HU207217B - Process for producing ray-sensibilizator composition - Google Patents

Abstract

Active agent of the pharmaceutical prod. is amidarone-t (2-butyl-3- (3',5'-diiodine-4'-beta-N-diethylamino-ethoxy-benzoyl) benzofuran-hydrochloride). - Prepn. is by using methods for prepn. of ionic radiation sensitisers(Dwg.0/0)

Description

FIELD OF THE INVENTION This invention relates to a process for the preparation of an ionizing radiation sensitizer containing amiodarone (chemically known as: 2-butyl-3- (3 ', 5'-diiodo-4' - [3-N-diethylaminoethoxybenzoyl) -benzofuran]. .

Amiodarone [Arch. Pharmacodyn., 139, 255 (1962)] is a benzofuran derivative which, due to its excellent therapeutic properties, has received worldwide attention among the antiarrhythmic / antianginal agents on the market.

With oral therapy (600, sometimes 800 to 1200 mg / day for 1-2 weeks, then 200 and 400600 mg / day to maintain effect), the physiological effect is significant after about 2 weeks and after about 5 weeks. When administered intravenously (5 mg / kg body weight for 20-120 minutes, then 15 mg / kg / day for 2-5 days, or 30 mg / kg for 12 hours, then 25 mg / kg for 36 hours), the physiological effect is shorter Who. Plasma concentrations of the agent may also be in the range of 3-7 mg / L.

The pharmacological properties of amiodarone known so far are briefly summarized below:

1. Electrophysiological effect (in case of long-term administration):

a) The duration of action potential increases in all cardiac tissues.

b) Phase 4 depolarization decreases.

2. The coronary artery causes dilation.

3. Generic vasodilator effect.

4. Noncompetitive α- and β-catecholamine receptor antagonism.

5. Vagolytic and vagomimetic effects are slight or not detectable.

6. It has little or no effect on the myocardial contraction.

7. Exceptionally long and individually variable elimination half-lives.

The mechanism of action is unknown. It is believed that its action on the myocardium is responsible for its undetected interaction with the thyroid hormone system, namely its ability to selectively inhibit the physiological effect of triiodothyronine [Amer. Heart J 106: 788 (1983)].

Occasional side effects associated with chronic administration of amiodarone have been reported to include bradycardia, pneumonitis, thyroid hormone dysfunction, bronchial asthma, phospholipoidosis, hepatitis, liver and kidney disorders, and skin disorders [Amer. Heart J, 106, 916 (1983); Circulation, 67, 45 (1983); Amer. Heart J 106, 906 (1983); Ann. Int. Med., 104, 348 (1986)].

According to the literature on anticancer radiation therapy, it is a common problem that healthy cells are damaged during radiation therapy. Therefore, intensive research is underway worldwide to develop radiation-sensitizing compounds that, after pretreatment, allow for significant radiation dose reduction.

It is an object of the present invention to provide a composition which significantly reduces the radiation dose suitable for killing tumor cells.

The present invention is based on the unexpected recognition that amiodarone may induce certain radical reactions by ionizing radiation. Surprisingly, it has been found that the compound, in a dilute aqueous solution, traps the solvated electrons known as strong reducing agents in a diffusion-driven process. This is indicated by the very high reaction rate coefficient of the process: k (e _aq ^_ + amiodarone) = (2.8 ± 0.4) x ^{10 10} dm ³ mol · 's ^_i .

The transient light absorption spectrum (λ _τηηχ = 345 nm) produced by the radiation impulse indicates the formation of a ketyl radical type transient, which, in the first decay process (k = 7x10 ⁴ s ~ '), has a stable absorbing property at 360370 nm.

HPLC showed that the end product of the process is the dehalogenated monoiodine derivative of amiodarone, which is identical to one of the major physiological metabolites of the drug.

We also found that the decay of the radiation-induced solvated electrons leads to an almost 100% probability of reductive dehalogenation of amiodarone.

Using similar experimental methods, we have studied the reaction of radicals with a lower reactivity with amiodarone, which are less reactive than the solvated electron. By radiolysis of alcoholic-aqueous solutions, selectively reduction experimental conditions were prepared, with the resulting α-hydroxy radicals being moderately reactive reducing agents.

It has been shown that the (CH ₃ ) ₂ COH radicals have undergone high chain initiation of reductive dehalogenation of amiodarone, while the likelihood of a similar reaction of the CH ₃ CHOH and CH ₂ OH radicals is about 40%.

Experimental results suggest that

amiodarone is readily dehalogenated by reducing radicals to form a reactive phenyl type as a complement product;

- the mono-iodine derivative of amiodarone, the main product of the reduction, is less reactive than the parent compound, and the second iodine atom of the molecule can only be converted to a hydrogen atom by a very high conversion method;

- the phenyl-type radical is stabilized by hydrogen atom abstraction from molecules containing labile hydrogen atoms.

According to the known chemical theory of radiosensitization, the negative charge produced by radiolysis in living cells is most likely localized on the thymine residue and the positive charge on the guanine residue. By high-resolution optical detection, it has been shown that the amiodarone receives an electron from a thymine anion produced by pulsed radiolysis. Thus, in line with the theory, it is expected that in the presence of amiodarone, the ion pair on DNA will have a longer life, increasing the likelihood of DNA damage. The phenyl radical formed during reductive dehalogenation following electron transfer may cause further damage to the nucleic acids.

