DD292134A5 - METHOD FOR PRODUCING A MEDIUM AGAINST VIRAL INFECTIONS, PREFERABLY AGAINST AIDS - Google Patents

Abstract

The invention relates to a process for the preparation of an agent against viral infections, preferably against AIDS. Field of application is the pharmaceutical industry. According to the invention, alkylglycerophosphocholine analogues of the general formula I, II or III are mixed with pharmaceutically acceptable carriers and / or excipients. Formulas I-III {Method; Medium; Pharmaceutical Industry; Alkylglycerophosphocholin analogues}

Description

in (ionone R = alkyl with 6 to 30C AtOmOn,

X = OP (O) OCHjCH ₂ A (CH ₃ ) J (phoaphocholine rust) and

6

Y = CI ₁ F ₁ OCHjCF ₃ '.

mean anti-HIV efficacy boi extremely low PAF effect. According to the invention, the pharmaceutical agent is prepared by mixing these compounds with usual pharmaceutically acceptable carriers and excipient. Preferably, the active ingredient is taken up in DMSO to give 2 niM of solution and worked up so that the agent is present as dose inho and can be administered systemically, ie orally or parenterally (intramuscularly, intravenously and subcutaneously) as such or in combination with other antiviral agents. For oral administration, the agent is in liquid form, for example as an aqueous or oily suspension, syrup, elixir, solution or capsules filled with liquid.

Means for parenteral administration are in ollgomoinone in the form of a solution or suspension of the compound used according to the invention together with conventional pharmaceutical carriers voi, for example in the form of an aqueous solution for intravenous injection or an oily suspension for intramuscular injection. Agents suitable for parontoral administration are obtained by dissolving 0.1 to 10% by weight of the compound of the invention in water or a carrier consisting of an aliphatic polyalcohol such as glycerol, propylene glycol or polyethylene glycols or a mixture thereof. The Polyäthylonglykole consist of a mixture of nonvolatile, usually liquid Polyäthylenglykolo, which are soluble in both water and in organic liquids and whose molecular weights range from 200 to 1500.

The preparation of the pharmaceutical agent is carried out by conventional ancestors, for example by sterile filtration and filling in ampoules or dropper bottles of a solution of the invention used in the compounds in injection water together with conventional additives such as sodium chloride, sodium hydrogen phosphate, disodium EDTA (Ethylenediaminotetraessigsäuredinatriumsalz), benzyl alcohol or sodium hydroxide Adjustment of pH. The duration of treatment depends on the type and severity of the disease. It generally extends over several weeks. Also useful is the therapy in combination with other antiviral agents. The compounds used according to the invention were prepared by methods known per se (Brachwitz, H., Laugen, P., Hintsche, R., Schildt, J., Chem. Phys. Lipids 31 [1982] 33-52; Brachwitz, H., Langen, P., Schildt, J., ibid 34 (1984) 355-362; Brachwitz, H., Franke, P., Hintsche, R., Langen, P., Schildt, J. "ibid. 36 (1986) 137-152).

Testing for anti-HIV efficacy

5 × 10 ⁵ H9 cells were infected with 2 × 10 ⁷ HIV-I particles and the compounds were added 5 hours later. After 4 days of culture, their influence on the HIV-induced cytopathic effect (CPE), on the production of HIV proteins ρ 15 and ρ 24 as well as on the activity of reverse transcriptase (RT) was investigated. The results are shown in Table 1. In addition, protein kinase C activity was measured.

Table 1: Anti-HIV effect of the agents described Zellzah! in uninfected control = 22.4 ± 3.7 x 10Vml

Number of cells in the infected control = 5.9 ± 1.2 x 10 ⁵ / ml

As a result, number of HIV-destroyed cells = 16.5 × 10 ⁵ / ml

connection concentration CPE RT ό inhibition ρ 24 (ΜΜ) 33 57 p15 26 2-chloro-1-deoxy- 1 81 89 36 76 1-O-hexadecyl-rac 3 17 61 85 62 glycero-3-phosphocholine 10 10 76 65 31 1-deoxy-ChloM 1 79 83 53 72 3-0-hexadecyl-rac 3 45 81 82 76 glycero-2-phosphocholine 10 40 71 78 57 1-chloro-1-deoxy-rac 1 93 86 62 85 2-O-hexadecylgly- 3 72 74 86 88 cero-3-phosphocholine 10 81

The concentrations of the compounds that cause 50% cell destruction are about 10-fold higher than those (3 μΜ) that provide 80 to 100% protection against cell destruction by HIV. The protein kinase C inhibition was about 50% at 3μΜ.

