RU2304584C1 - Derivatives of noscapine (variants), combinatory and focused libraries, pharmaceutical composition, methods for their preparing (variants) and using - Google Patents

Abstract

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of noscapine of the general formula (1)

or its racemates, optical isomers, or their pharmaceutically acceptable salts and/or hydrates possessing anticarcinogenic activity, and to a pharmaceutical composition as tablets, capsules or injection formulations placed into pharmaceutically acceptable package, ant to methods for their synthesis, and to a method for inhibition of proliferation by their using. In compounds of the formula (1) R¹ represents a substitute of amino-group chosen from alkyl; R² represents a substitute of cyclic system chosen from possibly substituted alkyl wherein substitutes are chosen from possibly substituted amino-group or azaheterocycle comprising possibly oxygen (O), sulfur (S) or nitrogen (N) atoms as an additional heteroatom, and added to alkyl group by nitrogen atom, possibly substituted aryl possibly substituted and possibly condensed heteroaryl comprising at least one heteroatom chosen from nitrogen, sulfur and oxygen atoms, possibly substituted sulfamoyl. Except for, invention relates to 3-(9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, 3-(9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, 5-(4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-9-carbaldehyde (or -9-carbonitrile, or -9-sulfonyl chloride, or -9-carboxylic acid) and 3-(9-methoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, and method for their synthesis. Also, invention relates to combinatory and focused libraries.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 5 tbl, 9 ex

Description

This invention relates to new derivatives of the natural alkaloid of noscapine or (S, R) -6,7-dimethoxy-3- (5,6,7,8-tetrahydro-4-methoxy-6-methyl-1,3-dioxolo [4 , 5-g] isoquinolin-5-yl) -1 (3H) -isobenzofuranone having physiological activity. More specifically, the present invention relates to the specific physiological activity of these compounds, allowing them to be used as “molecular tools” or active drug substances that block protein-protein interactions or cause programmed cell death (apoptosis), and also to a method for synthesizing such derivatives, to focused libraries containing these substances, to pharmaceutical compositions containing these compounds in the form of active substances, as well as to a method for treating cancer.

Noskapin (another name is narcotine) is an opium alkaloid, its content in the poppy Papaver somniferum L. Papaveraceae reaches 11%, but noscapine is completely non-narcotic. Noscapine is approved for use as an antitussive agent, is included in the United States Pharmacopeia (USP) (on the market since 1963), and is included as an active substance in the following drugs: Capval, Lyobex, Narcotussin, Tusscapine.

Of particular interest, however, are the recently discovered unique anticancer properties of noscapine [Ye K., Ke Y., Keshava N., Shanks J., Kapp J., Tekmal R., Petros J., Joshi H. Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells. Proc. Natl. Acad, Sci. USA 1998, 95: 1601-1606].

Due to the unusual mechanism of interaction of noscapine with tubulin (a protein that forms the cytoskeleton) [Zhou J, et.al. Brominated Derivatives of Noscapine Are Potent Microtubule-interfering Agents That Perturb Mitosis and Inhibit Cell Proliferation. Mol Pharmacol. 2003, 63: 799-807] it is effective in the case of resistant forms of tumors arising from treatment with other “antitubulin” preparations, such common as, for example, taxol or vincristine [Zhou, J. et al. Paclitaxel-resistant human ovarian cancer cells undergo c-Jun NH2-tenninal kinase-mediated apoptosis in response to noscapine. J Biol Chem. 2002, 277 (42): 39777]. The low toxicity of noscapine is also very attractive, especially when compared with other antitumor substances [Lang R., et.al. The alkaloid noscapine is a low toxicity agent with significant antitumor effect in melanoma. 62nd Annu Meet Soc Invest Dermatol (May 9-12, Washington DC) 2001, Abst 568]. The unique properties of noscapine, including its specific effect on microtubular dynamics, cell cycle arrest [Anderson JT, Ting AE, Boozer S., Brunder KR, Crumrine C., Danzig J., Dent T., Faga L., Harrington J., Hodnick W., Murphy S., Pawlowski G., Perry R., Raber A., Rundlett SE, Stricker-Krongrad A., Wang J., Bennani YL Identification of novel and improved antimitotic agents derived from noscapine. J Med Chem. 2005; 48 (23): 7096-8], the induction of c-Jun-mediated NH2-terminal kinase apoptosis, inhibition of tumor growth, the ability to cross the blood-brain barrier [Landen JW, Hau V., Wang M., Davis T., Ciliax B. , Wainer BH, Van Meir EG, Glass JD, Joshi HC, Archer DR Noscapine crosses the blood-brain barrier and inhibits glioblastoma growth. Clin Cancer Res. 2004, 10 (15): 5187-201], inhibition of the action of “hypoxia-induced factor HIF-1”, which plays an important role in tumor growth [Newcomb EW, Lukyanov Y., Schnee T., Alt MA, Lan L., Zagzag D Noscapine inhibits hypoxia-mediated HIF-1 alpha expression andangiogenesis in vitro: a novel function for an old drug. Int J Oncol. 2006 May; 28 (5): 1121-30.], As well as its extremely low toxicity, create great potential for the search for highly effective anticancer drugs of the new generation in the series of noscapine derivatives [Joshi H.C., Zhou J. Noscapine and analog as potential chemotherapeutic agents. Drug News Perspeci. 2000, 13 (9): 543-6]. In this regard, the design of new compounds of this type, focused libraries and pharmaceutical compositions including these compounds, as well as the development of methods for their preparation and use, are relevant.

As a result of studies aimed at the search for new physiologically active substances, leader compounds, the inventors obtained previously unknown derivatives of noscapine, which are characterized by physiological activity, a focused library, and a pharmaceutical composition comprising these compounds, developed methods for their preparation and use.

It should be noted that a large number of noscapine derivatives have been described, but with rare exceptions they are degradation products of one or two heterocyclic rings (for example, [Jacobson A. 1- (3-Phenylpropyl) -2-methyl-6,7-methylene-dioxy -8-methoxy-1,2,3,4-tetrahydroisoquinoline, a Pharmacologically Active Narcotine Derivative. J Med Chem. 1965: 697-698]). In those rare cases when the biocyclic structure of noscapine is preserved in the modified molecule, which ensures its physiological activity and contains the associated isoquinoline and benzofuran rings, the modification is carried out via N- (or O-) demethylation of noscapine (for example, (thio) carbamoyl analogues of N- demethylated noscapine [Aggarwala S., et al. A Convenient Synthesis of Aryl-Substituted N-Carbamoyl / N-Thiocarbamoyl Narcotine and Related Compounds. Helv Chim Acta. 2002, 85: 2458-2462], and also: [Joshi H., et.al. US 6376516 B1 04.23.2002; US 6673814 B2 06/01/2004]). Single examples of noscapine A derivatives containing a substituent in the 5-position of the isoquinoline ring are known (Table 1).

Table 1. Known substituted noscapines having substituents at the 5-position of the isoquinoline ring No. Formula Literature A-01

Zhou J, et.al. Mol Pharmacol. 2003, 63, 799-807. A-02

Aggarwala S., et al. Helv Chim Acta. 2002, 55, 2458-2462. A-03

A-04

Semonsky M. Collect. Czech Chem. Commun. 1951, 16/17, 358; CA 47, 19106. A-05

A-06

A-07

A-08

A-09

Sandoz Ltd. US Pat. 3056791, 1959. CA1963, 58, 5749a. A-10

A-11

A-12

A-13

Gadamer, et.al. Arch. Pharm. (Weinheim. Ger.) 1923, 267, 136. A-14

Hadacek J., et.al. Pubs Faculte sci. univ. Masarik. 1950, 320 (Rada E5), 23; CA 47: 44627. A-15

Aneja R., Vangapandu S.N., Lopus M., Chandra R., Panda D., Joshi H.C. Molecular Pharmacology Fast Forward. 2006, Publ. March 3, 2006 as doi: 10.1124 / mol. 105.021899. A-16

Aneja R., Lopus M., Zhou J., Vangapandu S., Ghaleb A., Yao J., Nettles J.H., Zhou B., Gupta M, Panda D., Chandra R., Joshi H.C. Cancer Res. 2006, 66 (7), 3782-3791. A-17

Freund, et. al. Chem. Ber. 1912, 45, 1175. A-18

Pat Appl. Publ. US 2002/0137762 A1, 2002. Intern. Appl. PCT / US00 / 11082, WO 00/64446, 2000. A-19

Pat. Appl. Publ. US 2002/0137762 A1, 2002. Intern. Appl. PCT / US00 / 11082, WO 00/64446, 2000. A-20

Pat. Appl. Publ. US 2002/0137762 A1, 2002. Intern. Appl. PCT / US00 / 11082, WO 00/64446, 2000.

To date, virtually no known derivatives of noscapine containing in the 5-position aryl, hetaryl, sulfamoyl, aminomethyl and other substituents.

The following are definitions of terms that are used in the description of this invention:

“Azaheterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a ring. An azaheterocycle may have one or more “cyclic” substituents.

“Aliphatic” radical means a radical obtained by removing a hydrogen atom from a non-aromatic CH bond. An aliphatic radical may additionally contain substituents — aliphatic or aromatic radicals defined in this section. aliphatic radicals Representatives include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkiloksialkil, aralkiloksikarbonilalkil, aralkyl, aralkynyl, aralkiloksialkenil, heteroaralkenyl, heteroaralkyl, geteroaralkiloksialkenil, geteroaralkiloksialkil, heteroaralkenyl, anelirovannye arylcycloalkyl, anelirovannye heteroarylcycloalkyl, anelirovannye arylcycloalkenyl, anelirovannye heteroarylcycloalkenyl, anelated arylheterocyclyl, anelated heteroarylheterocyclyl, an elated arylheterocyclenyl, anelated heteroarylheterocyclenyl.

"Alkenyl" means an aliphatic linear or branched hydrocarbon group containing from 2 to 7 carbon atoms and including a carbon-carbon double bond.

Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. An alkyl group may have one or more substituents, for example, such as halogen, alkenyloxy, cycloalkyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroaralkyloxy, heterocyclyl, heterocyclylalkyloxy, alkoxycarbonyl

hetaralkyloxycarbonyl or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= O) -, R _k ^a R _{k + 1} ^a NSO ₂ -, where R _k ^a and R _{k + 1} ^a independently, they are “amino substituents”, the meanings of which are defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or R _k ^a and R _{k + 1} ^a together with the N atom, with which they are connected, form through R _k ^a and R _{k + 1} ^a 4-7 membered heterocyclyl or heterocyclenyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbnylmethyl, benzyloxycarbonylmethylmethyl and pyridinyl. Preferred alkenyl groups are ethenyl, propenyl, n-butenyl, iso-butenyl, 3-methylbut-2-enyl, n-pentenyl and cyclohekeylbutenyl.

“Alkenyloxy” means an alkenyl-O— group in which alkenyl is defined in this section. Preferred alkenyloxy groups are allyloxy and 3-butenyloxy.

“Alkenyloxyalkyl” means an alkenyl-O-alkyl group in which alkyl and alkenyl are defined in this section.

"Alkyl" means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in a chain in which alkyl groups. Branched means that the alkyl chain has one or more "lower alkyl" substituents. Alkyl may have one or more identical or different substituents (“alkyl substituents”) including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbenyl, alkylthio, heteroaryo , aralkylthio, arylsulfonyl, alkylsulfonylheteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcyclic alkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (O) -, R _k ^a R _{k + 1} ^a NC (O) -, R _k ^a R _{k + 1} ^a NC (O) -, NC (= S) -, R _k ^a R _{k + 1} ^a NSO ₂ -, where R _k ^a and R _{k + 1} ^{a are} independently “amino substituents”, the meaning of which is defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or R _k ^a and R _{k + 1} ^a together with the N atom to which they are bonded, form a 4-7 membered heterocycle through Rka and Rk + 1a clyl or heterocyclenyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethylene . The preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or R _k ^a R _{k + 1} ^a N- , R _k ^a R _{k + 1} ^a NC (= O) -, annelated arylheterocyclenyl, annelated arylheterocyclyl.

“Alkyloxyalkyl” means an alkyl-O-alkyl group in which the alkyl groups are independent of each other and are defined in this section. Preferred alkyloxyalkyl groups are methoxyethyl, ethoxymethyl, n-butoxymethyl, methoxypropyl and isopropyloxyethyl.

“Alkyloxnacarbooyl” means an alkyl-O — C (= O) group in which alkyl groups are defined in this section. Preferred alkyloxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl, iso-propyloxycarbonyl, benzylcarbonyl and phenethylcarbonyl.

