WO2014026582A1 - Tenofovir diester compound, preparation method and use thereof, and pharmaceutical composition comprising the same - Google Patents
Tenofovir diester compound, preparation method and use thereof, and pharmaceutical composition comprising the same Download PDFInfo
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- WO2014026582A1 WO2014026582A1 PCT/CN2013/081304 CN2013081304W WO2014026582A1 WO 2014026582 A1 WO2014026582 A1 WO 2014026582A1 CN 2013081304 W CN2013081304 W CN 2013081304W WO 2014026582 A1 WO2014026582 A1 WO 2014026582A1
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- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
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- ODMDNPRWFGSQHZ-RGMNGODLSA-N butyl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.CCCCOC(=O)[C@H](C)N ODMDNPRWFGSQHZ-RGMNGODLSA-N 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
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- NZAWHYMFBXOGHQ-FJXQXJEOSA-N cyclohexyl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.C[C@H](N)C(=O)OC1CCCCC1 NZAWHYMFBXOGHQ-FJXQXJEOSA-N 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
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- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
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- ACCCMOQWYVYDOT-UHFFFAOYSA-N hexane-1,1-diol Chemical compound CCCCCC(O)O ACCCMOQWYVYDOT-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
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- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012257 pre-denaturation Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- YAQKNCSWDMGPOY-JEDNCBNOSA-N propan-2-yl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.CC(C)OC(=O)[C@H](C)N YAQKNCSWDMGPOY-JEDNCBNOSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 1
- 229960001355 tenofovir disoproxil Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
-
- 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
-
- 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
-
- 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
-
- 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
Definitions
- the present invention relates to the field of medicinal chemistry, and in particular to a tenofovir diester compound, a process for the preparation thereof, use thereof, and a pharmaceutical composition comprising the same.
- the acyclic nucleoside compounds adefovir and tenofovir have obvious advantages in preventing viral resistance, and they are resistant to cyclic nucleosides.
- the virus strain is effective, the incidence of drug resistance is low, and the toxicity is relatively small.
- the polarity is strong, and the biofilm permeability is poor, resulting in low bioavailability, making it impossible to be used as a drug in clinical applications.
- TDF diester prodrug tenofovir diisopropionyl Oxymethyl ester fumarate
- WO 2012/041015 A1 discloses the following: "Chinese patent (CN1810816A) introduces a fat-soluble oxiranyl ethyl long chain on a hydroxyl group of a phosphate group in the tenofovir molecule to give a hydroxyl group of a phosphate group in the molecular structure. A long chain oxirane/propyl monoester derivative of adefovir and tenofovir obtained by esterification and still in a free state.
- the compound is introduced not only after the introduction of long chain oxirane/propyl group
- the pharmacokinetic properties of the compound are improved, and another free hydroxyl group in the phosphate group can still be phosphorylated, participate in the virus replication process, and exert an antiviral effect, thereby retaining the antiviral activity of tenofovir.
- the introduction of the chain not only improves the pharmacokinetic properties of the compound but also retains the antiviral activity.”
- the compounds have completed preclinical tests, respectively, which not only proves that the compounds in the above patents are highly active and It is also resistant to drug resistance, and it is also found to be very toxic, and does not inhibit the enzymes that metabolize these drugs in the liver.
- the above compounds are all prodrugs of tenofovir, and the main purpose of modifying tenofovir is to improve its fat solubility, improve membrane permeability, and thereby improve the bioavailability of the human body.
- one hydroxyl group of a phosphate group is esterified while the other is still in a free state, so it is still a highly polar compound. The availability of materials still needs to be further improved.
- Another object of the invention is to provide a process for the preparation of said compounds.
- Another object of the invention is to provide the use of said compounds.
- Another object of the invention is to provide a pharmaceutical composition comprising the compound.
- the present invention provides a tenofovir diester compound represented by the formula (I), a salt thereof or a tautomer thereof,
- R a and R b are independently selected from R 2 or R 3 , and R a and R b are not simultaneously R 2 ;
- R c is selected from hydrogen or C 1 C 5 fluorenyl;
- the Ri is -OCH 2 (CH 2 ) m CH 2 OCH 2 (CH 2 ) n CH 3 , wherein m is an integer of 0 to 4, and n is an integer of 10 20 ;
- the R 3 is a residue obtained by removing an amine from an amino group of any natural or pharmaceutically acceptable amino acid, wherein the carboxyl group in the amino acid is esterified with a thiol group or an aryl group.
- amino acids include, but are not limited to, glycine, alanine, valine, leucine, isoleucine, phenylalanine, valine, tryptophan, serine, tyrosine, cysteine, Methionine, aspartic acid, glutamic acid, threonine, lysine, arginine or histidine.
- the structure is represented by the general formula ( ⁇ ),
- R 5 is independently selected from a C1 to C12 fluorenyl group, a C3 to C12 cycloalkane group, a C2 to C12 alkenyl group, a C2 to C12 alkynyl group, a C6 to C12 aryl group or a C6 to C12 aryl group. ⁇ .
- R4 and R 5 are independently selected from a sulfhydryl group of CI ⁇ C12, a cyclic fluorenyl group of C3 C12 or C6 ⁇ An aromatic group of C12.
- the R4 is selected from a methyl group, an ethyl group or a benzyl group.
- the m is an integer of 0 to 2; more preferably 0 or 1.
- n is an integer of 12 18; more preferably 14, 15 or 16.
- the present invention provides a compound represented by any one of the following structures, a salt thereof or a tautomer thereof:
- the compound represented by the formula (I) has an asymmetric center and has an S configuration or configuration
- the technical solution of the present invention includes all possible stereoisomers and a mixture of two or more isomers.
- the technical solution of the present invention also includes a cis isomer, a trans isomer or a mixture of these isomers. Among them, a single isomer can be isolated according to a conventional method or synthesized by stereoselective synthesis.
- the salt means a physiologically acceptable salt, that is, an organic salt and an inorganic salt of the compound of the present invention.
- Physiologically acceptable salts are well known in the art to those skilled in the art.
- Physiologically acceptable salts include, but are not limited to, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and the like, and organic Acid salts such as fumarate, acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, etc., or by other methods described in the literature, such as ion exchange The salt obtained.
- the preparation method of the present invention is as follows: a compound represented by the general formula (1-1) is used as a starting material, and a condensation reaction is carried out to obtain a monoester compound (1-2), and then a condensation reaction is carried out to obtain a general formula.
- the respective esterification processes are preferably: when the esterification substituent is Ri, the reactant is Alcohol HOCH 2 (CH 2 )mCH 2 OCH 2 (CH 2 ) nCH 3 (m, n is as defined above), using N-methylpyrrolidone as solvent, in the presence of triethylamine, hydrazine, hydrazine '-Dicyclohexylcarbodiimide is a complexing agent for dehydration condensation reaction.
- the reaction temperature during the reaction is 70 ° C - 110 ° C, and the reaction time is 7-15 hours.
- the reactant is isopropyl chloromethyl carbonate
- the condensation reaction is carried out in the presence of triethylamine using N-methylpyrrolidone as a solvent, and the reaction temperature during the reaction is 45 ° C. -75 °C, reaction time is 12-18 hours.
- the reactant is an amino acid ester hydrochloride
- N-methylpyrrolidone is used as a solvent
- triethylamine is a dehydrating agent
- 2,2'-dithiodipyridine or triphenylphosphine is used as a solvent.
- the mixture is subjected to a condensation reaction in which the reaction temperature is 45 V -85 V and the reaction time is 8-26 hours.
- the present invention provides the use of a compound according to any one of the above aspects, a salt thereof or a tautomer thereof for the preparation of a medicament for preventing or treating a tumor or a viral disease.
- the viral disease is a disease caused by HIV and/or a hepadnavirus.
- hepadnavirus is hepatitis B virus.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound according to any one of the above aspects, a salt thereof or a tautomer thereof, and a pharmaceutically acceptable carrier.
- compositions provided herein can be prepared according to methods known in the art to produce any dosage form suitable for human or animal use.
- the active ingredient is usually present in the pharmaceutical composition in an amount of from 0.1 to 95% by weight, or may be adjusted accordingly by those skilled in the art depending on the application.
- the pharmaceutical composition is selected from the group consisting of a tablet, a capsule, a pill, a powder, a granule, a suspension, an emulsion or an injection.
- the compound of the formula (I), a salt thereof or a tautomer thereof can be prepared according to known methods with pharmaceutically acceptable suitable pharmaceutical carrier materials such as fillers, fragrances, Flavoring agents, colorants, wetting agents,
- suitable pharmaceutical carrier materials such as fillers, fragrances, Flavoring agents, colorants, wetting agents,
- the excipient, the disintegrating agent or the surfactant is mixed by a known method, and is prepared into a liquid dosage form such as a solid dosage form or a suspension agent such as a tablet or the like.
- the pharmaceutical composition of the present invention can be prepared into a general preparation, a sustained release preparation, a controlled release preparation or a delivery system for various preparations and the like.
- the pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of enhancing the therapeutic effect for the purpose of administration.
- the tenofovir diester compound provided by the invention, the salt thereof or the tautomer thereof has novel structure, simple synthesis, reduced polarity of the compound, and better fat solubility than the existing tenofovir diester compound.
- the membrane permeability of the drug can be improved to improve bioavailability; in addition, the compound provided by the present invention also exhibits a strong antiviral effect, especially for HIV and hepadnavirus, the activity is superior to the existing one.
- the tenofovir diester compound which does not show obvious toxicity and has high safety, is suitable for the prevention and treatment of AIDS and hepatitis, and has a very broad application prospect.
- FIG. 1 is a high performance liquid chromatogram of the inventive compounds COP12-114 and CMX157 described in Experimental Example 1;
- FIG. 2 is a high performance liquid chromatogram of the inventive compounds COP130-114 and CMX157 described in Experimental Example 1;
- Fig. 4 is a high performance liquid chromatogram of the inventive compounds COP233 and TDF described in Experimental Example 1.
- the abscissa is time and the unit is minute.
- 1,3-propanediol (9.13 g, 0.12 mol), potassium t-butoxide (6.8 g, 0.06 mol) and tert-amyl alcohol (50 ml) were added in this order, and slowly added dropwise under reflux.
- NM 400 MHz, CDC1 3 ) ⁇ (ppm ): 0.88 (3H, t, CH 3 ), 1.06-1.49 (30H, m, 15 CH 2 ), 1.53- 1.654(2H, m, CH 2 ), 1.90 -2.10(1H, br, OH), 3.47(2H, t, OCH 2 ), 3.53 (2H, t, OCH 2 ), 3.73 (2H, t, OCH 2 ).
- L410 was synthesized in the same manner as in the synthesis of L114 to give 6-dodecyloxy-1-hexanol (L410).
- NM 400 MHz, CDC1 3 ) ⁇ (ppm ): 0.88 (3 ⁇ , t, CH 3 ), 1.14-1.34 (18H, m, 9 x CH 2 ), 1.35-1.42 (4H, m, 2 CH 2 ) , 1.48-1.64 (6H, m, 3 x CH 2 ), 1.93-2.01 (1H, br, OH), 3.28-3.48 (4H, m, 2 OCH 2 ), 3.62 (2H, t, OCH 2 ).
- L220 was synthesized in the same manner as in the synthesis of L114 to give 4-teledecyloxy-1-butanol (L220).
- Example 1 Preparation of C0P12-114 In a 50 ml round bottom flask, (R)-9-[2-(phosphomethoxy)propyl]adenine (tenofovir, PMPA) (1.3 g, 4.5 mmol), triethylamine (7 ml) were added in sequence.
- PMPA tenofovir
- COP02 (1.23 g, 3.04 mmol)
- L016 (1.11 g, 6.08 mmol) was mixed and dissolved in 10 ml of N-methylpyrrolidone, heated to 75 ° C and stirred for 15 minutes, then added dropwise.
- Example 4 Preparation of C0P12-220 In a 50 ml round bottom flask, COP02 (1.23 g, 3.04 mmol) and L220 (2.42 g, 6.08 mmol) were mixed and dissolved in 10 ml of N-methylpyrrolidone, heated to 90 ° C and stirred for 20 minutes, then added dropwise.
- tenofovir (PMPA) ( 1.18 g, 4.13 mmol), L-alanine ethyl ester hydrochloride (2.6 g, 17 mmol), 2,2'-dithiodipyridine were added in sequence.
- COP031 (9.7 g, 25 mmol) and L114 (15 g, 50 mmol) were added and dissolved in 65 ml of N-methylpyrrolidone. After heating to 85 ° C for 30 minutes, slowly add dropwise. 22 ml of triethylamine, and then the temperature was raised to 10 CTC, and dicyclohexylcarbodiimide (DCC) llg (dissolved in 16 ml of N-methylpyrrolidone) was added dropwise.
- DCC dicyclohexylcarbodiimide
- NM 400 MHz, CDC1 3 ), ⁇ (ppm ): 0.88 (3H, t, CH 3 ), 1.16-1.36 (36H, m, 15 x CH 2 and 2 x CH 3 ), 1.37 (3H, t, CH 3 ), 1.47-1.62(2H, m, CH 2 ), 3.35-3.68(6H, m, 3 x OCH 2 ), 3.76-4.20(8H, m, OCH 2 P, NCH 2 , COOCH 2 , OCH and NH), 4.28-4.45(lH, m, NCH), 6.15(2H, s, NH 2 ), 7.94-8.04 (lH, d, H on the anthracene ring), 8.28-8.37 (1 ⁇ , d, anthracene ring H).
- PMPA C0P034 C0P134-1 14 In a 50 ml round bottom flask, tenofovir (PMPA) ( 1.18 g, 4.13 mmol), L-alanine n-butyl ester hydrochloride (3.08 g, 0.017 mol), 2 , 2'-dithiodipyridine (1.82g, 8.26mmol), triethylamine (3.44g, 4.8ml, 34mol), triphenylphosphine (2.16g, 8.24mmol) and N-methylpyrrolidone (10ml) After stirring at 80 ° C for 12 h, the solvent was evaporated, and then ethyl acetate: EtOAc: EtOAc (EtOAc: EtOAc) .
- PMPA C0P035 C0P135-114 In a 50 ml round bottom flask, tenofovir (PMPA) ( 1.18 g, 4.13 mmol), L-alanine cyclohexyl ester hydrochloride (3.52 g, 17 mmol), 2, 2 were added in sequence. '-Dithiodipyridine (1.82 g, 8.26 mmol), triethylamine (3.44 g, 4.8 ml, 34 mol), triphenylphosphine (2.16 g, 8.24 mmol) N-methylpyrrolidone (10 ml), After the mixture was stirred at 75 ° C for 14 h, the solvent was evaporated. mjjjjjjjjj 45.1%. .
- Example 40 Pharmaceutical Formulation Containing Compound CO12-12-114
- the composition is as follows (tablet unit: 200 mg / tablet; capsule unit: 200 mg / tablet): Compound C0P12-114: lOOmg;
- Lactose 65mg
- Microcrystalline cellulose 5mg
- Carboxymethyl starch sodium 5mg;
- Magnesium stearate lmg.
- Test substances include: Determination of the fat solubility of the compounds of the present invention COP12-114 and CMX157, COP130-114 and CMX157, COP 131-114 and CMX 157, COP233 and TDF.
- the fat-soluble nature of the test substance is usually characterized by the length of time that different substances remain on the reversed-phase chromatogram under the same conditions. The higher the fat solubility of a substance, the longer the retention time of the substance on the reverse phase chromatogram.
- the retention times of the compounds of the present invention COP12-114, COP130-114, and C0P131-114 were 2.69 minutes, 7.542 minutes, and 2.648 minutes, respectively, and the retention time of the compound C0P233 was longer than that of the TDF. 0.542 minutes. This indicates that the fat solubility of the compound of the present invention is much higher than that of CMX157 and TDF, indicating that the membrane permeability is improved.
- HepG2.2.15 cells were cultured in a 24-well cell culture plate for 48 hours, and then the drug-containing culture solutions were added at different concentrations. The culture was continued for 9 days (changing every 3 days), and the supernatant was collected and subjected to real-time quantitative PCR detection by a fluorescent probe method. The results are shown in Table 1.
- HBV primer HBV upstream primer: 5,-TgT CCT ggT TAT CgC Tgg-3,
- HBV downstream primer 5,-CAA ACg ggC AAC ATA CCT T-3'
- HBV fluorescent probe sequence 5 '(FAM)-TgT gTC TgC ggC gTT TTA TCA T-(TAMRA)3,
- PCR pre-denaturation at 95 °C for 5 min; denaturation at 95 °C for 10 s, annealing and extension at 60 °C for 30 s, 40 cycles.
- the compounds C0P12-114, C0P131-114, C0P132-114, C0P133-114, C0P134-114, C0P135-114, C0P230, C0P231, C0P232, C0P233, C0P235 can effectively inhibit the replication of HBV virus DNA, and the effect is better than TDF.
- Test sample See Table 2.
- Experimental medium Dimethyl sulfoxide (DMSO), from Sigma, USA; 1.7 Main instruments and reagents: BS124S electronic balance: Sartorius, Germany; Centrifuge: Beckman, USA; C0 2 cell incubator: ShellAB, USA; Sirius chemiluminescence detector: Berthold, Germany; Trypsin: Invitrogen, USA; Streptomycin: American Invitrogen; Fetal bovine serum: Gibco, USA; Solution for lysing and luciferase detection: Promega, USA.
- test compound was dissolved in DMSO, added to the cell culture medium 15 minutes before infection, and the DMSO solvent was used as a blank control. Then add 0.5 ml of virus solution (diluted the virus stock to 0.1-0.5 ng p24/ml according to p24 concentration). 48 hours after infection, the supernatant was removed, 50 ⁇ M of cell lysate (Promega) was added to each well to lyse the cells, and 20 ⁇ M of cell lysate was added to 30 ⁇ L of luciferase substrate (Promega) using FB15 fluorescence detector. The relative activity of luciferase was determined by (Sirius) instrument, and the half-inhibitory concentration of the compound on wild-type HIV-1 replication was calculated using DMSO as a control. The detection data are shown in Table 2.
- the effect of compounds on cell survival was examined by MTS assay: 293T cells in logarithmic growth phase were seeded into 96-well plates at a cell density of 8000-10000 cells/well, each well 37 ⁇ , 37 °C, 5% CO 2 incubator After 24 hours of culture, the test compound was added, and DMSO was used as a blank control (final concentration: 0.1%), and the culture was continued for 44 hours at 37 ° C in a 5% CO 2 incubator. Add 2 ( ⁇ 1 MTS/PMS mixture) to each well, and continue to culture for 4 hours at 37 ° C in a 5% CO 2 incubator. On the enzyme-linked detector, the wavelengths are 490 nm and 650 nm ( The light absorption value (OD) of each well was measured, and the cell survival rate was calculated.
- OD light absorption value
- C0P134-114, C0P135-114, C0P230, C0P23 C0P233 or C0P234 can effectively inhibit the replication of wild-type HIV-1, and the half effective concentrations are COP12-114 (5.9 ⁇ 0.6nM), C0P130 (4.8 ⁇ 0.9nM), C0P131-114 (1.6 ⁇ 0.6nM), C0P132-114 (2.7 ⁇ 0.2nM), C0P133-114 (4.9 ⁇ 0.6nM), C0P134-114 (4.6 ⁇ 0.2nM), C0P135-114 (7.5 ⁇ 0.4nM), C0P230 (40 ⁇ 0.2nM), C0P231 (33.4 ⁇ 8.1nM), C0P233 (4.15 ⁇ 1.35nM) or COP234 (5.0 ⁇ 0.4nM), the half effective concentration of CMX157 and positive control AZT measured in parallel under the same conditions were 8.7. At ⁇ 1.8 nM and 24.3 nM, all compounds were not cytotoxic at a final concentration of ⁇ .
- the compound of the present invention exhibits a strong antiviral action, and has the advantages of low toxicity and good fat solubility, and is expected to be a novel drug for treating HIV infection.
- the present invention provides a tenofovir diester compound, a salt thereof or a tautomer thereof, and a process for the preparation thereof, a use thereof, and a pharmaceutical composition comprising the same.
- the compound provided by the invention has novel structure, simple synthesis, reduced polarity of the compound, and better fat solubility than the existing tenofovir diester compound, thereby improving the membrane permeability of the drug and improving the bioavailability;
- the compounds provided by the present invention also exhibit strong antiviral effects, especially for HIV and hepadnaviruses, which are superior to the existing tenofovir diesters and show no significant toxicity. It has high safety and is suitable for the prevention and treatment of AIDS and hepatitis. It has a very broad application prospect.
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Abstract
Disclosed is a Tenofovir diester compound shown as a general formula (I), a salt or tautomer thereof，as well as a preparation method and use thereof and a pharmaceutical composition comprising the same. The compound has good liposolubility, and strong anti-HIV effect and anti-HBV effect.
Description
替诺福韦双酯类化合物、 其制备方法、 用途以及包含其的药物组合物 技术领域 Tenofovir diester compound, preparation method thereof, use thereof and pharmaceutical composition containing the same
本发明涉及药物化学领域， 具体涉及一种替诺福韦双酯类化合物、 其制备方法、 用途 以及包含其的药物组合物。 The present invention relates to the field of medicinal chemistry, and in particular to a tenofovir diester compound, a process for the preparation thereof, use thereof, and a pharmaceutical composition comprising the same.
