WO2007133112A1

WO2007133112A1 - Noscapine derivatives (variants), combinatory and focused library, pharmaceutical composition, methods for the production (variants) and the use thereof

Info

Publication number: WO2007133112A1
Application number: PCT/RU2007/000138
Authority: WO
Inventors: Alexander Vasilievich Ivashchenko; Volodymyr Mikhailovich Kysil; Alexander Viktorovich Khvat; Sergey Viktorovich Malyarchuk; Ilya Matusovich Okun; Sergey Yevgenievich Tkachenko; Alexander Sergeevich Kyselev
Original assignee: Ivashchenko, Andrey Alexandrovich; Chemdiv, Ink
Priority date: 2006-05-12
Filing date: 2007-03-21
Publication date: 2007-11-22
Also published as: RU2304584C1

Abstract

The invention relates to novel substituted noscapine derivatives of general formula (1) or to the racemates or to optical isomers or to the pharmaceutically acceptable salts and/or hydrates thereof exhibiting antitumor activity, to a pharmaceutical composition in the form of tablets, capsules or injections placed into pharmaceutically acceptable packages, to methods for the production thereof and to a method for inhibiting proliferation with the use thereof. According to general formula (1) R1 is an aminogroup substituent selected from alkyl; R2 is a cyclic system substituent selected from possibly substituted alkyl, wherein the substituents are selected from a possibly substituted aminogroup or azaheterocycle which possibly contains O, S or N in the form of an additional heteroatom and linked to an alkyl group by a nitrogen atom, from possibly substituted aryl, possibly substituted and possibly condensed heteroaryl containing at least one heteroatom selected from nitrogen, sulphur and oxygen and from possibly substituted sulphamoil. The invention also relates to 3-(9-iodo-4-metoxy-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo-[4,5-g]isoquinoline-5-il)-6,7-dimetoxy-3H- isobenzofuran-1, 3-(9-chloromethyl-4-metoxy-6-methyl-5,6,7,8-tetrahydro [1,3]dioxolo-[4,5-g] isoquinoline-5-il)-6,7-dimetoxy-3H-isobenzofuran-1, 5-(4,5-dimetoxy-3-oxo- 1,3-dihydroisonenzofuran-1-il) -4-metoxy-6-methyl-5,6,7,8-tetrahydro [1,3]dioxolo-[4,5-g] isoquinoline-carbaldehyde (or-9-carbonitril, or -9-sulphonylchloride, or -9-carboxylic acid and to 3-(9-metoxymethyl-métoxy-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo-[4,5-g]isoquinoline-5-il)-6,7-dimetoxy-3H- isobenzofuran-1 and to the methods for the production thereof. Combinatory and focused libraries are also disclosed.

Description

Noscapine derivatives (options), combinatorial and focused libraries, pharmaceutical composition, methods for their preparation (options) and applications

Technical field

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-l, 3-dioxol [4 , 5-g] isoxinolin-5-yl) -l (3H) -isobenzofyranone 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 interprotein interactions (roteip-prototype ip) or cause programmed cell death (apoptosis), as well as to a method the synthesis of such derivatives, to focused libraries containing these substances, to pharmaceutical compositions containing these compounds in the form of active substances, and also to a method for treating cancer.

State of the art

Noskapin (another name is narcotine) is an opium alkaloid, its content in the poppy Parave somniferum L. Paraveraceae reaches 11%, but noscapine is completely non-narcotic. Noskapin is approved for use as an antitussive, included in the United States Pharmacoreia (USP) (on the market since 1963), and is included as an active substance in the following drugs: Sarval, Loubekh, Narcotussip, Tussarip.

(S, R) -Noscapine (NSC) Of particular interest, however, are the recently discovered unique anticancer properties of noscapine [Ye K., Ke Y., Kesha N., Shanks J., Carr J., T. R., Retros J., Joshi H. Orium alkoid pozsarip is aptitumor agate that arrests metarhas ap ipodus arorthosis ip dividipell slls. Roc. Natl. Acad. Sсi. 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. Variable Derivative of Nosarip Arte Rothept Michetubulétperferip Agert That Turbot Mettis apd IPHit CeIl Poliferatiop. MoI Pharmacol. 2003, 63: 799-807], it is effective in the case of resistant forms of tumors arising from the treatment with other anti-tubylinovymi drugs, such common, for example, taxol or vincristine [Zhou, J. et al. Raslithel-resistapt humap ovariap sapserlls uppergo s-Jшi NH2-terminal kipase-tediadéport aortis ip reserpso to possarip. J Biol Chet. 2002, 277 (42): 39777]. The low toxicity of noscapine is also very attractive, especially when compared with other antitumor substances [R. Lapg, et.al. The same alkoid posssarip is a louw tohisit agept with sigpifissapt aptumor effest ip melapoma. 62pd Appy Meat Sos Ipest Dertatol (Mau 9-12, Washington DC DC) 2001, Abst 568]. The unique properties of noscapine, including its specific effect on microtubular dynamics, cell cycle arrest [Update JT, Type AE, Bozer S., Group J. KR, Crumrine C, J. J., T. L., L. L., Harrington J., Hodnick W ., Murphu S., Rawlawski G., Reperu R., Reber A., Ruplett SE, Striker-Cropergrad A., Wang J., YL Ideptifiсtiop оf updated and approved by the team. J Mad Chet. 2005; 48 (23): 7096-8.], Induction of c-Jupe-mediated NH2-terminal kinase apoptosis, inhibition of tumor growth, ability to cross the blood-brain barrier [Lapdep JW, Nau V., Wang M., Davis T., Ciliax B. ., Waiper BH, Vap Meir EG, Glasss JD, Joshi HC, Archer DR Nosaripes sosse thе blod-braip barriere apd iphibits glioblastom groot. CHn Sapser Res. 2004, 10 (15): 5187-201], inhibition of the action of the “hypoxia-induced factor HIF-1”, which plays an important role in tumor growth [Nevsomb EW, Lukuapov Y., Schpee T., AN MA, Lan L., Zagzag D .Noscarip iphibits hurohia-mediad HIF-lalrha expresiop apdgiogepesis ip vitro: and I started fuppsiop for ap drug. IPT J Opt. 2006 Mau; 28 (5): 1121-30.], As well as its extremely low toxicity, create great potential for the search for highly effective anticancer drugs of a new generation in the series of noscapine derivatives [Joshi HC, Zhou J. Noscaripe apalogues ascetal chemotherapy agepts. Drug News Respres. 2000, 13 (9): 543-6]. In this regard, the design of new compounds of this type is relevant. focused libraries and pharmaceutical compositions comprising these compounds, as well as developing methods for their preparation and use.

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, [Jasob A. l- (3-Phenylpropyl) -2-methyl-6,7-methylene-dioxy -8-methoxy-l, 2,3,4-tetrahoudroisoquipolip, and Rhartasolisillo active natrix derivatives. J Med Chet. 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 cycles, the modification is carried out via N- (or O-) demethylation of noscapine (for example, (thio) carbamoyl analogues of N- demethylated noscapine [Aggarwal S., et al. A Compliance Supthеsis оf Arul-Substitut N-Сarbamoul / N-Thiosarbamoul Nаtocipe apd Relatome Сomroshids. HeIv Сhісht, 85: 2002; et.al. US 6,376,516 Bl 04.23.2002; US 6,673,814 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 in the 5-position of the isoquinoline ring.

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

Disclosure of invention

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

“Aheterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a cycle. An azaheterocycle may have one or more “cyclic substitutes”) systems. "Aliphatic" radical means a radical obtained by removing a hydrogen atom from a non-aromatic C-H 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, annelated arylcycloalkyl, annelated heteroarylcycloalkyl, annelated arylcycloalkenyl, annelated heteroarylcycloalkenyl, annelated arylheterocyclyl, annelated heteroarylheterocytes clyl, annelated arylheterocyclenyl, annelated 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, aralkoxycarbonyl, geteroaralkiloksikarbonil or _{^{_{^{R k a R k + i a}}}} N-, R k a R _{k +} i ^a NC (= O) -, R _k ^a R _{k +} i ^a NSO ₂ -, where R _k ^a and R _{k + ϊ} ^a independently represent amino group 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 + ϊ} ^a together with the N atom, with which they are connected, form through R / and R _{k + ϊ} ^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, methoxycarbonylmethyl, benzyloxycarbonylmethylmethyl and pyridine. Preferred alkenyl groups are ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, and cyclohexylbutenyl. “Alkenyloxy” means an alkenyl-O— group in which alkenyl is defined in this section. Allyloxy and 3-butenyloxy are preferred alkenyloxy groups.

