143491-57-0 Usage
Uses
1. Used in Pharmaceutical Industry:
Emtricitabine is used as an antiviral agent for the treatment of chronic hepatitis B and as a reverse transcriptase inhibitor for the treatment of HIV-1 infection. It has a strong antiviral activity with good safety and tolerance.
2. Used in Combination Therapy for HIV-1 Infection:
Emtricitabine is used in combination therapy for the treatment of HIV-1 infection, as it has been shown to be effective against HIV, HBV, and other viruses replicating in a similar manner.
3. Used in Anti-Alzheimer's Treatment:
Emtricitabine is also being explored for its potential use in anti-Alzheimer's treatment.
4. Used as an Internal Standard for Quantification:
Labeled Emtricitabine is used as an internal standard for the quantification of Emtricitabine by gas chromatography (GC) or liquid chromatography (LC) mass spectrometry.
5. Used in Research and Development:
Emtricitabine is used in research and development for the study of its mechanism of action, resistance patterns, and potential applications in various therapeutic areas.
New anti-HIV drugs
Emtricitabine was a novel nucleoside reverse transcriptase inhibitor successfully developed by Gilead Sciences, Inc., belonging to an anti-viral drugs and exhibits antiviral activity on HIV-1, HIV-2 and HBV. Its antiviral activity exhibits that it can specifically anti-HIV-1, HIV-2 and HBV while even with its drug concentration being raised to 100 mmol/L, it still exhibit no activity against HSV-1, HSV-2, HCMV, VZV, corona, yellow fever virus, respiratory syncytial virus, Rota, and influenza virus or rhinovirus. Even at a concentration lower than micromolar, the drug still exhibits potent inhibitor effect against the LAV strain and IIIB 1 of HIV virus and the ROD2 strain and ZY virus strain of HIV-2 with an IC50 value lower being 95 times lower than that of AZT (zidovudine).
It has been increasingly become the focus of the assessment of new drugs that whether new anti-HIV drug will produce cross-resistance to other kinds of antiviral resistant strains such as AZT, etc. The cross-resistance test of emtricitabine against AZT-resistant strains has demonstrated that although IC50 values ??for these resistant strains have been increased slightly, all kinds of virus strains are still relatively sensitive to emtricitabine. Instead, emtricitabine-resistant viral strains will exhibit significant cross-resistance to antiviral 3TC (lamivudine), but are still sensitive to AZT. Studies have shown that the drug can be used together with AZT with synergistic effect.
Emtricitabine exhibited strong antiviral activity in HBV generating cell lines HepG22.2.15 (PSA subspecies). It can dose-dependently reduce the number of extracellular and intracellular HBVDNA with the IC50 value being 10nmol/L; this value was comparable to another kind of HBV replication inhibitor 3TC. Interferon α nl (Wellferon), α 2a (Ro feron), α 2b (Intron A) can all the production of inhibit HBV viral particles and the accumulation of the intracellular replication virus in the chronic producing cells intracellular production. Combination of them associated with emtricitabine can produce a synergistic effect.
The in vivo anti-hepatitis activity of emtricitabine is investigated through the anti-HBV action in a kind of chimeric mouse model as well as the action of anti-woodchuck hepatitis virus (WHV) function in natural infected prairie dogs. In the mouse model, use different doses for oral administration of this drug to mouse of immune deficiency and carrying human tumors as well as producing human HBV, with the antibody capture/PcR experiment, it was found that the blood HBVDNA (Dane particle) was reduced in a dose-dependent manner with even a low dose of 3.5 mg/(kg ? d) also being able to produce significant inhibition while the level of intracellular replicated HBVDNA also exhibited a dose-dependent decrease; however, even at the highest dose (89 mg/(kg ? d )), the tumor size remained unchanged, suggesting that the drug has selective anti-HBV activity.
The above information is edited by the lookchem of Dai Xiongfeng.
