Novel 2,4-diaminothiazol-5-one derivatives

FIELD: chemistry.

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

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

6 cl, 1 tbl, 22 ex

 

The invention relates to new derivatives of 4-aminothiazole that inhibit cyclin-dependent kinases. These compounds and their pharmaceutically acceptable salts and esters possess antiproliferative activity and are used to treat or suppress the development of cancer, especially solid tumors. In addition, the present invention relates to pharmaceutical compositions containing such compounds, and to methods for treating or inhibiting the development of cancer, it is most preferable treatment and suppressing the growth of tumors of the breast, lung, colon and prostate. Finally, the present invention relates to new intermediate compounds, which are used for obtaining described in the text of the application of new derivatives of 4-aminothiazole.

Uncontrolled cell proliferation is a cancer marker. Tumor cells usually contain some form of damage to genes that directly or indirectly regulate the cell division cycle.

The development of cells in different phases of the cell cycle is regulated by a series of multienzyme complexes, consisting of a regulatory protein cyclina and kinases. Such kinases called cyclin-dependent kinases (Cdk). Kinase Cdk expressroute during the cell cycle, while the level of tsiklonov changes according to ustadji cell cycle.

Four main phases of the cell cycle are called G1, S, G2and M. the Key enzymes in the regulation of the cell cycle are cyclin D/Cdk4, cyclin D/Cdk6, cyclin E/Cdk2, cyclin A/Cdk2 and cyclin B/Cdk1 (also known as Cdc2/cyclin B). Cyclin D/Cdk4, cyclin D/Cdk6 and cyclin E/Cdk2 control the passage of G1phase and the transition from the G1- in S-phase by phosphorylation of the phosphoprotein pRb retinoblastoma. Cyclin A/Cdk2 regulates the passage of S phase, and cyclin B/Cdk1 controls the control point G2and regulates entry into M phase (mitosis).

The development of cell cycle regulated kinases Cdk1 (cdc2 and Cdk2 immediately after the G1when cells are transferred to cytokinesis. Therefore, it can be assumed that the inhibition of drugs these kinases Cdk not only blocks cell proliferation, but also initiates cell death by apoptosis. After the transition of cells through the control point G1and entry into S phase, they become independent from the stimulation of the growth factor for cell cycle progression.

After completion of DNA replication cells pass into the G2the phase of the cell cycle to prepare for the M phase and cytokinesis. It is established that the kinase Cdk1 regulates the passage of cells through the last two phases of the cell cycle in Association with cyclename a and B. For the full activation of Cdk1 associate about the x tsiklonov and specific phosphorylation (Morgan D.O., De Bondt H.L., Curr. Opin. Cell. Biol., 6, 239-246 (1994)). After activating complexes with Cdk1/cyclin prepare the cell for division during M phase.

The transition from phase G1in the S phase, as stated above, is regulated by a complex of Cdk4 with cyclin D and Cdk2 with cyclin E. These complexes phosphorylate the tumor suppressor protein retinoblastoma (pRb), releasing the transcription factor E2F and contributing expresii of genes required for S phase (Nevins J.R., Science, 258, 424-429 (1992), Lavia p, BioEssays, 21, 221-230 (1999)). The blocking activity of complexes of Cdk4/cyclin D and Cdk2/cyclin E stops the cell cycle in the phase of G1. For example, proteins of the INK4 family, including protein p16INK4athat blocks the kinase activity of the complex of Cdk4/cyclin D, causes a stop in the phase of G1(Sherr C.J., Science, 274, 1672-1677 (1996)). The specificity of the block is described in detail in the literature (see Vidal, A., Gene, 247, 1-15 (2000)).

Modern evidence suggests that the complex of Cdk4 with cyclin D3 also plays a role in the development of the cell cycle when passing phase G2. Inhibition of this complex protein P16 or using dominant negative Cdk4 leads to a stop in the phase of G2cells that do not Express pRb (Gabrielli B.G. and others, J. Biol. Chem., 274, 13961-13969 (1999)).

It is established that numerous defects in the way pRb observed in various cancer types. For example, overexpression of Cdk4 nabludaetsa is in cases of hereditary melanoma (Webster K.R., Exp. Opin. Invest. Drugs, 7, 865-887 (1998)), cyclin D sverkhekspressiya in many human cancers (Sherr C.J., Science, 274, 1672-1677 (1996)), P16 protein mutated or absent in many tumors (Webster K.R., Exp. Opin. Invest. Drugs, 7, 865-887 (1998)), a function of pRb lost due to mutations or deletions in many types of human cancer (R.A. Weinberg, Cell, 81, 323-330 (1995)). It is established that defects in this way influence the forecast. For example, the loss of P16 protein correlates with a negative prognosis for non-small cell lung carcinoma (NSCLC) and malignant melanoma (Tsihlias j, and others, Annu. Rev. Med., 50, 401-423 (1999)). Defects cycline D1 and/or pRb at the level of the gene and/or expression are present in more than 90% of cases of non-small cell lung cancer, suggesting that cyclin D1 and/or pRb represent an important stage in the process of lung carcinogenesis (Marchetti, A. and others, Int. J. Cancer, 75, 573-582 (1998)). In 49 out of 50 cases of carcinoma of the pancreas (98%) path pRb/pl6 suppressed solely due to the inactivation of the gene P16 protein and its associated Collina D (Schutte M. and others, Cancer Res., 57, 3126-3134 (1998)). The relationship between the expression of pRb and cyclin/cyclin-dependent kinases in a number of tissues described in article Teicher, VA, Cancer Chemother. Pharmacol., 46, 293-304 (2000).

In connection with the participation of the way Cdk4/cyclin D/pRb in processee of carcinogenesis in humans due to the regulation of the transition of the cell cycle from phase G1in phase S, and thanks to an efficient therapeutic effect when module is the formation of this path, there is a need to develop agents that inhibit or stimulate the individual stages of this journey. For example, the effect on cancer cells, antibodies, antisense oligonucleotides, and overexpression or adding proteins involved in this pathway. See, for example, Lukas J., and others, Nature, 79, 573-582 (1995), Nevins J.R., Science, 258, 424-429 (1992), Lim, I.K. and other, Molecular Carcinogenesis, 23, 25-35 (1998), Tam S.W., and others, Oncogene, 9, 2663-2674 (1994), Driscoll C., and others, Am.J. Physiol., 273 (Lung Cell. Mol. Physiol.), L941-L949 (1997) and Sang J. and others, Chin. Sci. Bull., 44, 541-544 (1999)).

The role of cdk kinases in the regulation of cell proliferation is thus completely proved. For example, as described above, there is a lot of data, confirming the possibility of using compounds, inhibiting the target in the ways of Cdk4, Cdk2 and Cdk1, as antiproliferative therapeutic agents. Thus, inhibitors of cell proliferation act as reversible cytostatic agents which are used in the treatment of pathological conditions associated with abnormal cell growth, such as various types of cancer and other disorders of cell proliferation, including, for example, the inflammatory process (e.g., benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, inflammatory disease of the key is ecnica, infection due to graft rejection), viral infections (including, without limitation, herpes virus, poxvirus, Epstein-Barr), autoimmune disease (e.g., common lupus, rheumatoid arthritis, psoriasis, inflammatory bowel disease), neurodegenerative disorders (including, without limitation, Alzheimer's disease and neurodegenerative diseases such as Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, muscular atrophy and cerebellar degeneration).

As inhibitors of Cdk kinases identified several classes of low molecular weight compounds: 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, para-terizidone and pyrazoles (Carlson and others, Cancer Res., 56, 2973-2978 (1996), De Azevedo and others, Eur. J. Biochem., 243, 518-526 (1997), A.J. Bridges, Exp. Opin. Ther. Patents., 5, 1245-1257 (1995), Reinhold and others, J. Biol. Chem., 278, 3803-3807 (1998), Kakeya, H., and others, Cancer Res., 58, 704-710 (1998), Harper J.W., Cancer Surveys, 29, 91-107 (1997), E.A. Harrington and others, Proc. Natl. Acad. Sci. USA, 95, 11945-11950 (1998), Meijer L., and others, Eur. J. Biochem., 267, 1-13 (2000), Garrett M.D., and others, Current Opin. Genetics Develop., 9, 104 to 111 (1999), Mgbonyebi O.R. and others, Cancer Res., 59, 1903-1910 (1999), Hoessel, etc., Nature Cell Biology, 1, 60-67 (1999), Zaherevitz and others, Cancer Res. 59, 2566-2569 (1999), Honma T., and others, 221stNational ACS Meeting., Medi 136 (2001). Sielecki T.M., and others, Bioorg. Med. Chem. Lett., 11, 1157-1160 (2001), Nugiel D.A., and others, J. Med. Chem., 44, 1334-1336 (2001), D.W. Fry and others, J. Biol. Chem., 276, 16617-15523 (2001), Soni R., and others, Biochem. Biophys. Res. Commun., 275, 877 (2000), Ryu C-K., and others, Bioorg. Med. Chem. Lett., 10, 461 (2000), Jeong H-W., and others, Bioorg. Med. Chem. Lett., 10, 1819 (2000), Toogood, etc., J. Med. Chem., 43, 4606-4616 (2000), Chong, W., Fischer, Curr. Opin. in Drug Discov. and Develop., 4, 623-634 (2001), WO 0009921845, Toogood. P., WO 0119825, Toogood, P., WO 0138315, Reich S.H., WO 0179198, Webster K. US 6262096.

