CN110437177B - Pleuromutilin derivative and preparation method and application thereof - Google Patents

Pleuromutilin derivative and preparation method and application thereof Download PDF

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CN110437177B
CN110437177B CN201910601978.6A CN201910601978A CN110437177B CN 110437177 B CN110437177 B CN 110437177B CN 201910601978 A CN201910601978 A CN 201910601978A CN 110437177 B CN110437177 B CN 110437177B
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张园园
谢川
吴春霞
王秀阳
衡新安
曾正兴
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Abstract

The invention relates to a compound of general formula (I)Pleuromutilin derivatives, stereoisomers, pharmaceutically acceptable salts or crystal forms thereof, or pharmaceutical compositions containing the pleuromutilin derivatives, as well as preparation methods and intermediates thereof and application of the pleuromutilin derivatives, the stereoisomers, pharmaceutically acceptable salts or crystal forms thereof in preparation of antibacterial drugs. The definition of the general formula (I) is consistent with the specification.

Description

Pleuromutilin derivative and preparation method and application thereof
Technical Field
The invention relates to a pleuromutilin derivative shown in a general formula (I), a stereoisomer, a pharmaceutically acceptable salt or a crystal form thereof, or a pharmaceutical composition containing the pleuromutilin derivative, a preparation method and an intermediate thereof, and application of the pleuromutilin derivative in preparation of antibacterial drugs.
Background
The discovery of antibiotics has great significance in the human development history, but now the bacterial drug resistance is increasingly serious due to the wide and long-term abuse of antibiotics in clinic, especially the appearance of 'superbacteria', which forms a great threat to the life safety of human beings. In order to cope with the situation that effective antibacterial drugs are reduced year by year and the number of drug-resistant bacteria is increased, an effective way for solving the troublesome global problem is urgently needed.
Pleuromutilin (formula 1)) is a tricyclic diterpene compound with good antibacterial activity isolated from higher fungi. Research shows that pleuromutilin is combined on 23S rRNA of bacterial ribosome 50S subunit, and its tricyclic mother nucleus is positioned in the Peptidyl Transferase (PTC) center of ribosome 50S subunit, so that a tight pocket is formed in A site, at the same time, its side chain portion covers tRNA combined P site, so that it can directly inhibit the formation of peptide bond, and can prevent the synthesis of bacterial protein. In recent years researchers have achieved better results in studies on the derivation of their side chains, such as tiamulin (Tamulin, (formula 2)) and Valnemulin (Valnemulin, (formula 3)) successfully approved as veterinary antibiotics in 1979 and 1999, respectively. In addition, azamolin (Azamulin, (formula 4)) entered clinical stage due to its excellent antibacterial effect in 1980, but was declared off due to its strong inhibitory effect on human cytochrome P450 and its low oral bioavailability and short half-life. In 2007, ryegrass smik (GlaxoSmithKline) developed ritamalin (Ratapamulin, (formula 5)), the first topical pleuromutilin-type antibacterial agent to be used in the treatment of human skin infections. Lafimulin (BC-3781, (formula 6)) is a novel semi-synthetic pleuromutilin antibacterial agent developed by Nabriva corporation for the treatment of acute bacterial skin and skin structure infections (abssi) and community-acquired bacterial pneumonia (CABP). The drug shows good safety and tolerance in clinical stage, and FDA receives two New Drug Applications (NDAs) of lefamulin oral and intravenous preparations for CABP submitted by Nabriva corporation in 2019 month 2.
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Pleuromutilins are developed more rapidly in veterinary medicine, but the effects in the human process are not fully reflected. Based on unmet clinical needs, the development of drugs with high antibacterial activity having a novel structure and a unique mechanism of action is imminent.
Disclosure of Invention
The invention relates to a pleuromutilin derivative which is novel in structure and has good antibacterial activity.
