RU2167877C2 - Derivatives of condensed polycyclic heterocyclic compounds and method of their synthesis - Google Patents

Abstract

FIELD: organic chemistry of heterocyclic compounds, pharmacy. SUBSTANCE: invention relates to novel condensed polycyclic heterocyclic compounds of the formula (I)

and method of their synthesis. Compounds of the formula (I) show low toxicity and high antitumor activity and can be used in pharmaceutical industry. Compounds correspond to the general structural formula (I) where ring A means benzene optionally substituted with oxo-group or bicyclic condensed ring where at least one ring is aromatic ring and taken among the group including: (1) naphthalene optionally hydrogenated at one ring and/or optionally substituted with halogen atom, hydroxy-group, lower alkyl optionally containing hydroxy-group, lower alkoxy-group, nitro-group, amino-group, lower acyl, oxo-group, cyano-group, benzenesulfonamido-group, substituted lower alkyl and lower acylamino-group; (2) indene optionally hydrogenated at ring and/or optionally substituted with oxo-group; (3) benzofuran optionally hydrogenated at one ring and/or optionally substituted with hydroxy- or oxo-group in heterocyclic ring; (4) isobenzopyrane optionally hydrogenated and/or optionally substituted with oxo-group; (5) benzothiophene optionally substituted with oxo-group; (6) benzopyrane optionally hydrogenated and/or optionally substituted with oxo-group; (7) benzodioxol; (8) quinoline and isoquinoline optionally hydrogenated at heterocyclic ring and/or optionally substituted with oxo-group or lower alkyl; ring B means pyrrole, 4H-1,4-oxazine, 4H-1,4-thiazine or 4(1H)-pyridone; ring C means monocyclic or bicyclic aromatic ring taken among: (1) phenyl optionally substituted with halogen atom, hydroxy-group, lower alkoxy-group, lower alkyl, nitro-group or amino-group; (2) naphthyl and (3) quinolyl; Y means the group of the formula -e-f where e means lower alkylene and f means lower alkylamino-group, di-lower alkylamino-group, pyrrolidinyl, N-(dimethylamino)-ethyl-N-methylamino-group and N-(hydroxy-ethyl)-N-methylamino-group; or their pharmacologically acceptable salts. Compounds of the formula (I) or their pharmacologically acceptable salts are synthesized by interaction of compound of the formula (II)

where rings Aa and Ca have values indicated for A and C where substituents can be protected; ring Ba means 4H-1,4-triazine, 4H-1,4-oxazine, 4(1H)-pyridone; fa has values of f indicated above; e has values indicated above with compound of the formula (III)

Description

 The invention relates to new derivatives of polycyclic heterocyclic compounds, a method for their preparation.

Однако сообщалось, что амонафид обнаруживал сильную токсичность в отношении костного мозга и низкую эффективность в клинических тестах, проводимых до сих пор [Drugs Fut. , 17, 832 (1992)]. В качестве тетрациклического соединения был описан азонафид [2-[2'- (диметиламино)этил] -1,2-дигидро-3H-дибенз(deh)изохинолин - 1,3-дион] , полученный превращением аминонафталиновой части амонафида в антрацен для усиления посредством этого противоопухолевой активности в преклинических тестах (WO9200281).The tricyclic compound amonafide [5-amino-2- [2- (dimethylamino) ethyl] -1H-benz [de] isoquinoline-1,3- (2H) -dione] is the most famous condensed polycyclic heterocyclic antitumor compound having in its molecule cyclic imido part

However, it was reported that amonafid showed strong bone marrow toxicity and low efficacy in clinical trials so far [Drugs Fut. 17, 832 (1992)]. As the tetracyclic compound, the [2- [2'- (dimethylamino) ethyl] -1,2-dihydro-3H-dibenz (deh) isoquinoline-1,3-dione] azonafide obtained by converting the aminonaphthalene part of amonafide to anthracene was described to enhance through this antitumor activity in preclinical tests (WO9200281).

 2- [2- (2- (dimethylamino) ethyl] pyrimido [5,6,1-de] acridine - were known as condensed, tetracyclic heterocyclic antitumor substances having a uracil structure in the molecule, in which the nitrogen atom was introduced; 1,3,7-trion [Farmaco, 47 1035 (1992)] and 2,3-dihydro-2- [2- (dimethylamino) ethyl] -1H, 7H-naphthylidino [3,2,1-ij] -quinazoline -1.3.7 (2H) -trion [J. Med. Chem., 37, 593 (1994)]. However, each of these compounds showed only weak antitumor activity in preclinical tests. There were no reports of either pentacyclic or hexacyclic fused heterocyclic antitumor substances of this type.

 The present invention aims to provide new compounds or new derivatives of fused pentacyclic and hexacyclic heterocyclic compounds having low toxicity and high antitumor activity. The aim of the present invention is also to provide a method for producing these compounds and medicinal compositions containing these compounds as an active ingredient.

Description of the invention
To achieve the above objectives, the inventors conducted intensive research to develop highly effective antitumor substances. As a result, they were able to find that the new condensed pentacyclic and hexacyclic heterocyclic compounds having a uracil structure in their molecule have high antitumor activity and low toxicity, which is the completion of this invention.

где кольцо A обозначает необязательно замещенное моноциклическое ароматическое кольцо или дициклическое конденсированное кольцо, в котором по меньшей мере одно из колец является ароматическим кольцом; кольцо В обозначает пиррол, 4H-1,4-оксазин, 4H-1,4-тиазин или 4(1H)-пиридон; кольцо C обозначает необязательно замещенное, моноциклическое или дициклическое конденсированное ароматическое кольцо; и Y обозначает группу, представленную формулой-e-f (где e обозначает низший алкилен и f обозначает амидино, гуанидино или амино, необязательно замещенные необязательно гидроксилированным или необязательно низшим алкиламинированным низшим алкилом;
при условии, что исключены случаи, когда кольца A и B оба представляют собой необязательно замещенные моноциклическое ароматическое кольцо.Thus, this invention relates to a compound represented by the following general formula (I), or a pharmaceutically acceptable salt thereof:

where ring A denotes an optionally substituted monocyclic aromatic ring or a dicyclic fused ring in which at least one of the rings is an aromatic ring; ring B is pyrrole, 4H-1,4-oxazine, 4H-1,4-thiazine or 4 (1H) -pyridone; ring C represents an optionally substituted, monocyclic or dicyclic fused aromatic ring; and Y represents a group represented by the formula-ef (wherein e is lower alkylene and f is amidino, guanidino or amino optionally substituted with optionally hydroxylated or optionally lower alkylated lower alkyl;
provided that the cases where rings A and B are both optionally substituted monocyclic aromatic ring are excluded.

 Further, the present invention relates to a medicinal composition containing a condensed polycyclic heterocyclic compound in the form of the above derivative in a pharmacologically effective dose or its pharmacologically acceptable salts and pharmacologically acceptable carriers.

 The invention further relates to a method for preventing or treating tumors by administering to a patient a derivative of a condensed polycyclic heterocyclic compound described above in a pharmacologically effective dose.

 In the definition of ring A in the above formula (I), the term “monocyclic aromatic ring” means an aromatic 5- or 6-membered ring, optionally containing at least one oxygen or sulfur atom. The term "dicyclic fused ring, where at least one of the rings is an aromatic ring" means a dicyclic fused ring in which each of the rings is a 5- to 8-membered ring, optionally containing at least one nitrogen, oxygen or sulfur atom, and at least one of the rings is an aromatic ring. There may be one to three substituents on these rings.

 Examples of ring A include benzene, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, pyrrole, thiazole and other dicyclic condensed structures, which may be partially hydrogenated and oxidized at the sulfur atom, if it is contained therein. These rings can be condensed with ring B at an arbitrary permissible chemical position.

Каждое из приведенных выше колец может иметь 1 - 3 заместителя. В случае двух или более заместителей, эти заместители могут быть одинаковыми или различными. Примеры заместителей включают гидрокси, оксо, циано, галоген, нитро, необязательно гидроксилированный или низший алкиламинированный низший алкил, низший алкокси, низший ацил, необязательно низший - алкилированный карбамоил и необязательно низший - алкилированный, низший - ацилированный, арилсульфонилированный или низший - алкилсульфонилированный амино.

Each of the above rings may have 1 to 3 substituents. In the case of two or more substituents, these substituents may be the same or different. Examples of substituents include hydroxy, oxo, cyano, halogen, nitro, optionally hydroxylated or lower alkylaminated lower alkyl, lower alkoxy, lower acyl, optionally lower alkylated carbamoyl and optionally lower alkylated, lower acylated, arylsulfonylated or lower alkylsulfonyl.

 The term “monocyclic or dicyclic fused aromatic ring”, as used in the definition of ring C, means a monocyclic or dicyclic aromatic hydrocarbon or aromatic heterocycle containing one or two nitrogen atoms. May contain 1 to 3 substituents on the ring (s).

 Examples of ring C include benzene, pyridine, pyrimidine, naphthalene, quinoline, isoquinodine, indole and quinazoline. These rings can be condensed with ring B at any chemically acceptable position.

 Each of the above rings may have 1 to 3 substituents. In the case of two or more substituents, these substituents may be the same or different. Examples of substituents include halogen, hydroxy, lower alkyl, lower alkoxy, nitro and optionally lower — alkylated or lower — acylated amino.

The term “lower alkyl group”, used in the definition of substituents of rings A and C and in the definition of Y in the above general formula (I), denotes a linear or branched C _1-6 alkyl group. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl groups , 1,2-dimethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2 , 3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methyl propyl. Among these groups, methyl, ethyl, n-propyl and isopropyl are preferred, with methyl and ethyl being the most desirable of all.

 The term "lower alkylene", as used in the definition of e in Y, refers to the residue obtained by the exclusion of one hydrogen atom from the lower alkyl group described above. If the amino group is replaced by two lower - alkyl groups in the definition of substituents, optionally located on rings A and C, and f in Y, these alkyl groups can be linked together to form a 5- or 6-membered ring.

 The lower alkoxy group in the definition of substituents optionally on rings A and C refers to groups derived from the aforementioned lower alkyl groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Among these lower alkoxy groups, methoxy and ethoxy groups are most preferred. Examples of a halogen atom are fluorine, chlorine and bromine.

 Examples of the lower acyl group include groups having 1-6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl and valeryl.

 The term “arylsulfonylated or lower-alkylsulfonylated amino” as used in the definition of a substituent, optionally located on Ring A, refers, for example, to an amino group, optionally p-toluenesulfonylated, methylsulfonylated or ethylsulfonylated.

 Derivatives of condensed polycyclic heterocyclic compounds represented by the above formula (I) sometimes form salts with acids. Salts of these compounds (I) are also included in the scope of this invention. Examples of salts with acids include salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, etc., and salts of organic acids such as acetate, lactate, succinate, fumarate, maleate, citrate, benzoate, methanesulfonate, p-toluenesulfonate and t .d.

 Not to mention the fact that this invention also includes hydrates of these compounds and their optical isomers, if any. Although the compound of the present invention exhibits strong antitumor activity, compounds that exhibit antitumor activity when metabolized, for example, oxidized, reduced, hydrolyzed or conjugated in vivo, are also included in this invention. In addition, the present invention includes compounds capable of forming compounds of the present invention during their metabolization, for example, during oxidation, reduction or hydrolysis in vivo.

 Compounds (I) of the present invention can be obtained in various ways. Typical examples of such production methods will now be described.

где кольца Aa и Ca соответственно обозначают необязательно защищенные кольца A и C; кольцо Ba обозначает 4H-1,4-оксазин, 4H-1,4-тиазин, 4(1H)-пиридон или пиррол; fa обозначает необязательно защищенный f; и e имеет указанные выше значения, с соединением, представленным следующей общей формулой (III):

где D и E одинаковы или различны и каждый из них обозначает удаляемую группу.1) A compound of general formula (I) can be prepared by reacting a compound represented by the following general formula (II):

where the rings Aa and Ca respectively denote optionally protected rings A and C; the Ba ring is 4H-1,4-oxazine, 4H-1,4-thiazine, 4 (1H) -pyridone or pyrrole; fa is optionally protected f; and e has the above meanings, with a compound represented by the following general formula (III):

where D and E are the same or different and each of them denotes a deleted group.

 This reaction is usually carried out by dissolving compound (II) in an aprotic solvent such as dimethylformamide, tetrahydrofuran or dioxane, adding 2-3 equivalents of sodium hydride and then adding compound (III).

Examples of compound (III) include phosgene, ethyl chlorocarbonate and N, N'-carbonyldiimidazole. This reaction is usually carried out in the temperature range from -50 ^o C to 150 ^o C.

 When the product thus obtained is protected by an amino or hydroxyl group, etc., the protecting groups can be removed by a conventional method, such as acid or alkali treatment or catalytic reduction, to give the desired compound (I).

где кольцо Ab обозначает дициклическое конденсированное кольцо, где по меньшей мере одно из колец является ароматическим кольцом и которое имеет низший ацил или оксогруппу, необязательно вместе с необязательно защищенным заместителем (заместителями); кольцо Bb обозначает пиррол, 4H-1,4-оксазин или 4H-1,4-тиазин; кольцо Cb обозначает моноциклическое ароматическое кольцо, необязательно имеющее защищенный заместитель (заместители); и Y имеет указанные выше значения, с карбонил-восстанавливающим агентом.2) Compound (I) can be obtained by reacting a compound represented by general formula (IV):

where the ring Ab denotes a dicyclic fused ring, where at least one of the rings is an aromatic ring and which has a lower acyl or oxo group, optionally together with an optionally protected substituent (s); the Bb ring is pyrrole, 4H-1,4-oxazine or 4H-1,4-thiazine; the Cb ring is a monocyclic aromatic ring, optionally having a protected substituent (s); and Y has the above meanings, with a carbonyl reducing agent.

 The reduction can be carried out using a method commonly used for the reduction of carbonyl groups. Preferred examples of such a process include catalytic reduction using a catalyst such as palladium-carbon, and reduction with a borane / pyridine complex or sodium boro-hydride.

 Next will be described a method of obtaining the starting compounds (II) used in this invention. Starting compounds (II) include known compounds and new compounds. New compounds can be obtained using or combining methods for the synthesis of known compounds that have already been reported in the literature.

The method of obtaining 1 is presented at the end of the description.
Compounds represented by general formula (IX) can be prepared using, for example, the Fischer method for the synthesis of indole and the Borsche method for the synthesis of tetrahydrocarbazole [Org. Syn. IV, 884 (1963). Namely, it can be obtained by heating a cyclic ketone represented by the formula (VII) and o-hydrazinoaromatic carboxylic acid in acetic acid or in a neutral solvent such as ethanol in the presence of an acid catalyst such as hydrochloric acid , sulfuric acid or zinc chloride In the case where the Ac ring in compound (IX) is an optionally substituted dicyclic fused structure in which one of the rings is an aromatic ring, it may be fused with the compound represented by general formula (VI) to give the desired compound (IIa). Compound (X) can be obtained by partially or completely dehydrogenating the non-aromatic ring in compound (IX) with a dehydrogenating agent. For example, for example, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, chloranil or palladium-carbon. The reaction is usually carried out at room temperature or by heating. If the Ac ring is a dicyclic fused structure in which both rings are non-aromatic rings, it is also possible to selectively dehydrogenate one of these rings by appropriate selection of the type and amount of reagent, reaction conditions, etc. The target compound (IIa) can be obtained by condensation of the compound (X) thus obtained with compound (VI). Condensation can be carried out, for example, according to an acid chloride method, an active ester method or a method with mixed carboxylic acid anhydrides, or using condensing agents such as 1,3-dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole or diphenylphosphorylazide.

 The method of obtaining 2 is presented at the end of the description.

 A compound represented by general formula (XIII) can be prepared by reacting a compound of general formula (XI) with a compound of general formula (XII). Preferred examples of the leaving groups K and L in compound (XII) are, respectively, nitro group and halogen. The reaction can be carried out by heating these compounds, optionally in the presence of a base such as triethylamine, sodium acetate or sodium hydroxide. The target compound (IIb) can be obtained by hydrolysis of the ester of compound (XIII) with alkali to compound (XIV), followed by condensation of this compound to form compound (VI) according to the method described in the preparation method (I).

 When using the compounds of this invention as a medicine, it can be administered orally or parenterally. Although the dose is not specifically limited and varies depending on the severity of the symptom, age, gender, body weight and patient sensitivity, method, time and intervals of administration, properties, type and specific active ingredients of the drug, etc., it can usually be administered an adult patient in a daily dose of from 1 to 3000 mg, preferably from 10 to 2000 mg, and even more preferably from 20 to 1000 mg in the form of 1-3 servings per day.

 To prepare a solid preparation for oral administration, the active agent is mixed with excipients and, if necessary, with binders, disintegrating agents, wetting agents, colorants, flavoring agents (substances that improve the taste and smell), etc. and the resulting mixture is formed into tablets, coated tablets, granules, micronized particles, powders, capsules, etc. by conventional methods.

 As fillers, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide can be used. As binders, for example, polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose and hydroxypropyl methyl cellulose can be used. As lubricants, for example, magnesium stearate, talc and silicon dioxide can be used. As colorants, pharmaceutically acceptable colorants can be used. As flavoring agents, for example, cocoa powder, aromatic acids, eucalyptus oil, Borneo camphor and powdered brown tree bark can be used, not to mention that these tablets or granules can be coated, if necessary, with sugar, gelatin and etc.

 For the preparation of injection forms, the active ingredient is mixed, if necessary, with pH adjusting agents, buffers, suspending agents, solubilizing agents, stabilizers, isotonic agents, preservatives, etc. and from the resulting mixture, intravenous, subcutaneous or intramuscular injection solutions are prepared by conventional methods. Then these drugs can be lyophilized in a conventional manner, if necessary.

 As suspending agents, for example, methyl cellulose, Polysorbate 80, hydroxyethyl cellulose, gum arabic, powdered tragacanth, sodium carboxymethyl cellulose and polyoxyethylene sorbitan monolaurate can be used.

 As solubilizing agents, for example, polyoxyethylene curable castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol and castor oil fatty acid ethyl esters can be used.

 As stabilizers, for example, sodium sulfite and sodium metasulfite can be used. As preservatives, for example, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol can be used.

 Pharmacological experimental examples will be given below to illustrate the effects of the compounds of this invention.

Experimental Example 1
In vitro antitumor test on P388 cells (mouse leukemia cells)
P388 cells suspended in RPMI1640 medium (manufactured by Sanko Junyaku) containing 10% fetal calf serum, penicillin (100 E / ml), streptomycin (100 μg / ml), 5 • 10 ^-5 M mercaptoethanol and 1 mM sodium pyruvate were pipetted into a 96-well U-bottom microplate at a ratio of 1.25 x 10 ³ cells (0.1 ml) per well and incubated in an incubator containing 5% carbon dioxide at 37 ^° C. for one day.

The compound of this invention was dissolved in dimethyl sulfoxide to obtain a concentration of 10 ^-2 M and then diluted with 10% fetal calf serum culture medium RPMI1640 to obtain a concentration of 10 ^-4 or 10 ^-5 M. Taking this concentration as the maximum level, three-fold serial dilution of the culture RPMI1640 medium containing 10% fetal calf serum. Then, the resulting dilutions were added to the incubation plate with P388 described above at a ratio of 0.1 ml per well, followed by incubation in an incubator containing 5% carbon dioxide at 37 ^° C. for 3 days.

где T обозначает поглощение лунки, содержащей тест-соединение, и C обозначает поглощение лунки, несодержащей тест-соединения.After incubation was completed, 0.05 ml per well of a solution of 3.3 mg / ml MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] was added and incubation was continued for another 2 hours. The microplate was centrifuged and the supernatant was aspirated from each well. Then the formazan thus formed was dissolved in 0.1 ml of dimethyl sulfoxide and its absorption, measured at 540 nm with a microplate reader, was taken as an indicator of the number of viable cells. In accordance with the following formula, the inhibition coefficient was calculated and the 50% inhibition concentration (IC ₅₀ ) of the test compound was determined:

where T is the absorption of the wells containing the test compound, and C is the absorption of the wells containing the test compound.

Table 1 summarizes the IC ₅₀ data thus obtained.

Experimental Example 2
In vivo Antitumor Test for M5076 (Reticular Cell Sarcoma of Mice)
M5076 cells (1 x 10 ⁶ cells per animal) were subcutaneously transplanted into the lateral part of each BDF1 mouse (females aged 6-7 weeks). The compound of this invention was dissolved in a 5% glucose solution. From the day after transplantation, a solution of the compound was administered intraperitoneally to animals once a day in accordance with each administration schedule. On the other hand, a 5% glucose solution was administered to the control group. The control group consisted of 10 animals, while each test group consisted of 5 animals.

где T обозначает средний вес опухоли тест-группы и C обозначает средний вес опухоли контрольной группы.On the 21st day after transplantation, tumors were removed and weighed. The tumor inhibition coefficient in each test group relative to the control group was determined in accordance with the following formula:

where T is the average tumor weight of the test group and C is the average tumor weight of the control group.

 Table 2 shows the results of this experiment.

Experimental Example 3
In vivo antitumor test on MX-1 (human breast cancer)
Pieces of the MX-1 tumor (approximately 1 mm ³ ) were subcutaneously transplanted into the lateral part of each naked mouse (BALB / C • nu / nu, females aged 6-7 weeks). The compound of this invention was dissolved in a 5% glucose solution. When the tumor volume reached 50 mm ³ (approximately on the 10th day after transplantation), a solution of the compound was administered intraperitoneally to the animals once a day in accordance with each administration schedule. On the other hand, a 5% glucose solution was administered to the control group. The control group consisted of 10 animals, while each test group consisted of 5 animals.

где T обозначает средний вес опухоли тест-группы и C обозначает средний вес опухоли контрольной группы.On the 22nd day after transplantation, the tumors were removed and weighed. The inhibition coefficient of tumor reproduction of each test group relative to the control group was determined in accordance with the following formula:

where T is the average tumor weight of the test group and C is the average tumor weight of the control group.

