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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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TIABENDAZOLE, тиабендазол , تياباندازول , 噻苯达唑 , チアベンダゾール;


ChemSpider 2D Image | Tiabendazole | C10H7N3S

Thiabendazole.svg

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;
1436
148-79-8 [RN]
1H-Benzimidazole, 2-(4-thiazolyl)-
2-(1,3-Thiazol-4-yl)-1H-benzimidazole
2-(4-Thiazoly)benzimidazole
205-725-8 [EINECS]
28558-32-9 [RN]
90507-06-5 [RN]
Arbotect [Trade name]
Benzimidazole, 2-(4-thiazolyl)-
Mintezol [Trade name]
N1Q45E87DT
MK 360 / MK-360 / NSC-525040 / NSC-90507

Tiabendazole (INNBAN), thiabendazole (AANUSAN), 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
CAS Registry Number: 148-79-8
CAS Name: 2-(4-Thiazolyl)-1H-benzimidazole
Additional Names: 4-(2-benzimidazolyl)thiazole
Manufacturers’ Codes: MK-360
Trademarks: Equizole (Merial); Mertect (Syngenta); Mintezol (Merck & Co.); Tecto (Syngenta)
Molecular Formula: C10H7N3S
Molecular Weight: 201.25
Percent Composition: C 59.68%, H 3.51%, N 20.88%, S 15.93%
Literature References: Prepd by the reaction of 4-thiazolecarboxamide with o-phenylenediamine in polyphosphoric acid: H. D. Brown et al., J. Am. Chem. Soc. 83, 1764 (1961); L. H. Sarett, H. D. Brown, US 3017415 (1962 to Merck & Co.). Synthesis of labeled thiabendazole: D. J. Tocco et al., J. Med. Chem. 7, 399 (1964). Alternate route of synthesis: V. J. Grenda et al., J. Org. Chem. 30, 259 (1965). Anthelmintic props: H. D. Brown et al., loc. cit.; K. C. Kates et al., J. Parasitol. 57, 356 (1971). Fungicidal props: H. J. Robinson et al., J. Invest. Dermatol. 42, 479 (1966). Systemic props in plants: D. C. Erwin et al., Phytopathology 58,860 (1968). Toxicity: H. J. Robinson et al., Toxicol. Appl. Pharmacol. 7, 53 (1965). Residue analysis: IUPAC Appl. Chem. Div., Pure Appl. Chem. 52, 2567 (1980). Comprehensive description: V. K. Kapoor, Anal. Profiles Drug Subs. 16, 611-639 (1986).
Properties: Colorless crystals, mp 304-305°. uv max (methanol): 298 nm (e 23330). Fluorescence max in acid soln: 370 nm (310 nm excitation). Max soly in water at pH 2.2: 3.84%. Soluble in DMF, DMSO. Slightly soluble in alcohols, esters, chlorinated hydrocarbons. LD50 in mice, rats, rabbits (g/kg): 3.6, 3.1, >3.8 orally (Robinson).
Melting point: mp 304-305°
Absorption maximum: uv max (methanol): 298 nm (e 23330)
Toxicity data: LD50 in mice, rats, rabbits (g/kg): 3.6, 3.1, >3.8 orally (Robinson)
Derivative Type: Hypophosphite
CAS Registry Number: 28558-32-9
Trademarks: Arbotect (Syngenta)
Properties: Amber liquid. d25 1.103.
Density: d25 1.103
Use: Fungicide for spoilage control of citrus fruit; for treatment and prevention of Dutch elm disease in trees; for control of fungal diseases of seed potatoes.
Therap-Cat: Anthelmintic (Nematodes).
Therap-Cat-Vet: Anthelmintic, fungicide.
Keywords: Anthelmintic (Nematodes).

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

FIGURE 1

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

Uses

Preservative

It is used primarily to control moldblight, 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 leadmercury, 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

Thiabendazole synthesis:[12] L. H. Sarett, H. D. Brown, U.S. Patent 3,299,081 (1967 to Merck & Co.).

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 preparation and activity studies:[15][16]

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.

front page image

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

One Pot Benzimidazole Synthesis.

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).

Kim-et-al-benzimidazole-JOC-20122

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.

thiabendazole

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

benzimidazolw-mechanism-Lee1One 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. 201176, 9577-9583.
(2) Tumulty, D.; Cao, K.; Homes, C.P. Org Lett. 2001, 3, 83.; Wu, Z. Rea. P.; Wickham, G.; Tetrahedron Lett. 200041, 9871.;  Chari, M.A.; Shobha, P.S.D.;  Mukkanti, K. J. Heterocycl. Chem.201047, 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. 200810, 3367.

References

  1. ^ “E233 : E Number : Preservative”http://www.ivyroses.com. Retrieved 2018-08-28.
  2. ^ Upadhyay MP, West EP, Sharma AP (January 1980). “Keratitis due to Aspergillus flavus successfully treated with thiabendazole”Br J Ophthalmol64 (1): 30–2. doi:10.1136/bjo.64.1.30PMC 1039343PMID 6766732.
  3. ^ Igual-Adell R, Oltra-Alcaraz C, Soler-Company E, Sánchez-Sánchez P, Matogo-Oyana J, Rodríguez-Calabuig D (December 2004). “Efficacy and safety of ivermectin and thiabendazole in the treatment of strongyloidiasis”Expert Opin Pharmacother5 (12): 2615–9. doi:10.1517/14656566.5.12.2615PMID 15571478. Archived from the original on 2016-03-06.
  4. ^ Portugal R, Schaffel R, Almeida L, Spector N, Nucci M (June 2002). “Thiabendazole for the prophylaxis of strongyloidiasis in immunosuppressed patients with hematological diseases: a randomized double-blind placebo-controlled study”Haematologica87 (6): 663–4. PMID 12031927.
  5. ^ Cha, HJ; Byrom M; Mead PE; Ellington AD; Wallingford JB; et al. (August 2012). “Evolutionarily Repurposed Networks Reveal the Well-Known Antifungal Drug Thiabendazole to Be a Novel Vascular Disrupting Agent”PLoS Biology10 (8): e1001379. doi:10.1371/journal.pbio.1001379PMC 3423972PMID 22927795. Retrieved 2012-08-21.
  6. ^ Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990., p. 970
  7. ^ Rosenblum, C (March 1977). “Non-Drug-Related Residues in Tracer Studies”. Journal of Toxicology and Environmental Health2 (4): 803–14. doi:10.1080/15287397709529480PMID 853540.
  8. ^ Sax, N.I. Dangerous Properties of Industrial Materials. Vol 1-3 7th ed. New York, NY: Van Nostrand Reinhold, 1989., p. 3251
  9. ^ UK Food Standards Agency: “Current EU approved additives and their E Numbers”. Retrieved 2011-10-27.
  10. ^ Australia New Zealand Food Standards Code“Standard 1.2.4 – Labelling of ingredients”. Retrieved 2011-10-27.
  11. ^ “Reregistration Eligibility Decision THIABENDAZOLE” (PDF). Environmental Protection Agency. Retrieved 8 January 2013.
  12. ^ Setzinger, Meyer; Painfield, North; Gaines, Water A.; Grenda, Victor J. (1965). “Novel Preparation of Benzimidazoles from N-Arylamidines. New Synthesis of Thiabendazole1”. The Journal of Organic Chemistry30: 259–261. doi:10.1021/jo01012a061.
  13. ^ Brown, H. D.; Matzuk, A. R.; Ilves, I. R.; Peterson, L. H.; Harris, S. A.; Sarett, L. H.; Egerton, J. R.; Yakstis, J. J.; Campbell, W. C.; Cuckler, A. C. (1961). “Antiparasitic Drugs. Iv. 2-(4′-Thiazolyl)-Benzimidazole, A New Anthelmintic”. Journal of the American Chemical Society83 (7): 1764–1765. doi:10.1021/ja01468a052.
  14. ^ Tocco, D. J.; Buhs, R. P.; Brown, H. D.; Matzuk, A. R.; Mertel, H. E.; Harman, R. E.; Trenner, N. R. (1964). “The Metabolic Fate of Thiabendazole in Sheep1”. Journal of Medicinal Chemistry7 (4): 399–405. doi:10.1021/jm00334a002.
  15. ^ Hoff, Fisher, ZA 6800351 (1969 to Merck & Co.), C.A. 72, 90461q (1970).
  16. ^ Hoff, D. R.; Fisher, M. H.; Bochis, R. J.; Lusi, A.; Waksmunski, F.; Egerton, J. R.; Yakstis, J. J.; Cuckler, A. C.; Campbell, W. C. (1970). “A new broad-spectrum anthelmintic: 2-(4-Thiazolyl)-5-isopropoxycarbonylamino-benzimidazole”. Experientia26 (5): 550–551. doi:10.1007/BF01898506.
  17. ^ Chronicles of Drug Discovery, Book 1, pp 239-256.
Tiabendazole
Thiabendazole.svg
Thiabendazole ball-and-stick.png
Clinical data
Trade names Mintezol, others
AHFS/Drugs.com International Drug Names
Pregnancy
category
Routes of
administration
By mouthtopical
ATC code
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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
NIAID ChemDB
ECHA InfoCard 100.005.206 Edit this at Wikidata
Chemical and physical data
Formula C10H7N3S
Molar mass 201.249 g/mol
3D model (JSmol)
Density 1.103 g/cm3
Melting point 293 to 305 °C (559 to 581 °F)