背景技术 Background technique
人类在病毒感染性疾病的治疗中， 病毒耐药性问题曰益突出。 与环状核苷类逆转录酶 抑制剂相比， 非环核苷化合物阿德福韦和替诺福韦在防止病毒耐药性问题上具有明显优 势， 其对耐环状核苷类药物的病毒株有效， 本身耐药发生率低， 且毒性相对较小。 但是， 由于磷酸酯基带负电荷， 极性较强， 生物膜透过性差， 导致生物利用度很低， 使其不能成 为药物应用于临床， 其双酯性前药替诺福韦双异丙酰氧基甲酯富马酸盐 （TDF ) [商品名： 韦瑞德 （Viread ), 其 IC50为 1.6μΜ]改善了药物的生物利用度， 于 2001年被 FDA批准上 巿， 是迄今为止抗病毒活性较强、 肾毒性又较低的治疗艾滋病药物。 但是， 据报道， 其人 体生物利用度仍只有 28%左右。 因此， 对阿德福韦和替诺福韦进行进一步的研究和改造具 有重要价值。 In the treatment of viral infectious diseases, the problem of viral resistance is highly beneficial. Compared with cyclic nucleoside reverse transcriptase inhibitors, the acyclic nucleoside compounds adefovir and tenofovir have obvious advantages in preventing viral resistance, and they are resistant to cyclic nucleosides. The virus strain is effective, the incidence of drug resistance is low, and the toxicity is relatively small. However, due to the negative charge of the phosphate group, the polarity is strong, and the biofilm permeability is poor, resulting in low bioavailability, making it impossible to be used as a drug in clinical applications. Its diester prodrug tenofovir diisopropionyl Oxymethyl ester fumarate (TDF) [trade name: Viread, IC50 of 1.6μΜ] improves the bioavailability of the drug, was approved by the FDA in 2001, is the antiviral activity so far Strong and less toxic drugs for the treatment of AIDS. However, it is reported that its human bioavailability is still only about 28%. Therefore, further research and modification of adefovir and tenofovir are of great value.
专利申请 WO 2012/041015A1公开了以下内容: "中国专利 （ CN1810816A )在替诺福 韦分子中磷酸基的一个羟基上引入脂溶性垸氧乙基长链， 使分子结构中磷酸基团的一个羟 基被酯化、一个仍处于游离状态， 得到阿德福韦和替诺福韦的磷酸长链垸氧乙 /丙基单酯衍 生物。 该化合物在引入长链垸氧乙 /丙基后， 不仅改善了化合物的药代动力学性质， 而且磷 酸基中另一个游离羟基仍可以被磷酸化、 参与病毒复制过程， 发挥抗病毒效果， 因而保留 了替诺福韦的抗病毒活性。 即脂溶性长链的引入既改善了化合物的药代动力学性质又保留 了抗病毒活性。"， 所述化合物已分别完成了临床前的各项检测， 不仅证明了上述专利中的 化合物有很高的活性和抗耐药性， 而且还发现其毒性也是很低的， 不会抑制肝脏内代谢这 些药物的酶系。 The patent application WO 2012/041015 A1 discloses the following: "Chinese patent (CN1810816A) introduces a fat-soluble oxiranyl ethyl long chain on a hydroxyl group of a phosphate group in the tenofovir molecule to give a hydroxyl group of a phosphate group in the molecular structure. A long chain oxirane/propyl monoester derivative of adefovir and tenofovir obtained by esterification and still in a free state. The compound is introduced not only after the introduction of long chain oxirane/propyl group The pharmacokinetic properties of the compound are improved, and another free hydroxyl group in the phosphate group can still be phosphorylated, participate in the virus replication process, and exert an antiviral effect, thereby retaining the antiviral activity of tenofovir. The introduction of the chain not only improves the pharmacokinetic properties of the compound but also retains the antiviral activity.", the compounds have completed preclinical tests, respectively, which not only proves that the compounds in the above patents are highly active and It is also resistant to drug resistance, and it is also found to be very toxic, and does not inhibit the enzymes that metabolize these drugs in the liver.
另一中国专利 CN101977610 A (专利名称： 治疗病毒感染的方法， 公开曰： 2011年 2 月 16日） 中的化合物 CMX157也是对替诺福韦及其衍生物进行的改造， 各种实验表明： 对 HIV病毒无论野生型还是各种突变耐药型， CMX157都显示出了很高的活性、很低的毒 性且与治疗 HIV的药物联合使用时有良好的协同作用，有着成为新的治疗艾滋病药物的前 景。 Another Chinese patent CN101977610 A (patent name: method for treating viral infections, published on February 16, 2011) is also a modification of tenofovir and its derivatives. Various experiments have shown: HIV virus, regardless of its wild type or various mutation-resistant forms, CMX157 has shown high activity, low toxicity and good synergy when used in combination with HIV-treated drugs. It has become a new drug for the treatment of AIDS. prospect.
上述化合物都是替诺福韦的前药， 其对替诺福韦加以改造的主要目的是提高其脂溶 性， 改善膜透过性， 进而提高人体的生物利用度， 然而上述两种前药的分子结构中磷酸基 团的一个羟基被酯化、 而另一个仍处于游离状态， 所以其仍是一种极性很大的化合物， 生
物利用度仍有待进一步的提高。 The above compounds are all prodrugs of tenofovir, and the main purpose of modifying tenofovir is to improve its fat solubility, improve membrane permeability, and thereby improve the bioavailability of the human body. In the molecular structure, one hydroxyl group of a phosphate group is esterified while the other is still in a free state, so it is still a highly polar compound. The availability of materials still needs to be further improved.
发明内容 Summary of the invention
为了进一步改善现有替诺福韦类化合物的脂溶性， 本发明的目的是提供一种替诺福韦 双酯类化合物、 其盐或其互变异构体。 In order to further improve the fat solubility of the existing tenofovir-like compounds, it is an object of the present invention to provide a tenofovir diester compound, a salt thereof or a tautomer thereof.
本发明的另一目的是提供所述化合物的制备方法。 Another object of the invention is to provide a process for the preparation of said compounds.
本发明的另一目的是提供所述化合物的用途。 Another object of the invention is to provide the use of said compounds.
本发明的另一目的是提供包含所述化合物的药物组合物。 Another object of the invention is to provide a pharmaceutical composition comprising the compound.
本发明提供了一种如通式（ I )所示的替诺福韦双酯类化合物、其盐或其互变异构体, The present invention provides a tenofovir diester compound represented by the formula (I), a salt thereof or a tautomer thereof,
所述通式 （ I ) 中， Ra、 Rb独立地选自 、 R2或 R3, 且 Ra、 Rb不同时为 R2; Rc选 自氢或 C1 C5的垸基； In the formula (I), R a and R b are independently selected from R 2 or R 3 , and R a and R b are not simultaneously R 2 ; R c is selected from hydrogen or C 1 C 5 fluorenyl;
所述 Ri为 -OCH2(CH2)mCH2OCH2(CH2)nCH3, 其中， m为 0 ~ 4的整数， n为 10 20 的整数； The Ri is -OCH 2 (CH 2 ) m CH 2 OCH 2 (CH 2 ) n CH 3 , wherein m is an integer of 0 to 4, and n is an integer of 10 20 ;
所述 R2为- OCH2OC(=0)OCH(CH3)2; The R 2 is - OCH 2 OC(=0)OCH(CH 3 ) 2 ;
所述 R3为任意天然或药用氨基酸的氨基脱去一个氢后的残基，其中，所述氨基酸中的 羧基被垸基或芳基酯化。 The R 3 is a residue obtained by removing an amine from an amino group of any natural or pharmaceutically acceptable amino acid, wherein the carboxyl group in the amino acid is esterified with a thiol group or an aryl group.
所述氨基酸包括但不限于甘氨酸、 丙氨酸、 缬氨酸、 亮氨酸、 异亮氨酸、 苯丙氨酸、 脯氨酸、 色氨酸、 丝氨酸、 酪氨酸、 半胱氨酸、 蛋氨酸、 天冬氨酸、 谷氨酸、 苏氨酸、 赖 氨酸、 精氨酸或组氨酸等。 The amino acids include, but are not limited to, glycine, alanine, valine, leucine, isoleucine, phenylalanine, valine, tryptophan, serine, tyrosine, cysteine, Methionine, aspartic acid, glutamic acid, threonine, lysine, arginine or histidine.
作为优选的技术方案， 所述 为通式 （ Π ) 示的结构，
As a preferred technical solution, the structure is represented by the general formula ( Π ),
其中， 、 R5独立地选自 C1 ~ C12的垸基、 C3 ~ C12的环垸基、 C2 ~ C12的烯基、 C2 ~ C12的炔基、 C6 ~ C12的芳基或 C6 ~ C12的芳垸基。 Wherein, R 5 is independently selected from a C1 to C12 fluorenyl group, a C3 to C12 cycloalkane group, a C2 to C12 alkenyl group, a C2 to C12 alkynyl group, a C6 to C12 aryl group or a C6 to C12 aryl group.垸基.
作为优选的技术方案， R4、 R5独立地选自 CI ~ C12的垸基、 C3 C12的环垸基或 C6 ~
C12的芳垸基。 As a preferred technical solution, R4 and R 5 are independently selected from a sulfhydryl group of CI ~ C12, a cyclic fluorenyl group of C3 C12 or C6 ~ An aromatic group of C12.
作为优选的技术方案， 所述 R4选自甲基、 乙基或苄基。 As a preferred technical solution, the R4 is selected from a methyl group, an ethyl group or a benzyl group.
作为优选的技术方案， 所述 选自甲基、 乙基、 丙基、 异丙基、 环丙基、 正丁基、 异 丁基、 仲丁基、 叔丁基、 环丁基、 正戊基、 新戊基、 异戊基、 环戊基、 3-甲基己基、 正己 基、 2,2-二甲基戊基、 2,3-二甲基戊基、 环己基、 正庚基、 正辛基、 正壬基、 正癸基、 正十 二垸基、 苯基或苄基。 As a preferred technical solution, the one selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl , neopentyl, isopentyl, cyclopentyl, 3-methylhexyl, n-hexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, cyclohexyl, n-heptyl, positive Octyl, n-decyl, n-decyl, n-dodecyl, phenyl or benzyl.
作为优选的技术方案， 所述 m为 0 ~ 2的整数； 更优选 0或 1。 As a preferred technical solution, the m is an integer of 0 to 2; more preferably 0 or 1.
作为优选的技术方案， 所述 n为 12 18的整数； 更优选 14、 15或 16。 As a preferred technical solution, the n is an integer of 12 18; more preferably 14, 15 or 16.
作为优选的技术方案， 本发明提供了以下结构中任一个所示的化合物、 其盐或其互变 异构体： As a preferred technical solution, the present invention provides a compound represented by any one of the following structures, a salt thereof or a tautomer thereof:
C0P12-014 C0P12-015
C0P12-014 C0P12-015
C0P12-016 C0P12-114
C0P12-016 C0P12-114
C0P12-1 15 C0P12-1 16
C0P12-1 15 C0P12-1 16
C0P130-114 C0P131- 114
C0P130-114 C0P131- 114
C0P132-114 C0P133-114 C0P132-114 C0P133-114
C0P134-114 C0P135-114 C0P134-114 C0P135-114
C0P230 C0P231
上述技术方案中， 通式 （ I )所示的化合物存在不对称中心， 具有 S构型或 构型， 本发明技术方案包括所有可能的立体异构体以及两种或多种异构体的混合物。 通式 （ I ) 所示的化合物如存在顺 /反异构体， 本发明技术方案亦包括其顺式异构体、 反式异构体或这 些异构体的混合物。 其中， 单一异构体可根据常规方法分离或通过立体选择合成制备。 C0P230 C0P231 In the above technical solution, the compound represented by the formula (I) has an asymmetric center and has an S configuration or configuration, and the technical solution of the present invention includes all possible stereoisomers and a mixture of two or more isomers. . For the compound represented by the formula (I), such as the presence of a cis/trans isomer, the technical solution of the present invention also includes a cis isomer, a trans isomer or a mixture of these isomers. Among them, a single isomer can be isolated according to a conventional method or synthesized by stereoselective synthesis.
上述技术方案中， 所述的盐是指生理上可接受的盐， 即本发明的化合物的有机盐和无 机盐。 生理上可接受的盐在所属领域是为本领域技术人员所熟知的。 生理上可接受的盐包 括但并不限于， 无机酸盐如盐酸盐、 氢溴酸盐、 磷酸盐、 硫酸盐、 高氯酸盐等， 以及有机
酸盐如富马酸盐、 乙酸盐、 草酸盐、 马来酸盐、 酒石酸盐、 柠檬酸盐、 琥珀酸盐、 丙二酸 盐等， 或通过文献所记载的其他方法如离子交换法所得到的盐。 In the above technical scheme, the salt means a physiologically acceptable salt, that is, an organic salt and an inorganic salt of the compound of the present invention. Physiologically acceptable salts are well known in the art to those skilled in the art. Physiologically acceptable salts include, but are not limited to, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and the like, and organic Acid salts such as fumarate, acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, etc., or by other methods described in the literature, such as ion exchange The salt obtained.
本发明提供的所述化合物的制备方法为： 以通式 （ 1 -1 )所示化合物为起始原料， 进 行缩合反应得到单酯类化合物（ 1 -2 ), 然后再进行缩合反应得通式（ I )所述的双酯类化 合物。 The preparation method of the present invention is as follows: a compound represented by the general formula (1-1) is used as a starting material, and a condensation reaction is carried out to obtain a monoester compound (1-2), and then a condensation reaction is carried out to obtain a general formula. The diester compound described in (I).
( 1 -1 ) ( 1 -2 ) ( I ) 上述制备方法中， 根据取代基 、 R2或 R3的不同， 相应的酯化过程分别优选为： 酯化取代基为 Ri时， 反应物为醇 HOCH2(CH2)mCH2OCH2(CH2)nCH3 ( m、 n的限定 同前）， 以 N-甲基吡咯垸酮为溶剂， 在三乙胺存在的环境下， Ν,Ν'-二环己基碳二亚胺为络 合剂进行脱水缩合反应， 反应过程中反应温度为 70°C-110°C , 反应时间为 7-15个小时。 (1 -1 ) ( 1 -2 ) ( I ) In the above preparation method, depending on the substituent, R 2 or R 3 , the respective esterification processes are preferably: when the esterification substituent is Ri, the reactant is Alcohol HOCH 2 (CH 2 )mCH 2 OCH 2 (CH 2 ) nCH 3 (m, n is as defined above), using N-methylpyrrolidone as solvent, in the presence of triethylamine, hydrazine, hydrazine '-Dicyclohexylcarbodiimide is a complexing agent for dehydration condensation reaction. The reaction temperature during the reaction is 70 ° C - 110 ° C, and the reaction time is 7-15 hours.
酯化取代基为 时， 反应物为氯甲基碳酸异丙酯， 以 N-甲基吡咯垸酮为溶剂， 在三 乙胺存在的环境下进行缩合反应，反应过程中反应温为 45 °C-75 °C ,反应时间为 12-18个小 时。 When the esterification substituent is used, the reactant is isopropyl chloromethyl carbonate, and the condensation reaction is carried out in the presence of triethylamine using N-methylpyrrolidone as a solvent, and the reaction temperature during the reaction is 45 ° C. -75 °C, reaction time is 12-18 hours.
酯化取代基为 时， 反应物为氨基酸酯盐酸盐， 以 N-甲基吡咯垸酮为溶剂， 三乙胺 为脱水剂， 2,2'-二硫二吡啶、 三苯基膦为络合剂， 进行缩合反应， 反应过程中反应温度为 45 V -85 V , 反应时间为 8-26个小时。 When the esterification substituent is used, the reactant is an amino acid ester hydrochloride, N-methylpyrrolidone is used as a solvent, triethylamine is a dehydrating agent, 2,2'-dithiodipyridine or triphenylphosphine is used as a solvent. The mixture is subjected to a condensation reaction in which the reaction temperature is 45 V -85 V and the reaction time is 8-26 hours.
本发明提供了以上技术方案任一项所述的化合物、 其盐或其互变异构体在制备用于预 防或治疗肿瘤或病毒性疾病的药物中的用途。 The present invention provides the use of a compound according to any one of the above aspects, a salt thereof or a tautomer thereof for the preparation of a medicament for preventing or treating a tumor or a viral disease.
其中， 所述病毒性疾病为艾滋病病毒和 /或嗜肝 DNA病毒引起的疾病。 Wherein the viral disease is a disease caused by HIV and/or a hepadnavirus.
其中， 所述嗜肝 DNA病毒为乙型肝炎病毒。 Wherein the hepadnavirus is hepatitis B virus.
本发明还提供了一种药物组合物， 其包括以上技术方案任一项所述的化合物、 其盐或 其互变异构体， 以及药学上可接受的载体。 The present invention also provides a pharmaceutical composition comprising the compound according to any one of the above aspects, a salt thereof or a tautomer thereof, and a pharmaceutically acceptable carrier.
本发明提供的药物组合物可根据本领域已知的方法制备， 制成适于人或动物使用的任 何剂型。 活性成分在所述药物组合物中的含量通常为 0.1-95重量％, 或可根据不同的应用 由本领域技术人员进行相应调整。 The pharmaceutical compositions provided herein can be prepared according to methods known in the art to produce any dosage form suitable for human or animal use. The active ingredient is usually present in the pharmaceutical composition in an amount of from 0.1 to 95% by weight, or may be adjusted accordingly by those skilled in the art depending on the application.
本发明提供的药物组合物中， 所述药物组合物选自片剂、 胶囊剂、 丸剂、 散剂、 颗粒 剂、 悬浮剂、 乳剂或注射剂。 In the pharmaceutical composition provided by the present invention, the pharmaceutical composition is selected from the group consisting of a tablet, a capsule, a pill, a powder, a granule, a suspension, an emulsion or an injection.
为制成不同剂型的药物组合物， 可将通式（I )的化合物、 其盐或其互变异构体按已知 方法与药学上可接受的合适制药载体物质如填充剂、 芳香剂、 调味剂、 着色剂、 润湿剂、
赋形剂、 崩解剂或表面活性剂等釆用已知的方法进行混合， 并被制成片剂等固体剂型或悬 浮剂等液体剂型等等。 For the preparation of pharmaceutical compositions of different dosage forms, the compound of the formula (I), a salt thereof or a tautomer thereof can be prepared according to known methods with pharmaceutically acceptable suitable pharmaceutical carrier materials such as fillers, fragrances, Flavoring agents, colorants, wetting agents, The excipient, the disintegrating agent or the surfactant is mixed by a known method, and is prepared into a liquid dosage form such as a solid dosage form or a suspension agent such as a tablet or the like.
本发明的药物组合物可以制成普通制剂， 也可制成缓释制剂、 控释制剂或向制剂及各 种微粒给药系统等。 The pharmaceutical composition of the present invention can be prepared into a general preparation, a sustained release preparation, a controlled release preparation or a delivery system for various preparations and the like.
为达到用药目的， 增强治疗效果， 本发明的药物组合物可用任何公知的给药方法进行 给药。 The pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of enhancing the therapeutic effect for the purpose of administration.
本发明提供的替诺福韦双酯类化合物、 其盐或其互变异构体结构新颖， 合成简便， 降 低了化合物极性，脂溶性优于现有的替诺福韦双酯类化合物，从而可改善药物的膜透过性， 以提高生物利用度； 此外， 本发明提供的化合物还显示出了较强的抗病毒作用， 尤其是对 于艾滋病毒和嗜肝 DNA病毒， 活性优于现有的替诺福韦双酯类化合物， 而且未显示出明 显的毒性， 安全性较高， 适用于预防与治疗艾滋病和肝炎的药物， 具有非常广阔的应用前 景。 The tenofovir diester compound provided by the invention, the salt thereof or the tautomer thereof has novel structure, simple synthesis, reduced polarity of the compound, and better fat solubility than the existing tenofovir diester compound. Thereby, the membrane permeability of the drug can be improved to improve bioavailability; in addition, the compound provided by the present invention also exhibits a strong antiviral effect, especially for HIV and hepadnavirus, the activity is superior to the existing one. The tenofovir diester compound, which does not show obvious toxicity and has high safety, is suitable for the prevention and treatment of AIDS and hepatitis, and has a very broad application prospect.
附图说明 DRAWINGS
图 1为实验例 1所述的本发明化合物 C0P12-114和 CMX157的高效液相色谱图； 图 2为实验例 1所述的本发明化合物 COP130-114和 CMX157的高效液相色谱图； 图 3为实验例 1所述的本发明化合物 C0P131-114和 CMX157的高效液相色谱图； 图 4为实验例 1所述的本发明化合物 C0P233和 TDF的高效液相色谱图。 1 is a high performance liquid chromatogram of the inventive compounds COP12-114 and CMX157 described in Experimental Example 1; FIG. 2 is a high performance liquid chromatogram of the inventive compounds COP130-114 and CMX157 described in Experimental Example 1; High performance liquid chromatograms of the inventive compounds COP131-114 and CMX157 described in Experimental Example 1; Fig. 4 is a high performance liquid chromatogram of the inventive compounds COP233 and TDF described in Experimental Example 1.
图中， 横坐标为时间， 单位为分钟。 In the figure, the abscissa is time and the unit is minute.
具体实施方式 detailed description
以下实施例用于说明本发明， 但不用来限制本发明的范围。 以下试剂如无特别说明均 为常见巿售试剂， 以下操作如无特殊说明均为本领域常用操作。 本发明实施方式所使用的 中间体的制备过程如下： The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention. The following reagents are common sales reagents unless otherwise specified. The following operations are commonly used in the art unless otherwise specified. The preparation process of the intermediate used in the embodiment of the present invention is as follows:
1、 3-十六垸氧基 -1-丙醇（L114 ) 的制备 1. Preparation of 3-hexadecyloxy-1-propanol (L114)
HOCH CH CH OH CH3(CH2)14CH2Br _ - _ CH3(CH2)14CH2OCH2CH2CH2OH HOCH CH CH OH CH 3 (CH 2 ) 14 CH 2 Br _ - _ CH 3 (CH 2 ) 14 CH 2 OCH 2 CH 2 CH 2 OH
L1 14 L1 14
在 250ml三口圆底烧瓶中， 依次加入 1,3-丙二醇 ( 9.13g, 0.12mol )、 叔丁醇钾 ( 6.8g, 0.06mol )和叔戊醇（50ml ), 回流状态下， 慢慢滴加溴代十六垸（ 12.17g, 12.2ml, 0.04mol ) 和四氢呋喃 （50ml ) 的混合液， 3小时滴完。 再回流搅拌 50小时后， 冷至室温， 将反应液 倾入 50ml水中， 搅拌， 用 10%的盐酸酸化至 pH=7, 加入正己垸 （ 100ml ) ,分出有机相， 水 相用正己垸萃取， 合并有机相， 有机相干燥浓缩后用正戊垸重结晶得到 3-十六垸氧基 -1-丙 醇 （L114 ) ( 7.8g, 0.026mol ), 收率： 65%。 In a 250 ml three-neck round bottom flask, 1,3-propanediol (9.13 g, 0.12 mol), potassium t-butoxide (6.8 g, 0.06 mol) and tert-amyl alcohol (50 ml) were added in this order, and slowly added dropwise under reflux. A mixture of hexadecyl bromide (12.17 g, 12.2 ml, 0.04 mol) and tetrahydrofuran (50 ml) was added dropwise over 3 hours. After refluxing for another 50 hours, it was cooled to room temperature, and the reaction liquid was poured into 50 ml of water, stirred, acidified to pH=7 with 10% hydrochloric acid, and then added to hexane (100 ml), the organic phase was separated, and the aqueous phase was extracted with n-hexane. The organic phase was combined, and the organic phase was dried and concentrated, and then recrystallized from n-pentane to give 3-hexyloxy-1-propanol (L114) ( 7.8 g, 0.026 mol), yield: 65%.
