EP1663198A1 - Pharmaceutical formulations of xanthogenates and inhibitors of viral nucleic acid replication (e.g. aciclovir) - Google Patents

Pharmaceutical formulations of xanthogenates and inhibitors of viral nucleic acid replication (e.g. aciclovir)

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Publication number
EP1663198A1
EP1663198A1 EP04764981A EP04764981A EP1663198A1 EP 1663198 A1 EP1663198 A1 EP 1663198A1 EP 04764981 A EP04764981 A EP 04764981A EP 04764981 A EP04764981 A EP 04764981A EP 1663198 A1 EP1663198 A1 EP 1663198A1
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Prior art keywords
pharmaceutical formulation
nucleic acid
formulation according
viral nucleic
inhibitor
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EP04764981A
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German (de)
French (fr)
Inventor
Eberhard Amtmann
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Shogoo Pharmaceuticals KK
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Shogoo Pharmaceuticals KK
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Publication of EP1663198A1 publication Critical patent/EP1663198A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to pharmaceutical formulations of xanthates in combination with inhibitors of viral nucleic acid replication and agents containing these formulations for the treatment of viral diseases.
  • Xanthates especially tricyclodecane-9yl xanthate (D609), are known as substances with antiviral and antitumoral activity, e.g. from "DNA and RNA virus species are inhibited by xanthates, a class of antiviral compounds with unique properties" Sauer-G; Amtmann-E; Melber-K; Knapp-A; Muller-K; Hummel- K; Scherm-A, in Proc-Natl-Acad-Sci-USA. 1984 Jun; 81 (11): 3263-7; "Selective killing of tumor cells by xanthates" Amtmann-E; Sauer-G, in Cancer-Lett. 1987 Jun; 35 (3rd ): 237-44 and US Patent No 4, 602, 037.
  • antiviral and antitumoral xanthates encounters the problem that relatively high active substance concentrations are required in order to be effective in the animal model. Since the concentration of the active ingredient is limited for both pharmacological and technical reasons, only a limited healing effect can be achieved even at the highest concentrations that can be used. The same problem affects common antiviral inhibitors such as acyclovir, valaciclovir or famciclovir.
  • a combination of xanthate derivatives such as D609 with inhibitors of viral nucleic acid replication such as acyclovir leads to a synergistic increase in activity.
  • concentrations of the xanthate up to five times the activity of aciclovir was observed in the cell culture.
  • the combination of D609 and acyclovir was able to survive all animals infected with HSV-1 can be reached. Each active ingredient applied alone caused only partial healing.
  • the present invention thus solves the above problem by providing a pharmaceutical formulation containing a xanthate and an inhibitor of viral DNA or RNA replication.
  • the formulation contains a xanthate of the general formula I.
  • R 1 represents an optionally substituted aryl or alkyl radical.
  • Ri is preferably an adamantyl, norbornyl, tricyclodecyl, benzyl, straight or branched C 3 -C 2 o-alkyl, C 3 -C 2 o-cycloalkyl, furyl, pyridyl, anthracyl, naphthyl -, Phenanthryl, perinaphtyl or quinuclidinyl radical, the above-mentioned straight or branched C 3 -C 2 o-alkyl radical being substituted by a hydroxyl, a C 4 -C 4 alkoxy group, a halogen atom or an amino group and the above C 3 - C 2 o-Cycloalkylrest can also be substituted by a hydroxyl, a C 1 -C 4 alkoxy or a CrC 4 alkyl group, a halogen atom or an amino group.
  • Ri particularly advantageous for Ri are cyclododecyl, dodecyl, undecyl, decyl, tricyclo [5.2.1, 2.6 ] decyl, nonyl, octyl, bicyclo [2.2.1] heptyl -, Cyclohexyl, Hexyl, Toluoyl residues. Very particularly advantageously an exo / exo-tricyclo [5.2.1.0 2 - 6] -decylrest.
  • R2 represents a metal atom, an optionally substituted alkyl, alkoxy, amino or ammonium group or halogen.
  • R2 represents a mono- or polyvalent metal atom, a straight C 1-8 alkyl radical, a C r C 6 substituted by hydroxy -Alkylrest, a C ⁇ C ß -alkoxy, an amino group, a a di (C 1 -C 6 alkyl) amino radical, a tri (C r C 6 alkyl) - ammonium radical, a halogen, 2,3-dihydroxypropyl or hydroxy- (C 1 -C 6 alkoxy) - methyl.
  • Sodium and potassium salts and dimethylglycyl and methyl esters are particularly advantageous.
  • the inhibitor of viral nucleic acid replication is preferably a nucleoside analog, and particularly advantageously bromodeoxyuridine (BudR), fluorodeoxyuridine (FudR), aciclovir, valaciclovir, penciclvir or famciclovir.
  • the inhibitor of viral nucleic acid replication can also be an inhibitor of viral helicase.
  • the inhibitor of viral nucleic acid replication can also be an inhibitor of a cellular enzyme.
  • Formulations in which 0.1 to 10 parts of inhibitor of viral nucleic acid replication are contained per part of xanthate have proven to be very suitable.
  • a ratio of xanthate to inhibitor of viral nucleic acid replication of 1: 1 is particularly advantageous.
  • the formulation according to the invention preferably additionally contains an ionic detergent as an activity-enhancing adjuvant, as is described in US Pat. No. 4,851,435.
  • a fatty acid with 6-19 C atoms or its salt is particularly preferred as adjuvant.
  • the potassium salts of decanoic, undecanoic or lauric acid are particularly preferred.
  • the activity-increasing adjuvant can also be a sulfate with an aliphatic radical of 8-18 C atoms. Na lauric sulfate is particularly preferred.
