GINKGOLIDE B DERIVATIVE AND SALT THEREOF, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

The present invention relates to the technical field of medicine, and to derivatives represented by formula 1 and formula 2 in which a carboxylic acid group is introduced into the structure of Ginkgolide B by means of a hydroxyl group at the 10-position and ester derivatives of carboxylic acid groups, and pharmaceutically acceptable organic or inorganic salts. Ginkgolide B is used as a parent body and is prepared by means of chemical structure modification so as to achieve the goals of improving solubility, increasing bioavailability and enhancing healing efficacy. The prepared compound and carboxylate salts thereof have significant platelet activating factor antagonism, an anticoagulant effect and an anti-acute cerebral ischemia effect, and can be used for preparing a drug for preventing and treating ischemic stroke, thrombosis, angina pectoris, cardiopulmonary infarction, as well as inflammation, asthma and other diseases related to a platelet activating factor.

##STR00001##

Claims

1. A compound represented by formula 1 or a pharmaceutically acceptable salt thereof, wherein: ##STR00034## L is heteroatom, substituted or unsubstituted C.sub.1-10 hydrocarbonylene, substituted or unsubstituted C.sub.1-10 heterohydrocarbonylene containing heteroatoms, or not existed, when L is heteroatom or L is substituted or unsubstituted C.sub.1-10 heterohydrocarbonylene containing heteroatoms, the heteroatoms are selected from one or more of oxygen, nitrogen and sulfur; when there are multiple heteroatoms, the heteroatoms are the same or different; R is hydrogen or substituted or unsubstituted C.sub.1-8 hydrocarbonyl; the substituent in the substituted C.sub.1-10 hydrocarbonylene, the substituted C.sub.1-10 heterohydrocarbonylene containing heteroatoms and the substituted C.sub.1-8 hydrocarbonyl is independently one or more of halogen, hydroxyl, C.sub.1-10 alkoxy, phenyl and C.sub.1-10 alkyl, and when multiple substituents exist, the substituents are the same or different; and the compound represented by the formula 1 is not ##STR00035##

2. The compound represented by formula 1 or the pharmaceutically acceptable salt thereof according to claim 1, wherein: the L is heteroatom, substituted or unsubstituted C.sub.1-10 alkylene, substituted or unsubstituted C.sub.2-10 alkenylene, substituted or unsubstituted C.sub.2-10 alkynylene, substituted or unsubstituted C.sub.3-10 cycloalkylene, substituted or unsubstituted C.sub.3-10 cycloalkenylene, substituted or unsubstituted C.sub.4-10 cycloalkynylene, substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted C.sub.1-10 heteroalkylene, substituted or unsubstituted C.sub.2-10 heteroalkenylene, substituted or unsubstituted C.sub.2-10 heteroalkynylene, substituted or unsubstituted C.sub.2-10 heterocycloalkylene, substituted or unsubstituted C.sub.2-10 heterocycloalkenylene, substituted or unsubstituted C.sub.2-10 heterocycloalkynylene, substituted or unsubstituted C.sub.1-10 heteroarylene, or not existed; or the R is hydrogen, substituted or unsubstituted C.sub.1-8 alkyl, substituted or unsubstituted C.sub.2-8 alkenyl, substituted or unsubstituted C.sub.2-8 alkynyl, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted C.sub.3-8 cycloalkenyl, substituted or unsubstituted C.sub.4-8 cycloalkynyl, or substituted or unsubstituted phenyl; or when the substituent in the substituted C.sub.1-10 hydrocarbonylene, the substituted C.sub.1-10 heterohydrocarbonylene containing heteroatoms and the substituted C.sub.1-8 hydrocarbonyl is halogen, the halogen is fluorine, chlorine, bromine or iodine; or when the substituent in the substituted C.sub.1-10 hydrocarbonylene, the substituted C.sub.1-10 heterohydrocarbonylene containing heteroatoms and the substituted C.sub.1-8 hydrocarbonyl is C.sub.1-10 alkoxy, the C.sub.1-10 alkoxy is C.sub.1-4 alkoxy; or when the substituent in the substituted C.sub.1-10 hydrocarbonylene, the substituted C.sub.1-10 heterohydrocarbonylene containing heteroatoms and the substituted C.sub.1-8 hydrocarbonyl is C.sub.1-10 alkyl, the C.sub.1-10 alkyl is C.sub.1-4 alkyl.

3. The compound represented by formula 1 or the pharmaceutically acceptable salt thereof according to claim 1, wherein: the L is heteroatom, substituted or unsubstituted C.sub.3-10 alkylene, substituted or unsubstituted C.sub.2-10 alkenylene, substituted or unsubstituted C.sub.2-10 alkynylene, substituted or unsubstituted C.sub.3-10 cycloalkylene, substituted or unsubstituted C.sub.3-10 cycloalkenylene, substituted or unsubstituted C.sub.4-10 cycloalkynylene, substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted C.sub.1-10 heteroalkylene, substituted or unsubstituted C.sub.2-10 heteroalkenylene, substituted or unsubstituted C.sub.2-10 heteroalkynylene, substituted or unsubstituted C.sub.2-10 heterocycloalkylene, substituted or unsubstituted C.sub.2-10 heterocycloalkenylene, substituted or unsubstituted C.sub.2-10 heterocycloalkynylene, substituted or unsubstituted C.sub.1-10 heteroarylene, or not existed; or the R is hydrogen, methyl, benzyl, substituted or unsubstituted C.sub.3-8 alkyl, substituted or unsubstituted C.sub.2-8 alkenyl, substituted or unsubstituted C.sub.2-8 alkynyl, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted C.sub.3-8 cycloalkenyl, substituted or unsubstituted C.sub.4-8 cycloalkynyl, or substituted or unsubstituted phenyl.

