Phosphatase cdc25 inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

 

The object of the present invention are novel inhibitors of the phosphatase cdc25.

Managing the transition between different phases of the cell cycle during mitosis or meiosis is ensured by the system of proteins, enzyme activity are associated with different States of phosphorylation. These States are controlled by two large classes of enzymes: kinases and phosphatases.

Synchronization of the different phases of the cell cycle also allows you to reorganize the cellular structure of each cycle of all living things in the world (bacteria, yeast, vertebrates, plants). Of kinases major role in controlling the cell cycle play kinase dependent of tsiklonov (CDK). Enzymatic activity of these different cdks is regulated by two other families of enzymes that work in the opposite direction (Jessus and Ozon,Prog. Cell Cycle Res.(1995),1, 215-228). First regroups these kinases, as Wee1 and Mik1, which inactivate CDK, phosphorylase certain amino acids (Den Haese al.,Mol. Biol. Cell(1995),6, 371-385). Second regroups phosphatases such as Cdc25, which can activate CDK, dephosphorylate residues of tyrosine and threonine in CDK (Gould al.,Science(1990),250, 1573-1576).

The phosphatases are divided into 3 groups: serine/threonine-phosphatase (PP-basics), tyrosine phosphatase (PTP-ases) and phosphatase, dual specificity (DSP basics). These phosphatases play the important role in the regulation of many cellular functions.

As for the phosphatase cdc25 human cdc25 proteins are encoded by 3 genes (cdc25-A cdc25-B and cdc25-C). In addition, the identified variants derived from alternative splicing of the gene cdc25B: cdc25Bl, cdc25B2 and cdc25B3 (Baldin al.,Oncogene(1997),14, 2485-2495).

The role of the phosphatase Cdc25 in oncogenesis known better, and mechanisms of action of these phosphatases is illustrated, in particular, in the following references: Galaktionov al.,Science(1995),269, 1575-1577; Galaktionov al.,Nature(1996),382, 511-517; and Mailand al.,Science(2000),288, 1425-1429.

About superexpression different forms of cdc25 reported in many classes of human cancers, for example:

Breast cancer: cf. Cangi al.,Résumé2984,AACR meeting, San Francisco, 2000);

- Lymphoma: Ms. Hernandez al.,Int. J. Cancer(2000),89, 148-152; and Hernandez al.,Cancer Res. (1998),58, 1762-1767;

- Cancer of the head and neck: cf. Gasparotto al.,Cancer Res. (1997),57, 2366-2368;

- Pancreatic cancer: cf. Junchao Guo al.,Oncogene(2004),23, 71-81.

In addition, the group E.Sausville reported an inverse correlation between the level of expression of cdc25-B in a sample of 60 lines and their sensitivity to inhibitors of CDK, suggesting that the presence of cdc25 can help overcome some of anticancer agents and, in particular, the CDK inhibitors (Hose al.,Proceedings of AACRAbstract 3571, San Francisco, 2000).

Thus, among other purposes, currently being p the lawsuit compounds, able to inhibit the phosphatase Cdc25, in order to use these compounds, in particular as anticancer agents.

The phosphatase Cdc25 also play a role in neurodegenerative diseases such as Alzheimer's disease (see Zhou and al.,Cell Mol. Life Sci. (1999),56(9-10), 788-806; Ding al.,Am. J. Pathol. (2000),157(6), 1983-90; Vincent al.,Neuroscience(2001),105(3), 639-50), so you can also consider it possible to use compounds having activity to inhibit these phosphatase for the treatment of these diseases.

Another problem on which the invention is directed, is the search for drugs to prevent or treat rejection in organ transplantation and for the treatment of autoimmune diseases. In these disorders/diseases involved improper activation of lymphocytes and monocytes/macrophages. However, the known drugs that suppress the immune system, have side effects, which could be reduced or modified products, specific purpose which are ways of signaling in hematopoietic cells that initiate and maintain inflammation.

The object of the invention is primarily to new inhibitors of the phosphatase cdc25 (in particular, the phosphatase cdc25-C), which are derived dimeric type benzothiazole-4,7-diones and benzox the evils-4,7-diones and meet the General formula (I)defined below. Given the above, these compounds can be used as medicines, in particular for the treatment and/or prevention of the following diseases or disorders:

the rapid inhibition of tumor growth, alone or in combination with another treatment;

the inhibition of proliferation of normal cells, alone or in combination with another treatment;

- neurodegenerative diseases such as Alzheimer's disease;

prevention of spontaneous alopecia;

- prevention of alopecia induced by exogenous products;

- prevention of alopecia induced by irradiation;

prevention of spontaneous or due to normal cells apoptosis;

warning meiosis and/or fertilization;

warning maturation of oocytes;

- all diseases/disorders, corresponding to the use of CDK inhibitors, and, in particular, non-tumorous proliferative diseases (e.g., angiogenesis, psoriasis or restenosis), proliferative tumor diseases, Parasitology (proliferation protozoa), viral infections, neurodegenerative diseases, myopathies; and/or

- all diseases/disorders, appropriate clinical use of vitamin K and its derivatives.

In addition, connection to the present is the invention due to their properties of inhibiting the phosphatase cdc25 is also suitable for use for inhibiting or preventing the rapid growth of microorganisms, in particular yeast. One of the advantages of these compounds is their low toxicity to healthy cells.

Now, the applicant has unexpectedly found that compounds corresponding to General formula(I)

in the form of the racemates, enantiomers or any combination of these forms, in which:

each of W and W' independently denotes O or S;

R1means one of the radicals-CH2-CR6R7-CH2-, -(CH2)m-X-(CH2)n-, -(CH2)p-[O-(CH2)q]r-O-(CH2)p- and -(CH2)s-CO-NR8-(CH2)t-in which each of m and n independently is an integer from 2 to 6, preferably an integer from 2 to 4 and more preferably an integer from 2 to 3), p and t each independently is an integer from 2 to 12 (preferably an integer from 2 to 8 and more preferably an integer from 2 to 6), q denotes an integer from 2 to 4, preferably an integer from 2 to 3), r is an integer from 0 to 4, preferably an integer from 0 to 2), s denotes an integer from 1 to 12 (preferably an integer from 1 to 8 and more preferably an integer from 1 to 6), X is selected from the radicals-NR5-, -S-CO-, -CR6R7-cycloalkyl and aryl, provided that when X is-S-, -CO-, - CR6R7-cycloalkyl or aryl, m and n are equal,

and R means a hydrogen atom or an alkyl or arylalkyl radical, possibly substituted from 1 to 3 times by substituents chosen independently from a halogen atom and an alkyl radical or alkoxy, and each of R6and R7independently means a hydrogen atom or an alkyl radical, and R8means a hydrogen atom or an alkyl or arylalkyl radical

or R1means

provided that →* means the place of connection to the General formula (I);

or R1means a radical -(CH2)w-N(Y)-(CH2)w-, in which Y is a radical

W" denotes O or S, and w is an integer from 2 to 3;

R2means a hydrogen atom or an alkyl or arylalkyl radical;

R3means a hydrogen atom or a halogen atom;

each of R4, R'4and R4independently means a hydrogen atom, alkyl radical, alkoxyalkyl radical, aryloxyalkyl radical, phenyl radical, with two deputies, which together form methylenedioxy or atlantooccipital, the radical-CH2-NR9R10the radical-CO-NR14R15or carbocyclic aryl or carbocyclic arylalkyl radical, possibly substituted from 1 to 4 times by substituents chosen independently from a halogen atom and alkiline is, haloalkylthio radical, alkoxy, haloalkoxy - or aryl radical,

or R4means radical

and R9whenever it occurs, is independently mean alkyl radical, and R10whenever it occurs, is independently means a hydrogen atom or alkyl radical, or R9and R10form together with the nitrogen atom a heterocycle with 4-7 chains containing from 1 to 2 heteroatoms, and links required for circuit heterocycle, independently selected from radicals-CR11R12-, -O-, -S-, and-NR13-, and R11and R12every time they meet, independently mean a hydrogen atom or an alkyl radical, and R13means alkyl or arylalkyl radical, or R13means phenyl radical, possibly substituted from 1 to 3 times by substituents chosen independently from a halogen atom and an alkyl radical or alkoxy,

and R14whenever it occurs, is independently mean alkyl radical, haloalkyl radical, cycloalkyl radical, cycloalkylcarbonyl radical, alkoxyalkyl radical, one of the carbocyclic or heterocyclic aryl radical or a carbocyclic or heterocyclic arylalkyl radical in which the aryl ring may substituted from 1 to 3 resumestate, selected independently from the group formed by halogen atom, alkyl radical, alkoxyalkyl, haloalkyl radical and radical-SO2-NH2,

or R14means radical

or R14means one of the radicals -(CH2)a-[O-(CH2)b]c-O-Alk, -(CH2)d-[O-(CH2)e]fNR16R17or -(CH2)g-A, where a, b and e each independently is an integer from 2 to 4, c is an integer from 1 to 4, f is an integer from 0 to 4, d is an integer from 2 to 12 (and preferably an integer from 2 to 8, in particular an integer from 2 to 6), and g denotes an integer from 1 to 12 (and preferably an integer from 1 to 8, in particular an integer from 1 to 6), Alk denotes an alkyl radical, R16means a hydrogen atom or alkyl, alkoxycarbonyl or alcoxycarbenium radical, R17means a hydrogen atom or an alkyl radical, and A means rich heterocycle comprising 1 to 2 heteroatoms, selected independently from O, N and S and which is connected with the group -(CH2)gthrough the link N or CH, with the specified rich heterocycle contains, in addition, from 2 to 6 additional units selected independently from-CHR18-, -CO-, -NR19-, -O - and-S-, and R18means a hydrogen atom or an alkyl radical, and R 19means a hydrogen atom, an alkyl radical or alkoxycarbonyl or alcoxycarbenium group,

and R15whenever it occurs, is independently means a hydrogen atom or an alkyl or arylalkyl radical, and R15can also mean a radical identical to R14when R14is a carbocyclic or heterocyclic alkyl, haloalkyl, alkoxyalkyl or arylalkyl radical, the aryl ring of which may substituted from 1 to 3 times by substituents chosen independently from the group formed by halogen atom, alkyl radical, alkoxyalkyl, haloalkyl radical and radical-SO2-NH2,

or R14and R15together with the nitrogen atom to which they are linked, form a saturated a heterocycle with 4-7 chains containing from 1 to 2 heteroatoms, and links required for circuit heterocycle, independently selected from radicals-CR20R21-, -O-, -S - and-NR22-, and R20and R21means a hydrogen atom or an alkyl or arylalkyl radical, and R22means-COR23or-SO2R24,

and R23means alkyl radical, a carbocyclic aryl radical, possibly substituted from 1 to 3 times by substituents chosen independently from the group formed by halogen atom, alkaline the radical and alkoxyalkyl, or R23means heterocyclic aryl radical or a saturated a heterocycle comprising 5-7 units and from 1 to 2 heteroatoms, selected independently from O, N and S (and, in particular, one of the radicals piperidine, piperazine derivatives, morpholine, thiomorpholine or 2-tetrahydrofuryl),

and R24means a hydrogen atom or an alkyl radical (and preferably an alkyl radical),

or, finally, R14and R15together with the nitrogen atom to which they are linked, form a heterocyclic aryl radical selected from the radicals

the aromatic ring of which may be from 1 to 3 times substituted by substituents selected independently from the group formed by alkyl radical and alkoxyalkyl;

provided that when R1means a radical -(CH2)w-N(Y)-(CH2)w-, W, W' and W" are the same (in other words, it means either O or S), R4, R'4and R4the same, and each of the nitrogen atoms adjacent to 1,3-benzothiazole-4,7-Dianova or 1,3-benzoxazole-4,7-Dianova cycle, attached in position 5 of the corresponding 1,3-benzothiazole-4,7-dinonogo or 1,3-benzoxazole-4,7-dinonogo cycle, or each attached at position 6 of the corresponding 1,3-benzothiazole-4,7-dinonogo or 1,3-benzoxazole-4,7-dinonogo cycle;

and their salts are strong inhibitor and phosphatase Cdc25 (and in particular, the phosphatase Cdc25C), making them suitable for use as anticancer agents.

Thus, the invention relates primarily to compounds of General formula(I)defined earlier, and to salts of such compounds.

Under cycloalkyl, unless otherwise specified, refers to cycloalkyl radical comprising from 3 to 7 carbon atoms.

Under carbocyclic or heterocyclic aryl refers to carbocyclic or heterocyclic system with 1-3 condensed cycles containing at least one aromatic cycle, and the system is called heterocyclic, when at least one of the cycles that it contains, includes at least one heteroatom (O, N, or S); when the carbocyclic or heterocyclic aryl radical is called substituted, if not further specified, this means that the specified carbocyclic or heterocyclic aryl radical substituted by from 1 to 3 times, preferably from 1 to 2 times, radical, different from the atom hydrogen, which, if not further specified, selected from a halogen atom and an alkyl or alkoxyalkyl; in addition, if not further specified, under the aryl is meant exclusively carbocyclic aryl.

Under arylalkyl within the present invention refers to alkyl-and the ilen radical.

Under-alkyl, unless specified optional, refers to a linear or branched alkyl radical comprising from 1 to 12 carbon atoms, preferably from 1 to 10 carbon atoms and more preferably 1 to 8 carbon atoms (and, in particular, from 1 to 6 carbon atoms).

Under linear or branched alkyl having from 1 to 6 carbon atoms, and includes, in particular, methyl, ethyl, sawn, ISO-propyl, boutigny, isobutylene, second-botilony and tert-boutigny, pentelenyi, neopentylene, isopentenyl, sexily, isohexyl radicals. Under haloalkyl understood, in particular, triptoreline radical. Under haloalkoxy understood, in particular, cryptomaterial. Under the carbocyclic aryl includes, in particular, phenyl and nattily radicals. Under arylalkyl understood, in particular, phenylalaline radicals, in particular benzyl radical. Under saturated cyclic carbon system comprising from 1 to 3 condensed cycles, independently selected from a 3-7-tier cycles are understood, in particular, cyclopropyl, cyclobutyl, tsiklogeksilnogo and adamantly radicals. Under the heterocyclic aryl, or heteroaryl, refers, in particular, thienyl, farnily, pyrrolidinyl, imidazolidinyl, diazolidinyl, oxazolidinyl and peredelnyj radicals. NAC is the end, under the halogen refers to fluorine atoms, chlorine, bromine or iodine.

Under the halogen or halogen atom refers to an atom of chlorine, bromine, fluorine or iodine.

Under alkoxy, if not specified optional, refers to a linear or branched alkoxyalkyl, numbering from 1 to 6 carbon atoms (and in particular from 1 to 4 carbon atoms).

Under haloalkyl refers to an alkyl radical in which at least one of the hydrogen atoms (and possibly all) substituted by halogen atom.

Under cycloalkylcarbonyl, alkoxyalkyl, haloalkyl and paloaltomedical understood accordingly cycloalkylcarbonyl, alkoxyalkyl, haloalkyl, haloalkoxy and arylalkyl radicals whose alkyl, cycloalkyl and aryl residues have the above values.

When you specify that a radical, possibly substituted from 1 to 4 times, it may preferably substituted from 1 to 3 times, more preferably possibly substituted 1 to 2 times and more preferably possibly replaced once.

Under salt compounds are understood to be the salt of the accession of the compounds with an organic or inorganic acid or, if necessary, with the base and, in particular, pharmaceutically acceptable salts of the compounds.

Under the pharmaceutically acceptable salt includes, in particular, salts attached to the I with inorganic acids, such as hydrochloride, bromohydrin, loggedout, sulfate, phosphate, diphosphate and nitrate or organic acids, such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluensulfonate, pamoate and stearate. In the scope of the present invention also includes, where applicable, the salts formed from bases such as sodium hydroxide or potassium. For other examples of pharmaceutically acceptable salts you can refer to the article "Salt selection for basic drugs",Int. J. Pharm.(1986),33, 201-217.

In certain cases, the compounds according to the present invention may contain asymmetric carbon atoms. Thus, the compounds according to the present invention have two possible enantiomeric forms, that is, the configuration of "R" and "S". The present invention includes both enantiomers and any combination of these forms, including racemic mixtures RS. For simplicity, when in the structural formula not specified any specific configuration, it should be understood that presents both enantiomeric forms and mixtures thereof.

As a General variant of the invention compounds of General formula(I)or their salts are those in which R1is not a radical -(CH2)w-N(Y)-(CH2)w-, and W and W' are the same, and R4and R'4the same; further, in the present description with the unity of General formula (I)in which R1is not a radical -(CH2)W-N(Y)-(CH2)W-, and W and W' are the same, and R4and R'4the same will be referred to as "compounds of General formula(I)D".

One particular aspect of this General variant of the invention relates to compounds of General formula(I)Din which each of W and W' means S, which further description will be referred to as "compounds of General formula(I)DS"and also to the salts of these compounds. The invention relates in particular to compounds of General formula(I)DSin which the link-N(R2)-R1-N(R2)- will be located so that it connects the provisions of 5 parts of 1,3-benzothiazole-4,7-dione, namely the compounds of the sub-option, the General formula(I)DS5

in which R1has the same meaning as the General formula(I)D,and R2, R3and R4have the same meaning as in the General formula(I)and to salts of these compounds. It relates also to compounds of General formula(I)DSin which the link-N(R2)-R1-N(R2located so that it connects positions 6 parts of 1,3-benzothiazole-4,7-dione, namely the compounds of the sub-option, the General formula(I)DS6

in which R1 has the same meaning as in General formula(I)Dand R2, R3and R4have the same meaning as in the General formula(I)and to salts of these compounds.

