Ginkgolide derivative and application thereof to pharmacy

Abstract

The invention provides a ginkgolide C derivative and application thereof to pharmacy. The ginkgolide C derivative has a structural formula shown in the description, wherein R1 represents -X-Ar, -X-Z-Ar, -X-COOH, -CO-Ar, -SO2-Ar, -X-Het., X1-CO-X2-NR4R5 or -X-NR4R5; X, X1 and X2 represent alkylidene groups with 1-8 carbon atoms; Z represents carbon, oxygen, sulfur or nitrogen; and Ar represents pyridyl, naphthyl, pyrimidyl and quinolyl. The ginkgolide C derivative is properly processed and then applied to pharmacy and can be used for greatly improving the bioavailability of an original compound, enhancing the curative effect of a medicine and embodying the pharmaceutical value of ginkgolide C.

Description

technical field

[0001] The present invention relates to a kind of compound derivative and its preparation method, and its application in pharmacy, especially relates to ginkgolide C derivative, its preparation method, and its application in pharmacy, and belongs to the field of medical technology. Background technique

[0002] In 1972, Benveniste et al discovered a factor that could strongly cause platelet aggregation from rabbit basophils. This factor is named platelet activating factor (hereinafter abbreviated as PAF). Hanahan et al. proved this factor in 1980 as an alkyl ether type phosphoglyceride with an acetyl group at the 2-position, namely 1-O-hexadecyl or octadecyl-2-acetyl-srl - Glycero-3-phosphocholine.

[0003] The physiological role of PAF has been extensively examined, and it is known that PAF is an important factor in a variety of physiological responses, including platelet aggregation, blood pressure reduction, immediate immune response, smooth muscle contr...

Examples

Embodiment 110

[0158] Example 1.10-(2'-Dimethylaminoethoxy)-Ginkgolide C Preparation and Structure Confirmation

[0159] Dissolve 600mg of ginkgolide C in 40mL of acetonitrile, add 300mg of N,N-dimethylchloroethylamine, 2.5g of potassium carbonate, and 300mg of potassium iodide in sequence, pass inert gas, heat and reflux for 2h, concentrate under reduced pressure, dissolve in chloroform, filter, The filtrate was concentrated. The obtained product was separated by column chromatography (eluent: ethyl acetate / petroleum ether=1 / 1) to obtain the desired product.

[0160] 1 H-NMR (DMSO-d 6 )δ7.26(s, 1H), 6.31(s, 1H), 6.05(s, 1H), 5.60(s, 1H), 5.31(d, 1H), 5.11(s, 1H), 4.55(d, 1H ), 4.30(t, 1H), 3.99(d, 1H), 3.50(t, 1H), 2.81(q, 1H), 2.60(d, 2H), 2.30(d, 2H), 2.15(s, 6H) , 1.60 (dd, 1H), 1.10 (d, 3H), 1.05 (s, 9H).

Embodiment 21

[0161] Example 2.10-(2'-Diethylaminoethoxy)-Ginkgolide C Preparation and Structure Confirmation

[0162] Dissolve 600mg of ginkgolide C in 40mL of acetonitrile, add 350mg of N,N-diethylchloroethylamine, 2.5g of potassium carbonate, 300mg of potassium iodide in sequence, pass inert gas, and heat to reflux for 2h. Concentrate under reduced pressure, dissolve in chloroform, filter, and concentrate the filtrate. The obtained product was separated by column chromatography (eluent: ethyl acetate / petroleum ether=1 / 1) to obtain the desired product.

[0163] 1 H-NMR (DMSO-d 6 )δ7.16(s, 1H), 6.20(s, 1H), 6.07(s, 1H), 5.26(d, 1H), 5.14(s, 1H), 4.65(d, 1H), 4.30(t, 1H ), 3.95(d, 1H), 3.52(t, 1H), 2.84(q, 1H), 2.60(d, 2H), 2.5(s, 4H), 2.30(d, 2H), 2.15(s, 6H) , 1.76 (dd, 1H), 1.21 (d, 3H), 1.10 (s, 9H).

Embodiment 310

[0164] Example 3.10-(4'-Chlorobenzyloxy)-Ginkgolide C Preparation and Structure Confirmation

[0165] Dissolve 600mg of ginkgolide C in 40mL of acetonitrile, add 1.0g of 4-chlorobenzyl iodide, 2.5g of potassium carbonate in sequence, pass inert gas, heat to reflux for 2h, concentrate under reduced pressure, dissolve in chloroform, filter, and concentrate the filtrate. The obtained product was separated by column chromatography (eluent: ethyl acetate / petroleum ether=1 / 1) to obtain the desired product.

