RU2028301C1 - Cis-chloro-n′-((2′--tetrahydrofuryl)-5-fluorouracilatodiammin- -platinum (ii) showing antitumor activity - Google Patents

Abstract

FIELD: organometallic compounds. SUBSTANCE: product - cis-chloro-N′-((2′--tetrahydrofuryl)-5-fluorouracilatodiammin- -platinum (II), yield is 65-70% , mol. mass is 463,75, at 218 C product is melted with decomposition. Reagent 1: [Pt(NH₃)2Cl₂]. Reagent 2: N′-((2′--tetrahydrofuryl)-5-fluorouracil. Reaction conditions: in aqueous-alkaline medium, at heating on the water bath. Synthesized compound is used in medicine. EFFECT: improved method of synthesis. 2 tbl

Description

The invention relates to new biologically active chemical compounds, as well as to the coordination compound cis-chloro-N1 (2 ¹ -tetrahydrofuryl) -5-fluorouracilatodiamine-platinum (II), which exhibits antitumor activity.

 It is known that some coordination compounds of platinum (II) with nitrogen-containing ligands exhibit biological activity, in particular antitumor. Most often, such ligands are ammonia and various amines [1].

 High antitumor activity is manifested by complex non-electrolytes of platinum (II) containing a group of cis-dichloroplatin. The greatest antitumor effect has cis-dichlorodiammineplatinum (II) [2] (DDP), which is the closest analogue of the claimed compound.

 DDP has a large spectrum of antitumor activity and is widely used to treat certain types of malignant neoplasms in humans.

However, this compound has low solubility (0.1% at 25 ° ^C) and high toxicity (LD ₅₀ = 10 mg / kg). During therapy with the drug DDP, there are such side effects as the occurrence of nausea, vomiting, damage to the intestines and kidneys, etc., which significantly limits its use.

 The aim of the invention is to expand the range of water-soluble and low-toxic platinum compounds with antitumor activity.

Предлагаемое соединение получают взаимодействием эквимолярных количеств цис-дихлородиамминплатины (II), N₁ (2¹-тетрагидрофурил)-5-фторурацила (C₈H₉N₂F = НФ) и гидроксида натрия в водном растворе при нагревании на водяной бане. Реакция протекает по схеме
цис-[Pt(NH₃)₂Cl₂] + НФ + NaOH ->>
->> цис-[Pt(NH₃)₂ФCl] + NaCl + H₂O Раствор испаряют досуха. Образовавшийся комплекс и хлорид натрия разделяют диметилформамидом (ДМФ), в котором хорошо растворим комплекс и нерастворим хлорид натрия. Из раствора ДМФ комплекс выделяют добавлением эфира. Соединение представляет собой светло-желтый рентгеноаморфный порошок, хорошо растворимый в воде, диметилформамиде, нерастворимый в спирте, ацетоне, эфире.The problem is achieved by the properties of the new platinum (II) compound containing in the cis position two ammonia molecules, one chlorine atom and one residue N ₁ (2 ¹ -tetrahydrofuryl) -5-fluorouracil of the formula I

The proposed compound is obtained by the interaction of equimolar amounts of cis-dichlorodiammineplatinum (II), N ₁ (2 ^1- tetrahydrofuryl) -5-fluorouracil (C ₈ H ₉ N ₂ F = NF) and sodium hydroxide in an aqueous solution when heated in a water bath. The reaction proceeds according to the scheme.
cis- [Pt (NH ₃ ) ₂ Cl ₂ ] + NF + NaOH - >>
- >> cis- [Pt (NH ₃ ) ₂ ФCl] + NaCl + H ₂ O The solution is evaporated to dryness. The resulting complex and sodium chloride are separated by dimethylformamide (DMF), in which the complex is highly soluble and insoluble in sodium chloride. From the DMF solution, the complex is isolated by adding ether. The compound is a light yellow X-ray amorphous powder, readily soluble in water, dimethylformamide, insoluble in alcohol, acetone, ether.

Chemical analysis data correspond to the compound [Pt (NH ₃ ) ₂ FCl].

 The correctness of the above formula, the purity and structure of the complex compound are confirmed by high performance liquid chromatography, thermogravimetric analysis, conductivity measurements, electron and IR spectroscopy, PMR spectroscopy (Table 1).

