RU2412166C1 - Cytotoxic linear heterocyclic derivatives of anthracenedione having in side chain cyclic diamines, active towards tumour cells with multidrug resistance - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to anthracenedione derivatives which are suitable for therapy of oncological diseases, having the formula:

, where W is a fragment of a five-member heterocycle containing one or two heteroatoms selected from N, O or S, optionally substituted with alkyl, halogen; Y is a monocyclic diamine residue containing an exocyclic amine group, or a polycyclic diamine with bridging amine groups, which is a compound in which two amine groups are involved in formation of 4- or 6-member ring systems containing 2-6 carbon atoms and bonded by one, two or three bridging atoms, where Y is optionally substituted with one or more substitutes selected from alkyl, halogenalkyl, halogen, hydroxyl, hydroxyalkyl, carbamoyl and CO₂R, where R denotes alkyl; X denotes alkylene, CO or SO₂; n and m are independently range from 0 to 2; Z¹ is selected from hydroxy, alkoxy -NH₂, -NHR¹, -NR¹R², where R¹ and R² denote alkyl, aminoalkylamino, halogen; Z² is selected from hydroxy, alkoxy, fluorine.

EFFECT: obtaining novel anti-tumour compounds.

1 cl, 18 ex, 3 tbl

Description

The invention relates to the pharmaceutical industry and relates to linear tetracyclic heterocyclic derivatives of anthraquinone (heterocyclic analogues of 5,12-naphthaquinquinone), their structure, methods of preparation and medical use as cytotoxic agents.

It is known that derivatives of 5,12-naphthacenquinone and a number of their synthetic analogues isolated from certain strains of microorganisms have high biological activity. Anthracycline antibiotics, which are tetrahydronaphthacinquinone glycosides, for example, doxorubicin, carminomycin, idarubicin (formulas 1a-c), are used in chemotherapy to treat a wide range of oncological diseases [Gauze G.F. Antitumor antibiotics. - M .: Medicine, 1987, 18-48]. Also known are tetracyclic linear derivatives of anthraquinone with annelated benzene or heterocyclic nucleus A, which have high cytotoxicity. So, the antibiotics UCE6 and topopyron B (formulas 2a, b) are superior in activity to the comparison drug camptothecin [Fujii N., et. al. Molecular Pharmacology, 1997, 57, 269; Khan Q.A., et. al. J. Amer. Chem. Soc., 2008, 130, 12888].

Along with valuable properties, clinically significant anthracyclines have some disadvantages, the main of which are high cardiotoxicity and the development of multidrug resistance (MDR) in tumor cells. In this regard, studies are underway on the chemical modification of natural antibiotics and the synthesis of new drugs with improved chemotherapeutic properties. The search for more affordable and effective antitumor drugs with reduced cardiotoxicity has led to the emergence of a new generation of anthracyclines and their analogues. However, all compounds of this class, approved for clinical use, are characterized by low activity against tumor cells with MDR, which often significantly limits their therapeutic potential. [Hill V.T., et al. Cancer Chemolher. Pharmacol 1989, 23, 140]. It is known that expression of the transmembrane transporter of P-glycoprotein (Pgp) and inactivation of the p53-mediated pathway of programmed cell death (apoptosis) are the most common mechanisms for the development of MDR of tumor cells during chemotherapy [Sarkadi B., et al. FEBS Lett. 2004, 567 (1), 116]. Therefore, drugs that are active against cell lines with genetically determined MDR mechanisms are especially interesting for creating new-generation antitumor agents. Despite the extensive search for antitumor agents in the series of anthracycline antibiotics and anthraquinone derivatives, which led to the discovery of synthetic analogues of anthracyclines (for example, mitoxantrone and amethantrone preparations (3a-b) [Zee-Cheng, R.K.Y .; Cheng, C.S. Drugs Future. 1983, 8, 228]), the biological activity of linear heterocyclic derivatives of anthracenedion remained poorly understood.

The present invention is intended to obtain new linear tetracyclic derivatives of anthracenedion with a heterocyclic ring A, possessing cytotoxic properties and active against tumor cells with activated resistance mechanisms. The present invention includes compounds corresponding to formula 4, and their pharmacologically acceptable salts, suitable for the treatment of cancer:

where W is a fragment of a five-membered heterocyclic nucleus (ring A) condensed with an anthracenedione nucleus in a bond of 2-3 (BD rings) and being a heterocycle containing from one to three heteroatoms selected from N, O, S, and at least three atoms carbon, two of which are common with the anthracenedione nucleus, and the third is linked to functional group X. Examples of a heterocyclic nucleus (ring A) including a pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole fragment optionally substituted with a substituent selected from alkyl, alkoxy, ami o, aminoalkyl, acylamino, acyloxy, halo, haloalkyl, hydroxy, hydroxyalkyl, imino, oxo. It is understood that multiple bonds in a heterocyclic fragment can take various resonant forms;

Y - means the remainder of the diamine, which is a monocyclic diamine containing an exocyclic amino group, or a polycyclic diamine containing bridging amino groups. Examples of monocyclic diamines with exocyclic amino groups used in the present invention in fragment Y of formula 4 include amino derivatives of azetidine, pyrrolidine, piperidine, homopiperidine and the like. The bicyclic diamines that can be used in the present invention in fragment Y of formula 4 are compounds in which two amino groups are involved in the formation of 4- and 6-membered ring systems containing from 2 to 6 carbon atoms and connected by one, two or three bridging atoms. Preferred examples of diamines Y include compounds of formulas 5-8 (monocyclic diamines with exocyclic amino groups) and 9-11 (polycyclic diamines with bridging amino groups).

Diamine Y may be optionally substituted with one or more substituents linked to the diamine moiety through a nitrogen or carbon atom selected from alkyl, alkenyl, alkoxy, aryl, acyl, halogen, haloalkyl, heteroaryl, hydroxy, hydroxyalkyl, carbamoyl, carboxyalkyl, cycloalkyl. Obviously, some cyclic diamines may exist as stereoisomers. The present invention includes all possible stereoisomers and geometric isomers in the form of optically pure compounds or mixtures with different contents of optical isomers, including racemic mixtures thereof.

X is a spacer group linking the remainder of said diamine Y to said heterocyclic nucleus A of a tetracyclic derivative of anthracenedione selected from alkylene, CO, SO, SO ₂ .

n and m mean the number of substituents Z ¹ and Z ² in the anthracenedione fragment, independently equal to from 0 to 2.

The substituents Z ¹ in ring B of the compounds of formula 4 mean substituents independently selected from alkyl, alkoxy, amino, aminoalkylamino, acylamino, halogen, haloalkyl, hydroxy, nitro, alkylsulfonylamino.

Ring D of compounds of formula 4 optionally contains Z substituents independently selected from the group: hydroxy, alkoxy, fluoro. It is known that the presence of such groups at the positions of the quinone fragment (for example, in ring D of anthracyclines la-b or in ring C of their synthetic analogues 3a-b), which do not cause significant steric difficulties in binding to DNA, in some cases leads to growth or a change in the spectrum of antitumor activity of anthraquin-containing drugs [Lown JW (Ed.) Anthracycline and Anthracendione based Anticancer Agents (Bioactive molecules), Elsevier, Science Publishers B.V .: Amsterdam, 1988, 6, 738 pp; Krohn K. (Ed.) Anthracycline chemistry and biology II. Mode of action, clinical aspects and new drugs. In Topics Current Chemistry; Springer: Heidelberg, 2008, 283, 224 pp; Swenton J.S. et. al. US pat. No. 4663445].

Obviously, the compounds of formula 4 can exist in the form of tautomers that differ in the position of multiple bonds and hydrogen atoms, and it is intended that the present invention include all tautomeric forms of the compounds.

In addition, the present invention relates to the use of such compounds as therapeutically active for the treatment of human diseases associated with an increased cell growth rate (i.e., hyperproliferation), especially oncological diseases of various origins. In addition to the present invention, there is provided a method of treatment comprising administering the above pharmaceutical composition to a subject with a disease.

The compounds of the present invention can be obtained in various ways, some of which are described below only illustrate the methods for their synthesis and modification of functional groups. The starting materials and reagents used in the preparation of compounds of formula 4 are commercial chemicals supplied by firms such as Aldrich Chemical Co., or they can be prepared by methods known to one skilled in the art, by the procedures described in the literature, using, if necessary protective groups.

Unless otherwise indicated, the reactions described in the application description are carried out at atmospheric pressure from about −78 ° C. to 180 ° C. in or without an inert solvent.

Typical schemes for the preparation of the compounds of the present invention are based on the interaction of tetracyclic linear heterocyclic derivatives of anthraquinone containing an —X-LG group in the side chain with cyclic diamines containing residue Y (Scheme A). It is understood that LG means a leaving group, for example, alkylsulfonyloxy, amino, arylsulfonyloxy, acyloxy, halogen, trialkylammonium groups and the like. In addition, it is understood that diamine Y, as well as the heterocyclic derivative of anthraquinone, may optionally contain protective or activating groups to increase the efficiency of the synthesis, removed or modified in subsequent stages of the synthesis.

