Novel pyrrole derivatives with histone deacetylase inhibiting activity

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrole derivatives of the formula I: , where R1 and R2 independently denote Ph; mono- or disubstituted in different positions of the ring Ph, where substitute denotes -OCH3; C5-heteroaryl with one heteroatom selected from O or S; R2 denotes H, NO2, NH2, C(O)NH2; R4 denotes H, a straight or branched C1-C6-alkyl; n equals the number of methylene groups and is between 1 and 8 inclusively; X denotes O, S, NH; Y NH, -CH2-; Z denotes O, S; W denotes -OH, hydroxylamine, hydrazine, alkylhydrazine.

EFFECT: compounds can inhibit histone deacetylase, which enables their use in cancer treatment.

10 cl, 9 dwg, 18 ex

 

The invention relates to new compounds derived from pyrrole, method of their production and their use as drugs for cancer treatment in the form of pharmaceutical compositions due to their inhibitory effect on some discontiuation.

Chemical synthesis of compounds with tri - and Tetra-substituted pyrrole rings can be performed in several ways using methodologies consistent or convergent synthesis (Sundberg, in Comprehensive Heterocyclic Chemistry; Katrizki, A. and Rees, C. W. Eds.; Pergamon: Oxford, 1984; Vol. 4, p. 313). One rather common way of obtaining is aromatization of substituted pyrrolidines (Fejes et al. Tetrahedron 2000, 56, 8545. Gupta et al. Synth. Commun. 1998, 28, 3151). Last heterocyclic compounds can, in turn, get in a convergent form using cycloaddition reaction between alkenes and isometamidium (Ayerbe et al. J. Org. Chem. 1998, 63, 1795. Vivanco et al. J. Am. Chem. Soc. 2000, 122, 6078). It is also known that the reaction of a combination of derivatives of carboxylic acids with hydroxylamine leads to the formation of hydroxamic acids (Reddy et al. Tetrahedron Lett. 2000, 41, 6285), in addition reactions between substituted amines and phosgene derivatives and thiophosgene produce through education intermediate isocyanates or thiocyanates of the corresponding N-hydroxylation, N-hydroxytamoxifen, N-(alkyl)aminoacetic and N-(alkyl)aminothio is echevin (Jain et al. Bioorg. Med. Chem. Lett. 2003, 13, 4223).

On the other hand, it is known that inhibitors discontiuation (HDAC) are a promising way to treat cancer through mechanisms blocking the growth of some tumors (McLaughin et al. Biochem. Pharm. 2004, 68, 1139. Kramer et al. Trends Endocrin. Met. 2001, 12, 294. Archer et al. Curr. Opin. Genet. Dev. 1999, 9, 171). Although detailed mechanisms of therapeutic action of the above inhibitors is not well known, there is General consensus that the inhibition of the active centers HDAC facilitates the access of certain genes to transcription factors by acetylation of histones, which are localized in certain areas of DNA which encodes proteins regulating cell cycle, such as cyclin-dependent kinases P21 (Archer et al. Proc. Natl. Acad. Sci. USA 1998, 95, 6791). Another advantage of this therapeutic goal is the fact that, as installed, only about 2% of the transcription of DNA into mRNA is modulated by HDAC inhibitors (McLaughin et al. Biochem. Pharm. 2004, 68, 1139), which must be the result of the low toxicity of these inhibitors, which were observed in clinical studies (Van Lint et al. Gen. Express 1996, 5, 245. Glaseret al. Mol. Cancer Ther. 2003, 2, 151). In the same way, it is established that the clinical suitability of the HDAC inhibitors can be improved through the use of a synergistic combination with other treatments to improve transcriptional profiles of genes that difficult time is United of resistance (Keen et al. Cancer Res. Treat. 2003, 81, 177. Egger et al. Nature 2004, 429, 457).

There are various collections of HDAC inhibitors, the General characteristics of which can be found in various reviews (Villar-Garea and Esteller Int. J. Cancer 2004, 112, 171 and Curr. Drug Metab. 2003, 4, 11. Grozinger et al. Chem. Biol. 2002, 9, 3. McLaughlin et al, Drug Discov. Today 2003, 8, 793. Monneret Eur. J. Med. Chem. 2005, 40, 1, Biel et al. Angew. Chem. Int. Ed. 2005, 44, 3186). In the General structure of the most active inhibitors characterized by a cyclic or polycyclic part of predominantly hydrophobic nature related carbon intermediate chain link that can coordinate with a metal ion of the active site of HDAC. In particular, describes the synthesis of 3-(4-aroyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide as HDAC inhibitors (cf. Mai et al. J. Med. Chem. 2004, 47, 1098). In this case, the intermediate circuit is unsaturated and regulations 3 and 5 of the pyrrole ring are unsubstituted, which leads to a linear molecular geometry.

Despite a number of inhibitors obtained synthetically, their therapeutic usefulness is not devoid of problems, among them it is necessary to specify the selectivity of inhibition of different HDAC, some of which are not suitable therapeutic targets in Oncology, toxicity, and chemical instability. In this context, the present invention describes a General method for the synthesis of novel HDAC inhibitors, which provides about is adowanie a large number of functional groups which results in a chemically stable molecules with various polycyclic systems, the dimensions of the connecting chains and links of coordination with the metal atom of the enzymes that inhibit.

The problem outlined in the present invention, therefore, should be resolved by the proposal of the compounds and compositions with high selectivity in the inhibition of different HDAC associated with the emergence and development of neoplastic processes, with high chemical stability and low toxicity. The proposed resolution of the problem involves the use of derivatives of pyrrole of formula I. These compounds are aryl or heteroaryl substituents in positions 3 and 5, as well as elektropitayuschie groups, such as the nitrate group in position 4, and heterogeneous groups in position 2, which consist of connecting groups of different nature and groups N-hydroxyacetone, N-alkylamino(aryl)urea, N-hydroxytamoxifen and N-(alkyl)amino, (aryl)thiourea for the coordination of the metal ion HDAC. These derivatives of pyrrole demonstrates a high ability to inhibit cell proliferation and tumor growth.

Briefly, it is assumed that the present invention solves the problem of the existing needs inhibitors discontiuation, making available such inhibitors possessing such advantages is the EU ETS, as good pharmacological properties, stability in the solid phase and in solution, the ease and efficiency of their chemical synthesis and the availability and diversity of the source of chemical compounds.

A brief description of graphic materials

The figure 1 shows the effect shown in vitro some of the compounds of the present invention, on the activity of orally bioavailable cell lines NST (carcinoma human colon) compared with the TSA (the acronym of trichostatin a) and SAHA (acronym of suberoylanilide hydroxamic acid), used as positive control.

The figure 2 shows the effect in vitro of representative examples of the considered compounds of the present invention, on the activity of orally bioavailable cell line MOLT4 (fibroblastic the human leukemia) compared to the TSA and SAHA, used as a positive control.

The figure 3 shows the quantitative data of the level of acetylation, obtained by applying NRSE (high performance capillary electrophoresis), histones H3 and H4 cell line promyelocytes human leukemia Jurkat treated some of the considered compounds of the present invention at a concentration of 10 ám.

The figure 4 shows the measurement data of the percentage of apoptotic and necrotic cells in the presence of different is oncentrate SAHA and two considered inhibitors of the present invention. Also includes data obtained with the control sample and the sample treated with DMSO. Data shown correspond to the data model NST carcinoma human colon.

The figure 5 shows the measurement data of the percentage of apoptotic and necrotic cells in the presence of various concentrations of SAHA and the two considered inhibitors of the present invention. Also includes data obtained with the control sample and the sample treated with DMSO. Data shown correspond to the data model HL60 acute myeloid leukemia person.

The figure 6 shows the inhibition of tumor growth carcinoma NST human colon in "Nude" mice with absence of the thymus gland, caused by intraperitoneal administration of some of the considered compounds of the present invention. Xenoplanets carried out vnutrikletochnym way and inhibitors were injected with intraperitoneal follows according to the method detailed in example 18.

The figure 7 shows the in vivo antitumor activity of some of the considered compounds of the present invention, seen in "Nude" mice with absence of the thymus gland on the model LT4 fibroblastoma human leukemia. Xenoplanets carried out vnutrikletochnym follows according to the method detailed in example No. 17.

Task this is part II of the invention are derivatives of pyrrole General formula I:

Thus, another objective of the present invention are methods of obtaining compounds of General formula I.

Another additional object of the invention is the use of these derivatives for the treatment of different cancers limit tumor growth by inhibiting the action of some orally bioavailable.

And finally, this invention has as objectives the receipt of pharmaceutical compositions, which may include any derivative of pyrrole General formula I and at least one acceptable pharmaceutical excipient.

Detailed description of the invention

First, the present invention provides certain compounds, which are derivatives of pyrrole, which have the following formula I:

where

R1and R3independently represent a phenyl radical; a mono - or politeley in different positions of the phenyl ring or C5-C10-heteroaryl group which contains at least one heteroatom of O, N or S;

R2represents a hydrogen atom or electrostrictively group such as the nitro-group; or amino - or aminogroup;

R4represents a hydrogen atom or an unbranched, branched or cyclic C1-C6-alkyl group;

n is the Chi is Lou methylene groups between 1 and 8 inclusive;

X represents a secondary amino group, oxygen atom or sulfur ion;

Y represents a group selected from methylene, substituted methylene, and a secondary amine;

Z is either an oxygen atom or a sulfur atom, and

W represents a group selected from hydroxyl, hydroxylamine, hydrazine and alkyl-, aryl - or literaryheroine.

