13311-84-7 Hazards Identification
Pictogram(s):
Signal:
Warning
GHS Hazard Statements:
H302 (92.9%): Harmful if swallowed [Warning Acute toxicity, oral]
H312 (85.81%): Harmful in contact with skin [Warning Acute toxicity, dermal]
H332 (88.39%): Harmful if inhaled [Warning Acute toxicity, inhalation]
H361 (90.32%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]
H373 (14.19%): Causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]
Precautionary Statement Codes:
P203, P260, P261, P264, P270, P271, P280, P301+P317, P302+P352, P304+P340, P317, P318, P319, P321, P330, P362+P364, P405, and P501
Hazard Classes and Categories:
Acute Tox. 4 (92.9%)
Acute Tox. 4 (85.81%)
Acute Tox. 4 (88.39%)
Repr. 2 (90.32%)
STOT RE 2 (14.19%)
Reproductive toxicity - Category 2
Specific target organ toxicity - Repeated exposure - Category 1 (liver, endocrine system, haemal system, genetic organs (men))
Hazardous to the aquatic environment (Acute) - Category 2
Hazardous to the aquatic environment (Long-term) - Category 1
13311-84-7 Usage
Uses
Used in Oncology:
Flutamide is used as an antiandrogen and antineoplastic (hormonal) agent for the treatment of prostate cancer in both castrates and noncastrates. It functions as a selective antagonist of the androgen receptor (AR), preventing androgens such as testosterone and its active metabolite dihydrotestosterone from binding to ARs in the prostate gland. This process inhibits androgen-dependent DNA and protein synthesis in the tumor cell, thereby preventing androgens from stimulating the growth of prostate cancer cells.
Used in Neurology:
Flutamide is also used as a neuroleptic, although its specific applications in this field are not detailed in the provided materials.
Used in Hyperandrogenism Treatment:
Besides prostate cancer, flutamide has been tested and/or used off-label for other hyperandrogenism-related disorders in women, such as benign prostatic hyperplasia, acne vulgaris, and hirsutism syndrome. It is effective in alleviating symptoms like acne, seborrhea, hirsutism, and androgenetic alopecia. However, due to its teratogenic potential, flutamide is restricted for premenopausal women and is used only in combination with effective contraception.
Limitations:
A limiting factor in the use of flutamide is hepatotoxicity, which occurs in 1% to 5% of patients. Although the hepatotoxicity is usually reversible following cessation of treatment, rare cases of death associated with hepatic failure have been reported in association with flutamide therapy. Additionally, diarrhea is a limiting side effect for some patients undergoing flutamide therapy.
References
https://en.wikipedia.org/wiki/Flutamide
https://pubchem.ncbi.nlm.nih.gov/compound/flutamide#section=Top
Originator
scheting (USA)
History
Flutamide was first described as a member of a series of N-acyl anilides synthesized at Monsanto in the 1960s during a compound finding program aiming at bacteriostatic agents. Soon after, at Schering Corp., the compound was characterized pharmacologically and further developed as SCH-13521. It was found that flutamide inhibits agonist action at the AR by replacing the agonist at the ligand binding site, being the first nonsteroidal compound possessing anti-androgenic activity in animals. In contrast to steroidal anti-androgens, for instance, cyproterone acetate, which also displays significant progestational activity, flutamide has no other hormonal activity. There is also no reduction of serum testosterone levels seen with flutamide but rather a slight increase in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) resulting in elevated serum testosterone levels. This accounts for the beneficial maintenance of libido and potency in sexually active patients. On the other hand, elevated serum estradiol levels resulting from peripheral testosterone aromatization leading to gynecomastia were observed in patients.
Indications
Flutamide is a prodrug possessing only weak androgen antagonistic activity of its own. It is oxidized in vivo to the active principle hydroxyflutamide (6) as primary metabolite.The elimination half-life of hydroxyflutamide is relatively short, 4–6.6 h in patients after a single oral 250 mg dose of flutamide. Therefore, oral dosing of 250 mg flutamide three times daily was applied clinically. The first introduction into clinical studies was achieved in 1975 as single agent in the first-line treatment of advanced prostate carcinoma. In the United States, flutamide was finally approved by FDA in 1989 for the treatment of metastatic prostate cancer in combination with a luteinizing hormone-releasing hormone (LHRH, also referred to as gonadotropin-releasing hormone (GnRH)) agonist, for instance, leuprorelin acetate (Leuprolide(R), Lupron(R)) or goserelin acetate (Zoladex(R)).The combined androgen blockade by flutamide plus an LHRH agonist or surgical castration was introduced in order to maximize the effects of androgen ablation. Flutamide also inhibits the secretion of androgens from the adrenal gland, which is not impaired by chemical castration with LHRH agonists or by surgical castration. In addition, the AR antagonist avoids the unacceptable initial tumor flare that occurs when LHRH agonists are given alone.