PAF activity

Alkylglycerophosphocholines are structural analogs of the platelet activating factor (PAF), which is a physiologically highly active compound. PAF analogs that have a significant PAF effect are not suitable for therapeutic use. It has now been found, surprisingly, that alkylglycerophosphocholines whose structure is modified by the introduction of a halogen substituent and which have the general formulas I and II show only a minor PAF effect. Halogen-containing alkyl glycerocholines, which also still an unnatural arrangement of Phosphocholingruppierung in the molecule, for. in the 2-position of the glycerol (general formula III), have virtually no significant PAF effect more. These findings are for a therapeutic use, especially for a longer one

ongoing AIDS therapy of paramount importance. The compounds of the general formulas I, II and III are therefore particularly suitable for rapid preparation and use as anti-HIV preparations. Table 2 shows the low PAF effect (aggregation of rabbit platelets) of some halogen-containing alkyl glycerophosphocholine analogues compared to Et-18-OCH ₃ and thus structural isomerone.

Table 2: Relative PAF effect (aggregation of rabbit platelets) of some alkylglycerophosphocholine analogues based on PAF (= 100%); For method see: Ostermann, G., et al., Thrombosis Research 43 (1986) 675-680

structural formula

% Effect structural formula

"/"Effect

O-ii

- O-CH-,

(Is-U-OCI-Iv)

0.17

Cl

Ο-ίΐ

0-CIL,

- O-Ps

0.42

r ~ Cl

<0.003

O-CH

"Y!

2.17

O CIL

(L 3

0,036

O ₁ OlJ

- X - O-R

0,003

0-i? Cl

0.021 X = -0 P (0) 0 CH _o CH ₉ N (CH,),

0 ^

embodiments

example 1 2g Liquid oral formulation 250 g active substance 300 g sucrose 150g glucose 0.15 g d-Sorbitol 0.5 g Agar Agar 0.05g methylparaben 10g Propylparaben Flavor (orange flavor) 100On Tartazingelb Purified water on

Example 2 Liquid oral formulation ^v Active ingredient 2 g Tragacanth 7 g

Glycerol 50 g

Sucrose 40Oo Methyl parabens 0.0 g Propylparabren 0.05 g flavoring

(Taste of black currant)

Red Dye No. 2CE.184 0.02g Purified water on 1000ml Example 3 Liquid oral forum release Active ingredient 2.4g Sucrose 400 g Tincture of bitter orange peel 20 g Tincture of sweet orange peel 15g Purified water to 1000 ml

Claims (1)

1. A process for the preparation of an agent against vlrala infections, preferably against AIDS, characterized in that halogenated Alkylglycerophosphocholin analogues of general formula I, II or III, Y = Cl, F, OCH ₂ CF ₃ mean, mixed with pharmaceutically acceptable carriers and / or excipients. 2. The method according to claim 1, characterized in that one dissolves the compounds of formula I ₁ Il or III in DMSO. Field of application of the invention The invention relates to the preparation of an agent against viral infections, preferably against AIDS. The field of application lies in the chemical and pharmaceutical industry. Characteristic of the known state of the art There are currently few drugs in the field of antiviral chemotherapy which have a required high selectivity. In many cases, it is insufficient to prevent virus replication without compromising the ability of the host cells to divide. This is also true for the agents used for the antiviral chemotherapy of AIDS, e.g. the AZT and other nucleosides that prevent the proliferation of causing HIV (human immunodeficiency virus), but also lead to unwanted cytotoxic side effects. Recently, evidence of HIV efficacy of 1-0-octadecyl-2-0-methyl-rac-glycero-3-phosphocholine (Et-18-OCHa) has been reported (Kucera, L, Iyer, N., Raben, A. , Modest, E., Daniel, L. and Piantadosi, C, Proc. 5. Internal Confidence on AIDS [Montreal], abstract WC0.21). Structurally, compounds of this type are similar to the so-called platelet activating factor (PAF), a physiologically highly active phospholipid produced by various cells. PAF effects already in concentrations of 10 ~ ⁷ to 10 "" MT platelet aggregation, blood pressure reduction, serotonin release among other things, ie, Alkylglyce'ophosphocholin analogues are, if they have significant PAF effect, unsuitable for therapeutic purposes. ET-18-OCH ₃ as well as the structural isomers of this compound show not inconsiderable PAF activity (Ostermann, G., Keuscher, H.-P., Lang, A., Till, U., Thrombosis Research 4311986] 675-680 ), see. Table 2. Object of the invention The invention aims to develop a process for the preparation of a suitable, technically useful agent against viral infections, preferably against AIDS based on phospholipids, which do not have the disadvantages of the hitherto known anti-HIV-active phospholipids. Explanation of the essence of the invention The invention has for its object to provide a corresponding pharmaceutical agent. It has now been found that halogen-containing Alkylglycerophosphocholin analogues of the general formulas I, II or III