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CN112898346B - Water-soluble polycyclic compounds, pharmaceutical compositions and uses thereof - Google Patents

Water-soluble polycyclic compounds, pharmaceutical compositions and uses thereof Download PDF

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CN112898346B
CN112898346B CN202110092671.5A CN202110092671A CN112898346B CN 112898346 B CN112898346 B CN 112898346B CN 202110092671 A CN202110092671 A CN 202110092671A CN 112898346 B CN112898346 B CN 112898346B
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CN112898346A (en
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张哲峰
请求不公布姓名
侯雯
李海德
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Nanjing Zhihe Medical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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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Abstract

The application discloses a water-soluble polycyclic compound, a pharmaceutical composition and application thereof, wherein the water-soluble polycyclic compound is shown as a formula (I), and the definition of each group is shown in the specification; the compound has effect in inhibiting influenza virus, and can be used for resisting influenza virus infection.

Description

Water-soluble polycyclic compounds, pharmaceutical compositions and uses thereof
Technical Field
The application relates to the technical field of pharmaceutical chemistry, in particular to a water-soluble polycyclic compound, a pharmaceutical composition and application thereof.
Background
Balo Sha Weizhi (baloxavir marboxil), trade name Xofluza TM The first single dose oral antiviral drug developed by salt wild pharmaceutical corporation was approved for sale in japan and the united states, respectively, in 2018.
Chinese patent CN103228653B discloses balofluo Sha Wei ester compounds having the chemical structure:
the medicine has inhibiting effect on viral cap dependent endonuclease, and can inhibit synthesis of viral protein by inhibiting synthesis of influenza virus mRNA, and finally inhibit virus proliferation.
Because influenza viruses are prone to developing resistance, there remains a need in the art for the development of highly effective or novel structural anti-influenza virus drugs.
Disclosure of Invention
The present inventors have developed a water-soluble polycyclic compound having an antiviral effect.
In one aspect, the present application provides a water-soluble polycyclic compound, tautomer, stereoisomer, or solvate thereof, as shown in (I):
in the formula (I), M 1 Is hydrogen, or alkali metal ion, or 1/2 alkaline earth metal ion, or 1/2 zinc ion, or ammonium;
M 2 is hydrogen, or alkali metal ion, or 1/2 alkaline earth metal ion, or 1/2 zinc ion, or ammonium;
l is- (CH) 2 ) n1 -(O-CH 2 ) n2 -or-O- (CH) 2 ) n1 -(O-CH 2 ) n2 -where n1 is 0, or 1, or 2; n2 is 0, or 1, or 2, or 3, or 4.
In an embodiment of the present application, the water-soluble polycyclic compound provided by the present application is represented by formula (II):
the definition of the substituent in the formula (II) is defined as the formula (I).
In an embodiment of the application, the ammonium comprises the following protonates of tromethamine, triethanolamine, triethylamine, arginine, lysine, ethanolamine, or N-methylglucamine.
In an embodiment of the present application, the alkali metal ions include lithium ions, sodium ions, and potassium ions.
In an embodiment of the present application, the alkaline earth metal ions include magnesium ions, calcium ions.
In some embodiments, M 1 Hydrogen, or sodium ion, or potassium ion, or ammonium; m is M 2 Is hydrogen, or sodium ion, or potassium ion, or ammonium.
In some embodiments, M 1 Is 1/2 alkaline earth metal ion, or 1/2Zinc ions; m is M 2 Is 1/2 alkaline earth metal ion, or 1/2 zinc ion.
In some embodiments, M 1 Is hydrogen; m is M 2 Is hydrogen.
In some embodiments, M 1 Is hydrogen, or sodium ion; m is M 2 Is sodium ion.
In some embodiments, M 1 Is sodium ion; m is M 2 Is sodium ion.
In some embodiments, M 1 Hydrogen, or potassium ions; m is M 2 Is potassium ion.
In some embodiments, M 1 Is potassium ion; m is M 2 Is potassium ion.
In some embodiments, L is- (CH) 2 ) n1 -(O-CH 2 ) n2 -where n1 is 0, or 1; n2 is 0, or 1, or 2.
In some embodiments, L is- (CH) 2 ) n1 -(O-CH 2 ) n2 -where n1 is 0; n2 is 0, or 1, or 2.
