US-00014 Empirical formula C.sub.22H.sub.28O.sub.12 Formula weight 484.44 Temperature 169.99 K Wavelength 1.34139 Å Crystal system Orthorhombic system Space group P2.sub.12.sub.12.sub.1 Unit cell dimensions a = 10.5391(3) Å, α = 90° b = 14.2167(4) Å, β = 90° c = 15.9116(5) Å, γ = 90° Unit cell volume 2384.05(12) Å.sup.3 Z 4 Density (calculated) 1.350 Mg/m.sup.3 Absorption coefficient 0.607 mm.sup.−1 F(000) 1024 Crystal size 0.12 × 0.1 × 0.05 mm.sup.3 Theta range for 5.148 to 54.935° data collection Index ranges −12 <= h <= 12, −15 <= k <= 17, −19 <= l <= 19 Reflections collected 21844 Independent reflections 4478 [R(int) = 0.0451] Refinement method Full-matrix least-squares on F.sup.2

20. A pharmaceutical composition comprising the crystal form of the compound represented by formula I-2 as claimed in claim 19 and a pharmaceutical adjuvant; the pharmaceutical composition is preferably a pharmaceutical composition for treating inflammatory bowel disease; the said inflammatory bowel disease is preferably ulcerative colitis.

21-23. (canceled)

24. A method of treating inflammatory bowel disease, comprising administrating a therapeutically effective amount of substance A to a patient; the substance A comprises a compound represented by formula A-1, a pharmaceutically acceptable salt thereof, a solvate thereof, a crystal form thereof, or a pharmaceutical composition thereof; ##STR00097## wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen, C.sub.1-4 alkyl, benzyl, —C(═O)R, or —C(═O)—O—R′; *, R.sup.5, R.sup.6, R.sup.8, and R.sup.9 are defined in claim 1.

Description

DESCRIPTION OF FIGURES

[0130] FIG. 1 is the crystal structure of compound I-2.

[0131] FIG. 2 is the colons morphology of the mice in each group in effect example 1.

MODE OF CARRYING OUT THE INVENTION

[0132] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product operation instruction.

EXAMPLE 1

[0133] ##STR00051##

[0134] Step 1: 4-Hydroxy-5-methyl-3(2H)-furanone (1.14 g, 10 mmol, CAS: 19322-27-1), copper acetate (905 mg, 5 mmol), and sodium acetate (680 mg, 5 mmol) were dissolved in 10 mL of acetone and 30 mL of glacial acetic acid, heated to 50° C., stirred and refluxed for 1 hour; then diluted with 150 mL of water, and extracted the product with 100 mL of petroleum ether. the crude product was concentrated and chromatographed on silica gel (ethyl acetate/petroleum ether: ½) to give 4-hydroxy-5-methyl-2-(1-methylethylidene)-3(2H)-furanone (1.23 g, 80% yield). .sup.1H NMR (400 MHz, CD.sub.3OD) δ(ppm): 2.36 (s, 3H), 2.31 (s, 3H), 2.05 (s, 3H). ESI-MS: 155 [M+1].sup.+.

[0135] Step 2: 4-Hydroxy-5-methyl-2-(1-methylethylidene)-3(2H)-furanone (1.54 g, 10 mmol), 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (6.15 g, 15 mmol, CAS: 572-09-8), and tetrabutylammonium bromide (4.83 g, 15 mmol, CAS: 1643-19-2) were dissolved in 50 mL of dichloromethane and heated to 35° C.; 75 mL of NaOH aqueous solution (1 mol/L) was further added. After stirring for 45 minutes, 300 mL of ethyl acetate was added to extract the organic phase; the organic phase was washed three times with NaOH aqueous solution (1 mol/L), twice with water, and once with brine; the crude product was concentrated and chromatographed on silica gel (ethyl acetate/petroleum ether: 1/1) to give 4-O-[(2,3,4,6-tetra-O -acetyl)-β-D-glucosyl]-5-methyl-2-(1-methylethylidene)-3(2H)-furanone as a white solid (0.97 g, 20% yield, compound I-2). .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 5.24-5.07 (m, 4H), 4.20 (br d, J=12.3 Hz, 1H), 4.11 (br d, J=12.2 Hz, 1H), 3.68 (m, 1H), 2.25 (s, 3H), 2.19 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H), 1.99 (s, 6H), 1.97 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ(ppm): 179.24, 170.67, 170.21, 170.01, 169.63, 168.30, 143.18, 135.65, 133.01, 99.75, 72.78, 72.01, 71.23, 68.52, 61.82, 20.94, 20.80, 20.74, 19.52, 17.25, 12.62. ESI-MS: 485 [M+1].sup.+.

