HRP950092A2 - Anthracycline disaccharides, process for their preparation, and pharmaceutical compositions containing them - Google Patents

Description

Field of invention

The present invention relates to compounds of the general formula (I) or formula (II):

[image]

where:

R is H or OH or OR7 group, and where R7 is CHO or COCH3 or an acyl residue of a carboxylic acid containing up to 6 carbon atoms;

r1 is H or OH or OCH3:

R 2 is H or F;

R 3 is H or OH;

R4 and r5 are the same or different, and are H or OH or NH2; and the bond symbol (→→) indicates that the substituents r3, R4 and r5 can be in the axial or equatorial position;

and to their pharmaceutically acceptable salts that have anticancer properties.

As can be seen from the formulas above, compounds (I) and (II) differ only in the spatial arrangement of glycosidic groups, and therefore can be represented by formula (A)

[image]

where the symbol (→→) indicates that the second carbohydrate residue, which is attached to the carbon in the 4' position of the first sugar, can be in both an axial and an excavator position.

The present invention also relates to methods of preparation of the mentioned compounds and their pharmaceutically acceptable salts, and to pharmaceutical preparations containing them.

Previous knowledge

Daunorubicin and doxorubicin are well-known antibiotics now used in clinical practice for the treatment of various solid tumors and leukemias (F. Arcamone in "Doxorubicin: Anticancer Antibiotics", A. C. Sartorelli, Ed., Academic Press, N. Y. 1981).

European patent no. EP A 0457215 includes products whose structure is similar to the compounds of this claim, but which have only one glycosidic group.

As is well known, however, the serious side effects caused by the anticancer agents currently in use impose restrictions on their use for a large number of patients who would otherwise benefit from treatment with them.

Furthermore, some important solid tumors, eg lung or ovarian, require extremely intensive treatment, and current treatments do not provide adequate results.

Therefore, it follows that there is a great need for a drug with high selectin inhibitory activity towards the proliferation of diseased cells compared to normal cells to come to the market.

Detailed description of the invention

The aim of the presented invention is to present new anticancer compounds, especially an anthracycline analogue in which the carbohydrate part contains a disaccharide residue.

The surprising discovery that the anthracycline disaccharides of the claim, in which the sugar directly attached to the aglycone never contains an amino group, shows greater anticancer activity and selectivity than previously known anthracyclines. It is worth pointing out that in known anthracyclines, which contain two or more carbohydrate residues, the sugar attached to the aglycone always contains a free or substituted amino group.

The compounds of the present invention are compounds of the general formula (I) and (II), as shown above, as well as their pharmaceutically acceptable salts, where R, R1, R2, R3, R4 and R5 are as defined above.

The present invention also relates to pharmaceutical preparations containing the mentioned compounds and corresponding salts formed with pharmaceutically acceptable acids, preferably with hydrochloric acid.

The following compounds are particularly preferred:

a) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-lyxo-exopyranosyl]dauno-rubicinone hydrochloride;

b) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-arabino-exopyranosyl]dauno-rubicinone hydrochloride;

c) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-lyxo-exopyranosyl]doxo-rubicinone hydrochloride:

d) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-arabino-exopyranosyl]doxo-rubicinone hydrochloride:

e) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-arabino-exopyranosyl]-4- demethoxy-daunorubicinone hydrochloride;

f) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-lyxo-exopyranosyl]-4- demethoxy-daunorubicinone hydrochloride;

g) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-lyxo-exopyranosyl]-4- demethoxy-doxorubicinone hydrochloride;

h) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-arabino-exopyranosyl]-4- demethoxy-doxorubicinone hydrochloride;

i) 7-O-[2,6-dideoxy-4-O-(2,3,4,6-tetradeoxy-4-amino-α-L-erythro-exopyrano-syl)-α-L-lyxo-exopyranosyl ]daunorubicinone hydrochloride;

j) 7-O-[2,6-dideoxy-4-O-(2,3,4,6-tetradeoxy-4-amino-α-L-erythro-exopyrano-syl)-α-L-lyxo-exopyranosyl ]-4-demetho-doxorubicinone hydrochloride;