In a preferred embodiment, the compounds of formula I are

- 6-(3,5-diphenyl-1H-pyrrol-2-carboxamido)hexanoic acid following structural formula:

- 6-(4-nitro-3,5-diphenyl-1H-pyrrol-2-carboxamido)hexanoic acid following structural formula:

- N-(5-(hydroxycarbamoyl)pentyl)-3-phenyl-5-(4-methoxyphenyl)-1H-pyrrol-2-carboxamide following structural formula:

- N-(5-(hydroxycarbamoyl)pentyl)-5-phenyl-3-(4-methoxyphenyl)-1H-pyrrol-2-carboxamide following structural formula:

- N-(5-(hydroxycarbamoyl)pentyl)-3-phenyl-5-(4-methoxyphenyl)-4-nitro-1H-pyrrol-2-carboxamide following structural formula:

- 1-(4-(3,5-bis-(3,5-acid)-1H-pyrrol-2-carboxamido)butyl)-3-hydroxyurea following structural formula:

- 1-(4-(5-(4-meth is xifei)-4-nitro-3-(thiophene-2-yl)-1H-pyrrol-2-carboxamido)butyl)-3-(2-methylamino)urea following structural formula:

Another aspect of the invention relates to various methods of preparing compounds of General formula I. Then will be described in the following methods a to E obtain the compounds of formula (Ia), (Ib), (Ic) and (Id). The aforementioned compound (Ia)-(Id) are compounds of the General formula which come in a range of General formula I.

Method And

Method And obtain the compounds of General formula (Ia):

where R1, R2, R3, R4, X and n have the meanings indicated above, includes a reaction mixture consisting of

a) 1H-pyrrole-2-carboxylic acid of the formula II

b) compounds of the formula III

NH-(CH2)n-R5(III)

where R5is alkoxycarbonyl,

C) a reagent for the activation of carboxyl groups and

d) a tertiary amine selected from cyclic or acyclic aliphatic amines with 3-10 carbon atoms and alkanolamides amines with 9-15 carbon atoms,

and reaction of the resulting product with a mixture of lithium hydroxide or sodium, dimethoxyethane and water.

For the purposes of the invention the reaction product of a mixture of four compounds of points from a) to d) can be obtained by adding one of the components in an organic solvent at temperatures from -85°C to +25°C, preferably at a temperature of about 0°C, p is ed by the addition of three other components. Then this mixture was incubated for a certain period of time for completion of the reaction, while the temperature of the mixture rises to ambient temperature. After completion of the reaction, the combination of the ester obtained after processing method, is subjected to reaction with a mixture of lithium hydroxide or sodium, dimethoxyethane and water, thereby obtaining, after appropriate processing, the compounds of General formula (Ia).

Method In

The method of obtaining compounds of General formula (Ib):

where R1, R2, R3, R4, X and n have the meanings indicated above, includes a reaction mixture consisting of

a) 1H-pyrrole-2-carboxylic acid of the formula II

b) compounds of the formula III

NH-(CH2)n-R5(III)

where R5is alkoxycarbonyl,

C) a reagent for the activation of carboxyl groups and

d) a tertiary amine selected from cyclic or acyclic aliphatic amines with 3-10 carbon atoms and alkanolamides amines with 9-15 carbon atoms,

and adding to the resulting product mixture of hydroxylamine hydrochloride and phenolphthalein in the presence of excess of sodium methoxide in methanol.

For the purposes of the invention the reaction product of a mixture of four compounds of points from a) to d) p is to be obtained by adding one of the components in an organic solvent at temperatures from -85°C to +25°C, preferably at a temperature of about 0°C, before adding the other three components. Then this mixture was incubated for a certain period of time for completion of the reaction, while the temperature of the mixture rises to ambient temperature. After completion of the reaction, the combination of the obtained ester is added to a mixture of hydroxylamine hydrochloride and phenolphthalein in the presence of excess of sodium methoxide in methanol. After completion of the reaction and after receive appropriate treatment of compounds of General formula (1b).

Way

The method of obtaining compounds of General formula (Ic)

where R1, R2, R3, R4X, Z and n have the meanings indicated above, includes a reaction mixture consisting of

a) 1H-pyrrole-2-carboxylic acid of the formula II

b) compounds of the formula III

NH-(CH2)n-R5(III)

where R5represents a tert-butoxycarbonyl (NHBoc) or benzyloxycarbonyl(NHCBz),

C) a reagent for the activation of carboxyl groups and

d) a tertiary amine selected from cyclic or acyclic aliphatic amines with 3-10 carbon atoms and alkanolamides amines with 9-15 carbon atoms,

unprotect the resulting product with application processing acid or hydrolysis and ricciardetto with phosgene or its equivalent, such as diphosgene, triphosgene or thiophosgene, obtaining isocyanate or thioisocyanate, which is treated with hydroxylamine.

For the purposes of the invention the reaction product of a mixture of four compounds of points from a) to d) can be obtained by adding one of the components in an organic solvent at temperatures from -85°C to +25°C, preferably at a temperature of about 0°C, before adding the other three components. Then this mixture was incubated for a certain period of time for completion of the reaction, while the temperature of the mixture rises to ambient temperature. Depending on the values of R5in compound III, i.e. depending on whether an R5tert-butoxycarbonyl (NHBoc) or benzyloxycarbonyl (NHCBz), the subsequent processing will be different. In the case when R5represents NHBoc, the resulting product should be subjected to acid treatment, preferably by reaction at ambient temperature with triperoxonane acid in a halogenated solvent. When R5represents NHCBz, the resulting product is subjected to hydrogenolysis, preferably by reaction with gaseous hydrogen or ammonium formate in alcohol with a short circuit as a solvent and in the presence of a heterogeneous palladium catalyst. In both cases, the Le unprotect receive primary amine, which is treated with phosgene or one of its derivatives, such as diphosgene or triphosgene, or thiophosgene. When the reaction is carried out with phosgene, diphosgene or triphosgene, the target compound (Ic) will have an oxygen atom as Z. If, on the other hand, the treatment is carried out by thiophosgene, Z is a sulfur atom.

After the reaction, or with phosgene (diphosgene, triphosgene) or thiophosgene receive the corresponding isocyanates or thioisocyanate, which is treated in situ with hydroxylamine to obtain the compounds of formula (Ic).

Method D

Method D of obtaining compounds of General formula (Id):

where R1, R2, R3, R4X, Z and n have the meanings indicated above and R6represents H, C1-C6-alkyl, aryl or heteroaryl with 5 or 6 members and 1 or more heteroatoms selected from O, N or S, and includes a reaction mixture consisting of

a) 1H-pyrrole-2-carboxylic acid of the formula II

b) compounds of the formula III

NH-(CH2)n-R5(III)

where R5represents a tert-butoxycarbonyl (NHBoc) or benzyloxycarbonyl (NHCBz),

C) a reagent for the activation of carboxyl groups and

d) a tertiary amine selected from cyclic or acyclic aliphatic amines with 3-10 carbon atoms and Alcanar the case of amines with 9-15 carbon atoms,

unprotect the resulting product with application processing acid or hydrolysis and reaction of the product with phosgene or its equivalents, such as diphosgene, triphosgene or thiophosgene, obtaining isocyanate or thioisocyanate, which is treated with hydrazine or alkyl-, aryl - or heteroderinae.

For the purposes of the invention the reaction product of a mixture of four compounds of points from a) to d) can be obtained by adding one of the components in an organic solvent at temperatures from -85°C to +25°C, preferably at a temperature of about 0°C, before adding the other three components. Then this mixture was incubated for a certain period of time for completion of the reaction, while the temperature of the mixture rises to ambient temperature. Depending on the values of R5in compound III, i.e. depending on whether an R5tert-butoxycarbonyl (NHBoc) or benzyloxycarbonyl (NHCBz), the subsequent processing will be different. In the case when R5represents NHBoc, the resulting product should be subjected to acid treatment, preferably by reaction at ambient temperature with triperoxonane acid in a halogenated solvent. When R5represents NHCBz, the resulting product is subjected to hydrogenolysis, preferably reacties gaseous hydrogen or ammonium formate in alcohol with a short circuit as a solvent and in the presence of a heterogeneous palladium catalyst. In both cases, after removing the protection receive a primary amine, which is treated with phosgene or one of its derivatives, such as diphosgene or triphosgene, or thiophosgene. When the reaction is carried out with phosgene, diphosgene or triphosgene, the target compound (Ic) will have an oxygen atom as Z. If, on the other hand, the treatment is carried out by thiophosgene, then Z is a sulfur atom.

After the reaction, or with phosgene (diphosgene, triphosgene) or thiophosgene receive the corresponding isocyanates or thioisocyanate, which is treated in situ with hydrazines or acylhydrazone to obtain the compounds of formula (Id).

Method E

Method E is an additional method of obtaining compounds of General formula (Id):

where R1, R2, R3, R4X, Z and n have the meanings indicated above and R6represents H, C1-C6-alkyl, aryl or heteroaryl with 5 or 6 members and 1 or more heteroatoms selected from O, N or S, which includes a reaction mixture consisting of

a) 1H-pyrrole-2-carboxylic acid of the formula II

b) compounds of the formula III

NH-(CH2)n-R5(III)

where R5is a 3-benzyloxyphenyl or 3-alkyl-, -aryl - or-heteroarenes,

C) a reagent for activating carboxyl the Oh group and

d) a tertiary amine selected from cyclic or acyclic aliphatic amines with 3-10 carbon atoms and alkanolamides amines with 9-15 carbon atoms.

If described in detail above, the reaction mix is carried out with N-benzyloxyacetophenone or-timeonline, you only need to select the corresponding N-hydroxyacetone or-thiourea by hydrogenolysis in the presence of a suitable catalyst. In the case of N-alkyl(aryl, heteroaryl)aminoacetyl or thioureas, if these radicals are already entered in the appropriate precursors (III), the reaction mix gives directly the expected end of the connection.

As a General element methods a-E reagent activating the carboxy group is preferably phenyldichlorophosphine, diethylphosphoramidite (DEPC) or system formed of 1-hydroxybenzotriazole and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.

The tertiary amine component is a common reagent for methods a and b, selected from cyclic or acyclic aliphatic amines with 3-10 carbon atoms and alkanolamides amines with 9-15 carbon atoms. This tertiary amine is preferably selected from N-methylpyrrolidine or N-methylmorpholine.

Preferred is also carrying out reactions between elements from a) to d) each way And since when is emeniem irradiated with microwaves.

