RU2081878C1 - Anthracycline glycoside and method of its synthesis - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: anthracycline glycoside of the general formula (I)

where: Z - methoxy; X - hydrogen or hydroxy; R₁- hydrogen or R₂ and R₃ are both hydroxy or one of R₂ and $$4 is hydrogen and other - hydroxy; or one of R₃ and R₄ is hydrogen and other - hydroxy; or their pharmaceutically acceptable salts at condition that: when Z and R₅ are both methoxy and R₁ and R₂ are both hydroxy then R₃ - hydroxy or R₅ and R₄ - hydrogen. Compound is synthesized by reductive alkylation of anthracycline glycoside of the formula (II) R₅ in polar organic solvent in the presence of reducing agent: 1-methoxy-2,2-hydroxyacetaldehyde of the formula (III)

Description

 The invention relates to anthracycline glycosides, to methods for their preparation and to pharmaceutical compositions containing them.

(I),
где Z обозначает водород или метокси, X обозначает водород или гидрокси, R₁ обозначает водород, фтор, гидрокси, метокси, амино, R₂ и R₃ обозначают гидрокси или один из R₂ и R₃ обозначает водород, нитро или амино, а другой обозначает водород, и R₄ и R₅ оба обозначают водород или один из R₄ и R₅ обозначает водород, а другой обозначает гидрокси, и их фармацевтически приемлемые соли, при условии, что: 1) когда R₂ и R₃ оба обозначают водород и Z обозначает водород, тогда R₁ обозначает гидрокси, фтор или амино; и 2) когда Z и R₁ обозначают метокси и R₂ и R₃ обозначают водород, тогда R₅ обозначает гидрокси или оба R₄ и R₅ обозначают водород.The invention provides anthracycline glycosides having the general formula I:

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

 Preferred pharmaceutically acceptable acid addition salts are hydrochloride salts.

(II),
где R₁, R₂, R₃, R₄, R₅ и x имеют вышеприведенные значения,
или их солей, например фармацевтически приемлемой кислой аддитивной соли, такой как хлористоводородная соль. Антрациклин-гликозиды формулы I, гдe Z= H, или фармацевтически приемлемую соль, полученную путем взаимодействия антрациклин-гликозида формулы II или его соли, например фармацевтически приемлемой кислой аддитивной соли, такой как хлористоводородная соль, с бис-(2-йодоэтил)эфиром и, если желательно, превращением антрациклин-гликозида формулы I, где Z обозначает H, в его фармацевтически приемлемую соль. Антрациклин-гликозид формулы I, гдe Z обозначает OCH₃ или его фармацевтически приемлемую соль, получают гидроалкилированием антрациклин-гликозида формулы I или его соли, например фармацевтически приемлемой кислой аддитивной соли, такой как хлористоводородная соль, с использованием хирального диальдегид 1-метокси-2,2'-оксидиацетальдегида формулы III:

(III),
например, при условиях, изложенных в заявке на патент США N 4672057, и, если желательно, превращением полученного антрациклин-гликозида формулы I, где Z обозначает OCH₃, в его фармацевтически приемлемую соль.Preferred entracycline glycoses of the general formula I include:
a) 4-demethyl-6-deoxy-3'-deamino-3 '- (4-morpholinyl) daunorubicin
(X = OH, R ₁ = R ₂ = R ₄ = OH, R ₃ = R ₅ = H, Z = H)
b) 4-demethoxy-4-amino-3'-deamino-3 '- (4 morpholinyl) 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'-deamino-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-N-deoxy-N-nitro-3'-deamino-3 '- (4-formolinyl) daunorubicin
(X = H, R ₁ = R ₅ = H, R ₂ = NO ₂ , R ₃ = R ₄ = OH, Z = H)
g) 4-demethoxy-6-deoxy-6-nitro-3'-deamino-3 '- (4-morpholinyl) daunorubicin
(X = H), R ₁ = R ₅ = H, R ₃ = NO ₂ , R ₃ = R ₄ = OH, Z = H)
h) 4-demethoxy-N-deoxy-N-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)
i) 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 = 0H, Z = H)
j) 3 - (- deamino-3 '- (2-methoxy-4-morpholinyl) -4'-epidoxorubicin
(X = OH, R ₁ = OCH ₃ , R ₂ = R ₃ = OH, R ₄ = H, R ₅ = OH, Z = OCH ₃ )
k) 3'-deamino-3 '- (2-methoxy-4-morpholinyl) -4'-deoxydoxorubicin
(X = OH, R ₁ = OCH ₃ , R ₂ = R ₃ = OH, R ₄ = R ₅ = H, Z = OCH ₃ )
l) 4-demethoxy-3'-deamino-3 '- (2-methoxy-4-morpholinyl) daunorubicin
(X = H, R ₁ = R ₅ = H, R ₂ = R ₃ = R ₄ = OH, Z = OCH ₃ )
m) 4-demethyl-3'-deamino-3 '- (2-methoxy-4-morpholinyl) daunorubicin
(X = H, R ₁ = R ₂ = R ₃ = R ₄ = OH, R ₅ = H, Z = OCH ₃ )
n) 4-demethyl-6-deoxy-3'-deamino-3 '- (2-methoxy-4-morpholinyl) doxorubicin
(X = OH, R ₁ = R ₂ = R ₄ = OH, R ₃ R ₅ = H, Z = OCH ₃ )
o) 4-demethoxy-4-amino-3'-deamino-3 '- (2-methoxy-4-morpholinyl) daunorubicin
(X = H, R ₁ = NH ₂ , R ₂ = R ₃ = R ₄ = OH, R ₅ = H, Z = OCH ₃ )
p) 4-demethoxy-N-deoxy-N-amino-3'diamino-3 '- (2-methoxy-4-morpholinyl) daunorubicin
(X = H, R ₁ = R ₅ H, R ₂ = NH ₂ , R ₃ = R ₄ = OH, Z = OCH ₃ )
q) 4-demethoxy-6-deoxy -6-amino-3'-deamino-3 '- (2-methoxy-4-morpholinyl) daunorubicin
(X = H, R ₁ = R ₅ = H ₅ , R ₃ = NH ₂ , R ₂ = R ₄ = OH, Z = OCH ₃ )
r) 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 anthracycline glycoside in accordance with the present invention are obtained by the formation of a morpholinyl or methoxy substituted morpholinyl ring in position C-3 'on the sugar component of the antitumor anthracycline glycosides of the general formula II:

(Ii)
where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and x have the above meanings,
or salts thereof, for example a pharmaceutically acceptable acid addition salt, such as a hydrochloride salt. An anthracycline glycoside of formula I, where Z = H, or a pharmaceutically acceptable salt obtained 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, with bis (2-iodoethyl) ether and if desired, by converting an anthracycline glycoside of formula I, where Z is H, to a pharmaceutically acceptable salt thereof. An anthracycline glycoside of formula I, where Z is OCH ₃ or a pharmaceutically acceptable salt thereof, is prepared by hydroalkylation of an anthracycline glycoside of formula I or a salt thereof, for example a pharmaceutically acceptable acid addition salt such as a hydrochloride salt, using chiral dialdehyde 1-methoxy-2, 2'-oxydiacetaldehyde of the formula III:

(III)
for example, under the conditions set forth in US Patent Application No. 4,672,057, and, if desired, converting the obtained anthracycline glycoside of formula I, where Z is OCH ₃ , into a pharmaceutically acceptable salt thereof.

 More specifically, the reaction for the preparation of 3 '- (4-morpholino) anthracycline derivatives of formula I is usually carried out using an excess of bis (2-iodo-ethyl) 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 solvent extraction. It can be purified by chromatography, for example column chromatography. It can be transformed into a hydrochloride salt, for example, by treatment with methanol hydrochloride.