  • Deoxycholic acid or a pharmaceutically acceptable salt thereof or a phosphonic acid is also suitable for the adjuvant.
  • xanthate according to WO 96/14841 in lipid- or steroid-based carrier substances.
  • the introduction into a carrier substance improves the tolerance of the agents.
  • the carrier substance is in particular a steroid such as cholesterol, cholestanol, cholanic acid, chondrillasterol and ⁇ , ⁇ , ⁇ Sisterol.
  • Xanthate and optionally adjuvant according to DE 101 17 728 are particularly preferably mixed with the carrier substance.
  • Cholesterol is very particularly preferred.
  • Also suitable as carrier substance are phospholipids, in particular phosphatidylcholine, phosphatidylserine,
  • a formulation containing aciclovir, the Na or K salt of decanoic acid and the exo / exo-tricyclo [5,2,1,0 2 ' 6 ] -9yl-xanthate is particularly preferred.
  • one part of xanthate contains one part of potassium salt of decanoic acid and one part of acyclovir.
  • Another particularly preferred formulation contains phosphatidylcholine or cholesterol, the Na or K salt of decanoic acid, exo / exo-tricyclo [5.2.1, 0 2.6 ] -9yl-xanthate and acyclovir.
  • one part of xanthate contains one part of decanoic acid, four parts of phosphatidylcholine or cholesterol and one part of acyclovir.
  • the present invention further provides, according to claims 11 to 16, agents for the treatment of viral, tumor or autoimmune diseases which contain the pharmaceutical formulation.
  • the compositions also contain customary carrier substances and / or customary auxiliaries.
  • Other active ingredients can also be included, provided that they do not impair the action or the stability of the xanthates and the inhibitors of viral nucleic acid replication.
  • Agents in the form of ointments are particularly preferred, a lipophilic substance being used as the ointment base.
  • Vaseline is preferably used as the ointment base.
  • the pharmaceutical formulations and agents containing them are suitable for the treatment of viral, tumor and autoimmune diseases.
  • Human lung carcinoma cells (Calu-6) were infected with 30 plaque-forming units of herpes simplex virus (Type-1, strain ANG) in linbro plates. Two hours after the infection, cell culture media (MEM, with 10% fetal calf serum, 0.85 g / l sodium bicarbonate and 0.5% carboxymethyl cellulose), which was either 0, 5 or 10 ⁇ g / ml exo / exo-tricyclo [5.2 , 1, 0 2 ' 6 ] -9yl-xanthate (D609) was added. At the same time, the cultures were treated with acyclovir. All approaches were carried out four times. The cells were incubated for 48 h at 37 ° C under CO 2 (5%). After the medium had been tipped over, the cells were fixed with 3% formalin and stained with 0.5% crystal violet. After drying at room temperature, the number of plaques formed was determined.
  • MEM herpes simplex virus
  • FIG. 1 The results are illustrated in FIG. 1, in which the mean number of plaques is plotted against the concentration of acyclovir.
  • the series without D609 is shown as squares, the series with 5 ⁇ g / ml D609 as circles and the series with 10 ⁇ g / ml D609 as triangles. It can clearly be seen that in the presence of concentrations D609 which are not effective on their own, the action of acyclovir starts at considerably lower concentrations at which acyclovir alone has no effect.
  • D609 was mixed together with the same part by weight of potassium salt of decanoic acid and four parts by weight of cholesterol in a mortar. Then propylene glycol (final concentration 10%) and petroleum jelly were added so that a concentration of 5% D609 was reached. In the same way, ointments containing 5% acyclovir or 5% D609 and 5% acyclovir were prepared. A placebo ointment was prepared analogously, which contained neither of the two active ingredients.
  • mice each (strain Balb-C) were shaved on the thigh and the skin was scored 6 times with a cannula on an area of 5x5 mm. Then were Apply 50 ⁇ l of an HSV-1 suspension (strain whale, 10 8 plaque-forming units / ml) with a cotton swab. Treatment was started four days after infection (twice daily). The symptoms “Spreading lesions”, “Paralysis of the hind legs” and survival were recorded.
  • HSV-1 suspension strain whale, 10 8 plaque-forming units / ml
  • FIGS. 2a to 2d The result is shown graphically in FIGS. 2a to 2d.
  • the number of animals with the corresponding symptoms is plotted against the number of days after infection.
  • Triangles indicate the surviving animals, squares the animals with paralysis of the hind legs and rhombuses the animals with spread lesions.
  • the combination product is therefore significantly more effective than the individual products.
  • With the combination preparation the survival of all animals as well as less symptoms and faster healing of the symptoms is achieved.

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Abstract

The invention relates to pharmaceutical formulations of xanthogenates and agents containing said formulations for use in the treatment of viral, cancer or autoimmune diseases. The pharmaceutical formulations contain a xanthogenate of formula (I), wherein R1 represents an optionally substituted aryl or alkyl group and R2 represents a metal atom, an optionally substituted alkyl, alkoxy, amino or ammonium group or halogen, and an inhibitor of viral nucleic acid replication such as e.g. aciclovir, valaciclovir, penciclovir, famciclovir, and optionally an excipient which reduces the irritating effects of xanthogenate and optionally an activity-increasing adjuvant.

Description

PHARMAZEUTISCHE FORMULIERUNGEN VON XANTHOGENATEN UND HEMMSTOFFEN DER VIRALEN NUKLEINSÄUREREPLIKATION ( Z . B . ACICLOVIR)PHARMACEUTICAL FORMULATIONS OF XANTHOGENATES AND INHIBITORS OF VIRAL NUCLEIC ACID REPLICATION (e.g. ACICLOVIR)
Die Erfindung betrifft pharmazeutische Formulierungen von Xanthogenaten in Kombination mit Hemmstoffen der viralen Nukleinsäurereplikation und Mittel, die diese Formulierungen enthalten, zur Behandlung von Viruserkrankungen.The invention relates to pharmaceutical formulations of xanthates in combination with inhibitors of viral nucleic acid replication and agents containing these formulations for the treatment of viral diseases.
