Derivatives of (2-aminophenyl)-amide of arylenecarboxilic acid as pharmaceutical preparations

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula I , in which stands for thiophendiyl, phenylene or pyridindiyl; R1 represents alkyl, alkenyl, alkinyl, which optionally contain one or several substitutes, selected from group including halogen, cyano-, nitro- amino group, -NH-alkyl and N(alkyl)2; or -CH2-(O-CH2-CH2-)mO-alkyl; -(CH2)n-O-alkyl; -(CH2)n-C(O)-NH-alkyl; -(CH2)n-NH-C(O)-alkyl; -(CH2)n-C(O)alkyl; -(CH2)n-C(O)-O-alkyl; or -(CH2)n-O-C(O)-alkyl; or group -NR3R4, in which R3 and R4 independently represent hydrogen; alkyl, alkenyl or alkinyl, which optionally contain one or several substitutes, selected from group including halogen, cyano-, nitro- amino group, -NH-alkyl and N(alkyl) 2; or -CH2-(O-CH2-CH2-)mO-alkyl; -(CH2)n-(O)-alkyl; -(CH2)n-C(O)-NH-alkyl; -(CH2)n-NH-C(O)-alkyl; -(CH2)n-C(O)alkyl; -(CH2)n-C(O)-O-alkyl; or -(CH2)n-O-C(O)-alkyl; n is 1-6; m is 1-4; and to its pharmaceutically acceptable salts. Invention also relates to medication.

EFFECT: obtaining novel biologically active compounds, intended for inhibition tumor cell proliferation.

25 cl, 6 ex

 

The present invention relates to new derivatives of (2-AMINOPHENYL)-amide arylenecarborane acid, to the way they are received, containing their medicines and to the use of these compounds as pharmaceutically active substances.

In EP-A described monosilane derivatives of o-phenylenediamine as inducers of cell differentiation. This type of connection is the object of the EP A. These compounds are described in these applications almost exclusively as a derivative of o-phenylene, monoarylamino derivatives of benzoic acid. However, there remains a need for compounds with improved properties such as improved portability, lower toxicity and fewer side effects.

Monosilane o-phenylendiamine known in the art as precursors used in obtaining the appropriate benzimidazole, such methods of synthesis are described, for example, in DE A2062265; FR2167954; Rastogi, R., and Sharma, S., Indian J.Chem., Sect. B, 21 B (5) (1982) 485-487; Moll, R., et al., Z.Chem. 17 (1977) 133-134, and Hassan, H., et al., Indian J.Chem. 39B (2000) 764-768.

Proposed in the present invention derivatives are new compounds of General formula

where And denotes theoffender, phenylene or pyridinyl;

R1denotes alkyl, alkenyl, quinil that optional is entrusted are substituted, or

-CH2-(O-CH2-CH2-)mO-alkyl;

-(CH2)n-O-alkyl;

-(CH2)n-C(O)-NH-alkyl;

-(CH2)n-NH-C(O)-alkyl;

-(CH2)n-C(O)alkyl;

-(CH2)n-C(O)-O-alkyl or

-(CH2)n-O-C(O)-alkyl; or

the group-NR3R4in which R3and R4independently represent

hydrogen;

alkyl, alkenyl or quinil that are not necessarily substituted or

-CH2-(O-CH2-CH2-)mO-alkyl;

-(CH2)n-(O)-alkyl;

-(CH2)n-C(O)-NH-alkyl;

-(CH2)n-N-C(O)-alkyl;

-(CH2)n-C(O)alkyl;

-(CH2)n-C(O)-O-alkyl or

-(CH2)n-O-C(O)-alkyl;

n is 1-6;

m is 1-4,

and their pharmaceutically acceptable salts.

Connections proposed in the present invention are inhibitors discontinuties (HDAC), and therefore demonstrate antiproliferative and inducing differentiation activity, resulting in inhibition of proliferation of tumor cells, induction of apoptosis and suppression of disease.

Transcriptional regulation is a major event in the differentiation, proliferation and apoptosis of cells. Transcriptional activation of genes determines the assignment of cells and for this reason, strictly regulates transcription of the I by many factors. One of the mechanisms of its regulation, which is an integral part of the process is the change in the tertiary structure of DNA, which affects transcription by modulating the accessibility of transcription factors to their target segments of DNA. The integrity of the nucleosome is regulated by the acetylation status of core histones. In hypoacetylation state nucleosomes are tightly Packed and therefore unavailable for transcription. On the other hand, the nucleosome relax in the acetylation of core histones, resulting becomes available for transcription. The acetylation status of histones depends on the balance of activity distancedistance (GAT) and discontinuties (HDAC). Recently, it was shown that HDAC inhibitors inhibits the growth and apoptosis of some types of cancer cells, including colorectal cancer, T-cell lymphoma and erythroleukemia cells. Considering the fact that apoptosis is a critical factor in the progression of cancer, HDAC inhibitors are promising tools for the treatment of cancer, as effective inducers of apoptosis (Koyama, Y., et al., Blood 96 (2000) 1490-1495).

Another disadvantage of many anticancer drugs is the lack of selectivity. They cannot effectively differentiate between tumor cells and normal cells, and therefore, side effects, manifested for normalnyh cells, limit their use in therapy. Up to the present time no satisfactory drugs and are therefore required is an anticancer drug with reduced toxicity and better tolerability and significant therapeutic effect. Connections proposed in the present invention unexpectedly discovered low toxicity with concurrent high antiproliferative and differentiating cell activity.

Objects of the present invention are the compounds of formula I, pharmaceutically acceptable salts and their enantiomeric forms, obtaining the above compounds containing their drugs and their manufacture, and application of the above mentioned compounds for the treatment or prevention of diseases, particularly diseases and disorders listed above, or in the preparation of the drugs.

When used in the present invention the term "alkyl" means a hydrocarbon group having a linear or branched chain containing from 1 to 14, preferably from 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, as well as their isomers. Alkyl groups optionally contain one or more Vice is her selected from the group comprising halogen, hydroxy-, cyano-, nitro-, amino group, -NH-alkyl and N(alkyl)2. Preferably, if an alkyl group one or more times substituted by fluorine or once substituted by a group-NH-alkyl or-N(alkyl)2. Examples of the fluorinated alkyl groups are performer, 2,2,2-triptorelin, perforated. Alkyl groups in the substituents-N(alkyl)2are the same or different alkyl groups and have the above defined meanings. Examples of the substituents-NH-alkyl and-N(alkyl)2are methylamino, ethylamino, propylamino, isopropylamino-, 1 butylamino-, 2-butylamino-, tert-butylamino-, dimethylamino-, diethylamino, dipropylamino, diisopropylamino-, di-1-butylamino-, di-2-butylamino-, di-tert-butylamino, ethylmethylamino, ethylpropylamine.

The term "alkenyl" means unsaturated alkyl chain as defined above, containing 1 or 2 isolated double bonds, preferably 1 double bond. Examples are 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl and 1-hexenyl.

The term "quinil" means unsaturated alkyl chain as defined above, containing a triple bond. Examples are 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 1-pentenyl and 1-hexenyl.

The term "optionally substituted" when used in this izobreteniya combination with alkenyl or quinil means the substitution of one or more hydrogen atoms in any of the above groups with halogen, hydroxy-, cyano-, nitro-, amino-, carbonyl group, -NH-alkyl or-N(alkyl)2.

The term "halogen" means fluorine, chlorine, bromine or iodine.

Option execute the present invention are the compounds of formula I, in which

And indicates theoffender, phenylene or pyridinyl;

R1refers to the group-NR3R4in which R3denotes hydrogen and R4is the same as defined above,

and their pharmaceutically acceptable salts.

Another variant of implementation of the present invention are the compounds of formula I, in which

And indicates theoffender, phenylene or pyridinyl;

R1denotes alkyl, alkenyl, quinil that are not necessarily replaced, or

-CH2-(O-CH2-CH2-)mO-alkyl;

-(CH2)n-O-alkyl;

-(CH2)n-C(O)-NH-alkyl;

-(CH2)n-NH-C(O)-alkyl;

-(CH2)n-C(O)alkyl;

-(CH2)n-C(O)-O-alkyl or

-(CH2)n-O-C(O)-alkyl;

n is 1-6;

m is 1-4,

and their pharmaceutically acceptable salts.

Another alternative implementation of the present invention are the compounds of formula I, in which

And denotes a thiophene-2,5-diyl;

R1means of alkenyl;

-(CH2)n-O-alkyl;

-(CH2)n-NH-C(O)-alkyl, or

-(CH2)n-C(O)alkyl;

n is avno 1-6,

and their pharmaceutically acceptable salts.

Such compounds are, for example:

(2-AMINOPHENYL)-amide 5-[(2-ethoxyacetylene)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-(Penta-4-emailmyname)-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(2-acetylaminofluorene)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-({2-[2-(2-methoxyethoxy)-ethoxy]-acetylamino}-methyl)-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(4-oxopentanoate)-methyl]-thiophene-2-carboxylic acid.

Another alternative implementation of the present invention are the compounds of formula I, in which

And denotes a thiophene-2,5-diyl;

R1refers to the group-NR3R4in which

R3denotes hydrogen;

R4means of alkenyl;

quinil;

-(CH2)n-(O)-alkyl;

-(CH2)n-NH-C(O)-alkyl, or

-(CH2)n-C(O)-O-alkyl;

n is 1-6,

and their pharmaceutically acceptable salts.

Such compounds are, for example:

(2-AMINOPHENYL)-amide 5-[3-(3-ethoxypropan)-freedomites]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(3-prop-2-injured)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[3-(2-acetylamino)-freedomites]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[3-(2-methoxyethyl)-freedomites]-thiophene-2-carbon is Oh acid,

(2-AMINOPHENYL)-amide 5-[(3-allylurea)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[3-(3-butoxypropyl)-freedomites]-thiophene-2-carboxylic acid,

ethyl ester of 4-{3-[5-(2-aminophenylamino)-thiophene-2-ylmethyl]-ureido}-butyric acid.

Another alternative implementation of the present invention are the compounds of formula I, in which

And denotes 1,4-phenylene;

R1means of alkenyl;

-CH2-(O-CH2-CH2-)mO-CH3;

-(CH2)n-O-alkyl or

-(CH2)n-NH-C(O)-alkyl;

n is 1-6;

m is 1-4,

and their pharmaceutically acceptable salts.

Such compounds are, for example:

N-(2-AMINOPHENYL)-4-[(2-ethoxyacetylene)-methyl]-benzamide,

N-(2-AMINOPHENYL)-4-(Penta-4-emailmyname)-benzamid,

N-(2-AMINOPHENYL)-4-({2-[2-(2-methoxyethoxy)-ethoxy]-acetylamino}-methyl)-benzamide,

4-[(2-acetylaminofluorene)-methyl]-N-(2-AMINOPHENYL)-benzamide.

Another alternative implementation of the present invention are the compounds of formula I, in which

And denotes 1,4-phenylene;

R1refers to the group-NR3R4in which

R3denotes hydrogen;

R4means of alkenyl;

quinil;

-(CH2)n-(O)-alkyl;

-(CH2)n-NH-C(O)-alkyl, or

-(CH2)n-C(O)-O-alkyl;

n is 1-6,

and their farm is citiesi acceptable salt.

Such compounds are, for example:

4-[3-(2-acetylamino)-freedomites]-N-(2-AMINOPHENYL)-benzamide,

N-(2-AMINOPHENYL)-4-[3-(2-methoxyethyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[3-(3-butoxypropyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[3-(3-ethoxypropan)-freedomites]-benzamid,

4-[(3-allylurea)-methyl]-N-(2-AMINOPHENYL)-benzamide,

N-(2-AMINOPHENYL)-4-[3-(3-isopropoxyphenyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[(3-prop-2-injured)-methyl]-benzamide,

methyl ester of 4-{3-[4-(2-aminophenylamino)-benzyl]-ureido}-butyric acid.

Another alternative implementation of the present invention are the compounds of formula I, in which

And denotes pyridine-2,5-diyl;

R1refers to the group-NR3R4in which

R3denotes hydrogen and

R4represents -(CH2)n-(O)-alkyl;

n is 1-6,

and their pharmaceutically acceptable salts.

This connection is, for example, N-(2-AMINOPHENYL)-6-[3-(3-butoxypropyl)-freedomites]-nicotinamide.

Another alternative implementation of the present invention are the compounds of formula I, in which

And denotes pyridine-2,5-diyl;

R1means of alkenyl or

-(CH2)n-O-alkyl;

n is 1-6,

and their pharmaceutically acceptable salts.

Such compounds are, for example:

N-(2-AMINOPHENYL)-6-[(methoxyethylamine)-methyl]-nicotinamide,

N-(2-AMINOPHENYL)-6-(Penta-4-emailmyname)-nicotinamide.