 In one embodiment of the present invention, an anthracycline glycoside of formula II or a salt thereof is dissolved in an anhydrous polar solvent, 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 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 silica gel column using a mixture of methylene chloride and methanol (98: 2 volume) as an eluting agent, the product is isolated in the form of a hydrochloride salt by adding a methanol solution of aqueous hydrogen chloride. Hydroalkylation to obtain derivatives of 3 '- (2-methoxy-4-morpholino) anthracycline of formula I is usually carried out using an excess of dialdehyde III. This dialdehyde can be prepared as described in US Patent Application No. 4,672,057. The reaction is usually carried out in a mixed aqueous polar organic medium, such as water-acetonitrile, typically at a pH of about 7. The reducing agent is usually an alkali metal cyanoborohydride, i.e. . sodium or potassium cyanoborohydride.

 The reaction can usually be completed in two hours at room temperature. The desired product is isolated from the reaction mixture, for example, by solvent extraction. It can be purified by column chromatography. The product can be transformed into a hydrochloride salt, for example, by treatment with methanol hydrochloride.

 In a second embodiment of the present invention, an anthracycline glycoside of formula II or a salt thereof is dissolved in a mixture of acetonitrile and water (1: 1 by volume) and reacted with an excess of aldehyde of formula III, added to the reaction mixture after 30 minutes, adjusted to pH 7, 4 in an aqueous solution of sodium cyanoborohydride, the mixture is extracted with n-butanol, the organic solvent is removed under reduced pressure, and after purification of the crude product on a silica gel column using a methylene chloride-methanol mixture (97: 3 by volume) as With the eluting agent, the desired product is isolated as the hydrochloride salt by the addition of a methanol solution of anhydrous hydrogen chloride.

The starting materials for preparing the new 3 '- (4-morpholino) - or 3' - (2-methoxy-4-morpholino) glycosides of the present invention are well known:
4'-epidoxorubicin (C1: X = OH, R ₁ = OCH ₃ , R ₂ = R ₃ = R ₅ OH, R ₄ H)
4'-deoxidoxorubicin (C2: X = OH, R ₁ = OCH ₃ , R ₂ = R ₃ = OH, R ₄ = R ₅ = H),
4-demethoxidaunorubicin (C3: X = H, R ₁ = R ₅ = H, R ₂ = R ₃ = R ₄ = OH) and
4-demethyldaunorubicin (C4: X = H, R ₁ = R ₂ = R ₃ = R ₄ = OH, R ₅ = H);
4-demethyl-6-deoxydoxorubicin (C5: X = H, R ₁ = R ₂ = R ₄ = OH, R ₃ = R ₅ = H / U.S. Patent Application 4,600,537);
4-demethoxy-4-aminodaunorubicin (C6: X = H, R ₁ = NH ₂ , R ₅ = H, R ₂ = R ₃ = R ₄ = OH) and
4-demethoxy-4-amino-4'-epidaunorubicin (C7: X = H, R ₁ = NH ₂ , R ₄ = H, R ₂ = R ₃ = R ₅ = OH) / Euro Patent Application No. 0288268);
4-demethoxy-4-fluorodaunorubicin (C8: X = H, R ₁ = F, R ₄ = H, R ₂ = R ₃ = R ₅ = OH) and
4-demethoxy-4-toro-4'-epidaunorubicin (C9: X = H, R ₁ = F, R ₄ = H, R ₂ = R ₃ = R ₅ = OH) / US patent application N 4697005 /;
4-demethoxy-N-deoxy-N-nitrodaunorubicin (C10: X = H, R ₁ = R ₅ = H, R ₂ = NO ₂ , R ₃ = R ₄ = OH) and
4-demethoxy-6-deoxy-6-nitrodaunorubicin (C11: X = H, R ₁ = R ₅ = H, R ₃ = NO ₂ , R ₂ = R ₄ = OH) / US patent application N 4684639 /;
4-demethoxy-N-deoxy-N-aminodaunorubicin (C12: X = H, R ₁ = R ₅ = H, R ₂ = NH ₂ , R ₃ = R ₄ = OH) and
4-demethoxy-N-deoxy-N-aminodoxorubicin (C13: X = OH, R ₁ = R ₅ = H, R ₂ = NH ₂ , R ₃ = R ₄ = OH) / US patent application N 4348388 /; as well as
4-demethoxy-6-deoxy-6-aminodaunorubicin (C14: X = H, R ₁ = R ₅ = H, R ₃ = NH ₂ , R ₂ = R ₄ = OH) and
4-demethoxy-6-deoxy-6-aminodoxorubicin (C15: X = OH, R ₁ = R ₅ = H, R ₃ = NH ₂ , R ₂ = R ₄ = OH) / European patent application N 0254484);
and salts thereof, such as hydrochloride salts.

