Novel (poly)aminoalkylaminoalkylamide, alkyl-urea or alkyl-sulfonamide derivatives of epipodophyllotoxin, method of obtaining thereof and method of application thereof in therapy as anti-cancer medications

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of epipodophyllotoxin, substituted in position 4 with possibly substituted chain of (poly)aminoalkylaminoalkylamide, or alkyl-urea, or alkyl-sulphonamide, of formula 1 where R represents hydrogen or C_1-4alkyl, A represents CO(CH₂)_n or CONH(CH₂)_n, where n equals 2, 3, 4 or 5, R1 represents H or C_1-4alkyl, R2 represents (CH₂)_m-NR3R4, where m equals 2, 3, 4 or 5, R3 represents H or C_1-4alkyl, R4 represents H, C_1-4alkyl or (CH₂)_p-NR5R6, where p equals 2, 3, 4 or 5, R5 represents H or C_1-4alkyl and R6 represents H, C₁-C₄alkyl or (CH₂)_q-NH₂, where q equals 2, 3, 4 or 5 or their pharmaceutically acceptable salts, as well as to methods of their obtaining and to their application as anti-cancer medication.

EFFECT: obtaining novel derivatives of epipodophyllotoxin.

11 cl, 19 ex

The present invention relates to new derivatives podofillotoksina, substituted in position 4 may substituted chain (poly)aminoethylethanolamine, or alkyl-sulfonamida, or alkyl-urea, method of their production and their use as pharmaceuticals, in particular as anti-cancer tools.

Compounds of the present invention are derived podofillotoksina, natural Lignan known as a therapeutic agent in cancer treatment. Other synthetic derivatives such as etoposide or teniposide, are part of therapeutic Arsenal for the treatment, in particular, small-cell lung cancer. These different compounds act by inhibiting the catalytic activity of topoisomerase II.

Thus, alkylamines Deputy at position 4β 4'-demethylpodophyllotoxin skeleton is spermine or spermidine-alkylamino unit or in the more General case (poly)aminoethylethanolamine unit. In addition, this Deputy is spermine or spermidine-alkyl-sulfonamidnuyu unit or in the more General case (poly)aminoalkylphosphonic unit. Among other things, this Deputy is spermine or spermidine-alkylosing unit, or more generally, the beam unit (poly)aminoethylethanolamine.

Derivatives of 4'-demethylepipodophyllotoxin known as inhibitors 2-topoisomerase. Their cytotoxic and antitumor activity were detected and shown, in particular, for etoposide, THOR 53 (Drugs of the Future 1996, 21, 1136), GL 331 (Medicinal Research Reviews, 1997, 17, 367) and NK 611 (Cancer Chemother. Pharmacol. 1996, 38, 217 and 541). Described compounds having amine chain benzylamine type, directly attached in position 4β podofillotoksina (J. Med. Chem. 1991, 34, 3346). In the patent application FR 2810321 describes derivatives podofillotoksina urethane or THIOCARBAMATE type, useful in the treatment of cancer. Also described in connection with amidon at position 4β (US 6566393; Acta Pharmaceutica Sinica (Yaoxue Xuebao), 1993, 28, 422; Acta Chem. Scand. 1993, 47, 1190; Anti-Cancer Drug Design 2001, 16, 305). The described connections with urea at position 4β (Heterocycles 1994, 39, (1), 361; J. Med. Chem. 2002, 45, 2294).

In the patent EP 0876374 describes how demethylation podofillotoksina and simple obtain 4'-demethylepipodophyllotoxin representing a synthetic intermediate connection when receiving etoposide and teniposide.

In the international application WO 03/082876 describes 4β-4"-[{2"-benzoyl substituted}aniline]-derivatives podofillotoksina, have anticancer activity.

The need for more effective therapies encourages the search for new molecules with different mechanisms of action, sent the s on the types of tumors, difficult or not curable at the present time, as well as existing bypass the problems of resistance. The presence of these new products also allows you to develop protocols, including the combined use of therapies that are more active against certain tumors.

The new compounds of the present invention provide a way of overcoming this problem.

Compounds described in the patent application WO 2005/100363 have acetamide group at position 4β podophyllotoxins units, and this grouping is related to the amine or polyamines chain. The authors have synthesized derivatives having alkylamino, urea or sulfonamidnuyu grouping and documented their cytotoxic and anticancer activity.

The present invention relates to compounds of General formula 1:

where:

R represents hydrogen or C_1-4alkyl,

And is(CH₂)_nwhere n is 2, 3, 4, or 5, or represents CONH(CH₂)_nwhere n has the same values as described above, or

And represents the SO₂(CH₂)_nwhere n has the same values as described above

R1 represents H or C_1-4alkyl,

R2 represents N or C_1-4alkyl, or

R2 m which may represent (CH ₂)_m-NR3R4, where R3 represents H or C_1-4alkyl, and m is 2, 3, 4 or 5,

R4 represents N or C_1-4alkyl, or

R4 may also represent (CH₂)_p-NR5R6, where R5 represents H or C_1-4alkyl, and p is 2, 3, 4 or 5, and

R6 represents H or C_1-4alkyl, or

R6 may also represent (CH₂)_q-NH₂where q is 2, 3, 4 or 5,

except for the connection, where a is(CH₂)₂where both R1 and R2 are N.

It is implied that the term "C_1-4alkyl"as defined in the present invention, refers to a saturated linear or branched hydrocarbon chain containing 1-4 carbon atoms. The sample group includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Thus, throughout this description, With₃and C₄is an alkyl group refers to both straight and branched groups.

This invention also relates to their salts, in particular their pharmaceutically acceptable water-soluble salts, in particular their salts accession inorganic or organic acids, as well as containing their pharmaceutical compositions and their use as pharmaceuticals, in particular intended for the treatment of cancer.

Urea, amide,urethane or sulfonamidnuyu derivatives podofillotoksina described in the literature and patents (Zhongguo Yaoke Daxue Xuebao 1993, 24, 134; WO 2004/000859; US 2004/0106676; J. Med. Chem. 2004, 47, 2365; Org. Biomol. Chem. 2005, 3, 1074; WO 2004/073375; Bioorg. Med. Chem. 2003, 11, 5135). Their activity indicates inhibitory activity against 2-topoisomerases and their utility as compounds with antitumor activity. However, the low solubility of these compounds makes their application difficult. Although the presence in the molecule of the basic nitrogen atom gives the possibility of obtaining soluble salts, it is not always obvious how to get the active connection having the desired anti-tumor properties.

In the literature, except for the patent application WO 2005/100363, there is no description of any connection with polyamine chain, "sewn" through the spacer in the 4β-position 4'-demethyl-4-methoxymethylethoxy.

Accordingly, the present invention describes a new polyamine derivatives podofillotoksina.

Compounds of the present invention have the structure of epipodophyllotoxin, substituted at position 4β urea unit connected to polyamines chain, such as, in particular, putrescine, spermine or spermidine, and other polyamines. Similarly this position 4β can be connected to the amide group, then regardless of whether connected or not connected with the last line spacer containing from 2 to 5 atoms of plastics technology : turning & the Yes, with polyamines, such as putrescine, spermine or spermidine or other polyamine.

In addition, the position 4β may be substituted sulfamethazine unit, which is connected in turn with polyamines chain, such as chain of putrescine, spermine or spermidine. System transport of polyamines have already been used for targeted delivery of cytotoxic polyamine analogues (Anna. Rev. Pharmacol. Toxicol. 1995, 35, 55; Medicine/Sciences 1996, 12, 745), but, it seems, without much success.

Described compounds having polyamine chain "attached" to the intercalating into DNA unit acridine (J. Org. Chem. 2000, 65, 5590; J. Med. Chem. 2002, 45, 5098) or indonesiaindonesia (J. Med. Chem. 2003, 46, 5712) type.

The feature of the compounds of the present invention lies in the fact that they are DNA-directed agents and successfully induce damage in the specified DNA, both qualitatively and quantitatively different from other known anti-cancer compounds such as etoposide.

The presence polyamines chain, such as, for example, a chain of putrescine, spermine or spermidine, has the advantage that it is the transport system of natural polyamines used cancer cell for proliferation (J. Cell. Physiol. 1993, 155, 399; Annu. Rev. Biochem. 1984, 53, 749). This has the advantage that the compounds of the present invention as the preferred path to the cancer cell is about comparison with other cells. Thus, the compounds of the present invention possess cytotoxic properties in vitro and antitumor properties in vivo.

In addition, an important advantage of these compounds is the presence of functional amino groups, providing good solubility in water, which makes these compounds suitable from the point of view of technology of drug production, the introduction of the ability distribution and bioavailability in the body. Therefore, the pharmacokinetic parameters are improved.

Preferred compounds according to the invention is selected from the following compounds:

amide number:

compound 1: 3-(2-diethylaminoethylamine)-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-propionamide

compound 2: 4-(2-diethylaminoethylamine)-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-butyramide

compound 3: 3-[(2-dimethylaminoethyl)-methylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-propionamide

compound 4: 4-[(2-dimethylaminoethyl)-methylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxo the-5-yl]-butyramide

compound 5: 3-dimethylamino-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,ad,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-propionamide

compound 6: 4-dimethylamino-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-butyramide

compound 7: 5-diethylaminopentane acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-amide

compound 8: 3-(2-diethylaminoethylamine)-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-propionamide

compound 9: 4-(2-diethylaminoethylamine)-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-butyramide

connection 10: 3-(2-diethylaminopropylamine)-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-propionamide

compound 11: 4-(2-diethylaminopropylamine)-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-butyramide

compound 12: 3-(2-aminoet is amino)-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-propionamide

connection 13: 3-(3-aminopropylene)-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-propionamide

compound 14: 3-(4-aminoethylamino)-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-propionamide

compound 15: 4-(3-aminopropylene)-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-butyramide

the connection 16: 4-(4-aminoethylamino)-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-butyramide

the connection 17: 5-(4-aminoethylamino)pentanol acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-amide

compound 18: 3-{3-[4-(3-aminopropylene)-butylamino]-propylamino}-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]the oil[2,3-d][1,3]dioxol-5-yl]-propionamide

connection 19: 3-{3-[3-(3-aminopropylene)-propylamino]-propylamino}-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]the oil[2,3-d][1,3]dioxol-5-yl]-propionamide

compound 20: 3-{4-[4-(4-aminoethylamino)-butylamino]-butylamino}-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]the oil[2,3-d][1,3]dioxol-5-yl]-propionamide

compound 21: 4-{3-[4-(3-aminopropylene)-butylamino]-propylamino}-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]the oil[2,3-d][1,3]dioxol-5-yl]-butyramide

the connection 22: 4-{3-[3-(3-aminopropylene)-propylamino]-propylamino}-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]the oil[2,3-d][1,3]dioxol-5-yl]-butyramide

the connection 23: 4-{4-[4-(4-aminoethylamino)-butylamino]-butylamino}-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-butyramide

compound 24: 5-{3-[4-(3-aminopropylene)-butylamino]-propylamino} pentanol acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-amide

compound 25: 5-{3-[3-(3-aminopropylene)-propylamino]-propylamino}pentanol acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-amide

compound 26: 5-{4-[4-(aminoethylamino)-butylamino]-butylamino}pentanol acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-amide

compound 27: 3-[3-(4-aminoethylamino)-propylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-propionamide

compound 28: 3-[4-(3-aminopropylene)-butylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-propionamide

compound 29: 3-[3-(3-aminopropylene)-propylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-propionamide

compound 30: 3-[4-(4-aminoethylamino)-butylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-propionamide

compound 31: 4-[3-(4-aminoethylamino)-propylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-butyramide

compound 32: 4-[4-(3-aminopropylene)-butylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-butyramide

compound 33: 4-[3-(3-aminopropylene)-propylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,dioxol-5-yl]-butyramide

compound 34: 4-[4-(4-aminoethylamino)-butylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-butyramide

compound 35: 5-[3-(4-aminoethylamino)-propylamino]pentanol acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-amide

connection 36: 5-[4-(3-aminopropylene)-butylamino]pentanol acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]the oil[2,3-d][1,3]dioxol-5-yl]-amide

compound 37: 5-[3-(3-aminopropylene)-propylamino]pentanol acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-amide

compound 38: 5-[4-(4-aminoethylamino)-butylamino]pentanol acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]the oil[2,3-d][1,3]dioxol-5-yl]-amide

compound 55: 5-[(2-dimethylaminoethyl)-methylamino]pentanol acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]the oil[2,3-d][1,3]dioxol-5-yl]-amide

connection 56: 4-amino-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-g is kageromaru[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-butyramide