Xanthogenate, insbesondere Tricyclodecan-9yl-xanthogenat (D609), sind als Substanzen mit antiviraler und antitumoraler Aktivität bekannt, z.B. aus „DNA and RNA virus species are inhibited by xanthates, a class of antiviral compounds with unique properties" Sauer-G; Amtmann-E; Melber-K; Knapp-A; Muller-K; Hummel- K; Scherm-A, in Proc-Natl-Acad-Sci-U-S-A. 1984 Jun; 81(11): 3263-7; "Selective killing of tumor cells by xanthates" Amtmann-E; Sauer-G, in Cancer-Lett. 1987 Jun; 35(3): 237-44 und U.S. Patent No 4, 602, 037.Xanthates, especially tricyclodecane-9yl xanthate (D609), are known as substances with antiviral and antitumoral activity, e.g. from "DNA and RNA virus species are inhibited by xanthates, a class of antiviral compounds with unique properties" Sauer-G; Amtmann-E; Melber-K; Knapp-A; Muller-K; Hummel- K; Scherm-A, in Proc-Natl-Acad-Sci-USA. 1984 Jun; 81 (11): 3263-7; "Selective killing of tumor cells by xanthates" Amtmann-E; Sauer-G, in Cancer-Lett. 1987 Jun; 35 (3rd ): 237-44 and US Patent No 4, 602, 037.
Die pharmazeutische Verwendung von antiviral und antitumoral wirksamen Xanthogenaten stößt auf das Problem, dass relativ hohe Wirkstoffkonzentrationen benötigt werden, um im Tiermodell Wirksamkeit zu zeigen. Da die Konzentration des Wirkstoffes sowohl aus pharmakologischen als auch aus technischen Gründen begrenzt ist, kann selbst bei den höchsten einsetzbaren Konzentrationen nur ein begrenzter Heileffekt erzielt werden. Das gleiche Problem betrifft die gebräuchlichen antiviralen Hemmstoffe wie Aciclovir, Valaciclovir oder Famciclovir.The pharmaceutical use of antiviral and antitumoral xanthates encounters the problem that relatively high active substance concentrations are required in order to be effective in the animal model. Since the concentration of the active ingredient is limited for both pharmacological and technical reasons, only a limited healing effect can be achieved even at the highest concentrations that can be used. The same problem affects common antiviral inhibitors such as acyclovir, valaciclovir or famciclovir.
Wir haben überraschend gefunden, dass durch eine Kombination von Xanthogenatderivaten wie D609 mit Hemmstoffen viraler Nukleinsäurereplikation wie Aciclovir eine synergistische Wirkungssteigerung eintritt. In Anwesenheit von niedrigen, antiviral unwirksamen Konzentrationen des Xanthogenats wurde eine bis zu fünffach höhere Wirkung von Aciclovir in der Zellkultur beobachtet. Im Tierversuch konnte durch die Kombination von D609 und Aciclovir das Überleben aller mit HSV-1 infizierter Tiere erreicht werden. Jeder Wirkstoff für sich alleine appliziert bewirkte nur eine Teilheilung.We have surprisingly found that a combination of xanthate derivatives such as D609 with inhibitors of viral nucleic acid replication such as acyclovir leads to a synergistic increase in activity. In the presence of low, antivirally ineffective concentrations of the xanthate, up to five times the activity of aciclovir was observed in the cell culture. In animal experiments, the combination of D609 and acyclovir was able to survive all animals infected with HSV-1 can be reached. Each active ingredient applied alone caused only partial healing.
Die vorliegende Erfindung löst somit das oben genannte Problem, indem eine pharmazeutische Formulierung bereitgestellt wird, die ein Xanthogenat und einen Hemmstof viraler DNA- oder RNA-Replikation enthält.The present invention thus solves the above problem by providing a pharmaceutical formulation containing a xanthate and an inhibitor of viral DNA or RNA replication.
Die Formulierung enthält ein Xanthogenat der allgemeinen Formel IThe formulation contains a xanthate of the general formula I.
wobei Ri für einen gegebenenfalls substituierten Aryl- oder Alkylrest steht. Vorzugsweise steht Ri für einen Adamantyl-, Norbornyl-, Tricyclodecyl-, Benzyl-, geraden oder verzweigten C3-C2o-Alkyl-, C3-C2o-Cycloalkyl-, Furyl-, Pyridyl-, Anthracyl-, Naphtyl-, Phenanthryl-, Perinaphtyl- oder Chinuclidinyl-Rest, wobei der obengenannte gerade oder verzweigte C3-C2o-Alkylrest durch eine Hydroxyl-, eine Cι-C4-Alkoxygruppe, ein Halogenatom oder eine Aminogruppe und der obengenannte C3-C2o-Cycloalkylrest ebenfalls durch eine Hydroxyl-, eine C1-C4- Alkoxy- oder eine CrC4-Alkylgruppe, ein Halogenatom oder eine Aminogruppe substituiert sein können. Besonders vorteilhaft für Ri sind Cyclododecyl-, Dodecyl-, Undecyl-, Decyl-, Tricyclo[5,2,1 ,02,6]-decyl-, nonyl-, octyl-, Bicyclo[2,2,1]- heptyl-, Cyclohexyl-, Hexyl-, Toluoyl- Reste. Ganz besonders vorteilhaft ist ein Exo/Exo-Tricyclo[5.2.1.02-6]-decylrest.where R 1 represents an optionally substituted aryl or alkyl radical. Ri is preferably an adamantyl, norbornyl, tricyclodecyl, benzyl, straight or branched C 3 -C 2 o-alkyl, C 3 -C 2 o-cycloalkyl, furyl, pyridyl, anthracyl, naphthyl -, Phenanthryl, perinaphtyl or quinuclidinyl radical, the above-mentioned straight or branched C 3 -C 2 o-alkyl radical being substituted by a hydroxyl, a C 4 -C 4 alkoxy group, a halogen atom or an amino group and the above C 3 - C 2 o-Cycloalkylrest can also be substituted by a hydroxyl, a C 1 -C 4 alkoxy or a CrC 4 alkyl group, a halogen atom or an amino group. Particularly advantageous for Ri are cyclododecyl, dodecyl, undecyl, decyl, tricyclo [5.2.1, 2.6 ] decyl, nonyl, octyl, bicyclo [2.2.1] heptyl -, Cyclohexyl, Hexyl, Toluoyl residues. Very particularly advantageously an exo / exo-tricyclo [5.2.1.0 2 - 6] -decylrest.
