BE820919A - DIURETIC FORMULAS - Google Patents

DIURETIC FORMULAS

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Publication number
BE820919A
BE820919A BE149401A BE149401A BE820919A BE 820919 A BE820919 A BE 820919A BE 149401 A BE149401 A BE 149401A BE 149401 A BE149401 A BE 149401A BE 820919 A BE820919 A BE 820919A
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Belgium
Prior art keywords
emi
carbon atoms
acid
thienyl
methyl
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BE149401A
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French (fr)
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Publication of BE820919A publication Critical patent/BE820919A/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
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    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
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    • C07C255/11—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton
    • C07C255/13—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
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    • C07C333/14—Dithiocarbamic acids; Derivatives thereof
    • C07C333/18—Esters of dithiocarbamic acids
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    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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    • C07C45/46—Friedel-Crafts reactions
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    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
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    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
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    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
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    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
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    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
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    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
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    • C07C59/40—Unsaturated compounds
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
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  • Animal Behavior & Ethology (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Description

       

  Formules de diurétiques. 

  
La présents invention concerne des compositions pharmaceutiques et particulièrement des préparations qui ont d'avantageuses propriétés diurétiques et/ou salurétiques. Par simplicité, on utilisera dans ce qui va suivre le terme "diurétique" dans un sens courant ou générique, pour désigner des médicaments qui provoquent la diurèse (augmentent l'excrétion de l'urine) et/ou la salurèse (augmentation de l'excrétion d'électrolytes).

  
Les diurétiques sont de précieux agents thérapeutiques en ce sens qu'ils sont utiles dans le traitement de maladies cardio-vasculaires et rénales. Leur application est indiquée dans le traitement de tous les genres et degrés de gravité d'états de déficiences cardiaques congestives pour lesquels il est

  
 <EMI ID=1.1> 

  
son des pertes résultantes en eau et en électrolytes on note une amélioration considérable dans l'oedème pulmonaire et périphérique, de la dyspnée, de l'orthopnée, de la toux, des ascites et de l'effusion pleurale.

  
Ces médicaments fournissent également une thérapie

  
 <EMI ID=2.1> 

  
dème qui est associé à la néphrose et certains types de néphrite. Leur administration donne lieu à une prompte excrétion du liquide retenue et des électrolytes, avec le bénéfice concomitant pour le patient. L'électrolyte qu'on désire excréter est le chlorure de sodium. 

  
Ces médicaments sont particulièrement utiles lors du traitement de l'hypertension et fournissent une thérapie rapide utile dans les formes bénignes, modérées et graves de la maladie.

  
Bien que les diurétiques sauvent souvent la vie en rai-,son des effets bénéfiques thérapeutiques précédents, la plupart d'entre eux ont des inconvénients liés à l'excrétion de quantités appréciables d'ions potassium. Lorsqu'une perte excessive en ions potassium se produit, il en résulte une grave faiblesse musculaire et une sensation d'extrême épuisement physique. Le  patient élimine les ions sodium indésirables en raison de l'action des médicaments diurétiques mais l'élimination des ions potassium qui n'est pas désirée, provoque un déséquilibre qu'on ne doit pas laisser persister. 

  
En plus de leurs autres effets, ces composés sont capables de conserver la concentration en acide urique dans le corps aux taux antérieurs au traitement ou souvent même effectuent une diminution de la concentration en acide urique. De nombreux diurétiques et salurétiques actuellement disponibles ont tendance, lors de l'administration, à induire l'hyperuricémie qui peut précipiter l'acide urique ou l'urate de sodium, ou les deux, dans le corps, ce qui peut provoquer des cas de goutte modérés à graves. Les composés selon la présente invention fournissent présentement un outil efficace pour traiter ceux des patients qui exigent un traitement diurétique et salurétique sans encourir de risque d'induction de la goutte.

  
La présente invention implique l'administration conjointe d'un acide (1-oxo-2,2-disubstitué-5-indanyloxy)-acétique avec des pyrrazinoyl-guanidines, sous forme de mélange ou sous forme de sel, avec une ptéridine sous forme de mélange ou sous forme de sel ou avec une spironolactone sous forme de mélange, ce qui réduit la quantité des ions potassium qui sont éliminés sans diminuer la quantité des ions sodium qui sont à éliminer.

  
Un autre avantage dans le cas des diurétiques sels de N-amidino-3,5-diamino-6-chloro-pyrazine-carboxamide de l'acide
(1-oxo-2,2-disubstitué-5-indanyloxy)-acétique, est leur insolubilité qui rend l'absorption gastro-intestinale des sels plus lente et plus graduelle, fournissant un procédé chimique pour parvenir au même effet que la micro-encapsulation.

  
Les acides [1-oxo-2,2-disubstitués-5-indanyloxy (ou thio)]-alcanoïques utiles selon la présente invention, qui comprennent les racémates et les énantiomères purs présentent la formule struturelle suivante :

  

 <EMI ID=3.1> 


  
dans laquelle A représente un atome d'oxygène ou de soufre, R représente un groupe alcoyle inférieur contenant de 1 à 5 atomes de carbone, comme les groupes méthyle, éthyle, n-propyle, isopropyle, n-butyle, isobutyle, tert.-butyle, n-pentyle et analogues; des groupes cycloalcoyle, par exemple un groupe cycloalcoyle contenant de 5 à 6 atomes de carbone nucléaires comme les groupes cyclopentyle, cyclohexyle et analogues, des groupes aryle comme le groupe phényle et des groupes aryles substitués dans lesquels le substituant est un groupe alcoyle inférieur,

  
un atome d'halogène, un groupe alcoxy inférieur, hydroxy, amino ou aminométhyle, un groupe thiényle et thiényle substitué dans lequel le substituant est un groupe alcoyle inférieur ou un

  
 <EMI ID=4.1> 

  
contenant de 1 à 5 atomes de carbone, comme les groupes méthyle, éthyle, n-propyle, isopropyle, n-butyle, isobutyle, tert.butyle, n-pentyle et analogues, un groupe alcényle inférieur contenant de 3 à 5 atomes de carbone, comme les groupes allyle, 1-, 2- ou 3-butényle, 1-, 2- ou 3- ou 4-pentényle et analogues, des groupes alcynyle inférieurs contenant de 3 à 5 atomes de

  
 <EMI ID=5.1> 

  
2-, 3- ou 4-pentynyle et analogues, un groupe phényl-alcoyle inférieur dans lesquels le groupe alcoyle inférieur contient de 1 à 3 atomes de carbone, comme les groupes benzyle, phénéthyle, phényl-propyle et analogues, les groupes phényl-alcényle inférieur dans lesquels le groupe alcényle inférieur contient de

  
2 à 5 atomes de carbone comme le groupe cinnamyle et analogues, des groupes aryle comme le groupe phényle, ou aryle substitué comme les groupes alcoyl(inférieur)-aryle ou halogéno-aryle; des groupes thiényle ou thiényle substitué comme les groupes alcoyl(inférieur)-thiényle ou halogéno-thiényle, ou bien R et R<1> peuvent être reliés ensemble avec les atomes de carbone auxquels ils sont fixés pour former un radical cycloalcoyle contenant de 3 à 7 atomes de carbone nucléaires, par exemple les groupes cyclopropyle, cyclobutyle, cyclopentyle, cyclohexyle,

  
 <EMI ID=6.1> 

  
un groupe méthyle, ou un atome d'halogène comme le chlore, le

  
 <EMI ID=7.1> 

  
ou un atome d'halogène comme le chlore, le brome, le fluor et

  
 <EMI ID=8.1>  chaîne hydrocarbylène contenant de 3 à 4 atomes de carbone, par

  
 <EMI ID=9.1> 

  
logues, et Y représente un radical alcoylène ou halogéno-alcoylène présentant un maximum de 4 atomes de carbone, qui contient de 1 à 3 atomes de carbone linéaires entre le groupe oxy (ou thio) et le groupe carboxy, par exemple les groupes méthylène, éthylidène, propylidène, isopropylidène, éthylène, triméthylène, fluorométhylène et analogues; la présente invention englobe les formes racémiques et les énantiomères des composés décrits.