[0136] Cultivation of single crystal: Compound I-2 (10 mg) was dissolved in anhydrous methanol (10 mL), water (4 mL) was added. After filtered, the filtrate was transferred to a 100 mL single-neck conical flask, and allowed to stand at 0-4° C. for 1-3 days. The single crystal was precipitated and collected for single crystal X-ray diffraction.

[0137] The configuration of compound I-2 was determined by crystal X-ray diffraction, the crystal form of compound I-2 was as described in the contents of the present invention, and the crystal structure of compound I-2 was shown in FIG. 1.

[0138] Step 3: 4-O-[(2,3,4,6-tetra-O-acetyl)-β-D-glucosyl]-5-methyl-2-(1-methylethylidene)-3(2H)-furanone (4.69 g, 10 mmol) was dissolved in 100 mL of methanol and sodium carbonate (5.3 g, 50 mmol) was added. After stirring for 4 h at room temperature, the crude product was concentrated after filtration and chromatographed on a C18-bonded silica gel (methanol, 50% (v/v) aqueous solution) to give Phoenicein [4-O-β-D-glucosyl-5-methyl-2-(1-methylethylidene)-3(2H)-furanone] as an off-white solid (1.90 g, 60% yield, Compound I-1). .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 4.74 (d, J=7.8 Hz, 1H), 3.84 (dd, J =12.0, 2.1 Hz, 1H), 3.69 (dd, J=12.0, 5.1 Hz, 1H), 3.45-3.27 (m, 4H), 2.35 (s, 3H), 2.30 (s, 3H), 2.05 (s, 3H). ESI-MS: 317 [M+1].sup.+.

EXAMPLE 2

[0139] ##STR00052##

[0140] Step 1: 4-Hydroxy-5-methyl-3(2H)-furanone (1.14 g, 10 mmol, CAS: 19322-27-1), 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (8.2 g, 20 mmol, CAS: 572-09-8), and tetrabutylammonium bromide (4.83 g, 15 mmol, CAS: 1643-19-2) were dissolved in 60 mL of dichloromethane and heated to 35° C.; 80 mL of aqueous NaOH (1 mol/L) was further added. After stirring for 45 minutes, 300 mL of ethyl acetate was added to extract the organic phase; the organic phase was washed three times with aqueous NaOH (1 mol/L), twice with water and once with brine; the crude product was concentrated and chromatographed on silica gel (ethyl acetate/petroleum ether: 1/1) to give 4-O-[(2,3,4,6-tetra-O-acetyl)-β-D-glucosyl]-5-methyl-3(2H)-furanone as a white solid (0.67 g, 15% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.24 (m, 1H), 5.12 (m, 3H), 4.48 (s, 2H), 4.23 (dd, J=12.2, 3.5 Hz, 1H), 4.15 (dd, J=12.5, 1.9 Hz, 1H), 3.72 (m, 1H), 2.24 (s, 3H), 2.12 (s, 3H), 2.07 (s, 3H), 2.02 (s, 6H). ESI-MS: 445 [M+1].sup.+.

[0141] Step 2: 4-O-[(2,3,4,6-tetra-O-acetyl)-β-D-glucosyl]-5-methyl-3(2H)-furanone (4.44 g, 10 mmol), copper acetate (905 mg, 5 mmol), and sodium acetate (680 mg, 5 mmol) were dissolved in 10 mL acetone and 30 mL glacial acetic acid, heated to 50° C., stirred and refluxed for 1 hour; then diluted with 150 mL of water, and extracted with 100 mL of petroleum ether; the crude product was concentrated and chromatographed on silica gel (ethyl acetate/petroleum ether: 1/1) to give 4-O-[(2,3,4,6-tetra-O-acetyl)-β-D-glucosyl]-5-methyl-2-(1-methylethylidene)-3(2H)-furanone as a white solid (1.94 g, 40% yield, Compound I-2).

