Known examples of the antibiotics of anthracycline type include daunomycin (daunorubicin; U.S. Pat. No. 3,616,242) and adriamycin (doxorubicin; U.S. Pat. No. 3,590,028), which both may be obtained from the culture broth of a microorganism of actinomycetes. These two compounds exhibit a wide range of antitumor spectra against a variety of experimental tumors and have been used as a chemotherapeutic agent in the clinic practice. Daunomycin and adriamycin are the compound of the general formula ##STR1## wherein R is a hydrogen atom or a hydroxyl group. Daunomycin (the compound of the formula (a) above where R is the hydrogen atom) and adriamycin (the compound of the formula (a) where R is the hydroxyl group) can show a fairly high antitumor activity against various kinds of tumors. However, these two compounds are not necessarily an antitumor agent which are completely satisfactory. Thus, daunomycin and adriamycin have been shown to exhibit wide antitumor spectra against the experimental tumors and also have widely been used as a valuable agent for the therapeutic treatment of tumors in the clinic practice. On the other hand, it is known that daunomycin and adriamycin can bring about heavy adverse side-effects that they can cause cardiac toxicity and a decrease in the number of leukocytes and falling-off of the hair in the patients who received the administration of these agents. It is reported that the glycoside linkage between the daunosaminyl group of the formula ##STR2## and the hydroxyl group at the 7-position of daunomycinone or adriamycinone is likely to be broken in vivo by the hydrolysis, and that the moiety of the aglycon as formed by the in vivo hydrolysis, namely the daunomycinone or adriamycinone shows a higher cardiac toxicity than the daunomycin or adriamycin itself.
In the past, therefore, some researches were already made in an attempt to provide new daunomycinrelated compounds which possess a higher anticancer activity and a lower toxicity than daunomycin and adriamycin. For instance, studies for discovering and producing new daumonycin-analogous compounds by fermentative methods, semi-synthetic methods, total synthetic methods or enzymatical conversion methods were conducted. Such particular compounds previously proposed include, for example, aclacinomycins A and B (F. Arcoamone "Topics in Antibiotic Chemistry" Vol. 2, pp. 102-279, published from Elis Horwood Limited, U.S.A.; and U.S. Pat. No. 3,988,315), 4'-O-tetrahydropyranyladriamycin (West Germany Patent No. 2,831,579 and Japanese patent publication No. 47194/81) and N-mono-benzyl- or N-di-benzyl-adriamycin (U.S. Pat. No. 4,177,264).
Further, the specification of U.S. Pat. No. 4,427,664 of Horton et al describes a chemical structure of compounds represented by the general formula ##STR3## wherein R.sup.1 is a hydrogen atom and R.sup.2 is a methoxy group; or R.sup.1 is a hydroxyl group and R.sup.2 is a methoxy group; or R.sup.1 and R.sup.2 are each a hydrogen atom; or R.sup.1 is a hydrogen and R.sup.2 is a hydroxyl group, and X is an iodine, chlorine, bromine or fluorine atom and Y is a hydroxyl group or acetoxy group, and which compounds are of such structure that an aglycon selected from the group consisting of daunomycinone, desmethoxydaunomycinone, adriamycinone and carminomycinone is linked through the oxygen atom at the 7-position thereof to the 1'-position of a sugar of a 2'-halo-.alpha.-L-hexopyranose of the .alpha.-L-manno type or .alpha.-L-talo type. The method of producing a compound of the above formula (b) which is described in the specification of U.S. Pat. No. 4,427,664 is the method wherein an aglycon such as daunomycinone and a glycal, for example, 3,4-di-O-acetyl-L-rhamnal or 3,4-di-O-acetyl-L-fucal, which corresponds to the sugar to be linked to said aglycon are dissolved together in substantially equimolar proportions in a mixture of aprotic organic solvents consisting of anhydrous acetonitrile and tetrahydrofuran and wherein to the resulting solution is then added an iodination agent such as N-iodosuccinimide together with a solvating agent such as dichloromethane at a low reaction temperature so that the aglycon reacts with the said glycal in such way that the glycal used is linked to the 7-hydroxyl group of the aglycon with accompanying by an alkoxyhalogenation of the glycal. According to this method of Horton et al, it happens as described in the specification of said U.S. Pat. No. 4,427,664, that the halogen atom as possessed by the halogenation agent employed is introduced into the 2'-position of the sugar moiety of the compound of the formula (b) formed as the reaction product, and that for instance, when N-iodosuccinimide is employed as the iodination agent, the iodine atom is introduced into the 2'-position of the sugar moiety of the reaction product as obtained.