  
Les acides préférés (1-oxo-2,2-substitué-5-indanyloxy
(ou thio)]alcanoïques, utiles selon la présente invention présentent la formule structurelle suivante :

  

 <EMI ID=10.1> 


  
dans laquelle R' représente un groupe alcoyle contenant 1 à 3 atomes de carbone comme les groupes méthyle, éthyle, n-propyle ou isopropyle ou cycloalcoyle contenant de 5 ou 6 atomes de carbone nucléaires comme les groupes cyclopentyle ou cyclo-  hexyle et R4 représente un groupe alcoyle inférieur contenant de 1 à 3 atomes de carbone, comme les groupes méthyle, éthyle, n-propyle ou isopropyle, un groupe phényle, alcoyl(inférieur)phényle dans lequel le groupe alcoyle inférieur contient de

  
1 à 3 atomes de carbone comme les groupes méthyle, éthyle, n-propyle ou isopropyle, halogénophényle, méthoxyphényle,

  
 <EMI ID=11.1> 

  
alcoyl(inférieur)-thiényle, dans lequel le groupe alcoyle inférieur contient de 1 à 3 atomes de carbone, comme les groupes

  
 <EMI ID=12.1> 

  
sont fixés pour former un radical cycloalcoyle contenant de 5 à 6 atomes de carbone nucléaires, comme les radicaux cyclopentyle,

  
 <EMI ID=13.1> 

  
identiques ou différents choisis parmi le groupe méthyle ou un atome de chlore, les formes racémiques et les énantiomères des composés décrits sont également inclus. 

  
 <EMI ID=14.1> 

  
alcanoiques particulièrement préférés selon la présente invention présentent la formule

  

 <EMI ID=15.1> 


  
 <EMI ID=16.1> 

  
1 à 3 atomes de carbone comme les groupes méthyle, éthyle,

  
 <EMI ID=17.1> 

  
nant 1 à 3 atomes de carbone comme les groupes méthyle, éthyle, n-propyle, isopropyle, phényle, p-chlorophényle ou thiényle,

  
 <EMI ID=18.1> 

  
parmi un groupe méthyle ou un atome de chlore.

  
Les composés suivants sont inclus parmi le groupe 

  
 <EMI ID=19.1> 

  
l'acide (1-oxo-2-méthyl-2-phényl-6,7-dichloro-5-indanyloxy)acétique,

  
 <EMI ID=20.1> 

  
acétique,

  
parmi lesquels on préfère tout particulièrement l'acide racémique et lévogyre (1-oxo-2-méthyl-2-phényl-6,7-dichloro-5-indanyloxy)acétique. Bien que ceux-ci soient les préférés parmi les diurétiques de la classe de l'acide indanyloxy-acétique, la présente invention englobe l'utilisation à leur place d'un quelconque des composés apparentés cités précédemment. 

  
- Pour parvenir aux résultats bénéfiques de la présente invention, le composé préféré de pyrazinoyl-guanidine est le  <EMI ID=21.1> 

  
ptéridine (ci-après désignée par."triamterene") ou la spironolactone.

  
La présente invention englobe aussi l'utilisation à

  
la fois de mélanges physiques en proportions variables des diurétiques d'acide (1-oxo-2,2-disubstitué-5-indanyloxy)-acétique et d'amiloride, triamterene ou de spironolactone, et les sels chimiques d'acide (1-oxo-2,2-disubstitué-5-indanyloxy)-acétique et d'amiloride et de triamterene.

  
Le sel d'amiloride et d'un acide (1-oxo-2,2-disubstitué5-indanyloxy)acétique se prépare par addition du composé d'acide

  
 <EMI ID=22.1> 

  
d'amiloride dans un solvant organique approprié miscible à l'eau comme le diméthylsulfoxyde et on verse ensuite la solution résultante dans l'eau, dont on sépare le sel désiré d'amiloride et de l'acide indanyloxy-acétique , et on le recueille par filtration.

  
La présente invention englobe des compositions pour l'administration orale dans lesquelles la proportion molaire

  
 <EMI ID=23.1> 

  
l'amiloride est comprise entre environ 0,2:1 et 4,0:1. Les propor.tions préférées entre l'acide (1-oxo-2,2-substitué-5-indanyloxy)-acétique et l'amiloride sont comprises entre 0,8:1 et 1,6:1. Dans le cas où l'acide indanyloxy-acétique est l'acide (1-oxo-2-

  
 <EMI ID=24.1> 

  
les poids absolus et les rapports pondéraux préférés correspondant aux proportions molaires indiquées ci-dessus, sont donnés au Tableau Ia ci-après. Les données correspondantes pour l'isomère lévogyre sont enregistrées au Tableau Ib : 

  

 <EMI ID=25.1> 


  

 <EMI ID=26.1> 
 

  

 <EMI ID=27.1> 


  

 <EMI ID=28.1> 
 

  
La présente invention concerne aussi des compositions pour l'administration orale dans lesquelles la proportion mo-

  
 <EMI ID=29.1> 

  
méthyl-2-phényl-6,7-dichloro-5-indanyloxy)-acétique, racémique les poids absolus et rapports pondéraux préférés correspondant aux proportions molaires indiquées ci-dessus sont donnés au Tableau IIa. Les données correspondantes pour l'isomère lévogyre sont enregistrés au Tableau IIb 
 <EMI ID=30.1> 
 <EMI ID=31.1> 
 
 <EMI ID=32.1> 
 <EMI ID=33.1> 
 La présente invention englobe des composition&#65533;our l'administration orale dans lesquelles la proportion molaire entre l'acide (1-oxo-2,2-disubstitué-5-indanyloxy)-acétique et la spironolactone est comprise entre environ 1:4,4 et 1:2,2. Dans le cas où l'acide indanyloxy-acétique est l'acide (1-oxo2-méthyl-2-phényl-6,7-dichloro-5-indanyloxy)-acétique racémique, les poids absolus et proportions pondérales préférés correspondant aux proportions molaires.indiquées ci-dessus, sont donnés

  
 <EMI ID=34.1> 

  
lévogyre sont enregistrées au Tableau IIIb. 

  

 <EMI ID=35.1> 


  

 <EMI ID=36.1> 
 

  

 <EMI ID=37.1> 


  

 <EMI ID=38.1> 
 

  
Des exemples représentatifs illustrant la présente invention sont les suivants :

EXEMPLE 1

  
 <EMI ID=39.1> 

  
2-méthyl-2-phényl-6,7-dichloro-5-indanyloxy)-acétique. On verse la solution limpide dans 200 ml d'eau en agitant vigoureusement. On filtre le sel de N-amidino-3,5-diamino-6-chloropyrazinecarboxamide et d'acide-(1-oxo-2-méthyl-2-phényl-6,7-dichloro-5indanyloxy)-acétique qui se sépare, on rince à l'eau et on sèche. Point de fusion 150[deg.]C.

  
 <EMI ID=40.1> 

  
Calculé : C = 48,46; H = 3,73; N = 16,48 

  
Trouvé : C = 48,11; H = 3,42; N = 16,19.

  
EXEMPLE 2 

  
Préparation du sel de 6-phényl-2,4,7-triamino-ptéridine et de l'acide (1-oxo-2-méthyl-2-phényl-6,7-dichloro-5-indanyloxy)-  acétique.

  
On ajoute à une solution chaude de 1,27 g (0,005 mole) de 6-phényl-2,4,7-triamino-ptéridine dans 25 ml de diméthylsulfoxyde, 1,85 g (0,005 mole) d'acide (1-oxo-2-méthyl-2-phényl6,7-dichloro-5-indanyloxy)-acétique. On verse la solution limpide dans 200 ml d'eau en agitant vigoureusement. On filtre le

  
 <EMI ID=41.1> 

  
pare, on rince à l'eau et on sèche.

  
EXEMPLE 3

  
 <EMI ID=42.1> 

  
On ajoute à une solution chaude de 1,15 g (0,005 mole) de N-amidino-3,5-diamino-6-chloropyrazine-carboxamide dans

  
25 ml de diméthylsulfoxyde, 1,85 g (0,005 mole) d'acide lévo-(1oxo-2-méthyl-2-phényl-6,7-dichloro-5-indanyloxy)-acétique. On verse la solution limpide dans 200 ml d'eau en agitant vigoureusement. On filtre le sel de N-amidino-3,5-diamino-6-chloropyrazine-carboxamide et d'acide Lévo-(1-oxo-2-méthyl-2-phényl6,7-dichloro-5-indanyloxy)-acétique qui se sépare, on rince à l'eau et on sèche.

