FR2523127A1 - N, S-DIACETYLCYSTEINE USEFUL AS A MUCOLYTIC AGENT, ITS MANUFACTURING PROCESS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME - Google Patents

N, S-DIACETYLCYSTEINE USEFUL AS A MUCOLYTIC AGENT, ITS MANUFACTURING PROCESS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME Download PDF

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FR2523127A1
FR2523127A1 FR8303958A FR8303958A FR2523127A1 FR 2523127 A1 FR2523127 A1 FR 2523127A1 FR 8303958 A FR8303958 A FR 8303958A FR 8303958 A FR8303958 A FR 8303958A FR 2523127 A1 FR2523127 A1 FR 2523127A1
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temperature
diacetylcysteine
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useful
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Fernando Montoro
Jose Calatayud
Manuel Luna
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Especialidades Latinas Medicamentos Universales SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to N,S-di-(acetyl)cysteine of the formula The invention also relates to a process for the preparation of this compound, in which cysteine hydrochloride or cysteine is dissolved in an alkali metal hydroxide solution at temperatures of not over 15 DEG C in a manner known per se and reacted with acetic anhydride at temperatures from -5 to +5 DEG C, and to medicaments containing this compound, in particular having mucolytic action.

Description

La présente invention concerne la N, S-diacétylcysteine de formule développée suivante

Figure img00010001
The present invention relates to N, S-diacetylcysteine of the following structural formula
Figure img00010001

L'invention concerne également la preparation de ce compose et ses applications thérapeutiques. The invention also relates to the preparation of this compound and its therapeutic applications.

Pour obtenir la N,S-diacétylcystéine, on part de la cystéine, sous forme soit de base libre, soit de chlorhydrate dont on acetyle le groupe amino et le groupe thiol en milieu alcalin par l'anhydride acetique. La réaction a lieu à une température qui peut varier entre -50C et +5"C, pendant une duree de 2 à 3 h, puis au repos pendant une nuit à là même temperature, après quoi on l'acidifie par l'acide chlorhydrique concentre ; on maintient en agitation pendant 3 h. On extrait le melange de réaction par l'acétate d'ethyle.  To obtain N, S-diacetylcysteine, one starts from cysteine, in the form of free base, or of hydrochloride of which the amino group is acetyle and the thiol group in alkaline medium by acetic anhydride. The reaction takes place at a temperature which can vary between -50 ° C. and + 5 ° C., for a period of 2 to 3 hours, then at rest for one night at the same temperature, after which it is acidified with hydrochloric acid. The mixture is stirred for 3 hours and the reaction mixture is extracted with ethyl acetate.

On sèche l'extrait organique sur sulfate de sodium anhydre et on l'évapore à siccite sous vide ; on lave le résidu solide plusieurs fois à l'éther méthylique. Le produit obtenu, la N, S-diacétylcystéine, est seche sous vide à 50-600C.The organic extract is dried over anhydrous sodium sulfate and evaporated to dryness in vacuo; the solid residue is washed several times with methyl ether. The product obtained, N, S-diacetylcysteine, is dried under vacuum at 50-600C.

L'exemple suivant illustre l'invention sans toutefois en limiter la portee. The following example illustrates the invention without limiting its scope.

EXEMPLE
Dans un réacteur de 10 litres, muni d'un agitateur, d'un bain réfrigérant, d'un thermomètre et d'une ampoule à brome, on dissout 725 g d'hydroxyde de sodium (18,1 mol) dans 4000 ml d'eau.EXAMPLE
In a 10 liter reactor equipped with a stirrer, a cooling bath, a thermometer and a dropping funnel, 725 g of sodium hydroxide (18.1 mol) are dissolved in 4000 ml of sodium hydroxide. 'water.

