EP0667777A1 - Xanthine derivatives for use as diuretics - Google Patents

Xanthine derivatives for use as diuretics

Info

Publication number
EP0667777A1
EP0667777A1 EP94900128A EP94900128A EP0667777A1 EP 0667777 A1 EP0667777 A1 EP 0667777A1 EP 94900128 A EP94900128 A EP 94900128A EP 94900128 A EP94900128 A EP 94900128A EP 0667777 A1 EP0667777 A1 EP 0667777A1
Authority
EP
European Patent Office
Prior art keywords
group
propyl
methyl
diuretic
benzyl
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.)
Withdrawn
Application number
EP94900128A
Other languages
German (de)
French (fr)
Inventor
Stefan Adamus
Wolfram Gaida
Christopher Meade
Ulrike Küfner-Mühl
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Publication of EP0667777A1 publication Critical patent/EP0667777A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • the present invention relates to the use of 8- (3-oxocyclopentyl) -1,3-dipropyl 7H-purine-2, 6- .dione and structure-like xanthines as diuretics.
  • Diuretics play an important role in the treatment of edema, hypertension and other diseases.
  • All animals received an oral water load of 5 ml / 100 g body weight using a pharyngeal tube.
  • KFM 19 was dissolved in water and administered together with the water load (1 ml solution, 4 ml water) orally in doses of 0.01, 0.03, 0.1 and 0.3 mg / kg by gavage.
  • Control animals received 5 ml of water.
  • the excreted urine volume was measured two and five hours after application; the sodium and potassium content was determined by flame photometry, the chloride content was determined mercurimetrically.
  • These compounds can also be used to treat diseases caused by disturbed chloride ion transport.
  • R3 is a residue selected from the group consisting of furan, tetrahydrofuran, tetrahydrofuranone, thiophene, dithiol, Dithian or tetrahydrop ran which can carry one of the following substituents methyl, ethyl, propyl, butyl, CHO, CH 2 OR 4 , CH 2 OR 7 , COOR 4 , CONR 5 Rg,
  • R3 is a cyclopentane or cyclohexane, substituted by methyl, ethyl, propyl, isopropyl, t-butyl, allyl, vinyl, phenyl or benzyl, where a hydroxyl group may be present as the geminal substituent;
  • R a , Rfc, CH 3 , C 2 H5 or R a and R] -. together -CH 2 -CH 2 -,
  • R 3 is a cyclopentanone or cyclohexanone
  • R 3 is a cycloalkane or cycloalkene with 4-8
  • Carbon atoms which can optionally be substituted by a straight-chain or branched alkenyl group having 2 to 4 carbon atoms, a cyclopentanone or cyclopentanol or cyclohexanone or cyclohexanol, which are in the ⁇ -position to the keto or hydroxyl group by C to C 4 alkenyl, C3 or C 4 alkynyl , Benzyl, -CH CH 2 CN, (CH 2 ) 3 NR 5 R5 R 5 equal to or different), CH 2 C00R 4 , CH 2 0R 4 can be substituted, where R 4 can be hydrogen, methyl, ethyl or propyl;
  • R 4 is hydrogen, an alkyl group with 1 to 3
  • R5 is hydrogen, an alkyl group having 1 to 3 carbon atoms; a cyclopropyl group, a benzyl group;
  • R 7 prolinoyl, CO- (CH 2 ) 0 - 3 -CH 3 ,
  • Another object of the present invention is the combination of compounds of general formula I, especially the compounds mentioned by name with loop diuretics - for example furosemide, bumetamides and etacrynic acid.
  • the compounds of general formula I can be administered orally or parenterally or as a suppository.
  • the compounds are present as active ingredients in conventional dosage forms, e.g. in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active ingredient, e.g. Tablets, dragées, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories, etc.
  • An effective dose of the compounds in the indication claimed according to the invention is between 5 and 100 mg per dose, preferably between 10 and 50 mg, for oral use.

Landscapes

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

Abstract

The invention concerns the use of 8-(3-oxocyclopentyl)-1,3-dipropyl-7H-purin-2,6-dione as a diuretic.