Overview of compounds inhibiting path Cdk4/cyclin D can be found in the literature, see W. Harris and S. Wilkinson, Emerging Drugs, 5, 287-297 (2000), Dumas J., Exp. Opin. Ther. Patents., 11, 405-429 (2001), Sielecki T. and others, J. Med. Chem., 43, 1-18 (2000), WO 99/21845, 6569878 B1, 2003/0220326 A1 and WO 2003011843 A1, and in each of the specified document describes 4-aminothiazole General formula

.

It is established that these compounds are inhibitors of cyclin-dependent kinases.

The present invention relates to new derivatives of 4-aminothiazole formula

,

where

R1selected from the group including

(a) (ness.)alkyl, substituted aryl,

(b)

and

(C)

R2choose comprising aryl, heteroaryl, cycloalkyl and heterocycle, each of which is substituted by 1-4 substituents, independent selected from the group including (a) (ness.)alkyl, (b) halogen, (C) OR5, (d) NH2and (e) NOsub> 2,

R3selected from the group comprising (a) H, (b) (ness.)alkyl, (C) CO2R6,

(d) C(O)R6, (e) SO2R6and (f) SO2NR5R6,

R4and R4'each independently selected from the group comprising (a) H, (b) (ness.)alkyl, optionally substituted by oxo groups, CO2R6, OR6and/or NH2(with) S(O)nR7, (d) OR8, (e) NR5R6and (f) CO2R6,

R5and R6each independently selected from the group comprising (a) N (b) N (c) (ness.)alkyl, (d) (ness.)alkyl, substituted groups, oxo, CO2R9, OR9and/or NR10R11, (e) aryl, optionally substituted with halogen, (f) heteroaryl, (g) N-aryl, where aryl group optionally substituted by one or more Halogens, and (h) aryl, substituted by halogen or CF3,

R7means (ness.)alkyl or aryl,

R8selected from the group comprising (a) H, (b) (ness.)alkyl, and (C) (ness.)alkyl, substituted NR5R6,

R9selected from the group comprising H and (ness.)alkyl,

R10and R11each independently selected from the group comprising H and (ness.)alkyl, and

n is 0, 1 or 2,

or their pharmaceutically acceptable salts or esters.

These compounds inhibit cyclin-dependent kinases. These compounds and their pharmaceutically acceptable salts and complex EF the market possess antiproliferative activity and are used in the treatment or suppression of cancer development first of all solid tumors.

The present invention relates also to pharmaceutical compositions comprising one or more compounds according to the invention or their pharmaceutically acceptable salt or ester and a pharmaceutically acceptable carrier or excipient.

In addition, the present invention relates to the use of compounds of formula I to obtain drugs for the treatment of cancer, preferably solid tumors, and more preferably breast cancer, lung, colon and prostate cancer.

In addition, the present invention relates to a method of treating or inhibiting the development of cancer, primarily for the treatment or suppression of the development of solid tumors, most preferably for the treatment or suppression of cancer of the breast, lung, colon and prostate cancer, and this method includes the introduction to a patient in need of such treatment, a therapeutically effective amount of compounds of formula I or its pharmaceutically acceptable salt or ester.

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

The terms used in the description of the application, have the following meanings.

"Aryl" means a monovalent monocyclic the cue or bicyclic aromatic carbocyclic hydrocarbon radical, preferably 6-10-membered aromatic cyclic system. Preferred aryl groups include, without limitation, phenyl, naphthyl, tolyl and xylyl.

"Cycloalkyl" means 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 the amount (of the material), which effectively prevents, reduces or suppresses the symptoms of disease or prolong the life of the subject in need of treatment.

"Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

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

"Heteroaryl" means an aromatic cyclic heterocyclic system containing up to two cycles. Preferred heteroaryl groups include, without limitation, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyridine, pyrazinyl, oxazolyl, tixall, chinoline, pyrimidine, imidazole, benzofuran and tetrazolyl.

"Heterocyclyl" means a saturated or partially unsaturated non-aromatic cyclic radical containing in the cycle of 3-8 atoms, of which 1-3 atoms are heteroatoms selected from nitrogen atoms, oxygen, S(O n(where n is an integer from 0 to 2), or their combinations, and the remaining atoms in the cycle are carbon atoms. Examples of preferred heterocyclyl are piperidine, piperazine, pyrrolidine, morpholine, indoline, tetrahydropyranyl, thiomorpholine, pentamethylbenzene and pentamethylbenzene.

"KI" is a measure of thermodynamic binding ligand/inhibitor (i.e. compounds according to the invention) with a protein target. Kidetermine as described below in example 18.

The term "(ness.)alkyl", used alone or as part of another term, for example, (ness.)alkylglycerol, means a saturated aliphatic hydrocarbon straight or branched chain, containing from 1 to 6 inclusive, preferably from 1 to 4 carbon atoms. Typical (ness.)alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl, hexyl, etc.

"Oxo" refers to the group =O.

"Pharmaceutically acceptable ester" means esterified compound of the formula I containing a carboxyl group and esters retain the biological activity and properties of the compounds of formula I and are oxidized in vivo (in the body) with the formation of the corresponding active carboxylic acid. Examples of ester groups, which are (in this case hydrolyzed) in vivo images of the of the corresponding carboxylic acids (R 40C(=O)OH), are (ness.)alkalemia esters, substituted by a group NR41R42where R41and R42mean (ness.)alkyl, or where NR41R42together form a monocyclic aliphatic heterocycle, such as pyrrolidine, piperidine, morpholine, N-methylpiperazine etc.; aryloxyalkyl esters of the formula R40C(=O)OCHR43OC(=O)R44where R43means hydrogen or methyl, and R44means (ness.)alkyl or cycloalkyl; esters of carbonic acid (carbonates) of the formula R40C(=O)OCHR43OC(=O)OR45where R43means hydrogen or methyl, and R45means (ness.)alkyl or cycloalkyl; or aminocarbonylmethyl esters of the formula R40C(=O)OCH2C(=O)NR41R42where R41and R42mean hydrogen or (ness.)alkyl, or where NR41R42together form a monocyclic aliphatic heterocycle, such as pyrrolidine, piperidine, morpholine, N-methylpiperazine, etc. In the description of the application of R40has values similar to the values of R2, R3, R4and R4'.

Examples (ness.)alilovic esters are methyl, ethyl and n-propyl esters, etc. Examples (ness.)alilovic esters, substituted by a group NR41R42are diethylaminoethylamine, 2-(4-morpholinyl)ethyl and 2-(4-methylpiperazin-1-yl)ethyl esters, etc. Examples aryloxyalkyl esters is the tsya pivaloyloxymethyl, 1-ecotoxicology and acetoxymethyl esters. Examples of esters of carbonic acid are 1-(ethoxycarbonyl)ethyl and 1-(cyclohexyloxycarbonyloxy)ethyl esters. Examples aminocarbonylmethyl esters are N,N-dimethylcarbamoyl and carbamoylmethyl esters.

For more information on examples and applications of esters for the delivery of pharmaceutical compounds contained in the monograph, Design of Prodrugs, Bundgaard H ed., Elsevier (1985). Cm. also .Ansel and others, Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th Ed., 108-109 (1995), Krogsgaard-Larsen and others, in Textbook of Drug Design and Development, 2d Ed., 152-191 (1996).

"Pharmaceutically acceptable salt" means ordinary acid additive salts or basic additive salts that retain the biological activity and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid-additives salts include salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and salts of organic acids such as para-toluensulfonate acid, salicylic acid, methanesulfonate acid, oxalic acid, succinic acid, citric acid, ablon the I acid, lactic acid, fumaric acid, etc. are Examples of basic additive salts include salts of ammonium, potassium, sodium and hydroxides of Quaternary ammonium bases such as hydroxide of Tetramethylammonium. Chemical modification of pharmaceutical compounds (i.e. medicines) with the formation of salts are known to pharmacologists and is used to improve the physical and chemical stability, improved hygroscopicity, flowability and solubility of compounds. See, for example, .Ansel and others, Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th Ed., 196, 1456-1457 (1995).

"Pharmaceutically acceptable"such as pharmaceutically acceptable carrier, excipient etc., means pharmacologically acceptable material and generally non-toxic to the subject, which is entered the specified connection.

"Substituted", such as substituted alkyl, means that substituent is one or more of the provisions, unless otherwise indicated, the substituents in each position independently selected from the specified values.

"Therapeutically effective amount" means an amount of at least one compound of formula I or its pharmaceutically acceptable salt or ester, which effectively inhibits the proliferation and/or prevents differentiation of human tumor cells, including cell lines of human cancers.

In the bottom of a preferred embodiment of the present invention provides compounds of formula I, where

R1selected from the group including (ness.)alkyl, substituted aryl,

and,

R2selected from the group including aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which contains 1-4 substituent, independently selected from the group comprising (ness.)alkyl, halogen, OR5, NH2and NO2,

R3selected from the group including CO2R6and SO2R6,

R4and R4'each independently selected from the group comprising H, (ness.)alkyl, optionally substituted by oxo groups, CO2R6, OR6and/or NH2; S(O)nR7, OR8, NR5R6and CO2R6,

R5and R6each independently selected from the group comprising N, N, (ness.)alkyl, substituted groups, oxo, CO2R9, OR9and NR10R11; aryl, optionally substituted with halogen, heteroaryl, N-aryl, where aryl optionally substituted (h) one or more halogen, aryl, substituted with halogen or CF3,

R7means (ness.)alkyl or aryl,

R8selected from the group comprising H, (ness.)alkyl and (ness.)alkyl, substituted by a group NR5R6,

R9selected from the group comprising H and (ness.)alkyl,

R10and R11each independently selected from the group comprising N (n is ZS.)alkyl, and

n is 0, 1 or 2,

or their pharmaceutically acceptable salts or esters.