Synthesis Reference

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

US5310923

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

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


1228646-70-5.png

Nalmefene sceletal.svg

str1

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)-

Formula
C21H25NO3. HCl. 2H2O
CAS
1228646-70-5
5096-26-9 free form
58895-64-0 (Nalmefene HCl)
Mol weight
411.9196

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

Approval Date Approval Type Trade Name Indication Dosage Form Strength Company Review Classification
2013-11-13 Marketing approval Respiratory depression Injection 1 ml:0.1 mg 灵宝市豫西药业 3.1类
2013-09-22 Marketing approval 抒纳 Respiratory depression Injection 1 ml:0.1 mg(以纳美芬计) 辽宁海思科制药 3.1类
2013-08-02 Marketing approval 乐萌 Respiratory depression Injection 1 ml:0.1 mg 成都天台山制药 3.1类
2012-12-31 Marketing approval Respiratory depression Injection 1 ml:0.1 mg (以C21H25NO3计) 北京四环制药
2012-05-15 Marketing approval Respiratory depression Injection 1 ml:0.1 mg 西安利君制药

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

str1

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.

PATENTS AND GENERICS

The original product patent was based on US 03814768 which expired in 1991. However, a number of patents cover formulations and use. Lundbeck and Biotie have a family based on WO 2010063292 which claims novel crystal forms and hydrate salts, in particular Nalmefene hydrochloride dihydrate, and their use in alcohol dependence.  There are European and US patents granted on this EP 02300479 will expire December 2029 and US-08530495 will expire August 2030.

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) (Ki = 0.24 nM) and as a weak partial agonist (Ki = 0.083 nM; Emax = 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) (Ki = 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.

Image result for nalmefene synthesis

PAPER

JMed. Chem197518, 259-262

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

PATENT

WO 2010136039

PATENT

US 3814768

Mol. Formula:   C21H25NO3
Appearance:   Off-White to Pale Yellow Solid
Melting Point:   182-185˚C
Mol. Weight:   339.43

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

Properties

  • Soluble in water up to 130 mg/mL, soluble in chloroform up to 0.13 mg/mL
  • pKa 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 :

Figure imgf000007_0001

Methyltriphenylphosphonium salt Methylene triphenylphosphorane Yhde

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

Figure imgf000007_0002

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

Figure imgf000019_0001

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

Figure US08598352-20131203-C00003

Lundbeck’s novel alcohol dependency drug has been endorsed by the National Institute for Health and Care Excellence (NICE) for use in Britain’s state health service.

read at

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
Nalmefene sceletal.svg

References

  1. ^ NCT00132119 ClinicalTrials.gov
  2. Jump up to:a b See: “Drug Record: Nalmefene”LiverToxNational Library of Medicine. 24 March 2016.
  3. ^ Label information. U.S. Food and Drug Administration“Archived copy” (PDF). Archived from the original on October 13, 2006. Retrieved 2014-11-07.
  4. ^ Based on: Stephens, Everett. “Opioid Toxicity Medication » Medication Summary”Medscape. WebMD LLC.
  5. ^ “Selincro 18mg film-coated tablets”. UK Electronic Medicines Compendium. September 2016.
  6. ^ “Technology appraisal guidance [TA325]: Nalmefene for reducing alcohol consumption in people with alcohol dependence”. NICE. 26 November 2014.
  7. Jump up to:a b Palpacuer, C; Laviolle, B; Boussageon, R; Reymann, JM; Bellissant, E; Naudet, F (December 2015). “Risks and benefits of nalmefene in the treatment of adult alcohol dependence: a systematic literature review and meta-analysis of published and unpublished double-blind randomized controlled trials”PLOS Medicine12 (12): e1001924. doi:10.1371/journal.pmed.1001924PMC 4687857PMID 26694529.
  8. Jump up to:a b Paille, François; Martini, Hervé (2014). “Nalmefene: a new approach to the treatment of alcohol dependence”Substance Abuse and Rehabilitation5 (5): 87–94. doi:10.2147/sar.s45666PMC 4133028PMID 25187751.
  9. ^ “Selincro”European Medicines Agency. Retrieved 3 November 2015.
  10. Jump up to:a b c d Bart, G; Schluger, JH; Borg, L; Ho, A; Bidlack, JM; Kreek, MJ (December 2005). “Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity?” (PDF)Neuropsychopharmacology30 (12): 2254–62. doi:10.1038/sj.npp.1300811PMID 15988468.
  11. ^ Bart G, Schluger JH, Borg L, Ho A, Bidlack JM, Kreek MJ (2005). “Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity?”Neuropsychopharmacology30 (12): 2254–62. doi:10.1038/sj.npp.1300811PMID 15988468.
  12. Jump up to:a b Linda P. Dwoskin (29 January 2014). Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Elsevier Science. pp. 398–. ISBN 978-0-12-420177-4.
  13. Jump up to:a b Niciu, Mark J.; Arias, Albert J. (2013). “Targeted opioid receptor antagonists in the treatment of alcohol use disorders”CNS Drugs27 (10): 777–787. doi:10.1007/s40263-013-0096-4ISSN 1172-7047PMC 4600601PMID 23881605.
  14. ^ “Nalmefene (new drug) Alcohol dependence: no advance”Prescrire International23(150): 150–152. 2014. PMID 25121147. (subscription required)
  15. ^ Stephen M. Stahl (15 May 2014). Prescriber’s guide: Stahl’s essential psychopharmacology. Cambridge University Press. pp. 465–. ISBN 978-1-139-95300-9.
  16. ^ Grosshans M, Mutschler J, Kiefer F (2015). “Treatment of cocaine craving with as-needed nalmefene, a partial κ opioid receptor agonist: first clinical experience”. International Clinical Psychopharmacology30 (4): 237–8. doi:10.1097/YIC.0000000000000069PMID 25647453.
  17. ^ Fulton, Brian S. (2014). Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies. John Wiley & Sons. p. 341. ISBN 9781118889572.
  18. ^ See: “Baxter discontinues Revex injection”Monthly Prescribing Reference website. Haymarket Media, Inc. 9 July 2008. Retrieved 10 October 2016.
  19. ^ “Drug Shortages”. FDA Center for Drug Evaluation and Research. Archived from the original on 26 December 2008.
  20. ^ “Efficacy of nalmefene in patients with alcohol dependence (ESENSE1)”.
  21. ^ “Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan”. The Pharma Letter. 22 December 2011.
  22. ^ “Selincro”European Medicines Agency. 13 March 2013.
  23. ^ “Alcohol cravings drug nalmefene granted approval in Scotland”. BBC News. 7 October 2013.
  24. ^ “Nalmefene granted approval in England”The Independent. 3 October 2014.
  25. ^ “Alcohol dependence treatment accepted for NHS use”. MIMS. 26 November 2014.
  26. ^ Bidlack, Jean M (2014). “Mixed κ/μ partial opioid agonists as potential treatments for cocaine dependence”. Adv. Pharmacol69: 387–418. doi:10.1016/B978-0-12-420118-7.00010-XPMID 24484983.
Nalmefene
Nalmefene sceletal.svg
Clinical data
Trade names Selincro
AHFS/Drugs.com Monograph
MedlinePlus a605043
License data
Routes of
administration
By mouth, intravenous
ATC code
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
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
ECHA InfoCard 100.164.948 Edit this at Wikidata
Chemical and physical data
Formula C21H25NO3
Molar mass 339.43 g/mol
3D model (JSmol)

