CN110655534A - Tenofovir lipid monoester compound and preparation method and application thereof - Google Patents
Tenofovir lipid monoester compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN110655534A CN110655534A CN201910257106.2A CN201910257106A CN110655534A CN 110655534 A CN110655534 A CN 110655534A CN 201910257106 A CN201910257106 A CN 201910257106A CN 110655534 A CN110655534 A CN 110655534A
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- China
- Prior art keywords
- compound
- integer
- tenofovir
- tfv
- pharmaceutically acceptable
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 79
- 229960004556 tenofovir Drugs 0.000 title claims abstract description 78
- -1 Tenofovir lipid Chemical class 0.000 title claims abstract description 35
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- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 9
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- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims description 96
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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
- 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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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/12—Antivirals
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Abstract
A tenofovir lipid monoester compound shown as a compound (1) or a pharmaceutically acceptable salt thereof,
Description
Technical Field
The invention relates to the field of chemical pharmacy, in particular to a tenofovir lipid monoester compound and a preparation method and application thereof.
Background
Tenofovir (TFV) is an acyclic nucleoside reverse transcriptase inhibitor with the strongest activity for resisting hepatitis B virus and HIV so far. Since the phosphonic acid in tenofovir is highly negatively charged under physiological acid-base conditions, it has the defects of poor intestinal tract penetration, poor cell penetration, limited distribution of target tissues, short plasma half-life, poor oral bioavailability, great toxic and side effects of the renal gastrointestinal tract and the like, thereby limiting the therapeutic effect of tenofovir on diseases.
Tenofovir Disoproxil Fumarate (TDF, US005935946A1), a prodrug of Tenofovir, has been marketed in 2001 for the treatment of hepatitis B and AIDS, and its antiviral component is Tenofovir. The tenofovir disoproxil fumarate is sequentially subjected to the following steps: (a) absorption into plasma by small intestine, (b) blood circulation into hepatitis B/AIDS target cells, (c) conversion to tenofovir by esterase hydrolysis and chemical hydrolysis, (d) phosphorylation of adenylate kinase to tenofovir monophosphate (TFV-MP), (e) further phosphorylation of nucleotide kinase to tenofovir diphosphate (TFV-DP) which can inhibit hepatitis B/AIDS virus, and exerting its therapeutic effect. (the metabolic mechanism is shown in FIG. 1).
The charge on the phosphonic acid in tenofovir is shielded in TDF, and the introduction of the ester increases the lipid solubility of the medicament, so that the penetrating power of the medicament on intestinal cell membranes is improved, and the oral bioavailability of the medicament is correspondingly improved. However, the structural modification is still not satisfactory clinically, for example, the structural modification has certain renal toxicity, large oral dose (150-300 mg), low bioavailability, liver enlargement caused by long-term administration, osteoporosis and the like. The bioavailability of the oral tenofovir disoproxil fumarate for dogs can reach 30 percent, the bioavailability of the oral tenofovir disoproxil fumarate for people is only 25 percent, and the bioavailability is influenced by food. The main reason is that ester hydrolase is widely distributed in vivo, so that the precursor drug of tenofovir disoproxil is mostly hydrolyzed into tenofovir with high negative charge before reaching hepatitis B/AIDS target cells. Tenofovir itself is not readily transported to target cells, but is actively transported to the proximal tubule of the kidney, resulting in some nephrotoxicity and poor oral bioavailability.
Tenofovir Alafenamide (Tenofovir Alafenamide Fumarate, TAF, WO2013116720a1), another prodrug of Tenofovir, has been marketed in 2016 for the treatment of hepatitis b and aids in 11 months. Unlike TDF, the metabolic mechanism of the liver-targeting pro-drugs of TAF is in turn: (a) absorption into plasma in the small intestine, (b) circulation of blood into hepatitis b/aids target cells, (c) hydrolysis of the carboxyl ester bond by serine protease cathepsin-a (a lysosomal enzyme with deamidase, esterase and carboxypeptidase activities), removal of isopropanol to release metastable metabolites, followed by intramolecular cyclization to remove phenolic groups, hydrolysis to tenofovir-alanine conjugate (TFV-Ala), (d) enzymatic chemical hydrolysis of the in vivo phosphoramidite to remove alanine to tenofovir, (e) phosphorylation of adenylate kinase to tenofovir monophosphate (TFV-MP), (f) further phosphorylation of nucleotide kinase to tenofovir diphosphate (TFV-DP) which inhibits hepatitis b/aids virus.
TAF is a liver-targeting highly potent prodrug of tenofovir. Clinically it is also easier to absorb in the small intestine than TDF, is stable in plasma, and 25 mg TAF exerts equivalent efficacy to 300mg TDF, only one-tenth the molar dose of TDF. The intake of small dose reduces the systemic exposure dose of tenofovir, thereby reducing the adverse reaction of kidney and bone.
Tenofovir lipid prodrug (Tenofovir mono-hexadecyloxypropy ester, HDP-TFV, WO2011100698A2) is another liver-targeting highly potent prodrug of Tenofovir and is currently in phase II clinical studies. The metabolic mechanism is that: (a) the small intestine absorbs into plasma, (b) the blood circulates into hepatitis B/AIDS target cells, (C) phosphoesterase-C promotes hydrolysis to obtain tenofovir, (d) adenylate kinase is phosphorylated into tenofovir monophosphate (TFV-MP), and (e) nucleotide kinase is further phosphorylated into tenofovir diphosphate (TFV-DP) capable of inhibiting hepatitis B/AIDS virus.
