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- Molecular FormulaC12H15NO5S
- Average mass285.316 Da
4-Thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2R)-tetrahydro-2-furanyl]-, (5R,6S)-
FaropenemCAS Registry Number: 106560-14-9
CAS Name: (5R,6S)-6-[(1R)-1-Hydroxyethyl]-7-oxo-3-[(2R)-tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Additional Names: fropenem; (5R,6S,8R,2¢R)-2-(2¢-tetrahydrofuryl)-6-hydroxyethylpenem-3-carboxylate
Molecular Formula: C12H15NO5S
Molecular Weight: 285.32
Percent Composition: C 50.51%, H 5.30%, N 4.91%, O 28.04%, S 11.24%
Literature References: Orally active, b-lactamase stable, penem antibiotic.Prepn: M. Ishiguro et al.,EP199446; eidem,US4997829 (1986, 1991 both to Suntory); eidem,J. Antibiot.41, 1685 (1988).Pharmacokinetics: A. Tsuji et al.,Drug Metab. Dispos.18, 245 (1990). In vitro antimicrobial spectrum: J. M. Woodcock et al.,J. Antimicrob. Chemother.39, 35 (1997). b-Lactamase stability: A. Dalhoff et al., Chemotherapy (Basel)49, 229 (2003).HPLC determn in plasma: R. V. S. Nirogi et al., Arzneim.-Forsch.55, 762 (2005). Clinical trial in urinary tract infections: S. Arakawa et al.,Nishinihon J. Urol.56, 300 (1994); in bacterial sinusitis: R. Siegert et al., Eur. Arch. Otorhinolaryngol.260, 186 (2003).
Derivative Type: Sodium salt
CAS Registry Number: 122547-49-3
Additional Names: Furopenem
Manufacturers’ Codes: ALP-201; SUN-5555; SY-5555; WY-49605
Trademarks: Farom (Daiichi)
Molecular Formula: C12H15NNaO5S
Molecular Weight: 308.31
Percent Composition: C 46.75%, H 4.90%, N 4.54%, Na 7.46%, O 25.95%, S 10.40%
Properties: [a]D22 +60° (c = 0.10).
Optical Rotation: [a]D22 +60° (c = 0.10)
Derivative Type: Daloxate
CAS Registry Number: 141702-36-5
CAS Name: (5R,6S)-6-[(1R)-1-Hydroxyethyl]-7-oxo-3-[(2R)-tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester
Additional Names: faropenem medoxomil
Manufacturers’ Codes: Bay-56-6854; SUN-208
Trademarks: Orapem (Replidyne)
Molecular Formula: C17H19NO8S
Molecular Weight: 397.40
Percent Composition: C 51.38%, H 4.82%, N 3.52%, O 32.21%, S 8.07%
Literature References: Prepn: H. Iwata et al., WO9203442; eidem, US5830889 (1992, 1998 both to Suntory).
Properties: Pale yellow crystals.
Therap-Cat: Antibacterial (antibiotics).
Keywords: Antibacterial (Antibiotics); ?Lactams; Penems.
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Faropenem was developed by Daiichi Asubio Pharma, which markets it in two forms.
- The sodium salt faropenem sodium, available under the trade name Farom, has been marketed in Japan since 1997. (CID 636379 from PubChem)
- The prodrug form faropenem medoxomil (also known as faropenem daloxate) has been licensed from Daiichi Asubio Pharma by Replidyne, which plans to market it in conjunction with Forest Pharmaceuticals. The trade name proposed for the product was Orapem, but company officials recently announced this name was rejected by the FDA.
As of 8 September 2015, Faropenem has yet to receive marketing approval in the United States, and was submitted for consideration by the United States Food and Drug Administration (FDA) on 20 December 2005. The new drug application dossier submitted included these proposed indications:
- acute bacterial sinusitis
- community-acquired pneumonia
- acute exacerbations of chronic bronchitis
- uncomplicated skin and skin structure infections
- urinary tract infections
The FDA refused to approve faropenem, an antibiotic manufactured by Louisville-based Replidyne. The FDA said the drug was “nonapprovable”, but did not refer to specific safety concerns about the product. The company will have to conduct new studies and clinical trials, lasting an estimated two more years, to prove the drug treats community-acquired pneumonia, bacterial sinusitis, chronic bronchitis, and skin infections.
In India it is available as Farobact 200/300ER CIPLA.
https://patents.google.com/patent/WO2008035153A2/enFaropenem is an orally active β-lactam antibiotic belonging to the penem group. Faropenem is chemically known as 6-(l-hydroxyethyl)-7-oxo-3-(oxolan-2-yl)-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid. The known forms of Faropenem are Faropenem sodium and the prodrug form, FaropenemMedoxomil (also known as Faropenem Daloxate). In view of the importance of the compound of the formula (I), several synthetic procedures to prepare the compound have been reported.US 4,997,829 provides process for the preparation of faropenem according to the following scheme. The process is exemplified with the allyl protected carboxyl group. One of the process involves the reaction of A- acetoxyazetidinone with tetrahydrothiofuroic acid, condensation with allyl glyoxalate in refluxing benzene, chlorination with thionyl chloride, reaction of triphenylphosphine with lutidine in hot THF, cyclization in refluxing toluene, deprotection of silyl protecting group with tetrabutylammonium fluoride, treating with triphenylphosphine and, treating with sodium 2-ethylhexanoate and (PP^)4Pd to result faropenem sodium. The process exemplified utilizes benzene as solvent, which is not environmentally acceptable. Tetrabutylammonium fluoride was used as desilylating agent that is expensive. Even though the description teaches that optically active compounds can be employed, the examples utilized the dl-compound of tetrahydrothiofuroic acid further requiring resolution.
Methods are provided for the synthesis of series of penem compounds in J Antibiotics 1988, 41(11), 1685-1693. The provided methods utilize sulfonylazetidinone as the starting materials. As one of the procedures gives lesser yield, another procedure was adopted which uses silver salts.Japanese patent, JP2949363 describes a process for deallylation and salt formation with an alkali metal salt of carboxylic acid in the presence of a catalytic amount of palladium complex for the preparation of faropenem.EP410727 describes a process for removing allyl group from a penem compound using cyclic 1,3-diketone such as dimedone.The yield and quality of the final product is always less in the above prior art methods. With the continued research, the present inventors have undertaken extensive studies for developing a process for the preparation of compound of formula (I), which is commercially viable, involves simple techniques such as crystallizations, with improved yields and quality of the product, and with lesser reaction time. None of the prior art suggests or teaches the techniques provided herein.The process is shown in Scheme-I as given below:
One-pot process for the preparation of Faropenem sodium:Sodium salt of R(+)-tetrahydrofuran-2-thiocarboxylic acid (67 g) in aqueous acetone was added slowly to a solution of AOSA (100 g) in acetone (200 mL) and stirred for 3 h at pH 8.0 to 8.5 using sodium bicarbonate solution.After completion of the reaction, the product was extracted with toluene. The combined toluene layer was washed with saturated sodium bicarbonate solution and brine solution. Toluene was removed under vacuum completely and the mass obtained, 3-(l’-tert-butyldimethylsilyloxyethyl)-4-(2′- tetrahydrofuranoylthio)-2-azetidinone was directly taken for next step.3-(r-tert-Butyldimethylsilyloxyethyl)-4-(2′-tetrahydrofuranoylthio)-2- azetidinone obtained was dissolved in toluene (1000 mL) and cooled to -10 to -5 °C under nitrogen. Triethylamine (124 mL) was added to it followed by allyl oxalyl chloride (82 g) at -10 to- 5 0C for 2 h. After completion of the reaction, cold water was added to the mass and washed with dilute hydrochloric acid and sodium bicarbonate solution. Toluene layer was separated and washed with purified water. The toluene layer containing compound of formula (VI) was concentrated under vacuum at 50 to 60 °C and taken for next step as such.Compound of formula (VI) (150 g) was dissolved in triethyl phosphite (150 mL), heated to 60 0C and stirred under nitrogen atmosphere. Toluene (3000 mL) was added, heated to 100 to 110 °C and stirred for 20- 24 h. Toluene was distilled under vacuum completely. Product obtained, allyl (1 ‘R,2″R,5R,6S)-6-(l 5-tert-butyldimethylsilyloxyethyl)-2-(2″-tetrahydrofuranyl) penem-3-carboxylate (VII) was directly taken for next step.Compound (VII) obtained was dissolved in DMF (700 mL) at 30 °C.Ammonium hydrogen difluoride (80 g) and NMP (210 mL) were added and stirred at room temperature for 25 to 35 h. The reaction mass was quenched into a mixture of water-ethyl acetate and stirred at room temperature. The ethyl acetate layer was separated and the aqueous layer extracted with ethyl acetate. ■ The combined ethyl acetate layer was washed with water followed by saturated sodium bicarbonate solution. The ethyl acetate layer was charcoal treated. The ethyl acetate layer containing allyl (l’R,2″R,5R,6S)-6-(l’-hydroxyethyl)-2-(2″- tetrahydrofuranyl)penem-3-carboxylate (XII) was partially distilled and taken for the next step.The ethyl acetate layer containing compound of formula (XII), Pd/C, sodium bicarbonate and purified water (1000 mL) were taken in an autoclave and maintained 5 to 10 kg pressure of hydrogen gas for 2-5 h. After completion of the reaction the Pd/C was filtered off and ethyl acetate layer separated. The pH of the mass was adjusted to 1.5 and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate twice. The combined ethyl acetate layer was carbon treated. Sodium-2-ethylhexanoate in ethyl acetate was added slowly and stirred. The precipitated title compound was filtered under vacuum, washed with acetone and dried. Dry weight of the product: 65-75 g.Example 9Purification of Faropenem sodiumCrude Faropenem sodium (50 g) was dissolved in purified water (200 mL) at 25-30 0C. The solution was charcoalised. Acetone (1500 mL) was added. The reaction mass was stirred further for 10 min. The precipitated solid was cooled to 0 —2 °C then filtered, washed with acetone and dried at room temperature. Weight of pure Faropenem sodium is 43 to 46 g (Purity 99.95%).Example 9aPurification of Faropenem sodiumCrude Faropenem sodium (50 g) was dissolved in purified water (200 mL) at 25-30 °C. Acetone (150O mL) was added. The reaction mass was stirred further for 10 min. The precipitated solid was cooled to 0-2 °C then filtered, washed with acetone and dried at room temperature. Weight of pure Faropenem sodium is 43 to 46 g (Purity 99.95%).
https://patents.google.com/patent/CN103880864B/enFaropenem sodium is developed by Japanese Suntory companies, and first penemss antibiosis in listing in 1997 Element, it are similar to the several carbapenem antibiotics for listing, strong with has a broad antifungal spectrum, antibacterial activity, to beta-lactamase Stably, the features such as also having good action to extended spectrumβ-lactamase producing strains, citrobacter, enterococcus and anaerobe etc.. It is first orally active, penems antibiotics stable to beta-lactamase in the world so far.Its structural formula As follows：
Report about Faropenem sodium preparation method is a lot, mainly has several as follows：1st, J. Antibiotics 1988, the method that reports in 41,1685, see below row reaction equation:
Acyl group substitution reaction is carried out in the basic conditions with 4-AA and three beneze methane thiols and obtains thio trityl as protecting group Aza cyclo-butanone, then when 2-TETRAHYDROFUROYL chlorine is connected with lactams, using silver nitrate as condensing agent, but nitric acid Silver is expensive, and cost is too high, while the silver chloride for generating is difficult to filter, is not suitable for large-scale production.2nd, the classical preparation method of United States Patent (USP) US4997829 report：There is acyl with (R) tetrahydrofuran -2- thiocarboxylic acids Base substitution reaction generates thioesters, then through condensation, chlorine replacement, intramolecular Witting cyclization, slough hydroxyl protecting group and carboxylic Base protection group obtains product, and this synthetic route yield is very low, while side chain is thio-compoundss, abnormal smells from the patient is extremely smelly, and prepares complexity, There is-fixed harm to human body and environment.It is also required in chloro building-up process using pungent thionyl chloride, these factors are all It is unfavorable for industrialized production
3rd, the method that reports in Chinese patent CN1314691 is as follows：
Said method route is shorter, is produced using one kettle way, more convenient.But said method is related to some other salt such as acetate using heavy metal palladium in last operation The deprotecting regent of compound and triphenyl phosphorus together as pi-allyl, metal palladium reagent is expensive, while triphenyl phosphorus are most More difficult removing in step afterwards, increases operation difficulty, affects product quality.Allyloxy is used easily to produce as protection group simultaneously A kind of double bond olefinic polymerization species impurity of life, affects product quality, reduces yield.Embodiment one(R) tetrahydrofuran -2- thiocarboxylic acids (198g, 1.5 mol) are put in 3L reaction bulbs, plus 1 mol/L hydrogen-oxygens Change sodium body lotion (I.5 L) to be adjusted at 5 DEG C of pH 9- 10,0-, Deca 4AA（287g, 1. 0mo l) acetone (1 L) Solution, drop are finished, and are adjusted to pH 8 or so, 2 h of room temperature reaction with 1 mol/L sodium hydroxide. and add water (500 ml) dilution, second Acetoacetic ester (600 ml x3) is extracted, and merges organic layer, successively with 5 % sodium bicarbonate solutions (300 ml x 2) and water (300 m1 x 2) is washed, and anhydrous sodium sulphate is dried, and is filtered, and filtrate concentrates, and obtains pale yellow oil (about 360 g), directly Input the next step.Embodiment twoThe mixing of concentrated solution as obtained above, triethylamine (l70g, 1.7 mol) and dichloromethane (1.5 L), 0-5 DEG C Deca chlorine oxalic acid is finished to p-Nitrobenzyl (414.1 g, 1 .7 mo l), drop, and equality of temperature reacts 2 h, and add water (1 L) dilution, Extracted with dichloromethane (500 ml x 4), merge organic layer, molten with water (300m1 x 2) and 5 % sodium bicarbonate successively Liquid (300 m1 x 2) is washed, anhydrous sodium sulfate drying, is filtered, and concentration obtains pale yellow oil (about 530g), direct plunges into The next step..Embodiment threeAbove-mentioned gained grease, dimethylbenzene (4L) and NSC 5284 (500ml) are mixed, heating reflux reaction 5h , reduce pressure and boil off dimethylbenzene and NSC 5284, residue ethyl acetate-hexane (1：5,1 L) recrystallization, obtain yellowish Color solid (334.3g, 61%, in terms of 4AA).Example IVAbove-mentioned solid (0.60 mol of 330g.) is dissolved in methanol (2 L), adds 1.0M hydrochloric acid (0.4 L), adds palladium carbon （15.0 g）, hydrogen is passed through, 40 DEG C of stirrings, response time are 16 h, and the pressure of system is 4atm, after reaction terminates, crosses and filters Catalyst is removed, is concentrated.Embodiment fiveThe product obtained after above-mentioned concentration is dissolved in tetrahydrofuran 600ml, the 2 ethyl hexanoic acid sodium of 100.0g is added Tetrahydrofuran（200ml）And water（200 ml）Mixed solution, 2 h are stirred at room temperature, have faint yellow solid generate, filter, be method Faropenem crude product 147.0g.Embodiment sixBy above-mentioned solid deionized water（2200ml）Acetone is slowly added under dissolved solution, stirring to start to become to solution Muddiness, when about adding acetone 750ml, solution starts to become cloudy, and stops adding, and continues stirring and allows its crystallize overnight, sucking filtration, acetone Washing, dries, and obtains the Faropenem sodium fine work 125.0g of white.
AU 8654460; EP 0199446; JP 1994128267; US 4997829
This compound is prepared by several related ways: 1) The reaction of silylated azetidinone (I) with tetrahydrofuran-2-thiocarboxylic acid (II) by means of NaOH in THF – water gives the azetidinone thioester (III), which is condensed with allyl glyoxylate in refluxing benzene yielding the hydroxyester (IV). The reaction of (IV) with SOCl2 affords the chloroester (V), which by reaction with triphenylphosphine by means of lutidine in hot THF is converted into the phosphoranylidene derivative (VI). The elimination of the silyl protecting group of (VI) with tetrabutylammonium fluoride gives the azetidinone (VII), which is cyclized in refluxing toluene yielding the (5R,6S)-6-[1(R)-hydroxyethyl]-2-[2(R)-tetrahydrofuryl]penem-3-carboxyli c acid allyl ester (VIII). Finally, this compound is hydrolyzed with triphenylphosphine, sodium 2-ethylhexanoate and Pd-tetrakis(triphenylphosphine). 2) The condensation of the silver salt of protected azetidinone (IX) with tetrahydrofuran-2(R)-carbonyl chloride (X) also yields the phosphoranylidene salt (VI). 3) Phosphoranylidene ester (VI) can also be cyclized first in refluxing benzene yielding the silylated penem ester (XI), which is deprotected with tetrabutylammonium fluoride to (VIII). 4) The hydrolysis of allyl ester (VIII) to the final product can also be performed with paladium tetrakis(triphenylphosphine) and sodium 4-(methoxycarbonyl)-5,5-dimethylcyclohexane-1,3-dione enolate in several different solvents such as methyl acetate, ethylacetate, tetrahydrofuran, dioxane, sec-butanol, acetonitrile, acetone, 2-butanone, 1,2-dichloroethane, chlorobenzene, toluene, or ethylene glycol dimethyl ether. 5) The preceding hydrolysis can also be performed with triphenylphosphine and paladium tetrakis(triphenylphosphine) with sodium propionate, sodium acetate or sodium lactate in tetrahydrofuran or acetone.
Treatment of the silylated azetidinone (I) with tritylmercaptan affords the tritylsulfanyl-azetidinone (II), which is converted into the silver salt (III) by reaction with AgNO3. Compound (III) is coupled with tetrahydrofuran-2(R)-carbonyl chloride (IV) — obtained by treatment of carboxylic acid (V) with thionyl chloride — providing the azetidinone thioester (VI). Coupling of azetidinone (VI) with allyl oxalyl chloride (VII) in CH2Cl2 by means of Et3N, followed by intramolecular Wittig cyclization by means of triethyl phosphite in refluxing xylene, affords penem (VIII). Alternatively, compound (VIII) can also be obtained as follows: Substitution of phenyl sulfonyl group of azetidinone (X) by tritylmercaptan by means of NaOH in acetone/water provides tritylsulfanyl-azetidinone (XI), which is condensed with allyl oxalyl chloride (VII) by means of DIEA in CH2Cl2 to give the oxalyl amide (XII). Compound (XII) is then treated with AgNO3 and pyridine in acetonitrile, providing the silver mercaptide (XIII), which is acylated with tetrahydrofuran-2(R)-carbonyl chloride (IV) in acetonitrile to afford the penem precursor (XIV). Penem (VIII) is obtained by intramolecular Wittig cyclization of (XIV) with P(OEt)3 in refluxing xylene. Finally, faropenem sodium can be obtained by removal of the tbdms protecting group of (VIII) by means of either Et3N tris(hydrogen fluoride) in ethyl acetate or tetrabutylammonium fluoride (TBAF) and HOAc in THF to give compound (IX). This is followed by allyl ester group removal of (IX), which can be performed under several different conditions: i) triphenylphosphine, sodium 2-ethylhexanoate and palladium tetrakis(triphenylphosphine); ii) palladium tetrakis(triphenylphosphine) and sodium 4-(methoxycarbonyl)-5,5-dimethylcyclohexane-1,3-dione enolate in several different solvents such as methyl acetate, ethyl acetate, tetrahydrofuran, dioxane, sec-butanol, acetonitrile, acetone, 2-butanone, 1,2-dichloroethane, chlorobenzene, toluene or ethylene glycol dimethyl ether; iii) triphenylphosphine and palladium tetrakis(triphenylphosphine) with sodium propionate, sodium acetate or sodium lactate in tetrahydrofuran or acetone; or iv) palladium acetate in the presence of P(OBu)3 and sodium propionate in THF.
Treatment of the silylated azetidinone (I) with tritylmercaptan affords the tritylsulfanylazetidinone (II), which by reaction with AgNO3 is converted into the silver salt (III). Compound (III) is coupled with tetrahydrofuran-2(R)-carbonyl chloride (IV) ?obtained by treatment of carboxylic acid (V) with thionyl chloride ?to provide the azetidinone thioester (VI). Alternatively, compound (VI) can be obtained by condensation of tetrahydrofuran-2(R)-thiocarboxylic S-acid (VII) ?obtained by treatment of carboxylic acid (V) with hydrogen sulfide ?with silylated azetidinones (I) or (VIII) by means of NaOH in THF/water. Condensation of azetidinone thioester (VI) with allyl glyoxylate (IX) in refluxing benzene gives the hydroxy ester (X), which is treated with SOCl2 to yield the chloro ester (XI). Reaction of compound (XI) with triphenylphosphine and lutidine in hot THF provides the phosphoranylidene derivative (XII), which is converted into (5R,6S)-6-[1(R)-hydroxyethyl]-2-[2(R)-tetrahydrofuryl]penem-3-carboxylic acid allyl ester, faropenem allyl ester (XIII) by removal of the silyl protecting group with tetrabutylammonium fluoride, followed by cyclization in refluxing toluene. Compound (XII) can also be obtained by condensation of the silver salt of protected azetidinone (XIV) with tetrahydrofuran-2(R)-carbonyl chloride (V).
Alternatively, faropenem allyl ester (XIII) can also be prepared by cyclization of compound (XII) in refluxing benzene to yield silylated penem allyl ester (XV), which is then deprotected with either tetrabutylammonium fluoride in AcOH or triethylamine tris(hydrogen fluoride) in methyl isobutyl ketone or toluene. Penem (XV) can also be synthesized by several related ways: a) By coupling of azetidinone (VI) with allyl oxalyl chloride (XVI) in CH2Cl2 by means of Et3N, followed by intramolecular Wittig cyclization by means of triethyl phosphite in refluxing xylene. b) Substitution of phenyl sulfonyl group of azetidinone (VIII) by tritylmercaptan by means of NaOH in acetone/water provides tritylsulfanyl-azetidinone (II), which is condensed with allyl oxalyl chloride (XVI) by means of DIEA in CH2Cl2 to give the oxalyl amide (XVII). Compound (XVII) is then treated with AgNO3 and pyridine in acetonitrile to provide the silver mercaptide (XVIII), which is acylated with tetrahydrofuran-2(R)-carbonyl chloride (IV) in acetonitrile to afford the penem precursor (XIX). Finally, compound (XV) is obtained by intramolecular Wittig cyclization of (XX) with P(OEt)3 in refluxing xylene.
