PL202545B1 - Carbohydrate derivatives of 5,11-dimethyl-5H-indole[2,3-b]quinoline and method for their obtaining as well as pharmaceuticals containing these derivatives - Google Patents

Description

The present invention relates to 5,11-dimethyl-5H-indolo [2,3-b] quinoline carbohydrate derivatives, their preparation and pharmaceutical compositions containing them.

The cytotoxic activity of indoloquinoline and its derivatives has been known for a long time (Arch. Pharm. Weinheim 321, 463-467, 1988). Systematic studies of the structure-activity relationship and biotransformation of indoloquinoline derivatives have allowed to establish that these compounds have the ability to intercalate DNA and form drug-DNA-topoisomerase II complexes (Biochem. Pharm. 44, 2149-2155, 1992 and J. Med. Chem. 37, 3503-3510, 1994), which places them among active compounds with relatively low molecular weights, having the ability to selectively bind to DNA.

Typically, ligands that bind to DNA attack other targets in the cell. The activity of the drug is a derivative of both intercalation with DNA and inhibition of replication enzymes or DNA repair systems.

Topoisomerases are enzymes that control DNA topology by cutting DNA strands and reassembling them after conformational changes have been made. These enzymes are involved in almost all DNA-mediated cellular processes: replication, transcription, chromosome segregation and mitosis. Their activity is related especially to neoplastic processes and diseases, their viral way. Interference with these processes by the formation of stable complexes of DNA and enzymes with indoloquinoline derivatives is responsible for the cytotoxic effect.

However, a serious disadvantage of the indole quinoline derivatives described so far is their low selectivity of action and unsatisfactory bioavailability, which is manifested by the negligible activity of these derivatives in vivo.

A group of new 11-methyl-5H-indole- [2,3-b] quinoline derivatives substituted with at least one alkoxyamino group and optionally with a methyl group attached to the nitrogen atom in the 5-position of the ring, was disclosed in the patent application P-353812. Preferred compounds with cytotoxic activity are alkoxyamine derivatives substituted at the 2 and 9 positions. Another group of 11-methyl-5H-indole- [2,3-b] quinoline derivatives are disclosed in the application P-353811. These derivatives, substituted with a carbohydrate group at the 2, 6 or 9 position of the ring, show not only favorable anti-tumor activity, but also good pharmacokinetic properties, in particular bioavailability.

The present invention provides a series of further 11-methyl-5H-indolo [2,3-b] quinoline derivatives having a methyl group at the 5-position on the ring, wherein the polycyclic, planar indolequinoline system is linked to a suitably selected substituent containing the carbohydrate system.

The invention is based on the compounds of formula 1 in which one of the R1 or R2 groups is -O- (CH2) nO-Su, where n = 2-6, and Su is a carbohydrate group, while the other of the R1 or R2 groups is an atom hydrogen or a C1-C6 alkyl group;

and the pharmaceutically acceptable salts thereof represented by the formula la, wherein X is the anion of an acid residue.

By the term "carbohydrate group" is understood a derivative of simple sugars: pentose, hexose, heptose or an amino sugar in cyclic or chain form.

A preferred group of compounds according to the invention are the 5,11-dimethyl-5H-indolo [2,3-b] quinoline derivatives of the formula I, wherein Su is a derivative of the amino sugars L-acosamine or L-daunosamine in the pyranose form.

Another preferred group are the 5,11-dimethyl-5H-indolo [2,3-b] quinoline derivatives in which the Su group is a pyranose derivative of 2-deoxy-hexose, such as D-glucose, D-galactose, D- mannose, L-rhamnose, or L-fucose.

The invention further comprises physiologically acceptable salts of the compounds of formula la, in particular addition salts formed with mineral acids or with organic acids.

Examples of suitable mineral acids are hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid. Examples of suitable organic acids are maleic, fumaric, succinic, itaconic, citraconic, oxalic, benzoic, p-aminobenzoic, ascorbic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, ethanesulfonic, benzenesulfonic, toluenesulfonic, glycol, glutamine, stearic or palmitic.

PL 202 545 B1

The present invention also provides a method for the preparation of the indoloquinoline carbohydrate derivatives represented by Formula 1.

Derivatives represented by formula 1 can be obtained by starting indoloquinolines in which the respective group R 1 or R 2 is a precursor of the group -O- (CH 2) nO-Su, where n = 2-6, in particular a hydroxyl or alkoxy group (which can be cleaved up to hydroxyl group), and the second R1 or R2 group is a hydrogen atom or a C1-C6 alkyl group.

In variant a) of the process according to the invention, the starting hydroxyl derivative of formula I, in which one of the groups R 1 or R 2 is OH and the other a hydrogen atom or a C1-C6 alkyl, is subjected to an alkylation reaction with an alkyl halide of formula 3:

Y- (CH2) nOW where:

Y is halogen, preferably bromine,

W is a functionalized protected carbohydrate group Su carbohydrate precursor, and n = 2-6;

the functional groups on the sugar part are then deprotected and the optionally obtained compound 1 converted in a known manner into a pharmaceutically acceptable salt of formula 1a.

An alternative process b) according to the invention is that the starting hydroxyl derivative of formula I, wherein one of the groups R 1 or R 2 is OH and the other is hydrogen or C 1 -C 6 alkyl, is alkylated with an alkyl halide of formula 4 :

Y- (CH2) nOR3 where:

Y - is a halogen atom;

R3 is a terminal hydroxyl protecting group, such as C1-C6 alkyl, C1-C6 acyl, or alkylsilyl;

n = 2-6;

and then the terminal hydroxyl group is deprotected and the resulting compound of formula I, in which one of the R1 or R2 groups is -O (CH2) nOH, where n = 2-6, which is a glycosyl acceptor, is subjected to the promoter reaction with the glycosyl donor being a precursor to the Su carbohydrate group, functional groups on the sugar part are deprotected and optionally compound 1 is converted into a pharmaceutically acceptable salt of formula 1a in a known manner.

In both variants of the process according to the invention, the alkylation reactions are carried out in an aprotic solvent in the presence of a base selected from metal hydrides, metal alcoholates or metal hydroxides. Preferably, the alkylation reactions are carried out in dimethylformamide in the presence of sodium hydride.

The halides Y- (CH2) nOW used as the alkylating agent in variant a) are obtained by reacting the corresponding alcohol halide with a 1-glycosyl derivative selected from the group of protected halides, esters, ethers and Su carbohydrate glycals. Preference is given to using a glycal in which the hydroxyl groups have been protected in the form of esters, ethers, silyl ethers, preferably acetic acid esters, and the amino groups - in the case of using amino sugar glycals such as L-acosamin or L-daunosamine - in the form of amides, carbamates , preferably benzyl carbamate, allyl carbamate, t-butyl carbamate or trichloroethyl carbamate.

