AU729218B2 - Use of cyanines, isocyanines and pseudoisocyanines as diuretics - Google Patents

Description

ii Description The invention concerns the use of cyanines, isocyanines and pseudocyanines to promote diuresis.

Cyanine-, isocyanine- and pseudocyanine-compounds are compounds known for a long time from the class of polymethine dyes.

DE 41 37 009 describes on the first occasion a pharmacological effect of these compounds, in fact their retarding effect on the biological transport systems for organic cations, in particular on the transport of noradrenaline. The effect on the transport of noradrenaline is also described in the J.Med.Chem.

36, 1993, 4208-4213 (Russ, Engel, Sch6mig) and in Arch.Pharm.

348, 1993, 458-465 (Russ, Sonna, Keppler, Baunach, Sch6mig).

Surprisingly, it has been noted that the administration of cyanine-, isocyanine- and pseudocyanine-compounds results in a strong diuretic and natriuretic effect, i.e. an increased elimination of water and common salt through the kidney. Also surprisingly, this pharmacological effect is not accompanied by an increase in the elimination of the renal potassium or a change in the glomerular filtration rate.

Therefore the subject matter of the invention is the use of cyanines, isocyanines and pseudocyanines of the general formulae (cI=C)n -C U-t= I I B r and (C=CH)n-CH= N-'

CX>

wherein n 0 to 6, and R and R' are the same or different and stand for hydrogen, a linear or branched alkyl-, alkenyl- or alkynyl-group each with up to 6 C-atoms, an epoxyalkyl group with up to 4 C-atoms, a non-substituted or substituted aryl- or aralkyl-group each with up to 12 C-atoms, a cyano group, a linear or branched cyanoalkyl-, cyanoalkenyl-, cyanoalkynyl-, dicyanoalkyl-, dicyanoalkenyl-, azidoalkyl-, azidoalkenyl-, halogenoalkyl-, dihalogenoalkyl- or trihalogenoalkyl-, halogenohydroxyalkyl-, hydroxyalkyl-, acyloxyalkyl-, dihydroxyalkyl-, alkoxyalkyl-, alkylthioalkyl-, alkylsulfinylalkyl-, alkylsulfonylalkyl-, cyanoalkoxyalkyl-, cyanoalkylthioalkyl-, isocyanoalkyl-, carboxyalkyl-, amidinoalkyl-, amidinothioalkyl-, (2nitroguanidino)alkyl-, cyanatealkyl-, isocyanatealkyl-, thiocyanatealkyl-, isothiocyanatealkyl- each with up to 6 Catoms, an arylsulfonyloxyalkyl- or alkylsulfonyloxyalkyl-group with up to 12 C-atoms, a linear or branched aminealkylgroup with up to 12 C atoms on a nitrogen atom non-substituted or mono-, di- or tri-substituted by benzyl- or alkyl-residues with 1 to 4 C-atoms or in the case of two substituents on nitrogen atom together with the nitrogen atom or one substituent on the nitrogen atom and one substituent of the alkyl chain and together with the nitrogen atom form a heterocyclic ring with 3 to 6 atoms, which may also contain oxygen atoms, sulphur atoms and/or further nitrogen atoms and may be substituted by alkyl residues with 1 to 4 atoms, wherein the alkyl chain may be substituted by further C,_ 4 alkyl residues, a hydroxy group or a

C,_

4 alkoxy group, an acylamino-alkyl residue with up to 6 Catoms, an alkoxycarbonyl-alkyl residue with up to 7 C-atoms, a residue

RI

-(CH

2

).-CON<

R2 3 with m 1 to 3, wherein RI and R 2 are the same or different and stand for hydrogen or an alkyl group with 1 to 6 atoms, an acyl group with 1 to 4 C-atoms or RI and R 2 together with an alkylenyl group with 2 to 4 atoms, which possibly may be substituted by a hydroxy group, an alkoxy group with 1 to 4 Catoms or an unsubstituted amine group or one substituted by mono- or di-substituted benzyl or alkyl with 1 to 4 C-atoms, as well as their pharmacologically non-toxic salts to increase the renal water and sodium elimination to reduce extracellular' volumes.

Compounds of the general Formula I are preferred, wherein n=O and R and R' are the same or different and stand for a linear or branched C._ alkyl group and quite particularly preferred for a methyl-, ethyl- or isopropyl-group.

For the purpose of cleaning and for galenical reasons the basic cyanine, isocyanine and pseudocyanine are preferably transferred into crystalline, pharmacologically tolerable salts. The salts are obtained in the usual manner by neutralising the bases with relevant inorganic or organic acids. As acids hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, perchloric acid, acetic acid, tartaric acid, lactic acid, citric acid, malic acid, salicylic acid, ascorbic acid, malonic acid, fumaric acid, oxalic acid or succinic acid can be used.

As a rule the acid additive salts are obtained in a manner known per se by mixing the free bases or their solutions with the relevant acid or their solutions in an organic solvent, e.g. a low alcohol like methanol, ethanol or 2-propanol or a low ketone, like acetone or 2-butanone or an ether like diethylether, diisopropylether, tetrahydrofuran or dioxan.

