DE2448428A1 - DIURETIC AGENTS - Google Patents
DIURETIC AGENTSInfo
- Publication number
- DE2448428A1 DE2448428A1 DE19742448428 DE2448428A DE2448428A1 DE 2448428 A1 DE2448428 A1 DE 2448428A1 DE 19742448428 DE19742448428 DE 19742448428 DE 2448428 A DE2448428 A DE 2448428A DE 2448428 A1 DE2448428 A1 DE 2448428A1
- Authority
- DE
- Germany
- Prior art keywords
- carbon atoms
- phenyl
- methyl
- lower alkyl
- acetic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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- C—CHEMISTRY; METALLURGY
- 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
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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
- A61K31/33—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
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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
- A61K31/56—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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- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- 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
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- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
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- C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C333/14—Dithiocarbamic acids; Derivatives thereof
- C07C333/18—Esters of dithiocarbamic acids
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- 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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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- 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
- C07C45/65—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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- 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
- C07C45/67—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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- C07C45/61—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
- C07C45/67—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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- C07C45/61—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
- C07C45/67—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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- C07C45/61—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
- C07C45/67—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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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- 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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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- 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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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
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- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
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- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- 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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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- 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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- C07D475/00—Heterocyclic compounds containing pteridine ring systems
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- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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- C07C2602/00—Systems containing two condensed rings
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- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
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- C07C2603/10—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
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Description
Die Erfindung betrifft pharmazeutische Präparate, die vorteilhafte diuretische und/oder saluretische Wirkungen aufweisen. Der Einfachheit halber wird der Ausdruck "diuretisch" hier im allgemeinen Sinne für Mittel angewandt, die Diurese (erhöhte TJrinausscheidung) und/oder.Salurese (erhöhte Blektrolytausscheidung) verursachen.The invention relates to pharmaceutical preparations that are advantageous have diuretic and / or saluretic effects. For the sake of simplicity, the term "diuretic" used here in the general sense for means that diuresis (increased TJrin excretion) and / or saluresis (increased electrolyte excretion) cause.
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Diuretika sind wertvolle therapeutische Mittel, da-sie sich zur Behandlung von kardiovaskulären Erkrankungen und Nierenerkrankungen eignen. Ihre Terwendung erfolgt zur Bekämpfung aller Arten und Schweregrade von auf Kongestion beruhendem Herzversagen, bei denen eine Besserung durch diuretische Therapie erforderlich ist. Auf Grund des Verlustes von Wasser und Elektrolyt wird bei peripherem Ödem, Lungenödem, Kurzatmigkeit, Orthopnöe,'Husten, Ascites und Pleuraerguss eine ausserordentlich starke Besserung festgestellt.Diuretics are valuable therapeutic agents as-they are suitable for the treatment of cardiovascular diseases and kidney diseases. They are used to combat All types and degrees of congestive heart failure that are relieved by diuretic Therapy is required. Due to the loss of water and electrolyte, peripheral edema, pulmonary edema, shortness of breath, Orthopnea, cough, ascites and pleural effusion showed an extraordinarily strong improvement.
509817/1230509817/1230
15 582ΓΒΥ O15 582ΓΒΥ O
Diese Mittel eignen sich auch, zui wirksamen Therapie hei verschiedenen Formen von Nierenödemen, z.B. von Ödem, das bei Nephrose und gewissen Arten von Nierenentzündungen auftritt. Ihre Darreichung führt zur sofortigen Ausscheidung von im Körper zurückgehaltener Flüssigkeit und zurückgehaltenen Elektrolyten mit einer entsprechenden Erleichterung für den Patienten. Der Elektrolyt, der ausgeschieden werden soll, ist Kochsalz. These agents are also suitable for effective therapy in various ways Types of kidney edema, such as the edema that occurs in nephrosis and certain types of kidney inflammation. Their administration leads to the immediate excretion of fluid retained in the body and retained electrolytes with a corresponding relief for the patient. The electrolyte to be eliminated is table salt.
Diese Mittel eignen sich besonders für die Behandlung der Hypertonie und ermöglichen eine wertvolle Therapie.bei milden, massigen und schweren Formen dieser Krankheit.These remedies are particularly suitable for the treatment of hypertension and enable valuable therapy. massive and severe forms of this disease.
Obwohl Diuretika wegen ihrer oben erwähnten günstigen therapeutischen Wirkungen oft lebensrettend sind, haben die meisten von ihnen den Nachteil, dass sie die Ausscheidung erheblicher Mengen an Kaliumionen zur Folge haben. Wenn ein zu starker Verlust an Kaliumionen auftritt, kommt es zu einer erheblichen Muskelschwäche und zu dem Gefühl äusserster physischer Erschöpfung. Der Patient scheidet auf Grund der Wirkung der diuretischen Mittel zwar die unerwünschten Natriumionen aus, jedoch entsteht durch die unbeabsichtigte Ausscheidung der Kaliumionen ein Ungleichgewicht, das man nicht andauern lassen darf.Although diuretics are beneficial therapeutic because of their above mentioned Effects are often life-saving, most of them have the disadvantage that they make the excretion more significant Amount of potassium ions. If there is too much loss of potassium ions, it will Significant muscle weakness and a feeling of extreme physical exhaustion. The patient leaves because of the effect The diuretic does remove the unwanted sodium ions, but is created by the inadvertent excretion of potassium ions an imbalance that cannot be allowed to persist.
Ausser ihren sonstigen Wirkungen .sind diese Verbindungen auch imstande, die Harnsäurekonzentration im Körper auf-dem vor der Behandlung bestehenden Spiegel zu halten, oder sogar eine Abnahme der Harnsäurekonzentration zu bewirken. Viele der gegenwärtig erhältlichen Diuretika und Saluretika haben die Tendenz, bei der Darreichung zur Hyperurikämie zu führen, wodurch Harnsäure oder Natriumurat oder beide Verbindungen im Körper ausgefällt werden können, so dass es zu milder oder schwerer Gicht kommt. Die Verbindungen gemäss der Erfingung stellen ein wirksames Mittel zur Verfügung, um Patienten, die einer diuretischen und saluretischen Behandlung bedürfen, ohne die Gefahr des Auftretens von Gicht zu behandeln.In addition to their other effects, these compounds are also able to keep the uric acid concentration in the body on-the-fly treatment to maintain existing levels or even cause uric acid levels to decrease. Many of the present available diuretics and saluretics have the tendency to lead to hyperuricemia when administered, whereby Uric acid or sodium urate or both compounds can be precipitated in the body, making it milder or too severe gout is coming. The compounds according to the invention provide an effective means of providing patients who needing diuretic and saluretic treatment without treating the risk of developing gout.
- 2 509817/1230 - 2 509817/1230
15 582ΓΒΥ 315 582ΓΒΥ 3
Die Erfindung, "betrifft die gleichzeitige Darreichung einer 2,2-disubstituierten (1-0xo-5-indanyloxy)-essigsäure mit einem Pyrazinoylguanidin als Gemisch oder Salz, mit einem Pteridin als Gemisch oder Salz oder mit Spironolacton als Gemisch, "wodurch, die Menge der ausgeschiedenen Kaliumionen herabgesetzt wird, ohne dass.auch die Menge der ausgeschiedenen Natriumionen vermindert wird.The invention "relates to the simultaneous administration of a 2,2-disubstituted (1-0xo-5-indanyloxy) acetic acid with a pyrazinoylguanidine as a mixture or salt, with a pteridine as a mixture or salt or with spironolactone as a mixture, "whereby, the amount of potassium ions excreted is reduced without the amount of sodium ions excreted is decreased.
Im Falle der N-Amidino-3>S-diamino-ö-chlorpyrazincarboxamidsalze der 2,2-disubstituierten (1-0xo-5-indanyloxy)-essigsäure-Diuretika besteht ein anderer Vorteil in ihrer Unlöslichkeit, so dass diese Salze im Magen-Darmkanal langsamer und allmählicher absorbiert werden und man durch eine chemische. Methode die gleiche Wirkung wie durch Mikroeinkapselung erzielt.In the case of the N-amidino-3> S-diamino-ö-chloropyrazinecarboxamide salts the 2,2-disubstituted (1-0xo-5-indanyloxy) acetic acid diuretics Another advantage is their insolubility, making these salts enter the gastrointestinal tract more slowly and gradually be absorbed and you get through a chemical. Method has the same effect as microencapsulation achieved.