The invention relates to a compound shown in a general formula (I), a stereoisomer and a pharmaceutically acceptable salt thereof, wherein
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A is selected from phenyl, and hydrogen on the phenyl is further selected from 1-4H and C 1-4 Alkoxy, NH 2 、NO 2 Or NR A R B Substituted with a substituent of (a);
R A 、R B each independently selected from H, C 1-4 Alkyl or-CO-C 1-4 An alkyl group.
Some embodiments of the invention relate to a compound of formula (I) and stereoisomers, pharmaceutically acceptable salts thereof, wherein
A is selected from phenyl, and hydrogen on the phenyl is further selected from 1-4H and OCH 3 、NH 2 、NO 2 Or NR A R B Substitution;
R A 、R B each independently selected from H, methyl, ethyl, formyl or acetyl.
Some embodiments of the present invention relate to a compound of formula (I) and stereoisomers, pharmaceutically acceptable salts thereof, wherein the compound is selected from one of the following structures (formula II-formula X):
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some embodiments of the present invention relate to a compound of formula (I) and stereoisomers, pharmaceutically acceptable salts thereof, wherein the salts are selected from hydrochloride, fumarate, malate, hydrobromide, succinate, phosphate, mesylate, or benzoate.
Some embodiments of the present invention relate to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, and stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or excipient.
Some embodiments of the invention relate to the application of the compound and the stereoisomer and the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in preparing medicaments for treating infectious diseases.
Some embodiments of the invention relate to the use as described above, wherein the infectious disease is selected from infectious diseases caused by mycoplasma or drug-resistant bacteria.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1: synthesis of 14a
Figure 505906DEST_PATH_IMAGE017
The first step is as follows: synthesis of 12a
Dissolving 4-fluoroacetophenone (500.0 mg, 3.6 mmol) and sodium hydroxide (144.8 mg, 3.6 mmol) in ethanol, stirring for 0.5 h under an ice bath condition, adding benzaldehyde (345.7 mg, 3.3 mmol) into the mixed solution, continuing to put the mixed solution under the ice bath condition, monitoring by TLC until the reaction is complete, adjusting the pH of the reaction solution to acidity by using 1M hydrochloric acid, adding a proper amount of water to completely separate out a solid, performing suction filtration, washing the solid with water, drying, and recrystallizing with ethanol to obtain 12a (496.3 mg, yield 67.3%).
The second step: synthesis of 13a
Compound 12a (300.0 mg, 1.3 mmol), potassium carbonate (366.5 mg, 2.7 mmol) and piperazine (228.4 mg, 2.7 mmol) were dissolved in DMF and placed at 110 o Heating and stirring until the reaction is complete, detecting by TLC until the reaction is complete, cooling the reaction solution to room temperature, adding a proper amount of water, extracting the reaction solution with DCM, back-extracting the obtained organic phase with water, drying over anhydrous magnesium sulfate, distilling under reduced pressure, and separating and purifying by column chromatography to obtain 13a (252.3 mg, yield 65.1%).
The third step: synthesis of 14a
Dissolving compound 9 (200.0 mg, 0.4 mmol) and NaI (67.5 mg, 0.5 mmol) in acetonitrile, stirring at 75 deg.C for 0.5 h, adding compound 13a (131.7 mg, 0.5 mmol) and potassium carbonate (103.8 mg, 0.8 mmol) into the above reaction solution, stirring, detecting by TLC, distilling under reduced pressure, and purifying by column chromatography to obtain 14a (145.6 mg, yield 59.4%, melting point 106.7-108.1) oC )。
1 H NMR(400 MHz, CDCl 3 ): δ (ppm) 8.01 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 15.6 Hz, 1H), 7.65 (m, 2H), 7.57 (d, J = 15.6 Hz, 1H), 7.46 – 7.37 (m, 3H), 6.92 (d, J = 8.8 Hz, 2H), 6.60 – 6.48 (m, 1H), 5.83 (d, J = 8.4, 1H), 5.37 (dd, J = 11.2, 1.4 Hz, 1H), 5.22 (dd, J = 17.2, 1.6 Hz, 1H), 3.48 – 3.34 (m, 5H), 3.26 (d, J = 17.2 Hz, 1H), 3.13 (d, J = 17.2 Hz, 1H), 2.80 – 2.63 (m, 4H), 2.41 – 2.06 (m, 5H), 1.80 (dd, J = 14.4, 2.4 Hz,1H), 1.74 – 1.49 (m, 5H), 1.47 (s, 3H), 1.43 – 1.36 (m, 1H), 1.35 – 1.29 (m, 1H), 1.19 (s, 3H), 1.17 – 1.10 (m, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H).
