Mdm2 and p53 interaction inhibitors

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I) and pharmaceutically acceptable salt thereof, where m denotes a direct bond; n equals 0, 1, 2, 3 or 4 and n equals zero indicates a direct bond; p equals 1; s denotes a direct bond; t denotes a direct bond; R1 and R2 each independently denotes hydrogen; A denotes a radical selected from , where R4 and R5 are each independently selected from hydrogen or C1-6alkyloxy; Z denotes a radical (b-2), where R6 and R7 each independently denotes hydrogen. The invention also describes a pharmaceutical composition for treating cancer and preparation method thereof, based on compounds of formula I, use of these compounds to obtain a medicinal agent, as well as a method of producing said compounds.

EFFECT: novel compounds which can be used as p53-MDM2 interaction inhibitors are obtained and described.

10 cl, ex, 2 tbl

 

The technical field to which the invention relates

The invention relates to compounds and compositions containing these compounds acting as inhibitors of the interaction between MDM2 and p53. In addition, the present invention provides methods of obtaining the disclosed inhibitors, compositions comprising them, and methods of their use, for example, as pharmaceuticals.

p53 is a tumor suppressor protein that plays a key role in regulating the balance between cell proliferation and stop/apoptosis cell growth. Under normal conditions the half-life of p53 is very short and, therefore, the content of p53 in cells is low. However, in response to damage cellular DNA or cellular stress (e.g., activation of an oncogene, the erosion of telomeres, hypoxia) levels of ρ53 increases. This increase in the level of p53 leads to activation of transcription of several genes that cause the cell to stop growth or apoptosis. Thus, an important function ρ53 is to prevent uncontrolled proliferation of damaged cells and, thereby, to protect the body from cancer.

MDM2 is a key negative regulator functions ρ53. It forms a negative autoregulatory loop by linking with and Inocencia transactivism domain of p53 and thus, MDM2 inhibits the ability of p53 to activate transcription and makes p53 target proteolytic degradation. Under normal conditions, this regulatory loop is responsible for maintaining low levels of p53. However, in tumors with p53 wild-type equilibrium concentration of active p53 can be increased by counteracting the interaction between MDM2 and p53. As a result, this will lead to a recovery mediated p53 Pro-apoptotic and anti-proliferative effects in these tumor cells.

MDM2 is a cellular protooncogene. Overexpression of MDM2 has been observed in several types of cancer. Increased expression of MDM2 occurs in a variety of tumors as a result of gene amplification or increased transcription or translation. The mechanism by which amplification of MDM2 promotes oncogenesis at least partially attributable to its interaction with p53. In cells with overexpression of MDM2 is blocked the protective function of p53, and, in this regard, cells become incapable of response to DNA damage or cellular stress by increasing the level of p53, which leads to the stop of cell growth and/or apoptosis. Accordingly, after DNA damage and/or cellular stress sverkhekspressiya MDM2 cells become free to continue proliferation and acquire oncogenic phenotype. In these conditions the s violation of the interaction between p53 and MDM2 will release p53 and therefore, will operate normal signals stop the growth and/or apoptosis.

MDM2 can also have separate functions in addition to the inhibition of p53. For example, it has been shown that MDM2 interacts directly with pRb-regulated transcription factor E2F1/DP1. This interaction may be critical for p53-independent oncogenic effects of MDM2. Domain E2F1 shows a striking similarity with the MDM2-binding domain of p53. Because of the interaction of MDM2 with p53 and E2F1 localized on the same binding site of MDM2, it is expected that the MDM2/p53 antagonists will not only activate the cellular p53, but also to regulate the impact of E2F1, which are usually not regulated in tumor cells.

In addition, therapeutic efficacy of damaging the DNA of the funds currently used (chemotherapy and radiotherapy)may be limited by the negative regulation of p53 by MDM2. Thus, if interrupted feedback inhibition of p53 by MDM2, an increase in functional levels ρ53 will increase therapeutic efficacy of such funds due to restoration of function of p53 wild-type, leading to apoptosis and/or treatment associated with p53 drug resistance. It was demonstrated that the combination of inhibition of MDM2 and obrigada DNA treatments in vivoleads to synergistic antitumor effects (Vousden K.H., Cell, Vol. 103, 691-694, 2000).

Thus, disruption of the interaction between MDM2 and ρ53 provides an approach for therapeutic intervention in tumors with wild type p53, possibly a manifestation of the anti-proliferative effects in tumor cells that do not have functional p53 and, in addition, can make sensitive to chemotherapy and radiotherapy oncogenic cells.

The level of technology

In JP 11130750, published may 18, 1999, describes among other substituted phenylaminopyrimidine derivatives as antagonists of the receptor 5-HT.

In EP 1129074, published may 18, 2000, describes Anthranilic acid amides as inhibitors of receptors of growth factors, vascular endothelial (VEGFR) and applicable for the treatment of angiogenic disorders.

In EP 1317443, published March 21, 2002, discloses tricyclic derivatives of tertiary amines, applicable as modulators of chemokine receptor CXCR4 or CCR5 for the treatment of human immunodeficiency virus and human immunodeficiency virus in cats.

In EP 1379239, published October 10, 2002, discloses N-(2-arylaryl)benzylamine as antagonists of the receptor 5-HT6.

In WO00/15357, published on 23 March 2000, described piperazine-4-phenyl derivatives as inhibitors wsimages the via between MDM2 and p53. In EP1137418, published June 8, 2000, presents tricyclic compounds to restore the conformational stability of the protein type p53.

In EP1443937, published may 22, 2003, describes substituted 1,4-benzodiazepines and their use as inhibitors of the interactions of MDM2-p53.

In EP 1458380, published on 26 June 2003, presents CIS-2,4,5-triphenylimidazole that inhibit the interaction of MDM2 protein with a p53-like peptides and possess antiproliferative activity.

In EP 1519932, published January 15, 2004, discloses bicrystalline compounds that bind to MDM2 and can be applied in cancer therapy.

At the present time, there is still a need for an effective and potent small molecules that inhibit the interaction between MDM2 and p53.

Compounds of the present invention differ from the prior art in terms of structure and their pharmacological activity and/or pharmacological effectiveness.

Description of the invention

The present invention provides compounds, compositions and methods that inhibit the interaction between MDM2 and p53 for the treatment of cancer. In addition, the compounds and compositions of the present invention is suitable for increasing the effectiveness of chemotherapy and radiation therapy.

The present invention relates to connected the pits of formula (I)

their N-oxide form, the additive salt or a stereochemical isomeric form, where

m is 0, 1 or 2 and when m is 0, it means a direct connection;

n is 0, 1, 2, 3 or 4 and, when n is 0, it means a direct connection;

p is 0 or 1 and when p is 0, it means a direct connection;

s is 0 or 1 and when s is 0, it means a direct connection;

t is 0 or 1 and when t is 0, it means a direct connection;

R1and R2each independently represents hydrogen, halogen, C1-6alkyl, C1-6alkyloxy, arils1-6alkyloxy, heteroaryl1-6alkyloxy, phenylthio, hydroxys1-6alkylsulphonyl, C1-6alkyl, substituted Deputy selected from amino, aryl and heteroaryl; or C3-7cycloalkyl, substituted Deputy selected from amino, aryl and heteroaryl;

A represents a radical selected from the

where R4and R5each independently selected from hydrogen, halogen, C1-6of the alkyl polyhalogen 1-6of alkyl, cyano, tsianos1-6of alkyl, hydroxys1-6of alkyl, hydroxy, amino, C1-6alkyloxy, C1-6alkylcarboxylic, methylsulfonylamino, aryl or heteroaryl;

Z represents a radical selected from the

where

R6and R7each independently selected from hydrogen, halogen, hydroxy, amino, C1-6of alkyl, nitro, polyhalogen1-6of alkyl, cyano, tsianos1-6of alkyl, tetrazoles1-6of alkyl, aryl, heteroaryl, arils1-6of alkyl, heteroaryl1-6of alkyl, aryl(hydroxy)C1-6of alkyl, heteroaryl(hydroxy)C1-6of alkyl, arylcarbamoyl, heteroarylboronic, C1-6alkylcarboxylic, arils1-6alkylcarboxylic, heteroaryl1-6alkylsulphonyl, C1-6alkyloxy, C3-7cycloalkylcarbonyl, C3-7cycloalkyl(hydroxy)C1-6of alkyl, aryls1-6alkalosis1-6of alkyl, C1-6alkalosis1-6alkalosis1-6of alkyl, C1-6alkylcarboxylic1-6of alkyl, C1-6allyloxycarbonyl1-6alkalosis1-6of alkyl, hydroxys1-6alkalosis1-6of alkyl, C1-6allyloxycarbonyl2-6alkenyl1-6alkalosis1-6of alkyl, C1-6allyloxycarbonyl, C1-6alkylcarboxylic, aminocarbonyl, hydroxys1-6of alkyl, amino1-6of alkyl, g is toxicarol, hydroxycarbonyl1-6the alkyl and -(CH2)v-(C(=O)r)-(CHR10)u-NR8R9; where

v is 0, 1, 2, 3, 4, 5 or 6 and when v is 0, it means a direct connection;

r is 0 or 1 and when r is 0, it means a direct connection;

u is 0, 1, 2, 3, 4, 5 or 6 and, when u is 0, it means a direct connection;

R10represents hydrogen or C1-6alkyl;

R8and R9each independently selected from hydrogen, C1-12of alkyl, C1-6alkylsulphonyl, C1-6alkylsulfonyl, arils1-6alkylsulphonyl, C3-7cycloalkyl, C3-7cycloalkylcarbonyl, -(CH2)k-NR11R12C1-12of alkyl, substituted Deputy selected from hydroxy, hydroxycarbonyl, cyano, C1-6allyloxycarbonyl, C1-6alkyloxy, aryl or heteroaryl; or C3-7cycloalkyl, substituted Deputy selected from hydroxy, C1-6alkyloxy, aryl, amino, arils1-6of alkyl, heteroaryl or heteroaryl1-6of alkyl; or R8and R9together with the nitrogen to which they are attached, can optionally form morpholinyl, piperidinyl, pyrrolidinyl, piperazinil or piperazinil, substituted Deputy selected from C1-6of alkyl, aryls1-6of alkyl, aryls1-6allyloxycarbonyl, heteroaryl1-6of alkyl, C3-7recloak the La and C 3-7cycloalkyl1-6of alkyl; where

k is 0, 1, 2, 3, 4, 5 or 6 and when k is 0, it means a direct connection;

R11and R12each independently selected from hydrogen, C1-6of alkyl, aryls1-6allyloxycarbonyl, C3-7cycloalkyl, C1-12of alkyl, substituted Deputy selected from hydroxy, C1-6alkyloxy, aryl and heteroaryl; and (C3-7cycloalkyl, substituted Deputy selected from hydroxy, C1-6alkyloxy, aryl, arils1-6of alkyl, heteroaryl, and heteroaryl1-6of alkyl; or

R11and R12together with the nitrogen to which they are attached, can optionally form morpholinyl, piperazinil or piperazinil, substituted C1-6allyloxycarbonyl;

aryl represents phenyl or naphthalenyl;

each phenyl or naphthalenyl optionally can be substituted one, two or three substituents, each of which is independently selected from halogen, hydroxy, hydroxys1-6of alkyl, C1-6of alkyl, amino, polyhalogen1-6the alkyl and C1-6alkyloxy; and each phenyl or naphthalenyl optionally may be substituted bivalent radical selected from methylenedioxy, Ethylenedioxy;

heteroaryl represents pyridinyl, indolyl, chinoline, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofur the Anil;

each pyridinyl, indolyl, chinoline, imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl optionally can be substituted one, two or three substituents, each of which is independently selected from halogen, hydroxy, C1-6of alkyl, amino, polyhalogen1-6of alkyl, aryl, arils1-6the alkyl or C1-6alkyloxy; and

each pyridinyl, indolyl, chinoline, imidazolyl, furanyl, thienyl, benzofuranyl or tetrahydrofuranyl optionally may be substituted bivalent radical selected from methylenedioxy or Ethylenedioxy.

The compounds of formula (I) may also exist in their tautomeric forms. Despite the fact that such forms are not directly indicated in the formula above, they refer to is included in the scope of the present invention.

A number of terms used in the preceding definitions and hereinafter below. These terms are sometimes used individually or in compound terms.

Used in the previous definitions and hereinafter halogen represents fluorine, chlorine, bromine and iodine; C1-6alkyl defines straight and branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 2-methylpropyl, 2-methylbutyl, 2-methyl is Intel etc.; hydraxis1-6alkyl defines substituted by hydroxy, straight and branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms; trihalomethyl determines methyl containing three identical or different halogen substituent, for example, trifluoromethyl; C3-7cycloalkyl includes cyclic hydrocarbon group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl etc.

The term "additive salt" includes salts, which are capable of forming compounds of formula (I) with organic or inorganic bases, such as amines, bases, alkali metal and alkaline earth metal base, or Quaternary ammonium bases, or with organic or inorganic acids such as mineral acids, sulfonic acid, carboxylic acid or phosphorus-containing acid.

