Heterocyclic aspartyl protease inhibitors

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

 

The text descriptions are given in facsimile form.

1. The compounds having structural formula

or a stereoisomer, tautomer or pharmaceutically acceptable salt or MES, in which
W means-C(=S) -, or-C(=O);
X is-N(R5)-;
U mean bond or -(C(R6)(R7))b-where b is 1;
R1, R2and R5independently selected from the group comprising H, Alky is with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkenyl with 3-7 carbon atoms in cycloalkyl parts and 1-6 carbon atoms in the alkyl part, geterotsiklicheskikh represents a 5-10 membered mono - or bicyclic system containing 1-2 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, substituted alkyl with 1-6 carbon atoms, aryl with 6-10 carbon atoms, arylalkyl with 6-10 carbon atoms in the aryl part and 1 to 6 carbon atoms in the alkyl part, heteroaryl represents a 5-10 membered mono - or bicyclic system containing 1-2 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, heteroalicyclic represents a 5-10 membered mono - or bicyclic system containing 1-2 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, substituted alkyl with 1-6 carbon atoms, or15,
R3, R4, R6and R7independently selected from the group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkenyl with 3-7 carbon atoms in cycloalkyl parts and 1-6 carbon atoms in the alkyl part, heteroseksualci represents a 5-10 membered mono - or bicyclic system containing 1-2 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, aryl with 6-10 carbon atoms, rilastil with 6-10 carbon atoms in the aryl part and 1 to 6 carbon atoms in the alkyl part, heteroaryl represents a 5-10 membered mono - or bicyclic system containing 1-2 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, heteroallyl represents a 5-10 membered mono - or bicyclic system containing 1-2 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, substituted alkyl with 1-6 atoms operared, -CH2-O-Si(R9)(R10)(R19), where R9and R10denote alkyl with 1-6 atoms operared, or R3and R4or R6and R7together with the carbon atom to which they are attached, combined with the formation of polycyclic groups such as
or;
where M stands for CH2-, A and b independently denote an aryl with 6-10 carbon atoms and q is 1;
R14means 0 substituents,
R15, R16and R17listed below is independently selected from the group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, quinil with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkenyl with 3-7 carbon atoms in cycloalkyl parts and 1-6 carbon atoms in the alkyl part, heteroseksualci represents a 5-10 membered mono - or bicyclic system containing 1-2 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, hetaeras cycloalkenyl, represents a 5-10 membered mono - or bicyclic system containing 1-2 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, substituted alkyl with 1-6 carbon atoms, aryl with 6-10 carbon atoms, arylalkyl with 6-10 carbon atoms in the aryl part and 1 to 6 carbon atoms in the alkyl part, heteroaryl represents a 5-10 membered mono-or bicyclic system containing 1-2 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, heteroallyl represents a 5-10 membered mono - or bicyclic system containing 1-2 heteroatoms, selected from the group comprising nitrogen, oxygen and sulfur, substituted alkyl with 1-6 carbon atoms, R18is alkyl with 1-6 carbon atoms, R18-cycloalkyl with 3-7 carbon atoms, R18-heteroseksualci represents a 5-10 membered mono - or bicyclic system containing 1-2 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, R18aryl with 6-10 carbon atoms, R18-arylalkyl with 6-10 carbon atoms in the aryl part and 1 to 6 carbon atoms in the alkyl part, or R15, R16and R17denote
;
where R23means from 0 to 2 substituents, m is 0 and n is 1 or 2;
R18means 1-2 substituent, independently selected from the group comprising the reel with 6-10 carbon atoms, nitro, halo, trifluoromethyl, cyano, C(O)OR19, -C(O)other20, -SR19, -OH, -OR20, -N(alkyl)2with 1-6 carbon atoms in each alkyl group,
or two pieces of R18neighboring carbon atoms can be linked to each other to form,or;
R19means alkyl with 1-6 carbon atoms or aryl with 6-10 carbon atoms;
R20means alkyl with 1-6 carbon atoms or aryl with 6-10 carbon atoms;
and where all alkyl, cycloalkyl, cycloalkenyl, heterocytolysine, geterotsiklicheskikh, aryl, arylalkyl, heteroaryl, heteroallyl, alkeline and alkyline group in R1, R2, R3, R4, R5, R6, R7independently may be substituted by 1 to 3 groups of R21independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms, -CN, -OR15, -C(O)R15, -C(O)OR15, -C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, -CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CHsub> 2-N(R15)C(O)OR16, -N3, -NO2and-S(O)2R15; and where alkyl with 1-6 carbon atoms, and cycloalkyl with 3-7 carbon atoms independently are unsubstituted or contain as substituents of 1 to 5 groups R22independently selected from the group comprising halogen, -CN or-OR15;
R23means alkyl with 1-6 carbon atoms;
provided that if W denotes-C(O) -, and U represents a bond, R1does not mean optionally substituted phenyl,
provided that either R1or R5does not mean alkyl, disubstituted group-CO(O)R15or-C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17or-N(R15)C(O)OR16);
provided that if R1means methyl, R2means N, W denotes-C(O) -, and U represents a relationship (R3, R4) does not imply (N, N), (phenyl, phenyl), (H, phenyl), (benzyl, H), (benzyl, phenyl), (isobutyl, N), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenfree, phenyl) or (CH3O-phenyl, NO2-phenyl);
provided that if R1and R5both mean N, W denotes-C(O) -, and U represents a relationship (R3, R4) does not imply (optionally substituted phenyl, optionally substituted benzyl), (optionally substituted phenyl, heteroaromatic)or (heteroaryl, heteroaromatic);
provided that, if R1means R21-aryl, or R21-arylalkyl, where R21means OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3or-S(O)2NR15R16;
where R15and R16independently selected from the group comprising N, the above alkyl, alkenyl, cycloalkyl, heteroseksualci, aryl and
heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heteroseksualci and R18-aryl, and U represents a bond; R5means N.