Another alternative implementation of the present invention are the compounds of formula I, in which

And denotes a thiophene-2,5-diyl;

pyridine-2,5-diyl or

1,4-phenylene;

R1refers to the group-NR3R4in which R3denotes hydrogen;

R4denotes alkyl, which is unsubstituted or once or several times substituted with

halogen;

-NH-alkyl or

-N(alkyl)2,

and their pharmaceutically acceptable salts.

Such compounds are, for example:

(2-AMINOPHENYL)-amide 5-[3-(2-dimethylaminoethyl)-freedomites]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[3-(2-diisopropylaminoethyl)-freedomites]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[3-(3-diethylaminopropyl)-freedomites]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[3-(3-dimethylamino-2,2-dimethylpropyl)-freedomites]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[3-(1-etylhexyl)-freedomites]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-(3-second-butylenediamine)-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[3-(2-methylbutyl)-freedomites]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-(3-isobutylether)-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[3-(3-dibutylamino)-freedomites]-thio the ene-2-carboxylic acid,

N-(2-AMINOPHENYL)-4-[(3-pentyurina)-methyl]-benzamide,

N-(2-AMINOPHENYL)-4-[3-(3-diethylaminopropyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[3-(3-dimethylamino-2,2-dimethylpropyl)-freedomites] -benzamid,

N-(2-AMINOPHENYL)-4-[3-(1-etylhexyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[3-(3-dibutylamino)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[3-(2-dimethylaminoethyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[3-(2-diisopropylaminoethyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[3-(2-methylbutyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-(3-isobutylether)-benzamid,

N-(2-AMINOPHENYL)-4-(3-second-butylenediamine)-benzamid,

N-(2-AMINOPHENYL)-6-[(3-pentyurina)-methyl]-nicotinamide,

N-(2-AMINOPHENYL)-6-[3-(1-etylhexyl)-freedomites]-nicotinamide.

Another alternative implementation of the present invention are the compounds of formula I, in which

And denotes a thiophene-2,5-diyl;

pyridine-2,5-diyl or

1,4-phenylene;

R1denotes alkyl, in which

the alkyl group is unsubstituted or once or several times substituted with

halogen;

-NH-alkyl or

-N(alkyl)2,

and their pharmaceutically acceptable salts.

Such compounds are, for example:

(2-AMINOPHENYL)-amide 5-[(4-methylpentylamino)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-(propionamide the l)-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-(bucillamine)-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-(isobutylamino)-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(2,2,3,3,3-pentafluoropropionate)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(2-ethylbutylamine)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(2,2,2-triptoreline)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(4-dimethylaminomethylene)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(3-methylbutylamine)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(2-dipropylenetriamine)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(2-dimethylaminoacetyl)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(3-methylpentylamino)-methyl]-thiophene-2-carboxylic acid,

N-(2-AMINOPHENYL)-4-(propenolatomethyl)-benzamid,

N-(2-AMINOPHENYL)-4-(isobutylamino)-benzamid,

N-(2-AMINOPHENYL)-4-[(4-methylpentylamino)-methyl]-benzamide,

N-(2-AMINOPHENYL)-4-[(2-ethylbutylamine)-methyl]-benzamide,

N-(2-AMINOPHENYL)-4-(bucillamine)-benzamid,

N-(2-AMINOPHENYL)-6-[(4-methylpentylamino)-methyl]-nicotinamide,

N-(2-AMINOPHENYL)-6-[(3-methylpentylamino)-methyl]-nicotinamide.

Another alternative implementation of the present invention is to connect the texts of the formula I, in which

And indicates theoffender, phenylene or pyridinyl;

R1refers to the group-NR3R4in which R3and R4independently represent alkyl, alkenyl or quinil that are not necessarily replaced,

or

-CH2-(O-CH2-CH2-)mO-flkr;

-(CH2)n-(O)-alkyl;

-(CH2)n-C(O)-NH-alkyl;

-(CH2)n-NH-C(O)-alkyl;

-(CH2)n-C(O)alkyl;

-(CH2)n-C(O)-O-alkyl or

-(CH2)n-O-C(O)-alkyl;

n is 1-6;

m is 1-4,

and their pharmaceutically acceptable salts.

Another alternative implementation of the present invention are the compounds of formula I, in which

And denotes 1,4-phenylene;

R1refers to the group-NR3R4in which R3and R4independently represent alkyl,

and their pharmaceutically acceptable salts.

This connection is, for example, N-(2-AMINOPHENYL)-4-(3-butyl-3-methyluridine)-benzamide.

Another alternative implementation of the present invention are the compounds of formula I-A

where And denotes a thiophene-2,5-diyl;

pyridine-2,5-diyl or

1,4-phenylene;

R5represents -(CH2)k-cyclopropyl;

-(CH2)k-cyclopentyl;

-(CH2)k-cyclohexyl;

-(CH2) k-cyclopent-2-enyl;

-(CH2)k-(5-oxopyrrolidin-2-yl);

-(CH2)k-(2-oxopyrrolidin-1-yl);

-NH-(CH2)k-cyclopropyl;

-NH-(CH2)k-cyclopentyl;

-NH-(CH2)k-cyclohexyl;

-NH-(CH2)k-cyclopent-2-enyl;

-NH-(CH2)k-(5-oxopyrrolidin-2-yl), or

-NH-(CH2)k-(2-oxopyrrolidin-1-yl);

k is 0-6,

and their pharmaceutically acceptable salts.

Such compounds are, for example:

(2-AMINOPHENYL)-amide 5-[(cyclopentanecarbonyl)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(2-cyclopent-2-Emilceramica)-methyl]-thiophene-2-carboxylic acid,

[5-(2-aminophenylamino)-thiophene-2-ylmethyl]-amide 5-oxopyrrolidin-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(3-cyclopentylpropionyl)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(3-cyclohexylpropionate)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(2-cyclopentylacetyl)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(2-cyclopropylacetylene)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-{3-[3-(2-oxopyrrolidin-1-yl)-propyl]-freedomites}-thiophene-2-carboxylic acid,

N-(2-AMINOPHENYL)-4-[(cyclopentanecarbonyl)-methyl]-benzamide,

N-(2-AMINOPHENYL)-4-[(2-cyclopent-2-Emilceramica)-methyl]benzamide,

N-(2-AMINOPHENYL)-4-[(3-cyclopentylpropionyl)-methyl]-benzamide,

N-(2-AMINOPHENYL)-4-{3-[3-(2-oxopyrrolidin-1-yl)-propyl]-freedomites}-benzamide,

N-(2-AMINOPHENYL)-4-(3-cyclopropylmethyl)-benzamid,

N-(2-AMINOPHENYL)-6-[(3-cyclopentylpropionyl)-methyl]-nicotinamide,

N-(2-AMINOPHENYL)-6-{3-[3-(2-oxopyrrolidin-1-yl)-propyl]-freedomites}-nicotinamide,

N-(2-AMINOPHENYL)-6-[(2-cyclopent-2-Emilceramica)-methyl]-nicotinamide,

N-(2-AMINOPHENYL)-6-[(2-cyclopentylacetyl)-methyl]-nicotinamide,

N-(2-AMINOPHENYL)-6-[(3-cyclohexylpropionate)-methyl]-nicotinamide.

Another variant of implementation of the present invention is a method of obtaining the proposed in the present invention (2-AMINOPHENYL)-amide derivative (acylaminoalkyl)-arylenecarborane acid of the formula I or their pharmaceutically acceptable salts

(a) the interaction of the compounds of formula II

in which a has the above specified values, and Y represents a suitable protective group,

with a compound of General formula III

in which R1denotes alkyl, alkenyl, quinil that are not necessarily replaced, or

-CH2-(O-CH2-CH2-)mO-alkyl;

-(CH2)n-O-alkyl;

-(CH2)n-C(O)-NH-alkyl;

-(CH2)n-NH-is(O)-alkyl;

-(CH2)n-C(O)alkyl;

-(CH2)n-C(O)-O-alkyl or

-(CH2)n-O-C(O)-alkyl,

or the interaction of the compounds of the formula II with the compound of the formula X

in which R3and R4independently represent

hydrogen;

alkyl, alkenyl, quinil that are not necessarily replaced, or

-CH2-(O-CH2-CH2-)mO-alkyl;

-(CH2)n-O-alkyl;

-(CH2)n-C(O)-NH-alkyl;

-(CH2)n-NH-C(O)-alkyl;

-(CH2)n-C(O)alkyl;

-(CH2)n-C(O)-O-alkyl or

-(CH2)n-O-C(O)-alkyl;

n is 1-6;

m is 1-4,

(b) subsequent removal of the protective group and

(C) if necessary, a transformation product in the pharmaceutically acceptable salt by adding a suitable acid or base.

The necessary starting materials for the above method can be obtained by standard techniques of organic chemistry. The receipt of such starting compounds are described in the accompanying non-limiting examples. Alternatively, the necessary starting substances can be obtained by methods similar to those shown, which are known to the chemist-organic chemistry General training.

The protective group for the amino group at the stage of (a) ways and methods of their removal (stage (b) is of the manual) is known from the chemistry of peptides. Examples are benzyloxycarbonyl (split off by hydrogenation or by using Hydrobromic acid in acetic acid), tert-butoxycarbonyl (dissociation of strong acids, such as triperoxonane acid, neat or in dichloromethane or hydrochloric acid (HCl) in dioxane), 9-fluorenylmethoxycarbonyl (removal of secondary amines, such as piperidine).

Obtaining compounds of General formula I will be described below in detail and in accordance with the nature of the group, and when R1means or doesn't mean the group NR3R4defined above.

The reaction of compounds of the formula II with compounds of formula III in which R1doesn't mean the group-NR3R4that usually involves a three-stage dorectory procedure. The first stage is activated carboxylate of formula III. This reaction is carried out in an inert solvent or diluent, such as dichloromethane, dioxane or tetrahydrofuran (THF), and in the presence of an activating reagent. Suitable reactive derivative of the acid is, for example, allalone, such as acylchlorides, resulting from the reaction of the acid and the acid chloride inorganic acid, such as thionyl chloride or dichlorohydrin oxalic acid; a mixed anhydride, for example an anhydride, popucauses is the reaction of the acid and chloroformiate, such as isobutylparaben; an active ester, for example an ester obtained by the reaction of the acid and a phenol such as pentafluorophenol; active ester obtained by the reaction of acid and N-hydroxybenzotriazole; acylated, such as azide, resulting from the reaction of the acid and azide such as diphenylphosphoryl; achilleid, such as cyanide, resulting from the reaction of an acid and a cyanide such as diethylphosphoramidite; or the reaction product of the acid and a carbodiimide, such as N-3-dimethylaminopropyl-N-ethylcarbodiimide or dicyclohexylcarbodiimide, or the reaction product of the acid with N,N'-carbodiimide; or the reaction product of acid and bronevich salts, such as O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylpropylenediamine; or the reaction product of acid and reagents based on phosphorus, for example bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride.

In the second stage, the compound of formula II is added to the solution. These techniques are well known to specialists in this field of technology. In principle, also applicable to all methods of synthesis of the amides used in the chemistry of peptides are described, for example, in Houben-Weyl, "Methods der organischen Chemie", Vol.XV/1 and XV/2.

If Y denotes tert-butoxycarbonyl, it can completely break down in the third stage by adding triperoxonane acid to the reaction mixture with getting connected to the I formula I. Alternatively, amide emit after the second stage and cleavage of the protective group Y is performed on a separate stage when the conditions of the reactions described above.

Obtaining the compounds of formula II, where And denotes phenyl, and Y denotes a tert-butoxycarbonyl (tert-butyl ether [2-(4-aminomethylbenzoic)-phenyl]-carbamino acid) described in the literature, for example in EP 0847992.

The preferred method of obtaining compounds of formula II in which And indicates 2,5-thiophene, involves removal of the allyl groups of the compounds IV

Cleavage of allyl groups can be performed, for example, using catalyzed by palladium reaction in the presence of Sultanovich acids, carboxylic acids, research, dimedone or N,N'-dimethylbarbituric acid as scavengers allyl.

The compounds of formula IV can be obtained by the reaction of compounds V

with the compound of the formula VI

in which Y represents a suitable protective group as defined above.

