Clotrimazole

• Molecular FormulaC₂₂H₁₇ClN₂
• Average mass344.837 Da

245-764-8 [EINECS]

2912

Bis-fenil-(2-clorofenil)-1-imidazolil-metano [Italian]

Bisphenyl-(2-chlorphenyl)-1-imidazolyl-methan [German]

Canesten [Trade name]

Canifug [Trade name]

Clotrimazole [BAN] [INN] [JAN] [USAN] [Wiki]

Clotrimazolum [Latin]

Empecid [Trade name]

Fungicip [Trade name]

G07GZ97H65

Gyne-Lotrimin [Trade name]

Imidazole, 1- (o-chloro-α,α-diphenylbenzyl)-

Lotrimin [Trade name]

Mono-baycuten [Trade name]

Mycelex [Trade name]

Mycelex G [Trade name]

Mycosporin [Trade name]

Pedisafe [Trade name]

Rimazole [Trade name]

Tibatin [Trade name]

Trimysten [Trade name]

UNII-G07GZ97H65

Clotrimaderm

Title: Clotrimazole CAS Registry Number: 23593-75-1 CAS Name: 1-[(2-Chlorophenyl)diphenylmethyl]-1H-imidazole Additional Names: 1-(o-chloro-a,a-diphenylbenzyl)imidazole; 1-[a-(2-chlorophenyl)benzhydryl]imidazole; 1-[(o-chlorophenyl)diphenylmethyl]imidazole; diphenyl-(2-chlorophenyl)-1-imidazolylmethane; 1-(o-chlorotrityl)imidazole Manufacturers’ Codes: FB-5097; Bay b 5097 Trademarks: Canesten (Bayer); Canifug (Wolff); Empecid (Bayer-Takeda); Gyne-Lotrimin (Schering-Plough); Lotrimin (Schering-Plough); Mono-Baycuten; Mycelex-G (Miles); Mycofug (Hermal); Mycosporin (Bayer); Pedisafe (Sagitta); Rimazole (Cheil Sugar); Tibatin (Dak); Trimysten Molecular Formula: C22H17ClN2 Molecular Weight: 344.84 Percent Composition: C 76.63%, H 4.97%, Cl 10.28%, N 8.12% Literature References: Prepn: K. H. Buechel et al., ZA 6805392; eidem, US 3705172 (1969, 1972 both to Bayer). Pharmacology: Plempel et al., Antimicrob. Agents Chemother. 1969, 271; eidem, Dtsch. Med. Wochenschr. 94, 1356 (1969). Clinical findings: Oberste-Lehn et al., ibid. 1365. Series of articles on prepn, toxicology, pharmacokinetics, clinical studies: Arzneim.-Forsch. 22,1260-1272, 1276-1299 (1972). Toxicity: D. Tettenborn, ibid. 1276. Comprehensive description: J. G. Hoogerheide, B. E. Wyka, Anal. Profiles Drug Subs. 11, 225-255 (1982). Properties: Crystals, mp 147-149°. A weak base, slightly sol in water, benzene, toluene; sol in acetone, chloroform, ethyl acetate, DMF. Hydrolyzes rapidly upon heating in aq acids. LD50 in male mice, rats (mg/kg): 923, 708 orally (Tettenborn). Melting point: mp 147-149° Toxicity data: LD50 in male mice, rats (mg/kg): 923, 708 orally (Tettenborn) Derivative Type: Hydrochloride Molecular Formula: C22H17ClN2.HCl Molecular Weight: 381.30 Percent Composition: C 69.30%, H 4.76%, Cl 18.60%, N 7.35% Properties: mp 159°. Melting point: mp 159° Therap-Cat: Antifungal. Therap-Cat-Vet: Antifungal. Keywords: Antifungal (Synthetic); Imidazoles.

Clotrimazole, sold under the brand name Canesten among others, is an antifungal medication.^[1] It is used to treat vaginal yeast infections, oral thrush, diaper rash, pityriasis versicolor, and types of ringworm including athlete’s foot and jock itch.^[1] It can be taken by mouth or applied as a cream to the skin or in the vagina.^[1]

Common side effects when taken by mouth include nausea and itchiness.^[1] When applied to the skin common side effects include redness and burning.^[1] In pregnancy, use on the skin or in the vagina is believed to be safe.^[1] There is no evidence of harm when used by mouth during pregnancy but this has been less well studied.^[1] When used by mouth, greater care should be taken in those with liver problems.^[1] It is in the azole class of medications and works by disrupting the cell membrane.^[1]

Clotrimazole was discovered in 1969.^[2] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.^[3] It is available as a generic medication.^[1] The wholesale cost in the developing world as of 2014 is 0.20–0.86 USD per 20 gram tube of cream.^[4] In the United States a course of treatment typically costs less than 25 USD.^[5]

It is commonly available without a prescription in various dosage forms, such as a cream, vaginal tablet, or as a prescription troche or throat lozenge (prescription only). Topically, clotrimazole is used for vulvovaginal candidiasis (yeast infection) or yeast infections of the skin. For vulvovaginal candidiasis (yeast infection), clotrimazole tablets and creams are inserted into the vagina. Troche or throat lozenge preparations are used for oropharyngeal candidiasis (oral thrush) or prophylaxis against oral thrush in neutropenic patients.

Clotrimazole is usually used 5 times daily for 14 days for oral thrush, twice daily for 2 to 8 weeks for skin infections, and once daily for 3 or 7 days for vaginal infections.^[6]

Clotrimazole may be compounded with a glucocorticoid, such as betamethasone, in a topical cream for the treatment of tinea corporis (ringworm), tinea cruris (jock itch) and tinea pedis (athlete’s foot). Although FDA approved, clotrimazole-betamethasone combination cream is not the preferred treatment for dermatophyte infections due to increased side effects from the topical glucocorticoid. Although temporary relief and partial suppression of symptoms may be observed with the combination therapy, glucocorticoids can elicit an immunosuppressive response and rebound effect that results in more severe infection typically requiring systemic antifungal agents to treat the disease. Combination creams are best avoided in order to improve treatment outcome, reduce the possibility of skin atrophy associated with prolonged topical glucocorticoid use, and to limit the cost of treatment. It can be effective in treating chronic paronychia. The preferred treatment of tinea infections is therefore with clotrimazole monotherapy.^[7]

Topical and oral clotrimazole can be used in both adults and children.

Additionally, clotrimazole may be used to treat the sickling of cells (related to sickle cell anemia).^[8][9]

Pregnancy

Small amounts of clotrimazole may be absorbed systemically following topical and vaginal administration. However, this may still be used to treat yeast infections in pregnant women.^[10]

Side effects

Side effects of the oral formulation include itching, nausea, and vomiting. >10% of patients using the oral formulation may have abnormal liver function tests. Side effects include rash, hives, blisters, burning, itching, peeling, redness, swelling, pain or other signs of skin irritation.^[1] For this reason, liver function tests should be monitored periodically when taking the oral clotrimazole (troche). When used to treat vulvovaginal candidiasis (yeast infection), <10% of patient have vulvar or vaginal burning sensation. <1% of patients have the following side effects: Burning or itching of penis of sexual partner; polyuria; vulvar itching, soreness, edema, or discharge ^[6][11][12]

Clotrimazole creams and suppositories contain oil which may weaken latex condoms and diaphragms.^[10]

Drug interactions

There are no known significant drug interactions with topical clotrimazole. However, with oral (troche) clotrimazole, there are multiple interactions as the medication is a CYP450 enzyme inhibitor, primarily CYP3A4. Thus, any medication that is metabolized by the CYP3A4 enzyme will potentially have elevated levels when oral clotrimazole is used. The prescribing physician should be aware of any medication the patient is taking prior to starting oral clotrimazole. Certain medications should not be taken with oral clotrimazole.^[11]

Mechanism of action

Clotrimazole works by inhibiting the growth of individual Candida or fungal cells by altering the permeability of the fungal cell wall. It binds to phospholipids in the cell membrane and inhibits the biosynthesis of ergosterol and other sterols required for cell membrane production.^[12][11] Clotrimazole may be fungistatic (slow fungal growth) or fungicidal (result in fungal cell death).^[1]

Society and culture

It is available as a generic medication.^[1] The wholesale cost in the developing world as of 2014 is 0.20–0.86 USD per 20gm tube of cream.^[4]In the United States a course of treatment typically costs less than 25 USD.^[5] In 2016 Canesten was one of the biggest selling branded over-the-counter medications sold in Great Britain, with sales of £39.2 million.^[13]

syn

 

CLIP

Fig 4. Open Babel bond-line chemical structure with annotated hydrogens.
Click to toggle size.

Spectrum Plot

Fig 5. ¹H NMR spectrum of C₂₂H₁₇ClN₂ in CDCL3 at 400 MHz.

Figure 7. 2D 13 C13 C refocused INADEQUATE spectrum of clotrimazole showing intramolecular contacts among 13 C resonances as marked in the molecular structure on the right. The full spectrum is included in the Figure S4. The 2D spectrum was acquired in 17 hr at 106 K on 400 MHz, 384 scans per increment, 2 s recycle delay and 80 t 1 increments of a 27.7 ?s.

2D 13C-13C refocused INADEQUATE spectrum of clotrimazole showing intramolecular contacts among 13C resonances as marked in the molecular structure on the right. The 2D spectrum was acquired in 17 hr at 106 K on 400 MHz.

PATENT

https://patents.google.com/patent/CN105566156A/en

The object of the present invention is to provide a method for synthesizing a pharmaceutical Clotrimazole intermediate o-chlorobenzonitrile, comprising the steps of:

[0004] (i) in a reaction container equipped with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. lmol, aniline (3) 3.6-3 · 9mol, nitromethane burning 310ml, chloro cuprous 1 · 56mol, hook are mixed, controlling the stirring speed 110-160rpm, the solution temperature increased to 110-115 ° C, 3-5h the reaction, the solution temperature increased to 130-135 ° C, the reaction 2-3h, solution temperature increased to 190-195 ° C, the reaction 90-120min, reducing the solution temperature to 15-20 ° C, was added 700 ml of saline solution, sodium bisulfite solution, 130ml, distilled under reduced pressure to collect 130-135 ° C fraction , washed with triethylamine in toluene and recrystallized to give crystals of o-chlorobenzonitrile (1).

[0005] wherein the mass fraction of nitromethane according to step (i) is 60-65%, of the salt solution in step (i) is ammonium nitrate, potassium iodide to any one of the steps of (i) mass fraction of sodium hydrogen sulfite solution was 40-45%, which pressure in the vacuum distillation of step (i) is 1.6-1.7kPa, triethylamine mass fraction of said step (i) is 70-75%, step (i) in toluene of the mass fraction of 90-95%. Throughout the reaction using the following reaction formula:

[0006

[0007 “not as good as Wu Ming 1 point Shi Bian: J Cheng less

A slave I anti Day “* 1, section A, J array low reaction temperature and reaction time, the reaction yield improved.

Detailed ways

[0008] The following examples with reference to specific embodiments of the present invention is further described:

Clotrimazole synthesis kinds drug intermediates of o-chlorobenzonitrile – [0009]

[0010] Example 1:

[0011] In a reaction vessel fitted with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. Lmol, aniline (3) 3.6111〇1, mass fraction of 60% nitromethane 3,101,111 chloride cuprous 1.56111 〇1, mixing, stirring speed control lOrpm 1, the solution temperature increased to 110 ° C, the reaction 3h, the solution temperature increased to 130 ° C, the reaction 2h, the solution temperature is raised to 190 ° (:, reaction 9011 ^ 11, reducing the solution temperature to 15 ° (:, 7,001,111 ammonium nitrate solution was added, the mass fraction of 40% sodium bisulfite solution was 130ml, 1.6kPa vacuum distillation, collecting the fraction 130-135 ° C, mass fraction of 70 washed% triethylamine, 90% toluene to a mass fraction of recrystallized to give crystals of o-chlorobenzonitrile 308.02g, yield 72%.

[0012] Example 2:

[0013] In a reaction vessel fitted with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. Lmol, aniline (3) 3.7111〇1, mass fraction of 62% nitromethane 31〇1111, 1.56111〇1 cuprous chloride, mixed, controlling the stirring speed of 130 rpm, the temperature was raised to 112 ° C, the reaction 4h, the solution temperature increased to 132 ° C, the reaction 2h, the solution temperature increased to 192 ° C, the reaction llOmin, reducing the solution temperature to 17 ° C, 700 ml of a solution of potassium iodide was added, the mass fraction of 42% sodium bisulfite solution 130ml, 1.65kPa vacuum distillation, collecting the fraction 130-135 ° C, mass fraction of 72% triethylamine washed, recrystallized from toluene to 92% mass fraction, to obtain crystals of o-chlorobenzonitrile 337.96g, yield 79%.

[0014] Example 3:

[0015] In a reaction vessel fitted with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. Lmol, aniline (3) 3.9111〇1, mass fraction of 65% nitromethane 31〇1111, 1.56111 〇1 cuprous chloride, mixed, controlling stirring speed 160 rpm, temperature was raised to 115 ° C, the reaction 5h, the solution temperature increased to 135 ° C, the reaction 3h, the solution temperature increased to 195 ° C, the reaction 120min, reducing the solution temperature to 20 ° C, was added 700 ml of a solution of ammonium nitrate, 45% mass fraction of sodium bisulfite solution was 130ml, 1.7kPa vacuum distillation, collecting the fraction 130-135 ° C, mass fraction of 75% triacetyl amine scrubbing, 95%, recrystallized from toluene to a mass fraction to obtain crystals of o-chlorobenzonitrile 350.80g, yield 82%.

PATENT

https://patents.google.com/patent/US5091540A/en

Clotrimazole, i.e. 1-(o.Cl-α,α-diphenylbenzyl)imidazole, of formula: ##STR1## is a known antimycotic for human use, and a fungicide useful against plant pathogenic fungi.

Methods for its preparation are described in various patents. In particular, U.S. Pat. No. 3,929,820 describes a process starting from chlorophenyldiphenyl methylchloride and imidazole in the presence of a neutralizing agent, such as triethylamine, in a polar organic solvent. The process is strictly limited by the use, as the medium for the reaction in question, of a solvent falling within the given definition, i.e. having a dielectric constant of at least 4.5 and preferably between 15 and 50. In all the examples of the implementation of the process according to the patent in question, acetonitrile (D=37.5) is used as solvent.

EXAMPLE

900 g of benzene and 117.5 g of aluminium chloride are placed in a 2 liter flask fitted with a reflux condenser, stirrer and drying tube.

The mixture is cooled to 0° C. and a solution of 150 g of o.chlorobenzotrichloride in 150 g of benzene is added while maintaining a temperature not exceeding 15° C. The mixture is heated carefully under reflux for 4 hours. HCl is evolved.

The reaction mixture is then cooled to ambient temperature and slowly poured into 300 g of concentrated hydrochloric acid and 800 g of ice, so as not to exceed 25° C. The aqueous layer is then separated and discarded.

The benzene solution is washed with a solution of 230 g of sodium chloride in 800 g of water. The benzene phase is separated and dried over anhydrous sodium sulphate for 1 hour, and then filtered.

45 g of imidazole in 70 g of triethylamine are added to the filtrate and the mixture heated for 3 hours at 45°-50° C. It is then cooled to ambient temperature and 500 g of water are added while stirring. The aqueous layer is separated and discarded, and the benzene phase washed with 200 g of water. The benzene layer is separated and evaporated to dryness under vacuum.

The residue is dissolved in 250 g of ethyl acetate while stirring. 250 g of water are added and the solution titrated to calculate the exact quantity of nitric acid to add.

The solution is cooled to 15° C. and the calculated nitric acid quantity is quickly added. Stirring is halted when precipitation commences, and the system left until precipitation is complete.

The product is centrifuged and washed with 300 g of ethyl acetate and then with 300 g of water.

The moist product is placed into the reaction flask and 300 g of water, 450 g of methylene chloride, 5 g of triethylamine and 110 g of 30% sodium hydroxide are added. The mixture is stirred until a solution forms and the solution then left until the phases separate.

The aqueous phase is washed with 100 g of methylene chloride, and the pooled organic phases are washed twice with 200 g of water each time.

The solution in methylene chloride is treated with YMS decolorizing carbon and filtered, the filter then being washed with methylene chloride which si recovered by distillation. The residue is taken up in 100 g of acetone and redistilled to completely eliminate the methylene chloride.

The residue is taken up in 900 g of acetone and heated to 50° C. to obtain a complete solution. YMS decolorizing carbon and triethylamine are added, the mixture filtered and washed with acetone. Part of the acetone is then removed by distillation, reducing the volume to about 500 c.c. The mixture is cooled to 0° C. and, after five hours, the product is centrifuged and washed with 100 g of acetone. It is dried at 60° C., to obtain 150 g of final product.

