CN104098644A - O-(piperidinyl) ethyl derivative of Cleistanone as well as preparation method and application thereof - Google Patents

Abstract

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

Description

O-(piperidinyl) ethyl derivatives of cleistanone Cleistanone, preparation method and use thereof

technical field

The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to O-(piperidinyl)ethyl derivatives of cleistanone, a preparation method and uses thereof.

Background technique

Heart failure (HF) refers to a pathophysiological state in which abnormal cardiac function causes the pumping volume of the heart to fail to meet the needs of tissue metabolism. The etiology is cardiac overload, limited relaxation of the myocardium itself, and initial myocardial damage caused by any reason; while infection, anemia, pregnancy, childbirth, cardiac rhythm disorder, pulmonary embolism, hyperthyroidism, diabetes, and heart inhibitors induce aggravated HF. Pathogenesis In the past, it was believed that the mechanism of HF development was abnormal hemodynamics; in the late 1980s, it was recognized that the activation of neuroendocrine hormones played an important role (activation of sympathetic ↑ NE ↑ RAS ↑ etc.); after the 1990s, it gradually became clear that " Myocardial remodeling is the basic mechanism leading to the occurrence and development of heart failure. Heart failure is divided into acute heart failure and chronic heart failure.

At present, there is no clinically effective drug for the treatment of heart failure. Most drugs have unavoidable toxic and side effects while relieving the symptoms of heart failure. Search for 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 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 modified the structure of the compound Cleistanone, obtained a new O-(piperidinyl) ethyl derivative of Cleistanone, and evaluated its anti-heart failure activity, which has Anti-heart failure activity.

Contents of the invention

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

The O-(piperidinyl) 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) Substitution reaction of O-bromoethyl derivative (II) of Cleistanone with piperidine to prepare O-(piperidinyl)ethyl derivative (III) of Cleistanone.

The preparation method of the O-(piperidinyl) 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 % sodium hydroxide solution; the mixture was stirred at 25 degrees Celsius for 24 h; after 24 h, the reaction solution was poured into ice water, immediately extracted twice with dichloromethane, and the organic phase solution was combined; then the organic phase solution was washed with water and saturated brine in sequence 3 times, then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure to remove the solvent to obtain the crude product; the crude product was purified by silica gel column chromatography, the mobile phase was: petroleum ether/acetone=100:1, v/v, and the yellow concentrate was collected The eluted band was obtained as a yellow solid of the O-bromoethyl derivative (II) of Cleistanone.

(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 852 mg of piperidine , the mixture was heated to reflux for 16 h; after the reaction, the reaction solution was poured into 20 mL of ice water, extracted three times with an equal amount of dichloromethane, and the organic phases were combined; the combined organic phases were washed with water and saturated brine in turn, and then washed with anhydrous Dry over sodium sulfate, 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=100:0.5, v/v, and the yellow concentrated elution band is collected to obtain Cleogenin O-(piperidinyl)ethyl derivative (III) of Cleistanone as a yellow colloidal solid 157.0 mg.

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

Pharmacodynamic experiments show that the O-(piperidinyl)ethyl derivative (III) of Cleistanone of the present invention has better anti-heart failure 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 ways

Example 1 Preparation of Compound Cleostanone

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).

Synthesis of O-bromoethyl derivatives (II) of cleistanone Cleistanone of embodiment 2

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

13C NMR (125 MHz, 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＝1.1 Hz), 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; found 547.3159.

Example 3 Synthesis of O-(piperidinyl) 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 piperidine (852 mg, 10 mmol) were added , and the mixture was heated to reflux for 16 h. After the reaction, the reaction solution was poured into 20 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-(piperidinyl)ethyl derivative of Cleistanone. Gummy solid (157.0 mg, 57%).

¹ H NMR (500 MHz, DMSO-d6) δ5.04(s,1H),4.85(s,1H),4.37(s,1H),3.54(s,2H),2.57(s,2H),2.47( dd,J＝44.3,41.4 Hz,6H),2.29(s,1H),2.22(s,1H),2.19(s,1H),1.82(s,1H),1.65(s,2H),1.58(d ,J＝8.0 Hz, 2H), 1.53–1.46(m, 6H), 1.39(t, J＝7.8 Hz, 5H), 1.30(dd, J＝21.8, 9.9 Hz, 4H), 1.16(d, J＝ 0.4 Hz, 2H), 1.06(s, 6H), 0.91(s, 1H), 0.88(s, 12H), 0.85–0.57(m, 4H).

¹³ C NMR (125 MHz, DMSO-d6) δ216.69(s), 154.70(s), 105.53(s), 74.75(s), 67.02(s), 59.85(s), 55.00(d, J=14.4 Hz), 52.87(s), 51.30(s), 48.09(s), 44.44(s), 42.38(s), 41.98(s), 40.93(s), 40.25(s), 39.07(s), 38.99( s), 37.34(s), 36.48(s), 33.66(s), 33.05(s), 30.10(s), 27.52(s), 26.16(s), 24.80(s), 24.59(s), 24.06( s), 23.65(s), 21.05(s), 18.56(s), 18.21(s), 17.28(s).