 The present 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. The composition can be formulated and administered in a conventional manner.

 The compounds of the present invention are useful in methods of treating a human or animal therapy. 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 Colou adenocarcinoma or Gross leukemia.

 The biological activity of the compounds of the present invention was tested in vitro against Lovo (human colon adenocarcinoma) and Lovo / Dx cells compared to doxorubicin. The results are shown in table. 1. The compounds of the present invention were also tested in vivo 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.

 In table 2, "bb" means that the tumor was implanted intravenously; "bb + 1" that intravenous treatment was started 1 day after tumor implantation. For the compound, the first three of ten mice used were considered to have survived long-term by the end of the experiment (90 days); * optimal dose: maximum permissible dose (LD10); ** -the average survival time of the treated mouse / average survival time of the control mouse x 100 /.

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

), 13,11 (c, IH,II-

, 5,53 (дд, J=3,5,1 Гц, IH, I'-

, 5,23 (дд, J=2,0,3,9 Гц, IH, 7-

), 4,74 (c, IH, 14-

), 4,40 (дд, J=2,5,4,8 Гц, IH,

4,06 (c, 3H, 4-

), 3,5-3,9 (м, 2Н,

), 3,38 (c, 3H,

), 3,17 (дд, J= 8,7, 8,7 Гц, IH, 4'-

), 2,72 (дд, J=2,5, 11,2 Гц, IH,

), 2,5-2,6 (м, IH, 3'-H), 2,3-2,6 (м, 2H,

), 2,23 (дд, J=4,8, 11,2 Гц, IH,

), 1,33 (д, J=6,0 Гц, 3H, 5'-

).Example 1. 3'-Deamino-3 '- (2-methoxy-4-morpholinyl) -4'-epidoxorubicin (j)
To a solution of 0.29 (0.5 mmol) of 4'-epidoxorubicin (C1) in 30 ml of a mixture of acetonitrile-water (1: 1) was added 0.65 g (5 mmol) of 1-methoxy-2,2-oxydiacetaldehyde (D ) dissolved in 10 ml of acetonitrile; The pH was adjusted to 7.4 with a solution of sodium hydrogencarbonate. After 30 minutes, the mixture is treated with a solution of 0.032 g (0.5 mmol) of sodium cyanoborohydride dissolved in 3 ml of water. After 15 minutes, the mixture was treated with water (50 ml) and extracted with n-butanol. The organic phase was evaporated under reduced pressure, and the residue was purified by flash chromatography on a silica gel column using a methylene chloride / methanol mixture (97: 3 by volume) as an eluting system to obtain 0.145 g (42% yield) of the title compound (j) , which is isolated in the form of a hydrochloride salt after treatment with an anhydrous methanol solution of hydrogen chloride, melting point 153-154 ^o C (decomposition): R _f : 0.17; PD-MS: m / z 644 (MH ⁺ ), 643 (M ^+. ); ¹ H-NMR (200 MHz, CDCl ₃ ) interalia δ: 13.91 (s, IH, 6-

), 13.11 (s, IH, II-

5.53 (dd, J = 3.5.1 Hz, IH, I'-

5.23 (dd, J = 2.0.3.9 Hz, IH, 7-

), 4.74 (s, IH, 14-

), 4.40 (dd, J = 2.5.4.8 Hz, IH,

4.06 (s, 3H, 4-

), 3.5-3.9 (m, 2H,

), 3.38 (s, 3H,

), 3.17 (dd, J = 8.7, 8.7 Hz, IH, 4'-

), 2.72 (dd, J = 2.5, 11.2 Hz, IH,

), 2.5-2.6 (m, IH, 3'-H), 2.3-2.6 (m, 2H,

), 2.23 (dd, J = 4.8, 11.2 Hz, IH,

), 1.33 (d, J = 6.0 Hz, 3H, 5'-

)

