WO2007073855A1

WO2007073855A1 - Use of adenosine a1 receptor agonists for the protection of renal cells against toxic effects caused by aminoglycosides during treatment of infectious diseases

Info

Publication number: WO2007073855A1
Application number: PCT/EP2006/011895
Authority: WO
Inventors: Christoph Freiberg; Igor Knezevic; Thomas Krahn; Karl Ziegelbauer; Manuela Braun; Nicole Diedrichs
Original assignee: Bayer Healthcare Ag
Priority date: 2005-12-23
Filing date: 2006-12-11
Publication date: 2007-07-05

Abstract

The present invention refers to the use of adenosine Al receptor agonists for the protection of renal cells against toxic effects caused by aminoglycosides during treatment of infectious diseases in human.

Description

Use of adenosine Al receptor agonists for the protection of renal cells against toxic effects caused by aminoglycosides during treatment of infectious diseases

Aminoglycosides including amikacin, gentamicin, isepamicin, kanamycin, neomycin, netilmicin, sisomycin, streptomycin and tobramycin are very effective antibiotics well suited to the treatment of severe bacterial infections in human and animals [Gilbert, D.N. (1995) Aminoglycosides. In Principles and practice of infectious diseases. Mandell, G.L., Bennet, J.E. and Dolin, R. (eds). New York, USA: Churchill Livingstone, pp. 279-306]. The first main adverse effect of this compound class is reversible nephrotoxicity [Mingeot-Leclercq, M.P., and Tulkens, P.M. (1999) Aminoglycosides: nephrotoxicity. Antimicrob Agents Chemother 43: 1003-1012]. A small but sizable proportion of the administered aminoglycoside dose (approximately 5%) is retained in the proximal tubular cells after glomerular filtration. Aminoglycosides accumulated by these cells are mainly localized in endosomal and lysosomal vacuoles. Daily administration of the human therapeutic dose or low multiples of that (typically 10 to 20 mg/kg of body weight for a laboratory rat) lead to changes in lysosomes of the proximal tubular cells accompanied by the accumulation of polar lipids. Aminoglycoside therapy can lead to tubular dysfunction and alterations including release of lysosomal enzymes, decreased reabsorption of filtered proteins, wasting of kalium, magnesium, calcium, and glucose, phospholipiduria, and cast excretion. In humans, renal failure may be the consequence. In animals, tubular alterations have been associated with the development of focal necrosis and apoptoses in the tubular epithelium. High doses (40 mg/kg or more for gentamicin) are necessary in animals to rapidly induce extended cortical necrosis and overt renal dysfunction. Histopathological studies support the concept that tubular necrosis, apoptosis and related phenomena are the primary cause of functional toxicity. However, it has not yet been demonstrated by which molecular mechanism the aminoglycosides exert the toxicity. Therefore, it is difficult to estimate which molecular principle could help to protect cells from the toxic effects of aminoglycosides.

One way to protect the kidney from toxic effects of drugs is the reduction of drug accumulation in renal cells. Adenosine Al-receptors (AAlRs), which are present on proximal tubular cells and mediate the cytoprotective action of adenosine, play an important role in drug accumulation. It has been shown that AAlR antagonists lead to a reduced gentamicin accumulation into proximal renal tubules in rats [Effect of KW-3902, a selective adenosine Al -receptor antagonist, on accumulation of gentamicin in the proximal renal tubules in rats. Yakugaku Zasshi 120: 801-805]. Indeed, it has been discovered that AAlR antagonists are important in preventing aminoglycoside-induced nephrotoxicity [Yao, K., Kusaka, H., Sato, K., and Karasawa, A. (1994) Protective effects of KW- 3902, a novel adenosine Al -receptor antagonist, against gentamicin-induced acute renal failure in rats. Jpn J Pharmacol 65: 167-170; WO2004075856].

Surprisingly, the inventors discovered that also AAlR agonists reduce the nephrotoxic effects of aminoglycosides. AAlR agonists exhibit cytoprotective effects [Lee, H.T., and Emala, CW. (2000) Adenosine Protects Against Anoxic Injury and Oxidant Injury in Human Renal Cells. American Society of Anesthesiologists, Annual meeting abstracts] and are described for applications in the treatment of cardiovascular diseases (angina, infarct, atrial arrhythmias), of metabolic diseases (diabetes, dyslipidemia) as well as of pain, nausea and emesis.

Several agonists of the adenosine Al receptor have been described in the art. These include compounds described in company information material (PJ-875, http://www.inotekcoφ.com/news/aug_30_2005.htm, Inotek) and in published patent applications WO99/24449, WO99/24450, WO99/24451, WO99/24452, WO98/01459, EP0322242, GB2226027, EP222330, WO98/08855, WO94/0707, WO99/67262, EP0322242, WO97/43300, WO98/16539 (Novo Nordisk A/S); WO98/04126 (Rhone-Poulenc Rorer Pharmaceuticals Inc.); WO98/01459 (Novo Nordisk A/S); WO00/23447 (Aventis Pharmaceuticals); WO02/069982, WO02/067262 (GlaxoSmithkline); US20050009776 (Aderis Pharmaceuticals); US20040043960, US20030232783 (CV Therapeutics), and WO 03/053441 (Bayer).

Typical AAlR agonist compounds are DTI-0009 or selodenoson (US20050009776; Aderis Pharmaceuticals, Hopkinton, MA, USA), CVT-510 or tecadenoson (US20040043960, US20030232783, CV Therapeutics, Palo Alto, CA, USA), PJ-875 (http://www.inotekcorp.com/news/aug_30_2005.htm; Inotek Pharmaceuticals, Beverly, MA, USA), GW-493838 (WO02/067262, registry no. 253124^6-8; compound name 3,4-Furandiol, 2- [6-[(4-chloro-2-fluorophenyl)amino]-9H-purin-9-yl]-5-[5-(l,l-dimethylethyl)-l,3,4-oxadiazol-2- yl]tetrahydro-, (2R,3R,4S,5S)- (9CI)] invented at Glaxo SmithKline) and substituted 2-thio-3,5- dicyano-4-phenyl-6-aminopyridines (WO 03/053441). The AAlR agonists are mainly adenosine analogues, the only compound class being non-analogous to adenosine is represented by the substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines (WO 03/053441).

The compounds useful in the invention are preferably selective agonists at the AAlR. I. e. the affinity for the AAlR is at least 2 times, preferably 5 times and more preferably 10 times greater than for the other adenosine receptors A2a, A2b and A3. Agonist selectivity of compounds against other human adenosine receptors can be determined as described previously (WO02/069982). Subject of this invention is the use of combinations of AAlR agonists and aminoglycosides in order to protect renal cells against toxic effects caused by aminoglycosides during treatment of infectious diseases in human and animals.

Preferred AAlR agonistic compounds, which may be used in combination with aminoglycosides, are for example described in WO99/24449, WO99/24450, WO99/24451, WO99/24452,

WO98/01459, EP0322242, GB2226027, EP222330, WO98/08855, WO94/0707, WO99/67262,

EP0322242, WO97/43300, WO98/16539 (Novo Nordisk AJS); WO98/04126 (Rhone-Poulenc

Rorer Pharmaceuticals Inc.); WO98/01459 (Novo Nordisk AJS); WO00/23447 (Aventis

Pharmaceuticals); WO02/069982 (GlaxoSmithkline); US20050009776 (Aderis Pharmaceuticals); US20040043960, US20030232783 (CV Therapeutics) included herein by reference in their entirety.

Particularly preferred AAlR agonists, which may be used in combination with aminoglycosides, of this invention are GW-493838 (Glaxo Group Limited), selodenoson (DT-0009 from Aderis), Tecadenoson (CVT-510 from CV Therapeutics) and PJ-875 from Inotek Pharmaceuticals.

Additional particularly preferred AAlR agonists, which may be used in combination with aminoglycosides, of the invention are substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines.