4. The compound represented by formula 1 or the pharmaceutically acceptable salt thereof according to claim 1, wherein: when the L is heteroatom, the heteroatom is oxygen or sulfur; or when the L is substituted or unsubstituted C.sub.3-10 alkylene, the C.sub.3-10 alkylene in the substituted or unsubstituted C.sub.3-10 alkylene is C.sub.3-5 alkylene; or when the L is substituted or unsubstituted C.sub.2-10 alkenylene, the C.sub.2-10 alkenylene in the substituted or unsubstituted C.sub.2-10 alkenylene is C.sub.3-6 alkenylene, or when the L is substituted or unsubstituted C.sub.2-10 alkynylene, the C.sub.2-10 alkynylene in the substituted or unsubstituted C.sub.2-10 alkynylene is C.sub.2-5 alkynylene; or when the L is substituted or unsubstituted C.sub.3-10 cycloalkylene, the C.sub.3-10 cycloalkylene in the substituted or unsubstituted C.sub.3-10 cycloalkylene is C.sub.3-8 cycloalkylene; or when the L is substituted or unsubstituted C.sub.3-10 cycloalkenylene, the C.sub.3-10 cycloalkenylene in the substituted or unsubstituted C.sub.3-10 cycloalkenylene is C.sub.3-8 cycloalkenylene; or when the L is substituted or unsubstituted C.sub.1-10 heteroalkylene containing heteroatoms, the C.sub.1-10 heteroalkylene in the substituted or unsubstituted C.sub.1-10 heteroalkylene containing heteroatoms is C.sub.1-6 heteroalkylene; or when the L is substituted or unsubstituted C.sub.2-10 heteroalkenylene, the C.sub.2-10 heteroalkenylene in the substituted or unsubstituted C.sub.2-10 heteroalkenylene is C.sub.2-5 heteroalkenylene; or when the L is substituted or unsubstituted C.sub.2-10 heteroalkynylene, the C.sub.2-10 heteroalkynylene in the substituted or unsubstituted C.sub.2-10 heteroalkynylene is C.sub.2-4 heteroalkynylene; or when the L is substituted or unsubstituted C.sub.2-10 heterocycloalkylene, the C.sub.2-10 heterocycloalkylene in the substituted or unsubstituted C.sub.2-10 heterocycloalkylene is C.sub.2-5 heterocycloalkylene; or when the L is substituted or unsubstituted C.sub.2-10 heterocycloalkenylene, the C.sub.2-10 heterocycloalkenylene in the substituted or unsubstituted C.sub.2-10 heterocycloalkenylene is C.sub.2-5 heterocycloalkenylene; or when the L is a substituted or unsubstituted C.sub.1-10 heteroarylene, the C.sub.1-10 heteroarylene in the substituted or unsubstituted C.sub.1-10 heteroarylene is C.sub.1-9 heteroarylene; or when the R is substituted or unsubstituted C.sub.3-8 alkyl, the C.sub.3-8 alkyl in the substituted or unsubstituted C.sub.3-8 alkyl is n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; or when the R is substituted or unsubstituted C.sub.2-8 alkenyl, the C.sub.2-8 alkenyl in the substituted or unsubstituted C.sub.2-8 alkenyl is C.sub.2-5 alkenyl; or when the R is substituted or unsubstituted C.sub.2-8 alkynyl, the C.sub.2-8 alkynyl in the substituted or unsubstituted C.sub.2-8 alkynyl is C.sub.2-5 alkynyl; or when the R is substituted or unsubstituted C.sub.3-8 cycloalkyl, the C.sub.3-8 cycloalkyl in the substituted or unsubstituted C.sub.3-8 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; or when the R is substituted or unsubstituted C.sub.3-8 cycloalkenyl, the C.sub.3-8 cycloalkenyl in the substituted or unsubstituted C.sub.3-8 cycloalkenyl is cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl.

5. The compound represented by formula 1 or the pharmaceutically acceptable salt thereof according to claim 1, wherein: the L is substituted or unsubstituted C.sub.2-10 alkenylene, substituted or unsubstituted C.sub.1-10 heteroalkylene, or not existed; or the R is hydrogen, methyl, benzyl, or substituted or unsubstituted C.sub.3-8 alkyl.

6. The compound represented by formula 1 or the pharmaceutically acceptable salt thereof according to claim 1, wherein: the L is —CH═CH—, —CH.sub.2OCH.sub.2—, —CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2—, or L is not existed, or the R is hydrogen, methyl or tert-butyl.

7. The compound represented by formula 1 or the pharmaceutically acceptable salt thereof according to claim 1, wherein, the compound represented by formula 1 or the pharmaceutically acceptable salt thereof is selected from any one of the following compounds: ##STR00036## ##STR00037##

8. A compound or a pharmaceutically acceptable salt thereof, wherein, the compound is represented by the structure of formula 2: ##STR00038## wherein: L is as defined in claim 1; and cations are cations formed from various inorganic and organic bases.

9. The compound or the pharmaceutically acceptable salt thereof according to claim 8, wherein, the compound represented by formula 2, wherein: L is as defined in claim 8; and the inorganic base in the cations formed by various inorganic bases and organic bases is sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, ammonium hydroxide or zinc hydroxide; or the organic base in the cations formed by various inorganic bases and organic bases is amine compound, or natural or non-natural amino acid compound.

10. The compound or the pharmaceutically acceptable salt thereof according to claim 8, wherein, the compound represented by formula 2, wherein: the cation in the compound is ##STR00039##

11. The compound or the pharmaceutically acceptable salt thereof according to claim 8, wherein, the compound represented by formula 2 is selected from any one of the following compounds: ##STR00040## ##STR00041## ##STR00042##

12. A method for preparing the compound represented by formula 1 or the pharmaceutically acceptable salt thereof according to claim 1, wherein, comprising: in an organic solvent, under the action of a base and a catalyst, Ginkgolide B and the compound represented by formula 3 are subjected to the ether-forming reaction as shown below to obtain the compound represented by formula 1, ##STR00043## wherein, R and L are as defined in claim 1, and X is halogen.

