Hydroxamate derivatives suitable as deacetylase inhibitors

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention relates to hydroxamate derivatives described by general formula I: , in which R1 represents H or linear C1-C6-alkyl; R2 hydrogen, С110-alkyl optionally substituted by 1-5 constituents selected from hydroxy, amino, hydroxyalkyl; C4-C9-cycloalkyl; aryl; C4-C9-heterocycloalkyl, C4-C9-heterocycloalkylalkyl containing 2 heteroatoms (nitrogen and/or oxygen); C4-C9-cycloalkylalkyl; arylalkyl; heteroarylalkyl containing 1-4 nitrogen atoms as heteroatoms; -(CH2)nC(O)R6, -(CH2)nOC(O)R6, -N(R12)C(O)-W; HONH-C(O)-CH=C(R1)arylalkyl, and (CH2)nR7; R3 and R4, identical or different, independently denote hydrogen, optionally OH-substituted C1-C6-alkyl; C(O)-O-W, or -N(R12)C(O)W; or R3 and R4 together with carbon atom, to which they are linked, represent C=O; or R2 together with carbon atom, to which it is linked, and R3 together with carbon atom, to which it is linked, can form C4-C9-heterocycloalkyl containing 2 nitrogen atoms as heteroatoms; or mixed aryl or non-aryl polyheterocyclic ring; R5 is selected from hydrogen; C1-C6-alkyl; C4-C9-cycloalkyl; C(O)-W; aryl optionally substituted by 1-2 constituents selected from halogen and hydroxyalkyl; heteroaryl containing nitrogen as heteroatom; arylalkyl; aromatic polycycle; polyheteroaryl containing 1-2 nitrogen atoms as heteroatoms and optionally substituted by 1-2 substituents selected from hydroxyalkyl, halogen, alkyl, and aryl; mixed aryl-nonaryl polyheterocycle containing nitrogen or oxygen atom as heteroatom and optionally substituted by groups -N-OH, =N-OH; n, n1, n2, and n3, identical or different, are independently selected from within a range of 0-6; X and Y, identical or different, are independently selected from hydrogen, halogen, and nitro group; or pharmaceutically acceptable salt thereof. Invention also relates to a pharmaceutical composition showing inhibitory activity toward hydroxamate derivative of general formula I in combination with one or several pharmaceutically acceptable carriers. Hydroxamate derivative of general formula I are also appropriate for treating proliferative disease and regulating p21 promoter.

EFFECT: enabled use of hydroxamate derivatives as deacetylase inhibitors.

42 cl, 6 tbl, 272 ex

 

Prerequisites to the creation of inventions

Reversible histone acetylation is a major regulator of gene expression, which acts by altering the accessibility of DNA to factors transcriptio. In normal cells to maintain balance discontinuties (HAD) and distancedistance together control the level of acetylation of histones. The inhibition HAD leads to the accumulation hyperacetylation of histones, which cause a variety of cellular responses.

The inhibitors HAD studied for their therapeutic effects on cancer cells. For example, it was reported that butyric acid and its derivatives, including sodium salt phenylalkanoic acid induce apoptosis in vitro in cell lines carcinoma of the colon human leukemia and retinoblastoma. However, butyric acid and its derivatives are not used pharmacological agents, because they have a tendency to rapid metabolism and very short half-life in vivo. Other inhibitors HAD, which are widely studied due to their antitumor activity, are trichostatin and toxin. Trichostatin And is an antifungal agent and an antibiotic and is a reversible inhibitor HAD mammals. Trioxin is a cyclic tetrapeptide and is irreversible inhib the torus HAD. Although trichostatin and trioxin studied for their antitumor activity, the instability of these compounds in vivo makes them less suitable as anticancer drugs. There remains a need in obtaining active compounds suitable for the treatment of tumors, including malignant tumors, that is efficient and sustainable.

Brief description of the invention

The present invention provides an effective deacetylase inhibitors, used as pharmaceutical agents, having the formula I

where

R1means hydrogen, halogen or linear (C1-C6)alkyl (especially methyl, ethyl or n-propyl, deputies, which are unsubstituted or substituted by one or more substituents described below for alkyl groups);

R2selected from hydrogen, (C1-C10)alkyl (e.g. methyl, ethyl or-CH2-CH2-HE), (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, (C4-C9)geterotsiklicheskikh, cycloalkenyl (for example, cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g., benzyl), heteroallyl (for example, pyridylmethyl), -(CH2)nC(O)R6, -(CH2)nOS(O)R6, aminoacyl, HON-C(O)-CH=C(R1)-arylalkyl the a - and -(CH 2)nR7;

R3and R4the same or different and independently of one another denote hydrogen, (C1-C6)alkyl, acyl or acylamino, or

R3and R4together with the carbon to which they are attached represent C=O, C=S or C=NR8or

R2together with the nitrogen to which it is linked, and R3together with the carbon to which it is linked, may form a (C4-C9)heteroseksualci, heteroaryl, polyetherols, nonaromatic polyheterocycles or mixed aryl and nearline polyheterocyclic ring;

R5selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, acyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), heteroallyl (for example, pyridylmethyl), aromatic political, nah political, mixed aryl and nearring of political, polyetheramine, nah polyheterocycles and mixed aryl and nearring of polyheterocycles;

n, n1n2and n3the same or different and independently from each other selected from 0-6, when n1means 1-6, each carbon atom can be optionally and independently substituted R3and/or R4;

X and Y are the same or different and independently from each other selected from hydrogen, halogen, (C1-the 4)alkyl such as CH3and CF3, NO2C(O)R1OR9, SR9, CN, and NR10R11;

R6selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, cycloalkenyl (for example, cyclopropylmethyl), aryl, heteroaryl, arylalkyl (for example, benzyl, 2-phenylethenyl), heteroallyl (for example, pyridylmethyl), OR12and NR13R14;

R7choose from OR15, SR15, S(O)R16, SO2R17, NR13R14and NR12SO2R6;

R8selected from hydrogen OR15, NR13R14, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, arylalkyl (e.g., benzyl) and heteroaromatic (for example, pyridylmethyl);

R9choose from (C1-C4)alkyl such as CH3and CF3, C(O)-alkyl, for example C(O)CH3and S(O)CF3;

R10and R11the same or different and independently from each other selected from hydrogen, (C1-C4)alkyl and-C(O)-alkyl;

R12selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, (C4-C9)geterotsiklicheskikh, aryl, mixed aryl and neurolingo of politicla, is heteroaryl, arylalkyl (e.g., benzyl) and heteroaromatic (for example, pyridylmethyl);

R13and R14the same or different and independently from each other selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, arylalkyl (e.g., benzyl), heteroallyl (for example, pyridylmethyl), aminoacyl, or

R13and R14means together with the nitrogen to which they relate, (C4-C9)heteroseksualci, heteroaryl, polyetherols, nonaromatic polyheterocycles or mixed aryl and nearly polyheterocycles;

R15selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, arylalkyl, heteroallyl and (CH2)mZR12;

R16choose from (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, polyetheramine, arylalkyl, heteroallyl and (CH2)mZR12;

R17choose from (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, aromatic political, heteroaryl, arylalkyl, heteroallyl, polyheteroarylenes and NR13R14;

m means an integer of wybrand the e from 0-6; and

Z is chosen from O, NR13, S and S(O)

or their pharmaceutically acceptable salt.

Compounds according to the present invention is applicable as active agents in pharmaceutical compositions that are particularly effective in the treatment of diseases associated with cell proliferation. The pharmaceutical composition contains an effective amount of this active agent along with other pharmaceutically acceptable excipients, carriers, fillers, diluents and the like. The term "pharmaceutically effective amount", as used in the context, means the number required to introduce the patient to achieve a therapeutic result, especially antitumor effect, such as suppression of proliferation of malignant tumor cells, benign tumor cells or other proliferative cells.

Detailed description of the invention

The present invention provides hydroxamate derivatives, such as hydroxamic acids, which are inhibitors deacetylase, preferably inhibitors of histone deacetylase. Hydroxamate derivatives are highly suitable for the treatment of tumors, including malignant tumors. Hydroxamate derivatives of the present invention have the following structure I

where

R1means hydrogen, halogen or linear (C1-C6)alkyl (especially methyl, ethyl or n-propyl, deputies, which are unsubstituted or substituted by one or more substituents described below for alkyl groups);

R2selected from hydrogen, (C1-C10)alkyl (preferably (C1-C6)alkyl, for example methyl, ethyl or-CH2-CH2-HE), (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, (C4-C9)geterotsiklicheskikh, cycloalkenyl (for example, cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g., benzyl), heteroalkyl (for example, pyridylmethyl), -(CH2)nC(O)R6, -(CH2)nOS(O)R6, aminoacyl, HON-C(O)-CH=C(R1)-arylalkyl - and -(CH2)nR7;

R3and R4the same or different and independently of one another denote hydrogen, (C1-C6)alkyl, acyl or acylamino, or

R3and R4together with the carbon to which they are attached represent C=O, C=S or C=NR8or

R2together with the nitrogen to which it is linked, and R3together with the carbon to which it is linked, may form a (C4-C9)heteroseksualci, heteroaryl, polyetherols, nonaromatic polyheterocycles or mixed aryl and Neary is inoe polyheterocyclic ring;

R5selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, acyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), heteroallyl (for example, pyridylmethyl), aromatic political, nah political, mixed aryl and nearring of political, polyetheramine, nah polyheterocycles and mixed aryl and nearring of polyheterocycles;

n, n1n2and n3the same or different and independently from each other selected from 0-6, when n1means 1-6, each carbon atom can be optionally and independently substituted R3and/or R4;

X and Y are the same or different and independently from each other selected from hydrogen, halogen, (C1-C4)alkyl such as CH3and CF3, NO2C(O)R1OR9, SR9, CN, and NR10R11;

R6selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, cycloalkenyl (for example, cyclopropylmethyl), aryl, heteroaryl, arylalkyl (for example, benzyl, 2-phenylethenyl), heteroallyl (for example, pyridylmethyl), OR12and NR13R14;

R7choose from OR15, SR15, S(O)R16, SO2R17, NR13R14and NR12SO2R6 ;

R8selected from hydrogen OR5, NR13R14, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, arylalkyl (e.g., benzyl) and heteroaromatic (for example, pyridylmethyl);

R9choose from (C1-C4)alkyl such as CH3and CF3, C(O)-alkyl, for example C(O)CH3and S(O)CF3;

R10and R11the same or different and independently from each other selected from hydrogen, (C1-C4)alkyl and-C(O)-alkyl;

R12selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, (C4-C9)geterotsiklicheskikh, aryl, mixed aryl and neurolingo of politicla, heteroaryl, arylalkyl (e.g., benzyl) and heteroaromatic (for example, pyridylmethyl);

R13and R14the same or different and independently from each other selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, arylalkyl (e.g., benzyl), heteroallyl (for example, pyridylmethyl), aminoacyl, or

R13and R14means together with the nitrogen to which they relate, (C4-C9)heteroseksualci, heteroaryl, polyetherols, nonaromatic polig tetracycl or mixed aryl and nearly polyheterocycles;

R15selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, arylalkyl, heteroallyl and (CH2)mZR12,

R16choose from (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, polyetheramine, arylalkyl, heteroallyl and (CH2)mZR12;

R17choose from (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, aromatic political, heteroaryl, arylalkyl, heteroallyl, polyheteroarylenes and NR13R14

m means an integer selected from 0-6; and

Z is chosen from O, NR13, S and S(O)

or their pharmaceutically acceptable salt.

When appropriate, the term "unsubstituted" means that no Deputy or the only Deputy is hydrogen.

Halide substituents selected from fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine.