Example 2. 4-Demethoxy-3'-deamino-3'-2-methoxy-4-morpholinyl) daunorubicin (I)
The synthesis of the title compound (I) was carried out in accordance with the procedure described in example I, starting with 4-demethoxide oxidoblastamine (C3). Yield 40%, melting point 150-151 ^o C (decomposition); R _f : 0.25; PD-MS m / z 627 (M ₊ .).

Additional examples
Example 3. 3'-Deamino-3 '- (2-methoxy-4-morpholinin) -4'deoxydoxorubicin (k)
The compound (k) indicated in the title of the example was prepared according to the procedure of Example 1 and using 4'-deoxydoxorubicin (C2) as the starting material. Yield 45% mp. 145-150 ^o (decomp.)
TLC on Kieselgel plates (Merk F ₂₅₄ ) using a methylene chloride / ethanol mixture (95: 5 by volume) as eluent:
R _f = 0.2; FD-MS; m / z 628 (MH ⁺ , 627 (M ^{+ '} ).

Example 4. 4-demethyl-6-deoxy-3'-deamino-3 '- (2-methoxy-4-morpholinin) doxorubicin (n)
The synthesis of compound (n) indicated in the title of the example was carried out according to the procedure of example 1 using n-demethyldoxorubicin (C5) as the starting material.

, 12,53 (c, IH, 4-

7,9-7,7 (м, 3H, 6-

, 2-H), 5,77 (g,J=5,7 Гц, IH, 4'-

), 5,42 ( gJ=5,9, 7,4 Гц, IH, 7-

), 4,54 (c, 2H,

OH), 4,0-2,7 (м, 15H, 5'-

, 4'-

, 3'-

, 10-

, (CH₃O)

eq-CH₂,

-CH₂N, O-CH-(OCH₃), N-

eq-CH(OCH₃),

, N-CHax-OH(

), 1,19 (g,J=6 Гц, 3H, 5'-

).Yield 38% mp 155-158 ^o C (decomp.)
TLC (Kieselgel plates, Merk F ₂₅₄ , eluent methylene chloride / ethanol 95: 5 by volume); R _f = 0.20; FD-MS; m / z 613 (M ⁺ ');
¹ H NMR (200 MHz DMSO) δ: 12.94 (s, IH, II-

12.53 (s, IH, 4-

7.9-7.7 (m, 3H, 6-

, 2-H), 5.77 (g, J = 5.7 Hz, IH, 4'-

), 5.42 (gJ = 5.9, 7.4 Hz, IH, 7-

), 4.54 (s, 2H,

OH), 4.0-2.7 (m, 15H, 5'-

, 4'-

, 3'-

, 10-

, (CH ₃ O)

eq-CH ₂ ,

-CH ₂ N, O-CH- (OCH ₃ ), N-

eq-CH (OCH ₃ ),

, N-CHax-OH (

), 1.19 (g, J = 6 Hz, 3H, 5'-

)

Example 5. 4-demethoxy-4-amino-3'-deamino-3'-deamino-3 '- (2-methoxy-4-morpholinyl) daunorubicin (0)
The synthesis of compound (O) indicated in the title of the example was carried out according to the procedure for example 1, using 4-demethoxy-4-aminodaunorubicin (C6) as the starting material.

