Mono and bis alkylamino-anthracyclines

Abstract: An anthracycline glycoside of general formula 1 : wherein R₁ is hydrogen or methoxy group; R₂ is hydrogen or hydroxy group, A and B both represent hydrogen or one of A and B is hydrogen and the other is hydroxy or a group of formula -OSO₂R₅ in which R₅ is C1-C4 alkyl or aryl optionally substituted by C1-C4 alkyl, nitro, amino, methoxy or halogen; R₃ is a hydrogen atom or a group of formula 2 and R₄ is a group of formula 2 -(CH₂) n -X 2 in which n is 2 or 3 and X is hydroxy group, a halogen or a group of formula OSO₂R₅ in which R₅ is as defined above and with the proviso that if R₂, X and A are an hydroxy group R₃=H, n must be 3; or a pharmaceutically acceptable salt thereof. Compounds of the invention have activity as antitumor agents. Processes for their preparation and pharmaceutical composition containing them are also disclosed.

Description: The present invention relates to new anthracycline glycosides, to processes for their preparation and to pharmaceutical compositions containing them. The invention provides antracyclines glycosides of general formula 1 in which the amino group of the sugar moiety bears mono or bis alkyl-substituted chains: wherein R₁ is hydrogen or methoxy group; R₂ is hydrogen or hydroxy group, A and B both represent hydrogen or one of A and B is hydrogen and the other is hydroxy or a group of formula -OSO₂R₅ in which R₅ is C1-C4 alkyl or aryl optionally substituted by C1-C4 alkyl, nitro, amino, methoxy or halogen; R₃ is a hydrogen atom or a group of formula 2 and R₄ is a group of formula 2 -(CH₂) n -X 2 in which n is 2 and X is hydroxy group, a halogen or a group of formula -OSO₂R₅ in which R₅ is as defined above and with the proviso that R₂, X and A cannot be a hydroxy group at the same time when R₃ = H or a pharmaceutically acceptable salt thereof. J. Med. Chem. 1986, 29 discloses N-(2-hydroxyethyl)doxorubicin obtained from hydrolyses of 3'-deamino-3'-(3-cyano-4-morpholinyl) doxorubicin. Compounds of the invention exibit antitumor activity. Example of compounds of the invention include: 1a : 4-demethoxy-N-(2-hydroxyethyl)daunorubicin [R₁=R₂=R₃=H, A=OH, B=H, R₄=(CH₂)₂OH] 1b : N,N-bis(2-hydroxyethyl)daunorubicin [R₁=OCH₃, R₂=H, A=OH, B=H, R₃=R₄=(CH₂)₂-OH] 1c : N,N-bis(2-hydroxyethyl)doxorubicin [R₁=OCH₃, R₂=OH, A=OH, B=H, R₃=R₄=(CH₂)₂-OH] 1d : 4-demethoxy-N,N-bis(2-hydroxyethyl)daunorubicin [R₁=R₂=H, A=OH, B=H, R₃=R₄=(CH₂)₂-OH] 1e :4-demethoxy-4'-O-methansulfonyl-N,N-bis(2-chloroethyl)-daunorubicin [R₁=R₂=H, A=OSO₂CH₃, B=H, R₃=R₄=(CH₂)₂-Cl] 1f : 4-demethoxy-N,N-bis(2-chloroethyl)daunorubicin [R₁=R₂=H, A=OH, B=H, R₃=R₄=(CH₂)₂-Cl] 1g : 4'-O-methansulfonyl-N,N-bis(2-chloroethyl)daunorubicin [R₁=OCH₃, R₂=H, A=OSO₂CH₃, B=H, R₃=R₄=(CH₂)₂-Cl] 1h : N,N-bis(2-chloroethyl)daunorubicin [R₁=OCH₃, R₂=H, A=OH, B=H, R₃=R₄=(CH₂)₂-Cl] 1i : 4'-epi-4'-O-methansulfonyl-N,N-bis(2-chloroethyl)-daunorubicin [R₁=OCH₃, R₂=H, A=H, B=OSO₂CH₃ R₃= R₄=(CH₂)₂-Cl] 1j : 4'-epi-N,N-bis(2-chloroethyl)daunorubicin [R₁=OCH₃, R₂=H, A=H, B=OH, R₃=R₄=(CH₂)₂-Cl] 1k : 4-demethoxy-4'-epi-4'-O-methansulfonyl-N,N-bis(2-chloro-ethyl)daunorubicin [R₁=R₂=H, A=H, B=OSO₂CH₃, R₃=R₄=(CH₂)₂-Cl] and pharmaceutically acceptable salts thereof, such as the hydrochloride salt. The compounds of the present invention can be prepared by several methods starting from compounds of formula 3 wherein