Pharmacological effects
Emtricitabine belongs to chemically synthesized nucleoside cytosine. Its mechanism of anti-HIV-1 is through multi-step in vivo phosphorylation generating active triphosphate which competitively inhibits the HIV-1 reverse transcriptase while competing with natural 5-phosphate cytosine by for penetrating into the viral DNA synthesis process, which ultimately leads to the synthesis of a DNA strand break. Its mechanism of HBV is because that the HBV replication process contains target site of emtricitabine, namely reverse transcription process. It has a low inhibitory effect on mammal DNA polymerases α, β, ε and mitochondrial DNA polymerase γ.
In vitro antiviral activity: in vitro laboratory used and clinical isolate anti-HIV viruses have been assessed in lymphoblastoid cell lines, MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% inhibitory concentration (IC50) value is in the range of 0.0013~0.158 μg/mL. In the combination study with nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitors (PI), it exhibited a synergistic effect. Most kinds of combined clinical study have not been carried out. In vitro tests have demonstrated that it has antiviral activity against HIV-1 (A, C, D, E, F and G subtypes) (IC50 values ??in the range of 0.007~0.075 μg/mL) while displaying specific inhibition activity against the HIV-2 type (IC50 values ??in the range of 0.007~1.5 μg/mL).
Pharmacokinetics
Pharmacokinetic assessment was performed in healthy volunteers and HIV-infected individuals. The pharmacokinetics of the two groups is similar with each other.
Absorption: oral administration gives rapid absorption with the drug being widely distributed. After administration of 1 to 2 hours, the plasma concentration reaches peak. 20 cases of HIV infected patients were subject to multiple fold doses of drugs through oral administration (mean ± SD) the plasma concentration peak of emtricitabine (Cmax) is 1.8 ± 0.7μg/mL. At 24 hours, the plasma drug concentration-time area under the curve (AUC) is 10.0 ± 3.1 (h ? μg)/mL. At 24h hours after administration, the average steady-state plasma concentration is 0.09μg/mL. The average bioavailability is 93%. At multiple folds of doses, the pharmacokinetics is in proportion with the dose (25~200mg).
Distribution: In vitro binding rate of emtricitabine to human plasma proteins is < 4%; when the concentration exceeds the range of 0.02~200 μg/mL, it exists in its free state. At the time of peak concentration, the ratio of plasma drug concentration and blood drug concentration is 1.0, and the ratio of the seminal fluid concentration and plasma drug concentration is 4.0.
Metabolism: In vitro studies have shown that emtricitabine is not an inhibitor of human CYP450 enzymes. Taking 14C-labeled emtricitabine with the prototype reaching the urine (86%) and it (14%). 13% of the dose is converted into three metabolites. The biotransformation substances include the oxidized sulfur portion for generating 3'-sulfoxide diastereomers (9%), and binding to glucuronide for formation of 2'-oxy-glucuronide (4%). Other metabolites have not been determined.
Excretion: The half life of the emtricitabine plasma concentration is about 10 hours. The renal clearance rate of emtricitabine is higher than the creatinine clearance rate, suggesting that it is excreted through glomerular filtration and tubular secretion, and there may be substance competing with it for the kidneys.
Pharmacokinetics
Oral absorption: capsules 93%
Cmax 200 mg oral once daily: 1.8 ± 0.7 mg/L
Plasma half-life: c. 10 h
Volume of distribution: 1.4 ± 0.3 L/kg
Plasma protein binding: <4%
Absorption and distribution
It is rapidly and extensively absorbed. There is moderate CNS penetration. The estimated semen:plasma ratio is approximately 4. There are presently no data on levels in breast milk.
Metabolism and excretion
It does not inhibit human cytochrome P450 enzymes. About 80% is excreted in the urine, the rest in feces. Renal clearance is greater than the estimated creatinine clearance, suggesting elimination by both glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are renally excreted. Exposure is significantly increased in renal insufficiency, but dose reductions are not generally recommended. It is unlikely that a dose adjustment would be required in the presence of hepatic impairment.