This reaction usually involves a two-stage dorectory procedure. The first stage is activated carboxylate compound V. This reaction is carried out in an inert solvent or diluent, such as dichloromethane, dioxane or THF, in the presence of antiviruses the reagent. Suitable reactive derivative of the acid is, for example, allalone, such as acylchlorides, resulting from the reaction of the acid and the acid chloride inorganic acid, such as thionyl chloride or dichlorohydrin oxalic acid; a mixed anhydride, for example an anhydride obtained by the reaction of the acid and chloroformiate, such as isobutylparaben; an active ester, for example an ester obtained by the reaction of the acid and a phenol such as pentafluorophenol; active ester obtained by the reaction of acid and N-hydroxybenzotriazole; acylated, such as azide, resulting from the reaction of the acid and azide such as diphenylphosphoryl; achilleid, such as cyanide, resulting in the reaction of the acid and a cyanide such as diethylphosphoramidite or the reaction product of the acid and a carbodiimide, such as N-3-dimethylaminopropyl-N-ethylcarbodiimide or dicyclohexylcarbodiimide, or the reaction product of the acid with N,N'-carbodiimide; or the reaction product of acid and bronevich salts, such as O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylethylenediamine, or the reaction product of acid and reagents based on phosphorus, for example bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride.

In the second stage, the compound of formula VI is added to the solution to obtain compound IV. These techniques are well known specialist is in this field of technology. In principle, also applicable to all methods of synthesis of the amides used in the chemistry of peptides are described, for example, in Houben-Weyl, "Methods der organischen Chemie", Vol.XV/1 and XV/2.

The compounds of formula V is obtained by hydrolysis of compounds of formula VII

in which R2denotes alkyl or optionally substituted benzyl.

When using in this case the alkyl has the above value. Examples R2are methyl, ethyl, tert-butyl, benzyl and p-methoxybenzyl. The conditions under which conduct the hydrolysis depend on the nature of the group R2. If R2denotes a methyl or ethyl group, the reaction is carried out in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, in an inert solvent or diluent, for example methanol, ethanol, dioxane, THF, water. If R2denotes tert-boutelou group, the reaction is carried out in the presence of acid, for example hydrochloric acid in an inert solvent, such as diethyl ether or dioxane, or triperoxonane acid in dichloromethane. If R2denotes a benzyl group, the reaction is carried out by hydrogenolysis in the presence as catalyst of a noble metal such as palladium or platinum, on a suitable carrier such as carbon.

Ester is 5-valiuminformation-2-carboxylic acid described in the literature, for example in the work Millot, N., et al., Synthesis 7 (2000) 941-948.

One preferred method of preparing compounds of the formula II, in which And indicates 2,5-pyridine includes the restoration of ceanography compounds VIII

The restoration of the nitrile can be performed, for example, hydrogen in the presence of a catalyst, for example palladium on coal or Raney Nickel, in a suitable solvent, such as THF, methanol, ethanol or dimethylformamide (DMF), optionally in the presence of, for example, HCl, triethylamine, ammonia or hydroxylamine.

One preferred method of preparing compounds of formula VIII involves the reaction of compound IX

with the compound of the formula VI

in which Y represents a suitable protective group as defined above.

The reaction can be conducted under conditions such as described for connection IV. 6-Canonicaldata acid described in the literature, for example in the work Vorbrueggen, H., and Krolikiewicz, K., Synthesis 4 (1983) 316-319.

Ureidomelamine General formula I, in which R1refers to the group-NR3R4defined above in the present invention, can be obtained by any method for which it is known that it is applicable for production of chemically related compounds. Such techniques proillyustriroval the s using the following typical examples. The necessary starting substances can be obtained by standard techniques of organic chemistry. The receipt of such starting compounds are described in the accompanying non-limiting examples. Alternatively, the necessary starting substances can be obtained by methods similar to those shown, which are known to the chemist-organic chemistry General training.

One preferred method of obtaining the above ureidopenicillin derivatives of compounds of formula I involves the reaction of compounds of formula II in which Y preferably denotes a tert-butoxycarbonyl, with an amine of the formula X

in which R3and R4have the values defined above.

This reaction usually involves a three-stage dorectory procedure. In the first stage, the compound X is introduced into the reaction carbodiimide in a suitable solvent, for example THF. In the second stage, the compound II is added to a reactive intermediate product to obtain the corresponding ureidopropionic. Finally, Y otscheplaut by adding triperoxonane acid to the reaction mixture and receive weidemeyerii derivatives of formula I.

Alternatively, wreid emit after the second stage and cleavage of the protective group Y is performed on a separate stage when the conditions of the reactions described above.

If Y convoy is achet tert-butoxycarbonyl, it can completely break down in the third stage by adding triperoxonane acid to the reaction mixture to obtain specified derivatives of the formula I.

Compounds of General formula I can contain one or more chiral centers and therefore may exist in racemic or optically active form. By known methods of the racemates can be separated into the enantiomers. For example, diastereoisomeric salts which can be separated by crystallization, obtained from racemic mixtures by reaction with an optically active acid, such as, for example, D - or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid. Alternatively, the separation of enantiomers can be accomplished by using chromatography on chiral phases for high performance liquid chromatography (HPLC), which are commercially available.

Connections proposed in the present invention can exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" means ordinary salts obtained by addition of acid, or salts obtained by addition of a base, which retain the biological effectiveness and properties of the compounds of formula I and are obtained from suitable non-toxic organic or inorganic acids or organic and the inorganic bases. Salt obtained by adding acids include, for example, those derived from inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those that are derived from organic acids, such as p-toluensulfonate acid, salicylic acid, methanesulfonate acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. Salts obtained by adding acids include those that are derived from the hydroxides of ammonium, potassium, sodium and Quaternary ammonium compounds, such as, for example, Tetramethylammonium. Chemical transformation of pharmaceutical compounds in salt method is well known to chemists pharmacists, to provide improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is described, for example, in the work of Ansel, H., et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed., 1995, pp.196 and 1456-1457.

Connections proposed in the present invention, and their pharmaceutically acceptable salts can be used as medicines, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example, in the de tablets, tablets, coated pills, capsules of hard and soft gelatin, solutions, emulsions or suspensions. However, the introduction can also be carried out rectally, for example in the form of suppositories, or parenterally, e.g. in the form of solutions for injection.

The abovementioned pharmaceutical preparations can be obtained by combining the compounds proposed in the present invention with pharmaceutically inert, inorganic or organic carriers. As such carriers for tablets, coated tablets, pills and capsules of hard gelatin can be used lactose, corn starch and its derivatives, talc, stearic acid and its salts, etc. For soft gelatin capsules of suitable carriers are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like, However, depending on the nature of the active substance in the case of soft gelatin capsules from the media are not usually required. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils, etc. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid and liquid polyols and the like

The pharmaceutical preparations can, moreover, contain preservatives, stabilizers, wetting agents, emulsifying agent is, sweeteners, colorants, flavoring agents, salts for modifying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically useful substances.

Medicinal products containing as active ingredients one or more compounds proposed in the present invention, together with pharmaceutically acceptable excipients are also the object of the present invention.

Another object of the present invention is the use of such drugs to treat cancer characterized by the inhibition of proliferation of tumor cells due to the induction of acetylation of histone in the indicated tumor cell.

Another object of the present invention is a method of inhibiting the proliferation of tumor cells, characterized by the induction of acetylation of histone in the indicated tumor cell by introducing into the indicated tumor cell an effective amount of one or more compounds proposed in the present invention.

The activity of the compounds proposed in the present invention, as HDAC inhibitors, demonstrated through analysis of acetylation cells. Histone acetylation is observed in cells RS. Strong acetylation inhibition means is isonicotinate connections. To assess the cytotoxicity of the compounds is carried out simultaneously monitoring the viability of the cells.

Cells RC, cell carcinoma of the prostate man, are sown in 1800 cells as well 384-well plate to micrometrology in RPMI 1640 (including 5% FCS (fetal calf serum), 2 mm glutamine and penicillin/streptomycin).

After 48 h at 37°With added pre-dissolved compounds at a final concentration of 1 μm. Connection pre-diluted in dimethyl sulfoxide at a ratio of 1:10 (DMSO) or in the environment, so that the final concentration of DMSO was 0.5%.

After incubation for 24 h, cell viability is determined by adding the reagent to the WST1 cell proliferation. After another 60 min to measure the optical density (OD) at 450 nm compared to 690 nm).

After analysis using WST1 prepare the layer of cells for carrying out enzyme-linked immunosorbent assay. Wednesday sucked off and the cells fixed in ethanol at -20°C for 60 minutes After washing the mixture SFR/Tween add blocking solution (STR (phosphate buffered saline)/ 5% FCS/Tween) and the layer of cells re-washed. Antibodies against histone H3 or H4 (antibodies against acetylated histone (polyclonal rabbit IgG), Upstate Biotechnologie) was added at a dilution of 1:200 for 60 minpro 37° C. as the second antibody used goat antibodies to rabbit IgG conjugate(H+L) human IgG adsorbed on the horseradish peroxidase (Dako) (dilution 1:2000). Cells are washed 3 times and peroxidase substrate ABTS allowed to react for 30-60 min at 37°C. the Reaction is stopped using oxalic acid and measure the OD at 405 nm.

Acetylation percentage calculated after subtracting the OD of blank sample:

the average OD of acetylation

the average OD of DMSO control *100%

the average OD of WSTI

the average OD of DMSO control

198
Table 1
Example No.Connection nameAcetylation cells (R, 1 µm) [% of control]
Reference compound CI 994152
4-1(2-AMINOPHENYL)-amide 5-[(4-methylpentylamino)-methyl]-thiophene-2-carboxylic acid170
4-3(2-AMINOPHENYL)-amide 5-[(2-ethoxyacetylene)-methyl]-thiophene-2-carboxylic acid194
4-6(2-AMINOPHENYL)-amide 5-(bucillamine)-thiophene-2-carboxylic acid238
6-8(2-AMINOPHENYL)-amide 5-[3-(2-methylbutyl)-freedomites]-thiophene-2-carboxylic acid
6-12(2-AMINOPHENYL)-amide 5-[(3-allylurea)-methyl]-thiophene-2-carboxylic acid170
6-13(2-AMINOPHENYL)-amide 5-(3-isobutylether)-thiophene-2-carboxylic acid178
4-31N-(2-AMINOPHENYL)-4-[(2-cyclopent-2-Emilceramica)-methyl]-benzamide176
6-19N-(2-AMINOPHENYL)-4-[3-(3-dimethylamino-2,2-dimethylpropyl)-freedomites]-benzamid205
6-25N-(2-AMINOPHENYL)-4-[3-(1-etylhexyl)-freedomites]-benzamid192
6-26N-(2-AMINOPHENYL)-4-[3-(3-ethoxypropan)-freedomites]-benzamid179
6-274-[(3-allylurea)-methyl]-N-(2-AMINOPHENYL)-benzamide175
6-28N-(2-AMINOPHENYL)-4-[3-(3-isopropoxyphenyl)-freedomites]-benzamid177
6-29N-(2-AMINOPHENYL)-4-(3-cyclopropylmethyl)-benzamide187
6-38N-(2-AMINOPHENYL)-6-[(3-pentyurina)-methyl]-nicotinamide178

The effect of the compounds proposed in the present invention, can be further assessed using the following tests.

The method

The male mice NMRI nu/nu (n=15 per group) aged 8-10 weeks is b) was subcutaneously injected 5· 106PC-3 cell carcinoma of the prostate. On the 10th day of animals with tumors with a volume of approximately 150 mm3was randomly divided into experimental groups. The investigated compound was administered in the form of microsuspension suspension of 7.5% gelatin 0,22% NaCl with the introduction of volume equal to 10 ml/kg, calculated on actual body weight. Oral administration was performed once a day for about 10-th to 27-th day of the treatment regimen for 5-7 times a week.

Tumor volume was determined by the following equation:

Tumor volume = 1/2ab2, where "a" and "b" indicate the long and short diameters of the tumor, respectively.

Now the present invention will be illustrated by the following non-limiting examples in which, unless stated otherwise:

(i) the evaporation was carried out on a rotary evaporator under vacuum and the procedure of processing carried out after removal of residual solids such as drying agents, performed by filtration;

(ii) operations were carried out at ambient temperature, i.e. in the range of 18-25°and in the atmosphere of inert gas such as argon or nitrogen;

(iii) chromatography on a column (flash method) and liquid chromatography under high pressure (ghvd) was performed on silica Merck Kieselgel or silica reversed-phase Merck Lichroprep RP-18, manufactured by Emagic, situated the address: Darmstadt, Germany;

(iv) the outputs are given for illustration only and are not necessarily the maximum attainable;

(v) melting points were determined using an automatic device for measuring the melting temperature Mettler SP62, the device with an oil bath or in a device with a Kofler hot plate;

(vi) the structures of the final products of the formula I were confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques (instrument Micromass Platform II using chemical ionization at atmospheric pressure or Micromass Platform ZMD using ionization elektrorazpredelenie);

(vii) intermediates are usually not characterized fully and purity were determined using thin-layer chromatography;

(viii) used the following abbreviations:

DMF N,N-dimethylformamide;

DMSO dimethyl sulfoxide;

THF tetrahydrofuran;

Meon methanol;

HCl, hydrochloric acid;

NaH sodium hydride

CH2Cl2dichloromethane;

H2SO4sulfuric acid;

MM (molecular weight) was found (determined by mass spectrometry);

MM calculated molecular weight (calculated from the chemical formula).