R₁, A and B are as defined above for formula 1 , R₆ is hydrogen, a hydroxyl group or an acidic sensitive masked group for the hydroxy group. Example of suitable protecting groups include those described in British Patent Application 9017024.2 filed 3.8.1990 entitled "New Linker for Bioactive Agents". Example of the starting compounds of formula 3 include daunorubicin [ 3a : R₁=OCH₃, R₂=H, A=OH, B=H], 4-demethoxy-daunorubicin [ 3b : R₁=R₂=H, A=OH, B=H], doxorubicin [ 3c : R₁=OCH₃, R₂=OH, A=OH, B=H], 4-demethoxy-4'-epi-daunorubicin [ 3d : R₁=R₂=H, A=H, B=OH], 4'-epi-daunorubicin [ 3e : R₁=OCH₃, R₂=H, A=H, B=OH], or masked derivative of doxorubicin at C-14. The compounds of general formula 1 can be prepared by alkylating the amino group of the sugar moiety using conventional methods. For instance, mono 2- or 3-hydroxy-alkylamino derivatives, which are compounds of formula 1 as defined above wherein R₃ is H or a group of formula 2 and R₄ is a group of formula 2 as defined above wherein X is a hydroxy group, can be prepared by a process comprising (i) reacting a compound of formula 3 as defined above, the compound of formula 3 being dissolved in a polar aprotic solvent, with an alkylating agent of general formula 4 X-(CH₂) n -Hal 4 wherein n is 2, X is hydroxy and Hal represents an halogen; and, if desired, (ii) purifying the resulting anthracycline glycosides of formula 1 on a chromatographic column; and/or, if desired, (iii) converting the anthracycline glycoside of formula 1 into a pharmaceutically acceptable acid addition salt thereof. Preferably the halogen in formula 4 is iodine or bromine. The polar aprotic solvent is preferably dry and is, for example, dimethylformamide or acetonitrile. The reaction is suitably conducted at a temperature from 20 to 30°C, typically for a time of from four to twenty four hours. Bis 2- or 3-hydroxy-alkylamino derivatives, which are compounds of formula 1 as defined above wherein R₃ and R₄ are a group of formula 2 as defined above wherein X is a hydroxy group, can also be prepared by the process as described above. The reaction time for step (i) is then typically 1 to 3 weeks. Bis 2-hydroxyethylamino compounds of general formula 1 can also be prepared by a process comprising (i) reacting a compound of formula 3 as defined above, preferably as free base, with ethylene oxide; and, if desired, (ii) purifying the resulting anthracycline glycoside of formula 1 on a chromatographic column; and/or, if desired, (iii) converting the anthracycline glycoside of formula 1 into a pharmaceutically acceptable acid addition salt thereof. Preferably the compound of formula 3 is first dissolved in a solvent comprising methanol and methylene chloride. Typically step (i) is conducted in the dark, and at a starting temperature of about -40°C. The temperature is then typically increased gradually to room temperature. Suitably it remains at room temperature for up 3 days. Anthracycline glycosides of general formula 1 as defined above in which R₂ is hydrogen and R₃ is H or a group of formula (CH₂) n -OSO₂R₅ and R₄ represents a group of formula (CH₂) n -OSO₂R₅, as defined above, can be prepared by a process comprising treating the corresponding mono or bis-hydroxyamino derivatives of formula 1 with a sulfonyl chloride of formula 5 Cl-SO₂R₅ 5 wherein R₅ is a residue as defined above; and, if