2. The compound according to claim 1, having the structure IB

3. The compound according to claim 2, in which U represents a relationship.

4. The compound according to claim 2, in which U represents-C(R6)(R7)-.

5. The compound according to claim 1, in which R2means N.

6. The compound according to claim 1, in which R3, R4, R6and R7independently selected from the group comprising aryl, heteroaryl, heteroaromatic, arylalkyl, cycloalkyl, heteroseksualci, alkyl and cycloalkenyl having specified in claim 1 the feature.

7. The compound according to claim 1, in which
U mean the link;
W means-C(O)-;
R1means H, alkyl, R21-alkyl, arylalkyl, R21-arylalkyl, cycloalkenyl, R21-cycloalkenyl, geterotsiklicheskikh or R21-gets recycleability,
R2means N;
R3means alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21-cycloalkenyl, R21-cycloalkyl, R21-aryl, or R21-arylalkyl;
R4means alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21-cycloalkenyl, R21-cycloalkyl, R21-aryl, or R21-arylalkyl;
R5means H, alkyl, R21-alkyl, arylalkyl, R21-arylalkyl, cycloalkenyl, R21-cycloalkenyl, geterotsiklicheskikh or R21-geterotsiklicheskikh;
R6means alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21-cycloalkenyl, R21-cycloalkyl, R21-aryl, or R21-arylalkyl;
R7means alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21-cycloalkenyl, R21-cycloalkyl, R21-aryl, or R21-arylalkyl;
R15, R16and R17mean N, R18-alkyl, alkyl or
R21means alkyl, aryl, halogen, -OR15, -NO2, -C(O)R15or-CH2-N(R15)C(O)N(R16)(R17);
n = 1;
m is 0;
R18means-OR20;
R20means aryl;
R23means alkyl, with the above-mentioned hydrocarbon residues are indicated in claim 1 of the feature is Ristiku.