Another private aspect of this common variant of the invention relates to compounds of General formula(I)Din which each of W and W' means Of which further description will be referred to as "compounds of General formula(I)DO"and also to the salts of these compounds. The invention relates in particular to compounds of General formula(I)DOin which the link-N(R2)-R1-N(R2)- will be located so that it is connected position 5 parts of 1,3-benzoxazole-4,7-dione, namely the compounds of the sub-option, the General formula(I)DO5

in which R1has the same meaning as in General formula(I)Dand R2, R3and R4have the same meaning as in the General formula(I)and to salts of these compounds. It relates also to compounds of General formula(I)DOin which the link-N(R2)-R1-N(R2located so that it connects positions 6 parts of 1,3-benzoxazole-4,7-dione, namely the compounds of the sub-option, the General formula(I)DO6

in which R1has the same meaning as in General is ormula (I)Dand R2, R3and R4have the same meaning as in the General formula(I)and to salts of these compounds.

Another common variant of the invention compounds of General formula(I)or their salts are such compounds in which R1is the radical -(CH2)w-N(Y)-(CH2)W-later in the description of the compounds of General formula(I)where R1means a radical -(CH2)W-N(Y)-(CH2)W-will be called the "compounds of General formula(I)T".

One particular aspect of this General variant of the invention relates to compounds of General formula(I)Twhere each of W, W' and W" means S, which in the remainder of this description will be referred to as "compounds of General formula(I)TS"and also to the salts of these compounds. The invention relates in particular to compounds of General formula(I)TSin which the link-N(R2)-R1-N(R2located so that it connects the provisions of 5 parts of 1,3-benzothiazole-4,7-dione, namely the compounds of the sub-option, the General formula(I)S5

in which w, R2, R3and R4have the same meaning as in the General formula(I)and to salts of these compounds. It relates also to compounds of General formula(I)TSwhich is asuume link-N(R 2)-R1-N(R2located so that it connects positions 6 parts of 1,3-benzothiazole-4,7-dione, namely the compounds of the sub-option, the General formula(I)S6

in which R1has the same meaning as in General formula(I)Tand R2, R3and R4have the same meaning as in the General formula(I)and to salts of these compounds.

Another private aspect of this common variant of the invention relates to compounds of General formula(I)Twhere each of W, W' and W" means O that in the remainder of this description will be referred to as "compounds of General formula(I)THEN"and also to the salts of these compounds. The invention relates in particular to compounds of General formula(I)THENin which the link-N(R2)-R1-N(R2)- will be located so that it connects the provisions of 5 parts of 1,3-benzoxazole-4,7-dione, namely the compounds of the sub-option, the General formula(I)TO

in which w, R2, R3and R4have the same meaning as in the General formula(I)and to salts of these compounds. It relates also to compounds of General formula(I)DOin which the link-N(R2)-R1-N(R2located so that it connects positions 6 parts of 1,3-benzoxa the ol-4,7-dione, namely, the compounds of the sub-option, the General formula(I)TO

in which w, R2, R3and R have the same meaning as in the General formula(I)and to salts of these compounds.

According to another common variant of the invention compounds of General formula(I)or their salts are those in which R1is not a radical -(CH2)W-N(Y)-(CH2)W-and one of W and W' is O, and other means S and/or R4and R'4are different; hereinafter in this description of the compounds of General formula(I)where R1doesn't mean the radical -(CH2)W-N(Y)-(CH2)W-and one of W and W' is O, and other means S and/or R4and R'4are different, will be referred to as "compounds of General formula(I)DM".

Preferably the compounds of General formula(I)or their salts are those which possess at least one of the following characteristics:

- R1means one of the radicals-CH2-CR6R7-CH2-, -(CH2)m-X-(CH2)n-, -(CH2)p-[O-(CH2)q]r-O-(CH2)p-, -(CH2)s-CO-NR8-(CH2)r-or R1means a radical -(CH2)W-N(Y)-(CH2)W-;

- R2means a hydrogen atom or a methyl, ethyl or benzyl, R is dical;

- R3means a hydrogen atom or a halogen atom;

- each of R4, R'4and R4independently means a hydrogen atom, alkyl radical, -CO-NR14R15or carbocyclic aryl or carbocyclic arylalkyl radical, possibly substituted from 1 to 4 times by substituents chosen independently from a halogen atom and alkyl, haloalkyl, alkoxy, haloalkoxy - or aryl radical.

More preferably the compounds of General formula(I)or their salts are those which possess at least one of the following characteristics:

- R1means one of the radicals -(CH2)m-X-(CH2)n-or R1means a radical -(CH2)W-N(Y)-(CH2)W- (and w means preferably 2);

- R2means a hydrogen atom or a methyl radical;

- each of R4, R'4and R4independently means a hydrogen atom, alkyl radical, -CO-NR14R15or carbocyclic aryl or carbocyclic arylalkyl radical, possibly substituted from 1 to 4 times by substituents chosen independently from a halogen atom (from halogen substituents preferred fluorine atoms and alkyl, triptorelin, alkoxy, triptoreline or phenyl radical.

Even more preferred compounds of General is ormula (I)or their salts are those which have at least one of the following characteristics:

- R1means -(CH2)m-X-(CH2)n-;

- R2means a hydrogen atom.

Even more preferred compounds of General formula(I)or their salts are such that:

- R1means one of the radicals-CH2-CR6R7-CH2-, -(CH2)m-X-(CH2)n-, -(CH2)p-[O-(CH2)q]r-O-(CH2)p-, -(CH2)s-CO-NR8-(CH2)t-or R1means a radical -(CH2)W-N(Y)-(CH2)W-;

Even more preferred compounds of General formula(I)or their salts are such where:

- R1means -(CH2)m-X-(CH2)n-.

In addition, generally speaking, we prefer compounds of General formula(I)(or their salts)that have at least one of the following characteristics:

- X is-NR5or CR6R7-;

- R8means a hydrogen atom or a methyl radical;

- R14whenever it occurs, is independently mean alkyl radical, cycloalkyl radical, cycloalkylcarbonyl radical, alkoxyalkyl radical, one of the carbocyclic aryl or carbocyclic or heterocyclic arylalkyl radical, and the ilen ring which may be substituted by from 1 to 3 times by substituents, selected independently from the group formed by halogen atom, alkyl radical and alkoxyalkyl,

or R14means one of the radicals -(CH2)a-[O-(CH2)b]c-O-Alk, -(CH2)d-[O-(CH2)e]rNR16R17or -(CH2)g-A, where a, b and e each independently represents 2 or 3, c is an integer from 1 to 3, f is an integer from 0 to 3, d is an integer from 2 to 6, and g is an integer from 1 to 6, Alk denotes an alkyl radical, R16means a hydrogen atom or alkoxycarbonyl radical, R17means a hydrogen atom or a methyl radical, and A means rich heterocycle comprising 1 to 2 heteroatoms, selected independently from O, N and S, and connect with the group -(CH2)g- link N or CH, with the specified rich heterocycle contains, in addition, from 2 to 6 additional units selected independently from-CHR18-, -CO-, -NR19-, -O - and-S-, and R18means a hydrogen atom or a methyl radical, and R19means a hydrogen atom, an alkyl radical or alkoxycarbonyl group,

or R14means radical

and R15'every time it occurs, independently means a hydrogen atom or an alkyl or arylalkyl radical, and R15can also mean a radical, identifying the tion R 14when R14means alkyl, alkoxyalkyl or arylalkyl carbocyclic or heterocyclic radical, aryl ring which may substituted from 1 to 3 times by substituents chosen independently from the group formed by halogen atom, alkyl radical and alkoxyalkyl,

or R14and R15together with the nitrogen atom to which they are linked, form a saturated 4-7-tier a heterocycle containing from 1 to 2 heteroatoms, and links required for circuit heterocycle, independently selected from radicals-CR20R21-, -O-, -S - and-NR22-, and R20and R21means a hydrogen atom or an alkyl or arylalkyl radical, and R22means-COR23or-SO2R24,

and R23means alkyl radical, a carbocyclic aryl radical, possibly substituted from 1 to 3 times by substituents chosen independently from the group formed by halogen atom, alkyl radical and alkoxyalkyl, or R23means heterocyclic aryl radical or a saturated a heterocycle selected from the radicals piperidine, piperazine derivatives, morpholine, thiomorpholine and 2-tetrahydrofuryl,

R24means a hydrogen atom or an alkyl radical;

or R14and R15together with the nitrogen atom to which they are linked, form a heterocyclic is Riley radical type

the aromatic ring of which may be from 1 to 3 times substituted by substituents selected independently from the group formed by alkyl radical and alkoxyalkyl.

Generally speaking, even more preferred are such compounds of General formula(I)(or their salts)that have at least one of the following characteristics:

- X is-NR5-where R5means methyl or arylalkyl radical, possibly substituted by alkoxy group (particularly methoxy);

- R8means a hydrogen atom;

- R14whenever it occurs, is independently mean alkyl radical, cycloalkyl radical, cycloalkylcarbonyl radical, alkoxyalkyl radical, one of the carbocyclic aryl or carbocyclic or heterocyclic arylalkyl radical, aryl ring which may be substituted from 1 to 3 times by substituents chosen independently from the group formed by halogen atom, alkyl radical and alkoxyalkyl,

or R14means one of the radicals -(CH2)d-[O-(CH2)e]fNR16R17or -(CH2)g-A, in which e represents 2 or 3, f is an integer from 0 to 3, d is an integer from 2 to 6, and g is an integer from 1 to 6, R16means a hydrogen atom or alkoxycarbonyl the local radical (and, in particular, tert-butoxycarbonyl), R17means a hydrogen atom, and A means rich heterocycle comprising 1 to 2 heteroatoms, selected independently from O, N and S and attached to the group -(CH2)g- link N or CH, with the specified rich heterocycle contains, in addition, from 2 to 6 additional units selected independently from-CHR18-, -CO-, -NR19-, -O - and-S-, and R18means a hydrogen atom or a methyl radical, and R19means a hydrogen atom, an alkyl radical or alkoxycarbonyl group (and, in particular, tert-butoxycarbonyl),

or R14means radical

and R15whenever it occurs, is independently means a hydrogen atom, and R15can also mean a radical identical to R14when R14means alkyl, alkoxyalkyl or arylalkyl carbocyclic or heterocyclic radical, aryl ring which may be substituted by from 1 to 3 times by substituents chosen independently from the group formed by halogen atom, alkyl radical, alkoxy radical,

or R14and R15together with the nitrogen atom to which they are linked, form a saturated 4-7-tier a heterocycle containing from 1 to 2 heteroatoms, and links required for circuit heterocycle selected n is dependent from the radicals-CR 20R21-, -O-, -S - and-NR22-, and R20and R21means a hydrogen atom or an alkyl radical, and R22means-COR23or-SO2R24,

and R23means alkyl radical, a carbocyclic aryl radical, possibly substituted from 1 to 3 times by substituents chosen independently from the group formed by halogen atom, alkyl radical and alkoxyalkyl, or R23means heterocyclic aryl radical or a saturated a heterocycle selected from the radicals piperidine, piperazine derivatives, morpholine, thiomorpholine and 2-tetrahydrofuryl,

R24means a hydrogen atom or an alkyl radical;

or R14and R15together with the nitrogen atom to which they are linked, form a heterocyclic aryl radical type

the aromatic ring of which may be from 1 to 3 times substituted by substituents selected independently from the group formed by alkyl radical and alkoxylation, in particular methoxy.

Generally speaking, even more preferred are such compounds of General formula(I)(or their salts)that have at least one of the following characteristics:

- X is-NR5-where R5means a methyl radical;

- R14whenever it occurs, is independently mean alkyl radical, recloak the local radical, cycloalkylcarbonyl radical, alkoxyalkyl radical, one of the carbocyclic aryl or carbocyclic or heterocyclic arylalkyl radicals, aryl ring which may be substituted by from 1 to 3 times by substituents chosen independently from the group formed by halogen atom, alkyl radical and alkoxyalkyl,

or R14means one of the radicals -(CH2)d-[O-(CH2)e]rNR16R17or -(CH2)g-A, in which e represents 2 or 3, f is an integer from 0 to 3, d is an integer from 2 to 6, and g is an integer from 1 to 6, R16means a hydrogen atom or alkoxycarbonyl radical (and, in particular tert-butoxycarbonyl), R17means a hydrogen atom, and A means rich heterocycle comprising 1 to 2 heteroatoms, selected independently from O, N and S and attached to the group -(CH2)g- link N or CH, with the specified rich heterocycle contains, in addition, from 2 to 6 additional units selected independently from-CHR18-, -CO-, -NR19-, -O - and-S-, and R18means a hydrogen atom or a methyl radical, and R19means a hydrogen atom, an alkyl radical or alkoxycarbonyl group (and, in particular, tert-butoxycarbonyl),

or R14means radical

and R15whenever it occurs, is independently means a hydrogen atom,

or R14and R15together with the nitrogen atom to which they are linked, form a saturated 4-7-tier a heterocycle containing from 1 to 2 heteroatoms, and links necessary to complete the heterocycle, independently selected from radicals-CR20R21-, -O-, -S - and-NR22-, and R20and R21means a hydrogen atom or a methyl radical, and R22means-COR23or-SO2R24,

and R23means alkyl radical, a carbocyclic aryl radical, possibly substituted from 1 to 3 times by substituents chosen independently from the group formed by halogen atom, alkyl radical and alkoxyalkyl, or R23means heterocyclic aryl radical or a saturated a heterocycle selected from the radicals piperidine, piperazine derivatives, morpholine and 2-tetrahydrofuryl,

R24means a hydrogen atom or an alkyl radical (and, in particular, alkyl radical, in particular methyl);

or R14and R15together with the nitrogen atom to which they are linked, form a heterocyclic aryl radical type

aromatic ring which may be substituted by methoxylation.

Of the compounds of General formula(I)preferred, in particular, the following compounds, described in the examples:

-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione);

-5,5'-[(methylimino)bis(ethane-2,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione);

-5,5'-[oxybis(ethane-2,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione);

-5,5'-(pentane-1,5-diyldiamine)bis(2-methyl-1,3-benzothiazole-4,7-dione);

-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione);

-6,6'-[(methylimino)bis(ethane-2,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione);

-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis{4,7-dioxo-N-[3-(2-oxopyrrolidin-1-yl)propyl]-4,7-dihydro-1,3-benzothiazol-2-carboxamide};

-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(2,5-differenl)-1,3-benzoxazole-4,7-dione];

-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(3,5-dibromophenyl)-1,3-benzoxazole-4,7-dione];

-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(2-chloro-6-terbisil)-1,3-benzoxazole-4,7-dione];

-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(3-bromophenyl)-1,3-benzoxazole-4,7-dione];

-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(4-bromophenyl)-1,3-benzoxazole-4,7-dione];

-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(3,5-differenl)-1,3-benzoxazole-4,7-dione];

-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(3-chlorophenyl)-1,3-benzoxazole-4,7-dione];

-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(4-forfinal)-1,3-benzoxazole-4,7-dione];

-6,6'-[(methylimino)bis(n is open-3,1-diimino)]bis[2-(4-bromo-3-were)-1,3-benzoxazole-4,7-dione];

-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(6-bromo-2-methyl-1,3-benzothiazole-4,7-dione);

-5,5',5"-[nitrilotri(propane-3,1-diimino)]Tris(2-methyl-1,3-benzothiazole-4,7-dione);

-5,5'-(2,2-DIMETHYLPROPANE-1,3-diyldiamine)bis(2-methyl-1,3-benzothiazole-4,7-dione);

-5,5'-[cyclohexane-1,4-diylbis(methylaniline)]bis(2-methyl-1,3-benzothiazole-4,7-dione);

-5,5'-[1,3-phenylenebis(methylaniline)]bis(2-methyl-1,3-benzothiazole-4,7-dione);

-5,5'-[ethane-1,2-diylbis(oxypropane-3,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione);

-6,6'-{(methylimino)bis[propane-3,1-diyl(methylimino)]}bis[2-(2,5-differenl)-1,3-benzoxazole-4,7-dione];

-N3-[2-(2,5-differenl)-4,7-dioxo-4,7-dihydro-1,3-benzoxazol-6-yl]-N1-(3-{[2-(2,5-differenl)-4,7-dioxo-4,7-dihydro-1,3-benzoxazol-6-yl]amino}propyl)-β-alaninate;

-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(1,3-benzothiazole-4,7-dione);

-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(morpholine-4-ylcarbonyl)-1,3-benzothiazole-4,7-dione];

-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(2-{[4-(morpholine-4-ylcarbonyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione);

-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(2-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione);

-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(2-{[4-(methylsulphonyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione);

-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis[N-(4-methodology Setenil)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide];

-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(pyrrolidin-1-ylcarbonyl)-1,3-benzothiazole-4,7-dione];

-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis[N-(4-forfinal)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide];

-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis[N-(4-methoxybenzyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide];

-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis{2-[(6-methoxy-3,4-dihydroquinoline-1(2H)-yl)carbonyl]-1,3-benzothiazole-4,7-dione};

-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(N-cyclohexyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide);

-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(2-{[4-(4-methoxybenzoyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione);

-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(2-{[4-(2-furoyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione);

-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(2-naphthyl)-1,3-benzothiazole-4,7-dione];

-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(1,3-benzodioxol-5-yl)-1,3-benzothiazole-4,7-dione];

-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(4-ethylphenyl)-1,3-benzoxazole-4,7-dione];

-N-(4-methoxyphenyl)-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl] amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide;

-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-6-yl)amino]propyl}amino)propyl]amino}-2-{[4-(tetrahydrofuran-2-carbonyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione;

N-ethyl-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide;

-5-({3-[(3-{[4,7-dioxo-2-(pyrrolidin-1-ylcarbonyl)-4,7-dihydro-1,3-benzothiazol-6-yl]amino}propyl)(methyl)amino]propyl} amino)-2-methyl-1,3-benzothiazole-4,7-dione;

-N-(4-methoxybenzyl)-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide;

-N-1,3-benzodioxol-5-yl-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide;

-2-[(6-methoxy-3,4-dihydroquinoline-1(2H)-yl)carbonyl]-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-1,3-benzothiazole-4,7-dione;

-2-{[4-(4-methoxybenzoyl)piperazine-1-yl]carbonyl}-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-1,3-benzothiazole-4,7-dione;

-5-({3-[(3-{[2-(4-methoxyphenyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-6-yl]amino}propyl)(methyl)amino]propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione;

-5-({3-[{3-[(4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}(methyl)amino]propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione;

-2-(2,5-differenl)-6-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amine is}-1,3-benzoxazole-4,7-dione;

-2-(4-ethylphenyl)-6-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-1,3-benzoxazole-4,7-dione;

-2-(2,5-differenl)-6-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-6-yl)amino]propyl}amino)propyl]amino}-1,3-benzoxazole-4,7-dione;

-5,5'-[[(4-methoxybenzyl)imino]bis(propane-3,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione);

-5,5'-[(methylimino)bis(butane-4,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione);

-2-methyl-5-{[3-(methyl{4-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]butyl}amino)propyl]amino}-1,3-benzothiazole-4,7-dione;

and salts of these compounds.