  
EXEMPLE 4

  
Préparation du sel de 6-phényl-2,4,7-triamino-ptéridine et d'a-

  
 <EMI ID=43.1> 

  
acétique.

  
On ajoute à une solution chaude de 1,27 g (0,005 mole) de 6-phényl-3,4,7-triamino-ptéridine dans 25 ml de diméthylsuif oxyde 1,85 g (0,005 mole) d'acide lévo-(1-oxo-2-méthyl-2phényl-6,7-dichloro-5-indanyloxy)-acétique. On verse la solution limpide dans 200 ml d'eau en agitant vigoureusement. On filtre le sel de 6-phényl-2,4,7-triamino-ptéridine de l'acide lévo-(1oxo-2-méthyl-2-phényl-6,7-dichloro-5-indanyloxy)-acétique qui se sépare, on rince à l'eau et on sèche.

  
On peut administrer les compositions et les sels de

  
la présente invention, sous une grande variété de formes thérapeutiques dans des véhicules classiques par exemple, pour l'administration orale, sous forme d'un comprimé. De même, le dosage quotidien des produits peut être varié dans une large gamme, par exemple sous forme de comprimés marqués contenant 2,5, 5, 10,
15, 25, 50 et 100 milligrammes de composants actifs pour adapter le dosage au patient à traiter. On administre de préférence la dose quotidienne en doses subdivisées réparties sur une période de 24 heures. Ces dosages sont bien inférieurs à la dose toxique ou léthale des produits.

  
Une forme de dosage combinée appropriée de la composition selon la présente invention peut être administrée par mélange de 5 mg d'un acide racémique [ 1 -oxo-2,2-di substitué -5-

  
 <EMI ID=44.1> 

  
5 mg d'amiloride, 50 mg de triamterene ou 25 mg de spironolactone avec 189 mg, 144 mg ou 169 mg respectivement de lactose et 1 mg de stéarate de magnésium et mise en place du mélange dans une capsule de gélatine n[deg.] 1. De façon similaire en utilisant une quantité plus importante du composant actif et moins de lactose, on peut placer dans des capsules de gélatine n[deg.] 1 d'autres formes de dosages. S'il est nécessaire, on peut préparer des comprimés, des pilules ou autres dosages combinés désirables, pour des compositions selon la présente invention par des procédés classiques. Une quantité efficace de composants actifs dans le mélange est ordinairement fournie avec un taux de dose compris entre environ 0,01 mg à environ 5,0 mg/kg de poids corporel. De préférence la gamme est comprise entre environ 0,05 et 2 mg/kg de poids corporel. 

  
Il entre également dans le cadre de la présente invention de combiner l'amiloride ou le triamterene sous forme de

  
 <EMI ID=45.1> 

  
alcanoique de structure (I) avec le lactose et le stéarate de magnésium sous forme de dose unitaire. Une quantité efficace du sel est ordinairement fournie avec un taux de dose d'environ 0,01 mg à environ 5 mg/kg de poids corporel. La gamme préférée est comprise entr&#65533;nviron 0,05 et 2 mg/kg de poids corporel.

  
Une forme de dose unitaire appropriée du sel d'amilo- 

  
 <EMI ID=46.1> 

  
et 1 mg de stéarate de magnésium. 

  
Les exemples suivants sont inclus pour illustrer la préparation des formes de dosages combinées représentatives, contenant un mélange d'acide (1-oxo-2,2-disubstitué-5-indanyloxy)-acétique et d'amiloride, de triamterene ou de spironolactone : 

  
EXEMPLE 5

  
Forme de dosage combinée en capsule remplie à sec :

  

 <EMI ID=47.1> 
 

EXEMPLE 6

  
Forme de dosage combinée en capsule remplie à sec :

  

 <EMI ID=48.1> 

EXEMPLE?

  
 <EMI ID=49.1> 

  

 <EMI ID=50.1> 

EXEMPLE 8

  
Forme de dosage combinée en capsule remplie à sec :

  

 <EMI ID=51.1> 


  
On mélange l'acide (1-oxo-2-méthyl-2-phényl-6,7-dichloro-5-indanyloxy)-acétique et le N-amidino-6-chloropyrazine-

  
 <EMI ID=52.1> 

  
nolactone et on broie en une poudre ? 60 puis on fait passer le lactose et le stéarate de magnésium à travers une toile à tamiser ? 60 (ouverture de maille environ 0,25 mm) sur la poudre et on mélange les composants combinés pendant 10 minutes, puis on remplit une capsule de gélatine sèche ? 1.

  
On prépare des formes de dosages similaires en capsules remplies à sec, en remplaçant le composant d'acide indanyloxy-acétique des exemples 4, 5, 7 et 8 par l'un quelconque des autres composés d'acide indanyloxy-acétique cités dans la présente invention. Si, dans les exemples 5, 7 et 8, l'un des autres diurétiques d'acide indanyloxy-acétique signalés

  
 <EMI ID=53.1> 

  
indanyloxy)-acétiqué, on doit en utiliser une quantité plus importante ou moindre en fonction de son activité diurétique relative connue par rapport à celle de l'acide (1-oxo-2-éthyl-2phényl-6,7-dichloro-5-indanyloxy)-acétique.

EXEMPLE ?

  
Forme de dosage combiné en capsule remplie à sec

Par capsule

  

 <EMI ID=54.1> 

EXEMPLE 10 

  
Forme de dosage combinée en capsule remplie à sec :

  

 <EMI ID=55.1> 


  
On mélange l'acide lévo-(1-oxo-2-méthyl-2-phényl-6,7dichloro-5-indanyloxy)-acétique et le N-amidino-3,5-diamino-6chloropyrazine-carboxamide, la 6-phényl-2,4,7-triamino-ptéridine ou la spironolactone et on broie à dimension d'environ 0,25 mm en une poudre, puis on fait passer le lactose et le stéarate de magnésium à travers une toile à tamiser 0,25 mm d'ouverture de maille, sur la poudre et on mélange les composants combinés pendant 10 minutes et on remplit une capsule de gélatine sèche

  
 <EMI ID=56.1> 

  
Les exemples suivants sont inclus pour illustrer la préparation de formes de dosages représentatifs contenant un sel  <EMI ID=57.1> 

  
EXEMPLE 11

  
Capsule remplie à sec :

  

 <EMI ID=58.1> 


  
On broie le sel d'amiloride et d'acide (1-oxo-2-méthyl2-phényl-6,7-dichloro-5-indanyloxy)-acétique en une poudre de 0,25 mm et on fait passer le lactose et le stéarate de magnésium à travers une toile à tamiser d'ouverture de maille de 0,25 mm sur la poudre, on mélange les composants combinés pendant 10 minutes puis on remplit une capsule en gélatine sèche

  
N[deg.] 1.

  
De façon similaire on peut préparer des capsules remplies à sec en remplaçant le composant d'acide indanyloxyacétique de l'exemple précédent par une quantité molaire équivalente d'autres composés d'acide indanyloxy-acétique cités dans la présente invention.

  
EXEMPLE 12

  
Capsule remplie à sec :

  

 <EMI ID=59.1> 


  
On broie le sel d'amiloride et d'acide lévo-(1-oxo-2-

  
 <EMI ID=60.1> 

  
poudre de dimension 0,25 mm et on fait passer le lactose et le stéarate de magnésium à travers une toile à tamiser de 0,25 mm d'ouverture de maille sur la poudre et on mélange des composants combinés pendant 10 minutes et on remplit une capsule de gélatine sèche N[deg.] 1.

  
Il est évident d'après la description précédente que

  
 <EMI ID=61.1> 

  
lactone et des acides [1-oxo-2,2-disubstitué-5-indanyloxy (ou thio)]-alcanoiques de structure I selon la présente invention, constituent une précieuse classe de produits qui n'avaient pas été préparés jusqu'à présent. Le spécialiste de cette question appréciera que les procédés décrits dans les exemples précédents sont purement illustratifs et susceptibles d'être largement modifiés et variés sans pour autant s'écarter de l'esprit de la présente invention.



  Diuretic formulas.