Alkyl substituents include linear or branched (C1-C6)alkyl, unless specified otherwise. Examples of relevant linear and branched (C1-C6)alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec. -butyl, tert.-butyl and that p is such. If not mentioned otherwise, the alkyl substituents include unsubstituted alkyl groups, and alkyl groups that are substituted by one or more appropriate substituents, including neopredelennosti (namely, one or more double or triple bonds), acyl, cycloalkyl, halogen, oxyalkyl, alkylamino, aminoalkyl, acylamino and OR15for example alkoxy. Preferred substituents for the alkyl groups include halogen, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.

Cycloalkyl substituents include (C3-C9)cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. If not noted otherwise, cycloalkyl substituents include unsubstituted cycloalkyl group and cycloalkyl group, which is substituted by one or more appropriate substituents, including (C1-C6)alkyl, halogen, hydroxy, aminoalkyl, oxyalkyl, alkylamino and OR15for example alkoxy. Preferred substituents cycloalkyl groups include halogen, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.

The above discussion and alkyl cycloalkyl deputies also applicable to the alkyl portions of the other substituents is not limited to such as alkoxy, bonds alkylamines, Alki the ketones, killkenny, heteroarylboronic, alkylsulfonyl and alkylating deputies and the like.

Heterocytolysine substituents include a 3-9-membered aliphatic ring, such as 4-7-membered aliphatic ring containing 1-3 heteroatom selected from nitrogen, sulfur and oxygen. Examples of relevant geterotsiklicheskikh substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrofuranyl, piperidyl, piperazin, tetrahydropyranyl, morpholino, 1,3-diazepan, 1,4-diazepan, 1,4-oxazepan and 1,4-Ossetian. If not noted otherwise, the rings are unsubstituted or substituted on the carbon atoms by one or more appropriate substituents, including (C1-C6)alkyl, (C4-C9)cycloalkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), heteroaromatic (for example, pyridylmethyl), halogen, amino, alkylamino and OR15for example alkoxy. Unless otherwise noted, the nitrogen heteroatoms are unsubstituted or substituted by hydrogen, (C1-C4)alkyl, arylalkyl (e.g., benzyl), heteroallyl (for example, pyridylmethyl), acyl, aminoacyl, alkylsulfonyl and arylsulfonyl.

Cycloalkyl substituents include compounds of formula -(CH2)n5-cycloalkyl, where n5means the number of 1-6. Appropriate cycloalkyl substituents include cyclopentylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like. Such substituents are unsubstituted or substituted in the alkyl part or in cycloalkenes part of the appropriate Deputy, including those mentioned above for alkyl and cycloalkyl.

Aryl substituents include unsubstituted phenyl and phenyl substituted by one or more substituents, including (C1-C6)alkyl, cycloalkyl (for example, cyclopropylmethyl), O(CO)alkyl, oxyalkyl, halogen, nitro, amino, alkylamino, aminoalkyl, alkylbetaine, nitrile, carboxylic, alkylsulfonyl, aminosulfonyl, arylsulfonyl and OR15such as alkoxy. Preferred substituents include (C1-C6)alkyl, cycloalkyl (for example, cyclopropylmethyl), alkoxy, oxyalkyl, halogen, nitro, amino, alkylamino, aminoalkyl, alkylbetaine, nitrile, carboxylic, alkylsulfonyl, arylsulfonyl and aminosulfonyl. The relevant examples of aryl groups include a (C1-C4)alkylphenyl, (C1-C4)alkoxyphenyl, triptoreline, methoxyphenyl, hydroxyethylene, dimethylaminophenyl, aminopropylene, carbamaxepine, methanesulfonyl and toluensulfonyl.

Aromatic politicly include naphthyl and naphthyl substituted by one or more appropriate substituents, including (C1-C6)alkyl, cycloalkenyl (n is an example, cyclopropylmethyl), oxyalkyl, halogen, nitro, amino, alkylamino, aminoalkyl, alkylbetaine, nitrile, carboxylic, alkylsulfonyl, arylsulfonyl, aminosulfonyl and OR15such as alkoxy.

Heteroaryl substituents include compounds with a 5-7-membered aromatic ring containing one or more heteroatoms, for example 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Typical heteroaryl substituents include furyl, thienyl, pyrrole, pyrazole, triazole, thiazole, oxazole, pyridine, pyrimidine, isoxazole, pyrazin and the like. If not noted otherwise, heteroaryl substituents are unsubstituted or substituted on a carbon atom by one or more appropriate substituents, including alkyl, alkyl substituents identified above, and other heteroaryl Deputy. The nitrogen atoms are unsubstituted or substituted, for example, R13; especially acceptable substituents on the nitrogen atom include hydrogen, (C1-C4)alkyl, acyl, aminoacyl, and sulfonyl.

Arylalkyl substituents include groups of the formula -(CH2)n5-aryl, -(CH2)n5-1-CH(aryl)-(CH2)n5-aryl or -(CH2)n5-1-CH(aryl)(aryl), where aryl and n5 defined above. Such arylalkyl substituents include benzyl, 2-phenylethyl, 1-phenylethyl, tolyl-3-propyl, 2-phenylpro the sludge, diphenylmethyl, 2-diphenylether, 5,5-dimethyl-3-fenilpentil and the like. Arylalkyl substituents are unsubstituted or substituted in the alkyl residue or aryl residue or as described above for alkyl and aryl substituents.

Heteroallyl substituents include groups of the formula -(CH2)n5-heteroaryl where heteroaryl and n5 defined above, and bridging group linked to a carbon or a nitrogen of the heteroaryl part, such as 2-, 3-or 4-pyridylmethyl, imidazolidinyl and pyrrolidyl. Heteroaryl substituents are unsubstituted or substituted as described above for heteroaryl and alkyl substituents.

Aminoaniline substituents include groups of formula-C(O)-(CH2)n-C(H)(NR13R14)-(CH2)n-R5where n, R13and R5described above. Appropriate aminoaniline substituents include natural and unnatural amino acids, such as glycidyl, D-tryptophanyl, L-leinil, D - or L-homoserine, 4-aminobutyryl, (±)-3-amino-4-hexenol.

Non-aromatic polycyclic substituents include bicyclic and tricyclic condensed ring systems where each ring can be 4-9 membered and each ring may contain 0, 1 or more double and/or triple bonds. Examples of non-aromatic political on the given decalin, octahedrons, perhydroanthracene, perpetrabant[f]azulene. Such substituents are unsubstituted or substituted as described above for cycloalkyl groups.

Mixed aryl and nearline polycyclic substituents include bicyclic and tricyclic condensed ring systems where each ring can be 4-9 membered, and at least one ring is aromatic. Examples of mixed aryl and nearring of political include methylenedioxyphenyl, biomedicinal, 1,2,3,4-tetrahydronaphthalen, dibenzosuberone, dihydroanthracene, 9H-fluoren. Such substituents are unsubstituted or substituted by a nitro-group or as described above for cycloalkyl groups.

Polyheteroarylenes substituents include bicyclic and tricyclic condensed ring systems where each ring independently of each other may be 5 - or 6-membered and contains one or more heteroatoms, for example 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur such that the condensed ring system is aromatic. Examples polyheteroarylenes ring systems include quinoline, isoquinoline, pyridorin, pyrrolopyridine, properidine, indole, benzofuran, benzothiophene, benzinga, benzoxazol, pyrroloquinoline and the like. If not noted otherwise, polyheteroarylenes substituents are unsubstituted or substituted on the carbon atom by one or more substituents, including alkyl, alkyl substituents identified above, and substituents of the formula-O-(CH2CH=CH(CH3)(CH2)1-3N. The nitrogen atoms are unsubstituted or substituted, for example, R13; especially acceptable substituents on the nitrogen atom include hydrogen, (C1-C4)alkyl, acyl, aminoacyl, and sulfonyl.

Nah polyheterocycles substituents include bicyclic and tricyclic condensed ring systems where each ring can be 4-9 membered, contain one or more heteroatoms, for example 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, and contain 0-1 or more carbon-carbon double or triple bonds. Examples of non-aromatic polyheterocycles include CIS-perhydrosqualene[f]pyridinyl, decahedrons[f][1,4]oxazepine, 2,8-dioxabicyclo[3.3.0]octane, hexahydrofuro[3,2-b]thiophene, perritopiloto[3,2-b]pyrrole, perhydroanthracene, perhydro-1H-dicyclopenta[b,e]Piran. If not noted otherwise, nah polyheterocycles substituents are unsubstituted or substituted on the carbon atom by one or more substituents, including alkyl and alkyl C is Mascitelli, identified above. The nitrogen atoms are unsubstituted or substituted, for example, R13; especially acceptable substituents on the nitrogen atom include hydrogen, (C1-C4)alkyl, acyl, aminoacyl, and sulfonyl.

Mixed aryl and nearline polyheterocycles substituents include bicyclic and tricyclic condensed ring systems where each ring can be 4-9 membered, contain one or more heteroatoms selected by their oxygen, nitrogen or sulfur, and at least one of the rings must be aromatic. Examples of aryl and nearring of polyheterocycles include 2,3-dihydroindole, 1,2,3,4-tetrahydroquinoline, 5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin, 5H-dibenzo[b,e][1,4]diazepin, 1,2-dihydropyrrolo[3,4-b] [1,5]benzodiazepine, 1.5-dihydropyrido[2,3-b][1,4]diazepin-4-one, 1,2,3,4,6,11-hexahydrobenzo[b]pyrido[2,3-e]diazepin-5-it. If not noted otherwise, mixed aryl and nearline polyheterocycles substituents are unsubstituted or substituted on the carbon atom by one or more appropriate substituents, including-N-OH, =N-OH, alkyl and alkyl substituents identified above. The nitrogen atoms are unsubstituted or substituted, for example, R13; especially acceptable substituents on the nitrogen atom include hydrogen, (C1-C4)alkyl, acyl, aminoach the l and sulfonyl.

Amino compounds the substituents include primary, secondary and tertiary amines and Quaternary amines in the form of a salt. Examples of aminecontaining substituents include mono - and dialkylamino, mono - and diarylamino, mono - and diarylamino, allerellie, alkylamino, alkylenediamine and the like.

Sulfonylurea substituents include alkylsulfonyl and arylsulfonyl, for example methanesulfonyl, benzazolyl, tosyl and the like.

Acyl substituents include groups of formula-C(O)W, -OC(O)-W, -C(O)-O-W and-C(O)NR13R14where W stands for R16hydrogen or cycloalkyl.

Acylaminoalkyl include groups of formula-N(R12)C(O)-W, - N(R12)C(O)-O-W and-N(R12)C(O)-NHOH, where R12and W are defined above.

In the case of R2Deputy NON-C(O)-CH=C(R1-arylalkyl means a group of the formula

where n4means 0-3, and X and Y are defined above.

Preferred values for each of the Deputy of the following:

R1means hydrogen, halogen or linear (C1-C4)alkyl;

R2selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, cycloalkenyl, aryl, heteroaryl, arylalkyl, heteroallyl, -(CH2)nC(O)R6, aminoacyl, and -(CH2)nR7;

R3and R4the same or different and independently from each other selected from hydrogen and (C1-C6)alkyl, or

R3and R4together with the carbon to which they are attached represent C=O, OS or C=NR8;

R5selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, arylalkyl, heteroaromatic, aromatic polycycle, nah polycycle, mixed aryl and neurolingo of politicla, polyetheramine, nah polyheterocycles and mixed aryl and neurolingo of polyheterocycles;

n, n1n2and n3the same or different and independently from each other selected from 0-6, when n stands for 1-6, each carbon atom is unsubstituted or independently substituted R3and/or R4;

X and Y are the same or different and independently from each other selected from hydrogen, halogen, (C1-C4)alkyl, CF3, NO2C(O)R1OR9, SR9, CN, and NR10R11;

R6selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, cycloalkenyl, aryl, heteroaryl, arylalkyl, heteroallyl, OR12and NR13R14;

R7choose from OR15, SR15, S(O)R162R17, NR13R14and NR12SO2R6;

R8selected from hydrogen OR15, NR13R14, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, arylalkyl and heteroallyl;

R9choose from (C1-C4)alkyl and C(O)-alkyl;

R10and R11the same or different and independently from each other selected from hydrogen, (C1-C4)alkyl and-C(O)-alkyl;

R12selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, arylalkyl and heteroallyl;

R13and R14the same or different and independently from each other selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, arylalkyl, heteroallyl and aminoacyl;

R15selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, arylalkyl, heteroallyl and (CH2)mZR12;

R16choose from (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, arylalkyl, heteroallyl and (CH2 )mZR12;

R17choose from (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, arylalkyl, heteroallyl and NR13R14,

m means an integer of 0-6; and

Z is chosen from o, NR13, S, S(O).