The U.S. Pat. No. 4,427,664 specification discloses an Experimental Example in which 3,4-di-O-acetyl-L-rhamnal of the formula ##STR4## where Ac denotes an acetyl group here and also hereinafter unless otherwise stated is reacted with daunomycinone and N-iodosuccinimide, with accompanying alkoxyhalogenation of said rhamnal compound, to produce 7-O-(3,4-di-O-acetyl-2,6-dideoxy-2-iodo-.alpha.-L-manno-hexopyranosyl)daun omycinone, as well as another Experimental Example in which 3,4-di-O-acetyl-L-fucal of the formula ##STR5## is reacted with daunomycinone and N-iodosuccinimide with accompanying alkoxyhalogenation of said fucal compound, to produce 7-O-(3,4-di-O-acetyl-2,6-dideoxy-2-iodo-.alpha.-L-talo-hexopyranosyl)dauno mycinone. However, this U.S. Patent specification does not disclose any further experimental Examples.
In the U.S. Pat. No. 4,427,664 specification, the formula (b) appearing therein refers to that X may broadly be an iodine, bromine, chlorine or fluorine atom, but there is not shown any Experimental Examples in which such a compound of the formula (b) where X is the bromine, chlorine or fluorine atom was virtually synthetized. If the one skilled in the art wishes to synthetize a compound of the above formula (b) where X is the bromine, chlorine or fluorine atom, it is expected that in accordance with the method of producing the compound of the formula (b) taught in the U.S. Pat. No. 4,427,664 specification, he will repeat the procedures of the two Experimental Examples as given in said U.S. patent specification using N-bromosuccinimide, N-chlorosuccinimide or N-fluorosuccinimide as the halogenation agent in place of the N-iodosuccinimide employed by Horton et al. Among the above-mentioned three compounds which are expectedly employable as the halogenation agent in place of the N-iodosuccinimide, a substance which is to be represented by the formula ##STR6## and which may be termed as N-fluorosuccinimide is unknown by now, because it is not described before in any literatures with respect to any process of preparing it and with respect to the physical and chemical properties of it, as far as we, the present inventors, have searched numerous literatures. Accordingly, it is evidently considered that a compound which may be termed as N-fluorosuccinimide is an actually unknown substance which was never prepared in the past prior to these days.
Besides, it is to be noted that the fluorine element which may be and have usually been considered to belong to the class or family of halogens is possessing an extraordinarily different and higher electric negativity than the other halogen elements, iodine, bromine and chlorine, and also that, as be well known, the fluorine element shows the chemical behaviors very much different from those of the other halogen elements. Accordingly, even when it is assumed that the N-fluorosuccinimide will have been prepared by any chemical process, it is highly probable that the properties of the chemical linkage between the fluorine atom and the succinimide group existing in the N-fluorosuccinimide as an imaginable compound would be very much different from the properties of the other sorts of a halo group linking to the succinimide group, and that such fluoro group is too strongly or too weakly linking to the succinimide group. For these reasons, it is very much hardly conceivable that the N-fluorosuccinimide can act as a fluorination agent to transfer its fluoro group into a second compound and bring about the fluorination of the latter compound. Accordingly, it is not presumable that the N-fluorosuccinimide, even if prepared, can serve especially as the fluorination agent required in the method of producing the compounds of the formula (b) which is described in the U.S. Pat. No. 4,427,664 specification.