JH NM ( 400 MHz, CDC13 ) δ ( ppm ): 0.88(3H, t, CH3), 1.14-1.37(26H, m, 13
CH2), 1.48-1.65(2H, m, CH2), 1.71-1.94(2H, m, CH2), 2.38-2.53(lH, br, OH), 3.43(2H, t, OCH2), 3.62(2H, t, OCH2), 3.78(2H, t, OCH2)。 J H NM ( 400 MHz, CDC1 3 ) δ (ppm ): 0.88 (3H, t, CH 3 ), 1.14-1.37 (26H, m, 13 CH 2 ), 1.48-1.65 (2H, m, CH 2 ), 1.71-1.94 (2H, m, CH 2 ), 2.38-2.53 (lH, br, OH), 3.43 (2H, t, OCH 2 ), 3.62 (2H, t, OCH 2 ), 3.78 (2H, t, OCH 2 ).
ESI-MS: [M+H]+ 301.3 , [M+Na]+323.2。 ESI-MS: [M+H] + 301.3, [M+Na]+323.2.
2、 2-十八焼氧基乙醇（L016 ) 的制备 2. Preparation of 2-octadecyloxyethanol (L016)
HOCH2CH2OH HOCH 2 CH 2 OH
CH3(CH2)i6CH2Br ^ CH3(CH2)16CH20CH2CH20H CH3(CH2)i6CH2Br ^ CH3(CH2)16CH20CH2CH20H
L016 L016
以合成 LI 14的相同过程合成得到 2-十八垸氧基乙醇 （ L016 )。 2-Eoctadecyloxyethanol (L016) was synthesized by the same procedure for the synthesis of LI 14 .
^ NM ( 400 MHz, CDC13 ) δ ( ppm ): 0.88(3H, t, CH3), 1.06-1.49(30H, m, 15 CH2), 1.53- 1.654(2H, m, CH2), 1.90-2.10(1H, br, OH), 3.47(2H, t, OCH2), 3.53(2H, t, OCH2), 3.73 (2H, t, OCH2)。 ^ NM ( 400 MHz, CDC1 3 ) δ (ppm ): 0.88 (3H, t, CH 3 ), 1.06-1.49 (30H, m, 15 CH 2 ), 1.53- 1.654(2H, m, CH 2 ), 1.90 -2.10(1H, br, OH), 3.47(2H, t, OCH 2 ), 3.53 (2H, t, OCH 2 ), 3.73 (2H, t, OCH 2 ).
ESI-MS: [M+H]+ 315.3 , [M+Na]+337.3。 ESI-MS: [M+H] + 315.3, [M+Na]+337.3.
3、 6-十二垸氧基 -1-己醇 ( L410 ) 的制备 Preparation of 3,6-dodecyloxy-1-hexanol (L410)
HOCH2(CH2)4CH2OH HOCH 2 (CH 2 ) 4 CH 2 OH
CH3(CH2)10CH2Br »► CH3(CH2)10CH2OCH2(CH2)4CH2OH CH 3 (CH 2 ) 10 CH 2 Br »► CH 3 (CH 2 ) 10 CH 2 OCH 2 (CH 2 ) 4 CH 2 OH
L410 以合成 L114的相同过程合成得到 6-十二垸氧基 -1-己醇 （L410 )。 L410 was synthesized in the same manner as in the synthesis of L114 to give 6-dodecyloxy-1-hexanol (L410).
^ NM ( 400 MHz, CDC13 ) δ ( ppm ): 0.88(3Η, t, CH3), 1.14-1.34(18H, m, 9 x CH2), 1.35-1.42(4H, m, 2 CH2), 1.48-1.64(6H, m, 3 x CH2), 1.93-2.01(1H, br, OH), 3.28-3.48(4H, m, 2 OCH2), 3.62(2H, t, OCH2)。 ^ NM ( 400 MHz, CDC1 3 ) δ (ppm ): 0.88 (3Η, t, CH 3 ), 1.14-1.34 (18H, m, 9 x CH 2 ), 1.35-1.42 (4H, m, 2 CH 2 ) , 1.48-1.64 (6H, m, 3 x CH 2 ), 1.93-2.01 (1H, br, OH), 3.28-3.48 (4H, m, 2 OCH 2 ), 3.62 (2H, t, OCH 2 ).
ESI-MS: [M+H]+ 287.3 , [M+Na]+309.3。 ESI-MS: [M+H] + 287.3, [M+Na]+309.3.
4、 4-二十二垸氧基 -1-丁醇（L220 ) 的制备 Preparation of 4, 4-docosyloxy-1-butanol (L220)
HOCH2(CH2)2CH2OH HOCH 2 (CH 2 ) 2 CH 2 OH
CH3(CH2)20CH2Br ► CH3(CH2)20CH2OCH2(CH2)2CH2OH CH 3 (CH 2 ) 20 CH 2 Br ► CH 3 (CH 2 ) 20 CH 2 OCH 2 (CH 2 ) 2 CH 2 OH
L220 以合成 L114的相同过程合成得到 4-二十二垸氧基 -1-丁醇 （ L220 )。 L220 was synthesized in the same manner as in the synthesis of L114 to give 4-teledecyloxy-1-butanol (L220).
JH NMR ( 400 MHz, CDC13 ) δ ( ppm ): 0.88(3Η, t, CH3), 0.99-1.46(38H, m, 19 CH2), 1.52-1.61(2H, m, CH2), 1.62-1.78(4H, m, 2 CH2), 1.95-2.67(1H, br, OH), J H NMR ( 400 MHz, CDC1 3 ) δ (ppm ): 0.88 (3Η, t, CH 3 ), 0.99-1.46 (38H, m, 19 CH 2 ), 1.52-1.61 (2H, m, CH 2 ), 1.62-1.78(4H, m, 2 CH 2 ), 1.95-2.67(1H, br, OH),
3.30-3.51(4H, m, 2 OCH2), 3.64(2H, t, OCH2)。 3.30-3.51 (4H, m, 2 OCH 2 ), 3.64 (2H, t, OCH 2 ).
ESI-MS: [M+H]+399.4。 ESI-MS: [M+H]+ 399.4.
实施例 1: C0P12-114的制备
在 50ml圆底烧瓶中， 依次加入（R ) -9-[2- (磷酸甲氧基） 丙基]腺嘌呤（替诺福韦， PMPA ) ( 1.3g, 4.5mmol )、 三乙胺（7ml, 5.08g, 50.2mmol )、 氯甲基碳酸异丙酯（ 0.265ml, 0.305g, 2mmol )和 N-甲基 -2-吡咯垸酮 （ 14ml ), 在 60°C下搅拌 15h后， 蒸除溶剂， 用乙 酸乙酯： 乙醇 =20： 1 (体积比）进行硅胶柱层析， 得中间化合物 C0P02 ( 0.68g, 1.68mmol ) 收率 37.3%。 Example 1: Preparation of C0P12-114 In a 50 ml round bottom flask, (R)-9-[2-(phosphomethoxy)propyl]adenine (tenofovir, PMPA) (1.3 g, 4.5 mmol), triethylamine (7 ml) were added in sequence. , 5.08g, 50.2mmol), isopropyl chloromethyl carbonate (0.265ml, 0.305g, 2mmol) and N-methyl-2-pyrrolidone (14ml), stirred at 60 ° C for 15h, then evaporated The solvent was subjected to silica gel column chromatography using ethyl acetate: ethanol = 20:1 (volume ratio) to afford intermediate compound COOP02 (0.68 g, 1.68 mmol) yield 37.3%.
在 50ml圆底烧瓶中， 将 C0P02 ( 1.23g , 3.04mmol )、 L114 ( 1.83 g, 6.09mmol )混合 溶于 10ml N-甲基吡咯垸酮中， 加热到 85 °C搅拌 10分钟后， 滴加三乙胺 2.5ml, 然后升温至 100°C , 再滴加 Ν,Ν'-二环己基碳二亚胺 1.24g (溶于 2ml N-甲基 -2-吡咯垸酮中）， 10CTC下搅 拌反应 8h后， 冷却至 45 °C , 混合液旋干， 加入二氯甲垸和甲醇为 2 : 1 (体积比） 的混合溶 剂 100ml充分溶解后过滤， 滤液旋干， 残余物硅胶柱层析分离后得到白色固体化合物 C0P12-114 ( 1.32g, 1.93 mmol ) 收率 63.5%。 In a 50 ml round bottom flask, COP02 (1.23 g, 3.04 mmol), L114 (1.83 g, 6.09 mmol) was mixed and dissolved in 10 ml of N-methylpyrrolidone, heated to 85 ° C and stirred for 10 minutes, then added dropwise. 2.5 ml of triethylamine, then warmed to 100 ° C, and then added dropwise 1.2, Ν '-dicyclohexylcarbodiimide 1.24g (dissolved in 2ml N-methyl-2-pyrrolidone), stirred at 10CTC After reacting for 8 hours, it was cooled to 45 ° C, and the mixture was spun dry. After adding 100 ml of a mixed solvent of 2:1 (volume ratio) of dichloromethane and methanol, the solution was dissolved, the filtrate was spun, and the residue was separated by silica gel column chromatography. After that, a white solid compound C0P12-114 (1. 32 g, 1.93 mmol) yield 63.5%.
JH NM ( 400 MHz, CDC13 ) δ (ppm): 0.88(3H , t, CH3), 1.08-1.38(35H, m, 13 x CH2和 3 CH3), 1.45-1.60(2H, m, CH2), 1.81-1.94(2H, m, CH2), 3.30-3.49(4H, m, 2 OCH2), 3.62-3.73(lH, m, OCH), 3.85-3.99(2H, m, OCH2), 4.05-4.43(4H, m, OCH2P 和 NCH2), 4.86-4.98(lH, m, COOCH), 5.54-5.71(2H, m, OCH20), 6.37(2H, s, NH2), 7.95-8.06(lH, d, 嘌呤环上的 H), 8.33(1H, s, 嘌呤环上的 H)。 J H NM ( 400 MHz, CDC1 3 ) δ (ppm): 0.88 (3H , t, CH 3 ), 1.08-1.38 (35H, m, 13 x CH 2 and 3 CH 3 ), 1.45-1.60 (2H, m , CH 2), 1.81-1.94 (2H , m, CH 2), 3.30-3.49 (4H, m, 2 OCH 2), 3.62-3.73 (lH, m, OCH), 3.85-3.99 (2H, m, OCH 2 ), 4.05-4.43 (4H, m, OCH 2 P and NCH 2 ), 4.86-4.98 (lH, m, COOCH), 5.54-5.71 (2H, m, OCH 2 0), 6.37 (2H, s, NH 2 ), 7.95-8.06 (lH, d, H on the anthracene ring), 8.33 (1H, s, H on the anthracene ring).
ESI-MS: [M+H]+ 686.3 , [M+Na]+708.3。 ESI-MS: [M+H] + 686.3, [M+Na]+708.3.
实施例 2 ： C0P12-016的制备 Example 2: Preparation of C0P12-016
JH NM ( 400 MHz, CDC13 ) δ ( ppm ): 0.88 (3H, t, CH3), 1.07-1.40(39H, m, 15 x CH2和 3 x CH3), 1.46-1.61(2H, m, CH2), 3.32-3.47(4H, m, 2 OCH2), 3.63-3.71(lH, m, OCH), 3.86-3.97(2H, m, OCH2), 4.06-4.41(4H, m, OCH2P和 NCH2), 4.87-4.96(lH, m, COOCH), 5.56-5.69 (2H, m, OCH20), 6.38(2H, s, NH2), 7.96-8.04(lH, d, 嘌呤环 上的 H), 8.33(1H, s, 嘌呤环上的 H)。 J H NM ( 400 MHz, CDC1 3 ) δ (ppm ): 0.88 (3H, t, CH 3 ), 1.07-1.40 (39H, m, 15 x CH 2 and 3 x CH 3 ), 1.46-1.61 (2H, m, CH 2 ), 3.32-3.47(4H, m, 2 OCH 2 ), 3.63-3.71(lH, m, OCH), 3.86-3.97(2H, m, OCH 2 ), 4.06-4.41(4H, m, OCH 2 P and NCH 2 ), 4.87-4.96 (lH, m, COOCH), 5.56-5.69 (2H, m, OCH 2 0), 6.38 (2H, s, NH2), 7.96-8.04 (lH, d, 嘌呤H) on the ring, 8.33 (1H, s, H on the ankle ring).
ESI-MS: [M+H]+ 700.4, [M+Na]+722.4。 ESI-MS: [M+H]+ 700.4, [M+Na]+722.4.
实施例 3: C0P12-410的制备 Example 3: Preparation of C0P12-410
在 50ml圆底烧瓶中， 将 C0P02 ( 1.23g, 3.04mmol )、 L410 ( 1.74 g, 6.08mmol )混合溶 于 10ml N-甲基吡咯垸酮中，加热到 90°C搅拌 30分钟后，滴加三乙胺 3ml,然后升温至 105 °C , 再滴加 Ν,Ν'-二环己基碳二亚胺 1.24g (溶于 2ml N-甲基 -2-吡咯垸酮中）， 105 °C下搅拌反应 14小时后， 冷却至室温， 混合液旋干， 加入二氯甲垸和甲醇为 2： 1 (体积比） 的混合溶剂 100ml充分溶解后过滤，滤液旋干，残余物硅胶柱层析分离后得到目标物 C0P12-410 ( 0.84g, 1.25 mmol ), 收率 41%。 In a 50 ml round bottom flask, COP02 (1.23 g, 3.04 mmol), L410 (1.74 g, 6.08 mmol) was mixed and dissolved in 10 ml of N-methylpyrrolidone, heated to 90 ° C and stirred for 30 minutes, then added dropwise. 3 ml of triethylamine, then warmed to 105 ° C, and then added dropwise Ν, Ν '-dicyclohexylcarbodiimide 1.24 g (dissolved in 2 ml of N-methyl-2-pyrrolidone), at 105 ° C After stirring the reaction for 14 hours, it was cooled to room temperature, and the mixture was spun dry. After adding 100 ml of a mixed solvent of 2:1 (volume ratio) of dichloromethane and methanol, the solution was dissolved, the filtrate was dried, and the residue was separated by silica gel column chromatography. The title compound (0:12 g, 1.25 mmol) was obtained, yield 41%.
^ NM ( 400 MHz, CDC13 ) δ ( ppm ): 0.88(3H, t, CH3), 1.07-1.39(31H, m, 9 x CH2、 2 CH2和 3 CH3), 1.44-1.61(4H, m, 2 CH2), 1.80-1.95(2H, m, CH2), 3.29-3.50(4H, m, 2 OCH2), 3.61-3.74(1H, m, OCH), 3.84-4.00(2H, m, OCH2), 4.04-4.44(4H, m, OCH2P禾口 NCH2), 4.85-4.99(lH, m, COOCH), 5.53-5.72(2H, m, OCH20), 6.36(2H, s, NH2), 7.94-8.07(lH, d, 嘌呤环上的 H), 8.32(1H, s, 嘌呤环上的 H)。 ^ NM ( 400 MHz, CDC1 3 ) δ (ppm ): 0.88 (3H, t, CH 3 ), 1.07-1.39 (31H, m, 9 x CH 2 , 2 CH 2 and 3 CH 3 ), 1.44-1.61 ( 4H, m, 2 CH 2 ), 1.80-1.95 (2H, m, CH 2 ), 3.29-3.50 (4H, m, 2 OCH 2 ), 3.61-3.74 (1H, m, OCH), 3.84-4.00 (2H , m, OCH 2 ), 4.04-4.44 (4H, m, OCH 2 P and NCH 2 ), 4.85-4.99 (lH, m, COOCH), 5.53-5.72 (2H, m, OCH 2 0), 6.36 ( 2H, s, NH 2 ), 7.94-8.07 (lH, d, H on the anthracene ring), 8.32 (1H, s, H on the anthracene ring).
ESI-MS: [M+H]+ 672.4, [M+Na]+694.4。 ESI-MS: [M+H] + 672.4, [M+Na]+ 694.4.
实施例 4: C0P12-220 的制备
在 50ml圆底烧瓶中， 将 C0P02 ( 1.23g, 3.04mmol )、 L220 ( 2.42 g, 6.08mmol )混合溶 于 10ml N-甲基吡咯垸酮中，加热到 90°C搅拌 20分钟后，滴加三乙胺 3ml,然后升温至 105 °C , 再滴加 Ν,Ν'-二环己基碳二亚胺 1.24g (溶于 2ml N-甲基 -2-吡咯垸酮中）， 105 °C下搅拌反应 10h后，冷却至室温， 混合液旋干，加入二氯甲垸和甲醇为 2： 1 (体积比）的混合溶剂 100ml 充分溶解后过滤， 滤液旋干， 残余物硅胶柱层析分离后得到目标物 C0P12-220 ( 1.13g, 1.45 mmol ), 收率 47.6%。 Example 4: Preparation of C0P12-220 In a 50 ml round bottom flask, COP02 (1.23 g, 3.04 mmol) and L220 (2.42 g, 6.08 mmol) were mixed and dissolved in 10 ml of N-methylpyrrolidone, heated to 90 ° C and stirred for 20 minutes, then added dropwise. 3 ml of triethylamine, then warmed to 105 ° C, and then added dropwise Ν, Ν '-dicyclohexylcarbodiimide 1.24 g (dissolved in 2 ml of N-methyl-2-pyrrolidone), at 105 ° C After stirring for 10 hours, the mixture was cooled to room temperature, and the mixture was spun dry. 100 ml of a mixed solvent of 2:1 (volume ratio) of methylene chloride and methanol was added thereto, and the mixture was thoroughly dissolved, and the filtrate was dried, and the residue was separated by silica gel column chromatography. The title compound (0.sup.12) (1.13 g, 1.45 mmol) was obtained in a yield of 47.6%.
JH NM ( 400 MHz, CDC13 ) δ ( ppm ): 0.88(3H, t, CH3), 1.06-1.37(47H, m, 19 x CH2和 3 x CH3), 1.43-1.59(4H, m, 2 CH2), 1.79-1.93(2H, m, CH2), 3.28-3.48(4H, m, 2 OCH2), 3.60-3.72(lH, m, OCH), 3.83-3.98(2H, m, OCH2), 4.03-4.42(4H, m, OCH2P 和 NCH2), 4.84-4.97(lH, m, COOCH), 5.52-5.70(2H, m, OCH20), 6.35(2H, s, NH2), 7.93-8.05(lH, d, 嘌呤环上的 H), 8.31(1H, s, 嘌呤环上的 H)。 J H NM ( 400 MHz, CDC1 3 ) δ (ppm ): 0.88 (3H, t, CH 3 ), 1.06-1.37 (47H, m, 19 x CH 2 and 3 x CH 3 ), 1.43-1.59 (4H, m, 2 CH 2 ), 1.79-1.93 (2H, m, CH 2 ), 3.28-3.48 (4H, m, 2 OCH 2 ), 3.60-3.72 (lH, m, OCH), 3.83-3.98 (2H, m , OCH 2 ), 4.03-4.42 (4H, m, OCH 2 P and NCH 2 ), 4.84-4.97 (lH, m, COOCH), 5.52-5.70 (2H, m, OCH 2 0), 6.35 (2H, s , NH 2 ), 7.93-8.05 (lH, d, H on the anthracene ring), 8.31 (1H, s, H on the anthracene ring).
ESI-MS: [M+H]+ 784.5 , [M+Na]+ 806.5。 ESI-MS: [M+H]+ 784.5, [M+Na]+ 806.5.
实施例 5: FC0P12-114的制备 Example 5: Preparation of FC0P12-114
JH NM ( 400 MHz, DMSO ) δ ( ppm ): 0.85(3Η, t, CH3), 1.04-1.12(3H, d, CH3), 1.12-1.33(32H, m, 13 x CH2和 2 x CH3), 1.34-1.51(2H, m, CH2), 1.62-1.81(2H, m, CH2), 3.21-3.39(4H, m, 2 OCH2), 3.80-4.06(5H, m, OCH、 OCH2P和 OCH2), 4.10-4.33(2H, m, NCH2), 4.75-4.89(lH, m, COOCH), 5.45-5.60(2H, m, OCH20), 6.63(2H, s, 富马 酸双键上的 H), 7.21(2H, s, NH2), 8.04(1H, s, 嘌呤环上的 H), 8.13(1H, s, 嘌呤环上的 H)，， 12.09-14.12(2H, s, 富马酸的两个 COOH)。
ESI-MS:[M+H]十 686.3。 J H NM ( 400 MHz, DMSO ) δ (ppm ): 0.85 (3Η, t, CH 3 ), 1.04-1.12 (3H, d, CH 3 ), 1.12-1.33 (32H, m, 13 x CH 2 and 2 x CH 3 ), 1.34-1.51(2H, m, CH 2 ), 1.62-1.81(2H, m, CH 2 ), 3.21-3.39(4H, m, 2 OCH 2 ), 3.80-4.06(5H, m, OCH, OCH 2 P and OCH 2 ), 4.10-4.33 (2H, m, NCH 2 ), 4.75-4.89 (lH, m, COOCH), 5.45-5.60 (2H, m, OCH 2 0), 6.63 (2H, s, H) on the double bond of fumaric acid, 7.21(2H, s, NH 2 ), 8.04 (1H, s, H on the anthracene ring), 8.13 (1H, s, H on the anthracene ring), 12.09 - 14.12 (2H, s, two COOH of fumaric acid). ESI-MS: [M+H] dec 686.3.