The lipid prodrug HDP-TFV of tenofovir is used for delivering drugs to the liver by utilizing a natural lipid uptake pathway. Clinically it is also easier to absorb in the small intestine, plasma stable and safe and effective than TAF, and 25 mg HDP-TFVF can exert equivalent efficacy to 300mg TDF, only one twelfth molar dose of TDF.
Another lipid prodrug HDDSB-TFV (Tenofovir mono-heptadecyldisfanylbutyl ester, J.Med.chem.2016,59,10244-10252) of Tenofovir contains disulfide bond reduction sensitive lipid, so far, has effective anti-hepatitis B/AIDS virus activity, has the best therapeutic index which is more than one hundred thousand, and is expected to become a new generation of lipid prodrug of Tenofovir.
The structures of the compounds TFV, TDF, TAF, HDP-TFV and HDDSB-TFV are shown as follows:
disclosure of Invention
The invention aims to provide a tenofovir lipid monoester compound shown as a compound (1) or a pharmaceutically acceptable salt thereof,
wherein X is selected from O, S or SS;
when X is selected from O, s is selected from an integer of 2-10, r is selected from an integer of 2-5, and t is selected from an integer of 0-17;
when X is selected from S, S is selected from an integer of 1-10, r is selected from an integer of 2-5, and t is selected from an integer of 0-17;
when X is selected from SS, s is selected from an integer of 1-10, r is selected from 3, and t is selected from an integer of 0-17.
According to an embodiment of the invention, in the compound (1), X is selected from O or SS;
when X is selected from O, s is selected from an integer of 2-4, r is selected from an integer of 2-3, and t is selected from an integer of 10-15;
when X is selected from SS, s is selected from an integer of 1-4, r is selected from 3, and t is selected from an integer of 10-15;
the pharmaceutically acceptable salt is selected from NH4Na, K, Ca or Mg salts.
As an example, the compound (1) is selected from the group consisting of,
as an example, the pharmaceutically acceptable salt of the compound (1) is selected from the group consisting of a compound,
the present invention also provides a process for producing the compound (1), comprising:
scheme 1:
1) chlorination: mixing Tenofovir (TFV), a chlorination aid and a chlorinating agent, and reacting to obtain a compound (3), wherein the chlorination aid is HCONR1 2,R1Are the same or different and are selected from C1-6Alkyl (e.g., methyl, ethyl);
2) esterification: carrying out esterification reaction on the compound (3) and ROH, and then carrying out hydrolysis reaction in the presence of acid to obtain a compound (1);
or
Scheme 2:
reacting tenofovir with a compound (6) to obtain a compound (1);
or
Scheme 3:
reacting tenofovir with a compound (7) to obtain a compound (1);
or
Scheme 4:
reacting hydroxypropyl adenine (HPA) with a compound (8), and performing acidolysis to obtain a compound (1);
wherein R is selected from [ (CH)2)rX]s(CH2)tCH3R, X, s, t have the definitions stated above;
y is selected from Cl, Br, I, MsO, TsO or TfO;
z is selected from MsO, TsO or TfO.
According to the preparation method of the present invention, in scheme 1,
the temperature of the chlorination step is-20-100 ℃, and preferably 0-50 ℃;
in a preferred technical scheme of the invention, the chlorination reaction is carried out in a solvent, wherein the solvent can be any one of or a combination of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane and 1, 2-dichloroethane;
in a preferred technical scheme of the invention, the chlorination aid in the chlorination step can be any one or combination of N, N-dimethylformamide and N, N-diethylformamide;
in a preferred technical scheme of the invention, the chlorinating agent in the chlorination step can be any one of oxalyl chloride and thionyl chloride or a combination thereof;
in the preferred technical scheme, the mol ratio of tenofovir to the chlorination auxiliary to the chlorinating agent in the chlorination step is 1: 1-5: 1-10; preferably 1: 1-2: 3-6;
in the preferred technical scheme of the invention, the temperature of the esterification reaction is-20-100 ℃, and preferably 0-50 ℃;
in a preferred technical scheme of the invention, the esterification reaction is carried out in a solvent, wherein the solvent can be any one or combination of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane and 1, 2-dichloroethane;
in the preferred technical scheme of the invention, the esterification reaction is carried out in the presence of alkali, and the alkali can be any one or the combination of triethylamine, N-diisopropylethylamine, N-methylmorpholine, pyridine, N-dimethylaminopyridine, 2, 6-dimethylpyridine and N, N-dimethylaniline;
in the preferable technical scheme of the invention, the molar ratio of the compound (3) in the esterification step to ROH to alkali is 1: 1-5: 1-10; preferably 1: 1-2: 1-5;
in the preferred technical scheme of the invention, the temperature in the acidolysis step is-20-100 ℃, and preferably 0-50 ℃;
in a preferred embodiment of the present invention, the acidolysis step is performed in a solvent, wherein the solvent may be any one or a combination of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, 1, 2-dichloroethane, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, isopropyl ether, methanol, ethanol, isopropanol, and water;
in a preferred technical scheme of the invention, the acid used in the acidolysis step can be any one or the combination of formic acid, acetic acid, hydrochloric acid, sulfuric acid and phosphoric acid;
in a preferable technical scheme of the invention, the molar ratio of the compound (4) to the acid in the acidolysis step is 1: 1-50; preferably 1: 10-20;
according to the preparation method of the present invention, in scheme 2,
the reaction temperature is-20 ℃ to 100 ℃, and preferably 0 ℃ to 90 ℃;
the reaction is carried out in a solvent which can be one, two or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, 1, 2-dichloroethane, N-dimethylformamide, N-diethylformamide, pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2, 6-dimethylpyridine, dimethylsulfoxide;
the reaction is carried out in the presence of a dehydrating agent which may be one, two or more of N, N, -dicyclohexylcarbodiimide, N, -diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, diethyl triphenylphosphine-azodicarboxylate, diisopropyl triphenylphosphine-azodicarboxylate, di-tert-butyl triphenylphosphine-azodicarboxylate;
the mol ratio of the tenofovir to the compound (6) to the dehydrating agent is 1: 1-5: 1-10; preferably 1:1 to 2:1 to 5.
