RU2057138C1 - Anthracycline-glycoside compounds or their pharmaceutically acceptable salts, method of synthesis of anthracycline-glycoside compounds or their pharmaceutically acceptable salts - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: products: anthracycline-glycoside compounds of the formula (I) where R₁ and R₂ are -H, respectively, or form together C₁- C₄-alkylylene with direct or branched chain; Y - radical of the formula (II) where R - H, lower alkyl, C-C-alkoxycarbonyl; n = 0 or a whole number from 1 to 6; Y - radical of the formula (III) where R₃ - H, C₁- C₆-alkoxycarbonyl; m = 1, 2, 3, or their pharmaceutically acceptable salts. Product is synthesized by action of corresponding 14-COCHX-derivative where X - halogen atom on the compound of the formula A-OOC-Y where A - H or alkaline metal; Y - as indicated above followed by conversion to the salts if necessary. Structure of the formulas I - III:

Synthesized compounds were used in medicine. EFFECT: improved method of synthesis. 3 cl, 2 tbl

Description

(I) где R₁ и R₂ представляют соответственно атом водорода или вместе образуют алкилиденовую группу с прямой или разветвленной цепочкой, содержащей 1-10 атомов углерода;
Y представляет группу

NHR₃ или

NR₃ R₃ представляет собой атом водорода, алкильную группу с прямой или разветвленной цепочкой, содержащую 1-10 атомов углерода, алкокси-карбонильную группу с прямой или разветвленной цепочкой, содержащей 1-10 атомов углерода, или 3-6-членную гетероциклическую группу, содержащую атом азота рядом с соседней алкиленовой группой;
R₄ и R₅ представляют собой соответственно атом водорода или алкильную группу, содержащую 1-5 атомов углерода;
n 0 или представляет собой целое число равное 1-10;
m целое число 1-5; и его фармацевтически приемлемым солям.The invention relates to new derivatives of anthracycline glycoside of the following formula (I)

(I) where R ₁ and R ₂ respectively represent a hydrogen atom or together form a straight or branched chain alkylidene group containing 1-10 carbon atoms;
Y represents a group

NHR ₃ or

NR ₃ R ₃ represents a hydrogen atom, a straight or branched chain alkyl group containing 1-10 carbon atoms, a straight or branched chain alkoxy carbonyl group containing 1-10 carbon atoms, or a 3-6 membered heterocyclic group, containing a nitrogen atom adjacent to an adjacent alkylene group;
R ₄ and R ₅ respectively represent a hydrogen atom or an alkyl group containing 1-5 carbon atoms;
n 0 or represents an integer equal to 1-10;
m is an integer of 1-5; and its pharmaceutically acceptable salts.

 Anthracycline antibiotics include fermented broth containing Actinomyces daunorubicin (US Pat. No. 3,997,662) and doxorubicin (US Pat. No. 3,590028).

 Anthracyclines have a broad-spectrum antitumor activity and are used as chemotherapeutic agents in the treatment of malignant tumors.

(A) где R представляет собой атом водорода или гидроксильную группу.The above anthracyclines have the following structural formula (A):

(A) where R represents a hydrogen atom or a hydroxyl group.

(B) где R представляет собой атом водорода или гидроксильную группу.In addition, a 2-fluoro-substituted derivative of anthracycline-A is known (Japanese Patent Publication No. Sho 62-145097)

(B) where R represents a hydrogen atom or a hydroxyl group.

 It is known to obtain a soluble derivative of compound (B) in the form of compound (C) (Japanese Patent Publication No. Sho 63-141992).

(C) где R представляет собой группу (СН)_mН (n 0 или n 1-6) или (СН)_n СООН (n0 или n= 1-10). Однако применение известных антрациклинов, таких как даунорубицин, доксорубицин и других, ограничивалось возникновением ряда нежелательных побочных эффектов. Одним из наиболее серьезных побочных эффектов указанных препаратов является их кардиотоксичность, что приводит к необходимости резко ограничивать дозировки и частоту введения, а это, в свою очередь, приводит к уменьшению их общей эффективности в качестве химиотерапевтических средств, используемых при лечении злокачественных опухолей.