References

1. ^ Jump up to:^{a b c d e f g h i j k l m} American Society of Health-System Pharmacists (8 February 2016). “Clotrimazole Monograph for Professionals”. http://www.drugs.com. Archived from the original on 28 October 2016. Retrieved 28 October 2016.
2. ^ Walker, S. R. (2012). Trends and Changes in Drug Research and Development. Springer Science & Business Media. p. 109. ISBN 9789400926592. Archived from the original on 2016-09-14.
3. ^ “WHO Model List of Essential Medicines (19th List)” (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
4. ^ Jump up to:^a b “Clotrimazole”. International Drug Price Indicator Guide. Archived from the original on 10 May 2017. Retrieved 28 October 2016.
5. ^ Jump up to:^a b Tarascon Pharmacopoeia 2016 Professional Desk Reference Edition. Jones & Bartlett Publishers. 2016. p. 176. ISBN 9781284095302. Archived from the original on 2016-10-28.
6. ^ Jump up to:^a b “Clotrimazole: MedlinePlus Drug Information”. The American Society of Health-System Pharmacists, Inc. Archived from the original on 18 April 2014. Retrieved 17 April2014.
7. ^ Moriarty, B; Hay, R; Morris-Jones, R (10 July 2012). “The diagnosis and management of tinea”. BMJ (Clinical research ed.). 345: e4380. doi:10.1136/bmj.e4380. PMID 22782730.
8. ^ Marieb & Hoehn, (2010). Human Anatomy and Physiology, p. 643. Toronto: Pearson
9. ^ Rodgers, Griffin. “Hydroxyurea and other disease-modifying therapies in sickle cell disease”. UpToDate. Archived from the original on 15 April 2014. Retrieved 14 April2014.
10. ^ Jump up to:^a b “Diseases Characterized by Vaginal Discharge”. CDC. Archived from the original on 28 April 2014. Retrieved 17 April 2014.
11. ^ Jump up to:^a b c “Clotrimazole”. DrugBank. Archived from the original on 17 April 2014. Retrieved 17 April 2014.
12. ^ Jump up to:^a b “Clotrimazole (Oral)”. Lexicomp Online. Archived from the original on 23 January 2015. Retrieved 17 April 2014.
13. ^ “A breakdown of the over-the-counter medicines market in Britain in 2016”. Pharmaceutical Journal. 28 April 2017. Retrieved 29 May 2017.

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Diclofenac Sodium

15307-79-6; Sodium diclofenac; Diclofenac sodium salt; Voltaren; Solaraze

Diclofenac, sold under the trade names Voltaren among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout.^[3] It is taken by mouth or applied to the skin.^[3] Improvements in pain typically occur within half an hour and last for as much as eight hours.^[3] It is also available in combination with misoprostol in an effort to decrease stomach problems.^[4]

Common side effects include abdominal pain, gastrointestinal bleeding, nausea, dizziness, headache, and swelling.^[3] Serious side effects may include heart disease, stroke, kidney problems, and stomach ulceration.^[4][3] Use is not recommended in the third trimester of pregnancy.^[3] It is likely safe during breastfeeding.^[4] It is believed to work by decreasing the production of prostaglandin.^[5] It blocks both cycloxygenase-1 (COX-1) and cycloxygenase-2 (COX-2).^[3]

Diclofenac was patented in 1965 by Ciba-Geigy and came into medical use in the United States in 1988.^[3][6] It is available as a generic medication.^[3] In the United States the wholesale cost per dose is less than US$0.15 as of 2018.^[7] In 2016 it was the 78th most prescribed medication in the United States with more than 9 million prescriptions.^[8] It is available as both a sodium and a potassium salt.^[4]

Medical uses

Diclofenac is used to treat pain, inflammatory disorders, and dysmenorrhea.^[9]

Pain

Inflammatory disorders may include musculoskeletal complaints, especially arthritis, rheumatoid arthritis, polymyositis, dermatomyositis, osteoarthritis, dental pain, temporomandibular joint (TMJ) pain, spondylarthritis, ankylosing spondylitis, gout attacks,^[10] and pain management in cases of kidney stones and gallstones. An additional indication is the treatment of acute migraines.^[11] Diclofenac is used commonly to treat mild to moderate postoperative or post-traumatic pain, in particular when inflammation is also present,^[10] and is effective against menstrual pain and endometriosis.

Diclofenac is also available in topical forms and has been found to be useful for osteoarthritis but not other types of long-term musculoskeletal pain.^[12]

It may also help with actinic keratosis, and acute pain caused by minor strains, sprains, and contusions (bruises).^[13]

In many countries,^[14] eye drops are sold to treat acute and chronic nonbacterial inflammation of the anterior part of the eyes (e.g., postoperative states). Diclofenac eye drops have also been used to manage pain for traumatic corneal abrasion.^[15]

Diclofenac is often used to treat chronic pain associated with cancer, in particular if inflammation is also present (Step I of the World Health Organization (WHO) scheme for treatment of chronic pain).^[16] Diclofenac can be combined with opioids if needed such as a fixed combination of diclofenac and codeine.

• Voltaren (diclofenac) 50 mg enteric coatedtablets

• Arthrotec (diclofenac and misoprostol) 50 mg tablets

• Dyloject (diclofenac) 2 ml for IV and IMadministration

• Sintofarm (diclofenac) for suppositoryadministration

Contraindications

• Hypersensitivity against diclofenac
• History of allergic reactions (bronchospasm, shock, rhinitis, urticaria) following the use of other NSAIDs such as aspirin
• Third-trimester pregnancy
• Active stomach and/or duodenal ulceration or gastrointestinal bleeding
• Inflammatory bowel disease such as Crohn’s disease or ulcerative colitis
• Severe insufficiency of the heart (NYHA III/IV)
• Pain management in the setting of coronary artery bypass graft (CABG) surgery
• Severe liver insufficiency (Child-Pugh Class C)
• Severe renal insufficiency (creatinine clearance <30 ml/min)
• Caution in patients with pre-existing hepatic porphyria, as diclofenac may trigger attacks
• Caution in patients with severe, active bleeding such as cerebral hemorrhage
• NSAIDs in general should be avoided during dengue fever, as it induces (often severe) capillary leakage and subsequent heart failure.
• Caution in patients with fluid retention or heart failure
• Can lead to onset of new hypertension or worsening of pre-existing hypertension
• Can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal^[17]

Adverse effects

Diclofenac consumption has been associated with significantly increased vascular and coronary risk in a study including coxib, diclofenac, ibuprofen and naproxen.^[18] Upper gastrointestinal complications were also reported.^[18] Major adverse cardiovascular events (MACE) were increased by about a third by diclofenac, chiefly due to an increase in major coronary events.^[18] Compared with placebo, of 1000 patients allocated to diclofenac for a year, three more had major vascular events, one of which was fatal.^[18] Vascular death was increased significantly by diclofenac.^[18]

Heart

In 2013, a study found major vascular events were increased by about a third by diclofenac, chiefly due to an increase in major coronary events.^[18] Compared with placebo, of 1000 people allocated to diclofenac for a year, three more had major vascular events, one of which was fatal.^[18] Vascular death was increased by diclofenac (1·65).^[18]

Following the identification of increased risks of heart attacks with the selective COX-2 inhibitor rofecoxib in 2004, attention has focused on all the other members of the NSAIDs group, including diclofenac. Research results are mixed, with a meta-analysis of papers and reports up to April 2006 suggesting a relative increased rate of heart disease of 1.63 compared to nonusers.^[19] Professor Peter Weissberg, Medical Director of the British Heart Foundation said, “However, the increased risk is small, and many patients with chronic debilitating pain may well feel that this small risk is worth taking to relieve their symptoms”. Only aspirin was found not to increase the risk of heart disease; however, this is known to have a higher rate of gastric ulceration than diclofenac. In Britain the Medicines and Healthcare Products Regulatory Agency (MHRA) said in June 2013 that the drug should not be used by people with serious underlying heart conditions—people who had suffered heart failure, heart disease or a stroke were advised to stop using it completely.^[20] As of January 15, 2015 the MHRA announced that diclofenac will be reclassified as a prescription-only medicine (POM) due to the risk of cardiovascular adverse events.^[21]

A subsequent large study of 74,838 Danish users of NSAIDs or coxibs found no additional cardiovascular risk from diclofenac use.^[22] A very large study of 1,028,437 Danish users of various NSAIDs or coxibs found the “Use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death (odds ratio, 1.91; 95% confidence interval, 1.62 to 2.42; and odds ratio, 1.66; 95% confidence interval, 1.06 to 2.59, respectively), with a dose-dependent increase in risk.”^[23]

Diclofenac is similar in COX-2 selectivity to celecoxib.^[24]

Gastrointestinal

• Gastrointestinal complaints are most often noted. The development of ulceration and/or bleeding requires immediate termination of treatment with diclofenac. Most patients receive a gastro-protective drug as prophylaxis during long-term treatment (misoprostol, ranitidine 150 mg at bedtime or omeprazole 20 mg at bedtime).

Liver

• Liver damage occurs infrequently, and is usually reversible. Hepatitis may occur rarely without any warning symptoms and may be fatal. Patients with osteoarthritis more often develop symptomatic liver disease than patients with rheumatoid arthritis. Liver function should be monitored regularly during long-term treatment. If used for the short-term treatment of pain or fever, diclofenac has not been found more hepatotoxic than other NSAIDs.
• As of December 2009, Endo, Novartis, and the US FDA notified healthcare professionals to add new warnings and precautions about the potential for elevation in liver function tests during treatment with all products containing diclofenac sodium.^[25]
• Cases of drug-induced hepatotoxicity have been reported in the first month, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.
• Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 week after initiating treatment with diclofenac.

Kidney

• NSAIDs “are associated with adverse renal [kidney] effects caused by the reduction in synthesis of renal prostaglandins“^[26] in sensitive persons or animal species, and potentially during long-term use in nonsensitive persons if resistance to side effects decreases with age. However, this side effect cannot be avoided merely by using a COX-2 selective inhibitor because, “Both isoforms of COX, COX-1 and COX-2, are expressed in the kidney… Consequently, the same precautions regarding renal risk that are followed for nonselective NSAIDs should be used when selective COX-2 inhibitors are administered.”^[26] However, diclofenac appears to have a different mechanism of renal toxicity.^{[citation needed]}
• Studies in Pakistan showed diclofenac caused acute kidney failure in vultures when they ate the carcasses of animals that had recently been treated with it. Drug-sensitive species and individual humans are initially assumed to lack genes expressing specific drug detoxification enzymes.^[27]

Mental health

• Mental health side effects have been reported. These symptoms are rare, but exist in significant enough numbers to include as potential side effects. These include depression, anxiety, irritability, nightmares, and psychotic reactions.^[28]

Mechanism of action

The primary mechanism responsible for its anti-inflammatory, antipyretic, and analgesic action is thought to be inhibition of prostaglandin synthesis by inhibition of the transiently expressed prostaglandin-endoperoxide synthase-2 (PGES-2) also known as cycloxygenase-2 (COX-2). It also appears to exhibit bacteriostatic activity by inhibiting bacterial DNA synthesis.^[29]

Inhibition of prostaglandin synthesis occurs systemically resulting in undesirable symptoms such as irritation of the gastric epithelium.^{[citation needed]} This is the main side effect of diclofenac. Diclofenac inhibits COX-2 with 20 times greater potency than the constitutively expressed isoenzyme COX-1^[30] and has, therefore, a somewhat lower incidence of gastrointestinal complaints than noted with aspirin which inhibits COX-1 to a greater extent.

The action of one single dose is much longer (6 to 8 hr) than the very short 1.2–2 hr half-life of the drug would indicate. This could be partly because it persists for over 11 hours in synovial fluids.^[31]

Diclofenac may also be a unique member of the NSAIDs. Some evidence indicates it inhibits the lipoxygenase pathways, thus reducing formation of the leukotrienes(also pro-inflammatory autacoids). It also may inhibit phospholipase A2 as part of its mechanism of action. These additional actions may explain its high potency – it is the most potent NSAID on a broad basis.^[32]

Marked differences exist among NSAIDs in their selective inhibition of the two subtypes of cyclooxygenase, COX-1 and COX-2. Much pharmaceutical drug design has attempted to focus on selective COX-2 inhibition as a way to minimize the gastrointestinal side effects of NSAIDs such as aspirin. In practice, use of some COX-2 inhibitors with their adverse effects has led to massive numbers of patient family lawsuits alleging wrongful death by heart attack, yet other significantly COX-selective NSAIDs, such as diclofenac, have been well tolerated by most of the population.^\

Besides the COX-inhibition, a number of other molecular targets of diclofenac possibly contributing to its pain-relieving actions have recently been identified. These include:

• Blockage of voltage-dependent sodium channels (after activation of the channel, diclofenac inhibits its reactivation also known as phase inhibition)^{[citation needed]}
• Blockage of acid-sensing ion channels (ASICs)^[33]
• Positive allosteric modulation of KCNQ- and BK-potassium channels (diclofenac opens these channels, leading to hyperpolarization of the cell membrane)

Ecological effects

Use of diclofenac for animals is controversial due to toxicity when eaten by scavenging birds that eat dead animals; the drug has been banned for veterinary use in many countries.

Use of diclofenac in animals has been reported to have led to a sharp decline in the vulture population in the Indian subcontinent – a 95% decline by 2003^[34] and a 99.9% decline by 2008. The mechanism is presumed to be renal failure;^[35] however, toxicity may be due to direct inhibition of uric acid secretion in vultures.^[36] Vultures eat the carcasses of livestockthat have been administered veterinary diclofenac, and are poisoned by the accumulated chemical,^[37] as vultures do not have a particular enzyme to break down diclofenac. At a meeting of the National Wildlife Board in March 2005, the Government of India announced it intended to phase out the veterinary use of diclofenac.^[38] Meloxicam is a safer alternative to replace use of diclofenac.^[39] It is more expensive than diclofenac, but the price is coming down as more pharmaceutical companies begin to manufacture it.

Steppe eagles have the same vulnerability to diclofenac as vultures and may also fall victim to it.^[40] Diclofenac has been shown also to harm freshwater fish species such as rainbow trout.^{[41][42][43][44]} In contrast, New World vultures, such as the turkey vulture, can tolerate at least 100 times the level of diclofenac that is lethal to Gyps species.^[45]

“The loss of tens of millions of vultures over the last decade has had major ecological consequences across the Indian Subcontinent that pose a potential threat to human health. In many places, populations of feral dogs (Canis familiaris) have increased sharply from the disappearance of Gyps vultures as the main scavenger of wild and domestic ungulatecarcasses. Associated with the rise in dog numbers is an increased risk of rabies“^[39] and casualties of almost 50,000 people.^[46] The Government of India cites this as one of the major consequences of a vulture species extinction.^[38] A major shift in the transfer of corpse pathogens from vultures to feral dogs and rats could lead to a disease pandemic, causing millions of deaths in a crowded country like India, whereas vultures’ digestive systems safely destroy many species of such pathogens. Vultures are long-lived and slow to breed. They start breeding only at the age of six and only 50% of young survive. Even if the government ban is fully implemented, it will take several years to revive the vulture population.^[47]

The loss of vultures has had a social impact on the Indian Zoroastrian Parsi community, who traditionally use vultures to dispose of human corpses in Towers of Silence, but are now compelled to seek alternative methods of disposal.^[39]

Despite the vulture crisis, diclofenac remains available in other countries including many in Europe.^[48] It was controversially approved for veterinary use in Spain in 2013 and continues to be available, despite Spain being home to around 90% of the European vulture population and an independent simulation showing that the drug could reduce the population of vultures by 1-8% annually. Spain’s medicine agency presented simulations suggesting that the number of deaths would be quite small.^[49][50]

Formulations and trade names

The name “diclofenac” derives from its chemical name: 2-(2,6-dichloranilino) phenylacetic acid. Diclofenac was first synthesized by Alfred Sallmann and Rudolf Pfister and introduced as Voltaren by Ciba-Geigy (now Novartis) in 1973, now by Glaxo SmithKline.^[51]

In the United Kingdom, United States, India, and Brazil diclofenac may be supplied as either the sodium or potassium salt; in China, it is most often supplied as the sodium salt, while in some other countries it is only available as the potassium salt.

Pennsaid is a minimally systemic prescription topical lotion formulation of 1.5% w/w diclofenac sodium, which is approved in the US, Canada and other countries for osteoarthritis of the knee.

Flector Patch, a minimally systemic topical patch formulation of diclofenac, is indicated for acute pain due to minor sprains, strains, and contusions. The patch has been approved in many other countries outside the US under different brand names.

