3-or di(2-chloroethyl)amino compoundsacyl(hydr)oxosteroid with antitumor activity

 

(57) Abstract:

The invention relates to the chemistry of steroids and related specifically to 3-OR-di-(2-chloroethyl)aminecontaining 11-acyl(HYDR)oxosteroid with antitumor activity General formula (I), where R = COCH2C6H4N(CH2CH2Cl)2; R1= -OCOCH3+ -CCH; -OCOC2H5+ -H; R2= H, OCOH, COCH3. The inventive substances are of interest to medicine. Describes new types of anticancer compounds with cytotoxic and anti-estrogenic activity as well as cytotoxic compounds, does not exhibit estrogenic side steps. table 2.

The invention relates to the chemistry of steroids, relates to new chemical compounds - 3-OR-di-(2-chloroethyl)aminecontaining 11-alpha-acyl(HYDR)oxosteroid with antitumor activity.

The scope of medicine with the use of the subject invention as potential drugs - germanification for the treatment of hormone-dependent tumors, as well as biology and biochemistry, where the claimed compounds can be used as chemical reagents for nucleic acids [Knorre, D. G. Vlasov Century. Century. // Bioorg. Chem. 1992. So 18. C. 1330-1340] testatika) in Oncology for the treatment of hormone-dependent tumors [Sof"ina Z. P., Lagova N. D. / / Sov. Med. Rev. Oncol. 1992. V. 4. R. 1-55] . The most widely as germanification apply derivatives of steroid hormones containing the grouping di-(2-chloroethyl)amine. Such compounds (analogs of the invention) is known in all the most important series of steroid hormones - androgens, estrogens, gestagens and corticosteroids [Nilsson T. , Jonsson G. // Cancer Chemother.Rep. 1975. V. 59. R. 229-232. Pat. 55-89299 (1980). Japan. Rehim. 1982. P].

Known drugs on the basis of the esters of the natural hormone estradiol with di-(2-chloroethyl)aminoarabinose acid ESTRACYT, ESTRAMUSTIN, BACTRAMYCIN [Kubota T. K., Yamada Y., Oka, S., Enomoto K. // Jap.J.Cancer Res. 1988. V. 79. R. 1224-1229; Cytotoxic Estrogens in Hormone Receptive Tumors. Ed. J. Raus. London, New York. 1980. P. 245-269]. One of the most effective tools in the treatment of prostate cancer is considered to be an antitumor drug ESTRACYT with estrogenic activity.

Germanosilicate cited in the examples analogs and prototypes - estratsita obtained on the basis of natural hormones that causes hormonal activity of germanification. It is their property, especially sex hormones, is undesirable in clinical application. It is known that on the basis of natural steroids cannot sozdannomu (antiestrogens, anti-androgens) [Mashkovsky M. D. // Medicines. Moscow. Medicine. So 2. C. 549-552. Namer M. // J. Steroid Biochem. 1988. V. 31. R. 719-730], it can be expected that such compounds will have high antitumor activity in combination cytotoxic effect with antihormone.

To create antitumor steroids, neobladder hormonal activity, as well as showing antihormone action, offers 3-OR di(2-chloroethyl)amino compounds steroids of General formula I

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where R = COCH2C6H4N(CH2CH2Cl)2;

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R2= H(a) SON (b,g), COCH3(b).

The claimed compounds have antitumor activity. When the compound (I b) exhibit antiestrogenic effect and have the most pronounced antitumor effect. The compound (I a,g) hormone is not active. Table 1 provides data on the study of antitumor activity of compounds (I-g) three models of tumors in mice: mammary adenocarcinoma Ca-755, sarcoma C-37 and melanoma B-16.

As follows from table 1, the inventive compounds have a wide range and exhibit high antitumor activity on wseh) and 96-99% (Ca-755). Comparator drug "Antracit" proved ineffective, moreover its introduction stimulated the growth of tumors C-37 and Ca-755 (the + sign means the stimulation of tumor growth).

It is essential that the compound (I b) and (I) for adenocarcinoma of the cause the cure of experimental animals 28.5% and 12.5%, respectively.

Table 2 presents data antitumor activity of compounds (I b) in DMBA-induced mammary tumors in rats in comparison with known anticancer drug antiestrogenic actions "tamoxifen", which led to its use as a "reference product".

The compound (I) after 30 days of injection causes regression of tumors in 45% of cases, i.e. at the level of tamoxifen. However, unlike him, this substance has a strong diuretic effect. Therapeutic effect of 4 weeks (I) is superior to tamoxifen 3.75 times. The compound (I b) duration of action is also superior to tamoxifen.

Thus, from the comparison of the claimed substances with prototype - extraciton and analogs can be stated that for the first time implemented in the structure of the claimed substances Association di-chloroethylnitrosourea the military honors. The claimed substances meet the criteria of "novelty" as first synthesized.

The study of the toxicity of the inventive substances for the BDF mice showed a strong difference. The most active antitumor steroids (I b) do not exhibit toxic properties in total doses of 500 mg/kg and 125 mg/kg, respectively. The compound (I g) is also non-toxic at a dose of 125 mg/kg, while the compound (I) exhibits toxicity in a total dose of 75 mg/kg In terms of human daily dose of compound (I) is 88 mg, 2 times higher than therapeutic dose of tamoxifen.

