CN111909204B - Tenofovir dipivoxil phenylpropionate phosphoramidate compound, and pharmaceutical composition and application thereof - Google Patents
Tenofovir dipivoxil phenylpropionate phosphoramidate compound, and pharmaceutical composition and application thereof Download PDFInfo
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- CN111909204B CN111909204B CN202010635351.5A CN202010635351A CN111909204B CN 111909204 B CN111909204 B CN 111909204B CN 202010635351 A CN202010635351 A CN 202010635351A CN 111909204 B CN111909204 B CN 111909204B
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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
- C07F9/65616—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 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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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
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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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
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a tenofovir dipivoxil phenylpropionate group phosphoramidate compound and a salt thereof, and also discloses a preparation method and a pharmaceutical composition containing the compound. Experiments prove that the compound has the activity of inhibiting HBV virus replication, and has the advantages of higher activity, large development coefficient and the like than the existing medicine tenofovir disoproxil fumarate (TAF) for treating AIDS. Experiments also prove that the compound also has the activity of inhibiting HIV-1 virus replication, and can be used for developing medicaments for treating AIDS or hepatitis B.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a tenofovir dipivoxil phenylpropionate phosphoramidate compound, a pharmaceutical composition containing the compound and application thereof.
Background
Hepatitis b, particularly chronic hepatitis b, has become a global public health problem, and it is counted that at present, more than 100 tens of thousands of people die of HBV infection and related diseases each year worldwide. However, there is no ideal therapeutic method and medicine for treating chronic hepatitis B. Therefore, how to effectively prevent and treat hepatitis B is a major problem in the 21 st century.
The current Chinese market for treating hepatitis B has gradually revealed respective disadvantages since the introduction of TAF (Wei Li) and ETV (entecavir).
In the "diagnosis and treatment of chronic hepatitis B prevention" of the American liver disease society in 2018, entecavir (ETV), tenofovir Disoproxil Fumarate (TDF) and propiophenone fumarate (TAF) are recommended as the preferred drugs for treating hepatitis B, and the three drugs have the advantages and disadvantages:
advantages of ETV: the side effect is small; disadvantages: has certain drug resistance and is forbidden for pregnant women;
TDF advantage: the antiviral effect is good, and very little drug resistance is achieved; disadvantages: has certain nephrotoxicity and has certain side effects on bones and kidneys after long-term application;
TAF advantage: compared with TDF, the antiviral effect is equivalent, the safety parameters of kidney and skeleton laboratory are improved, very little drug resistance is realized, and the dosage is only one twelfth of the dosage of one generation of tenofovir.
Wei Li (TAF) is a novel oral solution for treating hepatitis B, and although hepatitis B can not be completely cured, the efficacy is greatly improved, and the amount of hepatitis B virus can be well controlled. In clinical effect, TAF and TDF have the same clinical effect in treating hepatitis B, but the dosage of TAF is smaller, the toxicity is lower, and the TAF can play a larger role in drug resistance and combined treatment. However, as TAF comes into the human body and one molecule of phenol is required to fall off, the TAF compound preparation gradually shows non-negligible toxic and side effects after being marketed: lactic acidosis and severe hepatomegaly are combined with fatty liver.
Therefore, the development of new analogues of TAF, the maintenance of small changes in structure, the maintenance of excellent antiviral activity of TAF, and the better stability in blood plasma and the great significance of oral bioavailability are achieved.
In summary, although TDF and TAF compound preparations of Jili de company still have unique market at present as global AIDS/hepatitis B therapeutic drugs, the research of our TNF-based drugs for treating AIDS/hepatitis B still has great significance. Further improving the bioavailability of human body, improving activity, reducing toxic and side effects and fully playing the drug effect for treating hepatitis B and AIDS.
Disclosure of Invention
During prodrug studies on TAF analogs, it was unexpectedly found that the activity was increased after replacement of the benzene ring chain of TAF with the amino NHR chain, and the bioactivity selection factor SI was also increased, so that the dosage of the study sample was further reduced compared to TAF, i.e., the toxicity of TAF was further reduced while maintaining TAF activity, and the drug concentration in tissue cells, particularly hepatocytes, was significantly increased compared to TAF. Therefore, the tenofovir dipivoxil phenylpropionate phosphoramidate compound of the invention can remarkably improve the treatment effect on hepatitis B and AIDS, and greatly reduce the nephrotoxicity and bone toxicity caused by TDF or TAF. The following invention has been proposed.
