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Efavirenz
- Iupac Name：(4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1H-3,1-benzoxazin-2-one
- CAS No.: 154598-52-4
- Molecular Weight：315.676
- Modify Date.: 2022-11-05 04:33
- Introduction: Efavirenz D5 was launched as Sustiva in the US for the treatment of infection by HIV, the virus causing AIDS, in combination with other anti-retroviral agents.Efavirenz D5 is a non-nucleoside reverse transcriptase inhibitor (NNRTI) belonging to the 3,1-benzoxazin-2-one chemical class. It is the third non-nucleoside reverse transcriptase inhibitor to have been launched to date, after Nevirapine (1996) and Delavirdine (1997), increasing the arsenal of anti-HIV drugs for treating infected patients in dual or triple combination with nucleoside or other non-nucleoside RTIs, or protease inhibitors.Efavirenz D5 can be obtained by two related ways of six steps from 4-chloroaniline ; one of them is based on asymmetric synthesis by enantioselective addition of an acetylide to a trifluoroacetophenone. The anti-HIV activity of Efavirenz D5 was demonstrated against most wild-type and clinical strains of HIV-1, including those with the most frequently observed mutations. Efavirenz D5 has a better pharmacokinetic profile when compared with the preceding drugs of this class ; in particular, in a long-term experiment conducted in cynomolgus monkeys, Efavirenz D5 was shown to easily cross the blood brain barrier leading to an increase of the antiviral concentration in cerebrospinal fluid.
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1. Names and Identifiers
- 1.1 Name
- Efavirenz
- 1.2 Synonyms
(4S)-6-Chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (4S)-6-Chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-4H-3,1-benzoxazin-2-ol (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one 2H-3,1-Benzoxazin-2-one, 6-chloro-4-(2-cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-, (4S)- 4H-3,1-Benzoxazin-2-ol, 6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-, (4S)- DMP 266 Efavirenz (200 mg) EFAVIRNEZ MDP-266 Stocrin SUSTIVA
- 1.3 CAS No.
- 154598-52-4
- 1.4 CID
- 64139
- 1.5 EINECS(EC#)
- 1806241-263-5
- 1.6 Molecular Formula
- C14H9ClF3NO2 (isomer)
- 1.7 Inchi
- InChI=1S/C14H9ClF3NO2/c15-9-3-4-11-10(7-9)13(14(16,17)18,21-12(20)19-11)6-5-8-1-2-8/h3-4,7-8H,1-2H2,(H,19,20)/t13-/m0/s1
- 1.8 InChkey
- XPOQHMRABVBWPR-ZDUSSCGKSA-N
- 1.9 Canonical Smiles
- C1CC1C#CC2(C3=C(C=CC(=C3)Cl)NC(=O)O2)C(F)(F)F
- 1.10 Isomers Smiles
- C1CC1C#C[C@]2(C3=C(C=CC(=C3)Cl)NC(=O)O2)C(F)(F)F
2. Properties
- 2.1 Density
- 1.53
- 2.1 Melting point
- 139-141°C
- 2.1 Boiling point
- 340.6 °C at 760 mmHg
- 2.1 Refractive index
- 1.58
- 2.1 Flash Point
- 159.8 °C
- 2.1 Precise Quality
- 315.02700
- 2.1 PSA
- 38.33000
- 2.1 logP
- 4.21110
- 2.1 Solubility
- DMSO: soluble15mg/mL, clear
- 2.2 Λmax
- 247nm(MeOH)(lit.)