Die erfindungsgemäss verwendbaren 2,2-disubstituierten /Τ-Οχο-5-indanyloxy- (oder -thioJ7~alkancarbonsäuren, zu denen sowohl die Racemate als auch die reinen Enantiomeren gehören, haben die allgemeine FormelThe inventively used 2,2-disubstituted / Τ-Οχο-5-indanyloxy- (or -thioJ7 ~ al kancarbonsäuren to which both the racemates and the pure enantiomers are, have the general formula
-2O- 2 O
0
HO-C-Y-A'0
HO-CY-A '
in der A Sauerstoff oder Schwefel, R einen niederen Alkylrest mit 1 bis 5 Kohlenstoffatomen, wie Methyl, Äthyl, n-Propyl, Isopropyl, η-Butyl, Isobutyl, tert.Butyl, n-Pentyl und dergleichen, Cycloalkyl, z.B. Cycloalkyl mit 5 bis 6 Kernkohlenstoff atomen, wie Cyclopentyl, Cyclohexyl und dergleichen, Aryl, wie Phenyl, oder substituiertes Aryl, wobei der Substituent niederes Alkyl, Halogen, niederes Alkoxy, Hydroxy, Amino oder Aminomethyl sein kann, Thienyl oder substituiertes Thienyl, wobei der Substituent niederes Alkyl oder Halogen sein kann, R einen niederen Alkylrest mit 1 bis 5in which A is oxygen or sulfur, R is a lower alkyl radical with 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, Isopropyl, η-butyl, isobutyl, tert-butyl, n-pentyl and the like, Cycloalkyl, e.g. cycloalkyl with 5 to 6 core carbon atoms, such as cyclopentyl, cyclohexyl and the like, Aryl, such as phenyl, or substituted aryl, where the substituent is lower alkyl, halogen, lower alkoxy, hydroxy, Can be amino or aminomethyl, thienyl or substituted thienyl, the substituent being lower alkyl or Can be halogen, R is a lower alkyl radical with 1 to 5
— 3 — 509817/1230 - 3 - 509817/1230
15 582IBY Y15 582IBY Y
■Kohlenstoffatomen, wie Methyl, Äxhyl, n-Propyl, Isopropyl, η-Butyl, Isobutyl, tert.Butyl, n-Pentyl und dergleichen, einen niederen Alkenylrest mit 3 "bis 5 Kohlenstoffatomen, wie Allyl, 1-, 2- oder 3-Butenyl, 1-, 2-, 3- oder 4-Pentenyl und dergleichen, einen niederen Alkinylrest mit 3 bis 5 Kohlenstoffatomen, wie Propargyl, 1-, 2- oder 3-Butinyl, 1-, 2-, 3- oder 4-Pentinyl und dergleichen, Phenyl-nied.alkyl, worin die niedere Alkylgruppe 1 "bis 3 Kohlenstoffatome aufweist, wie Benzyl, Phenethyl, Phenylpropyl und dergleichen, Phenyl-nied,-alkenyl, worin die niedere Alkenylgruppe 2 bis 5 Kohlenstoffatome aufweist, wie Cinnamyl und dergleichen, Aryl, wie Phenyl, oder substituiertes Aryl, wie nied.Alkylaryl oder Halogenaryl, Thienyl oder substituiertes Thienyl, wie nied.Alkylthienyl oder Halogenthienyl bedeuten, oder R und R mit dem Kohlenstoffatom, an das sie gebunden sind, zu einem Cycloalkylrest mit 3 bis 7 Kernkohlenstoffatomen zusammengeschlossen sein können, z.B. Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl und dergleichen, X^ Wasserstoff, Methyl oder Halogen, wie Chlor, Brom, Fluor und der-■ carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, t-butyl, n-pentyl and the like, one lower alkenyl radical with 3 "to 5 carbon atoms, such as Allyl, 1-, 2- or 3-butenyl, 1-, 2-, 3- or 4-pentenyl and like, a lower alkynyl radical with 3 to 5 carbon atoms, such as propargyl, 1-, 2- or 3-butynyl, 1-, 2-, 3- or 4-pentynyl and the like, phenyl-lower alkyl, in which the lower alkyl group has 1 "to 3 carbon atoms, such as Benzyl, phenethyl, phenylpropyl and the like, phenyl-lower, -alkenyl, wherein the lower alkenyl group has 2 to 5 carbon atoms such as cinnamyl and the like, aryl such as Phenyl, or substituted aryl, such as lower alkylaryl or Haloaryl, thienyl or substituted thienyl, such as lower alkylthienyl or halothienyl, or R and R with the carbon atom to which they are attached to one Cycloalkyl radicals with 3 to 7 core carbon atoms can be joined together, e.g. cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl and the like, X ^ hydrogen, Methyl or halogen, such as chlorine, bromine, fluorine and the
2
gleichen, und X Methyl oder Halogen, wie Chlor, Brom oder2
same, and X is methyl or halogen, such as chlorine, bromine or
1 2 Fluor und dergleichen, bedeuten, oder X und X zusammen eine zweiwertige Kohlenwasserstoffkette mit 3 bis 4 Kohlenstoffatomen bilden können, wie Trimethylen, Tetramethylen, 1,3-Butadienylen und dergleichen, während Y einen Alkylen- oder Halogenalkylenrest mit maximal 4 Kohlenstoffatomen bedeutet, die 1 bis 3 lineare Kohlenstoffatome zwischen der Oxy- (oder Thio)- und der Carboxylgruppe enthalten.,. z.B. Methylen, Äthyliden, Propyliden, Isopropyliden, Ithylen, Trimethylen, Fluormethylen und dergleichen. Die Erfindung umfasst auch die racemischen Formen und die Enantiomeren dieser Verbindungen. 1 2 fluorine and the like, or X and X together are a divalent hydrocarbon chain having 3 to 4 carbon atoms can form, such as trimethylene, tetramethylene, 1,3-butadienylene and the like, while Y is an alkylene or haloalkylene radical with a maximum of 4 carbon atoms, the 1 to 3 linear carbon atoms between the Contain oxy (or thio) and the carboxyl group.,. e.g. Methylene, ethylidene, propylidene, isopropylidene, ethylene, trimethylene, Fluoromethylene and the like. The invention also includes the racemic forms and the enantiomers of these compounds.
Die bevorzugten 2,2-disubstituierten /Τ-Οχο-5-indanyloxy-(oder -thioJZ-alkancarbonsäuren gemäss der Erfindung haben die allgemeine FormelThe preferred 2,2-disubstituted / Τ-Οχο-5-indanyloxy- (or -thioJZ-alkanecarboxylic acids according to the invention the general formula
- 4 -509817/1230- 4 -509817/1230
15 582IBY15 582IBY
HOCCH0OHOCCH 0 O
IaYes
■ζ■ ζ
in der R- eine niedere Alkylgruppe mit 1 bis 3 Kohlenstoffatomen, wie Methyl, Äthyl, n-Propyl oder Isopropyl, oder eine Cycloalkylgruppe mit 5 oder 6 Kernkohlenstoffatomen, wie Cyclopentyl oder Cyclohexyl, und R eine niedere Alkylgruppe mit 1 Ms 3 Kohlenstoffatomen, wie Methyl, Äthyl, n-Propyl oder Isopropyl, Phenyl, nied.Alkylphenyl, wobei die niedere Alkylgruppe 1 Ms 3 Kohlenstoffatome aufweist, wie Methyl, Äthyl, n-Propyl oder Isopropyl, Halogenphenyl, Methoxyphenyl, Hydroxyphenyl, Aminophenyl, Aminomethylphenyl, Thienyl, nied.Alkylthienyl, wobei die niedere Alkylgruppe 1 bis 3 Kohlenstoff atome enthält, wie Methyl, Äthyl, n-Prapyl oder Isopropyl, Halogenthienyl bedeuten, oder R und R mit dem Kohlenstoffatom, an das sie gebunden sind, zu einem Cycloalkylrest mit 5 bis 6 Kernkohlenstoffatomen zusammengeschlossen sein können, wie Cyclopentyl, Cyclohexyl und dergleichen, während X und X gleich oder verschieden sein können und Methyl oder Chlor bedeuten. Die Erfindung umfasst auch die racemischen_Formen und die Enantiomeren dieser Verbindungen.in which R is a lower alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl or isopropyl, or a Cycloalkyl group with 5 or 6 core carbon atoms, such as cyclopentyl or cyclohexyl, and R is a lower alkyl group with 1 Ms 3 carbon atoms, such as methyl, ethyl, n-propyl or isopropyl, phenyl, lower alkylphenyl, the lower Alkyl group has 1 Ms 3 carbon atoms, such as methyl, Ethyl, n-propyl or isopropyl, halophenyl, methoxyphenyl, Hydroxyphenyl, aminophenyl, aminomethylphenyl, thienyl, lower alkylthienyl, the lower alkyl group being 1 to 3 carbon contains atoms, such as methyl, ethyl, n-prapyl or isopropyl, Halothienyl, or R and R with the carbon atom, to which they are bound together to form a cycloalkyl radical with 5 to 6 core carbon atoms can be, such as cyclopentyl, cyclohexyl and the like, while X and X can be the same or different and Mean methyl or chlorine. The invention also includes the racemic forms and the enantiomers of these compounds.