desired, (ii) purifying the resulting anthracyline glycoside of formula 1 on a chromatographic column. Typically step (i) is conducted in an aprotic solvent, such as methylene chloride. Suitably it is conducted in the presence of a tertiary amine, such as triethylamine or pyridine. It is also possible to prepare anthracycline glycoside derivatives of general formula 1 in which R₂ is a hydroxy group from the corresponding mono or bis-hydroxyamino compounds of formula 1 in which the C-14 hydroxy group, R₂=OH is masked with an acid sensitive protecting group. Mild acidic treatment of the latter produces the desired sulfonylalkylamino anthracycline. Compounds of general formula 1 in which X is a halogen can be prepared by a process comprising (i) dissolving an anthracycline glycoside of formula 1 as defined above, wherein R₃ is H or a group of formula (CH₂) n -OSO₂R₅ and R₄ is a group of formula (CH₂) n -OSO₂R₅ wherein R₅ is alkyl or aryl group, in an aprotic solvent and reacting the resulting solution with a corresponding halide salt; and, if desired, (ii) purifying the resulting anthracycline glycoside on a chromatographic column; and/or, if desired, (iii) isolating the desired compound as the corresponding hydrohalide. When X is chlorine, the corresponding chlorine salt may be, for example, pyridinium chloride. The aprotic solvent is, for example, acetone. The reaction is preferably conducted at room temperature. Anthracycline glycosides of general formula 1 as defined above in which X is chlorine, R₂ is hydrogen, both A and B represent hydrogen or one of A or B represent the group -OSO₂R₅ wherein R₅ is as defined above can be prepared by a process comprising (i) treating the corresponding mono or bis-hydroxyalkyl amino derivative of formula 1 as defined above in dry pyridine with sulfonyl chloride of formula 5 ; and, if desired (ii) purifying the resulting anthracycline glycoside on a chromatographic column; and/or, if desired, (iii) isolating the desired compound as the corresponding hydrohalide. Typically step (i) is conducted in the dark, and at a temperature of 0°C under nitrogen. Suitably, it remains at 0°C for up 16 hrs. It is also possible to prepare anthracycline glycoside derivatives of general formula 1 in which R₂ is a hydroxy group from the corresponding mono or bis-hydroxyalkyl amino compounds of formula 1 in which the C-14 hydroxy group, R₂=OH, is masked with an acid sensitive protecting group. Mild acidic treatment of the latter produces the desired chloroalkyl amino anthracycline derivative. The compounds of the invention have activity as antitumor agents. A mammal, for example a human, can therefore be treated by a method comprising administrating thereto, by an oral or parenteral route, a pharmaceutically effective amount of an anthracycline glycoside of formula 1 as defined above or a pharmaceutically acceptable acid addition salt thereof. The invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and, as an active principle, an anthracycline glycoside of formula 1 , or a pharmaceutically acceptable salt thereof. Conventional carriers or diluents may be used. The composition may be formulated and administred, for example intravenously, in conventional manner. The following Examples illustrate the invention without limiting it. Example 1 Preparation of: N,N-bis(2-hydroxyethyl)doxorubicin [R₁=OCH₃, R₂=OH, A=OH, B=H, R₃=R₄=(CH₂)₂-OH] ( 1c ) A mixture of doxorubicin ( 3c ) (0.15g, 0.258mmole), methanol and methylene chloride (25ml, 1:1 by volume) was poured in a well stopped round bottomed flask, cooled at -40°C and added with ethylene oxide (15ml). The reaction mixture was slowly brought at room temperature and kept for two days in the dark. After that, the solvents were removed under reduced pressure and the residue purified by flash chromatography on silicic acid column using as eluting system a mixture of methylene chloride and methanol (80:20 by volume). The title compound 1f (0.1g, yield 60%) was converted into hydrochloride salt by treatment with methanolic anhydrous hydrochloric acid. TLC on Kieselgel Plate F₂₅₄ (Merck), eluting system: methylene chloride, methanol, acetic acid, water (80:20:7:3 by volume) R f =0.36. FD-MS: m/e 631 (M⁺) ¹HNMR (200 MHz, DMSO d₆) δ: 1.13(d, J=6.6Hz, 3H, CH ₃-5'); 1.53 (m, 1H, H -2'eq); 1.94 (m, 1H, H -2'ax); 2.16 (m, 2H, CH ₂-8); 2.65 (m, 4H, N( CH ₂CH₂OH)₂) 2.82 (m, 1H, H -3'); 2.98 (m, 2H, CH ₂-10); 3.33 (m, 4H, N(CH₂ CH ₂OH)₂); 3.57 (m, 1H, H -4'); 4.00 (s, 3H, OCH ₃-4); 4.02 ( dq, J=<2, 6.6Hz, 1H, H -5'); 4.35 (bm, 3H, OH -4', N(CH₂CH₂ OH )₂); 4.56 (m, 2H, CH ₂-14); 4.84 (t, J=6.2Hz, 1H, OH -14); 4.98 (m, 1H, H -7); 5.30 (m, 1H, H -1'); 5.40 (s, 1H, OH -9); 7.67 (m, 1H, H -2); 7.93 (m, 2H, H -1, H -3); 13.28 (bs, 1H, OH- 11); 14.06 (s, 1H, OH -6). Example 2 Preparation of: 4-demethoxy-N,N-bis(2-hydroxyethyl)-daunorubicin [R₁=R₂H, A=OH, B=H, R₃=R₄=(CH₂)₂-OH] ( 1d ) Free base 4-demethoxydaunorubicin ( 3b ) (0.23 g, 0.5 mmol) was converted into the title compound 1g following the procedure described in Example 1. Yield: 0.15 g as hydrochloride salt after treatment with methanolic anhydrous hydrochloric acid. TLC on Kieselgel Plate F₂₅₄ (Merck), eluting system: methylene chloride, methanol, acetic acid, water (80:20:7:3 by volume) R f =0.38. FD-MS: m/e 585 (M⁺) ¹HNMR (200 MHz, DMSO d₆) δ: 1.13 (d, J=6.6Hz, 3H, CH ₃-5'); 1.55 (m, 1H, H-2 'eq); 1.93 (m, 1H, H-2' ax); 2.17 (m, 2H, CH ₂-8); 2.26 (s, 3H, CO CH ₃); 2.65 [m, 4H, N( CH ₂CH₂OH)₂]; 2.82 (m, 1H, H-3' ); 2.99 (m, 2H, CH ₂-10); 3.30 [m, 4H, N(CH₂ CH ₂OH)₂]; 3.59 (m, 1H, H-4 '); 4.06 (dq, J=<2, 6.6Hz, 1H, H-5 '); 4.35 [bm, 3H, OH-4', N(CH₂CH₂ OH )₂]; 4.96 (m, 1H, H-7 ); 5.30 (m, 1H, OH-9 ); 8.00 (m, 2H, H-2, H-3 ); 8.30 (m, 2H, H-1 , H-4 ); 13.35 (s, 1H, OH-11 ); 13.55 (s, OH-6 ). Example 3 Preparation of N,N-bis(2-hydroxyethyl)daunorubicin [R₁=OCH₃, R₂=H, A=OH, B=H, R₃=R₄B(CH₂)₂-OH] ( 1b ) The title compound 1e was prepared from daunorubicin ( 3a ) following the same procedure described in Example 2. TLC on Kieselgel Plate F₂₅₄ (Merck), eluting system: methylene chloride, methanol, acetic acid, water (80:20:7:3 by volume) R f =0.28 FD-MS: m/e 615 (M⁺) Example 4 Preparation of 4-demethoxy-4'-O-methansulfonyl-N,N-bis(2-chloroethyl)daunorubicin. [R₁=R₂=H, A=OSO₂CH₃, B=H, R₃=R₄=(CH₂)₂-Cl) ( 1e ) 4-demethoxy-N,N-bis(2-hydroxyethyl)daunorubicin ( 1d ) (0.3 g, 0.5 mmol) prepared as described in Example 2, was dissolved with dry pyridine (15 ml) cooled at 0°C and added with methansulfonyl chloride (1 ml) and kept overnight at 0°C under stirring with a nitrogen blanket. After that, the reaction mixture was poured into water/ice and extracted with methylene chloride. The organic layer was washed with cold