WO1998035678A1

WO1998035678A1 - Use of cyanines, isocyanines and pseudoisocyanines as diuretics

Info

Publication number: WO1998035678A1
Application number: PCT/DE1997/002997
Authority: WO
Inventors: Hartmut Osswald; Bernd Mühlbauer; Hermann Russ; Edgar Schömig
Original assignee: Hartmut Osswald; Muehlbauer Bernd; Hermann Russ; Schoemig Edgar
Priority date: 1997-02-17
Filing date: 1997-12-22
Publication date: 1998-08-20
Also published as: JP2001512448A; CA2281795A1; AU729218B2; GB9919041D0; DE19706161A1; EP0949924A1; GB2337202A; AU5748698A

Abstract

The invention relates to the use of cyanines, isocyanines and pseudoisocyanines in the production of medicaments for enhancing water and sodium separation by the kidneys, in order to reduce extracellular volume and for treating cardiac insufficiency.

Description

Use of cyanines, isocyanines and pseudoisocyanines as

Diuretics

description

The invention relates to the use of cyanines, isocyanines and pseudoisocyanines to promote diuresis.

Cyanine, isocyanine and pseudoisocyanine compounds have long been known compounds from the class of polymethine dyes.

DE 41 37 009 has for the first time described a pharmacological effect of these compounds, specifically their inhibitory effect on biological transport systems for organic cations, in particular noradrenaline transport. The effect on noradrenaline transport is also described in J. Med. Chem. 36, 1993, 4208-4213 (Russ, Engel, Schömig) and in Arch. Pharm. 348, 1993, 458-465 (Russ, Sonna, Keppler , Baunach, Schömig).

Surprisingly, it has now been found that the administration of cyanine, isocyanine and pseudoisocyanine compounds has a strong diuretic and natriuretic effect, i.e. an increased excretion of water and table salt is caused by the kidney. This pharmacological effect is surprisingly not accompanied by an increase in renal potassium excretion or a change in the glomerular filtration rate.

The invention therefore relates to the use of cyanines, isocyanines and pseudoisocyanines of the general formulas

R

wherein

n = 0 to 6, and

R and R are the same or different and are hydrogen, a straight-chain or branched alkyl, alkenyl or alkynyl group each having up to 6 C atoms, an epoxyalkyl group having up to 4 C atoms, an unsubstituted or substituted aryl or aralkyl group each with up to 12 carbon atoms, a cyano group, a straight-chain or branched cyanoalkyl, cyanoalkenyl, cyanoalkynyl, dicyanoalkyl, dicyanoalkenyl, azidoalkyl, azidoalkenyl, haloalkyl, di or trihaloalkyl, halohydroxyalkyl, hydroxyalkyl -, Acyloxyalkyl -, Dihydroxyalkyl-, Alkoxyalkyl -, Alkylthioalkyl-, Alkylsulfinylalkyl-, Alkylsulfonylalkyl-, Cyanoalkoxyalkyl-, Cyanoalkylthioalkyl-, Isocyanoalkyl-, Carboxyalkyl-, Amidinoalkyl-, Amidinothioalkyl-, (2-Nitroguanidino) alkyl-, Cyanatoalkyl - -, Thiocyanatoalkyl -, Isothiocyanatoalkyl- each with up to 6 C atoms, an arylsulfonyloxyalkyl or alkylsulfonyloxyalkyl group with up to 12 C atoms, a straight d-chain or branched aminoalkyl group with up to 12 carbon atoms on the nitrogen atom unsubstituted or mono-, di- or trisubstituted by benzyl or alkyl radicals with 1 to 4 carbon atoms or in the case of the two substituents on the nitrogen atom together with the nitrogen atom or a substituent on the nitrogen atom and a substituent of the alkyl chain and together with the nitrogen atom one Form a heterocyclic ring with 3 to 6 carbon atoms, which also contain oxygen, sulfur and / or further nitrogen atoms and can be substituted by alkyl radicals having 1 to 4 carbon atoms, the alkyl chain being substituted by further C 1 -C 4 -alkyl radicals, a hydroxyl group or a C _1- alkoxy group may be substituted, an acylaminoalkyl radical having up to 6 C atoms, an alkoxycarbonylalkyl radical having up to 7 C atoms, a radical

