WO2008014722A1 - Prenyl flavonoids,their preparation and use - Google Patents

Abstract

Prenyl flavonoids, their preparation and use. The prenyl flavonoids are shown by formula I,in which ring A is five or six carbon ring glucide, or disaccharide; R is substitute of hydroxy on ring A selected from H,COCmH2m+1(m is natural number from 1 to 6) and CmH2m+1(m is natural number from 1 to 6); n is natural number from 1 to 7; R1 is selected from H,C1-C6alkyl,C3-C8cycloalkyl,C2-C6alkenyl,C2-C6acyl or C7-C12aroyl;R2 and R3 are selected from H or C1-C6alkyl.The invention also provides a process for preparing the compounds above. The invention further provides a drug including the compounds above and their medicinal acceptable salt. The drug is used to cure or prevent such diseases relevant to cGMP-PDE V.

Description

 Isopentenyl flavonoid derivative, preparation method and use thereof

Technical field

 The present invention relates to a prenyl flavonoid derivative, a preparation method and use thereof. Background technique

 Male erectile dysfunction (ED) is a common and frequently-occurring disease in middle-aged and elderly men. Recent studies have shown that nitric oxide plays an important role in penile erection. With the physiological role of nitric oxide and the clarification of the NO/cGMP pathway, breakthroughs have been made in the research and development of therapeutic ED drugs. At the same time, studies on the mechanism of action of phosphodiesterase (PDE) isozymes have clarified that phosphodiesterase V (PDE5) inhibitors are effective drugs for the treatment of ED. s i ldenaf i l c i tra te (sildenafil) was the first oral drug to be treated by Pf izer and lasted in March 1998. However, there are side effects such as headache and facial flushing and visual disturbance. The side effects of sildenafil caused by visual impairment are mainly related to its inhibitory activity against PDE6 enzyme, ie, the selectivity for PDE5 enzyme is not high. Therefore, PDE5 inhibitors with high activity and high selectivity are hotspots for research and development of preventive dysfunction drugs.

 Isopentenyl flavonoids have a wide range of biological activities, such as antibacterial, antitumor, anti-HIV, anti-oxidant and inhibition of some enzymes, such as inhibition of phosphodiesterase. Although isopentenyl flavonoids are not widely distributed in plants, they have received extensive attention due to their high content, diverse structure and biological activity in some plants, such as epimedium.

Epimedium is the general name for Epimedi, a variety of plants of the genus Epimedium, also known as "Fairy Spleen", which is a commonly used ingredient in the prescription of traditional Chinese medicine nourishing and strong agent. Many varieties of this genus have medicinal use in China. "Shen Nong's Herbal Classic" is listed as a Chinese product, and all previous generations of the grass have been recorded, which is a strong and strong medicine. In the "Compendium of Materia Medica", it is said that it has the merits of "Yi Jing Qi, Jian Lu Gu, Bu Kuang Kuang, Qiang Xin" Effective. There have been many studies on the chemical constituents and pharmacological effects of the raw drug Epimedium or its extract. It has been found that icariin can be used to treat sexual dysfunction (CN1282584A). Summary of the invention

 SUMMARY OF THE INVENTION An object of the present invention is to provide a prenyl flavonoid derivative having good PDE5 inhibitory activity and a process for producing the same.

 The technical solution of the present invention is as follows:

 The present invention provides a prenyl flavonoid derivative as shown in Formula I:

¹ ; wherein, ring A is a pentokeose or a hexacarbose (eg, D-xylose, D-ribose, L-arabinose, D-glucose, D-galactose, L-rhamnose, etc.) or Disaccharides (eg, sesame, gentian, sugar, etc.). The saccharide compound and the flavonoid ring together constitute a compound of formula (I). R is a substituent of a hydroxyl group on the A ring, and may be selected from any of H, C0C _m H _2m+1 (m is a natural number of 1 - 6), and C _m H _2m+1 (m is a natural number of 1 - 6) n represents the number of substituents, which is any natural number from 1 to 7; ^ can be selected from H, C "C ₆ alkyl, C ₃ - C _s cycloalkyl, C ₂ - C ₆ alkenyl, C Any one of ₂ - C ₆ fatty acyl or C ₇ - C ₁₂ aroyl; R ₂ may be selected from any of !! or ^-^ alkyl; R ₃ may be selected from H, dC ₆ Any of the alkyl groups.

As an optimization, the above isopentenyl derivative is represented by the formulas IA, I IA, II IA, IVA, VA, VIA:

 D-glucoside D-galactoside

 ΙΑ IIA

 D-xyloside rutinoside

VIA, which may be selected from the group consisting of H, C "C ₆ alkyl, C ₃ - C _s cycloalkyl, C ₂ - chain ^, c ₂ -c ₆ fatty acyl: or C ₇ _C ₁₂ aroyl acyl R ₂ may be selected from any one of !! or - alkyl; R ₃ may be selected from any of H, C "C ₆ alkyl. R ₄ , R ₅ , R ₆ , R ₇ , R _s , ^ and ^. may be selected from any of H, C0C _m H _2m+1 (m is a natural number of 1 -6), C _m H _2m+1 (m is a natural number of 1 -6) .