Example 1

Step 1: {2-[(6-cyano-3-carbonyl)-amino]-phenyl}-carbamino acid tert-butyl methyl ether

To a solution of 444 mg (3.0 mmol) of 6-canonicalname the acid and 354 mg (3.5 mmol) of N-methylmorpholine in 7 ml of DMF at -20° With added 450 mg (3.3 mmol) of isobutylacetate. The reaction mixture was heated to 5°and added 625 mg (3.0 mmol) of mono-boc-o-phenylenediamine. The reaction mixture was heated at room temperature overnight and then was poured into 50 ml of 5% aqueous citric acid solution. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with bicarbonate and brine and dried over Na2SO4. The solvent is evaporated and the residue was subjected to chromatographicaliy (petroleum ether/ethyl acetate, 2:1) and received 795 mg (2,35 mmol) tert-butyl ether {2-[(6-cyano-3-carbonyl)-amino]-phenyl}-carbamino acid; melting point 183-184°C.

Step 2: {2-[(6-aminomethylpyridine-3-carbonyl)-amino]-phenyl}-carbamino acid tert-butyl methyl ether

In a flask under nitrogen atmosphere were placed 2920 mg (8,72 mmol) {2 - tert-butyl ether [(6-cyano-3-carbonyl)-amino]-phenyl}-carbamino acid and 1000 mg of Pd (10% on coal) and added to 10 ml of THF and 120 ml of methanol. Starting material was first made at atmospheric pressure and at room temperature for 3.5 hours, the Catalyst was filtered. The solvent is evaporated and the residue was subjected to chromatographicaliy (toluene/isopropanol/NH3(concentrated), 16:20:1) and received 2600 mg (7.6 mmol) of tert-butyl methyl ether {2-[(6-aminomethylpyridine-3-carbonyl)-amino]-phenyl}-carb is mirovoi acid; the exact MM [M+H] calculated value: 343,18; MM found [M+H]: 343,2.

Example 2

Stage 1: 5-valiuminformation-2-carboxylic acid

To a solution of 4.5 g (to 17.9 mmol) of the methyl ester 5-valiuminformation-2-carboxylic acid in 45 ml of methanol was added to 17.9 ml of 1 N. aqueous solution of KOH (to 17.9 mmol). The reaction mixture was stirred at 50°C for 16 h and 1 h at boiling under reflux. The solvent is evaporated, to the residue was added 20 ml of water and 9 ml of 2 N. aqueous HCl. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over Na2SO4. The solvent is evaporated and the residue was subjected to chromatographicaliy (ethyl acetate) and was received of 4.05 g (17,06 mmol) 5-valiuminformation-2-carboxylic acid; exact MM [M+H] calculated value: 238,09; MM found [M+H]: 238,3.

Step 2: {2-[(5-valiuminformation-2-carbonyl)-amino]-phenyl}-carbamino acid tert-butyl methyl ether

To a solution of 2.70 g (11,38 mmol) 5-valiuminformation-2-carboxylic acid in 50 ml of THF was added 2,03 g (12,51 mmol) carbodiimide. After 45 min at room temperature to the reaction mixture were added 2,48 g (11,95 mmol) of mono-boc-o-phenylenediamine and it was stirred for 3 h at room temperature. The solvent is evaporated and the residue was dissolved in ethyl acetate. The organic phase is twice washed nasy the military solution of NaHCO 3, 1 times with water and dried over Na2SO4. The solvent is evaporated and the residue was subjected to chromatographicaliy (ethyl acetate/heptane, 2:8) and received 4,10 g (9,59 mmol) tert-butyl ether {2-[(5-valiuminformation-2-carbonyl)-amino]-phenyl}-carbamino acid; exact MM [M+H] calculated value: 428,20; MM found [M+H]: 428,3.

Step 3: {2-[(5-aminomethylation-2-carbonyl)-amino]-phenyl}-carbamino acid tert-butyl methyl ether

The solution to 22.35 g (143,13 mmol) N,N'-dimethylbarbituric acid and 0.55 g (0,477 mmol) tetrakis(triphenylphosphine)palladium(0) in 200 ml of CH2Cl2added 10,20 g (23,86 mmol) tert-butyl ether valiuminformation-2-carbonyl)-amino]-phenyl}-carbamino acid.

After 1 h at 35°the solvent is evaporated and to the residue was added 0.1 G. of aqueous solution of HCl. The aqueous phase was extracted three times with diethyl ether and the combined organic phases were extracted with saturated solution of NaHCO3. An acidic aqueous phase was neutralized with saturated solution of NaHCO3and the combined aqueous phase was extracted three times with CH2Cl2. The organic phase was dried over Na2SO4. The solvent is evaporated and the residue was subjected to chromatographicaliy (dichloromethane/methanol, 9:1) and received 4,63 g (13,32 mmol) tert-butyl ether {2-[(5-aminomethylation-2-carbonyl)-amino]-phenyl}-carbonintensity; the exact MM [M+H] calculated value: 348,14; MM found [M+H]: 348,1.

Example 3

(2-AMINOPHENYL)-amide 5-[(3-methylpentylamino)-methyl]-thiophene-2-carboxylic acid

To a solution of 33,43 mg (in 0.288 mmol) 3-methylpentanoic acid in 1 ml of THF was added 46,67 mg (in 0.288 mmol) of 1,1'-carbodiimide. After 1 h at room temperature was added 100 mg (in 0.288 mmol) tert-butyl ether {2-[(5-aminomethylation-2-carbonyl)-amino]-phenyl}-carbamino acid and the reaction mixture was stirred for 3 h at room temperature. Was added 1.7 ml triperoxonane acid and 2 h at room temperature was carefully added to saturated aqueous solution of NaHCO3and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over Na2SO4. The solvent is evaporated and the residue was subjected to chromatographicaliy (ethyl acetate/heptane, 6:4), received 59.3 mg (0,171 mmol) (2-AMINOPHENYL)-amide 5-[(3-methylpentylamino)-methyl]-thiophene-2-carboxylic acid; exact MM [M+H] calculated value: 346,16; MM found [M+H]: 346,4.

Example 4

By the way, is similar to that described in example 3, and using well-known techniques described in the literature (for example, in standard textbooks, such as Houben-Weyl, "Methods der Organischen Chemie, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley&Sons, Inc., New York) received the following connections.

Table 2
Connection nameThe exact MM [M+H] calculated value [g/mol]Found MM [M+H] [g/mol]
4-1344,14344,2
(2-AMINOPHENYL)-amide 5-[(cyclopentanecarbonyl)-methyl]-thiophene-2-carboxylic acid
4-2346,16346,2
(2-AMINOPHENYL)-amide 5-[(4-methylpentylamino)-methyl]-thiophene-2-carboxylic acid

1H-NMR (400 MHz, CD3OD): δ=9,63 (s, 1H), charged 8.52 (t, J=6,1 Hz, 1H), 7,79 for 7.78 (m, 1H), 7,12-to 7.09 (m, 1H), 7,00-6,99 (m, 1H), 6,97-to 6.95 (m, 1H), 6,78-6,76 (m, 1H), 6,61-to 6.57 (m, 1H), 4,42 (d, J=6,1 Hz, 2H), 2,13 (t, J=7,6 Hz, 2H), 1.56 to to 1.39 (m, 3H), 0,86(d, J=6,1 Hz, 6H)
4-3334,12334,1
(2-AMINOPHENYL)-amide 5-[(2-ethoxyacetylene)-methyl]-thiophene-2-carboxylic acid

H-NMR (400 MHz, CD3OD): δ=9,63 (s, 1H), 8,48 (t, J=6,1 Hz, 1H), 7,79 for 7.78 (m, 1H), 7,11-to 7.09 (m, 1H), 7,01-7,00 (m, 1H). 6,99-to 6.95 (m, 1H), 6,78-6,76 (m, 1H), 6,61-6,56 (m, 1H), 4,89 (s, 2H), 4,47 (d, J=6,1 Hz, 2H), 3,89 ('s. 2H), 3,50 (q, J=6.9 Hz, 2H), 1,16 (t, J=6.8 Hz, 3H)
4-4304,11304,2
(2-AMINOPHENYL)-amide 5-(propenolatomethyl)-thiophene-2-carboxylic acid
4-5330,13 330,3
(2-AMINOPHENYL)-amide 5-(Penta-4-emailmyname)-thiophene-2-carboxylic acid
4-6318,13317,9
(2-AMINOPHENYL)-amide 5-(bucillamine)-thiophene-2-carboxylic acid
4-7340,11340,0
(2-AMINOPHENYL)-amide 5-(isobutylamino)-thiophene-2-carboxylic acid[M+Na][M+Na]
4-8
(2-AMINOPHENYL)-amide 5-[(2,2,3,3,3-pentafluoropropionate)-methyl]-thiophene-2-carboxylic acid394,06394,1
4-9
(2-AMINOPHENYL)-amide 5-[(2-acetylaminofluorene)-methyl]-thiophene-2-carboxylic acid347,12347,2
4-10
(2-AMINOPHENYL)-amide 5-[(2-ethylbutylamine)-methyl]-thiophene-2-carboxylic acid346,16346,2

Connection nameThe exact MM [M+H] calculated value [g/mol]Found MM [M+H] [g/mol]
4-11356,14356,2
(2-AMI is openil)-amide 5-[(2-cyclopent-2-Emilceramica)-methyl]-thiophene-2-carboxylic acid

1H-NMR (400 MHz, CD3OD): δ=9,62 (s, 1H), 8,53 (t, J=5.8 Hz, 1H), 7,79 for 7.78 (m, 1H), 7,12-7,10 (m, 1H), 7,01-7,00 (m, 1H), 6,99-to 6.95 (m, 1H), 6,78-6,76 (m, 1H), 6,61-to 6.57 (m, 1H), 5,75-5,72 (m, 1H), 5,68-the 5.65 (m, 1H), 4,88 (s, 2H), of 4.44 (d, J=5.6 Hz, 2H), 3.04 from-2,95 (m, 1H). 2,36-of 1.94 (m, 5H), 1,45 to 1.37 (m, 1H)
4-12408,16408,2
(2-AMINOPHENYL)-amide 5-({2-[2-(2-methoxyethoxy)-ethoxy]-acetylamino}-methyl)-thiophene-2-carboxylic acid
4-13346,12346,2
(2-AMINOPHENYL)-amide 5-[(4-oxopentanoate)-methyl]-thiophene-2-carboxylic acid
4-14359,12359,2
[5-(2-aminophenylamino)-thiophene-2-ylmethyl]-amide 5-oxopyrrolidin-2-carboxylic acid
4-15344,07344,1
(2-AMINOPHENYL)-amide 5-[(2,2,2-triptoreline)-methyl]-thiophene-2-carboxylic acid
4-16361,17361,2
(2-AMINOPHENYL)-amide 5-[(4-dimethylaminomethylene)-methyl]-thiophene-2-carboxylic acid
4-17372,17372,2
(2-AMINOPHENYL)-amide 5-[(3-cyclopentylpropionic is amino)-methyl]-thiophene-2-carboxylic acid

1H-NMR (400 MHz, CD3OD): δ=9,63 (s, 1H), charged 8.52 (t, J=6,1 Hz, 1H), 7,79 for 7.78 (m, 1H), 7,11-to 7.09 (m, 1H), 7,00-6,99 (m, 1H), 6,97-to 6.95 (m, 1H), 6,78-6,76 (m, 1H), 6,61-to 6.57 (m, 1H), 4,89 (s, 2H), 4,42 (d, J=5.6 Hz, 2H), to 2.13 (t, J=7,6 Hz, 2H), 1,76-to 1.67 (m, 3H), 1.60-to the 1.44 (m, 6H), 1,10-1,00 (m, 2H)
4-18386,19386,3
(2-AMINOPHENYL)-amide 5-[(3-cyclohexylpropionate)-methyl]-thiophene-2-carboxylic acid