In variant b) of the process according to the invention, the compound of formula I obtained by alkylation with a halide of formula 4, in which R1 or R2 is -O- (CH2) n-OR3, where the meaning of the substituents is defined above, is used as a glycosyl acceptor. by a glycosidic bond formation reaction carried out by one of the methods known in sugar chemistry to connect a glycosyl acceptor with a glycosyl donor.

In methods known from the literature, glycosyl 1-derivatives are used as glycosyl donors, such as halides, esters, ethers and glycals, the anomeric substituent of which can be converted into a good leaving group and the hydroxyl groups have been suitably protected as esters. , ethers, silyl ethers, preferably acetic acid esters, and amino groups in the form of amides, carbamates, preferably benzyl carbamate, allyl carbamate, t-butyl carbamate, or trichloroethyl carbamate.

Depending on the nature of the anomeric substituent, the glycosidation reaction can be carried out under acidic conditions in the presence of an acid promoter of the Lewis or Broensted acid type, or, in the case of an anomeric exchange reaction, under basic conditions. Suitable acids

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Lewis acids may be tin tetrachloride, aluminum trichloride, titanium tetrachloride, boron trifluoride, and suitable Broensted acids are, for example, 4-toluenesulfonic acid, trifluoric acid, triphenylphosphine hydrobromide, pyridine 4-toluenesulfonate.

As glycosyl donors in variant b) of the invention, glycals are preferably used. Reactions to attach a glycosyl acceptor to glycals are known, for example, from Journal of Organic Chemistry, 55, 5812-5813, 1990.

The glycosidation reaction is carried out in an aprotic solvent selected from the group of ethers, cyclic ethers, halogenated aliphatic and aromatic hydrocarbons, preferably dichloromethane or dichloroethane.

Preferably the glycosidation reaction is carried out in the presence of an acidic promoter, preferably in the presence of triphenylphosphine hydrobromide.

The glycosidation reaction is carried out at a temperature of -78 ° C to 80 ° C, preferably at room temperature, under an inert gas atmosphere.

The glycosidation reaction product is isolated by pouring the reaction mixture into water or an alkaline aqueous salt solution, preferably an aqueous sodium bicarbonate solution, or an acidic salt, preferably ammonium chloride, and extracting the reaction product with an organic solvent immiscible with the selected water. from the group of esters, ethers, cyclic ethers, halogenated aliphatic and aromatic hydrocarbons, preferably with ethyl acetate or dichloromethane. After the solvent has been removed, the reaction product can, if necessary, be purified by gel permeation chromatography or crystallization.

Regardless of the synthetic variant adopted, the last step involves the removal of groups protecting the hydroxyl and optionally amino functions in the carbohydrate substituent.

Protecting groups are removed by one of the commonly known methods of solvolysis or hydrogenolysis. In a preferred embodiment of the invention, the solvolysis of the esters is performed in an alcohol selected from the group of C1-C6 aliphatic alcohols, preferably methanol, in the presence of a base selected from the group of metal alkoxides, carbonates or hydroxides or tertiary aliphatic, aliphatic-aromatic and aromatic amines, preferably a carbonate. potassium.

Deprotection of the protecting group for an amine function, e.g., allyl carbamate, is performed in the presence of a palladium-triphenylphosphine complex.

The 5,11-dimethyl-5H-indolo [2,3-b] quinoline carbohydrate derivatives according to the invention are characterized by favorable physicochemical and pharmacological properties. The presence of a sugar substituent significantly increases the solubility of substances in body fluids, affinity to biopolymers, biodegradability, and thus pharmacokinetic properties, in particular bioavailability.

The compounds of the invention and their salts can be the active ingredient of pharmaceuticals for the treatment or prophylaxis of various types of human cancers, such as cancers of the head and neck, breast, cervix, prostate, lymphomas, sarcomas and adenomas, but not limited to those mentioned.

A pharmaceutical for the treatment and / or prevention of neoplastic diseases comprises at least one compound of formula 1 or a pharmaceutically acceptable addition salt thereof of formula la and at least one pharmaceutically acceptable carrier and / or diluent.

A pharmaceutical composition according to the invention containing a therapeutically effective amount of a novel compound of formula 1 or a pharmaceutically acceptable addition salt thereof of formula 1a is administered to the patient in need of treatment in a convenient pharmaceutical dosage unit form suitable for the type of agent by, for example, intravenously, intramuscularly, subcutaneously or orally.

The choice of drug dose and dosing regimen depends on the nature of the disease, age, weight and state of health of the patient, and can be determined by the skilled artisan based on known cancer treatment and prevention regimens. In the treatment of cancer, a suitable dose of a compound according to the invention may be 0.1 to 100 mg / kg / day, preferably 0.5 to 10 mg / kg / day. The appropriate dose may be administered to the patient once or several times daily, alone or in combination with other therapeutic substances. Such substances can be administered simultaneously in the form of one preparation or separate preparations, or successively in the sequence and intervals determined by the specialist.

The pharmaceutical composition of the invention may be formulated in a wide variety of pharmaceutical forms, well known to those skilled in the art, e.g. 18, Mack Publ. What.

PL 202 545 B1

Injection and infusion pharmaceutical forms include sterile aqueous, aqueous-organic and non-aqueous solutions, suspensions, dry substances, and solution or implantable tablets. For the preparation of the suspension, auxiliaries are used to ensure that the drug substance is evenly dispersed in the liquid phase, such as polysorbates, lecithin, polyoxyethylene-polyoxypropylene copolymers, peptisants such as phosphates, polyphosphates and citrates, water-soluble polymers such as carboxymethylcellulose, methylcellulose gums, polycellulose or gelatin. Injectables can contain pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity modifying agents, and preservatives. Dry substances are intended for the preparation of ex tempore solution or suspension by dilution with a suitable solvent.

Pharmaceutical forms for oral administration include tablets, pills, powders, granules, pellets or capsules, containing solid pharmaceutically acceptable carriers such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums. Tablets or granules may be coated or otherwise processed to provide a dosage unit that provides a beneficial sustained effect. A wide variety of materials may be used to form such protective or coating layers, including various polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, or cellulose acetate.

The following non-limiting examples illustrate the invention:

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2- [5- (a-L-Daunosaminyloxy) pentoxy] -5,11-dimethyl-5H-indolo [2,3-b] -quinoline (4)

2-Methoxy-11-methyl-6H-indolo [2,3-b] quinoline (Bioorg. Med. Chem., 1999, 7, 2457) (10 g, mM) was dissolved in xylene (150 ml) and dimethyl sulfate was added (10 ml). The mixture was stirred at reflux for 24 hours, then cooled, diluted with water, added with 25% NH3 aq. (until the precipitate dissolves) and extracted with chloroform. The combined organic extracts were washed with water, dried (MgSO4) and evaporated to dryness. The 2-methoxy-5,11-dimethyl-5H-indolo [2,3-bisquinoline thus obtained was used for the next step without further purification.