  
The present invention relates to pharmaceutical compositions and particularly to preparations which have advantageous diuretic and / or saluretic properties. For simplicity, the term “diuretic” will be used in what follows in a common or generic sense, to denote drugs which cause diuresis (increase excretion of urine) and / or saluresis (increase in urine output). excretion of electrolytes).

  
Diuretics are valuable therapeutic agents in that they are useful in the treatment of cardiovascular and renal diseases. Their application is indicated in the treatment of all types and degrees of severity of conditions of congestive heart failure for which it is

  
 <EMI ID = 1.1>

  
Its resulting losses of water and electrolytes there is a considerable improvement in pulmonary and peripheral edema, dyspnea, orthopnea, cough, ascites and pleural effusion.

  
These drugs also provide therapy

  
 <EMI ID = 2.1>

  
edema that is associated with nephrosis and certain types of nephritis. Their administration results in prompt excretion of retained fluid and electrolytes, with concomitant benefit to the patient. The electrolyte that we want to excrete is sodium chloride.

  
These drugs are particularly useful in the treatment of hypertension and provide rapid therapy useful in mild, moderate and severe forms of the disease.

  
Although diuretics are often life-saving due to the foregoing therapeutic beneficial effects, most of them have drawbacks related to the excretion of appreciable amounts of potassium ions. When an excessive loss of potassium ions occurs, it results in severe muscle weakness and a feeling of extreme physical exhaustion. The patient eliminates unwanted sodium ions due to the action of diuretic drugs, but the elimination of potassium ions, which is not desired, causes an imbalance which should not be allowed to persist.

  
In addition to their other effects, these compounds are able to keep the uric acid concentration in the body at pre-treatment levels or often even effect a decrease in the uric acid concentration. Many diuretics and saluretics currently available tend, when administered, to induce hyperuricemia which can precipitate uric acid or sodium urate, or both, in the body, which can cause cases of moderate to severe gout. The compounds according to the present invention presently provide an effective tool for treating those patients who require diuretic and saluretic treatment without incurring the risk of inducing gout.

  
The present invention involves the co-administration of a (1-oxo-2,2-disubstituted-5-indanyloxy) -acetic acid with pyrrazinoyl-guanidines, as a mixture or as a salt, with a pteridine in the form of as a mixture or in the form of a salt or with a spironolactone in the form of a mixture, which reduces the quantity of potassium ions which are eliminated without reducing the quantity of sodium ions which are to be eliminated.

  
Another advantage in the case of diuretics N-amidino-3,5-diamino-6-chloro-pyrazine-carboxamide salts of the acid
(1-oxo-2,2-disubstituted-5-indanyloxy) -acetic, is their insolubility which makes gastrointestinal absorption of salts slower and more gradual, providing a chemical process to achieve the same effect as micro- encapsulation.

  
The [1-oxo-2,2-disubstituted-5-indanyloxy (or thio)] - alkanoic acids useful according to the present invention, which comprise the racemates and the pure enantiomers have the following structural formula:

  

 <EMI ID = 3.1>


  
in which A represents an oxygen or sulfur atom, R represents a lower alkyl group containing from 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.- groups butyl, n-pentyl and the like; cycloalkyl groups, for example a cycloalkyl group containing from 5 to 6 nuclear carbon atoms such as cyclopentyl, cyclohexyl and the like, aryl groups such as phenyl and substituted aryl groups in which the substituent is a lower alkyl group,

  
a halogen atom, a lower alkoxy, hydroxy, amino or aminomethyl group, a thienyl and substituted thienyl group in which the substituent is a lower alkyl group or a

  
 <EMI ID = 4.1>

  
containing from 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, n-pentyl and the like, a lower alkenyl group containing from 3 to 5 carbon atoms , such as allyl, 1-, 2- or 3-butenyl, 1-, 2- or 3- or 4-pentenyl groups and the like, lower alkynyl groups containing from 3 to 5 atoms of

  
 <EMI ID = 5.1>

  
2-, 3- or 4-pentynyl and the like, a phenyl-lower alkyl group in which the lower alkyl group contains 1 to 3 carbon atoms, such as benzyl, phenethyl, phenyl-propyl and the like, phenyl- groups lower alkenyl in which the lower alkenyl group contains

  
2 to 5 carbon atoms such as cinnamyl group and the like, aryl groups such as phenyl, or substituted aryl such as (lower) alkyl-aryl or halo-aryl; thienyl or substituted thienyl groups such as alkyl (lower) -thienyl or halo-thienyl, or R and R <1> can be linked together with the carbon atoms to which they are attached to form a cycloalkyl radical containing from 3 to 7 nuclear carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

  
 <EMI ID = 6.1>

  
a methyl group, or a halogen atom such as chlorine,

  
 <EMI ID = 7.1>

  
or a halogen atom such as chlorine, bromine, fluorine and

  
 <EMI ID = 8.1> hydrocarbylene chain containing 3 to 4 carbon atoms, by

  
 <EMI ID = 9.1>

  
logues, and Y represents an alkylene or halo-alkylene radical having a maximum of 4 carbon atoms, which contains from 1 to 3 linear carbon atoms between the oxy (or thio) group and the carboxy group, for example methylene groups, ethylidene, propylidene, isopropylidene, ethylene, trimethylene, fluoromethylene and the like; the present invention encompasses the racemic forms and the enantiomers of the compounds described.

  
Preferred acids (1-oxo-2,2-substituted-5-indanyloxy
(or thio)] alkanoids, useful according to the present invention have the following structural formula:

  

 <EMI ID = 10.1>


  
in which R 'represents an alkyl group containing 1 to 3 carbon atoms such as methyl, ethyl, n-propyl or isopropyl or cycloalkyl groups containing 5 or 6 nuclear carbon atoms such as cyclopentyl or cyclohexyl groups and R4 represents a lower alkyl group containing 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl or isopropyl, a phenyl, (lower) alkyl phenyl group in which the lower alkyl group contains

  
1 to 3 carbon atoms such as methyl, ethyl, n-propyl or isopropyl, halogenophenyl, methoxyphenyl,

  
 <EMI ID = 11.1>

  
(lower) alkyl-thienyl, in which the lower alkyl group contains 1 to 3 carbon atoms, such as groups

  
 <EMI ID = 12.1>

  
are attached to form a cycloalkyl radical containing 5 to 6 nuclear carbon atoms, such as cyclopentyl radicals,

  
 <EMI ID = 13.1>

  
identical or different selected from a methyl group or a chlorine atom, the racemic forms and the enantiomers of the compounds described are also included.

  
 <EMI ID = 14.1>

  
particularly preferred alkanoics according to the present invention have the formula

  

 <EMI ID = 15.1>


  
 <EMI ID = 16.1>

  
1 to 3 carbon atoms such as methyl, ethyl,

  
 <EMI ID = 17.1>

  
n having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, phenyl, p-chlorophenyl or thienyl groups,

  
 <EMI ID = 18.1>

  
from a methyl group or a chlorine atom.

  
The following compounds are included in the group

  
 <EMI ID = 19.1>

  
(1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid,

  
 <EMI ID = 20.1>

  
acetic,

  
among which racemic and levorotatory (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid is very particularly preferred. Although these are preferred among the diuretics of the indanyloxyacetic acid class, the present invention encompasses the use in their place of any of the related compounds recited above.

  
- To achieve the beneficial results of the present invention, the preferred compound of pyrazinoyl-guanidine is <EMI ID = 21.1>

  
pteridine (hereinafter referred to as "triamterene") or spironolactone.

  
The present invention also encompasses the use to

  
both of physical mixtures in varying proportions of (1-oxo-2,2-disubstituted-5-indanyloxy) -acetic acid diuretics and amiloride, triamterene or spironolactone, and chemical salts of (1- oxo-2,2-disubstituted-5-indanyloxy) -acetic and amiloride and triamterene.

  
The salt of amiloride and an (1-oxo-2,2-disubstituted5-indanyloxy) acetic acid is prepared by adding the acid compound

  
 <EMI ID = 22.1>

  
of amiloride in a suitable water-miscible organic solvent such as dimethyl sulfoxide and then the resulting solution is poured into water, from which the desired salt of amiloride and indanyloxy-acetic acid are separated, and collected. by filtration.