实施例 6: YC0P12-016的制备 Example 6: Preparation of YC0P12-016
C0P12-016 YC0P12-016 C0P12-016 YC0P12-016
制备过程同实施例 5 (收率： 92% )。 The preparation procedure was the same as in Example 5 (yield: 92%).
实施例 7: C0P130的制备 Example 7: Preparation of C0P130
替诺福韦 C0P030 Tenofovir C0P030
在 500 ml的圆底烧瓶中， 加入替诺福韦 （7.2g, 25.1mmol )和无水乙腈（200ml ), 在 50°C下慢慢滴加二氯亚砜（ 1.8ml, 25mmol ), 滴完后升温至 80°C搅拌 2h, 在氮气保护下蒸 除溶剂，加入无水二氯甲垸（ 200ml )分散后，在 -3CTC下，加入 L-丙氨酸异丙酯盐酸盐（ 4.17g, 25mmol ), 慢慢滴加三乙胺（ 16.7ml, 120mmol ), 升温到 -10°C下反应 lh后， 用 10%的磷酸 二氢钠（质量百分比）洗有机相，分出有机相并经干燥浓缩后，经柱层析得到 C0P030 ( 4.4g, ll.Ommol ), 收率 43.81%。 In a 500 ml round bottom flask, tenofovir (7.2 g, 25.1 mmol) and anhydrous acetonitrile (200 ml) were added, and thionyl chloride (1.8 ml, 25 mmol) was slowly added dropwise at 50 ° C. After completion, the temperature was raised to 80 ° C and stirred for 2 h. The solvent was evaporated under a nitrogen atmosphere. After dissolving with anhydrous dichloromethane (200 ml), and then, under the -3 CTC, L-alanine isopropyl ester hydrochloride ( 4.17) was added. g, 25mmol), slowly add triethylamine (16. 7ml, 120mmol), and heat up to -10 ° C for 1h, then wash the organic phase with 10% sodium dihydrogen phosphate (mass%), separate the organic phase After drying and concentration, C0P030 (4.4 g, ll. Ommol) was obtained by column chromatography, yield 43.81%.
JH NM ( 400 MHz, DMSO ), δ ( ppm ): 0.92-0.98(3H, d, CH3), 1.11-1.36(9H, m, 3 x CH3), 2.82-2.92(3H, m, NCH和 2 x OCH), 3.82-3.94(2H, m, OCH2P), 4.13-4.38(2H, m, NCH2), 5.76(1H, s, NH), 7.18(2H, s, NH2), 8.13(1H, s, 嘌呤环上的 H), 8.24(1H, s, 嘌呤环上的 H)。 J H NM ( 400 MHz, DMSO ), δ ( ppm ): 0.92-0.98 (3H, d, CH 3 ), 1.11-1.36 (9H, m, 3 x CH 3 ), 2.82-2.92 (3H, m, NCH And 2 x OCH), 3.82-3.94 (2H, m, OCH 2 P), 4.13-4.38 (2H, m, NCH 2 ), 5.76 (1H, s, NH), 7.18(2H, s, NH 2 ), 8.13 (1H, s, H on the ankle ring), 8.24 (1H, s, H on the ankle ring).
ESI-MS: [M+H]+ 401.2, [M+Na]+423.1。
ESI-MS: [M+H] + 401.2, [M+Na]+423.1.
C0P030 C0P130 在 50ml圆底烧瓶中， 依次加入 C0P030 ( 2.0g, .0mmol )、 Ν,Ν-二甲基甲酰胺（ 25ml )、
1-溴 -3-十六垸氧丙垸 （ 1.8g, 5.0mmol )和三乙胺（0.85ml, 6.0mmol ), 在 80°C下搅拌 6h, 蒸除溶剂， 加入乙酸乙酯： 乙醇为 1： 1 (体积比） 的混合溶剂 100ml充分溶解后过滤， 滤 液旋干经柱层析得到白色固体 C0P130 ( 2.3g, 3.4mmol ), 收率 67.4%。 C0P030 C0P130 In a 50 ml round bottom flask, add COOP30 (2.0 g, .0 mmol), hydrazine, hydrazine-dimethylformamide (25 ml), 1-Bromo-3-hexadecane oxime (1.8 g, 5.0 mmol) and triethylamine (0.85 ml, 6.0 mmol), stirred at 80 ° C for 6 h, evaporated and evaporated. 100 ml of a mixed solvent of 1:1 (volume ratio) was sufficiently dissolved, and the mixture was filtered, and the filtrate was evaporated to dryness to afford white crystals of EtOAc (2.3 g, 3.4 mmol).
JH NMR ( 400 MHz, CDC13 ), δ ( ppm ): 0.88(3H, t, CH3), 1.21-1.37(38H, m, 13 x CH2和 4 x CH3), 1.4 m, CH2), 1.91-1.96(2H, m, CH2), 3.26-3.57(6H, m, 3 OCH2), 3.81-4.11(6H, m, OCH2P、NCH2和 2 OCH), 4.33-4.42(lH, m, NCH), 4.94-5.03(lH, m, NH), 6.04(2H, s, NH2), 8.00(1H, s, 嘌呤环上的 H), 8.34(1H, s, 嘌呤环上的 H)。 J H NMR ( 400 MHz, CDC1 3 ), δ (ppm ): 0.88 (3H, t, CH 3 ), 1.21-1.37 (38H, m, 13 x CH 2 and 4 x CH 3 ), 1.4 m, CH 2 ), 1.91-1.96(2H, m, CH 2 ), 3.26-3.57(6H, m, 3 OCH 2 ), 3.81-4.11 (6H, m, OCH 2 P, NCH 2 and 2 OCH), 4.33-4.42 ( lH, m, NCH), 4.94-5.03 (lH, m, NH), 6.04 (2H, s, NH 2 ), 8.00 (1H, s, H on the anthracene ring), 8.34 (1H, s, anthracene ring H).
ESI-MS: [M+H]+ 683.4, [M+Na]+705.4。 ESI-MS: [M+H] + 683.4, [M+Na] + 705.4.
实施例 8: COP130-016的制备 Example 8: Preparation of COP130-016
C0P030 COP 130-016 C0P030 COP 130-016
在 50ml圆底烧瓶中， 依次加入 C0P030 ( 2.0g, 5.0mmol )、 Ν,Ν-二甲基甲酰胺（ 25ml )、 2-十八垸氧小溴乙垸 （1.9g、 5.0mmol )和三乙胺 ( 0.85ml, 6.0mmol ), 在 80°C下搅拌 6h, 蒸除溶剂， 加入乙酸乙酯： 乙醇为 1： 1 (体积比） 的混合溶剂 100ml充分溶解后过滤， 滤 液旋干经柱层析得到白色固体 COP130-016 ( 2.48g, 3.56mmol ), 收率 71.2%。 In a 50 ml round bottom flask, successively added COOP030 (2.0 g, 5.0 mmol), hydrazine, hydrazine-dimethylformamide (25 ml), 2-octadecyloxybromoacetamidine (1.9 g, 5.0 mmol) and three Ethylamine (0.85 ml, 6.0 mmol) was stirred at 80 ° C for 6 h, and the solvent was evaporated. Ethyl acetate: Ethanol: 1:1 (volume ratio) of a mixed solvent, 100 ml, dissolved, and filtered. Chromatography gave a white solid COP130-016 ( 2.48 g, 3.56 mmol).
JH NMR ( 400 MHz, CDC13 ), δ ( ppm ): 0.88(3H, t, CH3), 1.22-1.38(42H, m, 15 x CH2和 4 x CH3), 1.48-1.58(2H, m, CH2), 3.26-3.58(6H, m, 3 x OCH2), 3.82-4.12(6H, m, OCH2P、 NCH2禾口 2 x OCH), 4.31-4.43(1H, m, NCH), 4.95-5.06(lH, m, NH), 6.05(2H, s, NH2), 8.00(1H, s, 嘌呤环上的 H), 8.33(1H, s, 嘌呤环上的 H)。 J H NMR ( 400 MHz, CDC1 3 ), δ (ppm ): 0.88 (3H, t, CH 3 ), 1.22-1.38 (42H, m, 15 x CH 2 and 4 x CH 3 ), 1.48-1.58 (2H , m, CH 2 ), 3.26-3.58(6H, m, 3 x OCH 2 ), 3.82-4.12 (6H, m, OCH 2 P, NCH 2 and 2 x OCH), 4.31-4.43 (1H, m, NCH), 4.95-5.06 (lH, m, NH), 6.05 (2H, s, NH 2 ), 8.00 (1H, s, H on an anthracene ring), 8.33 (1H, s, H on an anthracene ring).
ESI-MS: [M+H]+ 697.5 , [M+Na]+ 719.5。 ESI-MS: [M+H]+ 697.5, [M+Na]+ 719.5.
实施例 9: C0P130-412的制备 Example 9: Preparation of C0P130-412
C0P030 C0P130-412 C0P030 C0P130-412
在 50ml圆底烧瓶中， 依次加入 C0P030 ( 2.0g, 5.0mmol )、 Ν,Ν-二甲基甲酰胺（ 25ml )、
6-十四垸氧 -1-溴己垸 (1.9g、 5.0mmol)和三乙胺 (0.85ml, 6.0mmol ), 在 80°C下搅拌 6h, 蒸除溶剂， 加入乙酸乙酯： 乙醇为 1： 1 (体积比） 的混合溶剂 100ml充分溶解后过滤， 滤 液旋干经柱层析得到白色固体 C0P130-412 ( 1.2g, 3.17mmol), 收率： 63.4%。 In a 50 ml round bottom flask, COP030 (2.0 g, 5.0 mmol), hydrazine, hydrazine-dimethylformamide (25 ml), 6-tetradecyloxy-1-bromohexyl oxime (1.9 g, 5.0 mmol) and triethylamine (0.85 ml, 6.0 mmol), stirred at 80 ° C for 6 h, evaporated and evaporated. 100 ml of a mixed solvent of 1:1 (volume ratio) was sufficiently dissolved, and the mixture was filtered. The filtrate was purified by column chromatography to yield white crystals of EtOAc (1.
JH NM (400 MHz, CDC13 ), δ (ppm): 0.88(3H, t, CH3), 1.22-1.37(38H, m, 11 xCH2、 4 x CH3以及己二醇上的 2 x CH2), 1.46-1.59(2H, m, CH2), 1.89-1.98(4H, m, 2 CH2), 3.24-3.56(6H, m, 3 χ OCH2), 3.80-4.09(6H, m, OCH2P、 NCH2和 2x〇CH), 4.31-4.41(1H, m, NCH), 4.96-5.05(lH, m, NH), 6.04(2H, s, NH2), 8.00(1H, s, 嘌呤 环上的 H), 8.34(1H, s, 嘌呤环上的 H)。 J H NM (400 MHz, CDC1 3 ), δ (ppm): 0.88 (3H, t, CH 3 ), 1.22-1.37 (38H, m, 11 xCH 2 , 4 x CH 3 and 2 x on hexanediol) CH 2 ), 1.46-1.59(2H, m, CH 2 ), 1.89-1.98(4H, m, 2 CH 2 ), 3.24-3.56(6H, m, 3 χ OCH 2 ), 3.80-4.09(6H, m , OCH 2 P, NCH 2 and 2x〇CH), 4.31-4.41(1H, m, NCH), 4.96-5.05(lH, m, NH), 6.04(2H, s, NH 2 ), 8.00(1H, s , H) on the ankle ring, 8.34 (1H, s, H on the ankle ring).
ESI-MS: [M+H]+ 697.5, [M+Na]+ 719.5。 ESI-MS: [M+H]+ 697.5, [M+Na]+ 719.5.
实施例 10: C0P131-114 的制备 Example 10: Preparation of C0P131-114
在 250ml圆底烧瓶中， 依次加入 C0P031 ( 9.7g, 25mmol )、 L114 ( 15g, 50mmol )混合 溶于 65ml N-甲基吡咯垸酮中， 加热到 85°C搅拌 30分钟后， 慢慢滴加三乙胺 22ml, 然后升温 至 10CTC, 滴加二环己基碳二亚胺（DCC) llg (溶于 16ml N-甲基吡咯垸酮中）。 在 10CTC下 搅拌反应 10小时后， 冷却至 50°C, 旋干， 加入 500ml二氯甲垸： 甲醇 =1： 1 (体积比） 的混 合溶剂， 搅拌 1小时后抽滤， 多次冲洗滤饼， 合并滤液后干燥浓缩， 用二氯甲垸： 甲醇 =1： 1 (体积比）进行硅胶柱层析， 得到目标物 C0P131-114 (7.35g, llmmol), 收率 44%。 In a 250 ml round bottom flask, COP031 (9.7 g, 25 mmol) and L114 (15 g, 50 mmol) were added and dissolved in 65 ml of N-methylpyrrolidone. After heating to 85 ° C for 30 minutes, slowly add dropwise. 22 ml of triethylamine, and then the temperature was raised to 10 CTC, and dicyclohexylcarbodiimide (DCC) llg (dissolved in 16 ml of N-methylpyrrolidone) was added dropwise. After stirring the reaction at 10 CTC for 10 hours, it was cooled to 50 ° C, and dried, and 500 ml of a mixed solvent of dichloromethane: methanol = 1: 1 (volume ratio) was added. After stirring for 1 hour, the mixture was filtered, and the filter cake was washed several times. The filtrate was combined, dried and concentrated, and then applied to silica gel column chromatography with methylene chloride (methanol) = 1:1 (volume ratio) to give the title compound (0.sup.3).
^NM (400 MHz, CDC13 ), δ (ppm): 0.88(3H, t, CH3), 1.17-1.34(32H, m, 13 xCH2和 2xCH3), 1.37(3H, t, CH3), 1.46-1.61(2H, m, CH2), 1.75-1.98(2H, m, CH2), 3.33-3.66(6H, m, 3 x OCH2), 3.75-4.22(8H, m, OCH2P、 NCH2、 COOCH2、 OCH及 NH), 4.27-4.47(lH, m, NCH), 6.14(2H, s, NH2), 7.93-8.06(lH, d,嘌呤环上的 H), 8.27-8.39(1Η, d, 嘌呤环上的 H)。
ESI-MS: [M+H]+ 669.3 , [M+Na 691.3 = ^NM (400 MHz, CDC1 3 ), δ (ppm): 0.88 (3H, t, CH 3 ), 1.17-1.34 (32H, m, 13 xCH 2 and 2xCH 3 ), 1.37(3H, t, CH 3 ) , 1.46-1.61(2H, m, CH 2 ), 1.75-1.98(2H, m, CH 2 ), 3.33-3.66(6H, m, 3 x OCH 2 ), 3.75-4.22(8H, m, OCH 2 P , NCH 2 , COOCH 2 , OCH and NH), 4.27-4.47 (lH, m, NCH), 6.14 (2H, s, NH 2 ), 7.93-8.06 (lH, d, H on the anthracene ring), 8.27- 8.39 (1Η, d, H on the ankle ring). ESI-MS: [M+H] + 669.3 , [M+Na 691.3 =
实施例 11: C0P131-016的制备 Example 11: Preparation of C0P131-016
^ NM ( 400 MHz, CDC13 ), δ ( ppm ): 0.88(3H, t, CH3), 1.16-1.36(36H, m, 15 x CH2和 2 x CH3), 1.37(3H, t, CH3), 1.47-1.62(2H, m, CH2), 3.35-3.68(6H, m, 3 x OCH2), 3.76-4.20(8H, m, OCH2P、 NCH2、 COOCH2、 OCH及 NH), 4.28-4.45(lH, m, NCH), 6.15(2H, s, NH2), 7.94-8.04(lH, d, 嘌呤环上的 H), 8.28-8.37(1Η, d, 嘌呤环上的 H)。 ^ NM ( 400 MHz, CDC1 3 ), δ (ppm ): 0.88 (3H, t, CH 3 ), 1.16-1.36 (36H, m, 15 x CH 2 and 2 x CH 3 ), 1.37 (3H, t, CH 3 ), 1.47-1.62(2H, m, CH 2 ), 3.35-3.68(6H, m, 3 x OCH 2 ), 3.76-4.20(8H, m, OCH 2 P, NCH 2 , COOCH 2 , OCH and NH), 4.28-4.45(lH, m, NCH), 6.15(2H, s, NH 2 ), 7.94-8.04 (lH, d, H on the anthracene ring), 8.28-8.37 (1Η, d, anthracene ring H).
ESI-MS: [M+H]+ 683.4, [M+Na]+ 705.4。 ESI-MS: [M+H] + 683.4, [M+Na]+ 705.4.
实施例 12: C0P131-410的制备 Example 12: Preparation of C0P131-410
JH NM ( 400 MHz, CDC13 ), δ ( ppm ): 0.88(3H, t, CH3), 1.16-1.35(28H, m, 9 x CH2、 2 CH2A2 x CH3), 1.36(3H, t, CH3), 1.45-1.62(4H, m, 2 CH2), 1.74-1.99(2H, m, CH2), 3.32-3.67(6H, m, 3 x OCH2), 3.74-4.23(8H, m, OCH2P、 NCH2、 COOCH2、 OCH及 NH), 4.26-4.48(lH, m, NCH), 6.13(2H, s, NH2), 7.92-8.07(lH, d, 嘌呤环上的 H), 8.26-8.40(1Η, d, 嘌呤环上的 H)。 J H NM ( 400 MHz, CDC1 3 ), δ (ppm ): 0.88 (3H, t, CH 3 ), 1.16-1.35 (28H, m, 9 x CH 2 , 2 CH 2 A2 x CH 3 ), 1.36 ( 3H, t, CH 3 ), 1.45-1.62 (4H, m, 2 CH 2 ), 1.74-1.99 (2H, m, CH 2 ), 3.32-3.67 (6H, m, 3 x OCH 2 ), 3.74-4.23 (8H, m, OCH 2 P, NCH 2 , COOCH 2 , OCH and NH), 4.26-4.48 (lH, m, NCH), 6.13(2H, s, NH 2 ), 7.92-8.07 (lH, d, 嘌呤H) on the ring, 8.26-8.40 (1Η, d, H on the ankle ring).
ESI-MS: [M+H]+ 655.4, [M+Na]+ 677.4。 ESI-MS: [M+H]+ 655.4, [M+Na]+ 677.4.
实施例 13: C0P131-220的制备 Example 13: Preparation of C0P131-220
制备过程同实施例 10 (收率 32% )。
O NM ( 400 MHz, CDC13 ), δ ( ppm ): 0.88(3H, t, CH3), 1.15-1.33(44H, m, 19 x CH2和 2 x CH3), 1.36(3H, t, CH3), 1.44-1.60(4H, m, 2 CH2), 1.73-1.97(2H, m, CH2), 3.31-3.65(6H, m, 3 x OCH2), 3.73-4.21(8H, m, OCH2P、 NCH2、 COOCH2、 OCH及 NH), 4.25-4.46(lH, m, NCH), 6.12(2H, s, NH2), 7.91-8.05(1H, d,嘌呤环上的 H), 8.25-8.38(1Η, d, 嘌呤环上的 H)。 The preparation procedure was the same as in Example 10 (yield 32%). O NM ( 400 MHz, CDC1 3 ), δ (ppm ): 0.88 (3H, t, CH 3 ), 1.15-1.33 (44H, m, 19 x CH 2 and 2 x CH 3 ), 1.36 (3H, t, CH 3 ), 1.44-1.60(4H, m, 2 CH 2 ), 1.73-1.97(2H, m, CH 2 ), 3.31-3.65(6H, m, 3 x OCH 2 ), 3.73-4.21(8H, m , OCH 2 P, NCH 2 , COOCH 2 , OCH and NH), 4.25-4.46 (lH, m, NCH), 6.12(2H, s, NH 2 ), 7.91-8.05 (1H, d, H on the anthracene ring ), 8.25-8.38 (1Η, d, H on the ankle ring).
ESI-MS: [M+H]+ 767.5 , [M+Na]+ 789.5。 ESI-MS: [M+H]+ 767.5, [M+Na]+ 789.5.
实施例 14: C0P132-114 的制备 Example 14: Preparation of C0P132-114
在 250ml圆底烧瓶中， 依次加入 C0P032 ( 10.3g , 25mmol )、 L114 (15g, 50mmol ) 混 合溶于 65ml N-甲基吡咯垸酮中，加热到 85 °C搅拌 10分钟，滴加三乙胺 22ml后，升温至 100°C , 滴加二环己基碳二亚胺（DCC ) llg (溶于 16ml N-甲基吡咯垸酮中）， 在 105 °C下搅拌反应 14小时后， 冷却至 45 °C , 旋干， 加入二氯甲垸： 甲醇 =1 ： 1 ( 500ml ) (体积比） 的混合溶 剂，搅拌 1小时后抽滤， 多次冲洗滤饼，合并滤液后干燥浓缩，用二氯甲垸： 甲醇 =1： 1 (体 积比）硅胶柱层析， 得到目标物 C0P132-114 ( 6.72g, 9.65mmol ), 收率 38.6%。 In a 250 ml round bottom flask, successively add COOP032 (10. 3 g, 25 mmol), L114 (15 g, 50 mmol), and dissolve in 65 ml of N-methylpyrrolidone. Heat to 85 ° C for 10 minutes, add triethylamine dropwise. After 22 ml, the temperature was raised to 100 ° C, dicyclohexylcarbodiimide (DCC) llg (dissolved in 16 ml of N-methylpyrrolidone) was added dropwise, and the reaction was stirred at 105 ° C for 14 hours, and then cooled to 45. °C, spin dry, add methylene chloride: methanol = 1 : 1 (500ml) (volume ratio) of mixed solvent, stir for 1 hour, suction filtration, rinse the filter cake several times, combine the filtrate, dry and concentrate, use dichloro Formazan: methanol = 1 : 1 (by volume) silica gel column chromatography to give the title compound: EtOAc (EtOAc: EtOAc:
1H NM ( 400 MHz, CDC13 ), δ ( ppm ): 0.82-0.96(9Η, m, 3 χ CH3), 1.15-1.44(32Η, m, 13 CH2和 2 CH3), 1.47-1.59(2Η, m, CH2), 1.79-1.99(3H, m, CH2和 CH), 3.30-3.74(6H, m, 3 x OCH2), 3.76-4.18(8H, m, OCH2P、 NCH2、 COOCH2、 OCH及 NH), 4.31-4.44(1H, m, NCH), 6.57(2H, s, NH2), 7.99-8.08(lH, d, 嘌呤环上的 H), 8.28-8.36(1Η, d, 嘌呤 环上的 H)。 1H NM ( 400 MHz, CDC13 ), δ ( ppm ): 0.82-0.96 (9Η, m, 3 χ CH 3 ), 1.15-1.44 (32Η, m, 13 CH 2 and 2 CH 3 ), 1.47-1.59 (2Η , m, CH 2 ), 1.79-1.99 (3H, m, CH 2 and CH), 3.30-3.74 (6H, m, 3 x OCH 2 ), 3.76-4.18 (8H, m, OCH 2 P, NCH 2 , COOCH 2 , OCH and NH), 4.31-4.44 (1H, m, NCH), 6.57 (2H, s, NH 2 ), 7.99-8.08 (lH, d, H on the anthracene ring), 8.28-8.36 (1Η, d, H) on the ankle ring.