Connection nameThe exact MM [M+H] calculated value [g/mol]Found MM [M+H] [g/mol]
4-19332,14332,3
(2-AMINOPHENYL)-amide 5-[(3-methylbutylamine)-methyl]-thiophene-2-carboxylic acid
4-20403,22403,4
(2-AMINOPHENYL)-amide 5-[(2-dipropylenetriamine)-methyl]-thiophene-2-carboxylic acid
4-21333,14to 333.3
(2-AMINOPHENYL)-amide 5-[(2-dimethylaminoacetyl)-methyl]-thiophene-2-carboxylic acid
4-22358,16358,3
(2-AMINOPHENYL)-amide 5-[(2-cyclopentylacetyl)-methyl]-thiophene-2-arbonboy acid
4-23330,13330,3
(2-AMINOPHENYL)-amide 5-[(2-cyclopropylacetylene)-methyl]-thiophene-2-carboxylic acid
4-24338,19338,3
N-(2-AMINOPHENYL)-4-[(cyclopentanecarbonyl)-methyl]-benzamide
4-25298,16298,3
N-(2-AMINOPHENYL)-4-(propenolatomethyl)-benzamide
4-26312,17312,4
N-(2-AMINOPHENYL)-4-(isobutylamino)-benzamide
4-27328,17328,3
N-(2-AMINOPHENYL)-4-[(2-ethoxyacetylene)-methyl]-benzamide
4-28324,17324,3
N-(2-AMINOPHENYL)-4-(Penta-4-emailmyname)-benzamide
4-29340,2340,3
N-(2-AMINOPHENYL)-4-[(4-methylpentylamino)-methyl]-benzamide
4-30340,2340,4
N-(2-AMINOPHENYL)-4-[(2-ethylbutylamine)-methyl]-benzamide
1H-NMR (400 MHz, (CD3)2WITH): δ=9,62 (s, 1H), 8,44 (t, J=5.8 Hz, 1H), 7,94-7,92 (m. 2H), 7,39 was 7.36 (m, 2H), 7,17-to 7.15 (m, 1H), 6,99-to 6.95 (m, 1H), 6,79-6,77 (m, 1H), 6,61 return of 6.58 (m, 1H). 4,89 (s, 2H), 4,36 (d, J 5.6 Hz, 2H), 2,11-a 2.01 (m, 1H), of 1.55 and 1.33 (m, 4H), 0,81 (t, J=7,3 Hz, 6N)

Connection nameThe exact MM [M+H] calculated value [g/mol]Found MM [M+H] [g/mol]
4-31350,19350,3
N-(2-AMINOPHENYL)-4-[(2-cyclopent-2-Emilceramica)-methyl]-benzamide

1H-NMR (400 MHz, (CD3)2WITH): δ=9,62 (s, 1H), 8,43 (t, J=5.8 Hz, 1H), 7.95 is-a 7.92 (m, 2H), 7,37-7,35 (m, 2H), 7,17-to 7.15 (m, 1H), 6,99-to 6.95 (m, 1H), 6,79-6,77 (m, 1H), 6,62 return of 6.58 (m, 1H), 5,76-to 5.66 (m, 2H), 4,89 (s, 2H), 4,34 (d, J=5,1 Hz, 2H), 3.04 from-2,96 (m, 1H), 2,37-of 2.09 (m, 4H), 2,04-of 1.95 (m, 1H), 1,47-of 1.39 (m, 1H)
4-32310,16310,3
N-(2-AMINOPHENYL)-4-(bucillamine)-benzamide[N-N][N-N] AR)
4-33400,19400,3
N-(2-AMINOPHENYL)-4-({2-[2-(2-methoxyethoxy)-ethoxy]-acetylamino}-methyl)-benzamide[N-N][N-N](art)
4-34341,16341,3
4-[(2-acetylaminofluorene)-methyl]-N-(2-AMINOPHENYL)-benzamide
4-35366,22366,3
N-(2-AMINOPHENYL)-4-[(3-cyclopentylpropionyl)-methyl]-benzamide
4-36315,15315,2
N-(2-AMINOPHENYL)-6-[(2-methoxyethylamine)-methyl]-nicotinamide

1H-NMR (400 MHz, (CD3)2WITH): δ=9,79 (s, 1H), 9,10 (s, 1H), 8,51 (t, J=6,1 Hz, 1H), 8.31-of 8.28 (m, 1H), 7,42-7,40 (m, 1H), 7,19-7,17 (m, 1H), 7,02-6,98 (m, 1H), to 6.80-6.78 (m, 1H), 6,63-6,59 (m, 1H), 4,99 (br s, 2H), 4,50 (d, J=5.6 Hz, 2H), 3,94 (s, 2H), 3,39 (s, 3H)
4-37325,17325,2
N-(2-AMINOPHENYL)-6-(Penta-4-emailmyname)-nicotinamide

1H-NMR (400 MHz, (CD3)2WITH): δ=9,78 (s, 1H), 9,05 (s, 1H), 8,55 (t, J=5.8 Hz, 1H), 8,29 compared to 8.26 (m, 1H), 7,39-7,37 (m, 1H), 7,17-to 7.15 (m, 1H), 7,00-of 6.96 (m, 1H), 6,79-6,76 (m, 1H), 6,61-to 6.57 (m, 1H), of 5.89-5,79 (m, 1H), 5.08 to equal to 4.97 (m, 2H), equal to 4.97 (s, 2H), 4,42 (d, J=6,1 Hz, 2H), 2,30-to 2.29 (m, 4H)
4-38367,21367,2
N-(2-AMINOPHENYL)-6-[(3-cyclopentylpropionyl)-methyl]-nicotinamide

Connection nameThe exact MM [M+H]

the calculated value [g/mol]
Found MM

[M+H] [g/mol]
4-39351,18351,2
N-(2-amino the Nile)-6-[(2-cyclopent-2-Emilceramica)-methyl]-nicotinamide
4-40341,20341,2
N-(2-AMINOPHENYL)-6-[(4-methylpentylamino)-methyl]-nicotinamide
4-41341,20341,2
N-(2-AMINOPHENYL)-6-[(3-methylpentylamino)-methyl]-nicotinamide
4-42353,20353,2
N-(2-AMINOPHENYL)-6-[(2-cyclopentylacetyl)-methyl]-nicotinamide
4-43381,23381,2
N-(2-AMINOPHENYL)-6-[(3-cyclohexylpropionate)-methyl]-nicotinamide

Example 5

(2-AMINOPHENYL)-amide 5-[(3-prop-2-injured)-methyl]-thiophene-2-carboxylic acid

To a solution of 15.8 mg (in 0.288 mmol) in 1 ml THF was added to 46.7 mg (in 0.288 mmol) of 1,1'-carbodiimide. After 1 h at room temperature was added 100 mg (in 0.288 mmol) tert-butyl ether {2-[(5-aminomethylation-2-carbonyl)-amino]-phenyl}-carbamino acid and the reaction mixture was stirred for 1 h at room temperature. Was added 1.7 ml triperoxonane acid after 16 h at room temperature was carefully added to saturated aqueous solution of NaHCO3and the aqueous phase was extracted three times atilas what tatom. The combined organic phases were dried over Na2SO4and the solvent evaporated. The residue was purified using ghvd/mass spectrometry and received 75 mg (0,228 mmol) (2-AMINOPHENYL)-amide 5-[(3-prop-2-injured)-methyl]-thiophene-2-carboxylic acid; exact MM [M+H] calculated value: 329,11; MM found [M+H]: 329,3.

Example 6

By the way, is similar to that described in example 5, and using well-known techniques described in the literature (for example, in standard textbooks, such as Houben-Weyl, "Methods der Organischen Chemie, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), received the following connections.

Table 3
Connection nameThe exact MM [M+H] calculated value [g/mol]Found MM [M+H] [g/mol]
6-1362,16362,2
(2-AMINOPHENYL)-amide 5-[3-(2-dimethylaminoethyl)-freedomites]-thiophene-2-carboxylic acid
6-2418,23418,3
(2-AMINOPHENYL)-amide 5-[3-(2-diisopropylaminoethyl)-freedomites]-thiophene-2-carboxylic acid
6-3404,21404,3
(2-AMINOPHENYL)-amide 5-[3-(3-diethylaminopropyl)-freedomites]t is open-2-carboxylic acid
6-4404,21404,3
(2-AMINOPHENYL)-amide 5-[3-(3-dimethylamino-2,2-dimethylpropyl)-freedomites]-thiophene-2-carboxylic acid

1H-NMR (400 MHz, CD3OD): δ=7,80-7,79 (m, 1H), 7,31-7,25 (m, 2H), 7.18 in-7,07 (m, 3H), 4,56 (s, 2H), 3,18 (s, 2H), 2,99 (s, 2H), equal to 2.94 (s, 6H), 1,10 (s, 6H)
6-5377,16377,3
(2-AMINOPHENYL)-amide 5-[3-(3-ethoxypropan)-freedomites]-thiophene-2-carboxylic acid

1H-NMR (400 MHz, CD3OD): δ=7,83-of 7.82 (m, 1H), 7,45-7,41 (m, 4H), 7,07-7,06 (m, 1H), of 4.54 (s, 2H), 3,54-of 3.48 (m, 4H), 3,26-up 3.22 (m, 2H), 1,79-of 1.73 (m, 2H), 1,20 (t, J=7,1 Hz, 3H)
6-6389,2389,3
(2-AMINOPHENYL)-amide 5-[3-(1-etylhexyl)-freedomites]-thiophene-2-carboxylic acid
6-7347,15347,2
(2-AMINOPHENYL)-amide 5-(3-second-butylenediamine)-thiophene-2-carboxylic acid
6-8361,17361,3
(2-AMINOPHENYL)-amide 5-[3-(2-methylbutyl)-freedomites]-thiophene-2-carboxylic acid
6-9376,14376.3 on
(2-AMINOPHENYL)-amide 5-[3-(2-acetyl shall inatel)-freedomites]-thiophene-2-carboxylic acid

460,4
Connection nameThe exact MM [M+H] calculated value [g/mol]Found MM [M+H] [g/mol]
6-10416,18416,3
(2-AMINOPHENYL)-amide 5-{3-[3-(2-oxopyrrolidin-1-yl)-propyl]-freedomites}-thiophene-2-carboxylic acid
6-11349,13349,3
(2-AMINOPHENYL)-amide 5-[3-(2-methoxyethyl)-freedomites]-thiophene-2-carboxylic acid
6-12331,12331,4
(2-AMINOPHENYL)-amide 5-[(3-allylurea)-methyl]-thiophene-2-carboxylic acid
6-13347,15347,4
(2-AMINOPHENYL)-amide 5-(3-isobutylether)-thiophene-2-carboxylic acid

1H-NMR (400 MHz, CD3OD): δ=7,80-7,79 (m, 1H), was 7.36-7,21 (m, 4H), 7,06-7,05 (m, 1H), of 4.54 (s, 2H), 2,98 (d, J=6.6 Hz, 2H), 1,80 is 1.70 (m, 1H), 0,93 (d, J=6,6 Hz, 6N)
6-14405,2405,3
(2-AMINOPHENYL)-amide 5-[3-(3-butoxypropyl)-freedomites]-thiophene-2-carboxylic acid
6-15460,27
(2-AMINOPHENYL)-amide 5-[3-(3-dibutylamino)-freedomites]-thiophene-2-carboxylic acid
6-16405,16405,2
ethyl ester of 4-{3-[5-(2-aminophenylamino)-thiophene-2-ylmethyl]-ureido}-butyric acid
6-17355,21355,2
N-(2-AMINOPHENYL)-4-[(3-pentyurina)-methyl]-benzamide
6-18398,26398,3
N-(2-AMINOPHENYL)-4-[3-(3-diethylaminopropyl)-freedomites]-benzamid
6-19398,26398,3
N-(2-AMINOPHENYL)-4-[3-(3-dimethylamino-2,2-dimethylpropyl)-freedomites]-benzamide

1H-NMR (400 MHz, (CD3)2WITH): δ=9,63 (s, 1H), 7.95 is-to 7.93 (m, 2H), 7,38 and 7.36 (m, 2H), 7.18 in-7,16 (m, 1H), 7,00-of 6.96 (m. 1H), 6,80-of 6.78 (m, 1H), 6,62-6,59 (m, 1H), 6,47 (t, J=5.8 Hz, 1H), 5,98 (t, J=5.8 Hz, 1H), 4,89 (s, 2H), 4,30 (d, J=6,1 Hz, 2H), 2,94 (d, J=6,1, 2H), 2,23 (s, 6N), 2,07 (s, 2H), 0,81 (s, 6H)

Connection nameThe exact MM [M+H] calculated value [g/mol]Found MM [M+H] [g/mol]
6-20410,22410,2
N-(2-what AMINOPHENYL)-4-{3-[3-(2-oxopyrrolidin-1-yl)-propyl]-freedomites}-benzamide
6-21370,19370,2
4-[3-(2-acetylamino)-freedomites]-N-(2-AMINOPHENYL)-benzamide
6-22355,21355,3
N-(2-AMINOPHENYL)-4-(3-butyl-3-methyluridine)-benzamide
6-23343,18343,2
N-(2-AMINOPHENYL)-4-[3-(2-methoxyethyl)-freedomites]-benzamid
6-24399,24399,3
N-(2-AMINOPHENYL)-4-[3-(3-butoxypropyl)-freedomites]-benzamid
6-25383,24383,3
N-(2-AMINOPHENYL)-4-[3-(1-etylhexyl)-freedomites]-benzamide