In a preferred embodiment, compounds of the formula I R2means phenyl, preferably phenyl substituted by halogen, most preferably F, OR5where R5means (ness.)alkyl. In the most preferred embodiment, R2means phenyl, substituted one go two F and one group OR5where R5means (ness.) alkyl, preferably methyl.

In another preferred embodiment provides compounds of formula I in which R2has the values given above and R1means

where

R3selected from the group comprising H, CO2R6C(O)R6, SO2R6and SO2NR5R6,

R5and R6each independently selected from the group comprising H and (ness.)alkyl,

or their pharmaceutically acceptable salts or esters.

More preferred compounds mentioned above, in which R2means phenyl containing one, two or three substituent independently selected from the group comprising halogen or-O- (ness.) alkyl.

In yet another embodiment, the present invention provides compounds of formula I, where

R1means

;

R2mean 3-forfinal not necessarily replaced the first one or two substituents, selected from the group comprising-F, and-O-CH3,

R3selected from the group comprising H, CO2R6C(O)R6, SO2R6and SO2NR5R6,

R5and R6each independently selected from the group comprising H and (ness.)alkyl,

or their pharmaceutically acceptable salts or esters.

Examples of compounds of formula I, above, include, without limitation,

tert-butyl ether 4-[4-amino-5-(3-perbenzoic)thiazol-2-ylamino]piperidine-1-carboxylic acid,

tert-butyl ether 4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid,

tert-butyl ether 4-[4-amino-5-(2,3-debtor-6-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid,

[4-amino-2-(piperidine-4-ylamino)thiazol-5-yl](3-forfinal)methanon,

[4-amino-2-(piperidine-4-ylamino)thiazol-5-yl](3-fluoro-4-methoxyphenyl)methanon,

[4-amino-2-(piperidine-4-ylamino)thiazol-5-yl](2,3-debtor-6-methoxyphenyl)methanon,

1-[4-[4-amino-5-(3-perbenzoic)thiazol-2-ylamino]piperidine-1-yl]alanon,

[4-amino-2-(1-methanesulfonamido-4-ylamino)thiazol-5-yl](3-forfinal)methanon,

1-[4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-yl]alanon,

[4-amino-2-(1-methanesulfonamido-4-ylamino)thiazol-5-yl](3-fluoro-4-methoxyphenyl)methanon,

dimethylamide 4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-the laminitis]piperidine-1-sulfonic acid,

[4-amino-2-(1-methanesulfonamido-4-ylamino)thiazol-5-yl](2,3-debtor-6-methoxyphenyl)methanon and

[4-amino-2-(1-methanesulfonamido-4-ylamino)thiazol-5-yl](2,6-differenl)methanon.

In yet another embodiment of the invention R1means

where R4means S(O)nR7where R7means (ness.)alkyl, preferably methyl.

Most preferably, R4means-S(O)2CH3.

Examples of compounds of formula I, above, include the

[4-amino-2-(4-methanesulfonanilide)thiazol-5-yl](2,3-debtor-6-methoxyphenyl)methanon.

The claimed compounds of formula I, above, may exist as tautomers and structural isomers. Understood that the invention includes all tautomers and structural isomers of these compounds or a mixture of these isomers, and is not limited to any one tautomeric or isomeric form, represented in the above formula.

In another embodiment of the invention, examples of the compounds according to the invention include, without limitation, the following compounds (see table).

A1
A2
A3
A4
A5
A6

A7
A8
A9
A10
A11
A12
A13

A14
A15
A16
A17
A18
A19
A20

A21
A22
A23
A24
A25
A26
A27

A28
A29
A30
A31
A32

A33
A34
A35
A36
A37

Compounds of the present invention receive any known method. Suitable methods of synthesis of these compounds are given in the examples. In the General case is E. the compounds of formula I can be obtained by one of the following schema.

Cycle closing

Compounds according to the invention receive alkilirovanie and cyclization of some thiourea derivatives as shown in scheme 3, using known reactions. Derivatives of urea, which are used for these purposes include derivative nitroimidazolidin (Binu R., and others, Org. Prep. Proced Int., 1998, 30, 93-96 (1998)), 1-[(aristochromis)amino] - for 3,5-dimethylpyrazole (Jenardanan G.C. and others, Synth. Commun., 27, 3457-3462 (1997)) and N-(aminoiminomethyl)-N'-phenyltoloxamine (K.N. Rajasekharan, etc., Synthesis, 353-355 (1986)).

Other derivative of thiourea, which are used for producing compounds according to the invention using alkylation and cyclization is N-cyanothiophene (K. Gewald, etc., J. Prakt. Chem., 97-104 (1967). For example, as shown in the following scheme 3, N-cyanothiophene formula 6 is introduced into the reaction halogenoalkanes, such as bromeilles formula 4, at a temperature from about room temperature to about 65°C with the formation of the compounds of formula 7. Starting materials of the formula (2) and (4)that are not commercial drugs are indicated in the specific examples.

Scheme 1

Scheme 2

Scheme 3

In another embodiment of the compounds according to the invention is also obtained by the reaction of an immobilized on the resin methyl ester amino is iocommittee carbamodithioate formula 9 with bromeilles formula 4, as shown in the following scheme 4.

Scheme 4

Immobilized on the resin derived thiourea of formula 9 get by any method known to the expert in the field of organic chemistry. For example, such a connection can be obtained by the reaction of an immobilized on the resin salt toronja formula 8 with isothiocyanato formula 2 in the presence of a base such as tertiary amine (e.g. triethylamine or diisopropylethylamine) in an inert solvent such as a polar aprotic solvent (e.g. N,N-dimethylformamide). Usually the reaction is carried out at approximately room temperature. Then from immobilized on the resin derived thiourea of formula 9 get the connection formula 7, for example, when interacting with halogenoalkanes (for example, bromeilles formula 4) in a suitable inert solvent such as a polar aprotic solvent (e.g. N,N-dimethylformamide) at about room temperature.

Separation of a mixture of stereoisomers in optically pure stereoisomers (if the compound of formula I is a chiral compound)

The optional separation of the isomers of the formula I is carried out by known methods, such as chiral liquid chromatography high pressure (known as IHVR). Methods of separating isomers are known which are described in detail in the literature (see, for example, Jacques J., and others, Enantiomers, Racemates, and Resolutions", John Wiley and Sons, NY (1981). Methods of separation of chiral GHUR also known and are described in detail in the literature (see, for example, W.H. Pirkle and J. Finn, "Separation of Enantiomers by Liquid Chromatographic Methods" in the monograph "Asymmetric Synthesis", t.1, c.87-124, J.D. Morrison, Ed., Academic Press, Inc., NY (1983)).

The transformation of compounds of formula I containing group, a nitrogenous base, a pharmaceutically acceptable acid additive salt

The optional conversion of the compounds of formula I containing group, a nitrogenous base, a pharmaceutically acceptable acid additive salt is carried out by known methods. For example, the compound is treated with an inorganic acid such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the corresponding organic acid, such as acetic acid, citric acid, tartaric acid, methanesulfonate acid, para-toluensulfonate acid or the like

The transformation of compounds of formula I containing a carboxyl group, a pharmaceutically acceptable salt of alkaline metal

The optional conversion of the compounds of formula I containing a carboxyl group, a pharmaceutically acceptable salt of alkali metal is carried out by known methods. For example, the compound is treated with inorganic bases is observed such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.

The transformation of compounds of formula I containing a carboxyl group, a pharmaceutically acceptable ester

The optional conversion of the compounds of formula I containing a carboxyl group, a pharmaceutically acceptable ester carried out by known methods. Conditions for obtaining of ester depends on the stability of other functional groups in the conditions of the esterification reaction. If other groups are quite stable in an acid environment, the esterification is usually carried out by heating a solution of the compound in alcohol in the presence of a mineral acid (e.g. sulfuric acid). Other methods of obtaining esters, which are usually used if the connection is unstable in acidic environment include the interaction of compounds with alcohol in the presence of a condensing agent and optionally in the presence of additional agents that catalyze the reaction. Specialist in the field of organic chemistry there are many such condensing agents. As examples dicyclohexylcarbodiimide and triphenylphosphine/diethylazodicarboxylate. If the condensing agent is used dicyclohexylcarbodiimide, the reaction is usually carried out when handling acid-carbodiimide in prisutstvie the alcohol and optionally in the presence of catalytic amounts (0-10 mol.%) N,N-dimethylaminopyridine in inert restoritive, such as a halogenated hydrocarbon (e.g. dichloromethane) at a temperature of from about 0°C. to about room temperature, preferably at about room temperature. If the condensing agent is triphenylphosphine/diethylazodicarboxylate, the reaction is usually carried out when handling acid, triphenylphosphine and diethylazodicarboxylate in the presence of alcohol in an inert solvent, such as a simple ether (e.g. tetrahydrofuran) or an aromatic hydrocarbon (e.g. benzene) at a temperature of from about 0°C. to about room temperature, preferably at about 0°C.

Compositions/formulations

In another embodiment, the present invention includes pharmaceutical compositions containing at least one compound of formula I or its pharmaceutically acceptable salt or ester and pharmaceutically acceptable excipient and/or the media.

