Pyrazolepyrimidines

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat tumourous diseases, such as solid tumours, breast, lung, large intestine or prostate gland tumours. In compounds of formula

: R1 is selected from a group comprising: (a) saturated cyclic radical containing 3-8 ring atoms, from which 1-3 atoms are N atoms, which can contain up to four substitutes independently selected from a group comprising: (i) lower alkyl; and (ii) CO2R3, OR7 or S(O)nR8; (b) C6-C10aryl, which can contain up to four substitutes independently selected from a group comprising: (i) S(O)nR8, lower alkyl; OR7 and halogen; (c) C3-C8cycloalkyl, which can be substituted with NR5R6; and (d) lower alkyl, which can be substituted: (i) OR7, NR5R6; R2 is selected from a group comprising: (i) H; (ii) lower alkyl; (iii) C6-C10aryl which can be substituted with a halogen, lower alkyl, lower alkoxy group; R3 is selected from a group comprising: (i) H; (ii) lower alkyl; (iv) C3-C8cycloalkyl; R5 and R6 are independently selected from a group comprising: (i) H; (ii) lower alkyl; (iii) C3-C8cycloalkyl; (v) SO2R3; and (vi) CO2R3; R7 is selected from a group comprising H and lower alkyl; R8 is selected from a group comprising: (iii) NR5R6; (iv) lower alkyl; and n equals 1 or 2.

EFFECT: capacity to inhibit activity of cyclin-dependant kinase.

 

The present invention relates to new pyrazolopyrimidines formula I

New pyrazolopyrimidine have the ability to inhibit the activity of cyclin-dependent kinases, most preferably, cyclin-dependent kinase 1 (Cdk1), cyclin-dependent kinase 2 (Cdk2) and cyclin-dependent kinase 4 (Cdk4). These compounds and their pharmaceutically acceptable salts and esters exhibit antiproliferative activity and are used, among others, in the treatment or control of cancer, in particular solid tumors. The present invention also provides pharmaceutical compositions containing such compounds, and methods of treatment or control of cancer, most preferably, treatment or control of breast tumors, lung, colon and prostate.

Uncontrolled cell proliferation is a distinctive feature of cancer. Cells of the cancer, usually have some corrupted form of genes that directly or indirectly regulate the cell division cycle.

The passage of cells through the various phases of the cell cycle is regulated by a number multienzyme complexes, including regulatory protein, cyclin and kinase. These kinases called cyclin-dependent kinases (Cdks). Cdks Express throughout the cell cycle, while the levels of C the wedges vary depending on the phase of cell cycle.

Four main phases of cell cycle regulation is denoted as G1, S, G2and M was Found that some essential enzymes for the regulation of the cell cycle are cyclin D/Cd4, cyclin D/Cd6, cyclin E/Cd2, cyclin A/Cd2 and cyclin B/Cd1 (also known as Cdc2/cyclin B). Cyclin D/Cd4, cyclin D/Cd6, cyclin E/Cd2 control the passage through G1-phase and the transition G1-phase to S-phase through phosphorylation of retinoblastoma protein - pRb. Cyclin A/Cd2 regulates passage through S-phase, and cyclin B/Cd1 controls G2critical point and regulates the entry into M-phase (mitosis).

The passage of the cell cycle is regulated by Cdk1 (cdc2) and Cd2 before phase G1when cells are transferred to cytokinesis. As a consequence, drug inhibition of these Cds, apparently, not only inhibits cell proliferation, but also triggers apoptosis of the cells. If the cells were G1critical point and entered in S-phase, they become independent of stimulation by the growth factor for the continuation of the passage of the cell cycle.

Following the completion of DNA replication cells included in the G2-phase of the cell cycle and is ready for entry into M-phase and cytokinesis. Cdk1 has been shown to regulate the passage of cells through these later phases of the cell cycle together with both cyclename a and B. Full Cdk1 requires both binding cyclina, and specific fosforilirovanija (Morgan, D.., De Bondt, H.L., Curr. Opin. Cell. Biol., 1994, 6, 239-246). After activation of the Cdk1/cyclenbuy complex prepares the cell to divide in M-phase.

The transition from the G1-phase to S-phase, as determined above, is regulated by a complex of Cdk4 with cyclin D and Cdk2 complex with cyclin E. These complexes phosphorylate cellular suppressor protein the retinoblastoma (pRb), implementing the transcription factor E2F and triggering the expression of genes required for S-phase (Nevins, J.R., Science, 1992, 258, 424-429; Lavia, P. BioEssays, 1999, 21, 221-230). Blocking the activity of Cdk4/cyclin D and Cdk2/cyclin E complexes inhibit the cell cycle in the G1-phase. For example, proteins INK4 family, including RINK4athat block the kinase activity of Cdk4/cyclin D complex, causes inhibition in the phase of G1, (Sherr, .J., Science, 1996, 274, 1672-1677). Special literature reviewed in (Vidal, A.Gene, 2000, 247, 1-15).

Recently experiments have shown that the complex of Cdk4 with cyclin D3 also plays a role in cell cycle when passing through G2-phase. Inhibition of this complex by either P16 or using dominant negative Cdk4, leads to inhibition of G2-phase in cells that do not Express pRb (Gabrielli .G. et al., J.Biol. Chem., 1999, 274, 13961-13969).

Numerous defects in the course of metabolism pRb has been shown to be included in various types of cancer. For example, overexpression of Cdk4 was observed in cases of hereditary melanoma (Webster, .R., Exp. Opin. Invest. Drugs, 1988, 7, 865-887); cyclin D sverkhekspressiya in many types of cancer man (Sherr, .J., Science, 1996, 274, 1672-1677); P16 mutates or Delerium in many tumors (Webster, .R., Exp. Opin. Invest. Drugs, 1988, 7, 865-887); and pRb function is lost due to mutations or deletions in many types of cancer (Weinberg R.A., Cell, 1995, 81, 323-330). Defects in this metabolism, as has been shown, can be used to predict disease. For example, the absence of P16 is associated with poor prognosis of non-small cell lung carcinoma (NSCLC) and malignant melanoma (Tsihlias, J. et al., Annu. Rev. Med., 1999, 50, 401-423). Defects cycline D1 and/or pRb gene and/or expression level present in more than 90% of cases of samples of non-small cell carcinoma of the lung, indicating that cyclin D1 and/or pRb represent an important step in the lung tumor Genesis (Marchetti, A., et al., Int. J.Cancer, 1998, 75, 573-582). In 49 out of 50 cases of carcinoma of the pancreas (98%) pRb/p16 metabolic pathway was cancelled solely due to inactivation of P16 gene and associated Collina D (Shutte, M., et al.,Cancer Res., 1998, 57, 3126-3134). An overview of the relationship between expression of pRb and cyclin/cyclin-dependent kinases in several tissues is presented in Teicher, VA, Cancer Chemother. Pharmacol., 2000, 46, 293-304.

Because of the involvement dr4/cyclin D/pRb metabolism in cancer in humans through its role in the regulation of the flow cell cycle from G1to S-fasii potential positive therapeutic effect of the modulation of the metabolism, there is significant interest in agents that inhibit or promotirovat elements of this metabolism. For example, the impact on cancer cells using antibodies, antisense oligonucleotides, and overexpression or addition of proteins, involved in metabolism. See, for example, Lukas, J. et al., Nanure, 1995, 79, 573-582; Nevins J.R., Science, 1992, 258, 424-429; Lim, I.K. et al., Molecular Carcinogenesis, 1998, 23, 25-35; Tam, S.W. et al., Oncogene, 1994, 9, 2663-2674; Driscoll, C. et al., Am. J. Physiol., 1997, 273 (Lung Cell. Mol. Physiol,), 941-949; and Sang, J. et al., Chin. Sci. Bull., 1999, 44, 541-544).

The role of Cdks in the regulation of cell proliferation, thus firmly established. For example, as shown above, there is a vast part of the literature supporting the use of compounds inhibiting targets Cdk4, Cdk2 and Cdk1-metabolisme as antiproliferative therapeutic agents. Inhibitors of cell proliferation thereby act as reversible cytostatic agents used in the treatment of diseases which are peculiar aberrant cell growth, such as cancer and other cell proliferative diseases, including, for example, inflammation (eg, benign prostatic hypertrophy, familial adenomatosis, polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, inflammatory bowel disease, infectious graft rejection), viral is e infection (including, but not limited to, the herpes virus, smallpox virus, Epstein-Barr), autoimmune diseases (e.g. lupus, rheumatoid arthritis, psoriasis, inflammatory bowel disease), neurodegenerative diseases (including, but not limited to, Alzheimer's disease and neurodegenerative diseases (such as Parkinson's disease, amyotrophic lateral sclerosis, retinitis inflammation of the retina, spinal muscular atrophy and cerebellar degeneration).

Several different classes of small molecules identified as inhibitors of Cdks: olomoucine and other purine analogues, flavopiridol, staurosporine, UCN-01 and other indolocarbazole, 9-hydrometallation, indirubin, paulley, dailmotion, heatline, indefinately, [2,3-d]pyridopyrimidines, faceposing, aminothiazole, diaminetetra, pteridine and pyrazoles or example (Carlson et al., Cancer Res., 1996, 56, 2973-2978; De Azevedo et al., Eur. J. Biochem., 1997, 243, 518-526; Bridges, A.J., Exp. Opin. Ther. Patents, 1955, 5, 124512257; Reinhold Cancer Res., 1998, 58, 704-710, 3803-3807; Kakeya, H. et al., Cancer Res., 1998, 58, 704-710; Harper, J.W., Cancer Surveys, 1997, 29, 91-107; Harrington, E.A. et al., Proc. Natl. Acad. Sci. USA, 1998, 95, 11945-11950; Meijer, L., Eur. J. Biochem., 2000, 267, 1-13; Garrett, M.D. et al., Current Opin. Genetics Develop., 1999, 9, 104 to 111; Mgbonyebi, O, P. et al., Cancer Res., 1999, 59, 1903-1910; Hoessel en al., Nanure Cell Biology., 1999, 1, 60-67; Zaherevitz et al., Cancer Res., 1999, 59, 2466-2569; Honma, T. et al., 221StNational ACS Meeting, 2001: Medi 136; Sielecki, N.V. et al., Bioorg. Med. Chem. Lett., 2001, 11, 1157-1160; Nugiel, D., J. Med. Chem., 2001, 44, 1334-1336; Fry, D.W. et al., J. Biol. Chem.,2001, 276, 16617-15523; Sony, R., et al., Biochem. Biophys. Res. Commun., 2000, 275, 877; Ryu, C-K., et al., Bioorg. Med. Chem. Lett., 2000, 10, 461; Jeong, H-W., et al., Bioorg. Med. Chem. Lett., 2000, 10, 1819; Toogood et al., J. Med. Chem., 2000, 43, 4606-4616; Chong, W., Fischer, Current Opin. In Drug Discov. and Develop., 2001, 4, 623-634, WO 0009921845, Toogood, P., WO 0119825, Toogood, P., WO 0138315, Reich S.H., WO 0179198, Webster, K. US 6262096.

Class diaminopyrimidines represented by the compounds of the formula

any abscopal, as installed, Cdk4 and FAK3. Cm. WO 0012485 (company Astra Zeneca).

Application WO 9118887 (company Smith Kline Beecham) refers to diaminopyrimidines formula

inhibiting gastric secretion.

Application WO 0039101 (company Astra Zeneca) relates to pyrimidine compounds of the formula

acting as anticancer agents.

Application WO 0164653 (company Astra Zeneca) relates to pyrimidine compounds of the formula

acting as Cdk inhibitors and FAK inhibitors.

