Substituted oxazole derivatives and use thereof as tyrosine kinase inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

 

The technical field to which the invention relates.

The present invention relates to substituted derivatives of oxazole that selectively modulate, regulate and/or inhibit signal transmission mediated by certain natural and/or mutant tyrosine kinases involved in many human and animal diseases, such as disorders of cell proliferation, metabolic, allergic and degenerative disorders. More specifically, these compounds are potent and selective inhibitors of C-kit, bcr-abl and Flt-3.

The level of technology

Tyrosine kinase is a protein receptor type or precepting type that transfer of the terminal phosphate of ATP to tyrosine residues of proteins, activating or inactivating thus, the transmission path of the signal. It is known that these proteins are involved in many cellular mechanisms, which in the case of damage lead to such disorders as abnormal cell proliferation and migration, and inflammation.

Currently, there are about 58 receptors with tyrosinekinase activity. These include the well-known VEGF receptors (Kim et al., Nature 362, pp.841-844, 1993), receptors PDGP, c-kit, Flt-3 and the FLK family. These receptors can transmit signals to other tyrosine kinases, including Src, Raf, Frk, Btk, Csk, Abl, Fes/Fps, Fak, Jak, Ack, and so on

Among the receptors with tyrosinekinase Akti is of particular interest is C-kit. Indeed, c-kit is a key receptor that activates mast cells, which shows that they are directly or indirectly involved in numerous pathologies, for which the registered application WO 03/004007, WO 03/004006, WO 03/003006, WO 03/003004, WO 03/002114, WO 03/002109, WO 03/002108, WO 03/002107, WO 03/002106, WO 03/002105, WO 03/039550, WO 03/035050, WO 03/035049, US 60/359 .652, US 60/359651 and US 60/449861.

Discovered that fat cells present in the tissues of patients involved in, or contribute to the emergence of diseases such as autoimmune diseases (rheumatoid arthritis, inflammatory bowel disease (IBD)), allergic diseases, bone loss, cancer, such as solid tumors, leukemia and GIST, tumor angiogenesis, inflammatory diseases, interstitial cystitis, mastocytosis, a disease graft versus host disease, infectious diseases, metabolic disorders, fibrosis, diabetes, and diseases of the Central nervous system. It was shown that in these diseases mast cells participate in the destruction of tissues by releasing a mixture of various proteases and mediators, such as histamine, neutral proteases, lipid mediators origin (prostaglandins, thromboxanes and leukotrienes), and various cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-α, GM-CSF, MIP-1a, MIP-1b, MIP-2 and IFN-γ).

The receptor c-kit can also be constitutively activated by mutations that result is to abnormal cell proliferation and the development of diseases, such as mastocytosis (mutation D816V) and various cancers, such as GIST (c-kitΔ27, deletion podobrannogo domain).

From 60 to 70% of patients with acute myeloblastic leukemia (AML) have blast cells, which Express c-kit, the receptor for stem cell factor (SCF) (Broudy, 1997). SCF stimulates the growth of hematopoietic precursors and acts as a survival factor for AML blast cells. In some cases, AML (1 to 2%) was described mutation in the conservative remnant of the kinase domain (Kit816), leading to constitutive activation of c-kit (Beghini et al., 2000; Longley et al., 2001). This mutation, resulting in enhanced functions (substitution of Asp Val/Tyr), was identified in the fat cells of leukemic cell lines and in samples obtained from patients with mastocytosis (Longley et a., 1996). Preliminary results show that this mutation is expressed in most cases of systemic mastocytosis ([~60%], P Dubreuil, AFIRMM, research conducted currently on 300 patients).

For this reason, in order to loosen the fat cells responsible for these violations, it was suggested to make a target of c-kit.

The main objective underlying the present invention, therefore, is to find potent and selective compounds capable of inhibiting c-kit wild-type and/or mutant c-kit.

As inhibitors ti is sincinaty described many different compounds, for example, monocyclic, bicyclic or heterocyclic aryl bis-compounds (WO 92/20642), vinile-azaindole derivatives (WO 94/14808), 1-cyclopropyl-4-pyridyl-quinolones (US 5 330 992), sterilnye connection (US 5 217 999), styryl-substituted peredelnye connection (US 5 302 606), solenoidal and selenides (WO 94/03427), tricyclic polyhydroxylated compounds (WO 92/21660), compounds benzylphosphonic acid (WO 91/15495), derivatives of pyrimidine (US 5,521,184 and WO 99/03854), derivatives of indolinone and pyrrole-substituted indolinone (US 5792783, EP 934931, US 5834504, US 5883116, US 5883113, US 5886020, WO 96/40116 and WO 00/38519), as well as monocyclic, bicyclic aryl and heteroaryl bis-compounds (EP 584222, US 5656643 and WO 92/20642), derivatives of hintline (EP 602851, EP 520722, US 3772295 and US 4343940) and aryl and heteroaryl hinzelin (US 5721237, US 5714493, US 5710158 and WO 95/15758).

However, none of these compounds has not been described as a effective and selective inhibitor of c-kit or inhibitor ways of transformation of c-kit.

For the purposes of this invention we have found that compounds that demonstrate specific substitution derivatives oxazole, are potent and selective inhibitors of c-kit, bcr-abl, Flt-3, or ways of transformation of C-kit. These compounds are good candidates for the treatment of diseases, such as autoimmune diseases, inflammatory diseases, cancers and mastocytosis.

Disclosure of inventions

Thus, the present invention relates to compounds belonging to substituted derivatives of oxazole. These compounds may selectively inhibit signal transmission, including the tyrosine phosphokinase c-kit, bcr-abl, Flt-3 and their mutant forms.

In the first embodiment, the invention is directed to compounds having the formula I, which are either compounds in the form of free bases or pharmaceutically acceptable salt:

where the substituents A, b, b', Q and R1-R5 in the formula I are defined as follows:

A and b' are one of the following groups:

i) (R6)N(CH2)nwhere n is 0 or 1

ii) O(CH2)nwhere n is 0 or 1

iii) S(CH2)nwhere n is 0 or 1

iv) (CH2)nwhere n is 0, 1 or 2

v) C(O)(CH2)nwhere n is 0 or 1

or, if each of a and b' represent nitrogen, they together may form a bivalent radical having the formula:

where s and t each independently is 1 or 2, and X1 represents O, S, NR10, N[C(=O)R10] or (CH2)nwhere n is 0 or 1, and wherein each hydrogen in said formula (a) may be replaced by halogen or C1-4-alkyl.

In is one of the following groups:

i) (R6)N

ii) oxygen

iii) S(O)nwhere n is 0, 1 Il is 2

iv) CH(R6)(R7)

v)=δ, where δ represents an oxygen, sulfur, NH or N-CN

vi) C(R6)=C(R7)

vi) N=C(R6)

R6 and R7 each independently are hydrogen, C1-4-alkyl, C2-6-alkenyl,2-6-quinil,3-7-cycloalkyl, C1-4-halogenation,1-4-alkoxy, C1-4-hydroxyalkyl,1-4-alkylamino.

R1 is chosen from the groups listed below:

i) hydrogen, halogen (selected from F, Cl, Br or I), or

ii) alkyl1the group, representing a linear, branched or cycloalkyl group containing from 1 to 10 carbon atoms and optionally substituted by one or more heteroatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form pendantes functional group represented nitrogenous base; as well as trifluoromethyl, carboxyl, cyano, nitro, formyl; as well as CO-R, COO-R or CONH-R, SO2-R, and SO2NH-R wherein R represents a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted by at least one heteroatom, mainly halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form pendantes functional group represented by the nitrogenous base; and cycloalkyl, or aryl1or heteroaryl group, the optional is substituted on pendantes functional group nitrogenous base, or

iii) aryl1a group that represents a phenyl group or substituted phenyl group which can be substituted in any position of the ring with any combination of one or more substituents, such as

- halogen (selected from I, F, Cl or Br);

- alkyl1group;

- cycloalkyl, aryl or heteroaryl group, optionally substituted pendantes functional group nitrogenous base;

- trifluoromethyl, O-alkyl1carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl1N(alkyl1)(alkyl1), and amino, the latter nitrogen substituents optionally in the form pendantes functional group represented nitrogenous base;

- NHCO-R or NHCOO-R or NHCONH-R or NHSO2-R or NHSO2NH-R,

or CO-R or COO-R or CONH-R or SO2-R or SO2NH-R wherein R corresponds to hydrogen, alkyl1, aryl or heteroaryl, or

iv) heteroaryl1the group, which represents pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, indolyl, benzimidazole, benzoxazole, benzothiazole, hyalinella group, which optionally can be substituted in any position of the ring with any combination of one or more substituents, such as

- halogen (selected from F, Cl, Br or I);

- alkyl1group;

- cycloalkyl, aryl or heteroaryl group, optionally substituted pendantes functional group represented nitrogenous base,

- trifluoromethyl, O-alkyl1carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl1N(alkyl1)(alkyl1), and amino, the latter substituents of the nitrogen atom optionally in the form pendantes functional group represented nitrogenous base;

- NHCO-R or NHCOO-R or NHCONH-R or NHSO2-R or NHSO2NH-R,

or CO-R or COO-R or CONH-R or SO2-R or SO2NH-R wherein R corresponds to hydrogen, alkyl1or

v) O-aryl1or NH-aryl1or O-heteroaryl1or NH-heteroaryl1group,

vi) trifluoromethyl, O-alkyl1carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl1N(alkyl1)(alkyl1), and amino, the latter substituents of the nitrogen atom optionally in the form pendantes functional group represented nitrogenous base, or

vii) NHCO-R or NHCOO-R or NHCONH-R or NHSO2-R or NHSO2NH-R or CO-R or COO-R or CONH-R or SO2-R or SO2NH-R wherein R corresponds to hydrogen, alkyl1, aryl1or heteroaryl1.

