EP0085084A1 - Combined preparation with synergistic effect - Google Patents

Combined preparation with synergistic effect

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Publication number
EP0085084A1
EP0085084A1 EP82902444A EP82902444A EP0085084A1 EP 0085084 A1 EP0085084 A1 EP 0085084A1 EP 82902444 A EP82902444 A EP 82902444A EP 82902444 A EP82902444 A EP 82902444A EP 0085084 A1 EP0085084 A1 EP 0085084A1
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European Patent Office
Prior art keywords
hydrogen
group
hydroxyl group
component
formulas
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EP82902444A
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German (de)
French (fr)
Inventor
Kailash Kumar Gauri
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Robugen GmbH Pharmaceutische Fabrik
Robugen GmbH
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Robugen GmbH Pharmaceutische Fabrik
Robugen GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine

Definitions

  • the invention relates to a combination preparation with antiviral properties which promote wound healing, consisting of a component A and a component B according to claim 1, which work together in the sense of a synergism.
  • the preparation is intended for the treatment of viral infections, e.g. herpetic infections, on the other hand for the treatment of peripheral circulatory disorders, exogenous tissue damage and cerebral circulatory and metabolic disorders.
  • the preparation (A) is particularly characterized by pronounced antiulcerous and healing effects for ulcers from [Med.exp. 9 (1963), 202].
  • Actihaemyl Bok-Gulden Lomberg Chemische Fabrik GmbH
  • Solcoseryl Solco Basel AG
  • component B comprises:
  • a preferred embodiment of the invention is therefore a combination preparation of the above-mentioned dialysis concentrate (A) and a component (B), which consists of the subgroups (1 '), (2 ') and (3') with a ⁇ configuration at C 1 of the D-ribofuranosyl, 2-deoxy-D-ribofuranosyl and D-arabinofuranosyl group and corresponds to the following formulas I 'and II':
  • the aliphatic substituent with 1 to 10 carbon atoms has a straight or branched carbon chain, which can be saturated or unsaturated. This includes alkyl groups such as the methyl, ethyl, n-propyl or isopropyl group, alkenyl groups such as the vinyl, allyl or butenyl group, and alkynyl groups such as the ethynyl or propargyl group. Furthermore, the aliphatic radical R can carry one or more substituents, in particular hydroxyl groups, cycloalkyl groups and oxo groups. Examples of radicals R substituted in this way are the 2-hydroxyethyl, cyclopropylmethyl, acetyl and propionyl group.
  • R 2 means, inter alia, a C 2 -C 7 alkanoyloxy group, for example an acetyl, propionyl, butyryl or isobutyryl group. Of the possible meanings of R 2, however, the hydroxyl group is preferred.
  • the halogen atom represented by the symbol R 3 is a fluorine, bromine or iodine atom, but in particular a chlorine atom. However, hydrogen atom is preferred among the important R 3 .
  • 5-Aethyl-2'-deoxy-uridine which is known as a commercial preparation under the names Aedurid and Edurid (R) (Robugen GmbH), has proven particularly useful in the treatment of herpes infections.
  • R Aedurid and Edurid
  • 5-alkyl-2'-des oxy-uridine can normalize cancer-dysfunctional cell functions and / or increase the normal cells and thereby accelerate wound healing.
  • results have shown that the combination of dialysis concentrate A and the nucleoside analogues of formulas I and II has a generally synergistic effect on the action of the components alone.
  • the potentiation of the effect includes both the promotion of wound healing and the antiviral activity.
  • the synergistic effect can be shown in particular by the following experiment.
  • the animals are divided into six groups (with a total of six corneal wounds) and treated as follows:
  • 5-ethyl and 5-n-butyl derivatives behave similarly to 5-isopropyl-2'-deoxy-uridine: the effectiveness in terms of accelerating wound healing in rabbits when the compounds are used in the same molar ratio , is comparable to that of 5-isopropyl-2'-deoxy-uridine.
  • the second mentioned synergistic effect is illustrated by the combination with 5-ethyl-2'-deoxy-uridine.
