UA79925C2 - Variolin derivatives, process for the preparation thereof (variants) and use of these compounds as anti-cancer agents - Google Patents

Abstract

The invention provides variolin derivatives of formula (I), wherein: R1 and R2 are each independently selected from the group consisting of H, OH, OR, SH, SR, SOR, SO2R, NO2, NH2, NHR, N(R)2, NHCOR, N(COR)2, NHSO2R, CN, halogen, C(=O)H, C(=O)R, CO2H, CO2R, C1-C12 alkyl, C1-C12 haloalkyl, C2-C12 alkenyl, C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and substituted or unsubstituted heteroaromatic; and R3 is selected from the group consisting of H, OH and OMe; wherein the or each group R is independently selected from the group consisting of OH, C1-C12 alkyl, C1-C12 haloalkyl, C2-C12 alkenyl, C2-C12 alkynyl, substituted or unsubstitnted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted arylalkenyl and substituted or unsubstituted heteroaromatic, and wherein the group R1, R2 or R3 is a group of formula N(R)2 or N(COR)2, each of the R groups may be the same or different, or the two R groups, together with the nitrogen atom towhich they are attached, may form a 5-14 membered heterocyclic ring. These compounds display activity against a range of mammalian cancer cell lines. New synthetic routes to new and known variolin compounds, together with novel intermediates, are also disclosed. New antitumour activity of known variolin compounds is also described. (I)

Description

Description of the invention

The present invention relates to antitumor compounds, in particular, to new antitumor analogs of variolin

In deoxyvariolin B. The present invention also relates to methods of synthesis, in particular, to methods of obtaining both new compounds according to the present invention and known compounds of variolin B and deoxyvariolin B, including new intermediate compounds, the preparation of which is one of the constituent parts of such synthesis methods. In addition, the present invention relates to new, previously undescribed applications of known variolin compounds.

Variolins are a new class of marine alkaloids isolated from a rare, hard-to-reach species 70 of the Antarctic sponge Kygkraigiska magiaosa, a typical example of which is variolin B (1).

All variolins have a condensed tridoyi32"4,5|pyrrolo|1,2-c|- pyrimidine nucleus (2), in which either a heterocyclic aromatic ring or an ester group is attached to the C5 carbon atom, as is the case in variolin B (1 ) and variolini O (3). y 4 1 y t t v g

It is known that variolins have antitumor activity and other useful properties. The complete structure and antitumor activity of the specified and related compounds (described in the articles of M.V. Regt.

Temgapedgop, 1994, 50, 3987-92 and S. Tgitigshii ey aiYi., Teyapedgop, 1994, 50, 3993-4000)Y. However, so far it has been shown that the variolins described in these articles have only a limited spectrum of antitumor activity.

The limited availability of natural raw materials made it necessary to search for alternative methods of synthesis of natural compounds and related analogues.

The method of synthesis of the related deoxyvariolin B (4) is described in the article by M.AiYimage? ei ai., Teigganeagop o

Hek., 2001, 42, 315-317) (which was published before the filing date of this application, but after the priority dates). with (o) (o) 35 . and - as - "from The way of obtaining deoxyvariolin B, described in the above-mentioned article, cited as a reference, includes a total of no less than fourteen stages, in the process of which a condensed tricyclic pyridopyrrolopyrimidine nucleus is formed from 7-azaindole, then a heteroaryl coupling reaction is carried out for introduction of the fourth aromatic ring and intermediate compound (5) is obtained. By replacing the amino group with a sulfone group (6), deoxyvariolin B (4) is obtained. se) se) ime) sl ; name)

However, as indicated above, this method of synthesis is long and complicated. In addition, in the scientific literature 60 there is no description of the method of synthesis of variolin B (or any natural variolin).

Therefore, it is desirable to create a method that allows synthesizing deoxyvariolin B and its derivatives by performing a smaller number of stages compared to the method described above.

It is also desirable to create a method that allows the direct synthesis of variolin B, as well as its deoxy derivative. 65 In addition, it is desirable to obtain new compounds with antitumor activity that is comparable or exceeds the similar activity of natural variolin B.

The methods of synthesis according to the present invention include the first developed method of obtaining variolin B (1), provide a short and fast preparation of deoxyvariolin B (4) and intermediate compounds such as (5) and (6).

These intermediate compounds were used to obtain new antitumor compounds having a condensed tricyclic pyridopyrrolopyrimidine core of variolins.

In accordance with this invention, new methods of synthesis of variolin B, deoxyvariolin B and similar compounds have been developed, which take advantage of the hidden symmetry element of these compounds. The new approach makes it possible to create the structure of the variolin core, which includes a condensed pyridopyrrolopyrimidine core with a heterocyclic aromatic ring attached to it in the C5 position, due to the implementation of a smaller number of stages in 7/0 compared to the known synthesis method.

Thus, simple monoheteroaromatic molecules can be transformed into a number of new and known variolin derivatives with potential antitumor therapeutic effects.

Thus, the first object of this invention is the compound of formula (1):

Ku and Ko are independently selected from a group that includes H, ON, OK, ZN, ZK, OK, ZOH, MO», MN», MNE», MK)»

МНСОК, ШСОК)», МНЗО»К, СМ, halogen, С(-О)Н, С(О)К, СОН, СОХ, С4-C82alkyl, C.-C.iohaloalkyl, IS o)

Co-Sioalkenyl, Co-C42alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and substituted or unsubstituted heteroaromatic group; and

Ez is selected from the group consisting of H, OH and OMe; (o) where K or each of the groups K' is independently selected from the group including OH, C.-C.ioalkyl, C.4-C.haloalkyl,

C0-C10alkenyl, C0-C10alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted F c5 or unsubstituted arylalkenyl and substituted or unsubstituted heteroaromatic group; - and the group K/, Ko or Kz is a group of the formula M(K) » or M(ISOK)", all groups K" can have the same or different values or two groups K together with the nitrogen atom to which they are attached can form a 5-14-membered heterocyclic ring; " the aryl group and the aryl part of the aralkyl and arylalkenyl group is a carbocyclic aryl group having from 6 to 14 carbon atoms in the carbocyclic ring or in two or more condensed rings; - the aralkyl group is is a C-Svalkenyl group substituted by the above-mentioned aryl group; and the arylalkenyl group is a Co-Svalkenyl group substituted by the above-mentioned aryl group; "heteroaromatic group is a heterocyclic aromatic group having from 5 to 14 atoms in one ring or in two or more fused rings, in which at least one ring atom is selected from the group consisting of nitrogen, oxygen and sulfur atoms, and such heterocyclic aromatic group is fused with the above-mentioned aryl group; c o Substituents in aryl and heteroaromatic groups and in the aryl part of aralkyl and arylalkenyl groups are selected from the group that includes C.-Ci»alkyl, C.i.-Siohaloalkyl, C.i.-Soalkyl, C.-C-goalkylthio, MH» se) S.-Alkylamino, di(C--C.alkyl)amino, C-C.alkanoylamino, di(C--C.alkanoyl)amino, MO", SM and halogen; t 50 its derivatives, in which the nitrogen atom is quaternized, its salts and esters, sl with the exception of compounds in which:

Ku is amino, thiomethyl, methylsulfinyl or methylsulfonyl, Co is amino and Kz is hydrogen; or

K. and K" mean amino and Kz means hydroxy.

The present invention also relates to a method of synthesis of both the new variolin derivatives of formula (I) described above and the known variolin derivatives described in the prior art. o The second object of this invention is a method of obtaining the compound of formula (1): име) 60 b5 with where:

Ku and Ko are independently selected from a group that includes H, ON, OK, ZN, ZK, OK, ZOH, MO», MN», MNE», MK)»

МНСОК, ШСОК)», МНЗО»К, СМ, halogen, С-(О)Н, С(О)К, СОН, СОХ, С4-C82alkyl, C.-C.iohaloalkyl,

Co-Sigalkenyl, Co-C.2alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and substituted or unsubstituted heteroaromatic group; and

Ez is selected from the group consisting of H, OH and OMe; where K or each of the groups K' is independently selected from the group including OH, C.-C.ioalkyl, C.4-C.haloalkyl,

Co-Cihalkenyl, Co-C.ioalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted arylalkenyl, and substituted or unsubstituted heteroaromatic group; and where the Ki, Ko or Kz group is a group of the formula M(K)" or M(SOK)", where all K groups can have the same or different values or two K' groups together with the nitrogen atom to which they are attached, can form a 5-14-membered heterocyclic ring; the aryl group and the aryl part of the aralkyl and arylalkenyl group is a carbocyclic aryl group having from 6 to 14 carbon atoms in the carbocyclic ring or in two or more condensed rings; the aralkyl group is a C.-Svalalkyl group replaced by the above-mentioned aryl group; IS o) the arylalkenyl group is a Co-Svalkenyl group substituted by the above-mentioned aryl group; a heteroaromatic group is a heterocyclic aromatic group having from 5 to 14 atoms in one ring or in two or more fused rings in which at least one ring atom is selected from the group consisting of (o) nitrogen, oxygen and sulfur atoms, and such a heterocyclic aromatic group is condensed with the above-mentioned aryl group; F substituents in aryl and heteroaromatic groups and in the aryl part of aralkyl and arylalkenyl groups are selected from the group consisting of C.-Ci-alkyl, C.i.-Siohaloalkyl, C.i.-Soalkyl, C.-C-goalkylthio, MN",

C.4-C.alkylamino, di(C--C,.alkyl)amino, C4-C,.alkanoylamino, di(C--C,alkanoyl)amino, MO», SM and halogen; its derivatives, in which the nitrogen atom is quaternized, and its salts and esters, which includes the preparation of the intermediate compound of the formula (II) - si. ;" t -I i-o and se) mu » and sl where:

Ka, Koa and Kza mean any groups represented by K 4 , Ko and Kz, respectively, and all such groups in which the reactive functional groups are protected; and

Mi and Mo denote groups that can be removed to form a fused tricyclic pyridopyrrolopyrimidine ring structure. o As will be described below, the new compounds of formula (I) exhibit biological activity against various mammalian cancer cell lines. The antitumor activity of these compounds is directed against leukemia, lung cancer, colon cancer, kidney cancer, prostate cancer, ovarian cancer, breast cancer, sarcoma and melanoma. 60 In addition, the known compounds of formula (I) exhibit previously undescribed activity against a number of cancer diseases.

Thus, a third object of the present invention is a method of treating or preventing cancer in a mammal, which comprises administering to a mammal in need of such treatment an effective amount of a novel compound of the present invention. 65 A fourth object of the present invention is a method of treating or preventing cancers selected from ovarian cancer, kidney cancer, prostate cancer, breast cancer and melanoma in a mammal, which comprises administering to a mammal in need of such treatment an effective amount of a novel compound of this invention or a known variolin compound.

Other objects of this invention relate to the stages of synthesis of some preferred compounds, described in more detail below, and intermediate compounds, in particular, compounds of the formula (11) given above.

As defined herein, alkyl groups may be straight or branched chain groups preferably having from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, even more preferably from 1 to about 6 carbon atoms and most preferably 1, 2, C or 4 carbon atoms. Methyl, ethyl and propyl, including isopropyl, are particularly preferred 7/0 alkyl groups in the compounds of this invention. As used herein, the term "alkyl" refers, except where specifically stated, to cyclic and non-cyclic groups, wherein the cyclic groups contain at least three carbon atoms in the ring.

Haloalkyl groups are the above-mentioned alkyl groups (including cycloalkyl groups), which are substituted by one or more halogen atoms (predominantly fluorine, chlorine, bromine or iodine atoms) and preferably have from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, even more preferably from 1 to about 6 carbon atoms and most preferably 1, 2, 3 or 4 carbon atoms. Methyl, ethyl and propyl, including isopropyl groups substituted with 1, 2 or C halogen atoms, which may have the same or different values, in particular, fluoromethyl, fluorochloromethyl, trifluoromethyl and trichloromethyl, are particularly preferred haloalkyl groups in the compounds of this invention.

Preferred alkenyl and alkynyl groups in the compounds of this invention contain one or more unsaturated bonds and from 2 to about 12 carbon atoms, more preferably from 2 to about 8 carbon atoms, even more preferably from 2 to about 6 carbon atoms, most preferably 2, C or 4 carbon atoms. The terms "alkenyl" and "alkynyl" as used herein refer to both cyclic and noncyclic groups, with straight or branched chain noncyclic groups usually being more preferred. with

Preferred alkyl groups in the compounds of the present invention include groups containing one or more (but preferably only one) oxygen bonds and from 1 to about 12 carbon atoms, more preferably from 1 to (8) about 8 carbon atoms, even more preferably from 1 to about 6 carbon atoms and most preferably 1,2, C or 4 carbon atoms.

Preferred alkylthio groups in the compounds of this invention contain one or more (but preferably only one) simple thioester linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms and even more preferably from 1 to about 6 carbon atoms. Alkylthio groups containing 1, 2, 3 or 4 carbon atoms are particularly preferred. b

Preferred alkylsulfinyl groups in the compounds of the present invention include groups containing one or more sulfoxide (ZO) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms and even more preferably from 1 to about 6 carbon atoms. Alkylsulfinyl groups containing 1, 2, 3 or 4 carbon atoms are particularly preferred.

Preferred alkylsulfonyl groups in the compounds of this invention include groups containing one or more sulfonyl (505) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and even more preferably from 1 to about 6 carbon atoms . Alkylsulfonyl groups containing 1, 402.3 or 4 carbon atoms are particularly preferred. Preferred alkanoyl groups in the compounds of the present invention include groups containing one or more carbonyl (CO) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms; carbon and even more preferably from 1 to about b carbon atoms (including the carbon of the carbonyl group).

Alkanoyl groups containing 1, 2, 3 or 4 carbon atoms, in particular formyl, acetyl, propionyl, butyryl and isobutyryl groups, are particularly preferred. -I Preferred alkylamino groups in the compounds according to the present invention contain one or more (but preferably only one) MH bonds and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms and even more preferably from 1 to about b carbon atoms. Alkylamino groups containing 1, 2, C or 4 atoms

He) carbon, in particular methylamino, ethylamino, propylamino and butylamino groups, are particularly preferred.