In the process according to the invention, in scheme 3,
the reaction is preferably carried out in an inert gas atmosphere, for example in a nitrogen atmosphere;
the reaction temperature is-20 ℃ to 120 ℃, and preferably 0 ℃ to 100 ℃;
the reaction is carried out in a solvent which may be one, two or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, 1, 2-dichloroethane, N-dimethylformamide, N-diethylformamide, pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2, 6-dimethylpyridine, dimethylsulfoxide;
the reaction is carried out in the presence of a base, which may be one, two or more of magnesium isopropoxide, magnesium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, calcium hydride, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, N-dimethylaniline, aqueous ammonia;
in the reaction, the molar ratio of tenofovir to the compound (7) to the alkali is 1: 1-5: 1-10; preferably 1:1 to 2:1 to 5.
According to the preparation method of the present invention, in scheme 4,
the reaction temperature is-20 ℃ to 100 ℃, and preferably 0 ℃ to 80 ℃;
the reaction is carried out in a solvent which can be one, two or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, 1, 2-dichloroethane, N-dimethylformamide, N-diethylformamide, pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2, 6-dimethylpyridine, dimethylsulfoxide;
the reaction is carried out in the presence of a base, and the base used in the reaction may be one, two or more of magnesium isopropoxide, magnesium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium hydroxide, sodium hydroxide potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride, calcium hydride, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, N-dimethylaniline and aqueous ammonia.
In the reaction, the molar ratio of the hydroxypropyl adenine to the compound (8) to the alkali is 1: 1-5: 1-10; preferably 1:1 to 2:1 to 5.
According to the present invention, the method further comprises purifying the compound (1) obtained in any one of the schemes 1 to 4, for example, by crystallization, and specifically comprises: dissolving the product in a solvent, heating for dissolving, slowly cooling, and filtering to obtain a pure product of the compound (1).
In the preferred technical scheme of the invention, the heating and dissolving temperature in the purification step is-20-150 ℃, and the preferred temperature is-5-100 ℃;
in a preferred embodiment of the present invention, the solvent used in the purification step may be any one or two or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, 1, 2-dichloroethane, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, isopropyl ether, methanol, ethanol, and isopropanol, for example, a mixture solvent of methanol and dichloromethane.
The present invention also provides a process for producing a pharmaceutically acceptable salt of compound (1), which comprises:
and (2) carrying out neutralization reaction on the compound (1) and alkali to obtain a pharmaceutically acceptable salt of the compound (1).
In the preferred technical scheme of the invention, the temperature of the neutralization reaction is-20-100 ℃, and preferably 0-50 ℃;
in a preferred embodiment of the present invention, the solvent used in the neutralization reaction may be one, two or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, 1, 2-dichloroethane, methanol, ethanol, and isopropanol;
in a preferred technical scheme of the invention, the base in the salt forming step can be one, two or more of magnesium isopropoxide, magnesium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride and ammonia water;
in the preferable technical scheme, the molar ratio of the compound (1) to the alkali in the salt forming step is 1: 1-5; preferably 1: 1.
The method also comprises the step of purifying the obtained product after salification, wherein the purification step comprises the following steps: dissolving the product in solvent 1, heating to dissolve, adding solvent 2 which is difficult to dissolve the product, and filtering to obtain pure product of pharmaceutically acceptable salt of compound (1).
In the preferred technical scheme of the invention, the temperature of the purification step is-20-150 ℃, and the preferred temperature is-5-100 ℃;
in a preferred embodiment of the present invention, the solvent 1 in the purification step is selected from one, two or more of methanol, ethanol and isopropanol;
the solvent 2 is one or two or more selected from acetone, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, 1, 2-dichloroethane, ethyl acetate, isopropyl acetate, methyl tert-butyl ether and isopropyl ether.
The invention also provides application of the compound (1) and/or pharmaceutically acceptable salt thereof in preparing antiviral drugs.
Preferably, the virus is hepatitis B virus and/or HIV.
The present invention also provides a pharmaceutical composition comprising compound (1) and/or a pharmaceutically acceptable salt thereof.
Preferably, the pharmaceutical composition is used for treating hepatitis B and/or AIDS.
The pharmaceutical composition optionally further comprises an adjuvant.
The present invention also provides a method for treating hepatitis B and/or AIDS, comprising administering to a subject in need thereof an effective amount of the above pharmaceutical composition.
Advantageous effects
The compound (1) or the pharmaceutically acceptable salt thereof provided by the invention is a better liver-targeting tenofovir lipid monoester prodrug, and the drug can be quickly absorbed by small intestine after entering the body and selectively metabolized into the antiviral tenofovir in the liver. Can reduce the distribution, accumulation and systemic circulation level of tenofovir in blood, tissues and kidney, and avoid renal toxicity and possible osteoporosis.
Definition and description of terms
Unless otherwise indicated, the numerical ranges set forth in the specification and claims are equivalent to at least each and every specific integer numerical value set forth therein. For example, a numerical range of "1 to 10" is equivalent to reciting each integer value in the numerical range of "1 to 10," i.e., 1,2, 3, 4, 5, 6, 7, 8, 9, 10. It is to be understood that "more" in one, two, or more of the substituents used herein when describing substituents shall mean an integer ≧ 3, such as 3, 4, 5, 6, 7, 8, 9, or 10.