1H-NMR (400 MHz, (CD3)2WITH): δ=9,62 (s, 1H). 7,94-a 7.92 (m, 2H), 7,37-7,35 (m, 2H), 7.18 in-7,16 (m, 1H), 7,00-of 6.96 (m, 1H), 6,80-of 6.78 (m, 1H), 6,62-6,59 (m, 1H), of 6.26 (t, J=6,1 Hz, 1H), 5,79 (d, J=8.1 Hz, 1H), 4,89 (s, 2H), 4,28 (d, J=6,1 Hz, 2H), 3,65-3,55 (m, 1H), 1,35-of 1.26 (m, 8H), of 1.02 (d, J=6.6 Hz, 3H), of 0.87 (t, J=6.8 Hz, 3H)
6-26371,21371,3
N-(2-AMINOPHENYL)-4-[3-(3-ethoxypropan)-freedomites]-benzamide

1H-NMR (400 MHz, (CD3)2WITH): δ=9,62 (s, 1H), 7,94-a 7.92 (m, 2H), 7,37-7,35 (m, 2H), 7.18 in-7,16 (m, 1H), 7,00-of 6.96 (m, 1H), 6,80-of 6.78 (m,1H), 6,62-6,59 (m, 1H), 6.42 per (t, J=5.8 Hz, 1H), 6,00 (t, J=5.6 Hz, 1H), 4,89 (s, 2H), 4,28 (d, J=6,1 Hz, 2H), 3,42-to 3.35 (m, 4H), 3,10 was 3.05 (m, 2H), 1,65 is 1.58 (m, 2H), 1,11 (t, J=7,1 Hz, 3H)
6-27325,17325,2
4-[(3-allylurea)-methyl]-N-(2-AMINOPHENYL)-benzamide

1H-NMR (400 MHz, (CD3)2WITH): δ=9,63 (s, 1H), 7.95 is-to 7.93 (m, 2H), 7,38 and 7.36 (m, 2H), 7,19-7,17 (m, 1H), 7,00-of 6.96 (m, 1H), 6,80-of 6.78 (m, 1H), 6,63-6,59 (m, 1H), of 6.49 (t, J=6,1 Hz, 1H), x 6.15 (t, J=5.8 Hz, 1H), of 5.89-5,79 (m, 1H), 5,16-to 5.03 (m, 2H), 4,90 (s, 2H), 4,30 (d, J=6,1 Hz, 2H), 3,69-to 3.67 (m, 2H)

Connection nameThe exact MM [M+H] calculated value [g/mol]Found MM [M+H] [g/mol]
6-28385,22385,2
N-(2-AMINOPHENYL)-4-[3-(3-isopropoxyphenyl)-freedomites]-benzamid
6-29339,18339,2
N-(2-AMINOPHENYL)-4-(3-cyclopropylmethyl)-benzamide
6-30323,15323,2
N-(2-AMINOPHENYL)-4-[(3-prop-2-injured)-methyl]-benzamide
6-31385,19385,2
4-{3-[4-(2-aminophenylamino)-benzyl]-ureido}-butyric KIS is the notes methyl ether
6-32454,32454,4
N-(2-AMINOPHENYL)-4-[3-(3-dibutylamino)-freedomites] -benzamide

1H-NMR (400 MHz, (CD3)2WITH): δ=9,63 (s, 1H), 7,94-a 7.92 (m, 2H), 7,37-7,35 (m, 2H), 7.18 in-7,16 (m, 1H), 7,00-of 6.96 (m, 1H), 6,80-of 6.78 (m, 1H), 6,63-6,59 (m, 1H), 6,41 (t, J=5.8 Hz, 1H), 5,98 (t, J=5.6 Hz, 1H). 4,88 (s, 2H), 4,28 (d, J=5.6 Hz, 2H), 3,05-a 3.01 (m, 2H), 2,37-2,31 (m, 6H), 1,53 of 1.46 (m, 2H), 1,39 is 1.23 (m, 8H), to 0.88 (t, J=7,1, 6H)
6-33356,21356,3
N-(2-AMINOPHENYL)-4-[3-(2-dimethylaminoethyl)-freedomites]-benzamid
6-34412,27412,3
N-(2-AMINOPHENYL)-4-[3-(2-diisopropylaminoethyl)-freedomites]-benzamid
6-35355,21355,3
N-(2-AMINOPHENYL)-4-[3-(2-methylbutyl)-freedomites]-benzamid
6-36341,2341,2
N-(2-AMINOPHENYL)-4-(3-isobutylether)-benzamide
6-37341,2341,2
N-(2-AMINOPHENYL)-4-(3-second-butylenediamine)-benzamide
6-38356,21356,2
N-(2-AMINOPHENYL)-6-[(3-pentyurina)-methyl]-nicotinamide

Connection nameThe exact MM [M+H] calculated value [g/mol]Found MM [M+H] [g/mol]
6-39384,24384,2
N-(2-AMINOPHENYL)-6-[3-(1-etylhexyl)-freedomites]-nicotinamide

1H-NMR (400 MHz, (CD3)2WITH): δ=10,08 (s, 1H), which is 9.09 (s, 1H), 8,35-of 8.33 (m, 1H), 7,46-7,44 (m, 1H), 7,29-7,28 (m, 1H), 7,16 for 7.12 (m, 1H), 7,01-6,99 (m, 1H), 6.90 to-6,87 (m, 1H), gold 6.43 (br s, 1H), 6,02 (br d, J=7,6 Hz, 1H), and 4.40 (s,, 2H), 3,61-3,59 (m, 1H), 1,36-of 1.27 (m, 8H), was 1.04 (d, J=to 6.57 Hz, 3H), from 0.88 (t, J=6.8 Hz, 3H)
6-40400,23400,2
N-(2-AMINOPHENYL)-6-[3-(3-butoxypropyl)-freedomites]-nicotinamide

1H-NMR (400 MHz, (CD3)2WITH): δ=9,86 (s, 1H), 9,07 (s, 1H), 8,32-8,29 (m, 1H), 7,43-7,41 (m, 1H), 7,21-7,19 (m, 1H), 7,06-7,01 (m, 1H), 6,86-6,84 (m, 1H), 6,70 of 6.66 (m, 1H), 6,56-6,53 (m, 1H), 6,18 (t, J=5.3 Hz, 1H), 4,39 (d, J=4,6 Hz, 2H), 3,38 (t, J=6.3 Hz, 2H), 3,36 (t, J=6.3 Hz, 2H), 3,11-of 3.06 (m, 2H), 1,66-to 1.59 (m, 2H), 1,53-of 1.45 (m, 2H), 1,38-of 1.29 (m, 2H), 0,89 (t, J=7,3 Hz, 3H)
6-41411,21411,2
N-(2-AMINOPHENYL)-6-{3-[3-(2-oxopyrrolidin-1-yl)-propyl]-freedomites} -nicotinamide

where And denotes theoffender, phenylene or pyridinyl;

R1denotes alkyl, alkenyl, quinil that may or may not contain one or more substituents selected from the group comprising halogen, cyano-, nitro-, amino group, -NH-alkyl and N(alkyl)2;

or

-CH2-(O-CH2-CH2-)mO-alkyl; -(CH2)n-O-alkyl; -(CH2)n-C(O)-NH-alkyl; -(CH2)n-NH-C(O)-alkyl; -(CH2)n-C(O)alkyl; -(CH2)n-C(O)-O-alkyl; or -(CH2)n-O-C(O)-alkyl; or the group-NR3R4in which R3and R4independently represent hydrogen; alkyl, alkenyl or quinil that may or may not contain one or more substituents selected from the group comprising halogen, cyano-, nitro-, amino group, -NH-alkyl and N(alkyl)2; or-CH2-(O-CH2-CH2)mO-alkyl; -(CH2)n-(O)-alkyl; -(CH2)n-C(O)-NH-alkyl; -(CH2)n-NH-C(O)-alkyl; -(CH2)n-C(O)alkyl; -(CH2)n-C(O)-O-alkyl; or -(CH2)n-O-C(O)-alkyl;

n is 1-6;

m is 1-4;

and its pharmaceutically acceptable salts.

2. The compound according to claim 1, in which

And indicates theoffender, phenylene or pyridinyl;

R1refers to the group-NR3R4in which R3denotes hydrogen and R4is such as defined in claim 1; and its pharmaceutically acceptable salts.

3. The compound according to claim 1, in which And indicates theoffender, phenylene or pyridinyl; R1denotes alkyl, alkenyl, quinil that may or may not contain one or more substituents selected from the group comprising halogen, cyano-, nitro-, amino group, -NH-alkyl and N(alkyl)2; or-CH2-(O-CH2-CH2-)mO-alkyl; -(CH2)n-O-alkyl; -(CH2)n-C(O)-NH-alkyl; -(CH2)n-NH-C(O)-alkyl; -(CH2)n-C(O)alkyl; -(CH2)n-C(O)-O-alkyl; or -(CH2)n-O-C(O)-alkyl; n is 1-6; m is 1-4; and pharmaceutically acceptable salts.

4. The compound according to claim 1 or 3, in which And indicates thiophene-2,5-diyl; R1means of alkenyl; -(CH2)n-O-alkyl; -(CH2)n-NH-C(O)-alkyl or -(CH2)n-C(O)alkyl;

n is 1-6;

and its pharmaceutically acceptable salts.

5. The compound according to claim 4, in which the connection is a

(2-AMINOPHENYL)-amide 5-[(2-ethoxyacetylene)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-(Penta-4-emailmyname)-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(2-acetylaminofluorene)-methyl]-thiophene-2-to benovoy acid, (2-AMINOPHENYL)-amide 5-({2-[2-(2-methoxyethoxy)-ethoxy]-acetylamino}-methyl)-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(4-oxopentanoate)-methyl]-thiophene-2-carboxylic acid.

6. The compound according to claim 1 or 2, in which And indicates thiophene-2,5-diyl;

R1refers to the group-NR3R4in which R3denotes hydrogen; R4means of alkenyl; quinil; -(CH2)n-(O)-alkyl; -(CH2)n-NH-C(O)-alkyl, or

-(CH2)n-C(O)-O-alkyl;

n is 1-6;

and its pharmaceutically acceptable salts.

7. The connection according to claim 6, in which the connection is a

(2-AMINOPHENYL)-amide 5-[3-(3-ethoxypropan)-freedomites]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(3-prop-2-injured)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[3-(2-acetylamino)-freedomites]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[3-(2-methoxyethyl)-freedomites]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(3-allylurea)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[3-(3-butoxypropyl)-freedomites]-thiophene-2-carboxylic acid,

ethyl ester of 4-{3-[5-(2-aminophenylamino)-thiophene-2-ylmethyl]-ureido}-butyric acid.

8. The compound according to claim 1 or 3, where And denotes 1,4-phenylene; R1hereafter which includes alkenyl; -CH2-(O-CH2-CH2-)mO-CH3; -(CH2)n-O-alkyl or

-(CH2)n-NH-C(O)-alkyl;

n is 1-6;

m is 1-4;

and its pharmaceutically acceptable salts.

9. Connection of claim 8,

N-(2-AMINOPHENYL)-4-[(2-ethoxyacetylene)-methyl]-benzamide,

N-(2-AMINOPHENYL)-4-(Penta-4-emailmyname)-benzamid,

N-(2-AMINOPHENYL)-4-({2-[2-(2-methoxyethoxy)-ethoxy]-acetylamino}-methyl)-benzamide,

4-[(2-acetylaminofluorene)-methyl]-N-(2-AMINOPHENYL)-benzamide.

10. The compound according to claim 1 or 2, where And denotes 1,4-phenylene;

R1refers to the group-NR3R4in which R3denotes hydrogen;

R4means of alkenyl; quinil; -(CH2)n-(O)-alkyl; -(CH2)n-NH-C(O)-alkyl, or

-(CH2)n-C(O)-O-alkyl;

n is 1-6;

and its pharmaceutically acceptable salts.

11. Connection of claim 10,

4-[3-(2-acetylamino)-freedomites]-N-(2-AMINOPHENYL)-benzamide,

N-(2-AMINOPHENYL)-4-[3-(2-methoxyethyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[3-(3-butoxypropyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[3-(3-ethoxypropan)-freedomites]-benzamid,

4-[(3-allylurea)-methyl]-N-(2-AMINOPHENYL)-benzamide,

N-(2-AMINOPHENYL)-4-[3-(3-isopropoxyphenyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[(3-prop-2-injured)-methyl]-benzamide, methyl ester 4-{3-[4-(2-aminophenylamino)-benzyl]-ureido}-butyric acid.