(C) where R is a group (CH) _m H (n 0 or n 1-6) or (CH) _n COOH (n0 or n = 1-10). However, the use of known anthracyclines, such as daunorubicin, doxorubicin and others, was limited to the occurrence of a number of undesirable side effects. One of the most serious side effects of these drugs is their cardiotoxicity, which leads to the need to drastically limit the dosage and frequency of administration, and this, in turn, leads to a decrease in their overall effectiveness as chemotherapeutic agents used in the treatment of malignant tumors.

 Another disadvantage of these compounds is their relatively low solubility in water, and therefore these compounds are difficult to enter into the body in such quantities that would be effective in the treatment of certain forms of cancer.

 It was found that the compound of formula (I) and its salts exhibit good antitumor activity and are characterized by good solubility in isotonic and even neutral water.

(I) где R₁ и R₂ представляют соответственно атом водорода или вместе образуют алкилиденовую группу с прямой или разветвленной цепочкой, содержащей 1-10 атомов углерода;
Y представляет группу
-

R₃ представляет собой атом водорода, алкильную группу с прямой или разветвленной цепочкой, содержащую 1-10 атомов углерода, алкокси-карбонильную группу с прямой или разветвленной цепочкой, содержащей 1-10 атомов углерода или 3-6-членную гетероциклическую группу, содержащую атом азота рядом с соседней алкиленовой группой;
R₄ и R₅ представляют собой соответственно атом водорода или алкильную группу, содержащую 1-5 атомов углерода;
n 0 или представляет собой целое число равное 1-10;
m целое число от 1 до 5.Compound (I)

(I) where R ₁ and R ₂ respectively represent a hydrogen atom or together form a straight or branched chain alkylidene group containing 1-10 carbon atoms;
Y represents a group
-

R ₃ represents a hydrogen atom, a straight or branched chain alkyl group containing 1-10 carbon atoms, a straight or branched chain alkoxy carbonyl group containing 1-10 carbon atoms or a 3-6 membered heterocyclic group containing a nitrogen atom next to a neighboring alkylene group;
R ₄ and R ₅ respectively represent a hydrogen atom or an alkyl group containing 1-5 carbon atoms;
n 0 or represents an integer equal to 1-10;
m is an integer from 1 to 5.

 Thus, one of the objectives of the invention is the creation of a new derivative of anthracycline represented by formula (I) and its pharmaceutically acceptable salt.

 Another objective of the invention is to develop a method for producing an anthracycline derivative represented by formula (I) and pharmaceutically acceptable salts thereof.

 By said pharmaceutically acceptable salts are meant inorganic salts such as halides, phosphates, sulfates, nitrates, etc. organic salts such as acetates, methanesulfonates, benzosulfonates, p-toluenesulfonates and others. The title compound of formula (I) and its salts exhibit high antitumor activity when administered to animals and are less toxic than the other derivatives mentioned above.

(II) где R₁ и R₂ соответствуют вышеприведенным определениям;
Х представляет собой атом брома, хлора или йода, с соединением формулы (III)
А-OCOY (III) где Y имеет вышеприведенные определения;
А представляет собой атом водорода или щелочной металл.A compound of formula (I) is prepared by reacting a compound of formula (II) (where hydroxyl groups at 3 and 4 can be protected)

(II) where R ₁ and R ₂ correspond to the above definitions;
X represents an atom of bromine, chlorine or iodine, with a compound of formula (III)
A-OCOY (III) where Y has the above definitions;
A represents a hydrogen atom or an alkali metal.

где R₁, R₂, R₃, R₄, R₅ и А соответствуют вышеприведенным определениям.The protecting groups at positions 3 and 4, as well as the amino protecting group, are removed and then the resulting compound is converted, if necessary, into a pharmaceutically acceptable salt. A salt of the compound of formula (I), however, can be readily prepared during the above deprotection reaction. For example, in the preparation of a compound of formula (I) or a salt thereof in the case when X is bromo and the hydroxyl groups at 3 ′, 4 ′ are protected with isopropylidene, the reaction equation can be represented as follows:

where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and A correspond to the above definitions.

The reaction between the compound of formula (II) and the compound of formula (III) can be carried out in conventional solvents such as water; alcohols, for example ethanol; nitriles, e.g. acetonitrile; ketones, for example acetone or methyl ethyl ketone; cyclic and aromatic amines, for example pyridine, pyrrolidine or pyrroline; aromatic hydrocarbons, for example benzene, toluene; esters, for example dioxane, tetrahydrofuran; halogenated hydrocarbons, for example chloroform, dichloromethane; and amides, for example, formamide, dimethylformamide, dimethylacetamide, or mixtures thereof. The reaction may be carried out in the range from 0 ° ^C to the reflux temperature of the solvent for the time from 30 minutes to 48 hours.