“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 the chain. Branched means that the alkyl chain has one or more "lower alkyl" substituents. Alkyl may have one or more, same or different substituents (“alkyl substituents))), including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkyl , heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonylheteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated oalkenil, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or _{^{_{^{R k a Rk + i a N-}}}} , R k a Rk + i a NC (= O) -, R k a R k + ₁ ^a NC (= S) -, Rk ^a Rk + i ^a NSO ₂ ~, where R _k ^a and R _{k + 1} ^a independently represent “amino group substitutes”, 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 + i ^a together with the N atom to which they are bonded form through R _k ^a and Rк ₊ i ⁴ 4 - 7 member heterocyclyl or heterocyclenyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentil, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylmethyl methoxycarbonylmethyl and piridilmetiloksikarbonilmetil . 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 + i a}}}} N- , Rk ^a R _{k + ϊ} ^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.

“Alkyloxycarbonyl” means an alkyl-O — C (= O) group in which alkyl groups are defined in this section. Preferred alkyl hydroxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl tert-butyloxycarbonyl., 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, isopropoxy and n-butoxy.

"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 ^ R _{k +} ^ N is a group substituted or unsubstituted by “a substituent of the amino group”, Rk ^a and Rk ₊ D are defined in this section, for example, amino (H ₂ N-), methylamino, diethylamino, pyrrolidine, morpholine, benzylamino or phenethylamino. “Amino acid” means a natural amino acid or a non-natural amino acid, the meaning of which is defined in this section. Preferred amino acids are amino acids containing an α or β amino group. Examples of natural amino acids are α-amino acids, they can be alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, series, threonine and cysteine.

“Annelated cycle” (condensed cycle) means a bi- or polycyclic system in which the annelated cycle and the cycle or polycyclic with which it is “annealed” have at least two common atoms.

“Annelated apylheterocycloalkenyl” means annelated aryl and heterocycloalkenyl, the meaning of which is defined in this section. Annelated arylheterocycloalkenyl can bind through any possible atom of the ring system. The prefix "aza", "okca" or "tia" before "heterocycloalkenyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated arylheterocycloalkenyl may have one or more “substituent ring systems)), 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 annelated arylheterocycloalkenyls are indolinyl, Ш-2-oxoquinolinyl, 2H-1-oxoisoquinolinyl, 1,2-dihydroxinolinyl, and the like.

“Annelated apylheterocycloalkyl” means annelated aryl and heterocycloalkyl, the meaning of which is defined in this section. Annelated arylheterocycloalkyl can bind through any possible atom of the cyclic system. The prefix "aza", "okca" or "tia" before "heterocycloalkyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated arylheterocycloalkyl may have one or more “substituent ring systems)), 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-tetrahydroisoxinoline, 1,3-benzodiocol, and the like. “Annelated apylcycloalkenyl” means annelated aryl and cycloalkenyl, the meanings of which are defined in this section. Annelated arylcycloalkenyl can bind through any possible cyclic atom system. Annelated arylcycloalkenyl may have one or more “cyclic system substitutes,” which may be the same or different. Representatives of annelated arylcycloalkenyls are 1,2-dihydro-naphthalene, indene, etc.

“Annelated apylcycloalkyl” means annelated aryl and cycloalkyl, the meanings of which are defined in this section. Annelated arylcycloalkyl can bind through any possible atom of the cyclic system. Annelated arylcycloalkyl may have one or more “cyclic system substitutes,” which may be the same or different. Representatives of annelated arylcycloalkyls are indanine, 1,2,3., 4-tetrahydronaphthalene, 5,6,7,8-tetrahydronaphth-l-yl, etc.

“Annelated heteroapylcycloalkenyl” means annelated heteroaryl and cycloalkenyl, the meanings of which are defined in this section. Annelated heteroarylcycloalkenyl can bind through any possible atom of the cyclic system. The prefix "aza", "okca" or "tia" before "heteroapyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated heteroarylcycloalkenyl may have one or more “ring system substituents)), which may be the same or different. The nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide. Representatives of annelated heteroarylcycloalkenyls are 5,6-dihydroquinolinyl, 5,6-dihydroisoxinolinyl, 4,5-dihydro-lH-benimidazolyl, and the like. “Annelated heteroapylcycloalkyl” means annelated heteroaryl and cycloalkyl, the meanings of which are defined in this section. Annelated heteroarylcycloalkyl can bind through any possible atom of the cyclic system. The prefix "aza", "okca" or "tia" before "heteroapyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated heteroarylcycloalkyl may have one or more “ring system substituents)), which may be the same or different. The nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide. Representatives of annelated heteroarylcycloalkyls are 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoxinolinyl, 4,5,6,7-tetrahydro-IH-benzimidazolyl, and the like.

“Annelated heteroapylheterocycle” means annelated heteroaryl and heterocyclenyl, the meanings of which are defined in this section. Annelated heteroaryl heterocyclenyl may bind through any possible atom of the cyclic system. The prefix "aza", "okca" or "tia" before "heteroapyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated heteroarylheterocyclenyl may have one or more “cyclic system substitutes” that may be the same or different. The nitrogen atom in the heteroaryl moiety can 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 annelated heteroarylheterocyclenyls are l, 2-dihydro [2,7] naphthyridinyl, 7,8-dihydro [l, 7] naphthyridinyl, 6,7-dihydro-3H-imidazo [4,5-c] pyridyl, etc. “Annelated heteroapylheterocyclyl” means annelated heteroaryl and heterocyclyl, the meanings of which are defined in this section. Annelated heteroaryl heterocyclyl can bind through any possible atom of the ring system. The prefix "aza", "okca" or "tia" before "heteroapyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated heteroarylheterocyclyl may have one or more “cyclic system substitutes,” which may be the same or different. The nitrogen atom in the heteroaryl moiety can 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 annelated heteroaryl heterocyclyls are 2,3-dihydro-III-pyrpolo [3,4-b] quinolin-2-yl, 2,3-dihydro-III-pyrpolo [3,4-b] indol-2-yl, l, 2,3,4-tetrahydro [l, 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-phenethyl 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 an aryl-alkyl-NH— group in which the meanings of aryl and alkyl are defined in this section.

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

“Aralkylcylphonyl” means aralkyl-SO ₂ —the 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-naphthylenmethoxy 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 aralkyl-OC (= ^: O) -alkyl- group in which the meanings of aralkyl and alkyl are defined in this section. An example of an aralkoxycarbonylalkyl group is benzyloxycarbonylmethyl or benzyloxycarbonylethyl.

"Apyl" 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 “substituents of the cyclic system)), which may be the same or different. Representative aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be annelated with a non-aromatic ring system or heterocycle. “Apylcarbamoyl” means apyl-NHC (= O), the group in which the aryl value is defined in this section.

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

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

“Apylcylphone” means apyl-SO ₂ —the group in which the meaning of aryl is defined in this section.

"Apilthio" means an aryl-S- group in which the meaning of aryl is defined in this section. Representative arylthio groups are phenylthio and 2-naphthylthio. “Apoylamino” means an aroyl-NH group in which the meaning of aroyl is defined in this section.

“Apoyl" means apyl-C (= O), the group in which the meaning of aralkyl is defined in this section. Examples of aroyl groups are benzoyl, 1st 2nd naphthoyl. “Aromatic” radical means a radical obtained by removing a hydrogen atom from an aromatic C — H bond. The “aromatic” radical includes the 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, annelated cycloalkenylaryl, annelated cycloalkylaryl, annelated heterocyclylaryl, annelated heterocyclylaryl, heteroaryl, annelated cycloalkylheteroaryl, annelated cycloalkenylheteroaryl heteroeryl heteroaryl. “Aromatic cycle” means a planar cyclic system in which all atoms of the cycle participate in the formation of a single conjugation system including, according to the Hückel rule, (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 “hetero matric 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. The aromatic cycle may have one or more “substitutes for the cyclic)) system and can be annelated with a non-aromatic cycle, heteroaromatic or heterocyclic system.

“Acyl” means HC (= O) - or alkyl-C (= O) -, cycloalkyl-C (= O) -, heterocyclyl-C (= O) -, heterocyclyl-C (= O) -, apyl-C (= O) -, apylalkyl-C (= O) - or heteroapyl-C (= O) -, heteroapylalkyl-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 meaning of acyl 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-formylthiophen-2-yl) -benzoic acid or 2- (2-formylphenyl) -thiophene-3-boan. “1,2-vinyl vinyl radical” means a —CH═CH— group which contains one or more identical or different alkyl substituents, the meaning of which is defined in this section.

"Halogen" means fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred.

“Hetero-linked loop” means that a loop that attaches (annelates or condenses) to another loop or polycycle contains at least one heteroatom.

“Heteroapalkenyl” means a heteroaryl alkenyl group in which heteroaryl and alkenyl are defined in this section. Preferably, heteroarylalkenyl includes a lower alkenyl group. Representatives of heteroarylalkenyls are A-pyridylvinyl, thienylethenyl, imidazolylethenyl, pyrazinylethenyl and the like. “Heteroapalkyl” means a heteroaryl-alkyl group in which heteroaryl and alkyl are defined in this section. Representative heteroarylalkyls are pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, pyrazinylmethyl, and the like. “Heteroapalkyloxy” means a heteroarylalkyl-O— group in which heteroarylalkyl is defined in this section. Preferred heteroarylalkyloxy groups are 4-pyridylmethyloxy, 2-thienylmethyloxy and the like.