), 13,38 (c, IH, II-

), 7,68 (g,J=6,4 Гц, IH, I-

), 7,49 (gg, J=8.3 Гц, IH, 2-

, 6,95 (g,J=8,3 Гц, 3-

), 6,80 (broad 2H,

), 5,56 (g,J=3,2 Гц, IH, I'-H), 5,26 (gg, J=2,2, 3,8 Гц, IH, 7-H), 4,41 (gg, J= 2,5, 4,8 Гц, IH, (CH₃O)

eq-CH₂N), 3,5-3,9 (м, 2H,

-CH₂N), 3,38 [5, 3H, O-CH-(

), 3,17 (gg, J=8,7, 8,7 Гц, IH, 4'-

, 2,72 [gg, J=2,5, 11,2 Гц, IH, N-

eg-CH(OCH₃)] 2,5-2,6 (м, 3'-H), 2,3-2,6 (м, 2H, NCH₂O), 2,23 [gg, J= 4,8, 11,2 Гц, IH, N-

ax-CH(OCH₃)] 1,37 (g, J=6,6 Гц, 3H, 5'-CH₃).Yield 50% mp 143-147 ^o C (decomp.)
TLC (Kieselgel plates; Merk F ₂₅₄ ; eluent methylene chloride / ethanol-95: 5 by volume); Rf 0.27 FD-MS; m / z 513 (MH ⁺ ), 612 (M ^{+ '} )
¹ H NMR (200 MHz, CDCl ₃ ),
13.72 (s, IH, 6-

), 13.38 (s, IH, II-

), 7.68 (g, J = 6.4 Hz, IH, I-

), 7.49 (gg, J = 8.3 Hz, IH, 2-

6.95 (g, J = 8.3 Hz, 3-

), 6.80 (broad 2H,

), 5.56 (g, J = 3.2 Hz, IH, I'-H), 5.26 (gg, J = 2.2, 3.8 Hz, IH, 7-H), 4.41 (gg, J = 2.5, 4.8 Hz, IH, (CH ₃ O)

eq-CH ₂ N), 3.5-3.9 (m, 2H,

-CH ₂ N), 3.38 [5, 3H, O-CH- (

), 3.17 (gg, J = 8.7, 8.7 Hz, IH, 4'-

2.72 [gg, J = 2.5, 11.2 Hz, IH, N-

eg-CH (OCH ₃ )] 2.5-2.6 (m, 3'-H), 2.3-2.6 (m, 2H, NCH ₂ O), 2.23 [gg, J = 4 8, 11.2 Hz, IH, N-

ax-CH (OCH ₃ )] 1.37 (g, J = 6.6 Hz, 3H, 5'-CH ₃ ).

Example 6. 4-demethoxy-6-deoxy-6-amino-3'-deamino-3 '- (2-methoxy-4-morpholinyl) daunorubicin (q)
The synthesis of compound (q) indicated in the title of the example was carried out according to the procedure of example 1, using 4-demethoxy-6-aminodaunorubicin (C14) as the starting material.

), 8,2-8,3 (м, 2H, 1-H, 4-

), 8,04 (шир. 2H,

), 8,0-7,6 (м, 2H, 2-H, 3-

), 5,5 (g, J=2,9 Гц, IH, 1'-

), 5,01 (gg, J=3,9, 5,3 Гц, IH, 7-

), 4,40 [gg, J= 2,5, 4,8 Гц, IH, (CH₃O)

eg-CH₂N] 3,7-3,9 (м, 2H,

-CH₂N), 3,35 [c, 3H, O-CH-(

), 3,17 (gg, J=8,7, 8,7 Гц, IH, 4'-H, 2,70 [gg, J=2,5, 11,2 Гц, IH, N-HeqCH(OCH₃)] 2,5-2,6 (м, 3-

), 2,4-2,5 (м, 2H,

), 2,37 (c, 3H,

), 2,20 [gg, J=4,8, 11,2 Гц, IH, N-CHax-CH(OCH₃)] 1,10 (g, J= 6,6 Гц, 3H, 5'-

).Yield 38% mp 150-153 ^o C (decomp.)
TLC (Kieselgel plates, Merk F ₂₅₄ , eluent methylene chloride / ethanol 95: 5 by volume); Rf = 0.30 RD-MS; m / z 614 (M ^{+ '} ); ¹ H NMR (200 MHz, CDCl ₃ ), 14.1 (IH, 11-