The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical ingredient including, but not limited to, carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and/or excipients.
As used herein, reference to the term "subject" refers to subjects suffering from a disease, disorder or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment related to the methods and compositions provided herein, the mammal is a human.
As used herein, the term "treating" and other similar synonyms include alleviating, or ameliorating a symptom of a disease or disorder, preventing other symptoms, ameliorating, or preventing an underlying metabolic cause of a symptom, inhibiting a disease or disorder, e.g., arresting the development of a disease or disorder, alleviating a disease or disorder, ameliorating a disease or disorder, alleviating a symptom of a disease or disorder, or discontinuing a symptom of a disease or disorder, and further, the term encompasses prophylactic purposes. The term also includes obtaining a therapeutic effect and/or a prophylactic effect. The therapeutic effect refers to curing or ameliorating the underlying disease being treated. In addition, a cure or amelioration of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, e.g., an improvement in the condition of the patient is observed, although the patient may still be affected by the underlying disease. For prophylactic effect, the composition can be administered to a patient at risk of developing a particular disease, or to a patient presenting with one or more physiological symptoms of the disease, even if a diagnosis of the disease has not yet been made.
The term "effective amount" as used herein refers to an amount of at least one agent or compound sufficient to alleviate to some extent one or more of the symptoms of the disease or condition being treated upon administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.
The invention obtains a hydrogen spectrum (1HNMR), phosphorus spectrum (31PNMR) data was obtained using a 400MHz nuclear magnetic resonance instrument (bruker advance II 400MHz) from bruker. Tetramethylsilicon (TMS) was used as an internal standard and collected at room temperature. Chemical shifts (δ) are parts per million (ppm). The singlet is denoted as s, the doublet as d, the triplet as t, the quartet as q, the multiplet as m and the broad singlet as brs. The coupling constant is denoted as j in Hz. The deuterated solvent is deuterated chloroform (CDCl)3) Or deuterated dimethyl sulfoxide (DMSO-d)6)。
The instrument used to obtain Mass Spectrometry (MS) data in this invention is Shimadzu LC 2010EV, forward, giving the ion peak of molecular weight hydrogenation (MH)+)。
Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.
Drawings
FIG. 1 is a diagram of the metabolic mechanism of several compounds.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. The following examples are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of the invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Example 1Preparation of tenofovir mono (hexadecyloxyethoxyethoxyethyl) ester (HDEE-TFV)
1) Under the protection of nitrogen and the stirring at 15-25 ℃, slowly dripping 120 ml of oxalyl chloride into a mixture consisting of 100 g of Tenofovir (TFV), 50 g of N, N-dimethylformamide and 1L of dichloromethane, stirring and refluxing for 4-6 hours, and cooling to room temperature; concentrating under reduced pressure at 50 deg.C to remove volatile, adding 1L dichloromethane to dissolve residue;
2) slowly dripping a mixed solution of 125 g of Hexadecyloxyethanol (HDEE), 200 ml of triethylamine and 500 ml of dichloromethane into the dichloromethane solution obtained in the step 1) under the protection of nitrogen and the stirring at 0-10 ℃, stirring for 4 hours at room temperature, and concentrating under reduced pressure at 50 ℃ to remove volatile matters; adding 500 ml of ethyl acetate, stirring at room temperature to disperse uniformly, adding 500 ml of 3N hydrochloric acid, and continuing stirring for 5 hours;
3) the layers were allowed to settle, the aqueous layer was extracted with 200 ml ethyl acetate, adjusted to pH 3 with 35% sodium hydroxide and the aqueous layer was extracted with dichloromethane (500 ml x 2); the dichloromethane was distilled off under reduced pressure, and 500 ml of methanol and 30 ml of dichloromethane were added to the residue;
4) stirring, heating and dissolving, slowly cooling to 0-5 ℃, and continuously stirring for 1 hour at the temperature;
5) filtering, leaching filter cakes by acetone, and drying at 50 ℃ to obtain 180 g of tenofovir lipid monoester (HDEE-TFV) as white solid.
The characterization results of HDEE-TFV are shown below.
δ(1HNMR,DMSO-d6):0.86-0,92(m,3H),1.22(d,J=7.5Hz,3H),1,24-1,33(m,26H),1.45-1,63(m,2H),3.40-3,67(m,6H),3.68-3.77(m,2H),3.77-3.88(m,2H),3.96(dd,J=4.0,8,0Hz,1H),4.09-4.28(m,3H),4.28-4.33(m,1H),6,80(brs,3H),8.04(s,1H),8.16(s,1H)ppm;MS:600(M+H)。
Example 2Preparation of tenofovir mono (hexadecyloxyethoxyethoxyethyl) ester (HDEE-TFV)
1) Under anhydrous and anaerobic conditions, a mixture consisting of 100 g of Tenofovir (TFV), 125 g of Hexadecyloxyethanol (HDEE), 110 g of N, N, -dicyclohexylcarbodiimide and 600 ml of pyridine is stirred at 90 ℃ for 18 hours and then cooled to room temperature; filtering, leaching filter cakes by using dichloromethane, and concentrating the combined filtrate at 60 ℃ under reduced pressure to remove volatile matters;
2) adding 500 ml of ethyl acetate, stirring at room temperature to disperse uniformly, adding 500 ml of 3N hydrochloric acid, and continuing stirring for 30 minutes;
3) standing for layering, extracting the water layer with 200 ml ethyl acetate, and adjusting pH to 3 with 35% sodium hydroxide; the aqueous phase was extracted with dichloromethane (500 ml x 2); the dichloromethane was distilled off under reduced pressure, and 500 ml of methanol and 30 ml of dichloromethane were added to the residue;
4) stirring, heating and dissolving, slowly cooling to 0-5 ℃, and continuously stirring for 1 hour at the temperature;
5) filtering, leaching filter cakes by acetone, and drying at 50 ℃ to obtain 185 g of tenofovir disoproxil fumarate lipid monoester (HDEE-TFV) as a white solid.