Voltaren and Voltarol contain the sodium salt of diclofenac. In the United Kingdom, Voltarol can be supplied with either the sodium salt or the potassium salt, while Cataflam, sold in some other countries, is the potassium salt only. However, Voltarol Emulgel contains diclofenac diethylammonium, in which a 1.16% concentration is equivalent to a 1% concentration of the sodium salt. In 2016 Voltarol was one of the biggest selling branded over-the-counter medications sold in Great Britain, with sales of £39.3 million.^[52]

Diclofenac is available in stomach acid-resistant formulations (25 and 50 mg), fast-disintegrating oral formulations (25 and 50 mg), powder for oral solution (50 mg), slow- and controlled-release forms (75, 100 or 150 mg), suppositories (50 and 100 mg), and injectable forms (50 and 75 mg).

Diclofenac is also available over-the-counter in some countries: 12.5 mg diclofenac as potassium salt in Switzerland (Voltaren dolo), the Netherlands (Voltaren K), and preparations containing 25 mg diclofenac as the potassium salt in Germany (various trade names), New Zealand, Australia, Japan, (Voltaren Rapid), and Sweden (Voltaren T and Diclofenac T). Diclofenac as potassium salt can be found throughout the Middle East in 25 mg and 50 mg doses (Cataflam).

Solaraze (3% diclofenac sodium gel) is topically applied, twice a day for three months, to manage the skin condition known as actinic or solar keratosis. Parazone-DP is a combination of diclofenac potassium and paracetamol, manufactured and supplied by Ozone Pharmaceuticals and Chemicals, Gujarat, India. It is sold in Uruguay alone or, in combination with orphenadrine to treat muscle spasms/pain due to injuries (Dicloflex Ion).

On 14 January 2015, diclofenac oral preparations were reclassified as prescription-only medicines in the UK. The topical preparations are still available without prescription.^[53]

Diclofenac formulations are available worldwide under many different trade names.^[1]

Title: Diclofenac CAS Registry Number: 15307-86-5 CAS Name: 2-[(2,6-Dichlorophenyl)amino]benzeneacetic acid Additional Names: [o-(2,6-dichloroanilino)phenyl]acetic acid Trademarks: Motifene (Sankyo) Molecular Formula: C14H11Cl2NO2 Molecular Weight: 296.15 Percent Composition: C 56.78%, H 3.74%, Cl 23.94%, N 4.73%, O 10.80% Literature References: Prepn: NL 6604752; A. Sallmann, R. Pfister, US 3558690 (1966, 1971 both to Geigy). Pharmacology: Renaud, Lecompte, Thromb. Diath. Haemorrh. 24, 577 (1970), C.A. 74, 86215m (1971); Krupp et al., Experientia 29, 450 (1973). HPLC determn in plasma and urine: J. Godbillon et al., J. Chromatogr. 338, 151 (1985). Symposium on pharmacology and clinical experience: Semin. Arthritis Rheum. 15, Suppl. 1, 57-110 (1985); on pharmacology, efficacy and safety: Am. J. Med. 80, Suppl. 4B, 1-87 (1986). Comprehensive description: C. M. Adeyeye, P-K. Li, Anal. Profiles Drug Subs. 19, 123-144 (1990). Review of clinical trials in actinic keratosis: D. C. Peters, R. H. Foster, Drugs Aging 14, 313-319 (1999). Properties: Crystals from ether-petr ether, mp 156-158°. Melting point: mp 156-158° Derivative Type: Diethylammonium salt CAS Registry Number: 78213-16-8 Trademarks: Voltarol (Novartis) Molecular Formula: C14H11Cl2NO2.C4H11N Molecular Weight: 369.29 Percent Composition: C 58.54%, H 6.00%, Cl 19.20%, N 7.59%, O 8.66% Derivative Type: Sodium salt CAS Registry Number: 15307-79-6 Manufacturers’ Codes: GP-45840 Trademarks: Allvoran (TAD); Benfofen (Sanofi-Synthelabo); Dealgic (Pharmacia); Deflamat (Sankyo); Delphinac (Riemser); Dicloflex (Dexcel); Diclomax (Provalis); Diclophlogont (Azupharma); Dicloreum (Alfa); Duravolten (Dura); Ecofenac (Ecosol); Effekton (Teofarma); Lexobene (Merckle); Neriodin (Nagase); Novapirina (Novartis); Primofenac (Streuli); Prophenatin (Nipro); Rewodina (AWD); Rhumalgan (Sandoz); Voldal (Novartis); Voltaren (Novartis); Xenid (RPG) Molecular Formula: C14H10Cl2NNaO2 Molecular Weight: 318.13 Percent Composition: C 52.86%, H 3.17%, Cl 22.29%, N 4.40%, Na 7.23%, O 10.06% Properties: Crystals from water, mp 283-285°. uv max (methanol) 283 nm (e 1.05 ´ 105); (phosphate buffer, pH 7.2) 276 nm (e1.01 ´ 105). Soly at 25°C (mg/ml): deionized water (pH 5.2) >9; methanol >24; acetone 6; acetonitrile <1; cyclohexane <1; HCl (pH 1.1) <1; phosphate buffer (pH 7.2) 6. pKa 4. Partition coefficient (N-octanol/aq. buffer): 13.4. LD50 in mice, rats (mg/kg): ~390, 150 orally (Krupp). Melting point: mp 283-285° pKa: pKa 4 Log P: Partition coefficient (N-octanol/aq. buffer): 13.4 Absorption maximum: uv max (methanol) 283 nm (e 1.05 ´ 105); (phosphate buffer, pH 7.2) 276 nm (e 1.01 ´ 105) Toxicity data: LD50 in mice, rats (mg/kg): ~390, 150 orally (Krupp) Derivative Type: Potassium salt CAS Registry Number: 15307-81-0 Manufacturers’ Codes: CGP-45840B Trademarks: Cataflam (Novartis) Molecular Formula: C14H10Cl2KNO2 Molecular Weight: 334.24 Percent Composition: C 50.31%, H 3.02%, Cl 21.21%, K 11.70%, N 4.19%, O 9.57% Therap-Cat: Anti-inflammatory. Keywords: Anti-inflammatory (Nonsteroidal); Arylacetic Acid Derivatives.

Synthesis

The mechanism begins with the condensation of hydrazine onto a ketone (details not shown) to give a hydrazone. Under basic conditions, this hydrazone is deprotonated at nitrogen to give an anionic intermediate. In this case, the negative charge can be delocalized onto oxygen, resulting in an enolate structure. Typically, the negative charge is only shared between a nitrogen and carbon, so this substrate gives a particularly stable intermediate. Protonation of the enolate at carbon gives the first C-H bond necessary to form the product. A second deprotonation at nitrogen gives a similar flow of electrons to form another enolate structure, this time with cleavage of the C-N bond and release of nitrogen gas. Another C-protonation gives the lactam precursor to diclofenac. Cleavage of the amide with hydroxide (details not shown) gives the target.

Manufacturing Process
2, 6-Dichlorophenol is reacted with MMCA, Aniline and Chloro Acetyl Chloride and AlCl3 to yield (2, 6 –
Dichlorophenol) Indolinone is hydrolyzed using isopropyl alcohol and sodium hydroxide to give crude Diclofenac
Sodium. This on purification using deminerlised water and isopropyl alcohol gives the pure Diclofenac Sodium

CLIP

References

External links

• 
  Diclofenac: Drug Information Provided by Lexi-Comp: Merck Manual Professional

References

• • US 3 558 690 (Geigy; 26.1.1971; CH-prior. 8.4.1965, 25.2.1966, 30.3.1966, 20.12.1967).
  • DAS 1 543 639 (Ciba-Geigy; appl. 7.4.1966; CH-prior. 8.4.1965).
  • DAS 1 793 592 (Ciba-Geigy; appl. 7.4.1966; CH-prior. 8.4.1965).
  • US 3 652 762 (Ciba-Geigy; 28.3.1972; prior. 9.12.1968, 29.9.1969, 14.4.1970).
  • US 3 778 470 (Geigy; 11.12.1973; appl. 2.10.1970; prior. 4.4.1966).
  • CH 492 679 (Geigy; appl. 30.3.1966).

• Alternative synthesis:

  • DOS 2 613 838 (Ikeda Mohando; appl. 31.3.1976; J-prior. 31.3.1975).

Diclofenac

Clinical data
Trade names	Cataflam, Voltaren, others[1]
AHFS/Drugs.com	Monograph
MedlinePlus	a689002
Pregnancy category	AU: C US: C (Risk not ruled out) in 1st and 2nd trimester, D in 3rd trimester
Routes of administration	By mouth, rectal, intramuscular, intravenous(renal- and gallstones), topical
ATC code	D11AX18 (WHO) M01AB05 (WHO), M02AA15 (WHO), S01BC03 (WHO)
Legal status
Legal status	AU: S2 (Pharmacy only) – S4 UK: POM (Prescription only) (P for topical formulation) ℞-only in most preparations/countries, limited OTC in some countries, manufacture and veterinary use is banned in India, Nepal, and Pakistan due to imminent extinction of local vultures
Pharmacokinetic data
Protein binding	More than 99%
Metabolism	Liver, oxidative, primarily by CYP2C9, also by CYP2C8, CYP3A4, as well as conjugative by glucuronidation (UGT2B7) and sulfation;[2] no active metabolites exist
Elimination half-life	1.2–2 hr (35% of the drug enters enterohepatic recirculation)
Excretion	40% biliary 60% urine
Identifiers
IUPAC name[show]
CAS Number	15307-86-5
PubChem CID	3033
IUPHAR/BPS	2714
DrugBank	DB00586
ChemSpider	2925
UNII	144O8QL0L1
KEGG	D07816
ChEBI	CHEBI:47381
ChEMBL	ChEMBL139
PDB ligand	DIF (PDBe, RCSB PDB)
ECHA InfoCard	100.035.755
Chemical and physical data
Formula	C14H11Cl2NO2
Molar mass	296.148 g/mol
3D model (JSmol)	Interactive image

Diclofenac

//////////////Diclofenac Sodium

C1=CC=C(C(=C1)CC(=O)[O-])NC2=C(C=CC=C2Cl)Cl.[Na+]

Diclofenac Sodium

FDA Orange Book Patent

FDA Orange Book Patents: 1 of 21 (FDA Orange Book Patent ID)
Patent	9339551
Expiration	Oct 17, 2027
Applicant	HZNP
Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

FDA Orange Book Patents: 2 of 21 (FDA Orange Book Patent ID)
Patent	9339552
Expiration	Oct 17, 2027
Applicant	HZNP
Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

FDA Orange Book Patents: 3 of 21 (FDA Orange Book Patent ID)
Patent	9415029
Expiration	Jul 10, 2029
Applicant	HZNP
Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

FDA Orange Book Patents: 4 of 21 (FDA Orange Book Patent ID)
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Expiration	Jul 10, 2029
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Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

FDA Orange Book Patents: 5 of 21 (FDA Orange Book Patent ID)
Patent	9375412
Expiration	Jul 10, 2029
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Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

FDA Orange Book Patents: 6 of 21 (FDA Orange Book Patent ID)
Patent	8946292
Expiration	Mar 22, 2027
Applicant	JAVELIN PHARMS INC
Drug Application	N022396 (Prescription Drug: DYLOJECT. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

FDA Orange Book Patents: 7 of 21 (FDA Orange Book Patent ID)
Patent	9168305
Expiration	Oct 17, 2027
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Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

FDA Orange Book Patents: 8 of 21 (FDA Orange Book Patent ID)
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Expiration	Oct 17, 2027
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Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

FDA Orange Book Patents: 9 of 21 (FDA Orange Book Patent ID)
Patent	9220784
Expiration	Oct 17, 2027
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Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

FDA Orange Book Patents: 10 of 21 (FDA Orange Book Patent ID)
Patent	6407079
Expiration	Jun 18, 2019
Applicant	JAVELIN PHARMS INC
Drug Application	N022396 (Prescription Drug: DYLOJECT. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

FDA Orange Book Patents: 11 of 21 (FDA Orange Book Patent ID)
Patent	8252838
Expiration	Apr 21, 2028
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Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

FDA Orange Book Patents: 12 of 21 (FDA Orange Book Patent ID)
Patent	8618164
Expiration	Jul 10, 2029
Applicant	HZNP
Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

FDA Orange Book Patents: 13 of 21 (FDA Orange Book Patent ID)
Patent	8546450
Expiration	Aug 9, 2030
Applicant	HZNP
Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

FDA Orange Book Patents: 14 of 21 (FDA Orange Book Patent ID)
Patent	8217078
Expiration	Jul 10, 2029
Applicant	HZNP
Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

FDA Orange Book Patents: 15 of 21 (FDA Orange Book Patent ID)
Patent	8563613
Expiration	Oct 17, 2027
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Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

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Patent	8871809
Expiration	Oct 17, 2027
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Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

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Expiration	Oct 17, 2027
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Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

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Expiration	Jul 10, 2029
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Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

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Expiration	Oct 17, 2027
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Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

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Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

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Expiration	Oct 17, 2027
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Drug Application	N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

from FDA Orange Book

Aceclofenac

アセクロフェナク

• Molecular FormulaC₁₆H₁₃Cl₂NO₄
• Average mass354.185 Da

RPK779R03H

ацеклофенак[Russian][INN]

أسيكلوفيناك[Arabic][INN]

醋氯芬酸[Chinese][INN]

[({2-[(2,6-dichlorophenyl)amino]phenyl}acetyl)oxy]acetic acid

[2-(2,6-Dichloro-phenylamino)-phenyl]-acetic acid carboxymethyl ester

Aceclofenac

CAS Registry Number: 89796-99-6

CAS Name: 2-[(2,6-Dichlorophenyl)amino]benzeneacetic acid carboxymethyl ester

Additional Names: 2-[(2,6-dichlorophenyl)amino]phenylacetoxyacetic acid; glycolic acid [o-(2,6-dichloroanilino)phenyl]acetate ester

Manufacturers’ Codes: PR-82/3

Trademarks: Airtal (Prodes); Falcol (Bayer); Gerbin (Sanofi Winthrop); Preservex (BMS)

Molecular Formula: C16H13Cl2NO4

Molecular Weight: 354.18

Percent Composition: C 54.26%, H 3.70%, Cl 20.02%, N 3.95%, O 18.07%

Literature References: Prepn: A. V. Casas, ES8404783; idem,US4548952 (1984, 1985 both to Prodes). Gastrointestinal tolerance in rats in comparison with diclofenac, q.v.: V. Rimbau et al.,Farmaco Ed. Prat.43, 19 (1988). Clinical trial in comparison with acetaminophen, q.v., in episiotomal pain: A. Yscla, Drugs Exp. Clin. Res.14, 491 (1988). Clinical evaluation in rheumatoid arthritis: R. Ballesteros et al.,Clin. Trials J.27, 12 (1990).

Properties: White crystals from cyclohexane, mp 149-150°. uv max (ethanol): 275 nm (log e 4.14).

Melting point: mp 149-150°

Absorption maximum: uv max (ethanol): 275 nm (log e 4.14)

Therap-Cat: Anti-inflammatory; analgesic.

Keywords: Analgesic (Non-Narcotic); Anti-inflammatory (Nonsteroidal); Arylacetic Acid Derivatives.

UV-Vis spectra of Aceclofenac.

 Characterization of Aceclofenac by ¹H NMR spectroscopy

¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 3.896 (s, 2H, Aliphatic –CH₂), 4.634 (s, 2H, Aliphatic –CH₂), 6.279 (d J= 8.00H_Z, 1H, Aromatic), 6.887 (t, J = 7.2 Hz, 1H), 6.936 (s, 1H, NH), 7.039(t, J = 7.6 Hz, 1H, Aromatic), 7.225 (t J= 8.00 H_Z, 1H, Aromatic), 7.260 (d J= 8.00 H_Z, 1H, Aromatic), 7.537 (d J= 8.4H_Z, 2H, Aromatic), 13.076 (s, 1H, Carboxylic acid) …https://www.sciencedirect.com/science/article/pii/S2214180417301290

 

 

https://www.dea.gov/sites/default/files/pr/microgram-journals/2014/mj11-1_29-41.pdf

Aceclofenac is a nonsteroidal anti-inflammatory drug (NSAID) analog of diclofenac. It is used for the relief of pain and inflammation in rheumatoid arthritis, osteoarthritis and ankylosing spondylitis.

Aceclofenac (C16H13Cl2NO4), chemically [(2-{2, 6-dichlorophenyl) amino} phenylacetooxyacetic acid], is a crystalline powder with a molecular weight of 354.19. It is practically insoluble in water with good permeability. It is metabolized in human hepatocytes and human microsomes to form [2-(2′,6′-dichloro-4′-hydroxy- phenylamino) phenyl] acetoxyacetic acid as the major metabolite, which is then further conjugated. According to the Biopharmaceutical Classification System (BCS) drug substances are classified to four classes upon their solubility and permeability. Aceclofenac falls under the BCS Class II, poorly soluble and highly permeable drug.^[1]

Aceclofenac works by inhibiting the action of cyclooxygenase (COX) that is involved in the production of prostaglandins (PG) which is accountable for pain, swelling, inflammation and fever. The incidence of gastric ulcerogenicity of aceclofenac has been reported to be significantly lower than that of the other frequently prescribed NSAIDs, for instance, 2-folds lesser than naproxen, 4-folds lesser than diclofenac, and 7-folds lesser than indomethacin.