 Table 3 shows the results of this experiment.

 As these experimental data clearly show, the compounds of this invention have an excellent antitumor effect and are therefore applicable as an antitumor agent.

Examples
Now will be presented Examples of preparation showing the preparation of the starting compounds used in this invention, and Examples related to representative examples of the compounds of this invention. However, it should be understood that the invention is not limited to these examples only.

Раствор 5,00 г (34,2 ммоль) β -тетралона в уксусной кислоте (10 мл) добавляли каплями в суспензию 7,05 г (37,4 ммоль) гидрохлорида 2-гидразинобензойной кислоты в уксусной кислоте (40 мл) при 80^oC и полученную смесь нагревали с обратным холодильником в течение 3 часов и 45 минут. После возврата к комнатной температуре добавляли воду и образовавшийся таким образом осадок собирали фильтрованием, промывали водой, сушили и перекристаллизовывали из этанола с получением 5,2 г соединения, указанного в названии примера.Production Example 1
5,6-dihydro-7H-benzo [s] carbazole-8-carboxylic acid:

A solution of 5.00 g (34.2 mmol) of β-tetralone in acetic acid (10 ml) was added dropwise to a suspension of 7.05 g (37.4 mmol) of 2-hydrazinobenzoic acid hydrochloride in acetic acid (40 ml) at 80 ^o C and the resulting mixture was heated under reflux for 3 hours and 45 minutes. After returning to room temperature, water was added and the precipitate thus formed was collected by filtration, washed with water, dried and recrystallized from ethanol to obtain 5.2 g of the compound indicated in the title of the example.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.91 - 3.06 (m, 4H), 7.03 (t, J = 7.6 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.20-7.27 (m, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 11.29 (s, 1H).

3,29 г (14,3 ммоль) 2,3-дихлор-5,6-дициано-1,4- бензохинона добавляли к суспензии 2,97 г (11,3 ммоль) соединения Примера получения 1 в бензоле (200 мл) при комнатной температуре и полученную смесь перемешивали в течение 50 минут и затем нагревали с обратным холодильником в течение 3 часов и 20 минут. После возврата к комнатной температуре полученный таким образом осадок собирали фильтрованием и перекристаллизовывали из этанола с получением 2,76 г соединения, указанного в названии примера.Production Example 2
7H-Benzo [s] carbazole-8-carboxylic acid:

3.29 g (14.3 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added to a suspension of 2.97 g (11.3 mmol) of the compound of Production Example 1 in benzene (200 ml) at room temperature and the resulting mixture was stirred for 50 minutes and then heated under reflux for 3 hours and 20 minutes. After returning to room temperature, the precipitate thus obtained was collected by filtration and recrystallized from ethanol to obtain 2.76 g of the compound indicated in the title of the example.

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 7.39 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.3 Hz, 1H) , 7.70 (t, J = 7.3 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 8.00-8.07 (m, 3H), 8.79 ( d, J = 7.3 Hz, 1H), 8.87 (d, J = 7.3 Hz, 1H), 11.82 (s, 1H), 13.22 (br s, 1H).

2,52 г (15,5 ммоль) N,N'-карбонилдиимидазола добавляли к раствору 1,89 г (7,25 ммоль) соединения Примера получения 2 в диметилформамиде (60 мл) при комнатной температуре и полученную смесь перемешивали в течение 45 минут. Затем к ней добавляли 5,0 мл (45,5 ммоль) N,N'-диметилэтилендиамина и полученную смесь перемешивали в течение 2 часов и 40 минут. После концентрирования ее экстрагировали добавлением воды и этилацетата. Органический слой собирали, промывали водой, сушили над сульфатом натрия и концентрировали досуха с получением 2,47 г соединения, указанного в названии примера.Production Example 3
N- [2- (Dimethylamino) ethyl] -7H-benzo [c] carbazole-8-carboxamide:

2.52 g (15.5 mmol) of N, N'-carbonyldiimidazole was added to a solution of 1.89 g (7.25 mmol) of the compound of Production Example 2 in dimethylformamide (60 ml) at room temperature and the resulting mixture was stirred for 45 minutes . Then, 5.0 ml (45.5 mmol) of N, N'-dimethylethylenediamine was added thereto, and the resulting mixture was stirred for 2 hours and 40 minutes. After concentration, it was extracted with water and ethyl acetate. The organic layer was collected, washed with water, dried over sodium sulfate and concentrated to dryness to give 2.47 g of the title compound.

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.33 (s, 6H), 2.60 (t, J = 5.7 Hz, 2H), 3.63 (q, J = 5.7 Hz, 2H), 7.16 (br s, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.46-7.50 (m, 1H), 7.65-7.73 (m, 3H), 7.89 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 8.69 (d , J = 7.5 Hz, 1H), 8.74 (d, J = 8.2 Hz, 1H), 10.94 (br s, 1H).

1,17 г (12,4 ммоль) уксусного ангидрида добавляли к суспензии 5,1 г (38 ммоль) хлорида алюминия в дихлорметане (300 мл) при 0^oC и полученную смесь перемешивали в течение 20 минут. Затем к ней добавляли 2,16 г (8,28 ммоль) соединения Примера получения 2 и полученную смесь перемешивали при той же температуре в течение 4 часов и 30 минут. Затем реакционную смесь выливали в воду со льдом и экстрагировали смесью хлороформ-этанол. Органический слой собирали и концентрировали. Остаток очищали колоночной хроматографией на силикагеле с получением 1,45 г соединения, указанного в названии примера.Production Example 4
3-Acetyl-7H-benzo [s] carbazole-8-carboxylic acid:

1.17 g (12.4 mmol) of acetic anhydride was added to a suspension of 5.1 g (38 mmol) of aluminum chloride in dichloromethane (300 ml) at 0 ^° C and the resulting mixture was stirred for 20 minutes. Then, 2.16 g (8.28 mmol) of the compound of Production Example 2 was added thereto, and the resulting mixture was stirred at the same temperature for 4 hours and 30 minutes. Then the reaction mixture was poured into ice water and was extracted with a mixture of chloroform-ethanol. The organic layer was collected and concentrated. The residue was purified by silica gel column chromatography to obtain 1.45 g of the title compound.

291 мг (1,80 ммоль) N,N'-карбонилдиимидазола добавляли к раствору 247 мг (0,815 ммоль) соединения Примера получения 4 в диметилформамиде (7 мл) при охлаждении льдом. После возврата к комнатной температуре полученную смесь перемешивали в течение приблизительно 2 часов. Затем к ней добавляли 0,45 мл (4,1 ммоль) N, N'-диметилэтилендиамина и реакционную смесь возвращали к комнатной температуре и перемешивали при комнатной температуре в течение приблизительно 12 часов. После экстракции путем добавления воды и хлороформа органический слой собирали, сушили над сульфатом натрия и концентрировали досуха. Затем остаток очищали колоночной хроматографией на силикагеле с получением 140 мг соединения, указанного в названии примера. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.72 (s, 3H), 7.44 (t, J = 7.6 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 9.1 Hz, 1H), 8.14 (d, J = 9.1 Hz, 1H), 8.18 (dd, J = 9.8; 8 Hz, 1H), 8.79 (d, J = 1.9 Hz, 1H), 8.87 (d, J = 8.8 Hz, 1H), 8.91 (d, J = 7.6 Hz, 1H), 12.01 (s, 1H)
Production Example 5
3-Acetyl-N- [2- (dimethylamino) ethyl] -7H-benzo [c] carbazole-8-carboxamide:

291 mg (1.80 mmol) of N, N'-carbonyldiimidazole was added to a solution of 247 mg (0.815 mmol) of the compound of Production Example 4 in dimethylformamide (7 ml) under ice-cooling. After returning to room temperature, the resulting mixture was stirred for approximately 2 hours. Then, 0.45 ml (4.1 mmol) of N, N'-dimethylethylenediamine was added thereto, and the reaction mixture was returned to room temperature and stirred at room temperature for approximately 12 hours. After extraction by adding water and chloroform, the organic layer was collected, dried over sodium sulfate and concentrated to dryness. Then, the residue was purified by silica gel column chromatography to obtain 140 mg of the title compound.

6,8 г (38,2 ммоль) 1,2,3,4,5,8-гексагидро-1-оксо- 6-метоксинафталина растворяли в 50 мл тетрагидрофурана и добавляли к раствору 5 мл 1 н. соляной кислоты. После перемешивания при комнатной температуре в течение 1 часа к раствору добавляли этилацетат. Затем реакционную смесь промывали насыщенным водным раствором хлорида натрия и сушили над сульфатом магния. После концентрирования добавляли небольшое количество смеси н-гексан-этилацетат (1:1) и полученную смесь охлаждали в бане со смесью сухого льда-эфира. Полученный таким образом осадок извлекали фильтрованием и промывали небольшим количеством н-гексана с получением 4,8 г соединения, указанного в названии примера. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.29 (s, 6H), 2.53-2.61 (m, 2H), 2.74 (s, 3H), 3.52 (q, J = 5.9 Hz, 2H), 7.43 (t, J = 7.1 Hz, 1H), 7.97 (d, J = 7.1 Hz, 1H), 8, 10 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 8.20 (d, J = 1.8; 8.5 Hz, 1H), 8.72 (t, J = 5.9 Hz, 1H), 8.79-8.83 (m, 2H), 8.88 (d, J = 8.5 Hz, 1H), 12.17 (s , 1H)
Production Example 6
3,4,5,8-Tetrahydronaphthalene-1,6 (2H, 7H) -dione:

6.8 g (38.2 mmol) of 1,2,3,4,5,8-hexahydro-1-oxo-6-methoxynaphthalene were dissolved in 50 ml of tetrahydrofuran and 5 ml of 1N was added to the solution. of hydrochloric acid. After stirring at room temperature for 1 hour, ethyl acetate was added to the solution. Then, the reaction mixture was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After concentration, a small amount of a mixture of n-hexane-ethyl acetate (1: 1) was added and the resulting mixture was cooled in a bath with a mixture of dry ice-ether. The precipitate thus obtained was recovered by filtration and washed with a small amount of n-hexane to obtain 4.8 g of the compound indicated in the title of the example.

5,4 г (28,6 ммоль) гидрохлорида 2-гидразинобензойной кислоты и 4,7 г (34,3 ммоль) хлорида цинка добавляли к 300 мл ледяной уксусной кислоты. При перемешивании при ~ 85^oC добавляли 4,7 г (28,6 ммоль) соединения Примера получения 6 на протяжении ~ 5 минут. Затем полученную смесь перемешивали при той же самой температуре в течение приблизительно 2 часов, возвращали к комнатной температуре и осадок извлекали фильтрованием. После концентрации фильтрата к нему добавляли воду и полученный таким образом осадок извлекали фильтрованием. Эти осадки объединяли, сушили и затем растворяли в ≈ 500 мл диметилформамида. При перемешивании при комнатной температуре добавляли раствор 6,6 г (28,6 ммоль) 2,3-дихлор-5,6-дициано-1,4-бензохинона в тетрагидрофуране (20 мл) и полученную смесь перемешивали в течение приблизительно 30 минут. После концентрирования добавляли приблизительно 50 мл этанола и полученный таким образом осадок извлекали фильтрованием с получением 3,4 г соединения, указанного в названии примера. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.01 -2.11 (m, 2H), 2.30-2.37 (m, 2H), 2.45-2 51 (m, 4H), 2.68-2.76 (m, 2H), 3.05 (s, 2H)
Production Example 7
4-oxo-1,2,3,4-tetrahydro-7H-benzo [s] carbazole-8-carboxylic acid:

5.4 g (28.6 mmol) of 2-hydrazinobenzoic acid hydrochloride and 4.7 g (34.3 mmol) of zinc chloride were added to 300 ml of glacial acetic acid. While stirring at ~ 85 ^° C, 4.7 g (28.6 mmol) of the compound of Production Example 6 was added over ~ 5 minutes. The resulting mixture was then stirred at the same temperature for approximately 2 hours, returned to room temperature and the precipitate was recovered by filtration. After the filtrate was concentrated, water was added thereto, and the precipitate thus obtained was recovered by filtration. These precipitates were combined, dried and then dissolved in ≈ 500 ml of dimethylformamide. While stirring at room temperature, a solution of 6.6 g (28.6 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in tetrahydrofuran (20 ml) was added and the resulting mixture was stirred for approximately 30 minutes. After concentration, approximately 50 ml of ethanol was added, and the precipitate thus obtained was recovered by filtration to obtain 3.4 g of the title compound.

3,4 г (12,2 ммоль) соединения Примера получения 7 добавляли к 120 мл диметилформамида и перемешивали. Затем к смеси добавляли раствор 3,0 г (18,5 ммоль) N, N'-карбонилдиимидазола в диметилформамиде (30 мл). После перемешивания при комнатной температуре в течение 1 часа добавляли 3,2 г (36,3 ммоль) N,N'-диметилэтилендиамина. После перемешивания при той же самой температуре еще в течение 1 часа реакционную смесь концентрировали и добавляли к ней этилацетат. Затем ее промывали последовательно разбавленным водным аммиаком и водным раствором хлорида натрия, сушили над сульфатом магния и концентрировали досуха с получением 4,3 г соединения, указанного в названии примера. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.17-2.29 (m, 2H), 2.63-2.70 (m, 2H), 3.55 (t , J = 6.0 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 8.06 (dd, J = 0.8; 7.6 Hz, 1H), 8.48 (dd, J = 0.8; 7.6 Hz, 1H), 11 83 (s, 1H); 13.33 (br s, 1H)
Production Example 8
N- [2- (Dimethylamino) ethyl] -4-oxo-1,2,3,4-tetrahydro-7H-benzo [c] carbazole-8-carboxamide;

3.4 g (12.2 mmol) of the compound of Production Example 7 was added to 120 ml of dimethylformamide and stirred. Then, a solution of 3.0 g (18.5 mmol) of N, N'-carbonyldiimidazole in dimethylformamide (30 ml) was added to the mixture. After stirring at room temperature for 1 hour, 3.2 g (36.3 mmol) of N, N'-dimethylethylenediamine were added. After stirring at the same temperature for an additional 1 hour, the reaction mixture was concentrated and ethyl acetate was added thereto. Then it was washed with successively diluted aqueous ammonia and aqueous sodium chloride, dried over magnesium sulfate and concentrated to dryness to obtain 4.3 g of the compound indicated in the title of the example.

FAB mass spectrometry m / z: 350 ([M + H] ⁺ ).

Соединение, указанное в названии примера получали реакцией 2,3,4,7-тетрагидро-1H-инден-1,5(6H)-диона, который был синтезирован из 2,3,4,7-тетрагидро-5-метокси-1H-инден-1-она согласно способу, описанному в Примере получения 6, таким же образом, как это описано в способе Примера получения 7. ¹ H-NMR (CDCl ₃ ): δ (ppm): 2.30-2.40 (m ⁺ s, 2H + 6H), 2.62 (t, J = 6.0 Hz, 2H), 2.74-2.79 (m, 2H), 3.56-3.66 (m, 4H), 7.21 (br s, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.70 (dd, J = 0.8; 8.0 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.33 (dd, J = 0.8; 8.0 Hz, 1H), 10.91 (br s, 1H)
Production Example 9
2,3-dihydro-3-oxo-1H, 6H-cyclopenta [s] carbazole-7-carboxylic acid

The title compound was prepared by the reaction of 2,3,4,7-tetrahydro-1H-indene-1,5 (6H) -dione, which was synthesized from 2,3,4,7-tetrahydro-5-methoxy-1H -inden-1-one according to the method described in Production Example 6, in the same manner as described in the method of Production Example 7.

FAB mass spectrometry m / z: 266 ([M + H] ⁺ ).

Соединение, указанное в названии примера, получали из соединения Примера получения 9, таким же образом, как это описано в способе Примера получения 8. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.70-2.82 (m, 2H), 3.52-3.62 (m, 2H), 7.41 (t , J = 7.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 8.09 (dd, J = 0.8; 7.6 Hz, 1H), 8.39 (d, J = 7.6 Hz, 1H), 11.95 (s, 1H), 13.37 (br s, 1H)
Production Example 10
2,3-dihydro-N- [2-dimethylamino) ethyl] -3-oxo-1H, 6H-cyclopenta [c] carbazole-7-carboxamide:

The compound indicated in the title of the example was obtained from the compound of Production Example 9 in the same manner as described in the method of Production Example 8.

FAB mass spectrometry m / z: 336 ([M + H] ⁺ ).

(м.д.): 2,34 (с, 6H), 2,61 (т, J=6,0 Гц, 2H), 2,85-2,91 (м, 2H), 3,58-3,66 (м, 4H), 7,18 (шир. с, 1H), 7,36 (т, J=7,6 Гц, 1H), 7,49 (д, J=8,4 Гц, 1H), 7,71 (д, J=7,6 Гц, 1H), 7,88 (д, J=8,4 Гц, 1H), 8,22 (д, J=7,6 Гц, 1H), 10,95 (шир. с, 1H)
Пример получения 11
Метил 5,6,7,8-тетрагидро-9H-карбазол-1-карбоксилат:

Раствор 28 мл (0,270 моль) циклогексанона в уксусной кислоте (100 мл) добавляли каплями в суспензию 52 г (0,276 моль) гидрохлорида 2-гидразинобензойной кислоты в уксусной кислоте (500 мл) при 100^oC и полученную смесь нагревали с обратным холодильником в течение 6 часов. После возврата к комнатной температуре к смеси добавляли 1 л воды и полученный таким образом осадок собирали фильтрованием, промывали водой и сушили с получением 43 г порошка. Затем этот порошок растворяли в 500 мл ацетона. После добавления 37,5 мл (0,602 моль) метилиодида и 41,4 г (0,300 моль) безводного карбоната калия реакционную смесь нагревали с обратным холодильником в течение 2 часов. После возврата к комнатной температуре нерастворимые вещества отфильтровывали. После концентрирования фильтрата добавляли воду и полученный таким образом осадок извлекали фильтрованием с получением 45,7 г соединения, указанного в названии примера. ¹ H-NMR (CDCl ₃ ):

(ppm): 2.34 (s, 6H), 2.61 (t, J = 6.0 Hz, 2H), 2.85-2.91 (m, 2H), 3.58-3 66 (m, 4H), 7.18 (br s, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H) , 7.71 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 10 95 (bs, 1H)
Production Example 11
Methyl 5,6,7,8-tetrahydro-9H-carbazole-1-carboxylate:

A solution of 28 ml (0.270 mol) of cyclohexanone in acetic acid (100 ml) was added dropwise to a suspension of 52 g (0.276 mol) of 2-hydrazinobenzoic acid hydrochloride in acetic acid (500 ml) at 100 ^° C and the resulting mixture was heated under reflux for 6 o'clock. After returning to room temperature, 1 L of water was added to the mixture, and the precipitate thus obtained was collected by filtration, washed with water and dried to obtain 43 g of powder. Then this powder was dissolved in 500 ml of acetone. After adding 37.5 ml (0.602 mol) of methyl iodide and 41.4 g (0.300 mol) of anhydrous potassium carbonate, the reaction mixture was heated under reflux for 2 hours. After returning to room temperature, insoluble matters were filtered off. After concentrating the filtrate, water was added, and the precipitate thus obtained was recovered by filtration to obtain 45.7 g of the title compound.

45,7 г (0,199 моль) соединения Примера получения 11 растворяли в смеси тетрагидрофурана (500 мл) с водой (50 мл). В полученный раствор добавляли по каплям раствор 90,8 г (0,400 моль) 2,3-дихлор-5,6-дициано-1,4-бензохинона в тетрагидрофуране (200 мл) в атмосфере азота при охлаждении льдом. После перемешивания при комнатной температуре в течение 3 часов к раствору добавляли 1 л водного раствора карбоната калия с последующей экстракцией этилацетатом. Затем органический слой собирали, промывали водой, сушили над сульфатом магния и концентрировали. Остаток перекристаллизовывали из этанола с получением 39,7 г соединения, указанного в названии примера. ¹ H-NMR (CDCl ₃ ); δ (ppm): 1.85-1.97 (m, 4H), 2.70-2.74 (m, 2H), 2.76-2.80 (m, 2H), 3.97 (s, 3H), 7.09 (t, J = 7.6 Hz, 1H), 7.65-7.68 (m, 1H), 7.79 (dd, 1.1; 7.6 Hz, 1H), 9.39 (br s, 1H)
Production Example 12
Methyl 5-oxo-5,6,7,8-tetrahydro-9H-carbazole-1-carboxylate:

45.7 g (0.199 mol) of the compound of Production Example 11 was dissolved in a mixture of tetrahydrofuran (500 ml) with water (50 ml). To the resulting solution was added dropwise a solution of 90.8 g (0.400 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in tetrahydrofuran (200 ml) under a nitrogen atmosphere under ice-cooling. After stirring at room temperature for 3 hours, 1 L of an aqueous solution of potassium carbonate was added to the solution, followed by extraction with ethyl acetate. Then the organic layer was collected, washed with water, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give 39.7 g of the compound indicated in the title of the example.