EXAMPLE 3

[0142] ##STR00053##

[0143] 4-Hydroxy-5-methyl-2-(1-methylethylidene)-3(2H)-furanone (1.54 g, 10 mmol), 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (6.15 g, 15 mmol), and tetrabutylammonium bromide (4.83 g, 15 mmol, CAS: 1643-19-2) were dissolved in 60 mL of dichloromethane and heated to 35° C.; 75 mL of NaOH aqueous solution (1 mol/L) was further added. After stirring for 45 minutes, 300 mL of ethyl acetate was added to extract the organic phase; the organic phase was washed three times with NaOH aqueous solution (1 mol/L), twice with water, and once with brine; the crude product was concentrated and chromatographed on silica gel (ethyl acetate/petroleum ether: 1/1) to give 4-O-[(2,3,4,6-tetra-O-acetyl)-β-D-galactosyl]-5-methyl-2-(1-methylethylidene)-3(2H)-furanone as a white solid (2.31 g, 48% yield, compound I-4).

[0144] I-4: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 5.40 (d, J=2.7 Hz, 1H), 5.33 (dd, J=10.5, 8.0 Hz, 1H), 5.08 (d, J=8.0 Hz, 1H), 5.04 (dd, J=10.5, 3.5 Hz, 1H), 4.11 (m, 2H), 3.89 (t, J=6.7 Hz, 1H), 2.27 (s, 3H), 2.22 (s, 3H), 2.16 (s, 3H), 2.15 (s, 3H), 2.01 (s, 3H), 1.99 (s, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3): δ 179.36, 170.47, 170.38, 170.27, 170.15, 168.42, 143.18, 135.94, 132.99, 100.72, 71.02, 70.85, 68.74, 67.01, 61.15, 21.08, 20.81, 20.76, 20.71, 19.51, 17.25, 12.70. ESI-MS: 485 [M+1].sup.+.

EXAMPLE 4

[0145] ##STR00054##

[0146] Compound I-5 was prepared using a similar method to example 3.

[0147] I-5: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.31 (d, J=9.3 Hz, 1H), 5.27 (t, J=7.9 Hz, 1H), 5.21 (t, J=9.6 Hz, 1H), 5.16 (dd, J=9.2, 7.9 Hz, 1H), 4.02 (d, J=9.8 Hz, 1H), 3.72 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 2.12 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1.98 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 179.18, 170.02, 169.91, 169.66, 168.75, 167.12, 143.20, 135.39, 133.25, 99.40, 72.41, 72.00, 71.01, 69.54, 52.95, 20.90, 20.73, 20.62, 19.53, 17.26, 12.70. ESI-MS: 471 [M+1].sup.+.

EXAMPLE 5

[0148] ##STR00055##

[0149] Compound I-6 was prepared using a similar method to example 3.

[0150] I-6: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.34 (t, J=8.0 Hz, 1H), 5.30 (d, J=8.0 Hz, 1H), 5.16 (t, J=8.0 Hz, 1H), 5.14 (m, 1H), 4.17 (dd, J=12.2, 1.7 Hz, 1H), 4.02 (dd, J=12.3, 5.5 Hz, 1H), 3.70 (ddd, J=10.0, 5.4, 1.7 Hz, 1H), 2.25 (s, 3H), 2.18 (s, 3H), 1.97 (s, 3H), 1.19 (s, 9H), 1.16 (s, 9H), 1.14 (s, 9H), 1.12 (s, 9H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 179.05, 178.03, 177.20, 177.17, 176.66, 168.60, 143.19, 135.02, 132.56, 99.03, 72.43, 72.22, 71.25, 68.01, 61.69, 38.99, 38.93, 38.92, 38.85, 27.28(×3), 27.22(×3), 27.18(×3), 27.12(×3), 19.44, 17.23, 12.60. ESI-MS: 653 [M+1].sup.+.

EXAMPLE 6

[0151] ##STR00056##

[0152] I-1 (316 mg, 1 mmol) was dissolved in toluene-ethanol (4:1, 30 mL) solution, Sc(OTF)3 (7.38 mg, 0.015 mmol) and DEPC (186 mg, 1.15 mmol) were added. The solution was heated to 50° C. for 2 h, then quenched with dilute acetic acid (2.5%, 3.75 mL). The mixture was cooled to 20° C. and the aqueous layer was discarded, the organic layer was washed again with dilute acetic acid (2.5%, 3.75 mL), and the aqueous layer was discarded. The final organic layer was then concentrated and chromatographed on silica gel (dichloromethane/methanol: 10/1) to give compound I-7 (210 mg, 54% yield).

