RU2043360C1 - Anthracycline glycosides or their pharmaceutically acceptable salts showing antitumor properties, and a method of their synthesis - Google Patents

Abstract

FIELD: chemistry of glycosides. SUBSTANCE: product: anthracycline glycoside of the formula (I) where Z hydrogen or hydroxyl; R₁ hydrogen, hydroxyl or amino-group; R₂ and R₃ are both hydrogen or one of them hydrogen or amino-group and other hydroxyl, and one of R₄ and R₅ hydrogen and other hydroxy-group, or their pharmaceutically acceptable salts. Condition: if R₂ and R₃ are both hydroxyl then R₁ fluorine or amino-group. Reagent 1: corresponding 3'-aminoanthracycline glycoside of the formula (I) or its salt. Reagent 2: bis-(2-iodoethyl)-ester. Reaction conditions: interaction of indicated reagents followed by extraction of the end product with methylene chloride, chromatography purification and if necessary conversion to the required salt. EFFECT: improved method of synthesis. 3 cl

Description

 The invention relates to anthracycline glycosides, to methods for their preparation.

где Z водород, Х водород или гидрокси, R₁ водород, фтор, гидрокси или амино; R₂ и R₃ оба гидрокси или один из R₂ и R₃ водород или амино, а другой гидрокси при условии, что, когда R₂ и R₃ оба представляют собой гидрокси, R₁ представляет собой фтор или амино, и R₄ и R₅ оба представляют собой водород или один из R₄ и R₅ водород, а другой гидрокси и их фармацевтически приемлемые соли.The invention provides anthracycline glycosides having the general formula I

where Z is hydrogen, X is hydrogen or hydroxy, R _{1 is} hydrogen, fluoro, hydroxy or amino; R ₂ and R _{3 are} both hydroxy or one of R ₂ and R _{3 is} hydrogen or amino, and the other is hydroxy, provided that when R ₂ and R _{3 are} both hydroxy, R ₁ is fluoro or amino, and R ₄ and R ₅ both represent hydrogen or one of R ₄ and R ₅ hydrogen, and the other hydroxy and their pharmaceutically acceptable salts.

Preferred pharmaceutically acceptable acid addition salts are hydrochloride salts. Preferred anthracycline glycosides of general formula I include:
a) 4-methyl-6-deoxy-3'-deamino-3 '- (4-morpholinin) daunorubicin
(X = OH, R ₁ = R ₂ = R ₃ = OH, R ₃ = R ₅ = H, Z = H).

где R₁, R₂, R₃, R₄, R₅ и Х имеют приведенные значения, или из солей, например, фармацевтически приемлемой кислой аддитивной соли, такой, как хлористоводородная соль. Антрациклин-гликозиды формулы I, или фармацевтически приемлемую соль, получают путем взаимодействия антрациклин-гликозида формулы II или его соли, например, фармацевтически приемлемой кислой аддитивной соли такой, как хлористоводородная соль, pаствоpенной в безводном полярном растворителе, с бис(2-иодоэтил)эфиром, экстракцией продукта формулы I метиленхлоридом, очисткой хроматографическим методом и, при желании, превращением антрациклин-гликозида формулы I в его фармацевтически приемлемую соль.b) 4-demethoxy-4-amino-3'-deamino-3 '- (4-morpholinin) daunorubicin
(X = H, R ₁ = NH ₂ , R ₂ = R ₃ = R ₄ = OH, R ₅ = H, Z = H)
c) 4-demethoxy-4-amino-3'-deamino-3 '- (4-morpholinyl) -4'-epidaunorubicin (X = H, R ₁ = NH ₂ , R ₂ = R ₃ = R ₅ = OH, R ₄ = H, Z = H)
d) 4-demethoxy-4-fluoro-3'-diamino-3 '- (4-morpholinyl) daunorubicin (X = H, R ₁ = F, R ₂ = R ₃ = R ₄ = OH, R ₅ = H, Z = H)
e) 4-demethoxy-4-fluoro-3'-deamino-3 '- (4-morpholinyl) -4'-epidaunorubicin (X = H, R ₁ = F, R ₂ = R ₃ = R ₅ = OH, R ₄ = H, Z = H)
f) 4-demethoxy-11-deoxy-11-amino-3'-deamino-3 '' - (4-morpholinyl) daunorubicin (X = H, R ₁ = R ₅ = H, R ₂ = NH ₂ , R ₃ = R ₄ = OH, Z = H)
q) 4-demethoxy-6-deoxy-6-amino-3'-deamino-3 '- (4-morpholinyl) daunorubicin (X = H, R ₁ = R ₅ = H, R ₃ = NH ₂ , R ₂ = R ₄ = OH, Z = H)
h) 4-demethoxy-6-deoxy-6-amino-3'-deamino-3 '- (4-morpholinyl) -doxorubicin (X = OH, R ₁ = R ₅ = H, R ₃ = NH ₂ , R ₂ = R ₄ = OH, Z = H)
New antibiotics based on the anthracycline glycoside in accordance with the invention are obtained by forming a morpholinyl or methoxy substituted morpholinyl ring at position C-3 'on the sugar component of the antitumor anthracycline glycosides of the general formula II