ESI-MS: [M+H]+ 697.4, [M+Na]+ 719.3。 ESI-MS: [M+H]+ 697.4, [M+Na]+ 719.3.
实施例 15: C0P132-016的制备
Example 15: Preparation of C0P132-016
COP 132-016 制备过程同实施例 14 (收率 39% )。 The preparation procedure of COP 132-016 was the same as in Example 14 (yield 39%).
1H NM ( 400 MHz, CDC13 ), δ ( ppm ): 0.81-0.98(9H, m, 3 x CH3), 1.14-1.46(36H, m, 15 x CH2和 2 x CH3), 1.48-1.60(2H, m, CH2), 1.80-1.97(1H, m, CH), 3.32-3.72(6H, m, 3 x OCH2), 3.77-4.16(8H, m, OCH2P、 NCH2、 COOCH2、 OCH及 NH), 4.32-4.42 (IH, m, NCH), 6.58(2H, s, NH2), 7.98-8.09(lH, d, 嘌呤环上的 H), 8.27-8.38(1Η, d, 嘌呤 环上的 H)。 1H NM ( 400 MHz, CDC13 ), δ ( ppm ): 0.81-0.98 (9H, m, 3 x CH 3 ), 1.14-1.46 (36H, m, 15 x CH 2 and 2 x CH 3 ), 1.48-1.60 (2H, m, CH 2 ), 1.80-1.97 (1H, m, CH), 3.32-3.72 (6H, m, 3 x OCH 2 ), 3.77-4.16 (8H, m, OCH 2 P, NCH 2 , COOCH 2 , OCH and NH), 4.32-4.42 (IH, m, NCH), 6.58(2H, s, NH 2 ), 7.98-8.09 (lH, d, H on the anthracene ring), 8.27-8.38 (1Η, d , H) on the ring.
ESI-MS: [M+H]+ 711.5 , [M+Na]+ 733.5。 ESI-MS: [M+H] + 711.5, [M+Na]+ 733.5.
实施例 16: C0P132-410的制备 Example 16: Preparation of C0P132-410
JH NM ( 400 MHz, CDC13 ), δ ( ppm ): 0.81-0.97(9H, m, 3 x CH3), 1.14-1.45(28H, m, 9 x CH2、 2 x CH2及 2 x CH3), 1.46-1.60(4H, m, 2 CH2), 1.78-1.97(3H, m, CH2和 CH), 3.29-3.75(6H, m, 3 x OCH2), 3.75-4.19(8H, m, OCH2P、 NCH2、 COOCH2、 OCH 及 NH), 4.30-4.45(lH, m, NCH), 6.56(2H, s, NH2), 7.98-8.09(lH, d, 嘌呤环上的 H), 8.27-8.37(1Η, d, 嘌呤环上的 H)。 J H NM ( 400 MHz, CDC13 ), δ ( ppm ): 0.81-0.97 (9H, m, 3 x CH 3 ), 1.14-1.45 (28H, m, 9 x CH 2 , 2 x CH 2 and 2 x CH 3 ), 1.46-1.60(4H, m, 2 CH 2 ), 1.78-1.97 (3H, m, CH 2 and CH), 3.29-3.75 (6H, m, 3 x OCH 2 ), 3.75-4.19 (8H, m, OCH 2 P, NCH 2 , COOCH 2 , OCH and NH), 4.30-4.45 (lH, m, NCH), 6.56(2H, s, NH 2 ), 7.98-8.09 (lH, d, on the anthracene ring H), 8.27-8.37 (1Η, d, H on the ankle ring).
ESI-MS: [M+H]+ 683.4, [M+Na]+ 705.4。 ESI-MS: [M+H] + 683.4, [M+Na]+ 705.4.
实施例 17: C0P132-220 的制备 2。CH3
Example 17: Preparation 2 of C0P132-220. CH3
C0P032 COP 132-220 C0P032 COP 132-220
制备过程同实施例 14 (收率 31% )。
Ή NM ( 400 MHz, CDC13 ), δ ( ppm ): 0.80-0.95(9H, m, 3 x CH3), 1.13-1.43(44H, m, 19 x CH2和 2 x CH3) , 1.45-1.58(4H , m, 2 CH2) , 1.77-1.98(3H , m, CH2和 CH) ,The preparation procedure was the same as in Example 14 (yield 31%). Ή NM ( 400 MHz, CDC13 ), δ (ppm ): 0.80-0.95 (9H, m, 3 x CH 3 ), 1.13-1.43 (44H, m, 19 x CH 2 and 2 x CH 3 ) , 1.45-1.58 (4H , m, 2 CH 2 ) , 1.77-1.98 (3H , m, CH 2 and CH),
3.28- 3.73(6H, m, 3 x OCH2), 3.74-4.17(8H, m, OCH2P、 NCH2、 COOCH2、 OCH及 NH),3.28- 3.73(6H, m, 3 x OCH 2 ), 3.74-4.17 (8H, m, OCH 2 P, NCH 2 , COOCH 2 , OCH and NH),
4.29- 4.43(lH, m, NCH), 6.55(2H, s, NH2), 7.97-8.07(lH, d,嘌呤环上的 H), 8.26-8.35(1Η, d, 嘌呤环上的 H)。 4.29- 4.43(lH, m, NCH), 6.55(2H, s, NH 2 ), 7.97-8.07 (lH, d, H on the anthracene ring), 8.26-8.35 (1Η, d, H on the anthracene ring) .
ESI-MS: [M+H]+ 795.6, [M+Na]+ 817.6。 ESI-MS: [M+H]+ 795.6, [M+Na]+ 817.6.
实施例 18: C0P133-114 的制备 Example 18: Preparation of C0P133-114
在 250ml圆底烧瓶中， 依次加入 C0P033 ( 10.7g, 25mmol )、 L114 (15 g, 50mmol ) 混 合溶于 65ml N-甲基吡咯垸酮中， 加热到 85 °C搅拌 25分钟， 滴加三乙胺 22ml, 然后升温至 10CTC , 滴加二环己基碳二亚胺（DCC ) l lg (溶于 16ml N-甲基吡咯垸酮中）， 在 11CTC下搅 拌反应 12小时后， 冷却至室温， 旋干， 加入二氯甲垸： 甲醇 =1： 1 (体积比）（500ml ) 的 混合溶剂， 搅拌分散 1小时后抽滤， 多次冲洗滤饼， 合并滤液后干燥浓缩， 用二氯甲垸： 甲醇 =1： 1(体积比）硅胶柱层析，得到目标物 C0P133-114 ( 6.52g, 9.17mmol ),产率 36.7%。 In a 250 ml round bottom flask, add COOP03 (10. 7 g, 25 mmol), L114 (15 g, 50 mmol) in a mixture of 65 ml of N-methylpyrrolidone, and heat to 85 ° C for 25 minutes, add three B. 22 ml of amine, then the temperature was raised to 10 CTC, dicyclohexylcarbodiimide (DCC) l lg (dissolved in 16 ml of N-methylpyrrolidone) was added dropwise, and the reaction was stirred at 11 CTC for 12 hours, then cooled to room temperature and vortexed. Dry, add methylene chloride: methanol = 1: 1 (volume ratio) (500ml) of a mixed solvent, stir and disperse for 1 hour, suction filtration, rinse the filter cake several times, combine the filtrate, dry and concentrate, using dichloromethane: Methanol = 1 : 1 (volume ratio) silica gel column chromatography to give the title compound C0133-114 ( 6.52 g, 9.17 mmol), yield 36.7%.
JH NM ( 400 MHz, CDC13 ), δ (ppm): 0.78-1.00 (12H, m, 4 CH3), 1.14-1.46(32H, m, 13 x CH2和 2 x CH3), 1.47-1.60 (2H, m, CH2), 1.80-1.95 (2H, m, CH2), 3.25-3.52 (4H, m, 2 OCH2), 3.54 -3.64 (IH, m, OCH), 3.66-3.93 (4H, m,OCH2和 COOCH2), 3.99-4.20 (5H, m, OCH2P、 NCH2和 NH), 4.30-4.44 (IH, m, NCH), 6.67(2H, s, NH2), 7.93-8.11 (IH, d, 嘌呤环上 的 H), 8.32(1H, s, 嘌呤环上的 H)。 J H NM ( 400 MHz, CDC1 3 ), δ (ppm): 0.78-1.00 (12H, m, 4 CH 3 ), 1.14-1.46 (32H, m, 13 x CH 2 and 2 x CH 3 ), 1.47- 1.60 (2H, m, CH 2 ), 1.80-1.95 (2H, m, CH 2 ), 3.25-3.52 (4H, m, 2 OCH 2 ), 3.54 - 3.64 (IH, m, OCH), 3.66-3.93 ( 4H, m, OCH 2 and COOCH 2 ), 3.99-4.20 (5H, m, OCH 2 P, NCH 2 and NH), 4.30-4.44 (IH, m, NCH), 6.67(2H, s, NH 2 ), 7.93-8.11 (IH, d, H on the ankle ring), 8.32 (1H, s, H on the ankle ring).
ESI-MS: [M+H]+ 711.4, [M+Na]+733.4。 ESI-MS: [M+H]+ 711.4, [M+Na]+733.4.
实施例 19: C0P133-016 的制备
18 (收率 35% )。 Example 19: Preparation of C0P133-016 18 (yield 35%).
JH NMR (400 MHz, CDC13), δ (ppm): 0.77-1.02 (12H, m, 4 x CH3), 1.13-1.48(36H, m, 15 CH2和 2 CH3), 1.48-1.61 (2H, m, CH2), 3.27-3.50 (4H, m, 2 OCH2), 3.55 -3.62 (IH, m, OCH), 3.67-3.91 (4H, m,OCH2和 COOCH2), 3.97-4.19 (5H, m, OCH2P、 NCH2和 NH), 4.31-4.42 (IH, m, NCH), 6.68(2H, s, NH2), 7.94-8.10 (IH, d, 嘌呤环上的 H), 8.33(1H, s, 嘌呤环上的 H)。 J H NMR (400 MHz, CDC1 3 ), δ (ppm): 0.77-1.02 (12H, m, 4 x CH 3 ), 1.13-1.48 (36H, m, 15 CH 2 and 2 CH 3 ), 1.48-1.61 (2H, m, CH 2 ), 3.27-3.50 (4H, m, 2 OCH 2 ), 3.55 - 3.62 (IH, m, OCH), 3.67-3.91 (4H, m, OCH 2 and COOCH 2 ), 3.97- 4.19 (5H, m, OCH 2 P, NCH 2 and NH), 4.31-4.42 (IH, m, NCH), 6.68(2H, s, NH 2 ), 7.94-8.10 (IH, d, H on the anthracene ring ), 8.33 (1H, s, H on the ring).
ESI-MS: [M+H]+ 725.5 , [M+Na]+747.5。 ESI-MS: [M+H] + 725.5, [M+Na]+747.5.
实施例 20: C0P133-410 的制备 Example 20: Preparation of C0P133-410
JH NMR (400 MHz, CDC13), δ (ppm): 0.77-1.01 (12H, m, 4 x CH3), 1.13-1.47(28H, m, 9 CH2、 2 CH2和 2 CH3), 1.46-1.61 (4H, m, 2 CH2), 1.79-1.96 (2H, m, CH2), 3.24-3.53 (4H, m, 2 x OCH2), 3.53 -3.65 (IH, m, OCH), 3.67-3.94 (4H, m, OCH2和 COOCH2), 3.98-4.21 (5H, m, OCH2P、 NCH2和 NH), 4.29-4.45 (IH, m, NCH), 6.66(2H, s, NH2), 7.92-8.12 (IH, d, 嘌呤环 上的 H), 8.31(1H, s, 嘌呤环上的 H)。 J H NMR (400 MHz, CDC1 3 ), δ (ppm): 0.77-1.01 (12H, m, 4 x CH 3 ), 1.13-1.47 (28H, m, 9 CH 2 , 2 CH 2 and 2 CH 3 ) , 1.46-1.61 (4H, m, 2 CH 2 ), 1.79-1.96 (2H, m, CH 2 ), 3.24-3.53 (4H, m, 2 x OCH 2 ), 3.53 -3.65 (IH, m, OCH) , 3.67-3.94 (4H, m, OCH 2 and COOCH 2 ), 3.98-4.21 (5H, m, OCH 2 P, NCH 2 and NH), 4.29-4.45 (IH, m, NCH), 6.66 (2H, s , NH 2 ), 7.92-8.12 (IH, d, H on the anthracene ring), 8.31 (1H, s, H on the anthracene ring).
ESI-MS: [M+H]+ 697.5 , [M+Na]+719.5。 ESI-MS: [M+H]+ 697.5, [M+Na]+719.5.
实施例 21: C0P133-220 的制备 Example 21: Preparation of C0P133-220
ESI-MS: [M+H]+ 809.6, [M+Na]+ 831.6。 ESI-MS: [M+H]+ 809.6, [M+Na]+ 831.6.
实施例 22: C0P134-114 的制备 Example 22: Preparation of C0P134-114
PMPA C0P034 C0P134-1 14 在 50ml圆底烧瓶中， 依次加入替诺福韦 ( PMPA ) ( 1.18g, 4.13mmol )、 L-丙氨酸正丁 酯盐酸盐 ( 3.08g , 0.017mol )、 2,2' -二硫二吡啶（1.82g , 8.26mmol)、 三乙胺 ( 3.44g , 4.8ml,34mol )、 三苯基膦 （2.16g, 8.24mmol ) 和 N-甲基吡咯垸酮 （ 10ml ), 在 80°C下搅拌 12h后，蒸除溶剂，用乙酸乙酯： 乙醇 =10： 1 (体积比）硅胶柱层析，得到中间产品 C0P034 ( 0.807g, 1.95mmol ), 收率 47.2%。 PMPA C0P034 C0P134-1 14 In a 50 ml round bottom flask, tenofovir (PMPA) ( 1.18 g, 4.13 mmol), L-alanine n-butyl ester hydrochloride (3.08 g, 0.017 mol), 2 , 2'-dithiodipyridine (1.82g, 8.26mmol), triethylamine (3.44g, 4.8ml, 34mol), triphenylphosphine (2.16g, 8.24mmol) and N-methylpyrrolidone (10ml) After stirring at 80 ° C for 12 h, the solvent was evaporated, and then ethyl acetate: EtOAc: EtOAc (EtOAc: EtOAc) .
在 250ml圆底烧瓶中， 依次加入 C0P034 ( 10.4g, 25mmol )、 L114 (15 g, 50mmol ) 混 合溶于 65ml N-甲基吡咯垸酮中， 加热到 85 °C搅拌反应 30分钟， 滴加三乙胺 22ml, 然后升温 至 10CTC , 滴加二环己基碳二亚胺（DCC ) llg (溶于 16ml N-甲基吡咯垸酮中）， 在 10CTC下 搅拌反应 8小时后， 冷却至 45 °C , 旋干， 加入二氯甲垸： 甲醇 =1： 1 (体积比）（500ml ) 的 混合溶剂， 搅拌分散 1小时后抽滤， 多次冲洗滤饼， 合并滤液后干燥浓缩， 用二氯甲垸： 甲醇 =1： 1(体积比）硅胶柱层析，得到目标物 C0P134-114 ( 5.68g, 8.15mmol ),收率 32.6%。 In a 250 ml round bottom flask, successively add COOP034 (10. 4g, 25mmol), L114 (15g, 50mmol), and dissolve in 65ml of N-methylpyrrolidone. Heat to 85 °C, stir the reaction for 30 minutes, add three Ethylamine 22ml, then warmed to 10CTC, dicyclohexylcarbodiimide (DCC) llg (dissolved in 16ml N-methylpyrrolidone) was added dropwise, stirred at 10CTC for 8 hours, then cooled to 45 °C , spin dry, add methylene chloride: methanol = 1: 1 (volume ratio) (500ml) of mixed solvent, stir and disperse for 1 hour, suction filtration, rinse the filter several times, combine the filtrate, dry and concentrate, use dichloro垸: Methanol = 1 : 1 (volume ratio) silica gel column chromatography to give the title compound C0P134-114 ( 5.68 g, 8.15 mmol), yield 32.6%.
JH NMR (400 MHz, CDC13), δ (ppm): 0.84-0.95 (6H, m, 2 x CH3), 1.01-1.46 (34H, m, 13 CH2、 CH2和 2 CH3), 1.48-1.66 (4H, m, 2 CH2), 1.82-1.94 (2H, m, CH2), 3.31-3.70 (6H, m, 3 x OCH2), 3.77-4.20 (8H, m, OCH2P、 NCH2、 COOCH2、 OCH和 NH), 4.32-4.43 (IH, m, NCH), 6.65(2H, s, NH2), 7.96-8.10 (IH, d, 嘌呤环上的 H), 8.23-8.40(1Η, d, 嘌呤环上的 H)。 J H NMR (400 MHz, CDC1 3 ), δ (ppm): 0.84-0.95 (6H, m, 2 x CH 3 ), 1.01-1.46 (34H, m, 13 CH 2 , CH 2 and 2 CH 3 ), 1.48-1.66 (4H, m, 2 CH 2 ), 1.82-1.94 (2H, m, CH 2 ), 3.31-3.70 (6H, m, 3 x OCH 2 ), 3.77-4.20 (8H, m, OCH 2 P , NCH 2 , COOCH 2 , OCH and NH), 4.32-4.43 (IH, m, NCH), 6.65(2H, s, NH 2 ), 7.96-8.10 (IH, d, H on the anthracene ring), 8.23- 8.40 (1Η, d, H on the ankle ring).
ESI-MS: [M+H]+ 697.4, [M+Na]+719.3。 ESI-MS: [M+H]+ 697.4, [M+Na]+719.3.
实施例 23: C0P134-016 的制备
Example 23: Preparation of C0P134-016
C0P134-016 制备过程同实施例 22 (收率 31% )。 The preparation process of C0P134-016 was the same as in Example 22 (yield 31%).
JH NM (400 MHz, CDC13), δ (ppm): 0.83-0.97 (6H, m, 2 x CH3), 1.00-1.48 (38H, m, 15 CH2、 CH2和 2 CH3), 1.49-1.66 (4H, m, 2 CH2), 3.33-3.67 (6H, m, 3 χ OCH2), 3.78-4.18 (8H, m, OCH2P、 NCH2、 COOCH2、 OCH和 NH), 4.33-4.41 (IH, m, NCH), 6.67(2H, s, NH2), 7.97-8.11 (IH, d, 嘌呤环上的 H), 8.24-8.41(lH, d, 嘌呤环上的 H)。 J H NM (400 MHz, CDC1 3 ), δ (ppm): 0.83-0.97 (6H, m, 2 x CH 3 ), 1.00-1.48 (38H, m, 15 CH 2 , CH 2 and 2 CH 3 ), 1.49-1.66 (4H, m, 2 CH 2 ), 3.33-3.67 (6H, m, 3 χ OCH 2 ), 3.78-4.18 (8H, m, OCH 2 P, NCH 2 , COOCH 2 , OCH and NH), 4.33-4.41 (IH, m, NCH), 6.67(2H, s, NH 2 ), 7.97-8.11 (IH, d, H on the anthracene ring), 8.24-8.41 (lH, d, H on the anthracene ring) .
ESI-MS: [M+H]+ 711.5 , [M+Na]+ 733.5。 ESI-MS: [M+H] + 711.5, [M+Na]+ 733.5.
实施例 24: C0P134-410 的制备 Example 24: Preparation of C0P134-410
C0P034 C0P134-410 制备过程同实施例 22 (收率 30.6% )。 The preparation procedure of C0P034 C0P134-410 was the same as in Example 22 (yield 30.6%).
JH NMR (400 MHz, CDC13), δ (ppm): 0.83-0.96 (6H, m, 2 x CH3), 1.02-1.47 (30H, m, 9 x CH2、 2 x CH2、 CH2 和 2 x CH3), 1.47-1.67 (6H, m, 3 x CH2), 1.83-1.95 (2H, m, CH2), J H NMR (400 MHz, CDC1 3 ), δ (ppm): 0.83-0.96 (6H, m, 2 x CH 3 ), 1.02-1.47 (30H, m, 9 x CH 2 , 2 x CH 2 , CH 2 And 2 x CH 3 ), 1.47-1.67 (6H, m, 3 x CH 2 ), 1.83-1.95 (2H, m, CH 2 ),
3.30- 3.71 (6H, m, 3 x OCH2), 3.76-4.21 (8H, m, OCH2P、 NCH2、 COOCH2、 OCH和 NH),3.30- 3.71 (6H, m, 3 x OCH 2 ), 3.76-4.21 (8H, m, OCH 2 P, NCH 2 , COOCH 2 , OCH and NH),
4.31- 4.44 (IH, m, NCH), 6.64(2H, s, NH2), 7.95-8.11 (IH, d, 嘌呤环上的 H), 8.22-8.41(1Η, d, 嘌呤环上的 H)。 4.31- 4.44 (IH, m, NCH), 6.64(2H, s, NH 2 ), 7.95-8.11 (IH, d, H on the anthracene ring), 8.22-8.41 (1Η, d, H on the anthracene ring) .
ESI-MS: [M+H]+ 683.4, [M+Na]+ 705.4。 ESI-MS: [M+H] + 683.4, [M+Na]+ 705.4.