 Before carrying out this reaction, it is necessary to protect hydroxyl groups, and after its completion, protection can be removed. As the protecting group, an alkylene group with either a straight or branched chain can be used.

 The starting compound of formula (II) can be obtained from a known compound (Japanese Patent Publication No. Sho 62-145097).

 If it is desired to deprotect the hydroxyl groups of the compounds of formula (I), the protected compound is treated with an acid, for example formic, acetic, hydrochloric, sulfuric or phosphoric. The amino protecting group can also be easily eliminated.

 In the deprotection reaction, a proton-free solvent can be used, for example, water, alcohol, N, N-dimethylformamide, dimethyl sulfoxide, dioxane, ether, chloroform, tetrahydrofuran, dichloromethane, or mixtures thereof.

PRI me R 1. Obtaining 7-0- (2,6-dideoxy-2-fluoro-3,4, -0-isopropylidene-α-L-halopyranosyl) - adriamycin 14-0- [N- (tert - butyloxycarbonyl (Bec) glycinate]
To a solution of 14-bromo-7-0- (2,6-dideoxy-2-fluoro-3,4, -0-isopropylidene-α-L-talopyranosyl) daunomicenone (180 g) in an aqueous solution of acetone (8:26, 33 ml) Sodium N-tert-butyloxycarbonylglycinate (1.5 g) was added. The mixture was stirred for 20 hours and then distilled under reduced pressure to obtain a residue. The residue was extracted with chloroform, washed with water, saturated with a NaCl solution, and dried in vacuo. Then, the residue was purified using gel permeation chromatography (silica was used as a gel, and a solution of chloroform and methanol in a ratio of 20: 1 was used as an eluent), 121 mg of the title compound (59%) was obtained.

Melting point 142-143.5 ^about C.

6,4 Гц); 1,44 (с. 9Н, трет-бутил).NMR (CDCl ₃ , ppm, specific specific peak): 13.7; 13.1 (OHx2); 5.53 (dd. 1H, H-1 ', I _H-1'-H-2' = 5.6 Hz, I _H-1'-F 14 Hz; 4.01 (s. 3H, OCH ₃ ) ; 1.55 (s. 3H, CH ₃ ); 1.32 (s. 3H, CH ₃ ); 1.30 (d. 3H, CH ₃ , I

6.4 Hz); 1.44 (s. 9H, tert-butyl).

 PRI me R 2. Obtaining hydrochloride salt of 7-0- (2,6-dideoxy-2-fluoro-L-talopyranosyl) -adriamycin 14-0-glycinate.

The compound obtained in Example 1 was dissolved in 80% acetic acid solution (10 ml) and stirred at ⁸⁰ ° C for 3 hours. The solvent was removed by distillation under reduced pressure to obtain a residue. The residue was subjected to column chromatography using silica gel (eluent solution: chloroform: methanol 5: 1) to obtain 7-0- (2,6-dideoxy-2-fluoro-α-L-talopyranosyl) -adriamycinone 14-0-glycinate . This compound was dissolved in a small amount of dichloromethane. A saturated solution of HCl and ether was added dropwise to the resulting solution to obtain a red solid. The resulting red solid was washed with ether, centrifuged and dried to give the title compound as a hydrochloric acid salt (48 mg, 56%).

Melting point 179-185 ^about C.

6,1 Гц).NMR (CDCl ₃ , ppm specific peak): 14, 0, 13.2 (s. 1H, OHx2); 8.3 (broad s. 3H. -NH ₃ Cl); 7.9 (m, 2H, aromatic proton); 7.6 (m, 1H, aromatic proton); 4.0 (m. 5H, OCH ₃ , CO — CH ₂ —N); 1.2 (d. 3H, CH ₃ , I

6.1 Hz).

 PRI me R 3. Obtaining hydrochloride salt of 14-0-glycinate 7-0- (2,6-dideoxy-2-fluoro-α-L-talopyranosyl) -adriamycin.

