S, S-heptacyclic dimethyl acetal dimer and preparation and application thereof

Abstract

The invention discloses a dimer of S, S-heptacyclic dimethyl acetal, namely [S, S-heptacyclic dimethyl acetal] 2, a preparation method of the dimer and application of the dimer in treatment of inflammation. Experiments prove that the [S, S-heptacyclic dimethyl acetal] 2 disclosed by the invention not only has a good anti-inflammatory effect, but also has the anti-inflammatory effect remarkably stronger than that of the S, S-heptacyclic dimethyl acetal. Therefore, the invention provides an effective technical means for treating inflammation. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a dimer of S,S-heptacyclic dimethyl acetal, namely [S,S-heptacyclic dimethyl acetal]2, and to a preparation method thereof and application thereof in treating inflammation. The present invention belongs to the field of biomedicine. Background Art

[0002] The applicant has disclosed that the S,S-heptacyclic dimethyl acetal with the following structural formula is an intermediate of S,S-heptacyclic aldehyde; the applicant has disclosed that an oligopeptide can be introduced into the aldehyde group of S,S-heptacyclic aldehyde through an amination reduction reaction to prepare an antithrombotic S,S-heptacyclic ethyl oligopeptide; the applicant has disclosed that the S,S-heptacyclic dimethyl acetal with the following structural formula itself is a P-selectin inhibitor. At an oral dose of 1 μmol / kg / day, S,S-heptacyclic dimethyl acetal effectively inhibits tumor growth, at an oral dose of 1 μmol / kg, S,S-heptacyclic dimethyl acetal effectively inhibits arterial thrombosis, and at an oral dose of 1 μmol / kg, S,S-heptacyclic dimethyl acetal effectively inhibits venous thrombosis.

[0003]

[0004] The applicant knows that the aggregates of S,S-heptacyclic dimethyl acetal often show stronger biological activity. Therefore, the applicant prepared the dimer of S,S-heptacyclic dimethyl acetal of the present invention, namely [S,S-heptacyclic dimethyl acetal]2. The applicant screened the biological activities (including anti-arterial thrombotic activity, anti-venous thrombotic activity, thrombolytic activity, anti-tumor activity, anti-tumor metastasis activity and anti-inflammatory activity) that may be caused by [S,S-heptacyclic dimethyl acetal]2 inhibiting P-selectin. Through experimental data, the applicant found that the dimer of S,S-heptacyclic dimethyl acetal showed excellent anti-inflammatory activity. Based on these findings, the applicant proposed the present invention. Summary of the invention

[0005] The technical problem to be solved by the present invention is to propose an S,S-seven-ring dimethyl acetal dimer, namely [S,S-seven-ring dimethyl acetal] 2, establish a method for preparing the S,S-seven-ring dimethyl acetal dimer [S,S-seven-ring dimethyl acetal] 2, and further evaluate the anti-inflammatory activity of [S,S-seven-ring dimethyl acetal] 2. In order to achieve the above purpose, the present invention adopts the following technical means.

[0006] The first technical means is to propose the S,S-heptacyclic dimethyl acetal dimer with the following structure, namely [S,S-heptacyclic dimethyl acetal]2,

[0007]

[0008] The second technical means is to propose a method for preparing [S,S-heptacyclic dimethyl acetal] 2, which can be summarized into the following two steps:

[0009] 1. Prepare S,S-heptacyclic dimethyl acetal monomer according to the disclosed method;

[0010] 2Convert the S,S-heptacyclic dimethyl acetal monomer into the dimer [S,S-heptacyclic dimethyl acetal]2.

[0011] The third technical approach was to evaluate the anti-inflammatory activity of S,S-heptacyclic dimethyl acetal monomers and dimers in the xylene-induced mouse ear swelling model, further confirming the effective application of [S,S-heptacyclic dimethyl acetal]2 in the preparation of anti-inflammatory drugs.

[0012] Compared with the prior art, the present invention has the following beneficial effects:

[0013] The present invention discloses a dimer composed of two S,S-heptacyclic dimethyl acetals, namely [S,S-heptacyclic dimethyl acetal]2. Experiments show that compared with the prior art, the [S,S-heptacyclic dimethyl acetal]2 of the present invention has excellent anti-inflammatory activity, and its anti-inflammatory effect is significantly stronger than that of the S,S-heptacyclic dimethyl acetal monomer. Therefore, the present invention provides a more effective technical means for preparing inflammatory drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 The synthetic route of the dimer of S,S-heptacyclic dimethyl acetal [S,S-heptacyclic dimethyl acetal] 2: i) 1,1,3,3-tetramethoxypropane and trifluoroacetic acid; ii) Pd / C, hydrogen; iii) 2-(7-oxidized benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 1-hydroxybenzotriazole; iv) vortex for 15 minutes, then ultrasonicate for 4 hours.

[0015] Figure 2 FT-ICR-MS spectrum and qCID spectrum of the dimer of S,S-heptacyclic dimethyl acetal. DETAILED DESCRIPTION

[0016] In order to further illustrate the present invention, a series of embodiments are given below. These embodiments are purely illustrative and are only used to specifically describe the present invention and should not be construed as limiting the present invention.