13 C NMR (100 MHz, CDCl 3 ): δ (ppm) 217.1, 188.1, 169.0, 154.0, 143.2, 139.1, 135.3, 130.7, 130.1, 129.3, 128.9, 128.3, 122.0, 117.3, 113.6, 74.6, 68.5, 59.9, 58.2, 53.5, 52.6, 47.2, 45.5, 44.0, 41.8, 36.7, 36.1, 34.5, 30.5, 26.9, 26.4, 24.9, 16.8, 14.9, 11.5.
Example 2: synthesis of 14b
Preparation method reference example 1
Figure 369301DEST_PATH_IMAGE018
Yield 62.7% m.p. 118.2-119.9 o C
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.97 (d, J = 8.8 Hz, 2H), 7.75 (d, J= 15.6 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 15.6 Hz, 1H), 6.93 (d, J = 9.2 Hz, 2H), 6.89 (d, J = 9.6 Hz, 2H), 6.50 (m, 1H), 5.81 (d, J = 8.4 Hz, 1H), 5.34 (dd, J = 11.2, 1.2 Hz, 1H), 5.20 (dd, J = 17.2, 1.2 Hz, 1H), 3.84 (s, 3H), 3.40 (m, 5H), 3.24 (d, J = 16.8 Hz, 1H), 3.10 (d, J = 16.8 Hz, 1H), 2.69 (m, 4H), 2.44 – 2.28 (m, 1H), 2.28 – 2.03 (m, 4H), 1.82 – 1.73 (m, 1H), 1.58 (m, 5H), 1.45 (s, 3H), 1.36 (m, 1H), 1.30 (m, 1H), 1.16 (s, 3H), 1.11 (m, 1H), 0.88 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H).
13 C NMR (100 MHz, CDCl 3 ): δ (ppm) 217.1, 188.2, 169.0, 161.3, 153.9, 143.0, 139.1, 130.6, 130.0, 128.6, 128.1, 119.7, 117.3, 114.4, 113.6, 74.6, 68.5, 59.9, 58.2, 55.4, 52.6, 47.2, 45.5, 45.1, 44.0, 41.8, 36.7, 36.1, 34.5, 30.5, 26.9, 26.4, 24.9, 16.8, 14.9, 11.5.
Example 3: synthesis of 14c
Preparation method reference example 1
Figure 426119DEST_PATH_IMAGE019
Yield 64.5% m.p. 134.5-136.3 oC
1 H NMR(400 MHz, CDCl 3 ): δ (ppm) 7.99 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 15.6 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 15.6 Hz, 1H), 6.91 (d, J= 8.8 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 6.50 (dd, J = 17.2, 10.8 Hz, 1H), 5.82 (d, J = 8.4 Hz, 1H), 5.36 (dd, J = 11.2, 1.2 Hz, 1H), 5.21 (dd, J = 17.2, 1.2 Hz, 1H), 3.49 (s, 4H), 3.36 (m, 2H), 3.04 (s, 6H), 2.79 (s, 4H), 2.33 (m, 1H), 2.29 – 2.05 (m, 4H), 1.82 – 1.74 (m, 1H), 1.71 – 1.63 (m, 2H), 1.59 (m, 3H), 1.52 – 1.46 (m, 2H), 1.46 – 1.43 (s, 3H), 1.43 – 1.35 (m, 2H), 1.33 (s, 1H), 1.30 – 1.28 (m, 1H), 1.18 (s, 3H), 1.12 (m, 1H), 0.88 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H).