39,1 г (0,161 моль) соединения Примера получения 12 суспендировали в дифениловом эфире (150 мл). После добавления 10 г 10% палладия на угле полученную смесь нагревали с обратным холодильником в атмосфере азота в течение 3 часов. После остывания осажденные кристаллы и палладий на угле извлекали фильтрованием и промывали гексаном. Затем извлеченную смесь растворяли в горячем тетрагидрофуране и палладий на угле отфильтровывали. После концентрирования остаток перекристаллизовывали из этанола с получением 34,7 г соединения, указанного в названии примера. ¹ H-NMR (DMSO-d ₆ ); δ (ppm): 2.10-2.17 (m, 2H), 2.44-2.48 (m, 2H), 3.07 (t, J = 6.2 Hz, 2H), 3.96 (s, 3H), 7.28 (t, J = 7.7 Hz, 1H), 7.81 (dd, J = 1.3, 7.7 Hz, 1H), 8.25 (dd , J = 1.3; 7.7 Hz, 1H), 11.79 (br s, 1H)
Production Example 13
Methyl 5-hydroxy-9H-carbazole-1-carboxylate:

39.1 g (0.161 mol) of the compound of Production Example 12 were suspended in diphenyl ether (150 ml). After adding 10 g of 10% palladium-carbon, the resulting mixture was refluxed under nitrogen for 3 hours. After cooling, the precipitated crystals and palladium-carbon were removed by filtration and washed with hexane. Then, the extracted mixture was dissolved in hot tetrahydrofuran, and palladium-carbon was filtered. After concentration, the residue was recrystallized from ethanol to obtain 34.7 g of the compound indicated in the title of the example.

34,8 г (0,144 моль) соединения Примера получения 13 растворяли в ацетоне (550 мл). После добавления к раствору 68,5 мл (0,432 моль) бензилбромацетата, 64,8 г (0,432 моль) иодида натрия и 29,8 г (0,216 моль) безводного карбоната калия полученную смесь нагревали с обратным холодильником в течение 60 часов. После выдерживания для охлаждения полученный таким образом остаток отфильтровывали с последующим концентрированием. Затем проводили экстракцию путем добавления этилацетата и воды и органический слой собирали, промывали водой, сушили над сульфатом магния и концентрировали. К полученному остатку добавляли н-гексан для его отверждения. Затем его извлекали фильтрованием и перекристаллизовывали из этанола с получением 40,7 г бензилового эфира соединения заголовка. Этот продукт суспендировали в смеси тетрагидрофурана (600 мл) - метанол (500 мл). Затем к суспензии добавляли 12 г 10% палладия на угле и продукт гидрировали при атмосферном давлении при обычной температуре с получением 29,4 г соединения, указанного в названии примера. ¹ H-NMR (CDCl ₃ ): δ (ppm): 4.03 (s, 3H), 5.54 (s, 1H), 6.62 (dd, J = 0.6.7.9 Hz, 1H), 7.10 (dd, J = 0.6; 7.9 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 7.30 (t, J = 7 , 9 Hz, 1H), 8.05 (dd, J = 1.2; 7.9 Hz, 1H), 8.46-8.50 (m, 1H), 9.93 (br s, 1H)
Production Example 14
[1-Methoxycarbonyl-9H-carbazol-5-yl] hydroxyacetic acid:

34.8 g (0.144 mol) of the compound of Production Example 13 were dissolved in acetone (550 ml). After adding 68.5 ml (0.432 mol) of benzyl bromoacetate, 64.8 g (0.432 mol) of sodium iodide and 29.8 g (0.216 mol) of anhydrous potassium carbonate to the solution, the resulting mixture was heated under reflux for 60 hours. After cooling, the thus obtained residue was filtered off, followed by concentration. Then, extraction was performed by adding ethyl acetate and water, and the organic layer was collected, washed with water, dried over magnesium sulfate and concentrated. To the resulting residue was added n-hexane to cure it. It was then recovered by filtration and recrystallized from ethanol to give 40.7 g of benzyl ester of the title compound. This product was suspended in a mixture of tetrahydrofuran (600 ml) - methanol (500 ml). Then, 12 g of 10% palladium-carbon was added to the suspension, and the product was hydrogenated at atmospheric pressure at ordinary temperature to obtain 29.4 g of the compound indicated in the title of the example.

29,4 г (0,098 моль) соединения Примера получения 14 суспендировали в толуоле (500 мл). После добавления 36 мл (0,494 моль) тионилхлорида полученную смесь нагревали с обратным холодильником, пока смесь не становилась гомогенной. После концентрирования ее растворяли путем добавления к ней 500 мл дихлорметана и добавляли порциями 32,1 г (0,240 моль) хлорида аммония с перемешиванием при охлаждении льдом. Затем смесь возвращали к комнатной температуре и перемешивали в течение ночи, затем добавляли к ней смесь воды со льдом при охлаждении льдом. После перемешивания при комнатной температуре раствор концентрировали и добавляли к нему разбавленную соляную кислоту. Осадок извлекали фильтрованием, промывали последовательно водой и этанолом и сушили с получением 26,5 г порошка. Весь порошок растворяли в смеси тетрагидрофуран (350 мл) - метанол (250 мл) и затем добавляли к раствору 750 мл дегазированного раствора гидроксида натрия в атмосфере азота. После гидролиза сложного эфира при 50^oC к раствору добавляли 20 мл концентрированной соляной кислоты. Затем его экстрагировали смесью этилацетата с тетрагидрофураном и органический слой собирали, промывали водой, сушили над сульфатом магния и концентрировали. Остаток очищали колоночной хроматографией на силикагеле с получением 11,4 г соединения, указанного в названии примера. ¹ H-NMR (CD ₃ OD): δ (ppm): 4.02 (s, 3H), 4.90 (s, 2H), 6.67 (dd, J = 0.6; 8, 0 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.26 (dd, J = 0.6; 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 8.02 (dd, J = 1.1; 7.7 Hz, 1H), 8.63 (dd, J = 1.1; 7.7 Hz, 1H), 10, 87 (br s, 1H)
Production Example 15
2,3-dihydro-3-oxo-6H-furo [3,2-c] carbazole-7-carboxylic acid:

29.4 g (0.098 mol) of the compound of Production Example 14 were suspended in toluene (500 ml). After adding 36 ml (0.494 mol) of thionyl chloride, the resulting mixture was heated under reflux until the mixture became homogeneous. After concentration, it was dissolved by adding 500 ml of dichloromethane to it and 32.1 g (0.240 mol) of ammonium chloride were added portionwise with stirring under ice-cooling. The mixture was then returned to room temperature and stirred overnight, then a mixture of ice water and ice was added thereto under ice cooling. After stirring at room temperature, the solution was concentrated and dilute hydrochloric acid was added thereto. The precipitate was recovered by filtration, washed successively with water and ethanol, and dried to obtain 26.5 g of powder. The whole powder was dissolved in a mixture of tetrahydrofuran (350 ml) - methanol (250 ml) and then 750 ml of a degassed sodium hydroxide solution were added to the solution in a nitrogen atmosphere. After hydrolysis of the ester at 50 ^° C., 20 ml of concentrated hydrochloric acid was added to the solution. It was then extracted with a mixture of ethyl acetate with tetrahydrofuran and the organic layer was collected, washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 11.4 g of the title compound.

С применением 0,5 г (1,79 ммоль) соединения Примера получения 7 и 0,53 г (7,15 ммоль) N-метилэтилендиамина получали 0,49 г N-[2-(метиламино)этил]-4-оксо-1,2,3,4-тетрагидро-7H-бензо [с] карбазол-8-карбоксамида согласно способу, описанному в Примере получения 8. 0,49 г (1,46 ммоль) этого продукта, 0,25 г (1,74 ммоль) аллилбромида и 0,23г (1,78 ммоль) N,N-диизопропилэтиламина растворяли в тетрагидрофуране (30 мл) и перемешивали при 55^oC в течение приблизительно 5 часов. После охлаждения раствор разбавляли этилацетатом, промывали последовательно хлоридом натрия, сушили над сульфатом магния и концентрировали. Остаток очищали препаративной тонкослойной хроматографией с получением 0,24 г соединения, указанного в названии примера. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 5.00 (s, 2H), 7.41 (t, J = 7.7 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 8.07 (dd, J = 1.3; 7.7 Hz, 1H), 8.29 - 8.32 (m, 1H), 12.10 (br s, 1H)
Production Example 16
N- [2- (Allylmethylamino) ethyl] -4-oxo-1,2,3,4-tetrahydro-7H-benzo [c] carbazole-8-carboxamide:

Using 0.5 g (1.79 mmol) of the compound of Production Example 7 and 0.53 g (7.15 mmol) of N-methylethylenediamine, 0.49 g of N- [2- (methylamino) ethyl] -4-oxo- 1,2,3,4-tetrahydro-7H-benzo [c] carbazole-8-carboxamide according to the method described in Production Example 8. 0.49 g (1.46 mmol) of this product, 0.25 g (1, 74 mmol) of allyl bromide and 0.23 g (1.78 mmol) of N, N-diisopropylethylamine were dissolved in tetrahydrofuran (30 ml) and stirred at 55 ^° C for approximately 5 hours. After cooling, the solution was diluted with ethyl acetate, washed successively with sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by preparative thin layer chromatography to obtain 0.24 g of the compound indicated in the title of the example.

(м.д.): 2,28-2,40 (м+с, 2H+3H), 2,70 (т, J=6,0 Гц, 2H), 2,73-2,80 (м, 2H), 3,11-3,17 (м, 2H), 3,56-3,68 (м, 4H), 5,17-5,29 (м, 2H), 5,82-5,97 (м, 1H), 7,24 (шир. с, 1H), 7,33 (т, J=7,6 Гц, 1H), 7,42 (д, J= 8,4 Гц, 1H), 7,67 (дд, J=0,8; 7,6 Гц, 1H), 8,25 (д, J=8,4 Гц, 1H), 8,33 (дд, J= 0,8; 7,6 Гц, 1H), 10,88 (шир. с, 1H)
Пример получения 17
5-[1-(Аллилметиламино)этил]-12,13-дигидро-4H-бензо[с]пиримидо [5,6,1-jk] карбазол-4,6,10(5H,11H)-трион:

С применением 0,24 г (0,64 ммоль) соединения Примера получения 16, 0,23 г соединения заголовка получали согласно способу, описанному в Примере 2, за исключением процедуры, относящейся к гидрохлориду. ¹ H-NMR (CDCl ₃ ):

(ppm): 2.28-2.40 (m + s, 2H + 3H), 2.70 (t, J = 6.0 Hz, 2H), 2.73-2.80 (m, 2H), 3.11-3.17 (m, 2H), 3.56-3.68 (m, 4H), 5.17-5.29 (m, 2H), 5.82-5.97 ( m, 1H), 7.24 (br s, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7, 67 (dd, J = 0.8; 7.6 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.33 (dd, J = 0.8; 7.6 Hz , 1H), 10.88 (br s, 1H)
Production Example 17
5- [1- (Allylmethylamino) ethyl] -12,13-dihydro-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H, 11H) -trion:

Using 0.24 g (0.64 mmol) of the compound of Production Example 16, 0.23 g of the title compound was obtained according to the method described in Example 2, except for the procedure relating to the hydrochloride.

Суспензию 2,0 г (10,6 ммоль) гидрохлорида 2-гидразинобензойной кислоты в уксусной кислоте (20 мл) медленно кипятили при перемешивании и добавляли по каплям 1,2 мл (9,8 ммоль) 4-метилциклогексанона. Полученную смесь нагревали с обратным холодильником в течение 8 часов и затем давали ей остыть. После добавления воды полученный таким образом осадок извлекали фильтрованием, промывали водой и сушили с получением 1,96 г 6-метил-5,6,7,8-тетрагидро-9H-карбазол-1-карбоновой кислоты. Этот продукт растворяли в ацетоне (50 мл) и добавляли к раствору 2,1 мл (34 ммоль) метилиодида и 2,35 г (17 ммоль) безводного карбоната калия. Реакционную смесь нагревали с обратным холодильником при перемешивании в течение 2 часов, затем давали ей остыть и экстрагировали водой и этилацетатом. Органический слой собирали, промывали водой, сушили над сульфатом магния и концентрировали досуха. Таким образом были получены 1,49 г метил 6-метил-5,6,7,8-тетра-гидро-9H-карбазол-1-карбоксилата. Этот продукт суспендировали в дифениловом эфире (10 мл) и к суспензии добавляли 890 мг 10% палладия на угле. Полученную смесь нагревали с обратным холодильником при перемешивании в атмосфере азота в течение 1 часа. ¹ H-NMR (CDCl ₃ ): δ (ppm): 2.23-2.42 (m + s, 2H + 3H), 2.73-2.84 (m, 4H), 3.10 -3.15 (m, 2H), 3.53 (t, J = 6.4 Hz, 2H), 4.35 (t, J = 7.2 Hz, 2H), 5.08-5.22 ( m, 2H), 5.74-5.90 (m, 1H), 7.63 (t, J = 7.6 Hz, 1H), 8.19 (dd, J = 0.8; 7.6 Hz , 1H), 8.32 (dd, J = 0.8; 7.6 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.51 (d, J = 8, 4 Hz, 1H)
Production Example 18
Methyl 6-methyl-9H-carbazole-1-carboxylate:

A suspension of 2.0 g (10.6 mmol) of 2-hydrazinobenzoic acid hydrochloride in acetic acid (20 ml) was slowly boiled with stirring and 1.2 ml (9.8 mmol) of 4-methylcyclohexanone was added dropwise. The resulting mixture was heated under reflux for 8 hours and then allowed to cool. After adding water, the precipitate thus obtained was recovered by filtration, washed with water and dried to obtain 1.96 g of 6-methyl-5,6,7,8-tetrahydro-9H-carbazole-1-carboxylic acid. This product was dissolved in acetone (50 ml) and 2.1 ml (34 mmol) of methyl iodide and 2.35 g (17 mmol) of anhydrous potassium carbonate were added to the solution. The reaction mixture was refluxed with stirring for 2 hours, then allowed to cool and extracted with water and ethyl acetate. The organic layer was collected, washed with water, dried over magnesium sulfate and concentrated to dryness. Thus, 1.49 g of methyl 6-methyl-5,6,7,8-tetra-hydro-9H-carbazole-1-carboxylate was obtained. This product was suspended in diphenyl ether (10 ml) and 890 mg of 10% palladium on carbon was added to the suspension. The resulting mixture was heated under reflux with stirring in a nitrogen atmosphere for 1 hour.

 After cooling, the product was dissolved by adding tetrahydrofuran. Then the catalyst was filtered off and the filtrate was concentrated. After adding n-hexane, the crystals thus obtained were recovered by filtration to obtain 1.26 g of the compound indicated in the title of the example.

1,8 г (10 ммоль) N-бромсукцинимида и 220 мг (1,3 ммоль) α,α′-азобисизобутиронитрила добавляли к раствору 1,2 г (5 ммоль) соединения Примера получения 18 в четыреххлористом углероде (100 мл) и полученную смесь нагревали с обратным холодильником при перемешивании в течение 1 часа. После остывания смесь концентрировали и остаток очищали колоночной хроматографией на силикагеле с получением 1,13 г соединения, указанного в названии примера. ¹ H-NMR (CDCl ₃ ): δ (ppm): 2.54 (s, 3H), 4.02 (s, 3H), 7.22 (t, J = 7.8 Hz, 1H) , 7.27-7.31 (m, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.87-7.90 (m, 1H), 8.05 (dd, J = 1.1; 7.8 Hz, 1H), 8.21-8.25 (m, 1H), 9.82 (br s, 1H)
Production Example 19
Methyl 6-formyl-9H-carbazole-1-carboxylate:

1.8 g (10 mmol) of N-bromosuccinimide and 220 mg (1.3 mmol) of α, α′-azobisisobutyronitrile were added to a solution of 1.2 g (5 mmol) of the compound of Production Example 18 in carbon tetrachloride (100 ml) and the resulting the mixture was heated under reflux with stirring for 1 hour. After cooling, the mixture was concentrated and the residue was purified by silica gel column chromatography to obtain 1.13 g of the compound indicated in the title of the example.

2,6 г (25 ммоль) малоновой кислоты и 0,3 мл пиперидина добавляли к раствору 2,0 г (7,9 ммоль) соединения Примера получения 19 в пиридине (80 мл) и полученную смесь перемешивали в бане при 80^oC в течение 1 часа. Затем к ней добавляли 2,6 г (25 ммоль) малоновой кислоты при нагревании и перемешивании на протяжении 1 часа и полученную смесь нагревали с обратным холодильником еще в течение 1 часа. После остывания реакционную смесь выливали в смесь концентрированной соляной кислоты со льдом и образованный таким образом осадок извлекали фильтрованием, промывали водой и сушили с получением 1,8 г 3-(1-метоксикарбонил-9H-карбазол-6-ил) акриловой кислоты. Полученное соединение растворяли в ацетоне (70 мл) и добавляли к раствору 2 мл триэтиламина. При охлаждении льдом и перемешивании добавляли по каплям 0,64 мл (6,7 ммоль) этилхлорформиата и затем реакционную смесь перемешивали при той же самой температуре в течение 1 часа. Затем в нее добавляли по каплям раствор 870 мг (12 ммоль) азида натрия (90%) в 20 мл воды при охлаждении льдом и перемешивании. Реакционную смесь перемешивали при той же самой температуре в течение 1 часа и затем выливали в лед. Образованный таким образом осадок извлекали фильтрованием. Этот осадок добавляли вместе с 3 мл трибутиламина к дифениловому эфиру (20 мл) и нагревали до 260^oC. После остывания добавляли гексан и полученный таким образом осадок извлекали фильтрованием и промывали последовательно н-гексаном и этанолом с получением 1,39г соединения заголовка. ¹ H-NMR (CDCl ₃ ): δ (ppm): 4.05 (s, 3H), 7.36 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 8.03 (dd, J = 1.6; 8.4 Hz, 1H), 8.14 (dd, J = 1.2; 7.8 Hz, 1H), 8, 32-8.36 (m, 1H), 8.62-8.64 (m, 1H), 10.12 (s, 1H), 10.23 (br s, 1H)
Production Example 20
Methyl 1,2-dihydro-1-oxo-7H-pyrido [4,3-c] carbazole-8-carboxylate:

2.6 g (25 mmol) of malonic acid and 0.3 ml of piperidine were added to a solution of 2.0 g (7.9 mmol) of the compound of Production Example 19 in pyridine (80 ml), and the resulting mixture was stirred in a bath at 80 ^° C. within 1 hour. Then, 2.6 g (25 mmol) of malonic acid was added to it under heating and stirring for 1 hour, and the resulting mixture was heated under reflux for another 1 hour. After cooling, the reaction mixture was poured into a mixture of concentrated hydrochloric acid with ice and the precipitate thus formed was removed by filtration, washed with water and dried to obtain 1.8 g of 3- (1-methoxycarbonyl-9H-carbazol-6-yl) acrylic acid. The resulting compound was dissolved in acetone (70 ml) and 2 ml of triethylamine was added to the solution. While cooling with ice and stirring, 0.64 ml (6.7 mmol) of ethyl chloroformate was added dropwise, and then the reaction mixture was stirred at the same temperature for 1 hour. Then, a solution of 870 mg (12 mmol) of sodium azide (90%) in 20 ml of water was added dropwise thereto under ice-cooling and stirring. The reaction mixture was stirred at the same temperature for 1 hour and then poured into ice. The precipitate thus formed was recovered by filtration. This precipitate was added together with 3 ml of tributylamine to diphenyl ether (20 ml) and heated to 260 ^° C. After cooling, hexane was added and the precipitate thus obtained was filtered off and washed successively with n-hexane and ethanol to obtain 1.39 g of the title compound.

10 мл оксихлорида фосфора добавляли к 1,19 г (4 ммоль) соединения Примера получения 20 и полученную смесь нагревали с обратным холодильником. Спустя 3 часа реакционную смесь выливали в лед и нейтрализовали бикарбонатом натрия. Затем ее экстрагировали дихлорметаном. Органический слой собирали, промывали водой, сушили над сульфатом магния и концентрировали. Остаток очищали колоночной хроматографией на силикагеле с получением 390 мг метил 1-хлор-7H-пиридо[4,3-с]карбазол-8-карбоксилата. Этот продукт растворяли в смеси тетрагидрофуран-метанол и добавляли к раствору 1 мл триэтиламина. Затем проводили гидрирование в присутствии палладия на угле при атмосферном давлении при обычной температуре с получением 300 мг соединения, указанного в названии примера. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 4.01 (s, 3H), 6.73 (d, J = 7.0 Hz, 1H), 7.18-7, 24 (m, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 8.08 (dd, J = 1.3 ; 7.9 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 10.13 (dd, J = 1.3; 7.9 Hz, 1H), 11.36-11 , 42 (m, 1H), 11.93 (br s, 1H)
Production Example 21
Methyl 7H-pyrido [4,3-s] carbazole-8-carboxylate:

10 ml of phosphorus oxychloride was added to 1.19 g (4 mmol) of the compound of Production Example 20, and the resulting mixture was heated under reflux. After 3 hours, the reaction mixture was poured into ice and neutralized with sodium bicarbonate. Then it was extracted with dichloromethane. The organic layer was collected, washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 390 mg of methyl 1-chloro-7H-pyrido [4,3-c] carbazole-8-carboxylate. This product was dissolved in tetrahydrofuran-methanol and 1 ml of triethylamine was added to the solution. Hydrogenation was then carried out in the presence of palladium on carbon at atmospheric pressure at ordinary temperature to obtain 300 mg of the compound indicated in the title of the example.