It can be seen from the data in Table 1 (molecular conductivity values) that the complex is a non-electrolyte. The electronic absorption spectrum of the complex, like the spectrum of the free ligand, contains one maximum. A change in the absorption intensity upon transition from the free ligand to the complex indicates the anionic form of the ligand [3]. In the IR spectrum, there are no bands in the range 3000–3100 cm ^–1 corresponding to stretching vibrations νN ₃ –H [4], which indicates the deprotonated form of the ligand. Intensive absorption in the region of 312 cm ^–1 corresponds to the stretching vibration ν _Pt-Cl and indicates coordination of the chlorine atom [5]. In the NMR spectrum of H ¹ in a DMF solution, there is no wide signal with δ = 4.35 ppm, and there is also a shift of H (6) signals into a strong field by 0.2-0.3 ppm in a solution of D ₂ O and 0.43-0.45 ppm in DMF solution. This indicates that the ligand is deprotonated and bound to Pt (II) via the nitrogen atom of the heterocycle [1].

Thus, on the basis of the results obtained, it was concluded that a new complex compound cis-chloro-N ₁ (2 ¹ -tetrahydrofuryl) -5-fluorouracilatodiammineplatinum (II) was synthesized. (Conditional name "Platform").

The coordination compound "Platif" was tested for biological activity, the antitumor effect and toxicity were specifically studied in comparison with cis-dichlorodiammineplatinum (II) (DDP) and the original N ₁ - (2 ¹ -tetrahydrofuryl) -5-fluorouracil (NF).

The toxicity of cis-chloro-N ₁ (2 ¹ -tetrahydrofuryl) -5-fluorouracilatodiamine-platinum (II) preparation was studied on outbred mice using the Burns method. For this, male mice weighing 18-22 g were injected intraperitoneally once with freshly prepared solutions of the drug in saline in increasing doses: 300, 350, 400, 450, 500, 550, 600, 650, 700, 750 mg / kg. The death of animals was recorded within a month. The obtained values of LD ₅₀ and therapeutic dose D _ter. are given in table 2.

 The criterion of therapeutic efficacy of compounds is the percentage of inhibition of tumors and an increase in the life expectancy of animals (VL in%).

The antitumor activity of the drug was studied on C ₅₇ Bl, DBA / 2 mice, as well as white and outbred mice and rats using 4 strains of experimental tumors of various morphogenesis according to standard methods. For this, after inoculation of the corresponding strain, animals were injected intraperitoneally daily with a therapeutic dose of the claimed compound in saline. In total, animals were given 5-10 injections.

 Comparative data on the effect of the compounds "Platif", DDP and NF on the growth of transplanted tumors are presented in table.2.

 From the table. 2 shows that the claimed compound "Platif" has 50 times less toxicity than DDP and increased antitumor activity against Sarcoma-180 and Leukemia R-388.

Example 1. Preparation of cis-chloro-N ₁ (2 ¹ -tetrahydrofuryl) -5-fluorouracilatodi-amminplatinum (II).

To a suspension of 1,200 g of cis- [Pt (NH ₃ ) ₂ Cl ₂ ] in 44 ml of water was added a solution containing 0.8008 g of N ₁ (2 ^1- tetrahydrofuryl) -5-fluorouracil dissolved in 7.76 ml of 0.5155 mole of NaOH. The mixture for 1 hour on a water bath heated, evaporated twice at 35-40 ^{° C} and cooled in a refrigerator. The cooled solution was filtered and evaporated to dryness. DMF was added to the dry residue, insoluble sodium chloride was filtered off, and excess ether was added to the filtrate. The separated matter was filtered off, washed several times with ether, dried at ¹⁰⁰ ° C and analyzed. Product yield 65-70%.

PRI me R 2. The study of the antitumor activity and toxicity of the compound "Platif" was carried out on 30 mice of the line C ₅₇ Bl, DBA / 2 of both sexes weighing 18-20 g with transplantable tumors: sarcoma 180, erythromyelosis of Shvets, melanoma B-16 , and P-388 leukemia. The compound was administered in the form of a freshly prepared isotonic NaCl solution at a dose of 60 mg / kg, intraperitoneally 1 time per day for 5-10 days. The animals were killed one day after the last injection and the percent inhibition of tumor growth and the increase in the life span of the animals (VL) were determined.

 It was found that the claimed compound exhibits the highest antitumor activity against Schweit erythromyelosis, inhibits tumor growth by 91%, and also inhibits the growth of sarcoma 180 (Crocker) by 84.5%, leukemia P-388 - by 82%, melanoma B-16 - by 76%.

 Thus, the Platif compound is a very soluble drug (solubility 1 exceeds 200 times the solubility of DDP) with low toxicity, high antitumor effect and can be used to treat malignant tumors both independently and in combination with other chemotherapeutic agents, which especially valuable in cases where their use is complicated by toxicity or addiction to the body.

Claims (1)

CIS-CHLORO-N ₁ - (2 ¹ -TETRAHYDROFURIL) -5-fluorouracilathiamminplatin II, MANIFESTING ANTITUMOR ACTIVITY. Cis-chloro-N ₁ - (2 ¹ -tetrahydrofuryl) -5-fluorouracilatodiammineplatinum (II) of the formula

showing antitumor activity.

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