DE3930392A1 - Use of xanthine derivs. to reduce nephrotoxicity - Google Patents

Abstract

Use of xanthine derivs. of (I) for reducing the nephrotoxicity of pharmaceuticals and metabolites is new. Pharmaceutical compsns. contain a nephrotoxic component (II) plus at least one (I). Pref. (II) is amphotericin B and (I) is pentoxifyllin (3,7-dimethyl-1-(5-oxohexyl)-xanthine), propentofyllin (3-methyl-1-(5-oxohexyl)-propyl-xanthine) 1-(5-hydroxy-5-methyl-hexyl) and/or 7-ethoxymethyl-1-(5-hydroxy-5-methylhexyl) -methyl-xanthine. @(6pp Dwg.No.0/0)

Description

The present invention relates to the use of Xanthine derivatives and medicaments containing a Xanthine derivative for nephrotoxicity reduction.

It is already known that the nephrotoxicity of Medicinal ingredients by the simultaneous Processing of NaCl can be lowered (see J. Cancer Res. Clin. Oncol. 114, Suppl., P. 158, 1988). Furthermore, it has already been suggested that medicines Increased release of tumor necrosis factor (TNF) cause, with a TNF inhibitor, z. B. xanthine derivatives, to combine (see European Patent Application no. 8 91 09 312.2).

Surprisingly, it has now been found that certain Xanthine derivatives the nephrotoxicity of Reduce active ingredients and metabolic products can. The subject of the invention is therefore the use of a xanthine derivative for the reduction of nephrotoxicity of Active pharmaceutical ingredients and metabolic products.

Preferred xanthine derivatives are from the group of following connections:

• 1. Compounds of the formula I in which one of R¹ and R³ is a straight-chain alkyl, (ω-1) -oxoalkyl or (ω-1) -hydroxyalkyl group having 3 to 8 carbon atoms and the two other radicals R² and R³ or R¹ and R² is straight-chain or branched alkyl groups having 1 to 8 C atoms in the position of R¹ and R³ and 1 to 4 C atoms in the position of R², wherein the sum of the C atoms of these two alkyl substituents is at most 10,
• 2. Compounds of the formula II in which R is an alkyl radical having 1 to 4 C atoms,
• 3. Compounds of the formula III in the at least one of the radicals R⁴ and R⁶ is a tertiary hydroxyalkyl group of the formula represents, wherein R⁷ is an alkyl group having up to 3 carbon atoms and n is an integer from 2 to 5, and - if only one of R Reste or R⁶ is such a tertiary hydroxyalkyl of formula IIIa - the other radical for a hydrogen atom or an aliphatic hydrocarbon radical R⁸ having up to 6 C atoms whose carbon chain may be interrupted by up to 2 oxygen atoms or substituted by an oxo group or up to two hydroxy groups (wherein an oxo or hydroxy group present in the radical R⁸ preferably by at least 2 C atoms are separated from the nitrogen), and R⁵ represents an alkyl group having 1 to 4 C atoms,
• 4. prodrug forms of the compounds of formulas I to III and or
• 5. metabolites of the compounds of formulas I to III.

Among these compounds are in turn those of the formula I. particularly preferred which in the position of R¹ or R³ a Hexyl, 5-oxohexyl or 5-hydroxyhexyl carry. To they belong in particular

1-hexyl-3,7-dimethylxanthine,
(5-hydroxyhexyl) -3,7-dimethylxanthine 1,
3,7-dimethyl-1- (5-oxohexyl) xanthine,
(5-hydroxyhexyl) -1,3-dimethylxanthine 7-,
1,3-dimethyl-7- (5-oxohexyl) xanthine,
1- (5-hydroxyhexyl) -3-methyl-7-propylxanthine and
3-methyl-1- (5-oxohexyl) -7-propylxanthine (= propentofylline),
especially 3,7-dimethyl-1- (5-oxohexyl) -xanthine
(= Pentoxifylline).