“Alkylthio” means an alkyl-S group in which an alkyl group is defined in this section.

“Alkoxy” means an alkyl-O— group in which alkyl is defined in this section. Preferred alkyloxy groups are methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy.

“Alkoxycarbonyl” means alkyl-O — C (= O) —the group in which alkyl is defined in this section. Preferred alkoxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl and tert-butylcarbonyl.

“Alkoxycarbonylalkyl” means an alkyl-O — C (= O) -alkyl group in which alkyl is defined in this section. Preferred alkoxycarbonylalkyl groups are methoxycarbonylmethyl and ethoxycarbonylmethyl and methoxycarbonylethyl and ethoxycarbonylethyl.

“Amino group” means R _k ^a R _{k + 1} ^a is a group substituted or unsubstituted with “amino group substituent”, R _k ^a and R _{k + 1} ^a , the meaning of which is defined in this section, for example, amino (H ₂ N -), methylamino, diethylamino, pyrrolidine, morpholine, benzylamino or phenethylamino.

“Anelated cycle” (condensed cycle) means a bi- or poly-cyclic system in which the annelated cycle and the cycle or polycycle with which it is “anelated” have at least two atoms in common.

“Anelated arylheterocycloalkenyl” means annelated aryl and heterocycloalkenyl, the meanings of which are defined in this section. Anelated arylheterocycloalkenyl can bind through any possible atom of the cyclic system. The prefix "aza", "oxa" or "thia" before "heterocycloalkenyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Anelated arylheterocycloalkenyl may have one or more “cyclic system substituents,” which may be the same or different. The nitrogen and sulfur atoms in the heterocyclenyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of anelated arylheterocycloalkenyls are indolinyl, 1H-2-oxoquinolinyl, 2H-1-oxoisoquinolinyl, 1,2-dihydroquinolinyl, and the like.

“Anelated arylheterocycloalkyl” means annelated aryl and heterocycloalkyl, the meanings of which are defined in this section, Anelated arylheterocycloalkyl can be bonded through any possible atom of the cyclic system. The prefix "aza", "oxa" or "thia" before "heterocycloalkyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Anelated arylheterocycloalkyl may have one or more “cyclic system substituents,” which may be the same or different. The nitrogen and sulfur atoms in the heterocyclyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of annelated arylheterocycloalkyls are indolyl, 1,2,3,4-tetrahydroisoquinoline, 1,3-benzodiocol, and the like.

“Annelated arylcycloalkenyl” means annelated aryl and cycloalkenyl, the meanings of which are defined in this section. Annelated arylcycloalkenyl can bind through any possible atom of the cyclic system. Annelated arylcycloalkenyl may have one or more “cyclic system substituents,” which may be the same or different. Representatives of anelated arylcycloalkenyls are 1,2-dihydronaphthalene. inden, etc.

“Anelated arylcycloalkyl” means annelated aryl and cycloalkyl as defined in this section. Anelated arylcycloalkyl can bind through any possible atom of the cyclic system. Anelated arylcycloalkyl may have one or more “cyclic system substituents,” which may be the same or different. Representatives of anelated arylcycloalkenyls are indanine, 1,2,3,4-tetrahydronaphthalene, 5,6,7,8-tetrahydronaphth-1-yl, and the like.

“Annelated heteroarylcycloalkenyl” means annelated heteroaryl and cycloalkenyl, the meanings of which are defined in this section. Anelated heteroarylcycloalkenyl can bind through any possible atom of the cyclic system. The prefix "aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Anelated heteroarylcycloalkenyl may have one or more “cyclic system substituents,” which may be the same or different. The nitrogen atom in the heteroaryl moiety may be oxidized to N-oxide. Representatives of anelated heteroarylcycloalkenyls are 5,6-dihydroquinolinyl, 5,6-dihydroisoquinolinyl, 4,5-dihydro-1H-benimidazolyl, and the like.

“Annelated heteroarylalcycloalkyl” means annelated heteroaryl and cycloalkyl, the meanings of which are defined in this section. Anelated heteroarylcycloalkyl can bind through any possible atom of the cyclic system. The prefix "aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Anelated heteroarylcycloalkyl may have one or more “ring system substituents”, which may be the same or different. The nitrogen atom located in the heteroaryl part may be oxidized to N-oxide. Representatives of anelated heteroarylcycloalkenyls are 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydro-1H-benimidazolyl, and the like.

“Annelated heteroarylheterocyclenyl” means annelated heteroaryl and heterocyclenyl, the meanings of which are defined in this section. Anelated heteroarylheterocyclenyl can bind through any possible atom of the ring system. The prefix "aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Anelated heteroarylheterocyclenyl may have one or more “cyclic system substituents,” which may be the same or different. The nitrogen atom located in the heteroaryl part may be oxidized to N-oxide. The nitrogen and sulfur atoms in the heterocyclenyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of anelated heteroarylcycloalkenyls are 1,2-dihydro [2,7] naphthyridinyl, 7,8-dihydro [1,7] naphthyridinyl, 6,7-dihydro-3H-imidazo [4,5-c] pyridyl and the like. “Annelated heteroaryl heterocyclyl” means annelated heteroaryl and heterocyclyl, the meanings of which are defined in this section. Anelated heteroaryl heterocyclyl can bind through any possible atom of the cyclic system. The prefix "aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Anelated heteroaryl heterocyclyl may have one or more “cyclic system substituents,” which may be the same or different. The nitrogen atom in the heteroaryl moiety may be oxidized to N-oxide. The nitrogen and sulfur atoms in the heterocyclyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of anelated heteroarylcycloalkenyls are 2,3-dihydro-1H-pyrrolo [3,4-b] quinolin-2-yl, 2,3-dihydro-1H-pyrrolo [3,4-b] indol-2-yl, 1, 2,3,4-tetrahydro [1,5] naphthyridinyl and the like. “Aralkenyl” means an aryl-alkenyl group in which the meanings of aryl and alkenyl are defined in this section. For example, 2-phenethenyl is an aralkenyl group. “Aralkyl” means an alkyl group substituted with one or more aryl groups, in which the meanings of aryl and alkyl are defined in this section. Examples of aralkyl groups are benzyl, 2,2-diphenylethyl or phenethyl. "Aralkylamino" means aryl-alkyl-NH-, in which the meanings of aryl and alkyl are defined in this section.

“Aralkylsulfinyl” means an aralkyl-SO— group in which the meaning of aralkyl is defined in this section.

“Aralkylsulfonyl” means aralkyl-SO ₂ , a group in which the meaning of aralkyl is defined in this section.

“Aralkylthio” means an aralkyl-S- group in which the meaning of aralkyl is defined in this section.

“Aralkoxy” means an aralkyl-O— group in which the meaning of aralkyl is defined in this section. For example, benzyloxy or 1- or 2-naphthylenemethoxy are aralkyl groups.

“Aralkoxyalkyl” means an aralkyl-O-alkyl group in which the meanings of aralkyl and alkyl are defined in this section. An example of an aralkyl-O-alkyl group is benzyloxyethyl.

“Aralkoxycarbonyl” means aralkyl-O — C (= O) —the group in which the meaning of aralkyl is defined in this section. An example of an aralkoxycarbonyl group is benzyloxycarbonyl.

“Aralkoxycarbonylalkyl” means an aralkyl-O — C (═O) -alkyl group in which aralkyl and alkyl are defined in this section. An example of an aralkoxycarbonylalkyl group is benzyloxycarbonylmethyl or benzyloxycarbonylethyl.

“Aryl” means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. Aryl may contain one or more “cyclic system substituents”, which may be the same or different. Representative aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be anelated with a non-aromatic ring system or heterocycle. “Arylcarbamoyl” means aryl-NHC (= O), the group in which the meaning of aryl is defined in this section.

“Aryloxy” means an aryl-O— group in which the meaning of aryl is defined in this section. Representative aryloxy groups are phenoxy and 2-naphthyloxy. “Aryloxycarbonyl” means aryl-O — C (= O) —the group in which the meaning of aryl is defined in this section. Representative aryloxycarbonyl groups are phenoxycarbonyl and 2-naphthoxycarbonyl.

“Arylsulfinyl” means an aryl-SO— group in which the meaning of aryl is defined in this section.

"Arylsulfonyl" means aryl-SO ₂ - a group in which the meaning of aryl is defined in this section.

“Arylthio” means an aryl-S— group in which the meaning of aryl is defined in this section. Representative arylthio groups are phenylthio and 2-naphthylthio.

“Aroylamino” means aroyl-NH— group in which the meaning of aroyl is defined in this section.

“Aroyl” means aryl-C (= O) —the group in which the meaning of aralkyl is defined in this section. Examples of aroyl groups are benzoyl, 1- and 2-naphthoyl.

“Aromatic” radical means a radical obtained by removing a hydrogen atom from an aromatic CH bond. An “aromatic" radical includes aryl and heteroaryl rings defined in this section. Aryl and heteroaryl rings may additionally contain substituents — aliphatic or aromatic radicals defined in this section. Representative aromatic radicals include aryl, anelated cycloalkenylaryl, anelated cycloalknylaryl, anelated heterocyclylaryl, anelated heterocyclynaryl, heteroaryl, anelated cycloalkylheteroaryl, anelated cycloalkenyl heteroaryl, anelated heterocyclyl heteroaryl.

“Aromatic cycle” means a planar cyclic system in which all atoms of the cycle participate in the formation of a single conjugation system, which, according to the Hückel rule, includes (4n + 2) π-electrons (n is a non-negative integer). Examples of aromatic cycles are benzene, naphthalene, anthracene, and the like. In the case of “heteroaromatic cycles”, π-electrons and p-electrons of heteroatoms participate in the conjugation system; their total number is also equal to (4n + 2). Examples of such cycles are pyridine, thiophene, pyrrole, furan, thiazole and the like. An aromatic ring may have one or more “cyclic substituents” and can be annelated with a non-aromatic ring, heteroaromatic or heterocyclic ring.

“Acyl” means HC (= O) - or alkyl-C (= O) -, cycloalkyl-C (= O) -, heterocyclyl-C (= O) -, heterocyclylalkyl-C (= O) -, aryl -C (= O) - arylalkyl-C (= O) -, or heteroaryl-C (= O) -, heteroarylalkyl-C (= O) - a group in which alkyl-, cycloalkyl-, heterocyclyl-, heterocyclylalkyl, aryl -, arylalkyl, heteroaryl-, heteroarylalkyl are defined in this section.

“Acylamino” means an acyl-NH— group in which the acyl value is defined in this section.

"Bifunctional reagent" means a chemical compound having two reaction centers participating simultaneously or sequentially in the reactions. Examples of bifunctional reagents are reagents containing a carboxyl group and an aldehyde or ketone group, for example 2-formylbenzoic acid, 2- (2-oxo-ethylcarbamoyl) -benzoic acid, 2- (3-formyl-thiophen-2-yl) -benzoic acid or 2- (2-formylphenyl) thiophene-3-carboxylic acid.

“1,2-vinyl radical” means —CH = CH— group which contains one or more identical or different “alkyl substituents”, the meaning of which is given in this section.

“Halogen” means fluoro, chloro, bromo and iodo. Fluorine, chlorine and bromine are preferred.

“Heteroannelated cycle” means that a cycle that attaches (annelates or condenses) to another cycle or polycycle contains at least one heteroatom.

“Heteroaralkenyl” means a heteroaryl alkenyl group in which heteroaryl and alkenyl are defined in this section. Preferably, heteroarylalkenyl includes a lower alkynyl group. Representatives of heteroarylalkenyls are 4-pyridylvinyl, thienylethenyl, imidazolylethenyl, pyrazinylethenyl, and the like. “Heteroaralkyl” means a heteroaryl-alkyl group in which heteroaryl and alkyl are defined in this section. Representative heteroarylalkenes are pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, pyrazinylmethyl and the like. “Heteroaralkyloxy” means a heteroarylalkyl-O— group in which heteroarylalkyl is defined in this section. Representative heteroarylalkenes are 4-pyridylmethyloxy, 2-thienylmethyloxy and the like. “Heteroaroyl” means heteroaryl-C (= O), the group in which heteroaryl is defined in this section. Representative heteroarylalkenes are nicotinoyl, thienoyl, pyrazoloyl and the like.