The term "additive salt" also includes pharmaceutically acceptable salt, solvate complexes and metals and their salts, which are capable of forming compounds of formula (I).

The term "pharmaceutically acceptable salt" means a pharmaceutically acceptable acid-additive or basic additive salt. Pharmaceutically acceptable acid-additive or basically-and detune salt, as implied above, comprise therapeutically active non-toxic acid-additive and non-toxic primary additive salts, which are capable of forming compounds of formula (I). The compounds of formula (I), which have basic properties can be converted into their pharmaceutically acceptable acid additive salt by processing the basic form of a suitable acid. Suitable acids include, for example, inorganic acid, such as halogen acids, e.g. hydrochloric or Hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids, such as, for example, acetic, propanoic, hydroxyestra (glycolic acid), lactic, pyruvic, oxalic, malonic, succinic (i.e. batandjieva acid), maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, reklamowa, salicylic, p-aminosalicylic, AMOVA and the like acid.

The compounds of formula (I), which have acidic properties may be converted in their pharmaceutically acceptable basic additive salt by processing the acid form with a suitable organic or inorganic base. The corresponding salt forms of the base include, for example, and monavie salt, salts of alkali and alkaline earth metals, for example, salts of lithium, sodium, potassium, magnesium, calcium and the like, salts of organic bases, for example, salt, benzathine, N-methyl-D-glucamine, geranamine, and salts with amino acids such as, for example, arginine, lysine and the like.

The term acid-additive or basic additive salt also comprises the hydrates and forms with the addition of a solvent which is able to form compounds of formula (I). Examples of such forms are, for example, hydrates, alcoholate, and the like.

The term "metal complexes" refers to the complex formed between the compound of formula (I) and one or more organic or inorganic salt or metal salts. Examples of these organic or inorganic salts include the halides, nitrates, sulfates, phosphates, acetates, triptoreline, trichloracetate, propionate, tartratami, sulfonates, for example, methylsulfonate, 4-methylphenylsulfonyl, salicylates, benzoate and similar metals of the second main group of the periodic system, for example, salts of magnesium or calcium, third or fourth main group, for example, salts of aluminum, tin, lead, and the first to eighth transition group of the periodic system, such as, for example, chromium, manganese, iron, cobalt, Nickel, copper, zinc and the like.

p> The above term "stereochemical isomeric forms of the compounds of formula (I), defines all possible compounds consisting of the same atoms connected by the same sequence of relationships, but having different three-dimensional structures that are not equivalent, which can have compound of formula (I). If not included or indicated, the chemical designation of compounds comprises a mixture of all possible stereochemical isomeric forms, which specified the connection can have. This mixture may contain all of the diastereomers and/or enantiomers basic molecular structure of the compounds. All stereochemical isomeric forms of the compounds of formula (I), both in pure form and in mixtures with each other, included in the scope of the present invention.

Of particular interest are the compounds of formula (I), which are stereochemical clean.

Pure stereoisomeric forms of the compounds and intermediates referred to in this description, is defined as isomers, essentially free from other enantiomeric or diastereoisomeric forms of the same molecular structures of these compounds or intermediates. In particular, the term "stereoisomer pure" refers to compounds or intermediate compounds having a stereoisomeric excess on m is Nisha least 80% (i.e. at least 90% of one isomer and a maximum of 10% of the other possible isomers) to stereoisomeric excess of 100% (i.e. 100% of one isomer and no other), more specifically, the compounds or intermediate compounds having a stereoisomeric excess of 90% to 100%, even more specifically, having a stereoisomeric excess of from 94% to 100%, and most specifically, having a stereoisomeric excess of from 97% to 100%. The terms "enantiomerically pure" and "diastereomers clean" should be understood in the same way, but with respect to the enantiomeric excess, respectively, diastereomer excess discussed in the mixture.

Tautomeric forms of the compounds of formula (I) refers comprising such compounds of formula (I), where, for example, enol group is converted into ketogroup (keto-enol tautomerism).

The N-oxide forms of the compounds of formula (I) refers comprising such compounds of formula (I)where one or more atoms of nitrogen oxidized to the so-called N-oxide, more specifically, such N-oxides, where one or more piperidinovyh, piperazino or pyridazinyl of Izotov are N-oxidized.

The compounds of formula (I) can be converted into the corresponding N-oxide forms using the following well-known in the field of methods for converting a trivalent nitrogen into its N-oxide form. This reaction N, as a rule, can be carried out by reacting the parent substance of the formula (I) with a suitable organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali or alkaline earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include peroxyacids, such as, for example, benzonorbornadiene or halogensubstituted benzonorbornadiene, for example, 3-chlorobenzalmalononitrile, paracalanidae acid, for example, purakayastha acid, alkylhydroperoxide, for example, tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons such as toluene, ketones, for example, 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

The present invention also is intended to include all isotopes of atoms present in the compounds according to the invention. For example, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include C-13 and C-14.

In all cases used in this description, the term "compounds of formula (I)include also the N-oxide forms, the pharmaceutically acceptable acid-additive or main-Additiv what's salts and all stereoisomeric forms.

The first group representing the interest of compounds consists of those compounds of formula (I), which uses one or more of the following constraints:

a) m is 0;

b) n is 0 or 2;

c) p is 1;

d) s is 0;a

e) t is 0;

f) R1and R2each independently represents hydrogen;

g) A is a radical selected from (a-15), (a-21), (a-30), (a-39) or (a-40);

h) R4and R5each independently selected from hydrogen or C1-6alkyloxy;

i) Z is a radical (b-2); or

j) R6and R7each independently selected from hydrogen.

The second group of interesting compounds consists of those compounds of formula (I) and such compounds the groups described above, which uses one or more of the following constraints:

a) m is 0;

b) n = 2;

c) p is 1;

d) s is 0;a

e) t is 0;

f) R1and R2each independently represents hydrogen;

g) A is a radical selected from (a-21), (a-39) or (a-40);

h) R4and R5each independently selected from hydrogen or C1-6alkyloxy;

i) Z is a radical (b-2); or

j) R6and R7each independently selected from hydrogen.

A group of preferred compounds consists of those compounds of formula (I) or any subgroup, where m is 0; n is 0 or 2; p is 1; s is avno 0; t is 0; R1and R2each independently represents hydrogen; A represents a radical selected from (a-15), (a-21), (a-30), (a-39) or (a-40); R4and R5each independently selected from hydrogen or C1-6alkyloxy; Z is a radical (b-2); or R6and R7each independently selected from hydrogen.

The group of more preferred compounds consists of those compounds of formula (I) or any subgroup, where m is 0; n is 2; p is 1; s is 0; t is 0; R1and R2each independently represents hydrogen; A represents a radical selected from (a-21), (a-39) or (a-40); R4and R5each independently selected from hydrogen or C1-6alkyloxy; Z is a radical (b-2); or R6and R7each independently selected from hydrogen.

The most preferred compounds are compounds No. 2 connection # 3 connection # 5.

Conn. No. 2Conn. No. 3
Conn. No. 5

The compounds of formula (I), farmacevtichesky acceptable salts and N-oxide and stereochemical isomeric form can be obtained by conventional methods. The initial substance and some intermediate compounds are known compounds and are commercially available or can be obtained according to conventional reaction techniques known in this field.

A number of these ways to get will be described later in more detail. Other ways to obtain the final compounds of formula (I) described in the examples.

The compounds of formula (I) can be obtained by the interaction of the intermediate compounds of formula (II) with an intermediate compound of formula (III), where W is an appropriate leaving group, such as, for example, halogen, e.g. fluorine, chlorine, bromine or iodine, or a radical of sulfonyloxy, such as methylsulfonate, 4-methylphenylsulfonyl and the like. The reaction can be carried out in a reaction-inert solvent such as, for example, an alcohol, e.g. methanol, ethanol, 2-methoxyethanol, propanol, butanol and the like; ether such as 4,4-dioxane, 1,1'-oxybisethane and the like; a ketone, e.g. 4-methyl-2-pentanone; or N,N-dimethylformamide, nitrobenzene, acetonitrile, acetic acid, and the like. To absorb the acid that is released during the reaction, you can use the addition of a suitable base, such as, for example, carbonate or bicarbonate of alkali or alkaline earth metal, for example, triethylamine or Carbo is at sodium. A small amount of the corresponding metal iodide, e.g. sodium iodide or potassium, may be added to initiate the reaction. Mixing can increase the reaction rate. The reaction is conveniently carried out at a temperature in the range from room temperature to the boiling temperature of the reaction mixture under reflux, and, if required, the reaction can be carried out at elevated pressure.

The compounds of formula (I), where p is 1, called here the compounds of formula (I-a), can be obtained by converting intermediate compounds of formula (IV) with lithium aluminum hydride in a suitable solvent, such as tetrahydrofuran.

The compounds of formula (I-a) can also be obtained by interaction of the corresponding carboxaldehyde formula (VI) with an intermediate compound of formula (V) in the presence of an appropriate reagent such as sodium borohydride, for example, tetrahydroborate sodium or deposited on the polymer centripetality, in a suitable solvent such as an alcohol, e.g. methanol.

In the same way, the compounds of formula (I), where t is equal to 1, here called compounds of the formula (I-b)can be obtained by the interaction of the intermediate compounds of formula (II) with the appropriate carb is calderita formula (VII).

The compounds of formula (I), where s is 1, called here the compounds of formula (I-c)can be obtained by the interaction of the intermediate compounds of formula (VIII) with lithium aluminum hydride in a suitable solvent, such as tetrahydrofuran.

The compounds of formula (I) or their intermediate compounds can also be converted into each other by means known in the field of reactions or transformations of functional groups. Some of these transformations have already been described above. Other examples are the hydrolysis of esters of the corresponding carboxylic acids or alcohols; hydrolysis of amides of the corresponding carboxylic acids or amines; hydrolysis of the corresponding NITRILES amides; amino group of the imidazole or phenyl may be replaced by hydrogen by means known in the field reaction of diazotization and subsequent replacement of diazogroup hydrogen; alcohols can be converted to ethers and esters, primary amines can be converted into secondary or tertiary amines; the double bond can be gidrirovanny to the corresponding unary relations; iodine radical is the phenyl group can be converted to ester groups by the introduction of carbon monoxide in the presence of a suitable palladium catalyst.

Intermediate with the organisations of the formula (II), where m is 0 and s is 0, called the intermediate compounds of formula (II-a)can be obtained by reduction of the nitro group to the amine, based on the intermediate compounds of formula (IX)in the presence of a metal catalyst, such as Raney Nickel, and a suitable reductant, such as hydrogen, in a suitable solvent, such as methanol or ethanol.

Intermediate compounds of formula (X), where s is 0, can be obtained by the interaction of the intermediate compounds of formula (XI) with an intermediate compound of formula (XII) in the presence of appropriate reagents such as monohydrochloride N'-(ethylcarbodiimide)-N,N-dimethyl-1,3-propandiamine (EDC) and 1-hydroxy-1H-benzotriazole (HOBT). The reaction can be carried out in the presence of a base, such as triethylamine, in a suitable solvent such as a mixture of dichloromethane and tetrahydrofuran.

Intermediate compounds of formula (VI) can be obtained by the interaction of the intermediate compounds of formula (XIII) with lithium aluminum hydride in a suitable solvent, such as tetrahydrofuran.

Intermediate compounds of formula (VIII) can be obtained by the interaction of the intermediate compounds of formula (XIV) with an intermediate compound of formula (XV) in prisutstvie and iodide, 2-chloro-1-methylpyridine and triethylamine in a suitable solvent, such as acetonitrile.

Intermediate compounds of formula (IX), where p is 1, called here the intermediate compounds of formula (IX-a)can be obtained by the interaction of the intermediate compounds of formula (XVI) with an intermediate compound of formula (XVII), where Q is an appropriate leaving group, such as, for example, halogen, e.g. fluorine, chlorine, bromine or iodine, or C1-6alkyloxy, for example, metiloksi, diisopropylethylamine.

Intermediate compounds of formula (XIV) can be obtained by converting intermediate compounds of formula (XVIII) in the presence of sodium hydroxide and water in a suitable solvent, such as ethanol.

Intermediate compounds of formula (XVIII), where m is 0, called the intermediate compounds of formula (XVIII-a), can be obtained by the interaction of the intermediate compounds of formula (XVI) with an intermediate compound of formula (XIX), where Q is defined above, in a suitable solvent, such as diisopropylethylamine.

Intermediate compounds of formula (V), where m, n, and s is equal to 0, called the intermediate compounds of formula (V-a), can be obtained by converting intermediate compounds of formula (XX) with a solution hydrochlo the IDA.

Intermediate compounds of formula (XX) can be obtained by the interaction of the intermediate compounds of formula (XXI) with an intermediate compound of formula (III), where W is an appropriate leaving group, such as, for example, halogen. The reaction can be carried out in a reaction-inert solvent such as, for example, acetic acid.

