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Racecadotril

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ChemSpider 2D Image | Racecadotril | C21H23NO4S

Racecadotril

Molecular FormulaC₂₁H₂₃NO₄S
Average mass385.477 Da

(±)-Acetorphan
(RS)-Benzyl N-[3-(acetylthio)-2-benzylpropanoyl]glycinate
2-{[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]amino}acetic acid (phenylmethyl) ester7378
76K53XP4TO
81110-73-8[RN]
Benzyl N-[3-(acetylsulfanyl)-2-benzylpropanoyl]glycinate [ACD/IUPAC Name]
Cadotril
Dexecadotril[INN]
Glycine, N-[3-(acetylthio)-1-oxo-2-(phenylmethyl)propyl]-, phenylmethyl ester
Hidrasec [Trade name]
рацекадотрил[Russian][INN]
راسيكادوتريل[Arabic][INN]
消旋卡多曲[Chinese][INN]
RacecadotrilCAS Registry Number: 81110-73-8
CAS Name:N-[2-[(Acetylthio)methyl]-1-oxo-3-phenylpropyl]glycine phenylmethyl ester
Additional Names:N-[(R,S)-3-acetylthio-2-benzylpropanoyl]glycine benzyl ester; acetorphan
Trademarks: Hidrasec (GSK); Tiorfan (Bioprojet)
Molecular Formula: C21H23NO4S, Molecular Weight: 385.48
Percent Composition: C 65.43%, H 6.01%, N 3.63%, O 16.60%, S 8.32%
Literature References: Antisecretory enkephalinase inhibitor. Prepn: B. Roques et al.,EP38758 (1981); eidem,US4513009 (1985 to Bioprojet). Pharmacology: J.-M. Lecomte et al.,J. Pharmacol. Exp. Ther.237, 937 (1986). Effect on intestinal transit: J. F. Bergmann et al.,Aliment. Pharmacol. Ther.6, 305 (1992). Clinical trial in acute diarrhea: P. Baumer et al.,Gut33, 753 (1992); in children: E. Salazar-Lindo et al.,N. Engl. J. Med.343, 463 (2000). Symposium on pharmacology and clinical experience: Aliment. Pharmacol. Ther.13, Suppl. 6, 1-32 (1999). Review of clinical development: J.-C. Schwartz, Int. J. Antimicrob. Agents14, 75-79 (2000); J. M. Lecomte, ibid. 81-87.
Properties: White crystals from ether mp 89°., Melting point: mp 89°
Derivative Type: (S)-Form
CAS Registry Number: 112573-73-6
Additional Names: Ecadotril; sinorphan
Manufacturers’ Codes: Bay-y-7432
Molecular Formula: C21H23NO4S, Molecular Weight: 385.48
Percent Composition: C 65.43%, H 6.01%, N 3.63%, O 16.60%, S 8.32%
Literature References: Prepn: P. Duhamel et al.,EP318377; eidem,US5208255 (1989, 1993 both to Bioprojet); and pharmacology: B. Giros et al.,J. Pharmacol. Exp. Ther.243, 666 (1987). Clinical effect on plasma ANP levels in CHF: J. C. Kahn et al.,Lancet335, 118 (1990); on renal function: F. Schmitt et al.,Am. J. Physiol.267, F20 (1994). Clinical trial in heart failure: C. M. O’Connor et al.,Am. Heart J.138, 1140 (1999); J. G. F. Cleland, K. Swedberg, Lancet351, 1657 (1998).
Properties: mp 71°. [a]D25 -24.1° (c = 1.3 in methanol). LD50 i.v. in mice: >100 mg/kg (Duhamel, 1993).
Melting point: mp 71°
Optical Rotation: [a]D25 -24.1° (c = 1.3 in methanol)
Toxicity data: LD50 i.v. in mice: >100 mg/kg (Duhamel, 1993)
Therap-Cat: Antidiarrheal.
Keywords: Antidiarrheal; Neutral Endopeptidase Inhibitor.

Racecadotril is an anti-secretory enkephalinase inhibitor useful in the treatment of diarrhea.Racecadotril has been investigated for the basic science and treatment of Diarrhea, Acute Diarrhea, and Acute Gastroenteritis.

Racecadotril, also known as acetorphan, is an antidiarrheal medication which acts as a peripheral enkephalinase inhibitor.^[3] Unlike other opioid medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretory effect — it reduces the secretion of water and electrolytes into the intestine.^[3] It is available in France (where it was first introduced in ~1990) and other European countries (including Germany, Italy, the United Kingdom, Spain, Portugal, Poland, Finland, Russia and the Czech Republic) as well as most of South America and some South East Asian countries (including China, India and Thailand), but not in the United States. It is sold under the tradename Hidrasec, among others.^[4] Thiorphan is the active metabolite of racecadotril, which exerts the bulk of its inhibitory actions on enkephalinases.^[5]

Medical uses

Racecadotril is used for the treatment of acute diarrhea in children and adults and has better tolerability than loperamide, as it causes less constipation and flatulence.^[6]^[7] Several guidelines have recommended racecadotril use in addition to oral rehydration treatment in children with acute diarrhea.^[8]

Contraindications

Racecadotril has no contraindications apart from known hypersensitivity to the substance.^[9]^[10]

There is insufficient data for the therapy of chronic diarrhea, for patients with renal or hepatic failure, and for children under three months. Additional contraindications for the children’s formulation are hereditary fructose intolerance, glucose-galactose malabsorption and saccharase deficiency, as it contains sugar.^[7]^[9]

Racecadotril (CAS NO.: 81110-73-8), with its systematic name of Glycine, N-(2-((acetylthio)methyl)-1-oxo-3-phenylpropyl)-, phenylmethyl ester, (+-)-, could be produced through many synthetic methods.

Following is one of the synthesis routes: 2-Benzylacrylic acid (I) reacts with SOCl₂ in hot toluene to afford the acyl chloride (II), which is condensed with N-tosylglycine benzyl ester (III) in the presence of TEA in toluene to yield the corresponding amide (IV). Finally, this compound is condensed with thioacetic acid by heating at 80 °C to afford the target acylthio compound.

Racecadotril is a neutral endopeptidase inhibitor used as antidiarrheal in the treatment of chronic cardiac insufficiency and is available under the brand names Hidrasec and Tiorfan. Racecadotril is chemically known as N-[2-[(acetylthio) methyl]- l-oxo-3-phenylpropyl] glycine phenyl methyl ester, (herein after referred by its generic name racecadotril) and represented by the formula (I).

U.S. Patent No. US 4,513,009 describes amino acid derivatives including racecadotril, a pharmaceutical composition and a method of treatment.

The US’009 patent also discloses a process for the preparation of racecadotril which is illustrated by below scheme:

U.S. Patent No. US 6,835,851 B2 discloses a process for the preparation of racecadotril which is illustrated by scheme below:

European Patent No. EP 0501870B 1 discloses a process for the preparation of racec

Racecadotril

The use of coupling agents like hydroxyl benzotriazole (HOBT) and dicyclohexyl amine carbodiimide (DCC) generally induces the formation of side products such as dicyclohexylurea. These side products do lead to major problems, wherein purification by chromatography may be contemplated, but the side products are extremely difficult to remove on an industrial scale.

Consequently, efforts have been made to replace the peptidic coupling step

so as to avoid the formation of side products associated with the use of the coupling agents. Thus, it appears that, even if the preparation of N-(mercaptoacyl)amino acid derivatives from .alpha.-substituted acrylic acids by Michael addition of a thio acid and conversion of acid to acid chloride by using thionyl chloride and then coupling of an amino ester may be advantageous on a laboratory scale, such reactions are difficult to adapt on an industrial use.

The aforementioned processes described above involves expensive reagents such as hydroxyl benzotriazole (HOBT) and dicyclohexyl amine carbodiimide (DCC) and hazardous reagent like thionyl chloride thus rendering the processes expensive and not feasible on industrial scale.

SYNTHESIS BY WORLDDRUGTRACKER

Patent

https://www.google.com/patents/WO2013098826A1?cl=en

EXAMPLES

Example-1: Preparation of Racecadotril (I):

Step A) Preparation of 2-acetyIsulfanyI methyI-3-phenyI propionic acid (IV)

16.2 g of 2-benzylacrylic acid and 12.3 ml of thioacetic acid were were charged into a clean and dry R.B.flask and stirred at about 30°C for about 1 hour. The reaction mixture was heated to about 60°C and stirred for about 4 hours.The excess of thioacetic acid was distilled off completely to afford the title compound as residue. Yield: 23.8 g. Step B) Preparation of Racecadotril crude (la)

23.8 g. of 2-acetyl sulfanylmethyl-3-phenyl-propionic acid (IV), 200ml of methylene chloride and 16.7 ml of triethylamine were charged into a clean and dry R.B.flask. 10. 5 ml of ethylchloroformate was added at about -5°C. The resultant reaction mixture was stirred at about 0°C for about 30 min. 33.7 g of glycine benzyl ester p-tosyalte (II), 14 ml of triethylamine and 100ml of methylene chloride was added as a mixture to the reaction mass at about 0°C. Then the resultant reaction mixture was stirred at about 0°C for about 1 hr. followed by at about 30°C for about 30 min. After completion of the reaction as determined by TLC, the reaction mass was washed with 65 ml of distilled water, 65 ml 4% sodium bicarbonate solution and followed by 65 ml distilled water. The organic and aqueous phases were separated and the solvent was distilled completely, 2 x 50 ml Isopropyl alcohol was charged and again distilled off the solvent completely to give residue. The residue

obtained was triturated with a mixture of isopropyl alcohol 4 ml) and n-hexane (94 ml) at about 5°C to the title compound as crude. Yield: 34 g.

ExampIe-2: Purification of Racecadotril (Crude):

34 g. of crude Racecadotril and 35 ml of 20 % v/v aqueous .methanol were charged in a clean and dry R.B.flask and heated to about 65°C. 3g. of SP.carbon was charged and stirred at about 65°C for about 10 min. The reaction suspension was stirred at about 65°C for about 10 min. The reaction suspension was filtered on hyflow bed (diatomous earth) and washed the hyflow bed with 30 ml of aqueous methanol. The filtrate obtained was cooled to about 0°C for about 30 min. The solid separated was filtered and the solid obtained washed with 60 ml of precooled aqueous methanol to afford the pure racecadotril (I).

Yield: 29 g.; Purity by HPLC: 99.5 area %; The overall yield is 75.3%.

PATENT

https://www.google.com/patents/CN104356036A?cl=en

Example 1

The 40. 0g Racecadotril dissolved in 200ml of absolute ethanol and water bath heated to 40 ° C, and stir until the whole solution, stirring was stopped, the solution was placed in 15 ° C water bath was allowed to stand, when starting When there is precipitation of crystals, and then placed under the 0 ° C crystallization, after filtration, to 45 ° C under hot air drying cycle 6 hours to obtain 29. 2g, purity 99.6% of Racecadotril a polymorph crystals.

reflection angle X-ray powder diffraction pattern 20 at 4.3 °, 8.7 °, 13.2 °, 16.8 °, 17.8 ° and 20.0 ° at the show X-ray powder diffraction peaks. In 1135. 19CHT1,1551. 46CHT1,1644. 73CHT1,1687. 57CHT1, 1731. 35CHT1 and 3289. 20CHT1 displayed at an infrared absorption peak.

Clips

US 20020055645

PATENT

CN 104356036 A

Racecadotril, chemical name N_ [(R, S) -3- acetyl-mercapto-2-benzyl-propionyl)] glycine benzyl ester, is a neprilysin inhibitor, selectively, reversible inhibition of neprilysin, so that the inner protection from degradation of endogenous enkephalins, prolong the physiological activity of endogenous enkephalins in the digestive tract, mainly used in clinical treatment of children and adults with acute diarrhea. Its structural formula is as follows:

Racecadotril as enkephalinase inhibitors, developed in France in 1993 Bioprojet listed acute diarrhea treatment, trade name Tiorfan.

In W02011116490A1, US5945548 and CN101768095A and other documents, documented racecadotril the synthesis process, but did not report the crystal form; therefore the present inventors have not reported Racecadotril crystalline polymorph conduct further

Example 1

[0032] The 40. 0g Racecadotril dissolved in 200ml of absolute ethanol and water bath heated to 40 ° C, and stir until the whole solution, stirring was stopped, the solution was placed in 15 ° C water bath was allowed to stand, when starting When there is precipitation of crystals, and then placed under the 0 ° C crystallization, after filtration, to 45 ° C under hot air drying cycle 6 hours to obtain 29. 2g, purity 99.6% of Racecadotril a polymorph crystals.

[0033] reflection angle X-ray powder diffraction pattern 20 at 4.3 °, 8.7 °, 13.2 °, 16.8 °, 17.8 ° and 20.0 ° at the show X-ray powder diffraction peaks. In 1135. 19CHT1,1551. 46CHT1,1644. 73CHT1,1687. 57CHT1, 1731. 35CHT1 and 3289. 20CHT1 displayed at an infrared absorption peak.

SYN

EP 0038758

Alternatively, the condensation of dimethyl malonate (VI) with benzaldehyde (VII) by means of piperidine in refluxing toluene gives dimethyl benzylidenemalonate (VIII), which is reduced with H2 over Pd/C in toluene to yield the corresponding benzyl derivative (IX). The hydrolysis of (IX) with NaOH in water affords the benzylmalonic acid (X). Alternatively, intermediate (X) can also be obtained starting from diethyl malonate (XI), which is condensed with with benzaldehyde (VII) by means of piperidine in refluxing toluene to give diethyl benzylidenemalonate (XII). Reduction of (XII) with H2 over Pd/C in toluene yields the corresponding benzyl derivative (XIII), which is then hydrolized with NaOH in water. The monodecarboxylation of (X) and its condensation with paraformaldehyde and diethylamine in refluxing ethyl acetate provides 2-benzylacrylic acid (XIV), which is condensed with thioacetic acid (V) by heating at 70 C to afford 2-(acetylsulfanylmethyl)-3-phenylpropionic acid (XV). Finally, this compound is condensed with N-tosylglycine benzyl ester (XVI) by means of HOBt, DCC and TEA in THF.

SYN

EP 0729936

Reaction of benzaldehyde (I) with dimethyl malonate (II) in refluxing toluene in the presence of piperidine and HOAc provides dimethyl benzylidene malonate (III), which is then hydrogenated over Pd/C to afford dimethyl benzyl malonate (IV). Reduction of (IV) with LiAlH4 in refluxing THF furnishes 2-benzyl-1,3-propanediol (V), which is then subjected to reaction with vinyl acetate (VI) by means of Novozym 435 enzyme to yield diacetate (VII). Enantioselective removal of one acetyl group from (VII) by treatment with Pseudomonas fluorescens Lipase in acetone/phosphate buffer (pH = 7) at 30 C gives 3-acetoxy-2(S)-benzyl-propanol (S)-(VIII), which is then oxidized by means of Jones reagent in acetone/isopropanol to provide carboxylic acid (R)-(IX). The hydrolysis of (IX) with LiOH in THF/H2O gives 2(R)-benzyl-3-hydroxypropanoic acid (R)-(X). Alternatively, intermediate (X) can also be synthesized as follows: Condensation of benzaldehyde (I) with methyl acrylate (XV) by means of diaza-1,4-bicyclo[2.2.2.]octane affords methyl beta-hydroxy-alpha-methylene-benzenepropanoate (XVI), which is then subjected to hydrolysis with KOH in MeOH/H2O to yield carboxylic acid (XVII). Treatment of (XVII) with p-toluenesulfonic acid in refluxing HOAc gives (E)-2-(acetoxymethyl)-3-phenylpropionic acid (XVIII), which is finally converted into (X) by enantioselective hydrogenation in the presence of S-Binap and ruthenium catalyst [CodRu(all)2]. Derivative (R)-(X) is then converted into 3-(acetylsulfanyl)-2(S)-benzylpropionic acid (XI) by means of a Mitsunobu reaction with thioacetic acid, diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPh3). Compound (XI) is then subjected to optical purification by formation and isolation of the corresponding salt with (-)-ephedrine and subsequent hydrolysis with HCl to furnish enantiomerically pure (S)-(XII). Finally, carboxylic acid (S)-(XII) is converted into ecadotril by its coupling with benzyl glycinate (XIV), either by means of Et3N, DCC and HOBt in CHCl3, or by first reaction with thionyl chloride to give acid chloride (S)-(XIII) and subsequent coupling with glycinate (XIV) by means of Et3N in CH2Cl2.

SYN

The reaction of 2-benzylacrylic acid (I) with SOCl2 in hot toluene gives the acyl chloride (II), which is condensed with N-tosylglycine benzyl ester (III) by means of TEA in toluene to yield the corresponding amide (IV). Finally, this compound is condensed with thioacetic acid by heating at 80 C to afford the target acylthio compound.

FR 2816309; US 2002055645

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Side effects

The most common adverse effect is headache, which occurs in 1–2% of patients.^[7] Rashes occur in fewer than 1% of patients. Other described skin reactions include itching, urticaria, angioedema, erythema multiforme, and erythema nodosum.^[9]^[10]

Overdose

No cases of overdose are known. Adults have tolerated 20-fold therapeutic doses without ill effects.^[10]

Interactions

No interactions in humans have been described. Combining racecadotril with an ACE inhibitor can theoretically increase the risk for angioedema.^[9]^[10]

Racecadotril and its main metabolites neither inhibit nor induce the liver enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. They also do not induce UGT enzymes.^[10] This means that racecadotril has a low potential for pharmacokinetic interactions.

Pharmacology

Mechanism of action

Enkephalins are peptides produced by the body that act on opioid receptors with preference for the δ subtype.^[11] Activation of δ receptors inhibits the enzyme adenylyl cyclase, decreasing intracellular levels of the messenger molecule cAMP.^[7]

The active metabolite of racecadotril, thiorphan, inhibits enkephalinase enzymes in the intestinal epithelium with an IC₅₀ of 6.1 nM, protecting enkephalins from being broken down by these enzymes. (Racecadotril itself is much less potent at 4500 nM.)^[7]^[8] This reduces diarrhea related hypersecretion in the small intestine without influencing basal secretion. Racecadotril also has no influence on the time substances, bacteria or virus particles stay in the intestine.^[10]

Pharmacokinetics

Some metabolites of racecadotril.
top left: precursor to the active metabolite
top right: active metabolite
bottom row: inactive metabolites

Racecadotril is rapidly absorbed after oral administration and reaches C_max within 60 minutes. Food delays C_max by 60 to 90 minutes but does not affect the overall bioavailability. Racecadotril is rapidly and effectively metabolized to the moderately active S-acetylthiorphan the main active metabolite thiorphan, of which 90% are bound to blood plasma proteins. In therapeutic doses, racecadotril does not pass the blood–brain barrier. Inhibition of enkephalinases starts 30 minutes after administration, reaches its maximum (75–90% inhibition with a therapeutic dose) two hours after administration, and lasts for eight hours. The elimination half-life, measured from enkephalinase inhibition, is three hours.^[7]^[8]^[9]

Thiorphan is further metabolized to inactive metabolites such as the methyl thioether and the methyl sulfoxide. Both active and inactive metabolites are excreted, mostly via the kidney (81.4%), and to a lesser extent via the feces (8%).^[10]

Society and culture

Brand names

In both France and Portugal it is sold as Tiorfan and in Italy as Tiorfix. In India it is available as Redotril and Enuff.^[4]

References

^ https://www.ema.europa.eu/documents/psusa/racecadotril-list-nationally-authorised-medicinal-products-psusa/00002602/202003_en.pdf
^ Jump up to:^a ^b ^c ^d “SPC-DOC_PL 39418-0003.PDF” (PDF). Medicines and Healthcare Products Regulatory Agency. Bioprojet Europe Ltd. 26 December 2012. Retrieved 7 May 2014.
^ Jump up to:^a ^b Matheson AJ, Noble S (April 2000). “Racecadotril”. Drugs. 59 (4): 829–35, discussion 836–7. doi:10.2165/00003495-200059040-00010. PMID 10804038.
^ Jump up to:^a ^b Brayfield, A, ed. (13 December 2013). “Racecadotril”. Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 6 May 2014.
^ Spillantini MG, Geppetti P, Fanciullacci M, Michelacci S, Lecomte JM, Sicuteri F (June 1986). “In vivo ‘enkephalinase’ inhibition by acetorphan in human plasma and CSF”. European Journal of Pharmacology. 125 (1): 147–50. doi:10.1016/0014-2999(86)90094-4. PMID 3015640.
^ Fischbach, Wolfgang; Andresen, Viola; Eberlin, Marion; Mueck, Tobias; Layer, Peter (2016). “A Comprehensive Comparison of the Efficacy and Tolerability of Racecadotril with Other Treatments of Acute Diarrhea in Adults”. Frontiers in Medicine. 3: 44. doi:10.3389/fmed.2016.00044. ISSN 2296-858X. PMC 5064048. PMID 27790616.
^ Jump up to:^a ^b ^c ^d ^e ^f Dinnendahl, V; Fricke, U, eds. (1982). Arzneistoff-Profile (in German). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
^ Jump up to:^a ^b ^c Eberlin, Marion; Mück, Thomas; Michel, Martin C. (2012). “A Comprehensive Review of the Pharmacodynamics, Pharmacokinetics, and Clinical Effects of the Neutral Endopeptidase Inhibitor Racecadotril”. Frontiers in Pharmacology. 3: 93. doi:10.3389/fphar.2012.00093. ISSN 1663-9812. PMC 3362754. PMID 22661949.
^ Jump up to:^a ^b ^c ^d ^e Mediq.ch: racecadotril. Accessed 2019-12-30.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g Haberfeld, H, ed. (2019). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Hidrasec 100 mg-Hartkapseln.
^ Cumming, P (2019). “A Survey of Molecular Imaging of Opioid Receptors”. Molecules. 24 (22): 4190. doi:10.3390/molecules24224190. PMC 6891617. PMID 31752279.

External links

“Racecadotril”. Drug Information Portal. U.S. National Library of Medicine.

Clinical data

Trade names	Hidrasec, Tiorfan, Zedott, others
Other names	Benzyl 2-[3-(acetylthio)-2-benzylpropanamido]acetate
AHFS/Drugs.com	International Drug Names
Routes of administration	By mouth
ATC code	A07XA04 (WHO)
Legal status
Legal status	UK: POM (Prescription only)EU: Rx-only ^[1]
Pharmacokinetic data
Protein binding	90% (active metabolite thiorphan)^[2]
Metabolism	Liver-mediated^[2]
Onset of action	30 min
Elimination half-life	3 hours^[2]
Excretion	Urine (81.4%), feces (8%)^[2]
Identifiers
show IUPAC name
CAS Number	81110-73-8
PubChem CID	107751
DrugBank	DB11696
ChemSpider	96913
UNII	76K53XP4TO
KEGG	D08464
ChEMBL	ChEMBL2103772
CompTox Dashboard (EPA)	DTXSID8045513
ECHA InfoCard	100.214.352
Chemical and physical data
Formula	C₂₁H₂₃NO₄S
Molar mass	385.48 g·mol⁻¹
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
Melting point	89 °C (192 °F)
show SMILES
show InChI
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CN101103960A *	Jul 14, 2006	Jan 16, 2008	海南盛科生命科学研究院	Dry mixed suspension containing racecadotril and preparation method thereof
CN101768095A *	Dec 26, 2008	Jul 7, 2010	山东齐都药业有限公司	Preparation method of racecadotril
WO2001097803A1 *	Jun 20, 2001	Dec 27, 2001	Laboratoire Glaxosmithkline	Pharmaceutical preparations comprising racecadotril (acetorphan)
WO2013098826A1 *	Dec 26, 2011	Jul 4, 2013	Symed Labs Limited	“a process for the preparation of n-[2-[(acetylthio) methyl]-1-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof”

Reference

Reference
CN101103960A *	Jul 14, 2006	Jan 16, 2008	海南盛科生命科学研究院	Dry mixed suspension containing racecadotril and preparation method thereof
CN101768095A *	Dec 26, 2008	Jul 7, 2010	山东齐都药业有限公司	Preparation method of racecadotril
WO2001097803A1 *	Jun 20, 2001	Dec 27, 2001	Laboratoire Glaxosmithkline	Pharmaceutical preparations comprising racecadotril (acetorphan)
WO2013098826A1 *	Dec 26, 2011	Jul 4, 2013	Symed Labs Limited	“a process for the preparation of n-[2-[(acetylthio) methyl]-1-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof”
1	*	金庆平等: “神经内肽酶抑制剂消旋卡多曲(Racecadotril)的合成工艺研究“, 《中国现代应用药学杂志》, vol. 20, no. 7, 31 August 2003 (2003-08-31)

Reference
Citing Patent	Filing date	Publication date	Applicant	Title
US6013829 *	Feb 4, 1997	Jan 11, 2000	Societe Civile Bioprojet	Process for the asymmetric synthesis of S-acyl derivatives of 2-mercaptomethyl -3- phenyl propanoic acid, application to the synthesis of N-(mercaptoacyl) amino acid derivatives
US20040009956 *	Apr 29, 2003	Jan 15, 2004	Dehua Pei	Inhibition of protein tyrosine phosphatases and SH2 domains by a neutral phosphotyrosine mimetic
1	*	MOHAMED A.O. ET AL.: ‘Stability-indicating methods for the determination of racecadotril in the presence of its degradation products‘ BIOSCIENCE TRENDS vol. 3, no. 6, 2009, pages 247 – 252, XP055074337
CN104356036A *	Nov 7, 2014	Feb 18, 2015	山东齐都药业有限公司	Alpha crystal form of racecadotril and preparation method of alpha crystal form

///////////Racecadotril, рацекадотрил , راسيكادوتريل , 消旋卡多曲 , Antidiarrheal, Neutral Endopeptidase Inhibitor, Cadotril, Dexecadotril ,

CC(=O)SCC(CC1=CC=CC=C1)C(=O)NCC(=O)OCC1=CC=CC=C1

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CEFADROXIL

January 5, 2022 4:42 am / Leave a comment

CEFADROXIL

Molecular FormulaC₁₆H₁₇N₃O₅S
Average mass363.388 Da

(6R,7R)-7-{[(2R)-2-Amino-2-(4-hydroxyphenyl)acetyl]amino}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
256-555-6[EINECS]
50370-12-2[RN]
5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7-(((2R)-amino(4-hydroxyphenyl)acetyl)amino)-3-methyl-8-oxo-, (6R,7R)-
5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-, (6R,7R)-
цефадроксил [Russian] [INN]
سيفادروكسيل [Arabic] [INN]
头孢羟氨苄 [Chinese] [INN]

Cephos

Molecular FormulaC₁₆H₁₉N₃O₆S
Average mass381.404 Da

5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-, (6R,7R)-, monohydrate
66592-87-8[RN]
(6R,7R)-7-{[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrate
(6R,7R)-7-{[(2R)-2-Amino-2-(4-hydroxyphenyl)acetyl]amino}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrate (1:1)

Product Ingredients

INGREDIENT	UNII	CAS	INCHI KEY
Cefadroxil hemihydrate	J9CMF6461M	119922-85-9	AJAMDISMDZXITN-QXBGZBSVSA-N
Cefadroxil monohydrate	280111G160	66592-87-8	NBFNMSULHIODTC-CYJZLJNKSA-N
Cefadroxil sodium	SSZ6380I0I	42284-83-3	GQOVFIUWRATNJC-CYJZLJNKSA-M

CefadroxilCAS Registry Number: 66592-87-8
CAS Name: (6R,7R)-7-[[(2R)-Amino-(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohydrate
Additional Names: 7-[D-(-)-a-amino-a-(4-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate; p-hydroxycephalexine monohydrate
Manufacturers’ Codes: BL-S578; MJF-11567-3
Trademarks: Baxan (BMS); Bidocef (BMS); Cefa-Drops (Fort Dodge); Cefamox (BMS); Ceforal (Farmoffer); Cephos (CT); Duracef (BMS); Duricef (BMS); Kefroxil (Torre); Oracéfal (BMS); Sedral (BMS); Ultracef (BMS)
Molecular Formula: C16H17N3O5S.H2O
Molecular Weight: 381.40
Percent Composition: C 50.39%, H 5.02%, N 11.02%, O 25.17%, S 8.41%
Literature References: Semi-synthetic cephalosporin antibiotic. Prepn: NL6812382; L. B. Crast, Jr., US3489752 (1969, 1970 both to Bristol-Myers); T. Takahashi et al.,DE2216113; eidem,US3816253 (1972, 1974, both to Takeda). Prepn of crystalline monohydrate: D. Bouzard et al.,US4504657 (1985 to Bristol-Myers). Antimicrobial activity: R. E. Buck, K. E. Price, Antimicrob. Agents Chemother.11, 324 (1977). Pharmacology: M. Pfeffer et al.,ibid. 331; A. I. Hartstein et al.,ibid.12, 93 (1977). Review:J. Antimicrob. Chemother.10, Suppl. B, 1-162 (1982). Series of articles on clinical trials in respiratory tract infections: Drugs32, Suppl. 3, 1-56 (1986).Properties: White crystals, mp 197° (dec).
Melting point: mp 197° (dec)
Therap-Cat: Antibacterial.
Therap-Cat-Vet: Antibacterial.
Keywords: Antibacterial (Antibiotics); ?Lactams; Cephalosporins.

Cefadroxil is a cephalosporin antibiotic used in the treatment of various bacterial infections, such as urinary tract infections, skin and skin structure infections, and tonsillitis.

Cefadroxil (formerly trademarked as Duricef) is a broad-spectrum antibiotic of the cephalosporin type, effective in Gram-positive and Gram-negative bacterial infections. It is a bactericidal antibiotic.

It was patented in 1967 and approved for medical use in 1978.^[1]

DURICEF (cefadroxil) is a semisynthetic cephalosporin antibiotic intended for oral administration. It is a white to yellowish-white crystalline powder. It is soluble in water and it is acid- stable. It is chemically designated as 5-Thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[amino(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-, monohydrate[6R- [6α,7β(R*)]]-. It has the formula C₁₆H₁₇N₃O₅S•H₂0 and the molecular weight of 381.40. It has the following structural formula:

DURICEF (cefadroxil monohydrate) structural formula illustration

DURICEF (cefadroxil) film-coated tablets, 1 g, contain the following inactive ingredients: microcrystalline cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, polysorbate 80, simethicone emulsion, and titanium dioxide.

DURICEF (cefadroxil) for Oral Suspension contains the following inactive ingredients: FD&C Yellow No. 6, flavors (natural and artificial), polysorbate 80, sodium benzoate, sucrose, and xanthan gum.

DURICEF (cefadroxil) capsules contain the following inactive ingredients: D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40, gelatin, magnesium stearate, and titanium dioxide.

SYN

IR spectrum of pure cefadroxil drug.

Synthesis Reference

Leonardo Marsili, “Substantially anhydrous crystalline cefadroxil and method for producing it.” U.S. Patent US5329001, issued April, 1978.

US5329001

SYN

Antibiotics

R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006

Cefadroxil

Cefadroxil, [6R-[6α,7β(R)]]-3-methyl-8-oxo-7-[[amino(4-hydroxyphenyl) acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (32.1.2.14), is an analog of cephalexin and differs only in the presence of a hydroxyl group in the fourth position of the phenyl ring of phenylglycine, and is synthesized by a scheme analogous to the scheme of cephradin synthesis [90–96].

Cefadroxil has a broad spectrum of antimicrobial action; it is active with respect to Gram-positive and Gram-negative microorganisms. Like all of the other drugs described above, it acts as a bactericide by disrupting the process of restoring the membranes of bacteria. Synonyms of this drug are bidocef, cefadril, duracef, ultracef, and others.SYN

Cefadroxil

ATC:J01DA09

MW:363.39 g/mol
CAS-RN:50370-12-2
InChI Key:BOEGTKLJZSQCCD-UEKVPHQBSA-N
InChI:InChI=1S/C16H17N3O5S/c1-7-6-25-15-11(14(22)19(15)12(7)16(23)24)18-13(21)10(17)8-2-4-9(20)5-3-8/h2-5,10-11,15,20H,6,17H2,1H3,(H,18,21)(H,23,24)/t10-,11-,15-/m1/s1
EINECS:256-555-6
LD₅₀:>1.5 g/kg (M, i.v.); >10 g/kg (M, p.o.);
>1 g/kg (R, i.v.); >10 g/kg (R, p.o.);
>2 g/kg (dog, p.o.)

Synthesis

Substances

CAS-RN	Formula	Chemical Name	CAS Index Name
22252-43-3	C₈H₁₀N₂O₃S	7-amino-3-deacetoxycephalosporanic acid	5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-amino-3-methyl-8-oxo-, (6R-trans)-
53487-89-1	C₁₃H₁₅NO₅	d(–)-4-hydroxy-N-(2-methoxycarbonyl-1-methylethenyl)phenylglycine	Benzeneacetic acid, 4-hydroxy-α-[(3-methoxy-1-methyl-3-oxo-1-propenyl)amino]-, (R)-

PATENT

Seo, Dae-Won; WO 2005042543

https://patents.google.com/patent/WO2005042543A1/enOral cephalosporin antibiotics, including cefprozil, cefatrizine, and cefadroxii, commonly have a 4-hydroxyphenylglycine group, as represented by the following formula:

The compound of the above formula is cefprozil when A is -C=CH-CH₃, cefatrizine when A is 1 H-1 ,2,3-triazole-4-yl-thiomethyl, and cefadroxii when A is -CH₃. Conventionally, there have been known various processes for preparing oral cephalosporin antibiotics, such as cefprozil, cefatrizine, and cefadroxii, by reacting reactive derivatives of 4-hydroxyphenylglycine with 3-cephem compounds. For example, U.S. Patent No. 3,985,741 discloses a process for preparing a cefadroxii, which includes reacting 4-hydroxyphenylglycine and ethylchloroformate inN-methylmorpholine to obtain an anhydride, followed by reaction with7-amino-deacetoxy-cephalosporanic acid (7-ADCA). However, the yield and quality of the product are poor. U.S. Patent Nos. 4,520,022, 4,591 ,641 , and 4,661 ,590 disclose a condensation reaction between 4-hydroxyphenylglycine with a protected amino group and a cephem compound in the presence of Λ/.Λ/’-dicyclohexylcarbodimide. However,Λ/,Λ/’-dicyclohexylurea produced after the condensation reaction is not easily removed, which restricts industrial applications. U.S. Patent No. 4,336,376 discloses a process for preparing a cefadroxii, which includes reacting a 4-hydroxyphenylglycine salt having a protected amino group with trimethylsilyl-2-oxazolidinone to protect a 4-hydroxyl group followed by reaction with acylchloride to obtain a 4-hydroxyphenylglycine anhydride and then reaction with 7-ADCA. However, silylation is prerequisite and these reactions are annoying, and thus, this process is not suitable for industrial application. U.S. Patent No. 4,708,825 discloses a technique of reacting4-hydroxyphenylglycine having a substituted amino group with thionyl chloride using a gaseous hydrogen chloride to obtain a 4-hydroxyphenylglycyl chloride hydrochloride followed by reaction with a cephem compound. However, handling property of the thionyl chloride and the gaseous hydrogen chloride is poor, and thus, this technique is not suitable for industrial application. U.S. Patent Nos. 3,925,418, 4,243,819, and 4,464,307 disclose a process for producing 4-hydroxyphenylglycine using excess phosgene. However, difficulty in handling of highly toxic phosgene, removal of excess residual phosgene, and control of reaction conditions renders mass production difficult. As a process for preparing a reactive anhydride of 4-hydroxyphenylglycine, there are reported a method for the preparation of acid chloride using phosphorus pentachloride, phosphorus oxychloride, or thionyl chloride, and a method for the preparation of active ester using imidazole, mercaptobenzothiazole, or hydroxybenzotriazole. However, an acid chloride of 4-hydroxyphenylglycine has poor reactivity due to a hydroxyl group and an active ester of 4-hydroxyphenylglycine has poor reactivity and involves a side reaction. In addition, Korean Patent Laid-Open Publication Nos. 2002-69431 , 2002-69432, 2002-69437, and 2002-69440 disclose a process for preparing a pivaloyl or succinimide derivative of 4-hydroxyphenylglycine and a process for preparing a cephem compound such as cefprozil using the pivaloyl or succinimide derivative of 4-hydroxyphenylglycine. Meanwhile, there have been known various preparation processes for 3-(Z)-propenyl cephem derivative which is a compound useful as an intermediate for preparation of cefprozil which is an oral cephalosporin antibiotic. WO93/16084 discloses a process of selectively separating a 3-(Z)-propenyl cephem compound by means of a hydrochloride, metal, or tertiary amine salt of7-amino-3-(1-propen-1-yl)-3-cephem-carboxylic acid or by adsorption chromatography. However, there is a disadvantage in that separation and purification are cost-ineffective. U.K. Patent No. 2,135,305 discloses a process for preparing cefprozil from a4-hydroxyphenylglycine compound with a t-butoxycarbonyl-protected amino group and a cephem compound with a benzhydryl-protected carboxyl group. However, incorporation of a 3-propenyl group after acylation lowers reaction efficiency and high-performance liquid chromatography is required for isomer separation, which render industrial application difficult. U.S. Patent No. 4,727,070 discloses a technique of removing an E-isomer cefprozil from a mixture of 27E cefprozil, which includes incorporating an active group such as sodium imidazolidinone into the mixture of 2VE cefprozil by reaction of the mixture of 27E cefprozil with acetone followed by deprotection. However, purification by chromatography incurs enormous costs. In view of the above problems, Korean Patent Laid-Open Publication No.2002-80838 discloses a process for preparing a 3-(Z)-propenyl cephem compound by reacting a phosphoranylidene cephem compound with acetaldehyde in a mixed solvent essentially consisting of ether in the presence of a base. According to a disclosure in this patent document, ether is essentially used. In this respect, in the case of using methylenechloride or tetrahydrofuran, even when other reaction conditions, for example, reaction temperature, reaction duration, base, catalyst, and the like are adjusted, it is very difficult to adjust the content of the Z-isomer to more than 83%.DETAILED DESCRIPTION OF THE INVENTION Technical Goal of the Invention The present invention provides a process for simply preparing a cephalosporin antibiotic in high yield and purity using a novel reactive intermediate, i.e., a 4-hydroxyphenylglycine derivative. The present invention also provides a novel reactive intermediate, i.e., a 4-hydroxyphenylglycine derivative which is used in simply preparing a cephalosphorin antibiotic in high yield and purity, and a preparation process thereof. While searching for a process for stereospecifically preparing a novel3-(Z)-propenyl cephem derivative, the present inventors found that use of a mixed solvent including methylenechloride, isopropylalcohol, and water in a predetermined ratio can stereospecifically and efficiently produce the 3-(Z)-propenyl cephem derivative, which is in contrary to the disclosure in Korean Patent Laid-Open Publication No. 2002-80838. Therefore, the present invention also provides a process for stereospecifically preparing a 3-(Z)-propenyl cephem derivative using a mixed solvent including methylenechloride, isopropylalcohol, and water in a predetermined ratio.

