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WO1998035678A1 - Utilisation de cyanines, d'isocyanines et de pseudoisocyanines comme diuretiques - Google Patents

Utilisation de cyanines, d'isocyanines et de pseudoisocyanines comme diuretiques Download PDF

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Publication number
WO1998035678A1
WO1998035678A1 PCT/DE1997/002997 DE9702997W WO9835678A1 WO 1998035678 A1 WO1998035678 A1 WO 1998035678A1 DE 9702997 W DE9702997 W DE 9702997W WO 9835678 A1 WO9835678 A1 WO 9835678A1
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WO
WIPO (PCT)
Prior art keywords
methyl
quinolinium
methylethyl
ethyl
quinolinylidene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/DE1997/002997
Other languages
German (de)
English (en)
Inventor
Hartmut Osswald
Bernd Mühlbauer
Hermann Russ
Edgar Schömig
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to AU57486/98A priority Critical patent/AU729218B2/en
Priority to CA002281795A priority patent/CA2281795A1/fr
Priority to EP97953662A priority patent/EP0949924A1/fr
Priority to GB9919041A priority patent/GB2337202A/en
Priority to JP53520798A priority patent/JP2001512448A/ja
Publication of WO1998035678A1 publication Critical patent/WO1998035678A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • 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.
  • 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
  • n 0 to 6
  • 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-, Alkylsulfonylalky
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • MAP mean arterial blood pressure
  • UV urine time volume
  • UaV urine sodium excretion
  • 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 ⁇ g / kg DP24 and to 6.9 ⁇ 0.7 after furosemide.
  • IP22 urine time volume by infusion of 3 and 7.5 ⁇ g / kg / min iprecynium 22 (IP22) was increased by a factor of 2.5 to 50 ⁇ l / 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 ⁇ g / kg / min IP22 compared to time control animals and by 7.5 ⁇ g / kg / min IP22.
  • This IP22 dose therefore appears to be at least equieffective, if not stronger than DP24.
  • 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 ⁇ g / 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.
  • 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 ⁇ g / kg / 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 l ⁇ g / 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
  • 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
  • MAP mean arterial blood pressure GFR glomular filtration rate UV urine volume u Na v absolute sodium excretion

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

L'invention concerne l'utilisation de cyanines, d'isocyanines et de pseudoisocyanines pour la production de médicaments permettant d'augmenter la séparation de l'eau et du sodium par les reins en vue de réduire le volume extracellulaire et de traiter l'insuffisance cardiaque.
PCT/DE1997/002997 1997-02-17 1997-12-22 Utilisation de cyanines, d'isocyanines et de pseudoisocyanines comme diuretiques Ceased WO1998035678A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU57486/98A AU729218B2 (en) 1997-02-17 1997-12-22 Use of cyanines, isocyanines and pseudoisocyanines as diuretics
CA002281795A CA2281795A1 (fr) 1997-02-17 1997-12-22 Utilisation de cyanines, d'isocyanines et de pseudoisocyanines comme diuretiques
EP97953662A EP0949924A1 (fr) 1997-02-17 1997-12-22 Utilisation de cyanines, d'isocyanines et de pseudoisocyanines comme diuretiques
GB9919041A GB2337202A (en) 1997-02-17 1997-12-22 Use of cyanines,isocyaninines and pseudoisocyanines as diuretics
JP53520798A JP2001512448A (ja) 1997-02-17 1997-12-22 シアニン、イソシアニン及び疑似イソシアニンの利尿薬としての使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19706161A DE19706161A1 (de) 1997-02-17 1997-02-17 Verwendung von Cyaninen, Isocyaninen und Pseudoisocyaninen als Diuretika
DE19706161.3 1997-02-17

Publications (1)

Publication Number Publication Date
WO1998035678A1 true WO1998035678A1 (fr) 1998-08-20

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Application Number Title Priority Date Filing Date
PCT/DE1997/002997 Ceased WO1998035678A1 (fr) 1997-02-17 1997-12-22 Utilisation de cyanines, d'isocyanines et de pseudoisocyanines comme diuretiques

Country Status (7)