实施例 25: C0P134-220 的制备 Example 25: Preparation of C0P134-220
制备过程同实施例 22 (收率 29% )。 The preparation procedure was the same as in Example 22 (yield 29%).
lR NMR (400 MHz, CDC13), δ (ppm): 0.82-0.94 (6H, m, 2 χ CH3), 0.99-1.45 (46H, m, 19 x CH2、 CH2和 2 x CH3), 1.46-1.65 (6H, m, 3 x CH2), 1.80-1.93 (2H, m, CH2), 3.29-3.69 (6H, m,
3 OCH2), 3.75-4.19 (8H, m, OCH2P、 NCH2、 COOCH2、 OCH和 NH), 4.30-4.42 (1H, m, NCH) 6.63(2H, s, NH2), 7.94-8.09 (1H, d, 嘌呤环上的 H), 8.21-8.39(1H, d, 嘌呤环上的 H)。 lR NMR (400 MHz, CDC1 3 ), δ (ppm): 0.82-0.94 (6H, m, 2 χ CH 3 ), 0.99-1.45 (46H, m, 19 x CH 2 , CH 2 and 2 x CH 3 ) , 1.46-1.65 (6H, m, 3 x CH 2 ), 1.80-1.93 (2H, m, CH 2 ), 3.29-3.69 (6H, m, 3 OCH 2 ), 3.75-4.19 (8H, m, OCH 2 P, NCH 2 , COOCH 2 , OCH and NH), 4.30-4.42 (1H, m, NCH) 6.63(2H, s, NH 2 ), 7.94- 8.09 (1H, d, H on the ankle ring), 8.21-8.39 (1H, d, H on the ankle ring).
ESI-MS: [M+H]+ 795.6 , [M+Na]+ 817.6。 ESI-MS: [M+H]+ 795.6, [M+Na]+ 817.6.
实施例 26: C0P135-114 的制备 Example 26: Preparation of C0P135-114
PMPA C0P035 C0P135-114 在 50ml圆底烧瓶中， 依次加入替诺福韦 （PMPA ) ( 1.18g, 4.13mmol )、 L-丙氨酸环己 酯盐酸盐 ( 3.52g , 17mmol )、 2,2 ' -二硫二吡啶（1.82g,8.26mmol)、 三乙胺 ( 3.44g , 4.8ml,34mol )、 三苯基膦 （2.16g, 8.24mmol ) N-甲基吡咯垸酮 （ 10ml ), 在 75 °C下密闭 搅拌 14h后， 蒸除溶剂， 用乙酸乙酯： 乙醇 =20： 1-6： 1 (体积比）硅胶柱层析， 得到中间 产品 C0P035 ( 0.82g, 1.86mmol ), 收率 45.1%。 . PMPA C0P035 C0P135-114 In a 50 ml round bottom flask, tenofovir (PMPA) ( 1.18 g, 4.13 mmol), L-alanine cyclohexyl ester hydrochloride (3.52 g, 17 mmol), 2, 2 were added in sequence. '-Dithiodipyridine (1.82 g, 8.26 mmol), triethylamine (3.44 g, 4.8 ml, 34 mol), triphenylphosphine (2.16 g, 8.24 mmol) N-methylpyrrolidone (10 ml), After the mixture was stirred at 75 ° C for 14 h, the solvent was evaporated. mjjjjjjjjjjjjjj 45.1%. .
在 250ml圆底烧瓶中， 依次加入 C0P035 ( l lg, 25mmol )、 L114 (15 g, 50mmol ) 混合 溶于 65ml N-甲基吡咯垸酮中， 加热到 85 °C搅拌反应 30分钟， 滴加三乙胺 22ml, 然后升温至 10CTC , 滴加二环己基碳二亚胺 (DCC)l lg (溶于 16ml N-甲基吡咯垸酮中）， 在 115 °C下搅拌 16小时后， 冷却至室温， 旋干， 加入二氯甲垸： 甲醇 =1 : 1 (体积比）（500ml )的混合溶剂， 搅拌分散 1小时后抽滤，多次冲洗滤饼，合并滤液后干燥浓缩，用二氯甲垸： 甲醇 =1： 1 (体 积比）硅胶柱层析， 得到目标物 C0P135-114 ( 7.69g, 10.65mmol ), 收率 42.6%。 In a 250 ml round bottom flask, successively add COP035 (1 lg, 25 mmol), L114 (15 g, 50 mmol), and dissolve in 65 ml of N-methylpyrrolidone. Heat to 85 ° C, stir the reaction for 30 minutes, add three 22 ml of ethylamine, then warmed to 10 CTC, dicyclohexylcarbodiimide (DCC) l lg (dissolved in 16 ml of N-methylpyrrolidone) was added dropwise, stirred at 115 ° C for 16 hours, then cooled to room temperature. , Cyclone, add methylene chloride: methanol = 1 : 1 (volume ratio) (500ml) of mixed solvent, stir and disperse for 1 hour, suction filtration, rinse the filter cake several times, combine the filtrate, dry and concentrate, use dichloro垸: methanol = 1 : 1 (volume ratio) silica gel column chromatography to give the title compound EtOAc 135-114 ( 7.69 g, 10.65 mmol), yield 42.6%.
JH NM (400 MHz, CDC13) , δ (ppm): 0.88 (3H, t, CH3), 1.13-1.58 (40H, m, 13 x CH2、 CH2、 2 x CH3 及环己基上的 3 χ CH2), 1.62-1.74 (2H, m, CH2), 1.75-1.95 (4H, m, 环己基上的 2 CH2), 3.30-3.50 (4H, m, 2 OCH2), 3.53-3.65 (1H, m, 环己基上与氧相连的 CH), 3.69-4.23(7H, m, OCH2P、 NCH2、 OCH2及 OCH), 4.26-4.46 (1H, m, NCH), 4.62-4.84 (1H, d, NH), 6.50-6.87(2H, d, NH2), 7.99-8.07 (1H, d, 嘌呤环上的 H), 8.26-8.37(1Η, d, 嘌呤环上的 H)。 J H NM (400 MHz, CDC1 3 ) , δ (ppm): 0.88 (3H, t, CH 3 ), 1.13-1.58 (40H, m, 13 x CH 2 , CH 2 , 2 x CH 3 and cyclohexyl) 3 χ CH 2 ), 1.62-1.74 (2H, m, CH 2 ), 1.75-1.95 (4H, m, 2 CH 2 on cyclohexyl), 3.30-3.50 (4H, m, 2 OCH 2 ), 3.53 -3.65 (1H, m, CH attached to the oxygen on the cyclohexyl group), 3.69-4.23 (7H, m, OCH 2 P, NCH 2 , OCH 2 and OCH), 4.26-4.46 (1H, m, NCH), 4.62 -4.84 (1H, d, NH), 6.50-6.87(2H, d, NH 2 ), 7.99-8.07 (1H, d, H on the anthracene ring), 8.26-8.37 (1Η, d, H on the anthracene ring ).
ESI-MS: [M+H]+ 723.4 , [M+Na]+745.4。 ESI-MS: [M+H] + 723.4, [M+Na]+745.4.
实施例 27: C0P135-016 的制备 Example 27: Preparation of C0P135-016
JH NM (400 MHz, CDC13), δ (ppm): 0.88 (3Η, t, CH3), 1.12-1.60 (44H, m, 15 x CH2、 CH2、 2 x CH3及环己基上的 3 χ CH2), 1.75-1.95 (4H, m, 环己基上的 2 CH2), 3.32-3.46 (4H, m, 2 χ OCH2), 3.54-3.63 (IH, m, 环己基上与氧相连的 CH), 3.70-4.21(7H, m, OCH2P、 NCH2、 OCH2及 OCH), 4.27-4.44 (IH, m, NCH), 4.63-4.82 (IH, d, NH),6.51-6.85(2H, d, NH2)， 7.98-8.08 (IH, d, H), 8.27-8.35(lH, d, 嘌呤环上的 H)。 J H NM (400 MHz, CDC1 3 ), δ (ppm): 0.88 (3Η, t, CH 3 ), 1.12-1.60 (44H, m, 15 x CH 2 , CH 2 , 2 x CH 3 and cyclohexyl) 3 χ CH 2 ), 1.75-1.95 (4H, m, 2 CH 2 on cyclohexyl), 3.32-3.46 (4H, m, 2 χ OCH 2 ), 3.54-3.63 (IH, m, on cyclohexyl) Oxygen-linked CH), 3.70-4.21 (7H, m, OCH 2 P, NCH 2 , OCH 2 and OCH), 4.27-4.44 (IH, m, NCH), 4.63-4.82 (IH, d, NH), 6.51 - 6.85 (2H, d, NH 2 ), 7.98-8.08 (IH, d, H), 8.27-8.35 (lH, d, H on anthracene ring).
ESI-MS: [M+H]+ 737.5 , [M+Na]+759.5。 ESI-MS: [M+H] + 737.5, [M+Na]+759.5.
实施例 28: C0P135-410的制备 Example 28: Preparation of C0P135-410
C0P035 C0P135-410 制备过程同实施例 26 (收率 41% )。 The preparation procedure of C0P035 C0P135-410 was the same as in Example 26 (yield 41%).
JH NMR (400 MHz, CDC13), δ (ppm): 0.88 (3H, t, CH3), 1.12-1.59 (36H, m, 9 x CH2、 2 CH2、 CH2、2 x CH3和环己基上的 3 CH2), 1.61-1.75 (4Η, m, 2 CH2), 1.74-1.96 (4H, m, 环 己基上的 2 CH2), 3.29-3.51 (4H, m, 2 OCH2), 3.52-3.66 (IH, m,环己基上与氧相连的 CH), 3.68-4.24(7H, m, OCH2P、 NCH2、 OCH2和 OCH), 4.25-4.47 (IH, m, NCH), 4.61-4.85 (IH, d, NH), 6.49-6.88(2H, d, NH2), 7.98-8.08 (IH, d, 嘌呤环上的 H), 8.25-8.38(1Η, d, 嘌呤环上的 H)。 J H NMR (400 MHz, CDC1 3 ), δ (ppm): 0.88 (3H, t, CH 3 ), 1.12-1.59 (36H, m, 9 x CH 2 , 2 CH 2 , CH 2 , 2 x CH 3 And 3 CH 2 ) on the cyclohexyl group, 1.61-1.75 (4Η, m, 2 CH 2 ), 1.74-1.96 (4H, m, 2 CH 2 on cyclohexyl), 3.29-3.51 (4H, m, 2 OCH 2 ), 3.52-3.66 (IH, m, CH attached to the oxygen on the cyclohexyl group), 3.68-4.24 (7H, m, OCH 2 P, NCH 2 , OCH 2 and OCH), 4.25-4.47 (IH, m, NCH), 4.61-4.85 (IH, d, NH), 6.49-6.88 (2H, d, NH 2 ), 7.98-8.08 (IH, d, H on the anthracene ring), 8.25-8.38 (1Η, d, 嘌呤H) on the ring.
ESI-MS: [M+H]+ 709.5 , [M+Na]+731.5。 ESI-MS: [M+H]+ 709.5, [M+Na]+731.5.
实施例 29: C0P135-220的制备 Example 29: Preparation of C0P135-220
C0P035 C0P135-220 C0P035 C0P135-220
制备过程同实施例 26 (收率 32% )。 The preparation procedure was the same as in Example 26 (yield 32%).
JH NMR (400 MHz, CDC13), δ (ppm): 0.88 (3H, t, CH3), 1.11-1.57 (54H, m, 19 x CH2、 2 CH2、 2 CH3和环己基上的 3 CH2), 1.60-1.73 (2H, m, CH2), 1.73-1.94 (4H, m, 环己基上 的 2 x CH2), 3.28-3.49 (4H, m, 2 OCH2), 3.51-3.64 (IH, m,环己基上与氧相连的 CH), 3.67-4.22(7H, m, OCH2P、 NCH2、 OCH2和 OCH), 4.24-4.45 (IH, m, NCH), 4.60-4.83 (IH, d,
NH), 6.48-6.86(2H, d, NH2), 7.97-8.06 (1H, d, 嘌呤环上的 H), 8.24-8.36(1Η, d, 嘌呤环上的 J H NMR (400 MHz, CDC1 3 ), δ (ppm): 0.88 (3H, t, CH 3 ), 1.11-1.57 (54H, m, 19 x CH 2 , 2 CH 2 , 2 CH 3 and cyclohexyl) 3 CH 2 ), 1.60-1.73 (2H, m, CH 2 ), 1.73-1.94 (4H, m, 2 x CH 2 on cyclohexyl), 3.28-3.49 (4H, m, 2 OCH 2 ), 3.51 -3.64 (IH, m, CH attached to the oxygen on the cyclohexyl group), 3.67-4.22 (7H, m, OCH 2 P, NCH 2 , OCH 2 and OCH), 4.24-4.45 (IH, m, NCH), 4.60 -4.83 (IH, d, NH), 6.48-6.86(2H, d, NH 2 ), 7.97-8.06 (1H, d, H on the anthracene ring), 8.24-8.36 (1Η, d, on the anthracene ring
H)。 H).
ESI-MS: [M+H]+ 821.6, [M+Na]+ 843.6。 ESI-MS: [M+H]+ 821.6, [M+Na]+ 843.6.
实施例 30: FC0P131-114 的制备 Example 30: Preparation of FC0P131-114
C0P131-114 FC0P131-114 将等摩尔量的 C0P131-114 和富马酸溶于热的乙腈中， 回流搅拌 2小时， 室温下冷却 析晶， 滤出析出的固体并用乙醚洗涤得白色固体 FC0P131-114 (收率 89% )。 C0P131-114 FC0P131-114 Equimolar amount of COP131-114 and fumaric acid were dissolved in hot acetonitrile, stirred under reflux for 2 hours, cooled and crystallized at room temperature, and the precipitated solid was filtered and washed with diethyl ether to give white solid. (Yield 89%).
JH NM (400 MHz, DMSO), δ (ppm): 0.85 (3Η, t, CH3),1.04 (3H, t, CH3), 1.10- 1.33 (32H, m, 13 CH2和 2 CH3), 1.35-1.51 (2H, m, CH2), 1.66-1.79 (2H, m, CH2), 3.26-3.38 (4H, m, 2 x OCH2), 3.59-3.75 (2H, m, OCH2), 3.76-3.95 (4H, m, OCH2P、NH禾口 OCH), 4.01-4.29 (4H, m, NCH2和 COOCH2), 5.01-5.19(2H, s, NCH), 6.63(2H, s, 富马酸双键上的氢)， 7.19(2H, s, NH2), 8.04-8.10 (1H, d, 嘌呤环上的 H), 8.13(1H, s, 嘌呤环上的 H)。 J H NM (400 MHz, DMSO), δ (ppm): 0.85 (3Η, t, CH 3 ), 1.04 (3H, t, CH 3 ), 1.10- 1.33 (32H, m, 13 CH 2 and 2 CH 3 ), 1.35-1.51 (2H, m, CH 2 ), 1.66-1.79 (2H, m, CH 2 ), 3.26-3.38 (4H, m, 2 x OCH 2 ), 3.59-3.75 (2H, m, OCH 2 ), 3.76-3.95 (4H, m, OCH 2 P, NH and OCH), 4.01-4.29 (4H, m, NCH 2 and COOCH 2 ), 5.01-5.19 (2H, s, NCH), 6.63 (2H, s, hydrogen on the fumaric acid double bond), 7.19(2H, s, NH 2 ), 8.04-8.10 (1H, d, H on the anthracene ring), 8.13 (1H, s, H on the anthracene ring).
ESI-MS: [M+H]+ 669.3 , [M+Na]+691.3。 ESI-MS: [M+H] + 669.3, [M+Na] + 691.3.
实施例 31: YC0P135-114 的制备 Example 31: Preparation of YC0P135-114
C0P135- 114 YC0P135- 1 14 制备过程同实施例 30 (收率 87% )。 C0P135-114 YC0P135- 1 14 The preparation procedure was the same as in Example 30 (yield 87%).
实施例 32: C0P231的制备 Example 32: Preparation of C0P231
在 50ml圆底烧瓶中，依次加入 PMPA ( 1.3g, 4.5mmol )、三乙胺（ 7ml, 5.08g, 50.2mmol )、 氯甲基碳酸异丙酯 （0.265ml, 0.305g, 2mmol )和 N-甲基 -2-吡咯垸酮（14ml ), 在 60°C下 搅拌 15h后， 蒸除溶剂， 用乙酸乙酯： 乙醇 =10： 1 (体积比）硅胶柱层析， 得中间化合物
C0P02 ( 0.68g, 1.68mmol ) 收率 37.3%。 In a 50 ml round bottom flask, PMPA (1.3 g, 4.5 mmol), triethylamine (7 ml, 5.08 g, 50.2 mmol), isopropyl chloromethyl carbonate (0.265 ml, 0.305 g, 2 mmol) and N- were sequentially added. Methyl-2-pyrrolidone (14 ml), after stirring at 60 ° C for 15 h, the solvent was evaporated, and ethyl acetate: ethanol = 10: 1 (volume ratio) silica gel column chromatography to give intermediate compound The yield of C0P02 (0.68 g, 1.68 mmol) was 37.3%.
在 50ml圆底烧瓶中， 依次加入 C0P02 ( 8.47g, 21mmol ), L-丙氨酸乙酯盐酸盐 （ 6.6g, 43mmol )、 2,2' -二硫二吡啶 (9.03g, 41mmol)、 三乙胺 （ 11.04g, 15.2ml, 109mmol )、 三 苯基膦（11.2g, 43mmol ) 和吡啶 （25ml ), 在 65 °C下密闭搅拌 16h后， 蒸除溶剂， 用乙酸 乙酯： 乙醇 =7： 1 (体积比）硅胶柱层析， 得到目标物 C0P231 ( 4.4g, 8.76mmol ), 收率 41.7%。 In a 50 ml round bottom flask, COOP02 ( 8.47 g, 21 mmol), L-alanine ethyl ester hydrochloride (6.6 g, 43 mmol), 2,2'-dithiodipyridine (9.03 g, 41 mmol), Triethylamine (11.04 g, 15.2 ml, 109 mmol), triphenylphosphine (11.2 g, 43 mmol) and pyridine (25 ml) were stirred at 65 ° C for 16 h, then evaporated and evaporated. 7:1 (volume ratio) silica gel column chromatography gave the title compound EtOAc ( 4.4 g, 8.76 mmol), yield 41.7%.
JH NM (400 MHz, CDC13), δ (ppm): 1.16-1.44(15H, m, 5 x CH3), 3.57-4.27(8H, m, OCH、 NCH2、 OCH2P、 COOCH2及 NCH), 4.31-4.47(1H, m, COOCH), 4.85-5.00(lH, m, NH), 5.53-5.74 (2H, m, OCH20), 6.05-6.34(2H, d, NH2), 7.93-8.05 (IH, d, 嘌呤环上的 H), 8.26-8.42(1Η, d, 嘌呤环上的 H)。 J H NM (400 MHz, CDC1 3 ), δ (ppm): 1.16-1.44 (15H, m, 5 x CH 3 ), 3.57-4.27 (8H, m, OCH, NCH 2 , OCH 2 P, COOCH 2 and NCH), 4.31-4.47 (1H, m, COOCH), 4.85-5.00 (lH, m, NH), 5.53-5.74 (2H, m, OCH 2 0), 6.05-6.34 (2H, d, NH 2 ), 7.93-8.05 (IH, d, H on the ankle ring), 8.26-8.42 (1Η, d, H on the ankle ring).
ESI-MS: [M+H]+ 503.2, [M+Na]+525.2。 ESI-MS: [M+H] + 503.2, [M+Na]+525.2.
实施例 33: C0P232 的制备 Example 33: Preparation of C0P232
C0P02 C0P232 C0P02 C0P232
制备过程同实施例 32 (收率 39% )。 The preparation procedure was the same as in Example 32 (yield 39%).
JH NMR (400 MHz, CDC13), δ (ppm): 0.87-0.95(6H, m, 2 x CH3), 1.17-1.45(12H, m, 4 CH3), 1.84-2.00(1H, m, CH), 3.60-3.71(lH, m, OCH), 3.83-4.00(4H, m, COOCH、 COOCH2 及 NCH), 4.08-4.18(2H, m, OCH2P), 4.25-4.46 (2H, m, NCH2), 4.87-4.98(lH, m, NH), 5.57-5.73 (2H, m, OCH20) , 6.60(2H, s, NH2), 7.96-8.03 (IH, d, 嘌呤环上的 H), 8.29-8.36(1Η, d, 嘌呤环 上的 H)。 J H NMR (400 MHz, CDC1 3 ), δ (ppm): 0.87-0.95 (6H, m, 2 x CH 3 ), 1.17-1.45 (12H, m, 4 CH 3 ), 1.84-2.00 (1H, m , CH), 3.60-3.71 (lH, m, OCH), 3.83-4.00 (4H, m, COOCH, COOCH 2 and NCH), 4.08-4.18 (2H, m, OCH 2 P), 4.25-4.46 (2H, m, NCH 2 ), 4.87-4.98 (lH, m, NH), 5.57-5.73 (2H, m, OCH 2 0) , 6.60 (2H, s, NH 2 ), 7.96-8.03 (IH, d, anthracene ring H), 8.29-8.36 (1Η, d, H on the ankle ring).
ESI-MS: [M+H]+ 531.3 , [M+Na]+553.2。 ESI-MS: [M+H] + 531.3, [M+Na]+ 553.2.
实施例 34: C0P233的制备 Example 34: Preparation of C0P233
C0P02 C0P233 C0P02 C0P233
制备过程同实施例 32 (收率 31% )。 The preparation procedure was the same as in Example 32 (yield 31%).
JH NMR (400 MHz, CDC13), δ (ppm): 0.94(9H, s, 3 x CH3), 1.17-1.22(3H, d, CH3), 1.26-1.32(6H, m, 2 CH3), 1.40-1.46(3H, d, CH3), 3.60-3.87(3H, m, COOCH, OCH及 NCH),
3.88-3.95(2H, m, COOCH2), 4.08-4.39(4H, m, OCH2P和 NCH2), 4.86-4.97(lH, m, NH), 5.57-5.73(2H, m, OCH20), 6.46(2H, s, NH2), 7.99 (IH, s, 嘌呤环上的 H), 8.33(1H, s, 嘌呤环 上的 H). J H NMR (400 MHz, CDC1 3 ), δ (ppm): 0.94 (9H, s, 3 x CH 3 ), 1.17-1.22 (3H, d, CH 3 ), 1.26-1.32 (6H, m, 2 CH 3 ), 1.40-1.46(3H, d, CH 3 ), 3.60-3.87 (3H, m, COOCH, OCH and NCH), 3.88-3.95 (2H, m, COOCH 2 ), 4.08-4.39 (4H, m, OCH 2 P and NCH 2 ), 4.86-4.97 (lH, m, NH), 5.57-5.73 (2H, m, OCH 2 0 ), 6.46(2H, s, NH 2 ), 7.99 (IH, s, H on the anthracene ring), 8.33 (1H, s, H on the anthracene ring).