Preferred dialkylamino groups in the compounds of this invention contain one or more (but preferably only one) nitrogen atoms attached to two alkyl groups, each of which may contain from 1 to about 12 sp carbon atoms, more preferably from 1 to about 8 carbon atoms and even more preferably from 1 to about 6 carbon atoms. Alkyl groups can contain the same or different values. Dialkylamino groups, in which each alkyl group contains 1, 2, 3 or 4 carbon atoms, in particular dimethylamino, diethylamino, M-methylethylamino, dv M-ethylpropylamino, dipropylamino, dibutylamino and M-methylbutylamino groups, are particularly preferred.

Preferred alkanoylamino groups in the compounds of the present invention contain one MH-CO bond attached to (F) an alkyl group containing from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and even more preferably from 1 to about 6 carbon atoms. Alkanoylamino groups containing 1, 2, 3 or 4 carbon atoms, in particular formylamino, acetylamino, propionylamino and butyrylamino groups, are particularly preferred. The acetylamino group is the most preferred.

Preferred dialkanoylamino groups in the compounds of the present invention contain one nitrogen atom attached to the above two alkanoyl groups, which may have the same or different values and contain from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms and even more preferably from 1 to about 6 carbon atoms. Dialkanoylamino groups, in which each alkanoyl group contains 1, 2, C or 4 atoms of 65 Carbon, in particular diformylamino, formylacetylamino, diacetylamino, dipropionylamino and dibutyrylamino groups, are particularly preferred. A diacetylamino group is particularly preferred.

Preferred alkylsulfonylamino groups in the compounds of the present invention contain one MH-5O 5-bond attached to an alkyl group containing from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and even more preferably from 1 to about 6 carbon atoms. Alkylsulfonylamino groups,

Those containing 1, 2, 3 or 4 carbon atoms, in particular methanesulfonylamino, ethanesulfonylamino, propanesulfonylamino and butanesulfonylamino, are particularly preferred.

In the compounds of formula (I), K/ is preferably selected from the group including ОН, ОК, 5Н, ЗК, ОК, ЗОХ, МН».

МН, ШЧО)», МНСОК, ШЧСОК)», МНЗОК, (OK, SON, SOZHzh, C4-Si2alkyl, C.4-Siohaloalkyl, where KK or each of K" is independently selected from the group that includes OH, C.- C.oalkyl, C.4-C"haloalkyl, aryl (which may be optionally substituted by a group selected from C.4-Svalkylu, C.--Svalkoxy, S.-Svalkylthio, MH",

S.-Svalkylamino, di(C--Svalkyl)damino, MO", SM and halogen), aralkyl or arylalkenyl (the aryl part of which may be optionally substituted by a group selected from C/-Svalkylu, C--Svalkoxy, C .-Svalkiltio, MN",

C.-Salkylamino, di(C--Salkyl)amino, MO", CM and halogen), and when the Ki group is a group of the formula M(K)) 2" or M(SOK)", all groups K' can have the same or different values or two K' groups together with the nitrogen atom to which they are attached form a 5- to 12-membered heterocyclic ring.

More preferably, Ku is chosen from a group that includes OK, ZK, OK, MN», MNE», SHCHO)», MNSOK, SHSHOK)» and

MNZO»K, where K or each of K' is independently selected from the group consisting of C1-Salkyl, C4-Shaloalkyl, aryl (which may optionally be substituted by a group selected from C1-Salkyl, C-- Svaloxy and halogen), aralkyl (the aryl part of which may be optionally substituted by a group selected from C 4-Svalky, C--Svaloxy and a halogen), aralkenyl (the aryl part of which may be optionally substituted by a group selected from

S.-Svalkilu, S--Svalcox and halogen), and when the Ki group. represents a group of the formula M(K)» or M(ISOK)», two K' groups together with the nitrogen atom to which they are attached can form a 5-10-membered heterocyclic ring.

Even more preferably, K is selected from the group that includes C.-C., alkoxy, C.-C. alkylthio, C.-C. alkylsulfinyl, amino, C.-C. C.-C.alkanoylamino, di(Ci-C.alkanoyl)amino, C1-Sahalogenalkanoylamino, arylamino (where the oaryl part can be optionally substituted

a C.-C.alkyl group), benzylamino (where the phenyl part of the benzyl part may be optionally substituted with a C.-C.alkyl group), cinnamoylamino or dicinnamoylamino (where the phenyl part of each cinnamoyl part may be optionally substituted C.i.i.C., an alkyl group) or a 5-7-membered nitrogen-containing heterocyclic ring attached to another part of the molecule through its nitrogen atom. Most preferably, Ki is selected from the group consisting of methoxy, thiomethyl, methylsulfinyl, amino, methylamino, ethylamino, benzylamino, acetylamino, trifluoroacetylamino, diacetylamino, cinnamoylamino, c dicinnamoylamino, p-methoxybenzylamino, and piperidino. Gee!

Most preferably KK. is selected from the group consisting of amino, benzylamino, acetylamino, trifluoroacetylamino, diacetylamino, cinnamoylamino, dicinnamoylamino and p-methoxybenzylamino. me)

Co is mainly chosen from the group that includes ON, OK, ZN, ZK, ZOK, 502, MNo, MNK, M(K)o, MNSOK, i-

М(СОК)», МНЗО»К, С(чОК, СОН, СОХ, C.4-Sioalkyl and C.i-C1ohaloalkyl, where K' or each of K' is independently selected from the group including OH, C.- Sioalkyl, C.4-C/haloalkyl, aryl (which may be optionally substituted by a group selected from S.-Svalkylu, S.--Svaloxy, S.i-Svalkylthio, MH", S.-Svalkylamino, di( C--Svalkyl)duamino, MO", CM and halogen), aralkyl or arylalkenyl (the aryl part of which may be "optionally substituted by a group selected from C/-Svalkylu, C--Svalkoxy, S.i-Svalkylthio, MH », Si-Svalkylamino, with di(C--Svalkyl)amino, MO», SM and halogen), and when the Ko group is a group of the formula M(K)» or MISOK)», all . K" groups can have the same or different values or two K groups together with the nitrogen atom to which they are attached?" attached, form a 5-12-membered heterocyclic ring.

More preferably, Co is chosen from a group that includes OK, ZK, OK, MNo, MNK, ZK)», MNSOK, SHSOK» and

MOH, wherein or each of CC is independently selected from the group consisting of C1-Salkyl, C1-Shaloalkyl, aryl-I (which may optionally be substituted by a group selected from C1-Salkyl, C1-Salkyl and halogen), aralkyl (the aryl portion of which may be optionally substituted by a group selected from C 4-Salkyl, C--Swaloxy and i, halogen), aralkenyl (the aryl portion of which may be optionally substituted by a group selected from

Ge) S.-Svalkylu, C--Svalcoxy and halogen), and when the Ko group is a group of the formula M(K) » or M(ISOK)», two 5r Group K together with the nitrogen atom to which they are attached, can form a 5-10-membered heterocyclic ring. Even more preferably, Co is selected from the group consisting of C.-C.,alkyl, C.-C.alkylthio, C.-C.alkylsulfinyl, amino, C.-C.alkylamino, di(C.-C.alkyl)amino , C.-C.alkanoylamino, di(Ci-C.alkanoyl)amino,

S.-C.haloalkanoylamino, arylamino (where the aryl part can be optionally substituted

C.-C. alkyl group), benzylamino (where the phenyl part of the benzyl part can be optionally substituted by a C.-C. alkyl group), cinnamoylamino or dicinnamoylamino (where the phenyl part of the cinnamoyl part can be optionally substituted by C.i- C, an alkyl group) and a 5-7-membered nitrogen-containing heterocyclic (F, a ring attached to another part of the molecule through its nitrogen atom. ka Much more preferably, Co is selected from the group including thiomethyl, methylsulfinyl, amino, methylamino, ethylamino, acetylamino , diacetylamino, cinnamoylamino, and p-methoxybenzylamino. Most preferably, Co is selected from the group consisting of amino, acetylamino, diacetylamino, and p-methoxybenzylamino.

Ez mostly means N.

As should be apparent to one skilled in the art, the above preferred definitions of K 4 , K , and K 2 may be combined to form various combinations, and all compounds comprising such combinations of the above 65 preferred definitions are within the scope of this . A combination consisting of two of the above definitions is preferred, and a combination including all three of the preferred definitions is particularly preferred.

The following compounds are most preferred:

M'-bisacetyldeoxyvariolin;

M'-bisacetyl-M-acetyldeoxyvariolin;

M'-bisacetyl-M-bisacetyldeoxyvariolin;

M'-acetyldeoxyvariolin;

M'-acetyl-M-acetyldeoxyvariolin;

M'-biscinnamoyldeoxyvariolin;

M'-biscinnamoyl-M-cinnamoyldeoxyvariolin; 70 M'-methanesulfonyldeoxyvariolin;

M'-trifluoroacetyldeoxyvariolin; 2'-methoxydeoxyvariolin; 2'-piperidinyldeoxyvariolin;

M'-ethyldeoxyvariolin;

M'-butyl-M'-methyldeoxyvariolin;

M'-benzyldeoxyvariolin.

Compounds of formula (I) contain a basic group and therefore can form a salt. The type of such salts is of no fundamental importance to the present invention, provided that in the case of using this compound for therapeutic purposes, such salts must be pharmaceutically acceptable, i.e., more biologically active, approximately as biologically active, or no less biologically active than the free bases, and less toxic, about as toxic, or no more toxic than free bases. These properties can be easily evaluated by performing simple tests known to those skilled in the art. However, when the compound is used for other purposes (for example, as an intermediate in the process of obtaining another compound), the above limitation is optional. Examples of acceptable salts include salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, and phosphate; salts of organic acids such as acetate, benzoate, oxalate, maleate, fumarate, tartrate, citrate and succinate; and sulfonic acid salts such as methanesulfonate, i) benzenesulfonate and p-toluenesulfonate. Preferred salts are the hydrochloride, hydrobromide, tartrate, and succinate.

Some compounds of formula (I) contain a carboxyl group and therefore can form an ester. The type of such esters is not of fundamental importance for this invention, provided that in the case of using this compound for therapeutic purposes, the esters must be pharmaceutically acceptable, i.e. more biologically active, approximately the same biologically active or no less biologically active than free acids, and with less toxic, approximately as toxic or no more toxic than free acids. It is desirable that the ester group is physiologically removable, that is, that the ester is easily converted immediately into a free acid. These properties can be easily evaluated by performing simple tests known to those skilled in the art. Cha

The compounds of the present invention contain at least four tertiary amino groups, of which one or more groups (but preferably only one group) can be quaternized to form a quaternary ammonium salt. In this case, the counterion is also present; examples of acceptable counterions are given above with reference to salts. The method of quaternization of one or more nitrogen atoms is well known to specialists in this field. It is desirable that the group "attached to the tertiary amino group to form quaternary ammonium compounds represents a SI-Svalkiln Che)s group, most preferably a metal group. . Various derivatives of variolin of formula (I), including known compounds of variolin, are obtained by a new method, which is included in the scope of this invention.

A constituent part of the method according to this invention is the preparation of an intermediate compound of the following formula (PI): - t se) sho y. with 50 letters

Hn

ГФ) In the intermediate compound of formula (II), Ka, Koa and Kza mean any groups represented by K., K» and Kz, respectively, and all such groups in which the reactive functional groups are protected; and M and Mo denote groups that can be de-removed to form a fused tricyclic pyridopyrrolopyrimidine ring structure. Intermediate compounds of formula (II) are new compounds and are also included in the scope of this invention. 6o To obtain Kcha, Koa and Kza groups with protected reactive functional groups, any protective groups known in the field can be used. In this connection, you can refer to |I publication

TM. Sgeepe ei ai., "Rgoiesiime Sgoirzv ip Ogdapis Zupipeviv", addendum UMpeu "Zopv, 19911.

Any groups that can be removed to form a condensed tricyclic pyridopyrrolopyrimidine ring structure can be used as U and Mo groups. Group B is preferably a hydroxyl group or an unstable ester group, such as acetate, methanesulfonate,

p-toluenesulfonate or trifluoromethanesulfonate, more preferably a hydroxyl group. The "U" group is preferably a halogen atom, more preferably a chlorine atom.

It is desirable that the intermediate compound of formula (II) is symmetrical, that is, Ka and Coa should have the same

Value; as described below, this allows to obtain a given intermediate compound due to the addition of two equivalents of the reagent to the precursor substance, which in turn reduces the number of synthesis steps. More preferably, K.4 and Coa are methylthio groups.

The intermediate compound of formula (I) can be obtained in several ways. One preferred method involves the interaction of an intermediate compound of formula (IM): ch where Kaa and Xo have the above values and M is a metal, with a compound of formula (M): c schi 6) x where Kaa and Coa have the above values.

In the compound of formula (IM), the type of metal atom M is of no fundamental importance, provided that this compound is reactive enough to join the compound of formula (M). Examples of acceptable metallated compounds c include such compounds in which M is Her, Ma, K, Ma or 7p; in metalated compounds containing divalent metal ions, another counterion, such as a halogen, may also be present, or such a compound may be an organometallic compound. M mainly means and and. Gee!

The compound of the formula (IM) is usually obtained by metallation of the corresponding halogen-containing compound. Acceptable reagents are well known in the art, and such examples include the metal itself or another more active compound that metalates, for example, an alkyl metal derivative. Alkyllithium derivatives are preferred and butyllithium is particularly preferred.

The compound of the formula (M) is preferably obtained by the interaction of the intermediate compound of the formula (MI); "- -and

That: M

Ge) where Ka has the indicated values and M means metal, with the compound of formula 1 4-СО-1 5, where |. and 15 have the same or different values and represent a deletion group. In the compound of the formula (MI), the type of metal atom M is of no fundamental importance, provided that this compound is sufficiently reactive to join the compound of the formula GI. 4-CO-I 5. Examples of acceptable metallated compounds include those exemplified for the compound of formula (II). M mainly means | and.

A compound of the formula (MI) is usually obtained by metallation of a corresponding halogen-containing compound, i.e. a compound of the formula (MIP): 60 with MI where Ka has the above values and X represents a halogen atom, preferably bromine or iodine. A compound of formula (MY) in which K/a is methylthio and X is chlorine is commercially available.

Corresponding compounds, in which X represents an atom of another halogen, can be obtained from the corresponding chlorine-containing compound (as described in the scientific literature, see Ma)ea, A; Apiopzep, R.; Veppespe, T.; Opaneit, K.,

Teganpeagop, 1989, 45, 993, and in Reference Example 11 below.

