EP0946168A1 - Utilisation de disuccinate de diamine d'ethylene pour preparer un medicament a proprietes antivirales - Google Patents

Utilisation de disuccinate de diamine d'ethylene pour preparer un medicament a proprietes antivirales

Info

Publication number
EP0946168A1
EP0946168A1 EP97921801A EP97921801A EP0946168A1 EP 0946168 A1 EP0946168 A1 EP 0946168A1 EP 97921801 A EP97921801 A EP 97921801A EP 97921801 A EP97921801 A EP 97921801A EP 0946168 A1 EP0946168 A1 EP 0946168A1
Authority
EP
European Patent Office
Prior art keywords
edds
cations
medicament
viruses
substance
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.)
Withdrawn
Application number
EP97921801A
Other languages
German (de)
English (en)
Inventor
Hans Wilhelm Doerr
Kai Uwe Bindseil
Lutz MÜLLER-KUHRT
Holger Rabenau
Jindrich Cinatl
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.)
Doerr Hans-Wilhelm Prof Dr med
Analyticon AG Biotechnologie Pharmazie
Original Assignee
Doerr Hans-Wilhelm Prof Dr med
Analyticon AG Biotechnologie Pharmazie
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 Doerr Hans-Wilhelm Prof Dr med, Analyticon AG Biotechnologie Pharmazie filed Critical Doerr Hans-Wilhelm Prof Dr med
Publication of EP0946168A1 publication Critical patent/EP0946168A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]