[0153] I-7: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.70 (d, J=8.1 Hz, 1H), 4.44 (d, J=11.0 Hz, 1H), 4.32 (dd, J=11.7, 5.7 Hz, 1H), 4.17 (m, 2H), 3.70-3.51 (m, 2H), 3.41 (t, J=9.3 Hz, 1H), 3.29 (t, J=8.6 Hz, 1H), 2.27 (s, 3H), 2.24 (s, 3H), 2.05 (s, 3H), 1.29 (t, J=7.1 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 181.73, 171.69, 155.41, 143.22, 136.00, 134.72, 103.13, 75.81, 74.40, 72.07, 69.77, 66.73, 64.34, 19.73, 17.70, 14.37, 13.11. ESI-MS: 389 [M+1].sup.+.

EXAMPLE 7

[0154] ##STR00057##

[0155] 4-Hydroxy-5-methyl-2-cyclopentyl-3(2H)-furanone (1.80 g, 10 mmol), 2,3,4,6-tetra-O -acetyl-α-D-glucopyranosyl bromide (6.15 g, 15 mmol, CAS: 572-09-8), and tetrabutylammonium bromide (4.83 g, 15 mmol, CAS: 1643-19-2) were dissolved in 60 mL of dichloromethane and heated to 35° C.; 75 mL of NaOH aqueous solution (1 mol/L) was further added. After stirring for 45 minutes, 300 mL of ethyl acetate was added to extract the organic phase; the organic phase was washed three times with NaOH aqueous solution (1 mol/L), twice with water, and once with brine; the crude product was concentrated and chromatographed on silica gel (ethyl acetate/petroleum ether: 1/1) to give 4-O-[(2,3,4,6-tetra-O-acetyl)-β-D-glucosyl]-5-methyl-2-cyclopentyl-3(2H)-furanone as a white solid (2.51 g, 49% yield, compound I-8).

[0156] I-8: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 5.21-5.26 (m, 2H), 5.10-5.17 (m, 2H), 4.23 (dd, J=12.4, 4.4 Hz, 1H), 4.14 (dd, J=12.4, 2.4 Hz, 1H), 3.70 (m, 1H), 2.84 (t, J=6.6 Hz, 2H), 2.61 (t, J=7.2 Hz, 2H), 2.22 (s, 3H), 2.13 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H), 1.80 (m, 4H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 178.81, 170.69, 170.22, 170.02, 169.64, 168.68, 143.01, 140.87, 135.46, 99.68, 72.76, 71.95, 71.19, 68.45, 61.77, 31.05, 30.24, 26.80, 25.43, 20.96, 20.83, 20.75(×2), 12.72. ESI-MS: 511 [M+1].sup.+.

EXAMPLE 8

[0157] ##STR00058##

[0158] Compound I-9 was prepared using a similar method to example 7.

[0159] I-9: H NMR (400 MHz, CDCl.sub.3) δ 5.23 (t, J=8.5 Hz, 1H), 5.19-5.05 (m, 3H), 4.22 (dd, J=12.4, 7.6 Hz, 1H), 4.14 (dd, J=12.4, 2.4 Hz, 1H), 3.69 (m, 1H), 2.94 (t, J=5.8 Hz, 2H), 2.43 (t, J=6.0 Hz, 2H), 2.20 (s, 3H), 2.13 (s, 3H), 2.06 (s, 3H), 2.02 (s, 6H), 1.66 (m, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 179.80, 170.69, 170.23, 170.04, 169.65, 168.42, 140.96, 140.61, 135.83, 99.85, 72.73, 71.94, 71.18, 68.48, 61.79, 28.69, 27.87, 27.61, 26.27, 26.12, 20.97, 20.83, 20.76(×2), 12.66. ESI-MS: 525 [M+1].sup.+.

EXAMPLE 9

[0160] ##STR00059##

[0161] Compound I-10 was prepared using a similar method to example 7.

[0162] I-10: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 5.24 (t, J=6.4 Hz, 1H), 5.13 (m, 3H), 4.21 (dd, J=12.4, 5.6 Hz, 1H), 4.15 (dd, J=12.0, 2.4 Hz, 1H), 3.80 (m, 4H), 3.69 (m, 1H), 3.11 (m, 2H), 2.58 (t, J=5.6 Hz, 2H), 2.22(s, 3H), 2.13 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 179.82, 170.65, 170.22, 169.98, 169.62, 169.15, 140.89, 135.80, 133.88, 99.86, 72.68, 72.00, 71.15, 68.55, 68.43, 68.10, 61.75, 28.91, 26.93, 20.94, 20.83, 20.75(×2), 12.72. ESI-MS: 527 [M+1].sup.+.