“Heteroaryl” means an aromatic monocyclic or polycyclic system comprising from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are substituted with heteroatoms or heteroatoms such as nitrogen, sulfur or oxygen. The prefix "aza", "oxa" or "thia" before "heterocycloalkyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. The nitrogen atom in heteroaryl may be oxidized to N-oxide. A vegetarian can have one or more “cyclic system substituents,” which may be the same or different. Representative heteroaryls are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, isoxazolyl, isothiazolyl, tetrazolyl, ochazolyl, thiazolyl, pyrazolyl, furazanyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinazole, quinazole -a] pyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanil, indolyl, azaindolyl, benzimidazolyl, benzothiazenyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridine, imidazoinazole, azidazinoidinazole thienopyrrolyl, furopyrrolyl, etc.

“Heteroarylsulfonylcarbamoyl” means heteroaryl-SO ₂ —NH — C (= O) —the group in which heteroaryl is defined in this section.

“Heterocyclyl” means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one heteroatom in the ring, including aryl and heteroaryl, the meanings of which are given in this section. Preferred heteroatoms are nitrogen, oxygen and sulfur. An azaheterocycle may have one or more “cyclic” substituents.

“Heterocyclenyl” means a non-aromatic monocyclic or polycyclic system comprising from 3 to 13 carbon atoms, preferably from 5 to 13 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. The prefix "aza", "oxa" or "thia" in front of heterocyclenyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Heterocyclenyl may have one or more “ring system substituents”, which may be the same or different. The nitrogen and sulfur atoms in heterocyclenyl can be oxidized to N-oxide, S-oxide or S-dioxide. Representative heterocyclenyls are 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolyl, 2-pyrazolinyl, dihydrofuranyl, dihydrothiophenyl and the like.

“Heterocyclyl” means a non-aromatic saturated monocyclic or polycyclic system comprising from 3 to 10 carbon atoms, preferably from 5 to 6 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur. The prefix "aza", "oxa" or "thia" before heterocyclyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Heterocyclyl may have one or more “cyclic system substituents,” which may be the same or different. The nitrogen and sulfur atoms in the heterocyclyl can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of heterocyclyl are piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, thiazolidine, 1,4-dioxane, tetrahydrofuran, tetrahydrothiophene, etc.

“Heterocyclyloxy” means a heterocyclyl-O— group in which heterocyclyl is defined in this section.

"Hydrate" means a solvate in which water is a molecule or molecules of a solvent.

“Hydroxyalkyl” means a HO-alkyl group in which alkyl is defined in this section.

“Substituent” means a chemical radical that is attached to a scaffold (fragment), for example, “substituent alkyl”, “substituent of amino group”, “substituent carbamoyl”, “substituent of the cyclic system”, the meanings of which are defined in this section.

“Substituent alkyl” means a substituent attached to alkyl, alkenyl, the meaning of which is defined in this section. The alkyl substituent is hydrogen, alkyl, halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy. aryloxy, ariloksikarbnil, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkilsulfonilgeteroaralkiloksi, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= O) -, R _k ^a R _{k + 1} ^a NSO ₂ -, where R _k ^a and R _{k + 1} ^a independently d yz other represent "the substituents amino group", the meanings of which are defined in this section, for example a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or R _k ^a and R _{k + 1} ^a together with the atom N, with with which they are connected, form through R _k ^a and R _{k + 1} ^a 4-7 membered heterocyclyl or heterocyclenyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxy methyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylmethyl pyridylmethyloxycarbnylmethyl. The preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or R _k ^a R _{k + 1} ^a N- , R _k ^a R _{k + 1} ^a NC (= O) -, annelated arylheterocyclenyl, annelated arylheterocyclyl. The meaning of “alkyl substituents” is defined in this section.

“Substituent amino group” means a substituent attached to an amino group. Substituent amino group is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, geterotsiklilaminokarbonil, alkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroaryl heterocyclenyl, annelated heteroaryl heterocyclyl, anneliro anny arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonylalkyl, aralkoksikarbonilalkil, geteroaralkiloksikarbonilalkil. The meaning of “amino group substituents” is defined in this section.

“Urea carbamoyl” means a substituent attached to a carbamoyl group, the meaning of which is defined in this section. The carbamoyl substituent is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= O) -alkenylalkenyl annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl. Preferred carbamoyl substituents are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= O) -alkyl, alkyl arylheterocyclenyl, annelated arylheterocyclyl. The meaning of “carbamoyl substituents” is defined in this section.

“Nucleophilic substituent” means a chemical radical that binds to scaffold by reaction with nucleophilic reagents, for example, selected from the group of primary or secondary amines, alcohols, phenols, mercaptans and thiophenols.

“Substituent cyclic system” means a substituent attached to an aromatic or non-aromatic cyclic system, including hydrogen, alkylalkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, aryloxy, acyl, aroyl, halogen, nitro , cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, arylalkyloxyalkyl, heterocyclylalkyloxyalkyl, alkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, finil, arylsulfinyl, geterotsiklilsulfinil, alkylthio, arylthio, heterocyclylthio, heterocyclylthio, alkylsulfonylalkyl, arylsulfonylalkyl, geterotsiklilsulfonilalkil, alkylsulfinylalkyl, arylsulfinylalkyl, geterotsiklilsulfinilalkil, alkylthioalkyl, arylthioalkyl geterotsikliltioalkil, arilalkilsulfonilalkil, geterotsiklilalkilsulfonilalkil, arilalkiltioalkil, geterotsiklilalkiltioalkil, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, amidino, R _k ^a R _{k + 1} ^a N-, R _k ^a N =, R _k ^a R _{k + 1} ^a N-alkyl-, R _k ^a R _{k + 1} ^a NC (= O) - or R _k ^a R _{k +1} ^a NSO ₂ -, where R _k ^a and R _{k + 1} ^a ol independently, “amino substituents” as defined in this section, are, for example, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl, or a substituent R _k ^a R _{k + 1} ^a N-, in which R _k ^a may be acyl or aroyl, and the value of R _{k + 1} ^{a is} defined above, or “substituents of the cyclic system” are R _k ^a R _{k + 1} ^a NC (= O) -or R _k ^a R _{k + 1} ^a NSO ₂ -, in which R _k ^a and R _{k + 1} ^a together with the nitrogen atom to which they are bonded, form through R _k ^a and R _{k + 1} ^a 4-7 member heterocyclyl or heterocyclenyl.

“Electrophilic substituent” means a chemical radical that attaches to scaffold by reaction with an electrophilic reagent, for example, organic acids or their derivatives (anhydrides, imidazolides, halides), organic sulfonic acid esters or organic sulfonyl chlorides, organic haloformates, organic isocyanates and organic isothiocyanates.

“Substituted amino group” means R _k ^a R _{k + 1} ^a N-group in which R _k ^a and R _{k + 1} ^a are amino substituents as defined in this section.

“Substituted carboxyl” means a C (O) OR group. The substituted carboxyl has a substituent R, including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.

“Substituted mercapto group” means an SR, S (O) R or S (O2) R group in which the substituent R is alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meanings of which are defined in this section. “Protecting group” (PG) means a chemical radical that attaches to a scaffold or intermediate to synthesize the amino group in multifunctional compounds, including, but not limited to: an amide substituent such as formyl, optionally substituted acetyl (eg trichloroacetyl, trifluoroacetyl 3- phenylpropionyl and others), optionally substituted benzoyl and others; a carbamate substituent, such as optionally substituted C ₁ -C ₇ alkyloxycarbonyl, for example methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), etc .; optionally substituted C ₁ -C ₇ alkyl substituent, for example tert-butyl, benzyl, 2,4-dimethixibenzyl, 9-phenylfluorenyl and others; sulfonyl substituent, for example, benzenesulfonyl, p-toluenesulfonyl, etc. The Protective groups are described in more detail in the book: Protective groups in organic synthesis, Third Edition Greene, TW and Wuts, PGM 1999, p.494-653. John Wiley & Sons, Inc., New York, Chichester, Weinheim, Brisbane, Toronto, Singapore.

"Protected primary or secondary amine" means a group of the formula R _k ^a R _{k + 1} ^a N-, in which R _k ^a represents a protective group PG, and R _{k + 1} ^a represents hydrogen "Deputy amino groups, the value of which is defined in this section, for example, alkenyl, alkyl, aralkyl, aryl, annelated, arylcycloalkenyl, annelated, arylcycloalkyl, annelated, arylheterocyclenyl, annelated, arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaryl, heteroaryloalkyl, heteroaryloalkyl, l, anelated, heteroaryl heterocyclyl, anelated, heteroaryl heterocyclyl, heterocyclenyl or heterocyclyl.

“Imino group” means R _k ^a N = group substituted or unsubstituted with “amino group substituent”, R _k ³ , the meaning of which is defined in this section, for example, imino (HN =), methylimino (CH ₃ N =), ethylimino (C ₂ H ₅ N =), benzylimino (PhCH _z N =) or phenethylimino (PhCH ₂ CH ₂ N =).

"Inert substituent" (or "non-interfering", "Non-interfering substituent") means a low or non-reactive radical, including but not limited to C ₁ -C ₇ alkyl, C ₁ -C ₇ alkenyl, C ₁ -C ₇ alkynyl, C ₁ -C ₇ alkoxy, C ₇ -C ₁₂ aralkyl substituted with inert aralkyl substituents, C ₇ -C ₁₂ heterocyclylalkyl substituted with inert heterocyclylalkyl substituents. C ₇ -C ₁₂ alkaryl; C ₃ -C ₁₀ cycloalkyl. C ₃ -C ₁₀ cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C ₂ -C ₁₂ acoxyalkyl, C ₂ -C ₁₀ alkylsulfinyl, C ₂ -C ₁₀ alkylsulfonyl, (CH ₂ ) _m -O- (C ₁ -C ₇ alkyl), - (CH ₂ ) _m -N (C ₁ -C ₇ alkyl) _n , aryl substituted with halogens, inert substituents aryl substituted with inert substituents alkoxy, fluoroalkyl, aryloxyalkyl, heterocyclyl substituted with inert substituents heterocyclyl and nitroalkyl ; where m and n are from 1 to 7. Preferred “inert substituents” are C ₁ -C ₇ alkyl, C ₁ -C ₇ alkenyl, C ₁ -C ₇ alkynyl, C ₁ -C ₇ alkoxy, C ₇ -C ₁₂ aralkyl, C ₇ -C ₁₂ alkaryl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl substituted with inert substituents C ₁ -C ₇ alkyl, phenyl substituted with inert substituents phenyl, (CH ₂ ) _m -O- (C ₁ -C ₇ alkyl), - (CH ₂ ) _m -N (C ₁ -C ₇ alkyl) _n , aryl substituted with inert substituents aryl, heterocyclyl and substituted with inert substituents heterocyclyl.

“Carbamoyl” means C (= O) NR _k ^a R _{k + 1} ^a is a group. Carbamoyl may have one or more identical or different "carbamoyl substituents" R _k ^a and R _{k + 1} ^a , including hydrogen, alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meanings of which are defined in this section.

“Carbamoylaseheterocycle” means an azaheterocycle containing at least one carbamoyl group as a “substituent of the cyclic system,” the meaning of “azaheterocycle”, “a substituent of the cyclic system” and “carbamoyl group” are defined in this section.

“Carboxyl” means HOC (= O) - (carboxyl) group.

“Carboxyalkyl” means an HOC (= O) -alkyl group in which the meaning of alkyl is defined in this section.

“Carbocycle” means a mono- or polycyclic system consisting only of carbon atoms. Carbocycles can be either aromatic or alicyclic.

Alicyclic polycycles may have one or more common atoms. In the case of one common atom, spiro-carbocycles are formed (for example, spiro [2.2] pentane), in the case of two, various condensed systems (for example, decalin), in the case of three, bridge systems (for example, bicyclo [3.3.1] nonane), in the case of a larger number, various polyhedral systems (for example, adamantane). Alicycles can be “saturated”, for example, as cyclohexane, or “partially saturated”, for example, as tetralin.

“Combinatorial library” means a collection of compounds obtained by parallel synthesis designed to search for a hit or leader compound, as well as to optimize the physiological activity of a hit or leader, each library compound corresponding to a common scaffold and the library is a collection of related homologues or analogues.

“Methylene radical” means —CH ₂ - a group that contains one or two identical or different “alkyl substituents”, the meaning of which is defined in this section.

“Non-aromatic cycle” (saturated cycle or partially saturated cycle) means a non-aromatic cyclic or polycyclic system formally formed as a result of complete or partial hydrogenation of unsaturated C = C or C = N bonds. A non-aromatic ring may have one or more "substituents of the cyclic" system and may be annelated with aromatic, heteroaromatic or heterocyclic systems. Examples of non-aromatic rings are cyclohexane or piperidine, examples of a partially saturated ring are cyclohexene or piperidine.