Acceptable reagents and methods for metallating a compound of formula (MI) to give a compound of formula (MI) are well known in the art. Such examples include the metal itself or another more active compound that metalates, for example, an alkyl metal derivative. Alkyllithium derivatives are preferred and butyllithium is particularly preferred.

In the compound of the formula 1 ./-СО-1І 5 groups I. and 5" can have the same or different values and represent a group that is removed, the specific type of which is of no fundamental importance. Non-limiting examples of acceptable leaving groups are halogen, C -Salkyloxy, di(C4-Salkyl)damino, a nitrogen-containing heterocyclic group (especially 7/0 imidazole), or a labile ester group as defined in U above. Diethyl carbonate is a particularly preferred example. compounds of formula 1 3-СО-1 5.

In an alternative preferred embodiment of the invention, the compound of formula (II) is obtained by reacting the intermediate compound of formula (MI) described above with the intermediate compound of formula (MI):

IS

» M) where Kaa and Ho have the above values and 7 represents a deleting group.

In a compound of formula (MY), group 7 is a leaving group, examples of which are given above with reference to c

M1, Tsi 5. Especially preferably, if 7 represents a halogen atom, in particular chlorine, since two equivalents of the metalated compound of the formula (MI) can be added in its pure form to the compound of the formula (MI).

After removal of groups U 4 and Mo, the intermediate compound of the formula (II) is preferably cyclized to obtain the intermediate compound of the formula (II): . . Groups HU. and M" are preferably removed by the interaction of the intermediate compound of the formula (I) with a trialkylsilane of the formula КааКкъКЗіН, where Ка, Къ and Ко can have the same or different values, and each of them is

S.-Sig2alkyl group. Triethylsilane is preferably used as the indicated reagent.

This reaction is preferably carried out in the presence of an acid, the specific type of which does not have a fundamental -I value. A strong organic acid such as p-toluenesulfonic acid or trifluoroacetic acid is preferred, and trifluoroacetic acid is particularly preferred. ik The intermediate compound of formula (II) can then be converted into the compound of formula (I) as a result

Ge) interconversion of functional groups, the method of which is known to specialists in this area. As an example 5p, it can be noted that the amino groups of the known compound deoxyvariolin B (4), obtained by the method according to the present invention, can be easily converted into various functional derivatives, as shown in the scheme | and illustrated with examples below. name) 60 b5

Scheme Y 70 produced! - iv od / her -v | pits). dec, B, is a NN zbo SOMe s o sia byimazaz, where Ki» KE B; and Ka is similar to ІН or СОСНАІЕСНРІ s.c

According to an alternative approach, another group of analogs can be obtained by introducing a functional group at the C5 position of the heteroaromatic ring of variolins. This can be easily accomplished by oxidizing intermediate (5) (22) to the sulfone (6) or sulfoxide (22), followed by nucleophilic substitution reactions, as shown by F in Scheme III. m. shi s ;" -I se) se) with 50 sl

F) name) 60 b5

Yuken Ii.

Y x pd ; tek yo p. Z ny ro nti NA чТИЖ веш я Ж ! not yet

Hey, let me know. Ki Ko ze: 0 s» | and this is -Sh: I am, and KN: tya I ki I y y z M V SK shi. and here we are

Ше шчи ких Шо т Яку плим и - ШИР и Ж е вНы 4:

I t sht u g I re n

Che t Her Y I - s write I no V zh sha

Not one y: y, tiv) r sty Y rya , ; "a vd with sv t si

E pet Z av and that song ee seneon and I Ge»)

DE SCHE SCHE si : z svi" in t pet Inc dvi F sho 7 and -

Two particularly important interconversions have not been previously described for variolins.

Therefore, another object of this invention is a method of obtaining the compound of formula (I), where K and Co are amino groups and Kz has the values indicated above, which includes: "a) treatment of the compound of formula (II), where Ka and Kosa are is methylsulfinyl and K has the values indicated above, a compound of the formula МН»Ргой, where Ргой means an amino-protecting group, to obtain a compound of the formula (I), where Ka and Koa represent protected amino groups and Kza has the above values; and h» B) removal of the amino-protecting group to obtain a compound of formula (I), where K. and Ko are amino groups and "Ez has the values indicated above.

The type of amino protecting group is of no fundamental importance. Examples of acceptable protective groups, methods of their addition and removal are described in the edition of T.M. OSgeepe ei ai., "Rgoiesiime Ogotsirz ip Ogdapis Zupipeviv", doip -i UMieu 5 5opv, 1991), which is given as a reference. o The protective group is preferably a substituted or unsubstituted benzyl group or a phthalimide group, in particular, a p-methoxybenzyl (PMB) group. This group can be removed by any known method, e.g., under acidic conditions (especially in the presence of a strong organic acid, e.g., from 50 trifluoromethanesulfonic acid or trifluoroacetic acid), under oxidizing conditions, e.g., in the presence of dichlorodicyanobenzoquinone (000), or under reducing conditions, for example, in the presence of hydrogen and a palladium sl catalyst.

A preferred variant of this method is illustrated in scheme I below, where the conversion of disulfoxide (20) to deoxyvariolin B (4) is achieved by performing two steps via bis-amine (29). name) 60 b5 ob pat "Fasting and sitting in

Another object of this invention is a method of obtaining a compound of formula (I), where K/ is a methylthio or amino group, Ko is an amino group and Kz has the values specified in clause 1, from a compound of formula (II), where Ka | Koa is methylthio and Kza has the values indicated in clause 19, which includes: a) optional oxidation of a compound of formula (III), where K 14 and Kosa are methylthio, into a compound of formula (III), where Ka and Kosa are methylsulfinyl; and

B) treatment of the compound of formula (II), where Ka and Coa are methylthio or methylsulfinyl, with a reagent selected from sodium azide and ammonia. with

At the stage of optional oxidation a) of the method described above, any oxidant capable of oxidizing simple thioesters into sulfoxides can be used. Non-limiting examples of acceptable oxidants include hydrogen peroxide, sodium periodate, tert-Hyoxygen, sodium perborate, and peracids such as peracetic acid, m-chloroperbenzoic acid (m-Chloroperbenzoic acid) or magnesium monoperoxyphthalate (MMPP), of which peracids are preferred and m-chloroperbenzoic acid is particularly preferred. acid (tSRBA). oh

A preferred variant of this method is illustrated in the IM scheme below, where the intermediate compound (19) is converted to deoxyvariolin B (4) in one step via the sulfoxide intermediate (20):

Scheme of TU iy (22): i - chik zhishcinia - i I I "» ! - "y a is se) p.

The new technique used to create the core structure of variolin allows the synthesis of se) deoxyvariolin B (4) from a simple monoheteroaromatic starting substance (7) as a result of only five 7 50 stages. This synthesis is much shorter than the synthesis sequence of deoxyvariolin B described in the prior art. In an alternative version of this method, illustrated in scheme M below, the intermediate simple dithioether (19) is converted into thiodeoxyvariolin (5) in one step by treatment with an ammonia solution:

A particularly preferred variant of the method according to the present invention is illustrated in the MI diagram below.

The specific conditions for performing this method are described in detail in examples of compounds, examples of methods of preparation and reference examples.

The new method of synthesis according to the present invention makes it possible to create a structure of the varioline core, which includes a condensed pyridopyrrolopyrimidine core, which carries a heterocyclic aromatic ring in the C5 position, as Ge is shown in formula (13), from a simple monoheteroaromatic starting substance (7) as a result of performing all of (5) four stages.

IF) w: y.

M (is) and patsi Bai and her in. same I ;. What did he think about the 7th and the sth? I, Y "what about the widows?" yad: ay and "WHERE: .

Se SCHO mik nak d.

The same one Is He: I Z g -i MO pra, tuya sh VN sei -yazE- M u p-va NI A I

N p to her Hey I put and her with the same)

KO BEK Ne voly vya .. LJ: shcha sa u den TYA ko "1 eyes sl . she -

Direct manipulation of the functional group allows the conversion of intermediate compound (13) into the known 99 compound variolin B (1) through a further four steps, as illustrated in the figure below

GF) scheme MI!: ime) 60 b5 and I nplichyy ; children 6)

IF) yu s is s

The indicated short sequence of synthesis of eight stages using commercially available starting substance F (7) represents the first described method of synthesis of variolin B.

A similar technique provides rapid preparation of the key intermediate compound (19) used for the He) synthesis of deoxyvariolin B and related analogs, as illustrated in the MI scheme below! and "a 39 are further described in detail in the Examples of Compounds, Examples of Methods of Preparation, and Reference Examples.

The scheme of the Higher Secondary School - . "» and -and drinking se) 4

The above-described methods for obtaining variolin B or deoxyvariolin B can be easily modified to obtain other derivatives. In particular, this invention relates to new compounds that can be obtained from intermediate compounds obtained by a new method, which is included in the scope of this invention.

Thus, the present invention relates to methods of synthesis of variolin B (1), deoxyvariolin B (4) and 99 related intermediate compounds, such as the compound of formula (5), and to methods of obtaining variolin analogues. Paths

HF) synthesis in accordance with this invention includes several transformation stages that ensure obtaining the desired product. Each stage in itself represents a method that is within the scope of this invention. The present invention is not limited to the methods described and may include alternative methods, for example, a corresponding change in the order of the conversion stages if necessary. 60 In more detail, the synthesis of variolin B according to a particularly preferred embodiment of this invention includes the following eight stages: (a) conversion of commercially available 4-chloro-2-thiomethylpyrimidine (7) into an iodo-substituted compound (8); (5) interaction of compound (8) with diethyl carbonate to obtain a symmetrical ketone (9); (c) adding the compound (9) to a solution of the lithiated form of the pyridine derivative (11) to obtain the triaryl bo alcohol (12);

(a) successive deoxygenation and cyclization of triaryl alcohol (12) using triethylsilane in combination with trifluoroacetic acid; (e) oxidation of intermediate compound (13) with m-chloroperbenzoic acid (tCsPBA) into disulfoxide (14); (9) treatment of compound (14) with p-methoxybenzylamine to obtain bis-amine (15); (9) conversion of the methoxy group of compound (15) into alcohol (16) using sodium ethanethiolate; (n) removal of p-methoxybenzyl protecting groups of compound (16) ) using trifluoromethanesulfonic acid to obtain variolin B (1).

Such a synthesis is illustrated in the IC diagram below. These methods are discussed in more detail in 7/0 examples of compounds, examples of methods of preparation and reference examples. y o -y - t ini a se laik (o) inytyyn. yuyu y y se g sa cha "9 F

Gee)

EARLY and - » - And - ? with

GU y y a p sa g - and in what n , 2,

In another preferred modification, the starting material (7) is converted to deoxyvariolin B by (se) carrying out the following five further steps, which include: (a) converting the commercially available 4-chloro-2-thiomethylpyrimidine (7) into an iodo-substituted compound (8); (c) interaction of compound (8) with pyridine derivative (17) to obtain triaryl alcohol (18); co (c) deoxygenation and cyclization of triaryl alcohol (18), carried out sequentially, using sl triethylsilane in combination with trifluoroacetic acid; (4) oxidation of simple dithioether (19) with m-chloroperbenzoic acid (tsPBA) to disulfoxide (20); (e) treatment of compound (20) with an ammonia solution to obtain deoxyvariolin B (4).

Such a synthesis is illustrated in Scheme X below. These methods are discussed in more detail in the Examples of Compounds, Examples of Methods of Preparation, and Reference Examples. (F) ko bo b5

Scheme Х и я 7 - о и и 5

As should be apparent to a person skilled in the art, the described reaction schemes can be modified and/or combined in various ways and the compounds obtained as a result of such changes are within the scope of this invention. In particular, the starting substance and/or reagents and reactions can be changed to match other combinations of (Ge)-substituting groups in formulas (I) through (MIP).

Pharmaceutical compositions of F

Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) oral or liquid (solutions, suspensions or emulsions) forms intended for oral, topical or parenteral administration, which may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. For parenteral administration, these compositions must be sterile. "

The required doses of the compounds may vary depending on the specific drug, the route of administration and, in particular, the location, host and type of tumor to be treated. At the same time, it is necessary to take into account other factors, such as age, body weight, gender, diet, time of administration, rate of elimination from the body, the condition of the subject who needs it, the combination of drugs administered, sensitivity to drugs "" and the severity of the disease. Administration can be carried out continuously or periodically, taking into account the maximum permissible dose.

The compounds or compositions of the present invention can be administered by any suitable route, such as intravenous infusion, oral, intraperitoneal and intravenous administration. c Cytotoxic activity

The compounds of this invention were tested according to the test method described below. (Ce) A colorimetric assay using sulforhodamine B (SBC) was adapted for the quantitative measurement of cell growth and viability: |see ZKepyap, R.A. ei ai., U. Mai. Sapseg Ipvi, 1990, 82, 1107-1112). The specified analysis is performed using 9-well microplates for cell culture with a diameter of 1 mm (Raigsioif, 0. T.; 205; Moztapp, T. doigpai! oi Ittipoiodis! Me (podiz, 1983, 65, 55-63).

Most of the cell lines obtained from the American Type Culture Collection (ATCS) relate to various types of human malignant tumors. Cells are kept in medium KRMI 1640 with 1095 ЕВ5, containing O0.1g/l of penicillin and O.1g/l of streptomycin sulfate, and then incubated at 372C, 595 СО» and 9895 humidity. For experiments, cells are harvested from subconfluent cultures using trypsin and resuspended in fresh medium until seeding.

Cells are seeded on 96-well titration microplates in the amount of 5x1OZ cells/well in 195 μl aliquots of medium 60 and left to attach to the surface of the plate, growing the cells in a medium containing no medicinal product for 18 hours. Then the samples are exposed to bmcl aliquots of drugs in a concentration from 10 to 10-8μg/ml, dissolved in DMSO/EUN (0.295 in physiological solution with phosphate buffer). After exposure for 48 hours, the antitumor effect is measured by the ZKV method: the cells are fixed by adding 5 µl of cold 5095 (wt/vol) trichloroacetic acid (TCA) and incubated for 60 minutes at 40°C. Tablets are washed with deionized water and dried. Add to each well of the titration microplate

10O0μl of 5KV solution (0.495 wt/vol, in 195 acetic acid) and incubated for 10 minutes at room temperature. Unbound ZKV is removed by washing with 195 acetic acid. The tablets are air-dried and the bound dye is solubilized with Tris buffer. Optical density is measured by

With the help of an automatic spectrophotometer for reading tablets at one wavelength equal to 49 Ohm.