13. The method for preparing the compound represented by formula 1 or the pharmaceutically acceptable salt thereof according to claim 12, wherein: the X is fluorine, chlorine, bromine or iodine; or the organic solvent is one or more of halogenated hydrocarbon solvents, ether solvents, ketone solvents, nitrile solvents and amide solvents; or the base is organic base and/or inorganic base; or the catalyst is iodide; or the molar concentration of the Ginkgolide B in the organic solvent is 0.001 to 1 mol/L; or the molar ratio of the Ginkgolide B to the compound represented by formula 3 is 1:1 to 1:5; or the molar ratio of the Ginkgolide B to the base is 1:1 to 1:10; or the molar ratio of the Ginkgolide B to the catalyst is 1:1 to 1:5; or the reaction temperature of the ether-forming reaction is the temperature at which the organic solvent used is refluxed at normal temperature and atmospheric pressure.

14. A method for preparing the compound represented by formula 2 according to claim 8, wherein, the method comprises the steps of: in an organic solvent, under the action of an acid or a base, the compound represented by formula 1 is subjected to hydrolysis reaction as shown below to obtain a compound represented by formula 1 in which R is hydrogen; the compound represented by formula 2 is obtained by salt-forming reaction between the compound and various bases; ##STR00044## wherein L and cation are as defined in claim 8; and R is substituted or unsubstituted C.sub.1-8 hydrocarbonyl, the substituent in the substituted C.sub.1-8 hydrocarbonyl is one or more of halogen, hydroxyl, C.sub.1-10 alkoxy, phenyl and C.sub.1-10 alkyl.

15. The method for preparing the compound represented by formula 2 according to claim 14, wherein for the hydrolysis reaction: in an organic solvent, under the action of an acid or a base, the compound represented by formula 1 is subjected to hydrolysis reaction as shown below to obtain a compound represented by formula 1 in which R is H; or the base is inorganic base and/or organic base; or the acid is inorganic acid and/or organic acid; or the organic solvent is alcohol solvent and halogenated hydrocarbon solvent; or when the compound represented by formula 1 is subjected to the hydrolysis reaction under the action of the base, the molar ratio of the compound represented by formula 1 to the base is 1:1 to 1:10; or when the compound represented by formula 1 is subjected to the hydrolysis reaction under the action of the base, the reaction temperature of the hydrolysis reaction is the temperature at which the organic solvent used is refluxed at normal temperature and atmospheric pressure; or when that compound represented by formula 1 is subjected to the hydrolysis reaction under the action of the base, the reaction time of the present disclosure is 1 to 5 hour; or when the compound represented by formula 1 is subjected to the hydrolysis reaction under the action of the base, the molar concentration of the compound represented by formula 1 in the organic solvent is 0.001 to 1 mol/L; or when the compound represented by formula 1 is subjected to the hydrolysis reaction under the action of the acid, the molar ratio of the compound represented by formula 1 to the acid is 1:2 to 1:100; or when the compound represented by formula 1 is subjected to the hydrolysis reaction under the action of the acid, the molar concentration of the compound represented by formula 1 in the organic solvent is 0.001 to 1 mol/L; or when the compound represented by formula 1 is subjected to the hydrolysis reaction under the action of the acid, the reaction temperature of the hydrolysis reaction is 15 to 25° C.; or when the compound represented by formula 1 is subjected to the hydrolysis reaction under the action of the acid, the reaction time in the present disclosure is 1 to 5 hours.

16. The method for preparing the compound represented by formula 2 according to claim 14, wherein for the salt-forming reaction; in an organic solvent, the compound represented by formula 1 (R is hydrogen) is mixed with a base for salt-forming reaction; or the base is selected from inorganic base or organic base; or the organic solvent is alcohol solvent; or the molar concentration of the compound represented by formula 1 (R is hydrogen) in the organic solvent is 0.01 to 0.1 mol/L; or the molar ratio of the compound represented by formula 1 (R is hydrogen) to the base is 1:1 to 3; or the reaction temperature is 15 to 40° C.; or the reaction time is 1 to 4 hours.

17. A pharmaceutical composition, wherein, the pharmaceutical composition comprises a therapeutically effective dose of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof according to claim 1.

18. A method for preventing or treating diseases related to platelet activating factor in a subject in need thereof, comprising: administering an effective amount of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof according to claim 1 to the subject, the disease related to platelet activating factor is ischemic stroke, thrombosis, angina pectoris, cardiopulmonary infarction, and inflammation or asthma.

19. A method for preventing or treating diseases related to platelet activating factor in a subject in need thereof, comprising: administering an effective amount of the compound represented by formula 2 according to claim 8 to the subject, the disease related to platelet activating factor is ischemic stroke, thrombosis, angina pectoris, cardiopulmonary infarction, and inflammation or asthma.

20. A pharmaceutical composition comprising a therapeutically effective dose of the compound represented by formula 2 according to claim 8.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0124] FIG. 1, test results of anti-platelet aggregation activity in vitro of embodiment 1-21 (n=5, 1 μM),

[0125] Results: The compounds of the embodiments show obvious inhibitory effect on platelet aggregation, with blank as the standard 1, the platelet aggregation rate of Ginkgolide B at 1 μM concentration is 63.42%, and the platelet aggregation rate under the action of the compounds of each embodiment is lower than that of Ginkgolide B.

[0126] FIG. 2, evaluation results of embodiments 2, 7, 10, 12, 13, 14, 17 and 21 inhibiting platelet aggregation activity in SD rats (n=10, 50 mg/kg),

[0127] Results: The embodiments show obvious anti-aggregation activity on platelet aggregation in SD rats, the activities of the compounds of the embodiments are higher than that of Ginkgolide B except for embodiment 10, and the in vivo activities of embodiments 12, 13 and 14 are particularly significant (P<0.001), which could be applied to clinical anticoagulation and treatment of related diseases.

[0128] FIG. 3, evaluation results of the activity of embodiments 2, 7, 10, 12, 13, 14, 17 and 21 for reducing the area ratio of hemicerebral infarction in SD rats (n=10, 50 mg/kg),

[0129] Results: Compared with the model group, the compounds of each embodiment can obviously reduce the area ratio of hemicerebral infarction in rats, the activities of the compounds in the embodiments are smaller than that of Ginkgolide B group except for embodiment 10, and the activities of embodiments 12, 13 and 14 are particularly significant (P<0.001), which can be used for clinical treatment of cerebral ischemia and cerebral ischemia related diseases.