,

compound 57: 5 aminopentanoic acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]-dioxol-5-yl]-amide

connection 58: 3-(5-aminophenylamino)-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-propionamide

some of urea:

compound 39: 1-(4-aminobutyl)-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-urea

compound 40: 1-[4-(3-aminopropylene)-butyl]-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-urea

compound 41: 1-[3-(4-aminoethylamino)-propyl]-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-urea

compound 42: 1-[3-(3-aminopropylene)-propyl]-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-urea

compound 43: 1-[4-(4-aminoethylamino)-butyl]-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-urea

connect the FL 44: 1-{2-[3-(4-aminoethylamino)-propylamino]-ethyl}-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea

compound 45: 1-{2-[4-(3-aminopropylene)-butylamino]-ethyl}-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea

compound 46: 1-{4-[4-(4-aminoethylamino)-butylamino]-butyl}-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea

compound 47: 1-{3-[3-(3-aminopropylene)-propylamino]-propyl}-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea

compound 48: 1-{3-[4-(3-aminopropylene)-butylamino]-propyl}-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea

compound 49: 1-[2-{3-[4-(3-aminopropylene)-butylamino]-propylamino}-ethyl]-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-urea

compound 50: 1-[3-{3-[4-(3-aminopropylene)-butylamino]-propylamino}-propyl]-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-urea

compound 64: 1-[4-{3-[4-(3-aminopropylene)-butylamino]-propylamino}-bout the l]-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-urea

compound 65: 1-(5-{3-[4-(3-aminopropylene)-butylamino]-propylamino}-pentyl)-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-urea

compound 66: 1-{3-[3-(4-aminoethylamino)-propylamino]-propyl}-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea

compound 67: 1-{4-[3-(4-aminoethylamino)-propylamino]-butyl}-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea

compound 68: 1-{4-[4-(3-aminopropylene)-butylamino]-butyl}-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea

sulfa number:

compound 61: 2-(4-aminophenylamino)-econsultancy acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]the oil[2,3-d][1,3]dioxol-5-yl]-amide

compound 62: 2-[4-(4-aminoethylamino)-butylamino]-econsultancy acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]the oil[2,3-d][1,3]dioxol-5-yl]-amide

compound 63: 2-[3-(3-aminopropylene)-propyl what Mino]-econsultancy acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]the oil[2,3-d][1,3]dioxol-5-yl]-amide

connection 51: 2-(4-aminoethylamino)-econsultancy acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-amide

connection 52: 2-[3-(4-aminoethylamino)-propylamino]-econsultancy acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]the oil[2,3-d][1,3]dioxol-5-yl]-amide

compound 53: 2-[4-(3-aminopropylene)-butylamino]-econsultancy acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]the oil[2,3-d][1,3]dioxol-5-yl]-amide

compound 54: 2-{3-[4-(3-aminopropylene)-butylamino]-propylamino}-econsultancy acid 3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-amide

compound 59: 2-{3-[3-(3-aminopropylene)-propylamino]-propylamino}-econsultancy acid 3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-amide

compound 60: 2-{4-[4-(4-aminoethylamino)-butylamino]-butylamino}-econsultancy acid 3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-amide

and their salts accession inorganic or organic acids.

Compounds according to the invention are, for example, compounds of General formula 1, where:

- R represents a hydrogen atom or a C_1-4alkyl,

- A represents CO(CH₂)_n, CONH(CH₂)_nor SO₂(CH₂)_nwhere n is 2, 3, 4 or 5,

- R1 is a hydrogen atom or a C_1-4alkyl,

- R2 represents a hydrogen atom or a C_1-4alkyl or may represent (CH₂)_m-NR3R4, where m is 2, 3, 4 or 5,

- R3 represents a hydrogen atom or a C_1-4alkyl,

- R4 represents a hydrogen atom or a C_1-4alkyl or may represent (CH₂)_p-NR5R6, where p is 2, 3, 4 or 5,

- R5 is a hydrogen atom or a C_1-4alkyl, and

- R6 is a hydrogen atom or a C_1-4alkyl or may represent (CH₂)_q-NH₂where q is 2, 3, 4 or 5,

with the exception of compounds where a is(CH₂)₂or Rather it represents a SO₂(CH₂)₃and both R1 and R2 are N.

Preferably, R1 represents H, R3 represents H and R5 represents H. R may preferably be a hydrogen atom.

The compounds according to the invention are the Xia, for example, compounds of General formula 1, where a is(CH₂)_nor CONH(CH₂)_nwhere n is 2, 3, 4 or 5, with the exception of compounds where a is(CH₂)₂and both R1 and R2 are N.

The compounds according to the invention are, for example, such compounds of General formula 1, which are defined above, where R represents N.

The compounds according to the invention are, for example, such compounds of General formula 1, which are defined above, where R1 and R2 are not simultaneously H, when R represents N and a represents an O(CH₂)_nwhere n is 2, 3 or 4.

One specific embodiment of the invention refers to those compounds of General formula 1, which are defined above, where R2 represents (CH₂)_m-NR3R4, preferably R4 represents (CH₂)_p-NR5R6 and, in particular, m is 3 or 4, and p is 3 or 4, for example the compounds of General formula 1, where R6 represents H, C_1-4alkyl or (CH₂)_q-NH₂where q equals 3.

The present invention relates in particular to compounds of formula 1 selected from the group consisting of compounds 1-50, 55-58 and 64-68 described above, and their salts accession inorganic or organic acids.

More specifically, the compounds according to the invention can be selected from the group consisting the th of compounds 14-50 and 64-68, defined above, and their salts accession inorganic or organic acids.

For example, the compounds according to the invention can be selected from the group consisting of compounds 14, 16-18, 21-24, 27, 28, 31-36, 39 to 41, 44-50, 54, 64-68, defined above, and their salts accession inorganic or organic acids.

Isomeric compounds according to the invention is included in the scope of the invention.

In the present invention, the term "pharmaceutically acceptable"as used in this description implies that it is useful in the manufacture of a pharmaceutical composition, which is usually harmless, non-toxic and which are not biologically or otherwise undesirable, and which is suitable for pharmaceutical use in both veterinary and human.

As used herein, the term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable, as defined herein, and which have the desired pharmacological activity of the parent compound. In the framework of the present invention, the term more specifically refers salt attaching a pharmaceutically acceptable inorganic or organic acids.

Pharmaceutically acceptable acids include hydrochloric, Hydrobromic, sulfuric, phosphoric, acetic, trifter xunwu, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methansulfonate, camphor and sulfamoyl acid, but do not stop there. Compounds according to the invention are characterized by the fact that they are soluble in water due to the formation of inorganic or organic salts together with the basic nitrogen atoms of the side chain in position 4.

Another objective of the present invention is the use of compounds of formula 1 for anticancer therapy solid (liquid) tumors and solid tumors, such as melanoma, colorectal cancer, lung cancer, prostate cancer, bladder cancer, breast cancer, uterine cancer, esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, ovarian cancer, leukemia, particularly lymphoma and myeloma, cancer of the ear, nose and throat (ENT (ear, nose and throat) cancer) and cancer of the brain.

These compounds can be used in combination with other anticancer treatments, which can be cytotoxic or cytostatic, such as platinum derivatives, taxanes, vinylchloride, 5-FU (5-fluorouracil), to enhance their therapeutic efficacy for the treatment of tumors resistant to conventional therapies.

Another objective of the present invention is a method obtained the I of these compounds. This method involves applying podofillotoksina formula 2 as the starting material. In particular, in accordance with the method described in French patent FR 2742439 use the demethylation reaction podofillotoksina under the action of a pair of reagents - methionine (or dimethyl sulfide) and methanesulfonic acid in the presence or triperoxonane acid, or acetone and water to obtain 4'-dimethylamide-phallotoxin (4'-DMEP) formula 3. This connection can be subject of Ritter reaction in the presence of sulfuric acid or other strong acid with an organic nitrile of the formula Ra-CN, where Ra represents -(CH₂)_n-X or-CH=CH₂where n is 3, 4 or 5, and X represents a halogen atom such as a chlorine atom, to obtain the compounds of formula 4. Organic nitrile can be, in particular, chloroacetonitrile or more generally halogenoalkanes formula NC-(CH₂)_n-X.

Therefore, it may be formed intermediate compound, amide of formula 4A, where n is 3-5. When instead of halogenoalkanes interaction lead Acrylonitrile, get smart vinylamide formula 4b.

Amide compounds of formula 1, where a represents (CH₂)_n-X and R represents H, obtained as follows.

Intermediate compounds of formula 4 (4A or 4b) can be subjected to alkylation of the amine (monoamine, diamine or polyamines), particularly putrescine, spermidine or spermine, in a protected form. Polyamine contain several functional amino groups, so they must be protected by a protective group, leaving the free provision of primary amino groups to a good selectivity of the interaction. The specialist in this area is known for the choice of protective groups, such as benzyloxycarbonyl or tert-butyloxycarbonyl group, to protect those functional amino groups, which should not interact.

For example, the described spermin protected benzyloxycarbonyl (Z) or tert-butyloxycarbonyl (BOC) groups. Also described is Permitin, protected groups Z or VOS.

Thus, the alkylation reaction is carried out between a compound of formula 4 and the amine of the formula HNR1R2a in a protected form, where:

- R1 is as defined above,

- R2a represents a C_1-4alkyl, a protective group for the amine or (CH₂)_m-NR3aR4a, where m is as defined above,

- R3a represents a C_1-4alkyl or a protective group for the amine,

- R4a represents a C_1-4alkyl, a protective group for the amine or (CH₂)_p-NR5aR6a, where R such as defined above,

- R5a represents a C_1-4alkyl or a protective group for the amine,

- R6a represents a C_1-4alkyl, a protective group for the amine or (CH₂)_q-NR7aR8a, where q is as defined above,

- R7a represents H or a protective group for the amine, and

- R8a represents a protective group for an amine.