k) 7-O-[2,6-dideoxy-4-O-(2,3,4,6-tetradeoxy-4-amino-α-L-erythro-exopyrano-syl)-α-L-lyxo-exopyranosyl ]doxorubicinone hydrochloride;

l) 7-O-[2,6-dideoxy-4-O-(2,3,4,6-tetradeoxy-4-amino-α-L-erythro-exopyrano-syl)-α-L-lyxo exopyranosyl] -4-demethoxy-doxorubicinone hydrochloride;

m) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-lyxo-exopyranosyl]4-demethoxy -8-fluoro-daunorubicinone hydrochloride;

n) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-lyxo-exopyranosyl]4-demethoxy -8-fluoro-doxorubicinone hydrochloride;

Compounds of the general formula (I) and (II) can be prepared by a process consisting of the following steps:

(a) condensation of the compound of formula (III)

[image]

where R1 and R2 are as defined above, and R6 is H or the group OR7, wherein R7 represents the protecting group of the alcohol functional group, which is preferably selected from the following groups: acetyl-, dimethyltetrabutylsilyl- or p-methoxythenyldiphenylmethyl-,

with a compound of formula (IV) or formula (VI)

[image]

where R 8 represents H or protection of the -OH group, preferably p-nitrobenzoate; R9 and R10 are identical or different, and each can be H or a protecting group -OH, preferably p-nitrobenzoate, or they can be a protecting NH2 group, preferably trifluoroacetamide or allylcarboxamide, and X is a group that can generate a stable carbocation under condensation conditions, which is able to bind to the hydroxyl group at the C-7 position of the compound of formula (III), and said group X can be selected from the groups used in the glycosidation reaction: for example, a halogen such as chlorine or bromine, preferably chlorine, or p -nitro-benzoyloxy group. Therefore, compounds of formula (VI) or formula (VII) are obtained:

[image]

where R1, R2, R6, R8, R10 and the symbol (???) are as defined above;

(b) one (or more) deprotection reaction(s) with OH and/or NH2 in compounds of formula (VI) and (VII), whereby compounds of formula (I) and (II) are obtained, where R, R1 , R2, R4, R5 and the symbol (??? ) are as defined above;

(c) conversion, if necessary, of the aforementioned glycoside of formula (I) and (II) into the corresponding, pharmaceutically acceptable salt, preferably into the hydrochloride.

The reaction conditions for the glycolization of the compound of formula (III) with the compound of formula (IV) or (V) to form the compound of formula (VI) and (VII) may vary depending on the type of substituents present in the compounds of formula (IV) or (V).

Glycolization is performed in an internal organic solvent in the presence of a condensing agent.

Condensing agents are, for example, silver terifluoromethane sulfonate, silver perchlorate, a mixture of mercury (II) oxide and mercury (II) bromide, boron halides, titanium or tin tetrachloride or ion exchange resins, such as Amberlite.

Glycosidation is preferably carried out in a 1:1 to 1:3 molar ratio in an inert organic solvent, such as, for example, benzene, toluene, ethyl ether, tetrahydrofuran, dioxane, chloroform, methylene chloride or dichloroethane, and in their mixtures.

The reaction temperature can range from -40°C to 40°C, preferably from -20°C to 20°C, and the reaction time is from 15 minutes to 3 hours.

The reaction mixture may include a dehydrating agent, such as activated molecular sieves.

During or at the end of the reaction, an organic base, such as pyridine, collidine, N,N-dimethylaminopyridine, triethylamine or 1,8-bis-(dimethylamino)-naphthalene, can be added to the reaction mixture.

According to the presented invention, the removal of protective groups from the OH and/or NH2 group in the compound of formula (VI) and (VII), in order to form the compound of formula (I), can be performed under different conditions, depending on the type of protective group used.

When R9 and/or R10, identical or different, are protected NH2 groups such as trifluoroacetamide or protected OH groups such as p-nitrobenzoate and/or R8 is a protected OH group such as p-nitrobenzoate, and/or R6 is protected OH group such as acetate, deprotection reactions are carried out in a polar solvent such as water, methanol, ethanol, pyridine, dimethyltoramide or a mixture thereof, and in the presence of inorganic bases in a stoichiometric amount or in an excess of inorganic gauze, such as sodium, potassium, lithium or barium hydroxide or carbonate.