Example 9 Preparation of7-r2-amino-2-(4-hvdroxyphenyl)acetamido1-3-methyl-3-cephem-4-carboxylic acid(cefadroxii) The reaction solution obtained in step A of Example 1 was cooled to -40 ^°C and a solution obtained by dissolving 6.21 g (0.029mol) of 7-amino-3-methyl-3-cephem-4-carboxylic acid in 40 ml of methylenechloride, 10 ml of water, and 6.5 g of triethylamine was gradually dropwise added thereto for 1 hour. Then, the reaction mixture was incubated at the same temperature for 2 hours and cooled to 0^°C to obtain an insoluble solid. The insoluble solid was filtered. A filtrate was sent to a reactor and then stirred for 1 hour after addition of 20 ml of 6N HCI. The reaction solution was adjusted to pH of 3.2 by addition of 10% NaOH, stirred at0^°C for 2 hours, and filtered to give 9.1g (83%) of the titled compound as a white solid. H-NMR( δ , D₂0-d₂) : 1.79(3H, d, 8.6Hz, -CH₃), 3.22(1 H, d, 18Hz, 2-H),3.55(1 H. d. 18Hz, 2-H), 5.15(1 H, d, 4.6Hz, 6-H), 5.66(1 H, d, 4.6Hz, 7-H), 6.91 (2H, d,8.0Hz, phenyl-H), 7.38(2H, d, 8.0Hz, phenyl-H)

PAPER

Deshmukh, J. H.; Asian Journal of Chemistry 2010, V22(3), P1760-1768

Journal of the Chinese Chemical Society (Weinheim, Germany), 66(12), 1649-1657; 2019

Journal of the Indian Chemical Society, 93(6), 593-598; 2016

Biotechnology Letters, 34(9), 1719-1724; 2012

PATENT

WO 2011113486

By Gupta, Niranjan Lal et alFrom Indian, 184842, 30 Sep 2000

PAPER

European Journal of Organic Chemistry, (10), 1817-1820; 2001

PAPER

Organic Letters, 2(18), 2829-2831; 2000

The cephalosporin antibiotic Cefadroxil can be epimerized at the α-carbon of its amino acid side chain using pyridoxal as the mediator. By clathration with 2,7-dihydroxynaphthalene, the desired diastereomer can be selectively withdrawn from the equilibrating mixture of epimers. In this way, an asymmetric transformation of Cefadroxil can be accomplished. This opens the possibility of the production of Cefadroxil starting from racemic p-hydroxyphenylglycine, in contrast to the current industrial synthesis that employs the d-amino acid in enantiopure form.

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Medical use

Cefadroxil is a first-generation cephalosporin antibacterial drug that is the para-hydroxy derivative of cephalexin, and is used similarly in the treatment of mild to moderate susceptible infections such as the bacterium Streptococcus pyogenes, causing the disease popularly called strep throat or streptococcal tonsillitis, urinary tract infection, reproductive tract infection, and skin infections.

Cefadroxil is used as an antibiotic prophylaxis before dental procedures, for patients allergic to penicillins.

Spectrum of bacterial resistance and susceptibility

Cefadroxil has a broad spectrum of activity and has been effective in treating bacteria responsible for causing tonsillitis, and infections of the skin and urinary tract. The following represents MIC susceptibility data for a few medically significant microorganisms.^[2]

Escherichia coli: 8 μg/ml
Staphylococcus aureus: 1 – 2 μg/ml
Streptococcus pneumoniae: ≤1 – >16 μg/ml

Side effects

The most common side effects of cefadroxil are diarrhea (which, less commonly, may be bloody), nausea, upset stomach, and vomiting. Other side effects include^[3] rashes, hives, and itching.

Pharmacokinetics

Cefadroxil is almost completely absorbed from the gastrointestinal tract. After doses of 500 mg and 1 g by mouth, peak plasma concentrations of about 16 and 30 micrograms/ml, respectively, are obtained after 1.5 to 2.0 hours. Although peak concentrations are similar to those of cefalexin, plasma concentrations are more sustained. Dosage with food does not appear to affect the absorption of cefadroxil. About 20% of cefadroxil is reported to be bound to plasma proteins. Its plasma half-life is about 1.5 hours and is prolonged in patients with renal impairment.

Cefadroxil is widely distributed to body tissues and fluids. It crosses the placenta and appears in breast milk. More than 90% of a dose of cefadroxil may be excreted unchanged in the urine within 24 hours by glomerular filtration and tubular secretion; peak urinary concentrations of 1.8 mg/ml have been reported after a dose of 500 mg. Cefadroxil is removed by haemodialysis.

Dosage

Cefadroxil is given by mouth, and doses are expressed in terms of the anhydrous substance; 1.04 g of cefadroxil monohydrate is equivalent to about 1 g of anhydrous cefadroxil.

Veterinary use

It can be used for treating infected wounds on animals. Usually in powder form mixed with water, it has a color and smell similar to Tang. Given orally to animals, the amount is dependent on their weight and severity of infection.

References

^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 493. ISBN 9783527607495.
^ “Cefadroxil, Free Acid Susceptibility and Minimum Inhibitory Concentration (MIC) Data” (PDF).
^ “Cefadroxil side effects”. Drugs.

Clinical data

Trade names	Duricef
AHFS/Drugs.com	Monograph
MedlinePlus	a682730
Routes of administration	Oral
ATC code	J01DB05 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding	plasma protein
Metabolism	unknown
Elimination half-life	1.5 hours
Identifiers
show IUPAC name
CAS Number	66592-87-8
PubChem CID	47964
DrugBank	DB01140
ChemSpider	43629
UNII	280111G160
KEGG	D02353
ChEBI	CHEBI:53667
ChEMBL	ChEMBL1644
CompTox Dashboard (EPA)	DTXSID8022749
ECHA InfoCard	100.051.397
Chemical and physical data
Formula	C₁₆H₁₇N₃O₅S
Molar mass	363.39 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI
(what is this?) (verify)

////////////CEFADROXIL, цефадроксил , سيفادروكسيل , 头孢羟氨苄 , BL-S578; MJF-11567-3, BL S578, MJF 11567-3

[H][C@]12SCC(C)=C(N1C(=O)[C@H]2NC(=O)[C@H](N)C1=CC=C(O)C=C1)C(O)=O

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Cabergoline

January 3, 2022 9:32 am / Leave a comment

ChemSpider 2D Image | Cabaser | C26H37N5O2

Cabergoline

Cabaser

Molecular FormulaC₂₆H₃₇N₅O₂
Average mass451.604 Da

1-Ethyl-3-(3′-dimethylaminopropyl)-3-(6′-allylergoline-8’β-carbonyl)urea
5860
81409-90-7[RN]
(6aR,9R,10aR)-N-[3-(dimethylamino)propyl]-N-(ethylcarbamoyl)-7-prop-2-en-1-yl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide
(8b)-N-[3-(Dimethylamino)propyl]-N-[(ethylamino)carbonyl]-6-(2-propenyl)ergoline-8-carboxamide
(8β)-6-Allyl-N-[3-(dimethylamino)propyl]-N-(ethylcarbamoyl)ergoline-8-carboxamide
Ergoline-8-carboxamide, N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl]-6-(2-propen-1-yl)-, (8β)-
ergoline-8-carboxamide, N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl]-6-(2-propenyl)-, (8β)-
KE6167600, LL60K9J05T, UNII-LL60K9J05T,
каберголин
كابارغولين

卡麦角林,

FCE 21336
FCE-21336

Cabergoline
CAS Registry Number: 81409-90-7
CAS Name:(8b)-N-[3-(Dimethylamino)propyl]-N-[(ethylamino)carbonyl]-6-(2-propenyl)ergoline-8-carboxamide
Additional Names: 1-ethyl-3-(3¢-dimethylaminopropyl)-3-(6¢-allylergoline-8¢b-carbonyl)urea; 1-[(6-allylergoline-8b-yl)carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea
Manufacturers’ Codes: FCE-21336
Trademarks: Dostinex (Pharmacia & Upjohn)
Molecular Formula: C26H37N5O2, Molecular Weight: 451.60
Percent Composition: C 69.15%, H 8.26%, N 15.51%, O 7.09%
Literature References: Dopamine D2-receptor agonist. Prepn: P. Salvati et al.,BE888243; eidem,US4526892 (1981, 1985 both to Farmitalia Carlo Erba). Prepn and bioactivity: E. Brambilla et al.,Eur. J. Med. Chem.24, 421 (1989). Clinical pharmacology: C. Ferrari et al.,J. Clin. Endocrinol. Metab.63, 941 (1986). Veterinary trial as abortifacient in dogs: K. Post et al.,Theriogenology29, 1233 (1988). Clinical evaluation to prevent puerperal lactation: G. B. Melis et al.,Obstet. Gynecol.71, 311 (1988); in hyperprolactinemic disorders: C. Ferrari et al.,J. Clin. Endocrinol. Metab.68, 1201 (1989). Clinical trial in Parkinson’s disease: J. T. Hutton et al.,Neurology46, 1062 (1996).
Properties: White crystals from diethyl ether, mp 102-104°. Sol in ethyl alcohol, chloroform, DMF; slightly sol in 0.1 N HCl; very slightly sol in n-hexane. Insol in water. LD50 orally in male mice: >400 mg/kg (Brambilla).
Melting point: mp 102-104°
Toxicity data: Sol in ethyl alcohol, chloroform, DMF; slightly sol in 0.1 N HCl; very slightly sol in n-hexane. Insol in water. LD50 orally in male mice: >400 mg/kg (Brambilla)

Cabergoline diphosphate
85329-89-1
Derivative Type: Diphosphate
CAS Registry Number: 85329-89-1, Molecular Formula: C26H37N5O2.2H3PO4, Molecular Weight: 647.59
Percent Composition: C 48.22%, H 6.69%, N 10.81%, O 24.71%, P 9.57%
Properties: mp 153-155°., Melting point: mp 153-155°
Therap-Cat: Prolactin inhibitor; antiparkinsonian.
Therap-Cat-Vet: Prolactin inhibitor.
Keywords: Antiparkinsonian; Dopamine Receptor Agonist; Prolactin Inhibitor.

Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson’s disease, and for other indications. It is taken by mouth.

Cabergoline is an ergot derivative and a potent dopamine D₂ receptor agonist.^[1]

Cabergoline was patented in 1980 and approved for medical use in 1993.^[2]

Cabergoline is a dopamine receptor agonist used for the treatment of hyperprolactinemic conditions due to various causes.

Cabergoline, an ergot derivative, is a long-acting dopamine agonist and prolactin inhibitor. It is used to treat hyperprolactinemic disorders and Parkinsonian Syndrome. Cabergoline possesses potent agonist activity on dopamine D2 receptors.

Synthesis Reference

US4526892

PAPER

https://www.researchgate.net/publication/11103403_A_Practical_Synthesis_of_Cabergoline

N-[[(5R,8R,10R)-6-Allylergolin-8-yl]carbonyl]-N-[3-(di-methylamino)propyl]-N′-ethylurea (1). Compound 11 (40.13g, 72.7 mmol), H2O (200 mL), and 1 M aqueous hydrochloric acid(182 mL, 182 mmol) were combined and heated to 80 °C for 1 h.EtOAc (300 mL) was added to the light yellow solution. The pHwas adjusted to 10 with concentrated NH4OH (30 mL). Theorganic phase was separated and extracted with H2O(2×100mL). The aqueous layer was extracted with EtOAc (1 ×100 mL),and the combined organic layer was dried over Na2SO4, filtered,and concentrated to an amorphous solid. Cabergoline wasisolated in 94% yield (55% chemical yield overall from 8in highpurity (99 area % by HPLC): 1H NMR (CDCl3)δ1.18 (t, J)7.1 Hz, 3H), 1.76 (m, 2H), 1.85 (m, 2H), 2.23 (s, 6H), 2.34 (m,2H), 2.53-2.84 (m, 4H), 2.98 (m, 1H), 3.17 (m, 1H), 3.29-3.44(m, 4H), 3.55 (m, 1H), 3.83 (m, 2H), 5.19 (d, J)10.2 Hz, 1H),5.25 (d, J)16.8 Hz, 1H), 5.95 (m, 1H), 6.87 (m, 2H), 7.14 (m,2H), 8.88 (s, 1H), 9.45 (s, 1H); 13C NMR (100 MHz, CDCl3)δ14.7, 26.61, 31.31, 35.41, 40.04, 42.23, 43.21, 44.93, 55.61, 56.10,63.74, 108.7, 111.58, 113.10, 117.88, 118.36, 122.98, 126.02,132.67, 133.31, 133.83, 177.89.
1H AND 13 NMR IN CDCl3file:///C:/Users/Inspiron/Downloads/jo0203847_si_001.pdf

in dmso d6

SYN

DOI: 10.1016/0223-5234(89)90087-1

PATENT

https://patents.google.com/patent/EP1720869B1/en

6-Allyl-N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl]-ergoline-8β-carboxamide – international non-proprietary name cabergoline – of formula (I)is a potent dopamine agonist and is useful as anti-Parkinson drug and as prolactin inhibitor (Eur. J. Med. Chem. 1989, 24, 421-426 and United States Patent 5,382,669 ).
[0003]
Cabergoline (I) was firstly prepared according to United States Patent 4,526,892 by reaction of 6-allyl-ergoline-8β-carboxylic acid (II) with 1-[3-(dimethylamino)propyl)-3-ethylcarbodiimide (EDC) (Scheme 1).
[0004]
In this case both regioisomers (I) and (III) were obtained and the yield of the isolated cabergoline (I) is only approx. 21% as a consequence of isolation difficulties, considering that the yield of compound (II) prepared from (XIII) according to the state of the art is 70%.
[0005]
Eur. J. Med. Chem. 1989, 24, 421-426 describes another method for the preparation of Cabergoline (I), which is based on the direct reaction of 6-allyl-N-[3-(dimethylamino)propyl]-ergoline-8β-carboxamide (IV) with ethyl isocyanate (EtNCO) (Scheme 2).
[0006]
Since this reaction leads to equilibrium, it requires the use of a large excess of ethyl isocyanate (up to 40 equivalents) for reasonable conversion and must be conducted at above 100°C in toluene for several hours. The use of large quantities of toxic ethyl isocyanate under drastic reaction conditions presents a serious hazard for the large-scale preparation of cabergoline (I). In addition, conversion to (I) is incomplete and competitive acylation of the indole nitrogen forming compounds (V) and (VI) occurs. This side reaction complicates the product purification and reduces the yield, which is only approx. 58%, considering that the yield of compound (IV) prepared from (XIII) according to the state of the art is 72%.
[0007]
The method proposed in United States Patent 5,382,669 and Syn. Lett. 1995, 605-606 showed that catalysis by copper salts in the presence of phosphine ligands permitted the ethyl isocyanate reaction to be run at room temperature with only 3 equivalents of ethyl isocyanate. However, despite of moderation in reaction conditions the conversion and the ratio of cabergoline (I) and the byproducts (V and VI) are not much different from the uncatalyzed thermal reaction. The yield is only approx. 48% and 57%, considering that the yield of compound (IV) prepared from (XIII) according to the state of the art is 72%.
[0008]
J. Org. Chem. 2002, 67, 7147-7150 describes an ethyl isocyanate-free method for the production of cabergoline (I) that solves the problem of completing acylation of indole nitrogen, too.
[0009]
The first step is the protection of indole nitrogen of amide (IV) preferably as tert-butyl carbamate (VII).
[0010]
Extension of the amide side chain is done by deprotonation of compound (VII) with sodium hexamethyldisilazide (NaHMDS) followed by trapping the anion with phenyl chloroformate (PhOCOCl) to yield the phenyl carbamate (VTII).
[0011]
Reaction of compound (VII) with ethylamine hydrochloride (EtNH₂xHCl) gives BOC-cabergoline (IX) but also generates the ethylamide (X). The deprotection is done from the mixture of (IX) and (X) with 1N aqueous hydrochloric acid. The purified cabergoline (I) is then isolated by basification followed by chromatography on silica. (Scheme 3).
[0012]
In this approach the deprotonating step requires special cold reactor and strictly anhydrous circumstances. These requirements can hardly be satisfied in the course of large-scale preparation and the yield is only approx. 52%, considering that the yield of compound (VII) prepared from (XIII) according to the state of the art is 66%.
[0013]
According to US 2002/0177709 A1 Patent Application cabergoline (I) may be prepared by silylating amide (IV) with a silylating agent (e.g. trimethylsilyl trifluoromethane sulfonate – TMSOTf), reacting the obtained product (XI) with ethyl isocyanate (EtNCO) followed by desilylation of intermediate (XII) (Scheme 4).
[0014]
The disadvantage of this process is, that the silylating step requires strictly anhydrous circumstances. Otherwise, the reaction with ethyl isocyanate runs too long (24 hours) raising the safety hazard in the course of large-scale preparation and the yield is approx. 65%, considering that the yield of compound (IV) prepared from (XIII) according to the state of the art is 72%.
[0015]
Several crystalline forms of Cabergoline (I) are known.
[0016]
IL Farmaco 1995, 50 (3), 175-178 describes the preparation of crystalline form I. This solvated anhydrate product is crystallized from diethyl ether.
[0017]
WO 01/70740 A1 Patent Application describes a new process for the preparation of crystalline form I from the new crystalline form V. The form V – which is toluene solvate – is prepared from the mixture of the purified cabergoline (I) with toluene and diethyl ether by a long-lasting complicated process, at low reaction temperature, and the yield is only 45%. The crystalline form I is prepared by drying the form V in vacuum.
[0018]
WO 01/72746-A1 Patent Application describes the preparation of crystalline form VII from the crystalline form L By this process the suspension of form I in n-heptane or 1,4-dioxane is stirred for 48 hours, and then the suspension was filtered to obtain the crystalline form VII. The yield is 45.2%.
[0019]
WO 01/72747 A1 Patent Application describes the crystalline form II and a process for its preparation with approx. 70% yield by stirring the cabergoline (I) for several days in an organic solvent (eg. diethyl ether) at low temperature.
[0020]
Xenobiotica 1993, 23(12), 1377-1389, describes a comparison of the disposition and urinary metabolic pattern of ¹⁴C-cabergoline after single oral administration to rat, monkey and man. Among the potential metabolites of cabergoline a compound identified as FCE 27392 is disclosed, which corresponds to intermediate XIX of the preparation process of cabergoline according to the present invention.

The reaction procedure is shown in Scheme 5.

EXAMPLE 5Synthesis of 6-allyl-N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl]-ergoline-8β-carboxamide (I) (Cabergoline).

[0077]
To a suspension of 9.0 g (21.87 mmol) N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl)-ergoline-8β-carboxamide (XIX) in 250 ml of toluene 0.5 g of tetrakis(triphenylphosphine)palladium(0) and 5 ml of allyl acetate was added, and the reaction mixture was stirred at ambient temperature for 2 hours. The resulting mixture was washed with 100 ml of water. The organic layer was dried over anhydrous sodium sulphate. The dried solution was concentrated in vacuum and the product was purified on a silica plug to give 9.1 g (92.3%) of the title compound.
¹H NMR (DMSO-d₆, TMS, 500MHz) δ 1.10 (t, 3H, J=7.2Hz, CONHCH₂CH ₃); 1.47 (q, 1H, J=12.4Hz, H_β-9); 1.62-1.72 (m, 2H, CONCH₂CH ₂CH₂N(CH₃)₂); 2.15 (s, 6H, CONCH₂CH₂CH₂N(CH ₃)₂); 2.20-2.30 (m, 2H, CONHCH₂CH₂CH ₂N(CH₃)₂); 2.32-2.40 (m, 2H, H-5, H_β-7); 2.54 (dd, 1H, J=14.3Hz, 11.2Hz, H_α-4); 2.68-2.84 (m, 2H, H_α-9, H-10); 3.08 (ddd, 1H, J=11.3Hz, 3.1Hz, 1.8Hz, H_α-7); 3.14-3.22 (m, 2H, CONHCH ₂CH₃); 3.26 (dd, 1H, J=14.7Hz, 7.3Hz, H_x-N(6)CH ₂CH=CH₂); 3.28-3.38 (m, 2H, H_β-4, H-8); 3.48 (dd, 1H, J=14.7Hz, 5.8Hz, H_y-N(6)CH ₂CH=CH₂); 3.58-3.68 (m, 2H, CONCH ₂CH₂CH₂N(CH₃)₂); 5.15 (d, 1H, J=10.3Hz, H_x-N(6)CH₂CH=CH ₂); 5.24 (d, 1H, J=17.2Hz, Hy-N(6)CH₂CH=CH ₂); 5.88-5.98 (m, 1H, N(6)CH₂CH=CH₂); 6.75 (d, 1H, J=7.0Hz, H-12); 6.97 (s, 1H, H-2); 7.01 (t, 1H, J=7.5Hz, H-13); 7.13 (d, 1H, J=8.0Hz, H-14); 9.04 (t, 1H, J=5.0Hz, CONHCH₂CH₃); 10.60 (s, 1H, N(1)H).

EXAMPLE 6Production of amorphous form of Cabergoline (I)

[0078]

a) 10 g of chromatographically purified oily Cabergoline (I) was dissolved in 50 ml of acetone. The solution was concentrated in vacuum at 25-30°C to approx. 15 g. The obtained oily residue was dissolved in 40 ml of acetone, and the solution was concentrated in vacuum at 25-30°C to approx. 12 g. The obtained oily residue was dissolved in 30 ml of acetone again, and the solution was concentrated in vacuum at 25-30°C to 10 g. The obtained solid Cabergoline (I) was dried in vacuum at 25-30°C to solvent-free, to give 9.8 g (98%) of the title compound.
b) The same as in Example 6a, but employing methyl acetate as solvent, 9.85 g (98.5%) of the title compound was obtained.
c) The same as in Example 6a, but employing dichloromethane as solvent, 9.82 g (982%) of the title compound was obtained.

Patent

Publication numberPriority datePublication dateAssigneeTitleFamily To Family CitationsGB9205439D0 *1992-03-121992-04-22Erba Carlo SpaProcess for the synthesis of ergoline derivativesUS6696568B2 *2001-04-162004-02-24Finetech Ltd.Process and intermediates for production of cabergoline and related compoundsJP2004525187A *2001-04-162004-08-19フイネテク・リミテツドMethods and intermediates for the preparation of cabergoline and related compounds
Publication numberPriority datePublication dateAssigneeTitleFamily To Family CitationsEP1620101A4 *2003-05-082008-07-09Ivax Pharmaceuticals SroPolymorphs of cabergolineEP1925616A1 *2006-10-262008-05-28LEK Pharmaceuticals D.D.Process for the preparation of crystal forms of cabergoline via stable solvates of cabergolineWO2008104956A2 *2007-02-282008-09-04Ranbaxy Laboratories LimitedProcess for the preparation of amorphous cabergolineEP2083008A1 *2007-12-072009-07-29Axxonis Pharma AGErgoline derivatives as selective radical scavengers for neuronsWO2011154827A2 *2010-06-112011-12-15Rhodes TechnologiesTransition metal-catalyzed processes for the preparation of n-allyl compounds and use thereofCA2876321A1 *2012-06-222013-12-27Map Pharmaceuticals, Inc.Novel cabergoline derivatives
SYNBE 0894060; JP 58038282This compound can be obtained by two differents ways: 1) By condensation of 6-allyl-N-[3-(dimethylamino)propyl]ergolin-8-beta-caboxamide (I) with ethyl isocyanate (II) in refluxing toluene. 2) By condensation of 6-allylergolin-8-beta-carboxylic acid (III) with N-ethyl-N’-[3-(dimethylamino)propyl]carbodiimide (IV) in refluxing THF.

SYN

J Label Compd Radiopharm 1991,29(5),519

The synthesis of tritiated cabergoline by two similar routes has been described: 1) The acylation of 6-nor-dihydrolysergic acid methyl ester (I) with propargyl bromide yields the corresponding 6-propargyl derivative (II), which is hydrogenated with tritium gas over Pd/C in the presence of quinoline to give the ditritiated 6-allyl derivative (III). This compound is treated with 3-(dimethylamino)propylamine at 120 C, yielding the amide (IV), which is finally treated with ethyl isocyanate. 2) The reaction of the propargyl derivative (II) with 3-(dimethylamino)propylamine as before gives the amide (V). The reaction of (V) with ethyl isocyanate gives compound (VI), which is then hydrogenated with tritium as before.

SYNThe synthesis of [14C]-cabergoline has also been described: The reaction of 6-allylergoline-8beta-carboxylic acid methyl ester (I) with hydrazine in refluxing methanol gives the hydrazide (II), which by reaction with NaNO2-HCl in water is converted to the amine (III). The reaction of (III) again with NaNO2-HCl in water, followed by reaction with SnCl2, affords the chloro derivative (IV), which is condensed with [14C]-CNK in refluxing ethanol-water yielding the nitrile (V). Hydrolysis of (V) with NaOH in refluxing ethanol affords the acid (VI), which is finally condensed with N-ethyl-N’-[3-(dimethylamino)propyl]carbodiimide in DMF.

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Medical uses

Lactation suppression
Hyperprolactinemia^[3]
Adjunctive therapy of prolactin-producing pituitary gland tumors (prolactinomas);
Monotherapy of Parkinson’s disease in the early phase;
Combination therapy, together with levodopa and a decarboxylase inhibitor such as carbidopa, in progressive-phase Parkinson’s disease;
In some countries also: ablactation and dysfunctions associated with hyperprolactinemia (amenorrhea, oligomenorrhea, anovulation, nonpuerperal mastitis and galactorrhea);
Treatment of uterine fibroids.^[4]^[5]
Adjunctive therapy of acromegaly, cabergoline has low efficacy in suppressing growth hormone levels and is highly efficient in suppressing hyperprolactinemia that is present in 20-30% of acromegaly cases; growth hormone and prolactin are similar structurally and have similar effects in many target tissues, therefore targeting prolactin may help symptoms when growth hormone secretion can not be sufficiently controlled by other methods;

Cabergoline is frequently used as a first-line agent in the management of prolactinomas due to its higher affinity for D₂ receptor sites, less severe side effects, and more convenient dosing schedule than the older bromocriptine, though in pregnancy bromocriptine is often still chosen since there is less data on safety in pregnancy for cabergoline.

Off-label

It has at times been used as an adjunct to SSRI antidepressants as there is some evidence that it counteracts certain side effects of those drugs, such as reduced libido and anorgasmia. It also has been suggested that it has a possible recreational use in reducing or eliminating the male refractory period, thereby allowing men to experience multiple ejaculatory orgasms in rapid succession, and at least two scientific studies support those speculations.^[6]^[7]^{: e28–e33} Additionally, a systematic review and meta-analysis concluded that prophylactic treatment with cabergoline reduces the incidence, but not the severity, of ovarian hyperstimulation syndrome (OHSS), without compromising pregnancy outcomes, in females undergoing stimulated cycles of in vitro fertilization (IVF).^[8] Also, a study on rats found that cabergoline reduces voluntary alcohol consumption, possibly by increasing GDNF expression in the ventral tegmental area.^[9] It may be used in the treatment of restless legs syndrome.^{[citation needed]}

Pregnancy and lactation

Relatively little is known about the effects of this medication during pregnancy and lactation. In some cases the related bromocriptine may be an alternative when pregnancy is expected.^{[citation needed]}

Pregnancy: available preliminary data indicates a somewhat increased rate of congenital abnormalities in patients who became pregnant while treated with cabergoline.^{[citation needed]}. However, one study concluded that “foetal exposure to cabergoline through early pregnancy does not induce any increase in the risk of miscarriage or foetal malformation.”^[10]
Lactation: In rats cabergoline was found in the maternal milk. Since it is not known if this effect also occurs in humans, breastfeeding is usually not recommended if/when treatment with cabergoline is necessary.
Lactation suppression: In some countries cabergoline (Dostinex) is sometimes used as a lactation suppressant. It is also used in veterinary medicine to treat false pregnancy in dogs.

Contraindications

Hypersensitivity to ergot derivatives
Pediatric patients (no clinical experience)
Severely impaired liver function or cholestasis
Concomitant use with drugs metabolized mainly by CYP450 enzymes such as erythromycin and ketoconazole, because increased plasma levels of cabergoline may result (although cabergoline undergoes minimal CYP450 metabolism).
Cautions: severe cardiovascular disease, Raynaud’s disease, gastroduodenal ulcers, active gastrointestinal bleeding, hypotension.

Side effects

Side effects are mostly dose dependent. Much more severe side effects are reported for treatment of Parkinson’s disease and (off-label treatment) for restless leg syndrome which both typically require very high doses. The side effects are considered mild when used for treatment of hyperprolactinemia and other endocrine disorders or gynecologic indications where the typical dose is one hundredth to one tenth that for Parkinson’s disease.^{[citation needed]}

Cabergoline requires slow dose titration (2–4 weeks for hyperprolactinemia, often much longer for other conditions) to minimise side effects. The extremely long bioavailability of the medication may complicate dosing regimens during titration and require particular precautions.

Cabergoline is considered the best tolerable option for hyperprolactinemia treatment although the newer and less tested quinagolide may offer similarly favourable side effect profile with quicker titration times.

Approximately 200 patients with newly diagnosed Parkinson’s disease participated in a clinical study of cabergoline monotherapy.^[11] Seventy-six (76) percent reported at least one side effect. These side effects were chiefly mild or moderate:

GI tract: Side effects were extremely frequent. Fifty-three percent of patients reported side effects. Very frequent: Nausea (30%), constipation (22%), and dry mouth (10%). Frequent: Gastric irritation (7%), vomiting (5%), and dyspepsia (2%).
Psychiatric disturbances and central nervous system (CNS): Altogether 51 percent of patients were affected. Very frequent: Sleep disturbances (somnolence 18%, insomnia 11%), vertigo (27%), and depression (13%). Frequent: dyskinesia (4%) and hallucinations (4%).
Cardiovascular: Approximately 30 percent of patients experienced side effects. Most frequent were hypotension (10%), peripheral edema (14%) and non-specific edema (2%). Arrhythmias were encountered in 4.8%, palpitations in 4.3%, and angina pectoris in 1.4%.

In a combination study with 2,000 patients also treated with levodopa, the incidence and severity of side effects was comparable to monotherapy. Encountered side effects required a termination of cabergoline treatment in 15% of patients. Additional side effects were infrequent cases of hematological side effects, and an occasional increase in liver enzymes or serum creatinine without signs or symptoms.

As with other ergot derivatives, pleuritis, exudative pleura disease, pleura fibrosis, lung fibrosis, and pericarditis are seen. These side effects are noted in less than 2% of patients. They require immediate termination of treatment. Clinical improvement and normalization of X-ray findings are normally seen soon after cabergoline withdrawal. It appears that the dose typically used for treatment of hyperprolactinemia is too low to cause this type of side effects.

Valvular heart disease

In two studies published in the New England Journal of Medicine on January 4, 2007, cabergoline was implicated along with pergolide in causing valvular heart disease.^[12]^[13] As a result of this, the FDA removed pergolide from the U.S. market on March 29, 2007.^[14] Since cabergoline is not approved in the U.S. for Parkinson’s Disease, but for hyperprolactinemia, the drug remains on the market. The lower doses required for treatment of hyperprolactinemia have been found to be not associated with clinically significant valvular heart disease or cardiac valve regurgitation.^[15]^[16]

Interactions

No interactions were noted with levodopa or selegiline. The drug should not be combined with other ergot derivatives. Dopamine antagonists such as antipsychotics and metoclopramide counteract some effects of cabergoline. The use of antihypertensive drugs should be intensively monitored because excessive hypotension may result from the combination.

Pharmacology

Pharmacodynamics

Site	Affinity (K_i [nM])	Efficacy (E_max [%])	Action
D₁	214–32,000	?	?
D_2S	0.5–0.62	102	Full agonist
D_2L	0.95	75	Partial agonist
D₃	0.80–1.0	86	Partial agonist
D₄	56	49	Partial agonist
D₅	22	?	?
5-HT_1A	1.9–20	93	Partial agonist
5-HT_1B	479	102	Full agonist
5-HT_1D	8.7	68	Partial agonist
5-HT_2A	4.6–6.2	94	Partial agonist
5-HT_2B	1.2–9.4	123	Full agonist
5-HT_2C	5.8–692	96	Partial agonist
5-HT₃	>10,000	–	–
5-HT₄	3,000	?	?
5-HT₆	1,300	?	?
5-HT₇	2.5	?	Antagonist
α_1A	288–>10,000	0	Silent antagonist
α_1B	60–1,000	?	?
α_1D	166	?	?
α_2A	12–132	0	Silent antagonist
α_2B	17–72	0	Silent antagonist
α_2C	22–364	0	Silent antagonist
α_2D	3.6	?	?
H₁	1,380	?	?
M₁	>10,000	–	–
SERT	>10,000	–	–
Notes: All sites are human except α_2D-adrenergic, which is rat (no human counterpart).^[17] Negligible affinity (>10,000 nM) for various other receptors (β₁– and β₂-adrenergic, adenosine, GABA, glutamate, glycine, nicotinic acetylcholine, opioid, prostanoid).^[18] Sources: ^[17]^[19]^[20]^[18]^[21]

Cabergoline is a long-acting dopamine D₂ receptor agonist. In-vitro rat studies show a direct inhibitory effect of cabergoline on the prolactin secretion in the lactotroph cells of the pituitary gland and cabergoline decreases serum prolactin levels in reserpinized rats.^{[citation needed]} Although cabergoline is commonly described principally as a D₂ receptor agonist, it also possesses significant affinity for the dopamine D₃, and D₄, serotonin 5-HT_1A, 5-HT_2A, 5-HT_2B, and 5-HT_2C, and α₂-adrenergic receptors, as well as moderate/low affinity for the dopamine D₁, serotonin 5-HT₇, and α₁-adrenergic receptors.^[17]^[18]^[22] Cabergoline functions as an partial or full agonist at all of these receptors except for the 5-HT₇, α₁-adrenergic, and α₂-adrenergic receptors, where it acts as an antagonist.^[19]^[20]^[18] Cabergoline has been associated with cardiac valvulopathy due to activation of 5-HT_2B receptors.^[23]

Pharmacokinetics

Following a single oral dose, resorption of cabergoline from the gastrointestinal (GI) tract is highly variable, typically occurring within 0.5 to 4 hours. Ingestion with food does not alter its absorption rate. Human bioavailability has not been determined since the drug is intended for oral use only. In mice and rats the absolute bioavailability has been determined to be 30 and 63 percent, respectively. Cabergoline is rapidly and extensively metabolized in the liver and excreted in bile and to a lesser extent in urine. All metabolites are less active than the parental drug or inactive altogether. The human elimination half-life is estimated to be 63 to 68 hours in patients with Parkinson’s disease and 79 to 115 hours in patients with pituitary tumors. Average elimination half-life is 80 hours.