Application WO 0164654 (company Astra Zeneca) relates to pyrimidine compounds of the formula

acting as Cdk inhibitors and FAK inhibitors.

In addition, the application WO 0164656 (company Astra Zeneca) relates to pyrimidine compounds of the formula

acting as Cdk inhibitors and FAK inhibitors.

Overview of compounds inhibiting the metabolic pathway of Cdk4/cyclin D presents: Yarris, W. and Wilkison, S., Emerging Drugs., 2000, 5, 287-297; Dumas, J. Exp. Opin. Ther., Patents, 2000, 11, 405-429; Sielecki T.J. Med. Chem., 2000, 43, 1-18.

The present invention offers new pyrazolopyrimidine having the formula (I):

or their pharmaceutically acceptable salts or esters, where

R1choose from a group including:

(a) a heterocycle, which can contain up to four substituents independently selected from the group including:

(i) lower alkyl which can be substituted for IT, CO2R3, COR4, CONR5R6, NR5R6, OR7or S(O)nR8; and

(ii) CO2R3, COR4, CONR5R6, NR5R6, OR7or S(O)nR8;

(b) aryl, which may contain up to four substituents independently selected from the group including:

(i) S(O)nR8, NR5R6, lower alkyl, OR7, halogen or lower alkyl which may be substituted, HE, CO2R3, COR4, CONR5R6, NR5R6or or7;

(ii) COOH; and

(iii) carbonyl, substituted lower alkyl, OR7or NR5R6;

(C) cycloalkyl, which may be substituted OR7, NR5R6or S(O)nR8; and

(g) a lower alkyl which may be substituted:

(i) OR7, NR5R6, S(O)nR8NHS(O)nR8or CO2R3;

(ii) a heterocycle which may be substituted by lower alkyl, CO2R3or S(O)nR8;

(iii) heteroaryl, which may be substituted by lower alkyl, CO2R3or S(O)nR8;

and

(iv) aryl, which may be substituted by lower alkyl, CO2R3, halogen, COR4or NR5R6;

R2choose from a group including:

(i) H;

(ii) lower alkyl or lower alkyl which may be substituted, HE, CO2R3, COR4, CONR5R6, NR5R6, OR7;

(iii) aryl which may be substituted with halogen, NO2, CN, NR5R6, lower alkyl, lower alkoxygroup and lower alkyl substituted by halogen or or7;

(iv) heteroaryl, which may be substituted by lower alkyl, CO2R3, COR4, CONR5R6, NR5R6, halogen and lower alkyl which may be substituted by CO2R3, COR4, CONR5R6, NR5R6, OR7;

R3choose from a group including:

(i) H;

(ii) lower alkyl which may be substituted OR7, COR4, NR5R6or CONR5R6;

(iii) aryl, which may contain up to three substituents independently selected from the group comprising lower alkyl, halogen and NR5R6; and

(iv) cycloalkyl, which can be the replacement of the Yong HE or NH 2;

R4choose from a group including:

(i) H; and

(ii) lower alkyl which may be substituted OR7or NR5R6;

R5and R6independently from each other selected from the group including:

(i) H;

(ii) lower alkyl which can be substituted for IT, CO2R3, CONR10R11, SO2R3, OR7, NR10R11, heterocycle or heteroaryl;

(iii) cycloalkyl, which may be substituted by CO2R3, CONR10R11, SO2R4, OR7or NR10R11;

(iv) aryl, which may be substituted by CO2R3, CONR10R11, SO2R3, OR7, NR10R11, halogen, lower alkyl and lower alkyl substituted by halogen, CO2R3, CONR10R11, OR7, NR10R11or HE;

(v) SO2R3,

(vi) CO2R3and

(vii) COR3or

alternative, NR5R6may form a ring with the total number of ring atoms from 3 to 7, comprising in addition to the nitrogen atom is attached to R5and R6carbon ring atoms, called carbon ring atoms optionally substituted by one or more additional N or O ring atoms or a group of SO2, and named ring atoms optionally at that replaced IT, oxoprop is Oh, NR5R6, lower alkyl and lower alkyl, substituted OR7;

R7selected from the group comprising H and lower alkyl, optionally substituted NR5R6or or9;

R8choose from a group including:

(i) aryl, which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, NR5R6, halogen, lower alkyl or lower alkyl substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6and HE;

(ii) heteroaryl, which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, NR5R6, halogen, lower alkyl or lower alkyl substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6or HE;

(iii) NR5R6,

(iv) lower alkyl which may be substituted with halogen, CO2R3, CONR5R6, OR7, NR5R6or HE; and

(v) a heterocycle which may be substituted by CO2R3, COR3, SO2R3, CONR5R6, OR7or NR5R6;

R9selected from the group comprising H, lower alkyl, and lower alkyl, HE or substituted by halogen;

R10and R11independently from each other selected from the group including:

(i) H;

(ii) lower alkyl which may be substituted by HE, C 2R3, CONR5R6, SO2R3, OR7, NR5R6, heterocycle or heteroaryl;

(iii) cycloalkyl, which may be substituted by CO2R3, CONR5R6, SO2R3, OR7or NR5R6;

(iv) aryl, which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, NR5R6, halogen, lower alkyl or lower alkyl substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6or HE;

(v) SO2R3,

(vi) CO2R3and

(vii) COR3or

alternative, NR10R11may form a ring with the total number of ring atoms from 3 to 7, comprising in addition to the nitrogen atom is attached to R10and R11carbon ring atoms, called carbon ring atoms optionally substituted by one or more additional N or O ring atoms or a group of SO2, and named ring atoms, when having replaced IT, exography, NR5R6, lower alkyl and lower alkyl, substituted OR7;

and n=1 or 2.

These compounds inhibit cyclin-dependent kinases, most preferably, cyclin-dependent kinase 1 (Cdk1), cyclin-dependent kinase 2 (Cdk2) and cyclin-dependent kinase 4 (Cdk4). These compounds and their FA is matemticas acceptable salts and esters exhibit antiproliferative activity and are used among others, in the treatment or control of cancer, in particular solid tumors.

The present invention also provides pharmaceutical compositions comprising one or more compounds according to the invention or their pharmaceutically acceptable salts or esters, and pharmaceutically acceptable carrier or excipient.

The present invention further proposes a method of treatment or control of cancer, more preferably for the treatment or control of solid tumors, most preferably, treatment or control of breast tumors, lung, colon and prostate cancer, by administration of a patient in need of such treatment, an effective amount of the compounds of formula I or its pharmaceutically acceptable salt or a complex ester.

Finally, the present invention relates to new intermediate compounds used in obtaining the compounds of formula I.

In the present description uses the terms having the following values.

"Aryl" means a monovalent, monocyclic or bicyclic aromatic carbocyclic hydrocarbon radical, preferably 6-10-membered aromatic ring system. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl and xylyl.

"Carbonyl" means a radical of C=O.

"Cycloalkyl" oznacza the t non-aromatic, partially or fully saturated monovalent cyclic hydrocarbon radical containing from 3 to 8 atoms. Examples cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

"Effective amount" means an amount which is effective to prevent, alleviate or improve the symptoms of disease or prolong the life of the subject to be treated.

"Halogen" denotes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, more preferably fluorine.

"Heteroatom" means an atom selected from N, O or S.

"Heteroaryl" means an aromatic heterocyclic ring system containing up to two rings. Preferred heteroaromatic groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, tixall, chinoline, pyrimidinyl, imidazolyl, benzofuranyl and tetrazolyl.

"Heterocycle" or "heterocyclyl" means a saturated or partially unsaturated non-aromatic cyclic radical containing from 3 to 8 cyclic atoms in which from 1 to 3 cyclic atoms are heteroatoms selected from nitrogen, oxygen, S(O)n(where n denotes an integer from 0 to 2), or their combination, with the remaining ring atoms are carbon atoms. Examples of preferred heterocycles are what I piperidine, piperazine, pyrrolidine, morpholine, indoline, tetrahydropyran, thiomorpholine, pentamethylbenzene and pentamethylbenzene.

"IC50" refers to the concentration of individual compounds according to the invention required to inhibit 50% of specific measured activity. The value of the IC50can be measured, among others, as described in the examples.

"KI" relates to the measurement of thermodynamic binding ligand/inhibitor (i.e. connection according to the invention) with a protein target. KIit is possible to measure, among other things, as described in the examples.

"Lower alkyl" alone or in combination with another term, such as lower alkyl-heterocycle, means linear or branched saturated aliphatic hydrocarbon containing from 1 to 6, preferably from 1 to 4 carbon atoms. Typical lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl, hexyl and the like.

"The lowest alkoxygroup" separately, or in combination with another term, such as lower alkoxygroup-heterocycle means a linear or branched saturated aliphatic alkanol containing from 1 to 6, preferably from 1 to 4 carbon atoms. Typical low alkoxygroup include a methoxy group, ethoxypropan, propoxylate, isopropoxy, butoxypropyl, tert-butoxypropyl, 2-butox the group, phenoxypropan, hexachrome and the like.

"Oxoprop" means = O.

By "pharmaceutically acceptable complex ester" means standard derived esters of compounds of formula I having a carboxyl group, preserving the biological activity and properties of the compounds of formula I and fissile in vivo (in the organism) to the corresponding carboxylic acid. For more information on examples and applications of esters for the production of pharmaceutical compounds is available in Design of Prodrugs. Bundgaard H ed. (Elsevier, 1985)and H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995), p.108-109; Krogsgaard-Larsen, et. al., In Textbook of Drug Design and Development (2d Ed. 1996) str-191.

The term "pharmaceutically acceptable salt" refers to standard acid-additive or basic additive salts which retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic and inorganic acids or organic or inorganic bases. Examples of the acid additive salts include salts derived from inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and salts derived from organic acids such as the-toluensulfonate, salicylic acid, methanesulfonate acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Examples of primary additive salts include salts derived from hydroxides of ammonium, potassium, sodium and Quaternary ammonium bases such as, for example, a hydroxide of Tetramethylammonium. Technology chemical modification of pharmaceutical compounds (e.g. drugs) in salt to obtain compounds with improved physical and chemical stability, hygroscopicity, flowability and solubility are well known to chemists pharmacists. See, for example, N. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) str and 1456-1457.

The term "pharmaceutically acceptable" as, for example, pharmaceutically acceptable carrier, filler, etc. implies that they are pharmacologically acceptable and practically non-toxic in relation to the subject, which introduces the connection.

The term "substituted" means that the substitution can occur at one or more positions and, unless otherwise specified, the substituents in each area of the substitution is independently selected from specific options.

The term "therapeutically effective amount" means an amount of at least one specific compounds of formula I or its headlight is asepticheski acceptable salt or a complex ester, that significantly inhibits proliferation and/or prevents differentiation of human tumor cells, including cell lines of human tumors.

The present invention provides compounds of formula (I):

or their pharmaceutically acceptable salts or esters, where

R1choose from a group including:

(a) a heterocycle, which can contain up to four substituents independently selected from the group including:

(i) lower alkyl which can be substituted for IT, CO2R3, COR4, CONR5R6, NR5R6, OR7or S(O)nR8; and

(ii) CO2R3, COR4, CONR5R6, NR5R6, OR7or S(O)nR8;

(b) aryl, which may contain up to four substituents independently selected from the group including:

(i) S(O)nR8, NR5R6, lower alkyl, OR7, halogen or lower alkyl which may be substituted, HE, CO2R3, COR4, CONR5R6, NR5R6or or7;

(ii) COOH; and

(iii) carbonyl, substituted lower alkyl, OR7or NR5R6;

(C) cycloalkyl, which can be substituted OR7, NR5R6or S(O)nR8; and

(g) lower alkali that can be overridden are:

(i) OR7, NR5R6 , S(O)nR8NHS(O)nR8or CO2R3;

(ii) heterocycle which can be substituted by lower alkyl, CO2R3or S(O)nR8;

(iii) heteroaryl, which can be substituted by lower alkyl, CO2R3or S(O)nR8; and

(iv) Allami, which can be substituted by lower alkyl, CO2R3, COR4, halogen or NR5R6.