The invention relates also to the above-mentioned compounds of General formula(I)or their pharmaceutically acceptable salts as a drug.

The object of the invention is also pharmaceutical compositions containing as active substance a compound of General formula(I)or pharmaceutically acceptable salt of such a compound, with at least one pharmaceutically acceptable excipient.

Another object of the invention is the use of compounds of General formula(I)or their pharmaceutically acceptable salts for obtaining a medicinal product intended for the treatment of diseases/disorders, selected from the following diseases/disorders: proliferative tumor is new diseases (and, in particular, cancer), non-tumorous proliferative diseases, neurodegenerative diseases, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products, alopecia, caused by the radiation, autoimmune diseases, transplant rejection, inflammatory diseases and allergies.

In particular, compounds of General formula(I)or their pharmaceutically acceptable salts can be used to produce a medicinal product intended for the treatment of cancer, in particular breast cancer, lymphomas, cancer of the head and neck, lung cancer, colorectal cancer, prostate cancer and pancreatic cancer.

The invention relates, furthermore, to a method for treatment of one of these diseases/disorders, and these methods include the introduction of a patient suffering from the specified disease/specified disorder, a therapeutically effective amount of compounds of General formula(I)or pharmaceutically acceptable salts of such compounds.

Assume that the preferences indicated for the compounds of General formula(I)and their salts, applicable, with necessary changes, to the compounds of General formulas(I)D,(I)DS,(I)DS5(I)DS6(I)DO(I)DO5(I)DO6 (I)T(I)TS(I)TS5(I)TS6,(I)TO(I)TO5(I)TOor(I)DMand to medicines, pharmaceutical compositions and use according to the invention relating to the compounds and their pharmaceutically acceptable salts.

Pharmaceutical compositions containing a compound according to the invention can be in solid form, for example in the form of powders, granules, tablets, gelatin capsules, liposomes or suppositories. Suitable solid foundations can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine and wax.

Pharmaceutical compositions containing a compound according to the invention can also be in liquid form, for example in the form of solutions, emulsions, suspensions or syrups. Suitable liquid foundations can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.

The administration of a medicinal product according to the invention can be produced by topical, oral, parenteral, by intramuscular injection, etc.

Injected dose envisaged for drug agreement is but the invention, is from 0.1 mg to 10 g depending on the type of active connections.

According to the invention compounds of General formula(I)can be obtained by methods described below.

Obtaining compounds of General formula (I)

The following methods of obtaining given as an illustration and are not limiting.

Common methods

i) compounds of General formula(I)Din which R5is not arylalkyl:

Compounds of General formula(I)Din which R3means a hydrogen atom, and W, R2and R4are as previously defined, and R1such as defined previously, but where R5is not arylalkyl radical, can be obtained by the following method shown below in scheme 1.

Scheme 1

According to this method, compounds of General formula(I)in which R1, R2, R4and W such as described above, is obtained by treatment of compounds of General formula(A)amines of General formula R2HNR1Other2(hereinafter amines of General formula(B)in proton solvent such as methanol or ethanol, at a temperature, preferably component from 20°C to 80°C, and optionally in the presence of a base, such as diisopropylethylamine (Yasuyuki Kita al.,i> J. Org. Chem.(1996),61, 223-227).

ii) compounds of General formula(I)T:

Compounds of General formula(I)Tin which R3means a hydrogen atom, and W, R1, R2and R4such as previously defined, can be obtained by the method shown below in scheme 1.2. The reaction conditions are similar to conditions used for the synthesis presented in scheme 1.

Scheme 1.2

iii) compounds of General formula(I)Dor(I)Tin which R3is a halogen atom:

Generally speaking, the compounds of General formula(I)in which R3is a halogen atom (Hal)can be obtained (scheme 1.3, which shows only getting halogenated compounds of General formula(I)D), proceeding from compounds of General formula(I)in which R3means a hydrogen atom, for example, under the action of N-chlorosuccinimide or N-bromosuccinimide, in a suitable aprotic solvent such as dichloromethane or tetrahydrofuran (Paquette and Farley,J. Org. Chem. (1967),32, 2725-2731), under the action of an aqueous solution of sodium hypochlorite (Saveleva water) in a solvent such as acetic acid (Jagadeesh al.,Synth. Commun. (1998),28, 3827-3833), under the action of Cu(II) (a mixture of CuCl2/HgCl2) when heated in the presence of catalytic what about the amount of iodine in such a solvent, as acetic acid, (Thapliyal,Synth. Commun. (1998),28, 1123-1126), under the action of the agent, such as dichloroiodate designed in the presence of NaHCO3in a solvent such as a mixture of dichloromethane/methanol (Kordik and Reitz,J Org. Chem. (1996),61, 5644-5645), or when using chlorine, bromine or iodine in a solvent such as dichloromethane (J. Renault, S. Giorgi-Renault al.,J. Med. Chem. (1983),26, 1715-1719).

Scheme 1.3

iv) compounds of General formula(I)DMor compounds of General formula(I)where R5means arylalkyl radical:

iv.a) compounds of General formula(I)DMin which R1is -(CH2)s-CO-NR8-(CH2)rand if R1means -(CH2)m-X-(CH2)n-, then m = n, and R5is not arylalkyl radical:

Compounds of General formula(I)DMin which R2, R3, R4, R'4W and W' such as described above, and R1such as defined above, but is not -(CH2)s-CO-NR8-(CH2)t-and if R1means -(CH2)m-X-(CH2)n-, then m = n, and R5is not arylalkyl radical, can be obtained by the method shown below in scheme 1.4.

Scheme 1.4

According to this method connected the General formula I (I)DMproduced by processing the intermediate products of General formula(A)the stoichiometric quantity or a large excess of diamine of General formula(B)in proton solvent such as methanol or ethanol, at a temperature, preferably component from 20°C to 80°C, followed by treatment of the stoichiometric quantity of intermediate products of General formula(A'),such that R'4differs from R4and/or W differs from W', in the same conditions.

iv.b) compounds of General formula(I)DMwhere, if R1means -(CH2)m-X-(CH2)n-, m ≠ n, or R5means arylalkyl radical, and compounds of General formula(I)Dwhere, if R1means -(CH2)m-X-(CH2)n-, R5means arylalkyl:

Compounds of General formula(I)DMin which R2, R3, R4, R'4W and W' such as described above, and in which, if R1means -(CH2)m-X-(CH2)n-, m ≠ n, or R5means arylalkyl can be obtained by the method shown below in scheme 1.5. Compounds of General formula(I)Din which W, R2and R4such as previously defined, and such that if R1means a radical -(CH2)m-X-(CH2)n-, and X is-NR5-, R5oz ACHAT arylalkyl radical, possibly substituted, can be obtained by the method shown below in scheme 1.5 (in this case W = W' and R4= R4').

Scheme 1.5

According to this method, compounds of General formula(I)DMor(I)Dget nucleophilic substitution of the intermediate product of General formula(A.e)carrying a leaving group Z, such as methanesulfonate or toluensulfonate group, or halogen atom such as a bromine atom in the intermediate product of General formula(A.c),in the presence of a base, such as diisopropylethylamine, in a polar solvent, such as dimethylformamide. The intermediate products of General formula(A.c)get in the same conditions by nucleophilic substitution of intermediate products of General formula(A.b)primary amines of General formula R5NH2. The intermediate products of General formula(A.b)and(AU)receive, based on the intermediate products of General formula(A)and(A')accordingly, by reaction with amines of General formula other2-(CH2)m-Br and other2-(CH2)n-Br, respectively, in proton polar solvent, such as methanol, in the presence of a base, such as triethylamine, at a temperature, preferably component from 20°C to 80°C. the Intermediate products of the soup formula (A.b)and(A.e)can also be obtained from the intermediates of General formula(A.A.)and(A.d)accordingly, by reaction with para-toluensulfonate, for example, pyridine or dichloromethane in the presence of triethylamine. The intermediate products of General formula(A.A.)and(A.d)receive processing intermediates of General formula(A)and(A'),accordingly, the amines of General formula other2-(CH2)m-OH and other2-(CH2)n-OH, respectively, in proton solvent such as methanol or ethanol, at a temperature, preferably component from 20°C to 80°C.

iv.c) compounds of General formula(I)DMin which R1means -(CH2)s-CO-NR8-(CH2)tis:

Compounds of General formula(I)DMin which R2, R3, R4, R'4W and W' such as described above, and R1means -(CH2)s-CO-NR8-(CH2)t-can be obtained by the method shown below in scheme 1.6.

Scheme 1.6

According to this method, compounds of General formula(I)DMget treatment of compounds of General formula(A')amines of General formula(A.j)in proton solvent such as methanol or ethanol, at a temperature, preferably component from 20°C to 80°C. for Yourself intermediate about UKTI General formula (A.j)obtained after the removal of protection for the terminal amino group by a method known to the expert, from the intermediate products of General formula(A)that result in a reaction with amines of General formula(A.g)in the above-described conditions. The intermediate products of General formula(A.g)get classical methods of peptide binding and subsequent selective removal of protection from urethane groups, also traditional for the specialist.

The intermediate products of General formula(A)and(A'):

Since the compounds of General formula(A')are the same as compounds of General formula(A)below will be presented only obtain compounds of General formula(A).

i) W stands for a sulfur atom:

When W stands for a sulfur atom, compounds of General formula(A)in which R4has the same meaning as in General formula(I)can be obtained (scheme 2) by oxidation of compounds of General formula(A.ii)in which one of Q and Q' means an amino radical and the other denotes a hydrogen atom. Compounds of General formula(A.ii)obtained from compounds of General formula(A.i)in which one of V and V' means the nitro radical and the other denotes a hydrogen atom, after nitrogroup reduction under the action of hydrogen in the presence of palladium on coal or under the action of chloride of tin.

Scheme 2

Compounds of General formula(A.i)can be synthesized by methods already known to the expert (see, for example, patent application PCT WO 03/055868), or may be obtained according to the methods presented below in the schema.

When the compounds of General formula(A.i)these are that the methoxy group is in position 5 benzothiazoline ring receiving them can be carried out by the method shown below in scheme 3. According to this method 5-methoxy-1,3-benzothiazol-2-amine (purchase) convert the Sandmeyer method known to the expert, 2-bromo-5-methoxy-1,3-benzothiazole, which nitrous by the well-known specialist methods to obtain 2-bromo-5-methoxy-4-nitro-1,3-benzothiazole. The intermediate product of General formula(A.i)get in this case, by condensation with boric acid according to the method of Suzuki, a renowned specialist.

Scheme 3

When the compounds of General formula(A.i)are such that the methoxy group is in position 6 benzothiazoline cycle, obtaining them can be carried out by the method shown below in scheme 3.2. According to this method 6-methoxy-1,3-benzothiazol-2-amine (purchase) convert the Sandmeyer method known to the expert, 2-bromo-6-methoxy-1,3-benzothiazole, which nitrous by the well-known specialist of the method is m, to obtain 2-bromo-6-methoxy-7-nitro-1,3-benzothiazole. The intermediate product of General formula(A.i)get in this case, by condensation with boric acid according to the method of Suzuki, a renowned specialist.

Scheme 3.2

In the particular case when R4means the radical-CO-NR14R15intermediate products of General formula(A.i)can be obtained (scheme 4) from compounds of General formula(A.iii)in which V and V' such as defined above, and amines of General formula R14R15NH, using the classic conditions of peptide synthesis (M. Bodansky, The Practice of Peptide Synthesis, 145 (Springer - Verlag, 1984)), for example, in dichloromethane in the presence of coupling reagent such as hexaphosphate bromo-Tris-pyrrolidinone (PyBroP), in the presence of dimethylaminopyridine (DMAP) (Coste al.,Tetrahedron Lett. (1990),31, 669), or mixed (dimethylformamide/dichloromethane/dioxane: 1/1/1) in the presence of hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, diisopropylethylamine and catalytic amounts of dimethylaminopyridine, or through the formation of the intermediate carboxylic acid, obtained by adding a solution of oxalicacid in dichloromethane. With regard to compounds of General formula(A.iii)then they get oxidation carboxaldehyde General formula(A.iv)under the action of an oxidant, such voltage is emer, as sodium chlorite, in a buffer solution of sodium hydrogen phosphate (pH 3.5) and in aqueous solution of tert-butanol in the presence of 2-methyl-2-butene; and these aldehydes of General formula(A.iv)produced by oxidation of compounds of General formula(A.v)under the action of, for example, oxide of selenium in 1,4-dioxane at 80°C (Bu al.,J. Med. Chem.(2001),44, 2004-2014). Finally, compounds of General formula(A.v)in which V and V' such as defined above, can be obtained by methods already known to the expert (see, for example, patent application PCT WO 03/055868).

Scheme 4

In the particular case when R4means H, the intermediate products of General formula(A)can be obtained by decarboxylation of the intermediate products of General formula(A.iii)after heating for 2 hours at a temperature of from 40°C to 80°C, in an organic solvent such as dichloromethane or acetonitrile.

In the particular case when R4means the radical-CH2-NR9R10intermediate products of General formula(A.i)can be obtained (scheme 5) from compounds of General formula(A.vi)in which V and V' such as defined above, and amines of General formula R9R10NH, in a polar solvent in the presence of a base, such as diisopropylethylamine, and catalytic amounts of sodium iodide. Connect the texts of General formula (A.vi)get nitration by classical methods known to the expert, intermediate products of General formula(A.vii), which are obtained from compounds of General formula(A.viii), which are subjected to a radical reaction of the synthesized using N-bromosuccinimide in the presence of an initiator, such as 2,2'-azobis(2-methylpropionitrile) or Dibenzoyl peroxide, in an aprotic solvent such as carbon tetrachloride (CCl4), at a temperature, preferably component from the ambient temperature (i.e. approximately 25°C) to 80°C, and the irradiation of a UV lamp (Mylari al.,J. Med. Chem. (1991),34, 108-122).

Scheme 5

ii) W denotes an oxygen atom:

When W denotes an oxygen atom, compounds of General formula(A)in which R4has the same meaning as in General formula(I)can be obtained (scheme 6) by oxidation of compounds of General formula(A.ix)in which one of Q and Q' means an amino radical and the other denotes a hydrogen atom, or one of Q and Q' represents a hydroxyl radical, and the other a hydrogen atom by methods known to the expert (see, for example, patent application PCT WO 03/055868). Themselves compounds of General formula(A.ix)obtained by condensation of compounds of General formula(A.x)in which Q and Q' have the same meanings as above, for example, thioimidate General the formula (C)in proton solvent such as ethanol, at a temperature of from 25°C to the boiling point of the solvent (according to the method described, in particular, S. Rostamizadeh al.J. Chem Res. Synop,6, (2001), 227-228).

Scheme 6

Compounds of General formula(A.x)can be obtained by methods known to the expert, presented below in schemes 6.2 and 6.3.