 Further optimized, the above isopentenyl derivative is made of a compound of formula II

Among them, the A ring is a five-carbon ring sugar, a six carbon ring Sugar (eg D-xylose, D-ribose, L-arabinose, D-glucose, D-galactose, L-rhamnose, etc.) or disaccharides (eg: rutose, gentiobiose, bismuth) Sugar, etc.). The saccharide compound and the flavonoid ring together constitute a compound of formula (I). R is a substituent of a hydroxyl group on the ring A, and is selected from any one of H, C0C _m H _2m+1 (m is a natural number of 1 - 6), and C _m H _2m+1 (m is a natural number of 1 - 6) n represents the number of substituents, which is any natural number from 1 to 7; ^ can be selected from H, C "C ₆ alkyl, C ₃ -C _S cycloalkyl, C -C ₆ alkenyl, C ₂ -C Any of ₆ fatty acyl groups or C ₇ -C ₁₂ aroyl groups.

 The present invention also provides a process for producing the above isopentenyl derivative: The above isopentenyl derivative is obtained by an acylation reaction or an alkylation reaction from a phenolic hydroxyl group on a flavonoid ring or an alcoholic hydroxyl group on a saccharide ring.

 In the acylation reaction, the acylating reagent includes an acid anhydride and an acid chloride; the reaction solvent is anhydrous pyridine or dichloromethane; and the catalyst includes pyridine, triethylamine and 4-(anthracene, fluorenyl-dimethylamino)pyridine.

 In the alkylation reaction, the alkylating agent comprises methyl iodide, ethyl bromide or dimethyl sulfate and diethyl sulfate; the reaction solvent is acetone or hydrazine, hydrazine-dimethylformamide; the catalyst is potassium carbonate, Sodium hydroxide and potassium hydroxide.

 The present invention also provides a medicament for treating or preventing a disease associated with cGMP-specific phosphodiesterase V, which comprises a compound of the formula I and a pharmaceutically acceptable salt thereof.

 As an optimization, the above medicament contains any one or more of the compounds represented by formula IA, I IA, I I IA, IVA, VA or VIA and pharmaceutically acceptable salts thereof.

The above medicaments contain a compound of the formula IA and a pharmaceutically acceptable salt thereof, wherein the compound of the formula IA includes the following specifically specified conditions: ^ selected from H or CH ₃ , and R _{2 is} selected from H or CH ₃ , 11 ₃ ( _3⁄4 , R ₄ , R ₅ , R ₆ and R ₇ are H; or Ri, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R _{7 are} both H.

 The technical effects achieved by the present invention are as follows:

 The compound of formula I provided by the present invention is a novel selective PDE5 inhibitor which promotes penile erection in normal rats and has no significant difference compared to sildenafil.

The inhibitory activity of the compound of formula I provided by the present invention on PDE6 is much weaker than that of PDE5. Activity, which has strong selectivity for PDE5, predicts that the side effects of visually impaired compounds are smaller than sildenafil. detailed description

 The present inventors isolated from Epimedium extract (purchased in Chengdu Mudu Biotechnology Co., Ltd. on December 13, 2003, the plant material is mainly Epimedium, and the content of icariin is about 14.2%). Icyl glycoside-1, icariin-C, baumannin-1, baumannin-11, icariin, and esculentin, and icariin -I was structurally modified and found to be effective in inhibiting phosphodiesterase V (PDE5). Therefore, these compounds can be used to treat or prevent a variety of vascular disorders in mammals, including humans, including male (male) erectile dysfunction, female (female) sexual dysfunction, premature labor, dysmenorrhea, sexual prostatic hyperplasia, Bladder outlet obstruction, incontinence, unstable and variant Prinzmetal angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease, Raynaud's disease, inflammatory disease, bronchitis , chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterized by bowel movements (eg, irritable bowel syndrome).

 Icariin and icariin-I are isolated and extracted from the extract of Epimedium by an organic solvent or a mixed solvent of an organic solvent and water. Organic solvents which may be used include alcohols such as methanol, ethanol, butanol, etc., halogenated hydrocarbons such as dichloromethane, chloroform, etc., ethers such as diethyl ether, ketones such as acetone, esters such as ethyl acetate, hydrocarbons such as petroleum. Ether, n-hexane, etc. Icariin-I can also be obtained from the hydrolysis of icariin. The catalyst used in the hydrolysis includes sulfuric acid, p-toluenesulfonic acid, hydrochloric acid, phosphoric acid, acetic acid, etc. The solvents used include methanol, ethanol, DMF and Water, etc.