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
NALMEFENE
17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol
Sihuan Pharmaceutical Holdings Group Ltd a leading pharmaceutical company with the largest cardio-cerebral vascular drug franchise in China’s prescription market, announced that the new Category 3.1 drug, the Nalmefene Hydrochloride Injection received a new drug certificate (H20120078) and approval for production (2012S00818) from the State Food and Drug Administration. Nalmefene Hydrochloride is yet another generic drug for which the Company has received approval for production following the Roxatidine Acetate Hydrochloridefor Injection. It will be manufactured by Beijing Sihuan Pharmaceutical Co., Ltd., a wholly-owned manufacturing subsidiary of the Company.
Nalmefene hydrochloride is a next generation opioid (opium) receptor inhibitor following Naloxone and Naltrexone. The injection formulation of Naloxone hydrochloride was invented by Ohmeda Pharmaceuticals and was approved by the US Food and Drug Administration (FDA) in 1995. The clinical uses of Nalmefene hydrochloride include anti-shock, neuroprotection, treatment for acute morphine poisoning, drug relapse prevention, recovery from the after-effects of anesthesia such as respiratory and nerve center depression and the treatment of unconsciousness persons.
The drug is also effective for treating heart failure and spinal cord injuries, for cerebral protection, etc. Multi-centre, randomized, blind, and positive-controlled clinical research of Nalmefene hydrochloride of Sihuan Pharmaceutical were performed by the Peking University First Hospital, the First Affiliated Hospital of China Medical University, Xijing Hospital (The First Affiliated Hospital of the Fourth Military Medical College) and Qingdao Municipal Hospital.

Compared to Naloxone, Nalmefene demonstrates longer curative effects and fewer adverse reactions. With its high bioavailability, biological activities and biofilm penetration ability, it helps to regulate respiration, circulation, digestion, and the endocrine and nervous systems. It is becoming a substitute for Naloxone, and has been included in Part B of the National Medicine Catalogue. At present, the size of the Nalmefene hydrochloride market in China is approximately RMB1 billion. As a substitution for Naloxone hydrochloride, Nalmefene hydrochloride has enormous market potential.
Diseases of the central nervous system (CNS) are common in China, which has an immense patient base. Due to the rapid pace of modern life, accelerated urbanisation and mental stress, the demand for CNS medicines has seen rapid growth in recent years given the rising number of patients. According to IMS, the size of the CNS drug market now exceeds RMB 23 billion. With the CNS drug market expected to reach RMB 100 billion in 2020, the Group sees great potential and strong growth prospects in the market.Dr. Che Fengsheng, Chairman and CEO of Sihuan Pharmaceutical, said, “Nalmefene Hydrochloride has shown better characteristics for treatment and higher clinical value than Naloxone. Its market demonstrates great potential to expand. Leveraging Sihuan Pharmaceutical’s strong marketing capabilities and extensive sales and distribution network, we believe that our market share for Nalmefene Hydrochloride will see rapid growth, which will strengthen our position in drugs for the treatment of major diseases of the central nervous system. Together with other new products, this will in turn enhance the continuous development and growth of Sihuan Pharmaceutical in China’s prescription drug market and create value for the shareholders and the Company.”

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

REVEX (nalmefene hydrochloride) Structural Formula Illustration

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 pKa 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

Ifetroban イフェトロバン


Ifetroban.svg

ChemSpider 2D Image | 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 | C25H32N2O5

Ifetroban.png

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;
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
Benzenepropanoic acid, 2-[[(1S,2R,3S)-3-[4-[(pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-
3-[2-[[(1S,5S,6R)-5-[4-(pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]heptan-6-yl]methyl]phenyl]propanoic acid
Benzenepropanoic acid, 2-((3-(4-((pentylamino)carbonyl)-2-oxazolyl)-7-oxabicyclo(2.2.1)hept-2-yl)methyl)-, (1S-(exo,exo))-
BMS 180,291
BMS 180291-02
BMS180291
BMS 18029; BMS 180291; BMS 180291A; BMS-180291-02; Boxaban; CPI 211; Hepatoren; Portaban; Vasculan

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)

ChemSpider 2D Image | Ifetroban sodium | C25H31N2NaO5

Ifetroban sodium

  • Molecular FormulaC25H31N2NaO5
  • Average mass462.514 Da
  • Monoisotopic mass462.213074 Da
156715-37-6 [RN]
Benzenepropanoic acid, 2-[[(1S,2R,3S,4R)-3-[4-[(pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-, sodium salt (1:1)
Ifetroban sodium
Sodium 3-[2-({(1S,2R,3S,4R)-3-[4-(pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl}methyl)phenyl]propanoate

Image result for Aceclofenac DRUG FUTURE

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

Org Process Res Dev 1997,1(1),14

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 Disposition28 (8): 973–80. PMID 10901709. Retrieved 5 October 2016.
Ifetroban
Ifetroban.svg
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C25H32N2O5
Molar mass 440.53 g/mol
3D model (JSmol)

////////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

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


Aceclofenac.png

Aceclofenac

アセクロフェナク

  • Molecular FormulaC16H13Cl2NO4
  • Average mass354.185 Da
(2-{2-[(2,6-Dichlorophenyl)amino]phenyl}acetoxy)acetic acid [ACD/IUPAC Name]
(2-{2-[(2,6-Dichlorphenyl)amino]phenyl}acetoxy)essigsäure [German] [ACD/IUPAC Name]
5608
89796-99-6 [RN]
Aceclofenac [BAN] [INN] [JAN] [Wiki]
acéclofénac [French] [INN]
Aceclofenaco [Spanish] [INN]
Aceclofenacum [Latin] [INN]
Acide (2-{2-[(2,6-dichlorophényl)amino]phényl}acétoxy)acétique [French] [ACD/IUPAC Name]
Benzeneacetic acid, 2-[(2,6-dichlorophenyl)amino]-, carboxymethyl ester [ACD/Index Name]
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, ES8404783idem,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.
Fig. 9

 Characterization of Aceclofenac by 1H NMR spectroscopy

1H NMR (400 MHz, DMSO-d6δ (ppm) 3.896 (s, 2H, Aliphatic –CH2), 4.634 (s, 2H, Aliphatic –CH2), 6.279 (d J= 8.00HZ, 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 HZ, 1H, Aromatic), 7.260 (d J= 8.00 HZ, 1H, Aromatic), 7.537 (d J= 8.4HZ, 2H, Aromatic), 13.076 (s, 1H, Carboxylic acid) …https://www.sciencedirect.com/science/article/pii/S2214180417301290

str1str2str3str4

 

 

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 arthritisosteoarthritis 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.