  
The present invention encompasses compositions for oral administration in which the molar ratio

  
 <EMI ID = 23.1>

  
amiloride is from about 0.2: 1 to 4.0: 1. The preferred proportions between (1-oxo-2,2-substituted-5-indanyloxy) -acetic acid and amiloride are between 0.8: 1 and 1.6: 1. In the event that the indanyloxy-acetic acid is (1-oxo-2-

  
 <EMI ID = 24.1>

  
the absolute weights and the preferred weight ratios corresponding to the molar proportions indicated above are given in Table Ia below. The corresponding data for the levorotatory isomer are recorded in Table Ib:

  

 <EMI ID = 25.1>


  

 <EMI ID = 26.1>
 

  

 <EMI ID = 27.1>


  

 <EMI ID = 28.1>
 

  
The present invention also relates to compositions for oral administration in which the moderate proportion

  
 <EMI ID = 29.1>

  
methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic, racemic, the absolute weights and preferred weight ratios corresponding to the molar proportions indicated above are given in Table IIa. The corresponding data for the levorotatory isomer are recorded in Table IIb
 <EMI ID = 30.1>
 <EMI ID = 31.1>
 
 <EMI ID = 32.1>
 <EMI ID = 33.1>
 The present invention encompasses compositions for oral administration in which the molar ratio of (1-oxo-2,2-disubstituted-5-indanyloxy) -acetic acid and spironolactone is between about 1: 4 , 4 and 1: 2.2. In the case where the indanyloxy-acetic acid is racemic (1-oxo2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid, the absolute weights and preferred weight proportions corresponding to the molar proportions indicated above, are given

  
 <EMI ID = 34.1>

  
levorotatory are recorded in Table IIIb.

  

 <EMI ID = 35.1>


  

 <EMI ID = 36.1>
 

  

 <EMI ID = 37.1>


  

 <EMI ID = 38.1>
 

  
Representative examples illustrating the present invention are as follows:

EXAMPLE 1

  
 <EMI ID = 39.1>

  
2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic. The clear solution is poured into 200 ml of water with vigorous stirring. The salt of N-amidino-3,5-diamino-6-chloropyrazinecarboxamide and of- (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5indanyloxy) -acetic acid which separates is filtered, it is rinsed with water and dried. Melting point 150 [deg.] C.

  
 <EMI ID = 40.1>

  
Calculated: C = 48.46; H = 3.73; N = 16.48

  
Found: C, 48.11; H = 3.42; N, 16.19.

  
EXAMPLE 2

  
Preparation of 6-phenyl-2,4,7-triamino-pteridine salt and (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid.

  
To a hot solution of 1.27 g (0.005 mole) of 6-phenyl-2,4,7-triamino-pteridine in 25 ml of dimethylsulfoxide, 1.85 g (0.005 mole) of (1-oxo -2-methyl-2-phenyl6,7-dichloro-5-indanyloxy) -acetic. The clear solution is poured into 200 ml of water with vigorous stirring. We filter the

  
 <EMI ID = 41.1>

  
par, rinse with water and dry.

  
EXAMPLE 3

  
 <EMI ID = 42.1>

  
To a hot solution of 1.15 g (0.005 mol) of N-amidino-3,5-diamino-6-chloropyrazine-carboxamide in

  
25 ml of dimethylsulfoxide, 1.85 g (0.005 mol) of levo- (1oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid. The clear solution is poured into 200 ml of water with vigorous stirring. The salt of N-amidino-3,5-diamino-6-chloropyrazine-carboxamide and of Levo- (1-oxo-2-methyl-2-phenyl6,7-dichloro-5-indanyloxy) -acetic acid is filtered off which separated, rinsed with water and dried.

  
EXAMPLE 4

  
Preparation of the salt of 6-phenyl-2,4,7-triamino-pteridine and α-

  
 <EMI ID = 43.1>

  
acetic.

  
To a hot solution of 1.27 g (0.005 mole) of 6-phenyl-3,4,7-triamino-pteridine in 25 ml of dimethylsulfoxide is added 1.85 g (0.005 mole) of levo- (1 -oxo-2-methyl-2phenyl-6,7-dichloro-5-indanyloxy) -acetic. The clear solution is poured into 200 ml of water with vigorous stirring. The 6-phenyl-2,4,7-triamino-pteridine salt of levo- (1oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid which separates is filtered off. , rinsed with water and dried.

  
The compositions and salts of

  
the present invention, in a wide variety of therapeutic forms in conventional vehicles eg, for oral administration, in tablet form. Likewise, the daily dosage of the products can be varied over a wide range, for example in the form of labeled tablets containing 2.5, 5, 10,
15, 25, 50 and 100 milligrams of active ingredients to adapt the dosage to the patient to be treated. The daily dose is preferably administered in divided doses over a 24 hour period. These dosages are much lower than the toxic or lethal dose of the products.

  
A suitable combined dosage form of the composition according to the present invention can be administered by admixing 5 mg of a racemic acid [1 -oxo-2,2-di substituted -5-

  
 <EMI ID = 44.1>

  
5 mg of amiloride, 50 mg of triamterene or 25 mg of spironolactone with 189 mg, 144 mg or 169 mg respectively of lactose and 1 mg of magnesium stearate and placing the mixture in a gelatin capsule n [deg.] 1. Similarly by using more of the active component and less lactose, other dosage forms can be placed in gelatin capsules n [deg.] 1. If necessary, tablets, pills, or other desirable combined strengths for compositions according to the present invention can be prepared by conventional methods. An effective amount of active components in the mixture is ordinarily provided at a dose rate of from about 0.01 mg to about 5.0 mg / kg body weight. Preferably the range is between about 0.05 and 2 mg / kg of body weight.

  
It is also within the scope of the present invention to combine amiloride or triamterene in the form of

  
 <EMI ID = 45.1>

  
alkanoic acid of structure (I) with lactose and magnesium stearate in unit dose form. An effective amount of the salt is ordinarily provided at a dose rate of from about 0.01 mg to about 5 mg / kg of body weight. The preferred range is between about 0.05 and 2 mg / kg body weight.

  
A suitable unit dose form of the amilo- salt

  
 <EMI ID = 46.1>

  
and 1 mg of magnesium stearate.

  
The following examples are included to illustrate the preparation of representative combined dosage forms containing a mixture of (1-oxo-2,2-disubstituted-5-indanyloxy) -acetic acid and amiloride, triamterene or spironolactone:

  
EXAMPLE 5

  
Dry-filled capsule combination dosage form:

  

 <EMI ID = 47.1>
 

EXAMPLE 6

  
Dry-filled capsule combination dosage form:

  

 <EMI ID = 48.1>

EXAMPLE?

  
 <EMI ID = 49.1>

  

 <EMI ID = 50.1>

EXAMPLE 8

  
Dry-filled capsule combination dosage form:

  

 <EMI ID = 51.1>


  
(1-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid and N-amidino-6-chloropyrazine- are mixed.

  
 <EMI ID = 52.1>

  
nolactone and we grind it into a powder? 60 then pass the lactose and magnesium stearate through a sieve? 60 (mesh opening about 0.25 mm) on the powder and the combined components are mixed for 10 minutes, then a capsule is filled with dry gelatin? 1.

  
Similar dosage forms were prepared in dry-filled capsules, replacing the indanyloxy-acetic acid component of Examples 4, 5, 7 and 8 with any of the other indanyloxy-acetic acid compounds cited herein. invention. If, in Examples 5, 7 and 8, any of the other diuretics of indanyloxyacetic acid reported

  
 <EMI ID = 53.1>

  
indanyloxy) -acetic, a larger or smaller amount should be used depending on its known relative diuretic activity compared to that of (1-oxo-2-ethyl-2phenyl-6,7-dichloro-5- indanyloxy) -acetic.

EXAMPLE?