3D

*O*

0 Preferred compounds are: l-(l-methylethyl)-2-[[l-(l-methylethyl)-4(lH)quinolinylideno]methyl]-quinolinium and its perchlorate disprocynium 24; l-ethyl-2-[l-ethyl-4(1H)-quinolinylideno]methyl]-quinolinium and its iodid decynium 24; l-methyl-2- -methyl-2 (lH) -quinolinylideno ]methyl ]-quinolinium (mecynium 22); 1-methyl-2-[1-methyl-4(1H)-quinolinylideno]methyl]-quinolinium (mecynium 24); 1-methyl-2-[ [l-(l-methylethyl)-4(lH)-quinolinylideno]methyl 3quinolinium (isocynium 24); l-ethyl-2-[ [1-(l-methylethyl)-4(lH)-quinolinylideno]methyl]quinolinium; l-(l-methylethyl)-2-[ [l-(l-methyl-4(lH) quinolinylidene]methyl] -quinolinium; l-ethyl-2-[ [l-ethyl-2(lH)-quinolinylideno]methyl ]-quinolinium and its iodid decynium 22; l-ethyl-2-[ [l-(1-methtylethyl)-2(lH)-quinolinylideno]methyl]quinolinium and its iodid iprecynium 22; l-methyl-2-[ [l-(l-methtylethyl)-2(lH)-quinolinylideno]methyl]quinolinium; l-(l-methylethyl)-2-[ [l-(1-methylethyl)-2(1H)-quinolinylideno] methyl] -quinolinium; l-(l-methylethyl)-2-[ [l-(l-methyl-2 (lH)-quinolinylideno]methyl] -quinolinium; l-(l-methylethyl)-4-[ [l-(l-methylethyl)-4( 1H) quinolinylideno] methyl ]-quinolinium; l-ethyl-4-[ [l-ethyl-4(lH)-quinolinylideno]methyl]-quinolinium; l-methyl-4-[ [l-methyl-4(lH)-quinolinylideno]methyl]quinolinium; l-methyl-4-[[l-methylethyl)-4(1H)-quinolinylideno]methyl]quinolinium; l-ethyl-4-[[l-(l-methylethyl)-4(lH)-quinolinylideno]methyl]quinolinium; and l-(l-methylethyl)-4-[[l-methyl-4(1H)-quinolinylideno]methyl]quinolinium.

The manufacture of the above mentioned compounds is carried out analogously to the methods described in the literature, e.g.

F.M.Hamer, J. Chem. Soc. 1928, 206-215 and W.Bradley, S.Jeffrey, J. Chem. Soc. 1954, 2770-2778.

The compounds can be administered in the respective suitable formula enterally and parenterally in dosages of 0.01 to 500 mg/kg, preferably 0.01 to 50 mg/kg.

The compounds can be applied in liquid or solid form orally or parenterally. As injection solution principally water is used, which for injection solutions contains other additives like stabilising agents, solubilisers or buffer.

Such additives are, for example, tartrate and citrate buffer, ethanol, complex formers (like ethylene diamino-tetraacetic acid and its non-toxic salts) as well as high-molecular polymers (like fluid polyethylene oxide) to control the viscosity. Solid substrate materials are, for example, starches, lactose, mannite, methyl cellulose, talcum, highly dispersive silicic acid, high-molecular fatty acids (like stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid highmolecular polymers (like polyethylene glycol); preparations intended for oral application may contain, if requested, additional taste-improving or sweetening materials.

Pharmaceutical drugs to increase the diuresis and particularly the natriuresis are crucial for the treatment of hypertonia and cardiac muscle inadequacy.

The chronic congestive cardiac muscle inadequacy, called cardiac muscle inadequacy in the following, is one of the most important medical problems. It is the most frequent clinical diagnosis in patients over 65 years and shows an increasing tendency. Despite the great advances in its pathophysiological understanding as well as in the medicinal therapy the mortality rate of patients having severe cardiac muscle inadequacy is over 50 within 1 year. Edema, as a sign of inadequate pumping function of the heart, is a dominant symptom of this illness.

Medicines which promote the elimination of salt and water through the kidneys, are part of the accepted standard therapy for the various forms of cardiac muscle inadequacy. The therapeutic use of the available diuretics according to the state-of-the-art to fight cardiac muscle inadequacy by flushing out the edema, however, is encumbered with clinically relevant side-effects, like triggering hypocalcaemia. This hypocalcaemia, brought about by increased renal potassium elimination, increases, in turn, the cardiac muscle inadequacy and the toxicity of the digitalis preparations, which are also frequently used in the case of cardiac muscle inadequacy. An increased renal sodium elimination, while the elimination of the potassium remains constant, brought about by the substances according to the invention, in particular by disprocynium 24, is therefore particularly suitable to promote the flushing out of the edema in the case of a cardiac muscle inadequacy, without triggering the typical side-effect of the diuretics available at this stage. The equally observable lowering of the peripheral resistance of the vessel and thus of the arterial blood pressure by virtue of these substances is a beneficial and desirable side-effect in the therapy of cardiac muscle inadequacy.

