Tanshinone IIA derivatives and pharmaceutical application thereof

Abstract

The invention discloses a tanshinone IIA derivant and application in pharmacy, which is characterized by the following: the derivant constitutional formula is showed in the right chart; when R1 represents -Ar, R2,R3 represents hydrogen or alkyl with one to eight carbon atoms; or R2-N-R3 represents saturated heterocycle with nitrogen, imidazoline and its derivant, glyoxaline and its derivant, diethylenediamine and its derivant, piperidine and its derivant, morpholine and its derivant; when R1 represents -H, R2,R3 represents alkyl with three to eight carbon atoms, cycloalkyl and aromatic nucleus; or R2-N-R3 represents cyclohexylamine, imidazoline and its derivant, glyoxaline and its derivant, piperazine, piperazine and derivant of derivant. The derivant can improve the bioavailability of original chemical compoundm.

Description

technical field

[0001] The invention relates to a class of compound derivatives and their application in pharmacy, in particular to derivatives of tanshinone II A and their application in pharmacy, belonging to the technical field of medicine. Background technique

[0002] Salvia miltiorrhiza is the dry root and rhizome of Salvia miltiorrhiza Bge., a plant in the Labiatae family. It was first recorded in "Shen Nong's Materia Medica", and has been recorded in successive dynasties of herbal medicines. It is bitter in taste, slightly cold in nature, and enters the two meridians of Guixin and Liver. Tool dispelling blood stasis and relieving pain, promoting blood circulation to stimulate menstrual flow, clearing away heart-fire and eliminating troubles. Salvia miltiorrhiza is a traditional Chinese medicine for promoting blood circulation and removing blood stasis, and its commonly used preparations are mainly used to treat cardiovascular and cerebrovascular diseases. The chemi...

Examples

Embodiment 1

[0052] Example 1. 2-(diallylamine) methyl-tanshinone II A synthesis steps and structural confirmation

[0053] Mix 1.56g of tanshinone, 0.5mL of 37% formaldehyde solution, 2.4g of diallylamine, and 50mL of acetic acid, heat and reflux in an oil bath for 5h, remove the solvent from the mixture under reduced pressure to obtain a red solid, dissolve it in water, filter, and adjust the filtrate with alkali pH to 9, filtered, the filter cake was dried, and separated by silica gel column chromatography (eluent: chloroform / methanol=15 / 1) to obtain 1.15 g (yield 53%) of the expected compound.

[0054] 1 H-NMR (CDCl 3)δ7.71(d, 1H), 7.66(d, 1H), 5.31~5.45(m, 2H), 4.65~4.81(m, 4H), 3.50(s, 2H), 3.15(m, 2H), 2.55 ~2.71(m, 4H), 2.18(s, 6H), 2.07(s, 3H), 1.74(m, 2H), 1.61(m, 2H).

Embodiment 2

[0055] Example 2. Synthesis steps and structural confirmation of 2-(sodium iminodiacetate) methyl-tanshinone II A

[0056] Mix 1.56g of tanshinone, 0.5mL of 37% formaldehyde solution, 4.2g of iminodiacetic acid hydrochloride, and 50mL of acetic acid, heat and reflux in an oil bath for 5h, remove the solvent from the mixture under reduced pressure to obtain a red solid, dissolve in water, filter, and filtrate Add alkali to adjust the pH to 9, filter, dry the filter cake, and separate by silica gel column chromatography (eluent: chloroform / methanol=15 / 1) to obtain 1.41 g (yield 60%) of 2-iminodiacetic acid-tanshinone II A, and then dissolved in twice the molar amount of sodium bicarbonate solution, filtered to remove insoluble matter, and the filtrate was dried to obtain the desired compound.

[0057] 1 H-NMR (CDCl3) δ7.62(d, 1H), 7.56(d, 1H), 3.64(s, 2H), 3.35~3.51(m, 4H), 3.15(m, 2H), 2.09(s, 6H) ), 1.95(s, 3H), 1.75(m, 2H), 1.61(m, 2H).

Embodiment 3

[0058] Example 3. 2-(cyclohexylamine) methyl-tanshinone II A synthesis steps and structure confirmation

[0059] Mix 1.56g of tanshinone, 0.5mL of 37% formaldehyde solution, 2.5g of cyclohexylamine, and 50mL of acetic acid, heat and reflux in an oil bath for 5 hours, remove the solvent from the mixture under reduced pressure to obtain a red solid, dissolve it in water, filter, and adjust the pH of the filtrate to 9. Filter, dry the filter cake, and separate by silica gel column chromatography (eluent: chloroform / methanol=15 / 1) to obtain 1.41 g (yield 60%) of the expected compound.

