CN104188980B - O-(morpholinyl) ethyl derivatives of cleistanone Cleistanone, preparation method and use thereof - Google Patents

Abstract

The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to an O-(morpholinyl) ethyl derivative of cleistanone, a preparation method and its application in the preparation of anti-rhinitis drugs. The invention synthesizes a new O-(morpholinyl) ethyl derivative of Cleistanone, and discloses its preparation method. Pharmacological experiments show that the O-(morpholinyl) ethyl derivatives of Cleistanone of the present invention have the effect of anti-rhinitis, and have the value of developing anti-rhinitis drugs.

Description

O-(morpholinyl) ethyl derivatives of cleistanone Cleistanone, preparation method and its purpose

technical field

The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to an O-(morpholinyl) ethyl derivative of cleistanone, a preparation method and an application thereof.

Background technique

Rhinitis is a common and frequently-occurring disease in clinical practice. The occurrence of rhinitis is mainly related to allergic reactions and belongs to the category of immune inflammation. At present, antihistamine drugs such as terfenadine or antiallergic drugs such as tranilast and ketotifen are mainly used for the treatment of rhinitis, and these drugs have poor or ineffective effects on chronicity and recurrent rhinitis. Therefore, small molecular compounds with clear components, quality control, safety and high efficiency have potential value in the development of drugs for rhinitis treatment.

It is of great value to find compounds or lead compounds from natural products and carry out structural modification to obtain their derivatives, so as to obtain potential drugs with high efficiency and low toxicity.

For the treatment of rhinitis at present, there is no clinically effective drug, and most drugs have unavoidable toxic and side effects while relieving the symptoms of rhinitis. Search for compounds or lead compounds from natural products and carry out structural modification to obtain their derivatives, so as to obtain high-efficiency and low-efficiency drugs. Potential drugs for poisons are of great value.

The compound Cleistanone involved in the present invention was published in 2011 (Van Trinh ThiThanh et al., 2011. Cleistanone: A Triterpenoid from Cleistanthus indochinensis with a New Carbon Skeleton. Volume 2011, Issue 22, pages 4108–4111, August 2011) Compounds, we have modified the structure of the compound Cleistanone, obtained a new O-(morpholino) ethyl derivative of Cleistanone, and evaluated its anti-rhinitis activity, which has anti- Rhinitis activity.

Contents of the invention

The invention discloses an O-(morpholinyl) ethyl derivative of Cleistanone, the structure of which is:

The O-(morpholinyl) ethyl derivative (III) of Cleistanone of the present invention can be prepared by the following method:

(1) Reaction of Cleistanone (I) with 1,2-dibromoethane to obtain O-bromoethyl derivative (II) of Cleistanone;

(2) The O-bromoethyl derivative (II) of Cleistanone and morpholine undergo a substitution reaction to prepare the O-(morpholinyl)ethyl derivative (III) of Cleistanone.

The preparation method of the O-(morpholinyl) ethyl derivative (III) of further cleistanone Cleistanone is:

(1) Dissolve 440 mg of the compound Cleistanone (I) in 10 mL of benzene, add 0.04 g of tetrabutylammonium bromide, 3.760 g of 1,2-dibromoethane and 6 mL of 50% hydroxide Sodium solution; the mixture was stirred at 25 degrees Celsius for 24h; after 24h, the reaction solution was poured into ice water, extracted twice with dichloromethane immediately, and the organic phase solution was combined; then the organic phase solution was washed with water and saturated brine three times in sequence, and then Dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure to remove the solvent to obtain the crude product; the crude product is purified by silica gel column chromatography, the mobile phase is: petroleum ether/acetone=100:1, v/v, and the yellow concentrated elution band is collected as The O-bromoethyl derivative (II) of Cleistanone was obtained as a yellow solid.

(2) Dissolve 273 mg of O-bromoethyl derivative (II) of Cleistanone in 20 mL of acetonitrile, add 345 mg of anhydrous potassium carbonate, 84 mg of potassium iodide and 1742 mg of morpholine, and heat the mixture under reflux for 8 h After the reaction, the reaction solution was poured into 30 mL of ice water, extracted three times with an equal amount of dichloromethane, and the organic phase was combined; the combined organic phase was washed with water and saturated brine successively, dried with anhydrous sodium sulfate, and concentrated under reduced pressure Remove the solvent to obtain the crude product; the crude product is purified by silica gel column chromatography, the mobile phase is: petroleum ether/acetone=100:0.5, v/v, and the yellow concentrated elution band is collected to obtain the O-(morpholine 185.3 mg of a yellow solid of the ethyl derivative (III).

The compounds disclosed in the present invention can be made into pharmaceutically acceptable salts or pharmaceutically acceptable carriers.