Preferably, R1represents a heterocycle selected from the group comprising piperidine, piperazine or pyrrolidine; or aryl selected from the group comprising phenyl, tolyl and xylyl; or cycloalkyl selected from the group comprising cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; or lower alkyl selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl or hexyl. More preferably, R1selected from the group comprising substituted or unsubstituted piperidine, phenyl and

With2-C5alkyl groups. More preferably, R1substituted SO2CH3CH3SOON2CH3, SO2NH2, F, och3HE, NH2N(CH3).

R2choose from a group including:

H;

lower alkyl or lower alkyl which may be substituted, HE, CO2R3, COR4, CONR5R6;

aryl, which may be for the of Eden halogen, NO2, CN, NR5R6, lower alkyl, lower alkoxygroup and lower alkyl substituted by halogen or or7;

heteroaryl, which may be substituted by lower alkyl, CO2R3, COR4, CONR5R6, NR5R6, halogen and lower alkyl which may be substituted by CO2R3, COR4, CONR5R6, NR5R6, OR7.

Preferably, R2denotes hydrogen; or lower alkyl selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl and hexyl; or aryl selected from the group comprising phenyl, tolyl and xylyl. More preferably, R2selected from the group comprising hydrogen, methyl and phenyl which may be substituted by fluorine or methoxy group.

R3choose from a group including:

N;

lower alkyl which may be substituted OR7, COR4, NR5R6or CONR5R6;

aryl, which may contain up to three substituents independently selected from the group comprising lower alkyl, halogen and NR5R6; and

cycloalkyl, which can be replaced with HE or NH2.

Preferably, R3denotes hydrogen or lower alkyl selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl and hexyl. More preferably,R 3denotes hydrogen, methyl, ethyl, propyl, or isopropyl.

R4choose from a group including:

N; and

lower alkyl which may be substituted OR7or NR5R6.

Preferably, R4denotes hydrogen or lower alkyl selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl and hexyl. More preferably, R4denotes hydrogen, methyl, ethyl, propyl, or isopropyl.

R5and R6independently from each other selected from the group including:

N;

lower alkyl which can be substituted for IT, CO2R3, CONR10R11, SO2R3, OR7, NR10R11, heterocycle or heteroaryl;

cycloalkyl, which may be substituted by CO2R3, CONR10R11, SO2R4, OR7or N10R11;

aryl which may be substituted by CO2R3, CONR10R11, SO2R3, OR7, NR10R11, halogen, lower alkyl and lower alkyl substituted by halogen, CO2R3, CONR10R11, OR7, NR10R11or HE;

SO2R3,

CO2R3and

COR3.

Alternative, NR5R6may form a ring with the total number of ring atoms from 3 to 7, comprising in addition to the nitrogen atom, to which PR is connected to R 5and R6carbon ring atoms, called carbon ring atoms optionally substituted by one or more additional N or O ring atoms or a group of SO2, and named ring atoms optionally at that replaced IT, exography, NR5R6, lower alkyl and lower alkyl, substituted OR7.

Preferably, R5and R6independently from each other selected from the group comprising hydrogen or lower alkyl selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl and hexyl. More preferably, R5and R6denote hydrogen, methyl, ethyl, propyl or isopropyl.

R7selected from the group comprising H and lower alkyl, optionally substituted NR5R6or or9.

Preferably, R7denotes hydrogen or lower alkyl selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl and hexyl. More preferably, R7denotes hydrogen, methyl, ethyl, propyl, or isopropyl.

R8choose from a group including:

aryl which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, NR5R6, halogen, lower alkyl or lower alkyl substituted by halogen, CO2R3, CONR5R 6, OR7, NR5R6and HE;

heteroaryl, which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, NR5R6, halogen, lower alkyl or lower alkyl substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6or HE;

NR5R6,

lower alkyl which may be substituted with halogen, CO2R3, CONR5R6, OR7, NR5R6or HE; and

a heterocycle which may be substituted by CO2R3, COR3, SO2R3, CONR5R6, OR7or NR5R6.

Preferably, R8denotes hydrogen or lower alkyl selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl and hexyl. More preferably, R8denotes hydrogen, methyl, ethyl, propyl, or isopropyl.

R9selected from the group comprising H, lower alkyl, and lower alkyl, HE or substituted by halogen.

Preferably, R9denotes hydrogen or lower alkyl selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl and hexyl. More preferably, R9denotes hydrogen, methyl, ethyl, propyl, or isopropyl.

R10and R11independently from each other selected from the group including:

N;

2R3, CONR5R6, SO2R3, OR7, NR5R6, heterocycles or heteroaryl;

cycloalkyl, which may be substituted by CO2R3, CONR5R6, SO2R3, OR7or NR5R6;

aryl which may be substituted by CO2R3, CONR5R6, SO2R3, OR7, NR5R6, halogen, lower alkyl or lower alkyl substituted by halogen, CO2R3, CONR5R6, OR7, NR5R6or HE;

SO2R3,

CO2R3or

COR3.

Alternative, NR10R11may form a ring with the total number of ring atoms from 3 to 7, comprising in addition to the nitrogen atom is attached to R10and R11carbon ring atoms, called carbon ring atoms optionally substituted by one or more additional N or O ring atoms or a group of SO2, and named ring atoms, when having replaced IT, exography, NR5R6, lower alkyl and lower alkyl, substituted OR7.

Preferably, R10and R11independently from each other selected from the group comprising hydrogen or lower alkyl selected from the group comprising methyl, ethyl, propyl, isopropyl, BU the sludge, tert-butyl, 2-butyl, pentyl and hexyl. More preferably, R10and R11denote hydrogen, methyl, ethyl, propyl or isopropyl.

Examples of compounds of formula (I) include:

[3-(2,3-debtor-6-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine (example 16);

(1-methanesulfonamido-4-yl)-(1H-pyrazolo[3,4-d]pyrimidine-6-yl)amine (example 19);

(1 methylpiperidin-4-yl)-(3-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)amine (example 23);

[3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine (example 25);

[3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine (example 26);

[3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine (example 27);

(1-methanesulfonamido-4-yl)-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]amine; compound with triperoxonane acid (example 28);

[3-(2,6-differenl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine (example 29);

(1-methanesulfonamido-4-yl)-(3-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)amine (example 30);

[3-(3-forfinal)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine (example 31);

4-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]benzosulfimide; connection with triperoxonane acid (example 32);

[3-(2,6-ditto is phenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(4-forfinal)amine (example 33);

2-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]ethanol (example 34);

[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]pentane-1,5-diamine triperoxonane acid (example 35);

N'-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-N,N-DIMETHYLPROPANE-1,3-diamine (example 36);

N-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-N,N-dimethylpentane-1,5-diamine triperoxonane acid (example 37);

[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]phenylamine (example 38);

(4-methoxyphenyl)-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]amine triperoxonane acid (example 39);

[3-(2,6-differenl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(2-methoxyphenyl)amine triperoxonane acid (example 40);

4-(3-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]benzosulfimide triperoxonane acid (example 41);

2-(3-methyl)-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]ethanol; compound with triperoxonane acid (example 42);

ethyl ester of 4-[3-(3-forfinal)-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]piperidine-1-carboxylic acid; compound with triperoxonane acid (example 43);

(1 methylpiperidin-4-yl)-(3-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)amine (example 44).

Preferred examples of compounds of formula (I) include:

[3-(2,3-debtor-6-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methane sulfanilimide-4-yl)amine (example 16);

(1-methanesulfonamido-4-yl)-(1H-Piras the lo[3,4-d]pyrimidine-6-yl)amine (example 19);

[3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine (example 25);

[3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine (example 27);

(1-methanesulfonamido-4-yl)-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]amine; compound with triperoxonane acid (example 28);

[3-(3-forfinal)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine (example 31);

4-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]benzosulfimide; connection with triperoxonane acid (example 32);

The compounds disclosed in this description and the corresponding formula (I)shown above can be tautomeric or structural isomerism. It should be borne in mind that the invention encompasses any tautomeric or structural isomeric form of these compounds, or mixtures of such forms and is not limited to one tautomerism or structural isomeric form, shown in the formula above.

Compounds of the present invention can be obtained by any conventional methods. Suitable methods of synthesis of these compounds are given in the examples. In General, the compounds of formula (I) can be obtained according to any of the following synthetic schemes.

In General, these compounds can be obtained according to the accordance with the synthetic schemes, above. Appropriate methods for obtaining these compounds are given in the examples.

The optional separation of the isomeric structures of the formula (I) can be carried out according to known methods such as, for example, dissolution or chiral high-performance liquid chromatography (also known as HPLC). Separation methods are well known and summarized in "Enantiomers, Racemates and Resolutions" (Jacques, J., et al., John Willey and Sons, NY, 1981). Methods of chiral HPLC are also well known and summarized in the "Separation of Enantiomers by Liquid Chromatographic Methods" (Pirkle, W.H. and Finn, J. In "Asymmetric Synthesis", vol.1, Morrison, J.D., Academic Press, Inc., NY 1983, pp.87-124).

The optional conversion of the compounds of formula (I)having a basic nitrogen, in pharmaceutically acceptable acid additive salt can be carried out using standard methods. For example, the compound is treated with an inorganic acid such as, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, or the corresponding organic acid such as acetic acid, citric acid, tartaric acid, methanesulfonate acid, p-toluensulfonate and the like.

The optional conversion of the compounds of formula (I)having a carboxyl group, a pharmaceutically acceptable salt of the alkali metal can be made the standard methods. For example, the compound is treated with an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.

The optional conversion of the compounds of formula (I)having a carboxyl group, a pharmaceutically acceptable ester can be carried out by standard methods. Conditions of formation of ester depends on the stability of other functional groups in the molecule under reaction conditions. If other parts of the molecule stable in acidic conditions, the ester is usually obtained by heating in a solution of mineral acid (e.g. sulfuric acid) in alcohol. Other methods of obtaining of ester, which may be appropriate if the molecules are unstable in acidic conditions include treatment of the compound with an alcohol in the presence of a condensing agent and in the optional presence of additional agents, accelerating the reaction. A large number of such condensing agents known to any expert in the field of organic chemistry. Two examples are dicyclohexylcarbodiimide and triphenylphosphine/diethylazodicarboxylate. In the case when the condensing agent is used dicyclohexylcarbodiimide, the reaction is usually carried out with the use of acid to alcohol in the optional presence of catalytic amounts (0-10 mol.%) N,N-dimethylamine is pyridine, in an inert solvent type halogenated hydrocarbon (e.g. dichloromethane)at a temperature of from 0°C. to room temperature, preferably at room temperature. In the case when the condensing agent is triphenylphosphine/diethylazodicarboxylate, the reaction is usually carried out with the use of acid in alcohol, triphenylphosphine and diethylazodicarboxylate, in an inert solvent type, an ether (e.g. tetrahydrofuran) or an aromatic hydrocarbon (e.g. benzene)at a temperature of from 0°C. to room temperature, preferably about 0°C.

In an alternative embodiment, the present invention includes pharmaceutical compositions containing at least one compound of formula (I) or its pharmaceutically acceptable salt or ester and a pharmaceutically acceptable excipient and/or carrier.