HRMS (ESI): m/z [M+H] ⁺ calcd for C ₃₇ H ₆₂ NO ₂ : 552.4781; found: 552.4787.

Example 4 O-(piperidinyl) ethyl derivatives of Cleistanone anti-heart failure activity

(1) Experimental example: Therapeutic effect of O-(piperidinyl)ethyl derivatives of Cleistanone on acute heart failure in dogs

1 Materials: Animals - healthy adult dogs weighing 12.5-13.5 kg. Sodium pentobarbital (Sigma, imported sub-packaging, specification: 25g); Instruments: American BIC16-guided physiological recorder (produced by American BIC Company); electromagnetic flowmeter (MFV-3200): produced by Nippon Kohden Corporation.

2 Test methods and results

The dogs were randomly divided into the NS group (equal volume solvent), and the O-(piperidinyl)ethyl derivative of Cleistanone 1.0 mg/kg group was intragastrically administered, with 6 dogs in each group. After 12 hours of fasting, intravenous injection of pentobarbital sodium 40 mg/kg was anesthetized, endotracheal intubation, artificial respiration, monitoring of aortic pressure (AP) and electrocardiogram. The left thoracotomy was performed, and the catheter was inserted from the apex to the left ventricular pressure and its pressure change rate (±dp/dt _max ). A Waltan-Brodie strain bow was implanted in the anterior wall of the left ventricle, and the myocardial contractility was measured. Blood flow in the ascending aorta was measured with an electromagnetic flowmeter. Using ascending aortic flow as cardiac output (CO), calculate cardiac index (CI), stroke index (SI), stroke work (SW), and left ventricular work (LVW). All parameters are recorded with BIC physiological recorder. Half an hour after the operation, all parameters were stable. Pentobarbital sodium (0.5 mL/kg·min) was infused at a constant rate from the femoral vein, and acute heart failure was formed with ±dp/dt _max falling to about 1000 mHg/s as the main index. After the acute heart failure model was stabilized, the animals in each group were given corresponding drugs in the duodenum. T-test between groups was used for statistical analysis.

Table 1 The effect of O-(piperidinyl)ethyl derivatives of Cleistanone on the dp/dt of dogs with heart failure (n=6, X±s)

Compared with NS group, p<0.05, p<0.01

Table 2 Effect of O-(piperidinyl)ethyl derivatives of Cleistanone on heart work in dogs with heart failure (n=6, X±s)

Compared with before administration, *p<0.05, **p<0.01; compared with NS group, p<0.05, p<0.01

Result is as shown in table 1, 2, and the O-(piperidinyl) ethyl derivative of Cleistanone can increase SW, LVW, +dp/dt (compared with model group control group, p<0.05or p< 0.01). O-(piperidinyl)ethyl derivatives of Cleistanone can increase SW, LVW, +dp/dt of dogs with heart failure (compared with model group and control group, p<0.01or p<0.05).

Table 3 Effect of O-(piperidinyl)ethyl derivatives of Cleistanone on cardiac output in dogs with heart failure (n=6, X±s)

Compared with before administration, *p<0.05, **p<0.01; compared with NS group, p<0.05, p<0.01

The results are shown in Table 3. O-(piperidinyl)ethyl derivatives of Cleistanone can increase the cardiac output of dogs with heart failure (compared with the model control group, p<0.01or p<0.05). O-(piperidinyl)ethyl derivatives of Cleistanone can increase the cardiac output of dogs with heart failure (compared with the model control group, p<0.01or p<0.05).

Conclusion: O-(piperidinyl)ethyl derivatives of Cleistanone can significantly improve acute heart failure, and can be used to prepare medicines for treating or preventing acute heart failure.

(2) Effect of O-(piperidinyl)ethyl derivatives of Cleistanone on chronic heart failure rats

Test Method and Results

30 rats, half male and half male. 10 as a normal control group. Twenty rats were injected intraperitoneally with doxorubicin hydrochloride 2 mg/kg once a week for 6 weeks. At the fifth week, they were randomly divided into two groups, namely the normal NS group and the O-(piperidinyl)B group administered with Cleistanone by intragastric administration. Base derivatives 2.5mg/kg group. Gastric administration of O-(piperidinyl)ethyl derivatives of Cleistanone 2.5mg/kg group was administered intragastrically with O-(piperidinyl)ethyl derivatives of Cleistanone daily from the 5th week. sky. Anesthetized by intraperitoneal injection of 20% urethane 1.1g/kg, the trachea was surgically stripped and intubated, and the right common artery was freed at the same time, and a self-made ventricular cannula (diameter 1mm, filled with 1% heparin) was inserted through it, and the blood pressure curve was traced; Continue to insert, make it enter the left ventricle through the left arterial valve, trace the intraventricular pressure curve, automatically analyze and process the left ventricular systolic pressure (LVSP), the maximum rate of increase of ventricular pressure (+dp/dt _max ), the maximum rate of decrease of ventricular pressure (-dp/dt _max ) and measured myocardial maximum contraction velocity (Vpm) and other data. Another 10 rats were taken as the normal control group, without administration of doxorubicin hydrochloride, and the rest of the operations were the same as above, and the T-test between groups was used for statistical processing.