(м.д.): 4,04 (с, 3H), 7,48 (т, J=7,7 Гц, 1H), 8,00 (д, J=5,4 Гц, 1H), 8,02 (д, J=8,8 Гц, 1H), 8,14 (д, J=7,7 Гц, 1H), 8,28 (д, J= 8,8 Гц, 1H), 8,58 (д, J= 5,4 Гц, 1H), 9,06 (д, J=7,7 Гц, 1H), 10,22 (с, 1H), 12,11 (шир. с, 1H)
Пример получения 22
10-Hитро-7H-бензо[с]фенотиазин-8-карбоновая кислота:

5 мл 2 н. водного раствора гидроксида натрия добавляли к раствору 1,7 г (9,73 ммоль) 2-амино-1-нафталинтиона в этаноле (30 мл) и полученную смесь нагревали с обратным холодильником. К этой смеси добавляли 2,54 г (9,76 ммоль) метил-2-хлор-3,5-динитробензоата и полученную смесь нагревали с обратным холодильником в течение 1 часа. К этой смеси добавляли 10 мл 2 н. водного раствора гидроксида натрия и 40 мл этанола и полученную смесь нагревали с обратным холодильником еще в течение 10 часов. Затем смеси давали остыть до комнатной температуры и концентрировали. После добавления воды к смеси медленно добавляли 1 н. соляную кислоту при перемешивании для доведения величины pH до приблизительно 1. Осадок извлекали фильтрованием и промывали последовательно этанолом и метанолом с получением 1,14 г соединения, указанного в названии примера. ¹ H-NMR (DMSO-d ₆ )):

(ppm): 4.04 (s, 3H), 7.48 (t, J = 7.7 Hz, 1H), 8.00 (d, J = 5.4 Hz, 1H), 8, 02 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 7.7 Hz, 1H), 8.28 (d, 8.8 Hz, 1H), 8.58 ( d, J = 5.4 Hz, 1H), 9.06 (d, J = 7.7 Hz, 1H), 10.22 (s, 1H), 12.11 (br s, 1H)
Production Example 22
10-Nitro-7H-benzo [s] phenothiazine-8-carboxylic acid:

5 ml 2 n. an aqueous solution of sodium hydroxide was added to a solution of 1.7 g (9.73 mmol) of 2-amino-1-naphthalentione in ethanol (30 ml) and the resulting mixture was heated under reflux. 2.54 g (9.76 mmol) of methyl 2-chloro-3,5-dinitrobenzoate was added to this mixture, and the resulting mixture was heated under reflux for 1 hour. To this mixture was added 10 ml of 2 N. an aqueous solution of sodium hydroxide and 40 ml of ethanol and the resulting mixture was heated under reflux for another 10 hours. The mixture was then allowed to cool to room temperature and concentrated. After adding water, 1N was slowly added to the mixture. hydrochloric acid with stirring to bring the pH to about 1. The precipitate was recovered by filtration and washed successively with ethanol and methanol to obtain 1.14 g of the compound indicated in the title of the example.

10 мл трихлорида фосфора и 2 мл диметилформамида последовательно добавляли к суспензии 1,82 г (5,39 ммоль) соединения Примера получения 22 в хлороформе (60 мл) при 0^oC. Затем смеси давали медленно остыть до комнатной температуры и перемешивали ее в течение ночи. После полной отгонки растворителя из смеси при пониженном давлении к остатку добавляли 30 мл дихлорметана. При перемешивании при 0^oC в смесь добавляли по каплям раствор 5 мл N, N-диметилэтилендиамина в дихлорметане (30 мл). Затем реакционной смеси давали медленно остыть до комнатной температуры и перемешивали ее при комнатной температуре в течение 7 часов. Затем к ней добавляли насыщенный водный раствор бикарбоната натрия и полученную смесь перемешивали и фильтровали через целит для удаления из нее нерастворимых веществ. Органический слой извлекали, промывали последовательно водой и насыщенным водным раствором хлорида натрия, сушили над безводным сульфатом магния, концентрировали досуха и перекристаллизовывали из этанола с получением 956 мг соединения, указанного в названии примера. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 7.04 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 8.4 Hz, 1H) 7.55 (t, J = 8.4 Hz, 1H); 7.64 (d, J = 8.4 Hz; 1H); 7.68 (d, J = 8.4 Hz; 1H); 7 82 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8, 4 Hz, 1H), 7.90 (s, 1H), 8.35 (s, 1H), 11.37 (br s, 1H)
Production Example 23
N- [2- (Dimethylamino) ethyl] -10-nitro-7H-benzo [s] phenothiazine -8-carboxamide:

10 ml of phosphorus trichloride and 2 ml of dimethylformamide were successively added to a suspension of 1.82 g (5.39 mmol) of the compound of Production Example 22 in chloroform (60 ml) at 0 ^° C. Then the mixture was allowed to cool slowly to room temperature and it was stirred for nights. After the solvent was completely distilled off from the mixture under reduced pressure, 30 ml of dichloromethane was added to the residue. With stirring at 0 ^° C., a solution of 5 ml of N, N-dimethylethylenediamine in dichloromethane (30 ml) was added dropwise to the mixture. Then the reaction mixture was allowed to cool slowly to room temperature and it was stirred at room temperature for 7 hours. Then, a saturated aqueous solution of sodium bicarbonate was added to it, and the resulting mixture was stirred and filtered through celite to remove insoluble substances from it. The organic layer was removed, washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, concentrated to dryness and recrystallized from ethanol to obtain 956 mg of the compound indicated in the title of the example.

Соединение заголовка получали реакцией 5,6-дигидро-3- (4-метилбензолсульфонамидо)-7H-бензо[с]карбазол-8-карбоновой кислоты, которая была получена нагреванием с обратным холодильником 6-(4-метилбензолсульфонамидо)-2-тетралона и гидрохлорида 2-гидразинобензойной кислоты в ксилоле согласно способу, описанному в Примере получения 2. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.20 (s, 6H), 2.45 (t, J = 6.0 Hz, 2H), 3.37 (t, J = 6.0 Hz, H), 7.06 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 8.4 Hz, 1H), 7.56 (t, J = 8.4 Hz, 1H), 7.66 (t, J = 8.4 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8, 4 Hz, 1H), 7.93 (br s, 1H), 8.39 (d, J = 2.9 Hz, 1H), 9.50 (br s, 1H)
Production Example 24
3- (4-Methylbenzenesulfonamido) -7H-benzo [s] carbazole-8-carboxylic acid:

The title compound was prepared by reaction of 5,6-dihydro-3- (4-methylbenzenesulfonamido) -7H-benzo [c] carbazole-8-carboxylic acid, which was obtained by refluxing 6- (4-methylbenzenesulfonamido) -2-tetralone and 2-hydrazinobenzoic acid hydrochloride in xylene according to the method described in Production Example 2.

Суспензию 4,24 г (22,5 ммоль) гидрохлорида 1-нафталингидразина в уксусной кислоте (35 мл) медленно кипятили и при перемешивании добавляли в нее по каплям раствор 3,4 г (20,6 ммоль) 2-нитрофенилацетальдегида в уксусной кислоте (15 мл). После завершения добавления по каплям полученную смесь нагревали с обратным холодильником в течение 1 часа. Затем добавляли 20 мл смеси 1 н. соляной кислоты с уксусной кислотой и полученную смесь нагревали с обратным холодильником еще в течение 1 часа. После отгонки растворителя остаток растворяли добавлением к нему этилацетата. Органический слой промывали последовательно водным раствором бикарбоната натрия, водой и насыщенным водным раствором хлорида натрия и сушили над безводным сульфатом магния. После отгонки растворителя остаток очищали колоночной хроматографией на силикагеле с получением 1,91 г (выход 32%) 7-(2-нитрофенил)бенз[g]-индола. Затем полученный продукт растворяли в этилацетате (60 мл) и добавляли 200 мг оксида платины (IV). Затем проводили каталитическое восстановление при атмосферном давлении в атмосфере водорода при комнатной температуре с получением 1,7 г (выход 99%) 7-(2-аминофенил)бенз[g]индола. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.26 (s, 3H), 7.29 (t, J = 8.0 Hz, 2H), 7.35 (dt, J = 2.0; 7.6 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 6.8 Hz, 2H), 7.71 ( s, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.96 (dd, J = 2.0; 9.2 Hz, 1H), 8.01 (d, J = 8 8 Hz, 1H), 8.66 (d, J = 8.8 Hz, 1H), 8.79 (d, J = 8.0 Hz, 1H), 10.33 (s, 1H), 11, 76 (s, 1H)
Production Example 25
Ethyl 13H-benz [6,7] indolo [2,3-c] quinoline-12-carboxylate:

A suspension of 4.24 g (22.5 mmol) of 1-naphthalenehydrazine hydrochloride in acetic acid (35 ml) was slowly boiled and a solution of 3.4 g (20.6 mmol) of 2-nitrophenylacetaldehyde in acetic acid (dropwise) was added to it with stirring. 15 ml). After completion of the dropwise addition, the resulting mixture was heated under reflux for 1 hour. Then was added 20 ml of a mixture of 1 N. hydrochloric acid with acetic acid and the resulting mixture was heated under reflux for another 1 hour. After distilling off the solvent, the residue was dissolved by adding ethyl acetate to it. The organic layer was washed successively with an aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 1.91 g (32% yield) of 7- (2-nitrophenyl) benz [g] -indole. Then, the resulting product was dissolved in ethyl acetate (60 ml), and 200 mg of platinum (IV) oxide was added. Then, a catalytic reduction was carried out at atmospheric pressure in a hydrogen atmosphere at room temperature to obtain 1.7 g (99% yield) of 7- (2-aminophenyl) benz [g] indole.

 Then 20 ml of ethanol was added to 540 mg (2.1 mmol) of 7- (2-aminophenyl) benz [g] indole and 260 mg (2.5 mmol) of ethyl glyoxylate (polymer) and the resulting mixture was heated under reflux for 8 hours . After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 380 mg (53% yield) of the title compound.

457 мг (10,5 ммоль) гидрида натрия (55% в масле) добавляли к раствору 1,44 г соединения Примера получения 3 в диметилформамиде (50 мл) при комнатной температуре и полученную смесь перемешивали в течение 50 минут. Затем добавляли 1 мл (10,5 ммоль) этилхлорформиата при 0^oC и полученную смесь перемешивали при той же температуре в течение 2 часов и затем при комнатной температуре в течение 6 часов. После добавления воды осадок извлекали фильтрованием, промывали водой и сушили. Затем его растворяли в смеси дихлорметан-метанол и нерастворимые вещества отфильтровывали. После концентрирования последовательно добавляли этанол и концентрированную соляную кислоту. Образовавшийся таким образом гидрохлорид извлекали фильтрованием и перекристаллизовывали из этанола с получением 1,24 г соединения, указанного в названии примера. ¹ H-NMR (CDCl ₃ ): δ (ppm): 1.64 (t, J = 7.1 Hz, 3H), 4.74 (q, J = 7.1 Hz, 2H), 7 , 63-7.77 (m, 3H), 7.79 (d, J = 8.6 Hz, 1H), 7.70-7.85 (m, 1H), 8.06 (dd, J = 1 , 3; 7.7 Hz, 1H), 8.35 (dd, J = 0.7; 8.1 Hz, 1H), 8.45 (dd, J = 1.3; 8.4 Hz, 1H) 8.54 (d, J = 8.6 Hz, 1H), 8.79 (dd, J = 1.1; 8.2 Hz, 1H), 10.98 (br s, 1H)
Example 1
5- [2- (Dimethylamino) ethyl] -4H-benzo [s] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

457 mg (10.5 mmol) of sodium hydride (55% in oil) was added to a solution of 1.44 g of the compound of Production Example 3 in dimethylformamide (50 ml) at room temperature and the resulting mixture was stirred for 50 minutes. Then, 1 ml (10.5 mmol) of ethyl chloroformate was added at 0 ^° C., and the resulting mixture was stirred at the same temperature for 2 hours and then at room temperature for 6 hours. After adding water, the precipitate was removed by filtration, washed with water and dried. Then it was dissolved in a mixture of dichloromethane-methanol and insoluble matters were filtered off. After concentration, ethanol and concentrated hydrochloric acid were successively added. The hydrochloride thus formed was recovered by filtration and recrystallized from ethanol to obtain 1.24 g of the compound indicated in the title of the example.

Melting point: 254-255 ^o C (recrystallization from ethanol).

FAB mass spectrometry m / z: 358 ([M + H] ⁺ ).

(м.д.):2,90 (д, J=5,5 Гц, 6H), 3,49 (к, J=5,5 Гц, 2H), 4,42 (т, J=5,5 Гц, 2H), 7,67 (т, J=8,0 Гц, 1H), 7,78 (т, J=8,0 Гц, 1H), 7,83 (т, J=8,0 Гц, 1H), 8,14 (д, J=8,0 Гц, 1H), 8,19 (д, J=8,0 Гц, 1H), 8,23 (д, J=8,8 Гц, 1H), 8,62 (д, J=8,0 Гц, 1H), 8,86 (д, J=8,0 Гц, 1H), 9,02 (д, J=8,0 Гц, 1H), 9,70 (шир. с, 1H)
Элементный анализ: как C₂₂H₁₉N₃O₂•H₂O
рассчитано: C 64,15; H 5,38; N 10,20;
найдено: C 64,38; H 5,05; N 10,22. ¹ H-NMR (DMSO-d ₆ ):

(ppm): 2.90 (d, J = 5.5 Hz, 6H), 3.49 (q, J = 5.5 Hz, 2H), 4.42 (t, J = 5.5 Hz, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H) , 8.62 (d, J = 8.0 Hz, 1H), 8.86 (d, J = 8.0 Hz, 1H), 9.02 (d, J = 8.0 Hz, 1H), 9 , 70 (br s, 1H)
Elemental analysis: as C ₂₂ H ₁₉ N ₃ O ₂ • H ₂ O
calculated: C, 64.15; H 5.38; N, 10.20;
Found: C, 64.38; H 5.05; N, 10.22.

13,2 мг (0,549 ммоль) гидрида натрия добавляли к раствору 105 мг (0,282 ммоль) соединения Примера получения 5 в диметилформамиде (2,5 мл) при 0^oC и полученную смесь перемешивали при той же температуре в течение 1 часа и 10 минут и затем при комнатной температуре в течение 1 часа. Затем добавляли 53,6 мкл (0,564 ммоль) этилхлорформиата при 0^oC и полученную смесь перемешивали при той же температуре в течение 1 часа 20 минут. После экстракции путем добавления воды и хлороформа органический слой извлекали, сушили над сульфатом натрия и концентрировали. Остаток очищали колоночной хроматографией на силикагеле и превращали в гидрохлорид с использованием 1 н. хлористоводородной кислоты (этанол) с получением 106 мг соединения, указанного в названии примера.Example 2
11-Acetyl-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

13.2 mg (0.549 mmol) of sodium hydride was added to a solution of 105 mg (0.282 mmol) of the compound of Production Example 5 in dimethylformamide (2.5 ml) at 0 ^° C. and the resulting mixture was stirred at the same temperature for 1 hour and 10 minutes and then at room temperature for 1 hour. Then, 53.6 μl (0.564 mmol) of ethyl chloroformate was added at 0 ^° C. and the resulting mixture was stirred at the same temperature for 1 hour 20 minutes. After extraction by adding water and chloroform, the organic layer was removed, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography and converted to hydrochloride using 1N. hydrochloric acid (ethanol) to give 106 mg of the compound indicated in the title of the example.

Melting point: stains from approximately 240 ^o C and decomposes at approximately 250-254 ^o C.

FAB mass spectrometry m / z: 400 ([M + H] ⁺ ).

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.78 (s, 3H), 2.92 (s, H), 3.48-3.54 (m, 2H), 4.44 (t, J = 5.6 Hz, 2H), 7.80 (t, J = 7.5 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H), 8, 24 (dd, J = 2.3; 9.4 Hz, 1 H), 8.40 (d, J = 8.9 Hz, 1H), 8.68 (d, J = 8.9 Hz, 1H) 8.87-8.91 (m, 2H), 9.01 (d, J = 7.5 Hz, 1H), 9.88 (br s, 1H)
Elemental analysis: as C ₂₄ H ₂₁ N ₃ O ₃ • HCl • 2H ₂ O
calculated: C, 63.50; H 5.33; N, 9.26,
Found: C, 63.42; H 5.04; N, 9.16.

21 мкл (0,168 ммоль) комплекса боран/пиридин (~ 8 М) добавляли к суспензии 84 мг (0,211 ммоль) соединения, полученного преобразованием соединения Примера 2 в его свободное основание, в уксусной кислоте (1,5 мл) и полученную смесь перемешивали при 70^oC в течение 3 часов. Затем ее подкисляли добавлением 1 н соляной кислоты при комнатной температуре, перемешивали в течение 1 минуты и нейтрализовали насыщенным водным раствором бикарбоната натрия. Затем ее экстрагировали добавлением к ней смеси дихлорметана с этанолом. Органический слой собирали, промывали водой, сушили над сульфатом натрия и концентрировали. Остаток очищали препаративной тонкослойной хроматографией и превращали в гидрохлорид при помощи 1 н. хлористоводородной кислоты с получением 44 мг соединения, указанного в названии примера.Example 3 Hydrochloride
5- [2- (dimethylamino) ethyl] -11- (1-hydroxyethyl) -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione:

21 μl (0.168 mmol) of the borane / pyridine complex (~ 8 M) was added to a suspension of 84 mg (0.211 mmol) of the compound obtained by converting the compound of Example 2 to its free base in acetic acid (1.5 ml) and the resulting mixture was stirred at 70 ^o C for 3 hours. Then it was acidified by adding 1 N hydrochloric acid at room temperature, stirred for 1 minute and neutralized with saturated aqueous sodium bicarbonate. Then it was extracted by adding to it a mixture of dichloromethane with ethanol. The organic layer was collected, washed with water, dried over sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography and converted to hydrochloride using 1 N. hydrochloric acid to obtain 44 mg of the compound indicated in the title of the example.

Melting point: ~ 247 - 248 ^o C (decomposition) (recrystallization from ethanol).

FAB mass spectrometry m / z: 402 ([M + H] ⁺ ).

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 1.50 (d, J = 5.0 Hz, 3H), 2.92 (s, 6H), 3.49 (t, J = 5.7 Hz, 2H), 4.43 (t, J = 5.7 Hz, 2H), 4.95-5.05 (m, 1H), 5.45 (d, J = 4.2 Hz, 1H), 7.77 (t, J = 8.4 Hz, 1H), 7.84 (t, J = 8.4 Hz, 1H), 8.08-8.15 (m, 2H), 8.21 (d, J = 8.4 Hz, 1H), 8.59 (dd, J = 1.4; 8.4 Hz, 1H), 8.81 (d, J = 8.4 Hz, 1H ), 8.99 (d, J = 7.6 Hz, 1H), 9.90 (br s, 1H)
Elemental analysis: as C ₂₄ H ₂₄ N ₃ O ₃ Cl
calculated: C, 65.82; H 5.52; N, 9.60;
Found: C, 65.49; H 5.53; N, 9.49.

Раствор 4,9 г (14 ммоль) соединения Примера получения 8 в диметилформамиде (70 мл) добавляли по каплям в суспензию 0,9 г (37,5 ммоль) гидрида натрия в диметилформамиде (30 мл) при комнатной температуре и полученную смесь перемешивали при той же температуре в течение 2 часов. Затем добавляли 2,5 г (23 ммоль) этилхлорформиата при охлаждении льдом и перемешивании. Спустя 15 минут добавляли этилацетат и полученную смесь промывали последовательно разбавленным водным аммиаком и водным раствором хлорида натрия и сушили над сульфатом магния. После концентрирования добавляли метанол и кристаллы извлекали фильтрованием. Затем эти кристаллы суспендировали в метаноле и подкисляли добавлением 1 н. хлористоводородной кислоты при перемешивании. После перемешивания при комнатной температуре и концентрирования добавляли этанол и полученный осадок извлекали фильтрованием с получением 4,3 г соединения, указанного в названии примера.Example 4
12,13-dihydro-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H, 11 H) trion hydrochloride:

A solution of 4.9 g (14 mmol) of the compound of Production Example 8 in dimethylformamide (70 ml) was added dropwise to a suspension of 0.9 g (37.5 mmol) of sodium hydride in dimethylformamide (30 ml) at room temperature, and the resulting mixture was stirred at same temperature for 2 hours. Then, 2.5 g (23 mmol) of ethyl chloroformate was added under ice-cooling and stirring. After 15 minutes, ethyl acetate was added and the resulting mixture was washed successively with dilute aqueous ammonia and aqueous sodium chloride and dried over magnesium sulfate. After concentration, methanol was added and the crystals were removed by filtration. Then these crystals were suspended in methanol and acidified by adding 1 N. hydrochloric acid with stirring. After stirring at room temperature and concentration, ethanol was added and the resulting precipitate was recovered by filtration to obtain 4.3 g of the title compound.

Melting point: it stains from about 250 ^o C, gradually decomposes from about 260 ^o C and quickly decomposes at about 273-275 ^o C.

FAB mass spectrometry m / z: 376 ([M + H] ⁺ ).

(м.д.): 2,22-2,36 (м, 2H), 2,72-2,80 (м, 2H), 2,92 (с, 6H), 3,44-3,54 (м, 2H), 3,54-3,60 (м, 2H), 4,38-4,46 (м, 2H), 7,75 (т, J= 7,6 Гц, 1H), 8,17 (дд, J=0,8; 7,6 Гц, 1H), 8,25 (д, J=8,8 Гц, 1H), 8,41 (д, J=8,8 Гц, 1H), 8,61 (дд, J=0,8; 7,6 Гц, 1H), 9,52 (шир. с, 1H)
Элементный анализ: как C₂₂H₂₁N₃O₃•HCl•1H₂O
рассчитано: C 61,47; H 5,63; N 9,77;
найдено: C 61,47; H 5,57; N 9,77. ¹ H-NMR (DMSO-d ₆ ):

(ppm): 2.22-2.36 (m, 2H), 2.72-2.80 (m, 2H), 2.92 (s, 6H), 3.44-3.54 ( m, 2H), 3.54-3.60 (m, 2H), 4.38-4.46 (m, 2H), 7.75 (t, J = 7.6 Hz, 1H), 8.17 (dd, J = 0.8; 7.6 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8 , 61 (dd, J = 0.8; 7.6 Hz, 1H), 9.52 (br s, 1H)
Elemental analysis: as C ₂₂ H ₂₁ N ₃ O ₃ • HCl • 1H ₂ O
calculated: C, 61.47; H 5.63; N, 9.77;
Found: C, 61.47; H 5.57; N, 9.77.