Apply the compounds of formula I include those where each of R1X, Y, R3and R4means hydrogen, including those in which one of the n2and n3means zero, and the other is 1, especially those in which R2means hydrogen or-CH2-CH2OH.

One group hydroxamate derivatives are the compounds of formula Ia

where

n4means 0-3

R2selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, cycloalkenyl, aryl, heteroaryl, arylalkyl, heteroallyl, -(CH2)nC(O)R6, aminoacyl, and -(CH2)nR7;

R5' means heteroaryl, heteroaromatic (for example, pyridylmethyl), aromatic politicly, nonaromatic politicly, mixed aryl and nearline politicly, polyetherols or mixed aryl and nearline polyheterocyclic,

or their pharmaceutically acceptable salt.

Another suitable the soup group hydroxamate derivatives are the compounds of formula Ia

where

n4means 0-3,

R2selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, cycloalkenyl, aryl, heteroaryl, arylalkyl, heteroallyl, -(CH2)nC(O)R6, aminoacyl, and -(CH2)nR7;

R5' means aryl, arylalkyl, aromatic politicly, nonaromatic politicly and mixed aryl and nearline politicly; especially aryl, such as n-forfinal, n-chlorophenyl, n-O-(C1-C4)alkylphenyl, such as n-methoxyphenyl and n-(C1-C4)alkylphenyl; and arylalkyl, such as benzyl, ortho-, meta - or para-chlorbenzyl, ortho-, meta - or para-mono, di - or tri-O-(C1-C4)alkylbenzene, such as ortho-, meta - or para-methoxybenzyl, m,p-diethoxybenzene, o,m,p-trimethoxybenzyl, and ortho-, meta - or para-mono-, di - or tri-(C1-C4)alkylphenyl, such as p-were, m,m-diethylphenyl,

or their pharmaceutically acceptable salt.

Another interest group are the compounds of formula Ib

where

R2' are selected from hydrogen, (C1-C6)alkyl, (C4-C6)cycloalkyl, cycloalkyl (for example, cyclopropylmethyl), -(CH2)2-4OR21where R21means waters of the genus, methyl, ethyl, propyl, isopropyl, and

R5" means unsubstituted 1H-indol-3-yl, benzofuran-3-yl or quinoline-3-yl or substituted 1H-indol-3-yl, such as 5-fluoro-1H-indol-3-yl or 5-methoxy-1H-indol-3-yl, benzofuran-3-yl or quinoline-3-yl,

or their pharmaceutically acceptable salt.

Another interest group hydroxamate derivatives

form the compounds of formula Ic

where

the ring containing Z1that is aromatic or non-aromatic, non-aromatic rings are saturated or unsaturated,

Z1means oxygen, sulfur or NR20,

R18means hydrogen, halogen, (C1-C6)alkyl (methyl, ethyl, tert.-butyl), (C3-C7)cycloalkyl, aryl, such as unsubstituted phenyl or phenyl substituted 4-och3or 4-CF3or heteroaryl, such as 2-furanyl, 2-thiophenyl or 2-, 3-or 4-pyridyl;

R20means hydrogen, (C1-C6)alkyl, (C1-C6)alkyl(C3-C9)cycloalkyl (for example, cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g., benzyl), heteroaromatic (for example, pyridylmethyl), acyl (acetyl, propionyl, benzoyl), or sulfonyl (methanesulfonyl, econsultancy, benzazolyl, toluensulfonyl);

A1means 1, 2 or 3 substituent to the verge independently of one another denote hydrogen, (C1-C6)alkyl, -OR19, halogen, alkylamino, aminoalkyl or heteroaromatic (for example, pyridylmethyl);

R19selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, arylalkyl (e.g., benzyl), heteroallyl (for example, pyridylmethyl) and -(CH2CH=CH(CH3)(CH2)1-3N;

R2selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, cycloalkenyl, aryl, heteroaryl, arylalkyl, heteroallyl, -(CH2)nC(O)R6, aminoacyl, and -(CH2)nR7;

v is 0, 1 or 2,

R means 0-3,

q means 1-5 and r is 0, or

q is 0 and r is 1 to 5

or their pharmaceutically acceptable salt.

Other changing substituents such as described above.

Particularly useful compounds of formula Ic are those in which R2means hydrogen or -(CH2)pCH2HE, where p means 1-3, especially those wherein R1means hydrogen; such as those wherein R1means hydrogen, and X and Y denote each hydrogen, and where q means 1-3, and r is O, or where q denotes O, and r is 1-3, especially those where Z1mean NR20. Among these compounds, R2means prefer is Ino hydrogen or-CH 2-CH2-OH, and the sum of q and r is preferably 1.

Another interest group hydroxamate derivatives are the compounds of formula Id

where

Z1means oxygen, sulfur or NR20,

R18means hydrogen, halogen, (C1-C6)alkyl (methyl, ethyl, tert.-butyl), (C3-C7)cycloalkyl, aryl, such as unsubstituted phenyl or phenyl substituted 4-och3or 4-CF3or heteroaryl,

R20means hydrogen, (C1-C6)alkyl, (C1-C6)alkyl(C3-C9)cycloalkyl (for example, cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g., benzyl), heteroaromatic (for example, pyridylmethyl), acyl (acetyl, propionyl, benzoyl), or sulfonyl (methanesulfonyl, econsultancy, benzazolyl, toluensulfonyl);

A1means 1, 2 or 3 substituent which is independently from each other denote hydrogen, (C1-C6)alkyl, -OR19or halogen,

R19selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, (C4-C9)geterotsiklicheskie, aryl, heteroaryl, arylalkyl (e.g., benzyl) and heteroaromatic (for example, pyridylmethyl);

p denotes 0 to 3, and

q means 1-5, and r denotes 0 or

q is 0 and r is 1 to 5

or their pharmaceutically priemel who may salt.

Other changing substituents such as described above.

Particularly useful compounds of formula Id are those in which R2means hydrogen or -(CH2)pCH2OH, where R means 1-3, especially those wherein R1means hydrogen; such as those wherein R1means hydrogen, and X and Y denote each hydrogen, and where q means 1-3 and r is 0, or where q is 0 and r is 1-3. Among these compounds, R2means preferably hydrogen or-CH2-CH2HE, and the sum of q and r is preferably 1.

In addition, the present invention relates to compounds of formula Ie

or their pharmaceutically acceptable salts. Changing the substituents are as described above.

Particularly useful compounds of formula Ie are those in which R18means hydrogen, fluorine, chlorine, bromine, (C1-C4)alkyl group, substituted (C1-C4)alkyl group, (C3-C7)cycloalkyl group, unsubstituted phenyl, phenyl substituted in the para-position, or heteroaryl (e.g., peregrinae) ring.

Another group of useful compounds of formula Ie are those in which R2means hydrogen or -(CH2)pCH2HE, where p means 1-3, especially those wherein R1means hydrogen; such as those where R 1means hydrogen, and X and Y denote each hydrogen, and where q means 1-3 and r is 0, or where q is 0 and r is 1-3. Among these compounds, R2means preferably hydrogen or-CH2-CH2-OH, and the sum of q and r is preferably 1.

Another group of useful compounds of formula Ie are those in which R18means hydrogen, methyl, ethyl, tert.-butyl, trifluoromethyl, cyclohexyl, phenyl, 4-methoxyphenyl, 4-triptoreline, 2-furanyl, 2-thiophenyl or 2-, 3-or 4-pyridyl, where 2-farnily, 2-tofinally and 2-, 3-or 4-peredelnyj substituents are unsubstituted or substituted as described above for heteroaryl rings; R2means hydrogen or -(CH2)pCH2OH, where R means 1-3, especially those wherein R1means hydrogen, and X and Y denote each hydrogen, and where q means 1-3 and r is 0, or where q is 0 and r is 1-3. Among these compounds, R2means preferably hydrogen or-CH2-CH2HE, and the sum of q and r is preferably 1.

The compounds of formula Ie, where R20means hydrogen or (C1-C6)alkyl, especially hydrogen, are important members of each subgroup of compounds of formula Ie, described above.

N-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2,E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]meth is l]phenyl]-2E-2-propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salt are compounds of formula Ie, important.

In addition, the present invention relates to compounds of formula If

or their pharmaceutically acceptable salts. Changing substituents such as described above.

Useful compounds of formula If are those in which R2means hydrogen or -(CH2)pCH2OH, where R means 1-3, especially those wherein R1means hydrogen; such as those wherein R1means hydrogen, and X and Y denote each hydrogen, and where q means 1-3 and r is 0, or where q is 0 and r is 1-3. Among these compounds, R2means preferably hydrogen or-CH2-CH2HE, and the sum of q and r is preferably 1.

N-Hydroxy-3-[4-[[[2-(benzofur-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salt is a compound of formula If that is important.

The compounds described above are often used in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, where appropriate, pharmaceutically acceptable basic additive salt and acid additive salts, for example salts with metals, such as salts with alkali or alkaline-earth metals, ammonium salt, additive salts with organic amines, additive salts with amino acids and sulfonates. Acid-additive with and include additive salts with inorganic acids, such as hydrochloride, sulfate and phosphate, and additive salts with organic acids, such as alkylsulfonate, arylsulfonate, acetate, maleate, fumarate, tartrate, citrate and lactate. Examples of salts with metals are alkali metal salts such as lithium salt, sodium salt and potassium salt, salts with alkaline earth metals such as magnesium salt and calcium salt, aluminum salt and zinc salt. Examples of ammonium salts are ammonium salts and Tetramethylammonium salt. Examples of the basic additive salts are salts with morpholine and piperidine. Examples of the additive salts with amino acids are salts with glycine, phenylalanine, glutamic acid and lysine. Sulphonate salts include mesilate, toilet and salt benzosulfimide acid.

As obvious to the experts, many of deacetylase inhibitors according to the present invention contain asymmetric carbon atoms. Therefore, it should be understood that the individual stereoisomers, as expected, included in the scope of this invention.

Hydroxamate derivatives of the present invention can be obtained by known methods of organic synthesis. For example, hydroxamate derivatives can be obtained by the interaction of the methyl ester 4-formularies acid with tryptamine and then preframe is receiving the compounds obtained in hydroxamate derived. As an example, the methyl ester of 4-formularies acid (2) receive acid catalyzed esterification of 4-formularies acid (3) (Bull. Chem. Soc. Jpn. 1995; 68:2355-2362). An alternative method for obtaining 4-formicinae (2) is catalyzed by palladium condensation of methyl acrylate (4) with 4-bromobenzaldehyde (5).