R2 stellt ein Metallatom, eine gegebenenfalls substituierte Alkyl-, Alkoxy-, Amino- oder Ammoniumgruppe oder Halogen dar. Vorzugsweise steht R2 für ein ein- oder mehrwertiges Metallatom, einen geraden C^C8-Alkylrest, einen durch Hydroxy substituierten CrC6-Alkylrest, einen C^Cß-Alkoxyrest, eine Aminogruppe, einen einen Di-(C1-C6-Alkyl)-Aminorest, einen Tri-(CrC6-Alkyl)- ammoniumrest, ein Halogen, 2,3-Dihydroxypropyl oder Hydroxy-(C1-C6-alkoxy)- methyl. Besonders vorteilhaft sind Natrium- und Kalium-Salze sowie Dimethylglycyl- und Methylester.R2 represents a metal atom, an optionally substituted alkyl, alkoxy, amino or ammonium group or halogen. Preferably R2 represents a mono- or polyvalent metal atom, a straight C 1-8 alkyl radical, a C r C 6 substituted by hydroxy -Alkylrest, a C ^ C ß -alkoxy, an amino group, a a di (C 1 -C 6 alkyl) amino radical, a tri (C r C 6 alkyl) - ammonium radical, a halogen, 2,3-dihydroxypropyl or hydroxy- (C 1 -C 6 alkoxy) - methyl. Sodium and potassium salts and dimethylglycyl and methyl esters are particularly advantageous.
Der Hemmstoff viraler Nukleinsäurereplikation ist bevorzugt ein Nukleosid- analogon, und besonders vorteilhaft Bromdesoxyuridin (BudR), Fluordesoxyuridin (FudR), Aciclovir, Valaciclovir, Penciclvir oder Famciclovir.The inhibitor of viral nucleic acid replication is preferably a nucleoside analog, and particularly advantageously bromodeoxyuridine (BudR), fluorodeoxyuridine (FudR), aciclovir, valaciclovir, penciclvir or famciclovir.
Der Hemmstoff viraler Nukleinsäurereplikation kann auch ein Hemmstoff viraler Helikase sein.The inhibitor of viral nucleic acid replication can also be an inhibitor of viral helicase.
Der Hemmstoff viraler Nukleinsäurereplikation kann auch ein Hemmstoff eines zellulären Enzyms sein.The inhibitor of viral nucleic acid replication can also be an inhibitor of a cellular enzyme.
Formulierungen, in denen pro ein Teil Xanthogenat 0,1 bis 10 Teile Hemmstoff viraler Nukleinsäurereplikation enthalten sind, haben sich als gut geeignet erwiesen. Besonders vorteilhaft ist ein Verhältnis von Xanthogenat zu Hemmstoff viraler Nukleinsäurereplikation von 1 :1.Formulations in which 0.1 to 10 parts of inhibitor of viral nucleic acid replication are contained per part of xanthate have proven to be very suitable. A ratio of xanthate to inhibitor of viral nucleic acid replication of 1: 1 is particularly advantageous.
Vorzugsweise enthält die erfindungsgemäße Formulierung zusätzlich ein ionisches Detergens als Wirkungsverstärkendes Adjuvans, wie es in der US 4,851 ,435 beschrieben ist. Als Adjuvans ist eine Fettsäure mit 6 - 19 C-Atomen oder deren Salz besonders bevorzugt. Insbesondere bevorzugt sind die Kaliumsalze der Decan-, Undecan- oder Laurinsäure. Das die Aktivität erhöhende Adjuvans kann auch ein Sulfat mit einem aliphatischen Rest von 8-18 C-Atomen sein. Besonders bevorzugt ist Na-Laurinsulfat. Weiter kommt für das Adjuvans Deoxycholinsäure oder ein pharmazeutisch verträgliches Salz davon oder eine Phosphonsäure in Betracht. Es ist weiterhin bevorzugt, das Xanthogenat gemäß WO 96/14841 in Lipid- oder Steroid-basierende Trägersubstanzen zu Inkorporieren. Die Einbringung in eine Trägersubstanz verbessert die Verträglichkeit der Mittel. Die Trägersubstanz ist hierbei insbesondere ein Steroid wie Cholesterin, Cholestanol, Cholansäure, Chondrillasterol und α, ß, γ Sisterol.The formulation according to the invention preferably additionally contains an ionic detergent as an activity-enhancing adjuvant, as is described in US Pat. No. 4,851,435. A fatty acid with 6-19 C atoms or its salt is particularly preferred as adjuvant. The potassium salts of decanoic, undecanoic or lauric acid are particularly preferred. The activity-increasing adjuvant can also be a sulfate with an aliphatic radical of 8-18 C atoms. Na lauric sulfate is particularly preferred. Deoxycholic acid or a pharmaceutically acceptable salt thereof or a phosphonic acid is also suitable for the adjuvant. It is further preferred to incorporate the xanthate according to WO 96/14841 in lipid- or steroid-based carrier substances. The introduction into a carrier substance improves the tolerance of the agents. The carrier substance is in particular a steroid such as cholesterol, cholestanol, cholanic acid, chondrillasterol and α, β, γ Sisterol.