Obtaining a pre-specified compounds of the formula II is carried out in an organic solvent or in the absence of it and the irradiation of the microwaves in the first reaction mixture that includes:

a) nitroalkene with (E)- or (Z)-configuration the following formula IV

O2N-CH=CH-R3(IV)

where

R3has the values listed above;

b) Imin with (E)- or (Z)-configuration the following formula V

R1-CH=N-CH2-COOR6(V)

where

R1has the values listed above, and

R6represents C1-C6-alkyl or aryl group;

(C) a metal salt, preferably selected from lithium perchlorate, silver perchlorate or silver acetate, and

d) a tertiary organic base (amine)selected from cyclic or acyclic aliphatic bases with 3-10 carbon atoms and alkanolamides bases with 9-15 carbon atoms.

For the purposes of the invention the reaction mixture, consisting of four components, listed above, can be performed using microwave irradiation or the addition of one of the components is in excess relative to the other three in organic rest retele and at a temperature between -25°C and +25°C, preferably at a temperature of about +25°C. After completion of the reaction, cycloaddition receive a mixture of 2-alkoxycarbonylmethyl corresponding to the substituents selected for each specific reaction. This mixture is dissolved in cyclic simple ether, such as tetrahydrofuran, or simple acyclic ether with a high boiling point, such as bis-(2-methoxyethoxy) ether, also known as "diglyme", and add an oxidizing agent such as manganese dioxide, hydrogen peroxide or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. After some time at a temperature between +60°C and 250°C To obtain a mixture consisting of 2-alkoxycarbonyl-NH-pyrrole and the corresponding 2-alkoxycarbonyl-4-nitro-NH-pyrrole, components which can be divided by fractional crystallization or chromatography. Acids of General formula II get through alkaline hydrolysis previously obtained esters, preferably by processing them with lithium hydroxide or sodium in a mixture of water and dimethoxyethane.

An additional aspect of this invention relates to the use of these compounds of General formula I for the treatment of cancer. The mechanism of action of these compounds due to their antagonistic properties against orally bioavailable by blocking the synthesis of proteins responsible for regulation of such processes as apoptosis or growth CL is current and cell proliferation. These properties prevent or block the binding deacetylase and related enzymatic complexes with their natural substrates, such as lysine residues, N-acetylated at the ε-position terminal lysine of histone, so they remain a mono - or polyacetylenes condition.

The last aspect of the invention relates to a composition which comprises at least one of the compounds of General formula I and one or more acceptable pharmaceutical excipients. The compounds of formula I of the present invention can be introduced in the form of undiluted substance, as well as in the form of pharmaceutical preparations, although the introduction of a connection in the combined form is preferred. Combination therapy is preferably carried out with the use of the drug, which

i) contains only the compound of formula I;

ii) contains one or more excipients and/or substances vectors and

iii) may contain any additional therapeutically active substance.

Excipients, chemicals, carriers and excipients must be pharmaceutically and pharmacologically tolerant so that they can be combined with other components of the composition or preparation, and that they did not cause adverse effects in exposed treatment of the body.

The drug which include drugs, which are suitable for oral or parenteral administration (including subcutaneous, intradermal, intramuscular and intravenous), although the best route of administration will depend on the patient's condition.

Drugs can be in the form of a single dose and can be obtained according to known methods in the field of pharmacology. The number of active substances for administration may vary depending on the characteristics of therapy, although they usually vary between 1 mg and 500 mg per day in single or multiple doses.

To aid better understanding of the above concepts below are some working examples of the present invention. These examples are illustrative only.

Example 1

Getting 5-phenyl-3-(4-methoxyphenyl)-1H-pyrrole-2-carboxylic acid following structural formula:

and 5-phenyl-3-(4-methoxyphenyl)-4-nitro-1H-pyrrole-2-carboxylic acid following structural formula:

To a mixture of methyl-N-feniletilamina (14,17 g, 80,0 mmol) in acetonitrile (800 ml) was sequentially added triethylamine (12 ml, 80,0 mmol), silver acetate (1.98 g, to 11.9 mmol) and (E)-2-(4-methoxyphenyl)-1-nitroethane (14,33 g, 80,0 mmol). The development of the reaction is controlled by thin-layer chromatography. After completion of the reaction the mixture is filtered cher the C cushion celite and washed with saturated solution of NH 4Cl (2 x 150 ml) and water (2 × 150 ml). After drying over MgSO4the solution is evaporated under reduced pressure, thus obtaining a 26.5 g of a mixture of diastereoisomers of 5-phenyl-3-(4-methoxyphenyl)-2-methoxycarbonyl-4-nitropyridine. 12,22 g (34,27 mmol) of this mixture is dissolved in bis-(2-methoxyethanol) simple air (343 ml) in an atmosphere of inert gas and add manganese dioxide (29,8 g, 343 mmol). The reaction mixture is refluxed with stirring for 48 hours After this time the temperature of the mixture is brought to room temperature and the mixture filtered through a pad celite. The resulting solution was concentrated under reduced pressure, thus obtaining of 7.93 g of a mixture of 5-phenyl-3-(4-methoxyphenyl)-2-methoxycarbonyl-4-nitro-1H-pyrrole and 5-phenyl-3-(4-methoxyphenyl)-2-methoxycarbonyl-1H-pyrrole. The products are separated using flash column-chromatography, and each of them separately hydrolyzing, as indicated below. 10% NaOH (40 ml, aqueous solution) is added dropwise to a solution of the corresponding complex ether (4.0 mmol) in ethanol (100 ml)and the mixture is stirred at the boil under reflux. The development of the reaction is controlled by thin-layer chromatography. After completion of the reaction the mixture is cooled to 0°C, neutralized 1 N. HCl and extracted with methylene chloride (3 × 50 ml). The combined organic fractions dried over MgSO4and evaporated in ponie nom pressure, while receiving the corresponding carboxylic acid.

5-Phenyl-3-(4-methoxyphenyl)-2-methoxycarbonyl-1H-pyrrole-2-carboxylic acid: yield, 41% ; TPL 198°C (decomp.); IR 3467, 1643 cm-1;1H-NMR (δ ppm, DMSO-d6) 11,72 (s, 1H), 7,88 (d, 2H, J = 7,7 Hz), 7,51 (d, 2H, J = 8,4 Hz), 7,38 (t, 2H, J = 7,6 Hz), 7,26 (t, 1H, J = 7,2 Hz), 6,91 (d, 2H, J = 8,4 Hz), 6,69 (s, 1H), of 3.78 (s, 3H), 3,34 (user. s, 1H);13C-NMR (δ ppm, DMSO-d6) 162,5, 157,9, 134,4, 131,3, 131,2, 130,3, 128,6, 127,9, 127,0, 125,1, 119,8, 113,0, 112,9, 109,3, 55,0, 54,9. Anal. calc. for C18H15NO3: C 73,71; H, 5,15; N, 4,78. Found: C, 73,56; H, To 5.08; N, To 4.81%.

5-Phenyl-3-(4-methoxyphenyl)-4-nitro-1H-pyrrole-2-carboxylic acid: yield, 28%; TPL 190°C; IR 3437, 1663, 1493 cm-1;1H-NMR (δ ppm, DMSO-d6) EUR 7.57-7,52 (m, 2H), of 7.48-the 7.43 (m, 3H), from 7.24 (d, 2H, J = 8,4 Hz), 6.90 to (d, 2H, J = 8,4 Hz), 3,79 (s, 3H);13C-NMR (δ ppm, DMSO-d6) 161,6, 158,3, 133,5, 132,5, 131,1, 129,3, 129,0, 128,0, 124,5, 124,2, 121,1, 112,7, 54,9. Anal. calc for C18H14N2O5: C, 63,90; H, TO 4.17; N, 8,28. Found: C, 63,85; H, 4,20; N, 8.27 Per Cent.

Example 2

Obtaining 3-phenyl-5-(4-methoxyphenyl)-1H-pyrrole-2-carboxylic acid following structural formula:

and 3-phenyl-5-(4-methoxyphenyl)-4-nitro-1H-pyrrole-2-carboxylic acid following structural formula:

These compounds are obtained from the application of the method is essentially similar to the method of example 1, and the connections of the header received the t in the form of a yellow solid substance.

3-Phenyl-5-(4-methoxyphenyl)-1H-pyrrole-2-carboxylic acid: yield, 52%; TPL 251°C; IR 3457, 3316, 1618 cm-1;1H-NMR (δ ppm, DMSO-d6) 10,67 (user. s, 1H), 7,88 (d, 2H, J = 7.5 Hz), of 7.70 (d, 2H, J = 8.5 Hz), 7.23 percent (t, 2H, J = 7.5 Hz), 7,11 (t, 1H, J = 7,3 Hz), 6.87 in (d, 2H, J = 8.5 Hz), of 6.52 (s, 1H), 3,74 (s, 3H), 3,38 (user. s, 1H);13C-NMR (δ ppm, DMSO-d6) 166,1, 157,5, 137,1, 129,7, 128,9, 127,9, 126,9, 125,3, 125,2, 124,7, 113,9, 106,4, 54,9; Anal. calc. for C18H15NO3: C 73,71; H, 5,15; N, 4,78. Found: C, 73,48; H, 5,11; N, 4,79%.

3-Phenyl-5-(4-methoxyphenyl)-4-nitro-1H-pyrrole-2-carboxylic acid: yield 35%; TPL 106-107°C; IR 3407, 1668, 1507, 1351 cm-1;1H-NMR (δ ppm, CDCl3) to 9.32 (s, 1H), 7,54 (d, 2H, J = 8.6 Hz), 7,42-7,38 (m, 5H), 7,01 (d, 2H, J = 8.6 Hz), 3,88 (s, 3H);13C-NMR (δ ppm, CDCl3) 163,4, 161,1, 135,2, 133,2, 130,8, 130,3, 129,7, 128,7, 128,2, 127,8, 127,6, 120,6, 114,3, 114,2, 55,4; Anal. calc. for C18H14N2O5: C, 63,90; H, TO 4.17; N, 8,28. Found: C, 63,77; H, 4,19; N,8,30%.