  • Using 1% 5-ethy1-2'-deoxyuridine alone in rabbit herpes keratitis on the 6th day after treatment resulted in 72% inhibition of the lesions compared to the control during treatment with the combination of 1% 5-ethyl-2'doxy-uridine in solcoseryl caused an inhibition of 87%.
  • the synergistic effects are statistically significant.

Abstract

En combinant un concentré, obtenu à partir d'un dialysat de sang de veau déprotéine, avec un dérivé de l'uracile furanosylé de formule$(8,)$l'on obtient une préparation à effet synergique; cet effet est constatable par comparaison à l'activité de chacun de ses composants pris isolément et porte, par ailleurs, aussi bien sur l'activité antivirale, que sur une activité cicatrisante en cas de blessure. Dans les formules l'un des symboles a et b représente de l'hydrogène et l'autre de ces symboles représente de l'hydrogène ou le groupe hydroxyle; R1 représente de l'hydrogène ou un groupe aliphatique en C1 à C10; R2 représente un groupe hydroxyle, un groupe phosphorique ou un groupe alkanoyloxy en C1 à C7 et R3 représente de l'hydrogène ou un atome d'halogène. Une telle préparation peut s'utiliser aussi bien en thérapie des infections virales qu'en thérapie des troubles de la circulation périphérique ou cérébrale, ou en thérapie des blessures exogènes et des troubles du métabolisme.By combining a concentrate, obtained from a dialysate of deprotein calf blood, with a furanosylated uracil derivative of formula $ (8,) $, a preparation with a synergistic effect is obtained; this effect can be seen by comparison with the activity of each of its components taken in isolation and moreover relates both to antiviral activity and to healing activity in the event of injury. In the formulas one of the symbols a and b represents hydrogen and the other of these symbols represents hydrogen or the hydroxyl group; R1 represents hydrogen or a C1 to C10 aliphatic group; R2 represents a hydroxyl group, a phosphoric group or a C1-C7 alkanoyloxy group and R3 represents hydrogen or a halogen atom. Such a preparation can be used both in therapy of viral infections and in therapy of peripheral or cerebral circulation disorders, or in therapy of exogenous wounds and metabolic disorders.

Description

Kombinat ionspräparat mit Synergistischer Wirkung Combination preparation with synergistic effect
Gegenstand der Erfindung ist ein Kombinationspräparat mit antiviralen und die Wundheilung fördernden Eigenschaften, bestehend aus einer Komponente A und einer Komponente B gemäss Patentanspruch 1, welche im Sinne eines Synergismus zusammenwirken. Das Präparat soll einerseits zur Behandlung von Virusinfektionen, u.a. der herpetischen Infektionen, andererseits zur Behandlung von peripheren Durchblutungsstörungen, exogenen Gewebsschädigungen und zerebralen Durchblutungs- und Stoffwechselstörungen verwendet werden.The invention relates to a combination preparation with antiviral properties which promote wound healing, consisting of a component A and a component B according to claim 1, which work together in the sense of a synergism. On the one hand, the preparation is intended for the treatment of viral infections, e.g. herpetic infections, on the other hand for the treatment of peripheral circulatory disorders, exogenous tissue damage and cerebral circulatory and metabolic disorders.
Im folgenden wird die Erfindung ausführlich beschrieben.The invention will now be described in detail.
Die Komponente A und ihre Herstellung sind insbesondere in DE-PS 1.017.744 und 1.076.888 (Karl-Heinz Jaeger, H. Mittenzwei), DE-OS 1.949.195 (Istituto Nazionale Chimico Biologico Srl), 1.617-355 und 2.325-196 (Böttger KG), FR-PS 1.535.488 (W. Helmbold; Solco Basel AG), US-PS 2.912.359 (L. Anigstein et al), JP-AS 24.562/1976 (Taiho Yakuhin KK), 1281/1969 (T. Hirakawa) und 13-956/1969 (Yamakawa Boeki KK) beschrieben worden.Component A and its manufacture are particularly described in DE-PS 1.017.744 and 1.076.888 (Karl-Heinz Jaeger, H. Mittenzwei), DE-OS 1.949.195 (Istituto Nazionale Chimico Biologico Srl), 1.617-355 and 2.325- 196 (Boettger KG), FR-PS 1,535,488 (W. Helmbold; Solco Basel AG), US-PS 2,912,359 (L. Anigstein et al), JP-AS 24,562 / 1976 (Taiho Yakuhin KK), 1281 / 1969 (T. Hirakawa) and 13-956 / 1969 (Yamakawa Boeki KK).