Calculate means 4 standard deviations for data obtained using samples from three wells. In this way, it is possible to calculate some parameters of the cell reaction: (cI - growth inhibition, TO1 - complete growth inhibition (cytostatic effect) and IC - cell lysis (cytotoxic effect). 70 The results are shown in Tables 1 and 2 below. Although compounds (1 ), (4), (5) and (6) themselves are not within the scope of this invention, the results given in the tables indicate an antitumor activity that was not previously detected in the specified compounds.

This application claims priority over British patent applications Mo0017055.5, filed on July 11, 2000, and Mo0030689.4, filed on December 15, 2000. Both documents are included in this description of the invention as a reference in that 7/5 part of the description of the invention, which is not fully reflected in the description of the invention of this application. 0IB5O 5095 inhibition of growth

TI Complete inhibition of growth (cytostatic effect)

ІС50 5095 pure lysis of cells (cytotoxic effect) of the intestine

Thiodeoxyvariolin. 5

PA o marna kare p

F

(22) in relation to | vvoi zvo (206 forehead) and then 0000 avo6 000lvobo00ovob zvo Z . g" SHY eh shko she - se)

F z o u s l z o z y 65 2va 367,A MNVp mno N

81 zyuya 0 vome 0 mn yu svetr ti Go avt and Gizyu t cm 7 o; yu from sch

F

6 lalov your khivloya lov tv BOM F

From Examples -

The following examples describe methods of obtaining target and intermediate compounds according to the present invention.

In the examples of production methods, methods of production of known compounds included in the scope of this invention are described. Preparation of intermediate compounds, which are not included in the scope of this invention, is described in reference examples.

With the exception of specially determined cases, all reactions are performed in an inert atmosphere in pre-dried glassware. All organic extracts were washed with water and saturated salt solution and dried over Meso until concentrated in vacuo. Melting points were determined in a Kofler-heated apparatus and are uncorrected.

Example 1. Compound 13 -I so vyt

F yamst with 50 sl h 15 59 A mixture of triaryl alcohol 12 (100 mg, 0.237 mol) (obtained in example 16 below) and

HF) of trifluoroacetic acid (37 μl, 0.48 mol) is dissolved in 1,2-dichloroethane (O0.bml). Orange solution that

The HF formed is transferred to a Young tube with a rubber membrane containing triethylsilane (0.3Oml, 1.9mol). In a strong flow of argon, the membrane is replaced with a Teflon screw cap, and the hermetically sealed reaction vessel is heated at 1002 for 43 hours. The vessel is cooled, opened and the contents are diluted with CHCl (12 ml). The solution is neutralized with a 595% solution of MansSo»z (ml) and the phases are separated. The aqueous layer is re-extracted with SNeSi" and the organic extracts are treated in a standard way. The crude material was purified by flash chromatography on silica gel, eluting with a gradient (48-7595 EtOAc/hexanes), and obtained in the order of elution: ve (1) structure of the core of variolin 13 as a yellow solid (41mg, 47905):

T.p.: 192-1949C; "H NMR (500 MHz, SOSI5): δ 2.65 (s, ZN), 2.70 (s, ZN), 4.03 (s, ZN), 6.92 (d, U-5.4 Hz,

1H), 7.40 (d, 9-5.4Hz, 1H), 7.71 (d, 9U-6.8Hz, 1H), 7.98 (d, U-6.8Hz, 1H), 8, 48 (m, 2H); C NMR (75 MHz, SOSI): 5 14.1, 14.95 55.6, 101.9, 102.5, 108.5, 110.8, 117.7, 135.9, 138.6, 143 .5, 144.3, 154.2, 155.6, 159.6, 16111, 171.2; HEM5: calculated for C47Ni5M5O03285 (M") 369.0718, found 369.0720. and (2) uncyclized ether 13a as a viscous resin (28mg, 28905) ha

TN nMR (BO0MHZc, SOSIia): δ 2.36 (s, ЗН), 2.44 (s, ЗН), 3.84 (s, ЗН) 6.57 (d, 1-5.9HZ, 1Н), 6.80 (d,

U-5.9Hz, 1H), 7.17 (d, U-4.9Hz, 1), 7.79 (s, 1H), 8.27 (d, 9U-5.9Hz, 1H), 8, 30 (d, 9U-5.9Hz, 1H), 8.49 (d, U-4.9Hz, 183; C NMR (75MHz, SOS): 5 14.0 (x2), 56.2, 71.8 , 103.5, 106.4, 112.9, 120.8, 150.7, 152.5, 1571, 158.0, 166.0, 167.1, 167.3, 172.1, 172.4 НЕМ5: calculated for C 47Н162СИМ5О»3255 (Mu) 421.0434, found 421.0444.

Example 2. Compounds 14 and 15 are called Shi and Ge

ID t. and. SHY 1 about wah va, ; | . And sch. yІ S WHAT . Gee! cha and che F

Zo bis-sulfide 13 (37 mg, 0.1 mol) was dissolved in CHCl3 (Bml) under atmospheric conditions and cooled in a water bath with a temperature of -40°C. A pre-cooled (-402С) solution of m-chloroperbenzoic acid in SNCI3 (1Omg/ml) is added dropwise to the solution until the starting substance completely disappears (approximately 2 equiv. of t-SRBA was used) according to the results of TLC analysis. The solution is heated to room temperature and neutralized with a saturated solution

Mansoz. The resulting solution is re-extracted with CHClCl and after standard treatment a yellow solid is obtained, which is mainly a mixture of diastereomeric bis-sulfoxides. The crude mixture is used without purification, but the bis-sulfoxides 14 have the following spectroscopic characteristics: multiplets) 5 3.02 (m, ЗН), 3.19 (m,

ЗН), 4.12 (m, ЗН), 7.00-7.01 (m, 71Н), 7.98-7.99 (m, 1Н), 8.12-8.14 (m, 71Н) , 8.48-8.49 (m, 1H), 8.64-8.67 (m, another 75 1H), 8.79-8.81 (m, 1H).

The crude oxidized substance is heated with an excess of p-methoxybenzylamine (0.15 ml, 1.1 mol) at 8593 for (Ce) 15 hours. The crude red paste is purified by flash chromatography on silica gel, carrying out a gradient elution with (2.5-490o MeOn/СНоСИ2). The yellow fractions are re-chromatographed by gradient elution (from 5090

EtOAc/CH-SiO to 10095 EtOAc), and bis-amine 15 was obtained as a yellow solid (4 mg, 7895 over two steps). with T.p. 74-772s; "H NMR (BOOMHz, SOSIv): δ 3.81 (s, 6H), 3.99 (s, ZN), 4.66 (d, 9U-5.6Hz, 2H), 4.85 (d,

U-5.5Hz, 2H), 5.51 (m, 71H), 6.82 (d, 9U-5.6Hz, 1H), 6.89 -6.91 (m, 4H), 7.00 ( d, 9-5.2Hz, 1H), 7.29 (m, tn), 7.34 (d, U-8.5HzC, 2H), 7.39 (d, 9U-8.5HzC, 2H), 7.43 (m, 1H), 8.16 (d, 9U-5.6Hz, 1H), 8.26 (d, 9U-5.1Hz, 1H), 10.39 (m, LN)U; C NMR (75 MHz, SOSIv): δ 44.3, 44.9, 55.3 (2xCHNas), 55.5, 101.3, 101.6, 101.8, 111.4, 112.2, 114, 0 (hg), o 128.5, 128.8, 130.5, 131.4, 137.5, 141.5, 141.95 144.7, 148.7, 154.6 (width), 158 ,7, 158.9, 159.4, 160.9, 162.6; НЕМ5: calculated for С31НооМ7Оз (М") 547.2332, found 547.2334. imo) Example 3. Compound 16 60 b5

. In the heron In Lini 70 "o

Mann (6095, bOmg, 1.5 mol) was washed three times with petroleum ether and suspended in dry DMF (1/5 ml).

The stirred suspension was cooled on ice and ethanethiol (0.14 ml, 1.9 mol) was added dropwise. After 72 stops the evolution of gas, the clear solution is stirred at room temperature for 10 minutes. A portion of the Maz v Ei solution (1.1 ml) was added to a solution of bis-amine 15 (40 mg, 0.073mol) in dry DMF (1.5 ml) and the mixture was stirred at 502 for 7 hours. The resulting solution is cooled, an aqueous solution of MN Acetate is added, and the mixture is extracted with EtOAc (3 times). The organic extracts were washed three times with water to remove DMF and subjected to the usual work-up. The yellow solid formed is purified by flash chromatography on silica gel, using 396 Meon/CH 2Si as an eluent, and alcohol 16 is obtained as a yellow solid (Zamg, 8790). "YAN NMR (B5O00MHZts, SOSIia): 5 3.80 (s, ZN), 3.81 (s, ZN), 4.61 (d, U-5.5Hz, 2H), 4.85 (d, U -54Hz, 2H), 5.35 (m, 1), 6.76 (d, 9U-5.5Hz, 1H), 6.88-6.92 (m, 4H), 7.03 (d, 9U -6.8Hz, 71), 7.06 (d, 9U-5.7Hz, 1H), 7.32 (d, sch

U-84Hz, 2H), 7.40 (d, 9-8.4Hz, 2H), 7.68 (d, U-6.8Hz, 71H), 8.05 (d, 9U-5.5Hz, 71H ), 8.29 (d, 9U-5.7Hz, МН), 10.94 (m, 1Н), 15.75 (width с, 1Н); C NMR (75 MHz, SOSI): δ 44.3, 45.2, 55.3 (2xCHNa), 100.3, 100.5, 106.9, (o) 107.5, 111.4, 114, 1 (2хС), 128.8, 129.2, 130.2 (2хС), 137.5, 142.8, 143.8, 145.4, 149.7, 158.6, 158.9, 159, 0, 159.5, 159.8, 160.0; NKM5: calculated for SzoH27M7Oz (M") 533.2175, found 533.2185.

Example 4. Compound 19 right (22) of stomach F -5I m. cha t "

A mixture of alcohol 18 (obtained in example 17 below) (1.04 g, 2.65 mol), triethylsilane (3.4 ml, - with 21.5 mol) and trifluoroacetic acid (0.8 ml, 10.5 mol) is heated under reflux for From a hours. The resulting mixture is cooled, the red residue is dissolved in CHCl (40 ml) and a saturated solution of MansSoO3z is added. The brown mixture is stirred for 1 hour at room temperature and the layers are separated.

The aqueous layer is extracted with СНоСИ» (3х5Омл), the combined organic layers are dried, filtered and concentrated under reduced pressure. The red residue was purified by flash chromatography using ethyl acetate:hexane (1:4) - ethyl acetate:hexane (1:3) as an eluent, and pyridopyrrolopyrimidine 19 (0.3 g, 3390) was obtained as a pale yellow solid.

TN nMR (30 MHz, SOSIv): 8.64 (dd, 9-81 and 1.7Hz, 1H), 8.60 (dd, 9-4.6 and 1.7Hz, 1H), 8.51 (d, U-5.4Gu, se) 1H), 8.06 (d, U-64HzC, 1), 7.82 (d, U-6.6Hz, 1H), 7.51 (dd, 9U-8.5 and 4.6HzC, 1H), 7.34 (d, U-54Hz, 1H), 2.73 t 20 (s, ЗН), 2.68 (s, ЗН).

Example 5. Compounds 20 and 29 pe "y U i" the same Tu Her» Like ; sia y y y | Ka V. i

F) tal and I Mn still iy sa ro Her. r RN, : p i m TYA y, and NINannvny Shchy. WE Still

Bin She. r y U same: a 60 Sh same: y ostov YN sy Z 8 here is her p tik y y cy y Be

Oxidation of bis-sulfide 19 to bis-sulfoxide 20 is carried out by the method of example 2. b5 A mixture of p-methoxybenzylamine (2 ml) and bis-sulfinyldeoxyvariolin 20 (ZOmg, 8.1x10""mol) is stirred at 9522 for 2 hours and evaporated under reduced pressure . The red residue is purified by flash chromatography,

using dichloromethane as an eluent (OSMumeon (0295) - OSM/Meon (290), and obtain

MM-bis(p-methoxybenzyl)deoxyvariolin 29 (21 mg, 4990) as a yellow oil.

TN NMR (300 MHz, SOSIz): 10.4 (width, 1H), 8.56 (d, U-7.8Hz, 1H), 8.31 (d, 9U-54Hz, 1H), 8.27 (dd, 9-52 8501 LiYGTS, tn), 7.63 (d, 9U-6.8HZ, 1), 7.42-7.33 (m, 12Н), 6.98 (d, 9U-5, 4Hz, 1H), 6.93-6.89 (m, 4H), 5.52 (width, 1H), 4.89 (d, 9U-5.4Hz, 2H), 4.69 (d , U-5.9Hz, 2H), 3.81 (s, ЗН), 3.80 (s, ЗН).

Example 6. Compound 28a about CO "ap PN inno rn.

NO g -

Piperidine (0.04 ml, 0.4 mol) was added to a solution of sulfinyldeoxyvariolin 22 (7 mg, 2.1x10"" mol) (obtained in the following example of preparation method 5) in THF (2 ml). The yellow solution is stirred at 702C overnight and evaporated under reduced pressure. The yellow residue was purified by flash chromatography using OSM/MeOH (2965) - OSM/MeOH (3595) as an eluent to give piperidinyldeoxyvarioline 28a (5 mg, 7890) as a yellow oil.

TN nMR (300 MHz, SOSIv): 8.63 (dd, U-8.4 and 1.5 Hz, 1H), 8.38 (dd, 9-4.8 and 1.7 Hz, 1H), 8.35 ( d, U-54Hz, 1), 7.60 (d, 9U-6.6Hz, 1), 7.50 (d, U-6.6Hz, 1H), 7.46 (dd, 9U-8.0 and 4.6Hz, 1H), 6.84 (d, 9U-54Hz, 1H), 3.92 (width, 4H), 1.73 (width, 6H). M5 (electrospray ionization, EBI) 346 (M.n1). Ge

Example 7. Compound 285 o yu

And other things.