The compound was dissolved in a solution of 33% HBr in AcOH (150 ml) and heated to reflux with vigorous stirring for 24 hours (control of the reaction progress by TLC in CHCl3: MeOH = 95: 5). At this time, another 33% HBr / AcOH (50 mL) was added and the reaction continued for an additional 8 hours. The reaction mixture cooled to room temperature was poured into water (200 ml), basified with 25% NH3 solution, and then extracted with chloroform and CHCl3: MeOH solution (98: 2). The combined organic extracts were dried, concentrated by evaporation and the dry residue was purified by chromatography with gradually increasing polarity CHCl3: MeOH (98: 2> 95: 5>90:10> 80:20) as eluent. There was thus obtained 5,11-dimethyl-5H-indolo [2,3-b] quinolin-2-ol as a fine crystalline orange solid, mp decomposition above 280 ° C, yield 897 mg (10%); IR (KBr) v _has x: 2933, 1632, 1609, 1578, 1492, 1443, 1351, 1332, 1241, 1138, 1024, 738 cm ^-1 ; ¹ H NMR (DMSO-d6) δ: 9.78 (s, 1H), 8.19 (d, 1H, J 8 Hz), 7.84 (d, 1H, J 9 Hz), 7.59-7.34 (m, 4H), 7.14 (td, 1H, J 8, J 1 Hz), 4.24 (s, 3H), 3.03 (s, 3H); MS (EI, 70 eV), M / z (%): 262 (M ⁺ , 100), 247 (38); Anal. element. for C17H14N2O + ½H2O [271.32]: Calc .: C, 75.25; H, 5.57; N, 10.33%. Obtained: C, 75.20; H, 5.38; N, 10.15%.

The above 5,11-dimethyl-5H-indolo [2,3-b] quinolin-2-ol (2.62 g, 0.01 mol) was suspended in toluene (25 ml), 5-bromopentyl acetate (2.3 g, 0.011 mol), tetrabutylammonium bromide (0.3 g) and powdered KOH (2 g) and vigorously stirred at reflux for 30 min. After cooling, water (500 ml) was added, the organic layer was separated and the aqueous layer was extracted with toluene (3 x 20 ml). The combined toluene layers were washed with water (4 x 20 ml) and toluene was distilled off under reduced pressure. The residue was diluted with methanol (100 ml), K2CO3 (1.5 g) was added and stirred at room temperature for 24 hours. After distilling off the methanol under reduced pressure, the residue was diluted with water (50 ml) and extracted with chloroform (4 x 20 ml). The combined extracts were washed with water (2 x 20 ml), dried over magnesium sulfate and evaporated to give 5- (5,11-dimethyl-5H-indolo [2,3-b] quinolin-2-yloxy) pentanol in a yield of 2.5 g (71%). ¹ H NMR (CDCl 3, 200 MHz): δ: 8.17 (d, 1H, J 8 Hz), 7.75 (d, 1H, J 8 Hz), 7.68 (d, 1H, J 9.5), 7.58-7.49 (m, 2H), 7.40 (dd, 1H, J 9.5-3), 7.20 (dd, 1H, J 7.5-1), 4.34 (s, 3H), 4.13 (t, 2H, J 6), 3.793.69 (m, 2H), 3.09 (s, 3H), 1.94 (q, 2H, J7), 1.76-1.52 (m, 4H); MS (EI, 70 eV), M / z (%): 348 (M ⁺ , 100).

To a solution of 5- (5,11-dimethyl-5H-indolo [2,3-b] quinolin-2-yloxy) pentanol (0.696 g, 2 mmol) and 4-Op-nitrobenzoyl-3-N-allyloxycarbonyl-L- daunosamine (1.448 g, 4 mmol) in dry chloride

In addition of methylene (30 ml), HBr x Ph3P (1.72 g, 5 mmol) was added. The reaction mixture was protected with a CaCl2 tube. The reaction was carried out at room temperature for 7 days while stirring with a magnetic stirrer, then poured into a saturated solution of NaHCO3 (50 ml) and stirred for an additional 30 min. in room temperature. The organic layer separated in the separatory funnel was washed with water, dried (MgSO4), filtered and evaporated. The crude product was dissolved in CH2Cl2-methanol (1: 1) (20 ml), K2CO3 (1 g) was added and stirred at room temperature for 96 hours (TLC control CHCl3: MeOH = 80:20). The reaction mixture was diluted with water (20-30 ml), extracted with CH2Cl2: MeOH solution (98: 2), the combined organic extracts were washed with saturated NaHCO3 solution (pH ~ 7), water, dried. The crude product was purified by chromatography using CHCl3: MeOH: Et3N (80: 20: 0.06) and CHCl3: MeOH: Et3N (60: 20: 0.05) as the eluent.

2- [5- (aL-Daunosaminyloxy) pentoxy] -5,11-dimethyl-5H-indolo [2,3-b] quinoline was obtained as an orange solid. Yield 315 mg (33%). Mp 115-120 ° C; IR (KBr) v _max : 3367, 3201, 2930, 1634, 1575, 1490, 1441, 1335, 1283, 1241, 1213, 1120, 1020, 979, 738 cm ^-1 ; ¹ H NMR (DMSO-d6) δ: 8.23 (d, 1H, J 7.7 Hz), 7.93 (d, 1H, J 9.4 Hz), 7.70 (d, 1H, J 2.6 Hz), 7.57-7.41 (m, 3H ), 7.25-7.11 (m, 2H), 4.41 (m, 1H), 4.29 (s, 3H), 4.18 (AB, 2H), 3.79-3.48 (m, 2H), 3.13 (s, 3H), 2.98- 2.80 (m, 1H), 1.90-1.74 (m, 2H), 1.70-1.44 (m, 5H), 1.17 (d, 3H, J 6.4Hz); MS (EI, 70 eV), M / z (%): 477 (M ⁺ , 41), 377 (100), 348 (45), 275 (45), 262 (73); Anal. element. for C28H35N3O4 + ½H2O [486.61]: Calc .: C, 69.11; H, 7.45; N, 8.64%. Found: C, 69.23; H, 7.85; N, 8.80%.