[0017] Example 1 Preparation of (3S)-1-(2,2-dimethoxyethyl)-2,3,4,9-tetrahydro-β-carlin-3-carboxylic acid benzyl ester (1)

[0018] A mixture of CH2Cl2 (150 mL), 1,1,3,3-tetramethoxypropane (5 mL) and trifluoroacetic acid (3.5 mL) was stirred at 0°C for 40 minutes. Then L-Trp-OBzl (17 mmol, 5 g) was gradually added to the mixture. The resulting reaction mixture was stirred at 60°C for 8 hours. TLC (petroleum ether / ethyl acetate = 1 / 1) showed that L-Trp-OBzl disappeared. The reaction mixture was concentrated under reduced pressure to obtain a yellow oil, which was washed with saturated NaHCO3 aqueous solution (30 mL × 3) and saturated NaCl aqueous solution (30 mL × 3) in turn. The ethyl acetate layer was dried over anhydrous Na2SO4 for 8 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 4.3 g (63%) of the title compound. FT-ICR-MS (m / e): 395.1971 [M+H] + .

[0019] Example 2 Preparation of (3S)-1-(2,2-dimethoxyethyl)-2,3,4,9-tetrahydro-β-carlin-3-carboxylic acid (2)

[0020] 3.96 g (10.00 mmol) of (3S)-1-(2,2-dimethoxyethyl)-2,3,4,9-tetrahydro-β-carlin-3-carboxylic acid benzyl ester (1) was dissolved in 100 mL of CH3OH. 400 mg of Pd / C was added to the obtained solution, and after stirring to form a uniform suspension, a three-way device was installed, and a hydrogen bag and a vacuum water pump were connected respectively, and the air in the reaction bottle was removed by hydrogen. Then, hydrogen was passed through the suspension for 18 hours while stirring. TLC (petroleum ether / ethyl acetate = 1 / 1) showed that 1 disappeared. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 2.72 g (89%) of the title compound as a yellow solid. FT-ICR-MS (m / e): 303.1345 [MH] - .

[0021] Example 3 Preparation of S,S-heptacyclic dimethyl acetal (3S,S)

[0022] 2.64 g (8.7 mmol) of (3S)-1-(2,2-dimethoxyethyl)-2,3,4,9-tetrahydro-β-carline-3-carboxylic acid (2) was dissolved in 70 mL of anhydrous DMF. 3.96 g (10.44 mmol) of 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and 1.16 g (8.7 mmol) of 1-hydroxybenzotriazole (HOBt) were added to the solution at 0°C with stirring. The pH of the reaction solution was then adjusted to 9 with collidine and stirred for 24 hours. TLC (petroleum ether / ethyl acetate = 1 / 1) showed that 2 disappeared. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in 100 mL of ethyl acetate. The obtained solution was washed with saturated NaHCO3 aqueous solution (30 mL × 3), saturated NaCl aqueous solution (30 mL × 3), 5% KHSO4 aqueous solution (30 mL × 3), saturated NaCl aqueous solution (30 mL × 3), 5% NaHCO3 aqueous solution (30 mL × 3), and saturated NaCl aqueous solution (30 mL × 3). The ethyl acetate layer was dried over anhydrous sodium sulfate for 8 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.25 g of dark yellow solid, which was separated by silica gel column chromatography (CH2Cl2 / CH3OH=100 / 1) to obtain 122 mg (6%) of S,S-heptacyclic dimethyl acetal (3S,S), which was a light yellow solid. FT-ICR-MS (m / e): 573.2713 [M+H] + ;Mp:154-155℃; IR:3387.58,3304.14,2929.29,2834.98,1717.93,1645.10,1622.57,1451.41,1387.50,1362.79,1329.40,1 293.96,1260.09,1227.64,1187.42,1156.90,1119.90,1049.62,1009.11,845.91,781.17,740.26,675.85cm -1 ; 1HNMR (800MHz, DMSO-d6): δ / ppm=11.03(s,2H),7.56(d,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H),7.01(t,J=7.2Hz,2H),7.01(t,J= 7.2Hz,2H),5.46(t,J=6.0Hz,2H),4.28(dd,J1=11.5Hz,J2=5.4Hz,2H),4.19(t,J=5.6Hz,2H),3.41(dd,J1=15.2Hz,J2=5.4Hz 2H),3.14(s,6H),3.09(s,6H),3.00(m,2H),2.07(m,4H); 13 C NMR (200 MHz, DMSO-d6): δ / ppm=169.5, 136.4, 134.0, 126.3, 121.5, 119.3, 118.4, 112.0, 106.0, 101.0, 55.2, 52.7, 51.4, 48.7, 33.8, 21.8; HPLC purity: 99.2% (Waters RPC18, 4.6×250 mm, 5 μm, CH3CN / H2O=50 / 50, flow rate=1 mL / min).