Additional source materials can be obtained from 4-carboxyanhydride (6), and an example of a method illustrating the receipt of the aldehyde (9)below. The carboxyl group in the 4-carboxyanhydride (6) should be protected in the form of salelologa ether (for example, tert-butyldimethylsilyl ether) treatment with similiarites [e.g. tert-butyldimethylsilyl (TBDMS-C1)] and a base (e.g. triethylamine) in an appropriate solvent (e.g. dichloromethane). Formed silloway ether (7) can be subjected to reaction referirovanija (for example, rafinirovaniyu Horner-Emmons) with phosphonate ester (for example, triethyl-2-phosphonopropionic) in the presence of a base (e.g. sodium hydride) in an appropriate solvent (e.g. tetrahydrofuran, THF). Processing the generated diapir acid (for example, aqueous hydrochloric acid) leads to the hydrolysis salelologa ether, giving the acid (8). Selective recovery of carboxylic who function in compound (8) with, for example, the complex of borane-dimethyl sulfide in a solvent (such as THF) to give the intermediate alcohol. The intermediate alcohol could be oxidized to the aldehyde (9) many well-known ways, including, but without limitation, oxidation in Turn, periodate oxidation on Dess-Martin oxidation on Moffatt and the like.

Source derived aldehydes (2) and (9) can undergo reductive aminating with the formation of secondary or tertiary amines. This is illustrated by the reaction of methyl ester 4-formularies acid (2) with tryptamine (10) using as the reducing agent (NaBH(OAc)3) in dichloroethane (EDC) as the solvent with the formation of the amine (11). Can be used with other reducing agents, for example sodium borohydride (NaBH4and Lamborghini sodium (NaBH3CN), other solvents or mixtures of solvents in the presence or in the absence of acid catalysts (e.g., acetic acid and triperoxonane acid). Amin (11) can be converted directly into hydroxamic acid (12) by treatment with 50% aqueous hydroxylamine in an appropriate solvent (such as THF in the presence of a base, for example sodium hydroxide). There are other ways of education hydroxamates, including the reaction of ester with g is drochloride hydroxylamine and a base (for example, sodium hydroxide or sodium methylate) in an appropriate solvent or mixture of solvents (e.g. methanol, ethanol or a mixture of methanol/THF).

The aldehyde (2) may be subjected to reductive aminating with a variety of amines, examples of which, but without limitation, amines are presented in table 1.

An alternative synthesis of compounds according to this invention begins with reductive amination of 4-formularies acid (3), below, with 3-phenylpropylamine (13) using, for example, laborgerate sodium as a reducing agent in methanol and acetic acid as catalyst. The basic nitrogen atom in the formed amino acid (14) can be protected, for example, tert.-butoxycarbonyl (VOS) by reaction with di-tert.-BUTYLCARBAMATE with the formation of compound (15).

The carboxylic acid may be condensed with a protected hydroxylamine (e.g., O-traileraxlesystems) using a dehydrating agent (for example, hydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI)and catalyst (e.g., hydrate 1-hydroxybenzotriazole (NOUT)) in an appropriate solvent (such as DMF) education is soedineniya (16). Treatment of compound (16) a strong acid (for example, triperoxonane acid (TFA)) to give the hydroxamic acid (17) of the present invention. Additional examples of compounds that can be obtained in this way are:

Derivatives of tertiary amines can be obtained in numerous ways. Reductive amination of compound (30) with nicotinamidase (32) using laborgerate sodium as a reducing agent in dichloroethane in the presence of acetic acid as catalyst gives ester (34). Can be used with other reducing agents (e.g. sodium borohydride and triacetoxyborohydride sodium) in other solvents or mixtures of solvents in the presence or in the absence of an acid catalyst (e.g. acetic acid, triperoxonane acid and the like). Reaction of ester (34) with hydroxylamine hydrochloride and sodium hydroxide in methanol gives hydroxamate (36).

Examples of derivatives of tertiary amines obtained by this procedure include, but without limitation, the compounds listed in table 2.

An alternative way of obtaining tertiary amines is the interaction between the secondary and the ina with an alkylating agent in an appropriate solvent in the presence of a base. For example, heating a solution of amine (11) and bromide (40) in dimethyl sulfoxide (DMSO) in the presence of diisopropylethylamine gives tertiary amine (42). The reaction of the tertiary amine (42) with hydroxylamine hydrochloride and sodium hydroxide in methanol gives hydroxamate (43). Silyl group can be removed by a method known in the art. For example, hydroxamate (43) can be treated with acid, for example triperoxonane acid or fluoride, forming hydroxyethylene derivative (44).

Hydroxamate derivative or its salt is applicable for the preparation of pharmaceutical compositions, especially pharmaceutical compositions having any abscopal properties deacetylase, especially discontinuties. Studies in Nude mice demonstrate that hydroxamate derivatives cause inhibition discontinuties (HAD) and increase acetylation of histones in vivo, which trigger changes in gene expression that correlates with the inhibition of tumor growth.

In addition, the present invention encompasses pharmaceutical compositions comprising a pharmaceutically effective amount of one or more of the above compounds as active ingredient. The pharmaceutical compositions according to the invention is suitable for to the muscle insertion, such as oral or rectal, parenteral administration to mammals, including humans, for the treatment of tumors, as such or in combination with one or more pharmaceutically acceptable carriers.

Hydroxamate derivative suitable for the production of pharmaceutical compositions containing an effective amount of a derivative in combination or mixed with fillers or carriers, are applicable for intestinal or parenteral administration. Preferred are tablets and gelatin capsules, containing the active ingredient together with (a) diluents; (b) lubricants; (b) binding agents (tablets); optionally, (d) dezinfeciruyuhimi agents and/or (e) absorbents, colorants, flavors and sweeteners. Compositions for injection are preferably aqueous isotonic solutions or suspensions, and suppositories mainly prepared from fatty emulsions or suspensions. The compositions can be sterilized and/or contain auxiliary substances such as preservatives, stabilizers, wetting or emulsifying agents, substances that promote solubility, salts for regulating osmotic pressure and/or buffers. In addition, the composition may also contain other therapeutically valuable substances. Compositions prepared the usual ways the AMI mixing, granulating or coating, respectively, and they contain preferably 1-50% of the active ingredient.

The corresponding compositions consist of mixtures for parenteral administration, including aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostatic and dissolved substances, which give the composition isotonicity in the blood of the intended patient; and aqueous and non-aqueous sterile suspensions, which may contain suspendresume agents and thickening agents. The formulations may be presented in containers with a single dose or multiple doses, for example in tamannah ampoules and vials and may be stored in dried by sublimation (lyophilized) condition requiring only the addition of sterile liquid carrier, for example water for injections, immediately prior to use. Uncooked injection solutions and suspensions can be obtained from sterile powders, granules and tablets of the previously described type.

As discussed above, the compounds according to the present invention is applicable for the treatment of proliferative diseases. Proliferative disease is primarily a tumor disease (or cancer) (and/or any metastases). Compounds according to the invention is particularly useful for the treatment of tumors, the which is a cancer, breast cancer, cancer of the urinary tract, lung cancer, cancer of the gastrointestinal tract, epidermoid cancer, melanoma, ovarian cancer, pancreatic cancer, neuroblastoma, cancer of the head and/or neck cancer or bladder, or in a broader understanding kidney cancer, head or stomach; in particular: (i) a tumor of the breast; an epidermoid tumor, such as an epidermoid tumor of the head and/or neck tumors of the oral cavity; a lung tumor, such as small cell or non-small lung tumor; a tumor of the gastrointestinal tract, such as colorectal tumor, or a tumor of the genitourinary system, such as a tumor of the prostate (especially Gornostaeva tumors of the prostate gland); or (ii) a proliferative disease that is resistant to treatment with other chemotherapeutics; or (iii) a tumor that is resistant to treatment with other chemotherapeutics due to multidrug resistance.

In a broader understanding of the invention, the proliferative disease, in addition, may be a hyperproliferative condition, such as leukemia, hyperplasia, fibrosis (especially pulmonary, but also other types of fibrosis, such as renal fibrosis), angiogenesis, psoriasis, atherosclerosis and proliferation of smooth muscle in blood vessels, such as stenosis or restenosis after angiola the ticks.

Where mentioned tumor, a tumor disease, carcinoma or cancer, it is also understood that alternative or in addition, the presence of metastasis in the original organ or tissue and/or in any other situation, any location of the tumor and/or metastasis.

The connection is selectively toxic or more toxic to rapidly proliferating cells than for normal cells, especially human tumor cells, such as malignant tumors, the compound has significant antiproliferative effects and promotes differentiation, such as cell cycle arrest and apoptosis. In addition, hydroxamate derived induces P21 interacting with the complex of cyclin-CDK (cyclin-dependent kinase) protein, which causes or apoptosis, or stop various cell lines in the phase of G1.

The following examples, is meant to illustrate the invention and should not be construed as limiting it.

Example P1

Obtain N-hydroxy-3[4-[[[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide

Received methyl ester 4-formularies acid by addition of 4-formularies acid (25 g, 0,143 mol) in methanol and HCl (6.7 g, 0,18 mol). The resulting suspension was heated at boiling for 3 h, cooled and evaporated to dryness. The obtained yellow solid substance RA is tarali in ethyl acetate, the solution was washed with saturated sodium bicarbonate solution, dried (magnesium sulfate) and was evaporated, obtaining a pale yellow solid, which was used without further purification (25,0 g, 92%). To a solution of tryptamine (16.3 g, 100 mmol) and methyl ester 4-formularies acid (19 g, 100 mmol) in dichloroethane was added triacetoxyborohydride sodium (21 g, 100 mmol). After 4 h the mixture was diluted with 10% potassium carbonate solution, the organic phase was separated, the aqueous solution was extracted with methylene chloride. The combined organic extracts were dried (sodium sulfate), evaporated and the residue was purified flash chromatography, obtaining the methyl ester of 3-(4-{[2-(1H-indol-3-yl)ethylamino]methyl}phenyl)-(2E)-2-propanolol acid (29 g). A solution of potassium hydroxide (12.9 g, 87%, and 0.2 mol) in methanol (100 ml) was added to a solution of hydroxylamine hydrochloride (13,9 g of 0.2 mol) in methanol (200 ml), the formed precipitate. After 15 min the mixture was filtered the filter cake was washed with methanol, the filtrate was evaporated in vacuo to a volume of approximately 75 ml and the Mixture was filtered, and the volume brought with methanol to 100 ml of the Resulting solution of 2 M hydroxylamine was kept under nitrogen at -20°With up to two weeks. Then methyl ester 3-(4-{[2-(1H-indol-3-yl)ethylamino]methyl}phenyl)-(2E)-2-propanolol acid (2.20 g, of 6.50 mmol) was added to a 2 M solution of hydroxylamine in methanol (30 ml, 60 mmol) followed the m by addition of a solution of potassium hydroxide (420 mg, 6.5 mmole) in methanol (5 ml). After 2 h the reaction was added dry ice and the mixture was evaporated to dryness. The residue was dissolved in hot methanol (20 ml), cooled and stored overnight at -20°C. the resulting suspension was filtered, the solid washed with ice-methanol and dried in vacuum, obtaining N-hydroxy-3[4-[[[2-(1H-indol-3-yl)ethyl]amino]methyl]-phenyl]-2E-2-propenamide (m/z 336 [MN+]).

Example P2

Obtain N-hydroxy-3-[4-[[(2-hydroxyethyl)-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide

A solution of methyl ester of 3-(4-{[2-(1H-indol-3-yl)ethylamino]methyl)phenyl)-(2E)-2-propanolol acid (12,6 g of 37.7 mmole), (2 bromoethoxy)-tert.-butyldimethylsilyl (12.8 g, 53,6 mmole), diisopropylethylamine (7,42 g, 57,4 mmole) in DMSO (100 ml) was heated at 50°C. After 8 h the mixture was distributed between methylene chloride and water. The organic layer was dried (sodium sulfate) and was evaporated. The residue was chromatographically on silica gel, receiving methyl ester 3-[4-({[2-(tert.-butyldimethylsilyloxy)ethyl]-[2-(1H-indol-3-yl)ethyl]amino}methyl)-phenyl]-(2E)-2-propanolol acid (13.1 g). Following the procedure described to obtain hydroxamates derived in example 1, methyl ester of 3-[4-({[2-(tert.-butyldimethylsilyloxy)ethyl]-[2-(1H-indol-3-yl)ethyl]amino}methyl)-phenyl]-(2E)-2-propanolol acid (5.4 g, 11 mmol) was converted to N-hydroxy-3-[4-({[2-(tert.-butyldimethylsilyloxy)ethyl]-[2-(1H-ind the l-3-yl)ethyl]amino}methyl)-phenyl]-(2E)-2-propenamide (5,1 g) and used without further purification. Then hydroxamic acid (5.0 g, 13.3 mmole) was dissolved in 95% THF/N2About and was heated at 40-50°C for 4 h the Mixture was evaporated, the residue was purified by reversed-phase HPLC, receiving N-hydroxy-3-[4-[[(2-hydroxyethyl)-[2-(1H-indol-3-yl)ethyl]amino]methyl]-phenyl]-2E-2-propenamide in the form of a salt with triperoxonane acid (m/z 380 [MN+]).