 The compound (120 mg) obtained in Example 1 was dissolved in chloroform (1.5 ml) and methanol (15 ml) was added. Saturated HCl and ether solution (12 ml) was added and the mixture was stirred for 4 hours. After completion of the reaction, a significant portion of the solvent was distilled to obtain a residue. Ether was added to the residue to give a solid. This solid was filtered and dried to give the title compound (84 mg, 80%).

PRI me R 4. Obtaining 7-0- (2,6-dideoxy-2-fluoro-3,4-0-isopropylidene-α-L-talopyranosyl) - adriamycin 14-0 [N- (tert-butyl - xicarbonyl (Boc) - α-alaninate]
14-bromo-7-0 (2,6-dideoxy-2-fluoro-3,4-isopropylidene-α-L-talopyranosyl) daunomycinone (200 mg) was reacted with N- (tert-butyloxycarbonyl) - β- sodium alaninate (634 mg) according to a similar manner to that described in Example 1, the title compound (144 mg, 62%) was obtained as a red solid. A mixture of solvents such as benzene and acetone (4: 1) was used as an eluent during gel permeation chromatography with a silica gel.

Melting point 138-140.5 ^about C.

6,4 Гц); 1,4 (с. 9Н, трет-бутил).NMR (CDCl ₃ , ppm, dol. Specific peak): 13.8; 13.2 (s. Each 1H, OHx2); 5.5 (dd 1H, H-1, I _{H-1'-H-2 '} 5.6 Hz, I _H-1'-F 13.8 Hz); 4.1 (s. 3H, OCH ₃ ); 1.5, 1.4 (s. Each 3H, CH ₃ x2); 1.3 (d. 3H, CH ₃ , I

6.4 Hz); 1.4 (s. 9H, tert-butyl).

 PRI me R 5. Obtaining hydrochloride salt of 7-0- (2,6-dideoxy-2-fluoro-α-L-talopyranosyl) -adriamycinone 14-0-β-alaninate.

 The compound (140 mg) obtained in Example 4 was treated in a similar manner to that described in Example 3 to obtain the title compound (92 mg, 76%).

Melting point 195-200 ^about C.

6,5 Гц).NMR (DMCOd, ppm, specific specific peak); 14.0, 13.2 (s. Each 1H, OHx2); 7.9 (m, 5H, -NH ₃ Cl, 2H, aromatic proton); 7.6 (m, 1H, 1H, aromatic proton); 3.9 (s. 3H, OCH ₃ ); 1.1 (d. 3H, CH ₃ , I

6.5 Hz).

PRI me R 6. Obtaining 7-0- (2,6-dideoxy-3,4-0-isopropylidene-α-L-talopyranosyl) -adriamycinone 14-0- [6- (tert-butyloxycarbonite (Boc)) - aminohexanoate]
14-bromo-7-0- (2,6-dideoxy-2-fluoro-3,4-0-isopropylidene-α-L-talopyranosyl) daunomicenone (220 mg) was reacted with 6- (tert-butyl- hydroxycarbonylamino) sodium hexanoate (900 mg) according to a similar manner to that described in Example 1, the title compound (158 mg, 64%) was obtained as a red solid. A mixture of solvents such as benzene and acetone (4: 1) was used as an eluent in gel permeation chromatography with silica.

Melting point 130-132 ^about C.

' 6,4 Гц).NMR (CDCl ₃ , ppm specific peak): 13.8, 13.2 (s. 1H, OHx2); 4.5 (dd. H-1 ', I _H-1'-H-2' 5.5 Hz, I _H-1'-F 13.8 Hz); 4.0 (s. 3H, OCH ₃ ); 1.5 (s. 9H, t-butyl); 1.6, 1.5 (s. Each 3H, CH ₃ x2); 1.3 (d. 3H, CH ₃ , I

'6.4 Hz).

 PRI me R 7. Obtaining hydrochloride salt of 7-0- (2,6-dideoxy-2-fluoro-α-L-talopyranosyl) -adriamycinone 14-0- (6-aminohexanoate).

 The compound (150 mg) obtained in Example 6 was treated in a similar manner to that described in Example 3 to obtain the title compound (95 mg, 72%).

Melting point 188-192 ^about C.

' 6,4 Гц).NMR (DMCOd ₆ , ppm specific peak); 14.0, 13.2 (s. Each 1H, OHx2); 7.8 (m, 3H, aromatic proton and amino); 7.6 (m, 3H, aromatic proton and amino); 3.9 (s. 3H, OCH ₃ ); 1.3 (s. 6H, -CH ₂ -CH ₂ -CH ₂ -); 1.2 (d. 3H, CH ₃ , I

'6.4 Hz).