These pharmaceutical compositions can be administered orally, for example in the form of tablets, pills in the shell, coated tablets, hard or soft gelatin capsules, solutions, emulsions or suspensions. They can also be introduced rectally, for example in the form of suppositories, or parenterally, e.g. in the form of injection solutions. The pharmaceutical compositions of the present invention, including the compounds of formula (I) and/or their salts or esters, can be perceived by the s methods known from the prior art, i.e. by mixing, encapsulating, dissolving, granulating, emulsifying, included in the gel, drazhirovanija or lyophilization. These pharmaceutical preparations can be formulated with therapeutically inert, inorganic or organic carriers. At the same time as carriers for tablets, pellets in the shell, coated tablets and hard or soft gelatin capsules can be used lactose, corn starch or its derivatives, talc, stearic acid or its salts. Suitable carriers for soft gelatine capsules are vegetable oils, waxes and fats. Depending on the nature of the active substance not normally require any media in the case of hard gelatin capsules. Suitable carriers for the preparation of solutions and syrups are water, polyols, saccharose, invert sugar and glucose. Suitable carriers for injection are water, alcohols, polyols, glycerine, vegetable oil, phospholipids and surfactants. Suitable carriers for suppositories are natural or hydrogenated oils, waxes, fats and semi-liquid polyols.

The pharmaceutical preparations can also contain preserving agents, solubilizing agents, stabilizers, surfactants, emulsifiers, podcasti the ate, dyes, flavoring agents, salts for modifying the osmotic pressure, buffers, enrobing agents or antioxidants. They may also contain other therapeutically valuable substances, including additional active ingredients other than the compounds of formula (I).

As noted above, the compounds of the present invention, including the compounds of formula (I)are used in the treatment and control of disorders of cell proliferation, including cancer chemoprevention. Chemoprevention involves the inhibition of the development of early cancer by either blocking the initiation of mutagenic event or block the development of precancerous cells that have experienced the trauma of relapse inhibiting tumor. These compounds and compositions containing these compounds, are used, in particular, in the treatment or control of solid tumors such as, for example, tumors of the breast, colon, lung and prostate.

A therapeutically effective amount of the compounds of the present invention indicates the number of compounds that are effective to prevent, alleviate or improve the symptoms of disease or prolong the life of the subject to be treated. Determination of therapeutically effective amount is within the competence of the specialist in this field is ehniki.

Therapeutically effective amount or dosage of the compounds of the present invention can vary within wide limits and be installed by a method known from the prior art. This dosage should be adjusted according to individual requirements in each particular case, including the specific compound(s), subject to the introduction, the way of doing, the condition requiring treatment, and the patient to be treated. In General, in the case of oral or parenteral administration to adult humans weighing approximately 70 kg, a daily dose of from about 10 mg to 10000 mg, preferably from about 200 mg to 1000 mg, although the upper limit can be exceeded. The daily dose may be entered as a single dose, and in the case of parenteral administration can be used for a long intravenous infusion.

Compounds of the present invention can be used in combination (joint or separate introduction) with known anticancer treatments such as radiation therapy or with cytostatic or cytotoxic agents such as, for example, is not limited to, DNA interactive agents, such as cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase inhibitors I, such as CPT-11 or topotecan; t the Bulin interactivemedia agents, as, for example, paclitaxel, docetaxel or emotiona; hormonal agents, such as tamoxifen; inhibitors timedilation, such as 5-fluorouracil; and antimetabolites such as methotrexate. The compounds of formula (I) can also be used in combination with modulators of p53 TRANS-activation.

When forming a mixed dose of the above-described combination of drugs includes compounds of the present invention within the range of dosing described above, and the other pharmaceutically active agent or treatment within accepted for his dose. For example, the previously described Cdk1 inhibitor olomoucine, together with the well-known cytotoxic agents induces apoptosis. (J. Cell Sci., 1995, 108, 2829-2904). The compounds of formula (I) can also be entered sequentially with known anticancer or cytotoxic agents when a concomitant introduction or a combination of inappropriate. The present invention is not limited by the sequence of the introduction: the compounds of formula (I) can be introduced either before or after the introduction of anti-cancer or cytotoxic agent. Whereas, for example, the cytotoxic activity of Cdk inhibitor flavopiridol depends on the sequence with the introduction of its anti-cancer agent (Cancer Research, 1997, 57, 3375).

Examples

The following examples illustrate the preferred met the waters of the synthesis and application of compounds and products of the present invention. These examples and preparations illustrate and not limit the invention. It should be understood that there may be other cases that are in scope and consistent with the essence of the invention as defined in the accompanying claims.

Example 1: (2,4-dichloropyrimidine-5-yl)-(2,3-debtor-6-methoxyphenyl)methanol

Stir in a solution of 5-bromo-2,4-dichloropyrimidine (company Aldrich, to 3.02 g, 13,25 mmol) in 20 ml of THF at -30°C make dropwise isopropylaniline (company Aldrich, 2-molar solution in THF, 7,12 ml, 13,25 mmol) and stirred the mixture for 20 minutes Then add 2,3-debtor-6-methoxybenzaldehyde (firm Matrix, 2.28 g, 13,25 mmol), the mixture is heated to 0°C and stirred for 40 minutes the Reaction is stopped with a saturated solution of ammonium chloride and the resulting mixture extracted with ethyl acetate. The extract was dried over sodium sulfate. The solvent is removed on a rotary evaporator, and the solid is treated with hexane (8 ml), filtered off and dried, obtaining almost white solid. The output of 3.42 g (80.5 per cent). MS (M+N)+, 322.

Example 2: (2,4-dichloropyrimidine-5-yl)-(2,3-debtor-6-methoxyphenyl)metano

Alcohol (2.00 g, 6,23 mmol) dissolved in methylene chloride (20 ml) and with stirring, water (2 ml)followed by sodium bicarbonate (mg, 2.8 mmol), tetrabutylammonium (company Aldrich, 60 mg, 0.18 mmol) and TEMPO (company Aldrich, 10 mg, 0,062 mmole). The mixture is then cooled to 0°C and slowly add sodium hypochlorite (Aldrich company, active CI2are 5.8%, 8,78 ml), and then transferred into water and extracted with methylene chloride. The extract was dried over sodium sulfate. Removal of the solvent gives the product as a pale yellow solid. Yield 1.84 g (92%). MS (M+N)+, 319.

Example 3: 6-chloro-3-(2,3-debtor-6-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine

In a mixed solution of ketone (638 mg, 2 mmole) in THF contribute hydrazine (Aldrich company, 80 mg, 2.5 mmole) and the mixture stirred for 30 min at RT, and then at 50°C for 1 h, the Solvent removed and the solid is washed with water and dried, obtaining a yellow solid. Yield 580 mg (97%). MS (M+N)+, 297.

Example 4: (2,4-dichloropyrimidine-5-yl)-(2-methoxyphenyl)methanol

The compound is obtained from 5-bromo-2,4-dichloropyrimidine (company Aldrich) and 2-methoxybenzaldehyde (company Aldrich) with 77%yield by the method similar to that described in example 1.

NMR (300 MHz, CDCl3) δ is 8.75 (s, 1H), 7,34 (d, t, 1H, J=2 Hz, 8 Hz), 7,16 (d, d, 1H, J=1,8 Hz and 7.3 Hz), of 6.96 (d, 1H, J=7,3 Hz), to 6.95 (d, 1H, J=8 Hz), 6,21 (s, 1H), 3,85 (s, 3H), 3,148 (advanced s, 1H).

Example 5: (2,4-dichloropyrimidine-5-yl)-(2-methoxyphenyl)metano

/p>

The connection is obtained from (2,4-dichloropyrimidine-5-yl)-(2-methoxyphenyl)methanol (example 4) with 96%yield by the method similar to that described in example 2.

NMR (300 MHz, CDCl3) δ at 8.60 (s, 1H), to 7.84 (d, d 1H, J=2 Hz, 8 Hz), 7,60 (d, d, 1H, J=2 Hz and 7.3 Hz), 7,12 (d, 1H, J=7,3 Hz), to 6.95 (d, 1H, J=8 Hz), to 3.67 (s, 3H).

Example 6: 6-chloro-3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine

The connection is obtained from (2,4-dichloropyrimidine-5-yl)-(2-methoxyphenyl)methanone (example 5) with 35%yield by the method similar to that described in example 3.

MC(M+H)+, 261,11.

Example 7: (2,4-dichloropyrimidine-5-yl)-(3-forfinal)methanol

The compound is obtained from 5-bromo-2,4-dichloropyrimidine (company Aldrich) and 3-forventelige (company Aldrich) with 79%yield by the method similar to that described in example 1.

NMR (300 MHz, CDCl3) δ cent to 8.85 (s, 1H), 7,35 (m, 1H), 7,14 (m, 3H), 7,14 (m, 3H), 6,077 (s, 1H).

Example 8: (2,4-dichloropyrimidine-5-yl)-(3-forfinal)metano

The connection is obtained from (2,4-dichloropyrimidine-5-yl)-(3-forfinal)methanol (example 7) with 99%yield by the method similar to that described in example 2.

NMR (300 MHz, CDCl3) δ 8,632 (s, 1H), 7,52 (m, 4H), 7,43 (m, 1H), 5,303 (s, 1H).

Example 9: 6-chloro-3-(3-forfinal)-1H-pyrazolo[3,4-d]pyrimidine

The connection is obtained from (2,4-dichloropyrimidine-5-yl)-(3-forfinal)methanone (example 8) with 75%vyhoda the method, similar to that described in example 3. (M+N)+, 261 MS (M+N)+, 261.

Example 10: (2,4-dichloropyrimidine-5-yl)-(2,6-differenl)methanol

The compound is obtained from 5-bromo-2,4-dichloropyrimidine (company Aldrich) and 2,6-diferentialglea (company Aldrich) with 88%yield by the method similar to that described in example 1.

NMR (300 MHz, CDCl3) δ is 9.09 (s, 1H), 7,35 (m, 1H), 7,92 (m, 2H), 6.35mm (s, 1H), 2,67 (advanced s, 1H).

Example 11: (2,4-dichloropyrimidine-5-yl)-(2,6-differenl)metano

The connection is obtained from (2,4-dichloropyrimidine-5-yl)-(2,6-differenl)methanol (example 10) with 98%yield by the method similar to that described in example 2.

NMR (300 MHz, CDCl3) δ 8,79 (s, 1H), 7,56 (m, 1H),? 7.04 baby mortality (m, 2H).

Example 12: 6-chloro-3-(2,6-differenl)-1H-pyrazolo[3,4-d]pyrimidine

The connection is obtained from (2,4-dichloropyrimidine-5-yl)-(2,6-differenl)methanone (example 11) with 71%yield by the method similar to that described in example 3. MS (M+N)+, 267,08.

Example 13: (2,4-dichloropyrimidine-5-yl)phenylmethanol

The compound is obtained from 5-bromo-2,4-dichloropyrimidine (company Aldrich) and benzaldehyde (Aldrich company) with 79%yield by the method similar to that described in example 1.

NMR (300 MHz, CDCl3) δ 8,91 (s, 1H), was 7.36 (m, 5H), the 6.06 (d, 1H, J=3.0 Hz), 2,48 (extended m, 1H).

Example 14: (2,4-dichloropyrimidine-5-yl)hair dryer is leanon

The connection is obtained from (2,4-dichloropyrimidine-5-yl)phenylmethanol (example 13)

with 98%yield by the method similar to that described in example 2.

NMR (300 MHz, CDCl3) δ to 8.62 (s, 1H), 7,79 (m, 2H), of 7.70 (m, 1H), 7,54 (m, 2H).