Die noch stärker bevprzugten 2,2-disubstituierten ^/T-Oxö-5-indanyloxy-(oder -thioJT-alkancarbonsäuren gemäss der Erfindung haben die allgemeine FormelThe even more preferred 2,2-disubstituted ^ / T-oxo-5-indanyloxy- (or -thioJT-alkanecarboxylic acids according to the invention have the general formula
HOCCH0OHOCCH 0 O
Ib
7
in der R einen niederen Alkylrest mit 1 bis 3 Kohlenstoff-Ib
7th
in which R is a lower alkyl radical with 1 to 3 carbon
.. ft.. ft
atomen, wie Methyl, Äthyl, n-Propyl oder Isopropyl, R einenatoms, such as methyl, ethyl, n-propyl or isopropyl, R one
— 5 — 509817/1230- 5 - 509817/1230
15 582IBY 615 582IBY 6
niederen Alkylrest mit 1 bis 3 Kohlenstoffatomen, wie Methyl, Äthyl, n-Propyl, Isopropyl, Phenyl, p-Chlorphenyl oderlower alkyl radical with 1 to 3 carbon atoms, such as methyl, Ethyl, n-propyl, isopropyl, phenyl, p-chlorophenyl or
% λ% λ
Thienyl bedeuten, während X und X gleich oder verschieden sein können und Methyl oder Chlor bedeuten.Thienyl, while X and X are identical or different can be and mean methyl or chlorine.
Zu dieser stärker bevorzugten Gruppe gehören die folgenden Verbindungen:This more preferred group includes the following compounds:
(1-Oxo-2-methyl-2-phenyl-6,7-dichlor-5-indanyloxy)-essigsäure,(1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid,
laevo-(1-0xo-2-methyl-2-phenyl-6,7-dichlor~5-indanyloxy)~ essigsaure,laevo- (1-0xo-2-methyl-2-phenyl-6,7-dichloro ~ 5-indanyloxy) ~ acetic acid,
^Τ-Οχο-2-me thyl-2-(p-chlorphenyl)-6,7-dichlor-5-indanyloxy7'-essigsäure, ^ Τ-Οχο-2-methyl-2- (p-chlorophenyl) -6,7-dichloro-5-indanyloxy7'-acetic acid,
//T-0xo-2-methyl-2-(2-thienyl)-6,7-dichlor-5-indanyloxy7~ essigsäure, / / T-0xo-2-methyl-2- (2-thienyl) -6,7-dichloro-5-indanyloxy7 ~ acetic acid,
von denen die racemische und die laevo-(1-0xo-2-methyl-2-phenyl-6,7-dichlor-5-indanyloxy)-essigsäure besonders bevorzugt werden. Obwohl diese Verbindungen' die bevorzugten Diuretika der Klasse der Indanyloxyessigsäuren sind, umfasst die Erfindung auch die Verwendung irgendeiner der anderen,of which racemic and laevo- (1-0xo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid are particularly preferred. Although these compounds are 'the preferred diuretics are of the class of indanyloxyacetic acids, the invention also encompasses the use of any of the other
oben angegebenen, verwandten Verbindungen.related compounds identified above.
Um die günstigen Ergebnisse gemäss der Erfindung zu erzielen, ist die bevorzugte Pyrazinoylguanidinverbindung N-Aniidino-3,5-diamirio-6-chlorpyrazincarboxamid (Amilorid), welches im Schrifttum und in Patentschriften1 beschrieben ist. Statt dieser Verbindung kann man jedoch auch 6-Phenyl-2,4,7-triaminopteridin (nachstehend als "Triamteren" bezeichnet) oder Spironolacton verwenden.In order to achieve the favorable results according to the invention, the preferred pyrazinoylguanidine compound is N-aniidino-3,5-diamirio-6-chloropyrazinecarboxamide (amiloride), which is described in the literature and in patent documents 1 . Instead of this compound, however, it is also possible to use 6-phenyl-2,4,7-triaminopteridine (hereinafter referred to as "triamterene") or spironolactone.
Im Rahmen der Erfindung liegt die Verwendung von mechanischen Gemischen der 2,2-disubstituierten (1-0xo-5-indanyloxy)-essigsäure-Diuretika mit Amilorid, Triamteren oder Spironolaoton in verschiedenen Verhältnissen sowie die Verwendung von chemischen Salzen aus den 2,2-disubstituierten (1-0xo-5-indanyloxy)-essigsäuren und Amilorid oder Triarateren.The use of mechanical mixtures of the 2,2-disubstituted (1-0xo-5-indanyloxy) acetic acid diuretics lies within the scope of the invention with amiloride, triamterene or spironolaoton in various ratios, as well as the use of chemical Salts from the 2,2-disubstituted (1-0xo-5-indanyloxy) acetic acids and amiloride or triaraters.
- 6 5098 17/1230 - 6 5098 17/1230
■ - ■ "* 2Λ48428■ - ■ "* 2Λ48428
15 582IBY . % 15 582IBY. %
Das Amiloridsalz einer 2,2-disubstituieriren (1-Oxo-5-indanyloxy)-essigsaure wird hergestellt, indem man die 2,2-disubstituierte (1 -0xo-5-indanyloxy)-essigsäureverbindung zu einer Lösung von Amilorid in einem geeigneten, mit Wasser mischbaren organischen Lösungsmittel, wie Dimethylsulfoxid, zusetzt und die Lösung in Wasser giesst, aus dem das" gewünschte Amiloridsalz der Indanyloxyessigsaure ausfällt, so dass es abfiltriert werden kann.The amiloride salt of a 2,2-disubstituted (1-oxo-5-indanyloxy) acetic acid is made by removing the 2,2-disubstituted (1-oxo-5-indanyloxy) acetic acid compound is added to a solution of amiloride in a suitable, water-miscible organic solvent, such as dimethyl sulfoxide and the solution is poured into water from which the "desired amiloride salt of indanyloxyacetic acid precipitates, so that it can be filtered off.
■ Hie Erfindung umfasst Mittel für die orale Darreichung, "bei denen das Molverhältnis von 2,2-disubstituierter .(i-Oxo-5-indanyloxy)-essigsäure zu Amilorid im Bereich von etwa 0,2:1 "bis 4,0:1 liegt. Die bevorzugten Verhältnisse von 2,2-disubstituierter (i-Oxo-5-indanyloxy) -essigsäure zu Amilorid liegen im Bereich von 0,8:1 bis 1,6:1. Pur den Pail, dass als Indanyloxyessigsaure racemische (1-0xo-2-methyl-2-phenyl~ 6,7-dichlor~5-indanyloxy)-essigsäure verwendet wird, sind die bevorzugten absoluten Gewichtsmengen und Gewichtsverhältnisse, die den oben angegebenen Molverhältnissen entsprechen, in Tabelle I-a genannt. Die entsprechenden Werte für das laevo-Isomere finden sich in Tabelle I-b.■ The invention includes agents for oral administration, "at which is the molar ratio of 2,2-disubstituted. (i-Oxo-5-indanyloxy) acetic acid to amiloride ranges from about 0.2: 1 "to 4.0: 1. The preferred ratios of 2,2-disubstituted (i-Oxo-5-indanyloxy) acetic acid to amiloride in the range from 0.8: 1 to 1.6: 1. Pur den Pail that as Indanyloxyacetic acid racemic (1-0xo-2-methyl-2-phenyl ~ 6,7-dichloro-5-indanyloxy) acetic acid is used, the preferred absolute weight amounts and weight ratios are which correspond to the molar ratios given above, mentioned in Table I-a. The corresponding values for the laevo isomer can be found in Table I-b.