Description

XANTHINDERIVATE ALS DIURETISCHES MITTEL. XANTHINE DERIVATIVES AS A DIURETIC AGENT.
Die vorliegende Erfindung betrifft die Verwendung von 8- (3-Oxocyclopentyl) -1,3-dipropyl 7H-purin-2, 6- .dion und strukturähnlichen Xanthinen als Diuretika. Diuretika spielen eine wichtige Rolle in der Behandlung von Oedemen, Hypertonie und anderen Krankheiten.The present invention relates to the use of 8- (3-oxocyclopentyl) -1,3-dipropyl 7H-purine-2, 6- .dione and structure-like xanthines as diuretics. Diuretics play an important role in the treatment of edema, hypertension and other diseases.
Die diuretische Wirkung von Xanthinen ist prinzipiell bekannt, jedoch sind die bisher untersuchten Verbindungen relativ schwach wirksam (siehe Beutler J.J., Koomans H.A., Bijlsma J.A. Dorhout- ees E.J., J Pharmacol. exp. Ther. (1990) 255, 1314).The diuretic effect of xanthines is known in principle, but the compounds investigated to date are relatively weakly active (see Beutler J.J., Koomans H.A., Bijlsma J.A. Dorhouteses E.J., J Pharmacol. Exp. Ther. (1990) 255, 1314).
Überraschenderweise wurde jetzt entdeckt, daß 8- (3- Oxocyclopentyl) -1,3-dipropyl-7H-purin-2,6-dion (KF 19) ein sehr stark wirksames Diuretiku ist. Eine signifikante diuretische Wirkung ist bereits nach einer oralen Dosis von 0.03 mg/kg Körpergewicht (Ratte) beobachtet. Besondere Vorteile werden für Kombinationen der Substanzen dieser Anmeldung mit sogenannten "Schleifendiuretika" wie Furosemid, Bumetanid und Etacrynsäure erwartet. Die "Schleifendiuretika" sind stark wirksame Substanzen, die den Natrium-Transport in den distalen Tubuli der Nieren hemmen. Gleichzeitig wird die Chlorid-Resorption gehemmt (NaCl co-Transport) (Imai M, Eur. J. Pharmacol. (1977) 41, 409) . 8- (3-Oxocyclopentyl) -1,3-dipropyl-7H-purin-2,6-dion steigert die Natrium- und Chloridausschύttung ohne einen großen Effekt auf die Kaliumausscheidung. Es ist bekannt, daß Adenosin die Chloridsekretion beeinflussen kann. Deshalb ist es wahrscheinlich, daß die diuretischen Wirkungsmechanismen hauptsächlich Chlorid-Ionen-Transport betreffen und die Substanz mit Natriumchlorid-Resorption hemmenden Mitteln komplementarisch wirken wird. Beschreibung des TestverfahrensSurprisingly, it has now been discovered that 8- (3-oxocyclopentyl) -1,3-dipropyl-7H-purine-2,6-dione (KF 19) is a very potent diuretic. A significant diuretic effect was observed after an oral dose of 0.03 mg / kg body weight (rat). Particular advantages are expected for combinations of the substances of this application with so-called "loop diuretics" such as furosemide, bumetanide and etacrynic acid. The "loop diuretics" are highly effective substances that inhibit sodium transport in the distal tubules of the kidneys. At the same time, chloride absorption is inhibited (NaCl co-transport) (Imai M, Eur. J. Pharmacol. (1977) 41, 409). 8- (3-Oxocyclopentyl) -1,3-dipropyl-7H-purine-2,6-dione increases sodium and chloride release without a major effect on potassium excretion. It is known that adenosine can affect chloride secretion. Therefore, it is probable that the diuretic mechanisms of action mainly concern chloride ion transport and that the substance will act complementarily with agents inhibiting sodium chloride absorption. Description of the test procedure
Die Versuche wurden mit männlichen, wachen, nüchternen Ratten (ChbbrTHOM, SPF) im Gewicht von 240 - 280 g durchgeführt. Pro Dosis wurden 10 Tiere eingesetzt, jeweils zwei Tiere in einen Stoffwechselkäfig (n = 5) . Zur Anregung der Diurese erhielten alle Tiere eine orale Wasserlast von 5 ml/100 g Körpergewicht mittels Schlundsonde. KFM 19 wurde in Wasser gelöst und zusammen mit der Wasserlast (1ml Lösung, 4 ml Wasser) oral in den Dosen 0,01, 0,03, 0,1 und 0,3 mg/kg per Schlundsonde verabreicht. Kontrolltiere erhielten 5 ml Wasser. Zwei und fünf Stunden nach der Applikation wurde das ausgeschiedene Harnvolumen gemessen; der Natrium- und Kaliumgehalt wurde flammenphotometrisch, der Chloridgehalt mercurimetrisch bestimmt.The experiments were carried out with male, awake, fasting rats (ChbbrTHOM, SPF) weighing 240-280 g. 10 animals were used per dose, two animals each in a metabolic cage (n = 5). To stimulate diuresis, all animals received an oral water load of 5 ml / 100 g body weight using a pharyngeal tube. KFM 19 was dissolved in water and administered together with the water load (1 ml solution, 4 ml water) orally in doses of 0.01, 0.03, 0.1 and 0.3 mg / kg by gavage. Control animals received 5 ml of water. The excreted urine volume was measured two and five hours after application; the sodium and potassium content was determined by flame photometry, the chloride content was determined mercurimetrically.
Die Überprüfung der Ergebnisse auf statistische Signifikanz erfolgt nach DUNNETT (1984) .The results are checked for statistical significance according to DUNNETT (1984).
Tabelle ITable I
Beeinflussung der Urin- und Elektrolytausscheidung durch orale Gabe von 8- (3-Oxocyclopentyl) -1,3-dipropyl- 7H-purin-2,β-dion in fünf Stunden nach der ApplikationInfluence of urine and electrolyte excretion by oral administration of 8- (3-oxocyclopentyl) -1,3-dipropyl-7H-purine-2, β-dione in five hours after application