The protected functional amino group suitable for preventing the synthesis of undesirable side products in the reaction combinations, as in this case there is only one reactive site.

Obtaining various amines with protective groups are described in the following publications: Protective Groups in Organic Synthesis (Th. W. Greene, 2nd ed., John Wiley and Sons, 1991) or in the Synthesis 2002, 15, 2195; Bull. Chem. Soc. Jpn. 1998, 71, 699; Jet. Let. 1998, 39, 439 and 443; Tet. Let. 2001, 42, 2709; OPPI 1994, 26, 599; Synthesis 994, 37; J. Org. Chem. 1998, 63, 9723; Tet. Let. 1994, 35, 2057 and 2061, J. Med. Chem. 2004, 47, 6055; J. Med. Chem. 2003, 46, 5712; Tet. Let. 1995, 36, 9401; Tet. 2000, 56, 2449.

The protective group for the amine may, in particular, be a Z or BOC. Preferably, when all the protective group in the protected Amina will be the same.

In the alkylation reaction between a protected amine and a compound of formula 4 to obtain the compound of formula 5, and then, after removal of protection with functional amino groups, protected by a protective group for the amine (if such groups exist), the compound of formula 7a.

Thus, using a set of election protection with a protective group for an amine, such as BOC, or Z, professionals in this field can obtain the compounds of formula 7a.

Possible the last stage of the method according to the invention is the removal of protection with functional amino groups, protected by relevant groups.

The compounds will then be isolated from the reaction mixture according to methods well-known to specialists in this field of technology.

Compounds of the present invention contain chiral centers natural podofillotoksina. In the compound of formula 2 (4'-DMEP) the hydrogen atoms in positions 5, 5A, 8A and 9 are characterized by the following stoichiometry: 5α, 5α, β, 1-19β. In the compound of formula 3, the configuration of asymmetric carbon atoms are preferably the following: 5S, 5aS, 8aR, 9R.

Compounds of urea of the formula 10 is obtained from 4P-chloroacetamido-4'-demethylpodophyllotoxin formula 4A (n is 1, X represents Cl), in which the 4'-phenol protected by a protective group for hydroxyl Y, such as benzyloxycarbonyl group. As a result of processing thiourea is obtained aminosidine formula 8, where R represents H, in which the group in position 4' protected by a protective group Y, such as the group Z (benzyloxycarbonyl), with compounds of formula 8, where R is not H, can be obtained in accordance with the method described in US 7378419.

This compound of formula 8 (in particular, where R is H) then lead into interaction with isocyanates, such as halogenoalkanes formula O=C=N-(CH₂)_n-X, where X is a halogen, and n denotes the chain containing from 2 to 5 CH₂with obtaining the compounds of formula 9 (in accordance with the method described in Heterocycles 1994, 39, 361). This is an intermediate compound of formula 9 lead in interactions with protected mono-, di-, tri - or tetrame the AMI (formula HNR1R2a), as mentioned above, in conventional alkylation conditions, that is, in particular, at room temperature in DMF in the presence of triethylamine and KI obtaining compounds of formula 10A, and then, after removal of the protections in the 4'-position podophyllotoxin frame and protected with functional amino groups, to obtain the compounds of formula 10b.

The compounds will then be isolated from the reaction mixture according to methods well known to specialists in this field.

Urea can be obtained by using the compound of formula 8 (in particular, where R represents H) and phosgene or triphosgene, receiving no allocation of activated carbonyliron intermediate compounds. These intermediate compounds correspond to the following the following formula:

This intermediate connection the following lead in interacting directly with the protected amine, a diamine or polyamino formula H₂N-(CH₂)_n-NR1aR2a, where R1a represents H, C_1-4alkyl or a protective group for the amine and where R2a and n are such as defined above (where R1a is not H, when R2a represents a C_1-4alkyl or (CH₂)_m-NR3aR4a), obtaining the compounds of formula 10C, while the remaining stages of the synthesis performed, as described above (removal of protection with functional amino groups and phenol). P is Srednyaya stage removal of protections, carried out either in an acid medium in the case of a group VOS or by catalytic hydrogenation in the case of Z, leads to the production of free polyamino compounds of General formula 1, where a represents CONH(CH₂)_n.

However, alkylation of polyamines, which podophyllotoxin-halogenoalkane, is not an unambiguous response. One of the conditions of the process of this classically used alkylation is an alkaline environment. It is important to conduct the reaction in an alkaline environment, such as in the presence of triethylamine. The basicity of the environment can lead along with this process to obtaining a by-product resulting from the epimerization of the proton in position 2 leading to the CIS-lactoovo derivative of formula 11, or isomer of formula 1. However, using precision chromatography perhaps the selection of the desired TRANS-lactoovo derived. In the following examples shows an alternative way to prevent such possible epimerization. It consists in the formation of chain alanovoy acid protected polyamine (compound of formula 12, where R1a as defined above), then the combination of the obtained product by peptide combination with 4β-amino-4-deoxy-4'-demethylpodophyllotoxin formula 6 (in particular, where R represents the t a N) in accordance with the following reaction scheme:

This peptide combination is conducted preferably in the presence of TBTU, preferably with polyamino protected benzyloxycarbonylamino groups and containing grouping propionic, butyric or pentanol acids. The intermediate acid containing group having 2 carbon atoms (formula 12, n=2), get through the condensation with methyl acrylate similar to the receipt of the products described in Tet. 2006, 62, 8332. Intermediate acids of formula 12, where n is 3-5, get accepted by alkylation of an amine-protected halogenoalkanes complex ether, which is then amyraut to carboxylic acids. In the future receive the compounds of formula 7b, so that after removal of the protection from the protected functional amino group to obtain the compounds of formula 7.

The compounds will then be isolated from the reaction mixture according to methods well known to specialists in this field.

Sulfonamidnuyu compounds obtained as follows.

The compound of formula 8 (in particular, where R represents H) result in interaction with chloroethylsulphonic obtaining vinylsulfonate intermediate connections, as opposed to obtaining various protected polyamines remove protection carried out by a conventional hydrogenation in the presence of palladium on is in the case where the protective group Z, or in an acid medium in the case of a protective group BOC.

In the following non-limiting examples illustrate how the techniques used in this way

1. The intermediate compounds

The intermediate connection I 4-amino-4'-demethyl-4-methoxypropyl-toxin (formula 6, where R=N)

This connection receive, as described in patent application WO 2007/010007.

Stage 1: the Ritter reaction: getting 4β-chloroacetamido-4'-demethyl-4-methoxymethylethoxy Formula 4A (where n=1, and X=Cl)

To a suspension of 30 g (0,075 mol) of 4'-demethylepipodophyllotoxin formula 3 47.5 ml (0.75 mol) of chloroacetonitrile at room temperature is added dropwise 0.5 ml of concentrated sulfuric acid. The mixture is left to be mixed at this temperature for 1 hour, during this period of time is observed dissolution with subsequent resuspension of sediment. Add 300 ml of 2-propanol. The precipitate is filtered off, washed with 200 ml of 2-propanol and water to pH 7. The obtained white solid is dried under vacuum at 40°C with the receipt of 32.9 g chloracidobacterium the compounds of formula 4A (n=1, X=Cl), that is, with the release of 93%. TPL=240°C.

Stage 2: obtain 4-amino-4'-demethyl-4-methoxymethylethoxy (Formula 6, where R=N)

A suspension of 17 g (0,0358 mol) 4(3-chloroacetamido-4'-demethyl-4-methoxymethylethoxy, obtained above, in 75 ml of glacial acetic acid is heated to 80 is C With stirring. Add in one portion of 4.2 g (0,0537 mol) of thiourea. The mixture is left to be mixed at this temperature for 1 h 30 min, during this period of time is observed dissolution with subsequent resuspension of sediment. The reaction mixture is filtered while hot, washed with 75 ml of glacial acetic acid and diisopropyl ether. The obtained white solid is dried under vacuum at 40°C. to obtain 14.6 g of the compound of formula 6 in the form of the hydrochloride, which corresponds to a molar yield of 93%. TPL>260°C.¹H-NMR (DMSO) δ 8.63 (m, 2H), 8,32 (m, 1H), 7.23 (s, 1H, H₅), 6.60 (s, 1H, H₈), 6.18 (s, 2H, H_2'N_6'), 6.05 (d, 2H, J=2.1 Hz, OCH₂O), 4.73 (d, 1H, J=4.5 Hz, H₄), 4.56 (d, 1H, J=5.2 Hz, H₁), 4,34 (m, 2H, H_11aand H_11b), 3.65 (dd, 1H, J=5.2 Hz, H₂), 3.62 (s, 6H, 2×och₃), 3.06 (m, 1H, H₃).

The intermediate compound II: getting 4β-acrylamide-4'-demethyl-4-methoxymethylethoxy

To a suspension of 3 g (0,0075 mol) of 4'-demethylepipodophyllotoxin formula 3 in 10 ml of Acrylonitrile at room temperature, add a few drops of concentrated sulfuric acid. The mixture is left to be mixed at this temperature for 3 hours, during this period of time is observed dissolution with subsequent resuspension of sediment. Add 50 ml of 2-propanol. The precipitate is filtered off, washed with 2-propanol and water to pH 7. The obtained white solid is dried under vacuum at 40°C. to obtain 2.64 g acrylamide connection. TPL=180°C. TLC SiO₂(30:70 heptane:AcOEt): Rf=0.25 in. Anal. C₂₄H₂₃NO₃H₂O (MW=471,464): calculated% 61,14, N% 5,63, N% 2,66; found:% 60,84, N% 5,34, N% 2,97.

The intermediate compound III: getting 4β-chloroethylamino-4'-demethyl-4-methoxymethylethoxy

Stage 1: getting 4β-chloroethylamino-4-methoxymethylethoxy

This compound is obtained from podofillotoksina and 4-chlorobutyronitrile in accordance with the procedure described in stage 1 obtain the intermediate compound I for the interaction of chloroacetonitrile with 4'-demethylepipodophyllotoxin. TLC SiO₂(9:1 CH₂Cl₂:acetone): Rf=0,38; yield=71%.

Stage 2: getting 4β-chloroethylamino-4'-demethyl-4-deoxy-podofillotoksina (Formula 4A, where n=3 and X=Cl)

of 4.46 g of compound obtained in stage 1 above, are suspended with stirring in 21,16 ml methanesulfonic acid. Then add 1,93 g D,L-methionine and stirring is continued for 2 hours the Reaction mixture is poured with stirring into water and sludge. In the filtering and washing with water until a neutral pH is obtained after drying and removal of water of 2.26 g (yield=52%) of the product of demethylation. TLC SiO₂(9:1 CH₂Cl₂:acetone): Rf=0,20. Product IP is result directly without purification in the following stage alkylation.