 Preferred compounds of the invention include:

 3, 5-dihydroxy _4-methoxy _8_(3,3-dimethacrylyl) flavonoid _7_0_p_D - glucoside (TPN1217)

3,5,4-trimethoxy-8-(3,3-dimethylpropenyl) flavonoid-7-0-β-D-glucoside (TPN1258)

 3,4-dimethoxy-5-hydroxy-8-(3,3-dimethacrylyl) flavonoid-7_0_p_D-glucoside (TPN1259)

 3-ethoxy-5-hydroxy-4-ylmethoxy-8-(3,3-dimethylpropenyl) flavonoid -7-0-β-D-glucoside (TPN1271)

 3_ethoxy_5,4-dimethoxy_8_(3,3-dimethacrylyl) flavonoid-7-0_p_D-glucoside (TPN1273)

 3-acetoxy _5_hydroxy-4-dimethoxy _8_(3,3-dimethylpropenyl) flavonoid-7-0_β-D-glucoside (TPN1277)

 3-Acetoxy-5,4-dimethoxy-8-(3,3-dimethacrylyl)flavonoid-7_0_p_D_glucoside (TPN1278) The present invention provides a process for the preparation of a compound of formula (I). Also, the present invention also includes any novel intermediates in the preparation process and a process for the preparation thereof, such as a compound of the following formula (II) and a process for the preparation thereof.

Synthetic route: A compound of formula (I) can be prepared from a compound of formula (II) wherein ring A is a saccharide derivative in which the hydroxy group of the saccharide ring is substituted or unsubstituted, R is a substituent on ring A, and n represents a substituent. Number, n=l-7, represents H or C "C ₆ alkyl.

 II

Compounds of formula (I) may be prepared from compounds of formula (II) wherein R, A, n, R _{3 are} as claimed

As defined in 1), the phenolic hydroxyl group on the flavonoid ring or the alcoholic hydroxyl group on the sugar ring is subjected to an acylation reaction or an alkyl group. The flavonoid derivative obtained by the reaction, the acylating reagent comprises an acid anhydride and an acid chloride, preferably acetic anhydride, and the solvent mainly comprises anhydrous pyridine, anhydrous triethylamine, anhydrous dichloromethane, anhydrous chloroform, anhydrous dioxane and Anhydrous tetrahydrofuran or the like, preferably anhydrous pyridine or anhydrous dichloromethane, the catalyst includes pyridine, triethylamine and 4-(anthracene, fluorenyl-dimethylamino)pyridine, etc., preferably pyridine, the reaction temperature is generally 10 ° C - 25 . C, the reaction time is generally 1-12 hours; alkylating agents include halogenated hydrocarbons (such as: methyl iodide, ethyl bromide, etc.) and sulfates (dimethyl dimethyl sulfate and diethyl sulfate, etc.), the solvent is acetone and Ν, Ν-dimethylformamide, etc., the catalyst is an inorganic base (such as: potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide, etc.), the reaction temperature is generally 25 ° C-60 ° C, the reaction time is generally 2-20 hours.

 The present invention provides a prenyl flavonoid derivative prepared for the treatment or prevention of erectile dysfunction, female sexual dysfunction, premature labor, dysmenorrhea, benign prostatic hyperplasia, bladder outlet obstruction, incontinence, instability and variation of Pr inzme Ta l angina pectoris, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease, Raynaud's disease, inflammatory disease, bronchitis, chronic asthma, allergic asthma, allergic rhinitis Use of glaucoma, and human (or animal) drugs characterized by diseases of intestinal peristalsis (eg, irritable bowel syndrome).

 Pharmacological experiments show that these compounds can inhibit cGMP-specific phosphodiesterase, especially inhibit phosphodiesterase V (PDE5), and have a wide range of uses in the treatment or prevention of sexual dysfunction and diseases related to the improvement of vasoconstriction. . At the same time, it provides a theoretical basis for drug research and development, and has great application and development value.

 Biological activity test:

1. PDE5 inhibitory activity test of isopentenyl flavonoids

The inhibitory activity of prenyl flavonoids on human platelet PDE5 was determined by the method of Methods Enzymo l 1988, 159, 457-470. The results are shown in the following table: Inhibition of esterase V activity

2. Test of PDE6 inhibitory activity of isopentenyl flavonoids

The enzyme used in the enzyme inhibition activity test was a method similar to that reported in the literature (Thrombosis Res. 1991, 62, 31 and J. Biol. Chem. 1997, 272, 2714), and the bovine retina was appropriately treated and separated by FPLC. The enzyme required for the test. Once the enzyme is isolated, the enzyme inhibition activity test is carried out immediately. The enzyme inhibition test is performed by directly detecting the GMP scintillation proximity assay using the TRKQ7100 kit. This is roughly the case. In the presence of different inhibitor concentrations and a small amount of substrate, 10 is added. μ ΐ buffer (50 mM Tris/HCl pH 7.5, 8.3 mM MgC12, 1.7 mM EGTA), water to a final volume of ΙΟΟμ Ι, initiated with a fixed amount of enzyme, incubated at 30 ° C for 30 minutes, then with 50 μ 1 containing The reaction was terminated with zinc sulphate sulphate beads, and after shaking for 20 minutes, it was allowed to settle in the dark for 30 minutes, counted on a BECKMAN LS6500 MULTI-PURPOSE SCINTILLATION COUNTER, and then the half-inhibitory concentration of the compound of the present invention against the enzyme (ic _{5 ) was} calculated based on the count value. ), the results are shown in the following table:

 Inhibition of esterase VI activity

Results IC ₅ for PDE6. Far greater than IC ₅ for PDE5. , indicating that the compound is selective The method of et al. (International Journal of Impotence Research, 2002, 14, 251-255), Chen et al. (J. Urol., 1992, 147, 1124-1128) performed a penile erection test using a normal rat model.

 The test compound was suspended in 0.5% methylcellulose and orally administered to rats at a single dose of 200 mg/kg. After administration, the intracavernosal pressure (ICP) and arterial blood pressure (MBp) of the rat's penis were continuously observed within 3 hours. The ICP and MBp changes were analyzed before and after treatment by Chart data processing software. The ratio of ICP to MBp was used to evaluate the effect of drugs on nerve stimulation-induced erection. Finally, t-test was performed with SPSS10.0 software. Three or more rats were assigned to each group, and for the other two groups, only an equal amount of 0.5% methylcellulose or 20 mg/kg of sildenafil citrate was administered as a negative control group and The positive control group, the results are shown in the following table:

Table 3 Effect of sildenafil, TPN1217, TPN1258 and TPN1259 on ICP and BP in rats Compound dose (mg/kg) Before administration (ICP/BP) After administration (ICP/BP) Blank 24. 34 ± 1. 2 26. 01士2. 3

 36. 37 Silentina 20 24. 47 ± 0. 7

 4. 9*

TPN1259 40. 10 士

 200 27. 03士 2. 6

 6. 6**

TPN1258 200 25. 70 ± 2. 6 32. 39 士 5. 1

 200 45. 88 士士

TPN1217 29. 24 + 3. 6

8. 6* Note: *P<0.05 (pre-dose compared to post-dose), **ρ<ο. As a result, 0.5% CMC-Na was orally administered to the blank group, and there was no effect on ICP/BP after stimulation of the nerve. The sildenafil group (20 mg/kg ig.) and the TPN1217 group (200 mg/kg ig.) can increase the ICP/BP value, while the TPN1259 (200 mg/kg ig.) group can significantly increase the ICP/BP, while the TPN1258 group There was no statistically significant effect on the intracavernous pressure of the rats before and after administration.

 The following Preparations and Examples are intended to illustrate the invention in more detail, but are not intended to limit the invention.

The ¹ H-NMR of the present invention was carried out on a Mercury-400 nuclear magnetic resonance spectrometer (Varian), and the observation frequency of -R was 400.144 MHz.

 Mass spectrometry was performed on a MAT-95 mass spectrometer (Thermo Finnigan) with an ionization mode of EI 70V, a source temperature of 200 ° C, and an LR resolution of 1000.

 High pressure liquid chromatography: Agilent 1100 series, analytical column: ZORBAX Eel ipse XDB-C8 4.6 x 150 mm, semi-preparative column: GL Sciences Inertsil PREP-ODS 10 250 mm.

 Room temperature means 20-25 ° C. Preparation 1 Preparation of different solvent extracts of Epimedium

 Take 2 kg of dried extract of Epimedium, add water and methanol, extract 3 times with an equal volume of petroleum ether, concentrate the aqueous layer under reduced pressure, remove the methanol, add 4 times of equal volume of dichloromethane, and combine The chloromethane layer was concentrated under reduced pressure, and dichloromethane was evaporated to give methylene chloride extract. The aqueous layer extracted with dichloromethane was extracted four times with an equal volume of ethyl acetate. After filtration, concentrated under reduced pressure, and ethyl acetate was recovered to give ethyl acetate extract. The aqueous layer extracted with ethyl acetate was extracted four times with an equal volume of n-butanol, and the n-butanol layer was combined and concentrated under reduced pressure. Butanol gives n-butanol extract. Preparation 2 Separation of Icariin-I

The ethyl acetate extract of 4.5 g of Epimedium prepared in Preparation Example 1 was adsorbed on 9 g of silica gel, and the prepared silica gel column (4 x 70 cm) was dried, and chloroform/methanol = 9/1, 8/ 2. Dissolve in the order of 3/2, and collect the eluate containing icariin-I. After concentration under reduced pressure, the mixture was separated by HPLC and then recrystallized from methanol to yield 71 gram of icariin-1. Preparation 3 Separation of Icariin

50 g of the extract of Epimedium n-butanol prepared in Preparation Example 1 was adsorbed on 100 g of silica gel, and after drying, a prepared silica gel column (6 x 80 cm) was obtained, and chloroform/methanol = 8/2, 3/ The order of 2 was dissolved, and the eluate containing the icariin fraction was collected, concentrated, recrystallized from methanol, and confirmed by ¹ H-R, and analyzed by HPLC to obtain 6.025 g of icariin. Example 1 Preparation of Icariin-I