On laisse refroidir et, lorsque la température est de 50C, on ajoute par petites portions 1000 g de chlorhydrate de cysteine (6,3 mol), de telle sorte que la température ne dépasse pas 150C. On ajoute en refroidissant, par l'ampoule à brome, 1225 ml d'anhydride acetique, de façon à maintenir la temperature entre -5 C et +5 CC. On maintient en agitant à la temperature indiquee pendant 3 h et ensuite au repos pendant une nuit. On ajoute 1200 ml d'acide chlorhydrique concentre à une température de -50C +5"C et on agite pendant 3 h.On extrait le mélange de reaction 3 fois par 1500 ml d'acétate d'ethyle. On sèche l'extrait organique sur Na2S04 anhydre et on ltevapore à siccité sous vide et on lave le résidu 3 fois avec 2000 ml d'éther éthylique On
filtre le solide résultant, en suspension dans l'éther, et on le
sèche sous vide à 50-600C. It is allowed to cool and, when the temperature is 50 ° C., 1000 g of cysteine hydrochloride (6.3 mol) are added in small portions, so that the temperature does not exceed 150 ° C. 1225 ml of acetic anhydride are added with the addition of dropping funnel to the dropping funnel to maintain the temperature between -5 ° C. and + 5 ° C. Stirring is maintained at the indicated temperature for 3 hours and then at rest for one night. 1200 ml of concentrated hydrochloric acid are added at a temperature of -50 ° C. ± 5 ° C. and the mixture is stirred for 3 hours. The reaction mixture is extracted 3 times with 1500 ml of ethyl acetate. on anhydrous Na 2 SO 4 and evaporated to dryness in vacuo and the residue washed 3 times with 2000 ml of diethyl ether.
filter the resulting solid, suspended in ether, and
Vacuum dry at 50-600C.

Rendement : 84,7 %
Analyse élémentaire : C (%) H (%) N (%) S (%)
Trouvé 40,8 5,6 6,7 15,4
Calcule 40,97 5,40 6,82 15,62
Point de fusion : 1180C. Yield: 84.7%
Elemental analysis: C (%) H (%) N (%) S (%)
Found 40.8 5.6 6.7 15.4
Calculates 40.97 5.40 6.82 15.62
Melting point: 1180C.

Spectre infrarouge
Le spectre IR du produit Cen pastille de KBr) présente des bandes d'absorption à 3350, 1715, 1690, 1625, 1550, 1240 et 650 cm
Spectre de RMN :
Le spectre de RMN à 60 NHz d'une solution du produit dans le DMSO deutérie présente les signaux suivants

Figure img00020001
Infrared spectrum
The IR spectrum of the product KBr KB pellet) has absorption bands at 3350, 1715, 1690, 1625, 1550, 1240 and 650 cm.
NMR spectrum:
The 60 NHz NMR spectrum of a product solution in deuterated DMSO shows the following signals:
Figure img00020001

<tb> <SEP> Signal <SEP> Multiplicité <SEP> Integration <SEP>
<tb> (pprn <SEP> échelle <SEP> chez <SEP>
<tb> <SEP> 1,7 <SEP> singulet <SEP> 3H
<tb> <SEP> 2,2 <SEP> singulet <SEP> 3H
<tb> <SEP> 3,1 <SEP> doublet <SEP> 2H
<tb> <SEP> 4,2 <SEP> sextuplet <SEP> IH <SEP>
<tb> <SEP> 8,1 <SEP> doublet <SEP> 1H
<tb>
Pharmacologie
Les études toxicologiques, pharmacodynamiques et pharmacocinetiques realisees avec le produit selon l'invention sont indiquees ci-dessous.<tb><SEP> Signal <SEP> Multiplicity <SEP> Integration <SEP>
<tb> (pprn <SEP> scale <SEP> at <SEP>
<tb><SEP> 1.7 <SEP> singlet <SEP> 3H
<tb><SEP> 2.2 <SEP> singlet <SEP> 3H
<tb><SEP> 3.1 <SEP> doublet <SEP> 2H
<tb><SEP> 4.2 <SEP> sextuplet <SEP> IH <SEP>
<tb><SEP> 8.1 <SEP> doublet <SEP> 1H
<Tb>
Pharmacology
The toxicological, pharmacodynamic and pharmacokinetic studies carried out with the product according to the invention are indicated below.