The pharmacological effects are confirmed with the following comparative tests: Example 1, disprocynium 24: The diuresis of rats sedated with 80 mg/kg i.p. thiopental was determined by intravenously administering disprocynium 24 (DP24) before (VP) and after For comparison furosemide with strong effect, was applied as standard diuretic. The average arterial blood pressure (MAP), the urine volume per unit of time (UV) and the urine-sodium elimination (UNaV) were measured. The results of the tests are illustrated in the following table, wherein all values are stated per 100 g of body weight and as average value of the groups SEM.

Test MAP UV UNaV periods mm Hg ml/min jmmol/min Control VP 97 2 14.1 2.0 1.5 t 0.3 HP 96 3 16.5 t 2.9 2.2 t 0.3 DP24 VP 102 5 18.3 3.6 1.9 t 0.4 g/kg HP 101 5 40.3 t 6.7* 3.7 0.3* VP 98 4 12.6 2.6 1.7 0.3 300 fig/kg HP 74 3* 36.8 5.7* 8.0 0.7* Furosemid VP 103 4 15.8 4.4 1.5 0.3 2 mg/kg HP 97 6 59.0 16* 7.6 0.8* p<0.05 in double-sided paired t-test (HP vs. VP) The glomerular filtration rate (GFR) was not significantly different between the main and prior periods. The Na/K ratio, which was in the prior periods between 1 and 2, after 300 pg/kg DP24 increased to 21.3 4.2 and after furosemide to 6.9 0.7.

3 These data show, that DP24 does not influence the potassium elimination despite the considerable increase in the sodium elimination. This DP24 effect is in contrast to the known furosemide effect, wherein not only does the elimination of sodium increase strongly, but also that of the potassium, becoming apparent by a considerably smaller increase of the Na/K ratio. Furthermore, the data show that based on the dosage, the DP24 is approx. seven times more effective than furosemide, being the powerful standard diuretic.

Example 2, iprecynium 22: The urine volume per unit of time of sedated rats was increased by infusion of 3 and 7.5 gg/kg/min iprecynium 22 (IP22) by the factor of 2.5 to 50 pl/min/100g, when compared with the control animals. This IP22 dosage had approximately the same effect as DP24.

The elimination of sodium was increased by infusing 3 Mg/kg/min IP22 by the factor of 3 when compared with the control animals and 7 times by infusing 7.5 pg/kg/min IP22. Therefore this IP22 dosage seems to have the same effect, if not stronger, as DP24.

Example 3: According to the above experiments disprocynium 24 has proven itself as a diuretic with a new efficiency profile. The diuretic effect was more pronounced than in the case of the very effective known diuretic and, in contrast to these, they did not bring about kaliuresis. For this reason the following experiments were carried out with further compounds of the general formula. A dosage of 1 Mg/kg/min was chosen, whereby no circulation activity was expected based on prior experiments, which [dosage] was administered in these comparative experiment as a long-term infusion for approx. 1 hour.

In a thiopentally sedated state the renal and systemic haemodynamics and the elimination function of the kidneys were tested in male Sprague-Dawley rats (200-250 After two clearance periods by infusing an isotonic NaCI solution to determine the initial values (baseline) the compounds to be tested were infused with a dosage of 1 pg/kg/min (in isotonic NaCl with 1 DMSO) and two further clearance periods were carried out (experimental). Subsequently change was made again to isotonic NaCl to test whether the changes observed would normalise (recovery).

These experiments have shown that an increase of the natriuresis and diuresis by a factor of 2 to 3 can be observed already at very low dosages of around 1 gg/kg/min. Based on the dosage/effect diagram of disprocynium 24 a higher diuretic effect at higher dosages can also be expected for the other compounds investigated. In all investigations the natriuresis and the diuresis normalised after completing the infusion, which seems to prove a specific effect of the class of compounds according to the invention. With the tested dosages no physiologically significant changes have occurred in the systemic or renal haemodynamics with these diuretic and natriuretic effects and during the diuretic and natriuretic effects there was no increase in elimination of the potassium from the urine either.

The results of these tests are represented in Table 1.

Table 1 shows the average arterial blood pressure (MAP), the glomerular filtration rate (GFR), the urine volume per unit of time the absolute (UNV) and fractional (FENa) sodium elimination as well as the potassium elimination (UKV) of sedated rats, which received by infusion in the prior (baseline) and post (recovery) periods isotonic NaCl solution and the investigated compounds with a dosage of 1 Mg/kg/min in the experimental period.