R ¹ - (CH ₂ ) _m -CON <

R

with = 1 to 3, in which R ¹ and R ^{2 are the} same or different and represent hydrogen or an alkyl group with 1 to 6 C atoms, an acyl group with 1 to 4 C atoms or R and R ^ together form an alkylene group 2 to 4 carbon atoms, which may be substituted by a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms or an unsubstituted or an amino group mono- or disubstituted by benzyl or alkyl having 1 to 4 carbon atoms , as well as their pharmacologically acceptable salts for the manufacture of medicaments for increasing the renal water and sodium excretion to reduce the extracellular volume.

Preferred compounds of the general formula I are those in which n = 0 and R and R 'are identical or different and denote a straight-chain or branched C 1-6 alkyl group and very particularly preferably a methyl, ethyl or isopropyl group.

The basic cyanines, isocyanines and pseudoisocyanines are preferably converted into crystalline, pharmacologically acceptable salts for the purpose of purification and for galenical reasons. The salts are obtained in the usual way by neutralizing the bases with appropriate inorganic or organic acids. Examples of possible acids are hydrochloric acid, sulfuric 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. The acid addition salts are generally in a manner known per se by mixing the free base or its solutions with the corresponding acid or its solutions in an organic solvent, for example a lower alcohol such as methanol, ethanol or 2-propanol or a lower ketone such as acetone or 2-butanone or an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane.

Preferred connections are:

1- (1-methylethyl) -2- [[1- (1-methylethyl) -4 (IH) quinolinylidenes] methyl] quinolinium and its perchlorate disprocynium 24;

l-ethyl-2- [[l-ethyl-4 (IH) -quinolinylidenejmethyl] -quinolinium and its iodide decynium 24;

l-methyl-2- [[l-methyl-2 (IH) quinolinylidenes] methyl] quinolinium (Mecynium 22);

l-methyl-2- [[l-methyl-4 (IH) quinolinylidenes methyl] quinolinium (Mecynium 24);

l-methyl-2- [[1- (1-methylethyl) -4 (IH) -quinolinylidenejmethyl] quinolinium (isocyanin 24);

l-ethyl-2 - [[l- (l-methylethyl) -4 (1H) -quinolinylidenes] methyl] quinolinium;

l- (l-methylethyl) -2- [[l-methyl-4 (IH) -quinolinylidenejmethyl] quinolinium;

l-ethyl-2- [[l-ethyl-2 (IH) -quinolinylidenejmethyl] -quinolinium and its iodide decynium 22;

l-ethyl-2 - [[1- (1-methylethyl) -2 (IH) -quinolinylidenejmethyl] quinolinium and its iodide iprecynium 22;

l-methyl-2- [[1- (1-methylethyl) -2 (IH) quinolinylidenejmethyl] quinolinium; 1- (1-methylethyl) -2- [[1- (1-methylethyl) -2 (IH) quinolinylidenejmethyl] quinolinium;

l- (l-methylethyl) -2- [[l-methyl-2 (IH) -quinolinylidenejmethyl] quinolinium;

1- (1-methylethyl) -4- [[1- (1-methylethyl) -4 (IH) - quinolinyididene] methyl1] quinolinium;

l-ethyl-4- [[l-ethyl-4 (IH) quinolinylidenejmethyl] quinolinium;

l-methyl-4- [[l-methyl-4 (IH) quinolinylidenejmethyl] quinolinium;

l-methyl-4- [[1- (1-methylethyl) -4 (IH) -quinolinylidenejmethyl] quinolinium;

l-ethyl-4- [[1- (1-methylethyl) -4 (IH) quinolinylidenes] methyl1] quinolinium; and

l- (l-Methylethyl) -4- [[l-methyl-4 (IH) -quinolinylidenejmethyl] quinolinium.

The production of the above Connections are 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 enterally or parenterally in doses of 0.01 to 500 mg / kg, preferably 0.01 to 50 mg / kg, in the respectively suitable formulation.

The compounds can be administered orally or parenterally in liquid or solid form. Water, which contains the additives common to injection solutions such as stabilizing agents, solubilizers or buffers, is primarily used as the injection solution.

