2-acyloxy-4-morpholinyl anthracycline

Abstract: Anthracycline glycosides of formula 1: wherein R₁ is hydrogen or methoxy group; R₂ is hydrogen or hydroxy; both R₃ and R₄ represent hydrogen or one of R₃ and R₄ is hydroxy and the other of R₃ and R₄ a represents hydrogen; R₅ represents hydrogen atom or an acyl residue - COX in which X is a C₁-C₈ linear or branched alkyl chain, an aryl, an aryl lower alkyl, or a 5- or 6-membered heteroaromatic group are anti-tumour agents.

Description: The invention relates to a new anthracycline glycoside, to process for its preparation and to pharmaceutical compositions containing it. A new anthracycline glycoside antibiotic in which the 3'-nitrogen atom of the sugar moiety is enclosed in a 4-morpholino ring bearing an acyloxy substituent at position C-2 has now been found. The present invention therefore provides an anthracycline glycoside of formula 1 . wherein R₁ is a methoxy group; R₂ is hydroxy; R₄ represents hydrogen and R₃ represents a hydroxy group; R₅ represents an acyl residue -COX in which X is a phenyl group or a pharmaceutically acceptable salt thereof. Particularly preferred salts of the compound of the present invention are pharmaceutically acceptable addition salts such as the hydrochloride. The claimed compound of formula I is: (1a) 3'-deamino-3'-(2-benzoyloxy-4-morpholinyl)doxorubicin (R₁=OCH₃, R₂=R₃=OH, R₄=H, R₅=COC₆H₅), and its hydrochloride. The compound of formula 1 may be prepared by the formation of a substituted morpholinyl ring at C-3' on the sugar moiety of the anthracyclines through a reductive alkylation, based on using a dialdehyde of the general formula 2 , wherein R₅ has the same meaning as above reported. Accordingly, the present invention provides a process for the preparation of an anthracycline glycoside of formula 1 as above defined or a pharmaceutically acceptable salt thereof, which process consists of reacting an anthracycline of formula 3 , wherein R₁, R₂, R₃ and R₄ have the same meaning as above defined, or a salt thereof, with an aldehyde of formula 2 in the presence of a reducing agent such as an alkali metal cyanoborohydride and, if desired, converting the compound of formula 1 thus obtained into a pharmaceutically acceptable salt. The starting anthracycline of formula 3 is doxorubicin (3a: R₁=OCH₃, R₂=R₃=OH, R₄=H). The reductive alkylation is typically carried using an excess of the dialdehyde 2 . The reductive alkylation is generally carried out in a mixed aqueous polar organic medium, such as water-acetonitrile, generally at pH of about 6.5 in the presence of an alkali metal cyanoborohydride e.g. sodium or potassium cyanoborohydride. The reaction can be usually completed in two hours at room temperature. The desired product is isolated from the reaction mixture by solvent extraction and purified by column chromatography and may be obtained as its hydrochloride by treatment with methanolic hydrogen chloride. A dialdehyde of formula 2 is prepared via a Malaprade reaction on the 1-acyl derivative of a sugar, prepared as described in J.Org.Chem., 28 2999 (1963) and having formula 2' . wherein R₅ has the same meaning above reported. As a further aspect, the invention provides pharmaceutical compositions comprising the anthracycline glycoside of formula 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier. Conventional carriers and diluents may be used. The compositions may be formulated and administered in conventional manner. The compound of the invention is useful in methods of treatment of the human and animal body by therapy. It is useful as an anti-tumour agent. A therapeutically effective amount is administered to a patient having a tumour to ameliorate or improve the condition of the patient. An amount sufficient to inhibit the growth of the tumour may be administered. The following Example illustrates the invention. Example 1 Preparation of 1-benzoyloxy-2,2'-oxydiacetaldehyde ( 2 : R₅=COC₆H₅) 1-O-benzoyl-β-L-arabinopyranoside ( 2' : R₅=COC₆H₅) (0.8 g, 3.14 mmole), prepared as described in J.Org.Chem., 28 2999 (1963), was dissolved in water (50 ml) and treated with sodium periodate (1.4 g, 6.3 mmole) at 0°C for two hours. Barium chloride was added and the mixture was brought to pH 7 with sodium carbonate. The mixture was filtered, concentrated under reduced pressure and the title compound 2 was extracted with acetonitrile and used for the next step without further purification. TLC on Kieselgel Plate F₂₅₄ (Merck), eluting system methylene chloride/methanol (6/1 by volume) R f =0.84. Example 2 Preparation of 3'-deamino-3'-(2-benzoyloxy-4-morpholinyl) doxorubicin ( 1a : R₁=OCH₃, R₂=R₃=OH, R₄=H, R₅=COC₆H₅) To a solution of doxorubicin hydrochloride ( 3 , 0.3 g, 0.52 mmole) dissolved in a mixture of water (5 ml) and acetonitrile (13 ml) was added the solution of dialdehyde 2 prepared as described in Example 1. The pH was adjusted to 7.5 with triethylamine. After 15 minutes the pH was brought to 5.5 and the stirred mixture was treated with sodium cyanoborohydride (15mg) dissolved in water (1 ml). After seven minutes the mixture was worked up by dilution with water and extraction with methylene chloride. The organic phase was concentrated to small volume and purified on silicic acid column using as eluting system a mixture of methylene chloride/methanol (97/3 by volume) to give the title compound 1a (0.15 g) as the hydrochloride upon treatment with methanolic anhydrous hydrogen chloride. TLC on Kieselgel Plate F₂₅₄ (Merck), eluting system methylene chloride/methanol (10/1 by volume) Rf=0.63. FD-MS: m/z=733. ¹HNMR (200 MHz, CDCl₃) δ: 1.36 (d, J=6.5Hz, 3H, 5'- CH ₃); 1.80 (m, 2H, 2'- CH ₂); 2.16 (dd, J=4.1, 14.7Hz, 8- Hax ); 2.37 (dd, J=1.0, 14.7Hz, 1H, 8- Heq ); 2.4-2.7 (m, 4H, 3'- H , N CH ₂CH₂0, N CH (H)CH-O); 2.8-3.1 (m, 1H, NCH( H )-CH-O); 3.04 (d, J=19.0Hz, 1H, 10- Hax ); 3.28 (dd, J=1.0, 19.OHz, 1H, 10- Heq ); 3.68 (m, 1H, 4'- H ); 3.7-4.1 (m, 3H, 5'- H , NCH₂ CH ₂O); 4.07 (s, 3H, 4-O CH ₃; 4.68 (s, 1H, 9- OH ); 4.74 (m, 2H, CH ₂OH); 5.30 (m, 1H, 7- H ); 5.57 (m, 1H, 1'- H ); 6.19 (m, 1H, NCH₂- CH -O); 7.4-8.0 (m, 8H, Ph , 1- H , 2- H , 3- H ); 13.26 (s,1H 11- OH ); 13.98 (s, 1H, 6- OH ).