In short, the U.S. Pat. No. 4,427,664 specification describes the chemical structure of the compounds of the above formula (b) where X may broadly be a chlorine, bromine, iodine or fluorine atom. Of the compounds which are designated by the above formula (b), the compounds of the formula (b) where X is a chlorine or bromine atom are shown merely with reference to their chemical structure in the U.S. Pat. No. 4,427,664 specification but were actually not synthetized concretely. Nonetheless, it is admittable that N-chlorosuccinimide and N-bromosuccinimide are a chlorination or bromination agent already known and necessary and available as the halogenation agent in the process of producing such compound of the formula (b) where X=chlorine or bromine, according to said U.S. patent of Horton et al, and therefore it is deducible from the descriptions of the U.S. Pat. No. 4,427,664 specification that the production of such compounds of the formula (b) where X=chlorine or bromine and isolation of such compounds as produced are possible theoretically in accordance with the method of Horton et al as disclosed in said U.S. patent specification. In contrast, however, it is evident that the U.S. Pat. No. 4,427,664 specification does not disclose or teach a process for really producing such compound of the formula (b) where X is the fluorine atom, to such extent that the process would be workable by chemical experts in view of the disclosure of the U.S. Pat. No. 4,427,664, firstly, because the N-fluorosuccinimide which is deemed as necessary as the fluorination agent for the production of the compound of the formula (b) where X=fluorine, according to the disclosed method of Horton et al is a substance which is still unknown up to now and is very much suspicious to be able to act successfully as the necessary fluorination agent for the intended purpose, and secondly, because the U.S. Pat. No. 4,427,664 of Horton et al does nowhere teach how to prepare the N-fluorosuccinimide. Hence, it is worthy to say that such compound of the above formula (b) where X is the fluorine as shown in the U.S. Pat. No. 4,427,664 was a merely imaginary one which was thought by referring to its chemical structure on the papers in the specification of said U.S. patent and of which utility for the intended antitumor agent is very much suspicious. Accordingly, we, do not believe that such special compound of the formula (b) where X is the fluorine atom could be prepared by the chemical experts according to the disclosure of the U.S. Pat. No. 4,427,664.
Furthermore, in the U.S. Pat. No. 4,427,664 specification, there is described by the inventors, Horton et al that the compounds of the formula (b) exhibit the antitumor activities against mouse blood cancer cell, Leukemia P 388. More particularly, this U.S. patent specification describes such antitumor activity of 7-O-3,4-di-O-acetyl-2,6-dideoxy-2-ikodo-.alpha.-L-mannohexopyranosyl) daunomycinone (nominated as Compound NSC 331,962 by Horton et al) as tested against Leukemia P 388 but does not describe any data of the antitumor activity of 7-O-(3,4-di-O-acetyl-2,6-dideoxy-2-iodo-.alpha.-L-talohexopyranosyl)daunom ycinone (nominated as Compound NSC 327,472 by Horton et al). While, according to an article of Horton et al reported in the "Carbohydrate Research" Vol. 136, pp. 391-396 (1985), they obtained experimental results to show that said Compound NSC 331,962 exhibited an antitumor activity that the increase (in %) of survival days of the mice treated, as compared to the mice untreated (control) (namely, T/C, %), was 247% at a dosage of 50 mg/kg of the test compound when the mice as inoculated with Leukemia P 338 were treated by administration of the test compound; and that said Compound NSC 331,962 exhibited an antitumor activity that the increase (in %) of survival days of the mice treated, as compared to the mice untreated (T/C, %), was 196% at a dosage of 25 mg/kg of the test compound when the mice as inoculated with Leukemia L-1210 -were treated by administration of the test compound (a single dose per day, intraperitoneally given for 9 days). Also, the above-mentioned Compound NSC 327,472 experimentally showed such antitumor activities that the increase (%) of survival days of the Leukemia P 388-inoculated mice treated was 172% at a dosage of 12.5 mg/kg to 25 mg/kg of Compound NSC 327,472, whereas the increase (%) of survival days of the Leukemia P 388-inoculated mice treated decreased to 162% at a further increased dosage of 150 mg/kg of the tested compound.
Apart from the above-mentioned researches of Horton et al, we have made studies in an attempt to produce new daunomycin derivatives or adriamycin derivatives which have better antitumor activity and lower toxicity than daunomycin and adriamycin. As a result, we already succeeded to synthetize a few examples of such daunomycin derivative and adriamycin derivative in which the sugar moiety of daunomycin or adriamycin has chemically been modified and which are useful as the antitumor agent. Thus, we reported 4'-O-tetrahydropyranyl-daunomycins and -adriamycins (Japanese patent publication No. 47194/81); and 3'-deamino-3'-morpholino-daunomycins and -adriamycins (Japanese patent application first publication "KOKAI" No. 163393/82).