AI and

F m V pa Fu

Ethylamine (0.34 mL, 2M solution in MeOH) is added to a solution of sulfinyl-deoxyvariolin 22 (obtained in Example 5 below) (11 mg, 3.4 x 10'bmol) in THF (2 mL). The yellow solution is stirred at 709C overnight and evaporated under reduced pressure.The yellow residue was purified by flash chromatography using OSM/MeonH (290)-OSM/Meon (496) as eluent to give

M'-ethyldeoxyvariolin 286 (5.5 mg, 5390) in the form of a yellow oil. "

TN nMR (300 MHz, SOSIv): 8.67 (dd, U-7.9 and 1.4 Hz, 1H), 8.36 (d, U-44 Hz, yin), 8.22 (d, 9-4, 8Hz, yin), 7 s 7.52 (width, 2H), 7.45 (dd, 9U-7.8 and 41Hz, 7H), 6.93 (d, 9U-51IHC, 7), 3, 54 (d, 9U-6.8Hz, 2H), 1.29 (t, .U-7.O0Hz, ZN). (EBI) 306 (M'-1). and? Example 8. Compound 28c -I - Iz. Ж "ifoinn chenie gi NSCHIVV. what te se) with 50 . mk sl y

Butylmethylamine (0.029 ml, 0.24 mol) was added to a solution of sulfinyl-deoxyvariolin 22 (obtained in the following example of preparation method 5) (8 mg, 2.4 x 10' mol) in THF (2 ml). The yellow solution was stirred at 709 overnight and evaporated under reduced pressure. The yellow residue is purified by flash chromatography using OSM/MeonH (290)-OSM/Meon (496) as an eluent to give

M'-butylmethyldeoxyvariolin 28c (2mg, 6295 including the isolated starting substance) in the form of a yellow oil. where "YAN NMR (Z00MHz, SOSIv): 8.75 (d, 1H), 8.41 (dd, 1H), 8.39 (d, 9-5.5Hz, 1), 7.78 (d, 9 -6.5Hz, 1H), 7.68 (d, 1-6.5Hz, 1), 7.42 (dd, 9U-8.0 and 4.5Hzc, 1), 6.89 (d, U- 5.6 Hz, 1H), 3.60 (width s, 2H), 3.41 (s, ZN), 1.62 bo (width s, 4H), 1.05 (width s, ZN). (E5I) 348 (M.-1).

Example 9. Compound 284 b5 m -noMa

Y : And nn.

CHNE

"Sh-y-y

Benzylamine (0.05Oml, 0.45mol) was added to a solution of sulfinyldeoxy-variolin 22 (4mg, 1.2x10"mol) in THF (1.5ml). The yellow solution was stirred at 702 overnight and evaporated under reduced pressure. The yellow residue is purified by flash chromatography using OSM/MeEeOH (295)-OSM/Meon (4595) as an eluent to give

M'-benzyldeoxyvariolin 284 (2.1 mg, 4795) in the form of a yellow oil. 75 TN nNMR (30 MHz, SOSIz): 8.81 (width, 1H), 8.75 (d, U-7Hz, 1), 8.64 (d, U-6.0Hz, 1H), 7, 49-7.31 (m, 8H), 6.99 (d, U-6.2Hz, 1H), 4.78 (d, U-5.8Hz, 2H). (EZI) 368 (M.-1).

Example 10. Compound 27 sha.

Drive and tire. and cm - o

A solution of sulfonyl deoxyvariolin b (obtained in the following example of preparation method 5) (5.8 mg, 1.7x10"" mol) in MeonN (2 ml) is added to a solution of sodium methoxide in MeonN (2 ml) at 02C. The yellow solution is stirred at 242C for 4 hours, quenched with a saturated solution of MHCI and extracted with ethyl acetate (3x10ml). The combined organic layers are dried, filtered and evaporated under reduced pressure. The yellow residue M was purified by flash chromatography using OSM/MeEeOH (195) - OSM/MeOH (395) as an eluent, and methoxydeoxyvariolin 27 (2.6 mg, 53905) was obtained as a yellow solid. "YAN NMR (ZO0MHz, SOSIv): 8.78 (a9, 9U-8.1 and 1.5Hz, 1H), 8.51 (d, 9U-5.43Hz, 1H), 8.41 (dd, U -4.6 and 1.5Hz, Me. 1H), 7.69 (d, U-6.6HzC, 1H), 7.63 (d, U-b, bHz, 1H), 7.50 (dd, U-8.1 and 4.6Hz, 1H), 7.34 (d, 9U-54Hz, 18), 414 Fu (s, ZN). (EBI) 293 (M--1).

Example 11. Compound 26 -

These "now shsh

Same with » and g e

Trifluoroacetic anhydride (bmcl, 4.3x10" mol) is added to a solution of deoxyvariolin 4 (4mg, 1.4x10 mol) in -I THF (1.5ml). The yellow solution is stirred at 242C overnight and evaporated under reduced pressure. The yellow residue is dissolved in OSM (5ml) and washed with saturated Mancet solution with (4ml). The organic layer is dried, filtered and evaporated under reduced pressure. The yellow residue is purified by flash chromatography, (Te) using as eluent OSM/MeOH (295) - OSM/Meon (45905), and M'-trifluoroacetyldeoxy-variolin is obtained 50 25 (0.9 mg, 4395 including the isolated starting substance) in the form of a yellow oil.

TN nMR (30 MHz, SOSIv): 8.99 (dd, 9-84 and 1.1 Hz, 1H), 8.57 (d, 9-5.6 Hz, 1H), 8.42 (dd, 9-46 1.3Hz, sl 1H), 7.91 (d, 9-6.7HzC, 1H), 7.79 (d, U-6.6Hz, 1H), 7.58 (dd, U-8.3 and 4.3Hz, 1H), 7.52 (d, U-5.6Hz, 1H). (EBI) 374 (M.n1).

Example 12. Compound 25: i.

F! vo i I ZE Ne bo ME l i nii

Methanesulfonyl chloride (5.5 μl, Bx10'?mol) is added to a solution of deoxyvariolin 4 (obtained in the following example of preparation method 2 or 4) (Bmg, 1.8x10 mol) and EBM (5 μl, 3.x10 mol) in THF ( 1, Bml). The yellow solution is stirred at 242C overnight and evaporated under reduced pressure. The yellow residue is dissolved in OSM (5 ml) and washed with saturated Manso solution (4 ml). The organic layer is dried, filtered and concentrated under reduced pressure. The yellow residue was purified by flash chromatography using rosm/meon (2965) - OSM/Meon (495) as an eluent to give M'-methanesulfonyl-deoxyvarioline 25 (1.5 mg, 4695 including the isolated starting substance) as a yellow oil.

TN nMR (30 MHz, SOSIv): 8.89 (dd, 9U-7.9 and 1.1Hz, 1), 8.76 (d, 9U-5.7Hz, 1), 842 (dd, 9-42 and 1.2Gu, 1), 7.78 (d, U-6.4Hz, 1H), 7.72 (d, U-6.5Hz, 1H), 7.64 (d, 9U-5.6Hz, 1H ), 7.57 (dd, U-8.3 and 4.3HZ, 1H), 3.15 (s, ЗН).

Example 13. Compounds 24a and 245 4; 70 Wun-nk and I and and . : pllllnyshiiiiny and . 25 years old

Cinnamoyl chloride (OMCl, 5.4x10?mol) is added to a solution of deoxyvariolin 4 (5 mg, 1.8x10""mol) (obtained in the following example of the preparation method 2 or 4) and EIZM (12μl, 5x10 mol) in THF with (2ml ). Dimethylaminopyridine (OMAR) (mg, 0.9x10?mol) was added immediately in one portion, the yellow solution was stirred at 242C overnight and evaporated under reduced pressure.

The yellow residue is dissolved in OSM (5 ml) and washed with saturated Manso solution (4 ml). The organic layer is dried, filtered and evaporated under reduced pressure. The yellow residue is purified by flash chromatography, using as an eluent OSM/MeOH (195) - OSM/MesynH (4965), and M'-biscinnamoyl-deoxyvariolin 24a is obtained. MU (1 mg, 2195 based on the isolated starting material) and M'-biscinnamoyl-M-cinnamoyldeoxyvariolin 246 (0.bmg, 995 based on the isolated starting material) in the form of yellow oils. t (22) them and t OR -

Y d M 1 i y d zi ": - s y . ,» TN NMR (300MHz, SOSIv): 8.78 (d, U-6.4Hz, 1H), 8.69 (dd, 4-74 and 1.1GHz, 1H), 8.38 (dd, U- 4.6 and 1.2Hz, 1H), 7.91 (d, 9-15.3Hz, 2H), 7.64-7.32 (m, 14H), 6.90 (d, U-15.6Hz , 2H). (E5I) 560 (M.4Ma), 538 (M'-1). "and

Ge) chi g - tr m fo, sl Gu rya t n

Mo; name) ' And I

H NMR (30 MHz, SOSI»v): 8.82 (d, U-64 Hz, 1), 8.79 (dd, 9U-7.4 and 1.1 Hz, 1), 8.58 (dd, 9- 46 and 1.3Hz, in 1H), 8.01-7.82 (m, 4H), 7.71 (d, 9U-15.3Hz, 2H), 7.64 (dd, 9U-8.3 and 4.2Hz, 71H), 7.58-7.31 (m, 16H), 6.90 (d, -15.6Hz, ZN). (E5I) 668 (M.-1), 690 (M--Ma).

Example 14. Compounds 23Za, 236 and 23c b5 zho same where to t g her rov, k "Ж 7 y" : DE tn ovo y g biro; | fe: shchi and sh. eu oyu j r u

In M z: and blue in. dec o AVM o ot r

Acetyl chloride (3.5 μl, 4.8x10 mol) is added to a solution of deoxyvariolin 4 (Umg, 3.2x10 mol) (obtained in the following example of preparation method 2 or 4) and EM (Umkg, b,Bx10 mol) in THF (2 ml ).

The orange suspension was stirred at 242C overnight and evaporated under reduced pressure. The yellow residue is dissolved in OSM (5 ml) and washed with saturated Manso solution (4 ml). The organic layer is dried, filtered and concentrated under reduced pressure. The yellow residue is purified by flash chromatography, using it as an eluent

Osm/meon (2965) - OSM/Meon (595), and give M'-bisacetyldeoxyvariolin 23a (mg, 2695 including isolated starting material), M'-bisacetyl-M-acetyldeoxyvariolin 236 (mg, 2395 including isolated starting material ) and M'-bisacetyl-M-bisacetyldeoxyvariolin 23c (0.5 mg, 1095 including the isolated starting substance) in the form of yellow oils. with

In va y y a oyu da s (22) (22)

From TN nMR (Z00MHZc, SOSIv): 8.76 (d, U-5.6Hz, 1), 8.68 (dd, uU-6.9 and 1.1Hz, 1), 8.42 (dd, 9 -41 and 1.2Hz6, i- 1H), 7.73 (d, 9-6.6HzC, 1H), 7.66 (d, U-6.6HzC, 1H), 7.54-7.42 ( m, 2H), 2.41 (c, 6H). (EBI) 384 (M--Ma). "shi s g" p -I se)

TN NMR (300 MHz, SOSIv): 8.82 (d, 9U-5.6Hz, 1H), 8.72 (dd, U-7.8 and 1.2Hz, 1H), 8.53 (dd, 9- 44 and 1.2Hz, o 1), 7.90 (d, 9U-64Hz, 1), 7.87 (d, 9U-6.5Hz, 1), 7.70 (d, 9U-5.4Hz, 1H), 7.60 (dd, U-8.3 and 4.9Hz, 1H), 2.68 ko 20 (s, ЗН), 2.40 (s, 6H). (EBI) 426 (M-"Ma), 404 (M-n1). sl «y 600 ru o B with Ku 60 - y, v5 TN nNMR (Z00MGHts, SOSIv): 8.88 (d, 9-5, 4Hz, 1H), 8.63 (dd, 9U-8.3 and 1.7Hz, 1H), 8.56 (dd, 9-46 and 1.3Hz, 1H), 8.36 (d, 9U-6 ,7Hz, 1H), 7.99 (d, U-6.6Hz, 1), 7.75 (d, 9U-5.5Hz, 1H), 7.58 (dd, U-8.3 and 4, 6Hz, 1H), 2.43

(p. 12H). (EBI) 468 (M.-Ma).

Example 15. Compounds 234 and 23e! -

M

And sleep.

Acetyl chloride (1.5 μl, 1.8x10"" mol) is added to the solution of deoxyvariolin 4 (obtained in the following example of the preparation method 2 or 4) (5mg, 1.8x10"" mol) and EBM (4 μl, 2.7x10 mol) in THF (1.5 ml) at -782С. The orange suspension was stirred overnight, very slowly warming to room temperature, and then evaporated under reduced pressure. The yellow residue is dissolved in OSM (5 ml) and washed with a saturated solution of ManHCO3 (4 ml). The organic layer is dried, filtered and evaporated under reduced pressure.

The yellow residue is purified by flash chromatography, using as an eluent OSM/MeOH (195) - OSM/Meon o (4965), and M'-acetyl-M-acetyldeoxy variolin 234 (mg, 2695) and M'-acetyldeoxyvariolin 2Ze (0 .5mg, 10905) in the form of yellow oils.