Each R2, R3, R4 and R5 independently are selected from hydrogen, halogen (selected from F, Cl, Br or I), a linear or branched alkyl group containing from 1 to 10 carbon atoms and is obazatelno substituted by one or more heteroatoms, such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form pendantes functional group represented by the nitrogenous base; and trifloromethyl, C1-6-alkyloxy, amino, C1-6-alkylamino, di(C1-6-alkyl)amino, carboxyl, cyano, nitro, formyl, hydroxy, and CO-R, COO-R or CONH-R, SO2-R, and SO2NH-R wherein R corresponds to hydrogen, alkyl1, aryl or heteroaryl;

and where Q is chosen from the following groups:

i) alkyl1

ii) aryl1

iii) heteroaryl1,

as specified above.

In one of specific embodiments of the invention, the group Q is a substituted alkyl, aryl or heteroaryl group bearing pendant functional group nitrogenous base, represented, for example, structures from a to m shown below, where the wavy line and the line of the arrow corresponds to the point of connection to the main structure and having the formula I.

Also, for g-m arrow m which may indicate a connection point to the main structure via a phenyl group.

In addition, preferred compounds having formula I, II, III and IV, the invention relates to compounds in which R1 is pyridium or benzonitrile, which can be further substituted in any position of the ring with any combination of one or more substituents, such as

is hydrogen;

- halogen (selected from F, Cl, Br or I);

- alkyl1group;

- aryl1group;

- trifluoromethyl, O-alkyl1carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl1N(alkyl1)(alkyl1and amino, the latter atom substituents optionally in the form pendantes functional group represented nitrogenous base;

- NHCO-R or NHCOO-R or NHCONH-R or NHSO2-R or NHSO2NH-R,

or CO-R or COO-R or CONH-R or SO2-R or SO2NH-R wherein R corresponds to hydrogen, alkyl1or aryl1group.

Unless otherwise stated, for the purposes of the present invention, the term "alkyl group" means any linear or branched, substituted or unsubstituted C1-C10 alkyl group, such as C1-C4, or C1-C6, in particular methyl, ethyl group, through the group, preferably methyl. The term "alkenyl"used for the purposes of the present invention, refers to a C2-C6, in particular C2-C4, linear or branched chain substituted or unsubstituted alkenyl radika is s, containing from 2 to 30 carbon atoms, including, without limitation, ethynyl, propenyl, butenyl, pentenyl, hexenyl, etc. the Term "alkoxygroup" means any alkoxygroup having from 1 to 6 linear or branched, substituted or unsubstituted carbon atoms, in particular OCH3 group. The term "aryl group" means one or more aromatic rings having 5 to 6 carbon atoms, which may be conjugated or fused and substituted or unsubstituted. In particular, the aryl group may be phenyl or pyridium, and the substituents can be halogen atoms, cyano, amino, alkoxygroup, as defined above, alkyl groups, as defined above, or a nitro-group.

An example of preferred compounds having the above formula shown below:

001: N-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-C-phenyl-methane sulfonamide

TPL=258°C

002:4-{2-[5-(benzooxazol-2-ylamino)-2-methyl-phenylamino]-oxazol-5-yl}-benzonitrile

TPL=236°C

003: 4-{2-[5-(benzothiazol-2-ylamino)-2-methyl-phenylamino]-oxazol-5-yl}-benzonitrile

TPL=216-220°C

004: N1-benzooxazol-2-yl-4-methyl-N3-(5-pyridin-3-yl-oxazol-2-yl)-benzene-1,3-diamine

TPL=238°C

005: N1-(5-chloro-Bento Sasol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine

TPL=229°C

006: N1-(6-chloro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine

TPL>260°C

007: N1-(5-econsultancy-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine

TPL=252°C

008: 4-methyl-N1-(5-methyl-benzooxazol-2-yl)N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine

1H NMR (DMSO-d6, 300 MHz) δ=rate of 2.25 (s, 3H); 2.50 each (s, 3H); 6,91 (d, J=8,1, 1H); 7,14 (s, 1H); 7,20 (d, J=8,4, 1H); 7,33 (d, J=8,1, 1H); 7,47-7,53 (m, 3H); 7,79 (s, 1H); 8,13 (d, J=2,1, 1H); 8,53 (s, 1H); 8,55 (s, 1H); a 9.60 (s, 1H); 10,53 (s, 1H),

009: N1-(5-fluoro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine

TPL=170°C

010: N1-(6-fluoro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine

TPL=260°C

In addition to the specific compounds having the formula I, the invention is directed to compounds having the formula II below:

where Y represents oxygen, sulfur, NH or N-CN, Z represents oxygen, sulfur, N(R6) (CH2)nwhere n is 0, 1 or 2.

L is selected from alkyl1, aryl1or heteroaryl1as explained above.

R1, R2, R3, R4, R5 and R6 have the same meanings as described above.

An example is repectfully compounds, having the above formula is presented below:

011: 4-(2-{5-[3-(3-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamino}oxazol-5-yl)-benzonitrile

TPL=221°C

012: 4-(2-{5-[3-(3-cyano-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamino}oxazol-5-yl)-benzonitrile

TPL>260°C

013: 4-(2-{5-[3-(3-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamino}oxazol-5-yl)-benzamide

TPL>260°C

014: 1-(4-fluoro-phenyl)-3-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-imidazolidin-2-he

015: 1-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-3-(3-trifluoromethyl-phenyl)-imidazolidin-2-he

TPL=138-200°C

016: 1-(4-fluoro-phenyl)-3-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-tetrahydro-pyrimidine-2-he

In addition to the specific compounds having the formula I, the invention is directed to compounds having the formula III, below:

where n is an integer 0, 1 or 2.

M represents oxygen, sulfur or (CH2)nwhere n is 0, 1 or 2.

R is chosen from-N(R8)(R9), alkyl1, aryl1or heteroaryl1.

Each R8 and R9 is independently hydrogen, alkyl1, aryl1or courtesans what aryl 1.

R8 and R9 together may form a bivalent radical having the formula:

where v and w each independently is 1 or 2, and x2 represents CH2, O, S, NR10, or N[C(=O)R10], and each hydrogen in the above formula (b) may be replaced by halogen or C1-4-alkyl.

R10 represents hydrogen, C1-4-alkyl, C2-6alkenyl,2-6-quinil,3-7-cycloalkyl,1-4-halogenated, C1-6-alkoxy, C1-4-hydroxyalkyl.

R1, R2, R3, R4 and R5 have the meanings described above.

Examples

017: 1-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-3-phenyl-propane-1-he

TPL=138°C

018: 4-[2-(5-acetyl-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile

TPL=240°C

019: 4-(2-{5-[3-(4-fluoro-phenyl)-propionyl]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile

TPL=175°C

020: 4-{2-[2-methyl-5-(3-phenyl-propionyl)-phenylamino]-oxazol-5-yl}-benzonitrile

TPL=138°C

021: 4-(2-{5-[3-(3-fluoro-phenyl)-propionyl]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile

TPL=157°C

022: 4-[2-(5-acetyl-2-methyl-phenylamino)-oxazol-5-yl]-benzamide

TPL>260°C

In addition to the specific compounds having the formula I, the image is the buy is directed to compounds, having the formula IV, below:

G represents oxygen, sulfur, N(R11) or (CH2)nwhere n is 1 or 2.

H represents oxygen, N(R11) or (CH2)nwhere n is 1 or 2.

J is selected from N(R12)(R13), alkyl1, aryl1or heteroaryl1.

Each R12 and R13 is independently hydrogen, alkyl1, aryl1or heteroaryl1.

R12 and R13, together may form a bivalent radical having the formula:

where v and w each independently is 1 or 2, and x2 represents CH2, O, S, NR14 or N[C(=O)R14], and each hydrogen in the above formula (C) may be replaced by halogen or C1-4-alkyl.

Each R11 and R14 independently is hydrogen, C1-4-alkyl, C2-6-alkenyl,2-6-quinil,3-7-cycloalkyl,1-4-halogenation,1-6-alkoxy, C1-4-hydroxyalkyl.

R1, R2, R3, R4 and R5 have the meanings described above.

Examples

023: 1-(4-fluoro-phenyl)-2-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenylamino]-alanon

TPL=202°C

024: 1-(4-fluoro-phenyl)-2-{methyl-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-amino}-alanon

TPL=230°C

025: 4-({methyl-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-amino}-is cetyl)-benzonitrile

TPL=218°C

026: 2-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenylamino]-1-phenyl-alanon

TPL=152°C

027: 4-(2-{5-[2-(4-fluoro-phenyl)-2-oxo-ethylamino]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile

TPL=199°C

028: 4-(2-{5-[2-(4-cyano-phenyl)-2-oxo-ethylamino]-2-chloro-phenylamino}-oxazol-5-yl)-benzonitrile

029: N-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-benzyl]-benzamide

1H NMR (DMSO-d6, 300 MHz) δ=rate of 2.25 (s, 3H); of 4.45 (d, J=5,7, 2H); 6,99 (d, J=7,2, 1H); 7,17 (d, J=7,2, 1H); 7,45-7,52 (m, 5H); 7,72 (s, 2H); 7,88 (d, J=7,2, 2H); 8,49 (d, J=5,1, 2H); 9,05 (t, J=5,7, 1H); 9,54 (s, 1H).

030: 2-{methyl-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-amino}-1-phenyl-alanon

1H NMR (DMSO-d6, 300 MHz) δ=and 2.14 (s, 3H); 3,00 (s, 3H); 4,96 (s, 2H); 6,37 (d, J=9,2, 1H); to 6.95 (d, J=8,4, 1H); 7,13 (s, 1H); 7,42 (d, J=5,4, 2H); 7,52-the 7.65 (m, 4H); to 7.99 (d, J=7,2, 2H); 8,51 (d, J=5,7, 2H); 9,37 (s, 1H).

Compounds of the present invention can be obtained using the General Protocol described below.