Accordingly, substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines are represented by compounds of the formula (I)

in which

n represents a number 2, 3 or 4,

R¹ represents hydrogen or (Ci-C₄)-alkyl

and - -

R² represents pyridyl or thiazolyl which for its part may be substituted by (Ci-C₄)-alkyl, halogen, amino, dimethylamino, acetylamino, guanidino, pyridylamino, thienyl, furyl, imidazolyl, pyridyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, N-(Ci-C₄)- alkylpiperazinyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, optionally (C₁- C₄)-alkyl-substituted thiazolyl or phenyl which is optionally substituted up to three times by halogen, (Ci-C₄)-alkyl or (Ci-C₄)-alkoxy,

and their salts, hydrates, hydrates of the salts and solvates.

Depending on the substitution pattern, the compounds of the formula (I) can exist in stereoisomer^ forms which are either like image and mirror image (enantiomers) or not like image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. The racemic forms, like the diastereomers, can be separated in a known manner into the stereoisomerically uniform components. Likewise, the present invention also relates to the other tautomers of the compounds of the formula (I) and their salts.

Salts of the compounds of the formula (I) can be physiologically acceptable salts of the compounds according to the invention with mineral acids, carboxylic acids, or sulphonic acids. Particular preference is given, for example, to salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, trifluoroacetic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Salts which may be mentioned include salts with customary bases, such as, for example, alkali metal salts (for example sodium salts or potassium salts), alkaline earth metal salts (for example calcium salts or magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1 -ephenamine or methylpiperidine.

According to the invention, hydrates or solvates are those forms of the compounds of the formula (I) which, in solid or liquid state, form, by hydration with water or coordination with solvent molecules, a molecule compound or a complex. Examples of hydrates are sesquihydrates, mono- hydrates, dihydrates or trihydrates. Likewise, the hydrates or solvates of salts of the compounds according to the invention are also suitable.

Moreover, the invention also includes prodrugs of the compounds according to the invention. According to the invention, prodrugs are forms of compounds of the formula (I) which for their part may be biologically active or inactive, but which can be converted under physiological conditions (for example metabolically or solvolytically) into the corresponding biologically active form.

In the context of the present invention, the substituents have, unless defined otherwise, the following meanings:

Halogen generally represents fluorine, chlorine, bromine or iodine. Preference is given to fluorine, chlorine or bromine. Very particularly preferred are fluorine or chlorine.

(Ci-C₄)-Alkyl generally represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl and tert-butyl.

(Ci-C₄)-Alkoxy generally represents a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, sec-butoxy, isobutoxy and tert-butoxy.

Preference is given to compounds of the formula (I)

in which

n represents the number 2,

R¹ represents hydrogen, methyl or ethyl,

and

R² represents pyridyl or thiazolyl which for its part may be substituted by methyl, ethyl, fluorine, chlorine, amino, dimethylamino, acetylamino, guanidino, 2-pyridylamino, 4-pyridylamino, thienyl, pyridyl, morpholinyl, piperidinyl, optionally methyl-substituted thiazolyl or phenyl which is optionally substituted up to three times by chlorine or methoxy,

and their salts, hydrates, hydrates of the salts and solvates.

Particular preference is given to compounds of the formula (I) in which R¹ is hydrogen or methyl.

Particular preference is also given to compounds of the formula (I) in which

n represents the number 2,

R¹ represents hydrogen or methyl - - and

R² represents pyridyl or thiazolyl which for its part may be substituted by methyl, chlorine, amino, dimethylamino, acetylamino, guanidino, 2-pyridylamino, 4-pyridylamino, thienyl, pyridyl, morpholinyl, 2-methylthiazol-5-yl, phenyl, 4-chlorophenyl or 3,4,5- trimethoxyphenyl,

and their salts, hydrates, hydrates of the salts and solvates.

The present invention relates in particular to the following:

1. Pharmaceutical composition comprising at least one antimicrobial active aminoglycoside and at least one adenosine A 1 receptor agonist.

2. Pharmaceutical composition comprising at least one aminoglycoside in a therapeutically active dose for the treatment of infectious diseases and at least one adenosine A 1 receptor agonist in a therapeutically active dose for the protection against toxic effects caused by aminoglycosides.

3. Pharmaceutical composition according to counts 1 or 2, wherein the aminoglycoside is selected from the group consisting of amikacin, gentamicin, isepamicin, kanamycin, neomycin, netilmicin, sisomycin, streptomycin and tobramycin.

4. Pharmaceutical composition according to counts 1, 2, or 3, wherein the adenosine A 1 receptor agonist is selected from the group consisting of adenosine like adenosine A 1 receptor agonists.

5. Pharmaceutical composition according to counts 1, 2, or 3, wherein the adenosine A 1 receptor agonist is selected from the group consisting of non-adenosine like adenosine A 1 receptor agonists.

6. Pharmaceutical composition according to counts 1 - 5, wherein the adenosine A 1 receptor agonist is selected from the group consisting of PJ-875, DTI-0009 (selodenoson), CVT- 510 (tecadenoson), GW-493838, and substituted 2-thio-3,5-dicyano-4-phenyl-6-amino- pyridines.

7. Pharmaceutical composition according to count 6, wherein the adenosine A 1 receptor agonist is selected from the group consisting of compounds of the formula (T)

in which

n represents a number 2, 3 or 4,

R¹ represents hydrogen or (C]-C₄)-alkyl

and

R² represents pyridyl or thiazolyl which for its part may be substituted by (C_rC₄)- alkyl, halogen, amino, dimethylamino, acetylamino, guanidino, pyridylamino, thienyl, furyl, imidazolyl, pyridyl, moφholinyl, thiomoφholinyl, piperidinyl, piperazinyl, N-(Ci-C₄)-alkylpiperazinyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, optionally (Ci-C₄)-alkyl-substituted thiazolyl or phenyl which is optionally substituted up to three times by halogen, (C]-C₄)-alkyl or (C_r C₄)-alkoxy,

and their salts, hydrates, hydrates of the salts and solvates.

8. Pharmaceutical composition according to count 6, wherein the adenosine A 1 receptor agonist is a molecule selected from the group consisting of the molecules obtained by examples 1 - 27 and their salts, hydrates, hydrates of the salts and solvates.

9. Use of at least one adenosine A 1 receptor agonist in the preparation of a medicament useful for the protection against toxic effects of drugs.

10. Use according to count 9, wherein the toxic effects are caused by aminoglycosides.

11. Use according to count 9 or 10, wherein the toxic effects are nephrotoxic effects. - -

12. Use according to counts 9 -11, wherein the adenosine A 1 receptor agonist is selected from the group consisting of adenosine like adenosine A 1 receptor agonists.

13. Use according to counts 9 - 11, wherein the adenosine A 1 receptor agonist is selected from the group consisting of compounds of the formula (I)

in which

n represents a number 2, 3 or 4,

R¹ represents hydrogen or (Ci-C₄)-alkyl

and

R² represents pyridyl or thiazolyl which for its part may be substituted by (Ci-C₄)- alkyl, halogen, amino, dimethylamino, acetylamino, guanidino, pyridylamino, thienyl, furyl, imidazolyl, pyridyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, N-(Ci-C₄)-alkylpiperazinyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, optionally (C]-C₄)-alkyl-substituted thiazolyl or phenyl which is optionally substituted up to three times by halogen, (Ci-C₄)-alkyl or (Q-

C₄)-alkoxy,

and their salts, hydrates, hydrates of the salts and solvates.

14. Use according to count 13, wherein the adenosine A 1 receptor agonist is a molecule selected from the group consisting of the molecules obtained by examples 1 - 27, and their salts, hydrates, hydrates of the salts and solvates.

15. Use of counts 9 - 14, wherein the drug exhibiting toxic side effects is an antimicrobially active aminoglycoside. 16. Use of count 10 - 14, wherein the aminoglycoside is selected from the group consisting of amikacin, gentamicin, isepamicin, kanamycin, neomycin, netilmicin, sisomycin, streptomycin and tobramycin.