Example 3

Getting 5-(4-methoxyphenyl)-3-(thiophene-2-yl)-1H-pyrrole-2-carboxylic acid following structural formula:

and 5-(4-methoxyphenyl)-4-nitro-3-(thiophene-2-yl)-1H-pyrrole-2-carboxylic acid following structural formula:

These compounds are obtained from the application of the method is essentially similar to the method of example 1, and the connections of the header obtained as yellow solids.

5-(4-Methoxyphenyl)-3-(thiophene-yl)-1H-pyrrole-2-carboxylic acid: yield 54%; TPL 153-154°C; IR 3424, 3112, 2964, 1610 cm-1;1H-NMR (δ ppm, CDCl3) 8,29, (OSiR. s, 1H), 7,41 (d, 2H, J = 8.6 Hz), 7,10 (d, 1H, J = 5.0 Hz), 7,07 (d, 1H, J= 3.1 Hz), 7,02-6,98 (m, 2H), 6,92 (d, 2H, J= 8.6 Hz), to 6.58 (s, 1H), 3,82 (s, 3H);13C-NMR (δ ppm, CDCl3) 158,6, 139,2, 133,0, 127,4, 125,3, 121,8, 121,2, 120,4, 114,9, 114,4, 103,5, 71,9, 70,5, 59,0, 55,3; Anal. calc. for C16H13NO3S: C, 64,20; H, to 4.38; N, 4,68, found: C, 64,11; H, of 4.35; N, 4,70%.

5-(4-Methoxyphenyl)-4-nitro-3-(thiophene-2-yl)-1H-pyrrole-2-carboxylic acid: YIELD, 28%; TPL 180-181°C; IR 3408, 3120, 1610, 1511 cm-1;1H-NMR (5 ppm, DMSO-d6) 7,54 (da, 1H, J = 3,4 Hz), 7,49 (d, 2H, J = 8,3 Hz), 7,03 (user. s, 2H), 7,00 (d, 2H, J = 8,2 Hz), 3,81 (s, 3H);13C-NMR (8 ppm, DMSO-d6) 161,1, 135,1, 133,7, 130,1, 129,3, 127,3, 126,8, 120,1, 114,3, 65,9, 55,4, 15,2; Anal. calc. for C16H12N2O5S: C, 55,81; H, 3,51; N, 8,14. Found: C, 56,09; H, 3,49; N,8,14%.

Example 4

Getting 6-(3,5-diphenyl-1H-pyrrol-2-carboxamido)hexanoic acid following structural formula:

A solution of 3,5-diphenyl-1H-pyrrole-2-carboxylic acid (0.39 g, 1.5 mmol) and the hydrochloride of the methyl ester of 6-aminohexanoic acid (0.25 g, 1.5 mmol) in DMF (7.5 ml) cooled to 0°C. Successively added triethylamine (of 1.15 ml, 8.25 mol), 1-hydroxybenzotriazole (0,22 g of 1.65 mmol), hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.32 g, of 1.65 mmol) and N-methylmorpholin (0,165 ml, 1.5 mmol) and the mixture is stirred at 0°C for 2 h, and t is the treatment for another 96 h at ambient temperature. After this time, add ethyl acetate (300 ml) and the resulting solution washed with water (90 ml), 1 N. Na2S2O3(90 ml, aqueous solution), water (90 ml), NaHCO3(90 ml, saturated aqueous solution) and NaCl (90 ml, saturated aqueous solution) and NaCl (90 ml, saturated aqueous solution), dried over MgSO4and evaporated under reduced pressure, thus obtaining 0,47 g (1.2 mmol) of ester.

The obtained methyl ester are dissolved in the dimethyl ether of ethylene glycol (6 ml) and the solution cooled to 0°C. Then added dropwise 1 n LiOH solution (3.6 ml) and the resulting mixture was stirred at 0°C. Monitoring the development of the reaction carried out by thin-layer chromatography. After completion of the reaction add 3.6 ml of 10%aqueous citric acid solution (pH ≈ 6). The solution is extracted with methylene chloride (3 × 5 ml) and the combined organic fractions dried over MgSO4and evaporated under reduced pressure. The crude reaction product is triturated in diethyl ether, thus obtaining 0,42 g of a white solid.

Yield, 74%; TPL 228-229°C; IR 3427, 3246, 1608 cm-1;1H-NMR (δ ppm, DMSO-d6) of 13.05 (s, 1H), 8,73 (s, 1H), to 7.99 (d, 2H, J = 7,7 Hz), 7,52 (d, 2H, J = 7.5 Hz), of 7.36-7,29 (m, 4H), 7,21 (DD, 2H, J = 12,5 Hz, J' = 7.0 Hz), of 6.65 (s, 1H), 3,21 (DD, 2H, J = 11.3 Hz, J' = 5.6 Hz), was 2.05 (t, 2H, J = 6,6 Hz), 1,54-of 1.44 (m, 4H), 1,36-of 1.30 (m, 2H);13C-NMR (δ ppm, DMSO-d6) 177,5, 160,8, 136,1, 132,7, 131,8, 129,0, 128,5, 128,3, 127,6, 126,5, 125,9, 124,6, 1233, 108,3, 37,3, 28,8, 26,6, 25,5. Anal. calc. for C23H24N2O3: C, 73,38; H, TO 6.43; N, 7,44. Found: C, 73,45; H, 6,41; N,7,44 %.

Example 5

Getting 6-(4-nitro-3,5-diphenyl-1H-pyrrol-2-carboxamido)hexanoic acid following structural formula:

This connection is received with the application of the method is essentially similar to the method of example 4, and the connection header receive in the form of a yellow solid.

Yield, 71%; TPL 153-154°C; IR 3417, 3155, 1638, 1492 cm-1;1H-NMR (δ ppm, DMSO-d6) 7,58 (d, 2H, J = 7,2 Hz), was 7.36 (t, 2H, J = 7,2 Hz), 7,32-of 7.23 (m, 7H), 4,87 (user. s, 2H), of 3.07 (DD, 2H, J = 12.9 Hz, J' = 6.6 Hz), is 2.09 (t, 2H, J = 7,3 Hz), 1,46-of 1.40 (m, 2H), 1,35-of 1.29 (m, 2H), 1,18-1,12 (m, 2H);13C-NMR (δ ppm, DMSO-d6) 176,0, 161,9, 136,8, 134,4, 133,4, 131,8, 130,1, 129,0, 127,5, 127,4, 127,3, 126,3, 122,8, 71,0, 64,8, 57,9, 38,2, 35,0, 28,8, 26,0, 24,7, 15,1. Anal. calc. for C23H23N3O5: C, 65,55; N, 5,50; N, becomes 9.97 found: C, 65,37; N, 5,44; N, of 10.01%.

Example 6

Obtaining N-(5-(hydroxycarbamoyl)pentyl-3-phenyl-5-(4-methoxyphenyl)-1H-pyrrole-2-carboxamide following structural formula:

To a solution of hydroxylamine hydrochloride (0.26 g, 3.75 mmol) and phenolphthalein (1 mg) in methanol (1.25 ml) in an atmosphere of inert gas added dropwise an aliquot of sodium methoxide in methanol (obtained from a solution of 0.65 g of 12.0 mmol of sodium methoxide in 3.3 ml of methanol in the atmosphere is inert gas) as long yet to see a permanent pink color of the solution. Successively added methyl-6-(3-phenyl-5-(4-methoxyphenyl)-1H-pyrrol-2-carboxamide)hexanoate (0,53 g, 1.25 mmol), obtained from 3-phenyl-5-(4-methoxyphenyl)-1H-pyrrole-2-carboxylic acid and methyl ester hydrochloride 6-aminohexanoic acid according to the method in example 4, and sodium methoxide in methanol (5.0 mmol, 1.4 ml of previously obtained solution). The mixture is stirred for 26 h, observing the formation of a dense precipitate. After this time the reaction mixture are added water (3 ml). This solution is acidified with glacial acetic acid and extracted with methylene chloride (3 × 10 ml). The combined organic fractions dried over MgSO4and evaporated under reduced pressure, thus obtaining 0,46 g of the product of the header in the form of a white solid.

Yield, 87%; TPL 157-158°C; IR 3407, 3226, 1663, 1608 cm-1;1H-NMR (δ ppm, DMSO-d6) 11,44 (s, 1H), 10,34 (s, 1H), 8,66 (s, 1H), 7,73 (d, 2H, J = 7.8 Hz), 7,49 (d, 2H, J = 7,7 Hz), was 7.36 (t, 2H, J = 7,3 Hz), 7,30 (ta, 1H, J = 5,1 Hz), 7,26 (t, 2H, J = 7,3 Hz), 6,97 (d, 2H, J = 7.9 Hz), 6,56 (s, 1H), of 3.78 (s, 3H), and 3.16 (DD, 2H, J =12.0 Hz, J' = 5,9 Hz), 1.93 and (t, 2H, J = 7,2 Hz), 1,51-of 1.45 (m, 2H), 1,43-to 1.38 (m, 2H), 1,24-1,17 (m, 2H);13C-NMR (δ ppm, DMSO-d6) 168,9, 160,9, 158,2, 135,7, 132,8, 128,7, 127,9, 127,3, 126,2, 125,9, 124,3, 122,7, 114,0, 107,1, 55,1, 32,1, 28,7, 26,0, 24,8. Anal. calc. for C24H27N3O4: C, 68,39; H, 6,46; N, becomes 9.97, found: C, 68,25; H,6.42 per; N,9,98%.

Example 7

<> Obtaining N-(5-(hydroxycarbamoyl)pentyl-3-phenyl-5-(4-methoxycarbonyl)-4-nitro-1H-pyrrole-2-carboxamide following structural formula:

This connection is received with the application of the method is essentially similar to the method of example 6, and the connection header receive in the form of a yellow coloured solid.

