DE3520469A1 - Anthracyclines, process for their preparation, intermediates and pharmaceutical formulation - Google Patents

Abstract

A class of antitumour anthracycline glycosides of the general formula (I) and (II) is described: <IMAGE> in which R<1> = H, OCH3 and R<2> = H, OH. The starting material which is used represents 4'-epidaunorubicin or its 4-demethoxy analogue, which are reacted after protection of the amino group in the sugar component as benzophenone Schiff's base with trifluoromethanesulphonic anhydride to obtain the corresponding 4'-epi-4'-O-trifluoromethanesulphonates from which, after treatment with n-tetrabutylammonium fluoride and subsequent mild acid hydrolysis of the N-protective group, the daunorubicin derivatives of the formula (I) and (II) are obtained as a mixture of the free bases. Chromatography on a buffered silica gel column allows separation of compounds (I) and (II) which are finally isolated as hydrochlorides and, where appropriate, converted into their doxorubicin analogues via the corresponding 14-bromo derivatives and subsequent hydrolysis with aqueous sodium formate.

Description

New anthracyclines, processes for their preparation, intermediate compounds and pharmaceutical preparation The invention relates to anthracycline glycoside derivatives, a process for their manufacture and pharmaceutical preparations containing them contain, as well as intermediate compounds, which are suitable for the preparation of the glycosides are.

The invention provides anthracycline glycosides of the general formula (I) or (II): wherein RI represents a hydrogen atom or a methoxy group and R2 represents a hydrogen atom or a hydroxyl group, as well as pharmaceutically acceptable acid addition salts thereof.

Suitable acid addition salts include salts of inorganic acids, such as hydrohalic acids, especially hydrochloric acid, and salts of the organic Carboxylic acids and sulfonic acids, especially acetic acid.

The present invention thus provides daunorubicin and doxorubicin analogs which have a fluorine atom in the sugar component; In particular, the C-7 OH of the natural anthracyclinones, daunomycinones and adriamycinones, and of the fully synthetic 4-demethoxydaunomycinones and 4-demethoxyadriamycinones, are glycosidic to the new sugars 2,3,4,6-tetradesoxy-3-amino-4-fluoro-L -arabinohexopyranose (III) and 2,3,5,6-tetradeoxy-3-amino-5-fluoro-L-arabinohexofuranose or 2,3,5,6-tetradeoxy-3-amino-5-fluoro-D-xylohexofuranose ( IV) bound. The above nomenclatures for the sugar (IV) arise from the uncertainty with regard to the absolute configuration of the fluorine-bearing carbon atom.

The present invention also provides the intermediate compounds (III) and (IV), as well as the compounds (2) to (7), which are listed in the reaction scheme and which can be used to prepare compounds of the general formulas (I) and (II) suitable. The present invention further comprises a process for the preparation of a compound of the formula (I) or (II) which is characterized by protecting the amino group of a compound of the formula (V) wherein R1 has the meaning given in formulas (I) and (II), converting the 4'-hydroxy group into a fluorine substituent, removing the amino protective group and - if necessary - converting the 14-methyl group into a hydroxymethyl group and, if necessary, formation a pharmaceutically acceptable acid addition salt. The process according to the invention is summarized in the following reaction scheme: Reaction scheme The starting materials for the preparation of the new anthracyclines 6-9a, b are: 4'-epidaunorubicin (la) [see F. Arcamone et al, J. Med. Chem. 18, 703 (1975)] and 4-demethoxy-4 ' -epidaunorubicin (lb) [see A. Di Marco et al, Cancer Treat. Rep. 62, 375 (1978)].

To form the fluorine derivatives, the amino group is on the sugar component Protected as a benzophenone Schiff base 2a, b, followed by treatment with trifluoromethanesulfonic anhydride in anhydrous methylene dichloride and in the presence of an organic base such as dry Pyridine, the corresponding 4'-epi-4'-O-trifluoromethanesulfonate 3a, b in almost quantitative Yield results.

The reaction of 3a, b with a fluoride salt in an aprotic Solvent leads to a mixture of products 4-5a, b.