17. Use according to counts 9 - 16, wherein the adenosine A 1 receptor agonist and the drug exhibiting toxic side effects are administered sequentially or simultaneously to the patient.

18. Use according to count 17, wherein in the adenosine A 1 receptor agonist is administered before the drug exhibiting toxic side effects.

19. Use of a combination of at least one antimicrobial active aminoglycoside and at least one adenosine A 1 receptor agonist in the preparation of a medicament useful for the treatment of infectious diseases.

20. Use according to count 19, wherein the aminoglycoside is selected from the group consisting of amikacin, gentamicin, isepamicin, kanamycin, neomycin, netilmicin, sisomycin, streptomycin and tobramycin.

21. Use according to count 19 or 20, wherein wherein the adenosine A 1 receptor agonist is selected from the group consisting of adenosine like adenosine A 1 receptor agonists.

22. Use according to counts 19 or 20, wherein the adenosine A 1 receptor agonist is selected from the group consisting of non-adenosine like adenosine A 1 receptor agonists.

23. Use according to counts 19 - 22 wherein the adenosine A 1 receptor agonist is selected from the group consisting of compounds of the formula (T)

in which

n represents a number 2, 3 or 4, R¹ represents hydrogen or (Ci-C₄)-alkyl

and

R² represents pyridyl or thiazolyl which for its part may be substituted by (Ci-C₄)- alkyl, halogen, amino, dimethylamino, acetylamino, guanidino, pyridylamino, thienyl, furyl, imidazolyl, pyridyl, morpholinyl, thiomoφholinyl, piperidinyl, piperazinyl, N-(Ci-C₄)-alkylpiperazinyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, optionally (C_rC₄)-alkyl-substituted thiazolyl or phenyl which is optionally substituted up to three times by halogen, (Ci-C₄)-alkyl or (Ci- C₄)-alkoxy,

and their salts, hydrates, hydrates of the salts and solvates.

24. Use according to count 23, wherein the adenosine A 1 receptor agonist is a molecule selected from the group of molecules consisting of molecules as obtained by examples 1 - 27, and their salts, hydrates, hydrates of the salts and solvates.

25. Kit of parts, comprising at least one antimicrobial active aminoglycoside and at least one adenosine A 1 receptor agonist.

26. Kit of parts, comprising at least one aminoglycoside in a therapeutically active dose for the treatment of infectious diseases and at least one adenosine A 1 receptor agonist in a therapeutically active dose for the protection against toxic effects caused by aminoglycosides.

27. Kit of parts according to counts 25 or 26, wherein the aminoglycoside is selected from the group consisting of amikacin, gentamicin, isepamicin, kanamycin, neomycin, netilmicin, sisomycin, streptomycin and tobramycin.

28. Kit of parts according to counts 25 - 27, wherein the adenosine A 1 receptor agonist is selected from the group consisting of adenosine like adenosine A 1 receptor agonists.

29. Kit of parts according to counts 25 - 27, wherein the adenosine A 1 receptor agonist is selected from the group consisting of non-adenosine like adenosine A 1 receptor agonists.

30. Kit of parts according to counts 25 - 29, wherein the adenosine A 1 receptor agonist is selected from the group consisting of compounds of the formula (I)

in which

n represents a number 2, 3 or 4,

R¹ represents hydrogen or (C_rC₄)-alkyl

and

R² represents pyridyl or thiazolyl which for its part may be substituted by (Ci-C₄)- alkyl, halogen, amino, dimethylamino, acetylamino, guanidino, pyridylamino, thienyl, furyl, imidazolyl, pyridyl, moφholinyl, thiomorpholinyl, piperidinyl, piperazinyl, N-(Ci-C₄)-alkylpiperazinyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, optionally (Ci-C₄)-alkyl-substituted thiazolyl or phenyl which is optionally substituted up to three times by halogen, (Ci-C₄)-alkyl or (C_r C₄)-alkoxy,

and their salts, hydrates, hydrates of the salts and solvates.

31. Kit of parts according to count 30, wherein the adenosine A 1 receptor agonist is a molecule selected from the group consisting of molecules obtained by examples 1 - 27, and their salts, hydrates, hydrates of the salts and solvates.

32. Kit of parts according to counts 25 - 31, for the sequential administration of the active compounds.

33. Kit of parts according to counts 25 — 31, for the simultaneous administration of the active compounds.

34. Kit of parts according to counts 25 - 31, wherein the adenosine A 1 receptor agonist is administered first. 35. A method for the preparation of a kit of parts according to counts 25 - 34, comprising the steps of a) selecting at least one adenosine A 1 receptor agonist and at least one aminoglycoside, b) combining the selected compounds and thereby creating the kit of parts.

36. pharmaceutical combination comprising at least one antimicrobial active aminoglycoside and at least one adenosine A 1 receptor agonist.

37. A pharmaceutical combination comprising at least one aminoglycoside in a therapeutically active dose for the treatment of infectious diseases and at least one adenosine A 1 receptor agonist in a therapeutically active dose for the protection against toxic effects caused by aminoglycosides.

38. A pharmaceutical combination according to counts 36 or 37, wherein the aminoglycoside is selected from the group consisting of amikacin, gentamicin, isepamicin, kanamycin, neomycin, netilmicin, sisomycin, streptomycin and tobramycin.

39. A pharmaceutical combination according to counts 36 - 38, wherein the adenosine A 1 receptor agonist is selected from the group consisting of adenosine like adenosine A 1 receptor agonists.

40. A pharmaceutical combination according to counts 36 - 38, wherein the adenosine A 1 receptor agonist is selected from the group consisting of non-adenosine like adenosine A 1 receptor agonists.

41. A pharmaceutical combination combination according to counts 36 - 40, wherein the adenosine A 1 receptor agonist is selected from the group consisting of PJ-875, DTI-0009 (selodenoson), CVT-510 (tecadenoson), GW-493838, and substituted 2-thio-3,5-dicyano- 4-phenyl-6-aminopyridines.

42. A pharmaceutical combination according to count 36 - 41, wherein the adenosine A 1 receptor agonist is selected from the group consisting of compounds of the formula (I)

in which

n represents a number 2, 3 or 4,

R¹ represents hydrogen or (Ci-C₄)-alkyl

and

R² represents pyridyl or thiazolyl which for its part may be substituted by (Q -C₄)- alkyl, halogen, amino, dimethylamino, acetylamino, guanidino, pyridylamino, thienyl, furyl, imidazolyl, pyridyl, moφholinyl, thiomorpholinyl, piperidinyl, piperazinyl, N-(Ci -C₄)-alkylpiperazinyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, optionally (Ci-C₄)-alkyl-substituted thiazolyl or phenyl which is optionally substituted up to three times by halogen, (Ci-C₄)-alkyl or (Ci- C₄)-alkoxy,

and their salts, hydrates, hydrates of the salts and solvates.

43. A pharmaceutical combination according to count 42, wherein the adenosine A 1 receptor agonist is a molecule selected from the group consisting of molecules obtained by examples 1 - 27, and their salts, hydrates, hydrates of the salts and solvates.

44. Use of the compounds as defined in counts 36-43 for the preparation of a pharmaceutical combination for the treatment of nephrotoxic effects of aminoglycosides during antiinfective therapy.

Subject of this invention is the use of combinations of AAlR agonists and aminoglycosides in order to protect renal cells against toxic effects caused by aminoglycosides during treatment of infectious diseases in human and animals. Subject of this invention is the use of combinations of AAlR agonists and aminoglycosides in fixed combination or in variable combinations.

Preferred aminoglycosides, which may be used in combination with AAlR agonists, are amikacin, gentamicin, isepamicin, kanamycin, neomycin, netilmicin, sisomycin, streptomycin and tobramycin.