The therapeutic effect in treatment of hyperprolactinemia will typically persist for at least 4 weeks after cessation of treatment.

History

Cabergoline was first synthesized by scientists working for the Italian drug company Farmitalia-Carlo Erba in Milan who were experimenting with semisynthetic derivatives of the ergot alkaloids, and a patent application was filed in 1980.^[24]^[25]^[26] The first publication was a scientific abstract at the Society for Neuroscience meeting in 1991.^[27]^[28]

Farmitalia-Carlo Erba was acquired by Pharmacia in 1993,^[29] which in turn was acquired by Pfizer in 2003.^[30]

Cabergoline was first marketed in The Netherlands as Dostinex in 1992.^[24] The drug was approved by the FDA on December 23, 1996.^[31] It went generic in late 2005 following US patent expiration.^[32]

Society and culture

Brand names

Brand names of cabergoline include Cabaser, Dostinex, Galastop (veterinary), and Kelactin (veterinary), among others.^[33]

Research

Cabergoline was studied in one person with Cushing’s disease, to lower adrenocorticotropic hormone (ACTH) levels and cause regression of ACTH-producing pituitary adenomas.^[34]

References

^ J. Elks; C. R. Ganellin (1990). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 204–.
^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 533. ISBN 9783527607495.
^ UK electronic Medicines Compendium Dostinex Tablets Last Updated on eMC Dec 23, 2013
^ Sayyah-Melli, M; Tehrani-Gadim, S; Dastranj-Tabrizi, A; Gatrehsamani, F; Morteza, G; Ouladesahebmadarek, E; Farzadi, L; Kazemi-Shishvan, M (2009). “Comparison of the effect of gonadotropin-releasing hormone agonist and dopamine receptor agonist on uterine myoma growth. Histologic, sonographic, and intra-operative changes”. Saudi Medical Journal. 30 (8): 1024–33. PMID 19668882.
^ Sankaran, S.; Manyonda, I. (2008). “Medical management of fibroids”. Best Practice & Research Clinical Obstetrics & Gynaecology. 22 (4): 655–76. doi:10.1016/j.bpobgyn.2008.03.001. PMID 18468953. http://www.britishfibroidtrust.org.uk/journals/bft_Sankaran.pdf
^ Krüger TH, Haake P, Haverkamp J, et al. (December 2003). “Effects of acute prolactin manipulation on sexual drive and function in males”. Journal of Endocrinology. 179 (3): 357–65. CiteSeerX 10.1.1.484.4005. doi:10.1677/joe.0.1790357. PMID 14656205.
^ Hollander, Adam B.; Pastuszak, Alexander W.; Lipshultz, Larry I. (2016). “Cabergoline in the Treatment of Male Orgasmic Disorder—A Retrospective Pilot Analysis”. Journal of Sexual Medicine. 4 (4): e28–e33. doi:10.1016/j.esxm.2015.09.001. PMC 4822480. PMID 26944776.
^ Youssef MA, van Wely M, Hassan MA, et al. (March 2010). “Can dopamine agonists reduce the incidence and severity of OHSS in IVF/ICSI treatment cycles? A systematic review and meta-analysis”. Hum Reprod Update. 16 (5): 459–66. doi:10.1093/humupd/dmq006. PMID 20354100.
^ Carnicella, S.; Ahmadiantehrani, S.; He, D. Y.; Nielsen, C. K.; Bartlett, S. E.; Janak, P. H.; Ron, D. (2009). “Cabergoline Decreases Alcohol Drinking and Seeking Behaviors Via Glial Cell Line-Derived Neurotrophic Factor”. Biological Psychiatry. 66 (2): 146–153. doi:10.1016/j.biopsych.2008.12.022. PMC 2895406. PMID 19232578.
^ Colao, A; Abs R.; et al. (January 2008). “Pregnancy outcomes following cabergoline treatment: extended results from a 12-year observational study”. Clinical Endocrinology. 68 (1): 66–71. doi:10.1111/j.1365-2265.2007.03000.x. PMID 17760883. S2CID 38408935.
^ Rinne, U. K.; Bracco, F.; Chouza, C.; Dupont, E.; Gershanik, O.; Masso, J. F. M.; Montastruc, J. L.; Marsden, C. D.; Dubini, A.; Orlando, N.; Grimaldi, R. (1997-02-01). “Cabergoline in the treatment of early parkinson’s disease: Results of the first year of treatment in a double-blind comparison of cabergoline and levodopa”. Neurology. 48 (2): 363–368. doi:10.1212/WNL.48.2.363. ISSN 0028-3878. PMID 9040722. S2CID 34955541.
^ Schade, Rene; Andersohn, Frank; Suissa, Samy; Haverkamp, Wilhelm; Garbe, Edeltraut (2007-01-04). “Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation”. New England Journal of Medicine. 356 (1): 29–38. doi:10.1056/NEJMoa062222. PMID 17202453.
^ Zanettini, Renzo; Antonini, Angelo; Gatto, Gemma; Gentile, Rosa; Tesei, Silvana; Pezzoli, Gianna (2007-01-04). “Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson’s Disease”. New England Journal of Medicine. 356 (1): 39–46. doi:10.1056/NEJMoa054830. PMID 17202454.
^ “Food and Drug Administration Public Health Advisory”. Food and Drug Administration. 2007-03-29. Archived from the original on 2007-04-08. Retrieved 2007-04-27.
^ Bogazzi, F.; Buralli, S.; Manetti, L.; Raffaelli, V.; Cigni, T.; Lombardi, M.; Boresi, F.; Taddei, S.; Salvetti, A. (2008). “Treatment with low doses of cabergoline is not associated with increased prevalence of cardiac valve regurgitation in patients with hyperprolactinaemia”. International Journal of Clinical Practice. 62 (12): 1864–9. doi:10.1111/j.1742-1241.2008.01779.x. PMID 18462372. S2CID 7822137.
^ Wakil, A.; Rigby, A. S; Clark, A. L; Kallvikbacka-Bennett, A.; Atkin, S. L (2008). “Low dose cabergoline for hyperprolactinaemia is not associated with clinically significant valvular heart disease”. European Journal of Endocrinology. 159 (4): R11–4. doi:10.1530/EJE-08-0365. PMID 18625690.
^ Jump up to:^a ^b ^c Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (November 2002). “Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes”. J Pharmacol Exp Ther. 303 (2): 791–804. doi:10.1124/jpet.102.039867. PMID 12388666. S2CID 6200455.
^ Jump up to:^a ^b ^c ^d Sharif NA, McLaughlin MA, Kelly CR, Katoli P, Drace C, Husain S, Crosson C, Toris C, Zhan GL, Camras C (March 2009). “Cabergoline: Pharmacology, ocular hypotensive studies in multiple species, and aqueous humor dynamic modulation in the Cynomolgus monkey eyes”. Experimental Eye Research. 88 (3): 386–97. doi:10.1016/j.exer.2008.10.003. PMID 18992242.
^ Jump up to:^a ^b Newman-Tancredi A, Cussac D, Audinot V, Nicolas JP, De Ceuninck F, Boutin JA, Millan MJ (November 2002). “Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor”. J Pharmacol Exp Ther. 303 (2): 805–14. doi:10.1124/jpet.102.039875. PMID 12388667. S2CID 35238120.
^ Jump up to:^a ^b Newman-Tancredi A, Cussac D, Quentric Y, Touzard M, Verrièle L, Carpentier N, Millan MJ (November 2002). “Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT(1) and 5-HT(2), receptor subtypes”. J Pharmacol Exp Ther. 303 (2): 815–22. doi:10.1124/jpet.102.039883. PMID 12388668. S2CID 19260572.
^ https://web.archive.org/web/20210413033753/https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Cabergoline&doQuery=Submit+Query
^ National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Jul 24]. ChapelHill (NC): University of North Carolina. 1998-2013. Available from: “Archived copy”. Archived from the original on 2013-11-08. Retrieved 2014-03-04.
^ Cavero I, Guillon JM (2014). “Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy”. J Pharmacol Toxicol Methods. 69 (2): 150–61. doi:10.1016/j.vascn.2013.12.004. PMID 24361689.
^ Jump up to:^a ^b Council regulation (EEC) no 1768/92 in the matter of Application No SPC/GB94/012 for a Supplementary Protection Certificate in the name of Farmitalia Carlo Erba S. r. l.
^ Espace record: GB 202074566
^ US Patent 4526892 – Dimethylaminoalkyl-3-(ergoline-8′.beta.carbonyl)-ureas
^ Fariello, RG (1998). “Pharmacodynamic and pharmacokinetic features of cabergoline. Rationale for use in Parkinson’s disease”. Drugs. 55 (Suppl 1): 10–6. doi:10.2165/00003495-199855001-00002. PMID 9483165. S2CID 46973281.
^ Carfagna N, Caccia C, Buonamici M, Cervini MA, Cavanus S, Fornaretto MG, Damiani D, Fariello RG (1991). “Biochemical and pharmacological studies on cabergoline, a new putative antiparkinsonian drug”. Soc Neurosci Abs. 17: 1075.
^ Staff. News: Farmitalia bought by Kabi Pharmacia^{[permanent dead link]}. Ann Oncol (1993) 4 (5): 345.
^ Staff, CNN/Money. April 16, 2003 It’s official: Pfizer buys Pharmacia
^ FDA approval history
^ “Drugs@FDA: FDA Approved Drug Products – ANDA 076310”. http://www.accessdata.fda.gov. FDA.gov. Retrieved 14 December 2018.
^ “Cabergoline Uses, Side Effects & Warnings”. Archived from the original on 2015-12-30.
^ Miyoshi, T.; et al. (2004). “Effect of cabergoline treatment on Cushing’s disease caused by aberrant adrenocorticotropin-secreting macroadenoma”. Journal of Endocrinological Investigation. 27 (11): 1055–1059. doi:10.1007/bf03345309. PMID 15754738. S2CID 6660262.

External links

Cabergoline, Mayo Clinic

Clinical data

Trade names	Dostinex, others
AHFS/Drugs.com	Monograph
License data	US FDA: CABERGOLINE
Routes of administration	Oral
ATC code	G02CB03 (WHO) N04BC06 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	First-pass effect seen; absolute bioavailability unknown
Protein binding	Moderately bound (40–42%); concentration-independent
Metabolism	Hepatic, predominately via hydrolysis of the acylurea bond or the urea moiety
Elimination half-life	63–69 hours (estimated)
Excretion	Urine (22%), feces (60%)
Identifiers
show IUPAC name
CAS Number	81409-90-7
PubChem CID	54746
IUPHAR/BPS	37
DrugBank	DB00248
ChemSpider	49452
UNII	LL60K9J05T
KEGG	D00987
ChEBI	CHEBI:3286
ChEMBL	ChEMBL1201087
CompTox Dashboard (EPA)	DTXSID6022719
ECHA InfoCard	100.155.380
Chemical and physical data
Formula	C₂₆H₃₇N₅O₂
Molar mass	451.615 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI
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////////////////Cabergoline, UNII-LL60K9J05T, каберголин , كابارغولين ,卡麦角林 , FCE-21336

[H][C@@]12CC3=CNC4=CC=CC(=C34)[C@@]1([H])C[C@H](CN2CC=C)C(=O)N(CCCN(C)C)C(=O)NCC

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Zuclopenthixol

December 30, 2021 11:49 am / Leave a comment

Zuclopenthixol

Clopenthixol

Molecular FormulaC₂₂H₂₅ClN₂OS
Average mass400.965 Da

53772-83-1 [RN],

N05AF05

1-Piperazineethanol, 4-[(3Z)-3-(2-chloro-9H-thioxanthen-9-ylidene)propyl]-
5443
2-{4-[(3Z)-3-(2-Chloro-9H-thioxanthen-9-ylidene)propyl]piperazin-1-yl}ethanol
258-758-5[EINECS]
Z)-Clopenthixol
1-piperazineethanol, 4-(3-(2-chloro-9h-thioxanthen-9-ylidene)propyl)-
1-Piperazineethanol, 4-(3-(2-chlorothioxanthen-9-ylidene)propyl)-
1-Piperazineethanol, 4-[(3Z)-3-(2-chloro-9H-thioxanthen-9-ylidene)propyl]-

1-Piperazineethanol, 4-[3-(2-chloro-9H-thioxanthen-9-ylidene)propyl]-, (Z)-
4-[(3Z)-3-(2-Chloro-9H-thioxanthen-9-ylidene)propyl]-1-piperazineethanol
9H-Thioxanthene, 1-piperazineethanol deriv.
(Z)-Clopenthixol
Acuphase

Cisordinol
Clopixol
Clopixol depo
Zuclopenthixol
cis-(Z)-Clopenthixol
cis-Clopenthixol
α-Clopenthixol

Product Ingredients

INGREDIENT	UNII	CAS	INCHI KEY
Zuclopenthixol acetate	349S2ZHF05	85721-05-7	OXAUOBQMCDIVPQ-IOXNKQMXSA-N
Zuclopenthixol decanoate	TSS9KIZ5OG	64053-00-5	QRUAPADZILXULG-WKIKZPBSSA-N
Zuclopenthixol dihydrochloride	7042692VYN	58045-23-1	LPWNZMIBFHMYMX-MHKBYHAFSA-N

Zuclopenthixol hydrochloride
58045-23-1, MW: 473.8933

ZUCLOPENTHIXOL DECANOATE, CLOPENTHIXOL DECANOATE, CIS-

64053-00-5, Molecular Formula, C32-H43-Cl-N2-O2-S, Molecular Weight, 555.2227

Zuclopenthixol acetate

85721-05-7, C₂₄H₂₇ClN₂O₂S, 443.0ClopenthixolCAS Registry Number: 982-24-1
CAS Name: 4-[3-(2-Chloro-9H-thioxanthen-9-ylidene)propyl]-1-piperazineethanol
Additional Names: 2-chloro-9-[3-[4-(2-hydroxyethyl)-1-piperazinyl]propylidene]thiaxanthene
Molecular Formula: C22H25ClN2OS
Molecular Weight: 400.96
Percent Composition: C 65.90%, H 6.28%, Cl 8.84%, N 6.99%, O 3.99%, S 8.00%
Literature References: Thioxanthene neuroleptic. Prepn (configuration not specified): BE585338; P. V. Petersen et al.,US3116291 (1960, 1963 both to Kefalas A/S). Prepn of the pharmacologically active cis-isomer: BE816855; N. Lassen, US3996211 (1974, 1976 both to Kefalas A/S). Pharmacology: Cazzullo, Andreola, Acta Neurol.20, 162 (1965); Weissman, Mod. Probl. Pharmacopsychiatry2, 15 (1969); Moeller Nielsen, ibid. 23. Metabolism: Khan, Acta Pharmacol. Toxicol.27, 202 (1969). HPLC determn of isomers in serum: T. Aaes-Jorgensen, J. Chromatogr.188, 239 (1980). Series of articles on pharmacology and clinical studies: Acta Psychiatr. Scand.64, Suppl. 294, 1-77 (1981).
Properties: Colorless syrup. Sparingly sol in ether. Readily sol in methanol.
Derivative Type: Dihydrochloride
CAS Registry Number: 633-59-0
Manufacturers’ Codes: AY-62021; N-746
Trademarks: Ciatyl (Troponwerke); Sordenac (Lundbeck); Sordinol (Ayerst)
Molecular Formula: C22H25ClN2OS.2HCl
Molecular Weight: 473.89
Percent Composition: C 55.76%, H 5.74%, Cl 22.44%, N 5.91%, O 3.38%, S 6.77%
Properties: Crystals from ethanol, mp 250-260° (dec). Freely sol in water; sparingly sol in alcohol. Practically insol in other organic solvents. LD50 in male mice (mg/kg): 111 i.v. (Lassen).
Melting point: mp 250-260° (dec)
Toxicity data: LD50 in male mice (mg/kg): 111 i.v. (Lassen)

Derivative Type:cis(Z)-Form
CAS Registry Number: 53772-83-1
Additional Names: a-Clopenthixol; zuclopenthixol
Properties: Crystals, mp 84-85°.
Melting point: mp 84-85°

Derivative Type:cis(Z)-Form dihydrochloride
CAS Registry Number: 58045-23-1
Trademarks: Cisordinol (Lundbeck); Clopixol (HMR)
Properties: Crystals, mp 250-260° (dec). LD50 in male mice (mg/kg): 105 i.v. (Lassen).
Melting point: mp 250-260° (dec)
Toxicity data: LD50 in male mice (mg/kg): 105 i.v. (Lassen)
Therap-Cat: Antipsychotic.
Keywords: Antipsychotic; Thioxanthenes.
Zuclopenthixol is an antipsychotic indicated for the management of schizophrenia. The acuphase formulation is indicated for initial treatment of acute psychosis or exacerbation of psychosis, while the depot formulation is best for maintenance.Zuclopenthixol, also known as Zuclopentixol or Zuclopenthixolum, is an antipsychotic agent. Zuclopenthixol is a thioxanthene-based neuroleptic with therapeutic actions similar to the phenothiazine antipsychotics. It is an antagonist at D1 and D2 dopamine receptors. Major brands of zuclopenthixol are Cisordinol, Acuphase, and Clopixol. This drug is a liquid. This compound belongs to the thioxanthenes. These are organic polycyclic compounds containing a thioxanthene moiety, which is an aromatic tricycle derived from xanthene by replacing the oxygen atom with a sulfur atom. Known drug targets of zuclopenthixol include 5-hydroxytryptamine receptor 2A, D(1B) dopamine receptor, D(2) dopamine receptor, D(1A) dopamine receptor, and alpha-1A adrenergic receptor. It is known that zuclopenthixol is metabolized by Cytochrome P450 2D6. Zuclopenthixol was approved for use in Canada in 2011, but is not approved for use in the United States.

Zuclopenthixol (brand names Cisordinol, Clopixol and others), also known as zuclopentixol, is a medication used to treat schizophrenia and other psychoses. It is classed, pharmacologically, as a typical antipsychotic. Chemically it is a thioxanthene. It is the cis–isomer of clopenthixol (Sordinol, Ciatyl).^[1] Clopenthixol was introduced in 1961, while zuclopenthixol was introduced in 1978.

Zuclopenthixol is a D₁ and D₂ antagonist, α₁-adrenergic and 5-HT₂ antagonist.^[2] While it is approved for use in Australia, Canada, Ireland, India, New Zealand, Singapore, South Africa and the UK it is not approved for use in the United States.^[3]^[4]

Medical uses

Available forms

Zuclopenthixol is available in three major preparations:

As zuclopenthixol decanoate (Clopixol Depot, Cisordinol Depot), it is a long-acting intramuscular injection. Its main use is as a long-acting injection given every two or three weeks to people with schizophrenia who have a poor compliance with medication and suffer frequent relapses of illness.^[5] There is some evidence it may be more helpful in managing aggressive behaviour.^[6]
As zuclopenthixol acetate (Clopixol-Acuphase, Cisordinol-Acutard), it is a shorter-acting intramuscular injection used in the acute sedation of psychotic inpatients. The effect peaks at 48–72 hours providing 2–3 days of sedation.^[7]
As zuclopenthixol dihydrochloride (Clopixol, Cisordinol), it is a tablet used in the treatment of schizophrenia in those who are compliant with oral medication.^[8]

It is also used in the treatment of acute bipolar mania.

Dosing

As a long-acting injection, zuclopenthixol decanoate comes in a 200 mg and 500 mg ampoule. Doses can vary from 50 mg weekly to the maximum licensed dose of 600 mg weekly. In general, the lowest effective dose to prevent relapse is preferred. The interval may be shorter as a patient starts on the medication before extending to 3 weekly intervals subsequently. The dose should be reviewed and reduced if side effects occur, though in the short-term an anticholinergic medication benztropine may be helpful for tremor and stiffness, while diazepam may be helpful for akathisia. 100 mg of zuclopenthixol decanoate is roughly equivalent to 20 mg of flupentixol decanoate or 12.5 mg of fluphenazine decanoate.

In acutely psychotic and agitated inpatients, 50 – 200 mg of zuclopenthixol acetate may be given for a calming effect over the subsequent three days, with a maximum dose of 400 mg in total to be given. As it is a long-acting medication, care must be taken not to give an excessive dose.

In oral form zuclopenthixol is available in 10, 25 and 40 mg tablets, with a dose range of 20–60 mg daily.

Side effects

Chronic administration of zuclopenthixol (30 mg/kg/day for two years) in rats resulted in small, but significant, increases in the incidence of thyroid parafollicular carcinomas and, in females, of mammary adenocarcinomas and of pancreatic islet cell adenomas and carcinomas. An increase in the incidence of mammary adenocarcinomas is a common finding for D₂ antagonists which increase prolactin secretion when administered to rats. An increase in the incidence of pancreatic islet cell tumours has been observed for some other D₂ antagonists. The physiological differences between rats and humans with regard to prolactin make the clinical significance of these findings unclear.

Withdrawal syndrome: Abrupt cessation of therapy may cause acute withdrawal symptoms (eg, nausea, vomiting, or insomnia). Symptoms usually begin in 1 to 4 days of withdrawal and subside within 1 to 2 weeks.[1][2]

Other permanent side effects are similar to many other typical antipsychotics, namely extrapyramidal symptoms as a result of dopamine blockade in subcortical areas of the brain. This may result in symptoms similar to those seen in Parkinson’s disease and include a restlessness and inability to sit still known as akathisia, a slow tremor and stiffness of the limbs.^[8] Zuclopenthixol is thought to be more sedating than the related flupentixol, though possibly less likely to induce extrapyramidal symptoms than other typical depots.^[5] As with other dopamine antagonists, zuclopenthixol may sometimes elevate prolactin levels; this may occasionally result in amenorrhoea or galactorrhoea in severe cases. Neuroleptic malignant syndrome is a rare but potentially fatal side effect. Any unexpected deterioration in mental state with confusion and muscle stiffness should be seen by a physician.

Zuclopenthixol decanoate induces a transient dose-dependent sedation. However, if the patient is switched to maintenance treatment with zuclopenthixol decanoate from oral zuclopenthixol or from i.m. zuclopenthixol acetate the sedation will be no problem. Tolerance to the unspecific sedative effect develops rapidly.^[9]

SYN

Journal of the American Chemical Society (2019), 141(6), 2251-2256

https://pubs.acs.org/doi/10.1021/jacs.8b13907

Synthesis of Clopenthixol (4d)

Inside a nitrogen-filled glovebox, an oven-dried glass culture tube (Fischer Scientific part #14- 959-35A), equipped with a magnetic stirring bar, was charged with 2-chloro-9H-thioxanthen-9- one (245 mg, 1.0 mmol, 1 equiv), copper(II) acetate (0.91 mg, 0.0050 mmol, 0.0050 equiv), racBINAP (3.2 mg, 0.0050 mmol, 0.0050 equiv), and THF (1.0 mL). The tube was then fitted tightly with a Teflon-lined blow-out screw cap (Kimble-Chase part #73808-15425). The reaction tube was removed from the glovebox, and the mixture was stirred rapidly for 5 min. A balloon, connected to a 6 mL plastic syringe head, was filled with allene gas until its size was roughly 6 cm in diameter. A needle was attached to the head of the syringe. The reaction tube was evacuated by piercing the septum with a needle connected to a Schlenk line. Immediately after, the allene contained in the balloon was used to refill the reaction tube by piercing the septum with the needle. The balloon decreased to roughly half its original diameter during the refill process. The needle and balloon were left attached, and dimethoxy(methyl)silane (250 uL, 2.0 mmol, 2.0 equiv) was added to the reaction mixture using a 1 mL plastic syringe. The solution was then stirred overnight at rt. At this point, the flask was quickly evacuated by piercing the septum with a needle connected to a Schlenk line, and the headspace was refilled with dry nitrogen. This process was repeated a total of three times. THF (1 mL) solution containing 4e (367 mg, 1.2 mmol, 1.2 equiv), triphenylphosphine (11.5 mg, 0.044 mmol, 0.044 equiv), racDTBM-SEGPHOS (26.8 mg, 0.044 mmol, 0.044 equiv), and copper(II) acetate (3.6 mg, 0.040 mmol, 0.040 equiv) was added to the reaction mixture using a 1 mL plastic syringe. The reaction tube was heated to 40 °C by submersion in an oil bath overnight. After cooling to rt, the cap was removed and 4 M HCl in dioxane was slowly added to the reaction mixture (2.0 mL, WARNING: VIGOROUS HYDROGEN GAS EVOLUTION). The color of the reaction mixture turned to deep red, and after stirring for approximately 30 min, a tan precipitate evolved. After an additional 1 h, diethyl ether (10 mL) was added and the solids collected by filtration (950 mg). By LC/MS analysis, this solid contains mostly 4c (as the hydrochloride) with a trace amount of triphenylphosphine oxide. The entire solid was suspended in dry acetonitrile (1.0 mL) in another dry reaction tube, equipped with a magnetic stirring bar. Potassium carbonate (552 mg, 4 mmol) was added to the tube, which was then capped and placed under a nitrogen atmosphere using a needle connected to a Schlenk line. 2-bromoethanol (142 uL, 2 mmol) was added to the reaction mixture using a glass microsyringe, and the mixture was left to stir overnight at rt. After this time, the cap was removed, and the solution was diluted with water (10 mL). The mixture was extracted with dichloromethane (3 x 10 mL), and the combined organic phases was concentrated with the aid of a rotary evaporator. The mixture was purified by reverse phase preparative HPLC (C18 column, MeCN/water) to yield a 1.1:1 Z/E mixture of 4d as a yellow foamy solid (217 mg, 54% overall yield). The identity of 4d was confirmed by LC/MS analysis against a commercially available standard (Cayman Chemical) and by comparison of 1H NMR to the literature. 13 For further structural confirmation, a portion of 4d was repurified by HPLC to obtain pure (Z)-4d, the biologically active isomer, whose spectra have not been reported in the literature. 1H NMR (400 MHz, CDCl3) δ 7.43 (dd, J = 14.5, 6.2 Hz, 3H), 7.27 (q, J = 8.2 Hz, 4H), 7.17 (d, J = 8.3 Hz, 1H), 5.89 (t, J = 7.1 Hz, 1H), 3.60 (t, J = 5.4 Hz, 2H), 2.62 (t, J = 7.2 Hz, 2H), 2.58–2.35 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 140.2, 135.7, 133.4, 133.2, 132.7, 130.9, 130.4, 128.6, 127.3, 126.9, 126.8, 126.7, 126.2, 125.6, 59.2, 58.3, 57.7, 53.1, 52.8, 27.3.

SYN

Chemical Engineering & Technology (2016), 39(10), 1821-1827.

https://onlinelibrary.wiley.com/doi/10.1002/ceat.201500673

SYN

European Journal of Pharmaceutics and Biopharmaceutics (2012), 82(2), 437-456.

https://www.sciencedirect.com/science/article/abs/pii/S0939641112002263?

SYN

Organic Process Research & Development (2013), 17(9), 1142-1148.

https://pubs.acs.org/doi/10.1021/op400069e

SUN

CN 103214453

https://patents.google.com/patent/CN103214453A/enDiuril ton (Clopenthixol), chemistry 2-chloro-9-[3 ‘ by name-(N ‘-the 2-hydroxyethyl piperazine-N)-allyl group]-thioxanthene, this product is a kind of Thiaxanthene derivative, has significant antipsycholic action and special sedative effect, is particularly useful for the schizophrenia patient.Its activeconstituents is its alpha-isomer, i.e. zuclopenthixol (structural formula is seen Fig. 1); Have the stereotypy effect that anti-Ritalin causes, and the effect of anti-Apomorphine is arranged, this product energy rejection condition avoiding reaction and catalepsy are stronger 10 times than chlorpromazine.A little less than the cholinolytic effect, and antihistamine effect is strong.Zuclopenthixol is applicable to that treatment has psychosis, class Paranoia-illusion type schizophrenia, hebephrenia, the manic and anxiety periodic psychosis of anxiety and illusion symptom; The uneasiness that mental element causes, excitement, psychiatric disorder, the encephalatrophy process, post-traumatic psychosis, the proverb of trembling are absurd etc.Be particularly useful for elderly patients.Recorded the quality standard of zuclopenthixol sheet, zuclopenthixol dihydrochloride, Ciatyl Depot and zuclopenthixol acetic ester etc. in the British Pharmacopoeia, wherein the zuclopenthixol quality standard has stipulated that its content should be 95%-105%.But in actual industrial production, guarantee that zuclopenthixol reaches pharmaceutically acceptable purity, and β-isomer (structural formula is seen Fig. 2) content being limited in 5%, is a very thing of difficulty.About the preparation method of zuclopenthixol, mainly containing of bibliographical information is following several:As if the general separation of having described diuril ton isomer can be undertaken by the fractional crystallization of dihydrochloride among the BE585338A of nineteen fifty-nine application, and still, this separation method yield is extremely low, and complicated operation does not also have actual industrial use.Described the preparation method of diuril ton isomer mixture among the US3116291, wherein alpha-isomer is that the content of zuclopenthixol is 30%-35%.Obtain purer zuclopenthixol by diuril ton alkali being carried out fractional separation in the literary composition with ether organic solvent, but, instructed crystallization to come the purifying zuclopenthixol can not obtain good result, especially in isomer mixture, had under the situation of a large amount of impurity existence by diuril ton alkali.Embodiment 1: the preparation of diuril ton base1) preparation of 2-chloro-9-allyl group-9-thioxanthene alcohol100.00g (0.405mol) 2-chloro-9-thioxanthone is dissolved in the 600mL tetrahydrofuran (THF), 20 ℃ of-30 ℃ of stirrings, add magnesium powder 26g then, iodine 1g, splash into chlorallylene 65g (0.855mol), 40 ℃-50 ℃ are reacted 2h down, and the cooling back drips 20% sodium chloride aqueous solution 1000ml in reaction solution, stir 10min, filter insolubles, use dichloromethane extraction then 2 times, each 500ml, merge organic phase, water 500ml washing is told organic layer, dry after-filtration, filtrate is concentrated except that desolvating, obtain 105.40g2-chloro-9-allyl group-9-thioxanthene alcohol.2) preparation of 2-chloro-9-(2-propenylidene) thioxanthene100.00g (0.346mol) 2-chloro-9-allyl group-9-thioxanthene alcohol is dissolved in the 100ml toluene, solution is heated to 40 ℃, the Acetyl Chloride 98Min. of 1.34g (0.017mol) is dissolved in the diacetyl oxide of 41.19g (0.403mol) and drops in the above-mentioned solution, temperature is controlled at about 40 ℃, dropwise, it is complete until the TLC monitoring reaction that heating makes temperature of reaction rise to 50 ℃ of-55 ℃ of reactions, and concentrating under reduced pressure steams solvent, obtains 94.01g2-chloro-9-(2-propenylidene) thioxanthene.3) preparation of clopenthixol baseN-(2-hydroxyethyl) piperazine of getting 90.00g (0.332mol) 2-chloro-9-(2-propenylidene) thioxanthene and 215.21g (1.65mol) adds in the 1L four-hole boiling flask, stirs and is warming up to 100 ℃ of reactions, and TLC monitors to reacting completely.Vacuum oil pump concentrating under reduced pressure excessive N-(2-hydroxyethyl) piperazine, temperature is controlled at 100 ℃-135 ℃, and oil pump vacuum tightness is at 0.2-1mmHg.Distillation finishes, and adds the benzene of 400ml and the water of 100ml in gained oily matter, and 70 ℃ are stirred 15min, and separatory is used the water washing organic phase of 100ml again, and simultaneous temperature is controlled at 60 ℃-70 ℃, separatory; With organic phase concentrate resistates.This resistates is dissolved in the 300ml methylene dichloride, after add 10% hydrochloric acid soln and transfer pH to 2-3, stirring 10min, separatory, water discard dichloromethane extraction liquid with the dichloromethane extraction of 150ml; Above-mentioned water adds ammoniacal liquor and regulates pH=9-10, extract with methylene dichloride (300ml * 2) after stirring 10min, merge organic phase, use anhydrous sodium sulfate drying, suction filtration, filtrate decompression concentrate 109.32g diuril ton base, isomer proportion α/β is that 45/55 (the HPLC area normalization method: analytical column is 4.6 * 250mmAgilent C18 post, moving phase is acetonitrile: methyl alcohol: phosphoric acid buffer=20: 30: 50, flow velocity are 1mL/min; With this understanding, the retention time of zuclopenthixol is 12min, and the retention time of β-isomer is 16min).Embodiment 2: the preparation of zuclopenthixol Chlorodracylic acid ester 2HCl100.00g (0.250mol) α/β-diuril ton is dissolved in the ethyl acetate of 500ml, under 40 ℃ of conditions, drips the 100ml ethyl acetate that is dissolved with 52.48g (0.30mol) parachlorobenzoyl chloride, dropwise the back back flow reaction, complete until the TLC monitoring reaction.Remove the 300ml solvent under reduced pressure, be cooled to 4 ℃, remove by filter precipitation.Mother liquor is heated to 40 ℃, drips the concentrated hydrochloric acid aqueous solution of 12.50g (0.125mol) 37%, react about 1h after, cool off, have solid to separate out, filter 56.27g zuclopenthixol Chlorodracylic acid ester 2HCl.Purity (HPLC is the same) is 97.11%, and productive rate is 36.82%.Embodiment 3: the preparation of zuclopenthixol2HCl is dissolved in the methanol aqueous solution of 300ml80% with 45.25g (0.074mol) zuclopenthixol Chlorodracylic acid ester, adds the potassium hydroxide of 16.83mol (0.30mol) then.With mixture heating up to 50 ℃, insulation reaction 1h.Underpressure distillation removes and desolvates, and with toluene (200ml * 2) and water extraction, merges organic phase, and concentrating under reduced pressure is removed toluene; Residue obtainedly carry out recrystallization with hexanaphthene, the 25.51g dried crystals.Purity is 99.7%, and productive rate is 86.17%. ¹H?NMR(CDCl ₃，400MHz)，δ：7.10-7.46(7H，m)，5.98(1H，t)，3.41(2H，t)，2.46-2.52(14H，m)。Embodiment 4: the preparation of Ciatyl Depot 2HClThe zuclopenthixol of 50.00g (0.125mol) is dissolved in the methylene dichloride of 500ml, and to wherein dripping 28.60g (0.150mol) decanoyl chloride, back flow reaction is complete to the TLC monitoring reaction after dropwising under the room temperature.Underpressure distillation removes and desolvates, and adds the ethyl acetate of 300ml in residue, drips the ethyl acetate solution that contains hydrogenchloride again, is transferred to 3-4 until pH.After the cooling, filter, vacuum-drying gets 70.63g Ciatyl Depot 2HCl.Productive rate is 90.12%.Embodiment 5: the preparation of Ciatyl DepotThe Ciatyl Depot 2HCl of 60g (0.0957mol) is suspended in the t-butyl methyl ether of 400ml, drips water (250ml) solution of 13.22g (0.0957mol) salt of wormwood, stirring reaction 0.5h.Two are separated, and use 100ml water washing organic phase again, use the anhydrous sodium sulfate drying organic phase, filter, and organic solvent is removed in underpressure distillation, get the 51.29g Ciatyl Depot.Productive rate is 96.58%. ¹H?NMR(CDCl ₃，400MHz)，δ：7.12-7.50(7H，m)，5.90(1H，t)，4.35(2H，t)，3.41(2H，t)，2.97(2H，t)，2.32-2.57(10H，m)，2.06(2H，t)，1.64(2H，m)，1.30(12H，m)，0.88(3H，t)。