Besonders bevorzugt werden Xanthogenat und gegebenenfalls Adjuvans entsprechend der DE 101 17 728 mit der Trägersubstanz vermischt. Ganz besonders bevorzugt ist Cholesterin. Als Trägersubstanz eignen sich auch Phospholipide, insbesondere Phosphatidylcholin, Phosphatidylserin,Xanthate and optionally adjuvant according to DE 101 17 728 are particularly preferably mixed with the carrier substance. Cholesterol is very particularly preferred. Also suitable as carrier substance are phospholipids, in particular phosphatidylcholine, phosphatidylserine,
Phosphatidylinositol oder Stearylamin.Phosphatidylinositol or stearylamine.
Besonders bevorzugt ist eine Formulierung, die Aciclovir, das Na- oder K-Salz der Decansäure und das Exo/Exo-Tricyclo[5,2,1 ,02'6]-9yl-xanthogenat enthält. Insbesondere kommen auf einen Teil Xanthogenat ein Teil Kaliumsalz der Decansäure und ein Teil Aciclovir.A formulation containing aciclovir, the Na or K salt of decanoic acid and the exo / exo-tricyclo [5,2,1,0 2 ' 6 ] -9yl-xanthate is particularly preferred. In particular, one part of xanthate contains one part of potassium salt of decanoic acid and one part of acyclovir.
Eine weitere besonders bevorzugte Formulierung enthält Phosphatidylcholin oder Cholesterin, das Na- oder K-Salz der Decansäure, Exo/Exo-Tricyclo[5,2,1 ,02,6]-9yl- xanthogenat und Aciclovir. Insbesondere kommen auf einen Teil Xanthogenat ein Teil Decansäure, vier Teile Phosphatidylcholin oder Cholesterin und ein Teil Aciclovir.Another particularly preferred formulation contains phosphatidylcholine or cholesterol, the Na or K salt of decanoic acid, exo / exo-tricyclo [5.2.1, 0 2.6 ] -9yl-xanthate and acyclovir. In particular, one part of xanthate contains one part of decanoic acid, four parts of phosphatidylcholine or cholesterol and one part of acyclovir.
Die vorliegende Erfindung stellt gemäß Ansprüchen 11 bis 16 weiterhin Mittel zur Behandlung von Virus-, Tumor- oder Autoimmunerkrankungen bereit, die die pharmazeutische Formulierung enthalten. Die Mittel enthalten weiterhin übliche Trägersubstanzen und/oder übliche Hilfsstoffe. Es können auch weitere Wirkstoffe enthalten sein, soweit sie weder die Wirkung noch die Stabilität der Xanthogenate und der Hemmstoffe viraler Nukleinsäurereplikation beeinträchtigen. Insbesondere bevorzugt sind Mittel in Form von Salben, wobei als Salbengrundlage eine lipophile Substanz benutzt wird. Vorzugsweise wird als Salbengrundlage Vaseline benutzt.The present invention further provides, according to claims 11 to 16, agents for the treatment of viral, tumor or autoimmune diseases which contain the pharmaceutical formulation. The compositions also contain customary carrier substances and / or customary auxiliaries. Other active ingredients can also be included, provided that they do not impair the action or the stability of the xanthates and the inhibitors of viral nucleic acid replication. Agents in the form of ointments are particularly preferred, a lipophilic substance being used as the ointment base. Vaseline is preferably used as the ointment base.
Die erfindungsgemäßen pharmazeutischen Formulierungen und Mittel, die sie enthalten, eignen sich zur Behandlung von Virus-, Tumor- und Autoimmunerkrankungen.The pharmaceutical formulations and agents containing them are suitable for the treatment of viral, tumor and autoimmune diseases.
Die folgenden Beispiele erläutern die Erfindung weiter, ohne sie jedoch zu beschränken.The following examples illustrate the invention without, however, restricting it.
Beispiel 1example 1
Synergistische Steigerung der Hemmwirkung von Aciclovir auf dieSynergistic increase in the inhibitory effect of acyclovir on the
Vermehrung von Herpes simplex Viren durch das exo/exo-lsomer vonMultiplication of herpes simplex viruses by the exo / exo isomer of
Tricyclo[5,2,1,02,6]-9yl-xanthogenat.Tricyclo [5.2.1.0 2.6 ] -9yl-xanthate.