Example 3Preparation of tenofovir mono (hexadecyloxyethoxyethoxyethyl) ester (HDEE-TFV)
1) A mixture of 100 g Tenofovir (TFV), 20 g sodium hydroxide and 500 ml N, N-dimethylformamide was stirred at room temperature for 3 hours and concentrated at 80 ℃ under reduced pressure to remove volatiles; adding 500 ml of N, N-dimethylformamide and 150 g of hexadecyloxyethoxyethanol methanesulfonate (HDEEMs), stirring at 100 ℃ for 18 hours under the protection of nitrogen, and cooling to room temperature; then, the volatile matter was removed by concentration under reduced pressure at 80 ℃;
2) adding 500 ml of ethyl acetate, stirring at room temperature to disperse uniformly, adding 500 ml of 3N hydrochloric acid, and continuing stirring for 30 minutes;
3) standing for layering, extracting the water layer with 200 ml ethyl acetate, and adjusting pH to 3 with 35% sodium hydroxide; the aqueous phase was extracted with dichloromethane (500 ml x 2); the dichloromethane was distilled off under reduced pressure, and 500 ml of methanol and 30 ml of dichloromethane were added to the residue;
4) stirring, heating and dissolving, slowly cooling to 0-5 ℃, and continuously stirring for 1 hour at the temperature;
5) filtering, leaching filter cakes by acetone, and drying at 50 ℃ to obtain 183 g of tenofovir disoproxil fumarate lipid monoester (HDEE-TFV) as a white solid.
Example 4Preparation of tenofovir mono (hexadecyloxyethoxyethoxyethyl) ester (HDEE-TFV)
1) A mixture of 68 g of hydroxypropyl adenine (HPA), 220 g of HDEEPTs, 30 g of magnesium tert-butoxide and 500 ml of N, N-dimethylformamide was stirred at 80 ℃ for 6 hours, and then concentrated under reduced pressure to remove volatiles;
2) adding 500 ml of ethyl acetate, stirring at room temperature to disperse uniformly, adding 500 ml of 3N hydrochloric acid, and continuing stirring for 30 minutes;
3) standing for layering, extracting the water layer with 200 ml ethyl acetate, and adjusting pH to 3 with 35% sodium hydroxide; the aqueous phase was extracted with dichloromethane (500 ml x 2); the dichloromethane was distilled off under reduced pressure, and 500 ml of methanol and 30 ml of dichloromethane were added to the residue;
4) stirring, heating and dissolving, slowly cooling to 0-5 ℃, and continuously stirring for 1 hour at the temperature;
5) filtering, leaching filter cakes by acetone, and drying at 50 ℃ to obtain 188 g of tenofovir lipid monoester (HDEE-TFV) as white solid.
Example 5Preparation of tenofovir disoproxil (hexadecyldithiopropyl) ester (HDDSP-TFV)
1) Under the protection of nitrogen and the stirring at 15-25 ℃, 120 ml of oxalyl chloride is slowly dripped into a mixture consisting of 100 g of Tenofovir (TFV), 50 g of N, N-dimethylformamide and 1L of dichloromethane, stirred and refluxed for 4 hours, and then cooled to room temperature; concentrating under reduced pressure at 50 deg.C to remove volatile, adding 1L dichloromethane to dissolve residue;
2) under the protection of nitrogen and the stirring at 0-10 ℃, slowly dropwise adding a mixed solution of 130 g of hexadecyl dithio propanol (HDDSP), 200 ml of triethylamine and 500 ml of dichloromethane into the dichloromethane solution obtained in the step (1), stirring at room temperature for 4 hours, and concentrating under reduced pressure at 50 ℃ to remove volatile matters; adding 500 ml of ethyl acetate, stirring at room temperature to disperse uniformly, adding 500 ml of 3N hydrochloric acid, and continuing stirring for 5 hours;
3) the layers were allowed to settle, the aqueous layer was extracted with 200 ml ethyl acetate, adjusted to pH 3 with 35% sodium hydroxide and the aqueous layer was extracted with dichloromethane (500 ml x 2); the dichloromethane was distilled off under reduced pressure, and 500 ml of methanol and 30 ml of dichloromethane were added to the residue;
4) stirring, heating and dissolving, slowly cooling to 0-5 ℃, and continuously stirring for 1 hour at the temperature;
5) filtering, leaching filter cakes by acetone, and drying at 50 ℃ to obtain 185 g of tenofovir disoproxil fumarate lipid monoester (HDDSP-TFV) as a white solid.
Characterization data for HDDSP-TFV are shown below.