Scheme A

In other less preferred embodiments of the synthesis scheme for compounds of formula 4, the formation of a heterocyclic fragment (ring A) is possible by cyclization of anthracenedione derivatives with compounds containing a diamine Y fragment, or the formation of BD rings, cyclization of acyclic or cyclic intermediates containing a diamine Y residue and one, two or three cycles of a final condensed tetradicyclic system of compounds of formula 4.

Unless otherwise indicated, the singular forms used in the description and claims also include the plural forms.

The terms used in the description of the application and the claims have the meanings indicated below.

“Alkyl” means a straight or branched chain monovalent saturated hydrocarbon radical containing only carbon and hydrogen atoms and containing from 1 to 6 carbon atoms, inclusive. Examples of alkyl radicals include methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl and the like.

"Alkenyl" means a monovalent hydrocarbon radical containing from 2 to 6 carbon atoms, including at least one double bond, for example, ethenyl, propenyl, allyl, and the like.

“Alkylene” means a straight chain saturated divalent hydrocarbon radical containing from 1 to 6 carbon atoms or a branched chain saturated divalent hydrocarbon radical containing from 3 to 6 carbon atoms. For example, C2-C3 alkylene includes methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene.

"Alkoxy" means the radical -OR, where R is the above alkyl radical. Examples of alkoxy radicals include methoxy, ethoxy, isopropoxy, and the like.

“Alkylsulfonyloxy” means the radical —OSO ₂ R, where R is an alkyl group as defined above.

“Alkylthio” means the radical —SR, where R is the above alkyl. Examples of the alkylthio radical include methylthio, ethylthio and the like.

“Amino” means the groups —NH ₂ , —NHR ¹ , —NR ¹ R ² , where R ¹ and R ² each independently mean alkyl radicals. Examples of amino radicals include methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, and the like.

“Aminoalkyl” means an alkyl radical as defined above substituted by an amino group as defined above. Examples of aminoalkyl radicals include aminomethyl, methylaminomethyl, dimethylaminomethyl and the like.

“Aminoalkylamino” means a straight or branched chain saturated hydrocarbon radical containing from one to six carbon atoms bonded to the two amino groups indicated above, provided that no more than one amino group is attached to one carbon atom. Examples of aminoalkylamino radicals include 2-aminoethylamino, 2- (methylamino) ethylamino, 2- (ethylamino) ethylamino, 2 - [(2-hydroxyethyl) amino] ethylamino, 2- (dimethylamino) ethylamino, 2-aminopropylamino, 3-aminopropylamino.

“Aryl” means a monovalent cyclic aromatic hydrocarbon radical containing one or more condensed rings, of which at least one ring is aromatic, which is optionally substituted with a substituent selected from the group consisting of alkyl, amino, aminosulfonyl, alkoxy, alkylthio, halogen , haloalkyl, hydroxy, hydroxyalkyl, heteroaryl, nitro, carboxyalkyl, carbamoyl, sulfonylamino and / or cyano. Examples of aryl radicals include phenyl, naphthyl, biphenyl, and the like.

“Arylsulfonyloxy” means the radical —OSO ₂ R, where R is an aryl group as defined above.

“Acyl” means a group corresponding to the formula: —COR, —CSR, where R is hydrogen or alkyl, alkenyl, aryl, heteroaryl.

“Acylamino” means —N (R ¹ ) COR ² , —N (R ¹ ) CSR ² , where R ¹ and R ² each independently mean hydrogen, alkyl, alkenyl or hydroxyalkyl, aminoalkyl.

“Acyloxy” means a group corresponding to the formula: —OCOR, —OCSR, where R is hydrogen or alkyl, alkenyl, aryl, as defined above.

"Halogen" means the radical fluoro, bromo, chloro, iodo.

“Haloalkyl” means an alkyl radical as defined above, substituted at any position with one or more halogen atoms. Examples of the haloalkyl radical include 1-fluoromethyl, 1,2-difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloromethyl.

“Heteroaryl” means a monovalent aromatic carbocyclic radical containing one or more rings containing from 1 to 4 heteroatoms (selected from N, O or S) in the ring, and optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, amino, aminosulfonyl , halogen, haloalkyl, hydroxy, hydroxyalkyl, carboxyalkyl, carbamoyl, nitro, sulfonylamino, thioalkyl and / or cyano. Examples of heteroaryl radicals include imidazolyl, oxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, isoxazolyl, isothiazolyl, pyrazinyl, thiophenyl, furyl, pyranyl, pyridinyl, quinolinyl, isoquinolinylindinol, benzothiolazolinyl, benzothiolazolinyl, benzothiolazolinyl, benzothiolazolinyl, benzothiolazolinyl, benzothiolazolinyl, benzothiolazinyl, isoindolyl, quinolinyl, isoquinolinyl.

“Hydroxyalkyl” means an alkyl radical as defined above substituted with one, two or three hydroxy groups, provided that no more than one hydroxy group is attached to one carbon atom. Examples of hydroxyalkyl radicals include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl and the like.

“Hydroxyalkylamino” means the radical —NR ¹ R ² where R ¹ is hydrogen, alkyl or hydroxyalkyl, and R ² is the above hydroxyalkyl.

“Iminoalkyl” means a group corresponding to the formula: —C (═NH) R, where R is alkyl or haloalkyl.

“Carbamoyl” means a group corresponding to the formula: —CONR ¹ R ² , where R ¹ and R ² each independently mean hydrogen, alkyl, aryl, hydroxyalkyl, aminoalkyl.

“Carboxyalkyl” means a group corresponding to the formula: —CO ₂ R, where R is alkyl or hydroxyalkyl.

“Sulfonylamino” means the radical —N (R ¹ ) SO ₂ R ² , where R ¹ is hydrogen or an alkyl radical as defined above, and R ² is alkyl, haloalkyl, aryl, heteroaryl. Examples of alkylsulfonylamino radicals include methylsulfonylamino, trifluoromethylsulfonylamino, phenylsulfonylamino, and the like.

"Trialkylammonium" means a positively charged quaternary ammonium group [-NR ¹ R ² R ³ ] ⁺ , where R ¹ -R ³ each independently means alkyl or alkylene radicals, for example trimethylammonium, triethylammonium.

“Cycloalkyl” means a saturated monovalent cyclic hydrocarbon radical containing from 3 to 7 carbon atoms in the cycle and optionally substituted with substituents selected from the group consisting of alkyl, halogen, amino, alkylamino, aryl, heteroaryl and the like. The term cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "bioisostere" is used in a meaning commonly used in the field of medical chemistry [Lipinski C.A. Bioisosterism in Drug Design. Annual Reports in Medicinal Chemistry. 1986, 21, pp. 283-291]. In accordance with this generally accepted meaning, bioisosteres are called substituents or groups of atoms with similar physical or chemical properties that can impart similar biological properties to chemical compounds. Bioisosteric substitution allows modulating the biological or physical properties of compounds without making significant changes in the chemical structure of biologically active drugs. In accordance with generally accepted terminology, "classical bioisosteres" refers to atoms or groups of atoms having similar size, shape, number of atoms and electron density. “Nonclassical bioisosteres” are considered to be atoms or groups of atoms that do not have the structural similarity characteristic of classical bioisosteres, but which have similar biological activity. Examples of classical bioisosteres include substitution of the amino group with a hydroxyl group, replacement of the —CH═ bond in arenes or heteroarenes with the —N = fragment, and the like. Examples of non-classical bioisosteres include replacing a hydroxy group with an acylamino or sulfonylamino group; substitution of a halogen atom for trifluoromethyl or cyano groups; replacing the carboxyl group with a sulfamide group or with a tetrazole core; replacing -CH = CH- groups of aromatic nuclei with a heteroatom -S-, etc. These examples and a number of other bioisosteres are well known for various classes of biologically active substances and are described in the relevant literature [for example, in Silverman R.B. The Organic Chemistry of Drug Deign and Drug Action. 2-nd Edition. Elsevier, Academic Press: Amsterdam, 2004, 29-34; Lima L.M., Barreiro E.J. Bioisosterism: A Useful Strategy for Molecular Modification and Drug Design. Current Medicinal Chemistry, 2005,12, 23-49].

The term "isomers" means compounds with the same molecular formula, but differing in the nature or sequence of chemical bonds or spatial arrangement of atoms. Isomers that differ in the spatial arrangement of atoms are called “stereoisomers”. A carbon atom bonded to four different substituents is called a “chiral center”.

“Chiral compound” means a compound with one or more chiral centers. This compound has two enantiomeric forms with opposite chirality and can exist both as individual enantiomers and as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomers is called a "racemic mixture." Compounds containing more than one chiral center may exist as an individual diastereomer or as a mixture of diastereomers, which is called a "diastereomeric mixture". In the presence of a chiral center, stereoisomers can be characterized by the absolute configuration (R or S), which means the spatial arrangement of the substituents at the chiral center. These substituents associated with the chiral center are classified according to the rules of Kahn, Ingold and Prelog [Cahn et al., Angew. Chem., 1966, 75, 413].

"Tautomers" means compounds whose structures differ in the spatial arrangement of atoms, but are in equilibrium. The compounds of formula 4 may contain groups that may be in tautomeric equilibrium. It is understood that, if the compounds of formula 4 can exist in tautomeric forms, the present invention includes all tautomeric forms, and the names of the compounds do not exclude any tautomeric form.