  
Combined dosage form in dry-filled capsule

Per capsule

  

 <EMI ID = 54.1>

EXAMPLE 10

  
Dry-filled capsule combination dosage form:

  

 <EMI ID = 55.1>


  
Levo- (1-oxo-2-methyl-2-phenyl-6,7dichloro-5-indanyloxy) -acetic acid and N-amidino-3,5-diamino-6chloropyrazine-carboxamide, 6-phenyl -2,4,7-triamino-pteridine or spironolactone and grind to size of about 0.25 mm into a powder, then pass the lactose and magnesium stearate through a 0.25 mm sieve wire mesh opening, on the powder and mix the combined components for 10 minutes and fill a dry gelatin capsule

  
 <EMI ID = 56.1>

  
The following examples are included to illustrate the preparation of representative dosage forms containing a salt <EMI ID = 57.1>

  
EXAMPLE 11

  
Dry filled capsule:

  

 <EMI ID = 58.1>


  
The amiloride salt of (1-oxo-2-methyl2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid is ground to a 0.25 mm powder and the lactose and lactose are passed through. magnesium stearate through a sieve cloth with a 0.25 mm mesh opening onto the powder, the combined components are mixed for 10 minutes and then a dry gelatin capsule is filled

  
N [deg.] 1.

  
Similarly, dry-filled capsules can be prepared by replacing the indanyloxyacetic acid component of the previous example with an equivalent molar amount of other indanyloxy-acetic acid compounds recited in the present invention.

  
EXAMPLE 12

  
Dry filled capsule:

  

 <EMI ID = 59.1>


  
The salt of amiloride and levo- (1-oxo-2-

  
 <EMI ID = 60.1>

  
0.25 mm size powder and the lactose and magnesium stearate are passed through a 0.25 mm mesh size sieve cloth onto the powder and the combined components are mixed for 10 minutes and a filling is filled. dry gelatin capsule N [deg.] 1.

  
It is evident from the foregoing description that

  
 <EMI ID = 61.1>

  
lactone and [1-oxo-2,2-disubstituted-5-indanyloxy (or thio)] - alkanoic acids of structure I according to the present invention, constitute a valuable class of products which had not been prepared until now . Those skilled in this matter will appreciate that the methods described in the foregoing examples are purely illustrative and capable of being widely modified and varied without departing from the spirit of the present invention.

Claims (1)