[0130] FIG. 4, partial slice photos of blank model group, Ginkgolide B, embodiment 10, and embodiment 12 group (original pictures are in color),

[0131] Results: Embodiment 12 is significantly better than Ginkgolide B and embodiment 10, can significantly reduce the area ratio of hemicerebral infarction of acute cerebral ischemia in SD rats, and can be used for clinical anti-coagulation and anti-cerebral ischemia, and the treatment of related diseases.

DETAILED DESCRIPTION OF THE EMBODIMENT

Embodiment 1 Preparation of 10-O-(methoxyformylmethyl) Ginkgolide B

[0132] ##STR00013##

[0133] mg (0.5 mmol) of Ginkgolide B was dissolved in 20 mL of THF, 190 mg (2.0 mmol) of methyl chloroacetate, 166 mg (1.0 mmol) of KI and 310 mg (2.3 mmol) of potassium carbonate were added in turn, the mixture was heated, refluxed and stirred for 2 hours, and the plate layer was tracked until the substrate substantially disappeared, the post-treatment was carried out after the completion of the reaction, potassium carbonate was removed by filtration, the mother liquor was concentrated and the residue was separated by column chromatography to obtain a light yellow solid; then the residue was filtered and dried to obtain 121 mg of the product with a yield of 48%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.74 (dd, 1H, 8-H), 1.87 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 3.71 (s, 1H, —OCH.sub.3), 4.06 (m, 1H, 1-H), 4.42 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.63 (d, 1H, 2-H), 4.80 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.15 (d, 1H, 1-OH), 5.29 (s, 1H, 10-H), 5.33 (d, 1H, 6-H), 6.19 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH). MS (m/z): 497 (M+H.sup.+)

Embodiment 2 Preparation of 10-O-(methoxyformylallyl) Ginkgolide B

[0134] ##STR00014##

[0135] 300 mg (0.71 mmol) of Ginkgolide B was dissolved in 30 mL of THF, 251 mg (1.4 mmol) of methyl 4-bromo-2-butenoate, 232 mg (1.4 mmol) of KI and 434 mg (3.1 mmol) of potassium carbonate were added in turn, the mixture was heated, refluxed and stirred for 2 hours, and the plate layer was tracked until the substrate substantially disappeared, the post-treatment was carried out after the completion of the reaction, potassium carbonate was removed by filtration, the mother liquor was concentrated and the residue was separated by column chromatography to obtain a light yellow solid, then the residue was filtered and dried to obtain 192 mg of the product with a yield of 52.5%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.01 (s, 9H, t-Bu), 1.08 (d, 3H, 14-Me), 1.74 (dd, 1H, 8-H), 1.87 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 3.73 (s, 1H, —OCH.sub.3), 4.06 (m, 1H, 1-H), 4.42 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.63 (d, 1H, 2-H), 4.80 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.15 (d, 1H, 1-OH), 5.29 (s, 1H, 10-H), 5.33 (d, 1H, 6-H), 5.65 (m, 1H, —CH═), 5.76 (m, 1H, —CH═), 6.19 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH). MS (m/z): 523 (M+H.sup.+)

Embodiment 3 Preparation of 10-O-(tert-butoxyformylmethyl) Ginkgolide B

[0136] ##STR00015##

[0137] 300 mg (0.70 mmol) of Ginkgolide B was dissolved in 30 mL of THF, 276 mg (1.41 mmol) of tert-butyl bromoacetate, 235 mg (1.41 mmol) of KI and 434 mg (3.2 mmol) of potassium carbonate were added in turn, the mixture was heated, refluxed and stirred for 2 hours, and the plate layer was tracked until the substrate substantially disappeared, the post-treatment was carried out after the completion of the reaction, potassium carbonate was removed by filtration, the mother liquor was concentrated and the residue was separated by column chromatography to obtain light yellow needle-like crystals; then the residue was filtered and dried to obtain 220 mg of the product with a yield of 58%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 0.99 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.42 (s, 9H, —O-t-Bu), 1.70 (dd, 1H, 8-H), 1.86 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 4.05 (m, 1H, 1-H), 4.28 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.63 (d, 1H, 2-H), 4.65 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.13 (d, 1H, 1-OH), 5.25 (s, 1H, 10-H), 5.31 (d, 1H, 6-H), 6.19 (s, 1H, 12-H), 6.50 (s, 1H, 3-OH). MS (m/z): 539 (M+H.sup.+)

Embodiment 4 Preparation of 10-O-(methoxyformylmethoxyethyl) Ginkgolide B

[0138] ##STR00016##

[0139] 300 mg (0.70 mmol) of Ginkgolide B was dissolved in 30 mL of THF, 345 mg (1.41 mmol) of methyl iodoethoxyacetate, 235 mg (1.41 mmol) of KI and 434 mg (3.2 mmol) of potassium carbonate were added in turn, the mixture was heated, refluxed and stirred for 2 hours, and the plate layer was tracked until the substrate substantially disappeared, the post-treatment was carried out after the completion of the reaction, potassium carbonate was removed by filtration, the mother liquor was concentrated and the residue was separated by column chromatography to obtain light yellow needle-like crystals; then the residue was filtered and dried to obtain 219 mg of the product with a yield of 58%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 0.98 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.86 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 3.57 (m, 4H, —OCH.sub.2CH.sub.2O—), 3.92 (s, 3H, —OCH.sub.3), 4.05 (m, 1H, 1-H), 4.28 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.63 (d, 11H, 2-H), 4.65 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.13 (d, 1H, 1-OH), 5.25 (s, 1H, 10-H), 5.31 (d, 1H, 6-H), 6.19 (s, 1H, 12-H), 6.50 (s, 1H, 3-OH). MS (m/z): 541 (M+H.sup.+)

