CN110437177A - A kind of pleuromutilin derivative and its preparation method and application - Google Patents
A kind of pleuromutilin derivative and its preparation method and application Download PDFInfo
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- CN110437177A CN110437177A CN201910601978.6A CN201910601978A CN110437177A CN 110437177 A CN110437177 A CN 110437177A CN 201910601978 A CN201910601978 A CN 201910601978A CN 110437177 A CN110437177 A CN 110437177A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The present invention relates to pleuromutilin derivative described in a kind of logical formula (I) and its stereoisomers, pharmaceutically acceptable salt or crystal form, or the pharmaceutical composition comprising them, and their preparation method and intermediate, and in the purposes being used to prepare in antibacterials.Definition described in logical formula (I) is consistent with specification.
Description
Technical field
The present invention relates to pleuromutilin derivative described in a kind of logical formula (I) and its stereoisomer, can pharmaceutically connect
The salt or crystal form received, or the pharmaceutical composition comprising them and their preparation method and intermediate, and be used to prepare
Purposes in antibacterials.
Background technique
The discovery of antibiotic is of great significance in human development history, but now due to clinically long-term extensively abuse
Antibiotic causes bacterial drug resistance to get worse, especially the appearance of " superbacteria ", this constitutes safely human life huge
It is big to threaten.It is reduced year by year and the increasingly increased situation of drug tolerant bacteria to cope with effective antibacterials, there is an urgent need to find one
Effective way is planted to solve this intractable global problem
Pleuromutilin (Pleuromutilin, (formula 1)) is that the one kind separated from higher fungus has good antibacterial
The compound of active tricyclic diterpene class.Studies have shown that pleuromutilin is incorporated in the 23S rRNA of bacterial ribosome 50S subunit
On, it is located in center peptidyl transferase (PTC) of ribosomes 50S subunit by its tricyclic parent nucleus, forms one closely in the site A
Pocket, meanwhile, pendant moiety cover tRNA combination the site P, thus directly inhibition peptide bond formation, to prevent
The synthesis of bacterio protein, exactly this special mechanism of action make it be not easy to other class antibiotic and generate crossing drug resistant
Property.Researcher achieves preferable achievement, such as Tiamulin in the derivative research to its side chain in recent years
(Tamulin, (formula 2)) and valnemulin (Valnemulin, (formula 3)) were successfully approved in 1979 and 1999 respectively
Veterinary antibiotic.Furthermore 1980 Azamulin (Azamulin, (formula 4)) due to entering clinical with outstanding antibacterial effect
Stage, but declared due to the strong inhibition effect and its low oral administration biaavailability and short-half-life to human-cytochrome P450
Come to an end only.GlaxoSmithKline PLC (GlaxoSmithKline) company in 2007 develops his auspicious wonderful woods (Ratapamulin, (formula
5)), this is first for treating the external application pleuromulins antibacterial agent of human skin infection.Lafemulin (BC-
3781, (formula 6)) it is the novel semi-synthetic pleuromutilin antibacterial agent of one kind that Nabriva company develops, it is used for acute bacterial
The treatment of skin and skin structure infection (ABSSSI) and Community-acquired bacterial pneumonia (CABP).The drug is in clinic
Stage shows good safety and tolerance, FDA received in 2 months 2019 the submission of Nabriva company for treating
The lefamulin of CABP takes orally and two kinds of New Drug Application (NDAs) of intravenous formulations.
Pleuromutilin is relatively rapider in veterinary drug development, but the effect in mankind's process also fails to complete body
It is existing.Based on unsatisfied clinical demand, the drug for developing the relatively high antibacterial activity with novel structure, unique mechanism of action is compeled
In the eyebrows and eyelashes.
Summary of the invention
The present invention relates to a kind of structure novel and with the pleuromutilin derivative of good antibacterial activity.
The present invention relates to compound described in a kind of logical formula (I) and its stereoisomers, pharmaceutically acceptable salt, wherein
A is selected from phenyl, and the hydrogen on the phenyl is optionally further selected from H, C by 1-41-4Alkoxy, NH2、NO2Or NRARB
Substituent group replaced；
RA、RBIt is independently selected from H, C1-4Alkyl or-CO-C1-4Alkyl.
Some embodiments of the invention are related to compound and its stereoisomer described in a kind of logical formula (I), can pharmaceutically connect
The salt received, wherein
A is selected from phenyl, and the hydrogen on the phenyl is optionally further by 1-4 H, OCH3、NH2、NO2Or NRARBReplace；
RA、RBIt is independently selected from H, methyl, ethyl, formoxyl or acetyl group.
Some embodiments of the present invention are related to compound and its stereoisomer described in a kind of logical formula (I), pharmaceutically may be used
The salt of receiving, wherein the compound is selected from such as one of flowering structure (Formula II-Formula X):
Some embodiments of the present invention are related to compound described in a kind of logical formula (I) and its stereoisomer, pharmaceutically acceptable
Salt, wherein the salt is selected from hydrochloride, fumarate, malate, hydrobromate, succinate, phosphate, methanesulfonic acid
Salt or benzoate.