The reaction temperature can range from 0 to 50 °C, and the reaction time from 3 h to 48 h.

When R9 and/or R10 are protected NH2 groups such as allylcarboscamide, deprotection is performed in an inert organic solvent in the presence of a metal complex such as tetrabis(triphenylphosphine)palladium, as shown in, e.g., Tetrahedron Letters, 30, 3773 ( 1989), or tetracarbonyl-nickel, as shown in, e.g., J. Org. Chem., 38, 3233 (1973).

When R 6 is an OH protection group such as dimethyltetrabutylsilyl ether, deprotection is performed in an inert solvent in the presence of tetrabutylammonium fluoride, as shown, e.g., in J. of Antibiot., 37, 853 (1984).

When R 6 is an OH protection group such as p-methoxyphenylmethyl-ether, deprotection is performed in an acidic medium, eg, aqueous acetic acid, as shown in, eg, J. Org. Chem., 42, 3653 (1977).

Compounds of formula (III) are either known or can be prepared according to methods and procedures known in organic chemistry, as shown in, for example, Gazz. Chem. Ital., 114, 517 (1984), in Bull. Chem. Soc. Jpn., 59, 423 (1986), and in the above-mentioned Italian patent from the Applicant, the attachment of which is incorporated in the references shown here.

Compounds of formula (IV) or (V) are either known or can be prepared according to methods and procedures of disaccharide synthesis, which are known in organic chemistry [J. Carbohydr. Chem., 10, 8653 (1991); Carbohydr. Res., 74, 199 (1979); Carbohydr. Res., 208, 111 (1980); Tetrahedron, 46, 103 (1990)].

Alternatively, if desired, anthracycline glycosides of formula (I) and (II), where R1, R2, R3, R4 and R5 are as defined above and R is an OH group, can be prepared from glycosides of formula (I) and (II) or from the corresponding pharmaceutically acceptable salts, wherein R 1 , R 2 , R 3 , R 4 , R 5 , and the symbol (→→) are as defined above and R is H, by bromination of the carbon at position 14 with bromine and chloroform, followed by hydrolysis at room temperature temperature for a period of 48 h, and by acting on the resulting 14-bromo derivative with sodium formate.

If desired, the glycosides of formulas (I) and (II) can be converted into pharmaceutically acceptable salts, eg hydrochlorides, by treatment with hydrochloric acid in methanol.

The present invention also relates to pharmaceutical preparations which, as an active substance, contain a compound of formula (I) or formula (II), or a corresponding pharmaceutically acceptable salt, together with a pharmaceutically acceptable solvent or carrier.

According to the present invention, therapeutically effective doses of compounds of formula (I) or (II) are combined with an inert carrier. The preparations may be formulated in a conventional manner using conventional carriers.

The compounds of the invention are useful in the treatment of humans and other mammals. In particular, said compounds are good anticancer agents when administered in therapeutically effective doses.

The following examples illustrate the present invention in more detail

Example 1

7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L--lyxo-exopyranosyl]down

-rubicinon hydrochloride (compound of formula II, R=R1=R2=H, R3=R5=OH, R4=NH2)

Mixtures of 4-demethoxydaunorubicinone (compound of formula III, R1=R2=R6=H) (300 mg, 0.81 mmol) and 2,6-dideoxy-4-0-(2,3,6-trideoxy-4-O-p-nitrobenzoyl- 3-trifluoroacetamido-α-L-lyxo-exopyranosyl)-3-O-p-nitrobenzoyl-p-nitro-benzoate (compound of formula IV, R3=R5=p-nitrobenzoyloxy-, R4=trifluoroacetamido-, X=p-nitro-benzoyloxy -) (600 mg, 0.72 mmol) in methyl chloride (72 mL) and ethyl ether (24 mL) in the presence of molecular sieves (A4) was added at -20°C with trimethylsilyl triphthalate (266 μL, 1.44 mmol). The reaction mixture was stirred for 1 h, diluted with methylene chloride, washed with saturated sodium bicarbonate solution, and evaporated to dryness. The residue was separated by chromatography on silica gel (eluent CH2Cl2/EtOH 99/1), whereby 360 mg of 7-0-[2,6-dideoxy-4-O-(2,3,6-trideoxy-4-O-p- nitrobenzoyl-3-fluoroacetamido-α-L-lyxo-exopyranosyl)-3-O-p-nitro-benzoyl-α-L-lyso-exopyranosyl]-4-demethoxydaunorubicinone (compound of formula VII, R1=R2=R6=H, R8= R10=p-nitrobenzoyloxy-, R9=trifluoroacetamido-).