Embodiment 5 Preparation of 10-O-(methoxyformylmethoxyethoxyethyl) Ginkgolide B

[0140] ##STR00017##

[0141] 300 mg (0.70 mmol) of GinkgolideB was dissolved in 30 mL of THF, 360 mg (1.49 mmol) of methyl bromoethoxyacetate, 235 mg (1.41 mmol) of KI and 434 mg (3.2 mmol) of potassium carbonate were added in turn, the mixture was heated, refluxed and stirred for 2 hours, and the plate layer was tracked until the substrate substantially disappeared, the post-treatment was carried out after the completion of the reaction, potassium carbonate was removed by filtration, the mother liquor was concentrated and the residue was separated by column chromatography to obtain light yellow needle-like crystals; then the residue was filtered and dried to obtain 231 mg of the product with a yield of 56%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 0.98 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.86 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 3.52-3.59 (m, 8H, —OCH.sub.2CH.sub.2O—), 3.92 (s, 3H, —OCH.sub.3), 4.05 (m, 1H, 1-H), 4.28 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.63 (d, 1H, 2-H), 4.65 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.13 (d, 1H, 1-OH), 5.25 (s, 1H, 10-H), 5.31 (d, 1H, 6-H), 6.19 (s, 1H, 12-H), 6.50 (s, 1H, 3-OH). MS (m/z): 585 (M−H.sup.+)

Embodiment 6 Preparation of 4-(Ginkgolide B-10-oxy)-2-butenoic Acid

[0142] ##STR00018##

[0143] 500 mg (0.96 mmol) of the product of embodiment 2 was dissolved in 6 mL of anhydrous methanol, 51 mg (2.0 mmol) of lithium hydroxide was added thereto, the mixture was heated, refluxed and stirred, the plate layer was tracked until the substrate substantially disappeared, the reaction was completed after 3 hours, the pH value was adjusted to about 4-5 with dilute hydrochloric acid, part of methanol was evaporated, the mixture was placed allowing solid to precipitate, then filtered to obtain 393 mg of the product with a yield of 80.6%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.01 (s, 9H, t-Bu), 1.08 (d, 3H, 14-Me), 1.74 (dd, 1H, 8-H), 1.87 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 4.06 (m, 1H, 1-H), 4.42 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.63 (d, 1H, 2-H), 4.80 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.15 (d, 1H, 1-OH), 5.29 (s, 1H, 10-H), 5.33 (d, 1H, 6-H), 5.65 (m, 1H, —CH═), 5.76 (m, 1H, —CH═), 6.19 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH), 13.67 (s, 1H, —COOH). MS (m/z): 507 (M−H.sup.+)

Embodiment 7 Preparation of 2-(Ginkgolide B-10-oxy)acetic Acid

[0144] ##STR00019##

[0145] 1.18 g (2.19 mmol) of the product of embodiment 3 was dissolved in 10 mL of chloroform, and 10 mL of trifluoroacetic acid was added, and stirred at room temperature, the plate layer was tracked until the substrate substantially disappeared. After 2 hours, the post-treatment of the reaction was finished, and the solvent was evaporated under reduced pressure to obtain a light yellow solid, then the residue was filtered and dried to obtain 1.05 g of the product with a yield of 99%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.62 (d, 1H, 2-H), 4.71 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.28 (s, 1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH), 13.70 (s, 1H, —COOH). MS (m/z): 481 (M−H.sup.+)

Embodiment 8 Preparation of 2-(Ginkgolide B-10-oxyethoxy)acetic Acid

[0146] ##STR00020##

[0147] 200 mg (0.37 mmol) of the product of embodiment 4 was dissolved in 6 mL of anhydrous methanol, 25 mg (1.0 mmol) of lithium hydroxide was added thereto. Then the mixture was heated, refluxed and stirred, the plate layer was tracked until the substrate substantially disappeared, the reaction was completed after 3-4 hours. The pH was adjusted to about 4-5 with dilute hydrochloric acid, part of methanol was evaporated, the mixture was placed allowing solid to precipitate, then filtered to obtain 174 mg of the product with a yield of 91.9%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 0.98 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.86 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 3.57 (m, 4H, —OCH.sub.2CH.sub.2O—), 4.05 (m, 1H, 1-H), 4.28 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.63 (d, 1H, 2-H), 4.65 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.13 (d, 1H, 1-OH), 5.25 (s, 1H, 10-H), 5.31 (d, 1H, 6-H), 6.19 (s, 1H, 12-H), 6.50 (s, 1H, 3-OH), 12.8 (s, 1H, —COOH). MS (m/z): 525 (M−H.sup.+)

Embodiment 9 Preparation of 2-(Ginkgolide B-10-oxyethoxyethoxy)acetic Acid

[0148] ##STR00021##

[0149] 100 mg (0.17 mmol) of the product of embodiment 5 was dissolved in 5 mL of anhydrous methanol, 15 mg (0.6 mmol) of lithium hydroxide was added thereto, the mixture was heated, refluxed and stirred, the plate layer was tracked until the substrate substantially disappeared, the reaction was completed after 3-4 hours. The pH value was adjusted to about 4-5 with dilute hydrochloric acid, part of methanol was evaporated, the mixture was placed allowing solid to precipitate, then filtered to obtain 82 mg of the product with a yield of 84.6%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 0.98 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.86 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 3.54-3.64 (m, 8H, —OCH.sub.2CH.sub.2O—), 4.05 (m, 1H, 1-H), 4.28 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.63 (d, 1H, 2-H), 4.65 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.13 (d, 1H, 1-OH), 5.25 (s, 1H, 10-H), 5.31 (d, 1H, 6-H), 6.19 (s, 1H, 12-H), 6.50 (s, 1H, 3-OH), 13.5 (s, 1H, —COOH). MS (m/z): 569 (M−H.sup.+)

Embodiment 10 Preparation of 2-(Ginkgolide B-10-oxy)sodium Acetate

[0150] ##STR00022##

[0151] 200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7) was dissolved in 2 mL of absolute ethanol, 2 times the molar amount of Na.sub.2CO.sub.3 in methanol solution was added dropwise, the mixture was stirred at room temperature for 1 hour, an equal volume of absolute ether was added, the mixture was placed overnight allowing solid to precipitate to obtain 185 mg of the product, with a yield of 89.5%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.28 (s, 1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH). MS (m/z): 481 (M−H.sup.+, neg.).

