WO1994003173A1 - Use of 8-(3-oxocyclopentyl)-1,3-dipropyl-7h-purine-2,6-dione for the symptomatic treatment of cystic fibrosis - Google Patents

Use of 8-(3-oxocyclopentyl)-1,3-dipropyl-7h-purine-2,6-dione for the symptomatic treatment of cystic fibrosis Download PDF

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WO1994003173A1
WO1994003173A1 PCT/EP1993/002000 EP9302000W WO9403173A1 WO 1994003173 A1 WO1994003173 A1 WO 1994003173A1 EP 9302000 W EP9302000 W EP 9302000W WO 9403173 A1 WO9403173 A1 WO 9403173A1
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group
methyl
coor
propyl
substituted
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PCT/EP1993/002000
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German (de)
French (fr)
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Ulrike Küfner-Mühl
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Boehringer Ingelheim Kg
Boehringer Ingelheim International Gmbh
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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
    • 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

Definitions

  • the present invention relates to the use of 8- (3- ⁇ xocyclopentyl) -1,3-dipropyl-7H-purine-2,6-dione in particular in R (+) - 8- (3-oxocyclopentyl) -1,3-dipropyl - 7H-purine-2,6-dione of its (-) - enantiomer and structure-like compound for the symptomatic treatment of cystic fibrosis.
  • A. antagonists the efflux of chloride ions from CF PAC cells increases. The cells originate from a pancreatic adenocarcinoma cell line which was isolated from patients suffering from cystic fibrosis (CF). The action of the xanthine could be reduced by agonists, e.g. 2-chloroadenosine can be blocked. Interestingly, an increase in efflux was only observed in cells from patients with cystic fibrosis.
  • R 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, R, CH 3 , C 2 H 5 or
  • R_ is a cyclopentanone or cyclohexanone
  • R 3 is a cycloalkane or cycloalkene with 4-8
  • Carbon atoms which may be a straight-chain or branched
  • Carbon atoms can be substituted, a cyclopentanone or cyclopentanol or
  • Cyclohexanone or cyclohexanol which is in the ⁇ -position to the keto or hydroxy group by C_ to C 4 alkenyl, C 3 or
  • CH _ 6NRo, .R 1 - Rb c equal to or different
  • CH 2 COOR 4 CH 2 OR 4 can be substituted, where R 4 can be hydrogen, methyl, ethyl or propyl
  • R hydrogen, an alkyl group having 1 to 3 carbon atoms, a cyclopropyl group, a cyclopentyl group, benzyl an allyl group, a propargyl group, a triphenylmethyl group;
  • Hydrogen an alkyl group having 1 to 3 carbon atoms; a cyclopropyl group, a benzyl group;
  • the compounds of general formula I can be administered orally, parenterally as suppositories or by inhalation.
  • 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, dragees, xapsules, wafers, powders, solutions, propellant mixtures, 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.