Favorable response to flutamide was seen with advanced prostate carcinoma patients after single-agent treatment as well as after combination treatment. The progression of the disease was slowed and the lifetime of patients was extended. For instance, the National Cancer Institute (NCI) initiated a trial (INT-0036) and concluded that the combination of leuprolide with flutamide was more effective than leuprolide alone in patients with advanced prostate cancer. However, significant side effects were also reported.The most frequently observed adverse events are summarized in Table 1. Flutamide evidently amplifies some of the LHRH agonist-induced side effects.
Table 1 Side effects of LHRH antagonist alone and in combination with flutamide.
Indications
Flutamide (Eulexin) is a nonsteroidal androgen receptor
antagonist that inhibits androgen binding to its
nuclear receptor. It is effective in inducing prostatic regression
and is approved for the treatment of prostatic
carcinoma. For maximum clinical effectiveness it has to
be used in combination with a GnRH antagonist (e.g.,
leuprolide acetate) that inhibits androgen production.
Flutamide may eventually be used for the treatment of
hirsutism and male pattern baldness in women if a topical
preparation is developed.
Indications
Flutamide (Eulexin) is a nonsteroidal antiandrogen compound that competes with testosterone
for binding to androgen receptors. The drug is well absorbed
on oral administration. It is an active agent in
the hormonal therapy of cancer of the prostate and has
been shown to complement the pharmacological castration
produced by the gonadotropin-releasing hormone
(GnRH) agonist leuprolide. Flutamide prevents the
stimulation of tumor growth that may occur as a result
of the transient increase in testosterone secretion after
the initiation of leuprolide therapy. The most common
side effects of flutamide are those expected with androgen
blockade: hot flashes, loss of libido, and impotence.
Mild nausea and diarrhea occur in about 10% of patients.
Manufacturing Process
To a stirred, cooled solution of 100 g of 4-nitro-3-trifluoromethylaniline in 400 ml of pyridine, slowly and in a dropwise fashion, add 54 g of isobutyrylchloride and then heat the reaction mixture on a steam bath for 1.5 hours. Cool and pour the resulting mixture into ice water, filter and waterwash the crude anilide and crystallize the product of this example from benzene to obtain analytically pure material, MP 111.5°C to 112.5°C.
Therapeutic Function
Antiandrogen
Biochem/physiol Actions
Flutamide is a non-steroidal anti-androgen drug. It consists of a nitroaromatic structure. Flutamide is a potent competitor of testosterone and dihydrotestosterone receptors. It is a potent hepatotoxin.
Contact allergens
Flutamide is an antiandrogenic hormonal antineoplas tic drug that can induce photosensitivity and porphy ria-like eruption.
Mechanism of action
Flutamide is a nonsteroid drug that possesses antiandrogenic action. It blocks androgens
from binding with target tissues, thus preventing androgen action. The mechanism of
action is possibly also linked with a halt in dihydrotestosterone transport. It facilitates a
reduction in size and density of the prostate gland, and it reduces the amount of metastases
in such cancer, for which it is used in palliative treatment of prostate gland cancer.
Clinical Use
Flutamide is a pure antagonist, whereas 2-hydroxyflutamide is a more potent AR antagonist but also can activate the androgenic receptor at higher concentrations. These findings raise the possibility that increased conversion of flutamide to 2-hydroxyflutamide or accumulation of 2-hydroxyflutamide in cells may contribute to the anomalous responses to flutamide that are observed in some advanced prostate cancers.
Synthesis
Flutamide, 4-nitro-3-trifluoromethylisobutyranilide (29.2.15), a nonsteroid
antagonist of androgens, is made by acylating 4-nitro-3-trifluoromethylaniline with isobutyric acid chloride.
Drug interactions
Potentially hazardous interactions with other drugs
Anticoagulants: effects of coumarins enhanced
Metabolism
It is rapidly and extensively metabolised; the
major metabolite (2-hydroxyflutamide) possesses
anti-androgenic properties. Both flutamide and
2-hydroxyflutamide are more than 90% bound to plasma
proteins.Excretion is mainly in the urine with only minor amounts
appearing in the faeces
Check Digit Verification of cas no
The CAS Registry Mumber 13311-84-7 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 1,3,3,1 and 1 respectively; the second part has 2 digits, 8 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 13311-84:
(7*1)+(6*3)+(5*3)+(4*1)+(3*1)+(2*8)+(1*4)=67
67 % 10 = 7
So 13311-84-7 is a valid CAS Registry Number.