Das Präparat (A) zeichnet sich vor allem durch ausgeprägte antiulceröse und heilungsfördernde Wirkungen auf Geschwüre aus [Med.exp. 9 (1963), 202]. Unter den Markennamen Actihaemyl (Byk-Gulden Lomberg Chemische Fabrik GmbH) oder Solcoseryl (Solco Basel AG) hat es sich bereits während zwei Jahrzehnten bei den Indikationen periphere Durchblutungsstörungen arterieller und venöser Genese, Ulcus cruris arteriösum und varicosum, diabetische Gangrän, torpide Wunden, Dekubitus, Strahlenschäden, Verbrennungen, Hauttransplantationen und zerebrale Stoffwechselstörungen bewährt.The preparation (A) is particularly characterized by pronounced antiulcerous and healing effects for ulcers from [Med.exp. 9 (1963), 202]. Under the brand names Actihaemyl (Byk-Gulden Lomberg Chemische Fabrik GmbH) or Solcoseryl (Solco Basel AG), there have been indications of peripheral circulatory disorders of arterial and venous genesis, leg ulcers, arteriosis and varicosum, diabetic gangrene, torpid wounds, pressure ulcers for two decades , Radiation damage, burns, skin grafts and cerebral metabolic disorders are proven.
Die Komponente B umfasst, je nach der Bedeutung der Symbole a und b in den Formeln I und II:Depending on the meaning of symbols a and b in formulas I and II, component B comprises:
(1) wenn a Hydroxyl und b Wasserstoff bedeuten, Verbindungen der Uridin- und der 1α-D-Ribofuranosyluracil Reihe (Formel I) sowie der 3β- und der 3α-D-Ribo furanosyluracil-Reihe (Formel II),(1) when a is hydroxyl and b is hydrogen, compounds of the uridine and 1α-D-ribofuranosyluracil series (formula I) and the 3β and 3α-D-ribo furanosyluracil series (formula II),
(2) wenn a und b je Wasserstoff bedeuten, Verbindungen der 2' -Desoxy-uridin- und der 2' -Desoxy-lα-D-ribo furanosyl-uracil-Reihe (Formel I) sowie der 2' -Desoxy 3β- und der 2' -Desoxy-3α-D-ribofuranosyl-urac il Reihe (Formel II), und(2) if a and b are each hydrogen, compounds of the 2'-deoxy-uridine and the 2 '-deoxy-lα-D-ribo furanosyl-uracil series (formula I) and the 2'-deoxy 3β- and the 2'-deoxy-3α-D-ribofuranosyl-urac il series (formula II), and
(3) wenn A Wasserstoff und b Hydroxyl bedeuten, Verbindungen der 1β- und der lα-D-Arabino furanosyl-uracil Reihe (Formel I) sowie der 35- und der 3α-D-Arabino furanosyl-uracil-Reihe (Formel II).(3) when A is hydrogen and b is hydroxyl, compounds of the 1β- and lα-D-arabino furanosyl-uracil series (formula I) as well as the 35- and 3α-D-arabino furanosyl-uracil series (formula II) .
