Complex compounds of iron - ferrocenylphosphines with antitumor activity

 

(57) Abstract:

The invention relates to complex compounds of iron, used in medicine, namely to search for new treatments for cancer. As anticancer drugs are encouraged to apply esasterawan derivatives of ferrocene - ferrocenylphosphines, the General formula

< / BR>
where R = H, X = CF3(1), or R = H, X = CHF-CF3(2), or R = H, X = CF2-CHF2(3), or R = H, X = CHF-O-CF3(4), or R = CH3X = CHF=CF3(5). 3 table.

The invention relates to new biologically active compounds ferrocene derivative having antitumor activity, which can find application in medicine.

Known cyclopentadienyl complexes of titanium, vanadium, niobium, tantalum, iron, having a pronounced antitumor activity and low toxicity [1]

The closest analogues to the invention are complex compounds of iron salts of alkyl substituted ferritine with polietileninu [2] In vivo detected antitumor activity of these complexes in experiments with adenocarcinoma Ca755, malignant human tumors ("podkapsulnaya the TEC is I relatively low efficiency and relatively high toxicity.

The objective of the invention is to develop a new integrated iron compounds with antitumor activity and low toxicity.

The problem is solved with new complex compounds of iron - ferrocenylalkylaminophosphonate, of General formula:

< / BR>
where R is H, X CF3(1), or

R H, X CHF-CF3(2), or

R H, X, CF2-CHF2(3), or

R H, X CHF-O-CF3(4), or

R CH3X CHF-CF3(5),

with antitumor activity.

Ferrocenylphosphines can be obtained by the reaction of equimolar amounts of alpha-hydroxymethylpropane or alpha hydroxyethylpiperazine 2-polyferrocenylsilane the benzimidazole system methylenechloride (45 aqueous solution perftorirovannogo acid.

The composition and structure of ferrocenylphosphines the proposed formulas were confirmed by elemental analysis data, methods, mass, IR and PMR spectroscopy.

The following are specific examples of the preparation and study of biological activity of the proposed connections.

Synthesis of ferrocenylphosphines 1 5 conducted in the following way. To a mixture of 6 mmol alpha hydroxymethylfurfural under vigorous stirring was added 1.08 ml 45 aqueous solution perftorirovannogo acid. Stirring is continued for 5 min, then the reaction flask was added 15 ml of diethyl ether, the same amount of cold distilled water and 5 to 10 mg of ascorbic acid. After vigorous shaking of the mixture of organic yellow coloured solution is separated, washed with cold water (5 x 15 ml), the solvent removed, the residue is dried over calcium chloride.

Example 1. 1-Ferrocenylmethyl-2-triftoratsetata (1). Obtained according to the General method of alpha hydroxymethylfurfural and 2-triftoratsetata exit 96

Rf(hexane/ether 2 1) 0,32.

Found, With 59,43; H A 3.87; Fe 14,18; N 7,19.

C19H15F3FeN2.

Calculated With 59,40; H 3,94; Fe 14,54; N 7,29.

Mass spectrum: 384 M+.

PMR-spectrum (acetone-d6TMS): 4,18 (t, 2H), 4,27 (s, 5H, Cp), 4,50 (t, 2H), 5,50 (s, 2H, CH2), 7,41 (m, 2H, Ph), of 7.82 (m, 2H, Ph)

Example 2. 1-Ferrocenylmethyl-2-(alpha-hydrotherapeutic)benzimidazole (2). Obtained from hydroxymethylfurfural and 2-(alpha-hydrotherapeutic)benzimidazole according to the General method. Output: 100

Rf(hexane/ether 2 1) 0,26.

Found, C 57,84; H 4,12; Fe 13,45; N 6,37.

C20H16F4FeN2.

Calculated C 57,72; H A 3.87; Fe 13,42; N Of 6.73.

PMR-spectrum (APR: 416 M+.

Example 3. 1-Ferrocenylmethyl-2-(beta-hydrotherapeutic)benzimidazole (3). Derived from alpha-hydroxymethylfurfural and 2-(beta-hydrotherapeutic)benzimidazole according to the General method. Exit 85

Rf(benzene) 0.47.

Found, C 57,65; H 3,92; F 17,95; Fe 13,00; N 6,51.

C20H16F4Fe2N2.