- 7 -509817/1230- 7 -509817/1230
Absolutes Gewicht der BestandteileAbsolute weight of the components
(1-0xo-2-methyl-2-phenyl-6,7-diohlor-5-indanyloxy)-essig- (1-0xo-2-methyl-2-phenyl-6,7-diohlor-5-indanyloxy) -acetic-
saureacid
CD CO OOCD CO OO
OO IOO I
10 2510 25
AmiloridAmiloride
1010
5 '5 5 '5
I-aI-a
GewichtsverhältnisWeight ratio
(i-0xo-2-nethyl-2-phenyl-6,7-d
ichlor-5-indanyloxy)-essig-
säure : Amilorid(i-0xo-2-nethyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic-
acid: amiloride
(1-0xo-2-methyl-2-phenyl-6,7~dichlor-5-indanyloxy)-essigsäure :■■ Amilorid(1-0xo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid : ■■ amiloride
Tabelle I-bTable I-b
cncn
to coto co
Ni CO ONi CO O
Absolutes Gewicht der BestandteileAbsolute weight of the components
laevo-(1-Oxo-2-methyl-2-phenylc,7-dichlor-5-indanyloxy)- laevo- (1-oxo-2-methyl-2-phenylc, 7-dichloro-5-indanyloxy) -
2,52.5
2,52.5
ι ^ι ^
12,512.5
AmiloridAmiloride
laevo-(1-Gxo-2-m e t hy 1 - 2 - ph, e v.y 1 6,7-dicblor-5-indanyloxy)-essigsäure : Amiloridlaevo- (1-Gxo-2-met hy 1 - 2 - ph, e vy 1 6,7-dicblor-5-indanyloxy) -acetic acid: amiloride
laevo-(1-Oxo-2-nethyl-2-pher.yl-O,7-äicnlor-5-ind anylο xy)-e ssigciiure : Amiloridlaevo- (1-oxo-2-ethyl-2-pher.yl-O, 7-chloro-5-ind anylο xy) -e ssigciiure : Amiloride
LOLO
-F-OC-F-OC
15 582ΙΒΪ" JO 15 582ΙΒΪ " JO
Die Erfindung umfayat ferner Mittel für die orale Darreichung, in denen das Molverhältnis von 2,2-dinubstituierter (1-Oxo-5-indanyloxy)-ei3Hi^jäure zu Triainteren im Bei·«ioh vom etwa 1:7 bin 1:3,5 liegt. Pur den ij'all, dass als Indanyloxyessigsäure raceinische (1-0xo-2-methyl-i:'-phenyl-6, 7--diohlor-5-indanyloxy)-es£3igsäure verwendet wird, wind die bevorzugten absoluten Gewichtsnengen und Gewichtsverhältnisse, die den oben angegebenen I-Tolverhältniüsen entaproohen, in Tabelle II-a genannt. Die entsproulicnden Werte für dao laevo-Iaomere finden sich in Tabelle II-b.The invention also includes means for oral administration, in which the molar ratio of 2,2-dinubstituted (1-oxo-5-indanyloxy) -ei3Hi ^ jäure to Triainteren in Bei · «ioh from about 1: 7 am 1: 3.5. Pur den ij'all that as indanyloxyacetic acid raceinic (1-0xo-2-methyl-i: '- phenyl-6, 7-dichloro-5-indanyloxy) -es £ 3etic acid is used, the preferred absolute weight amounts and ratios that the entaproot the above I-Tol ratios, in Table II-a called. Find the corresponding values for dao laevo-Iaomers Table II-b.
' ■ I'■ I
- 10 -- 10 -
509817/1230509817/1230
BAD ORIGINAtBAD ORIGINAt
T a "b e 1 1 e II-aT a "b e 1 1 e II-a
Absolutes Gewicht der BestandteileAbsolute weight of the components
(1-0xo-2-methyl-2-phenyl-6,7-dichlor-5-iridanyloxy)-essig saure(1-0xo-2-methyl-2-phenyl-6,7-dichloro-5-iridanyloxy) -acetic acid acid
10
2010
20th
Triamteren Triamteren
50 .50 10050 .50 100
GewichtsverhältnisWeight ratio
(1-0xo-2-methyl-2-phenyl-6,7-dichlor-5-indanyloxy)-essigsäure : Triarnteren(1-0xo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid : Triarnteren
1:101:10
1:51: 5
1:51: 5
MolverhältnisMolar ratio
phenyl-6,7-dichlor-5-indanyloxy)-essigsäure : Triamterenphenyl-6,7-dichloro-5-indanyloxy) acetic acid : Triamteren
1:71: 7
1:3,51: 3.5
1:3,51: 3.5
Tabelle Il-bTable II-b
2Λ484282,48428
15 582IBY 4315 582IBY 43
Die Erfindimg umfasst ferner Mittel für die orale Darreichung, "bei denen das Molverhältnis von 2,2-disubstituierter (1-Oxo-5-indanyloxy)-essigsäure zu Spironolacton im Bereich von etwa 1:4,4 Ms 1:2,2 liegt. Pur den Pail, dass als Indanyloxyessigsäure racemische (Ι-Οχο-^-ΐηβΐΙι^Ι-^-ρΙιβ^Ι-β,Τ-αίοΙιΙοΓ-^- indanyloxy)-essigsäure verwendet wird, sind die "bevorzugten absoluten Gewichtsmengen und Gewichtsverhältnisse, die den oTben angegebenen Molverhältnissen entsprechen, in Tabelle . III-a genannt. Die entsprechenden Werte für das laevo-Isomere finden sich in Tabelle III-b.The invention also includes agents for oral administration "in which the molar ratio of 2,2-disubstituted (1-oxo-5-indanyloxy) acetic acid to spironolactone is in the range of about 1: 4.4 Ms 1: 2.2. Pur den Pail that as indanyloxyacetic acid racemic (Ι-Οχο - ^ - ΐηβΐΙι ^ Ι - ^ - ρΙιβ ^ Ι-β, Τ-αίοΙιΙοΓ - ^ - indanyloxy) acetic acid is used, the "preferred absolute weight amounts and weight ratios that satisfy the oT correspond to the molar ratios given in the table. III-a called. The corresponding values for the laevo isomer are found in Table III-b.
' ■ I'■ I
- 13 -509817/1230- 13 -509817/1230
der Bestandteile ■ ".Absolute weight
of the components ■ ".
lactonSpirono-
lactone
phenyl-6,7-dichlor-
5-indanyloxy)-essig
saure(1-oxo-2-methyl-2-
phenyl-6,7-dichloro
5-indanyloxy) vinegar
acid
phenyl-6,7-dichlor-
5-indanyloxy)-essig-
säure : Spironolaoton(1-0xo-2-methyl-2-
phenyl-6,7-dichloro
5-indanyloxy) vinegar
acid: Spironolaoton
Kjbland
Kj
phenyl-6,7-dichlor-
5-indanyloxy)-essig-
säure : Spironolacton(1-0xo-2-methyl-2-
phenyl-6,7-dichloro
5-indanyloxy) vinegar
acid: spironolactone
CDCD
CD
ca
ONJ,
approx
O
VJl
Iι
VJl
I.
der BestandteileAbsolute weight
of the components
25
50-25
25th
50
methyl-2-phenyl-
6,7-dichlor-5- ..
indanyloxy)- Spirono-
essigsäure lactonlaevo- (1-0x0-2-
methyl-2-phenyl-
6,7-dichloro-5- ..
indanyloxy) - Spirono-
acetic acid lactone
methyl-2-phenyl-
6,7-dichlor-5-
indanyloxy)-es-
sigsäure : Spironolactonlaevo- (1-0x0-2-
methyl-2-phenyl-
6,7-dichloro-5-
indanyloxy) -es-
acetic acid: spironolactone
. 5
102.5
. 5
10
methyl-2-phenyl-
6,7-dichlor-5- v
indanyloxy)-es
sigsäure : Spironolactonlaevo- (1-oxo-2-
methyl-2-phenyl-
6,7-dichloro-5- v
indanyloxy) -es
acetic acid: spironolactone
1:4,4
1:4,41: 8.8
1: 4.4
1: 4.4
1:51:10
1: 5
15 582ΓΒΥ /fc15 582ΓΒΥ / fc
Beispiel 1 . Example 1 .