where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and X are as indicated, or from salts, for example, a pharmaceutically acceptable acid addition salt, such as a hydrochloride salt. An anthracycline glycoside of formula I, or a pharmaceutically acceptable salt, is prepared by reacting an anthracycline glycoside of formula II or a salt thereof, for example, a pharmaceutically acceptable acid addition salt such as a hydrochloride salt dissolved in an anhydrous polar solvent, with bis (2-iodoethyl) ether extraction of the product of formula I with methylene chloride, purification by chromatographic method and, if desired, conversion of the anthracycline glycoside of formula I to its pharmaceutically acceptable salt.

 More specifically, the reaction for preparing 3 ′ - (4-morpholino) anthracycline derivatives of formula I is usually carried out using an excess of bis (2-iodoethyl) ether in an anhydrous polar organic solvent such as dimethylformamide. The reaction is usually carried out at room temperature. It can be completed in one day. The desired product is isolated from the reaction mixture, for example, by extraction with methylene chloride and purified by chromatography, for example, column. It can be transformed into a hydrochloride salt, for example, by treatment with a methanolic solution of hydrogen chloride.

 In one embodiment of the invention, the anthracycline glycoside of formula II or a salt thereof is dissolved in an anhydrous polar solvent and reacted at room temperature and for 24 hours with an excess of bis (2-iodoethyl) ether in the presence of triethylamine, the pH of the reaction mixture previously diluted with water, adjusted to 7.5 using an aqueous solution of sodium hydrogencarbonate, the reaction mixture was extracted with methylene chloride, the organic solvent was removed under reduced pressure and, after purification of the crude product on a si column using a mixture of methylene chloride and methanol (98: 2 vol.) as an eluting agent, the product is isolated in the form of a hydrochloride salt by adding a methanol solution of anhydrous hydrogen chloride.

The starting materials for the preparation of the new 3 '- (4-morpholino) - or 3' - (2-methoxy-4-morpholino) glycosides of the present invention are:
1) 4-dimethyl-6-deoxy-doxorubicin (C1: X = OH, R ₁ = R ₂ = R ₄ = OH, R ₃ = R ₅ = H) (US Patent Application 4,600,537)
2) 4-dimethoxy-4-amino-daunorubicin (C2: X = H, R ₁ = NH ₂ , R ₅ = H, R ₂ = R ₃ = R ₅ = OH) and 4-demethoxy-4-amino-4 '-epi-daunorubicin (C7: X = H, R ₁ = NH ₂ R ₄ = H, R ₂ = R ₃ = R ₅ = OH) (European Patent Application No. 0288268)
3) 4-demethoxy-4-fluoro-daunorubicin (C4: X = H, R ₁ = F, R ₄ = H, R ₂ = R ₃ = R ₅ = OH) and 4-demethoxy-4-fluoro-4 ' -epi-daunorubicin (C5: X = H, R ₁ = F, R ₄ = H, R ₂ = R ₃ = R ₅ = OH) (U.S. Patent Application No. 4,697,005).