Into a 500-liter flask, 1.50 g of icariin, 110 liters of ethanol, 110 liters of a 5% aqueous solution of sulfuric acid were sequentially added, and the mixture was stirred at 50 ° C for 24 hours, cooled to room temperature, concentrated under reduced pressure to remove ethanol, and added to 100 Torr. Saturated brine, extracted three times with ethyl acetate (200 liters each time), the ethyl acetate layer was washed twice with saturated aqueous solution of 0 ₃ (200 liters each time), washed once with 200 liters of saturated brine, anhydrous After drying over sodium sulfate, it was concentrated under reduced pressure, and then evaporated to ethylamine. Example 2 Synthesis of 3,4-dimethoxy-5-hydroxy-8-(3,3-dimethacrylyl)flavone _7_0_β_D-glucoside (TPN 1259)

3.3 g of icariin-I was added to a 1 liter flask, and dissolved in 500 liters of acetone, followed by the addition of 17.4 g of potassium carbonate and 6.0 liters of dimethyl sulfate, and the mixture was heated (40 ° C) for 11 hours, and cooled to room temperature. The reaction liquid was filtered, and the solid was washed with acetone. The filtrate was concentrated under reduced pressure. 'HNMR (400 MHz, DMSO-oO: δ 1.60 (3Η, s, H-4"), 1.72 (3H, s, H-5"), 3.16 (1H, br, H-glc), 3.30 (2H, Br, Hl"), 3.44 (3H, br, H-glc), 3.66 (1H, br, H-glc), 3.80 (3H, s, -0CH ₃ ) , 3.84 (1H, br, H-glc), 3.85 (3H, s, -0CH ₃ ) , 5.00 (1H, br, H-glc), 5.17 (1H, t, 7 = 6.9 Hz, H-2"), 6.61 (1H, s, H-6) , 7.15 (2H, d, 7 = 9.0 Hz, H-3, 5), 8.02 (2H, d, 7 = 9.0 Hz, H-2, 6), 12.41 (1H, s, -OH). EI -MS ml z 544. Example 3 Synthesis of 3,5,4-trimethoxy-8-(3,3-dimethacrylyl) flavonoid _7_0_β_D-glucoside (TPN1258)

To a 1 liter flask, 5.0 g of icariin-I was added, and after dissolving in 500 liters of acetone, 26.0 g of potassium carbonate and 18.0 liters of dimethyl sulfate were successively added, and the mixture was heated under reflux for 12 hours. The reaction solution was cooled to room temperature, water was added thereto, filtered, and the solid was washed with diluted aqueous hydrochloric acid. The solid obtained by filtration was purified by silica gel column chromatography to yield product (yield: 63%). ^: H NMR (400 MHz, DMS0— ο9: δ 1.61 (3H, s, H-4"), 1.73 (3H, s, H-5"), 3.12 (1H, br, H-glc), 3.32 (2H , d, 7 = 6.6 Hz, Hl"), 3.42 (3H, br, H-glc), 3.65 (1H, br, H-glc) , 3.73 (3H, s, -0CH ₃ ) , 3.74 (1H, br , H-glc) , 3.85 (6H, s, -0CH ₃ ) , 5.03 (1H, d, 7= 7.9 Hz, H-glc), 5.17 (1H, t, 7= 6.6 Hz, H-2"), 6.78 (1H, s, H-6), 7.13 (2H, d, 7= 9.0 Hz, H-3, 5 ), 7.99 (2H, d, 7 = 9.0 Hz, H-2, 6). EI -MS ml z 558.

Example 4 Synthesis of 3-acetoxy-5-hydroxy-4-ylmethoxy-8-(3,3-dimethylpropenyl)flavonoid-7-0-β-D-glucoside

0.6 g of icariin-1, 20 liters of anhydrous pyridine and 25 liters of anhydrous dichloromethane were sequentially added to a 100 liter round bottom flask, stirred under an ice salt bath, and 0.12 liters of acetic anhydride was added dropwise. In the reaction liquid, the internal temperature was maintained at 5 ° C or lower, and the reaction was carried out for 9 hours. After the completion of the reaction, 50 ml of a saturated ammonium chloride solution was added to the reaction mixture to terminate the reaction. The mixture was combined with EtOAc. The product was obtained in an amount of 0.31 g, yield: 48%. R (400 MHz, DMS0-d ₆ ): δ 1.62 (3Η, s, H-4"), 1.72 (3H, s, H-5"), 2.34 (3H, s, -OAc) , 3.17 (1H , m, H-glc) , 3.32 (2H, d, J = 7.2 Hz, Hl"), 3.46 (3H, br, H-glc), 3.62 (1H, dd, J = 6.6 Hz, J = 14.0 Hz, H-glc), 3.70 (1H, d, 7 = 10.3 Hz, H-glc), 3.86 (3H, s, -0CH ₃ ) , 5.02 (1H, d, J = 7.5 Hz, H-glc), 5.18 ( 1H, t, J= 7.2 Hz, H-2"), 6.78 (1H, s, H-6), 7.16 (2H, d, 7 = 9.0 Hz, H-3, 5), 7.87 (2H, d, 7 = 9.0 Hz, H-2, 6), 12.14 (1H, s, C ₅ -0H) . EI-MS ml z 572.