Example 15: 6-chloro-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine

The connection is obtained from (2,4-dichloropyrimidine-5-yl)phenyl)methanone (example 14) with 99%yield by the method similar to that described in example 3. MC(M+H)+, 231,08.

Example 16: [3-(2,3-debtor-6-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)Amin

To a solution of 6-chloro-3-(2,3-debtor-6-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (example 3, 148 mg of 0.50 mmole) in DMF (2.5 ml) contribute with stirring sodium bicarbonate (100 mg) and 1-methanesulfonamido-4-ylamine (125 mg, 0,70 mmole) and stirred the mixture at 100°C for 4 hours the Solvent is removed under reduced pressure and the residue treated with water. The solid is filtered off and dried. Recrystallization from a mixture of 2% methanol/dichloromethane gives 92 mg (42%) of nearly white matter. MS (M+N)+, 439.

Example 17: 2,4-dichloropyrimidine-5-carbaldehyde

Stir in a solution of 5-bromo-2,4-dichloropyrimidine (company Aldrich, 454 mg, 2 mmole) in THF at -78°C contribute diisopropylaniline (2-m is a regular solution in THF, of 1.05 ml, 2.1 mmole) and stirred the mixture for 20 min at -35°C. Then the solution is cooled to -78°C and add 1 ml of dry DMF. The mixture is stirred for 120 min at -78°C, and then stop the reaction by using 1-normal hydrochloric acid. The mixture is extracted with ethyl acetate and dried over sodium sulfate. The solvent is removed and the residue chromatographic getting 102 mg (28%) of brown solid.

NMR (300 MHz, CDCl3) δ (ppm) to 9.0 (s, 1H), 10,4 (s, 1H).

Example 18: 6-chloro-1H-pyrazolo[3,4-d]pyrimidine

In a mixed solution of hydrazine (Aldrich company, 62 mg, 2 mmole) in THF (5 ml) contribute 2,4-dichloropyrimidine-5-carbaldehyde (example 17, 176 mg, 1 mmol) and stirred the mixture at RT for 30 min Then the mixture was poured into water and extracted with ethyl acetate. The extract was dried over sodium sulfate, the solvent is removed, getting 128 mg (82%) of orange solid.

MS (M+N)+155.

Example 19: (1 methanesulfonanilide-4-yl)-(1H-pyrazolo [3,4-d]pyrimidines

To a stirred solution of 6-chloro-1H-pyrazolo[3,4-d] pyrimidine (example 18, 61 mg, 0.40 mmole) in DMF (2.5 ml) is added sodium bicarbonate (60 mg) and 1-methanesulfonamido-4-ylamine (85 mg, 0.48 mmol) and stirred the mixture at 100°C for 15 hours the Solvent is removed under reduced pressure, and the OS is atok treated with water and extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated, obtaining a solid substance, which after purification by HPLC with reversed phase represents a nearly white solid. Yield 29 mg (29%). MS (M+N)+, 297.

Example 20: 1-(2,4-dichloropyrimidine-5-yl)ethanol

To a stirred solution of 2,4-dichloropyrimidine-5-carbaldehyde (example 17, 1.01 g, 5.7 mmole) in THF (10 ml) at -78°C. slowly add methylanisole (company Aldrich, 3-molar solution in ether, 6,27 mmol, 2.1 ml) and further stirred the mixture for 2 h at -78°C. Then stop the reaction by using 1-normal hydrochloric acid (10 ml). The resulting mixture is extracted with ethyl acetate and dried over sodium sulfate. The solvent is removed, getting 1.07 g (97%) of a brown solid. MS (M+N)+, 193.

Example 21: 1-(2,4-dichloropyrimidine-5-yl)alanon

To a stirred suspension of 1-(2,4-dichloropyrimidine-5-yl)ethanol (example 20, and 1.00 g, 5.2 mmole) in a mixture with methylene chloride (30 ml), THF (8 ml) and water (2 ml) add tetrabutylammonium (company Aldrich, 50 mg, 0.15 mmol), TEMPO (Aldrich company, 9 mg, 0.05 mmol) and sodium bicarbonate (208 mg, 2.48 per mmol). The mixture is cooled to 0°C. and with stirring, add colorex (company Aldrich, active Cl2, 10-13%, 3.75 ml)and then stirred for 2 h is ri 0°C. Add water (10 ml), separated the organic layer and dried over sodium sulfate. After removal of the solvent is oil, which is purified by chromatography on silica gel (1% MeOH/CH2Cl2)to give a colorless oil. The output 232 g (23%).

MC(M+H)+, 191.

Example 22: 6-chloro-1-H-pyrazolo[3,4-d] pyrimidine

To a stirred solution of hydrazine (Aldrich company, is 102.4 mg, 3.2 mmole) in THF (5 ml) was added 1-(2,4-dichloropyrimidine-5-yl)alanon (example 21, 191 g, 1 mmol) and stirred the mixture at RT for 1 h Then the mixture was poured into water (5 ml) and extracted (three times 5 ml) mixture of ethyl acetate/THF in a 1:1 ratio. The extract was dried over sodium sulfate and concentrated, obtaining a solid substance. Yield 126 mg (75%).

MS (M+N)+, 169.

Example 23: (1 methylpiperidin-4-yl)-(3-methyl-1H-pyrazolo [3,4-d]pyrimidine-6-yl)amine

To a stirred solution of 6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (example 22, 56 mg, 0.3 mmole) in DMF (1.5 ml) was added 1-methylpiperidin-4-ylamine (46 mg, 0.40 mmol) and stirred the mixture at 100°C for 2 hours the Solvent is removed and the residue chromatographic (5% 7-normal solution of ammonia in MeOH/CH2Cl2)to give 45 mg (61%) of a white solid.

MS (M+N)+, 247.

Example 24: 6-chloro-3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d] pyrimidine

To a stirred solution of (2,4-dichloropyrimidine-5-yl)-(5-fluoro-2-methoxyphenyl)methanone (602 mg, 2 mmole) in THF (8 ml) is added hydrazine (company Aldrich, 98%, 64 mg, 2 mmole) and stirred the mixture for 20 minutes, then add the secondary portion of hydrazine (0.1 ml). The reaction ends after 5 minutes the Solvent is removed, the solid is washed with a mixture of water/acetonitrile in the ratio of 3:1, getting 456 g (82%) of yellow solid.

MS (M+N)+, 278.

Example 25: [3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)Amin

In mix a solution of 6-chloro-3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (example 24; 97 mg, 0.35 mmole) in DMF (4 ml) add sodium bicarbonate (60 mg) and 1-methanesulfonamido-4-ylamine (93 mg, of 0.52 mmole) and stirred the mixture at 100°C for 4 h, the Reaction mixture is cooled and transferred into water (60 ml). The solid is filtered off and dried, obtaining a yellow solid, which after purification by HPLC with reversed phase, is a slightly yellow solid. Yield 52 mg (35%).

MC (M+N)+, 421.

Example 26: [3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo [3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)Amin

The same method described in example 25, from 6-chloro-3-(5-fluoro-2-IU is oxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (example 24; 97 mg, 0.35 mmole) and N-(4-aminocyclohexane)methanesulfonamide (101 mg, of 0.52 mmole), receive 70 mg (46%) of yellow solid.

MS (M+N)+, 435.

Example 27: [3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)Amin

The same method described in example 25, from 6-chloro-3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (example 24; 103 mg, 0.37 mmole) and (3S,4S)-4-amino-1-methanesulfonamido-3-ol (115 mg, of 0.59 mmole), receive 70 mg (46%) of yellow solid.

MS (M+N)+, 437.

Example 28: 1-(methanesulfonamido-4-yl)-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]amine; compound with triperoxonane acid

The connection is obtained from 6-chloro-3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (example 6) and 1-methanesulfonamido-4-ylamine connection with triperoxonane the acid is obtained analogously to the method described in example 4 and purified by HPLC, getting salt triperoxonane acid (36%).

MS (M+N)+, 403,24.

Example 29: [3-(2,6-differenl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-1-(methanesulfonamido-4-yl)Amin

The connection is obtained from 6-chloro-3-(2,6-differenl)-1H-pyrazolo[3,4-d]pyrimidine (example 8) and 1-methanesulfonamido-4-ylamine; connection with triperoxonane acid get nelogicno method described in example 4 and purified by HPLC (Gilson)to give the free base (34,5%). MS (M+N)+, 409,22.

Example 30: 1-(methanesulfonamido-4-yl)-(3-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]amine

The connection is obtained from 6-chloro-3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (example 14) and 1-methanesulfonamido-4-ylamine; connection with triperoxonane the acid is obtained analogously to the method described in example 4 and purified by HPLC (Gilson)to give the free base (21%).

MS (M+H)+, 373,24.

Example 31: [3-(3-forfinal)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-1-(methanesulfonamido-4-yl)Amin

The connection is obtained from 6-chloro-3-(3-forfinal)-1H-pyrazolo[3,4-d]pyrimidine (example 9) and 1-methanesulfonamido-4-ylamine; connection with triperoxonane the acid is obtained analogously to the method described in example 4 and purified by HPLC (Gilson)to give the free base (6%).

MS (M+N)+, 391,25.

Example 32: 4-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]benzosulfimide; connection with triperoxonane acid

6-Chloro-3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (example 6; 50 mg, 0,192 mmole) and sulfanilamide (Aldrich company, or 47.6 mg, 0,276 mmole) is combined with 2-propanol (1 ml) in a microwave tube and heated at 170°C for 10 min in a microwave oven (Smith Synthesizer, Personal Chemistry). The mixture is then cooled suspension is filtered and the solid is collected and washed with cold 2-propanol. Purification by HPLC gives to 40.1 mg (41%) of the substance in the form of a salt triperoxonane acid. MS (M+N)+, 397,1.

Example 33: [3-(2,6-differenl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(4-forfinal)Amin

The connection is obtained from 6-chloro-3-(2,6-differenl)-1H-pyrazolo[3,4-d]pyrimidine (example 12) and 4-foronline (company Aldrich) similar to the method described in example 32 (160°C). Filtering and washing the reaction mixture with 2-propanol gives named the title compound (59%). MS (M+N)+, 342,1.

Example 34: 2-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]ethanol

The connection is obtained from 6-chloro-3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (example 6) and ethanolamine (firm AnaLar) similar to the method described in example 32. Purification by HPLC gives named in the title compound with a yield of 24 mg (37%). MS (M+N)+, of 286.2.

Example 35: [3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]pentane-1,5-diamine; compound with triperoxonane acid

The connection is obtained from 6-chloro-3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (example 6) and 1.5-diaminopentane (firm ACROS) similar to the method described in example 32 (microwave range at 10°C). Purification by HPLC gives salt triperoxonane acid (68%). MS (M+N)+, 327,3.

Example 36: N-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-N,N-DIMETHYLPROPANE-1,3-diamine

The connection is obtained from 6-chloro-3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (example 6) and 3-diamino(Propylamine) (company Aldrich) similar to the method described in example 32 (120°C). Get to 9.2 mg (12%) of free base, and purification by HPLC the mother liquor gives salt triperoxonane acid (50 mg, 49%). MS (M+N)+, 327,2.

Example 37: N-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-N,N-dimethylpentane-1,5-diamine; compound with triperoxonane acid

The connection is obtained from 6-chloro-3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (example 6) and 5-(dimethylamino)amylamine (firm Matrix) is similar to the method described in example 32 (120°C). Purification by HPLC gives salt triperoxonane acid (59%). MS (M+N)+, 355,25.