Yield, 84%; TPL 126-127°C; IR 3397, 3185, 1668, 1628, 1507, 1356 cm-1;1H-NMR (δ ppm, DMSO-d6) 12,59 (user. s, 1H), 10,33 (s, 1H), 8,66 (s, 1H), 7,53 (d, 2H, J = 8.5 Hz), 7,44-7,39 (m, 3H), 7,35 (d, 2H, J = 7.0 Hz), 7,03 (d, 2H, J = 8.5 Hz), of 6.71 (ta, 1H, J = 4.4 Hz), 3,82 (s, 3H), 3,03 (DD, 2H, J = 11,9 Hz, J' = 6,0 Hz), a 1.88 (t, 2H, J = 7,3 Hz), 1,40 is 1.34 (m, 2H), 1,24-of 1.18 (m, 2H), 1,03-to 0.96 (m, 2H);13C-NMR (δ ppm, DMSO-d6) 168,9, 159,9, 159,4, 133,3, 132,0, 131,1, 130,9, 129,9, 128,0, 127,6, 123,3, 121,4, 121,1, 113,5, 55,2, 32,0, 28,4, 25,7, 24,7. Anal. calc. for C24H26N4O6: C, 61,79; H, 5,62; N, 12,01 found: C, 61,71; H, 5,59; N, 12,04%.

For the purpose of more easily understanding the concepts mentioned in these last examples, in figure 1, below, shows the different stages of the synthesis, leading to the formation of compounds of the previous examples.

Example 8

Obtaining N-(5-(hydroxycarbamoyl)pentyl-3-(4-methoxyphenyl)-5-phenyl-1H-pyrrole-2-carboxamide following structural formula:

This compound is obtained using the procedure of, essentially the same method of example 6, and the connection header obtained as a pale yellow solid.

Yield, 80%; TPL 142°C; IR 3417, 3256, 1663, 1613, 1547, 1306 cm-1;1H-NMR (δ ppm, DMSO-d6) 12,59 (user. s, 1H), 10,33 (s, 1H), 8,66 (s, 1H), 7,53 (d, 2H, J=8.5 Hz), 7,44-7,39 (m, 3H), 7,35 (d, 2H, J=7.0 Hz), 7,03 (d, 2H, J=8.5 Hz), of 6.71 (ta, 1H, J=4.4 Hz), 3,82 (s, 3H), 3,03 (DD, 2H, J=12,43 Hz, J'=6,35 Hz), was 1.94 (t, 2H, J=7,3 Hz), 1,54-of 1.45 (m, 2H), 1,45 to 1.37 (m, 2H), 1,28-of 1.16 (m, 2H);13C-NMR (δ ppm, DMSO-d6) 169,0, 161,0, 158,0, 132,6, 131,6, 129,9, 128,6, 127,8, 127,2, 126,6, 124,5, 123,1, 113,4, 108,1, 55,0, 32,2, 28,8, 26,1, 24,9. Anal. calc. for C24H27N3O4: C, 68,39; N, 6,46; N, BECOMES 9.97. Found: C, 68,27; N, To 6.43; N, 9.99%Of.

Example 9

Obtaining N-(5-(hydroxycarbamoyl)pentyl-3-(4-methoxyphenyl)-5-(4-methoxyphenyl)-4-nitro-1H-pyrrole-2-carboxamide following structural formula:

This connection is received with the application of the method is essentially similar to the method of example 6, and the connection header obtained as a pale yellow solid.

Yield, 94%; TPL 155°C; IR 3397, 3155, 1638, 1497, 1356 cm-1;1H-NMR (δ ppm, DMSO-d6) 11,59 (s, 1H), 10,34 (s, 1H), 8,68 (s, 1H), 7,63-7,53 (m, 2H), 7,52-7,41 (m, 3H), 7,29 (d, 2H, J = 8.5 Hz), of 6.99 (d, 2H, J = 8.5 Hz), 6,72 (ta, 1H, J = 4.4 Hz), 3,80 (s, 3H), 3,05 (DD, 2H, J = 12,02 Hz, J'= 6,24 Hz), 1,89 (t, 2H, J = 7,3 Hz)of 1.50 and 1.33 (m, 2H), 1,33-of 1.16 (m, 2H), 1,14-0,98 (m, 2H);13C-NMR (δ ppm, DMSO- 6) 168,9, 159,4, 158,8, 133,0, 131,6, 131,2, 129,3, 129,1, 129,0, 128,0, 123,5, 121,0, 113,5, 55,0, 32,0, 28,3, 25,7, 24,6. Anal. calc. for C24H26N4O6: C, 61,79; H, 5,62; N, 12,01 found: C, 61,40; H, 5,77; N, 11,80%.

Example 10

Getting 4-(4-aminobutyl)-1-methylsemicarbazide following structural formula:

A mixture of di-tert-BUTYLCARBAMATE (10,9 g, 51 mmol) in methanol (30 ml) is added dropwise to a solution of 1,4-diaminobutane (11,12 g, 150 mmol) in triethylamine (30 ml, 215 mmol) and methanol (300 ml). The resulting mixture was stirred at ambient temperature for 16 hours After which time the triethylamine and methanol is evaporated under reduced pressure. The resulting oil is dissolved in methylene chloride (100 ml) and washed with 10% sodium carbonate (2 × 50 ml, aqueous solution). The organic phase is dried over MgSO4and evaporated under reduced pressure. So, get monogamistic Amin (7,8 g, 41,42 mmol).

To a solution of monoamino amine (6 g, 31,86 mmol) and triphosgene (3,48 g, 11,72 mmol) in methylene chloride (438 ml) dropwise at ambient temperature is added a solution of sodium bicarbonate (18,23 g, 63,72 mmol) in water (438 ml). The resulting two-phase system is vigorously stirred for 1.5 hours After this time the organic phase is decanted, dried over MgSO4and evaporated under reduced pressure. The resulting oil (43 g, 20 mmol) dissolved in methanol (6.8 ml) and slowly added dropwise at 0°C to another prior solution methylhydrazine (1.1 ml, to 20.8 mmol) and water (of 4.05 ml). The mixture is stirred for 45 min at 0°C. After this time the precipitate was separated by filtration and receive 3,492 g of a white solid substance, spectroscopic properties which were assessed as compatible with the properties of 4-(4-tert-butoxycarbonylamino)-1-methylsemicarbazide.

Another solution, triperoxonane acid (4,96 ml, 44 mmol) in methylene chloride (22 ml)slowly over 30 min added to the solution previously obtained precipitate (0,500 g, 1.92 mmol) in methylene chloride (27.5 ml) at 0°C. the Mixture is stirred for 2 hours. After this time, add toluene (50 ml) and evaporated under reduced pressure to half volume, repeating this process several times. In this way receive triptorelin ammonium salt (determined as 0.720 g, 2,63 mmol) connection header.

Yield, 68 %; IR 3387, 3115, 1673 cm-1;1H-NMR (δ ppm, DMSO-d6) 7,88 (s, 3H), 7,42-to 7.15 (m, 2H), 3,78-to 3.64 (m, 1H), to 3.58 (s, 3H), 3,16-of 2.97 (m, 2H), 2.95 and-by 2.73 (m, 2H), 1,80-to 1.38 (m, 4H);13C-NMR (δ ppm, DMSO-d6) 159,0, 158,6, 158,1, 157,7, 156,7, 51,1, 26,3, 24,3.

Example 11

Obtaining 1-(4-(5-(4-methoxyphenyl)-4-nitro-3-(thiophene-2-yl)-1H-pyrrol-2-carboxamido)butyl)-3-(2-methylamine)urea following structural formula:

A solution of 5-(4-methoxyphenyl)-4-nitro-3-(thiophene-2-yl)-1H-pyrrole-2-carboxylic acid (0,434 g, 1.25 mmol) and trifenatate ammonium salt of 4-(4-aminobutyl)-1-methylsemicarbazide (0,345 g, 1.25 mmol) in DMF (6,26 ml) cooled to 0°C. Then add triethylamine (0.98 in ml? 7.04 baby mortality mmol), 1-hydroxybenzotriazole (0,210 g, 1.37 mmol), hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (to 0.263 g, 1.37 mmol) and N-methylmorpholin (of 0.14 ml, 1.25 mmol). The resulting mixture is stirred for 2 h at 0°C and for a further 96 h at ambient temperature. After this time, add ethyl acetate (250 ml) and the resulting solution washed with water (80 ml), 1 N. Na2S2O3(80 ml, aqueous solution), water (80 ml), NaHCO3(80 ml, saturated aqueous solution) and NaCl (80 ml, saturated aqueous solution), dried over MgSO4and evaporated under reduced pressure, thus obtaining 0.400 g (0.82 mmol) of the compound of the header.

Output, 65,6% ; TPL 185-187°C; IR 3408, 3161, 1639, 1511 cm-1;1H-NMR (δ ppm, CDCl3): of 10.4 (s, 1H), 7,56 (DD, 1H, J = 5.5 Hz, J' = 0,8), 7,54 (d, 2H, J = 8.7 Hz), 7,20-to 7.15 (m, 3H), 6,98 (d, 2H, J = 8.7 Hz), 5,74 (t, 1H, J = 5,2 Hz), of 4.66 (s, 1H), 3,86 (s, 4H), to 3.67 (s, 3H), 3,13 totaling 3.04 (m, 4H), 1,31-1,24 (m, 4H);13C-NMR (δ ppm, CDCl3): 160,7, 159,6, 157,0, 134,6, 132,9, 131,5, 130,9, 129,5, 128,7, 127,6, 123,2, 121,1, 113,9, 113,7, 55,4, 52,1, 40,5, 38,7, 27,0, 26,2. The calculated molecular ion for C22H26N6O5S: m/z 486,14. Found: 471,1 (M+-Me).

Example 12/p>

Obtaining 1-(4-aminomethyl)-3-(benzyloxy)urea following structural formula:

The specified connection is received with the application of the method is essentially similar to the method of example 10, using benzylamine instead of methylhydrazine. After the previously described sequence add to unprotect the connection header get trifenatate the corresponding ammonium salt.

Yield, 68%; IR 3759, 3356, 1648 cm-1;1H-NMR (δ ppm, DMSO-d6) of 7.82 (s, 3H), 7,52-7,28 (m, 7H), to 5.00 (s, 2H), 3,09 of 2.92 (m, 2H), 2,90 of 2.68 (m, 2H), 1,68-of 1.32 (m, 4H);13C-NMR (δ ppm, DMSO-d6) 159,6, 158,2, 157,7, 136,4, 128,5, 128,1, 127,8, 77,2, 38,0, 26,6, 24,3, 24,0. The calculated molecular ion for C13H20N3O2: m/z 237,32 found 238,0.