“Heteroapoyl” means heteroapyl-C (= O), the group in which heteroaryl is defined in this section. Representative heteroaroyls are nicotinoyl, thienoyl, pyrazoloyl, etc.

“Heteroapyl” 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", "okca" or "tia" before "heteroapyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. The nitrogen atom in the heteroaryl may be oxidized to N-oxide. A vegetarian can have one or more “cyclic system substitutes,” which can 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, pyridoxyninyl phthalazinyl, imidazo [l, 2-a] pyridinyl, imidazo [2, lb] thiazolyl, benzofurazanil, indolyl, azaindolyl, benzimidazolyl, benzothiazenyl, quinolinyl, imidazolyl, thienopyridinopyridinyl, 2,4-thiazinyl, thienopyrrolyl, furopyrrolyl, etc. “Heteroapylcylphonylcarbamoyl” means heteroapyl-SO ₂ —NH-C (= O) —the group in which heteroaryl is defined in this section.

“Heterocycle” 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 hetero atom such as nitrogen, oxygen, sulfur and which contains at least , one carbon-carbon double bond or carbon-nitrogen double bond. The prefix "aza", "okca" or "thia" before 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 “cyclic system substitutes,” 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-pyrpolinyl, 3-pyrpolinyl, 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", "okca" 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 substitutes,” 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 attaches to the scaffold

(to a fragment), for example, an alkyl substituent "," amino group substituent ",

“Carbamoyl substituent”, “cyclic system substitute”, the values of which are defined in this section.

“Alkyl substituent” means a substituent attached to alkyl, alkenyl, the meaning of which is defined in this section. Alkyl substituent is hydrogen, alkyl, halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkilsulfonilgeteroaralkiloksi, annelated heteroarylcycloalkenyl , annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, anneliro arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl or R / R _{k +} GN-, R _k ^a R _{k + 1} ^a NC (= O) -, R _k ^a R _{k +} i ^a NSO ₂ -, where R / and R _{k +} i ^{a are} independently “amino group substituents”, the meanings of which are defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or R _k ^a and R _{k +} i ^a together with the N atom to which they are attached form through R _k ^a and R _{k +} i ^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-pentil, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylmethyl and methoxycarbonylmethyl piridilmetiloksikarbonilmetil . The preferred "alkyl substituents)) are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or _{R / R k + ^ N-,} R _k ^a Rk ₊ i ^a NC (= O) -, annelated arylheterocyclenyl, annelated arylheterocyclyl. The meaning of the alkyl substituents is defined in this section.

Amino group substituent "means a substituent attached to an amino group. The amino substituent is hydrogen, alkyl, cycloalkyl, aryl, geheroaril, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, geterotsiklilaminokarbonil, alkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated aryl eterotsiklenil, annelated arylheterocyclyl, alkoxycarbonylalkyl, aralkoksikarbonilalkil, geteroaralkiloksikarbonilalkil. The meaning of “Amino Group Substitutes” is defined in this section.

“Carbamoyl substituent” 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 / R _{k +} ^ N-, R _k ^a R _{k + 1} ^a NC (= O) -alkylarylalkenylalkenylalkenylalkenyl annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl. Preferred "zamectitelyami kapbamoilnymi" are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoksikarbonilalkil, geteroaralkiloksikarbonilalkil or _{^{_{^{R k a R k + i a}}}} N-, R k a R k + i a NC (= O) -alκil, annelated arylheterocyclenyl, annelated arylheterocyclyl. The meaning of “carbamoyl substitutes” is defined in this section.

"Nucleophilic substituent" means a chemical radical that is attached to scaffold by reaction with a nucleophilic reagent, 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, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, arylalkyloxyalkyl, geterotsiklilalkiloksialkil, alkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylsulfinyl, arylsulfinyl, geterotsiklilsulfinil, alkylthio, arylthio, heterocyclylthio, alkylsulfonylalkyl, arylsulfonylalkyl, geterotsiklilsulfonilalkil, alkylsulfinylalkyl, arylsulfinylalkyl, geterotsiklilsulfinilalkil, alkylthioalkyl, arylthioalkyl geterotsikliltioalkil, arilalkilsulfonilalkil, geterotsiklilalkilsulfonilalkil, arilalkiltioalkil, geterotsiklilalkiltioalkil, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, amidine o, 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 +} i ^a are independently “amino group substituents”, the meanings of which are defined in this section, 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 Rш ^{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 -, where R _k ^a and ^ in Ry- Este with the atom of nitrogen to which they are attached to, form through R _k ^a and R _{k + 1} ^a 4-7 membered heterocyclyl or heterocyclenyl.

“Electrophilic substituent” means a chemical radical that attaches to scaffold as a result of reaction with an electrophilic reagent, for example, selected from the group of organic acids or their derivatives (anhydrides, imidazolides, halides), ethers of organic sulfonic acids or organic sulfonyl chlorides, organic halides, organic isocyanides organic isothiocyanates.

“Amino amino group” means an R _k ^a R _{k + 1} ^a N group in which R _k ^a and R _{k +} i ^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 (02) R group in which the substituent R is alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meanings of which are defined in this section.

“Protection 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: amide a substituent such as formyl, optionally substituted acetyl (for example trichloroacetyl, trifluoroacetyl, 3-phenylpropionyl, etc.), optionally substituted benzoyl, etc .; 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-phenylphyloinyl and others; sulfonyl substituent, for example, benzenesulfonyl, p-toluenesulfonyl, etc. For more details, “Protective groups” are described in the book: Protective groups and organic supervisor, Third Edite Grepe, TW ap Wuts, PGM 1999, p. 494-653. Publishing house Johan Willeu & Sops, Ips, New York, Shikhester, Wehim, Vrisbape, Toropto, Sіpgarore.

Protected primary or secondary amine "means a group of the formula Rk ^a Rk ₊ i ^a N-, in which R _k ^a represents a protective group PG and R _{k +} i ^a represents hydrogen," a substituent of the amino group ", the meaning of which is defined in this section e.g. alkenyl, alkyl, aralkyl, aryl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaralkyl, heteroaryl, heteroaryl heteroaryl non-lined heteroaryl heterocyclenyl, annelated heteroaryl heterocyclyl, heterocyclenyl or heterocyclyl.

“Imino group” means Rk ^a N = a group substituted or unsubstituted with a “substitute amino group” Rk ^a , 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 ₂ N =) or phenethylimino (PhCH ₂ CH ₂ N =) ..

"Inert substituent (or" not interfering, "Nopperfer substitupt") means a low or non-reactive radical, including but not limited to C ₁ - C ₇ alkyl, C ₂ - C ₇ alkenyl, C ₂ - C ₇ alkynyl, C ₁ - C ₇ alkoxy, C ₇ - C ₁₂ aralkyl substituted with inert substituents of aralkyl, C ₇ - C ₁₂ heterocyclylalkyl, substituted with inert substituents of heterocyclylalkyl, C ₇ - C ₁₂ alkaryl, C ₃ - C ₁₀ cycloalkyl, C ₃ - C ₁₀ cycloalkenyl, phenyl, substituted phenyl, toluyl, xylene, biphenyl, C ₂ - C ₁₂ alkoxyalkyl, C ₂ - C ₁₀ alkylsulfinyl, C ₂ - C ₁₀ alkylsulfonyl, (CH ₂ ) _m -O- (C ₁ - C ₇ alkyl) , - (CH ₂ ) Hi-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 ₂ - C ₇ alkenyl, C ₂ - 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 ) I _n -N (C ₁ - C ₇ alkyl) _n , aryl substituted with inert substituents aryl, heterocyclyl and substituted with inert substituents heterocyclyl.

“Kambamoyl” 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 Rк ₊ Λ including hydrogen, alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.

“Carbamoylheterocycle” means an azaheterocycle containing as

“Substituent of the cyclic system” of at least one carbamoyl group.

The meanings of “heterocycle”, “cyclic system substitute” and “carbamoyl group” are defined in this section.

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

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

“Kapbocycle” 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 condensing systems (for example, decalin), in the case of three - bridge systems (for example, bicyclo [3.3.1] nonon), 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.

“Combinative 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 meanings of which are 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 cycle may have one or more “substituent cyclic)) systems 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.

“Non-natural amino acid” means an amino acid of a non-nucleic nature. Examples of unnatural amino acids are 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-cycloalkyl carboxylic acids, β-alanine, 2-alkyl-β-alanines, 2-cycloalkyl-β-alanines, 2-apyl-β-alanines, 2-heteroapyl-β-alanines, 2-heterocyclyl-β-alanines and (1-amino-cycloalkyl ) -cyclic acids in which the meanings of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are defined in this section.

“Optional aromatic cycle” means a cycle that 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.

“Optionally 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.

“1,3-Propylene radical” means —CH ₂ —CH ₂ —CH ₂ — a group that contains one or more identical or different “alkyl substituents”, the meanings of which are defined in this section. “Leader-compound” (“leader”) means a compound with outstanding (maximum) physiological activity associated with a specific biological target related to a specific (or several) pathology or disease.