“Unnatural amino acid” means an amino acid of a non-nucleic nature. Examples of unnatural amino acids include the D-isomers of natural α-amino acids, aminobutyric acid, 2-aminobutyric acid, γ-aminobutyric acid, N-α-alkylated amino acids, 2,2-dialkyl-α-amino acids, 1-amino-cycloalkylcarboxylic acids, β-alanine, 2-alkyl-β-alanines, 2-cycloalkyl-β-alanines, 2-aryl-β-alanines, 2-heteroaryl-β-alanines, 2-heterocyclyl-β-alanines and (1-amino-cycloalkyl ) -acetic acids in which the meanings of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are defined in this section.

“Optional aromatic cycle” means a cycle, which can be either an aromatic cycle or a non-aromatic cycle, the meanings of which are defined in this section.

“Optionally substituted radical” means a radical without substituents or containing one or more substituents.

“Optional annelated (condensed) cycle” means a condensed, non-condensed cycle, the meanings of which are defined in this section.

"Lower alkyl" means a linear or branched alkyl with 1-4 carbon atoms. “Parallel synthesis” means a method for conducting chemical synthesis of a combinatorial library of individual compounds.

The “1,3-propylene radical” means —CH ₂ —CH ₂ —CH ₂ — a group that contains one or more identical or different “alkyl substituents”, the meaning of which is defined in this section.

“Leader compound” (“leader”) means a compound with outstanding (maximum) physiological activity associated with a particular biotarget related to a specific (or several) pathology or disease.

“Hit compound” (“hit”) means a compound that exhibits the desired physiological activity during the initial screening process. “Sulfamoyl group” means R _k ^a R _{k + 1} ^a NSO ₂ is a group substituted or unsubstituted with “amino group substituent” R _k ^a and R _{k + 1} ^a , the meanings of which are defined in this section.

“Sulfonyl” means R — SO ₂ - a group in which R is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelated heteroarylcycloalkenyl, annelated heteroaryl heterocyclylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkyl the meaning of which is defined in this section.

“Template” means the general structural formula of a group of compounds or compounds included in a “combinatorial library”.

"Thiocarbamoyl" means R _k ^a R _{k + 1} ^a NC (= S) is a group. Thiocarbamoyl may have one or more identical or different "amino substituents" R _k ^a and R _{k + 1} ^a , the meaning of which is defined in this section, for example, including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section .

“Cycloalkyl” means a non-aromatic mono- or polycyclic system containing from 3 to 10 carbon atoms. Cycloalkyl may have one or more “ring system substituents”, which may be the same or different. Representative cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl and the like. Cycloalkyl can be anelated with an aromatic ring or heterocycle. Preferred “cyclic substituents” are alkyl, aralkoxy, hydroxy or R _k ^a R _{k + 1} ^a N, the meaning of which is defined in this section.

“Cycloalkylcarbonyl” means cycloalkyl-C (= O) —the group in which the meaning of cycloalkyl is defined in this section. Representatives of cycloalkylcarbonyl groups are cyclopropylcarbonyl or cyclohexylcarbonyl.

“Cycloalkoxy” means a cycloalkyl-O— group in which the meaning of cycloalkyl is defined in this section.

"Pharmaceutical composition" means a composition comprising a compound of formula I and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceiving agents, agents deliveries, such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial f agents, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, such as parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and distributors are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration is an active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

“Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, base salts can be prepared specifically based on the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like. (A detailed description of the properties of such salts is given in Berge S. M., et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like. In addition, tetraalkylammonium hydroxides, such as, for example, choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, the main amino acids can be used - lysine, ornithine and arginine.

“Focused library” means a combinatorial library, or a collection of several combinatorial libraries, or a collection of libraries and substances, specially organized in order to increase the likelihood of finding hits and leaders or to increase the efficiency of their optimization. The design of focused libraries, as a rule, is associated with a directed search for effectors (inhibitors, activators, agonists, antagonists, etc.) of specific biological targets (enzymes, receptors, ion channels, etc.).

“Fragment” (scaffold) means the structural formula of a part of a molecule characteristic of a group of compounds, or the molecular framework characteristic of a group of compounds or compounds included in a “combinatorial library.

"1,2-Ethylene radical" means -CH ₂ -CH ₂ - a group that contains one or more identical or different "alkyl substituents", the meaning of which is defined in this section.

The aim of the present invention are new azaheterocycles, a method for their preparation and use.)

This goal is achieved by substituted noscapines of the general formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates.

where: R ¹ represents an amino group substituent selected from alkyl; R ² represents a cyclic system substituent selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted and optionally fused heteroaryl containing at least one heteroatom selected from nitrogen, sulfur and oxygen, optionally substituted sulfamoyl, excluding compounds in which R ¹ = H, CH ₃ , 3-chlorophenylaminocarbonyl, R ² = Br; R ¹ = CH ₃ , R ² = Cl, NO ₂ , CH ₂ OH, CH ₃ C (O), CO ₂ CH ₃ , CH ₂ NHC (O) CH ₂ Cl, 2-piperidin-1-yl-acetal-aminomethyl, 2-morpholin-4-yl-acetyl-aminomethyl, acyloxymethyl.

According to the invention, more preferred compounds are derivatives of (R, S) -noscapine of the general formula 1.1:

where: Ar is aryl or heteroaryl.

According to the invention, more preferred compounds are also derivatives of (R, S) -noscapine of the general formula 1.2:

where: R ³ and R ⁴ independently from one another are the same or different substituents of the amino group selected from hydrogen, alkyl, aryl, or R ³ and R ⁴ together with the nitrogen atom to which they are bonded, are shorted through R ³ and R ⁴ azaheterocycle.

According to the invention, more preferred compounds are also derivatives of (R, S) -noscapine of the general formula 1.3:

where: R ³ and R ⁴ have the meaning indicated for compounds of General formula 1.2.

The most preferred compounds of general formula 1 are: 3- (9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4,5-g] isoquinoline-5- il) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (1), 3- (4-methoxy-6-methyl-9-chloromethyl-5,6,7,8-tetrahydro [1,3] -dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (2), 5- (4,5-dimethoxy-3-oxo-1,3 -dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinoline-9-carbaldehyde 1 (3), 5 - (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4, 5-g] isoquinoline-9-carbonitrile acid 1 (4) , 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxolo [ 4,5-g] isoquinoline-9-carboxylic acid 1 (5), 3- (9-methoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4 , 5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (6) and 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1 -yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinoline-9-sulfonyl chloride 1 (7):

The most preferred compounds of general formula 1.1 are: 3- (9-phenyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4,5-g] isoquinoline-5- il) -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (1), 3- (9-p-tolyl-4-methoxy-6-methyl-5; 6,7,8-tetrahydro [1, 3] dioxolo- [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (2), 3- [9- (4-methoxyphenyl) -4-methoxy -6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran1-one 1.1 (3 ), 3- [9- (4-chlorophenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (4), 3- [9- (4-trifluoromethyl il) -4-methoxy-6-methyl-5,6,7,8-tetra-hydro [1,3] dioxolo- [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H -isobenzofuran-1-one 1.1 (5), 3- [9- (4-dimethylaminophenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4 , 5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (6), 3- [9- (4-nitrophenyl) -4-methoxy-6-methyl-5 6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (7), 3- [9 - (4-ethoxycarbonylphenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy- 3H-isobenzofuran-1-one 1.1 (8),

3- [9- (4-fluorophenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6, 7-dimethoxy-3H-isobenzofuran-1-one 1.1 (9), 3- [9-m-tolyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [ 4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (10), 3- [9- (3-methoxyphenyl) -4-methoxy-6-methyl- 5,6,7,8-tetrahydro [1,3] -disolo [4,5-G] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (11), 3- [9- (3-chlorophenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6,7 -dimethoxy-3H-isobenzofuran-1-one 1.1 (12), 3- [9- (3-fluorophenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6,7-d imethoxy-3H-isobenzofuran-1-one 1.1 (13), 3- [9- (3-nitrophenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4 , 5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (14), 3- [9- (3-trifluoromethylphenyl) -4-methoxy-6-methyl-5 , 6,7,8-tetrahydro [1,3] -disolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-iso-benzofuran-1-one 1.1 (15), 3 - [9- (3,4-dimethylphenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (16),

3- [9- (3-pyridyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6 , 7-dimethoxy-3H-isobenzofuran-1-one 1.1 (17), 3- [9- (4-pyridyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (18), 3- [9- (2-pyridyl) -4-methoxy-6 methyl 5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (19) , 3- [9- (2-thienyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] - 6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (20), 3- [9- (3-thienyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3 ] -dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3 H-isobenzofuran-1-one 1.1 (21), 3- [9- (2-furyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] -disolo [4, 5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (22). 3- [9- (5-indolyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-G] isoquinolin-5-yl] -6 , 7-dimethoxy-3H-isobenzofuran-1-one 1.1 (23), 3- [9- (5-pyrimidinyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] -dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (24),

3- [9- (2-benzofuranyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6 , 7-dimethoxy-3H-isobenzofuran-1-one 1.1 (25), 3- [9- (3-dimethylaminophenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] -dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (26), 3- [9- (6-methoxypyridin-3-yl) -4 -methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] -dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (27), 3- [9- (3-carboxyphenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinoline-5 -yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (28), 3- [9- (4-carboxyphenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1.3 ] -dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (29), 3- [9- (3-carbamoylphenyl) -4-methoxy- 6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-l-one 1.1 (30 ), 3- [9- (4-isoquinolinyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (31), 3- [9- (4-pyridinyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1, 3] dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (32),

3- [9- (1-tert-butyloxycarbonylindol-2-yl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] -disolo [4,5-g] isoquinoline- 5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (33), 3- [9- (1-tert-butyloxycarbonyl-5-methoxyindol-2-yl-4-methoxy-6- methyl 5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (34), 3- [9- (3-hydroxyphenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6 , 7-dimethoxy-3H-isobenzofuran-l-one 1.1 (35), 3- [9- (4-hydroxyphenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (36), 3- [9- (4-methanesulfonate) onylphenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran -1-one 1.1 (37), 3- [9- (3-thienyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -disolo [4,5-g ] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (38), 3- [9- (5-indazolyl) -4-methoxy-6-methyl-5,6,7 , 8-tetrahydro [1,3] -disolo [4,5-g] isoquinolin-5-yl] -6,7-dimethoxy-3H-isobenzofuran-l-one 1.1 (39), 1- {4- [5 - (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4, 5-isoquinolin-9-yl] phenyl} -3-phenyl-urea 1.1 (40) or 1- {3- [5- (4,5-dimethoxy-3-oxo-1,3-dihydro-isobenzofuran-1 -yl) -4-metho xi-6-methyl-5,6,7,8-tetrahydro- [1,3] dioxolo [4,5-isoquinolin-9-yl] phenyl} -3-phenyl-urea 1.1 (41).

The most preferred compounds of general formula 1.2 are: 3- (9-benzylaminomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinoline-5 -yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1,2 (1), 3- (9-diethylaminomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [ 1,3] dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1,2 (2), 3- (9-N-pyrrolidinomethyl-4- methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 , 2 (3), 3- (9-N-piperidinomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinoline-5- il) -6,7-dimethoxy-3H-isobenzofuran-1 -one 1,2 (4), 3- (9-N-morpholinomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinoline -5-yl) -6,7-dimethoxy-3H-isobenzo-furan-1-one 1,2 (5), 3- (9-N-piperazinomethyl-4-methoxy-6-methyl-5,6,7 , 8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1,2 (6), 3- (9- aminomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran- 1-one 1.2 (7).

The most preferred compounds of general formula 1.3 are: 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8- tetrahydro- [1,3] dioxolo [4,5-g] isoquinolin-9-sulfonylamide 1,3 (1), 6,7-dimethoxy-3- [4-methoxy-6-methyl-9- (pyrrolidin-1 -sulfonyl) -5,6,7,8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -3H-isobenzofuran-1-one 1,3 (2), 6, 7-dimethoxy-3- [4-methoxy-6-methyl-9- (piperidin-1-sulfonyl) -5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinoline- 5-nl] -3H-isobenzofuran-1-one 1,3 (3), 6,7-dimethoxy-3- [4-methoxy-6-methyl-9- (morpholin-1-sulfonyl) -5,6, 7,8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinoline -5-yl] -3H-isobenzofuran-1-one 1.3 (4), 6,7-dimethoxy-3- [4-methoxy-6-methyl-9- (piperazin-1-sulfonyl) -5,6,7 , 8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -3H-isobenzofuran-1-one 1.3 (5), 5- (4,5-dimethoxy-3-oxo- 1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinoline-9-sulfonyl diethylamide 1, 3 (6), 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1, 3] dioxolo [4,5-g] isoquinolin-9-sulfonyl di (2-hydroxyethyl) amide 1.3 (7).