The intermediate compound IV: getting 4β-brompheniramine-4'-demethyl-4-methoxymethylethoxy

This connection will receive is similar to getting 4β-chloroacetamido-4'-demethyl-4-methoxymethylethoxy, stage 1 intermediate compound I, but using the appropriate reagent, i.e., 5-bromobutyronitrile. 4β-Brompheniramine-4'-demethyl-4-methoxymethylethoxy get with the release of 57%. TLC SiO₂(95:5 CH₂Cl₂:MeOH): Rf=0.28 In. The characteristic signals of the spectrum¹H-NMR (DMSO) δ 5.39 (t, 2H, J=6.4 Hz, CH₂Br), 2.17 (t, 2H, J=7.2 Hz, CH₂CO), 1.79 (m, 2H, CH₂), 1.66 (m, 2H, CH₂).

2. Obtaining the compounds according to the invention

Example 1: obtaining 3-dimethylamino-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]-propionamide or (4β-dimethylaminopropylamine)-4'-demethyl-4-methoxymethylethoxy) (Compound 5)

500 mg 4β-amino-4'-demethyl-4-methoxymethylethoxy formula 6 and 146 mg of 3-dimethylaminopropionic acid are dissolved with stirring in 50 ml of acetonitrile together with of 0.21 ml of triethylamine. Add 400 mg of TBTU and stirring is continued for 6 h at room temperature. The reaction mixture was poured into water (300 ml) and extracted with ethyl acetate (3×100 ml). The organic phase is dried over Na₂SO₄, filtered and evaporated. The residue is subjected to F. the ash-chromatography on SiO ₂(elution with a mixture of 78:20:2 CH₂Cl₂:MeOH:NH₄OH). After evaporation the residue is again subjected to chromatography on a preparative HPLC-column (X Bridge, OBD C18, 30×250 mm, 10 μm), gradient elution of CH₃CN/5 mm HCI (from 10/90 to 80/20). The fraction extracted with ethyl acetate (2×100 ml), dried and evaporated. The residue was transferred to salt, using a mixture of HCl in isopropanol and ethyl ether, filtered and dried to obtain 246 mg of the hydrochloride as a white powder. Yield=37%. TLC SiO₂(90:9:1 CH₂Cl₂:MeOH:NH₄OH): Rf=0,38. NMR reasons:¹H-NMR (DMSO) δ 8.36 (d, 1H, NH), 8.28 (s, 1H, OH), 6.76 (s, 1H, H₅), 6.53 (s, 1H, H₈), 6.24 (s, 2H, H_2'N_6'), 5.99 (d, 2H, J=8.4 Hz, OCH₂O), 5.16 (dd, 1H, H₄), 4.50 (d, 1H, J=5 Hz, H₁), 4.25 (t, 1H, H_11a), a 3.87 (t, 1H, H_11b), 3.62 (s, 6H, OMe), 3.11 (dd, 1H, H₂), with 2.93 (m, 1H, H₃), 2.42-2.55 (m, 2H, CH₂N), 2.24-2.33 (m, 2H, CH₂N), 2.12 (s, 6H, NMe₂). Mass spectrum (APCI), m/z=499, M-H+.

Example 2: obtain 4-dimethylamino-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-butyramide or (4β-dimethylaminobutyric)-4'-demethyl-4-methoxymethylethoxy) (Compound 6)

A solution of 570 mg of the intermediate compound III obtained above, stirred for 12 h in 25 ml of acetonitrile together with of 0.28 ml (5 EQ.) dimethylamine. Then the reaction mixture was poured on ice and add 1 HCl solution to pH 4. Extra the of conduct, using methylene chloride, and then the aqueous phase is alkalinized solution of NaHCO₃to pH 8. This phase is re-extracted with CH₂Cl₂, dried over Na₂SO₄, filtered and evaporated, receiving 100 mg orange foam. Hydrochloride form in methylethylketone, adding a solution of HCl in isopropanol (3 BC). Then the hydrochloride is filtered off, washed with methyl ethyl ketone, then with ethyl ether. After drying the obtained crystals represent 90 mg whitish powder. TLC SiO₂(90:10:1 CH₂Cl₂:MeOH:NH₄OH): Rf=0,47. TPL=169°C.¹H-NMR (DMSO) δ 8.35 (d, 1H, NH), 6.75 (s, 1H, H₅), 6.51 (s, 1H, H₈), 6.20 (s, 2H, H_2'H_6'), 5.96 (d, 2H, J=6.36 Hz, OCH₂O), 5.15 (dd, 1H, H₄), 4.47 (d, 1H, J=5 Hz, H₁), 4.26 (t, 1H, H_11a), 3.68 (t, 1H, H_11b), 3.59 (s, 6H, OMe), to 3.34 (m, 2H, CH₂N), 3.08 (dd, 1H, H₂), with 2.93 (m, 1H, H₃), 2.72 (s, 6H, NMe₂), 2.22 (m, 2H, CH₂CO)to 1.86 (m, 2H, CH₂). Anal. C₂₇H₃₃ClN₂O₈calculated% 55,43; N% 6,37; N% 6,06; detected% Is 55.74, N% 6,01, N% 4,68.

Example 3: obtaining 3-[(2-dimethylaminoethyl)-methylamino]-N-[9-(4-hydroxy-3,5-dimethoxybenzyl)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-propionamide or (4β-[3-[2-(N-methyl-N,N-dimethylamino-2-ethyl)]propionamide)]-4'-demethyl-4-methoxymethylethoxy) (Compound 3)

200 mg of the intermediate compound (II) dissolved in 20 ml THF and the reaction mixture dropwise make 1,15 m is N,N,N'-trimethylethylenediamine. The mixture is stirred for 12 h at room temperature and then evaporated to dryness. At this stage receive a mixture of 2 epimeres position 2 (CIS-lactone and TRANS-lactone). Flash chromatography (elution with a mixture of CH₂Cl₂:MeOH:NH₄OH 90:10:0.5) to receive 70 mg epimerase derived position 2 (CIS-lactone). TPL=178°C.¹H-NMR (DMSO) δ 8.41 (d, 1H, J=8.96 Hz, CONH), 8.29 (m, 1H, HE), 6.95 (s, 1H, H₈), 6.89 in (s, 1H, H₅), 6.42 (s, 2H, H_2'H_6'), 6.01 (d, 2H, J=4.04 Hz, OCH₂O), 5.08 (dd, 1H, J=6.6 Hz, H₄), 4,37 (s, 1H, H₁), 4.28 (t, 1H, J=9.2 Hz, H_11a), 4.01 (dd, 1H, J=4 Hz, J'=9.6, H_11b), 3.79 (dd, 1H, J=1.6 Hz, J'=10.8, N₂), 3.69 (s, 6H, OMe), 3,32 (m, 3H, H₃, COCH₂), 2.63-2.27 (m, 6H, CH₂N)2.194 (s, 3H, NMe), 2.101 (s, 6H, NMe₂).

Example 4: obtaining 5-diethylaminopentane acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]-dioxol-5-yl]-amide or (4β-diethylaminopentane-4'-demethyl-4-deoxy-podofillotoksina) (Compound 7)

700 mg of the brominated intermediate compound IV obtained above, mix in 3.3 ml of 2 M solution of dimethylamine in THF for 4 hours in nitrogen atmosphere. The solution was poured into ice and add a solution of HCl (0.1 N.) to pH 7. The solution is extracted with ethyl acetate, getting after drying over Na₂SO₄, filtration and evaporation 341 mg of oil, which is then purified flash chromatography on SiO₂97:7:0,7 CH ₂Cl₂:MeOH:NH₄OH) to give 200 mg of pure oil. The hydrochloride is formed by adding to the base, dissolved in isopropanol, the solution of hydrochloric acid ethanol to acidic pH values. TLC SiO₂(90:10:1 CH₂Cl₂:MeOH:NH₄OH): Rf=0,23. TPL (sticky substance)=224°C.¹H-NMR (DMSO) δ scored 8.38 (d, 1H, J=8.56 Hz, NH), 6.77 (s, 1H, H₅), 6.53 (s, 1H, H₈), 6.23 (s, 2H, H_2'H_6'), 5.99 (d, 2H, J=12.4 Hz, OCH₂O), 5.18 (dd, 1H, J=8.16 Hz, J'=4.76 Hz, H₄), 4.49 (d, 1H, J=5.12 Hz, H₁), 4.29 (t, 1H, J=8 Hz, H_11a), 3.73 (t, 1H, J=10.34 Hz, H_11b), 3.63 (s, 6H, OMe), 3.22 (dd, 1H, J=5.16 Hz, J'=14.3 Hz, H₂), and 3.3 (t, 2H, J=7.08 Hz, CH₂N), 2.93 (m, 1H, H₃), 2.71 (s, 6H, NMe₂), 2.20 (t, 2H, J=6.88 Hz, CH₂WITH), 1.59 (m, 4H, CH₂).

Example 5: obtain 5-[(2-dimethylaminoethyl)-methylamino]pentanol acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-amide or 4β-[5-[2-(N-methyl-N-dimethylamino-2-ethyl)]pentanone)]-4'-demethyl-4-methoxypropyl-toxin (Compound 55)

This connection receive similarly, to obtain compounds of Example 2, but using brominated intermediate compound IV and N,N,N'-trimethylethylenediamine. Get 4β[5-[2-(N-methyl-N-dimethylamino-2-ethyl)]pentanone)]-4'-demethyl-4-deoxy-podophyllotoxin mixed with his 8A-epimer. Flash chromatography (elution with a mixture of CH₂Cl₂:MeOH:NH₄OH, 95:5:0.5, and then 90:10:0,6) allows the separation shall be specified in the header connection. The dihydrochloride crystallized from isopropanol, adding hydrochloric ethanol. HPLC (Symmetry C8; elution with a mixture based buffer KH₂PO₄(3.4 g/l), brought to pH 4 by addition of H₃PO₄and CH₃CN (80/20)). Retention time (RT): 4,95 min¹H-NMR (DMSO) δ scored 8.38 (d, 1H, J=8.56 Hz, NH), 6.78 (s, 1H, H₅), 6.53 (s, 1H, H₈), 6.24 (s, 2H, H_2'H_6'), 6.00 (d, 2H, J=11.3 Hz, OCH₂O), 5.19 (dd, 1H, J=8.15 Hz, J'=4.6 Hz, H₄), 4.50 (d, 1H, J=4.8 Hz, H₁), 4.29 (t, 1H, J=8 Hz, H_11a), 3.72 (dd, 1H, H_11b), 3.63 (s, 6H, OMe), 3.53 (m, 2H, CH₂N), 3.08-3.24 (m, 5H, CH₂N, N₂), 2.93 (m, 1H, H₃), 2.84 (s, 6H, NMe₂), 2.79 (s, 3H, NMe), 2.20 (t, 2H, J=6.88 Hz, CH₂CO), 1.69 (t, 2H, CH₂), 1.57 (m, 2H, CH₂).