Herstellung des H-Amidino~3, 5-diamino-6--chlorpyrazincarboxamidsalzes von 0-Oxo-2-methyl--2-phenyl-6,7-dichlor~5-indanyloxy)-essigsäure Preparation of the H-Amidino ~ 3, 5-diamino-6-chlorpyrazine carboxamide salt of 0-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid
Eine heisse Lösung von 1,15 g (0,005 Mol) N-Amidino-3,5-diamino-6-chlorpyrazincarboxamid in 25 ml Dimethylsulfoxid wird mit 1,85 g (0,005 Mo.l) (1-0xo-2~niethyl-2-plienyl-6,7-dichlor-5-indanyloxy)-essigsäure versetzt. Die klare Lösung wird unter, starkem Rühren in 200 ml Wasser gegossen. Das sich abscheidende N-Amidino-^S-diamino-ö-chlorpyrazincarboxamidsalz von (i-0xo-2-methyl-2-phenyl-6,7-dichlor-5-indanyloxy)-essigsäure wird abfiltriert, mit Wasser gewaschen und getrocknet; P. 150° C.A hot solution of 1.15 g (0.005 mol) of N-amidino-3,5-diamino-6-chloropyrazine carboxamide In 25 ml of dimethyl sulfoxide, 1.85 g (0.005 mol. l) of (1-oxo-2-diethyl-2-plienyl-6,7-dichloro-5-indanyloxy) acetic acid is added offset. The clear solution is poured into 200 ml of water with vigorous stirring. The separating N-Amidino- ^ S-diamino-ö -chlorpyrazinecarboxamide salt of (i-0xo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid is filtered off, washed with water and dried; P. 150 ° C.
Analyseanalysis
Berechnet fürCalculated for
C24H22Cl3N7O5: C = 48,46 fo; H = 3,73 #; N = 16,48 96;C 24 H 22 Cl 3 N 7 O 5 : C = 48.46 fo; H = 3.73 #; N = 16.48 96;
gefunden: C = 48,11 #; H = 3,42 #; N = 1*6,19 #.found: C = 48.11 #; H = 3.42 #; N = 1 * 6.19 #.
Herstellung des 6-Phenyl-2,4,7-triaminopteridinsalzes von (i-Oxo-2-methyl-2-phenyl-6,7-dichlor-5-indanyloxy)-essigsäurePreparation of the 6-phenyl-2,4,7-triaminopteridine salt of (i-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid
Eine heisse Lösung von 1,27 g (0,005 Mol) 6-Phenyl-2,4,7-triaminopteridin in 25 ml Dimethylsulfoxid wird mit 1,85 g (0,005 Mol)"(1-0xo-2-methyl-2-phenyl-6,7-dichlor-5-indanyloxy)-essigsäure versetzt. Die klare Lösung wird unter star-r kern Rühren in 200 ml' Wasser gegossen. Das sich abs-cheidende 6-Phenyl-2,4,7-triaminopteridinsalz von (i-0xo-2-methyl-2-phenyl-6,7-dichlor~5-indanyloxy)-essigsäure wird abfiltriert, mit Wasser gewaschen und getrocknet.A hot solution of 1.27 g (0.005 mol) of 6-phenyl-2,4,7-triaminopteridine in 25 ml of dimethyl sulfoxide, 1.85 g (0.005 mol) of "(1-0xo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid offset. The clear solution is poured into 200 ml of water with strong stirring. The parting 6-phenyl-2,4,7-triaminopteridine salt of (i-0xo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid is filtered off, washed with water and dried.
Beispiel 3Example 3
Herstellung des N-Amidino^^-diamino-ö-ehlorpyrazincarboxamidsalzes von laevo-(i-0xo-2-methyl-2-phenyl-6,7-dichlor-5^indanyloxy) -essigsaure Preparation of the N-Amidino ^^ - diamino-ö-ehlorpyrazinecarboxamide salt of laevo- (i-0xo-2-methyl-2-phenyl-6,7-dichloro- 5 ^ indanyloxy) -acetic acid
Eine heisse Lösung von 1,15 g (0,005 Mol) N-Amidino-3,5-diamino-6-ehlorpyrazincarboxamid in 25 ml Dimethylsulfoxid wirdA hot solution of 1.15 g (0.005 mol) of N-amidino-3,5-diamino-6-chloropyrazine carboxamide in 25 ml of dimethyl sulfoxide
- 16 509817/1230 - 16 509817/1230
15 582IBY 4l· 15 582IBY 4l
mit 1,85 g (0,005 MoI) laevo-(1-Oxo-2-njethyl-2-phenyl-6,7-dichlor-5-indanyloxy)-essigsäure versetzt. Die klare Lösung wird unter starkem Rühren in 200 ml Wasser gegossen. Das sich abscheidende K-Amidino-3,5-diainino-6-chlorpyrazinearboxämidsalz der laevo-(i-Oxo^-methyl^-phenyl-e^-dichlor-S oxy)-essigsäure wird a"bfiltriert, mit Wasser gewaschen und getrocknet. .with 1.85 g (0.005 mol) laevo- (1-oxo-2-njethyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid offset. The clear solution is poured into 200 ml of water with vigorous stirring. That I precipitating K-amidino-3,5-diainino-6-chloropyrazine arboxemide salt the laevo- (i-Oxo ^ -methyl ^ -phenyl-e ^ -dichlor-S oxy) acetic acid is filtered off, washed with water and dried.
Beispiel 4Example 4
Herstellung des 6-Phenyl-2,4,7-triaminopteridinsalzes von laevo-(1-Oxo-2-methyl-2-phenyl-6,7~dichlor-5-indanyloxy)-essigsäure Preparation of the 6-phenyl-2,4,7-triaminopteridine salt of laevo- (1-oxo-2-methyl-2-phenyl-6,7 ~ dichloro-5-indanyloxy) acetic acid
Eine heisse Lösung von 1,27 g (0,005 Mol) 6-Phenyl-2,4,7-triaminopteridin in 25 ml Dirnethylsulfoxid wird mit 1,85 g (0,005 Mol) laevo-(i-0xo-2-methyl-2-phenyl-6,7-dichlor-5-indanyloxy)-essigsäure versetzt. Die klare Lösung wird unter starkem Rühren in 200 ml Wasser gegossen. Das sich abscheidende 6-Ehenyl-2,4,7-triaminopteridins'alz von Iaevo-(1-Oxo-2-methyl-2-phenyl-6,7-dichlor-5-indanyloxy)-essigsäure wird abfiltriert, mit Wasser gewaschen und getrocknet.A hot solution of 1.27 g (0.005 mol) of 6-phenyl-2,4,7-triaminopteridine in 25 ml of diethyl sulfoxide is 1.85 g (0.005 moles) laevo- (i-0xo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid offset. The clear solution is poured into 200 ml of water with vigorous stirring. The separating 6-Ehenyl-2,4,7-triaminopteridine salt of Iaevo- (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid is filtered off, washed with water and dried.