Kalium Chlorid uVal/lOOg uVal 100g x +. S x ± SxPotassium chloride uVal / lOOg uVal 100g x +. S x ± Sx
68.0 ± 13.9 65.2 + 10.7 101.1 + 14.6 88.5 + 10.168.0 ± 13.9 65.2 + 10.7 101.1 + 14.6 88.5 + 10.1
85.4 +_ 4.4 87.0 + 8.1 101.3 + 9.1 138.5 + 14.0**85.4 + _ 4.4 87.0 + 8.1 101.3 + 9.1 138.5 + 14.0 **
* x* x
0.3 5.8 + 0.2λJr 131.5 + 10.0** 119.8 + 8.4 174.1 + 18.50.3 5.8 + 0.2 λJr 131.5 + 10.0 ** 119.8 + 8.4 174.1 + 18.5
= p < 0.05, ** = = p < 0.01 Aufgrund dieser Befunde erscheint die genannte Verbindung wie auch deren strukturell ähnliche Verbindungen als Diuretika insbesondere zur Behandlung von Oedemen, der Hypertonie und anderen Indikationen dieser Genese geeignet.= p <0.05, ** = = p <0.01 Based on these findings, the compound mentioned and its structurally similar compounds appear to be suitable as diuretics, in particular for the treatment of edema, hypertension and other indications of this origin.
Geeignete strukturähnliche Xanthin-Derivate sind in den Europäischen Patentanmeldungen 374 808 und 487 673 beschrieben, auf die hiermit ausdrücklich Bezug genommen wird, insbesondere auf die dort als bevorzugt beschriebenen Bereiche und Ausführungsbeispiele.Suitable structurally similar xanthine derivatives are described in European patent applications 374 808 and 487 673, to which reference is hereby expressly made, in particular to the areas and exemplary embodiments described as preferred there.
Diese Verbindungen können auch zur Behandlung von Krankheiten eingesetzt werden, die durch einen gestörten Chlorid-Ionen Transport verursacht sind.These compounds can also be used to treat diseases caused by disturbed chloride ion transport.
Von Interesse sind daher auch Xanthine der allgemeinen FormelXanthines of the general formula are therefore also of interest
•worin • in what
R3 einen Rest, ausgewählt aus der Gruppe Furan, Tetrahydrofuran, Tetrahydrofuranon, Thiophen, Dithiol, Dithian oder Tetrahydrop ran der einen der folgenden Substituenten tragen kann Methyl, Ethyl, Propyl, Butyl, CHO, CH2OR4, CH2OR7, COOR4, CONR5Rg,R3 is a residue selected from the group consisting of furan, tetrahydrofuran, tetrahydrofuranone, thiophene, dithiol, Dithian or tetrahydrop ran which can carry one of the following substituents methyl, ethyl, propyl, butyl, CHO, CH 2 OR 4 , CH 2 OR 7 , COOR 4 , CONR 5 Rg,
R3 ein durchR 3 a through
-CH=CH-CONR5R6, -CH=C(COOR4)2 -CH = CH-CONR 5 R 6 , -CH = C (COOR 4 ) 2
(R4 gleich oder verschieden) ,(R4 the same or different),
-CH=C- (COOR4) - (CONR5R6) ,-CH = C- (COOR 4 ) - (CONR 5 R 6 ),
-CH=C (COOR4) (CH2OR4)-CH = C (COOR 4 ) (CH 2 OR 4 )
(R4 gleich oder verschieden) ,(R 4 the same or different),
-CH=C (COOR4) (CH2OR7) ,-CH = C (COOR 4 ) (CH 2 OR 7 ),
- (CH2)n.CONR5R6,- (CH 2 ) n. CONR 5 R 6 ,
-CH=C (CH2OR4)2,-CH = C (CH 2 OR 4 ) 2 ,
-CH=C (CH2OR7)2,-CH = C (CH 2 OR 7 ) 2 ,
-CH=C (CONR5R6)CH2OR4 oder-CH = C (CONR 5 R 6 ) CH 2 OR 4 or
-CH=C (CONR5Rg)CH2OR7 substituiertes Furan;-CH = C (CONR 5 Rg) CH 2 OR 7 substituted furan;
R3 ein Cyclopentan oder Cyclohexan, substituiert durch Methyl, Ethyl, Propyl, iso-Propyl, t-Butyl, Allyl, Vinyl, Phenyl oder Benzyl, wobei als geminaler Substituent eine Hydroxygruppe vorhanden sein kann;R3 is a cyclopentane or cyclohexane, substituted by methyl, ethyl, propyl, isopropyl, t-butyl, allyl, vinyl, phenyl or benzyl, where a hydroxyl group may be present as the geminal substituent;
R3 ein Cyclopentan oder Cyclohexan, substituiert durch Hydroxy, Methoxy, Ethoxy, Propyloxy, Trimethoxycarbonyl, iso-Propyloxy, gegebenenfalls substituiertes Benzyloxy, Allyloxy, Propargyloxy, -CH2-CO-OCH3, =C-CO-OCH3, -CH2-CH2-OH, -CH2-COOCH3, =CH-COOCH3, CH2-CH2-OH, =CH-CN, -(CH2)2NH2 R 3 is a cyclopentane or cyclohexane, substituted by hydroxy, methoxy, ethoxy, propyloxy, trimethoxycarbonyl, isopropyloxy, optionally substituted benzyloxy, allyloxy, propargyloxy, -CH 2 -CO-OCH 3 , = C-CO-OCH 3 , -CH 2 -CH 2 -OH, -CH 2 -COOCH 3 , = CH-COOCH 3 , CH 2 -CH 2 -OH, = CH-CN, - (CH 2 ) 2 NH 2
=NOH, -CH OH, OR4 mit R4 = Methyl oder Trityl, OR7 worin R7 COCH3, COC2H5, COC3H7, CO t-Butyl, -CO-Phenyl oder= NOH, -CH OH, OR 4 with R 4 = methyl or trityl, OR 7 wherein R 7 is COCH 3 , COC 2 H 5 , COC3H 7 , CO t-butyl, -CO-phenyl or
COCH2-Phenyl, gegebenenfalls substituiert, CO- Pyridyl, -CO- (N-Methyl-4H-pyridyl) , -CO- (Methylpyridyl) , -COCH2-CH=CH2, -CO CH2-C=CH; R3 einen RestCOCH 2 -phenyl, optionally substituted, CO-pyridyl, -CO- (N-methyl-4H-pyridyl), -CO- (methylpyridyl), -COCH 2 -CH = CH 2 , -CO CH 2 -C = CH; R3 a rest
mit Ra, Rfc, = CH3, C2H5 oder Ra und R]-. zusammen -CH2-CH2-,with R a , Rfc, = CH 3 , C 2 H5 or R a and R] -. together -CH 2 -CH 2 -,
R3 ein Cyclopentanon oder Cyclohexanon,R 3 is a cyclopentanone or cyclohexanone,
R3 ein Cycloalkan oder Cycloalken mit 4 - 8R 3 is a cycloalkane or cycloalkene with 4-8