[0060] 1 H-NMR (CDCl3) δ7.68(d, 1H), 7.52(d, 1H), 3.55(s, 2H), 3.21~3.32(m, 4H), 3.13(m, 2H), 2.12(s, 6H) ), 2.03(s, 3H), 1.75(m, 2H), 1.62(m, 2H), 1.52~1.61(m, 4H), 1.32~1.41(m, 4H).

technical field

[0001] The invention relates to a class of compound derivatives and their application in pharmacy, in particular to derivatives of tanshinone II A and their application in pharmacy, belonging to the technical field of medicine. Background technique

[0002] Salvia miltiorrhiza is the dry root and rhizome of Salvia miltiorrhiza Bge., a plant in the Labiatae family. It was first recorded in "Shen Nong's Materia Medica", and has been recorded in successive dynasties of herbal medicines. It is bitter in taste, slightly cold in nature, and enters the two meridians of Guixin and Liver. Tool dispelling blood stasis and relieving pain, promoting blood circulation to stimulate menstrual flow, clearing away heart-fire and eliminating troubles. Salvia miltiorrhiza is a traditional Chinese medicine for promoting blood circulation and removing blood stasis, and its commonly used preparations are mainly used to treat cardiovascular and cerebrovascular diseases. The chemi...

Examples

Embodiment 1

[0052] Example 1. 2-(diallylamine) methyl-tanshinone II A synthesis steps and structural confirmation

[0053] Mix 1.56g of tanshinone, 0.5mL of 37% formaldehyde solution, 2.4g of diallylamine, and 50mL of acetic acid, heat and reflux in an oil bath for 5h, remove the solvent from the mixture under reduced pressure to obtain a red solid, dissolve it in water, filter, and adjust the filtrate with alkali pH to 9, filtered, the filter cake was dried, and separated by silica gel column chromatography (eluent: chloroform / methanol=15 / 1) to obtain 1.15 g (yield 53%) of the expected compound.

[0054] 1 H-NMR (CDCl 3)δ7.71(d, 1H), 7.66(d, 1H), 5.31~5.45(m, 2H), 4.65~4.81(m, 4H), 3.50(s, 2H), 3.15(m, 2H), 2.55 ~2.71(m, 4H), 2.18(s, 6H), 2.07(s, 3H), 1.74(m, 2H), 1.61(m, 2H).

Embodiment 2

[0055] Example 2. Synthesis steps and structural confirmation of 2-(sodium iminodiacetate) methyl-tanshinone II A

[0056] Mix 1.56g of tanshinone, 0.5mL of 37% formaldehyde solution, 4.2g of iminodiacetic acid hydrochloride, and 50mL of acetic acid, heat and reflux in an oil bath for 5h, remove the solvent from the mixture under reduced pressure to obtain a red solid, dissolve in water, filter, and filtrate Add alkali to adjust the pH to 9, filter, dry the filter cake, and separate by silica gel column chromatography (eluent: chloroform / methanol=15 / 1) to obtain 1.41 g (yield 60%) of 2-iminodiacetic acid-tanshinone II A, and then dissolved in twice the molar amount of sodium bicarbonate solution, filtered to remove insoluble matter, and the filtrate was dried to obtain the desired compound.

[0057] 1 H-NMR (CDCl3) δ7.62(d, 1H), 7.56(d, 1H), 3.64(s, 2H), 3.35~3.51(m, 4H), 3.15(m, 2H), 2.09(s, 6H) ), 1.95(s, 3H), 1.75(m, 2H), 1.61(m, 2H).

Embodiment 3

[0058] Example 3. 2-(cyclohexylamine) methyl-tanshinone II A synthesis steps and structure confirmation

[0059] Mix 1.56g of tanshinone, 0.5mL of 37% formaldehyde solution, 2.5g of cyclohexylamine, and 50mL of acetic acid, heat and reflux in an oil bath for 5 hours, remove the solvent from the mixture under reduced pressure to obtain a red solid, dissolve it in water, filter, and adjust the pH of the filtrate to 9. Filter, dry the filter cake, and separate by silica gel column chromatography (eluent: chloroform / methanol=15 / 1) to obtain 1.41 g (yield 60%) of the expected compound.

[0060] 1 H-NMR (CDCl3) δ7.68(d, 1H), 7.52(d, 1H), 3.55(s, 2H), 3.21~3.32(m, 4H), 3.13(m, 2H), 2.12(s, 6H) ), 2.03(s, 3H), 1.75(m, 2H), 1.62(m, 2H), 1.52~1.61(m, 4H), 1.32~1.41(m, 4H).

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