- REVENDICATIONS - - CLAIMS - 1 - Composition médicamenteuse caractérisée en ce qu'elle comprend un composé d'acide indanyloxy-acétique de formule : <EMI ID=62.1> 1 - Drug composition characterized in that it comprises an indanyloxy-acetic acid compound of formula: <EMI ID = 62.1> dans laquelle R représente un groupe alcoyle inférieur avec 1 à in which R represents a lower alkyl group with 1 to 5 atomes de carbone, cycloalcoyle, aryle ou aryle substitué, thiényle ou thiényle substitué; R représente un groupe alcoyle inférieur avec 1 à 5 atomes de carbone, alcényle inférieur avec 5 carbon atoms, cycloalkyl, aryl or substituted aryl, thienyl or substituted thienyl; R represents a lower alkyl group with 1 to 5 carbon atoms, lower alkenyl with 3 à 5 atomes de carbone, alcynyle inférieur avec 5 ou 6 atomes 3 to 5 carbon atoms, lower alkynyl with 5 or 6 atoms de carbone nucléaire, phényle-alcoyle inférieur, dans lequel le groupe alcoyle a de 1 à 3 atomes de carbone ou phényl-alcényle inférieur ou aryle, ou arylesubstitué, thiényle ou thiényle <EMI ID=63.1> of nuclear carbon, phenyl-lower alkyl, in which the alkyl group has 1 to 3 carbon atoms or phenyl-lower alkenyl or aryl, or substituted aryl, thienyl or thienyl <EMI ID = 63.1> présente un atome d'hydrogène, un groupe méthyle ou un atome d'halogène et X<2> représente un groupe méthyle ou un atome d'ha- has a hydrogen atom, a methyl group or a halogen atom and X <2> represents a methyl group or a ha atom. <EMI ID=64.1> <EMI ID = 64.1> chaîne hydrocarbylène contenant 3 ou 4 atomes de carbone, et hydrocarbylene chain containing 3 or 4 carbon atoms, and Y représente un radical alcoylène ou halogéno-alcoylène contenant un maximum de 4 atomes de carbone, et le N-amidino-3,5- Y represents an alkylene or halo-alkylene radical containing a maximum of 4 carbon atoms, and N-amidino-3,5- <EMI ID=65.1> <EMI ID = 65.1> triamino-ptéridiné ou la spironolactone, dans laquelle la proportion molaire entre le composé d'acide indanyloxy-acétique et triaminopteridin or spironolactone, in which the molar ratio between the compound of indanyloxyacetic acid and <EMI ID=66.1> <EMI ID = 66.1> triamino-ptéridine est comprise entre environ 1:7 et 1:3,5 et triamino-pteridine is between about 1: 7 and 1: 3.5 and la proportion molaire entre l'acide indanyloxy-acétique et la spironolactone est comprise entre environ 1:4,4 et 1:2,2. <EMI ID=67.1> the molar ratio between indanyloxyacetic acid and spironolactone is between about 1: 4.4 and 1: 2.2. <EMI ID = 67.1> <EMI ID=68.1> <EMI ID = 68.1> <EMI ID=69.1> <EMI ID = 69.1> 3 atomes de carbone ou cycloalcoyle avec 5 ou 6 atomes de car- 3 carbon atoms or cycloalkyl with 5 or 6 carbon atoms <EMI ID=70.1> <EMI ID = 70.1> 1 à 3 atomes de carbone, phényle, alcoyl(inférieur)-phényle, le groupe alcoyle inférieur ayant de 1 à 3 atomes de carbone, 1 to 3 carbon atoms, phenyl, (lower) alkyl -phenyl, the lower alkyl group having 1 to 3 carbon atoms, <EMI ID=71.1> <EMI ID = 71.1> aminométhylphényle, thiényle, alcoyl(inférieur)-thiényle, le groupe alcoyle inférieur ayant de 1 à 3 atomes de carbone, ou aminomethylphenyl, thienyl, (lower) alkyl -thienyl, the lower alkyl group having 1 to 3 carbon atoms, or <EMI ID=72.1> <EMI ID = 72.1> l'atome de carbone auquel ils sont fixés pour former un radical cycloalcoyle contenant 5 ou 6 atomes de carbone nucléaires; the carbon atom to which they are attached to form a cycloalkyl radical containing 5 or 6 nuclear carbon atoms; <EMI ID=73.1> <EMI ID = 73.1> des radicaux choisis parmi un groupe méthyle ou un atome de chlore, sa forme racémique et ses énantiomères et le N-amidino3,5-diamino-6-chloropyrazine-carboxamide, la 6-phényl-2,4,7triamino-ptéridine ou la spironolactone dans laquelle la proportion molaire entre le composé d'acide indanyloxy-acétique et le radicals chosen from a methyl group or a chlorine atom, its racemic form and its enantiomers and N-amidino3,5-diamino-6-chloropyrazine-carboxamide, 6-phenyl-2,4,7triamino-pteridine or spironolactone in which the molar proportion between the compound of indanyloxyacetic acid and the <EMI ID=74.1> <EMI ID = 74.1> entre environ 0,4:1 et 4,0:1, la proportion molaire entre le composé d'acide indanyloxy-acétiquè et la 6-phényl-2,4,7triamino-ptéridine est comprise entre environ 1:7 et 1:3,5 et la proportion molaire entre le composé d'acide indanyloxy-acétique et la spironolactone est comprise entre environ 1:4,4 et 1:2,2. 3 - Composition médicamenteuse caractérisée en ce qu'elle comprend un composé d'acide indanyloxy-acétique de formule between about 0.4: 1 and 4.0: 1, the molar ratio of the indanyloxyacetic acid compound to 6-phenyl-2,4,7-triamino-pteridine is between about 1: 7 and 1: 3 , 5 and the molar ratio between the compound of indanyloxyacetic acid and spironolactone is between about 1: 4.4 and 1: 2.2. 3 - Medicinal composition characterized in that it comprises an indanyloxy-acetic acid compound of formula <EMI ID=75.1> <EMI ID = 75.1> <EMI ID=76.1> <EMI ID = 76.1> <EMI ID=77.1> <EMI ID = 77.1> atomes de carbone, phényle, p-chlorophényle ou thiényle; X<3> et X4 sont identiques ou différents et représentent des radicaux choisis parmi un groupe méthyle ou un atome de chlore, sa forme racémique ou ses énantiomères et le N-amidino-3,5-diamino-6- carbon atoms, phenyl, p-chlorophenyl or thienyl; X <3> and X4 are identical or different and represent radicals chosen from a methyl group or a chlorine atom, its racemic form or its enantiomers and N-amidino-3,5-diamino-6- <EMI ID=78.1> <EMI ID = 78.1> dine ou la spironolactone, dans laquelle la proportion molaire entre le composé d'acide indanyloxy-acétique et le N-amidino3,5-diamino-6-chloropyrazine-carboxamide est comprise entre environ 0,4:1 et 4,0:1, la proportion molaire entre le composé dine or spironolactone, wherein the molar ratio of the compound of indanyloxyacetic acid to N-amidino3,5-diamino-6-chloropyrazine-carboxamide is from about 0.4: 1 to 4.0: 1, the molar ratio between the compound <EMI ID=79.1> <EMI ID = 79.1> dine est comprise entre environ 1:7 et 1:3,5 et la proportion molaire entre le composé d'acide indanyloxy-acétique et la spironolactone est comprise entre environ 1:4,4 et 1:2,2. dine is between about 1: 7 and 1: 3.5 and the molar ratio between the compound of indanyloxyacetic acid and spironolactone is between about 1: 4.4 and 1: 2.2. 4 - Composition selon la revendication 3, caractérisée en ce que l'acide indanyloxy-acétique est l'acide (1-oxo-2-méthyl- 4 - Composition according to claim 3, characterized in that the indanyloxy-acetic acid is (1-oxo-2-methyl- <EMI ID=80.1> <EMI ID = 80.1> 5 - Composition selon la revendication 3, caractérisée en ce que l'acide indanyloxy-acétique est l'acide [1-oxo-2-méthyl- 5 - Composition according to claim 3, characterized in that the indanyloxy-acetic acid is [1-oxo-2-methyl- acid <EMI ID=81.1> <EMI ID = 81.1> 6 - Composition selon la revendication 3, caractérisée en ce que l'acide indanyloxy-acétique est l'acide [1-oxo-2-méthyl- 6 - Composition according to claim 3, characterized in that the indanyloxy-acetic acid is [1-oxo-2-methyl- acid <EMI ID=82.1> <EMI ID = 82.1> 7 - Composition selon la revendication 3, caractérisée en ce que l'acide indanyloxy-acétique est l'acide lévo-(1-oxo-2- 7 - Composition according to claim 3, characterized in that the indanyloxy-acetic acid is levo- (1-oxo-2- <EMI ID=83.1> 8 - Composition selon la revendication 4, caractérisée en ce que la proportion molaire entre l'acide (1-oxo-2-méthyl-2- <EMI ID = 83.1> 8 - Composition according to claim 4, characterized in that the molar proportion between the acid (1-oxo-2-methyl-2- <EMI ID=84.1> <EMI ID = 84.1> diamino-6-chloro-pyrazine-carboxamide est comprise entre 0,8:1 et 1,6:1, la proportion molaire entre l'acide (1-oxo-2-méthyl- diamino-6-chloro-pyrazine-carboxamide is between 0.8: 1 and 1.6: 1, the molar ratio between the acid (1-oxo-2-methyl- <EMI ID=85.1> <EMI ID = 85.1> 2;4,7-triamino-ptéridine est environ 1:3,5 et la proportion molaire entre l'acide (1-oxo-2-méthyl-2-phényl-6,7-dichloro-5indanyloxy)-acétique et la spironolactone est d'environ 1:2,2. 2; 4,7-triamino-pteridine is about 1: 3.5 and the molar ratio between (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5indanyloxy) -acetic acid and spironolactone is approximately 1: 2.2. <EMI ID=86.1> <EMI ID = 86.1> en ce que la proportion molaire entre l'acide [1-oxo-2-méthyl-2- <EMI ID=87.1> in that the molar ratio between the acid [1-oxo-2-methyl-2- <EMI ID = 87.1> amidino-3,5-diamino-6-chloropyrazine-carboxamide est comprise entre 0,8:1 et 1,6:1, la proportion molaire entre l'acide [1-oxo- amidino-3,5-diamino-6-chloropyrazine-carboxamide is between 0.8: 1 and 1.6: 1, the molar ratio between the acid [1-oxo- <EMI ID=88.1> <EMI ID = 88.1> est d'environ 1:2,2. is approximately 1: 2.2. 10 - Composition selon la revendication 6, caractérisée en ce que la proportion molaire entre l'acide [1-oxo-2-méthyl-2phényl-2-(2-thiényl)-6,7-dichloro-5-indanyloxy]-acétique et le N- 10 - Composition according to claim 6, characterized in that the molar proportion between the acid [1-oxo-2-methyl-2phenyl-2- (2-thienyl) -6,7-dichloro-5-indanyloxy] -acetic and the N- <EMI ID=89.1> <EMI ID = 89.1> d'environ 1:2,2. about 1: 2.2. 11 - Composition selon la revendication 7, caractérisée en ce que la proportion molaire entre l'acide lévo-(1-oxo-2-. 11 - Composition according to claim 7, characterized in that the molar proportion between levo- (1-oxo-2- acid. <EMI ID=90.1> <EMI ID = 90.1> est d'environ 1:4,4. 12 - Sel d'un acide indanyloxy-acétique de formule is about 1: 4.4. 