Table 1 Substance fClearance- Mecynium 22 1pg/kg/min Hecynium 24 lpg/kg/min Isocynium 24 ipg/kg/min Iprecynium 22 Ipg/kg/min Disprocynium 24 lpg/kg/min Period: Baseline Experimental Recovery Baseline Experimental Recovery Baseline Experimental Recovery Baseline Experimental Recovery Baseline Experimental Recovery

MAP

mm Hg 106 2 108 4 108 2 102 9 104 9 104 9 101 4 102 5 98 3 103 3 100 3 100 3 90 1 92 3 79 3

GFR

mi/lain 0.75 0.02 0.99 0.11 0.96 0.09 0.73 0.04 0.84 0.03 0.81 1 0.03 0.77 0.03 0.89 0.07 0.83 0.02 0.84 1 0.06 0.96 j 0.09 0.88 0.07 1.09 0.07 1.06 0.06 0.92 0.06

UV

P1/min 14.1 t 6.3 33.7 1.1 30.2 1 4.3 10.0.t 2.4 19.7 i 3.9 16.6 6.1 9.4 3.8 21.4 3.1 11.3 t 2.6 11.8 t 2.4 36.5 i 5.8 19.4 2.6 12.4 4.5 34.4 5.0 14.4 1 2.8 UNaV pmol fmin 0.39 1 0.02 1.59 1 0.22 2.62 0.42 0.99 1 0.08 2.54 1 0.21 2.03 1 0.61 0.85 0.12 1.52 t 0.21 1.44 0.15 0.90 T 0.12 4.69 1.0.83.

2.10 0.23 1.51*± 0.50 3.51 0.60 2.60 1 0.34 090 0.03 1.24 t 0.33.

1.95 0.15 0 98 0.13 2.18 0.11 1.88 t 0.37 0.75 0.23 1.35 0.13 1.23 0.25 0.82 0.13 3.45 0.40 1.74 t 0.12 0.90 0.13 3.40 0.41 0.82 0.18 FENa UKV pmo/min 0.57 0.24 0.60 0.06 0.55 0.03 1.01 1 0.10 1.00 0.10 0.76 0.09 1.10 t 0.06 0.92 0.05 0.54 0.08 0.62 0.15 0.89 0.17 0.97 0.28 0.84 0.16 0,84 0.14 0.73 0.14 MAP average arterial blood pressure GFR glomerural filtration rate UV urine volume per unit of time

U,

3 V absolute sodium elimination FE.. fractional sodium elimination UKV potassium elimination

Claims (10)

1. The use of at least one cyanine, isocyanine or pseudocyanine of the general formulae and CH)nr- 0O 00. atos, anndsbtttdo usiue rl raakl 0000 gopec ihu o1 -tmacaogop iero 0000 6 0 *Ilina.o branched alkyl-, alkenyl-, or alkynyl-u ec 0000 0~aos dcaoly- non-substituted, orsusidayl- or aalkeyl-, 0:000balned ynoalkyl,cynoalkeyl-, cyialnoalkl- 410 0 dicyanoxalkyl-, dicyanoalkyl-, azidolkyiol-,azdolkny- alogenolkiyky d algnolkl- or trihalogeynoalkoy-, l- anoklhydoxalkyl, hoyroalkyl-, ayloxyalkyl-, amidinoalkyl-, amidinothioalkyl-, (2-nitroguanidino)alkyl-, ~cyanatealkyl-, isocyanatealkyl-, thiocyanatealkyl-, isothiocyanatealkyl- each with up to 6 C-atoms, an arylsulfonyloxyalkyl- or alkylsulfonyloxyalkyl-group with up to 12 C-atoms, a linear or branched aminealkylgroup with up to 12 C atoms on a nitrogen atom non-substituted or mono-, di- or tri-substituted by benzyl- or alkyl-residues with 1 to 4 C-atoms or in the case of two substituents on nitrogen atom together with the nitrogen atom or one substituent on the nitrogen atom and one substituent of the alkyl chain and together with the nitrogen atom form a heterocyclic ring with 3 to 6 atoms, which may also contain oxygen atoms, sulphur atoms and/or further nitrogen atoms and may be substituted by alkyl residues with 1 to 4 atoms, wherein the alkyl chain may be substituted by further C_. 4 alkyl residues, a hydroxy group or a alkoxy group, an acylamino-alkyl residue with up to 6 C-atoms, an alkoxycarbonyl-alkyl residue with up to 7 C-atoms, a residue R I -(CH 2 ).-CON< R 2 with m 1 to 3, wherein R 1 and R2 are the same or different and stand for hydrogen or an alkyl group with 1 to 6 atoms, an acyl group with 1 to 4 C-atoms or R I and R 2 together with an alkylenyl group with 2 to 4 atoms, which possibly may be S substituted by a hydroxy group, an alkoxy group with 1 to 4 or an unsubstituted amine group or one substituted by mono- or di-substituted benzyl or alkyl with 1 to 4 C- atoms, as well as their pharmacologically non-toxic salts to increase the renal water and sodium elimination to reduce extracellular volumes, in a *:*patient in need of such treatment.

2. The use of at least one compound according to claim 1, wherein n=0 and R and R' are the same or different and stand for a linear or branched alkyl group.