PRI me R 8. Obtaining 7-0- (2,6-dideoxy-2-fluoro-3,4-0-isopropylidene-α-L-talopyranosyl) -adrinamycin 14-0- [N- (tert- butyl hydroxycarbonyl) -L-alaninate]
14-bromo-7-0- (2,6-dileoxy-2-fluoro-3,4-0-isopropylidene-L-talopyranosyl) daunomicenone (200 mg) was reacted with (tert-butyloxycarbonyl) -L-alaninate sodium (650 mg) according to the method of Example 1, the title compound (137 mg, 59%) was obtained as a red solid. For gel chromatography with silica, a mixture of solvents such as benzene and acetone (4: 1) was used as an eluent.

Melting point 148.5-151.0 ^about C.

' 6,5 Гц); 1,5 (д. 3Н, СН₃, I

7,1 Гц); 1,4 (с. 9Н, трет-бутил).NMR (CDCl ₃ , ppm specific peak): 13.8, 13.2 (s. 1H, OHx2); 5.5 (dd 1H, H-1 ', I _H-1'-H-2' 5.6 Hz); I _H-1'-F 13.8 Hz); 4.1 (s. 3H, OCH ₃ ); 1.5, 1.4 (s. Each 3H, CHx2); 1.3 (d. 3H, CH ₃ I

'6.5 Hz); 1.5 (d. 3H, CH ₃ , I

7.1 Hz); 1.4 (s. 9H, tert-butyl).

 PRI me R 9. Obtaining hydrochloride salt of 7-0- (2,6-dideoxy-2-fluoro-L-talopyranosyl) -adriamycinone 14-0-L-alaninate.

 The compound (130 mg) obtained in Example 8 was processed according to the method of Example 3 to obtain the title compound (90 mg, 80%).

Melting point 177-184 ^about C.

7,1 Гц); 1,3 (3Н, СН₃, I

' 6,5 Гц);
П р и м е р 10. Получение 7-0-(2,6-дидеокси-2-фторо-3,4-0-изопропилиден-L-тало- пиранозил)- адриамицинон 14-0[N(трет-бутилоксикарбонил)-L-валината]
Осуществляли взаимодействие 14-бромо-7-0-(2,6-дидеокси-2-фторо-3,4-0-изопро- пилиден- α-L-талопиранозил)дауномиценона (200 мг) с (трет-бутилоксикарбонил)-L-валинатом (700 мг) по способу, аналогичному описанному в примере 1, получали названное соединение (145 мг, 60%) в виде твердого вещества красного цвета. В качестве элюента при гельпроникающей хроматографии с оксидом кремния использовали смесь таких растворителей, как бензол и ацетон (4:1).NMR (DMSOd ₆ , ppm specific peak); 14.0, 23.2 (s. Each 1H, OHx2); 8.5 (broad s. 3H, -NH ₃ Cl); 7.9 (m. 2H, aromatic proton); 7.6 (m, 1H, aromatic proton); 3.9 (s. 3H, OCH ₃ ); 1.5 (d. 3H, CH ₃ , I

7.1 Hz); 1.3 (3H, CH ₃ , I

'6.5 Hz);
PRI me R 10. Obtaining 7-0- (2,6-dideoxy-2-fluoro-3,4-0-isopropylidene-L-thalopyranosyl) - adriamycin 14-0 [N (tert-butyloxycarbonyl) -L-valinate]
The reaction of 14-bromo-7-0- (2,6-dideoxy-2-fluoro-3,4-0-isopropylidene-α-L-talopyranosyl) daunomicenone (200 mg) with (tert-butyloxycarbonyl) -L -valinate (700 mg) according to a method similar to that described in example 1, the title compound (145 mg, 60%) was obtained as a red solid. A mixture of solvents such as benzene and acetone (4: 1) was used as an eluent in gel permeation chromatography with silica.

Melting point 137-139 ^about C.