13 C NMR(100 MHz, CDCl 3 ): δ (ppm) 217.2, 188.4, 169.0, 153.7, 151.8, 144.2, 139.1, 130.4, 130.2, 129.2, 123.1, 117.3, 116.8, 113.7, 111.9, 74.6, 68.4, 60.0, 58.2, 52.7, 47.3, 45.5, 45.0, 45.0, 41.8, 40.2, 36.8, 36.1, 34.5, 31.6, 30.5, 26.9, 26.4, 24.9, 22.7, 16.8, 14.9, 14.2, 11.6.
Example 4: synthesis of 14d
Preparation method reference example 1
Figure 36092DEST_PATH_IMAGE020
Yield 63.3% m.p. 159.6-161.3 o C
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 8.10 (s, 1H), 7.98 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 15.6 Hz, 1H), 7.59 (q, J = 9.2 Hz, 4H), 7.49 (d, J = 15.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.52 (dd, J = 17.2, 11.2 Hz, 1H), 5.82 (d, J = 8.4 Hz, 1H), 5.35 (d, J = 11.2 Hz, 1H), 5.21 (d, J = 17.6 Hz, 1H), 3.41 (m, 5H), 3.25 (d, J = 17.2 Hz, 1H), 3.11 (d, J = 17.2 Hz, 1H), 2.71 (m, 4H), 2.35 (m, 2H), 2.25 (m, 2H), 2.18 (d, J = 8.4 Hz, 3H), 2.15 – 2.01 (m, 3H), 1.78 (d, J = 14.4 Hz, 1H), 1.72 – 1.48 (m, 5H), 1.45 (s, 4H), 1.39 (m, 1H), 1.28 (m, 1H), 1.17 (s, 3H), 1.12 (m, 1H), 0.89 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H).
13 C NMR (100 MHz, CDCl 3 ): δ (ppm) 217.2, 188.2, 169.0, 154.0, 142.8, 139.1, 130.7, 129.2, 120.8, 119.8, 117.3, 113.6, 74.6, 68.5, 59.9, 58.2, 52.6, 47.1, 45.5, 45.1, 44.0, 41.8, 36.8, 36.1, 34.5, 30.4, 26.9, 26.5, 24.9, 24.6, 16.8, 14.9, 11.5.
Example 5: synthesis of 14e
Preparation method reference example 1
Figure 799649DEST_PATH_IMAGE021
58.5% yield melting point 138.6-140.3 oC
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 8.25 (d, J = 8.8 Hz, 2H), 7.98 (d, J= 8.8 Hz, 2H), 7.82 – 7.71 (m, 3H), 7.65 (d, J = 15.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.51 (dd, J = 17.2, 11.2 Hz, 1H), 5.80 (d, J = 8.4 Hz, 1H), 5.33 (d, J = 11.2 Hz, 1H), 5.20 (d, J = 17.2 Hz, 1H), 3.54 – 3.30 (m, 5H), 3.24 (d, J = 17.2 Hz, 1H), 3.10 (d, J = 17.2 Hz, 1H), 2.80 – 2.59 (m, 4H), 2.40 – 2.28 (m, 1H), 2.28 – 2.12 (m, 2H), 2.13 – 2.04 (m, 2H), 1.77 (m, 2H), 1.58 (m, 5H), 1.44 (s, 3H), 1.36 (m, 1H), 1.29 (m, 1H), 1.16 (s, 3H), 1.13 – 1.06 (m, 1H), 0.87 (d, J = 6.8 Hz, 3H), 0.73 (d, J = 6.8 Hz, 3H).
13 C NMR (100 MHz, CDCl 3 ): δ (ppm) 217.1, 187.0, 169.0, 154.3, 148.3, 141.6, 139.9, 139.1, 130.9, 128.8, 127.6, 125.9, 124.2, 117.3, 113.5, 74.6, 68.5, 59.8, 58.2, 52.5, 47.0, 45.5, 45.1, 44.0, 41.8, 36.7, 36.1, 34.5, 30.5, 26.9, 26.4, 24.9, 16.8, 14.9, 11.5.