Obtained by mild acid hydrolysis of the N-diphenylmethylene protecting group the new daunorubicin derivatives 6-7a, b, which are separated by chromatography.

The conversion of 6-7a, b to the corresponding doxo analogs 8-9a, b as is done in U.S. Patent 3,803,124 for the conversion of daunorubicin to doxorubicin about the 14-bromo derivative is described. The glycosides 6a (R1 = OCH3), 6b (R1 = H), 7a (R1 = OCH3), 7b (R1 = H) and the corresponding doxo derivatives: 8a (R1 = OCH3), 8b (R1 = H), 9a (R1 = OCH3) and 9b (R1 = H) are valuable anti-tumor agents represent.

The invention further comprises a pharmaceutical preparation which a general anthracycline glycoside Formula (I) or (II) or a pharmaceutically acceptable acid addition salt thereof as an active component together with a pharmaceutically acceptable carrier therefor.

The preparations can be carried out using conventional carriers can be made in the usual way.

The compounds of formulas (I) and (II) can be used therapeutically effective amounts are administered in conventional manner and in usual doses, as is the case with the use of daunorubicin and doxorubicin.

The compounds of formulas (I) and (II) are suitable for therapeutic use Treatment of the human or animal body. In particular, make the connections (I) and (II) are valuable anti-tumor agents.

The following examples are intended to explain the invention in more detail without to restrict this.

EXAMPLE 1 Preparation of 4'-Epi-N- (diphenylmethylene) daunorubicin (2a) A solution of 2 g of 4'-Epidaunorubicin (la) in 80 ml of dichloromethane was with Treated 1 g of benzophenone imine at 350C. After 4 hours the solvent was im Vacuum removed and the residue first triturated with hexane, around Eliminate traces of benzophenone imine, then from diethyl ether / hexane to obtain crystallized from 2a.

Melting point: 190 to 195po, FD-MS 691 (M +).

Rf 0.35 on TLC silica gel F 254 (Merck) using the solvent mixture Dichloromethane / acetone (8: 2 V / V) as eluent.

EXAMPLE 2 Preparation of 4'-Epi-4'-O-trifluoromethanesulfonate-N- (diphenylmethylene) daunorubicin (3a) To a solution of 2 g of 4'-epi-N- (diphenylmethylene) daunorubicin (2a) in 40 ml of anhydrous dichloromethane and 0.3 ml of dry pyridine, which at -100C under While maintaining nitrogen, a solution of 0.6 ml of trifluoromethanesulfonic anhydride became added in 10 ml of anhydrous dichloromethane. After 30 minutes the reaction mixture became diluted with dichloromethane and diluted with water, cold 0.1 N HC1, cold aqueous 5 % NaHCO3 and water.

The organic phase, dried over anhydrous sodium sulfate Was filtered off and the solvent removed in vacuo to give 3a became.

Rf 0.6 on TLC silica gel F 254 (Merck) using the solvent mixture Dichloromethane / acetone (95: 5 V / V) as eluent.

PMR (200 MHz, CDC13): 1.39 (d, J = 6.2 Hz, 3H, CH3), 1.79 (dd, J = 5.3, 13.6 Hz, 1H, H2 'eq); 2.07-2.2 (m, 1H, H2'ax); 2.34 (s, 3H, COCH3); 3.86 (ddd, J = 5.3, 9.5, 12.0 Hz, 1H, H-3 '); 3.96 (dq, J = 6.2, 9.5 Hz, 1H, H-5 '); 4.07 (s, 3H, OCH3), 4.97 (dd, J = 9.5, 9.5 Hz, 1H, H-4 '); 5.26 (dd, J = 2.4, 3.6 Hz, 1H, H-7); 5.46 (dd, J = <1, 3.5 Hz, 1H, H-1 '); 7.00-7.63 (m, 1OH, (Ph) 2C = N).