Example P3

Obtain N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]-phenyl]-2E-2-propenamide

A suspension of lithium aluminum hydride (17 g, 445 mmol) in anhydrous THF (1000 ml) was cooled to 0°and portions over 30 min was added 2-methylindol-3-glyoxylate (30 g, 148 mmol). The mixture was stirred at room temperature for 30 min, then maintained at boiling for 3 hours, the Reaction mixture was cooled to 0°and treated water (17 ml), 15% sodium hydroxide (water, 17 ml) and water (51 ml). The mixture was treated with magnesium sulfate, filtered and the filtrate was evaporated, obtaining 2-methyltryptamine, which was dissolved in methanol. To the solution was added methyl ether 4-formularies acid (16,9 g, and 88.8 mmole), then Lamborghini sodium (8,4 g) and acetic acid (1 EQ). After 1 h the reaction mixture was diluted with sodium bicarbonate (aqueous) and extracted with ethyl acetate. The organic extracts were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography, obtaining the methyl ester of 3-(4-{2-(2-methyl-1H-indol-3-yl)ethylamino]methyl}phenyl)-(2E)-2-propanolol acid. The ester was dissolved in methanol, was added 1.0 M solution of HCl in dioxane (1-1 .5 EQ), and then diethyl ether. The precipitate was separated by filtration, the solid is washed with diethyl ether and thoroughly dried, obtaining the hydrochloride of the methyl ester of 3-(4-{[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl}phenyl)-(E)-2-propanolol acid. It chilled with ice to a solution of methyl ester hydrochloride (14.9 g, and 38.6 mmole) and hydroxylamine (50% aqueous solution of 24.0 ml, about 391,2 mmole) was added 1.0 M sodium hydroxide (water, 85 ml). After 6 hours, cooled with ice, the solution was diluted with water and ammonium chloride (water, 0,86 M, 100 ml). The formed precipitate was separated by filtration, washed with water and dried, obtaining N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]-phenyl]-2E-2-propenamide (m/z 350 [MN+]).

Examples 1-265

The following compounds were obtained by methods similar to those disclosed in examples P1, P2 and P3.

Connection examples 1-265 inhibit the enzyme HAD (discontinuation) with IC50in the range of approx the RNO of 0.005 to 0.5 μm.

Example B1

Cell line H1299 (cells of the human lung carcinoma) and NST (cell tumors of the colon) were obtained from the American type culture collection, Rockville, MD. Cell lines were free of Mycoplasma infection (rapid detection from Gen-Probe, Inc., San Diego, CA) and infection with viruses (MAR-checked, MA BIOServices, Inc., Rockville, MD). Cell lines were propagated and increased in volume in medium RPMI 1640 containing 10% inactivated by heating fetal bovine serum FBS (Life Technologies, Grand Island, NY). Cell expansion for implantation was performed in cell factories (NUNC, obtained from Fisher Scientific, Sprigfield, NJ). Cells were collected at the confluence 50-90%off, washed once with HBSS (balanced salt solution Hanks)containing 10% FBS, and suspended in 100% HBSS.

Cell proliferation was measured with a commercial analytical set of MTS (Promega, Madison, Wis.), using an adaptation of published methods, such as those disclosed in the publication "Feasibility of drug screening with panels of human tumor cell lines microculture tetrazolium assay", M.C. Alley and others, Cancer Res., 1988; 48:589-601. The cells were placed in 96-cell cups for tissue cultures, the upper and lower rows left empty. Cells N and NST suspended in complete media at a density of 5,3x10 and 3,6X103cells/ml, respectively, and were added to 190 ál of the cell. Each cell line was made in one half cascio medium (200 μl) was added at the top and bottom rows. After 24 h in one of the cups was added 10 μl of MTS solution to determine the activity during the addition of the compound (T0). Cup incubated at 37°C for 4 h and the optical density OD490measured on the instrument Molecular Devices Thermomax at 490 nm using Softmax. Cup with T0served as a standard initial activity at the beginning of the experiment.

In 96-cell Cup held five serial dilutions (1:4) of each compound with the highest concentration at the edge of the Cup. Two cell lines were investigated with two connections per Cup. Were added in triplicate 10 μg each of the five dilutions and in column six or seven were added only full environment. The cups were incubated at 37°C for 72 h was Added a solution of MTS (for cups with T0and read through the 4 o'clock

In order to analyze the data, the average background value (one) subtracted from each value of the experimental cell; triple values were averaged for each dilution connection. To calculate the percentage growth used the following formula.

If X>T0the % growth = ((X-T0)/(GC-T0)) x 100,

if X<T0the % growth = (X-T0)/T0) x 100,

where T0= (average viability of the cells at zero time) - background value,

GC = average value of the raw tile is to (in three copies) - the background value,

X = average value processed by the connection of the cells (in three copies) - background value.

Inflicted on graph% growth against the concentration of the compound and used to calculate IC50using techniques of linear regression between data points to forecast the concentration of compounds at 50% inhibition.

The lactate N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (CMD1), N-hydroxy-3-[4-[[(2-hydroxyethyl)-[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide (CMD2), N-hydroxy-3-[4-[[[2-(5-methoxy-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (CMD3), N-hydroxy-3-[4-[[[2-(5-fluoro-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (CMD4), N-hydroxy-3-[4-[[[2-(benzofur-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (CMD5)having a purity of more than 95%, was dissolved in pure dimethyl sulfoxide (DMSO) to generate a source of diluent. The original solution was diluted with 5% dextrose injection (USP) before dosing. In addition, N-(2-AMINOPHENYL)-4-[N-pyridin-3-yl)methoxycarbonyl-aminomethyl]benzamide synthesized in accordance with example 48 EP 0847992 and used as control compounds (CMDC). Inhibition of cell growth in monolayer within 72 h under the action of the compounds was measured in three experiments and used to get znaczenia MTS-analysis. The results are shown in table B1.

Table B1
ConnectionGrowth in the monolayer, IC50(µm)
NST
CMD10,400,03
CMD20.150,01
CMD30,580,03
CMD40,280,03
CMD50,180,03
CMDC6,80,67

The results show that hydroxamate derivatives of the present invention have a high activity in suppressing the growth of tumor cells. In addition to the above results, it was found that the compounds selectively inhibit tumor cells, showing a slight inhibitory activity against tumour cells. Cells treated hydroxamate derivatives, have been also investigated for the induction of the P21 promoter, which is a key mediator stop cells in the phase of G1and differentiation. Hydroxamate derivatives activate the P21 promoter to easily detectable at concentrations at twice the range of their respective values ICsub> 50to inhibit the growth of H1299 cells in the monolayer. Without regard to any particular theory, correlation, apparently, suggests that inhibition of HDA leads to activation of transcription of genes that inhibit proliferation of tumor cells.

Example B2

HDA is partially purified from H1299 cells of human non-small cell lung carcinoma (obtained from the American type culture collection, 12301 Parklawn Drive, Rockville, MD 20852, USA). Cells were grown to confluence of 70-80% in RPMI medium in the presence of 10% FCS, collected and literally ultrasound. The lysate was centrifuged at 23, 420g for 10-15 min, the supernatant was applied to a column high resolution Hiload 26/10 Q-separate (Amersham Pharmacia Biotech) and were balanced with buffer containing 20 mm Tris-buffer, pH 8.0, 1 mm EDTA (ethylenediaminetetraacetic acid), 1 mm P-mercaptoethanol, 5% glycerol, 2 mg/ml Aprotinin, 1 μg/ml leupeptin and 400 mm PMSF (phenylmethylsulfonyl). Proteins were suirable in the aliquot 4 ml linear gradient of sodium chloride 0-500 mm in the above buffer at a flow rate of 2.5 ml/min. Each preparation of partially purified enzyme HDA was titrated to determine the optimal amount required for obtaining the ratio of signal to noise ratio of at least 5:1. Typically, 20-30 μl of partially purified HDA (5-10 mg protein/ml) is mixed with 2 μl of a solution of the compound in DMSO is ensete titration with deep holes (Beckman). Connection series was diluted in DMSO to obtain initial solutions with 20-multiples of the studied concentrations. The final concentration of compounds in the analysis were 10 μm, 2 μm, 400 nm, 80 nm and 16 nm at the final percentage of DMSO in each enzymatic reaction, equal to 0.1%. Each concentration of the compounds was investigated twice. The substrate used in the reaction, was a peptide with the amino acid sequence SGRGKGGKGLGKGGAKRHRKVLRD corresponding to the twenty-fourth N-terminal amino acid of the human histone H4, biotinylated at the N end and pentachlorophenol for each lysine residue with N-acetate. To initiate the reaction, the substrate was diluted in 10 μl of buffer A (100 mm Tris-buffer, pH 8.0, 2 mm EDTA)was added to the enzyme mixture and collected at the bottom of the tablet with a deep hole by centrifugation for 5 min at 1500 rpm After centrifugation the mixture incubated at 37°for 1.5 hours the Reaction was stopped by adding 20 μl of stop buffer (0,5 N. hydrochloric acid, 0.08 M acetic acid). At this point, the analysis took place before the robotic phase extraction or frozen for a few days at -80°C.

Extraction enzymatically split3N-acetate groups from the reaction mixture was carried out with the solvent TWO (tert-butylmethylamine ether), using the installation Tomtec Quadra 96. In PR the gram prescribed add 200 ál of TWO 96 "Globaloney" tablet. Installation is programmed to aspirate 50 μl of air, then 200 μl of TWO and, finally, 25 μl of air that is dispersed into each well of the plate. The contents of the deep wells were thoroughly stirred, selecting a pipette 160 ál and bringing them back ten times. Before adding TWO to the reaction mixture must "pre-wet the pipette tip with TBME to avoid cleavage of the solvent when migrating into a deep hole of the tablet. Organic and aqueous phase in a deep hole were separated by centrifugation at 1500 rpm for 5 min. Liquid scintillation mixture of Opti-Phase Supermix (200 ál) (Wallac) was added to each well of 96-hole tablet Trilux (Wallac). Tablets with deep holes and tablets Trilux again was placed on the installation, programmed to aspirate 25 μl of air into the pipette tip, and then 100 µl of the upper phase with TWO and carried her into the tablet Trilux. The solutions were mixed by a fence dropper and push it 50 ál of five times within the same cell. Tablet Trilux covered by a transparent film and read by liquid scintillation and luminescence counter 1450 MicroBeta Trilux (Wallac) with color/chemical suppression and correction of the number of decays in minutes

In order to determine the values of the IC50data were analyzed on a spreadsheet. The analysis requires correction background Lumine is zenzie, what is achieved by subtraction of the values of the number of disintegrations per minute for wells without N-substrate of the values of the pilot hole. The adjusted values of the number of disintegrations per minute along with the concentrations of compounds used for the calculation of the IC50using user-defined spline function. This function uses techniques from linear regression between data points to calculate the concentration of compounds that cause 50% inhibition. The results are shown in table B2.