water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silicic acid column using as eluting system a mixture of methylene chloride and acetone (97:3 by volume) to give the title compound 1e (0.1g, yield 30%). TLC on Kieselgel Plate F₂₅₄ (Merck), eluting system: methylene chloride, acetone (20:1 by volume) R f =0.48. FD-MS: m/e 680 (M⁺) ¹HNMR (200 MHz, CDCl₃) δ: 1.35 (d, J=6.5 Hz, 3H, CH₃ -5'); 1.8 - 2.4 (m, 4H, H-2'eq , H-2'ax , H-8ax , H-8eq ); 2.42 (s, 3H, CH₃ -CO); 3.06 (t, 4H, J=7.1 Hz, CH ₂-N- CH ₂); 3.17 (m, 1H, H-3 '); 3.43 (m, 4H, 2x CH ₂-Cl); 4.16 (m, 1H, H-5' ); 4.40 (s, 1H, OH -9); 4.91 (s, 1H, H-4' ); 5.30 (dd, J=2.1, 3.7 Hz, 1H, H-7 ); 5.60 (d, 1H, J=3.4 Hz, H-1 '); 7.85 (m, 2H, H-2, H-3); 8.37 (m, 2H, H-1, H-4 ); 13.55 (s, 1H, OH-11 ); 13.64 (s, 1H, OH-6). Example 5 Biological Assays 4-demethoxy-4'-O-methansulfonyl-N,N-bis(2-chloroethyl)-daunorubicin (compound 1e ) was tested "in vitro" as inhibitor of colony growth on two human cell lines: LoVo (colon adenocarcinama) and LoVo/DX (colon adenocarcinoma resistant to Doxorubicin) in comparison with 4-demethoxy-daunorubicin ( 3b ) and Doxorubicin ( 3c ) (Table 1). When compared with 4-demethoxydaunorubicin and Doxorubicin a striking higher activity on the doxorubicin-resistant cell line was observed for compound 1e . Compound 1h was also evaluated "in vivo" against P388 murine Leukemias, sensitive (Table 2) and resistant to Doxorubicin (Johnson). When tested on resistant Leukemia, compound 1h showed high activity (Table 3).

Claims: An anthracycline glycoside of general formula 1: wherein R₁ is hydrogen or methoxy group; R₂ is hydrogen or hydroxy group, A and B both represent hydrogen or one of A and B is hydrogen and the other is hydroxy or a group of formula -OSO₂R₅ in which R₅ is C1-C4 alkyl or aryl optionally substituted by C1-C4 alkyl, nitro, amino, methoxy or halogen; R₃ is a hydrogen atom or a group of formula 2 and R₄ is a group of formula 2 -(CH₂) n -X 2 in which n is 2 and X is hydroxy group, a halogen or a group of formula -OSO₂R₅ in which R₅ is as defined above and with the proviso that R₂, X and A cannot be a hydroxy group at the same time when R₃ = H ; or a pharmaceutically acceptable salt thereof. A compound according to claim 1 wherein, in formula 2, X is chlorine. A compound according to claim 1 which is selected from: 4-demethoxy-N-(2-hydroxyethyl)daunorubicin [R₁=R₂=R₃=H, A=OH, B=H, R₄=(CH₂)₂-OH] N,N-bis(2-hydroxyethyl)daunorubicin [R₁=OCH₃, R₂=H, A=OH, B=H, R₃=R₄=(CH₂)₂-OH] N,N-bis(2-hydroxyethyl)doxorubicin [R₁=OCH₃, R₂=OH, A=OH, B=H, R₃=R₄=(CH₂)₂-OH] 4-demethoxy-N,N-bis(2-hydroxyethyl)daunorubicin [R₁=R₂=H, A=OH, B=H, R₃=R₄=(CH₂)₂-OH] 4-demethoxy-4'-O-methansulfonyl-N,N-bis(2-chloroethyl)-daunorubicin [R₁=R₂=H, A=OSO₂CH₃, B=H, R₃=R₄=(CH₂)₂-Cl] 4-demethoxy-N,N-bis(2-chloroethyl)daunorubicin [R₁=R₂=H, A=OH, B=H, R₃=R₄=(CH₂)₂-Cl] 4'-O-methansulfonyl-N,N-bis(2-chloroethyl)daunorubicin [R₁=OCH₃, R₂=H, A=OSO₂CH₃, B=H, R₃=R₄=(CH₂)₂-Cl] N,N-bis(2-chloroethyl)daunorubicin [R₁=OCH₃, R₂=H, A=OH, B=H, R₃=R₄=(CH₂)₂-Cl] 4'-epi-4'-O-methansulfonyl-N,N-bis(2-chloroethyl)daunorubicin [R₁=OCH₃, R₂=H, A=H, B=OSO₂CH₃, R₃=R₄=(CH₂)₂-Cl] 4'-epi-N,N-bis(2-chloroethyl)daunorubicin [R₁=OCH₃, R₂=H, A=H, B=OH, R₃=R₄=(CH₂)₂-Cl] 4-demethoxy-4'-epi-4'-O-methansulfonyl-N,N-bis(2-chloro-ethyl)daunorubicin [R₁=R₂=H, A=H, B=OSO₂CH₃, R₃=R₄=(CH₂)₂-Cl] and pharmaceutically acceptable