EXAMPLE 3 Preparation of 2 ', 3', 4 ', 6'-tetradeoxy-3'-amino-4'-fluoro-L-arabino-hexopyranosyl-daunorubicin (6a) and 2 ', 3 (, 5' tetradeoxy-3'-amino-5'-fluoro-hexofuranosyl-daunorubicin (7a) To 1.5 g of 4'-Epi-4'-O-trifluoromethanesulfonate-N- (diphenylmethylene) daunorubicin (3a), dissolved in 8 ml of anhydrous dichloromethane, became a solution of anhydrous n-tetrabutylammonium fluoride (2 g) in 8 ml of anhydrous acetonitrile was added. The reaction mixture was taking Nitrogen held at OOC and stirring for 24 hours, then in 500 ml of ethyl acetate poured. The organic phase was washed with water over anhydrous sodium sulfate dried, filtered off and the solvent removed in vacuo.

The crude mixture containing 4a and 5a was made with 0.1 N HCl treated in methanol for 1 hour at room temperature, then diluted with water and extracted with dichloromethane to eliminate the aglycones.

The separated aqueous phase was adjusted to pH 8 with 0.1 N NaOH and extracted with dichloromethane. The organic phase was separated off with water washed, dried over anhydrous sodium sulfate and reduced in vacuo to a small Volume evaporated. The mixture was chromatographed on a silica gel column, which was buffered to pH 7 with 0.1 M sodium phosphate using dichloromethane-ethanol separated as the eluent, the fluorine derivative 6a, isolated as the free base (Melting point 2159C, FD-MS 529 (M +)): Rf 0.31 on TLC silica gel F 254 (Merck) using the solvent mixture dichloromethane / ethanol (9: 1 V / V) as the eluent.

PMR (200 MHz, Cd13): 1.34 (dd, 3H, 6.2 Hz); 1.59 (ddd, 1H, J = 4.0, 13.0, 13.0 Hz, H-2'ax); 2.03 (dddd, J = <1, 5.0, 5.0, 13.0 Hz, 1H, H-2'eq); 2.41 (s, 3H, COCH3), 3.1-3.3 (m, 1H, H-3 '); 3.85 (ddd, J = 50.0, 9.4, 9.4 Hz, 1H, H-4 '); 3.9-4.1 (m, 1H, H-5 '); 4.07 (s, 3H, OCH3); 5.27 (dd, J = 2.2, 4 Hz, 1H, H-7); 5.44 (ddd, J = (1, 3.9, 4.0 Hz, 1H, and the fluorine derivative 7a as free Base (melting point 2100C with decomposition, FD-MS 529 Rf 0.20 on TLC silica gel 254 (Merck) using the solvent mixture dichloromethane / ethanol (9: 1 V / V) as an eluent.

PMR (200 MHz, CDC13): 1.45 (dd, J = 6.4, 24.8 Hz, 3H, CH3CHF); 1.83-1.96 (m, 1H, H-2 '); 2.17 (ddb, J = 6.0, 13.0 Hz, 1H, H-2 '); 2.39 (s, 3H, COCH3); 3.57-3.82 (m, 2H, H-3 ', H-4'); 4.06 - (s, 3H, OCH3); 4.78 (ddq, J = 50.0, 6.4, 6.4 Hz, 1H, H-5 '), 5.17 (dd, J = 2.9, 4.0 Hz, 1H, H-7); 5.68 (bd, J = 5.5 Hz, 1H, H-1 ').

The free amino bases 6a and 7a were treated with methanolic HC1 converted into the corresponding hydrochloride.

EXAMPLE 4 Preparation of 2 ', 3', 4 ', 6'-tetradeoxy-3'-amino-4'-fluoro-L-arabinohexopyranosyl-doxorubicin (8a) A solution of 6a in a mixture of methanol and dioxane, as described in US Pat 3 803 124 is described, was with bromine to obtain the 14-bromo derivative treated, which after treatment with sodium formate led to compound 8a, which was converted into the hydrochloride by means of methanolic HC1.

EXAMPLE 5 Preparation of 21,3 ', 5', 6'-tetradeoxy-3'-amino-5'-fluoro-hexofuranosyl-doxorubicin (9a) Following the procedure outlined in Example 4, 7a converted into the doxorubicin analog and by treatment with methanolic HC1 isolated as the hydrochloride.