Further, we have made another studies to provide new compounds which are derived by chemical modification with a fluoro group of the 3'-position or 2'-position of kanamycin A and kanamycin B of the aminoglycosidic antibiotics. Thus, we have succeeded to synthetize 3'-deoxy-3'-fluorokanamycin A (Japanese patent application No. 161615/84; U.S. patent application Ser. No. 758,819; European patent application No. 85 4015757.7); 3'-deoxy-3'-fluorokanamycin B (Japanese patent application No. 262700/84); and 2',3'-dideoxy-2'-fluorokanamycin A (Japanese patent application No. 263759/84; U.S. Pat. application Ser. No. 807,485; European patent application No. 85 115901.2).
In this way, we already obtained many findings and experiences in the fluorine chemistry of sugars through our studies where the fluoro group is introduced into kanamycins of the glycosidic antibiotics. Based on these findings and experiences, we have now succeeded to synthetize as a new compound a 4-O-benzyl-protected derivative of methyl 2,6-dideoxy-2-fluoro-.alpha.-L-idopyranoside represented by the formula ##STR7## through a multi-stage process with starting from L-fucose of the formula ##STR8## Further, we succeeded to synthetize from the sugar compound of the above formula (g) methyl 2,6-dideoxy-2-fluoro-.alpha.-L-talopyranoside of the formula ##STR9## as a new compound, and further synthetize from the compound of the formula (h) 2,6-dideoxy-2-fluoro-.alpha.,.beta.-L-talopyranose of the formula ##STR10## as a new compound and also a 3,4-di-O-protected-2,6-dideoxy-2-fluoro-.alpha.-L-talopyranosyl halide of the formula ##STR11## wherein A' is a hydroxyl-protecting group, particularly an acyl group, especially a lower alkanoyl group such as acetyl or an aroyl group such as benzoyl and Y is a chlorine bromine or iodine atom, for example, 3,4-di-O-acetyl-2,6-dideoxy-2-fluoro-.alpha.-L-talopyranosyl bromide as a new compound.
Then, we have now succeeded to produce firstly 7-O-(2,6-dideoxy-2-fluoro-.alpha.-L-talopyranosyl)daunomycinone of the formula ##STR12## as a new compound by reacting the 3,4-di-O-protected-2,6-dideoxy-2-fluoro-.alpha.-L-talpyranosyl halide of the above formula (j) with the 7-hydroxyl group of daunomycinone and then removing the residual hydroxyl-protecting groups (A') from the resulting reaction product.
Furthermore, by converting the 14-methyl group of the compound of the above formula (k) into a hydroxymethyl group (--CH.sub.2 OH) by treatment with a mild oxidizing agent, we have now succeeded to produce firstly 7-O-(2,6-dideoxy-2-fluoro-.alpha.-L-talopyranosyl)adriamycinone of the formula ##STR13## as a new compound. We also have found that the new compound of the formula (k) and the new compound of the formula (l) have excellent antitumor activities and low toxicities and that the glycoside linkage at the 7-hydroxyl group of these new compounds shows a high stability against hydrolysis by acid. Accordingly, the new compound of the formula (k) and the compound of the formula (l) are interesting for use as antitumor agent owing to their low toxicities coupled with their excellent antitumor activities as demonstrated hereinafter. These new compounds of the formulae (k) and (l) have also high antibacterial activities and are useful as antibacterial agent.
Accordingly, there is provided an anthracycline derivative represented by a general formula ##STR14## wherein R is a hydrogen atom or a hydroxyl group (Japanese patent application No. 282798/85; U.S. patent application Ser. No. 942,773; European patent application No. 86 117 662.6).
Of the compounds of the general formula (m), 7-O-(2,6-dideoxy-2-fluoro-.alpha.-L-talopyranosyl)daunomycinone of the formula (k) is in the form of red colored solids having a specific optical rotation [.alpha.].sub.D.sup.25 +197.degree. (c 0.02, chloroform-methanol (1:1)). 7-O-2,6-dideoxy-2-fluoro-.alpha.-L-talopyranosyl)adriamycinone of the formula (l) is in the form of red colored solid having a specific optical rotation [.alpha.].sub.D.sup.25 +194.degree.(c 0.01, chloroform-methanol (1:1)).
We have confirmed by animal tests that the compounds of formula (m) exhibit significantly high antitumor activities on experimental tumors and that the level of their antitumor activities is much higher than those of daunomycin and adriamycin, coupled with an acceptably low level of toxicities. Some typical tests on experimental animal tumors are given below.