Hydrolysis of faropenem allyl ester (XIII) to faropenem sodium (XX) can be performed under several different conditions: i) triphenylphosphine, sodium 2-ethylhexanoate and palladium tetrakis(triphenylphosphine); ii) palladium tetrakis(triphenylphosphine) and sodium 4-(methoxycarbonyl)- 5,5-dimethylcyclohexane-1,3-dione enolate in several different solvents such as methyl acetate, ethyl acetate, tetrahydrofuran, dioxane, sec-butanol, acetonitrile, acetone, 2-butanone, 1,2-dichloroethane, chlorobenzene, toluene, or ethylene glycol dimethyl ether; iii) triphenylphosphine and palladium tetrakis(triphenylphosphine) with sodium propionate, sodium acetate or sodium lactate in tetrahydrofuran or acetone; and iv) palladium acetate in the presence of P(OBu)3 and sodium propionate in THF. Finally, faropenem daloxate can be directly obtained from faropenem sodium (XX) by esterification with 4-(iodomethyl)-5-methyl-1,3-dioxol-2-one (XXI) in DMF.
https://patents.google.com/patent/CN103059046A/enFaropenem (Faropenem), chemistry (5R, 6S)-6-[(1R)-hydroxyethyl by name]-2-[(2R)-and tetrahydrofuran (THF)] penem-3-carboxylic acid list sodium salt, by the first exploitation listing in 1997 years of Japanese Suntory company.This medicine is a kind of atypical beta-lactam penems antibiotics, has very strong anti-microbial activity, especially to the anti-microbial activities of the anerobes such as the gram positive organisms such as golden Portugal bacterium, penicillin-fast streptococcus pneumoniae, streptococcus faecium and bacteroides fragilis apparently higher than existing cynnematin, anti-gram-negative bacteria is active similar to oral cephalosporin, and is stable to various β-lactamases.Various clinical studyes show that this medical instrument has clinical effectiveness good, safe, the advantage that renal toxicity and neurotoxicity are little.Its structural formula is as follows:
For synthesizing of Faropenem, existing many reports in the prior art, for example CN101125857A has reported following synthetic route:
Take (3R, 4R)-3-[(R)-1-tert-butyl dimethyl silica ethyl]-4-[(R)-and acetoxyl group] nitrogen heterocyclic din-2-ketone is as starting raw material, and warp gets intermediate compound I with R-(+)-sulfo-tetrahydrofuran (THF)-2-formic acid condensation; Intermediate compound I is carried out acylation reaction with monoene propoxy-oxalyl chloride under the catalysis of alkali, get intermediate II; Intermediate II cyclization under the effect of triethyl-phosphite gets intermediate III; Intermediate III is sloughed hydroxyl protecting group through the effect of tetrabutylammonium, gets intermediate compound IV; Intermediate compound IV decarboxylize protecting group under [four (triphenylphosphine)] palladium and triphenylphosphine effect gets Faropenem.Find that after deliberation the method for the present synthetic Faropenem of reporting is all similar with the disclosed method of above-mentioned CN101125857A, all need remove in two steps the protecting group of hydroxyl and carboxyl, reaction scheme is longer.When removing above-mentioned protecting group, need to use a large amount of tetrabutylammonium and [four (triphenylphosphine)] palladium and triphenylphosphine; these reagent costs are high, toxicity is large; be unfavorable for large industrial production; and can introduce the heavy metal palladium; so that the heavy metal remnants in the Faropenem exceed standard, be not suitable for the production of bulk drug.And when adopting aforesaid method deprotection base, the yield in per step only can reach 60%-75%, has further increased production cost.Embodiment 6The preparation of FaropenemWith intermediate 3(364.5g, 0.8mol) use the 700mL acetic acid ethyl dissolution, to open and stir, 0 ℃ of lower dropping with the 36g trifluoroacetic acid after the dilution of 100mL ethyl acetate dripped off in 1 hour, 0 ℃ of lower reaction 2h that continues.Stopped reaction stirs the sodium bicarbonate aqueous solution of lower dropping 5%, until reaction solution pH is neutral.Emit water layer from the reactor lower end, discard.In reactor, add gradually the ethanolic soln of sodium bicarbonate, until till no longer including solid and separating out.Suction filtration, filter cake gets white solid powder 230g(productive rate 93.7% with acetone-water (10:3, v/v) recrystallization), M.P. 163-164 ℃, detect through HPLC, purity is 99.8%Reference examples 1(5R, 6S)-6-[(R)-1-hydroxyethyl]-2-[(R)-and the 2-TETRAHYDROFUROYL sulfenyl] preparation of penem-3-carboxylic acid propyleneWith (5R, 6S)-6-[(R)-the 1-tert-butyl dimethyl silica ethyl]-2-[(R)-and the 2-TETRAHYDROFUROYL sulfenyl] penem-3-carboxylic acid propylene (150g, 0.342mol) and ammonium bifluoride (59.5g, 1.025mmol) add successively among the 400mL DMF, 55～60 ℃ were reacted 5 hours, stopped reaction, suction filtration, filtrate adds water 800ml, uses ethyl acetate extraction, and organic phase is washed with 5% sodium hydrogen carbonate solution, anhydrous sodium sulfate drying, concentrated, gained incarnadine oily matter gets yellow solid 73g through the petrol ether/ethyl acetate recrystallization, yield 66%.Reference examples 2The preparation of Faropenem(the 5R that reference examples 1 is prepared, 6S)-6-[(R)-the 1-hydroxyethyl]-2-[(R)-and the 2-TETRAHYDROFUROYL sulfenyl] penem-3-carboxylic acid propylene (73g, 0.224mol), 6.5g triphenylphosphine, 6.5g [four (triphenylphosphine)] palladium adds among the 500mL methylene dichloride l successively, the ethyl acetate solution that adds the 2 ethyl hexanoic acid sodium preparation of 500mL 0.5M, stirring at room 1 hour, stopped reaction adds 15mL water in reaction solution, stir 30min, suction filtration, this solid is dissolved in the 100mL water again, adds decolorizing with activated carbon 30min, filter, filtrate adds in the 500mL acetone, place crystallization, get Faropenem 66g, yield 96%.Find that by contrast the total recovery that two steps of reference examples remove hydroxyl and carboxyl-protecting group only has about 63.4%, and single stage method of the present invention removes the yield of hydroxyl and carboxyl-protecting group and can reach more than 90%.Preparation method of the present invention can the one-step removal hydroxyl and carboxyl on protecting group, shortened the production cycle, the deprotecting regent cost is low, toxicity is little, can not cause heavy metal remaining, and have higher reaction yield, is fit to very much the industrial production of raw material medicine.
Publication numberPriority datePublication dateAssigneeTitleCN1939924A *2006-09-082007-04-04鲁南制药集团股份有限公司Industrial production of Fallopeinan sodiumWO2008035153A2 *2006-08-022008-03-27Orchid Chemicals & Pharmaceuticals LimitedProcess for the preparation of beta-lactam antibioticCN103059046A *2013-01-282013-04-24苏州二叶制药有限公司Preparation method of faropenemFamily To Family CitationsCN100522975C *2007-08-232009-08-05东北制药集团公司沈阳第一制药厂Method for preparing faropenemPublication numberPriority datePublication dateAssigneeTitleCN1884284A *2005-06-212006-12-27浙江金华康恩贝生物制药有限公司Process for the preparation of sodium faropenemCN1939924A *2006-09-082007-04-04鲁南制药集团股份有限公司Industrial production of Fallopeinan sodiumCN101125857A *2007-08-232008-02-20东北制药集团公司沈阳第一制药厂Method for preparing faropenemWO2008035153A2 *2006-08-022008-03-27Orchid Chemicals & Pharmaceuticals LimitedProcess for the preparation of beta-lactam antibiotic
Publication numberPriority datePublication dateAssigneeTitle
EP0410727A1 *1989-07-261991-01-30Suntory LimitedProcesses for removing allyl groupsUS4997829A *1985-03-091991-03-05Suntory LimitedPenem compounds, and use thereofEP0574940A1 *1992-06-181993-12-22Tanabe Seiyaku Co., Ltd.Method for removing the protecting group for carboxyl groupWO2007039885A1 *2005-10-052007-04-12Ranbaxy Laboratories LimitedA process for the preparation of faropenemFamily To Family Citations
Publication numberPriority datePublication dateAssigneeTitleCN102964357A *2012-11-112013-03-13苏州二叶制药有限公司Faropenem sodium and tablet thereofCN103059046A *2013-01-282013-04-24苏州二叶制药有限公司Preparation method of faropenemCN103880864A *2014-03-252014-06-25江苏正大清江制药有限公司Method for synthesizing faropenem sodiumCN104086516A *2014-07-182014-10-08成都樵枫科技发展有限公司Synthetic method of R-(+)-sulfotetrahydrofuran-2-formic acidCN101941981B *2009-07-032015-01-21湖南华纳大药厂有限公司Catalyst composition and method for preparing faropenem sodiumCN106860405A *2015-12-142017-06-20山东新时代药业有限公司A kind of faropenem sodium granules and preparation method thereofCN108840877A *2018-06-122018-11-20赤峰迪生药业有限责任公司A kind of preparation method of oxygen cephalosporin intermediate
- ^ Critchley IA, Brown SD, Traczewski MM, Tillotson GS, Janjic N (December 2007). “National and regional assessment of antimicrobial resistance among community-acquired respiratory tract pathogens identified in a 2005-2006 U.S. Faropenem surveillance study”. Antimicrob. Agents Chemother. 51 (12): 4382–9. doi:10.1128/AAC.00971-07. PMC 2168020. PMID 17908940.
- ^ Mushtaq S, Hope R, Warner M, Livermore DM (May 2007). “Activity of faropenem against cephalosporin-resistant Enterobacteriaceae”. J. Antimicrob. Chemother. 59 (5): 1025–30. doi:10.1093/jac/dkm063. PMID 17353220.
- ^ Milazzo I, Blandino G, Caccamo F, Musumeci R, Nicoletti G, Speciale A (March 2003). “Faropenem, a new oral penem: antibacterial activity against selected anaerobic and fastidious periodontal isolates”. J. Antimicrob. Chemother. 51 (3): 721–5. doi:10.1093/jac/dkg120. PMID 12615878.
- ^ Gettig JP, Crank CW, Philbrick AH (January 2008). “Faropenem medoxomil”. Ann Pharmacother. 42 (1): 80–90. doi:10.1345/aph.1G232. PMID 18094341. Archived from the original on 2013-02-03.
- ^ (Q1 06 Investor Conf Call)(CID 6918218 from PubChem)
|AHFS/Drugs.com||International Drug Names|
|ATC code||J01DI03 (WHO)|
|CompTox Dashboard (EPA)||DTXSID0046430|
|Chemical and physical data|
|Molar mass||285.31 g·mol−1|
|3D model (JSmol)||Interactive image|
|(what is this?) (verify)|
///////////Faropenem, ALP-201, SUN-5555, SY-5555, WY-49605, ANTIBACTERIALS, DIICHI, Daiichi Asubio Pharma
NEW DRUG APPROVALS
AUR-101, a ROR gamma inverse agonist for autoimmune disorders like psoriasis
AUR-101 is an ROR-gammaT inverse agonist in phase II clinical development at Aurigene for the treatment of patients with moderate-to-severe chronic plaque-type psoriasis.
- DrugsAUR 101 (Primary)
- IndicationsPlaque psoriasis
- FocusAdverse reactions; First in man
- SponsorsAurigene Discovery Technologies
- OriginatorAurigene Discovery Technologies
- ClassAntipsoriatics; Small molecules
- Mechanism of ActionNuclear receptor subfamily 1 group F member 3 inverse agonists
- Phase IIPsoriasis
- 28 Aug 2021No recent reports of development identified for phase-I development in Psoriasis(In volunteers) in Australia (PO, Tablet)
- 23 Apr 2021Aurigene Discovery Technologies plans a phase II INDUS-3 trial for Psoriasis in USA (PO) in May 2021 (NCT04855721)
- 15 Apr 2021Aurigene Discovery Technologies completes a phase II trial in Psoriasis in India (PO) (NCT04207801)
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AURIGENE ANNOUNCES FIRST PATIENT DOSED WITH AUR101 IN PHASE II STUDY IN PATIENTS WITH MODERATE TO SEVERE PSORIASIS
Aurigene Announces First Patient Dosed with AUR101 in Phase II Study in Patients with Moderate to Severe Psoriasis
Bangalore, February 17, 2020 — Aurigene, a development stage biotechnology company, today announced dose administration for the first patient in INDUS-2, a Phase II double blind placebo-controlled three-arm study of AUR101 in patients with moderate to severe psoriasis. AUR101 is an oral small molecule inverse agonist of RORγ and has shown desirable pharmacodynamic modulation of IL-17 and acceptable safety in a completed Phase I human study conducted in Australia.
“The initiation of this Phase II study under a US FDA IND represents a significant milestone for Aurigene, as it marks the first program which Aurigene has led from the bench side to the clinic all by itself,” said Murali Ramachandra, PhD, Chief Executive Officer of Aurigene. “We look forward to producing important clinical data by the end of 2020 to guide our future development plans and demonstrating Aurigene’s unique expertise in conducting Proof-of-Concept studies in a quality and fast-paced manner.”
About AUR101-201 and the Phase II Study of AUR101 in Patients with Moderate to Severe Psoriasis
The purpose of the Phase II multi-center, blinded, placebo-controlled, three-arm study is to evaluate the clinical activity of AUR101 in patients with moderate to severe psoriasis. In two of the arms, AUR101 will be administered twice daily, at 400 mg PO BID and 600 mg PO BID, for 12 weeks. Patients in the third arm will receive matched blinded placebo in a double dummy fashion. The trial is listed at clinicaltrials.gov with identifier NCT04207801.
Aurigene is a development stage biotech company engaged in discovery and clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases and a wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY,NYSE: RDY). Aurigene is focused on precision- oncology, oral immune checkpoint inhibitors, and the Th-17 pathway. Aurigene currently has several programs from its pipeline in clinical development. Aurigene has also submitted an IND to DCGI, India for a Phase IIb/III trial of CA-170, a dual inhibitor of PD-L1 and VISTA, in non-squamous NSCLC. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has partnered with many large and mid-pharma companies in the United States and Europe and has 15 programs currently in clinical development. For more information, please visit Aurigene’s website at https://www.aurigene.com/.
Signalling of multiple interleukin (IL)-17 family cytokines via IL-17 receptor A drives psoriasis-related inflammatory pathways
M.A.X. Tollenaere,J. Hebsgaard,D.A. Ewald,P. Lovato,S. Garcet,X. Li,S.D. Pilger,M.L. Tiirikainen,M. Bertelsen,J.G. Krueger,H. Norsgaard,First published: 01 April 2021 https://doi.org/10.1111/bjd.20090Citations: 2Funding sources LEO Pharma A/S funded this study.Conflicts of interest M.A.X.T., J.H., D.A.E., P.L., S.D.P., M.L.T., M.B. and H.N. are employees of LEO Pharma. J.G.K. received grants paid to his institution from Novartis, Pfizer, Amgen, Lilly, Boehringer, Innovaderm, BMS, Janssen, AbbVie, Paraxel, LEO Pharma, Vitae, Akros, Regeneron, Allergan, Novan, Biogen MA, Sienna, UCB, Celgene, Botanix, Incyte, Avillion and Exicure; and personal fees from Novartis, Pfizer, Amgen, Lilly, Boehringer, Biogen Idec, AbbVie, LEO Pharma, Escalier, Valeant, Aurigene, Allergan, Asana, UCB, Sienna, Celgene, Nimbus, Menlo, Aristea, Sanofi, Sun Pharma, Almirall, Arena and BMS.Data Availability Statement The gene array dataset described in this publication has been deposited in NCBI’s Gene Expression Omnibus and is accessible through GEO Series accession number GSE158448 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE158448).
10:35 Small Molecule Inhibitors of RORgamma and IRAK4 for the Treatment of Autoimmune Disorders
Susanta Samajdar, Ph.D., Director, Medicinal Chemistry, Aurigene Discovery Technologies Limited
Although biologics such as anti-TNFα antibody are fairly successful in the treatment of autoimmune disorders, there is significant unmet need due to heterogeneity in diseases and lack of response to established therapies in some patients. While biologics typically target one cytokine signaling pathway, small molecule therapeutics directed towards intracellular target(s) can interfere in the signaling from multiple cytokines potentially leading to improved response. Development of small molecule oral inhibitors of IRAK4 and RORgamma to target TLR/IL-R and Th17 pathway respectively will be discussed.
2448/CHE/2015 15.05.2015 IN
This application claims the benefit of Indian provisional application number 5641/CHE/2013 filed on 06th December 2013 which hereby incorporated by reference.
- KOTRABASAIAH UJJINAMATADA, Ravi
- PANDIT, Chetan
2-Quinolinecarboxamide, 6-(2,6-dimethyl-4-pyrimidinyl)-N-[[4-(ethylsulfonyl)phenyl]methyl]-5,6,7,8-tetrahydro-6-methyl-5-oxo-, (6S)-
Molecular Weight492.59, C26 H28 N4 O4 S
2013239366 CA 170
NEW DRUG APPROVALS
///////////////////////AUR 101, AURIGENE, ROR, IL-17, PHASE 2, CDSCO, Ravi Ujjinamatada, KOTRABASAIAH UJJINAMATADA Ravi, PANDIT Chetan, AUR101-201, plaque-type psoriasis
- Molecular FormulaC15H13N3O4S
- Average mass331.346 Da
1,1-Dioxyde de 4-hydroxy-2-méthyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide
2H-1,2-Benzothiazine-3-carboxamide, 4-hydroxy-2-methyl-N-2-pyridinyl-, 1,1-dioxide
CAS Registry Number: 36322-90-4
CAS Name: 4-Hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide
Additional Names: 3,4-dihydro-2-methyl-4-oxo-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide
Manufacturers’ Codes: CP-16171
Trademarks: Artroxicam (Coli); Baxo (Toyama); Bruxicam (Bruschettini); Caliment (Apotex); Erazon (Krka); Feldene (Pfizer); Flogobene (Farge); Geldene (Pfizer); Improntal (Kabi); Larapam (Lagap); Pirkam (DAK); Piroflex (Lagap); Reudene (ABC); Riacen (Chiesi); Roxicam (Gramon); Roxiden (Pulitzer); Sasulen (Andreu); Solocalm (Microsules); Zunden (Luitpold)Molecular Formula: C15H13N3O4S
Molecular Weight: 331.35
Percent Composition: C 54.37%, H 3.95%, N 12.68%, O 19.31%, S 9.68%
Literature References: Non-steroidal anti-inflammatory with long half-life. Prepn (keto form): J. Lombardino, DE1943265; idem,US3591584 (1970, 1971 to Pfizer).Synthesis and biological properties: J. Lombardino, E. Wiseman, J. Med. Chem.15, 848 (1972); J. Lombardino et al.,ibid.16, 493 (1973). Pharmacology: E. Wiseman et al.,Arzneim.-Forsch.26, 1300 (1976). Evaluation of ulcerogenic effects: G. Palacios et al.,Methods Find. Exp. Clin. Pharmacol.9, 353 (1987). Clinical pharmacology: L. Martinez et al.,ibid.10, 729 (1988). Review:eidem, in Pharmacological and Biochemical Properties of Drug Substancesvol. 3, M. E. Goldberg, Ed. (Am. Pharm. Assoc., Washington, DC, 1981) pp 324-346. Review of pharmacology and therapeutic efficacy: R. N. Brogden et al.,Drugs22, 165-187 (1981); eidem,ibid.28, 292-323 (1984). Symposium on clinical efficacy and safety: Am. J. Med.81, Suppl. 5B, 1-55 (1986). Comprehensive description: M. Mihalic et al.,Anal. Profiles Drug Subs.15, 509-531 (1986).
Properties: Crystals from methanol, mp 198-200°. pKa 6.3 (2:1 dioxane-water). LD50 orally in mice: 360 mg/kg (Wiseman).
Melting point: mp 198-200°
pKa: pKa 6.3 (2:1 dioxane-water)
Toxicity data: LD50 orally in mice: 360 mg/kg (Wiseman)
Derivative Type: Cinnamic acid ester
CAS Registry Number: 87234-24-0
Additional Names: Piroxicam cinnamate; cinnoxicam
Manufacturers’ Codes: SPA-S-510
Trademarks: Sinartrol (SPA); Zelis (Proter); Zen (Prophin)
Molecular Formula: C24H19N3O5S
Molecular Weight: 461.49
Percent Composition: C 62.46%, H 4.15%, N 9.11%, O 17.33%, S 6.95%
Derivative Type: Compd with b-cyclodextrinCAS Registry Number: 121696-62-6
Trademarks: Brexin (Chiesi); Cicladol (Master); Cycladol (Promedica)
Molecular Formula: C57H83N3O39S
Molecular Weight: 1466.33
Percent Composition: C 46.69%, H 5.71%, N 2.87%, O 42.55%, S 2.19%
Keywords: Anti-inflammatory (Nonsteroidal); Thiazinecarboxamides.
- LD50:250 mg/kg (M, p.o.);
216 mg/kg (R, p.o.);
108 mg/kg (dog, p.o.)
Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class used to relieve the symptoms of painful inflammatory conditions like arthritis. Piroxicam works by preventing the production of endogenous prostaglandins] which are involved in the mediation of pain, stiffness, tenderness and swelling. The medicine is available as capsules, tablets and (not in all countries) as a prescription-free gel 0.5%. It is also available in a betadex formulation, which allows a more rapid absorption of piroxicam from the digestive tract. Piroxicam is one of the few NSAIDs that can be given parenteral routes.
It is used in the treatment of certain inflammatory conditions like rheumatoid and osteoarthritis, primary dysmenorrhoea, postoperative pain; and act as an analgesic, especially where there is an inflammatory component. The European Medicines Agency issued a review of its use in 2007 and recommended that its use be limited to the treatment of chronic inflammatory conditions, as it is only in these circumstances that its risk-benefit ratio proves to be favourable.
See also: Nonsteroidal anti-inflammatory drug
As with other NSAIDs the principal side effects include: digestive complaints like nausea, discomfort, diarrhoea and bleeds or ulceration of the stomach, as well as headache, dizziness, nervousness, depression, drowsiness, insomnia, vertigo, hearing disturbances (such as tinnitus), high blood pressure, oedema, light sensitivity, skin reactions (including, albeit rarely, Stevens–Johnson syndrome and toxic epidermal necrolysis) and rarely, kidney failure, pancreatitis, liver damage, visual disturbances, pulmonary eosinophilia and alveolitis. Compared to other NSAIDs it is more prone to causing gastrointestinal disturbances and serious skin reactions.
In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.
Mechanism of action
See also: Nonsteroidal anti-inflammatory drug
The project that produced piroxicam began in 1962 at Pfizer; the first clinical trial results were reported in 1977, and the product launched in 1980 under the brand name “Feldene”. Major patents expired in 1992 and the drug is marketed worldwide under many brandnames.