Preferred AAlR agonistic compounds, which may be used in combination with aminoglycosides, are for example described in WO99/24449, WO99/24450, WO99/24451, WO99/24452, WO98/01459, EP0322242, GB2226027, EP222330, WO98/08855, WO94/0707, WO99/67262, EP0322242, WO97/43300, WO98/16539 (Novo Nordisk A/S); WO98/04126 (Rhone-Poulenc Rorer Pharmaceuticals Inc.); WO98/01459 (Novo Nordisk A/S); WO00/23447 (Aventis Pharmaceuticals); WO02/069982 (GlaxoSmithkline); US20050009776 (Aderis Pharmaceuticals); US20040043960, US20030232783 (CV Therapeutics) included herein by reference in their entirety.

45. Compounds of the formula (I)

in which

n represents a number 2, 3 or 4,

R¹ represents hydrogen or (Ci-C₄)-alkyl and

R² represents pyridyl or thiazolyl which for its part may be substituted by (C_rC₄)- alkyl, halogen, amino, dimethylamino, acetylamino, guanidino, pyridylamino, thienyl, furyl, imidazolyl, pyridyl, morpholinyl, thiomoφholinyl, piperidinyl, piperazinyl, N-(Ci-C₄)-alkylpiperazinyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, optionally (Q-C^-alkyl-substituted thiazolyl or phenyl which is optionally substituted up to three times by halogen, (Ci-C₄)-alkyl or (C₁- C₄)-alkoxy,

and their salts, hydrates, hydrates of the salts and solvates.

46. Compounds of the formula (I) according to the count 45,

in which

n represents the number 2,

R¹ represents hydrogen, methyl or ethyl,

and

R² represents pyridyl or thiazolyl which for its part may be substituted by methyl, ethyl, fluorine, chlorine, amino, dimethylamino, acetylamino, guanidino, 2- pyridylamino, 4-pyridylamino, thienyl, pyridyl, morpholinyl, piperidinyl, optionally methyl-substituted thiazolyl or phenyl which is optionally substituted up to three times by chlorine or methoxy,

and their salts, hydrates, hydrates of the salts and solvates.

47. Compounds of the formula (I) according to count 45,

in which

n represents the number 2,

R¹ represents hydrogen or methyl

and

R² represents pyridyl or thiazolyl which for its part may be substituted by methyl, chlorine, amino, dimethylamino, acetylamino, guanidino, 2-pyridylamino, 4- pyridylamino, thienyl, pyridyl, moφholinyl, 2-methylthiazol-5-yl, phenyl, 4- chlorophenyl or 3,4,5-trimethoxyphenyl,

and their salts, hydrates, hydrates of the salts and solvates.

48. Process for preparing compounds of the formula (I) as defined in count 45, characterized in that compounds of the formula (IT)

in which

n and R¹ are as defined in count 45,

are reacted with compounds of the formula (ID)

R²-CH₂-X m, in which

R² is as defined in Claim 1 and X represents a leaving group.

The present invention also provides a process for preparing compounds of the formula (I), characterized in that

compounds of the formula (H)

in which

n and R¹ are as defined above,

are reacted with compounds of the formula (III)

R²-CH₂-X (HI),

in which

R² is as defined above and X represents a suitable leaving group, by way of example and by way of preference halogen, in particular chlorine, bromine or iodine, or represents mesylate, tosylate, triflate or 1-imidazolyl,

if appropriate in the presence of a base.

The process described above can be illustrated in an exemplary manner by the formula scheme below:

(II) (I) Suitable solvents for the process according to the invention are all organic solvents which are inert under the reaction conditions. These include alcohols, such as methanol, ethanol and isopropanol, ketones, such as acetone and methyl ethyl ketone, acyclic and cyclic ethers, such as diethyl ether and tetrahydrofuran, esters, such as ethyl acetate or butyl acetate, hydrocarbons, such as benzene, xylene, toluene, hexane or cyclohexane, chlorinated hydrocarbons, such as dichloromethane, chlorobenzene or dichloroethane, or other solvents, such as dimethylformamide, acetonitrile, pyridine or dimethyl sulphoxide (DMSO). Water, too, is a suitable solvent. Preference is given to dimethylformamide. It is also possible to use mixtures of the solvents mentioned above.

Suitable bases are the customary inorganic or organic bases. These preferably include alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate, or alkali metal bicarbonates, such as sodium bicarbonate or potassium bicarbonate, or alkali metal alkoxides, such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or amides, such as sodium amide, lithium bis(trimethylsilyl)amide or lithium diisopropylamide, or organometallic compounds, such as butyllithium or phenyllithium, or 1 ,8-diazabicyclo- [5,4,0]undec-7-ene (DBU) or l,5-diazabicyclo[4.3.0]non-5-ene (DBN), or else amines, such as triethylamine and pyridine. Preference is given to the alkali metal carbonates and alkali metal bicarbonates.

Here, the base can be employed in an amount of from 1 to 10 mol, preferably from 1 to 5 mol, in particular from 1 to 4 mol, based on 1 mol of the compounds of the formula (H).

The reaction generally takes place in a temperature range of from -78°C to +140⁰C, preferably in the range from -78°C to +40°C, in particular at room temperature.

The reaction can be carried out at atmospheric, elevated or reduced pressure (for example in the range from 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.

The compounds of the formula (II) are known per se to the person skilled in the art or can be prepared by customary methods known from the literature, for example by reacting the corresponding benzaldehydes with cyanothioacetamide. Reference may be made in particular to the following publications, the respective content of which is expressly incorporated herein by way of reference:

• Dyachenko et al, Russian Journal of Chemistry, Vol. 33, No. 7, 1997, pages 1014 to 1017 and Vol. 34, No. 4, 1998, pages 557 to 563; • Dyachenko et al., Chemistry of Heterocyclic Compounds, Vol. 34, No. 2, 1998, pages 188 to 194;

• Qintela et al., European Journal of Medicinal Chemistry, Vol. 33, 1998, pages 887 to 897;

• Kandeel et al, Zeitschift fur Naturforschung 42b, 107 to 111 ( 1987).

Thus, for example, it is also possible to prepare compounds of the formula (II) from compounds of the formula (FV) by reaction with an alkali metal sulphide. This preparation method can be illustrated, by way of example, by the following formula scheme:

The alkali metal sulphide used is preferably sodium sulphide in an amount of from 1 to 10 mol, preferably from 1 to 5 mol, in particular from 1 to 4 mol, based on 1 mol of the compounds of the formula (IV).

Suitable solvents are all organic solvents which are inert under the reaction conditions. These include, for example, N,N-dimethylformarnide, N-methylpyrrolidinone, pyridine and acetonitrile. Preference is given to N,N-dirnethylformamide. It is also possible to use mixtures of the solvents mentioned above.

The reaction is generally carried out in a temperature range of from +20⁰C to +140⁰C, preferably in the range from +20⁰C to +120⁰C, in particular at from +60⁰C to +100⁰C.

The compounds of the formula (YS) are either commercially available or known to the person skilled in the art or can be prepared by customary methods. The compounds of the formula (IV) are either commercially available or known to the person skilled in the art or can be prepared by customary methods. Reference may be made, in particular, to the following publications, the respective content of which is expressly incorporated herein by way of reference.

• Kambe et al., Synthesis, 531 to 533 (1981);

• Elnagdi et al., Z. Naturforsch. 47b, 572 to 578 (1991).

A pharmaceutical composition of the aminoglycoside-AAlR agonist combination is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EM™ (BASF, Parsippany, NJ.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a pharmaceutically acceptable polyol like glycerol, propylene glycol, liquid polyetheylene glycol, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a polypeptide or antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.

Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.

Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. 4,522,811.

It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

In general, the therapeutic doses of aminoglycosides for treatment of bacterial infections in human and animals are combined with doses of AAlR agonists ranging from 0.01 to 5000 mg per day, preferably from 0.5 to 1000 mg per day. The daily dose of the AAlR agonist is given together with the aminoglycoside as a fixed combination or as separate doses administered in appropriate intervals, for instance, twice, three times, four times or more times per day. The formulations can contain between 0.1 and 99% active ingredients, appropriately 25 - 95% in tablets and capsules und 1 - 50% in case of liquid formulations, i. e. the active ingredients should present in quantities sufficient for administration of therapeutic doses.