When the compounds of General formula(A.ix)these are that the methoxy group is in position 5 benzoxazole cycle, obtaining compounds of General formula(A.x)can be carried out by the method shown below in scheme 6.2. According to this method 4-methoxy-2,6-dinitrophenol (described, in particular, P. Cotelle and J.-P. Catteau,Synth. Commun.,26, (1996), 4105-4112) restore, for example, under the action of hydrogen in the presence of palladium on charcoal, to obtain the corresponding compound of General formula(A.x).

Scheme 6.2

When the compounds of General formula(A.ix)these are that the methoxy group is in position 6 benzoxazole cycle, obtaining compounds of General formula(A.x)can be carried out by the method shown below in scheme 6.3. According to this method 5-methoxy-2-nitro-resorcinol (described, in particular, J.F. Grove al.J Chem. Soc.(1956), 1956-1963) restore, for example, the od action of hydrogen in the presence of palladium on charcoal, to obtain the corresponding compound of General formula(A.x).

Scheme 6.3

Preparation of amines of General formula(B):

Amines of General formula (B) are commercially available or can be easily obtained at the normal specialist methods.

EXAMPLES

As for the temperatures, which are given in the present text, the term "about XX°C" means that the temperature corresponds to the interval of plus or minus 10°C from the temperature XX°C, preferably to an interval of plus or minus 5°C from the temperature XX°C.

Unless otherwise noted, all used here is the technical and scientific terms have the same value, which is usually understood by a person skilled normal level in the area that includes the present invention.

The following examples are given to illustrate the above methods and in no way should be construed as limiting the scope of invention.

The melting temperature were measured using capillary installation Büchi 535.

NMR spectra were recorded using a spectrometer Bruker ARX 400. The chemical shift is expressed in parts per million (ppm) relative to tetramethylsilane (TMS), and the multiplicity of the signals is indicated as s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet).

The method used to determine in which the time of retention (t.r.) and molecular peak (MM+)

The compounds are characterized by their retention time (t.r.), expressed in minutes, determined by liquid chromatography (LC), and their molecular peak (MH+) determined by mass spectrometry (MS), uses a simple quadrupole mass spectrometer (Micromass, model Platform)equipped with a source of electrocapillary, with permission from 0.8 to 50% of the minimum point.

For the following examples 1-56 elution conditions corresponding to the above results, are as follows: elution with a mixture of acetonitrile-water-triperoxonane acid 50-950-0,2 (A) for 1 minute, then transfer mixture from (A) to a mixture of acetonitrile-water 950-50 (B) with a linear gradient over a period of 7.5 minutes, then elution of the pure mixture B for 2 minutes.

Example 1: 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione):

of 83.4 mg (or 0.57 mmol; 0.6 equivalent) of N-(3-aminopropyl)-N-methylpropan-1,3-diamine is added to 200 mg (0.95 mmol) of 5-methoxy-2-methyl-4,7-dioxopentanoate dissolved in 15 ml of anhydrous ethanol. The reaction mixture was stirred at 60°C for 2 hours, then the solvent is evaporated under reduced pressure. The residue is purified on a column of silica gel (eluent: 3%methanol in dichloromethane) and receive 30 mg (yield = 36%) of the expected product in the form of a red powder. Melting point: 94-96°C.

1H-NMR (DMSO d6, 400 MHz, δ) to 7.93 (t, 2H, 2NH); of 5.40 (s, 2H, 2CH); 3,20-3,15 (m, 4H); of 2.72 (s, 6H, 2CH3); 2,40-is 2.37 (m, 4H); 2,17 (s, 3H, CH3); 1,76-of 1.73 (m, 4H).

MS-LC: MH+ = 500,15; t.r. = 7,49 minutes

The compounds of examples 2-4 are obtained in a manner analogous to the method of example 1, and N-(3-aminopropyl)-N-methylpropan-1,3-diamine replace the corresponding amine.

Example 2: 5,5'-[(methylimino)bis(ethane-2,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione):

Red powder. Melting point: 188-190°C.

1H-NMR (DMSO d6, 400 MHz, δ): to 7.32 (t, 2H, 2NH); 5,43 (s, 2H, 2CH); 3,23-3,19 (m, 4H); of 2.72 (s, 6H, 2CH3); 2,66-2,62 (m, 4H); 2,31 (s, 3H, CH3).

MS-LC: MH+ = 472,18; t.r. = 7,31 minutes

Example 3: 5,5'-[oxybis(ethane-2,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione):

Red powder.

1H-NMR (DMSO d6, 400 MHz, δ): 7,53 (t, 2H, 2NH); of 5.50 (s, 2H, 2CH); 3,66-to 3.64 (m, 4H, 2CH2); 3,30 to be 3.29 (m, 4H, 2CH2); to 2.74 (s, 6H, 2CH3).

MS-LC: MH+ = 459,06; t.r. = 8,20 minutes

Example 4: 5,5'-(pentane-1,5-diyldiamine)bis(2-methyl-1,3-benzothiazole-4,7-dione):

Red powder.

1H-NMR (DMSO d6, 400 MHz, δ): 7,74 (t, 2H, 2NH); the 5.45 (s, 2H, 2CH); 3,17-of 3.12 (m, 4H, 2CH2); to 2.74 (s, 6H, 2CH3); 1,61-of 1.56 (m, 4H, 2CH2); of 1.36 and 1.33 (m, 2H, CH2).

MS-LC: MH+ = 457,11; t.r. = 8,97 minutes

The compounds of examples 5 and 6 were obtained in a manner analogous to the methods used to example 1, and 5-methoxy-2-methyl-4,7-dioxopentanoate replacing 6-methoxy-2-methyl-4,7-dioxopentanoate and, in addition, in the case of example 6 N-(3-aminopropyl)-N-meth is propan-1,3-diamine replace the corresponding amine.

Example 5: 6,6'-[(methylimino)bis(propane-3,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione):

Red powder. Melting point: 91-93°C.

1H-NMR (DMSO d6, 400 MHz, δ): 7,80 (t, 2H, 2NH); of 5.34 (s, 2H, 2CH); 3,20-3,15 (m, 4H); was 2.76 (s, 6H, 2CH3); 2,39-is 2.37 (m, 4H); 2,17 (s, 3H, CH3); 1,76-of 1.73 (m, 4H).

MS-LC: MH+ = 500,35; t.r. = 7,43 minutes

Example 6: 6,6'-[(methylimino)bis(ethane-2,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione):

Red powder.

1H-NMR (DMSO d6, 400 MHz, δ): 7,13 (t, 2H, 2NH); lower than the 5.37 (s, 2H, 2CH); 3,23-3,19 (m, 4H); 2,77 (s, 6H, 2CH3); 2,66-2,61 (m, 4H); 2,32 (s, 3H, CH3).

MS-LC: MH+ = 472,30; t.r. = 7,17 minutes

Compounds of examples 7-16 obtained in a manner analogous to the methods used to example 1, and 5-methoxy-2-methyl-4,7-dioxopentanoate replace the corresponding quinone.

Example 7: 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis{4,7-dioxo-N-[3-(2-oxopyrrolidin-1-yl)propyl]-4,7-dihydro-1,3-benzothiazol-2-carboxamide}:

Red powder. Melting point: 185-186°C.

1H-NMR (DMSO d6, 400 MHz, δ): 9,11 (t, 2H, 2NH); 8,18 (t, 2H, 2NH); 5,54 (C 2H5 2CH); 3,37-3,18 (m, 16H); 2.40 a (m, 4H); 2,22 (m, 4H); to 2.18 (s, 3H, CH3); of 1.92 (m, 4H); of 1.74 (m, 8H).

MS-LC: MH+ = 808,51; t.r. = to 7.61 minutes

Example 8: 6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(2,5-differenl)-1,3-benzoxazole-4,7-dione]:

Red powder. Melting point: 209-210°C.

1H-NMR (DMSO d6, 400 MHz, δ): 8,00 (m, 2H, H-arene.); of 7.82 (m, 2H, 2NH); 7,55 is 7.50 (4H, H-arene.); 5,31 (s, 2H, CH); 3,22-3,19 (m, 4H); 2,48 is 2.44 (m, 4H); 2,22 (s, 3H, CH3); 1,80-to 1.77 (m, 4H).

MS-LC: MH+ = 664,40; t.r. = 8,81 minutes

Example 9: 6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(3,5-dibromophenyl)-1,3-benzoxazole-4,7-dione]:

Red powder. Melting point: 227-228°C.

1H-NMR (CF3COOD, 400 MHz, δ): 7,94 (m, 4H, H-arene.); of 7.69 (m, 2H, H-arene.); 4,94 (s, 2H, 2CH); 3,34-of 3.27 (m, 6H); 3,20-3,13 (m, 2H); 2,84 (s, 3H, CH3); 2,17-to 2.06 (m, 4H).

MS-LC: MH+ = 903,90; t.r. = 10,11 minutes

Example 10: 6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(2-chloro-6-terbisil)-1,3-benzoxazole-4,7-dione]:

Red powder. Melting point: 165-167°C.

1H-NMR (DMSO d6, 400 MHz, δ): 7,87 (t, 2H, 2NH); of 7.48-7,39 (m, 4H, H-arene.); 7,34-7,29 (m, 2H, H-arene.); the 5.25 (s, 2H, 2CH); to 4.46 (s, 4H, 2CH2); 3,18-3,13 (m, 4H); 2,38-of 2.36 (m, 4H); of 2.15 (s, 3H, CH3); 1,73 is 1.70 (m, 4H).

MS-LC: MH+ = 724,44; t.r. = 9,13 minutes

Example 11: 6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(3-bromophenyl)-1,3-benzoxazole-4,7-dione]:

Red powder. Melting point: 199-200°C.

1H-NMR (DMSO d6, 400 MHz, δ): 8,08-8,00 (m, 6H, H-arene.); 7,81-7,79 (m, 2H, H-arene.); 7,54 is 7.50 (m, 2H, 2NH); from 5.29 (s, 2H, 2CH); 3,21-and 3.16 (m, 4H); to 2.42 (m, 4H); of 2.20 (s, 3H, CH3); 1,80-to 1.77 (m, 4H).

MS-LC: MH+ = 748,21; t.r. = 9,37 minutes

Example 12: 6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(4-bromophenyl)-1,3-benzoxazole-4,7-dione]:

Red powder. Melting point: 233-234°C.

1H-NMR (CF3COOD, 400 MHz, δ): 7,76-7,74 (m, 4H, H-arene.); 7,49-7,47 (m, 4H, H-arene.); 3,34-3,26 (m, 6H); 3,20-of 3.12 (m, 2H); 2,8 (s, 3H, CH3); 2,13-to 2.06 (m, 4H).

MS-LC: MH+ = 748,22; t.r. = 9,20 minutes

Example 13: 6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(3,5-differenl)-1,3-benzoxazole-4,7-dione]:

Red powder.

1H-NMR (DMSO d6, 400 MHz, δ): 8,20-8,17 (m, 2H); to 7.61-7,58 (m, 4H); 7,52-7,47 (m, 2H); 5,31 (s, 2H, 2CH); 3,21-3,17 (m, 4H); 2,44-to 2.41 (m, 4H); of 2.20 (s, 3H, CH3); 1,82 to 1.76 (m, 4H).

MS-LC: MH+ = 664,30; t.r. = 9,06 minutes

Example 14: 6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(3-chlorophenyl)-1,3-benzoxazole-4,7-dione]:

Red powder. Melting point: 196-197°C.

1H-NMR (DMSO d6, 400 MHz, δ): 8,00-to 7.95 (m, 6H, H-arene.); 7,68-7,66 (m, 2H, H-arene.); 7,58 (t, 2H, 2NH); from 5.29 (s, 2H, 2CH); 3,21-and 3.16 (m, 4H); 2,43 (m, 4H); of 2.21 (m, 3H, CH3); 1,80-to 1.77 (m, 4H).

MS-LC: MH+ = 660,26; t.r. = 9,11 minutes

Example 15: 6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(4-forfinal)-1,3-benzoxazole-4,7-dione]:

Red powder. Melting point: 204-205°C.

1H-NMR (DMSO d6, 400 MHz, δ): 8,10-of 8.06 (m, 4H, H-arene.); of 7.96 (t, 2H, 2NH); 7,41-7,37 (m, 4H, H-arene.); 5,28 (s, 2H, 2CH); 3,21-and 3.16 (m, 4H); 2,44 (m, 4H); of 2.21 (m, 3H, CH3); 1,80-to 1.77 (m, 4H).

MS-LC: MH+ = 628,32; t.r. = 8,70 minutes

Example 16: 6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(4-bromo-3-were)-1,3-benzoxazole-4,7-dione]:

Red powder.

MS-LC: MH+ = 776,17; t.r. = 9,76 minutes

Example 17: 5,5'-[(methylimino)bis(propane-3,1-diimino)] bis(6-bromo-2-methyl-1,3-benzothiazole-4,7-dione):

70 mg (0.2 mmol) of the compound of example 1 dissolved in 10 ml of acetic acid. Add mg (4.4 mmol; 2.2 EQ.) N-bromosuccinimide and the reaction mixture is stirred for 1 hour at ambient temperature. After concentration under reduced pressure the residue is purified by chromatography on a column of silica gel (eluent: dichloromethane/methanol 95/5) after the introduction of ethyl ether and filtration get the desired product in the form of a purple powder.

1H-NMR (DMSO d6, 400 MHz, δ): to 7.99 (s, 2H, 2NH); 3,83-with 3.79 (m, 4H); of 2.72 (s, 6H, 2CH3); 2,47 is 2.44 (m, 4H); 2,19 (s, 3H, CH3); of 1.78 (m, 4H).

MS-LC: MH+ = 655,96; t.r. = 7,83 minutes

The compound of example 18 is obtained by the method similar to the methods used to example 1, substituting N-(3-aminopropyl)-N-methylpropan-1,3-diamine corresponding triamine.

Example 18: 5,5',5"-[nitrilotri(propane-3,1-diimino)]Tris(2-methyl-1,3-benzothiazole-4,7-dione):

Red powder. Melting point 131-132°C.

1H-NMR (DMSO d6, 400 MHz, δ): 7,84-7,81 (m, 3H); 5,38 (s, 3H); 3,18-3,13 (m, 6H); a 2.71 (s, 9H, 3CH3); 2,49 at 2.45 (m, 6H); 1,79-of 1.74 (m, 6H).

MS-LC: MH+ = 720,24; t.r. = 7,70 minutes

Compounds of examples 19-22 obtained in a manner analogous to the methods used to example 1, and N-(3-aminopropyl)-N-methylpropan-1,3-diamine replace the corresponding diamine.

Example 19: 5,5'-(2,2-DIMETHYLPROPANE-1,3-diyldiamine)bis(2-methyl-1,3-benzothiazole-4,7-dione):

Red powder.

MS-LC: MH+ = 457,17; t.r. = 8,88 minutes

Example 20: 5,5'-[cyclohexane-1,4-diylbis(methylaniline)]bis (methyl-1,3-benzothiazole-4,7-dione):

Red powder. Melting point > 240°C.

The compounds of examples 23 and 24 obtained in a manner analogous to the methods used to example 1, and N-(3-aminopropyl)-N-methylpropan-1,3-diamine replace the corresponding diamine and 5-methoxy-2-methyl-4,7-dioxopentanoate replace 2-(2,5-differenl)-6-methoxy-1,3-benzoxazole-4,7-dione.

Example 23: 6,6'-{(methylimino)bis[propane-3,1-diyl(methylimino) ]}bis[2-(2,5-differenl)-1,3-benzoxazole-4,7-dione]:

Dark purple powder.

1H-NMR (DMSO d6, 400 MHz, δ): a 7.85-7,81 (m, 2H); EUR 7.57-of 7.48 (m, 4H); 5,49 (s, 2H); 3,66-3,63 (m, 4H); a 3.06 (s, 6H, 2CH3); 2,33-to 2.29 (m, 4H); of 2.09 (s, 3H, CH3); 1,78-of 1.74 (m, 4H).

MS-LC: MH+ = 692,34; t.r. = 8,76 minutes

Example 24: N3-[2-(2,5-differenl)-4,7-dioxo-4,7-dihydro-1,3-benzoxazol-6-yl]-N1-(3-{[2-(2,5-differenl)-4,7-dioxo-4,7-dihydro-1,3-benzoxazol-6-yl]amino}propyl)-β-alaninemia:

Red powder.

MS-LC: MH+ = 664,29; t.r. = 9,90 minutes

Example 25: 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(1,3-benzothiazole-4,7-dione):

25.1) 5-methoxy-4-nitro-1,3-benzothiazole:

25.1.1) 5-methoxy-4-nitro-1,3-benzothiazole-2-carbaldehyde:

12.8 g (0,115 mol; 6 equivalents) of selenium dioxide are added to 4,34 g (19,3 mmol) 5-methoxy-2-methyl-4-nitro-1,3-benzothiazole, dissolved in 180 ml of anhydrous dioxane. The reaction mixture was stirred at 80°C for 18 hours, then dissolved fraction otfit byvaut and the solvent is evaporated under reduced pressure. The expected aldehyde obtained as a yellow oil and purified on a column of silica gel (eluent: ethyl acetate/heptane: gradient from 30% to 70%). Melting point: 154-155°C.

1H-NMR (DMSO d6, 400 MHz, δ): 10,06 (s, 1H, CHO); charged 8.52-8,49 (d, 1H, H-arene); 7,80 for 7.78 (d, 2H, H-arene); Android 4.04 (s, 3H, OCH3).

