SU801483A1 - Derivatives of n-carbamidoalkyl-alpha-diazoketones or alpha-thiocarbamido-alkyl-alpha-diazoketones having antitumoral effect - Google Patents

Abstract

DERIVATIVES N-CARBAMIDOAP-KIL-OS-DIAZOKETONOV OR IT-THYOKARBAMY-DOALKYL-about-DIAZOKETONOV, possessing anti-tumor activity, -

Derivatives of N-carbamidoalkyl- - o (..- diazoketones or N-thiocarbamidoalkyl-about - diazoketones of the general formula O.o E-IN-C-Sh-CH- (CH ^) ^ CCHNjR-where, X is an oxygen atom or sulfur ", ^ - phenyl, methyl", R 'is a hydrogen atom ", benzyl; And = 0-1, with antitumor activity. with? (L

Description

four;:

00

The invention relates to new chemical compounds, specifically, to derivatives of N-carbamidoalkyl-about -diazoketones or N-thiocarbamidoalkyl-oi-diazoketones of the general form ™ O II, J-13H-C-NH-CH- (CH2) j CCHN2 d where X is an oxygen or sulfur atom; R is phenyl, methyl) R is a hydrogen atom, benzyl; h. 0-1. These compounds can be used in medicine, as anticancer drugs. The closest analogue of these compounds with antitumor activity is the aza series, as well as diazoxonorleucine (SDON), belonging to the class of amino acids. No other analogues in the literature have been identified. Azaserin inhibits the growth of some mouse transplantable tumors. The highest percentage of inhibition is in S-180 sarcoma (up to 80%) 1. However, these compounds are highly toxic (LDg 80 mg / kg), causing side effects in rats and mice. For this reason, the recommended dose for use is 2.5 mg per 1 kg of body weight (azaserine) and 0.1 mg / kg (DON) 2. In addition, a great disadvantage of DON is a potent cumulative toxic effect, resulting in damage to the intestine (hemorrhagic enteritis. The aim of the invention is to expand the range of effects on a living organism, namely, effective antitumor drugs with reduced toxicity. N-carbamidoalkyl-ei-diazoketones and N-thiocarbamidoalkyl-OC-diazoke tones of the general formula I) obtained by the known addition reaction of isocyanates or isothiocyanates to amines and their derivatives of D. These compounds are prepared by reacting aminoalkyl-ot-diazoketones of the general formula W O. T1H2-CH- (CH2) - CCHNj where R and n have the same meanings as in formula (I),. with isocyanates or isothiocyanates of general formula (ill): RN where R have the same meanings as in formula (1) in an organic solvent with an amine to isocyanate or isothiocyanate ratio of 1: 1.5 at room temperature followed by isolation of the target product famous tricks. Typically, the process is carried out in methylene chloride. The yields of the final products reach 80%. The by-products are not formed. The ratio of reagents and temperature conditions correspond to optimal conditions under which the yield of the product is greatest. The structure of the obtained compounds corresponding to formula (1) is unambiguously confirmed by NMR, IR, and UV spectroscopy, as well as by microanalysis data. Example. Preparation of 1-diazo-3H- (N-phenylthiocarbamido) propan-2-one (R-CgHj, R-H,,). To a solution of 1.38 g (0.014 mol) of 1-diazo-3-aminopropan-2-one in 100 ml of methylene chloride, 2.5 ml (0.021 mol) of phenyl isothiocyanate are added with stirring. The mixture is aged for 10-12 hours, filtered, the solvent is removed, and the residue is chromatographed on a column of AlgO. Eluent is chloroform. After recrystallization from benzene, 2.8 g (85%) are obtained, mp. 116-118c.Ri 0.5 (silufol, ethyl acetate-benzene 2: 1). Found,%: N 24, (J5. C, oH ,, N40S. Calculated,%: N 23.93. EXAMPLE 2. Preparation of 1-diazo-3N - (N-phenylthiocarbamido) -4-phenylbutane -2-it (R-С / И,, Я-СН "СЛН, п 0,) ... To a solution of 1.95 g (0.01 mol) of 1-diazo-3-amino-4-phenyl-butane-2 1.8 ml (0.015 mol) of phenyl isothiocyanate is added with stirring in 50 ml of methylene chloride at room temperature. The product is isolated by the method described in the previous example. The residue after chromatography crystallizes upon trituration with ether and cooling until Exit 2, 5 g (75%). M.P. 108-109C (benzene-hexane). Found: C 63.08; H 4.87, N 17, 40. SpN, Calculated,%: C 62.96, H 4.94, N 17.28. Compounds 3, 4, 5, 6 are prepared analogously, see Table 1. The compounds obtained were tested for biological activity. Table 2. The single-dose toxicity is determined by white outbred mice and evaluated by the method of Burns. The preparations are administered intraperitoneally in the form of aqueous-tween 10% solutions. 380 Determine the doses that cause 50% of the animals to die (H05e). Compared with azaserine and DON, in which LD5g is 80 mg / kg, the toxicity of the claimed compounds is 10 or more times less. The antitumor properties of the compounds obtained are studied in different strains of animal-borne malignant tumors: ascites sarcoma. 5-180, leukemia P-38, leukemia L.-1210. As therapeutic doses, the doses of drugs used were 1/2 to 1/3 of OTLD. Drugs are administered intraboin. As an indicator of antitumor activity, the percentage of inhibition of tumor growth at the total drug dose in mg per 1 kg of body weight or the percentage of life extension of mice with a vaccinated leucoma serves. Properties of N-carbamidoalkyl-about-diazoketones and N-thiocarbamidoalkyl-oi-diazoketones of formula Cl) The most active is the preparation (2) - 1-diazo-3K- (N-phenylthiocarbamido) -4-phenylbutan-2-one. At a dose of 400 mg / kg, it is more active than azaserine and DON and inhibits the growth of S - 180 sarcoma by 95%. However, its toxicity is 10 times less. The use of the claimed compounds as drugs will allow more than 10 times the range of applied therapeutic doses and, as a consequence, increase the effectiveness of the therapeutic effect of these drugs. The great advantage of the compounds obtained is the absence of a cumulation of the toxic effect characteristic of DON, which allows a wide variation in the modes of drug administration without an increase in the toxic effect and side effect. Table 1