Table B2
ConnectionThe enzyme activity HDA IC50(µm)
CMD1to 0.032
CMD20,063
CMD30,014
CMD40,014
CMD50,016
CMDC>10

Example B3

Cell line A non-small cell lung cancer person were purchased from the American type culture collection, Rockville, MD. The cell line was free from Mycoplasma infection (rapid detection from Gen-Probe, Inc., San Diego, CA) and infection with viruses (MAR-checked, MA BIOServices, Inc., Rockville, MD). The cell line was multiplied and increased in volume in medium RPMI 1640 containing 10% heat inactivated is of FBS (Life Technologies, Grand Island, NY). Cell expansion for implantation was performed in cell factories (NUNC, purchased from Fisher Scientific, Springfield, NJ). Cells were collected at the confluence 50-90%off, washed once with HBSS (balanced salt solution Hanks)containing 10% FBS, and suspended in 100% HBSS.

Obtained by an unrelated breeding Nude (nu/nu) female mice of ("Hsd:Athymic Nude-nu" from Harlan Sprague Dawley, IN) was anestesiologi metofane (Malinckrodt Veterinary, Inc.,Mundelem, IL), and 100 μl of cell suspension containing 1x107cells were injected with subcutaneously in the right axillary (lateral) region of each animal. Tumors were allowed to grow for about 20 days to reach a volume of approximately 100 mm3. In this time of mice with suitable carriers of tumour morphology and tumor size were sorted for research in groups of eight animals. The sorting process was given to groups that are balanced in relation to the average and maximum size of the tumor. Antitumor activity is expressed as % T/C, comparing the difference in tumor volumes for the group treated (T)and the group treated filler (S). Regression of tumors was calculated using the formula (1-T/T0) X100%, where T mean tumor volume for the group receiving treatment at the end of the experiment, and T0mean tumor volume at the beginning of the experiment.

Connection CMD1 has introduced nutrion is about once a day five times a week for three weeks at doses of 10, 25, 50 or 100 mg/kg of the Final concentration of DMSO was 10%. Each study group consisted of eight mice. Tumors were measured and recorded the weight of each animal. In the BR table shows the results on the 41st day.

Table B3
ConnectionDose (mg/kg)The mean tumor volume Δ*1(mm3±SEM*3)% T/CBody weight*2Δ% (% ± SEM*3)
10% DMSO/D5W*4-376±55-+11,9±0.2
CMD110121±2732+1,3±0,3
CMD12577±3220-0,9±0,3
CMD15057±1015-0,4±0,3
CMD110028±257+0,4±0,3
Note: *1. The difference between the average tumor volume of animals at the end of the experiment minus the mean value of the tumor volume at the beginning of the experiment.
*2. The difference between the body weight of animals at the end of the experiment minus the average value of missiouri at the beginning of the experiment.
*3. The average standard error.
*4. 5% dextrose for injection. Pharmacopoeia of the United States.

Example B4

Repeating the procedure of example B3 except that used the connection CMD2. The results are shown in table B4.

Table B4
ConnectionDose (mg/kg)The mean tumor volume Δ*1(mm3±SEM)% T/CBody weight Δ% (% ± SEM)
10% DMSO/D5W-135±43-+6,7±1,1
CMD22537±1627-4,2±2,5
CMD25029±1521-2,9±1,5

Example B5

Repeating the procedure of example B3 except that the cell line tumors of the colon NST used instead of the cell line A. Cell line NSC also obtained from the American type culture collection, Rockville, MD, and cell line was free from infection Mycoplasma infection and viruses. The results obtained on the 34th day, are shown in table B5.

Table B5
ConnectionDose (mg/kg)The mean tumor volume Δ (mm3±SEM)% T/CBody weight Δ% (% ± SEM)
10% DMSO/D5W-759±108--0,4±0,4
CMD150*10186±4025-7,4±0,8
CMD1100140±3818-3,2±0,4
Note: *10. In this group investigated seven mice.

Example B6

Repeating the procedure of example B4, except that the cell line tumors of the colon NST used instead of the cell line A. Cell line NSC also obtained from the American type culture collection, Rockville, MD, and cell line was free from infection Mycoplasma infection and viruses. The results obtained on the 34th day, are shown in table B6.

Table B6
ConnectionDose (mg/kg)The mean tumor volume Δ (mm3±SEM)%T/CBody weight Δ% (% ± SEM)
10% DMSO/DSW-759±108--0,4±0,4
CMD210422±7556-10,2±0,5
CMD225305±4740-7,0±0,2
CMD25097±3013is 7.3±0,3
CMD2100132±3017-9,4±0,4

Example B7

The binding of annexin V was used as a marker of early stages of apoptosis. Cells A, NST and normal human dermal fibroblasts (NDHF) separately processed four compounds (CMD1, CMD2, CMD3 and CMD4) for 24 or 48 h, stained with annexin V and compared with cells similarly treated with vehicle (DMSO). The cells were examined by fluorescence microscopy. Those who have undergone apoptosis, had a green fluorescent staining of the membrane. Viability was assessed by using a contrasting coloring iodide of propecia. Cells, detected by red fluorescence, were unsustainable. After 24 h of exposure with each of the four compounds in minor percentage of cells A and the predominant part of the cells NST surface was stained with annexin V. After 48 h of treatment the main part of the cell A and NCT stained with annexin V and/or iodide of propecia that decrees the Alo on the induction of compounds of apoptotic cell death. In contrast, cells NDHF was not observed noticeable staining with annexin V after 24 h of exposure and limited staining with annexin V with connection CMD3 after 48 hours, These data show that cells NDHF when processing connection are mainly non-stop growth, consistent with the characterization of cell cycle.

The staining results show that hydroxamate derivatives of the present invention cause apoptotic death of tumor cells, whereas normal fibroblasts predominantly undergo cell cycle arrest, which clearly demonstrates the electoral effectiveness of these connections.

1. Hydroxamate derivatives of the formula I

where

R1means H or a linear (C1-C6)alkyl;

R2selected from hydrogen, (C1-C10)alkyl, optionally substituted by 1-5 substituents selected from HE, amino, oxyalkyl; and (C4-C9)cycloalkyl; aryl; and (C4-C9)geterotsiklicheskie, (C4-C9)geterotsiklicheskikh containing 2 heteroatoms selected from nitrogen and oxygen; and (C4-C9)cycloalkenyl, arylalkyl, heteroallyl containing 1-4 nitrogen atom as a heteroatom; -(CH2)nC(O)Rsub> 6, -(CH2)nOC(O)6, -N(R12)C(O)-W; HONH-C(O)-CH=C(R1)arylalkyl and (CH2)nR7;

R3and R4the same or different and independently of one another denote hydrogen, (C1-C6)alkyl, optionally substituted by IT; or C(O)-O-W, or-N(R12)C(O)-W; or

R3and R4together with the carbon atom to which they are attached represent C=O, or

R2together with the nitrogen atom to which it is linked, and R3together with the carbon to which it is linked, may form a (C4-C9)heteroseksualci containing 2 nitrogen atom as a heteroatom; or a mixed aryl and nearline polyheterocyclic ring;

R5selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl, C(O)W; aryl, optionally substituted with 1-2 substituents selected from halogen, oxyalkyl; polyetheramine containing 1-2 nitrogen atom or oxygen as heteroatoms, optionally substituted by 1-2 substituents selected from oxyalkyl, halogen, alkyl, aryl; mixed aryl and neurolingo of polyheterocycles containing the nitrogen atom as heteroatom, optionally substituted-N-OH,=N-OH; arylalkyl, aromatic polycycle,

n, n1n2and n3the same or different and independently from each other is and is chosen from 0-6;

X and Y are the same or different and independently from each other selected from hydrogen, halogen, NO2;

R6choose from (C1-C6)alkyl, (C4-C9)cycloalkyl,

(C4-C9)geterotsiklicheskie with 1-2 heteroatoms, selected from nitrogen and oxygen, optionally substituted acetoxy, alkyl, -C(O)-W; aryl, optionally substituted with 1-2 substituents selected from alkyl, oxyalkyl and OS(O)-alkyl; heteroaryl with a nitrogen atom as a heteroatom; arylalkyl, optionally substituted oxyalkyl; OR12; NR13R14;

R7choose from OR15, SR15, SO2R17;

R12selected from hydrogen, (C1-C6)alkyl, (C4-C9)geterotsiklicheskie 2 heteroatoms selected from oxygen and nitrogen;

R13and R14the same or different and independently from each other selected from hydrogen, (C1-C6)alkyl, optionally substituted with 1-2 substituents selected from C3-C4cycloalkyl, oxyalkyl, halogen; aryl;

arylalkyl; heteroallyl with the nitrogen atom or sulfur as the heteroatom; or

R13and R14means together with the nitrogen to which they relate,

(C4-C9)heteroseksualci containing 1-2 nitrogen atom as gateroad the mA; nonaromatic polyheterocycles containing 3 heteroatoms selected from nitrogen and oxygen, or a mixed aryl and nearly polyheterocycles containing 2 heteroatoms selected from nitrogen or oxygen;

R15selected from hydrogen, (C1-C6)alkyl, (C4-C9)geterotsiklicheskie containing oxygen as the heteroatom, aryl, optionally substituted oxyalkylene, CF3; heteroaryl containing nitrogen as heteroatom; arylalkyl and (CH2)mZR12;

R16selected from C1-C6of alkyl; aryl, optionally substituted amino; kilakila; heteroaryl containing 1 heteroatom selected from nitrogen, oxygen, or sulfur; polyetherols containing oxygen as a heteroatom; and (CH2)mZR12;

R17choose from (C4-C9)geterotsiklicheskie containing a nitrogen atom and oxygen as heteroatoms; aryl;

m means an integer selected from 0-6; and

Z is chosen from O, NR13,

W is selected from hydrogen or R16;

or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where each of R1X, Y, R3and R4means hydrogen.

3. The compound according to claim 2, where one of the n2and n3mean 0, and the other is 1.

4. The compound according to claim 3, where R2means hydrogen or-CH 2-CH2HE.

5. The compound according to claim 1 of formula Ia

where

n4means 0-3,

R2selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl,

(C4-C9)geterotsiklicheskie, (C4-C9) cycloalkenyl, aryl, arylalkyl, heteroallyl containing 1-4 nitrogen atom as a heteroatom; -(CH2)nC(O)R6and -(CH2)nR7;

R5' means aromatic politics, mixed aryl and nearly polyheterocycles containing a nitrogen atom as a heteroatom, polyetherols containing 1-2 nitrogen atom and oxygen as heteroatoms, optionally substituted by 1-2 substituents selected from oxyalkyl, halogen, alkyl, aryl,

or its pharmaceutically acceptable salt.

6. The compound according to claim 1 of formula Ia

where

n4means 0-3,

R2selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl,

(C4-C9)geterotsiklicheskie, (C4-C9)cycloalkenyl, aryl, arylalkyl, heteroallyl containing 1-4 nitrogen atom as a heteroatom; -(CH2)nC(O)R6and -(CH2)nR7;

R5 ' means aryl, arylalkyl, aromatic politics, or its pharmaceutically acceptable salt.

7. The connection according to claim 6, where R5' means aryl or arylalkyl.

8. The connection according to claim 7, where R5' means n-forfinal, n-chlorophenyl, n-O(C1-C4)alkylphenyl, n-(C1-C4)alkylphenyl, benzyl.

9. The compound according to claim 1 of formula Ib

where

R2' are selected from hydrogen, (C1-C6)alkyl, (C4-C6)cycloalkyl,

(C4-C9)cycloalkenyl, -(CH2)2-4OR21where R21means hydrogen, methyl, ethyl, propyl or isopropyl, and

R5" means unsubstituted or substituted by 1-2 substituents selected from oxyalkyl, halogen, alkyl, aryl 1H-indol-3-yl, benzofuran-3-yl or quinoline-3-yl, or its pharmaceutically acceptable salt.