A tenofovir disoproxil propionate phosphoramidate compound comprising:
a) The structure of the compound (Ia) is shown below,
wherein R is 1 ＝R 2 ＝C 1 -C 12 An alkyl group; or (b)
b) A pharmaceutically acceptable salt prepared from the compound (Ia) as described in a) and an acid.
Further, when said R 1 、R 2 When the group is selected from isopropyl, ethyl, isobutyl, neopentyl, n-butyl, cyclohexyl, methyl or tert-butyl, the structural formula of the compound is respectively as follows:
further, the pharmaceutically acceptable salts are oxalate, malonate, succinate, fumarate, aspartate, citrate, salicylate, hydrochloride, sulfate, phosphate, and the molar ratio of acid to compound (Ia) is in the range of (0.5-1): 1.
Further, when said R 1 、R 2 When the group is selected from isopropyl, ethyl, isobutyl, neopentyl, n-butyl, cyclohexyl, methyl or tert-butyl, the fumarate has the following structural formula:
further, the fumarate salt is prepared from fumaric acid and the compound according to a molar ratio of 0.5:1.
In another aspect, the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir disoproxil phenylpropionate phosphoramidate compound, and at least one pharmaceutically acceptable carrier or excipient.
Further, the pharmaceutical composition further comprises a therapeutically effective amount of an additional therapeutic agent selected from at least one of a compound that inhibits HIV protease, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a viral capsid polymerization inhibitor, a non-catalytic site HIV integrase site inhibitor.
Further, the dosage form of the pharmaceutical composition is a tablet or a capsule.
The tenofovir dipivoxil phenylpropionate phosphoramidate compound disclosed by the invention can be applied to preparation of a medicament for preventing or treating viral diseases. Specific viral diseases are HIV-1 infection or HBV infection or HIV-1 and HBV simultaneous infection.
The compound of the invention has the excellent properties required by the medicaments for treating AIDS/hepatitis B through measurement, and is concretely as follows:
IC of Compound C0P371371 in an in vitro anti-hepatitis B Virus Activity Screen 50 6 times higher than TAF (positive control), the bioactivity selection factor SI is 4.0 times higher than TAF (positive control); IC of Compound C0P374374 50 Is 6 times that of TAF (positive control), and the bioactivity selection factor SI is 1.5 times that of TAF (positive control). The compound has higher activity of inhibiting virus replication than a class of anti-hepatitis B drugs TAF, has large biological activity selection coefficient in development, and is expected to be a drug for treating HBV infection. The compound of the invention integrates various good properties such as high activity, low toxicity, high bioavailability and the like, and has the prospect of becoming a new generation of medicaments for treating AIDS or hepatitis B.
Detailed Description
The following examples will provide those skilled in the art with a more complete understanding of the invention, but are not intended to limit the invention in any way. All the structures of the compounds are passed through 1 H NMR or MS determination.
The raw materials used in the invention are as follows: tenofovir, L-alanine ester hydrochloride, fumaric acid are all commercially available.
Example 1
Preparation of 9- [ (R) -2- [ [ bis [ [ (S) - (1-n-butoxycarbonyl-2-phenyl) ethyl ] amino ] phosphinyl ] methoxy ] propyl ] adenine (C0P 374374).
7.2g (25 mmol) of commercially available tenofovir (C0P 00) are weighed, added into a 250ml flask, 50g of thionyl chloride is added, the temperature is raised to 55 ℃ for 10 minutes, the temperature is further raised to 70 ℃ and then the mixture is stirred for 1 hour, the thionyl chloride is distilled under reduced pressure, 100ml of dry acetonitrile is added after the distillation is finished and the mixture is refluxed for 10 minutes at 85 ℃, the acetonitrile is evaporated to dryness under reduced pressure and cooled to room temperature, then 50ml of dry dichloromethane is added, the mixture is stirred for 0.5 hour, 19.4g (75 mmol,3 eq) of L-phenylalanine n-butyl hydrochloride (AH 374) is added, the mixture is stirred for 10 minutes, approximately 20ml of triethylamine is dripped, and the mixture is stirred for 0.5 hour.
Suction filtration, and after the filtrate was evaporated to dryness, 100ml of ethyl acetate was added. And washed twice with 100g of 5% potassium bicarbonate aqueous solution and twice with 100g of 20% sodium chloride aqueous solution, dried over anhydrous sodium sulfate, suction-filtered after drying, and the filtrate was evaporated to dryness. Ethyl acetate column chromatography gives C0P374374 about 8g (purity 98.2%).