- 2.3 Appearance
- white to slightly pink crystalline powder
- 2.4 Chemical Properties
- White to Slightly Pink Crystalline Powder
- 2.5 Color/Form
- Crystals from toluene:heptane
White to slightly pink crystalline powder
- 2.6 Physical
- Solid
- 2.7 pKa
- 10.2(at 25℃)
- 2.8 Water Solubility
- In water, 0.093 mg/L @ 25 deg C /Estimated/
- 2.9 StorageTemp
- <0°C
3. Use and Manufacturing
- 3.1 Definition
- ChEBI: 1,4-Dihydro-2H-3,1-benzoxazin-2-one substituted at the 4 position by cyclopropylethynyl and trifluoromethyl groups (S configuration) and at the 6 position by chlorine. A non-nucleoside reverse transcriptase inhibitor wit activity against HIV, it is used with other antiretrovirals for combination therapy of HIV infection.
- 3.2 General Description
- Efavirenz D5 (Sustiva)84 is also mandated for use with at leasttwo other antiretroviral agents. The compound is morethan 99% protein bound, and CSF concentrations exceedthe free fraction in the serum. Metabolism occurs in theliver. The half-life of a single dose of Efavirenz D5 is 52 to 76hours, and 40 to 55 after multiple doses (the drug inducesits own metabolism). Peak concentration is achieved in 3to 8 hours. Elimination is 14% to 34% in urine (as metabolites)and 16% to 41% in feces (primarily as Efavirenz D5).The oral dosage form is supplied as a capsule.
- 3.3 GHS Classification
- Signal: Danger
GHS Hazard Statements
Aggregated GHS information provided by 69 companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.
H302 (63.77%): Harmful if swallowed [Warning Acute toxicity, oral]
H319 (59.42%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]
H360 (59.42%): May damage fertility or the unborn child [Danger Reproductive toxicity]
H372 (52.17%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]
H400 (89.86%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]
H410 (92.75%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]
Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.
Precautionary Statement Codes
P201, P202, P260, P264, P270, P273, P280, P281, P301+P312, P305+P351+P338, P308+P313, P314, P330, P337+P313, P391, P405, and P501
- 3.4 Methods of Manufacturing
- Preparation: S. D. Young et al, European Patent Office 582455; eidem, United States of America patent 5519021 (1994, 1996 both to Merck & Co.)
- 3.5 Usage
- antiviral;reverse transcriptase inhibitor
4. Safety and Handling
- 4.1 Symbol
- GHS09
- 4.1 Hazard Codes
- N
- 4.1 Signal Word
- Warning
- 4.1 Risk Statements
- 50
- 4.1 Safety Statements
- 61
- 4.1 Exposure Standards and Regulations
- The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl efavirenz, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
- 4.2 Octanol/Water Partition Coefficient
- log Kow = 4.7 @ 25 deg C /Estimated/
- 4.3 Hazard Declaration
- H410
- 4.3 DisposalMethods
- SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.
- 4.4 RIDADR
- OTH
- 4.4 Caution Statement
- P273
- 4.4 Formulations/Preparations
- Oral: Capsules: 50 mg, Sustive, Bristol-Myers Squibb, 100 mg, Sustive, Bristol-Myers Squibb, 200 mg, Sustive, Bristol-Myers Squibb; Tablets: 600 mg, Sustive, Bristol-Myers Squibb
- 4.5 WGK Germany
- 3
- 4.5 RTECS
- DM3440000
- 4.5 Specification
-
?Efavirenz , its cas register number is 154598-52-4. It also can be called?(4S)-6-Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one ; (S)-6-Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one ; DMP 266 ; Stocrin ; Sustiva ; 2H-3,1-Benzoxazin-2-one, 6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-, (4S)- .It is a?white to slightly pink crystalline powder.
