BE897948A - NEW SULPIRIDE DERIVATIVE, PROCESS FOR OBTAINING SAME AND THERAPEUTIC USE - Google Patents

NEW SULPIRIDE DERIVATIVE, PROCESS FOR OBTAINING SAME AND THERAPEUTIC USE Download PDF

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Publication number
BE897948A
BE897948A BE0/211669A BE211669A BE897948A BE 897948 A BE897948 A BE 897948A BE 0/211669 A BE0/211669 A BE 0/211669A BE 211669 A BE211669 A BE 211669A BE 897948 A BE897948 A BE 897948A
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Prior art keywords
sulpiride
indomethacin
salt
water
new
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BE0/211669A
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French (fr)
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Espinos & Bofill Lab Sa
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Publication of BE897948A publication Critical patent/BE897948A/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/10Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C07D209/281-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Pyrrole Compounds (AREA)

Description

       

   <Desc/Clms Page number 1> 
 



  Description jointe à une demande de
BREVET BELGE déposée parla société dite : LABORATORIOS ESPINOS Y   BOFILL, S. A   ayant pour objet : Nouveau dérivé du sulpiride, son procédé d'obtention et son utilisation thérapeu- tique Qualification proposée : BREVET D'INVENTION Priorité d'une demande de brevet déposée en Espagne le 8 octobre 1982 sous le nO 516. 786 

 <Desc/Clms Page number 2> 

 
La présente invention concerne un composé nouveau dérivé du sulpiride, dont la formule développée est la suivante :

   
 EMI2.1 
 
 EMI2.2 
 Ce nouveau composé, dénommé l- méthoxY-3-indolylacétae de N- (l-éthyl-2-pyrrolidinyl)-méthyl-2méthoxY-5-sulfamoylbenzamide, se sous la forme d'un solide cristallin jaune qui fond à 156-1572C et qui est formé par l'union d'une molécule d'indométacine et d'une molécule de sulpiride, ce qui fait qu'il possède les propriétés thérapeutiques remarquables de l'indométacine par le sulpiride qui est uni à celle-ci moléculairement.

   En conséquence de cette combinaison, le nouveau produit conserve le pouvoir anti-inflammatoire de l'indométacine, favorise sa bio-disponibilité et diminue ses effets nuisibles sur l'estomac, L'invention a également pour objet un procédé pour l'obtention du composé dénommé l- (p-cblorobenzoyl) acétate de N- 

 <Desc/Clms Page number 3> 

    (p-cblorobenzoyl) -2-méthyl-5-benzamid.   Ce procédé est d'exécution facile, il permet d'utiliser des solvants ordinaires et il donne un produit de grande pureté. 



   Suivant le procédé de l'invention, on fait réagir, en proportions moléculaires, l'indométacine ou ses sels avec le sulpiride ou ses sels. En tant que sels de   l'indométacine,.   on peut utiliser un sel de l'indométacine-avec une base organique ou un sel de l'indométacine avec une base inorganique et, en tant que sel du sulpiride, un sel du sulpiride avec un acide organique ou un sel du sulpiride avec un acide inorganique. 



   Le milieu dans lequel on mène la réaction peut être choisi parmi l'eau, l'eau avec un solvant organique miscible à l'eau et un mélange de solvants organiques, ce milieu étant maintenu, pendant la réaction, à une température comprise entre   202C   et   80 C.   
 EMI3.1 
 



  Différents exemples de la préparation du l- (p-chlorobenzpyl)- 2-méthyl-5-méthoxY-3-indolylacétate de N-    (l-éthyl-2-pyrrolidinyl)-rnéthyl-2-méthoxY-5-sulfamoylbenzamide   sont donnés ci-après, sans qu'ils apportent la moindre limitation à la portée de l'invention. 



  Exemple 1
40 g d'indométacine sont mis en suspension, sous agitation, dans 250 ml d'acétate d'éthyle. 



   On chauffe   la : suspension à 602C   et on y ajoute 34 g de sulpiride. On continue à agiter et à chauffer pendant 15 minutes, puis on refroidit rapidement à la température ambiante. On filtre et on lave à l'acétate d'éthyle. 



   Le produit résultant est recristallisé dans 3250 ml   d'isopro-   panol. On obtient environ 60 g d'un solide jaune cristallin (rendement, 82 %) de point de fusion   156-l572C.   



  Exemple 2
A une solution de 30 g de triéthylamine dans 300 ml de méthanol, on ajoute, sous agitation et à la température ambiante, 100 g d'indométacine. 