25.1.2) 5-methoxy-4-nitro-1,3-benzothiazole-2-carboxylic acid:

A solution of 18 g of sodium chlorite and 18 g of sodium hydrogen phosphate in 180 ml of water are added dropwise in the remainder carbaldehyde entered in 420 ml of tert-butanol and 100 ml of 2-methyl-but-2-ene. The reaction mixture continued to stir for 18 hours at ambient temperature, then dissolved fraction is filtered, introduced into water and the resulting aqueous solution is acidified with 1M hydrochloric acid. The precipitate is filtered and washed with water. Acid is obtained in the form of a beige powder (m = 3.12 g; yield = 64%). Melting point: 140-142°C.

1H-NMR (DMSO d6, 400 MHz, δ): 8,45-8,43 (d, 1H, H-arene); 7,74-7,71 (d, 1H, H-arene); 3,99 (s, 3H, CH3).

MS-LC: MH+ = 254,99; t.r. = 8,20 minutes

25.1.3) 5-methoxy-4-nitro-1,3-benzothiazole:

3 g (to 11.8 mmol) 5-methoxy-4-nitro-1,3-benzothiazole-2-carboxylic acid are suspended in 200 ml of dichloromethane and warm at 60°C for 2 hours. Dichloromethane is evaporated under reduced pressure. 5-methoxy-4-nitro-1,3-benzothiazole obtained as a beige powder (m = 2 g; yield = 80%).

1H-NMR (DMSO d6, 40 MHz, δ): at 9.53 (s, 1H); 8,35 (d, 1H); of 7.60 (s, 1H).

MS-LC: MH+ = 211,01; t.r. = of 9.30 minutes

25.2) 5-methoxy-1,3-benzothiazole-4-amine:

730 mg (3.5 mmol) of 5-methoxy-4-nitro-1,3-benzothiazole was dissolved in 50 ml of methanol and added 73 mg (10%) palladium on coal to the reaction mixture, which was stirred at a hydrogen pressure of 2.5 bar for 18 hours. The catalyst is filtered off, then the solvent is evaporated under reduced pressure. Get 248 mg (yield = 40%) of 5-methoxy-1,3-benzothiazole-4-amine, which is used in the next step without additional purification.

MS-LC: MH+ = 181,08; t.r. = 7,97 minutes

25.3) 5-methoxy-1,3-benzothiazole-4,7-dione:

of 1.34 g (2.5 mmol; 1.8 equivalent) salt Free (nitrosodimethyl potassium, containing from 25 to 50% of water and methanol), dissolved in 40 ml of 0.3 m solution of sodium hydrogen phosphate, are added to a solution of 248 mg (1.4 mmol) of 5-methoxy-1,3-benzothiazole-4-amine in 9 ml of acetone. The reaction mixture was stirred at ambient temperature for 3 hours, then concentrated under reduced pressure. Educated product 3 times extracted with 50 ml dichloromethane and the aqueous phase is washed with 50 ml saturated aqueous solution of sodium chloride. The organic phases are combined, dried over sodium sulfate and the solvent is evaporated under reduced pressure. Get 248 mg (yield = 91%) of 5-methoxy-1,3-benzothiazole-4,7-dione, which is used in the next step without complement Inoi cleanup.

MS-LC: MH+ = 196,05; t.r. = 7,65 minutes

25.4) 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(1,3-benzothiazole-4,7-dione):

57 μl (from 0.37 mmol; 0,48 equivalent) of N-(3-aminopropyl)-N-methylpropan-1,3-diamine is added to 150 mg (0.77 mmol) of 5-methoxy-1,3-benzothiazole-4,7-dione, dissolved in 6 ml of ethanol. The reaction mixture was stirred at 85°C for 90 minutes, then the solvent is evaporated under reduced pressure and the expected product is purified by chromatography on a column of silica gel (eluent: a mixture of dichloromethane/methanol 94/6) and obtain 95 mg (yield = 26%) of 5,5'-[(methylimino)bis(propane-3,1-diimino)] bis(1,3-benzothiazole-4,7-dione) as a red powder. Melting point: p.223-224°C.

1H-NMR (DMSO d6, 400 MHz, δ): 9.28 are (s, 2H); 8,02 (t, 2H, 2NH); of 5.48 (s, 2H); 3.24 in-3,19 (m, 4H); 2,42-of 2.38 (m, 4H); to 2.18 (s, 3H, CH3); 1,78-of 1.74 (m, 4H).

MS-LC: MH+ = 472,19; t.r. = 7,32 minutes

Example 26: 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis [2-(morpholine-4-ylcarbonyl)-1,3-benzothiazole-4,7-dione]:

26.1) 5-methoxy-4-nitro-1,3-benzothiazole-2-carboxylic acid:

26.1.1) 5-methoxy-4-nitro-1,3-benzothiazole-2-carbaldehyde:

The experiment described in step 25.1.1 example 25.

26.1.2) 5-methoxy-4-nitro-1,3-benzothiazole-2-carboxylic acid:

The experiment described in step 25.1.2 example 25.

26.2) 5-methoxy-2-(morpholine-4-ylcarbonyl)-1,3-benzothiazole-4,7-dione:

26.2.1) 5-methoxy-2-(morpholine-4-ylcarbonyl)-4-who and Jethro-1,3-benzothiazole:

To 500 mg (1.97 mmol) of 5-methoxy-4-nitro-1,3-benzothiazole-2-carboxylic acid and 344 μl (1.97 mmol; 1 EQ.) diisopropylethylamine dissolved in 40 ml of dichloromethane, add 980 mg (2.1 mmol; 1.1 EQ.) hexaphosphate bromo-Tris-pyrrolidinone (PyBroP). The reaction mixture is stirred for 15 minutes at ambient temperature, then 202 μl (2.3 mmol; 1.2 EQ.) the research and dimethylaminopyridine on the tip of a spatula add in an environment that continues to be stirred for 18 hours at ambient temperature. Then filter out the undissolved fraction and the solvent is evaporated under reduced pressure. Then the residue purified on a column of silica gel (eluent: ethyl acetate/heptane: gradient from 30 to 70% for 40 minutes, then for 5 minutes at 70% ethyl acetate in heptane) and obtain 210 mg (yield = 33%) of the expected product in the form of a beige powder.

MS-LC: MH+ = 324,01; t.r. = 9,63 minutes

26.2.2) 5-methoxy-2-(morpholine-4-ylcarbonyl)-1,3-benzothiazole-4-amine:

To 210 mg (of 0.65 mmol) 5-methoxy-2-(morpholine-4-ylcarbonyl)-4-nitro-1,3-benzothiazole, dissolved in 10 ml of methanol, add 20 mg of 10%palladium on charcoal. Then the reaction mixture was put mixed for 18 hours in a hydrogen atmosphere. Then the catalyst is filtered off and the solvent is evaporated. Obtain 173 mg of the expected product (yield gross = 91%) as yellow is the asle, which is used in the next step without additional purification.

MS-LC: MH+ = 294,04; t.r. = a 9.09 minutes

26.2.3) 5-methoxy-2-(morpholine-4-ylcarbonyl)-1,3-benzothiazole-4,7-dione:

A solution of 570 mg (1,063 mmol; 1.8 EQ.) salt Free (nitrosodimethyl potassium, containing from 25 to 50% of water and methanol) in 0.3 m aqueous solution of sodium hydrogen phosphate (12 ml) was added dropwise to 173 mg (0.6 mmol) of 5-methoxy-2-(morpholine-4-ylcarbonyl)-1,3-benzothiazole-4-amine, dissolved in 5 ml of acetone. The reaction mixture was stirred at ambient temperature for 4 hours, then the acetone is evaporated and the environment injected in 10 ml of dichloromethane and washed 2 times with 7 ml of a saturated aqueous solution of sodium chloride. The organic phases are combined, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. Get 175 mg (yield gross = 99%) of the expected product in the form of a yellow powder, which is used in the next step without additional purification.

MS-LC: MH+ = 308,99; t.r. = 8,40 minutes

26.3) 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(morpholine-4-ylcarbonyl)-1,3-benzothiazole-4,7-dione]:

51 μl (0.32 mmol; 0.5 equivalent) of N-(3-aminopropyl)-N-methylpropan-1,3-diamine is added to 200 mg (of 0.65 mmol) 5-methoxy-2-(morpholine-4-ylcarbonyl)-1,3-benzothiazole-4,7-dione, dissolved in 15 ml of ethanol. The reaction mixture was stirred at 85°C for 2 hours, then the solvent of viparita the t under reduced pressure and the expected product is purified by chromatography on a column of silica gel (eluent: a mixture of dichloromethane/methanol 95/5), then recrystallization in a mixture of acetone and ethyl ether and receive a 110 mg (yield = 24%) of 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(morpholine-4-ylcarbonyl)-1,3-benzothiazole-4,7-dione] in the form of a red powder. Melting point = 207-208°C.

1H-NMR (DMSO d6, 400 MHz, δ): 8,17 (m, 2H, 2NH); 5,52 (s, 2H, 2CH); of 4.25 (m, 4H); of 3.69 (m, 12H); 3,25-3,20 (m, 4H); to 2.42 (m, 4H); of 2.20 (s, 3H, CH3); 1,79 to 1.76 (m, 4H).

MS-LC: MH+ = 698,30; t.r. = 7,66 minutes

Connection examples 27-37 obtained in a manner analogous to the methods used to example 26, substituting in the third stage morpholine appropriate amine and replacing the first stage in example 31 5-methoxy-2-methyl-4-nitro-1,3-benzothiazole, replacing 6-methoxy-2-methyl-7-nitro-1,3-benzothiazole.

Example 27: 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis (2-{[4-(morpholine-4-ylcarbonyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione):

Red powder. Melting point = 157-158°C.

1H-NMR (DMSO d6, 400 MHz, δ): 8,19 (t, 2H, 2NH); 5,52 (s, 2H, 2CH); 4,24 (m, 4H); 3,68 (m, 4H); 3,57 (m, 10H); 3,25-up 3.22 (m, 4H); 3,21-3,20 (m, 4H); 3,18-and 3.16 (m, 10H); 3,44-to 3.41 (m, 4H); of 2.20 (s, 3H, CH3); 1,79 to 1.76 (m, 4H).

MS-LC: MH+ = 922,43; t.r. = 7,60 minutes

Example 28: 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis (2-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione):

Red powder. Melting point 152-153°C.

1H-NMR (DMSO d6, 400 MHz, δ): 8,20 (t, 2H, 2NH); 5,52 (s, 2H, 2CH); 4,70 (t, 2H); 4,40-4,10 (m, 4H); 3,80-3,50 (m, 16H); 3,28-3,2 (m, 4H); 2,43-to 2.40 (m, 4H); of 2.20 (s, 3H, CH3); 2,03 is 2.01 (m, 4H); 1,84 to 1.76 (m, 8H).

MS-LC: MH+ 892,56; t.r. = 7,58 minutes

Example 29: 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis (2-{[4-(methylsulphonyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione):

Red powder.

MS-LC: MH+ = 852,42; t.r. = 7,89 minutes

Example 30: 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis[N-(4-methoxyphenyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide]:

Red powder.

MS-LC: MH+ = 770,38; t.r. 8,87 minutes

Example 31: 6,6'-[(methylimino)bis(propane-3,1-diimino)]bis [2-(pyrrolidin-1-ylcarbonyl)-1,3-benzothiazole-4,7-dione]:

Red powder. Melting point = 237-238°C.

1H-NMR (DMSO d6, 400 MHz, δ): to $ 7.91 (t, 2H, 2NH); the 5.45 (s, 2H, 2CH); 3,98 (t, 4H); of 3.54 (t, 4H); 3,20-3,18 (m, 4H); 2.40 a (t, 4H); to 2.18 (s, 3H, CH3); 1,97-of 1.94 (m, 4H); 1,87-of 1.84 (m, 4H); 1,78-of 1.74 (m, 4H).

MS-LC: MH+ = 666,32; t.r. = to $ 7.91 minutes

Example 32: 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis [N-(4-forfinal)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide]:

Red powder. Melting point = 262-263°C.

1H-NMR (DMSO d6, 400 MHz, δ): 11,00 (s, 2H, 2NH); compared to 8.26 (t, 2H, 2NH); a 7.85-of 7.82 (m, 4H); 7,20-to 7.15 (m, 4H); to 5.56 (s, 2H, 2CH); 3,25 is 3.23 (m, 4H); 2,44-to 2.41 (m, 4H); of 2.20 (s, 3H, CH3); 1,81-of 1.78 (m, 4H).

MS-LC: MH+ = 746,27; t.r. = 9,15 minutes

Example 33: 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis [N-(4-methoxybenzyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide]:

Red powder. Melting point = 174-175°C.

1NMR (DMSO d6, 400 MHz, δ): 9,63 (t, 2H, 2NH); 8,18 (t, 2H, 2NH); 7,27-of 7.25 (d, 4H); 6,88-6,85 (d, 4H); 5,54 (s, 2H, 2CH); 4,37 is 4.35 (d, 4H); 3,71 (s, 6H, 2CH3); 3,24-3,20 (m, 4H); 2,41-of 2.38 (m, 4H); 2,17 (s, 3H, CH3); 1,77-of 1.74 (m, 4H).

MS-LC: MH+ = 798,46; t.r. = 8,89 minutes

Example 34: 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis {2-[(6-methoxy-3,4-dihydroquinoline-1(2H)-yl)carbonyl]-1,3-benzothiazole-4,7-dione}:

Red powder. Melting point = 159-160°C.

1H-NMR (DMSO d6, 400 MHz, δ): 8,15 (m, 2H, 2NH); 6,79 of 6.68 (m, 6H); 5,52 (s, 2H, 2CH); 4,15-4,12 (m, 4H); and 3.72 (s, 6H, 2CH3); 3,24-3,20 (m, 4H); 2,81-2,77 (m, 4H); 2,42-2,39 (m, 4H); 2,19 (s, 3H, CH3); 2,00 is 1.91 (m, 4H); 1,78 is 1.75 (m, 4H).

MS-LC: MH+ = 650,48; t.r. = 9,12 minutes

Example 35: 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis (N-cyclohexyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide)

Red powder. Melting point = 145-146°C.

1H-NMR (DMSO d6, 400 MHz, δ): 8,90-8,88 (d, 2H, 2NH); 8,19 (t, 2H, 2NH); 5,54 (s, 2H, 2CH); 3.75 to and 3.72 (m, 2H); 3.25 to 3,20 (m, 4H); 2,42-2,39 (m, 4H); to 2.18 (s, 3H, CH3); 1,78-1,71 (m, 12H); 1,61-of 1.07 (m, 12H).

MS-LC: MH+ = 722,51; t.r. = 9,14 minutes

Example 36: 5,5'-[(methylimino)bis(propane-3,1-diimino)]bis (2-{[4-(4-methoxybenzoyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione):

Red powder. Melting point = 202-203°C.

1H-NMR (DMSO d6, 400 MHz, δ): 8,18 (t, 2H, 2NH); 7,43-7,41 (m, 4H); 7,00-6,98 (m, 4H); the 5.51 (s, 2H, 2CH); 4,29-4,47 (m, 4H); 3,79 (s, 6H, 2CH3); to 3.73-and 3.72 (m, 4H); 3,64-3,62 (m, 8H); 3,24-3,19 (m, 4H); 2,43-to 2.40 (m, 4H); 2,19 (s, 3H, CH3); 1,79 is 1.75 (m, 4H).

MS-LC: MH+ = 964,50; t.r. = at 8.36 minutes

Example 37: 5,5'-(methylimino)bis(propane-3,1-diimino)]bis(2 -{[4-(2-furoyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione):

Red powder. Melting point = 173-174°C.

1H-NMR (DMSO d6, 400 MHz, δ): 8,20 (t, 2H, 2NH); a 7.85 (s, 2H); 7,06 (s, 2H); only 6.64 (s, 2H); of 5.53 (s, 2H, 2CH); 4,33-4,32 (m, 4H); 3,82-of 3.77 (m, 12H); 3.25 to is 3.21 (m, 4H); 2,44-to 2.41 (m, 4H); of 2.20 (s, 3H, CH3); 1,79 to 1.76 (m, 4H).

MS-LC: MH+ = 884,37; t.r. = 8,04 minutes

The compound of example 38 obtained in a manner analogous to the methods used to example 26, the latter stage 5-methoxy-2-(morpholine-4-ylcarbonyl)-1,3-benzothiazole-4,7-dione replacing 6-methoxy-2-(2-naphthyl)-1,3-benzothiazole-4,7-dione.

Example 38: 6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2 -(2-naphthyl)-1,3-benzothiazole-4,7-dione]:

Red powder.