Die Gemische und Salze gemäss der Erfindung können in den verschiedensten therapeutischen Dosen in herkömmlichen Trägern, z.B. oral in Form von Tabletten, dargereicht werden. Die tägliche Dosis der Produkte kann ebenfalls innerhalb weiter Grenzen variieren, z.B. in Form von eingekerbten Ta-r bletten, die 2,5, 5,' 10, 15, 25, 50 und 100 mg Wirkstoff enthalten, um die Dosis je nach den Symptomen, die der zu behandelnde Patient aufweist, einstellen zu können. Die tägliche Dosis wird vorzugsweise in einzelnen Teildosen innerhalb 24 Stunden dargereicht. Die Dosen liegen weit unter der toxischen oder tödlichen Dosis der Produkte.·The mixtures and salts according to the invention can be used in the various therapeutic doses in conventional carriers, e.g. orally in the form of tablets. The daily dose of the products can also vary within wide limits, e.g. in the form of notched Ta-r tablets that contain 2.5, 5, 10, 15, 25, 50 and 100 mg of active ingredient to the dose depending on the symptoms of the to be treated Has patient to be able to adjust. The daily dose is preferably divided into individual divided doses within Given for 24 hours. The doses are well below the toxic or lethal dose of the products.
Eine geeignete kombinierte Dosisform der Mittel gemäss der Erfindung kann dargereicht werden, indem man 5 mg einer racemischen, 2,2-disubstituierten ^/Τ-Οχο-5-indanyloxy- (oder -thio_)/-alkancarbonsäure oder des reinen Enantiomeren dersel-A suitable combined dosage form of the agents according to the invention can be presented by adding 5 mg of a racemic, 2,2-disubstituted ^ / Τ-Οχο-5-indanyloxy- (or -thio _) / - alkanecarboxylic acid or the pure enantiomer of the same-
- 17 509817/1230 - 17 509817/1230
15 582IBY /?15 582IBY /?
lien mit 5 mg Amilorid, 50 mg Triamtereii oder 25 lüg Spironolacton sowie mit 189 mg, 144 mg bzw. 169 mg lactose und 1 mg Magnesiumstearat mischt und das Gemisch in eine Gelatinekapsel Nr. 1 einbringt. In ähnlicher Weise kann man andere Dosisformen in Gelatinekapseln Nr. 1 einbringen, indem man mehr Wirkstoff und weniger lactose verwendet. Im Bedarfsfalle können gepresste Tabletten, Pillen oder andere gewünschte kombinierte Dosen hergestellt werden, die auf übliche Weise in die Mittel gemäss der Erfindung eingearbeitet werden. Eine wirksame Wirkstoffmenge des Gemisches wird gewöhnlich in einer Dosis von 0,01 bis 5,0 mg je kg Körpergewicht dargereicht. Vorzugsweise liegt die Dosis im Bereich von etwa 0,05 "bis 2 mg je kg Körpergewicht.Lien with 5 mg amiloride, 50 mg Triamtereii or 25 lies spironolactone as well as with 189 mg, 144 mg or 169 mg lactose and 1 mg Magnesium stearate mixes and the mixture into a gelatin capsule No. 1 brings in. Similarly, one can incorporate other dosage forms into # 1 gelatin capsules by adding more Active ingredient and less lactose used. If necessary, compressed tablets, pills or any other desired combination can be used Doses are produced which are incorporated in the usual manner into the agents according to the invention. An effective one Active ingredient amount of the mixture is usually in one Dose from 0.01 to 5.0 mg per kg of body weight given. The dose is preferably in the range from about 0.05 "to 2 mg per kg of body weight.
Es liegt auch im Rahmen der Erfindung, das Amilorid- oder das Triamterensalz einer 2,2-disubstituierten ^/Τ-Οχο-5-indanyloxy-(oder -thio^-alkancarbonsäure &er allgemeinen Formel I mit Lactose und Magnesiumstearat in einer Einheitsdosisform zu kombinieren. Eine wirksame Menge des Salzes liegt dann gewöhnlich bei einer Dosis von etwa 0,01 mg bis etwa 5 mg je kg Körpergewicht. Vorzugsweise liegt die Salzdosis im Bereich von etwa 0,05 bis 2 mg je kg Körpergewicht.It is also within the scope of the invention to use the amiloride or triamterene salt of a 2,2-disubstituted ^ / Τ-Οχο-5-indanyloxy (or -thio ^ -alkanecarboxylic acid & general formula I. with lactose and magnesium stearate in a unit dosage form to combine. An effective amount of the salt then is usually at a dose of from about 0.01 mg to about 5 mg each kg body weight. The salt dose is preferably in the range from about 0.05 to 2 mg per kg of body weight.
Eine geeignete Einheitsdosisform des Amiloridsalzes einer 2,2-disubstituierten ^Τ-Οχο-5-indanyloxy- (oder -thioJ7~ alkancarbonsäure der allgemeinen ,Formel I besteht aus 10 bis 30 mg des betreffenden Salzes im Gemisch mit 189 mg, bzw. 169 mg Lactose und 1 mg Magnesiumstearat.A suitable unit dosage form of the amiloride salt of a 2,2-disubstituted ^ Τ-Οχο-5-indanyloxy- (or -thioJ7 ~ alkanecarboxylic acid of the general formula I consists of 10 to 30 mg of the salt in question mixed with 189 mg, or 169 mg lactose and 1 mg magnesium stearate.
Die folgenden Beispiele dienen zur Erläuterung der Herstellung repräsentativer kombinierter Dosisformen, die ein Gemisch aus einer 2,2-disubstituierten (1-0xo-5-indanyloxy)-essigsäure und Amilorid, Triamteren oder Spironolacton enthalten.The following examples serve to illustrate the preparation of representative combined dosage forms comprising a mixture of a 2,2-disubstituted (1-0xo-5-indanyloxy) acetic acid and amiloride, triamterene or spironolactone.
- 18 -- 18 -
509817/1230509817/1230
15 58.2IBY «/915 58.2IBY «/ 9
Beispiel 5Example 5
Je KapselPer capsule
(1 ■-0xo-2-methyl-2-ph.en.yl-6,7-dichlor-(1 ■ -0xo-2-methyl-2-ph.en.yl-6,7-dichloro-
5-indanyloxy)-essigsäure . 10 mg5-indanyloxy) acetic acid. 10 mg
N-Amidino-3»5-diamino-6-chlor-N-amidino-3 »5-diamino-6-chloro
pyrazincarboxamid 5 mgpyrazine carboxamide 5 mg
Lactose , . 184 mgLactose,. 184 mg
Magnesiumstearat 1 mgMagnesium stearate 1 mg
Kapsel (Grosse Nr. 1) . 200 mgCapsule (size no. 1). 200 mg
Bei s ρ i el 6At s ρ i el 6
Je KapselPer capsule
laeTO-(i-0xo-2-methyl-2-phenyl-6,7-dichlor-5-indanyloxy)-essigsäure laeTO- (i-0xo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid
lT-Amidino-3>S-diamino-o-chlorpyrazincarboxamid IT-Amidino-3> S-diamino-o-chloropyrazinecarboxamide
LactoseLactose
MagnesiumstearatMagnesium stearate
Kapsel (Grosse Nr. 1) " 200 mgCapsule (size no. 1) "200 mg
Beispiel 7Example 7
• Je Kapsel • Per capsule
(1 -0xo-2-aethyl*-2-phenyl-6', 7-diclilor-5-indanyloxy) -.essigsäure(1-oxo-2-ethyl * -2-phenyl-6 ', 7-diclilor-5-indanyloxy) -acetic acid
6-Phenyl-2,4,7-triaminopteridin6-phenyl-2,4,7-triaminopteridine
LactoseLactose
MagnesiumstearatMagnesium stearate
Kapsel (Grosse Nr. 1) 200 mgCapsule (size 1) 200 mg
- 19 5 0 9 8 17/1230 - 19 5 0 9 8 17/1230
15 582IBY 9Ö15 582IBY 9Ö
Beispiel 8Example 8
Je KapselPer capsule
(1 -0xo~2-methyl-2-plienyl-6,7-dichlor-(1-oxo ~ 2-methyl-2-plienyl-6,7-dichloro-
5-indanyloxy)-essigsäure 10 mg5-indanyloxy) acetic acid 10 mg
Spironolacton 25 mgSpironolactone 25 mg
Lactose 164 mgLactose 164 mg
Magnesiumstearat 1mgMagnesium stearate 1mg
Kapsel (Grosse Nr. 1) 200 mgCapsule (size 1) 200 mg
Die (i-0xo--2-methyl-2-phenyl-6,7-dichlor-5-indanyloxy)-essigsäure und das N-Amidino-ö-chlorpyrazincarboxamid, das 6-Phenyl-2,4,7-triaminopteridin oder das Spironolacton werden miteinander vermischt und auf Korngrössen unter 0,25 mm zerkleinert, worauf die Lactose und das Magnesiumstearat durch ein Siebtuch mit Maschenöffnungen von 0,25 mm auf das Pulver aufgesiebt und die vereinigten Bestandteile 10 .Minuten gemischt und dann in eine trockene Gelatinekapsel Nr*. 1 gefüllt werden.(I-0xo - 2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid and the N-amidino-ö-chloropyrazinecarboxamide, the 6-phenyl-2,4,7-triaminopteridine or the spironolactone are mixed with one another and crushed to grain sizes below 0.25 mm, whereupon the lactose and the magnesium stearate through a sieve cloth with mesh openings of 0.25 mm on the powder sieved and the combined ingredients mixed for 10 minutes and then in a dry gelatin capsule No. *. 1 filled will.