EXAMPLE 6 Preparation of 4-Demethoxy-4'-epi-4'-O-trifluoromethanesulfonate-N- (Diphenylmethylene) daunorubicin (3b) The title compound was prepared starting from 4-demethoxy-4'-epi-daunorubicin (lb) via its N-diphenylmethylene derivative (2b), which was prepared as described in Example 1.

Treatment of 2b with trifluoromethanesulfonic anhydride in anhydrous Dichloromethane and dry pyridine gave, after removal of the solvent, 4-demethoxy-4'-epi- 4'-O-trifluoromethanesulfonate-N-t-diphenylmethylene) daunorubicin (3b).

EXAMPLE 7 Preparation of 4-demethoxy-2 ', 3', 4'6'-tetradeoxy-3'-amino-4'-fluoro-L-arabino-hexopyranosyl-daunorubicin (6b) and 4-demethoxy-2 ', 3', 5 ', 6'-tetradeoxy-3'-amino-5'-fluorohexofuranosyl-daunorubicin (7b) Compound 3b was converted into its fluoro derivatives 6b and 7b by treatment with anhydrous n-Tetrabutylammonium fluoride in a mixture of anhydrous dichloromethane and dry acetonitrile as described in Example 3, converted.

Acid hydrolysis of the mixture revealed, after chromatography on a Silica gel column buffered to pH 7 using dichloromethane / ethanol as eluent, the pure 4-demethoxy-2 ', 3', 4 ', 6'-tetradeoxy-3'-amino-4'-fluoro-L-arabino-hexopyranosyl-daunorubicin (6b) and 4-demethoxy-2 ', 3', 5 ', 6'-tetradeoxy-3'-amino-5'-fluoro-hexofuranosyl-daunorubicin (7b).

Both compounds were treated with methanolic HC1 converted into the hydrochloride derivatives.

EXAMPLE 8 Preparation of 4-demethoxy-2 ', 3', 4 ', 6'-tetradeoxy-3'-amino-4'-fluoro-L-arabino-hexopyranosyl-doxorubicin (8b) The compound named in the title was obtained from compound 6b according to the method described in US Pat 3,803,124 described process and prepared by treatment with methanolic HC1 converted into the hydrochloride.

EXAMPLE 9 Preparation of 4-demethoxy-2 ', 3', 5 ', 6'-tetradeoxy-3'-amino-5' -fluoro-hexofuranosyl-doxorubicin (9b) The compound named in the title was made from of compound 7b by the process as described in US Pat. No. 3,803,124, and converted into the hydrochloride by treatment with methanolic HC1.

Claims (21)

