SU1188179A1 - Cis-dichlor-trans-dihydroxy-bis(isopropylamine-platinum (iv)) showing antitumor activity - Google Patents

Abstract

Cis-dachlor-trans-dihydroxy-by-is (isopropylamine) platinum (tY) form C) H xKNHCN (cN3) 2 NH2.CR (CH3) 2 it. exhibiting antitumor activity. §

Description

CO 1 The invention relates to a novel compound, namely cis-dichlorotrans-dihydroxy bis (isopropylamine) platinum ((V), exhibits antitumor activity and which can be used as an anticancer drug. The purpose of the invention is to find new effective antitumor drugs. which do not have dangerous side effects on the human body in comparison with the known A. Preparation of the crude product. The recrystallized (i Hj) Gig (26.8 h) was suspended in 50 ml of hot water and added to the resulting suspension at shaking 100 ml (100 volumes) of hydrogen, hydrogen. The reaction sludge was boiled for 0.5 "h until it turned yellow and color, after which the mixture was cooled and filtered. The residue on the filter was washed first with water, then ether and then dried in air. The yield of the air product was 10.5 g (35% of the theoretical). Data of elemental analysis of the obtained product: Calculated,%: C 16.55; H 4.87; N 6.43, About 11.03, C1 16.28. Found,%: C 16.59 - H 4.90; N 6.48; About 10.80; C1 16.20. The absorption spectrum of the hydroxyl group (0-H bond stretching vibrations) is present in the IR spectrum of the product in the region of 3515 cm. B. Preparation of the product from dimethylacetamide M and isolation of a practically pure product. The crude product (11 g), obtained as described above, was dissolved in NNdimethylacetamide (approximately 1 liter) and the resulting solution was filtered through a glass porous filter having porosity No. 4 to remove any non-dissolved impurities. Then the solution was cooled to within 2 hours, seeded to prevent supersaturation, i.e. to prevent the formation of a supersaturated solution, and leave it for a few days at -10 ° C. The crystalline precipitate formed over this time was filtered, 792 washed with diethyl ether and dried to constant weight. The removal of N N-dimethylacetamide to obtain a substantially pure desired product was carried out by heating the resulting crystals to 50 ° C or lower with a residual pressure of 0.1 mm Hg. for several days or until thermogravimetric analysis of the product and / or analysis by gas-liquid chromatography showed the absence of N-dimethylacetamide N in it. The step of dissolving the crude product obtained in the previous step A in dimethylacetamide can be carried out at ordinary room temperature, but it is preferable to use a slightly higher temperature, i.e. temperature not higher than about 40 ° C. Other purification stages that are optional, i.e. optionally and not always, include recrystallization of the crude product (obtained in step A) from a dilute hydrogen peroxide solution, followed by drying the resulting recrystallized product in vacuum at about 50 ° C and further filtering the solution of the product in N; N-dimethylacetamide (see stage B) through a layer of silica gel (with a particle size of 70-230 mesh) in order to remove any impurities of polyhydroxy platinum derivatives. The antitumor activity of CHIP (target product) was first investigated in relation to the plasma cell tumor AD1 / PC6A in compact BaLb species by Dr. Connors, who established the therapeutic index (..12), which is clearly better than the therapeutic index of cis-platinum related (cis- diamine-dichloro-platinum (II). Further, it was found that CHIP has activity against 11210, P388, B16 melanomas, Lewis pulmonary carcinoma, colon tumors in mice (26 and 28), and in all cases ILS 100% (Table. 1). This drug is cross-treated with cisplatin relative to L 1210, but has activity against L 1210, resistant to BCNY and cyclophosphamide. Animal study. 3 A preclinical study was carried out. After applying a dose of 10 mg / kg, the T 1/2 value for rats is 14 h for CHIP compared to with a value of 69 hours for cisplatin. For dogs, T 1/2 was 39 hours. In rats, 44% of this dose was excreted in the urine, and this amount increased to 58% for 26 hours. Anapodial excretion was observed in dogs - 45% (3 hours and 57% (24 hours). Three hours after use, the drug in the urine was completely in the form of metabolites that were not identified. Platinum levels c. kidney for CHIP and cisplatin are shown in Table. 