Compounds having the formula 4 can be obtained by condensation of azide having the General formula 1, with an isocyanate related to type 2, or isothiocyanato related to 3 types.

The group is in formulas 2 and 3 is nitro, cyano, CH2OH, CO2CH3, CONH2, SON or the group A-B-B'-q Group, A-(B-B'-Q is the same as described in formula I.

The reaction of the compound 1 or compound 2, or compound 3 in a solvent such as methylene chloride or dioxane, in the presence of triphenylphosphine, yields a product oxazoline type having the formula 4.

R1, R2, R3, R4 and R5 have the meanings described above.

The following example is intended to illustrate the present invention.

Example of synthesis of compounds

General information: All used chemicals were commercial products of analytical grade. The solvents were anhydrous products technical purity and were used without further purification. Dioxane before applying re-distilled in a stream of argon. The reaction course is monitored by means of thin layer chromatography, using thin-layer chromatographic plate coated with silica gel 60F 254 (Merck), which were examined under UV light. The multiplets in NMR spectra indicated as singlet (s), broadband singlet (br s), doublet (d), triplet (t), quadruplet (q) and multiplet (m), and the NMR spectra were recorded on a spectrometer "Bruker" 300 MHz.

Getting 4-azidoethyl-benzonitrile

To a solution of commercially available 4-bromacetyl-benzonitrile (5 g, to 22.32 mmol) in 150 ml of methanol EXT is ulali sodium azide (1,74 g, 26,78 mmol) and the contents stirred at room temperature for 2 hours After removal of the solvent the residue was treated with water (50 ml) and was extracted with dichloromethane (3×50 ml). The combined organic layers were dried over MgSO4and concentrated to obtain a solid yellow (3,90 g, 94%). This connection is used for the next stage without any further purification.

Getting 4-[2-(2-methyl-5-nitro-phenylamino)-oxazol-5-yl]-benzonitrile

To a 25 ml solution of 4-azidoethyl-benzonitrile (1.5 g, of 8.06 mmol) in dioxane was added 2-methyl-5-nitrophenyl isocyanate (1,43 mg of 8.06 mmol) (commercially available) and triphenylphosphine (2,11 g of 8.06 mmol). The reaction mixture was placed in an oil bath, preheated to 100°C., and was stirred for 30 minutes After evaporation of the solvent under reduced pressure, the solid residue was recrystallized from ethanol to obtain specified in the title compound as yellow microcrystals (1,16 g, 45%).

TPL>260°C

Getting 4-[2-(5-amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile

To a solution of 4-[2-(2-methyl-5-nitro-phenylamino)-oxazol-5-yl]-benzonitrile (500 mg, 1.56 mmol) in ethanol (15 ml) was added chloride dihydrate tin(II) (677 mg, 3 mmol). The reaction mixture was heated with reverse Kholodilin the com within 4 hours The mixture was then concentrated, was added a saturated aqueous solution of NaHCO3and the resulting suspension was extracted with ethyl acetate (3×15 ml). The combined organic layers were washed brine (30 ml), dried over anhydrous MgSO4and concentrated. The residue was subjected to chromatography on a column of alumina (dichloromethane/ethanol: 99/1). 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was obtained in the form of a powder pale yellow (172 mg, 38%).

TPL=236°C

1H NMR (DMSO-d6) δ=and 2.14 (s, 3H); 4,91 (br s, 2H); and 6.25 (dd, J=7,8-1,9, 1H); PC 6.82 (d, J=8,0, 1H); 7,01 (d, J=2,4, 1H); to 7.68 (m, 3H); to 7.84 (d, J=8,5, 2H); which 9.22 (s, 1H).

Getting 4-(2-{5-[2-(4-fluoro-phenyl)-2-oxo-ethylamino]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile

To a solution of 4-[2-(5-amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile (60 mg, 0,207 mmol) in dimethylacetamide (3 ml) was added 4-florfenicol bromide (45 mg, 0,207 mmol), NaHCO3(18 mg, 0,207 mmol). The mixture was stirred at room temperature for 2 hours After removal of solvent, the residue was treated with saturated aqueous NaHCO3(10 ml) and was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with saline (20 ml), dried over MgSO4and concentrated. 4-(2-{5-[2-(4-Fluoro-phenyl)-2-oxo-ethylamino]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile was received which after chromatography on a column of silica gel (dichloromethane/ethanol: 98/2) (38 mg, 43%) as a solid beige color.

TPL=199°C

1H NMR (DMSO-d6) δ=2,12 (s, 3H); to 4.62 (d, J=4,8, 2H); of 5.81 (t, J=4,8, 1H); 6,37 (d, J=6,0, 1H); 6,91 (d, J=8,1, 1H); was 7.08 (s, 1H); 7,37 (m, 2H); to 7.67 (m, 3H); 7,83 (d, J=8,4, 2H); to 8.14 (m, 2H); of 9.30 (s, 1H).

Getting 4-[2-(5-acetyl-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile

In the same way as described for 4-[2-(2-methyl-5-nitro-phenylamino)-oxazol-5-yl]-benzonitrile, from 4-azidoethyl-benzonitrile (2.70 g, 14.5 mmol) and 1-(3-isothiocyanato-4-methyl-phenyl)-ethanone (2,22 g, 11.6 mmol) was obtained specified in the header connection (1,43, 31%) as a solid yellow color.

1H NMR (DMSO-d6) δ=2,41 (s, 3H); at 2.59 (s, 3H); 7,41 (d, J=7,8, 1H); to 7.67 (dd, J=7,8-1,6, 1H); of 7.75 (s, 1H); 7,79 (d, J=8,4, 2H); 7,72 (d, J=8,4, 2H); 8,51 (d, J=1,6, 1H); 9,73 (s, 1H).

Getting 4-{2-[2-methyl-5-(3-phenyl-propionyl)-phenylamino]-oxazol-5-yl}-benzonitrile

To a solution of 4-[2-(5-acetyl-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile (100 mg, 0,315 mmol) and benzaldehyde (or 0.035 ml, 0.35 mmol) in ethanol under stirring was added dropwise 1 ml of 30%aqueous NaOH solution at 0°C. then the mixture was stirred at room temperature for 16 h and poured into ice-cold water (approximately 10 ml). The precipitate was filtered off, washed with diethyl ether, and dried under reduced pressure.

The obtained solid yellow dissolved methanole (2 ml) and THF (2 ml), was treated with palladium on coal (10%, 20 mg) and hydrogenosomal. The catalyst was removed by filtration through zelany filter. The filtrate is evaporated under reduced pressure to obtain specified in the title compound (77 mg, 60%) as yellow powder.

1H NMR (DMSO-d6) δ=2,41 (s, 3H); 2,98 (t, J=7,7, 2H); to 3.36 (t, J=7,7, 2H); 7.23 percent (m, 1H); 7,32 (m, 4H); 7,40 (d, J=7,8, 1H); of 7.69 (dd, J=7,8-1,6, 1H); 7,72 (s, 1H); 7,89 (d, J=8,4, 2H); 7,94 (d, J=8,4,2H); charged 8.52 (d, J=1,6, 1H); 9,73 (s, 1H).

Getting 4-bromoacetophenone, HBr salt

Bromine (24 g, 150 mmol) in 4 ml of 45%HBr under vigorous stirring was added dropwise to a solution of 4-acetylpyridine (18 g, 148 mmol) in acetic acid containing 45%HBr (165 ml)at 70°C. the Mixture with vigorous stirring and left at 70°C for 3 hours the Mixture was cooled and the precipitate was collected by filtration and washed with a mixture of petroleum ether/methanol (1/1, 100 ml, 40-65°C)to obtain a 35.8 g of white crystals (85%).

Receive (2-methyl-5-nitro-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine

To a solution of 4-bromoacetophenone hydrobromide (5 g, 17.8 mmol) in 80 ml of water was added sodium azide (1,16 g, 17.8 mmol)and the contents stirred at room temperature for 30 minutes, the Reaction mixture was cooled to 0°C. was slowly treated with saturated aqueous NaHCO3to pH 6-7 was extracted with dichloromethane (3×30 ml) and the volume of yennie the organic phase was dried over MgSO 4concentrated at room temperature under reduced pressure to a final volume of 25 ml and was diluted with dioxane (30 ml). The resulting solution was concentrated to remove residual dichloromethane (low boiling). To the final volume (25 ml) at 0°C was added 2-methyl-5-nitrophenylhydrazine (1,58 g, 8.9 mmol) (commercially available product) and in portions triphenylphosphine (2,62 g, 8.9 mmol). The reaction mixture then was stirred for 1 h at room temperature and was heated for another 2 h at 100°C. After evaporation of the solvent under reduced pressure the residue was led in a mixture of dichloromethane/ethanol (10 ml/5 ml), to obtain the connection specified in the header, in the form of yellow crystals (0.9 g, 34%).

TPL >220°C

Receive (2-methyl-5-amino-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine

A solution of (2-methyl-5-nitro-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine (1 g, 3,39 mmol) in ethanol (50 ml) was treated with 10%Pd/C (120 mg), was added dropwise hydrazinehydrate (3,50 ml, 112,5 mmol) within 10 min the Reaction mixture was stirred at room temperature for 30 min and then was heated under reflux for 2 hours, the Hot solution was filtered through a small zelany filter, and the catalyst was washed with hot ethanol. The filtrate was concentrated under reduced pressure to obtain accidenly product. It was purified by chromatography on a column of silica gel (dichloromethane/ethanol: 97/3). Got 720 mg (80%) (2-methyl-5-amino-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine as a pale yellow powder.

TPL=158°C

1H NMR (DMSO-d6) δ=and 2.14 (s, 3H); 4,96 (bs, 2H); 6.30-in (dd, J=8,1-2,1, 1H); 6.87 in (d, J=8,1, 1H);? 7.04 baby mortality (d, J=2,1, 1H); 7,50 (d, J=6,0, 2H); 8,58 (d, J=6,0, 2H); 7,76 (s, 1H); 9.28 are (s, 1H).