salts thereof. A compound according to any of claims 1 to 3 which is a hydrochloride salt. A process for the preparation of an anthracycline glycoside of formula 1 as defined in claim 1 wherein one of R₃ is hydrogen or a group of formula 2 and R₄ is a group of formula 2 as defined in claim 1 wherein X is a hydroxy group, or a salt thereof; the process comprising: (i) reacting a compound of formula 3: wherein R₁ is hydrogen or a methoxy group and R₆ is hydrogen, a hydroxy group or an acid sensitive group, the compound of formula 3 being dissolved in a polar aprotic solvent, with an alkylating agent of formula 4 : X-(CH₂) n -Hal 4 wherein n is 2, X is hydroxy group and Hal is a halogen; and, if desired, (ii) purifying the resulting anthracycline glycosides of formula 1 on a chromatographic column; and/or, if desired, (iii) converting the anthracycline glycoside of formula 1 into a pharmaceutically acceptable acid addition salt thereof. A process according to claim 5 wherein the polar aprotic solvent is dimethylformamide or acetonitrile. A process according to claim 5 or 6 wherein step (i) is conducted at a temperature of from 20°C to 30°C for 4 to 24 hours. A process according to claim 5 or 6 wherein step (i) is conducted at a temperature of from 20°C to 30°C for 1 to 3 weeks. A process according to any of claims 5 to 8 wherein, in formula 4 , the halogen denoted by Hal is bromine or iodine. A process according to any of claims 5 to 9 wherein step (ii) is performed on silica gel column using, as eluent, methylene chloride methanol (80:20 v/v). A process according to any one of claims to 10 wherein, in step (iii), the anthracycline glycoside is converted into its hydrochloride salt by treatment with anhydrous hydrogen chloride. A process for the preparation of an anthracycline glycoside of formula 1 as defined in claim 1, wherein both R₃ and R₄ are a group of formula 2 as defined in claim 1 in which n is 2 and X is a hydroxy group, or a salt thereof; the process comprising: (i) reacting a compound of formula 3 , as defined in claim 5, with ethylene oxide; and, if desired, (ii) purifying the resulting anthracycline glycoside of formula 1 on a chromatographic column; and/or, if desired, (iii) converting the anthracycline glycoside of formula 1 into a pharmaceutically acceptable acid addition salt thereof. A process according to claim 12 wherein, in step (i), the compound of formula 3 is first dissolved in a methylene chloride:methanol solvent. A process according to claim 12 or 13 wherein step (i) is conducted in the dark at a starting temperature of -40°C, the temperature being subsequently increased to room temperature. A process according to claim 14 wherein the temperature is mantained at room temperature for up to 3 days. A process for the preparation of an anthracycline glycoside of formula 1 , or salt thereof, as defined in claim 1, wherein R₂ is hydrogen and R₃ is H or a group of formula (CH₂) n -OSO₂ R₅ and R₄ represents a group of formula (CH₂) n -OSO₂R₅ wherein R₅ is C1-C4 alkyl or aryl optionally substituted by C1-C4 alkyl, nitro, amino, methoxy or halogen, the process comprising (i) reacting an anthracycline glycoside of formula 1 , as defined in claim 1 wherein one or both of R₃ and R₄ is a group of formula 2 , in which X is a hydroxy group, with a sulfonyl chloride of formula 5 : Cl-SO₂-R₅ 5 wherein