The compounds of formula (I) and some intermediate compounds may have at least one stereogenic center in their structure. Such stereogenic centers can be represented in the R - or S-configuration.

Some compounds of formula (I) and some intermediate compounds in the present invention may contain asymmetric carbon atom. Stereochemical pure isomeric forms of these compounds and these intermediate compounds can be obtained using well-known in this field techniques. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic methods, for example, countercurrent distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures of primary conversion of these racemic mixtures in a mixture of diastereoisomeric what she or compounds with suitable separating agents, such as, for example, chiral acids; then physical separation of these mixtures of diastereomeric salts or compounds using, for example, selective crystallization, chromatography with supercritical mobile phase or chromatographic techniques, e.g. liquid chromatography and the like methods; and the final conversion of these selected diastereomeric salts or compounds into the corresponding enantiomers. Stereochemical pure isomeric form can also be obtained from pure stereochemical isomeric forms of the appropriate intermediates and starting compounds, providing stereospecific flow of intermediate reactions.

The compounds of formula (I), their pharmaceutically acceptable acid additive salts and stereoisomeric forms have valuable pharmacological properties, which consists in inhibition of the interaction between p53 and MDM2.

Used in the present description, the term "MDM2" means a protein resulting from the expression of the mdm2 gene. The value of this term MDM2 encompasses all proteins encoded by mdm2, their mutants, alternate layers of their proteins and their phosphorylated proteins. In addition, as used in the present description, the term "MDM2" includes analogs of MDM2, for example, MDMX, also known as MDM4, and homologues and analogues MDM2 other animal is, for example, the homologue of HDM2 person or similar HDMX person.

Used in the present description, the term "inhibitory interaction" or "inhibitor interaction" refers to the prevention or reduction in direct or indirect Association of one or more molecules, peptides, proteins, enzymes or receptors; or the prevention or decrease of the normal activity of one or more molecules, peptides, proteins, enzymes or receptors.

The term "inhibitor of the interaction between p53 and MDM2" or "inhibitor of p53-MDM2" is used herein to describe an agent that increases the expression of p53 in the analysis described in C.1. This increase could be caused by one or more of the following mechanisms of action, but is not limited to the above:

- inhibition of the interaction between p53 and MDM2,

- direct linking with either MDM2 or p53 protein,

- interaction with the overlying or underlying targets, such as kinases, or enzymatic activity that is included in the ubiquitination or SUMO modification,

- isolation or transportation of MDM2 and p53 in different cell compartments

- modulation of proteins, binding to MDM2, for example (but not limited to the above), p73, E2F-1, Rb, p21wafl or cipl,

- reactivation or breach of MDM2 expression and/or activity of MDM2, e.g. the (but not limited to the above), impact on its cellular localization, post-translational modification, nuclear export or ubiquitylation activity,

- direct or indirect stabilization of p53, for example, by holding it in functional block form, or by preventing its aggregation

- increased expression of p53 or the expression of members of the p53 family, for example, p63 and p73,

- increased activity of p53, such as (but not limited to the above), by increasing its transcriptional activity and/or

- increased expression of genes and proteins p53-signaling pathway, such as (but not limited to the above), p21wafl, cipl, MIC-I (GDF-15), PIG-3 and ATF-3.

Thus, the present invention discloses compounds of formula (I) for use as pharmaceuticals.

In addition, the present invention also relates to the use of compounds to obtain drugs for the treatment of disorders caused by the interaction of the p53-MDM2, where the specified compound is a compound of formula (I).

Used in this document, the term "treatment" or "treating" includes any disease and/or condition in an animal, in particular human, and includes: (i) prevention of disease and/or condition occurring in a subject which may be predisposed to the disease and/or condition, but to Oromo not yet diagnosed; (ii) inhibiting the disease and/or condition, i.e., the relief of their development; (iii) facilitation of the disease and/or condition, i.e., the weakening of symptoms and/or improvement.

The term "disorder caused by the interaction of the p53-MDM2" means any unwanted or harmful condition, which leads to inhibition or inhibits the interaction between the MDM2 protein and p53 or other cellular proteins that induce apoptosis, induce cell death or regulate the cell cycle.

The present invention also provides a method of treating disorders caused by the interaction of the p53-MDM2, by introducing an effective amount of the compounds of the present invention to a patient, e.g. a mammal (and more particularly human), when the need for such treatment.

Compounds of the present invention may have antiproliferative effects in tumor cells, even if these cells are devoid of functional p53. More specifically, the compounds of the present invention may have antiproliferative effects in tumor cells with wild type p53 and/or in tumors with overexpression of MDM2.

Thus, the present invention also provides a method of inhibiting tumor growth by introducing an effective amount of compound according to the present izobreteny the patient, for example, a mammal (and more particularly human), when the need for such treatment.

Examples of tumors that can inhibit, include, but are not limited to, lung cancer (e.g. adenocarcinoma and including non-small cell lung cancer), pancreatic cancer (e.g. pancreatic cancer, such as, for example, exocrine pancreatic cancer), colon cancer (e.g. colorectal carcinomas, such as, for example, adenocarcinoma of colon cancer and adenoma of the rectum), esophageal cancer, squamous carcinoma of the oral cavity, tongue cancer, stomach cancer, nasopharynx cancer, hematopoietic tumors of lymphoid series (e.g., acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), non-jackinsky lymphoma, Hodgkin's disease, myeloid leukemia (such as acute myelogenous leukemia (AML)), follicular thyroid cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal origin (e.g., fibrosarcoma and rhabdomyosarcoma, melanoma, teratocarcinoma, neuroblastoma, brain tumors, gliomas, benign tumor of the skin (for example, keratoacanthomas), breast cancer (e.g., progressive breast cancer), kidney cancer, ovarian cancer, cervical cancer, endometrial cancer, cancer bladder, prostate cancer including the advanced disease, testicular the diversified forms of cancer, osteosarcoma, head and neck cancer and epidermal carcinoma.

Compounds of the present invention can also be used for the treatment and prevention of inflammatory conditions.

Thus, the present invention also provides a method for the treatment and prevention of inflammatory conditions by introducing an effective amount of the compounds of the present invention to a patient, e.g. a mammal (and more particularly human), when the need for such treatment.

Compounds of the present invention can also be used to treat autoimmune diseases and conditions. The term "autoimmune disease" understand any disease in which the immune system of the animal reacts to hostile autoantigen. The term "autoantigen" refers to any antigen, which is usually present in the body of the animal. Characteristic of autoimmune diseases include, but are not limited to, Hashimoto's thyroiditis, grave's disease, multiple sclerosis, pernicious anemia, Addison disease, insulin dependent diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus (SLE or lupus), dermatomyositis, Crohn's disease, Wegener's granulomatosis, a disease glomerular antibotulinal membrane, antiphospholipid syndrome, dermatitis herpetiformis, allergic encephalomyelitis, glomerulo the Frith, diffuse membranous glomerulopathy syndrome Goodpasture, myasthenic syndrome Lambert-Eaton myasthenia gravis, bullous pemphigoid, polyendocrinopathy, Reiter syndrome and the syndrome of muscle stiffness.

Thus, the present invention also provides a method of treating autoimmune diseases and conditions, and treatment of diseases associated with conformational instability incorrectly Packed protein by introducing an effective amount of the compounds of the present invention to a patient, e.g. a mammal (and more particularly human), when the need for such treatment.

Compounds of the present invention can also be used to treat diseases associated with conformational instability incorrectly Packed proteins. Examples of diseases associated with conformational instability incorrectly Packed proteins include, but are not limited to, cystic fibrosis (CFTR), Marfan syndrome (fibrillin), amyotrophic lateral sclerosis (superoxide dismutase), scurvy (collagen), a disease maple syrup (complex dehydrogenase alpha-ketoacids), imperfect osteogenesis (type Pro-alpha procollagen), a disease of Creutzfeldt-Jakob disease (prion), Alzheimer's disease (beta-amyloid), familial amyloidosis (lysozyme), cataract (crystalline), family hypercholesterole is, s (LDL receptor), deficiency of inhibitor α-I-trypsin, disease, Tay-Sachs (beta hexosaminidase), retinitis pigmentosa (rhodopsin) and leprechaunism (insulin receptor).

Thus, the present invention also provides a method of treating diseases associated with conformational instability incorrectly Packed protein by introducing an effective amount of the compounds of the present invention to a patient, e.g. a mammal (and more particularly human), when the need for such treatment.

In view of their useful pharmacological properties, the compounds according to the present invention can be formulated into various pharmaceutical forms for the purpose.

To prepare the pharmaceutical compositions of the present invention an effective amount of a particular compound, in the form of a basic additive or acid additive salt, as an active ingredient together in a homogeneous mixture with a pharmaceutically acceptable carrier which can accommodate a wide variety of forms depending on the received desired shape for insertion. These pharmaceutical compositions are desirable in unit dosage form suitable, preferably, for administration orally, rectally, subcutaneously, or by parenteral injection. For example, for the preparation of compositions in a dosage form for the General application can be used any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols and the like in the case of liquid preparations for oral administration such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binding agents, dezintegriruetsja agents and the like in the case of powders, pills, capsules and tablets.

Because of its ease of use, tablets and capsules represent the most advantageous standard dosage form for oral administration, in which case, obviously, use solid pharmaceutical carriers. For parenteral compositions, the carrier will usually contain sterile water, at least in the main part, although there may be other ingredients to improve solubility. Injectable solutions can be prepared, for example, such a carrier which contains a salt solution, a glucose solution or a mixture of saline and glucose solution. Suspension for injection can also be prepared such, for which use the appropriate liquid carriers, suspendresume agents and the like. In the compositions suitable for subcutaneous administration, the carrier optionally contains increasing penetration of the agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in not the most proportions, adding them does not cause a significant adverse impact on the skin. These additives can facilitate introduction into the skin and/or may be useful for the preparation of the required compositions. These compositions can be introduced in various ways, for example, in the form of a transdermal patch, point the way, in the form of ointment. Especially advantageous to prepare the above-mentioned pharmaceutical composition in a standard dosage form for each application and uniform dosages. Standard dosage form used in the description and claims of this document, refers to physically discrete units suitable as unit doses, each unit containing a given quantity of active ingredient calculated to provide the desired therapeutic effect in combination with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including scored tablets and coated tablets), capsules, pills, sachets of powder, pills, solutions or suspensions for injection, fit into a teaspoon amount that will fit into a tablespoon of the number, and the like, and some of their multiples.

Compounds of the present invention is administered in a quantity sufficient to inhibit the interaction between MDM2 IR or other protein which induces apoptosis, induces cell death or regulates the cell cycle.

Oncogenic potential of MDM2 is determined not only by its ability to suppress p53, but also its ability to regulate other suppressing tumor proteins, for example, the retinoblastoma protein pRb and closely related transcription factors E2F1.

Thus, the connection of the present invention is administered in a quantity sufficient to modulate the interaction between MDM2 and transcription factor E2F.

Qualified in this field specialists can easily determine the effective amount from the test results presented later in this document. Typically, it is assumed that therapeutically effective amount may be from 0.005 mg/kg to 100 mg/kg body weight and, specifically, from 0.005 mg/kg to 10 mg/kg of body weight. It may be expedient to introduce the required dose in the form of one, two, three, four or more sub-doses at appropriate intervals of time during the day. These sub-doses may be prepared in a standard dosage forms, for example, containing from 0.5 to 500 mg and, specifically, from 10 mg to 500 mg of the active ingredient at a standard dosage form.

Another aspect of the present invention provides a combination of an inhibitor of p53-MDM2 with another anticancer agent, the person who but for use as a medicinal product, more specifically, for the treatment of cancer or related diseases.