Definitions

  • the invention relates to the use of ethylenediamine disuccinate including compatible salt-forming ions and the protonated form for the manufacture of a medicament with antiviral properties which also has an immunosuppressive effect.
  • (S, S) -N, N '-ethylenediamine disuccinate is described in detail in the publication by Takaaki NISHIKIORI et al. (1984), The Journal of Antibiotics, Vol. 37, No. 4: 426-427.
  • (S, S) - N, N'-ethylenediamine disuccinate can be obtained from actinomycetes and can also be prepared synthetically (JA Neal and NJ rose (1968), Inorg. Chem. Vol. 7; 2405-2412). It inhibits phospholipase C and D. If (S, S) - N, N'-ethylenediamine disuccinate is administered intraperitoneally to mice, the antibody production and the DTH reaction (delayed type hypersensitivity) are suppressed.
  • CMV cytomegaloviruses
  • the viruses are ubiquitous. The infection of the population varies from 30% to 85%, yes 95%. The infection runs inconspicuously in adults with a functional immune system and shows at most unspecific symptoms, such as fatigue and slightly increased body temperature.
  • CMV infections focus on pulmonary diseases, inflammation of the arteries and gastrointestinal disorders. In AIDS patients, CMV infections cause most deaths.
  • Foscarnet is an antiviral substance with selective activity against human viruses of the herpes group, such as herpes simplex, varicella zoster, Epstein-Barr and cytomegaloviruses as well as hepatitis viruses.
  • the antiviral effect is based on the inhibition of viral enzymes, such as DNA polymerases and reverse transcriptases.
  • Foscarnet has a virostatic effect on cytomegaloviruses, but the viruses cannot be eliminated (Lutz Schneider (1991), Pharmaceutical Newspaper, Vol. 136, No. 46, 33-36).
  • An essential problem of the cytomegalovirus infection is the necessity of the sometimes lifelong long-term treatment of the patients.
  • Ganciclovir is described in the publication by Lutz Schneider (1990), Pharmazie, Vol. 135, No. 37, 2396 to 2400.
  • Ganciclovir is one of the nucleoside antimetabolites derived from 2'-deoxiguanosine. It carries an acyclic side chain instead of the 2'-deoxyribose and differs from aciclovir only by an additional hydroxymethyl group in the side chain.
  • Ganciclovir is approved for the treatment of life or eyesight-threatening cytomegalovirus infections in patients with acquired immunodeficiency or medicinal immunosuppression, for example after organ transplants.
  • ganciclovir is also effective in other human pathogenic herpes viruses (HSV 1 and 2, Varicella zoster and Epstein-Barr), its use is prohibited because of the high rate of side effects such infections. Ganciclovir leads to neutropenia, and it has also been observed that mice develop tumors during the treatment. Another disadvantage is that the cytomegaloviruses have recently become more resistant to this substance (Stanat et al. (1991), Lancet, Vol. 337: 1292-1293).
  • WO 94/22438 (DINU, filing date: December 29, 1993) describes diethylenetriaminepentaacetic acid for the treatment of herpes simplex, varicella zoster, encephalomyelitis, polyradiculomiritis, multiple sclerosis, but not of cytomegaloviruses.
  • Immunosuppressants such as cyclosporin A or tacrolimus, have been used successfully in organ transplants to avoid or mitigate rejection reactions. The disadvantage of this is of course the susceptibility of the treated patients to serious complications caused by viral and bacterial infections. Infection with cytomegaloviruses is particularly worth mentioning in this context.
  • the technical problem underlying the invention is to provide a compound with an antiviral effect which also has an immunosuppressive effect.
  • the substance to be used according to the invention is significantly more effective in terms of its antiviral activity. Compared to the substance desferrioxamine, the substance according to the invention is more effective by a factor of 30.
  • the antiviral effect of the substance according to the invention can be modulated by adding iron (II) and iron (III) ions. Antiviral activity is reduced by a factor of 2 to 3, but is not completely eliminated. Thus it becomes obvious that the formation of iron chelate has an observable effect when acting as an antiviral agent, but it is also evident that this effect alone is not sufficient to explain the antiviral effect.
  • the substance according to the invention can be used very selectively against cytomegaloviruses. Concentrations of the substance according to the invention which have an antiviral effect have no effect on cell growth. The therapeutic index is therefore very high. The substance according to the invention is therefore of great clinical importance.
  • cytomegaloviruses can be used against cytomegaloviruses, but has no influence on certain other viruses, such as adenoviruses (ATTC strain: GB type 3), varicella zoster viruses (ATCC strain: Maclntyre) and herpes simplex viruses (HSV -Vero) has.
  • adenoviruses ATCC strain: GB type 3
  • varicella zoster viruses ATCC strain: Maclntyre
  • HSV -Vero herpes simplex viruses
  • the invention further comprises the ethylene diamine succinate according to the invention and its salts and / or acid groups.
  • the salts inevitably result from the environment and the physical state of the substance.
  • (S, S) -N, N '-ethylenediamine disuccinate in which the cations from the group of magnesium (II) -, aluminum (III) -, calcium (II) -, manganese (II) -, iron (II) -, iron (III) -, cobalt (II), nickel (II) -, copper (II) -, zinc (II) - ions and further lithium, potassium and sodium ions are selected or mixtures thereof previously mentioned ions are. Lithium, manganese (II), calcium (II), potassium and sodium ions are also particularly preferred.
  • the (S, S) -N, N'-ethylenediamine disuccinate is preferred, in which the salts comprise organic cations.
  • (S, S) -N, N '-ethylenediamine disuccinate in which the cations from the group of the primary; secondary or tertiary amines (e.g. ethanolamine, diethanoiamine, triethanolamine, morpholine, glucamine, N, N-dimethylglucamine and N-methylglucamine), lysine, arginine or ornithine are selected or the cations are mixtures of the cations mentioned above.
  • secondary or tertiary amines e.g. ethanolamine, diethanoiamine, triethanolamine, morpholine, glucamine, N, N-dimethylglucamine and N-methylglucamine
  • lysine, arginine or ornithine are selected or the cations are mixtures of the cations mentioned above.
  • a mixture of organic and inorganic salts is included in the invention.
  • the substance (S, S) -N, N'-ethylenediamine disuccinate is preferred as a medicament if it forms a composition with pharmacologically acceptable auxiliaries and carriers.
  • auxiliaries and carriers are described in Remington's Pharmaceutical Science, 15th ed. Mack Publishing Company, East Pennsylvania (1980).
  • the compositions can be prepared by known methods.
  • the (S, S) -N, N'-ethylenediamine disuccinate according to the invention has pharmacological properties and can therefore be used as an active pharmaceutical ingredient.
  • the invention also includes a medicament containing the (S, S) -N, N '-ethylenediamine disuccinate.
  • the substance (S, S) -N, N'-ethylenediamine disuccinate according to the invention has an activity against cytomegaloviruses.
  • the substance according to the invention shows an antiviral inhibition (IC 50 value) at concentrations of 4 ⁇ g / ml. Higher concentrations can be used without disturbing the test system.
  • the substance according to the invention can thus be used in a concentration of 0.5 to 100 ⁇ g / ml.
  • test results of this in vitro test show that the substance according to the invention can be used as a medicament or for medical treatment. These test results can easily be transferred from the in vitro test system to an in vivo system, since the antiviral test system is an established test set-up which serves to detect the antiviral activity (Gerna et al., (1992) Antiviral. Res. Vol. 19: 333-345). EDDS can therefore be used according to the invention for the treatment or prevention of cytomegalovirus infections, the substance also acting as an immunosuppressant. It can be used as an inhibitor in mammals, especially humans, for the treatment of the aforementioned disease.
  • the invention further provides
  • a pharmacological composition for the treatment or prevention of cytomegaloviruses which comprises a substance according to the invention and at least one pharmaceutical auxiliary and / or carrier.
  • Different doses are suitable for the therapeutic effect. They depend, for example, on the salts used, on the host, on the type of administration and on the type and severity of the conditions to be treated.
  • the daily doses range from 1 to 500 mg per kg. Include body weight.
  • a recommended daily dose is in the range from 1 to 50 mg per kg of body weight, a dose of 5 to being most preferred 30 mg per kg body weight.
  • this dose is expediently administered in partial doses up to four times a day. Satisfactory results can be expected if the substance according to the invention is administered subcutaneously or intravenously. Oral administration is also possible.
  • Antiviral activity cells and viruses used
  • HFF Human foreskin fibroblasts
  • EMEM Eagle's minimal essential medium
  • the CMV laboratory strain AD169 is used.
  • the viruses are propagated in EMEM culture medium with a 4% addition of fetal calf serum (maintenance medium).
  • the virus titer is determined by determining what are known as immediate early antigen forming units (I.E.F.U.) which are formed in the preservation medium (Gerna et al. (1992), Antiviral. Res., Vol. 19: 333-345).
  • IC 50 value represents the concentration of active ingredient which lowers the production rate of the antigen by 50%.
  • the sub- punches have an IC 50 value of 4 ⁇ g / ml ⁇ 1 ⁇ g / ml.
  • the cell vitality is measured in an HFF cell culture using an MTT assay.
  • the result is expressed by the TC 50 value, which is the concentration at which 50% of the cells tested are still vital. It is 435 ⁇ g / ml in HFF cells for the substances according to the invention.
  • the quotient TC S0 / IC 50 is formed from both values in order to determine the therapeutic index. In the substances according to the invention, this is 109 (Gerna et al. (1992) Antiviral Res. Vol. 19: 333-345).
  • lymphocyte cultures were prepared in mixed lymphocyte cultures (MLC) or with 1% phytohaemaglutinin (PHA) in a total volume of 200 ⁇ l culture medium. 18 to 20 hours before the measurement, 0.1 ⁇ Ci methyl [ 3 H] thymidine (NEN, Germany) was added. Radioactively labeled DNA was harvested on filter membranes (Schleicher & Schüll, Germany). The radioactivity was quantified using a scintillation counter (Zinsser, Germany). The PBL sample affects peripheral blood lymphocytes as a control standard.
  • MLC mixed lymphocyte cultures
  • PHA phytohaemaglutinin