Influence of Structure on the Spectroscopic Properties of the Polymorphs of Piroxicam
https://patents.google.com/patent/CN101210013A/enIn the glassed steel reaction vessels of 2000L, add first ethyl ester thing 140Kg, dimethylbenzene 1500L, silica gel 10Kg.Be warming up to 100 ℃ of amino pyrrole 52Kg of adding 2-, continue to be warming up to the solvent refluxing temperature, keep refluxing slowly, steam the ethanol of reaction generation and the mixture of dimethylbenzene simultaneously, TLC follows the tracks of reaction, and reaction in 4.5-5 hour finishes.Underpressure distillation, the control temperature in the kettle is no more than 70 ℃, when the system volume be about cumulative volume 1/3 the time stop distillation, be cooled to normal temperature, stir 6-8h and filter, be i.e. crude product.Crude product adds methyl alcohol 1500L and adds the 15Kg gac, refluxes 30 minutes, filters, and is cooled to normal temperature, stirs 6-8h, methyl alcohol drip washing, 60-70 ℃ is dried by the fire 3-5h, measure product 140.5Kg, yield 85%.Press Cp2005 version standard detection, outward appearance; Off-white color, content 〉=99%.Methanol mother liquor reclaims methyl alcohol to overall 1/3 o’clock, and cooling stirring at normal temperature 6-8h filters and collects product, oven dry measure product 10Kg, yield 5.7%, this product meet the Cp2005 version and require to add up to yield.Add up to yield 90.7%.PAPER Bulletin of the Korean Chemical Society, 26(11), 1771-1775; 2005
|CAS-RN||Formula||Chemical Name||CAS Index Name|
|79-04-9||C2H2Cl2O||chloroacetyl chloride||Acetyl chloride, chloro-|
|29209-30-1||C11H11NO5S||3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide||2H-1,2-Benzothiazine-3-carboxylic acid, 3,4-dihydro-2-methyl-4-oxo-, methyl ester, 1,1-dioxide|
|29209-29-8||C10H9NO5S||3-methoxycarbonyl-4-oxo-3,4-dihydro-2H-1,2-benzothiazine 1,1-dioxide||2H-1,2-Benzothiazine-3-carboxylic acid, 3,4-dihydro-4-oxo-, methyl ester, 1,1-dioxide|
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- ^ Weintraub M, Jacox RF, Angevine CD, Atwater EC (1977). “Piroxicam (CP 16171) in rheumatoid arthritis: a controlled clinical trial with novel assessment techniques”. Journal of Rheumatology. 4 (4): 393–404. PMID 342691.
- Dean L (2019). “Piroxicam Therapy and CYP2C9 Genotype”. In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 30742401. Bookshelf ID: NBK537367.
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|Trade names||Feldene, others|
|Other names||Piroksikam, piroxikam|
|ATC code||M01AC01 (WHO) M02AA07 (WHO), S01BC06 (WHO)|
|Legal status||AU: S4 (Prescription only)CA: ℞-onlyUK: POM (Prescription only)US: ℞-onlyEU: Rx-only |
|Metabolism||Liver-mediated hydroxylation and glucuronidation|
|Elimination half-life||50 hours|
|CompTox Dashboard (EPA)||DTXSID5021170|
|Chemical and physical data|
|Molar mass||331.35 g·mol−1|
|3D model (JSmol)||Interactive image|
NEW DRUG APPROVALS
- MW:142.16 g/mol
- InChI Key:GMZVRMREEHBGGF-UHFFFAOYSA-N
- LD50:9200 mg/kg (M, i.v.); 2 g/kg (M, p.o.)
CAS Registry Number: 7491-74-9
CAS Name: 2-Oxo-1-pyrrolidineacetamide
Additional Names: 2-pyrrolidoneacetamide; 2-pyrrolidinoneacetamide; 2-ketopyrrolidine-1-ylacetamide; 1-acetamido-2-pyrrolidinone
Manufacturers’ Codes: UCB-6215
Trademarks: Avigilen (Riemser); Axonyl (Pfizer); Cerebroforte (Azupharma); Encetrop (Alpharma); Gabacet (Sanofi-Synthelabo); Geram (UCB); Nootrop (UCB); Nootropil (UCB); Nootropyl (UCB); Norzetam (UCB); Normabraïn (UCB); Piracebral (Hexal); Piracetrop (Holsten); Sinapsan (Rodleben)Molecular Formula: C6H10N2O2
Molecular Weight: 142.16
Percent Composition: C 50.69%, H 7.09%, N 19.71%, O 22.51%
Literature References: Prepn: H. Morren, NL6509994; eidem,US3459738 (1966, 1969 both to U.C.B.). Pharmacology: Giurgea et al.,Arch. Int. Pharmacodyn. Ther.166, 238 (1967); Giurgea, Moyersoons, ibid.188, 401 (1970); Giurgea et al.,Psychopharmacologia20, 160 (1971). Metabolism and biochemical studies: Gobert, J. Pharm. Belg.27, 281 (1972). Clinical studies: W. J. Oosterveld, Arzneim.-Forsch.30, 1947 (1980); G. Chouinard et al.,Psychopharmacol. Bull.17, 129 (1981); in dyslexia: M. Di Ianni et al.,J. Clin. Psychopharmacol.5, 272 (1985).Properties: Crystals from isopropanol, mp 151.5-152.5°.
Melting point: mp 151.5-152.5°
Piracetam is in the racetams group, with chemical name 2-oxo-1-pyrrolidine acetamide. It is a derivative of the neurotransmitter GABA and shares the same 2-oxo-pyrrolidone base structure with pyroglutamic acid. Piracetam is a cyclic derivative of GABA (gamma-aminobutyric acid). Related drugs include the anticonvulsants levetiracetam and brivaracetam, and the putative nootropics aniracetam and phenylpiracetam.Piracetam is a drug marketed as a treatment for myoclonus and a cognitive enhancer. Evidence to support its use is unclear, with some studies showing modest benefits in specific populations and others showing minimal or no benefit. Piracetam is sold as a medication in many European countries. Sale of piracetam is not illegal in the United States, although it is not regulated nor approved by the FDA so it must be marketed as a dietary supplement.
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A 2001 Cochrane review concluded that there was not enough evidence to support piracetam for dementia or cognitive problems. A 2005 review found some evidence of benefit in older subjects with cognitive impairment. In 2008, a working group of the British Academy of Medical Sciences noted that many of the trials of piracetam for dementia were flawed.
Depression and anxiety
Some sources suggest that piracetam’s overall effect on lowering depression and anxiety is higher than on improving memory. However, depression is reported to be an occasional adverse effect of piracetam.
Peripheral vascular effects of piracetam have suggested its use potential for vertigo, dyslexia, Raynaud’s phenomenon and sickle cell anemia. There is no evidence to support piracetam’s use in sickle cell crisis prevention or for fetal distress during childbirth. There is no evidence for benefit of piracetam with acute ischemic stroke, though there is debate as to its utility during stroke rehabilitation.
Piracetam has been found to diminish erythrocyte adhesion to vascular wall endothelium, making any vasospasm in the capillary less severe. This contributes to its efficacy in promoting microcirculation, including to the brain and kidneys.
Symptoms of general excitability, including anxiety, insomnia, irritability, headache, agitation, nervousness, tremor, and hyperkinesia, are occasionally reported. Other reported side effects include somnolence, weight gain, clinical depression, weakness, increased libido, and hypersexuality.
According to a 2005 review, piracetam has been observed to have the following side effects: hyperkinesia, weight gain, nervousness, somnolence, depression and asthenia.
The LD50 for oral consumption in humans has not been determined. The LD50 is 5.6 g/kg for rats and 20 g/kg for mice, indicating extremely low acute toxicity. For comparison, in rats the LD50 of vitamin C is 12 g/kg and the LD50 of table salt is 3 g/kg.
Mechanisms of action
Piracetam’s mechanism of action, as with racetams in general, is not fully understood. The drug influences neuronal and vascular functions and influences cognitive function without acting as a sedative or stimulant. Piracetam is a positive allosteric modulator of the AMPA receptor, although this action is very weak and its clinical effects may not necessarily be mediated by this action. It is hypothesized to act on ion channels or ion carriers, thus leading to increased neuron excitability. GABA brain metabolism and GABA receptors are not affected by piracetam
Piracetam improves the function of the neurotransmitter acetylcholine via muscarinic cholinergic (ACh) receptors, which are implicated in memory processes. Furthermore, piracetam may have an effect on NMDA glutamate receptors, which are involved with learning and memory processes. Piracetam is thought to increase cell membrane permeability. Piracetam may exert its global effect on brain neurotransmission via modulation of ion channels (i.e., Na+, K+). It has been found to increase oxygen consumption in the brain, apparently in connection to ATP metabolism, and increases the activity of adenylate kinase in rat brains. Piracetam, while in the brain, appears to increase the synthesis of cytochrome b5, which is a part of the electron transport mechanism in mitochondria. But in the brain, it also increases the permeability of some intermediates of the Krebs cycle through the mitochondrial outer membrane.
Piracetam inhibits N-type calcium channels. The concentration of piracetam achieved in central nervous system after a typical dose of 1200 mg (about 100 μM) is much higher than the concentration necessary to inhibit N-type calcium channels (IC50 of piracetam in rat neurons was 3 μM).
Society and culture
In 2009 piracetam was reportedly popular as a cognitive enhancement drug among students.
Piracetam is an uncontrolled substance in the United States meaning it is legal to possess without a license or prescription.
In the United States, piracetam is not approved by the Food and Drug Administration. Piracetam is not permitted in compounded drugs or dietary supplements in the United States. Nevertheless, it is available in a number of dietary supplements.
In the United Kingdom, piracetam is approved as a prescription drug Prescription Only Medicine (POM) number is PL 20636/2524 for adult with myoclonus of cortical origin, irrespective of cause, and should be used in combination with other anti-myoclonic therapies.
In Japan piracetam is approved as a prescription drug.
In Hungary, piracetam was a prescription-only medication, but as of 2020, no prescription is required and piracetam is available as an over-the-counter drug under the name Memoril Mite, and is available in 600 mg pills.
According to the literature reports, the synthetic route of piracetam can be divided into four synthetic methods: α-pyrrolidone method, glycine method, succinic anhydride method and one-step synthesis method: I. α-pyrrolidone method, 2-pyrrolidone is a lactam, which can react with a strong base (sodium hydride or potassium hydride, sodium methoxide) to generate pyrrolidone metal salt, which can be further combined with halogenated ester or halogen Substitute amide reaction to generate N-alkylated product. In 1966, a method for preparing piracetam by reacting pyrrolidone and chloroacetamide in 1,4-dioxane with sodium hydrogen as a strong base was reported. The specific synthetic route is shown in Scheme 1:
 In this process, due to the high price of dioxane, industrial production is still difficult. On the basis of the above process, Xu Yungen used dimethyl sulfoxide as the solvent and sodium methoxide as the acid binding agent to synthesize piracetam in the presence of the phase transfer catalyst benzyltriethylammonium chloride. Due to the difficulty of solvent recovery, the cost of this route is relatively high. In 1981, Zhou Renxing et al. used sodium methoxide as a strong base to extract methanol in toluene by fractional distillation to convert pyrrolidone into the corresponding sodium salt, and then react with ethyl chloroacetate. The resulting ethyl pyrrolidone ethyl acetate was subjected to ammonolysis. Piracetam can be produced. The specific synthetic route is shown in Scheme 2.[00141
 Because the ammonolysis is carried out in a methanol solution of ammonia, the calculated amount of ethanol generated during the ammonolysis contaminates the methanol solution of ammonia used, which affects the recycling of the methanol solution of ammonia, and is therefore not conducive to process production. 2. Glycine method, glycine and its derivatives can be used as starting materials for the synthesis of pyroacetamide. Glycine can be prepared by γ-chlorination butylation, amination and cyclization. According to a British patent report in 1979, glycine trimethylsilyl ester was first condensed with γ-chlorobutyryl chloride, and the corresponding acid chloride was subjected to ammonolysis, and finally cyclized to produce piracetam. The specific synthesis method is as Scheme 3 Shown
 In this type of synthesis route, some raw materials are not easily available, which restricts industrial production. 3. Succinic acid method, succinic acid is heated and dehydrated to generate succinic anhydride, succinic anhydride then reacts with glycine to generate an aminolysis product, and the aminolysis product is reduced by sodium tetrafluoroborate, and piracetam can be synthesized by aminolysis , The specific synthetic route is shown in SCheme4. 
 Because sodium tetrafluoroborate is used as a reducing agent, it is expensive, and it is difficult to expand the scale of industrial production. Succinimide generates sodium salt under the action of metal sodium, and its sodium salt reacts with chloroacetamide to generate N-alkylated product. The alkylated product can be electrolytically reduced to obtain piracetam. Since electrolytic reduction is still in the research stage in our country, the production cost of this method is relatively high. 4. One-step synthesis method, using ethyl 4-chloro-n-butyrate in the presence of sodium bicarbonate, using anhydrous ethanol as a solvent, and glycinamide hydrochloride under heating and refluxing to obtain piracetam in one step, The specific synthetic route is shown in S Cheme5.
 In this route, glycinamide hydrochloride is very easy to absorb moisture and agglomerate to affect the reaction rate, and the reaction is not easy to control, so it is difficult to achieve industrial production.
With absolute ethanol as the solvent, ethyl 4-chloro-n-butanoate and glycinamide hydrochloride were refluxed for 20 h in the presence of sodium bicarbonate to obtain central stimulant piracetam. After recrystallization from isopropanol, the yield was about 58％ with a purity of 99.6％.
|CAS-RN||Formula||Chemical Name||CAS Index Name|
|105-39-5||C4H7ClO2||ethyl chloroacetate||Acetic acid, chloro-, ethyl ester|
|61516-73-2||C8H13NO3||ethyl 2-oxo-1-pyrrolidineacetate||1-Pyrrolidineacetic acid, 2-oxo-, ethyl ester|
Example 1 A method for synthesizing piracetam, which includes the following steps: Preparation of α-pyrrolidone sodium salt: A 1000 mL three-necked flask was equipped with mechanical stirring, a constant pressure dropping funnel and a thorn-shaped fractionating column. The upper end of the fractionation column is connected with a thermometer, a condenser and a 500mL receiving flask. Under mechanical stirring, 46 mL (0.60 mol) of α-pyrrolidone and 250 mL of toluene were sequentially added to the three-necked flask. When the temperature of the reaction system reached 70°C, a methanol solution of sodium methoxide (28.4% (w/w); 114.0 g; 0.60 mol) was added dropwise under reduced pressure, and the distillate was collected. After the dropwise addition is completed, the temperature is increased, and the normal pressure is distilled until the distillate is completely distilled out, and the reaction is completed. Preparation of α-pyrrolidone methyl acetate: remove the fractionation device, connect a thermometer and a condenser, and connect a dropping funnel above the condenser. When the temperature of the reaction system drops to 60°C, a toluene solution of 58 mL (0.66 mol) of methyl chloroacetate is slowly added dropwise, and the reaction temperature is controlled to 80-100°C. Oh。 After the addition is complete, the insulation reaction is 5. Oh. Cool to room temperature, filter with suction, and distill the filtrate under reduced pressure. Collect the fraction (18mmHg) at 100~105°C to obtain α-pyrrolidone methyl acetate, and measure its content by HPLC (area normalization method). [C18 column (4.6mmX 200mm, 5 μm) was used for purity determination; acetonitrile-dipotassium hydrogen phosphate/phosphate buffer solution (10:90) was used as the mobile phase (the pH value of phosphoric acid was adjusted to 6.0); the flow rate was 1 . OmL/min; detection wavelength is 205nm; injection volume is 20yL] Preparation of Piracetam: Put about 130 mL of methanol in a 500 mL three-necked flask, and vent ammonia to saturation. The obtained ammonia/methanol solution was mixed with 100. Og α-pyrrolidone methyl acetate and placed in a reaction kettle, reacted at 50~65°C for 10 h, allowed to cool, filtered with suction, and the filter cake was dried. The purification of piracetam: 25.50g crude piracetam and 100mL isopropanol were sequentially added in a 500mL three-necked flask, heated to reflux for 40min, activated carbon was added, reflux stirring, hot filtration, and the resulting properties were all white As a powdery solid, the filter cake was dried overnight at 50°C in a vacuum drying oven to obtain 20.85 g of a white solid with a yield of 81.76% (calculated as α-pyrrolidone, the same below).Example 2 Preparation of α-pyrrolidone sodium salt: A 1000 mL three-necked flask was equipped with mechanical stirring, a constant pressure dropping funnel and a thorn-shaped fractionating column. The upper end of the fractionation column is connected with a thermometer, a condenser and a 500mL receiving flask. Under mechanical stirring, 46 mL (0.60 mol) of α-pyrrolidone and 250 mL of toluene were sequentially added to the three-necked flask. When the temperature of the reaction system reached 100°C, a methanol solution of sodium methoxide (28.4% (w/w)); 114. Og; 0.60 mol) was added dropwise under reduced pressure, and the distillate was collected. After the addition is complete, add toluene, increase the temperature, and distill at normal pressure until the distillate is completely distilled out, and the reaction is complete. Preparation of α-pyrrolidone methyl acetate: remove the fractionation device, connect a thermometer and a condenser, and connect a dropping funnel above the condenser. When the temperature of the reaction system drops to 60°C, a mixed solution of 63 mL (0.72 mol) of methyl chloroacetate and 30 mL of toluene is slowly added dropwise, and the reaction temperature is controlled to 80-100°C. Oh。 After the addition is complete, the insulation reaction is 5. Oh. Cool to room temperature, filter with suction, and distill the filtrate under reduced pressure. Collect the fraction (18mmHg) at 100~105°C to obtain methyl α-pyrrolidone acetate, and measure its content by HPLC (area normalization method). [C18 column (4.6mmX 200mm, 5 μm) was used for purity determination; acetonitrile-dipotassium hydrogen phosphate/phosphate buffer solution (10:90) was used as the mobile phase (the pH value of phosphoric acid was adjusted to 6.0); the flow rate was 1 .OmL/ min; detection wavelength is 205nm; injection volume is 20 μL] Preparation of Piracetam: Put about 130 mL of methanol in a 250 mL three-necked flask, and ventilate ammonia to saturation. The obtained ammonia/methanol solution was mixed with 50.0 g of α-pyrrolidone methyl acetate and placed in a reaction kettle, reacted at 50~65°C for 12 hours, allowed to cool, filtered with suction, and the filter cake was dried. Purification of piracetam: 25.50g crude piracetam and 75mL methanol were sequentially added to a 500mL three-necked flask, heated to reflux for 40min, added activated carbon 0.5g, refluxed for 1h, hot filtered, magnetically stirred Under the conditions, the activated carbon was filtered out, and the properties were all white powdery solids, and the filter cake was dried overnight at 50°C in a vacuum drying oven to obtain 21.02g of white solids with a yield of 82.42%.Embodiment 3 Preparation of α-pyrrolidone sodium salt: A 1000 mL three-necked flask was equipped with mechanical stirring, a constant pressure dropping funnel and a thorn-shaped fractionating column. The upper end of the fractionating column is connected with a thermometer, a condenser and a 1000 mL receiving bottle. Under mechanical stirring, 46 mL (0.60 mol) of α-pyrrolidone and 250 mL of toluene were sequentially added to the three-necked flask. When the temperature of the reaction system reached 70°C, a methanol solution of sodium methoxide (28.4% (w/w)); 114. Og; 0.60 mol) was added dropwise under reduced pressure, and the distillate was collected. After the dropwise addition is completed, the temperature is increased, and the normal pressure is distilled until the distillate is completely distilled out, and the reaction is completed. Preparation of α-pyrrolidone methyl acetate: remove the fractionation device, connect a thermometer and a condenser, and connect a dropping funnel above the condenser. A mixed solution of 79 mL (0.90 mol) of methyl chloroacetate and 50 mL of toluene was slowly added dropwise, and the reaction temperature was controlled to 70-90°C. Oh。 After the addition is complete, the insulation reaction is 5. Oh. Cool to room temperature, filter with suction, and distill the filtrate under reduced pressure. Collect the fraction (18mmHg) at 100~105°C to obtain methyl α-pyrrolidone acetate, and measure its content by HPLC (area normalization method). [C 18 column (4.6mmX 200mm, 5 μm) was used for purity determination; acetonitrile-dipotassium hydrogen phosphate/phosphate buffer solution (10:90) was used as the mobile phase (the pH value of phosphoric acid was adjusted to 6.0); the flow rate was 1.0mL/min; The detection wavelength is 205nm; The injection volume is 20 μL) Preparation of Piracetam: Put about 130 mL of methanol in a 250 mL three-necked flask, and vent ammonia to saturation. The obtained ammonia/methanol solution was mixed with 100. Og α-pyrrolidone methyl acetate and placed in a reaction kettle, reacted at 50~65°C for 14h, allowed to cool, filtered with suction, and the filter cake was dried. Purification of piracetam: 25.50g crude piracetam and 125mL ethanol were sequentially added in a 500mL three-necked flask, heated to reflux for 40min, added activated carbon 0.5g, refluxed for 1h, hot filtered, magnetically stirred Activated carbon was filtered off under conditions to obtain white powdery solids in all properties, and the filter cake was dried overnight at 50°C in a vacuum drying oven to obtain 20.24 g of white solids with a yield of 79.37%.Example 4 Preparation of α-pyrrolidone sodium salt: A 1000 mL three-necked flask was equipped with mechanical stirring, a constant pressure dropping funnel and a thorn-shaped fractionating column. The upper end of the fractionation column is connected with a thermometer, a condenser and a 500mL receiving flask. Under mechanical stirring, 46 mL (0.60 mol) of α-pyrrolidone and 250 mL of toluene were sequentially added to the three-necked flask. When the temperature of the reaction system reached 60°C, a methanol solution of sodium methoxide (28.4% (w/w); 114.0 g; 0.60 mol) was added dropwise under reduced pressure, and the distillate was collected. After the dropwise addition is completed, the temperature is increased, and the normal pressure is distilled until the distillate is completely distilled out, and the reaction is completed. Preparation of α-pyrrolidone methyl acetate: remove the fractionation device, connect a thermometer and a condenser, and connect a dropping funnel above the condenser. A mixed solution of 105 mL (1.20 mol) of methyl chloroacetate and 70 mL of toluene was slowly added dropwise, and the reaction temperature was controlled to be 60~70°C. Oh。 After the addition is complete, the insulation reaction is 5. Oh. Cool to room temperature, filter with suction, and distill the filtrate under reduced pressure. Collect the fraction (18mmHg) at 100~105°C to obtain methyl α-pyrrolidone acetate, and measure its content by HPLC (area normalization method). [C 18 column (4.6mmX 200mm, 5 μm) was used for purity determination; acetonitrile-dipotassium hydrogen phosphate/phosphate buffer solution (10:90) was used as the mobile phase (the pH value of phosphoric acid was adjusted to 6.0); the flow rate was 1.0mL/min; The detection wavelength is 205nm; The injection volume is 20 μL) Preparation of Piracetam: Put about 130 mL of methanol in a 500 mL three-necked flask, and ventilate ammonia to saturation. The obtained ammonia/methanol solution was mixed with 100. Og α-pyrrolidone methyl acetate and placed in a reaction kettle, reacted at 50~65°C for 16h, allowed to cool, filtered with suction, and the filter cake was dried. The purification of piracetam: 25.50g crude piracetam and 100mL methanol were sequentially added into a 500mL three-necked flask, heated to reflux for 40min, added activated carbon, refluxed for dissolution, hot filtered, and the properties were all white powders The solid, the filter cake was dried overnight at 50°C in a vacuum drying oven to obtain 20.69 g of a white solid, with a yield of 81. 13%. Chemical analysis of the white crystals synthesized in each of the foregoing examples, and the obtained physical property values are as follows, thereby confirming that the synthesized product is piracetam. Melting point: 151.6-152. (TC ESI-MS m / z: 165. 06 [M + Na] + 1H-NMR (400MHz, DMS〇-d6, ppm) δ ： 7. 38 (s, 1H), 7. 09 (s, 1H), 3. 74 (s, 2H), 3. 36 (t, J =7. 08Hz, 2H), 2. 23 (t, J = 7. 84Hz, 2H), I. 93 (m, 2H). 13C-NMR(100MHz, DMS0-d6, ppm) δ : 17. 80, 30. 42, 45. 28, 47. 74, 170. 21，174. 90.