Indications
1. Emtricitabine is combined with other antiviral drugs for treating adult HIV-1 infection. Patients should be those who haven’t been subject to treatment by reverse transcriptase inhibitors or those who have received reverse transcriptase inhibitors with virus having been suppressed.
2. It can be used for the treatment of chronic hepatitis B.
Side effects
In the clinical applications, for patients who are subject to emtricitabine and other antiviral drugs, the most common adverse reactions include headache, diarrhea, nausea and rash with the extent from being mild to moderate to severe. About 1% of patients discontinued medication due to the above reasons. The frequency of all kinds of adverse reactions is comparable with the control group quite but with the skin pigmentation being slightly higher in the emtricitabine group. Skin pigmentation usually significantly appears in the palm/foot, being generally mild and not accompanied by other symptoms. The clinical significance and the mechanism are not clear.
Side effects
At least 10% of patients suffer headache, diarrhea, nausea,
fatigue, dizziness, depression, insomnia, abnormal dreams,
rash, abdominal pain, asthenia, increased cough and rhinitis.
Skin hyperpigmentation is common (≥10%) in pediatric
patients. Emtricitabine competes with lamivudine for
the enzymes involved in intracellular phosphorylation; their
co-
administration is contraindicated.
Precautions
This product is mainly excreted by the kidneys, so patients with renal insufficiency should reduce the administered amount upon taking this drug.
Pregnant women, when taking emtricitabine, may get an adverse effect on the fetus and newborn. This product can also be secreted through breast milk which may also affect the infant. Therefore, it is generally not recommended for pregnant and lactating women to use this product unless in situation of considering save the mother's life.
It has not been established of the children's safety basis. Therefore, it is not recommended for children. Elderly should be cautious when choosing the dose. They can apply appropriate reduction on the dose according to the actual conditions of liver, kidney, heart function decline, associated diseases and the effects of other kinds of drugs.
The impact of excessive drugs is unknown, if there is drug overdose, monitoring should be carried out. Apply maintenance dose treatment when necessary.
Originator
Emory University (US)
Acquired resistance
Resistance is associated with a substitution in the HIV-1 reverse
transcriptase gene at codon 184 (M184V/I). Emtricitabineresistant
isolates are cross-resistant to lamivudine. HIV-1 isolates
with the K65R substitution in the reverse transcriptase
coding region have reduced susceptibility.
Pharmaceutical Applications
A synthetic nucleoside analog of cytosine, formulated for oral use.
Clinical Use
Treatment of HIV infection (in combination with other antiretroviral drugs)
Synthesis
Emcitritabine (VII) was discovered by
researchers at Emory University and licensed to Triangle
Pharmaceuticals, which started the development work before
being acquired by Gilead. Because emcitritabine (VII)
belongs to an important structural class of nucleosides with
marketed drugs, such as 3TC, several processes for the
manufacture of this class of oxathiolane nucleosides have
appeared in patents and scientific literature.