0,5 г (1,2 ммоль) соединения Примера 4 растворяли в смеси воды (50 мл) с метанолом (25 мл) и добавляли 1,2 мл 1 н. хлористоводородной кислоты. Затем проводили гидрирование в присутствии палладия на угле в атмосфере водорода при давлении приблизительно 4,5 кг/см². После подтверждения завершения реакции тонкослойной хроматографией катализатор отфильтровывали и остаток концентрировали приблизительно до 2/3. После добавления 50 мл воды и 5 мл концентрированного водного аммиака полученную смесь экстрагировали этилацетатом. Органический слой извлекали, промывали водным раствором хлорида натрия, сушили над сульфатом магния и концентрировали. Остаток очищали колоночной хроматографией на силикагеле с получением 0,35 г соединения, указанного в названии примера.Example 5
5- [2- (Dimethylamino) ethyl] -10-hydroxy-10,11,12,13-tetrahydro-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) - dion:

0.5 g (1.2 mmol) of the compound of Example 4 was dissolved in a mixture of water (50 ml) with methanol (25 ml) and 1.2 ml of 1N was added. hydrochloric acid. Then, hydrogenation was carried out in the presence of palladium on carbon in a hydrogen atmosphere at a pressure of approximately 4.5 kg / cm ² . After confirmation of the completion of the reaction by thin layer chromatography, the catalyst was filtered off and the residue was concentrated to approximately 2/3. After adding 50 ml of water and 5 ml of concentrated aqueous ammonia, the resulting mixture was extracted with ethyl acetate. The organic layer was removed, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 0.35 g of the title compound.

FAB mass spectrometry m / z: 378 ([M + H] ⁺ ).

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.92-2.30 (m, 4H), 2.37 (s, 6H), 2.70 (t, J = 6.8 Hz , 2H), 3.06-3.32 (m, 2H), 4.32 (t, J = 6.8 Hz, 2H), 4.95 (br t, J = 4.8 Hz, 1H) 7.52 (t, J = 7.6 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 8.09 (dd, J = 0.8; 7.6 Hz, 1H), 8.15 (dd, J = 0.8; 7.6 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H).

Elemental analysis: as C ₂₂ H ₂₃ N ₃ O ₃ • 1H ₂ O
calculated: C, 66.82; H 6.37; N, 10.63;
Found: C, 67.10; H 6.03; N, 10.34.

Соединение Примера 5 разделяли на колонке для разделения оптических стереоизомеров [Chiralcel OD, проводимой Daicel; элюируя смесью н-гексан/2-пропанол (7: 3 - 6:4)]. Фракцию, элюирующуюся раньше, концентрировали досуха с получением соединения заголовка.Example 6
(+) - 5- [2- (Dimethylamino) ethyl] -10-hydroxy-10,11,12,13-tetrahydro
4H-benzo [s] pyrimido [5,6,1-jk] carbazole-4,6 (5H) -dione:

The compound of Example 5 was separated on a column for the separation of optical stereoisomers [Chiralcel OD, conducted by Daicel; eluting with n-hexane / 2-propanol (7: 3-6: 4)]. The fraction eluting earlier was concentrated to dryness to give the title compound.

Melting point: ~ 160-162 ^o C
FAB mass spectrometry m / z: 378 ([M + H] ⁺ ).

¹ H-NMR (CDCl ₃ ): δ (ppm): 1.90-2.30 (m, 4H), 2.43 (s, 6H), 2.77 (t, J = 6.4 Hz, 2H), 3.04-3.31 (m, 2H), 4.34 (t, J = 6.8 Hz, 2H), 4.95 (br t, J = 4.8 Hz, 11 -1), 7.51 (t, J = 7.6 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H ), 8.13 (d, J = 7.6 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H).

Elemental analysis: as C ₂₂ H ₂₃ N ₃ O ₃ • 0.75H ₂ O
calculated: C, 67.59; H 6.32; N, 10.75;
Found: C, 67.34; H 5.93; N, 10.48.

Rotation angle [α] $\genfrac{}{}{0ex}{}{\text{2}}{\text{D}}$ ⁷ : 9.8 ^° (C = 1.0, CHCl ₃ ).

Названное соединение получали из соединения примера получения 10 согласно способу, описанному в Примере 2.Example 7
11,12-dihydro-5- [2- (dimethylamino) ethyl] -4H hydrochloride, 10H cyclopenta [s] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H) -trione:

The named compound was obtained from the compound of Production Example 10 according to the method described in Example 2.

Melting point: stains from about 255 ^o C and gradually decomposes from about 265 ^o C.

FAB mass spectrometry m / z: 362 ([M + H] ⁺ ).

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.83-2.94 (m, 8H), 3.45 (br s, 2H), 3.64 (br t , J = 6.0 Hz, 2H), 4.42 (br t, J = 6.0 Hz, 2H), 7.79 (t, J = 7.6 Hz, 1H), 7.97 (d , J = 8.4 Hz, 1H), 8.19 (dd, J = 0.8; 7.6 Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.55 (dd, J = 0.8; 7.6 Hz, 1H), 9.44 (br s, 1H).

Elemental analysis: as C ₂₁ H ₁₉ N ₃ O ₃ • HCl • 0.75H ₂ O
calculated: C 61.31; H 5.27; N, 10.21;
Found: C, 61.17; H 5.04; N, 10.16.

590 мг (2,2 ммоль) соединения Примера получения 15 растворяли в диметилформамиде (20 мл). После добавления 720 мг (4,4 ммоль) N,N'-карбонилдиимидазола полученную смесь перемешивали при комнатной температуре в течение 30 минут. Затем к смеси добавляли 0,97 мл (8,8 ммоль) N,N-диметилэтилендиамина и полученную смесь перемешивали в течение ночи с последующим концентрированием. К остатку добавляли воду и полученную смесь экстрагировали смесью этилацетат-тетрагидрофуран. Органический слой извлекали, промывали последовательно насыщенным водным раствором бикарбоната натрия и водой и сушили над сульфатом магния. После концентрирования остаток очищали колоночной хроматографией на силикагеле с получением 250 мг 2,3-дигидро-N-[2-(диметиламино) этил]-3-оксо-6H-фуро[3,2-с]карбазол-7-карбоксиамида. Этот продукт растворяли в диметилформамиде (10 мл). После добавления 60 мг (1,5 ммоль) гидрида натрия (60% в масле) смесь перемешивали в атмосфере азота в течение 30 минут. После добавления 0,145 мл (1,5ммоль) этилхлорформиата при охлаждении льдом полученную смесь перемешивали в течение 30 минут и затем подкисляли добавлением к ней 1 н. соляной кислоты. После концентрирования добавляли насыщенный водный раствор бикарбоната натрия и полученную смесь экстрагировали смесью этилацетат-тетрагидрофуран. Органический слой извлекали, промывали водой, сушили над сульфатом магния, концентрировали и очищали колоночной хроматографией на силикагеле. Затем продукт суспендировали в этаноле (20 мл). После добавления 1 мл 1 н. соляной кислоты и перемешивания кристаллы извлекали фильтрованием с получением 175 мг соединения, указанного в названии примера.Example 8
8- [2- (Dimethylamino) ethyl] -7H-furo [3,2-c] pyrimido [5,6,1-jk] carbazole-3,7,9 (2H, 8H) trion hydrochloride:

590 mg (2.2 mmol) of the compound of Production Example 15 was dissolved in dimethylformamide (20 ml). After adding 720 mg (4.4 mmol) of N, N'-carbonyldiimidazole, the resulting mixture was stirred at room temperature for 30 minutes. Then, 0.97 ml (8.8 mmol) of N, N-dimethylethylenediamine was added to the mixture, and the resulting mixture was stirred overnight, followed by concentration. Water was added to the residue, and the resulting mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was removed, washed successively with saturated aqueous sodium bicarbonate and water, and dried over magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography to obtain 250 mg of 2,3-dihydro-N- [2- (dimethylamino) ethyl] -3-oxo-6H-furo [3,2-c] carbazole-7-carboxiamide. This product was dissolved in dimethylformamide (10 ml). After adding 60 mg (1.5 mmol) of sodium hydride (60% in oil), the mixture was stirred under nitrogen for 30 minutes. After adding 0.145 ml (1.5 mmol) of ethyl chloroformate under ice-cooling, the resulting mixture was stirred for 30 minutes and then acidified by adding 1N to it. of hydrochloric acid. After concentration, saturated aqueous sodium bicarbonate was added, and the resulting mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was removed, washed with water, dried over magnesium sulfate, concentrated and purified by silica gel column chromatography. Then the product was suspended in ethanol (20 ml). After adding 1 ml of 1 N. hydrochloric acid and stirring, the crystals were removed by filtration to obtain 175 mg of the compound indicated in the title of the example.

Melting point: it stains from approximately 240 ^o C and decomposes at approximately 270 - 273 ^o C.

FAB mass spectrometry m / z: 364 ([M + H] ⁺ ).

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.89 (br s, 6H), 3.42-3.50 (m, 2H), 4.39-4.45 (m, 2H), 5.14 (s, 2H), 7.78 (t, J = 7.7 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.17 (dd, J = 0.8; 7.7 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.43 (dd, J = 0.8; 7.7 Hz, 1H), 9.62 (br s, 1H).

Elemental analysis: as C ₂₀ H ₁₇ N ₃ O ₄ • HCl • 0.15H ₂ O
calculated: C 59.68; H 4.58; N, 10.44;
Found: C, 59.64; H 4.49; N, 10.33.

105,5 мг (0,29 ммоль) соединения Примера 8 растворяли в уксусной кислоте (1 мл). Затем добавляли 36 мкл 8 М комплекса боран/пиридин с перемешиванием при комнатной температуре. Полученную смесь перемешивали в течение 4,5 часов. После добавления 30 мкл 8 М комплекса борна/пиридин полученную смесь продолжали перемешивать в течение ночи и концентрировали. Затем ее экстрагировали добавлением воды, насыщенного водного раствора бикарбоната натрия и хлороформа. Органический слой сушили над безводным сульфатом натрия и концентрировали. Остаток очищали колоночной хроматографией на силикагеле. Полученный таким образом продукт перекристаллизовывали из смеси этанол/диизопропиловый эфир с получением 22,6 мг соединения, указанного в названии примера.Example 9
2,3-dihydro-8- [2- (dimethylamino) ethyl] -3-hydroxy-7H-furo [3,2-c] pyrimido [5,6,1-jk] carbazole-7.9 (8H) - dion

105.5 mg (0.29 mmol) of the compound of Example 8 was dissolved in acetic acid (1 ml). Then 36 μl of an 8 M borane / pyridine complex was added with stirring at room temperature. The resulting mixture was stirred for 4.5 hours. After adding 30 μl of an 8 M complex of boron / pyridine, the resulting mixture was continued to stir overnight and concentrated. Then it was extracted by adding water, a saturated aqueous solution of sodium bicarbonate and chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography. The product thus obtained was recrystallized from ethanol / diisopropyl ether to give 22.6 mg of the title compound.

0,23 г (0,57 ммоль) соединения Примера получения 17 и 95 мг (0,1 ммоль) трис (трифенилфосфин) родийхлорида растворяли в 20 мл смеси ацетонитрила с водой (84: 16). Затем полученную смесь нагревали в атмосфере азота для отгонки растворителя, добавляя одновременно смесь ацетонитрила с водой (84:16) для поддержания на постоянном уровне объема смеси. После продолжения этой операции в течение ~ 3 часов исчезновение исходных соединений подтверждали тонкослойной хроматографией. Затем реакционную смесь концентрировали приблизительно до 1/4 и экстрагировали этилацетатом. Органический слой собирали, промывали последовательно разбавленным водным аммиаком и водным раствором хлорида натрия, сушили над сульфатом магния и концентрировали. Остаток очищали препаративной тонкослойной хроматографией и затем превращали в его гидрохлорид согласно способу, описанному в Примере 4 с получением 0,1 г соединения указанного в названии примера. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.24 (s, 6H), 2.56 (t, J = 6.8 Hz, 2H), 4.15 (t, J = 6.8 Hz, 2H), 4.56 (dd, J = 2.8; 10.0 Hz, 1H), 4.84 (dd, J = 6.8; 10.0 Hz, 1H), 5.43-5.49 (m, 1H), 5.80 (d, J = 5.6 Hz, 1H), 7.61-7.67 (m, 2H), 7.97 (d, J = 8.4 Hz, 1H), 8.02 (dd, J = 0.8: 7.6 Hz, 1H), 8.22 (dd, J = 0.8; 7.6 Hz, 1H)
Example 10
12,13-dihydro-5- [2- (methylamino) ethyl] -4H-benzo [s] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H, 11H) trion hydrochloride:

0.23 g (0.57 mmol) of the compound of Production Example 17 and 95 mg (0.1 mmol) of tris (triphenylphosphine) rhodium chloride were dissolved in 20 ml of a mixture of acetonitrile with water (84: 16). Then the resulting mixture was heated under nitrogen to distill off the solvent, while adding a mixture of acetonitrile with water (84:16) to maintain a constant volume of the mixture. After continuing this operation for ~ 3 hours, the disappearance of the starting compounds was confirmed by thin layer chromatography. Then the reaction mixture was concentrated to approximately 1/4 and extracted with ethyl acetate. The organic layer was collected, washed successively with dilute aqueous ammonia and aqueous sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by preparative thin layer chromatography and then converted to its hydrochloride salt according to the method described in Example 4 to give 0.1 g of the compound of the title example.

Melting point: it stains from about 250 ^o C, gradually decomposes from about 260 ^o C and quickly decomposes at ~ 267 - 269 ^o C.

FAB mass spectrometry m / z: 362 ([M + H] ⁺ ).

¹ H-NMR (DMSO-d ₆ • D ₂ O): δ (ppm): 2.24-2.34 (m, 2H), 2.59 (s, 3H), 2.76 (broad t, J = 6.0 Hz, 2H), 3.31 (br. t, J = 5.2 Hz, 2H), 3.56 (br. t, J = 6.0 Hz, 2H), 4 , 36 (br t, J = 5.2 Hz, 2H), 7.75 (t, J = 8.0 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8 24 (d, J = 8.8 Hz, 1H). 8.39 (d, J = 8.8 Hz, 1H), 8.59 (d, J = 8.0 Hz, 1H)
Elemental analysis: as C ₂₁ H ₁₉ N ₃ O ₃ • HCl • 0.2H ₂ O
Calculated: C 62.83; H 5.12; N, 10.47;
Found: C, 62.78; H 5.09; N, 10.36.

Соединение заголовка получали реакцией соединения Примера получения 7 с 1-(2-аминоэтил) пирролидином согласно способам, описанным в Примере получения 8 и Примере 4.Example 11
12,13-dihydro-5- [2- (1-pyrrolidinyl) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H, 11H) -trione hydrochloride :

The title compound was prepared by reacting the compound of Production Example 7 with 1- (2-aminoethyl) pyrrolidine according to the methods described in Production Example 8 and Example 4.

Melting point: stains from approximately 235 ^o C and gradually decomposes from approximately 260 ^o C.

FAB mass spectrometry m / z: 402 ([M + H] ⁺ ).

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 1.86 (br s, 2H), 2.01 (br s, 2H), 2.23 - 2.32 (m , 2H), 2.71-2.79 (m, 2H), 3.15 (br s, 2H), 3.46-3.74 (br t + m, J = 6.0 Hz, 4H + 2H), 4.40 (br t, J = 5.2 Hz, 2H), 7.73 (t, J = 8.0 Hz, 1H), 8.15 (d, J = 8.0 Hz , 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.57 (d, J = 8.0 Hz, 1H ), 10.10 (br s, 1H).

Elemental analysis: as C ₂₄ H ₂₃ N ₃ O ₃ • HCl • 1.5H ₂ O
calculated: C 62.00; H 5.85; N, 9.04;
Found: C, 62.27; H 5.49; N, 9.03.

Названное соединение получали реакцией соединения Примера получения 2 с 1-(2-аминоэтил)пирролидином согласно способам, описанным в Примере получения 3 и Примере 1.Example 12
5- [2- (1-Pyrrolidinyl) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

The title compound was prepared by reacting the compound of Production Example 2 with 1- (2-aminoethyl) pyrrolidine according to the methods described in Production Example 3 and Example 1.

FAB mass spectrometry m / z: 384 ([M + H] ⁺ ).

(м. д. ): 1,78-1,92 (м, 2H), 1,94-2, 06 (м, 2H), 3,08-3,22 (м, 2H), 3,56 (т, J=5,6 Гц, 2H), 3,60-3,70 (м, 2H), 4,41 (т, J=5,6 Гц, 2H), 7,66 (т, J=7,6 Гц, 1H), 7,75 (т, J=8,0 Гц, 1H), 7,81 (т, J=8,0 Гц, 1H), 8,11 (д, J=7,6 Гц, 1H), 8,18(д, J=8,0 Гц, 1H), 8,21 (д, J=9,2 Гц, 1H), 8,60 (д, J= 9,2 Гц, 1H), 8,83 (д, J=8,0 Гц, 1H), 8,98 (д, J=7,6 Гц, 1H), 10,29 (шир. с, 1H). ¹ H-NMR (DMSO-d ₆ ):

(ppm): 1.78-1.92 (m, 2H), 1.94-2, 06 (m, 2H), 3.08-3.22 (m, 2H), 3.56 ( t, J = 5.6 Hz, 2H), 3.60-3.70 (m, 2H), 4.41 (t, J = 5.6 Hz, 2H), 7.66 (t, J = 7 6 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 9.2 Hz, 1H), 8.60 (d, J = 9.2 Hz, 1H), 8.83 (d, J = 8.0 Hz, 1H), 8.98 (d, J = 7.6 Hz, 1H), 10.29 (br s, 1H).

Elemental analysis: as C ₂₄ H ₂₁ N ₃ O ₃ • HCl • H ₂ O
calculated: C, 65.83; H 5.52; N, 9.60;
Found: C, 66.04; H 5.57; N, 9.53.

Раствор 200 мг (0,49 ммоль) соединения Примера получения 23 в тетрагидрофуране (15 мл) перемешивали при комнатной температуре и добавляли последовательно 0,5 мл триэтиламина и 200 мкл (2,09 ммоль) этилхлорформиата. После перемешивания при комнатной температуре в течение ночи реакционную смесь концентрировали и экстрагировали добавлением к ней воды, насыщенного водного раствора бикарбоната натрия и дихлорметана. Органический слой промывали последовательно водой и насыщенным водным раствором хлорида натрия, сушили над безводным сульфатом магния и концентрировали досуха. Остаток перекристаллизовывали из этанола с получением 104 мг свободного основания соединения заголовка. Затем этот продукт суспендировали в метаноле и добавляли концентрированную хлористоводородную кислоту при перемешивании. Затем полученную смесь концентрировали досуха с получением соединения, указанного в названии примера.Example 13
2- [2- (Dimethylamino) ethyl] -5-nitro-1H-benzo [c] pyrimido [5,6,1-kl] phenothiazine-1,3 (2H) dione hydrochloride:

A solution of 200 mg (0.49 mmol) of the compound of Production Example 23 in tetrahydrofuran (15 ml) was stirred at room temperature and 0.5 ml of triethylamine and 200 μl (2.09 mmol) of ethyl chloroformate were successively added. After stirring at room temperature overnight, the reaction mixture was concentrated and extracted with water, a saturated aqueous solution of sodium bicarbonate and dichloromethane. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to dryness. The residue was recrystallized from ethanol to give 104 mg of the free base of the title compound. This product was then suspended in methanol and concentrated hydrochloric acid was added with stirring. Then, the resulting mixture was concentrated to dryness to obtain the compound indicated in the title of the example.

Названное соединение получали с использованием 4-оксо-4,5,6,7-тетрагидро-бензо[b]тиофена и гидрохлорида 2-гидразинобензойной кислоты в качестве исходных соединений и повторением процедур Примеров получения 1,2 и 3 и Примера 2. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.90 (s, 6H), 3.49 (br s, 2H). 4.38 (t, J = 5.6 Hz, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7, 82 (d, J = 9.2 Hz, 1H), 7.96 (t, J = 8.8 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 8.09 ( d, J = 8.4 Hz, 1H), 8.49-8.52 (m, 1H), 8.59-8.62 (m, 1H), 9.72 (br t, 1H)
Example 14
2- [2- (Dimethylamino) ethyl] -1H-pyrimido [5,6,1-jk] thieno [3,2-a] carbazole-1,3 (2H) dione hydrochloride:

The title compound was prepared using 4-oxo-4,5,6,7-tetrahydro-benzo [b] thiophene and 2-hydrazinobenzoic acid hydrochloride as the starting compounds and repeating the procedures of Production Examples 1,2 and 3 and Example 2.

Названное соединение получали согласно процедуре, описанной в Примере 2. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.92 (br s, 6H), 3.44-3.57 (m, 2H), 4.44-4.51 (m, 2H), 7.74 (t, J = 7.6 Hz, 1H), 7.98 (d, J = 5.6 Hz, 1H), 8.13 (dd, J = 0.8; 7.6 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.65 (dd, J = 0, 8; 7.6 Hz, 1H), 8.84 (d, J = 5.6 Hz, 1H), 9.53 (br s, 1H)
Example 15
2,3-dihydro-9- [2- (dimethylamino) ethyl] -4H hydrochloride, 8H-pyrano [3,2-c] pyrimido [5,6,1-jk] carbazole-4,8,10 (9H) Trion:

The named compound was obtained according to the procedure described in Example 2.

FAB mass spectrometry m / z: 378 ([M + H] ⁺ ).

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.88 (s, 6H), 2.99 (t, J = 6.4 Hz, 2H), 3.46 (br. s, 2H), 4.40 (br t, J = 5.6 Hz, 2H), 4.89 (t, J = 6.4 Hz, 2H), 7.73 (t, J = 7.6 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 8.42 (d, J = 7.6 Hz, 1H), 9.68 (br s, 1H)
Elemental analysis: as C ₂₁ H ₁₉ N ₃ O ₄ • HCl • 1.25H ₂ O
calculated: C 57.80; H 5.20; N, 9.63;
Found: C, 57.99; H 5.07; N, 9.69.

