CN112898346A - Water-soluble polycyclic compound, and pharmaceutical composition and application thereof - Google Patents

Water-soluble polycyclic compound, and pharmaceutical composition and application thereof Download PDF

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CN112898346A
CN112898346A CN202110092671.5A CN202110092671A CN112898346A CN 112898346 A CN112898346 A CN 112898346A CN 202110092671 A CN202110092671 A CN 202110092671A CN 112898346 A CN112898346 A CN 112898346A
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CN112898346B (en
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张哲峰
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 System
    • 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

Abstract

The invention 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 detailed in the specification; the compound has inhibitory effect on influenza virus, and can be used for resisting influenza virus infection.

Description

Water-soluble polycyclic compound, and pharmaceutical composition and application thereof
Technical Field
The invention relates to but is not limited to the technical field of pharmaceutical chemistry, and particularly relates to a water-soluble polycyclic compound, a pharmaceutical composition and application thereof.
Background
Baroxavir disoproxil (baloxavir marboxil), trade name XofluzaTMIs the first single-dose oral administration developed by Yanye pharmaceutical corporationAntiviral drugs, approved for marketing in japan and the united states in 2018, respectively.
Chinese patent CN103228653B discloses a baroxavir ester compound, whose chemical structure is:
Figure BDA0002913275350000011
the medicine has inhibitory effect on virus cap-dependent endonuclease, and can inhibit synthesis of virus protein by inhibiting synthesis of influenza virus mRNA, and finally inhibit virus proliferation.
Because influenza viruses are susceptible to drug resistance, there is still a need in the art to develop 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 invention provides a water-soluble polycyclic compound, tautomer, stereoisomer, or solvate thereof, represented by (I):
Figure BDA0002913275350000021
in the formula (I), M1Is hydrogen, or an alkali metal ion, or 1/2 an alkaline earth metal ion, or 1/2 a zinc ion or ammonium;
M2is hydrogen, or an alkali metal ion, or 1/2 an alkaline earth metal ion, or 1/2 a zinc ion or ammonium;
l is- (CH)2)n1-(O-CH2)n2-or-O- (CH)2)n1-(O-CH2)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 invention, the present invention provides a water-soluble polycyclic compound represented by formula (II):
Figure BDA0002913275350000022
the definition of the substituents in formula (II) is as defined for formula (I).
In embodiments herein, the ammonium includes the following protonates of tromethamine, triethanolamine, triethylamine, arginine, lysine, ethanolamine, or N-methylglucamine.
In embodiments herein, the alkali metal ions include lithium ions, sodium ions, and potassium ions.
In embodiments herein, the alkaline earth metal ions include magnesium ions, calcium ions.
In some embodiments, M1Is hydrogen, or sodium ion, or potassium ion, or ammonium; m2Is hydrogen, or sodium ion, or potassium ion, or ammonium.
In some embodiments, M11/2 alkaline earth metal ions, or 1/2 zinc ions; m21/2 alkaline earth metal ions, or 1/2 zinc ions.
In some embodiments, M1Is hydrogen; m2Is hydrogen.
In some embodiments, M1Is hydrogen, or sodium ion; m2Is a sodium ion.
In some embodiments, M1Is a sodium ion; m2Is a sodium ion.
In some embodiments, M1Is hydrogen, or potassium ion; m2Is a potassium ion.
In some embodiments, M1Is a potassium ion; m2Is a potassium ion.
In some embodiments, L is- (CH)2)n1-(O-CH2)n2-, where n1 is 0, or 1; n2 is 0, or 1, or 2.
In some embodiments, L is- (CH)2)n1-(O-CH2)n2-, where n1 is 0; n2 is 0, or 1, or 2.
In some embodiments, L is- (CH)2)n1-(O-CH2)n2-，Where n1 is 1; n2 is 0, or 1, or 2.
In some embodiments, L is-O- (CH)2)n1-(O-CH2)n2-, where n1 is 2; n2 is 0, or 1, or 2.