Les essais de toxicite aiguë ont prouve que la DL50 par voie orale du produit de l'invention est très superieure à 5000 mg/kg ( cette dose, aucun decès ne s'est produit), le produit etant considéré comme non toxique, suivant le critère de Hodge et
Steamer.Acute toxicity tests have shown that the oral LD50 of the product of the invention is very much greater than 5000 mg / kg (this dose, no deaths occurred), the product being considered non-toxic, following the Hodge criterion and
Steamer.

Les essais de toxicite chronique ont ete réalisés sur des chiens beagles eut des rats Sprague-Dawley, avec administration quotidienne pendant 6 et 3 mois, respectivement, aux doses suivantes : chiens, 20 et 100 mg/kg ; rats, 100, 300 et 900 mg/kg. Chronic toxicity tests were performed on Beagle dogs with Sprague-Dawley rats, administered daily for 6 and 3 months, respectively, at the following doses: dogs, 20 and 100 mg / kg; rats, 100, 300 and 900 mg / kg.

Dans aucune des experiences, on n'a trouve de différences significatives entre les animaux traités et les animaux temoins. In none of the experiments were significant differences found between the treated animals and the control animals.

Le produit selon l'invention a démontré son activité pharmacologique, aussi bien "in vitro" que "in vivo", à la différence des produits de référence. La N-acetyl-cysteine est active "in vitro", ne l'étant pas "in vivo" du fait que ses groupes actifs sont inactivés par les mucines digestives. La carboxyméthylcystéine, au contraire, ne présente pas d'activité pharmacologique "in vivo", ses groupes actifs étant protégés, ce qui, d'autre part, lui permet de passer la barrière digestive sans être inactivée. The product according to the invention has demonstrated its pharmacological activity, both "in vitro" and "in vivo", unlike the reference products. N-acetyl-cysteine is active "in vitro", not being "in vivo" because its active groups are inactivated by digestive mucins. Carboxymethylcysteine, on the contrary, does not exhibit pharmacological activity "in vivo", its active groups being protected, which, on the other hand, allows it to pass the digestive barrier without being inactivated.

Les études pharmacodynamiques ont été réa- lisées aussi bien "in vitro" que "in vivo". L'étude de l'action "in vitro" sur la viscosite de la secretion bronchiale d'origine hospitalière a été definie à l'aide d'un microviscosimètre Well
Brookfield. Le produit, objet de l'invention,a démontre un effet mucolytique de 87,10 % à une concentration de 0,05M, tandis qu'à cette meme concentration l'action de la carboxymethylcysteine était pratiquement nulle. L'activité pharmacologique "in vivo" a été démontrée sur le bronchospasme histaminique, induit sur le cobaye, selon la technique de Konsett-Rossler. La methode se base sur la mesure de la dilatation pulmonaire sur des animaux soumis à respiration constante.Pharmacodynamic studies have been performed both "in vitro" and "in vivo". The study of the "in vitro" action on the viscosity of the bronchial secretion of hospital origin was defined using a microviscosimeter Well
Brookfield. The product, object of the invention, demonstrated a mucolytic effect of 87.10% at a concentration of 0.05M, while at this same concentration the action of carboxymethylcysteine was virtually zero. "In vivo" pharmacological activity has been demonstrated in guinea pig induced histamine bronchospasm using the Konsett-Rossler technique. The method is based on the measurement of pulmonary dilatation in animals subjected to constant respiration.

Le produit selon l'invention a donné les résultats suivants Dose mg/kg Voie Inhibition > %, # #
1 p.o. 7,4 + 1,5
1 i.d. 14,9 + 3,7
1 i.v. 8,9 t:2,2
La sécrétion bronchopulmonaire du rat "in vivo" a également ete étudiée selon la technique de Dalham4 en induisant la sécrétion bronchiale par injection sous-cutanee de pilocarpine (0,2 mg/kg). On a mesuré les volumes sécrétés pendant 3 h, tant chez les animaux traités avec le produit selon l'invention que chez les animaux témoins traites avec le serum physiologique. L'administration orale du produit à 50 mg/kg produit une augmentation moyenne de la sécrétion de 35,7 %, cette augmentation étant de 25 % pour la carboxyméthylcystéine et nulle pour la N-acétylcystéine. The product according to the invention gave the following results Dose mg / kg Inhibition channel>%, # #
1 in 7.4 + 1.5
1 id 14,9 + 3,7
1 iv 8,9 t: 2,2
Bronchopulmonary secretion of the rat "in vivo" was also studied according to the Dalham technique4 by inducing bronchial secretion by subcutaneous injection of pilocarpine (0.2 mg / kg). The secreted volumes were measured for 3 h, both in the animals treated with the product according to the invention and in the control animals treated with the physiological saline. Oral administration of the product at 50 mg / kg produced a mean increase in secretion of 35.7%, this increase being 25% for carboxymethylcysteine and zero for N-acetylcysteine.