EXAMPLE 10

[0163] ##STR00060##

[0164] Compound I-11 was prepared using a similar method to example 7.

[0165] I-11: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.81 (s, N—H), 5.24 (t, J=8.9 Hz, 1H), 5.13 (m, 3H), 4.19 (m, 2H), 3.70 (m, 1H), 3.52-3.16 (m, 6H), 2.91 (br s, 2H), 2.24 (s, 3H), 2.12 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) 6179.79, 170.65, 170.55, 170.23, 169.92, 169.61, 141.48, 135.77, 126.60, 99.94, 72.60, 72.08, 71.10, 68.32, 61.68, 44.43(×2), 24.25, 21.85, 20.93, 20.87, 20.75(×2), 12.85. ESI-MS: 526 [M+1].sup.+.

EXAMPLE 11

[0166] ##STR00061##

[0167] Compound I-12 was prepared using a similar method to example 7.

[0168] I-12: .sup.1H NMR (400 MHz, CDCl.sub.3): δ 5.10-5.27 (m, 4H), 4.11-4.25 (m, 2H), 3.73 (m, 4H), 3.56 (m, 1H), 3.10 (m, 2H), 2.58 (m, 2H), 2.24(s, 3H), 2.15 (s, 3H), 2.13 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H). ESI-MS: 568 [M+1].sup.+.

[0169] Effect Example 1: Therapeutic Effect of Compound I-1 on Ulcerative Colitis

[0170] 1. Experimental Procedure

[0171] 1.1 Experimental Animals and Experimental Conditions

[0172] Thirty 10-week-old male C57 mice, SPF class animal house, temperature 20-26° C., humidity 40%-70%, alternating light-dark periods (12 h/12 h).

[0173] 1.2 Grouping and Administration

[0174] Quarantine-qualified animals with similar weights were selected for the experiment. The mice were randomly grouped according to their weights, with five mice in each group, as shown in Table 1:

TABLE-US-00002 TABLE 1 Group Administration Dosage (mg/kg) Solvent 1 Blank control intraperitoneal 0 sterile group injection water 2 Ulcerative colitis intraperitoneal 0 sterile model group injection water (dextran sodium sulphate) 3 Positive control intramuscular 50 olive group injection oil (cyclosporine A) 4 Low-dose intraperitoneal 10 sterile treatment group injection water (Compound I-1) 5 Middle-dose intraperitoneal 20 sterile treatment group injection water (Compound I-1) 6 High-dose intraperitoneal 40 sterile treatment group injection water (Compound I-1)

[0175] 1.3 Experimental Method

[0176] Mice in the blank control group were given normal drinking water throughout the experiment. The other 5 groups of mice were given drinking water containing 2% dextran sodium sulphate (DSS) from day 1 to day 5, normal drinking water from day 6 to day 7, drinking water containing 2% dextran sodium sulphate from day 8 to day 12, and normal drinking water from day 13 to day 14. The experiment ended on day 14.

[0177] Animals in the blank control group and ulcerative colitis model group were given sterile water intraperitoneally from day 1, once a day; the other 4 groups were administered according to table 1, once a day, until the end of the experiment on day 14. Two hours after the first day of administration, the mice were started to drink water containing dextran sodium sulphate.

[0178] 1.4 Measurement and Tissue Collection

[0179] (1) The mice were weighed daily.

[0180] (2) Blood samples were collected from the orbital vein on day 14 and stored at −80° C.

[0181] (3) On day 14, the mice were sacrificed by cervical vertebra dislocation, the colon was removed and a small amount of fecal was taken from the colon and left as a sample. The colon length and colon weight were measured. A portion of the colon and the fecal sample was stored at −80° C.

[0182] 2. Experimental Results

[0183] As shown in Tables 2 and 3, the weight of the mice in the ulcerative colitis model group was significantly reduced to 74.18% of the initial body weight compared to the blank control group, and compound I-1 had a significant ameliorating effect on the reduction in the weight of mice and showed a dose-dependent enhancement.