Abstract

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

Description

Verwendung von 8-(3-Oxocvclopentyl)- 1.3-dipropyl-7H-purin-2.6-dion zur symptomatischen Behandlung der zvstischen Fibröse Use of 8- (3-oxocclopentyl) - 1,3-dipropyl-7H-purine-2,6-dione for the symptomatic treatment of the fibrous nerve
Die vorliegende Erfindung betrifft die Verwendung von 8-(3-θxocyclopentyl)-1,3-dipropyl-7H-purin-2,6-dion insbesonere in R(+)-8-(3-Oxocyclopentyl)-1,3-dipropyl- 7H-purin-2,6-dion seines (-)-Enantiomeren und Strukturähnliche Verbindung zur symptomatischen Behandlung der zystischen Fibröse.The present invention relates to the use of 8- (3-θxocyclopentyl) -1,3-dipropyl-7H-purine-2,6-dione in particular in R (+) - 8- (3-oxocyclopentyl) -1,3-dipropyl - 7H-purine-2,6-dione of its (-) - enantiomer and structure-like compound for the symptomatic treatment of cystic fibrosis.
Die zystische Fibröse - auch als Mukoviszidose bekannt - ist eine erbliche StoffWechselstörung, hervorgerufen durch einen genetischen Defekt eines bestimmten Chromosoms. Nur homocygote Merkmalträger erkranken. Der genetische Defekt führt zu einer Dysfunktion exokriner Drüsen. Durch eine vermehrte Produktion und erhöhte Viskosität des Sekrets der mukösen Drüsen in den Bronchien kann es zu schweren Komplikationen im Bereich der Atemwege kommen. Erste Untersuchungen haben gezeigt, daß in A.-Antagonisten den Efflux von Chloridionen von CF PAC Zellen erhöhen. Die Zellen entstammen einer pankreas adenocarcinoma Zellinie, die von an cystischer Fibröse (CF) erkrankten Patienten isoliert wurde. Die Wirkung des Xanthins konnte durch Agonisten, wie z.B. 2-Chloradenosin blockiert werden. Interessanterweise wurde eine Erhöhung des Effluxes nur bei solchen Zellen beobachtet, die von an cystischer Fibröse erkrankten Patienten stammten.Cystic fibrosis - also known as cystic fibrosis - is an inherited metabolic disorder caused by a genetic defect in a particular chromosome. Only homozygous traits become ill. The genetic defect leads to dysfunction of exocrine glands. Increased production and increased viscosity of the secretions of the mucous glands in the bronchi can lead to serious complications in the area of the respiratory tract. Initial studies have shown that in A. antagonists the efflux of chloride ions from CF PAC cells increases. The cells originate from a pancreatic adenocarcinoma cell line which was isolated from patients suffering from cystic fibrosis (CF). The action of the xanthine could be reduced by agonists, e.g. 2-chloroadenosine can be blocked. Interestingly, an increase in efflux was only observed in cells from patients with cystic fibrosis.
Ausgehend von diesen Befunden kann erwartet werden, daß bei Patienten die an Mukoviszidose erkrankt sind, der gestörte Elektrolythaushalt der Zellen reguliert und die Symptome der Erkrankung gemildert werden. Von besonderem Interesse ist das 8-(3-0xocyclopentyl)-l,3- dipropyl-7H-purin-2,6 dion-wie auch das optisch aktiveBased on these findings, it can be expected that in patients with cystic fibrosis, the disturbed electrolyte balance of the cells can be regulated and the symptoms of the disease can be alleviated. Of particular interest is 8- (3-0xocyclopentyl) -l, 3- dipropyl-7H-purine-2,6 dione as well as the optically active
R(+)-8-(3-θxocyclopentyl)-1,3-dipropyl-7H-purin-2,6-dion,da aufgrund seiner selektiven hohen A -antagonisti¬ schen Wirkung und seiner unerwartet guten Wasser¬ löslichkeit in vivo allen anderen bisher bekannten Al-Adenosin-Rezeptor- Antagonisten überlegen ist7 Die Verbindung selbst, wie auch ihre pharmakologische Wirkung als Therapeutikum zur symptomatischen Behandlung degenerativer Alterserkrankungen, ist aus der Europäischen Patentanmeldung 374 808 beschrieben. Die Herstellung der Verbindung - auch als R(+)-l,3-Dipropyl-8- (3-oxocyclopentyl)-xanthin bezeichnet - erfolgt nach an sich bekannten Verfahren, wie z.B. in den Beispielen 2a, 2b und 16 der genannten Patentanmeldung, auf