L'étude pharmacocinetique du compose selon l'invention a ete déterminée après administration orale2 en doses uniques de 500 mg/kg, à differents groupes de rats. The pharmacokinetic study of the compound according to the invention was determined after oral administration in single doses of 500 mg / kg to different groups of rats.

On a determine la concentration du produit dans le sérum à differents moments, après son administration orale, par chromatographie en phase gazeuse, après avoir transforme au prealable le compose en son derivé triméthyl-s;lyîé. Les résultats obtenus indiquent que le composé selon l'invention est stable dans le suc gastrique (il y a seulement hydrolyse de 10 X après 7 ou 8 h), il est rapidement absorbé, atteignant les teneurs sanguines maxinales 2-3 h après son administration orale. Il reste plus longtemps dans l'organisme que la S-carboxyméthylcystéine, ayant été détecté dans des échantillons de sérum prélevées 15 h après son administration. The concentration of the product in the serum was determined at different times, after oral administration, by gas chromatography, after having first converted the compound to its trimethylsulfate derivative. The results obtained indicate that the compound according to the invention is stable in the gastric juice (there is only hydrolysis of 10 X after 7 or 8 hours), it is rapidly absorbed, reaching the maximum blood levels 2-3 hours after its administration. oral. It remains longer in the body than S-carboxymethylcysteine, which has been detected in serum samples collected 15 hours after administration.

Exemple de capsules (quantités par capsule)
Produit selon l'invention 200 mg
Amidon 100 mg
Lactose 81 mg
"Âéros il" 10 mg
Polyvinylpyrrolidone 8 mg
Stéarate de magnesium 6 mg
Exemple de sachets (quantites par sachet)
Produit selon l'invention 100 mg
Saccharose 250 mg
Polyvinylpyrrolidone 10 mg
Colorant 1 mg
Arme 20 mg
Saccharine 5 mg
Il est entendu que l'invention n'est pas limitée aux modes de realisation préférées décrits ci-dessus à titre d'illustration et que l'homme de l'art peut y apporter diverses modifications et divers changements sans toutefois s'écarter du cadre et de l'esprit de l'invention. Example of capsules (quantities per capsule)
Product according to the invention 200 mg
Starch 100 mg
Lactose 81 mg
"Heeros it" 10 mg
Polyvinylpyrrolidone 8 mg
Magnesium stearate 6 mg
Example of sachets (quantities per sachet)
Product according to the invention 100 mg
Sucrose 250 mg
Polyvinylpyrrolidone 10 mg
Dye 1 mg
Weapon 20 mg
Saccharin 5 mg
It is to be understood that the invention is not limited to the preferred embodiments described above by way of illustration and that those skilled in the art may make various modifications and changes thereof without departing from the scope of the invention. and the spirit of the invention.

Claims (5)