The aim of this invention is a method for producing compounds of General formula 1, or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates.

According to this invention, methods have been developed for the preparation of derivatives of (R, S) -noscapine, allowing to maintain the optical activity inherent in the original alkaloid.

According to this invention, a method for producing 3- (9-iodine-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (1) consisting in the action of ICl on (R, S) -noscapine NSC in acetic acid according to the following scheme:

According to this invention, a method for producing 3- (9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] -disolo [4,5-g] isoquinolin-5-yl) is developed -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (2), which consists in the action of thionyl chloride on 3- (9-hydroxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [ 1,3] -dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one A-04 according to the following scheme:

According to this invention, a method for producing 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1 , 3] dioxolo [4,5-g] isoquinoline-9-carbaldehyde 1 (3) consisting in the action of hexamethylenetetramine 2 on 3- (9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] -dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-l-one 1 (2) in an organic solvent medium according to the following scheme:

According to this invention, a method for producing 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1 , 3] dioxolo [4,5-g] isoquinoline-9-carbonitrile 1 (4), which consists in the action of copper (1) cyanide on 3- (9-bromethoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one A01 or 9-iodine-4-megoxy-6-methyl-5, 6,7,8-tetrahydro [1,3] dioxolo- [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (1) in an aprotic solvent according to following diagram:

According to this invention, a method for producing 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1 , 3] dioxolo [4,5-g] isoquinoline-9-carboxylic acid 1 (5) by hydrolysis of 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy- 6-methyl-5,6,7,8-tetrahydro [l, 3] dioxolo [4,5-g] isoquinoline-9-carbonitrile 1 (4) according to the following scheme:

According to this invention, a method for producing 3- (9-methoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (6) by the reaction of 3- (9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] -disolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (2) with methanol in the presence of a base according to the following scheme:

According to this invention, a method for producing 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1 , 3] dioxolo [4,5-g] isoquinoline-9-sulfonyl chloride 1 (7) consisting in the action of chlorosulfonic acid on (R, S) -noscapine NSC according to the following scheme:

According to this invention, a method for producing derivatives of (R, S) -noscapine of the general formula 1.1 is obtained by reacting 3- (9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo - [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one A-01 or its iodide analog 1 (1) in the presence of a paladium catalyst with an aryl or heteroaryl boron derivatives of the General formula 3 according to the following scheme:

where Ar has the meanings indicated above in the definition of formula 1.1. As boric (get) arylating agents, use (get) arylboronic acids 3 (Z = H), alkyl esters of these acids 3 (Z = alkyl C ₁ -C ₄ ), or cyclic esters of these acids, for example,

.

.

Cross-coupling is carried out in a polar aprotic solvent (dimethylformamide, N-methylpyrrolidone, dimethoxyethane or the like), in the presence of 1-5 equivalents of an inorganic base (carbonates, fluorides, bicarbonates or fully substituted alkali and alkaline earth metal phosphates, for example cesium carbonate, potassium fluoride, as well as silver phosphate) and 5-25 mol.% of the catalyst, which is used as palladium chloride or acetate, as well as their complexes with organophosphorus ligands, such as triphenylphosphine. The reaction is carried out by heating at a temperature of 100-170 ° C, under or without microwave irradiation.

Most preferred is a stereospecific method for the synthesis of noscapine derivatives of general formula 1.1, characterized in that the cross-combination of A-01 and (get) arylboric acids is carried out in polar aprotic solvents (e.g. dimethoxyethane) in the presence of 3-4 equivalents of cesium carbonate and 10-20 pier % complex of palladium chloride with triphenylphosphine at 130-150 ° C under the influence of microwave irradiation.

According to this invention, a method for producing derivatives of (R, S) -noscapine of general formula 1.2 is developed by reacting 3- (9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] - dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (2) with amines R ³ R ¹ NH of general formula 4 in an organic solvent medium according to the following scheme:

According to this invention, the developed method for producing derivatives of (R, S) -noscapine of the general formula 1.2 consists in reductive amination of 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6 -methyl-5,6,7,8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinoline-9-carbaldehyde 1 (3) amines of the general formula 4 in an organic solvent medium according to the following scheme:

According to this invention, the developed method for producing derivatives of (R, S) -noscapine of the general formula 1.3 consists in the interaction of 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6- methyl 5,6,7,8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinoline-9-sulfonyl chloride 1 (7) with amines of the general formula 4 according to the following scheme:

In addition, the compounds of general formula 1 of the present invention can form hydrates or pharmaceutically acceptable salts. Inorganic acids and organic acids, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzene sulfonic acid, can be used. , paratoluenesulfonic acid.

According to this invention, the compounds of general formula 1, or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates can be used as an active ingredient for the treatment and prevention of influenza and acute viral respiratory diseases, in addition, in this invention also The proposed method for the treatment and prevention of these diseases, including the introduction of sick or susceptible to these diseases patients chemical compounds of the present invention in effective therapist ble doses.

An object of the present invention is a new combinatorial library for determining leader compounds.

This goal is achieved by a combinatorial library for determining leader compounds, consisting of compounds of the general formula 1.

An object of the present invention is a new focused library for determining leader compounds.

This goal is achieved by a focused library for determining leader compounds containing at least one compound of the general formula 1.

The aim of the present invention are a new pharmaceutical composition having anticancer activity.

The goal is achieved by a pharmaceutical composition containing, as an active ingredient, compounds of the general formula 1, or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates, as well as a pharmaceutically acceptable excipient. By pharmaceutically acceptable excipients are meant diluents, excipients and / or carriers used in the pharmaceutical field. The compounds of general formula 1 of the present invention can be used in combination with other active ingredients, provided that they do not cause undesirable effects, for example, allergic reactions.

If it is necessary to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed for the manufacture of various forms, and they may include traditional pharmaceutical carriers, for example, oral forms (such as tablets, gelatine capsules, pills, solutions or suspensions); injection forms (such as injectable solutions or suspensions, or dry powder for injection, which only requires the addition of water for injection before use); local forms (such as ointments or solutions).

The carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical industry to obtain common forms, including: in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless are used agents, flavoring agents of taste; antiseptic agents, solubilizers, stabilizers are used in injection forms. In local forms, bases, diluents, lubricants, antiseptic agents are used. Pharmaceutical preparations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically). If any medicinal substance is not stable under the conditions of the stomach, it can be used to make tablets coated with a film of a substance soluble in the stomach or intestines.

In addition, the clinical dosage of a compound of general formula 1, or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion organism, as well as depending on the age, gender and stage of the patient’s disease. In this case, the daily dose in adults is usually 10 ~ 500 mg, preferably 50 ~ 300 mg. Therefore, during the preparation of the pharmaceutical compositions of the present invention in dosage units, the aforementioned effective dosage must be considered, with each dosage unit containing 10-500 mg of the compound of general formula 1, preferably 50-300 mg. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).

The aim of the present invention is a method of treating and preventing the development of various diseases of warm-blooded animals and people associated with tumor growth, in particular various types of human cancers.

This goal is achieved by administering to a warm-blooded animal or human a pharmaceutical composition containing, as an active ingredient, compounds of the general formula 1, or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates, as well as pharmaceutically acceptable excipients.

The aim of the present invention are antimitotic compounds and substances for experimental (in vivo, in vitro) studies of processes that stop cell division, used as "pharmacological tools".

This goal is achieved by the use of compounds of general formula 1 as antimitotic compounds and substances for experimental (in vivo, in vitro) studies of processes that stop cell division as “pharmacological tools”.

The following are specific examples that illustrate but do not limit its scope.

Example 1. 2- (9-Bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4,5-g] isoquinolin-5-yl) -6, 7-dimethoxy-3H-isobenzofuran-1-one A-01. To a solution of 1.03 g (2.5 mmol) of NSC in 10 ml of AcOH, 0.61 g (2.5 mmol) of a solution of HBr in AcOH is added, after which a solution of 0.8 g (5 mmol) of bromine in 2 ml of AcOH is added dropwise (after the addition of HBr, precipitation of NSC bromide hydrate is possible, which dissolves during bromination). After 15 minutes of stirring, the reaction mixture was poured onto 60 ml of a saturated ammonia solution cooled to ° C. The colorless precipitate formed is filtered off, washed thoroughly with water, dried, and 63% A-01 is obtained. NMR- ¹ H (CDCl ₃ , TMS): d 7.03 (Jo = 8.4 Hz, 1H, 5-H), d 6.30 (Jo = 8.4 Hz, 1H, 4-H), s 6.02 (2H, 2'-H ), d 5.49 (J = 4.8 Hz, 1H, 3-H), d 4.33 (J = 4.8 Hz, 1H, 5'-H), s 4.09 (3H, OCH ₃ ), s 3.98 (3H, OCH ₃ ), s 3.88 (3H, OCH ₃ ), m 2.6-2.8 (2H, 7'-H), s 2.51 (3H, 6'-CH ₃ ), m 2.42-2.50 (1H, 8'-H). m 1.92-2.01 (1H, 8'-H); NMR- ¹³ C (CDCl ₃ , TMS): 168.03, 152.36, 147.83, 146.58, 141.32. 140.02, 134.22, 130.38, 119.69, 119.05, 118.42, 117.53, 101.10, 95.61, 81.32, 62.32, 60.97. 59.46, 56.85, 48.46, 45.23, 25.96.

Example 2. 3- (9-Iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4,5-g] isoquinolin-5-yl) -6, 7-dimethoxy-3H-isobenzofuran-1-one 1 (1). A solution of 206 mg (0.5 mmol) NSC in 4 ml of AcOH) was mixed with 100 mg (0.6 mmol) of ICl and stirred for 3 hours at 50 ° C (reaction control using LC-MS). The reaction mass is neutralized with ammonia while cooling with ice. The precipitate is filtered off, washed with water and dried. 246 mg (71%) 1 (1) is obtained. ¹ H NMR (400 MHz, CDCl ₃ , TMS): δ 7.02 (d, 7 = 8.4 Hz, 1H), 6.27 (d, J = 8.4 Hz, 1H), 6.01 (s, 2H), 5.48 (d, 1H , 1H, 7 = 4.0 Hz), 4.32 (d, 1H, 7 = 4.0 Hz), 4.10 (s, 3H), 3.99 (s, 3H), 3.88 (s, 3H), 2.65-2.74 (m, 1H) , 2.51 (s, 3H), 2.42-2.62 (m, 2H), 1.89-1.96 (m, 1H), ¹³ C NMR (100 MHz, CDCl ₃ , TMS): δ 168.01, 152.35, 149.89, 147.85, 141.35. 140.95, 133.08, 133.03, 119.74, 119.39, 118.37, 117.54, 100.28, 81.34, 69.32, 62.33, 61.12. 59.48, 56.87, 49.13, 45.25, 30.97.

Example 3. 3- (9-Chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] -disolo [4,5-g] isoquinodin-5-yl) -6, 7-dimethoxy-3H-isobenzofuran-1-one hydrochloride 1 (2). A solution of 0.45 g (0.27 ml, 3.75 mmol) of SOCl ₂ in 3 ml of dichloromethane was added dropwise to a solution of 1.11 g (2.5 mmol) of 5-HOCH ₂ -NSC A-04 in 10 ml of dichloromethane, maintaining the temperature of the reaction mixture in the range of 0-3 ° С . The mixture is stirred at this temperature for 20 minutes, after which it is allowed to warm to room temperature and stirred for another 2.5 hours. The solvent is removed on a rotary evaporator at a temperature not exceeding 20 ° C, the residue is dissolved in acetone and reprecipitated with ether, kept for several hours in a refrigerator. a solid hygroscopic substance is filtered off, which is used in further syntheses without further purification. 1.18 g (95%) of 1 (2) are obtained. NMR- ¹ H (CDCl ₃ , TMS): d 7.65 (Jo = 8.3 Hz, 1H, 5-H), d 7.30 (Jo = 8.3 Hz, 1H, 4-H), br.s (1H, 3-H ), d 5.95 (J = 1.5 Hz, 1H, 2'-H), d. 5.89 (J = 1.5 Hz, 1H, 2'-H), br.s. 5.22 (1H, 5'-H), d 4.64 (J = 11.0 Hz, 1H, 9-CH ₂ -Cl), d 4.49 (J = 11.0 Hz, 1H, 9-CH ₂ -Cl), m 4.10-4.21 (1H, 7'-H), s 3.98 (3H, OCH ₃ ), s 3.91 (3H, OCH ₃ ), m 3.44-3.53 (1H, 7'-H), s 3.26 (3H, OCH ₃ ), m 3.10-3.30 (2H, 8'-H), br.s 2.88 (3H, 6'-CH ₂ ); NMR- ¹³ C (CDCl ₃ , TMS): 166.52, 152.79, 149.48, 147.69, 14.27, 139.20, 133.29. 125.92, 119.57, 118.90, 117.12, 110.63, 107.63, 101.72, 78.61, 62.21, 62.17, 58.47, 56.99, 44.76, 39.89, 36.69, 18.19.