A protected suspension of glycosides of the compound of formula (VII) (R1=R2=R6=H, R8=R10=p-nitrobenzoyloxy-, R9=trifluoroacetamido-) (120 mg, 0.117 mmol) in 17.6 mL of a 0.1 M solution of Ba(OH)2 in H2O/MeOH 1/1 was stirred for 3 h at room temperature. The reaction mixture was neutralized with a 0.2 M sodium bisulfate solution, extracted with chloroform, the organic extracts were combined, dried over anhydrous sodium sulfate, evaporated to dryness and treated with a 0.02 M HCl solution. The acidic aqueous solution was washed with chloroform and lyophilized, whereby 62 mg of the desired product was obtained (compound of formula II, R=R1=R2=H, R3=R5=OH, R4=NH2). Utilization is 93%. The NMR data are as follows:

1H-NMR (DMSO-d6) δ 1.05 (d, 3H), 1.15 (d, 3H), 1.5-1.95 (m, 4H), 2.1 (m, 2H), 2.25 (s. 3H), 2.95 (dd, 2H), 3.55 (s, 2H), 3.8 (m, 1 H), 3.95 (m, 1 H), 4.15 (q, 1 H), 4.35 (q, 1 H), 4.6 (d, 1 H), 4.9 (broad s, 2H), 5.25 (broad s, 1H), 5.35 (d, 1H), 5.55 (s, 1H), 7.95 (broad s, 2H), 8.25 (broad s, 2H).

The following compounds of formulas (I) and (II) were also obtained according to the analogous procedure:

7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L--lyxo-exopyranosyl]dauno-rubicinone hydrochloride (compound of formula II, R=R2=H, R1=OCH3, R3=R5=OH, R4=NH2)

1H-NMR (DMSO-d6) δ 1.05 (d, 3H), 1.15 (d, 3H), 1.35-2.15 (m, 6H), 2.25 (s, 3H), 2.95 (dd, 2H), 3.55 (s, 2H), 3.8 (m, 1H), 3.95 (m, 1H), 4.05-4.2 (m+q, 2H), 4.35 (q, 1H), 4.9 (broad s, 2H), 5.25 (d, 1H ), 7.65 (m, 1H), 7.9 (d, 2H).

7-O-[2,6-dideoxy-4-0-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L--arabino-exopyranosyl]dauno-rubicinone hydrochloride (compound of formula I, R=R2=H, R1=OCH3, R3=R5=OH, R4=NH2)

1H-NMR (DMSO-d6) δ 1.13 (d, 3H), 1.15 (d, 3H), 1.45-1.85 (m, 4H), 2.05 (m, 2H), 2.15 (s, 3H), 2.87 (dd, 2H), 2.98 (m, 1H), 3.5 (m, 1H), 3.6(m, 1H), 3.85 (q, 1H), 3.9 (q, 1H), 3.9 (s, 2H), 4.84 (m , 2H), 5.13 (broad s, 1 H), 5.28 (s, 1 H), 5.32 (d, 1 H), 5.55 (s, 1 H), 7.55 (m, 1 H), 7.8 (m, 2H ).

7-O-[2,6-dideoxy-4-0-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyrazonyl)-α-L-arabino-exopyranosyl]-4-demethoxy- daunorubicinone hydrochloride (compound of formula I, R=R1=R2=H, R3=R5=OH, R4=NH2)

1H-NMR (DMSO-d6) δ 1.1 (d, 3H), 1.2 (d, 3H), 1.5-1.95 (m, 4H), 2.05-2.2 (m, 2H), 2.25 (s, 3H), 2.95 ( dd, 2H), 3.1 (t, 1H), 3.4 (m, 1H), 3.6 (broad s, 1H), 3.65 (m, 1H), 3.85-4.00 (q+q, 2H), 3.9 (m, 1 H), 4.95 (d, 1 H), 5.2 (d, 1 H), 5.4 (broad s, 2H), 5.7 (s, 1 H), 7.95 (m, 2H), 8.25 (m, 2H).