12. The compound according to claim 1 or 2, where And denotes pyridine-2,5-diyl;

R1refers to the group-NR3R4in which

R3denotes hydrogen, and

R4represents -(CH2)n-(O)-alkyl;

n is 1-6;

and its pharmaceutically acceptable salts.

13. The connection section 12,

N-(2-AMINOPHENYL)-6-[3-(3-butoxypropyl)-freedomites]-nicotinamide.

14. The compound according to claim 1 or 3, where And denotes pyridine-2,5-diyl;

R1means of alkenyl or -(CH2)n-O-alkyl;

n is 1-6;

and its pharmaceutically acceptable salts.

15. Connection 14

N-(2-AMINOPHENYL)-6-[(2-methoxyethylamine)-methyl]-nicotinamide,

N-(2-AMINOPHENYL)-6-(Penta-4-emailmyname)-nicotinamide.

16. The compound according to claim 1 or 2, in which And indicates thiophene-2,5-diyl; pyridine-2,5-diyl or 1,4-phenylene;

R1refers to the group-NR3R4in which R3denotes hydrogen;

R4denotes alkyl, which is unsubstituted or one or

several times substituted with halogen; -NH-alkyl or-N(alkyl)2;

and its pharmaceutically acceptable salts.

17. Connected to the I P16, (2-AMINOPHENYL)-amide 5-[3-(2-dimethylaminoethyl)-freedomites]-thiophene-2-carboxylic acid (2-AMINOPHENYL)-amide 5-[3-(2-diisopropylaminoethyl)-freedomites]-thiophene-2-carboxylic acid (2-AMINOPHENYL)-amide 5-[3-(3-diethylaminopropyl)-freedomites]-thiophene-2-carboxylic acid (2-AMINOPHENYL)-amide 5-[3-(3-dimethylamino-2.2-dimethylpropyl)-freedomites]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[3-(1-etylhexyl)-freedomites]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-(3-second-butylenediamine)-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[3-(2-methylbutyl)-freedomites]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-(3-isobutylether)-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[3-(3-dibutylamino)-freedomites]-thiophene-2-carboxylic acid,

N-(2-AMINOPHENYL)-4-[(3-pentyurina)-methyl]-benzamide,

N-(2-AMINOPHENYL)-4-[3-(3-diethylaminopropyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[3-(3-dimethylamino-2,2-dimethylpropyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[3-(1-etylhexyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[3-(3-dibutylamino)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[3-(2-dimethylaminoethyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[3-(2-diisopropylaminoethyl)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-[3-(2-IU is rbutil)-freedomites]-benzamid,

N-(2-AMINOPHENYL)-4-(3-isobutylether)-benzamid,

N-(2-AMINOPHENYL)-4-(3-second-butylenediamine)-benzamid,

N-(2-AMINOPHENYL)-6-[(3-pentyurina)-methyl]-nicotinamide,

N-(2-AMINOPHENYL)-6-[3-(1-etylhexyl)-freedomites]-nicotinamide.

18. The compound according to claim 1 or 3, in which

And denotes a thiophene-2,5-diyl;

pyridine-2,5-diyl or

1,4-phenylene;

R1denotes alkyl; which alkyl group is unsubstituted or once or several times substituted with halogen; -NH-alkyl or-N(alkyl)2;

and its pharmaceutically acceptable salts.

19. Connection p,

(2-AMINOPHENYL)-amide 5-[(4-methylpentylamino)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-(propenolatomethyl)-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-(bucillamine)-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-(isobutylamino)-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(2,2,3,3,3-pentafluoropropionate)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(2-ethylbutylamine)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(2,2,2-triptoreline)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(4-dimethylaminomethylene)-methyl]-thiophene-2-carboxylic acid is,

(2-AMINOPHENYL)-amide 5-[(3-methylbutylamine)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(2-dipropylenetriamine)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(2-dimethylaminoacetyl)-methyl]-thiophene-2-carboxylic acid,

(2-AMINOPHENYL)-amide 5-[(3-methylpentylamino)-methyl]-thiophene-2-carboxylic acid,

N-(2-AMINOPHENYL)-4-(propenolatomethyl)-benzamid,

N-(2-AMINOPHENYL)-4-(isobutylamino)-benzamid,

N-(2-AMINOPHENYL)-4-[(4-methylpentylamino)-methyl]-benzamide,

N-(2-AMINOPHENYL)-4-[(2-ethylbutylamine)-methyl]-benzamide,

N-(2-AMINOPHENYL)-4-(bucillamine)-benzamid,

N-(2-AMINOPHENYL)-6-[(4-methylpentylamino)-methyl]-nicotinamide,

N-(2-AMINOPHENYL)-6-[(3-methylpentylamino)-methyl]-nicotinamide.

20. The compound according to claim 1, in which

And indicates theoffender, phenylene or pyridinyl;

R1refers to the group-NR3R4in which R3and R4independently represent alkyl, alkenyl or quinil that may or may not contain one or more substituents selected from the group comprising halogen, cyano-, nitro-, amino group, -NH-alkyl and N(alkyl)2; or-CH2-(O-CH2-CH2-)mO-alkyl; -(CH2)n-(O)-alkyl; -(CH2)n-C(O)-NH-alkyl; -(CH2 )n-NH-C(O)-alkyl; -(CH2)n-C(O)alkyl; -(CH2)n-C(O)-O-alkyl; or

-(CH2)n-O-C(O)-alkyl;

n is 1-6;

m is 1-4;

and its pharmaceutically acceptable salts.

21. The compound according to claim 1 or 20, where And denotes 1,4-phenylene;

R1refers to the group-NR3R4in which R3and R4independently represent alkyl;

and its pharmaceutically acceptable salts.

22. Connection item 21 in which the compound is a

N-(2-AMINOPHENYL)-4-(3-butyl-3-methyluridine)-benzamide.

23. The drug is designed to inhibit proliferation of tumor cells, containing as active ingredients one or more compounds according to any one of claims 1 to 22, together with pharmaceutically acceptable excipients.

24. Drug for item 23, intended for inhibiting the proliferation of tumor cells by the induction of acetylation of histone in the indicated tumor cell.

25. Drug for item 23, intended for the treatment of cancer.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns to new diamides of pyrimidine-4,6-dicarboxylic acid of I formula, selective inhibitors of collagenases possessing properties which concern to the metalloproteinase superfamily and the matrix metalloproteinases. The bonds render influence on hyperactivity of the matrix metalloproteinase-13 (MMP-13) and thus do not render influence on MMP-3 and MMP-8. In the formula I R1 means an atom of hydrogen, R2 means - (C1-C6)-alkyl where alkyl is unitary replaced by phenyl where phenyl is replaced 1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 identical or different and independently from each other mean i) atom of hydrogen or ii) - (C1-C6)-alkyl or R9 and R10 together with atom of nitrogen to which they are bound, form 5, 6-links the sated cycle, and instead of one or two other atoms of carbon there can be also a heteroatom from an oxygen row, sulphur and nitrogen, and in case of nitrogen atoms of nitrogen independently from each other can be unsubstituted or substituted with (C1-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-SN, 3) -O-(C0-C6)-alkyl-C(O)-N(R9)-(R10) where R9 and R10 have the specified above value, 4) -(C0-C6)-alkyl-C(O)-N (R8)-(C0-C6)-alkyl-N(R9)-(R10) where R8 means hydrogen, R9 and R10 have the specified above value, 5) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-Het, and R8 has the specified above value, and Het means the sated or nonsaturated monocyclic heterocyclic system with number of links from 3 to 6 which contains in a cycle of 1 or 2 identical or different heteroatoms from a number nitrogen, oxygen and sulphur and unsubstituted or one-, two- or triple independently from each other is replaced by halogen, b) hydroxy,) -(C1-C6)-alkyl, and alkyl is unsubstituted or one-, two- or triple is substituted by halogen, d)=0,e)-Het, R4 and R5 or R5 and R6 together with atom of Carboneum to which they are bound, independently from each other form 5 or 6-unit cycle which is sated and contains one or two heteroatoms from an oxygen row.

EFFECT: obtaining of bonds which can find application for treatment of degenerate diseases of joints, such as osteoarthritis, rheumatic disease.

7 cl, 3 tbl, 117 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention concerns to 3,4-disubstituted tsiklobuten-1,2-diones of the formula I or their pharmaceutically to comprehensible salts or solvates, . A is chosen from the group including

X=-O-, -NH-, -S-,

.

n=1-5

B is chosen from the group including

. The bonds can be used at treatment of mediated chemokine diseases, such as acute both chronic inflammatory diseases and a cancer. The pharmaceutical composition and application of bonds I are also described.

EFFECT: obtaining of bonds which can be used at treatment of mediated chemokine diseases, such as acute both chronic inflammatory diseases and cancer.

50 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: compound of formula I , its diastereomers or salts, where dot line represents optional double bond, m and p independently stand for 0, 1, 2 or 3; R1 stands for H, -N(R8)-C(O)-NR6R7, -N(R8)-S(O)2-NR6R7, -N(R8)-C(O)-N(R8a)-S(O)2-NR6R7, etc.; R1a stands for H or group OH; or R1 or R1a together form oxo; or R1 and R1a together with carbon atom, to which they are bound, form optionally substituted oxo spiro-condensed heterocyclic group, representing fully saturated 5-member monocyclic group, containing 2 nitrogen atoms; R2 stands for heteroaryl, (heteroary)alkyl, representing 5-6-member aromatic ring, contaning 1 nitrogen atom and/or 1 atom of oxygen and/or sulphur, and optionally condensed with aryl ring; aryl, (aryl)alkyl, alkyl, alkenyl or cycloalkyl, representing partly or fully saturated C3-C6 monocyclic structure, any of which can be optionally, independently, substituted with one or more groups T1, T2 or T3; J stands for bond, C1-4 alkylene, R3 stands for -R5, -C(Z1)-R5, -N(R8a1)-C(Z1)-R5, -N(R8a1)-C(Z1)-O-R5, -N(R8a1)-S(O)2-R5; R4 stands for alkyl, halogenalkyl, cycloalkyl, aryl, which can be optionally condensed with heteroaryl 6-member ring, containing 1-2 heteroatoms, selected from group SO2, N, etc.; R5 stands for -NR6aR7a or heteroaryl, (heteroaryl)alkyl, representing 5-6-member aromatic ring, which contains 1-3 nitrogen atoms and/or 1 or 2 atoms of oxygen or sulphur, optionally condensed with heteroaryl ring, representing 6-member aromatic ring, containing 1 nitrogen atom, etc.; R6a, R7a independently represent H, alkyl, aryl, (aryl)alkyl, heteroaryl, representing 5-6-member aromatic ring, which contains 1-2 nitrogen atoms, optionally condensed with aryl or heteroaryl ring, representing 6-member aromatic ring with 1 nitrogen atom; any of which can be optionally, independently, substituted with one or more groups T1c, T2c or T3c; R6, R7, R8, R8a, R8a1 R8a2, and R9, independently, represent H, alkyl, hydroxy, alkoxy, (hydroxy)alkyl, (alkoxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, -NR12R13, cycloalkyl, (cycloalkyl)alkyl, optionally condensed with aryl; aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, etc.; R10, R10a, R11 and R11a, independently, represent H, alkyl, aryl, (aryl)alkyl, , hydroxy, (hydroxy)alkyl; heteroaryl, (heteroaryl)alkyl, representing 5-member aromatic ring, which contains 2 nitrogen atoms, or R11 and R11a can together form oxogroup, or R10a can together with R11a form bond, or R10 can together with R9 form saturated 3-4-member cycle; R12 and R13, independently, represent H, alkyl; W represents =NR8a2, =N- CO2R8a2, =N- CN; X represents C(=O), C=N-CN; Z1represents =O, or =N-CN; RX represents one optional substituent, bound with any suitable carbon atom in cycle, independently selected from T1g, T2g or T3g. Compounds of formula I are applied for manufacturing medication for treatment of IKur-mediated disorders.

EFFECT: cycloalkyl compounds, useful as inhibitors of potassium channels function.

13 cl, 694 ex, 1 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: chemistry.

SUBSTANCE: in compound of general formula I or its pharmaceutically acceptable salts or N-oxides R1 stands for , R2 stands for R3 stands for C0-4alkyl.

EFFECT: possibility to use compounds in elaboration of anti-cancer pharmaceutical preparations.

11 cl, 1 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: compounds of formula (I) can be efficient with respect to diseases, in which phosphorylation of Tau protein takes place. , R3 stands for CONR1R2, where R1 and R2 can be substituted with heterocycle; R5, R6, R7 independently on each other are selected from halogen and phenyl; R1, R2 independently on each other stand for hydrogen, (C1-C6)alkyl or together with nitrogen of group CONR1R can form heterocycle.