Menschliche Lungenkarzinomzellen (Calu-6) wurden mit 30 plaquebildenden Einheiten Herpes simplex Viren (Type-1 , Stamm ANG) in Linbroplatten infiziert. Zwei Stunden nach der Infektion wurde Zellkulturmediun (MEM, mit 10 % fötalem Kälberserum, 0,85 g/l Natriumbikarbonat und 0,5 % Carboximethylzellulose), das entweder 0, 5 oder 10 μg/ml Exo/Exo-Tricyclo[5,2,1 ,02'6]-9yl-xanthogenat (D609) enthielt, zugegeben. Gleichzeitig wurden die Kulturen mit Aciclovir behandelt. Alle Ansätze wurden 4-fach ausgeführt. Die Zellen wurden für 48 h bei 37 °C untder CO2-Begasung (5 %) inkubiert. Nach Abkippen des Mediums wurden die Zellen mit 3 % Formalin fixiert und mit 0,5 % Kristallviolett gefärbt. Nach Trocknen bei Raumtemperatur wurde die Zahl der gebildeten Plaques bestimmt.Human lung carcinoma cells (Calu-6) were infected with 30 plaque-forming units of herpes simplex virus (Type-1, strain ANG) in linbro plates. Two hours after the infection, cell culture media (MEM, with 10% fetal calf serum, 0.85 g / l sodium bicarbonate and 0.5% carboxymethyl cellulose), which was either 0, 5 or 10 μg / ml exo / exo-tricyclo [5.2 , 1, 0 2 ' 6 ] -9yl-xanthate (D609) was added. At the same time, the cultures were treated with acyclovir. All approaches were carried out four times. The cells were incubated for 48 h at 37 ° C under CO 2 (5%). After the medium had been tipped over, the cells were fixed with 3% formalin and stained with 0.5% crystal violet. After drying at room temperature, the number of plaques formed was determined.
In den Kulturen ohne D609 wurden 32,75 ± 11 Plaques gezählt. In Anwesenheit von 5 oder 10 μg/ml D609 wurden 32 ± 3 Plaques und 33 ± 6 Plaques gezählt. D.h. D609 hatte bei diesen Konzentrationen keinen Effekt auf die Plaquebildung. Bei einer Konzentration von 0,16 μM Aciclovir wurde die Zahl der Plaques auf 30 ± 11 reduziert. Dieser Effekt war nicht signifikant (Studenf t-Test p = 0,4).In the cultures without D609, 32.75 ± 11 plaques were counted. In the presence of 5 or 10 μg / ml D609, 32 ± 3 plaques and 33 ± 6 plaques were counted. That is, D609 had no effect on plaque formation at these concentrations. At a concentration of 0.16 μM acyclovir, the number of plaques was reduced to 30 ± 11. This effect was not significant (Studenf t test p = 0.4).
In Anwesenheit von 10 μg/ml D609 wurde bei einer Konzentration von 0,16 μM Aciclovir die Zahl der Plaques auf 9,5 ± 5,1 reduziert. Dieser Effekt war signifikant (Studenf t-Test p = 0,014).In the presence of 10 μg / ml D609, the number of plaques was reduced to 9.5 ± 5.1 at a concentration of 0.16 μM aciclovir. This effect was significant (Studenf t test p = 0.014).
Die Ergebnisse sind in Figur 1 veranschaulicht, bei der die mittlere Anzahl der Plaques gegen die Konzentration Aciclovir aufgetragen ist. Die Messreihe ohne D609 ist als Quadrate, die Messreihe mit 5 μg/ml D609 als Kreise und die Messreihe mit 10 μg/ml D609 als Dreiecke eingezeichnet. Man sieht deutlich, dass in Anwesenheit von allein nicht wirksamen Konzentrationen D609 die Wirkung des Aciclovir bereits bei erheblich niedrigeren Konzentrationen einsetzt, bei denen Aciclovir allein keine Wirkung zeigt.The results are illustrated in FIG. 1, in which the mean number of plaques is plotted against the concentration of acyclovir. The series without D609 is shown as squares, the series with 5 μg / ml D609 as circles and the series with 10 μg / ml D609 as triangles. It can clearly be seen that in the presence of concentrations D609 which are not effective on their own, the action of acyclovir starts at considerably lower concentrations at which acyclovir alone has no effect.
Beispiel 2Example 2
Steigerung der Wirkung von Aciclovir auf den Verlauf einer experimentellenIncrease the effect of acyclovir on the course of an experimental
Infektion mit Herpes simplex Viren in Mäusen durch das exo/exo-lsomer vonHerpes simplex virus infection in mice by the exo / exo isomer of
Tricyclo[5,2,1,02'6]-9yl-xanthogenat.Tricyclo [5,2,1,0 2 ' 6 ] -9yl-xanthate.
D609 wurde zusammen mit dem gleichen Gewichtsanteil Kaliumsalz der Decansäure und vier Gewichtsteilen Cholesterin im Mörser gemischt. Danach wurden Propylenglycol (Endkonzentration 10 %) und Vaseline zugegeben, so dass eine Konzentration von 5 % D609 erreicht war. Auf die gleiche Weise wurden Salben, die 5 % Aciclovir bzw. 5% D609 und 5 % Aciclovir enthielten, hergestellt. Analog wurde eine Placebo-Salbe hergestellt, die keinen der beiden Wirkstoffe enthielt.D609 was mixed together with the same part by weight of potassium salt of decanoic acid and four parts by weight of cholesterol in a mortar. Then propylene glycol (final concentration 10%) and petroleum jelly were added so that a concentration of 5% D609 was reached. In the same way, ointments containing 5% acyclovir or 5% D609 and 5% acyclovir were prepared. A placebo ointment was prepared analogously, which contained neither of the two active ingredients.
Je 10 Mäuse (Stamm Balb-C) wurden am Oberschenkel rasiert und mit einer Kanüle auf einer Fläche von 5x5 mm 6 mal die Haut geritzt. Anschließend wurden mit einem Wattestäbchen 50 μl einer HSV-1 Suspension (Stamm Wal, 108 plaque- bildende Einheiten/ml) aufgetragen. Vier Tage nach der Infektion wurde mit der Behandlung begonnen (2 mal täglich). Es wurden die Symptome "Ausgebreitete Läsionen", "Lähmungen der Hinterbeine" und das Überleben protokolliert.10 mice each (strain Balb-C) were shaved on the thigh and the skin was scored 6 times with a cannula on an area of 5x5 mm. Then were Apply 50 μl of an HSV-1 suspension (strain whale, 10 8 plaque-forming units / ml) with a cotton swab. Treatment was started four days after infection (twice daily). The symptoms "Spreading lesions", "Paralysis of the hind legs" and survival were recorded.