3. The use of at least one compound according to claim 1, wherein n=O and R and R' are the same or different and stand for a methyl-, ZA^RA4thyl- or isopropyl-group. The use of at least one compound according to claim 1, namely l-(1-methylethyl)-2-[ [1-(l-methylethyl)-4(lH)- quinolinylideflo]methyl ]-quinoliflium and its perchiorate disprocynium 24; l-ethyl-2-[ l-ethyl-4 (lH)-quinolinylidelo]methyl 1-quinolinium and its iodid decynium 24; 1-methyl-2- [l-methyl-2 (lH) -quinolinylidelo ]methyl] quinolinium (mecynium 22); l-methyl-2-[ l-methyl-4( 1H)-quinolinylidelo]mfethYl]- quinolinium (mecynium 24); 1-methyl-2-[ [1-(1-methylethyl)-4(1H)- quinolinylideno]methyl]quiolilium (isocynium 24); quinolinium; l-(l-methylethyl)-2-[ [l-(l-methyl-4(1H) quinolinylidene] methyl] -quinolinium; :1 1-ethyl-2-[ [l-ethyl-2(lH)-quilOlinylideflo]Tethyl]> quinolinium and its iodid decynium 22; 1-ty*-[l htlty)2(H-unliyieo methyl]-quinoliflium and its iodid iprecynium 22; methyl]-quinoliiufl i-(i-methylethyl)-2-[ [l-(l-methylethyl)-2(1H)- quinolinylideno] methyl ]-quinolinium; l-(l-methylethYl)-2-[ [l-(l-methyl-2(lH)-quilolinylidelo] methyl] -quinolinium; l-(l-methylethYl)-4-[ [l-(l-methylethyl)-4(lH) quinolinylideno] methyl ]-quinolinium; quinolni [l hl4l)-unlnldeomty ~quinolinium; i1-methyl-4-[ [1-methylethlH)-q4(lqiflny li deflomeethll> quinolinium; quinolinium; and methyl -quinolinium.i to promote diuresis and/or natriuresis in a patient in need of such treatment. Use of pharmaceutical drugs containing in addition to the usual auxiliary and basic materials at least one compound according to any one of claims I to 4 to increase diuresis and in particular natriuresis and to treat hypertonia and cardiac muscle inadequacy, in a patient in need of such treatment.

6. The use of a pharmaceutical drug containing quinolinylideno]methyl]hquinolinium and its perchiorate disprocynium 24; *3 i -ethyl-2-[ j-ethyl-4(lH)-quinolinylideno]methyl]-quinolinium and its iodid decynium 24; methyl2[l-methyl-2(lH)quinolinylideno]methyl]- quinoliniUm (mecynium 22); l-methyl-2-[l-methYl-4( lH)-quinolinylidenollfethyl I- quinolinium (mecynium 24); l-methyl-2-[ [1-(l-methylethyl)-4(lH)-quinolinylideno] methyl]-quinolinium (isocynium 24); l-ethyl-2-[ [l-(1-methylethyl)-4(lH)-quinolinylideno]methyl]- quinolinium; l-(l-methylethyl)-2-[ [1-(l-methyl-4(lH) quinolinylidene] methyl] -quinolinium; l-ethyl-2-[ [l-ethyl-2(lH)-quinolinylideno]methylj- quinolinium and its iodid decynium 22; l-ethyl-2-[ [l-(l-methtylethyl)-2(lH)-quinolinylideno] methyl]-quinolinium and its iodid iprecynium 22; l-methyl-2-[ [l-(l-methtylethyl)-2(lH)-quinolinylideno] methyl ]-quinolinium; l-(l-methylethyl)-2-[ [l-(l-methylethyl)-2(1H)- quinolinylideno ]methyl ]-quinolinium; l-(l-methylethyl)-2-[ [l-(l-methyl-2(lH)-quinolinylideno] methyl] -quinolinium; l-(l-methylethyl)-4-[ [l-(l-methylethyl)-4(lH) quinolinylideno] methyl ]-quinolinium; l-ethyl-4-[ [l-ethyl-4(lH)-quinolinylideno]methyl]- quinolinium; l-methyl-4-[ [l-methyl-4(lH)-quinolinylideno]methyl quinolinium; l-methyl-4-[ [l-methylethyl)-4(lH)-quinolinylideno]methyl]- quinolinium; 1-ethyl-4-[ [l-(l-methylethyl)-4(lH)-quinolinylideno]methyl]- quinolinium; or 1-(1-methylethyl)-4-[ [1-methyl-4(1H)-quinolinylideno] methyl]-quinolinium on its own or in combination of one or several of the compounds, to promote diuresis and/or naturesis in a patient in need of such treatment.