4) 4-demethoxy-11-deoxy-11-amino-daunorubicin (C6: X = H, R ₁ = R ₅ = H, R ₂ = NH ₂ , R ₃ = R ₄ = OH) and 4-demethoxy-11 -deoxy-11-amino-doxorubicin (C13: X = OH, R ₁ = R ₅ = H, R ₂ = NH ₂ , R ₃ = R ₄ = OH) (US patent application N 4348388), and
5) 4-demethoxy-6-deoxy-6-amino-daunorubicin (C8: X = H, R ₁ = R ₅ = H, R = NH-R ₂ = R ₄ = OH) and 4-demethoxy-6-deoxy -6-amino-doxorubicin (C9: X = OH, R ₁ = R ₅ = H, R ₃ = NH ₂ , R ₂ = R ₄ = OH) (Europatent application N 0254484) and their salts, in particular hydrochloric .

 The invention provides pharmaceutical compositions comprising an anthracycline glycoside of formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier. Conventional carriers and diluents may be used. Methods of preparation and administration of the composition are conventional.

 The compounds of the invention are used in the treatment of a human or animal. They are also suitable as antitumor agents. A therapeutically effective amount of a compound is administered to the patient. An amount sufficient to inhibit tumor growth can be administered. The tumor may be Colon adenocarcinoma or Gross leukemia.

 The biological activity of the compounds of the present invention was tested in vitro against Lovo cells (human colon adenocarcinomas) and Lovo / DX compared to doxorubicin. The results are shown in table. 1 (in vitro activity). The compounds of the present invention were also tested in vitro against leukemia of P388 and P388 / DX mice in comparison with doxorubicin. The results are shown in table.2. All compounds were tested in the form of their hydrochlorides.

The following examples illustrate the invention. Measurements using thin layer chromatography (TLC) were performed on Kieselgel plates (Merck F ₂₅₄ ) using methylene chloride / ethanol (95/5 by volume) as eluent. "Merck" is a trademark.

 PRI me R 1. 4-Dimethyl-5-deoxy-3'-deamino-3 '- (4-morpholinyl) doxorubicin (a).

To a solution of 0.15 g (0.27 mmol) of 4-dimethyl-6-deoxydoxorubicin hydrochloride (C1) in 5 ml of anhydrous dimethylformamide, 1 g (3.07 mmol) of bis (2-iodoethyl) ether and 0.075 ml (0.535 mmol) are added. ) triethylamine. The reaction mixture was stirred at room temperature for one day, then the mixture was diluted with 100 ml of water and the pH was adjusted to 7.5 with an aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with methylene chloride three times. The organic phase was dried in the presence of anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column using methylene chloride / methanol (98: 2 by volume) as the eluent system to obtain 70 mg (42% yield) of the compound (a) indicated in the preform, which was isolated as the hydrochloride salt after adding the methanol solution of anhydrous hydrogen chloride . Melting point 161-162 ^{° C} (dec): R _f: 0,19; PD-MS: m / z 583 (M ₊ .);
¹ H-NMR (200 MHz, DMSO) inter alia δ: 12.94 (s, 1H, 11-OH), 12.53 (s, 1H, 4-OH), 7.9-7.7 (m, 3H, 6-H, 1-H, 2-H), 5.77 (d, J = 5.7 Hz, 1H, 4'-OH), 5.42 (d, J = 5.9, 7, 4 Hz, 1H, f = H), 4,54 (s, 2H, CH ₂ OH), 4,0-2,7 (m, 13H, 5 ^of -H, 4'-H, 10-CH _2, CH ₂ OCH ₂ , CH ₂ NCH ₂ ), 1.19 (d, J = 6.4 Hz, 3H, 5'-CH ₃ ).

 PRI me R 2. 4-Dimethoxy-4-amino-3'-deamino-3 '' - (4-morpholinyl) daunorubicin (b).

According to the procedure described in Example 1, the title compound (b) was prepared starting from 4-demethoxy-4-amino-daunorubicin (C2). Yield: 80% Melting point 167-168 ^{° C} (dec); R _f : 0.33; PD-MS: m / Z = 582 (M ₊ ).

¹ H-NMR (200 MHz, CDCl ₃ ) inter alia δ 13.73 (s, 1H, 6-OH), 13.40 (s, 1H, 11-OH), 7.67 (d, J = 6, 4 Hz, 1H, 1-H), 7.49 (dd, J = 6.4, 8.3 Hz, 1H, 2-H), 6.97 (d, J = 8.3 Hz, 3-H ), 6.81 (broad, 2H, NH ₂ ), 5.56 (d, J = 3.2 Hz, 1H, 1'-H), 5.26 (dd, J = 2.2, 3.8 Hz, 1H, 7-H), 3.68 (m, 4H, CH ₂ OCH ₂ ), 2.6-2.3 (m, 6H, CH ₂ NCH ₂ ) 2.42 (s, 3H, OCH ₃ ), 1.38 (d, J = 6.6 Hz, 3H, 5'-CH ₃ ).