' 6,4 Гц); 1,0 (д. д. 6Н, -CH(CH₃).NMR (CDCl, ppm specific peak): 13.9, 13.2 (s. 1H, OHx2); 5.5 (dd 1H, H-1 ', I _H-1'-H-2' 5.5 Hz, I _H-1'-F 13.8 Hz); 4.0 (s. 3H, OCH ₃ ); 1.4 (s. 9H, tert-butyl); 1.3 (d. 3H, CH ₃ , I

'6.4 Hz); 1.0 (dd. 6H, -CH (CH ₃ ).

 PRI me R 11. Obtaining hydrochloride salt of 7-0- (2,6-dideoxy-2-fluoro-α-L-talopyranosyl) -adriamycinone 14-0-L-valinate.

 The compound (140 mg) obtained in Example 10 was processed according to the method of Example 3 to obtain the title compound (90 mg, 74%) as a red solid.

Melting point 164-168 ^about C.

' 6,5 Гц); 1,0 (д.д. 6Н, -CH(CH₃).NMR (DMCO-d ₆ , ppm specific peak): 14.0, 13.2 (s. 1H, OHx2); 8.4 (broad s. 3H, NH ₃ Cl); 7.9 (m, 2H, aromatic proton); 7.6 (m, 1H, aromatic proton); 4.0 (s. 3H, OCH ₃ ); 1.2 (d. 3H, CH ₃ , I

'6.5 Hz); 1.0 (dd. 6H, -CH (CH ₃ ).

PRI me R 12. Obtaining 7-0- (2,6-dideoxy-2-fluoro-3,4-0-isopropylidene-α-L-talopyranosyl) -adriamycin 14-0- [N- (tert- butyl hydroxycarbonyl) -L-proline]
14-bromo-7-0- (2,6-dideoxy-2-fluoro-3,4-0-isopropylidene-α-L-talopyranosyl) daunomycinone (200 mg) and N (tert-butyloxy-carbonyl) -L- proline (900 mg) was treated according to the method of Example 1 to obtain the title compound (150 mg, 62%) as a red solid. For gel chromatography with silica, a mixture of solvents such as benzene and acetone (4: 1) was used.

Melting point 145.5-148.5 ^about C.

NMR (CDCl ₃ , ppm specific peak): 13.8, 13.2 (s. 1H, OHx2); 5.5 (dd. 1H. H-1 ', I _H-1'-H-2' 5.5 Hz, I _H-1'-F 13.8 Hz); 4.0 (s. 3H, OCH ₃ ); 1.4 (s. 9H, tert-butyl).

 PRI me R 13. Obtaining hydrochloride salt of 7-0- (2,6-dideoxy-2-fluoro-α-L-talopyranosyl) -adriamycinone 14,0-L-proline.

 The compound (140 mg) obtained in Example 12 was treated in a similar manner to that described in Example 9 to obtain the title compound (94 mg, 77%) as a red solid.

Melting point 180-185 ^about C.

' 6,3 Гц).NMR (DMCO-d ₆ , ppm specific peak): 14.0, 13.1 (s, each 1H, OHx2); 10.2, 9.1 (2 broad s each, 1H, -NH ₃ Cl); 7.9 (m, 2H, aromatic proton); 7.6 (m, 1H, aromatic proton); 3.9 (s. 3H, OCH ₃ ); 1.2 (d. 3H, CH ₃ , I

'6.3 Hz).

 Biological activity.

Experiment 1. The antitumor activity of the compounds of the invention was studied in CDF mice affected by murine L1210 leukemia. Healthy female CDF mice were infected by intraperitoneal injection of L1210 leukemia cells in an amount of 1 × 10 ⁵ per animal. Infected mice were exposed to the test compounds at various dosages, which were introduced into the abdominal cavity on the first, fifth and ninth day after the administration of leukemia cells (the first injection was made 24 hours after the administration of leukemia cells). For comparison, doxorubicin hydrochloride was also administered. All test compounds and doxorubicin hydrochloride were dissolved in filtered (0.22 μm) distilled water. The condition of the animals was recorded 60 days after infection with leukemia cells and the survival of these animals was compared with indicators for animals from the control group that were infected with the same tumor cells, but received therapy in the form of the introduction of filtered physiological saline. The results are shown in Table 1, where T / C (c) values were determined as the quotient of dividing the average survival time of mice receiving the test compounds by the survival time of mice from the control group, which was then multiplied by 100. The survival time of mice after tumor cell administration It was found in 60 days. An increase in T / C (c) indicates an increase in the antitumor activity of the compound.