Ähnliche kombinierte Dosisformen in trockengefüllten Kapseln werden hergestellt, indem man die in den Beispielen 4, 5, 7 und 8 beschriebenen Indanyloxyessigsaurederivate durch eine der anderen Indanyloxyessigsäureverbindungen gemäss der Erfindung ersetzt. Wenn man in den Beispielen 5, 7 und 8 anstelle der (1-Oxo-2-methyl-2-phenyl-6,7-dichlor-5-indanyl-·· oxy)-essigsäure eines der anderen, oben genannten "Ihdanyloxyessigsäure-Diuretika verwendet, setzt man dieses Derivat je nach seiner bekannten relativen diuretischen Aktivität in bezug auf (i-Oxo-2-methyl-2-phenyl-6,7-dichlor-5-indanyloxy)-essigsäure in entsprechend grö'sseren oder geringeren Mengen zu.Similar combined dosage forms in dry-filled capsules are prepared by following the steps described in Examples 4, 5, 7 and 8 described indanyloxyacetic acid derivatives by one of the other indanyloxyacetic acid compounds according to the invention replaced. If, in Examples 5, 7 and 8, instead of the (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyl- oxy) acetic acid one of the other "idanyloxyacetic acid diuretics" mentioned above when using this derivative, reference is made to its known relative diuretic activity to (i-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid in correspondingly larger or smaller amounts.
- 20 -- 20 -
5 0 9 8 17/12305 0 9 8 17/1230
15 582IBT Q415 582IBT Q4
Beispiel 9Example 9
laevo- (1 -Oxo^-methyl^-phenyl-e,7-dichlor-5-indanyloxy)-essigsäure laevo- (1-oxo ^ -methyl ^ -phenyl-e, 7-dichloro-5-indanyloxy) -acetic acid
6-Phenyl-2,4,7-triaminopteridin6-phenyl-2,4,7-triaminopteridine
LactoseLactose
MagnesiumstearatMagnesium stearate
Kapsel (G-rösse Nr. 1 ) 200 mgCapsule (size No. 1) 200 mg
Beispiel 10Example 10
Je KapselPer capsule
laeYO-(1-0xo-2-methyl-2-phenyl-6,7-diehlor-5-indanyloxy)-essigsäure laeYO- (1-0xo-2-methyl-2-phenyl-6,7-diehlor-5-indanyloxy) -acetic acid
Spironolacton LactoseSpironolactone lactose
MagneslumstearatMagnesium stearate
Kapsel (G-rösse Nr. 1) ' ' 200 mgCapsule (size No. 1) '' 200 mg
Die laevo-(1-Oxo-2-methyl~2-phenyl-6,7-dichlor-5-indanyloxy)-essigsäure wird mit dem N-Amidino-3,5-dlamino-6-chlorpyrazincartoxamid, dem 6-Phenyl-2,4,7-triaminopteridin oder dem Spironolacton gemischt und das Gemisch, auf Teilchengrössen unter 0,25 mm zerkleinert, worauf man die Lactose und das, Magnesiumstearat durch ein'Siebtuch mit Maschenweiten von 0,25 mm auf das Pulver aufsiebt und die vereinigten' Bestandteile 10 Minuten mischt und sodann in eine trockene Gelatinekapsel Nr. 1 einfüllt.Laevo- (1-oxo-2-methyl ~ 2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid is with the N-Amidino-3,5-dlamino-6-chlorpyrazincartoxamid, the 6-phenyl-2,4,7-triaminopteridin or the Spironolactone mixed and the mixture, based on particle sizes crushed below 0.25 mm, whereupon the lactose and the magnesium stearate through a sieve cloth with mesh sizes of 0.25 mm sieve on the powder and the combined 'ingredients Mix for 10 minutes and then pour into a # 1 dry gelatin capsule.
Die folgenden Beispiele dienen zur Erläuterung der Herstellung von repräsentativen Dosisformen, die ein Amiloridsalz einer 2,2-disubstituierten (1-0xo-6,7-dichlor-5-indanyloxy)-essigsäure enthalten.The following examples serve to illustrate the preparation of representative dosage forms containing an amiloride salt of a 2,2-disubstituted (1-oxo-6,7-dichloro-5-indanyloxy) acetic acid contain.
- 21 -- 21 -
5 09817/12305 09817/1230
15 582IBY 92.15 582IBY 92.
Beispiel 11Example 11
Je KapselPer capsule
N-Amidino-3,5-diamino-6-chlorpyrazincarboxamidsalz von (1-0xo-2-methyl-2~phenyl-6,7^dichlor-5-indanyloxy)-essigsäure N-Amidino-3,5-diamino-6-chloropyrazine carboxamide salt of (1-0xo-2-methyl-2 ~ phenyl-6,7 ^ dichloro-5-indanyloxy) acetic acid
LactoseLactose
Magnesiumstearat . .Magnesium stearate. .
Kapsel (Grosse Nr. 1) 200 mgCapsule (size 1) 200 mg
Das Amiloridsalz von (T-indanyloxy)-essigsäure wird zu einem Pulver mit Teilchengrössen unter 0,25 mm vermählen, worauf man die Lactose und das Magnesiumstearat durch ein Siebtuch mit Maschenweiten von 0,25 mm auf das Pulver aufsiebt und die vereinigten Bestandteile 10 Minuten miteinander mischt und sodann in eine trokkene G'elatinekapsel Nr. 1 einfüllt.The amiloride salt of (T-indanyloxy) acetic acid is ground to a powder with particle sizes below 0.25 mm, whereupon the lactose and the Magnesium stearate through a sieve cloth with mesh sizes of 0.25 mm on the powder and the combined ingredients Mix together for 10 minutes and then pour into a dry gelatine capsule No. 1.
Ähnliche trockengefüllte Kapseln'können hergestellt werden, indem man das Indanyloxyessigsäurederivat des obigen Beispiels durch eine molar äquivalente Menge einer anderen Indanyloxyessigsäureverbindung gemäss der Erfindung ersetzt.Similar dry-filled capsules can be made by substituting the indanyloxyacetic acid derivative of the above example with a molar equivalent amount of another indanyloxyacetic acid compound replaced according to the invention.
' Je Kapsel ' Per capsule
N-Amidino-3,S-diamino-ö-chlorpyrazin-N-amidino-3, S-diamino-ö-chloropyrazin-
carboxamidsalz von laevo-(1-0xo-2-roethyl-carboxamide salt of laevo- (1-0xo-2-roethyl-
2-phenyl-6,7-dichlor-5-indanyloxy)-essigsäure 2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid
LactoseLactose
MagnesiumstearatMagnesium stearate
Kapsel (Grosse Nr. 1) 200 mgCapsule (size 1) 200 mg
- 22 -- 22 -
509817/1230509817/1230
15 582IBY ί315 582IBY ί3
Das Amiloridsalz der laevo-(i-0xo-2-methyl-2-phenyl-6,7-dichlor-5-indanyloxy)-essigsäure wird zueinem .Pulver mit Teilchengrössen unter 0,25 mm vermählen, worauf man die Lactose und das Magnesiumstearat durch ein Siebtueh mit Maschenöffnungen von 0,25 mm auf das Pulver aufsiebt und die vereinigten Bestandteile sodann 10 Minuten miteinander vermischt und in eine trockene Gelatinekapsel Nr. 1 einfüllt.The amiloride salt of laevo- (i-0xo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) -acetic acid becomes a .powder with particle sizes Grind below 0.25 mm, whereupon the lactose and magnesium stearate are passed through a sieve with mesh openings sieve 0.25 mm on the powder and the combined The ingredients are then mixed together for 10 minutes and filled into a dry gelatin capsule No. 1.