Example 13

Obtaining 1-(4-(3,5-bis-(3,5-acid)-1H-pyrrol-2-carboxamido)butyl)-3-(benzyloxy)urea following structural formula:

This compound is obtained by application of the method is essentially similar to the method of example 11, from 3,5-bis-(3,5-acid)-1H-terracarbon acid and trifenatate ammonium salt of 1-(4-aminobutyl)-3-(benzyloxy)urea.

Yield, 81%; IR 3407, 3216, 1688, 1597 cm-1;1H-NMR (δ ppm, CDCl3) 9,87 (s, 1H), 7,44-to 7.32 (m, 5H), 7,13 (s, 1H), 6,77 (d, 2H, J=2.0 Hz), 6,62 (d, 2H, J=2.2 Hz), 6,50 (d, 2H, J=2,6 Hz), to 6.43 (t, 1H, J=2.0 Hz), 6,03 (t, 1H, =5,5 Hz), 5,62 (t, 1H, J=5.3 Hz), 4,80 (s, 2H), 3,85 (s, 6N), 3,82 (C, 6N), or 3.28 (DD, 2H, J=11,9 Hz, J'= 5,9 Hz)and 3.15 (DD, 2H, J = a 12.7 Hz, J'= 6.5 Hz), 1.41 to of 1.29 (m, 4H);13C-NMR (δ ppm, CDCl3) 161,2, 160,0, 137,6, 135,4, 134,1, 133,2, 130,8, 129,2, 128,8, 128,7, 127,7, 122,2, 110,0, 107,4, 103,0, 100,0, 99,8, 78,6, 72,3, 10,1, 68,1, 55,4, 39,1, 38,8, 27,1, 26,6. Molecular ion calculated for C33H38N4O7; m/z 602,68 found: 603,2.

Example 14

Obtaining 1-(4-(3,5-bis-(3,5-acid)-1H-pyrrol-2-carboxamido)butyl)-3-hydroxyacetone following structural formula

Get solution of 1-(4-(3,5-bis-(3,5-acid)-1H-pyrrol-2-carboxamido)butyl)-3-(benzyloxy)urea (0,200 g, 0.33 mmol) in ethyl acetate (66 ml) and ethanol (16.5 ml), to which is added the catalyst, 10% Pd-C (0,116 g, 0.11 mmol). The mixture was stirred at ambient temperature in a stream of hydrogen for 5 hours. After this time the resulting suspension is filtered through celite and the filtrate concentrated under reduced pressure. This way receive the product title in the form of a colorless oil.

Yield, 71% ; IR 3416, 3244, 2948, 1598 cm-1;1H-NMR (δ ppm, CDCl3) to 10.3 (s, 1H), 6,78 (s, 2H), 6,60 (d, 2H, J = 1.7 Hz), 6,53-6,44 (m, 2H), to 6.39 (s, 1H), 6,17-of 6.02 (m, 1H), 4,81 (s, 1H), 3,86-of 3.78 (m, 13H), 3,34-and 3.16 (m, 4H), 1,48-of 1.33 (m, 4H);13C-NMR (δ ppm, CDCl3) 161,2, 137,6, 134,6, 134,5, 133,3, 128,3, 122,1, 122,0, 109,7, 107,5, 103,3, 99,9, 55,6, 55,5, 39,0, 38,9, 38,7, 27,2, 27,0, 26,8. The calculated molecular ion for C26H32N 4O7: m/z 512,55. Found: 513,2 (M+), 497,1 (M+-HE).

For the purpose of more easily understanding the concepts mentioned in these last examples, in scheme 2, below, shows the different stages of the synthesis, leading to the compounds mentioned in examples 10, 11, 12, 13 and 14.

Example 15

Measurement of in vitro inhibitory ability against activity discontiuation

To better illustrate the methods used in this example and the following example, the results obtained with the compounds indicated in figure 3, which includes the derived chiral pyrrolidine, given the purpose of comparing the activity of this cyclic system the pyrrole of the present invention.

To determine the inhibitory capacity of the synthesized compounds against orally bioavailable an in vitro study was performed by incubation of nuclear extract cell lines NST and MOLT4 and labeled with tritium acetylated histones with different concentrations of the synthesized compounds, after which the concentration of the selected acetyl groups was measured using a scintillation counter.

The nuclear extract

Cells (8 × 106in the suspension was centrifuged at a speed of 800 rpm./m is h for 5 min, washed with PBS and resuspended in 2 ml of buffer A (10 mm Tris, pH 7.5, 15 mm KCl, 2 mm MgCl2, 0.1 mm EDTA, 2 mm 2-mercaptoethanol, 1 tablet of protease inhibitor without EDTA per 50 ml buffer). Added 135 μl of buffer (50 mm Tris, 1 M KCl, 30 mm MgCl2, 0.1 mm EDTA, 2 mm 2-mercaptoethanol), the mixture was then centrifuged at 2,7 × 103about./min at 4°C for 5 min and supernatant was removed. The precipitate after centrifugation resuspendable in 2 ml of buffer a and mixed 5 times in the homogenizer in 2 ml of the Suspension is centrifuged at 7.8 × 103about./min at 4°C for 8 min, the precipitate after centrifugation resuspendable in 2 ml of buffer a and mixed 5 times in the homogenizer. In the homogenizer was added 200 μl of ammonium sulfate and the mixture is then stirred for 30 min on a rotary mixer at 4°C. the Mixture was centrifuged at 12 × 103about./min at 4°C for 10 min and supernatant were dialyzed in the membrane MWCO 3500 for 2 h at 4°C in 200 ml of buffer C (20 mm Tris, pH 7.5, 10% glycerol, 1 mm EDTA, 1 mm 2-mercaptoethanol, 1.5 mm MgCl21 tablet of protease inhibitor without EDTA per 50 ml buffer). After this time the contents of the membranes were isolated and used for the study, which is described below.

Measurement of in vitro inhibitory activity of compounds

To 30 μl of nuclear extract derived using the specified method, was added 55 μl Boo the EPA (see above), 5 μl of a solution of the corresponding inhibitor and 10 ál labeled with tritium hyperacetylation of histones and the resulting mixture incubated at 37°C for 1 h

The incubation was stopped by the addition of 37.5 μl of a solution of chloride-hydrogen acid (final concentration, 1 M) and acetic acid (final concentration 0.4 M). To the resulting mixture was added 700 μl of ethyl acetate, the mixture was centrifuged at 10000 rpm./min for 5 min and, finally, the upper phase (which contained selected tsitirovaniyu acetic acid) was used for scintillation counting. Samples for scintillation account was obtained by mixing 500 ál of the upper phase and 5 ml of scintillation fluid.

The most representative data obtained by the above method, shown in figures 1 and 2. The results on figure 1 correspond to the cell line NSC, and the results of figure 2 correspond to the cell line MOLT4.

Example 16

The measurement of the total scintillation histone

A quantitative measure of the degree of acetylation of histones H3 and H4 was carried out using the method described below.

Cell line human Jurkat (promyelocytic leukemia) were treated for 24 h with different concentrations of the considered compounds, inhibiting HDAC. After this time the cores were isolated by adding to the cells RSB buffer (10 mm Tris, pH 7.5 10 mm NaCl and 3 mm magnesium chloride) with 1% Nonidet-P40 and a protease inhibitor. For the extraction of histones nuclei was added 0.25 M chloride-hydrogen acid and the mixture was stirred for 16 h at 4°C. Then the histones were besieged by the addition of 8 volumes of acetone. The mixture of histones were separated using high performance liquid chromatography (HPLC) with reversed phase C18 column with a gradient of acetonitrile (20-60%) 0.3% triperoxonane acid.

Division palleroni, mono-, di-, tri - and tetracationic derivatives of each fraction of histones H3 and H4 was performed using high-performance capillary electrophoresis (NRSE) with capillary silicon dioxide (60,2 cm × 75 μm, effective length 50 cm). Used by elution conditions were: 25°C, voltage 12 kV, detector absorbance at 214 nm and the elution buffer 110 mm phosphate (pH 2.0) and theorm-cellulose (0,03% wt./vol.).

Before each input system was washed for 3 min with 0.1 M NaOH followed by another washing with 0.5 M H2SO4within 2 min and balanced buffer for elution for 3 minutes Wash buffers and solutions were obtained with the use of water Milli-Q filtered through a pore size of 0.45 μm. Samples were injected under a pressure of 0.3 psi for 3 seconds. All samples were analyzed in duplicate.

Some representative data obtained with different the considered compounds of this image is the shadow, shown in figure 3.

Example 17

Measurement of induction of apoptosis

Determining the number of apoptotic cells was performed by studying the changes in permeability of the cytoplasmic membrane with the use of flow cytometrical analysis and with the use of commercial set YoPro© as a coloring agent. The method used is described below. Cell lines NST and HL60 human (106cells per treatment) were treated with various concentrations of the considered compounds of HDAC inhibitors of the present invention within 24 hours After this period, cells were washed twice with cold 1X PBS, resuspendable in 1 ml of 1X PBS and 1 μl of YoPro© and added 1 μl of iodide of propecia. The mixture was incubated on ice with protection from light for 30 min. Number of apoptotic cells was measured using flow cytometry.

The most representative data shown in figures 4 and 5. Data corresponding model carcinoma of the colon NST person presented on figure 4. Data corresponding to a model of acute myeloid leukemia L60 person presented on figure 5.

Example 18

Measurement of biological activity in vivo

To determine the validity of some of the described compounds on tumor growth in vivo were studied using females naked mice against which the 6 weeks without the thymus gland (Harlam Sprague Dawley, Indianapolis, IN, USA). For studies 2×106cell line NSC (carcinoma of the colon) and 107of MOLT4 cells (T-cell acute lymphoblastic leukemia person), resuspending in PBS, was inoculable subcutaneously at a final volume of inoculation of 200 μl/animal. When the tumors had reached an average volume of 100 mm3each mouse was administered a daily dose of 200 μl of a 20 μm solution of the corresponding compound by intraperitoneal injection (10 mg/kg). Control group mice were injected with 200 µl PBS to simulate stress inoculation. Mice were weighed every 24 h and tumor volume was measured using calibrated millimeter measurement devices, assuming a spherical geometry for tumors (volume = d3× π/6). When tumor volume reached 1-1 .5 cm3(Ethical-Humanitarian Human End Point), mice were killed and tumors were removed and weighed.