PATENTCN110903230A *2019-12-042020-03-24Beijing Yuekang Kechuang Pharmaceutical Technology Co., Ltd.An industrialized preparation method of Pramiracetam sulfate
PATENTCN104478779A2015-04-01New synthetic method of nootropic drug Piracetam
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- ^ Nickolson VJ, Wolthuis OL (October 1976). “Effect of the acquisition-enhancing drug piracetam on rat cerebral energy metabolism. Comparison with naftidrofuryl and methamphetamine”. Biochemical Pharmacology. 25 (20): 2241–4. doi:10.1016/0006-2952(76)90004-6. PMID 985556.
- ^ Tacconi MT, Wurtman RJ (1986). “Piracetam: physiological disposition and mechanism of action”. Advances in Neurology. 43: 675–85. PMID 3946121.
- ^ Yeh HH, Yang YH, Ko JY, Chen SH (July 2006). “Rapid determination of piracetam in human plasma and cerebrospinal fluid by micellar electrokinetic chromatography with sample direct injection”. J Chromatogr A. 1120 (1–2): 27–34. doi:10.1016/j.chroma.2005.11.071. PMID 16343512.
- ^ Bravo-Martínez J, Arenas I, Vivas O, Rebolledo-Antúnez S, Vázquez-García M, Larrazolo A, García DE (October 2012). “A novel CaV2.2 channel inhibition by piracetam in peripheral and central neurons”. Exp Biol Med (Maywood). 237 (10): 1209–18. doi:10.1258/ebm.2012.012128. PMID 23045722.
- ^ Li JJ, Corey EJ (2013). Drug Discovery: Practices, Processes, and Perspectives. John Wiley & Sons. p. 276. ISBN 9781118354469.
- ^ Schmidt D, Shorvon S (2016). The End of Epilepsy?: A History of the Modern Era of Epilepsy Research 1860-2010. Oxford University Press. p. 69. ISBN 9780198725909.
- ^ Medew J (1 October 2009). “Call for testing on ‘smart drugs'”. Fairfax Media. Retrieved 29 May 2014.
- ^ “Erowid Piracetam Vault: Legal Status”.
- ^ Jann Bellamy (26 September 2019). “FDA proposes ban on curcumin and other naturopathic favorites in compounded drugs”. Science-Based Medicine.
- ^ “Nootropil Tablets 800 mg”. (emc).
- ^ “UCB’s piracetam approved in Japan”. The Pharma Letter. 25 November 1999.
- ^ “Guidance Document on the Import Requirements for Health Products under the Food and Drugs Act and its Regulations (GUI-0084)”. Health Canada / Health Products and Food Branch Inspectorate. 1 June 2010. Retrieved 15 December 2019.
- UCB Pharma Limited (2005). “Nootropil 800 mg & 1200 mg Tablets and Solution”. electronic Medicines Compendium. Datapharm Communications. Archived from the original on 7 December 2006. Retrieved 8 December 2005.
Gouliaev AH, Senning A (May 1994). “Piracetam and other structurally related nootropics”. Brain Research. Brain Research Reviews. 19 (2): 180–222. doi:10.1016/0165-0173(94)90011-6. PMID 8061686. S2CID 18122566.
|Trade names||Breinox, Dinagen, Lucetam, Nootropil, Nootropyl, Oikamid, Piracetam and many others|
|AHFS/Drugs.com||International Drug Names|
|By mouth, parenteral, or vaporized|
|ATC code||N06BX03 (WHO)|
|Legal status||AU: S4 (Prescription only)CA: UnscheduledUK: POM (Prescription only)US: Unscheduled (Not permitted as drug or supplement)|
|Onset of action||Swiftly following administration. Food delays time to peak concentration by 1.5 h approximately to 2–3 h since dosing.|
|Elimination half-life||4–5 h|
|CompTox Dashboard (EPA)||DTXSID5044491|
|Chemical and physical data|
|Molar mass||142.158 g·mol−1|
|3D model (JSmol)||Interactive image|
|Melting point||152 °C (306 °F)|
///////////UCB 6215, Nootropic, PIRACETAM
NEW DRUG APPROVALS
REACH (EC 1907/2006)aims to improve the protection of human health and the environment through the better and earlier identification of the intrinsic properties of chemical substances. This is done by the four processes of REACH, namely the registration, evaluation, authorisation and restriction of chemicals. REACH also aims to enhance innovationand competitiveness of the EU chemicals industry.
“No data no market”: the REACH Regulation places responsibility on industry to manage the risks from chemicals and to provide safety information on the substances. Manufacturers and importers are required to gather information on the properties of their chemical substances, which will allow their safe handling, and to register the information in a central database in theEuropean Chemicals Agency (ECHA)in Helsinki. The Agency is the central point in the REACH system: it manages the databases necessary to operate the system, co-ordinates the in-depth evaluation of suspicious chemicals and is…
View original post 4,663 more words
Chemical Formula: C22H27NO3S
Molecular Weight: 385.522
Drug Name：VCH-759Research Code：VX-759; BCH-27759; VCH-759
VX-759; BCH-27759; VCH-759; VX759; BCH27759; VCH759; VX 759; BCH 27759; VCH 759; NNI-1
- 3-[[(trans-4-Methylcyclohexyl)carbonyl](1-methylethyl)amino]-5-phenyl-2-thiophenecarboxylic acid
- 3-[Isopropyl(trans-4-methylcyclohexylcarbonyl)amino]-5-phenylthiophene-2-carboxylic acid
- NNI 1
MOA：NS5B inhibitorIndication：HCV infectionStatus：Phase Ⅱ (Discontinued)Company：Vertex (Originator)
|Synonyms||VX-759 sodium saltBCP17193|
VCH-759 had been in phase II clinical trials by ViroChem Pharma (acquired by Vertex in 2009) for the treatment of HCV infection. However, this research has been discontinued.
Infection with HCV is a major cause of human liver disease throughout the world. In the US, an estimated 4.5 million Americans are chronically infected with HCV. Although only 30% of acute infections are symptomatic, greater than 85% of infected individuals develop chronic, persistent infection. Treatment costs for HCV infection have been estimated at $5.46 billion for the US in 1997. Worldwide over 200 million people are estimated to be infected chronically. HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants. Chronic HCV infection accounts for 30% of all cirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year by the year 2010.
Due to the high degree of variability in the viral surface antigens, existence of multiple viral genotypes, and demonstrated specificity of immunity, the development of a successful vaccine in the near future is unlikely. Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection. However, adverse side effects are commonly associated with this treatment: flu-like symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia induced by ribavirin (Lindsay, K. L. (1997) Hepatology 26 (suppl 1 ): 71 S-77S). This therapy remains less effective against infections caused by HCV genotype 1 (which constitutes -75% of all HCV infections in the developed markets) compared to infections caused by the other 5 major HCV genotypes. Unfortunately, only -50-80% of the patients respond to this treatment (measured by a reduction in serum HCV RNA levels and normalization of liver enzymes) and, of responders, 50-70% relapse within 6 months of cessation of treatment. Recently, with the introduction of pegylated interferon (Peg-IFN), both initial and sustained response rates have improved substantially, and combination treatment of Peg-IFN with ribavirin constitutes the gold standard for therapy. However, the side effects associated with combination therapy and the impaired response in patients with genotype 1 present opportunities for improvement in the management of this disease.
First identified by molecular cloning in 1989 (Choo, Q-L et al (1989) Science 244:359-362), HCV is now widely accepted as the most common causative agent of post-transfusion non A, non-B hepatitis (NANBH) (Kuo, G et al (1989) Science 244:362-364). Due to its genome structure and sequence homology, this virus was assigned as a new genus in the Flaviviridae family. Like the other members of the Flaviviridae, such as flaviviruses (e.g. yellow fever virus and Dengue virus types 1-4) and pestiviruses (e.g. bovine viral diarrhea virus, border disease virus, and classic swine fever virus) (Choo, Q-L et al (1989) Science 244:359-362; Miller, R.H. and R.H. Purcell (1990) Proc. Natl. Acad. Sci. USA 87:2057-2061 ), HCV is an enveloped virus containing a single strand RNA molecule of positive polarity. The HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5′ nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang CY et al ‘An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5′ noncoding region’ RNA- A Publication of the RNA Society. 1 (5): 526-537, 1995 JuL). This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins. This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2nd Edition, p931-960; Raven Press, N.Y.). Following the termination codon at the end of the long ORF, there is a 3′ NTR which roughly consists of three regions: an – 40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the “3′ X-tail” (Kolykhalov, A. et al (1996) J. Virology 70:3363-3371 ; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun. 215:744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N. et al (1996) Virology 223:255-261 ). The 3′ NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.
The NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S. E. et al (1996) EMBO J. 15:12-22), encodes an RNA-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases. The NS5B protein is fairly well conserved both intra-typically (-95-98% amino acid (aa) identity across 1 b isolates) and inter-typically (-85% aa identity between genotype 1 a and 1 b isolates). The essentiality of the HCV NS5B RdRp activity for the generation of infectious progeny virions has been formally proven in chimpanzees (A. A. Kolykhalov et al.. (2000) Journal of Virology, 74(4): 2046-2051 ). Thus, inhibition of NS5B RdRp activity (inhibition of RNA replication) is predicted to be useful to treat HCV infection.
Although the predominant HCV genotype worldwide is genotype 1, this itself has two main subtypes, denoted 1a and 1 b. As seen from entries into the Los Alamos HCV database
(www.hcv.lanl.gov) (Table 1 ) there are regional differences in the distribution of these subtypes: while genotype 1 a is most abundant in the United States, the majority of sequences in Europe and Japan are from genotype 1 b.
Based on the foregoing, there exists a significant need to identify synthetic or biological compounds for their ability to inhibit replication of both genotype 1 a and genotype 1 b of HCV.
To a mixture of methyl S-^trans^-methylcyclohexyOcarbonylKI-methylethy^aminol-S-phenyl-2-thiophenecarboxylate (Intermediate 31 ) (390 mg) in THF/MeOH/water (3:2:1, vol/vol, 40 ml. total) was added lithium hydroxide monohydrate (246 mg). The mixture was stirred at room temperature for 20 hours, the solvents removed in vacuo, and the residue partitioned between water (40 ml.) and ethyl acetate (40 ml_). The organic layer was dried
(Na2SC>4), evaporated and triturated with ether to give the title compound.
MS calcd for (C22H27NO3S+ H)+: 356
MS found (electrospray): (M+H)+ =356
Compounds A, B, C and D may be made according to the processes described in WO2002/100851 or as described hereinabove.
Structures of Compounds A, B, C and D are shown below for the avoidance of doubt.
The compounds of Formula (I) which have been tested demonstrate a surprisingly superior potency as HCV polymerase inhibitors, as shown by the IC5O values in the cell-based assays across both of the 1 a and 1 b genotypes of HCV, compared to Compounds A, B, C and D. Accordingly, the compounds of Formula (I) are of great potential therapeutic benefit in the treatment and prophylaxis of HCV.
Bioorganic & Medicinal Chemistry Letters (2016), 26(18), 4536-4541.
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|Application Id||Application Number||Application Date||Country||Title|
|US333830037||16610899||04.05.2018||US||IDENTIFICATION AND TARGETED MODULATION OF GENE SIGNALING NETWORKS|
|US77274496||13661508||26.10.2012||US||COMPOUNDS AND METHODS FOR THE TREATMENT OR PREVENTION OF FLAVIVIRUS INFECTIONS|
|US73506396||13172477||29.06.2011||US||Thiophene analogues for the treatment or prevention of flavivirus infections|
|EP29858255||10185737||11.06.2002||EP||Thiophene derivatives as antiviral agents for flavivirus infection|
|US73326585||13081780||07.04.2011||US||Compounds and methods for the treatment or prevention of <i>Flavivirus </i>infections|
|JP272602128||2010103706||28.04.2010||JP||COMPOUND AND METHOD FOR TREATMENT OR PREVENTION OF FLAVIVIRUS INFECTION|
|EP11167270||09167203||11.06.2002||EP||Thiophene derivatives as antiviral agents for flavivirus infection|
|CN83819886||200910139375.5||11.06.2002||CN||Thiophene derivatives as antiviral agents for flavivirus infection|
|US42846304||12097840||20.12.2006||US||Antiviral 2-Carboxy-Thiophene Compounds|
|WO2007071434||PCT/EP2006/012442||20.12.2006||WO||ANTIVIRAL 2-CARBOXY-THIOPHENE COMPOUNDS|
|US41429134||11042442||26.01.2005||US||Compounds and methods for the treatment or prevention of <i>Flavivirus </i>infections|
|CN82792692||02815768.0||11.06.2002||CN||Thiophene derivatives used as antiviral agent against flavivirus infections|
|EA95398282||200400022||11.06.2002||EA||COMPOUNDS AND METHODS FOR THE TREATMENT OR PREVENTION OF FLAVIVIRUS INFECTIONS|
|US40367952||10166031||11.06.2002||US||Compounds and methods for the treatment or prevention of Flavivirus infections|
|KR588271||1020037016240||11.12.2003||KR||THIOPHENE DERIVATIVES AS ANTIVIRAL AGENTS FOR FLAVIVIRUS INFECTION|
|EP14092312||02742563||11.06.2002||EP||THIOPHENE DERIVATIVES AS ANTIVIRAL AGENTS FOR FLAVIVIRUS INFECTION|
|WO2002100851||PCT/CA2002/000876||11.06.2002||WO||THIOPHENE DERIVATIVES AS ANTIVIRAL AGENTS FOR FLAVIVIRUS INFECTION|
////////////////VX-759, BCH-27759, VCH-759, VX759, BCH27759, VCH759, VX 759, BCH 27759, VCH 759, NNI-1
NEW DRUG APPROVALS
- Molecular FormulaC26H17ClF9N3O3
- Average mass625.870 Da
On 9 September 2021, the Committee for Medicinal Products for Veterinary Use (CVMP) adopted a positive opinion1, recommending the granting of a variation to the terms of the marketing authorisation for the veterinary medicinal product Frontpro. The marketing authorisation holder for this veterinary medicinal product is Boehringer Ingelheim Vetmedica GmbH. ,,,, https://www.ema.europa.eu/en/medicines/veterinary/summaries-opinion/frontpro-previously-known-afoxolaner-merial
Frontpro is currently authorised as chewable tablets for use in dogs. The variation concerns the change of legal status from prescription-only to non-prescription veterinary medicine. Additionally, the applicant is adding the list of local representatives to the package leaflet.
Detailed conditions for the use of this product are described in the summary of product characteristics (SPC), for which an updated version reflecting the changes will be published in the revised European public assessment report (EPAR) and will be available in all official European Union languages after the variation to the marketing authorisation has been granted by the European Commission.
|Name||Frontpro (previously known as Afoxolaner Merial)|
|Agency product number||EMEA/V/C/005126|
|International non-proprietary name (INN) or common name||afoxolaner|
|Date opinion adopted||09/09/2021|
|Company name||Boehringer Ingelheim Vetmedica GmbH|
|Medicine||Frontpro (previously known as Afoxolaner Merial)|
|Pharmacotherapeutic Classes||Ectoparasiticides for systemic use|
|Status||This medicine is authorized for use in the European Union|
|Company||Boehringer Ingelheim Vetmedica GmbH|
European Medicines Agency (EMA)
|Active Substance||afoxolaner, milbemycin oxime|
|INN/Common name||afoxolaner, milbemycin oxime|
|Pharmacotherapeutic Classes||Endectocides, Antiparasitic products, insecticides and repellents, milbemycin oxime, combinations|
|Status||This medicine is authorized for use in the European Union|
|Company||Boehringer Ingelheim Vetmedica GmbH|
|Pharmacotherapeutic Classes||Isoxazolines, Ectoparasiticides for systemic use|
|Status||This medicine is authorized for use in the European Union|
|Company||Boehringer Ingelheim Vetmedica GmbH|
European Medicines Agency (EMA)
A particularly active isoxazoline compound, 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,24rifluoroethyl)amino]ethyl]-l-naphthalenecarboxamide, is known by the nonproprietary name afoxolaner. Afoxolaner has the following chemical structure:
Other isoxazoline compounds that have been found to be highly active against parasitic insects and arachnids are known by the nonproprietary names fluralaner (see US 7,662,972, which is incorporated herein by reference), sarolaner (see US 8,466, 15, incorporated herein by reference) and lotilaner (see, for example US 8,383,659, incorporated herein by reference). The structures of these compounds are shown below:
In addition, published patent application nos. US 2010/0254960 Al, WO 2007/070606
A2, WO 2007/123855 A2, WO 2010/003923 Al, US7951828 & US7662972, US 2010/0137372 Al, US 2010/0179194 A2, US 2011/0086886 A2, US 2011/0059988 Al, US 2010/0179195 Al and WO 2007/075459 A2 and U.S. Patent No. 7,951,828 (all incorporated herein by reference) describe various other parasiticidal isoxazoline compounds.
It is known in the field that isoxazoline compounds having a chiral quaternary carbon atom such as the carbon atom adjacent to the oxygen on the isoxazoline ring of the compounds described above have at least two optical isomer (enantiomers) that are mirror images of each other. Furthermore, it is sometimes the case with biologically active compounds that one of the enantiomers is more active than the other enantiomer. In addition, it is sometimes the case that one enantiomer of a biologically active compound is less toxic than the other enantiomer.
Therefore, with optically active compounds it is desirable to utilize the enantiomer that is most active and less toxic (eutomer). However, isolating the most active enantiomer from a mixture can be costly and result in waste of up to half of the racemic mixture prepared.
Processes to prepare certain isoxazoline compounds enriched in an enantiomer using some cinchona alkaloid-derived phase transfer catalysts have been described. For example, US 2014/0206633 Al, US 2014/0350261 Al, WO 2013/116236 Al and WO 2014/081800 Al (incorporated herein by reference) describe the synthesis of certain isoxazoline active agents enriched in an enantiomer using cinchona alkaloid-based chiral phase transfer catalysts. Further, Matoba et al., Angew. Chem. 2010, 122, 5898-5902 describes the chiral synthesis of certain pesticidal isoxazoline active agents. However, these documents do not describe the processes and certain catalysts described herein.
Example 7: Preparation of (S)-afoxolaner using chiral phase transfer catalyst (Ilia- 13-1):
1) Starting material (IIA-1) (200g, 1.Oeq, 94.0%) and DCM (6 L, 30 volumes) were placed into a 10 L reactor, the solid was dissolved completely.
2) The mixture was cooled to 0°C, and some starting material precipitated out.
3) The catalyst (Ilia- 13-1) (7.56g, 3% mol, 95.0%) was added to the mixture and the resulting mixture cooled further to -10° C.
4) Hydroxylamine (64.9 g, 3.0 eq, 50% solution in water) was added to a solution of NaOH (52.5g, 4. Oeq, in 5v water) in a separate reactor and stirred for 30 minutes.
5) The resulting hydroxylamine/NaOH solution was then added dropwise to the 10 L reactor containing (IIA-1) over about 4 hours.
6) The resulting mixture was stirred for 12 hours at -10°C and monitored for the extent of reaction until the amount of starting material was < 1.0% by HPLC.
7) The mixture was then warmed to 10°C, 1 liter of water was added and the mixture was stirred for 10 minutes.
8) The mixture was allowed to settle to separate the two phases, and the organic layer was collected.
9) The organic layer was then washed with 2 liters of water, the layers were allowed to separate again and the organic layer was collected.
10) The organic layer was washed with 1 liter of brine, the layers allowed to separate and the organic layer was collected and dried over Na2S04 (200 g).
11) The dried organic layer was concentrated under vacuum to about 2 volumes.
12) Toluene (2 L, 10 volumes) was charged to the concentrated mixture and concentration under vacuum was continued to about 5 volumes. Solvent exchange was repeated twice again.
13) The resulting solution was placed into a 2.0 L reactor and heated to 55-60°C.
14) Cyclohexane (300 ml, 1.5 volumes) was added at 55-60°C.
15) The mixture was then cooled to 40 °C over 1.5 hours and then stirred at 40°C for 3 hours.
16) The mixture was then cooled to 25 °C over 2 hours and stirred at 25°C for a further 3 hours.
17) The resulting mixture was cooled to 0-5 °C over 1 hour and stirred at 5 °C for 12 hours, at which time the mixture was filtered to isolate the product.
18) The filter cake was washed with cold toluene/ Cyclohexane (3 : 1, 1000 ml, 5 volumes).
19) The product was obtained as a white solid. (171.5g, chiral purity > 99.0% by area using the chiral HPLC method described in Example 3, chemical purity > 99.0% by area (HPLC), yield: 83.6%, assay purity: 92%). The 1H NMR and LCMS spectra are consistent with the structure of (^-afoxolaner as the toluene solvate. Figure 3 shows the 1H NMR spectra of (S)-afoxolaner in DMSO-d6 and Figure 4 shows the 1H NMR spectra of afoxolaner (racemic) for comparison. The chiral purity of the product was determined using the chiral HPLC method described in Example 3. Figure 5 shows the chiral HPLC chromatogram of afoxolaner (racemic) and Figure 6 shows the chiral HPLC chromatogram of the product (^-afoxolaner showing one enantiomer.
Example 8: Alternate Process to prepare (^-afoxolaner
An alternate process for the preparation of (S)-afoxolaner was conducted. Some of the key variations in the alternate process are noted below.
1. 1 kilogram of compound (IIA-1) (1 eq.) and 9 liters of DCM are charged to a reactor and stirred to dissolve the compound.
2. The mixture is cooled to about 0° C and 50 grams (5 mole %) of the chiral phase transfer catalyst (Ilia- 13-1) and 1 liter of DCM are charged and the resulting mixture is cooled to about -13° C.