   On verse la solution obtenue sur une autre solution de 94 g de sulpiride dans 280 ml d'acide acétique N. On agite pendant 15 minutes environ. La solution obtenue est évaporée sous vide et le résidu de la concentration est recristallisé à partir d'isopropanol. 

 <Desc/Clms Page number 4> 

 



   On obtient environ 160 g de cristaux jaunes, de point de fusion   l56-l57QC.   



  Exemple 3 
 EMI4.1 
 50 g d'indométacine sont dissous température ambiante a dans 1400 ml de soude caustique 0, 1   N.   



   En une opération séparée, on dissout 47 g de sulpiride dans 140 ml d'acide acétique   N   et on dilue la solution avec 1000   ml   d'eau distillée. 



   Les deux solutions sont mélangées sous agitation. On continue à agiter la solution obtenue à la température ambiante pendant 15 minutes et on concentre sous vide. Le résidu solide obtenu est recristallisé dans l'isopropanol. 



   On obtient environ 78-80 g d'une poudre jaune cristallisée ayant un point de fusion de   156-157± ? C.   



  Exemple 4
On prépare une solution de 100 g (0,28 mol) d'indométacine 
 EMI4.2 
 et de 30 g (0, 3) de triéthylamine dans 300 ml de méthanol à une température de   402C.   



   En une opération séparée, on prépare une autre solution de 100 g (0,26 mole) de chlorhydrate de sulpiride dans 300 ml d'eau distillée à une température de   702C. \  
On filtre les deux solutions et on les mélange à   702C   ; puis on agite le mélange à cette température pendant l heure. La solution est refroidie et abandonnée au réfrigérateur pendant quelques heures. On filtre le solide qui se sépare et on le lave   avec un mélan-   ge de méthanol et d'eau (1 :   l).   



   Finalement, on recristallise dans 7, 5 1 d'isopropanol. On 
 EMI4.3 
 obtient 150 g d'un solide cristallin jaune, de point de fusion 156-157 C (rendement, 83 %). 



  La formule de la molécule est C-. CIN. 



  34 39 4 8 
L'analyse   élémentaire   de la substance obtenue a donné les résultats suivants : calculé : C = 58,40, H = 5, 62, N =   8, 01, Cl   =   5, 07, S =   4,59 trouvé : C =   58,} 4, H   =   5, 6 ,   N =   8, 04, Cl   =   5, 05, S =   4,50. 



   Dans son spectre IR, on observe les bandes d'absorption 

 <Desc/Clms Page number 5> 

 suivantes :
3370 cm-1 ........... (2,97 nm) 
 EMI5.1 
 3320 cm.......... (3, 01 nm) 1650 06 nm) -1 1610 cm.......... (6, 21 nm) 1230 cm-.......... (8, i3 nm) 860 cm.......... 11, 6 nm) 825 (12, 1 nm) -1 810 cm.......... 3 nm) 
800 cm.......... (12, 5 nm) 
Le nouveau composé selon la présente invention possède les propriétés anti-inflammatoires de l'indométacine, potentialisée par le sulpiride, et en a donc les indications thérapeutiques. 



  Il est avantageusement utilisé sous forme de compositions thérapeutiques dont il constitue un ingrédient actif, en présence   d'exclu   pients et diluants classiques.



   <Desc / Clms Page number 1>
 



  Description attached to a request for
BELGIAN PATENT filed by the company known as: LABORATORIOS ESPINOS Y BOFILL, S. A relating to: New derivative of sulpiride, its process of obtaining and its therapeutic use Qualification proposed: PATENT OF INVENTION Priority of a patent application filed in Spain on October 8, 1982 under No. 516. 786

 <Desc / Clms Page number 2>

 
The present invention relates to a new compound derived from sulpiride, the structural formula of which is as follows:

   
 EMI2.1
 
 EMI2.2
 This new compound, called l- methoxY-3-indolylacetae of N- (1-ethyl-2-pyrrolidinyl) -methyl-2methoxY-5-sulfamoylbenzamide, is in the form of a yellow crystalline solid which melts at 156-1572C and which is formed by the union of an indomethacin molecule and a sulpiride molecule, which means that it has the remarkable therapeutic properties of indomethacin by the sulpiride which is molecularly united to it.

   As a result of this combination, the new product retains the anti-inflammatory power of indomethacin, promotes its bio-availability and reduces its harmful effects on the stomach. The invention also relates to a process for obtaining the compound referred to as N- (p-cblorobenzoyl) acetate

 <Desc / Clms Page number 3>

    (p-cblorobenzoyl) -2-methyl-5-benzamid. This process is easy to perform, it allows the use of ordinary solvents and it gives a product of high purity.