In some embodiments, L is- (CH) 2 ) n1 -(O-CH 2 ) n2 -where n1 is 1; n2 is 0, or 1, or 2.
In some embodiments, L is-O- (CH) 2 ) n1 -(O-CH 2 ) n2 -where n1 is 2; n2 is 0, or 1, or 2.
In some embodiments, the present application provides the above water-soluble polycyclic compound selected from the following compounds:
or the monosodium, disodium, monopotassium or dipotassium salt or 1/2 zinc salt of the above compound.
In another aspect, the present application provides pharmaceutical compositions comprising the above water-soluble polycyclic compounds, tautomers, stereoisomers, and solvates thereof.
The application discloses a pharmaceutical composition, which is composed of the compound, isomer or solvate thereof of the application as an active ingredient or a main active ingredient and a pharmaceutically acceptable carrier.
In a third aspect, the present application also provides a process for preparing a water-soluble polycyclic compound represented by formula (I), the process comprising the steps of:
the substituents referred to in the above schemes are as defined for the corresponding groups in formula (I).
In the preparation route of the present application, the compounds of formula (III) can be synthesized according to the prior art.
In a fourth aspect, the present application provides the use of the water-soluble polycyclic compounds, tautomers, stereoisomers, and pharmaceutically acceptable salts thereof, as described above, for the anti-influenza virus treatment and/or prophylaxis of diseases caused by influenza virus.
The water-soluble polycyclic compounds of the present application may be formulated as pharmaceutical compositions for administration to a patient in a variety of suitably selected modes of administration, including systemic, e.g., oral or parenteral, by intravenous, intramuscular, transdermal or subcutaneous, and the like.
In some embodiments of the present application, the water-soluble polycyclic compound of the present application, lactose and calcium stearate are mixed, crushed, granulated and dried to produce granules of suitable size. Then, calcium stearate is added, and compression molding is performed to prepare tablets.
In some examples of the present application, the water-soluble polycyclic compound of the present application, lactose and microcrystalline cellulose are mixed, granulated, and tableted to prepare an orally disintegrating tablet.
In some embodiments of the application, the water-soluble polycyclic compound of the application and phosphate buffer are mixed to prepare an injection.
In some examples of the present application, the water-soluble polycyclic compound of the present application and lactose are mixed and pulverized, thereby producing an inhalant.
Definition:
forms part of the present application are pharmaceutically acceptable solvates which may be crystalline hydrates or with other solvents such as ethanol and the like.
The water-soluble polycyclic compound has an inhibitory effect on viruses and inhibits the proliferation of the viruses. The water-soluble polycyclic compound can be used as an antiviral drug with a novel structure.
In some embodiments of the application, the use of the water-soluble polycyclic compounds of the application in the preparation of anti-influenza virus drugs; in some specific embodiments, the influenza virus of the present application is an influenza a virus.
Detailed Description
The following examples will allow one skilled in the art to more fully understand the application, but are not intended to limit the application in any way, all compounds having the structure shown in the figures via MS, 1 H-NMR determination.