These pharmaceutical compositions can be administered orally by the way, for example, in the form of tablets, coated tablets, pills, hard or soft gelatin capsules, solutions, emulsions or suspensions. The composition can also enter the rectal method, for example, in the form of suppositories, or parenterally way, for example, in the form of injection solutions.

The pharmacist is ical composition of the present invention, including the compounds of formula I and/or their pharmaceutically acceptable salts or esters, get known in the art method, for example, using the processes of mixing, encapsulating, dissolving, granulating, emulsifying, inclusions in the matrix, drazhirovanija or lyophilization. These pharmaceutical preparations can be processed in a mixture with therapeutically inert, inorganic or organic carriers. Upon receipt of tablets, coated tablets, dragées and hard gelatin capsules as these carriers are lactose, corn starch or its derivatives, talc, stearic acid or its salts. Suitable carriers for soft gelatin capsules include vegetable oils, waxes and fats. Depending on the nature of the active compounds in the case of soft gelatin capsules usually do not require any media. Suitable carriers upon receipt 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 hardened oils, waxes, fats and semi-liquid polyols.

Pharmaceutical compositions may also include preservatives, solubilis the dominant agents stabilizing agents, wetting agents, emulsifying agents, sweeteners, colorants, flavoring agents, salts for regulating the osmotic pressure, buffer substances, coating agents and antioxidants. In addition, they can contain other therapeutically valuable compounds, including additional active ingredients that are different from the compounds of formula I.

Dosing

As indicated above, the compounds of the present invention, including the compounds of formula I, are used for the treatment or suppression of disorders of cell proliferation, including cancer chemoprevention. Chemoprophylaxis means the inhibition of the development of invasive cancer by suppressing the induction of mutagenic process or suppress the development of precancerous cells that have been exposed to factors aimed at the suppression of recurrent tumor. These compounds and compositions containing these compounds, especially suitable for the treatment or inhibition of growth of solid tumors such as tumors of the breast, colon, lung and prostate.

A therapeutically effective amount of the compounds of the present invention means the amount of compound that when administered to a subject effectively prevent, suppress the symptoms of the disease or reduce the intensity or prolongs the life of the subject, in need of treatment. Therapeutically effective amount determined by the treating physician.

Therapeutically effective amount or dose of a compound of the present invention varies over a wide range and is determined in a known manner. This dose should be adjusted to the individual requirements in each particular case depending on the type of the entered connection (connection), the method of administration, the condition to be treated, and the condition of the patient. In General, oral or parenteral administration to adult humans weighing approximately 70 kg is suitable daily dose is from about 10 mg to about 10000 mg, preferably from about 200 mg to about 1000 mg, although the upper limit can be exceeded depending on the indications. The daily dose can be administered as a single dose or divided doses, or when parenteral dose can be administered by continuous infusion.

Combination

The compound of the present invention can be used in combination (simultaneous or sequential introduction) with known anticancer treatments such as radiation therapy or with cytostatic or cytotoxic agents, such as, but not limited to, DNA interactive agents, t is Kimi, as cisplatin or doxorubicin, a topoisomerase II inhibitors such as etoposide, an inhibitor of topoisomerase I, such as CPT-11 or topotecan, agents that interact with microtubules, such as paclitaxel, docetaxel, or epothilone, 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.

If the medicinal product is obtained in the form of fixed-dose a combination of the above include the compounds of the present invention at doses indicated above, and the other pharmaceutically active agent or treatment given interval specified doses. For example, recently found that the inhibitor of cdk1, ovomucin has a synergistic effect with known cytotoxic agents, causing apoptosis (J. Cell Sci., 108, 2897-2904 (1995)). The compounds of formula I can also be entered sequentially with known anticancer or cytotoxic agents when a simultaneous introduction or the introduction of combination is impossible. In the present invention, the circuit is not limited to: compounds of formula I can be entered before or after administration of the known anticancer or cytotoxic agent. For example, ototoxicity activity inhibitor of cdk flavopiridol depends on the subsequent introduction of anticancer agents (Cancer Research, 57, 3375 (1997).

Examples

The following examples illustrate the preferred methods of synthesizing and using the compounds and compositions of the present invention. These examples and preparations do not limit the scope of the invention. Assume that within the essence and scope of the invention defined by the claims, there are various variants and modifications.

Example 1

tert-Butyl ether 4-isothiocyanatobenzene-1-carboxylic acid

tert-Butyl ether 4-aminopiperidin-1-carboxylic acid (5.0 g, 25 mmol, firm Astatech, Inc.) was dissolved in dimethylformamide (120 ml), cooled to -15°C. and the solution was slowly added thiocarbonyldiimidazole (4.8 g, 27 mmol, firm Aldrich) in dimethylformamide (100 ml), cooled to -10°C. the Mixture was stirred at room temperature for 14 h, the solvent was removed in vacuo, the residue was dissolved in methylene chloride (200 ml) and washed twice with water. Then the solvent was removed and the resulting residue triturated in hexane and filtered. In the resulting solution was added Norit, filtered through a layer of celite and the solvent was removed, it was obtained tert-butyl ether 4-isothiocyanatobenzene-1-carboxylic acid (5.7 g, yield 94%) as oil. MS-NR (EI(+)): 242 (MM).

Example 2

2-Bromo-1-(3-forfinal)alanon

In the region of the target 1-(3-propenyl)ethanone (14.0 g, 100 mmol, Aldrich company) in dioxane (250 ml) at 12-15°C for 30 min was added dropwise a solution of bromine (17 g, 105 mmol) in dioxane (120 ml). The resulting mixture was stirred for 15 min and removed most of the solvent. The obtained residue was transferred into hexane (200 ml), washed twice with water, dried over magnesium sulfate and the solvent was removed, it was obtained 2-bromo-1-(3-forfinal)Etalon.

1H-NMR (300 MHz, CDCl3,): δ 3,71 (s, 2H, CH2), 7,30-to 7.77 (m, 4H, aromatic.).

Example 3

tert-Butyl ether 4-[4-amino-5-(3-perbenzoic)thiazol-2-ylamino]piperidine-1-carboxylic acid

In a mixture of tert-butyl methyl ether 4-isothiocyanatobenzene-1-carboxylic acid (2.4 g, 10 mmol, example 1), cyanamide (0,42 g, 10 mmol, Aldrich company) in tert-butyl alcohol (5 ml) and acetonitrile (35 ml) at 20°C for 15 min was added to a solution of tert-butoxide potassium (1.0 M solution in THF, 10 ml, 10 mmol, Aldrich company). Then to the mixture was added 2-bromo-1-(3-forfinal)alanon (2.0 g, 9.2 mmole, example 2), the resulting suspension was stirred for 2 h, the solvent was removed and the solid residue was purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane, 60% to 70%), was obtained tert-butyl ester 4-[4-amino-5-(3-perbenzoic)thiazol-2-ylamino]piperidine-1-carboxylic acid (2.4 g, yield 57%).

1N-the Mr (300 MHz, DMSO-d6): δ of 1.36 (m, 2H, NCH2), of 1.41 (s, 9H, SN3), a 1.88 (m, 2H, NCH2), 2,88 (user., 2H, NCH2), 3.6 and 4.0 (m, 1H, CH), a 3.87 (m, 2H, NCH2), 7,31 (t, 1H, aromatic.), 7,38 (d, 1H, aromatic.), of 7.48 (t, 1H, aromatic.), 7,51 (q, 1H, aromatic.), 8,01 (user., 1H, NH), 8,48 (user,, 1H, NH), 8,70 (user., 1H, NH).

Example 4

tert-Butyl ether 4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid

tert-Butyl ether 4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid was obtained by bromirovanii 1-(3-fluoro-4-methoxyphenyl)ethanone (company Aldrich) in the same way as described in example 2, and the subsequent cyclization of the resulting product as described in example 3. MS-BP: Rasch. 451,1810, neid. 451,1813 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ of 1.37 (m, 2H, CH2), of 1.41 (s, 9H, SN3), of 1.80 (m, 2H, CH2), 2,78 (user., 2H, NCH2), of 3.32 (m, 2H, NCH2), 3,6-4,0 (user., 1H, CH), 3,85 (m, 3H, och3), 7,22 (t, 1H, aromatic.), was 7.45 (d, 1H, aromatic.), of 7.48 (m, 1H, aromatic.), 7,94 (user., 1H, NH), 8,45 (user., 1H, NH), 8,65 (user., 1H, NH).

Example 5

tert-Butyl ether 4-[4-amino-5-(2,3-debtor-6-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid

tert-Butyl ether 4-[4-amino-5-(2,3-debtor-6-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid was obtained by bromirovanii 1-(2,3-debtor-6-methoxyphenyl)ethanone (FYR is and Matrix) same as described in example 2, and the subsequent cyclization of the resulting product as described in example 3. MS-NR (ES(+/-)): 468 (MM).

1H-NMR (300 MHz, DMSO-d6): δ to 1.48 (m, 2H, CH2), with 1.92 (m, 2H, CH2), to 2.55 (s, 9H, SN3), a 2.75 (m, 2H, CH2), 3,39 (m, 2H, CH2), 3,6-4,0 (user., 1H, CH), 3,81 (s, 3H, och3), 6,92 (m, 1H, aromatic.), to 7.50 (m, 1H, aromatic.), 7,6 (2× of user., 1H, NH), 7,8 (user., 1H, NH), to 7.99 (m, 1H, aromatic.), 9,0 (user., 1H, NH).