0.1 g of the compound of Example 4, 18 liters of acetone, 0.12 g of anhydrous potassium carbonate and 0.083 liter of dimethyl sulfate were sequentially added to a 50 liter round bottom flask, and stirred under reflux with nitrogen for 20 hours. After the completion of the reaction, the reaction mixture was concentrated. EtOAc EtOAc (EtOAc m. The product was obtained in 0.05 g, yield: 49%. R (400 MHz, C ₅ D ₅ N): δ 1.43 (3Η, s, H-4") , 1.61 (3H, s, H-5"), 3.50 (3H, s, -OAc) , 3.76 ( 1H, m, H-glc), 3.78 (6H, s, -0CH ₃ ) , 4.02 (2H, d, 7 = 7.2 Hz, Hl"), 4.15 (4H, br, H-glc), 4.44 (1H, d, J = 11.4 Hz, H-glc), 5.40 (1H, t, 7= 7.2 Hz, H-2"), 5.53 (1H, d, 7 = 7.2 Hz, H-glc), 6.91 (2H, d , 7= 9.0 Hz, H-3, 5), 7.10 (1H, s, H-6), 8.02 (2H, d, 7= 9.0 Hz, H-2, 6). EI -MS ml z 586. Example 6 Synthesis of 3-ethoxy-5-hydroxy-4-methoxy-8-(3,3-dimethylpropenyl) flavonoid _7_0_β ϋ-glucoside (TPN1271)

0.2 g of icariin-1, 50 liters of acetone, 1 gram of anhydrous potassium carbonate, 0.125 g of potassium iodide and 0.5 liter of ethyl bromide were added to a 100 liter flask, and heated under nitrogen (40 C). 20 hours. After the reaction, the reaction solution was concentrated, 1M dilute hydrochloric acid was added thereto to adjust the pH of about 7, and extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous _2,804, filtered and concentrated, the product was recrystallized from methanol to give 0.19 g, Yield: 88%. 'HNMR (400 MHz, DMS0-d ₆ ): δ 1.22 (3Η, t, 7 = 7.0 Hz, -CH ₂ CH ₃ ) , 1.59 (3H, s, H-4"), 1.71 (3H, s, H -5"), 3.14 (1H, m, H-glc), 3.28 (2H, d, 7 = 7.2 Hz, Hl"), 3.43 (3H, br, H-glc), 3.65 (1H, dd, 7= 6.6 Hz, J= 14.0 Hz, H-glc), 3.68 J = 10.3 Hz, H-glc), 3.84 (3H, s, -0CH ₃ ) , 4.03 (2H, q, 7 = -CH ₂ CH ₃ ) , 4.97 (1H, d, 7 = 7.8 Hz, H-glc ), 5.16 (1H, t, J = H-2"), 6.77 (1H, s, H-6), 7.12 (2H, d, J = 9.1 Hz, H-3, 02 (2H, d, 7 = 9.1 Hz, H-2, 6). EI-MS ml z 558. Example 7 3_ethoxy-5,4-dimethoxy-8-(3,3-dimethylpropenyl) flavonoids_7_0_ Synthesis of β-D-glucoside

0.2 g of the compound of Example 7, 50 liters of acetone, 0.5 g of potassium carbonate and 0.34 liter of dimethyl sulfate were sequentially added to a 100 liter round bottom flask, and stirred under reflux for 11 hours under a nitrogen atmosphere. After the completion of the reaction, the reaction mixture was concentrated, and then the mixture was evaporated to dryness. The product obtained by isolation and purification was 0.043 g, Yield: 21. Oy H. R (400 MHz, DMS0-d ₆ ): δ 1.21 (3 Η, t, 7 = 7.1 Hz, -CH ₂ CH ₃ ) , 1.60 (3H, s , H-4"), 1.72 (3H, s, H-5"), 3.12 (1H, m, H-glc), 3.32 (2H, d, J = ΊΛ Hz, Hl"), 3.43 (3H, br , H-glc), 3.65 (1H, dd, 7= 7.6 Hz, 7= 15.0 Hz, H-glc), 3.74 (1H, d, 7 = 9.7 Hz, H-glc), 3.84 (6H, s, - 0CH ₃ ) , 3.97 (2H, q, 7= 7.1 Hz, -CH ₂ CH ₃ ) , 5.03 (1H, d, J= Ί. Ί Hz, H-glc), 5.16 (1H, t, 7= 7.2 Hz , H-2"), 6.59 (1H, s, H-6), 7.13 (2H, d, 7 = 8.9 Hz, H-3, 5), 8.05 (2H, d, 7 = 8.9 Hz, H-2 , 6). EI -MS ml z 572. :Synthesis of propylene-based flavonoids _7_0_ β _ϋ-glucoside