Image result for aceclofenac

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.

str1 str2 str3

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

ES 2046141

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

  1. ^ Karmoker, J.R.; Sarkar, S.; Joydhar, P.; Chowdhury, S.F. (2016). “Comparative in vitro equivalence evaluation of some Aceclofenac generic tablets marketed in Bangladesh” (PDF)The Pharma Innovation Journal5: 3–7. Retrieved 2016-09-01.
Sources

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
  • Use:non-steroidal anti-inflammatory, analgesic, non-selective cyclooxigenase inhibitor
  • Chemical name:2-[(2,6-dichlorophenyl)amino]benzeneacetic acid carboxymethyl ester
  • Formula:C16H13Cl2NO4
  • 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
Aceclofenac.png
Clinical data
Trade names Hifenac, Cincofen, Zerodol, Nacsiv, Acenac, others
AHFS/Drugs.com International Drug Names
Routes of
administration
oral, topical
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.169.686 Edit this at Wikidata
Chemical and physical data
Formula C16H13Cl2NO4
Molar mass 353.02161 g/mol
3D model (JSmol)

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

Diclofenac Sodium


Diclofenac sodium.png

Diclofenac Sodium

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

Molecular Formula: C14H10Cl2NNaO2
Molecular Weight: 318.129 g/mol

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 paingastrointestinal bleeding, nausea, dizziness, headache, and swelling.[3] Serious side effects may include heart diseasestrokekidney 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 arthritisrheumatoid arthritispolymyositisdermatomyositisosteoarthritis, dental pain, temporomandibular joint (TMJ) pain, spondylarthritisankylosing spondylitisgout 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.

Contraindications

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 (misoprostolranitidine 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-inflammatoryantipyretic, 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 ZealandAustraliaJapan, (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]

Diclofenac
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

Image result for diclofenac synthesis

Last step

Proposed mechanism

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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

Image result for diclofenac nmr

Image result for diclofenac nmr

References

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  33. ^ Voilley N, de Weille J, Mamet J, Lazdunski M: Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors. J Neurosci. 2001 Oct 15;21(20):8026-33.
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  35. ^ Swan, Gerry E.; Cuthbert, Richard; Quevedo, Miguel; Green, Rhys E.; Pain, Deborah J.; Bartels, Paul; Cunningham, Andrew A.; Duncan, Neil; Meharg, Andrew A.; Oaks, J. Lindsay; Parry-Jones, Jemima; Shultz, Susanne; Taggart, Mark A.; Verdoorn, Gerhard; Wolter, Kerri (2006-06-22). “Toxicity of diclofenac to Gyps vultures”Biology Letters2 (2): 279–282. doi:10.1098/rsbl.2005.0425ISSN 1744-9561PMC 1618889PMID 17148382.
  36. ^ Naidoo V, Swan GE (August 2008). “Diclofenac toxicity in Gyps vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction”. Comp. Biochem. Physiol. C Toxicol. Pharmacol149 (3): 269–74. doi:10.1016/j.cbpc.2008.07.014PMID 18727958.
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  39. Jump up to:a b c Swan G, Naidoo V, Cuthbert R, Green RE, Pain DJ, Swarup D, Prakash V, Taggart M, Bekker L, Das D, Diekmann J, Diekmann M, Killian E, Meharg A, Patra RC, Saini M, Wolter K (2006). “Removing the threat of diclofenac to critically endangered Asian vultures”PLoS Biol4 (3): e66. doi:10.1371/journal.pbio.0040066PMC 1351921PMID 16435886.
  40. ^ Phadnis, Mayuri (May 28, 2014). “Eagles fall prey to vulture-killing chemical”Pune Mirror. Retrieved May 28, 2014.
  41. ^ Schwaiger J, Ferling H, Mallow U, Wintermayr H, Negele RD (2004). “Toxic effects of the non-steroidal anti-inflammatory drug diclofenac. Part I: Histopathological alterations and bioaccumulation in rainbow trout”. Aquat. Toxicol68 (2): 141–150. doi:10.1016/j.aquatox.2004.03.014PMID 15145224.
  42. ^ Triebskorn R, Casper H, Heyd A, Eikemper R, Köhler HR, Schwaiger J (2004). “Toxic effects of the non-steroidal anti-inflammatory drug diclofenac. Part II: Cytological effects in liver, kidney, gills and intestine of rainbow trout (Oncorhynchus mykiss)”. Aquat. Toxicol68(2): 151–166. doi:10.1016/j.aquatox.2004.03.015PMID 15145225.
  43. ^ Schwaiger & Triebskorn (2005). UBA-Berichte 29/05: 217-226.
  44. ^ Triebskorn R, Casper H, Scheil V, Schwaiger J (2007). “Ultrastructural effects of pharmaceuticals (carbamazepine, clofibric acid, metoprolol, diclofenac) in rainbow trout (Oncorhynchus mykiss) and common carp (Cyprinus carpio)”. Anal Bioanal Chem387 (4): 1405–16. doi:10.1007/s00216-006-1033-xPMID 17216161.
  45. ^ Rattner BA, Whitehead MA, Gasper G, Meteyer CU, Link WA, Taggart MA, Meharg AA, Pattee OH, Pain DJ (2009). “Apparent tolerance of turkey vultures (Cathartes aura) to the non-steroidal anti-inflammatory drug diclofenac”. Environmental Toxicology and Chemistry27 (11): 2341–2345. doi:10.1897/08-123.1PMID 18476752.
  46. ^ Walker, Matt (August 6, 2008). “Rabies tragedy follows loss of India’s vultures”New Scientist.
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External links

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
Diclofenac.svg
Diclofenac 3D.png
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, intramuscularintravenous(renal- and gallstones), topical
ATC code
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 CYP2C8CYP3A4, 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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
ECHA InfoCard 100.035.755 Edit this at Wikidata
Chemical and physical data
Formula C14H11Cl2NO2
Molar mass 296.148 g/mol
3D model (JSmol)

Diclofenac

    • ATC:M01AB05; M02AA15; S01BC03
  • Use:anti-inflammatory, antirheumatic
  • Chemical name:2-[(2,6-dichlorophenyl)amino]benzeneacetic acid
  • Formula:C14H11Cl2NO2
  • MW:296.15 g/mol
  • CAS-RN:15307-86-5
  • InChI Key:DCOPUUMXTXDBNB-UHFFFAOYSA-N
  • InChI:InChI=1S/C14H11Cl2NO2/c15-10-5-3-6-11(16)14(10)17-12-7-2-1-4-9(12)8-13(18)19/h1-7,17H,8H2,(H,18,19)
  • EINECS:239-348-5
  • LD50:170 mg/kg (M, p.o.);
    62.5 mg/kg (R, p.o.)

