Racecadotril;

CAS 81110-73-8;

Acetorphan; Benzyl 2-(3-(acetylthio)-2-benzylpropanamido)acetate; Tiorfan; CADOTRIL;

benzyl 2-[[2-(acetylsulfanylmethyl)-3-phenylpropanoyl]amino]acetate

Molecular Formula:	C21H23NO4S
Molecular Weight:	385.47662 g/mol

 

LAUNCHED  1993 BIOPROJET IN FRANCE

2010 IN CHINA

Racecadotril, also known as acetorphan, is an antidiarrheal drug which acts as a peripherally acting enkephalinase inhibitor.^[2] 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 UK and Spain) 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 tradenames Hidrasec or, in France, Tiorfan.^[4] In Italy it is sold under the tradename Tiorfix.^[4]

Thiorphan is the active metabolite of racecadotril, which exerts the bulk of its inhibitory actions on enkephalinase.^[5]

Racecadotril, also known as acetorphan, is an antidiarrheal drug which acts as a peripherally acting enkephalinase inhibitor. Unlike other 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. It is available in India (It was first introduced in 1993 and is widely used in France) and other European countries, as well as most of South America and some South East Asian countries, but not in the United States. It is sold under the tradenames Hidrasec or, in France, Tiorfan. In Italy it is sold under the tradename Tiorfix.

In india trade names  REDOTTIL, ZEDOTT .

A small randomized controlled trial found racecadotril to significantly reduce the duration and volume of watery diarrhea in children when given as an adjunct to oral rehydration therapy.

Racecadotril, also known as acetorphan, is an antidiarrheal drug which acts as a peripherally acting enkephalinase inhibitor. Unlike other 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. It is available in India (It was first introduced in 1993 and is widely used in France) and other European countries, as well as most of South America and some South East Asian countries, but not in the United States. It is sold under the tradenames Hidrasec or, in France, Tiorfan. In Italy it is sold under the tradename Tiorfix.

In india trade names  REDOTTIL, ZEDOTT .

A small randomized controlled trial found racecadotril to significantly reduce the duration and volume of watery diarrhea in children when given as an adjunct to oral rehydration therapy.

Indication & Dosage      

Acute diarrhoea

Adult: 100 mg tid, up to 7 days.

Administration – May be taken with or without food.

Special Precautions  –    Renal insufficiency, pregnancy, lactation.

Adverse Drug Reactions –  Vomiting, nausea, constipation, abdominal pain, thirst, vertigo and headache.

Mechanism of Action

Racecadotril increases the availability of endogenous opioids (enkephalins) by inhibiting the membrane-bound enkephalinase. These enkephalins activate δ-opioid receptors in the GI tract. This leads to a reduction in cAMP mucosal levels, resulting in a reducted secretion of water and electrolytes in the intestinal lumen.  Onset: Within 30 min.

Foreign Names

Racecadotrilum (Latin)

Racecadotril (German)

Racécadotril (French)

Racecadotrilo (Spanish)

 

Brand Names

AD             –  Hetero, India

Aquasec    –  Micro Nova, India

Cadotril    – Medifarma, Peru

Diarfix      –  CristerS, France

Dirasec     –  Abbott, India

Du La Bao  –  Baili Pharmaceutical, China

Enuff          –  Hetero, India

Feng Hai Ting – Zhengda Fenghai Pharmaceutical, China

Hidrasec   – Abbott, China;       Abbott, Philippines;                 Bagó, Ecuador;                Ferrer, Costa Rica; Ferrer, Dominican Republic;          Ferrer, Guatemala;            Ferrer, Honduras;                     Ferrer, Mexico; Ferrer, Nicaragua;    Ferrer, Panama;     Ferrer, El Salvador;    Fournier, Bulgaria;    Fournier, Romania; Galenica, Greece;     Laboratoire Sophartex, Vietnam;      Leti, Venezuela;      Silesia, Chile;

Solvay, Thailand

Hidrasec Children (pediatric) –  Fournier, Bulgaria

Hidrasec Infants (pediatric)-Fournier, Bulgaria

Hydral     –  Alembic, India

Lomorest   –  Zuventus, India

Mo Ni Ka   –  Hailing, China

Mold       –  Aversi, Georgia

Pedidot    –  Elder, India

Racaril    -East West, India

Racedot    –  Macleods, Georgia

Race-F     –  Bestochem, India

Racotil    –  Cipla, India

Racy       –  Abbott, India

Redotil    –  Dr. Reddy’s, India

Resorcal Lactantes/Ninos (pediatric) – Andromaco, Chile

Resorcal   – Andromaco, Chile

Tiorfan    – Abbott, Germany; Bago, Brazil; Bioproject, Tunisia; Bioprojet, France; CPH, Portugal; Ferrer, Peru; Ferrer Farma, Spain

Tiorfan Infantil – CPH, Portugal

Tiorfan Niños (pediatric) – Ferrer, Peru

Tiorfan nourrissons (pediatric) – Bioproject, Tunisia

Tiorfanor  – Bioprojet, France

Tiorfast   – Bioprojet, France

Tiorfix    – Costanzafarma, Italy

Zomatril   –  FDC, India

See also

• Ecadotril, the (S)-enantiomer of racecadotril

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.

research.

References

• 1 “SPC-DOC_PL 39418-0003.PDF” (PDF). Medicines and Healthcare Products Regulatory Agency. Bioprojet Europe Ltd. 26 December 2012. Retrieved 7 May 2014.
• 2Matheson AJ, Noble S (April 2000). “Racecadotril”. Drugs 59 (4): 829–35; discussion 836–7. doi:10.2165/00003495-200059040-00010. PMID 10804038.
• 3Matheson, AJ; Noble, S (April 2000). “Racecadotril.”. Drugs 59 (4): 829–35; discussion 836–7. doi:10.2165/00003495-200059040-00010. PMID 10804038.
• 4Brayfield, A, ed. (13 December 2013). “Racecadotril”. Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 6 May 2014.
• 5Spillantini 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.
• 6 http://www.ingentaconnect.com/content/govi/pharmaz/2006/00000061/00000012/art00005?crawler=true

 

Racecadotril

Systematic (IUPAC) name
(RS)-Benzyl N-[3-(acetylthio)-2-benzylpropanoyl]glycinate
Clinical data
Trade names	Hidrasec, Tiorfan
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
Legal status
Legal status	UK: POM (Prescription only)
Pharmacokinetic data
Protein binding	90% (active thiorphan metabolite)[1]
Metabolism	Liver-mediated[1]
Biological half-life	3 hours[1]
Excretion	Urine (81.4%), feces (8%)[1]
Identifiers
CAS Number	81110-73-8
ATC code	A07XA04 (WHO)
PubChem	CID 107751
ChemSpider	96913
UNII	76K53XP4TO
ChEMBL	CHEMBL2103772
Synonyms	Benzyl 2-[3-(acetylthio)-2-benzylpropanamido]acetate
Chemical data
Formula	C21H23NO4S
Molar mass	385.47662 g/mol
Chirality	Racemic mixture

/////////Racecadotril,  acetorphan,  antidiarrheal drug

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