Receive (5-isothiocyanato-2-methyl-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine

To a solution of (2-methyl-5-amino-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine (500 mg, 1.88 mmol) in dichloromethane (70 ml) was added 1,1-thiocarbonyl-di-2(1H)-pyridine (525 mg, and 2.26 mmol). The mixture was stirred at room temperature overnight. After evaporation of the solvent under reduced pressure the residue was chromatographically on a column of silica gel (ethyl acetate/heptane: 50/50)to obtain 528 mg (91%) solid beige color that is specified in the header.

1H NMR (DMSO-d6) δ=a 2.36 (s, 3H); 7,10 (dd, J=8,1-2,1, 1H); to 7.32 (d, J=8,1, 1H); 7,56 (d, J=6,0, 2H); 7,86 (s, 1H); 8,08 (d, J=2,1, 1H); to 8.62 (d, J=6,0, 2H); 9,80 (s, 1H).

Obtain N1-(5-chloro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzyl-1,3-diamine

To a solution of (5-isothiocyanato-2-methyl-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine (120 mg, 0,39 mmol) in DMF (8 ml) was added 2-amino-4-chloro-phenol (61 mg, 0.43 mmol). The mixture was stirred at room temperature during the night and added the yellow oxide of mercury (II) (72 mg, 0,39 mmol). The mixture was stirred at room temperature for 1 h, the precipitate was filtered through a small zelany filter. The filtrate was concentrated under reduced pressure to obtain the crude product. It was chromatographically on a column of silica gel (dichloromethane/ethanol: 95/5)to obtain 112 mg (69%) solid yellow color that is specified in the header.

1H NMR (DMSO-d6) δ=and 2.26 (s, 3H); 7,14 (dd, J=8,7-2,1, 1H); 7,22 (d, J=8,7, 1H); 7,40 (d, J=2,1, 1H); 7,47-7,53 (m, 4H); 7,79 (s, 1H); to 8.12 (d, J=2,1, 1H); 8,53 (s, 1H); 8,55 (s, 1H); being 9.61 (s, 1H); 10,77 (s, 1H).

Getting 4-(2-{5-[3-(3-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile

To a solution of 4-[2-(5-amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile (558 mg, 2 mmol) and chloroacetaldehyde (50% wt./mass. in water, 628 mg, 4 mmol) in acetonitrile (60 ml)was added at room temperature NaBH3CN (253 mg, 4 mmol) and dropwise acetic acid (0.4 ml). The mixture was stirred at room temperature for 1 h was Added ethyl acetate (50 ml) and saturated aqueous solution of NaHCO3(50 ml). The organic layer was washed with saline (20 ml), dried over MgSO4and concentrated to obtain a solid yellow color. It was dissolved in toluene (40 ml) and treated under reflux for 2 h, 1-fluoro-3-isocyanatobenzene (274 mg, 2 IMO is b). After evaporation of the solvent under reduced pressure the crude product was dissolved in isopropanol (60 ml) and was treated with tert-piperonyl potassium (1.8 g, 16 mmol) at room temperature for 5 hours was Added water (20 ml), the organic layer was separated, dried over MgSO4and concentrated. The crude product was chromatographically on a column of silica gel (dichloromethane/ethanol: 95/5)to obtain 408 mg (45%) solid beige color that is specified in the header.

1H NMR (DMSO-d6) δ=and 2.26 (s, 3H); 3,98 (s, 4H); 6,90 (t, J=9,0, 1H); 7,20 (bs, 2H); 7,33-7,42 (m, 2H); 7,65 is 7.85 (m, 6H); 8,19 (s, 1H); 9,82 (s, 1H).

Getting 4-(2-{5-[3-(3-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile

The compound 4-(2-{5-[3-(3-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile (30 mg, of 0.066 mmol) was treated in EtOH (2 ml), 3 N NaOH solution (1 ml). The resulting mixture was stirred at reflux for 3 hours After cooling to room temperature, was added 1 N HCl solution to pH 6-7 and the precipitate was filtered to obtain solid yellow (9 mg, 29%)specified in the header.

ES/MS: m/z=471[M-H]-.

In the second embodiment of the invention relates to pharmaceutical compositions comprising a compound described above.

Such medicinal products which may take the form of a pharmaceutical composition, suitable for oral administration, which may be made in appropriate dosages using pharmaceutically acceptable carriers well known in this technical field. Such carriers enable you to make a pharmaceutical composition in the form of tablets, pills, coated tablets, capsules, liquids, gels, syrups, casic, suspensions, etc. for the patient. In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising eccipienti and tools that facilitate processing of the active compounds into preparations that can be applied in the pharmaceutical industry. Further details on the technology and the introduction can be found in the latest edition Remington''s Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).

The composition of the present invention may also take the form of a pharmaceutical or cosmetic composition for topical use.

Such compositions may be presented in the form of a gel, paste, ointment, cream, lotion, liquid suspensions, aqueous, aqueous-alcoholic or oily solutions or dispersion systems, similar to a lotion or serum, or anhydrous or lipophilic gels, or emulsions of liquid or semi-solid consistency of the milk type, obtained by dispersion of a fatty phase in aq the phase or Vice versa, or of suspensions or emulsions of soft, semi-solid consistency similar to cream or gel, or, alternatively, in the form of microemulsions, of microcapsules, of microparticles or of vesicular dispersion systems of ionic and/or nonionic type. These songs get according to standard methods.

The composition in accordance with the present invention includes any ingredient that is commonly used in dermatology and cosmetics. It may include at least one ingredient selected from hydrophilic or lipophilic gelling funds, hydrophilic or lipophilic active agents, preserving agents, softening agents, polymers which increase the viscosity, moisturizers, surfactants, preservatives, antioxidants, solvents, and fillers, antioxidants, solvents, fragrances, fillers, protective agents, bactericidal agents, odor absorbers and colorants.

As oils that may be used in the present invention, can be mentioned mineral oils (liquid paraffin), vegetable oils (liquid fraction of the oil Shea, sunflower oil), animal oils, synthetic oils, silicone oils (cyclomethicone) and fluorinated oils. Fatty alcohols, fatty acids (stearic acid) and waxes (paraffin wax, Carnauba wax, beeswax vos is) can also be used as fatty substances.

As emulsifiers that may be used in the present invention, consider literallayout, Polysorbate 60 and the mixture of PEG-6/PEG-32/picoliters.

As hydrophilic gelling funds can be marked carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate/alkylacrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, clays and natural gums, and as lipophilic gelling funds may be mentioned modified clays such as bentonite, metal salts of fatty acids such as aluminum stearates and hydrophobic silica, or alternatively, ethylcellulose and polyethylene.

As hydrophilic active agents can be used proteins or protein hydrolysates, amino acids, polyols, urea, allantoin, sugars and derivatives of sugars, vitamins, starch and plant extracts, in particular extracts of Aloe Vera.

As lipophilic active agents can be used retinol (vitamin a) and its derivatives, tocopherol (vitamin E) and its derivatives, essential fatty acids, ceramides and essential oils. When using these substances give the skin extra moisturizing or emollient properties.

In addition, the composition may be included in Ernesto-active substance, to ensure deeper penetration of the compound capable of depleting mast cells, such as the tyrosine kinase inhibitor, preferably an inhibitor of c-kit and/or bcr-abl.

In addition to the prescribed ingredients invention includes substances that increase the permeability selected, for example, from the group consisting of mineral oil, water, ethanol, triacetin, glycerin and propylene glycol; binders, selected, for example, from the group consisting of polyisobutylene, polyvinyl acetate and polyvinyl alcohol and thickeners.

Chemical methods of improving local absorption of drugs is well known in this technical field. For example, the compounds can increase the permeability include sodium dodecyl sulfate (Dugard, P.H. and Sheuplein, R.J., "Effects of Ionic Surfactants on the Permeability of Human Epidermis: An Electrometric Study," J. Ivest. DermatoL, V.60, pp.263-69, 1973), the oxide laurylamine (Johnson et al., US 4411893), azone (Rajadhyaksha, US 4405616 and 3989816) and decelerated (Sekura, D.L. and Scala, J., "The Percutaneous Absorption of Alkylmethyl Sulfides, "Pharmacology of the Skin, Advances In Biolocy of Skin, (Appleton-Century Craft) V.12, pp.257-69, 1972). It was found that increasing the polarity of the head amphoteric molecules increases their ability to increase the permeability, but by strengthening their ability to irritate the skin (Cooper, .R. and Berner, B., "Interaction of Surfactants with Epidermal Tissues: Physiochemical Aspects," Surfactant Science Series, V.16, Reiger, M.M. ed. (Marcel Dekker, Inc.) pp195-210, 1987).

The second class of chemical amplifying means generally referred to as co-solvents. These substances are relatively easy topically absorbed, and using a variety of mechanisms provide increased permeability for certain drugs. Ethanol (Gale et. al., US 4615699 and Campbell et. al., US 4460372 and 4379454), dimethylsulfoxide (US 3740420 and 3743727 and US 4575515) and derivatives of glycerol (US 4,322,433) are a few examples of compounds that have demonstrated the ability to increase the absorption of various compounds.

The pharmaceutical compositions of the invention can also be intended for introduction of aerosol composition on the target areas of the respiratory tract of the patient.

The device and methodology for the implementation of the aerosol spray composition of the medicinal product are disclosed in US patent 5906202. The composition preferably represent solutions, for example aqueous solutions, alcoholic solutions, aqueous/alcoholic solutions, salt solutions, colloidal suspensions and microcrystalline suspension. For example, the sprayed particles comprise the active ingredient mentioned above, and the media (for example, pharmaceutically active drug acting on the respiratory system, and the media), the particles are formed by forcing the composition through a nozzle, which preferably has the form of g is bcoi porous membrane. The particles have a size that is small enough so that when the particles are formed, they remain suspended in the air within the time required, for example, the patient could inhale the particles into the lungs.