3. A solution of 19% (w/w) hydroxylamine sulfate (294 g, 1.1 eq.) (made with 294 grams of ( H2OH)H2S04 and 141 grams of NaCl in 1112 mL of water) and 4.4 equivalents of NaOH as a 17.6% (w/w) solution (286 grams NaOH and 158 grams of NaCl in 1180 mL water) are charged to the reaction mixture simultaneously.
4. The resulting reaction mixture was aged about 20 hours at about -13° C and then checked for reaction conversion by HPLC (target < 0.5% by area);
5. After completion of the reaction, water (3 vol.) was added at about 0° C. Then, a solution of 709 g of KH2P04 in 4.2 liters of water are added to the mixture to adjust the pH (target 7-8) and the resulting mixture is stirred at about 20° C for 30 minutes.
6. The layers are allowed to settle, the aqueous layer is removed and the organic layer is washed with 3 liters of water twice.
Crystallization of Toluene Solvate
1. After the extraction/washing step, the dichloromethane is removed by distillation under vacuum to about 1-2 volumes and toluene (about 5-10 volumes) is added.
2. The volume is adjusted by further distillation under vacuum and/or addition of more toluene to about 5-6 volumes. The mixture is distilled further while maintaining the volume to completely remove the dichloromethane reaction solvent.
3. The mixture is then cooled to about 10° C and seeded with afoxolaner (racemic compound) and stirred at the same temperature for at least 2 hours;
4. The mixture is heated to about 55-65° C, aged for at least 17 hours and then the solid is filtered off. The filtered solid is washed with toluene;
5. The combined filtrate and wash is adjusted to a volume of about 5-6 volumes by
distillation under vacuum and/or toluene addition;
6. The resulting mixture is cooled to about 10° C and aged for at least 5 hours then filtered.
The cake is washed with toluene.
7. The cake is dried at 50° C under vacuum to obtain a toluene solvate of (S)-afoxolaner containing between about 6% and 8% toluene.
Re-crystallization from cyclohexane/ethanol
The toluene solvate of (S)-afoxolaner was subsequently re-crystallized from a mixture of cyclohexane and ethanol to remove the associated toluene and to further purify the product.
1. 591 grams of the (S)-afoxolaner toluene solvate were charged to a vessel along with 709 mL of ethanol (1.2 vol.) and 1773 mL of cyclohexane (3 vol.) and the mixture heated to about 60° C.
2. To the resulting mixture was added an additional 6383 mL of cyclohexane with stirring.
3. The resulting mixture was cooled to about 30° C and then heated again to 60° C. This process was repeated once.
4. The mixture was slowly cooled to 10° C and stirred for at least 5 hours.
5. The resulting slurry was filtered and the cake washed with cyclohexane.
6. The cake was dried at 50° C under vacuum to provide 453.7 grams of (S)-afoxolaner
Example 9: Comparative selectivity of benzyloxy-substituted chiral phase transfer catalyst (Illa-13) with other cinchona alkaloid-based chiral phase transfer catalysts.
The selectivity of the formation of (S)-afoxolaner from compound IIA-1 as shown above was studied with sixteen chiral phase transfer catalysts (PTC) of different structures. The reaction was conducted using conditions similar to those of example 7. The ratio of (^-afoxolaner and (R)-afoxolaner in the reaction mixture was determined by chiral HPLC using the method described in Example 3. The results of the study are provided in Table 2 below.
No. Chiral PTC Ratio of (S)- to (R)-afoxolaner
16 50% : 50%
As shown in the table, the catalyst in which the group R in the structure of formula (Ilia) is 3,4,5-tribenzyloxy phenyl results in a surprising improved selectivity for the (S)-enantiomer compared with other quinine-based phase transfer catalysts in which the group corresponding to R in formula (Ilia) is another group.
Example 10: Improvement of Chiral Purity of (<S)-afoxolaner by Crystallization from Toluene
A sample of reaction mixture containing a ratio (HPLC area) of 92.1 :7.9, (^-afoxolaner to (R)-afoxolaner, was concentrated to dryness and the residue was crystallized from toluene and from ethanol/cyclohexane using a process similar to that described in Example 8. The isolated crystalline solid was analyzed by chiral HPLC to determine the relative amounts of (S)-afoxolaner and (R)-afoxolaner (HPLC method: column – Chiralpak AD-3 150 mm x 4.6 mm x 3.0 μηι, injection volume – 10 μΐ., temperature – 35° C, flow – 0.8 mL/minute, mobile phase -89% hexane/10% isopropanol/1% methanol, detection – 312 nm). The ratio of (^-afoxolaner to (R)-afoxolaner in the solid isolated from the toluene crystallization was found to be 99.0 : 1.0 while the ratio of (S)-afoxolaner to (R)-afoxolaner in the solid crystallized from ethanol/cyclohexane was found to be 95.0 : 5.0.
The example shows that the crystallization (^-afoxolaner from an aromatic solvent such as toluene results in a significant improvement of chiral purity of the product. This is very unexpected and surprising.
Example 1 1 : Comparative selectivity of benzyl oxy vs. alkoxy-substituted chiral phase transfer catalyst of Formula (Ilia- 13)
Three chiral phase transfer catalysts of Formula (IIIa-13), wherein the phenyl ring is substituted with three alkoxy groups and three benzyloxy groups (R = methyl, ethyl and benzyl); R’=OMe, W=vinyl and X=chloro were evaluated in the process to prepare of (,S)-IA from compound IIA-1
as shown below.
The amount of solvents and reagents and the reaction and isolation conditions were as described in Example 7 above. The same procedure was used for each catalyst tested. It was found that the selectivity of the tri-benzyloxy catalyst was surprisingly significantly better than the two alkoxy-substituted catalysts, as shown by the chiral purity of the product. Furthermore, it was found that using the tri-benzyloxy substituted phase transfer catalyst the resulting chemical purity was also much better. The superior selectivity of the benzyloxy-substituted catalyst is significant and surprising and cannot be predicted. Chiral phase transfer catalysts containing a phenyl substituted with benzyloxy and alkoxy groups were found to be superior to catalysts substituted with other groups such as electron-withdrawing groups and alkyl groups. The chiral purity and chemical purity of the product produced from the respective phase-transfer catalysts is shown in the Table 3 below:
IP.com Journal (2009), 9(9B), 35.
It acts as an antagonist at ligand-gated chloride channels, in particular those gated by the neurotransmitter gamma-aminobutyric acid (GABA-receptors). Isoxazolines, among the chloride channel modulators, bind to a distinct and unique target site within the insect GABA-gated chloride channels, thereby blocking pre-and post-synaptic transfer of chloride ions across cell membranes. Prolonged afoxolaner-induced hyperexcitation results in uncontrolled activity of the central nervous system and death of insects and acarines.
Afoxolaner is the active principle of the veterinary medicinal products NexGard (alone) and Nexgard Spectra (in combination with milbemycin oxime). They are indicated for the treatment and prevention of flea infestations, and the treatment and control of tick infestations in dogs and puppies (8 weeks of age and older, weighing 4 pounds (~1.8 kilograms) of body weight or greater) for one month. These products are administered orally and poisons fleas once they start feeding.
The marketing authorization was granted by the European Medicines Agency in February 2014, for NexGard and January 2015, for Nexgard Spectra, after only 14 and 12 months of quality, safety and efficacy assessment performed by the Committee for Medicinal Products for Veterinary Use (CVMP). Therefore, long-term effects are not known.
List of excipients
- Maize starch
- Soy protein fines
- Beef braised flavouring
- Povidone (E1201)
- Macrogol 400 (reputed laxatives)
- Macrogol 4000 (reputed laxatives)
- Macrogol 15 hydroxystearate (reputed laxatives)
- Glycerol (E422)
- Triglycerides, medium-chain
Additionally in NexGard Spectra:
Afoxolaner is recommended to be administered at a dose of 2.7–7 mg/kg dog’s body weight.
Toxicity for mammals
According to clinical studies performed prior marketing:
- The oral toxicity profile of afoxolaner consists of a diuretic effect (rats only), effects secondary to a reduction in food consumption (rats and rabbits only) and occasional vomiting and/or diarrhoea (dogs, 120 and 200 mg/kg bodyweight (bw)) following high oral doses. No treatment-related effects on vomiting or diarrhoea were noted following oral doses of up to 31.5 mg/kg bw in the pivotal target animal safety study, nor in the EU field trial.
- mild gastrointestinal effects (vomiting, diarrhoea), pruritus, lethargy, anorexia, and neurological signs (convulsions, ataxia and muscle tremors) have been reported in less than 0.1% of 10,000 animals treated, including isolated reports, most reported adverse reactions being self-limiting and of short duration,
- (in combination with milbemycin oxime): vomiting, diarrhoea, lethargy, anorexia, and pruritus were observed in 0.2 to 1% of 10,000 animals treated and were generally self-limiting and of short duration,
- In vitro studies reported that afoxolaner can bind to dopamine and norepinephrine cellular transport receptor systems and the CB1 receptor; inhibition of these catecholaminergic systems and certain types of competitive binding at CB1 receptors may mediate pharmacodynamic effects of diuresis, decreased food consumption, and decreased body weight in animals.
According to post-marketing safety experience:
- (in combination with milbemycin oxime): erythema and neurological signs (convulsions, ataxia and muscle tremors) have been reported in less than 0.1% of 10,000 animals treated, including isolated reports,
- The US FDA reports that some drugs in this class (isoxazolines), including afoxalaner, can have adverse neurologic effects on some dogs, such as muscle tremors, ataxia, and seizures.
- Extralabel use of afoxolaner in a pet pig has been described without any adverse effects. Experimental use in commercial pigs also did not result in any adverse effects.
Selectivity in insects over mammalians
In vivo studies (repeat-dose toxicology in laboratory animals, target animal safety, field studies) provided by MERIAL, the company that produces afoxolaner-derivative medicines, did not show evidence of neurological or behavioural effects suggestive of GABA-mediated perturbations in mammals. The Committee for Medicinal Products for Veterinary Use (CVMP) therefore concluded that binding to dog, rat or human GABA receptors is expected to be low for afoxolaner.
Selectivity for insect over mammalian GABA-receptors has been demonstrated for other isoxazolines. The selectivity might be explained by the number of pharmacological differences that exist between GABA-gated chloride channels of insects and vertebrates.
- Shoop WL, Hartline EJ, Gould BR, Waddell ME, McDowell RG, Kinney JB, Lahm GP, Long JK, Xu M, Wagerle T, Jones GS, Dietrich RF, Cordova D, Schroeder ME, Rhoades DF, Benner EA, Confalone PN: Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs. Vet Parasitol. 2014 Apr 2;201(3-4):179-89. doi: 10.1016/j.vetpar.2014.02.020. Epub 2014 Mar 14. [Article]
- ^ Jump up to:a b c “Frontline NexGard (afoxolaner) for the Treatment and Prophylaxis of Ectoparasitic Diseases in Dogs. Full Prescribing Information” (PDF) (in Russian). Sanofi Russia. Retrieved 14 November 2016.
- ^ “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 70” (PDF). World Health Organization. pp. 276–7. Retrieved 14 November 2016.
- ^ Jump up to:a b c d “NexGard Spectra product information – Annex I “Summary of product characteristics”” (PDF). European Medicines Agency. Retrieved 13 November 2019.
- ^ Shoop WL, Hartline EJ, Gould BR, Waddell ME, McDowell RG, Kinney JB, et al. (April 2014). “Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs”. Veterinary Parasitology. 201 (3–4): 179–89. doi:10.1016/j.vetpar.2014.02.020. PMID 24631502.
- ^ Beugnet F, deVos C, Liebenberg J, Halos L, Fourie J (25 August 2014). “Afoxolaner against fleas: immediate efficacy and resultant mortality after short exposure on dogs”. Parasite. 21: 42. doi:10.1051/parasite/2014045. PMC 4141545. PMID 25148564.
- ^ Beugnet F, Crafford D, de Vos C, Kok D, Larsen D, Fourie J (August 2016). “Evaluation of the efficacy of monthly oral administration of afoxolaner plus milbemycin oxime (NexGard Spectra, Merial) in the prevention of adult Spirocerca lupi establishment in experimentally infected dogs”. Veterinary Parasitology. 226: 150–61. doi:10.1016/j.vetpar.2016.07.002. PMID 27514901.
- ^ “Boehringer-Ingelheim companion-animals-product NexGard (afoxolaner)”. Boehringer Ingelheim International GmbH. Retrieved 13 November 2019.
- ^ “CVMP Assessment Report for NEXGARD SPECTRA(EMEA/V/C/003842/0000)” (PDF). European Medicines Agency. Retrieved 14 November 2019.
- ^ Jump up to:a b c d “CVMP assessment report for NexGard (EMEA/V/C/002729/0000)” (PDF). European Medicines Agency. Retrieved 14 November 2019.
- ^ “Committee for Medicinal Products for Veterinary Use (CVMP) – Section “Role of the CVMP””. European Medicines Agency. Retrieved 14 November 2019.
- ^ Jump up to:a b c “NexGard product information – Annex I “Summary of product characteristics”” (PDF). European Medicines Angency. Retrieved 14 November 2019.
- ^ Medicine, Center for Veterinary. “CVM Updates – Animal Drug Safety Communication: FDA Alerts Pet Owners and Veterinarians About Potential for Neurologic Adverse Events Associated with Certain Flea and Tick Products”. http://www.fda.gov. Retrieved 2018-09-22.
- ^ Smith, Joe S.; Berger, Darren J.; Hoff, Sarah E.; Jesudoss Chelladurai, Jeba R. J.; Martin, Katy A.; Brewer, Matthew T. (2020). “Afoxolaner as a Treatment for a Novel Sarcoptes scabiei Infestation in a Juvenile Potbelly Pig”. Frontiers in Veterinary Science. 7: 473. doi:10.3389/fvets.2020.00473. PMC 7505946. PMID 33102538.
- ^ Bernigaud, C.; Fang, F.; Fischer, K.; Lespine, A.; Aho, L. S.; Mullins, A. J.; Tecle, B.; Kelly, A.; Sutra, J. F.; Moreau, F.; Lilin, T.; Beugnet, F.; Botterel, F.; Chosidow, O.; Guillot, J. (2018). “Efficacy and Pharmacokinetics Evaluation of a Single Oral Dose of Afoxolaner against Sarcoptes scabiei in the Porcine Scabies Model for Human Infestation”. Antimicrobial Agents and Chemotherapy. 62 (9). doi:10.1128/AAC.02334-17. PMC 6125498. PMID 29914951.
- ^ Casida JE (April 2015). “Golden age of RyR and GABA-R diamide and isoxazoline insecticides: common genesis, serendipity, surprises, selectivity, and safety”. Chemical Research in Toxicology. 28 (4): 560–6. doi:10.1021/tx500520w. PMID 25688713.
- ^ Hosie AM, Aronstein K, Sattelle DB, ffrench-Constant RH (December 1997). “Molecular biology of insect neuronal GABA receptors”. Trends in Neurosciences. 20 (12): 578–83. doi:10.1016/S0166-2236(97)01127-2. PMID 9416671. S2CID 5028039.
|Trade names||NexGard, Frontpro|
|License data||US DailyMed: Afoxolaner|
|By mouth (chewables)|
|ATCvet code||QP53BE01 (WHO)|
|Legal status||US: ℞-onlyEU: Rx-onlyOTC (RU)|
|Bioavailability||74% (Tmax = 2–4 hours)|
|Elimination half-life||14 hours|
|Excretion||Bile duct (major route)|
|CompTox Dashboard (EPA)||DTXSID50148921|
|Chemical and physical data|
|Molar mass||625.88 g·mol−1|
|3D model (JSmol)||Interactive image|
///////////// afoxolaner, A1443, AH252723
NEW DRUG APPROVALS
C21 H18 Cl F N4 O4
444.84CN109134365 discloses an active compound or medicinal salt with multi-target effects of VEGFR1~3, fibroblast growth factor receptor 1~3, RET, Kit and PDGFR, and its chemical structure formula is as follows: Formula I:
Chemical name: 4-(2-Fluoro-3chloro-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoline carboxamide, the drug name is fluvatinib. The compound has strong activity and provides a potential new treatment option for patients with tumors such as liver and kidney.
At 20-30°C, 4-chloro-7-methoxyquinoline-6-carboxamide (550.0 g) was added to the reaction kettle. At 20-30°C, DMSO (16.5L) was added to the reactor. At 20-30°C, 2-fluoro-3chloro-4-aminophenol was added to the reactor. At 20-35°C, sodium tert-butoxide (229g) was slowly added to the reaction kettle under stirring for 10-15 minutes. The reaction kettle was heated to 96°C (internal temperature) in 1.5 hours. The reaction was stirred at 96-100°C for 6.5 hours, and no 4-amino-3-chloro-2 fluorophenol remained. The reaction was cooled to 20-30°C. Under stirring, 23.1L of water was slowly added to the reaction solution. During the process, a dark brown solid was precipitated. Keep the internal temperature below 40°C. Stir at 30-40°C for 0.5 hour. Cool to 20-30°C and filter. At 20-30°C, the filter cake and 3.5L of water are added to the reactor. Stir for 0.5 hour at 20-30°C. filter. At 20-30°C, the filter cake and 4.0L of water are added to the reactor. Stir for 0.5 hour at 20-30°C. After filtering, the filter cake was dried in a vacuum dryer at 40°C for 18 hours (phosphorus pentoxide used as a desiccant, and the oil pump was vacuumed). The solid was pulverized to obtain 758 g of off-white solid and dried at 40° C. for 18 hours (phosphorus pentoxide was used as the desiccant, and the oil pump was vacuumed) to obtain Example 1A.LCMS(ESI)m/z:362.0[M+1] +1 H NMR (400MHz, DMSO-d 6 ) δppm 8.68 (br s, 2H), 7.82-7.96 (m, 1H), 7.67-7.82 (m, 1H), 7.46-7.59 (m, 1H), 7.12-7.26 (m, 1H), 6.67-6.80 (m, 1H), 6.43-6.58 (m, 1H), 5.84 (s, 2H), 4.04 (s, 3H).Example 1B
Example 1A (6.05g) was added to a three-necked flask containing NMP (60mL), pyridine (1.32g) and phenyl chloroformate (5.20g) were added to the reaction system, and the reaction system was at room temperature (25-30°C). ) After stirring for 1 hour, the reaction was complete. Cyclopropylamine (2.84g) was also added to the reaction system. The reaction solution was stirred at room temperature (25-30°C) for 0.5 hours. The reaction was completed. Add 20 mL of ethanol to the reaction system and stir. Tap water (500 mL) was added to the reaction system, a solid was precipitated, filtered, and the filter cake was spin-dried under reduced pressure to obtain a crude product (orange solid, 5.26 g); the crude product was passed through a chromatography column (DCM: MeOH = 20/1～10 /1) Purification to obtain the product (orange solid, 3.12 g), the product was added with 4 mL of absolute ethanol and stirred at room temperature for 18 hours, filtered, the filter cake was washed with 1 mL of ethanol, and dried under reduced pressure to obtain Example 1B. This compound is obtained by adding 1 equivalent of hydrochloric acid, sulfuric acid or methanesulfonic acid in acetone or ethanol solution to obtain the corresponding salt.LCMS(ESI)m/z:445.0[M+1] +1 H NMR (400MHz, DMSO-d 6 ) ppm 8.66-8.71 (m, 2H), 8.12-8.20 (m, 2H), 7.72-7.93 (m, 2H), 7.45 (t, J = 9.16 Hz, 1H) ,7.28(d,J=2.76Hz,1H),6.58(d,J=5.02Hz,1H),4.05(s,3H),2.56-2.64(m,1H),0.38-0.77(m,4H)Example 1
Example 1B (1.5g, 3.37mmol) was added to EtOH (45mL), the reaction temperature was raised to 60°C, at this temperature, CH 3 SO 3 H (324.07mg, 3.37mmol, 240.05μL) was added dropwise to the reaction In the solution, after the dripping is completed, the reaction solution is dissolved, and the temperature of the reaction solution is naturally cooled to 15-20°C under stirring, and the reaction solution is stirred at this temperature for 2 hours. A large amount of brown solid precipitated, filtered, and the filter cake was rinsed with absolute ethanol (5 mL), and the obtained filter cake was spin-dried under reduced pressure at 50° C. without purification, and Example 1 was obtained.LCMS(ESI)m/z:445.0[M+1] +1 H NMR(400MHz,DMSO-d 6 )δppm 9.02(d,J=6.53Hz,1H)8.72(s,1H)8.18-8.27(m,2H)7.87-8.03(m,2H)7.65(s,1H )7.53(t,J＝9.03Hz,1H)7.32(br s,1H)7.11(d,J＝6.27Hz,1H)4.08(s,3H)2.55-2.62(m,1H)2.35(s,3H) 0.34-0.75(m,4H)
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021143954&tab=FULLTEXT&_cid=P12-KSZPW4-91508-1Example 1 Preparation of fluvatinib crystal form I
Add the free base of fluvatinib of formula I (50mg, 112.40umol) to EtOH (2mL), stir at 15-20℃ for 12h, filter to obtain a filter cake, add the filter cake to 200mL acetone, stir at 15-20℃ After 12h, filter and spin-dry the filter cake under reduced pressure at 40°C to obtain fluvatinib solid. The result of XRPD detection is shown in Figure 1, named as the crystalline form I of fluvatinib, and the detection results of DSC and TGA are shown in Figure 2. And Figure 3.
Example 2 Preparation of crystal form I of fluvatinib mesylate (also referred to herein as “fluvatinib mesylate”)
The 4-[3-chloro-4-(cyclopropylaminocarbonylamino)-2-fluoro-phenoxy]-7-methoxy-quinoline-6-carboxamide i.e. fluvatinib (0.5g, 1.12mmol) was added to EtOH (10mL) solvent, heated to 55～60℃, and methanesulfonic acid (108.02mg, 1.12mmol, 80.02μL, 1eq) was added to the reaction flask under stirring at this temperature, and the reaction solution was dissolved. , The reaction solution was cooled to 20 ~ 30 ℃, stirred at this temperature for 1 h, a brown solid precipitated out under vacuum filtration, the filter cake was rinsed with ethanol (2mL*2), and the filter cake was spin-dried at 40 ~ 50 ℃ under reduced pressure. The solid product, named as the crystalline form I of fluvatinib mesylate, was tested by XRPD, DSC, and TGA. The XRPD test results are shown in Table 1 and Figure 4 below, and the DSC and TGA test results are shown in Figure 5. Melting point is about 232-237°C.
NEW DRUG APPROVALS
- Manganese, dichloro((4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-eicosahydro-7,11-nitrilo-7H-dibenzo(b,H)-5,13,18,21-tetraazacycloheptadecine-kappaN5,kappaN13,kappaN18,kappaN21,kappaN22)-, (pb-7-11-2344’3′)-
- A superoxide dismutase mimetic.
- GC 4419
- For the Reduction of The Severity and Incidence of Radiation and Chemotherapy-Induced Oral Mucositis
Avasopasem manganese, also known as GC4419, is a highly-selective small molecule mimetic of superoxide dismutase (SOD) being investigated for the reduction of radiation-induced severe oral mucositis.1,2 This drug has potential application for radiation-induced esophagitis and oral mucositis, in addition to being currently tested against COVID-19.