Embodiment 11 Preparation of 2-(Ginkgolide B-10-oxy)ammonium Acetate

[0152] ##STR00023##

[0153] 200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7) was dissolved in 2 mL of absolute ethanol, 2 times the molar amount of ammonia in methanol solution was added dropwise, and the mixture was stirred at room temperature for 2 hours, then the solvent was evaporated under reduced pressure, 10 mL of ether was added for washing, and then the mixture was filtered to obtain 197 mg of light yellow solid with a yield of 96.3%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.28 (s, 1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH), 8.10 (br-s, 4H, NH). MS (m/z): 481 (M−H.sup.+, neg.).

Embodiment 12 Preparation of 2-(Ginkgolide B-10-oxy)lysine Acetate

[0154] ##STR00024##

[0155] 200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7) was dissolved in 2 mL of absolute ethanol, equal molar amount of lysine in methanol solution was added dropwise, and the mixture was stirred at room temperature for 2 hours, then the solvent was evaporated under reduced pressure, 10 mL of ether was added for washing, and then the mixture was filtered to obtain 255 mg of light yellow solid with a yield of 98.1%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.28 (s, 1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH), 1.25 (m, 2H, CH.sub.2), 1.78 (m, 2H, CH.sub.2), 2.03 (m, 2H, CH.sub.2), 3.33 (m, 2H, CH.sub.2), 3.48 (m, 1H, CH), 6.82 (br-s, 6H, NH). MS (m/z): 481 (M−H.sup.+, neg.).

Embodiment 13 Preparation of 2-(Ginkgolide B-10-oxy)arginine Acetate

[0156] ##STR00025##

[0157] 200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7) was dissolved in 2 mL of absolute ethanol, 1.5 times the molar amount of arginine in methanol solution was added dropwise, and the mixture was stirred at room temperature for 2 hours, then the solvent was evaporated under reduced pressure, 10 mL of ether was added for washing, and then the mixture was filtered to obtain 243 mg of light yellow solid with a yield of 92.5%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.28 (s, 1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH), 1.28 (m, 2H, CH.sub.2), 1.35 (m, 2H, CH.sub.2), 1.82 (m, 2H, CH.sub.2), 3.49 (m, 1H, CH), 6.32-7.01 (br-s, 7H, N—H). MS (m/z): 481 (M−H.sup.+, neg.).

Embodiment 14 Preparation of 2-(Ginkgolide B-10-oxy)histidine Acetate

[0158] ##STR00026##

[0159] 200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7) was dissolved in 2 mL of absolute ethanol, 1.8 times the molar amount of histidine in methanol solution was added dropwise, and the mixture was stirred at room temperature for 2 hours, then the solvent was evaporated under reduced pressure, 10 mL of ether was added for washing, and then the mixture was filtered to obtain 259 mg of light yellow solid with a yield of 99.1%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.28 (s, 1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH), 2.90-3.16 (m, 2H, CH.sub.2), 4.49 (m, 1H, CH), 7.72 (s, 1H, CH), 8.91 (s, 1H, CH), 6.30-7.01 (br-s, 3H, N—H), 10.25 (br-s, 2H, N—H). MS (m/z): 481 (M−H.sup.+, neg.).

Embodiment 15 Preparation of 2-(Ginkgolide B-10-oxy)triethylamine Acetate

[0160] ##STR00027##

[0161] 200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7) was dissolved in 2 mL of absolute ethanol, 2 times the molar amount of triethylamine in methanol solution was added dropwise, and the mixture was stirred at room temperature for 2 hours, then the solvent was evaporated under reduced pressure, 10 mL of ether was added for washing, and then the mixture was filtered to obtain 184 mg of light yellow solid with a yield of 76.9%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.28 (s, 1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH), 1.03 (t, 9H, CH.sub.3—CH.sub.2), 3.05 (q, 6H, CH.sub.3—CH.sub.2), 9.25 (br-s, 1H, N—H). MS (m/z): 481 (M−H.sup.+, neg.).

Embodiment 16 Preparation of 2-(Ginkgolide B-10-oxy)diethylamine Acetate

[0162] ##STR00028##

[0163] 200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7) was dissolved in 2 mL of absolute ethanol, equal molar amount of diethylamine in methanol solution was added dropwise, and the mixture was stirred at room temperature for 2 hours, then the solvent was evaporated under reduced pressure, 10 mL of ether was added for washing, and then the mixture was filtered to obtain 178 mg of light yellow solid with a yield of 78.2%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.28 (s, 1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH), 1.05 (t, 6H, CH.sub.3—CH.sub.2), 3.07 (q, 4H, CH.sub.3—CH.sub.2), 8.27 (br-s, 2H, N—H). MS (m/z): 481 (M−H.sup.+, neg.).

Embodiment 17 Preparation of 2-(Ginkgolide B-10-oxy) n-pentylamine Acetate

[0164] ##STR00029##

[0165] 200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7) was dissolved in 2 mL of absolute ethanol, 3 times the molar amount of n-pentylamine in methanol solution was added dropwise, and the mixture was stirred at room temperature for 2 hours, then the solvent was evaporated under reduced pressure, 10 mL of ether was added for washing, and then the mixture was filtered to obtain 193 mg of light yellow solid with a yield of 82.7%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.28 (s, 1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH), 1.05 (m, 3H, CH.sub.3—CH.sub.2), 1.25-1.30 (m, 4H, —CH.sub.2—CH.sub.2), 2.05 (m, 2H, —CH.sub.2), 3.37 (m, 2H, —CH.sub.2), 7.27-7.55 (br-s, 3H, N—H). MS (m/z): 481 (M−H.sup.+, neg.).

Embodiment 18 Preparation of 2-(Ginkgolide B-10-oxy) pyrrolidine Acetate

[0166] ##STR00030##

[0167] 200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7) was dissolved in 2 mL of absolute ethanol, 1.5 times the molar amount of pyrrolidine in methanol solution was added dropwise, and the mixture was stirred at room temperature for 2 hours, then the solvent was evaporated under reduced pressure, 10 mL of ether was added for washing, and then the mixture was filtered to obtain 183 mg of light yellow solid with a yield of 80.7%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.28 (s, 1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH), 2.02 (m, 4H, —CH.sub.2), 3.17 (m, 4H, —CH.sub.2), 7.27-7.55 (br-s, 2H, N—H). MS (m/z): 481 (M−H.sup.+, neg.).