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2- [2- (a-L-Acosaminyloxy) ethoxy] -5,11-dimethyl-5H-indolo [2,3-b] quinoline

Allyl alcohol (12 ml) and tin tetrachloride (5 mol%) were added to a solution of 3,4-di-O-acetyl-L-rhamnal (25 g; 0.12 mol) in methylene chloride (100 ml) cooled to 0 ° C. . The mixture was stirred for 12 hours at room temperature. At this time, the mixture was diluted with methylene chloride (200 mL) and poured into vigorously stirred saturated NaHCO3 solution. The layers were separated and the aqueous phase was extracted with methylene chloride (2 x 100 ml). After drying and evaporation of the solvent, a crude glycoside reaction mixture was obtained. The crude product was dissolved in methylene chloride (50 ml) and after cooling to 0 ° C, chlorosulfonic isocyanate (1.2 eq.) Was added. The mixture was kept at 0 < 0 > C for 1 hour then poured into an aqueous solution containing KI and NaHCO3. After 15 minutes of vigorous stirring, the phases were separated and the aqueous solution was extracted with ethyl acetate. The combined organic phases were dried and evaporated. The residue was crystallized from a mixture of Et2O and hexane to give pure 4-O-acetyl-3-N-allyloxycarbonyl-L-acosamin. Yield 13.78 g (45%). Mp 103-104 ° C; ¹ H NMR (CDCl3) δ: 6.35 (dd, 1H, J 75.9, J 2.2 Hz, H-1), 5.90 (m, 1H, -CH =), 5.26 (m, 2H, = CH2), 4.80 (dd , 1H, J 8.4, J 9.7 Hz, 4-H), 4.67 (dd, 1H, J 2.2 Hz, H-2), 4.55 (m, 3H, NH, CH2), 4.46 (m, 1H, J 8.8 Hz , H-3), 4.04 (dq, 1H J 9.7 Hz, H-5), 2.10 (s, 3H, OAc), 1.28 (d, 3H, J 6.2 Hz, H-6).

4-O-acetyl-3-N-allyloxycarbonyl-L-acosaminal (6 g; 23.5 mM) was dissolved in 40 ml of dry THF, palladium tetrakis (triphenylphosphine) (375 mg) and formic acid (25 ml) were added. The progress of the reaction was monitored by TLC in hexane: ethyl acetate 1: 1. The product with the free amino group was not isolated. After completion of the reaction, the temperature of the reaction mixture was brought to ca. 0 ° C (ice / water bath), Et3N (16 ml; 11.5 mmol) and CF3COOEt (6 ml) were added dropwise. The reaction was carried out for 48 hours at room temperature while stirring with a magnetic stirrer. At this time, the reaction mixture was poured into an excess of saturated NH4Cl solution, stirred for 15 minutes, transferred to a separating funnel, and extracted with CHCl3. The combined organic layers were washed with water and dried. The crude product was purified by chromatography using hexane: ethyl acetate (95: 5) as the eluent. Obtained 4-O-acetyl-3-N-trifluoroacetyl-L-acosaminal) as a white fine crystalline solid. Yield 2.39 g (38%). Mp 154-158 ° C; IR (KBr) Vmax: 3290, 3103, 1746, 1704, 1656, 1559, 1381, 1238, 1185, 1060, 907, 728 cm ^-1 ; ¹ H NMR (CDCl3) δ: 6.56 (bs, 1H), 6.43 (dd, 1H, J 5.8, J 1.8 Hz), 4.86 (dd, 1H, J 9.3, J 8.6 Hz), 4.76 (dd, 1H, J 5.8, J 2.0 Hz), 4.66 (dd, 1H, J 5.8, J 2.0 Hz), 4.08 (dq, 1H, J 9.5, J 6.2 Hz), 2.11 (s, 3H), 1.31 (d, 3H, J 6.4 Hz); MS (EI, 70 eV), M / z (%): 224 (M ⁺ -Ac ^- , 0.86), 206 (M ⁺ -Ac ^- -F, 4.55), 192 (100); Anal. element. for C10H12NO4F3 [267.20]: Calc .: C, 44.95; H, 4.53; N, 5.24%. Received: C, 45.03; H, 4.73; N, 5.16%.

To a solution of (4-O-acetyl-3-N-trifluoroacetyl-L-acosaminal) (2 g; 7.48 mmol) in dry CH2Cl2 (60 ml) was added 2-bromoethanol (1.87 g; 14.96 mmol) and HBr. Ph3P (400 mg). The mixture was stirred for 48 hours at room temperature. The reaction mixture was poured into excess saturated NaHCO3 solution, stirred for 15 minutes, then transferred to a separatory funnel. Extracted with methylene chloride, the combined organic extracts were washed with water and dried. After evaporating

After solvent, the product was purified by chromatography using hexane: ethyl acetate (5: 1) as the eluent system.

After crystallization (Et₂O) obtained 2- (4-O-acetyl-3-W-trifluoroacetyl-α-L-acosaminyloxy) bromoethane as a fine crystalline white solid. Yield 1.064 g (36%). M.p. 125-130 ° C; IR (KBr) v_max: 3304, 3114, 2982, 1742, 1705, 1567, 1380, 1241, 1181, 1043, 1024, 998, 936, 727 cm^-1;¹H NMR (CDCl3) δ: 6.95 (bs, 1H), 4.91 (bd, 1H, J 2.7 Hz), 4.59 (dd, 1H, 2 x J 10.1 Hz), 4.48 (m, 1H), 4.04 (dq, 1H , J 6.2, J 9.3 Hz), 3.94 (m, 1H), 3.77 (m, 1H), 3.50 (AB, 2H), 2.31 (ddd, 1H, J 15.2, J 4.3, J 1.2 Hz), 2.08 (s , 3H), 1.77 (m, 1H), 1.19 (d, 3H, J 6.2Hz); MS (EI, 70 eV), M / z (%): 349 (M⁺-Ac 1.04), 287 (9), 268 (8), 197 (40), 107 (11), 95 (20); Anal. element. for C12H17NO5F3Br [392.17]: Calc .: C, 36.75; H, 4.37; N, 3.57; Br, 20.38%. Received: C, 37.05; H, 4.80; N, 3.45; Br, 20.47%.

To a solution of 5,11-dimethyl-5H-indolo [2,3-b] quinolin-2-ol (393 mg, 1.5 mmol) in dry DMF (20 ml), 60% NaH was added at a temperature below 0 ° C. (3 mmoles). After 30 minutes, a solution of 2- (4-O-acetyl-3-N-trifluoroacetyl-α-L-acosaminyloxy) bromoethane (588 mg, 1.5 mmol) in DMF (10 mL) was added. The reaction flask was secured with a tube with a drying agent. The reaction was carried out below 0 ° C for about 15 minutes, then the cooling bath was removed and the reaction was continued at room temperature until at least one of the starting materials had disappeared. The progress of the reaction was monitored by TLC using CHCl3: MeOH. The reaction mixture was poured into excess saturated NH4Cl solution, stirred for 30 minutes, transferred to a separating funnel and extracted with CHCl3: MeOH solution (98: 2). The combined organic layers were washed with water and saturated NaHCO3 solution and dried. After evaporation of the solvent, the crude product (5,11-dimethyl-5H-indole- [2,3-b] -quinoline glycoside derivative) was dissolved in CH2Cl2: MeOH (1: 1) (20 ml), K2CO3 (20-30 % by weight of crude product), stirred at room temperature 48-96 hours (TLC control CHCl3: MeOH = 80:20). The reaction mixture was diluted with water (20-30 ml), extracted with CH2Cl2: MeOH solution (98: 2), the combined organic extracts were washed with saturated NaHCO3 solution (pH ~ 7), water, dried. The crude product was purified by chromatography using CHCl3: MeOH: Et3N (80: 20: 0.06) and CHCl3: MeOH: Et3N (60: 20: 0.05) as the eluent.