“Optional” or “optionally” means that a subsequent event or circumstance may occur, but does not necessarily occur, and that the description includes instances where this event or circumstance will occur and instances where it will not occur. For example, the term "optionally substituted" when used in connection with the term "aryl", "heteroaryl" means aryl or heteroaryl, which optionally and independently contains from one to four substituents selected from the group consisting of alkyl, alkoxy, amino, acyloxy hydroxy, halogen, haloalkyl, hydroxyalkyl, carboxyalkyl, carbamoyl, nitro, cyano.

“Leaving group” means a group whose name is usually associated with its use in synthetic organic chemistry, i.e. means an atom or group that is substituted under reaction conditions. Examples of the leaving group include alkylsulfonyloxy or arylsulfonyloxy (such as methanesulfonyloxy, trifluoromethanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, tosyloxy), acyloxy, halogen, amino, trialkylammonium groups and the like.

The term "protective group" refers to a group suitable for blocking a functional group under the conditions of the reactions, as described in literature [Green T.W., Wuts P.G.M. Protective Groups in Organic Synthesis. J. Wiley & Sons, N.-Y., 1991, 351 pp]. Examples of such groups for blocking an amino group include tert-butoxycarbonyl (Boc), adamantyloxycarbonyl (Adoc), fluorenylmethyloxycarbonyl (Fmoc) and carbonibenzyloxy (Cbz), ethoxycarbonyl, acetyl groups and the like. An example of such groups for blocking a carboxy group includes tert-butyl, methyl, ethyl, benzyl groups and the like. An example of such groups for blocking a hydroxy group includes methyl, ethyl, benzyl, methoxymethyl, benzyloxymethyl, trimethylsilyl, acetyl and the like.

"Inert organic solvent" means a solvent inert under the reaction conditions described herein, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, chloroform, dichloromethane, dichloroethane, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine and the like. Unless otherwise indicated, the solvents used in the reactions of the present invention are inert solvents.

"Pharmaceutically acceptable" means a material that is used in the manufacture of a pharmaceutical composition and which is usually non-toxic, biologically or otherwise safe and includes material that is acceptable in both veterinary medicine and pharmaceuticals.

"Pharmaceutically acceptable salts" of a compound means salts that are pharmaceutically acceptable and which possess the necessary pharmacological activity of the parent compound. Such salts include: (1) acid addition salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like, or organic acids such as acetic acid, benzoic acid, citric acid, fumaric acid , glutamic acid, glycolic acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, toluenesulfonic acid, and the like. or (2) salts formed by replacing an acidic proton (in OH, NH or SH groups) present in the parent compound with a metal ion, for example, an alkali metal ion, alkaline earth metal ion or aluminum ion, or the formation of a proton coordination compound with an organic or inorganic base. Suitable organic bases include diethanolamine, ethanolamine, triethanolamine and the like. Suitable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide, and the like. Pharmaceutically acceptable salts are intended to include solvates or crystalline forms (polymorphic formations) of said acid addition salt. Preferred pharmaceutically acceptable salts are salts of acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc and magnesium salts.

The term “solvates” means solvated forms containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds are able to retain a fixed number of solvent molecules in the crystal lattice, forming a solvate. Hydrates are formed if water is used as the solvent, and alcoholates are formed if the solvent is alcohol.

“Subject” means mammals, i.e. means any member of the mammalian class, including humans, primates, farm animals such as cattle, horses, sheep, goats and pigs, domestic animals such as rabbits, dogs and cats, laboratory animals, including rodents such as rats, mice and guinea pigs, etc. The term subject does not mean a specific age or gender.

“Therapeutically effective amount” means an amount of a compound that, when administered to a subject to treat a pathological condition, is sufficient to exert a pharmacological effect in the treatment of the pathological condition of the subject. The therapeutically effective amount varies depending on the type of compound, the pathological condition to be treated, the severity of the disease, the age and relative health of the subject, the method and form of administration, the opinion of the attending physician or practicing veterinarian, and other factors.

The term "pharmacological action" used in the description of the application includes the results of exposure to the subject, in which the intended purpose of therapy is achieved. For example, a pharmacological action means such effects that lead to a cure or slow development, to prevent relapse of the disease.

Typical compounds of the invention and some schemes for their synthesis are provided in a number of examples described below.

Scheme B

Example 1

(S) -4,11-dihydroxy-3 - [(pyrrolidin-3-ylamino) methyl] -1H-naphtho (2,3-f] indol-5,10-dione dihydrochloride

A solution of 50 mg (0.1 mmol) of 4,11-dihydroxy-3 - [(dimethylamino) methyl] -1H-naphtho [2,3-f] indole-5,10-dione iodomethylate ( a , Scheme B ), prepared as previously the described method [Shchekotikhin AE et. al., Bioorg. Med. Chem., 2005, 13, 2285] and 0.1 g (2.5 mmol) of (S) -tert-butyl 3-amino-1-pyrrolidinecarboxylate in chloroform (10 ml) are boiled for 1 hour. The mixture is diluted with chloroform, washed with water, with a NaHCO ₃ solution. , dried and evaporated. The residue was purified by column chromatography (chloroform-methanol, 10: 1 → 2: 1). Obtain 33 mg (70%) of Boc derivative b , which is dissolved in methanol (0.5 ml) and 0.5 ml of a solution of (1H) HCl in ether is added. The mixture was stirred for 6 hours and the red precipitate of dihydrochloride was filtered off . Yield 26 mg (56%). Mp 254-255 ° C (decomp.). ¹ H NMR (400 MHz, D ₂ O), δ, m. D .: 7.72 (1H, d, J = 7.5, ⁹ H), 7.59 (1H, d, J = 7.5, ⁶ H), 7.45 ( 2H, m, H ^7.8 ), 7.18 (1H, s, H ² ), 4.17 (3H, m, CH ₂ NCH ₂ CH), 3.83 (1H, m, NCH ₂ CH), 3.62 (1H, m, NCH ₂ CH ₂ ), 3.50 (2H, m, NCH ₂ CH ₂ , CH), 2.62 (1H, m, J = 7.5, CH ₂ CH ₂ CH), 2.29 (1H, m, J = 7.0, CH ₂ CH ₂ CH). Mass spectrum, m / z ( _Irel ,%): 377 (12) [M] ⁺ , 358 (12), 308 (20), 293 (100), 279 (90), 263 (14). Found,%: C 53.30, H 5.17, N 8.81. C ₂₁ H ₁₉ N ₃ O ₄ · 2HCl · H ₂ O. Calculated,%: C 53.86, H 4.95, N 8.97, M 377.12.

Example 2

(R) -4,11-dihydroxy-3 - [(pyrrolidin-3-ylamino) methyl] -1H-naphtho [2,3-f] indol-5,10-dione dihydrochloride

Obtained by a method similar to that described in example 1, from 4,11-dihydroxy-3 - [(dimethylamino) methyl] -1H-naphtho [2,3-f] indole-5,10-dione iodomethylate ( a , Scheme B ) and (R) -tert-6utyl 3-amino-1-pyrrolidinecarboxylate. Yield 55%. T. pl. 255-256 ° C (decomp.). HPLC (GraseSmart RP-18 column, 6 × 250 mm, LW = 260 nm; eluent: A — H ₃ PO ₄ (0.01 m), B — MeCN; gradient B 10 → 40% (30 min)): exit time 19.3 min, purity 99.8%. ¹ H NMR (400 MHz, D ₂ O), δ, m. D .: 7.76 (1H, d, J = 7.5, ⁹ H), 7.64 (1H, d, J = 7.5, ⁶ H), 7.45 ( 2H, m, H ^7.8 ), 7.13 (1H, s, H ² ), 4.40 (3H, m, CH ₂ CH ₂ CH), 3.88 (1H, m, NCH ₂ CH), 3.60 (2H, m, NCH ₂ CH ₂ , CH), 3.50 (1H, m, NCH ₂ CH ₂ ), 2.64 (1H, m, J = 7.5, CH ₂ CH ₂ CH), 2.32 (1H, m, J = 7.0, CH ₂ CH ₂ CH). Mass spectrum, m / z ( _Irel ,%): 377 (12) [M] ⁺ , 358 (14), 308 (23), 293 (100), 279 (92), 263 (15). Found,%: C 53.75, H 5.31, N 9.18. C ₂₁ H ₁₉ N ₃ O ₄ · 2HCl · H ₂ O. Calculated,%: C 53.86, H 4.95 N 8.97. M 377.12.