R₅ is as defined above; and, if desired, (ii) purifying the resulting anthracycline of formula 1 on chromatographic column. A process according to claim 16 wherein step (i) is conducted in an aprotic solvent in the presence of a tertiary amine. A process according to claim 17 wherein the tertiary amine is triethylamine or pyridine. A process for the preparation of an anthracycline glycoside of formula 1 , as defined in claim 1 wherein one or both of R₃ and R₄ represent a group of formula 2 wherein X is a chlorine atom, or a salt thereof the process comprising (i) dissolving an anthracycline glycoside of formula 1 as defined in claim 1 wherein R₃ is H or a group of formula (CH₂) n -OSO₂R₅ and R₄ is a group of formula (CH₂) n -OSO₂R₅, wherein R₅ is a C1-C4 alkyl or aryl optionally substituted, in an aprotic solvent and reacting the resulting solution with a halide salt and, if desired, (ii) purifying the resulting anthracycline glycoside on a chromatographic column; and/or, if desired, (iii) isolating the desired compound as the corresponding hydrohalide. A process according to claim 19 wherein, in step (i), the aprotic solvent is acetone or dimethylformamide. A process according to claim 19 or 20 wherein step (i) is performed at room temperature. A process according to any one of claims 19 to 21 wherein, in step (i), the halide salt is n-tetrabytylammonium chloride. A process for the preparation of an anthracycline glycoside of formula 1 as defined in claim 1 wherein one or both of R₃ and R₄ represent a group of formula 2 wherein X is a chlorine atom and both A and B represent hydrogen or one of A or B represents a group of formula -OSO₂R₅ wherein R₅ is C1-C4 alkyl or aryl optionally substituted, or a salt thereof the process comprising (i) dissolving an anthracycline glycoside of formula 1 as defined in claim 1 wherein one or both of R₃ and R₄ is a group of formula 2 as defined in claim 1 in which X is hydroxy group, in dry pyridine and reacting the resulting solution with a sulfonyl chloride of formula 5 : Cl-SO₂R₅ 5 wherein R₅ is as defined above; and, if desired (ii) purifying the resulting anthracycline glycoside on a chromatographic column; and/or, if desired, (iii) isolating the desired compound as the corresponding hydrohalide. A process according to claim 23 wherein, in step (i), the compound of formula 1 is first dissolved in dry pyridine. A process according to claim 23 or 24 wherein step (i) is conducted in the dark at 0°C. A process according to claim 25 wherein the temperature is maintained at 0°C for up 16 hours. A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and, as an active principle, an anthracycline glycoside of formula 1 , or a pharmaceutically acceptable salt thereof, as defined in claim 1. An anthracycline glycoside of formula 1 or a pharmaceutically acceptable salt thereof, as defined in claim 1, for use in a method of treatment of the human or animal body by therapy. An anthracycline glycoside or salt thereof, according to claim 28, for use as an anti-tumor agent.

Inventors: BARGIOTTI ALBERTO, CARUSO MICHELE, FAIARDI DANIELLA, MONGELLI NICOLA, SUARATO ANTONINO, BARGIOTTI, ALBERTO, CARUSO, MICHELE, FAIARDI, DANIELLA, MONGELLI, NICOLA, SUARATO, ANTONINO
Applicants: PHARMACIA SPA, PHARMACIA S.P.A.
Application year: 1992
Main classification: C07H15
IPC codes: A61P35, A61K31, C07H15