2- [2- (aL-Acosaminyloxy) ethoxy] -5,11-dimethyl-5H-indolo [2,3-b] quinoline was obtained as an orange solid. Yield 327 mg (50%). Mp 80-85 ° C; IR (KBr) v _max : 3350, 2924, 1630, 1574, 1490, 1448, 1355, 1280, 1239, 1225, 1128, 1058, 981, 758 cm ^-1 ; ¹ H NMR (DMSO-d6) δ: 8.20 (d, 1H, J 7.3 Hz), 7.89 (d, 1H, J 9.2 Hz), 7.68 (d, 1H, J 2.7 Hz), 7.57-7.40 (m, 3H ), 7.14 (td, 1H, J 8.1, J 1.5 Hz), 4.97 (bs, 1H), 4.86 (d, 1H, J 2.7 Hz), 4.32 (AB, 2H), 4.25 (s, 3H), 3.98- 3.72 (m, 2H), 3.53 (dq, 1H, J 9.2, J 6.2 Hz), 3.28 (bs, 2H), 3.08 (s, 3H), 2.91-2.63 (m, 2H), 1.88 (ddd, 1H, J 13.1, J 3.8, J <0.5 Hz), 1.43 (ddd, 1H, J 13.1, J 3.4, J 9.6 Hz), 1.13 (d, 1H, J 6.2 Hz); MS (EI, 70 eV), M / z (%): 435 (M ⁺ , 74), 335 (57), 306 (91), 262 (100); Anal. element. for C25H29N3O4 + 2H2O [471.54]: Calc .: C, 63.68; H, 7.05; N, 8.91%. Received: C, 64.04; H, 7.06; N, 8.69%.

P r z k ł a d 3.

9- [2- (a-L-Acosaminyloxy) ethoxy] -5,11-dimethyl-5H-indolo [2,3-b] quinoline (11)

9-Methoxy-11-methyl-6H-indolo [2,3-b] quinoline (Bioorg. Med. Chem., 1999, 7, 2457) (10 g, 38 mM) was dissolved in xylene (150 ml) and sulfate was added dimethyl (10 ml). After stirring at reflux for 24 hours, it was cooled, diluted with water and 25% NH3 aq. (until the precipitate dissolves) and extracted with chloroform. The combined organic extracts were washed with water, dried (MgSO4) and evaporated to dryness. The thus obtained 9-methoxy-5,11-dimethyl-5H-indolo [2,3-b] quinoline was used for the next step without further purification.

The obtained compound was dissolved in a solution of 33% HBr in AcOH (150 ml) and heated to reflux with vigorous stirring for 24 hours (control of the reaction progress by TLC in CHCl3: MeOH = 95: 5). At this time, another 33% HBr / AcOH (50 mL) was added and the reaction continued for an additional 8 hours. The reaction mixture cooled to room temperature was poured into water (200 ml), basified with 25% NH3 solution, and then extracted with chloroform and CHCl3: MeOH solution (98: 2). The combined organic extracts were dried, concentrated by evaporation and the dry residue was purified by chromatography with gradually increasing polarity CHCl3: MeOH (98: 2> 95: 5>90:10> 80:20) as eluent. 5,11-dimethyl-5H-indolo [2,3-b] quinolin-9-ol was obtained: fine crystalline brown red solid, mp decomposition above 280 ° C, yield 2.09 g (21%); IR (KBr) v _max : 2924, 1626, 1572, 1528, 1496, 1452, 1283, 1216, 1131, 816, 745 cm ^-1 ; ¹ H NMR (DMSO-d6) δ: 8.98 (s, 1H), 8.28 (dd, 1H, J 8, J 1 Hz), 7.91 (dd, 1H, J 9, J 1 Hz), 7.82 (ddd, 1H , J 8, J 1, J 1.5 Hz), 7.61 (d, 1H, J 2 Hz), 7.48 (ddd, 1H, J 8, J 6.5, J 1 Hz), 7.38 (d, 1H, J 8.5 Hz) , 6.95 (dd, 1H, J 8.5, J 1.5 Hz), 4.22 (s, 3H), 3.08 (s, 3H); MS (EI, 70 eV), M / z (%): 262

PL 202 545 B1 (M ⁺ , 100), 247 (44); Anal. element. for C17H14N2O + 1½H2O [289.33]: Calc .: C, 70.57; H, 5.92; N, 9.68%. Obtained: C, 70.43; H, 5.34; N, 9.59%.

To a solution of 9-hydroxyindoloquinoline (393 mg, 1.5 mmol) in dry DMF (20 ml) below 0 ° C, 60% NaH (3 mmol) was added. After 30 minutes, a solution of 2- (4-O-acetyl-3-N-trifluoroacetyl-α-L-acosaminyloxy) bromoethane (588 mg, 1.5 mmol) in DMF (10 mL) was added. The reaction flask was secured with a tube with a drying agent. The reaction was carried out below 0 ° C for about 15 minutes, then the cooling bath was removed and the reaction was continued at room temperature until at least one of the starting materials had disappeared. The progress of the reaction was monitored by TLC using CHCl3: MeOH. The reaction mixture was poured into excess saturated NH4Cl solution, stirred for 30 minutes, transferred to a separating funnel and extracted with CHCl3: MeOH solution (98: 2). The combined organic layers were washed with water, saturated NaHCO3 solution, and dried. After evaporation of the solvent, the crude product (5,11-dimethyl-5H-indole- [2,3-b] -quinoline glycoside derivative) was dissolved in CH2Cl2: MeOH (1: 1) (20 ml), K2CO3 (20-30 % by weight of crude product), stirred at room temperature 48-96 hours (TLC control CHCl3: MeOH = 80:20). The reaction mixture was diluted with water (20-30 ml), extracted with CH2Cl2: MeOH solution (98: 2), the combined organic extracts were washed with saturated NaHCO3 solution (pH ~ 7), dried with water. The crude product was purified by chromatography using CHCl3: MeOH: Et3N (80: 20: 0.06) and CHCl3: MeOH: Et3N (60: 20: 0.05) as the eluent.