The most representative data is shown in figures 7 and 8. Data related to the model carcinoma NST human colon presented in figure 7. The figure 8 presents the data related to the model fibroblastoma leukemia MOLT4 human.

1. Derived pyrrole General formula I

where R1and R3independently represent a phenyl radical; a mono - or disubstituted in different positions of the phenyl ring, where the Deputy of t is possessing a methoxy group; or5-heteroaryl group which contains one heteroatom of O or S;
R2represents a hydrogen atom or electrostrictively group such as the nitro-group or amino - or aminogroup;
R4represents a hydrogen atom or an unbranched or branched C1-C6is an alkyl group;
n equals the number of methylene groups between 1 and 8 inclusive;
X represents a secondary amino group, or an oxygen atom or a sulfur atom;
Y represents a group selected from methylene, and a secondary amine;
Z is either an oxygen atom or a sulfur atom, and
W represents a group selected from hydroxyl, hydroxylamine, hydrazine and acylhydrazone.

2. Derived pyrrole General formula I according to claim 1, selected from
[1] 6-(3,5-diphenyl-1H-pyrrol-2-carboxamido)hexanoic acid following structural formula:

[2] 6-(4-nitro-3,5-diphenyl-1H-pyrrol-2-carboxamido)hexanoic acid following structural formula:

[3] N-(5-(hydroxycarbamoyl)pentyl)-5-phenyl-3-(4-methoxyphenyl)-1H-pyrrole-2-carboxamide following structural formula:

[4] N-(5-(hydroxycarbamoyl)pentyl)-3-phenyl-5-(4-methoxyphenyl)-1H-pyrrole-2-carboxamide following structural formula:

[6] 1-(4-(3,5-bis-(3,5-acid)-1H-pyrrol-2-carboxamido)butyl)-3-hydroxyacetone following structural formula:

[7] 1-(4-(5-(4-methoxyphenyl)-4-nitro-3-(thiophene-2-yl)-1H-pyrrol-2-carboxamido)butyl)-3-(2-methylamino)urea following structural formula:

[8] N-(5-hydroxycarbamoyl)pentyl-3,5-diphenyl-4-nitro-1H-pyrrol-2-carboxamid the following formula:

3. The method of obtaining compounds of General formula (Ia):

where R1, R2, R3, R4, X and n have the meanings indicated above, which includes a reaction mixture consisting of
a) 1H-pyrrole-2-carboxylic acid of the formula II

b) compounds of the formula III

where R5is alkoxycarbonyl,
c) a reagent for the activation of carboxyl groups and
d) a tertiary amine selected from cyclic or acyclic aliphatic amines with 3-10 carbon atoms and alkanolamides amines with 9-15 carbon atoms,
and reaction of the resulting product with a mixture of lithium hydroxide or sodium, dimethoxyethane and water.

4. Way obtained the I compounds of General formula (Ib):

where R1, R2, R3, R4, X and n have the meanings indicated above, which includes the reaction mixture, consisting of
a) 1H-pyrrole-2-carboxylic acid of the formula II

b) compounds of the formula III

where R5is alkoxycarbonyl,
c) a reagent for the activation of carboxyl groups and
d) a tertiary amine selected from cyclic or acyclic aliphatic amines with 3-10 carbon atoms and alkanolamides amines with 9-15 carbon atoms,
and adding the resulting product to a mixture of hydroxylamine hydrochloride and phenolphthalein in the presence of excess of sodium methoxide in methanol.

5. The method of obtaining compounds of General formula (Ic):

where R1, R2, R3, R4X, Z and n have the meanings specified above, comprising a reaction mixture consisting of
a) 1H-pyrrole-2-carboxylic acid of the formula II

b) compounds of the formula

c) a reagent for the activation of carboxyl groups and
d) a tertiary amine selected from cyclic or acyclic aliphatic amines with 3-10 carbon atoms and alkanolamides amines with 9-15 carbon atoms, and hydrogenolysis obtained at the previous step.

6. The way the floor is possible compounds of General formula (Id):

where R1, R2, R3, R4X, Z and n have the meanings indicated above and R6represents a C1-C6-alkyl, comprising the reaction of a mixture consisting of
a) 1H-pyrrole-2-carboxylic acid of the formula II

b) compounds of the formula III

where R5represents 1-C1-C6-alkylsalicylate,
c) a reagent for the activation of carboxyl groups and
d) a tertiary amine selected from cyclic or acyclic aliphatic amines with 3-10 carbon atoms and alkanolamides amines with 9-15 carbon atoms.

7. Derived pyrrole according to claim 1 for use in the treatment of cancer.

8. Derived pyrrole according to claim 2 for use in the treatment of cancer.

9. Use of derivatives of pyrrole according to claim 1 or 2 for the manufacture of a medicinal product for the treatment of cancer.

10. Pharmaceutical composition having an action to inhibit discontiuation comprising the compound according to claim 1 or 2 and at least pharmaceutically acceptable excipient.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclopenta[b]benzofuranyl derivatives of formula wherein substitutes R1, R2, R3, R4, R5, R6 and R7 and n are specified in the patent clam. These compounds exhibit properties of NF-kB-activity and/or AP-1 inhibitor/modulator. Also, the inventive subject matter are methods for preparing intermediate compounds thereof, a pharmaceutical composition containing them, administration thereof for prevention and/or treatment of inflammatory and autoimmune diseases, neurodegenerative diseases and hyperproliferative diseases caused by NF-kB- and/or AP-1-activity, and a method for prevention and/or treatment of said diseases.

EFFECT: preparation of new cyclopenta[b]benzofuranyl derivatives.

21 cl, 3 tbl, 151 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compound described by formula where R1 represents a monocyclic nitrogen-containing heterocyclic group optionally condensed with heterocycle with the monocyclic nitrogen-containing heterocyclic group optionally condensed with heterocycle, optionally having 1 to 5 substitutes chosen from a group consisting of (1) halogen atom, (2) cyano, (3) hydroxy, (4) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (5) amino, (6) mono- C1-6 alkylamino, (7) C1-6 alkoxycarbonyl and (8) C1-6 alkyl optionally having 1 to 3 halogen atoms, R2 represents (i) C6-14 aryl group optionally substituted by 1 to 5 substitutes chosen of a group consisting of (1) halogen atom, (2) cyano, (3) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (4) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (5) C1-6alkylcarbonyl, (6) C1-6 alkylsulphonyl, (7) C1-6 alkylthionyl, (8) C3-7 cycloalkyl, (9) C1-6 alkyl group optionally having 1 to 3 halogen atoms, and (10) C1-6 alkyl group substituted by 1 to 3 hydroxy, (ii) a thienyl group optionally substituted by 1 to 4 substitutes chosen from a group consisting of (1) cyano and (2) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (iii) a pyridyl group optionally substituted by 1 to 4 substitutes chosen from a group consisting of (1) halogen atom, (2) 5-10-members aromatic heterocyclic group containing carbon atom, and 1 or 2 presentations of 1-4 heteroatoms chosen from nitrogen atom, sulphur atom and oxygen atom, and (3) C1-6 alkyl group optionally having 1 to 3 halogen atoms, or (iv) a bipyridyl group optionally substituted by 1 to 3 halogen atoms, each R3 and R4 represents hydrogen atom, or one of R3 and R4 represents hydrogen atom, and another represent a lower alkyl group, halogen atom or a cyanogroup, and R5 represents an alkyl group, or to its salt. Also, the invention refers to a pharmaceutical composition showing an acid secretion inhibitory effect enabled by the compound of formula I, to a method for treatment or prevention, besides, to application of the compound of formula I for preparing a pharmaceutical composition for treatment or prevention of a number of diseases presented in the patent claim.

EFFECT: preparation of the new compounds showing the acid secretion inhibitory effect and exhibiting antiulcerant action.

20 cl, 92 ex, 24 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel 4-(1H-indol-3-yl)-but-3-en-2-one derivatives of general formula 3: , : which can be used in synthesis of novel preparations for pharmaceutical and agricultural purposes. The method involves mixing 2-alkyl-5-(2-amino-4-alkylphenyl)-furans 1 with aromatic and heteroaromatic aldehydes 2 in acetic acid in equimola ratio at temperature 35°C for 40 minutes in the presence of 0.01 ml hydrochloric acid.

EFFECT: improved method.

2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

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

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

15 cl, 1 tbl, 94 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel thiophene derivatives of formula (I): ,

where the ring system A is characterised by formula ,

R1 denotes hydrogen, C1-C5alkyl or C1-C5alkoxy, R2 denotes hydrogen, C1-C5alkyl, C1-C5alkoxy or trifluoromethyl, R3 denotes hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH, -CH2-(CH2)n-CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2-(CH2)m-NR31R32, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy, 2-morpholin-4-ylethoxy, 3-morpholin-4-ylpropoxy, 3-[(pyrrolidin-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidin-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropoxy; R31 denotes hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, 2-(C1-C5)alkoxyethyl, 3-(C1-C5)alkoxypropyl, 2-aminoethyl, 2-(C1-C5alkylamino)ethyl or 2-(di-(C1-C5alkyl)amino)ethyl; R32 denotes hydrogen, methyl, ethyl, m equals 1 or 2; n equals 1; and R4 denotes hydrogen, (C1-C5)alkyl or halogen, and configuration isomers thereof, such as optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts of said compounds of formula (I), synthesis thereof and use as therapeutically active compounds.

EFFECT: compounds have the effect of immunosuppressive agents.

20 cl, 2 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): , optical isomers of said compounds, as well as salts thereof having peroxisome proliferator-activated receptor subtype y (PPARy) modulating property. Values of R1, R2, X, Ar1 and Ar2 are given in the formula of invention.