), 8.2-8.3 (m, 2H, 1-H, 4-

), 8.04 (br 2H,

), 8.0-7.6 (m, 2H, 2-H, 3-

), 5.5 (g, J = 2.9 Hz, IH, 1'-

), 5.01 (gg, J = 3.9, 5.3 Hz, IH, 7-

), 4.40 [gg, J = 2.5, 4.8 Hz, IH, (CH ₃ O)

eg-CH ₂ N] 3.7-3.9 (m, 2H,

-CH ₂ N), 3.35 [s, 3H, O-CH- (

), 3.17 (gg, J = 8.7, 8.7 Hz, IH, 4'-H, 2.70 [gg, J = 2.5, 11.2 Hz, IH, N-HeqCH (OCH ₃ )] 2.5-2.6 (m, 3-

), 2.4-2.5 (m, 2H,

), 2.37 (s, 3H,

), 2.20 [gg, J = 4.8, 11.2 Hz, IH, N-CHax-CH (OCH ₃ )] 1.10 (g, J = 6.6 Hz, 3H, 5'-

)

Claims (4)

1. Anthracycline glycoside of the general formula I

where Z is methoxy;
X is hydrogen or hydroxy;
R _{1 is} hydrogen or methoxy;
R ₂ and R _{3 are} hydroxy or one of R ₂ and R ₃ is hydrogen and the other is hydroxy;
R ₄ and R _{5 are} hydrogen or one of R ₄ and R ₅ is hydrogen and the other is hydroxy,
or its pharmaceutically acceptable salts, provided that when Z and R _{1 are} both methoxy and R ₂ and R _{3 are} both hydroxy, then R _{5 is} hydroxy or R ₄ and R _{5 are} hydrogen.  2. Anthracycline glycoside according to claim 1, characterized in that it is selected from 3'-deamino-3 '- (2-methoxy-4-morpholinyl) -4'-deoxydoxorubicin or its hydrochloride salt, 4-demethoxy-3'- deamino-3 '- (2-methoxy-4-morpholinyl) daunorubicin or its hydrochloride salt, 4-demethyl-6-deoxy-3'-deamino-3' - (2-methoxy-4-morpholinyl) -doxorubicin or its hydrochloride salt, 4-demethoxy-4-amino-3'-deamino-3 '- (2-methoxy-4-morpholinyl) daunorubicin or its hydrochloride salt and 4-demethoxy-6-deoxy-6-amino-3'- deamino-3′- (2-methoxy-4-morpholinyl) daunorubicin or its hydrochloride salt. 3. The method of obtaining anthracycline glycoside of General formula I

where Z is methoxy;
X is hydrogen or hydroxy;
R _{1 is} hydrogen or methoxy;
R ₂ and R _{3 are} both hydroxy or one of R ₂ and R _{3 is} hydrogen and the other is hydroxy;
R ₄ and R _{5 are} hydrogen or one of R ₂ and R ₃ is hydrogen and the other is hydroxy,
or its pharmaceutically acceptable salts, provided that when Z and R _{1 are} both methoxy and R ₂ and R _{3 are} both hydroxy, then R _{5 is} hydroxy or both R ₄ and R _{5 are} hydrogen,
characterized in that the reductive alkylation of anthracycline glycoside of the general formula II is carried out in an aqueous polar organic solvent and in the presence of a reducing agent

where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and X are as defined above,
or its salts using 1-methoxy-2,2'-oxydiacetaldehyde of the formula III

followed by removal of the solvent and, if necessary, converting the resulting anthracycline glycoside of formula I into its pharmaceutically acceptable salt.  4. The method according to p. 3, characterized in that the anthracycline glycoside of formula II or a salt thereof dissolved in a mixture of acetonitrile and water (1 1, volumes) is reacted with an excess of the aldehyde of formula III after 30 minutes in the reaction mixture at pH 7 , 4 add an aqueous solution of sodium cyanoborohydride, the mixture is extracted with n-butanol, the organic solvent is removed under reduced pressure and after purification of the crude product on a silica gel column using a mixture of methylene chloride-methanol (97 3, v / v) as the eluting agent, the target product and oliruyut in the form of the hydrochloride salt by addition of a methanolic solution of anhydrous hydrogen chloride.

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