Example 38: [3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]phenylamine

The connection is obtained from 6-chloro-3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (example 6) and aniline (Aldrich company) is similar to the method described in example 32 (175°C). Named the title compound is obtained with a yield of 69% MS (M+N)+, 318,2.

Example 39: (4-methoxyphenyl)-[3-(2-methoxyphenyl-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]benzosulfimide; connection with triperoxonane acid

The connection is obtained from 6-chloro-3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d] pyrimidine (example 6) and p-anisidine (company Aldrich) similar to the method described in example 32 (175°C). Purification by HPLC gives named the title compound as a salt triperoxonane acid with a yield of 59%. MS (M+N)+, 348,2.

Example 40: [3-(2,6-differenl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(2-methoxyphenyl)amine; compound with triperoxonane acid

The connection is obtained from 6-chloro-3-(2,6-differenl)-1H-pyrazolo[3,4-d]pyrimidine (example 12) and o-anisidine (company Aldrich) similar to the method described in example 32 (160°C). Purification by HPLC gives salt triperoxonane acid with a yield of 42%. MS (M+N)+, 354,1.

Example 41: 4-(3-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]benzosulfimide; connection with triperoxonane acid

The connection is obtained from 6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (example 22) and sulfanilamide (Aldrich company) is similar to the method described in example 32 (175°C). Purification by HPLC gives named the title compound as a salt triperoxonane acid with a yield of 13%. MS (M+N)+, 305,0.

Example 42: 2-(3-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]ethanol; compound with triperoxonane acid

The connection is obtained from 6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (example 22) and ethanolamine (firm AnaLar) similar to the method described in example 32 (120°C). Purification by HPLC gives salt triperoxonane acid with a yield of 56%. MS (M+N)+, 193,9.

Example 43: ethyl ester of 4-[3-(3-forfinal)-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]piperidine-1-carboxylic acid: the compound with triperoxonane acid

The connection is obtained from 6-chloro-3-(3-forfinal)-1H-pyrazolo[3,4-d]pyrimidine (example 9) and ethyl-4-amino-1-piperidinecarboxylate (company Aldrich) similar to the method described in example 32 (160°C). Purification by HPLC gives compound as a salt triperoxonane acid with a yield of 18%. MS (M+N)+, 385,1.

Example 44: 1-(methylpiperidin-4-yl)-(3-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl] amine

The connection is obtained from 6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (example 22) and 4-amino-N-methylpiperidine (company Aldrich) similar to the method described in example 32 (175°C). MS (M+N)+, 247.

Example 45

Pharmacological properties of the compounds of the present invention are confirmed by a number of pharmacological assays. The following as examples of pharmacological tests carried out with the compounds according to the invention and their salts. Compounds according to the invention show Cdk4/cyclin D activity reffering to what Chinami IC 50and Ki equal to less than 1.0 μm. In addition, the antiproliferative activity of some compounds according to the invention, has been tested on cell lines NST in the tissues of the human colon, showed the value of the IC50obtained at the MMT analysis, comprising less than 30 microns, preferably less than 5 microns.

Analyses kinases

To determine the inhibition of Cdk4, Cdk2 and Cdk1 activity of the kinase assays are performed using FlashPlateTManalyses (NENTM-Life Science Products). FlashPlate assays carried out using recombinant human cyclin B-Cdk1, human cyclin E-Cdk2 or human cyclin D1-Cdk4 complexes. GST-cyclin E (GST-cycE), Cdk2, GST-cyclin B (GST-cycB), Cdk1, GST-Cdk4 and cyclin D1 (cycD1) cDNA clones in baculovirus vectors provided by Dr. W. Harper from Baylor College of Medicine, Houston, TX. Proteins coexpressed in High FiveTMinsect cells and complex purified using glutathione Sepharose resin (Pharmacia, Piscataway, NJ), as previously described (J.W.Harper et al., Cell, 1993, 75, 805-816). 6x-Histidine-tagged truncated form of the protein retinoblastoma (Rb) (amino acid 386-928) are used as substrate for cycD1-Cdk4, cycB-Cdk1 and cycE-Cdk2 assays (expression plasmid provided by Dr. Veronica Sillivan, Departament of Molecular Virology, Roshe Research Centre, Welwyn Garden City, United Kingdom). Rb protein is a natural substrate for phosphorylation using Cdk4, Cdk2 and Cdk1 (see Herwig and Strauss, Eur. J.Biochem., vol.246 (1997), pp.581-601 and what can be found there reference).

The expression 62Kd control protein IPTG inducible promoter in M15 line E.coli. Cells are lysed by ultrasound and conduct clearing lysates at pH 8.0 through filled with Ni-melirovanie agarose column pre-treated with a 1 mm imidazole. The resin is then washed several times with buffer with gradually decreasing pH to 6.0 and outyouth 500 ml of imidazole. Alteromonas protein is subjected to dialysis with 20 mm HEPES pH 7.5, 30% glycerol, 200 mm NaCl and 1 mm DTT. In purified Rb fused protein was quantitatively estimated the protein concentration was divided into aliquots and stored at -70°C.

For all three analyses kinases described in this description, 96-mesh-Flash the tablet cover Rb protein at 10 μg/ml using 100 µl of the cell. Tablets incubated at 4°C overnight or for 3 h at room temperature on the vibrator. To control non-specific phosphorylation of a single row of cells cover 100 μl/cell buffer coating (20 mm HEPES, 0.2 M NaCl). The tablets are then washed twice with a buffer for laundering (0,01% Tween 20 in phosphate-bateriafina brine). Compounds to be tested ("test compounds") is added to the cells five times the final concentration. Reactions initiate immediate addition of 40 μl of reaction mixture (25 mm HEPES, 20 mm MgCl2, 0,002% Tween 20, 2 mm DTT, 1 μm ATP, 4 nm R-APR), is adding a sufficient amount of enzyme gives impulses, at least ten times greater than background values. Tablets incubated at room temperature on the vibrator for 30 min, and then washed four times with buffer to launder, sealed and read on a TopCount scintillation counter (Packard Instrument Co., Downers Grove, IL). The percentage inhibition of Rb phosphorylation, which is a measure of the inhibition of Cdk activity, determined according to the following formula:

where "test connection" refers to the average number of pulses per minute of the test doublets, "non-specific" refers to the average number of pulses per min, when cyclin D/Cdk and others have been added, and "total" refers to the average number of pulses per min, when no connection was not added. The value of the IC50denotes the concentration of the test compound, which is 50% reduces induced protein kinase introduction of radio frequency identification under the described test conditions.

The results of in vitro experiments are presented below in table 1.

Cellular analyses (analysis of cell proliferation using dye thiazolyl blue)

Proliferation was assessed by analysis of the staining dye thiazolyl blue according to the method proposed by Denizot and Lang (Denizot, F. and Lang, R., J.Immunol. Methods, 1986, 89, 271-277). Was used cell line NSC, cell is INIA colorectal carcinoma obtained from a typical American collection of cell cultures (ATSS; Rockville, MD). Cells grown in McCoy''s 5A medium supplied with 10% FCS (fetal calf serum) and L-glutamine. Cells are placed in tablets with the appropriate sowing density, giving a tenfold logarithmic growth compared with the analysis in 96-honeycomb tablet with tissue culture. Tablets incubated over night at 37°C in a humid incubator with 5% carbon dioxide. The next day, test compounds on the series 4 times was diluted to final concentration in the appropriate medium containing 1.2% of DMSO. One-fourth of each of the final volume of each dilution was added to the doublet in tablets containing cells. The same volume of 1.2% DMSO in medium was added to the number of "control cells" so that the final concentration of DMSO in each cell was 0.3%. An experiment in which cells were not added to cells, served as a "blind experience". An experiment in which cells were not added inhibitor, served as the "control without inhibitor. The tablets were returned to the incubator and when setting time points (defined by the curve of growth) tablets were analyzed as described below.

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium (thiazolyl blue; MTT; firm SIGMA) is added to each well to a final concentration of 1 mg/ml Tablets returned to the incubator for 2.5-3 h at 37°C. MTT-containing media is removed and the formed formazan metabolite dissolved in 100%ethanol with shaking for 15 min at RT. The optical density reading is carried out in titrations the microplate-reader (dynamic and molecular devices tablet readers are interchangeable) at a wavelength of 570 nm relative to 650 nm. The percent inhibition (% INH) is calculated by subtracting the optical density of the blind experience of all cells, and then subtracting the ratio of average optical density of each test duplicate (SAVE) to the average control (CAVE) of 1,00. The final number is then multiplied by 100 (% INH=(1,00-SAVE/CAVE)×100). The concentration at which received 50%inhibition of cell proliferation, determined from linear regression graph of concentration against the percentage of inhibition (in logarithmic scale). The value of the IC50also presented below in table 1.

This table presents the value of the IC50compounds of examples with Cdk4, Cdk2 and Cdk1 kinase assays, and the value of the IC50in cellular assays (MTT)

Table 1
Number exampleCdk4
IC50(µm)
Cdk2
IC50(µm)
Cdk1
IC50(µm)
MTT
IC50(µm)
160,041 0,244not determined4,5
190,2780,0330,2319,16
230,2780,2781,14not determined
250,0420,077not determinednot determined
260,1990,114not determinednot determined
270,0040,275not determined1,7
280,0140,0180,1071,2
290,2780,2780,86732
300,1280,1790,262 3,93
310,01850,231,13630
32being 0.0360,009not determinednot determined
332,52,5not determinednot determined
340,3440,594not determinednot determined
351,1191,852not determinednot determined
360,2780,278not determinednot determined
370,2780,278not determinednot determined
380,278,278 not determinednot determined
390,2780,278not determinednot determined
400,2780,278not determinednot determined
410,2780,024not determinednot determined
420,2780,278not determinednot determined
430,2780,278not determinednot determined
440,2780,278not determinednot determined

Example 46

Manufacturing tablets

RoomIngredients mg tablet
1Connection And*525100250500750
2Anhydrous lactose1038335193857
3Croscamellose sodium668163248
4Povidone K556122436
5Magnesium stearate111369
The total mass 120120150300600900
* Connection And represents the connection according to the invention

Method of manufacturing:

Mixed numbers 1, 2 and 3 in a suitable mixer for 15 minutes

Granularit powder mixture from stage 1 to 20% solution of Povidone K (number 4).

The dried granulate from stage 2 at 50°C.

Miss granulate from stage 3 through a suitable milling equipment.

Add the number 5 to pulverized to granules of stage 4 and mix for 3 minutes

Push the granules of stage 5 through a suitable press.

Example 47

Manufacturing capsules

RoomIngredientsmg/capsule
1Connection And*525100250500
2Anhydrous lactose159123148 --
3Corn starch2535403570
4Talc1015101224
5Magnesium stearate12236
Total filled weight200200300300600
* Connection And represents the connection according to the invention

Method of manufacturing:

Mixed numbers 1, 2 and 3 in a suitable mixer for 15 minutes

Add numbers 4 and 5 and mix for 3 minutes

Loaded into a suitable capsule.

Example 48

Preparation of injection solution/emulsion

RoomIngredientmg/ml
1*Connection And1 mg
2PEG 40010-50 mg
3Lecithin20-50 mg
4Soybean oil1-5 mg
5Glycerin8-12 ml
6Water (as needed)to 1 ml
*Connection And represents the connection according to the invention

Method of preparation:

Dissolve room 1 room 2.

Add the numbers 3, 4, and 5 to # 6, and stir until the formation of a dispersion, and then homogenized before the formation of a translucent dispersion.

Through a sterile filter with pores of 0.2 μm filter, and fill in the bubbles.