“Compound-hit” (“hit”) means a compound that exhibits the desired physiological activity during the initial screening process.

“Sweet group” means R _k ^a R _{k +} i ^a NSO ₂ is a group substituted or unsubstituted by “a substituent of the amino group” R _k ^a and R _{k +} i ^a , the meanings of which are defined in this section.

"Cylfonyl" means R-SO ₂ - a group in which R is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelated heteroarylcycloalkenyl, annelated heteroaryl heterocyclylalkenyl, annelated heteroaryl heterocyclylalkylalkyl the meaning of which is defined in this section. “Template” means the general structural formula of a group of compounds or compounds included in the “combinational library)).

"Thiocarbamoyl" means R _k ^a R _{k +} i ^a NC (= S) is a group. Thiocarbamoyl may have one or more identical or different “amino group substitutes” R _k ^a and R _{k +} i ^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 “substituents of the cyclic system)), 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 annelated with an aromatic ring or heterocycle. Preferred “substituents of the cyclic system)) are alkyl, aralkoxy, hydroxy or R _k ^a R _{k +} i ^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 perceptive means, means deliveries such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents you, 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 provided with a variety of antibacterial and antifungal agents, for example, 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 of the 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 forms of administration and rectal forms of administration. "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 prepared in situ during the synthesis, isolation or purification of 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 Werg SM, et al., "PHARMACEUTAL 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, for example, such as 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.

“Focussed 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 “combinational library)).

“1,2-Ethyl radical” means —CH ₂ —CH ₂ — a group that contains one or more of the same or different “alkyl substituents”, the meanings of which are 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.

1 where: R is an amino substituent selected from alkyl; R 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 = H, CH ₃ , 3-chlorophenylamino-carbonyl, R = Br; R = 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-l-yl-acetyl-aminomethyl, 2 morpholin-4-ylacetyl-aminomethyl, acyloxymethyl. According to the invention, more preferred compounds are derivatives of (R, S) -nocapine of the general formula 1.1:

where: Ar represents aryl or heteroaryl.

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

where: R ³ and R ⁴ have the meanings 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 [l, 3] dioxolo- [4,5-g] isoxinolin-5- il) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (1), 3 ~ (4-methoxy-6-methyl-9-chloromethyl-5,6,7,8-tetrahydro [l, 3] -dio-colo [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-l-one 1 (2), 5- (4,5-dimethoxy-3-oxo-l, 3 -dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-

5,6,7,8-tetrahydro- [l, 3] dioxole [4,5-g] isoxinolin-9-carbaldehyde 1 (3), 5- (4,5-dimethoxy-3-oxo-l, 3- dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxole [4,5-g] isoxynolin-9-carbonitrile acid 1 (4), 5 - (4,5-dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxol [4, 5-g] isoxynolin-9-carboxylic acid 1 (5), 3- (9-methoxymethyl ^ -methoxy-b-methyl-Sjb ^^ - tetrahydrofljЗJ-diaxolo ^ jЗ-gZisoquinolin-S-yl) -6, 7-dimethoxy-3H-isobenzofyran-l-one 1 (6) and 5- (4,5-dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl b, 7,8-tetrahydro- [l, 3] dioxole [4,5-g] isoxinolin-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 [l, 3] dioxolo- [4,5-g] isoxinoline-5- il) -b, 7-dimethoxy-3H-isobenzofyran-1-one 1.1 (1), 3- (9-p-tolyl-4-methoxy-6-methyl-5,6,7,8- tetrahydro [l, 3] dioxol- [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (2), 3- [9- (4-methoxyphenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxol- [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran- l-OH 1.1 (3), 3- [9- (4-chlorophenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l, 3] di-oxo [4,5- g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-1-one 1.1 (4), 3- [9- (4-trifluoromethylphenyl) -4-methoxy-6-methyl-5,6, 7,8-tetra-hydro [l, 3] dioxol- [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isoben-zofyran-1-one 1.1 (5), 3- [9- (4-dimethylaminophenyl) -4-methoxy-6-methyl-5,6,7,8-tetra-hydro [l, 3] dioxol- [4,5-g] isoxinolin-5-yl] -6 , 7-Dimethoxy-3H-isoben-zofyran-l-one 1.1 (6), 3- [9- (4-nitrophenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] di okco o [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (7), 3- [9- (4-ethoxycarbonylphenyl) -4-methoxy-6- methyl-5,6,7,8-tetra-hydro [l, 3] dioxol [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (8) ,

3- [9- (4-fluorophenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] di-oxo [4,5-g] isoxinolin-5-yl] - 6,7-dimethoxy-3H-isobenzofyran-l-1.1 1.1 (9), 3- [9-m-tolyl-4-methoxy-6-methyl-5 ₃ 6,7,8-tetrahydro [l, 3] dioxol - [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-1-one 1.1 (10), 3- [9- (3-methoxyphenyl) -4-methoxy-6- methyl-5,6,7,8-tetrahydro [l, 3] -dioxol [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-1-one 1.1 (11), 3- [9- (3-chlorophenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-l-he 1.1 (12), 3- [9- (3-fluorophenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (13), 3- [9- (3-nitrophenyl) - 4 -methoxy-6-methyl-5,6,7,8-t etahydro [l, 3] di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-1-one 1.1 (14), 3- [9- (3-triflumethylphenyl ) -4-methoxy-6-methyl-5,6,7,8-tetra-hydro [l, 3] -dioxol [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-ZH- isobenzofyran-1-one 1.1 (15), 3- [9- (3,4-dimethylphenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [1, 3] -dioxol [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzo-fyran-l-one 1.1 (16),

1.1 (13) 1.1 (14) 1.1 (15) 1.1 (16) 3- [9- (3-pyridyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dio-colo [4,5-g] isoxinolin-5-yl] -6 , 7-dimethoxy-3H-isobenzofyran-l-1.1 1.1 (17), 3- [9- (4-pyridyl) -4-methoxy-6-methyl-5,6,7 ₅ 8-te'hydrohydro [l ₅ 3] -di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-1-one 1.1 (18), 3- [9- (2-pyridyl) -4 -methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] - di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-l -one 1.1 (19), 3- [9- (2-thienyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] di-oxo [4,5-g ] isoxinolin-5-yl] - 6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (20), 3- [9- (3-thienyl) -4-methoxy-6-methyl-5,6,7 , 8-tetrahydro [l, 3] -di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-1-one 1.1 (21), 3- [9- (2-pyryl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] - di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (22), 3- [9- (5-indolyl) -4-methoxy -6-methyl-5,6,7,8-tetrahydro [l, 3] -di-oxo [4,5-g] isoxinolin-5-yl] - 6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (23), 3- [9- (5-pyrimidinyl) -4-methoxy-b-methyl-5,6,7,8-tetrahydro [l, 3] di-oxo [4,5-g] isoxinoline -5-yl] -6,7-dimethoxy-3H-isobenzofyran-1-one 1.1 (24),

1.1 (21) 1.1 (22) 1.1 (23) 1.1 (24) 3- [9- (2-benzofyranyl) -4-methoxy-b-methyl-5,6,7,8-tetrahydro [l, 3] di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (25), 3- [9- (3-dimethylaminophenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (26), 3- [9- (6-methoxypyridine-3- sludge) - 4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-ZH -isobenzofyran-l-one 1.1 (27), 3- [9- (3-carboxyphenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -di-oxo [4 , 5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (28), 3- [9- (4-carboxyphenyl) -4-methoxy-6-methyl-5 , 6,7,8-tetrahydro [l, 3] -di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-1-one 1.1 (29), 3 - [9- (3-to apamoylphenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-ZH -isobenzofyran-l- it 1.1 (30), 3- [9- (4-isoxynolininyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -dis-oxo [4 , 5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (31), 3- [9- (4-pyrvinyl) -4-methoxy-6-methyl-5 , 6,7,8-tetrahydro [l, 3] -di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (32),