New anthracyclines, processes for their production, intermediate compounds and pharmaceutical preparation. PATENT CLAIMS 1. Antitumor anthracycline glycoside of the general formula (I) or (II) wherein R1 represents a hydrogen atom or a methoxy group and R2 represents a hydrogen atom or a hydroxy group, or a pharmaceutically acceptable acid addition salt thereof. 2. 2 ', 3', 4 ', 6'-tetradeoxy-3'-amino-4'-fluoro-L-arabinohexopyranosyl-daunorubicin or a pharmaceutically acceptable acid addition salt thereof. 3. 4-Demethoxy-2 ', 3', 4 ', 6'-tetradeoxy-3'-amino-4'-fluoro-L-hexopyranosyl-daunorubicin or a pharmaceutically acceptable acid addition salt thereof. 4. 2 ', 3', 4 ', 6'-tetradeoxy-3'-amino-4'-fluoro-L-arabinohexopyranosyl-doxorubicin or a pharmaceutically acceptable acid addition compound thereof. 5. 4-Demethoxy-2 ', 3', 4 ', 6'-tetradeoxy-3'-amino-4'-fluoro-L-arabino-hexopyranosyl-doxorubicin or a pharmaceutically acceptable acid addition salt thereof. 6.. ' 2 ', 3', 5 ', 6' -tetradeoxy-3 '-amino-5' -fluoro-hexofuranosyl-daunorubicin or a pharmaceutically acceptable acid addition salt thereof. 7. 4-Demethoxy-2 ', 3', 5 ', 6'-tetradeoxy-3'-amino-5'-fluoro-hexofuranosyl-daunorubicin or a pharmaceutically acceptable acid addition salt thereof. 8. 2 ', 3l, 5', 6'-tetradeoxy-3'-amino-5'-fluoro-hexofuranosyl-doxorubicin or a pharmaceutically acceptable acid addition salt thereof. 9. 4-Demethoxy-2 ', 3', 5 ', 6'-tetradeoxy-3'-amino-5'-fluoro-hexofuranosyl-doxorubicin or a pharmaceutically acceptable acid addition salt thereof. 10. A process for the preparation of a compound of the formula (I) or (II), characterized by protecting the amino group of a compound of the formula (V) wherein R1 has the meaning given in relation to the formula (I) and (II), converting the 4'-hydroxy group into a fluorine substituent, removing the amino protective group and - if necessary - converting the 14-methyl group into a hydroxymethyl group, and optionally subsequent formation of a pharmaceutically acceptable acid addition salt. 11. A process for the preparation of a glycosidic compound of general formula (I) or (II) according to claim 1, wherein R is a hydrogen atom or represents a methoxy group and R2 represents a hydrogen atom or a hydroxyl group means that it is noted that 4'-epi-daunorubicin or its 4-demethoxy analog, dissolved in dichloromethane, with benzophenone imine at one temperature are implemented by 350C, while obtaining their corresponding 4'-Epi-N- (diphenylmethylene) derivatives, the following in anhydrous dichloromethane and in the presence of dry pyridine at a temperature of -100C under nitrogen with trifluoromethanesulfonic anhydride treated to obtain the corresponding 4'-Epi-N- (diphenylmethylene) -4'-O-trifluoromethanesulfonate, those in anhydrous dichloromethane at a temperature of OOC and under nitrogen 24 hours are reacted with anhydrous n-tetrabutylammonium fluoride, wherein on the subsequent shift of a group made up of trifluoromethanesulfonate releases a mixture of N-protected derivatives of the formula (I) and (II) (R1 = H, OCH3; R2 = H) is obtained, treating said mixture by means of mild acid hydrolysis, separating the free glycosidic bases by chromatography on a buffered silica gel column and Isolate the same as the corresponding hydrochloride - if so desired - finally via their 14-bromine derivatives and subsequent hydrolysis with Sodium formate into the corresponding doxorubicin analogs of the formula (I) and (II) (R1 = H, OCH3; R2 = OH) which are well converted into the form of the corresponding Hydrochloride can be isolated. 12. Pharmaceutical preparation, thereby g e k e n n n -z e i c h n e t that the active ingredient is an anthracycline glycoside according to one or more of claims 1 to 5 or with the aid of a method as in one or several of claims 10 and 11 is described, was produced together with a pharmaceutically acceptable carrier therefor. 13. Compounds of the formula (I) or (II) as defined in claim 1 are for use in the therapeutic treatment of the human or animal Body. 14. A compound or salt thereof according to claim 12 for treatment of a tumor. 15. A method for producing a compound as claimed in claim 1 and is essentially described in the following examples. 16. A compound which is suitable as an intermediate compound for the preparation of a compound according to claim 1 and which has the following formula (V) wherein R³ is selected from: where R4 is an amino or a protected amino group and R5 is a fluorine, hydroxy or trifluoromethylsulfonyloxy group. 17. A compound according to claim 16, characterized in that g e k e n n -z e i c h n e t that R4 is amine. 18. A compound according to claim 16, characterized in that it k e n n -z e i c h n e t that R4 is a diphenylmethyleneimino group. 19. Compound according to one or more of claims 16 to 18, by noting that R5 means fluorine. 20. A compound useful as an intermediate for the preparation of a compound of the formula (I) as defined in claim 1 and having the following formula (III) 21. A compound which is suitable as an intermediate compound for the preparation of a compound of the formula (II) as defined in claim 1 and which has the formula (IV)