Such additives are, for example, tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediamine tetraacetic acid and its non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Celebrations Carriers are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular polymers (such as polyethylene glycol); Preparations suitable for oral administration can optionally contain additional flavorings and / or sweeteners.

Medicines to increase diuresis, particularly natriuresis, are essential for the treatment of hypertension and heart failure.

Chronic congestive heart failure, hereinafter referred to as heart failure, is one of the most important problems in medicine. It is the most common clinical diagnosis in patients over 65 years of age and shows an increasing incidence. Despite great advances in pathophysiological understanding and drug therapy, the 1-year mortality rate for patients with severe cardiac insufficiency is over 50%. Edema as a sign of the insufficient pumping function of the heart are the main symptoms of this disease. In the various forms of cardiac insufficiency, drugs that increase salt and water excretion via the kidneys are part of the recognized therapy standard. However, the therapeutic use of the diuretics available according to the prior art to combat cardiac insufficiency by flushing out the edema is associated with clinically relevant side effects such as induction of hypocalemia. This hypocalemia, due to the increase in renal potassium excretion, in turn increases the cardiac insufficiency and the toxicity of the digitalis preparations, which are also frequently used for cardiac insufficiency. An increased renal sodium excretion with unchanged potassium excretion, which is caused by the substances according to the invention, in particular Disprocynium 24, is therefore particularly suitable for promoting edema exudation in the case of cardiac insufficiency without the typical side effect of the diuretics previously available trigger. The lowering of the peripheral vascular resistance and thus the arterial blood pressure by these substances, which is also to be observed, is a favorable and desired side effect in the therapy of cardiac insufficiency.

The pharmacological effects were confirmed by the following comparative tests:

Example 1, Disprocynium 24:

At 80 mg / kg i.p. In thiopental anesthetized rats, the diuresis was determined before (VP) and after (HP) intravenous administration of Disprocynium 24 (DP24). For comparison, furosemide was applied as a standard diuretic with a strong effect. The mean arterial blood pressure (MAP), the urine time volume (UV) and the urine sodium excretion (UNaV) were measured. The test results are shown in the table below, in which all values are given per 100 g body weight and as mean values of the groups ± SEM.

* p <0.05 in the two-sided paired t-test (HP versus VP)

The glomerular filtration rate (GFR) was not significantly different between main and previous periods. The sodium / potassium ratio, which was between 1 and 2 in the previous periods, rose to 21.3 ± 4.2 after 300 μg / kg DP24 and to 6.9 ± 0.7 after furosemide. These data show that DP24 excretes potassium unaffected despite massive increase in

Sodium excretion. This DP24 effect is in contrast to the well-known furosemide effect, in which not only the sodium excretion increases strongly, but also the potassium excretion increases, visible by the much smaller increase in the sodium / potassium ratio. The data further show that, based on the dose, DP24 is about seven times more effective than the powerful diuretic standard furosemide.

Example 2, Iprecynium 22:

In anesthetized rats, the urine time volume by infusion of 3 and 7.5 μg / kg / min iprecynium 22 (IP22) was increased by a factor of 2.5 to 50 μl / min / 100 g compared to time control animals. This IP22 dose is approximately equieffective to DP24.

The sodium excretion was increased by a factor of 3 by infusion of 3 μg / kg / min IP22 compared to time control animals and by 7.5 μg / kg / min IP22. This IP22 dose therefore appears to be at least equieffective, if not stronger than DP24.

Example 3:

Disprocynium 24 has been shown to be a diuretic with a novel activity profile based on the above experiments. The diuretic effect was more pronounced than that of the previously known potent diuretics and, in contrast to these, they did not cause potassium uresis. The following tests were therefore carried out with other compounds of the general formulas. A dosage of 1 μg / kg / min was chosen, at which none due to the preliminary tests Circulatory efficacy was to be expected, which were used in this comparative experiment as a continuous infusion over approximately 1 hour.