Das Ergebnis ist in den Figuren 2a bis 2d graphisch dargestellt. Aufgetragen ist die Anzahl der Tiere mit den entsprechenden Symptomen gegen die Anzahl der Tage nach der Infizierung. Dreiecke kennzeichnen jeweils die überlebenden Tiere, Quadrate die Tiere mt Lähmungen der Hinterbeine und Rauten die Tiere mit ausgebreiteten Läsionen.The result is shown graphically in FIGS. 2a to 2d. The number of animals with the corresponding symptoms is plotted against the number of days after infection. Triangles indicate the surviving animals, squares the animals with paralysis of the hind legs and rhombuses the animals with spread lesions.
Bei der Behandlung mit der Placebo-Salbe ohne Wirkstoff lässt sich in Figur 2a erkennen, dass nach 14 Tagen nur 3 Tiere überlebten und zuvor alle Tiere ausgebreitete Läsionen und 7 Tiere Lähmungen aufwiesen. In den Figuren 2b und 2c ist durch Behandlung mit D609 (2b) bzw. Aciclovir (2c) die Überlebensrate höher, Läsionen und Lähmungen werden fast vollständig geheilt. Bei der Kombination von D609 und Aciclovir in Figur 2d überleben alle Tiere, Läsionen und Lähmungen werden vollständig geheilt und treten auch in geringerem Ausmaß auf.In the treatment with the placebo ointment without active ingredient, it can be seen in FIG. 2a that only 14 animals survived after 14 days and all animals had previously spread lesions and 7 animals had paralysis. In Figures 2b and 2c, treatment with D609 (2b) or acyclovir (2c) increases the survival rate, and lesions and paralysis are almost completely healed. With the combination of D609 and acyclovir in Figure 2d, all animals survive, lesions and paralysis are completely healed and also occur to a lesser extent.
Das Kombinationspräparat ist somit deutlich besser wirksam als die Einzelpräparate. Mit dem Kombinationspräparat wird das Überleben aller Tiere sowie eine geringere Symptomatik und eine schnelleres Abheilen der Symptome erreicht. The combination product is therefore significantly more effective than the individual products. With the combination preparation, the survival of all animals as well as less symptoms and faster healing of the symptoms is achieved.

Claims

Patentansprüche claims
1. Pharmazeutische Formulierung, enthaltend ein Xanthogenat der Formel I1. Pharmaceutical formulation containing a xanthate of the formula I.
wobei Ri für einen gegebenenfalls substituierten Aryl- oder Alkylrest steht und R2 für ein Metallatom, eine gegebenenfalls substituierte Alkyl-, Alkoxy-, Amino- oder Ammoniumgruppe oder Halogen steht, und einen Hemmstoff der viralen Nukleinsäurereplikation, sowie gegebenenfalls ein die Aktivität des Xanthogenats erhöhendes Adjuvans und einen die Reizwirkung reduzierenden Trägerstoff. wherein Ri stands for an optionally substituted aryl or alkyl radical and R2 stands for a metal atom, an optionally substituted alkyl, alkoxy, amino or ammonium group or halogen, and an inhibitor of viral nucleic acid replication, and optionally an adjuvant which increases the activity of the xanthate and a stimulant reducing vehicle.
2. Pharmazeutische Formulierung nach Anspruch 1, dadurch gekennzeichnet, dass Ri einen Adamantyl-, Norbornyl-, Tricyclodecyl-, Benzyl-, geraden oder verzweigten C3-C2o-Alkyl-, C3-C2o-Cycloalkyl-, Furyl-, Pyridyl-, Anthracyl-, Naphtyl-, Phenanthryl-, Perinaphtyl- oder Chinuclidinyl-Rest darstellt, wobei der obengenannte gerade oder verzweigte C3-C2o-Alkylrest durch eine Hydroxyl-, eine C-ι-C4-Alkoxygruppe, ein Halogenatom oder eine Aminogruppe und der obengenannte C3-C2o-Cycloalkylrest ebenfalls durch eine Hydroxyl-, eine C-i- C4-Alkoxy- oder eine Cι-C4-Alkylgruppe, ein Halogenatom oder eine Aminogruppe substituiert sein können.2. Pharmaceutical formulation according to claim 1, characterized in that Ri is an adamantyl, norbornyl, tricyclodecyl, benzyl, straight or branched C 3 -C 2 o-alkyl, C 3 -C 2 o-cycloalkyl, furyl -, Pyridyl, anthracyl, naphthyl, phenanthryl, perinaphtyl or quinuclidinyl radical, the above-mentioned straight or branched C 3 -C 2 o-alkyl radical being substituted by a hydroxyl, a C 1 -C 4 alkoxy group , a halogen atom or an amino group and the above-mentioned C3-C 2 o-cycloalkyl radical may also be substituted by a hydroxyl, a C 1 -C 4 -alkoxy or a C 1 -C 4 -alkyl group, a halogen atom or an amino group.
3. Pharmazeutische Formulierung nach Anspruch 2, dadurch gekennzeichnet, dass Ri ein Cyclododecyl-, Dodecyl-, Undecyl-, Decyl-, Tricyclo[5,2,1 ,02'6]- decyl-, nonyl-, octyl-, Bicyclo[2,2,1]-heptyl-, Cyclohexyl-, Hexyl- oder Toluylrest ist. 3. Pharmaceutical formulation according to claim 2, characterized in that Ri is a cyclododecyl, dodecyl, undecyl, decyl, tricyclo [5.2.1, 0 2 ' 6 ] - decyl, nonyl, octyl, bicyclo Is [2,2,1] heptyl, cyclohexyl, hexyl or toluyl.