Aceclofenac should not be given to people with porphyria or breast-feeding mothers, and is not recommended for children. It should be avoided near term in a pregnant woman because of the risk of having a patent ductus arteriosus in the neonate.

SYN

Manufacturing Process for Aceclofenac
Stage-1
T Butanol and Chloro Acetyl Chloride react in presence of NN Dimethyl Aniline at low temperature. After reaction
organics mass wash with water and sodium bicarbonate solution to get stage-1

Stage-2
Stage-I react with Diclofenac Sodium in presence of TBAB in Toluene media, further react with formic acid and
reaction mass quenching in water and product is isolated by filtration. Finally Crude Aceclofenac purified in ethyl
acetate and charcoal. Pure product isolated by filtration.

SYN’

EP 0119932; US 4548952

Alkylation of the sodium salt of diclofenac (I) with benzyl bromoacetate (II) in hot DMF yielded the (arylacetoxy)acetate (III). Subsequent hydrogenolysis of the benzyl ester of (III) in the presence of Pd/C gave the title carboxylic acid. Alternatively, the benzyl ester group of (III) was cleaved by means of the combination of chlorotrimethylsilane and sodium iodide. This method of selective ester hydrolysis with in situ generated iodotrimethylsilane was also applied to the corresponding methyl (IV) and tert-butyl (V) esters. In a related procedure, tert-butyl ester (V) was prepared by alkylation of diclofenac (VI) with tert-butyl bromoacetate (VII) in the presence of tertiary amines. Selective cleavage of the tert-butyl ester group of (V) was then performed by treatment with either trifluoroacetic or formic acid.

SYN

Aceclofenac was prepared by selective hydrolysis of other labile ester precursors. Alkylation of diclofenac sodium (I) with tetrahydropyranyl chloroacetate (IX), prepared by protection of chloroacetic acid (VIII) with dihydropyran, furnished the tetrahydropyranyl ester of aceclofenac (X), which was then deprotected by treatment with HCl. Similarly, the preparation of aceclofenac was reported by acidic hydrolysis of the analogous tetrahydrofuranyl ester (XI).

References

Sources

• British National Formulary 55, March 2008; ISBN 978-0-85369-776-3 p. 537

References

• • EP 119 932 (Prodes; appl. 19.3.1984; E-prior. 21.3.1983).
  • US 4 548 952 (Prodes; 22.10.1985; appl. 15.3.1984; E-prior. 21.3.1983).

• Alternative synthesis:

  • ES 2 020 146 (Prodesfarma; appl. 29.5.1990).

• • ATC:M01AB16

• MW:354.19 g/mol
• CAS-RN:89796-99-6
• InChI Key:MNIPYSSQXLZQLJ-UHFFFAOYSA-N
• InChI:InChI=1S/C16H13Cl2NO4/c17-11-5-3-6-12(18)16(11)19-13-7-2-1-4-10(13)8-15(22)23-9-14(20)21/h1-7,19H,8-9H2,(H,20,21)
• LD₅₀:121 mg/kg (M, p.o.)

Aceclofenac

Clinical data
Trade names	Hifenac, Cincofen, Zerodol, Nacsiv, Acenac, others
AHFS/Drugs.com	International Drug Names
Routes of administration	oral, topical
ATC code	M01AB16 (WHO) M02AA25 (WHO)
Legal status
Legal status	UK: POM (Prescription only)
Identifiers
IUPAC name[show]
CAS Number	89796-99-6
PubChem CID	71771
ChemSpider	64809
UNII	RPK779R03H
KEGG	D01545
ChEBI	CHEBI:31159
ChEMBL	ChEMBL93645
ECHA InfoCard	100.169.686
Chemical and physical data
Formula	C16H13Cl2NO4
Molar mass	353.02161 g/mol
3D model (JSmol)	Interactive image
SMILES[hide] Clc2cccc(Cl)c2Nc1ccccc1CC(=O)OCC(=O)O
InChI[hide] InChI=1S/C16H13Cl2NO4/c17-11-5-3-6-12(18)16(11)19-13-7-2-1-4-10(13)8-15(22)23-9-14(20)21/h1-7,19H,8-9H2,(H,20,21)  Key:MNIPYSSQXLZQLJ-UHFFFAOYSA-N

//////////Aceclofenac, ацеклофенак , أسيكلوفيناك , 醋氯芬酸 , アセクロフェナク

Ifetroban イフェトロバン

3-[2-({(1S,2R,3S)-3-[4-(Pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl}methyl)phenyl]propanoic acid

• Molecular FormulaC₂₅H₃₂N₂O₅
• Average mass440.532 Da
• 143443-90-7;

Ifetroban is a potent and selective thromboxane receptor antagonist.^[1]

Ifetroban has been used in trials studying the treatment of Skin Diseases, Autoimmune Diseases, Pathologic Processes, Scleroderma, Limited, and Scleroderma, Diffuse, among others.

This compound belongs to the class of organic compounds known as phenylpropanoic acids. These are compounds with a structure containing a benzene ring conjugated to a propanoic acid.

• OriginatorBristol-Myers Squibb
• DeveloperBristol-Myers Squibb; Cumberland Pharmaceuticals; Vanderbilt-Ingram Cancer Center
• ClassAntiasthmatics; Antihypertensives; Antiplatelets; Heterocyclic bicyclo compounds; Oxazoles; Small molecules
• Mechanism of ActionThromboxane A2 receptor antagonists

• Phase IIAsthma; Hepatorenal syndrome; Portal hypertension; Solid tumours; Systemic scleroderma

• DiscontinuedCoronary thrombosis; Peripheral vascular disorders; Thrombosis

• 12 Dec 2018Phase-II clinical trials in Solid tumours (Metastatic disease, Late-stage disease, Second-line therapy or greater, Recurrent) in USA (PO) (NCT03694249)
• 13 Nov 2018Efficacy and adverse events data from a phase II trial in Portal hypertension released by Cumberland Pharmaceuticals
• 03 Oct 2018Vanderbilt-Ingram Cancer Center and Cumberland Pharmaceuticals plans a phase II trial for Solid tumours (Metastatic disease, Late-stage disease, Second-line therapy or greater, Recurrent) (PO, capsule) (NCT03694249)

Ifetroban sodium

• Molecular FormulaC₂₅H₃₁N₂NaO₅
• Average mass462.514 Da
• Monoisotopic mass462.213074 Da

SYN

BMS-180291 sodium salt was prepared from optically active 7-oxabicyclo[2.2.1]heptane lactol (I): The interphenylene side chain was introduced by deprotonation of (I) with ethylmagnesium bromide (0.95 eq.) followed by treatment with excess aryl Grignard (II) to afford crystalline diol (III). The extraneous benzylic hydroxyl group in (III) was removed by reduction with hydrogen in the presence of Pearlman’s catalyst to give alcohol (IV). Transformation of the alpha-side chain silyloxy carbinol of (IV) to a carboxymethyl ester was accomplished by initial protection of the omega-side chain alcohol as the acetate (Ac2O/py) followed by oxidation under Jones conditions and then exposure of the resulting crude acetate-acid to methanolic hydrogen chloride to afford crystalline alcohol-ester (V). Oxidation of (V) under Jones conditions furnished acid-ester (VI). The oxazole side chain was introduced into (VI) via serine-derived amino alcohol (VII). Standard coupling of acid (VI) with (VII) mediated by water-soluble carbodiimide (EDAC) gave amide (VIII). Acyclic side chain intermediate (VIII) was converted into oxazole (X) in three steps by mesylation followed by treatment with triethylamine to furnish cyclized oxazoline (IX). Dehydrogenation of (IX) employing a novel oxidative protocol (1) involving treatment with a mixture of copper (II) bromide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in chloroform/ethyl acetate solvent yielded oxazole (X). Saponification of (X) followed by acidification afforded (BMS-180291) as a white solid which could be purified by recrystallization from acetonitrile. The water-soluble sodium salt (XI) was available as a precipitate from BMS-18091 by treatment with sodium methoxide/methanol in acetone.

SYN

The interphenylene side chain was introduced by deprotonation of (I) with ethylmagnesium bromide (0.95 eq.) followed by treatment with excess aryl Grignard (II) to afford crystalline diol (III). The extraneous benzylic hydroxyl group in (III) was removed by reduction with hydrogen in the presence of Pearlman’s catalyst to give alcohol (IV). Transformation of the alpha-side chain silyloxy carbinol to a carboxy methyl ester was accomplished by initial protection of the omega-side chain alcohol as the acetate (Ac2O/pyr) followed by oxidation under Jones conditions and then exposure of the resulting crude acetate-acid to methanolic hydrogen chloride to afford crystalline alcohol-ester (V). Oxidation of (V) under Jones conditions furnished acid-ester (VI). The oxazole side chain was introduced into (VI) via serine-derived amino alcohol (VII). Standard coupling of acid (VI) with (VII) mediated by water-soluble carbodiimide (EDAC) gave amide (VIII). Acyclic side chain intermediate (VIII) was converted into oxazole (X) in three steps by mesylation followed by treatment with triethylamine to furnish cyclized oxazoline (IX). Dehydrogenation of (IX) employing a novel oxidative protocol involving treatment with a mixture of copper (II) bromide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in chloroform/ethyl acetate solvent yielded oxazole (X). Saponification of (X) followed by acidification afforded (XI) (BMS-180291) as a white solid which could be purified by recrystallization from acetonitrile. The water-soluble sodium salt was available as a precipitate from (XI) by treatment with sodium methoxide/methanol in acetone.

SYN

The synthesis of [1S-(1alpha,2alpha,3alpha,4alpha)]-2-[2-[2-(methoxycarbonyl)ethyl]benzyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylic acid (VI), a key intermediate in the synthesis of 203961 [see scheme 20396101a] has been presented: This compound has been obtained by two similar ways: 1) The condensation of L-valinol (XII) with anhydride (XXII) catalyzed by oxalic acid gives imide (XIII), which is treated with ethylmagnesium chloride, the Grignard reagent (XIV) and NaBH4 yielding intermediate (XV). This intermediate, without isolation, is treated with HCl in THF to afford the substituted benzaldehyde (XVI), which is condensed with trimethyl phosphonoacetate (XVII) and DBU in acetonitrile giving the propenoic ester (XVIII). Finally, this compound is submitted to a simultaneous reduction and hydrogenolysis with H2 over a Pearlman catalyst in methanol to provide the target of [1S-(1alpha,2alpha,3alpha,4alpha)]-2-[2-[2-(methoxycarbonyl)ethyl]benzyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylic acid (VI). 2) The preceding reaction sequence can also be performed using (S)-2-phenylglycinol (XIX) instead of the L-valinol (XII) yielding the previously reported benzaldehyde (XVI) through the imide (XX) and the nonisolated intermediate (XXI).

References

1. ^ Dockens, RC; Santone, KS; Mitroka, JG; Morrison, RA; Jemal, M; Greene, DS; Barbhaiya, RH (August 2000). “Disposition of Radiolabeled Ifetroban in Rats, Dogs, Monkeys, and Humans”(PDF). Drug Metabolism and Disposition. 28 (8): 973–80. PMID 10901709. Retrieved 5 October 2016.

Ifetroban

Identifiers
IUPAC name[show]
CAS Number	143443-90-7
PubChem CID	23724921
ChemSpider	58452
UNII	E833KT807K
KEGG	D04500
ChEMBL	ChEMBL2146062
Chemical and physical data
Formula	C25H32N2O5
Molar mass	440.53 g/mol
3D model (JSmol)	Interactive image
SMILES[show]

////////Ifetroban, BMS 18029, BMS 180291, BMS 180291A, BMS-180291-02, Boxaban, CPI 211, Hepatoren, Portaban, Vasculan, イフェトロバン

CCCCCNC(=O)C1=COC(=N1)C2C3CCC(C2CC4=CC=CC=C4CCC(=O)O)O3

Nalmefene hydrochloride dihydrate, ナルメフェン塩酸塩水和物

2019/1/8, PMDA, JAPAN, Selincro,

In January 2019, Otsuka received regulatory approval in Japan

Antialcohol dependence, Narcotic antagonist, Opioid receptor partial agonist/antagonist

Morphinan-3,14-diol, 17-(cyclopropylmethyl)-4,5-epoxy-6-methylene-, hydrochloride, hydrate (1:1:2), (5α)-

JF-1; NIH-10365; ORF-11676; SRD-174, Lu-AA36143

APPROVED 1995 USA

Trade Name：Revex^®   MOA：Opioid receptor antagonist     Indication：Respiratory depression

Company：Baxter (Originator)

17- (cyclopropylmethyl)-4,5-alpha-epoxy-6-methylenemorphinan-3,14-diol

(5α)-17-(Cyclopropylmethyl)-4,5-epoxy-6-methylenemorphinan-3,14-diol;

(-)-Nalmefene;

6-Deoxo-6-methylenenaltrexone; 6-Desoxy-6-methylenenaltrexone;

JF 1; Nalmetrene; ORF 11676;

CHINA 2013

EMA  LINK

In February 2013, EC approval in all EU member states was granted for the reduction of alcohol consumption in adults with alcohol dependence

Nalmefene hydrochloride dihydrate is a white or almost white crystalline powder. The chemical name is 17-(Cyclopropylmethyl)-4,5-α-epoxy-6-methylene-morphinan-3,14-diol hydrochloride dihydrate, has the following molecular formula C21H25NO3 ⋅ HCl ⋅ 2 H2O

Nalmefene hydrochloride dihydrate is very soluble in water and is not hygroscopic. Nalmefene hydrochloride dihydrate is a chiral compound, containing 4 asymmetric carbon atoms. Only one crystal form of Nalmefene hydrochloride dihydrate has been identified. Nalmefene hydrochloride dihydrate does not melt, but becomes amorphous after dehydration.

The structure of nalmefene hydrochloride dihydrate was demonstrated by elemental analysis, IR, UV/Vis, 1 H-NMR and 13C-NMR spectroscopy as well as MS spectrometry. Its crystal structure was analysed by X-ray diffraction and specific optical rotation was determined. It has been shown that no polymorphic forms were observed.

Nalmefene hydrochloride was approved by the U.S. Food and Drug Administration (FDA) on Apr 17, 1995. It was developed and marketed asRevex^® by Baxterin in the US.
Nalmefene  is an opioid receptor antagonist. It acts as a silent antagonist of the μ-opioid receptor and as a partial agonist of the κ-opioid receptor, it also possesses affinity for the δ-opioid receptor. Revex^® is indicated for the complete or partial reversal of opioid drug effects, including respiratory depression, induced by either natural or synthetic opioids. It is also indicated in the management of known or suspected opioid overdose.

Revex^® is available as a sterile solution for intravenous, intramuscular and subcutaneous administration in two concentrations, containing 100 μg or 1.0 mg of nalmefene free base per mL. The recommended dose is initiating at 0.25 μg/kg followed by 0.25 μg/kg incremental doses at 2-5 minute intervals for reversal of postoperative opioid depression, stopping as soon as the desired degree of opioid reversal is obtained.

Nalmefene (trade name Selincro), originally known as nalmetrene, is an opioid antagonist used primarily in the management of alcohol dependence. It has also been investigated for the treatment of other addictions such as pathological gambling.^[1]

Nalmefene is an opiate derivative similar in both structure and activity to the opioid antagonist naltrexone. Advantages of nalmefene relative to naltrexone include longer half-life, greater oral bioavailability and no observed dose-dependent liver toxicity.^[2]

As with other drugs of this type, nalmefene may precipitate acute withdrawal symptoms in patients who are dependent on opioid drugs, or more rarely when used post-operatively, to counteract the effects of strong opioids used in surgery.

Medical uses

Opioid overdose

Intravenous doses of nalmefene have been shown effective at counteracting the respiratory depression produced by opioid overdose.^[3]

This is not the usual application for this drug, for two reasons:

• The half-life of nalmefene is longer than that of naloxone. One might have thought this would make it useful for treating overdose involving long-acting opioids: it would require less frequent dosing, and hence reduce the likelihood of renarcotization as the antagonist wears off. But, in fact, the use of nalmefene is not recommended in such situations. Unfortunately, opioid-dependent patients may go home and use excessive doses of opioids in order to overcome nalmefene’s opioid blockade and to relieve the discomfort of opioid withdrawal. Such large doses of opioids may be fatal. This is why naloxone (a shorter-acting drug) is normally a better choice for overdose reversal.^[4]
• In addition, injectable nalmefene is no longer available on the market.