In jeder der obigen Gruppen (1), (2) und (3) werden jene Verbindungen bevorzugt, welche die Untergruppe mit ß-Konfiguration am. C1 des Zuckerrestes bilden. Bevorzugte Ausführungsform der Erfindung ist also ein Kombinationspräparat aus den oben erwähnten Dialysekonzentrat (A) und einer Komponente (B), welche aus den Untergruppen (1'), (2') und (3') mit ß-Konfiguration an C1 der D-Ribofuranosyl-, 2-Desoxy-D-ribofuranosyl- und D-Arabinofuranosyl- gruppe besteht und den folgenden Formeln I' und II' entspricht:In each of the above groups (1), (2) and (3) those compounds are preferred which form the subgroup with the .beta.-configuration at. C 1 of the sugar residue. A preferred embodiment of the invention is therefore a combination preparation of the above-mentioned dialysis concentrate (A) and a component (B), which consists of the subgroups (1 '), (2 ') and (3') with a β configuration at C 1 of the D-ribofuranosyl, 2-deoxy-D-ribofuranosyl and D-arabinofuranosyl group and corresponds to the following formulas I 'and II':
Der aliphatische Subs tituent mit 1 bis 10 Kohlenstoffatomen (R1) weist eine gerade oder verzweigte Kohlenstoffkette auf, welche gesättigt oder ungesättigt sein kann. Darunter fallen also Alkylgruppen, wie die Methyl-, Aethyl-, n-Propyl- oder Isopropylgruppe, Alkenylgruppen, wie die Vinyl-, Allyl- oder Butenylgruppe, und Alkinylgruppen, wie die Aethinyl- oder Propargylgruppe. Ferner kann der aliphatische Rest R einen oder mehrere Substituenten tragen, insbesondere Hydroxylgruppen, Cycloalkylgruppen und Oxogruppen. Beispiele derart substituierter Reste R sind die 2-Hydroxyäthyl-, Cyclopropylmethyl-, Acetyl- und Propionylgruppe.The aliphatic substituent with 1 to 10 carbon atoms (R 1 ) has a straight or branched carbon chain, which can be saturated or unsaturated. This includes alkyl groups such as the methyl, ethyl, n-propyl or isopropyl group, alkenyl groups such as the vinyl, allyl or butenyl group, and alkynyl groups such as the ethynyl or propargyl group. Furthermore, the aliphatic radical R can carry one or more substituents, in particular hydroxyl groups, cycloalkyl groups and oxo groups. Examples of radicals R substituted in this way are the 2-hydroxyethyl, cyclopropylmethyl, acetyl and propionyl group.
Das Symbol R2 bedeutet unter anderem eine C2-C7- Alkanoyloxygruppe, beispielsweise' eine Acetyl-, Propionyl-, Butyryl- oder Isobutyrylgruppe. Allerdings wird von den möglichen Bedeutungen von R2 die Hydroxylgruppe bevorzugt.The symbol R 2 means, inter alia, a C 2 -C 7 alkanoyloxy group, for example an acetyl, propionyl, butyryl or isobutyryl group. Of the possible meanings of R 2, however, the hydroxyl group is preferred.
Daraus ergeben sich in jeder der oben erwähnten Untergruppen (1'), (2') und (3') bevorzugte Verbindungen der Formeln I' und II', in welchen R2 die Hydroxylgruppe darstellt. Am meisten bevorzugt wird also jenes Kombinationspräparat, in welchem die Komponente B aus einer Verbindung der Formel I' oder II', mit R2 = OH, besteht.This results in preferred compounds of each of the above-mentioned subgroups (1 '), (2') and (3 ') Formulas I 'and II', in which R 2 represents the hydroxyl group. Most preferred is that combination preparation in which component B consists of a compound of the formula I 'or II', with R 2 = OH.
Das durch das Symbol R3 dargestellte Halogenatom ist ein Fluor-, Brom- oder Jodatom, insbesondere aber ein Chloratom. Von den Bedeutuigen von R3 wird jedoch das Wasserstoffatom bevorzugt.The halogen atom represented by the symbol R 3 is a fluorine, bromine or iodine atom, but in particular a chlorine atom. However, hydrogen atom is preferred among the important R 3 .