Monosodium salt

  • Formula:C14H10Cl2NNaO2
  • MW:318.14 g/mol
  • CAS-RN:15307-79-6
  • EINECS:239-346-4
  • LD50:116 mg/kg (M, i.v.); 390 mg/kg (M, p.o.);
    117 mg/kg (R, i.v.); 150 mg/kg (R, p.o.)

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

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

Diclofenac Sodium

structure depiction
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)
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)
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)
FDA Orange Book Patents: 4 of 21 (FDA Orange Book Patent ID)
Patent 9370501
Expiration Jul 10, 2029
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 5 of 21 (FDA Orange Book Patent ID)
Patent 9375412
Expiration Jul 10, 2029
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
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)
FDA Orange Book Patents: 7 of 21 (FDA Orange Book Patent ID)
Patent 9168305
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 8 of 21 (FDA Orange Book Patent ID)
Patent 9168304
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 9 of 21 (FDA Orange Book Patent ID)
Patent 9220784
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
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)
FDA Orange Book Patents: 11 of 21 (FDA Orange Book Patent ID)
Patent 8252838
Expiration Apr 21, 2028
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
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)
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)
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)
FDA Orange Book Patents: 15 of 21 (FDA Orange Book Patent ID)
Patent 8563613
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 16 of 21 (FDA Orange Book Patent ID)
Patent 8871809
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 17 of 21 (FDA Orange Book Patent ID)
Patent 9066913
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 18 of 21 (FDA Orange Book Patent ID)
Patent 8741956
Expiration Jul 10, 2029
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 19 of 21 (FDA Orange Book Patent ID)
Patent 9101591
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 20 of 21 (FDA Orange Book Patent ID)
Patent 9132110
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)
FDA Orange Book Patents: 21 of 21 (FDA Orange Book Patent ID)
Patent 9539335
Expiration Oct 17, 2027
Applicant HZNP
Drug Application N204623 (Prescription Drug: PENNSAID. Ingredients: DICLOFENAC SODIUM)

Clotrimazole


Clotrimazole.svg

Clotrimazole

  • Molecular FormulaC22H17ClN2
  • Average mass344.837 Da
1-((2-Chlorophenyl)diphenylmethyl)-1H-imidazole (9CI)
1-(o-Chloro-a,a-diphenylbenzyl)imidazole
1-[(2-Chlorophenyl)(diphenyl)methyl]-1H-imidazole
1-[(o-Chlorophenyl)diphenylmethyl]imidazole
1-[a-(2-Chlorophenyl)benzhydryl]imidazole
1H-Imidazole, 1-[(2-chlorophenyl)diphenylmethyl]-
1H-Imidazole, 1-[(2-chlorophenyl)-diphenylmethyl]
23593-75-1 [RN]
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
Clotrimazole
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 6805392eidem, 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 infectionsoral thrushdiaper rashpityriasis 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]

Medical uses

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

Clotrimazole (Canesten) antifungal cream

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]

Image result for clotrimazole synthesis

syn

 Image result for clotrimazole synthesis
str3
d (4) as a white crystal (yield 91%). mp 130- 133 0 C; Rf = 0.37; IR (neat) νmax/cm-1 3064, 1489, 1443, 1210, 750; 1 H NMR (300 MHz, CDCl3) δ (ppm): 7.48 (s, 1H), 7.41-7.44 (m 1H), 7.32-7.37 (m, 7H), 7.26-7.29 (m, 1H), 7.19-7.23 (m, 4H), 7.07 (s, 1H), 6.92 (dd, 1H, J = 1.5, 6.3 Hz), 6.76 (s, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm): 151.1, 150.5, 148.9, 144.5, 140.3, 138.0, 137.7, 137.3, 135.5, 135.2, 135.1, 133.8, 127.0, 68.9; m/z calcd for C19H14Cl [M-Imid]+ 277.0784, found 277.0780.
Clip

CLIP

Open Babel bond-line chemical structure with annotated hydrogens.<br>Click to toggle size.

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

Spectrum Plot

<sup>1</sup>H NMR spectrum of C<sub>22</sub>H<sub>17</sub>Cl<sub></sub>N<sub>2</sub> in CDCL3 at 400 MHz.<br>Click to toggle size.

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

Image

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

Figure CN105566156AD00041

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.comArchived 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 9789400926592Archived 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 GuideArchived 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 9781284095302Archived 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.e4380PMID 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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Eflornithine, эфлорнитин , إيفلورنيثين , 依氟鸟氨酸 , エフロルニチン


Figure

Eflornithine.svg

ChemSpider 2D Image | Eflornithine | C6H12F2N2O2

Eflornithine

DFMO, RMI-71782ATC:P01CX03, BRN 2250529 / HSDB 7923 / MDL 71782 / RFI 7178 / RMI 71782

Ornithine, 2-(difluoromethyl)-
UNII:ZQN1G5V6SR
ZQN1G5V6SR
эфлорнитин [Russian] [INN]
إيفلورنيثين [Arabic] [INN]
依氟鸟氨酸 [Chinese] [INN]
エフロルニチン
5551
67037-37-0 [RN]
70052-12-9 CAS
a-Difluoromethylornithine
(RS)-2,5-diamino-2-(difluoromethyl)pentanoic acid
  • Use:hirsutism treatment inhibitor of ornithine decarboxylase
  • Chemical name:2-(difluoromethyl)-dl-ornithine
  • Formula:C6H12F2N2O2, MW:182.17 g/mol
  • CAS-RN:67037-37-0
  • LD50:>3000 mg/kg (M, i.p.); >5000 mg/kg (M, p.o.);
    1364 μg/kg (R, intracerebral)

Eflornithine, also known as α-difluoromethylornithine (DFMO), is an Active Pharmaceutical Ingredient (API) on the World Health Organization’s list of essential medicines. DFMO is used to treat the second stage of African trypanosomiasis (sleeping sickness). In addition, DFMO is also used to treat opportunistic infections with Pneumocystis carinii pneumonia, a form of pneumonia found in people with a weak immune system suffering from conditions such as acquired immunodeficiency syndrome (AIDS) It has also been explored as chemopreventive agent in cancer therapy with minor success. Today, its main use is to treat excessive facial hair growth on women (hirsutism). The topical cream (Vaniqa) significantly reduces the psychological burden of those affected.\

Eflornithine is a prescription drug indicated in the treatment of facial hirsutism (excessive hair growth). Eflornithine hydrochloride cream for topical application is intended for use in women suffering from facial hirsutism and is sold by Allergan, Inc. under the brand name Vaniqa. Besides being a non-mechanical and non-cosmetic treatment, eflornithine is the only non-hormonal and non-systemic prescription option available for women who suffer from facial hirsutism. Eflornithine for injection against sleeping sickness was manufactured by Sanofi Aventis and sold under the brand name Ornidyl in the USA. It is now discontinued. Eflornithine is on the World Health Organization’s List of Essential Medicines.