Avasopasem manganese is a superoxide dismutase mimetic that rapidly and selectively converts superoxide to hydrogen peroxide and oxygen in order to protect normal tissue from radiation therapy-induced damage.1 This drug is currently being investigated against oral mucositis, esophagitis, and COVID-19.
Transition metal pentaaza 15-membered macrocyclic ring complexes having the macrocyclic ring system corresponding to Formula A have been shown to be effective in a number of animal and cell models of human disease, as well as in treatment of conditions afflicting human patients.
For example, in a rodent model of colitis, one such compound, GC4403, has been reported when administered by intraperitoneal (ip) injection to significantly reduce the injury to the colon of rats subjected to an experimental model of colitis (see Cuzzocrea et al., Europ. J. Pharmacol., 432, 79-89 (2001)).
GC4403 administered ip has also been reported to attenuate the radiation damage arising both in a clinically relevant hamster model of acute, radiation-induced oral mucositis (Murphy et al., Clin. Can. Res., 74(13), 4292 (2008)), and lethal total body irradiation of adult mice (Thompson et al., Free Radical Res., 44(5), 529-40 (2010)).
Similarly, another such compound, GC4419, administered ip has been shown to attenuate VEGFr inhibitor-induced pulmonary disease in a rat model (Tuder, et al., Am. J. Respir. Cell Mol. Biol., 29, 88-97 (2003)), and to increase the anti-tumor activity of anti-metabolite and anti-mitotic agents in mouse cancer models (see, e.g., WO2009/143454). In other studies, GC4419 and GC4403 have been shown to be similarly potent in various animal models of disease. Additionally, another such compound, GC4401, administered ip has been shown to provide protective effects in animal models of septic shock (S. Cuzzocrea, et. al., Crit. Care Med., 32(1 ), 157 (2004)) and pancreatitis (S. Cuzzocrea, et. al., Shock, 22(3), 254-61 (2004)).
 Certain of these compounds have also been shown to possess potent anti-inflammatory activity and prevent oxidative damage in vivo. For example, GC4403 administered ip has been reported to inhibit inflammation in a rat model of inflammation (Salvemini, et.al., Science, 286, 304 (1999)), and prevent joint disease in a rat model of collagen-induced arthritis (Salvemini et al., Arthritis & Rheumatism, 44(12), 2009-2021 (2001)). In addition, these compounds have been reported to possess analgesic activity and to reduce inflammation and edema by systemic administration in the rat-paw carrageenan hyperalgesia model, see, e.g., U.S. Pat. No. 6,180,620.
 Compounds of the class comprising GC4419 have also been shown to be safe and effective in the prevention and treatment of disease in human subjects. For example, GC4419 administered by intravenous (iV) infusion has been shown to reduce oral mucositis in head-and-neck cancer patients undergoing chemoradiation therapy (Anderson, C, Phase 1 Trial of Superoxide Dismutase (SOD) Mimetic GC4419 to Reduce Chemoradiotherapy (CRT)-lnduced Mucositis (OM) in Patients (pts) with Mouth or Oropharyngeal Carcinoma (OCC), Oral Mucositis Research Workshop,
MASCC/ISOO Annual Meeting on Supportive Care in Cancer, Copenhagen, Denmark (June 25, 2015)).
 However, the administered dose when delivered systemically, for example by a parenteral route, can be limited in animal models and particularly in humans by systemic exposure and resulting toxicity that appears to be similar in nature among the pentaaza 15-membered macrocyclic ring dismutase mimetics of Formula A, particularly GC4403, GC4419, GC4401 and related compounds sharing the dicyclohexyl and pyridine motif in the macrocycle ring (e.g., compounds sharing the dicyclohexyl and pyridine motif generally include compounds according to Formula (I) below herein having W as an unsubstituted pyridine moiety, and wherein U and V are transcyclohexanyl fused rings) . For example, the maximum tolerated dose of GC4403 delivered as a 30-minute iv infusion in humans is 25 mg, or roughly 0.35 mg/kg in a 70-kg subject, and similar limitations exist for animal parenteral dosing. Thus, the efficacy of treatment of conditions such as local inflammatory disease or tissue damage of the alimentary canal may be limited when using systemic delivery of GC4403 and similar compounds.
 In each of these compounds comprising the pentaaza 15-membered macrocyclic ring of Formula A, the five nitrogens contained in the macrocyclic ring each form a coordinate covalent bond with the manganese (or other transition metal coordinated by the macrocycle) at the center of the molecule. Additionally, manganese (or other appropriate transition metal coordinated with the macrocycle) forms coordinate covalent bonds with “axial ligands” in positions perpendicular to the roughly planar macrocycle. Such coordinate covalent bonds are characterized by an available “free” electron pair on a ligand forming a bond to a transition metal via donation and sharing of the electron pair thus forming a two-electron bond between the metal and the donor atom of the ligand (Cotton, F.A. & G. Wilkinson, Advanced Inorganic Chemistry, Chapter 5, “Coordination Compounds”, 2nd revised edn., Interscience Publishers, p.139 (1966); lUPAC Gold Book, online version http://goldbook.iupac.org/C01329.html). The coordinate covalent nature of the bonds between manganese (or other such appropriate transition metal) and the five macrocyclic ring nitrogens and between manganese (or other such transition metal) and each of the two chloro axial ligands is evidenced, for example, by the “single crystal” X-ray crystal structure of GC4403 (Fig. 11 ) and GC4419 (Fig. 12).
 Coordination compounds contrast with ionic compounds, for example, salts, where in the solid state the forces between anions and cations are strictly coulombic electrostatic forces of attraction between ions of opposite charge. Thus, in salts, discrete cations and anions provide the force to maintain the solid state structure; e.g., such as the chloride ion and the sodium ion in a typical salt such as sodium chloride (Cotton, F.A. & G. Wilkinson, Advanced Inorganic Chemistry, Chapter 5, “The Nature of Ionic Substances”, 2nd revised edn., Interscience Publishers, pp. 35-36, 45-49 (1966).
 Although pentaaza 15-membered macrocyclic ring complexes have been disclosed in the literature for a number of anti-inflammatory indications, the representative disclosures discussed above illustrate that such compounds are generally administered by intraperitoneal (ip) or intravenous (iv) injection to potentiate systemic bioavailability. Local (e.g. topical) administration has been reported as ineffective in animal models of inflammatory disease, particularly when measured against the efficacy of systemic administration methods (Murphy et al., Clin. Can. Res., 74(13), 4292 (2008); WO 2008/045559). One research group has reported inhibition of colonic tissue injury and neutrophil accumulation by intracolonic administration of a prototype pentaaza macrocycle superoxide dismutase mimetic (MnPAM) (having a different structure from GC4403), though that disclosure neither addresses systemic bioavailability of the compounds described therein, nor explore limitations resulting from systemic bioavailability impacting safety and/or efficacy of that specific compound (Weiss et al., J. Biol. Chem., 271(42): 26149-26156 (1996); Weiss, R. and Riley, D., Drugs Future, 21 (4): 383-389 (1996)).
 Aspects of the present disclosure provide for formulations of pentaaza macrocyclic ring complexes of the class comprising GC4419, GC4403, and GC4401 that exhibit limited systemic bioavailability when administered orally (e.g. less than 20%, less than 15%, and even less than 10% bioavailability when dosed in appropriate oil-based formulations; see Table 1 and when combined with other formulations even less than 5%, and even less than 1%; see Example 28). In general, drug absorption from the gastrointestinal tract occurs via passive uptake so that absorption is favored when the drug is in a non-ionized (neutral) and lipophilic form. See, e.g., Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, Ninth Edition, p. 5-9 (1996). Without wishing to be limited to any particular theory, this is also believed to be the case for this class of compounds, as exemplified by GC4403, where the axial ligands are both chloro moieties forming a coordinate covalent bond to the manganese and a neutral complex results:
The Mn(ll) pentaaza macrocyclic ring dichloro complexes, such as GC4419, GC4401, GC4444, and GC4403 (structures shown below) were synthesized using literature procedures. For GC4403 the chiral R,R-diaminocyclohexane is utilized as starting material,2 whereas for GC4419, the mirror-image enantiomer of GC4403, the chiral S,S-diaminocyclohexane is utilized instead.3,4 The remainder of the synthesis of GC4419 can be identical in all respects to the method published for GC4403.2 The synthesis of the GC4401 complex was reported previously in reference 5.
 The synthesis of GC4444 which contains the additional 11-R-Methyl substituent generating a fifth chiral center on carbon (and is also derived from R,R-diaminocyclohexane) is made from the corresponding chiral tetraamine whose synthesis was published in reference 6 as Example 5C.
Syntheses of Axial Ligand Derivatives
 The same Mn(II) pentaaza macrocyclic ring dichloro complexes (GC4419, GC4403, GC4444 and GC4401 ) were also used as the starting material precursors for the syntheses of other axial ligand bound derivatives using a generic synthesis scheme in which a large excess of a salt of an anion is used to displace the chloro ligand thereby generating the new compound.
 Synthesis of Manganese(ll)bis-acetato[(4aS,13aS,17aS,21aS)-1,2,3,4,48,5,6,12,13,13a,14,15,16,17, 17a,18,19,20,21,21a- Eicosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10] tetraazacycloheptadecine-KN5, κΝ13, κΝ18, κΝ21, κΝ22]-, [bis-Acetato (GC4419)]. GC4701
 Using a 500-mL Erlenmeyer, 100 mL of deionized (“DI”) water was added to 5.3 g of GC4419; the mixture was stirred vigorously for 15-20 min, then sonicated for 5 min. The resulting light brownish suspension was filtered through a 10-20 μ fritted funnel (ca. 0.3 g of solid material remained in the funnel). The resulting clear solution was added into a sodium acetate solution (ca. 429 mmol, 21 equiv in 100 mL DI water) as a stream in one portion. No solid separated and the yellowish solution was stirred for 5 additional min. The solution was transferred to a separatory funnel and extracted (3 X 50 mL) with dichloromethane. The organic layers were separated, combined, and transferred back into a separatory funnel. The dichloromethane solution was back-extracted (2 X 50 mL) with aqueous sodium acetate (32 g/100 mL). The dichloromethane layer was dried over MgSO4 (ca. 10 g) for 30 min (w/stirring), filtered using a 10-20 μ fritted funnel, and the solution taken to dryness using a rotavap. To the yellow oily solid resulting from taking the solution to dryness was added methanol (50 mL). This solution was then again taken to dryness on the rotovap to yield a light yellow foam/glass. This material was dried in vacuo at room temperature for two days.
 The isolated yellowish brittle (4.11 g, 75% yield based on GC4419) was analyzed by HPLC and showed a purity of 99.7% and elemental analysis showed 0.98 wt. % residual chlorine. The elemental analysis is consistent with the expected bis-(acetato) structure C25H41MnN5O4●2H2O. Anal Cal’d: C, 53.00% ; H, 8.01 %; N, 12.36%, and Mn, 9.70%. Anal Found: C, 53.10% ; H, 8.34% ; Mn, 9.86%, N, 12.56%, and CI (as total halogen content), 0.98 wt. %.
https://patents.google.com/patent/WO2002071054A1/enSuperoxide dismutase (SOD) enzymes are enzymes that catalyze the dismutation of the free radical superoxide, the one-electron reduction product of molecular oxygen. The dismutation of the free radical superoxide involves the conversion of this one-electron reduction product of molecular oxygen to the nonradical molecular oxygen. Superoxide dismutase enzymes are a class of oxidoreductases which contain either Cu/Zn, Fe, or Mn at the active site. Superoxide dismutase (SOD) mimetic compounds are low molecular weight catalysts which mimic the natural enzyme function of the superoxide dismutase enzymes. Thus, superoxide dismutase mimetic compounds also catalyze the conversion of superoxide into oxygen and hydrogen peroxide, rapidly eliminating the harmful biologically generated superoxide species that are believed to contribute to tissue pathology in a number of diseases and disorders. These diseases and disorders include reperfusion diseases, such as those following myocardial infarct or stroke, inflammatory disorders such as arthritis, and neurological disorders such as Parkinson’s disease. Chem Reviews, 1999 vol 99, No. 9, 2573-2587.Superoxide dismutase mimetic compounds possess several advantages over the superoxide dismutase enzymes themselves in that their chemical properties can be altered to enhance stability, activity and biodistribution while still possessing the ability to dismutase the harmful superoxide. Superoxide dismutase mimetic compounds have generated intense interest and have been the focus of considerable efforts to develop them as a therapeutic agent for the treatment of a wide range of diseases and disorders, including reperfusion injury, ischemic myocardium post-ischemic neuropathies, inflammation, organ transplantation and radiation induced injury. Most of the superoxide dismutase mimics currently being developed as therapeutic agents are synthetic low molecular weight manganese-based superoxide dismutase mimetic compounds. Chem Reviews, 2576. Superoxide dismutase mimetic compounds are metal complexes in which the metal can coordinate axial ligands. Examples of such metal complexes include, but are not limited to, complexes of the metals Mn and Fe. Many of the complexes of the metals Mn and Fe do not possess superoxide dismutase activity but possess properties that enable them to be put to other therapeutic and diagnostic uses. These therapeutic and diagnostic uses include MRI imaging enhancement agents, peroxynitrite decomposition catalysts, and catalase mimics. These metal complexes, however, share the structural similarity of possessing a metal that can coordinate exchangeable ligands. These metal complexes exist in water as a mixture of species in which various ligands are possible. An illustration of such a mixture is provided by M40403 , a Mn(π) complex of a nitrogen-containing fifteen membered macrocyclic ligand, shown in Scheme 1. One of the forms for this metal complex is the dichloro complex, which when dissolved in water another form is generated where one of the chloride anions immediately dissociates from the metal generating the [Mn(Cl)(aquo)]+ complex. The problem in aqueous solvent systems or any solvent which has a potential donor atom is that there are a variety of potential ligands available to coordinate axially to the Mn(π) ion of the complex, hi conducting an analysis of a sample containing a metal complex by high performance liquid chromatography (HPLC) the chromatogram tends to be very broad and unresolved due to the presence of the various species of complexes, as shown in Scheme 1. This phenomena makes the identification and quantification of metal complexes by standard HPLC techniques quite difficult. Therefore, in light of the developing roles of metal complexes as therapeutics in the treatment of various disorders and diagnostic agents, a substantial need exists for an effective and workable high performance liquid chromatography method for analyzing metal complexes.
Scheme 1An additional complication which exists is the issue of the acid stability of the metal complex. As the pH decreases, the rate at which the complex becomes protonated and experiences instability increases. This presents particular problems for the use of HPLC as a method of detection and quantification of the metal complexes because the mobile phase used for reverse phase HPLC frequently contains mixtures of organic solvents and water in various combinations with trifluoroacetic acid. The trifluoroacetic acid is commonly present between about 0.1 to about 0.5% by weight. The presence of the trifluoroacetic acid causes the complex to dissociate. This dissociation destroys the potential of any such method to be used for release testing for purity. Furthermore, the trifluoroacetate anion causes the formation of some of the trifluoroacetato complex which could possess a different retention time from the chloro complexes thus, confusing the chromatography. Thus, the phenomenon of ligand exchange, coupled with the acid instability of the metal complexes, provides considerable challenges to the effort to detect and quantify metal complexes using HPLC. These challenges and needs have surprisingly been met by the invention described below.Analytical HPLC is a powerful method to obtain information about a sample compound including information regarding identification, quantification and resolution of a compound. HPLC has been used particularly for the analysis of larger compounds and for the analysis of inorganic ions for which liquid chromatography is unsuitable. Skoog, D.A., West, M.A., Analytical Chemistry, 1986, p. 520. As an analytical tool HPLC takes advantage of the differences in affinity that a particular compound of interest has for the stationary phase and the mobile phase (the solvent being continuously applied to the column). Those compounds having stronger interactions with the mobile phase than with the stationary phase will elute from the column faster and thus have a shorter retention time. The mobile phase can be altered in order to manipulate the interactions of the target compound and the stationary phase. In normal-phase HPLC the stationary phase is polar, such as silica, and the mobile phase is a nonpolar solvent such as hexane or isopropyl ether. In reversed- phase HPLC the stationary phase is non-polar, often a hydrocarbon, and the mobile phase is a relatively polar solvent. Since 1974 when reversed-phase packing materials became commercially available, the number of applications for reversed- phase HPLC has grown, and reversed- phase HPLC is now the most widely used type of HPLC. Reversed-phase HPLC’s popularity can be attributed to its ability to separate a wide variety of organic compounds. Reversed-phase chromatography is especially useful in separating the related components of reaction mixtures, and therefore is a useful analytical tool for determining the various compounds produced by reactions. To create a non-polar stationary phase silica or synthetic polymer based adsorbents are modified with hydrocarbons. The most popular bonded phases are Cl, C4, C8 and C18. Silica based adsorbents modified with trimethylchlorosilane (Cl) and butyldimethylchlorosilane (C4) have a few applications in HPLC, mainly for protein separation or purification. These adsorbents show significant polar interactions. Octyl (C8) and octadecyl (C18) modified adsorbents are the most widely used silica based adsorbents, with almost 80% of all HPLC separations being developed with these adsorbents.The most important parameter in reversed-phase HPLC is the mobile phase. The type of mobile phase employed in the HPLC will have a significant effect on the retention of the analytes in the sample, and varying the composition of the mobile phase allows the chromatographer to adjust the retention times of target components in the mixture to desired values. This ability provides the HPLC method with flexibility. The mobile phase in reversed-phase chromatography has to be polar and it also has to provide reasonable competition for the adsorption sites for the analyte molecules. Solvents that are commonly employed as eluent components in reversed-phase HPLC are acetonitrile, dioxane, ethanol, methanol, isopropanol, tetrahydrofuran, and water. In reversed phase HPLC of high molecular weight biological compounds, the solvents acetonitrile, isopropanol or propanol are most frequently used. Popular additives to the mobile phase for the improvement of resolution include mixtures of phosphoric acid and amines and periϊuorinated carboxylic acids, especially trifluoroacetic acid (TFA). HPLC exploits the differences in affinity that a particular compound of interest has for the stationary phase and the mobile phase. This phenomenon can be utilized to separate compounds based on the differences in their physical properties. Thus, HPLC can be used to separate stereoisomers, diastereomers, enantiomers, mirror image stereoisomers, and impurities. Stereoisomers are those molecules which differ from each other only in the way their atoms are oriented in space. The particular arrangement of atoms that characterize a particular stereoisomer is known as its optical configuration, specified by known sequencing rules as, for example, either + or – (also D or L) and/or R or S. Stereoisomers are generally classified as two types, enantiomers or diastereomers. Enantiomers are stereoisomers which are mirror-images of each other. Enantiomers can be further classified as mirror-image stereoisomers that cannot be superimposed on each other and mirror-image stereoisomers that can be superimposed on each other. Mirror- image stereoisomers that can be superimposed on each other are known as meso compounds. Diastereomers are stereoisomers that are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, solubilities in a given solvent, densities, refractive indices, etc. Diastereomers can usually be readily separated from each other by conventional methods, such as fractional distillation, fractional crystallization, or chromatography, including HPLC.Enantiomers, however, present special challenges because their physical properties are identical. They generally cannot be separated by conventional methods, especially if they are in the form of a racemic mixture. Thus, they cannot be separated by fractional distillation because their boiling points are identical and they cannot be separated by fractional crystallization because their solubilites are identical (unless the solvent is optically active). They also cannot be separated by conventional chromatography such as HPLC because (unless the adsorbent is optically active) they are held equally onto the adsorbent. HPLC methods employing chiral stationary phases are a very common approach to the separation of enantiomers. To be able to separate racemic mixtures of stereoisomers, the chiral phase has to form a diastereomeric complex with one of the isomers, or has to have some other type of stereospecific interaction. The exact mechanism of chiral recognition is not yet completely understood. In reversed-phaseHPLC a common type of chiral bonded phase is chiral cavity phases.The ability to be able to separate diastereomers and enantiomers by HPLC is a useful ability in evaluating the success of synthetic schemes. It is often desirable to separate stereoisomers as a means of evaluating the enantiomeric purity of production samples. All references listed herein are hereby incorporated by reference in their entiretyExamples 1 (traditional mobile phase) and 2 (mobile phase containing excess of salt of a coordinating anion).
Scheme 2 Any metal complex possessing a metal that is capable of coordinating a monodentate ligand can be used in the present invention. Examples of such metal complexes include, but are not limited to, complexes of the metals Mn and Fe. The metal complexes of the invention preferably have therapeutic and diagnostic utilities. These therapeutic and diagnostic utilities include, but are not limited to, use as superoxide dismutase mimetic compounds, MRI imaging enhancement agents, peroxynitrite decomposition catalysts, and catalase mimics. The preferred metal complexes for use in the invention are superoxide dismutase mimetic compounds. Examples of such superoxide dismutase mimetic compounds include, but are not limited to, the following complexes of the metals Mn and Fe. Iron based superoxide dismutase mimetics include, but are not limited to, Fera(salen) complexes, Fera(l,4,7,10,13-pentaazacyclopentadecane) derivatives and Feffl(porphyrinato) complexes. Manganese based superoxide dismutase mimetic compounds include, but are not limited to, metal complexes containing manganese(π) or manganese(m). Examples of manganese based superoxide dismutase mimetic compounds include Mnm(porphyrinato) complexes, Mnffl(salen) complexes, and Mnπ(l ,4,7, 10, 13-pentaazacyclopentadecane) derivatives. Mnπ(l ,4,7, 10,13- pentaazacyclopentadecane) derivatives are more preferred for use in the invention. Examples of Mnπ(l,4,7,10,13-pentaazacyclopentadecane) derivatives preferred for use in the invention include, but are not limited to, M40403 and M40401, as shown in Scheme 3 below.Furthermore, stereoisomers of all of the above metal complexes can be used in the process of the present invention. Diastereomers of the same metal complexes can also be detected and separated by the method of the present invention. As it is often desirable to separate stereoisomers as a means of evaluating the chemical and optical purity of production samples, the metal complexes can also comprise products of a reaction stream. Enantiomers of any of the metal complexes referenced above can be used in the chiral HPLC method of the invention for the separation of enantiomers of a metal complex.
M40484Scheme 3The ligand is a coordinating anion that binds to the metal cation of the metal complex. The coordinating anion can serve as an axial ligand for a superoxide dismutase mimetic compound. Examples of such anions include, but are not limited to, chloride anions, thiocyanate anions, stearate anions, acetate anions, trifluoroacetate anions, carboxylate anions, formate anions, or azide anions. Preferred anions include chloride anions, thiocyanate anions, and formate anions. More preferred anions are chloride anions. The more preferred anions in the chiral HPLC embodiment of the invention are thiocyanate anions. When present in an excess, the thiocyanate anions bind to the coordinating metal of the complexes preferentially to the chloride anions. An excess of thiocyanate anions will produce the bis(thiocyanato) complexes of M40403 and M40419 as shown in Scheme 4.