Verbindungen der oben erwähnten Untergruppe (1') und ihre Herstellung sind u.a. von J. Shapira inCompounds of subgroup (1 ') mentioned above and their preparation include by J. Shapira in
(1962), 1918, M. Muraoka et al. in Chem.Pharm.Bull. 18 (1970), 261 und 269, E.H. Hamamura et al. in J. Med.Chem. 15 (1972), 1061, U. Niedballa et al. in J.Org.Chem. 39 (1974), 3654 und neuerdings von C. Nakayama et al. und A. Szemzo et al. in J. Carbohydr. Nucleosides, Nucleotides 6 (1979), 295 bzw. 7 (1980), 365, beschrieben worden. Die Herstellung erfolgte zwecks Prüfung der Verbindungen auf Antitumor und antivirale Eigenschaften.(1962), 1918, M. Muraoka et al. in Chem.Pharm.Bull. 18 (1970), 261 and 269, E.H. Hamamura et al. in J. Med.Chem. 15 (1972), 1061, U. Niedballa et al. in J.Org.Chem. 39 (1974), 3654 and more recently by C. Nakayama et al. and A. Szemzo et al. in J. Carbohydr. Nucleosides, Nucleotides 6 (1979), 295 and 7 (1980), 365, respectively. The preparation was carried out for the purpose of testing the compounds for antitumor and antiviral properties.
Verbindungen der Untergruppe (2') und ihre Herstellung sind in der DE-OS 1.620.185 (Robugen GmbH) und von A. Szabolcs et al. in J. Carbohydr.Nucleosides,Compounds of subgroup (2 ') and their preparation are described in DE-OS 1.620.185 (Robugen GmbH) and by A. Szabolcs et al. in J. Carbohydr.Nucleosides,
Nucleotides 2 (1975), 197, beschrieben worden. In dieser Reihe zeichnen sich gewisse Verbindungen durch antivirale Wirkung, u.a. gegen den Herpes-Virus, und Antitumorwirkungen aus. Besonders bewährt bei der Behandlung von Herpesinfektionen hat sich das 5-Aethyl-2'-desoxy-uridin, als Handelspräparat unter den Namen Aedurid bzw. Edurid (R) (Robugen GmbH) bekannt. Zudem ist in neuerer Zeit gefunden worden (DE-OS 2.918.260; Robugen GmbH), dass 5-Alkyl-2'-des oxy-uridine die Normalisierung krebsentarteter Zellfunktionen und/oder eine Vermehrung der normalen Zellen und dadurch eine Beschleunigung der Wundheilung bewirken können.Nucleotides 2 (1975), 197. In this series, certain compounds are characterized by antiviral activity, including against the herpes virus, and antitumor effects. 5-Aethyl-2'-deoxy-uridine, which is known as a commercial preparation under the names Aedurid and Edurid (R) (Robugen GmbH), has proven particularly useful in the treatment of herpes infections. In addition, it has recently been found (DE-OS 2.918.260; Robugen GmbH) that 5-alkyl-2'-des oxy-uridine can normalize cancer-dysfunctional cell functions and / or increase the normal cells and thereby accelerate wound healing.
Ueberraschenderweise wurde nun gefunden, dass durch kombinierte Verabreichung des 5-Isopropyl-2'-desoxyuridins, welches allein verabreicht keine therapeutisch brauchbaren antiviralen Wirkungen hat, und des oben beschriebenen Dialysekonzentrates (Komponente A) eine aus- geprägte antivirale Wirkung zustande kommt. Ebenso unerwartet war aber auch die Feststellung einer ähnlichen Potenzierung der Wirkungen bei der Förderung der Wundheilung: wird die Komponente A mit einer Dosis des 5- Isopropyl-2'-desoxy-uridins kombiniert, welche an sich keine Förderung der Wundheilung bewirkt, so heilt die Wunde bedeutend rascher als unter der Wirkung der Komponente A allein.Surprisingly, it has now been found that combined administration of 5-isopropyl-2'-deoxyuridine, which has no therapeutically useful antiviral effects when administered alone, and the dialysis concentrate described above (component A) results in a pronounced antiviral effect. However, it was also unexpected to find a similar potentiation of the effects in promoting wound healing: if component A is combined with a dose of 5-isopropyl-2'-deoxy-uridine, which in itself does not promote wound healing, it heals Wound significantly faster than with component A alone.