Calculated With 57,72; H A 3.87; F 18,26; Fe 13,42; N Of 6.73.

IR-spectrum (KBr tablet, cm-1): 3110, 2940, 2870, 1480, 1440, 1340, 1260, 1230, 1217, 1120, 1040, 944, 840, 820.

Example 4. 1-Ferrocenylmethyl-2-(cryptomaterial)benzimidazole) (4). Derived from alpha-hydroxymethyl-ferrocene and 2-(cryptomaterial)benzimidazole according to the General method. The output 93

Rf(benzene) 0,29.

Tpl.125 127oC.

Found, C 56,03; H 3,72; F 16,95; N 6,16.

C20H16F4FeN2.

Calculated C 56,03; H To 3.73; F 17,58; N 6,48.

PMR-spectrum(acetone-d6TMS): to 4.15 (s, 2H), 4,28 (s, 5H, Cp), 4,55 (s, 2H), 5,50 (s, 2H, CH2), 7,35, to 7.75 (m, 4H, Ph), 7,60 (s, 1H, CHF).

Mass spectrum: 432 M+.

IR-spectrum (KBr tablet, cm-1): 3108, 3007, 1540, 1479, 1438, 1240, 1191, 1110, 1018, 826.

Example 5. 1-(alpha-Adilfaranj)-2-(alpha-hydroterra-foradil)benzimidazole (5). Obtained from (alpha-hydroxyethyl)-ferrocene and 2-(alpha-hydro is practical product, the output 73

Tpl.121 124oC.

Rf(hexane/ether 2 1) 026.

PMR-spectrum (acetone-d6TMS): 192 to 2.06 (m, 3H, CH3), 4,00 4,37 (m, 9H, Cp), 4,77 (user. s, 1H, CH), 6.42 per 6,94 (m, 1H, CHF), 7,07 to 7.75 (m, 4H, Ph).

Mass spectrum (m/z): 430 M+.

Test compounds 1 to 5 on the antitumor activity were conducted in the Moscow research oncological Institute. P. A. Herzen.

Acute toxicity of drugs has been studied in intact animals (mice-female line C57B1/6) in 5 successive series of experiments using increasing doses of drugs. Observations have shown that at doses of 1000 1580 mg/kg of the investigated drugs are not toxic. Higher doses were not studied due to the limited solubility of drugs. Therefore, when choosing a therapeutic dose for testing the antitumor effectiveness for LD50conditionally adopted a dose of 1000 mg/kg (for products 2, 3 and 4) and 1580 mg/kg for drugs 1 and 5.

Autopsy of the animals that received the drugs in these maximum doses, and found no significant pathologic-anatomic changes in the liver, kidneys and adrenal glands as compared with intact control animals.

F1 weighing 18 to 22 g Used strains adenocarcinoma (Ca 755), epidermoid carcinoma Lewis lung (LLC), sarcoma (S 37), ascitic Ehrlich tumor (UAE), lymphoid leukaemia (L 1210) and lymphocytic leukemia (P-388). Perebivka Ca 755, S 37 carried out subcutaneously, LLC subcutaneously and intramuscularly, L 1210 and the AEO subcutaneously and intraperitoneally. Preparations 1 5 introduced intramuscularly, intraperitoneally or orally. The effectiveness of therapy is determined by the duration of the latent period of tumor growth rate of tumors and longevity of animals in the experimental and control groups. Registered General condition of the animals. At autopsy visually assessed the condition of the liver, adrenal glands, lung, and lymphoid organs (thymus, spleen, lymph nodes).

The proposed ferrocenylphosphines (drugs 1 5) show relatively high antitumor effectiveness in the treatment of animals with transplantable tumors, and leukemias and ascitic tumors.

The undoubted advantage of the proposed compounds is their significantly lower toxicity in comparison with the toxicity of the currently applied in clinical practice preparations based metallocomplexes from other anticancer drugs such to that, apparently, do not exert immunosuppressive effects on the body of the animal.

Complex iron compounds with antitumor activity and low toxicity, characterized in that they represent ferrocenylphosphines General formula

< / BR>
where R is H, X CF3(1) or

R H, X CHF CF3(2) or

R H, X, CF2CHF2(3) or

R H, X CHF 0 CF3(4) or

R CH3X CHF CF3(5).

 

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