InChI:InChI=1/C11H11F4NO/c1-6(2)10(17)16-7-3-4-9(12)8(5-7)11(13,14)15/h3-6H,1-2H3,(H,16,17)
13311-84-7Relevant academic research and scientific papers
Ghaffarzadeh, Mohammad,Rahbar, Sahar
, p. 200 - 201 (2014)
Flutamide has been synthesised conveniently in high yields and by an economically beneficial method. Benzotrifluoride was first nitrated and the product was reduced and acylated in one pot in the presence of iron powder and isobutyric acid to produce 3-trifluoroisobutyranilide. Finally, flutamide was produced by further nitration.
Pedersen, Simon S.,Donslund, Aske S.,Mikkelsen, Jesper H.,Bakholm, Oskar S.,Papp, Florian,Jensen, Kim B.,Gustafsson, Magnus B. F.,Skrydstrup, Troels
, p. 7114 - 7123 (2021)
A series of pharmaceutically relevant small molecules and biopharmaceuticals bearing aliphatic carboxamides have been successfully labeled with carbon-13. Key to the success of this novel carbon isotope labeling technique is the observation that 13C-labeled NiII-acyl complexes, formed from a 13CO insertion step with NiII-alkyl intermediates, rapidly react in less than one minute with 2,2’-dipyridyl disulfide to quantitatively form the corresponding 2-pyridyl thioesters. Either the use of 13C-SilaCOgen or 13C-COgen allows for the stoichiometric addition of isotopically labeled carbon monoxide. Subsequent one-pot acylation of a series of structurally diverse amines provides the desired 13C-labeled carboxamides in good yields. A single electron transfer pathway is proposed between the NiII-acyl complexes and the disulfide providing a reactive NiIII-acyl sulfide intermediate, which rapidly undergoes reductive elimination to the desired thioester. By further optimization of the reaction parameters, reaction times down to only 11 min were identified, opening up the possibility of exploring this chemistry for carbon-11 isotope labeling. Finally, this isotope labeling strategy could be adapted to the synthesis of 13C-labeled liraglutide and insulin degludec, representing two antidiabetic drugs.
3-(Ethoxycarbonyl)-1-(5-methyl-5-(nitrosooxy)hexyl)pyridin-1-ium cation: A green alternative to tert-butyl nitrite for synthesis of nitro-group-containing arenes and drugs at room temperature
Chaudhary, Renu,Natarajan, Palani,Rani, Neetu,Sakshi,Venugopalan, Paloth
supporting information, (2019/12/30)
Due to their remarkable properties, task-specific ionic liquids have turned out to be progressively popular over the last few years in the field of green organic synthesis. Herein, for the first time, we report that a new task-specific nitrite-based ionic liquid such as 3-(ethoxycarbonyl)-1-(5-methyl-5-(nitrosooxy)hexyl)pyridin-1-ium bis(trifluoromethanesulfonyl)imides (TS-N-IL) derived from biodegradable ethyl nicotinate indeed acted as an efficient and eco-friendly reagent for the synthesis of highly valuable nitroaromatic compounds and drugs including nitroxynil, tolcapone, niclofolan, flutamide, niclosamide and nitrazepam. The bridging of an ionic liquid with nitrite group not only increases the yield and rate of direct C[sbnd]N bond formation reaction but also allows easy product separation and recyclability of a byproduct. Nonvolatile nature, easy synthesis, merely stoichiometric need and mildness are a portion of the extra focal points of TS-N-IL while contrasted with tert-butyl nitrite an outstanding and highly-flammable reagent utilized largely in organic synthesis.
Synthesis method of drug intermediate flutamide
-
Paragraph 0008; 0010-0028, (2018/06/21)
The invention discloses a synthesis method of a drug intermediate flutamide. N-hexane, m-trifluoromethylaniline, isobutyric anhydride, NaOH, m-isobutyramidobenzotrifluoride, sodium hydrogen carbonateand ethyl orthosilicate are used as main raw materials; a method of combining a sol-gel method with calcination is utilized; SiO2 is used as a carrier; a perfluorosulfonic resin solution is directly dispersed on a porous SiO2 colloid serving as a skeleton; a mixing-ratio relation among raw materials is strictly explored; a catalyst for preparing the flutamide from the isobutyric anhydride, which has certain crystal form, grain size, pore structure and specific area and high mechanical strength is developed; the raw materials used by the synthesis method are according to the following mixing ratios in which a mass ratio of the isobutyric anhydride to the m-trifluoromethylaniline is 2 to 1, a volume ratio of the n-hexane to the NaOH is 2 to 1, and the volume ratio of concentrated sulfuric acid to concentrated nitric acid is 10 to 1; a preparation method of the flutamide has the characteristics of simpleness, easiness, feasibleness, short preparation period and the like, and the raw materials and the catalyst which are used in a technical process have high efficiency, wide application ranges and an excellent catalytic effect on the preparation of the flutamide from the isobutyric anhydride, are simple, convenient, quick and extremely environment-friendly, moreover, are easily recovered and can be regenerated.