   According to the process of the invention, indomethacin or its salts are reacted, in molecular proportions, with the sulpiride or its salts. As the salts of indomethacin ,. one can use a salt of indomethacin with an organic base or a salt of indomethacin with an inorganic base and, as the salt of sulpiride, a salt of sulpiride with an organic acid or a salt of sulpiride with an acid inorganic.



   The medium in which the reaction is carried out can be chosen from water, water with an organic solvent miscible with water and a mixture of organic solvents, this medium being maintained, during the reaction, at a temperature between 202C and 80 C.
 EMI3.1
 



  Different examples of the preparation of 1- (p-chlorobenzpyl) - 2-methyl-5-methoxY-3-indolylacetate of N- (1-ethyl-2-pyrrolidinyl) -nethyl-2-methoxY-5-sulfamoylbenzamide are given below. -after, without them bringing the slightest limitation to the scope of the invention.



  Example 1
40 g of indomethacin are suspended, with stirring, in 250 ml of ethyl acetate.



   The suspension is heated to 602C and 34 g of sulpiride are added thereto. Continue to stir and heat for 15 minutes, then cool quickly to room temperature. It is filtered and washed with ethyl acetate.



   The resulting product is recrystallized from 3250 ml of isopropanol. About 60 g of a yellow crystalline solid are obtained (yield, 82%) of melting point 156 -1572C.



  Example 2
To a solution of 30 g of triethylamine in 300 ml of methanol, 100 g of indomethacin is added, with stirring and at room temperature.



   The solution obtained is poured onto another solution of 94 g of sulpiride in 280 ml of acetic acid N. The mixture is stirred for approximately 15 minutes. The solution obtained is evaporated in vacuo and the residue of the concentration is recrystallized from isopropanol.

 <Desc / Clms Page number 4>

 



   About 160 g of yellow crystals are obtained, with a melting point of 156-557QC.



  Example 3
 EMI4.1
 50 g of indomethacin are dissolved at room temperature in 1400 ml of 0.1N caustic soda



   In a separate operation, 47 g of sulpiride are dissolved in 140 ml of acetic acid N and the solution is diluted with 1000 ml of distilled water.



   The two solutions are mixed with stirring. The solution obtained is further stirred at room temperature for 15 minutes and concentrated in vacuo. The solid residue obtained is recrystallized from isopropanol.



   Approximately 78-80 g of a yellow crystallized powder are obtained, having a melting point of 156-157 ±? vs.



  Example 4
A solution of 100 g (0.28 mol) of indomethacin is prepared
 EMI4.2
 and 30 g (0.3) of triethylamine in 300 ml of methanol at a temperature of 402C.



   In a separate operation, another solution of 100 g (0.26 mole) of sulpiride hydrochloride in 300 ml of distilled water is prepared at a temperature of 702C. \
The two solutions are filtered and mixed at 702C; then the mixture is stirred at this temperature for 1 hour. The solution is cooled and left in the refrigerator for a few hours. The solid which separates is filtered and washed with a mixture of methanol and water (1: 1).



   Finally, recrystallized from 7.5 l of isopropanol. We
 EMI4.3
 obtains 150 g of a yellow crystalline solid, melting point 156-157 C (yield, 83%).



  The formula of the molecule is C-. CIN.



  34 39 4 8
Elemental analysis of the substance obtained gave the following results: calculated: C = 58.40, H = 5.62, N = 8.01, Cl = 5.07, S = 4.59 found: C = 58 ,} 4, H = 5, 6, N = 8, 04, Cl = 5, 05, S = 4.50.



   In its IR spectrum, we observe the absorption bands

 <Desc / Clms Page number 5>

 following:
3370 cm-1 ........... (2.97 nm)
 EMI5.1
 3320 cm .......... (3, 01 nm) 1650 06 nm) -1 1610 cm .......... (6, 21 nm) 1230 cm -..... ..... (8, i3 nm) 860 cm .......... 11, 6 nm) 825 (12, 1 nm) -1 810 cm .......... 3 nm)
800 cm .......... (12.5 nm)
The new compound according to the present invention has the anti-inflammatory properties of indometacin, potentiated by sulpiride, and therefore has therapeutic indications.



  It is advantageously used in the form of therapeutic compositions of which it constitutes an active ingredient, in the presence of excluded pients and conventional diluents.