When nalmefene is used to treat an opioid overdose, doses of nalmefene greater than 1.5 mg do not appear to give any greater benefit than doses of only 1.5 mg.

Alcohol dependence

Nalmefene is used in Europe to reduce alcohol dependence^[5] and NICE recommends the use of nalmefene to reduce alcohol consumption in combination with psychological support for people who drink heavily.^[6]

Based on a meta analysis, the usefulness of nalmefene for alcohol dependence is unclear.^[7] Nalmefene, in combination with psychosocial management, may decrease the amount of alcohol drunk by people who are alcohol dependent.^[7][8] The medication may also be taken “as needed”, when a person feels the urge to consume alcohol.^[8]

Side effects

The following adverse effects have been reported with nalmefene:

Very Common (≥1⁄10)[edit]

• Insomnia
• Dizziness
• Headache
• Nausea

Common (≥1⁄100 to <1/10)[edit]

• Decreased appetite
• Sleep disorder
• Confusional state
• Restlessness
• Libido decreased (including loss of libido)
• Somnolence
• Tremor
• Disturbance in attention
• Paraesthesia
• Hypoaesthesia
• Tachycardia
• Palpitations
• Vomiting
• Dry mouth
• Diarrhoea
• Hyperhidrosis
• Muscle spasms
• Fatigue
• Asthenia
• Malaise
• Feeling abnormal
• Weight decreased

The majority of these reactions were mild or moderate, associated with treatment initiation, and of short duration.^[9]

Pharmacology

Pharmacodynamics

Nalmefene acts as a silent antagonist of the μ-opioid receptor (MOR) (K_i = 0.24 nM) and as a weak partial agonist (K_i = 0.083 nM; E_max = 20–30%) of the κ-opioid receptor (KOR), with similar affinity for these two receptors but a several-fold preference for the KOR.^[10]

^[11][12] In vivo evidence indicative of KOR activation, such as elevation of serum prolactin levels due to dopamine suppression and increased hypothalamic-pituitary-adrenal axisactivation via enhanced adrenocorticotropic hormone and cortisol secretion, has been observed in humans and animals.^[10][13] Side effects typical of KOR activation such as hallucinations and dissociation have also been observed with nalmefene in human studies.^[14] It is thought that the KOR activation of nalmefene might produce dysphoria and anxiety.^[15] In addition to MOR and KOR binding, nalmefene also possesses some, albeit far lower affinity for the δ-opioid receptor (DOR) (K_i = 16 nM), where it behaves as an antagonist.^[10][12][16]

Nalmefene is structurally related to naltrexone and differs from it by substitution of the ketone group at the 6-position of naltrexone with a methylene group (CH₂). It binds to the MOR with similar affinity relative to naltrexone, but binds “somewhat more avidly” to the KOR and DOR in comparison.^[10][13]

Pharmacokinetics

Nalmefene is extensively metabolized in the liver, mainly by conjugation with glucuronic acid and also by N-dealkylation. Less than 5% of the dose is excreted unchanged. The glucuronide metabolite is entirely inactive, while the N-dealkylated metabolite has minimal pharmacological activity.^{[citation needed]}

Chemistry

Nalmefene is a derivative of naltrexone and was first reported in 1975.^[17]

Society and culture

United States

In the US, immediate-release injectable nalmefene was approved in 1995 as an antidote for opioid overdose. It was sold under the trade name Revex. The product was discontinued by its manufacturer around 2008.^[18][19] Perhaps, due to its price, it never sold well. (See § Opioid overdose, above.)

Nalmefene in pill form, which is used to treat alcohol dependence and other addictive behaviors, has never been sold in the United States.^[2]

Europe

Lundbeck has licensed nalmefene from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.^[20] In 2011 they submitted an application for their drug termed Selincro to the European Medicines Agency.^[21] The drug was approved for use in the EU in March 2013.^[22] and in October 2013 Scotland became the first country in the EU to prescribe the drug for alcohol dependence.^[23] England followed Scotland by offering the substance as a treatment for problem drinking in October 2014.^[24] In November 2014 nalmefene was appraised and approved as a treatment supplied by Britain’s National Health Service (NHS) for reducing alcohol consumption in people with alcohol dependence.^[25]

Research

Nalmefene is a partial agonist of the κ-opioid receptor and may be useful to treat cocaine addiction.^[26]

SYN

Nalmefene (CAS NO.: 55096-26-9), with its systematic name of Morphinan-3,14-diol, 17-(cyclopropylmethyl)-4,5-epoxy-6-methylene-, (5alpha)-, could be produced through many synthetic methods.

Following is one of the synthesis routes:
By a Wittig reaction at naltrexone (I) with triphenylmethylphosphonium bromide (II) in DMSO in the presence of NaH as base.

PAPER

J. Med. Chem. 1975, 18, 259-262

https://pubs.acs.org/doi/pdf/10.1021/jm00237a008

PATENT

WO 2010136039

PATENT

US 3814768

Nalmefene (trade name Selincro), originally known as nalmetrene, is an opioid receptor antagonist developed in the early 1970s,^[1] and used primarily in the management of alcohol dependence, and also has been investigated for the treatment of other addictions such as pathological gambling and addiction to shopping.

Nalmefene is an opiate derivative similar in both structure and activity to the opiate antagonist naltrexone. Advantages of nalmefene relative to naltrexone include longer half-life, greater oral bioavailability and no observed dose-dependent liver toxicity. As with other drugs of this type, nalmefene can precipitate acute withdrawal symptoms in patients who are dependent on opioid drugs, or more rarely when used post-operatively to counteract the effects of strong opioids used in surgery.

Nalmefene differs from naltrexone by substitution of the ketone group at the 6-position of naltrexone with a methylene group (CH₂), which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors, and is known as a “universal antagonist” for its ability to block all three.

In clinical trials using this drug, doses used for treating alcoholism were in the range of 20–80 mg per day, orally.^[2] The doses tested for treating pathological gambling were between 25–100 mg per day.^[3] In both trials, there was little difference in efficacy between the lower and higher dosage regimes, and the lower dose (20 and 25 mg, respectively) was the best tolerated, with similar therapeutic efficacy to the higher doses and less side effects. Nalmefene is thus around twice as potent as naltrexone when used for the treatment of addictions.

Intravenous doses of nalmefene at between 0.5 to 1 milligram have been shown effective at counteracting the respiratory depression produced by opiate overdose,^[4] although this is not the usual application for this drug as naloxone is less expensive.

Doses of nalmefene greater than 1.5 mg do not appear to give any greater benefit in this application. Nalmefene’s longer half-life might however make it useful for treating overdose involving longer acting opioids such as methadone, as it would require less frequent dosing and hence reduce the likelihood of renarcotization as the antagonist wears off.

Nalmefene is extensively metabolised in the liver, mainly by conjugation with glucuronic acid and also by N-dealkylation. Less than 5% of the dose is excreted unchanged. The glucuronide metabolite is entirely inactive, while the N-dealkylated metabolite has minimal pharmacological activity.

Lundbeck has licensed the drug from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.^[5] In 2011 they submitted an application for their drug termed Selincro to the European Medicines Agency.^[6] It has not been available on the US market since at least August 2008.^{[citation needed]}

Side effects

• Common: drowsiness, hypertension, tachycardia, dizziness, nausea, vomiting
• Occasional: fever, hypotension, vasodilatation, chills, headache
• Rare: agitation, arrhythmia, bradycardia, confusion, hallucinations, myoclonus, itching^[7]

Properties

• Soluble in water up to 130 mg/mL, soluble in chloroform up to 0.13 mg/mL
• pK_a 7.6
• Distribution half-life: 41 minutes

Nalmefene is a known opioid receptor antagonist which can inhibit pharmacological effects of both administered opioid agonists and endogenous agonists deriving from the opioid system. The clinical usefulness of nalmefene as antagonist comes from its ability to promptly (and selectively) reverse the effects of these opioid agonists, including the frequently observed depressions in the central nervous system and the respiratory system.

Nalmefene has primarily been developed as the hydrochloride salt for use in the management of alcohol dependency, where it has shown good effect in doses of 10 to 40 mg taken when the patient experiences a craving for alcohol (Karhuvaara et al, Alcohol. Clin. Exp. Res., (2007), Vol. 31 No. 7. pp 1179-1187). Additionally, nalmefene has also been investigated for the treatment of other addictions such as pathological gambling and addiction to shopping. In testing the drug in these developmental programs, nalmefene has been used, for example, in the form of parental solution (Revex).

Nalmefene is an opiate derivative quite similar in structure to the opiate antagonist naltrexone. Advantages of nalmefene compared to naltrexone include longer half- life, greater oral bioavailability and no observed dose-dependent liver toxicity. Nalmefene differs structurally from naltrexone in that the ketone group at the 6- position of naltrexone is replaced by a methylene (CH₂) group, which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors (K and δ receptors) and is known as a “universal antagonist” as a result of its ability to block all three receptor types.

Nalmefene can be produced from naltrexone by the Wittig reaction. The Wittig reaction is a well known method within the art for the synthetic preparation of olefins (Georg Wittig, Ulrich Schόllkopf (1954). “Uber Triphenyl-phosphin- methylene ah olefinbildende Reagenzien I”. Chemische Berichte 87: 1318), and has been widely used in organic synthesis.

The procedure in the Wittig reaction can be divided into two steps. In the first step, a phosphorus ylide is prepared by treating a suitable phosphonium salt with a base. In the second step the ylide is reacted with a substrate containing a carbonyl group to give the desired alkene.

The preparation of nalmefene by the Wittig reaction has previously been disclosed by Hahn and Fishman (J. Med. Chem. 1975, 18, 259-262). In their method, naltrexone is reacted with the ylide methylene triphenylphosphorane, which is prepared by treating methyl triphenylphosphonium bromide with sodium hydride (NaH) in DMSO. An excess of about 60 equivalents of the ylide is employed in the preparation of nalmefene by this procedure.

For industrial application purposes, the method disclosed by Hahn and Fishman has the disadvantage of using a large excess of ylide, such that very large amounts phosphorus by-products have to be removed before nalmefene can be obtained in pure form. Furthermore, the NaH used to prepare the ylide is difficult to handle on an industrial scale as it is highly flammable. The use of NaH in DMSO is also well known by the skilled person to give rise to unwanted runaway reactions. The Wittig reaction procedure described by Hahn and Fishman gives nalmefene in the form of the free base. The free base is finally isolated by chromatography, which may be not ideal for industrial applications.

US 4,535,157 also describes the preparation of nalmefene by use of the Wittig reaction. In the method disclosed therein the preparation of the ylide methylene triphenylphosphorane is carried out by using tetrahydrofuran (THF) as solvent and potassium tert-butoxidc (KO-t-Bu) as base. About 3 equivalents of the ylide are employed in the described procedure.

Although the procedure disclosed in US 4,535,157 avoids the use of NaH and a large amount of ylide, the method still has some drawbacks which limit its applicability on an industrial scale. In particular, the use of THF as solvent in a Wittig reaction is disadvantageous because of the water miscibility of THF. During the aqueous work-up much of the end product (nalmefene) may be lost in the aqueous phases unless multiple re-extractions are performed with a solvent which is not miscible with water.

Furthermore, in the method described in US 4,535,157, multiple purification steps are carried out in order to remove phosphine oxide by-products of the Wittig reaction. These purification steps require huge amounts of solvents, which is both uneconomical and labor extensive requiring when running the reaction on an industrial scale. As in the case of the Wittig reaction procedure described by Hahn and Fishman (see above) the Wittig reaction procedure disclosed in US 4,535,157 also yields nalmefene as the free base, such that an additional step is required to prepare the final pharmaceutical salt form, i.e. the hydrochloride, from the isolated nalmefene base.

US 4,751,307 also describes the preparation of nalmefene by use of the Wittig reaction. Disclosed is a method wherein the synthesis is performed using anisole (methoxybenzene) as solvent and KO-t-Bu as base. About 4 equivalents of the ylide methylene triphenylphosphorane were employed in this reaction. The product was isolated by extraction in water at acidic pHs and then precipitating at basic pHs giving nalmefene as base.

Even though the isolation procedure for nalmefene as free base is simplified, it still has some disadvantages. The inventors of the present invention repeated the method disclosed in US 4,751,307 and found that the removal of phosphine oxide by-products was not efficient. These impurities co-precipitate with the nalmefene during basifϊcation, yielding a product still contaminated with phosphorus byproducts and having, as a consequence, a low chemical purity, as illustrated in example 2 herein.

There is therefore a need within the field to improve the method of producing nalmefene by the Wittig reaction. In particular, there is a need for a method that is readily applicable on a large industrial scale and which avoids the use of water- miscible solvents, such as THF, in the Wittig reaction, and permits easy isolation of nalmefene in a pure form suitable for its transformation to the final pharmaceutical salt form.

………………………………..

http://www.google.com/patents/EP2435439A1?cl=en

present invention the Wittig reaction may be performed by mixing a methyltriphenylphosphonium salt with 2- methyltetrahydrofuran (MTHF) and a suitable base to afford the ylide methylene triphenylphosphorane :

Methyltriphenylphosphonium salt Methylene triphenylphosphorane Yhde

The preformed ylide is subsequently reacted ‘in situ’ with naltrexone to give nalmefene and triphenylphosphine oxide (TPPO):

Naltrexone Yhde    Nalmefene TPPO

Example 1 Methyltriphenylphosphonium bromide (MTPPB, 25.8 Kg) was suspended in 2- methyltetrahydrofuran (MTHF, 56 litres). Keeping the temperature in the range 20-25⁰C, KO-t-Bu (8.8 kg) was charged in portions under inert atmosphere in one hour. The suspension turned yellow and was stirred further for two hours. An anhydrous solution of naltrexone (8.0 Kg) in MTHF (32 litres) was then added over a period of one hour at 20-25⁰C. The suspension was maintained under stirring for a few hours to complete the reaction. The mixture was then treated with a solution of ammonium chloride (4.2 Kg) in water (30.4 litres) and then further diluted with water (30.4 litres). The phases were separated, the lower aqueous phase was discarded and the organic phase was washed twice with water (16 litres). The organic phase was concentrated to residue under vacuum and then diluted with dichloromethane (40 litres) to give a clear solution. Concentrated aqueous hydrochloric acid (HCl 37%, 2 litres) was added over one hour at 20- 25⁰C. The suspension was stirred for at least three hours at the same temperature, and then filtered and washed with dichloromethane (8 litres) and then with acetone (16 litres). The solid was then re-suspended in dichloromethane (32 litres) at 20-25⁰C for a few hours and then filtered and washed with dichloromethane (16 litres), affording 9.20 Kg of nalmefene hydrochloride, corresponding to 7.76 kg of nalmefene hydrochloride (99.7% pure by HPLC). Molar yield 89%.

HPLC Chromatographic conditions

Column: Zorbax Eclipse XDB C-18, 5 μm, 150 x 4.6 mm or equivalent Mobile Phase A: Acetonitrile / Buffer pH = 2.3 10 / 90

Mobile Phase B: Acetonitrile / Buffer pH = 2.3 45 / 55

Buffer: Dissolve 1.1 g of Sodium Octansulfonate in 1 L of water. Adjust the pH to 2.3 with diluted

H₃PO₄. Column Temperature: 35°C

Detector: UV at 230 nm

Flow: 1.2 ml/min

Injection volume: 10 μl

Time of Analysis: 55 minutes

Example 2

The procedure described in US 4,751,307 was repeated, starting from 1Og of naltrexone and yielding 8.5g of nalmefene. The isolated product showed the presence of phosphine oxides by-products above 15% molar as judged by 1HNMR.

Example 3.

Methyltriphenylphosphonium bromide (MTPPB, 112.9g) was suspended in 2- methyltetrahydrofuran (MTHF, 245 ml). Keeping the temperature in the range 20- 25°C, KO-t-Bu (38.7 g) was charged in portions under inert atmosphere in one hour. The suspension was stirred for two hours. An anhydrous solution of naltrexone (35 g) in MTHF (144 ml) was then added over a period of one hour at 20-25⁰C. The suspension was maintained under stirring overnight. The mixture was then treated with a solution of glacial acetic acid (17.7 g) in MTHF. Water was then added and the pH was adjusted to 9-10. The phases were separated, the lower aqueous phase was discarded and the organic phase was washed twice with water. The organic phase was concentrated to residue under vacuum and then diluted with dichloromethane (175 ml) to give a clear solution. Concentrated aqueous hydrochloric acid (HCl 37%, 10. Ig) was added over one hour at 20- 25°C. The suspension was stirred and then filtered and washed with dichloromethane and acetone. The product was dried affording 38.1g of Nalmefene HCl. Example 4

Example 3 was repeated but the Wittig reaction mixture after olefmation completeness was treated with acetone and then with an aqueous solution of ammonium chloride. After phase separation, washings, distillation and dilution with dichloromethane, the product was precipitated as hydrochloride salt using HCl 37%. The solid was filtered and dried affording 37.6 g of Nalmefene HCl.