To ensure the above conditions, the compounds of the present invention can be advantageously used in combination with one or more drugs, more specifically, with other anticancer agents. Examples of anti-cancer tools include, but are not limited to:

coordination compounds of platinum, for example, cisplatin, carboplatin or oxaliplatin;

- taxonomie compounds, such as paclitaxel or docetaxel;

inhibitors of topoisomerase I, such as camptothecine connection, for example irinotecan or topotecan;

inhibitors of topoisomerase II, such as antitumor epipodophyllotoxin or derivatives podofillotoksina, for example etoposide or teniposide;

- anticancer Vinca alkaloids for example vinblastine, vincristine or vinorelbine;

- antitumor derivatives of nucleosides, for example, 5-fluorouracil, leucovorin, gemcitabine or capecitabine;

- alkylating agents such as nitrogen mustard or nitrosoanatabine, for example, cyclophosphamide, chlorambucil, carmustine, thiotepa, matalan or lomustin;

- antitumor derivatives anthracycline, for example, daunorubicin, doxorubicin, doxil, idarubitsin or mitoxantrone;

- molecules, which are the two who are targets of IGF-1 receptors, for example, microrotation;

derivatives of tetracaine, for example, tetracetic A;

- glucocorticoids, such as prednisone;

- antibodies, such as trastuzumab (HER2 antibody), rituximab (CD20-antibody), gemtuzumab, cetuximab, pertuzumab or bevacizumab;

- receptor antagonists or selective estrogen receptor modulators estrogen, for example, tamoxifen, fulvestrant, toremifene, droloxifene, faslodex or raloxifene;

- aromatase inhibitors such as exemestane, anastrozole, letrazole and vorozole;

- differentiating agents such as retinoids, vitamin D, or retinoic acid, and means blocking the metabolism of retinoic acid (RAMBA)for example accutane;

inhibitors of DNA methyltransferase, for example, azacytidine or decitabine;

- antifolates, for example, pemetrexed disodium;

antibiotics, for example, actinomycin D, bleomycin, mitomycin C, dactinomycin, karminomitsin or daunomycin;

the antimetabolites, such as Clofarabine, aminopterin, cytosine arabinoside or methotrexate;

- inducing apoptosis tools and protivougonnye tools, such as inhibitors of Bcl-2, for example, YC 137, BH 312, ABT 737, hossipole, HA 14-1, TW 37 or cekanova acid;

the tubulin-binding means, for example, complestatin, colchicine or nocodazole;

inhibitors of kinases, for example, flavopiridol, imatinib Meuse the lat, erlotinib or gefitinib;

inhibitors farnesyltransferase, for example, tipifarnib;

inhibitors gasconductivity (HDAC), for example, sodium butyrate, suberoylanilide-hydroxamic acid (SAHA), depsipeptide (FR 901228), NVP-LAQ824, R306465, JNJ-26481585 or trichostatin;

inhibitors of the ubiquitin-proteasome path, for example, PS-341, 41 MLN or bortezomib;

- Yondelis;

- inhibitors of telomerase, for example, teamstation;

inhibitors of matrix metalloproteinases, for example, batimastat, marimastat, prinostit or metastat.

As stated above, the compounds of the present invention may also have therapeutic applications in tumor cells sensitive to chemotherapy and radiation therapy.

Therefore, compounds of the present invention can be used as a "radiosensibility" and/or "chemosensitizer", or may be presented in combination with other "radiosensitisation" and/or "chemosensitization".

Used in the present description, the term "radiosensibility" is defined as a molecule, preferably a low molecular weight, applied to animals in therapeutically effective amounts to increase the sensitivity of cells to ionizing radiation and/or contributing to the treatment of diseases that can be treated with radiation therapy.

Used the first in the present description, the term "chemosensitization" is defined as a molecule, preferably a low molecular weight, applied to animals in therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and/or contributing to the treatment of diseases that can be treated with chemotherapy.

In the literature suggested several mechanisms for the principle of radio sensibilizators, including: radio sensibilizators hypoxic cells (for example, the compounds 2-intorimidazole and connections dioxide benzotriazine), simulating oxygen or other conduct, such bioreductive means during hypoxia; radio sensibilizators neypatinga cells (for example, halogenated pyrimidines), which may represent analogues of DNA bases and preferably included in the DNA of cancer cells and, thereby, contribute to the destruction of DNA molecules under the action of radiation and/or impede the normal mechanisms of DNA repair; and various other potential mechanisms of action have been put forward as a hypothesis for radio sensibilizators when treatment of diseases.

Many cancer therapies currently use the radio sensibilizators in combination with x-ray irradiation. Examples of radio sensibilizators activated by x-rays include, but are not limited to, the following: metro is eazol, misonidazole, dexmethylphenidate, pilonidal, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromosuccinimide (BUdR), 5-iododeoxyuridine (IUdR), bromosuccinimide, ftordezoksiuridin (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives thereof.

In photodynamic therapy (PDT) of cancer using visible light as the sensitizing activator means. Examples of photodynamic radio sensibilizators include, but are not limited to: hematoporphyrin derivatives, Photofrin, derivatives benzoporphyrin, Ethiopian tin, foobarred, bacteriochlorophyll-naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives thereof.

The radio sensibilizators can be used in combination with a therapeutically effective amount of one or more compounds including, but not limited to: compounds which promote the incorporation of radio sensibilizators in the target cells; compounds which control the flow of therapeutic substances, nutrients and/or oxygen to the target cells; chemotherapeutic agents that act on the tumor with additional irradiation or without it, or other therapeutically effective compounds for treating cancer or other diseases.

Hamasen habilitator can be used in combination with a therapeutically effective amount of one or more compounds including, but not limited to: compounds which promote the incorporation of chemosensitization in the target cells; compounds which control the flow of therapeutic substances, nutrients and/or oxygen to the target cells; chemotherapeutic agents that act on the tumor, or other therapeutically effective compounds for treating cancer or other diseases. Calcium antagonist, such as verapamil, have been proven in combination with anticancer means to ensure sensitivity to chemotherapy in tumor cells that are resistant to conventional chemotherapeutic means, and to enhance the effectiveness of such compounds are susceptible to medicines malignant entities.

In view of their useful pharmacological properties, the components of the combinations according to the present invention, that is, other drug and inhibitor of the p53-MDM, can be formulated in various pharmaceutical forms for administration. Components can be made separately in individual pharmaceutical compositions or a single pharmaceutical composition comprising both.

The present invention thus also relates to pharmaceutical compositions containing another drug and inhibitor of p53-MDM2 together with one or more pharmaceutical carriers.

The present invention additionally relates to the use of the combinations according to the present invention for obtaining a pharmaceutical composition for inhibiting the growth of tumor cells.

The present invention additionally relates to a product containing as a first active ingredient an inhibitor of p53-MDM2 according to the present invention and as a second active ingredient an anti-cancer agent, as a combined preparation for simultaneous, separate or sequential use for the treatment of patients suffering from cancer.

Other drug and inhibitor of p53-MDM2 can be entered simultaneously (e.g. in separate or single composition) or sequentially in any order. In the latter case, two connections imposed during the period and in the amount and manner sufficient to ensure achievement of beneficial or synergistic effect. It should be accepted that the preferred method, the order of introduction, the relative dosage amounts and regimes for each component of the combination will depend on the specific of another drug and an inhibitor of p53-MDM2, routes of administration, the particular type of tumor and the particular patient being treated. The best way, the order of introduction, dosiro is by the number and the mode can be easily determined by the person skilled in the art by using conventional methods and on the basis of the information in the present description.

The coordination compound of platinum is mainly administered in a dose of from 1 to 500 mg per square meter (mg/m2) the surface area of the body, for example, from 50 to 400 mg/m2specifically, for cisplatin at a dose of approximately 75 mg/m2and for carboplatin approximately 300 mg/m2in the course of treatment.

Taxonomie connection is mostly administered in the dose of from 50 to 400 mg per square meter (mg/m2) the surface area of the body, for example, from 75 to 250 mg/m2specifically, paclitaxel at a dose of from about 175 to 250 mg/m2and for docetaxel approximately 75 to 150 mg/m2in the course of treatment.

Camptothecine connection is mostly administered in the dose of from 0.1 to 400 mg per square meter (mg/m2) the surface area of the body, for example, from 1 to 300 mg/m2specifically, for irinotecan at a dose of from about 100 to 350 mg/m2and for topotecan approximately 1 to 2 mg/m2in the course of treatment.

Antitumor derivative podofillotoksina mostly administered in a dose of from 30 to 300 mg per square meter (mg/m2) the surface area of the body, for example, from 50 to 250 mg/m2specifically, for etoposide at a dose of approximately from 35 to 100 mg/m2and for teniposide from approximately 50 to 250 mg/m2in the course of treatment.

Antitumor alkaloid barvin is and mostly administered in the dose of from 2 to 30 mg per square meter (mg/m 2) the surface area of the body, specifically, for vinblastine at a dose of about 3 to 12 mg/m2for vincristine at a dose of approximately 1 to 2 mg/m2and for vinorelbine at a dose of from about 10 to 30 mg/m2in the course of treatment.

Antitumor derived mainly nucleoside is administered in a dose of from 200 to 2500 mg per square meter (mg/m2) the surface area of the body, for example, from 700 to 1500 mg/m2specifically, for 5-FU at a dose of from 200 to 500 mg/m2for gemcitabine at a dose of from about 800 to 1200 mg/m2and for involving capecitabine from about 1000 to 2500 mg/m2in the course of treatment.

Alkylating agents such as nitrogen mustard or nitrosoanatabine, mostly administered in the dose of from 100 to 500 mg per square meter (mg/m2) the surface area of the body, for example, from 120 to 200 mg/m2specifically, for cyclophosphamide at a dose of approximately from 100 to 500 mg/m2for hlorambuzila at a dose of approximately 0.1 to 0.2 mg/kg, for carmustine at a dose of approximately from 150 to 200 mg/m2and for lomustina at a dose of approximately from 100 to 150 mg/m2in the course of treatment.

Antitumor derivative anthracycline mostly administered in the dose of from 10 to 75 mg per square meter (mg/m2) the surface area of the body, for example, from 15 to 60 mg/m2specifically, for doxorubicin at a dose of priblizitelen is from 40 to 75 mg/m 2for daunorubicin dose of from about 25 to 45 mg/m2and for idarubitsina in a dose of from about 10 to 15 mg/m2in the course of treatment.

Antiestrogenic tool mainly administered in a dose of from about 1 to 100 mg daily, depending on specific tools and treatment conditions. Tamoxifen is mainly administered orally in a dose of from 5 to 50 mg, preferably from 10 to 20 mg twice daily, continuing treatment for a sufficient time to achieve and consolidate therapeutic effect. Toremifene mainly administered orally at a dose of about 60 mg once daily, continuing treatment for a sufficient time to achieve and consolidate therapeutic effect. Anastrozole mainly administered orally at a dose of approximately 1 mg once a day. Droloxifene mainly administered orally at a dose of approximately 20-100 mg once a day. Raloxifene mainly administered orally at a dose of about 60 mg once a day. Exemestane mainly administered orally at a dose of approximately 25 mg once a day.

Antibodies predominantly administered in a dose of from about 1 to 5 mg per square meter (mg/m2) the surface area of the body, or as it is known in this area, unless otherwise known. Trastuzumab mostly administered in a dose of from 1 to 5 mg per square meter (mg/is 2) the surface area of the body, specifically, from 2 to 4 mg/m2in the course of treatment.

These doses can be entered, for example, once two or more times in the course of treatment, which is usually repeated, for example, every 7, 14, 21 or 28 days.

The compounds of formula (I), their pharmaceutically acceptable acid additive salts and stereoisomeric forms may have significant diagnostic properties, namely that they can be used for detection or identification of interaction of the p53-MDM2 in a biological sample, including the detection and measurement of complex formation between the labeled compound and/or p53 and/or MDM2 and/or other molecules, peptides, proteins, enzymes or receptors.

The methods of detection or identification may be used in connection labeled aiming agents, such as radioactive isotopes, enzymes, fluorescent substances, luminescent substances, etc. are Examples of radioactive isotopes include125I131I3H and14C. Enzymes are usually detectivesyme due to conjugation with a suitable substrate, which, in turn, catalyzes detektiruya reaction. Their examples include, for example, beta-galactosidase, beta-glucosidase, alkaline phosphatase, peroxidase and malate dehydrogenase, preferably horseradish peroxidase. Fluorescent substances which include STV, for example, luminal derived lyuminola, luciferin, acorin and luciferase.

Biological samples can be determined in the form of tissues or body fluids. Examples of body fluids are cerebrospinal fluid, blood, plasma, serum, urine, sputum, saliva, etc.

The following examples illustrate the present invention.

Experimental part

Hereinafter, “DCM” means dichloromethane, “DIPE” means diisopropyl ether, “EtOAc” means ethyl acetate, “EtOH” refers to ethanol, “MeOH” means methanol, and “THF” means tetrahydrofuran.

The melting temperature.

For a number of compounds, designated (Kofler), the melting temperature was measured using a table of Kofler, consisting of a heated plate with a linear temperature gradient, a sliding pointer and a temperature scale in degrees Celsius.

IHMS

General methods

HPLC gradient was obtained with the use of the system Alliance HT 2795 (Waters), including Quaternary pump with degasser, auto sampler and detector diode matrix (DAD). Flow from the column was directed into the MS detector. The MS detector was equipped with a source of ionization elektrorazpredelenie. The voltage on the capillary needle was 3 kV and the source temperature was maintained at 100°C for LCT (time-of-flight mass spectrometer with Z-spray is from Waters). Nitrogen was used as a gas atomizer. Data collection was performed using data systems Waters-Micromass MassLynx-Openlynx.

The way A

In addition to the General procedure: reversed phase HPLC was performed on a column (Xterra RP C18 (5 μm, a 3.9×150 mm) with a flow rate of 1.0 ml/min at 30°C. Two mobile phases (mobile phase A: 100% 7 mm ammonium acetate; mobile phase B: 100% acetonitrile); used to change the parameter gradient from 85% A, 15% B (shutter speed for 3 minutes) to 20% A, 80% B for 5 minutes, holding at 20% A and 80% B for 6 minutes and restore the initial settings for 3 minutes. Used injected volume : 20 µl. The cone voltage was 20 V for positive and negative ionization mode. Mass spectra were obtained by scanning from 100 to 900 in 0.8 seconds using the delay scan in 0.08 seconds.