Some embodiments of the present invention are related to a kind of pharmaceutical composition, and described pharmaceutical composition contains treatment effective dose
Compound and its stereoisomer of the present invention or pharmaceutically acceptable salt and pharmaceutically acceptable carrier or
Person's excipient.
Some embodiments of the present invention are related to compound and its stereoisomer of the present invention, pharmaceutically acceptable
Salt or pharmaceutical composition of the present invention, in the application being used to prepare in infectious disease medicament.
The above-mentioned application that some embodiments of the present invention are related to, the infectious diseases are selected from by mycoplasma or drug resistance
Microbial infectious diseases.
Specific embodiment
The synthesis of embodiment 1:14a
Step 1: the synthesis of 12a
4- fluoro acetophenone (500.0 mg, 3.6 mmol) and sodium hydroxide (144.8 mg, 3.6 mmol) are dissolved in second
It is placed in alcohol under condition of ice bath and stirs 0.5 h, then above-mentioned mixed solution is added in benzaldehyde (345.7 mg, 3.3 mmol)
In continue to be placed under condition of ice bath, TLC is monitored to fully reacting, is adjusted reaction solution pH to acidity with the hydrochloric acid of 1M, is added appropriate
Water solid is precipitated completely, filter, solid is washed with water, dry, with ethyl alcohol recrystallization to get to 12a (496.3 mg, produce
Rate 67.3%).
Step 2: the synthesis of 13a
By compound 12a (300.0 mg, 1.3 mmol), potassium carbonate (366.5 mg, 2.7 mmol) and piperazine
(228.4 mg, 2.7 mmol), which are dissolved in DMF, is placed in 110oC heating stirring is detected to having reacted to TLC to fully reacting
Entirely, its reaction solution is cooled to room temperature to it and suitable water is added, extract reaction solution with DCM, then organic with water back extraction gained
Phase, anhydrous magnesium sulfate is dry, vacuum distillation, can obtain 13a (252.3 mg, yield 65.1%) through column chromatography for separation purification.
Step 3: the synthesis of 14a
Compound 9 (200.0 mg, 0.4 mmol) and NaI (67.5 mg, 0.5 mmol) are dissolved in acetonitrile and are placed in 75
DEG C 0.5 h of stirring, then by compound 13a (131.7 mg, 0.5 mmol) and potassium carbonate (103.8 mg, 0.8 mmol)
It is added in above-mentioned reaction solution and continues to stir, TLC detection is evaporated under reduced pressure after reaction, and crude product can be obtained through column chromatography for separation purification
14a (145.6 mg, yield 59.4%, fusing point 106.7-108.1 oC)。
1H NMR(400 MHz, CDCl3): 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).
13C NMR (100 MHz, CDCl3): 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.
The synthesis of embodiment 2:14b
Preparation method reference implementation example 1
62.7% fusing point 118.2-119.9 of yieldoC
1H NMR (400 MHz, CDCl3): 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).
13C NMR (100 MHz, CDCl3): 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.
The synthesis of embodiment 3:14c
Preparation method reference implementation example 1
64.5% fusing point 134.5-136.3 of yield oC
1H NMR(400 MHz, CDCl3): 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).
13C NMR(100 MHz, CDCl3): 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.
The synthesis of embodiment 4:14d
Preparation method reference implementation example 1
63.3% fusing point 159.6-161.3 of yieldoC
1H NMR (400 MHz, CDCl3): 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).
13C NMR (100 MHz, CDCl3): 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.
The synthesis of embodiment 5:14e
Preparation method reference implementation example 1
58.5% fusing point 138.6-140.3 of yield oC
1H NMR (400 MHz, CDCl3): 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).
13C NMR (100 MHz, CDCl3): 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.
The synthesis of embodiment 6:14f
Preparation method reference implementation example 1
56.3% fusing point 102.9-104.2 of yield oC
1H NMR (400 MHz, CDCl3): 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).
13C NMR (100 MHz, CDCl3): 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.
The synthesis of embodiment 7:14g
Preparation method reference implementation example 1
57.8% fusing point 106.3-107.8 of yieldoC
1H NMR (400 MHz, CDCl3): 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).
13C NMR (100 MHz, CDCl3): 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.
The synthesis of embodiment 8:14h
Preparation method reference implementation example 1
89.76% fusing point 122.5-124.1 of yieldoC
1H NMR (400 MHz, CDCl3): 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).
13C NMR (100 MHz, CDCl3): 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.
The synthesis of embodiment 9:14i
Preparation method reference implementation example 1
93.4% fusing point 132.5-133.9 of yield oC
1H NMR (400 MHz, CDCl3): 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).
13C NMR (100 MHz, CDCl3): 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.