7. A method of increasing renal water and sodium elimination in a patient in need of such treatment comprising administering an effective amount of at least one cyanine, isocyanine or pseudocyanine of the general formulae R l(C=CH)n- CH R (CK= CH)n-- I I oand S((Ct= CH)n-- CH= M R wherein n 0 to 6, and R and R' are the same or different and stand for hydrogen, a linear or branched alkyl-, alkenyl- or alkynyl-group each with up to 6 C-atoms, an epoxyalkyl group with up to 4 C- atoms, a non-substituted or substituted aryl- or aralkyl- group each with up to 12 C-atoms, a cyano group, a linear or branched cyanoalkyl-, cyanoalkenyl-, cyanoalkynyl-, dicyanoalkyl-, dicyanoalkenyl-, azidoalkyl-, azidoalkenyl-, 17 halogenoalkyl-, dihalogenoalkyl- or trihalogenoalkyl-, halogenohydroxyalkyl-, hydroxyalkyl-, acyloxyalkyl-, dihydroxyalkyl-, alkoxyalkyl-, alkylthioalkyl-, alkylsulfinylalkyl-, alkylsulfonylalkyl-, cyanoalkoxyalkyl-, cyanoalkylthioalkyl-, isocyanoalkyl-, carboxyalkyl-, amidinoalkyl-, amidinothioalkyl-, (2-nitroguanidino)alkyl-, cyanatealkyl-, isocyanatealkyl-, thiocyanatealkyl-, isothiocyanatealkyl- each with up to 6 C-atoms, an arylsulfonyloxyalkyl- or alkylsulfonyloxyalkyl-group with up to 12 C-atoms, a linear or branched aminealkylgroup with up to 12 C atoms on a nitrogen atom non-substituted or mono-, di- or tri-substituted by benzyl- or alkyl-residues with 1 to 4 C-atoms or in the case of two substituents on nitrogen atom together with the nitrogen atom or one substituent on the nitrogen atom and one substituent of the alkyl chain and together with the nitrogen atom form a heterocyclic ring with 3 to 6 atoms, which may also contain oxygen atoms, sulphur atoms and/or further nitrogen atoms and may be substituted by alkyl residues with 1 to 4 atoms, wherein the alkyl chain may be substituted by further C_ alkyl S residues, a hydroxy group or a C_ alkoxy group, an acylamino-alkyl residue with up to 6 C-atoms, an alkoxycarbonyl-alkyl residue with up to 7 C-atoms, a residue R2 with m 1 to 3, wherein R, and R2 are the same or different and stand for hydrogen or an alkyl group with 1 to 6 atoms, an acyl group with 1 to 4 C-atoms or RI and R 2 together with an alkylenyl group with 2 to 4 atoms, which possibly may be substituted by a hydroxy group, an alkoxy group with 1 to 4 C-atoms or an unsubstituted amine group or one substituted by mono- or di-substituted benzyl or alkyl with 1 to 4 C- atoms or a pharmaceutically non-toxic salt thereof. 18

8. A method of promoting diuresis and/or natriuresis in a patient in need of such treatment comprising administering an effective amount of at least one of quinolinylideno]methyl ]-quinolinium and its perchiorate disprocynium 24; l-ethyl-2-[l-ethyl-4( 1H)-quinolinylideno]methyl]-quinolinium and its iodid decynium 24; 1-methyl-2- [l-methyl-2 (lH) -quinolinylideno Imethyl] quinolinium (mecyniun 22); l-methyl-2- [l-methyl-4 (lH) -quinolinylideno jmethyl J- quinolinium (mecynium 24); l-methyl-2- [l(1-l-methylethyl (lH) quinolinylidenolmethyl]-quinolinium (isocynium 24); l-ethyl-2-[ [l-(l-methylethyl.)-4(lH)-quinolinylidenojmethyl]- quiriolinium; l-(l-methylethyl)-2-[ [l-(l-methyl-4(lH) quinolinylidene] methyl] -quinolinium; l-ethyl-2-IIfl-ethyl-2(lH)-quinolinylidenolxethyl]- quinolinium and its iodid decynium 22; 1-ethyl-2-[ [1-(1-methtylethyl)-2(lH)-quinolinylideno] :0 methyl]-quinoliniun and its iodid iprecynium 22; 1-methyl-2-[ [1-(l-methtylethyl)-2(1H)-quinolinylideno] methyl 3-quinolinium; i-(l-methylethyl)-2-([1l-(l-methylethyl)-2(lH)- quinolinylideno] methyl 3-quinolinium; (-methylethyl)-2-( [l-(l-methyl-2(lH)-.quinolinylideno] ethyl] -quinolinium; 19 l-(l-methylethyl)-4-[ 1-methylethyl)-4(lH) quinolinylideno] methyl 1-quinolinium; l-ethyl-4-[ [l-ethyl-4(lH)-quinolinylideno]lethyl]- quinolinium; l-methyl-4-[ [l-methyl-4(lH)-quinolinylideno]methyl]- quinolinium; 1-methyl-4-[ [l-methylethyl)-4(lH)-quinolinylidenolmethyl quinol inium; l-ethyl-4-([1l-(1-methylethyl)-4(lH)-quinolinylideno]methyl quinolinium; and l-(l-met~hylethyl)-4-[ [l-methyl-4(lH)-Quinolinylideno] methyl]I-quinoliniugi