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, NL An anthracycline glycoside of formula 1: wherein R₁ is a methoxy group; R₂ is hydroxy; R₄ represents hydrogen and R₃ is hydroxy, R₅ represents an acyl residue -COX in which X is a phenyl group; or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is 3'-deamino-3'-(2-benzoyloxy-4-morpholinyl)doxorubicin or its hydrochloride. A process for preparing a compound according to claim 1, which process consists of (i) reacting an anthracycline glycoside of formula 3 ; wherein R₁, R₂, R₃ and R₄ are as defined in claim 1, or a salt thereof, with an aldehyde of formula 2 wherein R₅ is as defined in claim 1, in the presence of a reducing agent and, if desired, converting the compound of formula 1 thus obtained to a pharmaceutically acceptable salt. A process, according to to claim 3, which is carried out in a mixed aqueous polar organic medium, at pH of about 6.5, in the presence of an alkali metal cyanoborohydride as reducing agent, for two hours, at room temperature, to provide a glycoside of formula 1 as defined in claim 1 as a free base and which comprises treating the product thus obtained with methanolic hydrogen chloride and isolating the compound according to claim 1 as its hydrochloride. A pharmaceutical composition comprising an anthracycline glycoside of formula 1 , as defined in claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier. An anthracycline glycoside of formula 1 as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy. A compound according to claim 6 for use as an anti-tumour agent. Claims for the following Contracting States : ES, GR A process for the preparation of an anthracycline glycoside of formula 1: wherein R₁ is a methoxy group; R₂ is hydroxy; R₄ represents hydrogen and R₃ represents a hydroxy group; R₅ represents a -COX acyl group and X represents a phenyl group, which process consists of (i) reacting an antracycline glycoside of formula 3 ; wherein R₁, R₂, R₃ and R₄ are as above defined or a salt thereof, with an aldehyde of formula 2 wherein R₅ is as defined above, in the presence of a reducing agent and, if desired, converting the compound of formula 1 thus obtained to a pharmaceutically acceptable salt. A process according to claim 1 which is carried out in a mixed aqueous polar organic medium, at pH of about 6.5, in the presence of an alkali metal cyanoborohydride as reducing agent, for two hours, at room temperature, to provide a glycoside of formula 1 as defined in claim 1 as a free base and which comprises treating the product thus obtained with methanolic hydrogen chloride and isolating the compound according to claim 1 as its hydrochloride.

Inventors: BARGIOTTI ALBERTO, FAIARDI DANIELA, SUARATO ANTONINO, BARGIOTTI, ALBERTO, FAIARDI, DANIELA, SUARATO, ANTONINO
Applicants: ERBA CARLO SPA, FARMITALIA CARLO ERBA S.R.L.
Application year: 1991
Main classification: C07H15
IPC codes: A61K31, C07H19, A61P35, C07H15