, R - H, n -0, X S 116-118

(benzene)

, H, R-CH CgHj, n 0 108-109

. X S Benzhexane)

, to -H, 115-116

(benzene)

4R CfeHj, l, n-q, 85-87

X-0 (benzene)

5R, 123-124

different benzene) 72-73 6 R —CH. , К,, benzene) Toxicity n antitumor activity of -Phf "HCNHCH, COCHW" 6 C / jP, 2PhNHCNHCbCOCHN2 70 diazoelectric compounds same 900

85

23.93

75

17.28

Table 2200 / 2E 800 900 C, H, N, OS 30,29 f tl, 14 l V K-carbaidealCl-1b100 / 72 200/60 400/95100/3 400/33 400/59 &PhNHCIIHCH; CH COCI N, s.

6 СН, ИСНМСН2СНгСОСН "г HOOCCNCNjOCOCHNj

Nun

2aaserin

For strains P-388 and 1210, the %% life extension is shown

table 2

400/21

900 400/35 900

80 1.25 / 25 2.5 / 50 5/75

Claims (1)

DERIVATIVES OF N-CARBAMNDOALKYL-K. -DIAZOKETONES OR N-THIOCARBES OF DOALKYL-OB-DIAZOKETONES, POSSESSING ANTITUMOR ACTIVITY Derivatives of N-carbamidoalkyl <£. II n I-NH- C-BN-CH- (CH ₂ ) flCCHNj R 'where, X is an oxygen or sulfur atom, K is phenyl, methyl ', R 'is a hydrogen atom *, benzyl; V) = 0-1 having antitumor activity.