MS-LC: MH+ = 724,40; t.r. = to 9.57 minutes

Example 39: 6,6'-[(methylimino)bis(propane-3,1-diimino)]bis [2-(l,3 - benzodioxol-5-yl)-1,3-benzothiazole-4,7-dione]:

39.1) 2-(1,3-benzodioxol-5-yl)-6-methoxy-1,3-benzothiazole-4,7-dione:

39.1.1) of 2-bromo-6-methoxy-1,3-benzothiazol-2-amine:

20 g (111 mmol) of 6-methoxy-1,3-benzothiazol-2-amine are dissolved in 400 ml of acetonitrile, then 13,2 ml (111 mmol; 1 equivalent) of nitrite, tert-butyl and 29 g (130 mmol; 1.2 equivalents) CuBr2add in the reaction medium, which is then stirred at 80°C for 2 hours. The solvent is evaporated under reduced pressure, then the residue is introduced into 250 ml ethyl acetate and washed 2 times with 200 ml of water. The organic phase is dried over sodium sulfate, then the solvent is evaporated under reduced giving the situation and get 24 g (yield = 89%) of 2-bromo-6-methoxy-1,3-benzothiazol-2-amine, which is used without additional purification in the next step.

MS-LC: MH+ = 243,98; t.r. = 10,89 minutes

39.1.2) of 2-bromo-6-methoxy-7-nitro-1,3-benzothiazole:

24 g (100 mmol) of 2-bromo-6-methoxy-1,3-benzothiazol-2-amine are dissolved in 30 ml of sulfuric acid at 0°C, then added dropwise 30 ml of nitric acid (density of 1.41). Stirred for 30 minutes at 0°C, then 1 hour at ambient temperature. After neutralization of the reaction mixture is 35% (13,5M) solution of soda formed product 3 times extracted with 100 ml dichloromethane. The organic phase is dried over sodium sulfate, then the solvent is evaporated under reduced pressure and the thus obtained solid substance is injected in dichloromethane, filtered and washed with a mixture of dichloromethane/heptane 1:1. The mother liquor is purified by chromatography on a column of silica gel (eluent: a mixture of ethyl acetate/heptane 1:1). Get to 9.9 g (yield = 35%) of 2-bromo-6-methoxy-7-nitro-1,3-benzothiazole in the form of orange powder.

MS-LC: MH+ = 288,75; t.r. = 10,70 minutes

39.1.3) 2-(1,3-benzodioxol-5-yl)-6-methoxy-7-nitro-1,3-benzothiazole:

To a suspension of 1.1 g (3,82 mmol) of 2-bromo-6-methoxy-7-nitro-1,3-benzothiazole and 133 mg (0,115 mmol; 0.03 equivalent) tetrakis-triphenylphosphine in 30 ml of 1,2-dimethoxyethane add 0,697 g (4.2 mmol; 1.1 equivalents) of 1,3-benzodioxol-5-yl-boronic acid and a solution of 1.2 g (11,35 mmol; 3 equivalents) CT is onata of sodium in 15 ml of water. The reaction mixture was stirred at 90°C for 4 hours, then after concentration under reduced pressure was added 100 ml of ethyl acetate in the medium, which is then washed 2 times with 75 ml saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, then the solvent is evaporated under reduced pressure and the residue purified by chromatography on a column of silica gel (eluent: a mixture of ethyl acetate/heptane 1:2). Get 0,960 g (yield 76%) of 2-(1,3-benzodioxol-5-yl)-6-methoxy-7-nitro-1,3-benzothiazole in the form of a beige powder.

MS-LC: MH+ = 331,06; t.r. = 11,38 minutes

39.1.4) 2-(1,3-benzodioxol-5-yl)-6-methoxy-1,3-benzothiazol-7-amine:

Suspended 0.96 g (2.9 mmol) of 2-(1,3-benzodioxol-5-yl)-6-methoxy-7-nitro-1,3-benzothiazole in 100 ml of methanol. 96 mg (10%) palladium on coal added to the reaction mixture, which was stirred at a hydrogen pressure of 2.5 bar for 18 hours. The catalyst is filtered off, then the solvent is evaporated under reduced pressure. Obtain 0.45 g (yield = 52%) of 2-(1,3-benzodioxol-5-yl)-6-methoxy-1,3-benzothiazol-7-amine, which is used in the next step without additional purification.

MS-LC: MH+ = 301,10; t.r. = 10,48 minutes

39.1.5) 2-(1,3-benzodioxol-5-yl)-6-methoxy-1,3-benzothiazole-4,7-dione:

1.45 g (2.7 mmol; 1.8 equivalent) salt Free dissolved in 45 ml of a 0.3 m solution of sodium hydrogen phosphate, is added to 0.45 g (1.5 mmol) of 2-(1,3-b is zodiacal-5-yl)-6-methoxy-1,3-benzothiazol-7-amine, dissolved in 15 ml of acetone. The reaction mixture was stirred at ambient temperature for 5 hours, then concentrated under reduced pressure. Educated product 3 times extracted with 50 ml dichloromethane and the aqueous phase is washed with 50 ml saturated aqueous solution of sodium chloride. The organic phases are combined, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The expected product is purified by chromatography on a column of silica gel (eluent: a mixture of dichloromethane/methanol 95:5). Obtain 0.2 g (yield = 43%) of 2-(1,3-benzodioxol-5-yl)-6-methoxy-1,3-benzothiazole-4,7-dione as a yellow powder.

MS-LC: MH+ = 316,07; t.r. = 10,14 minutes

39.2) 6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(1,3-benzodioxol-5-yl)-1,3-benzothiazole-4,7-dione]:

The experiment is the same as described for example 26, and at the last stage 5-methoxy-2-(morpholine-4-ylcarbonyl)-1,3-benzothiazole-4,7-dione to replace 2-(1,3-benzodioxol-5-yl)-6-methoxy-1,3-benzothiazole-4,7-dione.

Red powder.

MS-LC: MH+ = 712,45; t.r. = 8,57 minutes

The compound of example 40 receives a manner analogous to the methods used to example 1, and 5-methoxy-2-methyl-4,7-dioxopentanoate replace 2-(4~ethylphenyl)-6-methoxy-1,3-benzoxazole-4,7-dione.

Example 40: 6,6'-[(methylimino)bis(propane-3,1-diimino)]bis [2-(4-ethylphenyl)-1,3-benzoxazole-4,7-dione]:

Red p is rosak. Melting point = 216-217°C.

1H-NMR (CF3COOD, 400 MHz, δ): 7,88-7,86 (d, 4H); 7.24 to 7,22 (m, 4H); 3,33-of 3.31 (m, 6H); 3,19-3,14 (m, 2H); and 2.83 (s, 3H, CH3); 2.57 m) is 2.51 (q, 4H, 2CH2); 2,13-of 2.09 (m, 4H); 1,06-of 1.02 (t, 6H, 2CH3).

MS-LC: MH+ = 648,35; t.r. = 8,81 minutes

Example 41: N-(4-methoxyphenyl)-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino) propyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide:

41.1) 5-({3-[(3-aminopropyl)(methyl)amino]propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione:

Dissolve 1.6 g (of 7.65 mmol) 5-methoxy-2-methyl-1,3-benzothiazole-4,7-dione in 250 ml of dichloromethane. Add 6,17 ml (to 38.3 mmol, 5 equivalents) of N-(3-aminopropyl)-N-methylpropan-1,3-diamine and the reaction mixture is stirred for 2 hours at ambient temperature, then washed 3 times with 100 ml of water. The organic phase is again combined, dried over sodium sulfate and the solvent is evaporated under reduced pressure.

Get the desired product as a red oil, which is used in the next step without additional purification.

1H-NMR (DMSO d6, 400 MHz, δ): the 5.45 (s, 1H); 3,21-3,17 (t, 2H); to 2.75 (s, 3H, CH3); 2,72-2,61 (m, 2H); 2,37-of 2.30 (m, 4H); to 2.13 (s, 3H, CH3); 1,73 was 1.69 (m, 2H); 1,55-of 1.52 (m, 2H).

MS-LC: MH+ = 323,21; t.r. = minutes of 6.96

41.2) 5-methoxy-N-(4-methoxyphenyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide:

The experiment is the same as described for stage 26.2.1 and morpholine substituted 4-(methoxyphenyl) - amine.

1H-NMR (DMSO d6, 400 MHz, δ): 11,03 (s, 1H, NH); 7,79 to 7.75 (d, 2H); 6,97-6,93 (d, 2H); 6,37 (s, 1H); 3,90 (s, 3H, CH3); of 3.75 (s, 3H, CH3).

MS-LC: MH+ = 345,08; t.r. = 10,07 minutes

41.3) N-(4-methoxyphenyl)-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl] amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide:

5-({3-[(3-aminopropyl)(methyl)amino]propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione is dissolved in 250 ml of ethanol and add 2,12 g (6,16 mmol; 0.8 equivalent) of 5-methoxy-N-(4-methoxyphenyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazole-2-carboxamide. The reaction mixture was stirred at 60°C for 4 hours, then the solvent is evaporated under reduced pressure. Then the resulting residue is purified by chromatography on a column of silica gel (eluent: dichloromethane/methanol: 95/5) and obtain 450 mg (yield = 9%) of N-(4-methoxyphenyl)-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazole-2-carboxamide in the form of a red powder. Melting point = 141-142°C.

1H-NMR (DMSO d6, 400 MHz, δ): 10,87 (s, 1H, NH); compared to 8.26 (t, 1H, NH); a 7.92 (t, 1H, NH); 7,78-to 7.77 (d, 2H); 6,97-to 6.95 (d, 2H); to 5.56 (s, 1H); of 5.39 (s, 1H); 3,76 (s, 3H, CH3); at 3.25-3.15 in (2m, 4H); to 2.67 (s, 3H, CH3); 2,43-of 2.38 (m, 4H); to 2.18 (s, 3H, CH3); 1,79 is 1.75 (m, 4H).

MS-LC: MH+ = 635,21; t.r. = 8,31 minutes

Translation methanesulfonate:

In the experiment using methods known to the expert.

Converted into a salt compound precipitates in the form of a red powder.

Connection examples 42-48 obtained in a manner analogous to the methods used to example 41, and the first step of example 42 5-methoxy-2-methyl-1,3-benzothiazole-4,7-dione substituted 6-methoxy-2-methyl-1,3-benzothiazole-4,7-dione and at the second stage, 4-(methoxyphenyl)amine replace the corresponding amine.

Example 42: 5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-6-yl)amino]propyl}amino)propyl]amino}-2-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione:

Red powder. Melting point = 121-122°C.

1H-NMR (DMSO d6, 400 MHz, δ): 8,24 (m, 1H, NH); for 7.78 (t, 1H, NH); of 5.53 (s, 1H); 5,31 (s, 1H); 4,70 (t, 1H); 4,18 is 4.35 (m, 2H); 3,55-of 3.80 (m, 8H); 3,24-3,16 (2m, 4H); 3,03-to 2.99 (m, 4H); a 2.75 (s, 3H, CH3); 2,42-to 2.40 (m, 4H); to 2.18 (s, 3H, CH3); 2,08-to 1.98 (m, 2H); 1,78 to 1.76 (m, 2H).

MS-LC: MH+ = 696,40; t.r. = 7,49 minutes

Example 43: N-ethyl-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide:

Red powder. Melting point = 107-108°C.

1H-NMR (DMSO d6, 400 MHz, δ): 9,16 (t, 1H, NH); 8,17 (t, 1H, NH); to 7.93 (t, 1H, NH); of 5.53 (s, 1H); of 5.40 (s, 1H); 3,22-3,19 (m, 4H); 3,01-to 2.99 (m, 2H); 2.71 to (s, 3H, CH3); 2,42-to 2.40 (m, 2H); to 2.18 (s, 3H, CH3); 1,77-1,72 (m, 6H); of 1.13 (t, 3H, CH3).

MS-LC: MH+ = 557,15; t.r. = 7,68 minutes

Example 44: 5-({3-[(3-{[4,7-dioxo-2-(pyrrolidin-1-ylcarbonyl)-4,7-dihydro-1,benzothiazol-6-yl]amino}propyl)(methyl)amino]propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione:

Red powder.

1H-NMR (DMSO d6, 400 MHz, δ): a 7.92 (t, 1H, NH); of 7.75 (t, 1H, NH); of 5.48 (s, 1H); of 5.39 (s, 1H); 4,00 (t, 2H); 3,55 (t, 2H); 3,21-3,15 (m, 4H); a 2.71 (s, 3H, CH3); 2,42-to 2.40 (m, 4H); to 2.18 (s, 3H, CH3); 1,98-of 1.93 (m, 2H); 1,90-of 1.84 (m, 2H); 1,78 is 1.75 (m, 4H).

MS-LC: MH+ = 583,27; t.r. = 7,74 minutes

Example 45: N-(4-methoxybenzyl)-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino) propyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide:

Red powder.

1H-NMR (DMSO d6, 400 MHz, δ): 9,65 (t, 1H, NH); 8,17 (t, 1H, NH); 7,94 (t, 1H, NH); 7,28-7,26 (d, 2H); 6.89 in-6,87 (d, 2H); of 5.53 (s, 1H); of 5.40 (s, 1H); to 4.38-4,37 (d, 2H, CH2); and 3.72 (s, 3H, CH3); 3,22-3,18 (m, 4H); 3,01-to 2.99 (m, 2H); 2,69 (s, 3H, CH3); 2,42-to 2.40 (m, 2H); to 2.18 (s, 3H, CH3); 1,77-1,72 (m, 6H).

MS-LC: MH+ = 649,31; t.r. = 8,28 minutes

Example 46: N-1,3-benzodioxol-5-yl-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide:

Red powder.

MS-LC: MH+ = 649,36; t.r. = 8,42 minutes

Example 47: 2-[(6-methoxy-3,4-dihydroquinoline-1(2H)-yl)carbonyl]-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-1,3-benzothiazole-4,7-dione:

Red powder.

MS-LC: MH+ = 675,33; t.r. = 8,40 minutes

Example 48: 2-{[4-(4-methoxybenzoyl)piperazine-1-yl]carbonyl}-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-1,3-benzothiazole-4,7-dione:

1H-NMR (DMSO d6, 400 MHz, δ): compared to 8.26 (t, 1H, NH); 7,89 (t, 1H, NH); 7,44-7,42 (d, 2H); 7,01-of 6.99 (d, 2H); 5,52 (s, 1H); are 5.36 (s, 1H); 4,28-4,27 (m, 2H); of 3.80 (s, 3H, CH3); 3,74-to 3.64 (m, 4H); 3,22-3,14 (m, 6H); 2,69 (s, 3H, CH3); 2,44-to 2.40 (m, 4H); 2,19 (s, 3H, CH3); 1,78 is 1.75 (m, 4H).

MS-LC: MH+ = 732,32; t.r. = 8,01 minutes

Example 49: 5-({3-[(3-{[2-(4-methoxyphenyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-6-yl]amino}propyl)(methyl)amino]propyl} amino)-2-methyl-1,3-benzothiazole-4,7-dione:

49.1) 6-methoxy-2-(4-methoxyphenyl)-1,3-benzothiazole-4,7-dione:

The experiment is the same as described for intermediate example 39.1, and 1,3-benzodioxol-5-Voronova acid at the third stage is replaced by 4-methoxyphenylacetic acid.

MS-LC: MH+ = 302,10; t.r. = 10,29 minutes

49.2) 5-({3-[(3-{[2-(4-methoxyphenyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-6-yl]amino}propyl)(methyl)amino]propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione:

The experiment is the same as that described for example 41, and at the last stage 5-methoxy-N-(4-methoxyphenyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide substituted 6-methoxy-2-(4-methoxyphenyl)-1,3-benzothiazole-4,7-dione.

Red powder.

MS-LC: MH+ = 592,35; t.r. = 8,25 minutes

Example 50: 5-({3-[{3-[(4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}(methyl)amino]propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione:

The experiment is the same as that described for example 41, and at the last stage 5-methoxy-N-(4-shall ethoxyphenyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide replacing 5-methoxy-1,3-benzothiazole-4,7-dione.

Red powder.

1H-NMR (DMSO d6, 400 MHz, δ): 9.28 are (s, 1H); 8,02 (t, 1H, NH); to 7.95 (t, 1H, NH); 5,46 (s, 1H); 5,41 (s, 1H); 3,21-3,18 (m, 4H); of 2.72 (s, 3H, CH3); 2,41-of 2.38 (m, 4H); to 2.18 (s, 3H, CH3); 1,77-of 1.74 (m, 4H).

MS-LC: MH+ = 486,23; t.r. = 7,45 minutes

Example 51: 2-(2,5-differenl)-6-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino) propyl]amino}-1,3-benzoxazole-4,7-dione:

The experiment is the same as that described for example 41, and at the last stage 5-methoxy-N-(4-methoxyphenyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamid replace 2-(2,5-differenl)-6-methoxy-1,3-benzoxazole-4,7-dione.

Melting point = 149-150°C.

1H-NMR (DMSO d6, 400 MHz, δ): 8,03 (t, 1H, NH); 7,93-7,88 (m, 2H); to 7.61-7,58 (m, 2H); of 5.39 (s, 1H); 5,33 (s, 1H); 3,21-3,15 (m, 4H); in 2.68 (s, 3H, CH3); 2,43-of 2.38 (m, 4H); to 2.18 (s, 3H, CH3); 1,78 is 1.75 (m, 4H).

MS-LC: MH+ = 582,22; t.r. = 8,14 minutes

Translation methanesulfonate:

0,378 g (of 0.65 mmol) of 2-(2,5-differenl)-6-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl} amino)propyl]amino}-1,3-benzoxazole-4,7-dione is dissolved in 50 ml of acetone and added dropwise to 46.4 μl (0.7 mmol; 1.1 equivalent) methanesulfonic acid. Methanesulfonate is deposited in the form of a red powder. Melting point = 99-100°C.