SYN

https://patents.google.com/patent/WO2017121755A1/enPreparation of ZU3:9-(3-(4-(2-hydroxyethyl)piperazinyl)propylidene)-thioxanthene

ZU3To a solution of 9-oxothioxanthene (1.0 equiv.) in THF at reflux were added a solution of cyclopropylmagnesium bromide in THF (1.0 equiv.) and stirred during 2 hours. The mixture was cooled down at room temperature and a solution of hydrogen bromide in acetic acid (4 eq.) was added and stirred at room temperature. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography to obtain 9- (3bromopropylidene)thioxanthene in 30% yield.Then, to a solution of 9-(3bromopropylidene)thioxanthene in acetonitrile at reflux was added N-(2-hydroxyethyl)piperazine (1,5 eq.), potassium iodide (0.1 eq.) and potassium carbonate (3 eq.). The mixture was stirred at reflux then concentrated in vacuo and purified by silica gel column chromatography to afford ZU3 with 98% purity (HPLC). HPLC analysis (BEH C18 type, mobile phase: H20/ acetonitrile (HCOOH 0.1%)) : t_R = 1.68 min. Preparation of ZUf:l-(3-(9H-thioxanthen-9-ylidene)propyl)piperidine-4-carboxylic acid), ZU4 (9-(3-(4- (ethylacetate) iperidine)propylidene)-thioxanthene

To a solution of 9-(3-bromopropylidene)thioxanthene in acetonitrile at reflux was added N-ethylacetate piperidine (1,5 eq.), potassium iodide (0.1 eq.) and potassium carbonate (3 eq.). The mixture was stirred at reflux then concentrated in vacuo and purified by silica gel column chromatography to afford ZU4 as a brown oil with a purity of 97% in HPLC analysis HPLC analysis (BEH C18 type, mobile phase: H20/acetonitrile (HCOOH 0.1%)) : t_R = 2.07 min.The compound ZU4 was stirred during 2 hours at reflux in a mixture of THF and a solution of NaOH in water. After phase separation, the aqueous layer was extracted twice by diethyl ether. The global organic layer was, then, washed by a saturated solution of NaCl, dried over MgSC^, filtered and concentrated in vacuo to afford ZUf HPLC analysis (BEH CI 8 type, mobile phase: H20/acetonitrile (HCOOH 0.1%)) : t_R = 2.24 min.Preparation of ZU5:(Z)-2-(4-(3-(2-chloro-9H-thioxanthen-9-ylidene)propyl)piperazin-l-yl)ethylacetate

To a solution of ZU (4-[3-(2-chloro-9H-thioxanthen-9-ylidene)propyl]-l- piperazineethanol) (leq.) in dichloromethane was added acetic anhydride (1.5 eq.), 4- dimethylaminopyridine (0,1 eq.) and trimethylamine (1 eq.). The mixture was stirred at room temperature and then concentrated in vacuo to afford ZU5 as a yellow oil with 97% of purity (HPLC). HPLC analysis {BEH C18 type, mobile phase: H20/acetonitrile (HCOOH 0.1%)): t_R = 2.44 minPreparation of ZUe and ZU6:l-(3-(9H-xanthen-9-ylidene)propyl)piperidine-4-carboxylic acidand eth -(3-(9H-xanthen-9-ylidene)propyl)piperidine-4-carboxylate

To a solution of 9-oxoxanthene (1.0 equiv.) in THF at reflux were added a solution of cyclopropylmagnesium bromide in THF (1.0 equiv.) and stirred during 2 hours. The mixture was cooled down at room temperature and a solution of hydrogen bromide in acetic acid (4 eq.) was added and stirred at room temperature. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography to obtain 9- (3bromopropylidene)-oxoxanthene.Then, to a solution of 9-(3bromopropylidene)-oxoxanthene in acetonitrile at reflux was added Ethyl 4-piperidinecarboxylate (1,5 eq.), potassium iodide (0.1 eq.) and potassium carbonate (3 eq.). The mixture was stirred at reflux then concentrated in vacuo and purified by silica gel column chromatography to obtain ZU6 ZU6 is then dissolved in a mixture of THF and a solution of NaOH in water. After phase separation, the aqueous layer was extracted twice by diethyl ether. The global organic layer was, then, washed by a saturated solution of NaCl, dried over MgSC^, filtered and concentrated in vacuo to afford ZUe as a white solid with a purity up to 97% in HPLC. Preparation of ZUc:(Z)-2-(4-(3-(2-(trifluoromethyl)-9H-thioxanthen-9-ylidene)propyl)piperazin-l-yl) ethanamine

EtOH, reflux, 2hPurification withHCI buffer

To a solution of ZU1 (2-[4-[3-[2-(trifiuoromethyl)thioxanthen-9- ylidene]propyl]piperidin-l-yl] ethanol) (leq.) in THF was added diethylazodicarboxylate, phtalimide and triphenylphosphine. The solution was stirred at room temperature during 3 hours and then concentrated in vacuo. The crude oil was then dissolved in ethanol, hydrazine was added and the mixture was stirred at reflux during 2 hours. The crude product obtained after concentration was purified via a reversed phase chromatography using HCI as buffer to afford the compound ZUc as an hydrochloride salt (orange solid). [M+H]⁺ (ESI+) : 434. HPLC analysis (BEH C18 type, mobile phase: H20/acetonitrile (HCOOH 0.1%)): t_R = 2.04 min Preparation of ZUd:(Z)-l-(2-fluoroethyl)-4-(3-(2-(trifluoromethyl)-9H-thioxanthen-9-ylidene)propyl) iperazine

To a solution of flupenthixol in dichloromethane was added at -10°C diethylamino sulfur trifluoride. The mixture was then stirred at room temperature. The crude product was purified via a reversed phase chromatography using HC1 as buffer to afford the compound ZUd as a hydrochloride salt (orange solid) with 97% purity in HPLC. HPLC analysis (BEH C18 type, mobile phase: H20/acetonitrile (HCOOH 0.1%)): t_R = 3.59 min.Compounds ZU, ZUa, ZUb, ZU1, ZU2The following compounds can be easily found in commerce: 

Example 2: Ebselen oxide derivatives

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Pharmacology

Pharmacodynamics

Cisordinol 10 mg tablet

Zuclopenthixol antagonises both dopamine D₁ and D₂ receptors, α₁-adrenoceptors and 5-HT₂ receptors with a high affinity, but has no affinity for cholinergic muscarine receptors. It weakly antagonises the histamine (H₁) receptor but has no α₂-adrenoceptor blocking activity^{[citation needed]}.

Evidence from in vitro work and clinical sources (i.e. therapeutic drug monitoring databases) suggests that both CYP2D6 and CYP3A4 play important roles in zuclopenthixol metabolism.^[11]

Pharmacokinetics

History

Zuclopenthixol was introduced by Lundbeck in 1978.^[22]

References

^ Sneader, Walter (2005). Drug discovery: a history. New York: Wiley. p. 410. ISBN 0-471-89980-1.
^ Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics Life sciences 1984 Apr 16;34(16):1529-40.
^ Green, Alan I.; Noordsy, Douglas L.; Brunette, Mary F.; O’Keefe, Christopher (2008). “Substance abuse and schizophrenia: Pharmacotherapeutic intervention”. Journal of Substance Abuse Treatment. 34 (1): 61–71. doi:10.1016/j.jsat.2007.01.008. ISSN 0740-5472. PMC 2930488. PMID 17574793.
^ Sweetman, Sean C., ed. (2009). “Anxiolytic Sedatives Hypnotics and Antipsychotics”. Martindale: The complete drug reference (36th ed.). London: Pharmaceutical Press. pp. 1040–1. ISBN 978-0-85369-840-1.
^ Jump up to:^a ^b da Silva Freire Coutinho E, Fenton M, Quraishi SN (1999). “Zuclopenthixol decanoate for schizophrenia”. The Cochrane Database of Systematic Reviews. John Wiley and Sons, Ltd. (2): CD001164. doi:10.1002/14651858.CD001164. PMC 7032616. PMID 10796607. Retrieved 2007-06-12.
^ Haessler F, Glaser T, Beneke M, Pap AF, Bodenschatz R, Reis O (2007). “Zuclopenthixol in adults with intellectual disabilities and aggressive behaviours”. British Journal of Psychiatry. 190 (5): 447–448. doi:10.1192/bjp.bp.105.016535. PMID 17470962.
^ Lundbeck P/L (1991). “Clopixol Acuphase 50 mg/mL Injection Clopixol Acuphase 100 mg / 2 mL Injection”. Lundbeck P/L. Retrieved 2007-06-12.
^ Jump up to:^a ^b Bryan, Edward J.; Purcell, Marie Ann; Kumar, Ajit (16 November 2017). “Zuclopenthixol dihydrochloride for schizophrenia”. The Cochrane Database of Systematic Reviews. 2017 (11): CD005474. doi:10.1002/14651858.CD005474.pub2. ISSN 1469-493X. PMC 6486001. PMID 29144549.
^ “Summary of Product Characteristics” (PDF).
^ Jump up to:^a ^b ^c ^d ^e “TGA eBS – Product and Consumer Medicine Information Licence”.
^ Davies SJ, Westin AA, Castberg I, Lewis G, Lennard MS, Taylor S, Spigset O (2010). “Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies”. Acta Psychiatrica Scandinavica. 122 (6): 445–453. doi:10.1111/j.1600-0447.2010.01619.x. PMID 20946203. S2CID 41869401.
^ Parent M, Toussaint C, Gilson H (1983). “Long-term treatment of chronic psychotics with bromperidol decanoate: clinical and pharmacokinetic evaluation”. Current Therapeutic Research. 34 (1): 1–6.
^ Jump up to:^a ^b Jørgensen A, Overø KF (1980). “Clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. III. Serum levels”. Acta Psychiatrica Scandinavica. Supplementum. 279: 41–54. doi:10.1111/j.1600-0447.1980.tb07082.x. PMID 6931472.
^ Jump up to:^a ^b Reynolds JE (1993). “Anxiolytic sedatives, hypnotics and neuroleptics.”. Martindale: The Extra Pharmacopoeia (30th ed.). London: Pharmaceutical Press. pp. 364–623.
^ Ereshefsky L, Saklad SR, Jann MW, Davis CM, Richards A, Seidel DR (May 1984). “Future of depot neuroleptic therapy: pharmacokinetic and pharmacodynamic approaches”. The Journal of Clinical Psychiatry. 45 (5 Pt 2): 50–9. PMID 6143748.
^ Jump up to:^a ^b Curry SH, Whelpton R, de Schepper PJ, Vranckx S, Schiff AA (April 1979). “Kinetics of fluphenazine after fluphenazine dihydrochloride, enanthate and decanoate administration to man”. British Journal of Clinical Pharmacology. 7 (4): 325–31. doi:10.1111/j.1365-2125.1979.tb00941.x. PMC 1429660. PMID 444352.
^ Young D, Ereshefsky L, Saklad SR, Jann MW, Garcia N (1984). Explaining the pharmacokinetics of fluphenazine through computer simulations. (Abstract.). 19th Annual Midyear Clinical Meeting of the American Society of Hospital Pharmacists. Dallas, Texas.
^ Janssen PA, Niemegeers CJ, Schellekens KH, Lenaerts FM, Verbruggen FJ, van Nueten JM, et al. (November 1970). “The pharmacology of fluspirilene (R 6218), a potent, long-acting and injectable neuroleptic drug”. Arzneimittel-Forschung. 20 (11): 1689–98. PMID 4992598.
^ Beresford R, Ward A (January 1987). “Haloperidol decanoate. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in psychosis”. Drugs. 33 (1): 31–49. doi:10.2165/00003495-198733010-00002. PMID 3545764.
^ Reyntigens AJ, Heykants JJ, Woestenborghs RJ, Gelders YG, Aerts TJ (1982). “Pharmacokinetics of haloperidol decanoate. A 2-year follow-up”. International Pharmacopsychiatry. 17 (4): 238–46. doi:10.1159/000468580. PMID 7185768.
^ Larsson M, Axelsson R, Forsman A (1984). “On the pharmacokinetics of perphenazine: a clinical study of perphenazine enanthate and decanoate”. Current Therapeutic Research. 36 (6): 1071–88.
^ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia. Elsevier. pp. 1102–. ISBN 978-0-8155-1856-3.

External links

Product information for Zuclopenthixol (CLOPIXOL), provided by the Therapeutic Goods Administration — https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05705-3

Clinical data

Trade names	Clopixol
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: C
Routes of administration	Oral, IM
Drug class	Typical antipsychotic
ATC code	N05AF05 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)UK: POM (Prescription only)In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	49% (oral)
Protein binding	98%
Metabolism	Hepatic (CYP2D6 and CYP3A4-mediated)
Elimination half-life	20 hours (oral), 19 days (IM)
Excretion	Feces
Identifiers
show IUPAC name
CAS Number	53772-83-1 85721-05-7 (acetate) 64053-00-5 (decanoate)
PubChem CID	5311507
DrugBank	DB01624
ChemSpider	4470984
UNII	47ISU063SG
KEGG	D03556
ChEBI	CHEBI:51364
ChEMBL	ChEMBL53904
CompTox Dashboard (EPA)	DTXSID3048233
ECHA InfoCard	100.053.398
Chemical and physical data
Formula	C₂₂H₂₅ClN₂OS
Molar mass	400.97 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI
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/////////zuclopenthixol, N05AF05, Clopenthixol, Cisordinol, Clopixol

OCCN1CCN(CC\C=C2\C3=C(SC4=C2C=C(Cl)C=C4)C=CC=C3)CC1

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Aztreonam

December 28, 2021 12:27 pm / Leave a comment

Aztreonam

Molecular FormulaC₁₃H₁₇N₅O₈S₂
Average mass435.433 Da

(2S,3S)-3-{[(2Z)-2-(2-Ammonio-1,3-thiazol-4-yl)-2-{[(2-carboxy-2-propanyl)oxy]imino}acetyl]amino}-2-methyl-4-oxo-1-azetidinesulfonate2-[[(Z)-[1-(2-amino-4-thiazolyl)-2-[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methyl-propanoic acid
278-839-9[EINECS]
5159
78110-38-0[RN]
UA2451400
азтреонам [Russian] [INN]
أزتريونام [Arabic] [INN]
氨曲南 [Chinese] [INN]
AztreonamCAS Registry Number: 78110-38-0
CAS Name: [2S-[2a,3b(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid
Additional Names: azthreonam
Manufacturers’ Codes: SQ-26776
Trademarks: Azactam (BMS); Primbactam (Menarini)
Molecular Formula: C13H17N5O8S2, Molecular Weight: 435.43
Percent Composition: C 35.86%, H 3.94%, N 16.08%, O 29.40%, S 14.73%
Literature References: The first totally synthetic monocyclic b-lactam (monobactam) antibiotic. It has a high degree of resistance to b-lactamases and shows specific activity vs aerobic gram-negative rods.
Prepn: R. B. Sykes et al.,NL8100571 (1981 to Squibb), C.A.96, 181062x (1982).
Fast-atom-bombardment mass spectra: A. I. Cohen et al.,J. Pharm. Sci.71, 1065 (1982). Activity vs gram-negative bacteria: R. B. Sykes et al.,Antimicrob. Agents Chemother.21, 85 (1982). Series of articles on structure-activity, in vitro and in vivo properties, pharmacokinetics: J. Antimicrob. Chemother.8, Suppl. E, 1-148 (1981).
Toxicology: G. R. Keim et al.,ibid. 141. Mechanism of action study: A. D. Russell, J. R. Furr, ibid.9, 329 (1982). Comparative stability to renal dipeptidase: H. Mikami et al.,Antimicrob. Agents Chemother.22, 693 (1982). Human pharmacokinetics: E. A. Swabb et al.,ibid.21, 944 (1982).
Clinical evaluation in urinary tract infection: C. Donadio et al.,Drugs Exp. Clin. Res.13, 167 (1987). Clinical efficacy in neonatal sepsis: S. Sklavunu-Tsurutsoglu et al.,Rev. Infect. Dis.13, Suppl. 7, S591 (1991). Comprehensive description: K. Florey, Anal. Profiles Drug Subs.17, 1-39 (1988).
Properties: White crystalline, odorless powder, dec 227°. Very slightly sol in ethanol, slightly sol in methanol, sol in DMF, DMSO. Practically insol in toluene, chloroform, ethyl acetate.
Derivative Type: Disodium salt
Molecular Formula: C13H15N5Na2O8S2, Molecular Weight: 479.40
Percent Composition: C 32.57%, H 3.15%, N 14.61%, Na 9.59%, O 26.70%, S 13.38%
Properties: LD50 (mg/kg): 3300 i.v. in mice; 6600 i.p. in rats (Keim).
Toxicity data: LD50 (mg/kg): 3300 i.v. in mice; 6600 i.p. in rats (Keim)
Therap-Cat: Antibacterial.
Keywords: Antibacterial (Antibiotics); ?Lactams; Monobactams.
Aztreonam is a beta-lactam antibiotic used to treat select aztreonam sensitive gram negative bacteria.

Product Ingredients

INGREDIENT	UNII	CAS	INCHI KEY
Aztreonam lysine	XNM7LT65NP	827611-49-4	KPPBAEVZLDHCOK-JHBYREIPSA-N

A monocyclic beta-lactam antibiotic originally isolated from Chromobacterium violaceum. It is resistant to beta-lactamases and is used in gram-negative infections, especially of the meninges, bladder, and kidneys. It may cause a superinfection with gram-positive organisms.

Aztreonam, sold under the brand name Azactam among others, is an antibiotic used primarily to treat infections caused by gram-negative bacteria such as Pseudomonas aeruginosa.^[1]^[2] This may include bone infections, endometritis, intra abdominal infections, pneumonia, urinary tract infections, and sepsis.^[1] It is given by intravenous or intramuscular injection or by inhalation.^[1]

Common side effects when given by injection include pain at the site of injection, vomiting, and rash.^[1] Common side effects when inhaled include wheezing, cough, and vomiting.^[1] Serious side effects include Clostridium difficile infection and allergic reactions including anaphylaxis.^[1] Those who are allergic to other β-lactam have a low rate of allergy to aztreonam.^[1] Use in pregnancy appears to be safe.^[1] It is in the monobactam family of medications.^[1] Aztreonam inhibits cell wall synthesis by blocking peptidoglycan crosslinking to cause bacterial death.^[1]

Aztreonam was approved for medical use in the United States in 1986.^[1] It was removed from the World Health Organization’s List of Essential Medicines in 2019.^[3]^[4] It is available as a generic medication.^[1] It is a manufactured version of a chemical from the bacterium Chromobacterium violaceum.^[5]

Medical uses

Nebulized forms of aztreonam are used to treat infections that are complications of cystic fibrosis and are approved for such use in Europe and the US; they are also used off-label for non-CF bronchiectasis, ventilator-associated pneumonia, chronic obstructive pulmonary disease, mycobacterial disease, and to treat infections in people who have received lung transplants.^[6]

Aztreonam has strong activity against susceptible Gram-negative bacteria, including Pseudomonas aeruginosa. It is resistant to some beta-lactamases, but is inactivated by extended-spectrum beta-lactamases.

It has no useful activity against Gram-positive bacteria or anaerobes. It is known to be effective against a wide range of bacteria including Citrobacter, Enterobacter, E. coli, Haemophilus, Klebsiella, Proteus, and Serratia species.^[7] The following represents minimum inhibitory concentration (MIC) susceptibility data for a few medically significant microorganisms.

Staphylococcus aureus 8 – >128 μg/ml
Staphylococcus epidermidis 8 – 32 μg/ml
Streptococcus pyogenes 8 – ≥128 μg/ml

^[8]

Synergism between aztreonam and arbekacin or tobramycin against P. aeruginosa has been suggested.^[9]

SYN

ACS Medicinal Chemistry Letters, 11(2), 162-165; 2020

https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00534

Aztreonam, first discovered in 1980, is an FDA approved, intravenous, monocyclic beta-lactam antibiotic. Aztreonam is active against Gram-negative bacteria and is still used today. The oral bioavailability of aztreonam in humans is less than 1%. Herein we describe the design and synthesis of potential oral prodrugs of aztreonam.

A stirring mixture of CES1 (20 mg, 2200 Units) in a 15 mM solution of sodium phosphate monobasic (enzyme grade) in acetonitrile-d3 / D2O (1 mL; ratio of 2.5 : 97.5) was heated at 37 °C for 5 min. 2-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2- dimethyl-4-(pivaloyloxy)butoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)-2-methylpropanoic acid TFA salt 28c (10 mg, 14 µmol) was added, and the suspension was stirred for 70 min at 37 °C. Over the course of the reaction a fine precipitate formed. The mixture was filtered through a 25 mm, 0.45 µM glass fiber syringe filter (Pall Corporation Acrodisc). The filtrate was analyzed by 1H-NMR spectroscopy to reveal that 3,3-dimethyltetrahydrofuran was released as one of the products. The presence of 3,3-dimethyltetrahydrofuran was confirmed by 1H-NMR analysis of the same sample spiked with 2 µL of authentic materialSYN Faming Zhuanli Shenqing, 106520857,

SYN

Synthesis Reference

Neal G. Anderson, Carl F. Anderson, “Delta form of aztreonam and preparation thereof.” U.S. Patent US4826973, issued January, 1983.

US4826973

SYN

https://patents.google.com/patent/US7145017B2/enAztreonam is a monobactam antibiotic disclosed in U.S. Pat. No. 4,775,670, which is incorporated by reference herein in its entirety. Aztreonam has the chemical name (Z)-2-[[[(2-amino-4-thiazolyl)[[(2S,-3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2-methylpropionic acid. Aztreonam is also known as [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid and (2S, 3S)-3-[[2-[2-amino-4-thiazolyl]-(Z)-2[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidine-1-sulfonic acid.Aztreonam has the structure:

Aztreonam is known to exist in various polymorphic forms including the α, β, δ, and γ forms.U.S. Pat. No. 4,775,670 discloses a process for making Aztreonam, a compound of formula I:

The process includes acylating a compound of formula IV:

The acylation entails reacting a compound of formula IV with a carboxylic acid or the corresponding carboxylic acid halide or carboxylic acid anhydride (R₁—OH) in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance capable of forming an active ester in situ such as N-hydroxybenzotriazole. U.S. Pat. No. 4,775,670 discloses that when the acyl group (R₁) contains reactive functional groups, such as amino or carboxyl groups, it may be necessary to first protect those functional groups, then carry out the acylation reaction, and finally deprotect the resulting product. The deprotection is carried out by reaction of the acylation product with trifluoroacetic acid in the presence of anisole under anhydrous conditions.Similarly, U.S. Pat. No. 4,946,838 discloses a process for making crystalline anhydrous Aztreonam comprising reacting the diphenylmethyl ester of Aztreonam ([3S-[3β(Z),4α]]-3-[[(2-amino-4-thiazolyl)[(1-diphenylmethoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid) with trifluoroacetic acid in the presence of anisole under anhydrous conditions to produce the α-form of Aztreonam. The α-form is recrystallized from an anhydrous organic solvent to produce the β-form of Aztreonam. The β-form is anhydrous, substantially non-hygroscopic and more stable than the α-form.U.S. Pat. No. 5,254,681 discloses a process for preparing monobactams of formula (I):

wherein R is acyl. The process comprises acylating azetidin with 2-(2-amino-4-thiazolyl)-2-(Z)-(alkoxyimino) acetic acid in the presence of 1-hydroxy-benzotriazole and dicyclohexylcarbodiimide.U.S. Pat. No. 5,194,604 discloses a process and intermediates for making beta-lactams having aminothiazole(iminooxyacetic acid)acetic acid sidechains of formula (I), such as Aztreonam. The process comprises acylating a compound of formula III:

with a compound of formula (II):

in which R⁷is

wherein

is a 4, 5, 6 or 7 membered heterocyclic ring having at least one nitrogen atom in the ring or such a group fused to a phenyl or substituted phenyl ring, to form a compound of formula (I):

wherein R₁–R₆are as defined in U.S. Pat. No. 5,194,604.U.S. Pat. No. 4,652,651, which is incorporated by reference herein in its entirety, discloses a process for making 1-sulpho-2-oxoazetidine derivatives of the formula (I):

in which Het is an optionally amino-substituted, 5- or 6-membered, aromatic heterocycle containing 1 or 2 nitrogen atoms and optionally also an oxygen or sulphur atom, R₁may be lower alkoxycarbonyl-lower alkyl and R₂may be lower alkyl. The process entails acylating a compound of formula (II):

in which R₂₀equals R₂and R₃is hydrogen or sulpho, with a thioester of the formula (III):

in which Het is as above and R₁₀has any of the values of R₁. U.S. Pat. No. 4,652,651 discloses that where R10 is a lower alkoxycarbonyl-lower alkyl group, for example the t-butoxycarbonylmethyl group, this can be converted, if desired, into the corresponding carboxylower alkyl group by treatment with a strong acid such as trifluoroacetic acid (optionally in the presence of anisole), hydrochloric acid or p-toluenesulphonic acid at a low temperature such as −10° C. to room temperature.There remains a need in the art for a process of making Aztreonam which does not require anhydrous reaction conditions and which also enables high yield and high purity. The present invention answers this need.

SUMMARY OF THE INVENTIONThe invention is based on the discovery that Aztreonam can be produced by reacting [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid with aqueous acid. The process of the invention, enables yields of between 70–75% and purities above 98%, preferably above 99%. The inventive aqueous process is advantageous over the prior art anhydrous processes in that the reaction conditions are more mild, there is no need to clean the final product and there is no need to keep the system dry. Thus, the aqueous process is less expensive than the anhydrous processes.The present invention is directed to a process for preparing [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid by hydrolyzing the ester group of [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid. The hydrolysis may be effected by reacting the ester with aqueous acid, at elevated temperatures.One reaction scheme for carrying out the process is shown below:

EXAMPLE 15.4 g Azetidin is dissolved in 20 ml acetonitrile (or dimethyl formamide) with the assistance of 5 ml of triethylamine at room temperature. The solution is cooled to 0° C. A solution of 4 g TAEM in 25 ml THF is added with magnetic stirring. If the color disappears, 8 g TAEM in 50 ml THF is added. After 10 minutes, another 4.1 g TAEM in 25 ml THF is added. The solution is stirred at 0° C. for an additional hour. The pH is adjusted to about 4–5 with a freshly prepared TFA solution (TFA-THF 1:4, V/V). Being careful not to evaporate the acetonitrile, the THF is evaporated (weight loss is about 90 g) at 30° C. under vacuum. The remaining residue is diluted with 200 ml ethylacetate and then extracted with 100 ml and then 50 ml of distilled water. The aqueous extracts are combined and washed twice with 50 ml ethylacetate after readjustment of the pH to about 4–5. The dissolved ethylacetate is removed from the aqueous phase by vacuum at 30° C. 10–15 g KCl (or NaCl) is dissolved. The solution is acidified with HCl solution (cc. HCl-distilled water 1:4, V/V) with stirring (approx. 10 ml). The solution is cooled to 0° C. with slow stirring and crystallization occurs. The resulting suspension is refrigerated overnight (at about 5° C.). The suspension is filtered on a glass filter, and the crystals are washed with chilled water. The washed crystals are dried at room temperature. The product, Aztreonam t-butyl ester, is about 12.5–13 g white solid, which is sufficiently pure for the next step.

EXAMPLE 265 g Azetidine is dissolved in a mixture of 240 ml acetonitrile and 60 ml triethylamine. When dissolution is complete, TAEM is added in four portions. The suspension is stirred for 20–30 min, then diluted with 500 ml EtOAc and 500 ml water and stirred for 5–10 min. The pH of the emulsion is set to 5 with 2.4 M HCl solution. After the phases separate, the pH of the aqueous phase is checked. If the pH is between 4.20 and 5.30, the two phases are filtered and separated, otherwise more HCl is added. The upper phase is diluted with 900 ml ethylacetate and extracted with 2×500 ml water (faster phase separation). The combined aqueous phase is diluted with 500 ml water and washed with 2×500 ml ethylacetate. The dissolved ethylacetate is removed from the aqueous phase by vacuum. The aqueous phase is acidified further to pH 2 with 2.4 M HCl solution. The solution is stirred and cooled. Crystallization starts soon. The suspension is stirred and cooled to 0° C., stirring at this temperature overnight. The suspension is filtered, washed with chilled water, dried at 38° C. in air-circulated oven for 3 h. The yield is approx. 116–120 g of Aztreonam t-butyl ester.

EXAMPLE 3Aztreonam t-butyl ester (113.6 g, 0.231 mol) is suspended in 975 ml water at 60° C. with stirring and 325 ml trifluoroacetic acid is added. The solution is stirred for 60 min., then it is cooled slowly using an ice-water bath. After the product precipitates, the suspension is refrigerated overnight. The product is filtered on a glass-filter, suspended in 240 ml chilled water and filtered again. The filtrate is re-suspended in 360 ml cold acetone and filtered. The latter step is repeated and the product is dried at room temperature to yield 61.6 g Aztreonam (water content: 15–16%).

EXAMPLE 4Aztreonam t-butyl ester (18.0 g, 0.0366 mol) is suspended in 144 ml water at 60° C. with stirring and 40 ml aqueous hydrochloric acid (1:1, V/V) is added. The solution is stirred for 60 min, then 37 ml 5.4 M NaOH solution is added. The solution is cooled slowly using an ice-water bath. After the product precipitates, the suspension is refrigerated overnight. The product is filtered on a glass-filter, suspended in 50 ml chilled water and filtered again. The filtrate is re-suspended in 70 ml cold acetone and filtered. The latter step is repeated and the product is dried at room temperature to yield 8.3 g Aztreonam (water content: 15–16%). The crude Aztreonam is crystallized.

EXAMPLE 5Aztreonam t-butyl ester (100.00 g, Assay as is: 97.2%, 0.19796 mol)) is suspended in a mixture of 450 ml water and 5 ml trifluoroacetic acid. The suspension, which slowly becomes clear, is heated to 58° C. with stirring and 100 ml trifluoroacetic acid is added. The solution is stirred for 105 min at 60–63° C. The solution is added to chilled water (450 ml) with efficient stirring and the resulting slurry is cooled further to 25° C. After two hours it is cooled to 0° C. and stirred for 18 hours. The product is filtered on a glass-filter and washed with 300 ml chilled water. The product is suspended in 650 ml chilled water, then filtered and washed with 300 ml cold acetone. The product is suspended in 400 ml cold acetone and filtered and dried in an air-ventilation oven at 30° C. for 30 min. Yield: 66.6 g (63%, according to assays) Aztreonam (Assay: 100.5%, water content: 18.0%).HPLC Impurity Profile:

Aztreonam: 99.22%
Aztreonam t-butyl ester: 0.44%
HPLC Impurity Profile of Sample from Reaction Mixture:
Aztreonam: 82.20%
Aztreonam t-butyl ester: 0.43%
Aztreonam, open-chained: 7.22%
Other main degradation product (RRT=0.56): 5.24%

EXAMPLE 6Aztreonam t-butyl ester (27.11 g, Assay as is: 96.5%, 0.05328 mol) is suspended in a mixture of 122 ml water and 1.35 ml cc. HCl. The suspension is heated to 62° C. with stirring and 30 ml cc. HCl is added. The suspension, which becomes clear after approx. 15 min, (then the product starts to precipitate), is stirred for 30 min at 63–65° C. Chilled water (162 ml) is added with efficient stirring and the resulting slurry is cooled further to 25° C. After two hours it is cooled to 0° C. and stirred for 2 hours. The product is filtered on a glass-filter, washed twice with 120 ml chilled water, twice with 125 ml cold acetone and filtered. The product is dried at room temperature overnight. Yield: 19.44 g (72%, according to assays) Aztreonam (Assay: 100.1%, water content: 14.4%).HPLC Impurity Profile:

Aztreonam: 99.65%
Aztreonam t-butyl ester: 0.21%
HPLC Impurity Profile of Sample from Reaction Mixture:
Aztreonam: 89.43%
Aztreonam t-butyl ester: 0.26%
Aztreonam, open-chained: 4.70%
Other main degradation product (RRT=0.56): 1.47%

SYN

Manufacturing Process

This mixture was sterilized for 15 minutes at 121°C at 15 lbs/inch2 steam pressure prior to use. The fermentation flasks were incubated at 25°C for 40 to 45 hours on a of rotary shaker. A 250 liter batch of Agrobacterium radiobacter A.T.C.C. No. 31700 is fermented in a 100 gallon steel vessel with a media and operating conditions described below. Culture of Agrobacterium radiobacter grown out on agar slants, pH 7.3 consisted of yeast extract (1 g), beef extract (1 g), NZ amine A (2 g), glucose (10 g), agar (15 g) in 1000 ml distilled water. Loopful of surface growth from agar slant was used as the source of incolumn. Medium of oatmeal (20 g), tomato paste (20 g) tapped water to 1000 ml, pH 7, was sterilized for 15 min at 121°C at 15 lbs/inch2 steam pressure prior to use. 100 ml of the medium, containing incolumn is incubated at 25°C for about 24 hours on a rotary shaker. It was added to a mixture of yeast extract (5 g), glucose (10 g) in 1 L distilled water and incubated for about 42 hours at 25°C in 100 gallon stainless steel fermentation vessel.
During incubation, the broth is agitated at 155 r.p.m. and aerated at rate of 10.0 cubic feet per minute. An antifoam agent (Ucon LB625, Union Carbide) was added as needed. The fermentation beer was adjusted to pH 4 with aqueous HCl and calls separated by centrifugation. The supernatante (200 L) was extracted with 40 L of 0.05 m cetyldimethylbenzyl ammonium chloride in dichloromethane and extract concentrated in vacuo to 5.5 L. The concentrate was then extracted with solution of 177 g of sodium thiocyanate in 2 L of water, adjusting the mixture of pH 4.35 with phosphoric acid. The aqueous extract was concentrated in vacuo to 465 ml and added to 1840 ml of methanol. Solids are filtrated yielded 194 g of crude solid product. It was dissolved and chromatographed on a 5×106.5 cm column of Sephadex G-10 three times and after concentrating in vacuo gave 3.5 g of crude antibiotic M53 (azetreonam) which was chromatographed at first on QAE Sephadex A- 25 (liner gradient, prepared from 2.5 L of water and 2.5 L of 0.25 M sodium nitrate). Then the residue (fractions 26-75) gave M53 (natrium salt) after evaporation. It was triturated with methanol and the souble fraction, 0.40 g was chromatographed on a 2.5×20 cm column of Diaion HP20AG, eluting at 2 ml per minute with water and collecting 20 ml fractions. Fractions 26-75 gave 51.9 mg of antibiotic M53 (sodium salt).

Chemical Synthesis

Aztreonam, (Z)-2[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]cabamoyl]methylen]amino]oxy]-2-methylpropionoic acid (32.1.4.9), is synthesized from tert-butyloxycarbonylthreonine, which is reacted with O-benzylhydroxylamine in the presence of dicyclohexylcarbodimide and 1-hydroxybenzotriazole, to form the benzyl hydroxamide derivative (32.1.4.1). This product undergoes a reaction with triphenylphosphine and ethyl azodicarboxylate, which results in the cyclodehydration of the product to (3S-trans)-N-benzyloxy-3-tert-butyloxycarbonylamino-4-methyl-azetidinone (32.1.4.2). Debenzylating this by hydrogen reduction using a palladium on carbon catalyst forms (3S-trans)-N-hydroxy-3-tertbutyloxycarbonyl-amino-4-methyl-azetidinone (32.1.4.3). The hydroxyl group in this compound is removed by reducing it with titanium trichloride, which forms azetidinone (32.1.4.4). Removing the tert-butyloxycarbonyl protection using trifluoroacetic acid and subsequent acylation of the resulting product with the benzyl chloroformate gives (3S-trans)-benzyloxycarbonylamino-4-methylazetidinone (32.1.4.5). Sulfonating this product with a mixture of sulfur trioxide and dimethylformamide gives the corresponding N-sulfonic acid. Turning the resulting Nsulfonic acid into a potassium salt by reacting it with potassium hydrophosphate, followed by replacing the potassium cation with a tetrabutylammonium cation by reacting it with tetrabutylammonium sulfate gives the product (32.1.4.6). Reducing this with hydrogen using a palladium on carbon catalyst gives 3-amino-4-methyl-monobactamic acid (32.1.4.7). Acylating this with (Z) 2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino] 4-thiazoleacetic acid in the presence of dicyclohexylcarbodiimide and 1-hydroxy-benzotriazole gives the diphenylmethyl ester of the desired aztreonam (32.1.4.8), which is hydrolyzed to aztreonam (32.1.4.9) using trifluoroacetic acid.