The claimed compounds can be obtained from synthesized by a known method [Miasnikov Century. M // A. S. 1395639 (1988). Of the USSR. B. I. 1988. N. 18] 11-hydroxysteroid formula (II) and their respective 11-acyl derivatives (where R1and R2similar to the substituents for formula (I), by reaction with p-[di- (2-chloroethyl)]aminophenylarsonic acid (HAPC) in the presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMA).

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where

R2= H(a) SON (b,g), COCH3(b).

Examples of specific solutions

General method for the preparation of 3-p-[di-(2-chloroethyl)]aminophenylacetamido formula (I):

A mixture of 1.0 mmole St - 0 h (monitoring by TLC). The yellow solution after separation of dicyclohexylamine washed sequentially 4 N. HCl 1 N. NaHCO3, dried Na2SO4. The residue after removal of solvent chromatographic on SiO2by selecting the product with a mixture of benzene-ethyl acetate 10:1.

Example 1. 3-p-[di-(2-chloroethyl)] aminophenylacetate-11 - hydroxy-17-acetoxy-17-itinerante-1,3,5(10)-triene (Ia)

1.55 g of the Steroid (IIA) in 50 ml of CH2Cl2handle HAFC, DCC and DMA 6 h, as described above, and chromatographic on 15 g of SiO2. Obtain 1.22 g (45,5%) of compound (I) in the form of a colorless foam. []D-70o(from 0.92, CHCl3), UV spectrummaxnm (Ig E): 260,5 (4,47), 298 (3,42). IR spectrum, KBr. cm-1: 3450-3470 (HE); 3295 (CCH); 1740, 1230-1240 (OAc, OCyt); 1485, 1515, 1615 (ar. ). PMR-spectrum, CDCl3, M. D.: of 0.87 (s, 3H, 18-CH3); 2,04 (s, 3H, OAc); 2,63 (s, 1H, CCH); 4,2 (m, 1H, J = 10 and 5 Hz, 11-H); 3,66 and 3,72 (ush.s, 10H, N(C2H4Cl)2and COCH2Ph); 6,60 - of 8.06 (m, 7H, Har). Found, %: C 66,90; H 6,82; Cl 11,57. C34H39NO5Cl2. Calculated, %: C 66,65; H 6,41; Cl 11,59.

In reaction is also 23% of diapir I [R=R2=COCH2C6H4N(C2H4Cl)2].

Example 2. The acetate (I).

0.32 g of the Steroid (I) will acetimidoyl 2 ml of a mixture of acetic anhydride-feast through SiO2receive 0.27 g (79% I a; 36% II) acetate (I) in the form of colorless powder. An analytical sample: so pl. 148-150oC (ether). []D-80,1o(c 0,89, CHCl3). UV spectrum*: 261 (4,34). The IR spectrum of the*, CCl4cm-1: 3320 (CCH); 1740-1750, 1235-1240; 1495, 1520, 1618. PMR spectrum: 0,935 (s, 3H); 2,04 (s, 3H); of 2.08 (s, 3H, 11-SLA); 2,66 (s, 1H); 3,67 and 3.75 (ush.S., 10H); of 5.40(m, 1H, J = 10 and 5 Hz, 11-H); 6,67-7,26 (m, 7H). Found, %: C 65,84; H 6,20; Cl 10,63. C36H41NO6Cl2. Calculated, %: C 66,04; H 6,30; Cl 10,84.

Example 3. Formate (I b).

0,38 g Formate (II) in 25 ml of CH2Cl2handle HAFC, DCC and DMA, as described above, 6 h and obtain 0.35 g (55,5%) of colorless crystals of the compound (I b). An analytical sample: so pl. 130-131,5oC (ether). []D-88,1o; (0,70, CHCl3). UV spectrum*: 260,5 (to 4.38); 297 (bend) (3,39). The IR spectrum of the*: 3285; 1730-1750, 1240; 1496, 1525, 1620. PMR-spectrum+: to 0.94 (s, 3H); 2,04 (s, 3H); to 2.65 (s, 1H); 3,67 and to 3.73 (ush.s, 10H), and 5.5 (m, 1H, J = 10 and 5 Hz); 6,66 - 7,25 (m, 7H); to 8.14 (s, 1H, OCOH). Found, %: C 65,58; H To 6.43; Cl Of 11.15. C35H39NO6Cl2. Calculated, %: C 65,62; H 6,13; N 11,08.

Example 4. 3-[di-(2-chloroethyl)]aminophenylacetate-11 formyloxy-17-propionyloxy-1,3,5(10)-triene (I d).

0,37 g Formate (II g) in 20 ml of CH2Cl2handle HAFC, DCC and DMA 24 h and gender,55). The IR spectrum of the*: 1720-1740, 1240, 1185, 1497, 1525, 1620. PMR-spectrum*: 0,84 (s, 3H); of 1.13 (t, 3H, J = 7,7 Hz, OCOCH2CH3); 3,66 and 3,72 (ush.S., 10H); was 4.76 (m, 7H, J = 8.0 Hz, 17-H); 5,54 (m, 7H, J = 10 and 5 Hz, 11-H); 6,60-7,35 (m, 7H); of 8.09 (s, 1H). Found, %: C 64,91; H 7,05; Cl 11,35. C34H41NO6Cl2. Calculated, %: C 64,75; H 6,55; Cl Of 11.26.

3-OR di(2-Chloroethyl)amino compounds 11-acyl(HYDR)oxosteroid General formula I

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where R = COCH2C6H4N(CH2CH2Cl)2;

< / BR>
R2= H, OCOH, COCH3,

with antitumor activity.

 

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