12 - Salt of an indanyloxyacetic acid of formula <EMI ID=91.1> <EMI ID = 91.1> dans laquelle R représente un groupe alcoyle inférieur avec de in which R represents a lower alkyl group with 1 à 5 atomes de carbone, cycloalcoyle, aryle ou aryle substitué, thiényle ou thiényle substitué; R représente un groupe alcoyle inférieur avec 1 à 5 atomes de carbone, alcényle avec 3 à 5 atomes de carbone alcynyle inférieur avec 5 à 6 atomes de carbone nucléaires, phénylalcoyle inférieur, où le groupe alcoyle inférieur a 1 à 3 atomes de carbone ou phényl-alcényle inférieur, ou aryle ou aryle substitué,thiényle ou thiényle substitué; ou 1 to 5 carbon atoms, cycloalkyl, aryl or substituted aryl, thienyl or substituted thienyl; R represents a lower alkyl group with 1 to 5 carbon atoms, alkenyl with 3 to 5 carbon atoms lower alkynyl with 5 to 6 nuclear carbon atoms, phenyl lower alkyl, where the lower alkyl group has 1 to 3 carbon atoms or phenyl -lower alkenyl, or aryl or substituted aryl, thienyl or substituted thienyl; or <EMI ID=92.1> <EMI ID = 92.1> bone auquel ils sont fixés pour former un groupe cycloalcoyle bone to which they are attached to form a cycloalkyl group <EMI ID=93.1> <EMI ID = 93.1> atome d'hydrogène, un groupe méthyle ou un atome d'halogène et hydrogen atom, a methyl group or a halogen atom and <EMI ID=94.1> <EMI ID = 94.1> <EMI ID=95.1> <EMI ID = 95.1> lène contenant 3 ou 4 atomes de carbone, et Y représente un radical alcoylène ou halogéno-alcoylène contenant un maximum de lene containing 3 or 4 carbon atoms, and Y represents an alkylene or halo-alkylene radical containing a maximum of 4 atomes de carbone. 4 carbon atoms. <EMI ID=96.1> <EMI ID = 96.1> <EMI ID=97.1> <EMI ID = 97.1> <EMI ID=98.1> <EMI ID=99.1> <EMI ID = 98.1> <EMI ID = 99.1> thiényle, alcoyl(inférieur)-thiényle, le groupe alcoyle inférieur ayant 1 à 3 atomes de carbone ou halogéno-thiényle, ou bien R<3> thienyl, (lower) alkyl -thienyl, lower alkyl having 1 to 3 carbon atoms or halo-thienyl, or R <3> et R4 peuvent être reliés avec l'atome de carbone auquel ils sont attachés pour former un radical cycloalcoyle contenant 5 ou 6 atomes de carbone nucléaires, X<3> et X4 sont des radicaux identiques ou différents choisis parmi un groupe méthyle et un atome de chlore, sa forme racémique et ses énantiomères. and R4 can be linked with the carbon atom to which they are attached to form a cycloalkyl radical containing 5 or 6 nuclear carbon atoms, X <3> and X4 are identical or different radicals chosen from a methyl group and an atom of chlorine, its racemic form and its enantiomers. 14 - Sel d'un acide indanyloxy-acétique de formule : 14 - Salt of an indanyloxyacetic acid of formula: <EMI ID=100.1> <EMI ID = 100.1> <EMI ID=101.1> <EMI ID = 101.1> <EMI ID=102.1> <EMI ID = 102.1> rieur avec 1 à 3 atomes de carbone, phényle, p-chlorophényle ou thiényle, X<3> et X sont identiques ou différents et représentent des radicaux choisis parmi un groupe méthyle ou un atome de chlore, sa forme racémique ou ses énantiomères. laughing with 1 to 3 carbon atoms, phenyl, p-chlorophenyl or thienyl, X <3> and X are identical or different and represent radicals chosen from a methyl group or a chlorine atom, its racemic form or its enantiomers. 15 - Sel selon la revendication 14 caractérisé en ce que l'acide indanyloxy-acétique est l'acide (1-oxo-2-méthyl-2- 15 - Salt according to claim 14 characterized in that the indanyloxy-acetic acid is (1-oxo-2-methyl-2- <EMI ID=103.1> <EMI ID = 103.1> 16 - Sel selon la revendication 14, caractérisé en ce que l'acide indanyloxy-acétique est l'acide lévo-(1-oxo-2méthyl-2-phényl-6,7-dichloro-5-indanyloxy)-acétique. 16 - Salt according to claim 14, characterized in that the indanyloxy-acetic acid is levo- (1-oxo-2methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid. 17 - Sel selon la revendication 14, caractérisé en ce que l'acide indanyloxy-acétique est l'acide [1-oxo-2-méthyl-2- 17 - Salt according to claim 14, characterized in that the indanyloxy-acetic acid is [1-oxo-2-methyl-2- acid <EMI ID=104.1> <EMI ID=105.1> <EMI ID = 104.1> <EMI ID = 105.1> 19 - Sel de triamterene d'acide indanyloxyacétique de formule : 19 - Indanyloxyacetic acid triamterene salt of formula: <EMI ID=106.1> <EMI ID = 106.1> dans laquelle R est un radical alcoyle inférieur ayant de 1 à 5 atomes de carbone, un radical cycloalcoyle, aryle ou aryle substitué, thiényle ou thiényle substitué; R est un radical alcoyle inférieur ayant de 1 à 5 atomes de carbone, un radical alcényle inférieur ayant de 3 à 5 atomes de carbone, un radical alcynyle inférieur ayant de 3 à 5 atomes de carbone, phénylalcoyle inférieur dans lequel la portion alcoyle inférieure présente de 1 à 3 atomes de carbone ou phénylalcényle inférieur dans lequel la portion alcényle inférieur présente de 2 à 5 atomes de carbone, aryle ou aryle substitué, thiényle ou thiényle substitué; P et in which R is a lower alkyl radical having from 1 to 5 carbon atoms, a cycloalkyl, substituted aryl or aryl, thienyl or substituted thienyl radical; R is a lower alkyl radical having 1 to 5 carbon atoms, a lower alkenyl radical having 3 to 5 carbon atoms, a lower alkynyl radical having 3 to 5 carbon atoms, lower phenyl alkyl in which the lower alkyl portion has from 1 to 3 carbon atoms or lower phenylalkenyl in which the lower alkenyl portion has from 2 to 5 carbon atoms, aryl or substituted aryl, thienyl or substituted thienyl; P and <EMI ID=107.1> <EMI ID = 107.1> ils sont attachés pour former un radical cycloalcoyle ayant de 3 they are attached to form a cycloalkyl radical having 3 <EMI ID=108.1> <EMI ID = 108.1> gène ou le radical méthyle et X<2> est un radical méthyle ou un gene or methyl radical and X <2> is a methyl radical or a <EMI ID=109.1> <EMI ID = 109.1> hydrocarbylène contenant de 3 ou 4 atomes de carbone, et Y est un radical alcoylène ou haloalcoylène contenant un maximum de 4 atomes de carbone, sa forme racémique et ses énantiomères. hydrocarbylene containing 3 or 4 carbon atoms, and Y is an alkylene or haloalkylene radical containing a maximum of 4 carbon atoms, its racemic form and its enantiomers. 20 - Sel de triamterene d'un acide indanyloxyacétique de formule : - <EMI ID=110.1> dans laquelle R<3> est un radical alcoyle inférieur ayant de 1 à 5 atomes de carbone un radical cycloalcoyle ayant 5 ou 6 atomes 20 - Triamterene salt of an indanyloxyacetic acid of the formula: - <EMI ID = 110.1> in which R <3> is a lower alkyl radical having from 1 to 5 carbon atoms a cycloalkyl radical having 5 or 6 atoms <EMI ID=111.1> <EMI ID = 111.1> 1 à 3 atomes de carbone, phényle, alcoyle inférieur phényle, la portion alcoyle inférieure ayant de 1 à 3 atomes de carbone halogénophényle, méthoxyphényle, hydroxyphényle, aminophényle, aminométhylphényle, thiényle, alcoyl inférieur thiényle, la portion alcoyle inférieur ayant de 1 à 3 atomes de carbone ou 1 to 3 carbon atoms, phenyl, lower alkyl phenyl, the lower alkyl portion having from 1 to 3 carbon atoms halophenyl, methoxyphenyl, hydroxyphenyl, aminophenyl, aminomethylphenyl, thienyl, lower alkyl thienyl, the lower alkyl portion having from 1 to 3 carbon atoms or <EMI ID=112.1> <EMI ID = 112.1> avec l'atome de càrbone sur lequel ils sont fixés,un radical cycloalcoyle contenant 5 ou 6 atomes de carbone dans le cycle; with the carbon atom to which they are attached, a cycloalkyl radical containing 5 or 6 carbon atoms in the ring; <EMI ID=113.1> <EMI ID = 113.1> énantiomères. enantiomers. 21 - Sel de triamterene d'un acide indanyloxyacétique de formule : 21 - Triamterene salt of an indanyloxyacetic acid of formula: <EMI ID=114.1> <EMI ID = 114.1> <EMI ID=115.1> <EMI ID = 115.1> <EMI ID=116.1> <EMI ID = 116.1> 1 à 3 atomes de carbone, un radical phényle, p-chlorophényle ou thiényle, X et X qui sont semblables ou différents représentent un radical méthyle ou un atome de chlore, ses formes racéiniques et ses énantiomères. 1 to 3 carbon atoms, a phenyl, p-chlorophenyl or thienyl radical, X and X which are the same or different represent a methyl radical or a chlorine atom, its root forms and its enantiomers. 22 - Sel de triamterene selon la revendication 21, caractérisé en ce que l'acide indanyloxyacétique est l'acide 22 - Triamterene salt according to claim 21, characterized in that the indanyloxyacetic acid is the acid <EMI ID=117.1> <EMI ID = 117.1> acétique. acetic. 23 - Sel triamterene selon la revendication 21, caractérisé en ce que l'acide indanyloxyacétique est l'acide levo-(1oxo-2-méthyl-2-phényl-6,7-dichloro-5-indanyloxy)acétique. 23 - Triamterene salt according to claim 21, characterized in that the indanyloxyacetic acid is levo- (1oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid. 24- - Sel triamterene selon la revendication 21, caractérisé en ce que l'acide indanyloxyacétique est un acide [1-oxo- 24- - Triamterene salt according to claim 21, characterized in that the indanyloxyacetic acid is an acid [1-oxo- <EMI ID=118.1> <EMI ID = 118.1> 25 - Sel triamterene selon la revendication 21, caractérisé en ce que l'acide indanyloxyacétique est l'acide [1-oxo2-méthyl-2-(2-thiényl)-6,7-dichloro-5-indanyloxy]acétique. 25 - The triamterene salt of claim 21, characterized in that the indanyloxyacetic acid is [1-oxo2-methyl-2- (2-thienyl) -6,7-dichloro-5-indanyloxy] acetic acid. 26 - A titre de médicament nouveau un sel selon l'une des revendications 12 à 25. 26 - As a new drug, a salt according to one of claims 12 to 25.
BE149401A 1973-10-11 1974-10-10 DIURETIC FORMULAS BE820919A (en)

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