2. The tissue levels in the plasma tissue system for CHIP are presented in Table. 3. The pharmacokinetics of CHIP in rats was studied using a platinum tag emitting gamma particles. Compared with cisplatin and cistrans-dichloro-dihydroxybis (cyclopropylamine) platinum P (CP), after the CIS application of CHIP, the levels of platinum in the blood and most of the tissues decreased sharply, but the residual label was maintained for a long time. Increased absorption by the kidneys and spleen within 14 days suggests that there is a second wave from other tissues (Table 4). Such increased retention of radiation-labeled CHIP compared to cisplatin and CP may imply that CHIP has great potential for cumulative toxicity. Research on people x. The data obtained from the phase 1 study on the half-life of all platinum, filtered platinum, and unchanged drug, together with the study of urine samples, are summarized in Table 5. A small group of patients was studied on the pharmacokinetics of cisplatin and CHIP labeled with Pt. Comparative data obtained in the study of blood and urine samples are presented in Table. 6 and 7. Toxicity when tested on animals. The preclinical toxicological study of CHIP was carried out on 794 four animal, rat, dog and monkey animals. Usually, comparable toxicity was observed, which depended on the applied dose and was reversible at non-lethal doses. The values of LBjj) for several routes and application modes on the four indicated animal species are shown in Table 8. The most sensitive species of animals were dogs. Toxicity was indicated by diarrhea, often with blood, vomiting, loss of appetite, weight loss, loss of hair and hair. In all species of animals, suppression of the activity of the spinal cord and atrophy of the tissue was observed, with leukopeni acting on both lymphocytes and neutrophils as a common symptom. At high dosages, pathological changes in the kidneys (nephrosis) were observed in rats and dogs, and similar symptoms were observed in one monkey (on which a single lethal dose of 480 mg / m was used). Biochemical changes, which could be judged by hepatitis and renal toxicity, were observed in sick dogs and one monkey, but the corresponding pathological changes were not always observed. Although the medication and rats showed less cumulative toxicity with repeated use, the cumulative lethal effect of dogs on dogs for 5-10 days, but was absent if the drug was used for 20 days. When tested in five monkeys of unit dosages of degree IV, having values of 240, 360, 480 and 480 mg / m, only the highest values in lethal dosages were found in one of two animals, and, unlike in transitional hematological changes, only in one monkey clinical or pathological changes related to toxicity were observed. This animal had a loss of appetite, polydipsi, hypothermia, and bloody diarrhea. Hair loss and weight loss were observed. Death occurred on the 7th day and took place

pathological changes caused by severe toxicity to the bone marrow, kidneys, spleen, thymus and gastrointestinal tract.

T a b l and c a 1 Antitumor activity of CHIP

Continuation of table 2

Distribution of radiolabelled cisplatin and CHIP in tissues of male rats (Wistar) after applying a dose of 10 mci (expressed as the dose applied per 1 g of tissue l 10)

Table

one

2

34

48

Research in the laboratory of Roswell Park (phase 1) study of the half-plasma period of total platinum, filtered platinum and unchanged drug, and% in urine

208 20 8 184

179 81

Table 5

45.5 77.0

42.0 31.5

16.5

15.0

ъ1

- the value of the two-phase 1/2 period was not determined; - two-phase T 1/2 period - 36 hours

Determination of platinum complexes in the blood

ten

1188179 Sale Table 5

Table 6

Excretion of platinum complexes with urine

Table 7

Claims (2)

CIS-Dnor-trans-dihydroxy-bis (isopropylamine) platinum (IV) of the ^formula OH C1 _X 1 _x F ₂ CH (CH ₃ ) _g C1 ^X | ^x nn ₂ si (sn ₃ ) ₂ he showing antitumor activity. 2 eleven