10. The connection according to claim 9, where R5" means substituted by 1-2 substituents selected from oxyalkyl, halogen, alkyl, aryl 1H-indol-3-yl or benzofuran-3-yl.

11. The compound according to claim 1 of formula Ic

where

the ring containing Z1that is aromatic or non-aromatic, non-aromatic rings are saturated or unsaturated,

Z1means oxygen or NR20;

R18OSN which denotes hydrogen, halogen, (C1-C6)alkyl, aryl,

R20means hydrogen, (C1-C6)alkyl, aryl;

A1means 1, 2 Deputy, which independently of one another denote hydrogen, (C1-C6)alkyl;

R2selected from hydrogen, (C1-C6)alkyl, (C4-C9)cycloalkyl,

(C4-C9)geterotsiklicheskie, (C4-C9)cycloalkenyl, arylalkyl, heteroallyl, -(CH2)nC(O)R6, -(CH2)nR7;

v is 0, 1 or 2; R means 0-3;

q means 1-5 and r is 0 or q is 0 and r is 1 to 5

or its pharmaceutically acceptable salt.

12. Connection to item 11, where Z1means N-R20.

13. Connection to item 11, where R2means hydrogen or-CH2-CH2-OH, and the sum of q and r is 1.

14. The compound according to claim 1 of formula Id

where

Z1means oxygen or NR20,

R18means hydrogen, halogen, (C1-C6)alkyl, unsubstituted phenyl,

R20means hydrogen, (C1-C6)alkyl, aryl,

A1means 1, 2 Deputy, which independently of one another denote hydrogen, (C1-C6)alkyl, -OR19or halogen, R19selected from hydrogen, (C1-C6 )alkyl,

p denotes 0 to 3, and

q means 1-5, and r denotes 0 or

q is 0 and r is 1 to 5

or its pharmaceutically acceptable salt.

15. The connection 14, where R2means hydrogen or-CH2-CH2HE, and the sum of q and r is 1.

16. The connection 11 of the formula Ie

or its pharmaceutically acceptable salt.

17. Connection P16, where R18means hydrogen, fluorine, chlorine, bromine, (C1-C4)alkyl, phenyl.

18. Connection P16, where R2means hydrogen or -(CH2)pCH2OH and where p means 1-3.

19. Connection p, where R1means hydrogen, and X and Y denote each hydrogen, and where q means 1-3 and r is 0, or where q is 0 and r is 1-3.

20. Connection P16, where R18means hydrogen, methyl, ethyl, tert.-butyl, phenyl.

21. Connection claim 20, where R2means hydrogen or -(CH2)pCH2OH.

22. Connection item 21, where p means 1-3.

23. Connection p.22, where R1means hydrogen, and X and Y denote each hydrogen, and where q means 1-3 and r is 0 or q is 0 and r is 1-3.

24. Connection item 23, where R2means hydrogen or-CH2-CH2OH, and the sum of q and r is 1.

25. Connection P16, where R20means hydrogen or (C1-C6)al the mud.

26. Connection P16 selected from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide, or its pharmaceutically acceptable salt.

27. Connection p representing N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide, or its pharmaceutically acceptable salt.

28. Connection p, which means N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salt.

29. The compound according to claim 1 of formula If

or its pharmaceutically acceptable salt.

30. The connection clause 29, where R2means hydrogen or -(CH2)pCH2OH, and p means 1-3.

31. Connection item 30, where R1means hydrogen, X and Y denote each hydrogen, where q means 1-3 and r is 0 or q is 0 and r is 1-3.

32. Connection p, where R2means hydrogen or-CH2-CH2HE, and the sum of q and r is 1.

33. The connection clause 29, which means N-hydroxy-3-[4-[[[2-(2-benzofur-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salt.

34. Pharmaceutical is Kai composition, possessing inhibitory activity against deacetylase, characterized in that it includes a pharmaceutically effective amount hydroxamate derivative of the formula I according to claims 1-32 in combination with one or more pharmaceutically acceptable carriers.

35. The pharmaceutical composition according to clause 34, where the compound of formula I is chosen from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide, or its pharmaceutically acceptable salt.

36. The pharmaceutical composition according p, where the compound of formula I is N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide, or its pharmaceutically acceptable salt.

37. The pharmaceutical composition according p, where the compound of formula I is N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salt.

38. The pharmaceutical composition according p, where the compound of formula I is N-hydroxy-3-[4-[[[2-(2-benzofur-3-yl)ethyl] amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salt.

39. A method of treating a proliferative disease in a mammal, which includes the introduction is referred to the mammal the compounds of formula I according to claim 1.

40. The method according to § 39, where the compound of formula I is chosen from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]-phenyl]-2E-2-propenamide, or its pharmaceutically acceptable salt.

41. The method of regulation of the P21 promoter, which includes the introduction of the compounds of formula I according to claim 1.

42. The method according to paragraph 41, where the compound of formula I is chosen from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl] amino]methyl]phenyl]-2E-2-propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]-phenyl]-2E-2-propenamide, or its pharmaceutically acceptable salt.

Priority items:

01.09.2000 item 27 and 36;

18.05.2001 p, 27, 35, 38, 40, 42;

30.08.2001 10-25, 28-34, 37, 39, 41.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel 4-phenyl-substituted tetrahydroisoquinolines of the formulae: (IA) , (IB) , (IIA) , (IIB) , (IIIA) and (IIIC) wherein values X and R1-R7 are given in the invention description. Proposed compounds show selective binding of neurotransmitters and therefore they can be used in treatment of different neurological or psychological disorders, for example, ADHD. Also, invention relates to a pharmaceutical composition based on proposed compounds and to a method for treatment.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

36 cl, 1 dwg, 16 tbl, 131 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing properties of inhibitors of protein kinase p38. In the formula (I) A means nitrogen atom (N) or -CH; R1 means hydrogen atom, alkyl or aralkyl; R2 means (C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, (R'')2NCO-alkylene- (wherein each R'' means independently hydrogen atom or (C1-C6)-alkyl), (C3-C7)-cycloalkyl substituted optionally with hydroxy-group, 6-membered heterocyclyl comprising nitrogen, oxygen or sulfur atom or its oxides as heteroatoms and wherein nitrogen-containing heterocyclyl can be substituted with (C1-C4)-alkylsulfonyl group, optionally substituted phenyl wherein substitutes are chosen from halogen atoms and lower alkoxy-group; X means oxygen atom (O), -NR3 or sulfur atom (S) wherein R3 means (C1-C6)-alkyl or phenyl; Y means a chemical bond, O, C(=O), -CH(OR'), -CHR' or S wherein R' means hydrogen atom; R means phenyl optionally substituted with one or some substitutes chosen from halogen atoms, lower alkyl and lower alkoxy-group. Proposed compounds can be used, for example, in treatment of inflammatory diseases, among them intestine disease, Alzheimer's disease, Crohn's disease, cerebrospinal sclerosis, asthma and can be used in development of viral diseases also.

EFFECT: valuable medicinal properties of compounds.

11 cl, 5 sch, 1 tbl

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention relates to an agent used against acid-resistant microorganisms containing derivative of pyridone carboxylic acid as an active component, its pharmaceutically acceptable salt or its hydrate that elicits high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms. Invention describes agent used against acid-resistant microorganisms containing compound represented by the following formula (I) its salt or its hydrate as an active component wherein R1 represents cyclic alkyl group comprising 3-6 carbon atoms that can comprise substitute(s) chosen from halogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; A1 represents incomplete structure represented by the formula (2): wherein X2 represents halogen atom, alkyl group comprising 1-6 carbon atoms or alkoxy-group comprising 1-6 carbon atoms; A1, A2 and A3 form incomplete structure of the formula: in common with carbon atoms combined with them; X1 represents halogen atom; Y represents hydrogen atom; Z represents phenylpiperazine substitute. Invention provides synthesis of pyridone carboxylic acid eliciting high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms in combination with good pharmacokinetics indices and safety.

EFFECT: valuable biological property of agent.

10 cl, 9 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel derivative of 5-methoxy-8-aryl[1,2,4]-triazole[1,5-a]pyridine of the general formula (I): wherein R1 means hydrogen, halogen atom or lower alkoxy-group; R2 means -C(O)-phenyl wherein ring can be unsubstituted or substituted with one or two substitutes chosen from group consisting of halogen atom, lower alkyl, lower alkoxy-group or trifluoromethyl, or it means -C(O)-furanyl or -C(O)-thiophenyl wherein rings are not substituted or substituted with halogen atom, and its pharmaceutically acceptable salts. Proposed compounds can be used in treatment of diseases associated with adenosine A2 receptors. Also, invention describes a medicinal agent used in treatment of diseases associated with adenosine A2A receptors containing compound of the formula (I) and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of agent.

8 cl, 1 tbl, 1 ex

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

SUBSTANCE: invention relates to a synthetic quinolone agent that is effective as medicinal agents, veterinary preparations, drugs used in fishing industry or as antibacterial preserving agents. Invention describes compound represented by the following general formula (I): as its separate isomers or their mixture, its salt and their hydrates wherein R1 represents cyclic alkyl group comprising 3-6 carbon atoms that can comprise a substitute chosen from halogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; R4 represents hydrogen atom, amino-group, hydroxyl group; A represents nitrogen atom or part of structure as given in the invention claim; each R5 and R6 represents independently alkyl group comprising 1-6 carbon atoms or hydrogen atom; n means a whole number 1 or 2. Also, invention describes antibacterial agent and therapeutic agent based on compounds of the formula (I) used in treatment of infectious disease, a method for preparing antibacterial agent, a method for preparing a medicinal agent used in treatment of infectious disease and using compound of the formula (I) for preparing an antibacterial agent and using compound of the formula (I) for preparing a medicinal agent used in treatment of infectious disease. Invention provides novel compounds possessing useful biological properties.

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

35 cl, 2 tbl, 15 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes derivatives of pyrido[2,1-a]isoquinoline of the formula (I): wherein R1 means (lower)-alkyl, unsubstituted phenyl, phenyl mono-, di- or tri-substituted with (lower)-alkyl or (lower)-alkoxy-group, pyrrolyl, pyridynyl or (lower)-alkyl substituted with cycloalkyl or phenyl; each among R2, R and R4 means independently hydrogen, halogen atom, hydroxy-, (lower)-alkoxy-group or (lower)-alkenyl wherein (lower)-alkoxy-group and (lower)-alkenyl are optionally substituted with groups: (lower)-alkoxycarbonyl, unsubstituted phenyl, phenyl substituted with di-(lower)-alkylamine or cyano-group, thiazolyl substituted with (lower)-alkyl, pyridinyl or morpholino-group; R5 means hydrogen atom, (lower)-alkyl or phenyl optionally substituted with halogen atom, (lower)-alkoxy- or hydroxy-group; R6 means hydrogen atom, (lower)-alkyl or hydroxy-(lower)-alkyl; or R and R6 in common with carbon atoms to which they are bound form phenanthridine; R7 means hydrogen atom or (lower)-alkyl. Also, invention describes a method for synthesis of compounds of the formula (I) and preparing a pharmaceutical composition. Proposed compounds are used in treatment or prophylaxis of diseases associated with enzyme DPP-IV, i. e. dipeptidyl peptidase IV, such as diabetes mellitus and firstly non-insulin dependent diabetes mellitus and disturbed tolerance to glucose.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 107 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel derivatives of 8-methoxy[1,2,4]triazolo[1,5-a]pyridine of the general formula (I): wherein R1 means unsubstituted phenyl or phenyl substituted with one substitute chosen from group including halogen atom, trifluoromethyl, (lower)-alkyl, (lower)-alkoxy-, acetylamino-group, acetyl, (lower)-alkenyl, -C(O)O-(lower)-alkyl or thio(lower)-alkyl, or thiophenyl possibly substituted with halogen atom, or indolyl; R2 means unsubstituted phenyl or phenyl substituted with a single substitute chosen from group including halogen atom, (lower)-alkyl, halogen-(lower)-alkyl or (lower)-alkoxy-group, or thiophenyl possibly substituted with (lower)-alkyl, their pharmaceutically acceptable salts, and pharmaceutical preparation based on thereof. Novel compounds possess antagonistic effect on adenosine A2A-receptors and can be used in medicine for stimulation of the central nervous system activity and as enhancers of cognitive ability.