5. MSDS
2.Hazard identification
2.1 Classification of the substance or mixture
Acute toxicity - Oral, Category 4
Eye irritation, Category 2
Reproductive toxicity, Category 1B
Specific target organ toxicity \u2013 repeated exposure, Category 1
Hazardous to the aquatic environment, short-term (Acute) - Category Acute 1
Hazardous to the aquatic environment, long-term (Chronic) - Category Chronic 1
2.2 GHS label elements, including precautionary statements
| Pictogram(s) |    |
| Signal word | Danger |
| Hazard statement(s) | H302 Harmful if swallowed H319 Causes serious eye irritation H360 May damage fertility or the unborn child H372 Causes damage to organs through prolonged or repeated exposure H400 Very toxic to aquatic life H410 Very toxic to aquatic life with long lasting effects |
| Precautionary statement(s) | |
| Prevention | P264 Wash ... thoroughly after handling. P270 Do not eat, drink or smoke when using this product. P280 Wear protective gloves/protective clothing/eye protection/face protection. P201 Obtain special instructions before use. P202 Do not handle until all safety precautions have been read and understood. P260 Do not breathe dust/fume/gas/mist/vapours/spray. P273 Avoid release to the environment. |
| Response | P301+P312 IF SWALLOWED: Call a POISON CENTER/doctor/\u2026if you feel unwell. P330 Rinse mouth. P305+P351+P338 IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. P337+P313 If eye irritation persists: Get medical advice/attention. P308+P313 IF exposed or concerned: Get medical advice/ attention. P314 Get medical advice/attention if you feel unwell. P391 Collect spillage. |
| Storage | P405 Store locked up. |
| Disposal | P501 Dispose of contents/container to ... |
2.3 Other hazards which do not result in classification
none
6. Synthesis Route
154598-52-4Total: 36 Synthesis Route
8. Other Information
- 8.0 Merck
- 14,3521
- 8.1 Indications and action
- Efavirenz is used in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1(HIV-1) infection in adults and in pediatric patients at least 3 months old and weighing at least 3.5 kg. Efavirenz takes effect through inhibiting the activity of viral RNA-directed DNA polymerase(i.e., reverse transcriptase)[1, 11]. Antiviral activity of efavirenz is largely dependent on intracellular conversion to the active triphosphorylated form[1]. The rate of efavirenz phosphorylation varies, depending on the specific targeted cell type. It is generally proposed that inhibition of reverse transcriptase interferes with the generation of DNA copies of viral RNA, thus inhibiting the synthesis of new virions[1]. Intracellular enzymes subsequently eliminate the HIV particle that previously had been uncoated, and left unprotected, during entry into the host cell. Thus, reverse transcriptase inhibitors are virustatic and do not eliminate HIV from the body[1]. Even though human DNA polymerase is less susceptible to the pharmacologic effects of triphosphorylated efavirenz, this action may nevertheless account for some of the drug's toxicity. Efavirenz is an NNRTI of HIV-1, and its activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase. HIV-2 reverse transcriptase is not inhibited by Efavirenz[12,13].
- 8.2 Drug resistance
- Despite the good antiretroviral activity of efavirenz in vitro, repeated passage of HIV-1 in the presence of drug leads to a rapid selection of drug-resistant HIV-1 strains. A single mutation in the HIV-1 genome can increase the 50% inhibitory concentration(IC50) by up to 100-fold[14]. Clinical studies confirmed that resistant viruses also rapidly emerge in vivo, when efavirenz is used in the context of persistent viral replication[15]. The K103N mutation is most frequently the first resistance mutation to be selected[16,17]. However, the majority of patients go on to develop additional mutations, most commonly L100I, V106M, V108I, Y181C/I, Y188L, G190A/S and P225H[16,17] Although the Y181C mutation only reduces efavirenz susceptibility approximately twofold, efavirenz is often ineffective because of the fact that most patients failing a NNRTI-containing regimen harbour multiple different NNRTI-resistance mutations that are not detectable by standard genotyping. Double mutants are associated with higher levels of resistance to efavirenz. Joly et al[17]. Observed that, after switching to a non-NNRTI-containing regimen because of virological failure, NNRTI resistance mutations persist in two-thirds of the patients after 1 year. Thus, NNRTI mutations do not decrease replicative capacity, and, therefore, there is apparently no benefit in continuing NNRTI therapy once resistance has emerged.