Example 6: obtain 4-amino-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-butyramide or (4β-aminobutane-4'-demethyl-4-methoxymethylethoxy) (Compound 56)

Step 1: to a solution of 1 g of 4β-amino-4'-demethyl-4-methoxymethylethoxy formula 6 in 50 ml of acetonitrile was added with stirring 510 mg of 4-tert-butoxycarbonylmethylene acid (Bioorg. Med. Chem. Lett. 2005, 15, 1969), together with and 0.40 ml of triethylamine. Then add 800 mg of TBTU and stirring is continued at room temperature for 5 hours, the Reaction mixture was poured into water and extracted with ethyl acetate. After evaporation of the solvent the residue is purified flash chromatography on SiO₂ 2Cl₂to a mixture of 90:9:1 CH₂Cl₂:MeOH:NH₄OH). Preparative chromatography on X Bridge C18, OBD, 30×250 mm, 10 μm, eluent: gradient from 10:90 CH₃CN/H₂O to 90:10 CH₃CN/N₂About can be obtained after evaporation containing pure compound fractions 460 mg of a colorless oil. Yield=31%. TLC SiO₂(90:9:1 CH₂Cl₂:MeOH:NH₄OH): Rf=0,20,¹H-NMR (DMSO) δ 8.25 (s, 1H, HE), 8.22 (d, 1H, J=8 Hz, NH amide), 6.79 (m, 1H, NH carbamate), 6.76 (s, 1H, H₅), 6.52 (s, 1H, H₈), 6.24 (s, 2H, H_2'H_6'), 6.00 (d, 2H, J=13.2 Hz, OCH₂O), 5.17 (dd, 1H, J=8 Hz, J'=4.4 Hz, H₄), 4.49 (d, 1H, J=4.8 Hz, H₁), 4.27 (t, 1H, J=8 Hz, H_11a), 3.74 (t, 1H, J=9.6 Hz, H_11b), 3.62 (s, 6H, OMe), 3.15 (dd, 1H, J=14.4 Hz and J'=5.2 Hz, H₂), 2.89-2.96 (m, 3H, H₃and CH₂N), 2.13 (t, 2H, J=7.2 Hz, CH₂WITH), 1.62 (m, 2H, CH₂), 1.36 (s, 9H, t-Bu).

Stage 2: intermediate carbamate, obtained in stage 1 above, was stirred at room temperature for 4 h in 25 ml of CH₂Cl₂in the presence of 25 ml of HCl in isopropanol (3,3 M). After evaporation obtain a white precipitate, which is filtered, washed with ethyl ether and dried, obtaining 275 mg of the hydrochloride as a white powder. Yield 67%. TPL=284°C. TLC SiO₂(90:9:1 CH₂Cl₂:MeOH:NH₄OH): Rf=0,18; MS (ESI+) m/z=485 (M-H+).¹H-NMR (DMSO) δ 8.44 (d, 1H, J=7.6 Hz, amide NH), 8.27 (m, 1H, HE), 7.91 (m, 2H, NH₂and HCl), 6.77 (s, 1H, H₅), 6.53 (s, 1H, H₈), 6.24 (s, 2H, H_2'H_6'), 6.00 (d, 2H, J=11.6 Hz, OCH 2O), 5.19 (d, 1H, J=4.4 Hz, H₄), 4.52 (d, 1H, J=5.2 Hz, H₁), or 4.31 (t, 1H, J=8 Hz, H_11a), 3.74 (m, 1H, H_11b), 3.63 (s, 6H, OMe), 3.17 (dd, 1H, J=14 Hz and J'=4.8 Hz, H2), 2.95 (m, 1H, H₃), 2.81 (t, 2H, J=7.6 Hz, CH₂N), 2.27 (t, 2H, J=7.2 Hz, CH₂CO), 1.83 (m, 2H, CH₂).

Example 7: obtain 5-aminopentanoic acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]-dioxol-5-yl]-amide or (4β-aminopentanoic-4'-demethyl-4-methoxymethylethoxy) (Compound 57)

This connection will receive is similar to obtaining a connection from Example 6 above, but using 5-tert-butoxycarbonylamino acid.

Example 8: in the same manner as in Example 6, but using instead 4-tert-butoxycarbonylmethylene acid corresponding protected diamino-, triamine or terminologija acid with propionic chain (which is obtained using methyl acrylate similar to the way in publishing Tetrahedron 2006, 62, 8335), synthesized compounds 8, 10, 12, 13, 14, 29, 30, 27, 28, 58, 19, 20 and 18 formula 1 (where A=CO(CH₂)_n, n=2).

Example 9: getting 2-{3-[4-(3-aminopropylene)-butylamino]-propylamino}-econsultancy acid 3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-amide or (4β-2-{3-[4-(3-aminopropylene)-butylamino-propylamino}-ethanallen-amido-4'-demethyl-4-methoxymethylethoxy) (With the Association 54)

Stage 1: getting 4β-vinylsulfonate-4'-benzyloxycarbonyl-4'-demethyl-4-methoxymethylethoxy

500 mg 4β-amino-4-deoxy-4'-benzyloxycarbonyl-4'-demethylepipodophyllotoxin formula 8 was dissolved in 20 ml of CH₂Cl₂together with 0.4 ml of triethylamine. Dropwise with stirring, 0.1 ml of 2-chlorate-sulphonylchloride in 5 ml of CH₂Cl₂at -15°C. Stirring is continued for 15 min, then the mixture is left to warm to ambient temperature and stirring is continued for 4 hours Then the reaction mixture was poured into water and extracted with CH₂Cl₂. The combined organic phases, dried over Na₂SO₄, filtered and evaporated. The residue is purified flash chromatography elute with a gradient from pure heptane to pure AcOEt. The obtained fractions containing pure compound, evaporated, getting 220 mg of a foam. Yield=55%. TLC SiO₂(90:9:1 CH₂Cl₂:MeOH:NH₄OH): Rf=0,7;¹H-NMR (DMSO) δ 8.03 (d, 1H, J=8.56 Hz, NH), 7.40 (m, 5H, Ar), 7.02 (dd, 1H, J=at 16.36 Hz, J'=9.8 Hz, HC=), 6.91 (s, 1H, H₅), 6.53 (s, 1H, H₈), 6,33 (s, 2H, H_2'H_6'), 6.15 (d, 1H, J=16.4 Hz, HC=), 6.09 (d, 1H, J=9.8 Hz, HC=), 6.01 (d, 2H, J=11.3 Hz, OCH₂O), 5.23 (s, 2H, CH₂Ph), 4.67 (dd, 1H, J=8.24 Hz, J'=4.4 Hz, H₄), 4.59 (d, 1H, J=5.4 Hz, H₁), or 4.31 (t, 1H, J=8.04 Hz, H_11a), 4.13 (t, 1H, H_11b), 3.63 (s, 6H, OMe), 3.28 (dd, 1H, J=5.36 Hz and J'=18.48 Hz, H₂), 2.97 (m, 1H, H₃).

Stage 2: add N1,N2,N3-the tribe is ilexibility

220 mg of the vinyl derivative obtained in the above stage dissolved in 10 ml of methanol. To the reaction mixture are added 220 mg of N1,N2,N3-dibenzylethylenediamine and stirring is continued for 5 days at room temperature. After evaporation under vacuum, water is added and the mixture extracted with ethyl acetate. After drying the organic phase, filtration and evaporation are clean flash chromatography (gradient elution from pure heptane to pure AcOEt and then to a mixture of 90:9:1 AcOEt:MeOH:NH₄OH). Receive 70 mg of Tetra-substituted compounds obtained as a result of the merger, that is, with the release of 16% (TRANS-lactoovo connection). Also get another epimerase position 2 compound (CIS-lactonase connection).

Analysis of TRANS-lactoovo compound: TLC SiO₂(90:9:1 CH₂Cl₂:MeOH:NH₄OH): Rf=0,6. Analytical HPLC: X Bridge C8, a 4.6×250 mm, 5 μm, eluent: 80:20 CH₃CN:H₂O-KH₂PO₄6.8 g/l, pH=4, flow rate 1 ml/min, RRT=3,55 min MS (ESI+) m/z=1094.

Stage 3: the hydrogenolysis protective groups

70 mg of the above TRANS-lactoovo derived placed in an atmosphere of hydrogen in the mixture of 10 ml of methanol and 5 ml of CH₂Cl₂. Add 0.25 ml of HCl in isopropanol together with 50 mg of 10%palladium on coal. Vigorous stirring is continued for 5 hours the Catalyst is filtered off,washed with methanol, the residue is evaporated under vacuum and transferred into ethyl ether for crystallization of the hydrochloride, which is filtered off and dried under vacuum. Receive 30 mg of crystals of the hydrochloride (yield 63%). TPL=191°C. Analytical HPLC: X Bridge C8, a 4.6×250 mm, 5 μm, eluent: 15:85 CH₃CN:H₂O-KH₂PO₄6.8 g/l, pH 4, flow rate 1 ml/min, RRT=14,08 min MS (ESI+) m/z=692 (M-H+).

Example 10: compound 51, 52, 53, 59, 60, 61, 62 and 63 can be synthesized in the same manner as in Example 9, using the appropriate protected monoamines, diamines, triamines and tetraamines by condensation with 4-β-vinylsulfonate-4'-benzyloxycarbonyl-4'-demethyl-4-methoxymethylethoxy obtained in stage 1 of Example 9.

Example 11: obtain 4-{3-[4-(3-aminopropylene)-butylamino]-propylamino}-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6.8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-butyramide or (4-{3-4-{3-[4-(3-aminopropylene)-butylamino]-propylamino}-butyramide-4'-demethyl-4-methoxymethylethoxy) (Compound 21)

This compound is synthesized in accordance with one of the 2 following methods.

Method 1: alkylation of chlorinated derivative (intermediate compound (III)

This compound is produced by way similar to Example 2. Use the higher chlorinated intermediate compound III and condense with t is benzyloxycarbonyl-spermine (described in Tet. Let. 1998, 39, 439) to obtain 4-β-4-{3-[4-(3-aminopropylene)-butylamino]-propylamino}-butyramide-4'-demethyl-4-methoxymethylethoxy after hydrogenolysis in accordance with the same method as in stage 3 of Example 9.

Method 2: peptide combination

Stage 1: 7.51 g of dibenzylethylenediamine (Z-spermine) (Tet. Let. 1998, 39, 439) with stirring and dissolved in 150 ml of acetonitrile. Added to 2.1 ml of triethylamine, then 2.25 g of methylbromide and then 900 mg of cesium carbonate. The reaction mixture was refluxed for 20 h under stirring. The mixture was poured into water and extracted with ethyl acetate (3×200 ml), the organic phase dried over Na₂SO₄, filtered and evaporated. The residue is subjected to flash chromatography on SiO₂(gradient elution from pure CH₂Cl₂to a mixture of 70% CH₂Cl₂and 30% of a mixture of 9:1 MeOH:NH₄OH). Allocate 2,48 g monoalkylamines ester derived spermine: methyl-4-[3-(benzyloxycarbonyl-{4-[benzyloxycarbonyl-(3-benzyloxycarbonylamino-propyl)-amino]butyl}-amino)-propylamino]-butyrate of the formula 12A (in the form of complex methyl ester, where In=N)

TLC SiO₂(90:9:1 CH₂Cl₂:MeOH:NH₄OH): Rf=0.4 are. Other chromatographic fractions contain dialkylamino derived derived spermine.