Method B

In addition to the General procedure: reversed phase HPLC was performed on a column (Xterra RP C18 (5 μm, a 3.9×150 mm) with a flow rate of 1.0 ml/min at 30°C. Two mobile phases (mobile phase A: 100% 7 mm ammonium acetate; mobile phase B: 100% acetonitrile); used to change the parameter gradient from 100% A (exposure for 1 minute) to 50% A, 50% B for 4 minutes, holding at 50% A and 50% B within 9 minutes and restore the initial settings for 3 minutes. Used the led volume of 20 µl. The cone voltage was 20 In the positive ionization mode and 20 In the negative ionization mode. Mass spectra were obtained by scanning from 100 to 900 in 0.8 seconds using the delay scan in 0.08 seconds.

A. Obtaining intermediates.

Example A1

The production of intermediate compounds 1

A mixture of benzo[b]furan-3-one (400 mg, 0,0029 mol) and N-methoxy-N-methyl(triphenylphosphorane)ndimethylacetamide (1.19 g, 0,0032 mol) in xylene (10 ml) was stirred at 135°C for 35 hours. The reaction extinguished with water and increased the basicity of a saturated solution of sodium bicarbonate. The mixture was extracted with EtOAc, the organic layer was separated, dried (MgSO4), filtered and the solvent evaporated. The residue was purified column chromatography on silica gel (40-63 μm) (eluent: EtOAc/cyclohexane 50/50). Pure fractions were collected and the solvent evaporated to obtain 210 mg (32%) of intermediate compound 1 in the form of a brown oil.1H-NMR (300 MHz, CDCl3) δ 7,63 (m, 2H), 7,46 (d, 1H, J=7,1), 7,25 (m, 2H), 3,84 (s, 2H), 3,70 (s, 3H), up 3.22 (s, 3H). MS (ES+) m/z 220 (M+1).

Example A2

a)Obtaining the intermediate 2

A mixture of 1H-pyrrolo[2,3-b]pyridine-3-ethanamine (0.014 mol), 1-fluoro-4-nitrobenzene (0.015 mol) and DIPE (0,048 mol) was stirred at 210°C for 30 minutes. DIPE evaporated. OS the dock was dissolved in a mixture of DCM/MeOH. The organic layer was washed with 10% potassium carbonate, dried (MgSO4), filtered and the solvent evaporated. The residue (2 g) was purified column chromatography on silica gel (15-40 μm) (eluent: DCM/MeOH/NH4OH 97/3/0,3). Pure fractions were collected and the solvent evaporated to obtain 0.152 g (28%) of intermediate compound 2, melting point 201°C (Kofler).

b)The production of intermediate compound 3

A mixture of intermediate compound 2 (0,004 mol) and Raney Nickel (1 g) in MeOH (20 ml) was first made at room temperature for 2 hours under a 3 bar pressure, then filtered through celite. Celite washed with MeOH. The filtrate was evaporated to obtain 0,92 g (100%) of intermediate compound 3.

Example A3

a)Obtain intermediate compound 4

A mixture of imidazo[1,2-a]pyridine-3-acetonitrile (0,028 mol) and Rh/Al2O35% (4.5 g) in EtOH (45 ml) and MeOH/NH3(12.5 ml) was first made at room temperature for 72 hours under a 3 bar pressure, then filtered through celite. Celite was washed with a mixture of DCM/EtOH. The filtrate was evaporated. The residue was dissolved in DCM. The organic layer was washed with 10% potassium carbonate, dried (MgSO4), filtered and the solvent evaporated to obtain 3.4 g (73%) of intermediate compound 4.

b)Obtaining an intermediate compound 5

A mixture of intermediate compound 4 (0,006 mol), 1-fluoro-4-nitrobenzene (to 0.007 mol) and DIPE (0,021 mol) was heated at 210°C for 30 minutes. DIPE evaporated. The crude oil was diluted with DCM and EtOH (90/10). The organic layer was washed with 10% potassium carbonate, dried (MgSO4), filtered and the solvent evaporated. The residue (1.3 g) was purified column chromatography on silica gel (20-45 μm) (eluent: DCM/MeOH 98/2). Pure fractions were collected and the solvent evaporated. The residue (0.36 g) was led from acetonitrile. The precipitate was filtered and dried to obtain 0,199 g of intermediate compound 5, melting point 171°C (Kofler).

c)Obtaining an intermediate compound 6

A mixture of intermediate compound 5 (of 0.003 mol) and Raney Nickel (1 g) in MeOH (20 ml) was first made at room temperature for 3 hours under a 3 bar pressure, then filtered through celite. Celite washed with MeOH. The filtrate was evaporated to obtain 1 g (>100%) of intermediate compound 6.

Example A4

a)Obtaining an intermediate compound 7

A mixture of 1-fluoro-4-nitrobenzene (0,0083 mol), 1H-indol-5-amine (0,0076 mol) and DIPE (0,0166 mol) was stirred at 210°C for 18 hours, then was swallowed up in DCM. The organic layer was washed 3 N. hydrochloric acid, then NaHCO3, dried (MgSO4), filtered and evaporated solution is tel. The residue was absorbed in EtOH. The precipitate was filtered off, washed with diethyl ether and dried to obtain 1.08 g (65%) of intermediate compound 7, melting point 180°C.

b)Obtaining an intermediate compound 8

A mixture of intermediate compound 7 (to 0.0039 mol) and Raney Nickel (1 g) in MeOH (20 ml) was first made at room temperature for 2 hours under a 3 bar pressure, then filtered through celite. Celite was washed with a mixture of DCM/MeOH. The filtrate was evaporated to obtain 1 g (>100%) of intermediate compound 8.

Example A5

Obtaining an intermediate compound (9)

1,1'-Carboxaldehydes (315 mg, 0,0019 mol) was added dropwise to a solution of (6-methoxybenzophenone-3-yl)acetic acid (400 mg, 0,0019 mol) in DCM (10 ml). The mixture was stirred for 3 hours at room temperature. Added hydrochloride O N dimethylhydroxylamine (190 mg, 0,0019 mol) and the mixture was stirred for 4 hours at room temperature. The reaction was suppressed by ice and increased the basicity of 4 N. the sodium hydroxide solution. The mixture was extracted with DCM, the organic layer was separated, dried (MgSO4), filtered and the solvent evaporated. The residue was purified column chromatography on silica gel (40-63 μm) (eluent: EtOAc/cyclohexane 50/50). Pure fractions were collected and the solvent evaporated to obtain 410 is g (85%) of intermediate compound 9 as a colourless oil.

1H-NMR (300 MHz, CDCl3) δ rate of 7.54 (m, 2H), 6,99 (s, 1H), to 6.88 (d, 1H, J=6,4), 3,83 (s, 3H), 3,79 (s, 2H), 3,69 (s, 3H), 3,21 (s, 3H).

Example A6

a)Obtaining an intermediate compound 10

A mixture of 1,1-dimethylethylene ether (3-iodine-2-thienyl)carbamino acid (0,0105 mol), ethyl ester of 4-bromo-2-butenova acid (0,0158 mol) and potassium carbonate (0,021 mol) in N,N-dimethylformamide (100 ml) was stirred for 16 hours at room temperature. Added triphenylphosphine (0.001 mol) and palladium acetate (0,0005 mol). The mixture was stirred for 8 hours at 70°C, then washed with water. The organic layer was separated with EtOAc, dried (MgSO4) and the solvent evaporated. The residue was purified column chromatography on silica gel (eluent: EtOAc/cyclohexane 10/90) to give 2.3 g (70%) of intermediate compound 10.

b)Obtaining an intermediate compound (11)

A solution of intermediate compound 10 (0,0016 mol) in THF (10 ml) was stirred at -78°C in argon atmosphere. A solution of N,O-dimethylhydroxylamine HCl (to 0.0004 mol) in THF (40 ml) was stirred at -78°C in argon atmosphere. Utility (1.6 M in hexane) (0,016 mol) was added dropwise at -78°C to a solution of N,O-dimethylhydroxylamine HCl (to 0.0004 mol). The mixture was stirred at room temperature for 20 minutes, then was cooled to -78°C. was Added dropwise races the thief intermediate compound 10. The mixture was stirred at -78°C for 2 hours, poured into a saturated solution of NH4Cl at -78°C and was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated. The residue was purified column chromatography on silica gel (eluent: EtOAc/cyclohexane from 10/90 to 30/70). Pure fractions were collected and the solvent evaporated to obtain 0.4 g (77%) of intermediate compound (11).

c)Obtaining an intermediate compound 12

Intermediate compound 11 (0,0012 mol) was dissolved in DCM and absorbed on silica gel. The mixture was stirred at 60°C for 24 hours in vacuum. The residue was purified column chromatography on silica gel (eluent: EtOAc/cyclohexane 80/20). Pure fractions were collected and the solvent evaporated to obtain (62%) of intermediate compound 12.

d)Obtaining an intermediate compound 13

Alumoweld lithium (0,0008 mol) at 0°C was slowly added to a solution of intermediate compound 12 (0,0008 mol) in THF (4 ml, anhydrous). The mixture was stirred at 0°C for 1 hour, then poured on ice, washed with 5% KHSO4and was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated to obtain intermediate compound 13. The product is directly used in the following with the adiya's reaction.

B. obtain the final compounds

Example B1

Getting connection 1

1 n solution of lithium aluminum hydride in THF (0,65 ml) was added dropwise at 0°C to a suspension of intermediate 1 (162 mg, 0,00065 mol) in THF (4 ml). The mixture was stirred at 0°C for 1 hour. The reaction was suppressed at 0°C by slow addition of 5% solution of potassium bisulfate in water and was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated to obtain benzofuran-3-ylacetamide.

To a solution of N-4-pyridinyl-1,4-benzydamine in MeOH (3 ml) and acetic acid (4 drops) was added cyanoborohydride sodium (57 mg, 0,00091 mol) and aldehyde obtained above, dissolved in MeOH (1 ml). The mixture was stirred at room temperature for 18 hours. Then the solvent evaporated, the remaining oil was swallowed up in EtOAc and washed with saturated solution of sodium bicarbonate. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated. The residue was purified column chromatography on silica gel (40-63 μm) (eluent: DCM/MeOH 95/5). Pure fractions were collected and the solvent evaporated to obtain 41 mg (20%) of compound 1, the melting point of 152-154°C.

1H-NMR (300 MHz, MeOH-d4) δ 7,98 (d, 2H, J=6,6), to 7.59 (m, 2H), 7,43 (d, 1H, J=7,4), from 7.24 (m, 2H), 7,00 (DD, 2H, J=8,7, J=3.3V), of 6.68 (m, 4H), of 3.45 (t, 2H, J=7,2), 2,98 (t, 2H, J=7,2). S (ES+) m/z 330 (M+1).

Example B2

Getting connection 2

A mixture of intermediate compound 3 (0,004 mol) and hydrochloride of 4-bromopyridine (0,004 mol) in acetic acid (5 ml) was stirred at 140°C for 15 minutes, then evaporated. The residue was dissolved in a mixture of DCM/MeOH. The organic layer was washed with 10% potassium carbonate solution, dried (MgSO4), filtered and the solvent evaporated. The residue (1 g) was purified column chromatography on silica gel (15-40 μm) (eluent: DCM/MeOH/NH4OH 90/10/1). Pure fractions were collected and the solvent evaporated. The residue (0.74 g, 63%) was led from acetonitrile. The precipitate was filtered and washed with getting 0,541 g of compound 2, melting point 182°C (Kofler).

1H-NMR (DMSO-d6) δ 2,96 (2H, t, J=7,Hz), 3,30 (2H, t, J=7,Hz), 5,6 (1H, OST, J=7,Hz), to 6.58 (4H, m), to 6.95 (2H, d, J=7,Hz), 7,03 (1H, m), 7,33 (1H, m), of 7.96 (1H, d, J=7,Hz), 8,03 (2H, d, J=7,Hz), 8,17-8,21 (1H, m), by 8.22 (1H, USS), 11,38 (1H, USS). IHMS (ES+) m/z 330 (M+1), Rt=7,10, method A.

Example B3

Obtain compound 3

Hydrochloride 4-bromopyridine (0,004 mol) was added to a solution of intermediate compound 6 (0,004 mol) in acetic acid (10 ml). The mixture was heated at 140°C for 15 minutes in a microwave oven. Acetic acid evaporated. The crude oil was dissolved in a mixture of DCM/EtOH (90/10). The organic layer was washed with potassium carbonate, sushi and (MgSO 4), filtered and the solvent evaporated. The residue (1 g) was purified column chromatography on silica gel (15-40 μm) (eluent: DCM/MeOH/NH4OH from 90/10/0,5 to 90/10/1). Pure fractions were collected and the solvent evaporated to obtain 0,63 g (48%) of compound 3.