The active ingredients can be included in common formulations using inert, non-toxic, pharmaceutically appropriate carriers, excipients, solvents, vehicles, emulsifying and dispersing agents.

Examplary auxiliary substances are: water, non-toxic organis solvents such as paraffϊnes, crop oils (e.g. sesame oil), alcohols (e. g. ethanol, glycerol), glycoles (e. g. polyethylene glycole), solid carriers such as natural or synthetic stone powder (E. g. talcum, silicates), sugars (e. g. lactose), emulsifying and dispersing agents (e. g. polyvinyl pyrrolidone) and other agents such as magnesium sulfate.

In case of the oral administration tablets can contain additives such as sodium citrate together with aggregates such as starch, gelatine. Aqueous preparations for the oral application can include flavour or colouring additives.

The pharmaceutical combinations of the present invention can be administered at any time and in any effective form. For example, the compounds can be administered simultaneously, e.g., as a single composition or dosage unit (e.g., a pill or liquid containing both compositions), or they can be administered as separate compositions, but at the same time (e.g., where one drug is administered intravenously and the other is administered orally or intramuscularly). The drugs can also be administered sequentially at different times. Agents can be formulated conventionally to achieve the desired rates of release over extended period of times, e.g., 12-hours, 24-hours. This can be achieved by using agents and/or their derivatives which have suitable metabolic half-lives, and/or by using controlled release formulations.

The drug combinations can be synergistic, e.g., where the joint action of the drugs is such that the combined effect is greater than the algebraic sum of their individual effects. Thus, reduced amounts of the drugs can be administered, e.g., reducing toxicity or other deleterious or unwanted effects, and/or using the same amounts as used when the agents are administered alone, but achieving greater efficacy. The reduced amounts of the drugs can be lower then used in a standard therapy wherein e.g. the single drug is administered. Experimental part:

The protective effect of AAlR agonists against aminoglycoside-caused toxicity can be tested in in vitro cell culture models.

Dulbecco's Minimum Essential Medium supplemented with 1% Penicillin/Streptomycin, 1% L- glutamine and 10% fetal calf serum (Invitrogen/Gibco) is inoculated with rat kidney epithelial-like cells (type NRK-52e; inoculum size 5x10⁴ cells per ml). After a 1-hour exposure of the cells with and without different concentrations of AAlR agonists at 37 ⁰C in ambient air with 5% CO₂ different amounts of an aminoglycoside is added. The cells grow for three days. Their viability is monitored at the final day by a 2-hours incubation with EZ4U, a tetrazolium compound which is metabolized by living cells to a dye quantifiable by optical density measurement. The ingredients and the protocol for eukaryotic viability assays with the EZ4U readout in 96-well microtitre plate format is available from Biomedica (Vienna, Austria).

The in vitro assays measuring the viability of cells can also be performed with other kidney cell lines. Preferred cell lines are freshly isolated or primary cultures from proximal tubules of the kidney from rat or other animals. Other preferred cell lines include permanent kidney cells, such as the MDCK (canine kidney) epithelial cell line, LLC-PKl (porcine kidney) proximal tubulus cells or human kidney cells (HK-2). Cell lines more distantly related to kidney cells are also suitable for testing such as human embryonal kidney cells or the epithelial Chinese hamster ovary (CHO) cell line. The latter cells are appropriate as far as they are genetically modified, in order to express the AAlR.

Besides EZ4U other dyes are appropriate for the measurement of cell viability. The physiological status of the cells exposed to aminoglycosides and AAlR agonists can be monitored by additional readouts, for instance: (1) release of lactate dehydrogenase [cytotoxicity detection kit (LDH), Roche Applied Science, catalogue number 11644793001 (1644793)]; (2) specific, quantitative detection of caspase 3 activity in cellular lysates for the detection of early apoptotic processes (Caspase 3 Activity Assay; Roche Applied Science, catalogue number 12012952001); (3) mitochondrial damage (ApoSENSORTM ADP/ATP Ratio Assay; Biovision, Mountain View, California, USA, catalog number K255-200); (4) oxidative stress determination (ApoGSHTM Glutathione Colorimetric Detection Kit, Biovision, catalogue number K261-100); (5) measurement of lipid peroxidation (Lipid Peroxidation Assay Kit, Calbiochem, San Diego, CA, USA, catalogue number 437634-100T); (6) determination of the degree of phospholipidosis by measurement of intact phospholipids according to previously reported protocols [Aubert-Tulkens, G., Van Hoof, F., and Tulkens, P. (1979) Gentamicin-induced lysosomal phospholipidosis in cultured rat fibroblasts. Quantitative ultrastructural and biochemical study. Lab Invest 40: 481-491]; (7) in situ detection of DNA fragmentation as described previously [El Mouedden, M., Laurent, G., Mingeot- Leclercq, M.P., and Tulkens, P.M. (2000) Gentamicin-induced apoptosis in renal cell lines and embryonic rat fibroblasts. Toxicol Sci 56: 229-239]; (8) assessment of mitochondrial membrane integrity and of lysosomal membrane integrity as described recently [Servais, H., Van Der Smissen, P., Thirion, G., Van der Essen, G., Van Bambeke, F., Tulkens, P.M., and Mingeot- Leclercq, M.P. (2005) Gentamicin-induced apoptosis in LLC-PKl cells: involvement of lysosomes and mitochondria. Toxicol Appl Pharmacol 206: 321-333]; (9) gene expression status: The expression levels of most of the rat genes can be monitored using DNA microarray technology as previously described [Steiner, G., Suter, L., Boess, F., Gasser, R., de Vera, M.C., Albertini, S., and Ruepp, S. (2004) Discriminating different classes of toxicants by transcript profiling. Environ Health Perspect 112: 1236-1248].

The protective effect of AAlR agonists against aminoglycoside-caused toxicity can be tested in animal models, preferably in rats.

Animals are treated with gentamicin at doses of 10 and 40 mg/kg/12 h during 4 and 10 days combined with either saline or AAlR agonists at various doses [for instance, at 1, 3 and 10 mg/kg of N6-cyclopentyladenosine (CPA, Sigma Aldrich)]. Animal groups other than those employed for urine analysis are killed 15 to 18 h after the last injection of gentamicin (days 5 and 11). Animal blood is collected from the stump for the assay of serum creatinine and blood urea nitrogen (BUN), two markers of renal function. Creatinine (procedure number 555) and BUN (procedure number 535) kits were obtained from Sigma Diagnostics. Both kidneys are rapidly removed and bisected. The renal cortex of the kidneys is separated by sharp dissection and immediately immersed in drops of ice-cold electron microscopy fixative (2% glutaraldehyde, 4% sucrose, 0.1 M phosphate buffer, pH 7.4), minced to obtain small (approximately 1 mm3) tissue blocks, and kept overnight at 4°C in the same fixative. Histopathological abnormalities such as the size of lysosomes in proximal tubular cells are estimated by electron microscopy (computer-assisted morphometry). Urine analysis is performed separately for experimental animals. Urine is collected over a period of 24 h (under mineral oil to prevent evaporation) on day 0 of treatment and 2, 4, and 8 days after starting drug administration. Urine is centrifuged (1,430 3 g) for 15 min, and enzymatic activities of NAG, b-Gal, and g-GT are assayed in supematants on the day of urine collection. Enzymuria related to drug administration are documented by the assays of N-acetylglucosaminidase (NAG), b- galactosidase (b-Gal), and g-glutamyl-transpeptidase (g-GT) activities according to established procedures [Maruhn, D. (1976) Rapid colorimetric assay of beta-galactosidase and N-acetyl-beta- glucosaminidase in human urine. Clin Chim Acta 73: 453-461; Persijn, J.P., and van der SHk, W. (1976) A new method for the determination of gamma-glutamyltransferase in serum. J CHn Chem Clin Biochem 14: 421-427]. (Maruhn, 1976; Persijn and van der SHk, 1976) - -

The combination therapy of gentamicin with CPA leads to a reduction of histopathological abnormalities including reduction of the size of lysosomes) and decrease of renal enzymes measurable in the urine. The gentamicin-induced elevations of serum creatinine and BUN levels are diminished by CPA.