Example 3

(S) -3 - [(3-Aminopyrrolidin-1-yl) methyl] -4,11-dihydroxy-1H-naphtho [2,3-f] indole-5,10-dione dihydrochloride

Obtained by a method similar to that described in example 1, from 4,11-dihydroxy-3 - [(dimethylamino) methyl] -1H-naphtho [2,3-f] indole-5,10-dione iodomethylate ( a , Scheme B ) and (S) -3- (tert-butoxycarbonylamino) pyrrolidine. Yield 64%. T. pl. 255-258 ° C (decomp.). HPLC (Gemini 100A C-18 column, 6 × 250 mm, LW = 260 nm; eluent: A — HCO ₂ NH ₄ (0.2%), B — MeCN; gradient B 10 → 50% (30 min)): exit time 22.6 min, 99.4% purity. ¹ H NMR (400 MHz, D ₂ O), δ, m. D .: 7.61 (1H, d, J = 7.5, ⁹ H), 7.52 (1H, d, J = 7.5, ⁶ H), 7.40 ( 1H, t, J = 7.5, H ⁵ ), 7.35 (1H, t, J = 7.5, H ⁷ ), 7.13 (1H, s, H ² ), 4.37 (2H, s, CH ₂ N), 4.16 (1H dd, J = 7.4, NCH ₂ CH), 3.85 (1Н, m, NCH ₂ CH), 3.60 (1Н, m, NCH ₂ CH ₂ ), 3.49 (2Н, m, NCH ₂ CH ₂ , СН), 2.59 (1H, m, J = 7.4, CH ₂ CH ₂ CH), 2.28 (1H, m, J = 7.0, CH ₂ CH ₂ CH). Mass spectrum, m / z ( _Irel ,%): 377 (12) [M] ⁺ , 358 (14), 293 (100), 279 (80), 263 (15). Found,%: C 54.08, H 4.78, N 9.25. C ₂₁ H ₁₉ N ₃ O ₄ · 2HCl · H ₂ O. Calculated,%: C 53.86, H 4.95, N 8.97. M 377.12.

Example 4

(R) -3 - [(3-Aminopyrrolidin-1-yl) methyl] -4,11-dihydroxy-1H-naphtho [2,3-f] indole-5,10-dione dihydrochloride

Obtained by a method similar to that described in example 1, from 4,11-dihydroxy-3 - [(dimethylamino) methyl] -1H-naphtho [2,3-f] indole-5,10-dione iodomethylate ( a , Scheme B ) and (R) -3- (tert-butoxycarbonylamino) pyrrolidine. Yield 65%. Mp 255-256 ° C (decomp.). ¹ H NMR (400 MHz, D ₂ O), δ, m. D .: 7.62 (1H, d, J = 7.5, ⁹ H), 7.52 (1H, d, J = 7.5, ⁶ H), 7.42 ( 1H, t, J = 7.5, H ⁵ ), 7.38 (1H, t, J = 7.5, H ⁷ ), 7.13 (1H, s, H ² ), 4.35 (2H, s, CH ₂ N), 4.18 (1H dd, J = 7.4, NCH ₂ CH), 3.82 (1Н, m, NCH ₂ CH), 3.60 (1Н, m, NCH ₂ CH ₂ ), 3.44 (2Н, m, NCH ₂ CH ₂ , СН), 2.63 (1H, m, J = 7.4, CH ₂ CH ₂ CH), 2.22 (1H, m, J = 7.0, CH ₂ CH ₂ CH). Mass spectrum, m / z ( _Irel ,%): 377 (11) [M] ⁺ , 358 (16), 293 (100), 279 (89), 263 (19). Found,%: C 53.72, H 5.14, N 8.82. C ₂₁ H ₁₉ N ₃ O ₄ · 2HCl · H ₂ O. Calculated,%: C 53.86, H 4.95, N 8.97. M 377.12.

Example 5

3 - ({(1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl} methyl) -4,11-dihydroxy-1H-naphtho [2,3-f] indole-5, 10-dione dihydrochloride

Obtained by a method similar to that described in example 1, from 4,11-dihydroxy-3 - [(dimethylamino) methyl] -1H-naphtho [2,3-f] indole-5,10-dione iodomethylate ( a , Scheme B ) and (1S, 4S) -N- (tert-butoxycarbonyl) -2,5-diaza-bicyclo [2.2.1] heptane. Yield 61%. Mp 246-247 ° C (decomp.). ¹ H NMR (400 MHz, D ₂ O), δ, ppm, J = (Hz).. 7.48 (. 1H, br s, ⁹ H), 7.38-7.24 (3H, br m, H ^{6. , 7.8} ), 7.12 (1H, s, H ² ), 4.68 (1H, s, CH), 4.57 (1H, s, CH), 4.39 (1H, d, J = 15.2, CH ₂ N), 4.30 (1H, d, J = 14.1, CH ₂ N), 3.75 (2H, t, J = 12.6, NCH ₂ CH), 3.61 (2H, d, J = 12.6, NCH ₂ CH), 2.63 (1H, d, J = 12.3, CHCH ₂ CH), 2.32 (1H, d, J = 12.3, CHCH ₂ CH). Mass spectrum, m / z ( _Irel ,%): 389 (8) [M] ⁺ , 370 (13), 293 (100), 279 (83), 263 (16). Found,%: C 55.22, H 5.09, N 9.01. C ₂₂ H ₁₉ N ₃ O ₄ · 2HCl · H ₂ O. Calculated,%: C 55.01, H 4.83, N 8.75. M 389.12.

Scheme B

Example 6

3 - {(1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl} methyl-11-hydroxy-4- [2- (dimethylamino) ethyl] amino-1H-naphtho [2,3 -f] indole-5,10-dione

Stage 1

3 - ({(1S, 4S) -5- (tert-butoxycarbonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl} methyl) -4,11-dimethoxy-1H-naphtho [2,3 -f] indole-5,10-dione

A solution of 100 mg (0.2 mmol) of 4,11-dimethoxy-3 - [(dimethylamino) methyl] -1H-naphtho [2,3-f] indole-5,10-dione iodomethylate ( a , Scheme B ), prepared as previously the described method (Shchekotikhin AE et. al., Bioorg. Med. Chem., 2007, 15, 2651) and 0.2 g (5 mmol) (1S, 4S) -N- (tert-butoxycarbonyl) -2,5-diaza- bicyclo [2.2.1] heptane in chloroform (10 ml) is boiled for 30-40 minutes. The mixture was diluted with chloroform, washed with water, NaHCO ₃ solution, dried and evaporated. The residue was purified by column chromatography (chloroform — methanol — conc. NH ₄ OH, 10: 2: 0 → 10: 3: 1). Yield 76 mg (74%). ¹ H NMR (400 MHz, CDCl _3), 8, ppm, J = (Hz): 9.58 (. 1H, broad 1, NH), 8.21 (2H, m, H ^{6 '9),} 7.69 ( 2H, m, H ^7.8 ), 7.36 (1H, br.sd.H ₂ ), 4.39 (0.5H, s, CH), 4.28 (0.5H, s, CH), 4.10 (2H, m, CH ₂ H), 4.06 (3H, s, OMe), 4.02 (3H, s, OMe), 3.58 (1H, m, NCH ₂ CH), 3.27 (1H, m, NCH ₂ CH), 2.89 (1H, m, NCH ₂ CH), 2.80 (1H, m, NCH ₂ CH), 1.86 (1H, m, CHCH ₂ CH), 1.70 (1H, m, CHCH ₂ CH), 1.45 (9H, s, t-Bu). Found,%: С 67.10, Н 6.23, N 8.27. C ₂₉ H ₃₁ N ₃ O ₆ . Calculated,%: С 67.30, Н 6.04, N 8.12.

Stage 2

3 - ({(1S, 4S) -5- (tert-butoxycarbonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl} methyl) -4- [2- (dimethylamino) ethyl] amino-11 -methoxy-1H-naphtho [2,3-f] indole-5,10-dione

Solution 65 mg (0.125 mmol) 3 - ({(1S, 4S) -5- (tert-butoxycarbonyl) -2,5-diaza-bicyclo [2.2.1] heptan-2-yl} methyl) -4.11- dimethoxy-1H-naphtho [2,3-f] indole-5,10-dione ( b , Scheme B ) in 50 ml of THF and 0.3 ml of N, N-dimethylethylenediamine are heated at 30 ° C. for 4-5 hours. During this time, the color of the reaction mixture changes from dark yellow to raspberry. The mixture is cooled and diluted with water and acetic acid is added to pH 8.0. The main product is extracted with chloroform (4 × 20 ml), the extract is washed with water, dried and evaporated. The residue was purified by column chromatography (chloroform-methanol, 10: 0 → 2: 1) and the product was crystallized from benzene-n-heptane (1: 4). Yield 38 mg (53%) as raspberry crystals. Mp 145-149 ° C. ¹ H NMR spectrum (400 MHz, CDCl ₃ ), δ, ppm, J = (Hz): 9.42 (1H, br.s, NH), 9.20 (1H, br.s, NH), 8.24 (2H, m, H ^6.9 ), 7.67 (2H, m, H ^7.8 ), 7.22 (1H, br.s, H ₂ ), 4.43 (0.5H, s, CH), 4.28 (0.5H, s, CH), 4.03 (3H, s, OMe), 3.93 (2H, m, CH ₂ N), 3.60 (2H, m, CH), 3.20-2.80 (5H, m, CH), 2.59 (2H, m, CH ₂ NMe ₂ ), 2.28 (3H, s, NMe ₂ ), 2.27 (3H, s, NMe ₂ ), 1.92 (1H, m, CHCH ₂ CH), 1.73 (1H, m, CHCH ₂ CH), 1.48 (9H, s, t-Bu). Mass spectrum, m / z ( _Irel ,%): 573 (12) [M] ⁺ , 473 (100). C ₃₂ H ₃₉ N ₅ O ₅ . Calculated M: 573.22.