die hiermit inhaltlich Bezug genommen wird.R (+) - 8- (3-θxocyclopentyl) -1,3-dipropyl-7H-purine-2,6-dione, because of its selective high A -antagonistic effect and its unexpectedly good water solubility in vivo, all is superior to other previously known Al-adenosine receptor antagonists7 The compound itself, as well as its pharmacological action as a therapeutic agent for the symptomatic treatment of degenerative aging diseases, is described in European patent application 374 808. The preparation of the compound - also referred to as R (+) - 1,3-dipropyl-8- (3-oxocyclopentyl) xanthine - takes place according to processes known per se, such as e.g. in Examples 2a, 2b and 16 of the cited patent application, to which reference is hereby made.
Geeignete Strukturähnliche Xanthin-Derivate sind auch 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 also 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.
Von Interesse sind daher auch Xanthine der allgemeinen FormelXanthines of the general formula are therefore also of interest
worin
Figure imgf000004_0001
wherein
Figure imgf000004_0001
einen Rest, ausgewählt aus der Gruppe Furan, Tetrahydrofuran, Tetrahydrofuranon, Thiophen, Dithiol, Dithian oder Tetrahydropyran der einen der folgenden Substituenten tragen kanna residue selected from the group consisting of furan, tetrahydrofuran, tetrahydrofuranone, thiophene, dithiol, Dithian or tetrahydropyran which can carry one of the following substituents
Methyl, Ethyl, Propyl, Butyl, CHO,Methyl, ethyl, propyl, butyl, CHO,
CH2OR4, CH2OR-_, COOR4,
Figure imgf000005_0001
CH 2 OR 4 , CH 2 OR-_, COOR 4 ,
Figure imgf000005_0001
R_ ein durchR_ on by
-CH=CH-CONR5R6, -CH=C(COOR4)2 -CH = CH-CONR 5 R 6 , -CH = C (COOR 4 ) 2
(R4 gleich oder verschieden),(R 4 the 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) (CH2OR?),-CH = C (COOR 4 ) (CH 2 OR ? ),
-(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 (C0NR[;Rc)CH 0Ry1 oder 5 6 2 4-CH = C (C0NR [; R c ) CH 0R y1 or 5 6 2 4
-CH=C (CONR5 6)CH2OR7 substituiertes Furan;-CH = C (CONR 5 6 ) CH 2 OR 7 substituted furan;
R, 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;R, 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_ 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,R_ 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,
-CH2-COOCH3, =CH-COOCH3, CH2-CH2-OH, =C-CN, -(CH2)2 H2
Figure imgf000006_0001
-CH 2 -COOCH 3 , = CH-COOCH 3 , CH 2 -CH 2 -OH, = C-CN, - (CH 2 ) 2 H 2
Figure imgf000006_0001
=NOH, -CH2OH, OR4 mit R4 = Methyl oder Trityl,= NOH, -CH 2 OH, OR 4 with R 4 = methyl or trityl,
OR? worin R? COCH3, COC2H5,OR ? where R ? COCH 3 , COC 2 H 5 ,
COC3H?,COC 3 H ? .
CO t-Butyl, -CO-Phenyl oderCO t-butyl, -CO-phenyl or
COCH2-Phenyl, gegebenenfalls substituiert, CO-Pyridyl,COCH 2 -phenyl, optionally substituted, CO-pyridyl,
-CO-(N-Methyl-4H-pyridyl) ,-CO- (N-methyl-4H-pyridyl),
-CO-(Methylpyridy1) , -COCH2-CH=CH2.-CO- (methylpyridy1), -COCH 2 -CH = CH 2 .
-CO CH2-C=CH;-CO CH 2 -C = CH;
Figure imgf000006_0002
mit R , R, = CH3, C2H5 oder
Figure imgf000006_0002
with R, R, = CH 3 , C 2 H 5 or
Ra„ und R,b zusammen -CH2„-CH2-,Ra "and R, b together -CH2" -CH2-,
R_ ein Cyclopentanon oder Cyclohexanon,R_ 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 verzweigteCarbon atoms, which may be a straight-chain or branched
Alkenylgruppe mit 2 bis 4Alkenyl group with 2 to 4
Kohlenstoffatomen substituiert sein kann, ein Cyclopentanon oder Cyclopentanol oderCarbon atoms can be substituted, a cyclopentanone or cyclopentanol or
Cyclohexanon oder Cyclohexanol, die in α-Position zur Keto- oder Hydroxygruppe durch C_ bis C4 Alkenyl, C3 oderCyclohexanone or cyclohexanol, which is in the α-position to the keto or hydroxy group by C_ to C 4 alkenyl, C 3 or
C4 Alkinyl, Benzyl, -CH2CH2C ,C 4 alkynyl, benzyl, -CH 2 CH 2 C,
(CH_)_ 6NRo,.R1- Rbc gleich oder verschieden), CH2COOR4, CH2OR4 substituiert sein können, wobei R4 Wasserstoff, Methyl, Ethyl oder Propyl bedeuten können;(CH _) _ 6NRo, .R 1 - Rb c equal to or different), CH 2 COOR 4 , CH 2 OR 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,