1H-NMR (D2O, 400 MHz, δ): 7,58 (m, 1H); 7,47 (m, 1H); 7,37-7,31 (m, 1H); to 5.21 (s, 1H); to 5.08 (s, 1H); 3,35-is 3.21 (m, 8H); only 2.91 (s, 3H, CH3); to 2.74 (s, 3H, CH3); of 2.51 (s, 3H, CH3); 2,09-to 2.06 (m, 4).

MS-LC: MH+ = 582,34; t.r. = 8,45 minutes

Example 52: 2-(4-ethylphenyl)-6-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino) propyl]amino}-1,3-benzoxazole-4,7-dione:

The experiment is the same as that described for example 41, and at the last stage 5-methoxy-N-(4-methoxyphenyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamid replace 2-(4-ethylphenyl)-6-methoxy-1,3-benzoxazole-4,7-dione.

1H-NMR (DMSO d6, 400 MHz, δ): 8,03 shed 8.01 (d, 2H); of 7.90-8,00 (2m, 2H, 2NH); of 7.48-7,46 (d, 2H); of 5.40 (s, 1H); 5,28 (s, 1H); 3,20-3,17 (m, 4H); 2,73 of 2.68 (q, 2H); to 2.65 (s, 3H, CH3); 2,42-to 2.40 (m, 4H); 2,19 (s, 3H, CH3); 1,78 is 1.75 (m, 4H); to 1.24 (t, 3H, CH3).

MS-LC: MH+ = 574,24; t.r. = 8,40 minutes

Example 53: 2-(2,5-differenl)-6-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-6-yl)amino]propyl}amino) propyl]amino}-1,3-benzoxazole-4,7-dione:

The experiment is the same as that described for example 41, and the first step 5-methoxy-2-methyl-1,3-benzothiazole-4,7-dione substituted 6-methoxy-2-methyl-1,3-benzothiazole-4,7-dione, and at the last stage 5-methoxy-N-(4-methoxyphenyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamid replace 2-(2,5-differenl)-6-methoxy-1,3-benzoxazole-4,7-dione.

Red powder.

1H-NMR (DMSO d6, 400 MHz, δ): 8,03 (t, 1H, NH); to $ 7.91 (m, 1H); 7,80 (t, 1H, NH); to 7.61-to 7.59 (m, 2H); of 5.34 (s, 1H); 5,33 (s, 1H); 3,21-3,17 (m, 4H); of 2.72 (s, 3H, CH3); 2,42-of 2.38 (m, 4H); to 2.18 (s, 3H, CH3); 1,78-of 1.74 (m, 4H).

MS-LC: MH+ = 582,31; t.r. = 8,07 minutes

Example 5: 5,5'-[[(4-methoxybenzyl)imino]bis(propane-3,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione):

54.1) 5-[(3-bromopropyl)amino]-2-methyl-1,3-benzothiazole-4,7-dione:

To 1 g (4,78 mmol) 5-methoxy-2-methyl-1,3-benzothiazole-4,7-dione, dissolved in 100 ml of methanol, add of 1.57 g (7,17 mmol; 1.5 equivalents) of bromhidrosis 3-bromopropylamine and of 1.02 ml (7,17 mmol; 1.5 equivalents) of triethylamine. The reaction mixture is stirred for 2 hours at 60°C, and then the solvent is evaporated under reduced pressure and the residue purified via chromatography on a column of silica gel (eluent: dichloromethane/methanol: 97/3). Get 5-[(3-bromopropyl)amino]-2-methyl-1,3-benzothiazole-4,7-dione as a red oil.

MS-LC: MH+ = 314,99; t.r. = 9,13 minutes

54.2) 5-({3-[(4-methoxybenzyl)amino]propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione:

To 0.35 g (1.11 mmol) of 5-[(3-bromopropyl)amino]-2-methyl-1,3-benzothiazole-4,7-dione, dissolved in 15 ml of dimethylformamide, add 160 ál (1,22 mmol; 1.1 equivalents) of 4-methoxybenzylamine, 213 μl (1,22 mmol; 1.1 equivalents) of diisopropylethylamine and sodium iodide at the tip of a spatula. The reaction mixture was subjected to microwave irradiation at constant stirring for 5 minutes at 180°C. Then the solvent is evaporated under reduced pressure and the reaction residue is introduced into dichloromethane, washed with 3 times 50 ml of water. The organic phases are combined, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The expected product is distilled is by chromatography on a column of silica gel (eluent: dichloromethane/methanol: 95/5) and receive in the form of a red oil.

MS-LC: MH+ = 372,15; t.r. = to 7.64 minutes

54.3) 5,5'-[[(4-methoxybenzyl)imino]bis(propane-3,1-diimino)] bis(2-methyl-1,3-benzothiazole-4,7-dione):

To the 23.6 mg (64 μmol) of 5-({3-[(4-methoxybenzyl)amino] propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione, dissolved in 5 ml of acetonitrile, add 22 ál (128 mmol; 2 equivalents) of diisopropylethylamine, 21 mg (64 mmol; 1 equivalent) of 5-[(3-bromopropyl)amino]-2-methyl-1,3-benzothiazole-4,7-dione and the sodium iodide on the tip of a spatula. The reaction mixture was subjected to microwave irradiation at constant stirring at 165°C for 15 minutes, then the solvent is evaporated under reduced pressure and the reaction residue is introduced into dichloromethane, washed with 3 times 50 ml of water. The organic phase is again combined, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The expected product is purified by chromatography on a column of silica gel (eluent: dichloromethane/methanol: 93/7) and receive in the form of a red oil.

MS-LC: MH+ = 606,23; t.r. = 7,95 minutes

Example 55: 5,5'-[(methylimino)bis(butane-4,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione):

55.1) tert-butyl[4-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)butyl]methylcarbamate:

2 g (9.9 mmol) of tert-butyl(4-aminobutyl)methylcarbamate and of 1.46 g (9.9 mmol; 1 equivalent) of 2-benzofuran-1,3-dione are dissolved in 50 ml of toluene and the reaction mixture is refluxed in the Techa is their 24 hours in the unit Dean-stark. The solvent is evaporated under reduced pressure and the expected product was then purified on a column of silica gel (eluent: dichloromethane/methanol: 90/10).

MS-LC: MH+ = 333,26; t.r. = 10,90 minutes

55.2) 2-[4-(methylamino)butyl]-1H-isoindole-1,3(2H)-dione:

0.6 g (1.8 mmol) of tert-butyl[4-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)butyl]methylcarbamate dissolved in 865 ml (10,8 mmol; 6 equivalents) triftormetilfullerenov acid and the reaction mixture is stirred for 2 hours at ambient temperature. The solvent is evaporated, then the excess acid 3 times cooperat with 50 ml dichloromethane. The expected product is used without further purification in the next step.

MS-LC: MH+ = 233,19; t.r. = 7,38 minutes

55.3) 2,2'-[(methylimino)Tibetan-4,1-diyl]bis(1H-isoindole-1,3(2H)-dione):

209 mg (0.9 mmol) of 2-[4-(methylamino)butyl]-1H-isoindole-1,3(2H)-dione is dissolved in 5 ml of tetrahydrofuran, then add 385 μl (2.7 mmol; 3 equivalents) of triethylamine and 254 mg (0.9 mmol; 1 equivalent) of 2-(4-bromobutyl)-1H-isoindole-1,3(2H)-dione in the reaction mixture, which is subjected to microwave irradiation at constant stirring for 25 minutes at 165°C. the precipitate otfiltrovat and the filtrate concentrated under reduced pressure. The expected product is purified by chromatography on a column of silica gel (eluent: dichloromethane/methanol: 95/5).

MS-LC: MH+ = 434,25; t.r. = of 8.37 minutes

55.4) N-(4-aminobutyl)-N-meth is butan-1,4-diamine:

144 mg (0.33 mmol) of 2,2'-[(methylimino)Tibetan-4,1-diyl]bis (1H-isoindole-1,3(2H)-dione) was dissolved in 2 ml ethanol and add 65 μl (0.73 mmol; 2.2 equivalent) 35% hydrazine hydrate in the reaction mixture, which is subjected to microwave irradiation at constant stirring at 150°C for 30 minutes. The solvent is evaporated under reduced pressure and the excess hydrazine hydrate is removed joint 4-fold evaporation from 15 ml of ethanol. 100 ml of ethanol is added to the reaction mixture, which is acidified to pH 1 1H. solution of hydrochloric acid in ethyl ether. Reaction medium was concentrated under reduced pressure, and then is introduced into 50 ml of ethanol and the formed white precipitate was filtered, washed with 3 times 20 ml of water and removed. The filtrate is alkalinized to pH 12 with 2 m soda solution, and then concentrated under reduced pressure and used in the next step without additional purification.

1H-NMR (DMSO d6, 400 MHz, δ) 3,13-3,10 (m, 4H); 2,24-of 2.20 (m, 4H); of 2.08 (s, 3H, CH3); 1,38 is 1.34 (m, 4H).

MS-LC: MH+ = 174,29; t.r. = 8,99 minutes

55.5) 5,5'-[(methylimino)bis(butane-4,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione):

6 mg (34 μmol) of N-(4-aminobutyl)-N-methylbutane-1,4-diamine are added to a solution of 15 mg (71 mmol; 2.1 equivalent) 5-methoxy-2-methyl-1,3-benzothiazole-4,7-dione in 1.5 ml of ethanol, and then the reaction mixture was stirred at 60°C for 1 hour. After that, the solvent is evaporated PR is the reduced pressure and the desired product as a red oil is obtained by chromatographic purification on a column of silica gel (eluent: dichloromethane/methanol: 95/5).

MS-LC: MH+ = 527,69; t.r. = 10,13 minutes

Example 56: 2-methyl-5-{[3-(methyl{4-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]butyl}amino)propyl]amino}-1,3-benzothiazole-4,7-dione:

56.1) 2-{3-[[4-(1,3-dioxo-1,3-dihydro-1H-isoindole-2-yl)butyl](methyl)amino]propyl}-1H-isoindole-1,3(2H)-dione:

The experiment is the same as that described for example 55.3, and 2-(4-bromobutyl)-1H-isoindole-1,3(2H)-dione to replace 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione.

MS-LC: MH+ = 420,24; t.r. = 8,19 minutes

55.2) N-(3-aminopropyl)-N-methylbutane-1,4-diamine:

The experiment is the same as that described for example 55.4.

56.3) 2-methyl-5-{[3-(methyl{4-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]butyl}amino)propyl]amino}-1,3-benzothiazole-4,7-dione:

The experiment is the same as that described for example 55.5, and N(4-aminobutyl)-N-methylbutane-1,4-diamine is substituted for N-(3-aminopropyl)-N-methylbutane-1,4-diamine.

Pharmacological study of the compounds according to the invention

The test Protocol

i) Measurement of phosphatase activity of purified recombinant enzyme Cdc25C

The phosphatase activity of protein MBP-Cdc25C was estimated by dephosphorylating 3-O-methylfluoranthene (OMFP) 3-O-methylfluoranthene (OMF) determining the fluorescence of the reaction product at 475 nm. This experience allows us to identify inhibitors of recombinant cdc25 enzyme. aluchemie fused protein MBP-Cdc25C described in the patent application WO 01/44467.

The reaction is conducted in the format of a 384-well plate at final volume of 50 µl. Protein MBP-Cdc25C (obtained as described above) is stored in the next wash buffer: 20 mm Tris-HCl pH to 7.4; 250 mm NaCl; 1 mm EDTA; 1 mm dithiothreitol (DTT); 10 mm maltose. It is diluted to a concentration of 60 μm in the following reaction buffer: 50 mm Tris-HCl pH to 8.2; 50 mm NaCl; 1 mm DTT; 20% glycerol. Measurement of background noise is carried out with the buffer without added enzyme. The products are tested at decreasing concentrations ranging from 40 μm. The reaction is initiated by adding 500 μm final solution OMFP (prepared immediately before use, on the basis of the stock solution of 12.5 mm in DMSO 100% (Sigma #M2629)). After 4 hours at 30°C in disposable 384-hole tablet fluorescence measured at a wavelength of 475 nm, read by the apparatus for reading tablets Victor2(EGG-Wallac). Determination of the concentration inhibiting 50% of the enzymatic reaction, is calculated for three independent experiments. For linear regression analysis leave only the values contained in the linear part of the sigmoid.

ii) characterization of the anti-proliferative activity:

As an example, studied the effect of treatment with compounds of the above examples of two cell lines of human Mia-Paca2 and DU145. Cell lines DU145 (prostate cancer cells cancer in humans) and Mia-PaCa2 cells pancreatic cancer in humans) were purchased from American Tissue Culture Collection (Rockville, Maryland, USA). The cells were placed in 80 ml of Eagle medium modified by Dulbecco (Gibco-Brl, Cergy-Pontoise, France)supplemented with 10% fetal calf serum inactivated by heating (Gibco-Brl, Cergy-Pontoise, France), 50,000 units/l of penicillin and 50 mg/l streptomycin (Gibco-Brl, Cergy-Pontoise, France), and 2 mm glutamine (Gibco-Brl, Cergy-Pontoise, France) were seeded in 96-well plate on day 0. Cells were treated on day 1 for 96 hours at concentrations of each of the test compounds, increasing to 10 μm. At the end of this period was conducted quantitative assessment of cell proliferation by a colorimetric test based on the splitting of the salt tetrazol WST1 by mitochondrial dehydrogenase in viable cells, which leads to the formation of formazan (Boehringer Mannheim, Meylan, France). These tests were performed twice with 8 definitions of the tested concentrations. For each test compound values that are in the linear part of the sigmoid, left for linear regression analysis and used to assess inhibitory concentration CI50. The products were dissolved in dimethyl sulfoxide (DMSO) to 10-2M and used in the end in the culture with 0.1% DMSO.

Test results

a) Compounds of examples 1-5, 7, 8, 10, 14, 15, 17, 18, 20, 22, 25-28, 31-37, 41-45, 47, 48, 50, 51 and 53 have CI50less than or equal to 1 μm for the activity of phosphatase cleansing the tion of recombinant Cdc25 enzyme-C. As for the compounds of examples 6, 11 and 23, they have CI50less than or equal to 5 μm for the phosphatase activity of purified recombinant Cdc25 enzyme-C.

b) Compounds of examples 1-8, 10, 11, 14, 15, 17, 18, 20, 22, 25-28, 31-37, 41-45, 48, 50, 51 and 53 have CI50equal to or less than 10 μm for cell proliferation lines Mia-Paca2.

c) Compounds of examples 1-8, 10, 11, 14, 15, 17, 18, 20, 22, 25, 26, 31-37, 41-45, 48, 50 and 53 have CI50equal to or less than 10 μm for cell proliferation lines DU-145.

1. The connection that meets the General formula (I)

in the form of a racemate, enantiomer, or any combination of these forms, in which: each of W and W' independently denotes O or S;
R1means one of the radicals-CH2-CR6R7-CH2-, -(CH2)m-X-(CH2)n-, -(CH2)p-[O-(CH2)q]r-(CH2)pand -(CH2)s-CO-NR8-(CH2)rin which each of m and n independently is an integer from 2 to 6, preferably an integer from 2 to 4 and more preferably an integer from 2 to 3), R and t each independently is an integer from 2 to 12 (preferably an integer from 2 to 8 and more preferably an integer from 2 to 6, q is an integer from 2 to 4, preferably an integer from 2 to 3), r is an integer from 0 to 4, preferably an integer from 0 to 2), s means aleecia from 1 to 12 (preferably an integer from 1 to 8, more preferably an integer from 1 to 6), X is selected from the radicals-NR5-, -CR6R7-cycloalkyl and phenyl, provided that when X is-CR6R7-cycloalkyl or phenyl, m and n are equal,
and R5means a hydrogen atom or an alkyl or benzyl radical, possibly substituted from 1 to 3 times by substituents chosen independently from alkyl or alkoxy radical, R6and R7each independently means a hydrogen atom or an alkyl radical, and R8means a hydrogen atom,
or R1meansor
provided that →* means the place of connection to the General formula (I);
or R1means a radical -(CH2)w-N(Y)-(CH3)w-, in which Y represents a radical

W"means O or S, and w is an integer from 2 to 3;
R2means a hydrogen atom or an alkyl radical;
R3means a hydrogen atom or a halogen atom;
each of R4, R'4and R4independently means a hydrogen atom, alkyl radical, a radical-CO-NR14R15or phenyl, nattily or benzyl radical, possibly substituted from 1 to 4 times by substituents chosen independently from a halogen atom and an alkyl or alkoxy radical,
or R4means radical or,
R14whenever it occurs, is independently mean alkyl radical, cycloalkyl radical, phenyl or benzyl radical, a phenyl ring which may be substituted by from 1 to 3 times by substituents chosen independently from the group formed by halogen atom, alkyl radical, alkoxy radical,
or R14means radical,
or R14means a radical -(CH2)g-And where g denotes an integer from 1 to 6 and indicates a rich heterocycle comprising 1 to 2 heteroatoms N and coupled with the group -(CH2)g- link N or CH, with the specified rich heterocycle contains, in addition, from 2 to 6 additional units selected independently from-CHR18-, -CO-, and R18means a hydrogen atom or an alkyl radical,
and R15whenever it occurs, is independently means a hydrogen atom,
or R14and R15together with the nitrogen atom to which they are linked, form a saturated 4-7-tier a heterocycle containing from 1 to 2 heteroatoms, and links required for circuit heterocycle, independently selected from radicals-CR20R21-, -O - and-NR22-, and R20and R21means a hydrogen atom, and R22means-COR23or-SO2R24,
p is item R 23means phenyl radical, possibly substituted from 1 to 3 times alkoxy radical, or R23means purely radical or a saturated, a heterocycle comprising from 5 to 7 units and from 1 to 2 heteroatoms, selected independently from O and N (and, in particular, one of the radicals piperidine, piperazine derivatives, morpholine, thiomorpholine or 2-tetrahydrofuryl),
R24means alkyl radical,
or, finally, R14and R15together with the nitrogen atom to which they are linked, form a heterocyclic aryl radical selected from the radicals
and
the aromatic ring of which may be from 1 to 3 times a substituted alkoxy radical;
provided that when R1means a radical -(CH2)w-N(Y)-(CH2)w-, W, W'and W"are the same (in other words, it means either O or S), R4, R'4and R4are the same, and each of the nitrogen atoms adjacent to 1,3-benzothiazole-4,7-donovin or 1,3-benzoxazole-4,7-donovin cycle, attached in position 5 of the corresponding 1,3-benzothiazole-4,7-dinonogo or 1,3-benzoxazole-4,7-dinonogo cycle, or each attached at position 6 of the corresponding 1,3-benzothiazole-4,7-dinonogo or 1,3-benzoxazole-4,7-dinonogo loop;
or a salt of such compounds.