Pharmacodynamic experiments show that the O-(morpholinyl)ethyl derivative (III) of Cleistanone of the present invention has better anti-rhinitis effect. The pharmaceutically acceptable salts of the present invention have the same medicinal effects as the compounds thereof.

The present invention will be described in further detail below through examples, but the protection scope of the present invention is not limited by any specific examples, but is defined by the claims.

detailed description

Example 1 Preparation of Compound Cleistanone

The preparation method of the compound Cleistanone (I) refers to the literature published by Van Trinh Thi Thanh et al. (Van Trinh Thi Thanh et al., 2011. Cleistanone: A Triterpenoid from Cleistanthus indochinensis with a New Carbon Skeleton. pages 4108–4111, August 2011).

Example 2 Synthesis of O-Bromoethyl Derivatives (II) of Cleistanone

Compound I (440 mg, 1.00 mmol) was dissolved in 10 mL of benzene, and tetrabutylammonium bromide (TBAB) (0.04 g), 1,2-dibromoethane (3.760 g, 20.00 mmol) and 6 mL of 50% sodium hydroxide solution. The mixture was stirred at 25 °C for 24 h. After 24 hours, the reaction solution was poured into ice water, extracted twice with dichloromethane immediately, and the organic phase solutions were combined. Then the organic phase solution was washed with water and saturated brine three times successively, then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether/acetone=100:1, v/v), and the yellow concentrated elution band was collected to obtain compound II as a yellow solid (344 mg, 63%).

1H NMR (500MHz, DMSO-d ₆ )δ5.04(s, 1H), 4.82(s, 1H), 3.94(d, J=26.5Hz, 1H), 3.87(d, J=26.5Hz, 2H), 3.57(s,2H),2.40(d,J=14.0Hz,1H),2.39(d,J=14.0Hz,1H),2.27(s,1H),2.21(s,1H),2.15(s,1H ),1.82(s,1H),1.62(s,2H),1.57(d,J=3.3Hz,1H),1.54(d,J=3.3Hz,1H),1.50(d,J=1.2Hz,1H ), 1.47(d, J=1.2Hz, 1H), 1.39(d, J=15.3Hz, 2H), 1.34(d, J=15.3Hz, 1H), 1.26(dd, J=32.6, 13.7Hz, 4H ), 1.13 (d, J=18.0Hz, 2H), 1.05 (s, 6H), 0.98 (s, 1H), 0.88 (s, 12H), 0.78 (s, 3H), 0.74 (s, 1H).

13C NMR (125MHz, DMSO-d6) δ216.59(s), 154.50(s), 105.23(s), 74.63(s), 69.85(s), 59.71(s), 52.55(s), 51.21(s) ,47.92(s),44.10(s),42.25(s),41.73(s),40.64(s),40.16(s),38.88(s),38.65(s),37.21(s),36.23(s) ,33.34(d,J=1.1Hz),32.96(s),29.91(s),27.18(s),26.03(s),24.23(s),23.96(s),20.77(s),18.48(s) , 17.98(s), 16.93(s).

HRMS(ESI) m/z[M+H] ⁺ calcd for C ₃₂ H ₅₂ BrO ₂ :547.3151; found547.3159.

Example 3 Synthesis of O-(morpholinyl) ethyl derivatives (III) of cleistanone Cleistanone

Compound II (273 mg, 0.5 mmol) was dissolved in 20 mL of acetonitrile, anhydrous potassium carbonate (345 mg, 2.5 mmol), potassium iodide (84 mg, 0.5 mmol) and morpholine (1742 mg, 20 mmol) were added thereto, and the mixture was heated to reflux for 8 h. After the reaction was completed, the reaction solution was poured into 30 mL of ice water, extracted three times with an equal amount of dichloromethane, and the organic phases were combined. The combined organic phases were successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether/acetone=100:0.5, v/v), and the yellow concentrated elution band was collected to obtain the yellow color of the O-(morpholino)ethyl derivative of Cleistanone. Solid (185.3 mg, 67%).

¹ H NMR(500MHz,DMSO-d6)δ5.11(s,1H),4.81(s,1H),4.39(s,1H),3.51(d,J=17.7Hz,6H),2.59(s,2H ),2.47(s,4H),2.32(t,J=36.5Hz,2H),2.24(s,1H),2.20(s,1H),2.11(s,1H),1.79(d,J=90.0Hz ,3H),1.59(d,J=7.0Hz,2H),1.40(d,J=4.2Hz,2H),1.35(d,J=14.5Hz,3H),1.30–1.16(m,4H),1.11 (d,J=6.5Hz,2H),1.02(s,6H),0.82(d,J=8.5Hz,13H),0.73(s,3H),0.65(s,1H).