8. The connection according to claim 7, in which
R3, R4, R6and R7mean
,,or;
and
R1and R5means H, CH3,
,,,,
or.

9. The compound according to claim 1, selected from the group including








10. The compound according to claim 1, in which
U mean the link;
W means-C(O)-;
R1means H, alkyl, R21-alkyl, arylalkyl, R21-arylalkyl, cycloalkenyl, R21-cycloalkenyl, geterotsiklicheskikh or R21-geterotsiklicheskikh,
R2means N;
R3means alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, R21-alkyl,R 21-cycloalkenyl, R21-cycloalkyl, R21-aryl, R21-arylalkyl, heteroallyl, heteroaryl, heteroseksualci, R21-heteroallyl, R21-heteroaryl or R21-heteroseksualci;
R4means alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21-cycloalkenyl, R21-cycloalkyl, R21-aryl, R21-arylalkyl, heteroallyl, heteroaryl, heteroseksualci, R21-heteroallyl, R21-heteroaryl or R21-heteroseksualci;
R5means H, alkyl, R21-alkyl, arylalkyl, R21-arylalkyl, cycloalkenyl, R21-cycloalkenyl, geterotsiklicheskikh or R21-geterotsiklicheskikh;
R6means alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21-cycloalkenyl, R21-cycloalkyl, R21-aryl, R21-arylalkyl, heteroallyl, heteroaryl, heteroseksualci, R21-heteroallyl, R21-heteroaryl or R21-heteroseksualci;
R7means alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21-cycloalkenyl, R21-cycloalkyl, R21-aryl, R21-arylalkyl, heteroallyl, heteroaryl, heteroseksualci, R21-heteroallyl, R21-heteroaryl or R21-heteroseksualci;
R15, R16and R 17mean N, cycloalkyl, cycloalkenyl, R18-alkyl, alkyl, aryl, R18-aryl, R18-arylalkyl, arylalkyl,or
n is 1 or 2;
m is 0;
R18means-OR20or halogen;
R20means aryl;
R21means alkyl, aryl, R22is alkyl with 1-6 carbon atoms, R22aryl with 6-10 carbon atoms, halogen, -N(R15)(R16), -OR15, -NO2, -C(O)R15, -N(R15)C(O)R16, -CH2-N(R15)C(O)N(R16)(R17or-N(R15)C(O)N(R15)(R17);
R22means-OR15or halogen,
R23means alkyl, with the above-mentioned hydrocarbon and heterocyclic residues are specified in claim 1 the feature.

11. The compound according to claim 1, selected from the group including




























12. Pharmaceutical composition having the properties of the inhibitor aspirinplease comprising an effective amount of a compound according to claim 1 and a pharmaceutically effective carrier.

13. The use of compounds according to claim 1 for the manufacture of a medicine for inhibiting aspirinplease.

14. The use of compounds according to claim 1 for the manufacture of a medicinal product on the I treatment of cardiovascular diseases, violations of the cognitive and neurodegenerative diseases, and inhibition of the human immunodeficiency virus, plasmepsin, cathepsin D and protozoal enzymes.

15. The application 14, in which the drug is intended to treat disorders cognitive or neurodegenerative diseases.

16. The application indicated in paragraph 15, in which the drug is intended for treatment of Alzheimer's disease.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula (I): , where R1 denotes hydrogen; R2 denotes adamantine which is unsubstituted or substituted with a hydroxy group or halogen; R3 denotes trifluoromethyl, pyrazole, triazole, piperidine, pyrrolidine, hydroxymethylpiperidine, benzylpiperazine, hydroxypyrrolidine, tert-butylpyrrolidine, hydroxyethylpiperazine, hydroxypiperidine or thiomorpholyl group; R4 denotes cyclopropyl, tert-butyl, -CH(CH3)2CH2OH, methyl, -CF3 or -(CH2)nCF3 group, where n equals 1 or 2; R5 denotes hydrogen or lower alkyl which is unsubstituted or substituted with a halogen, as well as pharmaceutically acceptable salts thereof.

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17 cl, 99 ex, 1 tbl

FIELD: chemistry.

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EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: chemistry; medicine.

SUBSTANCE: inventions relate to novel marked with tritium analogue of physiologically active compound- uniformly marked with tritium tylosin of formula: . Said compound is drastic antibiotic.

EFFECT: extension of assortment of marked analogues of physically active compound, which are applied in organic chemistry, in biology and in medicine.