Io)

Yar sch y F va, y- ' Y «

TN nMR (30 MHz, SOSIv): 8.83 (dd, 9U-7.4 and 1.4Hz, 1H), 8.52 (d, 9U-6.2Hz, 1), 8.41 (dd, 9- 42 and 1.A4Gu, o) with 1H), 7.75-7.71 (m, 2H), 7.56-7.48 (m, 1H), 7.39 (d, U-6.3HzC, 1Н), 2.43 (s, ЗН). (EBI) 342 (M'.Ma). with n and Mn and 238 se) with 50 sl

TN nMR (300 MHz, SOSIv): 8.91 (dd, U-7.4 and 1.4 Hz, 1), 8.58 (d, 9U-6.2 Hz, 1H), 8.52 (dd, 4- 42 and 1.4Gu, 1H), 8.19 (d, U-64Hz, 1H), 8.03 (width, 1H), 7.85 (d, 9U-6.5Hz, 1H), 7, 61 (dd, U-8.3 and 4.9Hz, 1H), 7.39 (d, 3-6, IHC, 1H), 2.65 (s, ЗН), 2.43 (s, ЗН). (E5I) 384 (M'Ma). iF) Example 16. Compound 12 ime) 60 b5

"

B and you are right eggs - and 70 | TNE c and 44 Me 2-chloro-4-methoxypyridine (11) (reference example 3) (0.633 g, 4.41 mol) is dissolved in freshly distilled

THF (18 ml) and the reaction mixture is cooled to a temperature below -902C. n-"Vysh!i in hexanes (1.6M solution, 2.9ml, 4.5mol) was added to the stirred solution over 17 minutes, maintaining the temperature below -972F. The orange solution is stirred at -782C for 1 hour, as a result of which it acquires a dark red color. The reaction mixture is again cooled to a temperature below -902C and a solution of ketone (9) (1.14g, 4.09mol) in THF (10ml) is added within 11 minutes, maintaining the temperature below -902C. The dark mixture is stirred at -7892C7 for 3.5 hours, quenched with methanol and allowed to warm to room temperature. Then the reaction mixture is shaken with an aqueous solution of MNACI, extracted with ethyl acetate (3 times) and subjected to standard treatment. The crude mixture is purified by flash chromatography on silica gel, carrying out gradient elution (70-7595 E(Ac/hexanes), and triaryl alcohol 12 is obtained in the form of a cream solid with 29 (MZ2g, 76906). o

TN nMR (BOO0MHZc, SOSIv): 5 2.49 (s, 6H), 3.43 (s, ЗН), 6.55 (s, 1H), 6.76 (d, 9U-5.4Hz, 1H) , 7.39 (d, 4-5.4Hz, 2H), 8.25 (d, 9-5.4Hz, 1H), 8.46 (d, U-5.4Hz, 2); C NMR (75 MHz, SOSIv): 5 14.1, 55.8, 78.0, 1071, 113.7, 124.8, 149.8, 152.3, 157.2, 165.9, 171.0 , 171.1; IR (SOSI solution"): 3344cm"!; NEMO: calculated for yuyu

P.7Niv SIM (MU) 421.0434, found 421.0448. with

Example 17. Compound 18 (22)

M and - and VO; TNE | - with | -os n M. am -5 and "me 47 sh in 38 ik You (6b,9ml, 2.5M solution in hexane) is added dropwise to a solution of iodopyrimidine 8 (reference example 1) so (4.3Zg, 17mol) in THF (5Oml) at -1002C. The black solution was stirred for 30 minutes at the same temperature. 5o Using a cannula, a solution of 2-chloronicotinoyl chloride 17 (1g, 5.7mol) in THF (7ml) previously cooled to -782C was added intensively. the colored red mixture is stirred for 3 hours at -959C and then a saturated solution of MNACI (500ml) is added. The layers are separated and the aqueous layer is extracted with diethyl ether (3x100ml). The combined organic layers are dried, filtered and concentrated under reduced pressure. The red residue is purified by flash -chromatography, using ethyl acetate:hexane (1:3.5) - ethyl acetate:hexane (1:1.5) as an eluent, and alcohol 18 (1.3 g, 58905) was obtained as a pale orange solid.

Gee! TN nMR (Z0OMHZc, SOSIv): 8.56 (d, 9U-51GHz, 2), 8.37 (dd, 9U-4.7 and 1.5Hz, 71H), 7.39 (d, U-51Hz, 2H), 7.22 (dd, U-7.8 and 1.9Hz, 1H), 7.17 (dd, 9U-7.8 1 4.4Hz, 1H), 2.48 (s, 6H). Example of a method of preparation 1. Compound 1 (variolin) (This compound is not included in the scope of this invention) with k

Y. ; . and

RMENIM and

Alcohol 16 (obtained in example 3 above) (ZZmg, 0.06b2mol) was dissolved in pure trifluoromethanesulfonic acid (0.4ml) under atmospheric conditions. The flask is hermetically closed and the dark red solution is left to stand at room temperature for 5 hours. Then the flask is cooled on ice and Meson (2 ml) is added dropwise. As a result of the addition of a concentrated aqueous solution of ammonia (2 ml), a bright yellow precipitate is formed. The suspension is injected into the upper part of a chromatographic column containing silica for reversed-phase chromatography, which is pre-equilibrated for 5090 s

Meon/water. The yellow suspension is injected into a column with 2096 MeOH/water (5 Oml). The polarity of the eluting solvent system is reduced to the 8096 MeOH/water system (5 Oml) and then to the 85906 MeOH/water system, which contains 0.190

TFOK, after which the elution of the yellow product begins. The bright yellow fractions are combined and concentrated in vacuo, thus obtaining variolin B in the form of its trifluoroacetate (salt). Add Meon (1Oml) and then a concentrated aqueous solution of ammonia (1-2ml), obtaining the free base. The solvents are removed under reduced pressure, the product is dried (352C, 0.0Zmm Na) overnight and variolin B (1) (1Omg, 55905) is obtained, which is identical to the natural substance in all its characteristics. at. (22)

Example of the method of preparation 2. Compound 4 (deoxyvariolin) (This compound is not included in the scope of this invention)

A solution of tSRVA (Aiaghisi, 7095) (98 mg, 0.39 mol) in OSM (4 ml), previously dried over Ma»25O, is added dropwise (se) to a cooled (-302C) solution of the simple dithioether 19 (example 4) (b1 mg , 0.18 mol) in OSM (5 ml). so The yellow solution is stirred for 15 minutes at 02С. A saturated aqueous solution of Ma»52O»z (5 ml) is added and the organic layer is washed with a saturated solution of ManHsSoO»z (bBml). The combined aqueous layers are extracted with OSM ko (3x1Oml). The combined organic extracts are dried, filtered and concentrated. The yellow residue is poured into a hermetically closed test tube with dioxane (4 ml) and 3295 ammonia solution (8 ml) is added. The brown mixture is stirred for 14 hours at 8592C. The resulting yellow mixture is evaporated in vacuo, OHsM/MeeOH (10:11) (1 mL) is added, and the solvent is evaporated under reduced pressure. The yellow solid was purified by 5B flash chromatography using ХОСМ/МеоНН (290) - ОСМ/Меон (595) as eluent to give deoxyvariolin 4 (14mg, 2990, 2 steps) as a yellow solid.

F, "H NMR (300 MHz, DMSO): 8.92 (dd, U-8.1 and 1.5Hz, 1H), 8.45 (dd, 9-46 and 1.4Hz, 1H), 8.22 (d, U-5.5Hz, 1H), ko 7.68 (d, 9-6.6HzC, 1H), 7.63 (d, U-6.6HzC, 1H), 7.58 (dd, U -8.1 and 4.6 Hz, 1H), 7.06 (d, 9-54 Hz, 1H). (EBI) 278 (M--1).

Example of the preparation method 3. Compound 5 (thiodeoxyvariolin) in (This compound is not included in the scope of this invention)

Not the same: M I "DE shchi zak.

Because / pa and se shk In is I and - ik. их Я. - ke -х и эх Ш still show 70 y" Й я. shlh 2 El v nyk DI Y: N "V

WHAT? ; 5 Tent grove. k teriavtichno COVENANT: IV s v ie d n y g. (7 Kg also and IZ How: ta tse - yag a E TU t i y U test tube i Uayy

Not AI and: But let her.

3295 ammonia solution (3 ml) is added to a solution of simple dithioether 19 (example 4) (12 mg, 0.035 mol) in dioxane (2 ml). The brown mixture is stirred for 14 hours at 859 in a sealed tube.

The resulting yellow mixture is evaporated under vacuum, OSM (5 ml) is added, the solution is dried and the solvent is evaporated under reduced pressure. The yellow solid was purified by flash chromatography using rsom/meon (295) - OSM/Meon (3595) as eluent to give thiodeoxyvariolin 5 (8mg, 7395) as a yellow solid. with

TN nMR (300 MHz, SOSIv): 8.72 (dd, 9U-8.1 and 1.5Hz, 1H), 8.48 (d, 9U-5.4Hz, 1H), 8.39 (dd, 9- 48 and 1.6Gu, o 1), 7.66 (d, U-6.8Hz, 1), 7.56 (d, 9U-6.7Hz, 1H), 7.48 (dd, 9U-8, 1 and 4.6Hz, 1H), 7.32 (d, 9U-5.3Hz, 1H), 2.67 (s, ЗН). (EBI) 309 (М--1).

Example of the method of preparation 4. Compound 4 (deoxyvariolin) (This compound is not included in the scope of this invention) ис) сч чуМНРМВ МН, ий (22) | that i - trifluoromethanesulfonic acid "still shi s dae g" RMVN i sh 4 i-o M", M-bis(p-methoxybenzyl)deoxyvariolin, 29 (example 5) (15 mg, 2.9x10?mol) treated with pure (Se ) with trifluoromethanesulfonic acid (1.5 ml) and stirred for 17 hours at 24 2 C. The black solution t 50 is evaporated under reduced pressure, the black suspension is dissolved in OSM (4 ml) and washed with a saturated solution

MansSoOz (ml). The aqueous layer was extracted with OCM (Zhbml) and the combined organic layers were dried, filtered and evaporated. The brown residue was purified by flash chromatography using OSM/MeOH (196)-Rhom/Meon (55965) as eluent to give deoxyvariolin 4 (1.5 mg, 1995) as a yellow solid. "H NMR (300 MHz, DMSO): 8.92 (dd, U-8.1 and 1.5Hz, 1H), 8.45 (dd, 9-46 and 1.4Hz, 1H), 8.22 (d , U-5.5Hz, 1H), 22 7.68 (d, 1-6.6Hz, 1H), 7.63 (d, U-6.6Hz, 1H), 7.58 (dd, 9-81 and 4.6Hz, 1H), 7.06 (d, U-5.4Hz, 1H). (EBI) 278 (M--1).

GF! Example of the method of preparation 5. Compounds 6 and 22 (These compounds are not included in the scope of this invention) 60 b5

V I - D i Zla BYY iz i, ak: I saw the best Go "5. and g; "and im iechyutu and S and i 22 c

A solution of tSRVA (Alagisn, 7095) (7/Omg, 0.3O0mol) in OSM (3ml), previously dried over Maz5Od, is added dropwise to a solution of thiodeoxyvariolin 5 (ZOmg, 0.1Zmol) in OSM (7ml). The yellow solution is stirred for 2 hours at 242C. A saturated aqueous solution of Ma»52Oz (bml) is added and the organic layer is washed with a saturated solution of ManHsSO»z (bBml). The combined aqueous layers are extracted with OSM (3x2O0ml). The combined organic extracts are dried, filtered and concentrated. The yellow residue was purified by flash chromatography using OSM/MeOH (295) - OSM/Meon (55965) as an eluent to give sulfinyldeoxyvariolin 22 (15mg, 3590) as a yellow oil and sulfonyldeoxyvariolin 6 (25mg, 5895) as a yellow solid . vome cm (8) -

IS) from what sch (22)

TN nMR (Z00MHz, SOSIv): 8.86 (dd, U-8.1 and 1.5Hz, IN), 8.74 (d, 9-5.6Hz, 1H), 8.43 (dd, 4- 46 and 1.3Hz, 1), 7.77 (d, 9U-6.8Hz, 1), 7.72 (d, U-6.6Hz, 1H), 7.67 (d, 9U-5.8Hz , 1H), 7.54 (dd, U-8.0 and 4.6Hz, 1H), 3.02 Me zv (s, ЗН). (EBI) 325 (M). Cha

C 4 : ; t vra K. i and. - with Z! ko i ' pr p v i» shi sh.- s

TN nMR (300 MHz, SOSIv): 8.80 (dd, U-8.1 and 1.4 Hz, 1), 8.71 (d, 9-5.6 Hz, 1H), 8.41 (dd, 4- 48 ii 1.4Hz, 1H), 7.76 (d, 9-5.6HzC, 1H), 7.74 (d, U-6.4HzC, 1H), 7.64 (d, U-6.4HzC , 1H), 7.52 (dd, U-8.2 and 4.8Hz, 1H), 3.40 (s, ЗН). (Se) Reference example 1. Compound 8 2 ml ime) 7o і poshany vliy sl t (F) Iodopyrimidine 8 is obtained by an experimental method (described in the scientific literature: Mai)eey, A...;

GI Apiopsep, 0.; Veppespe, T.; Opaneit, K. Teigapedgop 1989, 45, 993).

Reference example 2. Compound 9 60 b5 r distillate carbonate s on M ikh I I t vy Mam MM y VMe Va yi i 8 V

Pre-cooled (-972C) solution of n-Vysh! and in hexanes (1.55M, 10.00ml, 15.5mol) was slowly added over 21 minutes to a solution of 4-iodo-2-methylthiopyrimidine (8) (3.90g, 15.5mol) in freshly distilled THF (47ml) at -972C (bath with a mixture of methanol and liquid M 2). They carefully monitor that the temperature does not rise above -972C. After the addition is complete, the black mixture is stirred for 30 minutes at -972C, after which a pre-cooled (-972C) solution of diethyl carbonate (0.94ml, 7.vmol) in THF (4ml) is added over about 3 minutes. The mixture is kept for 15 minutes at -972С, after which the bath is left to heat up to -359С7 for 2 hours and then to room temperature. The reaction mixture is shaken with an aqueous solution

MNASI and extract EIUAs (Z times). The crude substance is subjected to the usual processing and partially purified by vacuum distillation in a Kugelror apparatus (1602C, 0.0Zmm Na). The product is then purified by flash chromatography on d) silica gel using a gradient elution (25, 30 and then 50956 EtOAc/hexanes) to give pure ketone 9 as a yellow solid (1.14g, 53905).

T.p. 106-1072C; "H NMR (500 MHz, SOSI»v): δ 2.51 (s, 6H), 7.54 (d, U-4.9Hz, 2H), 8.79 (d, U-4.9Hz, 2H) ; ZS NMR oyu zo (75MHz, SOSIz): 5 14.2, 114.9, 158.8, 159.2, 173.2, 190.7; IR (KVh aivs): 1695cm7; NEM5: calculated for

S.4NiomMaO 3285 (M") 278.0296, found 278.0289.