The invention includes a system described in patent US 5556611:

- liquid-gas system (LPG is used as a gas propellant (for example, low-boiling FCHC or propane, butane) in the container under pressure,

- aerosol containing suspended matter (particles of the active substance is suspended in solid form in the liquid phase of the propellant),

- gas system under pressure (use a compressed gas, such as nitrogen, carbon dioxide, nitrous oxide, air).

Thus, in accordance with the present invention created a pharmaceutical preparation in which the active substance is dissolved or dispersed in a suitable non-toxic environment, and the above solution or dispersion system ground to the aerosol state, that is, very carefully distributed in gas-carrier. It is technically possible to do, for example, in the form of an aerosol packaging propellants, aerosols, pump type, or other devices known, in fact, for spraying liquids and spray solids, which, in particular, allow precise individual on the stenosed.

Therefore, the invention is also directed to an aerosol device comprising compounds described above, and the specified composition, preferably a metering valves.

The pharmaceutical compositions of the present invention can also be designed for intranasal administration.

A specialist in this area of technology will be easily understood pharmaceutically acceptable carriers for introducing connections at the nasal mucous surface. These carriers are described in "Remington''s Pharmaceutical Sciences 16th edition, 1980, Ed. By Arthur Osol, a detailed description of which is included here by reference.

The choice of suitable carriers depends upon the specific type of introduction. For insertion through the upper respiratory tract, the composition may be prepared in the form of a solution, such as water or isotonic saline, buffered or non-buffer solution or suspension for intranasal administration in the form of drops or spray solution. Preferably such solutions or suspensions are isotonic with respect to the secretions of the nose and have approximately the same pH value, for example, in the approximate range from pH 4.0 to pH 7.4 or pH 6.0 to pH 7.0. Buffers should be physiologically compatible, and they include, for example, phosphate buffers. For example, the described tapicesmedio, reduces swelling of the nasal cavity, which is buffered to approximately pH 6.2 (Remington's, Id., str). Clearly, the ordinary technician can easily determine the appropriate amount of salt and pH for non-toxic water carrier for nasal administration and/or for introduction into the upper respiratory tract.

Conventional intranasal carriers include nasal gels, creams, pastes or ointments viscosity component, for example, from about 10 to about 3000 centipoise, or you can also apply the media, with an approximate viscosity of from 2500 to 6500 centipoise or higher, to ensure longer contact with the surface of the mucous membrane of the nose. Such compositions with viscous media can be, for example, based on alkylaryl and/or other biologically compatible media with high viscosity, are well known in the art (see, for example, work Remington's cited above). The preferred alkylsalicylate, for example, is the methylcellulose in the approximate concentration range from 5 to 1000 or more mg per 100 ml of media. More preferably, the concentration of methyl cellulose is, for example, from about 25 mg to about 100 ml of media.

Also may include other ingredients, such as known in this technical field preservatives, dyes, lubricating or viscous mineral is s or vegetable oil, perfumes, natural or synthetic plant extracts, such as essential oils, and moisturizers and agents that increase viscosity, such as glycerin, to provide additional strength, preserving humidity and a pleasant texture and odor of the composition. For nasal administration of solutions or suspensions in accordance with the present invention in this field of technology, there are different devices for the formation of droplets, droplets and mist.

Created dispenser measuring unit dosages which includes a pipette or spray device containing a solution or suspension intended for drug delivery in the form of drops or in the form of atomized liquid, and which contains one or more doses taken medicines, and this dispenser is another aim of the present invention. The invention also includes a kit containing one or more single anhydrous doses of the compounds, together with any necessary salts and/or buffer substances, preservatives, dyes, etc. ready for preparation of a solution or suspension after adding a suitable amount of water.

Another aspect of the invention is directed to the use of the above compounds in the manufacture of medicines. In other words, izopet the tion includes a method of treating diseases, associated with the unregulated transduction of c-kit, comprising introducing an effective amount of the compound to a mammal in need of such treatment, as defined above.

In particular, the invention is directed to a method of treatment of a disease selected from autoimmune diseases, allergic diseases, bone loss, cancers, such as leukemia and GIST, angiogenesis, tumors, inflammatory diseases, inflammatory bowel diseases (IBD), interstitial cystitis, mastocytosis, infectious zabolevanii, metabolic disorders, fibrosis, diabetes and disorders of the Central nervous system, including the introduction of an effective amount of the compounds specified above, to a mammal in need of such treatment.

The above compounds are useful in the manufacture of medicinal products for the treatment of diseases associated with unregulated transduction of c-kit, including, without limitation, the following diseases:

- neoplastic diseases such as mastocytosis, mastocytoma dogs, solid tumor, and stromal tumor of the gastrointestinal tract of man ("GIST"), small cell lung cancer, non-small cell lung cancer, acute malacitana leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, colorectal carcinoma, carcinoma Gelu the ka, stromal tumors of the gastrointestinal kishechnogo tract, testicular cancers, glioblastomas, solid tumors and astrocytomas,

- angiogenesis of tumors,

metabolic diseases such as diabetes mellitus and its chronic complications; obesity, type II diabetes; hyperlipidemia and dyslipidemia; atherosclerosis; hypertension and cardiovascular disease,

allergic diseases such as asthma, allergic rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, nodosa erythema, poly-form erythema, cutaneous necrotizing vasculitis and cutaneous inflammation caused by insect bites and infestation of blood-sucking parasites

- interstitial cystitis

- loss of bone mass (osteoporosis),

- inflammatory diseases such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition,

- autoimmune diseases such as multiple sclerosis, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, focal and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, vulgar (TB) lupus, dermatomyositis, polymyositis syndrome Segre is a, nodular panarteritis, autoimmune enteropathy, as well as proliferative glomerulonephritis,

- the disease is graft versus host disease or graft rejection in the transplantation of any organ, including the kidney, pancreas, liver, heart, lung, and bone marrow,

- other autoimmune diseases, which includes the present invention, chronic active hepatitis and chronic fatigue syndrome,

- disorders associated with the formation of subepidermal vesicles, such as pemphigus,

- vasculitis,

HIV,

- diseases associated with dysfunction of melanocytes, such as hyperplanes arising from dysfunction of melanocytes and including lentigines, solar and senile skin pigmentation, melanosis, moles and malignant melanoma. In this sense, the invention encompasses the use of compounds described above, for the manufacture of pharmaceutical or cosmetic composition for bleaching human skin,

- disorders of the CNS, such as psychiatric disorders, migraine, pain, memory loss and degeneration of nerve cells. In particular, the method in accordance with the present invention are useful for the treatment of the following disorders: depression, including delimitable violation, cyclothymic violation, bipolar depression, severe or "melancholic will stifled depression, atypical depression, resistant depression, seasonal depression; anorexia, bulimia, premenstrual syndrome, post-menopausal syndrome, and other syndromes, such as mental retardation and loss of concentration, pessimistic worry, agitation, self-deprecation, reduced libido; pain, including acute pain, postoperative pain, chronic pain, nociceptive pain, pain caused by cancer, neuropathic pain, psychogenic syndromes pain; anxiety disorders, including anxiety associated with hyperventilation and cardiac arrhythmia, phobic disorders, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder; mental-threatening conditions such as acute anxiety with panic reaction, including psychosis, delusional disorder, phobias, mania, delirium; dissociative episodes, including dissociative amnesia, dissociative Fugue, and the split-brain syndrome personality, depersonalization, catatonia, seizures; mental-threatening conditions, including suicidal behavior, untidiness, violent or aggressive behavior, trauma, borderline and acute psychosis; schizophrenia, including paranoid schizophrenia, JV is Tannoy schizophrenia, catatonic schizophrenia, disorganized schizophrenia,

- neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, prion disease, a disease of motor neurons (MND) and amyotrophic lateral sclerosis (ALS),

- offences related to abuse of psychoactive substances mentioned here, which include, without limitation, addicted to drugs, drug abuse, addiction to drugs, drug dependence, withdrawal and overdose,

- ischemia brain,

- fibrosis,

muscular dystrophy Duchenne.

As for mastocytosis, the invention provides the use of compounds as defined above for the treatment of various categories that can be classified as follows:

Category I consists of two sub-categories IA and IB). Category IA are diseases in which the infiltration of fat cells occurs only in the skin. This category represents the most common form of the disease and includes: (i) pigment urticaria, the most common form of skin mastocytosis, which is particularly common in children, ii) diffuse cutaneous mastocytosis, iii) single mastocytoma and iv) some rare subtypes such as bullet the first, erythrodermic and teleangiectatic mastocytosis. These forms are characterized by a very good prognosis with spontaneous remission in children and very dull for adults. Duration of survival in this form of the disease is usually comparable to the life expectancy of the General population, and the transition to another form of mastocytosis rarely see. Category IB presents indolent systemic disease (SM) involvement with or without involvement of the skin. These forms are far more common in adults than in children. The disease is often slow, but can sometimes appear symptoms of mastocytosis with aggressive or symptoms of malignant mastocytosis, leading to progressive damage to organ function.

Category II includes mastocytosis with an associated hematological disorder, such as myeloproliferative or myelodysplastic syndrome, or acute leukemia. This malignant mastocytosis usually does not affect the skin. The progression of the disease usually depends on the type of the associated hematologic disorders, which determines the prognosis.

Category III presents systemic mastocytosis with aggressive, which usually occurs in massive infiltration of multiple organs abnormal fat cells. Patients with this aggressive form of the flow is zabolevaniya the most notable characteristic of myeloproliferative disorders symptoms of peripheral blood. Disease progression can be very rapid, like acute leukemia, or some patients may exhibit longer survival.