Example 6

[4-Amino-2-(piperidine-4-ylamino)thiazol-5-yl](3-forfinal)metano

tert-Butyl ether 4-[4-amino-5-(3-perbenzoic)thiazol-2-ylamino]piperidine-1-carboxylic acid (0,82 g of 1.95 mmole, example 3) was dissolved in a mixture triperoxonane acid (16 ml) and methylene chloride (30 ml), was kept for 1 h, the solvent was removed, the residue was dissolved in methylene chloride (300 ml), washed with 10% solution of Na2CO3(50 ml), dried over Na2SO4and concentrated, this has been solid. The product is triturated in ethyl ether and filtered, it was received [4-amino-2-(piperidine-4-ylamino)thiazol-5-yl](3-forfinal)methanon (450 mg, yield 72%). MS-NR (ES(+/-)): 320 (MM).

1H-NMR (300 MHz, DMSO-d6,): δ to 1.38 (m, 2H, CH2), a 1.88 (m, 2H, CH2), 2,95 (m, 2H, CH2), 3,32 (user., 2H, CH2), 3,6-4,0 (user., 1H, CH), of 3.78 (s, 3H, och3), 7,31 (t, 1H, aromatic.), 7,38 (d, 1H, aromatic.), of 7.48 (t, 1H, aromatic.), 7,51 (q, 1H, aromatic.), 8,01 (user.,1H, NH), 8,48 (user., 1H, NH), 8,70 (user., 1H, NH).

Example 7

[4-Amino-2-(piperidine-4-ylamino)thiazol-5-yl](3-fluoro-4-methoxyphenyl)metano

[4-Amino-2-(piperidine-4-ylamino)thiazol-5-yl](3-fluoro-4-methoxyphenyl)methanon (220 mg, yield 90%) was obtained by removal of the protective groups of the tert-butyl ester 4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid (0,30 g of 0.66 mmole, example 4) in the same way as described in example 6. MS-NR (ES(+/-)): 350 (MM).

1H-NMR (300 MHz, DMSO-d6): δ of 1.36 (m, 2H, CH2), a 1.75 (m, 2H, CH2), 2,88 (user., 2H, CH2), of 3.32 (m, 2H, CH2), 3,2-3,4 (user., 1H, NCH), of 3.78 (s, 3H, och3), of 7.23 (t, 1H, aromatic.), of 7.48 (t, 1H, aromatic.), a 7.62 (t, 1H, aromatic.), 8,01 (user., 1H, NH), 8,48 (user., 1H, NH), 8,70 (user., 1H, NH).

Example 8

[4-Amino-2-(piperidine-4-ylamino)thiazol-5-yl](2,3-debtor-6-methoxyphenyl)metano

[4-Amino-2-(piperidine-4-ylamino)thiazol-5-yl](2,3-debtor-6-methoxyphenyl)methanon (123 mg, yield 52%) was obtained by removal of the protective groups of the tert-butyl ester 4-[4-amino-5-(2,3-debtor-6-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid (0,30 g of 0.64 mmole, example 5) in the same way as described in example 6. MS-NR (ES(+/-)): 368 (MM).

1H-NMR (300 MHz, DMSO-d6): δ to 1.38 (m, 2H, CH2), of 1.78 (m, 2H, CH2), 2.91 in (user., 2H, CH2), to 3.35 (m, 3H, CH and NCH2in ), 3.75 (s, 3H, och3 ), to 6.95 (m, 1H, aromatic.), the 7.43 (m, 1H, aromatic.), 8,01 (user., 1H, NH), 8,48 (user., 1H, NH), 8,70 (user., 1H, NH).

Example 9

1-[4-[4-Amino-5-(3-perbenzoic)thiazol-2-ylamino]piperidine-1-yl]alanon

[4-Amino-2-(piperidine-4-ylamino)thiazol-5-yl]-(3-forfinal)methanon (0.10 g, 0.31 in mmole, example 6) was dissolved in a mixture of tetrahydrofuran (20 ml), chloroform (6 ml) and pyridine, cooled to -10°C. Then was added acetylchloride (0,032 g, 43 mmole), was stirred at room temperature for 0.5 h, diluted with chilled methylene chloride (100 ml), washed twice with a 10% solution of Na2CO3(water.), dried over Na2SO4, solvent was removed and the residue was separated from a mixture of tetrahydrofuran and hexane, was obtained 1-[4-[4-amino-5-(3-perbenzoic)thiazol-2-ylamino]piperidine-1-yl]alanon (35 mg, 30%yield). MS-BP: Rasch. 363,1286, neid. 363,1288 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ 1.28 (in m, 1H, CH), of 1.41 (m, 1H, CH), with 1.92 (m, 2H, CH2), a 2.75 (t, 1H, NCH), 3,14 (t, H, NCH), of 3.32 (s, 3H, PINES3), 3,6-4,0 (user., 1H, CH), of 3.77 (d, 1H, NCH), 4,22 (d, 1H, NCH), 7,31 (t, 1H, aromatic.), 7,38 (d, 1H, aromatic.), of 7.48 (t, 1H, aromatic.), 7,51 (q, 1H, aromatic.), 8,01 (user., 1H, NH), 8,48 (user., 1H, NH), 8,72 (user., 1H, NH).

Example 10

[4-Amino-2-(1-methanesulfonamido-4-ylamino)thiazol-5-yl](3-forfinal)metano

[4-Amino-2-(1-methanesulfonamido-4-ylamino)thiazol-5-yl](3-forfinal)methanon (35 mg, o is d 40%) was obtained in the interaction [4-amino-2-(piperidine-4-ylamino)thiazol-5-yl](3-forfinal)methanone (0.09 g, of 0.28 mmole, example 6) and methanesulfonamide same way as described in example 9. MS-BP: Rasch. 399,0956, neid. 399,0960 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ of 1.54 (m, 2H, CH2), 2,03 (m, 2H, CH2), is 2.88 (m, 5H, NCH2and SCH3), 3,6-4,0 (user., 1H, CH), 3,51 (d, 2H, NCH2), to 7.32 (t, 1H, aromatic.), 7,38 (d, 1H, aromatic.), of 7.48 (t, 1H, aromatic.), 7,52 (q, 1H, aromatic.), 7,99 (user., 1H, NH), 8,48 (user., 1H, NH), 8,77 (user., 1H, NH).

Example 11

1-[4-[4-Amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-yl]alanon

1-[4-[4-Amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-yl]alanon (100 mg, yield 77%) was obtained in the interaction [4-amino-2-(piperidine-4-ylamino)thiazol-5-yl](3-fluoro-4-methoxyphenyl)methanone (0.125 g, of 0.36 mmole, example 7) and acetylchloride same way as described in example 9. MS-BP: Rasch. 393,1391, neid. 393,1396 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ 1,38 (dm, 2H, CH2), with 1.92 (m, 2H, CH2), 2,02 (s, 3H, PINES3), was 2.76 (t, 1H, NCH), 3,26 (t, 1H, NCH), 3,6-4,0 (user., 1H, CH), of 3.77 (m, 1H, NCH), 3,90 (s, 3H, och3), 4,22 (m, 1H, NCH), of 7.23 (t, 1H, aromatic.), 7,47 (t, 1H, aromatic.), to 7.50 (t, 1H, aromatic.), 7,9-8,5 (user., 2H, 2NH), 8,69 (user., 1H, NH).

Example 12

[4-Amino-2-(1-methanesulfonamido-4-ylamino)thiazol-5-yl](3-fluoro-4-methoxyphenyl)metano

[4-Amino-2-(1-methanesulfonamido-4-ylamino)thiazol-5-yl](3-fluoro-4-methoxyphenyl)methanon (30 mg, Ihad 23%) was obtained in the interaction [4-amino-2-(piperidine-4-ylamino)thiazol-5-yl](3-fluoro-4-methoxyphenyl)methanone (0.11 g, at 0.31 mmole, example 7) and methanesulfonamide same way as described in example 9. MS-BP (EI): Rasch. 428,0988, neid. 428,0982 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ of 1.46 (m, 2H, CH2), a 2.01 (m, 2H, CH2), 2,90 (m, 5H, CH2and SCH3), 3,55 (m, 2HCH2), 3,6-4,0 (user., 1H, CH), 3,91 (s, 3H, och3), from 7.24 (t, 1H, aromatic.), 7,47 (t, 1H, aromatic.), to 7.59 (t, 1H, aromatic.), 7,9-8,5 (user., 2H, 2NH), 8,71 (user., 1H, NH).

Example 13

Dimethylamide 4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-sulfonic acid

Dimethylamide 4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-sulfonic acid (30 mg, yield 22%) was obtained in the interaction [4-amino-2-(piperidine-4-ylamino)thiazol-5-yl](3-fluoro-4-methoxyphenyl)methanone (0.08 g, of 0.022 mmole, example 7) and dimethylsulfoxide same way as described in example 9, except that as the catalyst used diisopropylethylamine, and the product was purified on a short column of silica gel (pre-cleaning product used ethyl acetate). MS-BP: Rasch. 458,1327, neid. 458,1331 (M+N)+.

1H-NMR (300 MHz, DMSO-d6,): δ is 1.51 (m, 2H, CH2), of 1.97 (m, 2H, CH2), 2,77 (s, 6H, 2×NCH2), to 2.99 (m, 2H, CH2), 3,52 (m, 2H, CH2), 3,6-4,0 (user., 1H, CH), with 3.89 (s, 3H, och3), 7,9-8,5 (user., 2H, 2NH), 8,71 (user., 1H, NH).