9. A method of increasing diuresis and in particular naturesis, and treating 0 hypertonia and cardiac muscle inadequacy in a patient in need of such treatment comprising administering an effective amount of at least one compound according to any one of claims I to 4. A method of promoting diuresis and/or naturesis in a patient in need of such treatment comprising administering an effective amount of at least one *09. pharmaceutical drug containing 0 l-(l-methylethyl)-2-[[l-(1-methylethyl)-4(lH)- quinolinylidenolmethyl ]-quinolinium and its perchiorate disprocynium 24; 0. 01-ethyl-2-[ 1-ethyl- 1H) -quinolinylideno]methyl 1-quinolinium and its iodid decynium 24; 1-methyl-2-II1-methyl-2( 1H)-quinoliriylideno]methyl]- quinolinium (mecynium 22); S4 quinolinium (mecynium 24); 1-methyl-2-[ [1-(1-methylethyl)-4(H)-quioliylideto] methyl]-quinolinium (isocynium 24); l-ethyl-2-I(1-(1-methylethyl)-4(1H)-quinolinyliden]methyl quinolinium; 1-(1-methylethyl)-2-[ [1-(1-methyl-4(lH) quinolinylidene] methyl] -quinolinium; l-ethyl-2-[ [l-ethyl-2(1H)-quinolinylideno]methyl]- quinolinium and its iodid decynium 22; l-ethyl-2-[ [1-(l-methtylethyl)-2(lH)-quinolinylideno] methyl]-quiriolinium and its iodid iprecynium 22; 1-mnethyl-2-[ [l-(l--methtylethyl lH)-quinolinylideno] methyl ]-quinolinium; 1-(1-methylethyl)-2-[ [1-(1-methylethyl)-2 (lH)- quinolinylideno]methyl ]-quinolinium; 1-(1-methylethyl)-2-( (l-(l-methyl-2(1H)-quinolinylidenoI methyl] -quinolinium; quinolinylideno] methyl ]-quinolinium; l-ethyl-4-[ [l-ethyl-4(lH)-quinolinylideno]methyl]- quinolinium; l-methyl-4-[ [l-methyl-4(IH)-quinolinylideno]methyl J- quinolinium; l-ethyl-4-[ [l-lmethylethyl)-4(lH)-quinolinylideno]methyl]- or l-(l-methylethyl)-4-[ [i-methyl-4(1lH)-quinolinylideno] methyl]-quinolinium on its own or in combination of one or several of the compounds.

11. A method of increasing renal water and sodium elimination in a patient in need of such treatment comprising administering an effective amount of at least one cyanine, isocyanine or pseudocyanine of the general formulae $(Ciec)nL 011- H a' I I I C CK I ff and (CI CH)n- CHIi R' ~wherein n =0 to 6, and R and R' are the same or different and stand for hydrogen, a linear or branched alkyl-, alkenyl- or alkynyl-group each with up to 6 C-atoms, an epoxyalkyl group with up to 4 C- atoms, a non-substituted or substituted aryl- or aralkyl- group each with up to 12 C-atoms, a cyano group, a linear or branched cyanoalkyl-, cyanoalkenyl-, cyanoalkynyl-, dicyanoalkyl-, dicyanoalkenyl-, azidoalkyl-, azidoalkenyl-, 22 halogenoalkyl-, dihalogenoalkyl- or trihalogenoalkyl-, halogenohydroxyalkyl-, hydroxyalkyl-, acyloxyalkyl-, dihydroxyalkyl-, alkoxyalkyl-, alkylthioalkyl-, alkylsulfinylalkyl-, alkylsulfonylalkyl-, cyanoalkoxyalkyl-, cyanoalkylthioalkyl-, isocyanoalkyl-, carboxyalkyl-, amidinoalkyl-, amidinothioalkyl-, (2-nitroguanidino)alkyl-, cyanatealkyl-, isocyanatealkyl-, thiocyanatealkyl-, isothiocyanatealkyl- each with up to 6 C-atoms, an arylsulfonyloxyalkyl- or alkylsulfonyloxyalkyl-group with up to 12 C-atoms, a linear or branched aminealkylgroup with up to 12 C atoms on a nitrogen atom non-substituted or mono-, di- or tri-substituted by benzyl- or alkyl-residues with 1 to 4 C-atoms or in the case of two substituents on nitrogen atom together with the nitrogen atom or one substituent on the nitrogen atom and one substituent of the alkyl chain and together with the nitrogen atom form a heterocyclic ring with 3 to 6 atoms, which may also contain oxygen atoms, sulphur atoms and/or further nitrogen atoms and may be substituted by alkyl residues with 1 to 4 atoms, wherein the S. alkyl chain may be substituted by further alkyl residues, a hydroxy group or a alkoxy group, an S acylamino-alkyl residue with up to 6 C-atoms, an S alkoxycarbonyl-alkyl residue with up to 7 C-atoms, a residue -(CH 2 ).-CON< with m 1 to 3, wherein RI and R 2 are the same or different and stand for hydrogen or an alkyl group with 1 to 6 atoms, an acyl group with 1 to 4 C-atoms or RI and R 2 together with an alkylenyl group with 2 to 4 atoms, which possibly may be substituted by a hydroxy group, an alkoxy group with 1 to 4 C-atoms or an unsubstituted amine group or one substituted by mono- or di-substituted benzyl or alkyl with 1 to 4 C- atoms or a pharmaceutically non-toxic salt thereof substantially as herein described with reference to at least one of the accompanying Examples. 23