Example 1
Step 1: synthesis of Compound 2
3.64 g of triethyl phosphate, 8.46 g of trifluoromethanesulfonic anhydride, 3.16 g of pyridine and 150 ml of dichloromethane are added into a reaction bottle, and after the reaction is carried out for 0.5 hour at room temperature by stirring, 13.46 g of compound 1 is added into the system, and the reaction is continued for 5 hours. The system was concentrated to dryness, crystallized from ethyl acetate and petroleum ether and filtered to give compound 2 about 8.52 g, yield 45%, MS: m/z474.13[ M+H ]] + 。
Step 2: synthesis of Compound 3
8g of compound 2 and 35 ml of dichloromethane are added into a reaction bottle, 16 ml of trifluoroacetic acid is added dropwise under stirring at room temperature, and the temperature is not higher than 30 ℃. After 3 hours at room temperature, the system was concentrated to dryness and crystallized from ethyl acetate and petroleum ether to give 5.55 g of compound 3 in 88% yield, MS: m/z374.13[ M+H ]] + 。
Step 3: synthesis of Compound 4
Under the protection of nitrogen, 5 g of a compound 3,3.54 g of a compound INT-1 and 3.86 g of triphenylphosphine are added into a reaction bottle, 60 ml of dichloromethane is added into the system, the temperature of the system is reduced to below 5 ℃,3 g of DIAD is added, the system is slowly warmed to room temperature and stirred for 12 hours, the system is concentrated to dryness, about 40 ml of ethanol aqueous solution (ethanol: water=1:2, volume ratio) is used for pulping and filtering to obtain a crude product, and 6.72 g of a compound 4 is obtained by crystallizing the crude product by ethyl acetate and petroleum ether, the yield is 81 percent, MS: m/z620.14[ M+H ]] + 。
Step 4: synthesis of Compound DSC701
Under the protection of nitrogen, 5 g of compound 4 and 100 ml of anhydrous dichloromethane are added into a reaction bottle, 9.88 g of trimethyl bromosilane is added dropwise under the condition that the system is stirred at room temperature, and the temperature is maintained to be not higher than 30 ℃. After the completion of the reaction, the system was stirred at room temperature for 48 hours until the reaction was completed. The system was slowly added dropwise with 20 ml of water and 20 ml of methanol and stirring was continued at room temperature for 30 minutes. The system was concentrated to dryness and isopropanol and water were added to crystallize to give 3.82 g of product DSC701 in 84% yield, MS: m/z564.19[ M+H ]] + ，562.20[M-H] - ，1H-NMR(D2O)δ：2.92-3.18(1H，t)，3.33(2H，s)，3.41-3.46(1H，t)，3.55-3.60(1H，t)，3.67-3.75(1H，d)，3.88-3.92(1H，d)，4.03-4.08(1H，d)，4.22-4.43(1H，m)，4.47-4.55(1H，m)，5.42-5.46(1H，d)，5.55(1H，s)，5.85-5.88(1H，d)，6.77-6.98(2H，m)，7.00-7.32(4H，m)，7.45-7.50(1H，s)。
Example 2
Step 1: synthesis of Compound 9
6.75 g of Compound 1 and 2.08 g of magnesium ethoxide are introduced into a reaction flask, 50 ml of DMF is added, and the system is reacted at 70℃for 1 hour. 12.89 g of diethyl p-toluenesulfonyloxymethyl phosphonate was added at 70℃and the reaction was continued at 70℃for 8 hours. The system is added with water for crystallization and filtration to obtain crude product, which is crystallized by ethyl acetate and petroleum ether and filtered to obtain compound 9 with the yield of about 8.87 g, the yield of 91 percent, MS: m/z488.20[ M+H ]] + 。
Step 2: synthesis of Compound 10
8.5 g of compound 9 and 35 ml of dichloromethane are added into a reaction bottle, 17 ml of trifluoroacetic acid is added dropwise under stirring at room temperature, and the temperature is not higher than 30 ℃. After 3 hours at room temperature, the system was concentrated to dryness and crystallized from ethyl acetate and petroleum ether to give 5.74 g of compound 10 in 85% yield, MS: m/z388.71[ M+H ]] + 。
Step 3: synthesis of Compound 11
Under the protection of nitrogen, 5 g of a compound 10,3.41 g of a compound INT-1 and 3.72 g of triphenylphosphine are added into a reaction bottle, 50 ml of dichloromethane is added into the system, the temperature of the system is reduced to below 5 ℃, 2.89 g of DIAD is added, the system is slowly warmed to room temperature and stirred for 12 hours, the system is concentrated to dryness, about 40 ml of ethanol aqueous solution (ethanol: water=1:2, volume ratio) is used for pulping and filtering to obtain a crude product, and 6.54 g of a compound 11 is obtained by crystallizing the crude product by using ethyl acetate and petroleum ether, the yield is 80 percent, MS: m/z634.15[ M+H ]] + 。