 PRI me R 3. 4-Demethoxy-fluoro-3'-deamino-3 '- (4-morpholinyl) -4'-epidaunorubicin (e).

According to the procedure described in Example 1, the title compound (e) was prepared starting from 4-demethoxy-4-fluoro-4'-epa-daunorubicin (C5). Yield 62.5% Melting point 161-162 ^{° C} (dec); R _f : 0.3; PD-MS m / z 586 (MH ₊ ), 585 (M +.); ¹ H-NMR (200 MHz. DMSO) inter alia δ: 13.61 (s, 1H, 6-OH), 13.19 (s, 1H, 11-OH), 8.17 (dd, J = 1, 2, 7.8 Hz, 1H-1-H), 7.99 (dd, J = 4.6, 7.8, 8.2 Hz, 1H, 2-H), 7.77 (ddd, 1, 2 8.2, 11.7 Hz, 1H, 3-H), 5.37 (d, J = 3.2 Hz, 1H, 1 '= H), 5.02 (m, 1H, 7-H) 3.88 (m, 4H, CH ₂ OCH ₂ ), 3.8-3.2 (m, 6H, 4'-H, 3'-H, CH ₂ NCH ₂ ) 2.26 (s, 3H, COSH ₃ ), 1.25 (d, J = 6.3 Hz, 5'-CH ₃ ).

 PRI me R 4. 4-Demethoxy-6-deoxy-6-amino-3'-deamino-3 '- (4-morpholino) -doxorubicin (r).

According to the procedure described in Example 1, the title compound (r) was prepared starting from 4-demethoxy-6-deoxy-6-amino-doxorubicin (C9). Yield: 45% Melting point 156-158 ^{° C} (decomposition). PD-MS: m / z 584 (M ₊ .). ¹ H-NMR (200 MHz, CDCl ₃ ) inter alia δ: 1.11 (d, J = 6.6 Hz, 3H, 5'-CH ₃ ), 2.3-2.6 (m, 8H, CH ₂ NCH ₂ ), 5.02 (dd, J = 3.9, 5.3 Hz, 1H, 7-H), 5.4 (d, J = 2.9 Hz, 1H, 1'-H), 7.7-8.0 (m, 2H, 2-H), 8.06 (wide, 2H, NH ₂ ), 8.2-8.3 (m, 2H, 1-H, 4-H), 14.2 (1H, 11-OH).

Claims (2)

1. Anthracycline glycosides of the general formula

where Z is hydrogen;
X is hydrogen or hydroxy;
R _{1 is} hydrogen, fluoro, hydroxy or amino;
R ₂ and R _{3 are} both hydroxy or one of them is hydrogen or an amino and the other is hydroxy
R ₄ and R _{5 are} one hydrogen and the other is hydroxy
or their pharmaceutically acceptable salts, provided that when R ₂ and R _{3 are} both hydroxy groups, then R _{1 is} fluoro or an amino group having antitumor properties. 2. A method of producing anthracycline glycosides of the general formula I

where Z is hydrogen;
X is hydrogen or hydroxy;
R _{1 is} hydrogen, fluoro, hydroxy or amino;
R ₂ and R _{3 are} both hydroxy or one of them is hydrogen or an amino and the other is hydroxy
R ₄ and R _{5 are} one hydrogen and the other is a hydroxy group,
or their pharmaceutically acceptable salts, provided that when R ₂ and R _{3 are} both hydroxy, then R _{1 is} fluoro or an amino group, wherein the anthracycline glycoside of general formula II

where R ₁ R ₅ and X have the indicated meanings,
or a salt thereof, dissolved in an anhydrous polar solvent, is reacted with bis (2-iodoethyl) ether, then the product of formula I is extracted with methylene chloride, purified by chromatography and, if necessary, followed by translation of the target product into its pharmaceutically acceptable salt.

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