0.257 g of icariin-I, 10 liters of anhydrous pyridine, 30 gram of DMAP and 0.25 liters of acetic anhydride were sequentially added to a 25 liter round bottom flask and stirred at room temperature for 4 hours. After the completion of the reaction, the reaction mixture was stirred to dryness, and the mixture was evaporated. 0.133 g, Yield: 37%. NMR (400 MHz, CDC1 ₃ ): δ 1.66 (3Η, s, H-4"), 1.71 (3H, s, H-5"), 2.04 (3H, s, glc-OAc), 2.05 (3H, s , glc-OAc), 2.07 (3H, s, glc-OAc), 2.13 (3H, s, glc-OAc), 2.36 (3H, s, -OAc) , 3.42 (2H, d, 7 = 6.6 Hz, Hl "), 3.89 (3H, s, 0CH ₃ ) , 3.93 (H, ddd, J = 10.0 Hz, J = 2.2 Hz, 7 = 6.0 Hz, H-glc), 4.18 (1H, dd, 7= 12.3 Hz, J= 2.2 Hz, H-glc), 4.29 (1H, dd, J= 12.3 Hz, 7 = 6.0 Hz, H-glc), 5.09 (1H, t, 7 = 6.4 Hz, H-2"), 5.16 ( 1H, dd, 7 = 9.0 Hz, 7= 10.0 Hz, H-glc), 5.18 (1H, d, 7= 6.9 Hz, H-glc), 5.32 (1H, t, 7= 9.0 Hz, H-glc) , 5.36 (1H, dd, J= 6.9 Hz, 7= 9.0 Hz, H-glc), 6.54 (1H, s, H-6), 7.00 (2H, d, 7 = 8.8 Hz, H-3, 5) , 7.82 (2H, d, 7 = 8.8 Hz, H-2, 6), 12.21 (1H, s, C ₅ -0H) . EI -MS ml z 740. Example 9 3, 2", 3", 4 Synthesis of "6"-pentaacetoxy-5,4-dimethyl: _8_(3,3-dimethacrylyl) flavonoid _7_0_ β ϋ-glucoside

74 g of the compound of Example 8, 2 liters of DMF, 50 gram of potassium hydroxide and 20 microliters of iodomethane were sequentially added to a 10 liter round bottom flask and stirred at room temperature for 3 h. After completion of the reaction the reaction mixture was added to saturated ammonium chloride solution, the organic phase was washed with saturated brine and extracted three times with ethyl acetate, dried over anhydrous sulfate, filtered and concentrated _2804, purified by silica gel column chromatography to give the product 21 grams, yield: 28%. R (400 MHz, CDC1 ₃ ): δ 1.66 (3Η, s, H-4"), 1.75 (3H, s, H-5"), 2.04 (3H, s, glc-OAc), 2.05 (3H, s, glc-OAc), 2.07 (3H, s, glc-OAc), 2.11 (3H, s, glc-OAc), 2.46 (3H, s, -OAc) , 3.54 (2H, d, 7= 6.4 Hz, Hl"), 3.78 (3H, s, -0CH ₃ ) , 3.89 (3H, s, -0CH ₃ ) , 3.95 (H, ddd, J= 10.0 Hz, J= 2.3 Hz, J= 6.3 Hz, H-glc ), 4.20 (1H, dd, J = 12.3 Hz, 7 = 2.3 Hz, H-glc), 4.29 (1H, dd, J = 12.3 Hz, J = 6.3 Hz, H-glc), 5.09 (1H, t, 7 = 6.4 Hz, H-2"), 5.16 (1H, dd, J = 9.0 Hz, J = 10.0 Hz, H-glc), 5.18 (1H, d, J = 6.9 Hz, H-glc), 5.32 ( 1H, t, 7 = 9.0 Hz, H-glc), 5.36 (1H, dd, 7 = 6.9 Hz, 7 = 9.0 Hz, H-glc), 6.74 (1H, s, H-6), 7.01 (2H, d, 7 = 9.0 Hz, H-3, 5), 8.05 (2H, d, 7 = 9.0 Hz, H-2, 6). EI -MS ml z 754.