TABLE-US-00003 TABLE 2 Average weight of mice in each group Blank Ulcerative Positive Low-dose Middle-dose High-dose control colitis model control treatment treatment treatment Group group group group group group group Day 1/g 27.9 27.8 27.8 27.9 27.8 27.6 Day 2/g 27.9 27.7 27.7 28.1 27.8 27.6 Day 3/g 28.0 27.6 27.7 28.0 27.9 27.6 Day 4/g 28.0 27.6 27.7 28.0 27.9 27.6 Day 5/g 28.1 26.7 27.4 27.2 27.5 27.3 Day 6/g 28.1 25.8 27.4 26.3 27.2 27.2 Day 7/g 28.1 24.8 27.3 25.9 26.7 26.8 Day 8/g 28.1 23.9 27.3 25.6 26.2 26.3 Day 9/g 28.1 22.8 27.2 25.3 25.9 25.8 Day 10/g 28.4 22.1 27.1 24.9 25.6 25.6 Day 11/g 28.5 21.7 26.9 24.4 25.3 25.5 Day 12/g 28.6 21.4 26.7 24.1 25.0 25.4 Day 13/g 28.7 21.0 26.6 23.8 24.8 25.3 Day 14/g 28.7 20.7 26.6 23.7 24.7 25.2

TABLE-US-00004 TABLE 3 Rate of change in weight of mice in each group Blank Ulcerative Positive Low-dose Middle-dose High-dose control colitis model control treatment treatment treatment Group group group group group group group Day 1/% 100.0 100.0 100.0 100.0 100.0 100.0 Day 2/% 100.2 99.5 99.6 100.6 100.1 99.9 Day 3/% 100.4 99.1 99.4 100.5 100.3 100.0 Day 4/% 100.4 99.1 99.4 100.3 100.3 100.0 Day 5/% 100.6 96.1 98.5 97.6 99.1 99.1 Day 6/% 100.6 92.9 98.3 94.3 97.8 98.7 Day 7/% 100.9 89.1 98.3 93.0 96.0 97.0 Day 8/% 100.9 85.8 98.1 91.6 94.3 95.3 Day 9/% 100.9 82.0 97.9 90.8 93.2 93.5 Day 10/% 102.0 79.6 97.3 89.1 92.2 92.7 Day 11/% 102.4 78.1 96.8 87.5 91.1 92.2 Day 12/% 102.7 76.8 96.0 86.4 90.0 92.0 Day 13/% 102.9 75.6 95.6 85.3 89.2 91.5 Day 14/% 102.9 74.3 95.5 84.9 88.8 91.4

[0184] As shown in Table 4, compared with the blank control group, the colon length of mice in the ulcerative colitis model group was significantly shortened, and the average length was shortened from 7.18 cm to 5.02 cm. The administration of compound I-1 could gradually restore the length of the colon to normal and showed a dose-dependent effect, the high-dose treatment group was even better than the positive control group.

TABLE-US-00005 TABLE 4 Average colon length of mice in each group Blank Ulcerative Positive Low-dose Middle-dose High-dose control colitis model control treatment treatment treatment Group group group group group group group Colon 7.18 5.02 6.36 5.46 6.04 6.52 length/cm

[0185] As shown in Table 5, compared with the blank control group, the colon weight of mice in the ulcerative colitis model group was significantly increased.

TABLE-US-00006 TABLE 5 Average colon weight of mice in each group Blank Ulcerative Positive Low-dose Middle-dose High-dose control colitis model control treatment treatment treatment Group group group group group group group Colon 0.1786 0.2017 0.1840 0.1909 0.2115 0.2129 weight/g

[0186] As shown in Table 6, compared with the blank control group, the unit colon weight (colon weight/colon length) of mice in the ulcerative colitis model group was significantly increased. The administration of compound I-1 could significantly improve the unit colon weight, and the high-dose group showed the best performance.

TABLE-US-00007 TABLE 6 Unit colon weight of mice in each group Blank Ulcerative Positive Low-dose Middle-dose High-dose control colitis model control treatment treatment treatment Group group group group group group group Unit colon 0.0249 0.0395 0.0289 0.0351 0.0351 0.0327 weight (g/cm)

[0187] As shown in Tables 2 to 6 and FIG. 2, after intraperitoneal administration of different concentrations, the reduction of weight and shortening of colon length of mice in the treatment groups were significantly relieved. Compared with the ulcerative colitis model group, the unit colon weight in the treatment groups showed a decreasing trend.