Finally, category IV mastocytosis includes technology leukemia characterized by the presence of circulating mast cells and their precursors, representing more than 10% of blood leukocytes. This form is probably the most rare type of leukemia in humans, and has a very poor prognosis, similar to quickly progressive malignant variant of mastocytosis. Technology leukemia may meet or de novo, or as the last stage of liver urticaria or system mastocytosis.

The invention also provides, as illustrated, the method of treatment of recurrent bacterial infections, "awake" after asymptomatic periods of infections such as bacterial cystitis. In particular, the invention can be used to treat bacterial infections that cause expression of FimH, with the participation of such bacteria as gram-negative enteric bacteria, including E. coli, Klebsiella pneumoniae, Serratia marcescens, Citrobactor freudii and Salmonella typhimurium. In this way the treatment of bacterial infections is of interest independent, sequential or simultaneous introduction of at least one antibiotic selected is from about bacitracin, cephalosporins, penicillins, aminoglycosides, tetracyclines, streptomycin and macrolide antibiotics such as erythromycin; fluoroquinolones, atomizing, sulfonamides and trimethoprim.

In one preferred embodiment the invention is directed to a method of treatment of malignant diseases such as mastocytosis, mastocytoma dogs, solid tumor, and stromal tumor of the gastrointestinal tract of man ("GIST"), small cell lung cancer, non-small cell lung cancer, acute malacitana leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, colorectal carcinoma, carcinoma of the stomach, gastrointestinal stromal tumors-kishechnogo tract, testicular cancers, glioblastomas, and astrocytomas, including the introduction of a compound as described herein to a human or mammal, particularly dogs and cats in need of such treatment.

In another preferred embodiment the invention is directed to a method of treating allergic diseases such as asthma, allergic rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, nodosa erythema, poly-form erythema, cutaneous necrotizing vasculitis and cutaneous inflammation caused by insect bites, and invasion to awesomeme parasites involving the introduction of a compound as described herein to a human or mammal, particularly dogs and cats in need of such treatment.

In another preferred embodiment the invention is directed to a method for treating inflammatory diseases such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition comprising introducing the compound, as described herein, a person in need of such treatment.

In another preferred embodiment the invention is directed to a method of treating autoimmune diseases such as multiple sclerosis, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, focal and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, vulgar (TB) lupus, dermatomyositis, polymyositis, Sjogren syndrome, nodular panarteritis, autoimmune enteropathy, as well as proliferative glomerulonephritis, comprising introducing the compound, as described herein, a person in need of such treatment.

In another preferred embodiment the invention is directed to a method of treating disease graft versus host disease or graft rejection in the transplantation of any organ, including the kidney, jeludocnuu gland, liver, heart, lung, and bone marrow, including the introduction of compounds as described herein, a person in need of such treatment.

Example: analysis of the inhibition of the LC in vitro

Progress

Analysis of C-Kit WT and mutant C-Kit (JM and kinase domain 816)

Analyses of proliferation

Cells were washed twice in PBS before seeding in the amount of 5·104cells per well in 96-well plates in three repetitions and stimulated or hematopoietic growth factors (HGF), or in their absence. After 2 days of cultivation was added 37 Bq (1,78 TBq/mmol) [3H] thymidine (Amersham Life Science, UK) for 6 hours. The cells were collected and filtered through glass fiber filters and measured the incorporation of [3H] thymidine using a scintillation counter.

For analysis of proliferation of all medicines received in the form of 20 mm spare solutions and stored them at -80°C. Fresh dilution in PBS was made before each experiment. Drugs dissolved in DMSO, was added at the beginning of the cultivation. Control cultures were treated with appropriate dilutions of DMSO. The results are presented in percent, where 100% accept proliferation in the absence of inhibitor.

Cells

Mouse and human Ba/F3 kit, Ba/F3 mkitΔ27 (deletion podobrannogo domain) and hkitD816V were obtained from murine IL-3-dependent Ba/F3 proB lymphoid cells. Glue the full line FMA3 and R represent cells mastocytoma, expressing endogenous mutant forms of Kit, i.e. forms with a deletion within the reading frame at the site codons 573-579 receptor, encoding a murine podobrannyi domain. Line leukemic MS-cells HMC-1 person expresses a double point mutation (i.e. mutation JM-V560G and mutation of the kinase domain kitD816V), whereas subclan α155 HMC1 expresses only the mutation JM-V560G.

The analysis thus and immunoblot analysis

For each analysis was literally and immunoprecipitates 5·106cells Ba/F3 and BA/F3 cells with different mutations of c-kit, as described in the work Beslu et al, 1996, except that cells were stimulated with 250 ng/ml rmKL. Cell lysates were immunoprecipitated with rabbit immune serum to the cytoplasmic domain of KIT or with antibodies to mouse KIT (Rottapel et al., 1991), or with antibodies to human KIT (Santa Cruz). Hybridization in the immunoblot analysis was performed or 4G10-antibody to phosphotyrosine (UBI), or with a suitable rabbit immunobiologii to the KIT, or with other antibodies (described in paragraph antibodies). Then membranes were incubated with either goat antibodies to mouse IgG, conjugated with HRP or goat antibodies to rabbit IgG, conjugated with HRP (Immunotech). Interesting proteins are then visualized after incubation with ECL reagent (Amersham).

Experimental results

The experiment is Antalya results for various compounds in accordance with the present invention, obtained using the protocols described above are presented in the table:

Inhibition in vitro of various compounds directed against c-Kit WT, c-Kit JMΔ27 and c-Kit D816V.
TargetIC50 (µM)Connection
c-Kit WTIC50<1 μm001; 002; 004; 011; 017; 021; 028; 030
c-Kit JM Δ27IC50<1 μm001; 017; 027; 028; 029; 030
c-Kit D816VIC50≤1 µM001; 002; 011; 017; 021; 030

1. The compound of the formula I

where the substituents A, b, b', Q, and R1-R5in formula I are defined as follows:
A and b' are one of the following groups:
i) (R6)N(CH2)nwhere n is 0 or 1;
ii) (CH2)nwhere n is 0, 1 or 2;
iii) C(O)(CH2)nwhere n is 0 or 1;
or, if each of a and b' represent nitrogen, they together may form a bivalent radical of the formula

where s and t each independently is 1 or 2 and X1represents (CH2)nwhere n is 0 or 1;
is one of the following groups:
i) (R6N;
ii) oxygen;
iii) C=δ, where δ represents oxygen or sulfur;
iv) C(R6)=C(R7);
R6and R7each independently are hydrogen, C1-4-alkyl;
R1choose from the groups listed below:
i) phenyl group, substituted by one or more Deputy, such as:
- halogen selected from F, Cl, Br or I, or
- alkyl1group;
- aryl1or heteroaryl group1;
is cyano, NH-alkyl1N(alkyl1)(alkyl1and amino;
- NHCO-R or NHCOO-R or COO-R or CONH-R, where R represents hydrogen or alkyl1group, or
ii) pyridinoline group which may be substituted by one Deputy, such as
- halogen selected from I, F, Cl or Br;
- alkyl1group;
- aryl1group;
is cyano, NH-alkyl1N(alkyl1)(alkyl1and amino;
- NHCO-R or NHCOO-R or COO-R or CONH-R, where R represents hydrogen or alkyl1group;
each R2, R3, R4and R5independently selected from hydrogen or linear or branched alkyl group containing from 1 to 10 carbon atoms;
Q is chosen from the following groups:
i) alkyl1;
ii) aryl1;
iii) heteroaryl1,
where
- alkyl1group means a linear or branched group containing 1-10 atoms of plastics technology : turning & the Yes, nitrogen, the latter optionally in the form of a primary side nitrogen-containing functional group, which represents a piperazine, piperidine, substituted C1-4the alkyl, morpholine;
- aryl1the group represents phenyl or phenyl which can be substituted in any position of the ring with any combination of one or more substituents, such as
- halogen selected from I, F, Cl or Br;
- C1-4alkyl group;
- heteroaryl1group;
- trifluoromethyl, cyano;
- heteroaryl1the group is a pyridyl, thiazolyl, imidazolyl, pyrazolyl, furanyl, oxazolyl, isoxazolyl, benzimidazole, benzoxazole, benzothiazole, which may be optionally substituted in any position of the ring with any combination of one or more substituents, such as
- halogen selected from F, Cl, Br or I;
-alkyl1group;
-SO2-R, where R corresponds With the1-4the alkyl.

2. The compound according to claim 1 of formula II

where Y represents oxygen or sulfur, Z is a (CH2)nwhere n is 0 or 1, L is selected from alkyl1, aryl1or heteroaryl1and R1, R2, R3, R4, R5and R6defined in claim 1.

3. The compound according to claim 1 of formula III

where n is an integer , 1 or 2;
M represents (CH2)nwhere n is 0, 1 or 2;
R is selected from alkyl1, aryl1or heteroaryl1and
R1, R2, R3, R4and R5have the meanings described above.

4. The compound according to claim 1 of formula IV

where G represents N(R11) or (CH2)nwhere n is 1 or 2;
N represents oxygen or N(R11);
J is selected from alkyl1, aryl1or heteroaryl1;
R11is hydrogen or C1-4-alkyl;
R1, R2, R3, R4and R5have the meanings described above.