1.1 (29) 1.1 (30) 1.1 (31) 1.1 (32) 3- [9- (l-tert-butyloxycarbonylindinol-2-yl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] - di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (33), 3- [9- (l-tert-butyloxycarbonyl-5-methoxy-indole-2-yl-4-meth b-methyl-5,6,7,8-tetrahydro [l, 3] -di-oxo [4,5-g] isoxinolin-5-yl] -b, 7-dimethoxy-3H-isobenzofyran-l-one 1.1 (34), 3- [9- (3-hydroxyphenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] di-oxo [4,5-g] isoxynoline- 5-yl] -6,7-dimethoxy ~ 3H-yubobenzofyran-l-one 1.1 (35), 3- [9- (4-hydroxyphenyl) -4-methoxy-6-methyl-5,6,7,8- tetrahydro [l, 3] -di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (36), 3- [9- (4- methanesulfonylphenyl) -4- methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -di-oxo [4,5-g] isoxinolin-5-yl] -6 , 7-dimethoxy-3H-isobenzofyran-1-one 1.1 (37), 3- [9- (3-thienyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -di-oxo [4 ₅ 5-g] isoxinolin-5-yl] -b, 7-dimethoxy-3H-isobenzofyran-l-one 1.1 (38), 3- [9- (5-indazolyl) -4-methoxy -6-methyl-5,6,7,8-tetrahydro [l, 3] -di-oxo [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (39), l- {4- [5- (4,5-dimethoxy-3-oxp-l, 3-dihydro-isobenzofyran-l-yl) -4-methoxy-6-methyl-5, b, 7 , 8-tetrahydro- [l, 3] dioxole [4,5-isoxinolin-9-yl] phenyl} -3-phenyl urea 1.1 (40) or 1- {3- [5- (4,5-dimethoxy) -3-oxcr-l, 3-dihydro-isobenzofyran-l-yl) -4-methoxy-b-methyl-5,6,7,8-tetrahydro- [l, 3] dioxole [4,5-isoxinoline-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-tetra-hydro [l, 3] dioxol [4,5-g] isoxinolin-5 -yl) -6,7-dimethoxy-3H-isobenzofyran-l-one 1.2 (1), 3- (9-diethylaminomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxol [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzo-fyran-l-one 1.2 (2), 3- (9-N-pyrpolidinomethyl-4-methoxy- 6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxole [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzo-fyran-l-one 1.2 (3), 3- (9-N-piperidinomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxolo [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzo-fyran-l-one 1.2 (4), 3- (9-N-morpholinomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l , 3] oxycolo [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzo-fyran-l-one 1.2 (5), 3- (9-N-piperazinomethyl-4-methoxy-6- methyl-5,6,7,8-tetrahydro- [l, 3] dioxol [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzo-fyran-1-one 1.2 (6 ), 3- (9-aminomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l, 3] dio-colo [4,5-g] isoxinolin-5-yl) -6 , 7-dimethoxy-3H-isobenzo-fyran-l-one 1.2 (7).

1.2 (1) 1.2 (2) 1.2 (3) 1.2 (4)

The most preferred compounds of general formula 1.3 are: 5- (4,5-dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5,6,7,8- tetrahydro- [l, 3] dioxol [4,5-g] isoxinolin-9-sulfonylamide 1.3 (1), 6,7-dimethoxy-3- [4-methoxy-6-methyl-9- (pyrpolidin-l-cylfo -nyl) -5,6,7,8-tetrahydro- [l, 3] dioxole [4,5-g] isoxinolin-5-yl] -ZH-isobenzofyran-l-one 1.3 (2), 6.7- dimethoxy-3- [4-methoxy-6-methyl-9- (piperidin-l-sulfonyl) -5,6,7,8-tetrahydro- [l, 3] dioxol [4,5-g] isoxinolin-5- silt] - ZN-isobenzofuran-1-one 1.3 (3), 6,7-dimethoxy-3 - [4-methoxy-6-methyl-9- (morpholin-1 - sulfonyl) -5,6,7, 8-tetrahydro- [l, 3] dioxol [4,5-g] isoxinolin-5-yl] -ZH-isobenzofyran-1-one 1.3 (4), 6,7-dimethoxy-3- [4-methoxy-6 -methyl-9- (piperazin-l-sulfonyl) -5,6,7,8-tetrahydro- [l, 3] dioxole [4,5-g] isoxinolin-5-yl] -ZH-isobenzofyran-l-one 1.3 (5), 5- (4,5-dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-me oxy-6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxole [4,5-g] isoxynolin-9-sulfonyl diethylamide 1.3 (6), 5- (4,5-dimethoxy-3 -oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxol [4,5-g] isoxinoline-9-cyprilon di (2-hydroxyethyl) amide 1.3 (7).

1.3 (5) 1.3 (6) 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 the present invention, methods have been developed for the preparation of derivatives of (R, S) -nocapine, which allow preserving the optical activity inherent in the starting alkaloid.

According to this invention, a method for producing 3- (9-iodine-4-methoxy-b-methyl-5,6 ₅ 7,8-tetrahydro [l, 3] dio-colo- [4,5-g] isoxinolin-5-yl) is developed -6,7-dimethoxy-3H-isobenzofyran-1-one 1 (1), consisting in the action of ICl on (R, S) -scapine 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 [l, 3] -dioxol [4,5-g] isoxinolin-5-yl) is developed -6,7-dimethoxy-3H-isobenzofyran-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 [ l, 3] -dio-colo [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-l-one A-04 according to the following scheme:

According to this invention, a method for producing 5- (4,5-dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l , 3] dioxol [4,5-g] isoxynolin-9-carbaldehyde 1 (3), which consists in the action of hexamethylenetetramine 2 on 3- (9-chloromethyl-4-methoxy-6-methyl-5,6,7,8- tetrahydro [l, 3] - dioxol [4,5-g] isoxinolin-5-yl) -b, 7-dimethoxy-3H-isobenzofyran-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-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l , 3] dioxol [4,5-g] isoxinolin-9-carbonitrile 1 (4), which consists in the action of copper (I) cyanide on 3- (9-bromo-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxol- [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-l-one A-Ol or 9-iodine-4-methoxy-6-methyl- 5,6,7,8-tetrahydro [l, 3] dioxol- [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-1-one 1 (1) in an aprotic environment solvent according to the following scheme:

A-01: Y = Br, 1 (1): Y = I ¹ ( ⁴ )

According to this invention, a method for producing 5- (4,5-dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5, b, 7,8-tetrahydro- [l , 3] dioxol [4,5-g] isoxynolin-9-carboxylic acid 1 (5) by hydrolysis of 5- (4,5-dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy 6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxole [4,5-g] isoxinolin-9-carbonitride 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 [l, 3] -dio-colo [4,5-g] isoxynolin-5-yl) is developed -6,7-dimethoxy-3H-isobenzofyran-1-one 1 (6) by the interaction of 3- (9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -di -oxo [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-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-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l , 3] [4,5-g] isoxynolin-9-sulfonyl chloride 1 (7), consisting in the action of chlorosulfonic acid on (R, S) -scapine NSC according to the following scheme:

According to this invention, a method for producing derivatives of (R ₃ S) - noscapine of general formula 1.1 is developed, which consists in the interaction of 3- (9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxol- [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-1-one A-Ol or its iodide analog 1 (1) in the presence of a palladium catalyst with an aryl- or heteroaryl boron derivatives of the general formula 3 according to the following scheme:

A-01, 1 (1) 1.1 where Ar has the meanings indicated above in the definition of formula 1.1. As boric (get) apyrilating agents, use (get) apylobric acids 3 (Z = H), alkyl esters of these acids 3 (Z = alkyl C ₁ -C ₄ ) or cyclic esters of these acids, for example,

4,4,5,5-tetramethyl [1,3,2] dioxane

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 ⁰ C, in the conditions of microwave irradiation or without it.

Most preferred is a stereospecific method for the synthesis of noscapine derivatives of the general formula 1.1, characterized in that the cross-combination of A-01 and (get) acylboric acids is carried out in polar aprotic solvents (for example, dimethoxyethane) in the presence of 3-4 equivalents of cesium carbonate and 10-20 mol. % complex of palladium chloride with triphenylphosphine at 130-150 ⁰ C under the influence of microwave irradiation.

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

1 (2) 1.2

According to this invention, the developed method for the preparation of (R, S) -nocapine derivatives of the general formula 1.2 consists in reductive amination of 5- (4,5-dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6 -methyl-5,6,7,8-tetrahydro- [l, 3] dioxol [4,5-g] isoxinolin-9-carbaldehyde 1 (3) amines 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) -nocapine of the general formula 1.3 consists in the interaction of 5- (4,5-dimethoxy-3-oxo-1, 3-dihydroisobenzofyran-1-yl) -4-methoxy-6- methyl-5,6,7,8-tetrahydro- [l, 3] dioxol [4,5-g] isoxinolin-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, this invention also provides a 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.

The aim 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.

The aim 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 is a new pharmaceutical composition having anticarcinogenic activity.

The goal is achieved by a pharmaceutical composition containing, as an active ingredient, the compounds of general formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates, as well as pharmaceutically acceptable excipients. 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 field to obtain common forms, including: binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, are used in oral forms colorless agents, flavoring agents; 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 the compounds of general formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates in patients may be adjusted depending on the therapeutic the effectiveness and bioavailability of the active ingredients in the body, the speed of their metabolism and excretion from the body, 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 as dosage units, the above effective dosage must be taken into account, with each dosage unit of the preparation 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 (ip vivo, ip vitro) studies of processes that stop cell division, used as “pharmaceutical tools)).