Kohlenstoffatomen, welches gegebenenfalls durch eine geradkettige oder verzweigte Alkenylgruppe mit 2 bis 4 Kohlenstoffatomen substituiert sein kann, ein Cyclopentanon oder Cyclopentanol oder Cyclohexanon oder Cyclohexanol, die in α-Position zur Keto- oder Hydroxygruppe durch C bis C4 Alkenyl, C3 oder C4 Alkinyl, Benzyl, -CH CH2CN, (CH2)3NR5R5 R5 gleich oder verschieden) , CH2C00R4, CH20R4 substituiert sein können, wobei R4 Wasserstoff, Methyl, Ethyl oder Propyl bedeuten können;Carbon atoms, which can optionally be substituted by a straight-chain or branched alkenyl group having 2 to 4 carbon atoms, a cyclopentanone or cyclopentanol or cyclohexanone or cyclohexanol, which are in the α-position to the keto or hydroxyl group by C to C 4 alkenyl, C3 or C 4 alkynyl , Benzyl, -CH CH 2 CN, (CH 2 ) 3 NR 5 R5 R 5 equal to or different), CH 2 C00R 4 , CH 2 0R 4 can be substituted, where R 4 can be hydrogen, methyl, ethyl or propyl;
R Norbonan oder Norbonen - gegebenenfalls substituiert,R norbonane or norbornene - optionally substituted,
R4 Wasserstoff, eine Alkylgruppe mit 1 bis 3R 4 is hydrogen, an alkyl group with 1 to 3
Kohlenstoffatomen, eine Cyclopropylgruppe, eine Cyclopentylgruppe, Benzyl eine Allylgruppe, eine Propargylgruppe, eine Triphenylmethylgruppe;Carbon atoms, a cyclopropyl group, a cyclopentyl group, benzyl an allyl group, a propargyl group, a triphenylmethyl group;
R5 Wasserstoff, eine Alkylgruppe mit 1 bis 3 Kohlenstoffatomen; eine Cyclopropylgruppe, eine Benzylgruppe;R5 is hydrogen, an alkyl group having 1 to 3 carbon atoms; a cyclopropyl group, a benzyl group;
Rδ Wasserstoff, Methyl, Ethyl, Propyl, -(CH2)n-NH2 (n=2-8) , - (CH2)nNEt2 (n=2,3) oder - (CH2)3-0- (CH2)4. 0- (CH2)3-NH , N-Benzyl-piperidin-4-yl- , oder R5 und Rg zusammen mit dem Stickstoffatom einen Piperidin-, Piperazin-, Morpholinrest, der gegebenenfalls durch C1-C4 Alkylrest - bevorzugt Methyl substituiert sein kann; Rδ is hydrogen, methyl, ethyl, propyl, - (CH 2 ) n -NH 2 (n = 2-8), - (CH 2 ) n NEt 2 (n = 2,3) or - (CH 2 ) 3-0 - (CH 2 ) 4 . 0- (CH 2 ) 3-NH, N-benzyl-piperidin-4-yl-, or R5 and Rg together with the nitrogen atom form a piperidine, piperazine, morpholine residue which is optionally substituted by C1-C 4 alkyl residue - preferably methyl can be;
R7 Prolinoyl, CO- (CH2) 0-3-CH3,R 7 prolinoyl, CO- (CH 2 ) 0 - 3 -CH 3 ,
(-) - Menthoxyacetyl, ein über eine Carbonylgruppe verknüpfter Camphansäurerest, Abietinoyl, Benzoyl, 4-Aminobutyroyl, 3,4,5-Trihydroxybenzoyl, 3,4,5- Trimethoxybenzoyl, ein Nicotinsäure- , Isonicotinsäure- oder Picolinsäurerest, N- Methylnicotinsäurerest, N-Methyl-4H- Nicotinsäurerest bedeuten können, sowie gegebenenfalls deren Säureadditionssalze bedeuten.(-) - Menthoxyacetyl, a camphanoic acid residue linked via a carbonyl group, abietinoyl, benzoyl, 4-aminobutyroyl, 3,4,5-trihydroxybenzoyl, 3,4,5-trimethoxybenzoyl, a nicotinic acid, isonicotinic or picolinic acid residue, N-methylnicotinic acid residue N-methyl-4H-nicotinic acid residue can mean, and optionally their acid addition salts.
Von besonderem Interesse in diesem Zusammenhang ist die Verwendung von 8- (3-Oxocyclopentyl) -1,3-di-n-propyl-7H-purin- 2,6-dion oder eines seiner Enantiomere (+) -8- (3-Oxocyclo- pentyl) -1,3-di-n-propyl-7H-purin-2,6-dion oder (-)-8-(3- Oxocyclopentyl) -1,3-di-n-propyl-7H-purin-2,6-dion als Diuretikum.Of particular interest in this context is the use of 8- (3-oxocyclopentyl) -1,3-di-n-propyl-7H-purine-2,6-dione or one of its enantiomers (+) -8- (3- Oxocyclopentyl) -1,3-di-n-propyl-7H-purine-2,6-dione or (-) - 8- (3-oxocyclopentyl) -1,3-di-n-propyl-7H-purine -2,6-dione as a diuretic.
Von Interesse ist ebenfalls die Verwendung von 8- (3- Hydroxycyclopentyl) -1,3-di-n-propyl-7H-pyrin-2,6-dion oder seiner Enantiomere als Diuretikum.Of interest is also the use of 8- (3-hydroxycyclopentyl) -1,3-di-n-propyl-7H-pyrine-2,6-dione or its enantiomers as a diuretic.
Ein weiterer Gegenstand der vorliegenden Erfindung ist die Kombination von Verbindungen der allgemeinen Formel I, besonders der namentlich aufgeführten Verbindungen mit Schleifendiuretika - beispielsweise Furosemid, Bumetamide und Etacrynsäure.Another object of the present invention is the combination of compounds of general formula I, especially the compounds mentioned by name with loop diuretics - for example furosemide, bumetamides and etacrynic acid.
Die Verbindungen der allgemeinen Formel I können oral oder parenteral oder als Zäpfchen verabreicht werden. Die Verbindungen liegen hierbei als aktive Bestandteile in üblichen Darreichungsformen vor, z.B. in Zusammensetzungen, die im wesentlichen aus einem inerten pharmazeutischen Träger und einer effektiven Dosis des Wirkstoffes bestehen, wie z.B. Tabletten, Dragees, Kapseln, Oblaten, Pulver, Lösungen, Suspensionen, Emulsionen, Sirupe, Suppositorien usw. Eine wirksame Dosis der Verbindungen bei der erfindungsgemäß beanspruchten Indikation liegt bei oraler Anwendung zwischen 5 und 100 mg pro Dosis, bevorzugt zwischen 10 und 50 mg. The compounds of general formula I can be administered orally or parenterally or as a suppository. The compounds are present as active ingredients in conventional dosage forms, e.g. in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active ingredient, e.g. Tablets, dragées, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories, etc. An effective dose of the compounds in the indication claimed according to the invention is between 5 and 100 mg per dose, preferably between 10 and 50 mg, for oral use.