Derivatives

Monohydrochloride

  • Formula:C6H12F2N2O2 • HCl
  • MW:218.63 g/mol
  • CAS-RN:68278-23-9
  • EINECS:269-532-0

Monohydrochloride monohydrate

  • Formula:C6H12F2N2O2 • HCl • H2O
  • MW:236.65 g/mol
  • CAS-RN:96020-91-6

Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis (sleeping sickness) and excessive hair growth on the face in women.[1][2] Specifically it is used for the 2nd stage of sleeping sickness caused by T. b. gambiense and may be used with nifurtimox.[1][3] It is used by injection or applied to the skin.[1][2]

Common side effects when applied as a cream include rash, redness, and burning.[2] Side effects of the injectable form include bone marrow suppression, vomiting, and seizures.[3] It is unclear if it is safe to use during pregnancy or breastfeeding.[3] It is recommended typically for children over the age of 12.[3]

Eflornithine was developed in the 1970s and came into medical use in 1990.[4] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] There is no generic version as of 2015 in the United States.[6] In the United States the injectable form can be obtained from the Centers for Disease Control and Prevention.[3] In the 1990s the cost of a course of treatment in Africa was 210 USD.[7] In regions of the world where the disease is common eflornithine is provided for free by the World Health Organization.[8]

https://www.google.com/patents/US4330559

Medical uses

Sleeping sickness

Sleeping sickness, or trypanosomiasis, is treated with pentamidine or suramin (depending on subspecies of parasite) delivered by intramuscular injection in the first phase of the disease, and with melarsoprol and eflornithine intravenous injection in the second phase of the disease. Efornithine is commonly given in combination with nifurtimox, which reduces the treatment time to 7 days of eflornithine infusions plus 10 days of oral nifurtimox tablets.[9]

Eflornithine is also effective in combination with other drugs, such as melarsoprol and nifurtimox. A study in 2005 compared the safety of eflornithine alone to melarsoprol and found eflornithine to be more effective and safe in treating second-stage sleeping sickness Trypanosoma brucei gambiense.[10] Eflornithine is not effective in the treatment of Trypanosoma brucei rhodesiense due to the parasite’s low sensitivity to the drug. Instead, melarsoprol is used to treat Trypanosoma brucei rhodesiense.[11] Another randomized control trial in Uganda compared the efficacy of various combinations of these drugs and found that the nifurtimox-eflornithine combination was the most promising first-line theory regimen.[12]

A randomized control trial was conducted in Congo, Côte d’Ivoire, the Democratic Republic of the Congo, and Uganda to determine if a 7-day intravenous regimen was as efficient as the standard 14-day regimen for new and relapsing cases. The results showed that the shortened regimen was efficacious in relapse cases, but was inferior to the standard regimen for new cases of the disease.[13]

Nifurtimox-eflornithine combination treatment (NECT) is an effective regimen for the treatment of second stage gambiense African trypanosomiasis.[14][15]

Trypanosome resistance

After its introduction to the market in the 1980s, eflornithine has replaced melarsoprol as the first line medication against Human African trypanosomiasis (HAT) due to its reduced toxicity to the host.[13] Trypanosoma brucei resistant to eflornithine has been reported as early as the mid-1980s.[13]

The gene TbAAT6, conserved in the genome of Trypanosomes, is believed to be responsible for the transmembrane transporter that brings eflornithine into the cell.[16] The loss of this gene due to specific mutations causes resistance to eflornithine in several trypanosomes.[17] If eflornithine is prescribed to a patient with Human African trypanosomiasis caused by a trypanosome that contains a mutated or ineffective TbAAT6 gene, then the medication will be ineffective against the disease. Resistance to eflornithine has increased the use of melarsoprol despite its toxicity, which has been linked to the deaths of 5% of recipient HAT patients.[13]

Excess facial hair in women

The topical cream is indicated for treatment of facial hirsutism in women.[18] It is the only topical prescription treatment that slows the growth of facial hair.[19] It is applied in a thin layer twice daily, a minimum of eight hours between applications. In clinical studies with Vaniqa, 81% percent of women showed clinical improvement after twelve months of treatment.[20] Positive results were seen after eight weeks.[21] However, discontinuation of the cream caused regrowth of hair back to baseline levels within 8 weeks.[22]

Vaniqa treatment significantly reduces the psychological burden of facial hirsutism.[23]

Chemo preventative therapy

It has been noted that ornithine decarboxylase (ODC) exhibits high activity in tumor cells, promoting cell growth and division, while absence of ODC activity leads to depletion of putrescine, causing impairment of RNA and DNA synthesis. Typically, drugs that inhibit cell growth are considered candidates for cancer therapy, so eflornithine was naturally believed to have potential utility as an anti-cancer agent. By inhibiting ODC, eflornithine inhibits cell growth and division of both cancerous and noncancerous cells.

However, several clinical trials demonstrated minor results.[24] It was found that inhibition of ODC by eflornithine does not kill proliferating cells, making eflornithine ineffective as a chemotherapeutic agent. The inhibition of the formation of polyamines by ODC activity can be ameliorated by dietary and bacterial means because high concentrations are found in cheese, red meat, and some intestinal bacteria, providing reserves if ODC is inhibited.[25] Although the role of polyamines in carcinogenesis is still unclear, polyamine synthesis has been supported to be more of a causative agent rather than an associative effect in cancer.[24]

Other studies have suggested that eflornithine can still aid in some chemoprevention by lowering polyamine levels in colorectal mucosa, with additional strong preclinical evidence available for application of eflornithine in colorectal and skin carcinogenesis.[24][25] This has made eflornithine a supported chemopreventive therapy specifically for colon cancer in combination with other medications. Several additional studies have found that eflornithine in combination with other compounds decreases the carcinogen concentrations of ethylnitrosourea, dimethylhydrazine, azoxymethane, methylnitrosourea, and hydroxybutylnitrosamine in the brain, spinal cord, intestine, mammary gland, and urinary bladder.[25]

Contraindications

Topical

Topical use is contraindicated in people hypersensitive to eflornithine or to any of the excipients.[26]

Throughout clinical trials, data from a limited number of exposed pregnancies indicate that there is no clinical evidence that treatment with Vaniqa adversely affects pregnant women or fetuses.[26]

By mouth

When taken by mouth the risk-benefit should be assessed in people with impaired renal function or pre-existing hematologic abnormalities, as well as those with eighth-cranial-nerve impairment.[27] Adequate and well-controlled studies with eflornithine have not been performed regarding pregnancy in humans. Eflornithine should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus. However, since African trypanosomiasis has a high mortality rate if left untreated, treatment with eflornithine may justify any potential risk to the fetus.[27]

Side effects

Eflornithine is not genotoxic; no tumour-inducing effects have been observed in carcinogenicity studies, including one photocarcinogenicity study.[28] No teratogenic effects have been detected.[29]

Topical

The topical form of elflornithine is sold under the brand name Vaniqa . The most frequently reported side effect is acne (7–14%). Other side effects commonly (> 1%) reported are skin problems, such as skin reactions from in-growing hair, hair loss, burning, stinging or tingling sensations, dry skin, itching, redness or rash.[30]

Intravenous

The intravenous dosage form of eflornithine is sold under the brand name Ornidyl. Most side effects related to systemic use through injection are transient and reversible by discontinuing the drug or decreasing the dose. Hematologic abnormalities occur frequently, ranging from 10–55%. These abnormalities are dose-related and are usually reversible. Thrombocytopenia is thought to be due to a production defect rather than to peripheral destruction. Seizures were seen in approximately 8% of patients, but may be related to the disease state rather than the drug. Reversible hearing loss has occurred in 30–70% of patients receiving long-term therapy (more than 4–8 weeks of therapy or a total dose of >300 grams); high-frequency hearing is lost first, followed by middle- and low-frequency hearing. Because treatment for African trypanosomiasis is short-term, patients are unlikely to experience hearing loss.[30]

Interactions

Topical

No interaction studies with the topical form have been performed.[26]

Mechanism of action

Figure 1
(A) 3D structure of L-Ornithine
(B) 3D structure of Eflornithine. This molecule is similar to the structure of L-Ornithine, but its alpha-difluoromethyl group allows interaction with Cys-360 in the active site

Eflornithine ODC Reaction Mechanism

Description

Eflornithine is a “suicide inhibitor,” irreversibly binding to ornithine decarboxylase (ODC) and preventing the natural substrate ornithine from accessing the active site (Figure 1). Within the active site of ODC, eflornithine undergoes decarboxylation with the aid of cofactor pyridoxal 5’-phosphate (PLP). Because of its additional difluoromethyl group in comparison to ornithine, eflornithine is able to bind to a neighboring Cys-360 residue, permanently remaining fixated within the active site.[29]

During the reaction, eflornithine’s decarboxylation mechanism is analogous to that of ornithine in the active site, where transamination occurs with PLP followed by decarboxylation. During the event of decarboxylation, the fluoride atoms attached to the additional methyl group pull the resulting negative charge from the release of carbon dioxide, causing a fluoride ion to be released. In the natural substrate of ODC, the ring of PLP accepts the electrons that result from the release of CO2.