M40419 M40419-(SCN)2Scheme 4An example of the use of the acetate anion as the coordinating anion with M40403 is shown in Scheme 5 below. Scheme 6 illustrates the use of the formate anion as the coordinating anion with M40403.
M40403 M40403-(OAc)2Scheme 5
M40403 M40403-(Formate)2Scheme 6The coordinating anion is supplied by a salt of the coordinating anion. Salts of the chloride anion include, but are not limited to, sodium chloride, lithium chloride, potassium chloride, ammonium chloride, or tetraalkylammonium chloride. Preferred salts of the chloride anion include sodium chloride, lithium chloride and tetrabutylammonium chloride. Salts of the thiocyanate anion include, but are not limited to, sodium thiocyanate, potassium thiocyanate, ammonium thiocyanate, or lithium thiocyanate. Preferred salts of the thiocyanate anion include sodium thiocyanate and potassium thiocyanate. Salts of the acetate anion include, but are not limited to, potassium acetate, sodium acetate, ammonium acetate, ammonium trifluoroacetate and lithium acetate. Preferred salts of the acetate anion include ammonium acetate. Salts of the formate anion include, but are not limited to, potassium formate, sodium formate, ammonium formate and lithium formate. Preferred salts of the formate anion include ammonium formate. Salts of the cyanate anion include but are not limited to, sodium cyanate, potassium cyanate, or ammonium cyanate. Salts of the carboxylate anion include, but are not limited to, potassium carboxylate, ammonium carboxylate and sodium carboxylate. Salts of the stearate anion include, but are not limited to, lithium stearate and sodium stearate. Salts of the azide anion include, but are not limited to, sodium azide, potassium azide, and lithium azide. The salt added to the mobile phase can also be a mixture of any of these salts. Examples include a mixture of tetrabutylammonium chloride and lithium chloride.EXAMPLESExperimental For Examples 1-8 Chemicals, Solvents and MaterialsAll solvents used in the study were HPLC grade or equivalent. All chemicals were ACS reagent grade or equivalent.HPLC System and Data AnalysisThe HPLC chromatography was performed using a Gilson system (Model 306 pump, Model 155 UN-V detector, Model 215 liquid handler, Unipoint Software,Win98), a Narian system (Model 310 pump, Model 340 UN-N detector, Model 410 autosampler Star Workstation, Win98) or SSI system (Acuflow Series IN pump, Acutect 500 UV-N detector, Alcott Model 718 autosampler, HP Model 3395 integrator).Example 1HPLC Analysis of M40403 using Method 1
M40403 Method 1: Analytical Column: Waters YMC ODS-AQ S5 120A (4.6 x 50 mm); System A: 0.1% trifluoroacetic acid in H2O; System B: 0.08% trifluoroacetic acid in acetonitrile; Gradient: 10-50% system B over 10 min; Flow rate: 3ml/min; Detector wavelength: 265. Injected 20 μl of stock solution of M40403 prepared by dissolving 1 mg in 1 ml of water and diluting with 1 ml of system A. The HPLC chromatogram of M40403 using method 1 is shown in Figure 1. Example 2 HPLC Analysis of M40403 using Method 2Method 2: Analytical Column: Waters YMC 9DS-AQ S5 12θΛ (4.6 x 50 MM); System A: 0.5 N aqueous NaCl; System B: 1 :4 water/CH3CN; Gradient: 10-50% system B over 9 min; Flow rate: 3mL/min; Detector wavelength: 265 nm. Injected 20 μl of stock solution of M40403 prepared by dissolving 1 mg in 1 ml of system A. The HPLC chromatogram of M40403 using method 2 is shown in Figure 2.Example 3 HPLC Analysis of M40403 using Method 3Method 3: Analytical Column: Waters Symmetry Shield RP18, 5 μm, 250 x 4.6 mm;Mobile Phase: Acetonitrile: 0.125 M Tetrabutylammonium Chloride in water (pH 6.5), 5%: 95% H20(v/v); Flow rate: 1 mL/min; Detection wavelength: 265nm. Injected 20 μl of stock solution of M40403 prepared by dissolving 1 mg in 1 ml of mobile phase. The HPLC chromatogram of M40403 using method 3 is shown in Figure 3.The HPLC chromatogram of M40403 and related compounds using method 3 is shown in Figure 3a. Method 3 allows a separation of M40402 (bisimine of M40403), M40414 (monoimine of M40403) and M40475 (free ligand of M40403) (see chromatogram in Figure 3a).Example 4HPLC Analysis of M40403 using Method 4Method 4: Analytical Column: Waters Symmetry Shield RP18, 5 μm, 250 x 4.6 mm; Mobile Phase: Acetonitrile: 0.125 M Tetrabutylammonium Chloride and 0.5 M LiCl in water (pH 6.5), 5%: 95% H20 (v/v); Flow rate: lmL/min; Detection wavelength: 265 nm. Injected 20 μl of stock solution of M40403 prepared by dissolving 1 mg in 1 ml of system A. The HPLC chromatogram of M40403 using method 4 is shown in Figure 4.The HPLC chromatogram of M40403 and related compounds using method 4 is shown in Figure 4a. Method 4 allows a separation of M40402 (bisimine of M40403), M40414 (monoimine of M40403) and M40475 (free ligand of M40403) and all diastereomers of M40403 (see chromatogram in Figure 4a).Example 5 HPLC Analysis of M40401 using Method 1
M40401 Method 1: Analytical Column: Waters YMC ODS-AQ S5 120A (4.6 x 50 mm); System A: 0.1 % trifluoroacetic acid in H2O; System B: 0.08% trifluoroacetic acid in acetonitrile; Gradient: 10-50% system B over 10 min; Flow rate: 3ml/min; Detector wavelength: 265. Injected 20 μl of stock solution of M40401 prepared by dissolving 1 mg in 1 ml of water and diluting with 1 ml of system A. The HPLC chromatogram of M40401 using method 1 is shown in Figure 5.Example 6 HPLC with various NaCl concentrations:An HPLC was taken of M40401 with various concentrations of NaCl.Analytical Column: Waters YMC 9DS-AQ S5 120 A (4.6 x 50 mm);System A: (A) H2O (no NaCl) ; (B) 0.01 M NaCl in water; (C) 0.5 M NaCl in water;System B: acetonitrile; Gradient: 0-100% system B over 10 min; Flow: 3 ml/min;Detector wavelength: 265 nm. Injected 20 μl of stock solution of M40401 prepared by dissolving 1 mg in 1 ml of system A. The HPLC chromatogram of M40401 using various NaCl concentrations is shown in Figure 6. Example 7 HPLC Analysis of M40401 using Method 2Method 2: Analytical Column: Waters YMC ODS-AQ S5 12θΛ (4.6 x 50 MM); System A: 0.5 N aqueous NaCl; System B: 1 :4 water/CH3CN; Gradient 1 : 10-50% system B over 9 min; Flow rate: 3 mL/min; Detector wavelength: 265 nm. Injected 20 μl of stock solution of M40403 prepared by dissolving 1 mg in 1 ml of system A.The HPLC chromatogram of M40401 using method 2 is shown in Figure 7. Method 2 allows a separation of M40472 (bisimine of M40401), M40473 (monoimine of M40401), free ligand of M40403 and two isomers of M40401 (M40406, M40404).Example 8HPLC Analysis of M40401 using Method 3Method 3: Analytical Column: Waters Symmetry Shield RP18, 5 m, 250 4.6 mm; Mobile Phase: Acetonitrile: 0.125 M Tetrabutylammom‘um Chloride in H20 (pH 6.5), 5: 95%) H20 (v/v); Flow rate: lmL/min; Detection wavelength: 265 nm. The HPLC chromatogram of M40401 using method 3 is shown in Figure 8.Method 3 allows a separation of M40472 (bisimine of M40401), M40473 (monoimine of M40401), free ligand of M40403 and two isomers of M40401 (M40406, M40404).Example 9 HPLC Analysis of M40401 using Method 4Method 4: Analytical Column: Waters Symmetry Shield RP18, 5 μm, 250 x 4.6 mm;Mobile Phase: Acetonitrile: 0.125 M Tetrabutylammonium Chloride and 0.5 M LiCl in water (pH 6.5), 5: 95%> H2O (v/v); Flow rate: 1 mL/min; Detection wavelength: 265 nm; Injected 20 μl of stock solution of M40401 prepared by dissolving 1 mg in 1 ml of a mobile phase. The HPLC chromatogram of M40401 using method 4 is shown in Figure 9.The HPLC chromatogram of M40401 and related compounds using method 4 is shown in Figure 9a. Method 4 allows a separation of M40472 (bisimine of M40401), M40473 (monoimine of M40401), free ligand of M40403 and two isomers of M40401 (M40406, M40404). Example 10HPLC of M40403-(HCOO“)2 Using Formate AnionAn HPLC of M40403 employing the formate anion was taken. Analytical Column: Waters YMC 9DS-AQ S5 120 A (4.6 x 50 mm); System A: 0.025 M ammonium formate in water; System B: 1 : 4 = 0.125 M ammonium formate in water/ acetonitrile; Gradient: 0-100% system B over 10 min; Flow: 3 ml/min;Detector wavelength: 265 nm. Injected 20 μl of stock solution of M40403-(Formate)2 prepared by dissolving 1 mg in 1 ml of system A. The HPLC chromatogram of M40403-(HCOO“)2 is shown in Figure 10.Example 11 HPLC of M40403-(OAc)2 Using Acetate AnionAn HPLC of M40403 employing the acetate anion was taken.Analytical Column: Waters YMC 9DS-AQ S5 120 A (4.6 x 50 mm); System A: 0.025 M ammonium acetate in water; System B: 1: 4 = 0.125 M ammonium acetate in water/ acetonitrile; Gradient: 0-100% system B over 10 min; Flow: 3 ml/min;Detector wavelength: 265 nm. Injected 20 μl of stock solution of M40403-(OAc)2 prepared by dissolving 1 mg in 1 ml of system A. The HPLC chromatogram of M40403 -(OAc)2 is shown in Figure 11.Example 12An HPLC method to separate the diastereomers of superoxide dismutase mimetic compound M40403. Four stereoisomer mixtures were prepared (Part A) as shown in Schemes 5-9 and then separated (Part B) via reversed-phase high performance liquid chromatography. Part A: Synthesis of Stereoisomers Of M40403M40403 is synthesized from its single-isomer, tetra-amine precursor M40400 in the reaction shown in Scheme 7.
M40403Scheme 7The various stereoisomers of M40403 are synthesized from the various isomers of 1,2-diaminocyclohexane which provides the chiral carbon centers in M40403. The 1,2-diaminocyclohexane isomers used to prepare the R,R+R,S) M40403 stereoisomer mixture of Set 1 are shown in Scheme 6. Similarly, the 1,2-diaminocyclohexane isomers used to prepare the (R,R+S,S) M40403 stereoisomer mixture of Set 2 are shown in Scheme 7. The 1,2-diaminocyclohexane isomers used to prepare the (R,S+R,S) M40403 stereoisomer mixture of Set 3 are shown in Scheme 8. The 1,2- diaminocyclohexane isomers used to prepare the (S,S+R,S) M40403 stereoisomer mixture of Set 4 are shown in Scheme 9. As shown in Schemes 6-9 the M40403 diastereomers are prepared by template cyclization, followed by reduction with sodium borohydride.
Scheme 11Table 1
Part B: Separation of Stereoisomer MixturesChemicals, Materials, and MethodsTetrabutylammonium chloride hydrate (98%, 34,585-7) was purchased from Aldrich Chemical Company. Sodium chloride (99.6%, S-9888) was purchased from Sigma Chemical Company. All other solvents (HPLC-grade unless otherwise indicated) and reagents were purchased from Fisher Scientific and were of the finest grade available. The SymmetryShield® RP18 column (4.6 mm x 250 mm, 5 μm particle size) and its corresponding guard column were purchased from Waters Corporation. Reversed-Phase HPLC ExperimentsPreparation of Standard SolutionsHPLC Mobile phased was an aqueous solution consisting of 0.125 M tetrabutylammonium chloride (TBAC) and 0.5 M LiCl, prepared by adding tetrabutylammonium chloride hydrate (36.99 g) and solid LiCl (21.2 g) to a 1 L volumetric flask, diluting to volume with Millipore water, and inverting the flask several times to obtain a homogeneous solution. The resulting solution was filtered through a 0.45 μm nylon filter prior to use. Mobile phase B was HPLC-grade acetonitrile. Samples of each diastereoisomer set for HPLC-UN analysis were prepared at concentrations of ~ 3.0 mg/mL in a 50:50 mixture of 0.5 M LiCl in MeOH:
SOLID STATE FORMS OF AVASOPASEM MANGANESE AND PROCESS FOR PREPARATION THEREOF
Avasopasem manganese (GC4419), has the following chemical structure:
 Avasopasem manganese is a highly selective small molecule superoxide dismutase (SOD) mimetic which is being developed for the reduction of radiation-induced severe oral mucositis (SOM). The compound is described in U.S. Patent No. 8,263,568.
 Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state (13C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
 Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the
dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
 Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Avasopasem manganese.
Preparation of starting materials
 Avasopasem manganese can be prepared according to methods known from the literature, for example U.S. Patent No. 8,263,568. Alternatively, Avasopasem manganese can be prepared by the template method reported for the enantiomeric analogue GC4403, which has the formula:
GC4403 is disclosed in International Appl. No. WO 98/58636 (as compound SC-72325) and Riley, D.P, and Schall, O.F., Advances in Inorganic Chemistry (2007), 59, 233-263. Thus, GC4403 can be synthesized via the template route described in the literature using the chiral R,R-l,2-diamminocyclohexane [Salvemini, D., et ah, Science (1999), 286, 304-6 , and Aston, K, et al., Inorg. Chem. (2001), 40(8), 1779-89] Avasopasem manganese (GC4419) can be prepared by the same method except that the chiral R,R-l,2-diamminocyclohexane is replaced with S,S-1 ,2-diamminocyclohexane.
Example 1: Preparation of Avasopasem manganese Form AMI
 Avasopasem manganese (0.1 grams) was dissolved in dichloromethane (0.5 ml) at 25-30°C in a test tube. The solution was filtered through 0.45 micron filter and the clear solution was subjected to slow solvent evaporation at 25°C by covering the tube with paraffin film with a pin hole. After, 2 days, the obtained solid was analyzed by XRD- Form AMI; as shown in Figure 1
- GlobeNewswire: Galera Therapeutics Announces Avasopasem Manganese Improved Markers of Chronic Kidney Disease in Patients Receiving Cisplatin [Link]
- Galera Therapeutics: AVASOPASEM (GC4419) [Link]
///////////AVASOPASEM, Avasopasem manganese, GC-4419, GC4419, GC 4419, M 40419, M40419; M-40419, SC 72325A, SC-72325A, SC72325A,
NEW DRUG APPROVALS
PropofolCAS Registry Number: 2078-54-8
CAS Name: 2,6-Bis(1-methylethyl)phenolAdditional Names: 2,6-diisopropylphenol; disoprofol
Manufacturers’ Codes: ICI-35868
Trademarks: Ansiven (Abbott); Diprivan (AstraZeneca); Disoprivan (AstraZeneca); Rapinovet (Schering-Plough Vet.)Molecular Formula: C12H18OMolecular Weight: 178.27Percent Composition: C 80.85%, H 10.18%, O 8.97%
Literature References: Prepn: A. J. Kolka et al.,J. Org. Chem.21, 712 (1956); 22, 642 (1957); G. G. Ecke, A. J. Kolka, US2831898 (1958 to Ethyl Corp.); T. J. Kealy, D. D. Coffman, J. Org. Chem.26, 987 (1961); B. E. Firth, T. J. Rosen, US4447657 (1984 to Universal Oil Products). Chromatographic study: J. K. Carlton, W. C. Bradbury, J. Am. Chem. Soc.78, 1069 (1956). Animal studies: J. B. Glen, Br. J. Anaesth.52, 731 (1980).Pharmacokinetics: H. K. Adam et al.,ibid. 743; idem,ibid.55, 97 (1983). Determn in blood: eidem,J. Chromatogr.223, 232 (1981). Comparative studies vs other injectable anesthetics: B. Kay, D. K. Stephenson, Anaesthesia35, 1182 (1980); D. V. Rutter et al.,ibid. 1188. Use in i.v. anesthesia: E. Major et al.,ibid.37, 541 (1982). Cardiovascular effects: D. Al-Khudhairi et al.,ibid. 1007. Pharmacology of emulsion formulation: J. B. Glen, S. C. Hunter, Br. J. Anaesth.56, 617 (1984). Series of articles on pharmacology and clinical experience: Postgrad. Med. J.61, Suppl. 3, 1-169 (1985).
Properties: bp30 136°. bp17 126°. mp 19°. nD20 1.5134. nD25 1.5111. d20 0.955.Melting point: mp 19°Boiling point: bp30 136°; bp17 126°Index of refraction:nD20 1.5134; nD25 1.5111Density: d20 0.955Therap-Cat: Anesthetic (intravenous).Therap-Cat-Vet: Intravenous anesthetic (dogs and cats).Keywords: Anesthetic (Intravenous).SYN
Prepn: A. J. Kolka et al., J. Org. Chem. 21, 712 (1956); 22, 642 (1957); G. G. Ecke, A. J. Kolka, US 2831898 (1958 to Ethyl Corp.); T. J. Kealy, D. D. Coffman, J. Org. Chem. 26, 987 (1961); B. E. Firth, T. J. Rosen, US 4447657 (1984 to Universal Oil Products).SYN
A commercially viable manufacturing process for propofol (1) is described. The process avoids acid–base neutralization events during isolation of intermediate, 2,6-di-isopropylbenzoic acid (3) and crude propofol, and thus simplifies the synthesis on industrial scale to a considerable extent. Syntheses of five impurities/related substances (USP and EP) are also described.
Propofol is used during surgeries for sedation and an injectable grade with purity > 99.90% is desired by the medical community. An embodiment of the present invention provides an economically feasible, industrial process for the manufacture of high purity injectable grade Propofol. An embodiment of the present invention relates to a process and novel strategy for purification of 2,6-diisopropylphenol (Propofol) and similar products.
 Propofol is a sterile injectable drug that appears in the USP, EP and IP Monographs. Drug product is manufactured by using high purity drug substance 2,6-di-isopropylphenol commonly known as Propofol.
 Propofol is used to put patients to sleep and keep them asleep during general anesthesia for surgery or other medical procedures. It is used in adults as well as children 2 months and older. Propofol is frequently used as a sedative, and has a rapid onset of action and a short recovery period. Propofol slows the activity of brain and nervous system. Propofol is also used to sedate a patient who is under critical care and needs a mechanical ventilator (breathing machine). Propofol is a hypnotic alkylphenol derivative. When formulated for intravenous induction of sedation and hypnosis during anaesthesia, Propofol facilitates inhibitory neurotransmission mediated by gamma- Aminobutyric acid (GABA). Propofol is associated with minimal respiratory depression and has a short half-life with a duration of action of 2 to 10 minutes.
 Propofol is commonly used parenteral anesthetic agent in the United States, extensively used for minor and outpatient surgical procedures because of its rapid onset and reversal of action, and in intensive care units (ICUs) for maintaining coma. Propofol has been associated with rare instances of idiosyncratic acute liver injury; in addition, prolonged high dose Propofol therapy can cause the “Propofol infusion syndrome” which is marked by brady arrhythmias, metabolic acidosis, rhabdomyolysis, hyperlipidemia and an enlarged or fatty liver.
 Friedel-Craft’s alkylation of phenol using propylene gas in the presence of Lewis acid (LA) catalysts is a commonly used method for the synthesis of Propofol and is well documented in a number of publications and patents [Ecke, G. G., Kolka, A. J. US 2,831,898 A, 1958. Firth, B. E., Rosen, T. J. US 4,447,657, 1984. Akio, T., Yoshiaki, I., Hidekichi, H., Kiyoji, K., Takashi, K., Masanobu, M. EP 0169359A1, 1986. Ecke, G. G., Kolka, A. J. US 3,271,314, 1966. Napolitano, J. P. US 3,367,981 A, 1968. Goddard L. E. US 3,766,276, 1973. Firth, B. E. US 4,275,248, 1981, etc.]
 A number of patents and published literature describe the manufacture of Propofol. US. Pat. No. 4,275,248; W0200034218; EP169359; US. Pat. No. 3,367,981; US. Pat. No.
3,271,314; US. Pat. No. 3,766,276; US. Pat. No. 2,831,898; US.Pat.No.2,207,753; GB1318100; U.S. Pat. No. 4,391,998; US. Pat. No. 4,774, 368; US. Pat. No. 5,589,598; US. Pat. No. 6,362,234; etc. EP 0511947, discloses purification of Propofol that is obtained by alkylation of phenol and purified by crystallization at -10 to -20°C (melting point of Propofol is 18°C). This patent also describes purification using non-polar solvents such as Petroleum ether or Hexane, where solvent residue is removed by distillation or evaporation and finally Propofol is obtained using fractional distillation under high vacuum.
 Continuous separation of a mixture of Propofol with phenolic impurities and methanol is described in an U.S. Pat. No. 5,264,085. U.S. Pat. No. 5,705,039 describes the purification of impure 2,6-diisopropylphenol first using continuous distillation and then distilling pure Propofol under high vacuum.
 Patent CN103360219A describes purification wherein 2,6-diisopropyl phenol is reacted with benzoyl chloride to generate ‘benzoic acid-2, 6-diisopropyl benzene ester’, which is then purified to yield Propofol. The patent discloses that an adsorbent is added at the rectifying stage, so that impurities with similar chemical structures and boiling points are effectively removed; the content of a single impurity in the product is not higher than 0.01%; the total impurity is not higher than 0.05%.
 CN105601477A describes purification of Propofol wherein crude Propofol is purified with three-stage distillation method; the crude Propofol enters feeding tank protected by nitrogen and is charged into first-stage film distillation system through pump; then the product is fed to second-stage molecular distillation system and low boiling point impurities are removed; finally, the processed product is charged into third-stage molecular distiller through a pump, high-boiling-point impurities are separated, and the colourless or yellowish high-purity Propofol is obtained.