TCDA: Practical Synthesis and Application in the Trifluoromethylation of Arenes and Heteroarenes
Wang, Jian,Zhang, Xiaomin,Wan, Zehong,Ren, Feng
, p. 836 - 839 (2016/05/19)
A practical synthesis of the reagent trimethylsilyl chlorodifluoroacetate (TCDA) is reported on 50 g scale. The trifluoromethylation with TCDA was optimized, and the reaction shows very broad scope with respect to electron-deficient, -neutral, -rich aryl/heteroaryl iodides, as well as excellent functional group tolerability, such as ester, amide, aldehyde, hydroxyl, and carboxylic acid. The reagent was also applied to the late-stage trifluoromethylation of three medicinally relevant compounds. Additionally, the building block trifluoromethylpyridine and one drug related molecule Boc-Fluoxetin were synthesized in 10 g scale by this method, demonstrating its practical applications in process chemistry.
Palladium-Catalyzed Synthesis of Aryl Amides through Silanoate-Mediated Hydrolysis of Nitriles
McPherson, Christopher G.,Livingstone, Keith,Jamieson, Craig,Simpson, Iain
supporting information, p. 88 - 92 (2015/12/26)
A procedure for the formation of aryl amides through the palladium-catalyzed coupling of nitriles and aryl bromides, via the formation of intermediary silanoate derived imidate species is reported. Optimization was undertaken and examples of the process are described that furnish the products in up to 86% isolated yield.
An azobenzene-containing metal-organic framework as an efficient heterogeneous catalyst for direct amidation of benzoic acids: Synthesis of bioactive compounds
Hoang, Linh T. M.,Ngo, Long H.,Nguyen, Ha L.,Nguyen, Hanh T. H.,Nguyen, Chung K.,Nguyen, Binh T.,Ton, Quang T.,Nguyen, Hong K. D.,Cordova, Kyle E.,Truong, Thanh
supporting information, p. 17132 - 17135 (2015/12/04)
An azobenzene-containing zirconium metal-organic framework was demonstrated to be an effective heterogeneous catalyst for the direct amidation of benzoic acids in tetrahydrofuran at 70°C. This finding was applied to the synthesis of several important, representative bioactive compounds.
Mild and Efficient Cobalt-Catalyzed Cross-Coupling of Aliphatic Amides and Aryl Iodides in Water
Tan, Bryan Yong-Hao,Teo, Yong-Chua
supporting information, p. 1697 - 1701 (2015/07/20)
A convenient protocol for the C-N cross-coupling of aliphatic amides and iodobenzene is demonstrated using a simple and inexpensive Co(C2O4)·2H2O/N,N′-dimethylethylenediamine (DMEDA) catalytic system in water. Good yields of N-arylated products were isolated (up to 85%) and the protocol has been successfully applied to the synthesis of the anticancer drug, flutamide.
PRODUCTION OF RED BLOOD CELLS AND PLATELETS FROM STEM CELLS
-
, (2014/03/24)
This disclosure provides methods of making a megakaryocyte-erythroid progenitor cell (MEP), comprising differentiating a stem cell into a MEP in culture in the presence of an aryl hydrocarbon receptor (AhR) agonist. In some embodiments the stem cell is a pluripotent stem cell. In some embodiments the MEP co-expresses CD41 and CD235. In some embodiments the number of MEPs produced in the culture increases exponentially. Methods of making a red blood cell (RBC) by culturing a MEP in the presence of an AhR agonist are also provided. Methods of making a megakaryocyte and/or a platelet, comprising culturing a MEP in the presence of an AhR modulator are also provided. In some embodiments the AhR modulator is an AhR antagonist. This disclosure also provides compositions comprising at least 1 million MEPs per ml and compositions in which at least 50% of the cells are MEPs.
THERAPEUTIC FOR HEPATIC CANCER
-
, (2011/02/18)
A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