Accordingly, the present invention provides amio2 as an active ingredient

GB 207 217 Β Darone (Chemical name: 2-butyl-3- (3'-5'-diiodo-4'-P-N-diethylaminoethoxybenzoyl) -benzofuran hydrochloride) and ionizing radiation sensitizing preparation and process for its preparation . The process involves converting the active ingredient, which is prepared in a known manner, into a radiation sensitizing pharmaceutical composition by admixing with auxiliary and auxiliary substances used in medicine.

In a preferred embodiment of the method of the invention, the composition comprising amiodarone is formulated as an injection or infusion.

The present invention further provides a method of treating tumors comprising using 10-50 mg / kg body weight of amiodarone as a radiation sensitiser in a known radiotherapy treatment.

The process of the present invention is illustrated by the following examples:

1. To detect radiation sensitization, we investigated cell membrane lipid peroxidation in the liver microsomal fractions of experimental animals treated with amiodarone in vivo. The process was followed by measuring the yield of malondialdehyde (MDA) as a function of radiation dose.

Active ingredient used: amiodarone (150 mg / 3 ml ampoule)

Experimental animals: Male Wistar rats weighing 150-200 g

Treatment mode: oral, (p. P.), Ca. 500 mg / kg body weight / day for 30 days, mixed with food

Radiation source: ^ Co-y, 1750 TBq nominal activity, wreathed arrangement, dose rate 18 kGy / min

The liver microsomes were irradiated in the form of an air-saturated aqueous suspension (ca. 10 mg / ml protein) at room temperature with continuous shaking and the amount of MDA produced in samples taken at different irradiation times was determined. The results are shown in Table 1 in comparison with the control samples not receiving amiodarone treatment.

The amount of radiation-induced lipid peroxidation in the amiodarone-treated samples was significantly higher than that of the untreated samples, indicating that amiodarone significantly increased the rate of radiation-induced degradation of the cell membrane. As the radiation dose increases, the sensitizing effect (B / A) of amiodarone is reduced, indicating a loss of microsome-enriched drug.

Table 1 ⁶⁰ Co-γ irradiated lipid peroxidation (nmoles of MDA / mg protein, ± 10%) in liver microsomes of in vivo treated rats

Radiation dose, kGy 0.73 1.47 2.20 Control (A) 0.46 4.1 12.4 Amodarone (B) 9.2 21.2 32.5 B / A 20 5.2 2.6

2, Detailed animal experiments were performed as follows:

Active ingredient used: amiodarone (150 mg / 3 ml ampoule)

Experimental animals: male mice from Swiss outbred and BDF, inbred hybrid strains, body weight: 23-25 mg / kg

Treatment method: intraperitoneal (i.p.) dilution with isotonic sodium chloride solution

Radiation: ^ Co-y; Rotacert (Siemens) type device, focal length 80 cm, tubeless use, dose rate 1.4 Gy / min

In combination treatments, amiodarone and radiation were administered at doses that did not in themselves induce lethal toxicity. According to our studies, this dose is 200 mg / kg for amiodarone and 8.0 Gy for radiation treatment (see Table 2).

The data in Table 3 indicate that amiodarone pretreatments at different time points (-24, -6, -5, -1 hours) relative to radiation treatment significantly increased the sensitivity of the mice to whole-body irradiation. Compared to the 100% survival of the radiation-only control group, the survival rate was 30-60% in the amikodarone-treated groups. The times applied did not significantly affect the radiosensitization effect of amiodarone. The sensitizing effect of the 24-hour pretreatment was greatest.

Therefore, the main advantage of the present invention is that it enables the preparation of a pharmaceutical composition which has a very significant radiation sensitizing effect in the radiation treatment of cancer.

Table 2

Dose-dependent effect on survival of mice

Treatment Dose Survivor / All animal Comment Amioda- rone 500 mg / kg 0/7 100% destruction within 24 hours 400 mg / kg 0/7 100% destruction within 24 hours 350 mg / kg 5/7, 3/5 300 mg / kg 5 / 6.5 / 6 250 mg / kg 6 / 6.5 / 5.4 / 5 200 mg / kg 7 / 7.6 / 6, 5 / 5.5 / 5 Dose-dependent effect of Co ⁶⁰ whole-body irradiation on survival in mice Treatment Dose Survivor / All animals Co. ⁶⁰ 9.0 Gy 2.7 8.5 Gy 4/7 8.0 Gy 7/7, ΊΠ

HU 207 217 B

Table 3

Influence of Amiodarone on whole-body irradiation sensitivity of Swiss mice

Treatment Dose Treatment time (relative to radiation) Survival / Összcs chin As a percentage of survivors amiodarone 200 mg / kg 0 ” ^h 7/7 100 Co ⁶⁰ Control 8.0 Gy "0" ^h 7/7 100 7/7 100 amiodarone 200 mg / kg -24 ^h 2/7 29 Co ⁶⁰ * 8.0 Gy "0" ^h amiodarone 200 mg / kg -6 ^h 3/7 43 Co ⁶⁰⁺ 8.0 G "0" ^h 2/6 33 amiodarone 200 mg / kg -5 ^h 3/7 43 Co ⁶⁰ * 8.0 Gy "0" ^h Amidoarone 200 mg / kg -l ' ¹ 3/7 43 ^{CoEl +} 8.0 Gy "0" ^h 4/6 66

PATENT CLAIMS

Claims (2)

PATENT CLAIMS A process for the preparation of a composition sensitizing to ionizing radiation, characterized in that amiodarone (chemically known as: 2-butyl-3- (3'5'-diiodo-4'-pN-diethylaminoethoxybenzoyl) -benzofuran hydrochloride) is prepared in a known manner. radiation sensitizer mixed with auxiliary substances used in medicine 25 actives. 2. The method of claim 1, wherein the amiodarone-containing composition is prepared as an injection or infusion composition.