Preparation examples for AAlR agonists being substituted 2-thio-3,5-dicyano-4-phenyl-6- aminopyridines:

Example 1

2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(3-pyridinylmethyl)sulphanyl]pyridine-3,5- dicarbonitrile

Step 1:

4-(2-Methoxyethoxy)benzaldehyde

146.5 g (1.2 mol) of 4-hydroxybenzaldehyde are dissolved in DMF, and 2O g (0.12 mol) of potassium iodide, 134.6 g (1.2 mol) of potassium tert-butoxide and 170.2 g (1.8 mol) of 2- chloroethyl methyl ether are added. The reaction mixture is stirred at 80⁰C for 16 h. For work-up, the reaction mixture is concentrated under reduced pressure. The residue is taken up in 1 1 of ethyl acetate and extracted with 0.5 1 of IN aqueous sodium hydroxide solution. The ethyl acetate phase is dried using magnesium sulphate and concentrated under reduced pressure. The residue obtained after concentration is distilled under high vacuum (b.p. = 100⁰C at 0.45 mbar). This gives 184.2 g (85% of theory) of product.

MS (ESIpos): m/z = 181 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃): δ = 3.5 (s, 3H); 3.8 (tr, 2H); 4.2 (tr, 2H); 7.0 (d, 2H); 7.8 (d, IH); 9.9 (s, IH). Step 2:

2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanylpyridine-3,5-dicarbonitrile

18 g (100 mmol) of 4-(2-methoxyethoxy)benzaldehyde, 1O g (200 mmol) of cyanothioacetamide and 20.2 g (200 mmol) of N-methylmorpholine in 100 ml of ethanol are heated under reflux for 3 h. After cooling, the precipitated crystals are filtered off with suction, washed with a little ethanol and dried under reduced pressure. This gives 12 g (31% of theory) of product which contains 0.5 mol equivalent of N-methylmorpholine.

MS (ESIpos): m/z = 327 (M+H)⁺

¹H-NMR (300 MHz, DMSO-dβ): δ = 2.8 (tr, 4H, N-methylmorpholine signal); 3.3 (s, 3H); 3.7 (m, 2H + 4H N-methylmorpholine signal); 4.2 (tr, 2H); 7.1 (d, 2H); 7.4 (d, 2H); 7.6 (s, broad, 2H).

- -

Step 3:

4.28 g (11.36 mmol; the starting material contained 0.5 mol equivalent of N-methylmorpholine; accordingly, the purity was 86.6%) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6- sulphanylpyridine-3,5-carbonitrile are dissolved in 40 ml of DMF p.a. 3.34 g (39.75 mmol) of sodium bicarbonate and 2.48 g (15.1 mmol) of 3-picolyl chloride hydrochloride are then added. The suspension is stirred at RT overnight, 40 ml of ethanol are added and the mixture is then heated to about 40⁰C. 19 ml of water are then added dropwise. The precipitate is filtered off with suction and dried under reduced pressure. This gives 3.70 g (78% of theory) of product.

MS (ESIpos): m/z = 418 (M+H)⁺

¹H=NMR (300 MHz, DMSO-(I₆): δ = 3.3 (s, 3H); 3.7 (tr, 2H); 4.2 (tr, 2H); 4.5 (s, 2H); 7.1 (d, 2H); 7.35 (dd, IH); 7.45 (d, 2H); 7.9 (d tr, IH); 8.1 (s, broad, 2H); 8.45 (dd, IH); 8.75 (d, IH).

Example2

2-Amino-6-[(2-chloro-l,3-thiazol-4-yl)methylsulphanyl]-[4-(2-methoxyethoxy)phenyl]pyridine- 3,5-dicarbonitrile

100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanylpyridine-3,5- dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 77.2 mg (0.46 mmol) of 4-chloromethyl-2-chloro-l,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40⁰C under reduced pressure. This gives 123 mg (88% of theory) of product.

MS (ESIpos): m/z = 458 (M+H)⁺

¹H=NMR (300 MHz, DMSO-dβ): δ = 3.3 (s, 3H); 3.7 (tr, 2H); 4.2 (tr, 2H); 4.5 (s, 2H); 7.1 (d, 2H); 7.45 (d, 2H); 7.8 (s, IH); 8.05 (s, broad, 2H).

Example 3

2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-phenyl-l,3-thiazol-4-yl)methylsulphanyl]pyridine- 3,5-dicarbonitrile

100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanylpyridine-3,5- dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 96.4 mg (0.46 mmol) of 4-chloromethyl-2-phenyl-l,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40⁰C under reduced pressure. This gives 149 mg (97% of theory) of product.

MS (ESIpos): m/z = 500 (M+H)⁺

¹H=NMR (300 MHz, DMSOd₆): δ = 3.3 (s, 3H); 3.7 (tr, 2H); 4.2 (tr, 2H); 4.5 (s, 2H); 7.1 (d, 2H); 7.5 (m, 5H); 7.8 (s, IH); 7.9 (m, 2H); 8.05 (s, broad, 2H).

Example 4

2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-thiophen-2-yl)-l,3-thiazol-4-yl)- methylsulphanyl]pyridine-3,5-dicarbonitrile

100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanylpyridine-3,5- dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 96.4 mg (0.46 mmol) of 4-chloromethyl-2-(thiophen-2-yl)-l,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40⁰C under reduced pressure. This gives 146 mg (84% of theory) of product.

MS (ESIpos): m/z = 506 (M+H)⁺

¹H=NMR (300 MHz, DMSO-dβ): δ = 3.3 (s, 3H); 3.7 (tr, 2H); 4.2 (tr, 2H); 4.6 (s, 2H); 7.15 (m, 3H); 7.5 (d, 2H); 7.65 (d, IH); 7.75 (d, IH); 7.8 (s, IH); 8.1 (s, broad, 2H).

- -

Example 5

2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-(thiophen-3-yl)-l,3-thiazol-4-yl)- methylsulphanyl]pyridine-3,5-dicarbonitrile

100 mg (0.31 mmol) of 2-arnino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanylpyridine-3,5- dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 96.4 mg (0.46 mmol) of 4-chloromethyl-2-(thiophen-3-yl)-l,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40⁰C under reduced pressure. This gives 141 mg (82% of theory) of product.

MS (ESIpos): m/z = 506 (M+H)⁺

¹H=NMR (300 MHz, DMSOd₆): δ = 3.3 (s, 3H); 3.7 (tr, 2H); 4.2 (tr, 2H); 4.6 (s, 2H); 7.15 (d, 2H); 7.5 (d, 2H); 7.55 (d, IH); 7.7 (dd, IH); 7.8 (s, IH); 8.1 (s, broad, 2H); 8.15 (d, IH).

Example 6

2-Amino-6-({[2-(4-chlorophenyl)-l,3-thiazol-4-yl]methyl}sulphanyl)-4-[4-(2- hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile

Step 1:

2-Amino-4-[4-(2-hydroxyethoxy)phenyl]-6-sulphanylpyridine-3,5-dicarbonitrile

12.46 g (75 mmol) of 4-(2-hydroxyethoxy)benzaldehyde, 15.02 g (150 mmol) of cyanothioacetamide and 15.15 g (150 mmol) of N-methylmorpholine are initially charged in 75 ml of ethanol and heated under reflux for 3 h. After cooling, the reaction solution is concentrated under reduced pressure. The residue is dissolved in IN aqueous sodium hydroxide solution and washed twice with ethyl acetate. The aqueous sodium hydroxide phase is acidified with IN hydrochloric acid and the precipitated crystals are filtered off with suction and dried under reduced pressure at 45⁰C. This gives 12.05 g (51% of theory) of product.

MS (ESIpos): m/z = 313 (M+H)⁺, 330 (M+NH^

¹H=NMR (300 MHz, DMSO-d*): δ = 3.7 (t, 2H); 4.1 (t, 2H); 7.1 (d, 2H); 7.4 (d, 2H); 8.0 (br s, 2H).