δ(1HNMR,DMSO-d6):0.84-0.94(m,3H),1.32(d,J=7.5Hz,3H),1.23-1.54(m,25H),1.62-1.72(m,2H),1.89-1,99(m,2H),2.55-2,70(m,4H),3.44-3.60(m,2H),3.93(dd,J=4.0,8,0Hz,1H),4.06-4.24(m,3H),4.28-4.38(m,1H),6,83(brs,3H),8.06(s,1H),8.18(s,1H)ppm;MS:618(M+H)。
Example 6Preparation of tenofovir disoproxil (hexadecyldithiopropyl) ester (HDDSP-TFV)
1) Under anhydrous and oxygen-free conditions, a mixture consisting of 100 g of Tenofovir (TFV), 130 g of hexadecyl dithio propanol (HDDSP), 110 g of N, N, -dicyclohexyl carbodiimide and 600 ml of pyridine is stirred at 90 ℃ for 18 hours and then cooled to room temperature; filtering, leaching filter cakes by using dichloromethane, and concentrating the combined filtrate at 60 ℃ under reduced pressure to remove volatile matters;
2) adding 500 ml of ethyl acetate, stirring at room temperature to disperse uniformly, adding 500 ml of 3N hydrochloric acid, and continuing stirring for 30 minutes;
3) the layers were allowed to settle, the aqueous layer was extracted with 200 ml ethyl acetate, adjusted to pH 3 with 35% sodium hydroxide and the aqueous layer was extracted with dichloromethane (500 ml x 2); the dichloromethane was distilled off under reduced pressure, and 500 ml of methanol and 30 ml of dichloromethane were added to the residue;
4) stirring, heating and dissolving, slowly cooling to 0-5 ℃, and continuously stirring for 1 hour at the temperature;
5) filtering, leaching filter cakes by acetone, and drying at 50 ℃ to obtain 190 g of tenofovir disoproxil fumarate lipid monoester (HDDSP-TFV) as a white solid.
Example 7Preparation of tenofovir disoproxil (hexadecyldithiopropyl) ester (HDDSP-TFV)
1) A mixture of 100 g Tenofovir (TFV), 20 g sodium hydroxide and 500 ml N, N-dimethylformamide was stirred at room temperature for 3 hours and concentrated at 80 ℃ under reduced pressure to remove volatiles; adding 500 ml of N, N-dimethylformamide and 155 g of hexadecyl dithiopropanol methanesulfonate (HDDSPMs), stirring at 100 ℃ for 18 hours under the protection of nitrogen, and cooling to room temperature; then, the volatile matter was removed by concentration under reduced pressure at 80 ℃;
2) adding 500 ml of ethyl acetate, stirring at room temperature to disperse uniformly, adding 500 ml of 3N hydrochloric acid, and continuing stirring for 30 minutes;
3) the layers were allowed to settle, the aqueous layer was extracted with 200 ml ethyl acetate, adjusted to pH 3 with 35% sodium hydroxide and the aqueous layer was extracted with dichloromethane (500 ml x 2); the dichloromethane was distilled off under reduced pressure, and 500 ml of methanol and 30 ml of dichloromethane were added to the residue;
4) stirring, heating and dissolving, slowly cooling to 0-5 ℃, and continuously stirring for 1 hour at the temperature;
5) filtering, leaching filter cakes by acetone, and drying at 50 ℃ to obtain 188 g of tenofovir disoproxil monoester (HDDSP-TFV) as white solid.
Example 8Preparation of tenofovir disoproxil (hexadecyldithiopropyl) ester (HDDSP-TFV)
1) A mixture of 68 g of hydroxypropyl adenine (HPA), 230 g of HDDSPTs, 30 g of magnesium tert-butoxide and 500 ml of N, N-dimethylformamide was stirred at 80 ℃ for 6 hours and then concentrated under reduced pressure to remove volatiles;
2) adding 500 ml of ethyl acetate, stirring at room temperature to disperse uniformly, adding 500 ml of 3N hydrochloric acid, and continuing stirring for 30 minutes;
3) the layers were allowed to settle, the aqueous layer was extracted with 200 ml ethyl acetate, adjusted to pH 3 with 35% sodium hydroxide and the aqueous layer was extracted with dichloromethane (500 ml x 2); the dichloromethane was distilled off under reduced pressure, and 500 ml of methanol and 30 ml of dichloromethane were added to the residue;
4) stirring, heating and dissolving, slowly cooling to 0-5 ℃, and continuously stirring for 1 hour at the temperature;
5) filtering, leaching filter cakes by acetone, and drying at 50 ℃ to obtain 193 g of tenofovir disoproxil fumarate lipid monoester (HDDSP-TFV) as a white solid.
Example 9Tenofovir Mono (Hexadecyloxyethoxyethyl) ester (HDE)E-TFV) preparation of sodium salt
1) 100 g of tenofovir disoproxil (hexadecanooxyethoxyethyl) acetate (HDEE-TFV) was dissolved in a mixed solvent composed of 100 ml of methanol and 900 ml of dichloromethane with stirring at room temperature, and 30 g of 30% sodium methoxide solution in methanol was slowly added; after stirring for 1 hour, concentrating under reduced pressure at 50 deg.C to remove volatile;
2) adding 350 ml of ethanol, stirring at 60 ℃ to dissolve, adding 350 ml of acetone, and continuously stirring at room temperature for 20 hours;
3) continuously stirring for 48 hours at the temperature of 0-5 ℃, filtering, and leaching a filter cake with 200 ml of acetone;
4) decompression drying at 40 deg.c to obtain tenofovir disoproxil monoester (HDDSP-TFV) sodium salt in 99 g and white solid purity of 99.8%.