It is believed that the methyl group at position 4 increases the stability of the beta-lactam ring with respect to most beta-lactamases, and at the same time it does not induce formation of beta-lactamase as cephalosporins and imipenems do.

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Spectrum of activity

Acinetobacter anitratus, Escherichia coli, Pseudomonas aeruginosa, and Proteus mirabilis are generally susceptible to aztreonam, while some staphylococci, Staphylococcus aureus, Staphylococcus haemolyticus and Xanthomonas maltophilia are resistant to it. Furthermore, Aeromonas hydrophila, Citrobacter koseri (Citrobacter diversus), Pantoea agglomerans (Enterobacter agglomerans), Haemophilus spp. and Streptococcus pyogenes have developed resistance to aztreonam to varying degrees.^[10]

Aztreonam is often used in people who are penicillin allergic or who cannot tolerate aminoglycosides.^{[medical citation needed]}

Administration[edit]

Aztreonam is poorly absorbed when given orally, so it must be administered as an intravenous or intramuscular injection (trade name Azactam ), or inhaled (trade name Cayston) using an ultrasonic nebulizer. In the United States, the Food and Drug Administration (FDA) approved the inhalation form on 22 February 2010, for the suppression of P. aeruginosa infections in patients with cystic fibrosis.^[11] It received conditional approval for administration in Canada and the European Union in September 2009,^[11] and has been fully approved in Australia.^[12]

Side effects

Reported side effects include injection site reactions, rash, and rarely toxic epidermal necrolysis. Gastrointestinal side effects generally include diarrhea and nausea and vomiting. There may be drug-induced eosinophilia. Because of the unfused beta-lactam ring there is somewhat lower cross-reactivity between aztreonam and many other beta-lactam antibiotics, and it may be safe to administer aztreonam to many patients with hypersensitivity (allergies) to penicillins and nearly all cephalosporins.^[13] There is a much lower risk of cross-sensitivity between aztreonam and other beta-lactam antibiotics than within other beta-lactam antibiotics. However, there is a higher chance of cross-sensitivity if a person is specifically allergic to ceftazidime, a cephalosporin. Aztreonam exhibits cross-sensitivity with ceftazidime due to a similar side chain.^[14]

Mechanism of action

Aztreonam is similar in action to penicillin. It inhibits synthesis of the bacterial cell wall, by blocking peptidoglycan crosslinking. It has a very high affinity for penicillin-binding protein-3 and mild affinity for penicillin-binding protein-1a. Aztreonam binds the penicillin-binding proteins of Gram-positive and anaerobic bacteria very poorly and is largely ineffective against them.^[13] Aztreonam is bactericidal, but less so than some of the cephalosporins.^{[medical citation needed]}

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l “Aztreonam”. The American Society of Health-System Pharmacists. Retrieved 8 December 2017.
^ British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 381. ISBN 9780857111562.
^ World Health Organization (2019). Executive summary: the selection and use of essential medicines 2019: report of the 22nd WHO Expert Committee on the selection and use of essential medicines. Geneva: World Health Organization. hdl:10665/325773. WHO/MVP/EMP/IAU/2019.05. License: CC BY-NC-SA 3.0 IGO.
^ World Health Organization (2019). The selection and use of essential medicines: report of the WHO Expert Committee on Selection and Use of Essential Medicines, 2019 (including the 21st WHO Model List of Essential Medicines and the 7th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization. hdl:10665/330668. ISBN 9789241210300. ISSN 0512-3054. WHO technical report series;1021.
^ Yaffe SJ, Aranda JV (2010). Neonatal and Pediatric Pharmacology: Therapeutic Principles in Practice. Lippincott Williams & Wilkins. p. 438. ISBN 9780781795388.
^ Quon BS, Goss CH, Ramsey BW (March 2014). “Inhaled antibiotics for lower airway infections”. Annals of the American Thoracic Society. 11 (3): 425–34. doi:10.1513/annalsats.201311-395fr. PMC 4028738. PMID 24673698.
^ Mosby’s Drug Consult 2006 (16th ed.). Mosby, Inc. 2006.
^ “Aztreonam Susceptibility and Minimum Inhibitory Concentration (MIC) Data” (PDF). toku-e.com. 3 February 2020.
^ Kobayashi Y, Uchida H, Kawakami Y (December 1992). “Synergy with aztreonam and arbekacin or tobramycin against Pseudomonas aeruginosa isolated from blood”. The Journal of Antimicrobial Chemotherapy. 30 (6): 871–2. doi:10.1093/jac/30.6.871. PMID 1289363.
^ “Aztreonam spectrum of bacterial susceptibility and Resistance” (PDF). Retrieved 15 May 2012.
^ Jump up to:^a ^b Larkin C (22 February 2010). “Gilead’s Inhaled Antibiotic for Lungs Wins Approval”. BusinessWeek. Archived from the original on 2 March 2010. Retrieved 5 March 2010.
^ “FDA approves Gilead cystic fibrosis drug Cayston”. BusinessWeek. 23 February 2010. Retrieved 5 March 2010.
^ Jump up to:^a ^b AHFS Drug Information 2006 (2006 ed.). American Society of Health-System Pharmacists. 2006.
^ Terico, AT; Gallagher, JC (December 2014). “Beta-lactam hypersensitivity and cross-reactivity”. Journal of Pharmacy Practice. 27 (6): 530–44. doi:10.1177/0897190014546109. PMID 25124380. S2CID 19275020.

External links

“Aztreonam”. Drug Information Portal. U.S. National Library of Medicine.

Clinical data

Trade names	Azactam, Cayston, others
AHFS/Drugs.com	Monograph
License data	EU EMA: by INN
Pregnancy category	AU: B1
Routes of administration	Intravenous, intramuscular, inhalation
ATC code	J01DF01 (WHO)
Legal status
Legal status	UK: POM (Prescription only)US: ℞-onlyEU: Rx-only
Pharmacokinetic data
Bioavailability	100% (IM) 0.1% (by mouth in rats) Unknown (by mouth in humans)
Protein binding	56%
Metabolism	Liver (minor %)
Elimination half-life	1.7 hours
Excretion	Kidney
Identifiers
show IUPAC name
CAS Number	78110-38-0
PubChem CID	5742832
DrugBank	DB00355
ChemSpider	4674940
UNII	G2B4VE5GH8
KEGG	D00240
ChEBI	CHEBI:161680
ChEMBL	ChEMBL158
CompTox Dashboard (EPA)	DTXSID0022640
ECHA InfoCard	100.071.652
Chemical and physical data
Formula	C₁₃H₁₇N₅O₈S₂
Molar mass	435.43 g·mol⁻¹
3D model (JSmol)	Interactive image
Melting point	227 °C (441 °F) (dec.)
show SMILES
show InChI
(verify)

Patent

Publication numberPriority datePublication dateAssigneeTitleEP0070024A11981-07-131983-01-19E.R. Squibb & Sons, Inc.The crystalline anhydrous form of (3S-(3 alpha(z),4 beta))-3-(((2-amino-4-thiazolyl)(1-carboxy-1-methylethoxy)-imino)-acetyl)-amino)-4-methyl-2-oxo-1-azetidinesulfonic acid, method for its preparation, mixture and pharmaceutical composition containing itUS4529698A1981-01-191985-07-16E. R. Squibb & Sons, Inc.Process for preparing a 2-oxo-1-azetidinesulfonic acid saltUS4652651A1983-05-311987-03-24Hoffmann-La Roche Inc.Process for the manufacture of 1-sulpho-2-oxoazetidine carboxylic acid intermediates via catalytic ester cleavageUS4775670A1980-09-291988-10-04E. R. Squibb & Sons, Inc.2-oxo-1-azetidinesulfonic acid saltsEP0297580A11987-07-011989-01-04E.R. Squibb & Sons, Inc.Amorphous form of aztreonamUS4826973A1984-07-201989-05-02E. R. Squibb & Sons, Inc.Delta form of aztreonam and preparation thereofUS4923998A1977-03-141990-05-08Fujisawa Pharmaceutical Company, Ltd.Cephem and cepham compounds and processes for preparation thereofUS4946838A1981-07-131990-08-07E. R. Squibb & Sons, Inc.Crystalline anhydrous aztreonamUS5194604A1990-06-291993-03-16E. R. Squibb & Sons, Inc.Process and intermediates for beta-lactams having aminothiazole(iminooxyacetic acid)acetic acid sidechainsUS5254681A1989-08-021993-10-19Consiglio Nazionale Delle RicercheProcess for preparing monobactames and their intermediate productPL165700B11991-10-151995-01-31PanMethod of obtaining z2/2-aminothiazolyl-4/-2/-t-butoxycarbonyl-1-methylethoxyimine/ acetic acidWO2002051356A22000-12-272002-07-04Salus Pharma, Inc.Inhalable aztreonam for treatment and prevention of pulmonary bacterial infectionsWO2003018578A12001-08-272003-03-06Aurobindo Pharma Ltd.Method for producing beta form of crystalline anhydrous aztreonamUS20040062721A12000-12-272004-04-01Montgomery Alan BruceInhalable aztreonam lysinate formulation for treatment and prevention of pulmonary bacterial infectionsWO2004052333A12002-12-112004-06-24Pari GmbhPharmaceutical compositions for the pulmonary delivery of aztreonamUS20050014739A12003-05-152005-01-20Viktor GyollaiAztreonam beta polymorph with very low residual solvent contentUS20050032775A12003-07-022005-02-10Viktor GyollaiAztreonam L-lysine and methods for the preparation thereof

Publication numberPriority datePublication dateAssigneeTitle

Family To Family CitationsCN1802371A2003-05-152006-07-12特瓦药厂有限公司Aztreonam beta-polymorph with very low residual solvent contentAU2004256124B2 *2003-07-022011-04-28Corus Pharma, Inc.Aztreonam L-lysine and methods for the preparation thereofWO2006122253A1 *2005-05-092006-11-16Sicor, Inc.Process for making aztreonamWO2007083187A2 *2006-01-162007-07-26Orchid Chemicals & Pharmaceuticals LimitedAn improved process for the preparation of monobactam antibioticCN101412715B *2008-12-162010-04-14海南百那医药发展有限公司Aztreonam compound and preparation thereofCN102127068B *2010-12-312012-08-29山西普德药业股份有限公司Method for synthesizing aztreonam compoundCN102311431B *2011-08-302014-12-10海南海药股份有限公司Method for preparing anhydrous beta-aztreonamCN105017241B *2015-06-242018-03-06山东罗欣药业集团股份有限公司A kind of aztreonam compound and its preparation

////////////////Aztreonam, SQ 26776, antibacterial, lactam, monobactam, UA2451400, азтреонам , أزتريونام , 氨曲南 ,

C[C@H]1[C@H](NC(=O)C(=N/OC(C)(C)C(=O)O)\C2=CSC([NH3+])=N2)C(=O)N1S([O-])(=O)=O

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CLOBETASOL

December 22, 2021 12:29 pm / 1 Comment on CLOBETASOL

Clobetasol propionate

Molecular FormulaC₂₅H₃₂ClFO₅
Average mass466.970 Da

CCI 4725, CCI-4725, GR 2/925, GR-2/925,(8S,9R,10S,11S,13S,14S,16S,17R)-17-(chloroacetyl)-9-fluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl propanoate
246-634-3[EINECS], 25122-46-7[RN]
(11β,16β)-21-chloro-9-fluoro-11-hydroxy-16-methyl-3,20-dioxopregna-1,4-dien-17-yl propanoate

Active Moieties

NAME	KIND	UNII	CAS	INCHI KEY
Clobetasol	prodrug	ADN79D536H	25122-41-2	FCSHDIVRCWTZOX-DVTGEIKXSA-N

Clobetasol
CAS Registry Number: 25122-41-2
CAS Name: (11b,16b)-21-Chloro-9-fluoro-11,17-dihydroxy-16-methylpregna-1,4-diene-3,20-dione
Molecular Formula: C22H28ClFO4, Molecular Weight: 410.91
Percent Composition: C 64.30%, H 6.87%, Cl 8.63%, F 4.62%, O 15.57%
Literature References: Topical corticosteroid. Prepn: Elks et al.,DE1902340; eidem,US3721687 (1969, 1973 both to Glaxo). Review of pharmacology and clinical efficacy in skin disorders: E. A. Olsen, R. C. Cornell, J. Am. Acad. Dermatol.15, 246-255 (1986).
Derivative Type: 17-Propionate
CAS Registry Number: 25122-46-7
Manufacturers’ Codes: GR-2/925
Trademarks: Clobesol (GSK); Dermovate (GSK); Olux (Connetics); Psorex (GSK); Temovate (GSK)
Molecular Formula: C25H32ClFO5
Molecular Weight: 466.97
Percent Composition: C 64.30%, H 6.91%, Cl 7.59%, F 4.07%, O 17.13%
Properties: White or almost white colorless, crystalline powder, mp 195.5-197°. [a]D +103.8° (c = 1.04 in dioxane). uv max (ethanol): 237 nm (e 15000). Insol in water.
Melting point: mp 195.5-197°
Optical Rotation: [a]D +103.8° (c = 1.04 in dioxane)
Absorption maximum: uv max (ethanol): 237 nm (e 15000)
Therap-Cat: Glucocorticoid; anti-inflammatory.
Keywords: Glucocorticoid.
Clobetasol propionate is a corticosteroid used to treat corticosteroid-responsive dermatoses and plaque psoriasis.

Clobetasol propionate is a corticosteroid used to treat skin conditions such as eczema, contact dermatitis, seborrheic dermatitis, and psoriasis.^[2] It is applied to the skin as a cream, ointment, or shampoo.^[2]^[3] Use should be short term and only if other weaker corticosteroids are not effective.^[3] Use is not recommended in rosacea or perioral dermatitis.^[2]

Common side effects include skin irritation, dry skin, redness, pimples, and telangiectasia.^[2] Serious side effects may include adrenal suppression, allergic reactions, cellulitis, and Cushing’s syndrome.^[2] Use in pregnancy and breastfeeding is of unclear safety.^[4] Clobetasol is believed to work by activating steroid receptors.^[2] It is a US Class I (Europe: class IV) corticosteroid, making it one of the strongest available.

Clobetasol propionate was patented in 1968 and came into medical use in 1978.^[5] It is available as a generic medication.^[3] In 2019, it was the 180th most commonly prescribed medication in the United States, with more than 3 million prescriptions.^[6]^[7]

SYNTHESIS OF KEY INTERMEDIATE

SYN

DE 1902340

US 3992422

DE 2613875

EP 72200

WO 2012122452

CN 112110972

PATENT

IN 201821008147

Clobetasol propionate (C25H32ClFO5); CAS Registry No.[25112-46-7]; IUPAC name: 17-(2′- Chloroacetyl)-9-fluoro-l l-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,l 1,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] propionate is a potent halogen adrenal corticosteroid of the gluco-corticoid class used to treat various skin disorders including eczema and psoriasis. It is also highly effective for contact dermatitis caused by exposure to poison ivy/oak.In the US 3721687Apatentshow use of methanesulfonyl chloride and Pyridine as base to protect alcohol and at the time of LiCI reaction results with 10-15%ene impurity and less yield.In the methanesulfonyl chloride step used with pyridine as base which is a hazardous.Mesyl compound converted to Clobetasol propionate by using LiCl in Dimethylformamide reaction at IOO-IlO0C forms 10-15% with ene impurity. The synthesis of Clobetasol propionate results in small quantities of the eneimpurity. Clobetasol propionate desired compound to be with impurities which must be minimized. Ene impurity can be reduced to very low levels by reaction itself. However, if used recrystallization reduce ene impurity it is time consuming and very expensive. Further, because recrystallizations have high losses, unacceptably low yields.

Example I: Betamethasone to betamethasone 17- propionate To a 100 ml 4-neck round bottom flask (RBF) equipped with halfmoon stirrer, thermowelland addition funnel, mounted in a tub bath, was charged betamethasone (5.0g, 0.0127mole), Dimethylformamide (20ml). Cooled the reaction mass to 10-15°C. Slowly added trimethyl ortho propionate (3.42g, 0.0255mole) and p-toluenesulfonic acid (PTSA)(0.30g, 0.00174 mole) to the reaction mass at 10-15°C. Stirred the contents 10-15°C for 4 hr. The reaction was monitored for completion by TLC. Further continued stirring at the same temperature for Ihr till reaction complies by TLC. After reaction completion, added H2SO4UP to pH=1.0-2.0 in to reaction mass.Reaction mass was quenched in Purified water (25ml) at 25-30°C. Cooled reaction mass temperature to 0-5°C. Stirred for I hr and filtered and washed with Purified water (10mlX2). Suck dried under vacuum completely to get cream coloured solid. Dried in tray drier at 50-55°C.Dry weight-5.40g(94.50%); HPLC: 98.5%;mp215-218°C. IR (KBr, on’):3454.90, 3370.99 (-OH); 1719.86, 1659.10 (C=O)iC25H33FO6;

MS 448.52m/z 449.2255 [M+H]; 1HNMR (300MHz, CDCl3S ppm): Spectrum is recorded on Varian, and Tetra Methyl Silane (TMS) as internal standard. 1H-NMR Spectrum shows Aromatic-HK-7.17-7.22(d,lH); Hj-6.37-6.38 (d,lH);Hr6.14 (s,lH); HF-4.04-4.06(s,2H);HE2.23-2.28 (q,2H);Hc-l.39-1.43 (d,3H); HB-1.14 (t,3H);HA-0.96-2.96 (m,20H). 13CMR (300MHz, CDCl3Sppm): 8.692 (CH2-CH3); 16.693; 19.664; 21.353; 23.042; 27.568; 30.387; 36.456; 43.400; 46.547; 47.422; 71.760; 93.547; 124.307; 125.728; 127.903; 129.222; 130.443; 132.472; 145.632; 153.044; 167.424; 175.031 (O-C=O); 185.772 (Cyclic C=O); 196.732 (CH-CO-CH2-OH).

Example 2: Betamethasone 17- propionateto betamethasone 21-tosylate 100ml 4-neck RBF equipped with halfmoon stirrer, thermowell, reflux condenser mountained in water bath, was charged Stage-1 (5.0g, O.Olllmole), Dimethylformamide (20ml). Added 4-Dimethylaminopyridine as base (4.10g, 0.0335mole) and p-toluenesulfonyl chloride (4.24.Og, 0.0222mole)slowly, Stirredfor2-3 hr at 25-30°C. Stirred reaction mass at 25-30°C till reaction complies by TLC.As such reaction mass used insitue for next step. Reaction mass aliquot taken (2ml) and quenched in DM water (20ml), precipited material fdtered and washed with DM water (20ml). Suck dried well. Dried in tray drier at 50-55°C to get dry white solid. Dry weight-0.598g, (89.0%); HPLC: 98.5%; mp-170-175°C (dec). IR (KBr,cm”1):3291.91, 2980.39 (-OH); 1739.15, 1661.99 (C=O); C32H39FO8S; MS 602.71mA 603.2317 [M+H]; 1HNMR (300MHz, CDCl3Sppm): Spectrum is recorded on Varian, and Tetra Methyl Silane (TMS) as internal standard. 1H-NMR Spectrum shows Aromatic-Ηκ7.17-7.22(d,lH); Hj-6.37-6.38 (d,lH);Hr6.14 (s,lH); HG-4.334-4.393 (m,lH);HF-3.846- 4.007(d,2H);HE-2.273-2.349 (q,2H);HD-l.671-1.688 (s,lH); Hc-I-306-1.331 (d,3H); Hb1.055-1.105 (t,3H);HA-0.941 -2.634 (m,18H).13CMR (300MHz, CDCl3Sppm): 9.055 (CH2- CH3); 17.244; 20.002; 21.353; 23.168; 27.901; 30.622; 33.508; 34.881; 36.783; 43.642; 46.637; 47.330; 48.113; 48.417; 66.613; 70.902; 93.801; 102.732; 124.415; 129.324; 130.443; 132.472; 145.632; 153.583; 168.042; 174.853 (O-C=O); 186.208 (Cyclic C=O); 205.491 (CH-CO-CH2-OAr).

Example 3:Betamethasone 21-tosylateto Clobetasol propionate As such reaction mass used insitue for next step. Added. lithium chloride (LiCl)1.04 gm (0.0245mole). Stirred the reaction mass at 60-65°C for 5-6 hr.Reaction completion checked by TLC.After reaction completion, Added DM water (200ml). Stirred the reaction mass at 10-15°C for Ihr and Filtered washed with DM water (30mlx2).Dried in oven at 50-55°C to get white crystalline powder. Dry weight-4.42gm, (85.0%); HPLC:99.70%;mp-158-161°C. IR (KBr, cm_1):3299.62, 2976.53 (-OH); 1734.32, (C=0);1662.95 (C=C);C25H32C1F05; MSΑβ6.9Ίτη/ζ 467 [M+H];’HNMR (300MHz, CDCl35ppm): Spectrum is recorded on Varian, and Tetra Methyl Silane (TMS) as internal standard. 1H-NMR Spectrum shows AromaticHk-7.094-7. 128(d,IH); Hj-6.267-6.307 (d,lH); Hr6.066-6.076 (s,IH); H0-4.334-4.393 (m,lH); Hf-3.846-4.007 (d,2H); HE-2.273-2.349 (q,2H); Hd-I .671-1.688 (s,lH); Hc-1.306- 1.331 (d,3H); Hb-I .055-1.105 (t,3H); HA-0.941-2.634 (m,17H).13CMR (300MHz, CDCl35ppm): 8.692 (CH2-CH3); 16.693; 19.664; 21.353; 23.042; 27.568; 30.387; 36.456; 41.104; 46.547; 47.422; 71.760; 93.547; 124.307; 125.728; 127.903; 129.222; 130.443; 132.472; 145.632; 153.044; 168.312; 173.101 (O-C=O); 185.802 (Cyclic C=O); 204.602(CH-CO-CH2-C1)

SYN

Ruben Vardanyan, Victor Hruby, in Synthesis of Best-Seller Drugs, 2016

Synthesis of clobetasol propionate (27.1.13) starts from the known betamethasone 17-propionate (27.1.26), a potent glucocorticoid steroid with antiinflammatory and immunosuppressive properties, which was mesylated with methanesulfonyl chloride in pyridine to produce 9α-fluoro-11β-hydroxy-21-methylsulfonyloxy-16β-methyl 17-propionyloxypregna-1,4-diene-3,20-dione (27.1.27). The obtained product was refluxed in acetone, DMF, and dry LiCl mixture to produce the desired clobetasol propionate (27.1.13) [34] (Scheme 27.2.).

Clobetasol propionate, its structural formula (formula (I)), is a potent halogen-containing adrenocorticoid drug, has strong anti-inflammatory, anti-pruritic and vasoconstrictive effects, and its anti-inflammatory effect is approximately hydrogenated It is 112 times that of cortisone, and it is also used to treat neurodermatitis, contact dermatitis, eczema, discoid lupus erythematosus and other symptoms. It is currently widely used in clinical practice. It has been very popular in the international market and ranks among the top hormones. At present, there are only a few domestic companies in normal production, and the total yield is about 88%.[0003]

[0004] Formula (I).[0005] The process route for the production of synthetic clobetasol propionate is complex, technically difficult, and product quality requirements are strict. This is due to the complex structure of corticosteroids. The chemical structure of this type of drug is composed of three six-membered rings and one five-membered ring fused together to form a special molecular structure composed of 21 carbon atoms, with special molecular configuration steric effects and steric barriers. Group role. The functional groups on the drug structure interfere with each other, which makes the chemical reaction very complicated. It is manifested in many synthetic process steps, low raw material utilization rate, large amount of auxiliary materials, long production cycle, and many side reactions. The reaction process has various problems such as a large amount of solvents, a large amount of waste water and waste gas, and difficulty in recycling. Low technical indicators, low cost and other aspects.[0006] US patent, patent number 3721687, discloses two synthetic processes.[0007] Process method (1) adopts 9a-fluoro-113-hydroxy-16a-methyl-17 oxopropyl-1,4-diene-3,20-dione to synthesize clobetasol propionate, 9a -Fluoro-11-hydroxy-16 a -methyl-17oxopropyl-1,4-diene-3,20-dione and lithium chloride mixture, mixed with dimethylformamide (DMF) in acetone The solution is refluxed for four days, the solution is moved to a vacuum, ethanol, methanol, and acetone are added, and the mixture is refluxed for another 4 days. Most of the solution is moved to a vacuum, water is added to the residue, the crude product is put into the ether solution, and the mixture is passed through with chloroform. The aluminum is purified by filtration and recrystallized with ethanol to produce clobetasol propionate as a raw material. Method I uses too much acetone, and there is a certain risk of operation.[0008] Process method 2 adopts 21-chloro-9a-fluoro-1I@ -hydroxy-16a-methyl-17_oxopropyl-4ene-3,20-dione to synthesize clobetasol propionate Cable. Dissolve 21-chloro-9 a -fluoro-11 P -hydroxy-16 a -methyl-17oxopropyl_4ene-3,20-dione in acetone, cool in an ice bath, and add slowly while stirring Chromic acid (prepared by chromic acid: add 53.3ml of concentrated sulfuric acid to 250ml of water and add 66.7g of chromium trioxide); 4 hours later, the mixture reaches room temperature, ether is added, and it is left for another 20 minutes. The mixture is washed with water, and then the solution is moved to a vacuum ; The residue is recrystallized with acetone-petroleum ether, which pollutes the environment. In the past, organic solvents were not safe for production operations. [0009] Chinese patent, application number 200610053511.5, provides a method of mixing betamethasone 17-propionate sulfonate and anhydrous lithium chloride in a ratio of 1:1 to 2 and dissolving in dimethylformamide ( DMF), the chlorination reaction is carried out; second, after the chlorination reaction is complete, it is separated by ice water, and then centrifuged to dry, after drying, the crude clobetasol propionate is obtained; third, the clobetasol propionate is crude The crude tasol is dissolved in methanol or ethanol, activated carbon is added, decolorized, filtered, and the activated carbon is recovered; fourth, the filtrate is concentrated under reduced pressure, crystallized, dehydrated, and dried to obtain the raw material of clobetasol propionate. It has the characteristics of easy availability of starting materials, simple reaction steps, less dangerous and harmful solvents, mature technology, and convenient industrial production.[0010] The process route is as follows:[0011]

[0012] Clobetasol propionate uses betamethasone as the starting material, goes through the steps of cyclic ester-hydrolysis-sulfonation-chlorination, and then undergoes rough refinement to obtain clobetasol propionate-a refined substance, and then undergoes dissolution , Filtration, concentration, cooling, centrifugation, and drying to obtain clobetasol propionate. But its process route is longer, there are many influencing factors, and there are many side reactions. Moreover, the solvents used are very polluting and difficult to recycle.

Example 1[0034] 20g of Betamethasone 17-ester obtained by cyclic ester hydrolysis reaction was dissolved in 150ml of acetone, and after fully stirring and dissolving, 6g of ZnCl2 was added, and the temperature was raised to 35°C, and then 30g of BTC was introduced, After the BTC is passed, the reaction is kept warm for 3 hours. After the reaction is completed, the temperature is 40°C, and the concentration is reduced under reduced pressure until the solution contains 30ml of acetone. Then 300ml of drinking water is added for water separation and filtration. After drying for 16 hours at °C, 19.64 g of crude clobetasol propionate was obtained. The yield was 98.2%, and the crude clobetasol propionate content was 96.9% after analysis.Example 2[0036] 20g of betamethasone 17-ester compound obtained by cyclic ester hydrolysis reaction was dissolved in 150ml of acetone, and after fully stirring and dissolving, 7.2g of FeCl3 was added, heated to 30°C, and then 24g of BTC was introduced After the BTC is passed, the reaction is kept warm for 2 hours. After the reaction is completed, the solution is concentrated under reduced pressure at a temperature of 35°C until the solution contains 20ml of acetone, and then 300ml of drinking water is added for water precipitation, filtered, and finally at the temperature After drying for 10 hours at 85°C, 19.5 g of crude clobetasol propionate was obtained. The yield was 97.5%, and the crude clobetasol propionate content was 95.6% after analysis.Example 3[0038] 20g of Betamethasone 17-ester obtained by the cyclic ester hydrolysis reaction was dissolved in 150ml of acetone, and after fully stirring and dissolving, 4g of AlCl3 was added and the temperature was raised to 35°C, and then 28g of BTC was introduced, After the BTC is passed through, the reaction is kept warm for 4 hours. After the reaction is completed, the temperature is 30°C, and concentrated under reduced pressure until the solution contains 20ml of acetone. Then 300ml of drinking water is added for water precipitation, filtered, and finally at a temperature of 75 After drying for 18 hours at °C, 19.62g crude clobetasol propionate was obtained. The yield was 98.1%, and the crude clobetasol propionate content was 95.8% after analysis.Example 4[0040] The betamethasone 17-ester 20g obtained by the cyclic ester hydrolysis reaction was dissolved in 100ml of acetone, and after being fully stirred to dissolve, 4g of ZnCl3 was added, heated to 40°C, and then passed into 25g of BTC, After the BTC is passed, the reaction is kept for 5 hours. After the reaction is completed, the temperature is 40°C, and the concentration is reduced under reduced pressure until the solution contains 20ml of acetone. Then 200ml of drinking water is added for water precipitation, filtered, and finally at a temperature of 80°C. After drying for 18 hours at °C, 19.54 g of crude clobetasol propionate was obtained. The yield was 97.7%, and the crude clobetasol propionate content was 96.2% after analysis.[0041] Example 5 [0042] 20g of Betamethasone 17-ester obtained by cyclic ester hydrolysis reaction was dissolved in 200ml of acetone, and after fully stirring and dissolving, 8g of ZnCl3 was added and the temperature was raised to 50°C. Then pass in 40g BTC. After passing the BTC, keep it warm and react for 3 hours. After the reaction is completed, perform vacuum concentration at a temperature of 40°C until the solution contains 40ml of acetone, and then add 400ml of drinking water for hydrolysis. Filter, and finally dry at 85°C for 18 hours to obtain 19.58 g of crude clobetasol propionate. The yield was 97.9%, and the crude clobetasol propionate content was 96.9% after analysis.Example 6[0044] 20g of betamethasone 17-ester compound obtained by cyclic ester hydrolysis reaction was dissolved in 80ml of acetone, and after fully stirring and dissolving, 6g of ZnCl3 was added, and after the temperature was raised to 40°C, 25g of BTC was introduced, After the BTC is passed, the reaction is kept for 3 hours. After the reaction is completed, it is concentrated under reduced pressure at a temperature of 40°C, and concentrated until the solution contains 10ml of acetone. Then 150ml of drinking water is added for water precipitation, filtered, and finally at a temperature of 85°C. After drying for 18 hours at °C, 19.3g crude clobetasol propionate was obtained. The yield was 96.5%, and the crude clobetasol propionate content was 96.5% after analysis.
Publication numberPriority datePublication dateAssigneeTitleUS3721687A *1968-01-191973-03-20Glaxo Lab Ltd3-keto-delta 4-9alpha-halo-11-oxygenated-16-methyl or methylene-17alpha-acyloxy-20-keto-21-halo pregnenesCN1923842A *2006-09-112007-03-07Zhejiang Dingtai Pharmaceutical Co., Ltd.Manufacturing method of clobetasol propionate
Publication numberPriority datePublication dateAssigneeTitleFamily To Family CitationsCN105646630A *2015-08-102016-06-08Shandong Taihua Biological Technology Co., Ltd.One-pot Preparation of Clobetasol Propionate IntermediateCN112110972A *2019-06-212020-12-22Henan Lihua Pharmaceutical Co., Ltd.A kind of preparation method of clobetasol propionateCN112028957A *2020-07-292020-12-04Henan Lihua Pharmaceutical Co., Ltd.A kind of clobetasol propionate intermediate and preparation method

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Medical uses

Clobetasol propionate is used for the treatment of various skin disorders including eczema, herpes labialis,^[8] psoriasis, and lichen sclerosus. It is also used to treat several auto-immune diseases including alopecia areata, lichen planus (auto immune skin nodules), and mycosis fungoides (T-cell skin lymphoma). It is used as first-line treatment for both acute and chronic GVHD of the skin.^[9]

Clobetasol propionate is used cosmetically by dark-skinned women for skin whitening, although this use is controversial. The U.S. Food and Drug Administration has not approved it for that purpose, and sales without a prescription are illegal in the U.S. Nonetheless, skin-whitening creams containing this ingredient can sometimes be found in ethnic beauty supply stores in New York City and on the internet. It is also sold internationally, and does not require a prescription in some countries. Whitening creams with clobetasol propionate, such as Hyprogel, can make skin thin and easily bruised, with visible capillaries, and acne. It can also lead to hypertension, elevated blood sugar, suppression of the body’s natural steroids, and stretch marks, which may be permanent.^[10]

Clobetasol propionate is, along with mercury and hydroquinone, “amongst the most toxic and most used agents in lightening products.” Many products sold illegally have higher concentrations of clobetasol propionate than is permitted for prescription drugs.^[11]

Contraindications

According to the California Environmental Protection Agency, clobetasol propionate should not be used by pregnant women, or women expecting to become pregnant soon, as studies with rats shows a risk of birth defects:^[12]

“Studies in the rat following oral administration at dosage levels up to 50 mcg/kg per day revealed that the females exhibited an increase in the number of resorbed embryos and a decrease in the number of living fetuses at the highest dose. Pregnancy: Teratogenic Effects (i.e., possibility of causing abnormalities in fetuses): Pregnancy Category C: Clobetasol propionate has not been tested for teratogenicity when applied topically; however, it is absorbed percutaneously, and when administered subcutaneously it was a significant teratogen in both the rabbit and mouse. Clobetasol propionate has greater teratogenic potential than steroids that are less potent. There are no adequate and well-controlled studies of the teratogenic effects of clobetasol propionate in pregnant women. Temovate Cream and Ointment should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.”

Forms

Clobetasol propionate is marketed and sold worldwide under numerous names, including Clobex, Clob-x (Colombia), Clovate, Clobet (Biolab Thailand) Clonovate (T.O. Chemicals, Thailand), Cormax (Watson, US), Haloderm (Switzerland, by ELKO Org), Pentasol (Colombia), Cosvate, Clop (Cadila Healthcare, India), Propysalic (India), Temovate (US), Dermovate^[13] (GlaxoSmithKline, Canada, Estonia, Pakistan, Switzerland, Portugal, Romania, Israel), Olux, ClobaDerm, Tenovate, Dermatovate, Butavate, Movate, Novate, Salac (Argentina), and Powercort, Lotasbat and Kloderma (Indonesia), Lemonvate (Italy), Delor (Ethiopia), Psovate (Turkey).