1H-NMR (DMSO-d6) δ 1,75-of 1.93 (4H, m), 2,65-2,78 (4H, m), 3,32 (2H, s), 3,70 (2H, t, J=6,1 Hz), 5,62 (1H, OST, J=7,Hz), 6,58-6,53 (5H, m), to 6.95 (2H, d, J=7,Hz), with 8.05 (2H, d, J=7,Hz), 8,24 (1H, ). IHMS (ES+) m/z 334 (M+1), Rt=5,18, method B. the melting point of 256°C (Kofler).

Example B4

Getting connections 4

Hydrochloride 4-bromopyridine (0.002 mol) was added to a solution of intermediate compound 8 (0,0022 mol) in acetic acid (2.8 ml). The mixture was heated at 110°C for 30 minutes, poured into ice-cold water and increased the basicity of a 10% potassium carbonate. The precipitate was filtered and dried. The residue (0,739 g) was purified column chromatography on a kromasil (5 μm) (eluent: DCM/MeOH/NH4OH from 96/4/0,4 to 88/12/1,2). Pure fractions were collected and the solvent evaporated to obtain 0,018 g of compound 4.

1H-NMR (DMSO-d6) δ 6,32 (1H, USS), of 6.68 (1H, d, J=5,GC)and 6.9 (1H, DD, J=10,2 Hz, J=2,5Hz), 6,55 (2H, d, J=10,2 Hz), 7,0 (2H, d, J=10,2 Hz), 7,27 (1H, m), 7,32 (1H, d, J=10,2 Hz), and 7.7 (1H, USS), 8,17 (1H, DD, J=10,2 Hz, J=2,5Hz), of 8.37 (1H, USS), or 10.9 (1H, USS). IHMS (ES+) m/z 301 (M+1), Rt=7,73, method A.

Example B5

Getting connection 5

1 N. a solution of alumina is of Idrija lithium in THF (1.0 ml) was added dropwise at 0°C to a suspension of intermediate 9 (249 mg, 0,0010 mol). The mixture was stirred at 0°C for 1 hour. The reaction was suppressed at 0°C by slow addition of 5% solution of potassium bisulfate in water and was twice extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated to obtain (6-methoxybenzophenone-3-yl)acetaldehyde.

To a solution of N-4-pyridinyl-1,4-benzydamine in MeOH (5 ml) and acetic acid (5 drops) was added cyanoborohydride sodium (90 mg, 0,0014 mol) and aldehyde obtained above, dissolved in MeOH (1 ml). The mixture was stirred at room temperature for 18 hours. Then the solvent evaporated, the remaining oil was swallowed up in EtOAc and washed with saturated solution of sodium bicarbonate. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated. The residue is washed with MeOH and dried to obtain 125 mg (34%) of compound 5, the melting point 184-186°C.

1H-NMR (300 MHz, DMSO-d6) δ 8,23 (s, 1H), 8,01 (DD, 2H, J=6,3, J=1,5), 7,71 (s, 1H), 7,51 (d, 1H, J=8,5), 7,14 (d, 1H, J=2,1), 6,92 (d, 2H, J=8,6), 6,85 (DD, 1H, J=8,5, J=2,2), to 6.58 (m, 4H), 5,64 (t, 1H, J=5,6), of 3.77 (s, 3H), 3,30 (t, 2H, J=7,0), 2,48 (t, 2H, J=7,0). MS (ES+) m/z 360 (M+1).

Example B6

Getting connection 6

Acetic acid (few drops), then the intermediate compound 13 (of 0.0004 mol) was added dropwise to a solution of N-4-pyridinyl-1,4-benzydamine (0,0008 mol) and cyanoborohydride sodium (0.001 mol) in MeH (4 ml). Intermediate compound 13 (of 0.0004 mol) was dissolved in MeOH (4 ml). The mixture was stirred at room temperature for 20 hours, poured into water, washed with saturated NaHCO3and was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated. The residue was purified column chromatography on silica gel (eluent: DCM/MeOH 85/15). Pure fractions were collected and the solvent evaporated to obtain 0,086 g (34%) of compound 6.

In table F-1 lists the compounds that were obtained in one of the examples above.

Table F-1
Conn. No. 1; Etc. [B1]; TPL 152-154°CConn. No. 2; Etc. [B2]; TPL 182°C
Conn. No. 3; Etc. [B3]; TPL 256°CConn. No. 4; Etc. [B4]

Conn. No. 6; PR. [B6}
Conn. No. 5; PR. [B5]; TPL 184-186°C

C. Pharmacological examples:

The ability of compounds to keep p53 in A2780 cells was determined by enzyme immunoassay associated with p53 enzyme. Analysis of p53 is a sandwich method of enzyme immunoassay using two polyclonal antibodies. A polyclonal antibody specific for p53, was immobilized on the surface of plastic wells. Any of p53 present in the subject analysis, the sample will bind to the immobilized antibody. Biotinylated polyclonal antibody as the detector also detects p53 protein and will also contact any of p53, which was withheld immobilized antibody. Antibody as a detector, in turn, binds with streptavidin conjugated to horseradish peroxidase. Horseradish peroxidase catalyzes the conversion of a chromogenic substrate o-phenylenediamine, the intensity of which is proportional to the amount of protein p53, is associated with the tablet. The number of the colored reaction product was determined using a spectrophotometer. Quantitative determination reached by constructing a standard curve using known concentrations of purified recombinant HIS-tagged p53 (see example C.1).

Cellular activity of the compounds of formula (I) defined in the op is for the U87MG cells using a colorimetric analysis at the cellular toxicity or survival (see example C.2).

Tumor cells U87MG represent cells in human glioblastoma with wild type p53. In such cell lines MDM2 controls the expression of p53.

C.1. p53 ELISA

The A2780 cells (ATCC) were cultured in RPMI 1640, supplemented with 10% fetal calf serum (FCS), 2 mm L-glutamine and gentamicin at 37°C in a humidified incubator with 5% CO2.

The A2780 cells were seeded at 20,000 cells per well of 96-hole tablet, were cultured for 24 hours and were treated with compound for 16 hours in a humidified incubator at 37°C. After incubation, the cells were washed once with phosphate buffered saline and added 30 μl, per well, slightly salt RIPA buffer (20 mm Tris, pH 7.0, 0.5 mm EDTA, 1% Nonidet P40, 0.5% of the DOC, of 0.05% SDS, 1 mm PMSF, 1 μg/ml Aprotinin and 0.5 μg/ml leupeptin). The tablets were placed on ice for 30 minutes for complete lysis. P53 protein was determined in the lysates using the sandwich ELISA described below.

High binding polystyrene EIA/RIA 96-well plates (Costar 9018) were coated immobilized antibody pAb1801 (Abcam ab28-100) at a concentration of 1 μg/ml in covering the buffer (0.1m NaHCO3pH of 8.2), 50 μl per well. The antibody was left to bind overnight at 4°C. the Coated tablets were washed once with phosphate buffered saline (PBS)/0.05% of Twin 20 was added 300 μl of blocking buffer (PBS, 1% bovine albumin, Siva ODI (BSA)) for an incubation period of 2 hours at room temperature. Purified recombinant HIS-tagged protein p53, in the range of 3-200 ng/ml, was obtained in blocking buffer and used as the standard.

Tablets twice washed with PBS/0,05% Twin 20 and a blocking buffer or added standards for 80 µl/well. The standards were added 20 μl of buffer for lysis. The samples were added to other wells in 20 μl of lysate per well. After incubation over night at 4°C tablets were washed twice in PBS/0,05% Twin 20. Aliquot 100 μl of the second polyclonal antibody p53(FL-393) (Tebubio, sc-6243) at a concentration of 1 μg/ml in blocking buffer was added to each well and left for 2 hours to bind at room temperature. The tablets were washed three times with PBS/0,05% Twin 20. Added anti-rabbit antibody HRP (sc-2004, Tebubio) at a concentration of 0.04 µg/ml in PBS/1% BSA and incubated for 1 hour at room temperature. Tablets, three times washed with PBS/0,05% Twin 20 was added 100 μl of substrate buffer substrate buffer quickly prepared before use by adding 1 tablet 10 mg o-phenylenediamine (OPD) from Sigma and 125 μl of 3% H2O2to 25 ml of OPD buffer: 35 mm citric acid, 66 mm Na2HPO4pH of 5.6). After 5-10 minutes, color reaction was stopped by adding 50 μl of stop buffer (1 M H2SO4) per well. The absorption at two wavelengths 490/655 nm was measured using a reader Biorad microplate click the analyzed results.

In each experiment carried out in parallel a control (containing no drug) and clean (not containing cells or drugs) incubation. The value of pure incubation subtracted from all values of the control and test samples. For each sample the value of p53 (in units of absorption) were expressed as percentage of the content of p53 in the control samples. The percentage saving of more than 140% was defined as significant. In this document the effects of the studied compounds is expressed as the minimum dose that gives at least 140% of the value of p53 present in the control (LAD) sample (see table F-2).

C2. Analysis of cell proliferation

All the compounds were dissolved in DMSO and further dilution was prepared in culture medium. Final concentration of DMSO never exceeded 0.1 percent (vol./about.) in the analysis of cell proliferation. Control samples contained U87MG cells and DMSO without connections and clean samples contained only DMSO without cells.

The U87MG cells were seeded in 96-well plates to the cell culture at 3000 cells/well/100 ál. After 24 hours the medium was changed and added a connection and/or a solvent to a final volume of 200 μl. After 4 days of incubation the medium was replaced with 200 μl of fresh medium and cell growth was assessed using analysis, cos the bath on MTT. Thus, 25 μl of MTT solution (0.5% of MTT studied benchmark from Serva in phosphate buffered saline) was added to each well and cells additionally incubated for 2 hours at 37°C. Then the medium was carefully pumped out and the blue product MTT-formosanum was dissolved by adding to each well 25 ál of 0.1 m glycine, and 100 µl of DMSO. The tablets were shaken for 10 minutes on a shaker for microplates, and then measured the absorbance at 540 nm using a reader Biorad microplate.

In the experiment, the results for each of the experimental conditions represent the average of three repeated holes. The purpose of the primary screening of the compounds were tested at a single fixed concentration of 10-5Meters For active compounds, the experiments were repeated to build a complete curve concentration-response. In each experiment carried out in parallel a control (containing no drug) and clean (not containing cells or drugs) incubation. The value of pure incubation subtracted from all values of the control and test samples. For each sample the value of the cell growth (in units of absorption) were expressed as percentages of the average cell growth in control samples. If acceptable, the values of the IC50 (the concentration of drug required to reduce cell growth by 50% relative to the control sample) was calculated using statistical analysis to estimate values (Finney, D.J., Probit analysis, 2ndEd. Chapter 10, Graded Responses, Cambridge University Press, Cambridge 1962). In this document the effects of the studied compounds expressed as IC50(the negative value of the logarithm of the value of the IC50) (see table F-2).

In some experiments, the analysis of proliferation adapted for use in 384-well culture plates (see table F-2).

5,15
Table F-2
In table F-2 shows the results for the compounds investigated according to the examples C.1 and C.2.
Conn. No.A2780 p53-elisaCell proliferation pI50
384 wells
Cell proliferation pI50
96 wells
11.0E-055,49
23.0E-06are 5.36
33.0E-06
41.0E-065,85
51.0E-055,35
61.0E-05<5

D. Example of composition: tablets film coated

Preparation of core tablets

A mixture of 100 g of compound of formula (I), 570 g lactose and 200 g starch are thoroughly mixed, and then moistened with a solution of 5 g of dodecyl sulfate and 10 g polyvinylpyrrolidone approximately 200 ml of water. Mix the wet powder was sieved, dried and again sieved. Then was added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All are thoroughly mixed and extruded into pellets to obtain 10,000 tablets each containing 10 mg of the compounds of formula (I).

Floor

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol was added 5 g of ethyl cellulose in 150 ml of dichloromethane. Then added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol to 10 g of liquid polyethylene glycol and dissolved in 75 ml of dichloromethane. The latter solution was added to the previous and then added 2.5 g of octadecanoate m is fester, 5 g of polyvinylpyrrolidone and 30 ml of concentrated dye suspension and a fully homogenized. Core tablets were coated with this mixture in the apparatus for cover.

1. The compound of formula (I),

its pharmaceutically acceptable salt, where m represents a direct bond;
n is 0, 1, 2, 3 or 4 and, when n is 0, it means a direct link;
p is 1;
s is a direct link;
t represents a direct bond;
R1and R2each independently represents hydrogen;
Rather it represents a radical selected from

where R4and R5each independently selected from hydrogen or C1-6alkyloxy;
Z represents a radicalwhere R6and R7each independently represents hydrogen.