Embodiment 19 Preparation of 2-(Ginkgolide B-10-oxy)morpholine Acetate

[0168] ##STR00031##

[0169] 200 mg (0.41 mmol) of 2-(Ginkgolide B-10-oxy) acetic acid (embodiment 7) was dissolved in 2 mL of absolute ethanol, 1.5 times the molar amount of morpholine in methanol solution was added dropwise, and the mixture was stirred at room temperature for 2 hours, then the solvent was evaporated under reduced pressure, 10 mL of ether was added for washing, and then the mixture was filtered to obtain 202 mg of light yellow solid with a yield of 86.6%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 1.00 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.82 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.80 (q, 1H, 14-H), 4.05 (d, 1H, 1-H), 4.29 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.62 (d, 1H, 2-H), 4.75 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.28 (s, 1H, 10-H), 5.32 (d, 1H, 6-H), 5.50 (s, 1H, 1-OH), 6.18 (s, 1H, 12-H), 6.48 (s, 1H, 3-OH), 3.52 (m, 4H, —CH.sub.2), 4.20 (m, 4H, —CH.sub.2), 7.28-7.35 (br-s, 2H, N—H). MS (m/z): 481 (M−H.sup.+, neg.).

Embodiment 20 Preparation of 2-(Ginkgolide B-10-oxyethoxy)sodium Acetate

[0170] ##STR00032##

[0171] 250 mg (0.48 mmol) of 2-(Ginkgolide B-10-oxyethoxy) acetic acid (embodiment 8) was dissolved in 5 mL of absolute ethanol, 1.2 times the molar amount of sodium carbonate in methanol solution was added dropwise, and the mixture was stirred at room temperature for 2 hours, then the solvent was evaporated under reduced pressure, 10 mL of ether was added for washing, and then the mixture was filtered to obtain 208 mg of light yellow with a yield of 79.1%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 0.98 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.86 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 3.57 (m, 4H, —OCH.sub.2CH.sub.2O—), 4.05 (m, 1H, 1-H), 4.30 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.63 (d, 1H, 2-H), 4.63 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.13 (d, 1H, 1-OH), 5.25 (s, 1H, 10-H), 5.31 (d, 1H, 6-H), 6.19 (s, 1H, 12-H), 6.50 (s, 1H, 3-OH). MS (m/z): 525 (M−H.sup.+, Neg.)

Embodiment 21 Preparation of 2-(Ginkgolide B-10-oxyethoxy)N-methyl-D-glucosamine Acetate

[0172] ##STR00033##

[0173] mg (0.48 mmol) of 2-(Ginkgolide B-10-oxyethoxy) acetic acid (embodiment 8) was dissolved in 5 mL of absolute ethanol, 1.5 times the molar amount of N-methyl-D-glucosamine in methanol solution was added dropwise, and the mixture was stirred at room temperature for 2 hours, then the solvent was evaporated under reduced pressure, 20 mL of ether was added for washing, and then the mixture was filtered to obtain 245 mg of light yellow solid with a yield of 70.8%. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 0.98 (s, 9H, t-Bu), 1.09 (d, 3H, 14-Me), 1.70 (dd, 1H, 8-H), 1.86 (ddd, 1H, 7α-H), 2.13 (dd, 1H, 7β-H), 2.79 (q, 1H, 14-H), 3.57 (m, 4H, —OCH.sub.2CH.sub.2O—), 4.05 (m, 1H, 1-H), 4.28 (d, 1H, J=16 Hz, 10-CH.sub.2—), 4.63 (d, 1H, 2-H), 4.65 (d, 1H, J=16 Hz, 10-CH.sub.2—), 5.13 (d, 1H, 1-OH), 5.25 (s, 1H, 10-H), 5.31 (d, 1H, 6-H), 6.19 (s, 1H, 12-H), 6.50 (s, 1H, 3-OH), 2.85 (s, 3H, CH.sub.3), 3.35-3.39 (m, 9H, CH, OH), 3.58-3.62 (m, 4H, CH.sub.2*2), 8.89 (br-s, 2H, NH). MS (m/z): 525 (M−H.sup.+)

Embodiment 22 In Vitro Anti-Platelet Aggregation Activity Evaluation Experiment

[0174] Experimental method: New Zealand white rabbits were anesthetized with sodium pentobarbital (2%, 2 mL/kg), about 40 mL of blood was obtained by abdominal aortic puncture, and the supernatant was collected as platelet-rich serum (PRP) after centrifugation at 1000 rpm/min for 10 min, the remaining blood was centrifuged at 4000 rpm/min for 10 min, and the supernatant was collected as platelet-poor serum (PPP); blank control group: 100 μL PRP+100 μL normal saline; drug group: 100 μL PRP+100 μL 0.05% DMSO dissolved drug (Ginkgolide B was positive control group), and the final drug concentration was 1 μM. After incubation for 5 min, 2 μL PAF(10× final concentration was 145 nm) was added; the platelet aggregation rate was measured by a platelet aggregation instrument, and each sample was repeated for five groups, the obtained aggregation rates were divided by the average value of the blank control group to obtain corrected values for comparison.

[0175] The results showed that the compounds of each embodiment exhibited obvious inhibitory effect on platelet aggregation, with blank as the standard 1, the platelet aggregation rate of Ginkgolide B at 1 μM concentration was 63.42%, and the platelet aggregation rate of the compounds of each embodiment was lower than that of Ginkgolide B, the specific data are shown in Table 1 and FIG. 1. Embodiments 2, 7, 12, 13, 14, 17 and 21 are compounds with significant activity.