Названное соединение получали с использованием процедур Примера 2.Example 16
9- [2- (Dimethylamino) ethyl] -4H hydrochloride, 8H-pyrano [3,2-c] pyrimido [5,6,1-jk] carbazole-4,8,10 (9H) trion:

The named compound was obtained using the procedures of Example 2.

FAB mass spectrometry m / z: 376 ([M + H] ⁺ ).

(м.д.): 2,89 (с, 6H), 3,46 (шир. с, 2H), 4,43 (шир. т, J= 5,6 Гц, 2H), 6,55 (д, J=6,0 Гц, 1H), 7,83 (т, J=7,6 Гц, 1H), 8,23 (дд, J=0,8, 7,6 Гц, 1H), 8,34 (д, J=8,8 Гц, 1H), 8,48 (д, J=8,8 Гц, 1H), 8,54 (д, J=6,0 Гц, 1H), 8,65 (дд, J=0,8; 7,6 Гц, 1H), 9,52 (шир. с, 1H)
Пример 17
Гидрохлорид 9-[2-(диметиламино)этил] -1H-фуро[3,2-а]пиримидо [5,6,1-jk] карбазол-1,3(2H)-диона:

Соединение заголовка получали с использованием 4-оксо-4,5,6,7-тетрагидробензо[b] фурана и гидрохлорида 2-гидразинобензойной кислоты и повторением процедур Примеров получения 1, 2 и 3 и Примера 2. ¹ H-NMR (DMSO-d ₆ ):

(ppm): 2.89 (s, 6H), 3.46 (br s, 2H), 4.43 (br t, J = 5.6 Hz, 2H), 6.55 (d , J = 6.0 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 8.23 (dd, J = 0.8, 7.6 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.48 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 6.0 Hz, 1H), 8.65 (dd , J = 0.8; 7.6 Hz, 1H), 9.52 (br s, 1H)
Example 17
9- [2- (Dimethylamino) ethyl] -1H-furo [3,2-a] pyrimido [5,6,1-jk] carbazole-1,3 (2H) dione hydrochloride:

The title compound was prepared using 4-oxo-4,5,6,7-tetrahydrobenzo [b] furan and 2-hydrazinobenzoic acid hydrochloride and repeating the procedures of Production Examples 1, 2 and 3 and Example 2.

Соединение заголовка получали с использованием в качестве исходных соединений α -тетралона и гидрохлорида 2-гидразинобензойной кислоты и повторением процедур Примеров получения 1, 2 и 3 и Примера 2. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.91 (br s, 6H), 3.40-3.55 (m, 2H), 4.41-4.51 (m, 2H), 7.72 (t, J = 7.6 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 8.4 Hz , 1H), 8.09 (d, J = 7.6 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H ), 8.61 (d, J = 7.6 Hz, 1H), 9.46 (br s, 1H)
Example 18
2- [2- (Dimethylamino) ethyl] -1H-benzo [a] pyrimido [5,6,1-jk] carbazole-1,3 (2H) dione hydrochloride:

The title compound was prepared using α-tetralone and 2-hydrazinobenzoic acid hydrochloride as starting materials and repeating the procedures of Production Examples 1, 2 and 3 and Example 2.

Соединение заголовка получали реакцией соединения Примера получения 2 с N, N-диметил-1,3-пропандиамином согласно процедуре, описанной в Примере получения 3 и Примере 1. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.89 (s, 6H), 4.49 (br s, 2H), 4.49 (t, J = 5.5 Hz, 2H), 7.64-7.71 (m, 2H), 7.74 (t, J = 8.0 Hz, 1H), 8.11-8.18 (m, 3H), 8.44 (d, J = 8.3 Hz, 1H), 8.66 (d, J = 8.0 Hz, 1H), 9.59 (br s, 1H), 9.76 (d, J = 8, 3 Hz, 1H)
Elemental analysis: as C ₂₂ H ₁₉ N ₃ O ₂ • HCl • 0.2H ₂ O
calculated: C, 66.48; H 5.17; N, 10.57;
Found: C, 66.47; H 5.20; N 10.51
Example 19
5- [3- (Dimethylamino) propyl] -4H-benzo [s] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

The title compound was obtained by the reaction of the compound of Production Example 2 with N, N-dimethyl-1,3-propanediamine according to the procedure described in Production Example 3 and Example 1.

FAB mass spectrometry m / z: 372 ([M + H] ⁺ ).

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.03-2.13 (m, 2H), 74, s (6H), 3.19 (t, J = 8 , 0 Hz, 2H), 4.12 (t, J = 6.0 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 9.6 Hz, 1H), 8.58 (d, J = 9.6 Hz, 1H), 8.80 (t, J = 8.4 Hz, 1H) 8.94 (d, J = 8.0 Hz, 1H); 9.69 (br s, 1H)
Elemental analysis: as C ₂₃ H ₂₁ N ₃ O ₂ • HCl • 0.3H ₂ O
calculated: C, 66.84; H 5.51; N, 10.17;
Found: C, 66.75; H 5.45; N, 10.03.

Соединение заголовка получали с использованием 2 - инданона и гидрохлорида 2-гидразинобензойной кислоты и повторением процедур Примеров получения 1 и 3 и Примера 2.Example 20
2- [2- (Dimethylamino) ethyl] -1H hydrochloride, 11H-indeno [1 ', 2': 4,5] pyrrolo [3,2,1-ij] quinazolin-1,3 (2H) -dione:

The title compound was prepared using 2-indanone and 2-hydrazinobenzoic acid hydrochloride and repeating the procedures of Production Examples 1 and 3 and Example 2.

(м.д.):3,02 (с,6H), 3,53 (т, J=5,8 Гц, 2H), 4,10 (с, 2H), 4,50 (т, J=5,8 Гц, 2H), 7,28 (дт, J=1,2; 7,6 Гц, 1H), 7,41 (дт, J= 1,0; 7,6 Гц, 1H), 7,56-7,59 (м, 1H), 7,62 (т, J=7,7 Гц, 1H), 7,76-7,79 (м, 1H), 8,02 (дд, J=0,8; 7,7 Гц, 1H), 8,25 (дд, J=0,8; 7,7 Гц, 1H)
Пример 21
Гидрохлорид 7-[2-(диметиламино)этил] -6H,14H-бензо[а]пиримидо[5,6,1-de] акридин-6,8,14(7H)-триона:

Названное соединение получали согласно процедуре, описанной в Примере 2. ¹ H-NMR (DMSO-d ₆ ):

(ppm): 3.02 (s, 6H), 3.53 (t, J = 5.8 Hz, 2H), 4.10 (s, 2H), 4.50 (t, J = 5 , 8 Hz, 2H), 7.28 (dt, J = 1.2; 7.6 Hz, 1H), 7.41 (dt, J = 1.0; 7.6 Hz, 1H), 7.56 -7.59 (m, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.76-7.79 (m, 1H), 8.02 (dd, J = 0.8 ; 7.7 Hz, 1H), 8.25 (dd, J = 0.8; 7.7 Hz, 1H)
Example 21
7- [2- (Dimethylamino) ethyl] -6H hydrochloride, 14H-benzo [a] pyrimido [5,6,1-de] acridine-6,8,14 (7H) -trione:

The named compound was obtained according to the procedure described in Example 2.

Названное соединение получали с использованием 6-метокси- β -тетралона и гидрохлорида 2-гидразинобензойной кислоты и повторением процедур Примеров получения 24 и 3 и Примера 2. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.91 (br s, 6H), 3.50-3.56 (m, 2H), 4.49 (t, J = 5.7 Hz, 2H), 7.64-7.69 (m, 1H), 7.77-7.82 (m, 1H), 7.87-7.92 (m, 1H), 7, 98-8.03 (m, 1H), 8.37-8.40 (m, 1H), 8.43-8.46 (m, 1H), 8.63 (dd, J = 0.5; 8 , 8 Hz, 1H), 9.26 (s, 1H), 9.81 (dd, J = 0.7, 8.6 Hz, 1H), 10.04 (br s, 1H)
Example 22
5- [2- (Dimethylamino) ethyl] -11-methoxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

The title compound was prepared using 6-methoxy-β-tetralone and 2-hydrazinobenzoic acid hydrochloride and repeating the procedures of Production Examples 24 and 3 and Example 2.

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.93 (d, J = 4.6 Hz, 6H), 3.47-3.54 (m, 2H), 3, 94 (s, 3H), 4.39-4.45 (m, 2H), 7.46 (dd, J = 2.2; 9.0 Hz, 1H), 7.62 (d, J = 2, 2 Hz, 1H), 7.78 (t, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 9.0 Hz , 1H), 8.59 (d, J = 9.0 Hz, 1H), 8.78 (d, J = 9.0 Hz, 1H), 9.01 (d, J = 8.4 Hz, 1H ), 9.16 (br s, 1H)
Elemental analysis: as C ₂₃ H ₂₁ N ₃ O ₃ • HCl • 1.5H ₂ O
calculated: C 61.26; H 5.59; N, 9.32;
Found: C, 61.08; H 5.46; N, 9.40.

Названное соединение получали с использованием 5-метокси- β -тетралона и гидрохлорида 2-гидразинобензойной кислоты и повторением процедур Примеров получения 1, 2 и 3 и Примера 2.Example 23
5- [2- (Dimethylamino) ethyl] -10-methoxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

The title compound was prepared using 5-methoxy-β-tetralone and 2-hydrazinobenzoic acid hydrochloride and repeating the procedures of Production Examples 1, 2 and 3 and Example 2.

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.89 (s, 6H), 3.44-3.51 (m, 2H), 4.04 (s, 3H), 4.40 (t, J = 6.2 Hz, 2H), 7.12 (d, J = 8.2 Hz, 1H), 7.72 (t, J = 8.5 Hz, 1H), 7, 73 (dt, J = 3.4; 8.2 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.41 (d, J = 8.5 Hz, 1H), 8.52 (dd, J = 1.0; 8.5 Hz, 1H), 8.88 (d, J = 8.5 Hz, 1H ), 9.93 (br s, 1H)
Elemental analysis: as C ₂₃ H ₂₁ N ₃ O ₃ • HCl • 1.3H ₂ O
calculated: C, 61.76; H 5.54; N, 9.40;
Found: C, 61.89; H 5.32; N, 9.45.

Названное соединение получали согласно способу, описанному в Примере 2.Example 24
Dihydrochloride of 2- [2- (dimethylamino) ethyl] -1H-benzo [b] pyrimido- [1,6,5-lm] -4-azacarbazole-1,3 (2H) -dione:

The named compound was obtained according to the method described in Example 2.

Названное соединение получали согласно способу, описанному в Примере 2. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.90 (s, 6H), 3.47-3.55 (m, 2H), 4.48 (t, J = 6 , 3 Hz, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.86-7.95 (m, 3H), 8.36-8.44 (m, 3H), 9 24-9.29 (m, 1H); 10.41 (br s, 1H)
Example 25
1,2-dihydro-9- [2- (dimethylamino) ethyl] -4H hydrochloride, 8H-pyrano [3,4-c] pyrimido [5,6,1-jk] carbazole-4,8,10 (9H) Trion:

The named compound was obtained according to the method described in Example 2.

Названное соединение получали с использованием 7-метокси- β -тетралона и гидрохлорида 2-гидразинобензойной кислоты и повторением процедур Примеров 1,2 и 3 и Примера 2. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.89 (s, 6H), 3.47 (t, J = 6.0 Hz, 2H), 3.64 (t, J = 6.0 Hz, 2H), 4.38 (t, J = 6.0 Hz, 2H), 4.68 (t, J = 6.0 Hz, 2H), 7.73 (t, J = 7.6 Hz, 1H), 8.15 (t, J = 7.6 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.44 (d, J = 8, 8 Hz, 1H), 8.55 (d, J = 7.6 Hz, 1H), 9.82 (br s, 1H)
Example 26
5- [2- (Dimethylamino) ethyl] -12-methoxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

The title compound was prepared using 7-methoxy-β-tetralone and 2-hydrazinobenzoic acid hydrochloride and repeating the procedures of Examples 1,2 and 3 and Example 2.

304 мг (1,91 ммоль) 3-амино-2-нафтола, 477 мг (1,81 ммоль) метил 2-хлор-3,5-динитрбензоата и 178 мг (2,17 ммоль) ацетата натрия суспендировали в смеси воды (5 мл) с этанолом (10 мл) и нагревали с обратным холодильником в течение 7 часов. После добавления 3 мл 2 н. водного раствора гидроксида натрия реакционную смесь нагревали с обратным холодильником еще в течение 2,5 часов и затем давали ей остыть до комнатной температуры. После добавления 10 мл 1 н. соляной кислоты полученный таким образом осадок извлекали фильтрованием и промывали последовательно водой, 1 н. соляной кислотой и этанолом с получением 430 мг 3-нитро-12H-бензо[b] феноксазин-1 карбоновой кислоты. Затем этот продукт обрабатывали согласно способам, описанным в Примере получения 23 и Примере 13, с получением соединения, указанного в названии примера. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.85 (br s, 6H), 3.35-3.46 (m, 2H), 4.08 (s, 3H ), 4.39 (br s, 2H), 7.32 (dd, J = 2.2; 8.8 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7 99 (d, J = 1.7 Hz, 1H), 8.09-8.19 (m, 3H), 8.48 (d, J = 8.8 Hz, 1H), 8.97 (d, J = 7.8 Hz, 1H), 9.25 (br s, 1H)
Example 27
2- [2- (Dimethylamino) ethyl] -5-nitro-1H-benzo [b] pyrimido [5,6,1-jk] phenoxazine-1,3 (2H) dione hydrochloride:

304 mg (1.91 mmol) of 3-amino-2-naphthol, 477 mg (1.81 mmol) of methyl 2-chloro-3,5-dinitrbenzoate and 178 mg (2.17 mmol) of sodium acetate were suspended in a mixture of water ( 5 ml) with ethanol (10 ml) and heated under reflux for 7 hours. After adding 3 ml of 2 N. an aqueous solution of sodium hydroxide, the reaction mixture was heated under reflux for another 2.5 hours and then allowed to cool to room temperature. After adding 10 ml of 1 N. hydrochloric acid, the precipitate thus obtained was recovered by filtration and washed successively with water, 1N. hydrochloric acid and ethanol to obtain 430 mg of 3-nitro-12H-benzo [b] phenoxazine-1 carboxylic acid. Then this product was processed according to the methods described in Production Example 23 and Example 13 to obtain the compound indicated in the title of the example.

(м.д.): 2,89 (с, 6H), 3,45 (т, J=5,2 Гц, 2H), 4,40 (т, J=5,2 Гц, 2H), 7,47 (т, J=8,0 Гц, 1H), 7,52 (т, J=8,0 Гц, 1H), 7,69 (с, 1H), 7,86 (д, J=6,8 Гц, 1H), 7,88 (д, J=8,0 Гц, 1H), 8,19 (д, J=2,4 Гц, 1H), 8,34 (д, J=2,4 Гц, 1H), 9,05 (с, 1H), 9,82 (шир. с, 1H)
Пример 28
Гидрохлорид 2-хлор-5-[2-(диметиламино)этил] -4H-бензо[с] пиримидо [5,6,1-jk]карбазол-4,6(5H)-диона:

Названное соединение получали с использованием в качестве исходных соединений β -тетралона и гидрохлорида 5-хлор-2-гидразинобензойной кислоты и повторением процедур Примеров получения 1,2 и 3 и Примера 2. ¹ H-NMR (DMSO-d ₆ ):

(ppm): 2.89 (s, 6H), 3.45 (t, J = 5.2 Hz, 2H), 4.40 (t, J = 5.2 Hz, 2H), 7, 47 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 9.05 (s, 1H), 9.82 (br s, 1H)
Example 28
2-chloro-5- [2- (dimethylamino) ethyl] -4H-benzo [s] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

The named compound was obtained using β-tetralone and 5-chloro-2-hydrazinobenzoic acid hydrochloride as starting compounds and the procedures of Production Examples 1,2 and 3 and Example 2 were repeated.

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.89 (s, 6H), 3.39-3.53 (m, 2H), 4.38-4.48 (m , 2H), 7.68-7.75 (m, 1H), 7.81-7.89 (m, 1H), 8.13 (d, J = 1.6 Hz, 1H), 8.22 ( d, J = 8.4 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.94 (d, J = 8.4 Hz, 1H), 9.14 (d, J = 1.6 Hz, 1H), 9.46 (br s, 1H)
Elemental analysis: as C ₂₂ H ₁₈ N ₃ O ₂ Cl • HCl • 1.75H ₂ O
calculated: C 57.46; H 4.93; N, 9.14;
Found: C, 57.65; H 4.57; N, 8.76.

Названное соединение получали омылением сложного эфира соединения Примера получения 20 и затем повторением процедур Примера получения 3 и Примера 2.Example 29
9- [2- (Dimethylamino) ethyl] -8H-pyrido [4,3-c] pyrimido [5,6,1-jk] carbazole-1,8,10 (2H, 9H) trion hydrochloride:

The title compound was obtained by saponification of the ester of the compound of Production Example 20 and then repeating the procedures of Production Example 3 and Example 2.

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.90 (br s, 6H), 3.43-3.53 (m, 2H), 4.40-4.46 (m, 2H), 6.80-6.83 (m, 1H), 7.34-7.38 (m, 1H), 7.73 (t, J = 7.9 Hz, 1H), 8, 01 (d, J = 8.9 Hz, 1H), 8.18 (dd, J = 0.9, 7.9 Hz, 1H), 8.89 (d, J = 8.9 Hz, 1H), 9.52 (br s, 1H), 9.91 (dd, J = 0.9; 7.9 Hz, 1H), 11.67-11.71 (m, 1H)
Elemental analysis: as C ₂₁ H ₁₈ N ₄ O ₃ • HCl • 1.3H ₂ O
calculated: C, 58.08; H 5.01; N, 12.90;
Found: C, 57.94; H 4.78; N, 12.72.

Названное соединение получали согласно способу, описанному в Примере получения 2.Example 30
5- [2- (Dimethylamino) ethyl] -4H-quino [4 ', 3', -4,5] pyrrolo [3,2,1-ij] quinazolin-4,6 (5H) dione hydrochloride:

The named compound was obtained according to the method described in Production Example 2.

FAB mass spectrometry m / z: 359 ([M + H] ⁺ ) ⁺ ] /
¹ H-NMR (DMSO-d ₆ + D ₂ O): δ (ppm): 2.94 (s, 6H), 3.54 (br t, J = 5.6 Hz, 2H), 4.47 (br t, J = 5.6 Hz, 2H), 7.89 (t, J = 7.6 Hz, 1H), 7.91-7.99 (m, 2H), 8.30 -8.37 (m, 2H), 8.89-8.95 (m, 1H), 9.16 (d, J = 7.6 Hz, 1H), 9.97 (s, 1H)
Elemental analysis: as C ₂₁ H ₁₈ N ₄ O ₂ • 2HCl • 0.5H ₂ O
calculated: C 57.28; H 4.81; N, 12.72;
Found: C, 57.28; H 4.97; N, 12.60.

268 мг (0,641 ммоль) свободного основания соединения Примера 27 растворяли в уксусной кислоте (10 мл) и добавляли 10% палладий на угле. Затем проводили каталитическое восстановление при комнатной температуре в атмосфере азота. После отфильтровывания палладия на угле через целит фильтрат концентрировали. Затем к нему добавляли воду и насыщенный водный раствор бикарбоната натрия и полученную смесь перемешивали при комнатной температуре. Осадок извлекали фильтрованием, промывали водой и суспендировали в метаноле. После добавления концентрированной соляной кислоты полученную смесь перемешивали при комнатной температуре. Таким образом ее превращали в гомогенный раствор и затем образовывался осадок. Этот осадок извлекали фильтрованием с получением 179 мг соединения указанного в названии примера.Example 31
5-amino-2- [2- (dimethylamino) ethyl] -1H-benzo [b] pyrimido [5,6,1-kl] phenoxazine-1,3 (2H) dione hydrochloride:

268 mg (0.641 mmol) of the free base of the compound of Example 27 was dissolved in acetic acid (10 ml) and 10% palladium on carbon was added. Then, a catalytic reduction was carried out at room temperature in a nitrogen atmosphere. After filtering off the palladium on carbon through celite, the filtrate was concentrated. Then, water and a saturated aqueous sodium bicarbonate solution were added thereto, and the resulting mixture was stirred at room temperature. The precipitate was recovered by filtration, washed with water and suspended in methanol. After adding concentrated hydrochloric acid, the resulting mixture was stirred at room temperature. Thus, it was turned into a homogeneous solution and then a precipitate formed. This precipitate was recovered by filtration to obtain 179 mg of the title compound.

Названное соединение получали с использованием 8-метокси- β -тетралона и гидрохлорида 2-гидразинобензойной кислоты в качестве исходных соединений и повторением процедур Примеров получения 1,2 и 3 и Примера 2. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.89 (s, 6H), 3.43 (t, J = 5.6 Hz, 2H), 4.34 (t, J = 5.6 Hz, 2H), 6.76 (s, 1H), 6.96 (s, 1H), 7.38-7.48 (m, 2H), 7.59 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 9.15 (s, 1H), 9.65 (br s, 1H )
Example 32
5- [2- (Dimethylamino) ethyl] -13-methoxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride;

The title compound was prepared using 8-methoxy-β-tetralone and 2-hydrazinobenzoic acid hydrochloride as the starting compounds and repeating the procedures of Production Examples 1,2 and 3 and Example 2.

¹ H-NMR (DMSO-d ₆ + D ₂ O): δ (ppm): 2.91 (br s, 6H), 3.40-3.53 (m, 2H), 4.23 (s, 3H), 4.40-4.49 (m, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.61 (, J = 8.0 Hz, 1H), 7.72-7.79 (m, 2H), 8.15 (d, J = 8.0 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.82 (d , J = 8.8 Hz, 1H), 9.09 (d, J = 8.0 Hz, 1H), 9.35 (br s, 1H)
Elemental analysis: as C ₂₃ H ₂₁ N ₃ O ₃ • HCl • 0.65H ₂ O
calculated: C, 63.42; H 5.39; N, 9.65;
Found: C, 63.31; H 5.14; N, 9.68.