References

^ “Clobetasol Propionate Topical Ointment 0.05% Information – Drug Encyclopedia”. Kaiser Permanente.
^ Jump up to:^a ^b ^c ^d ^e ^f “Clobetasol Propionate Monograph for Professionals”. Drugs.com. American Society of Health-System Pharmacists. Retrieved 13 April 2019.
^ Jump up to:^a ^b ^c British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 1210. ISBN 9780857113382.
^ “Clobetasol topical Use During Pregnancy”. Drugs.com. Retrieved 13 April 2019.
^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 487. ISBN 9783527607495.
^ “The Top 300 of 2019”. ClinCalc. Retrieved 16 October 2021.
^ “Clobetasol – Drug Usage Statistics”. ClinCalc. Retrieved 16 October 2021.
^ Hull C, McKeough M, Sebastian K, Kriesel J, Spruance S (March 2009). “Valacyclovir and topical clobetasol gel for the episodic treatment of herpes labialis: a patient-initiated, double-blind, placebo-controlled pilot trial”. Journal of the European Academy of Dermatology and Venereology. 23 (3): 263–7. doi:10.1111/j.1468-3083.2008.03047.x. PMID 19143902. S2CID 205588376.
^ E. Fougera and Co. “CLOBETASOL PROPIONATE CREAM USP, 0.05% CLOBETASOL PROPIONATE OINTMENT USP, 0.05%<“. NIH Daily Med.
^ Saint Louis C (January 15, 2010). “Creams Offering Lighter Skin May Bring Risks”. New York Times.
^ Gbetoh MH, Amyot M (October 2016). “Mercury, hydroquinone and clobetasol propionate in skin lightening products in West Africa and Canada”. Environmental Research. 150: 403–410. Bibcode:2016ER….150..403G. doi:10.1016/j.envres.2016.06.030. hdl:1866/19006. PMID 27372064.
^ Office of Environmental Health Hazard Assessment (August 22, 1997). “Chemicals Under Consideration For Possible Listing Via The “Formally Required To Be Labeled Or Identified” Mechanism”. California Environmental Protection Agency. Archived from the original on 2001-07-20. Retrieved 2007-05-06.
^ “DERMOVATE 0.05% W/V OINTMENT – Clobetasol Topical(0.05% w/v) Glaxo SmithKline Pharmaceuticals Ltd”. GNH. Retrieved 2021-07-16.

External links

“Clobetasol propionate”. Drug Information Portal. U.S. National Library of Medicine.

Clinical data

Pronunciation	/kloʊˈbeɪtəsɒl/^[1]
Trade names	Temovate, Clobex, Cormax, others
AHFS/Drugs.com	Monograph
License data	US DailyMed: Clobetasol_propionate
Pregnancy category	AU: B3
Routes of administration	Topical
ATC code	D07AD01 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Identifiers
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CAS Number	25122-46-7
PubChem CID	32798
IUPHAR/BPS	7062
DrugBank	DB01013
ChemSpider	30399
UNII	779619577M
KEGG	D01272
ChEBI	CHEBI:31414
ChEMBL	ChEMBL1159650
CompTox Dashboard (EPA)	DTXSID6045907
ECHA InfoCard	100.042.380
Chemical and physical data
Formula	C₂₅H₃₂ClFO₅
Molar mass	466.97 g·mol⁻¹
3D model (JSmol)	Interactive image
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//////////////////Clobetasol propionate, CCI 4725, CCI-4725, GR 2/925, GR-2/925, Glucocorticoid, anti-inflammatory

[H][C@@]12C[C@H](C)[C@](OC(=O)CC)(C(=O)CCl)[C@@]1(C)C[C@H](O)[C@@]1(F)[C@@]2([H])CCC2=CC(=O)C=C[C@]12C

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SEVELAMER

December 22, 2021 4:19 am / Leave a comment

SEVELAMER

2-(chloromethyl)oxirane;prop-2-en-1-amine

CAS 52757-95-6, Molecular Formula, (C3-H7-N.C3-H5-Cl-O)x, Molecular Weight, 149.6198, HSDB 7608

Sevelamer hydrochloride [USAN]
152751-57-0, (C3-H7-N.C3-H5-Cl-O.Cl-H)x-, 186.0807, GT 16-026A

A crosslinked polymeric amine that binds PHOSPHATES and BILE ACIDS; it is nonabsorbed; used for hyperphosphatemia during HEMODIALYSIS and in END-STAGE RENAL DISEASE; used like calcium acetate.

Sevelamer carbonate [USAN]
845273-93-0, (C3-H7-N.C3-H5-Cl-O)x-.x-C-H2-O3, 211.6436, GT335-012

A polymeric amine that binds phosphate and is used to treat HYPERPHOSPHATEMIA in patients with kidney disease.

Drug Name：Sevelamer Carbonate,

Trade Name：Renvela^®

MOA：Phosphate binder

Indication：Hyperphosphatemia

Company：Genzyme (Originator)

Sales：$1,037.9 Million (Y2015);
$902.9 Million (Y2014);
$997.5 Million (Y2013);
$842.4 Million (Y2012);
$581 Million (Y2011);ATC Code：

Sevelamer Carbonate was first approved by the U.S. Food and Drug Administration (FDA) on Jul 19, 2007, then approved by European Medicine Agency (EMA) on Jun 21, 2009. However, till 2013, China Food and Drug Administration approved this drug. It was developed by Genzyme, and the trade name is Renvela^®. On the other hand, US FDA firstly approved Sevelamer HCl (Renagel^®) on Oct 30, 1998.

Renvela^® is a non-absorbed phosphate binding crosslinked polymer, containing multiple amines separated by one carbon from the polymer backbone. These amines exist in a protonated form in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the gastrointestinal tract and decreasing absorption, sevelamer carbonate lowers the phosphate concentration in the serum (serum phosphorus).

Renvela^® is available as film-coated tablet for oral use, containing 800 mg of free sevelamer carbonate on an anhydrous basis. The initial dose is 0.8 or 1.6 grams orally three times per day with meals.SevelamerCAS Registry Number: 52757-95-6
CAS Name: 2-Propen-1-amine polymer with (chloromethyl)oxirane
Additional Names: allylamine polymer with 1-chloro-2,3-epoxypropane; allylamine-epichlorohydrin copolymer; poly(allylamin-co-N,N¢-diallyl-1,3-diamino-2-hydroxypropane)
Literature References: Polymeric non-absorbed phosphate binder consisting of polyallylamine crosslinked with epichlorohydrin to form a hydrogel where 40% of the amines are protonated. Follows the general formula of (C3H7N.C3H5ClO)n. Binds dietary phosphate leading to increased fecal excretion, decreased absorption and decreased serum phosphorous levels. Prepd not claimed: S. R. Holmes-Farley et al.,WO9505184; eidem,US5496545 (1995, 1996 both to GelTex). Mechanism of action: S. R. Holmes-Farley et al.,J. Macromol. Sci. Pure Appl. Chem.A36, 1085 (1999). Determn of phosphate binding capacity: J. R. Mazzeo et al.,J. Pharm. Biomed. Anal.19, 911 (1999). Clinical studies in end stage renal disease: E. A. Slatopolsky et al.,Kidney Int.55, 299 (1999).
Derivative Type: Hydrochloride
CAS Registry Number: 152751-57-0
Manufacturers’ Codes: PB-94; GT16-026A
Trademarks: Renagel (Genzyme)
Properties: Insol in water. Hydrophilic.
Therap-Cat: Antihyperphosphatemic.
Keywords: Antihyperphosphatemic.

Sevelamer (rINN) is a phosphate binding medication used to treat hyperphosphatemia in patients with chronic kidney disease. When taken with meals, it binds to dietary phosphate and prevents its absorption. Sevelamer was invented and developed by GelTex Pharmaceuticals. Sevelamer is marketed by Sanofi under the brand names Renagel (sevelamer hydrochloride) and Renvela (sevelamer carbonate).

Chemistry and pharmacology

Sevelamer consists of polyallylamine that is crosslinked with epichlorohydrin.^[1] The marketed form sevelamer hydrochloride is a partial hydrochloride salt being present as approximately 40% amine hydrochloride and 60% sevelamer base. The amine groups of sevelamer become partially protonated in the intestine and interact with phosphate ions through ionic and hydrogen bonding.

Medical uses

Sevelamer is used in the management of hyperphosphatemia in adult patients with stage 4 and 5 chronic kidney disease (CKD) on hemodialysis. Its efficacy at lowering phosphate levels is similar to that of calcium acetate, but without the accompanying risk of hypercalcemia and arterial calcification.^[2]^[3] In patients with CKD, it has also been shown to reduce triglycerides and LDL, and increase HDL.^[4]

This is a phosphate binder.

Contraindications

Sevelamer therapy is contraindicated in hypophosphatemia or bowel obstruction. In hypophosphatemia, sevelamer could exacerbate the condition by further lowering phosphate levels in the blood, which could be fatal.^[5]

Adverse effects

Common adverse drug reactions (ADRs) associated with the use of sevelamer include: hypotension, hypertension, nausea and vomiting, dyspepsia, diarrhea, flatulence, and/or constipation.

Other effects

Sevelamer can significantly reduce serum uric acid.^[6] This reduction has no known detrimental effect and several beneficial effects, including reducing hyperuricemia, uric acid nephrolithiasis, and gout.

Sevelamer is able to sequester advanced glycation end products (AGEs) in the gut, preventing their absorption into the blood. AGEs contribute to oxidative stress, which can damage cells (like beta cells, which produce insulin in the pancreas). As Vlassara and Uribarri explain in a 2014 review on AGEs, this may explain why sevelamer, but not calcium carbonate (a phosphate binder that does not sequester AGEs), has been shown to lower AGEs in the blood, as well as oxidative stress and inflammatory markers.^[7]

SYN

https://www.oatext.com/polymer-and-heterocyclic-compounds-their-utility-and-application-as-drug.php

Sevelamer hydrochloride (Renagel VR ) was the first polymeric phosphate control and removal of excess phosphate is of benefit to patients with chronic kidney disease CKD where dialysis is unable to maintain safe phosphorus levels. Sevelamer limits the absorption of dietary phosphorus by binding phosphate in the intestine through ionic interaction with the polyamine polymer. Sevelamer is across linked form of poly(allylamine) containing primary and secondary aliphatic amine residues and was approved for the treatment of hyperphosphatemia by the FDA in 1998.The following Scheme 5 shows the synthetic lines for Sevelamer hydrochloride.

Scheme 5. Represent the formation of poly allylamine as a residue of sevelamer structure

Synthesis of Sevelamer Hydrochloride. Approximately 40 percent of the amine moieties are in the HCl form. Crosslinking degree is 10%.

SYN

The synthesis of Sevelamer consists of crosslinkung poly(allylamine hydrochloride) with epichlorohydrin. The product is washed, dried and ground to the desired particle size to give the active substance.

SynRoute 1

Reference：1. US2009155368A1.Route 2

Reference：1. WO2011099038A2.

2. CN103159880A.Route 3

Reference：1. WO2010146603A1.Route 4

Reference：1. CN102796262A.

SYN

https://patents.google.com/patent/US20100331516A1/en

The present invention relates to the process for preparation of carbonate salt of amine polymers, preferably Poly(allylamine-co-N,N′-diallyl-1,3-diamino-2-hydroxypropane)carbonate Formula-I, an antihyperphosphatemic agent.
a, b=number of primary amine groups a+b=9
c=number of crosslinking groups c=1
m=large number to indicate extended polymer network

Sevelamer carbonate is non-absorbable polymer marketed as Renvela™ by Genzyme Corporation. It is known chemically as poly(allylamine-co-N,N′-diallyl-1,3-diamino-2-hydroxypropane) carbonate salt. It was developed as a pharmaceutical alternative to Sevelamer hydrochloride (Renagel®). Renvela™ contains Sevelamer carbonate, a non-absorbed phosphate binding crosslinked polymer, free of metal and calcium. It contains multiple amines separated by one carbon from the polymer backbone. These amines exist in a protonated form in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the dietary tract and decreasing absorption, Sevelamer carbonate lowers the phosphate concentration in the serum.
[0004]
Sevelamer carbonate is an anion exchange resin with the same polymeric structure as Sevelamer hydrochloride in which carbonate replaces chloride as the counterion. While the counterions differ for the two salts, the polymer itself, the active moiety, is the same. The protonated amines can be indirectly measured as carbonate content in meq/gm. Renvela™ is used in End Stage Renal Disease (ESRD) which leads to hyperphosphatemia due to retention of phosphorous. This condition can lead to ectopic calcification. Renvela™ binds dietary phosphate in GI tract and thus controls the serum phosphate levels. The potency of Renvela™ is measured in terms of its Phosphate Binding Capacity (PBC) by Phosphate Assay (PA). Treatment of hyperphosphatemia includes reduction in dietary intake of phosphate, inhibition of intestinal phosphate absorption with phosphate binders, and removal of phosphate with dialysis. Sevelamer carbonate taken with meals has been shown to control serum phosphorus concentrations in patients with CKD who are on dialysis. Currently Sevelamer hydrochloride is used to cure hyperphosphatemia. As a consequence ESRD patients still need a high dosage of Renagel® to meet clinical end-points, leading to adverse effect such as gastrointestinal discomfort and problems with patient compliance. But systemic acidosis development or worsening of pre-existing acidosis has been reported in many patients on long term dialysis who are given Sevelamer hydrochloride (Perit Dial Int. 2002, 22, 737-738, Nephron 2002, 92, 499-500, Kidney Int. 2004, 66, S39-S45, Ren. Fail 2005, 27,143-147).
[0005]
Administration of Sevelamer hydrochloride adds to metabolic acid load because the resin removes some bicarbonate or bicarbonate precursor (mainly short chain fatty acid anions) from the body and replaces it with chloride. Each molecule of chloride contributed to the body in exchange for carbonate or bicarbonate precussor is equivalent to a molecule of hydrochloric acid added to the body, so the tendency of patients on long term haemodialysis to acidosis is inevitably increased when they take Sevelamer hydrochloride. (Kidney Int., 2005; 67: 776-777)
[0006]
This problem can be countered by an increase in the dialysate concentration of bicarbonate used in each dialysis session. A more fundamental solution, suitable for both dialyzed and non-dialyzed patients, would be the administration of Sevelamer free base, or any other suitable resin, not as the chloride but as body suitable counterion such as bicarbonate. Anion exchange resins have traditionally been synthesized in the chloride form, but the chloride in the current Sevelamer preparation is of no benefit to patients with renal failure. A change in the formulation of Sevelamer from its current chloride form to Sevelamer attached to bicarbonate would convert an acid load into a mild alkali load. (Cli. Sci. 1963; 24:187-200)
[0007]
U.S. Pat. No. 6,858,203 relates to phosphate-binding polymers provided for removing phosphate from the gastrointestinal tract. These polymers are useful for the treatment of hyperphosphatemia.
[0008]
WO 2006/050315 describes pharmaceutical compositions comprising a carbonate salt of an aliphatic amine polymer wherein the monovalent anion can prevent or ameliorate acidosis, in particular acidosis in patients with renal disease.
[0009]
HPLC Ion Chromatography PA method is used for the determination of PBC of Sevelamer HCl which can be adopted for determining the carbonate content from Sevelamer carbonate (J R Mazzeo et al, J. Pharm. Biomed. Anal. 19 (1999) 911-915).
[0010]
Our co-pending application number 1402/MUM/2006 dated 1 Sep. 2006 discloses process for preparation of Sevelamer HCl having phosphate binding capacity in the range of about 5.0 meq/gm to about 6.0 meq/gm and chloride content in the range of about 3.74 to about 5.60 meq/gm.
[0011]
The prior art mentioned above discussed advantages of Sevelamer carbonate over Sevelamer hydrochloride thus there remains need for commercially viable and industrially useful process for the preparation of Sevelamer carbonate having consistency in phosphate binding capacity, degree of cross linking, chloride content and carbonate content.

The reaction is represented by the following reaction scheme:
[0078]
100 gm Sevelamer hydrochloride was dispersed in 500 ml purified water and sodium hydroxide solution [20 gm sodium hydroxide dissolved in 500 ml purified water] was added to the obtained suspension followed by stirring at 25-35° C. for 30 minutes. The obtained material was filtered and wet cake was stirred in 1.0 L purified water for an hour. The material was filtered and cake was washed twice. Wet cake was dried at 50-90° C. for 5-6 hrs to get Sevelamer base (70 gm). LOD: 0.4% Chloride content: Nil.

Example 2

[0079]
10 gm Sevelamer was suspended in 200 ml water and stirred. Carbon dioxide gas was purged into the obtained suspension at 25-35° C. for 8 hrs using dry ice. The obtained material was filtered and washed with 100 ml water [3×100] and the wet cake was dried on rotavapor at 90-95° C. to get Sevelamer carbonate (11.5 gm). Yield—115% w/w [Chloride content: 0.3%, Phosphate binding: 5.75 mMole/g, Carbonate content: 4.78 meq/g and Degree of crosslinking—16.4%], Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.

Example 3

[0080]
10 gm Sevelamer was added to 200 ml water and reacted with carbon dioxide gas under pressure at 25-35° C. for 7-8 hrs with stirring. The obtained material was filtered and washed with 100 ml water thrice [3×100]. The wet cake thus obtained was dried on rotavapor at 90-95° C. to get Sevelamer carbonate (11.3 gm). Yield—113% w/w Degree of crosslinking—16.4%, Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.

Example 4

[0081]
Sevelamer (7 gm) was added to 150 ml water and reacted with carbon dioxide gas under pressure at 60-65° C. for 7-8 hrs with stirring. The material obtained was filtered and washed with 100 ml purified water thrice [3×100]. The wet cake thus obtained was dried on rotavapor at 90-95° C. to get Sevelamer carbonate (9.3 gm).
[0082]
Yield—120% w/w Degree of crosslinking—16.4%, Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.

Example 5

[0083]
Sevelamer (7 gm) was added to 150 ml water and reacted with carbon dioxide gas by purging under pressure at 60-65° C. for 7-8 hrs with stirring. The material obtained was filtered and washed with 100 ml purified water thrice [3×100]. The wet cake thus obtained was dried on rotavapor at 90-95° C. to get Sevelamer carbonate (9.0 gm).
[0084]
[Degree of crosslinking—16.4%, Chloride content: 0.5%, Phosphate binding: 5.56 mMole/g and Carbonate content: 4.46 meq/g] Yield—110% w/w Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.

Example 6

[0085]
Sevelamer hydrochloride (10 gm) was treated Sodium hydroxide solution (2M) for 1 hr at temperature 25 to 35° C. to get Sevelamer base. Filter the free base and was added to 150 ml water and reacted with carbon dioxide gas by purging under pressure at 60-65° C. for 7-8 hrs with stirring. The material obtained was filtered and washed with 100 ml purified water thrice [3×100]. The wet cake thus obtained was dried on rotavapor under vacuum at 90-95° C. to get Sevelamer carbonate (9.3 gm). Yield—120% w/w.
[0086]
[Degree of crosslinking—16.4%, Chloride content: 0.2%, Phosphate binding: 5.45 mMole/g and Carbonate content: 4.36 meq/g].
[0087]
Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.

Example 7

[0088]
Sevelamer hydrochloride (10 gm) was treated sodium hydroxide solution (2M) for 1 hr at temperature 25 to 35° C. to get Sevelamer base. Filter the free base and was added to 100 ml water. Sodium bicarbonate (10 gm dissolved in 1000 ml purified water) solution was added at temperature 60-65° C. for 4 hrs with stirring. Sevelamer Carbonate thus obtained was filtered and again subjected to for treatment of sodium bicarbonate solution (10 gm in 1000 ml). Reaction mixture was heated for 4 hrs at 60-65° C. with stirring. The material obtained was filtered and washed with 100 ml purified water thrice [3×100]. The wet cake thus obtained was dried under vacuum tray dryer at 80-90° C. for 24 hrs and further dried in atmospheric tray dryer at 100° C. for 36 hrs to get Sevelamer carbonate (9.0 gm). The loss of drying of material was about 5-7% achieved as per requirement. Yield—120% w/w, [Degree of crosslinking—16.4%, Chloride content: 0.01%, Phosphate binding: 5.68 mMole/g and Carbonate content: 4.85 meq/g]

Example 8

[0089]
Sodium hydroxide pellets (41 gm) is dissolved in 600 ml methanol at 25-35° C. and polyallylamine hydrochloride (100 gm) is added to it followed by stirring for 5-6 hrs at temperature 25-35° C. The obtained reaction mass is filtered through hyflobed and filtrate is concentrated to reduce to half volume and the separated inorganic salt is filtered off over hyflobed. The obtained filtrate is concentrated completely under vacuum to get sticky mass (61 gm) of polyallylamine. Yield—61% w/w

Example 9

[0090]
Polyallylamine (27.5 gm) dissolved in 100 ml water is charged into 1 L SS 316 autoclave and interacted with carbon dioxide gas under pressure (5.0 Kg/cm²). Initially 2-3 Kg/cm2 gas is consumed by the reaction mass and exotherm is observed from 28 C to 35° C. Then 5 Kg/cm²pressure is maintained for 5-6 hours. After completion of the reaction the reaction mass is slowly added to 700 methanol and stirred for 3-4 hours. The separated solid (31 gm) is filtered, washed with 50 ml methanol and dried at 40-50° C. in vacuum oven. Yield—112% w/w

Example 10

[0091]
Polyallylamine carbonate (20 gm) is dissolved in 30 ml water and cooled at 5-15° C. under stirring. The aqueous sodium hydroxide solution [dissolving 4.23 gm sodium hydroxide pellets into 4.2 ml of water] is added to reaction mass dropwise at 10-15° C. with continued stirring for 30 minutes. 101 ml toluene and 0.6 ml SPAN-85 is added to it and heated at 55-60° C. Epichlorohydrin (1.06 gm) is added to the reaction mass followed by stirring and heating for 3 hrs. The reaction mass is cooled at 25-35° C. and filtered through Buchner funnel. The obtained wet cake is added to 1 L acetone followed by stirring for 1 hour to get solid which was filtered through Buchner funnel. The aqueous organic washings are repeated for 7-10 times till polymer is free from excess alkalinity and the obtained wet cake is dried at 40-50° C. on rotavapor and then at 90-95° C. till constant weight of polymer is obtained (9 gm). Yield—45% w/w, Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.

Example 11

[0092]
Polyallylamine carbonate (20 gm) is dissolved in 30 ml water and cooled at 5-15° C. under stirring. The aqueous sodium hydroxide solution [dissolving 4.23 gm sodium hydroxide pellets into 4.2 ml of purified water] is added to obtained reaction mass dropwise at 10-15° C. with continued stirring for 30 minutes. 150 ml water and 0.6 ml SPAN-85 is added to it and heated at 60-80° C. Epichlorohydrin (1.06 gm) is added followed by stirring and heating is continued for 3 hours. The reaction mass is cooled at 25-35° C. and filtered through Buchner funnel. The obtained wet cake is added to 1 L acetone followed by stirring for 1 hour to get solid which is filtered through Buchner funnel. This aqueous organic washings are repeated for 7-10 times till the polymer is free from excess alkalinity and the obtained material is dried at 40-50° C. on rotavapor and/or Fluidised bed dryer then at 90-95° C. till constant weight of polymer is obtained (9 gm).

Example 12

[0093]
Polyallylamine carbonate (20 gm) is dissolved in 30 ml water and cooled at 5-15° C. under stirring. The aqueous sodium hydroxide solution [dissolving 4.23 gm sodium hydroxide pellets into 4.2 ml of purified water] is added to the obtained reaction mass dropwise at 10-15° C. with continued stirring for 30 minutes. 150 ml water and 0.6 ml SPAN-85 is added to it and heated at 60-80° C. Epichlorohydrin (1.06 gm) is added followed by stirring and heating is continued for 3 hours. The reaction mass is cooled at 25-35° C. and filtered through Buchner funnel. The obtained wet cake is added to 1 L isopropyl alcohol (IPA) followed by stirring for 1 hour to get solid which is filtered through Buchner funnel. The obtained material is washed with water and organic solvents for 4-5 times till the polymer is free from excess alkalinity. The obtained wet cake is dried under vacuum tray dryer at 80-90° C. for 24 hrs and further dried in atmospheric tray dryer at 100° C. for 36 hrs till constant weight of dried polymer is obtained (15 gm). The loss on drying of material is around 6% as per requirement.

Example 13

[0094]
In 1 L SS 316 autoclave, 75 gm allylamine and 200 ml water is charged and carbon dioxide gas under pressure (5 Kg/cm2) is purged into autoclave for 3-4 hours followed by stirring. Nitrogen gas is purged for 15 minutes. 9.8 gm VA-086 is added to the reaction mass and stirred at 70-80° C. for 12 hours and this solution is added to 1 L methanol under stirring. The separated material is filtered and washed with 100 ml methanol, suck dried and dried in vacuum oven at 50-60° C. to get 90 gm of polyallylamine carbonate. Yield—120% w/w

Example 14

[0095]
Polyallylamine carbonate (20 gm) dissolved in 30 ml water is cooled at 5-15° C. under stirring and sodium hydroxide solution [dissolving 4.23 gm sodium hydroxide pellets into 4.2 ml of purified water] is added to the obtained reaction mass dropwise at 10-15° C. followed by continued stirring for 30 minutes. 101 ml toluene and 0.6 ml SPAN-85 is added to it and heated at 55-60° C. Epichlorohydrin (1.06 gm) is added and reaction mass is stirred and heated for 3 hours. Then it is cooled to 25-35° C. and filtered through Buchner funnel. The wet cake obtained is added to 1 to 1.5 L acetone followed by stirring for 1 hour to get solid which is filtered through Buchner funnel. The washings are repeated for 7-10 times till polymer is free from excess alkalinity. Wet cake (9 gm) is dried at 40-50° C. on rotavapor and then at 90-95° C. till constant weight of polymer is obtained. Yield—45% w/w

Example 15

[0096]
Sevelamer hydrochloride (10 gm) was added to 10% aqueous sodium bicarbonate solution at 25-35° C. and stirred for 7-8 hrs. The material obtained was filtered and washed with 100 ml purified water thrice and the wet cake was dried on rotavapor at 90-95° C. to get Sevelamer carbonate (7.5 gm). Yield—75% w/w
[0097]
Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate.
[0098]
[Chloride content: 0.4%, Phosphate binding: 5.45 mMole/g and Carbonate content: 4.85 meq/g]

Example 16

[0099]
Sevelamer hydrochloride (10 gm) was added to 10% aqueous sodium bicarbonate solution. The mixture was stirred at 60-65° C. for 4 hrs. The material obtained was filtered and the obtained wet cake was again subjected to the treatment of 10% sodium bicarbonate solution. Reaction mixture was heated for 4 hrs at 60-65° C. with stirring. The material obtained was filtered and washed with 100 ml purified water four times and the wet cake was dried on rotavapor under vacuum at 90-95° C. to get Sevelamer carbonate (7.5 gm). Yield—75% w/w, Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate, [Chloride content: 0.03%, Phosphate binding: 5.25 mMole/g and Carbonate content: 4.65 meq/g].

Example 17

[0100]
Sevelamer hydrochloride (10 gm) was added into 130 ml solution of sodium bicarbonate (10 gm NaHCO3 in 130 ml water) and the mixture was stirred at 60-65° C. for 4 hrs. The material was filtered using Buckner funnel assembly. The obtained wet cake was added into 130 ml solution of sodium bicarbonate (10 gm NaHCO3 in 130 ml water) and stirred at 60-65° C. for 4 hrs. The material was filtered using Buckner funnel assembly and the wet cake was washed by stirring it in 100 ml water for 1 hr at 60-65° C. The material was filtered using Buckner funnel assembly. The wet cake was washed twice at 60-65° C. and dried on rotavapor at 90-95° C. to get Sevelamer carbonate (8.5 gm). Yield—75% w/w, Chloride content: 0.03%

Example 18

[0101]
Sevelamer hydrochloride (1.1 Kg) was added into 15.5 L solution of sodium bicarbonate (1.1 Kg NaHCO₃in 14.3 L water). The obtained mixture was stirred at 60-65° C. for 4 hrs. The obtained material was filtered by centrifuge filter. The obtained wet cake was added into 15.5 L solution of sodium bicarbonate (1.1 Kg NaHCO₃in 14.3 L water) and maintained stirring at 60-65° C. for 4 hrs. The material was filtered by centrifuge filter assembly and obtained wet cake was stirred in 11 L water for 1 hr at 60-65° C. The material was filtered by centrifuge filter and the washing of wet cake was repeated at 60-65° C. for two more times. The obtained wet cake was dried in air tray dryer (ATD) at 90-100° C. for 30-36 hrs and LOD was checked after every five hours till LOD was in the range of 5 to 10%. to get Sevelamer carbonate (0.995 Kg), [Chloride content: 0.03%, Phosphate binding capacity: 5.5 mmole/gm, Carbonate content: 5.1 meq/gm]

Example 19

[0102]
Sevelamer hydrochloride (10 gm) was added to sodium bicarbonate solution (10 gm in 200 ml) at 25-35° C. The reaction mixture was heated for 4 hrs at 60-65° C. with stirring. Sevelamer Carbonate thus obtained was filtered and again subjected to treatment of Sodium bicarbonate solution (10 gm in 200 ml). Reaction mixture was heated for 4 hrs at 60-65° C. with stirring. The material was filtered off and washed with 100 ml purified water four times (4×100 ml) and the wet cake was dried under vacuum tray dryer at 80-90° C. for 24 hrs and further dried in atmospheric tray dryer at 100° C. for 36 hrs till constant weight of dried polymer was obtained. The loss on drying of material was around 6% (Limit: 4-10%), achieved as per requirement. Sevelamer carbonate (7.5 gm) was obtained which can be sieved through 30 mesh for uniformity of the sample. Yield—75% w/w. Solid state ¹³C NMR shows prominent peak at 164 ppm which is for carbon of carbonate. [Chloride content: 0.02%, Phosphate binding: 5.56 mMole/g and Carbonate content: 4.74 meq/g].

Example 20

[0103]
10 g wet cake of Sevelamer carbonate was subjected to drying in air tray dryer at 80-100° C. at atmospheric pressure for 36 hours and LOD was measured after every five hours. LOD: 7.5% Yield: 3.1 gm

Example 21

[0104]
100 g wet cake of Sevelamer carbonate was subjected to drying in air tray dryer at 80-100° C. at atmospheric pressure for 37 hours and LOD was measured. LOD: 8.4% Yield: 30 gm

Example 22

[0105]
10 g wet cake of Sevelamer carbonate was subjected to drying in vacuum tray dryer at 50-100° C. at reduced pressure for 24 hours and LOD was measured. LOD: 8.5% Yield: 3.2 gm

Example 23

[0106]
100 g wet cake of Sevelamer carbonate was subjected to drying in vacuum tray dryer at 50-100° C. at reduced pressure for 24 hours and LOD was measured. LOD: 8.9% Yield: 31 gm

Example 24

[0107]
10 Kg wet cake of Sevelamer carbonate was subjected to drying in fluidized bed dryer at 80-100° C. for 16 hours and LOD was measured after every five hours. LOD: 7.9% Yield: 3.4 kg

Example 25

[0108]
15 Kg wet cake of Sevelamer carbonate was subjected to drying in fluidised bed dryer at 80-110° C. for 16 hours and LOD was measured. LOD: 8.8% Yield: 4.9 kg.

Example 26

[0109]
10 g wet cake of Sevelamer carbonate was subjected to drying in rotary evaporator at 50-100° C. at reduced pressure for 16 hours and LOD was measured after every five hours.
[0110]
LOD: 9.1% Yield: 3.1 gm

Example 27

[0111]
100 g wet cake of polyallylamine carbonate is subjected to drying in rotary evaporator at 50-100° C. at reduced pressure for 16 hours and LOD is measured. LOD: 8.9% Yield: 33 gm.

SYN

https://patents.google.com/patent/CN102675510A/enHyperphosphatemia is a kind of patient’s disease on one’s body that often appears at renal tubal dysfunction, hypothyroidism, acute acromegaly or phosphoric acid salt drug overdose; Its treatment is normal adopts the pharmacotherapy of regimen or oral phosphorus adsorbent to carry out; But it has been generally acknowledged that the regimen effect is relatively poor, the use of phosphorus adsorbent is essential.In recent years; Discover that the compound that contains the polyallylamine structure has good phosphorus adsorptive power (as: USP 5496545,20040191212, Chinese patent 95193521.6 etc.), crosslinked polyallylamine class medicine is evident in efficacy especially; Wherein, SEVELAMER (Sevelamer) is because of its good clinical manifestation, and granted listing is used to treat hyperphosphatemia.The structural formula of SEVELAMER is following:
Synthesizing of crosslinked polyallylamine class medicine SEVELAMER (Sevelamer); Be to react by polyallylamine hydrochloride and linking agent; Different because of used linking agent, the phosphorus adsorptive power of product has than big-difference, and the most option table chloropharin of the present document of reporting is a linking agent.For example: in USP 5496545; Introduced the synthetic of a series of crosslinked allyl amine polymers oral, that the phosphorus adsorptive power is arranged, listed linking agent has: Epicholorohydrin, 1,4-butanediol diglycidyl ether, 1; 2-ethylene glycol bisthioglycolate glycidyl ether, 1; 3-propylene dichloride, 1,2-ethylene dichloride, 1,3-dibromopropane, 1; 2-ethylene dibromide, succinyl dichloride, dimethyl succinate salt, TDI, acrylate chloride and pyromellitic dianhydride, preferred cross-linking agents is an Epicholorohydrin.U.S. Pat 5496545 described SEVELAMER building-up processes are: in the alkaline aqueous solution, polyallylamine hydrochloride and Epicholorohydrin carry out crosslinking reaction under room temperature, react agglutination thing after 18 hours; Pour into and make its curing in the Virahol; Filter, repeatedly washing back redispersion is in water, after the filtration; Be scattered in a large amount of Virahols, obtain product through filtration, drying.The required reaction times of this technology is longer, and multiple times of filtration and washing in the operating process need be used a large amount of organic solvents, and in the series product, the highest phosphorus adsorptive power is 3.1mmol/g.Embodiment 1: sevelamer hydrochloride syntheticIn the 500mL flask; Add 46.2g (0.374mol) PAH hydrochloride, the 108.0mL deionized water dissolving adds sodium hydroxide and regulates pH=10-11; Drip the toluene solution of 11.0g (0.042mol) 1-chloro-3-p-toluenesulfonyl-2-propyl alcohol, heat up in 70-75 ℃ of reaction 4 hours.Reaction finishes, and adds hydrochloric acid and regulates pH=1-2, filters, and obtains the sevelamer hydrochloride bullion.The sevelamer hydrochloride bullion is scattered in the 300.0mL deionized water, and hydro-oxidation sodium is regulated pH=10.0-11.0, filters; Deionized water wash; The gained white solid through pulverizing, gets product sevelamer hydrochloride 38.8g again 70 ℃ of vacuum-dryings 8 hours; The phosphorus adsorptive value is 5.5mmol/g, and chloride ion content is 16.5%.Embodiment 2: carbonic acid SEVELAMER syntheticIn the 500mL flask; Add 150.0g (0.404mol; Weight concentration is 30%) the PAH hydrochloride aqueous solution; Add sodium hydroxide and regulate pH=10-11, drip the acetonitrile solution of 13.0g (0.042mol) 1-bromo-3-p-toluenesulfonyl-2-propyl alcohol, heat up in 70-75 ℃ of reaction 4 hours.Reaction finishes, and adds hydrochloric acid and regulates pH=1-2, filters, and obtains the sevelamer hydrochloride bullion.The sevelamer hydrochloride bullion is scattered in the 300.0mL deionized water, adds yellow soda ash and regulate pH=8.5-9.5, filter; Deionized water wash, gained white solid are 70 ℃ of vacuum-dryings 8 hours, again through pulverizing; Get product carbonic acid SEVELAMER 36.4g, the phosphorus adsorptive value is 5.4mmol/g.Embodiment 3: carbonic acid SEVELAMER syntheticIn the 500mL flask; Add 46.2g (0.374mol) PAH hydrochloride, the 108.0mL deionized water dissolving adds sodium hydroxide and regulates pH=10-11; Drip the toluene solution of 7.9g (0.042mol) 1-chloro-3-methylsulfonyl-2-propyl alcohol, heat up in 70-75 ℃ of reaction 4 hours.Reaction finishes, and adds hydrochloric acid and regulates pH=1-2, filters, and obtains the sevelamer hydrochloride bullion.The sevelamer hydrochloride bullion is scattered in the 300.0mL deionized water, and hydro-oxidation sodium is regulated pH=12.0-12.5, feeds dioxide gas to saturated; Filter; Deionized water wash, gained white solid are 70 ℃ of vacuum-dryings 8 hours, again through pulverizing; Get product carbonic acid SEVELAMER 40.5g, the phosphorus adsorptive value is 5.0mmol/g.