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

On utilise le disuccinate de diamine d'éthylène-(S,S)-N,N' (EDDS) qui répond à la formule (I), dans laquelle M = H+ et/ou désigne un cation pharmaceutiquement acceptable, pour préparer un médicament pour le traitement d'infections par des cytomégalovirus à propriétés immunodépressives.
EP97921801A 1996-04-27 1997-04-26 Utilisation de disuccinate de diamine d'ethylene pour preparer un medicament a proprietes antivirales Withdrawn EP0946168A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19616992A DE19616992C1 (de) 1996-04-27 1996-04-27 Verwendung von Ethylendiamindisuccinat zur Behandlung von Infektionen mit Cytomegalieviren
DE19616992 1996-04-27
PCT/EP1997/002175 WO1997040827A1 (fr) 1996-04-27 1997-04-26 Utilisation de disuccinate de diamine d'ethylene pour preparer un medicament a proprietes antivirales

Publications (1)

Publication Number Publication Date
EP0946168A1 true EP0946168A1 (fr) 1999-10-06

Family

ID=7792705

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97921801A Withdrawn EP0946168A1 (fr) 1996-04-27 1997-04-26 Utilisation de disuccinate de diamine d'ethylene pour preparer un medicament a proprietes antivirales

Country Status (6)

Country Link
US (1) US6140367A (fr)
EP (1) EP0946168A1 (fr)
AU (1) AU2772997A (fr)
CA (1) CA2252779A1 (fr)
DE (1) DE19616992C1 (fr)
WO (1) WO1997040827A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2333704A (en) * 1998-01-31 1999-08-04 Procter & Gamble Contrasting compositions for magnetic resonance imaging comprising a complex of ethylene diamine disuccinic acid and one or more paramagnetic metal ions
GB2333703A (en) * 1998-01-31 1999-08-04 Procter & Gamble Complexing agents (eg N,N'-ethylenediamine disuccinic acid) in reduction of enzyme activity & hence treatment of enzymatic dermatitis, skin rash and malodour

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4704233A (en) * 1986-11-10 1987-11-03 The Procter & Gamble Company Detergent compositions containing ethylenediamine-N,N'-disuccinic acid
FI932171A7 (fi) * 1990-11-14 1993-05-13 Procter & Gamble Happivalkaisuainejärjestelmiä sisältävät fosfaatittomat automaattiasti anpesuainekoostumukset ja menetelmä niiden valmistamiseksi
GB2288812B (en) * 1994-04-26 1998-08-26 Procter & Gamble Cleansing compositions
US5466867A (en) * 1994-07-11 1995-11-14 Albemarle Corporation Method for producing [S,S]-ethylenediamine-N,N'-disuccinic acid from its calcium salt

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9740827A1 *

Also Published As

Publication number Publication date
WO1997040827A1 (fr) 1997-11-06
CA2252779A1 (fr) 1997-11-06
US6140367A (en) 2000-10-31
DE19616992C1 (de) 1997-09-11
AU2772997A (en) 1997-11-19

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Inventor name: CINATL, JINDRICH

Inventor name: RABENAU, HOLGER

Inventor name: MUELLER-KUHRT, LUTZ

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