Die weitere Untersuchung der oben geschildertenFurther investigation of the above
Ergebnisse hat gezeigt, dass die Kombination des Dialysekonzentrates A und der Nucleosidanaloga der Formeln I und II, gegenüber der Wirkung der Komponenten allein, allgemein synergistisch wirkt. Die Potenzierung der Wirkung umfasst sowohl die Förderung der Wundheilung als auch die antivirale Aktivität.Results have shown that the combination of dialysis concentrate A and the nucleoside analogues of formulas I and II has a generally synergistic effect on the action of the components alone. The potentiation of the effect includes both the promotion of wound healing and the antiviral activity.
Der synergistische Effekt kann insbesondere durch folgenden Versuch gezeigt werden.The synergistic effect can be shown in particular by the following experiment.
Gemessen wird die Beeinflussung der Regeneration lamellär keratektomierter Kaninchen nach der Methode von Wollensak und Kypke [Albrecht von Graefes Arch.Klin. Ophthalmol. 168 (1965), 102]. Dabei werden 18 Kaninchen durch intravenöse Verabreichung von Pentobarbital-Natrium narkotisiert und deren Hornhäute werden unter dem Operationsmikroskop nach Einschneiden bis zur Hälfte der Hornhautdicke mittels eines 7,5 mm Trepanmessers präpariert; die Grosse der derart gesetzten künstlichen Wunden beträgtThe influence on the regeneration of lamellar keratectomized rabbits is measured using the method of Wollensak and Kypke [Albrecht von Graefes Arch.Klin. Ophthalmol. 168 (1965), 102]. 18 rabbits anesthetized by intravenous administration of pentobarbital sodium and their corneas are prepared under the surgical microscope after incision up to half the thickness of the cornea using a 7.5 mm trepan knife; the size of the artificial wounds set in this way is
50 mm2. Die Tiere werden in sechs Gruppen (mit insgesamt sechs Hornhautwunden) verteilt und folgendermassen behandelt:50 mm 2 . The animals are divided into six groups (with a total of six corneal wounds) and treated as follows:
Die Ergebnisse der Untersuchung sind in der folgenden Tabelle zusammengefasst. 5-Isopropyl-2'-desoxy uridin allein bewirkt in 0,1%iger Konzentration keine, in 0,5%iger Konzentration nur eine geringgradige, Solcoseryl allein in 20%iger Konzentration eine geringe Beschleunigung der Wundheilung. Wird aber eine 0,1%ige bzw. 0,5%ige Lösung von Isopropyldesoxyuridin in Solcoseryl gleicherweise, 7 mal im Tag auf die Experimentalwunden aufgetra gen, so kommt es zu einer raschen Abheilung der Hornhaut defekte. Die Wirkung der Kombination ist der Behandlung mit Solcoseryl allein ebenfalls überlegen. The results of the investigation are summarized in the following table. 5-isopropyl-2'-deoxy uridine alone does not accelerate wound healing in 0.1% concentration, only slightly in 0.5% concentration, solcoseryl alone in 20% concentration. However, if a 0.1% or 0.5% solution of isopropyl deoxyuridine in solcoseryl is applied to the experimental wounds 7 times a day, the corneal defects will heal quickly. The effect of the combination is also superior to treatment with Solcoseryl alone.
Dem 5-Isopropyl-2'-desoxy-uridin ähnlich verhalten sich in diesem Versuch das 5-Aethyl- und das 5-n-Butylderivat: die Wirksamkeit inbezug auf die Beschleunigung der Wundheilung beim Kaninchen, wenn die Verbindungen im gleichen molaren Verhältnis angewendet werden, ist mit jener des 5-Isopropyl-2'-desoxy-uridins vergleichbar.In this experiment, 5-ethyl and 5-n-butyl derivatives behave similarly to 5-isopropyl-2'-deoxy-uridine: the effectiveness in terms of accelerating wound healing in rabbits when the compounds are used in the same molar ratio , is comparable to that of 5-isopropyl-2'-deoxy-uridine.