Example 10Preparation of Tenofovir mono (hexadecyl dithio propyl) ester (HDDSP-TFV) sodium salt
1) 100 g of tenofovir disoproxil (hexadecyldithiopropyl) ester (HDDSP-TFV) was dissolved in a mixed solvent composed of 100 ml of methanol and 900 ml of dichloromethane with stirring at room temperature, and 35 g of 25% sodium methoxide solution in methanol was slowly added; after stirring for 1 hour, concentrating under reduced pressure at 50 deg.C to remove volatile;
2) adding 350 ml of ethanol, stirring at 60 ℃ to dissolve, adding 350 ml of acetone, and continuously stirring at room temperature for 20 hours;
3) continuously stirring for 48 hours at the temperature of 0-5 ℃, filtering, and leaching a filter cake with 200 ml of acetone;
4) vacuum drying at 40 deg.c to obtain tenofovir disoproxil monoester (HDDSP-TFV) sodium salt in 98.7 g and white solid in 99.8% purity.
Example 11Results of oral bioavailability study
The oral bioavailability of test compounds (TFV, TDF, TAF, HDEE-TFV, HDDSP-TFV) was investigated by comparison with the assay of the test compound (TFV, TDF, HDDSP-TFV) in the urine after oral and intravenous administration in mice, as disclosed in the reference (Clin. chem.1992,38,480-48; J.Med. chem.1994,37, 1857-1864).
Dissolving the compounds to be detected (TFV, TDF, TAF, HDEE-TFV and HDDSP-TFV) with dimethyl sulfoxide, and diluting the solution to the required concentration by using a phosphate buffer solution to respectively prepare the solutions of the compounds to be detected (TFV, TDF, TAF, HDEE-TFV and HDDSP-TFV) with the required concentrations.
48 BACLB/c mice weighing 20-25 g were randomly divided into four groups of 12 mice each. After fasting the mice for 12h, preparing a physiological saline solution of 15 mg/ml by using an intravenous injection solution of a compound to be detected (TFV, TDF, TAF, HDEE-TFV and HDDSP-TFV), and administering the solution by tail vein injection; the test compound (TFV, TDF, TAF, HDEE-TFV, HDDSP-TFV) solution for oral administration is prepared into an aqueous solution with the concentration of 3 mg/ml and containing 5 percent of dimethyl sulfoxide for gastric lavage and administration. The intravenous and oral administration of the test compound corresponded to 30 mg/Kg of TFV.
After 48h of administration, urine of each group of mice was collected, and the content of the test compound (TFV, TDF, TAF, HDEE-TFV, HDDSP-TFV) in the urine was determined.
The bioavailability of the oral administration was calculated according to the following formula and the results are shown in table 1.
Bioavailability [ M ]1]0-48h/[M2]0-48hX100%。
Wherein [ M1]0-48hThe total amount of drug excreted in urine within 48 hours after oral administration, [ M ]2]0-48hThe total amount of the drug excreted in urine within 48 hours after intravenous administration.
TABLE 1 results of oral bioavailability study
As can be seen from Table 1, HDEE-TFV, HDDSP-TFV and especially HDDSP-TFV of the present invention have better oral bioavailability than TFV, TDF, TAF.
Example 12Research on metabolism of rat liver cells into tenofovir diphosphate
1) Rat hepatocytes: male Sprague Dawley rats weighing 250-300 g of their foraging weight were selected and rat hepatocytes 20mg/ml (wet weight) and greater than 85% Trypan Blue (Trypan Blue) activity were prepared as disclosed in the reference (J.cell.biol.1969,43, 506-520; Eur.J.biochem.1982,122, 87-93);
2) buffer solution: a buffered solution of Krebs (Krebs) sodium bicarbonate containing glucose at a concentration of 20mM and Bovine Serum Albumin (BSA) at 1 mg/ml; continuously stirring for 48 hours at the temperature of 0-5 ℃, filtering, and leaching a filter cake with 200 ml of acetone;
3) aqueous acetonitrile solution: 60% acetonitrile in water containing 0.1mg/ml dicyclohexylcarbodiimide (DCCD) and 0.1% (by volume) ammonium hydroxide;
4) culturing 10 mu M of a compound to be detected (TFV, TDF, TAF, HDEE-TFV, HDDSP-TFV), 2ml of a buffer solution and rat hepatocytes for 2h at 37 ℃, wherein the compound to be detected (TFV, TDF, TAF, HDEE-TFV, HDDSP-TFV) is dissolved by dimethyl sulfoxide and diluted to a required concentration by a phosphate buffer solution to prepare a solution of the compound to be detected (TFV, TDF, TAF, HDEE-TFV, HDDSP-TFV) with the required concentration respectively;
5) the cell suspension obtained in step 1) was subjected to 1600. mu.l aliquots and centrifuged. Discarding the supernatant, retaining the precipitate, respectively adding 500 μ l acetonitrile water solution, and vigorously vortex and shake; 14000 rpm/min centrifugation;
6) taking the supernatant for LC-MS/MS analysis. The content of the test compound (TFV, TDF, TAF, HDEE-TFV, HDDSP-TFV) metabolized into tenofovir diphosphate in rat hepatocytes is quantitatively detected by MS/MS mode detection and compared with lamivudine-5' -triphosphate standard, and the result is shown in Table 2.
TABLE 2 study of the metabolism of the Compounds in rat hepatocytes to Tenofovir diphosphate
As can be seen from Table 2, HDEE-TFV, HDDSP-TFV and HDDSP-TFV of the present invention are more easily metabolized into the pharmaceutically active ingredient in the liver than TFV, TDF and TAF.