12. A method of promoting diuresis and/or natriuresis in a patient in need of such treatment comprising administering an effective amount of at least one of l-(l-methylethyl)-2-t [l-(l-methylethyl)-4(lH)- quinoliflyliderio]methyl )-quinolinium and its perchiorate disprocynium 24; l-ethyl-2- -ethyl-4 (lH) -quinolinylideno ]methyl ]-quinolinium and its iodid decynium 24; 1-methyl-2-[ l-methyl-2( lH)-quinolinylideno]methyl]- quinolinium (mecynium 22); 1-methyl-2-[1-methyl-4 (lH)-quinolinylidenojmethyl I- quinolinium (mecynium 24); l-methyl-2-[ [i-(l-methylethyl)-4(lH)- quinolinylidenolmethyl ]-quinolinium (isocynium 24); l-ethyl-2-[ [1-(l-methylethyl (1H)-quinolinylidenojmethyl quinolinium; 1-(1-methylethyl)-2-[ [1-(1-rnethyl-4(1H) quirzoJinylidene] methyl] -quinolinium; l-ethyl-2-( [1-ethyl-2(lH)-quinolinylideno]methyl]- quinolinium and its jodid decynium 22; l-ethyl-2-[ [1-(l-methtylethyl)--2(lH)-quinolinylideno] methyl]-quinolinium and its lodid iprecynium 22; 1-methyl-2-[ [1-(1-methtylethyl)-2(lH)-qujnolinylideno] methyl]-quinolinium; l-(l-methylethyl)-2-([1l-(1-methylethyl)--2(lH)- quinolinylideno] methyl 1-quinolinium; (l-methylethyl)-2-( (1-(l-methyl-2(1H)-quinolinylideno] X/O-1 li1/q hyl I -quinolinium; 24 i-(i-methylethyl)-4-[ (i-(1-methylethyl)-4(1H) qluinolinylidenol methyl ]-quinoliniun; i-ethyl-4-E [l-ethyl-4(H)-quiflolifylideflo]mfethyl- quinol inium; quinol inium; 1-ethyl-4-[1-( -methylethyl)-4( H)-quinolinylidenomethyl quinolinium;ad i-methylethyl)-4-[ [1-methyl-4 (lH)-qruinolinylideno] methyl ]-quinoiliuEi substantially as herein described with reference to at least one of t he accompanying Examples. *13. A method increasing diuresis and in particular naturesis, and treating hypertonia and cardiac muscle inadequacy in a patient in need of such treatment comprising administering an effective amount of at least one compound according to any one of claims I to 4 substantially as herein described with reference to at least one of the accompanying Examples.

14. A method of promoting diuresis and or naturesis in a patient in need of such treatment comprising administering an effective amount of at least one pharmaceutical drug containing 1-(1-inethylethyl)-2- [[1-(1-InthYlethyl)-4(1H)- quinolinyliderio]methyl 1-quinolinium and its perchiorate disprocynium 24; l-ethyl-2-( 1-ethyl-4( IH)-quinoliriylidenolmethyl 3-quinolinium and its iodid decynium 24; i-methyl-2- (l-methyl-2 H) -quinolinylideno ~methy1 I- CRA4I quinolinium (iecynium 22); quinolinium (mecyniuu 24); l-maethyl-2-[I-(1-methylethyl)-4(1H)-quinolinylideno] methyl]-quinolinium (isocyniui 24); I-ethyl-2-[(lI-(l-methylethyl)-4(1H)-quinolinylideno]methyl]. quinol inium; 1-(1-maethylethyl)-2-( [1-(1-methyl-4(1H) quinolinylidene] methyl] -quinolinium; 1-ethyl-2-[ t1-ethyl-2(lH)-quinolinylideno]methyl]- quinolinium and its iodid decynium 22; 1-ethyl-2-[ 1-methtyletllyl)-2( lH)-guinolinylideno) maethylJ-quinolinium and its iodid iprecynium 22; 1-mnethyl-2-( [J-(1-iethtylethyl )-2(lH)-quinolinylldeno] methyl ]-quiriolinium; l-(1-methylethyl)-2-[ [1-(1-methylethyl)-2(lH)- quinolinylidenolmethyl ]-quinolinium; *0 as l-(l-methylethyl)-2-( t1-(1-methyJ.-2(1H)-quinolinylideno] O:S methyl] -guinolinium; a.* 0. 000 l-(l-methylethyl)-4-( E1-(1-methylethyl)-4(lH) quinolinylideno] methyl] -quinolinium; *00a* quinolinium; S0. quinolinium; a. 0, :l-methyl-4-([1l-methylethyl)-4( 1H)-quinolinylideno ]methyl quinolinium; l-ethyl-4-[ [l-(l-methylethyl)-4(lH)-quinolinylideno]methyl quinolinium; or 1-(1-methylethyl)-4-[ (l-methyl-4(1H)-quinolinylideno] methyl ]-quinoliniuu on its own or in combination of one or several of the compounds substantially as herein described with reference to at least one of the accompanying Examples. Dated this 2 nd day of November 2000 ILARTMUT OSSWALD By his patent attorneys CALLINAN LAWRIE, *.6e