Example 6: synthesis of 14f
Preparation method reference example 1
Figure 102454DEST_PATH_IMAGE022
Yield 56.3% m.p. 102.9-104.2 oC
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 8.51 (t, J = 1.6 Hz, 1H), 8.23 (m, 1H), 8.02 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 15.6 Hz, 1H), 7.67 (d, J = 15.6 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.51 (dd, J = 17.2, 11.2 Hz, 1H), 5.82 (d, J = 8.4 Hz, 1H), 5.35 (dd, J = 11.2, 1.2 Hz, 1H), 5.21 (dd, J = 17.2, 1.2 Hz, 1H), 3.51 (s, 4H), 3.36 (dd, J = 10.4, 6.8 Hz, 2H), 2.76 (s, 4H), 2.34 (m 1H), 2.29 – 2.19 (m, 2H), 2.18 – 2.05 (m, 2H), 1.78 (dd, J = 14.4, 2.4 Hz, 1H), 1.74 – 1.63 (m, 3H), 1.63 – 1.47 (m, 4H), 1.45 (s, 3H), 1.38 (m, 1H), 1.31 (m, 1H), 1.17 (s, 3H), 1.12 (m, 1H), 0.88 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H).
13 C NMR (100 MHz, CDCl 3 ): δ (ppm) 217.1, 187.0, 168.9, 154.2, 148.7, 140.0, 139.1, 137.2, 134.3, 130.9, 129.9, 127.6, 124.7, 124.2, 122.1, 117.3, 113.5, 74.6, 68.5, 59.8, 58.2, 52.5, 47.0, 45.5, 45.1, 41.8, 36.7, 36.1, 34.5, 30.4, 26.9, 26.4, 24.9, 16.8, 14.9, 11.5.
Example 7: synthesis of 14g
Preparation method reference example 1
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Yield 57.8% melting point 106.3-107.8 o C
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 8.16 (dd, J = 8.0, 1.2 Hz, 1H), 7.74 (m, 1H), 7.67 – 7.59 (m, 1H), 7.50 (dd, J = 7.6, 1.2 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 15.6 Hz, 1H), 6.89 – 6.79 (m, 3H), 6.50 (dd, J = 17.6, 11.2 Hz, 1H), 5.82 (d, J = 8.4 Hz, 1H), 5.35 (dd, J = 11.2, 1.6 Hz, 1H), 5.21 (dd, J = 17.2, 1.6 Hz, 1H), 3.35 (m, 6H), 2.72 (s, 4H), 2.33 (m, 1H), 2.30 – 2.14 (m, 2H), 2.10 (m, 2H), 1.78 (dd, J = 14.4, 2.8 Hz, 1H), 1.71 – 1.58 (m, 3H), 1.59 – 1.46 (m, 4H), 1.44 (s, 3H), 1.41 – 1.34 (m, 1H), 1.30 (m, 1H), 1.17 (s, 3H), 1.12 (m, 1H), 0.89 (d, J = 6.8 Hz, 3H), 0.73 (d, J = 6.8 Hz, 3H).
13 C NMR (100 MHz, CDCl 3 ): δ (ppm) 217.1, 192.9, 169.0, 152.9, 147.0, 139.1, 136.8, 133.8, 130.4, 130.2, 128.9, 124.5, 124.2, 122.5, 117.3, 114.7, 74.6, 68.5, 59.9, 58.2, 52.6, 47.4, 45.5, 45.1, 44.0, 41.8, 36.7, 36.1, 34.5, 30.5, 26.9, 26.4, 24.9, 16.8, 14.9, 11.5.