Example 5 Preparation of Nalmefene HCl dihydrate from Nalmefene HCl Nalmefene HCl (7.67 Kg, purity 99.37%, assay 93.9%) and water (8.6 litres) were charged into a suitable reactor. The suspension was heated up to 80⁰C until the substrate completely dissolved. Vacuum was then applied to remove organic solvents. The resulting solution was filtered through a 0.65 μm cartridge and then diluted with water (2.1 litres) that has been used to rinse the reactor and pipelines. The solution was cooled down to 50⁰C and 7 g of Nalmefene HCl dihydrate seeding material was added. The mixture was cooled to 0-5⁰C over one hour with vigorous stirring and then maintained under stirring for one additional hour. The solid was filtered of and washed with acetone. The wet product was dried at 25°C under vacuum to provide 5.4 Kg of Nalmefene HCl dihydrate (purity 99.89%, KF 8.3% , yield 69%).

………………….

http://www.google.com/patents/EP2316456A1?cl=en

……………………

http://www.google.com/patents/US8598352

http://www.clinicalleader.com/doc/nice-endorses-lundbeck-s-alcohol-dependency-drug-for-use-in-uk-0001

A structural analog of Naltrexone (N285780) with opiate antagonist activity used in pharmaceutical treatment of alcoholism. Other pharmacological applications of this compound aim to reduce food cravings, drug abuse and pulmonary disease in affected individuals. Used as an opioid-induced tranquilizer on large animals in the veterinary industry. Narcotic antagonist.

NALMEFENE

References

Nalmefene

Clinical data
Trade names	Selincro
AHFS/Drugs.com	Monograph
MedlinePlus	a605043
License data	EU EMA: by INN
Routes of administration	By mouth, intravenous
ATC code	N07BB05 (WHO)
Legal status
Legal status	UK: POM (Prescription only)
Pharmacokinetic data
Protein binding	45%
Metabolism	hepatic
Elimination half-life	10.8 ± 5.2 hours
Excretion	renal
Identifiers
IUPAC name[show]
CAS Number	55096-26-9  58895-64-0 (HCl)
PubChem CID	5284594
IUPHAR/BPS	1628
ChemSpider	4447642
UNII	TOV02TDP9I
ChEMBL	ChEMBL982
ECHA InfoCard	100.164.948
Chemical and physical data
Formula	C21H25NO3
Molar mass	339.43 g/mol
3D model (JSmol)	Interactive image
SMILES[hide] OC(C1=C2[C@@]34[C@H]5O1)=CC=C2C[C@@H](N(CC4)CC6CC6)[C@]3(O)CCC5=C
InChI[hide] InChI=1S/C21H25NO3/c1-12-6-7-21(24)16-10-14-4-5-15(23)18-17(14)20(21,19(12)25-18)8-9-22(16)11-13-2-3-13/h4-5,13,16,19,23-24H,1-3,6-11H2/t16-,19+,20+,21-/m1/s1  Key:WJBLNOPPDWQMCH-MBPVOVBZSA-N

Nalmefene

17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol

march 1 2013

Lundbeck will be celebrating news that European regulators have issued a green light for Selincro, making it the first therapy approved for the reduction of alcohol consumption in dependent adults.

Selincro (nalmefene) is a unique dual-acting opioid system modulator that acts on the brain’s motivational system, which is dysregulated in patients with alcohol dependence.

The once daily pill has been developed to be taken on days when an alcoholic feels at greater risk of having a drink, in a strategy that aims to reduce – rather than stop – alcohol consumption, which some experts believe is a more realistic goal.

Clinical trials of the drug have shown that it can reduce alcohol consumption by approximately 60% after six months treatment, equating to an average reduction of nearly one bottle of wine per day.

In March last year, data was published from two Phase III trials, ESENSE 1 and ESENSE 2, showing that the mean number of heavy drinking days decreased from 19 to 7 days/month and 20 to 7 days/month, while TAC fell from 85 to 43g/day and from 93 to 30g/day at month six. However, the placebo effect was also strong in the studies.

According to Anders Gersel Pedersen, Executive Vice President and Head of Research & Development at Lundbeck, Selincro “represents the first major innovation in the treatment of alcohol dependence in many years,” and he added that its approval “is exciting news for the many patients with alcohol dependence who otherwise may not seek treatment”.

Alcohol dependence is considered a major public health concern, and yet it is both underdiagnosed and undertreated, highlighting the urgent need for better management of the condition.

In Europe, more than 90% of the 14 million patients with alcohol dependence are not receiving treatment, but research suggests that treating just 40% of these would save 11,700 lives each year.

The Danish firm said it expects to launch Selincro in its first markets in mid-2013, and that it will provide the drug as part of “a new treatment concept that includes continuous psychosocial support focused on the reduction of alcohol consumption and treatment adherence”.

Nalmefene (Revex), originally known as nalmetrene, is an opioid receptor antagonistdeveloped in the early 1970s, and used primarily in the management of alcoholdependence, and also has been investigated for the treatment of other addictions such aspathological gambling and addiction to shopping.

Nalmefene is an opiate derivative similar in both structure and activity to the opiate antagonist naltrexone. Advantages of nalmefene relative to naltrexone include longer half-life, greater oral bioavailability and no observed dose-dependent liver toxicity. As with other drugs of this type, nalmefene can precipitate acute withdrawal symptoms in patients who are dependent on opioid drugs, or more rarely when used post-operatively to counteract the effects of strong opioids used in surgery.

Nalmefene differs from naltrexone by substitution of the ketone group at the 6-position of naltrexone with a methylene group (CH₂), which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors, and is known as a “universal antagonist” for its ability to block all three.

1. US patent 3814768, Jack Fishman et al, “6-METHYLENE-6-DESOXY DIHYDRO MORPHINE AND CODEINE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALTS”, published 1971-11-26, issued 1974-06-04
2.  Barbara J. Mason, Fernando R. Salvato, Lauren D. Williams, Eva C. Ritvo, Robert B. Cutler (August 1999). “A Double-blind, Placebo-Controlled Study of Oral Nalmefene for Alcohol Dependence”. Arch Gen Psychiatry 56 (8): 719.
3.  Clinical Trial Of Nalmefene In The Treatment Of Pathological Gambling
4.  http://www.fda.gov/cder/foi/label/2000/20459S2lbl.pdf
5. “Efficacy of Nalmefene in Patients With Alcohol Dependence (ESENSE1)”. “Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan”. thepharmaletter. 22 December 2011.
6. Nalmefene Hydrochloride Drug Information, Professional

REVEX (nalmefene hydrochloride injection), an opioid antagonist, is a 6-methylene analogue of naltrexone. The chemical structure is shown below:

Molecular Formula: C₂₁H₂₅NO₃•HCl

Molecular Weight: 375.9, CAS # 58895-64-0

Chemical Name: 17-(Cyclopropylmethyl)-4,5a-epoxy-6-methylenemorphinan-3,14-diol, hydrochloride salt.

Nalmefene hydrochloride is a white to off-white crystalline powder which is freely soluble in water up to 130 mg/mL and slightly soluble in chloroform up to 0.13 mg/mL, with a pK_a of 7.6.

REVEX is available as a sterile solution for intravenous, intramuscular, and subcutaneous administration in two concentrations, containing 100 µg or 1.0 mg of nalmefene free base per mL. The 100 µg/mL concentration contains 110.8 µg of nalmefene hydrochloride and the 1.0 mg/mL concentration contains 1.108 mg of nalmefene hydrochloride per mL. Both concentrations contain 9.0 mg of sodium chloride per mL and the pH is adjusted to 3.9 with hydrochloric acid.

Concentrations and dosages of REVEX are expressed as the free base equivalent of nalmefene

////////////////////JF-1, NIH-10365, ORF-11676, SRD-174, JAPAN 2019, FDA 1995, Nalmefene hydrochloride dihydrate, ナルメフェン塩酸塩水和物 , Nalmefene, ema 2013, china, 2013, Lu-AA36143

TIABENDAZOLE

CAS: 148-79-8

• Molecular FormulaC₁₀H₇N₃S
• Average mass201.248 Da
• тиабендазол [Russian] [INN]
  تياباندازول [Arabic] [INN]
  噻苯达唑 [Chinese] [INN]
• チアベンダゾール;

Tiabendazole (INN, BAN), thiabendazole (AAN, USAN), TBZ (and the trade names Mintezol, Tresaderm, and Arbotect) is a preservative^[1]

2-Substituted benzimidazole first introduced in 1962. It is active against a variety of nematodes and is the drug of choice for strongyloidiasis. It has CNS side effects and hepatototoxic potential. (From Smith and Reynard, Textbook of Pharmacology, 1992, p919)

Thiabendazole, 2-(4′-thiazolyl)-benzimidazole (TBZ) (I) is an important anthelmintic and fungicidal agent widely used in pharmaceutical, agriculture and food industry. Owing to the commercial importance of thiabendazole, the various synthetic routes are disclosed in the literature for preparing this pharmacologically and fungicidally active compound.

The various literature discloses the synthesis of thiabendazole by using aniline, 4-cyanothiazole and hydrogen chloride in polychlorobenzene such as dichloro- or a trichlorobenzene solvent under high pressure reaction conditions to obtain N-phenyl-(thiazole-4-amidine)-hydrochloride (amidine hydrochloride). This amidine hydrochloride is then treated with hypohalites such as sodium or potassium hypochlorite, sodium hypobromite and calcium hypochlorite in presence of base such as alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide; or an alkali metal carbonate or bicarbonate such sodium carbonate, sodium bicarbonate to obtain thiabendazole.

NMR

The US patent no. US 3,274,208 discloses the process for preparation of amidine hydrochloride by reacting 4-cynothiazole and aniline in presence of aluminum chloride at 180 °C. The amidine hydrochloride is purified by acid base treatment.

The US patent no. US 3,299,081 (henceforth patent ‘081) discloses the process for preparation of N-phenyl-(thiazole-4-amidine)-hydrochloride (amidine hydrochloride) and thiabendazole by heating together 4-cyanothiazole and aniline hydrochloride and purging of excess dry hydrogen chloride gas under pressure (15 psig) reaction condition in a 1,2-dichlorobenzene solvent at 135 to 140 °C using closed reactor. The amidine hydrochloride is isolated by filtration and it is then cyclized to N-chloro-N’-phenyl-(thiazole-4-amidine) intermediate by reaction with sodium hypochlorite in water-methanol solvent, further the intermediate is then converted to thiabendazole by treatment with potassium hydroxide in ethanol. The preferred embodiment of the said patent discloses the use of excess hydrogen chloride in a polychlorobenzene medium to achieve higher yields of amidine hydrochloride. The reaction with gas under pressure is exothermic, so the reaction is unsafe.

As per the background of the patent ‘081, the prior art processes were disclosed that the N-aryl amidines could be prepared by reacting together a nitrile and an aromatic amine in the presence of a metal catalyst such as aluminum chloride or zinc chloride. The process involved the use of a metallic halide as an additional substance in the reaction mixture with the result that metal complexes are obtained which have to be decomposed and the metal removed before pure amidine compounds can be recovered. It was also known to prepare N-aryl amidines by reacting the nitrile and the aromatic amine hydrochloride in a solvent such as ether in the absence of metallic halide. The process referred to affords only poor yields of the desired amidine. Hence, neither of these methods are entirely satisfactory.

13C NMR

The US patent no. US 3,299,082 discloses the process for preparation of N-phenyl-(thiazole-4-amidine)-hydrochloride (amidine hydrochloride) by reacting aniline and 4-cyanothiazole in in the presence of a Friedel Crafts type catalyst such as aluminum chloride at temperature 180 °C. The amidine hydrochloride is reacted with hydroxylamine hydrochloride, in presence of base such as sodium bicarbonate and water as solvent to obtain N-phenyl-(thiazole-4-hydroxyamidine) which is then treated with alkyl or aryl sulfonyl halide such methane sulfonyl chloride in the presence of a base such as pyridine to obtain thiabendazole.

The US patent no. US 3,325,506 discloses the process for preparation of thiabendazole by reacting amidine hydrochloride with hypohalites such as sodium or potassium hypochlorite, sodium hypobromite and calcium hypochlorite in presence of base such as alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide; or an alkali metal carbonate or bicarbonate such sodium carbonate, sodium bicarbonate in water or mixtures of water and organic solvents to obtain thiabendazole.

The significance of by-products from reactions in process development work arises from the need to control or eliminate their formation which might affect product cost, process safety, product purity and environmental health. Very few reactions go to 100% completion in the desired sense. Even when conversion is 100% selectivity is not 100%. Most reactions are accompanied by by-products which arise as a direct consequence of a primary synthetic step including work-up and isolation and as a result of various types of side reactions. By-products from the latter type also include tars, polymeric materials, and coloring matters. The level of some by-products from side reactions depends frequently on the batch size.

MASS

In the pharmaceutical industry, an impurity is considered as any other inorganic or organic material, or residual solvents other than the drug substances, or ingredients, arise out of synthesis or unwanted chemicals that remains with APIs. Organic impurities are those substances which are formed in the drug substance during the process of synthesis of drug product or even formed during the storage of drug product. This type of impurity includes-intermediate, starting material, degradation product, reagents, ligands, catalyst and by product. Inorganic impurities present mainly include heavy metals, residual solvents, inorganic salts, filter aids, charcoal, reagent, ligands and catalyst.

Impurity profiling includes identification, structure elucidation and quantitative determination of impurities and degradation products in bulk drug materials and pharmaceutical formulations. Impurity profiling has gained importance in modern pharmaceutical analysis since an unidentified, potentially toxic impurities are hazardous to health and the presence of unwanted impurities may influence bioavailability, safety and efficacy of APIs. Now days, not only purity profile but also impurity profile has become mandatory according to various regulatory authorities. The International Conference on Harmonization (ICH) has published guidelines on impurities in new drug substances, products, and residual solvents.

IR

The prior art processes for preparing thiabendazole suffer from inherent drawbacks and inconveniences, such as low yields, additional reaction steps, high-pressure and unsafe reaction conditions. Moreover, the prior art processes for preparation of thiabendazole are end up with surplus level of potential impurities such as 4-chloro thiabendazole (V) or 5-chloro thiabendazole (VI). Also, the prior processes are silent about these impurities. Since, the strict regulations of the regulatory authorities pertaining to the presence of impurities in the active ingredient, it is highly essential to align the research inline with the guidelines of the regulatory authorities in accordance to appropriate regulations and limits to register and commercialize the product in respective countries.

(V) (VI)

Hence, with objective of developing the short process, more direct and less expensive methods, significant improvement in the art for preparation of thiabendazole with controlled level of 4-chloro thiabendazole or 5-chloro thiabendazole impurities, residual solvents (methanol, benzene) and heavy metals (selenium, cobalt, molybdenum), the inventors of the instant invention are motivated to pursue the research to synthesize thiabendazole in under atmospheric conditions with high yield and high chemical purity for agricultural and pharmaceutical use.

CLIP

http://www.inchem.org/documents/jecfa/jecmono/v31je04.htm

Uses

Preservative

It is used primarily to control mold, blight, and other fungal diseases in fruits (e.g. oranges) and vegetables; it is also used as a prophylactic treatment for Dutch elm disease.

Use in treatment of aspergillosis has been reported.^[2]

Used in anti-fungal Purple wallboards (optiSHIELD AT, mixture of azoxystrobin and thiabendazole).

Parasiticide

As an antiparasitic, it is able to control roundworms (such as those causing strongyloidiasis),^[3] hookworms, and other helminth species which attack wild animals, livestock and humans.^[4]

Angiogenesis inhibitor

Genes responsible for the maintenance of cell walls in yeast have been shown to be responsible for angiogenesis in vertebrates. Tiabendazole serves to block angiogenesis in both frog embryos and human cells. It has also been shown to serve as a vascular disrupting agent to reduce newly established blood vessels. Tiabendazole has been shown to effectively do this in certain cancer cells.^[5]

Pharmacodynamics

TBZ works by inhibition of the mitochondrial, helminth-specific enzyme, fumarate reductase, with possible interaction with endogenous quinone.^[6]

Other

Medicinally, thiabendazole is also a chelating agent, which means it is used medicinally to bind metals in cases of metal poisoning, such as lead, mercury, or antimony poisoning.

In dogs and cats, thiabendazole is used to treat ear infections.