EFFECT: obtaining novel biologically active compounds.

4 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) X stands for C, N; R1 stands for H or (lower) alkyl, R2 stands for 9(lower) alkyl, -(CH2)n-R2a; R2a stands for C3-C8cycloalkyl, optionally and independently mono-, di-, tri- or tetrasubstituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent saturated heterocyclic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent heteroaromatic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, C3-C6cycloalkyl; R3 stands for C3-C6cycloalkyl, being optionally and independently mono-, di- or tri- or tetra-substituted with groups: OH, (lower) alkyl, (lower)alkoxy, phenyl, which optionally and independently is mono-, di- or tri- or tetra-substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; R4 stands for 5- or 6-member single-valent heteroaromatic ring, containing from one to two nitrogen heteroatoms, said heteroaromatic ring being optionally and independently mono-, di- or tri- substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, halogen; naphtyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; or phenyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, nitro, halogenated (lower)alkyl, halogenated (lower)alkoxy, cyano, (lower)alkylsulfonyl, -NR7R8; or two neighbouring substituents in said phenyl residue together represent -O-(CH2)p-O-, -(CH2)2-C(O)NH-; R5 and R6 each independently represent H, (lower)alkyl; R7 and R8 each independently represent hydrogen, (lower)alkyl, or R7 and R8 together with nitrogen atom, to which they are bound, form 5- or 6- member saturated or aromatic heterocyclic ring, which optionally contain nitrogen as additional heteroatom; said saturated or aromatic heterocyclic ring, being optionally substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy; m equals 1 or 2, n equals 0 or 1, p equals 1, 2 or 3; or their pharmaceutically acceptable salts.

EFFECT: increased antagonistic activity of compounds.

19 cl

FIELD: chemistry.

SUBSTANCE: in novel substituted aryl ketones of formula (I) Z stands for groupings and A1, A2, A3, R1, R2, R3, R4, R5, R6, R7, X and Y and m are such as given in formula of invention. In substituted aryl carboxylic acid of formula (II) and derivative of aryl carboxylic acid of formula (III) A1, A2, A3, R1, R2, X and Y are such as given in item 1 of invention formula, R12 stands for allyl, which are intermediate products. Also described is means to fight undesirable plants based on formula (I) compound.

EFFECT: increased herbicidal activity.

7 cl, 3 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to acidylated heteroarylcondensed cycloalkenylamines with formula I in any of their stereoisomeric form or in form of their mixtures in any ratio, or their pharmaceutical salts, where in formula I: ring A represents an aromatic 6-member ring, containing 1 nitrogen atom, or a 5-member aromatic ring, containing 1 sulphur atom; one or two of R1, R2, R3 and R4 is independently chosen from a group consisting of hydrogen, halogen or C1-C4-alkyl, and the other R1, R2, R3 and R4 represent hydrogen; R5 represents an Ar group or Hetar group. Description is also given of a pharmaceutical composition based on compound with formula I and use of the latter.

EFFECT: regulation of the expression of the enzyme endothelial NO-synthesis.

10 cl, 31 ex

FIELD: medicine; pharmacology.

SUBSTANCE: present invention is referred to the method of obtaining of glycopyrroniumbromide stereoisomers or an iodide-formula: from an admixture where A- = Br or I, R means phenyl or thienyl.

EFFECT: obtaining with high output of biologically active diastereoisomer glycopyrroniumbromide or iodide.

1 cl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns to new diamides of pyrimidine-4,6-dicarboxylic acid of I formula, selective inhibitors of collagenases possessing properties which concern to the metalloproteinase superfamily and the matrix metalloproteinases. The bonds render influence on hyperactivity of the matrix metalloproteinase-13 (MMP-13) and thus do not render influence on MMP-3 and MMP-8. In the formula I R1 means an atom of hydrogen, R2 means - (C1-C6)-alkyl where alkyl is unitary replaced by phenyl where phenyl is replaced 1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 identical or different and independently from each other mean i) atom of hydrogen or ii) - (C1-C6)-alkyl or R9 and R10 together with atom of nitrogen to which they are bound, form 5, 6-links the sated cycle, and instead of one or two other atoms of carbon there can be also a heteroatom from an oxygen row, sulphur and nitrogen, and in case of nitrogen atoms of nitrogen independently from each other can be unsubstituted or substituted with (C1-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-SN, 3) -O-(C0-C6)-alkyl-C(O)-N(R9)-(R10) where R9 and R10 have the specified above value, 4) -(C0-C6)-alkyl-C(O)-N (R8)-(C0-C6)-alkyl-N(R9)-(R10) where R8 means hydrogen, R9 and R10 have the specified above value, 5) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-Het, and R8 has the specified above value, and Het means the sated or nonsaturated monocyclic heterocyclic system with number of links from 3 to 6 which contains in a cycle of 1 or 2 identical or different heteroatoms from a number nitrogen, oxygen and sulphur and unsubstituted or one-, two- or triple independently from each other is replaced by halogen, b) hydroxy,) -(C1-C6)-alkyl, and alkyl is unsubstituted or one-, two- or triple is substituted by halogen, d)=0,e)-Het, R4 and R5 or R5 and R6 together with atom of Carboneum to which they are bound, independently from each other form 5 or 6-unit cycle which is sated and contains one or two heteroatoms from an oxygen row.

EFFECT: obtaining of bonds which can find application for treatment of degenerate diseases of joints, such as osteoarthritis, rheumatic disease.

7 cl, 3 tbl, 117 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention concerns bonds, applicable for treatment of diseases mediated by the HIV virus, formula I where X1 is chosen from R5O, R5S(O)n, R5CH2, R5CH2O, R5CH2S(O)n, R5OCH2 and R5S(O)nCH2; R1 and R2 are chosen from H, NH2, alkyl, haloalkyl, cycloalkyl, alkoxy, alkylthio, halogen, alkylamino, dialkylamino, nitro and cyano; or in common form-CH=CH-CH=CH- or five-term heterocycle with the heteroatom chosen from O and S; R3 is chosen from H, halogen, nitro and cyano; R4 is chosen from H, NH2, alkyl, haloalkyl, cycloalkyl, alkoxy, alkylthio, halogen, alkylamino, dialkylamino, nitro and cyano; R5 the pyridine-N-oxide, indole, chinoline, chinoline-N-oxide is chosen from alkyl, cycloalkyl and unessentially replaced phenyl, naphthyl, pyridinil; R7 and R8 are chosen from H, NH2, an alkylamin, dialkylamine and unessentially substituted C1-C6alkyl; n is chosen from 0, 1, 2.

EFFECT: obtaining of new inhibitors by reverse transcriptase.

2 cl, 46 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to compounds of formula (I) or their pharmaceutically acceptable salts, where Q represents optionally substituted with 1-3 substituents, determined in formula, phenyl or pyridyl or pyrodazinyl; R2 represents C1-6alkyl or aminogroup, determined in item 1 of formula or C1-6alkyl, substituted with said aminogroup; bond between oxygen atom O* and adjacent carbon atom C1 or (i) is double bond, which determines carbonyl group [C(=O)], where R6 represents C1-6alkyl or cyclopropyl; or (ii) represents simple bond, where, in case of simple bond, said oxygen atom O*, is in addition bound to group R6 and, taken together with R6 and with adjacent nitrogen atom, determines optionally substituted with C1-6alkyl, oxadiazolyl ring, bond between C1 and adjacent nitrogen atom being double bond.

EFFECT: obtaining medications which are useful in obtaining medications for treatment of conditions connected with p38 kinase and/or in obtaining medications for treatment of inflammatory diseases or conditions in patient.

8 cl, 6 tbl, 88 ex

FIELD: chemistry.

SUBSTANCE: obtaining optically active 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl)-1H-benzo[d]imidazole, demonstrating anti-ulcer activity, by enantioselective oxidation by organic proxides of 5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methyltio)-1H-benzo[d]imidazole in presence of catalyst in organic solvent, as catalyst, preliminary obtained in situ complex of vanadium salt with chiral Shiff base, described by general formulas III and IV, , is used, substituents R1, R2, R3, R4 can be similar or different and can be hydrogen atom, alkyl group (including ones which contain halogen atoms), alkyloxy group (including ones containing halogen atoms), nirtogroup, dialkylamino group, halogen; R5 is optically active substituent; reaction is carried out at reduced temperature with possible presence of organic base with further product isolation by usual methods.

EFFECT: novel compounds possess useful biological properties.

1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: method lies in enantioselective oxidation with organic peroxides of (S)-5-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methylthio)-1H-benzo[d]imidazole in presence of catalytic complex of titanium (IV) with simultaneously two chiral ligands: chiral diol (preferably D-diethyltartrate) and chiral amine (preferably N,N-dimethyl-(R)-1-phenylethylamin).

EFFECT: increase of target product or its salt output.

1 cl, 1 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) HetAr represents pyrimidinyl or thiadiasolyl; R1 and R2 represent H; A represents C1-C2-alkyl; B represents aryl(CH2)0-3-O-C(O)-or arylcyclopropyl-C(O)-, in which aryl can be substituted with 1-5 substituents, each substituent represents C1-C4-alkyl. Invention also relates to pharmaceutical composition and to application of compounds of item 1. Obtaining novel compounds, as well as pharmaceutical composition possessing NMDA/NR2B antagonist activity.

EFFECT: increase of composition efficiency.

13 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: compounds of formula (I) can be efficient with respect to diseases, in which phosphorylation of Tau protein takes place. , R3 stands for CONR1R2, where R1 and R2 can be substituted with heterocycle; R5, R6, R7 independently on each other are selected from halogen and phenyl; R1, R2 independently on each other stand for hydrogen, (C1-C6)alkyl or together with nitrogen of group CONR1R can form heterocycle.

EFFECT: obtaining novel biologically active compounds.

4 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) X stands for C, N; R1 stands for H or (lower) alkyl, R2 stands for 9(lower) alkyl, -(CH2)n-R2a; R2a stands for C3-C8cycloalkyl, optionally and independently mono-, di-, tri- or tetrasubstituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent saturated heterocyclic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent heteroaromatic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, C3-C6cycloalkyl; R3 stands for C3-C6cycloalkyl, being optionally and independently mono-, di- or tri- or tetra-substituted with groups: OH, (lower) alkyl, (lower)alkoxy, phenyl, which optionally and independently is mono-, di- or tri- or tetra-substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; R4 stands for 5- or 6-member single-valent heteroaromatic ring, containing from one to two nitrogen heteroatoms, said heteroaromatic ring being optionally and independently mono-, di- or tri- substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, halogen; naphtyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; or phenyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, nitro, halogenated (lower)alkyl, halogenated (lower)alkoxy, cyano, (lower)alkylsulfonyl, -NR7R8; or two neighbouring substituents in said phenyl residue together represent -O-(CH2)p-O-, -(CH2)2-C(O)NH-; R5 and R6 each independently represent H, (lower)alkyl; R7 and R8 each independently represent hydrogen, (lower)alkyl, or R7 and R8 together with nitrogen atom, to which they are bound, form 5- or 6- member saturated or aromatic heterocyclic ring, which optionally contain nitrogen as additional heteroatom; said saturated or aromatic heterocyclic ring, being optionally substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy; m equals 1 or 2, n equals 0 or 1, p equals 1, 2 or 3; or their pharmaceutically acceptable salts.

EFFECT: increased antagonistic activity of compounds.

19 cl

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds -acidified arylcycloalkylamins of formula I in any of their stereoisomeric forms or in form of their mixture in any ratio, or their pharmaceutically acceptable salts, where in formula I : R1 represents aryl, not obligatory substituted with one or two similar or different substitutes, selected from group that includes C1-C6-alkyl and halogen; R2 represents aryl or heteroaryl, which represents residue of 5-6-member aromatic monocyclic heterocycle, containing 1-2 nitrogen atoms as heteroatom and/or 1 sulfur atom or oxygen atom, or residue of 9-10-member aromatic bicyclic heterocycle, containing 1-2 nitrogen atoms as heteroatom, each of which is unsubstituted or contains 1-3 similar or different substitutes, selected from group, consisting of halogens, NH2, unsubstituted C1-C10-alkyl, C1-C10 -alcoxy, C1-C10-alkylamino and di(C1-C10-alkyl)amino, and at least monosubstituted C1-C10-alkyl, etc., n represents 1, 2, 3 or 4. Invention relates to pharmaceutical composition, stimulating expression of endothelial NO synthase, based on said compounds, as well as application of compounds of formula I for production of medication for stimulating expression of endothelial NO-synthase and for treatment of such cardiovascular diseases as atherosclerosis, thrombosis, coronary artery disease, hypertension and impaired cardiac function.

EFFECT: invention ensures enhancing composition and treatment method efficiency.

9 cl, 2 tbl, 41 ex

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