Reference example 3. Compound 11 F (22)

ROS, M. alanine y. 4-methoxy-2-pyridone (10) (0.805 g, 6 b, 4 mol) and freshly distilled ROSIZ (ml) are heated at reflux with a refrigerator for 15 hours. The excess DEW is removed in vacuo, the viscous oil formed is cooled on ice and carefully neutralized with a saturated solution of MansSoO. The mixture is extracted with EtOAc (3 times) and the extracts are worked up in the usual way, obtaining a brown oil. The obtained substance is partially purified by vacuum distillation in a Kugelror apparatus (1002, 0.07 mm Na). The distillate is triturated with -45% petroleum ether and the white precipitate is filtered off. The filtrate is concentrated, the product is finally purified by flash chromatography on silica gel using 3090 E(OdAbs/hexanes) as an eluent, and (Ce) 2-chloro-4-methoxypyridine (11) is obtained as a colorless oil (0.586g, 63905). 50

Claims (50)

The formula of the invention is sl 1. The compound of formula (1): Ech (), --- I 7 te F) Ez M - He) same s, 60 - M M ih um go b5 where: each of Ku and Ko is independently selected from the group that includes H, OH, OK, 5H, ZK, OK, ZO, MO», MN», MN, MK)», MNSOK, ShSOK)», MNZO»K, SM, halogen, C(I-O)H, (OK, SON, SOZH, C.4-C3o alkyl, C4-C12 haloalkyl, Co-C1o alkenyl, Co-C4o alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and substituted or an unsubstituted heteroaromatic group; and Ez is selected from the group consisting of OH and OMe; where the group K or each of the groups K' is independently selected from the group consisting of OH, C.4-C40 alkyl, C.4-C12 haloalkyl, Co -C10 alkenyl, C0-C40 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted arylalkenyl and substituted or unsubstituted heteroaromatic group; 70 and when the group K; or Ko represents a group of the formula MЩ(К)" or Х( SOC)", all K' groups can have the same or different values or two K groups together with the nitrogen atom to which they are attached can form a 5-14-membered heterocyclic ring; an aryl group and an aryl part of an aralkyl and arylalkenyl group are a carbocyclic aryl group containing from 6 to 14 carbon atoms in a carbocyclic ring or in two or more fused rings; the aralkyl group is a C-C alkyl group substituted by the above-mentioned aryl group; the arylalkenyl group is a Co-Ce alkenyl group substituted by the above-mentioned aryl group; heteroaromatic group is a heterocyclic aromatic group containing from 5 to 14 atoms in one ring or in two or more fused rings, in which at least one ring atom is selected from the group consisting of nitrogen, oxygen and sulfur atoms, as well as the described heterocyclic an aromatic group condensed with the above aryl group; Substituents in aryl and heteroaromatic groups and in the aryl part of aralkyl and arylalkenyl groups are selected from the group that includes C.-C40 alkyl, C4-C10 haloalkyl, C4-C10 alkoxy, C.4-C10 alkylthio, MH. C.4-Su alkylamino, di(C--Su; alkyl)amino, C-C, alkanoylamino, di(C--C,. alkanoyl)amino, MO», SM and halogen; its derivatives, in which the nitrogen atom is quaternized, and their salts and esters, (8) with the exception of compounds in which: K. and K" mean amino and Kz means hydroxy. 2. The compound according to claim 1, in which K/ is selected from the group that includes ОН, ОК, ЗН, ЗК, ОК, ЗО, МНо, МНЕ", М(К)", у зо МНСОк, МСОк)», МНЗОоК, (OK, SON, CO, C.-C.12 alkyl, C.41-C.10 haloalkyl, where the K" group or each of the K' groups is independently selected from the group including OH, C.-C.2 alkyl, C.4-C.40 haloalkyl, aryl (which may be optionally substituted with a group selected from C.4-Ce alkyl, C--Ce alkoxy, C.4i-Ce alkylthio, MH", C.4-Ce alkylamino, He! di(C--C . alkyl)damino, MO», CM and halogen), aralkyl or arylalkenyl (the aryl part of which can be optionally substituted by a group selected from C.4-Ce alkyl, C4--Cv alkoxy, C4-Cv alkylthio, MH» . SORK)", all K groups can have the same or different values or two K' groups together with the nitrogen atom to which they are attached form a 5-12-membered heterocyclic ring. Z. The compound according to claim 1, in which K is selected from the group including OK, ZK, 5OK, MNo, MNK, MK)", MNSOK, M(SOK)" and MNZOZH, where the group K' or each of the groups K ' is independently selected from the group consisting of C.4-Cv alkyl, C4-Cv" Haloalkyl, aryl (which may optionally be substituted by a group selected from C.-Cv alkyl, C--Cv alkoxy and pl") c halogen), aralkyl (the aryl part of which may be optionally substituted by a group selected from C.4-Ce alkyl, C--Cv alkoxy and halogen), aralkenyl (the aryl part of which can be optionally substituted by a group selected from C.4-Ce alkyl, C.-Cv alkoxy and halogen), and in which, when the K group represents a group of the formula M(K)" or M(SOK)", two K groups together with the nitrogen atom to which they are attached can form a 5-10-membered heterocyclic ring. -I 4. The compound according to claim 1, in which K 4 is selected from the group that includes C.-C, alkoxy, C.4-C; alkylthio, C4-C/ alkylsulfinyl, amino, C--C; alkylamino, di(C--C; alkyl)amino, C--C, alkanoylamino, di(C4i-C;. alkanoyl)amino, and C.-C, haloalkanoylamino, arylamino (where the aryl part can be optionally substituted (C 4-C/ He) alkoxy group), benzylamino (where the phenyl part of the benzyl part can be optionally substituted by a C1-C 6 oxy group), cinnamoylamino or dicinnamoylamino (where the phenyl part of each cinnamoyl part can be optionally substituted with C o.- C, an alkoxy group) or a 5-7-membered nitrogen-containing heterocyclic ring, c is attached to the remaining part of the molecule through its nitrogen atom. 5. The compound according to claim 1, in which K is selected from the group consisting of methoxy, thiomethyl, methylsulfinyl, amino, methylamino, ethylamino, benzylamino, acetylamino, trifluoroacetylamino, diacetylamino, cinnamoylamino, dicinnamoylamino, p-methoxybenzylamino and piperidino. b. The compound according to claim 1, in which K 4 is selected from the group consisting of amino, benzylamino, acetylamino, F) trifluoroacetylamino, diacetylamino, cinnamoylamino, dicinnamoylamino and p-methoxybenzylamino. ka 7. Compound according to claim 1, in which Co is selected from the group that includes ON, OK, ZN, ZK, ZOK, ZO, MN", MN", MSH(K)", MNSOv, ShSHOK)", MNZOK, (OK . may be optionally substituted by a group selected from C 4-Ce alkyl, C-C alkyl, C.-C alkylthio, MH", C.4-C alkylamino, di(Ci-C alkyldamino, MO", CM and halogen), aralkyl or arylalkenyl (the aryl part of which may be optionally substituted by a group selected from C 4-Cv alkyl, C--Cv alkoxy, C-Cv alkylthio, MH", C4-C/ alkylamino, di(C4 -C; alkyl)amino, MO", CM and halogen), and in which, when the Ko group is a group of the formula M(K 2 65 or MSH(SOK)", all groups K' can have the same or different values or two groups K' together with the nitrogen atom to which they are attached form a 5-12-membered heterocyclic ring. 8. Compound according to claim 1, in which Co is selected from the group including OK, ZK, 5OK, MNo, MNK, MK)", MNSOK, M(SOK)" and MNZOZH, where the group K' or each of the groups K' independently selected from the group consisting of C.4-Cv alkyl, C.4-Cv haloalkyl, aryl (which may be optionally substituted by a group selected from C.1-Ce alkyl, C--Cv alkoxy and halogen), aralkyl ( the aryl portion of which may be optionally substituted with a group selected from C.4-Ce alkyl, C--Cv alkoxy and halogen), aralkenyl (the aryl part of which may be optionally substituted by a group selected from C.4-Ce alkyl, C--Cv alkoxy and halogen), and in which, when the Ko group is a group of the formula M(K)" or M(SOK)", two K groups together with the nitrogen atom to which they are attached can form a 5-10-membered heterocyclic ring. 70 9. The compound according to claim 1, in which K" is selected from the group including C.-C, alkoxy, C.4-C; alkylthio, С.4-Су/ alkylsulfinyl, amino, С4-С, alkylamino, di(С4-С; alkyl)amino, С4--С; alkanoylamino, di(C--C; alkanoyl)amino, C4-C haloalkanoylamino, arylamino (where the aryl part may be optionally substituted by a C.-C, alkyl group), benzylamino (where the phenyl part of the benzyl part may be optionally substituted by a C 4-C/ alkyl group), cinnamoylamino or di-cinnamoylamino (where the phenyl part of each cinnamoyl part y/5 May be optionally substituted by a C 4-C 6 alkyl group) and a 5-7-membered nitrogen-containing heterocyclic ring attached to the remaining part of the molecule through its nitrogen atom. 10. The compound according to claim 1, in which Co is selected from the group consisting of thiomethyl, methylsulfinyl, amino, methylamino, ethylamino, acetylamino, diacetylamino, cinnamoylamino and p-methoxybenzylamino. 11. The compound according to claim 17, in which K» is selected from the group consisting of amino, acetylamino, diacetylamino, and p-methoxybenzylamino. 12. The compound according to claim 1, in which Kz means OH. 13. The compound according to claim 1, in which Kz means ОМе. 14. A compound according to any one of claims 1-13, having antitumor activity, for obtaining a pharmaceutical composition. high school 15. A compound according to any one of claims 1-13, having an antitumor activity that is suitable for the treatment or prevention of cancer. and) 16. The compound according to any one of claims 1-143, having antitumor activity, suitable for the preparation of a pharmaceutical composition for the treatment or prevention of cancer. 17. The compound of the following formula: ю Б в ' s «Й о а : я х и - х M их - « в, м - s ? ts which represents the compounds with the numbers indicated in the table below, in which K./, Ko, Kz have the values "" indicated in the table: - o F yuyu? methyl, EyY - ethyl, Vy - butyl, Ac - acetyl and MNRMV - p-methoxybenzylamino. 18. The compound according to claim 17, which has antitumor activity, for obtaining a pharmaceutical composition. 19. A compound according to claim 17, having antitumor activity, which is suitable for the treatment or prevention of cancer. 20. The compound according to claim 17, which has antitumor activity, is suitable for the preparation of a pharmaceutical composition for the treatment or prevention of cancer. 70 21. The method of obtaining the compound of formula (1): . alkyl, C-C, haloalkyl, C0-C4 alkenyl, C0-C4 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted o or unsubstituted heteroaromatic group, and Ez is selected from the group consisting of OH and OMe, where the group K or each of the groups K' is independently selected from the group consisting of OH, C.4-C.40 alkyl, C.4-C.12 or 20 haloalkyl, C.o-C.40 alkenyl, C.o-C.10 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted arylalkenyl and a substituted or unsubstituted heteroaromatic group; c and when the group K. or Ko represents a group of the formula M(K)" or MISOK)", all groups K E" may have the same du or different value or two K groups together with the nitrogen atom to which they are attached can form 5-14- -lens heterocyclic ring; Me. the aryl group and the aryl part of the aralkyl and arylalkenyl group is a carbocyclic aryl group having from 6 to 14 carbon atoms in the carbocyclic ring or in two or more condensed rings; the aralkyl group is a C-C alkyl group substituted by the above-mentioned aryl group; the arylalkenyl group is a Co-Ce alkenyl group substituted by the above-mentioned aryl group; heteroaromatic group is a heterocyclic aromatic group having from 5 to 14 atoms in one ring or in two or more fused rings in which at least one ring atom is selected from the group consisting of nitrogen, oxygen and sulfur atoms, and also described heterocyclic aromatic group, condensed with the specified . above by an aryl group; "" substituents in aryl and heteroaromatic groups and in the aryl part of aralkyl and arylalkenyl groups are selected from the group that includes C.-C42 alkyl, C4-C4o haloalkyl, C4-C4o alkoxy, C4-C4o alkylthio, MH", C4-C4 alkylamino , di(C4i-C; alkyl)amino, C4-C; alkanoylamino, di(C4i-C; alkanoyl)amino, MO", SM and halogen; - And its derivatives, in which the nitrogen atom is quaternized, its salts and esters, ee, which includes cyclization of the intermediate compound of formula (11): (Ce) Ez in (PU, ime) i-m sl M and Ba ti st | She DI te o) Eza bo de: Ka, Koa and Kza mean any groups represented by the designations K 4, K» and Ka, respectively, and all such groups in which reactive functional groups are protected; and Mi and Mo denote groups that can be removed to form a condensed tricyclic pyridopyrrolopyrimidine ring structure, obtaining a compound of the formula (PP): b5 Ra -x (B), IJ x M sn-it za g - 170 MM x dm E la and, if necessary, the transformation of any of the groups marked as K cha, Koa and Kza, into any of groups, 75 marked as K., K» and Kz, respectively. 22. The method according to claim 21, where U. means a hydroxyl group. 23. The method according to claims 21 or 22, where U" means a chlorine atom. 24. The method according to any one of claims 21-23, where Cla-Coa. 25. The method according to claim 24, where K.4 and Koza mean methylthio groups. 26. The method according to any one of claims 21-25, in which acid catalyzes. 27. The method according to any one of claims 21-26, which includes the interaction of an intermediate compound of the formula (II) with a trialkylsilane of the formula КаКкбкозиН, where Ка, К, and Ко can have the same or different values, and each of them is C.4 -C42 alkyl group. 28. The method according to any of claims 21-27, in which the intermediate compound of the formula (II) is obtained as a result of the interaction of the intermediate compound of the formula (IM): o Eza (M), tk i M yu - M t sch de Kaa i Xo has the values specified in claim 21, and M is a metal, with a compound of formula (M): claim 21. 29. The method according to any one of claims 21-27, in which the intermediate compound of the formula (II) is obtained as a result of the interaction: with" the compound of the formula (MI): M Echas, shen and this. BAK se; Mik ; ; ; . where Ka has the values as defined in claim 21 and M is a metal, with an intermediate compound of the formula (MI): ov. p m) for ! followed by M and (F; where Kaa and Xo are as defined in claim 21, and 7 means a leaving group. GI 30. The method according to claim 21, where Ku and K" are amino groups and Kz is , specified in claim 1, which includes: a) treatment of the compound of formula (I), where Ka and Cod represent methylsulfinyl, and Kza has the values specified in Vol. 21, a compound of the formula MNoRg'oi, where Rgoi means an amino protecting group, with the formation of a compound of the formula (III), where Ka and Coa represent a protected amino group and Kza has the values specified in claim 21; and B) removal of the amino-protecting group with the formation of a compound of formula (I), where K 4 and Ko are amino groups, and Kz has the values specified in claim 21. 