TABLE-US-00001 TABLE 1 Test results of anti-platelet aggregation activity in vitro of Embodiment 1-21 Platelet Compound aggregation rate number (%, 1 μM) blank 100 Embodiment 1 29.98 Embodiment 2 10.30 Embodiment 3 26.10 Embodiment 4 46.70 Embodiment 5 39.34 Embodiment 6 45.67 Embodiment 7 17.66 Embodiment 8 23.68 Embodiment 9 34.99 Embodiment 10 39.34 Embodiment 11 56.53 Embodiment 12 12.23 Embodiment 13 15.66 Embodiment 14 19.74 Embodiment 15 24.65 Embodiment 16 28.87 Embodiment 17 21.90 Embodiment 18 26.45 Embodiment 19 35.77 Embodiment 20 45.32 Embodiment 21 18.64 Ginkgolide B 63.42

Embodiment 23 Evaluation Experiment of Anticoagulant Activity in SD Rats

[0176] Experimental method: Rats were randomly divided into 10 rats in each group, and each group was given the corresponding test drug (50 mg/kg) by gavage after weighing, once a day for 3 days. One hour after the last administration, the rats were anesthetized, 8 mL of blood was taken from femoral artery, and the whole blood was anticoagulated with 3.8% sodium citrate, the whole blood anticoagulated with sodium citrate (3.8% trisodium citrate:whole blood=1:9) was centrifuged for 10 min at 800 r/min, and the upper plasma obtained at this speed was platelet-rich plasma (PRP), after PRP was sucked out, the remaining blood was centrifuged at 3000 r/min for 10 min, the plasma obtained at this speed was platelet poor plasma (PPP).

[0177] 150 μL of PRP in each group was sucked and added to the 96-well plate (adjusted to zero by PPP), and ADP inducer was added, the absorbance value A1 was measured at the wavelength of 650 nm in the microplate reader, which was the absorbance value of each group at 0 min; the oscillation mode of the microplate reader was turned on, and the absorbance value A2 was detected again after 5 min, which was the absorbance value of each group at 5 min. Since the addition of ADP would cause platelet aggregation and change the light permeability, the maximum platelet aggregation rate (PAGM) within 5 min was measured according to this principle.

Maximum platelet aggregation rate (PAGM)=(A1−A2)/A1×100

[0178] The results are shown in table 2 and FIG. 2: all the embodiments exhibit obvious anti-aggregation activity on platelet aggregation in SD rats, the activities of the embodiments were higher than those of Ginkgolide B except for embodiment 10. The in vivo activities of embodiments 12, 13 and 14 were particularly significant, which could be applied to clinical anticoagulation and treatment of related diseases.

TABLE-US-00002 TABLE 2 Test results of anti-platelet aggregation activity in vitro of Embodiment 2, 7, 10, 12, 13, 14, 17 and 21 (n = 10). Average maximum platelet Standard No. aggregation rate (%) deviation (SD, %) Solvent group 51.45 12.10 Ginkgolide B 39.57 11.41 Embodiment 2 32.60  9.50 Embodiment 7 35.20  7.50 Embodiment 10 42.20  9.52 Embodiment 12 22.65  8.65 Embodiment 13 21.25  7.65 Embodiment 14 26.82  9.47 Embodiment 17 34.20  8.60 Embodiment 21 29.35  7.79

Embodiment 24 Evaluation Experiment of Anti-Acute Cerebral Ischemia Activity

[0179] Methods: SD rats were weighed and randomly divided into 10 rats in each group, and were anesthetized by intraperitoneal injection of 15% chloral hydrate 300 mg/kg, their left lateral position was fixed on the rat operating table, and the left temporal top and face were shaved and disinfected with 75% ethanol, the skin was cut between the left eye and left ear, the temporal muscle and masseter muscle were passively separated, and the wing plate of the temporal bone was exposed, under the operating microscope, a 2 mm×2 mm bone window was ground with a cranial drill 1 mm from the union of the temporal bone and the temporal scalene near the mouth, and the skull was pried open with a pry bar. At this time, a relatively straight blood vessel with few branches can be seen through the dura mater, that is, the middle cerebral artery. Bipolar electrocoagulation forceps were used to cauterize the olfactory tract from 1 mm to the inferior cerebral vein, which completely blocked the blood flow. The temporal muscle and skin were sutured in turn, and then the rat was administered by gavage (50 mg/kg). After the rats were awakened, they were put back into their cages and continued to be reared for 24 h.

[0180] The rats were anesthetized by intraperitoneal injection of 15% chloral hydrate 300 mg/kg again, the brains were decapitated, the olfactory bulb, cerebellum and brain stem were removed, quick-frozen in the refrigerator at −20° C. for about 15 min, and then the frozen brains were cut into 7 slices. The brain slices were stained in 1% TTC dye solution (incubated at 37° C. in the dark for about 5-10 min), the infarcted area of brain slices after staining was white, while the non-infarcted area was rose red; after staining was completed, the brain slices were moved to 10% formaldehyde solution and kept away from light for 24 hours, finally, a digital camera was used to take pictures, the areas of frontal and reverse infarcted areas and non-infarcted areas were measured by image analysis software (ImageJ, version: 1.4.3.67), and the ratio of infarcted areas in the total infarcted cerebral hemisphere was calculated.

[0181] The experimental results are shown in table 3 and FIG. 3: compared with the model group, the compounds of each embodiment can obviously reduce the ratio of hemispheric infarction area in rats. The hemispheric infarction area of each group was smaller than that of Ginkgolide B group except for embodiment 10, and the activities of embodiments 12, 13 and 14 were particularly significant, which can be used for clinical treatment of cerebral ischemia and cerebral ischemia related diseases.

[0182] FIG. 3. evaluation results of the activity of embodiments 2, 7, 10, 12, 13, 14 and 21 for reducing the hemicerebral infarction area ratio in SD rats(n=10)

TABLE-US-00003 Average area ratio of standard Compound hemicerebral infarction (%) deviation Model group 31.91 1.66 Ginkgolide B 26.12 6.04 Embodiment 2 21.56 4.35 Embodiment 7 25.14 4.56 Embodiment 10 29.61 3.00 Embodiment 12 18.83 5.75 Embodiment 13 20.14 5.27 Embodiment 14 17.98 4.76 Embodiment 17 25.31 5.13 Embodiment 21 22.66 3.67

[0183] Although the specific embodiments of the present disclosure have been described above, those skilled in the art should understand that these are only examples, various changes or modifications can be made to these embodiments without departing from the principle and essence of the present invention. Therefore, the protection scope of the present disclosure is defined by the appended claims.