Stage 2: 2,48 g this monoalkyl is one of the intermediate from step 1 was placed in 30 ml of acetonitrile together with 0.45 ml of triethylamine. Dropwise with stirring to 0.55 ml benzylchloride in 5 ml of acetonitrile at room temperature and the mixture is left to mix for 2 hours, the Reaction mixture was poured into water, extracted with ethyl acetate, the organic phase dried over Na₂SO₄, filtered and evaporated. Hold flash chromatography (gradient elution from pure CH₂Cl₂to a mixture consisting of 90% CH₂Cl₂and 10% MeOH:NH₄OH (9:1)). Obtain 0.95 g Tetra-substituted derivative spermine: methyl-4-{benzyloxycarbonyl-[3-(benzyloxycarbonyl-{4-[benzyloxycarbonyl-(3-benzyloxycarbonylamino)-amino]-butyl}-amino)-propyl]-amino}-butyrate, corresponding to the formula 12A, where V=Z, in the form of a colorless oil. Yield 32%. TLC SiO₂(90:10:1 CH₂Cl₂:MeOH:NH₄OH) Rf=0,79.¹H-NMR (DMSO) δ 7.32 (m, 21 H, NH and 4Ph), 5.03 and 5.00 (2s, 8H, CH₂of benzyl), 3.54 (m, 3H, OMe), 3.14 (m, N, CH₂N), 2.97 (m, 2H, CH₂N), 2.27 (m, 2H, CH₂WITH), 1.62-1.67 (m, 6N, CH₂), 1.37 (m, 2H, CH₂).

Stage 3. The above ester (0.95 g) is refluxed with stirring in 60 ml of a mixture of Meon:water (50:50) and in the presence of 1.7 ml 1 N. NaOH for 1 h After cooling, the mixture is acidified using 1 N. HCl to pH 2 and extracted with ethyl acetate, getting the corresponding carboxylic acid: 4-{benzyloxycarbonyl-[3-(benzyloxycarbonyl-{4-[benzyloxycarbonyl-(3-benzyl shall xterminator)-amino]-butyl}-amino)-propyl]-amino}-butyric acid in the form of a colorless oil in quantitative yield. TLC SiO₂(95:5 CH₂Cl₂:MeOH): Rf=0,32.¹H-NMR (DMSO) δ 7.32 (m, N, NH and 4Ph), 4.99 and 5.04 (2s, 8H, CH₂of benzyl), 3.14 (m, 12H, CH₂N), 2.97 (m, 2H, CH₂N), 2.15 (m, 2H, CH₂CO), 1.66 (m, 6N, CH₂), 1.37 (m, 4H, CH₂). ESI-MS m/z=825 M-H+).

Stage 4: 510 mg 4β-amino-4'-demethyl-4-methoxymethylethoxy (Intermediate compound (I)obtained as mentioned above was dissolved in 20 ml of acetonitrile in the presence of 950 mg of the acid obtained in the preceding stage, and 0.34 ml of triethylamine. Add in one portion 370 mg of TBTU and stirring is continued at room temperature for 2 hours, the Reaction mixture was poured into water and extracted with ethyl acetate, the organic solution is washed with b (brine), dried, filtered and evaporated. The residue is purified flash chromatography (elution CH₂Cl₂:MeOH (90:10)) and then preparative HPLC (X-Bridge C18, 10 μm, OBD, 30×250 mm), gradient elution of CH₃CN:H₂O from 10:90 to 50:50. Obtain 430 mg (yield 30%) protected derivative spermine and podofillotoksina.¹H-NMR (DMSO) δ 8.23 (d, 1H, J=8.16 Hz, NH), 7.32 (m, 4 Ph), 6.78(s, 1H, H₅), 6.52 (s, 1H, H₈), 6.23 (s, 2H, H_2'N_6'), 5.98 (d, 2H, J=17.08 Hz, OCH₂O), 5.19 (dd, 1H, H₄), 4.99 and 5.03 (2s, 8H, CH₂of benzyl), 4.49 (d, 1H, J=4.8 Hz, H₁), 4.29 (t, 1H, J=7.2 Hz, H_11a), 3.73 (m, 1H, H_11b), 3.62 (s, 6H, OMe), 3.15 (m, 13H, CH₂N and N₂), 2.96 (m, 3H, CH₂N and N₃), 2.10 (m, 2H, CH₂WITH), 1.61-1.68 (m, 6H, CH_{2 ), 1.37 (m, 4H, CH2).}

Stage 5: This is cleaned tetramethylcyclopropane compound (430 mg) dissolved in a mixture of methanol (20 ml) and CH₂Cl₂(10 ml). Add 5 equivalents of HCl in isopropanol. Environment in the presence of 50 mg of 10%palladium on coal placed for 8 h in an atmosphere of hydrogen with vigorous stirring. The catalyst is filtered off, washed with methanol and then the filtrate is evaporated. The residue is subjected to chromatography on a preparative HPLC-column (Xbridge C18, 10 μm, OBD, 30×250 mm) with elution with 5 mm HCl solution. The fractions containing the compound is subjected to freeze-drying to obtain 115 mg of a white solid. TPL=229°C. Analytical purity: 98,25% (the analysis. HPLC: Xbridge C8, chromatography (15:85) CH₃CN:H₂O-KHPO₄6.8 g/l at pH 4).

¹H-NMR (DMSO) δ 8.47(d, 1H, J=8.28 Hz, NH), 6.78 (s, 1H, H₅), 6.53 (s, 1H, H₈), 6.23 (s, 2H, H_2'H_6'), 6.00 (d, 2H, J=10.2 Hz, OCH₂O), 5.19 (dd, 1H, J=7.72 Hz, J'=4.68 Hz, H₄), 4.49 (d, 1H, J=4.96 Hz, H₁), 4.29 (t, 1H, J=7.8 Hz, H_11a), 3.75 (t, 1H, J=9.8 Hz, H_11b), 3.62 (s, 6H, OMe), 3.24 (dd, 2H, J=14.28 Hz, J'=4.8 Hz, H₂), 2.89-3.00 (m, 15H, H₃and CH₂N), 2.29 (m, 2H, CH₂WITH), 1.88-2.08 (m, 6H, CH₂), 1.73 (m, 4H, CH₂).

Example 12: in the same way as described in Example 11, following Method 2 peptide combinations are given the following compounds of formula 1 (where A=CO(CH₂)_nn=3, 4 or 5): 2, 4, 6, 15, 16, 17, 33, 34, 32, 31, 37, 38 35, 36, 22, 23, 25, 26, 24, 9, 11, 55 and 56, using the appropriate protected monoamines, diamines, triamine or tetraamine, "attached", as described in Stage 1 of Example 11, Method 2, ethyl-bromobutyrate or ethyl-bromopropionate. The introduction phase protection (Stage 2), saponification (Stage 3), combination (Stage 4) and remove the protection (Stage 5) is conducted in the same manner.

Example 13: obtain 1 -{3-[4-(3-aminopropylene)-butylamino]-propyl}-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea (Compound 48)

Stage 1: getting 4β-chloroacetamido-4'-demethyl-4'-benzyloxycarbonyl-4-methoxymethylethoxy

of 19.6 g of 4β-chloroacetamido-4'-demethyl-4-methoxymethylethoxy formula 4A (X=Cl, n=1), intermediate compound I obtained in stage 1, are dissolved in 400 ml of THF, then add 10 ml of pyridine. Next, with stirring at room temperature add 6.5 ml of benzylchloride dissolved in 50 ml of THF. The reaction mixture was stirred at ambient temperature for 6 hours after the reaction solution was poured into 300 ml of 1 N. HCl, then extracted with ethyl acetate (2×200 ml). The organic phase is dried over Na₂SO₄, filtered and evaporated, getting 27.9 g of the crude intermediate compound. TLC (95:5 CH₂Cl₂:MeOH): Rf=0,29. This intermediate compound is used directly in Stage 2.

27.9 g of the intermediate obtained in Stage 1 above is dissolved in 120 ml of dimethylacetamide, 24 ml of acetic acid and 24 ml of water. All this heated up to 80°C With stirring. At this stage add the thiourea (to 4.81 g) and the reaction mixture is support at this temperature for 12 hours After cooling, the reaction mixture is slowly poured into a saturated solution of NaHCO₃(500 ml). Then extracted with ethyl acetate (200 ml) and the organic phase washed with a saturated solution of NaHCO₃and then a saturated solution of NaCl. The organic phase is separated, dried over Na₂SO₄, filtered and evaporated. The residue is subjected to flash chromatography (gradient from pure heptane, CH₂Cl₂to 90:10 CH₂Cl₂:MeOH)to give 13.8 g 4β-amino-4'-demethyl-4'-benzyloxycarbonyl-4-methoxymethylethoxy formula 8. Going beyond stage 2=63%. TLC (95:5 CH₂Cl₂:MeOH): Rf Of 0.55.

Stage 3: obtain 1-{3-[4-(3-tert-butoxycarbonylamino)-tert-butoxycarbonylamino]-tert-butoxycarbonylamino}-3β-[9-(4-benzyloxycarbonyloxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea

500 mg of the intermediate obtained in Stage 2 above, was dissolved with stirring in 30 ml of CH₂Cl₂together with of 0.13 ml of triethylamine. With stirring at 0°C is tmosphere nitrogen add a solution of 100 mg of triphosgene in 20 ml of CH ₂Cl₂. After reaching room temperature is added dropwise a solution of 500 mg trios-spermine (Tet. 2000, 56, 2449) and 0.13 ml of triethylamine in 20 ml of CH₂Cl₂. The reaction mixture was stirred at room temperature for 3 h Then the reaction mixture was poured into a saturated solution of NaHCO₃and after that extracted, using CH₂Cl₂. The organic phase is dried over Na₂SO₄, filtered and evaporated. The residue is subjected to flash chromatography on SiO₂(by elution from a pure CH₂Cl₂to a mixture of 90:10 CH₂Cl₂:MeOH)to give 370 mg of a yellow oil. Yield 37%. TLC SiO₂(CH₂Cl₂:MeOH 90:10): Rf Of 0.65.¹H-NMR (DMSO) δ 7.4 (s, 5H, arene. H), 6.81 (s, 1H, H₅), 6.53 (s, 1H, H₈), 6.35mm (s, 2H, H_2'N_6'), 5.98 (d, 2H, J=7 Hz, OCH₂O), 5.23 (s, 2H, CH₂Ar), 5.03 (dd, 1H, H₄), 4.60 (d, 1H, J=5.2 Hz, H₁), 4,32 (t, 1H, J=7.6 Hz, H_11a), 3.81 (t, 1H, J=10 Hz, H11a), 3.63 (s, 6H, OMe), 2.87 (m, 14H, H₂N₃CH₂N), 1.56 (m, 2H, CH₂), 1.37(m, 33H, CH₂CH₃).

Stage 4: obtain 1-{3-[4-(3-tert-butoxycarbonylamino)-tert-butoxycarbonylamino]-tert-butoxycarbonylamino}-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]-dioxol-5-yl]-urea

740 mg of the protected (trios - and 4'O-benzyloxycarbonylamino) intermediate compound, n is obtained in Stage 3 above, dissolved with stirring in 20 ml of methanol with 100 mg of 10%palladium on coal and incubated in an atmosphere of hydrogen for 2 h with vigorous stirring. The solution is filtered from the catalyst, washed with Meon and then evaporated to dryness. The residue is subjected to flash chromatography on SiO₂(gradient from CH₂Cl₂to 90:10 CH₂Cl₂:MeOH), then preparative HPLC (X-Bridge, OBD C18, 10 μm, 30×250 mm) with elution from 20.80 CH₃CN:H₂O to 100% CH₃CN inclusive. After extraction fractions with ethyl acetate, drying over Na₂SO₄, filtration and evaporation obtain 630 mg of 1-{3-[4-(3-tert-butoxycarbonylamino)-tert-butoxycarbonylamino-butyl]-tert-butoxycarbonylamino}-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea as a colorless oil. Yield 97%. TLC SiO₂(90:10:1 CH₂Cl₂:MeOH:NH₄OH): Rf=0,58.