5. The compound according to claim 1, chosen from:
- 4-{2-[5-(benzothiazol-2-ylamino)-2-methyl-phenylamino]-oxazol-5-yl}-benzonitrile,
- 4-{2-[5-benzothiazol-2-immino)-2-methyl-phenylamino]-oxazol-5-yl}benzonitrile,
- N1-benzooxazol-2-yl)-4-methyl-N3-(pyridin-3-yl-oxazol-2-yl)-benzene-1,3-diamine,
- N1-(5-chloro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine,
- N1 -(6-chloro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine,
- N-(5-econsultancy-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine,
- 4-methyl-N1-(5-methyl-benzooxazol-2-yl)-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine,
- N-(5-fluoro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine,
-N1-(6-chloro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-1,3-diamine,
- 4-(2-{5-[3-(3-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile,
- 4-(2-{5-[3-(3-cyano-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamino}oxazol-5-yl)-benzonitrile,
- 4-(2-{5-[3-(3-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamino}-oxazol-5-yl)-benzamid,
- 1-(4-fluoro-phenyl)-3-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]imidazolidin-2-it,
- 1-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-3-(3-trifluoromethyl-phenyl)-imidazolidin-2-it,
- 1-(4-fluoro-phenyl)-3-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-tetrahydro-pyrimidine-2-it,
- 1-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-3-phenyl-propane-1-he,
- 4-[2-(5-acetyl-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile,
- 4-(2-{5-[3-(4-fluoro-phenyl)-propionyl]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile,
- 4-{2-[2-methyl-5-(3-phenyl-propionyl)-phenylamino]-oxazol-5-yl}-benzonitrile,
- 4-(2-{5-[3-(3-fluoro-phenyl)-propionyl]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile,
- 4-[2-(5-acetyl-2-methyl-phenylamino)-oxazol-5-yl] -benzamide,
- 1-(4-fluoro-phenyl)-2-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenylamino]-Etalon,
- 1-(4-fluoro-phenyl)-2-{methyl-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-amino}-Etalon,
- 4-({methyl-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-amino}-acetyl)-benzonitrile,
- 2-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenylamino]-1-phenyl-Etalon,
- 4-(2-{5-[2-(4-fluoro-phenyl)-2-oxo-e is ylamino]-2-methyl-phenylamino}-oxazol-5-yl)-benzonitrile,
- N-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-benzyl]-benzamide,
- 2-{methyl-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-amino}-1-phenyl-Etalon.

6. The connection according to one of claims 1 to 4, where R1is pyridium or benzonitrile, which can be further substituted in any position of the ring with any combination of one or more substituents, such as
- halogen selected from F, Cl, Br or I;
- alkyl1group;
- aryl1group;
is cyano, NH-alkyl1N(alkyl1)(alkyl1and amino;
- NHCO-R or NHCOO-R or COO-R or CONH-R, where R represents hydrogen, alkyl1group.

7. Pharmaceutical composition having the properties of an inhibitor of c-kit containing compound according to one of claims 1 to 6 and a pharmaceutically acceptable carrier for the treatment of a disease selected among neoplastic, allergic, inflammatory and autoimmune diseases.

8. The pharmaceutical composition according to claim 7, containing a pharmaceutically acceptable carrier suitable for oral or topical use.

9. The use of compounds according to one of claims 1 to 6 for the manufacture of a medicinal product having the properties of an inhibitor of c-kit and is intended for treatment of a disease selected among neoplastic, allergic, inflammatory and autoimmune diseases.

10. Skin is tion according to claim 9, wherein the neoplastic disease is selected from among such as mastocytosis, mastocytoma dogs and stromal tumor of the gastrointestinal tract of man (GIST).

11. The use according to claim 9, wherein the allergic disease is a asthma.

12. The use according to claim 9, wherein the inflammatory disease is a rheumatoid arthritis.

13. The use according to claim 9, wherein the autoimmune disease is a multiple sclerosis.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of general formula I

,

and a pharmaceutically acceptable salt thereof, where X denotes CH2, CHF or S, Y denotes CN, R1, R2, R3 and R4 denotes hydrogen, n equals 1, m equals 0 or 1, R denotes R11, R12 or R13, where R11 includes at least one group selected from the following b) or c), where optionally substituted heterocyclic and heteroaryl groups are bonded with a noradamantyl part either directly or through a methylene adjacent group or a C-C bond or C-N bond; b) the substituted 5-member heteroaryl group, in which the heteroaryl ring is a monocyclic aromatic ring system, includes two or more heteroatoms selected from nitrogen and oxygen; c) the heterocyclic group is optionally substituted with a C1-C3 alkyl or oxo group, where the heterocyclic ring system is a 5-9-member mono- or bicyclic ring system with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where heteroatoms can also be present as functional groups, where the heterocyclic ring system can contain one or two double bonds, and where the monocyclic heterocyclic ring can be condensed with a phenyl ring, R12 is selected from hydrogen, halogen, hydroxy, amino and C1-C4 alkoxy; R13 is a substituted phenyl, where the substitutes, which can be identical or different, include at least one group selected from a) hydrogen; b) nitro, amino; c) the saturated or unsaturated monocyclic heterocyclic ring system is optionally substituted with one or more groups selected from C1-C3 alkyl and oxo, where the heterocyclic ring system is a 5-member ring with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where the heteroatoms can also be present as functional groups. The present invention also relates to a pharmaceutical composition having dipeptidyl peptidase IV inhibiting activity, methods of obtaining the novel compound of formula I and use in treating type II diabetes and diabetic complications as well as for treating dyslipidaemia, hypercholesteremia, obesity and hyperglycaemia.

EFFECT: novel dipeptidyl peptidase IV inhibitors.

10 cl, 1 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat such diseases as hypertension, congestive heart failure, cardiac hypertrophy and others. In formula I R1 denotes a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-imidazolyl, 2-thiazolyl, 2-benzothienyl, 4-benzofuryl, 4-benzothienyl, 7-benzofuryl, 2,3-dihydro-7-benzofuryl, 7-benzothienyl, 1,3-benzodioxol-4-yl, 7-indazolyl, or 8-quinolinyl, optionally substituted with 1-3 substitutes, and X and Y each denotes a single bond; R2 denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, 5-pentenyloxy, 3,33-trifluoropropyl, 4,4-difluoropentyl, 3-(cyclopropyl)propyl, 4-(cyclopropyl)butyl, 3-hydroxypropyl, 4-hydroxybutyl, 4-hydroxypentyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 2-hydroxyethoxy etc, given in the claim; R3 denotes H, F, OH, methoxy, ethoxy, 3-hydroxypropoxy, acetylamino, propionylamino, (2-methylpropionyl)amino, or butanoylamino; A denotes 2,4-disubstituted morpholine with R1XCR2R3Y, bonded on the second position and Q bonded on the fourth position, 1,3-disubstituted piperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-dibustituted-3-methylpiperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-disubstituted benzene or 1,3-disubstituted cyclohexane; Q denotes Q1, Q2, Q4, Q5, Q9, or Q10 given in the claim, to which A and N are bonded on cut-off bonds, R4 denotes H or methyl.

EFFECT: obtaining novel compounds having aspartic protease inhibitor properties, particularly renin inhibitor.

10 cl, 1 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula where: R1 denotes COORa1, CONRa2Ra2', CONRa4ORa4', where: each of Ra1 and Ra4 denotes a hydrogen atom; each of Ra2 and Ra2' denotes a hydrogen atom; Ra4' denotes a lower alkyl; or R1 denotes a heterocyclic group selected from the following groups, where Y2 denotes a hydrogen atom or a lower alkyl: R2 denotes O, S, SO, SO2; R3 denotes a phenyl which is substituted with 2 substitutes selected from halogen, CF3; X2 denotes CH or N; W denotes the following residue: where: W1 denotes CH or S; W2 denotes CH; W3 denotes C or N; and at least one of W1, W2 and W3 denotes a carbon atom; or pharmaceutically acceptable salt or ester thereof. The invention also relates to a pharmaceutical composition having Avrora A selective inhibitory action, which, along with a pharmaceutically acceptable carrier or diluent, contains at least one compound of formula I a an active ingredient.

EFFECT: aminopyridine or aminopyrazine derivatives which inhibit growth of tumour cells based on Avrora A kinase selective inhibitory action.

11 cl, 3 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, where R1 denotes C1-C8-alkylaminocarbonyl, which is optionally substituted with a 5- or 6-member heterocyclic ring containing 3-4 ring heteroatoms selected from a group consisting of oxygen, nitrogen and sulphur, where the ring can be optionally substituted with C1-C8-alkyl or C1-C8-alkoxy group ; R2 denotes C1-C3-alkyl or a halogen; one of R3 and R4 denotes R6, and the other denotes R7; R5 denotes hydrogen or halogen; R6 denotes hydrogen, hydroxy group amino group, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxy, -OR8 or C1-C8-halogenalkyl; R7 denotes hydrogen, OR11, halogen, carboxy, -SO2R8, cyanogroup or C1-C8-halogenalkyl, or when R4 denotes R7, then R7 can also denote -NR12 R13 ; R8 R11 independently denote C1-C8-alkyl or C3-C8-cycloalkyl, which can be optionally substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group or di-C1-C8-alkyl)amino group; any R9 denotes C1-C8-alkyl or C3-C8-cycloalkyl, which can optionally be substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group, di(C1-C8-alkyl)amino group or a 5- or 6-member heterocyclic ring containing one or two ring heteroatoms selected from a group consisting of oxygen and nitrogen, where the ring can optionally be substituted with C1-C8-alkyl, and R10 denotes hydrogen or C1-C8-alkyl; or R9 and R10 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which can contain one or two additional nitrogen heteroatoms, where the ring can be optionally substituted with C1-C8-alkyl; any R12 denotes C1-C8-alkyl or C3-C8-cycloalkyl which can be optionally substituted with di(C1-C8-alkyl)aminogroup, and R13 denotes hydrogen or C1-C8-alkyl; or R12 and R13 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which contains one or two additional nitrogen heteroatoms, where the ring can optionally be substituted with C1-C8-alkyl.

EFFECT: possibility of using the compounds to produce a pharmaceutical agent for treating diseases mediated by phosphatidylinositol-3 kinase.

6 cl, 3 tbl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention relates to hydroximoyl-tetrazole derivatives of formula (I), , where T is a tetrazole substitute, A is a phenyl or heterocycle, L1 and L2 are different linker groups, and Q is a carbocycle, use thereof as fungicide active agents, particularly in form of fungicide compositions, and methods of controlling phytopathogenic fungi, especially plants, using said compounds or compositions.