Example 14

[4-Amino-2-(1-meanswhen piperidin-4-ylamino)thiazol-5-yl](2,3-debtor-6-methoxyphenyl)metano

[4-Amino-2-(1-methanesulfonamido-4-ylamino)thiazol-5-yl](2,3-debtor-6-methoxyphenyl)methanon (50 mg, yield 90%) was obtained in the interaction [4-amino-2-(piperidine-4-ylamino)thiazol-5-yl](2,3-debtor-6-methoxyphenyl)methanone (0.05 g, of 0.14 mmole, example 8) and methanesulfonamide same way as described in example 9, except that in as the catalyst used diisopropylethylamine. LC/MS-HP: 446 (MM, M+H).

1H-NMR (300 MHz, DMSO-d6): δ 1.57 in (m, 2H, CH2), with 1.92 (m, 2H, CH2), 2,85 (m, 5H, SCH3and NCH2), 3,53 (m, 2H, NCH2), 3,6-4,0 (user., 1H, CH), 3,88 (s, 3H, och3), 6,72 (m, 1H, aromatic.), 7,42 (m, 1H, aromatic.), 7,6 (2× of user., 1H, NH), 7,8 (user., 1H, NH), to 7.99 (m, 1H, aromatic.), 9,0 (user., 1H, NH).

Ki CDK1 is 0.001 μm, Ki CDK2 is 0.001 μm, Ki CDK4 makes 0.002 microns.

Example 15

Isothiocyanato-4-methanesulfonate

4-Methanesulfonanilide (2.4 g, 14 mmol) was dissolved in a mixture of water (30 ml) and hydrochloric acid (9 ml, 37%), the resulting solution at room temperature was added dropwise thiophosgene (1.5 g, 13.2 mmole) and thoroughly stirred for 1 h Then the resulting suspension was filtered, the filter residue washed with water and dried over P2O5when this received 1-isothiocyanato-4-methanesulfonate (2.4 g, yield 85%).

1H-NMR (300 MHz, COCl3): δ 3,09 s, 3H, CH3), 7,41 (d, 2H, aromatic.), 7,98 (d, 2H, aromatic.).

Example 16

[4-Amino-2-(4-methanesulfonanilide)thiazol-5-yl](2,3-debtor-6-methoxyphenyl)metano

[4-Amino-2-(4-methanesulfonanilide)thiazol-5-yl](2,3-debtor-6-methoxyphenyl)methanon (15 mg, yield 12%) was obtained in two stages: first bromisovali 1-(2,3-debtor-6-methoxyphenyl)alanon (firm Matrix) in the same way as described in example 2, then got diamentional same way as described in example 3. The obtained solid was purified by chromatography on a column of silica gel (eluent: 2.5% methanol/methylene chloride), the purified product is triturated in ether and separated by filtration. MS-BP: Rasch. 440,0545, neid. 440,0545 (M+N)+.

1H-NMR (300 MHz, DMSO-d6,): δ 3,18 (s, 3H, SCH3), 3,68 (s, 3H. Och3), to 6.95 (m, 1H, aromatic.), to 7.50 (m, 1H, aromatic.), 7,74 (dd, 4H, aromatic.), 8,2 (user., 1H, NH), 11,21 (s, 1H, NH).

Example 17

[4-Amino-2-(1-methanesulfonamido-4-ylamino)thiazol-5-yl](2,6-differenl)metano

2-Methylisothiazolinone resin (34350-95)

In a mixture of ethanol and 1,4-dioxane (500 ml, 1:4) was added to the Merrifield resin (50 g, the capacity of 4.3 mmole Cl/g, the company Fluka) and thiourea (5 EQ., 82 g, 1.8 mol, the firm Aldrich) and the resulting mixture was shaken at 85°C for 5 days. Then the mixture was filtered, the obtained resin was washed three times what dimetilformamidom (3×50 ml), isopropanol (3×50 ml), dichloromethane (3×50 ml) and ethyl ether (3×50 ml) and the product was dried in a desiccator for 3 days, it was received 77,5 g 2-Methylisothiazolinone resin off-white color (capacity 3 mmole/g according to microanalysis).

Resin, modified tert-butyl ester 4-[3-(2-methylisothiourea)coreycorey-1-carboxylic acid

Into a flask of 100 ml was placed resin containing Methylisothiazolinone resin (2.9 g, example 17A), a solution of tert-butyl methyl ether 4-isothiocyanatobenzene-1-carboxylic acid in dimethylformamide (example 1) and diisopropylethylamine (4 equiv.) and the resulting mixture was shaken at room temperature overnight. The reaction mixture was filtered and the product washed three times with dimethylformamide (3×30 ml), isopropanol (3×30 ml), dichloromethane (3×30 ml) and diethyl ether (3×30 ml) and dried in a desiccator for 3 days, when it received the product off-white color (3,93 g, a capacity of 1.8 mmole/g).

tert-Butyl ether 4-[4-amino-5-(2,6-differentail)thiazol-2-ylamino-piperidine-1-carboxylic acid

Into the flask was placed a mixture of dimethylformamide (betw., 10 ml), the resin, modified tert-butyl ester 4-[3-(2-methylisothiourea)touraid]piperidine-1-carboxylic acid (0,60 g at 1.08 mmole), 2-bromo-1-(2,6-differenl)ethane is on (0,616 g, 2.6 mmole, 2 EQ., example 2), diisopropylethylamine immobilized on the polymer (PS-DIEA, the firm Aldrich, 823 mg, 3 EQ.) and was shaken overnight. Then the reaction mixture was added to the resin-acceptor, PS-trisamin (0,612 g, 2.5 EQ., the company Argonaut), was intensively shaken overnight and filtered through a short cartridge with silica gel. The resulting resin was washed with dichloromethane (3×10 ml) and the washing solution were combined with the original filtrate. The combined solution was concentrated and was purified on a column of silica gel, was obtained tert-butyl ester 4-[4-amino-5-(2,6-differentail)thiazol-2-eliminability-1-carboxylic acid (0,276 g, yield 62%) as a solid off-white color.

[4-Amino-2-(piperidine-4-ylamino)thiazol-5-yl](2,6-differenl)metano

Into a flask containing tert-butyl ester 4-[4-amino-5-(2,6-differentitate-2-ylamino]piperidine-1-carboxylic acid (0,276 g to 0.63 mmole), was added 4n. HCl (2 ml) in 1,4-dioxane (10 ml) and the reaction mixture was stirred at room temperature for 2 hours Then the mixture was concentrated and the residue triturated in ethyl ether, was obtained the crude [4-amino-2-(piperidine-4-ylamino)thiazol-5-yl](2,6-differenl)methanon (0,262 g)which was used in the next stage without additional purification.

[4-Amino-2-(1-methanesulfonamido-4-ylamino)t is evil-5-yl](2,6-diftorhinolonom

Into the flask was placed [4-amino-2-(piperidine-4-ylamino)thiazol-5-yl](2,6-differenl)methanon (0.25 g, crude product obtained in the previous phase), dichloromethane (betw., 1.5 ml) and methanesulfonamide (3 EQ., 155 μl), the mixture was added diethylethanolamine (6 EQ., 697 μl) and the reaction mixture was stirred at room temperature overnight. The mixture is then concentrated and the product was purified on a column of silica gel, it was received [4-amino-2-(1-methanesulfonamido-4-ylamino)thiazol-5-yl](2,6-differenl)methanon (0,38 g) as a solid light brown color (the total yield 15%). MS-BP: Rasch. 417,0861, neid. 417,0865 (M+N)+.

1H-NMR (400 MHz, DMSO-d6,): δ 1,45-of 1.57 (m, 2H, CH2), 1,95-2,05 (m, 2H, CH2), 2,82-2,90 (m, 5H, CH3CH2), 3,45-3,55 (m, 2H, CH2), 3,6-4,0 (user., 1H, CH), 7,14-7,20 (m, 2H, aromatic.), 7,45-of 7.55 (m, 1H, aromatic.), 8,15-8,25 (user., 1H, NH2), 8,7-8,9 (user., 1H, NH).

Ki against CDK1 is of 0.003 μm, in respect of CDK2 to 0.005 microns, in respect of CDK4 0,006 mm.

Pharmacological properties of the compounds of the present invention is assessed using a variety of methods of pharmaceutical analysis. Pharmacological tests described below, is carried out with the use of the compounds according to the invention and their salts. Compounds according to the invention show activity against kinases, in the example, Ki against cdk4 is less than 3 μm, preferably less than 0.5 μm, Ki against cdk2 is less than 8 μm, preferably less than 0.5 μm, and Ki against cdk1 is less than 10 μm, preferably less than 0.5 microns.

Example 18

Analysis of kinase activity

Determination of Ki

The experiment was performed using recombinant complexes of cyclin/B-human CDK1, cyclin a/E-CDK2 person or cyclin/D-CDK4. The cDNA clones GST-cycline E (GST-cycE), CDK2, GST-cyclina (GST-cycB), CDK1, GST-CDK4 and cycline D1 (cycD1) in baculovirus vectors were obtained from Dr. Harper (Dr. W.Harper, Baylor College of Medicine, Houston, TX). Proteins are jointly expressed in insect cells High Five™ and the complex was purified on glutathione-sepharose (firm Pharmacia, Piscataway, NJ)as described previously (Harper J.W., and others, Cell 75, 805-816 (1993)). In the analysis of cycD1-CDK4, cycB-CDK1 and the cycE-CDK2 as a substrate used labeled hexaglycine shortened form of the retinoblastoma protein (Rb) (fragment 386-928) (expression plasmid provided by Dr. Veronica Sullivan, Department of Molecular Virology, Roche Research Centre, Welwyn Garden City, United Kingdom). Protein Rb is a natural substrate phosphorylation by kinases CDK4, CDK2 and CDK1 (see Herwig and Strauss, Eur. J. Biochem., 246, 581-601 (1997) and the references listed in the description of the application).