¹³ C NMR (125MHz, DMSO-d6) δ216.37(s), 154.55(s), 105.98(s), 73.28(s), 69.13(s), 66.17(s), 58.23(s), 54.02(s) ),53.01(s),52.77(s),51.83(s),48.12(s),46.23(s),42.97(s),41.13(s),40.99(s),39.93(s),38.92(s ),38.67(s),37.13(s),36.59(s),33.21(s),32.13(s),29.41(s),27.38(s),26.01(s),24.33(s),23.12(s ), 20.13(s), 19.13(s), 17.25(s), 16.16(s).

HRMS (ESI): m/z [M+H] ⁺ calcd for C ₃₆ H ₆₀ NO ₃ : 554.4573; found: 554.4579.

Example 4 O-(morpholino) ethyl derivatives of Cleistanone anti-rhinitis activity

Experimental Example 1 Effect of O-(morpholino)ethyl derivatives of Cleistanone on ovalbumin-induced allergic rhinitis in rats

Male SD rats, weighing 180-220 g, were intraperitoneally injected with 1 mg of ovalbumin and 10 mg of aluminum hydroxide gel, and then injected once every other day, a total of 7 times. From the 14th day, 10ul of 1mg/ml ovalbumin physiological saline solution was instilled into the nasal cavities of both sides of the rat every day, 7 times in total. Immediately after the last infusion, observe the number of times the rats sneeze and wipe their noses within 30 minutes, and the test drug is orally administered 1 hour before the last infusion of ovalbumin.

It can be seen from Table 1 that the O-(morpholinyl)ethyl derivative of Cleistanone (10 mg/kg) significantly inhibited the sneezing and scratching nasal reactions in rats with allergic rhinitis induced by ovalbumin.

Table 1 Effect of O-(morpholino) ethyl derivatives of Cleistanone of the present invention on ovalbumin-induced allergic rhinitis in rats

*p<0.05, **p<0.01, compared with the control group

Experimental Example 2 Effect of O-(morpholinyl) ethyl derivatives of Cleistanone of the present invention on rat rhinitis caused by histamine

Male SD rats, weighing 180-220g, were given 1 hour after oral administration of the test drug, and 10ul of 1M histamine saline solution was instilled into the nasal cavities on both sides, and the number of sneezing and nasal wiping of the rats within 30 minutes was observed.

It can be seen from Table 2 that the O-(morpholino) ethyl derivative (10 mg/kg) of Cleistanone of the present invention significantly reduces the number of sneezing in rats with rhinitis caused by histamine, and tends to inhibit the response to scratching the nose.

Table 2 The effect of O-(morpholino) ethyl derivatives of Cleistanone of the present invention on histamine-induced rhinitis in rats

*p<0.05, **p<0.01, compared with the control group

Experimental example 3 The effect of O-(morpholino) ethyl derivatives of Cleistanone of the present invention on the increase of nasal cavity vascular permeability in rats caused by ovalbumin and histamine

Male SD rats, weighing 180-220g, were used to observe the increase of nasal vascular permeability caused by ovalbumin and histamine in active sensitization rats and normal rats respectively. The sensitization method of the rats was the same as the allergic rhinitis test. On the 14th day after the initial immunization, rats were intraperitoneally injected with pentobarbital sodium 40mg/kg, and after anesthesia, a cannula was intubated from the trachea to the nasal cavity. Rinse the nasal cavity with saline for 10 minutes, then inject 5ml/kg of 1% Evans blue physiological saline solution into the rat tail vein, and collect the perfusate for 10 minutes after 3 minutes. In the sensitized rats and normal rats, the perfusate contains ovalbumin respectively 1mg/ml and histamine 40ug/ml, the perfusate collected from the nasal cavity was centrifuged at 1200×g for 10 minutes, and the Evans blue concentration in the supernatant was measured colorimetrically at 620nm, 1 hour before the test drug was perfused with antigen or histamine Oral administration.

It can be seen from Table 3 that the O-(morpholinyl)ethyl derivative of Cleistanone (10 mg/kg) of the present invention significantly inhibited the nasal vascular permeability of rats with allergic rhinitis induced by ovalbumin.

Table 3 The effect of O-(morpholino) ethyl derivatives of Cleistanone of the present invention on the increase of nasal cavity vascular permeability in rats induced by ovalbumin

**p<0.01, compared with the control group

It can be seen from Table 4 that 10 mg/kg of the O-(morpholino) ethyl derivative of Cleistanone of the present invention significantly reduces the nasal cavity vascular permeability of rats induced by histamine.

Table 4 The effect of O-(morpholino) ethyl derivatives of Cleistanone of the present invention on the increase of nasal blood flow permeability in rats caused by histamine

**p<0.01, compared with the control group

Conclusion: Oral administration of O-(morpholino)ethyl derivatives of Cleistanone can inhibit the scratching of the nose, sneezing response and increase of nasal vascular permeability induced by antigen (ovalbumin) and histamine in rats Therefore, it can be used to prepare medicine for treating rhinitis.