ESI-MS: [M+H]+ 545.4, [M+Na]+567.3。 ESI-MS: [M+H]+ 545.4, [M+Na]+ 567.3.
实施例 35: C0P234 的制备 Example 35: Preparation of C0P234
制备过程同实施例 32 (收率 32.2% )。 The preparation procedure was the same as in Example 32 (yield 32.2%).
JH NM (400 MHz, CDC13), δ (ppm): 0.93(3H, t, 3 x CH3), 1.18-1.44(14H, m, 4 C¾ 和 CH2), 1.55-1.67(2H, m, CH2), 3.58-3.95 (3H, m, OCH、 COOCH和 NCH), 3.96-4.07 (2H, m， COOCH2) ,4.08-4.41 (4H, m, OCH2P和 NCH2), 4.85-4.98(lH, m, NH), 5.53-5.72 (2H, m, OCH20), 6.26(2H, s, NH2), 7.96-8.04 (IH, d, 嘌呤环上的 H), 8.33(1H, s, 嘌呤环上的 H)。 J H NM (400 MHz, CDC1 3 ), δ (ppm): 0.93 (3H, t, 3 x CH 3 ), 1.18-1.44 (14H, m, 4 C3⁄4 and CH 2 ), 1.55-1.67 (2H, m , CH 2 ), 3.58-3.95 (3H, m, OCH, COOCH and NCH), 3.96-4.07 (2H, m, COOCH 2 ) , 4.08-4.41 (4H, m, OCH 2 P and NCH 2 ), 4.85- 4.98(lH, m, NH), 5.53-5.72 (2H, m, OCH 2 0), 6.26(2H, s, NH 2 ), 7.96-8.04 (IH, d, H on the anthracene ring), 8.33 (1H , s, H) on the ring.
ESI-MS: [M+H]+ 531.2, [M+Na]+553.2。 ESI-MS: [M+H] + 531.2, [M+Na]+ 553.2.
实施例 36: C0P235 的制备 Example 36: Preparation of C0P235
C0P02 C0P235 C0P02 C0P235
制备过程同实施例 32 (收率 32.3% )。 The preparation procedure was the same as in Example 32 (yield 32.3%).
JH NMR (400 MHz, CDC13), δ (ppm): 1.01-1.26 (12H, m, 4 CH3), 1.27-1.53 (6H, m, 环 己基上的 3 x CH2), 1.59-1.70 (2H, m, 环己基上的 CH2), 1.71-1.81 (2H, m, 环己基上的 CH2), 3.70-3.98 (4H, m, NCH、 OCH、 环己基上与氧相连的 CH和 NH), 4.11-4.30 (2H, m, OCH2P), 4.60-4.86(2H, m, NCH2), 5.38-5.56(3H, m, OCH20和 COOCH), 7.20(2H, s, NH2), 8.05-8.09(lH, d, 嘌呤环上的 H), 8.13(1H, s, 嘌呤环上的 H)。 J H NMR (400 MHz, CDC13), δ (ppm): 1.01-1.26 (12H, m, 4 CH3), 1.27-1.53 (6H, m, 3 x CH 2 on cyclohexyl), 1.59-1.70 (2H , m, CH 2 on cyclohexyl), 1.71-1.81 (2H, m, CH 2 on cyclohexyl), 3.70-3.98 (4H, m, NCH, OCH, CH and NH attached to the oxygen on the cyclohexyl) , 4.11-4.30 (2H, m, OCH 2 P), 4.60-4.86 (2H, m, NCH 2 ), 5.38-5.56 (3H, m, OCH 2 0 and COOCH), 7.20(2H, s, NH 2 ) , 8.05-8.09 (lH, d, H on the ankle ring), 8.13 (1H, s, H on the ankle ring).
ESI-MS: [M+H]+ 557.3 , [M+Na]+579.2。 ESI-MS: [M+H] + 557.3, [M+Na] + 579.2.
实施例 37: C0P230 的制备
Example 37: Preparation of C0P230
C0P02 C0P230 C0P02 C0P230
制备过程同实施例 32 (收率 36% )。 The preparation procedure was the same as in Example 32 (yield 36%).
JH NM (400 MHz, CDC13), δ (ppm): 1.14-1.42(18H, m, 6 x CH3), 3.55-3.71(lH, m, OCH), 3.75-4.07 (3H, m, 2 COOCH和 NH), 4.08-4.24 (2H, m, OCH2P), 4.29-4.45(lH, m, NCH), 4.84-5.10(2H, m, NCH2), 5.54-5.74 (2H, m, OCH20), 6.45(2H, s, NH2), 7.95-8.04 (1H, d: 嘌呤环上的 H), 8.27-8.38(1Η, d, 嘌呤环上的 H)。 J H NM (400 MHz, CDC1 3 ), δ (ppm): 1.14-1.42 (18H, m, 6 x CH 3 ), 3.55-3.71 (lH, m, OCH), 3.75-4.07 (3H, m, 2 COOCH and NH), 4.08-4.24 (2H, m, OCH 2 P), 4.29-4.45 (lH, m, NCH), 4.84-5.10 (2H, m, NCH 2 ), 5.54-5.74 (2H, m, OCH 2 0), 6.45(2H, s, NH 2 ), 7.95-8.04 (1H, d : H on the anthracene ring), 8.27-8.38 (1Η, d, H on the anthracene ring).
ESI-MS: [M+H]+ 517.2, [M+Na]+539.1。 ESI-MS: [M+H] + 517.2, [M+Na]+539.1.
实施例 38: FC0P230 的制备 Example 38: Preparation of FC0P230
C0P230 FC0P230 C0P230 FC0P230
将等摩尔量的 C0P230 和富马酸溶于乙腈中， 回流搅拌 2小时,室温下冷却析晶， 滤出 析出的固体并用乙醚洗涤得白色固体 FC0P230 (收率 89% )。 An equimolar amount of C0P230 and fumaric acid were dissolved in acetonitrile, and the mixture was stirred under reflux for 2 hours, and the crystals were crystallised by cooling at room temperature, and the precipitated solid was filtered and washed with diethyl ether to give a white solid, EtOAc (yield: 89%).
JH NMR (400 MHz, DMSO), δ (ppm): 1.04 (3H, t, CH3), 1.12- 1.28 (15H, m, 5 x CH3), 3.67-4.00 (4H, m, OCH2P、 NCH及 OCH), 4.12-4.31 (2H, m, NCH2), 4.75-4.95 (2H, m, NH、 COOCH), 5.37-5.59 (3H, m, OCH20和 COOCH), 6.63(2H, s, 富马酸双键上的 H), 7.22(2H, s, NH2), 8.06-8.10 (lH, d, 嘌呤环上的 H), 8.14(1H, s, 嘌呤环上的 H, 12.22-14.23(2H, br, 富马 酸的两个 COOH)。 J H NMR (400 MHz, DMSO), δ (ppm): 1.04 (3H, t, CH 3 ), 1.12- 1.28 (15H, m, 5 x CH 3 ), 3.67-4.00 (4H, m, OCH 2 P , NCH and OCH), 4.12-4.31 (2H, m, NCH 2 ), 4.75-4.95 (2H, m, NH, COOCH), 5.37-5.59 (3H, m, OCH 2 0 and COOCH), 6.63 (2H, s, H) on the double bond of fumaric acid, 7.22(2H, s, NH 2 ), 8.06-8.10 (lH, d, H on the anthracene ring), 8.14 (1H, s, H on the anthracene ring, 12.22 -14.23 (2H, br, two COOH of fumaric acid).
ESI-MS: [M+H]+ 517.3。 ESI-MS: [M+H] + 517.3.
实施例 39: YC0P235 的制备 Example 39: Preparation of YC0P235
C0P235 YC0P235 C0P235 YC0P235
制备过程同实施例 38 (收率 82% )。 The preparation procedure was the same as in Example 38 (yield 82%).
实施例 40含有化合物 C0P12-114的药物制剂
组成成分如下 （片剂单位为： 200mg/片； 胶囊剂单位为： 200mg/粒）: 化合物 C0P12-114: lOOmg; Example 40 Pharmaceutical Formulation Containing Compound CO12-12-114 The composition is as follows (tablet unit: 200 mg / tablet; capsule unit: 200 mg / tablet): Compound C0P12-114: lOOmg;
乳糖： 65mg; Lactose: 65mg;
淀粉： 24mg; Starch: 24mg;
微晶纤维素： 5mg; Microcrystalline cellulose: 5mg;
羧甲淀粉钠： 5mg; Carboxymethyl starch sodium: 5mg;
硬脂酸镁： lmg。 Magnesium stearate: lmg.
实验例 1 脂溶性测试 Experimental Example 1 Fat Soluble Test
测试物质包括： 本发明化合物 COP12-114与 CMX157、 COP130-114与 CMX157、 COP 131 - 114与 CMX 157、 COP233与 TDF脂溶性大小的测定。 Test substances include: Determination of the fat solubility of the compounds of the present invention COP12-114 and CMX157, COP130-114 and CMX157, COP 131-114 and CMX 157, COP233 and TDF.
测试物质的脂溶性大小， 通常通过不同物质在相同条件下， 在反向液相色谱图上的保 留时间的长短来表征。 物质的脂溶性越高， 则表现为该物质在反向液相色谱图上的保留时 间越长。 The fat-soluble nature of the test substance is usually characterized by the length of time that different substances remain on the reversed-phase chromatogram under the same conditions. The higher the fat solubility of a substance, the longer the retention time of the substance on the reverse phase chromatogram.
在色谱条件：色谱柱： AgilentZorBaxSB-C18(250x4.6mm.id.5 m);流动相：甲醇 /水 =98： 2(v： v); 检测波长： 254nm; 流速： l.Oml/min; 柱温： 30°C下， CMX157的保留时间为 2.983 分钟， 化合物 COP12-114的保留时间为 5.673分钟。 如图 1所示。 In the chromatographic conditions: column: AgilentZorBaxSB-C18 (250 x 4.6 mm. id. 5 m); mobile phase: methanol / water = 98: 2 (v: v); detection wavelength: 254 nm; flow rate: l.Oml / min; Column temperature: The retention time of CMX157 was 2.983 minutes at 30 °C, and the retention time of compound COP12-114 was 5.673 minutes. As shown in Figure 1.
在色谱条件：色谱柱： AgilentZorBaxSB-C18(250x4.6mm.id.5 m);流动相：甲醇 /水 =95： 5(v： v); 检测波长： 254nm; 流速： l.Oml/min; 柱温： 30°C下， CMX157的保留时间为 1.784 分钟， 化合物 COP130-114的保留时间为 9.326分钟。 如图 2所示。 In the chromatographic conditions: column: AgilentZorBaxSB-C18 (250 x 4.6 mm. id. 5 m); mobile phase: methanol / water = 95: 5 (v: v); detection wavelength: 254 nm; flow rate: l.Oml / min; Column temperature: The retention time of CMX157 was 1.784 minutes at 30 °C, and the retention time of compound COP130-114 was 9.326 minutes. as shown in picture 2.
在色谱条件：色谱柱： AgilentZorBaxSB-C18(250x4.6mm.id.5 m);流动相：甲醇 /水 =98： 2(v： v); 检测波长： 254nm; 流速： l.Oml/min; 柱温 30°C下， CMX157的保留时间为 2.962 分钟， 化合物 COP131-114的保留时间为 5.610分钟。 如图 3所示。 In the chromatographic conditions: column: AgilentZorBaxSB-C18 (250 x 4.6 mm. id. 5 m); mobile phase: methanol / water = 98: 2 (v: v); detection wavelength: 254 nm; flow rate: l.Oml / min; At a column temperature of 30 ° C, the retention time of CMX157 was 2.962 minutes, and the retention time of compound COP131-114 was 5.610 minutes. As shown in Figure 3.
在色谱条件： 色谱柱： AgilentZorBax SB-Cl 8(250x4.6 mm.id.5 m); 流动相： 甲醇： 水 = ( 80 : 20, v/v ); 检测波长： 254nm; 流速： l.Oml/min; 柱温： 30°C下， TDF的保留时间 为 3.627分钟， 化合物〔0?233的保留时间为4.169分钟。 如图 4所示。 In the chromatographic conditions: Column: AgilentZorBax SB-Cl 8 (250 x 4.6 mm. id. 5 m); Mobile phase: Methanol: Water = (80: 20, v/v); Detection wavelength: 254 nm; Flow rate: l. Oml/min; Column temperature: The retention time of TDF was 3.627 minutes at 30 ° C, and the retention time of compound [0?233 was 4.169 minutes. As shown in Figure 4.
根据上述脂溶性测试可知， 本发明化合物 COP12-114、 COP130-114, C0P131-114分别 比 CMX157的保留时间延长了 2.69分钟、 7.542分钟、 2.648分钟， 化合物 C0P233的保留时间 比 TDF的保留时间延长了 0.542分钟。 这表明本发明化合物的脂溶性比 CMX157和 TDF的脂 溶性高出了许多， 从而表明提高了膜透过性。 According to the above fat solubility test, the retention times of the compounds of the present invention COP12-114, COP130-114, and C0P131-114 were 2.69 minutes, 7.542 minutes, and 2.648 minutes, respectively, and the retention time of the compound C0P233 was longer than that of the TDF. 0.542 minutes. This indicates that the fat solubility of the compound of the present invention is much higher than that of CMX157 and TDF, indicating that the membrane permeability is improved.
实验例 2 抗 HBV病毒活性的测定 Experimental Example 2 Determination of anti-HBV virus activity
体外细胞模型： HepG2 2.215细胞 In vitro cell model: HepG2 2.215 cells
HepG2.2.15细胞在 24孔细胞培养板中培养 48小时后， 加入所配不同浓度含药培养液，
继续培养 9天（每 3天换液一次）， 收集上清液， 用荧光探针法进行实时定量 PCR检测， 结果 见表 1。 HepG2.2.15 cells were cultured in a 24-well cell culture plate for 48 hours, and then the drug-containing culture solutions were added at different concentrations. The culture was continued for 9 days (changing every 3 days), and the supernatant was collected and subjected to real-time quantitative PCR detection by a fluorescent probe method. The results are shown in Table 1.
HBV引物： HBV上游引物： 5，-TgT CCT ggT TAT CgC Tgg-3， HBV primer: HBV upstream primer: 5,-TgT CCT ggT TAT CgC Tgg-3,
HBV下游引物： 5，-CAA ACg ggC AAC ATA CCT T-3' HBV downstream primer: 5,-CAA ACg ggC AAC ATA CCT T-3'
HBV荧光探针序列： 5 '(FAM)-TgT gTC TgC ggC gTT TTA TCA T-(TAMRA)3， HBV fluorescent probe sequence: 5 '(FAM)-TgT gTC TgC ggC gTT TTA TCA T-(TAMRA)3,
PCR: 95 °C预变性 5min; 95 °C变性 10s , 60 °C退火和延伸共 30s, 40个循环。 PCR: pre-denaturation at 95 °C for 5 min; denaturation at 95 °C for 10 s, annealing and extension at 60 °C for 30 s, 40 cycles.
表 1 体外抗乙肝病毒活性筛选表 Table 1 In vitro anti-hepatitis B virus activity screening table
实验结论： Experimental results:
化合物 C0P12-114、 C0P131-114、 C0P132-114、 C0P133-114、 C0P134-114、 C0P135-114、 C0P230、 C0P231、 C0P232、 C0P233、 C0P235可有效抑制 HBV病毒 DNA的复制， 效果优于 TDF。 The compounds C0P12-114, C0P131-114, C0P132-114, C0P133-114, C0P134-114, C0P135-114, C0P230, C0P231, C0P232, C0P233, C0P235 can effectively inhibit the replication of HBV virus DNA, and the effect is better than TDF.
实验例 3 抗 HIV-1病毒活性的测定 Experimental Example 3 Determination of anti-HIV-1 virus activity
1.实验材料 Experimental material
1.1供试品： 见表 2。 1.2对照品： 阳性对照品齐多夫定。 1.3细胞株： 名称： 293T; 来源： ATCC; 保存条件： 液氮。 1.4病毒株： 名称： VSVG/ HIV-l(NL4-3); 保存条件： -80 °C ; 1.5 培养基： 名称： DMEM培养基， RPMI-1640 , FBS , 来源： 美国 Gibco公司， 配制方法： RPMI-1640/DMEM + 10%FBS„ 1.6实验用介质： 二甲基亚砜 (DMSO) , 来源于美国 Sigma; 1.7主要仪器及试剂： BS124S电子天平： 德国 Sartorius公司； 离心机： 美国 Beckman公司； C02细胞培养箱： 美国 ShellAB公司； Sirius化学发光检测仪： 德国 Berthold公司； 胰蛋白酶： 美国 Invitrogen公司； 青链霉素： 美国 Invitrogen公司； 胎牛血清： 美国 Gibco公司； 细胞裂
解液及荧光素酶检测试剂盒： 美国 Promega公司。 1.1 Test sample: See Table 2. 1.2 Control: Positive control zidovudine. 1.3 cell line: Name: 293T; Source: ATCC; Storage conditions: liquid nitrogen. 1.4 Virus strain: Name: VSVG/HIV-l (NL4-3); Storage conditions: -80 °C; 1.5 Culture medium: Name: DMEM medium, RPMI-1640, FBS, Source: Gibco, USA, Preparation method: RPMI-1640/DMEM + 10%FBS„ 1.6 Experimental medium: Dimethyl sulfoxide (DMSO), from Sigma, USA; 1.7 Main instruments and reagents: BS124S electronic balance: Sartorius, Germany; Centrifuge: Beckman, USA; C0 2 cell incubator: ShellAB, USA; Sirius chemiluminescence detector: Berthold, Germany; Trypsin: Invitrogen, USA; Streptomycin: American Invitrogen; Fetal bovine serum: Gibco, USA; Solution for lysing and luciferase detection: Promega, USA.
2.实验方法： 转染前一天， 按 2.2 X 106个细胞的密度接种 293T细胞到 100mm培养皿中， 用改良的磷酸钙沉淀法共转染 3 μ gVSV-G质粒和 8 μ g野生型 HIV-1核心基因， 转染后 16小 时，用 PBS冲洗细胞并换新鲜的培养基继续培养 32小时，收集上清并经 0.45mm的滤膜过滤， 生成野生型 HIV-1重组病毒颗粒 VSVG/HIV-WT; 感染前一天， 将 293T细胞按每孔 6 x 104的 密度接种到 24孔板上， 用 DMSO溶解待测化合物， 于感染前 15分钟加入细胞培养液中， DMSO溶剂作空白对照， 再加入 0.5 ml病毒液 （根据 p24浓度将病毒原液稀释至 0.1-0.5 ng p24/ml )。 感染后 48小时， 去除上清， 每孔中加入 50 μΐ细胞裂解液 （ Promega )裂解细胞， 再将 20 μΐ细胞裂解产物加入至 30 μΐ荧光素酶底物中（Promega ),用 FB15荧光检测器（ Sirius ) 仪器测定细胞荧光素酶的相对活性， 以 DMSO作对照， 计算化合物对野生型 HIV-1复制的半 数抑制浓度， 检测数据见表 2。 2. Experimental method: One day before transfection, 293T cells were seeded at a density of 2.2 X 10 6 cells into a 100 mm culture dish, and co-transfected with 3 μg of VSV-G plasmid and 8 μg of wild type by modified calcium phosphate precipitation. HIV-1 core gene, 16 hours after transfection, the cells were washed with PBS and cultured for another 32 hours in fresh medium. The supernatant was collected and filtered through a 0.45 mm filter to generate wild-type HIV-1 recombinant virus particles VSVG/ HIV-WT; One day before infection, 293T cells were seeded into a 24-well plate at a density of 6 x 10 4 per well. The test compound was dissolved in DMSO, added to the cell culture medium 15 minutes before infection, and the DMSO solvent was used as a blank control. Then add 0.5 ml of virus solution (diluted the virus stock to 0.1-0.5 ng p24/ml according to p24 concentration). 48 hours after infection, the supernatant was removed, 50 μM of cell lysate (Promega) was added to each well to lyse the cells, and 20 μM of cell lysate was added to 30 μL of luciferase substrate (Promega) using FB15 fluorescence detector. The relative activity of luciferase was determined by (Sirius) instrument, and the half-inhibitory concentration of the compound on wild-type HIV-1 replication was calculated using DMSO as a control. The detection data are shown in Table 2.
应用 MTS法检测化合物对细胞存活的影响： 将对数生长期的 293T细胞按 8000~10000个 /孔的细胞密度接种至 96孔板中， 每孔 ΙΟΟμΙ, 37 °C , 5%C02培养箱中培养 24h后， 加入待测 化合物， 并以 DMSO为空白对照 （终浓度为 0.1% ), 37 °C , 5%C02培养箱中继续培养 44小 时。 向每孔中加入 2(^ 1 MTS/PMS现配的混合液， 37°C , 5%C02培养箱中继续培养 4h后显 色。 在酶联检测仪上， 波长 490 nm和 650 nm (本底） 处检测各孔的光吸收值（OD ), 并计 算细胞的存活率。 The effect of compounds on cell survival was examined by MTS assay: 293T cells in logarithmic growth phase were seeded into 96-well plates at a cell density of 8000-10000 cells/well, each well 37μΙ, 37 °C, 5% CO 2 incubator After 24 hours of culture, the test compound was added, and DMSO was used as a blank control (final concentration: 0.1%), and the culture was continued for 44 hours at 37 ° C in a 5% CO 2 incubator. Add 2 (^ 1 MTS/PMS mixture) to each well, and continue to culture for 4 hours at 37 ° C in a 5% CO 2 incubator. On the enzyme-linked detector, the wavelengths are 490 nm and 650 nm ( The light absorption value (OD) of each well was measured, and the cell survival rate was calculated.