However, only the synthesis described in the latest patent
filed for the manufacture of emcitritabine (VII) and one other
efficient synthesis from the Liotta group will be described . The synthesis started with diacylation
with butyryl chloride (62) of the 2-butene-1,4-diol (61) in
methyl t-butylether at 0°C to room temperature in the presence of triethylamine to give diacylated product 63 in
95% yield. Ozonolysis followed by reduction with thiourea
provided a mixture of hemiacetal 64 mixed with acetals,
dimers and trimers in 97% yield, which was used in the next
step directly. The hemiacetal mixture was reacted with
thioacetic acid in toluene at 85°C for 3 hr to give the crude
keto oxathiolane mixture, which was purified by vacuum
distillation in a 2-in Pope Scientific wiped film still to
remove impurities and collect about 92% pure 66 in 54%
yield. Also mentioned in the patent is the potential use of
enzymatic resolution of the isomers as reported previously. This keto oxathiolane 66 was reduced at 5°C with
lithium aluminum t-butoxide, which was prepared in situ
via reaction of LAH and t-butanol, and the resulting lactol
was trapped with acetic anhydride in the presence of DMAP
in the same reaction vessel to give, after workup, 87% yield
of the key intermediate acetate 67. The bis-silyl protected 5-
fluorocytosine 68, prepared in situ by reacting 5-
fluorocytosine (71) with HMDS, was reacted with acetate 67
in the presence of trimethylsilyliodide at 0°C to room
temperature to give a 1:1 mixture of alpha and beta-anomers
69 and 70. Pure 69 could be isolated by recrystallization
from toluene. Cleavage of the butyryl group with a strongly
basic DOWEX SBR resin in methanol at room temperature
gave emcitritabine (VII) in 81% yield. An alternate concise
synthesis reported by Liotta et al is worth mentioning.
This synthetic route accessed the key thioxalane acetate 76 as
the TBDMS ether in four steps from allyl alcohol 72. The key step to the preparation of the final compound was the
coupling of the bis-silyl 5-fluorocytosine (68) with acetate
76 with tin tetrachloride in a stereoselective manner, after
cleavage of the silyl groups and recrystallization, to give
pure cis isomer emcitritabine (VII) in excellent yield.
Drug interactions
Potentially hazardous interactions with other drugs
Antivirals: avoid concomitant use with lamivudine.
Orlistat: absorption of emtricitabine possibly
reduced.
Metabolism
There is limited metabolism of emtricitabine. The
biotransformation of emtricitabine includes oxidation of
the thiol moiety to form the 3'-sulphoxide diastereomers
(approximately 9% of dose) and conjugation with glucuronic
acid to form 2'-O-glucuronide (approximately 4% of dose).
Emtricitabine is primarily excreted by the kidneys
with complete recovery of the dose achieved in urine
(approximately 86%) and faeces (approximately 14%).
13% of the emtricitabine dose was recovered in urine as
three metabolites
Check Digit Verification of cas no
The CAS Registry Mumber 143491-57-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,3,4,9 and 1 respectively; the second part has 2 digits, 5 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 143491-57:
(8*1)+(7*4)+(6*3)+(5*4)+(4*9)+(3*1)+(2*5)+(1*7)=130
130 % 10 = 0
So 143491-57-0 is a valid CAS Registry Number.
InChI:InChI=1/C8H10FN3O3S/c9-4-1-12(8(14)11-7(4)10)5-3-16-6(2-13)15-5/h1,5-6,13H,2-3H2,(H2,10,11,14)
143491-57-0Relevant articles and documents
Immobilization of cholesterol esterase for use in multiple batch biotransformations to prepare (-)- FTC (emtricitabine)
Osborne, Andrew P.,Brick, Dean,Ruecroft, Graham,Taylor, Ian N.
, p. 670 - 672 (2006)
2′,3′-Dideoxy-5-fluoro-3′-thiacytidine [(-)-FTC], the active ingredient in the antiviral drug emtricitabine (Emtriva), was prepared by a bioresolution process using cholesterol esterase immobilized on Accurel PP to resolve optical isomers of racemic FTC butyrate. Cholesterol esterase was immobilized at 1.9-kg scale. Recycling studies were carried out with racemic FTC butyrate that indicated a high degree of immobilized cholesterol esterase stability resulting in 15 successive cycles of use (14 recycles). Racemic FTC butyrate (～8 kg, 200 g/L) was resolved with immobilized cholesterol esterase using a 1-pentanol/potassium dihydrogen phosphate buffer-solvent system to give (-)-FTC·HCl (98% ee, 2.17 kg, 31% molar yield based on racemic FTC butyrate).