[0188] Effect example 2: Therapeutic effect of compound I-2, I-4, I-5, and I-6 on ulcerative Colitis

[0189] 1. Experimental Procedure

[0190] 1.1 Experimental Animals and Experimental Conditions

[0191] Thirty-five 10-week-old male C57 mice, SPF class animal house, temperature 20-26° C., humidity 40%-70%, alternating light-dark periods (12 h/12 h).

[0192] 1.2 Grouping and Administration

[0193] Quarantine-qualified animals with similar weights were selected for the experiment. The mice were randomly grouped according to their weights, with five mice in each group, as shown in Table 7:

TABLE-US-00008 TABLE 7 Group Administration Dosage (mg/kg) Solvent 1 Blank control oral gavage 0 sterile group water 2 Ulcerative colitis oral gavage 0 sterile model group water (dextran sodium sulphate) 3 Positive control oral gavage 30 olive group (SASP) oil 4 Treatment group I-2 oral gavage 40 sterile (compound I-2) water 5 Treatment group I-4 oral gavage 40 sterile (compound I-4) water 6 Treatment group I-5 oral gavage 40 sterile (compound I-5) water 7 Treatment group I-6 oral gavage 40 sterile (compound I-6) water

[0194] Mice in the blank control group were given normal drinking water throughout the experiment. The other 6 groups of mice were given drinking water containing 2% dextran sodium sulphate from day 1 to day 5, normal drinking water from day 6 to day 7, drinking water containing 2% dextran sodium sulphate from day 8 to day 12, and normal drinking water from day 13 to day 14. The experiment ended on day 14. All groups were administered by oral gavage once a day according to table 7, until the end of the experiment on day 14.

[0195] 1.3 Measurement and Tissue Collection

[0196] (1) The mice were weighed daily.

[0197] (2) Blood samples were collected from the orbital vein on day 14 and stored at −80° C.

[0198] (3) On day 14, the mice were sacrificed by cervical vertebra dislocation, the colon was removed and a small amount of fecal was taken from the colon and left as a sample. The colon length and colon weight were measured. A portion of the colon and the fecal sample was stored at −80° C.

[0199] 2. Experimental Results

[0200] The experimental results are shown in Tables 8 to 9:

TABLE-US-00009 TABLE 8 Average weight of mice in each group Blank Ulcerative Positive Treatment Treatment Treatment Treatment control colitis model control group group group group Group group group group I-2 I-4 I-5 I-6 Day 1/g 27.36 26.82 26.8 26.86 26.72 26.9 26.9 Day 2/g 27.44 26.88 26.86 26.9 26.76 26.92 26.94 Day 3/g 27.46 26.74 26.82 26.82 26.72 26.88 26.9 Day 4/g 27.36 26.76 26.8 26.86 26.72 26.9 26.9 Day 5/g 27.4 26.04 26.52 26.58 26.44 26.58 26.64 Day 6/g 27.36 25.44 25.74 26.48 26.36 26.32 26.2 Day 7/g 27.42 24.34 24.38 25.18 24.82 25.3 24.52 Day 8/g 27.52 23.44 22.92 23.78 23.44 23.6 24.38 Day 9/g 27.18 22.88 22.3 23.64 23.3 23.24 24.42 Day 10/g 27.4 22.28 22.34 23.64 23.3 23.24 24.42 Day 11/g 27.5 22.08 22.68 24.72 24.02 24.2 24.66 Day 12/g 27.66 22.2 23.14 24.82 24.14 24.48 24.94 Day 13/g 27.76 22.26 23.52 24.8 24.5 24.5 24.72 Day 14/g 27.76 22.18 23.52 24.92 24.68 24.68 24.5

TABLE-US-00010 TABLE 9 Average colon length of mice in each group Blank Ulcerative Positive Treatment Treatment Treatment Treatment control colitis model control group group group group Group group group group I-2 I-4 I-5 I-6 Colon 7.1 5.8 6.0 6.2 6.2 6.0 5.9 length/cm

[0201] The results showed that the weight of mice in the ulcerative colitis model group was significantly lower compared to the blank control group, and oral gavage administration of compounds I-2, I-4, I-5, and I-6 had a significant improvement in the reduction of weight in mice, and all of compounds I-2, I-4, I-5, and I-6 were better than the positive control drug salazosulfapyridine (SASP).