The expression of a protein of 62 kDa conducted under the control of the IPTG-inducible promoter in cells of strain Ml5 E. coli. Cells were literally during sonication, the lysate at pH 8.0 n is carried on a column with Ni-agarose, pre-washed 1 mm solution of imidazole. Then the sorbent is washed several times in buffer solutions, gradually reducing the pH to 6.0, and protein was suirable 500 mm solution of imidazole. The eluate were dialyzed against buffer solution of the following composition: 20 mm HEPES solution, pH 7.5, 30% glycerol, 200 mm NaCl and 1 mm DTT. In samples of purified hybrid protein Rb was determined by the concentration of protein was divided into aliquot parts and stored at -70°C.

Analyses were carried out using the HTRF method using a hybrid of the proteins listed above, CDK1, CDK2 and CDK4. Reactions were performed in 96-well tablets, and fluorescence was determined in 384-well plates. The analysis was performed at concentrations three times higher than the corresponding Km for ATP.

In the analysis of CDK4 original solutions of the analyzed compounds were diluted three times (3×) to final concentration of the buffer solution of the following composition: 25 mm Hepes, pH 7.0, 6.25 mm MgCl2, 1.5 mm DTT, 135 μm ATP. The concentration of DMSO was less than was 4.76%. To the wells of the 96-hole tablet was placed in 20 μl of a solution of the analyzed compounds. Kinase reactions were initiated by addition of 40 μl in the wells of the reaction mixture of the following composition: 0,185 μm Rb, of 2.25 µg/ml CDK4 in 25 mm HEPES, pH 7.0, 6.25 mm MgCl2, 0,003% tween-20, 0.3 mg/ml BSA, 1.5 mm DTT. Control wells did not contain CDK4. The plates were incubated at 37°C for 30 min with shaking. To the AP reaction was stopped by adding 15 μl into the hole of 1.6 μm solution of antibodies, antiphospho-Rb (Ser 780) (company Cell Signaling Inc.) in 25 mm Hepes, pH 7.0, 24 mm EDTA, 0.2 mg/ml BSA. Incubation was carried out at 37°C for 30 min, and then the wells were added to 15 μl in the hole, 3 nm) anti-rabbit IgG labeled reagent LANCE Eu-W1024, and 60 nm conjugate allophycocyanin/anti-His6 (firm PerkinElmer, Life Sciences) in 25 mm Hepes, pH 7.0, 0.5 mg/ml BSA. Incubation continued at 37°C for another 1 h After incubation, 35 μl of the reaction mixture at the double repetition of each well was transferred into a 384-well black plates and determined the fluorescence intensity on the tablet reader ViewLux or Victor V (firm PerkinElmer Life Sciences) with the wave excitation 340 nm and the wave emission 615 and 665 nm.

The value of the IC50(the concentration of the analyzed compounds in which the fluorescence observed in the control wells, reduced by 50%) was calculated by comparison with the background at 665 nm, normalized to the europium (615 nm). For competitive inhibitors of the ATP inhibition constant Ki was calculated by the following equation Ki=IC50/(1+[S]/Km), where [S] denotes the concentration of substrate (ATP), a Km means a constant Michaelis-Menten for ATP.

Analyses using kinases CDK1 and CDK2 was performed according to the same methodology with minor changes of the concentrations of reagents and proteins.

Buffer solutions, in which dissolved the analyzed compounds and enzymes contained 10 mm MgCl2.

In the analysis of CDK1 and CDK2 concentration of ATP was 162 μm and 90 is km, respectively. CDK1 used at a concentration (reagent solution) 0.15 ng/µl, and CDK2 at a concentration of 0.06 ng/ál. The concentration of reagents in the solution for detection was 3-12 nm Eu-Ab and 60-90 nm APC-is6, the ratio of signal to background was at least 10:1.

Example 19

The tablet formulation
No.Ingredientsmg tablet
1Connection And*525100250500750
2Anhydrous lactose1038335193857
3Crosscarmelose (Na-salt)668163248
4 Povidone K556122436
5Magnesium stearate111369
The total mass120120150300600900
* Connection And connection means according to the invention.

Method get

Mix components 1, 2 and 3 in an appropriate mixer for 15 minutes

Granularit the mixture obtained in stage 1, in the presence of 20% solution of povidone K30 (component 4).

The dried granules obtained in stage 2 at 50°C.

Pass the granules obtained in stage 3 through a suitable mill.

To grind the granules obtained in stage 4, add the component 5 and the mixture is stirred for 3 minutes

Pressing the granulate obtained in stage 5, on the appropriate media.

Example 20/p>

The capsules
No.Ingredientsmg/capsule
1Connection And*525100250500
2Anhydrous lactose159123148--
3Corn starch2535403570
4Talc1015101224
5Magnesium stearate12236
The total mass of filler200200300300600
* Connection And connection means according to the invention.

Method get

Mix components 1, 2 and 3 in an appropriate mixer for 15 minutes

Add components 4 and 5 and mix for 3 minutes

The mixture is filled capsules.

Example 21

Receiving injection solution/emulsion
No.Ingredientsmg/ml
1Connection And*1 mg
2PEG 40010-50 mg
3Lecithin20-50 mg
4Soybean oil1-5 mg
5Glycerin8-12 m the
6Water q.s.1 ml
* Connection And connection means according to the invention.

Method get

Dissolve the component 1 in component 2.

To the component 6 adds the components 3, 4 and 5, and the mixture is stirred until the formation of a dispersion, and then homogenized.

To the mixture obtained in stage 2, add the solution obtained in stage 1, homogenize until a clear solution is formed.

The solution is sterilized by filtration through a filter with pore diameter of 0.2 μm and fill the bottles.

Example 22

Receiving injection solution/emulsion
No.Ingredientsmg/ml
1Connection And*1 mg
2Glucotrol10-50 mg
3Lecithin20-50 mg
4Soybean oil1-5 mg
5Glycerin8-12 mg
6Waterq.s. 1 ml
* Connection And connection means according to the invention.

Receiving injection solution/emulsion

Dissolve the component 1 in component 2.

To the component 6 adds the components 3, 4 and 5, and the mixture is stirred until the formation of a dispersion, and then homogenized.

To the mixture obtained in stage 2, add the solution obtained in stage 1, homogenize until a clear solution is formed.

The solution is sterilized by filtration through a filter with pore diameter of 0.2 μm and fill the bottles.

While the present invention is illustrated in a specific and preferred options for its implementation, for the person skilled in the art it is obvious that due to the experiments and the use of the present invention in practice, it may be various changes and modifications. Thus, it is understood that the present invention is not limited to the description of the application as defined by the attached claims and their equivalents.

1. The compound of the formula

where R1means
< / br> R3selected from the group consisting of H, CO2R6C(O)R6, SO2R6and SO2NR5R6,
R5and R6each independently selected from the group comprising H and (ness.)alkyl,
R2means phenyl containing one, two or three substituent independently selected from the group comprising halogen or-O-(ness.)alkyl, and
its pharmaceutically acceptable salts or esters.

2. The compound according to claim 1, where R2mean 3-forfinal, optionally substituted by one or two substituents selected from the group comprising-F, and-O-CH3.

3. The compound according to claim 1, selected from the group including
tert-butyl ether 4-[4-amino-5-(3-perbenzoic)thiazol-2-ylamino]piperidine-1-carboxylic acid,
tert-butyl ether 4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid,
tert-butyl ether 4-[4-amino-5-(2,3-debtor-6-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid,
[4-amino-2-(piperidine-4-ylamino)thiazol-5-yl](3-forfinal)methanon,
[4-amino-2-(piperidine-4-ylamino)thiazol-5-yl](3-fluoro-4-methoxyphenyl)methanon,
[4-amino-2-(piperidine-4-ylamino)thiazol-5-yl](2,3-debtor-6-methoxyphenyl)methanon and
1-[4-[4-amino-5-(3-perbenzoic)thiazol-2-ylamino]piperidine-1-yl]alanon.

4. The compound according to claim 1, selected from the group including
[4-amino-2-(1-methanesulfonamido-4-yl) - Rev. Ino)thiazol-5-yl](3-forfinal)methanon,
1-[4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-yl]alanon,
[4-amino-2-(1-methanesulfonamido-4-ylamino)thiazol-5-yl](3-fluoro-4-methoxyphenyl)methanon,
dimethylamide 4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-sulfonic acid,
[4-amino-2-(1-methanesulfonamido-4-ylamino)thiazol-5-yl](2,3-debtor-6-methoxyphenyl)methanon and
[4-amino-2-(1-methanesulfonamido-4-ylamino)thiazol-5-yl](2,6-differenl)methanon.

5. Pharmaceutical composition having inhibitory activity against cyclin-dependent kinases, comprising as active ingredient an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.

6. The pharmaceutical composition according to claim 5, suitable for parenteral administration.



 

Same patents:

FIELD: chemistry.

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

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

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

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

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

3 tbl

FIELD: medicine.

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

EFFECT: improvement of composition efficacy.

18 cl, 4 ex

FIELD: chemistry.

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

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

13 cl, 18 ex

FIELD: chemistry.