In male Sprague-Dawley rats (200-250 g), the renal and systemic hemodynamics and the excretion function of the kidney were examined under thiopental anesthesia. After two Cleareance periods with infusion of isotonic NaCl solution to determine the initial values (baseline), the compounds to be tested were infused at a dosage of 1 μg / kg / min (in isotonic NaCl with 1% DMSO) and two further clearance periods were carried out (Experimental). It was then switched again to isotonic NaCl in order to check whether the observed changes normalized (recovery).

These experiments showed that an increase in natriuresis and diuresis by a factor of 2 to 3 can be observed even at a very low dose in the range of 1 μg / kg / min. In view of the dose-response curve of Disprocynium 24, a higher diuretic effect can also be expected at higher doses for the other compounds examined. In all experiments natriuresis and diuresis normalized after the end of the infusion, which speaks for a specific effect of the class of compounds according to the invention. For the diuretic and natriuretic effects, there was no physiologically significant change in the systemic or renal hemodynamics in the tested dose, and there was no increase in potassium excretion in the urine during the diuretic and natriuretic effects.

The results of these tests are shown in Table 1.

Table 1 shows the mean arterial blood pressure (MAP), the glomular filtration rate (GFR), the urine time volume (UV), the absolute (U _Na V) and fractional (FE _Na ) sodium excretion as well as the potassium excretion (U _K V) of anesthetized rats in pre- (baseline) and post- (recovery) periods isotonic NaCl solution and in the experimental period the compounds examined were infused at a dosage of 1 μg / kg / min. TABLE 1

Substance clearance- MAP GFR UV "Na ^v ^FE Na U _K V

Period mm Hg ml / m. -n μl / min μmol / min g, o μmol / min

Mecynium 22 Baseline 106 ± 2 0.75 ± 0.02 14.1 ± 6.3 0.39 ± 0.02 0.90 ± 0.03 0.57 ± 0.24 lμg / kg / min Experimental 108 ± 4 0.99 ± 0.11 33.7 ± 1.1 1.59 ± 0.22 1.24 ± 0.33 0.60 ± 0.06

Recovery 108 ± 2 0.96 ± 0.09 30.2 + 4.3 2.62 ± 0.42 1.95 ± 0.15 0.55 ± 0.03

Mecvnium 24 Baseline 102 ± 9 0.73 ± 0.04 10.0 ± 2.4 0.99 ± 0.08 0 98 i 0.13 1.01 ± 0.10

Iμg / kg / min Experimental 104 ± 9 0.84 ± 0.03 19.7 ± 3.9 2.54 ± 0.21 2.18 ± 0.11 1.00 ± 0.10

Recovery 104 ± 9 0.81 + 0.03 16.6 + 6.1 2.03 ± 0.61 1.88 ± 0.37 0.76 ± 0.09

Isocynium 24 Baseline 101 ± 4 0.77 ± 0.03 9.4 ± 3.8 0.85 ± 0.12 0.75 ± 0.23 1.10 ± 0.06 lμg / kg / min Experimental 102 ± 5 0.89 ± 0.07 21.4 + 3.1 1.52 ± 0.21 1.35 ± 0.13 0.92 ± 0.05

Recovery 98 ± 3 0.83 ± 0.02 11.3 ± 2.6 1.44 + 0.15 1.23 ± 0.25 0.54 ± 0.08

Iprecynium 22 Baseline 103 ± 3 0.84 ± 0.06 11.8 ± 2.4 0.90 ± 0.12 0.82 ± 0.13 0.62 ± 0.15 lμg / kg / min Experimental 100 ± 3 0.96 i 0.09 36.5 ± 5.8 4.69 ± 0.83 3.45 ± 0.40 0.89 ± 0.17

Recovery 100 ± 3 0.88 + 0.07 19.4 ± 2.6 2.10 ± 0.23 1.74 ± 0.12 0.97 ± 0.28

Disprocynium 24 Baseline 90 ± 1 1.09 ± 0.07 12.4 ± 4.5 1.51 ± 0.50 0.90 ± 0.13 0.84 ± 0.16 lμg / kg / min Experimental 92 ± 3 1.06 ± 0.06 34.4 ± 5.0 3.51 ± 0.60 3.40 ± 0.41 0.84 ± 0.14