Der zweiterwähnte synergistische Effekt wird durch die Kombination mit 5-Aethyl-2'-desoxy-uridin erläutert. Unter der Anwendung von 1%igem 5-Aethy1-2'-desoxyuridin allein kommt es bei der Herpes-Keratitis des Kaninchens am 6. Tag nach der Behandlung zu einer Hemmung der Läsionen von 72% gegenüber der Kontrolle, während die Behandlung mit der Kombination von 1% 5-Aethyl-2'desoxy-uridin in Solcoseryl eine Hemmung von 87% bewirkt. Die Auswertung am 11. Tag führt zu einem ähnlichen Ergebnis: Hemmung durch die Kombination = 90%, durch 5-Aethyl2'-desoxy-uridin allein = 80%.The second mentioned synergistic effect is illustrated by the combination with 5-ethyl-2'-deoxy-uridine. Using 1% 5-ethy1-2'-deoxyuridine alone in rabbit herpes keratitis on the 6th day after treatment resulted in 72% inhibition of the lesions compared to the control during treatment with the combination of 1% 5-ethyl-2'doxy-uridine in solcoseryl caused an inhibition of 87%. The evaluation on the 11th day leads to a similar result: inhibition by the combination = 90%, by 5-ethyl2'-deoxy-uridine alone = 80%.
Die synergistischen Effekte sind statistisch signifikant. The synergistic effects are statistically significant.

Claims

P a t e n t a n s p r ü c h e Patent claims
1.) Kombinationspräparat mit antiviralen und die Wundheilung fördernden Eigenschaften, bestehend aus (A) einem Dialysekonzentrat aus deproteinisiertem Kälberblut, welches sämtliche Blutbestandteile mit einem Molekulargewicht unterhalb von 10' 000 enthält, und (B) einem Furanosyl-uracil der allgemeinen Formel I oder II:1.) Combination preparation with antiviral properties which promote wound healing, consisting of (A) a dialysis concentrate from deproteinized calf blood, which contains all blood components with a molecular weight below 10,000, and (B) a furanosyluracil of the general formula I or II :
in welchen Formeln die gewellte Linie α- oder β-Konfigura tion an C1 des Zuckerrestes angibt, eines von a und b Wasserstoff, das andere Wasserstoff oder die Hydroxylgruppe darstellt, R1 Wasserstoff oder eine aliphatische Gruppe mit 1 bis 10 Kohlenstoffatomen, R2 die Hydroxyl oder Phosphorsäuregruppe (-OPO3H2) oder eine Alkanoyloxy gruppe mit 2 bis 7 Kohlenstoffatomen und R3 Wasserstoff oder ein Halogenatom bedeuten. in which formulas the wavy line indicates α or β configuration at C 1 of the sugar residue, one of a and b is hydrogen, the other is hydrogen or the hydroxyl group, R 1 is hydrogen or an aliphatic group with 1 to 10 carbon atoms, R 2 the hydroxyl or phosphoric acid group (-OPO 3 H 2 ) or an alkanoyloxy group having 2 to 7 carbon atoms and R 3 is hydrogen or a halogen atom.
2. Kombinationspräparat nach Anspruch 1, dadurch gekennzeichnet, dass die Komponente B einer der folgenden Formeln entsoricht: 2. Combination preparation according to claim 1, characterized in that component B disposes of one of the following formulas:
in welchen a, b, R 1, R2 und R3 die in Anspruch 1 genanntenin which a, b, R 1 , R 2 and R 3 are those mentioned in claim 1
Bedeutungen haben.Have meanings.
3. Kombinationspräparat nach Anspruch 2, dadurch gekennzeichnet, dass die Komponente B einer der Formeln I' und II' entspricht, in welchen a, b, R1 und R3 die in Anspruch 1 genannten Bedeutungen haben und R2 die Hydroxyl oder die Phosphorsäuregruppe darstellt.3. Combination preparation according to claim 2, characterized in that component B corresponds to one of the formulas I 'and II', in which a, b, R 1 and R 3 have the meanings given in Claim 1 and R 2 is the hydroxyl or the phosphoric acid group represents.