Claims

Patentansprüche Claims
1. Verwendung von Verbindungen der allgemeinen Formel I1. Use of compounds of general formula I
worinwherein
R3 einen Rest, ausgewählt aus der Gruppe Furan, Tetrahydrofuran, Tetrahydrofuranon, Thiophen, Dithiol, Dithian oder Tetrahydropyran der einen der folgenden Substituenten tragen kann Methyl, Ethyl, Propyl, Butyl, CHO, CH OR4, CH20R7, C00R4, CONR5R6,R 3 is a radical selected from the group consisting of furan, tetrahydrofuran, tetrahydrofuranone, thiophene, dithiol, dithiane or tetrahydropyran, which can carry one of the following substituents: methyl, ethyl, propyl, butyl, CHO, CH OR 4 , CH 2 0R 7 , C00R 4 , CONR 5 R 6 ,
R3 ein durchR 3 a through
-CH=CH-CONR5R6, -CH=C(COOR4)2 (R gleich oder verschieden) ,-CH = CH-CONR 5 R 6 , -CH = C (COOR 4 ) 2 (R same or different),
-CH=C (COOR4) (CONR5R6) ,-CH = C (COOR 4 ) (CONR 5 R 6 ),
-CH=C (COOR4) (CH2OR4) (R4 gleich oder verschieden) ,-CH = C (COOR 4 ) (CH 2 OR 4 ) (R 4 the same or different),
-CH=C (COOR4) (CH2OR7) , - (CH2)n-C0NR5R6,-CH = C (COOR 4 ) (CH 2 OR 7 ), - (CH 2 ) n -C0NR 5 R 6 ,
-CH=C (CH20R4)2,-CH = C (CH 2 0R 4 ) 2 ,
-CH=C (CH20R7)2,-CH = C (CH 2 0R 7 ) 2 ,
-CH=C (CONR5Rg)CH2OR4 oder-CH = C (CONR 5 Rg) CH 2 OR 4 or
-CH=C (C0NR5Rg) CH20R7 substituiertes Furan;-CH = C (C0NR 5 Rg) CH 2 0R 7 substituted furan;
R3 ein Cyclopentan oder Cyclohexan, gegebenenfalls substituiert durch Methyl, Ethyl, Propyl, iso- Propyl, t-Butyl, Allyl, Vinyl, Phenyl oder Benzyl, wobei als geminaler Substituent eine Hydroxygruppe vorhanden sein kann;R 3 is a cyclopentane or cyclohexane, optionally substituted by methyl, ethyl, propyl, isopropyl, t-butyl, allyl, vinyl, phenyl or benzyl, a hydroxyl group being able to be present as the geminal substituent;
R3 ein Cyclopentan oder Cyclohexan, substituiert durch Hydroxy, Methoxy, Ethoxy, Propyloxy, Trimethoxycarbonyl, iso-Propyloxy, gegebenenfalls substituiertes Benzyloxy, Allyloxy, Propargyloxy, -CH2-C0-0CH3, =C-C0-0CH3, -CH2-CH2-OH, -CH2-COOCH3, =CH-C00CH3, CH2-CH2-OH, =C-CN,R 3 is a cyclopentane or cyclohexane, substituted by hydroxy, methoxy, ethoxy, propyloxy, trimethoxycarbonyl, isopropyloxy, optionally substituted benzyloxy, allyloxy, propargyloxy, -CH 2 -C0-0CH 3 , = C-C0-0CH 3 , -CH 2 -CH 2 -OH, -CH 2 -COOCH 3 , = CH-C00CH 3 , CH 2 -CH 2 -OH, = C-CN,
=NOH, -CH OH, OR4 mit R4 = Methyl oder Trityl, 0R7 worin R7 COCH3, COC H5, COC3H7, CO t-Butyl, -CO-Phenyl oder C0CH2-Phenyl, gegebenenfalls substituiert, CO-Pyridyl, -CO- (N- Methyl-4H-pyridyl) , = NOH, -CH OH, OR 4 with R 4 = methyl or trityl, 0R 7 in which R 7 COCH3, COC H 5 , COC 3 H 7 , CO t-butyl, -CO-phenyl or C0CH 2 -phenyl, optionally substituted , CO-pyridyl, -CO- (N-methyl-4H-pyridyl),
1010
- CO- (Methylpyridyli •COCH2-CH=CH2, -CO CH2-C=CH;- CO- (methylpyridyli • COCH 2 -CH = CH 2 , -CO CH 2 -C = CH;
*3 einen Rest* 3 a rest
mit Ra, RD = CH3, C2H5 oder Ra und Rj-, zusammen -CH2-CH2-,with R a , R D = CH 3 , C 2 H5 or R a and Rj-, together -CH 2 -CH 2 -,
R- ein Cyclopentanon oder Cyclohexanon,R- a cyclopentanone or cyclohexanone,
*3 ein Cycloalkan oder Cycloalken mit 4 - 8 Kohlenstoffatomen, welches durch eine geradkettige oder verzweigte Alkenylgruppe mit 2 bis 4 Kohlenstoffatomen substituiert sein kann, ein Cyclopentanon oder Cyclopentanol oder Cyclohexanon oder Cyclohexanol, die in α-Position zur Keto- oder Hydroxygruppe durch C2 bis C4 Alkenyl, C3 oder C Alkinyl, Benzyl, -CH2CH2CN, (CH2)3NR5R5 R5 gleich oder verschieden) , CH2COOR4, CH2OR4 substituiert sein können, wobei R4 Wasserstoff, Methyl, Ethyl oder Propyl bedeuten können,-* 3 a cycloalkane or cycloalkene with 4 - 8 carbon atoms, which can be substituted by a straight-chain or branched alkenyl group with 2 to 4 carbon atoms, a cyclopentanone or cyclopentanol or cyclohexanone or cyclohexanol which is in the α-position to the keto or hydroxy group by C 2 to C 4 alkenyl, C 3 or C alkynyl, benzyl, -CH 2 CH 2 CN, (CH 2 ) 3 NR 5 R5 R 5 identical or different), CH 2 COOR4, CH 2 OR 4 , where R 4 Can mean hydrogen, methyl, ethyl or propyl,