300 мг (1,1 ммоль) соединения Примера получения 21 растворяли в смеси тетрагидрофуран (10 мл) - метанол (10 мл). После добавления 5 мл 1 н. гидроксида натрия полученную смесь нагревали с обратным холодильником в течение 1 часа. Затем 7H-пиридо[4,3-с] карбазол-8-карбоновую кислоту, выделенную общепринятым способом, растворяли в диметилформамиде (40 мл) и добавляли к раствору 360 мг (2,2 ммоль) N,N'-карбонилдиимидазола. После перемешивания при комнатной температуре в течение 30 минут добавляли 0,48 мл (4,4 ммоль) N, N-диметилэтилендиамина и полученную смесь перемешивали в течение ночи. После концентрирования ее экстрагировали добавлением воды и этилацетата. Органический слой собирали, промывали последовательно насыщенным водным раствором бикарбоната натрия и водой и сушили над безводным сульфатом магния. После концентрирования остаток очищали колоночной хроматографией на силикагеле с получением 250 мг N-[2-(диметиламино)этил]-7H-пиридо[4,3-с]карбазол-8- карбоксамида. Затем этот продукт использовали в реакции и обрабатывали, как описано в Примере 2, с получением 110 мг соединения, указанного в названии примера.Example 33
9- [2- (Dimethylamino) ethyl] -8H-pyrido [4,3, -c] pyrimido [5,6,1-jk] carbazole-8,10 (9H) dione dihydrochloride;

300 mg (1.1 mmol) of the compound of Production Example 21 was dissolved in a mixture of tetrahydrofuran (10 ml) - methanol (10 ml). After adding 5 ml of 1 N. sodium hydroxide, the resulting mixture was heated under reflux for 1 hour. Then, 7H-pyrido [4,3-c] carbazole-8-carboxylic acid, isolated by the conventional method, was dissolved in dimethylformamide (40 ml) and 360 mg (2.2 mmol) of N, N'-carbonyldiimidazole was added to the solution. After stirring at room temperature for 30 minutes, 0.48 ml (4.4 mmol) of N, N-dimethylethylenediamine was added, and the resulting mixture was stirred overnight. After concentration, it was extracted with water and ethyl acetate. The organic layer was collected, washed successively with saturated aqueous sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography to obtain 250 mg of N- [2- (dimethylamino) ethyl] -7H-pyrido [4,3-c] carbazole-8-carboxamide. Then this product was used in the reaction and processed as described in Example 2 to give 110 mg of the compound indicated in the title of the example.

Melting point: stains from approximately 270 ^o C and decomposes at 279 ^o C.

Соединение заголовка получали реакцией соединения Примера получения 2 с N, N-диметил-1,4-бутандиамином согласно способам, описанным в Примере получения 3 и Примере 1. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.89-2.93 (m, 6H), 3.49-3.54 (m, 2H), 4.46 (t , J = 6.0 Hz, 2H), 7.85 (t, J = 7.6 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.40-8.44 (m, 2H), 8.79 (d, J = 6.4 Hz, 1H), 9.04 (d, J = 9.2 Hz, 1H), 9.23 (d, J = 7.6 Hz , 1H), 10.10 (br s, 1H), 10.44 (s, 1H)
Elemental analysis: C ₂₁ H ₁₈ N ₄ O ₂ • 2HCl • 2H ₂ O
calculated: C, 53.97; H 5.18; N, 11.99;
Found: C, 54.11; H 4.99; N 11.99
Example 34 Hydrochloride
5- [4- (dimethylamino) butyl] -4H-benzo [s] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione:

The title compound was obtained by the reaction of the compound of Production Example 2 with N, N-dimethyl-1,4-butanediamine according to the methods described in Production Example 3 and Example 1.

FAB mass spectrometry m / z: 386 ([M + H] ⁺ ).

(м.д.): 1,68-1,85 (м, 4H), 2,74 (с, 6H), 3,09 (шир. т, J= 6,4 Гц, 2H), 4,10 (шир. т, J=6,4 Гц, 2H), 7,64-7,70 (м, 1H), 7,75 (т, J=7,6 Гц, 1H), 7,79-7,85 (м, 1H), 8,11 (д, J=7,6 Гц, 1H), 8,16-8,24 (м, 2H), 8,62 (д, J=8,8 Гц, 1H), 8,83 (д, J=8,4 Гц, 1H), 8,97 (д, J=7,6 Гц, 1H), 9,99 (шир. с, 1H)
Элементный анализ: C₂₄H₂₃N₃O₂•HCl•0,5H₂O
рассчитано: C 66,89; H 5,85; N 9,75;
найдено: C 66,54; H 5,71; N 9,66. ¹ H-NMR (DMSO-d ₆ ):

(ppm): 1.68-1.85 (m, 4H), 2.74 (s, 6H), 3.09 (br t, J = 6.4 Hz, 2H), 4.10 (br t, J = 6.4 Hz, 2H), 7.64-7.70 (m, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.79-7, 85 (m, 1H), 8.11 (d, J = 7.6 Hz, 1H), 8.16-8.24 (m, 2H), 8.62 (d, J = 8.8 Hz, 1H ), 8.83 (d, J = 8.4 Hz, 1H), 8.97 (d, J = 7.6 Hz, 1H), 9.99 (br s, 1H)
Elemental analysis: C ₂₄ H ₂₃ N ₃ O ₂ • HCl • 0.5H ₂ O
calculated: C, 66.89; H 5.85; N, 9.75;
Found: C, 66.54; H 5.71; N, 9.66.

Названное соединение получали по способу, описанному в Примере 2.Example 35
11-cyano-5- [2- (dimethylamino) ethyl] -4H-benzo [s] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

The named compound was obtained by the method described in Example 2.

Названное соединение получали, как описано в Примере 2. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.93 (s, 6H), 3.48-3.55 (m, 2H), 4.46 (t, J = 5 6 Hz, 2H), 7.83 (t, J = 8.2 Hz, 1H), 8.10 (dd, J = 1.3, 8.9 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.38 (d, J = 8.9 Hz, 1H), 8.79 (d, J = 8.9 Hz, 1H), 8.88 (d, J = 1 , 3 Hz, 1H), 9.04 (d, J = 8.9 Hz, 1H), 9.10 (d, J = 8.2 Hz, 1H)
Example 36
9- [2- (Dimethylamino) ethyl] -8H-pyrido [2,3-c] pyrimido [5,6,1-jk] carbazole-8,10 (9H) dione dihydrochloride:

The named compound was obtained as described in Example 2.

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.92 (s, 3H), 2.93 (s, 3H), 3.46-3.58 (m, 2H), 4.41-4.51 (m, 2H), 7.82 (t, J = 8.0 Hz, 1H), 7.92 (dd, J = 4.8; 8.4 Hz, 1H), 8 21 (d, J = 8.0 Hz, 1H), 8.40 (d, 9.2 Hz, 1H), 8.92 (d, 9.2 Hz, 1H), 9.10 (d, J = 8.0 Hz, 1H), 9.14 (dd, J = 0.8; 4.8 Hz, 1H), 9.47 (dd, J = 0.8; 8.4 Hz, 1H), 9.86 (br s, 1H)
Elemental analysis: C ₂₁ H ₁₈ N ₄ O ₂ • 2HCl • 0.75H ₂ O
calculated: C 56.70; H 4.87; N, 12.59;
Found: C, 56.78; H 4.82; N, 12.36.

Названное соединение получали с использованием β-тетралона и 5-нитро-2-гидразинобензойной кислоты в качестве исходных продуктов и повторением процедур Примеров получения 1,2 и 3 и Примера 2.Example 37
5- [2- (Dimethylamino) ethyl] -2-nitro-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

The named compound was obtained using β-tetralone and 5-nitro-2-hydrazinobenzoic acid as starting materials and by repeating the procedures of Production Examples 1,2 and 3 and Example 2.

Названное соединение получали с использованием β -тетралона и гидрохлорида 2-гидразино-5-метилбензойной кислоты и повторением процедур Примеров получения 1,2 и 3 и Примера 2. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.89 (s, 6H), 3.44-3.52 (m, 2H), 4.45 (t, J = 5 , 2 Hz, 2H), 7.73 (t, J = 8.1 Hz, 1H), 7.90 (t, J = 8.1 Hz, 1H), 8.23 (d, J = 8.1 Hz, 1H), 8.35 (d, J = 9.2 Hz, 1H), 8.63 (d, J = 9.2 Hz, 1H), 8.80 (d, J = 1.8 Hz, 1H), 8.94 (d, J = 8.1 Hz, 1H), 9.64 (d, J = 1.8 Hz, 1H), 9.75 (br s, 1H)
Example 38
5- [2- (Dimethylamino) ethyl] -2-methyl-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

The title compound was prepared using β-tetralone and 2-hydrazino-5-methylbenzoic acid hydrochloride and repeating the procedures of Production Examples 1,2 and 3 and Example 2.

(м.д.): 2,71 (с, 3H), 2,90 (шир. с, 6H), 3,38-3,55 (м, 2H), 4,39-4,46 (м, 2H), 7,66-7,72 (м, 1H), 7,81-7,88 (м, 1H), 7,97-8,00 (м, 1H), 8,18-8,23 (м, 1H), 8,22-8,27 (м, 1H), 8,63 (д, J=9,2 Гц, 1H), 8,88-8,95 (м, 2H)
Элементный анализ: C₂₃H₂₁N₃O₂•HCl•1,5H₂O
рассчитано: C 63,52; H 5,79; N 9,66;
найдено: C 63,63; H 5,48; N 9,70. ¹ H-NMR (DMSO-d ₆ ):

(ppm): 2.71 (s, 3H), 2.90 (br s, 6H), 3.38-3.55 (m, 2H), 4.39-4.46 (m, 2H), 7.66-7.72 (m, 1H), 7.81-7.88 (m, 1H), 7.97-8.00 (m, 1H), 8.18-8.23 ( m, 1H), 8.22-8.27 (m, 1H), 8.63 (d, J = 9.2 Hz, 1H), 8.88-8.95 (m, 2H)
Elemental analysis: C ₂₃ H ₂₁ N ₃ O ₂ • HCl • 1.5H ₂ O
calculated: C, 63.52; H 5.79; N, 9.66;
Found: C, 63.63; H 5.48; N, 9.70.

Названное соединение получали, как описано в Примере 2.Example 39
1,2-dihydro-9- [2- (dimethylamino) ethyl] -8H-pyrido [3,4-c] pyrimido [5,6,1-jk] carbazole-4,8,10 (3H, 9H) hydrochloride Trion:

The named compound was obtained as described in Example 2.

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.88 (br s, 6H), 3.37-3.52 (m, 2H), 3.50-3.64 (m, 4H), 4.36-4.44 (m, 2H), 7.73 (t, J = 7.6 Hz, 1H), 8.11 (br s, 1H), 8.15 ( dd, J = 0.8; 7.6 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8, 57 (dd, J = 0.8; 7.6 Hz, 1H)
Elemental analysis: C ₂₁ H ₂₀ N ₄ O ₃ • HCl • H ₂ O
calculated: C 58.54; H 5.38; N 13.00;
Found: C, 58.50; H 5.49; N, 12.77.

Названное соединение получали, как описано в Примере 2.Example 40
8- [2- (Dimethylamino) ethyl] -7H-1,3-dioxolo [4,5-c] pyrimido [5,6,1-jk] carbazole-7.9 (8H) dione hydrochloride:

The named compound was obtained as described in Example 2.

Названное соединение получали с использованием 6-бром- β -тетралона и гидрохлорида 2-гидразинобензойной кислоты и повторением процедур Примеров получения 1, 2 и 3 и Примера 2. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.90 (br s, 6H), 3.42-3.49 (m, 2H), 4.36-4.42 (m, 2H), 6.35 (s, 2H), 7.29 (d, J = 8.4 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 8.10 (dd, J = 0.8; 7.7 Hz, 1H), 8.27 (dd, J = 0.8; 7.7 Hz, 1H), 9.35 (br s, 1H)
Example 41
11-bromo-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

The title compound was prepared using 6-bromo-β-tetralone and 2-hydrazinobenzoic acid hydrochloride and repeating the procedures of Production Examples 1, 2 and 3 and Example 2.

FAB mass spectrometry m / z: 436 ([M + H] ⁺ ), 438 ([M + 2 + H] ⁺ ).

(м.д.): 2,90 (с, 6H), 3,48 (шир. с, 2H), 4,42 (т, J= 5,6 Гц, 2H), 7,77 (т, J=7,6 Гц, 1H), 7,89 (дд, J = 2,0; 8,8 Гц, 1H), 8,14 (д, J=7,2 Гц, 1H), 8,20 (д, J=8,8 Гц, 1H), 8,47 (д, J=2,0 Гц, 1H), 8,63 (д, J=8,8 Гц, 1H), 8,79 (д, J=9,2 Гц, 1H), 8,97 (д, J=8,0 Гц, 1H), 9,74 (шир. с, 1H)
Элементный анализ: C₂₂H₁₈N₃O₂Br•HCl•0,6H₂O
рассчитано: C 54,64; H 4,21; N 8,69;
найдено: C 54,36; H 3,94; N 8,56. ¹ H-NMR (DMSO-d ₆ ):

(ppm): 2.90 (s, 6H), 3.48 (br s, 2H), 4.42 (t, J = 5.6 Hz, 2H), 7.77 (t, J = 7.6 Hz, 1H), 7.89 (dd, J = 2.0; 8.8 Hz, 1H), 8.14 (d, J = 7.2 Hz, 1H), 8.20 (d , J = 8.8 Hz, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.79 (d, J = 9.2 Hz, 1H), 8.97 (d, J = 8.0 Hz, 1H), 9.74 (br s, 1H)
Elemental analysis: C ₂₂ H ₁₈ N ₃ O ₂ Br • HCl • 0.6H ₂ O
calculated: C 54.64; H 4.21; N, 8.69;
Found: C, 54.36; H 3.94; N, 8.56.

Example 42
2- [2- (Dimethylamino) ethyl] -1H-benzo [b] pyrimido [5,6,1-jk] carbazole-1,3 (2H) dione hydrochloride :.

Названное соединение получали, как описано в Примере 2.

The named compound was obtained as described in Example 2.

FAB mass spectrometry m / z: 358 ([M + H] ⁺ ).

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.90 (br s, 6H), 3.39-3.53 (m, 2H), 4.37-4.48 (m, 2H), 7.60-7.70 (m, 2H), 7.73 (t, J = 7.6 Hz, 1H), 8.13 (dd, J = 0.8; 7.6 Hz, 1H), 8.16-8.20 (m, 1H), 8.21-8.26 (m, 1H), 8.66 (dd, J = 0.8; 7.6 Hz, 1H) 8.86 (s, 1H); 8.93 (s, 1H)
Elemental analysis: C ₂₂ H ₁₉ N ₃ O ₂ • HCl
calculated: C, 67.09; H 5.12; N, 10.67;
Found: C, 66.94; H 5.22; N, 10.65.

Названное соединение получали из соединения Примера 4, как описано в Примере 5.Example 43
5- [2- (Dimethylamino) ethyl] -10,11,12,13-tetrahydro-4H-benzo [b] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

The named compound was obtained from the compound of Example 4, as described in Example 5.

FAB mass spectrometry m / z: 362 ([M + H] ⁺ ).

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 1.79-2.01 (m, 4H), 2.89 (s, 6H), 2.90 (br t, J = 6.0 Hz, 2H), 3.24 (br t, J = 6.0 Hz, 2H), 3.46 (br t, J = 5.6 Hz, 2H), 4.39 (br t, J = 6.0 Hz, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 8.06 (d , J = 8.0 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 8.41 (dd, J = 0.8; 8.0 Hz, 1H), 9.74 (br s, 1H)
Elemental analysis: C ₂₂ H ₂₃ N ₃ O ₂ • HCl • 0.75H ₂ O
calculated: C, 64.23; H 6.25; N, 10.21;
Found: C, 64.35; H 6.20; N, 10.15.

Названное соединение получали, как описано в Примере 2.Example 44
12,13-dihydro-11,11-dimethyl-5- [2- (dimethylamino) ethyl] -4H-benzo [s] pyrimido [5,6,1-jk] carbazole-4,6,10 (5H, hydrochloride 11H) -trione:

The named compound was obtained as described in Example 2.

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 1.20 (s, 6H), 2.13 (t, J = 6.1 Hz, 2H), 2.88 (s, 6H), 3.43 (br s, 2H), 3.52 (t, J = 6.1 Hz, 2H), 4.38 (t, J = 5.7 Hz, 2H), 7.71 ( t, J = 7.4 Hz, 1H), 8.11 (d, J = 7.4 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 7.4 Hz, 1H), 10.08 (br s, 1H)
Elemental analysis: C ₂₄ H ₂₅ N ₃ O ₃ • HCl • H ₂ O
calculated: C, 62.94; H 6.16; N, 9.18;
Found: C, 63.06; H 6.27; N, 9.14.

Названное соединение получали с использованием β тетралона и гидрохлорида 2-гидразино-5-метоксибензойной кислоты и повторением процедур Примеров получения 1,2 и 3 и Примера 2.Example 45
5- [2- (Dimethylamino) ethyl] -2-methoxy-4H-benzo hydrochloride [with pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione:

The title compound was prepared using β tetralone and 2-hydrazino-5-methoxybenzoic acid hydrochloride and repeating the procedures of Production Examples 1,2 and 3 and Example 2.

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.89 (br s, 6H), 3.40-3.52 (m, 2H), 4.03 (s, 3H ), 4.40 (t, J = 6.0 Hz, 2H), 7.60 (d, J = 2.4 Hz, 1H), 7.63-7.70 (m, 1H), 7.76 -7.85 (m, 1H), 8.17 (dd, J = 0.4; 8.4 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.49 ( d, J = 2.4 Hz, 1H), 8.57 (d, J = 8.8 Hz, 1H), 8.84 (dd, J = 0.4; 8.4 Hz, 1H), 9, 57 (br s, 1H)
Elemental analysis: C ₂₃ H ₂₁ N ₃ O ₃ • HCl • H ₂ O
calculated: C, 62.51; H 5.47; N, 9.51;
Found: C, 62.44; H 5.22; N, 9.48.

Соединение Примера 22 нагревали с обратным холодильником в 47% бромистоводородной кислоте. Затем реакционную смесь каталитически восстанавливали при комнатной температуре с использованием палладия на угле в качестве катализатора. Полученный продукт превращали в гидрохлорид общепринятым способом с получением соединения, указанного в названии примера.Example 46
5- [2- (Dimethylamino) ethyl] -11-hydroxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

The compound of Example 22 was heated under reflux in 47% hydrobromic acid. The reaction mixture was then catalytically reduced at room temperature using palladium-carbon as a catalyst. The resulting product was converted to the hydrochloride in a conventional manner to give the compound indicated in the title of the example.

Соединение Примера 37 гидрировали в присутствии катализатора палладия на угле при обычной температуре при атмосферном давлении с получением соединения, указанного в названии примера. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.92 (d, J = 5.5 Hz, 6H), 3.48 (q, J = 5.5 Hz, 2H) 4.41 (t, J = 5.5 Hz, 2H), 7.36-7.42 (m, 2H), 7.73 (t, J = 8.1 Hz, 1H), 8.00 ( d, J = 9.4 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 8.49 (d, J = 8.1 Hz, 1H), 8.71 (d, J = 9.4 Hz, 1H), 8.94 (d, J = 8.1 Hz, 1H), 9.60 (br s, 1H), 10.01 (br s, 1H)
Example 47
2-amino-5- [2- (dimethylamino) ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione dihydrochloride:

The compound of Example 37 was hydrogenated in the presence of a palladium-carbon catalyst at ordinary temperature at atmospheric pressure to obtain the compound indicated in the title of the example.

Соединение Примера получения 24 обрабатывали, как описано в Примере получения 3, с получением N-[2-(диметиламино)этил]-3- (4-метилбензолсульфонамидо)-7H-бензо[с]карбазол-8- карбоксамида. Затем этот продукт реагировал с гидридом натрия и этилхлорформиатом в диметилформамиде при охлаждении льдом с образованием 5-[2-(диметиламино)этил]-11-(N-этоксикарбонил-4 -метилбензолсульфонамидо)-4H-бензо[с] пиримидо[5,6,1-jk] карбазол-4,6(5H)-диона. Затем этот продукт обрабатывали 1 н. водным раствором гидроксида натрия в смеси метанол-тетрагидрофуран (1:1) и затем превращали в гидрохлорид общепринятым способом с последующей перекристаллизацией из этанола с получением соединения, указанного в названии примера. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.89 (d, J = 4.1 Hz, 6H), 3.44-3.51, (m, 2H), 4 40 (t, J = 5.8 Hz, 2H), 7.67 (t, J = 8.2 Hz, 1H), 7.77 (s, 1H), 7.84 (t, J = 8, 2 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.22 (d, J = 9.3 Hz, 1H), 8.57 (d, J = 9.3 Hz , 1H), 8.61 (d, J = 8.2 Hz, 1H), 8.63 (s, 1H), 9.94 (br s, 1H)
Example 48
5- [2- (Dimethylamino) ethyl] -11- (4-methylbenzenesulfonamido) -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

The compound of Production Example 24 was treated as described in Production Example 3 to obtain N- [2- (dimethylamino) ethyl] -3- (4-methylbenzenesulfonamido) -7H-benzo [c] carbazole-8-carboxamide. This product was then reacted with sodium hydride and ethyl chloroformate in dimethylformamide under ice cooling to give 5- [2- (dimethylamino) ethyl] -11- (N-ethoxycarbonyl-4-methylbenzenesulfonamido) -4H-benzo [c] pyrimido [5,6] , 1-jk] carbazole-4,6 (5H) -dione. Then this product was treated with 1 N. an aqueous solution of sodium hydroxide in a mixture of methanol-tetrahydrofuran (1: 1) and then converted into the hydrochloride in a conventional manner, followed by recrystallization from ethanol to obtain the compound indicated in the title of the example.

