WO1983000436A1

WO1983000436A1 - Combined preparation with synergic effect

Info

Publication number: WO1983000436A1
Application number: PCT/EP1982/000163
Authority: WO
Inventors: Gmbh Pharmazeutische Fabrik Robugen
Original assignee: Gauri, Kailash, Kumar
Priority date: 1981-08-04
Filing date: 1982-08-04
Publication date: 1983-02-17
Also published as: EP0085084A1

Abstract

By combining a concentrate, obtained from a dialysate of deproteinized calf blood, with a derivative of furanosylated uracil having the formule <IMAGE> there is obtained a preparation having a synergic effect; said effect is verifiable by comparison with the activity of each of its components, each of them taken separately, and bears both on an antiviral activity and a healing activity in case of wound. In the formulas, one of the symbols a and b represents a hydrogen atom and the other one represents a hydrogen atom or a hydroxyl group; R<1> represents a hydrogen atom or an aliphatic group from C1 to C10; R<2> represents a hydroxyl group, a phosphoric group or an alkanoyloxy group from C1 to C7 and R<3> represents hydrogen or a halogen atom. Such a preparation may be used in the therapy of viral infections as well as in the therapy of troubles of peripheral or cerebral circulation, or in the therapy of exogenous wounds and metabolism troubles.

Description

Combination preparation with synergistic effect

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.

The invention will now be described in detail.

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).

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.

Depending on the meaning of symbols a and b in formulas I and II, component B comprises:

(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) 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) 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 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':

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.

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.

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.

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 .

Compounds 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 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.

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. 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.

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.

Further investigation of the above

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 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 mm ² . The animals are divided into six groups (with a total of six corneal wounds) and treated as follows:

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.

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.

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%.

The synergistic effects are statistically significant.

Claims

Patent claims

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 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. Combination preparation according to claim 1, characterized in that component B disposes of one of the following formulas:

in which a, b, R ¹ , R ² and R ^{3 are} those mentioned in claim 1

Have meanings.

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. 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

R ^{3 represent} hydrogen.

5. 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

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. 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.