Stage 5: obtain 1-{3-[4-(3-aminopropylene)-butylamino]-propyl}-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea

630 mg trios-protected intermediate compound mentioned above is dissolved in 10 ml of HCl in isopropanol (3 M) and then leave to mix for 6 h at room temperature. Wednesday evaporated to dryness and then the residue Perrin is placed in ethanol. Precipitated precipitated hydrochloride is filtered off, washed with absolute ethanol and ethyl ether. Receive 391 mg of salt, that is, the output is 78%. TLC SiO₂(40:40:20 CH₂Cl₂:MeOH:NH₄OH): Rf=0,55. TPL=166°C. Purity by HPLC 97% (analytical HPLC X Bridge 15:85 CH₃CN:H₂O; 6.8 g/l KH₂PO₄- pH 4, RT=8,08). ESI-MS, m/z=628 (M-H+). Anal. C₃₂H₄₅N₅O₈·3HCl·4,4H₂O=813,39 calculated:% 52,14, N% 6,56, N% 9,50; found:% 51.89ˆ, N% 5,95, N% 9,58.¹H-NMR (DMSO, D₂O) δ 6.82 (s, 1H, H₅), 6.52 (s, 1H, H₈), 6.24 (s, 2H, H_2'H_6'), 5.98 (d, 2H, J=10 Hz, och₂Oh), 5.01 (d, 1H, J=4 Hz, H₄), 4.51 (d, 1H, J=4.8 Hz, H₁), 4,35 (t, 1H, J=8 Hz, H_11a), 3.84-of 3.94 (m, Na, H₂O), 3.63 (s, 6N, OMe), 3.17 (m, 3H, H2, CH₂N), 2.95 (m, 11H, N3, CH₂N), 1.94 (m, 2H, CH₂), 1.76 (m, 2H, CH₂), 1.68 (m, 2H, CH₂).

Example 14: in the same way as described in Example 13, compound 39, 40, 41, 42, 43, 47 and 48 can be obtained by following the same method described in Stage 3, but using the appropriate protected diamines, triamines and tetraamines. Stage removal protection is held, as described in Stage 4 in relation to the hydrogenolysis of the group Z, or as described in Stage 5 with respect to removal of groups VOS.

Example 15: connection of urea 44, 45 and 49 receive in accordance with Example 2 by alkylation, but using protected triamine or tetraamine instead of dimethylamine proizvodnje 1-chloroethyl-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea (described in Heterocycles 1994, 39, 361) instead of intermediate compound III. Stage removal protection carried out as described in Example 13 in Stage 4 and Stage 5.

Example 16: compound urea 46, 47, 64, 65, 66, 67 and 68 receive in accordance with the procedure described in Stage 3 of Example 13, but using 3-globabilization, 4-chlorotriazine, 5-chlorphentermine (Bull. Soc. Chim. Fr. 1959, 611) instead of triphosgene that leads to obtaining the relevant alkylation. The following stages were carried out as indicated in Example 15.

Example 17: the connection 50: 1-[3-{3-[4-(3-aminopropylene)-butylamino]-propylamino}-propyl]-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea also receive in accordance with the principle of the process outlined in Example 13, but using the appropriate reagent.

Stage 1: obtain (3-tert-butoxycarbonylamino)-[4-(tert-butoxycarbonyl-{3-[3-(1,3-dioxo-1,3-dihydroindol-2-yl)propylamino]-propyl}-amino)-butyl]-carbamino acid complex tert-butyl methyl ether

To a solution of trios-spermine (Tet. 2000, 56, 2449) (6 g; and 11.2 mmol; 1 EQ.) in 100 ml of acetonitrile is added N-(3-bromopropyl)phthalimide (3 g; and 11.2 mmol; 1 EQ.) and cesium carbonate (7.2 g; of 22.4 mmol; 2 EQ.). The medium is refluxed with stirring for 8 hours After evaporation it was poured into water (400 ml) and EXT Airout AcOEt (3×200 ml). The organic phase was washed with saturated aqueous NaCl, separated, dried over Na₂SO₄and evaporated. The residue is subjected to flash chromatography on SiO₂and elute with a gradient from pure CH₂Cl₂to a mixture of CH₂Cl₂:MeOH:NH₄OH (80:18:2)to give after evaporation 2,31 g colorless oil (yield 30%). TLC SiO₂(90:9:1 CH₂Cl₂:MeOH:NH₄OH): Rf=0.5 in. MS: m/z=690 (M-H+).

Stage 2: obtain [3-(tert-butoxycarbonyl-{4-[tert-butoxycarbonyl-(3-tert-butoxycarbonylamino)-amino]-butyl}-amino)-propyl]-[3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-propyl]-carbamino acid complex tert-butyl methyl ether

The compound obtained in the above Stage 1 (2,31 g; 3.3 mmol; 1 EQ.), dissolve in 50 ml of THF with stirring. Then dropwise at room temperature, add a solution of BOC₂O (0.8 g; 3.7 mmol; 1.1 EQ.) in 10 ml of THF. Stirring is continued for 4 h, then the medium was poured into water, extracted with AcOEt (3×100 ml), dried (Na₂SO₄), filtered and evaporated. The residue is subjected to flash chromatography with a gradient from pure heptane to pure AcOEt. After evaporation receive 1,49 g (yield 56%).

Stage 3: obtain (3-aminopropyl)-[3-(tert-butoxycarbonyl-{4-[tert-butoxycarbonyl-(3-tert-butoxycarbonyl-aminopropyl)-amino]-butyl}-amino)-propyl]-carbamino acid complex is th tert-butyl ether (aminopropyl-Tetravex-spermine)

Connection with the above Stage 2 (1,49 g; 1.88 mmol; 1 EQ.) refluxed in 50 ml of EtOH in the presence of hydrazine hydrate (0.5 ml; 16,1 mmol; 8,5 EQ.) within 6 hours the Cooled medium is filtered, washed with EtOH and evaporated. The residue is subjected to flash chromatography on SiO₂(gradient elution from pure CH₂Cl₂to a mixture of 80:18:2 CH₂Cl₂:MeOH:NH₄OH inclusive). After evaporation of the fractions containing pure compound, receive 1,09 g colorless oil (yield 88%). TLC SiO₂(90:9:1 CH₂Cl₂:MeOH:NH₄OH): Rf=0.34 in. MS: m/z=660 (M-H+).

Stage 4: the combination of aminopropyl-Tetravex-spermine with 4β-amino-4'-demethyl-4'-benzyloxycarbonyl-4-methoxymethylethoxy

4β-Amino-4'-demethyl-4'-benzyloxycarbonyl-4-methoxymethylethoxy obtained in Stage 2 of Example 13, (0.88 g; 1.6 mmol; 1 EQ.) dissolved with stirring in 100 ml of CH₃CN together with a 0.23 ml (1.6 mmol; 1 EQ.) of triethylamine and cooled to 0°C. Then added dropwise a solution of triphosgene (0.17 g; of 0.58 mmol; 0,35 EQ.). Then after reaching room temperature is added dropwise a solution of the mixture of intermediate compounds, aminopropyl-Tetravex-spermine obtained in the above Stage 3 (1,09 g; 1.6 mmol; 1 EQ.), and 0.23 ml (1.6 mmol; 1 EQ.) of triethylamine in 30 ml of CH₂Cl₂. Poluparallelnye for 3 h the mixture was poured into a solution of NaHCO ₃and extracted with CH₂Cl₂(3×100 ml). The organic phase is separated, dried over Na₂SO₄, filtered and evaporated, receiving the remnant that purify flash chromatography (gradient from pure CH₂Cl₂to 90:10 CH₂Cl₂:MeOH). After evaporation gain of 1.37 g (68%) protected derivative of urea as a white foam. TLC SiO₂(95:5 CH₂Cl₂:MeOH): Rf=0,62. Analytical HPLC: column, Xbridge C8, 5 μm, a 4.6×250 mm, elution with 80:20 CH₃CN:H₂O, RRT=7,7 minutes

Stage 5: remove the protection in position 4'

Hydrogenolysis of the derivative obtained in Stage 4, (1,37 g), performed using 50 mg of 10%palladium on coal in 100 ml Meon with vigorous stirring for 8 hours the Catalyst is filtered off and the filtrate evaporated to dryness. The remainder of the first purified flash chromatography on SiO₂with elution with a gradient from pure heptane to pure AcOEt, and then HPLC (X bridged 8, OBD, 30×250 mm) with a gradient from CH₃CN:H₂O (50:50) to clean CH₃CN. Obtain 0.95 g (yield=78%) compounds, which removed the protection in position 4'. TLC SiO₂(95:5 CH₂Cl₂:MeOH): Rf=0,33. Analytical HPLC: column, Xbridge C8, 5 μm, a 4.6×250 mm, elution with 80:20 CH₃CN:H₂O, RRT=4,7 minutes

Step 6: obtain 1-[3-{3-[4-(3-aminopropylene)-butylamino]-propylamino}-propyl]-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8 is,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea by removal of the protective groups VOS

The compound obtained in the above Stage 5 (0.95 g; to 0.72 mmol), dissolved in 10 ml of CH₂Cl₂in the presence of HCl in isopropanol (3 M, 10 ml) with stirring for 4 hours the precipitate is filtered off and then washed with Et₂O, gaining 0.6 g (94%) of a white powder of 1-[3-{3-[4-(3-aminopropylene)-butylamino]-propylamino}-propyl]-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea. TPL=213°C. MS: m/z=685 (M-H+).

3. Pharmacological test

Example 18: pharmacological in vitro tests

Use the test for cytotoxicity. It measures the inhibition of cell growth on line A person (non-small cell lung cancer).

Tumor cells A seeded in 96-well plates in RPMI medium 1640 containing no phenol red (Seromed), which adds 5% fetal calf serum (100 µl/well; 1,25×10⁴cells/ml). After incubation for 24 h at 37°C in an incubator with 5% CO₂Wednesday replaced with the medium containing the test compound, then the tablets incubated in the next 48 hours cell Survival assessed by measuring the luminescence after removal of the deposition of ATP from the environment using the solution for cell lysis, solution luciferase and solution luciferin included in the kit ATP-lite-M™, follow recommended the Nations of the manufacturer (Packard, Rungis, France). Each experimental condition was tested at least three times in six repetitions.