In some embodiments, the present invention provides the above water-soluble polycyclic compound selected from the group consisting of:
Figure BDA0002913275350000031
Figure BDA0002913275350000041
or the mono-sodium salt, di-sodium salt, mono-potassium salt or di-potassium salt of the above compounds or 1/2 zinc salt.
In another aspect, the present invention provides a pharmaceutical composition comprising the above water-soluble polycyclic compound, tautomer, stereoisomer, and solvate thereof.
The invention discloses a pharmaceutical composition, which is prepared from the compound, isomer or solvate thereof as an active ingredient or a main active ingredient and a pharmaceutically acceptable carrier.
In a third aspect, the present invention also provides a route for the preparation of a water-soluble polycyclic compound of formula (I), the route comprising the steps of:
Figure BDA0002913275350000042
the substituents referred to in the above schemes are defined as for the corresponding groups in formula (I).
In the preparation routes of the present application, the compounds of formula (III) can be synthesized according to the prior art.
In a fourth aspect, the present invention provides the above water-soluble polycyclic compounds, tautomers, stereoisomers, and pharmaceutically acceptable salts thereof, which are useful against influenza virus, for treating and/or preventing diseases caused by influenza virus.
The water-soluble polycyclic compounds of the present invention may be formulated as pharmaceutical compositions for administration to a patient in accordance with a variety of suitably selected modes of administration, including systemically, e.g., orally or parenterally, intravenously, intramuscularly, transdermally, or subcutaneously, and the like.
In some embodiments of the invention, the water-soluble polycyclic compound of the invention, lactose and calcium stearate are mixed, milled, granulated and dried to form granules of suitable size. Then, calcium stearate was added thereto, and compression molding was performed to prepare a tablet.
In some embodiments of the invention, the orally disintegrating tablet is prepared by mixing the water-soluble polycyclic compound of the present invention, lactose and microcrystalline cellulose, granulating, and tabletting.
In some embodiments of the invention, the water-soluble polycyclic compound of the invention is mixed with a phosphate buffer to form an injection.
In some embodiments of the present invention, the water-soluble polycyclic compound of the present invention and lactose are mixed and pulverized to prepare an inhalant.
Defining:
the invention is also directed to a pharmaceutically acceptable solvate, which may be a crystalline hydrate or a crystalline form with other solvents, such as ethanol.
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 invention, the use of a water-soluble polycyclic compound of the invention in the preparation of a medicament against influenza virus; in some specific embodiments, the influenza virus of the present invention is an influenza a virus.
Detailed Description
The following examples will allow one skilled in the art to more fully understand the present invention, but without limiting it in any way, all structures of the compounds are described by MS,1H-NMR determination.
Example 1
Figure BDA0002913275350000061
Step 1: synthesis of Compound 2
Figure BDA0002913275350000062
3.64 g of triethyl phosphate, 8.46 g of trifluoromethanesulfonic anhydride, 3.16 g of pyridine and 150 ml of dichloromethane were added to a reaction flask, and after the reaction was stirred at room temperature for 0.5 hour, 13.46 g of Compound 1 was added to the system, and the reaction was continued for 5 hours. The system was concentrated to dryness, crystallized from ethyl acetate and petroleum ether, filtered to give compound 2, about 8.52 g, 45% yield, MS: m/z474.13[ M + H ]]+。
Step 2: synthesis of Compound 3
Figure BDA0002913275350000063
8g of compound 2 and 35 ml of dichloromethane are added into a reaction bottle, and 16 ml of trifluoroacetic acid is added dropwise into the system while stirring at room temperature, wherein the temperature is not higher than 30 ℃. After 3 hours reaction 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, yield 88%, MS: m/z374.13[ M + H ]]+。