Example 49

Preparation of injection solution/emulsion

tr>
RoomIngredientmg/ml
1*Connection And1 mg
2Glucotrol10-50 mg
3Lecithin20-50 mg
4Soybean oil1-5 mg
5Glycerin8-12 ml
6Waterto 1 ml
* Connection And represents the connection according to the invention

Method of preparation:

Dissolve room 1 room 2.

Add the numbers 3, 4, and 5 to # 6, and stir until the formation of a dispersion, then homogenize.

Add the solution from stage 1 to a mixture of stage 2 and homogenize before the formation of a translucent dispersion.

Through a sterile filter with pores of 0.2 μm filter, and fill in the bubbles.

Although the invention is illustrated with reference to specific and preferred options, specialists in the art should be obvious that variations and modifications can be made without going beyond the scope of experimentation and p is ACTICE of the present invention. Thus, the invention is not limited to the above description but is defined by the claims and its equivalents.

1. The compound of formula (I):

or its pharmaceutically acceptable salt, where
R1choose from a group including:
(a) a saturated cyclic radical containing 3 to 8 ring atoms of which from 1 to 3 atoms are N, which can contain up to four substituents independently selected from the group including:
(i) lower alkyl; and
(ii) CO2R3, OR7or S(O)nR8;
(b)6-C10aryl, which may contain up to four substituents independently selected from the group including:
(i) S(O)nR8, lower alkyl, OR7and halogen;
(in)3-C8cycloalkyl, which may be substituted by NR5R6;
(g) a lower alkyl which may be substituted:
(i) OR7, NR5R6;
R2choose from a group including:
(i) H;
(ii) lower alkyl;
(iii)6-C10aryl which may be substituted with halogen, lower alkyl, lower alkoxygroup;
R3choose from a group including:
(i) H;
(ii) lower alkyl;
(iv)3-C8cycloalkyl;
R5and R6independently from each other selected from the group including:
(i) H;
(ii) lower alkyl;
(iii)3 -C8cycloalkyl;
(v) SO2R3;
(vi) CO2R3;
R7selected from the group comprising H and lower alkyl;
R8choose from a group including:
(iii) NR5R6;
(iv) lower alkyl; and
n is 1 or 2.

2. The compound according to claim 1, where R1selected from the group including piperidine, piperazine, pyrrolidine, phenyl, tolyl, xylyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl and hexyl.

3. The compound according to claim 2, where R1selected from the group including piperidine, phenyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl and pentyl.

4. The compound according to claim 1, where R1represents piperidine, substituted SO2CH3CH3SOON2CH3or HE; phenyl; phenyl substituted SO2NH2F or co3; or lower alkyl, substituted HE, NH2or N(CH3)2.

5. The compound according to claim 1, where R2selected from the group comprising H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl, hexyl, phenyl, tolyl and xylyl.

6. The compound according to claim 1, where R2denotes H, methyl or phenyl which may be substituted by fluorine or methoxy group.

7. The compound according to claim 1, selected from the group including
[3-(2,3-debtor-6-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine;
(1-methanesulfonamido-4-yl)-(1H-feast of the ash[3,4-d]pyrimidine-6-yl)amine;
(1 methylpiperidin-4-yl)-(3-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)amine;
[3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine;
(1-methanesulfonamido-4-yl)-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]amine; compound with triperoxonane acid;
[3-(2,6-differenl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine;
(1-methanesulfonamido-4-yl)-(3-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)amine;
[3-(3-forfinal)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine.

8. The compound according to claim 1, selected from the group including
4-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]benzosulfimide; connection with triperoxonane acid;
[3-(2,6-differenl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(4-forfinal)amine;
2-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]ethanol;
[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]pentane-1,5-diamine; compound with triperoxonane acid;
N'-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-N,N-DIMETHYLPROPANE-1,3-diamine;
N-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-N,N-dimethylpentane-1,5-diamine; compound with triperoxonane acid;
[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]phenylamine;
(4-methoxyphenyl)-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]amine; compound with triperoxonane acid;
[3-(2,differenl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(2-methoxyphenyl)amine; connection with triperoxonane acid;
4-(3-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]benzosulfimide; connection with triperoxonane acid.

9. The compound according to claim 1, selected from the group including
2-(3-methyl)-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]ethanol; compound with triperoxonane acid;
ethyl ester of 4-[3-(3-forfinal)-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]piperidine-1-carboxylic acid; compound with triperoxonane acid;
(1 methylpiperidin-4-yl)-(3-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)amine.

10. The compound according to claim 1, which represents [3-(2,3-debtor-6-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine.

11. The compound according to claim 1, which represents a (1-methanesulfonamido-4-yl)-(1H-pyrazolo[3,4-d]pyrimidine-6-yl)amine.

12. The compound according to claim 1, which represents [3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine.

13. The compound according to claim 1, which represents [3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4-yl)amine.

14. The compound according to claim 1, which represents a (1-methanesulfonamido-4-yl)-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]amine; compound with triperoxonane acid.

15. The compound according to claim 1, which represents [3-(3-forfinal)-1H-pyrazolo[3,4-d]pyrimidine-6-yl]-(1-methanesulfonamido-4 and is)Amin.

16. The compound according to claim 1, which represents 4-[3-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino]benzosulfimide; connection with triperoxonane acid.

17. Pharmaceutical composition having anti-proliferative activity, comprising an effective amount of the compounds of formula (I)

or its pharmaceutically acceptable salts, where R1and R2defined in claim 1, and pharmaceutically acceptable filler.

18. Pharmaceutical composition for 17 intended for the preparation of drugs for the treatment of cancer.

19. The pharmaceutical composition according to 17 for the treatment of solid tumors.

20. Pharmaceutical composition for 17 intended for the preparation of drugs for the treatment of tumors of the breast, lung, colon or prostate.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I and to their pharmaceutically acceptable salts exhibiting inhibitory activity in relation to kinases chosen from Abl, Bcr-Abl, Bmx, BTK, b-RAF, c-RAF, CSK, cSRC, Fes, FGER3, Elt3, 1KKα, 1KKβ, JNK1α1, JNK2α2, Lck, Met, MKK4, MKK6, p70S6K, PAK2, PDGFRα, PKA, PKCα, PKD2, ROCK-II, Ros, Rsk1, SAPK2α, SAPK2β, SAPK3, SAPK4, SGK, Syk, Tie2 and TrkB. In compounds of formula I , n is equal to 1, m is equal to 0, Y1 is chosen from N and CR5, and R5 represents hydrogen, Y2 represents O, R1 represents hydrogen, R2 is chosen from hydrogen and C1-C6alkyl, R3 is chosen from a group including hydrogen, C1-C6alkyl, C1-C6alkoxy, R4 is chosen from NR5C(O)R6 and -C(O)NR5R6 where R5 is chosen from hydrogen and C1-C6 alkyl, and R6 represents phenyl optionally substituted with 1-3 radicals chosen of a group including NR3R3, halogen-substituted C1-C6alkyl, C5-C6heteroaryl(C0-C4)alkyl where heteroaryl contains 1-2 heteroatoms chosen from N and O, C5-C6heterocyclo(C0-C4)alkyl, where heterocyclyl contains 1-2 heteroatoms of N, and C5-C6heterocyclo(C0-C4)alkoxy where heterocyclyl contains 1-2 heteroatoms of N, and any heteroaryl or heterocyclyl contained in R6 is optionally substituted by 1-3 radicals independently chosen from a group including C1-C6alkyl and hydroxy(C1-C6)alkyl.

EFFECT: producing the compounds which can find application for treatment or prevention of diseases or disorders associated with abnormal or unregulated kinase activity, such as proliferative diseases, diseases of immune and nervous system.

8 cl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel chemical compound - 1-(2-isopropoxyethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo [3,2-d]pyrimidin-4-one and pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds and use thereof. Disclosed compound has myeloperoxidase enzyme inhibiting properties.

EFFECT: compounds are especially useful in treating and preventing neuroinflammatory disorders such as Parkinson's disease, cardiovascular disorders and respiratory disorders.

3 cl, 1 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and pharmaceutically acceptable salts thereof, where substitutes R1-R4 are as defined in claim 1. Said compounds have 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme inhibiting activity.

EFFECT: compounds can be used in form of a pharmaceutical composition.

15 cl, 1 tbl, 94 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazopyrazines of formula where Q1 and R1 have the values specified in the patent claim, and to their pharmaceutically acceptable salts showing IGF-1R enzyme inhibiting activity and applicable for treatment and/or prevention of various diseases and conditions which are sensitive to tyrosine kinase inhibition.

EFFECT: preparation of the compounds showing IGF-1R enzyme inhibiting activity.

27 cl, 294 ex

Chemical compounds // 2405780

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I): , in which: R1 and R2 are independently specified from hydrogen, C1-6alkyl, C1-6alkoxy and cyclopropyl; X1, X2 and X3 independently represent =N- or =CR10; R3 and R10 are independently specified from hydrogen, halogen, nitro, cyano, amino, carboxy, carbamoyl, C1-6alkyl, N-(C1-6alkyl)amino, N,N(C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkoxycarbonyl; R4 represents hydrogen; R5 and R6 are independently specified from hydrogen, hydroxy and C1-6alkyl where R5 and R6 independently can be optionally substituted in carbon atom with one or more R16 where R16 represents hydroxy; A represents a single link or C1-2alkylene; where specified C1-2alkylene can be optionally substituted with one or more R18; the ring C represents a saturated, partially saturated or unsaturated mono- or bicyclic ring containing 5 or 6 atoms in which at least one atom can be specified from nitrogen, sulphur or oxygen which can be linked with carbon or nitrogen atom where the -CH2- group can be optionally substituted with -C(O)- and ring sulphur atom can be optionally oxidised to produce S-oxide; R7 is specified from halogen and C1-6alkyl where R7 can be optionally substituted in carbon atom with halogen; n is equal to 0.1 or 2; where R7 values can be equal or different; and R18 is independently specified from halogen and hydroxy; or its pharmaceutically acceptable salt. Also the invention refers to their pharmaceutical compositions and methods for preparation and application thereof for cancer treatment.

EFFECT: preparation of new compounds which can find application for cancer treatment.

23 cl, 96 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of N-(5-[3-(thiophene-2-carbonyl)-pyrazole[1,5-a]pyrimidin-7-yl]-2-fluoro-phenyl}-N-methyl-acetamide in polymorphic modification B, in which (5-amino-1H-pyrazol-4-yl)-thiophen-2-yl-methanone reacts with N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide in a solvent selected from a group comprising acetic acid, propionic acid and methanoic acid at 50°C until boiling point of the mixture is reached. (C1-C4)-alcohol is then added to the obtained mixture at temperature of 40°C-80°C, after which the obtained mixture is kept for at least 30 minutes a temperature of 30°C- 55°C for initiating crystallisation. The crystalline product is then separated.

EFFECT: method of obtaining a compound in polymorphic modification B, which can be used in medicine in treating and preventing anxiety, epilepsy, sleep disorders and insomnia.

8 cl, 3 dwg, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of derivatives in the family of pyrrole[3,4-c]carbazole, and specifically to a method for synthesis of novel 2-R1-6-R2-5-aryl-pyrrole[3,4-c]carbazole-1,3(2H,6H)-diones of formula I: , where R1=:C1-C6 alkylphenyl, C1-C6 dialkylphenyl, C1-C6 dialkylphenyl dioxy C1-C6 alkyl; R2=C1-C6 alkyl; Ar=phenyl, C1-C6 alkyl phenyl, oxyalkylphenyl, halophenyl, having potential anticancer activity. The method involves reacting 1-R2-indolin-2-ones of general formula II with oxalyl chloride and 4-aryl-3-butenoic acid of general formula III, reacting the formed 3-(2-chloro-1-R2-1H-indol-3-yl)-4-[(E)-2-arylethenyl]furan-2,5-diones of general formula IV with R1-amines of general formula R1-NH2 V, and then photocyclisation of the formed 1-alkyl-3-(2-chloro-1-R2 -1H-indol-3-yl)-4-[(E)-2-arylethenyl]-1H-pyrrole-2,5-diones of general formula VI, where R1, R2 and Ar assume values listed above.