Thiabendazole is also used as a food additive,^[7][8] a preservative with E number E233 (INS number 233). For example, it is applied to bananas to ensure freshness, and is a common ingredient in the waxes applied to the skins of citrus fruits. It is not approved as a food additive in the EU,^[9] Australia and New Zealand.^[10]

Safety

The substance appears to have a slight toxicity in higher doses, with effects such as liver and intestinal disorders at high exposure in test animals (just below LD₅₀ level).^{[citation needed]} Some reproductive disorders and decreasing weaning weight have been observed, also at high exposure. Effects on humans from use as a drug include nausea, vomiting, loss of appetite, diarrhea, dizziness, drowsiness, or headache; very rarely also ringing in the ears, vision changes, stomach pain, yellowing eyes and skin, dark urine, fever, fatigue, increased thirst and change in the amount of urine occur.^{[citation needed]} Carcinogenic effects have been shown at higher doses.^[11]

Synthesis

Intermediate arylamidine 2 is prepared by the dry HCl catalyzed addition of aniline to the nitrile function of 4-cyanothiazole (1). Amidine (2) is then converted to its N-chloro analog 3by means of NaOCl. On base treatment, this apparently undergoes a nitrene insertion reaction (4) to produce thiabendazole (5). Note the direction of the arrow is from the benzene to the nitrene since the nitrene is an electrophilic species.

Alternative route of synthesis: 4-thiazolecarboxamide with o-phenylenediamine in polyphosphoric acid.^[13]

Synthesis of labeled thiabendazole:^[14]

Analogues

Cambendazole (best of 300 agents in an extensive study),^[17] is made by nitration of tiabendazole, followed by catalytic hydrogenation to 2, and acylation with Isopropyl chloroformate.

Additionally, tiabendazole was noted to exhibit moderate anti-inflammatory and analgesic activities, which led to the development of KB-1043.

PATENT

WO-2019016834

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019016834&tab=PCTDESCRIPTION&maxRec=1000

The present invention relates to an improved process for preparing thiabendazole of formula (I) with high yield, high purity, in economical and commercially viable manner for agricultural and pharmaceutical use.

Process for preparing thiabendazole with higher yield, purity, in an economical and commercially viable manner. Thiabendazole is an important anthelmintic and fungicidal agent widely used in pharmaceutical, agriculture and food industry. Represents the first filing from the Hikal Ltd and the inventors on thiabendazole.

The structural details of the 4-chloro thiabendazole (V) and 5-chloro thiabendazole (VI) impurities are as follow.

1. 4-Chloro thiabendazole:

(a) FT-IR study: The FT-IR spectrum was recorded in the KBr pellet using ABB FTLA-2000 FT-IR Spectrometer. The IR data is tabulated below.

Frequency (cm^“1) Assignment (s)

1576.37 C=C stretching

1309.16 C-N stretching

3073.38 N-H stretching

(b) NMR spectral data:

NMR experiment was carried out on 400 MHz Bruker spectrometer using DMSO as solvent. The chemical shifts are reported on the δ scale in ppm relative DMSO at 2.5 ppm. The 1H spectra displayed in respectively. The NMR assignment of 4-chloro thiabendazole is shown below.

Proton assignments of 4-Chloro thiabendazole:

s-singlet, d-doublet, t -triplet, q- quartet, dd-doublet of doublet, br-broad, m-multiplet.

2. 5-Chloro thiabendazole:

(a) FT-IR study:

The FT-IR spectrum was recorded in the KBr pellet using ABB FTLA- 2000 Spectrometer. The IR data is tabulated below.

(b) NMR spectral data:

NMR experiment was carried out on 400 MHz Bruker spectrometer using DMSO-d₆ as solvent. The chemical shifts are reported on the δ scale in ppm relative DMSO-d₆ at 2.50

ppm. The 1H spectra displayed in respectively. The NMR assignment of 5-chloro thiabendazole is shown below.

Proton assignments 5-Chloro thiabendazole:

s-singlet, d-doublet, q-quartet m-multiplet, br-broad.

Examples

Example 1: Preparation of amidine hydrochloride (IV)

To the 4-neck, 1 lit RBF, fixed with thermo pocket, condenser and hydrogen chloride (HC1) gas inlet, 100 g (0.908 moles, 1.0 eq) of 4-cyanothiazole, 386 (3.86 V) ml of 1,2-dichlorobenzene and 86.02 (0.924 moles, 1.02 eq) g of aniline were charged. The reaction mass was heated to 55 to 60 °C and hydrogen chloride (HC1) gas was purged till exotherm ceased. Then the temperature of the reaction mass was raised to 135 to 140 °C and again dry HC1 gas was purged till 4-cyanothiazole was reduced to less than 0.2 % (w/w) analyzed by HPLC. The reaction mass was cooled to 45 to 50° C and 500 mL of water was charged and the reaction mass was stirred for half an hour. The pH of the reaction mass was adjusted between 3 to 5 using caustic lye. The reaction mass was filtered through hyflo bed, and bed was washed with 50 (0.5 V) mL of water. The organic layer was separated, and the aqueous layer was charged back to the RBF. 20 g of activated charcoal was added in aqueous layer under stirring at 45 to 50 °C. The reaction mass was heated to 55 to 60 °C and maintained under stirring for 1.0 hour. The reaction mass was filtered through the hyflo bed under

vacuum, and bed was washed with 50 mL of hot water and suck dried till no more filtrate collected. 300-400 mL of water was distilled from the aqueous layer at 55 °C under 50 m bar of vacuum. Then the reaction mass was cooled to 0 to 5 °C and maintained under stirring for 1 hour. The obtain amidine hydrochloride was filtered by using Buckner funnel and suck dried till no more filtrate collected from it. The wet cake was dried under vacuum at 55 to 60 °C to get 189 g (86.83% yield, HPLC purity 99.85%) of amidine hydrochloride.

Example 2: Preparation of thiabendazole (I)

The 5 lit RBF was fixed with over head stirrer, thermo pocket, condenser and addition funnel. 185 g (0.772 moles, 1.0 eq.) of amidine hydrochloride and 1536 mL (7.33V) of water were charged. The reaction mass was cooled to 0 to 5 °C. 1233 mL of methanol was added to the mass and the pH of the reaction mass was adjusted between 9 to 10 by using 5N sodium carbonate solution. The reaction mass was warmed to 10 to 15 °C and 415.35 g (12.57 % w/w, 0.91 eq.) sodium hypochlorite was slowly added by maintaining temperature between 10 to 15 °C. The reaction mass was stirred at same temperature for half an hour. Then the reaction mass was heated to 60 to 65 °C and 46.15 g (12.57 % w/w, 0.1 eq) sodium hypochlorite was added. The reaction mass was stirred at 60 to 65 °C for 1.0 hour and the reaction mass was cooled to 30 to 40 °C. The reaction mass was filtered, the bed was washed with 925 mL of water (5.0 V) and suck dried for 10 minutes to get 238 g (152 g on dry basis, 97.82 % yield, HPLC purity 99.77%) of thiabendazole.

Example 3: Purification of thiabendazole (I)

The 5 lit RBF was fixed with over head stirrer, thermo pocket, condenser and addition funnel. 224 g of wet crude thiabendazole (145 g on dry basis) was charged at 25 to 30 °C. 2392 mL (16.5 V) of water was charged and the reaction mass was heated to 75 to 80 °C. The pH of the reaction mass was adjusted between 1 to 2 by adding concentrated hydrochloride. Then 21.75 g (15 %, w/w) activated charcoal was added and the reaction mass was stirred for 1.0 hour at 75 to 80 °C. The reaction mass was filtered through hyflo bed and the bed was washed with 1445 mL (1.0 V) of hot water. The aqueous layer was charged back to clean RBF and cooled to 0 to 5 °C and stirred for 10 hours. The solid was filtered and suck dried under vacuum to get 224 g wet cake of thiabendazole hydrochloride (135 g on dry basis).

1261 niL (10 V w.r.t dry thiabendazole hydrochloride) was charged and then 224 g wet cake of thiabendazole hydrochloride was added. The reaction mass was heated to 70 to 80 °C and maintained under stirring for half an hour to get clear solution. The pH of the reaction mass was adjusted to 7 to 8 by using liquor ammonia. The reaction mass was cooled to 25 to 30 °C and stirred for 1.0 hour. The reaction mass was filtered, and the wet cake was slurry washed twice with 1350 mL (10V x 2 times). Then the bed was washed with 675 mL (5.0 V) water. The solid was dried under vacuum at 60 to 70 °C to afford 119 g (79.33% yield, HPLC purity 99.96%) of pure thiabendazole.

CLIP

Fig. 5 Raman spectrum of solid thiabendazole, and SERS spectra of ethanol – water solutions on a re-used 3 m m thick Au woodpile array. Spurious bands from impurities are marked with asterisks.

CLIP

Fig. 6 (A) Proton NMR spectrum of thiabendazole in DMSO-d 6 solution. (B) Plots of normalized selective relaxation rate enhancements of H1/ H2, H14, and H12. [TBZ] ¼ 2 Â 10 À3 mol L À1 , [DNA] ¼ 1, 2, 5, 10, 20 Â 10 À5 mol L À1 , pH ¼ 7.4, T ¼ 298 K. (C) Equilibrium constant of the TBZ-DNA system. [DNA] ¼ 2 Â 10 À5 mol L À1 , [TBZ] ¼ 2, 2.5, 3, 3.5, 4 Â 10 À3 mol L À1 , pH ¼ 7.4, T ¼ 298 K.

CLIP

Thiabendazole has been prepared by heating thiazole-4-carboxamide and benzene-1,2-diamine in polyphosphoric acid (Scheme 13) (1961JA(83)1764). An alternative synthesis involves 4-carboxythiazole (CA 162 590253 (2015), CA 62 90958 (1964)) or 4-cyanothiazole (CA 130 110264 (1996), CA 121 57510 (1994)) as starting materials. A different approach to the synthesis of thiabendazole has been described starting from N-arylamidines; in the presence of sodium hypochlorite and a base, N-arylamidine hydrochlorides are transformed to benzimidazoles via formation of N-chloroamidine intermediate followed by ring closure in a stepwise or concerted mechanism (1965JOC(30)259).

CLIP

https://www.gaylordchemical.com/one-pot-benzimidazole-synthesis/

One Pot Benzimidazole Synthesis.

 FEBRUARY 5, 2012 ADMIN SYNTHESIS CORNER

A recent report (1) from workers at Chonnam National University (Gwangju, Korea)  describes a benzimidazole synthesis which:

• produces good product yields (40-98%, for about 30 examples)
• and proceeds in one pot from three readily available components: sodium azide, an aldehyde, and 2-haloanilines
• shows good functional group tolerance(nitro-, ester-, chloro-, and various heterocyclic functionalities on the aldehyde or haloaniline component).

The Benzimidazole Synthesis of Lee and coworkers (1)

Naturally, there are many established ways to synthesize benzimidazoles, which are important substances used in the design of bioactive substances (2).  Recent work has sought to address specific drawbacks associated with these methods, which can include harsh reaction conditions and complicated product mixtures.

Further developments have focused on the use of 2-haloacetanilides, 2-haloarylamidines, arylamino oximes, and N-arylbenzimidamides (3).  This work notable due to the useful anthelmintic properties. Anthelmintic agents work to kill or repel intestinal worms. A review (3) discusses the synthesis of benzimidazoles, and cites the breakthrough discovery of thiabendazole by researchers at Merck in 1961.  Thiabendazole was found to have potent broad spectrum activity against gastrointestinal parasites.

Early thiabendazole synthesis (3)

The initial synthesis of thiabendazole occured via dehydrative cyclization of 1,2 diaminobenzenze in polyphosphoric acid (PPA). The commercialized process involved the conversion of N-arylamidines using hypochlorite (4). Although this process can be performed in ‘one-pot’ fashion it is more typically performed in two steps.

The ‘one-pot’ benzimidazole synthesis described by Lee et. Al. is showcased by its ability to produce thiabendazole in one step, from readily available starting materials (2-haloanilines, thiazole-4-carboxaldehyde) – in 97% yield.

Their work builds on the report of Driver and coworkers (5) that showed that benzimidazoles could be had from 2-azidoanilines in good yield. Indeed, Lee proposes a mechanism that produces an azidoaldimine intermediate, which foregoes the multistep preparation of 2-azidoaniline starting materials.

One proposed mechanistic pathway is shown, with the following steps:

• initial in situ formation of an aldimine, via addition of aniline to an aldehyde;
• Ar-X insertion of the copper catalyst;
• Cu-azide association, with transfer of azide to the aromatic ring;
• loss of nitrogen with concomitant ring formation, and catalyst regeneration

One mechanistic explanation proposed by Lee and coworkers (1).

In developing their method, they investigated a number of factors:

• Solvent.  DMSO outperformed other polar solvents (NMP, DMF, DMAc).  Less polar solvents failed (toluene, diglyme).
• Source of Copper catalyst. The oxidation state of copper was not a factor, as Cu(I) and Cu(II) salts showed similar performance.
• Ligand Evaluation. Ligand selection was not a large factor. Several were tested; ultimately TMEDA was selected.
• Substituents on the aniline / pyridyl component. Base sensitive substituents were tolerated (benzoate ester) and 3-Cl groups were fine. The sensitivity to a broad range of substituents (the usual EWD- and ED-groups) was not rigorously determined
• Nature of the haloaniline. Although both bromo- and iodoaniline examples were given, the predominance of iodoaniline examples suggests it was prefered by the authors for unstated reasons.
• Reactivity of various aldehyde reactants. Aldehydes of varying classes were evaluated. Yields from aromatic substrates bearing ED groups(benzaldehyde, 4-Cl benzaldehyde, 4-methoxybenzaldehyde) produced the highest product yields.  Aliphatic aldehydes produced noticeably lower yields, with the curious exception of pivaldehyde. Several heterocyclic aldehydes (2- furyl- and 2-thionylaldehyde were tested and provided good results.

A synopsis of the Lee Procedure follows:

CuCl (0.1 mmol), haloaniline (2.0 mmol), TMEDA (0.1 mmol), NaN3 (4.0 mmol), aldehyde (2.4 mmol) were combined in DMSO  mL), The mixture was heated at 120 C for 12 hours. After cooling to room temperature the mixture was poured onto EtOAc (50 mL), washed with brine (25 mL) and water (25 mL). The organic phase was dried over Mg2SO4, and the residue from evaporation was purified by column chromatography (1:1 hexane / EtOAc mobile phase).

Artie McKim.

(1) Kim, Y.; Kumar, M.R.; Park, N.; Heo, Y.; Lee, S. J. Org. Chem. 2011, 76, 9577-9583.
(2) Tumulty, D.; Cao, K.; Homes, C.P. Org Lett. 2001, 3, 83.; Wu, Z. Rea. P.; Wickham, G.; Tetrahedron Lett. 2000, 41, 9871.;  Chari, M.A.; Shobha, P.S.D.;  Mukkanti, K. J. Heterocycl. Chem.2010, 47, 153.
(3) Townsend, L.B.; Wise, D.S. Parasitology Today 6, 4 (1990) 107-112.
(4) Grenda, V. J.; Jones, R.E; Gal,G.; Sletzinger J. Org Chem. 30 (1965), 259-261.
(5) Shen, M.; Driver, T.G. Org Lett. 2008, 10, 3367.

References

• Thiabendazole, Extension Toxicology Network
• Medicinenet: Thiabendazole – Oral

Tiabendazole

Clinical data
Trade names	Mintezol, others
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: B3
Routes of administration	By mouth, topical
ATC code	D01AC06 (WHO) P02CA02 (WHO) QP52AC10 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	Сmax 1–2 hours (oral administration)
Metabolism	GI tract
Elimination half-life	8 hours
Excretion	Urine (90%)
Identifiers
IUPAC name[show]
CAS Number	148-79-8
PubChem CID	5430
IUPHAR/BPS	7304
DrugBank	DB00730
ChemSpider	5237
UNII	N1Q45E87DT
KEGG	D00372
ChEMBL	ChEMBL625
NIAID ChemDB	007903
ECHA InfoCard	100.005.206
Chemical and physical data
Formula	C10H7N3S
Molar mass	201.249 g/mol
3D model (JSmol)	Interactive image
Density	1.103 g/cm3
Melting point	293 to 305 °C (559 to 581 °F)
SMILES[hide] [nH]1c2ccccc2nc1c3cscn3
InChI[hide] InChI=1S/C10H7N3S/c1-2-4-8-7(3-1)12-10(13-8)9-5-14-6-11-9/h1-6H,(H,12,13)  Key:WJCNZQLZVWNLKY-UHFFFAOYSA-N

Synthesis Reference

Lynn E. Applegate, Carl A. Renner, “Preparation of high purity thiabendazole.” U.S. Patent US5310923, issued October, 1977.