2. The compound according to claim 1, where
m represents a direct bond; n is 0 or 2; R is 1; s is a direct bond; t represents a direct bond; R1and R2each independently represent hydrogen; a is a radical selected from (a-15), (a-21), (a-30), (a-39) or (40); R4and R5each independently selected from hydrogen or C1-6al is iloxi; Z is a radical (b-2); or R6and R7each independently selected from hydrogen.

3. The compound according to claim 1, where m represents a direct bond; n is 2; R is 1; s is a direct bond; t represents a direct bond; R1and R2each independently represents hydrogen; a represents a radical selected from (a-21), (a-39) or (40); R4and R5each independently selected from hydrogen or C1-6alkyloxy; Z is a radical (b-2); or R6and R7each independently selected from hydrogen.

4. The compound according to claim 1, where connection is a connection # 2 connection # 3 connection # 5.

5. The compound according to claims 1, 2, 3 or 4 for use as a drug for cancer treatment.

6. Pharmaceutical composition for treating cancer containing pharmaceutically acceptable carriers and as active ingredient a compound according to claims 1 to 4 in therapeutically effective amounts.

7. A method of obtaining a pharmaceutical composition according PP, where the pharmaceutically acceptable carriers and a compound according to claims 1-4 mixed directly.

8. The use of compounds according to claim 1, 2, 3 or 4 to obtain drugs for cancer treatment.

9. A method of obtaining a compound according to claim 1, including interaction Prohm is filling the compounds of formula (II) with an intermediate compound of formula (III), where W represents an appropriate leaving group, such as, for example, halogen,

where the values of the variables specified in claim 1.

10. A method of obtaining a compound according to claim 1, providing for the conversion of intermediate compounds of formula (IV) in the compounds of formula (I), where p is 1, referred to here as the compounds of formula (1-a), in the presence of lithium aluminum hydride in a suitable solvent,

where the values of the variables specified in claim 1.



 

Same patents:

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: present invention relates to novel derivatives of bicyclic imdazo-3-lylamines of general formula and corresponding physiologically transportable salts thereof, where A1 denotes a nitrogen atom or a C-R1a-group, A2 denotes a nitrogen atom or a C-R1b-group, A3 denotes a C-R1c-group, A4 denotes a nitrogen atom or a C-R1d-group, R1a, R1b, R1c, R1d independently denote hydrogen, halogen, -C(=O)-OR12, -OR16, a straight or branched, saturated, unsubstituted or halogen-tri-substituted C1-10-aliphatic residue, or an unsubstituted phenyl residue which can be bonded through a straight or branched C1-5-alkylene group, or R1b and R1c or R1c and R1d together with a C-C-bridge bonded to them optionally form an unsubstituted annelated phenyl residue, R2 and R3 independently denote hydrogen, -C(=O)-R2b, (CH2)q -C(=O)-R21, where q equals 1, -(CH2)r- C(=O)-O-R22, where r equals 1, a straight or branched, saturated unsubstituted C1-16-aliphatic residue, saturated, unsubstituted C4-8-cycloaliphatic residue which can be bonded through a straight or branched C1-5-alkylene group, or an unsubstituted or at least mono-substituted phenyl or heteroaryl residue which can be bonded through a straight or branched C1-5-alkylene group, or R2 and R3 together with the nitrogen atom with which they are bonded to as a ring member form a saturated heterocycloaliphatic residue which is piperidine or pyrrolidine, R12, R16, R20, R21 and R22 independently denote hydrogen, straight or branched, saturated C1-4-aliphatic residue or an unsubstituted or at least mono-substituted phenyl residue, which can be bonded through a straight or branched C1-5-alkylene group, M1 denotes a phenyl or heteroaryl residue which can be substituted with an additional substitute which is methyl or -CH2-CN, M2 denotes an unsubstituted or at least mono-substituted phenyl or heteroaryl residue, wherein the heteroaryl is selected from a group consisting of the following residues: furyl (furanyl), thienyl (thiophenyl), imidazolyl, thiazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl and quinolyl, the expression "at least mono-substituted" in association with "phenyl" or "heteroaryl" relates to a phenyl or heteroaryl residue which can be substituted with 1 or 2 substitutes independently selected from a group comprising halogen, , -CN, -NO2, -OH, -NH2, -CH2-NH2, -C(=O)-OH, C1-C5alkyl, -CH2-O-C1-C5alkyl, -C2-C5alkenyl, -S-C1-C5alkyl, -O-C1-C5alkyl, -CF3, -O-CF3, -NH-C1-C5alkyl, -N-(C1-C5alkyl)2, -C(=O)-O-C1-C5alkyl, -C(=O)-H, -C(=O)-C1-C5alkyl, -NH-S(=O)2-C1-C5alkyl, -NH-C(O)-C1-C5alkyl, -S(=O)2-NH2,-S(=O)2-NH-C1-C5alkyl, -CH2OH, -C(=O)-NH2, -Si(phenyl)2[C1-C5alkyl], (1,3)-dioxolanyl, phenyl and pyrrolyl. The invention also relates to methods of producing compounds of formula I, a medicinal agent based on compounds of formula I, use of compounds of formula I to prepare the medicinal agent.

EFFECT: obtaining novel derivatives of bicyclic imidazo-3-ylamines of general formula I, used to regulate the mGluR5-receptor.

30 cl, 3 tbl, 365 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I): or its pharmaceutically acceptable salt where Q is 2,6-pyrimidyl; where Q is optionally substituted by 1-5 substitutes JQ; Z is a link or NH; R1 is H; R2 is H; R3 is halogen or -(U)m-X where m is equal to 0; X is H or halogen; JQ is halogen, OCF3, -(Vn)-R", -(Vn)-CN or -(Vn)-(C1-4 halogenaliphatic group) where JQ is not H; V is C1-10aliphatic group where up to three methylene groups are substituted by GV where Gv is selected from -NH-, -NR-, -O-, -S-, -CO2-, -C(O)CO-, -C(O), -C(O)NH-, -C(O)NR-, -C(=N-CN)-, -NHCO-, -NRCO-, -NHSO2-, -NRSO2-, -NHC(O)NH-, -NRC(O)NH-, -NHC(O)NR-, -NRC(O)NR or -SO2-; and where V is optionally substituted by 1-6 substitutes JV; R" is H or an optionally substituted group selected from C1-6aliphatic group, C3-10cycloaliphatic group, C6-10aryl, 5-10-member heteroaryl or 5-10-member heterocyclyl; or two R" groups on the same substitute or various substitutes together with atom (s) whereto each group R" is attached, form optionally substituted 3-8-member heterocyclyl; where each optionally substituted R" group is independently and optionally substituted by 1-6 substitutes JR; R is an optionally substituted group selected from C1-6aliphatic group and C6-10aryl where each group R is independently and optionally substituted by 1-4 substitutes JR; each Jv and JR are independently selected from halogen, L, - (Ln)-R', - (Ln)-N(R')2, -(Ln)-OR', C1-4haloalkyl, -(Ln)-CN, - (Ln)-OH, -CO2R', -CO2H or -COR'; or two Jv, JR groups on the same substitute or various substitutes together with atom (s) whereto each group JV and JR is attached, form a 5-7-member saturated, unsaturated or partially saturated ring; R' is H or C1-6aliphatic group; L is C1-6aliphatic group where up to three methylene units are substituted by -C(O)-; each n is independently equal to 0 or 1. Besides, an invention refers to of a pharmaceutical composition for ROCK or JAK kinase inhibition on the basis of the given compounds, to a method of ROCK or JAK kinase activity inhibition, and also to application of the compounds of formula I, for preparing a drug where Q, Z, R1, R2 and R3 are those as described in cl. 1 of the patent claim, effective as protein kinase inhibitors, especially JAK and ROCK families kinase inhibitors.

EFFECT: there are prepared and described new compounds which can find the application in medicine.

42 cl, 6 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: described is a compound of general formula: [1], where R1 denotes an optionally substituted C2-C12 alkyl, aryl or heterocyclic group which can be a mono- or bicyclic 5-11-member radical, where the heteroatoms can be nitrogen, oxygen or sulphur; X1 denotes C2-C4 an alkylene group; X2 denotes a bond; X3 denotes a group of general formula NR3 or CR4R5NR3 (where R3 denotes a hydrogen atom, optionally substituted lower alkyl group or imino-protective group) and R4 and R5 are identical or different, and each denotes a hydrogen atom or a lower alkyl group or bond; X4 denotes a lower alkylene or lower alkenylene or lower alkynylene group, which can be substituted with one or more oxo groups or a bond; X5 denotes a sulphur atom or bond; Y1 denotes an optionally substituted divalent 4-, 5- or 6-member alicyclic hydrocarbon residue or an optionally subsituted divalent 5- or 6-member alicyclic amine residue, where the heteroatoms can be nitrogen or oxygen; Z1, Z2, Z3, Z4, Z5 and Z6 are identical or different, and each denotes a nitrogen atom or a group of general formula CR7 (where R7 denotes a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted amino group, or an amino group substituted with one or more C1-6 alkyl groups, a lower alkyl group, a cycloalkyl, a lower alkoxy group or a monocyclic 5-member heterocyclic group which can be substituted with one or more halogen atoms, where the heteroatoms can be nitrogen, acid or sulphur or a group of general formula Q1CO2R10 (where R10 denotes a carboxyl-protective group and Q1 denotes a lower alkenylene group), provided that at least one of Z3, Z4, Z5 and Z6 denotes a nitrogen atom, or salt thereof. The invention also describes an antimicrobial agent based on said compound.

EFFECT: novel compounds which can be used as antimicrobial agents are obtained and described.

25 cl, 176 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds with chymase inhibiting activity.

14 cl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), in which X denotes N or CR3, M denotes (CH2)m; m equals 0 or 1, R1 denotes H or lower alkyl which can be substituted with a group selected from a group consisting of mono- or di-lower alkylamino and -O-lower alkyl, R2 denotes H or lower alkyl, R3 denotes H or lower alkyl substituted with a group selected from a group consisting of halogen, mono- or di-lower alkylamino and cyclic amino, R41 denotes H or pyridine which can be substituted with a cyano group, R42 denotes a bridged polycyclic hydrocarbon or a bridged azacyclic hydrocarbon, each of which can be substituted, R5 denotes a group selected from a group consisting of halogen, cyano, lower alkyl-carbonyl, lower alkyl-oxycarbonyl, hydroxycarbonyl, formyl, amidinooxycarbonyl, guanidinooxycarbonyl, guanidino, carbamoyl, -C(=O)-5- or -6-member heterocycloalkyl, -C(=O)-5- or -6-member heteroaryl, lower alkyl, lower alkenyl, -O-lower alkyl, 5- or 6-member heterocycloalkyl and 5-member heteroaryl, each of which can be substituted, provided that when R5 denotes a 5-member heteroaryl, X denotes -CR3; or R41 and R15 can be bonded through a defined functional group to form divalent groups shown below: (I-A) (I-B) or (I-C), in which RA denotes H or acyl, which can be substituted, provided that the term "substituted" with respect to R4 and/or R5 denotes substitution with one or more substitutes selected from a group comprising the following substitutes: (a). halogen; (b) -OH, -O-R2, -O-phenyl, -OCO-RZ-OCONH-RZ oxo (=O); (c) -SH, -S-R2, -S-phenyl, -S-heteroaryl, -SO-R2, -SO-phenyl, -SO-heteroaryl, -SO3H, -SO2-RZ, -SO2-phenyl, - SO2-heteroaryl, sulphamoyl, which can be substituted with one or two RZ groups; (d) amino, which can be substituted with one or two RZ groups, -NHCO-RZ, -NHCO-phenyl, -NHCO2-RZ, -NHCONH2, -NHCONH-RZ, -NHSO2-R0, -NHSO2-phenyl, -NHSO2NH2, -NO2, =N-O-RZ; (e) -CHO, -CO-RZ, -CO2H, -CO2-RZ, carbamoyl, which can be substituted with one or two RZ groups, -CO-cyclic amino, -COCO-RZ, cyano; (f) RZ; (g) phenyl, which can be substituted with one or more groups selected from substitutes described above in paragraphs from (a) to (f), a 5- or 6-member heterocycloalkyl, a 5- or 6-member heteroaryl, a 5- or 6-member heterocycloaryl; or pharmaceutically acceptable salts thereof. The invention also relates to a method of producing compounds of formula II, a pharmaceutical composition based on said compounds which is a Janus kinase 3 inhibitor, a method of treating and/or preventing different immunopathological diseases, including autoimmune diseases, inflammatory diseases and allergic diseases.

EFFECT: novel compounds are obtained and described, which can be used as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transmission or diseases caused by pathological cytokine signal transmission.