31. The method according to claim 21, where K. means a methylthio- or amino group, Ko means an amino group and Kz has the value 65 specified in claim 21, which includes: a) optional oxidation of the compound of formula (I), where K is 44 and Code stand for methylthio and Kza has the meaning, specified in claim 21, in the compound of formula (I), where Ka and Koza represent methylsulfinyl; and B) treating the compound of formula (II), where Ka and Coa are methylthio or methylsulfinyl, with a reagent selected from sodium azide and ammonia. 32. The method of obtaining the compound of formula (1): OK, ZOH, MO», MN», MNE", MK)», MNSOKk, ShSOK)", MNZO»K, SM, halogen, С(-О)Н, (OK, SON, SOZ, C4-C3o alkyl, C1-C40 haloalkyl, C0-C40 alkenyl, C0-C40 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic group; and Ez is selected from the group consisting of OH and OMe; where the K group or each of the K' groups is independently selected from the group consisting of OH, C..C.io alkyl, C.sub.4.C.sub.12 Ha haloalkyl, C.sub.C.sub.0 alkenyl, C.sub.C.sub.Cio alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted arylalkenyl and a substituted or unsubstituted heteroaromatic group; i9) and when the group K; or Ko represents a group of the formula MЩ(К) » or M(СОК)», all groups K' can have the same or different values or two groups K together with the nitrogen atom to which they are attached, can form a 5-14-lene heter ocyclic ring; the aryl group and the aryl part of the aralkyl and arylalkenyl group is a carbocyclic aryl group having from 6 to 14 carbon atoms in the carbocyclic ring or in two or more condensed rings; C aralkyl group is a C-C alkyl group substituted by the above-mentioned aryl group; Gee! the arylalkenyl group is a Co-Sev alkenyl group substituted by the above-mentioned aryl group; heteroaromatic group is a heterocyclic aromatic group having from 5 to 14 atoms in one b ring or in two or more fused rings in which at least one ring atom is selected from the group consisting of nitrogen, oxygen and sulfur atoms, and the described heterocyclic aromatic group condensed with the above-mentioned aryl group; Substituents in aryl and heteroaromatic groups and in the aryl part of aralkyl and arylalkenyl groups "are selected from the group that includes C.-C.15 alkyl, C4-C4o haloalkyl, C4-C1" alkoxy, C4-C4o alkylthio, MH", C4- C/ alkylamino, di(C4-C; alkyl)amino, C4-C4 alkanoylamino, di(C4i-C4 alkanoyl)amino, MO», SM and halogen; - from its derivatives, in which the nitrogen atom is quaternized, from its salts and complex esters, and" which includes the following stages: a) transformation of the compound of the formula (MI): where Ka has the above values and X means a halogen atom, in the compound of the formula (MI) specified in claim 29; part B) the interaction of the compound of the formula (MI) with the compound of the formula 1.-СО-/5, where I and 5" have the same or different values and represent a group that can be removed to form a compound of the formula (M) specified in claim 28; c) interaction of a compound of the formula (M) with a compound of the formula (IM) specified in claim 28 to form a compound of the formula (II), indicated in claim 21; a) cyclization of the compound of formula (II) to form the compound of formula (ІІ), indicated in claim 21; Ф) e) transformation, if necessary, of any groups designated as K cha, Koa and Kza, U are any groups denoted by ka as Ku, E» and Kz, respectively. 33. The method of obtaining the compound of formula (1): 60 b5 (), Ni vk 7 me g M nt Z g - 170 M M x dm go de: Ku i Ko are independently chosen from the group that includes N, ОН, ОК, ЗН, ZK, ОК, ЗОЖ, МО», МН» . "alkenyl, C0-C4" alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic group; and Ez is selected from the group consisting of OH and OMe; wherein the group K or each of the groups K' is independently selected from the group consisting of OH, C.4-C30 alkyl, C4.C12 haloalkyl, C0-C10 alkenyl, C0-C40 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted arylalkenyl and substituted or unsubstituted heteroaromatic group; and when the Ki or Ko group is a group of the formula MSH(K)"" or M(SOK)", all the K' groups can have the same or different values or two K groups together with the nitrogen atom to which they are attached can form Ha b 9-14-membered heterocyclic ring, aryl group and aryl part of the aralkyl and arylalkenyl group is a carbocyclic aryl i9) group having from 6 to 14 carbon atoms in the carbocyclic ring or in two or more condensed rings; aralkyl group is a C-C alkyl group substituted by the above-mentioned aryl group; the arylalkenyl group is a Co-Sev alkenyl group substituted by the above-mentioned aryl group; A heteroaromatic group is a heterocyclic aromatic group having from 5 to 14 atoms in one ring or in two or more fused rings, in which at least one ring atom is selected from the group consisting of nitrogen, oxygen and sulfur atoms, and described heterocyclic aromatic group, condensed with. o the above-mentioned aryl group; Substituents in aryl and heteroaromatic groups and in the aryl part of aralkyl and arylalkenyl groups are selected from the group that includes C.-C.10 alkyl, C4-C40 haloalkyl, C4.C» alkoxy, C4-C40 alkylthio, MH», C4- C4 - alkylamino, di(C--C.alkyl)amino, C4-C; alkanoylamino, di(C4i-Slalkanoyl)amino, MO", SM and halogen; its derivatives, in which the nitrogen atom is quaternized, its salts and esters, "which includes the following stages: a) conversion of the compound of the formula (MIIII), indicated in claim 32, into the compound of the formula (IM), indicated in claim 29; - with B) the interaction of the compound of formula (MI) with the compound of formula (MI) specified in claim 29, with the formation of the compound of formula (II) specified in claim 21; "» c) cyclization of the compound of the formula (II) with the formation of the compound of the formula (II), specified in claim 21; a) conversion, if necessary, of any groups designated as Kcha, Koa and Kza, into any groups, marked as Ku, K" and Kz, respectively. -I 34. A pharmaceutical composition containing an effective amount of a pharmacologically active compound together with a carrier or diluent, wherein said pharmacologically active compound is a compound according to any one of claims 1-13 or 17. (Se) 35. A method of treating or preventing cancer in a mammal, comprising administering to a mammal in need of such treatment an effective amount of a compound according to each of claims 1-13 or 17. 36. Compound of formula (1): sl (), Ni vk 7 me Ez M nt F. then | question - in M M their dm go de: 65 Ku i Ko are independently selected from a group that includes H, ON, OK, ZN, ZK, OK, ZOH, MO», MN», MNE», MK)», MNSOK, ШСОК)», МНЗООК, СМ, halogen, С(-О)Н, (ОК, СОН, СО, С4-С4о alkyl, С.--Сию haloalkyl, So-S." alkenyl, Co-C, 4" alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and substituted or unsubstituted heteroaromatic group; and Ez is selected from the group consisting of H, OH and OMe; where the group K or each of the groups K' is independently selected from the group consisting of OH, C.4-C40 alkyl, C.4-C12 haloalkyl, C0-C10 alkenyl, C0-C40 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted arylalkenyl and substituted or unsubstituted heteroaromatic group; and when group K; or Co represents a group of the formula MЩ(К)» or М(СОК)», all K' groups can have the same or different values or two K groups together with the nitrogen atom to which they are attached can form 7/0./5-14-membered heterocyclic ring; the aryl group and the aryl part of the aralkyl and arylalkenyl group is a carbocyclic aryl group having from 6 to 14 carbon atoms in the carbocyclic ring or in two or more condensed rings; aralkyl group is a C-C alkyl group substituted by the above-mentioned aryl group; the arylalkenyl group is a Co-Cv alkenyl group substituted by the above-mentioned aryl group; heteroaromatic group is a heterocyclic aromatic group having from 5 to 14 atoms in one ring or in two or more fused rings, in which at least one ring atom is selected from the group consisting of nitrogen, oxygen and sulfur atoms, and the described heterocyclic an aromatic group condensed with the above aryl group; Substituents in aryl and heteroaromatic groups and in the aryl part of aralkyl and arylalkenyl groups 2o are selected from the group that includes C.-C.12 alkyl, C4-C1» haloalkyl, C4-C10 alkoxy, C4-C12 alkylthio, МН», C4- Su alkylamino, di(C4-Su; alkyl)amino, C4--C; alkanoylamino, di(C--Su alkanoyl)amino, MO", SM and halogen; its derivatives, in which the nitrogen atom is quaternized, its salts and esters, which have anticancer activity, are intended for the treatment or prevention of cancers selected from ovarian cancer, kidney cancer, prostate cancer, breast cancer and melanoma. high school 37. A method of treating or preventing cancers in a mammal selected from ovarian cancer, kidney cancer, prostate cancer, breast cancer, and melanoma, comprising administering to a mammal in need of i) such treatment, an effective amount of a compound of formula (1): Ech (), I her 7 me r I Sho s her F Sh--- s, F | pc M them and - I! re and B. "where: s Ku ii Ko are independently selected from a group that includes H, OH, OK, ZN, ZK, OK, ZOH, MO", MN", MNE", MK)", ts MNSOK, ShSHOK)" . substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic group; and Ez is selected from the group consisting of H, OH, and OMe; -I wherein the group K or each of the groups K' is independently selected from the group consisting of OH, C.4-C40 alkyl, C.4-C12 haloalkyl, C0-C10 alkenyl, C0-C40 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkenyl and substituted or unsubstituted heteroaromatic group; (Ce) and when the Ki or Ko group is a group of the formula МЩ(К)»» or М(СОК)», all K' groups can have the same or different values or two K groups together with the nitrogen atom to which they are attached can form di 5 -14--lens heterocyclic ring, sl aryl group and aryl part of ar alkyl and arylalkenyl group is a carbocyclic aryl group having from 6 to 14 carbon atoms in a carbocyclic ring or in two or more condensed rings; aralkyl group is a C-C alkyl group substituted by the above-mentioned aryl group; the arylalkenyl group is a Co-Sev alkenyl group substituted by the above-mentioned aryl group; a heteroaromatic group is a heterocyclic aromatic group having from 5 to 14 atoms in one F, ring or in two or more fused rings, in which at least one ring atom is selected from the group consisting of nitrogen, oxygen and sulfur atoms, and also described heterocyclic aromatic group condensed with the above aryl group; the substituents in aryl and heteroaromatic groups and in the aryl part of aralkyl and arylalkenyl groups are selected from the group that includes C.-C.15 alkyl, C.4-C.40 haloalkyl, C.4-C.4" alkoxy, C.4.Co. alkylthio, MH", C.4-C.4 alkylamino , di(C4-Su; alkyl)amino, C4--C; alkanoylamino, di(C--Su alkanoyl)amino, MO", SM and halogen; its derivatives, in which the nitrogen atom is quaternized, its salts and/or esters. 38. Compound of formula (I): b5 cha (1), p- i-m M and 70 MO. the same Kw de Ka, Koa; Kza, U 4 and Xo have the values specified in claim 21. 39. The compound according to item C8, in which U represents a hydroxyl group. 40. The compound according to claims 38 or 39, in which U" represents a chlorine atom. 41. A compound according to any one of claims 38-40, wherein Cla-Coa. 42. The compound according to claim 41, in which K.4 and Code mean methylthio groups. 43. The method of obtaining the compound of formula (1): is selected from the group consisting of the groups ЗCH z, 5BOCH»5, 502CHaz, MNo and MH Me (4-methoxybenzyl); and Ge!Ez is H; Zo which involves the cyclization of the intermediate compound of formula (II) i-Echa (B . V. Kv se) where: o Echa and Koa represent ZSN z, Kza represents hydrogen; In 14 means hydrogen or a hydroxyl group; Xo 5p means chlorine atom; ime) to obtain a compound of the formula (IP): represents hydrogen, and, if necessary, converting 65 any of the groups designated as Ka and Coa into any of the groups designated as K. and Ko in formula (I), respectively. 44. The method according to claim 43, where U. means a hydroxyl group. 45. The method according to claim 43, in which acid is catalyzed. 46. The method according to claim 43, which includes the interaction of the intermediate compound of formula (II) with triethylsilane. 47. The method according to claim 43, in which the intermediate compound of the formula (II) is obtained as a result of the interaction of the intermediate compound of the formula (MI): ) Ra SOM, va Ey sho M and de Kza represents hydrogen, and U» and 7 both mean chlorine atom. 48. The method according to claim 43, where each of K. and K" represents a 4-methoxybenzylamino group, which includes: a) oxidation of the compound of formula (II) to obtain a compound of formula (I), where K. and K" independently represent ZOSN" or 5О2СН"; and B) treatment of the compound of formula (I), where Ki and Co independently represent ZOSN with or 5O»CH3 4-methoxybenzylamine, thereby obtaining a compound of formula (I), where each of Ki and Co represents a 4-methoxybenzylamino group. 49. The method according to claim 48, which additionally includes removal of the 4-methoxybenzyl group to obtain a compound of the formula i) (I), where each of Ku and Ko represents an amino group. 50. The method according to claim 48, where at stage a) a compound of formula (I) is obtained, in which each of Ku and Ko is a BOSN group. yu zo 51. The method of obtaining the compound of formula (1): Co is independently selected from the group consisting of the groups 5CHz, BOCH»z, 502CHaz, MH» and MH(4-methoxybenzyl); and Kz is H; which includes the following stages: a) conversion of the compound of the formula (MI): - Bcha-. M. M) Sho 8 TO Sho 2 with 50 x sp in the compound of the formula (MI): M.O Bas g 1a M M (g) z m where Ka represents ZCH", X means chlorine or iodine atom, and M means lithium; vo r) the interaction of the compound of the formula (MI) with the compound of the formula (MI): Ra Co MI) in - 65 - Mo with the formation of the compound of the formula (I): Echa (1) z i ke M sht M moh Tu Eza de: Ka and Koa are ZSN z, Kza is hydrogen; In 4 means hydrogen or a hydroxyl group; and ХУ" and 7 both mean a chlorine atom; c) cyclization of the compound of formula (I) to form the compound of formula (111): Echa M (PO, ia g o - their o M M dm Eva yuyu where each of Ka and Kod represent ZSN 5, and Kza represents hydrogen, c a) transformation, if necessary, of any of the groups marked as K 44 and Koa, into any of the groups designated as Ku and Co in formula (I), respectively. me) (22) Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 12, 10.08.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. shi s ;" -I se) se) with 50 sl F) name) 60 b5