4. Kombinationspräparat nach Anspruch 3, dadurch gekennzeichnet, dass die Komponente B einer der Formeln I' und II' entspricht, in welchen a, b und R1 die in Anspruch 1 genannten Bedeutungen haben, R2 die Hydroxylgruppe und4. Combination preparation according to claim 3, characterized in that component B corresponds to one of the formulas I 'and II', in which a, b and R 1 have the meanings given in claim 1, R 2 is the hydroxyl group and
R3 Wasserstoff darstellen.R 3 represent hydrogen.
5. Kombinationspräparat nach Anspruch 3, dadurch gekennzeichnet, dass die Komponente B einer der Formeln I' und II' entspricht, in welchen a Wasserstoff oder die5. Combination preparation according to claim 3, characterized in that component B corresponds to one of the formulas I 'and II', in which a is hydrogen or
Hydroxylgruppe, b Wasserstoff und R2 die Hydroxylgruppe darstellen und R1 und R3 die in Anspruch 1 genannten Bedeutungen haben. Hydroxyl group, b is hydrogen and R 2 is the hydroxyl group and R 1 and R 3 are as defined in claim 1.
6. Kombinationspräparat nach Ansprüchen 4 und 5, dadurch gekennzeichnet, dass die Komponente B der Formel I' entspricht, in welcher a wasserstoff oder die Hydroxylgruppe, b wasserstoff und R2 die Hydroxylgruppe darstellen und R1 die in Anspruch 1 genannten Bedeutungen hat. 6. Combination preparation according to claims 4 and 5, characterized in that component B corresponds to formula I ', in which a is hydrogen or the hydroxyl group, b is hydrogen and R 2 is the hydroxyl group and R 1 has the meanings given in claim 1.
EP82902444A 1981-08-04 1982-08-04 Combined preparation with synergistic effect Withdrawn EP0085084A1 (en)

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HU196038B (en) * 1987-08-07 1988-09-28 Mta Koezponti Kemiai Kutato In Process for producing antiherpetic pharmaceutics for external use, containing 5-isopropyl-2'-beta-deoxy-uridine
US5137724A (en) * 1990-05-23 1992-08-11 Stichting Rega Vzw Combinations of TS-inhibitors and viral TK-inhibitors in antiherpetic medicines
WO1995001097A1 (en) * 1993-06-30 1995-01-12 Board Of Regents, The University Of Texas System Nucleotide preparation and uses thereof in wound healing
US6342484B1 (en) 1993-06-30 2002-01-29 Board Of Regents, The University Of Texas Systems Method and compositions for promotion of wound treatment
CN101230090B (en) * 2007-01-24 2011-11-02 中国生化制药工业协会 Blood peptide X and derivative thereof as well as preparation method and use thereof

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FR1396003A (en) * 1964-04-21 1965-04-16 Upjohn Co Process for the production of a 1-beta-d-arabino-furanosyluracil
FR1455087A (en) * 1964-05-08 1966-04-01 Schwarz Biores Blood preservation process
US3553192A (en) * 1968-07-15 1971-01-05 Robugen Gmbh Substituted (2'-deoxyribosyl) uracil compounds, compositions containing same and process of making and using same
DE2147094A1 (en) * 1971-09-21 1973-04-05 Robugen Gmbh Virustatics - contg thymidine in high concn
DE2166220A1 (en) * 1971-09-21 1973-09-13 Robugen Gmbh Virustatic compsns - contg thymidine
DE2841898A1 (en) * 1978-09-26 1980-04-03 Robugen Gmbh ANTIVIRAL AGENT BASED ON 5-LOW-RIGALKYL-2'-DESOXYURIDINE-5 'MONOPHOSPHATES
EP0015584A3 (en) * 1979-03-12 1980-12-10 Kailash Kumar Dr. Prof. Gauri Nucleotides, methods for their preparation and medicaments
DE2930904A1 (en) * 1979-07-30 1981-02-19 Kailash Kumar Dr Gauri Antitumour use of 5-alkyl-pyrimidine nucleoside derivs. - as potentiators of 5-fluoro-uracil

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