Example 4. 5- (4,5-Dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinoline-9-carbaldehyde 1 (3).

A solution of 200 mg (0.4 mmol) of hydrochloride 1 (2) in 2 ml of water is mixed with 0.6 ml of 1N NaOH. The resulting emulsion was extracted with chloroform, the extract was dried with anhydrous Na ₂ SO ₄ , concentrated to 2 ml and boiled with 70 mg (0.5 mmol) of hexamethylenetetramine. The reaction mass is cooled, the precipitate is filtered off, washed with ether, dried and dissolved in 3 ml of water. The resulting solution was boiled for 2 hours, cooled and extracted with chloroform. The extract was dried with anhydrous Na ₂ SO ₄ , concentrated and mixed with i-PrOH-ether. The precipitate was separated, dried, and 1 (3) was obtained as hydrochloride, NMR- ¹ N (400 MHz, CDCl ₃ ): 10.21 (1H, s); 7.75 (1H, d, J = 7.6 Hz); 7.29 (1H, d, J = 7.6 Hz); 6.58 (1H, br.m), 6.04 (1H, s), 6.00 (1H, s), 5.29 (1H, br, M), 4.01-4.12 (1H, m), 3.99 (3H, s), 3.91 ( 3H, s); 3.67-3.75 (1H, m); 3.42-3.52 (1H, m); 3.31-3.40 (1H, m); 3.35 (3H, s); 2.91 (3H, s); 2.91 (3H, s); 1.84 (br.s); Hydrochloride 1 (3) is dissolved in water, neutralized with aqueous ammonia, the precipitate is filtered off and dried to give 102 mg (46%) 1 (3), ¹ N NMR (400 Hz, CDCl ₃ ): 10.26 (1H, s); 7.05 (1H, d, J = 8.4 Hz); 6.51 (1H, d, J = 8.4 Hz); 6.08 (2H, s); 5.43 (1H, d, 5.1 Hz), 4.29 (1H, d, J = 5.1 Hz); 4.10 (3H, s); 4.08 (3H, s); 3.89 (3H, s); 3.13-3.19 (1H, m); 2.82-2.87 (1H, m); 2.51 (3H, s); 2.39-2.50 (2H, m), ¹³ C NMR (100 MHz, CDCl ₃ ): 187.2: 168.0; 153.3; 152.4; 147.9; 145.1; 141.7; 133.5; 133.3; 119.5; 118.6; 118.1; 117.4; 111.4; 102.1; 81.2; 62.3; 61.0; 59.6; 56.8; 47.8; 45.1; 23.4.

Example 5. General method for producing 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1 , 3] dioxolo [4,5-g] isoquinoline-9-carbonitrile 1 (4).

A mixture of 0.2 mmol of 3- (9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4,5-g] isoquinolin-5-yl) -6, 7-dimethoxy-3H-isobenzofuran-1-one A-01 or 3- (9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4,5 -g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (1), 36 mg (0.4 mmol) of CuCN and 2 ml of dimethylformamide are stirred for 24 hours at 130 ° C in an inert atmosphere. The reaction mass is cooled to 4 ° C and 15 ml of ammonia and 15 ml of chloroform are added with stirring. The organic layer was separated, washed with water, dried over Na ₂ SO ₄ , filtered, the resulting solution was stirred for 15 minutes with activated carbon, filtered and concentrated. The precipitate is filtered off and recrystallized from isopropanol. Obtain 1 (4), ¹ N NMR (400 MHz, CDCl ₃ , TMS): 7.06 (d, J = 8.1 Hz, 1H, 5-H), 6.46 (d, J = 8.1 Hz, 1H), 6.06 (d , 1H, J = 1.1 Hz), 6.05 (d, 1H, J = 1.1 Hz), 5.42 (d, J = 4.8 Hz, 1H), 4.23 (d, J = 4.8 Hz, 1H). 4.09 (s, 3H), 4.04 (s, 3H), 3.88 (s, 3H), 2.73-2.87 (m, 2H), 2.52-2.55 (m, 1H), 2.50 (s, 3H), 2.18-2.24 ( m, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ): 168.0; 152.7; 152.3; 148.2; 144.5; 141.5; 133.9; 133.7; 119.6; 118.9; 118.8; 117.5; 114.0; 102.4; 87.3; 81.0; 62.5; 61.0; 59.8; 57.0; 47.7; 45.1; 24.6.

Example 6. 3- (9-Methoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] -disolo [4,5-g] isoquinolin-5-yl) -6, 7-dimethoxy-3H-isobenzofuran-1-one 1 (5).

0.5 ml of diisopropylethylamine is added to a suspension of 100 mg (0.2 mmol) 1 (2) in 3 ml of MeOH, the mixture is boiled until the initial hydrochloride is completely dissolved, cooled, treated with water, the precipitated oil is extracted with EtOAc, the organic layer is dried over Na ₂ SO ₄ , the solvent is evaporated, the solvent is evaporated , the residue was purified by flash chromatography (hexane - EtOAc from 40 to 60%) to obtain 69 mg (75%) 1 (5) as an oil-like slowly crystallizing substance. ¹ H NMR (CDCl ₃ , TMS): d 6.94 (Jo = 8.4 Hz, 1H, 5-H), d 6.14 (Jo = 8.4 Hz, 1H, 4-H), s 5.96 (2H, 2'-H) , d 5.53 (J = 4.8 Hz, 1H, 3-H), d 4.39 (J = 4.8 Hz, 1H, 5'-H), s 4.39 (2H, 9-CH ₂ -O), s 4.09 (3H, OCH ₃ ), s 4.02 (3H, OCH ₃ ), s 3.85 (3H, OCH ₃ ), s 3.34 (2H, OCH ₃ ), m 2.56-2.72 (2H, 7'-H), s 2.53 (3H, 6 '-CH ₃ ), m 2.33-2.40 (1H, 8'-H), m 1.84-1.96 (1H, 8'-H); ¹³ C NMR (CDCl ₃ , TMS): 168.16, 152.23. 147.98, 147.72, 141.33, 140.38, 133.23, 132.27, 120.08, 118.24, 117.77, 117.57, 110.38, 100.87, 81.82, 65.03, 62.31, 61.07, 59.40, 57.78, 56.83, 49.50, 46.06, 23.58.

Example 7. General method for producing 3- (9-aryl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-ones of the general formula 1.1.

7.17 (d, 2H, J=8.8 Hz), 7.00 (d, 1=8.1 Hz, 1H), 6.95 (d, 2H, J=8.8 Hz), 6.11 (d, 1H, J=8.1 Hz,), 5.98 (d, 1H, J=1.1 Hz), 5.91 (d, 1H, J=1.1 Hz), 5.55 (d, 1H, J=4.0 Hz), 4.49 (d, 1H, J=4.0 Hz), 4.11 (s, 3Н), 4.03 (s. 3Н), 3.90 (s, 3Н), 3.84 (s, 3Н), 2.65-2.70 (m, 1H), 2.56 (s, 3Н), 2.15-2.30 (m, 2H), 1.66-1.73 (m, 1H); 3-[9-(3-пиридил)-4-метокси-6-метил-5,6,7,8-тетрагидро[1,3]-диоксоло[4,5-g]изохинолин-5-ил]-6,7-диметокси-3Н-изобензофуран-1-он 1.1(17), NMR-¹H (CDCl₃, TMS): dd 8.58 (J=4.8 Hz, J=1.5 Hz, 1H, Py-H), d 8.50 (J=1.5 Hz, 1H, Py-H), m 7.60-7.64 (1H, Py-H), m 7.33-7.38 (1H, Py-H), d 7.03 (Jo=8.4 Hz, 1H, 5-H), d 6.18 (J=8.4 Hz, 1H, 4-H), d 6.00 (J=1.5 Hz, 2'-H). d 5.93 (J=1.5 Hz, 2'-H), d 5.54 (J=4.8 Hz, 1H, 3-H), d 4.50 (J-4.8 Hz, 1H, 5'-H), s 4.11 (6H, ОСН₃), s 3.91 (3Н, ОСН₃), m 2.59-2.65 (1H, 7'-H), s 2.56 (3Н, 6'-СН₃), m 2.16-2.24 (2H, 7'Н, 8'-H), m 1.69-1.77 (1H, 8'-H), NMR-¹³C (CDCl₃, TMS): 167.99, 152.44, 150.86, 148.49, 147.81, 146.51, 140.93, 140.35, 137.41, 133.83, 130.84, 130.29, 123.17, 120.53, 118.34, 117.83, 117.67, 112.66, 101.03, 81.92, 62.33, 61.17, 59.58, 56.95, 50.75, 46.47, 26.98; 3-[9-(4-пиридил)-4-метокси-6-метил-5,6,7,8-тетрагидро[1,3]-диоксоло[4,5-g]изохинолин-5-ил]-6,7-диметокси-3Н-изобензофуран-1-он 1.1(18): NMR-¹H (CDCl₃, TMS): d 8.64 (J=5.9 Hz, 2H, Py-H), d 7.19 (J=5.9 Hz, 2H, Py-H), d 7.03 (Jo=8.4 Hz, 1H, 5-H), d 6.20 (Jo=8.4 Hz, 1H, 4-H), d 6.01 (J=1.5 Hz, 2'-H), d 5.94 (J=1.5 Hz, 2'-H), d 5.53 (J=4.8 Hz, 1H, 3-H), d 4.48 (J=4.8 Hz, 1H, 5'-H), s 4.12 (3Н, ОСН₃), s 4.10 (3Н, ОСН₃), s 3.91 (3Н, ОСН₃), m 2.61-2.69 (1H, 7'-H), s 2.56 (3Н, 6'-СН₃), m 2.16-2.28 (2Н, 7'Н, 8'-Н), m 1.72-1.83 (1H, 8'-Н); NMR-¹³С (CDCl₃, TMS): 167.96, 152.44, 149.75, 147.87, 146.20, 142.47, 141.03, 140.60. 133.84, 130.44, 124.99, 120.50, 118.48, 117.89, 117.68, 113.61, 101.09, 81.84, 62.35, 61.17. 59.58, 56.99, 50.62, 46.64, 26.97; 3-[9-(5-пиримидинил)-4-метокси-6-метил-5,6,7,8-тетрагидро[1,3]-диоксоло[4,5-g]изохинолин-5-ил]-6,7-диметокси-3Н-изобензофуран-1-он 1.1(24), ¹H NMR (400 MHz, CDCl₃, TMS):

9.17 (s, 1H), 8.68 (s, 2Н), 7.03 (d, J=8.4 Hz, 1H), 6.22 (d, J=8.4 Hz, 1H), 6.03 (d, J=1.1 Hz), 5.96 (d, J=1.1 Hz), 5.52 (d, J=4.1 Hz, 1H), 4.49 (d, J=4.1 Hz, 1H), 4.11 (s, 6H), 3.91 (s, 3Н), 2.65-2.70 (m, 1H), 2.57 (s, 3Н), 2.17-2.27 (m, 2Н), 1.77-1.85 (m, 1H); 4-(5R)-5-[(18)-(4,5-диметокси-3-оксо-1,3-дигидро-2-бензофуран-1-ил]-4-метокси-6-метил-5,б,7,8-тетрагидро-[1,3]диоксоло[4,5-g]изохинолин-9-илбензолкарбоксамид 1.1(25), ¹H NMR (400 MHz, CDCl₃, TMS):