EFFECT: preparation of compositions based on said compounds, as well as use of said compounds in cosmetic and pharmaceutical industry.

11 cl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel 5-6-member nitrogen-containing heterocyclic compounds, selected form derivatives of pyridine, pyrimidine, imidasoline, oxadiasoline, such as, for instance , which possess inhibiting activity with respect to aspartylprotease, such as "ВАСЕ-1".

EFFECT: obtaining pharmaceutical composition, method of aspartylprotease inhibition aimed at application of compounds for preparation of medication intended for treatment of state, mediated by aspartylprotease, such as "ВАСЕ-1".

4 cl, 1 tbl, 1832 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclopenta[b]benzofuranyl derivatives of formula wherein substitutes R1, R2, R3, R4, R5, R6 and R7 and n are specified in the patent clam. These compounds exhibit properties of NF-kB-activity and/or AP-1 inhibitor/modulator. Also, the inventive subject matter are methods for preparing intermediate compounds thereof, a pharmaceutical composition containing them, administration thereof for prevention and/or treatment of inflammatory and autoimmune diseases, neurodegenerative diseases and hyperproliferative diseases caused by NF-kB- and/or AP-1-activity, and a method for prevention and/or treatment of said diseases.

EFFECT: preparation of new cyclopenta[b]benzofuranyl derivatives.

21 cl, 3 tbl, 151 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel AMPA receptor antagonists - 1H-quinazoline-2,4-dione derivatives, selected from the group: N-(6-imidazol-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-morpholin-4-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrrol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(7-nitro-2,4-dioxo-6-[1,2,4]triazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrrolidin-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-azetidin-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-[1,2,3]triazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-morpholin-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(2,4-dioxo-6-[1,2,4]triazol-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; (2,4-dioxo-6-[1,2,4]triazol-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)amide ethanesulphonic acid; N-(6-imidazol-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(2,4-dioxo-6-thiomorpholin-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(6-[1,4]oxazepan-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide and N-(6-azetidin-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide and physiologically acceptable salts thereof.

EFFECT: compounds can be used in treating such diseases as epilepsy and schizophrenia.

9 cl, 106 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula (IIa)

and its salt, involving use of protective groups which can be easily incorporated into the compound, have large mass, are stable in the presence of organometallic reagents and be easily, and with high output, removed from in an acidic medium, as well as to novel intermediate compounds used during steps of this method, having general formula (IVe)

, where R5 and R'5 independently denote C1-C7-alkyl, R6 and R8 denote hydrogen, R7 and R9 together form C2-C5-alkylene.

EFFECT: easy production of angiotensin receptor blocker.

8 cl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of 1H-imidazole of formula I, in which R1 represents hydrogen, halogen atom, C1-3-alkyl group, and said C1-3-alkyl groupcan include 1-3 fluorine atoms or R1 represents cyclopropyl, piano, or methylsulfanyl group, R2 represents phenyl group, which can be substituted with 1 substituent Y, selected from methoxy, chlorine, fluorine, trifluoromethyl and cyano, or R2 represents pyridyl group, on condition that R2 is not 6-methyl-2-pyridyl group, or R2 represents fully saturated 6-7-member monocyclic, condensed bicyclic ring system or benzothiazolyl, benzodioxane or thiazole group, and said groups can be substituted by 1 fluorine atom, or R2 represents group of general formula CH2-R5, in which R5 represents phenyl group or fully saturated 7-member condensed bicyclic carbocyclic ring system, or R5 represents piperidine or tetrahydrofuran ring system, which can be substituted by methyl, or R2 represents methylsulfonylamino(C3)alkyl group, R3 represents hydrogen, halogen atom, C1-6-alkylsulfonyl, cyanogroup, or R3 represents C1-8-alkyl group, and said C1-8-alkyl group can be substituted by 1-3 fluorine atoms, or R3 represents phenyl group, which is substituted by substituent Y, where Y has value, specified above, or R3 represents furanyl group, R4 represents one of subgroups (i) or (ii), where R6 represents C4-8-branched or linear alkyl group or naphtyl group, R7 represents hydrogen atom, linear C1-6-alkyl group, R8 represents C2-6-alkyl group, substituted by 1-3 fluorine atoms, or R8 represents C3-8-cycloalkyl group, piperidine group, C3-8-cycloalkyl- C1-2-alkyl group, tetrahydrofuranyl- C1-2-alkyl group, C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-2-alkyl group, C6-10-tricycloalkyl group, C6-10-tricycloalkyl-C1-2-alkyl group, and said groups can be substituted by 1-3 substituents, selected from methyl or hydroxyl, or R8 represents phenyl group, substituted by 1-2 substituents Y, specified above, or R8 represents naphtyl, 1,2,3,4-tetrahydronaphtyl or indanyl group, and said groups can be substituted by 1 substituent Y, or R8 represents phenyl- C1-3-alkyl group, diphenyl- C1-3-alkyl group, and said groups can be substituted ob their phenyl ring by 1 substituent Y, where Y has value specified above, or R8 represents benzyl group, substituted by 2 substituents Y, or R8 represents quinilinyl, pyridinyl, benzimidazole or naphtylmethyl group which can be substituted by substituent Y, where Y has value, specified above, or R8 represents asabicyclo[3,3,0]octanyl group, on condition that R8 is neither 6-methoxybenzothiazole-2-yl group, nor [3-chlor-5-(trifluoromethyl)pyrid-2-yl]methyl group, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, non-aromatic, monocyclic or bicyclic heterocyclic group, including only one nitrogen atom, having 7-10 ring atoms, which can be subslituted by 3 C1-3-alkyl groups, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, monocyclic heterocyclic group, optionally including another N atom, having 6 ring atoms, and said heterocyclic group is substituted by C1-3-alkyl groups, on condition that R7 and R8 together with nitrogen atom, to which they are bound, do not form trimethylsubstituted asabicyclo[3,3,0]octanyl group, as well as their stereoisomers and pharmacologically acceptable salts of said formula (I) compounds and their stereoisomers Invention also relates to intermediate compounds of formula XIV, pharmaceutical composition based on formula I compound, method of obtaining such pharmaceutical composition and application of formula T compound.

EFFECT: obtained are novel derivatives of IH-imidazole, which are modulators of cannabinoid CB2-receptors.

8 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel 4-(1H-indol-3-yl)-but-3-en-2-one derivatives of general formula 3: , : which can be used in synthesis of novel preparations for pharmaceutical and agricultural purposes. The method involves mixing 2-alkyl-5-(2-amino-4-alkylphenyl)-furans 1 with aromatic and heteroaromatic aldehydes 2 in acetic acid in equimola ratio at temperature 35°C for 40 minutes in the presence of 0.01 ml hydrochloric acid.

EFFECT: improved method.

2 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

FIELD: medicine.

SUBSTANCE: invention refers to a polymer derivative of cytidine antimetabolite of formula (1) which can be used as an antineoplastic drug: (1), where R is hydrogen or alkyl; A is hydrogen, acyl or alkoxycarbonyl; m is within 3 to 200; n is within 5 to 2000; X is a residue of cytidine antimetabolite, hydroxyl or a hydrophobic substitute, and X means a residue of cytidine antimetabolite in amount 3-100 % m, hydroxyl in amount 0-95 % m and the hydrophobic substitute in amount 0-80 % m.

EFFECT: preparation of new antineoplastic compounds.

8 cl, 5 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 4(5)-(2-hetaryl) and 4(5)-(2-hetaryl)-2-(2'-hetaryl)-imidazoles of general formula R=2-furyl, 2-thienyl; R'H; and R=2-furyl, 2-thienyl; R'=2-furyl is obtained using 2-bromoacetylfuran (thiophene) of general formula 2-thienyl and aldehydes in the presence of copper acetate, synthesis of a 2-bromoacetylfuran (thiophene) precursor is carried out by reacting 2-acetylfuran (thiophene) with copper (II) bromide.

EFFECT: increased safety of the process.

2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, specifically to 4-substituted-3-(1-alkyl-2-chloro-1H-indol-3-yl)furan-2,5-diones of general formula I , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R3=phenyl, naphthyl, 2-phenyl-1-ethenyl, thienyl, furyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, synthesis method thereof and use as compounds capable of photochemical generation of stable fluorophores of formula II, which can be used, for instance in information storage systems, particularly as photosensitive components of material for three-dimensional recording and storage of information. The invention also relates to novel 4,5-substituted-6-alkyl-1H-furo[3,4-c]carbazole-1,3(6H)diones of general formula II , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R4=H, R5=phenyl, R4, R5=benzo, naphtho, thieno, furo, pyrrolo, benzothieno, benzofuro, indolo, method for synthesis of said compounds and use as fluorophores.

EFFECT: obtaining novel compounds and possibility of using said compounds as fluorophores.

14 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel malononitryl derivatives of formula (I), which can be applied to fight pest insects. In formula (I) R1 represents hydrogen atom; R2 represents hydrogen atom; R represents hydrogen atom; R4 represents C1-C5-alkyl group substituted with at least one halogen atom, C2-C5-alkenyl group; R5 represents hydrogen atom, halogen atom, C1-C5-alkyl group; at least one of X1, X2 and X3 values represents CR6, the other represent nitrogen atoms; R represents hydrogen atom, halogen atom, cyanogroup, nitrogroup, formyl group, C1-C5-alkyl group optionally substituted with at least one halogen atom, C1-C5-alkyltiogroup, substituted with at least one halogen atom, C2-C6-alkylcarbonyl group substituted with at east one halogen atom, C2-C5-alkoxycarbonyl group or group (CH2)mQ, where m = 0, and Q stands for phenyl; and in case when one of R5 and R6 is bonded with two atoms in adjacent positions or two R6 are bonded with two atoms in adjacent positions, they can be bonded to each other in end positions with formation of C2-C6-alkandiyl group, or C4-C6-alkenediyl group. Invention also relates to composition and method used to fight pest-insects.

EFFECT: obtaining novel malononitryl derivatives of formula (I), which can be applied to fight pest-insects.

11 cl, 90 ex

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