Recovery 79 ± 3 0.92 + 0.06 14.4 ± 2.8 2.60 ± 0.34 0.82 ± 0.18 0.73 ± 0.14

MAP mean arterial blood pressure GFR glomular filtration rate UV urine volume u _Na v absolute sodium excretion

FE _Na fractional sodium excretion

U _K V potassium excretion

Claims

Patent claims

1. Use of cyanines, isocyanines and pseudoisocyanines of the general formulas

and

where n = 0 to 6, and

R and R are the same or different and hydrogen, a straight-chain or branched alkyl, alkenyl or alkynyl group each with up to 6 carbon atoms, an epoxyalkyl group with up to 4 carbon atoms, an unsubstituted or substituted aryl or aralkyl group each with up to 12 carbon atoms, a cyano group, a straight-chain or branched cyanoalkyl, cyanoalkenyl, cyanoalkynyl, dicyanoalkyl, dicyanoalkenyl, azidoalkyl, azidoalkenyl, haloalkyl, di- or trihaloalkyl, halohydroxyalkyl, hydroxyalkyl - , acyloxyalkyl, dihydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cyanoalkoxyalkyl, cyanoalkylthioalkyl, isocyanoalkyl, carboxyalkyl, amidinoalkyl, amidinothioalkyl - , (2-Nitroguanidino)alkyl- , Cyanatoalkyl, isocyanatoalkyl, thiocyanatoalkyl, isothiocyanatoalkyl- each up to 6 C atoms, an aryl sulfonyal oxyalkyl or alkylsulfonyloxyalkyl group with up to 12 C atoms, a straight-chain or branched amino alkyl group with up to 12 C atoms om unsubstuted or mono-, di- or tri-substituted by benzyl or alkyl radicals with 1 to 4 carbon atoms or in which two substituents on the nitrogen atom together with the nitrogen atom or one substituent on the nitrogen atom and a substituent on the alkyl chain and together with the nitrogen atom a heterocyclic ring 3 to 6 C atoms, which can also contain oxygen, sulfur and / or further nitrogen atoms and can be substituted by alkyl radicals with 1 to 4 C atoms, the alkyl chain being replaced by further C-^^ -alkyl radicals, a hydroxy group or a C ₁ - ₄ alkoxy group can be substituted, an acylaminoalkyl radical with up to 6 carbon atoms, an alkoxycarbonylalkyl radical with up to 7 carbon atoms, a radical

^RJ

(CH ₂ ) _m -CON<

R' with m = 1 to 3, in which R and R are the same or different and represent hydrogen or an alkyl group with 1 to 6 carbon atoms, an acyl group with 1 to 4 carbon atoms or

R 1 and R2 together represent an alkylene group with 2 to 4 carbon atoms, which may optionally be mono- or disubstituted by a hydroxy group, an alkoxy group with 1 to 4 carbon atoms or an unsubstituted or mono- or disubstituted by benzyl or alkyl with 1 to 4 carbon atoms Amino group can be substituted, as well as their pharmacologically acceptable salts for the production of drugs to increase renal water and sodium excretion to reduce extracellular volume.

Use of compounds according to claim 1, in which n = 0 and R and R' are the same or different and represent a straight-chain or branched C ₁ - ₆ alkyl group.

3. Use of compounds according to claim 1, in which n = 0 and R and R 'are the same or different and represent a methyl, ethyl or isopropyl group.

4. Use of compounds according to claim 1, namely 1- (1-methylethyl) -2- [[1- (1-methylethyl) -4 (IH) - quinolinylidene] methyl] -quinolinium and its perchlorate disprocynium 24;

1-Ethyl -2- [ [l-ethyl-4 (IH) -quinolinylidenejmethyl] - quinolinium and its iodide decynium 24;

1 -Methyl-2- [ [l-methyl-2 (IH) -quinolinylidenejmethyl] - quinolinium (Mecynium 22); l-Methyl-2-[[l-methyl-4 (IH)-quinolinylidenejmethyl]-quinolinium (Mecynium 24);

1-Methyl-2-[[1-(1-methylethyl)-4(IH)-quinolinylidene]methyl]-quinolinium (isocynium 24);