Figure imgf000007_0001
Figure imgf000007_0001
R. Wasserstoff, eine Alkylgruppe mit 1 bis 3 Kohlenstoffatomen, eine Cyclopropylgruppe, eine Cyclopentylgruppe, Benzyl eine Allylgruppe, eine Propargylgruppe, eine Triphenylmethylgruppe;R. hydrogen, an alkyl group having 1 to 3 carbon atoms, a cyclopropyl group, a cyclopentyl group, benzyl an allyl group, a propargyl group, a triphenylmethyl group;
Wasserstoff, eine Alkylgruppe mit 1 bis 3 Kohlenstoffatomen; eine Cyclopropylgruppe, eine Benzylgruppe;Hydrogen, an alkyl group having 1 to 3 carbon atoms; a cyclopropyl group, a benzyl group;
R, Wasserstoff, Methyl, Ethyl, Propyl,R, hydrogen, methyl, ethyl, propyl,
-<CH2)n-NH2 (n=2-8),- <CH 2 ) n -NH 2 (n = 2-8),
-(CH2)nNEt2 (n=2,3) oder- (CH 2 ) n NEt 2 (n = 2.3) or
-(CH2)3-0-(CH2)4-0-(CH2)3-NH2 - (CH 2 ) 3 -0- (CH 2 ) 4 -0- (CH 2 ) 3 -NH 2
, N-Benzyl-piperidin-4-yl-, oder R5 und, N-benzyl-piperidin-4-yl-, or R 5 and
R, zusammen mit demR, along with the
Stickstoffatom einen Piperidin-,Nitrogen atom a piperidine,
Piperazin-, Morpholinrest, der gegebenenfalls durch C,-C4 AlkylrestPiperazine, morpholine, optionally by C, -C 4 alkyl
- bevorzugt Methyl substituiert sein kann; R? Prolinoyl, CO-(CH2)0_3-CH3,- can preferably be substituted methyl; R ? 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 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 mean their acid addition salts.
Die Verbindungen der allgemeinen Formel I können oral, parenteral als Zäpfchen oder inhalativ 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, Xapseln, Oblaten Pulver, Lösungen, Treibgasmischungen, Suspensionen, Emulsionen, Sirupe, Suppsitorien 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, parenterally as suppositories or by inhalation. 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, dragees, xapsules, wafers, powders, solutions, propellant mixtures, 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
Verwendung von Verbindungen der allgemeinen Formel- IUse of compounds of general formula I
Figure imgf000009_0001
Figure imgf000009_0001
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, CH2OR4, CH2OR7, COOR4, CO R5R6,R 3 is a radical selected from the group furan, tetrahydrofuran, tetrahydrofuranone, thiophene, dithiol, dithiane or tetrahydropyran which can carry one of the following substituents: methyl, ethyl, propyl, butyl, CHO, CH 2 OR 4 , CH 2 OR 7 , COOR 4 , CO R 5 R 6 ,
R3 ein durchR 3 a through
-CH=CH-CONR5Rg, -CH=C(COOR4)2 (R4 gleich oder verschieden) , -CH=C (COOR4) (CO R5R6), -CH=C (COOR4) (CH2OR4) ( 4 gleich oder verschieden) , -CH=C (COOR4) (CH2OR?), -(CH2)n-CONR5R6,-CH = CH-CONR 5 Rg, -CH = C (COOR 4 ) 2 (R 4 same or different), -CH = C (COOR 4 ) (CO R 5 R 6 ), -CH = C (COOR 4 ) (CH 2 OR 4 ) ( 4 the same or different), -CH = C (COOR 4 ) (CH 2 OR ? ), - (CH 2 ) n -CONR 5 R 6 ,
-CH=C (CH20R4)2,-CH = C (CH 2 0R 4 ) 2 ,
-CH=C (CH20R?)2,-CH = C (CH 2 0R ? ) 2 ,
-CH=C (CONR5Rg)CH2OR4 oder-CH = C (CONR 5 R g ) CH 2 OR 4 or
-CH=C (CONR5R6)CH2OR? substituiertes Furan;-CH = C (CONR 5 R 6 ) CH 2 OR ? substituted furan;
R ein Cyclopentan oder Cyclohexan,R is cyclopentane or cyclohexane,
3 substituiert durch Methyl, Ethyl, Propyl, iso-Propyl, t-Butyl, Allyl, Vinyl, Phenyl oder Benzyl, wobei als geminaler Substituent eine Hydroxygruppe vorhanden sein kann;3 substituted by methyl, ethyl, propyl, iso-propyl, t-butyl, allyl, vinyl, phenyl or benzyl, where a hydroxyl group may be present as the geminal substituent;
R_ ein Cyclopentan oder Cyclohexan, substituiert durch Hydroxy, Methoxy,R_ is a cyclopentane or cyclohexane, substituted by hydroxy, methoxy,
Ethoxy, Propyloxy, Trimethoxycarbonyl, iso-Propyloxy, gegebenenfalls substituiertes Benzyloxy, Allyloxy,Ethoxy, propyloxy, trimethoxycarbonyl, iso-propyloxy, optionally substituted benzyloxy, allyloxy,
Propargyloxy,Propargyloxy,