Step 4: synthesis of Compound 703
Under the protection of nitrogen, 5 g of compound 11 and 100 ml of anhydrous dichloromethane are added into a reaction bottle, 9.66 g of trimethyl bromosilane is added dropwise under the condition that the system is stirred at room temperature, and the humidity is maintained to be not higher than 30 ℃. After the completion of the reaction, the system was stirred at room temperature for 48 hours until the reaction was completed. The system was slowly added dropwise with 20 ml of water and 20 ml of methanol and stirring was continued at room temperature for 30 minutes. The system was concentrated to dryness and isopropanol and water were added to crystallize to give 3.65 g of product DSC703 in 81% yield, MS: m/z578.09[ M+H ]] + ，576.22[M-H] - ， 1 H-NMR(D2O)δ：2.95-3.22(1H，t)，3.31(2H，s)，3.43-3.48(1H，t)，3.58-3.63(1H，t)，3.67-3.77(1H，d)，3.86-3.90(2H，m)，4.02-4.07(1H，d)，4.12(1H，dd)，4.24-4.46(1H，m)，4.45-4.56(1H，m)，5.42-5.44(1H，d)，5.58(1H，s)，5.84-5.87(1H，d)，6.73-6.98(2H，m)，7.03-7.30(4H，m)，7.41-7.48(1H，s)。
Example 3: synthesis of DSC711
Referring to a procedure analogous to the above route synthesis, 770mg of compound DSC711, HPLC:96.55; MS: m/z608.29[ M+H ]] + ，606.20[M-H] - ；1H-NMR(D2O)δ：2.95-3.22(1H，t)，3.31(2H，s)，3.44-3.48(1H，t)，3.57-3.62(1H，t)，3.66-3.75(1H，d)，3.88-3.92(1H，d)，4.03-4.09(1H，d)，4.21-4.41(3H，m)，4.46-4.59(3H，m)，5.43-5.48(1H，d)，5.52(1H，s)，5.82-5.88(1H，d)，6.76-6.93(2H，m)，7.02-7.34(4H，m)，7.48-7.51(1H，s)；
The following examples can also be synthesized by the same method as the above examples, using a commercially available compound or an intermediate compound appropriately synthesized from a commercially available compound.
Example 4: synthesis of DSC701 phosphate:
2 g of DSC701 and 20 ml of ethanol are added into a reaction bottle to be dissolved, 50% sodium hydroxide aqueous solution is added dropwise into the system at room temperature, the pH value is adjusted, a large amount of solid is precipitated, and the system is filtered, so that the monosodium phosphate salt of DSC701 (the salt is easy to dissolve in water and the solubility in purified water is more than 0.1 g/ml) can be obtained.
Example 5: synthesis of DSC711 zinc phosphate salt:
2 g DSC711 and 40 ml water are added into a reaction bottle, 330mg zinc hydroxide is added into the system at the temperature of 60 ℃, stirring is continued for 30 minutes under the heating condition, the system is concentrated to remove most of the water, 2.38g of zinc phosphate salt of DSC711 can be obtained after freeze-drying, and the yield is 107 (containing part of crystal water), (the salt is easy to dissolve in water, and the solubility in purified water is more than 0.1 g/ml).
Example 6: solubility test of Compounds in Water
The organisms were tested for their solubility in water according to the pharmacopoeia 2020 edition method: 1.0000g of the test sample ground into fine powder is weighed, added into water with a certain volume at 15+/-2 ℃, shaken vigorously for 30 seconds every 5 minutes, and the dissolution condition within 30 minutes is observed, and if no solute particles are visible, the test sample is regarded as complete dissolution, and each group of laboratories is repeated three times. The result shows that the novel compound synthesized by the application has better water solubility, wherein the water solubility of phosphate is greater than that of phosphate compound, and the water solubility of phosphate compound is greater than that of Yu Baluo Sha Weizhi (baloxavir marboxil);
example 7: in vitro anti-influenza virus activity screening
The test principle is as follows: MDCK (canine kidney) cells were used as virus hosts, and the degree of cytopathic effect (CPE) caused by the inhibitory viruses of the samples was determined.
Virus strain: influenza A/han-defenses/359/95 (H3N 2), stored at 80 ℃.
Sample treatment: samples were made up with DMSO as stock solution and then 3-fold diluted with culture medium, 8 dilutions each.