Step 2:

2-Amino-6-( { [2-(4-chlorophenyl)- 1 ,3-thiazol-4-yl]methyl } sulphanyl)-4-[4-(2- hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile

6.91 g (22.12 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-sulphanylpyridine-3,5- dicarbonitrile are dissolved in 150 ml of DMF. 7.44 g (66.35 mmol) of 1,8- diazabicyclo[5.4.0]undec-7-ene and 10.8 g (44.24 mmol) of 4-chloromethyl-2-(4-chlorophenyl)- 1,3-thiazole are then added. The suspension is stirred at RT overnight, 50 g of silica gel are added and the mixture is concentrated under reduced pressure. The substance mixture on the silica gel is purified by chromatography on silica gel (mobile phase: toluene to toluene/ethyl acetate, 1 :1 mixture). This gives 5.5 g (47% of theory) of product.

MS (ESIpos): m/z = 521 (M+H)⁺

¹H=NMR (300 MHz, DMSO-de): δ =3.7 (dt, 2H); 4.1 (t, 2H); 4.6 (s, 2H); 4.9 (t, IH); 7.1 (d, 2H); 7.4 (d, 2H); 7.5 (d, 2H); 7.9 (m, 3H); 8.1 (br s, 2H).

- -

Example 7

2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-pyridinylmethyl)sulphanyl]pyridine-3,5- dicarbonitrile

100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanylpyridine-3,5- dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 75.4 mg (0.46 mmol) of 2-picolyl chloride hydrochloride are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40⁰C under reduced pressure. This gives 104 mg (81% of theory) of product.

MS (ESIpos): m/z = 418 (M+H)⁺

¹H=NMR (300 MHz, DMSO-d₆): δ =3.3 (s, 3H); 3.7 (tr, 2H); 4.2 (tr, 2H); 4.6 (s, 2H); 7.1 (d, 2H); 7.4 (dd, IH); 7.45 (d, 2H); 7.65 (d, IH); 7.75 (tr, IH); 8.0 (s, broad, 2H); 8.5 (d, IH).

Example 8

2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-methyl-l,3-thiazol-4-yl)methylsulphanyl]pyridine- 3,5-dicarbonitrile

100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanylpyridine-3,5- dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 90.5 mg (0.61 mmol) of 4-chloromethyl-2-methyl-l,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction and dried at 40⁰C under reduced pressure. This gives 88.8 mg (66.2% of theory) of product.

MS (ESIpos): m/z = 438 (M+H)⁺

- -

Example 9

2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-amino-l,3-thiazol-4-yl)methylsulphanyl]pyridine- 3 ,5 -dicarbonitrile

100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanylpyridine-3,5- dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 68.3 mg (0.46 mmol) of 4-chloromethyl-2-amino-l,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40⁰C under reduced pressure. This gives 115.9 mg (86.2% of theory) of product.

MS (ESIpos): m/z = 439 (M+H)⁺

Example 10

2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-(2-pyridyl)-l,3-thiazol-4-yl)methyl- sulphanyl]pyridine-3,5-dicarbonitrile

50 mg (0.15 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanylpyridine-3,5- dicarbonitrile are dissolved in 1 ml of DMF. 51.5 mg (0.61 mmol) of sodium bicarbonate and 58.6 mg (0.23 mmol) of 4-chloromethyl-2-(2-pyridyl)-l,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40⁰C under reduced pressure. This gives 67.4 mg (87.9% of theory) of product.

MS (ESIpos): m/z = 501 (M+H)⁺

Example 11

2-Amino-4-[4-(2-hydroxyethoxy)phenyl]-6-{[(2-methyl-l,3-thiazol-4-yl)methyl]- sulphanyl}pyridine-3,5-dicarbonitrile

31.2 mg (0.1 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-sulphanylpyridine-3,5- dicarbonitrile are dissolved in 0.3 ml of DMF. 33.6 mg (0.4 mmol) of sodium bicarbonate and 26.7 mg (0.15 mmol) of 4-methyl-2-chloro-l,3-thiazole hydrochloride are then added. The suspension is shaken at RT overnight, filtered, and purified by preparative HPLC [column: Macherey-Nagel VP 50/21 Nucleosil 100-5 C18 Nautilus, 20 x 50 mm; flow rate: 25 ml/min; gradient (A = acetonitrile, B = water + 0.3% trifluoroacetic acid): 0 min 10% A; 2.0 min 10% A; 6.0 min 90% A; 7.0 min 90% A; 7.1 min 10% A; 8.0 min 10% A; detection: 220 nm]. Concentration of the appropriate fraction gives 20.2 mg (47.7% of theory) of product.

MS (ESIpos): m/z = 424 (M+H)⁺

Example 12

2-Amino-6- { [(2 -amino- 1 ,3-thiazol-4-yl)methyl]sulphanyl } -4-[4-(2-hydroxyethoxy)- phenyl]pyridine-3 ,5 -dicarbonitrile

31.2 mg (0.1 mmol) of 2-ammo-4-[4-(2-hydroxyethoxy)phenyl]-6-sulphanylpyridine-3,5- dicarbonitrile are dissolved in 0.3 ml of DMF. 33.6 mg (0.4 mmol) of sodium bicarbonate and 22.3 mg (0.15 mmol) of 4-amino-2-chloro-l,3-thiazole are then added. The suspension is shaken at RT overnight, filtered, and purified by preparative HPLC [column: Macherey-Nagel VP 50/21 Nucleosil 100-5 Cl 8 Nautilus, 20 x 50 mm; flow rate: 25 ml/min; gradient (A = acetonitrile, B = water + 0.3% trifluoroacetic acid): 0 min 10% A; 2.0 min 10% A; 6.0 min 90% A; 7.0 min 90% A; 7.1 min 10% A; 8.0 min 10% A; detection: 220 run]. Concentration of the appropriate fraction gives 35.7 mg (84.1% of theory) of product.

MS (ESIpos): m/z = 425 (M+H)⁺

Example 13

2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-({[2-(4-moφholinyl)-l,3-thiazol-4-yl]- methyl}sulphanyl)pyridine-3,5-dicarbonitrile

Step 1:

4-[4-(Chloromethyl)-l ,3-thiazol-2-yl]morpholine

11.51 g (78.76 mmol) of 4-moφholinecarbothioamide and 10.00 g (78.76 mmol) of dichloroacetone in 100 ml of ethanol are heated under reflux for one hour. The colourless solid which precipitates from the pink solution is, after cooling, filtered off with suction and washed twice with ethanol. This gives 12.96 g (75% of theory) of product.

MS (ESIpos): m/z = 219 (M+H)⁺

Step 2:

2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-( { [2-(4-morpholinyl)- 1 ,3 -thiazol-4-yl]- methyl}sulphanyl)pyridine-3,5-dicarbonitrile

2 g (6.13 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanylpyridine-3,5-dicarbonitrile and 2.68 g (12.26 mmol) of 4-(4-(chloromethyl)-l,3-thiazol-2-yl]morpholine are dissolved in dry DMF (50 ml), and 1.83 ml (12.26 mmol) of DBU are added. After 3 hours of stirring at RT, the solvent is removed using a rotary evaporator and the residue is purified by preparative HPLC (column: Kromasil 100 Cl 8 250 x 20 mm, 10 μm; acetonitrile/water gradient: 3 minutes of 10% acetonitrile which is then, over a period of 30 minutes, increased to 80% acetonitrile; flow rate: 25 ml/min). This gives 1.70 g (55% of theory) of product.

MS (ESIpos): m/z = 509 (M+H)⁺

¹H-NMR (300 MHz, DMSOd₆): δ = 3.3 (m, 7H); 3.7 (m, 6H); 4.2 (tr, 2H); 4.4 (s, 2H); 6.95 (s, IH); 7.15 (d, 2H); 7.45 (d, 2H); 8.0 (s, broad, 2H).