2. The compound according to claim 1, featuring the be fact, what R1is not a radical - (CH2)w-N(Y)-(CH2)w-, W and W'are the same, and R4and R'4are the same;
or a salt of such compounds.

3. The compound according to claim 1, wherein R1is not a radical - (CH2)w-N(Y)-(CH2)w-and one of W and W' is Oh, and another means S and/or R4and R'4are different.

4. The compound according to any one of claims 1 to 3, characterized in that it has at least one of the following characteristics:
- R1means - (CH2)m-X-(CH2)n-;
- R2means a hydrogen atom or a salt of such compounds.

5. The compound according to claim 1 or 2, wherein R1means one of the radicals-CH2-CR6R7-CH2-, - CH2)m-X-(CH2)n-, -(CH2)p-[O-(CH2)q]r-O-(CH2)p- and -(CH2)s-CO-NR8-(CH2)r;
or a salt of such compounds.

6. The compound according to claim 1 or 2, wherein R1means - (CH2)m-X-(CH2)n;
or a salt of such compounds.

7. The compound according to claim 1, characterized in that it is selected from
the following connections:
-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione);
-5,5'-[(methylimino)bis(ethane-2,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-d is he);
-5,5'-[oxybis(ethane-2,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione);
-5,5'-(pentane-1,5-diyldiamine)bis(2-methyl-1,3-benzothiazole-4,7-dione);
-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione);
-6,6'-[(methylimino)bis(ethane-2,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione);
-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis{4,7-dioxo-N-[3-(2-oxopyrrolidin-1-yl)propyl]-4,7-dihydro-1,3-benzothiazol-2-carboxamide};
-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(2,5-differenl)-1,3-benzoxazole-4,7-dione];
-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(3,5-dibromophenyl)-1,3-benzoxazole-4,7-dione];
-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(2-chloro-6-terbisil)-1,3-benzoxazole-4,7-dione];
-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(3-bromophenyl)-1,3-benzoxazole-4,7-dione];
-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(4-bromophenyl)-1,3-benzoxazole-4,7-dione];
-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(3,5-differenl)-1,3-benzoxazole-4,7-dione];
-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(3-chlorophenyl)-1,3-benzoxazole-4,7-dione];
-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(4-forfinal)-1,3-benzoxazole-4,7-dione];
-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(4-bromo-3-were)-1,3-benzoxazole-4,7-dione];
-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(6-bromo-2-methyl-1,3-benzothiazole-4,7-dione);
-5,5',5"-[nitrilotri(propane-3,1-diimino)]Tris(2-m is Teal-1,3-benzothiazole-4,7-dione);
-5,5'-(2,2-DIMETHYLPROPANE-1,3-diyldiamine)bis(2-methyl-1,3-benzothiazole-4,7-dione);
-5,5'-[cyclohexane-1,4-diylbis(methylaniline)]bis(2-methyl-1,3-benzothiazole-4,7-dione);
-5,5'-[1,3-phenylenebis(methylaniline)]bis(2-methyl-1,3-benzothiazole-4,7-dione);
-5,5'-[ethane-1,2-diylbis(oxypropane-3,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione);
-6,6'-{(methylimino)bis[propane-3,1-diyl(methylimino)]}bis[2-(2,5-differenl)-1,3-benzoxazole-4,7-dione];
-N3-[2-(2,5-differenl)-4,7-dioxo-4,7-dihydro-1,3-benzoxazol-6-yl]-N1-(3-{[2-(2,5-differenl)-4,7-dioxo-4,7-dihydro-1,3-benzoxazol-6-yl]amino}propyl)-β-alaninate;
-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(1,3-benzothiazole-4,7-dione);
-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(morpholine-4-ylcarbonyl)-1,3-benzothiazole-4,7-dione];
-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(2-{[4-(morpholine-4-ylcarbonyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione);
-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(2-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione);
-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(2-{[4-(methylsulphonyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione);
-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis[N-(4-methoxyphenyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide];
-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(pyrrolidin-1-ylcarbonyl)-1,3-benzothiazole-4,7-dione];
-5,5'-[(methylimino)bis(prop is n-3,1-diimino)]bis[N-(4-forfinal)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide];
-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis[N-(4-methoxybenzyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide];
-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis{2-[(6-methoxy-3,4-dihydroquinoline-1(2H)-yl)carbonyl]-1,3-benzothiazole-4,7-dione};
-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(N-cyclohexyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide);
-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(2-{[4-(4-methoxybenzoyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione);
-5,5'-[(methylimino)bis(propane-3,1-diimino)]bis(2-{[4-(2-furoyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione);
-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(2-naphthyl)-1,3-benzothiazole-4,7-dione];
-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(1,3-benzodioxol-5-yl)-1,3-benzothiazole-4,7-dione];
-6,6'-[(methylimino)bis(propane-3,1-diimino)]bis[2-(4-ethylphenyl)-1,3-benzoxazole-4,7-dione];
-N-(4-methoxyphenyl)-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide;
-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-6-yl)amino]propyl}amino)propyl]amino}-2-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazine-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione;
N-ethyl-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide;
-5-({3-[(3-{[4,7-dioxo-(pyrrolidin-1-ylcarbonyl)-4,7-dihydro-1,3-benzothiazol-6-yl]amino}propyl)(methyl)amino]propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione;
-N-(4-methoxybenzyl)-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide;
-N-1,3-benzodioxol-5-yl-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-2-carboxamide;
-2-[(6-methoxy-Z,4-dihydroquinoline-1(2H)-yl)carbonyl]-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-1,3-benzothiazole-4,7-dione;
-2-{[4-(4-methoxybenzoyl)piperazine-1-yl]carbonyl}-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-1,3-benzothiazole-4,7-dione;
-5-({3-[(3-{[2-(4-methoxyphenyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-6-yl]amino}propyl)(methyl)amino]propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione;
-5-({3-[{3-[(4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}(methyl)amino]propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione;
-2-(2,5-differenl)-6-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-1,3-benzoxazole-4,7-dione;
-2-(4-ethylphenyl)-6-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-1,3-benzoxazole-4,7-dione;
-2-(2,5-differenl)-6-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-6-yl)amino]propyl}amino)propyl]amino}-1,3-benzoxazole-4,7-dione;
-5,5'-[[(4-methoxime the ZIL)imino]bis(propane-3,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione);
-5,5'-[(methylimino)bis(butane-4,1-diimino)]bis(2-methyl-1,3-benzothiazole-4,7-dione);
-2-methyl-5-{[3-(methyl{4-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]butyl}amino)propyl]amino}-1,3-benzothiazole-4,7-dione;
or a salt of such compounds.

8. The compound of General formula (I), characterized in that it is a-2-(2,5-differenl)-6-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-1,3-benzoxazole-4,7-dione, or a salt of such compounds.

9. The compound of General formula (I) according to claim 1 or 8, or a pharmaceutically acceptable salt of such compounds as drugs having inhibitory activity against the phosphatase cdc25.

10. Pharmaceutical composition having inhibitory activity against the phosphatase cdc25, containing as active ingredient a compound of General formula (I) according to claim 1 or 8, or a pharmaceutically acceptable salt of such compounds with at least one pharmaceutically acceptable excipient.

11. The use of compounds of General formula (I) according to claim 1 or 8, or pharmaceutically acceptable salts of such compounds for obtaining a medicinal product intended for the treatment of diseases/disorders, selected from the following diseases/disorders: proliferative tumor diseases, proliferative nonneoplastic diseases the Oia, neurodegenerative diseases, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products, alopecia, caused by the radiation, autoimmune diseases, transplant rejection, inflammatory diseases and allergies.

12. The application of claim 11, characterized in that the drug is intended to treat cancer.

13. The application of item 12, wherein the cancer is assigned to a treatment selected from breast cancer, lymphomas, cancer of the head and neck, lung cancer, colon cancer, prostate cancer and pancreatic cancer.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on CDK1 kinase. In formula I , R1 is hydrogen or R2-(X)n-; X is a lower alkylene or cyclic lower alkylene; R2 denotes ; where denotes phenyl; cycloalkyl containing 3-6 carbon atoms; 4-6-member heterocycloalkyl ring having 3-5 carbon atoms and 1-2 oxygen atoms; R5, R6 and R7 are independently selected from a group containing hydrogen or halide; R4 is hydrogen or -(O)k(CH2CH2O)y-R10; R19 is hydrogen; R20 is hydrogen or -C(O)-R11; R10 and R11 is a lower alkyl; n and k are equal to 0 or 1; y is an integer from 0 to 3.

EFFECT: obtaining a pharmaceutical composition with inhibitory effect on CDK1 kinase, containing one or more of the disclosed compounds.

15 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (XXI) where values of R1, Y, Ra and Rb are given in subparagraphs 1 and 2 of the formula of invention, as phosphatidylinositol-3-kinase inhibitors, a pharmaceutical composition based on said compounds and their use.

EFFECT: compounds can be used for treating and preventing diseases mediated by phosphatidylinositol-3-kinase.

5 cl, 5 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts and esters. The disclosed compounds have inhibitory effect on cyclin-dependant kinase. In formula I R1 denotes , R3 is selected from a group consisting of H, CO2R6, C(O)R6, SO2R6 and SO2NR5R6, R5 and R6 are each independently selected from a group which includes H and (lower)alkyl, R2 is phenyl which contains one, two or three substitutes independently selected from a group which includes halogen or -O-(lower)alkyl.

EFFECT: preparation of a pharmaceutical composition which contains an effective amount of a formula I compound as an active ingredient.

6 cl, 1 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention describes a phenothiazine derivative, specifically 2-(1-(2-(2-chloro-10H-phenothiazin-10-yl)-2-oxoethyl)-5-methyl-1H-1,2,4-triazol-3-yl)phenol of formula I: .

EFFECT: obtaining compounds with hypotensive and antiarrhythmic activity during intraperitoneal administration.

3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to methods for producing 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzotiazin-3-carboxamides-1,1-dioxide (meloxicam) of formula of a high degree purity. In one of the ways potassium salt monohydrate of meloxicam of formula is dissolved, which is produced by interaction of meloxicam formula (II) with potassium hydroxide or potassium carbonate dissolved in water or in a mixture of water and organic solvent and, if desired, crystallisation of this monohydrate potassium salt of meloxicam of formula (I) in water or in a mixture of water and organic solvent, insoluble impurities are removed and the resulting solution is processed with organic or inorganic acid and crystallise meloxicam. The invention also refers to potassium salt monohydrate of meloxicam of formula (I) and method of its production, as well as to anti-inflammatory pharmaceutical composition based on it.

EFFECT: improvement of composition efficacy.

18 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: claimed compounds show effect on receptor activated by peroxysome proliferate δ (PPARδ). In formula I: [Formula I] , [Formula VII] , [Formula VI] , A is R1 is C1-4alkyl group; R3 groups are different and denote halogen atom or C1-4alkyl group substituted or unsubstituted by halogen; R4 is R5 is hydrogen atom or hydroxyl group; the other radicals are as defined in the invention claim. Also invention refers to methods of compound I obtainment, to intermediary compounds VI, VII and methods of their obtainment, to medicines of diabetes, obesity, atherosclerosis, hyperlipidemia treatment and prevention, containing thiazole derivative of the formula I as active component.

EFFECT: enhanced activity of derivatives.

21 cl, 10 tbl, 102 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to cyclic derivatives of aminobenzoic acid and to their pharmaceutically acceptable salts of general formula , in which ring Ar is a phenyl group, a 5-member aromatic heterocyclic group containing 1-2 heteroatoms selected from nitrogen, sulphur and oxygen, or a benzothiazolyl group; where the said groups can have 1-2 substitutes selected from a group comprising lower alkyl; a phenyl group; a phenyl group substituted with 1-2 halogens; a phenyl group substituted with a lower alkoxy group; a phenyl group substituted with a halogen-substituted lower alkyl group; a phenoxy group substituted with a halogen; a halogen; Z is an oxygen atom or -(CH2)-n (where n equals 0, 1 or 2); Y is C1-C4 alkylene, C2-C4 alkenylene or general formula (2) -T-A-U- (2) in which T is a single bond, C1-C4 alkylene or C2-C4 alkenylene; U is single bond, C1-C4 alkylene; values of the rest of radicals are given in the formula of invention.

EFFECT: obtaining a PPARα, agonist which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid, and an agent which reduces the level of lipids which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid.

12 cl, 16 tbl, 184 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula 1 , where R1, R2, R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, alkylcarboxylate, alkyl, alkenyl, cycloalkyl, nitro, sulfonyl chloride, sufonyl hydrazide, alkyl sulfonyl, heterocycylsulfonyl, heteroarylsufonyl, sulfonamide, alkyl-NH-SO2-, cycloalkyl-NH-SO2-, heterocyclyl-NH-SO2-, heteroalkyl-NH-SO2-, heteroarylalkyl-NH-SO2-, heterocyclyl, heteroaryl, guanidinocarbonyl, guanidine, -NR'R" and N=R'"; R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, halogenalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, aminoalkyl, mono- or dialkyl substituted aminoalkyl, cycloalkylaminoalkyl, aralkylaminoalkyl, alkoxyaralkylaminoalkyl, heterocyclylalkyl, heterocyclylaminoalkyl, heterocyclylalkylaminoalkyl, heterocyclylalkyl-N(alkyl) alkyl, heteroarylalkyl, heteroaralkylaminoalkyl, alkoxyaralkyl-N(alkyl)alkyl, aralkyl-N(alkyl)alkyl, alkoxycarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl alkylcarbonyl; R'" is selected from heterocyclyl, cycloalkyl and alkyl; where the alkyl is unsubstituted or substituted with 1, 2 or 3 identical or different substitutes selected from halogen, halogen alkyl, hydroxy, alkoxy, alkylamino, carbonyl, cycloalkylamino, nitro, cycloalkyl, aryl, heteroaryl and heterocyclyl; aryl is (C6-C10)aryl which is unsubstituted or substituted with 1-2 identical or different substitutes selected from nitro, alkyl, alkoxy, halogen, halogenalkyl, amino and mono or dialkylamino-; heteroaryl is a 5- or 6-member ring system containing 1, 2 or 3 atoms in the ring selected from N, O and S, which is unsubstituted or substituted with 1-2 identical or different groups selected from halogen, nitro, amino, alkylamino, alkyl, alkoxy and cycloalkyl; heterocyclyl is a 5- or 6-member ring system containing 1, 2 or 3 atoms in the ring selected from N, O and S, which is unsubstituted or substituted with 1-2 identical or different groups selected from alkyl, cycloalkyl, hydroxyalkyl, alkylaminoalkyl, cycloalkylalkyl, cycloalkylcarbonyl, heterocyclylalkyl, heteroarylalkyl, heteroarylcarbonyl, arylalkyl and oxo; and guanidino and guanidinocarbonyl are unsubstituted or substituted with 1, 2 or 3 identical or different groups selected from alkyl and alkylcarbonyl; provided that at least one of R1, R2, R3, R4, R5, R6, R7 or R8 is guanidine or guanidine carbonyl; U is C(O), CRaRb, O or NRa; V is CRaRb or NRa; and W is S(O)m; where Ra is H, alkyl, cycloalkyl or alkenyl; Rb is H, alkyl, OH or ORa, and m equals 1 or 2; or to pharmaceutically acceptable salts thereof. The invention also relates to a method of obtaining formula 1 compounds, to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining new biologically active compounds which are sodium/proton exchange (Na+/H+) (NHE) inhibitors.

19 cl, 203 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

Up!