1 H NMR(400MHz,CDCl 3 )δ,(ppm):0.85-0.98(6H,dt,2×CH 3 )，1.02-1.15(3H,d,CH 3 ),1.25-1.41(4H,m,2×CH 2 )，1.45-1.67(4H,m,2×CH 2 ),2.73-2.98(5H,m,OCH and 2×CH 2 ),3.01-3.54(4H,m,2×NH and OCH 2 P),3.70-4.12(6H,m,2×NCH and 2×COOCH 2 ),4.13-4.36(2H,m,NCH 2 ),6.27(2H,s,NH 2 ) 7.00-7.38 (10H, m, hydrogen on two benzene rings), 7.88 (1H, s, H on a purine ring), 8.32 (1H, s, H on a purine ring).
ESI-MS:[M+H]+694.7
Example 2
Preparation of 9- [ (R) -2- [ [ bis [ [ (S) - (1-n-butoxycarbonyl-2-phenyl) ethyl ] amino ] phosphinyl ] methoxy ] propyl ] adenine fumarate (FC 0P 374374).
Equivalent amounts of 9- [ (R) -2- [ [ bis [ [ (S) - (1-n-butoxycarbonyl-2-phenyl) ethyl ] amino ]
The phosphinyl-methoxy-propyl-adenine (C0P 374374) and fumaric acid were dissolved in hot acetonitrile, stirred under reflux for 2 hours, cooled at room temperature for crystallization, the precipitated solid was filtered off and washed with acetonitrile to give 9- [ (R) -2- [ [ bis [ [ (S) - (1-n-butoxycarbonyl-2-phenyl) ethyl ] amino-phosphinyl-methoxy-propyl ] adenine fumarate (FC 0P 374374).
Example 3
In vitro assay of anti-HBV Virus Activity of Compounds of the invention
1. In vitro cell model HepG2.2.15 cells
Determination of anti-hepatitis B Virus Activity of Compounds by dot blot method
2.1 HepG2.2.15 cells (4X 10) 4 Cells/well) to 96-well plates, 5% cultured overnight at 37 ℃.
2.2 the next day, the compounds were diluted and different concentrations of compounds were added to the culture wells. The final concentration of DMSO in the culture was 1%.1 μM Entecavir (ETV) as a 100% inhibition control; 1% DMSO was used as a 0% inhibition control.
2.3 day five, fresh medium containing the compound was changed.
2.4 eighth and ninth days, the culture medium in the culture wells was removed and the cells were harvested for dot hybridization.
3. Results: see table one.
Table one: cytotoxicity of the compounds, extracellular anti-HBV activity (HepG2.2.15)
4. Conclusion of experiment:
4.1 the positive compound TAF has expected inhibition effect on replication of hepatitis B virus in HepG2.2.15 cells, and the experiment is proved to be effective and reliable.
4.2 anti-hepatitis B Virus Activity. In the dot hybridization experiments, the activity of each of the compounds to be tested in the table 2 above against hepatitis B virus was 6 times that of TAF (positive control). And the development coefficients SI are higher than the inhibition rate of the positive control TAF.
4.3 this fully demonstrates: compared with the existing anti-HBV drug TAF, the compound has higher activity of inhibiting virus replication, and is expected to become a new generation drug for treating HBV infection.
Example 4
Formulation and process
The pharmaceutical composition of the invention can be prepared into tablets or capsules according to a general preparation method of oral pharmaceutical preparations, and the unit content of the tablets or capsules of the compound of the invention with 5mg dosage is as follows:
watch II
| Name of the name | Ratio/mg |
| Compounds of the invention | 2.50 |
| Lactose and lactose | 1.65 |
| Starch | 0.66 |
| Microcrystalline cellulose | 0.08 |
| Carboxymethyl starch sodium | 0.08 |
| Stearic acid magnesium salt | 0.03 |
。
Claims (4)
1. A tenofovir disoproxil phosphoramidate compound or a pharmaceutically acceptable salt thereof, wherein the structural formula of the tenofovir disoproxil phosphoramidate compound is selected from one of the following structural formulas:
the pharmaceutically acceptable salt is fumarate, and the structural formula of the fumarate is selected from one of the following structural formulas:
2. the tenofovir disoproxil phosphoramidate compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the molar ratio of fumaric acid of the fumarate to the tenofovir disoproxil phosphoramidate compound is in the range of (0.5-1): 1.
3. a pharmaceutical composition comprising a therapeutically effective amount of a tenofovir disoproxil phosphoramidate compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, and at least one pharmaceutically acceptable carrier or excipient.
4. Use of a tenofovir dipivoxil phenylpropionate compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 in the manufacture of a medicament for the prevention or treatment of HBV infection viral diseases.
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