14 cl, 579 ex, 72 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to RSV replication inhibitors of formula (I) or salts thereof or stereochemically isomeric forms, where R is a radical of formula (a) or (b) . Q is hydrogen or C1-6alkyl substituted with a heterocycle selected from oxazolidine, morpholinyl and hexahydrooxazepine. Alk denotes C1-6alkanediyl. X is O; -a1=a2-a3=a4 - is -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH- or -CH=CH-CH=N-; R1 is selected from optionally substituted pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyrrolyl. R2 is C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, Ar-C1-6alkyloxyC1-6alkyl, C3-7cycloalkyl, Ar-C1-6alkyl. R3 is cyano. Ar is phenyl o substituted phenyl. The invention also relates to pharmaceutical compositions containing compounds (I) and a method of producing compounds (I).

EFFECT: high efficiency of the compositions.

9 cl, 20 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (IC-2), to their pharmaceutically acceptable salts, N- oxides or solvates. In formula (IC-2) Z represents carbomoyl group, which can be replaced with C1-4 alkyl or hydroxy; R1 represents C1-8 alkyl or C1-8 alkoxy; R4 and R4-1 each independently represent hydrogen atom or C1-8 alkyl; m represents integer number from 1 to 5, when m equals 2 or larger number, all R1 can have same or different values. Invention also relates to compounds, representing 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-napthlenyl}methyl)-3-azetidinecarbonic acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalinyl}methyl)-3- azetidinecarbonic acid and other, given in formula of claimed invention.

EFFECT: obtaining pharmaceutical composition, which has agonistic activity with respect to EDG-1, EDG-6 and/or EDG-8, containing as active component invention compound, to method of prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8 invention compounds, to method of prevention and/or treatment of disseminated sclerosis and method of immune reaction suppression and/or induction of lymphopenia, to application of invention compounds for obtaining medication for prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8, to application of compounds for obtaining medication for prevention and/or treatment of disseminated sclerosis, to application of compounds for obtaining immunodepresant and/or medication inducing lymphopenia and to crystal forms of some individual compounds.

17 cl, 10 dwg, 5 tbl, 251 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel bicyclic derivatives of general formula (I)

(values of radicals are given in the description) and a pharmaceutical composition containing said derivatives, as well as use of said novel compounds to treat or inhibit symptomatic diseases where CEPT is involved, and a method of treating said diseases.

EFFECT: high efficiency of using compounds when treating diseases.

14 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 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: pharmaceutical compositions containing at least one compound of formula (IIIa) or (IIIb) or (IVa) or (IVb), where -X- and Y are described in the claims, or pharmaceutically acceptable salts, esters or amides thereof and a pharmaceutically acceptable carrier, which can be used in processes with modulation or E- and P-selectin expression.

EFFECT: obtaining low-molecular non-glycoside and non-peptide compounds, capable of creating antagonism to selectin-mediated processes.

11 cl, 38 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , isomer thereof of formula IA , mixture of isomers thereof IA/C , synthesis method thereof, as well as methods of producing compounds of formula IVA from compounds of formula IA, involving reduction and removal of protection from compounds of formula IA via hydrogenolysis using H2 and a catalytic amount of Pd/C, in the presence of trifluoroacetic acid to obtain a compound of formula VA; further reaction of this compound with Cbz-t-leu-OH, EDC and HOBt to obtain a compound of formula VIA; reaction of compound VIA with H2 and a catalytic amount of Pd/C in the presence of citric acid to obtain an amine and reaction of said amine and 4-amino-3-chlorobenzoic acid in the presence of CDMT and NMM to obtain a compound of formula IVA.

EFFECT: fewer synthesis steps and high output while using dynamic crystallisation.

13 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel carbamoyl benzotriazole derivatives of general formula , (values of radicals are given in the description), tautomers thereof and pharmaceutically acceptable salts and use thereof as endothelial lipase inhibitors.

EFFECT: improved properties of the derivatives.

11 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), which have protein kinase inhibiting properties and can be used in treating diseases which are dependent on any one or more protein kinases from FGFR1, FGFR2, FRF3 and/or FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2 and/or Ret Such diseases can be proliferative diseases, for example bladder cancer, breast cancer and multiple myeloma. In formula

the left-side ring , right-side ring , there are the following fragments, denoted "left-side ring" and "right-side ring", respectively: where X denotes C-R5, and Y and Z both denote N. The left-side ring corresponds to fragment (A):

n equals 0, 1, 2, 3, 4 or 5, X1 denotes hydrogen, where R1 denotes a group of formula Rz-NRa-, where Ra denotes hydrogen and Rz is selected from (1) a straight or branched C1-C4alkyl or (2) a group of formula , where ring A denotes phenyl, cyclohexenyl, cyclohexyl or pyridyl, m equals 0, 1 or 2, one or each of Rb is independently selected from a group -L2-NRcRd; -L2-RING, where RING denotes a 5- or 6-member saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen and oxygen, optionally substituted, as indicated below, halogen; hydroxy; amino; cyano, and a straight or branched C1-C4alkyl optionally substituted with one or more halogens and/or one or two hydroxy groups, wherein the hydroxy and amino groups are in turn optionally substituted on at least one heteroatom with one or, if necessary, more C1-C7aliphatic groups, where L2 denotes a direct bond, a link selected from a group comprising -O-, -S-, -C(O)-, -OC(O)-, -NRaC(O)-, -C(O)-NRa -OC(O)-NRa, -NRa-; or denotes a straight C1-C4alkyl which is optionally interrupted and/or ends in one terminal fragment or in two terminal fragments with the said link, and where Rc and Rd are each independently selected from a group comprising hydrogen and straight or branched C1-C4alkyl, or Rc and Rd together with a neighbouring nitrogen atom form a 5- or 6-member heterocyclic ring which optionally contains an additional heteroatom selected from nitrogen and oxygen, and optionally substituted as indicated below, said optionally substituted rings are independently substituted with 0, 1, 2, 3, 4 or 5 C1-C7aliphatic substitutes which are optionally substituted with one or more halogen atoms; R2 denotes hydrogen or C1-C4alkyl; R3 denotes hydrogen or straight or branched C1-C4alkyl or straight C1-C4alkyl substituted with a 5- or 6-member saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms in the ring, selected from nitrogen, oxygen and sulphur; R4 is selected from hydroxy, protected hydroxy group, alkoxy, alkyl, trifluoromethyl and halogen, where the alkyl or alkyl part of the alkoxy is straight or branched and contains 1, 2, 3 or 4 carbon atoms; or R5 denotes hydrogen or C1-C4alkyl; or pharmaceutically acceptable salts, hydrates, solvates, ethers, N-oxides thereof, optionally in form of trans-isomers thereof.

EFFECT: improved properties of the compound.

38 cl, 1 tbl, 231 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (11) given below and pharmaceutically acceptable salts thereof: chemical formula 1

in which: each of G1, G2, G3 and G8 independently denotes -N=, -CR1= or -C(-G9-X)=; one of G1, G2, G3 and G8 is-C(-G9-X)=; X is C1-6 alkyl (where C1-6 can be optionally substituted with a group selected from a halogen atom, hydroxy, cyano and -NR56R57), aryl, heterocycle (where the heterocycle denotes a 5-9-member saturated or unsaturated cyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulphur atoms, and can be a monocycle or condensed ring, and can be optionally substituted with a halogen atom, C1-6 alkyl; C1-6 alkoxy, R33R34NCS-, R3R4NCO-); G9 denotes a single bond, an oxygen atom, a sulphur atom, ring G6 denotes a divalent aryl group or divalent pyridyl group (where the divalent pyridyl group can be optionally substituted with a halogen atom); A is a group of formula (2) given below, or a group of formula (3) given below. Chemical formula 2

, chemical formula 3 , G4 is an oxygen atom or sulphur atom; G5 is an oxygen atom or sulphur atom; G7 is an oxygen atom, -CR42R43-, -CONR44-, -NR44CO, -NR45-, CR42R43NR45-, -S-, -NR44S(=O)2-; R1 is a hydrogen atom, a halogen atom, cyano, C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a halogen atom), carbamoyl or C2-7 alkynyl (where C2-7 alkynyl can be optionally substituted with C1-4 acyl); when G2 or G3 denotes -CR1=, then G8 is -C(-G9-X)=, and X is R3R4NCO-, R33R34NCS-; when G8 is -CR1=, then G3 denotes -C(-G9-X)=, and X is R3R4NCO, or R33R34NCS-; when G1 or G8 denotes -CR4 then G2 is -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; or when G2 is -CR1=, then G1 denotes -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; R1 can form a single bond or -CH2- with R4 or R34; R2 denotes hydroxy or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from a halogen atom, hydroxy, C1-6 alkoxy, formyl and -CO2R50); R3, R4, R9 and R10 each independently denotes a hydrogen atom, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, a halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R6 and R7 each independently denotes a hydrogen atom, C1-6 alkoxy, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R33 and R34 each independently denotes a hydrogen atom, C1-6 alkyl, the combination of R3 and R4 together with a nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom or C1-6 alkyl; the combination of R6 and R7 together with the nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom, C1-6 alkyl or an oxo group; R45 is a hydrogen atom, R13 and R14 each independently denotes a hydrogen atom, C1-6 alkyl or COR32; R56 and R57 each independently denotes a hydrogen atom or C1-6 alkyl, and R5, R8, R28, R29, R32, R42, R43, R44, and R50 each independently denotes a hydrogen atom or C1-6 alkyl. The invention also relates to a pharmaceutical composition, as well as to a medicinal agent for treating cell proliferative disorder.

EFFECT: obtaining novel biologically active compounds having inhibitory effect on cell proliferation.

15 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound selected from N-((1S)-1-{4-[2-fluoro-1-(fluoromethyl)ethoxy]phenyl}ethyl)-2-(7-nitro-1H-benzimidazol-1-yl)acetamide, 2-(7-nitro-1H-benzimidazol-1-yl)-N-{1-[6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl]ethyl}acetamide, N-[1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamde and N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide. The invention also relates to use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds which are useful in treating VR1 mediated disorders or acute and chronic algesic disorders are obtained.

6 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of general formula I and pharmaceutically acceptable salts thereof, where R1 is selected from a group comprising aryl and alkyl, optionally substituted hydroxy; R2 is selected from a group comprising hydrogen and alkyl; R3 is selected from a group comprising hydrogen and -X-A, where X is selected from a group comprising -C(O)- and -S(O)2-; and A is selected from a group comprising hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle and optionally substituted cycloalkyl, where the optionally substituted groups are substituted with 1-2 substitutes selected from a group comprising alkyl, substituted alkyl, alkoxy, substituted amine which is a -NRR group, substituted aryloxy, heteroaryl, heterocycle, halogen, hydroxy and -S(O)2-R9, where R9 is an alkyl; or R1 and R3 together with a carbon atom bonded to R1 and a nitrogen atom bonded to R3 form a heterocyclic or substituted heterocyclic group; R4 is selected from a group comprising hydrogen, linear alkyl, -alkylene-aminoacyl-, -alkylene-hydroxy-, -[alkylene]p-nitrogen-containing heterocycle, -[alkylene]p-nitrogen-containing substituted heterocycle, -[alkylene]p-nitrogen-containing heteroaryl, -[alkylene]p-nitrogen-containing substituted heteroaryl and -[alkylene]p-NR10R11, where p equals 0 or 1, the alkylene contains 1-5 carbon atoms and can have 1 or 2 substitutes selected from a group comprising amine, hydroxy and halogen, aminoacyl relates to a group -C(O)NRR, where each R is independently selected from a group comprising hydrogen and alkyl, R10 and R11 are independently selected from a group comprising hydrogen, alkyl, substituted alkyl, -S(O)2-alkyl, substituted aryl, substituted heteroaryl, cycloalkyl, or when R10 is hydrogen, R11 is hydroxy, alkoxy or substituted alkoxy; or when R1 and R3 together with carbon and nitrogen atoms respectively bonded to them do not form a heterocyclic or a substituted heterocyclic group, R3 and R4 together with a nitrogen atom to which they are bonded form a spiro-condensed heterocyclic group; R5 is selected from a group comprising L-A1, where L is selected from a group comprising C1-C5alkylene, where the alkylene is defined above; and A1 is selected from a group comprising aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle; and one of R6 or R7 is selected from a group comprising aryl and heteroaryl, each of which can optionally be substituted with -(R8)m, where m equals a whole number from 1 to 2, and the other of R6 or R7 is selected from a group comprising hydrogen, halogen and alkyl; or R6 as well as R7 denotes hydrogen; R8 is selected from a group comprising cyano, alkyl, -CF3, alkoxy, halogen, where alkyl, aryl, aryloxy, cycloalkyl, heterocycle, heteraryl and substituted alkyl, aryl, aryloxy, cycloalkyl, heterocycle and heteroaryl are described in claim 1. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula I, a method of inhibiting KSP and use of the composition to prepare a medicinal agent.

EFFECT: novel imidazole derivatives are useful as kinesin spindle protein inhibitors for treating cancer.

25 cl, 27 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 5-nitrofuran derivatives of formula I: where R=piperidino, pyrrolidineo, diethylamino, morpholino.

EFFECT: presented preparation of new biologically active compounds which exhibit antimicrobial activity.

1 cl, 4 ex, 2 tbl

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

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