1-Ethyl-2-[[1-(1-methylethyl)-4(IH)-quinolinylidene]methyl]quinolinium;

1-(1-Methylethyl)-2-[[l-methyl-4(IH)-quinolinylidene]methyl]-quinolinium;

1-Ethyl -2- [ [1-ethyl -2 (IH) -quinolinylidenejmethyl] - quinolinium and its iodide decynium 22; l-Ethyl-2-[[1-(1-methylethyl)-2(IH)-quinolinylidenejmethyl]quinolinium and its iodide iprecynium 22;

1-Methyl-2-[[1-(1-methylethyl)-2(IH)-quinolinylidene]methyl]-quinolinium;

1-(1-Methylethyl)-2-[[1-(1-methylethyl)-2(IH)-quinolinylidene]methyl]-quinolinium;

1-(1-Methylethyl)-2-[[l-methyl-2(IH)-quinolinylidene]methyl]-quinolinium;

1-(1-Methylethyl)-4-[[1-(1-methylethyl)-4(IH)-quinolinylidene]methyl]-quinolinium; l-Ethyl-4-[[l-ethyl-4(IH)-quinolinylidenejmethyl]-quinolinium; l-Methyl-4-[[l-methyl-4(IH)-quinolinylidene]methyl]-quinolinium;

1-Methyl-4-[[1-(1-methylethyl)-4(IH)-quinolinylidene]ethyl]-quinolinium; 1 -Ethyl -4- [ [1- (1-methylethyl) -4(1H) -quinolinylidenejmethyl] - quinolinium; and

1-(1-Methylethyl)-4-[[l-methyl-4(IH)-quinolinylidene]methyl]-quinolinium.

5. Medicines containing, in addition to the usual auxiliary and carrier substances, compounds mentioned in claims 1 to 4 for increasing diuresis and in particular natriuresis and for treating hypertension and chronic congestive myocardial insufficiency.

6. Containing medicines

1-(1-Methylethyl)-2-[[1-(1-methylethyl)-4(IH)-quinolinylidene]methyl]-quinolinium and its perchlorate

Disprocynium 24; l-Ethyl-2-[[l-ethyl-4 (IH)-quinolinylidenejmethyl]-quinolinium and its iodide decynium 24;

1-Methyl -2- [ [l-methyl-2 (IH) -quinolinylidenejmethyl] - quinolinium (Mecynium 22);

1-Methyl-2-[[l-methyl-4 (IH)-quinolinylidenejmethyl]-quinolinium (Mecynium 24); l-Methyl-2-[[1-(1-methylethyl)-4(IH)-quinolinylidene]methyl]-quinolinium (isocynium 24); l-Ethyl-2-[[1-(1-methylethyl)-4(IH)-quinolinylidenejmethyl]quinolinium;

1-(1-Methylethyl)-2-[[l-methyl-4(IH)-quinolinylidenejmethyl]-quinolinium; l-Ethyl-2-[[l-ethyl-2(IH)-quinolinylidenejmethyl]-quinolinium and its iodide decynium 22; l-Ethyl-2-[[1-(1-methylethyl)-2(IH)-quinolinylidenejmethyl]quinolinium and its iodide iprecynium 22;

1-Methyl-2-[[1-(1-methylethyl)-2(IH)-quinolinylidene]methyl]-quinolinium;

1-(1-Methylethyl)-2-[[l-methyl-2(IH)-quinolinylidene]methyl]-quinolinium;

1-(1-Methylethyl)-4-[[1-(1-methylethyl)-4(IH)- quinolinylidene]methyl]-quinolinium; l-Ethyl-4-[[l-ethyl-4(IH)-quinolinylidenejmethyl]-quinolinium; l-Methyl-4-[[l-methyl-4(IH)-quinolinylidenejmethyl]-quinolinium; l-Methyl-4-[[1-(1-methylethyl)-4(IH)-quinolinylidene]methyl]-quinolinium; l-Ethyl-4-[[1-(1-methylethyl)-4(IH)-quinolinylidenejmethyl]quinolinium; or

1-(1-Methylethyl)-4-[[l-methyl-4(IH)-quinolinylidene]methyl]-quinolinium alone or in combination of one or more of the

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