[0166] 1 H-NMR (CDCl 3 )δ7.35~7.18(m, 2H), 7.25~7.089(m, 2H), 7.18(s, 1H), 6.15(s, 1H), 5.89(s, 1H), 5.22(brs, 1H), 5.03 (ABq, 2H), 4.85(s, 1H), 4.54(d, 1H), 3.85(d, 1H), 2.95(q, 1H), 2.28(s, 1H), 2.04(brs, 1H), 1.28( d, 3H), 1.65(dd, 1H), 1.14(s, 9H).

technical field

[0001] The present invention relates to a kind of compound derivative and its preparation method, and its application in pharmacy, especially relates to ginkgolide C derivative, its preparation method, and its application in pharmacy, and belongs to the field of medical technology. Background technique

[0002] In 1972, Benveniste et al discovered a factor that could strongly cause platelet aggregation from rabbit basophils. This factor is named platelet activating factor (hereinafter abbreviated as PAF). Hanahan et al. proved this factor in 1980 as an alkyl ether type phosphoglyceride with an acetyl group at the 2-position, namely 1-O-hexadecyl or octadecyl-2-acetyl-srl - Glycero-3-phosphocholine.

[0003] The physiological role of PAF has been extensively examined, and it is known that PAF is an important factor in a variety of physiological responses, including platelet aggregation, blood pressure reduction, immediate immune response, smooth muscle contr...

Examples

Embodiment 110

[0158] Example 1.10-(2'-Dimethylaminoethoxy)-Ginkgolide C Preparation and Structure Confirmation

[0159] Dissolve 600mg of ginkgolide C in 40mL of acetonitrile, add 300mg of N,N-dimethylchloroethylamine, 2.5g of potassium carbonate, and 300mg of potassium iodide in sequence, pass inert gas, heat and reflux for 2h, concentrate under reduced pressure, dissolve in chloroform, filter, The filtrate was concentrated. The obtained product was separated by column chromatography (eluent: ethyl acetate / petroleum ether=1 / 1) to obtain the desired product.

[0160] 1 H-NMR (DMSO-d 6 )δ7.26(s, 1H), 6.31(s, 1H), 6.05(s, 1H), 5.60(s, 1H), 5.31(d, 1H), 5.11(s, 1H), 4.55(d, 1H ), 4.30(t, 1H), 3.99(d, 1H), 3.50(t, 1H), 2.81(q, 1H), 2.60(d, 2H), 2.30(d, 2H), 2.15(s, 6H) , 1.60 (dd, 1H), 1.10 (d, 3H), 1.05 (s, 9H).

Embodiment 21

[0161] Example 2.10-(2'-Diethylaminoethoxy)-Ginkgolide C Preparation and Structure Confirmation

[0162] Dissolve 600mg of ginkgolide C in 40mL of acetonitrile, add 350mg of N,N-diethylchloroethylamine, 2.5g of potassium carbonate, 300mg of potassium iodide in sequence, pass inert gas, and heat to reflux for 2h. Concentrate under reduced pressure, dissolve in chloroform, filter, and concentrate the filtrate. The obtained product was separated by column chromatography (eluent: ethyl acetate / petroleum ether=1 / 1) to obtain the desired product.

[0163] 1 H-NMR (DMSO-d 6 )δ7.16(s, 1H), 6.20(s, 1H), 6.07(s, 1H), 5.26(d, 1H), 5.14(s, 1H), 4.65(d, 1H), 4.30(t, 1H ), 3.95(d, 1H), 3.52(t, 1H), 2.84(q, 1H), 2.60(d, 2H), 2.5(s, 4H), 2.30(d, 2H), 2.15(s, 6H) , 1.76 (dd, 1H), 1.21 (d, 3H), 1.10 (s, 9H).

Embodiment 310

[0164] Example 3.10-(4'-Chlorobenzyloxy)-Ginkgolide C Preparation and Structure Confirmation

[0165] Dissolve 600mg of ginkgolide C in 40mL of acetonitrile, add 1.0g of 4-chlorobenzyl iodide, 2.5g of potassium carbonate in sequence, pass inert gas, heat to reflux for 2h, concentrate under reduced pressure, dissolve in chloroform, filter, and concentrate the filtrate. The obtained product was separated by column chromatography (eluent: ethyl acetate / petroleum ether=1 / 1) to obtain the desired product.

[0166] 1 H-NMR (CDCl 3 )δ7.35~7.18(m, 2H), 7.25~7.089(m, 2H), 7.18(s, 1H), 6.15(s, 1H), 5.89(s, 1H), 5.22(brs, 1H), 5.03 (ABq, 2H), 4.85(s, 1H), 4.54(d, 1H), 3.85(d, 1H), 2.95(q, 1H), 2.28(s, 1H), 2.04(brs, 1H), 1.28( d, 3H), 1.65(dd, 1H), 1.14(s, 9H).

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