Stage 3

3 - {(1S, 4S) -2,5-Diazabicyclo [2.2.1] heptan-2-yl} methyl-11-hydroxy-4- [2- (dimethyl-amino) ethyl] amino-1H-naphtho [2 , 3-f] indole-5,10-dione dihydrochloride

To a stirred solution 30 mg (0.05 mmol) 3 - ({(1S, 4S) -5- (tert-butoxycarbonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl} methyl) -4- [2 - (dimethylamino) ethyl] amino-11-methoxy-1H-naphtho [2,3-f] indole-5,10-dione ( c , Scheme B ) 1.5 ml (1.5 mmol) of 1M- are added to 20.0 ml of dry dichloroethane solution of BBr ₃ × SMe ₂ in dichloromethane, boiled for 30 minutes, cooled, methanol (2.0 ml) was added dropwise and evaporated. The residue was partitioned between a warm mixture of n-butanol (50 ml) and a 2% aqueous solution of Na ₂ CO ₃ (30 ml). The extract was washed with water, dried and evaporated. The raspberry oil obtained after evaporation of the solution was dissolved in methanol (3.0 ml) and 5.0 ml of a solution of (1N) HCl in ether was added. The mixture was kept in the freezer overnight and a dark crimson crystalline precipitate was filtered off. Yield 15 mg (51%) of trihydrochloride d (Scheme B ) with mp. 229-231 ° C (decomp.). ¹ H NMR (400 MHz, D ₂ O), δ, ppm, J = (Hz).. 7.76 (. 1H, br s, ⁹ H), 7.46 (1H, s, ₂ H), 7.39- 7.25 (3H, br. M, H ^6.7.8 ), 4.50 (2H, s, CH), 4.40 (2H, m, CH), 3.64 (1H, m, CH), 3.50 (5H, m, CH) ), 3.24 (2H, m, CH), 2.78 (6H, s, NMe ₂ ), 2.45 (1H, d, J = 12.3, CHCH ₂ CH), 2.34 (1H, d, J = 12.3, CHCH ₂ CH) . Found,%: C 53.46, H 5.99, N 12.11. C ₂₆ H ₂₉ N ₅ O ₃ · 3HCl · H ₂ O. Calculated,%: C 53.20, H 5.84, N 11.93.

Scheme D

Example 7

4,11-dihydroxy-2-methyl-N- (3-pyrrolidinyl) anthra [2,3-b] furan-5,10-dione-3-carboxamide hydrochloride

A suspension of 100 mg (0.3 mmol) of 4,11-dihydroxy-2-methylanthra [2,3-b] furan-5,10-dion-3-carboxylic acid ( a , Scheme D ) obtained by the previously described method [Gorelik M .V., Mishina EV, ZhORKh, 1983.19, 2185] in 10 ml of toluene and 0.2 ml (2.8 mmol) of SOCl _{2 are} boiled with vigorous stirring for 40 minutes, after which the reaction mass is evaporated. The residue was dissolved in hot chloroform and 0.18 g (1 mmol) of tert-butyl 3-amino-1-pyrrolidinecarboxylate was added. The reaction mass is boiled for 10 minutes, washed with a solution of (1%) NaHCO ₃ , water, dilute HCl, water, dried and evaporated. The residue was purified by column chromatography (chloroform-methanol, 10: 1 → 5: 1), the resulting red powder was dissolved in hot chloroform, and 3.0 ml of a solution of (1N) HCl in methanol was added. The mixture was stirred for 6 hours and the red precipitate was filtered off. Yield 73 mg (55%) of 4,11-dihydroxy-2-methyl-N- (3-pyrrolidinyl) anthra [2,3-b] furan-5,10-dion-3-carboxamide hydrochloride. Mp 228-231 ° C. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm, J = (Hz): 9.29 (1H, br.s, NH ₂ ), 8.93 (1H, d , J = 6.0, NH), 8.16 (2H, m, H ^6.9 ), 7.90 (2H, m, H ^7.8 ), 4.55 (1H, m, CH), 3.50 (2H, m, CH ₂ ) , 3.33 (1H, m, CH ₂ ), 3.17 (1H, m, CH ₂ ), 2.62 (3H, s, CH3), 2.23 (1H, m, J = 7.3, CH ₂ CH ₂ CH), 1.99 (1H , m, J = 8.4, CH ₂ CH ₂ CH). Mass spectrum, m / z ( _Irel ,%): 406 (7) [M] ⁺ , 337 (38), 321 (100), 304 (71), 290 (24). Found,%: C 59.78, H 4.21, N 6.20. C ₂₂ H ₁₈ N ₂ O ₆ .HCl. Calculated,%: C 59.67, H 4.32, N 6.33. M406.14.

Example 8

4.11-dihydroxy-2-methyl-3 - [(3-amino-1-pyrrolidinyl) carbonyl] anthra [2,3-b] furan-5,10-dione hydrochloride

Obtained by the method similar to that described in example 7, from 4,11-dihydroxy-2-methylanthra [2,3-b] furan-5,10-dion-3-carboxylic acid ( a , scheme D ) and 3- (tert β-butoxycarbonylamino) pyrrolidine. Yield 59% hydrochloride. Mp 244-246 ° S.Spektr ¹ H NMR (400 MHz, D ₂ O), 6 m. D .: 7.16 (4H, m, H ^6,9,7,8), 3.89 (1H, m, NCH ₂ ), 3.80 (1H, m, NCH ₂ ), 3.58 (1H, m, NCH ₂ ), 3.49 (1H, m, NCH ₂ ), 3.29 (1H, m, CH), 2.35 (3H, s, Me), 2.23 (1H, m, J = 7.1, CH ₂ CH ₂ CH), 1.19 (1H, m, J = 8.6, CH ₂ CH ₂ CH). Mass spectrum, m / z ( _Irel. %): 406 (21) [M] ⁺ , 389 (45), 321 (100), 294 (82), 265 (23). Found,%: C 59.38, H 4.15, N 6.45. C ₂₂ H ₁₈ N ₂ O ₆ .HCl. Calculated,%: C 59.67, H 4.32, N 6.33. M 406.14.

Scheme D

Example 9

4,11-dihydroxy-3 - [(pyrrolidin-3-ylamino) methyl] anthra [2,3-b] thiophene-5,10-dione

Stage 1

3 - {[1- (tert-Butoxycarbonyl) pyrrolidin-3-yl] amino} methyl-4,11-dimethoxy-anthra [2,3-b] thiophen-5,10-dione

A solution of 0.10 g (0.24 mmol) of 3-bromomethyl-4,11-dimethoxyantra [2,3-b] thiophene-5,10-dione ( a , Scheme D ) obtained according to the previously described method [Sinkevich Yu. .B. et al., CGS, 2007, 1478], 0.085 g (0.5 mmol), tert-butyl 3-amino-1-pyrrolidine carboxylate and 0.5 ml (0.6 mmol) of N, N-diisopropylethylamine in 20.0 ml of chloroform. Wash the solution with water, dry and evaporate. The residue was purified by column chromatography (chloroform-methanol, 10: 0 → 3: 1). Yield 101 mg (80%), yellow, slowly crystallizing oil. Yield 62%, yellow crystals. Mp 139-142 ° C. ¹ H NMR (400 MHz, CDCl _3), δ, m. D .: 8.25 (2H, m, ^6.9 H), 7.77 (2H, m, ^7.8 H), 7.56 (1H, s, H ² ), 4.19 (2H, s, CH ₂ N), 4.13 (3H, s, OMe), 4.08 (3H, s, OMe), 3.48 (2H, m, CH ₂ ), 3.30 (2H, m, CH ₂ ), 3.13 (1Н, m, СН), 2.12 (1Н, br.s, NH), 2.00 (1Н, m, СН ₂ ), 1.73 (1Н, m, СН ₂ ), 1.42 (9Н, s, t- Bu). ¹³ C NMR spectrum (100 MHz, CDCl ₃ ), δ, ppm: 182.99 (С = О), 182.68 (С = О), 154.55, 154.48 (NCO ₂ ), 152.87, 144.25,138.29,138.15, 137.77 , 134.51,134.04, 122.02, 120.84, 79.12, 133.61 (2CH), 129.42, 129.26 (СН), 126.71 (СН), 126.51 (СН), 56.62, 55.61 (СН), 51.85, 51.15 (СН ₂ ), 47.30 ( CH ₂ ), 44.37, 44.03 (CH ₂ ), 32.17, 31.33 (CH ₂ ), 63.60 (CH ₃ ), 61.99 (CH ₃ ), 28.44 (t-Bu). Mass spectrum, m / z ( _Irel. %): 522 (100) [M] ⁺ . Found,%: C 64.11, H 5.65, N 5.43. C ₂₈ H ₃₀ N ₂ O ₆ S. Calculated,%: C 64.35, H 5.79, N 5.36. M 522.18.