    

Claims (8)

EMI6.1  EMI6.1   REVENDICATIONS - ----- 1. Nouveau dérivé du sulpiride, dénommé l- méthyl-5-méthoxY-3-indolylacétate de N- méthyl-2-méthoxY-5-sulfamoylbenzamide, ayant pour formule EMI6.2 et étant un produit d'addition moléculaire formé d'une molécule d'indométacine et d'une molécule de sulpiride. CLAIMS - ----- 1. New derivative of sulpiride, called 1-methyl-5-methoxY-3-indolylacetate of N-methyl-2-methoxY-5-sulfamoylbenzamide, having the formula  EMI6.2  and being a molecular adduct formed from an indomethacin molecule and a sulpiride molecule. 2. Procédé pour l'obtention d'un dérivé nouveau du sulpiride EMI6.3 dénommé l- N- (1-étbyl-2-pyrrolidinyl) caractérisé en ce qu'on fait réagir, en proportions moléculaires, l'indométacine et le sulpiride, soit tels quels, soit sous forme de leurs sels, dans un milieu choisi parmi l'eau, l'eau avec un solvant organique miscible à l'eau, un solvant organique et un mélange de solvants organiques, ce milieu étant maintenu à une température comprise entre 20 C et 80 C, puis on isole et on purifie <Desc/Clms Page number 7> le compose obtenu dans la réaction. 2. Method for obtaining a new derivative of sulpiride  EMI6.3  called l- N- (1-etbyl-2-pyrrolidinyl) characterized in that indomethacin and sulpiride are reacted, in molecular proportions, either as such or in the form of their salts, in a medium chosen from water, water with an organic solvent miscible with water, an organic solvent and a mixture of organic solvents, this medium being maintained at a temperature between 20 ° C. and 80 ° C., then isolated and purified  <Desc / Clms Page number 7>  the compound obtained in the reaction. 3. Procédé selon la revendication 2, caractérisé en ce que l'indométacine est utilisée sous la forme d'un sel de l'indométa- cine avec une base organique. EMI7.1 e e3. Method according to claim 2, characterized in that indomethacin is used in the form of a salt of indomethacin with an organic base.  EMI7.1  e e 4. Procédé selon revendication 2, caractérisé en ce que l'indométacine est utilisée sous la forme d'un sel de l'indométacine avec une base inorganique. 4. Method according to claim 2, characterized in that indomethacin is used in the form of a salt of indomethacin with an inorganic base. 5. Procédé selon la revendication 2, caractérisé en ce que le sulpiride est utilisé sous la forme d'un sel du sulpiride avec un acide organique.   5. Method according to claim 2, characterized in that the sulpiride is used in the form of a salt of the sulpiride with an organic acid. 6. Procédé selon la revendication 2, caractérisé en ce que le sulpiride est utilisé sous la forme d'un sel du sulpiride avec un acide minéral. 6. Method according to claim 2, characterized in that the sulpiride is used in the form of a salt of the sulpiride with a mineral acid. 7. Utilisation du composé selon la revendication 1 comme agent anti-inflammatoire. 7. Use of the compound according to claim 1 as an anti-inflammatory agent. 8. Composition thérapeutique contenant comme ingrédient actif le composé selon la revendication l, et des excipients et diluants classiques. 8. Therapeutic composition containing as active ingredient the compound according to claim 1, and conventional excipients and diluents.
BE0/211669A 1982-10-08 1983-10-07 NEW SULPIRIDE DERIVATIVE, PROCESS FOR OBTAINING SAME AND THERAPEUTIC USE BE897948A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
ES516786A ES516786A0 (en) 1982-10-08 1982-10-08 PROCEDURE FOR OBTAINING A NEW DERIVATIVE OF THE SULPIRIDE.

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BE897948A true BE897948A (en) 1984-01-30

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JP (1) JPS5988463A (en)
BE (1) BE897948A (en)
DE (1) DE3336762A1 (en)
ES (1) ES516786A0 (en)
FR (1) FR2534254B1 (en)
GB (1) GB2129792B (en)
PT (1) PT77463B (en)

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AU2003227517A1 (en) * 2002-05-23 2003-12-12 Danmarks Farmaceutiske Universitet Pharmacologically active salts

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AT370721B (en) * 1981-02-24 1983-04-25 Ciba Geigy Ag METHOD FOR PRODUCING NEW SALTS OF 2- (2,6-DICHLORANILINO) -PHENYLACETIC ACID, THE

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FR2534254B1 (en) 1985-07-12
DE3336762A1 (en) 1984-04-12
FR2534254A1 (en) 1984-04-13
PT77463B (en) 1986-02-26
GB2129792A (en) 1984-05-23
JPS5988463A (en) 1984-05-22
ES8407042A1 (en) 1984-09-01
PT77463A (en) 1983-11-01
GB2129792B (en) 1986-02-12
GB8326619D0 (en) 1983-11-09
ES516786A0 (en) 1984-09-01

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