*3 Norbonan oder Norbonen - gegebenenfalls substituiert,* 3 norbonane or norbornene - optionally substituted,
1 i 1 i
R4 Wasserstoff, eine Alkylgruppe mit 1 bis 3R 4 is hydrogen, an alkyl group with 1 to 3
Kohlenstoffatomen, eine Cyclopropylgruppe, eine Cyclopentylgruppe, Benzyl eine Allylgruppe, eine Propargylgruppe, eine Triphenylmethylgruppe;Carbon atoms, a cyclopropyl group, a cyclopentyl group, benzyl an allyl group, a propargyl group, a triphenylmethyl group;
R5 Wasserstoff, eine Alkylgruppe mit 1 bis 3R5 is hydrogen, an alkyl group with 1 to 3
Kohlenstoffatomen; eine Cyclopropylgruppe, eine Benzylgruppe;Carbon atoms; a cyclopropyl group, a benzyl group;
Rg Wasserstoff, Methyl, Ethyl, Propyl, -(CH2)n-NH2 (n-2-8), -(CH2)nNEt2 (n=2,3) oder -(CH2)3_0- (CH )4-0- (CH2) 3-NH2, N-Benzyl-piperidin-4-yl- , oder R5 und Rg zusammen mit dem Stickstoffatom einen Piperidin- , Piperazin- , Morpholinrest, der gegebenenfalls durch ^- ^ Alkylrest - bevorzugt Methyl substituiert sein kann;Rg is hydrogen, methyl, ethyl, propyl, - (CH 2 ) n -NH 2 (n-2-8), - (CH 2 ) n NEt 2 (n = 2,3) or - (CH 2 ) 3 _0- (CH) 4-0- (CH 2 ) 3-NH 2 , N-benzyl-piperidin-4-yl, or R5 and Rg together with the nitrogen atom form a piperidine, piperazine, morpholine residue, which may be replaced by ^ - ^ Alkyl radical - preferably methyl may be substituted;
Prolinoyl, CO- (CH ) 0-3-CH3,Prolinoyl, CO- (CH) 0-3-CH3,
(-) -Menthoxyacetyl, ein über eine Carbonylgruppe verknüpfter Camphansäurerest, Abietinoyl, Benzoyl, 4-Aminobutyroyl, 3,4,5-Trihydroxybenzoyl, 3,4,5- Trimethoxybenzoyl, ein Nicotinsäure- , Isonicotinsäure- oder Picolinsäurerest, N- Methylnicotinsäurerest, N-Methyl-4H- Nicotinsäurerest bedeuten können, sowie gegebenenfalls deren S ureadditionssalze bedeuten, als Diurethikum. (-) -Mentoxyacetyl, a camphanic acid residue linked via a carbonyl group, abietinoyl, benzoyl, 4-aminobutyroyl, 3,4,5-trihydroxybenzoyl, 3,4,5-trimethoxybenzoyl, a nicotinic acid, isonicotinic acid or picolinic acid residue, N-methylnicotinic acid residue N-methyl-4H-nicotinic acid residue can mean, and optionally their acid addition salts, as a diuretic.
2. Verwendung von 8- (3-Oxocyclopentyl) -1, 3-di-n-propyl-7E- purin-2, 6-dion oder (+) -8- (3-0xocyclo-pentyl) -1,3-di-n- propyl-7H-purin-2, 6-dion oder (-) -8- (3-Oxocyclopentyl) -1,3- di-n-propyl-7H-purin-2, 6-dion als Diuretikum.2. Use of 8- (3-oxocyclopentyl) -1, 3-di-n-propyl-7E-purine-2, 6-dione or (+) -8- (3-0xocyclopentyl) -1,3- di-n-propyl-7H-purine-2, 6-dione or (-) -8- (3-oxocyclopentyl) -1,3-di-n-propyl-7H-purine-2, 6-dione as a diuretic.
•3. Verwendung von 8-- (3-Hydroxycyclopentyl) -1,• 3. Using 8-- (3-hydroxycyclopentyl) -1,
3-di-n-propyl-7H- purin-2,6-dion oder eines seiner Enantiomere als Diuretikum.3-di-n-propyl-7H-purine-2,6-dione or one of its enantiomers as a diuretic.
4. Arzneimittel enthaltend eine Verbindung wie in Anspruch l, 2 oder 3 definiert in Kombination mit einem Schleifen- Diuretikum.4. Medicament containing a compound as defined in claim 1, 2 or 3 in combination with a loop diuretic.
5. Verwendung von einer Verbindung wie in einem der Ansprüche 1, 2 oder 3 definiert zur Herstellung eines Arzneimittels mit diuretischer Wirkung 5. Use of a compound as defined in any one of claims 1, 2 or 3 for the manufacture of a medicament with a diuretic effect
EP94900128A 1992-11-13 1993-11-11 Xanthine derivatives for use as diuretics Withdrawn EP0667777A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4238367 1992-11-13
DE4238367A DE4238367A1 (en) 1992-11-13 1992-11-13 Diuretic
PCT/EP1993/003158 WO1994011000A1 (en) 1992-11-13 1993-11-11 Xanthine derivatives for use as diuretics