9- [2- (aL-Acosaminyloxy) ethoxy] -5,11-dimethyl-5H-indolo [2,3-b] quinoline was obtained as a brown red solid. Yield 240 mg (37%). Mp 92-95 ° C; IR (KBr) v _max : 3349, 2927, 1631, 1567, 1528, 1494, 1455, 1377, 1280, 1208, 1129, 1060, 981, 815, 747 cm ^-1 ; ¹ H NMR (DMSO-d6) δ: 8.31 (d, 1H, J 7.7 Hz), 7.94-7.79 (m, 2H), 7.74 (d, 1H, J 2.3 Hz), 7.52 (dd, 1H, J = 7. J 2.7 Hz), 7.12 (dd, 1H, J 8.5, J 23 Hz), 4.94 (bs, 1H), 4.86 (d, 1H, J 2.7 Hz), 4.23 (bs, 5H), 3.96-3.70 (m, 2H), 3.62-3.47 (m, 1H), 3.10 (s, 3H), 2.96-2.65 (m, 2H), 1.90 (ddd, 1H, J 12.8, J 3.9 Hz), 1.45 (ddd, 1H, J 12.8 , 2 x 73.9 Hz), 1.14 (d, 1H, J 6.2); MS (EI, 70 eV), M / z (%): 435 (M ⁺ , 3), 335 (2), 306 (24), 277 (100), 261 (57), 245 (15) 199 (19 ), 150 (26); Anal. element. for C25H29N3O4 + 3H2O [489.55]: Calc .: C, 61.34; H, 7.21; N, 8.58%. Found: C, 61.69; H, 7.07; N, 8.23%.

P r z k ł a d 4

9- [5- (a-L-Daunosaminyloxy) pentoxy] -5,11-dimethyl-5H-indolo [2,3-b] quinoline

5,11-Dimethyl-5H-indolo [2,3-b] quinolin-9-ol (2.62 g, 0.01 mol) was suspended in toluene (25 ml), 5-bromopentyl acetate (2.3 g 0.011 mol), tetrabutylammonium bromide (0.3 g) and powdered KOH (2 g) and vigorously stirred at reflux for 30 min. After cooling, water (500 ml) was added, the organic layer was separated and the aqueous layer was extracted with toluene (3 x 20 ml). The combined toluene layers were washed with water (4 x 20 ml) and toluene was distilled off under reduced pressure. The residue was diluted with methanol (100 ml), K2CO3 (1.5 g) was added and stirred at room temperature for 24 hours. After distilling off the methanol under reduced pressure, the residue was diluted with water (50 ml) and extracted with chloroform (4 x 20 ml). The combined extracts were washed with water (2 x 20 ml), dried over magnesium sulfate and evaporated to give 5- (5,11-dimethyl-5H-indolo [2,3-b] quinolin-9-yloxy) pentanol in a yield of 2.5 g (71%). IR (KBr), k _max : 3164, 2938, 2862, 1635, 1565, 1528, 1495, 1454, 1280, 1206, 1078, 1029; ¹ H NMR (CDCl 3, 200 MHz): δ 8.20 (d, 1H, J 8 Hz), 7.78-7.72 (m, 3H), 7.66 (d, 1H, J 8.5), 7.51-7.42 (m, 1H), 7.17 (dd, 1H, J 9-2.5), 4.33 (s, 3H), 4.10 (t, 2H, 76), 3.77-3.68 (m, 2H), 3.13 (s, 3H), 1.90 (q, 2H, J 6), 1.74-1.58 (m, 4H); MS (EI, 70 eV), M / z (%): 348 (M ⁺ , 21), 261 (100).

To a solution of 5- (5,11-dimethyl-5H-indolo [2,3-b] quinolin-9-yloxy) pentanol (0.696 g, 2 mmol) and 4-Op-nitrobenzoyl-3-N-allyloxycarbonyl-L- daunosamine (1.448 g, 4 mmol) in dry methylene chloride (30 ml) was added HBr x Ph3P (1.72 g, 5 mmol). The reaction mixture was protected with a CaCl2 tube. The reaction was carried out at room temperature for 7 days while stirring with a magnetic stirrer, then poured into a saturated solution of NaHCO3 (50 ml) and stirred for an additional 30 min. in room temperature. The organic layer separated in the separatory funnel was washed with water, dried (MgSO4), filtered and evaporated. The crude product was dissolved in CH2Cl2-methanol (1: 1) (20 ml), K2CO3 (1 g) was added and stirred at room temperature for 96 hours (TLC control CHCl3: MeOH = 80:20). The reaction mixture was diluted with water (20-30 ml), extracted with CH2Cl2: MeOH solution (98: 2), the combined organic extracts were washed with saturated NaHCO3 solution (pH ~ 7), water, dried. The crude product was purified by chromatography using CHCl3: MeOH: Et3N (80: 20: 0.06) and CHCl3: MeOH: Et3N (60: 20: 0.05) as the eluent.

PL 202 545 B1

9- [5- (aL-Daunosaminyloxy) pentoxy] -5,11-dimethyl-5H-indolo [2,3-b] quinoline was obtained as dark red fine crystalline solid. Yield 392 mg (55%). Mp 130-132 ° C; IR (KBr) v _max : 3166, 2931, 1635, 1566, 1527, 1494, 1456, 1278, 1205, 1121, 1028, 977, 753 cm ^-1 ; ¹ H NMR (DMSO-d6) δ: 8.32 (dd, 1 H, 7 8.1 7 0.9 Hz), 7.95-7.89 (m, 2H), 7.72 (d, 1 H, 7 2.1 Hz), 7.53-7.46 (m, 2H), 7.10 (dd, 1H, J 8.6, J 2.6 Hz), 4.71 (dd, 1H, 72.6 Hz), 4.54-4.30 (m, 1H), 4.24 (s, 3H), 4.07 (AB, 2H), 3.70 (q, 1H, J 6.4 Hz), 3.60-3.48 (m, 1H), 3.10 (s, 3H), 2.90 (m, 1H), 1.88-1.70 (m, 2H), 1.63-1.42 (m, 5H ). 1.07 (d, 3H, 76.4Hz); MS (EI, 70 eV), M / z (%): 477 (M ⁺ , 93), 377 (57), 275 (28), 261 (100); Anal. element. for C28H35N3O4 + H2O [495.61]: Calc .: C, 67.86; H, 7.52; N, 8.47%. Found: C, 67.56; H, 7.49; N, 8.13%.