Stage 2

4,11-dihydroxy-3 - [(pyrrolidin-3-ylamino) methyl] anthra [2,3-b] thiophene-5,10-dione dihydrochloride

To a solution of 70 mg (0.19 mmol) of anthratiophenedione 270 in 20.0 ml of AcOH, 5.0 conc. HBr solution, boil for 4 hours with vigorous stirring and evaporate. The residue was partitioned in a hot mixture of n-butanol (50 ml) and a 1% aqueous solution of NaHCO ₃ (20 ml). The extract was washed with water, dried and evaporated. The residue was purified by column chromatography (CHCl ₃ -MeOH-conc. NH ₄ OH, 10: 2: 0 → 10: 3: 1). The residue was dissolved in a warm solution of (1N) HCl, the product precipitated with acetone, washed with Et ₂ O, and dried. Yield 41 mg (68%) of red crystals of dihydrochloride 278. mp. 252-254 ° C (decomp.). ¹ H NMR spectrum (400 MHz, D ₂ O), δ, ppm, J = (Hz): 7.93 (1Н, s, Н ² ), 7.61 (2Н, m, Н ^6.9 ), 7.46 ( 2H, m, H ^7.8 ), 4.42 (2H, m, CH ₂ N), 4.24 (1H, dd, J = 7A, NCH ₂ CH), 3.90 (1H, dd, J = 5.1, J = 8.2, NCH ₂ CH), 3.63 (1H, m, NCH ₂ CH ₂ ), 3.56 (1H, m, CH), 3.49 (1H, m, NCH ₂ CH ₂ ), 2.65 (1H, m, J = 7.0, CH ₂ CH ₂ CH), 2.27 (1H, m, J = 7.1, CH ₂ CH ₂ CH). Mass spectrum, m / z ( _Irel. %): 394 (18) [M] ⁺ , 310 (100), 296 (76). Found,%: C 52.14, H 4.76, N 5.95, S 6.74. C ₂₁ H ₁₈ N ₂ O ₄ S. 2HCl. H ₂ O. Calculated,%: C 51.96, H 4.57, N 5.77, S 6.61. M 394.10.

Example 10

3 - [(3-aminopyrrolidin-1-yl) methyl] -4,11-dihydroxyantra [2,3-b] thiophen-5,10-dione

Stage 1

3 - {[3- (tert-Butoxycarbonylamino) pyrrolidin-1-yl] methyl} -4,11-dimethoxyanthra [2,3-b] thiophen-5,10-dione

Obtained by the method similar to that described in example 9, stage 1, from 3-bromomethyl-4,11-dimethoxyanth [2,3-b] thiophene-5,10-dione ( a , Scheme D ) and 3- (tert-butoxycarbonylamino ) pyrrolidine. Yield 85%, yellow crystals. Mp 98-99 ° C. ¹ H NMR spectrum (400 MHz, CDCl ₃ ), δ, ppm, J = (Hz): 8.25 (2H, m, H ^6.9 ), 7.76 (2H, m, N ^7.8 ), 7.62 (1H, s, H ² ), 5.22 (1H, br.s.d, J = 6.4, NH), 4.22 (1H, m, CH), 4.08 (5H, s, CH ₂ N, OMe ), 4.04 (3H, s, OMe), 2.97 (1H, m, CH ₂ ), 2.82 (1H, m, CH ₂ ), 2.71 (1H, d, J = 7.4, CH ₂ ), 2.51 (1H, dd , J = 7.4, J = 8.4, CH ₂ ), 2.33 (1H, m, CH ₂ ), 1.68 (1H, m, CH ₂ ), 1.43 (9H, s, t-Bu). NMR spectrum ¹³ (С, 400 MHz, CDCl ₃ ), δ, ppm: 182.93 (С = O), 182.71 (С = О), 155.32 (NCO ₂ ), 155.28, 152.65, 143.77, 138.02, 137.57, 134.55, 134.02, 121.88, 120.55, 79.21, 133.49 (CH), 133.43 (CH), 130.00 (CH), 126.65 (CH), 126.43 (CH), 49.81 (CH), 61.52 (CH ₂ ), 54.78 (CH ₂ ), 52.95 (CH ₂ ), 32.51 (CH ₂ ), 63.05 (CH ₃ ), 61.89 (CH ₃ ), 28.31 (t-Bu). Found,%: C 64.02, H 5.43, N 5.22. C ₂₈ H ₃₀ N ₂ O ₆ S. Calculated,%: C 64.35, H 5.79, N 5.36.

Stage 2

3 - [(3-Aminopyrrolidin-1-yl) methyl] -4,11-dihydroxyantra [2,3-b] thiophen-5,10-dione dihydrochloride

Obtained by the method similar to that described in example 9, stage 2, from 3 - {[3- (tert-butoxycarbonylamino) pyrrolidin-1-yl] methyl} -4,11-dimethoxyanth [2,3-b] thiophen-5, 10-dione ( b , Scheme D ). Yield 41% dihydrochloride, red crystals. Mp 245-247 ° C (decomp.). ¹ H NMR (400 MHz, D ₂ O), δ, m. D .: 8.00 (1H, s, ² H), 7.63 (2H, m, ^6.9 H), 7.48 (2H, m, H ^{7 , 8} ), 4.65 (2H, s, CH ₂ N), 4.25 (1Н, m, NCH ₂ CH), 3.95 (1Н, m, NCH ₂ CH), 3.73 (1Н, m, NCH ₂ CH ₂ ), 3.59 (2H, m, NCH ₂ CH ₂ , CH), 2.69 (1H, m, CH ₂ CH ₂ CH), 2.28 (1H, m, CH ₂ CH ₂ CH). Mass spectrum, m / z ( _Irel. %): 394 (11) [M] ⁺ , 367 (32), 310 (100), 296 (71). Found,%: C 52.10, H 4.67, N 6.03, S 6.43. C ₂₁ H ₁₈ N ₂ O ₄ S. 2HCl. H ₂ O. Calculated,%: C 51.96, H 4.57, N 5.77, S 6.61. M 394.10.

Example 11

3 - {[(2S, 4S) -4-amino-2- (hydroxymethyl) pyrrolidin-1-yl] methyl} -4,11-dihydroxyantra [2,3-b] thiophen-5,10-dione dihydrochloride

Stage 1

4,11-Dimethoxy-3 - {[((2S, 4S) -4- (ethoxycarbonylamino) -2- (hydroxymethyl) pyrrolidin-1-yl] methyl} -antra [2,3-b] thiophen-5,10- dion

Obtained by a method similar to that described in example 9, stage 1, from 3-bromomethyl-4,11-dimethoxyanth [2,3-b] thiophene-5,10-dione ( a , Scheme D ) and (2S, 4S) - 4- (ethoxycarbonylamino) -2- (hydroxymethyl) pyrrolidine. Yield 72%, yellow crystals. Mp 144-147 ° C. ¹ H NMR (400 MHz, CDCl _3), δ, ppm, J = (Hz).. 8.20 (2H, m, ^6.9 H), 7.73 (2H, m, ^7.8 H), 7.66 (1Н, s, Н ² ), 5.77 (1Н, br.s.d, J = 8.1, NH), 4.44 (1Н, d, J = 14.3, СН), 4.21 (1Н, m, СН ₂ ), 4.11 (3Н , s, OMe), 4.03 (3Н, s, OMe), 4.02 (2Н, m, СН ₂ ) 3.85 (2Н, t, СН ₂ ), 3.57 (1Н, d, J = 11.4, СН), 3.01 (1Н d, J = 11.4, CH), 2.85 (1H, m, CH ₂ ), 2.57 (1H, m, CH ₂ ), 2.44 (1H, m, CH ₂ ), 1.80 (1H, m, CH ₂ ), 1.43 (3H, t, J = 7.1, CH ₃ ). Found,%: C 63.11, H 5.64, N 5.12. C ₂₉ H ₃₂ N ₂ O ₇ S. Calculated,%: C 63.03, H 5.84, N 5.07.

Stage 2

3 - {[(2S, 4S) -4-amino-2- (hydroxymethyl) pyrrolidin-1-yl] methyl} -4,11-dihydroxyantra [2,3-b] thiophen-5,10-dione dihydrochloride

To a solution of 70 mg (0.13 mmol) 4,11-dimethoxy-3 - {[(2S, 4S) -4- (ethoxycarbonylamino) -2- (hydroxymethyl) pyrrolidin-1-yl] methyl} -antra [2,3- b] thiophene-5,10-dione ( b , Scheme D ), in 20.0 ml of AcOH, 4.0 ml of conc. HBr solution, boil for 8 hours with vigorous stirring and evaporate. The residue was diluted with water (10 ml), boiled for 1 h, neutralized with a 1% aqueous solution of NaHCO ₃ to pH7, and the product was extracted with hot n-butanol (2 × 30 ml). The extract was washed with water, dried and evaporated. The residue was purified by column chromatography (chloroform — methanol — conc. NH ₄ OH, 10: 2: 0 → 5: 3: 1). The residue is treated with 5 ml of a solution of (1N) HCl in MeOH, boiled for 10 minutes, cooled and the red precipitate is filtered off, washed with MeOH, dried. Yield 38 mg (65%) of dihydrochloride, red crystals. Yield 44%, red crystals. Mp 246-249 ° C (decomp.). ¹ H NMR (400 MHz, D ₂ O), δ, m. D .: 8.06 (1H, s, ² H), 7.74 (2H, m, ^6.9 H), 7.60 (2H, m, H ^{7 , 8} ), 4.83 (1H, d, J = 7A, CH ₂ N), 4.43 (1H, d, J = 7A, CH ₂ N), 4.30 (1H, m, CH), 4.09 (2H, m, NCH ₂ ), 3.98 (1H, m, CH), 3.81 (1H, m, NCH ₂ ), 3.66 (1H, m, NCH ₂ ), 2.90 (1H, m, CH ₂ ), 2.24 (1H, m, CH ₂ CH ₂ CH). Found,%: C 49.87, H 4.74, N 5.44, S 6.21. C ₂₂ H ₂₀ N ₂ O ₅ S. 2HCl. 2H ₂ O. Calculated,%: C 49.54, H 4.91, N 5.25, S 6.01.