The remaining fluoride atom that resides attached to the additional methyl group creates an electrophilic carbon that is attacked by the nearby thiol group of Cys-360, allowing eflornithine to remain permanently attached to the enzyme following the release of the second fluoride atom and transimination.

Evidence

Figure 2
Experimental Evidence for Eflornithine End Product[31]

The reaction mechanism of Trypanosoma brucei‘s ODC with ornithine was characterized by UV-VIS spectroscopy in order to identify unique intermediates that occurred during the reaction. The specific method of multiwavelength stopped-flow spectroscopy utilized monochromatic light and fluorescence to identify five specific intermediates due to changes in absorbance measurements.[32] The steady-state turnover number, kcat, of ODC was calculated to be 0.5 s-1 at 4 °C.[32] From this characterization, the rate-limiting step was determined to be the release of the product putrescine from ODC’s reaction with ornithine. In studying the hypothetical reaction mechanism for eflornithine, information collected from radioactive peptide and eflornithine mapping, high pressure liquid chromatography, and gas phase peptide sequencing suggested that Lys-69 and Cys-360 are covalently bound to eflornithine in T. brucei ODC’s active site.[31] Utilizing fast-atom bombardment mass spectrometry (FAB-MS), the structural conformation of eflornithine following its interaction with ODC was determined to be S-((2-(1-pyrroline-methyl) cysteine, a cyclic imine adduct. Presence of this particular product was supported by the possibility to further reduce the end product to S-((2-pyrrole) methyl) cysteine in the presence of NaBH4 and oxidize the end product to S-((2-pyrrolidine) methyl) cysteine (Figure 2).[31]

Active site

Figure 3
Active Site of ODC Formed by Homodimerization (Green and White Surface Structures)
(A) Ornithine in the Active Site of ODC, Cys-360 highlighted in yellow
(B) Product of Eflornithine Decarboxylation bound to Cys 360 (highlighted in yellow). The pyrroline ring blocks ornithine from entering the active site
Derived from Grishin, Nick V., et al. “X-ray structure of ornithine decarboxylase from Trypanosoma brucei: the native structure and the structure in complex with α-difluoromethylornithine.” Biochemistry 38.46 (1999): 15174-15184. PDB ID: 2TOD

Eflornithine’s suicide inhibition of ODC physically blocks the natural substrate ornithine from accessing the active site of the enzyme (Figure 3).[29] There are two distinct active sites formed by the homodimerization of ornithine decarboxylase. The size of the opening to the active site is approximately 13.6 Å. When these openings to the active site are blocked, there are no other ways through which ornithine can enter the active site. During the intermediate stage of eflornithine with PLP, its position near Cys-360 allows an interaction to occur. As the phosphate of PLP is stabilized by Arg 277 and a Gly-rich loop (235-237), the difluoromethyl group of eflornithine is able to interact and remain fixated to both Cys-360 and PLP prior to transimination. As shown in the figure, the pyrroline ring interferes with ornithine’s entry (Figure 4). Eflornithine will remain permanently bound in this position to Cys-360. As ODC has two active sites, two eflornithine molecules are required to completely inhibit ODC from ornithine decarboxylation.

History

Eflornithine was initially developed for cancer treatment at Merrell Dow Research Institute in the late 1970s, but was found to be ineffective in treating malignancies. However, it was discovered to be highly effective in reducing hair growth,[33] as well as in the treatment of African trypanosomiasis (sleeping sickness),[34] especially the West African form (Trypanosoma brucei gambiense).

Hirsutism[]

In the 1980s, Gillette was awarded a patent for the discovery that topical application of eflornithine HCl cream inhibits hair growth. In the 1990s, Gillette conducted dose-ranging studies with eflornithine in hirsute women that demonstrated that the drug slows the rate of facial hair growth. Gillette then filed a patent for the formulation of eflornithine cream. In July 2000, the U.S. Food and Drug Administration (FDA) granted a New Drug Application for Vaniqa. The following year, the European Commission issued its Marketing Authorisation.

Sleeping sickness treatment

The drug was registered for the treatment of gambiense sleeping sickness on November 28, 1990.[35] However, in 1995 Aventis (now Sanofi-Aventis) stopped producing the drug, whose main market was African countries, because it did not make a profit.[36]

In 2001, Aventis and the WHO formed a five-year partnership, during which more than 320,000 vials of pentamidine, over 420,000 vials of melarsoprol, and over 200,000 bottles of eflornithine were produced by Aventis, to be given to the WHO and distributed by the association Médecins sans Frontières (also known as Doctors Without Borders)[37][38] in countries where sleeping sickness is endemic.

According to Médecins sans Frontières, this only happened after “years of international pressure,” and coinciding with the period when media attention was generated because of the launch of another eflornithine-based product (Vaniqa, for the prevention of facial-hair in women),[36]while its life-saving formulation (for sleeping sickness) was not being produced.

From 2001 (when production was restarted) through 2006, 14 million diagnoses were made. This greatly contributed to stemming the spread of sleeping sickness, and to saving nearly 110,000 lives.

Society and culture

Available forms

Vaniqa is a cream, which is white to off-white in colour. It is supplied in tubes of 30 g and 60 g in Europe.[30] Vaniqa contains 15% w/w eflornithine hydrochloride monohydrate, corresponding to 11.5% w/w anhydrous eflornithine (EU), respectively 13.9% w/w anhydrous eflornithine hydrochloride (U.S.), in a cream for topical administration.

Ornidyl, intended for injection, was supplied in the strength of 200 mg eflornithine hydrochloride per ml.[39]

Cost

In 2000, the cost for the 14-day regimen was US $500; a price that many in countries where the disease is common cannot afford.[13]

Market

Vaniqa, granted marketing approval by the US FDA, as well as by the European Commission[40] among others, is currently the only topical prescription treatment that slows the growth of facial hair.[19] Besides being a non-mechanical and non-cosmetic treatment, it is the only non-hormonal and non-systemic prescription option available for women who suffer from facial hirsutism.[18] Vaniqa is marketed by Almirall in Europe, SkinMedica in the USA, Triton in Canada, Medison in Israel, and Menarini in Australia.[40]

Ornidyl, the injectable form of eflornithine hydrochloride, is licensed by Sanofi-Aventis, but is currently discontinued in the US.[41]

Clip

Scalable Continuous Flow Process for the Synthesis of Eflornithine Using Fluoroform as Difluoromethyl Source

 Center for Continuous Flow Synthesis and Processing (CC FLOW)Research Center Pharmaceutical Engineering GmbH (RCPE)Inffeldgasse 13, 8010 Graz, Austria
 Institute of ChemistryUniversity of Graz, NAWI GrazHeinrichstrasse 28, A-8010 Graz, Austria
§ Microreactor Technology, Lonza AG, CH-3930 Visp, Switzerland
 Institute of Inorganic ChemistryGraz University of TechnologyStremayrgasse 9, 8010 Graz, Austria
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00318
Abstract Image