US5310923

/////////////////MK 360, MK-360, NSC-525040,  NSC-90507, チアベンダゾール, TIABENDAZOLE, тиабендазол , تياباندازول , 噻苯达唑 , 

Viloxazine

• Molecular FormulaC₁₃H₁₉NO₃
• Average mass237.295 Da

Morpholine, 2-[(2-ethoxyphenoxy)methyl]-

UNII:5I5Y2789ZF

Viloxazine hydrochloride

OQW30I1332

35604-67-2

Polymorph

FORM A , B US226136693, US2011032013

Viloxazine (trade names Vivalan, Emovit, Vivarint and Vicilan) is a morpholine derivative and is a selective norepinephrine reuptake inhibitor (NRI). It was used as an antidepressant in some European countries, and produced a stimulant effect that is similar to the amphetamines, except without any signs of dependence. It was discovered and brought to market in 1976 by Imperial Chemical Industries and was withdrawn from the market in the early 2000s for business reasons.

Clip

https://www.sciencedirect.com/science/article/pii/S0040402015302659

Patent

US 20180265482

https://patentscope.wipo.int/search/en/detail.jsf?docId=US226136693&tab=PCTDESCRIPTION&maxRec=1000

Uses

Viloxazine hydrochloride was used in some European countries for the treatment of clinical depression.^[4][5]

Side effects

Side effects included nausea, vomiting, insomnia, loss of appetite, increased erythrocyte sedimentation, EKG and EEG anomalies, epigastric pain, diarrhea, constipation, vertigo, orthostatic hypotension, edema of the lower extremities, dysarthria, tremor, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, seizure, (there were three cases worldwide, and most animal studies (and clinical trials that included epilepsy patients) indicated the presence of anticonvulsant properties, so was not completely contraindicated in epilepsy,^[6]) and increased libido.^[7]

Drug interactions

Viloxazine increased plasma levels of phenytoin by an average of 37%.^[8] It also was known to significantly increase plasma levels of theophylline and decrease its clearance from the body,^[9] sometimes resulting in accidental overdose of theophylline.^[10]

Mechanism of action

Viloxazine, like imipramine, inhibited norepinephrine reuptake in the hearts of rats and mice; unlike imipramine, it did not block reuptake of norepinephrine in either the medullae or the hypothalami of rats. As for serotonin, while its reuptake inhibition was comparable to that of desipramine (i.e., very weak), viloxazine did potentiate serotonin-mediated brain functions in a manner similar to amitriptyline and imipramine, which are relatively potent inhibitors of serotonin reuptake.^[11] Unlike any of the other drugs tested, it did not exhibit any anticholinergic effects.^[11]

It was also found to up-regulate GABA_B receptors in the frontal cortex of rats.^[12]

Chemical properties

It is a racemic compound with two stereoisomers, the (S)-(–)-isomer being five times as pharmacologically active as the (R)-(+)-isomer.^[13]

History

Viloxazine was discovered by scientists at Imperial Chemical Industries when they recognized that some beta blockers inhibited serotonin reuptake inhibitor activity in the brain at high doses. To improve the ability of their compounds to cross the blood brain barrier, they changed the ethanolamine side chain of beta blockers to a morpholine ring, leading to the synthesis of viloxazine.^{[14]:610[15]:9} The drug was first marketed in 1976.^[16] It was never approved by the FDA,^[5] but the FDA granted it an orphan designation (but not approval) for cataplexy and narcolepsy in 1984.^[17] It was withdrawn from markets worldwide in 2002 for business reasons.^[14][18]

As of 2015, Supernus Pharmaceuticals was developing formulations of viloxazine as a treatment for ADHD and major depressive disorder under the names SPN-809 and SPN-812.^[19][20]

Research

Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bedwetting) in children, both of those times versus imipramine.^[21][22] By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.^[23]

In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM^[24] without really improving daytime somnolence.^[25]

In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy.^[18]

Viloxazine has also been studied for the treatment of alcoholism, with some success.^[26]

While viloxazine may have been effective in clinical depression, it did relatively poorly in a double-blind randomized controlled trial versus amisulpride in the treatment of dysthymia.^[27]

It is also under investigation as a treatment for attention deficit hyperactivity disorder.^[28]

REFERNCES

Viloxazine

Clinical data
Routes of administration	By mouth, intravenous infusion[1]
ATC code	N06AX09 (WHO)
Legal status
Legal status	In general: uncontrolled
Pharmacokinetic data
Elimination half-life	2–5 hours
Excretion	Renal[2]
Identifiers
IUPAC name[show]
CAS Number	46817-91-8  35604-67-2 (HCl salt)
PubChem CID	5666
ChemSpider	5464
UNII	5I5Y2789ZF
KEGG	D08673
ChEMBL	ChEMBL306700
ECHA InfoCard	100.051.148
Chemical and physical data
Formula	C13H19NO3
Molar mass	237.295 g/mol g·mol−1
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES[hide] O(c1ccccc1OCC)CC2OCCNC2
InChI[hide] InChI=1S/C13H19NO3/c1-2-15-12-5-3-4-6-13(12)17-10-11-9-14-7-8-16-11/h3-6,11,14H,2,7-10H2,1H3  Key:YWPHCCPCQOJSGZ-UHFFFAOYSA-N

/////////////////Viloxazine, ヴィロキサジン , Emovit, Vivalan, Emovit, Vivarint, Vicilan

Cenobamate
CAS: 913088-80-9
Chemical Formula: C10H10ClN5O2
Molecular Weight: 267.67

Related CAS #: 913088-80-9   913087-59-9

Synonym: YKP-3089; YKP3089; YKP3089; Cenobamate

IUPAC/Chemical Name: (R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl carbamate

• 2H-Tetrazole-2-ethanol, α-(2-chlorophenyl)-, carbamate (ester), (αR)- (9CI)
• (1R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl carbamate
• Carbamic acid (R)-(+)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl ester
• 2H-Tetrazole-2-ethanol, α-(2-chlorophenyl)-, 2-carbamate, (αR)-

Cenobamate, also known as YKP-3089, is a novel new antiepileptic drug candidate. Cenobamate showed broad-spectrum anticonvulsant activity. Cenobamate entered into clinical trials and was discontinued in 2015.

PATENT

WO 2006112685

SK HOLDINGS CO., LTD. [KR/KR]; 99 Seorin-dong Jongro-ku Seoul 110-110, KR

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006112685

Patent

US 20100323410

PATENT

WO 2011046380

https://patentscope.wipo.int/search/en/detail.jsf%3Bjsessionid=9CF54FB903EC3DFB7B3237259E6419EB.wapp2?docId=WO2011046380&recNum=36&office=&queryString=&prevFilter=%26fq%3DOF%3AIL%26fq%3DICF_M%3A%22C07D%22&sortOption=Relevance&maxRec=1345

In terms of a selection of reaction, as there are two reaction sites in each (R)-2-aryl-oxirane and tetrazole, the ring-opening reaction therebetween affords the substitution of 1N- or 2N-tetrazole at the benzyl or terminal position, resulting in a mixture of a total of 4 positional isomers. Therefore, individual positional isomers are low in production yield and difficult to isolate and purify.

Preparation Example 1: Preparation of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one

To a suspension of 2-bromo-2′-chloroacetophenone (228.3 g, 0.978 mol) and potassium carbonate (161.6 g, 1.170 mol) in acetonitrile (2000 mL) was added a 35 w/w% 1H-tetrazole dimethylformamide solution (215.1 g, 1.080 mol) at room temperature. These reactants were stirred for 2 h at 45℃ and distilled under reduced pressure to remove about 1500 mL of the solvent. The concentrate was diluted in ethyl acetate (2000 mL) and washed with 10% brine (3 x 2000 mL). The organic layer thus separated was distilled under reduced pressure to afford 216.4 g of an oily solid residue. To a solution of the solid residue in ethyl acetate (432 mL) was slowly added heptane (600 mL). The precipitate thus formed was filtered at room temperature and washed to yield 90.1 g (0.405 mol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one (hereinafter referred to as 1N ketone ).

¹H-NMR(CDCl ₃) 8.87(s, 1H), d7.77(d, 1H), d7.39-7.62(m, 3H), d5.98(s, 2H)

Preparation Example 2: Preparation of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one

After the filtration of Preparation Example 1, the filtrate was concentrated and dissolved in isopropanol (100 mL), and to which heptane (400 mL) was then added to complete the crystallization. Filtering and washing at 5℃ afforded 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one (hereinafter referred to as “2N ketone”) as a solid. 94.7 g (0.425 mol).

¹H-NMR(CDCl ₃) d8.62(s, 1H), d7.72(d, 1H), d7.35-7.55(m, 3H), d6.17(s, 2H)

PREPARATION EXAMPLE 3: Preparation of Alcohol Compound of (R)-Configuration by enantioselective enzymatic reduction via various oxidoreductases

The following four solutions were prepared as follows:

Enzyme Solution 1

Competent Escherichia coli StarBL21(De3) cells (Invitrogen) were transformed with the expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 1. The Escherichia coli colonies transformed with the resulting expression constructs were then cultivated in 200 mL of LB medium (1% tryptone, 0.5 % yeast and 1% sodium chloride) with 50 micrograms/mL of ampicillin or 40 micrograms/mL of kanamycin, respectively, until an optical density of 0.5, measured at 550 nm, was achieved. The expression of the desired recombinant protein was induced by the addition of isopropylthiogalactoside (IPTG) to a concentration of 0.1 mM. After 16 hours of induction at 25 ℃ and 220 rpm, the cells were harvested and frozen at -20 ℃. In the preparation of the enzyme solutions, 30 g of cells were resuspended in 150 mL of triethanolamine buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8) and homogenized in a high pressure homogenizer. The resultant enzyme solution was mixed with 150 mL glycerol and stored at -20℃.

Enzyme Solution 2

RB791 cells ( E.coli genetic stock, Yale, USA) were transformed with the expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 2. The Escherichia coli colonies transformed with the resulting expression constructs were then cultivated in 200 mL of LB medium (1% tryptone, 0.5 % yeast and 1% sodium chloride) with 50 micrograms/mL of ampicillin or 40 micrograms/mL of kanamycin, respectively, until an optical density of 0.5, measured at 550 nm, was achieved. The expression of the desired recombinant protein was induced by the addition of isopropylthiogalactoside (IPTG) to a concentration of 0.1 mM. After 16 hours of induction at 25℃ and 220 rpm, the cells were harvested and frozen at -20℃. In the preparation of the enzyme solutions, 30 g of cells were resuspended in 150 mL of triethanolamine buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8) and homogenized in a high pressure homogenizer. The resultant enzyme solution was mixed with 150 mL glycerol and stored at -20℃.

Enzyme Solution 3

Enzyme solutions 3 was prepared in the same manner as described in Enzyme solution 1 except that expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 3 instead of expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 1 was used.

Enzyme Solution 4

Enzyme solutions 4 was prepared in the same manner as described for enzyme solution 2 except that expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 4 instead of expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 2 was used.

Different oxidoreductases contained in each enzyme solutions 1 to 4 were examined as follows for the conversion of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one (1N ketone) and 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one (2N ketone) to the corresponding 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-ol (hereinafter, referred to as 1N alcohol ) and 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (hereinafter, referred to as “2N alcohol”), respectively.

Reaction batch A

160 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8)

100 ㎕ NADPH (40 mg/ml)

40 ㎕ 2-propanol

50 ㎕ enzyme solution 1

2 mg 1N ketone or 2N ketone

Reaction batch B

160 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8)

100 ㎕ NADPH (40 mg/ml)

40 ㎕ 2-propanol

50 ㎕ enzyme solution 2

2 mg 1N ketone or 2N ketone

Reaction batch C

350 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8)

0,05 mg NADP

50 ㎕ enzyme solution 3

10 mg 1N ketone or 2N ketone

250 ㎕ 4-methyl-2-pentanol

50 ㎕ enzyme (oxidoreductase from Thermoanerobium brockii) solution for regeneration of cofactor

Reaction batch D

350 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8

0,05 mg NADP

50 ㎕ enzyme solution 4

10 mg 1N ketone or 2N ketone

250 ㎕ 4-methyl-2-pentanol

50 ㎕ enzyme (oxidoreductase from Thermoanerobium brockii) solution for regeneration of cofactor

After 24h of incubating each reaction batch A, B, C and D, 1 mL of acetonitrile was added to each reaction batch which was centrifuged and transferred into a HPLC analysis vessel for enantiomeric excess and conversion. Conversion and ee-value of products are listed in Table 1 below calculated using the following equations:

Conversion Rate (%) = [(Area of Product)/(Area of Reactant + Area of Product)]x100

ee-value(%) = [(Area of R-Configuration – Area of S-Configuration)/(Area of R-Configuration + Area of S-Configuration)] x 100

Table 1 [Table 1] 

PREPARATION EXAMPLE 4: Enzymatic reduction via oxidoreductase SEQ NO: 2

For the conversion of 1N/2N ketone to R-1N/R-2N alcohol, 30㎕ of the enzyme solution 2 containing the oxidoreductase SEQ NO: 2 were added to a mixture of 300㎕ of a buffer (100 mM TEA, pH 8, 1mM MgCl2, 10% glycerol), 100mg of a mixture of 1N ketone and 2N ketone (1N:2N=14%:86%), 0.04mg NADP and 300㎕ 2-butanol. The reaction mixture was incubated at room temperature under constant thorough mixing. After 48 hours, more than 98% of the ketones were reduced to an alcohol mixture of the following composition(R-2N alcohol 80%; S-2N alcohol 0%; R-1N alcohol 20%, S-1N alcohol 0%; 1N ketone 0%; 2N ketone 0%).

After general work up and recrystallization with ethyl acetate/hexane, optically pure alcohols were obtained as below:

(R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-ol (1N alcohol

¹H-NMR(CDCl ₃) d8.74(s, 1H), d7.21-7.63(m, 4H), d5.57(m, 1H), d4.90(d, 1H), d4.50(d, 1H), d3.18(d, 1H);

(R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (2N alcohol)

¹H-NMR(CDCl ₃) d8.55(s, 1H), d7.28-7.66(m, 4H), d5.73(d, 1H), d4.98(d, 1H), d4.83(d, 1H), d3.38(br, 1H).

Preparation of Carbamate

Preparation Example 5: Preparation of Carbamic Acid (R)-1-(2-Chlorophenyl)-2-(tetrazol-2-yl)ethyl ester

50ml of the enzyme solution 2 containing the oxidoreductase SEQ NO: 2 were added to a mixture of 250ml of a buffer (100 mM TEA, pH 8, 1mM MgCl2, 10% glycerol), 50g (225mmol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one(2N ketone), 4mg NAD, 300 ml of 2-propanol and 150mL of butyl acetate. The reaction mixture was stirred at room temperature. After 48 hours more than 98% of 2N ketone was reduced to corresponding (R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (R-2N alcohol) with >99%ee values. To this resulting mixture, 500mL of ethyl acetate was added. After being separated, the organic layer thus formed was washed with 10% brine (3 x 500mL). The organic layer thus formed was dried over magnesium sulfate and filtered and the filtrate was distilled under reduced pressure to give 50.4g (224 mmol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (R-2N alcohol, optical purity 99.9%) as an oily residue. To this resulting crude product, 450mL of tetrahydrofuran was added. After cooling to -15℃, 38g (267mmol) of chlorosulfonyl isocyanate was slowly added and stirred at -10℃ for 2 h. The slow addition of water induced termination of the reaction. The resulting solution was concentrated under reduced pressure until about 300 mL of the solvent was removed. The concentrate was diluted with 600mL of ethyl acetate and washed with 10% brine (3 x 500 mL). The organic layer was concentrated under reduced pressure and the concentrate was dissolved in isopropanol (90 mL) to which heptane (180 mL) was slowly added, leading to the completion of crystallization. The precipitate thus obtained was filtered and washed to afford 51.8 g (194 mmol) of carbamic acid (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl ester (optical purity 99.9%).

¹H-NMR(Acetone-d ₆) d8.74(s, 1H), d7.38-7.54(m, 4H), d6.59(m, 1H), d6.16(Br, 2H), d4.90(d, 1H), d5.09(m, 2H)

As described hitherto, carbamate compounds with high optical and chemical purity can be produced with an economical benefit in accordance with the present invention.

Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.

AMINO ACID SEQUENCES

SEQ ID NO 1: Oryctolagus cuniculus from rabbit DSMZ 22167

SEQ ID NO 2: Candida magnoliae DSMZ 22052 protein sequence carbonyl reductase

SEQ ID NO 3: Candida vaccinii CBS7318 protein sequence carbonyl reductase

SEQ ID NO 4: Candida magnoliae CBS6396 protein sequence carbonyl reductase

NUCLEIC ACID SEQUENCES

SEQ ID NO 5: Oryctolagus cuniculus from rabbit DSMZ 22167

SEQ ID NO 6: Candida magnoliae DSMZ 22052 nucleic acid sequence carbonyl reductase

SEQ ID NO 7: Candida vaccinii CBS7318 nucleic acid sequence carbonyl reductase

SEQ ID NO 8: Candida magnoliae CBS6396 nucleic acid sequence carbonyl reductase