Table 4 Effect of O-(piperidinyl)ethyl derivatives of Cleistanone on cardiac function in rats with chronic heart failure (n=10)

Compared with NS group, ^△ : p<0.05, ^△△ : p<0.01

The test result of table 4 shows that the O-(piperidinyl) ethyl derivative 2.5mg/kg of Cleistanone can significantly raise the LVSP of the heart failure rat caused by doxorubicin hydrochloride, +dp/dt _max ,-dp/dt The reduction of _max and Vpm (compared with NS group, P<0.01).

Conclusion: O-(piperidinyl)ethyl derivatives of Cleistanone have significant effects on treating or preventing chronic heart failure, and can be used to prepare medicines for treating or preventing chronic heart failure.

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

Take 20 grams of O-(piperidinyl) 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-(piperidinyl) ethyl derivative capsules of Cleistanone involved in the present invention

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

Claims (10)

1. A kind of O-(piperidinyl) ethyl derivatives and pharmaceutically acceptable salts thereof of cleistanone Cleistanone having a structure shown in formula III: . 2. the preparation method of the O-(piperidinyl) 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) Substitution reaction of O-bromoethyl derivative (II) of Cleistanone with piperidine to prepare O-(piperidinyl)ethyl derivative (III) of Cleistanone. the . 3. the preparation method of the O-(piperidinyl) 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 % sodium hydroxide solution; the mixture was stirred at 25 degrees Celsius for 24 h; after 24 h, the reaction solution was poured into ice water, immediately extracted twice with dichloromethane, and the organic phase solution was combined; then the organic phase solution was washed with water and saturated brine in sequence 3 times, then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure to remove the solvent to obtain the crude product; the crude product was purified by silica gel column chromatography, the mobile phase was: petroleum ether/acetone=100:1, v/v, and the yellow concentrate was collected The eluted band was obtained as a yellow solid of the O-bromoethyl derivative (II) of Cleistanone. the (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 852 mg of piperidine , the mixture was heated to reflux for 16 h; after the reaction, the reaction solution was poured into 20 mL of ice water, extracted three times with an equal amount of dichloromethane, and the organic phases were combined; the combined organic phases were washed with water and saturated brine in turn, and then washed with anhydrous Dry over sodium sulfate, 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=100:0.5, v/v, and the yellow concentrated elution band is collected to obtain Cleogenin O-(piperidinyl)ethyl derivative (III) of Cleistanone as a yellow colloidal solid 157.0 mg. the 4. The application of the O-(piperidinyl)ethyl derivative (III) of Cleistanone as claimed in claim 1 and the pharmaceutically acceptable salt thereof in anti-heart failure drugs. the 5. A kind of O-(piperidinyl) ethyl derivatives of cleistanone Cleistanone having a structure shown in formula III as claimed in claim 4 and the application of pharmaceutically acceptable salts thereof in anti-heart failure drugs , characterized in that: the heart failure is acute heart failure. the 6. A kind of O-(piperidinyl) ethyl derivatives of cleistanone Cleistanone having a structure shown in formula III as claimed in claim 5 and the application of pharmaceutically acceptable salts thereof in anti-heart failure drugs , characterized in that: the O-(piperidinyl) ethyl derivatives of Cleistanone and pharmaceutically acceptable salts thereof increase cardiac work in acute heart failure. the 7. A kind of O-(piperidinyl) ethyl derivatives of cleistanone Cleistanone having a structure shown in formula III as claimed in claim 5 and the application of pharmaceutically acceptable salts thereof in anti-heart failure drugs , characterized in that: the O-(piperidinyl)ethyl derivatives of the cleistanone Cleistanone and pharmaceutically acceptable salts thereof increase the cardiac output of acute heart failure. the 8. A kind of O-(piperidinyl) ethyl derivatives of cleistanone Cleistanone having a structure shown in formula III as claimed in claim 4 and the application of pharmaceutically acceptable salts thereof in anti-heart failure drugs , characterized in that: the heart failure is chronic heart failure. the 9. A kind of O-(piperidinyl) ethyl derivatives of cleistanone Cleistanone having the structure shown in formula III as claimed in claim 8 and the application of pharmaceutically acceptable salts thereof in anti-heart failure drugs , characterized in that: the O-(piperidinyl)ethyl derivatives of Cleistanone and pharmaceutically acceptable salts thereof increase left ventricular systolic pressure in chronic heart failure. the 10. A kind of O-(piperidinyl) ethyl derivatives of cleistanone Cleistanone having a structure shown in formula III as claimed in claim 8 and the application of pharmaceutically acceptable salts thereof in anti-heart failure drugs , characterized in that: the O-(piperidinyl) ethyl derivatives of Cleistanone and pharmaceutically acceptable salts thereof increase the maximum rise rate of ventricular intraventricular pressure and maximum myocardial contraction velocity of chronic heart failure. the