Particularly preferred compounds of the formula III are those Compounds in which R⁵ represents a methyl or ethyl group stands. Equally preferred are those compounds of Formula III, in which only one of the two radicals R⁴ or R⁶ is the above-defined tertiary hydroxyalkyl group represents. Further preferred are such compounds, in where R⁷ is a methyl group and n is an integer from 3 to 5, so that the tertiary hydroxyalkyl IIIa either [(ω-1) -hydroxy- (ω-1) -methyl] -pentyl, -hexyl or heptyl, especially those in which R⁵ is methyl or ethyl.  

Furthermore, those compounds of formula III especially to emphasize in which R⁴ the tertiary Hydroxyalkyl group and R⁶ is hydrogen, alkyl, Hydroxyalkyl or alkoxyalkyl each having 1 to 4 carbon atoms such as the 7-ethoxymethyl-1- (5-hydroxy-5- methylhexyl) -3-methylxanthine and the 1- (5-hydroxy-5- methylhexyl) -3-methylxanthine.

Another embodiment of the invention is that the Oxoalkylxanthine of the formula I and II or the Hydroxyalkylxanthines of the formula I and III are not per se, but are used in prodrug form, from the first in the Organism the therapeutically effective xanthine compounds with the substituents defined in formulas I, II and III can be released by biotransformation. Therefor For example, the acetalated Oxoalkylxanthine, in the carbonyl groups through the structural element of Formula IV

and the O-acylated hydroxyalkylxanthines with the structural element of the formula (V)

R¹¹-CO-O- (V)

in place of the hydroxy function in question, where R⁹ and Each R¹⁰ an alkyl group having up to 4 carbon atoms or together an ethylene, trimethylene or Represent tetramethylene group and R¹¹ is an alkyl radical up to 4 carbon atoms or optionally substituted phenyl or pyridyl.

The preparation of xanthine derivatives is z. B. in the DE-B-12 33 405, DE-B-12 35 320 or DE 35 25 801 A1 described. The xanthine derivatives are useful in different active substances and also endogenous substances  such as As metabolites to nephrotoxicity Reduce. Particularly pronounced occurs the reduction of Nephrotoxicity when administering amphotericin B in Appearance.

The xanthine derivatives can be used alone, in combination with the nephrotoxic drug ingredient in separate dosage units (simultaneously or in temporal sequence) as well as with the nephrotoxic Drug ingredient are administered mixed.

The present invention also relates to medicaments which characterized in that they have at least one nephrotoxic ingredient and at least one xanthine derivative to reduce nephrotoxicity.

The compounds and medicines mentioned can be applied in different ways. For example, you can intravenous, intramuscular, intraperitoneal, subcutaneous or be administered orally.

In the case of the medicaments according to the invention, the ratio from nephrotoxic compound to xanthine derivative one sweep over wide area. To prefer is one Weight ratio of about 1: 100 to about 100: 1, especially preferably from about 1:10 to about 10: 1.

The preparation of medicaments according to the invention also belongs to the subject of the present invention, takes place by the nephrotoxic compound and at least a xanthine derivative, optionally with further additives, and / or excipients in a suitable dosage form to be brought. The additional or auxiliary materials come from the Group of carriers, preservatives and others usual auxiliaries. For example, for oral Dosage forms Excipients such as starch, eg. Potato,  Corn or wheat starch, cellulose or their derivatives, in particular microcrystalline cellulose, silicon dioxide, various sugars such as lactose, magnesium carbonate and / or calcium phosphates. It continues advantageous to the oral dosage forms adjuvants add the compatibility of the medication improve, such as As slime and resins. For the purpose of better compatibility, the drugs can also be in shape be administered by gastric juice-insoluble capsules. About that In addition, it may be advantageous to the dosage form, or a component of the combined preparation, a Add retarding, optionally in the form of permeable membranes, such as. As those on cellulose or Polystyrene resin base, or ion exchanger.