1 cl, 1 dwg, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I) possessing inhibitory effect on production of interleukin-12 (IL-12) wherein R1 represents group of the formula , aryl or heteroaryl; each among R2 and R4 represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy group; R3 represents Rc, alkenyl, -ORc, -OC(O)Rc, -SRc, -NRcCORd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcSO2Rd, -CORc, -C(O)ORc or -C(O)NRcRd; R5 represents hydrogen atom (H); n = 0, 1, 2, 3, 4, 5 or 6; X represents oxygen atom (O) or -NRc; Y represents a covalent bond. -CH2, O or -NRc; Z represents nitrogen atom (N); one of values U and V represents N and another represents -CRc; W represents O, sulfur atom (S) or -S(O)2 wherein each radical among Ra and Rb represents independently H, (C1-C6)-alkyl, aryl or heteroaryl; each radical among Rc and Rd represents independently H, (C1-C6)-alkyl, phenyl, heteroaryl, cyclyl, heterocyclyl or (C1-C6)-alkylcarbonyl wherein term "aryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring; term "heteroaryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring that comprises at least one heteroatom, such as O, N or S as a part of cyclic system and wherein other atoms mean carbon; term "cyclyl" and "heterocyclyl" relate to partially or completely saturated monocyclic or bicyclic system comprising from 4 to 14 carbons in rings wherein heterocyclic ring comprises one or some heteroatoms (for example, O, N or S) as part of cyclic system and wherein other atoms mean carbon, and under condition that when X represents -NH, Y represents a covalent bond, n = 0, and R3 represents H or CH3 then R1 doesn't mean thiazolyl or pyrimidinyl. Also, invention relates to a pharmaceutical composition and a method for treatment of disorder associated with hyperproduction of interleukin-12.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

49 cl, 43 ex

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

SUBSTANCE: invention relates to amide derivative represented by the following formula [1]:

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EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 2 tbl, 83 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

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

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to a derivative copernicia and their pharmaceutically acceptable salts of General formula I

< / BR>
where R1represents a methyl group, R2represents a methyl group, R4represents a hydroxy-group and X represents a methylene group; R1represents a methyl group, R2represents a hydrogen atom, R4represents a hydroxy-group and X represents a methylene group; R1represents a methyl group, R2represents a methyl group, R4represents a hydrogen atom and X represents a methylene group; R1represents a hydrogen atom, R2represents a hydrogen atom, R4represents a hydroxy-group and X represents a methylene group; or R1represents a methyl group, R2represents a methyl group, R4represents a hydroxy-group and X represents a sulfur atom

FIELD: chemistry.

SUBSTANCE: medicine-ligand conjugates are powerful cytotoxins in which the medicine is bonded to the ligand through a peptide, hydrazine or disulphide linker.

EFFECT: agents are highly effective.

63 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry, and specifically to compounds of general formula I , where A is an oxygen atom, an alkylene, alkenyl or hetero alkylene group, in which the CH2 group is substituted with a NH group, where the said groups can be optionally substituted with OH, =O or CH2OH groups, X1, X2, X3, X4 and X5 independently represent nitrogen atoms or groups of formula CH or CR4, Cy is cycloalkylene or heterocycloalkylene group containing at least one nitrogen atom, R1 is a hydrogen atom, an alkyl or alkyloxy group, R2 is a halogen atom, a hydroxy group, an alkyl or heteroalkyl residue, where the said groups can be optionally substituted with OH, NH2 groups and/or a =O group, R3 is a group of formula -B-Y, in which B denotes an alkylene, alkenyl or heteroalkylene group, where the said groups can be optionally substituted with OH, NH2, COOH groups or a =O group, and Y is an optionally substituted phenyl, optionally substituted heteroaryl group containing 5 or 6 ring atoms, or an optionally substituted bicyclic heterocycle in which one ring is phenyl or pyridyl, and the other is a 5-, 6- or 7-member heteroaryl or heterocycloalkyl group which contains up to 3 heteroatoms selected from nitrogen, oxygen and sulphur atoms, R4 is a halogen atom, n equals 0, 1 or 2 and m equals 0 or 1, or their pharmaceutically acceptable salts, solvates and hydrates. The invention also relates to a pharmaceutical composition based on the formula I compound and use of the compound or the pharmaceutical composition to treat bacterial infections.

EFFECT: obtaining novel compounds possessing useful biological properties.

12 cl, 7 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 compounds of general formula (I') which have inhibitory effect on ALK kinase: , where n' is selected from 1 and 2; R'2 is selected from halogen; R'3 is selected from -S(O)2NR'5R'6, -S(O)2R'6 and -C(O)NR'5R'6, where R'5 is selected from hydrogen and C1-6alkyl, and R'1 is selected from C1-6alkyl; and R'1 is selected from phenyl which is substituted with 3 radicals independently selected from C2-6alkoxy group, C1-6alkyl, -X'R'4 and -OXR'4, where X' denotes a bond, and R'4 is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, where R'4 can be optionally substituted with 1-3 radicals independently selected from C1-6 alkyl, provided that the following compound is excluded .