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References

^ Ramsdell R (June 1999). “Renagel: a new and different phosphate binder”. review. ANNA Journal. 26 (3): 346–7. PMID 10633608.
^ Burke SK (September 2000). “Renagel: reducing serum phosphorus in haemodialysis patients”. review. Hospital Medicine. 61 (9): 622–7. doi:10.12968/hosp.2000.61.9.1419. PMID 11048603.
^ Habbous S, Przech S, Acedillo R, Sarma S, Garg AX, Martin J (January 2017). “The efficacy and safety of sevelamer and lanthanum versus calcium-containing and iron-based binders in treating hyperphosphatemia in patients with chronic kidney disease: a systematic review and meta-analysis”. review. Nephrology, Dialysis, Transplantation. 32 (1): 111–125. doi:10.1093/ndt/gfw312. PMID 27651467.
^ Patel L, Bernard LM, Elder GJ (February 2016). “Sevelamer Versus Calcium-Based Binders for Treatment of Hyperphosphatemia in CKD: A Meta-Analysis of Randomized Controlled Trials”. review. Clinical Journal of the American Society of Nephrology. 11 (2): 232–44. doi:10.2215/CJN.06800615. PMC 4741042. PMID 26668024.
^ Emmett M (September 2004). “A comparison of clinically useful phosphorus binders for patients with chronic kidney failure”. review. Kidney International Supplements. 66 (90): S25–32. doi:10.1111/j.1523-1755.2004.09005.x. PMID 15296504.
^ Locatelli F, Del Vecchio L (May 2015). “Cardiovascular mortality in chronic kidney disease patients: potential mechanisms and possibilities of inhibition by resin-based phosphate binders”. review. Expert Review of Cardiovascular Therapy. 13 (5): 489–99. doi:10.1586/14779072.2015.1029456. PMID 25804298. S2CID 32586527.
^ Vlassara H, Uribarri J (January 2014). “Advanced glycation end products (AGE) and diabetes: cause, effect, or both?”. review. Current Diabetes Reports. 14 (1): 453. doi:10.1007/s11892-013-0453-1. PMC 3903318. PMID 24292971.

External links

“Sevelamer”. Drug Information Portal. U.S. National Library of Medicine.
“Sevelamer hydrochloride”. Drug Information Portal. U.S. National Library of Medicine.
“Sevelamer carbonate”. Drug Information Portal. U.S. National Library of Medicine.

Clinical data

Pronunciation	(/sɛˈvɛləmər/ or /sɛˈvɛləmɪər/)
Trade names	Renagel, Renvela
AHFS/Drugs.com	Monograph
MedlinePlus	a601248
License data	EU EMA: by INNUS DailyMed: Sevelamer
Pregnancy category	AU: B3
Routes of administration	By mouth
ATC code	V03AE02 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)US: ℞-onlyEU: Rx only
Pharmacokinetic data
Bioavailability	0%
Excretion	Feces 100%
Identifiers
show IUPAC name
CAS Number	52757-95-6
PubChem CID	3085017
DrugBank	DB00658
ChemSpider	2341997
UNII	941N5DUU5C
KEGG	D08512as HCl: D01983
ChEMBL	ChEMBL1201492
CompTox Dashboard (EPA)	DTXSID80872282
Chemical and physical data
Formula	[(C₃H₇N)_a+b.(C₉H₁₇N₂O)_c]_m where a+b:c = 9:1
Molar mass	variable
(what is this?) (verify)

//////////////////////SEVELAMER, HSDB 7608, GT335-012, GT 16-026A, PB 94, Antihyperphosphatemic

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METHOCARBAMOL

December 21, 2021 10:35 am / Leave a comment

Methocarbamol

Molecular FormulaC₁₁H₁₅NO₅
Average mass241.240 Da
метокарбамол , ميثوكاربامول , 美索巴莫

1,2-Propanediol, 3-(2-methoxyphenoxy)-, 1-carbamate
208-524-3[EINECS]
2-Hydroxy-3-(2-methoxyphenoxy)propyl carbamate
532-03-6[RN]
MethocarbamolCAS Registry Number: 532-03-6
CAS Name: 3-(2-Methoxyphenoxy)-1,2-propanediol 1-carbamate
Additional Names: 3-(o-methoxyphenoxy)-2-hydroxypropyl 1-carbamate; 2-hydroxy-3-(o-methoxyphenoxy)propyl 1-carbamate; guaiacol glyceryl ether carbamate
Manufacturers’ Codes: AHR-85Trademarks: Neuraxin; Miolaxene (Lepetit); Lumirelax; Etroflex; Delaxin (Ferndale); Robamol (Cenci); Traumacut (Brenner-Efeka); Tresortil; Relestrid; Robaxin (Robins)
Molecular Formula: C11H15NO5, Molecular Weight: 241.24Percent Composition: C 54.77%, H 6.27%, N 5.81%, O 33.16%
Literature References: Prepn from 3-(o-methoxyphenoxy)-2-hydroxypropyl chlorocarbonate: Murphey, US2770649 (1956 to A. H. Robins). Comprehensive description: S. Alessi-Severini et al.,Anal. Profiles Drug Subs. Excip.23, 371-399 (1994).
Properties: Crystals from benzene, mp 92-94°. uv max (water): 222, 274 nm (E1%1cm 298, 94). 1og P -0.06. Soly in water at 20°: 2.5 g/100 ml. Sol in alcohol, propylene glycol. Sparingly sol in chloroform. Practically insol in n-hexane.
Melting point: mp 92-94°
Absorption maximum: uv max (water): 222, 274 nm (E1%1cm 298, 94)
Therap-Cat: Muscle relaxant (skeletal).
Therap-Cat-Vet: Muscle relaxant (skeletal).
Keywords: Muscle Relaxant (Skeletal).

Methocarbamol, sold under the brand name Robaxin among others, is a medication used for short-term musculoskeletal pain.^[3]^[4] It may be used together with rest, physical therapy, and pain medication.^[3]^[5]^[6] It is less preferred in low back pain.^[3] It has limited use for rheumatoid arthritis and cerebral palsy.^[3]^[7] Effects generally begin within half an hour.^[3] It is taken by mouth or injection into a vein.^[3]

Methocarbamol is a CNS depressant indicated with rest, physical therapy and other treatments to control the discomfort associated with various acute musculoskeletal conditions.

Methocarbamol was developed in the early 1950s as a treatment for muscle spasticity and the associated pain.^6,7 It is a guaiacol glyceryl ether.⁷

Methocarbamol tablets and intramuscular injections are prescription medicines indicated in the United States as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions.^Label,9 In Canada, methocarbamol can be sold as an over the counter oral medicine at a lower dose that may be combined with acetaminophen or ibuprofen.¹⁰ A combination product with acetylsalicylic acid and codeine is available in Canada by prescription.¹⁰

Methocarbamol was FDA approved on 16 July 1957.⁸

Common side effect include headaches, sleepiness, and dizziness.^[3]^[8] Serious side effects may include anaphylaxis, liver problems, confusion, and seizures.^[4] Use is not recommended in pregnancy and breastfeeding.^[3]^[4] Because of risk of injury, skeletal muscle relaxants should generally be avoided in geriatric patients.^[3] Methocarbamol is a centrally acting muscle relaxant.^[3] How it works is unclear, but it does not appear to affect muscles directly.^[3]

Methocarbamol was approved for medical use in the United States in 1957.^[3] It is available as a generic medication.^[3]^[4] It is relatively inexpensive as of 2016.^[9] In 2019, it was the 136th most commonly prescribed medication in the United States, with more than 4 million prescriptions.^[10]^[11]

SYN

CN 109970606

SYN

Synthesis of methocarbamol from guaifenesin. (a) methocarbamol and (b) β-isomer of methocarbamol.

SYN

https://www.sciencedirect.com/science/article/abs/pii/S0957416607003801

The muscle relaxant methocarbamol 2 and tranquilizer mephenoxalone 3, as well as intermediate cyclic carbonate 4, have been prepared in enantiopure form by starting from enantiopure guaifenesin 1 easily available by an entrainment resolution procedure. Thermal investigations reveal that 2 is probably a conglomerate forming substance, 3 forms a stable racemic compound, and 4 occupies an intermediate position. The enantiomeric excess of a binary phase eutectic point for these substances comprises 0%, 85%, and 10%, respectively.

Graphical abstract

PATENT

US 2770649

https://patents.google.com/patent/US2770649A/en

PAPER

Journal of pharmaceutical sciences (1970), 59(7), 1043-4

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Medical use

Methocarbamol is a muscle relaxant used to treat acute, painful musculoskeletal spasms in a variety of musculoskeletal conditions.^[12] However, there is limited and inconsistent published research on the medication’s efficacy and safety in treating musculoskeletal conditions, primarily neck and back pain.^[12]

Methocarbamol injection may have a beneficial effect in the control of the neuromuscular spasms of tetanus.^[6] It does not, however, replace the current treatment regimen.^[6]

It is not useful in chronic neurological disorders, such as cerebral palsy or other dyskinesias.^[3]

Currently, there is some suggestion that muscle relaxants may improve the symptoms of rheumatoid arthritis; however, there is insufficient data to prove its effectiveness as well as answer concerns regarding optimal dosing, choice of muscle relaxant, adverse effects, and functional status.^[7]

Comparison to similar agents

The clinical effectiveness of methocarbamol compared to other muscle relaxants is not well-known.^[12] One trial of methocarbamol versus cyclobenzaprine, a well-studied muscle relaxant, in those with localized muscle spasm found there was no significant differences in their effects on improved muscle spasm, limitation of motion, or limitation of daily activities.^[12]

Contraindications

There are few contraindications to methocarbamol. They include:

Hypersensitivity to methocarbamol or to any of the injection components.^[6]
For the injectable form, suspected kidney failure or renal pathology, due to large content of polyethylene glycol 300 that can increase pre-existing acidosis and urea retention.^[6]

Side effects

Methocarbamol is a centrally acting skeletal muscle relaxant that has significant adverse effects, especially on the central nervous system.^[3]

Potential side effects of methocarbamol include:

Most commonly drowsiness, blurred vision, headache, nausea, and skin rash.^[8]
Possible clumsiness (ataxia), upset stomach, flushing, mood changes, trouble urinating, itchiness, and fever.^[13]^[14]
Both tachycardia (fast heart rate) and bradycardia (slow heart rate) have been reported.^[14]
Hypersensitivity reactions and anaphylatic reactions are also reported.^[5]^[6]
May cause respiratory depression when combined with benzodiazepines, barbiturates, codeine, or other muscle relaxants.^[15]
May cause urine to turn black, blue or green.^[13]

While the product label states that methocarbamol can cause jaundice, there is minimal evidence to suggest that methocarbamol causes liver damage.^[8] During clinical trials of methocarbamol, there were no laboratory measurements of liver damage indicators, such as serum aminotransferase (AST/ALT) levels, to confirm hepatotoxicity.^[8] Although unlikely, it is impossible to rule out that methocarbamol may cause mild liver injury with use.^[8]

Elderly

Skeletal muscle relaxants are associated with an increased risk of injury among older adults.^[16] Methocarbamol appeared to be less sedating than other muscle relaxants, most notably cyclobenzaprine, but had similar increased risk of injury.^[15]^[16] Methocarbamol is cited along with “most muscle relaxants” in the 2012 Beers Criteria as being “poorly tolerated by older adults, because of anticholinergic adverse effects, sedation, increased risk of fractures,” noting that “effectiveness dosages tolerated by older adults is questionable.”^[17]

Pregnancy

Methocarbamol is labeled by the FDA as a pregnancy category C medication.^[6] The teratogenic effects of the medication are not known and should be given to pregnant women only when clearly indicated.^[6]

Overdose

There is limited information available on the acute toxicity of methocarbamol.^[5]^[6] Overdose is used frequently in conjunction with CNS depressants such as alcohol or benzodiazepines and will have symptoms of nausea, drowsiness, blurred vision, hypotension, seizures, and coma.^[6] There are reported deaths with an overdose of methocarbamol alone or in the presence of other CNS depressants.^[5]^[6]

Abuse

Unlike other carbamates such as meprobamate and its prodrug carisoprodol, methocarbamol has greatly reduced abuse potential.^[18] Studies comparing it to the benzodiazepine lorazepam and the antihistamine diphenhydramine, along with placebo, find that methocarbamol produces increased “liking” responses and some sedative-like effects; however, at higher doses dysphoria is reported.^[18] It is considered to have an abuse profile similar to, but weaker than, lorazepam.^[18]

Interactions

Methocarbamol may inhibit the effects of pyridostigmine bromide.^[5]^[6] Therefore, methocarbamol should be used with caution in those with myasthenia gravis taking anticholinesterase medications.^[6]

Methocarbamol may disrupt certain screening tests as it can cause color interference in laboratory tests for 5-hydroxy-indoleacetic acid (5-HIAA) and in urinary testing for vanillylmandelic acid (VMA) using the Gitlow method.^[6]

Pharmacology

Mechanism of action

The mechanism of action of methocarbamol has not currently been established.^[3] Its effect is thought to be localized to the central nervous system rather than a direct effect on skeletal muscles.^[3] It has no effect on the motor end plate or the peripheral nerve fiber.^[6] The efficacy of the medication is likely related to its sedative effect.^[3] Alternatively, methocarbamol may act via inhibition of acetylcholinesterase, similarly to carbamate.^[19]

Pharmacokinetics

In healthy individuals, the plasma clearance of methocarbamol ranges between 0.20 and 0.80 L/h/kg.^[6] The mean plasma elimination half-life ranges between 1 and 2 hours, and the plasma protein binding ranges between 46% and 50%.^[6] The elimination half-life was longer in the elderly, those with kidney problems, and those with liver problems.^[6]

Metabolism

Methocarbamol is the carbamate derivative of guaifenesin, but does not produce guaifenesin as a metabolite, because the carbamate bond is not hydrolyzed metabolically;^[8]^[6] its metabolism is by Phase I ring hydroxylation and O-demethylation, followed by Phase II conjugation.^[6] All the major metabolites are unhydrolyzed carbamates.^[20]^[21] Small amounts of unchanged methocarbamol are also excreted in the urine.^[5]^[6]

Society and culture

Methocarbamol was approved as a muscle relaxant for acute, painful musculoskeletal conditions in the United States in 1957.^[8] Muscle relaxants are widely used to treat low back pain, one of the most frequent health problems in industrialized countries. Currently, there are more than 3 million prescriptions filled yearly.^[8] Methocarbamol and orphenadrine are each used in more than 250,000 U.S. emergency department visits for lower back pain each year.^[22] In the United States, low back pain is the fifth most common reason for all physician visits and the second most common symptomatic reason.^[23] In 80% of primary care visits for low back pain, at least one medication was prescribed at the initial office visit and more than one third were prescribed two or more medications.^[24] The most commonly prescribed drugs for low back pain included skeletal muscle relaxants.^[25] Cyclobenzaprine and methocarbamol are on the U.S. Medicare formulary, which may account for the higher use of these products.^[16]

Economics

The generic formulation of the medication is relatively inexpensive, costing less than the alternative metaxalone in 2016.^[26]^[9]

Marketing

Generic methocarbamol 750mg tablet.

Methocarbamol without other ingredients is sold under the brand name Robaxin in the U.K., U.S., Canada^[27] and South Africa; it is marketed as Lumirelax in France, Ortoton in Germany and many other names worldwide.^[28] In combination with other active ingredients it is sold under other names: with acetaminophen (paracetamol), under trade names Robaxacet and Tylenol Body Pain Night; with ibuprofen as Robax Platinum; with acetylsalicylic acid as Robaxisal in the U.S. and Canada.^[29]^[30] However, in Spain the tradename Robaxisal is used for the paracetamol combination instead of Robaxacet.^{[citation needed]} These combinations are also available from independent manufacturers under generic names.^{[citation needed]}

Research

Although opioids are a typically first line in treatment of severe pain, several trials suggest that methocarbamol may improve recovery and decrease hospital length of stay in those with muscles spasms associated with rib fractures.^[31]^[32]^[33] However, methocarbamol was less useful in the treatment of acute traumatic pain in general.^[34]

Long-term studies evaluating the risk of development of cancer in using methocarbamol have not been performed.^[5]^[6] There are currently no studies evaluating the effect of methocarbamol on mutagenesis or fertility.^[5]^[6]

The safety and efficacy of methocarbamol has not been established in pediatric individuals below the age of 16 except in tetanus.^[5]^[6]

References

^ “Robaxin-750 – Summary of Product Characteristics (SmPC)”. (emc). 8 August 2017. Retrieved 19 April 2020.
^ Sica DA, Comstock TJ, Davis J, Manning L, Powell R, Melikian A, Wright G (1990). “Pharmacokinetics and protein binding of methocarbamol in renal insufficiency and normals”. European Journal of Clinical Pharmacology. 39 (2): 193–4. doi:10.1007/BF00280060. PMID 2253675. S2CID 626920.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r “Methocarbamol Monograph for Professionals”. Drugs.com. American Society of Health-System Pharmacists.
^ Jump up to:^a ^b ^c ^d British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 1093. ISBN 9780857113382.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ “Robaxin- methocarbamol tablet, film coated”. DailyMed. 18 July 2019. Retrieved 19 April 2020.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x “Robaxin- methocarbamol injection”. DailyMed. 10 December 2018. Retrieved 19 April 2020.
^ Jump up to:^a ^b Richards, Bethan L.; Whittle, Samuel L.; Buchbinder, Rachelle (18 January 2012). “Muscle relaxants for pain management in rheumatoid arthritis”. The Cochrane Database of Systematic Reviews. 1: CD008922. doi:10.1002/14651858.CD008922.pub2. ISSN 1469-493X. PMID 22258993.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “Methocarbamol”. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 30 January 2017. PMID 31643609.
^ Jump up to:^a ^b Fine, Perry G. (2016). The Hospice Companion: Best Practices for Interdisciplinary Care of Advanced Illness. Oxford University Press. p. PT146. ISBN 978-0-19-045692-4.
^ “The Top 300 of 2019”. ClinCalc. Retrieved 16 October 2021.
^ “Methocarbamol – Drug Usage Statistics”. ClinCalc. Retrieved 16 October 2021.
^ Jump up to:^a ^b ^c ^d Chou, Roger; Peterson, Kim; Helfand, Mark (August 2004). “Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review”. Journal of Pain and Symptom Management. 28 (2): 140–175. doi:10.1016/j.jpainsymman.2004.05.002. ISSN 0885-3924. PMID 15276195.
^ Jump up to:^a ^b “Methocarbamol”. MedlinePlus. Retrieved 18 April 2020.
^ Jump up to:^a ^b “Methocarbamol Side Effects: Common, Severe, Long Term”. Drugs.com. Retrieved 18 April 2020.
^ Jump up to:^a ^b See, Sharon; Ginzburg, Regina (1 August 2008). “Choosing a skeletal muscle relaxant”. American Family Physician. 78 (3): 365–70. ISSN 0002-838X. PMID 18711953.
^ Jump up to:^a ^b ^c Spence, Michele M.; Shin, Patrick J.; Lee, Eric A.; Gibbs, Nancy E. (July 2013). “Risk of injury associated with skeletal muscle relaxant use in older adults”. The Annals of Pharmacotherapy. 47 (7–8): 993–8. doi:10.1345/aph.1R735. ISSN 1542-6270. PMID 23821610. S2CID 9037478.
^ “Beers Criteria Medication List”. DCRI. Retrieved 18 October 2020.
^ Jump up to:^a ^b ^c Preston KL, Wolf B, Guarino JJ, Griffiths RR (1992). “Subjective and behavioral effects of diphenhydramine, lorazepam and methocarbamol: evaluation of abuse liability”. Journal of Pharmacology and Experimental Therapeutics. 262 (2): 707–20. PMID 1501118.
^ PubChem. “Methocarbamol”. pubchem.ncbi.nlm.nih.gov. Retrieved 6 July 2020.
^ Methocarbamol. In: DRUGDEX System [intranet database]. Greenwood Village, Colorado: Thomson Healthcare; c1974–2009 [cited 2009 Feb 10].
^ Bruce RB, Turnbull LB, Newman JH (January 1971). “Metabolism of methocarbamol in the rat, dog, and human”. J Pharm Sci. 60 (1): 104–6. doi:10.1002/jps.2600600120. PMID 5548215.
^ Friedman BW, Cisewski D, Irizarry E, Davitt M, Solorzano C, Nassery A, et al. (March 2018). “A Randomized, Double-Blind, Placebo-Controlled Trial of Naproxen With or Without Orphenadrine or Methocarbamol for Acute Low Back Pain”. Annals of Emergency Medicine. 71 (3): 348–356.e5. doi:10.1016/j.annemergmed.2017.09.031. ISSN 1097-6760. PMC 5820149. PMID 29089169.
^ Chou, Roger; Huffman, Laurie Hoyt (2 October 2007). “Medications for Acute and Chronic Low Back Pain: A Review of the Evidence for an American Pain Society/American College of Physicians Clinical Practice Guideline”. Annals of Internal Medicine. 147 (7): 505–14. doi:10.7326/0003-4819-147-7-200710020-00008. ISSN 0003-4819. PMID 17909211. S2CID 32719708.
^ Cherkin, D. C.; Wheeler, K. J.; Barlow, W.; Deyo, R. A. (1 March 1998). “Medication use for low back pain in primary care”. Spine. 23 (5): 607–14. doi:10.1097/00007632-199803010-00015. ISSN 0362-2436. PMID 9530793. S2CID 23664539.
^ Luo, Xuemei; Pietrobon, Ricardo; Curtis, Lesley H.; Hey, Lloyd A. (1 December 2004). “Prescription of nonsteroidal anti-inflammatory drugs and muscle relaxants for back pain in the United States”. Spine. 29 (23): E531–7. doi:10.1097/01.brs.0000146453.76528.7c. ISSN 1528-1159. PMID 15564901. S2CID 72742439.
^ Robbins, Lawrence D. (2013). Management of Headache and Headache Medications. Springer Science & Business Media. p. PT147. ISBN 978-1-4612-2124-1.
^ “ROBAXIN product appearance in Canada”. ctchealth.ca. Retrieved 13 December 2021.
^ “Methocarbamol”. Drugs.com. Retrieved 12 May 2018.
^ “New Drugs and Indications Reviewed at the May 2003 DEC Meeting” (PDF). ESI Canada. Archived from the original (PDF) on 10 July 2011. Retrieved 14 November 2008.
^ “Tylenol Body Pain Night Overview and Dosage”. Tylenol Canada. Archived from the original (website) on 31 March 2012. Retrieved 23 April 2012.
^ Patanwala, Asad E.; Aljuhani, Ohoud; Kopp, Brian J.; Erstad, Brian L. (October 2017). “Methocarbamol use is associated with decreased hospital length of stay in trauma patients with closed rib fractures”. The American Journal of Surgery. 214 (4): 738–42. doi:10.1016/j.amjsurg.2017.01.003. ISSN 0002-9610. PMID 28088301.
^ Deloney, Lindsay; Smith, Melanie; Carter, Cassandra; Privette, Alicia; Leon, Stuart; Eriksson, Evert (January 2020). “946: Methocarbamol reduces opioid use and length of stay in young adults with traumatic rib fractures”. Critical Care Medicine. 48 (1): 452. doi:10.1097/01.ccm.0000633320.62811.06. ISSN 0090-3493.
^ Smith, Melanie; Deloney, Lindsay; Carter, Cassandra; Leon, Stuart; Privette, Alicia; Eriksson, Evert (January 2020). “1759: Use of methocarbamol in geriatric patients with rib fractures is associated with improved outcomes”. Critical Care Medicine. 48 (1): 854. doi:10.1097/01.ccm.0000649332.10326.98. ISSN 0090-3493.
^ Aljuhani, Ohoud; Kopp, Brian J.; Patanwala, Asad E. (2017). “Effect of Methocarbamol on Acute Pain After Traumatic Injury”. American Journal of Therapeutics. 24 (2): e202–6. doi:10.1097/mjt.0000000000000364. ISSN 1075-2765. PMID 26469684. S2CID 24284482.

External links

“Methocarbamol”. Drug Information Portal. U.S. National Library of Medicine.

Clinical data

Trade names	Robaxin, Marbaxin, others
AHFS/Drugs.com	Monograph
MedlinePlus	a682579
License data	US DailyMed: Methocarbamol
Pregnancy category	AU: B2
Routes of administration	By mouth, intravenous
ATC code	M03BA03 (WHO) M03BA53 (WHO) M03BA73 (WHO)
Legal status
Legal status	CA: OTCUK: POM (Prescription only) ^[1]US: ℞-only
Pharmacokinetic data
Metabolism	Liver
Elimination half-life	1.14–1.24 hours^[2]
Identifiers
show IUPAC name
CAS Number	532-03-6
PubChem CID	4107
IUPHAR/BPS	6829
DrugBank	DB00423
ChemSpider	3964
UNII	125OD7737X
KEGG	D00402
ChEBI	CHEBI:6832
ChEMBL	ChEMBL1201117
CompTox Dashboard (EPA)	DTXSID6023286
ECHA InfoCard	100.007.751
Chemical and physical data
Formula	C₁₁H₁₅NO₅
Molar mass	241.243 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI
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Sica DA, Comstock TJ, Davis J, Manning L, Powell R, Melikian A, Wright G: Pharmacokinetics and protein binding of methocarbamol in renal insufficiency and normals. Eur J Clin Pharmacol. 1990;39(2):193-4. [Article]
Bruce RB, Turnbull LB, Newman JH: Metabolism of methocarbamol in the rat, dog, and human. J Pharm Sci. 1971 Jan;60(1):104-6. [Article]
Witenko C, Moorman-Li R, Motycka C, Duane K, Hincapie-Castillo J, Leonard P, Valaer C: Considerations for the appropriate use of skeletal muscle relaxants for the management of acute low back pain. P T. 2014 Jun;39(6):427-35. [Article]
Crankshaw DP, Raper C: Mephenesin, methocarbamol, chlordiazepoxide and diazepam: actions on spinal reflexes and ventral root potentials. Br J Pharmacol. 1970 Jan;38(1):148-56. doi: 10.1111/j.1476-5381.1970.tb10343.x. [Article]
Muir WW 3rd, Sams RA, Ashcraft S: The pharmacology and pharmacokinetics of high-dose methocarbamol in horses. Equine Vet J Suppl. 1992 Feb;(11):41-4. [Article]
Authors unspecified: Methocarbamol-A New Lissive Agent. Can Med Assoc J. 1958 Dec 15;79(12):1008-9. [Article]
O’DOHERTY DS, SHIELDS CD: Methocarbamol; new agent in treatment of neurological and neuromuscular diseases. J Am Med Assoc. 1958 May 10;167(2):160-3. [Article]
FDA Approved Drug Products: Robaxin [Link]
FDA Approved Drug Products: Robaxin Intramuscular Injection [Link]
Pfizer Canada: Robax [Link]

////////////////Methocarbamol, метокарбамол , ميثوكاربامول , 美索巴莫, AHS 85, Muscle Relaxant

COC1=C(OCC(O)COC(N)=O)C=CC=C1

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L-CARNOSINE

December 21, 2021 5:05 am / Leave a comment

L-CARNOSINE

Molecular FormulaC₉H₁₄N₄O₃
Average mass226.232 Da

(2S)-2-(3-aminopropanamido)-3-(1H-imidazol-5-yl)propanoic acid
(E)-N-(3-Amino-1-hydroxypropylidene)-L-histidine [ACD/IUPAC Name]
206-169-9[EINECS], 305-84-0[RN]
8HO6PVN24Wカルノシン , Dragosine, Ignotin, Ignotine, Karnozin, L-Carnosine, N-(β-Alanyl)-L-histidine, NSC 524045, Sevitin, β-Alanylhistidine
CarnosineCAS Registry Number: 305-84-0CAS Name: b-Alanyl-L-histidine
Additional Names: ignotine
Molecular Formula: C9H14N4O3, Molecular Weight: 226.23
Percent Composition: C 47.78%, H 6.24%, N 24.77%, O 21.22%
Literature References: Naturally occurring dipeptide found in large amounts in skeletal muscle. Also present in other tissues such as brain, cardiac muscle, kidney. Water soluble antioxidant; functions as a free-radical scavenger. Isoln: Gulewitsch, Amiradzibi, Ber.33, 1902 (1900); Wolff, Wilson, J. Biol. Chem.95, 495 (1932); 109, 565 (1935). Synthesis from histidine and b-iodo- or b-nitropropionyl chloride: Baumann, Ingvaldsen, ibid.35, 271 (1918); Barger, Tutin, Biochem. J.12, 406 (1918). Later syntheses: Sifford, du Vigneaud, J. Biol. Chem.108, 753 (1935); R. A. Turner, J. Am. Chem. Soc.75, 2388 (1953); F. J. Vinick, S. Jung, J. Org. Chem.48, 392 (1983). Crystal structure: H. Itoh et al.,Acta Crystallogr.33B, 2959 (1977). Possible role in wound healing: D. E. Fischer et al.,Proc. Soc. Exp. Biol. Med.158, 402 (1978). Review of physiological properties and therapeutic potential: S. E. Gariballa, A. J. Sinclair, Age Ageing29, 207-210 (2000).
Properties: Crystals from aqueous ethanol, mp 262° (dec) (Vinick, Jung); also reported as mp 260° (capillary tube) and as mp 308-309° (Dennis bar) (Sifford, du Vigneaud). [a]D25 +21.0° (c = 1.5 in water). pK1 2.64; pK2 6.83; pK3 9.51. Alkaline reaction. One gram dissolves in 3.1 ml water at 25°.
Melting point: mp 262° (dec) (Vinick, Jung); mp 260° (capillary tube) and as mp 308-309° (Dennis bar) (Sifford, du Vigneaud)
pKa: pK1 2.64; pK2 6.83; pK3 9.51
Optical Rotation: [a]D25 +21.0° (c = 1.5 in water)
Derivative Type: Nitrate
CAS Registry Number: 5852-98-2
Molecular Formula: C9H15N5O6, Molecular Weight: 289.25
Percent Composition: C 37.37%, H 5.23%, N 24.21%, O 33.19%
Properties: Crystals, dec 222°. [a]D20 +24.1° (c = 1.5 in water). Very sol in water.
Optical Rotation: [a]D20 +24.1° (c = 1.5 in water)
Derivative Type: Hydrochloride
CAS Registry Number: 5852-99-3
Molecular Formula: C9H15ClN4O3, Molecular Weight: 262.69
Percent Composition: C 41.15%, H 5.76%, Cl 13.50%, N 21.33%, O 18.27%
Properties: Crystals, dec 245°. Very sol in water.
Derivative Type: D-Form
CAS Registry Number: 5853-00-9
Properties: Crystals, mp 260°. [a]D28 -20.4° (c = 1.5).
Melting point: mp 260°
Optical Rotation: [a]D28 -20.4° (c = 1.5)

Carnosine (beta-alanyl-L-histidine) is a dipeptide molecule, made up of the amino acids beta-alanine and histidine. It is highly concentrated in muscle and brain tissues.^{[citation needed]} Carnosine was discovered by Russian chemist Vladimir Gulevich.^[2]

Carnosine is naturally produced by the body in the liver^[3] from beta-alanine and histidine. Like carnitine, carnosine is composed of the root word carn, meaning “flesh”, alluding to its prevalence in meat.^[4] There are no plant-based sources of carnosine,^[5] however synthetic supplements do exist.

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

SYN

WO2009033754 PAGE: 98 claimed protein

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009033754

SYN

US 4446149 A 1984

JP 02221230 A 1990

Showa Igakkai Zasshi 1974, V34(3), P271-83

Russian Journal of General Chemistry 2007, V77(9), P1576-1579

Chemische Berichte 1961, V94, P2768-78

Farmaco, Edizione Scientifica 1968, V23(9), P859-69

Paper

Journal of the American Chemical Society 1953, V75, P2388-90

+21.9 °

Conc: 3.0 g/100mL;water ; Wavlenght: 589.3 nm; Temp: 20 °C

Annali di Chimica (Rome, Italy) 1968, V58(11), P1431-4

DE 3540632 A1 1986

Z. physiol. Chem. 1914, V87, P1-11

PAPER

Chemistry – A European Journal (2003), 9, (8), 1714-1723.

PAPER

Journal of Magnetic Resonance (2003), 164, (2), 256-269.

SYN

WO 2001064638

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2001064638

Example 1
(S) -2- (Cyanoacetylamino) -3- (l_ * H-imidazol-4-yl) propionic acid, sodium salt

To a solution of sodium ethoxide obtained by dissolving 5.57 g (0.24 mol) of sodium in 800 ml of ethanol was added 40.0 g (0.26 mol) of L-histidine at room temperature. After 15 minutes, 44.12 g (0.39 mol) of ethyl cyanoacetate were added and the suspension was refluxed for 16 hours. After cooling to room temperature, the mixture was filtered. The yellowish filtrate was concentrated in vacuo, the residue was slurried in ethyl acetate, filtered, washed with ethyl acetate and purified by flash chromatography on silica gel (eluent: gradient ethyl acetate → methanol / ethyl acetate 3: 1).
Yield: 28.42 g (46%)
1HNMR (DMSO- ^ ₆, 00 MHz): δ = 8,28 (d, 1H); 7,45 (s, 1H); 6,7 (s, 1H); 5,5 (br. s, 1H); 4,12-4,20 (m, 1H); 3,65 (s, 2H); 2,95-3,05 (m, 1H); 2,8-2,9 (m, 1H).
¹³C NMR (DMSO- ₆, 100 MHz): δ = 174,05; 161,09; 134,25; 131,97; 119,66; 116,43; 54,83; 29,13; 25,20.

Example 2
(• S) -2- (Cyanoacetylamino) -3- (1-δ-imidazol-4-yl) propionic acid, sodium salt

9.80 g of sodium hydride (60% in mineral oil) and 50.6 g
(0.51 mol) were added at room temperature to a suspension of 40.0 g (0.26 mol) of L-histidine in 750 ml of N, N-dimethylformamide Given methyl cyanoacetate. The mixture was heated to 155 ° C. for 2 h in an open flask and the solution thus obtained was analyzed by means of HPLC.
Histidine (8 area%) and (S) -2- (cyanoacetylamino) -3- (1H-imidazol-4-yl) propionic acid sodium salt (38 area%) were identified.

Example 3
(S) -2- (Cyanoacetylamino) -3- (l-ö ^r -imidazol-4-yl) propionic acid

To a solution of sodium ethoxide obtained by dissolving 4.02 g (0.175 mol) of sodium in 280 ml of ethanol, 28.27 g (0.18 mol) of L-Ηistidine were added at room temperature. The mixture was heated slowly and 30.92 g (0.27 mol) of ethyl cyanoacetate were added dropwise at a temperature of 60.degree. The mixture was heated further and the ethanol was distilled off, the amount of ethanol distilled off being continuously replaced in portions by N, N-dimethylformamide. At the end of the reaction, the temperature of the solution was 130 ° C. The mixture was stirred at this temperature for a further 2 hours. The brown reaction mixture (200 g) was cooled to 50 ° C. and 30 g of concentrated hydrochloric acid were metered in. About 70 g of solvent (Η ₂O / N, N-dimethylformamide mixture) distilled off. The viscous suspension was mixed with 200 g of acetone, cooled to -10 ° C. and filtered. For recrystallization, the residue was dissolved in water and the pH was adjusted to 5.0. On cooling (<5 ° C.) a white solid precipitated out, which was filtered off, washed with ethanol and dried at 40 ° C./20 mbar.
Yield: 26.39 g (66%).
IR (KBr): v = 3421, 3240, 3149, 3059, 2970, 2255, 1653, 1551, 1396, 1107, 1088, 979, 965, 826, 786, 638 cm ^{is “1} .
1HΝMR (DMSO-c ₆ , 400 MHz): δ = 11.0 (br., 2H); 8.50 (d, 1H); 7.68 (s, 1H); 6.85 (s, 1H); 4.35-4.48 ( m, 1H); 3.68 (s, 2H); 2.92-3.03 (, 1H); 2.82-2.91 (m, 1H).

¹³ C NMR (DMSO- ₆ , 100 MHz): δ = 172.23; 161.92; 134.55; 132.70; 116.73; 115.87; 52.80; 28.68; 25.06.
LC-MS: mlz = 223 ([M + H]), 205, 177, 156, 110.
The optical purity was determined to be> 99.8% on a sample obtained according to the above procedure. The determination was carried out by hydrolysis of the amide bond (6 N hydrochloric acid, 110 ° C., 24 h), followed by derivatization of the released histidine with trifluoroacetic anhydride and isobutyl chloroformate. A D-histidine content of <0.1% was detected by gas chromatography on a chiral stationary phase.