The nephrotoxicity-lowering effect of xanthine derivatives could be demonstrated experimentally in the following way:

Mice were given 9 times intravenously over 11 days with pentoxifylline, amphotericin B and amphotericin B in Combination with pentoxifylline and with one Solvent control treated. To judge the Nephrotoxicity of the respective administered substances the following substances are determined in the experimental animals:

creatinine:
A disturbed creatinine clearance caused by a damaged kidney leads to an increased content of serum creatinine (hypercreatininaemia)
Urea:
Elevated serum levels are commonly observed in severe renal impairment. A reduced urea clearance leads to an increased content in the serum
Potassium:
As potassium ions are up to 95% excreted by the kidneys, hyperkaliaemia is a clear sign of severe renal impairment.

Table 1

Pathophysiological findings in the serum of mice.

9 times intravenously (11 days)

Measurements from pooled sera of 3 mice each

Table 2 shows the mortalities in the 3 examined Groups of mice.

Pentoxifyllinkontrolle 0 dead mice of 21 Amphotericin B 11 dead mice of 21 combination 1 dead mouse of 21

The results of the described experiment prove that Nephrotoxicity-lowering effect of xanthine derivatives.

Furthermore, the nephrotoxicitätssenkende effect can be the xanthine derivatives by histological examination of Determine the test animals.

56 mice with glucose, pentoxifylline, Amphotericin B or the combination of pentoxifylline / Amphotericin B over a period of 11, 25, 39 or 53 Days treated intravenously.  

After the indicated experimental times were 4 animals each killed and serum for serological examinations taken. The kidneys were in Bouin's mixture fixed, worked up according to usual histological technique and PAS-stained.

Histopathological studies show that in the Pentoxifylline group only very marginal changes too are different from those of the solvent control (Glucose) differ only insignificantly.

In contrast, the kidneys are the only ones with Amphotericin B treated mice that had survived, Significant damage of the tubular apparatus on: So find necrosis (possibly predominantly) in early stages distal tubules with signs of regeneration and in later stages of atrophy are preferred in marrow-near Bark sections, while mainly proximal Nephron sections dilate as a result of a drainage obstruction, here z. T. protein cylinder contain, be druckatrophisch and - like the distal ones - with a broadening of the Basal membrane respond. In the area of affected nephrons occur macrophagocytic reactions and pronounced, scar-like interstitial connective tissue proliferation. For an additional glomerular involvement is found no sure morphological correlate.

In contrast to the amphotericin-treated animals indicates the group of combination treated in total significantly reduced kidney damage; this phenomenon can be determined both by the intensity and the Demonstrate spectrum of pathological findings that Both are equally limited.

From the o. G. Observations can be concluded that in present model the nephrotoxic properties of Amphotericin B by the additional administration of pentoxifylline be significantly reduced.

Claims (7)

1. Use of a xanthine derivative for lowering the Nephrotoxicity of active pharmaceutical ingredients and Metabolic products. 2. Medicament, characterized in that it is at least a nephrotoxic component and at least one Contains xanthine derivative for the reduction of nephrotoxicity. 3. Medicament, characterized in that it Amphotericin B and at least one xanthine derivative for Reduction of nephrotoxicity contains. 4. Medicament according to claims 2 or 3, characterized characterized in that the xanthine derivative pentoxifylline and / or propentofylline. 5. Use of a xanthine derivative for the production of Medicinal products for the reduction of nephrotoxicity of a Drug ingredient. 6. Use of a xanthine derivative according to claim 1 or 5, characterized in that the xanthine derivative Pentoxifylline or propentofylline is. 7. Use for the preparation of medicaments according to Claim 2 or 3, characterized in that at least one nephrotoxic drug ingredient and at least one xanthine derivative optionally with Additives and / or auxiliaries in a suitable Dosage form is brought.