(м.д.): 2,28 (с, 3H), 2,90 (с, 6H), 3,48 (шир. с, 2H), 4,41 (т, J=5,6 Гц, 2H), 7,33 (д, J=9,2 Гц, 2H), 7,60 (д, J=8,8 Гц, 1H), 7,70-7,78 (м, 3H), 7,82 (с, 1H), 8,09 (д, J=9,2 Гц, 1H), 8,12 (д, J=8,0 Гц, 1H), 8,54 (д, J=8,4 Гц, 1H), 8,76 (д, J =8,4 Гц, 1 H), 8,94 (д, J=8,4 Гц, 1H), 9,56 (шир. с, 1H), 10,68 (с, 1H)
Пример 49
Дигидрохлорид 11-амино-5-[2-(диметиламино) этил] -4H-бензо[с] пиримидо[5,6,1-jk]карбазол-4,6(5H)-диона:

341 мг (0,648 ммоль) свободного основания соединения Примера 48 и 419 мг (4,45 ммоль) фенола нагревали с обратным холодильником в 47% бромистоводородной кислоте (15 мл) в течение 9 часов и 30 минут и затем давали остыть до комнатной температуры. Затем реакционную смесь подщелачивали добавлением к ней насыщенного водного раствора бикарбоната натрия. Затем полученную смесь экстрагировали добавлением к ней этилацетата и тетрагидрофурана. Органический слой промывали последовательно водой и насыщенным водным раствором хлорида натрия и сушили над безводным сульфатом магния. Органический слой концентрировали и полученный остаток перекристаллизовывали из этанола с получением 141 мг свободного основания соединения заголовка. Затем это свободное основание превращали в гидрохлорид общепринятым способом с получением соединения, указанного в названии примера. ¹ H-NMR (DMSO-d ₆ ):

(ppm): 2.28 (s, 3H), 2.90 (s, 6H), 3.48 (br s, 2H), 4.41 (t, J = 5.6 Hz, 2H ), 7.33 (d, J = 9.2 Hz, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.70-7.78 (m, 3H), 7.82 (s, 1H), 8.09 (d, J = 9.2 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.54 (d, J = 8.4 Hz , 1H), 8.76 (d, J = 8.4 Hz, 1 H), 8.94 (d, J = 8.4 Hz, 1H), 9.56 (br s, 1H), 10, 68 (s, 1H)
Example 49
11-amino-5- [2- (dimethylamino) ethyl] -4H-benzo [s] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione dihydrochloride:

341 mg (0.648 mmol) of the free base of the compound of Example 48 and 419 mg (4.45 mmol) of phenol were heated under reflux in 47% hydrobromic acid (15 ml) for 9 hours and 30 minutes and then allowed to cool to room temperature. Then the reaction mixture was made alkaline by adding to it a saturated aqueous solution of sodium bicarbonate. Then, the resulting mixture was extracted by adding ethyl acetate and tetrahydrofuran to it. The organic layer was washed sequentially with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated and the resulting residue was recrystallized from ethanol to give 141 mg of the free base of the title compound. This free base was then converted to the hydrochloride in a conventional manner to give the compound indicated in the title of the example.

4 мл триэтиламина и 2 мл уксусного ангидрида последовательно добавляли к суспензии 141 мг (0,379 ммоль) свободного основания соединения Примера 49 в дихлорметане (20 мл) с перемешиванием при комнатной температуре и перемешивание продолжали в течение 16 часов. После концентрирования к остатку добавляли 30 мл метанола. Затем полученную смесь подщелачивали добавлением к ней водного раствора бикарбоната натрия. Осадок извлекали фильтрованием и промывали водой. Полученное таким образом твердое вещество суспендировали в этаноле и добавляли концентрированную соляную кислоту с перемешиванием при комнатной температуре. После дополнительного добавления метанола и дихлорметана перемешивание продолжали. После концентрирования добавляли этанол и полученную смесь нагревали с обратным холодильником и затем давали ей остыть до комнатной температуры. Осадок извлекали фильтрованием с получением 148 мг соединения, указанного в названии примера.(Free base) ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.22 (s, 6H), 2.55 (t, J = 6.8 Hz, 2H), 4, 14 (t, J = 6.8 Hz, 2H), 5.50-5.53 (m, 2H), 7.06 (d, J = 2.0 Hz, 1H), 7.22 (dd, J = 2.4; 9.2 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 8.03 (d , J = 8.0 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.52 (d, J = 9.2 Hz, 1H), 8.84 (d, J = 7.6 Hz, 1H)
Example 50
11-acetamido-5- [2- (dimethylamino) ethyl] -4H-benzo [s] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

4 ml of triethylamine and 2 ml of acetic anhydride were successively added to a suspension of 141 mg (0.379 mmol) of the free base of the compound of Example 49 in dichloromethane (20 ml) with stirring at room temperature and stirring was continued for 16 hours. After concentration, 30 ml of methanol was added to the residue. Then, the resulting mixture was made alkaline by the addition of an aqueous solution of sodium bicarbonate. The precipitate was recovered by filtration and washed with water. The solid thus obtained was suspended in ethanol, and concentrated hydrochloric acid was added with stirring at room temperature. After additional addition of methanol and dichloromethane, stirring was continued. After concentration, ethanol was added and the resulting mixture was refluxed and then allowed to cool to room temperature. The precipitate was recovered by filtration to obtain 148 mg of the title compound.

FAB mass spectrometry m / z: 415 ([M + H] ⁺ ).

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.13 (s, 3H), 2.90 (s, 3H), 2.91 (s, 3H), 3.44- 3.52 (m, 2H), 4.42 (t, J = 5.6 Hz, 2H), 7.76 (t, J = 8.0 Hz, 1H), 7.89 (dd, J = 1 6; 9.2 Hz, 1H), 8.06-8.14 (m, 2H), 8.52 (d, J = 1.6 Hz, 1H), 8.54 (d, J = 9.2 Hz, 1H), 8.79 (d, J = 8.8 Hz, 1H), 8.98 (d, J = 8.0 Hz, 1H), 9.60 (br s, 1H), 10, 35 (s, 1H)
Elemental analysis: C ₂₄ H ₂₂ N ₄ O ₃ • HCl • 0.6H ₂ O
calculated: C, 62.43; H 5.28; N, 12.13;
Found: C, 62.54; H 5.03; N, 11.82.

Названное соединение получали, как описано в Примере 2.Example 51
5- [2- [N- [2- (Dimethylamino) ethyl] -N-methylamino] ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) - dihydrochloride dione:

The named compound was obtained as described in Example 2.

(м.д.): 2,20 (с, 6H), 2,42 (т, J=7,2 Гц, 2H), 2,45 (с, 3H), 2,63 (т, J=7,2 Гц, 2H), 2,81 (т, J=7,2 Гц, 2H), 4,35 (т, J=7,2 Гц, 2H), 7,59 (т, J=7,8 Гц, 1H), 7,64 (т, J=7,8 Гц, 1H), 7,74 (т, J=7,8 Гц, 1H), 8,01 (д, J=9,2 Гц, 1H), 8,03 (д, J=7,8 Гц, 1H), 8,14 (д, J=7,8 Гц, 1H), 8,56-8,61 (м, 2H), 8,66 (д, J=9,2 Гц, 1H),
Элементный анализ: C₂₅H₂₆N₄O₂•2HCl•0,8H₂O
рассчитано: C 59,83; H 5,78; N 11,17;
найдено: C 59,83; H 6,02; N 11,16.(Free base) ¹ H-NMR (CDCl ₃ ):

(ppm): 2.20 (s, 6H), 2.42 (t, J = 7.2 Hz, 2H), 2.45 (s, 3H), 2.63 (t, J = 7 , 2 Hz, 2H), 2.81 (t, J = 7.2 Hz, 2H), 4.35 (t, J = 7.2 Hz, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.56-8.61 (m, 2H), 8, 66 (d, J = 9.2 Hz, 1H),
Elemental analysis: C ₂₅ H ₂₆ N ₄ O ₂ • 2HCl • 0.8H ₂ O
calculated: C 59.83; H 5.78; N, 11.17;
Found: C, 59.83; H 6.02; N, 11.16.

Названное соединение получали, как описано в Примере 2.Example 52
5- [2- [N- (2-hydroxyethyl) -N-methylamino] ethyl] -4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

The named compound was obtained as described in Example 2.

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.93 (s, 3H), 3.14-3.80 (m, 2H), 3.71-3.80 (m , 2H), 4.40-4.49 (m, 2H), 5.33-5.39 (m, 1H), 7.64-7.70 (m, 1H), 7.73-7.86 (m, 2H), 8.10-8.26 (m, 3H), 8.59-8.65 (m, 1H), 8.83-8.89 (m, 1H), 9.00-9 , 04 (m, 1H), 9.60 (br s, 1H)
Elemental analysis: C ₂₃ H ₂₁ N ₃ O ₃ • HCl • 1.1H ₂ O
calculated: C, 62.26; H 5.25; N, 9.47;
Found: C, 62.08; H 5.55; N, 9.47.

Названное соединение получали обработкой соединения Примера 45, как описано в Примере 46.Example 53
5- [2- (Dimethylamino) ethyl] -2-hydroxy-4H-benzo [c] pyrimido [5,6,1-jk] carbazole-4,6 (5H) dione hydrochloride:

The title compound was obtained by treating the compound of Example 45 as described in Example 46.

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.89 (br s, 6H), 3.39-3.54 (m, 2H), 4.32-4.46 (m, 2H), 7.53-7.56 (m, 1H), 7.65-7.71 (m, 1H), 7.81-7.87 (m, 1H), 8.19 (d , J = 8.0 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.35-8.39 (m, 1H), 8.60 (d, J = 8, 8 Hz, 1H), 8.73 (d, J = 8.0 Hz, 1H), 9.29-9.39 (br 1H), 10.25 (s, 1H)
Elemental analysis: C ₂₂ H ₁₉ N ₃ O ₃ • HCl • H ₂ O
calculated: C, 61.76; H 5.18; N, 9.82;
Found: C, 6.92; H 4.90; N, 9.84.

Названное соединение получали с использованием метокси-1- тетралона и гидрохлорида 2-гидразинобензойной кислоты и повторением процедуры Примера 18.Example 54
2- [2- (Dimethylamino) ethyl] -9-methoxy-1H-benzo [a] pyrimido [5,6,1-jk] carbazole-1,3 (2H) dione hydrochloride:

The title compound was prepared using methoxy-1-tetralone and 2-hydrazinobenzoic acid hydrochloride and repeating the procedure of Example 18.

(м.д.): 2,92 (с, 6H), 3,46-3,55 (м, 2H), 4,02 (с, 3H), 4,42-4,46 (м, 2H), 7,16 (д, J=7,1 Гц, 1H), 7,60 (т, J=7,1 Гц, 1H), 7,73 (т, J=7,1 Гц, 1H), 8,12 (д, J=7,1 Гц, 1H), 8,34-8,44 (м, 2H), 8,63 (д, J=7,1 Гц, 1H), 9,28 (д, J=9,2 Гц, 1H), 9,78 (шир. с, 1H)
Пример 55
Дигидрохлорид 9-[2-(1-пирролидинил)этил] -8H-пиридо[2,3-с] пиримидо[5,6,1-jk]карбазол-8,10 (9H)-диона:

Названное соединение получали, как описано в Примере 36. ¹ H-NMR (DMSO-d ₆ ):

(ppm): 2.92 (s, 6H), 3.46-3.55 (m, 2H), 4.02 (s, 3H), 4.42-4.46 (m, 2H) 7.16 (d, J = 7.1 Hz, 1H), 7.60 (t, J = 7.1 Hz, 1H), 7.73 (t, J = 7.1 Hz, 1H), 8 12 (d, J = 7.1 Hz, 1H), 8.34-8.44 (m, 2H), 8.63 (d, J = 7.1 Hz, 1H), 9.28 (d, J = 9.2 Hz, 1H), 9.78 (br s, 1H)
Example 55
9- [2- (1-Pyrrolidinyl) ethyl] -8H-pyrido [2,3-c] pyrimido [5,6,1-jk] carbazole-8,10 (9H) dione dihydrochloride:

The named compound was obtained as described in Example 36.

Названное соединение получали, как описано в Примере 36. ¹ H-NMR (DMSO-d ₆ + D ₂ O): δ (ppm): 1.84-1.94 (m, 2H), 2.01-2.13 (m, 2H), 3 , 13-3.25 (m, 2H), 3.57-3.64 (m, 2H), 3.65-3.74 (m, 2H), 4.43-4.49 (m, 2H) 7.85 (t, J = 7.6 Hz, 1H), 7.94 (dd, J = 4.4, 8.4 Hz, 1H), 8.23 (d, J = 7.6 Hz, 1H), 8.37 (d, J = 9.2 Hz, 1H), 8.92 (d, J = 9.2 Hz, 1H), 9.05 (d, J = 7.6 Hz, 1H) 9.12 (dd, J = 1.6; 4.4 Hz, 1H); 9.40-9.45 (m, 1H)
Example 56
9- [2- (Dimethylamino) ethyl] -13-fluoro-8H-pyrido [2,3-c] pyrimido [5,6,1-jk] carbazole-8,10 (9H) dione dihydrochloride:

The named compound was obtained as described in Example 36.

Названное соединение получали, как описано в Примере 36. ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.92 (s, 3H), 2.93 (s, 3H), 3.47-3.55 (m, 2H), 4.41-4.47 (m, 2H), 7.69 (dd, J = 8.4; 12.0 Hz, 1H), 7.93 (dd, J = 4.4; 8.4 Hz, 1H), 8.29 (dd, J = 4.4; 8.4 Hz, 1H), 8.45 (d, J = 9.2 Hz, 1H), 8.97 (d, J = 9.2 Hz, 1H), 9.10-9.15 (m, 1H), 9.25-9.31 (m, 1H)
Example 57
9- [2- (Dimethylamino) ethyl] -3-methyl-8H-pyrido [2,3-c] pyrimido [5,6,1-jk] carbazole-8,10 (9H) dione dihydrochloride:

The named compound was obtained as described in Example 36.

-карболин-6,8(7H)-дион:

1,06 г (3,1 ммоль) соединения Примера получения 25 растворяли в смеси метанола (20 мл) с тетрагидрофураном (20 мл). После добавления к раствору 1 н. водного раствора гидроксида натрия (10 мл) полученную смесь нагревали с обратным холодильником в течение 1 часа и затем ей давали остыть. Затем к ней добавляли 1 н. водный раствор соляной кислоты (10 мл) и растворитель отгоняли. К остатку добавляли N,N-диметилформамид (50 мл). Далее добавляли 770 мг (4 ммоль) гидрохлорида 1-этил-3-(3-диметиламинопропил) карбодиимида, 540 мг (4 ммоль) 1-гидроксибензотриазола и 0,4 мл (3,7 ммоль) N,N-диметилэтилендиамина и полученную смесь перемешивали при комнатной температуре в течение ночи. Затем к ней добавляли водный раствор бикарбоната натрия и смесь экстрагировали этилацетатом. Органический слой промывали водой и насыщенным водным раствором хлорида натрия, сушили над безводным сульфатом магния и затем концентрировали. Полученный таким образом остаток промывали этанолом и извлекали фильтрованием с получением 660 мг промежуточного продукта (выход 55%). ¹ H-NMR (DMSO-d ₆ ): δ (ppm): 2.93 (s, 3H), 2.95 (s, 6H), 3.51-3.57 (m, 2H), 4.44-4.50 (m, 2H), 7.86 (t, J = 8.0 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 8.25 (d , J = 8.0 Hz, 1H), 8.39 (d, J = 9.2 Hz, 1H), 8.98 (d, J = 9.2 Hz, 1H), 9.09 (d, J = 8.0 Hz, 1H), 9.55 (d, J = 8.8 Hz, 1H)
Example 58
7- [2- (Dimethylamino) ethyl] -6H-benzo [c, i] pyrimido [1,6,5-lm] -

-carboline-6.8 (7H) -dione:

1.06 g (3.1 mmol) of the compound of Production Example 25 was dissolved in a mixture of methanol (20 ml) with tetrahydrofuran (20 ml). After adding to the solution 1 N. an aqueous solution of sodium hydroxide (10 ml), the resulting mixture was heated under reflux for 1 hour and then allowed to cool. Then, 1N was added to it. aqueous hydrochloric acid (10 ml) and the solvent was distilled off. N, N-dimethylformamide (50 ml) was added to the residue. Next, 770 mg (4 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 540 mg (4 mmol) of 1-hydroxybenzotriazole and 0.4 ml (3.7 mmol) of N, N-dimethylethylenediamine and the resulting mixture were added stirred at room temperature overnight. Then, an aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. The residue thus obtained was washed with ethanol and recovered by filtration to obtain 660 mg of an intermediate product (55% yield).

 100 mg (0.26 mmol) of this intermediate was dissolved in N, N-dimethylformamide (20 ml) and 22 mg (0.55 mmol) of sodium hydride (60% in oil) was added to the solution under a stream of hydrogen gas. After stirring the resulting mixture for 1 hour, 0.046 ml (0.6 mmol) of methyl chloroformate was added to it at room temperature. Then the mixture was immediately acidified with 1 N. hydrochloric acid and then slightly alkalinized with a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated to dryness. The residue was purified by silica gel column chromatography to obtain 25 mg of the title compound (yield 24%).

FAB mass spectrometry m / z: 409 ([M + H] ⁺ ).

¹ H-NMR (CDCl ₃ ): δ (ppm): 2.39 (s, 6H), 2.80 (t, J = 6.7 Hz, 2H), 4.51 (t, J = 6.7 Hz, 2H), 7.66-7.78 (m, 2H), 7.85-7.93 (m, 2H), 8.01-8.07 (m, 2H), 8.51 (d, J = 8.6 Hz, 1H), 8.57-8.63 (m, 1H), 8.73-8.79 (m, 1H), 9.74 (dd, J = 0.7 ; 8.6 Hz, 1H).

Claims (9)

1. Derivatives of condensed polycyclic heterocyclic compounds of the general formula I

where ring A denotes benzene, optionally substituted oxo, or a dicyclic fused ring in which at least one of the rings is an aromatic ring and is selected from the group consisting of: 1) naphthalene, optionally hydrogenated in one ring and / or optionally substituted with halogen , hydroxy, lower alkyl, optionally containing hydroxy, lower alkoxy, nitro, amino, lower acyl, oxo, cyano, benzenesulfonamido, substituted lower alkyl, and lower acylamino; 2) indene, optionally hydrogenated in one ring and / or optionally substituted oxo; 3) benzofuran, optionally hydrogenated in one ring and / or optionally substituted with hydroxy or oxo in a heterocyclic ring; 4) isobenzopyran, optionally hydrogenated and / or optionally substituted oxo; 5) benzothiophene, optionally substituted by oxo; b) benzopyran, optionally hydrogenated and / or optionally substituted oxo; 7) benzodioxol; and 8) quinoline and isoquinoline, optionally hydrogenated in a heterocyclic ring and / or optionally substituted with oxo or lower alkyl;
ring B is pyrrole, 4H-1,4-oxazine, 4H-1,4-thiazine or 4 (1H) -pyridone;
ring C represents a monocyclic or dicyclic aromatic ring selected from: 1) phenyl optionally substituted with halogen, hydroxy, lower alkoxy, lower alkyl, nitro or amino; 2) naphthyl and 3) quinolyl;
Y is a group represented by the formula -e-f, where e is lower alkylene and f is lower alkylamino, di-lower alkylamino, pyrrolidinyl, N- (dimethylamino) ethyl-N-methylamino and N- (hydroxyethyl) -N-methylamino;
or their pharmacologically acceptable salts.  2. The compound according to claim 1, where ring A is naphthalene, which is optionally substituted as indicated in claim 1, and optionally hydrogenated in one ring, or its pharmacologically acceptable salts.  3. The compound according to claim 1, where ring A represents quinoline, isoquinoline, 4H-1-benzopyran, 1H-2-benzopyran, 1,3-benzodioxol, benzofuran, isobenzopyran, benzothiophene, which are optionally substituted as indicated in claim 1, optionally hydrogenated in one ring and fused to ring B with a benzene ring, or pharmacologically acceptable salts thereof.  4. The compound according to claim 1, where ring A is tetralin or indan, and is fused to ring B with a benzene ring, its pharmacologically acceptable salts.  5. The compound according to claim 1, where ring A is an oxo-substituted tetralin or indan, and is fused to ring B with a benzene ring, or pharmacologically acceptable salts thereof.  6. The compound according to claim 1, where ring A is optionally substituted as indicated in claim 1, chroman or isochroman, tetrahydrofuran or tetrahydroisobenzopyran, and fused to ring B with a benzene ring, or pharmacologically acceptable salts thereof.  7. The compound according to claim 1, where ring B is pyrrole, or its pharmacologically acceptable salts.  8. The compound of claim 1, wherein ring C is optionally substituted with halogen, lower alkyl, lower alkoxy, amino, nitro, phenyl hydroxy, or pharmacologically acceptable salts thereof. 9. A method of producing compounds according to claim 1 or its pharmacologically acceptable salts, characterized in that the compounds of general formula II are reacted

where rings Aa and Ca have the meanings indicated in claim 1 for rings A and C, respectively, in which the corresponding substituents are optionally protected;
Ba ring is 4H-1,4-oxazine, 4H-1,4-thiazine, 4 (1H) -pyridone;
fa has the meanings indicated in claim 1;
e has the meaning specified in paragraph 1,
with a compound of general formula III

where D and E are the same or different, and each represents a deleted group,
with the removal of the protective group or groups, if any, from the product thus obtained.

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