P r z k ł a d 5

9- [5- (a-L-Daunosaminyloxy) pentoxy] -5,11-dimethyl-5H-indolo [2,3-b] -quinoline (13)

4-O-acetyl-3-N-allyloxycarbonyl-L-acosaminal (6 g; 23.5 mM) was dissolved in methanol (120 ml), K2CO3 (1.5 g) was added and stirred for 2 hours at room temperature. It was then neutralized with acetic acid and evaporated to dryness under reduced pressure. The residue was dissolved in methylene chloride (150 ml) and methanesulfonyl chloride (1.2 eq) and pyridine (1.2 eq) were added. The mixture was stirred at room temperature for 12 hours, then poured into water and extracted with CH2Cl2. The combined organic layers were washed with water, dried and concentrated to give the crude 4-O-mesyl-3-N-allyloxycarbonyl-L-acosamin. The crude product was dissolved in DMF (60 ml) and sodium 4-nitrobenzoate (3 eq.) Was added. The mixture was heated for 10 hours at 125 ° C, then cooled, poured out into water and extracted with methylene chloride. The combined organic extracts were concentrated after drying and the residue was purified by column chromatography eluting with hexane: Et2O (4: 1). 4-Op-nitrobenzoyl-3-N-allyloxycarbonyl-L-daunosaminal was obtained as a yellowish oil. Yield 568 mg (40%). ¹ H NMR (CDCl3) δ: 8.27 (m, 4H, Ar-C6H4), 6.47 (dd, 1H, J 6.2, J 2.2 Hz, H-1), 5.85 (m, 1H, -CH =), 5.58 ( bd, 1H, J 3.9 Hz, H-4), 5.22 (m, 2H, = CH2), 4.60 (m, 5H, H-2, H-3, NH, CH2 allyl), 4.21 (bq, 1H, J 6.6, <0.5 Hz, H-5), 1.28 (d, 3H, J 6.6 Hz, H-6).

The obtained compound (6 g; 23.5 mM) was dissolved in 40 ml of dry THF, palladium tetrakis (triphenylphosphine) (375 mg) and formic acid (25 ml) were added. The progress of the reaction was monitored by TLC in hexane: ethyl acetate 1: 1. The product with the free amino group was not isolated. After completion of the reaction, the temperature of the reaction mixture was brought to ca. 0 ° C (ice / water bath), Et2N (16 ml; 11.5 mmol) and CF3COOEt (6 ml) were added dropwise. The reaction was carried out for 48 hours at room temperature while stirring with a magnetic stirrer. At this time, the reaction mixture was poured into an excess of saturated NH4Cl solution, stirred for 15 minutes, transferred to a separating funnel, and extracted with CHCl3. The combined organic layers were washed with water and dried. The crude product was purified by chromatography using hexane: ethyl acetate (3: 1; 2: 1) as the eluent. 4-Op-nitrobenzoyl-3-N-trifluoroacetyl-L-daunosamine was obtained as a light yellow solid. Yield 1.059 g (17%). Mp 140-143 ° C; IR (KBr) v _max : 3393, 3287, 3072, 2978, 2921, 1740, 1669, 1648, 1628, 1602, 1550, 1521, 1342, 1242, 1167, 1108, 1073, 989, 856 cm ^-1 ; ¹ H NMR (CDCl3) δ: 8.31-8.24 (m, 2H), 7.98-7.91 (m, 2H), 6.77 (bd, 1 H, 2 x 78.6 Hz), 6.48 (dd, 1H, J 6.3, J 2.4 Hz ), 4.97-4.91 (m, 1H), 4.68 (ddd, 1H, J 6.3, J 1.9 Hz), 4.13 (bq, 1H, J <0.5, J 6.6 Hz), 3.83 (m, 1H), 1.38 (d , 3H, J 6.6 Hz); MS (EI, 70 eV), M / z (%): 261 (M ⁺ -NHTFA ^- -H ⁺ , 2), 260 (13), 245 (100), 150 (95), 104 (27); Anal. element for C15H13N2O6F3 + 2 Et3N [576.66]: Calc .: C, 56.24; H, 7.52; N, 9.71%. Found: C, 56.34; H, 8.98; N, 9.24%.

To a solution of (4-Op-nitrobenzoyl-3-N-trifluoroacetyl-L-daunosamine) (2.3 g; 4 mmol) in dry CH2Cl2 (30 ml) was added 5-bromopentanol (1.34 g; 8 mmol) and HBr. Ph3P (200 mg). The mixture was stirred for 48 hours at room temperature. The reaction mixture was poured into excess saturated NaHCO3 solution, stirred for 15 minutes, then transferred to a separatory funnel. Extracted with methylene chloride, the combined organic extracts were washed with water and dried. After evaporation of the solvent, the product was purified by chromatography using as eluent system hexane: ethyl acetate (3: 2; 3: 1). 5- (4-Op-nitrobenzoyl-3-W-trifluoroacetyl-αL-daunosaminyloxy) bromopentane was obtained as a yellow oil, used in the next step without purification. Yield 692 mg (32%). ¹ H NMR (CDCl3) δ: 8.22 (m, 2H, pNBz), 7.96 (m, 2H, pNBz), 7.7-7.4 (m), 6.91 (bd, 1H, J 8.6 Hz, NH), 4.89 (bd, 1H, J 3.5 Hz, H-1), 4.60 (m, 1H, H-3), 4.08 (bq, 1H, J 6.6, J <0.5 Hz, H-5), 3.67 (m, 2H), 3.42 ( m, 3H), 1.91 (m, 2H), 1.62 (m, 6H), 1.25 (d, 3H, J 6.6Hz).

60% NaH was added to a solution of 5,11-dimethyl-5H-indolo [2,3-b] quinolin-9-ol (393 mg, 1.5 mmol) in dry DMF (20 ml) at a temperature below 0 ° C. (3 mmoles). After 30 minutes, the solution was added

PL 202 545 B1

2- (4-O-acetyl-3-W-trifluoroacetyl-α-L-daunosaminyloxy) bromopentane (812 mg, 1.5 mmol) in DMF (10 mL). The reaction flask was secured with a tube with a drying agent. The reaction was carried out below 0 ° C for about 15 minutes, then the cooling bath was removed and the reaction was continued at room temperature until at least one of the starting materials had disappeared. The progress of the reaction was monitored by TLC using CHCl3: MeOH. The reaction mixture was poured into excess saturated NH4Cl solution, stirred for 30 minutes, transferred to a separating funnel and extracted with CHCl3: MeOH solution (98: 2). The combined organic layers were washed with water and saturated NaHCO3 solution and dried. After evaporation of the solvent, the crude product (5,11-dimethyl-5H-indole- [2,3-b] -quinoline glycoside derivative) was dissolved in CH2Cl2: MeOH (1: 1) (20 ml), K2CO3 (20-30 % by weight of crude product), stirred at room temperature for 96 hours (TLC control CHCl3: MeOH = 80:20). The reaction mixture was diluted with water (30 ml), extracted with CH2Cl2: MeOH solution (98: 2), the combined organic extracts were washed with saturated NaHCO3 solution (pH ~ 7), dried with water. The crude product was purified by chromatography using CHCl3: MeOH: Et3N (80: 20: 0.06) and CHCl3: MeOH: Et3N (60: 20: 0.05) as the eluent. 9- [5- (α-L-daunosaminyloxy) pentoxy] -5,11-dimethyl-5H-indolo [2,3-b] quinoline was obtained in a yield of 358 mg (50%).