12 g of the Example 9 compound, 1 liter of methanol and 100 μl of potassium hydroxide solution (2 mol/liter) were sequentially added to a 10 liter round bottom flask, and stirred at room temperature for 0.5 h. After completion of the reaction the reaction mixture was added to saturated ammonium chloride solution, the organic phase was washed with saturated brine and extracted three times with ethyl acetate, dried over anhydrous after _2804, filtered and concentrated, the product was recrystallized from methanol to give 8 milligrams, Yield: 92%. R (400 MHz, DMS0-d ₆ ): δ 1.62 (3Η, s, H-4"), 1.74 (3H, s, H-5"), 3.17 (1H, br, H-glc), 3.30 ( 2H, br, Hl"), 3.46 (3H, br, H-glc) 3.65 (1H, br, H-glc), 3.70 (1H, br, H-glc), 3.81 (3H, s, -0CH ₃ ) , 3.87 (3H, s, -0CH ₃ ) , 5.00 (1H, d, J = 6.0 Hz, H-glc), 5.19 (1H, t, 7= 6.8 Hz, H-2"), 6.62 (1H, s , H-6), 7.17 (2H, d, 7 = 9.0 Hz, H-3, 5), 8.04 (2H, d, 7 = 9.0 Hz, H-2, 6). EI-MS ml z 544. Example 11 Synthesis of 4-methoxy-8-(3,3-dimethylpropenyl) flavonoid-7-0_p-D-glucoside diphenol sodium salt

 Add 200 grams of icariin-I to a 100 liter flask, dissolve it with 20 liters of ethanol and 2 liters of DMF, then add 0.5 liters of sodium hydroxide solution (1 mol/L) and stir at room temperature for 1 hour. Concentrated to a small volume, a solid precipitated, and the product obtained was filtered, 185 g, yield: 85.5%. EI-MS mlz 574.

Claims

Profit request

among them,

 Ring A is a five-carbon ring sugar, a six-carbon ring sugar or a disaccharide;

R is a substituent of a hydroxyl group at the A ring, and is selected from any one of H, C0C _m H _2m+1 (m is a natural number of 1 _ 6), and C _m H _2m+1 (m is a natural number of 1 -6) ;

 n represents the number of substituents, and is any natural number from 1 to 7;

Any one selected from the group consisting of H, C "C ₆ alkyl, C ₃ -C _S cycloalkyl, C ₂ -alkenyl, C ₂ -C ₆ fatty ac or C ₇ -C ₁₂ aroyl;

R ₂ may be selected from any of H or d_C ₆ alkyl;

R ₃ may be selected from any of H, dC _b fluorenyl.

The isopentenyl flavonoid derivative according to claim 1, wherein the isopentenyl flavonoid derivative is represented by the formulas IA, IIA, IIIA, IVA, VA, VIA:

 among them,

Any one selected from the group consisting of H, d_C ₆ alkyl, C ₃ —C _S cyclodecyl, ( ₂ —(alkenyl, C ₂ —C ₆ fatty acyl or C ₇ _C aroyl;

R ₂ may be selected from any of H or dC ₆ alkyl;

R ₃ may be selected from any of H, d_C ₆ alkyl;

R ₄ , R ₅ , R ₆ , R ₇ , R _s , ^ and ^. Any one of H, C0C _ffl H _2ffl+1 (m is a natural number of 1 -6), and C _m H _2m+1 (m is a natural number of 1 - 6) may be selected.

The isopentenyl flavonoid derivative according to any one of claims 1 to 2, wherein the isopentenyl flavonoid derivative is prepared from a compound of the formula II:

 II where

 Ring A is a five-carbon ring sugar, a six-carbon ring sugar or a disaccharide;

R is a substituent of a hydroxyl group on the A ring, and is selected from any one of H, C0C _m H _2m+1 (m is a natural number of 1 _ 6), and C _m H _2m+1 (m is a natural number of 1 - 6) ;

 n represents the number of substituents, and is any natural number from 1 to 7;

R ₃ may be selected from any of H, dC ₆ alkyl groups.

 A process for producing the isopentenyl flavonoid derivative according to any one of claims 1 or 2, which is obtained by an acylation reaction or an alkylation reaction from a phenolic hydroxyl group on a flavonoid ring or an alcoholic hydroxyl group on a saccharide ring. Description

The method for preparing an isopentenyl flavonoid derivative according to claim 4, wherein in the acylation reaction, the acylating reagent comprises an acid anhydride and an acid chloride; and the reaction solvent is anhydrous pyridine or dichloromethane; The catalyst includes pyridine, triethylamine and 4-(anthracene, fluorenyl-dimethylamino)pyridine.

 The method for producing an isopentenyl flavonoid derivative according to claim 4, wherein in the alkylation reaction, the alkylating agent comprises methyl iodide, ethyl bromide or dimethyl sulfate and sulfuric acid. Diethyl ester; the reaction solvent is acetone or hydrazine, hydrazine-dimethylformamide; the catalyst is potassium carbonate, sodium hydroxide and potassium hydroxide.

 A medicament for treating or preventing a disease associated with cGMP-specific phosphodiesterase V, characterized in that the medicament comprises a compound of the formula I and a pharmaceutically acceptable salt thereof.

 The drug according to claim 7, wherein the drug contains any one or more of the compounds represented by formula IA, I IA, II IA, IVA, VA or VIA or is pharmaceutically acceptable. salt.