-CH2-CO-OCH3, =C-CO-OCH3,-CH 2 -CO-OCH 3 , = C-CO-OCH 3 ,
-CH2-CH2-OH,-CH 2 -CH 2 -OH,
-CH2-COOCH3, =CH-COOCH3,-CH 2 -COOCH 3 , = CH-COOCH 3 ,
CH2-CH2-OH, =C-CN, -(CH2)2NH2 CH 2 -CH 2 -OH, = C-CN, - (CH 2 ) 2 NH 2
Figure imgf000010_0001
=NOH, -CH2OH, OR4 mit R4 = Methyl oder Trityl,
Figure imgf000010_0001
= NOH, -CH 2 OH, OR 4 with R 4 = methyl or trityl,
OR7 worin R? COCH3, COC2H5, COC3H7,OR 7 where R ? COCH 3 , COC 2 H 5 , COC 3 H 7 ,
CO t-Butyl, -CO-Phenyl oder COCH_-Phenyl, gegebenenfalls substituiert, CO-Pyridyl, -CO-(N-Methyl-4H-pyridyl) , -CO-(Methylpyridyl) , -COCH2-CH=CH2,CO t-butyl, -CO-phenyl or COCH_-phenyl, optionally substituted, CO-pyridyl, -CO- (N-methyl-4H-pyridyl), -CO- (methylpyridyl), -COCH 2 -CH = CH 2 ,
-CO CH2-C=CH; R3 einen Rest-CO CH 2 -C = CH; R 3 is a residue
Figure imgf000011_0001
Figure imgf000011_0001
mit Ra. R. υ = CH_ ά, C-_jHC oderwith Ra. R. υ = CH_ ά, C-_jH C or
Ra„ und Rb. zusammen -CH2-CH2_-Ra "and Rb. together -CH2-CH2_-
R3 ein Cyclopentanon oder Cyclohexanon,R 3 is a cyclopentanone or cyclohexanone,
R_ ein Cycloalkan oder Cycloalken mit 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, C_ oder C4 Alkinyl, Benzyl, -CH2CH2CN, (CH2)3NR5Rg 5 gleich oder verschieden), CH2COOR4, CH2OR4 substituiert sein können, wobei R4 Wasserstoff, Methyl, Ethyl oder Propyl bedeuten können;R_ is a cycloalkane or cycloalkene with 4 to 8 carbon atoms, which may optionally 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 hydroxyl group by C " to C 4 alkenyl, C_ or C 4 alkynyl, benzyl, -CH 2 CH 2 CN, (CH 2 ) 3 NR 5 R g 5 identical or different), CH 2 COOR 4 , CH 2 OR 4 , where R 4 can be hydrogen, methyl, ethyl or propyl;
R3 Norbonan oder Norbonen - gegebenenfalls substituiert,R 3 norbonane or norbornene - optionally substituted,
Figure imgf000011_0002
ÖO R4 Wasserstoff, eine Alkylgruppe mit 1 bis 3
Figure imgf000011_0002
ÖO R 4 is hydrogen, an alkyl group with 1 to 3
Kohlenstoffatomen, eine Cyclopropylgruppe, eine Cyclopentylgruppe, Benzyl eine Allylgruppe, eine Propargylgruppe, eine Triphenyl ethylgruppe;Carbon atoms, a cyclopropyl group, a cyclopentyl group, benzyl an allyl group, a propargyl group, a triphenyl ethyl group;
R5 Wasserstoff, eine Alkylgruppe mit 1 bis 3 Kohlenstoffatomen; eine Cyclopropylgruppe, eine Benzylgruppe;R 5 is hydrogen, an alkyl group having 1 to 3 carbon atoms; a cyclopropyl group, a benzyl group;
R Wasserstoff, Methyl, Ethyl, Propyl, -(CH2)n-NH2 (n=2-8), -(CH2)nNEt2 (n=2,3) oder -(CH2)3-0-(CH2)4-0-(CH2)3-NH2 , N-Benzyl-piperidin-4-yl-, oder R und Rb,. zusammen mit demR 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 2 , N-benzylpiperidin-4-yl-, or R and Rb ,. together with the
Stickstoffatom einen Piperidin-, Piperazin-, Morpholinrest, der gegebenenfalls durch C,-C. Alkylrest - bevorzugt Methyl substituiert sein kann;Nitrogen atom is a piperidine, piperazine, morpholine residue which may be replaced by C, -C. Alkyl radical - preferably methyl may be substituted;
R? Prolinoyl, CO-(CH2)0_3~CH3,R ? 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, zur symptomatischen Behandlung der cystischen Fibröse. 2. Verwendung von 8-(3-Oxocyclopentyl)-l,3-di- propyl)-7H-purin-2,6-dion oder (+)-8-(3-Oxocyclo- pentyl)-l,3-dipropyl)-7H-purin-2,6-dion oder (-)-8-(3-Oxocyclopentyl)-l,3-dipropyl)-7H-purin -2,6-dion zur symptomatischen Behandlung der cystischen Fibröse. (-) - Menthoxyacetyl, 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, as well as their acid addition salts if necessary, for the symptomatic treatment of cystic fibrosis. 2. Use of 8- (3-oxocyclopentyl) -1, 3-di-propyl) -7H-purine-2,6-dione or (+) - 8- (3-oxocyclopentyl) -1, 3-dipropyl ) -7H-purine-2,6-dione or (-) - 8- (3-oxocyclopentyl) -l, 3-dipropyl) -7H-purine -2,6-dione for the symptomatic treatment of cystic fibrosis.
PCT/EP1993/002000 1992-08-01 1993-07-28 Use of 8-(3-oxocyclopentyl)-1,3-dipropyl-7h-purine-2,6-dione for the symptomatic treatment of cystic fibrosis WO1994003173A1 (en)