EFFECT: method for synthesis of novel derivatives having potential anticancer activity.

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound - a sodium salt of 2-ethylthio-6-nitro-1,2,4-triazole[5,1-c]-1,2,4-triazin-7-one dihydrate of formula (1)

.

EFFECT: higher antiviral activity which can be used in medicine, stockbreeding and poultry farming.

2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) in form of (R) or (S) isomers, separately or in a mixture, as well as their physiologically acceptable salts and hydrates, having vitronectin receptor antagonist properties. In formula (I)

G denotes Het-NH-CO-, Het-NH-CH2-, Het-; Het denotes a mono- or bicyclic system, where each ring is a 5- or 6-member aromatic or non-aromatic ring, where at least one of the rings contains 1-2 nitrogen atoms as heteroatoms, where Het is unsubstituted or substituted with R9 groups; R1 denotes H, (C6-C14)-aryl, (C6-C14)aryl(C1-C4)alkyl; amino, unsubstituted, mono-or disubstituted with alkyl and/or acyl, containing 1-4 C atoms; R2 denotes H, halogen, nitro-group; alkyl containing 1-4 C atoms; amino, unsubstituted, mono- or disubstituted with alkyl and/or acyl containing 1-4 C atoms; a -(CH2)0-2-OR5 group; R3 denotes H, -CO2R5, -SO2R5 or mono- or bicyclic system, where each ring denotes a 5- or 6-member aromatic or non-aromatic ring, where at least one of the rings contains 1-4 heteroatoms selected from N, O or S, unsubstituted or substituted with R9 radicals; R4 denotes OH, (C1-C8)alkoxy-; amino, unsubstituted, mono- or disubstituted with (C1-C4)alkyl; or an aminoacid residue; R5 denotes (C1-C8)alkyl; (C6-C14)aryl; (C6-C14)aryl(C1-C4)alkyl; (C3-C12)cycloalkyl or (C3-C12)cycloalkyl(C1-C4)alkyl; bi- and tricycloalkyl(C1-C4)alkyl. Aryls, alkyls, cycloalkyls are not substituted or substituted with R9 groups; R9 denotes halogen, amino, nitro, hydroxyl, (C1-C4)alkyloxy-, carboxy, (C1-C4)alkyloxycarbonyl-, (C1-C8)alkyl, unsubstituted or substituted with halogen atoms; phenyl. The invention also relates to a methods for synthesis of formula (I) compounds, a medicinal agent and a pharmaceutical composition containing said compounds, as well as use thereof in preparing the medicinal agent.

EFFECT: improved properties of the compound.

21 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to anthracenedione derivatives which are suitable for therapy of oncological diseases, having the formula:

, where W is a fragment of a five-member heterocycle containing one or two heteroatoms selected from N, O or S, optionally substituted with alkyl, halogen; Y is a monocyclic diamine residue containing an exocyclic amine group, or a polycyclic diamine with bridging amine groups, which is a compound in which two amine groups are involved in formation of 4- or 6-member ring systems containing 2-6 carbon atoms and bonded by one, two or three bridging atoms, where Y is optionally substituted with one or more substitutes selected from alkyl, halogenalkyl, halogen, hydroxyl, hydroxyalkyl, carbamoyl and CO2R, where R denotes alkyl; X denotes alkylene, CO or SO2; n and m are independently range from 0 to 2; Z1 is selected from hydroxy, alkoxy -NH2, -NHR1, -NR1R2, where R1 and R2 denote alkyl, aminoalkylamino, halogen; Z2 is selected from hydroxy, alkoxy, fluorine.

EFFECT: obtaining novel anti-tumour compounds.

1 cl, 18 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to anthracenedione derivatives which are suitable for therapy of oncological diseases, having the formula:

, where W is a fragment of a five-member heterocycle containing one or two heteroatoms selected from N, O or S, optionally substituted with alkyl, halogen; Y is a monocyclic diamine residue containing an exocyclic amine group, or a polycyclic diamine with bridging amine groups, which is a compound in which two amine groups are involved in formation of 4- or 6-member ring systems containing 2-6 carbon atoms and bonded by one, two or three bridging atoms, where Y is optionally substituted with one or more substitutes selected from alkyl, halogenalkyl, halogen, hydroxyl, hydroxyalkyl, carbamoyl and CO2R, where R denotes alkyl; X denotes alkylene, CO or SO2; n and m are independently range from 0 to 2; Z1 is selected from hydroxy, alkoxy -NH2, -NHR1, -NR1R2, where R1 and R2 denote alkyl, aminoalkylamino, halogen; Z2 is selected from hydroxy, alkoxy, fluorine.

EFFECT: obtaining novel anti-tumour compounds.

1 cl, 18 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel group of chemical-pharmaceutical bioconjugates, which can be obtained by indirect synthesis by means of molecular spacer between hyaluronic caid and/or its derivatives and medications with anti-tumour activity, belonging to different groups, method of their obtaining. Invention also relates to anti-tumour pharmaceutical compositions and three-dimensional biomaterials based on said conjugate.

EFFECT: novel derivatives, depending on bond type and substitution degree, have different physical-chemical properties, which improve their tolerance and efficiency and ensure possibility of more accurate modulating dosage by using mechanism of active targeting.

31 cl, 4 dwg, 16 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to oncology, and can be used in treatment of mammary gland cancer (MGC). Method is realised in the following way. After confirmation of malignant character of tumour tissue in patient sampling of 200 ml of blood from peripheral vein into reservoir with hemopreservative is carried out, after that it is centrifuged with separation of plasma, which is combined with cyclophosphane in amount 400 mg/m2, doxorubincin in dose 40 mg/m2 is introduced into erythrocyte mass; both reservoirs are incubated in thermostat for 30 minutes at temperature 37°C. After that, sucking of blood from the place of tumour tissue sampling is carried out with further introduction into it of 200 mg of cyclophosphane diluted in 5 ml of physiological solution. Tissue of mammary gland around tumour is infiltrated with incubated plasma with cyclophosphane, and erythrocyte mass with doxorubicin is introduced intravenously by drop infusion.

EFFECT: application of the invention makes it possible to increase efficiency of MGC treatment due to creation of maximal concentration of chemical preparations in leision focus and prevention of tumour process dissemination.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medications and deals with application of miliacin as medication which increases antitumour effect of methotrexate.

EFFECT: extension of arsenal of medications, which increase antitumour effect of methotrexate.

3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to photosensitiser, which represents nanostructured water dispersion based on bacteriochlorin p derivative, namely methyl ester of O-ethyloxime N-etoxycycloimide bacteriochlorin p C38H46N6O6. Invention also relates to method of said photosensitiser obtaining, including reaction of methyl ester of bacteriopurpurin in main solvent with etoxyamine chlorhydrate at room temperature for 72-80 hours, which is finished after displacement of spectral maximum of reaction mixture absorption to 802 nm. Invention also relates to method of photodynamic therapy, which includes introduction of said photosensitiser and irradiation of pathologic part with optic irradiation in spectrum range 790-810 nm 0.7-5 hours after introduction.

EFFECT: invention ensures high efficiency and selectivity of action of photodynamic therapy of large-size tumours and pigment tumours, including melanoma.

6 cl, 5 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, in particular to pharmaceutical composition for treatment of oncologic diseases in form of phospholipid nanoparticles with size 10-30 nm, which includes phosphatidelcholin, maltose and doxorubicine with the following ratio of components, wt. %: phosphatidelcholin 20-43, maltose 55-78, doxorubicine 2-8. Composition is accumulates in tumour tissue more actively and slows down tumour growth in mice with carcinoma LLC more efficiently in comparison with free doxorubicine.

EFFECT: composition represents freeze-dries powder, stable in long storage, which dissolving in water gives nanophpospholipid particles with included doxorubicine.

3 dwg, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new capmtotecin derivatives of a following structure of formula (I) where R1 represents H, C1-C4alkyl, branched C1-C4alkyl or vinyl, as well as to a pharmaceutical composition exhibiting antineoplastic activity and based on the given compounds, and to application thereof for making a drug for treating tumours.

EFFECT: there are produced and described new compounds which exhibit high antineoplastic activities and have good water-solubility; they can be applied for creating new drugs.

7 cl, 3 ex, 3 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to novel derivatives of cis-2,4,5-triarylimidazoline of general formula I and pharmaceutically acceptable salts thereof, where X1 is selected from a group comprising lower alkoxy; X2 and X3 are independently selected from a group comprising hydrogen, halogen, cyano, lower alkyl, lower alkoxy, piperidinyl, -NX4X5, -SO2NX4X5, -C(O)NX4X5, -C(O)X6, -SOX6, -SO2X6, -NC(O)-lower alkoxy, -C≡C-X7, provided that both X2 and X3 do not denote hydrogen, lower alkyl or lower alkoxy, provided that when X2 or X3 denote hydrogen, the other does not denote lower alkyl, lower alkoxy or halogen, provided that when X2 denotes -HX4X5, X3 does not denote hydrogen, X2 and X3 together can form a ring selected from 5-7-member unsaturated rings which can contain three heteroatoms selected from S, N and O, X4 and X5 are independently selected from a group comprising hydrogen, lower alkyl, lower alkoxy, lower alkyl, substituted by a lower alkoxy, -SO2-lower alkyl, -C(O)piperazinyl-3-one; X6 is selected from a group comprising lower alkyl, morpholine, piperidine, pyrrolidine; X7 is selected from a group comprising hydrogen, lower alkyl, trifluoromethyl; Y1 and Y2 are independently selected from a group comprising halogen; R is selected from a group comprising lower alkoxy, piperidinyl substituted with a five-member heterocyclic ring which contains one nitrogen heteroatom, piperidinyl substituted with a hydroxy, -CH2OH or -C(O)NH2, piperazinyl substituted with one or two R1 [1,4]diazepanyl, substituted R1, R1 can denote one or two substitutes selected from a group comprising oxo, lower alkyl substituted with one R2, -C(O)R3, -SO2-lower alkyl, -SO2-five-memer heterocyclyl, which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl; R2 is selected from a group comprising -SO2-lower alkyl, hydroxy, lower alkoxy, -NH-SO2-lower alkyl, -cyano, -C(O)R4; R3 is selected from a group comprising a five-member heterocyclyl which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl, lower alkyl, lower alkenyl, lower alkyl substituted with a six-member heterocyclyl selected from piperidinyl, piperazinyl, 3-oxopiperazinyl, morpholinyl, C3-cycloalkyl; R4 is selected from a group comprising hydroxy, morpholine, piperidine, 4-acetylpiperazinyl, -NR5R6; R5 and R6 are independently selected from a group comprising hydrogen, lower alkyl, lower alkyl substituted with lower alkoxy or cyano, lower alkoxy and C3-cycloalkyl. The invention also relates to a pharmaceutical composition based on the formula I compound, use of the formula I compound in preparing a medicinal agent and a method for synthesis of the formula I compound.

EFFECT: novel derivatives of cis-2,4,5-triarylimidazoline of general formula I are obtained, which can be used to treat diseases, based on reaction of the MDM2 protein with p53-like protein, particularly as anticancer agent.

54 cl, 412 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

Up!