Asymmetric preparation method for Emtricitabine
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Paragraph 0028; 0036; 0038, (2019/11/21)
The invention provides an asymmetric preparation method for Emtricitabine. The preparation method comprises the steps of subjecting L-menthyl chloroformate, which serves as a raw material, to condensation with 2-halo ethanol, carrying out oxidation so as to obtain a stable intermediate, i.e., an aldehyde alcohol menthyl ester, subjecting the intermediate to condensation with 2,5-dihydroxyl-1,4-dithiane, carrying out halogenation, then, carrying out coupling with silanized 5-flucytosine, then, carrying out hydrolyzing, then, carrying out salt forming with salicylic acid, and finally, carrying out recrystallization, thereby obtaining purified Emtricitabine. According to the method, raw materials employed in a whole synthesis process are cheap and readily available, thus, the synthesis cost of the Emtricitabine disclosed by the invention is reduced greatly, the synthesis process is simple, the synthesis conditions are moderate, and the obtained Emtricitabine is relatively high in yield; and meanwhile, a chiral substrate is easy to remove during synthesis, produced pollutants, i.e., waste gases, waste water and waste residues are few, and thus, the method is applicable to industrial large-scale production of the Emtricitabine.
Preparation method of emtricitabine (by machine translation)
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Paragraph 0027; 0034; 0036, (2019/11/21)
The synthesis cost of the emtricitabine is greatly reduced, the synthetic process is simple, 5 - the (S)- (+) - synthesis conditions are mild, the chiral substrate is easily removed in the synthesis process, 2,5 - the generated triwaste pollutants are few, and the entreabine is suitable for large-scale production of entreabine 5 . (by machine translation)
Preparation method for emtricitabine isomer
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Paragraph 0087; 0088; 0090; 0091, (2019/04/26)
The invention discloses a preparation method for an embritabine isomer. The preparation method comprises the following steps: with Solketal as a starting material, allowing the Solketal to undergo a six-step reaction of esterification, hydrolysis, oxidation, condensation cyclization, acetylation and glycosylation condensation so as to synthesize four mixture intermediates of emtricitabine; and splitting the four isomer intermediates into a cis-isomer mixture and a trans-isomer mixture through a chiral reagent. According to the invention, by adoption of a simple starting material, a mixture forsplitting key intermediates of four optical isomers of the emtricitabine is synthesized through the six-step reaction, and chiral acid is utilized to split the four isomers into a mixture of cis andtrans isomers, so the preparation method provided by the invention has the advantages of simple and convenient operation, high yield and high isomer chiral purity.
Asymmetric synthesis method of emtricitabine
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Paragraph 0027; 0028; 0034-0036, (2019/10/29)
The present invention provides an asymmetric synthesis method of emtricitabine. L-menthyl chloroformate is used as raw material to condense with 2-chloro-1-ethanol, then hydrolyze under the conditionof catalyst to obtain acetaldehyde alcohol optically active ester which is then induced by chiral promoter to condense with 2, 5-dihydroxyl-1,4-dithiane to give trans 5-hydroxyl-1,3-oxythiacyclopentane-2-methyl-L-menthol carbonate, the trans 5-hydroxyl-1,3-oxythiacyclopentane-2-methyl-L-menthol carbonate is halogenated and coupled with silanized 5-fluorocytosine, emtricitabine is obtained by removing the chiral auxiliary agent under the condition of weak alkalinity. As that raw materials used in the whole synthesis process are cheap and easy to obtain, the raw material utilization ratio is high, so that the synthesis cost of the emtricitabine is greatly reduced, and the synthesis process is simple, the synthesis condition is mild, the yield of the obtained emtricitabine is high, meanwhile,the chiral assistant is easy to remove in the synthesis process, the three waste pollutants generated are less, and the preparation method is suitable for the large-scale industrial production of theemtricitabine.