Example 4
L-Carnosine

To a solution of 1.90 g (7.8 mmol) of (<S) -2- (cyanoacetylamino) -3- (1H-imidazol-4-yl) propionic acid sodium salt (prepared according to Example 1) in 50 ml of ethanol / conc.
Ammonia solution (V: V- 4: 1) were given 0.3 g of rhodium / activated charcoal (5% Rh). The

The mixture was hydrogenated at 110 ° C. and 45 bar for 1 hour. The catalyst was then filtered off and the filtrate was adjusted to pH 8.2 with formic acid. After the solution had been concentrated in vacuo, the residue was suspended in 200 ml of ethanol and heated to 60 ° C. for 30 minutes. The product was filtered off, washed successively with ethanol, ethyl acetate and diethyl ether and finally dried.
Yield: 1.33 g (76%)
1H NMR (D ₂ O, 400 MΗz): δ = 7.70 (s, 1Η); 6.93 (s, 1Η); 4.43-4.50 (m, 1Η); 3.20-3.28 (m, 2Η); 3.11-3.19 (m, 1H); 2.95-3.03 (m, 1H); 2.61-2.71 (m, 2H).
The optical purity was determined by the method described in Example 3 to be 99.5%.

Example 5
(S) -2- (Cyanoacetylamino) -3- (1-O-imidazol-4-yl) propionic acid methyl ester

To a solution of sodium methoxide obtained by dissolving 0.94 g (40.7 mmol; 1.95 equiv.) Of sodium in 100 ml of methanol, 5.0 g (20.4 mmol) were added at room temperature

L-histidine methyl ester dihydrochloride added. After 30 minutes, 3.03 g
(30.6 mmol) of methyl cyanoacetate were added and the mixture was left on for 16 hours

Boiled under reflux. After cooling to room temperature, the mixture was filtered.

The yellowish filtrate was concentrated in vacuo and the residue was purified by means of flash chromatography on silica gel (eluent: gradient ethyl acetate – »ethyl acetate / methanol 3: 1).
Yield: 1.51 g (31%)
1H MR (OMSO-de, 400 MHz): δ = 8.65 (d, 1H); 7.52 (s. 1H); 6.8 (s, 1H); 4.45 ^ 1.55 (m,

1H); 3,69 (s, 2H); 3,62 (s, 3H); 3,3 (br., 1H); 2,82-2,98 (m, 2H).

Example 6
L-Carnosine

1.76 g of Rh / C (0.4 mol% of pure Rh based on the starting material used) in a mixture of 94.2 g of ammonia solution (25% in H ₂ O) and 62.8 g of methanol were placed in a 1 liter pressure autoclave . The autoclave was closed, the contents were heated to 90 ° C. and 40 bar hydrogen was injected. A solution of 20.0 g (0.09 mol) (* S) -2- (cyanoacetylamino) -3- (1H-imidazol-4-yl) propionic acid (prepared according to Example 3) was then within one hour Mixture 94.2 g ammonia solution (25% in Η ₂O) and 62.8 g of methanol are metered in. After a one hour post-reaction at 90 ° C., the reaction mixture was cooled to room temperature. The pressure in the autoclave was released and the catalyst was filtered off over activated charcoal. An HPLC in-process analysis showed that the clear greenish reaction solution (326.2 g) contained 5.74% (m / m) carnosine, which corresponds to a selectivity of 92% with complete conversion. The reaction mixture was then concentrated to approx. 60 g on a rotary evaporator. As a result of the dropwise addition of 174 g of ethanol, a white solid precipitated out, which was filtered off and dried at 50 ° C./20 mbar.

Ausbeute: 13,0 g (64%)
1H NMR (D₂O, 400 MHz): δ = 7,70 (s, 1H); 6,93 (s, 1H); 4,43-4,50 (m, 1H); 3,20-3,28 (m, 2H); 3,11-3,19 (m, 1H); 2,95-3,03 (m, 1H); 2,61-2,71 (m, 2H).
^I3C NMR (D₂0, 100 MHz): δ = 178,58; 172,39; 136,46; 133,90; 118,37; 55,99; 36,65; 33,09; 29,74.
LC-MS: m/z = 227 ([M+H]⁺), 210, 192, 164, 146, 136, 110.

Example 7
L-Carnosine

In a 1 liter pressure autoclave, a solution of 10.00 g (45.0 mmol) (S) -2- (cyanoacetylamino) -3 was added to 0.88 g of Rh / C (0.4 mol% of pure Rh based on the starting material used) – (1H-imidazol-4-yl) propionic acid (prepared according to Example 3) in a mixture of 157 g conc. NΗ ₃/ Methanol (m / m = 3: 2) was added. The autoclave was closed and flushed twice with 40 bar nitrogen and once with hydrogen. The mixture was heated to 90 ° C. and 40 bar hydrogen was injected. After 3 h at 90 ° C., the reaction mixture was cooled to room temperature, the autoclave was depressurized and the catalyst was separated off by filtration. An in-process analysis (HPLC) showed that the reaction solution (147.2 g) contained 6.38% (m / m) carnosine, which corresponds to a selectivity of 92% when the conversion is complete. The reaction mixture was then concentrated to 41.2 g on a rotary evaporator. 124 g of ethanol were added dropwise at room temperature and the flask was placed in a refrigerator overnight. The next day the precipitate was filtered off, washed with ethanol and dried in a drying cabinet at 40 ° C./20 mbar. 7.96 g (78%) of a slightly greenish solid with a content (HPLC) of 98.0% (m / m) were obtained.

Example 8
L-Carnosine

The procedure was as described in Example 7, with the difference that 5% Rh on aluminum oxide was used as the catalyst. Under these conditions, L-carnosine was formed with 83% selectivity.

Example 9
L-Carnosine

4.5 g of Raney cobalt (doped with 0.3% iron) in 195 g of methanol were placed in a 1 liter pressure autoclave. A solution of 30.0 g (0.135 mol) (S) -2- (cyanoacetylamino) -3- (1H-imidazol-4-yl) propionic acid (prepared according to Example 3) in 375 g ammonia solution (25% in Η O) was admitted. The autoclave was closed and flushed twice with 40 bar nitrogen. Then 45 bar of hydrogen were injected and the contents were heated to 100 ° C. within half an hour. After an after-reaction of 3 hours at 100 ° C., the reaction mixture was cooled to room temperature and the pressure in the autoclave was released. An HPLC in-process analysis showed that the reaction solution (590.8 g) contained 4.68% (mim) carnosine, which corresponds to a selectivity of 91% with complete conversion.

Example 10
L-Carnosine

In a 100 ml
pressure autoclave were to a solution of 2.0 g (9.0 mmol) (ιS) -2- (cyanoacetylamino) -3- (lH-imidazol-4-yl) propionic acid (prepared according to Example 3) in a Mixture of 25 g of ammonia solution (25% in Η ₂ O) and 13 g of methanol, 1.1 g of Raney nickel (doped with 1.8% molybdenum) were added. The autoclave was closed and placed in an oil bath preheated to 100.degree. After 10 minutes, 50 bar of hydrogen were injected. After 2.5 hours at 100 ° C., the reaction mixture was
cooled to room temperature and the pressure on the autoclave was released. An HPLC in-process analysis showed that the reaction solution (39.4 g) contained 4.54% (m / m) carnosine, which, with a conversion of 99%, corresponds to a selectivity of 89%.

Example 11
L-Carnosine

In a 1 liter pressure autoclave, 4.50 g of Raney cobalt (doped with 0.3% iron) in a mixture of 285 g of conc. Ammonia / methanol (mim = 1.9: 1) submitted. The autoclave was closed and flushed twice with 40 bar nitrogen. Then 45 bar of hydrogen were injected and the mixture was heated to 100.degree. A solution of 30.0 g (0.135 mol) of (S) -2- (cyanoacetylamino) -3- (1H-imidazol-4-yl) propionic acid (prepared according to Example 3) in a mixture of 285 g was then obtained within one hour conc. Ammonia / methanol (m / m = 1.9: 1) metered in. After a one hour post-reaction at 100 ° C., the reaction mixture was cooled to room temperature. The pressure in the autoclave was released and the catalyst was filtered off. A ΗPLC in-process analysis showed that the reddish brown reaction solution (310.5 g) contained 9.57% (m / m) carnosine,

Example 12
(S) -2- (Cyanoacetylamino) -3- (3-methyl-3-ö ^r -imidazol-4-yl) propionic acid, sodium salt

0.50 g (2.95 mmol) of 3-methyl-L-histidine were added at 40 ° C. to a solution of 0.20 g (2.94 mmol) of sodium ethoxide in 5.60 g of ethanol. The clear solution was heated to 60 ° C. and 0.50 g (4.43 mmol) ethyl cyanoacetate was added dropwise. The mixture was refluxed for 1 hour. Then 10 mg (0.15 mmol) of imidazole were added. The ethanol was then slowly distilled off and the amount of ethanol distilled off was continuously replaced in portions by N, N-dimethylformamide. After a subsequent reaction time of 2 h at 125 ° C., the reaction mixture was carefully concentrated and the residue was purified by means of flash column chromatography on silica gel (eluent: gradient ethyl acetate → ethyl acetate / methanol 2: 1). 0.49 g (64%) of a slightly yellowish solid were obtained.

DC: R_f ^•= 0,46 (Ethanol/H₂O 3:7).
1H NMR (DMSO-öfe, 400 MHz): δ = 7,91 (d, 1H); 7,38 (s, 1H); 6,58 (s, 1H); 3,97 (q, 1H);

3,68 (s, 2H); 3,50 (s, 3H); 3,01 (dd, 1H); 2,85 (dd, 1H).
¹³C NMR (DMSO-^6, 100 MHz): δ = 171,54; 160,80; 136,95; 128,68; 126,91; 116,40;

54,26; 30,65; 25,97; 25,11.
LC-MS: m/z = 237 ([M+H]⁺), 219, 193, 191, 176, 166, 164, 150, 109.

Example 13
(S) -2- (3-aminopropionylamino) -3- (3-methyl-3Jϊ-imidazol-4-yl) propionic acid
(= anserine)

To a solution of 0.20 g (0.77 mmol) (5) -2- (cyanoacetylamino) -3- (3-methyl-3H-imidazol-4-yl) propionic acid sodium salt (prepared according to Example 12) in 2 , 4 g of methanol and 1.6 g of ammonia solution (25% in Η ₂ O), 16 mg of rhodium / Al ₂ O ₃ (5% Rh) were added. The mixture was hydrogenated at 85 ° C. and 50 bar for 1 hour. The catalyst was then filtered off. Anserine could be clearly detected in the filtrate by means of thin-layer chromatography, HPLC (by co-injection with a commercial reference substance) and LC-MS.
Gross yield: approx. 45%.
TLC: R _f = 0.25 (ethyl acetate / methanol / Ammom ^‘ ak H ₂ O 43: 35: 8: 10).
LC-MS: m / z = 241 ([M + H] ⁺), 224, 206, 180, 170, 126, 109.

SYN

Synthesis of L-carnosine from two amino acids β -alanine-amide and L-histidine

SYN

https://pubs.rsc.org/en/content/articlelanding/2019/cy/c9cy01622h

L-Carnosine (L-Car, β-alanyl-L-histidine) is a bioactive dipeptide with important physiological functions. Direct coupling of unprotected β-Ala (β-alanine) with L-His (L-histidine) mediated by an enzyme is a promising method for L-Car synthesis. In this study, a new recombinant dipeptidase (SmPepD) from Serratia marcescens with a high synthetic activity toward L-Car was identified by a genome mining approach and successfully expressed in Escherichia coli. Divalent metal ions strongly promoted the synthetic activity of SmPepD, with up to 21.7-fold increase of activity in the presence of 0.1 mM MnCl₂. Higher temperature, lower pH and increasing substrate loadings facilitated the L-Car synthesis. Pilot biocatalytic syntheses of L-Car were performed comparatively in batch and continuous modes. In the continuous process, an ultra-filtration membrane reactor with a working volume of 5 L was employed for catalyst retention. The dipeptidase, SmPepD, showed excellent operational stability without a significant decrease in space–time yield after 4 days. The specific yield of L-Car achieved was 105 g_Car g_catalyst⁻¹ by the continuous process and 30.1 g_Car g_catalyst⁻¹ by the batch process. A nanofiltration membrane was used to isolate the desired product L-Car from the reaction mixture by selectively removing the excess substrates, β-Ala and L-His. As a result, the final L-Car content was effectively enriched from 2.3% to above 95%, which gave L-Car in 99% purity after ethanol precipitation with a total yield of 60.2%. The recovered substrate mixture of β-Ala and L-His can be easily reused, which will enable the economically attractive and environmentally benign production of the dipeptide L-Car.

Graphical abstract: A green-by-design bioprocess for l-carnosine production integrating enzymatic synthesis with membrane separation

SYNhttps://patents.google.com/patent/US20170211105A1/en

Carnosine is a dipeptide of the amino acids beta-alanine and histidine. It is highly concentrated in muscle and brain tissues.
[0005]
β-Alanine (or beta-alanine) is a naturally occurring beta amino acid, which is an amino acid in which the amino group is at the β-position from the carboxylate group (i.e., two atoms away).
[0006]
β-Alanine is not used in the biosynthesis of any major proteins or enzymes. It is formed in vivo by the degradation of dihydrouracil and carnosine. It is a component of the naturally occurring peptides carnosine and anserine and also of pantothenic acid (vitamin B5), which itself is a component of coenzyme A. Under normal conditions, β-alanine is metabolized into acetic acid.
[0007]
β-Alanine is the rate-limiting precursor of carnosine, which is to say carnosine levels are limited by the amount of available β-alanine, not histidine. Supplementation with β-alanine has been shown to increase the concentration of carnosine in muscles, decrease fatigue in athletes and increase total muscular work done.
[0008]
Carnosine and beta-alanine are popular dietary supplements currently produced using chemical methods. Beta-alanine is also a synthetic precursor to pantothenic acid, the essential vitamin B5. Beta-alanine can also be used as a monomer for the production of a polymeric resin (U.S. Pat. No. 4,082,730).
[0009]
Naturally, carnosine is produced exclusively in animals from beta-alanine (via uracil) and histidine. In yeasts and animals, beta-alanine is typically produced by degradation of uracil. Chemically, carnosine can be synthesized from histidine and beta-alanine derivatives. For example, the coupling of an N-(thiocarboxy) anhydride of beta-alanine with histidine has been described (Vinick et al. A simple and efficient synthesis of L-carnosine. J. Org. Chem, 1983, 48(3), pp. 392-393).
[0010]
Beta-alanine can be produced synthetically by Michael addition of ammonia to ethyl- or methyl-acrylate. This requires the use of the caustic agent ammonia and high pressures. It is also natively produced in bacteria and yeasts in small quantities. In bacteria, beta-alanine is produced by decarboxylation of aspartate. Lysates of bacteria have been used in biocatalytic production from aspartate (Patent CN104531796A).
[0011]
There remains a need in the industry for a safer, more economical system for the production of carnosine and beta-alanine.

[0105]
The present disclosure provides methods for the biosynthetic production of beta-alanine and carnosine using engineered microorganisms of the present invention.
[0106]
In one embodiment, a method of producing beta-alanine is provided. The method comprises providing a fermentation media comprising a carbon substrate, contacting said media with a recombinant yeast microorganism expressing an engineered beta-alanine biosynthetic pathway wherein said pathway comprises an aspartate to beta-alanine conversion (pathway step a), and culturing the yeast in conditions whereby beta-alanine is produced.
[0107]
In another embodiment of the present invention, a method of producing carnosine is provided. The method comprises providing a fermentation media comprising a carbon substrate, contacting said media with a recombinant yeast microorganism expressing an engineered carnosine biosynthetic pathway wherein said pathway comprises (i) an aspartate to beta-alanine conversion (pathway step a) and (ii) a beta-alanine to carnosine conversion (pathway step b), and culturing the yeast in conditions whereby carnosine is produced.
[0108]
In another embodiment of the present invention, a method of producing carnosine via biotransformation is provided. The method comprises providing a media comprising a carbon substrate and exogenously added beta-alanine, contacting said media with a recombinant yeast microorganism expressing an engineered carnosine biosynthetic pathway wherein said pathway comprises (i) a beta-alanine to carnosine conversion (pathway step b), and culturing the yeast in conditions whereby carnosine is produced.
[0109]
Some embodiments of the present invention comprise yeast strains designated ca1 and ca2 and are derived from S. cerevisiae strain S288C. Each encodes at least 2 foreign genes under inducible Gal promoters. Strain ca1 also contains an additional gene, panM. The specific proteins encoded by each strain and their sequences, source, and accession numbers are provided in Table 1. The genes for these proteins are synthesized with yeast-optimized codon usage, assembled into singular genetic cassettes, and then inserted into the HO locus of S288C under URA2 selection. Strains ca1 and ca2 served as parent strains to derivatives comprising various heterologous genes. Ca2 served as a parent strain for ca7, ca8, ca9, ca10, ca11, ca12, ca14, ca15 in which the carnosine synthase is a different ortholog. Strain ca1 served as the parent strain to strains ca19, ca20, ca21, ca22, ca23, ca24, ca27, and ca28 in which the aspartate decarboxylase is a different ortholog. The specific proteins encoded by each strain and their sequences, source, and accession numbers are provided in Table 2.
[0110]
Aspartate, histidine, and the cofactors involved in the carnosine and beta-alanine pathway are universal to all organisms, and thus the host organism could be any genetically tractable organism (plants, animals, bacteria, or fungi). Amongst yeasts, other species such as S. pombe or P. pastoris are plausible alternatives. Within the S. cerevisiae species, other strains more amenable to large-scale productions, such as CENPalpha, may be utilized.
[0111]
The Gal promoter used in embodiments of the present invention could be replaced with constitutive promoters, or other chemically-inducible, growth phase-dependent, or stress-induced promoters. Heterologous genes of the present invention may be genomically encoded or alternatively encoded on plasmids or yeast artificial chromosomes (YACs). All genes introduced could be encoded with alternate codon usage without altering the biochemical composition of the system. All enzymes used in embodiments of the present invention have extensive orthologs in the biosphere that could be encoded as alternatives.
[0112]
Aspartate, histidine, and the cofactors involved in this pathway are universal to all organisms, and thus the host organism could be any genetically tractable organism (plants, animals, bacteria, or fungi). Among yeast, other species such as S. pombe or P. pastoris are plausible alternatives. Within the S. cerevisiae species, other strains more amenable to large scale productions, such as CENPalpha, may be preferable. The panD gene can replaced with orthologs from other bacteria. Examples include Corynebacterium glutamicum Escherichia coli, Helicobacter pylori, Tribolium castaneum, Pectobacterium carotovorum, Actinoplanes sp. SE50/110, Taoultella ornithinolytica, Methanocaldococcus jannaschii DSM 2661 and Methanocaldococcus bathoardescens. This is shown in Table 2. Carnosine synthase is natively found in mammals, birds, and reptiles. Therefore, the chicken enzyme used in ca1 and ca2 could be replaced by various orthologs. Examples include Gorilla gorilla, Falco perefrinus, Allpiucator mississsippiensis, Ailuoropoda melanoleuca, Ursus maritimus, Python bivittatus, and Orcinus orca. This is shown in Table 2.

Culture Conditions

[0113]
The growth medium used to test for production of carnosine by the engineered strains was Teknova SC Minimal Broth with Raffinose supplemented with 1% galactose.
[0114]
A variety of purification protocols including solid phase extraction and cation exchange chromatography may be employed to purify the desired products from the culture supernatant or the yeast cell pellet fraction.

SYN

https://pdfs.semanticscholar.org/4dc4/f6e93a62e630429c7830f117ab2564e124a2.pdf?_ga=2.190125161.395277661.1640054641-1458054132.1640054641

Names

Preferred IUPAC name(2S)-2-(3-Aminopropanamido)-3-(3H-imidazol-4-yl)propanoic acid
Other namesβ-Alanyl-L-histidine
Identifiers
CAS Number	305-84-0
3D model (JSmol)	Interactive image Interactive image
ChEBI	CHEBI:15727
ChEMBL	ChEMBL242948
ChemSpider	388363
ECHA InfoCard	100.005.610
IUPHAR/BPS	4559
KEGG	C00386
PubChem CID	439224
UNII	8HO6PVN24W
CompTox Dashboard (EPA)	DTXSID80879594
show InChI
show SMILES
Properties
Chemical formula	C₉H₁₄N₄O₃
Molar mass	226.236 g·mol⁻¹
Appearance	Crystalline solid
Melting point	253 °C (487 °F; 526 K) (decomposition)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Biosynthesis

Carnosine is synthesized within the body from beta-alanine and histidine. Beta-alanine is a product of pyrimidine catabolism^[6] and histidine is an essential amino acid. Since beta-alanine is the limiting substrate, supplementing just beta-alanine effectively increases the intramuscular concentration of carnosine.^[7]^[8]

Physiological effects

pH buffer

Carnosine has a pK_a value of 6.83, making it a good buffer for the pH range of animal muscles.^[9] Since beta-alanine is not incorporated into proteins, carnosine can be stored at relatively high concentrations (millimolar). Occurring at 17–25 mmol/kg (dry muscle),^[10] carnosine (β-alanyl-L-histidine) is an important intramuscular buffer, constituting 10-20% of the total buffering capacity in type I and II muscle fibres.

Anti-oxidant

Carnosine has been proven to scavenge reactive oxygen species (ROS) as well as alpha-beta unsaturated aldehydes formed from peroxidation of cell membrane fatty acids during oxidative stress. It also buffers pH in muscle cells, and acts as a neurotransmitter in the brain. It is also a zwitterion, a neutral molecule with a positive and negative end.^{[citation needed]}

Antiglycating

Carnosine acts as an antiglycating agent, reducing the rate of formation of advanced glycation end-products (substances that can be a factor in the development or worsening of many degenerative diseases, such as diabetes, atherosclerosis, chronic kidney failure, and Alzheimer’s disease^[11]), and ultimately reducing development of atherosclerotic plaque build-up.^[12]^[13]^[14]

Geroprotective

Carnosine is considered as a geroprotector.^[15] Carnosine can increase the Hayflick limit in human fibroblasts,^[16] as well as appearing to reduce the telomere shortening rate.^[17] Carnosine may also slow aging through its anti-glycating properties (chronic glycolysis is speculated to accelerate aging).^[18]

Other

Carnosine can chelate divalent metal ions.^[12]

Carnosine administration has been shown to have cardioprotective properties, protecting against ischaemia-reperfusion injury, and doxorubicin-induced cardiomyopathy.^[19]

Carnosine demonstrated neuroprotective effects in multiple animal studies.^[20]^[21]^[22]

Research has demonstrated a positive association between muscle tissue carnosine concentration and exercise performance.^[23]^[24]^[25] β-Alanine supplementation is thought to increase exercise performance by promoting carnosine production in muscle. Exercise has conversely been found to increase muscle carnosine concentrations, and muscle carnosine content is higher in athletes engaging in anaerobic exercise.^[23]

Carnosine appears to protect in experimental ischemic stroke by influencing a number of mechanisms that are activated during stroke. It is a potent pH buffer and has anti matrix metalloproteinase activity, antioxidant and antiexcitotoxic properties and protects the blood brain barrier [26], [27], [28], [29], [30], [31], [32]. [33], [34], [35].

References

^ “C9625 L-Carnosine ~99%, crystalline”. Sigma-Aldrich.
^ Gulewitsch, Wl.; Amiradžibi, S. (1900). “Ueber das Carnosin, eine neue organische Base des Fleischextractes”. Berichte der Deutschen Chemischen Gesellschaft. 33 (2): 1902–1903. doi:10.1002/cber.19000330275.
^ Trexler, Eric T.; Smith-Ryan, Abbie E.; Stout, Jeffrey R.; Hoffman, Jay R.; Wilborn, Colin D.; Sale, Craig; Kreider, Richard B.; Jäger, Ralf; Earnest, Conrad P.; Bannock, Laurent; Campbell, Bill (2015-07-15). “International society of sports nutrition position stand: Beta-Alanine”. Journal of the International Society of Sports Nutrition. 12: 30. doi:10.1186/s12970-015-0090-y. ISSN 1550-2783. PMC 4501114. PMID 26175657.
^ Hipkiss, A. R. (2006). “Does chronic glycolysis accelerate aging? Could this explain how dietary restriction works?”. Annals of the New York Academy of Sciences. 1067 (1): 361–8. Bibcode:2006NYASA1067..361H. doi:10.1196/annals.1354.051. PMID 16804012. S2CID 41175541.
^ Alan R. Hipkiss (2009). “Chapter 3: Carnosine and Its Possible Roles in Nutrition and Health”. Advances in Food and Nutrition Research.
^ “beta-ureidopropionate + H2O => beta-alanine + NH4+ + CO2”. reactome. Retrieved 2020-02-08. Cytosolic 3-ureidopropionase catalyzes the reaction of 3-ureidopropionate and water to form beta-alanine, CO2, and NH3 (van Kuilenberg et al. 2004).
^ Derave W, Ozdemir MS, Harris R, Pottier A, Reyngoudt H, Koppo K, Wise JA, Achten E (August 9, 2007). “Beta-alanine supplementation augments muscle carnosine content and attenuates fatigue during repeated isokinetic contraction bouts in trained sprinters”. J Appl Physiol. 103 (5): 1736–43. doi:10.1152/japplphysiol.00397.2007. PMID 17690198. S2CID 6990201.
^ Hill CA, Harris RC, Kim HJ, Harris BD, Sale C, Boobis LH, Kim CK, Wise JA (2007). “Influence of beta-alanine supplementation on skeletal muscle carnosine concentrations and high intensity cycling capacity”. Amino Acids. 32 (2): 225–33. doi:10.1007/s00726-006-0364-4. PMID 16868650. S2CID 23988054.
^ Bate-Smith, EC (1938). “The buffering of muscle in rigor: protein, phosphate and carnosine”. Journal of Physiology. 92 (3): 336–343. doi:10.1113/jphysiol.1938.sp003605. PMC 1395289. PMID 16994977.
^ Mannion, AF; Jakeman, PM; Dunnett, M; Harris, RC; Willan, PLT (1992). “Carnosine and anserine concentrations in the quadriceps femoris muscle of healthy humans”. Eur. J. Appl. Physiol. 64 (1): 47–50. doi:10.1007/BF00376439. PMID 1735411. S2CID 24590951.
^ Vistoli, G; De Maddis, D; Cipak, A; Zarkovic, N; Carini, M; Aldini, G (Aug 2013). “Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation”. Free Radic. Res. 47: Suppl 1:3–27. doi:10.3109/10715762.2013.815348. PMID 23767955. S2CID 207517855.
^ Jump up to:^a ^b Reddy, V. P.; Garrett, MR; Perry, G; Smith, MA (2005). “Carnosine: A Versatile Antioxidant and Antiglycating Agent”. Science of Aging Knowledge Environment. 2005 (18): pe12. doi:10.1126/sageke.2005.18.pe12. PMID 15872311.
^ Rashid, Imran; Van Reyk, David M.; Davies, Michael J. (2007). “Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro”. FEBS Letters. 581 (5): 1067–70. doi:10.1016/j.febslet.2007.01.082. PMID 17316626. S2CID 46535145.
^ Hipkiss, A. R. (2005). “Glycation, ageing and carnosine: Are carnivorous diets beneficial?”. Mechanisms of Ageing and Development. 126 (10): 1034–9. doi:10.1016/j.mad.2005.05.002. PMID 15955546. S2CID 19979631.
^ Boldyrev, A. A.; Stvolinsky, S. L.; Fedorova, T. N.; Suslina, Z. A. (2010). “Carnosine as a natural antioxidant and geroprotector: From molecular mechanisms to clinical trials”. Rejuvenation Research. 13 (2–3): 156–8. doi:10.1089/rej.2009.0923. PMID 20017611.
^ McFarland, G; Holliday, R (1994). “Retardation of the Senescence of Cultured Human Diploid Fibroblasts by Carnosine”. Experimental Cell Research. 212 (2): 167–75. doi:10.1006/excr.1994.1132. PMID 8187813.
^ Shao, Lan; Li, Qing-Huan; Tan, Zheng (2004). “L-Carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts”. Biochemical and Biophysical Research Communications. 324 (2): 931–6. doi:10.1016/j.bbrc.2004.09.136. PMID 15474517.
^ Hipkiss, A. R. (2006). “Does Chronic Glycolysis Accelerate Aging? Could This Explain How Dietary Restriction Works?”. Annals of the New York Academy of Sciences. 1067 (1): 361–8. Bibcode:2006NYASA1067..361H. doi:10.1196/annals.1354.051. PMID 16804012. S2CID 41175541.
^ McCarty, Mark F; DiNicolantonio, James J (2014-08-04). “β-Alanine and orotate as supplements for cardiac protection”. Open Heart. 1 (1): e000119. doi:10.1136/openhrt-2014-000119. ISSN 2053-3624. PMC 4189254. PMID 25332822.
^ Virdi, Jasleen Kaur; Bhanot, Amritansh; Jaggi, Amteshwar Singh; Agarwal, Neha (2020-10-02). “Investigation on beneficial role of l -carnosine in neuroprotective mechanism of ischemic postconditioning in mice: possible role of histidine histamine pathway”. International Journal of Neuroscience. 130 (10): 983–998. doi:10.1080/00207454.2020.1715393. ISSN 0020-7454. PMID 31951767. S2CID 210710039.
^ Rajanikant, G.K.; Zemke, Daniel; Senut, Marie-Claude; Frenkel, Mark B.; Chen, Alex F.; Gupta, Rishi; Majid, Arshad (November 2007). “Carnosine Is Neuroprotective Against Permanent Focal Cerebral Ischemia in Mice”. Stroke. 38 (11): 3023–3031. doi:10.1161/STROKEAHA.107.488502. ISSN 0039-2499. PMID 17916766.
^ Min, Jiangyong; Senut, Marie-Claude; Rajanikant, Krishnamurthy; Greenberg, Eric; Bandagi, Ram; Zemke, Daniel; Mousa, Ahmad; Kassab, Mounzer; Farooq, Muhammad U.; Gupta, Rishi; Majid, Arshad (October 2008). “Differential neuroprotective effects of carnosine, anserine, and N -acetyl carnosine against permanent focal ischemia”. Journal of Neuroscience Research. 86 (13): 2984–2991. doi:10.1002/jnr.21744. PMC 2805719. PMID 18543335.
^ Jump up to:^a ^b Culbertson, Julie Y.; Kreider, Richard B.; Greenwood, Mike; Cooke, Matthew (2010-01-25). “Effects of Beta-Alanine on Muscle Carnosine and Exercise Performance:A Review of the Current Literature”. Nutrients. 2 (1): 75–98. doi:10.3390/nu2010075. ISSN 2072-6643. PMC 3257613. PMID 22253993.
^ Baguet, Audrey; Bourgois, Jan; Vanhee, Lander; Achten, Eric; Derave, Wim (2010-07-29). “Important role of muscle carnosine in rowing performance”. Journal of Applied Physiology. 109 (4): 1096–1101. doi:10.1152/japplphysiol.00141.2010. ISSN 8750-7587. PMID 20671038.
^ Varanoske, Alyssa N.; Hoffman, Jay R.; Church, David D.; Wang, Ran; Baker, Kayla M.; Dodd, Sarah J.; Coker, Nicholas A.; Oliveira, Leonardo P.; Dawson, Virgil L.; Fukuda, David H.; Stout, Jeffrey R. (2017-09-07). “Influence of Skeletal Muscle Carnosine Content on Fatigue during Repeated Resistance Exercise in Recreationally Active Women”. Nutrients. 9 (9): 988. doi:10.3390/nu9090988. ISSN 2072-6643. PMC 5622748. PMID 28880219.

show v t e Peptides: neuropeptides

26. Kim EH, Kim ES, Shin D, Kim D, Choi S, Shin YJ, Kim KA, Noh D, Caglayan AB, Rajanikant GK, Majid A, Bae ON. Carnosine Protects against Cerebral Ischemic Injury by Inhibiting Matrix-Metalloproteinases. Int J Mol Sci. 2021 Jul 13;22(14):7495. doi: 10.3390/ijms22147495. PMID: 34299128; PMCID: PMC8306548.

27. Jain S, Kim ES, Kim D, Burrows D, De Felice M, Kim M, Baek SH, Ali A, Redgrave J, Doeppner TR, Gardner I, Bae ON, Majid A. Comparative Cerebroprotective Potential of d- and l-Carnosine Following Ischemic Stroke in Mice. Int J Mol Sci. 2020 Apr 26;21(9):3053. doi: 10.3390/ijms21093053. PMID: 32357505; PMCID: PMC7246848.

28. Kim ES, Kim D, Nyberg S, Poma A, Cecchin D, Jain SA, Kim KA, Shin YJ, Kim EH, Kim M, Baek SH, Kim JK, Doeppner TR, Ali A, Redgrave J, Battaglia G, Majid A, Bae ON. LRP-1 functionalized polymersomes enhance the efficacy of carnosine in experimental stroke. Sci Rep. 2020 Jan 20;10(1):699. doi: 10.1038/s41598-020-57685-5. PMID: 31959846; PMCID: PMC6971073.

29. Schön M, Mousa A, Berk M, Chia WL, Ukropec J, Majid A, Ukropcová B, de Courten B. The Potential of Carnosine in Brain-Related Disorders: A Comprehensive Review of Current Evidence. Nutrients. 2019 May 28;11(6):1196. doi: 10.3390/nu11061196. PMID: 31141890; PMCID: PMC6627134.

30. Davis CK, Laud PJ, Bahor Z, Rajanikant GK, Majid A. Systematic review and stratified meta-analysis of the efficacy of carnosine in animal models of ischemic stroke. J Cereb Blood Flow Metab. 2016 Oct;36(10):1686-1694. doi: 10.1177/0271678X16658302. Epub 2016 Jul 8. PMID: 27401803; PMCID: PMC5046161.

31. Baek SH, Noh AR, Kim KA, Akram M, Shin YJ, Kim ES, Yu SW, Majid A, Bae ON. Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage. Stroke. 2014 Aug;45(8):2438-2443. doi: 10.1161/STROKEAHA.114.005183. Epub 2014 Jun 17. PMID: 24938837; PMCID: PMC4211270.

32. Bae ON, Majid A. Role of histidine/histamine in carnosine-induced neuroprotection during ischemic brain damage. Brain Res. 2013 Aug 21;1527:246-54. doi: 10.1016/j.brainres.2013.07.004. Epub 2013 Jul 11. PMID: 23850642.

33. Bae ON, Serfozo K, Baek SH, Lee KY, Dorrance A, Rumbeiha W, Fitzgerald SD, Farooq MU, Naravelta B, Bhatt A, Majid A. Safety and efficacy evaluation of carnosine, an endogenous neuroprotective agent for ischemic stroke. Stroke. 2013 Jan;44(1):205-12. doi: 10.1161/STROKEAHA.112.673954. Epub 2012 Dec 18. PMID: 23250994; PMCID: PMC3678096.

34. Min J, Senut MC, Rajanikant K, Greenberg E, Bandagi R, Zemke D, Mousa A, Kassab M, Farooq MU, Gupta R, Majid A. Differential neuroprotective effects of carnosine, anserine, and N-acetyl carnosine against permanent focal ischemia. J Neurosci Res. 2008 Oct;86(13):2984-91. doi: 10.1002/jnr.21744. PMID: 18543335; PMCID: PMC2805719.

35. Rajanikant GK, Zemke D, Senut MC, Frenkel MB, Chen AF, Gupta R, Majid A. Carnosine is neuroprotective against permanent focal cerebral ischemia in mice. Stroke. 2007 Nov;38(11):3023-31. doi: 10.1161/STROKEAHA.107.488502. Epub 2007 Oct 4. PMID: 17916766.

////////L-CARNOSINE, カルノシン , b-Alanyl-L-histidine, ignotine, 8HO6PVN24W, カルノシン , Dragosine, Ignotin, Ignotine, Karnozin, L-Carnosine, N-(β-Alanyl)-L-histidine, NSC 524045, Sevitin, β-Alanylhistidine

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