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)
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)
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.
where R denotes H, C1-C7alkyl and halogen; R1denotes H or halogen, provided that in the 4th position R1not denotes bromine or iodine; R2denotes H or CF3; R3denotes N or C1-C7alkyl; R4denotes H, halogen, C1-C7alkyl and others; R5denotes N or C1-C7alkyl; X represents-C(O)N(R5)-, -N(R5)-C(O)- or-C(O)O-; Y represents -(CH2)n-, -O-, -S-, -SO2-, -C(O)- or N(R5’)-; R5’means (ness.)alkyl; Z represents =N-, -CH= or-C(C1)=; n denotes a number from 0 to 4; and their pharmaceutically acceptable salts
where R1- CH3or-CH2HE, R2-CH2HE, X-Y - linkage of formula (a) or (C)
where R6- H, lower alkyl, W is O, S or-CH2-, Ar1, Ar2the cycles of formula (e), (j), (k), (m)
R8, R9, R11, R12- H, lower alkyl, halogen, HE, CF3,
where R13, R14- lower alkyl, CF3, R15- H, acetyl, trimethylsilyl, tetrahydropyranyl, or their salts
-OR SIG6N(R7)-, where R6- alkyl, R5choose from the group of alkyl, aryl, including heteroaryl, -COR7, -SO2R7and-COR10where R7Is H, alkyl or aryl, including heteroaryl, R2Is F, Cl, Br, J, alkyl, aryl, including heteroaryl, formyl, acyl, C(O)NR7R10or C(O)or SIG7, m = 0, 1, or 2, R3selected from the group comprising R7OR7N(R7)(R10) and CH(R7)C(O)R8, R8is R7OR7and NR7R10, R9is hydrogen, alkyl, aryl, including heteroaryl, -C(O)R10, -SO2R10, -C(S)OTHER10, -C(NH)NH(R10), -C(O)OTHER10, R10- H, alkyl, or aryl, including heteroaryl, and in each case, it is not necessarily different from R7X represents an ion halogen provided that 1) when two alkyl groups are the same carbon or nitrogen, they are not necessarily linked together with the formation of a cyclic structure, and (2) nitrogen heteroaryl ring R1
< / BR>where AG represents a radical selected from formulas (a) and (b) below:
< / BR>R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)
FIELD: medicine, oncohematology.
SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.
EFFECT: higher efficiency of therapy.
1 ex, 5 tbl