The results show that the compounds according to the invention possess strong cytotoxic properties. Inhibitory concentration 50 (IC₅₀), which represents the concentration of test compound that provides the inhibition of cell proliferation by 50%, for example, for the connection 21: IC₅₀=1,7×10^-9M or for connection 48: IC₅₀=1,2×10^-8M

Example 19: pharmacological tests in vivo

Experimental model of tumor R. The model used represents a model of murine leukemia R (Tumor Models in Cancer Research. Teicher, B.A. ed., Humana Press Inc., Totowa, NJ. pp.23-40, 2002), which is supported by consistent intraperitoneally transplants in mice DBA/2 (DBA mice/2JIco, Charles River), as described previously (Classic in vivo cancer models: Three examples of mouse models used in experimental therapeutics. Current Protocols in Pharmacology Unit 5.24: 5.24.1-5.24.16, 2001).

The experiment is carried out according to previously described Protocol (Cancer Chemother. Pharmacol. 1998, 41, 437-447). It involves the implantation of 10⁶leukemia cell R one mouse hybrid mice C2DF1 (CD2F1/CrlIBR, Charles River, St Aubin-les-Elbeuf, France) intravenously on zero day. After that, animals are randomly distributed in the cells for the treatment and control cells, test compounds administered in view of the single injection intraperitoneally by the next day after transplantation of the tumor, on the 1st day. Then every day monitor animals are weighed twice a week and record some clinical response. Survival rate (survival rate) is a parameter used to assess antitumor activity. The increased survival rate is defined as the ratio of T/C_survival(%), which corresponds to: (average survival rate for being treated group/average survival rate for the control group)×100. The ratio T/C_survivalcalculated for each dose, and the highest obtained value is reached the maximum increase in the survival rate (maximum activity), which by definition is called the optimal ratio T/C_survival.

The results show that these compounds cause a significant increase in the survival rate for animals with leukemia R.

For example, the connection 21 from Example 11 demonstrates the value of the optimal T/C_survivalequal to 186%at a dose of 0.16 mg/kg, which indicates that treatment with this compound causes an increase of the survival rate of animals at 86%. In fact, in accordance with the criteria of the NCI (National cancer Institute) the value of T/C_survivalis considered significant if it is less than the second least 120% (Semin. Oncol. 1981, 8, 349-361).

The relative decrease in body weight of animals along with optimum activity of the compounds is much below the threshold of toxicity according to NCI criteria (Ann. Oncol. 1994, 5, 415-422).

REDUCTION

The compound of General formula 1:

where:
- R represents hydrogen or C_1-4alkyl,
- A represents CO(CH₂)_nor CONH(CH₂)_nwhere n is 2, 3, 4 or 5,
- R1 represents H or C_1-4alkyl,
- R2 represents (CH₂)_m-NR3R4, where m is 2, 3, 4 or 5,
- R3 represents H or C_1-4alkyl,
- R4 represents H, C_1-4alkyl or (CH₂)_p-NR5R6, where p is 2, 3, 4 or 5,
- R5 represents H or C_1-4alkyl, and
- R6 represents H, C₁-C₄alkyl or (CH₂)_q-NH₂where q is 2, 3, 4 or 5,
or its pharmaceutically acceptable salt.

2. The compound of General formula 1 according to claim 1, in which R represents H.

3. The compound of General formula 1 according to claim 1, in which m is 3 or 4, p is 3 or 4, and q is 3.

4. The compound of General formula 1 according to claim 1, where it is selected from the following compounds:
compound 3: 3-[(2-dimethylaminoethyl)-methylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-propionamide,
compound 21: 4-{3-[4-(3-aminopropylene)-butylamino]-cuts is but}-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-butyramide,
compound 48: 1-{3-[4-(3-aminopropylene)-butylamino]-propyl}-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-urea,
compound 50: 1-[3-{3-[4-(3-aminopropylene)-butylamino]-propylamino}-propyl]-3-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil-[2,3-d][1,3]dioxol-5-yl]-urea,
compound 55: 5-[(2-dimethylaminoethyl)-methylamino]pentanol acid N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro-[3',4':6,7]-the oil[2,3-d][1,3]dioxol-5-yl]-amide.

5. The compound of formula 1 according to any one of claims 1 to 4 for use as a drug for cancer treatment.

6. The compound of formula 1 according to claim 5 for use as a medicine intended for cancer treatment solid (liquid) tumors and solid tumors, such as melanoma, colorectal cancer, lung cancer, prostate cancer, bladder cancer, breast cancer, uterine cancer, esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, ovarian cancer, leukemia, particularly lymphoma and myeloma, cancer of the ear, nose and throat and cancer of the brain.

7. The use of the compounds of formula 1 according to any one of claims 1 to 4 for the manufacture of a medicinal product intended for cancer treatment solid (liquid) tumors and solid tumors, such as is economy, colorectal cancer, lung cancer, prostate cancer, bladder cancer, breast cancer, uterine cancer, esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, ovarian cancer, leukemia, particularly lymphoma and myeloma, cancer of the ear, nose and throat and cancer of the brain.

8. The method of obtaining the compounds of formula 1 according to any one of claims 1 to 4, where a is(CH₂)_nand R represents H, where n is as defined in claim 1, comprising the following successive stages:
(a) the conduct of Ritter reaction between the compound of the following formula 3:

and a nitrile of the formula Ra-CN, where Ra represents -(CH₂)_n-S or-CH=CH₂n represents 3, 4 or 5, and X represents a halogen atom such as a chlorine atom, to obtain the compounds of the following formula 4:

(b) conducting the alkylation reaction between the amine in a protected form formulas HNR1R2a where:
- R1 as defined in claim 1,
- R2a represents (CH₂)_m-NR3aR4a, where m is such as defined in claim 1,
- R3a represents a C_1-4alkyl or a protective group for the amine,
- R4a represents a C_1-4alkyl, a protective group for the amine or (CH₂)p-NR5aR6a, where p is such as defined in claim 1,
- R5a represents a C_1-4alkyl or a protective group for the mine,
- R6a represents a C_1-4alkyl, a protective group for the amine or (CH₂)q-NR7aR8a, where q is as defined in claim 1,
- R7a represents H or a protective group for the amine and
- R8a represents a protective group for an amine,
and a compound of formula 4 obtained in the previous phase, to obtain the compounds of the following formula 5:

where R2a as defined above, and R1 and n are such as defined in claim 1,
(c) may remove protection with functional amino groups, protected by a protective group for an amine, to obtain the compounds of the following formula 5A:

where R1, R2 and n are such as defined in claim 1, and
(d) isolation of the compound obtained in the previous phase from the reaction mixture.

9. The method of obtaining the compounds of formula 1 according to any one of claims 1 to 4, where a represents CONH(CH₂)_nwhere n is as defined in claim 1, comprising the following successive stages:
(a) interaction of the compounds of the following formula 8:

where R is as defined in claim 1, and Y represents a protective group for hydroxyl, such as benzyloxycarbonyl,
with an isocyanate of the formula O=C=N-(CH₂)_n-X, where n is as defined in claim 1, and X represents a halogen atom such as chlorine atom, obtaining soedineniya following formula 9:

(b) conducting the alkylation reaction between the amine in a protected form formulas HNR1R2a, where
- R1 as defined in claim 1,
- R2a represents a C_1-4alkyl, a protective group for the amine or (CH₂)_m-NR3aR4a, where m is such as defined in claim 1,
- R3a represents a C_1-4alkyl or a protective group for the amine,
- R4a represents a C_1-4alkyl, a protective group for the amine or (CH₂)_p-NR5aR6a, where p is such as defined in claim 1,
- R5a represents a C_1-4alkyl or a protective group for the amine,
- R6a represents a C_1-4alkyl, a protective group for the amine or (CH₂)_q-NR7aR8a, where q is as defined in claim 1,
- R7a represents H or a protective group for the amine and
- R8a represents a protective group for an amine,
and a compound of formula 9 obtained in the previous phase, to obtain the compounds of the following formula 10A:

where Y and R2a such as defined above, and R1 and n are such as defined in claim 1,
(c) removing the protection from a functional phenolic group and may remove protection with functional amino groups, protected by a protective group for the amine in the compound of formula 10A, obtained in the previous phase, to obtain the compounds of the following formula 10b:

where R, R1, R2 and n are such as defined in claim 1, and
(d) isolation of the compound obtained in the previous phase from the reaction mixture.

10. The method of obtaining the compounds of formula 1 according to any one of claims 1 to 4, where a represents CONH(CH₂)_nwhere n is as defined in claim 1, comprising the following successive stages:
(a) the interaction of the compounds of formula 8,

where R is as defined in claim 1, and Y represents a protective group for hydroxyl, such as benzyloxycarbonyl,
with phosgene or triphosgene with intermediate activated carbonyliron connection
(b) conducting the alkylation reaction between the amine in a protected form formula H₂N-(CH₂)_n-NR1aR2a, where
- R1a represents a C_1-4alkyl or a protective group for the amine and
- R2a represents a C_1-4alkyl, a protective group for the amine or (CH₂)_m-NR3aR4a, where m is such as defined in claim 1,
- R3a represents a C_1-4alkyl or a protective group for the amine,
- R4a represents a C_1-4alkyl, a protective group for the amine or (CH₂)_p-NR5aR6a, where p is such as defined in claim 1,
- R5a represents a C_1-4alkyl or a protective group for the amine,
- R6a represents a C_1-4alkyl, a protective group for the amine or (CH₂)_q-NR7aR8a, where q is as defined in claim 1,
- R7a, not only is em a H or a protective group for the amine and
- R8a represents a protective group for an amine,
and intermediate activated carbonyliron compound obtained in the previous phase, to obtain the compounds of the following formula 10C:

where R and n are such as defined in claim 1, and Y, R1a and R2a such as defined above,
(c) removing the protection from a functional phenolic group and may remove protection with functional amino groups, protected by a protective group for the amine in the compound of formula 10C obtained in the previous phase, to obtain the compounds of formula 10b,

where R, R1, R2 and n are such as defined in claim 1, and
(d) isolation of the compound obtained in the previous phase from the reaction mixture.

11. The method of obtaining the compounds of formula 1 according to any one of items 1 to 4, where a is(CH₂)_nwhere n is as defined in claim 1, comprising the following successive stages:
(a) conduct peptide combination between a compound of the following formula 6:

where R is as defined in claim 1,
and the acid of the following formula 12:

where
- R1a represents a C_1-4alkyl or a protective group for the amine and
- R2a represents a C_1-4alkyl, a protective group for the amine or (CH₂)_m-NR3aR4a, where m is such that the AK defined in claim 1,
- R3a represents a C_1-4alkyl or a protective group for the amine,
- R4a represents a C_1-4alkyl, a protective group for the amine or (CH₂)_p-NR5aR6a, where p is such as defined in claim 1,
- R5a represents a C_1-4alkyl or a protective group for the amine,
- R6a represents a C_1-4alkyl, a protective group for the amine or (CH₂)_q-NR7aR8a, where q is as defined in claim 1,
- R7a represents H or a protective group for the amine and
- R8a represents a protective group for an amine,
and n are such as defined in claim 1,
obtaining compounds of the following formula 7b:

where R1a and R2a such as defined above, and R and n are such as defined in claim 1,
(b) may remove the protection with functional amino groups, protected by a protective group for an amine, to obtain the compounds of the following formula 7:

where R, R1, R2 and n are such as defined in claim 1, and
(c) isolation of the compound obtained in the previous phase from the reaction mixture.