Claims (20)

1. Compounds of general formula (I) or general formula (II) [image] indicated that R is H or OH or OR7 group, and where R7 is CHO or COCH3 or an acyl residue of a carboxylic acid containing up to 6 carbon atoms; R1 is H or OH or OCH3: R 2 is H or F; R 3 is H or OH; R 4 and R 5 are the same or different, and each is H or OH or NH 2 ; and the bond symbol (→→) indicates that the substituents R3, R4 and R5 can be in the axial or equatorial position; and their pharmaceutically acceptable salts. 2. Compounds of formula (I) or (II) according to claim 1, characterized in that they belong to the group consisting of: a) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-lyxo-exopyranosyl]dauno-rubicinone hydrochloride; b) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-Ixo-exopyranosyl)-α-L-arabino-exopyranosyl]daunorubicinone hydrochloride; c) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-lyxo-exopyranosyl]doxorubicinone hydrochloride; d) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-arabino-exopyranosyl]doxorubicinone hydrochloride; e) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-arabino-exopyranosyl]-4- demethoxy-daunorubicinone hydrochloride; f) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-lyxo-exopyranosyl]-4- demethoxy-daunorubicinone hydrochloride; g) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-lyxo-exopyranosyl]-4- demethoxy-doxorubicinone hydrochloride; h) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-arabino-exopyranosyl]-4- demethoxy-doxorubicinone hydrochloride; i) 7-O-[2,6-dideoxy-4-O-(2,3,4,6-tetradeoxy-4-amino-α-L-erythro-exopyrano-syl)-α-L-lyxo-exopyranosyl ]daunorubicinone hydrochloride; j) 7-O-[2,6-dideoxy-4-O-(2,3,4,6-tetradeoxy-4-amino-α-L-erythro-exopyrano-syl)-α-L-lyxo-exopyranosyl ]-4-demethoxy-doxorubicinone hydrochloride; k) 7-O-[2,6-dideoxy-4-O-(2,3,4,6-tetradeoxy-4-amino-α-L-erythro-exopyrano-syl)-α-L-lyxo-exopyranosyl ]doxorubicinone hydrochloride; l) 7-O-[2,6-dideoxy-4-O-(2,3,4,6-tetradeoxy-4-amino-α-L-erythro-exopyrano-syl)-α-L-lyxo-exopyranosyl ]-4-demethoxy-doxorubicinone hydrochloride; m) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-lyxo-exopyranosyl]4-demethoxy -8-fluoro-daunorubicinone hydrochloride; n) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-exopyranosyl)-α-L-lyxo-exopyranosyl]4-demethoxy -8-fluoro-doxorubicinone hydrochloride; 3. Procedure for preparing compounds of general formula (I) or general formula (II) [image] where R is H or OH or OR7 group, and where R7 is CHO or COCH3 or an acyl residue of a carboxylic acid containing up to 6 carbon atoms; R1 is H or OH or OCH3: R 2 is H or F; R 3 is H or OH; R 4 and R 5 are the same or different, and each is H or OH or NH 2 ; and the bond symbol (→→) indicates that the substituents R3, R4 and R5 can be in the axial or equatorial position; and their pharmaceutically acceptable salts. characterized by the fact that it consists of the following steps: i) condensation of the compound of the general formula (III) [image] where R1 and R2 are as defined above, and R6 is H or the group OR7, wherein R7 represents the protecting group of the alcohol functional group, which is selected from the following groups: acetyl-, dimethyltetra-butylsilyl- or p-methoxyphenyldiphenylmethyl-, with a compound of formula (IV) or formula (V): [image] where R8 represents H or protection of the -OH group; R9 and R10 are identical or different, and each is H or the protection of the -OH group, or the protection of the NH2 group, and X is a group selected from halogen or p-nitrobenzoyloxy group, whereby compounds of formula (VI) or (VII) are formed: [image] where R1, R2, R6, R8, R10 and the symbol (→→) are as defined above; ii) one and/or more deprotection reactions with OH and/or NH2 groups from compounds of formula (VI) and (VII), resulting in compounds of formula (I) and (II), where R, R1, R2, R4 , R5 and the symbol (???? ) are as defined above; iii) possible conversion of compounds of formulas (I) and (II) into corresponding pharmaceutically acceptable salts 4. Process for the preparation of compounds of formulas (I) and (II) according to patent claim 1, where R1, R2, R3, R4 and R5 are as defined above, and R is the OH group, or their pharmaceutically acceptable salts indicated that consists of the following steps: i) bromination of carbon in position 14 in compounds of formula (I) or (II) or their pharmaceutically acceptable salts, where R1, R2, R3, R4, R5 and the symbol (→→) are as defined above, ii) hydrolysis of the resulting 14-bromo derivative to obtain compounds of formula (I) and (II), where R1, R2, R3, R4 and R5 are as defined above, and R is the OH group. 