EFFECT: more effective use of the compounds.

13 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: described are novel diaminotriazole compounds of general formula

(values of radicals are given in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, a method of inhibiting JAK2 and JAK3 kinase activity and use of the novel compounds to produce a medicinal agent for treating several diseases.

EFFECT: high efficiency of the compounds.

19 cl, 3 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: invention relates to 6-piperidinyl-substituted isoquinoline derivatives of formula (I)

, where values of radicals are given in the claim, and compositions containing said compounds.

EFFECT: said compounds and compositions can be useful in treating and preventing diseases associated with Rho-kinase and mediated by Rho-kinase through myosin light chain phosphatase phosphorylation.

31 cl, 378 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an immunodepressant based on a heterocyclic compound of formula

or to its pharmaceutically acceptable salt where X represents a nitrogen atom or CH, both or one of R1 or R2 represents a hydrogen atom, hydroxyl, a halogen atom, an amino group, C1-C6 alkoxy or C1-C6 alkyl: R3 represents a hydrogen atom, difluoromethyl, an amino group, methyl or hydroxymethyl; R4 or R5 represents a hydrogen atom or C1-C6 alkyl; R6 represents morpholino (optionally substituted by one or two C1-C6 alkyl groups), pyrrolidinyl (optionally substituted by hydroxy C1-C6 alkyl), piperidine (which is optionally substituted by an oxygen atom, hydroxyl, formyl or C1-C6 alkyl), piperazinyl (optionally substituted by one or two oxygen atoms, where a nitrogen atom in position 4 is optionally substituted by a substitute selected from a groups consisting of formyl, C1-C6 hydroxyalkyl, C1-C6 alkoxycarbonyl, C1-C6 oxoalkyl, furoyl, benzoyl, methoxybenzoyl, benzylcarbonyl, dimethylcarbamoyl, diethylcarbamoyl, morpholinocarbonyl and methoxyacetyl) or 1,4-diazepano (optionally substituted by one oxygen atom where a nitrogen atom in position 4 is optionally substituted by a substitute selected from a group consisting of formyl, C1-C6 oxoalkyl). Also, the invention refers to a heterocyclic compound of general formula

and to an anticancer drug based on the compound of formula (II).

EFFECT: there are produced new immunodepressant based on the compound of formula (I) and compound of formula (II) which can be used as anticancer drugs.

12 cl, 8 tbl, 60 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the compounds of formula (I): where R denotes cycloalkyl, heterocyclil, aryl, alkyl-O-C(O)-, alkanoyl or alkyl where each cycloalkyl, heterocyclil and aryl does not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, cyano group, alkoxy group, alkyl-O-C(O)-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil, and where each alkyl-O-C(O)-, alkyl, alkoxy group and heterocyclil does not necessarily have additional 1 to 3 substitutes chosen from the group including a hydroxy group, alkyl, halogen, carboxy group, alkoxy group, alkyl-O-C(O)-, alkanoyl, alkyl-SO2-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil; R2 denotes alkyl, cycloalkyl, cycloalkylalkyl- or alkoxy group where alkyl does not necessarily contain from 1 to 3 substitutes chosen from the alkoxy group or halogen; R3 denotes R8-O-C(O)-, (R8)(R9)N-C(O)-, R8-C(O)-, where R8 and R9 independently denote alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- or nonaromatic heterocyclil where each alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- and nonaromatic heterocyclil do not necessarily contain from 1 to 3 substitutes chosen from the group including a hydroxy group, carboxy group, alkyl-O-C(O)-, alkyl-C(O)-O- and alkanoyl; R4 and R5 independently denote hydrogen, alkyl, alkynyl, alkoxy group, cycloalkyl, arylalkyl-, cycloalkylalkyl-, heteroarylalkyl-, monoalkylamino-C(O)-, dialkylcmino-C(O)- or dialkylamino-C(O)-alkyl-, where both these alkyl groups do not necessarily form a ring and where each alkyl, alkynyl, cycloalkyl, arylalkyl-, cycloalkylalkyl- heteroarylalkyl-, monoalkylamino-C(O)-, dialkylamino-C(O)- or dialkylamino-C(O)-alkyl- do not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, carboxy group and alkoxy group; R6 and R7 independently denote hydrogen, halogenalkyl, halogen, dialkylamino group, alkoxy group, halogenalkoxy group, heteroaryl or alkyl-S(O)2- where each heteroaryl does not necessarily contain from 1 to 3 substitutes chosen from alkyl; where "heterocyclil" denotes fully saturated or nonsaturated aromatic or nonaromatic cyclic group that is represented by 5- or 6-membered monocyclic ring system containing at least one heteroatom chosen from nitrogen, oxygen and sulphur atoms; "heteroaryl" denotes 5- or 6-membered monocyclic ring system containing from 1 to 4 heteroatoms chosen from N, O and S; or to their pharmaceutically acceptable salts and their optical isomers, or to mixtures of the optical isomers. The invention also refers to the method of inhibition of the specimen's CETP activity, to the way of treatment of the specimen's abnormality or disease mediated by CETP or responsive to CETP inhibition, to the pharmaceutical composition, and to application of the formula (I) compounds.

EFFECT: production of new bioactive compounds that inhibit the CETP.

10 cl, 71 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to new compounds of formula I-9 where q is represented by 1; R11 is represented by C3-8-alkyl; C3-8-cycloalkyl or C3-8-cycloalkyl-C1-3-alkyl; A is represented by phenyl substituted by one or more substituting groups independently chosen from R12; and R12 is represented by -(CH2)-NR13R14; R13 is represented by C1-6-alkylcarbanil; and R14 is represented by hydrogen; and to the pharmaceutically acceptable salts of such compounds and to the pharmaceutical compositions based on such compounds. It has been revealed that the compounds of formula I-9 are histamine NZ-receptor antagonists and thus that they can be used in treatment of diseases connected with expression of such receptors.

EFFECT: compounds of formula I-9 can be used in treatment of diseases connected with expression of histamine NZ-receptors.

6 cl, 216 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): where R1 and R2 represent hydrogen and a group which is hydrolysed in a physiological environment, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a group of pyridine N-oxide according to formula A, B or C which is attached as shown by an unmarked linking: where R4, R5, R6 and R7 independently represent aryl, heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio, C6-C12-aryloxy or C6-C12-arylthio group, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, or heteroaryl group; or where two or more residues R4, R5, R6 and R7 taken together represent an aromatic ring, and where P represents a central part, preferentially chosen from regioisomers 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazine-2,4-diyl, 1,2,4-triazine-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1R-pyrrol-2,5-diyl, where alkyl is presented by methyl, thiazol-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidine-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, benzole-1,3-diyl and (Z)-1-cyanoethene-1,2-diyl, and where the regioisomers of the central part include both regioisomers produced by exchanging the nitrocatechol fragment and the -(X)n-(Y)m-R3 fragment. Also, the invention refers to a method for making a compound of formula I, as well as to a method for treating an individual suffering central and peripheral nervous system disorders, to a pharmaceutical composition based on the compounds of formula I, and also to their application for preparing the drug and as COMT inhibitor.

EFFECT: there are produced and described new compounds which show a potentially effective pharmaceutical properties in treating a number of central and peripheral nervous system disorders.

25 cl, 64 ex, 3 tbl

Mglur5 modulators // 2439068

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel compounds of general formula I:

(where values R1-R5, X and Z are defined in invention description), pharmaceutical composition, which contains them, and application of claimed compounds as MGLUR5 modulators for inhibition of transient relaxations of lower esophageal sphincter or for treatment or prevention of gastroesophageal reflux disease.

EFFECT: obtaining compounds for treatment or prevention of gastroesophageal reflux disease.

14 cl, 87 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazolidinone derivatives of formula and pharmaceutically acceptable salts thereof, where X denotes N or CH; R1 denotes a lower alkyl, fluoro-lower alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-lower alkyl, phenyl, naphthyl, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of a halide, lower alkyl, fluoro-lower alkyl, lower alkoxy group and fluoro-lower alkoxy group; R2 denotes lower alkyl, halide-lower alkyl, lower alkenyl, C3-C6-cycloalkyl, pheny, phenyl-lower alkyl, tetrahydropyran, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide; R3 denotes phenyl or heteroaryl (pyridinyl, thienopyridinyl, benzoisothiazolyl, benzooxazolyl, tetrahydropyrazinyl, pyrazinyl), where the phenyl or heteroaryl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide, CN, lower alkyl, fluoro-lower alkyl, lower alkoxy group; R4, R5, R6, R7, R8, R9, R10 and R11 independently denote hydrogen or lower alkyl. The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: obtaining novel imidazolidinone derivatives, having LXRalpha or LXRbeta receptor agonist activity.

26 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula where: R1 denotes COORa1, CONRa2Ra2', CONRa4ORa4', where: each of Ra1 and Ra4 denotes a hydrogen atom; each of Ra2 and Ra2' denotes a hydrogen atom; Ra4' denotes a lower alkyl; or R1 denotes a heterocyclic group selected from the following groups, where Y2 denotes a hydrogen atom or a lower alkyl: R2 denotes O, S, SO, SO2; R3 denotes a phenyl which is substituted with 2 substitutes selected from halogen, CF3; X2 denotes CH or N; W denotes the following residue: where: W1 denotes CH or S; W2 denotes CH; W3 denotes C or N; and at least one of W1, W2 and W3 denotes a carbon atom; or pharmaceutically acceptable salt or ester thereof. The invention also relates to a pharmaceutical composition having Avrora A selective inhibitory action, which, along with a pharmaceutically acceptable carrier or diluent, contains at least one compound of formula I a an active ingredient.

EFFECT: aminopyridine or aminopyrazine derivatives which inhibit growth of tumour cells based on Avrora A kinase selective inhibitory action.

11 cl, 3 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

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