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

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

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

EFFECT: enhanced activity of derivatives.

21 cl, 10 tbl, 102 ex

FIELD: chemistry.

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

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

24 cl, 75 ex, 290 tbl

FIELD: chemistry.

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

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

12 cl, 16 tbl, 184 ex

FIELD: chemistry.

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

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

19 cl, 203 ex, 2 tbl

FIELD: chemistry.

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

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

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

11 cl, 288 ex

FIELD: medicine.

SUBSTANCE: invention concerns derivatives of thiazolidine-4-one of general formula (I) and general formula (II), to their isomers and pharmaceutically acceptable salts which can be used as a medical product with immunosuppressive activity. In formulae (I) and (II), R1 and R14 independently represent lower alkyl, lower alkenyl; cycloalkyl; 5,6,7,8-tetrahydronaphth-1-yl; phenyl group or phenyl group independently mono- or disubstituted with lower alkyl, halogen, lower alkoxy or group -CF3; R2 and R15 independently represent lower alkyl; allyl; cyclopropyl; or di- lower alkylamino; R3 represents -NR5R6 or -O-CR7R8-CR9R10-(CR11R12)n-O-R13; R23 represents hydrogen; hydroxycarbonyl-lower alkyl or 1-glyceryl. Values of the other radicals are specified in the patent claim. The invention also concerns application of one or more compounds of general formula (I) or (II) for preparation of a medical product with immunosuppressive activity.

EFFECT: agent exhibits improved efficiency.

24 cl, 1 tbl, 157 ex

FIELD: medicine.

SUBSTANCE: invention is related to derivatives of isothiourea of formula I, including their pharmaceutically acceptable salts, which possess properties of antagonist CXCR4. In compounds of formula I , where R1 means remainder of formula (a) , (b) or (c) , R2 means -(CR22R23)1-3-, R3 and R8 each means S, R4 and R5 each independently means C3-C12cycloalkyl, C1-C12alkyl or saturated C8-C12 polycyclic hydrocarbon remainder, such as adamantine, non-substituted phenyl or non-substituted benzyl unnecessarily substituted with group R25, R6 means H or C1-C6alkyl, R7 means CH, R9 means direct connection or -(CR22R23)1-2-, R10-R15 each means H, R16-R23 each independently means H, C1-C6alkyl, or R20 and R21 together with carbon atoms, to which they are connected, create a benzene ring, and R25 has one of values given above for R16-R23.

EFFECT: improved method for production of derivatives of isothiourea.

5 cl, 1 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention can be used for treating or preventing diseases and conditions, mediated by peroxisome proliferator activated gamma receptor (PPARγ). In formula (I) W represents a COOH group or -COOC-C1-C4alkyl; Y represents NH; Z represents S or O; X represents O; R1-R6 each independently represents a hydrogen atom or substitute, chosen from a group consisting of: C1-C4-alkyl, thienyl or phenyl, where phenyl is optionally substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, a halogen atom; -NO2 and -CN; A represents C1-C4-alkyl, -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, aryl, chosen from a group consisting of phenyl, naphthyl, or heteroaryl, chosen from a group consisting of oxazolyl, isoxazolyl, thienyl, pyridyl, thiazolyl, thiadiazolyl, benzo[b]thienyl, imidazolyl, indolyl and carbazolyl, where aryl and heteroaryl are substituted or not substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, phenyl and a halogen atom; and n is an integer from 0 to 4. The invention also relates to a pharmaceutical composition, containing the invented compound as an active component, use of the compounds to make a medicinal agent, and method of treatment.

EFFECT: obtaining new biologically active compounds.

22 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula (I) and its pharmaceutically acceptable salts and esters. Compounds of the present invention are characterised with properties of DGAT-1 inhibitor. In general formula (I) , Q represents O, S or NR5; A represents a linker chosen from where p is equal to 1 or 2, and , where m is equal to 0, and n is equal to 1, 2, 3 or 4, or m is equal to 1, while n is equal to 1, 2 or 3, where specified linker is optionally substituted with one or two groups R8; R1 and R2 are independently chosen from hydrogen, haloid; R3 is chosen from hydrogen, (C1-C6)alkyl optionally substituted with hydroxyl and phenyl optionally substituted with haloid; R4 is chosen from hydrogen, nitro and (C1-C6)alkyl; or R3 and R4 together with carbon atoms whereto attached, can form benzene ring optionally substituted with 1-2 substitutes. The invention also concerns compounds of formula (Ia) and (Ib) with structural formulas presented in the patent claim, and also to a pharmaceutical composition, a medical product, to application of compounds for making a medical product and compound process.

EFFECT: new compounds possess useful biological activity.

19 cl, 2 tbl, 7 dwg, 215 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl, naphthyl, 5-6-membered heterocyclyl comprising oxygen (O), nitrogen (N) or sulfur atom (S) as heteroatoms and wherein phenyl, naphthyl and heterocyclyl are optionally substituted with 1-3 substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy, nitro; di-(C1-C6)-alkylamino or (C1-C6)-alkoxy groups; R2 means hydrogen atom; R3 means (C1-C6)-alkyl or trifluoromethyl; A1 means C-R3 or nitrogen atom; A2 means piperidine or pyrrolidine wherein nitrogen atom in piperidine or pyrrolidine ring is added to A3 wherein A3 means -S(O)2- or -C(O)-; n = 0, 1 or 2. Also, invention relates to a pharmaceutical composition based on compounds proposed by the invention. Proposed compounds possess properties of NPY receptors antagonists and can be used in treatment arthritis, diabetes mellitus, nutrition disorders, obesity and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 1 tbl, 1 dwg, 26 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel cyclic compounds of the formula (I) and (II) or tier pharmaceutically acceptable salts wherein radical values given in formula (I) and (II) are indicated in the invention description. Also, invention relates to a pharmaceutical composition containing at least one compound of the formula (I), and to using these compounds for preparing a drug. Invention provides synthesis of novel compounds and preparing a compositions containing hereof that possess inhibitory activity with respect to protein-tyrosine kinase.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

24 cl, 3 tbl, 582 ex

FIELD: organic chemistry, biochemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel diaminothiazoles of the formula (I) , their pharmaceutically acceptable salts and esters, and to a pharmaceutical composition based on thereof. Proposed compounds inhibit activity of cyclin-dependent kinase 4 (Cdk4), shows selectivity with respect to Cdk2 and Cdk1 and can be used in treatment against cancer, in particular, against solid tumors. In the general formula (I) R2 and R3 represent hydrogen atom; R4 is chosen from group comprising lower alkyl, (C3-C6)-cycloalkyl, O-lower alkyl, halogen atom, -NO2, S-lower alkyl, -CF3 and -CN; R5 is chosen from group comprising hydrogen atom, O-lower alkyl, lower alkyl, halogen atom and -OH, or, alternatively, R4 and R in common with two carbon atoms and a bond binding them belonging to benzene cycle (C) to which R4 and R5 are bound can form a cycle consisting of 5-6 atoms comprising one or two heteroatoms chosen from oxygen atom and optionally substituted with (C1-C4)-alkyl; R6 and R are chosen independently from group comprising hydrogen atom, lower alkyl and -COOR12, or, alternatively, group -NR6R7 can mean cycle consisting of 5-6 atoms optionally comprising heteroatom chosen from nitrogen or oxygen atoms; R8 and R9 are chosen independently from group comprising hydrogen atom and lower alkyl; R10 is chosen from group comprising hydrogen atom, lower alkyl, lower alkyl substituted with hydroxyl, and -COOR12; R11 is chosen from group comprising hydrogen atom, lower alkyl and -COOR12 wherein R12 means lower alkyl; m can mean 1 or 2; n can mean 0, 1 or 2 under condition that if m means 2 and R4 means fluorine atom then R5 is not hydrogen atom, and under condition if m means 1 and R4 means lower alkyl then R5 is not hydroxyl.

EFFECT: valuable biochemical and medicinal properties of compounds and pharmaceutical compositions.

20 cl, 6 sch, 3 tbl, 153 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to new derivatives of 2-arylimino-2,3-dihydrothiazoles of the general formula (I): wherein radical values R1, R2, R3 and R4 are given in the claim invention. New compounds are useful in treatment of pathological states or diseases wherein one or some somatostatin receptors are implicated, for example, acromegaly, hypophysis adenomas or gastroenteropancreatic endocrine tumors with carcinoid syndrome and gastroenteric bleedings.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

14 cl, 2825 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

The invention relates to new and nitrate salts of heterocyclic compounds of formulas (a) and (b), where R is hydrogen, alkoxyl, R1- alkyl, alkoxyl, R2is hydrogen, alkyl, R3- alkyl, alkoxyl, X denotes N-R11or oxygen, R11means the free valence, Y represents N-R16, sulfur or alkyl, R16means hydrogen; other values radicals presented in the description of the invention

FIELD: medicine.

SUBSTANCE: group of inventions relates to experimental medicine and can be applied for amplification of apoptosis or cytolytic activity in cells of mammals. Method and application by invention include bringing mammalian cells in contact with effective quantity of Apo- 2-ligand receptors agonist and resting or unprocessed NK-cells, said agonist is selected from Apo-2-ligand polypeptide, agonistic DR5 antibody and agonistic DR4 antibody.

EFFECT: application of inventions allows amplification of apoptosis and cytolysis induction in tumour cells due to activation by Apo-2-ligand receptors agonist of resting NK-cells.

26 cl, 1 tbl, 18 dwg, 5 ex

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