[0202] Effect Example 3: Therapeutic Effect of Compound I-1, I-2, and I-7 to I-12 on Ulcerative Colitis

[0203] 1. Experimental Procedure

[0204] 1.1 Experimental Animals and Experimental Conditions

[0205] Fifty 10-week-old male C57 mice, SPF class animal house, temperature 20-26° C., humidity 40%-70%, alternating light-dark periods (12 h/12 h).

[0206] 1.2 Grouping and Administration

[0207] Quarantine-qualified animals with similar weights were selected for the experiment. The mice were randomly grouped according to their weights, with five mice in each group, as shown in Table 10:

TABLE-US-00011 TABLE 10 Group Administration Dosage (mg/kg) Solvent 1 Blank control oral gavage 0 sterile group water 2 Ulcerative colitis oral gavage 0 sterile model group water (dextran sodium sulphate) 3 Treatment group I-1 oral gavage 40 sterile (compound I-1) water 4 Treatment group I-2 oral gavage 40 sterile (compound I-2) water 5 Treatment group I-7 oral gavage 40 sterile (compound I-7) water 6 Treatment group I-8 oral gavage 40 sterile (compound I-8) water 7 Treatment group I-9 oral gavage 40 sterile (compound I-9) water 8 Treatment group I-10 oral gavage 40 sterile (compound I-10) water 9 Treatment group I-11 oral gavage 40 sterile (compound I-11) water 10 Treatment group I-12 oral gavage 40 sterile (compound I-12) water

[0208] Mice in the blank control group were given normal drinking water throughout the experiment. The other 9 groups of mice were given drinking water containing 2% dextran sodium sulphate from day 1 to day 7. All groups were administered by oral gavage once a day according to table 10, until the end of the experiment.

[0209] 1.3 Measurement and Tissue Collection

[0210] (1) The mice were weighed daily.

[0211] (2) Blood samples were collected from the orbital vein on day 7 and stored at −80° C.

[0212] (3) On day 7, the mice were sacrificed by cervical vertebra dislocation, the colon was removed and a small amount of fecal was taken from the colon and left as a sample. The colon length and colon weight were measured. A portion of the colon and the fecal sample was stored at −80° C.

[0213] 2. Experimental Results

[0214] The experimental results are shown in Tables 11 to 12:

TABLE-US-00012 TABLE 11 Average weight of mice in each group Weight of mice Day 1/g Day 2/g Day 3/g Day 4/g Day 5/g Day 6/g Day 7/g Blank control group 21.05 21.38 21.40 21.15 20.80 21.38 21.43 Ulcerative colitis 21.82 21.97 21.92 21.68 20.40 19.52 18.47 model group Treatment group I-1 21.33 20.97 20.80 20.85 20.53 20.13 19.82 Treatment group I-2 21.53 21.42 21.25 20.97 20.72 20.27 19.27 Treatment group I-7 21.47 21.62 21.18 20.82 20.13 20.07 19.88 Treatment group I-8 21.85 21.97 21.77 21.33 20.62 20.52 20.32 Treatment group I-9 21.20 21.17 20.92 20.47 20.03 19.42 19.38 Treatment group I-10 21.95 21.60 21.18 21.27 20.90 20.13 19.25 Treatment group I-11 21.62 21.30 21.10 20.97 20.32 19.93 19.30 Treatment group I-12 21.25 21.22 21.13 20.62 20.10 16.32 18.88

TABLE-US-00013 TABLE 12 Average colon length of mice in each group Blank ulcerative Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment control colitis model group group group group group group group group Group group group I-1 I-2 I-7 I-8 I-9 I-10 I-11 I-12 Colon 7.2 5.1 6.2 5.8 5.4 6.1 6.3 5.8 6.2 5.7 length/cm

[0215] The results showed that the weight of mice in the ulcerative colitis model group was significantly lower compared to the blank control group; except for compound I-11, all the tested compounds by oral gavage administration had a significant improvement in the reduction of weight in mice. In addition, oral gavage administration of I-1, I-8, I-9, and I-11 can gradually restore the colon length.

[0216] Although the examples of the invention have been described herein, those skilled in the art should understand that the examples are merely illustrative, and various changes may be made to the examples without departing from the principle and spirit of the invention. Therefore, the scope of the invention is to be limited by the appended claims.