7.86 (d, 2Н, J=8.4 Hz), 7.35 (d, 2Н, J=8.4 Hz), 7.03 (d, J=8.0 Hz, 1H). 6.20 (d, J=8.0 Hz, 1H), 5.59 (br.s, 1H). 5.99 (d, 1H, J=1.5 Hz), 5.93 (d, 1H, J=1.5 Hz), 5.75 (br.s, 1H), 5.54 (d, 1H, J=4.0 Hz, 1H), 4.50 (d, 1H, J=4.0 Hz), 4.11 (s, 3Н), 4.09 (s, 3Н), 3.91 (s, 3Н), 2.65-2.70 (m, 1H), 2.56 (s, 3Н), 2.17-2.25 (m, 2Н), 1.70-1.78 (m, 1H) и другие 3-(9-арил-4-метокси-6-метил-5,6,7,8-тетрагидро[1,3]диоксоло-[4,5-g]изохинолин-5-ил)-6,7-диметокси-3Н-изобензофуран-1-он 1.1, комбинаторная библиотека которых представленна в таблице 2.A mixture of 246 mg (0.5 mol) A-01, 0.6 mmol arylboronic acid 2, 70 mg (0.1 mmol) PdCl ₂ (PPh ₃ ) ₂ , 652 mg (2 mmol) Cs ₂ (CO ₃ ) ₂ in 5 ml of degassed DME is heated in a microwave oven at 140 ° C for 30 min, the reaction mixture is filtered through celite, the precipitate is washed with a DME filter, the combined filtrate is evaporated to dryness, the residue is treated several times with 2N HCl, each time bringing to a slight boil with stirring and decanting the aqueous layer from the resinous residue. Activated carbon is added to the combined aqueous solution, brought to a boil, filtered hot through celite, the filtrate is cooled and treated with an excess of an aqueous solution of NH ₃ . The precipitate, after keeping the mixture in the refrigerator for 2-3 hours, is filtered off, washed with plenty of water, and 160 mg of a colorless product 1.1 are obtained. If necessary, the substance can be further purified by flash chromatography (hexane gradient of ethyl acetate from 60 to 80%), including: 3- (9-phenyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran 1.1 (1), NMR- ¹ H (CDCl ₃ , TMS): m 7.38-7.44 (2H, Ar-H), m 7.31-7.36 (1H, Ar-H), m 7.23-7.26 (2H, Ar-H), d 7.02 (Jo = 8.4 Hz, 1H, 5-H), d 6.13 ( Jo = 8.4 Hz, 1H, 4-H), d 5.98 (.1 = 1.5 Hz, 2'-H), d 5.92 (J = 1.5 Hz, 2'-H), d 5.55 (J = 4.8 Hz, 1H , 3-H), d 4.51 (J-4.8 Hz, 1H, 5'-H), s 4.11 (3H, OCH ₃ ), s 4.10 (3H, OCH ₃ ), s 3.90 (3H, OCH ₃ ), m 2.57-2.61 (1H, 7'-H), s 2.56 (3H, 6'-CH ₃ ), m 2.14-2.25 (2H, 7'H, 8'-H), m 1.62-1.731 (1H, 8 ' -H), NMR- ¹³ C (CDCl ₃ , TMS): 168.10, 152.34, 147.74, 146.06, 141.04, 139.71. 134.23, 133.81, 130.90, 130.02, 128.26, 127.478, 120.60, 117.95, 117.88, 116.57, 100.88, 82.05, 62.33, 61.19, 59.58, 56.97, 50.97, 46.85, 27.14; 3- [9- (4-methoxyphenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [1,3] dioxolo- [4,5-g] isoquinolin-5-yl] - 6,7-dimethoxy-3H-isobenzofuran-1-one 1.1 (3), ¹ H NMR (400 MHz, CoCl ₃ , TMS):

7.17 (d, 2H, J = 8.8 Hz), 7.00 (d, 1 = 8.1 Hz, 1H), 6.95 (d, 2H, J = 8.8 Hz), 6.11 (d, 1H, J = 8.1 Hz,), 5.98 (d, 1H, J = 1.1 Hz), 5.91 (d, 1H, J = 1.1 Hz), 5.55 (d, 1H, J = 4.0 Hz), 4.49 (d, 1H, J = 4.0 Hz), 4.11 (s , 3H), 4.03 (s. 3H), 3.90 (s, 3H), 3.84 (s, 3H), 2.65-2.70 (m, 1H), 2.56 (s, 3H), 2.15-2.30 (m, 2H), 1.66-1.73 (m, 1H); 3- [9- (3-pyridyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6 , 7-dimethoxy-3H-isobenzofuran-1-one 1.1 (17), NMR- ¹ H (CDCl ₃ , TMS): dd 8.58 (J = 4.8 Hz, J = 1.5 Hz, 1H, Py-H), d 8.50 (J = 1.5 Hz, 1H, Py-H), m 7.60-7.64 (1H, Py-H), m 7.33-7.38 (1H, Py-H), d 7.03 (Jo = 8.4 Hz, 1H, 5-H ), d 6.18 (J = 8.4 Hz, 1H, 4-H), d 6.00 (J = 1.5 Hz, 2'-H). d 5.93 (J = 1.5 Hz, 2'-H), d 5.54 (J = 4.8 Hz, 1H, 3-H), d 4.50 (J-4.8 Hz, 1H, 5'-H), s 4.11 (6H, OCH ₃ ), s 3.91 (3H, OCH ₃ ), m 2.59-2.65 (1H, 7'-H), s 2.56 (3H, 6'-CH ₃ ), m 2.16-2.24 (2H, 7'H, 8 '-H), m 1.69-1.77 (1H, 8'-H), NMR- ¹³ C (CDCl ₃ , TMS): 167.99, 152.44, 150.86, 148.49, 147.81, 146.51, 140.93, 140.35, 137.41, 133.83, 130.84 , 130.29, 123.17, 120.53, 118.34, 117.83, 117.67, 112.66, 101.03, 81.92, 62.33, 61.17, 59.58, 56.95, 50.75, 46.47, 26.98; 3- [9- (4-pyridyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6 , 7-dimethoxy-3H-isobenzofuran-1-one 1.1 (18): NMR- ¹ H (CDCl ₃ , TMS): d 8.64 (J = 5.9 Hz, 2H, Py-H), d 7.19 (J = 5.9 Hz , 2H, Py-H), d 7.03 (Jo = 8.4 Hz, 1H, 5-H), d 6.20 (Jo = 8.4 Hz, 1H, 4-H), d 6.01 (J = 1.5 Hz, 2'-H ), d 5.94 (J = 1.5 Hz, 2'-H), d 5.53 (J = 4.8 Hz, 1H, 3-H), d 4.48 (J = 4.8 Hz, 1H, 5'-H), s 4.12 ( 3H, OCH ₃ ), s 4.10 (3H, OCH ₃ ), s 3.91 (3H, OCH ₃ ), m 2.61-2.69 (1H, 7'-H), s 2.56 (3H, 6'-CH ₃ ), m 2.16-2.28 (2H, 7'H, 8'-H), m 1.72-1.83 (1H, 8'-H); NMR- ¹³ C (CDCl ₃ , TMS): 167.96, 152.44, 149.75, 147.87, 146.20, 142.47, 141.03, 140.60. 133.84, 130.44, 124.99, 120.50, 118.48, 117.89, 117.68, 113.61, 101.09, 81.84, 62.35, 61.17. 59.58, 56.99, 50.62, 46.64, 26.97; 3- [9- (5-pyrimidinyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -6 , 7-dimethoxy-3H-isobenzofuran-1-one 1.1 (24), ¹ H NMR (400 MHz, CDCl ₃ , TMS):

9.17 (s, 1H), 8.68 (s, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.22 (d, J = 8.4 Hz, 1H), 6.03 (d, J = 1.1 Hz), 5.96 ( d, J = 1.1 Hz), 5.52 (d, J = 4.1 Hz, 1H), 4.49 (d, J = 4.1 Hz, 1H), 4.11 (s, 6H), 3.91 (s, 3H), 2.65-2.70 ( m, 1H), 2.57 (s, 3H), 2.17-2.27 (m, 2H), 1.77-1.85 (m, 1H); 4- (5R) -5 - [(18) - (4,5-dimethoxy-3-oxo-1,3-dihydro-2-benzofuran-1-yl] -4-methoxy-6-methyl-5, b 7,8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinolin-9-ylbenzenecarboxamide 1.1 (25), ¹ H NMR (400 MHz, CDCl ₃ , TMS):

7.86 (d, 2H, J = 8.4 Hz), 7.35 (d, 2H, J = 8.4 Hz), 7.03 (d, J = 8.0 Hz, 1H). 6.20 (d, J = 8.0 Hz, 1H); 5.59 (br.s, 1H). 5.99 (d, 1H, J = 1.5 Hz), 5.93 (d, 1H, J = 1.5 Hz), 5.75 (br.s, 1H), 5.54 (d, 1H, J = 4.0 Hz, 1H), 4.50 (d , 1H, J = 4.0 Hz), 4.11 (s, 3H), 4.09 (s, 3H), 3.91 (s, 3H), 2.65-2.70 (m, 1H), 2.56 (s, 3H), 2.17-2.25 ( m, 2H), 1.70-1.78 (m, 1H) and other 3- (9-aryl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4,5 -g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1.1, the combinatorial library of which is shown in Table 2.

Table 2. Combinatorial library of 3- (9-aryl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4,5-g] isoquinolin-5-yl) -6.7 -dimethoxy-3H-isobenzofuran-1-ones 1.1. No. Formula Like weight (M) LC-MS, m / z (M + H) 1.1 (1)

489.53 490 1.1 (2)

503.56 594 1.1 (3)

519.56 520 1.1 (4)

523.97 524 1.1 (5)

557.53 558

1.1 (6)

532.60 533 1.1 (7)

534.53 535 1.1 (8)

561.59 562 1.1 (9)

507.52 508

1.1 (10)

503.56 504 1.1 (11)

519.56 520 1.1 (12)

523.97 524 1.1 (13)

507.52 508

1.1 (14)

534.53 535 1.1 (15)

557.53 558 1.1 (16)

517.58 518 1.1 (17)

490.52 491

1.1 (18)

490.52 491 1.1 (19)

490.52 491 1.1 (20)

495.56 496 1.1 (21)

495.56 496

1.1 (22)

479.49 480 1.1 (23)

528.57 529 1.1 (24)

491.51 492 1.1 (25)

529.55 530

1.1 (26)

532.60 533 1.1 (27)

520.54 521 1.1 (28)

533.54 534 1.1 (29)

533.54 534

1.1 (30)

532.56 533 1.1 (31)

540.58 541 1.1 (32)

479.49 480 1.1 (33)

628.69 629

1.1 (34)

658.71 659 1.1 (35)

505.53 506 1.1 (36)

505.53 506 1.1 (37)

567.62 568

1.1 (38)

495.56 496 1.1 (39)

529.55 530 1.1 (40)

623.67 624 1.1 (41)

623.67 624

Example 7. General method for producing 3- (9-aminomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinolin-5-yl) -b, 7-dimethoxy-3H-isobenzofuran-1-one 1.2.

To a solution of 1 ml of amine in 3 ml of MeOH add 100 mg (0.2 mmol) 1 (2), the mixture is brought to a boil, cooled, treated with water, extracted with ethyl acetate, the organic layer is dried over Na ₂ SO ₄ , the solvent is evaporated, the residue is purified flash chromatography (20% hexane in EtOAc — pure EtOAc) gives 1.2, including: 3- (9-M-morpholinomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3 ] dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1.2 (5), NMR- ¹ H (CoCl ₃ , TMS): d 6.90 (Jo = 8.1 Hz, 1H, 5-H), d 6.11 (Jo = 8.1 Hz, 1H, 4-H), d 5.94 (J = 1.5 Hz, 1H. 2'-H), d 5.92 (J = 1.5 Hz, 1H , 2'-H), d 5.54 (J = 4.4 Hz, 1H, 3-H), d 4.40 (J = 4.4 Hz, 1H, 5'-H). s 4.10 (3H, OCH ₃ ), s 4.01 (3H, OCH ₃ ), s 3.86 (3H, OCH ₃ ), m 3.65-3.69 (4H, CH ₂ -O-CH ₂ ), d 3.42 (J = 12.5 Hz , 1H, 9'-CH), d 3.37 (J = 12.5 Hz, 1H, 9'-CH), m 2.64-2.72 (2H, 7'-H), s 2.54 (3H, 6'-CH ₃ ), m 2.40-2.46 (4H, CH ₂ -N-CH ₂ ), m 2.31-2.39 (1H, 8'-H), m 1.88-1.98 (1H, 8'-H); NMR- ¹³ C (CDCl ₃ , TMS): 168.11, 152.20, 148.10, 147.792, 141.47, 139.698, 132.99, 132.594, 120.17, 118.05, 117.67, 117.52, 110.23, 100.61, 81.88, 67.19, 62.32, 61.08, 59.38, 56.85 , 53.26, 52.99, 49.90, 46.27, 24.16 and other 3- (9-aminomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-ones 1.2, the combinatorial library of which is presented in table 3.