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

The best embodiment of the invention

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

Example 1. 3- (9-Bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxol- [4,5-g] isoxinolin-5-yl) -6, 7-dimethoxy-3H-isobenzofyran-l-one A-Ol. 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 was added, after which a solution of 0.8 g (5 mmol) of bromine in 2 ml of AcOH was added dropwise (after adding HBr possible formation of a precipitate of NSC ₃ bromide which dissolves during bromination). After 15 minutes of stirring, the reaction mixture was poured onto 60 ml of a saturated ammonia solution cooled to ^{0 °} C. The colorless precipitate formed is filtered off, washed thoroughly with water, dried, and 63% A-Ol is obtained. NMR- ¹ H (CDCl ₃ , TMS): d 7.03 (Jo = 8.4 Hz, IH, 5-H), d 6.30 (Jo = 8.4 Hz, IH, 4-H), s 6.02 (2H, 2'-H ), d 5.49 (J = 4.8 Hz, IH, 3-H), d 4.33 (J = 4.8 Hz, IH ₅ 5'-H), s 4.09 (ЗН, OCH ₃ ), s 3.98 (ЗН, OCH ₃ ) , s 3.88 (ZN, OCH ₃ ), m 2.6-2.8 (2H, 7'-H), s 2.51 (ZN, 6'-CH ₃ ), m 2.42-2.50 (IH, 8'-H), m 1.92 - 2.01 (IH, 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 [l, 3] Dioxol- [4,5-g] isoxinolin-5-yl) -6, 7-dimethoxy-3H-isobenzofyran-l-one 1 (1). A solution of 206 mg (0.5 mmol) of 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, J = 8.4 Hz, IH), 6.27 (d, J = 8.4 Hz, IH), 6.01 (s, 2H), 5.48 (d, IH , IH, J = 4.0 Hz), 4.32 (d, IH, J = 4.0 Hz), 4.10 (s, ZN), 3.99 (s, ZN), 3.88 (s, ZN), 2.65-2.74 (m, IH) , 2.51 (s, ЗН), 2.42-2.62 (m, 2H), 1.89-1.96 (m, IH), 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 [l, 3] -Di-oxo [4,5-g] isoxinolin-5-yl) - 6,7-dimethoxy-3H-isobenzofyran-l-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 C. The mixture was stirred at this temperature for 20 minutes, after which it was allowed to warm to room temperature and stirred for another 2.5 hours. The solvent was removed on a rotary evaporator at a temperature not exceeding 20 ^° C, the residue was dissolved in acetone and reprecipitated with ether, and kept in the refrigerator for several hours. filter the solid hygroscopic substance that is used 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, IH, 5-H), d 7.30 (Jo = 8.3 Hz, IH, 4-H), br.s (IH, 3-H ), d 5.95 (J = I.5 Hz, IH, 2'-H), d. 5.89 (J = 1.5 Hz, IH ₃ 2'-H), br.s. 5.22 (IH, 5'-H), d 4.64 (J = I LO Hz, IH, 9-CH ₂ -Cl), d 4.49 (J = I LO Hz, IH, 9-CH ₂ -Cl), m 4.10 -4.21 (IH, 7'-H), s 3.98 (ЗН, OCH ₃ ), s 3.91 (ЗН, OCH ₃ ), m 3.44-3.53 (IH, 7'-H), s 3.26 (ЗН, OCH ₃ ) m 3.10-3.30 (2H, 8'-H), br.s 2.88 (ZN, 6'-CH ₃ ); 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-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxol [4,5-g] isoxinolin-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 IN 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-Pron ether. The precipitate was separated, dried, and 1 (3) was obtained as hydrochloride, NMR- ¹ H (400 MHz, CDC13): 10.21 (IH, s); 7.75 (IH, d, J = 7.6 Hz); 7.29 (IH, d, J = 7.6 Hz); 6.58 (IH, br.m), 6.04 (IH, s), 6.00 (IH, s), 5.29 (IH, br. M), 4.01-4.12 (IH, t), 3.99 (ЗН, s), 3.91 ( ZN, s); 3.67-3.75 (IH, t); 3.42-3.52 (IH, t); 3.31-3.40 (IH, t); 3.35 (ZN, s); 2.91 (ZN, s); 2.91 (ZN, 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 H NMR (400 Hz, CDC13): 10.26 (W, s); 7.05 (IH, d, J = 8.4 Hz); 6.51 (IH, d, J = 8.4 Hz); 6.08 (2H, s); 5.43 (IH, d, 5.1 Hz), 4.29 (IH, d, J = 5.1 Hz); 4.10 (ZN, s); 4.08 (ZN, s); 3.89 (ZN, s); 3.13-3.19 (IH, m); 2.82-2.87 (IH, m); 2.51 (ZN, s); 2.39-2.50 (2H, m), ¹³ C NMR (100 MHz, CDC13): 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. The General method of obtaining 5- (4,5-dimethoxy ~ 3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l , 3] dioxol [4,5-g] isoxinolin-9-carbonitrile 1 (4).

A mixture of 0.2 mmol of 3- (9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxolo- [4,5-g] isoxinolin-5-yl) -6, 7-dimethoxy-3H-isobenzofyran-l-one A-Ol or 3- (9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxol- [4,5 -g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-1-one 1 (1), 36 mg (0.4 mmol) of CuCN and 2 ml of dimethylformamide are stirred for 24 hours at 130 ⁰ C in an inert atmosphere. The reaction mass is cooled to 4 ^° C and 15 ml of ammonia and 15 ml are added with stirring. chloroform. 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 was filtered off and recrystallized from isopropanol. Obtain 1 (4), ¹ H NMR (400 MHz, CDC13, TMS): 7.06 (d, J = 8.1 Hz, IH, 5-H), 6.46 (d, J = 8.1 Hz, IH), 6.06 (d, IH, J = I.1 Hz), 6.05 (d, IH, J = Ll Hz), 5.42 (d, J = 4.8 Hz, IH), 4.23 (d, J = 4.8 Hz, IH), 4.09 (s, 3H), 4.04 (s, 3H), 3.88 (s, 3H), 2.73-2.87 (m, 2H), 2.52-2.55 (m, IH), 2.50 (s, 3H), 2.18-2.24 (m, IH) ; ¹³ C NMR (100 MHz, CDC13): 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 [l, 3] -Di-oxo [4,5-g] isoxinolin-5-yl) - 6,7-dimethoxy-3H-isobenzofyran-l-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 , and 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. H NMR (CDCl ₃ , TMS): d 6.94 (Jo = 8.4 Hz, IH, 5-H), d 6.14 (Jo = 8.4 Hz, IH, 4-H), s 5.96 (2H, 2'-H), d 5.53 (J = 4.8 Hz, IH, 3-H), d 4.39 (J = 4.8 Hz, IH, 5'-H), s 4.39 (2H, 9-CH ₂ -O), s 4.09 (S, OCH ₃ ), s 4.02 (ЗН, OCH ₃ ), s 3.85 (ЗН, OCH ₃ ), s 3.34 (2H, OCH ₃ ), m 2.56-2.72 (2H, 7'-H), s 2.53 (ЗН, 6 ' -CH ₃ ), m 2.33-2.40 (IH, 8'-H), m 1.84-1.96 (IH, 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-apyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxol- [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-1-ones of the general formula 1.1.