Aus der obigen Beschreibung geht hervor, dass Gemische und Salze von Amilorid, Triamteren oder Spironolac.ton einerseits und einer 2,2-disubstituierten ^Τ-Οχο-5-indanyloxy- (oder -thioJT-alkancarbonsäure der allgemeinen·Pormel I gemäss der Erfindung andererseits wertvolle.Produkte darstellen, die bisher noch,nicht hergestellt worden sind.From the above description it can be seen that mixtures and Salts of amiloride, triamterene or spironolac.ton on the one hand and a 2,2-disubstituted ^ Τ-Οχο-5-indanyloxy- (or -thioJT-alkanecarboxylic acid of the general formula I according to Invention, on the other hand, represent valuable products that so far, have not been produced.
5098 17/12305098 17/1230
Claims (1)
1:4,4 "beträgt. ■11. Substance composition according to claim 7, characterized in that the molar ratio of laevo- (1-0xo-2-methyl-2-ph.enyl-6,7-dichloro-5-indanyloxy) acetic acid to N-amidino-3, 5 ~ diamino-6-chloropyrazinecarboxamide is in the range from 0.4! 1 to 0.8: 1, the molar ratio of laevo- (1-0xo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy ) acetic acid to 6-phenyl-2,4,7-triaminopteridine about 1: 7.0 and the molar ratio of laevo- (1-0xo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy) acetic acid to spironolactone for example
1: 4.4 ". ■
Cycloalkyl, Aryl oder substituiertes Aryl, Ihienyl oder substituiertes Thienyl, E niederes Alkyl mit 1 bis 5
Kohlenstoffatomen, -niederes Alkenyl mit 3 bis 5 Kohlenstoffatomen, niederes Alkinyl mit 3 bis 5 Kohlenstoffatomen, Phenyl-nied.alkyl, wobei die niedere Alkylgruppe 1 bis 3 Kohlenstoffatome aufweist, oder Phenyl-nied.alkenyl, Aryl oder substituiertes Aryl, Thieny]'oder substituiertes Thienyl bedeuten oder R und R mit dem Kohlenstoffatom, an das sie gebunden sind, zu einem Cycloalkylrest mit 3 bis 7 Kernkohlenstoffatomen zusammengeschlossen sein können, X Wasserstoff, Methyl oder HaIo-wherein R is lower alkyl having 1 to 5 carbon atoms,
Cycloalkyl, aryl or substituted aryl, ihienyl or substituted thienyl, E is lower alkyl with 1 to 5
Carbon atoms, -lower alkenyl with 3 to 5 carbon atoms, lower alkynyl with 3 to 5 carbon atoms, phenyl-lower alkyl, where the lower alkyl group has 1 to 3 carbon atoms, or phenyl-lower alkenyl, aryl or substituted aryl, thieny] ' or substituted thienyl or R and R can be joined together with the carbon atom to which they are bonded to form a cycloalkyl radical with 3 to 7 core carbon atoms, X is hydrogen, methyl or halo
während Y Alkylen oder Halogenalkylen mit maximal 4 Kohlenstoffatomen bedeutet.can be joined together to form a divalent hydrocarbon chain with 3 or 4 carbon atoms,
while Y denotes alkylene or haloalkylene with a maximum of 4 carbon atoms.
aufweist, Aryl, subsbituiertes Aryl, Thienyl oder substituiertes Thienyl bedeuben oder R und R mib dem Kohlenstoffatom, an das sie gebunden sind, zu einem Cycloalkyl-in which R is lower alkyl with ΐ to 5 carbon atoms, .. Cycloalkyl, aryl, substituted aryl, thienyl "or substituted thienyl, R is lower alkyl with 1 to 5 carbon atoms ·, lower alkenyl with 3 to 5 carbon atoms, lower alkynyl with 3 to 5 carbon atoms, phenyl-lower, alkyl, where the lower alkyl group has 1 Ws carbon atoms, or phenyl-lower alkenyl, where the lower alkenyl group has 2 to 5 carbon atoms
has, aryl, substituted aryl, thienyl or substituted thienyl or R and R mib the carbon atom to which they are attached to a cycloalkyl
HOCCHoO0
HOCCHoO
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US40573673A | 1973-10-11 | 1973-10-11 | |
US49294174A | 1974-07-31 | 1974-07-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
DE2448428A1 true DE2448428A1 (en) | 1975-04-24 |
Family
ID=27019216
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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DE19742448428 Ceased DE2448428A1 (en) | 1973-10-11 | 1974-10-10 | DIURETIC AGENTS |
Country Status (10)
Country | Link |
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CA (2) | CA1031336A (en) |
CY (1) | CY1072A (en) |
DE (1) | DE2448428A1 (en) |
FR (1) | FR2247214B1 (en) |
GB (1) | GB1475177A (en) |
HK (1) | HK43580A (en) |
IE (1) | IE39926B1 (en) |
IL (1) | IL45778A (en) |
KE (1) | KE3066A (en) |
NL (1) | NL7412823A (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4334088A (en) * | 1979-04-09 | 1982-06-08 | Mead Johnson & Company | 2-Alkynyl-5-indanyloxyacetic acids |
US4291168A (en) * | 1979-04-09 | 1981-09-22 | Mead Johnson & Company | Silylated indanyloxyacetates |
NZ200641A (en) * | 1981-07-13 | 1985-12-13 | Merck & Co Inc | Pharmaceutical compositions containing(+)and(-)enantiomers of indacrinone |
US4510322A (en) * | 1981-07-13 | 1985-04-09 | Merck & Co., Inc. | Indacrinone having enhanced uricosuric |
-
1974
- 1974-09-27 NL NL7412823A patent/NL7412823A/en not_active Application Discontinuation
- 1974-10-03 IE IE2045/74A patent/IE39926B1/en unknown
- 1974-10-03 CA CA210,650A patent/CA1031336A/en not_active Expired
- 1974-10-03 CA CA210,649A patent/CA1034498A/en not_active Expired
- 1974-10-04 IL IL45778A patent/IL45778A/en unknown
- 1974-10-07 GB GB4337374A patent/GB1475177A/en not_active Expired
- 1974-10-07 CY CY1072A patent/CY1072A/en unknown
- 1974-10-08 FR FR7433809A patent/FR2247214B1/fr not_active Expired
- 1974-10-10 DE DE19742448428 patent/DE2448428A1/en not_active Ceased
-
1980
- 1980-07-21 KE KE3066A patent/KE3066A/en unknown
- 1980-08-14 HK HK435/80A patent/HK43580A/en unknown
Non-Patent Citations (2)
Title |
---|
C.A., 93, 1980, Nr. 143218h * |
EHRHART - RUSCHIG: Arzneimittel, 2, 1972, S. 350 * |
Also Published As
Publication number | Publication date |
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NL7412823A (en) | 1975-04-15 |
CA1034498A (en) | 1978-07-11 |
IL45778A0 (en) | 1974-12-31 |
CY1072A (en) | 1980-10-24 |
GB1475177A (en) | 1977-06-01 |
HK43580A (en) | 1980-08-22 |
FR2247214B1 (en) | 1977-11-04 |
IE39926B1 (en) | 1979-01-31 |
FR2247214A1 (en) | 1975-05-09 |
CA1031336A (en) | 1978-05-16 |
IE39926L (en) | 1975-04-11 |
AU7391574A (en) | 1976-04-08 |
KE3066A (en) | 1980-08-08 |
IL45778A (en) | 1979-09-30 |
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