表 2 药理筛选结果表 Table 2 Pharmacological screening results table
给药途 剂量 Dosing route
化合物 药理模型 细胞 抑制率 （％) 溶剂 备注 径 (mol/L) Compound pharmacological model cell inhibition rate (%) solvent remarks diameter (mol/L)
1 10"8 74.8土2.9 1 10" 8 74.8 soil 2.9
VSVG/ 293T 感染前 VSVG/ 293T before infection
C0P12-114 3 If)-9 38.4土1.6 DMSO IC50=5.4nM C0P12-114 3 If)- 9 38.4 soil 1.6 DMSO IC 50 =5.4nM
HIV-luc 细胞 加药 HIV-luc cell dosing
1 10"9 9.0土 4.2 1 10" 9 9.0 soil 4.2
VSVG/ 293T 感染前 1 10"8 76.6土 0.76 VSVG/ 293T before infection 1 10" 8 76.6 soil 0.76
C0P130-114 IC50=4.16nM C0P130-114 IC 50 =4.16nM
HIV-luc 细胞 加药 3 If)-9 39.6土 1.26 DMSO HIV-luc cell dosing 3 If)- 9 39.6 soil 1.26 DMSO
1 10"8 95.3土 0.2 1 10" 8 95.3 soil 0.2
VSVG/ 293T 感染前 VSVG/ 293T before infection
C0P131-114 3 If)-9 75.0土 1.6 DMSO IC50=1.2nM C0P131-114 3 If)- 9 75.0 soil 1.6 DMSO IC 50 =1.2nM
HIV-luc 细胞 加药 HIV-luc cell dosing
1 10"9 42.6土 2.6 1 10" 9 42.6 soil 2.6
1 10"8 91.8土 0.6 1 10" 8 91.8 soil 0.6
VSVG/ 293T 感染前 VSVG/ 293T before infection
C0P132-114 3 10"9 60.2土 1.7 DMSO IC50=2.5nM C0P132-114 3 10" 9 60.2 soil 1.7 DMSO IC 50 =2.5nM
HIV-luc 细胞 加药 HIV-luc cell dosing
1 10"9 24.1土 2.0 1 10" 9 24.1 soil 2.0
1 10"8 79.4土 0.8 1 10" 8 79.4 soil 0.8
VSVG/ 293T 感染前 VSVG/ 293T before infection
C0P133-114 3 10"9 40.3土 3.8 DMSO IC50=4.5nM C0P133-114 3 10" 9 40.3 soil 3.8 DMSO IC 50 = 4.5nM
HIV-luc 细胞 加药 HIV-luc cell dosing
1 10"9 17.0土 1.0 1 10" 9 17.0 soil 1.0
C0P134-114 VSVG/ 293T 感染前 1 10"8 80.8土 1.2 DMSO IC50=4.4nM
HIV-luc 细胞 加药 3 If)-9 42.2土 0.2 C0P134-114 VSVG/ 293T before infection 1 10" 8 80.8 soil 1.2 DMSO IC 50 =4.4nM HIV-luc cell dosing 3 If)- 9 42.2 soil 0.2
1 If)-9 15.1土 2.5 1 If)- 9 15.1 soil 2.5
1 10"9 64.2土 1.5 1 10" 9 64.2 soil 1.5
VSVG/ 293T 感染前 VSVG/ 293T before infection
C0P135-114 3 10"9 35.6土 5.8 DMSO IC50=7.2nM C0P135-114 3 10" 9 35.6 soil 5.8 DMSO IC 50 = 7.2nM
HIV-luc 细胞 加药 HIV-luc cell dosing
1 10"9 17.4土 2.7 1 10" 9 17.4 soil 2.7
1 10"8 79.8土 0.2 1 10" 8 79.8 soil 0.2
VSVG/ 293T 感染前 VSVG/ 293T before infection
C0P233 3 10"9 50.7土 0.6 DMSO IC50=2.8nM C0P233 3 10" 9 50.7 soil 0.6 DMSO IC 50 =2.8nM
HIV-luc 细胞 加药 HIV-luc cell dosing
1 10"9 27.4土 3.1 1 10" 9 27.4 soil 3.1
1 10"8 80.0土0.1 1 10" 8 80.0 soil 0.1
VSVG/ 293T 感染前 VSVG/ 293T before infection
C0P234 3 10"9 35.4土 4.0 DMSO IC50=4.7nM C0P234 3 10" 9 35.4 soil 4.0 DMSO IC 50 =4.7nM
HIV-luc 细胞 加药 HIV-luc cell dosing
1 10"9 6.7土 0.4 1 10" 9 6.7 soil 0.4
1 10"8 66.9土 0.9 1 10" 8 66.9 soil 0.9
VSVG/ 293T 感染前 VSVG/ 293T before infection
CMX157 3 10"9 30.3±2.1 DMSO IC50=7.4nM CMX157 3 10" 9 30.3 ± 2.1 DMSO IC 50 = 7.4nM
HIV-luc 细胞 加药 HIV-luc cell dosing
1 10"9 8.2土 6.2 1 10" 9 8.2 soil 6.2
1 10"7 91.3土 1.4 1 10" 7 91.3 soil 1.4
齐多 夫定 VSVG/ 293T 感染前 IC50=24.3nM Zidovudine VSVG/ 293T IC 50 = 24.3 nM before infection
1 10"8 46.9土 0.2 DMSO 1 10" 8 46.9 soil 0.2 DMSO
( AZT ) HIV-luc 细胞 加药 ( AZT ) HIV-luc Cell Dosing
1 10"9 2.7土 4.3 1 10" 9 2.7 soil 4.3
3.结论: 化合物 COP12-114、 C0P13O-114、 C0P131-114、 C0P132-114、 C0P133-114、 3. Conclusion: Compounds COP12-114, C0P13O-114, C0P131-114, C0P132-114, C0P133-114,
C0P134-114, C0P135-114, C0P230、 C0P23 C0P233或 C0P234可有效抑制野生型 HIV-1 的复制， 其半数有效浓度分别为、 COP12-114(5.9±0.6nM)、 C0P130(4.8±0.9nM)、 C0P131-114(1.6±0.6nM) 、 C0P132-114(2.7±0.2nM) 、 C0P133-114(4.9±0.6nM) 、 C0P134-114(4.6±0.2nM) 、 C0P135-114(7.5±0.4nM) 、 C0P230(40±0.2nM) 、 C0P231(33.4±8.1nM), C0P233(4.15±1.35nM)或 C0P234(5.0±0.4nM) , 在相同条件下平行测 定的 CMX157和阳性对照 AZT半数有效浓度分别为 8.7±1.8nM和 24.3nM,所有化合物在终浓 度 ΙΟμΜ时均无细胞毒性。 C0P134-114, C0P135-114, C0P230, C0P23 C0P233 or C0P234 can effectively inhibit the replication of wild-type HIV-1, and the half effective concentrations are COP12-114 (5.9±0.6nM), C0P130 (4.8±0.9nM), C0P131-114 (1.6±0.6nM), C0P132-114 (2.7±0.2nM), C0P133-114 (4.9±0.6nM), C0P134-114 (4.6±0.2nM), C0P135-114 (7.5±0.4nM), C0P230 (40±0.2nM), C0P231 (33.4±8.1nM), C0P233 (4.15±1.35nM) or COP234 (5.0±0.4nM), the half effective concentration of CMX157 and positive control AZT measured in parallel under the same conditions were 8.7. At ±1.8 nM and 24.3 nM, all compounds were not cytotoxic at a final concentration of ΙΟμΜ.
本发明化合物显示出较强的抗病毒作用， 而且还具有很低的毒性和良好的脂溶性等优 点， 有望成为治疗 HIV感染的新型药物。 The compound of the present invention exhibits a strong antiviral action, and has the advantages of low toxicity and good fat solubility, and is expected to be a novel drug for treating HIV infection.
工业实用性 Industrial applicability
本发明提供一种替诺福韦双酯类化合物、 其盐或其互变异构体， 本发明还提供了其制 备方法、 用途以及包含其的药物组合物。 本发明提供的化合物结构新颖， 合成简便， 降低 了化合物极性， 脂溶性优于现有的替诺福韦双酯类化合物， 从而可改善药物的膜透过性， 以提高生物利用度； 此外， 本发明提供化合物还显示出了较强的抗病毒作用， 尤其是对于 艾滋病毒和嗜肝 DNA病毒， 活性优于现有的替诺福韦双酯类化合物， 而且未显示出明显 的毒性， 安全性较高， 适用于预防与治疗艾滋病和肝炎的药物， 具有非常广阔的应用前景。
The present invention provides a tenofovir diester compound, a salt thereof or a tautomer thereof, and a process for the preparation thereof, a use thereof, and a pharmaceutical composition comprising the same. The compound provided by the invention has novel structure, simple synthesis, reduced polarity of the compound, and better fat solubility than the existing tenofovir diester compound, thereby improving the membrane permeability of the drug and improving the bioavailability; The compounds provided by the present invention also exhibit strong antiviral effects, especially for HIV and hepadnaviruses, which are superior to the existing tenofovir diesters and show no significant toxicity. It has high safety and is suitable for the prevention and treatment of AIDS and hepatitis. It has a very broad application prospect.
Claims
1、 一种如通式（ I )所示的替诺福韦双酯类化合物、 其盐或其互变异构体, 1. A tenofovir diester compound represented by general formula (I), its salt or its tautomer,
所述通式 （ I ) 中， Ra、 Rb独立地选自 、 R2或 R3, 且 Ra、 Rb不同时为 2; ！^选自氢或 C1 C5的垸基； In the general formula (I), R a and R b are independently selected from R 2 or R 3 , and R a and R b are not 2 at the same time; ! ^Selected from hydrogen or C1 C5 alkyl group;
所述 Ri为 -OCH2(CH2)mCH2OCH2(CH2)nCH3, 其中， m为 0~4的整数， n为 10-20的整数； The Ri is -OCH 2 (CH 2 ) m CH 2 OCH 2 (CH 2 ) n CH 3 , where m is an integer from 0 to 4, and n is an integer from 10 to 20;
所述 R2为- OCH2OC(=0)OCH(CH3)2; The R 2 is -OCH 2 OC(=0)OCH(CH 3 ) 2 ;
所述 为任意天然或药用氨基酸的氨基脱去一个氢后的残基， 其中， 所述 氨基酸中的羧基被垸基或芳基酯化。 Said is the residue obtained by removing one hydrogen from the amino group of any natural or medicinal amino acid, wherein the carboxyl group in said amino acid is esterified with an alkyl group or an aryl group.
2、 根据权利要求 1所述的化合物、 其盐或其互变异构体， 其特征在于， 所 述 R3为通式 （ Π )所示的结构，
2. The compound according to claim 1, its salt or its tautomer, characterized in that, the R 3 is a structure represented by the general formula (Π),
其中， 、 R5独立地选自 C1~C12的垸基、 C3-C12的环垸基、 C2~C12 的烯基、 C2 C12的炔基、 C6 C12的芳基或 C6 C12的芳垸基。 Among them, R 5 is independently selected from C1~C12 alkyl group, C3-C12 cycloalkyl group, C2~C12 alkenyl group, C2 C12 alkynyl group, C6 C12 aryl group or C6 C12 arylalkyl group.
3、 根据权利要求 2所述的化合物、 其盐或其互变异构体， 其特征在于， 、 R5独立地选自 C1 C12的垸基、 C3 C12的环垸基或 C6 C12的芳垸基。 3. The compound according to claim 2, its salt or its tautomer, characterized in that, R 5 is independently selected from C1 C12 alkyl group, C3 C12 cycloalkyl group or C6 C12 arylene group base.
4、 根据权利要求 2或 3所述的化合物、 其盐或其互变异构体， 其特征在于, 所述 R4选自甲基、 乙基或苄基。 4. The compound according to claim 2 or 3, its salt or its tautomer, characterized in that said R4 is selected from methyl, ethyl or benzyl.
5、 根据权利要求 2-4任一项所述的化合物、 其盐或其互变异构体， 其特征 在于， 所述 选自甲基、 乙基、 丙基、 异丙基、 环丙基、 正丁基、 异丁基、 仲 丁基、 叔丁基、 环丁基、 正戊基、 新戊基、 异戊基、 环戊基、 3-甲基己基、 正己 基、 2,2-二甲基戊基、 2,3-二甲基戊基、 环己基、 正庚基、 正辛基、 正壬基、 正
癸基、 正十二垸基、 苯基或苄基。 5. The compound according to any one of claims 2 to 4, its salt or its tautomer, characterized in that, the compound is selected from the group consisting of methyl, ethyl, propyl, isopropyl and cyclopropyl , n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, neopentyl, isopentyl, cyclopentyl, 3-methylhexyl, n-hexyl, 2,2- Dimethylpentyl, 2,3-dimethylpentyl, cyclohexyl, n-heptyl, n-octyl, n-nonyl, n- Decyl, n-dodecyl, phenyl or benzyl.
6、 根据权利要求 1-5任一项所述的化合物、 其盐或其互变异构体， 其特征 在于， 基酸为： 甘氨酸、 丙氨酸、 缬氨酸、 亮氨酸、 异亮氨酸、 苯丙氨酸、 脯氨酸、 色氨酸、 丝氨酸、 酪氨酸、 半胱氨酸、 蛋氨酸、 天冬氨酸、 谷氨酸、 苏 氨酸、 赖氨酸、 精氨酸或组氨酸。 6. The compound according to any one of claims 1 to 5, its salt or its tautomer, characterized in that the amino acid is: glycine, alanine, valine, leucine, isoleucine Amino acid, phenylalanine, proline, tryptophan, serine, tyrosine, cysteine, methionine, aspartic acid, glutamic acid, threonine, lysine, arginine or Histidine.
7、 根据权利要求 1-6任一项所述的化合物、 其盐或其互变异构体， 其特征 在于， 所述 m为 0 ~ 2的整数； 优选 0或 1。 7. The compound, salt or tautomer thereof according to any one of claims 1 to 6, characterized in that m is an integer from 0 to 2; preferably 0 or 1.
8、 根据权利要求 1-7任一项所述的化合物、 其盐或其互变异构体， 其特征 在于， 所述 n为 12 ~ 18的整数； 优选 14、 15或 16。 8. The compound, salt or tautomer thereof according to any one of claims 1 to 7, characterized in that n is an integer from 12 to 18; preferably 14, 15 or 16.
9、 根据权利要求 1-8任一项所述的化合物、 其盐或其互变异构体， 其特征 在于， 为以下结构中任一个所示的化合物、 其盐或其互变异构体： 9. The compound according to any one of claims 1 to 8, its salt or its tautomer, characterized in that it is a compound represented by any one of the following structures, its salt or its tautomer :
C0P12-014 C0P12-015 C0P12-014 C0P12-015
C0P12-016 C0P12-114 C0P12-016 C0P12-114
C0P12-1 15 C0P12-1 16 C0P12-1 15 C0P12-1 16
C0P130-114 C0P131- 1 14
C0P130-114 C0P131- 1 14
C0P132-114 C0P133-114 C0P132-114 C0P133-114
C0P134-114 C0P135-114 C0P134-114 C0P135-114
C0P230 C0P231 C0P230 C0P231
C0P232 C0P233
C0P232 C0P233
10、 权利要求 1-9 任一项所述的化合物的制备方法， 其特征在于， 以通式 ( 1-1)所示化合物为起始原料， 进行缩合反应得到单酯类化合物 （ 1-2), 然 后再进行缩合反应得通式 （ I )所述的双酯类化合物。
10. The method for preparing the compound according to any one of claims 1 to 9, characterized in that the compound represented by the general formula (1-1) is used as a starting material, and a condensation reaction is performed to obtain a monoester compound (1-2 ), and then perform a condensation reaction to obtain the diester compound described in the general formula (I).
-2 -2
11、 权利要求 1-9任一项所述的化合物、 其盐或其互变异构体在制备用于预 防或治疗肿瘤或病毒性疾病的药物中的用途。 11. Use of the compound according to any one of claims 1 to 9, its salt or its tautomer in the preparation of medicaments for preventing or treating tumors or viral diseases.
12、 根据权利要求 11所述的用途， 其特征在于， 所述病毒性疾病为艾滋病 病毒和 /或嗜肝 DNA病毒引起的疾病。 12. The use according to claim 11, characterized in that the viral disease is a disease caused by HIV and/or hepatotropic DNA virus.
13、 根据权利要求 12所述的用途， 其特征在于， 所述嗜肝 DNA病毒为乙 型肝炎病毒。 13. The use according to claim 12, characterized in that the hepatotropic DNA virus is hepatitis B virus.
14、 一种药物组合物， 其特征在于， 其包括： 权利要求 1-9任一项所述的化 合物、 其盐或其互变异构体， 以及药学上可接受的载体。
14. A pharmaceutical composition, characterized in that it includes: the compound according to any one of claims 1 to 9, its salt or its tautomer, and a pharmaceutically acceptable carrier.
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012102868791A CN102786549B (en) | 2012-08-13 | 2012-08-13 | Tenofovir diester compounds with activity of inhibiting HIV-1 (human immunodeficiency virus-1) virus replication and preparation method and pharmaceutical use thereof |
| CN201210286879.1 | 2012-08-13 | ||
| CN201310134491.4 | 2013-04-17 | ||
| CN201310134492.9 | 2013-04-17 | ||
| CN201310134492.9A CN103232490B (en) | 2013-01-31 | 2013-04-17 | Nucleoside compounds with HIV-1/HBV viral replication inhibition activity, preparation methods thereof, and antiviral applications thereof |
| CN201310134160.0A CN103224530B (en) | 2012-08-13 | 2013-04-17 | Tenofovir disoproxil compounds, and preparation method and application thereof in anti-virus aspects |
| CN201310134491.4A CN103242366B (en) | 2012-08-13 | 2013-04-17 | Tenofovir disoproxil fumarate compounds, preparation method and application to antiviral field |
| CN201310134160.0 | 2013-04-17 |
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| PCT/CN2013/081304 WO2014026582A1 (en) | 2012-08-13 | 2013-08-12 | Tenofovir diester compound, preparation method and use thereof, and pharmaceutical composition comprising the same |
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| WO (1) | WO2014026582A1 (en) |
Cited By (4)
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| CN107179355A (en) * | 2016-03-11 | 2017-09-19 | 广东东阳光药业有限公司 | A kind of separation detection tenofovir Chinese mugwort draws phenol amine and its method about material |
| CN108137630A (en) * | 2016-09-23 | 2018-06-08 | 鲁汶天主教大学 | It is fluorinated the prodrug of acyclic nucleoside phosphate ester |
| CN109485676A (en) * | 2017-12-21 | 2019-03-19 | 深圳市塔吉瑞生物医药有限公司 | For antiviral novel nucleoside reverse transcriptase inhibitor |
| US12110305B2 (en) | 2020-08-07 | 2024-10-08 | Gilead Sciences, Inc. | Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use |
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| CN102786549B (en) * | 2012-08-13 | 2013-07-03 | 洛阳聚慧投资股份有限公司 | Tenofovir diester compounds with activity of inhibiting HIV-1 (human immunodeficiency virus-1) virus replication and preparation method and pharmaceutical use thereof |
| CN103242366B (en) * | 2012-08-13 | 2014-08-20 | 洛阳聚慧投资股份有限公司 | Tenofovir disoproxil fumarate compounds, preparation method and application to antiviral field |
| CN103232490B (en) * | 2013-01-31 | 2015-06-10 | 洛阳聚慧投资股份有限公司 | Nucleoside compounds with HIV-1/HBV viral replication inhibition activity, preparation methods thereof, and antiviral applications thereof |
| CN103224530B (en) * | 2012-08-13 | 2014-10-29 | 洛阳聚慧投资股份有限公司 | Tenofovir disoproxil compounds, and preparation method and application thereof in anti-virus aspects |
| CN105001262B (en) * | 2014-04-18 | 2017-09-01 | 四川海思科制药有限公司 | The phosphonaminate of aryl substitution and its application medically |
| CN106188192B (en) * | 2015-04-29 | 2019-09-10 | 刘沛 | Nucleosides phosphoramidic acid/the phosphate derivatives and its medical usage of the amino-acid ester containing D- |
| CN106167504A (en) * | 2015-11-04 | 2016-11-30 | 洛阳聚慧医药科技有限公司 | Acyclonucleosides phosphamide D amino acid ester derivative and the preparation of salt thereof and in the application of anti-virus aspect |
| CN106565785B (en) * | 2016-11-09 | 2019-11-12 | 周雨恬 | One kind having the active nucleoside phosphoramidate class compound of Anti-HBV activity/HIV and its salt and purposes |
| EP3719027A4 (en) * | 2017-12-21 | 2020-12-16 | Shenzhen TargetRx, Inc. | Novel antiviral nucleoside reverse transcriptase inhibitor |
| CN108101942B (en) * | 2017-12-26 | 2020-12-04 | 深圳科兴药业有限公司 | Method for synthesizing potential impurities in production of tenofovir alafenamide hemifumarate |
| CN108623632A (en) * | 2018-08-17 | 2018-10-09 | 上海麦步医药科技有限公司 | A kind of tenofovir Chinese mugwort draws the preparation method of phenol amine |
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| CN107179355A (en) * | 2016-03-11 | 2017-09-19 | 广东东阳光药业有限公司 | A kind of separation detection tenofovir Chinese mugwort draws phenol amine and its method about material |
| CN108137630A (en) * | 2016-09-23 | 2018-06-08 | 鲁汶天主教大学 | It is fluorinated the prodrug of acyclic nucleoside phosphate ester |
| CN109485676A (en) * | 2017-12-21 | 2019-03-19 | 深圳市塔吉瑞生物医药有限公司 | For antiviral novel nucleoside reverse transcriptase inhibitor |
| US11447512B2 (en) | 2017-12-21 | 2022-09-20 | Shenzhen Targetrx, Inc. | Antiviral nucleoside reverse transcriptase inhibitor |
| US12110305B2 (en) | 2020-08-07 | 2024-10-08 | Gilead Sciences, Inc. | Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102786549A (en) | 2012-11-21 |
| CN102786549B (en) | 2013-07-03 |
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