A mixture of 246 mg (0.5 mol) A-Ol, 0.6 mmol arylboronic acid 2, 70 mg (0.1 mmol) PdO ₂ (PPh ₃ ) ₂ , 652 mg (2 mmol) Cs ₂ (CO ₃ ) ₂ in 5 ml of degassed DME in a microwave oven at 140 ° C for 30 minutes, 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 aqueous solution 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 [l, 3] dioxol- [4,5-g] isoxinolin-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 (IH, Ar-H), rn7.23-7.26 (2H, Ar-H), d 7.02 (Jo = 8.4 Hz, IH, 5-H), d 6.13 (Jo = 8.4 Hz, IH, 4-H), d 5.98 (J = I.5 Hz, 2'-H), d 5.92 (J = I.5 Hz, 2'-H), d 5.55 (J = 4.8 Hz, IH, 3-H), d 4.51 (J = 4.8 Hz, IH, 5'-H), s 4.11 (S, OCH ₃ ), s 4.10 (S, OCH ₃ ), s 3.90 (S, OCH ₃ ), m 2.57-2.61 (IH, 7'-H), s 2.56 (ЗН, 6'-CH ₃ ), m 2.14-2.25 (2H, 7'H, 8'-H), m 1.62-1.731 ( IH, 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- [l, 3] dioxolo- [4,5-g] isoxinolin-5-yl] - 6,7-dimethoxy-3H-isobenzofuran-l-1.1 (3), ¹ H NMR (400 MHz, CDCl ₃ , TMS): D 7.17 (d, 2H, J = 8.8 Hz), 7.00 (d, J = 8.1 Hz, IH), 6.95 (d, 2H, J = 8.8 Hz), 6.11 (d, IH, J = 8.1 Hz,), 5.98 (d, IH, J = Ll Hz), 5.91 (d, IH, J = Ll Hz), 5.55 (d, IH, J = 4.0 Hz), 4.49 (d, IH, J = 4.0 Hz), 4.11 (s, ZN), 4.03 (s, ZN), 3.90 (s, ZN), 3.84 (s, ZN), 2.65-2.70 (m, IH), 2.56 (s, ZN), 2.15-2.30 (m, 2H), 1.66-1.73 (m, IH); 3- [9- (3-pyridyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dio-colo [4,5-g] isoxinolin-5-yl] - 6,7-dimethoxy-3H-isobenzofuran-l-1.1 1.1 (17), NMR- ¹ H (CDCl ₃ , TMS): dd 8.58 (J = 4.8 Hz, J = I.5 Hz, IH, Py-H ), d 8.50 (J = I .5 Hz, IH, Py-H), m 7.60-7.64 (IH, Py-H), m 7.33-7.38 (IH, Py-H), d 7.03 (Jo = 8.4 Hz , IH, 5-H), d 6.18 (J = 8.4 Hz, IH, 4-H), d 6.00 (J = I.5 Hz, 2'-H), d 5.93 (J = I.5 Hz, 2 '-H), d 5.54 (J = 4.8 Hz, IH, 3-H), d 4.50 (J = 4.8 Hz, IH, 5'-H), s 4.11 (6H, OCH ₃ ), s 3.91 (ЗН, OCH ₃ ), m 2.59-2.65 (IH, 7'-H), s 2.56 (ЗН, 6'-CH ₃ ), m 2.16-2.24 (2H, 7'H, 8'-H), m 1.69-1.77 (IH, 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 [l, 3] di-oxo [4,5-g] isoxinolin-5-yl] - 6,7-dimethoxy-3H-isobenzofuran-l-1.1 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, IH, 5-H) ₃ d 6.20 (Jo = 8.4 Hz, IH, 4-H), d 6.01 (J = I .5 Hz, 2'-H), d 5.94 (J = I .5 Hz, 2'-H), d 5.53 (J = 4.8 Hz, IH, 3-H), d 4.48 (J = 4.8 Hz, IH, 5'- H), s 4.12 (ZN, OCH ₃ ), s 4.10 (ZN, OCH ₃ ), s 3.91 (ZN, OCH ₃ ), m 2.61-2.69 (IH, 7'-H) ₅ s 2.56 (ZN, 6 ' -CH ₃ ), m 2.16-2.28 (2H, 7'H, 8'-H), m 1.72-1.83 (IH, 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-HHpHMHAHHHn) ^ - MeTOKCH-O-MeTHn-S ₃ OJ ₅ S-tetrahydro [l, 3] -di-okolo [4,5-g] isoxinolin-5-yl] -6, 7-dimethoxy-3H-isobenzofyran-l- 1.1 (24), ¹ H NMR (400 MHz, CDCl ₃ , TMS): D 9.17 (sDN), 8.68 (s, 2H), 7.03 (d, J = 8.4 Hz , IH), 6.22 (d, J = 8.4 Hz, IH), 6.03 (d, J = I.1 Hz), 5.96 (d, J = Ll Hz), 5.52 (d, J = 4.1 Hz, IH), 4.49 (d, J = 4.1 Hz, IH), 4.11 (s, 6H), 3.91 (s, 3H), 2.65-2.70 (m, IH), 2.57 (s, 3H), 2.17-2.27 (m, 2H) 1.77-1.85 (m, IH); 4- (5R) -5 - [(lS) - (4,5-dimethoxy-3-oxo-l, 3-dihydro-2-benzofyran-l-yl] -4-methoxy-6-methyl-5,6 , 7,8-tetrahydro- [l, 3] dioxole [4,5-g] isoxinolin-9-ylbenzenecarboxamide 1.1 (25), ¹ H NMR (400 MHz, CDCl ₃ , TMS): D 7.86 (d, 2H, J = 8.4 Hz), 7.35 (d, 2H, J = 8.4 Hz), 7.03 (d, J = 8.0 Hz, IH), 6.20 (d, J = 8.0 Hz, IH), 5.59 (br.s, IH) , 5.99 (d, IH, J = I.5 Hz), 5.93 (d, IH, J = I.5 Hz), 5.75 (br.s, - IH), 5.54 (d, IH, J = 4.0 Hz, IH), 4.50 (d, IH, J = 4.0 Hz), 4.11 (s, 3H), 4.09 (s, 3H), 3.91 (s, 3H), 2.65-2.70 (m, IH), 2.56 (s, 3H ), 2.17-2.25 (m, 2H), 1.70-1.78 (m, IH) and other 3- (9-apyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1, 3] dioxol- [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-1-one 1.1, the combinatorial library of which is shown in Table 2.

Table 2. Combinatorial library of 3- (9-apyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxolo- [4,5-g] isoxinolin-5-yl) - 6,7-dimethoxy

ZH-isobenzofyran-1-compounds 1.1

Example 7. General method for producing 3- (9-aminomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxolo [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzo-fyran-1-ones 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-N-morpholinomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l, 3 ] dioxole [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzo-fyran-l-one 1.2 (5), NMR- ¹ H (CDCl ₃ , TMS): d 6.90 ( Jo = 8.1 Hz, W, 5-H), d 6.11 (Jo = 8.1 Hz, IH, 4-H), d 5.94 (J = 1.5 Hz, IH, 2'-H), d 5.92 (J = I. 5 Hz, IH, 2'-H), d 5.54 (J = 4.4 Hz, IH, 3-H), d 4.40 (J = 4.4 Hz ₅ IH, 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, IH , 9'-CH) ₅ d 3.37 (J = 12.5 Hz, IH, 9'-CH), m 2.64-2.72 (2H, 7'-H) ₅ s 2.54 (ЗН, 6'-CH ₃ ), m 2.40 -2.46 (4H, CH ₂ -N-CH ₂ ), m 2.31-2.39 (IH, 8'-H), m 1.88-1.98 (IH, 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- [l, 3] dioxolo [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzo-fyran-l-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- [l, 3] dioxole [4,5-g] isoxinolin-5-yl) - 6,7-dimethoxy-3H-isobenzofyran-

1-on 1.2

Example 8. General method for producing 6,7-Dimethoxy-3- [4-methoxy-6-methyl-9- (sylphamoyl) -5,6,7,8-tetrahydro- [l, 3] dioxol [4,5- g] isoxinolin-5-yl] -CH - isobenzofyran-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-l-sulfonyl) -5,6,7,8-tetrahydro- [l, 3] dioxole [ 4,5-g] isoxinolin-5-yl] -ZH-isobenzofuran-l-one 1.3 (5), NMR- ¹ H (CDCl ₃ , TMS): d 7.07 (Jo = 8.4 Hz, IH, 5-H) , d 6.40 (Jo = 8.4 Hz, IH, 4-H), d 6.07 (J = I.5 Hz, 2'-H), d 6.06 (J = 1.5 Hz, 2'-H), d 5.40 (J = 4.8 Hz, IH, 3-H), d 4.37 (J = 4.8 Hz, IH, 5'-H), s 4.10 (S, OCH ₃ ), s 4.09 (S, OCH ₃ ), s 3.88 (S, 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 (IH, 7 ' -H), s 2.52 (ЗН, 6'-CH ₃ ), m 2.33-2.41 (IH ₅ 8'-H), m 2.11-2.20 (IH, 8'-H), NMR- ¹³ C (CDCl 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- (sylfamoyl) -5,6,7,8-tetrahydro- [l, 3] di about [4,5-g] isoxinolin-5-yl] -CH - isobenzofyran-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- (sylphamoyl) -5,6,7,8-tetrahydro- [l, 3] dioxole [4,5-g ] isoxinolin-5-yl] -ZH- isobenzofyran-1-one 1.3

Example 9. Testing the anticancer activity of compounds of the general formula 1. A focused library of noscapines of the general formula 1 was tested for their ability to suppress cell growth in four tumor lines: DLD-I - 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. Profile proliferation of tumor cells was measured using Alamar Blue dye, which allows the number of living cells to be determined photometrically. The overall effect of inhibition of cell growth and death was calculated as a percentage of the Alamar Blue signal in experimental samples and Alamar Blue signal in control experiments in which tumor cell cultures were treated only with pure DMSO. Table 5 presents the results of a test of anticancer activity for some of the tested compounds of general formula 1, moreover, a stronger suppression of cell growth is expressed by a large number.

Table 5. Suppression of tumor cell proliferation under the action of compounds of the general formula 1.

T-47D DU- 145 DLD-I Jurkat-T

Compound

10 μM 30 μM 10 μM 30 μM 10 μM 30 μM l μM Z μM 10 μM 30 μM

Noscapine 3 34 5 20 2 20 2 7 20 89

Noscapine HCl 9 17 3 16 7 18 2 4 18 92

A-Ol 39 45 39 58 23 39 2 32 94 91

1 (8) 22 -2 0 4 5 7 -1 4 8 8

1 (5) 8 7 -2 6 14 18 0 7 6 14

1 (3) 13 13 9 10 16 19 5 8 9 16

1 (3) HCl 6 11 17 15 11 17 3 9 10 17

1.2 (5) -1 -1 0 4 6 14 12 8 2 15

1.3 (4) 4 16 2 10 18 17 10 15 5 13

1.2 (7) 13 15 14 13 9 14 8 12 7 15

1.1 (1) 12 43 -1 18 16 31 0 8 24 56

1.1 (19) 3 5 4 -1 7 12 3 7 5 13

1.1 (18) 10 15 5 -4 6 17 1 5 12 19

1 (1) 5 28 86 94

Industrial applicability

The invention can be used in medicine, veterinary medicine, biochemistry.