- 8.3 Adverse reactions
- Efavirenz administration has been frequently associated with the manifestation of neuropsychiatric disorders including dizziness, confusion, lethargy, impaired concentration, amnesia, hallucinations, abnormal dreams, and insomnia[18, 19]. Anxiety, depression, and suicide have also been reported[20, 21]. Animal studies also confirm that Efavirenz affects anxiety-related behavior and cognitive performance[22,23].
Symptoms commonly appear in the first week of treatment[24-26], and most reports indicate that they usually disappear or reduce in severity after several weeks[21,24]. However, in a cross-sectional study of patients treated with Efavirenz, the psychiatric effects remained for up to 200 days, with a reduction in symptoms after this period[27]. A prospective study showed that neuropsychiatric symptoms occurred in the first 2 weeks of treatment but that those patients who continued to take Efavirenz showed an improvement in symptoms and were able to tolerate continued treatment[28]. Another study demonstrated that neuropsychiatric disorders might persist in patients chronically treated with Efavirenz[29]. Adverse effects and interactions of Efavirenz can affect the CNS.
- 8.4 Precaution
- The following tips should be concerned[30]:
You should not use efavirenz if you are allergic to it. The patients should consult his/her doctor if he/she has ever had liver disease(including hepatitis B or C), a seizure, mental illness or psychosis, heart disease or if he/she has alcoholism or injection drug administration history.
Since efavirenz can harm the unborn baby or cause birth defects, pregnant should be disabled. Use 2 forms of birth control, including a barrier form(condom, cervical cap, contraceptive sponge, or diaphragm with spermicide gel) to prevent pregnancy while you are using efavirenz and for at least 12 weeks after your last dose. Tell your doctor if you become pregnant during treatment. It should not be noted that hormonal contraception(birth control pills, injections, implants, skin patches, and vaginal rings) might fail in preventing pregnancy while you are taking efavirenz.
Women with HIV or AIDS should not breast-feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.
- 8.5 Chemical Properties
- White to Slightly Pink Crystalline Powder
- 8.6 Uses
- antiviral;reverse transcriptase inhibitor
- 8.7 Uses
- For use in combination treatment of HIV infection (AIDS)
- 8.8 Uses
- A nonnucleoside HIV-1 reverse transcriptase inhibitor. Antiviral
- 8.9 Definition
- ChEBI: 1,4-Dihydro-2H-3,1-benzoxazin-2-one substituted at the 4 position by cyclopropylethynyl and trifluoromethyl groups (S configuration) and at the 6 position by chlorine. A non-nucleoside reverse transcriptase inhibitor wit activity against HIV, it is used with other antiretrovirals for combination therapy of HIV infection.
- 8.10 Brand name
- Sustiva (Bristol-Myers Squibb).
9. Computational chemical data
- Molecular Weight: 315.676g/mol
- Molecular Formula: C14H9ClF3NO2
- Compound Is Canonicalized: True
- XLogP3-AA: 4
- Exact Mass: 315.0273907
- Monoisotopic Mass: 315.0273907
- Complexity: 519
- Rotatable Bond Count: 1
- Hydrogen Bond Donor Count: 1
- Hydrogen Bond Acceptor Count: 5
- Topological Polar Surface Area: 38.3
- Heavy Atom Count: 21
- Defined Atom Stereocenter Count: 1
- Undefined Atom Stereocenter Count: 0
- Defined Bond Stereocenter Count: 0
- Undefined Bond Stereocenter Count: 0
- Isotope Atom Count: 0
- Covalently-Bonded Unit Count: 1
- CACTVS Substructure Key Fingerprint: AAADccByMYAEAAAAAAAAAAAAGAAAAAAAAAA8QAAAAAAAAACxAAAAHwIQAAAADU6BmDAwyILABADIEiRCWAiCAAAhBwAIiAAAbokIJiLBs5mMMAhm1AFI6AeQwOAOgABAIAACAAAAAIBAAAQAAAAAAAAAAA==
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