Example 12

4,11-dihydroxy-3 - [(piperidin-4-ylamino) methyl] anthra [2,3-b] thiophene-5,10-dione

Stage 1

4,11-dimethoxy-3 - ({[[1- (ethoxycarbonyl) -4-piperidinyl] amino} methyl) anthra [2,3-b] thiophen-5,10-dione

Obtained by the method similar to that described in example 9, stage 1, from 3-bromomethyl-4,11-dimethoxyanth [2,3-b] thiophene-5,10-dione ( a , Scheme D ) and ethyl 4-amino-1 -piperidinecarboxylate. Yield 66%, yellow crystals. Mp 151-152 ° S.Spektr ¹ H NMR (400 MHz, CDCl _3), δ, ppm, J = (Hz).. 8.25 (2H, m, ^6.9 H), 7.78 (2H, m, H ^7.8 ), 7.61 (1H, s, H ² ), 4.24 (2H, s, CH ₂ N), 4.13 (3H, s, OMe), 4.12 (4H, m, OCH ₂ , N (CH ₂ ) ₂ ), 4.08 (3H, s, OMe), 2.85 (2H, t, J = 11.6, N (CH ₂ ) ₂ ), 2.72 (1H, m, NHCH), 1.93 (2H, d, J = 10.3, CH ₂ ), 1.40 (2H, m, CH ₂ ), 1.45 (3H, t, J = 7.1, Me). Found,%: C 63.43, H 5.31, N 5.43. C ₂₉ H ₃₂ N ₂ O ₇ S. Calculated,%: C 63.76, H 5.55, N 5.51.

Stage 2

4,11-dihydroxy-3 - [(piperidin-4-ylamino) methyl] anthra [2,3-b] thiophene-5,10-dione dihydrochloride

A solution of 90 mg (0.18 mmol) of 4,11-dimethoxy-3 - ({[1- (ethoxycarbonyl) -4-piperidinyl] amino} methyl) anthra [2,3-b] thiophene-5,10-dione ( b Scheme D ) in a mixture of 20.0 ml of AcOH and 4.0 ml of conc. HBr solution, boil with vigorous stirring for 12 hours and evaporated. The residue was diluted with 20 ml of water, neutralized with a 1% aqueous NaHCO ₃ solution to pH 7, and the product was extracted with hot n-butanol (2 × 30 ml). The extract was washed with water, dried and evaporated. The residue was purified by column chromatography (chloroform — methanol — conc. NH ₄ OH, 10: 2: 0 → 10: 3: 1). The residue is treated with 5 ml of a solution of HCl (1N) in MeOH, boiled for 5 minutes, cooled and the red precipitate is filtered off, washed with MeOH, dried. Yield 40 mg (49%) of dihydrochloride, red crystals. Mp 263-265 ° C (decomp.). ¹ H NMR (400 MHz, D ₂ O), δ, ppm: J = (Hz).. 7.90 (1H, s, ² H), 7.55 (4H, m, H ^6,7,8,9) 4.38 (2H, s, CH ₂ N), 3.70 (3H, m, N (CH ₂ ) ₂ , NH ₂ CH), 3.23 (2H, t, J = 12.2, N (CH ₂ ) ₂ ), 2.51 ( 2H, d, J = 13.7, CH ₂ ), 2.05 (2H, m, CH ₂ ). Found,%: C 53.15, H 4.71, N 5.54, S 6.62. C ₂₂ H ₂₀ N ₂ O ₄ S. 2HCl. H ₂ O. Calculated,%: C 52.91, H 4.84, N 5.61, S 6.42.

Scheme E

Example 13

11-Hydroxy-4- [2- (dimethylamino) ethyl] amino-3 - [(pyrrolidin-3-ylamino) methyl] anthra [2,3-b] thiophen-5,10-dione

Stage 1

3 - {[1- (tert-butoxycarbonyl) pyrrolidin-3-yl] amino} methyl-4- [2- (dimethylamino) ethyl] amino-11-methoxyanthra [2,3-b] thiophen-5,10-dione

Prepared from 3 - {[1- (tert-butoxycarbonyl) pyrrolidin-3-yl] amino} methyl-4,11-dimethoxyanth [2,3-b] thiophen-5,10-dione (Example 9, Step 1) and N, N-dimethylethylenediamine according to the procedure similar to that described in example 6, stage 2. The main product from the mixture after extraction is isolated by column chromatography (chloroform - methanol - conc. NH ₄ OH, 10: 2: 0 → 10: 3: 1). Yield 72%, burgundy crystals. Mp 165-167 ° C (decomp.). ¹ H NMR spectrum (400 MHz, CDCl ₃ ), δ, ppm, J = (Hz): 9.02 (1H, br.s, NH), 8.24 (2H, m, H ^6.9 ), 7.73 ( 2H, m, H ^7.8 ), 7.47 (1H, s, H ² ), 4.17 (2H, s, CH ₂ N), 4.07 (3H, s, OMe), 3.49 (2H, m, CH ₂ ), 3.32 (2H, m, CH ₂ ), 3.16 (3H, m, NCH ₂ , CH ₂ ), 2.51 (2H, m, CH ₂ NMe ₂ ), 2.23 (6H, s, NMe ₂ ), 2.20 (2H, m , NH, CH ₂ ), 1.75 (1H, m, CH ₂ ), 1.44 (9H, s, t-Bu). Mass spectrum, m / z ( _Irel. %): 578 (4) [M] ⁺ , 478 (45), 394 (47), 380 (33), 306 (100), 292 (23). Found,%: C 63.13, H 6.60, N 10.01. C ₃₁ H ₃₈ N ₄ O ₅ S. Calculated,%: C 64.34, H 6.62, N 9.68. M 578.72.

Stage 2

11-Hydroxy-4- [2- (dimethylamino) ethyl] amino-3 - [(pyrrolidin-3-ylamino) methyl] anthra [2,3-b] thiophene-5,10-dione trihydrobromide

To a solution of 75 mg (0.13 mmol) 3 - {[1- (tert-butoxycarbonyl) pyrrolidin-3-yl] amino} methyl-4- [2- (dimethylamino) ethyl] amino-11-methoxyanthra [2,3-b ] thiophene-5,10-dione in 20.0 ml of AcOH add 3.0 conc. HBr solution, boil for 3 hours with stirring and evaporate. The residue was dissolved in hot water and the impurities were extracted with warm n-butanol. The aqueous phase is evaporated to a volume of 3-4 ml and the product precipitated with an excess of acetone. The precipitate is filtered off, washed with acetone and dried. Yield 42 mg (45%) of trihydrobromide, burgundy crystals. Mp 225-228 ° C (decomp.). ¹ H NMR (400 MHz, D ₂ O), δ, ppm, J = (Hz).. 8.26 (1H, s, H ^2), 8.10 (1H, d, H ^9), 7.79 (1H, d, H ⁶ ), 7.73 (1H, t, H ⁸ ), 7.63 (1H, t, H ⁷ ), 4.76 (2H, s, CH ₂ N), 4.24 (1H, dd, J = 7.4, NCH ₂ CH ), 3.85 (1Н, dd, J = 5.1, J = 8.2, NCH ₂ CH), 3.68 (2Н, m, НСН ₂ СН ₂ , СН), 3.58 (2Н, m, HNCH ₂ CH ₂ ), 3.49 (1Н m, NCH ₂ CH ₂ ), 3.42 (2Н, m, CH ₂ NMe ₂ ), 2.96 (6Н, s, NMe ₂ ), 2.65 (1Н, m, СН ₂ СН ₂ СН), 2.33 (1Н, m, CH ₂ CH ₂ CH). Found,%: C 40.74, H 4.66, N 7.78, S 4.54. C ₂₅ H ₂₈ N ₄ O ₃ S. 3HBr. 2H ₂ O. Calculated,%: C 40.39, H 4.75, N 7.54, S 4.31.

Examples of biological activity

Example A

The study of the antiproliferative activity of the claimed compounds was carried out in vitro tests on tumor cell cultures of murine leukemia L 1210/0 and malignant human T-lymphocytes of the lines Molt4 / C8, СЕМ / 0. Data on antiproliferative activity (IC ₅₀ is a concentration that inhibits cell growth by 50%) of the compounds of the invention are shown in Table 1, where the structure and numbers of examples (described above) are indicated for each compound, as well as data on the antiproliferative activity of the adriamycin comparison drug ( ADR). The determination of IC ₅₀ was carried out using the MTT test according to the method described in the literature [Mossman, T.J. Immmunol. Methods, 1983, 65, 55].

As can be seen from the data presented, the compounds that are the subject of the present invention and described in the examples have antiproliferative action in micromolar and submicromolar concentrations, in some cases exceeding the comparison drug adriamycin.