EFFECT: design of a method of inhibiting and using compounds for making a medicinal agent for treating diseases which respond to ALK kinase inhibition.

7 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where D is pyrrolidine, X is a radical selected from a group containing C=O, SO2, (C=O)-NH, CH2, O-(C=O), (C=O)-O, (C=S)-NH, Y is a radical selected from a group containing - (CH2)n-E-(CH2)m-L-(CH2)k, where E is O, k, m and n are separately and independently equal to 0, 1, 2 and 3, Z is an alkyl, where the alkyl is CH2 or CH2CH2, A is a radical selected from a group containing benzyl, substituted benzyl, phenyl, substituted phenyl, alkyl and substituted alkyl, cycloalkyl, heterocyclyl, aryl, alkyloxyalkyl, substituted alkyloxyalkyl, alkyloxyaryl, B is a radical of formula (II) , where R1 is selected from a group containing H, alkyl and substituted alkyl, cycloalkyl, R2 is selected from a group containing H, benzyl, substituted benzyl, phenyl, substituted phenyl, alkyl and substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, substituted cycloalkylalkyl, G is an amino group which is substituted by a heteroaryl or substituted heteroaryl, and where Q and L each independently denotes a radical selected from a group containing (C=O)-NH, NH, CH2, NH-(C=O)-NH, NH-(C=O), NH-SO2, NRc, (C=O)-NRc, and where Ra, Rb, Rc and Rd each independently denotes a radical selected from a group containing H, alkyl, cycloalkyl, heterocyclyl, aryl, substituted aryl, as well as to use of these compounds as integrin inhibitor and for making a medicinal and a diagnostic agent, to a pharmaceutical composition based on these compounds and to methods of treating integrin-associated condition.

EFFECT: novel compounds which are integrin inhibitors and can be used to treat diseases where angiogenesis inhibition is necessary are obtained and described.

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

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

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

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

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I

where A, B and D each denotes N or CR5, where one of A, B and D denotes N, R1 denotes OR6, R2 denotes halogen, C1-C4alkyl, halogen(C1-C4)alkyl or OR7, R3 denotes a heteroarylalkyl group in which the heteroaryl fragment contains 5-6 atoms in the ring, at least one of which is an N atom, and the alkyl fragment with a branched or straight chain contains 1-5 carbon atoms, R4 denotes C3-C10cyclalkyl, C6-C14aryl, unsubstituted or substituted with one or more substitutes selected from a group comprising halogen, alkoxy, terazol-5-yl, 2-(heterocyclyl)tetrazol-5-yl or a carboxy group; heteroaryl containing 5-6 atoms in the ring; heterocyclic group saturated or partially saturated, containing 5-6 atoms in the ring, at least one of which is an N atom, unsubstituted or substituted with one or more substitutes selected from a group comprising alkoxy, alkoxyalkoxy, oxo, alkoxycarbonyl, alkylsulfanyl, alkylsufonyl or phenylsulfonyl; R5 denotes H; R6 denotes H or C1-C4alkyl with a branched or straight chain, unsubstituted or substituted with one or more halogens, R7 denotes H or C1-C12alkyl with a branched or straight chain, unsubstituted or substituted with one or more substitutes selected from a group which includes halogen; C3-C10cyclalkyl; saturated heterocyclic group containing 5-6 atoms in the ring, at least one of which is an O atom, or a heterocylcylalkyl group in which the heterocyclic fragment is saturated, partially saturated or unsaturated and contains 5-10 atoms in the ring, at least one of which is an O atom; or to a pharmaceutically acceptable salt thereof, as well as to a pharmaceutical composition for inhibiting PDE4 enzyme activity and to use of the said compound to prepare a medicinal agent.

EFFECT: novel compounds which can be used in medicine are obtained and described.

65 cl, 17 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel methods for synthesis of formula I compound (Iclaprim) which relates to dihydrofolate reductase inhibitors

,

as well as to intermediate compounds used in said methods.

EFFECT: design of novel efficient methods for synthesis of formula I compound (Iclaprim).

13 cl, 2 tbl, 30 ex

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