Derivatives of platinum tetrachloride and method for their preparing

FIELD: chemistry of metalloorganic compounds, medicine, oncology.

SUBSTANCE: invention relates to derivatives of platinum tetrachloride and to a method for their preparing also. Invention proposes compounds of the formula PtCl4 x 2 Li wherein Li represents N-(2-nitroxyethyl)nicotinamide or N-(2-nitroxyethyl)isonicotinamide, or nicotine hydroxamic acid, or isonicotine hydroxamic acid. Also, invention proposes a method for preparing these compounds that involves interaction of pyridine carboxylic acid nitroxyethylamides or hydroxamic acids, or their hydrochlorides with potassium hexachloroplatinate followed by isolation of the end product. Invention provides synthesis of the unknown early chelate platinum compounds that are physiologically active substances and can be used in medicinal practice instead cisplatin as effective anti-metastatic medicinal agents with low toxicity.

EFFECT: improved preparing method, enhanced and valuable medicinal properties of compounds.

2 cl, 3 ex

 

The invention relates to a derivative of platinum tetrachloride, which are physiologically active substances having antimetastatic effect, and can be used in medical practice with chemotherapy for cancer patients. Specifically, the present invention relates to complex compounds of tetravalent platinum formula:

where Li-N-(2-nitroxyethyl)isonicotinamide, or N-(2-nitroxyethyl)nicotinamide, or nicotinamidase acid, or isonicotinohydrazide acid.

Known for high antimetastatic activity of cisplatin(CIS-diamminedichloroplatinum), which is widely used in medical practice as antimetastatic drugs. Index of inhibiting metastasis in a number of experimental tumors reaches during treatment with this drug to 92%. However, it has a high General toxicity, and nephro - and neurotoxicity. In addition, some types of tumors are resistant against this drug called cisplatin.

The present invention is to develop a previously unknown complex compounds of tetravalent platinum formula (1), which possess less toxicity to warm-blooded animals and higher antimetastatic activity.

The proposed compounds are the new, in the literature are not described not described and the way they are received.

This goal is achieved by a method characterized in that nitroacetanilide or hydroxamic acid pyridineboronic acids or their hydrochloride exposed to hexachloroplatinate potassium or sodium, followed by separation of the target product.

The invention is characterized by the following examples.

Example 1. CIS-Bis[(2-nitroxyethyl)nicotinamide-N]tetrachloroplatinate (IV). To a solution of 3 g (6.6 mmol) of hexachloroplatinate of sodium in 50 ml of water at 30-40°was added to the solution and 2.79 g (13,2 mmol) N-(2-nitroxyethyl)nicotinamide in 180 ml of water, the reaction mixture was stirred for another 5 h and was filtered yellow crystalline precipitate was dried at room temperature. Obtained 3.8 g (75.8 per cent) of CIS-bis (2-nitroxyethyl)nicotinamide-N]tetrachlorethene (IV) with TPL 183-184,5°C. Found (%): 25,45; N. Of 2.54; N 11,28; Cl 18,51; Pt 25,58. C16H18N6O8PtCl4. Calculated: 25,31; N. Of 2.38; N 11,06; Cl 18,67; Pt 25,69. An NMR spectrum1H (DMSO-d6J/Hz): 9,26 (TWS. 1H, NH); 9,23 [C, d, 1H, J(PtH)26,8, N (2)]; 8,82 [d, DD, 1H, JPtH) 26,6, N(6)]; 8,77 [d, 1H, J 6,7, (H4)]; a 7.85 (m, 1H, J 6,7, N(5)); of 4.66 (t, 2H, J 4,6, CH2O); the 3.65 (dt, 2H, J 4,6, 5,9 CH2N).

Example 2. CIS-Bis[(2-nitroxyethyl)isonicotinamide-N]tetrachloroplatinate (IV). The synthesis was performed analogously to example 1. From 3.5 g (7.19 mmol) of hexachloroplatinate potassium in 250 ml of water S3,1 g (14.6 mmol) of N-(2-nitroxyethyl)isonicotinamide obtained 3.8 g (69,5%) of CIS-bis [N-(2-nitroxyethyl)isonicotinamide-N]tetrachloroplatinate (IV). Found (%): 25,19; H 2,50; N 10,78; CL Holds 18.52; Pt 25,29. C16H18N6O8Cl4Pt25,18. Calculated (%): 25,31; N. Of 2.38; N 11,06; Cl 18,62; Pt 25,69. An NMR spectrum1H (DMSO-d6, J/Hz): 9,37 (Ust, 1H, J 5,9, NH); 8,90 (d, 2H, J=5,6; J (Pt-H)=28,3; N2N6); 8,02 (d, 2H, J=5.6 AND N3N4); of 4.67 (t, 2H, J=4,7, CH2O); 3,66 (dt 2H, J=4,7; 5,9 CH2N).

Example 3. CIS-Bis[hydroxysuccinimide-N]tetrachloroplatinate (IV). To a solution of 2.5 g (5.14 mmol) of hexachloroplatinate potassium in 250 ml of water at room temperature was added a solution of 1.5 g (10.84 mmol) isonicotinohydrazide acid in 7 ml of water. After mixing of the reagents, the reaction mass was kept several days at room temperature and was filtered yellow crystalline precipitate, washed his ice water and alcohol, dried at room temperature in air. The obtained CIS-bis[hydroxysuccinimide-N]tetrachloroplatinate (IV) with TPL 175°C (decomp.). The weight of 1.65 g, yield 52,3%.

An NMR spectrum1H (DMSO-d6, J/Hz): 11.90 (s, 1H, HE); 9.64 (USS, 1H, NH); 8.85 (d+DD, 2H, J=6.7, JPtH=28.6, JH-H=6.8 (H(2), N(6)); 8.01 (d, 2H, Jn-n=6.6, N(3), N(5)).

Thus, the proposed method of obtaining compounds of formula (1) can achieve the goal of the invention and to obtain previously unknown derivatives of platinum tetrachloride, which can be used in medical practice as an effective antimetastatic is rest instead of cisplatin.

Tests on acute toxicity were performed in the laboratory of experimental cancer chemotherapy IPCP RAS by intraperitoneal administration of the drug in water or 10%twin mice weighing 22-24, the test Results showed that the claimed complex compounds of tetravalent platinum have LD50- lethal dose 50 - level 370-750 mg/kg This data allows us to include the claimed compounds to lower toxicity or non-toxic substances. The synthesized metal complexes allow to inhibit the process of metastasis in melanoma b-16 and the Lewis lung carcinoma in 96-99%.

1. Derivatives of platinum tetrachloride formulas (1)

PtCl4·2Li (1)

where Li = N-(2-nitroxyethyl)nicotinamide or N-(2-nitroxyethyl)isonicotinamide, or nicotinamidase, or isonicotinohydrazide acid.

2. The method of obtaining derivatives of platinum tetrachloride formula (I)

PtCl4·2Li (I)

where Li = N-(2-nitroxyethyl)nicotinamide or N-(2-nitroxyethyl)isonicotinamide, or nicotinamidase acid, or isonicotinohydrazide acid, characterized in that nitroacetanilide or hydroxamic acid pyridineboronic acid is subjected to interaction with hexachloroplatinate potassium, followed by separation of the target product.



 

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< / BR>
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< / BR>
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1 ex, 5 tbl

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