Example 5 Preparation of O-(morpholino) ethyl derivative tablet of Cleistanone involved in the present invention

Take 20 grams of O-(morpholino) ethyl derivatives of Cleistanone or one of its pharmaceutically acceptable salts, add 180 grams of conventional excipients for tablet preparation, mix well, and make 1000 tablets with a conventional tablet machine.

Example 6 Preparation of O-(morpholino) ethyl derivative capsules of Cleistanone involved in the present invention

Get 20 grams of O-(morpholino) ethyl derivatives of Cleistanone or one of its pharmaceutically acceptable salts, add conventional excipients such as starch 180 grams for the preparation of capsules, mix well, and make 1000 capsules .

Claims (9)

1. A kind of O-(morpholinyl) ethyl derivatives and pharmaceutically acceptable salts thereof of cleistanone Cleistanone having a structure shown in formula III: 2. the preparation method of the O-(morpholinyl) ethyl derivative of cleistanone Cleistanone as claimed in claim 1, is characterized in that: (1) Reaction of Cleistanone (I) with 1,2-dibromoethane to obtain O-bromoethyl derivative (II) of Cleistanone; (2) The O-bromoethyl derivative (II) of Cleistanone and morpholine undergo a substitution reaction to obtain the O-(morpholinyl) ethyl derivative (III) of Cleistanone; 3. the preparation method of the O-(morpholinyl) ethyl derivative of cleistanone Cleistanone as claimed in claim 2 is characterized in that: (1) Dissolve 440 mg of the compound Cleistanone (I) in 10 mL of benzene, add 0.04 g of tetrabutylammonium bromide, 3.760 g of 1,2-dibromoethane and 6 mL of 50% hydroxide Sodium solution; the mixture was stirred at 25 degrees Celsius for 24h; after 24h, the reaction solution was poured into ice water, extracted twice with dichloromethane immediately, and the organic phase solution was combined; then the organic phase solution was washed with water and saturated brine three times in sequence, and then Dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure to remove the solvent to obtain the crude product; the crude product is purified by silica gel column chromatography, the mobile phase is: petroleum ether/acetone=100:1, v/v, and the yellow concentrated elution band is collected as A yellow solid of the O-bromoethyl derivative (II) of Cleistanone was obtained; (2) Dissolve 273 mg of O-bromoethyl derivative (II) of Cleistanone in 20 mL of acetonitrile, add 345 mg of anhydrous potassium carbonate, 84 mg of potassium iodide and 1742 mg of morpholine, and heat the mixture under reflux for 8 h After the reaction, the reaction solution was poured into 30 mL of ice water, extracted three times with an equal amount of dichloromethane, and the organic phase was combined; the combined organic phase was washed with water and saturated brine successively, dried with anhydrous sodium sulfate, and concentrated under reduced pressure Remove the solvent to obtain the crude product; the crude product is purified by silica gel column chromatography, the mobile phase is: petroleum ether/acetone=100:0.5, v/v, and the yellow concentrated elution band is collected to obtain the O-(morpholine 185.3 mg of a yellow solid of the ethyl derivative (III). 4. The application of O-(morpholinyl) ethyl derivatives (III) and pharmaceutically acceptable salts thereof of Cleistanone in the preparation of anti-rhinitis drugs, characterized in that: the rhinitis is caused by antigens rhinitis, 5. the application of the O-(morpholinyl) ethyl derivative (III) and the pharmaceutically acceptable salt thereof of Cleistanone according to claim 4 in the preparation of anti-rhinitis drugs is characterized in that: The antigen is ovalbumin. 6. the application of the O-(morpholinyl) ethyl derivative (III) and pharmaceutically acceptable salt thereof of Cleistanone according to claim 5 in the preparation of anti-rhinitis drugs is characterized in that: The above-mentioned derivatives inhibited the frequency of nose scratching and sneezing response induced by ovalbumin. 7. the application of the O-(morpholinyl) ethyl derivative (III) and pharmaceutically acceptable salt thereof in the preparation of anti-rhinitis medicine of cleistanone Cleistanone according to claim 5 is characterized in that: The derivatives inhibit the increase of nasal vascular permeability induced by ovalbumin. 8. The application of O-(morpholinyl) ethyl derivative (III) of Cleistanone and its pharmaceutically acceptable salt in the preparation of anti-rhinitis medicine, characterized in that: the rhinitis is caused by histamine rhinitis, 9. the application of the O-(morpholinyl) ethyl derivative (III) and the pharmaceutically acceptable salt thereof of Cleistanone according to claim 8 in the preparation of anti-rhinitis medicine is characterized in that: The above-mentioned derivatives can inhibit the number of times of scratching the nose, sneezing response and increase of nasal vascular permeability induced by histamine.