Table 1. Antiproliferative activity (IC ₅₀ , μM) of heterocyclic analogues of 5,12-naphthacenquinone for leukemia cells L 1210/0 and T-lymphocytes Molt 4 / C8 and CEM / 0. # Example Structure IC ₅₀ (μM) L 1210/0 Molt 4 / C8 CEM / 0 one

0.08 ± 0.04 0.42 ± 0.01 0.94 ± 0.26 2

0.07 ± 0.05 0.36 ± 0.01 0.76 ± 0.26 3

0.7 ± 0.22 1.2 ± 0.1 1.3 ± 0.4 four

0.7 ± 0.22 1.5 ± 0.1 1.6 ± 0.24 5

1.5 ± 0.1 1.7 ± 0.1 3.1 ± 0.5 6

2.1 ± 0.2 2.0 ± 0.1 1.7 ± 0.4 7

0.1 ± 0.04 0.31 ± 0.05 0.58 ± 0.32 8

34 ± 21 17 ± 6 40 ± 28 9

1.5 ± 0.3 0.84 ± 0.26 1.1 ± 0.3 10

2.0 ± 0.7 1.4 ± 0.1 2.1 ± 0.4 12

0.8 ± 0.2 0.4 ± 0.1 1.1 ± 0.4 eleven

1.1 ± 0.5 0.2 ± 0.1 1.2 ± 0.4 13

1.2 ± 0.1 1.8 ± 0.3 2.1 ± 0.6 ADR

0.37 ± 0.07 0.20 ± 0.02 0.056 ± 0.01

Example B

The study of the antiproliferative activity of the compounds of the present invention was also carried out on a culture of tumor cells of the K562 leukemia lines and its subline K562 / 4 with expression of P-glycoprotein. The expression of such transporters on the cell surface is one of the most common mechanisms for the emergence of multidrug resistance of tumors [Shtil AA, Grinchuk TM, et. al. Int. J. Oncol. 2000, 17, 387-392]. The data of these experiments, including the IC ₅₀ (µM) for the compounds of the invention and the adriamycin comparison drug (ADR), as well as the resistance index value (IR - ratio of IC ₅₀ for subline K562 / 4 to IC ₅₀ for line K562) are given in table 2 .

As can be seen from the data presented, the compounds that are the subject of the present invention and described in the examples for activity against cells with multidrug resistance, due to the expression of the P-gp transporter, are superior to the comparison drug adriamycin and / or have a lower resistance index.

Example B

A study of the antiproliferative activity of the compounds of the present invention was also carried out on a culture of tumor cells of colon cancer HCT116 and its subline HCT116p53CO of its isogenic subline with deletion of the p53 gene. It is well known that mutations leading to inactivation of p53 are often found in tumor cells and can lead to the development of MDR for a number of chemotherapeutic agents, including ADR [Wang Q., Beck WT Cancer Res., 1998, 58, 5762]. The data of these experiments, including the IC ₅₀ for the compounds of the invention and the adriamycin comparison drug (ADR), as well as the resistance index value (IR is the ratio of IC ₅₀ for subline HCT116r53CO to IC ₅₀ for line HCT116) are shown in Table 3.

As can be seen from the data presented, the compounds of the present invention and described in the examples for activity against multidrug-resistant cells caused by deletion of the p53 gene are superior to the comparison drug adriamycin and have a lower resistance index.

Table 2. Antiproliferative activity (IC ₅₀ , μM) of heterocyclic analogs of 5,12-naphthaquinquinone and resistance index (IR) for K562 leukemia cells and K562i / 4 subline with MDR due to P-gp expression. # Example Structure IC ₅₀ (µM) IR K562 K562 / 4 one

0.5 ± 0.1 1.7 ± 0.1 3.4 2

0.5 ± 0.1 0.3 ± 0.06 0.6 3

0.8 ± 0.1 0.4 ± 0.1 0.5 four

0.6 ± 0.1 0.9 ± 0.2 1.5 5

4.7 ± 0.5 9.0 ± 1.1 1.9 6

6.6 ± 1.5 20.4 ± 3.6 3.1 7

7.4 ± 0.2 25.3 ± 4.5 3.4 8

4.1 ± 0.6 15.9 ± 1.1 3.9 9

1.1 ± 0.2 4.5 ± 0.6 4.1 10

2.1 ± 0.1 3.7 ± 0.8 1.7 12

1.4 ± 0.1 4.8 ± 0.7 3.4 eleven

2.1 ± 0.3 2.7 ± 0.6 1.3 13

2.1 ± 0.1 2.6 ± 1.3 1.2 ADR

0.8 ± 0.2 7.0 ± 0.3 8.8

Table 3. Antiproliferative activity (IC ₅₀ , μM) of hetarene anthraquinones and resistance index (IR) for intestinal carcinoma cells HCT116 and its subline HCT116p53CO with MDR caused by deletion of the p53 gene. # Example Structure IC ₅₀ (μM) IR HCT116 NST116r53KO one

0.4 ± 0.1 0.6 ± 0.2 1.5 2

0.5 ± 0.1 0.3 ± 0.12 0.6 3

0.3 ± 0.2 0.8 ± 0.1 2.7 four

0.7 ± 0.3 0.8 ± 0.2 1.1 ADR

1.4 ± 0.1 4.4 ± 0.4 3.1

Example D

Antitumor activity of (R) -4,11-dihydroxy-3 - [(pyrrolidin-3-ylamino) methyl] -1H-naphtho [2,3-f] indole-5,10-dione dihydrochloride with a single use

The antitumor activity of the dihydrochloride of (R) -4,11-dihydroxy-3 - [(pyrrolidin-3-ylamino) methyl] -1H-naphtho [2,3-f] indole-5,10-dione (described in Example 2) was investigated with a single administration in mice with P388 lymphoma. Male BDF1 mice were vaccinated intraperitoneally with 10 ⁶ P388 ascites lymphoma cells per day 0. The drug was dissolved in physiological saline at 0.1-0.2% concentration and was administered once intraperitoneally one day after transplantation.

When using the naphthoindoldione described in Example 2, a dose-dependent significant increase in the life span of mice was obtained in the dose range from 10 to 90 mg / kg. The average life expectancy reached 11.3-14.2 days, respectively, which corresponds to T / C = 124-140% (p <0.05) in the absence of signs of toxicity. At a dose of 80 mg / kg (R) -4,11-dihydroxy-3 - [(pyrrolidin-3-ylamino) methyl] -1H-naphtho [2,3-f] indole-5,10-dione is equally effective with doxorubicin used in a single dose of 8 mg / kg according to the level of effect and control over the generalization of the process.

Example D

Antitumor activity of dihydrochloride of (R) -4,11-dihydroxy-3 - [(pyrrolidin-3-ylamino) methyl] -1H-naphtho [2,3-f] indole-5,10-dione with repeated use

The antitumor activity of the dihydrochloride of (R) -4,11-dihydroxy-3 - [(pyrrolidin-3-ylamino) methyl] -1H-naphtho [2,3-f] indole-5,10-dione (described in Example 2) was investigated when administered five times in mice with P388 lymphoma. Male BDF1 mice were inoculated intraperitoneally with 10 ⁶ P388 ascites lymphoma cells per day 0. The drug was dissolved in physiological saline at 0.1-0.2% concentration and was administered intraperitoneally five times every 24 hours after transplantation.

When five times the use of naphthoindoldione described in example 2, at a dose of 25 mg / kg (total dose of 125 mg / kg), a significant increase in the life expectancy of mice was obtained. The average life expectancy in this case reached 13.3-16.2 days, respectively, which corresponds to T / C = 145-150% (p <0.05) in the absence of signs of toxicity.

Claims (1)

Linear heterocyclic derivatives of anthracenedion containing cyclic diamines in the side chain, as well as their pharmacologically acceptable salts, suitable for the treatment of cancer and corresponding to the formula:

where W is a fragment of a five-membered heterocycle condensed with an anthracenedione nucleus in a 2-3 bond and being a heterocycle containing from one to two heteroatoms selected from N, O, S, and at least three carbon atoms, two of which are common with the anthraquinone nucleus and the third is linked to functional group X, including a fragment of pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, optionally substituted with alkyl, halogen;
Y - means the residue of a monocyclic diamine containing an exocyclic amino group, or a polycyclic diamine with bridged amino groups, which is a compound in which two amino groups are involved in the formation of 4-6-membered ring systems containing from 2 to 6 carbon atoms and connected by one two or three bridging atoms, including diamines of the formulas

,
where Y may be optionally substituted with one or more substituents linked to the diamine residue via a nitrogen or carbon atom selected from alkyl, haloalkyl, halogen, hydroxyl, hydroxyalkyl, carbamoyl and carboxyalkyl;
X - means a group linking the remainder of the specified diamine with the specified heterocyclic derivative of anthracenedione, selected from alkylene and CO, SO ₂ ;
n and m mean the number of substituents Z ¹ and Z ² independently equal to from 0 to 2; Z ¹ substituents are independently selected from hydroxy, alkoxy, amino and aminoalkylamino, halo;
Z ² substituents are independently selected from hydroxy and alkoxy, fluoro;
where carboxyalkyl means a —CO ₂ R group, where R is alkyl;
where amino means the groups —NH ₂ , —NHR ¹ , —NR ¹ R ² , where R ¹ and R ² each independently mean alkyl radicals;
where aminoalkylamino means a straight or branched chain saturated hydrocarbon radical containing from one to six carbon atoms bonded to the two amino groups indicated above, provided that no more than one amino group is attached to one carbon atom.