And step 3: synthesis of Compound 4
Figure BDA0002913275350000071
Adding 5 g of compound 3, 3.54 g of compound INT-1 and 3.86 g of triphenyl phosphorus into a reaction bottle under the protection of nitrogen, adding 60 ml of dichloromethane into the system, cooling the system to below 5 ℃, adding 3 g of DIAD, slowly raising the temperature to room temperature, stirring for 12 hours, concentrating the system to dryness, and adding an ethanol aqueous solution (ethanol: water is 1: 2, volume: volume)Volume ratio) about 40 ml of slurry is filtered to obtain a crude product, the crude product is crystallized by ethyl acetate and petroleum ether to obtain 6.72 g of compound 4, the yield is 81%, and the mass ratio of MS: m/z620.14[ M + H ]]+。
And 4, step 4: synthesis of Compound DSC701
Figure BDA0002913275350000072
Under the protection of nitrogen, 5 g of compound 4 and 100 ml of anhydrous dichloromethane are added into a reaction bottle, and 9.88 g of trimethyl bromosilane is dropwise added into the system under stirring at room temperature, and the temperature is maintained to be not higher than 30 ℃. The system is stirred for 48 hours at room temperature after the dripping is finished until the reaction is finished. 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 crystallized by the addition of isopropanol and water 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
Figure BDA0002913275350000081
Step 1: synthesis of Compound 9
Figure BDA0002913275350000082
6.75 g of Compound 1 and 2.08 g of magnesium ethoxide were added to a reaction flask, and 50 ml of DMF was added to the reaction flask, and the reaction was carried out at 70 ℃ for 1 hour. 12.89 g of diethyl p-toluenesulfonyloxymethylphosphonate was added at 70 ℃ and the reaction was continued at 70 ℃ for 8 hours. Adding water into the system for crystallization and filtration to obtain a crude product, crystallizing the crude product by using ethyl acetate and petroleum ether, and filtering to obtain a compound 9 of about 8.87 g,yield 91%, MS: m/z488.20[ M + H ]]+。
Step 2: synthesis of Compound 10
Figure BDA0002913275350000091
8.5 g of compound 9 and 35 ml of dichloromethane were added to a reaction flask, and 17 ml of trifluoroacetic acid was added dropwise to the system with stirring at room temperature of not higher than 30 ℃. After 3 hours reaction 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 ]]+。
And step 3: synthesis of Compound 11
Figure BDA0002913275350000092
Under the protection of nitrogen, 5 g of compound 10, 3.41 g of 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 system is cooled to below 5 ℃, 2.89 g of DIAD is added, the mixture is slowly heated to room temperature and stirred for 12 hours, the system is concentrated to be dry, about 40 ml of ethanol aqueous solution (ethanol: water is 1: 2, volume ratio) is used for pulping and filtering to obtain crude product, and the crude product is crystallized by ethyl acetate and petroleum ether to obtain 6.54 g of compound 11, the yield is 80%, and MS: m/z634.15[ M + H ]]+。
And 4, step 4: synthesis of Compound 703
Figure BDA0002913275350000101
Under the protection of nitrogen, 5 g of compound 11 and 100 ml of anhydrous dichloromethane are added into a reaction bottle, and 9.66 g of trimethyl bromosilane is dropwise added into the system under stirring at room temperature, and the humidity is maintained to be not higher than 30 ℃. The system is stirred for 48 hours at room temperature after the dripping is finished until the reaction is finished. 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 is concentrated to be dry, isopropanol and water are added for crystallization to obtain 3.65 g of DSC703 product with the yield of 81 percent,MS：m/z578.09[M+H]+，576.22[M-H]-，1H-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
Figure BDA0002913275350000102
Referring to a method analogous to the synthesis of the above route, 770mg of compound DSC711 is synthesized, HPLC: 96.55 parts; 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 compounds of the following examples can also be synthesized by the same method as in the above examples, using commercially available compounds or intermediate compounds appropriately synthesized from commercially available compounds.