REVENDICATIONS 1. Nouveau compose caractérisé en ce qu'il correspond à la N S-diacetylcysteine dont la formule est la suivante1. New compound characterized in that it corresponds to N S-diacetylcysteine whose formula is as follows
Figure img00050001
Figure img00050001
 2. Procédé de préparation du compose selon la revendication 1, caracterise en ce que l'on dissout le chlorhydrate de cys téine ou la base libre dans l'hydroxyde de sodium à une température qui ne depasse pas 15 C, on ajoute lentement de l'anhydride acétique à cette solution en maintenant la temperature entre -50C et 50C, on fait reagir en agitant pendant 2 à 3 h à une température comprise entre -50C et 50C et puis, au repos, pendant une nuit à une temperature inferieure à OOC, on ajoute lentement de l'acide chlorhydrique concentre en agitant et en maintenant la temperature entre -50C et 50C, on maintient l'agitation dans ce même intervalle de tem perature pendant 3 h, on extrait par l'acétate d'ethyle, on sèche extrait organique sur Na2SO4 anhydre et on amène à siccité, on lave le residu solide 3 fois par l'éther éthylique, on filtre la suspension et on sèche le solide sous vide. 2. Process for the preparation of the compound according to claim 1, characterized in that the cysteine hydrochloride or the free base is dissolved in sodium hydroxide at a temperature not exceeding 15 C. Acetic anhydride to this solution while maintaining the temperature between -50C and 50C, is reacted with agitation for 2 to 3 hours at a temperature between -50C and 50C and then, at rest, overnight at a temperature below OOC Concentrated hydrochloric acid is slowly added with stirring and the temperature is maintained at -50 ° C. to 50 ° C., the stirring is maintained in the same temperature range for 3 hours, and the mixture is extracted with ethyl acetate. The organic extract is dried over anhydrous Na 2 SO 4 and brought to dryness, the solid residue is washed 3 times with ethyl ether, the suspension is filtered and the solid is dried under vacuum. 3. Nouveau medicament, utile notamment comme agent mucolytique et antihistaminique, caractérisé en ce qu'il consiste en N, S-dlacétylcysteine selon la revendication 1.3. New drug, useful in particular as a mucolytic and antihistaminic agent, characterized in that it consists of N, S-dlacetylcysteine according to claim 1. 4. Compositions pharmaceutiques, caractérisées en ce qu'elles contiennent comme ingrédient actif le médicament selon la revendication 3, en association avec des excipients et vehicules acceptables en pharmacie.4. Pharmaceutical compositions, characterized in that they contain as active ingredient the drug according to claim 3, in association with excipients and vehicles acceptable in pharmacy. 5. Forme d'administration des compositions selon la revendication 4. 5. Form of administration of the compositions according to claim 4.
FR8303958A 1982-03-11 1983-03-10 N, S-DIACETYLCYSTEINE USEFUL AS A MUCOLYTIC AGENT, ITS MANUFACTURING PROCESS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME Withdrawn FR2523127A1 (en)

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ES510320A ES510320A0 (en) 1982-03-11 1982-03-11 "PROCEDURE FOR OBTAINING N, N, -DIAZETYL CYSTEINE".

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DE (1) DE3307236A1 (en)
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FR (1) FR2523127A1 (en)
IT (1) IT1165580B (en)
PT (1) PT76148B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0106341A2 (en) * 1982-10-20 1984-04-25 Takeda Chemical Industries, Ltd. Physiologically active substance P-23924, its production and use
USRE34414E (en) * 1982-10-20 1993-10-19 Takeda Chemical Industries, Ltd. Physiologically active substance P-23924, its production and use

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Publication number Priority date Publication date Assignee Title
FR4619M (en) * 1965-02-01 1966-11-28

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FR4619M (en) * 1965-02-01 1966-11-28

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IL FARMACO EDIZIONE SCIENTIFICA, volume 31, no. 11, novembre 1976, M. PORTELLI et al. "Synthesis of N-acetylcysteine compounds", pages 768-775 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0106341A2 (en) * 1982-10-20 1984-04-25 Takeda Chemical Industries, Ltd. Physiologically active substance P-23924, its production and use
EP0106341A3 (en) * 1982-10-20 1986-10-15 Takeda Chemical Industries, Ltd. Physiologically active substance p-23924, its production and use
USRE34414E (en) * 1982-10-20 1993-10-19 Takeda Chemical Industries, Ltd. Physiologically active substance P-23924, its production and use

Also Published As

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IT1165580B (en) 1987-04-22
BR8300798A (en) 1983-11-16
PT76148A (en) 1983-02-01
ES8305322A1 (en) 1983-04-01
IT8347886A0 (en) 1983-03-10
ES510320A0 (en) 1983-04-01
PT76148B (en) 1985-11-25
DE3307236A1 (en) 1983-10-13

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