Table 3. Combinatorial library of 3- (9-aminomethyl-4-methoxy-6-methyl-5.6,7,8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy -3H-isobenzofuran-1-ones 1.2. No. Formula Like weight (M) LC-MS, m / z (M + H) 1.2 (1)

518.57 519 1.2 (2)

498.58 499 1.2 (3)

496.57 497 1.2 (4)

510.59 511 1.2 (5)

512.56 513

1.2 (6)

511.58 512 1.2 (7)

442.47 443

Example 8. General method for producing 6,7-Dimethoxy-3- [4-methoxy-6-methyl-9- (sulfamoyl) -5,6,7,8-tetrahydro [1,3] dioxolo [4,5- g] isoquinolin-5-yl] -3H-isobenzofuran-1-ones 1.3.

To a chlorosulfonic acid (1 ml) cooled to 0 ° C, 103 mg (0.25 mmol) of NSC are added with stirring. The mixture was stirred in the cold for 0.5 h, after which it was transferred to ice. The solid is separated by centrifugation, washed with ice water with repeated centrifugation. The resulting sulfonyl chloride 1 (6) is dissolved in dioxane and treated with 0.5 mmol of amine. The solution was stirred for 20 minutes, treated with water, the precipitated solid was separated by centrifugation, washed with water, dried, recrystallized from propanol-2. Obtain 1.3, including 6,7-dimethoxy-3- [4-methoxy-6-methyl-9- (morpholin-1-sulfonyl) -5,6,7,8-tetrahydro [1,3] dioxolo [ 4,5-g] isoquinolin-5-yl] -3H-isobenzofuran-1-one 1.3 (5), NMR- ¹ H (CoCl ₃ , TMS): d 7.07 (Jo = 8.4 Hz, 1H, 5-H) , d 6.40 (Jo = 8.4 Hz, 1H, 4-H), d 6.07 (J = 1.5 Hz, 2-H), d 6.06 (J-1.5 Hz, 2'-H), d 5.40 (J = 4.8 Hz , 1H, 3-H), d 4.37 (J = 4.8 Hz, 1H, 5'-H), s 4.10 (3H, OCH ₃ ), s 4.09 (3H, OCH ₃ ), s 3.88 (3H, OCH ₃ ) , m 3.72-3.77 (4H, CH ₂ -O-CH ₂ ), m 3.15-3.25 (5H, CH ₂ -O-CH ₂ , 7'-H), m 2.81-2.88 (1H, 7'-H) , s 2.52 (3H, 6'-CH ₃ ), m 2.33-2.41 (1H, 8'-H), m 2.11-2.20 (1H, 8'-H), NMR- ¹³ C (CoCl ₃ , TMS): 167.87, 152.50, 148.55, 147.86. 143.77, 141.07, 133.93, 132.41, 119.78, 119.69, 118.50, 117.52, 111.18, 101.77, 81.34, 66.44, 62.30, 61.21, 59.67, 56.81, 49.35, 45.86, 45. 93, 24.96 and other 6,7-dimethoxy-3 - [4-methoxy-6-methyl-9- (sulfamoyl) -5,6,7,8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -3H-isobenzofuran- 1-ones 1.3, the combinatorial library of which is presented in table 4.

Table 4. Combinatorial library of 6,7-dimethoxy-3- [4-methoxy-6-methyl-9- (sulfamoyl) -5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinoline- 5-yl] -3H-isobenzofuran-1-ones 1.3. No. Formula Like weight (m) LC-MS, m / z (M + H) 1.3 (1)

492.51 493 1.3 (2)

546.60 547 1.3 (3)

560.63 561 1.3 (4)

562.60 563 1.3 (5)

561.62 562 1.3 (6)

548.62 549 1.3 (7)

580.62 581

Example 9. Testing the anticancer activity of compounds of general formula 1. A focused library of nascopins of general formula 1 was tested for their ability to inhibit cell growth in four tumor lines: DLD-1 - colorectal adenocarcinoma; DU-145 - metastatic prostate cancer; T-47D - Metastatic Breast Cancer; and Jurkat - T Leukemia. For this, cell cultures were maintained in a standard nutrient medium containing specified concentrations of the studied compounds. The substances were introduced into the medium in the form of solutions in DMSO. The proliferation profile of tumor cells was measured using an Alamar Blue dye, which allows photometric determination of the number of living cells. The overall effect of inhibition of cell growth and death was calculated as a percentage of the Alamar Blue signal in the experimental samples and the Alamar Blue signals in control experiments in which tumor cell cultures were treated only with pure DMSO. Table 5 presents the results of the anticancer activity test for some of the tested compounds of general formula 1, with more pronounced inhibition of cell growth expressed in a large number.

Table 5. Suppression of tumor cell proliferation under the action of compounds of the general formula 1. Compound T-47d DU-145 DLD-1 Jurkat-t 10 μM 30 μm 10 μM 30 μm 10 μm 30 μm 1 μM 3 μM 10 μM 30 μm Noskapin 3 34 5 twenty 2 twenty 2 7 twenty 89 Noscapine HCl 9 17 3 16 7 eighteen 2 four eighteen 92 A-01 39 45 39 58 23 39 2 32 94 91 1 (8) 22 -2 0 four 5 7 -one four 8 8 1 (5) 8 7 -2 6 fourteen eighteen 0 7 6 fourteen 1 (3) 13 13 9 10 16 19 5 8 9 16 1 (3) HCl 6 eleven 17 fifteen eleven 17 3 9 10 17 1.2 (5) -one -one 0 four 6 fourteen 12 8 2 fifteen 1.3 (4) four 16 2 10 eighteen 17 10 fifteen 5 13 1.2 (7) 13 fifteen fourteen 13 9 fourteen 8 12 7 fifteen 1.1 (1) 12 43 -one eighteen 16 31 0 8 24 56 1.1 (19) 3 5 four -one 7 12 3 7 5 13 1.1 (18) 10 fifteen 5 -four 6 17 one 5 12 19 1 (1) 5 28 86 94

Claims (20)

1. Substituted noscapine of general formula 1, or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates

where R ¹ represents an amino group substituent selected from alkyl; R ² represents a cyclic system substituent selected from optionally substituted alkyl, where the substituents are selected from a possibly substituted amino group, or an azaheterocycle, optionally containing O, S or N as an additional heteroatom, and attached by a nitrogen atom to an alkyl group, possibly substituted aryl, substituted and possibly fused heteroaryl containing at least one heteroatom selected from nitrogen, sulfur and oxygen, optionally substituted sulfamoyl, excluding compounds in which R ¹ = H, CH _3, 3-hlorfenilaminokarbonil, a R2 = Br or R1 = _CH3, a R2 = Cl, NO _2, CH ₂ OH, CH ₃ C (O), CO ₂ CH _3, CH ₂ NHC ( O) CH ₂ Cl, 2-piperidin-1-yl-acetyl-aminomethyl, 2-morpholin-4-yl-acetylaminomethyl, acyloxymethyl, 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) - 4-methoxy-6-methyl-5,6,7,8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinolin-9-methyl. 2. The compounds according to claim 1, which are substituted (R, S) -noscapine of the General formula 1.1

where Ar is aryl or heteroaryl. 3. The compounds according to claim 1, which are substituted (R, S) -noscapine of General formula 1.2

where R ³ and R ^4, independently of one another, are the same or different amino substituents selected from hydrogen, alkyl, aryl, or R ³ and R ⁴ together with the nitrogen atom to which they are attached form an azaheterocycle. 4. The compounds according to claim 1, which are substituted (R, S) -noscapine of the General formula 1.3

where R ³ and R ⁴ have the meaning indicated for compounds of General formula 1.2. 5. Compounds of 3- (9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (1), 3- (9-chloromethyl-4-methoxy-6-metal-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (2), 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran -1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinoline-9carbaldegin 1 (3), 5- (4, 5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinoline-9-carbonitrile 1 (4), 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenz furan-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxolo [4,5-g] isoquinoline-9-carboxylic acid 1 (5), 3 - (9-methoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy- 3H-isobenzofuran-1-one 1 (6) or 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7, 8-tetrahydro- [1,3] dioxolo [4,5-] isoquinolin-9-sulfonyl chloride 1 (7)

6. The method of obtaining 3- (9-iodine-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4,5-g] isoquinolin-5-yl) -6 , 7-dimethoxy-3H-isobenzofuran-1-one 1 (1) according to claim 5, by the action of IC1 on (R, S) -noscapine NSC in acetic acid according to the following scheme:

7. A method of obtaining 3- (9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] -di-oxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (2) according to claim 5 by the action of thionyl chloride on 3- (9-hydroxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro - [1,3] -dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one A-04 according to the following scheme:

8. The method of obtaining 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3 ] dioxolo [4,5-g] isoquinoline-9-carbaldehyde 1 (3) according to claim 5 by the action of hexamethylenetetramine on 3- (9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [ 1,3] -dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (2) in an organic solvent. 9. The method of obtaining 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3 ] dioxolo [4,5-g] isoquinoline-9-carbonitrile 1 (4) according to claim 5, by the action of copper (1) cyanide on 3- (9-bromo (or iodine) -4-methoxy-6-methyl-5, 6,7,8-tetrahydro [l, 3] dioxolo- [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-l-one A-01 in an aprotic solvent according to the following scheme:

10. Method for the production of 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3 ] dioxolo [4,5-g] isoquinoline-9-carboxylic acid 1 (5) according to claim 5 by hydrolysis of 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4- methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxolo [4,5-g] isoquinoline-9-carbaldehyde 1 (4). 11. A method of obtaining 3- (9-methoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] -dioxolo [4,5-g] isoquinolin-5-yl) -6 , 7-dimethoxy-3H-isobenzofuran-1-one 1 (6) according to claim 5 by the interaction of 3- (9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] -dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (2) with methanol in the presence of a base. 12. The method of obtaining 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3 ] dioxolo [4,5-g] isoquinoline-9-sulfonyl chloride 1 (7) according to claim 5 by the action of chlorosulfonic acid on (R, S) -noscapine NCS according to the following scheme:

13. The method of producing compounds according to claim 1 or 2 by the interaction of 3- (9-bromo (or iodo) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3] dioxolo- [4, 5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one of formula A-01 in the presence of a palladium catalyst with aryl or heteroaryl boron derivatives of the general formula Ar-B (OZ) ₂ , where Ar has the meanings indicated above in the definition of formula 1.1, Z = H, alkyl C ₁ -C ₄ , or

14. The method of obtaining 3- (9-aminomethyl-4-methoxy-6-methyl-5, b, 7,8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinolin-5-yl) -b , 7-dimethoxy-3H-isobenzo-furan-1-ones 1.2 according to claim 1 or 3 by the interaction of 3- (4-methoxy-6-methyl-9-chloromethyl-5,6,7,8-tetrahydro [1, 3] dioxolo [4,5-g] isoquinolin-5-yl) -6,7-dimethoxy-3H-isobenzo-furan-1-ones 1 (2) with the corresponding amine in an organic solvent. 15. The method of obtaining 3- (9-aminomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinolin-5-yl) -6 , 7-dimethoxy-3H-isobenzo-furan-1-ones 1.2 according to claim 1 or 3 by reductive amination of 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [1,3 ] dioxolo [4,5-g] isoquinoline-9-carbaldehyde 1 (3) with the corresponding amine in an organic solvent. 16. The method of obtaining 6,7-dimethoxy-3- [4-methoxy-6-methyl-9- (sulfamoyl) -5,6,7,8-tetrahydro [1,3] dioxolo [4,5-g] isoquinolin-5-yl] -3H-isobenzofuran-l-ones 1.3 according to claim 1 or 4 by the reaction of 5- (4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl) -4-methoxy- 6-methyl-5,6,7,8-tetrahydro- [1,3] dioxolo [4,5-g] isoquinoline-9-sulfonyl chloride 1 (7) with the corresponding amine. 17. A combinatorial library for determining leader compounds, consisting of compounds of general formula 1 according to claim 1. 18. A focused library for determining leader compounds, consisting of compounds of general formula 1 according to claim 1. 19. A pharmaceutical composition having anticancer activity, in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package containing, as an active substance, at least one compound of the general formula 1 according to claim 1 or its pharmaceutically acceptable salts. 20. A method for inhibiting cell proliferation by administering a pharmaceutical composition according to claim 19.