The development of a scalable telescoped continuous flow procedure for difluoromethylation of a protected amino acid with fluoroform (CHF3, R-23) gas and subsequent high temperature deprotection to provide eflornithine, an important Active Pharmaceutical Ingredient (API), is described. Eflornithine is used for the treatment of sleeping sickness and hirsutism, and it is on the World Health Organization’s list of essential medicines. Fluoroform is produced in large quantities as a side product in the manufacture of polytetrafluoroethylene (PTFE, Teflon). Fluoroform is an ozone-benign and nontoxic gas, but its release into the environment is forbidden under the Kyoto protocol owing to its high global warming potential. The existing manufacturing route to eflornithine uses chlorodifluoromethane (CHClF2, R-22) which will be phased out under the Montreal protocol; therefore, the use of the fluoroform presents a viable cost-effective and more sustainable alternative. The process parameters and equipment setup were optimized on laboratory scale for the two reaction steps to improve product yield and scalability. The telescoped flow process utilizing fluoroform gas was operated for 4 h to afford the target molecule in 86% isolated yield over two steps with a throughput of 24 mmol/h.

1hydrochloride monohydrate as colorless powder. (17.05 g, 72.3 mmol, 86% yield). Mp. 228 °C;

1H NMR (300.36 MHz, D2O): δ = 6.46 (t, 2JHF = 52.8 Hz, 1H), 3.05 (t,3JHH = 7.6 Hz, 2H), 2.25–1.97 (m, 2H), 1.96–1.79 (m, 1H), 1.76–1.59 (m, 1H) ppm.

13C NMR (75 MHz, D2O): δ = 167.8 (d, 3JCF = 6.4 Hz), 114.0 (dd, 1JCF = 249.7 Hz, 1JCF = 247.0 Hz), 64.5 (dd, 2JCF = 20.4 Hz, 2JCF = 18.7 Hz), 38.8 (d, 3JCF = 7.3 Hz), 31.6 (d, 4JCF = 3.2 Hz), 20.8 ppm.

19F NMR (282 MHz, D2O): δ = −126.28 (dd, 2JFF = 283.5 Hz, 2JHF = 52.4 Hz), – 131.76 (dd, 2JFF = 283.5 Hz, 2JHF = 52.4 Hz) ppm.

str1 str2 str3

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External links

References

    • Bey, P. et al.: J. Org. Chem. (JOCEAH) 44, 2732 (1979).
    • Metcalf, B.W. et al.: J. Am. Chem. Soc. (JACSAT) 100, 2551 (1978).
    • US 4 413 141 (Merrell-Toraude; 1.11.1983; appl. 17.9.1982; prior. 11.7.1977, 2.7.1979).
    • US 4 330 559 (Merrell-Toraude; 18.5.1982; appl. 3.2.1981; prior. 11.7.1977, 10.4.1979).
  • synthesis of (–)-isomer:

    • EP 357 029 (Merrell Dow; appl. 30.8.1989; USA-prior. 31.8.1988).
  • pharmaceutical composition:

    • BE 881 209 (Merrell-Toraude; appl. 16.5.1980; USA-prior. 10.4.1979).
  • combination with interferon:

    • US 4 499 072 (Merrell Dow; 12.2.1985; appl. 24.1.1983; prior. 29.11.1982).
Eflornithine
Eflornithine.svg
Eflornithine-3D-vdW.png
Clinical data
Trade names Vaniqa, others
Synonyms α-difluoromethylornithine or DFMO
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • C
Routes of
administration
intravenous, topical
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100% (Intravenous)
Negligible (Dermal)
Metabolism Not metabolised
Elimination half-life hours
Excretion Kidneys
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C6H12F2N2O2
Molar mass 182.17 g·mol−1
3D model (JSmol)

/////////////ZQN1G5V6SR, эфлорнитин إيفلورنيثين 依氟鸟氨酸 , Eflornithine, エフロルニチン

FDA permits marketing of two devices that detect parathyroid tissue in real-time during surgery


DRUG REGULATORY AFFAIRS INTERNATIONAL

FDA permits marketing of two devices that detect parathyroid tissue in real-time during surgery
Today, the U.S. Food and Drug Administration permitted marketing of two devices that provide real-time location of parathyroid tissue during surgical procedures such as thyroidectomy (surgery to remove all or part of the thyroid) and parathyroidectomy (surgery to remove one or more parathyroid glands).
“For some patients with parathyroid disease, treatment may mean a surgical procedure,” said Binita Ashar, M.D., director of the Division of Surgical Devices in the FDA’s Center for Devices and Radiological Health.  “Real-time identification of parathyroid tissue during surgery can provide surgeons… Continue reading.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624982.htm?utm_campaign=11022018_PR_FDA%20authorizes%20devices%20to%20detect%20parathyroid%20tissue%20in%20during%20surgery&utm_medium=email&utm_source=Eloqua

November 2, 2018

Release

Today, the U.S. Food and Drug Administration permitted marketing of two devices that provide real-time location of parathyroid tissue during surgical procedures such as thyroidectomy (surgery to remove all or part of the thyroid) and parathyroidectomy (surgery to remove one or…

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Statement from FDA Commissioner Scott Gottlieb, M.D., on findings from the romaine lettuce E. coli O157:H7 outbreak investigation and FDA’s efforts to prevent future outbreaks


DRUG REGULATORY AFFAIRS INTERNATIONAL

tatement from FDA Commissioner Scott Gottlieb, M.D., on findings from the romaine lettuce E. coli O157:H7 outbreak investigation and FDA’s efforts to prevent future outbreaks

Earlier this year, we experienced the largest E. coli O157:H7 outbreak the country has seen in the last decade, leaving hundreds sick and claiming the lives of five people who consumed contaminated romaine lettuce.
We’re committed to taking necessary actions to prevent future outbreaks like this and to improving the safety of leafy greens available in the marketplace. Since the next romaine growing season for the Yuma region is underway, it’s critical for all of us to understand what happened so we can identify the changes that can prevent future outbreaks and reduce the scope of any problems that could arise.
Since the first signs of the outbreak appeared…Continue reading

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624867.htm?utm_campaign=11012018_Statement_findings%20from%20the%20romaine%20lettuce%20E.%20coli%20O157%3AH7&utm_medium=email&utm_source=Eloqua

November 1, 2018

Statement

Earlier this year, we experienced the largest E. coli

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FDA warns patients and doctors about risk of inaccurate results from home-use device to monitor blood thinner warfarin


DRUG REGULATORY AFFAIRS INTERNATIONAL

FDA warns patients and doctors about risk of inaccurate results from home-use device to monitor blood thinner warfarin

The U.S. Food and Drug Administration today is warning patients and doctors, who use at-home or in-the-office medical devices to monitor levels of the blood thinner, warfarin, that certain test strips used with the devices may provide inaccurate results and should not be relied upon to adjust the drug dosage. Roche Diagnostics issued a voluntary recall of certain test strip lots used with its CoaguChek test meter devices. The recall involves more than 1.1 million packages of CoaguChek XS PT Test Strips that were distributed nationwide from Jan. 12, 2018 to Oct. 29, 2018. Today, the FDA announced this action as…Continue reading 

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624904.htm?utm_campaign=11012018_PR_FDA%20warns%20of%20inaccurate%20test%20results%20for%20device%20to%20monitor%20warfarin&utm_medium=email&utm_source=Eloqua

November 1, 2018

Release

The U.S. Food and Drug Administration today is warning patients and doctors, who use at-home or in-the-office medical devices to monitor levels of…

View original post 768 more words

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