Example 13Investigation of anti-HBV viral Activity
The influence of the compound on the replication of hepatitis B virus and HIV in vitro is determined by adopting a cell culture method. In the research of anti-hepatitis B virus activity, the sample cytotoxicity test method comprises the following steps: the test cells were prepared into 10 ten thousand cells per ml, inoculated into a cell culture plate, 96-well plate, 100. mu.l/well, 37 ℃ and 5% CO2After 24 hours of culture, the cells were tested after growth into monolayers. The target compound and the control medicinal culture solution are prepared into required concentration, then added into a 96-hole cell culture plate, and the medicinal solution with the same concentration is added once per day for every 4 holes, and simultaneously the drug-free control group is added. And (5) observing cytopathic effect, and observing the cytopathic effect degree under a microscope for 8 days. The test method for inhibiting the activity of the hepatitis virus by the sample comprises the following steps: inoculating 10 ten thousand cells per ml into cell culture plate, 96-well plate, 100 microliter per well, 37 deg.C, 5% CO2Culturing for 24 hr, adding the medicine, setting cell control group, and changing the original concentration liquid medicine or control culture solution once in 4 days. Extracting HBV-DNA by molecular cloning experiment after cell lysis. Hybridizing each sample spot, autoradiography, measuring the A value of each hybridization point, calculating the HBV-DNA content of the cell control and administration group by using the regression equation of the standard curve, and calculating the half Effective Concentration (EC)50) The results are shown in Table 3.
TABLE 3 investigation of the anti-HBV Activity of the Compounds
As can be seen from Table 3, HDEE-TFV, HDDSP-TFV and HDDSP-TFV of the present invention have better anti-HBV virus activity than TFV, TDF and TAF.
Example 14Degrees of anti-HIV-1 Virus Activity
Adding 8 liquid medicines with different dilution concentrations and positive control liquid medicines into 96-hole cell culture, repeating 2 holes for each dilution, and setting cell control; then 2x105Cells/ml 100. mu.l were seeded in 96-well drug-containing cell culture plates. Placing at 37 ℃ and 5% CO2And culturing in a saturated humidity incubator, and observing cytopathic effect every day. According to the operation steps provided by the HIV-1P24 antigen kit, the content of HIV-1P24 antigen in cell culture supernatant on the 4 th day (96 hours) after medicine adding is measured, and the half Effective Concentration (EC) of the medicine is calculated50) The results are shown in Table 4;
TABLE 4 Degrees of the Activity of the Compounds against HIV-1 Virus
As can be seen from Table 4, HDEE-TFV, HDDSP-TFV and especially HDDSP-TFV of the present invention have better anti-HIV activity than TFV, TDF and TAF.
In conclusion, the experimental data of the embodiments 11 to 14 show that the HDEE-TFV and the HDDSP-TFV, especially the HDDSP-TFV, have better liver targeting property, bioavailability, safety and effectiveness, and further have better antiviral effect.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A tenofovir lipid monoester compound shown as a compound (1) or a pharmaceutically acceptable salt thereof,
wherein X is selected from O, S or SS;
when X is selected from O, s is selected from an integer of 2-10, r is selected from an integer of 2-5, and t is selected from an integer of 0-17;
when X is selected from S, S is selected from an integer of 1-10, r is selected from an integer of 2-5, and t is selected from an integer of 0-17;
when X is selected from SS, s is selected from an integer of 1-10, r is selected from 3, and t is selected from an integer of 0-17.
2. The compound of claim 1, wherein in the compound (1), X is selected from O or SS;
when X is selected from O, s is selected from an integer of 2-4, r is selected from an integer of 2-3, and t is selected from an integer of 10-15;
when X is selected from SS, s is selected from an integer of 1-4, r is selected from 3, and t is selected from an integer of 10-15.
5. a process for the preparation of compound (1) according to any one of claims 1 to 4, which comprises:
scheme 1:
1) chlorination: mixing Tenofovir (TFV) with a chlorination aid and a chlorinating agent, and reacting to obtain a compound (3); the chlorination auxiliary agent is HCONR1 2,R1Are the same or different and are selected from C1-6An alkyl group;
2) esterification: carrying out esterification reaction on the compound (3) and ROH, and then carrying out hydrolysis reaction in the presence of acid to obtain a compound (1);
or
Scheme 2:
reacting tenofovir with a compound (6) to obtain a compound (1);
or
Scheme 3:
reacting tenofovir with a compound (7) to obtain a compound (1);
or
Scheme 4:
reacting hydroxypropyl adenine (HPA) with a compound (8), and performing acidolysis to obtain a compound (1);
r is selected from [ (CH)2)rX]s(CH2)tCH3;
Y is selected from Cl, Br, I, MsO, TsO or TfO;
z is selected from MsO, TsO or TfO.
6. A process for preparing a pharmaceutically acceptable salt of a compound of any one of claims 1 to 4, comprising: and (3) carrying out neutralization reaction on the compound (1) and alkali to obtain a pharmaceutically acceptable salt of the compound (1).
7. Use of the compound (1) according to any one of claims 1 to 4 and/or a pharmaceutically acceptable salt thereof for the preparation of an antiviral medicament.
8. The use of claim 7, wherein the virus is hepatitis B virus and/or HIV.
9. A pharmaceutical composition comprising the compound (1) according to any one of claims 1 to 4 and/or a pharmaceutically acceptable salt thereof.
10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is used for treating hepatitis b and/or aids.
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Non-Patent Citations (3)
Title |
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GIESLER, KYLE E. ET AL.: "Next-Generation Reduction Sensitive Lipid Conjugates of Tenofovir: Antiviral Activity and Mechanism of Release", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
GIESLER, KYLE E. ET AL.: "Reduction Sensitive Lipid Conjugates of Tenofovir: Synthesis,Stability, and Antiviral Activity", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
TOMÁŠ TICHY ET AL.: "New prodrugs of Adefovir and Cidofovir", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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