[0023] Example 4 Preparation of S,S-heptacyclic dimethyl acetal 3S,S dimer [S,S-heptacyclic dimethyl acetal] 2

[0024] 100 mg of S,S-heptacyclic dimethyl acetal (3S,S) powder was dissolved in 5 mL of ultrapure water. The resulting solution was vortexed for 15 minutes and then ultrasonicated for 4 hours until the solution was completely colorless and transparent. The colorless and transparent solution was concentrated to dryness under reduced pressure to obtain the dimer of S,S-heptacyclic dimethyl acetal (3S,S), namely [S,S-heptacyclic dimethyl acetal] 2. The structure of [S,S-heptacyclic dimethyl acetal] 2 was confirmed by ultra-high resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). The FT-ICR-MS spectrum gave the assembly mode of 3S,S in solution analyzed by qCID of FT-ICR-MS. Figure 2It is the FT-ICR-MS spectrum and qCID spectrum of 3-S, S. The peak with mass number 1167.50148 is the peak of two molecules of 3-S, S plus Na (theoretical value is 1167.51674), and the theoretical value is consistent with the measured value. Under the conditions of FT-ICR-MS, the peak of two molecules of 3-S, S plus Na was bombarded, and the cleavage peak was seen at the mass number 595.24867, which is the peak of one molecule of 3-S, S plus Na (theoretical value is 595.25325), and the theoretical value is consistent with the measured value. The theoretical value of the peak of two molecules of 3-S, S plus Na is consistent with the measured value, and the theoretical value of the peak of one molecule of 3-S, S plus Na is consistent with the measured value, which supports that the existence form of 3-S, S in the solution is dimer.

[0025] Example 5 Evaluation of the anti-inflammatory activity of [S,S-heptacyclic dimethyl acetal] 2

[0026] The anti-inflammatory effect of [S,S-heptacyclic dimethyl acetal]2 was evaluated in the mouse ear swelling model induced by xylene. ICR male mice (weight 25±2g) were rested at room temperature of 25℃ for 2 days, with free access to water and food, and randomly divided into groups, with 10 mice in each group. Mice were orally administered with normal saline (0.3mL / 100g) or aspirin suspension in normal saline (dose of 167μmol / kg) or [S,S-heptacyclic dimethyl acetal]2 in normal saline solution (dose of 0.1μmol / kg) or S,S-heptacyclic dimethyl acetal in normal saline solution (dose of 1μmol / kg). 30 minutes after oral administration, 30μL of xylene was evenly applied to the left auricle of the mouse. Two hours later, the mouse was anesthetized with ether and killed by breaking the cervical vertebra. The left and right ears were cut off, and a round ear piece was taken at the same position of the two ears with a 7mm diameter puncher. The ear pieces were weighed, and the weight difference between the two ears was used as the swelling degree. That is, the degree of swelling = the weight of the left ear disc – the weight of the right ear disc.

[0027] The data in Table 1 show that an oral dose of 0.1 μmol / kg of [S,S-heptacyclic dimethyl acetal] 2 effectively inhibits the inflammatory response induced by xylene (P<0.01 compared with saline). The data in Table 1 also show that the anti-inflammatory activity of an oral dose of 0.1 μmol / kg of [S,S-heptacyclic dimethyl acetal] 2 is significantly stronger than the anti-inflammatory activity of an oral dose of 1 μmol / kg of S,S-heptacyclic dimethyl acetal. The data in Table 1 further show that the anti-inflammatory activity of an oral dose of 0.1 μmol / kg of [S,S-heptacyclic dimethyl acetal] 2 is significantly stronger than the anti-inflammatory activity of an oral dose of 167 μmol / kg of aspirin (P<0.01 compared with aspirin). [S,S-heptacyclic dimethyl acetal] 2 has outstanding technical effects.

[0028] Table 1 Anti-inflammatory activity of [S,S-heptacyclic dimethyl acetal] 2

[0029] Therapeutic agents dose Ear swelling, mean ± SD mg Normal saline 10mL / kg 10.01±1.22 aspirin 167 μmol / kg 6.99±1.11 <![CDATA[[S,S-Cycloheptane dimethyl acetal]2]]> 0.1 μmol / kg <![CDATA[3.67±0.32 a ]]> S,S-heptacyclic dimethyl acetal 1μmol / kg <![CDATA[7.01±1.03 b ]]>

[0030] a) Compared with normal saline and aspirin, P<0.01; b) Compared with normal saline, P<0.01, compared with aspirin, P>0.05; n=10.

Claims

1. A dimer of S,S-heptacyclic dimethyl acetal, characterized in that: The dimer is of the following structure: [S,S-heptacyclic dimethyl acetal]2, 2. A method for preparing the dimer of S,S-heptacyclic dimethyl acetal according to claim 1, characterized in that: The method includes the following steps: 1) Preparation of S,S-heptacyclic dimethyl acetal; 2) Preparation of [S,S-heptacyclic dimethyl acetal] 2.

3. Use of the dimer of S,S-heptacyclic dimethyl acetal according to claim 1 in the preparation of anti-inflammatory drugs.

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