4. Pharmazeutische Formulierung nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass R2 ein Natrium- oder Kaliumatom oder eine Dimethylglycylester- oder Methylestergruppe ist.4. Pharmaceutical formulation according to one of claims 1 to 3, characterized in that R2 is a sodium or potassium atom or a dimethylglycyl ester or methyl ester group.
5. Pharmazeutische Formulierung nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass der Hemmstoff der viralen Nukleinsäurereplikation ein Nukleosidanalogon ist.5. Pharmaceutical formulation according to one of claims 1 to 4, characterized in that the inhibitor of viral nucleic acid replication is a nucleoside analog.
6. Pharmazeutische Formulierung nach Anspruch 5, dadurch gekennzeichnet, dass der Hemmstoff der viralen Nukleinsäurereplikation ausgewählt ist unter Aciclovir, Valaciclovir, Penciclovir und Famciclovir.6. Pharmaceutical formulation according to claim 5, characterized in that the inhibitor of viral nucleic acid replication is selected from aciclovir, valaciclovir, penciclovir and famciclovir.
7. Pharmazeutische Formulierung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass je ein Teil Xanthogenat 1 bis 10, vorzugsweise 2 bis 4 Teile Hemmstoff der viralen Nukleinsäurereplikation enthalten sind.7. Pharmaceutical formulation according to one of the preceding claims, characterized in that one part of xanthate 1 to 10, preferably 2 to 4 parts of inhibitor of viral nucleic acid replication are contained.
8. Pharmazeutische Formulierung nach einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, dass als Adjuvans ein ionisches Detergens, vorzugsweise eine Fettsäure mit 6 bis 19 C-Atomen oder ein Alkylsulfat mit 8 bis 18 C- Atomen enthalten ist.8. Pharmaceutical formulation according to one of claims 1 to 7, characterized in that an adjuvant is an ionic detergent, preferably a fatty acid with 6 to 19 carbon atoms or an alkyl sulfate with 8 to 18 carbon atoms.
9. Pharmazeutische Formulierung nach einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, dass als Adjuvans Deoxycholinsäure oder ein pharmazeutisch verträgliches Salz davon enthalten ist.9. Pharmaceutical formulation according to one of claims 1 to 7, characterized in that deoxycholic acid or a pharmaceutically acceptable salt thereof is contained as adjuvant.
10. Pharmazeutische Formulierung nach einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, dass als Adjuvans eine Phosphonsäure enthalten ist.10. Pharmaceutical formulation according to one of claims 1 to 7, characterized in that a phosphonic acid is contained as adjuvant.
11. Pharmazeutische Formulierung nach Ansprüche 1 bis 10, dadurch gekennzeichnet, dass zusätzlich als Trägerstoff Cholesterin enthalten ist. 11. Pharmaceutical formulation according to claims 1 to 10, characterized in that cholesterol is additionally contained as a carrier.
12. Mittel zur Behandlung von Virus-, Tumor- oder Autoimmunerkrankungen, dadurch gekennzeichnet, dass es eine pharmazeutische Formulierung gemäß mindestens einem der Ansprüche 1 bis 11 enthält.12. Agent for the treatment of viral, tumor or autoimmune diseases, characterized in that it contains a pharmaceutical formulation according to at least one of claims 1 to 11.
13. Mittel nach Anspruch 12, dadurch gekennzeichnet, dass es Tricyclo[5,2,1 ,02,6]-decan-9-yl-xanthogenat als Xanthogenat, Cholesterin oder Phosphatidylcholin als Trägerstoff, das Natrium- oder Kaliumsalz der Decansäure als Adjuvans enthält und der Hemmstoff der viralen Nukleinsäurereplikation ausgewählt ist unter Aciclovir, Valaciclovir, Penciclovir und Famciclovir.13. Composition according to claim 12, characterized in that it is tricyclo [5,2,1, 0 2,6 ] -decan-9-yl-xanthate as xanthate, cholesterol or phosphatidylcholine as carrier, the sodium or potassium salt of decanoic acid Contains adjuvant and the inhibitor of viral nucleic acid replication is selected from aciclovir, valaciclovir, penciclovir and famciclovir.
14. Mittel nach Anspruch 13, dadurch gekennzeichnet, dass es als Hemmstoff der viralen Nukleinsäurereplikation Aciclovir enthält.14. Composition according to claim 13, characterized in that it contains aciclovir as an inhibitor of viral nucleic acid replication.
15. Mittel nach indesten einem der Ansprüche 12-14, dadurch gekennzeichnet, dass es ein Teil Xanthogenat, ein Teil Hemmstoff der viralen Nukleinsäurereplikation, vier Teile Trägerstoff und ein Teil Adjuvans enthält.15. Agent according to any one of claims 12-14, characterized in that it contains one part of xanthate, one part of inhibitor of viral nucleic acid replication, four parts of carrier and one part of adjuvant.
16. Mittel nach einem der Ansprüche 12 bis 14, dadurch gekennzeichnet, dass es eine Salbe ist, die die pharmazeutische Formulierung in einer lipophilen Substanz, vorzugsweise Vaseline, enthält. 16. Composition according to one of claims 12 to 14, characterized in that it is an ointment that contains the pharmaceutical formulation in a lipophilic substance, preferably petroleum jelly.
EP04764981A 2003-09-17 2004-09-09 Pharmaceutical formulations of xanthogenates and inhibitors of viral nucleic acid replication (e.g. aciclovir) Withdrawn EP1663198A1 (en)

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