Results of biological research

The 5,11-dimethyl-5H-indolo [2,3-b] quinoline derivatives of the invention were tested for biological activity on selected tumor cell lines. Human cervical cancer cells KB were used in the research. The cytotoxic potency was expressed as the concentration which inhibited the growth of 50% of the cells (ID50).

The results of the determinations of selected compounds are presented in Table 1.

No relationship R1 (item 2) R2 (position 9) n Su ID50 ^ g / mL) 4 -O- (CH2) n-O-Su H. 5 2-deoxy-a-L-daunosaminyl 1.46 +/- 1.00 8 -O- (CH2) n-O-Su H. 2 2-deoxy-α-L-acosaminyl 0.45 +/- 0.07 11 -O- (CH2) n-O-Su H. 2 2-deoxy-α-L-acosaminyl 1.19 +/- 0.55 13 -O- (CH2) n-O-Su H. 5 2-deoxy-a-L-daunosaminyl 0.43 +/- 0.09

Patent claims

Claims (13)

Patent claims 1. 5,11-dimethyl-5H-indolo [2,3-b] quinoline carbohydrate derivatives of the general formula I, in which one of the groups R1 or R2 is -O- (CH2) nO-Su, where n = 2-6 and Su is a carbohydrate group while the other of the R1 or R2 groups is a hydrogen atom or a C1-C6 alkyl group; and the pharmaceutically acceptable salts thereof represented by the formula la, wherein X is the anion of an acid residue. 2. 5,11-dimethyl-5H-indolo [2,3-b] quinoline carbohydrate derivatives according to claim 1; The method of claim 1, wherein the carbohydrate group is derived from the amino sugar L-acosamine or L-daunosamine in pyranose form. 3. The 5,11-dimethyl-5H-indolo [2,3-b] quinoline carbohydrate derivatives according to claim 1; 2. The process of claim 1, wherein the carbohydrate group is a pyranose 2-deoxy-hexose derivative, preferably D-glucose, D-galactose, D-mannose, L-rhamnose or L-fucose. 4. A method for the preparation of 5,11-dimethyl-5H-indolo [2,3-b] quinoline derivatives of formula 1, in which one of the R1 or R2 groups is -O- (CH2) nO-Su, where n = 2-6, and Su is a carbohydrate group while the other of R1 and R2 groups is a hydrogen atom or a C1-C6 alkyl group, characterized in that the 5,11-dimethyl-5H-indolo [2,3-b] quinoline derivative is Formula 1, wherein one of the R1 or R2 groups is a hydroxyl group and the other R1 or R2 group is a hydrogen atom or a C1-C6 alkyl group a) subjecting to an alkylation reaction with an alkyl halide of formula 3: Y- (CH2) nOW where: Y is halogen, preferably bromine, PL 202 545 B1 W is a functional protected Su carbohydrate group, and n = 2-6; or b) undergo an alkylation reaction with an alkyl halide of formula 4 Y- (CH2) nOR3 in which: Y - is a halogen atom; R3 is a terminal hydroxyl protecting group, such as C1-C6 alkyl, C1-C6 acyl, or alkylsilyl; n = 2-6, then the terminal hydroxyl group is deprotected and the resulting compound of formula 1, in which R1 or R2 is a group -O (CH2) nOH, where n = 2-6, is reacted in the presence of the promoter with the glycosyl donor being a precursor to the Su carbohydrate group; then c) in compound 1 obtained according to the method a) or b) the functional groups on the sugar part are deprotected and, optionally, the compound 1 is converted into a pharmaceutically acceptable salt of formula 1a. 5. The method according to p. 4. A process as claimed in claim 4, characterized in that the alkylation reactions in variant a) and in variant b) are carried out in an aprotic solvent in the presence of a strong base selected from the group of metal hydrides, metal alcoholates or metal hydroxides. 6. The method according to p. 4. The process of claim 4, characterized in that a glycal is used as the glycosyl donor in the glycosidation reaction in which the hydroxyl groups have been protected in the form of an ester, ether, silyl ether, preferably acetic acid ester, and optional amino groups in the form of an amide or carbamate, preferably benzyl carbamate. , allyl carbamate, t-butyl carbamate or trichloroethyl carbamate. 7. The method according to claim 4. The process of claim 4, wherein the alkyl halide Y- (CH2) nOR3 in variant b) is protected as an acetic acid ester. 8. The method according to p. The process of claim 4, characterized in that the glycosidation reaction is carried out in the presence of an acidic promoter selected from the group of Lewis or Broensted acids, preferably in the presence of triphenylphosphine hydrobromide. 9. The method according to p. The process of claim 4, characterized in that the glycosidation reaction is carried out in an aprotic solvent selected from the group of ethers, cyclic ethers, halogenated aliphatic and aromatic hydrocarbons, preferably in dichloromethane or dichloroethane. 10. The method according to claim 4, characterized in that the glycosidation reaction is carried out at a temperature of -78 ° C to 80 ° C, preferably at room temperature, under an inert gas atmosphere. 11. The method according to p. 4. The method of claim 4, characterized in that the protection of the terminal hydroxyl group in variant b) is removed by solvolysis in an alcohol selected from the group of C1-C6 aliphatic alcohols, preferably in methanol, in the presence of a base selected from the group of metal alkoxides, carbonates or hydroxides or tertiary aliphatic amines , aliphatic-aromatic and aromatic, preferably potassium carbonate. 12. The method according to p. 4. The process of claim 4, wherein the amine deprotection reaction of the carbohydrate is carried out in the presence of a palladium triphenylphosphine complex. 13. Pharmaceutical for the treatment and / or prevention of neoplastic diseases, comprising the active substance and pharmaceutically acceptable carriers and / or diluents, characterized in that the active substance is a 5,11-dimethyl-5H-indolo [2,3-b] quinoline carbohydrate derivative of general formula I, in which one of the groups R1 or R2 is -O- (CH2) nO-Su, where n = 2-6 and Su is a carbohydrate group, while the other of the groups R1 or R2 is a hydrogen atom or a group C1-C6 alkyl where n = 2-6; or a pharmaceutically acceptable salt thereof represented by the formula la, wherein X is the anion of an acid residue.