Applications Claiming Priority (8)

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DEP4225501.5 1992-08-01
DE4225501 1992-08-01
DEP4230397.4 1992-09-11
DE4230397 1992-09-11
DEP4230398.2 1992-09-11
DE4230398 1992-09-11
DE4236867 1992-10-31
DEP4236867.7 1992-10-31

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5646156A (en) * 1994-04-25 1997-07-08 Merck & Co., Inc. Inhibition of eosinophil activation through A3 adenosine receptor antagonism
WO1999038532A2 (en) * 1998-01-28 1999-08-05 Link Technology, Inc. Methods for the prevention and treatment of fibrosis and sclerosis

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0374808A2 (en) * 1988-12-22 1990-06-27 Boehringer Ingelheim Kg Xanthin derivatives having an adenosin-antagonist activity
WO1992000297A1 (en) * 1990-06-22 1992-01-09 Boehringer Ingelheim Kg New xanthine derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0374808A2 (en) * 1988-12-22 1990-06-27 Boehringer Ingelheim Kg Xanthin derivatives having an adenosin-antagonist activity
WO1992000297A1 (en) * 1990-06-22 1992-01-09 Boehringer Ingelheim Kg New xanthine derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PROC. NATL. ACAD. SCI. U.S.A., Vol. 89, No. 12, 15 June 1992, pages 5562-5566, O. EIDELMAN et al., "A1 Adenosine - Receptor Antagonists Activate Chloride Efflux From Cystic Fibrosis Cells". *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5646156A (en) * 1994-04-25 1997-07-08 Merck & Co., Inc. Inhibition of eosinophil activation through A3 adenosine receptor antagonism
WO1999038532A2 (en) * 1998-01-28 1999-08-05 Link Technology, Inc. Methods for the prevention and treatment of fibrosis and sclerosis
WO1999038532A3 (en) * 1998-01-28 1999-09-30 Link Technology Inc Methods for the prevention and treatment of fibrosis and sclerosis
US6117445A (en) * 1998-01-28 2000-09-12 Link Technology Inc. Methods for the prevention and treatment of fibrosis and sclerosis

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