Example 8:14h Synthesis
Preparation method reference example 1
Figure 794652DEST_PATH_IMAGE024
Yield 89.76% m.p. 122.5-124.1 o C
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.98 (d, J = 8.8 Hz, 2H), 7.69 (d, J= 15.6 Hz, 1H), 7.49 (d, J = 15.6 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.93 (s, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.71 (dd, J = 8.0, 1.6 Hz, 1H), 6.51 (dd, J = 17.6, 11.2 Hz, 1H), 5.81 (d, J = 8.4 Hz, 1H), 5.35 (dd, J = 11.2, 1.6 Hz, 1H), 5.20 (dd, J = 17.6, 1.6 Hz, 1H), 3.45 (t, J = 4.8 Hz, 4H), 3.36 (s, 1H), 3.28 (d, J = 17.2 Hz, 1H), 3.14 (d, J = 17.2 Hz, 1H), 2.75 (m, 4H), 2.41 – 2.29 (m, 1H), 2.29 – 2.18 (m, 2H), 2.17 – 2.04 (m, 3H), 1.77 (dd, J = 14.4, 2.6 Hz, 1H), 1.71 – 1.46 (m, 5H), 1.45 (s, 3H), 1.40 – 1.34 (m, 1H), 1.33 – 1.27 (m, 1H), 1.17 (s, 3H), 1.14 – 1.08 (m, 1H), 0.88 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H).
13 C NMR (100 MHz, CDCl 3 ): δ (ppm) 217.2, 188.2, 169.0, 154.0, 146.9, 143.5, 139.1, 136.4, 130.7, 129.8, 128.4, 121.9, 118.8, 117.3, 117.0, 114.5, 113.6, 74.6, 68.5, 59.9, 58.2, 52.6, 47.2, 5.5, 45.0, 44.0, 41.8, 36.7, 36.1, 34.5, 30.5, 26.9, 26.4, 24.9, 16.9, 14.9, 11.5.
Example 9: synthesis of 14i
Preparation method reference example 1
Figure 412716DEST_PATH_IMAGE025
Yield 93.4% m.p. 132.5-133.9 oC
1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.98 (d, J = 8.8 Hz, 2H), 7.73 (d, J= 15.6 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 15.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 6.53 (dd, J = 17.2, 11.2 Hz, 1H), 5.82 (d, J = 8.4 Hz, 1H), 5.35 (d, J = 11.2 Hz, 1H), 5.21 (d, J = 17.2 Hz, 1H), 3.42 (t, J = 4.8 Hz, 4H), 3.36 (m, 1H), 3.25 (d, J = 17.2 Hz, 1H), 3.10 (d, J = 17.2 Hz, 1H), 2.70 (m, 4H), 2.40 – 2.30 (m, 1H), 2.29 – 2.14 (m, 2H), 2.13 – 2.02 (m, 2H), 1.78 (m, 1H), 1.72 – 1.53 (m, 8H), 1.45 (s, 4H), 1.41 – 1.31 (m, 3H), 1.17 (s, 3H), 1.12 (m, 1H), 0.88 (d, J = 6.8 Hz,3H), 0.74 (d, J= 6.8 Hz, 3H).
13 C NMR (100 MHz, CDCl 3 ): δ (ppm) 217.2, 188.4, 169.0, 153.8, 148.8, 143.9, 139.1, 130.5, 130.3, 128.9, 125.5, 117.8, 117.32, 114.9, 113.7, 74.6, 68.5, 59.9, 58.2, 52.6, 47.3, 45.5, 45.1, 44.0, 41.8, 36.7, 36.1, 34.5, 30.5, 26.9, 26.4, 24.9, 16.8, 14.9, 11.6.
In vitro antibacterial Activity Studies of some of the objects of the invention
Experimental methods
Minimum Inhibitory Concentration (MIC) test method
1. Experimental strains: selecting methicillin-resistant staphylococcus aureus (ATCC 33591), methicillin-resistant staphylococcus aureus (ATCC 43300), common strains escherichia coli (ATCC 25922) and staphylococcus aureus (ATCC 25923) as MIC value determination strains.