The antibacterial activity in vitro research of partial target object of the present invention
Experimental method
Minimum inhibitory concentration (MIC) test method
1, methicillin-resistant staphylococcus aureus (ATCC33591) and methicillin-resistant staphylococcus Portugal experimental strain: are chosen
Grape coccus (ATCC43300) and common strain Escherichia coli (ATCC25922) and staphylococcus aureus
(ATCC25923) bacterial strain is measured for MIC value.
2, drug dilution: using ethyl alcohol and sterile water as solvent, dissolving synthesis compound and Tiamulin and dilute respectively,
Being configured to concentration is 1280 μ gmL-1Mother liquor, be placed in refrigerator be protected from light be sealed it is spare.
3, prepared by bacterium solution: taking each tested bacterium to be activated, picking monoclonal colonies match bacterium solution in 0.9% physiological saline
It is set to 0.5 Maxwell concentration (1.5 × 108 CFU·mL-1), the sterile broth bouillon of Mueller-Hinton (MHB) is used afterwards
10 times of dilution is spare.
4, it is right as the positive that known compound 7 and Tiamulin that side chain is modified by single phenylpiperazine positive control: are chosen
According to.
5, MIC is measured: remaining hole is separately added into 100 μ L MHB in addition to edge hole and secondary series hole in 96 orifice plates, to
160 μ L MHB and 40 μ L mother liquors are added in second hole.Compound and positive control are diluted respectively using doubling dilution,
It is diluted to 128-0.25 μ gmL altogether-1The dilution of 10 various concentration gradients, then 100 are added to hole every in addition to edge hole
μ L bacterium supernatant liquid, mixes well, and 200 μ L of sterile water finally is added to the every hole of edge hole.37o18-24 h of C constant temperature incubation, observation
The growing state of tested bacterium is MIC value of the medicine to the tested bacterium with the drug minimum concentration of no growth；It is sun with Tiamulin
Property control, to prepare the equivalent ethanol solution of compound concentration as negative control, every plant of tested bacterium carries out 3 parallel laboratory tests, real
It tests and is repeated 3 times.Experimental result is shown in Table 1.
Table 1: partial target object MIC test result
Conclusion: compound 14c-i shows excellent antibacterial effect to staphylococcus aureus standard persister, with the positive
Control Tiamulin compare, the antibacterial activity of the compounds of this invention has all obtained the raising of several times, wherein compound 14c, 14f,
14g, 14h and 14i are superior to positive control Tiamulin to the antibacterial effect of four kinds of bacterial strains.Especially compound 14h and 14i pairs
The MIC of the antibody-resistant bacterium ATCC33591 and ATCC43300 of two kinds of staphylococcus aureuses reach 0.5 μ gmL-1, more wonderful than safe
Rhzomorph is about 16 times high, while can reach 1 μ gmL to the MIC of gram-positive bacteria Escherichia coli ATCC25922-1, than safe wonderful bacterium
Element is 32 times strong.Based on the above results, the compound in the present invention shows good antibacterial effect mostly.It is expected treatment by gold
Bacterium infection caused by staphylococcus aureus and Escherichia coli.
Claims (7)
1. compound described in a kind of logical formula (I) and its stereoisomer, pharmaceutically acceptable salt, wherein
A is selected from phenyl, and the hydrogen on the phenyl is optionally further selected from H, C by 1-41-4Alkoxy, NH2、NO2Or NRARB's
Replaced substituent group；RA、RBIt is independently selected from H, C1-4Alkyl or-CO-C1-4Alkyl.
2. compound according to claim 1 and its stereoisomer, pharmaceutically acceptable salt, in which: A is selected from benzene
Base, the hydrogen on the phenyl is optionally further by 1-4 H, methoxyl group, NH2、NO2Or NRARBReplace；RA、RBIt is independent
Selected from H, methyl, ethyl, formoxyl or acetyl group.
3. compound according to claim 2 and its stereoisomer, pharmaceutically acceptable salt, wherein the compound selects
One of flowering structure freely:
。
4. compound and its stereoisomer, pharmaceutically acceptable salt according to claim 1 to 3, wherein
The salt is selected from hydrochloride, fumarate, malate, hydrobromate, succinate, phosphate, mesylate or benzene first
Hydrochlorate.
5. a kind of pharmaceutical composition, described pharmaceutical composition contains described in any one of claim 1-4 for the treatment of effective dose
Compound and its stereoisomer or pharmaceutically acceptable salt and pharmaceutically acceptable carrier or excipient.
6. compound described in claim 1-4 any one and its stereoisomer, pharmaceutically acceptable salt or right
It is required that pharmaceutical composition described in 5, in the application being used to prepare in infectious disease medicament.
7. application according to claim 6, the infectious diseases is selected to be infected as caused by mycoplasma or drug-fast bacteria
Property disease.
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| US20050143393A1 (en) * | 2000-11-11 | 2005-06-30 | Dean David K. | Pleuromutilin derivatives with antimicrobial activity |
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| US20050143393A1 (en) * | 2000-11-11 | 2005-06-30 | Dean David K. | Pleuromutilin derivatives with antimicrobial activity |
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