Figure BDA0002913275350000111
Example 4: synthesis of DSC701 phosphate:
2 g of DSC701 and 20 ml of ethanol are added into a reaction bottle for dissolution, 50% sodium hydroxide aqueous solution is dripped into the system at room temperature, the pH value is adjusted, a large amount of solid is precipitated, and the system is filtered to obtain the monosodium phosphate of the DSC701 (the monosodium phosphate is easily dissolved in water, and the solubility in purified water is more than 0.1 g/ml).
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 when the system is heated to 60 ℃, the stirring is continued for 30 minutes under the heating condition, the system is concentrated to remove most of the water, and then the zinc phosphate salt of DSC711 can be obtained by freeze-drying, 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 testing of Compounds in Water
The solubility of organisms in water was tested according to the pharmacopoeia 2020 edition method: weighing 1.0000g of the test sample ground into fine powder, adding the test sample into water with a certain volume at 15 +/-2 ℃, strongly shaking for 30 seconds every 5 minutes, observing the dissolution condition within 30 minutes, and if no visible solute particles exist, determining that the test sample is completely dissolved, and repeating the test sample for three times in each group of laboratories. The results show that the novel compound synthesized by the invention 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 baloxavir (baloxavir marboxil);
example 7: in vitro anti-influenza virus activity screening
The test principle is as follows: MDCK (dog kidney) cells are taken as virus hosts, and the degree of cytopathic effect (CPE) caused by virus inhibition of the samples is determined.
Virus strain: influenza A/hanfang/359/95 (H3N2) and storage at-80 deg.C.
Sample treatment: samples were made up as stock solutions in DMSO, and then diluted 3-fold with culture medium, 8 dilutions each.
The test method comprises the following steps: inoculating MDCK cells into 96-well culture plate, and placing 5% CO2And cultured at 37 ℃. Infecting influenza virus 1/210-5 after 24hr, adsorbing for 2 hr, discarding virus solution, adding maintenance solution containing samples with different dilutions, setting cell control hole and virus control hole, and adding 5% CO2And cultured at 37 ℃. Observing the pathological change degree (CPE) of each group of cells when the pathological change degree (CPE) of the virus control group reaches 4+, and respectively calculating the half Toxic Concentration (TC) of the sample to the cells by using a Reed-Muench method50) And half maximal Inhibitory Concentration (IC) against virus50)。
TABLE 1 screening for anti-influenza Virus Activity
Figure BDA0002913275350000121
Example 8: SD rat DSC703, DSC711 and metabolism test of Barosavir ester injection
Male SD rats were cannulated in the jugular vein and the experiment was started three days after acclimation, and divided into 3 groups of 3 animals each, based on the animal body weight measured the day before dosing. Three compounds (DSC703, DSC711 and baroxavir acetate, 1.88mg/kg calculated as baroxavir acetate) were administered separately by injection, separately in 5.443mL 5% DMSO: 30% PEG 400: dissolving with 65% H2O solvent, vortex, and filtering with 0.22 μm filter membrane to obtain clear solution. Approximately 0.25mL of whole blood was taken from the jugular vein in K2EDTA anticoagulant tubes before and 0.033, 0.083, 0.17, 0.25, 0.5, 1, 2, 4, 8, 24hr post-administration. After all time points were completed, rats were decapped and sacrificed by CO2 asphyxiation. Blood samples were centrifuged at 3000rpm for 5 minutes at 4 ℃ within 1 hour after collection. Transferring the centrifugally collected plasma to a new centrifugal tube with a label, temporarily storing the plasma in a refrigerator at the temperature of-20 ℃, and handing the plasma to a biological sample manager for storing the plasma in the refrigerator at the temperature of-80 ℃ after all samples are collected. mu.L of plasma sample, 5. mu.L of diluent, 200. mu.L of precipitant containing internal standard carbamazepine (100ng/mL) are added, vortex for 5min, centrifuge at 4500rpm for 15min, 50. mu.L of supernatant is taken and added into 100. mu.L of pure water, and 10.0. mu.L of sample is injected. The experimental data were statistically described using mean and Standard Deviation (SD) using Microsoft EXCEL. The results are as follows:
TABLE 2 concentration of Barosavir in plasma after intravenous sample DSC703 in Male SD rats (ng/mL)
Figure BDA0002913275350000131
TABLE 3 concentration of Barosavir in plasma after intravenous sample DSC711 in Male SD rats (ng/mL)
Figure BDA0002913275350000132
Figure BDA0002913275350000141
TABLE 4 concentration of Barosavir in plasma after intravenous injection of samples of Barosavirate in Male SD rats (ng/mL)
Figure BDA0002913275350000142
NC: not calculated, Not calculated.
