Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-07-06
1997-02-04
Spivack, Phyllis G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514568, 514471, 514562, A61K 3119, A61K 3134, A61K 3152
Patent
active
055998178
DESCRIPTION:
BRIEF SUMMARY
This application is a '371 of PCT/EP93/03158 filed Oct. 11, 1993.
The present invention relates to the use of 8-(3-oxocyclopentyl)-1,3-dipropyl-7H-purine-2,6-dione and xanthines of similar structure as diuretics. Diuretics play an important part in the treatment of oedema, hypertension and other illnesses.
The diuretic effect of xanthines is known in principle, but the compounds investigated hitherto have a relatively weak activity (see Beutler J. J., Koomans H. A., Bijlsma J. A. Dorhout-Mees E. J., J. Pharmacol. exp. Ther. (1990) 255, 1314).
Surprisingly, it has now been found that 8-(3oxocyclopentyl)-1,3 -dipropyl-7H-purine-2,6-dione (KFM 19) is an extremely effective diuretic. A significant diuretic effect is observed at an oral dose of only 0.03 mg/kg of body weight (in the rat). Particular advantages are expected from combining the substances of this application with so-called loop diuretics such as furosemide, bumetanide and ethacrynic acid. The "loop diuretics" are highly effective substances which inhibit the transporting of sodium in the distal tubuli of the kidneys. At the same time, chloride resorption 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 the excretion of sodium and chloride without having any great effect on potassium excretion. It is known that adenosine can influence chloride secretion. Therefore it is probable that the diuretic mechanisms of activity mainly affect the transport of chloride ions and the substance works in a complementary manner with agents inhibiting sodium chloride resorption.
DESCRIPTION OF THE TEST PROCEDURE
The tests were carried out with conscious male rats (Chbb:THOM, SPF) weighing 240-280 g which had been fasting. 10 animals were used for each dose, with two animals in each metabolic cage (n=5). In order to stimulate diuresis, all the animals were given water by oral route in an amount of 5 ml/100 g of body weight by oesophageal tube. KFM 19 was dissolved in water and administered orally together with the water (1 ml solution, 4 ml water) by oesophageal tube in doses of 0.01, 0.03, 0.1 and 0.3 mg/kg. The control animals were given 5 ml of water. Two and five hours after administration, the volume of urine excreted was measured; the sodium and potassium contents were determined by flame photometry and the chloride content by mercurimetry.
The results were checked for statistical significance according to DUNNETT (1984).
Table I
Influence on the excretion of urine and electrolyte of the oral administration of 8-(3-oxocyclopentyl)-1,3-dipropyl-7H-purine-2,6-dione in five hours after administration
__________________________________________________________________________ Volume of
Dose urine Sodium Potassium
Chloride
mg/kg
ml/100 g
uVal/100 g
uVal/100 g
uVal 100 g
p.o. x .+-. Sx
x .+-. Sx x .+-. Sx
x .+-. Sx
__________________________________________________________________________
Control
3.9 .+-. 0.5
32.3 .+-. 8.4
68.0 .+-. 13.9
65.2 .+-. 10.7
0.01 4.7 .+-. 0.3
45.9 .+-. 7.0
101.1 .+-. 14.6
88.5 .+-. 10.1
0.03 4.1 .+-. 0.4
51.7 .+-. 6.6
85.4 .+-. 4.4
87.0 .+-. 8.1
0.1 5.1 .+-. 0.2*
81.1 .+-. 8.1*
101.3 .+-. 9.1
138.5 .+-. 14.0**
0.3 5.8 .+-. 0.2**
131.5 .+-. 10.0**
119.8 .+-. 8.4
174.1 .+-. 18.5**
__________________________________________________________________________
* = p < 0.05,
** = p < 0.01
In the light of these findings, the above-mentioned compound as well as the structurally similar compounds appear to be suitable as diuretics, particularly for the treatment of oedema, hypertension and other indications of this kind.
Suitable xanthine derivatives of similar structure are described in European Patent Applications 374 808 and 487 673, to which reference is expressly made, particularly the ranges and embodiments described by way of example as being preferred.
These compounds may also be used for treating illnesses caused by disrupted transport of chloride ions.
Xanthines of ge
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Adamus Stefan
Gaida Wolfram
K ufner-Muhl Ulrike
Meade Christopher
Boehringer Ingelheim KG
Raymond Robert P.
Rieder Wendy E.
Spivack Phyllis G.
Stempel Alan R.
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