Publications (1)

Publication Number Publication Date
EP0667777A1 true EP0667777A1 (en) 1995-08-23

Family

ID=6472821

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94900128A Withdrawn EP0667777A1 (en) 1992-11-13 1993-11-11 Xanthine derivatives for use as diuretics

Country Status (18)

Country Link
US (1) US5599817A (en)
EP (1) EP0667777A1 (en)
JP (1) JPH08503204A (en)
KR (1) KR950703964A (en)
CN (1) CN1090493A (en)
AU (1) AU5465094A (en)
BG (1) BG99638A (en)
CA (1) CA2148473A1 (en)
CZ (1) CZ123595A3 (en)
DE (1) DE4238367A1 (en)
FI (1) FI952311A (en)
HU (1) HUT72496A (en)
IL (1) IL107589A0 (en)
MX (1) MX9307082A (en)
PL (1) PL308992A1 (en)
SK (1) SK60795A3 (en)
WO (1) WO1994011000A1 (en)
ZA (1) ZA938453B (en)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1386609A1 (en) * 1998-04-24 2004-02-04 Cv Therapeutics Adenosine A1 receptor antagonist containing composition and method for restoring diuretic and renal function
ES2211079T3 (en) * 1998-04-24 2004-07-01 Cv Therapeutics COMPOSITION CONTAINING AN ADENOSINE A1 RECEIVER ANTAGONIST AND METHOD TO RESTORE DIURETIC AND RENAL FUNCTION.
EP0970696A1 (en) * 1998-05-05 2000-01-12 Kyowa Hakko Kogyo Co., Ltd. Combination of loop diuretics with adenosine A1-receptor antagonists
US20040229901A1 (en) * 2003-02-24 2004-11-18 Lauren Otsuki Method of treatment of disease using an adenosine A1 receptor antagonist
NZ543109A (en) * 2003-04-25 2008-06-30 Novacardia Inc Method of improved diuresis in individuals with impaired renal function
US20060293312A1 (en) * 2003-04-25 2006-12-28 Howard Dittrich Method of improved diuresis in individuals with impaired renal function
US20050239759A1 (en) * 2004-04-16 2005-10-27 Lauren Otsuki Method of treatment of disease using an adenosine A1 receptor antagonist and an aldosterone inhibitor
CN101466383A (en) * 2006-06-16 2009-06-24 美国诺华卡迪亚公司 Prolonged improvement of renal function comprising infrequent administration of an AAIRA
US20090197900A1 (en) * 2007-03-29 2009-08-06 Howard Dittrich Methods of treating heart failure and renal dysfunction in individuals with an adenosine a1 receptor antagonist
US20080242684A1 (en) * 2007-03-29 2008-10-02 Howard Dittrich Methods of administration of adenosine a1 receptor antagonists
WO2010011824A1 (en) * 2008-07-25 2010-01-28 Concert Pharmaceuticals, Inc. Novel xanthine compounds