The testing method comprises the following steps: MDCK cells are inoculated into 96-hole culture plates and placed with 5% CO 2 Culturing at 37 ℃. After 24 hours, 1/210-5 of influenza virus is infected, the virus solution is removed after adsorption for 2 hours, a maintenance solution containing samples with different dilutions is added, and a cell control hole and a virus control hole are simultaneously arranged, and 5% CO is added 2 Culturing at 37 ℃. Observing cytopathic degrees (CPE) of each group when the virus control group has a pathological degree (CPE) of 4+, and calculating half-Toxic Concentration (TC) of the sample on cells by using a Reed-Muench method 50 ) And half-maximal Inhibitory Concentration (IC) against virus 50 )。
TABLE 1 screening for anti-influenza Virus Activity
Example 8: metabolic assays of SD rats injected with DSC703, DSC711 and baluo Sha Weizhi
Male SD rats were cannulated for jugular vein and the experiment was started three days later, with 3 groups of 3 animals each based on animal body weight measured on the day prior to dosing. Three compounds (DSC 703, DSC711 and Ballon Sha Weizhi, 1.88mg/kg based on Ballon Sha Weizhi) were administered by injection, respectively, with 5.447 ml5% DMSO:30% peg400: the solvent 65% H2O was dissolved and vortexed to give a clear solution which was filtered through a 0.22 μm filter. Before and after administration, 0.033, 0.083, 0.17, 0.25, 0.5, 1, 2, 4, 8, 24hr, about 0.25mL of whole blood was taken from the jugular vein in K2EDTA anticoagulant tubes. After all time points are taken out, the rat is cervical and sacrificed after CO2 asphyxiation. The blood samples were centrifuged at 3000rpm at 4℃for 5 minutes within 1 hour after collection. Transferring the centrifugally collected plasma to a new labeled centrifuge tube, temporarily storing in a refrigerator at-20 ℃, and after all samples are collected, delivering the collected plasma to a biological sample manager and storing in the refrigerator at-80 ℃. 50. Mu.L of plasma sample, 5. Mu.L of diluent, 200. Mu.L of precipitant containing internal standard carbamazepine (100 ng/mL), vortexing for 5min, centrifuging at 4500rpm for 15min, adding 50. Mu.L of supernatant to 100. Mu.L of pure water, and injecting 10.0. Mu.L. The experimental data were statistically described using Microsoft EXCEL using mean and Standard Deviation (SD). The results were as follows:
TABLE 2 concentration of Ballon Sha Wei in plasma after intravenous injection of sample DSC703 in Male SD rats (ng/mL)
TABLE 3 concentration of Ballon Sha Wei in plasma after intravenous sample DSC711 in Male SD rats (ng/mL)
TABLE 4 concentration of Ballo Sha Wei in plasma after intravenous injection of sample Ballo Sha Weizhi in Male SD rats (ng/mL)
NC: not calculated, cannot be calculated.
As can be seen from table 4, balo Sha Weizhi is rapidly converted to balo Sha Wei following administration by injection, but as can be seen from tables 2 and 3, little or no balo Sha Wei is detected within 24 hours after administration by injection of compounds DSC703 and DSC711, indicating that compounds DSC703 and DSC711 are not metabolized to balo Sha Wei;
taken together, it can be seen that the compounds of the present application have good water solubility and better antiviral activity than balo Sha Weizhi, and are not metabolized to balo Sha Wei in vivo.
The present application has been described in terms of several embodiments, but the description is illustrative and not restrictive, and it will be apparent to those of ordinary skill in the art that many more embodiments and implementations are possible within the scope of the described embodiments.

Claims (3)

1. A water-soluble polycyclic compound selected from the following compounds:
or the monosodium, disodium, monopotassium or dipotassium salt or 1/2 zinc salt of the above compound.
2. A pharmaceutical composition comprising the water-soluble polycyclic compound of claim 1, and a monosodium salt, a disodium salt, a monopotassium salt or dipotassium salt or a 1/2 zinc salt thereof.
3. Use of the water-soluble polycyclic compound according to claim 1 and its monosodium salt, disodium salt, monopotassium salt or dipotassium salt or 1/2 zinc salt, or the pharmaceutical composition according to claim 2 in the preparation of a medicament for anti-influenza virus.
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WO2024098273A1 (en) * 2022-11-09 2024-05-16 石家庄迪斯凯威医药科技有限公司 Anti-influenza virus phosphate ester compound and use thereof
CN116284048B (en) * 2023-05-18 2023-08-15 长沙晶易医药科技股份有限公司 Compound and preparation method, pharmaceutical composition and application thereof

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