A Suitqable to preparation method
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Paragraph 0042; 0064-0066, (2019/04/02)
The invention discloses a Suitqable to preparation method. Refined pure 5 S - (5 '- fluorocytosine yl - 1') - 1, 3 - oxathiolane - 2 - ethoxy carbonyl - (1 'R, 2'S, 3' R) - menthyl ester; in the weak base and the solvent removed under the condition of chiral L - menthol get products Suitqable to. The invention required the starting raw material is cheap, mild reaction conditions, the atom utilization rate is high, the operation technique is simple, the reagents used in the environmental protection, the resulting high purity, reach the medical standard, is suitable for the industrial production of kindness or gemcitabine.
Emtricitabine synthesis method
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Paragraph 0028; 0035; 0036; 0038, (2019/11/29)
The invention provides an emtricitabine synthesis method, which comprises: carrying out condensation on cheap and easily available dihaloacetic acid as a raw material and L-menthol, hydrolyzing to obtain menthyl glyoxylate hydrate, condensing with 2,5-dihydroxy-1,4-dithiane, carrying out halogenation, coupling with silylated 5-flucytosine, reducing, carrying out salt forming with salicylic acid toobtain emtricitabine salicylate, and finally re-crystallizing to obtain optically pure emtricitabine. According to the present invention, the whole synthesis process has characteristics of inexpensive and easily available raw materials, simple synthesis process and mild synthesis conditions, such that the synthesis cost of emtricitabine is substantially reduced; various raw materials have characteristics of good reaction selectivity and high utilization rate, such that the yield of the obtained emtricitabine is high; and the chiral substrate is easily removed during the synthesis, and the generated three-waste pollutants are less, such that the method is suitable for industrial large-scale production of emtricitabine.
Benzoic acid Suitqable to salt, its preparation method and uses the benzoic acid Suitqable to salt preparation Suitqable to method
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Paragraph 0026-0027, (2018/11/03)
The invention discloses emtricitabine benzoate, a preparation method thereof, and a method of preparing emtricitabine from emtricitabine benzoate, and belongs to the biochemistry field. Emtricitabine benzoate is a novel compound, has not been reported before, and is not recorded in any product catalogue. The emtricitabine benzoate is prepared by combining benzoic acid and emtricitabine in a water phase or an organic phase. When benzoic acid and emtricitabine are combined in a water phase or an organic phase, emtricitabine benzoate can be easily separated from the reaction system. By adding organic base or inorganic base into the water phase/organic phase reaction system, emtricitabine benzoate can be decomposed to obtain emtricitabine. By preparing emtricitabine from emtricitabine benzoate, after the reactions, emtricitabine can be easily separated from the reaction system, the purity of the obtained emtricitabine is more than 99%, and the yield is usually more than 80%.
Preparation method for emtricitabine hydrohalide
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Paragraph 0075; 0076, (2017/08/27)
The invention discloses a preparation method for emtricitabine hydrohalide. The preparation method for the emtricitabine hydrohalide provided by the invention comprises the following steps: subjecting crude emtricitabine and hydrogen halide to a salt-forming reaction in an alcohol solvent so as to obtain emtricitabine hydrohalide, wherein the HPLC purity of the crude emtricitabine is larger than 85%; the hydrogen halide is selected from the group consisting of hydrogen chloride, hydrogen bromide or hydrogen iodide; and X is selected from the group consisting of chlorine, bromine or iodine. The preparation method provided by the invention has the advantages of simple operation, simple and convenient postprocessing and high yield; and the prepared emtricitabine product has high purity, can reach standards of raw medicines, has an HPLC purity larger than 99.60% and a largest single impurity less than 0.10%, is low in production cost, and is applicable to industrial production.
PROCESS FOR PRODUCING LAMIVUDINE AND EMTRICITABINE
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Page/Page column 22; 23; 24, (2018/01/20)
This invention provides for flow and batch synthesis processes for the production of Lamivudine and Emtricitabine, including flow and batch synthesis processes wherein at least of the synthesis steps are conducted in a solvent free environment.