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1201997A (en) * 1967-08-04 1970-08-12 Yissum Res Dev Co New substituted purines and purine derivatives
US3624215A (en) * 1970-06-25 1971-11-30 Abbott Lab 8-substituted theophyllines as anti-anxiety agents
US4696932A (en) * 1984-10-26 1987-09-29 The United States Of America As Represented By The Department Of Health And Human Services Biologically-active xanthine derivatives
US4755517A (en) * 1986-07-31 1988-07-05 Warner-Lambert Company Derivatives of xanthine, pharmaceutical compositions and methods of use therefor
JP2843634B2 (en) * 1989-03-06 1999-01-06 協和醗酵工業株式会社 Xanthine derivative
JPH06102662B2 (en) * 1989-09-01 1994-12-14 協和醗酵工業株式会社 Xanthine derivative

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9411000A1 *

Also Published As

Publication number Publication date
PL308992A1 (en) 1995-09-18
HU9501397D0 (en) 1995-06-28
BG99638A (en) 1996-04-30
AU5465094A (en) 1994-06-08
SK60795A3 (en) 1996-05-08
CA2148473A1 (en) 1994-05-26
DE4238367A1 (en) 1994-05-19
CN1090493A (en) 1994-08-10
IL107589A0 (en) 1994-02-27
KR950703964A (en) 1995-11-17
CZ123595A3 (en) 1995-12-13
FI952311A0 (en) 1995-05-12
JPH08503204A (en) 1996-04-09
HUT72496A (en) 1996-05-28
FI952311A (en) 1995-05-12
US5599817A (en) 1997-02-04
MX9307082A (en) 1994-05-31
ZA938453B (en) 1994-05-13
WO1994011000A1 (en) 1994-05-26

Similar Documents

Publication Publication Date Title
DE2856393C2 (en) Medicines used to treat Parkinson&#39;s disease
DE60026855T2 (en) SYNERGISTIC COMBINATION OF ROFLUMILAST AND SALMETEROL
DE69310065T2 (en) Use of 2- (3,4-dimethoxycinnamoyl) aminobenzoic acid for the manufacture of a medicament for the treatment of restenosis
DE69805983T2 (en) COUGH-RESISTANT COMPOSITIONS CONTAINING THEOBROMINE
WO1994011000A1 (en) Xanthine derivatives for use as diuretics
EP1923073B1 (en) Combination medication comprising a PDE-5 inhibitor
EP0038438B1 (en) Substituted 1,2,5-oxadiazole-2-oxides for use as medicaments and medicaments containing them
EP1032572B1 (en) Pyranones, method for the production and use thereof
DE2520978A1 (en) DOSAGE UNITS OF SOLID MEDICINAL FORMS FOR ORAL ADMINISTRATION, IN PARTICULAR OF HYDRO-SOLUBLE XANTHINE DERIVATIVES
DE60315426T2 (en) PHARMACEUTICAL COMPOSITION CONTAINING A PDE4 OR PDE3 / 4 INHIBITOR AND A HISTAMINE RECEPTOR ANTAGONIST
DE69907387T2 (en) Use of hydantoin derivatives for the manufacture of a medicament for the treatment of refractory vasculitis.
EP4167996B1 (en) Metamizole derivatives for the prevention and treatment of pulmonary hypertension
DE69001526T2 (en) Use of trifluoromethylphenyltetrahydropyridines for the manufacture of medicaments for combating intestinal motility disorders.
DE69125204T2 (en) Therapeutic use of histamine H3 agonists, new active ingredients and use in the manufacture of drugs
DE69007050T2 (en) Protection against chemically induced kidney damage from methimazole.
DE2451933C2 (en)
DE3205149C2 (en)
WO1994003173A1 (en) Use of 8-(3-oxocyclopentyl)-1,3-dipropyl-7h-purine-2,6-dione for the symptomatic treatment of cystic fibrosis
DE2630015C3 (en) 4,5,6,7-tetrahydro-3 (4-methoxyphenyl) indazole and medicaments containing this compound
DE2823267C2 (en)
DE3141970A1 (en) MEDICINES FOR TREATING DISEASES GENERATED BY THE VIRUS OF THE HERPES GROUP
DE2145359B2 (en) SINGLE-SQUARE BRACKET ON BUTE- (2) YLIDENHYDRAZINO SQUARE BRACKET FOR PHTHALAZINE DERIVATIVES
DE3887426T2 (en) Eperisone as a hypotonic.
DE4324944A1 (en) Use of 1,3-di:propyl-7H-purin-2,6-di:one derivs. - for treatment of the symptoms of cystic fibrosis and to restore the electrolyte balance of the cells
DE1617336C2 (en) Medicines for angina pectoris

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19950613

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BOEHRINGER INGELHEIM KG

Owner name: BOEHRINGER INGELHEIM PHARMA KG

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BOEHRINGER INGELHEIM PHARMA KG

Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH

17Q First examination report despatched

Effective date: 19981201

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19991012