Country Link
EP (1) EP0949924A1 (fr)
JP (1) JP2001512448A (fr)
AU (1) AU729218B2 (fr)
CA (1) CA2281795A1 (fr)
DE (1) DE19706161A1 (fr)
GB (1) GB2337202A (fr)
WO (1) WO1998035678A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2020067055A1 (ja) * 2018-09-26 2021-09-16 株式会社林原 抗神経変性疾患剤

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2919447A1 (de) * 1978-05-17 1979-11-22 Takeda Chemical Industries Ltd Tumorhemmendes mittel
EP0417941A2 (fr) * 1989-08-30 1991-03-20 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Utilisation d'un colorant cyanine dans un agent antitumoral
EP0540400A1 (fr) * 1991-10-28 1993-05-05 Synthelabo Dérivés de quinoléine, utile comme angiotensine II antagonistes
DE4137009A1 (de) * 1991-11-11 1993-05-13 Schoemig Edgar Priv Doz Dr Hemmstoffe von zellulaeren transportsystemen fuer organische kationen

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2919447A1 (de) * 1978-05-17 1979-11-22 Takeda Chemical Industries Ltd Tumorhemmendes mittel
EP0417941A2 (fr) * 1989-08-30 1991-03-20 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Utilisation d'un colorant cyanine dans un agent antitumoral
EP0540400A1 (fr) * 1991-10-28 1993-05-05 Synthelabo Dérivés de quinoléine, utile comme angiotensine II antagonistes
DE4137009A1 (de) * 1991-11-11 1993-05-13 Schoemig Edgar Priv Doz Dr Hemmstoffe von zellulaeren transportsystemen fuer organische kationen

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
FRIEDGEN ET AL.: "The role of extraneuronal amine transport systems for the removal of extracellular catecholamines in the rabbit", NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, vol. 354, no. 3, 1996, pages 275 - 286, XP002068597 *
GRAEFE ET AL.: "1,1'-Diisopropyl-2,4'-cyanine (disprocynium24), a potent uptake2 blocker, inhibits the renal excretion of catecholamines", NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, vol. 356, no. 1, 1997, pages 115 - 125, XP002068601 *
KOSCHIER ET AL.: "The competitive inhibition of Tetraethylammonium Transport caused by 2,4,5-trichlorophenoxyacetate (2,4,5-T) in renal cortical slices", PHARMACOLOGIST, vol. 18, no. 2, 1976, pages 150, XP002068599 *
MÜHLBAUER ET AL.: "Disprocynium24 induces a dopamine-independent, eukaliuric diuresis and natriuresis in the anaesthetized rat", NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, vol. 356, no. 6, 1997, pages 846 - 849, XP002068600 *
RUSS ET AL.: "Isocyanines and Pseudoisocyanines as a Novel Class of Potent Noradrenaline Transport inhibitors: Synthesis, Detection, and Biological Activity", J. MED. CHEM., vol. 36, no. 26, 1993, pages 4208 - 4213, XP002068598 *
RUSS ET AL.: "Pharmacodynamic and alpha1-adrenoceptor antagonistic properties of two cyanine-type inhibitors of extraneuronal monoamine transport", NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, vol. 354, no. 3, 1996, pages 268 - 274, XP002068596 *
SOARES-DA-SILVA ET AL.: "THE CYANINE DERIVATIVE, 1,1-DIETHYL-2,4-CYANINE DECYNIUM 24) IS A POTENT INHIBITOR OF THE RENAL TUBULAR UPTAKE OF L-DOPA", BROITISH JOURNAL OF PHARMACOLOGY, vol. 112, 1994, pages 527P, XP002068603 *
ULLRICH ET AL.: "Luminal transport system for choline+ in relation to the other organic cation transport systems in the rat proximal tubule", PFLÜGERS ARCHIV - EUR. J. PHYSIOL, vol. 432, no. 3, 1996, pages 471 - 485, XP002068602 *

Also Published As

Publication number Publication date
CA2281795A1 (fr) 1998-08-20
EP0949924A1 (fr) 1999-10-20
GB2337202A (en) 1999-11-17
AU729218B2 (en) 2001-01-25
GB9919041D0 (en) 1999-10-13
DE19706161A1 (de) 1998-08-20
JP2001512448A (ja) 2001-08-21
AU5748698A (en) 1998-09-08

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