5. The process according to patent claim 3, characterized in that the compound of formula (IV) or (V) in step i) is one in which R8 is H or the protection of an OH group such as p-nitrobenzoate, R9 and R10, identical or different, each represents a H or protecting OH group, such as a p-nitrobenzyl- or NH2 group protected by a trifluoroacetyl or allyloxycarbonyl group. 6. The process according to claim 3, characterized in that step i) is performed in the presence of a condensation agent selected from the following group: silver triflate, silver perchlorate, a mixture of mercury(II)-oxide and mercury(II)-bromide , trimethylsilyl triphthalate, p-toluenesulfonic acid, trifluoroacetic acid, boron halides, tin tetrachloride, titanium tetrachloride or Amberlite type ion exchange resin. 7. The process according to claim 3 and 6, characterized in that the compound of formula (III) is dissolved in an inert organic solvent and that the condensation is performed in the presence of molecular sieves as a dehydrating agent. 8. The method according to patent claim 6 and 7, characterized in that an organic base selected from the following group was added to the reaction mixture during the reaction: pyridine, collidine, N,N-dimethylaminopyridine, triethylamine or 1,8-bis-(dimethylamino)- naphthalene. 9. Process according to patent claim 3, characterized in that said halogen in step i) is chlorine or bromine. 10. The method according to patent claim 3, characterized by the fact that in step ii) the removal of the trifluoroacetyl group, which is the protection of the NH2 functional group and/or the p-nitrobenzoyl group and/or the acetyl group, which are protected by the OH functional groups, is achieved by the action of the selected inorganic base from the following group: sodium, lithium or barium hydroxide or carbonate. 11. The method according to patent claim 3, characterized by the fact that in step ii) the removal of the allyloxycarbonyl group, which is the protection of the NH2 functional group, is achieved by the action of a nickel or palladium organic complex. 12. The method according to patent claim 3, characterized in that in step ii) the removal of the methoxyphenyldiphenylmethyl group, which is the protection of the OH functional group, is achieved by the action of an organic acid. 13. The method according to claim 12, characterized in that the organic acid is acetic acid. 14. The method according to patent claim 3, characterized by the fact that in step ii) the removal of the dimethyltetrabutylsilyl group, which protects the OH functional group, is achieved in the presence of tetrabutylammonium fluoride. 15. The method according to patent claim 3, characterized in that in step iii) the compounds of formulas (I) and (II) are converted into pharmaceutically acceptable hydrochlorides. 16. Process according to patent claim 4, characterized in that in step i) the bromination is carried out with bromine in chloroform. 17. Process according to patent claim 4, characterized in that in step ii) the hydrolysis is performed with sodium formate. 18. Pharmaceutical preparations characterized in that they contain at least one compound from patent claims 1 or 2 or their pharmaceutically acceptable salts, in combination with a pharmaceutically acceptable carrier or solvent. 19. Use of compounds according to patent claims 1 and 2, or their pharmaceutically acceptable salts indicated thereby, for the production of anticancer agents. 20. Pharmaceutical preparations, characterized by the fact that they act as anticancer agents, which as an active ingredient contain at least one compound according to claim 1 or 2 or a corresponding pharmaceutically acceptable salt, combined with a pharmaceutically acceptable carrier or solvent.