The examples listed in Table 3 were prepared analogously to Example 13. The chloromethylthiazoles used as starting materials are either commercially available or can be prepared analogously to step 1 in Example 13.

Table 3:

Claims

2. Pharmaceutical composition according to claim 1, wherein the aminoglycoside is selected from the group consisting of amikacin, gentamicin, isepamicin, kanamycin, neomycin, netilmicin, sisomycin, streptomycin and tobramycin.

3. Pharmaceutical composition according to claims 1 or 2, wherein the adenosine A 1 receptor agonist is selected from the group consisting of PJ-875, DTI-0009 (selodenoson), CVT-510 (tecadenoson), GW-493838, and substituted 2-thio-3,5-dicyano-4-phenyl-6- aminopyridines.

4. Pharmaceutical composition according to claim 3, wherein the adenosine A 1 receptor agonist is selected from the group consisting of compounds of the formula (I)

in which

n represents a number 2, 3 or 4,

R¹ represents hydrogen or (Ci-C₄)-alkyl

and

R² represents pyridyl or thiazolyl which for its part may be substituted by (Ci-C₄)- alkyl, halogen, amino, dimethylamino, acetylamino, guanidino, pyridylamino, thienyl, furyl, imidazolyl, pyridyl, morpholinyl, thiomorpholinyl, piperidinyl, pipera∑άnyl, N-(Ci -C₄)-alkylpiperazinyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, optionally (Ci-C₄)-alkyl-substituted thiazolyl or phenyl which is optionally substituted up to three times by halogen, (d-C₄)-alkyl or (Ci- C₄)-alkoxy,

and their salts, hydrates, hydrates of the salts and solvates.

5. Use of at least one adenosine A 1 receptor agonist in the preparation of a medicament useful for the protection against toxic effects of drugs.

6. Use according to claim 5, wherein the toxic effects are caused by aminoglycosides.

7. Use according to claim 5 or 6, wherein the toxic effects are nephrotoxic effects.

8. Use according to claims 5 - 7, wherein the adenosine A 1 receptor agonist is selected from the group consisting of compounds of the formula (I)

in which

n represents a number 2, 3 or 4,

R¹ represents hydrogen or (Ci-C₄)-alkyl

and

R² represents pyridyl or thiazolyl which for its part may be substituted by (Ci-C₄)- alkyl, halogen, amino, dimethylamino, acetylamino, guanidino, pyridylamino, thienyl, furyl, imidazolyl, pyridyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, N-(Ci-C₄)-alkylpiperazinyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, optionally (Ci-C₄)-alkyl-substituted thiazolyl or phenyl which is optionally substituted up to three times by halogen, (Ci-C₄)-alkyl or (C₁-

C₄)-alkoxy, and their salts, hydrates, hydrates of the salts and solvates.

9. Use according to claims 5 -8, wherein the drug exhibiting toxic side effects is an aminoglycoside which is selected from the group consisting of amikacin, gentamicin, isepamicin, kanamycin, neomycin, netilmicin, sisomycin, streptomycin and tobramycin.

10. Use according to claims 5 - 9, wherein the adenosine A 1 receptor agonist and the drug exhibiting toxic side effects are administered sequentially or simultaneously to the patient.

11. Use according to claims 5 - 10, wherein in the adenosine A 1 receptor agonist is administered before the drug exhibiting toxic side effects.

12. Use of a combination of at least one antimicrobial active aminoglycoside and at least one adenosine A 1 receptor agonist in the preparation of a medicament useful for the treatment of infectious diseases.

13. Use according to claim 12, wherein the aminoglycoside is selected from the group consisting of amikacin, gentamicin, isepamicin, kanamycin, neomycin, netilmicin, sisomycin, streptomycin and tobramycin.

14. Use according to claim 13, wherein the adenosine A 1 receptor agonist is selected from the group consisting of compounds of the formula (I)

in which

n represents a number 2, 3 or 4,

R¹ represents hydrogen or (Q-G^-alkyl

and R² represents pyridyl or thiazolyl which for its part may be substituted by (Ci-C₄)- alkyl, halogen, amino, dimethylamino, acetylamino, guanidino, pyridylamino, thienyl, furyl, imidazolyl, pyridyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, N-(Ci -C₄)-alkylpiperazinyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, optionally (Ci-C₄)-alkyl-substituted thiazolyl or phenyl which is optionally substituted up to three times by halogen, (Ci-C₄)-alkyl or (Ci- C₄)-alkoxy,

and their salts, hydrates, hydrates of the salts and solvates.

15. Kit of parts, comprising at least one antimicrobial active aminoglycoside and at least one adenosine A 1 receptor agonist.

16. Kit of parts, comprising at least one aminoglycoside in a therapeutically active dose for the treatment of infectious diseases and at least one adenosine A 1 receptor agonist in a therapeutically active dose for the protection against toxic effects caused by aminoglycosides.

17. Kit of parts according to claims 15 or 16, wherein the aminoglycoside is selected from the group consisting of amikacin, gentamicin, isepamicin, kanamycin, neomycin, netilmicin, sisomycin, streptomycin and tobramycin.

18. Kit of parts according to claims 15 - 17, wherein the adenosine A 1 receptor agonist is selected from the group consisting of compounds of the formula (I)

in which

n represents a number 2, 3 or 4,

R¹ represents hydrogen or (Ci-C₄)-alkyl and

R² represents pyridyl or thiazolyl which for its part may be substituted by (Ci-C₄)- alkyl, halogen, amino, dimethylamino, acetylamino, guanidino, pyridylamino, thienyl, furyl, imidazolyl, pyridyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, N-(Ci -C₄)-alkylpiperazinyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, optionally (Ci-C₄)-alkyl-substituted thiazolyl or phenyl which is optionally substituted up to three times by halogen, (Ci-C₄)-alkyl or (Q - C₄)-alkoxy,

and their salts, hydrates, hydrates of the salts and solvates.

19. Kit of parts according to claims 15 - 18, for the sequential administration of the active compounds.

20. Kit of parts according to claims 15 - 18, for the simultaneous administration of the active compounds.

21. A method for the preparation of a kit of parts according to claims 15 - 20, comprising the steps of a) selecting at least one adenosine A 1 receptor agonist and at least one aminoglycoside, b) combining the selected compounds and thereby creating the kit of parts.

22. A pharmaceutical combination comprising at least one antimicrobial active aminoglycoside and at least one adenosine A 1 receptor agonist.

23. A pharmaceutical combination according to claim 22, wherein the aminoglycoside is selected from the group consisting of amikacin, gentamicin, isepamicin, kanamycin, neomycin, netilmicin, sisomycin, streptomycin and tobramycin.

24. A pharmaceutical combination combination according to claims 22 or 23, wherein the adenosine A 1 receptor agonist is selected from the group consisting of PJ-875, DTI-0009 (selodenoson), CVT-510 (tecadenoson), GW-493838, and substituted 2-thio-3,5-dicyano-

4-phenyl-6-aminopyridines.

25. A pharmaceutical combination according to claim 24, wherein the adenosine A 1 receptor agonist is selected from the group consisting of compounds of the formula (I)

in which

n represents a number 2, 3 or 4,

R¹ represents hydrogen or (Ci-C₄)-alkyl

and

R² represents pyridyl or thiazolyl which for its part may be substituted by (C_rC₄)- alkyl, halogen, amino, dimethylamino, acetylamino, guanidino, pyridylamino, thienyl, furyl, imidazolyl, pyridyl, moφholinyl, thiomorpholinyl, piperidinyl, piperazinyl, N-(Ci-C₄)-alkylpiperazinyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, optionally (C_rC₄)-alkyl-substituted thiazolyl or phenyl which is optionally substituted up to three times by halogen, (C_rC₄)-alkyl or (Q- C₄)-alkoxy,

and their salts, hydrates, hydrates of the salts and solvates.

26. Use of the compounds as defined in claims 22-25 for the preparation of a pharmaceutical combination for the treatment of nephrotoxic effects of aminoglycosides during antiinfective therapy.