As can be seen from table 4, baroxavir acetate rapidly converts to baroxavir after injection, but as can be seen from tables 2 and 3, little or no baroxavir is detected within 24 hours after injection by compound DSC703 and DSC711, indicating that compound DSC703 and DSC711 do not metabolize to baroxavir;
in conclusion, compared with the baloxavir disoproxil, the compound of the invention has good water solubility and better antiviral activity, and can not be metabolized into the baloxavir in vivo.
The present application describes embodiments, but the description is illustrative rather than limiting 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 embodiments described herein.

Claims (14)

1. A water-soluble polycyclic compound, tautomer, stereoisomer, or solvate thereof, according to (I):
Figure FDA0002913275340000011
in the formula (I), M1Is hydrogen, or an alkali metal ion, or 1/2 an alkaline earth metal ion, or 1/2 a zinc ion or ammonium;
M2is hydrogen, or an alkali metal ion, or 1/2 an alkaline earth metal ion, or 1/2 a zinc ion or ammonium;
l is- (CH)2)n1-(O-CH2)n2-or-O- (CH)2)n1-(O-CH2)n2-where n1 is 0, or 1, or 2; n2 is 0, or 1, or 2, or 3, or 4.
2. The water-soluble compound of claim 1, having formula (II):
Figure FDA0002913275340000012
the substituents in formula (II) are as defined for formula (I) in claim 1.
3. A compound according to claim 1 or 2, wherein M is1Is hydrogen, or sodium ion, or potassium ion, or 1/2 zinc ion or ammonium; m2Is hydrogen, or sodium ion, or potassium ion, or 1/2 zinc ion, or ammonium.
4. A compound according to claim 1 or 2, wherein M is1Is hydrogen; m2Is hydrogen.
5. A compound according to claim 1 or 2, wherein M is1Is hydrogen, or sodium ion; m2Is a sodium ion.
6. A compound according to claim 1 or 2, wherein M is1Is a sodium ion; m2Is a sodium ion.
7. A compound according to claim 1 or 2, wherein M is1Is hydrogen, or potassium ion; m2Is a potassium ion.
8. A compound according to claim 1 or 2, wherein M is1Is a potassium ion; m2Is a potassium ion.
9. The compound of claim 1 or 2, wherein L is-, (L-a)CH2)n1-(O-CH2)n2-, where n1 is 0, or 1; n2 is 0, or 1, or 2.
10. The compound of claim 1 or 2, wherein L is- (CH)2)n1-(O-CH2)n2-, where n1 is 0; n2 is 0, or 1, or 2.
11. The compound of claim 1 or 2, wherein L is- (CH)2)n1-(O-CH2)n2-, where n1 is 1; n2 is 0, or 1, or 2.
12. A compound according to claim 1 or 2, selected from the following compounds:
Figure FDA0002913275340000021
Figure FDA0002913275340000031
or the mono-sodium salt, di-sodium salt, mono-potassium salt or di-potassium salt of the above compounds or 1/2 zinc salt.
13. A pharmaceutical composition comprising a tautomer, stereoisomer, or solvate of a water-soluble polycyclic compound of any one of claims 1 to 12.
14. Use of a water-soluble polycyclic compound tautomer, stereoisomer, or solvate thereof according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 13 for the preparation of a medicament for the treatment of influenza virus.
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CN116284048A (en) * 2023-05-18 2023-06-23 长沙晶易医药科技股份有限公司 Compound and preparation method, pharmaceutical composition and application 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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