 The proposed compounds were less toxic than doxorubicin hydrochloride, which at a dose of 16 mg / kg showed a significant decrease in T / C compared with T / C at a dosage of 8 mg / kg. The proposed compounds did not have such toxicity. As shown in table 1, most of the proposed compounds showed greater antitumor activity compared with doxorubicin hydrochloride. Moreover, the compounds of Example 3 at doses of 32 mg / kg, 16 mg / kg and 8 mg / kg cured mice with particularly strong tumor development.

 Experiment 2. In the laboratory, the inhibitory activity of the compounds of the invention against murine leukemia L1210 cells was determined by slightly modified analysis using tetrazolium (Cancer Research, February 1987, v. 47, pp. 936-942).

The mouse L1210 mouse leukemia cells were exponentially placed in 96-well microtiter plates, with a density of 1x10 ⁵ cells per well. As the medium for growing cell culture, RPMI 1640 material (Roswell Rark Memorial Institutes, 1640) was used, supplemented with 10% thermally activated cow embryo serum (FBS), 2 mmol L-glucatilin, penicillin G with sodium (100 units per 1 ml of nutrient medium) and streptomycin sulfate (1 mg per 1 ml of culture medium).

 Then, the proposed anthracycline compounds and dexorubicin hydrochloride were added to increase the final concentrations from 1 ng / ml to 300 ng / ml. Control samples did not contain the drug.

Cells were incubated for 72 hours at ³⁷ ° C in an atmosphere of CO (10%) and air (90%). At the end of this period, 50 μl of MTT solution (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) (2 mg per 1 ml in phosphate-buffered saline) and cell cultures were added to each well incubated at ³⁷ ° C for 4 hours in a CO ₂ incubator, MTT is reduced to water insoluble MTT formazan (1- (4,5-dimethylthiazol-2-yl) -3,5-difenilfor- IASA) mitochondrial sutstsinatdegidrogenazoy only alive cells. At the end of the incubation, 200 μl of the top-floating layer was removed and the MTT formazan crystal was dissolved by adding 200 μl of dimethyl sulfoxide and mixing into the mixture.

 Immediately after this, the dishes were examined using a scanning multi-cell spectrophotometer with a resolution of 540 nm (immunosorbent analyzer of the enzyme type from Biotech Instruments Inc. Burlingor, Vermont).

 Absorption values are adjusted for unrelated control values.

 Absorption values are directly proportional to the number of living cells. A value of 1 IC 50 was determined as corresponding to a 50% decrease in absorption compared to untreated control samples and was calculated from the dose response curve. The obtained values are given in table.2.

 As can be seen from table 2, all tested compounds, with the exception of example 7, were more cytotoxic to mouse leukemia L1210 cells than doxorubicin hydrochloride.

Claims (2)

1. Anthracycline-glycoside compounds of General formula I

where R ₁ and R ₂ - hydrogen or together form a C ₁ - C ₄ -alkylidene group with a straight or branched chain;
Y is a group of the general formula

where R ₃ is hydrogen, lower alkyl or C ₁ -C ₆ alkoxycarbonyl;
R ₄ and R ₅ are hydrogen or C ₁ -C ₆ straight or branched chain alkyl;
n = 0 or a number from 1 to 6,
or Y is a group of the general formula

where R ₃ is hydrogen, C ₁ is C ₆ alkoxycarbonyl;
m = 1,2,3,
or their pharmaceutically acceptable salts. 2. A method of obtaining anthracycline-glycoside compounds of General formula I

where R ₁ and R ₂ - hydrogen or together form a C ₁ - C ₄ -alkylidene group with a straight or branched chain;
Y is a group of the general formula

where R ₃ is hydrogen, lower alkyl or C ₁ -C ₆ alkoxycarbonyl;
n = 0 or a number from 1 to 6,
or Y is a group of the general formula

where m = 1,2,3;
R ₃ is hydrogen, C ₁ is C ₆ alkoxycarbonyl,
or their pharmaceutically acceptable salts, characterized in that the compound of General formula II

where R ₁ and R ₂ have the indicated meanings;
X is bromine, chlorine or iodine,
react with a compound of formula III
A-OOC-Y,
where Y has the indicated meanings;
A is hydrogen or an alkali metal,
or a pharmaceutically acceptable salt thereof, to give compound I, which, if necessary, is converted into a salt.

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