Claims

Claim

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 substituent of the cyclic system selected from optionally substituted alkyl, where the substituents are selected from optionally substituted amino group or azaheterocycle, optionally containing as an additional heteroatom O, S or N, and attached by a nitrogen atom to the alkyl group, 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, and R ² = Br or R ¹ = CH ₃ and 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-l-ylacetyl-aminomethyl, 2-morpholine-4-ylacetyl-aminomethyl, acyloxymethyl, 5-(4,5-dimethoxy-3-oxo-l,3-dihydroisobenzophyran-l-yl)-4-methoxy-6-methyl-5, b.7, 8-tetrahydro-[l,3]dioxolo[4,5-g]isoxynoline-9-methyl.

2. Compounds according to claim l, which are substituted (R,S)-nocapine of general formula 1.1:

1.1 where: Ar represents aryl or heteroaryl.

3. Compounds according to claim l, which are substituted (R,S)-nocapine of general formula 1.2:

where: R ³ and R ⁴ independently represent the same or different amino group substituents selected from hydrogen, alkyl, aryl, or R and R together with the nitrogen atom to which they are bonded form an azaheterocycle.

4. Compounds according to claim l, which are substituted (R,S)-nocapine of general formula 1.3:

where: R ³ and R ⁴ have the meaning given for compounds of general formula 1.2.

5. Compounds according to claim l, representing 3-(9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro[l,3]dioxolo-[4,5-g]isoxynoline- 5-yl)-6,7-dimethoxy-3H-isobenzophyran-l-one 1(1), 3-(9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-teparido[l, 3]-dioxolo[4,5- g]isoxylin-5-yl)-6,7-dimethoxy-3H-isobenzophyran-l-one 1(2), 5-(4,5-dimethoxy-3-oxo-l ,3-dihydroisobenzophyran-l-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoxynoline-9-carbaldehyde 1(3) , 5-(4,5-dimethoxy-3-oxo-l ,3- Dihydroisobenzophyran-l-yl)-4-methoxy-6-methyl-5D7,8-tetrahydro-[l,3]dioxolo[4,5-g]isoxynolin-9-carbonitrile 1(4), 5-(4,5 -dimethoxy-3-oxo-l,3-dihydroisobenzophyran-l-yl)-4-methoxy-6-methyl-5,6,7 ₅ 8-tetrahydro-[l,3]dioxolo[4,5-g]isoxynoline -9-carboxylic acid 1(5), 3-(9-methoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro[l,3]-dioxolo[4,5- g]isoxynoline- 5-yl)-6,7-dimethoxy-3H-isobenzophyran-l-one 1(6) or 5-(4,5-dimethoxy-3-oxo-l,3~dihydroisobenzophyran-l-yl)-4-methoxy -6-methyl-5,6,7,8-teparido-[l,3]dioxolo[4,5-g]isoxynoline-9-sulfonyl chloride 1(7):

6. Method for obtaining 3-(9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro[l,3]dioxolo-[4,5-g]isoxylin-5-yl)-6 ,7-dimethoxy-3H-isobenzophyran-l-one 1(1) according to claim 5 by the action of ICl on (R,S)-noscapine NSC in acetic acid according to the following scheme:

N.S.C.

7. Method for obtaining 3-(9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro[l,3]-di-oxolo[4,5-g]isoxynolin-5-yl) -6,7-dimethoxy-3H-isobenzophyran-l-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 -[l,3]-dioxolo[4,5-g]isoxynolin-5-yl)-6,7-dimethoxy-3H-isobenzophyran-l-one A-04 according to the following scheme:

A-04 1(2)

8. Method for obtaining 5-(4,5-dimethoxy-3-oxo-l,3-dihydroisobenzophyran-l-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[l,3 ]dioxolo[4,5-g]isoxynoline-9-carbaldehyde 1(3) according to paragraphs. 1 or 5 by the action of hexamethylenetetramine on 3-(9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro[l,3]-dioxolo[4,5-g]isoxynolin-5-yl) -6,7-dimethoxy-3H-isobenzofuran-1-one 1(2) in an organic solvent.

9. Method for preparing 5-(4,5-dimethoxy-3-oxo-l,3-dihydroisobenzophyran-l-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[l,3 ]dioxolo[4,5-g]isoxynoline-9-carbonitrile 1(4) according to claim 5 by the action of copper (I) cyanide on 3-(9-bromine (or iodine)-4-methoxy-6-methyl-5, 6,7,8-tetrahydro[l,3]dioxolo-[4,5-g]isoxynolin-5-yl)-6,7-dimethoxy-3H-isobenzofuran-l-one A-Ol or 1(1) in medium of an aprotic solvent according to the following scheme:

A-01: Y = Br, 1(1): Y = I 1(4)

10. Method for obtaining 5-(4,5-dimethoxy-3-oxo-l,3-dihydroisobenzophyran-l-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[l,3 ]dioxolo[4,5-g]isoxynoline-9-carboxylic acid 1(5) according to claim 5 by hydrolysis of 5-(4,5-dimethoxy-3-oxo-l,3-diridoisobenzophyran-l-yl)-4- methoxy-6-methyl-5,6,7,8-tetrahydro-[l,3]dioxolo[4,5-g]isoxynoline-9-carbaldehyde 1(4).

11. Method for obtaining 3-(9-mexoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro[l,3]-dioxolo[4,5-g]isoxylin-5-yl)-6 ,7-dimexoxy-3H-isobenzophyran-l-one 1(6) according to claim 5 by the reaction of 3-(9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro[l,3] - di-oxolo[4,5-g]isoxylin-5-yl)-b,7-dimethoxy-3H-isobenzophyran-l-one 1(2) with methanol in the presence of a base.

12. Method for obtaining 5-(4,5-dimethoxy-3-oxo-l,3~dihydroisobenzophyran-l-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[l,3 ]dioxolo[4,5-g]isoxynoline-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. Method for obtaining compounds according to claim. 1 or 2 reaction 3-(9-bromo(or iodine)-4-methoxy-6-methyl-5,6,7,8-tetrahydro[l,3]dioxolo-[4,5-g]isoxynoline-5- yl)-6,7-dimethoxy-3H-isobenzophyran-1-one of the formula A-Ol in the presence of a palladium catalyst with aryl or heteroarylboron derivatives of the general formula Ar-B(OZ) ₂ , where: Ar has the meanings indicated above when determining formula 1.1; Z=H, alkyl C ₁ -C ₄ or

14. Method for obtaining 3-(9-aminomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[l,3]dioxolo[4,5-g]isoxynolin-5-yl)-6 ,7-dimethoxy-3H-isobenzo-furan-l-ones 1.2 to p.p. 1 or 3 reaction of 3-(4-methoxy-6-methyl-9-chloromethyl-5,6,7,8-tetrahydro-[l,3]dioxolo[4,5-g]isoxylin-5-yl)-6 ,7-dimethoxy-3H-isobenzophyran-l-ones 1(2) with the corresponding amine in an organic solvent.

15. Method for obtaining 3-(9-aminomethyl-4~methoxy-6-methyl-5,6,7,8-tetrahydro-[l,3]dioxolo[4,5-g]isoxynolin-5-yl)-6 ,7-dimethoxy-3H-isobenzophyran-l-ones 1.2 according to paragraphs. 1 or 3 reductive, amination of 5-(4,5-dimethoxy-3-oxo-l,3-dihydroisobenzophyran-l-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[l ,3]dioxolo[4,5-g]isoxynoline-9-carbaldehyde 1(3) with the appropriate amine in an organic solvent.

16. Method for obtaining 6,7-dimethoxy-3-[4-methoxy-6-methyl-9-(sylfamoyl)-5,6,7,8-tetrahydro-[l,3]dioxolo[4,5-g] isoxynolin-5-yl]-3H-isobenzophyran-l-ones 1.3 according to pp. 1 or 4 by the reaction of 5-(4,5-dimethoxy-3-oxo-l,3-dihydroisobenzophyran-l-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[l,3 ]dioxolo[4,5-g]isoxynoline-9-sulfonyl chloride 1(7) with the corresponding amine.

17. Combinatorial library for determining leading compounds, consisting of compounds of general formula 1 according to claim 1.

18. Focused library for determining lead compounds, consisting of compounds of general formula 1 according to claim 1.

19. A pharmaceutical composition with anticarcinogenic activity, in the form of tablets, capsules or injections placed in pharmaceutically acceptable packaging, containing as an active substance at least one compound of general formula 1 according to claim 1 or its pharmaceutically acceptable salts.

20. A method of suppressing cell proliferation by introducing a pharmaceutical composition according to claim 19.