 In another prior art disclosure, after completion of the reaction, the final product is isolated and purified by high-vacuum distillation. Alkylation of phenol using propylene gas at high pressure and high temperature is reported. Several impurities like 2,4-diisopropyl and 2,4,6-triisopropyl phenol are the major side products along with the corresponding Isopropyl ether. All these impurities need to be controlled at a limit of NMT 0.05% or less in the final API for it to be pharmaceutically acceptable. In another prior art disclosure, isopropanol was used as the propylating agent instead of direct propylene gas. In this method propylene is generated in situ using IPA and strong acid like sulfuric acid and catalysts like Aluminoslicate [See Baltalksne, A. E.; Zitsmanis, A. H. SU 443019, 1974. Jain, K. P., Edaki, D. U., Minhas H. S., Minhas G. S. WO/2011/ 161687 Al, 2011. Wu, M. US 4,391,998, 1983]
 Another method is to use of protected phenol, where 4-chloro or 4-carboxylic acid substituted phenol is used as starting material along with Isopropanol in sulfuric acid, followed by removal of the 4-substituent to give Propofol [Baltalksne, A. E.; Zitsmanis, A. H. SU 443019, 1974. Jain, K. P., Edaki, D. U., Minhas H. S., Minhas G. S. WO/2011/ 161687 Al, 2011. Wu, M. US 4,391,998, 1983. Tsutsumi, S.; Yoshizawa, T.; Koyama, K. Nippon Kagaku Zasshi 1956, 77, 737-738. Paiocchi, M. US 5,589,598, 1996. Nieminen, K., Essen, P. US 5,175,376, 1992. Keller, S., Schlegel, J. WO/2012/152665 Al, 2012.] The final purification is carried out by high- vacuum distillation to get highly pure Propofol. Since the para position is blocked, related impurities such as 2,4-isopropyl and 2,4,6-triisopropyl derivatives are avoided. In this approach, intermediate is purified before converting to crude Propofol using either de-chlorination by hydrogenation or de-carboxylation before vacuum distillation for final purification.
 It is reported in the literature that 4-hydroxybenzoic acid is used as starting material for alkylation with isopropyl alcohol in sulfuric acid. In that method 2,6-diisopropyl-4-hydroxy benzoic acid gets formed, which is extracted in toluene either in presence of an acid or the impurities are extracted in toluene under alkaline condition. The decarboxylation is carried out using solvents like monoethylene glycol or ethoxyethanol at high temperature. At the end of decarboxylation, crude Propofol is isolated by extracting into toluene. The advantage is Propofol does not form sodium salt under the conditions, but all other acidic impurities form sodium salt and thus do not get extracted in toluene. The toluene containing Crude Propofol is distilled to recover toluene and then vacuum distilled to obtain pure Propofol. [Chen, T; Chen, X.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2006, 128, 87-89. Lau, S.; Keay, B. Can. J. Chem. 2001, 79, 1541-1545]
 In summary, strategies disclosed in prior art for the production of 2,6-diisopropylphenol (Propofol) predominantly involve synthesis starting from phenol or by using protected 4-position of phenol like, 4-hydroxybenzoic acid, 4-chlorophenol (references: Baltalksne, A. E.; Zitsmanis, A. H. SU 443019, 1974. Jain, K. P., Edaki, D. U., Minhas H. S., Minhas G. S. WO/2011/ 161687 Al, 2011. Wu, M. US 4,391,998, 1983. Tsutsumi, S.; Yoshizawa, T.; Koyama, K. Nippon Kagaku Zasshi 1956, 77, 737-738. Paiocchi, M. US 5,589,598, 1996. Nieminen, K., Essen, P. US 5,175,376, 1992. Keller, S., Schlegel, J. WO/2012/152665 Al, 2012). Processes described in the literature generally propose purification of crude 2,6-diisopropylphenol by ‘high vacuum distillation or molecular distillation’.
 The phenols are susceptible to oxidation, formation of polymeric and color impurities. There are processes where repeated vacuum distillation has been carried out to obtain desired purity of product. Sometimes, to reduce the oxidized and colored impurities, reduction of impurities by catalytic hydrogenation is also used.
 Propofol that does not meet Pharmaceutical grade may be manufactured by several processes generally known to persons of skill in the art and described in prior art, but purification of Propofol to consistently achieve high purity required for the injectable drug substance using an economical and industrial process remains a challenge.
 Commercially available concentrated sulfuric acid (30 Kg) was diluted with water (2.26 Kg) at low temperature (0-15°C). Methyl 4-hydroxybenzoate (5 Kg 32.79 mol.) was added to this diluted sulfuric acid at 5 to 10 °C with stirring. After complete addition, isopropyl alcohol (5.9 Kg 98.16 mol.) was gradually added to the reaction content, controlling the temperature at 0-15 °C. The reaction mixture was then heated at 60-70°C and continued to complete di-isopropylation and ester hydrolysis to yield methyl-4-hydroxybenzoate. The conversion was checked on TLC or by HPLC for the complete conversion of methyl-4 hydroxybenzoate to 3, 5 -Diisopropyl 4-hydroxybenzoic acid.
 The reaction contents were cooled at room temperature and carefully charged into a stirred, precooled mixture of water (50 L) and Toluene (40 L) at (0 to 5°C). The mixture was stirred and maintained below 15°C for about 30 to 60 minutes.
 The content was then heated at 25 to 30°C, stirred for 30 min., allowed to settle into two layers. The water layer was extracted again with toluene and discarded. The toluene layers, containing the product 3, 5-Diisopropyl 4-hydroxybenzoic acid, were combined and extracted with about 25 L of 10 % NaOH. The aqueous layer containing the sodium salt of 3, 5 -Di-isopropyl 4-hydroxybenzoic acid was acidified with concentrated HC1 (about 9 Kg) to precipitate 3, 5-Diisopropyl 4-hydroxybenzoic acid, filtered, and washed with water (about 50 L) to yield 3, 5 -diisopropyl 4-hydroxybenzoic acid (about 45-60 %)
 To the mixture of 3, 5-diisopropyl 4-hydroxybenzoic acid (3 Kg, 13.5 mol.) in ethylene glycol (5.0 Kg, 80.55 mol.) was added sodium hydroxide (1.25 Kg, 31.25 mol.) for decarboxylation. The reaction mixture was heated at 145 ± 5°C till completion of
decarboxylation by monitoring using TLC or HPLC (or solubility in bicarbonate of precipitated product). After complete decarboxylation, the reaction mixture was cooled at 40 to 45 °C, under nitrogen environment and diluted with water (about 15 L) and allowed to settle. The oily product layer was separated and washed with water (6L) to isolate crude Propofol (i.e., 2,6-diisopropyl phenol) and stored under nitrogen. The isolated volatile Crude Propofol (along with carry over ppm ethylene glycol and NaOH) was then subjected to steam distillation purification process as described below.
 The Crude Propofol is purified by using one of the steam distillation processes as described below.
 The Crude Propofol layer is added to purified water in a reactor (preferably glass lined reactor), and slowly heated to boiling to co-distil Pure Propofol along with water under normal atmospheric pressure and the high volatile initial fraction is isolated first. The biphasic layers of main distillate, are separated and the liquid layer of Propofol is treated with dehydrating agent to absorb dissolved moisture in Pure Propofol under nitrogen or argon. The transparent Pure Propofol liquid layer is then filtered through ultrafme Micron filter (0.45 and 0.2 micron) under nitrogen (or argon) pressure and isolated in controlled environment to obtain pharmaceutical injectable grade Pure Propofol of more than 99.90% purity.
 The Crude Propofol liquid layer is charged into a reactor with steam distillation arrangement, like steam purging dip tube, column, heat exchanger and receivers. Pure steam is purged in the reactor at controlled pressure to co-distil Pure Propofol with water. The layers are allowed settle and water layer is kept aside for recirculation. The transparent Pure Propofol transparent liquid layer is then filtered through ultrafme Micron filter (0.45 and 0.2 micron) under nitrogen (or argon) pressure and isolated in controlled environment to obtain pharmaceutical injectable grade Pure Propofol of more than 99.90% purity.
 The Crude Propofol layer is added to purified water in a reactor (preferably glass lined or Hastelloy reactor) and slowly heated at boiling to co-distil Pure Propofol along with water under mild vacuum. The biphasic layers are separated and the liquid layer of Propofol is treated with dehydrating agent to absorb dissolved moisture in Pure Propofol under nitrogen (or argon). The transparent Pure Propofol liquid layer is then filtered through ultrafme Micron filter (0.45 and 0.2 micron) under nitrogen (or argon) pressure and isolated in controlled environment to obtain pharmaceutical injectable grade Pure Propofol of more than 99.90% purity.
 The Crude Propofol layer is added to reactor containing purified water and 0.1 to 1% antioxidant and 0.1 to 0.5% sodium hydroxide and slowly heated to boiling to co-distil Pure Propofol along with water. The biphasic layers are separated and the liquid layer of Propofol is treated or passed through column packed with dehydrating agent to absorb dissolved moisture in Pure Propofol. The transparent Pure Propofol liquid layer is then filtered through ultrafme Micron filter (0.45 and 0.2 micron) under nitrogen (or argon) pressure and isolated in controlled environment to obtain pharmaceutical injectable grade Pure Propofol of more than 99.90% purity.
 The crude Propofol liquid layer is treated with preferably neutral or basic activated carbon (about 2-5%) and filtered under nitrogen. The filtered liquid is collected, under nitrogen, in distillation reactor containing purified water is slowly heated to boiling to co-distil Pure Propofol along with water under normal pressure or mild vacuum. The co-distilled biphasic layers are separated and the liquid layer of Propofol, is treated under nitrogen, with or passed through column packed with dehydrating agent to absorb dissolved moisture trapped in Pure Propofol. The transparent Pure Propofol liquid layer is then filtered through ultrafme Micron filter (0.45 and 0.2 micron) under nitrogen (or argon) pressure and isolated in controlled environment to obtain pharmaceutical injectable grade Pure Propofol of more than 99.90% purity.
Example No. 2:
 Friedel-Crafts reaction was performed as described in Example 1. Decarboxylation was performed by using KOH instead of NaOH by following the same procedure as described in Example 1.
Example No. 3:
 Decarboxylation was performed as per operations described in Example 1. After complete decarboxylation, the reaction mixture was cooled at 40 to 45°C, under nitrogen environment and diluted with water (about 15 L) The biphasic mixture subjected to steam distillation by any of the purification methods described in Example 1.
Example No. 4:
 Friedel-Crafts reaction was performed as described in Example 1. The reaction contents were cooled at room temperature and carefully charged at 0 to 5°C into a sodium hydroxide solution to basic pH at stirred. The aqueous alkaline solution was extracted twice with toluene or hexane. The aqueous layer was acidified with HC1 to precipitate 3, 5-diisopropyl-4-hydroxybenzoic acid. The wet product was washed with water, dried and decarboxylated using sodium hydroxide in ethylene glycol as solvent at 145±5°C. The reaction contents were cooled to room temperature, diluted with water and acidified and then Crude Propofol was extracted twice in toluene. The toluene layer was washed with water, bicarbonate and with water then distilled to obtain crude oily layer of Propofol (>99% pure). This Crude Propofol was then purified by using purification steam distillation by any of the purification methods described in Example 1.
 Continuous steam distillation of crude Propofol by purging pure steam. Continuous steam distillation of Crude Propofol was carried out using a feed pump for feeding liquid Crude Propofol (prepared by one of the processes described in this application or other literature) to the steam distillation system connected to a pure steam generator. Steam at 1-10 kg pressure was purged in the steam distillation system at controlled rate and the co-distilled Pure Propofol with water was cooled using heat exchanger and continuous separator. The residue was discharged from bottom valve at defined time intervals. The water layer was recycled to steam generator and Pure Propofol was dehydrated, filtered and collected in controlled environment as described in Example 1.
Propofol, marketed as Diprivan, among other names, is a short-acting medication that results in a decreased level of consciousness and a lack of memory for events. Its uses include the starting and maintenance of general anesthesia, sedation for mechanically ventilated adults, and procedural sedation. It is also used for status epilepticus if other medications have not worked. It is given by injection into a vein, and the maximum effect takes about two minutes to occur and typically lasts five to ten minutes. Propofol is also used for medical assistance in dying in Canada.
Common side effects of propofol include an irregular heart rate, low blood pressure, a burning sensation at the site of injection and the cessation of breathing. Other serious side effects may include seizures, infections due to improper use, addiction, and propofol infusion syndrome with long-term use. The medication appears to be safe for use during pregnancy but has not been well studied for use in this case. It is not recommended for use during a cesarean section. It is not a pain medication, so opioids such as morphine may also be used, however whether or not they are always needed is not clear. Propofol is believed to work at least partly via a receptor for GABA.
Propofol was discovered in 1977 and approved for use in the United States in 1989. It is on the World Health Organization’s List of Essential Medicines and is available as a generic medication. It has been referred to as milk of amnesia (a play on “milk of magnesia“), because of the milk-like appearance of the intravenous preparation, and because of its tendency to suppress memory recall. Propofol is also used in veterinary medicine for anesthesia.
To induce general anesthesia, propofol is the drug used almost always, having largely replaced sodium thiopental. It can also be administered as part of an anesthesia maintenance technique called total intravenous anesthesia, using either manually programmed infusion pumps or computer-controlled infusion pumps in a process called target controlled infusion (TCI). Propofol is also used to sedate individuals who are receiving mechanical ventilation but not undergoing surgery, such as patients in the intensive care unit. In critically ill patients, propofol is superior to lorazepam both in effectiveness and overall cost. Propofol is relatively inexpensive compared to medications of similar use due to shorter ICU stay length. One of the reasons propofol is thought to be more effective (although it has a longer half-life than lorazepam) is because studies have found that benzodiazepines like midazolam and lorazepam tend to accumulate in critically ill patients, prolonging sedation. Propofol has also been suggested as a sleep aid in critically ill adults in the ICU, however, the effectiveness of this medicine at replicating the mental and physical aspects of sleep for people in the ICU are not clear.
Propofol is often used instead of sodium thiopental for starting anesthesia because recovery from propofol is more rapid and “clear”.
Propofol is also used for procedural sedation. Its use in these settings results in a faster recovery compared to midazolam. It can also be combined with opioids or benzodiazepines. Because of its rapid induction and recovery time, propofol is also widely used for sedation of infants and children undergoing MRI. It is also often used in combination with ketamine with minimal side effects.
In March 2021, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for Propofol‐Lipuro 1% to maintain sedation via continuous infusion in people greater than age sixteen with suspected or confirmed COVID‑19 who require mechanical ventilation in an intensive care unit ICU setting. In the circumstances of this public health emergency, it would not be feasible to require healthcare providers to seek to limit Fresenius Propoven 2% Emulsion or Propofol-Lipuro 1% only to be used for patients with suspected or confirmed COVID‑19; therefore, this authorization does not limit use to such patients.
The US state of Missouri added propofol to its execution protocol in April 2012. However, Governor Jay Nixon halted the first execution by the administration of a lethal dose of propofol in October 2013 following threats from the European Union to limit the drug’s export if it were used for that purpose. The United Kingdom had already banned the export of medicines or veterinary medicines containing propofol to the United States.
Recreational use of the drug via self-administration has been reported but is relatively rare due to its potency and the level of monitoring required for safe use. Critically, a steep dose-response curve makes recreational use of propofol very dangerous, and deaths from self-administration continue to be reported. The short-term effects sought via recreational use include mild euphoria, hallucinations, and disinhibition.
Recreational use of the drug has been described among medical staff, such as anesthetists who have access to the drug. It is reportedly more common among anesthetists on rotations with short rest periods, as usage generally produces a well-rested feeling. Long-term use has been reported to result in addiction.
Attention to the risks of off-label use of propofol increased in August 2009 due to the Los Angeles County coroner’s conclusion that music icon Michael Jackson died from a mixture of propofol and the benzodiazepine drugs lorazepam, midazolam, and diazepam on June 25, 2009. According to a July 22, 2009 search warrant affidavit unsealed by the district court of Harris County, Texas, Jackson’s physician, Conrad Murray, administered 25 milligrams of propofol diluted with lidocaine shortly before Jackson’s death. Even so, as of 2016, propofol was not on a US Drug Enforcement Administration schedule.
One of propofol’s most common side effects is pain on injection, especially in smaller veins. This pain arises from activation of the pain receptor, TRPA1, found on sensory nerves and can be mitigated by pretreatment with lidocaine. Less pain is experienced when infused at a slower rate in a large vein (antecubital fossa). Patients show considerable variability in their response to propofol, at times showing profound sedation with small doses.
Additional side effects include low blood pressure related to vasodilation, transient apnea following induction doses, and cerebrovascular effects. Propofol has more pronounced hemodynamic effects relative to many intravenous anesthetic agents. Reports of blood pressure drops of 30% or more are thought to be at least partially due to inhibition of sympathetic nerve activity. This effect is related to the dose and rate of propofol administration. It may also be potentiated by opioid analgesics. Propofol can also cause decreased systemic vascular resistance, myocardial blood flow, and oxygen consumption, possibly through direct vasodilation. There are also reports that it may cause green discolouration of the urine.
Although propofol is heavily used in the adult ICU setting, the side effects associated with propofol seem to be of greater concern in children. In the 1990s, multiple reported deaths of children in ICUs associated with propofol sedation prompted the FDA to issue a warning.
As a respiratory depressant, propofol frequently produces apnea. The persistence of apnea can depend on factors such as premedication, dose administered, and rate of administration, and may sometimes persist for longer than 60 seconds. Possibly as the result of depression of the central inspiratory drive, propofol may produce significant decreases in respiratory rate, minute volume, tidal volume, mean inspiratory flow rate, and functional residual capacity.
Diminishing cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure are also characteristics of propofol administration. In addition, propofol may decrease intraocular pressure by as much as 50% in patients with normal intraocular pressure.
A more serious but rare side effect is dystonia. Mild myoclonic movements are common, as with other intravenous hypnotic agents. Propofol appears to be safe for use in porphyria, and has not been known to trigger malignant hyperpyrexia.
As with any other general anesthetic agent, propofol should be administered only where appropriately trained staff and facilities for monitoring are available, as well as proper airway management, a supply of supplemental oxygen, artificial ventilation, and cardiovascular resuscitation.
Because of its lipid base, some hospital facilities require the IV tubing (of continuous propofol infusions) to be changed after 12 hours. This is a preventive measure against microbial growth and infection.
Propofol infusion syndrome
Main article: Propofol infusion syndrome
A rare, but serious, side effect is propofol infusion syndrome. This potentially lethal metabolic derangement has been reported in critically ill patients after a prolonged infusion of high-dose propofol, sometimes in combination with catecholamines and/or corticosteroids.
Propofol has been proposed to have several mechanisms of action, both through potentiation of GABAA receptor activity and therefore acting as a GABAA receptor positive allosteric modulator, thereby slowing the channel-closing time. At high doses, propofol may be able to activate GABAA receptors in the absence of GABA, behaving as a GABAA receptor agonist as well. Propofol analogs have been shown to also act as sodium channel blockers. Some research has also suggested that the endocannabinoid system may contribute significantly to propofol’s anesthetic action and to its unique properties. EEG research upon those undergoing general anesthesia with propofol finds that it causes a prominent reduction in the brain’s information integration capacity.
A 20 ml ampoule of 1% propofol emulsion, as sold in Australia by Sandoz
Propofol is highly protein-bound in vivo and is metabolised by conjugation in the liver. The half-life of elimination of propofol has been estimated to be between 2 and 24 hours. However, its duration of clinical effect is much shorter, because propofol is rapidly distributed into peripheral tissues. When used for IV sedation, a single dose of propofol typically wears off within minutes. Propofol is versatile; the drug can be given for short or prolonged sedation, as well as for general anesthesia. Its use is not associated with nausea as is often seen with opioid medications. These characteristics of rapid onset and recovery along with its amnestic effects have led to its widespread use for sedation and anesthesia.
John B. Glen, a veterinarian and researcher at Imperial Chemical Industries (ICI) spent 13 years developing propofol, an effort which led to the awarding to him of the prestigious 2018 Lasker Award for clinical research. Propofol was originally developed as ICI 35868. It was chosen for development after extensive evaluation and structure–activity relationship studies of the anesthetic potencies and pharmacokinetic profiles of a series of ortho-alkylated phenols.
First identified as a drug candidate in 1973, clinical trials followed in 1977, using a form solubilised in cremophor EL. However, due to anaphylactic reactions to cremophor, this formulation was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil/propofol mixture in water. The emulsified formulation was relaunched in 1986 by ICI (now AstraZeneca) under the brand name Diprivan. The currently available preparation is 1% propofol, 10% soybean oil, and 1.2% purified egg phospholipid as an emulsifier, with 2.25% glycerol as a tonicity-adjusting agent, and sodium hydroxide to adjust the pH. Diprivan contains EDTA, a common chelation agent, that also acts alone (bacteriostatically against some bacteria) and synergistically with some other antimicrobial agents. Newer generic formulations contain sodium metabisulfite or benzyl alcohol as antimicrobial agents. Propofol emulsion is a highly opaque white fluid due to the scattering of light from the tiny (about 150-nm) oil droplets it contains: Tyndall Effect.
A water-soluble prodrug form, fospropofol, has been developed and tested with positive results. Fospropofol is rapidly broken down by the enzyme alkaline phosphatase to form propofol. Marketed as Lusedra, this formulation may not produce the pain at injection site that often occurs with the conventional form of the drug. The U.S. Food and Drug Administration (FDA) approved the product in 2008. However fospropofol is a Schedule IV controlled substance with the DEA ACSCN of 2138 in the United States unlike propofol.
By incorporation of an azobenzene unit, a photoswitchable version of propofol (AP2) was developed in 2012, that allows for optical control of GABAA receptors with light. In 2013, a propofol binding site on mammalian GABAA receptors has been identified by photolabeling using a diazirine derivative. Additionally, it was shown that the hyaluronan polymer present in the synovia can be protected from free-radical depolymerization by propofol.
NEW DRUG APPROVALS
- ^ “Propofol”. Drugs.com. Retrieved 2 January 2019.
- ^ Ruffle JK (November 2014). “Molecular neurobiology of addiction: what’s all the (Δ)FosB about?”. Am J Drug Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711.
Propofol is a general anesthetic, however its abuse for recreational purpose has been documented (120). Using control drugs implicated in both ΔFosB induction and addiction (ethanol and nicotine), similar ΔFosB expression was apparent when propofol was given to rats. Moreover, this cascade was shown to act via the dopamine D1 receptor in the NAc, suggesting that propofol has abuse potential (119)
- ^ “Diprivan- propofol injection, emulsion”. DailyMed. Retrieved 17 April 2021.
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|Wikimedia Commons has media related to Propofol.|
- “Propofol”. Drug Information Portal. U.S. National Library of Medicine.
- GB patent 1472793, John B Glen & Roger James, “Pharmaceutical Compositions”, published 1977-05-04, assigned to Imperial Chemical Industries Ltd
|Trade names||Diprivan, others|
|License data||US DailyMed: Propofol|
|Physical: very low (seizures)|
Psychological: no data
|ATC code||N01AX10 (WHO)|
|Legal status||AU: S4 (Prescription only)CA: ℞-onlyUK: POM (Prescription only)US: ℞-only In general: ℞ (Prescription only)|
|Onset of action||15–30 seconds|
|Elimination half-life||1.5–31 hours|
|Duration of action||~5–10 minutes|
|CompTox Dashboard (EPA)||DTXSID6023523|
|Chemical and physical data|
|Molar mass||178.275 g·mol−1|
|3D model (JSmol)||Interactive image|