2. Diluting the medicine: using ethanol and sterile water as solvents, respectively dissolving and diluting the synthetic compound and tiamulin to prepare the tiamulin with the concentration of 1280 mug.mL -1 The mother liquor is placed in a refrigerator to be sealed and stored in dark for standby.
3. Preparing bacterial liquid: activating each test bacterium, selecting monoclonal colony in 0.9% physiological saline, and making into bacterial liquid with concentration of 0.5 McLeod (1.5 × 10) 8 CFU·mL -1 ) Then diluted 10-fold with Mueller-Hinton sterile broth (MHB) for use.
4. Positive control: the known compound 7 with a side chain modified by monophenylpiperazine and tiamulin were selected as positive controls.
5. MIC determination: in the 96-well plate, 100. Mu.L of MHB was added to the wells other than the edge well and the second row of wells, and 160. Mu.L of MHB and 40. Mu.L of the mother liquor were added to the second well, respectively. The compound and the positive control are respectively diluted by a two-fold dilution method to 128-0.25 mu g/mL -1 Adding 10 dilutions with different concentration gradients, adding 100 μ L of bacterial suspension into each well except the edge hole, mixing well, and adding 200 μ L of sterile water into each edge hole. 37 o C, culturing at constant temperature for 18-24 h, observing the growth condition of the tested bacteria, and taking the lowest concentration of the medicament without growth as the MIC value of the medicament to the tested bacteria; taking tiamulin as a positive control, taking an ethanol solution with the same compound concentration as a negative control, performing 3 parallel experiments on each strain of test bacteria, and repeating the experiments for 3 times. The results are shown in Table 1.
Table 1: MIC test results for part of the target
Figure 886422DEST_PATH_IMAGE026
And (4) conclusion: the compound 14c-i shows excellent antibacterial effect on standard drug-resistant strains of staphylococcus aureus, and compared with a positive control tiamulin, the antibacterial activity of the compound is improved by multiple times, wherein the antibacterial effect of the compounds 14c, 14f, 14g, 14h and 14i on four strains is better than that of the positive control tiamulin. In particular, the MICs of the compounds 14h and 14i against two drug-resistant strains of Staphylococcus aureus ATCC33591 and ATCC43300 reach 0.5. Mu.g.mL -1 Is about 16 times higher than tiamulin, and simultaneously the MIC of the tiamulin to gram-positive bacterium Escherichia coli ATCC25922 can reach 1 mu g/mL -1 Is 32 times stronger than tiamulin. In combination with the above results, most of the compounds of the present invention showed excellent antibacterial effects. Can be used for treating bacterial infection caused by Staphylococcus aureus and Escherichia coli.

Claims (5)

1. A compound of formula (I) and pharmaceutically acceptable salts thereof, wherein
Figure 16131DEST_PATH_IMAGE001
A is selected from phenyl, and hydrogen on the phenyl is further optionally substituted by 1 methoxy or NH 2 、NO 2 Or NR A R B Substitution; r is A 、R B Each independently selected from H, methyl or formyl.
2. The compound according to claim 1, wherein the compound is selected from one of the following structures:
Figure 563787DEST_PATH_IMAGE002
Figure 671551DEST_PATH_IMAGE003
Figure 410575DEST_PATH_IMAGE004
Figure 95634DEST_PATH_IMAGE005
Figure 446981DEST_PATH_IMAGE006
Figure 533886DEST_PATH_IMAGE007
Figure 945275DEST_PATH_IMAGE008
Figure 852052DEST_PATH_IMAGE009
Figure 7089DEST_PATH_IMAGE010
。
3. a compound according to any one of claims 1-2, wherein the salt is selected from the group consisting of hydrochloride, fumarate, malate, hydrobromide, succinate, phosphate, methanesulphonate or benzoate, and pharmaceutically acceptable salts thereof.
4. A pharmaceutical composition comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt of any one of claims 1-3, and a pharmaceutically acceptable carrier or excipient.
5. The use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4, for the manufacture of a medicament for the treatment of infectious diseases caused by staphylococcus aureus, escherichia coli.
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