EFFECT: valuable medicinal properties of compounds and pharmaceutical preparation.

10 cl, 1 tbl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of naphthyridine of the formula (I): or their salts wherein R1 means phenyl or phenyl substituted with one or two substitutes chosen from group including cyano-group, halogen atom, carboxyl, aminocarbonyl group and others; R2 means (C3-C8)-cycloalkyl substituted with carboxyl or (C1-C8)-alkoxycarbonyl. Compounds of the formula (I) and their salts possess inhibitory effect with respect to activity of phosphodiesterase isozyme 4 (PDE4) and can be used for preparing a medicinal agent in treatment of obstructive or inflammatory disease of respiratory ways.

EFFECT: valuable medicinal properties of compounds, improved method of synthesis.

8 cl, 1 tbl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes 8-amino-[1,2,4]triazolo-[1,5-a]pyridine-6-carboxylic acid amide of the formula (I): wherein R1 means -NR'R'' wherein R'1 and R'' represent independently of one another lower alkyl, -(CH2)n-C(O)NRaRb, -(CH2)n-pyridinyl, -(CH2)n-phenyl, -(CH2)n-CN, -(CH2)n-O-lower alkyl or -(CH2)n-(C3-C8)-cycloalkyl; or R' and R'' form in common with nitrogen atom (N) 5- or 6-membered nonaromatic ring system wherein the latter can comprise additionally one heteroatom - oxygen (O) or sulfur (S) atom and wherein indicated ring system can be unsubstituted or substituted with one or two substitutes chosen from group consisting of lower alkyl, -C(O)NRaRb or group -(CH2)n-O-lower alkyl; each Ra and Rb represents independently hydrogen atom or lower alkyl; R2 means phenyl or heteroaryl representing pyridinyl, furanyl substituted possibly with halogen atom, or lower alkyl, thiophenyl substituted possibly with lower alkyl, or thiazolyl radical, and its pharmaceutically acceptable salts also. Compounds can be used in treatment of disease associated with adenosine A2-receptors.

EFFECT: valuable medicinal properties of compounds.

12 cl, 1 tbl, 108 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to novel derivatives of urea of the general formula (I): and their pharmaceutically acceptable salts wherein A represents -CH- or nitrogen atom; R1 represents (C3-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C10)-alkyl, 6-membered nitrogen-containing heterocycle, 6-membered nitrogen-containing heterocyclyl-(C1-C10)-alkyl, phenyl, phenyl-(C1-C10)-alkyl, 5-10-membered heteroaryl or 5-10-membered heteroaryl-(C1-C10)-alkyl, and others; R2 represents hydrogen atom, (C1-C6)-alkyl, (C0-C2)-alkyl-(C3-C10)-cycloalkyl, (C0-C2)-alkylphenyl, (C3-C10)-cycloalkyl-(C0-C2)-alkyl or phenyl-(C0-C2)-alkyl; R5 represents (C1-C6)-alkyl, (C3-C10)-cycloalkyl, 6-membered nitrogen-containing heterocyclyl, and others; L1 represents -S-, -S(O)-, -S(O2)-, -C(O)-, -N(Rc)-, -CH2-, and others; L2 represents a covalent bond, -O-, -C(O)-, -OC(O)-, -N(Rc)-, and others; W represents oxygen (O) or sulfur (S) atom; Z represents -C(O)ORd wherein Rc, Rd and Re represents hydrogen atom or alkyl; Rb represents -ORe, -NO2, halogen atom, -CN, -CF, (C1-C6)-alkyl; p represents a whole number from 0 to 4. Compounds of the formula (I) and their salts possess antagonistic activity with respect to α4-integrin and can be used in medicine for inhibition or prophylaxis of cellular adhesion in patient body mediated by α4β1- and/or α4β7-integrins.

EFFECT: improved methods of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 180 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes substituted benzoylpyrazoles of the general formula (I): wherein Q means oxygen atom (O); R1 means alkyl with 1-6 carbon atoms; R2 means hydrogen atom; R3 and R4 mean independently of one another hydrogen atom, halogen atom, alkyl with 1-4 carbon atoms substituted with halogen atom; R5 means hydrogen atom, alkyl with 1-6 carbon atoms; Y means hydrogen atom; Z means alkoxyamino-group with 1-6 carbon atoms, alkylamino-group with 1-6 carbon atoms, substituted alkoxy-group with 1-4 carbon atoms, N-alkylalkoxyamino-group with 1-4 carbon atoms, phenyl substituted with halogen atom, monocyclic heterocyclyl, heterocyclylamino-group, group -N=(heterocyclyl) chosen from the group: furyl, tetrahydrofurylmethylamino-group, isoxazolyl, dihydroisoxazolyl (isoxazolinyl), tetrahydroisoxazolyl (isoxazolidinyl), tetrahydro-(2H)-1,2-oxazine-2-yl, dihydrothiazolyl (thiazolinyl), oxadiazolylamino-, thiadiazolylamino-group, piperidinyl, piperidinylamino-group, 2-oxo-1,3-diazacyclohexyl, morpholinyl, morpholinylamino-group, respectively, and substituted if necessary with alkyl with 1-4 carbon atoms, halogenalkyl with 1-4 carbon atoms, cycloalkyl with 3-6 carbon atoms involving their all possible tautomeric forms and possible salts. Also, invention describes a herbicide agent based in proposed compounds. Proposed compounds possess herbicide activity.

EFFECT: valuable properties of compounds and agent.

4 cl, 5 tbl, 77 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds of the general formula (I): wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents hydrogen atom, -CO-R3 wherein R3 represents (C2-C6)-alkyl substituted optionally with halogen atom, -CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom or (C1-C4)-alkyl; R5 represents (C1-C8)-alkyl, (C2-C8)-alkenyl and others; Y represents compound of the formula: wherein R7 represents hydrogen atom or (C1-C4)-alkyl; R8 represents (C5-C8)-alkyl, (C4-C8)-cycloalkyl and others; X represents oxygen atom or sulfur atom and others. Also, invention relates to pharmaceutically acceptable salts of these compounds. Compounds of the formula (I) possess hypoglycemic and/or hypolipidemic activity and can be used in medicine in treatment of diabetes mellitus, hyperlipidemia, hyperglycemia, diseases caused by resistance to insulin and other diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 3 tbl, 131 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel aromatic compounds that can be used in treatment of diseases or pathological states accompanying by inflammation, for example, chronic inflammation diseases. Invention describes compound of the formula (II): wherein G means phenyl, pyridinyl, pyrazolyl and wherein G is substituted with one or some groups R1, R2 or R3; Ar means naphthyl; X means (C5-C8)-cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo-groups, phenyl, furanyl, pyridinyl or pyrazolyl; Y means a bond or saturated either unsaturated branched or unbranched (C1-C4)-carbon chain wherein one or some methylene groups are optionally and independently substituted with oxygen (O) or nitrogen (N) atoms; Y is optionally substituted with oxo-group; Z means phenyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, morpholinyl, thiomorpholinyl, piperidinyl, piperidinonyl, piperazinyl, pentamethylenesulfoxidyl wherein each of them is optionally substituted with 1-3 (C1-C6)-alkyls or group -CONH2, (C1-C6)-alkyl, nitrile, hydroxy-group, (C1-C6)-alkoxy-group, secondary or tertiary amine wherein amine nitrogen is bound covalently with (C1-C3)-alkyl or (C1-C5)-alkoxyalkyl, tetrahydrofuranyl-(C1-C3)-alkyl, nitrile-(C1-C3)-alkyl, carboxamide-(C1-C3)-alkyl; R1 means independently in each case (C1-C10)-alkyl which is optionally partially or completely halogenated and optionally substituted with 1-3 hydroxy-groups, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl wherein each of them is optionally substituted with 1-3 groups -CN, halogen atom, (C3-C6)-alkynyl branched or unbranched carbon chain and one or some methylene groups is optionally replaced for atom O and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R2 means branched or unbranched (C1-C6)-alkyl that is optionally partially or completely halogenated, branched or unbranched (C1-C4)-alkoxy-group that in each case is optionally partially or completely halogenated, halogen atom, (C1-C6)-alkoxy-group, hydroxy-group, mono- or di-(C1-C4)-alkyl-amino-group, group -OR6, nitro-group or group mono- or di-(C1-C4)-alkyl-amino-S(O)2 that is optionally partially or completely halogenated, or group -H2NSO2; R3 in each case means independently phenyl, pyridinyl, pyrimidyl, pyrrolidinyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, (C1-C4)-alkynyl group or branched or unbranched (C1-C6)-alkoxy-group wherein each of them is optionally partially halogenated, -OR18 or (C1-C6)-alkyl optionally substituted with group -OR18, amino-group or mono- either di-(C1-C5)-alkyl-amino-group, (C2-C6)-alkynyl branched or unbranched carbon chain wherein one or some methylene groups are optionally replaced for atom O, and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R6 means (C1-C4)-alkyl that is optionally partially or completely halogenated; in each case R18 means independently hydrogen atom, (C1-C4)-alkyl; W means atom O, and its pharmaceutically acceptable derivatives. Also, invention describes a pharmaceutical composition containing these compounds and a method for treatment of disease mediated by cytokines and based on indicated compounds. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

12 cl, 1 tbl, 38 ex

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

SUBSTANCE: invention relates to novel oxazolidinones of the general formula (I): , their pharmaceutically acceptable salts, hydrates and salt hydrates that inhibit factor Xa selectively and possess anti-thrombosis effect. Also, invention relates to a method for synthesis of these compounds (variants) and using the known substituted oxazolidinones of the general formula (A): as agent inhibiting factor Xa selectively and possessing anti-thrombosis effect, and to a medicinal agent based on at least one compound of the formula (I) or at least one compound of the general formula (A). Values of substitutes R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are given in the invention claim.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and agent.

10 cl, 2 tbl, 252 ex

FIELD: organic chemistry, chemical technology, insecticides.

SUBSTANCE: invention relates to derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide represented by the general formula (I): wherein R represents (C1-C6)-alkyl group that can be substituted with one or some halogen atoms; R1 represents hydrogen atom, (C1-C6)-alkyl group that can be substituted with one or some substituted chosen from group of substitutes A, (C2-C6)-alkenyl group or acyl group; X represents group of the formula -C-R2 or nitrogen atom; each among R2 and R3 represents independently hydrogen atom, halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from group of substitutes A, (C3-C7)-cycloalkyl group, (C2-C6)-alkenyl group, (C3-C7)-cycloalkenyl group, formyl group, group of the formula: -CH=NOR4 (wherein R4 represents hydrogen atom or (C1-C6)-alkyl group, cyano-group, phenyl group that can be substituted with one or some substitutes chosen from group of substitutes B, 5- or 6-membered heterocyclic group (heterocycle comprising 1-2 heteroatoms that are similar and chosen from nitrogen atom), (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or phenoxy-group. The group of substitutes A represents group consisting of halogen atom, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group, cyano-group and phenyl group. The group of substitutes B represents group consisting of halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from above given group of substitutes A, (C1-C6)-alkoxy-group that can be substituted with one or some substitutes chosen from above given group of substitutes A, or its salt. Also, invention relates to insecticide comprising a derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide or its salt as an active component and a carrier optionally. Also, invention relates to a method for synthesis of derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide. Invention provides synthesis of derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide possessing the high insecticide activity.

EFFECT: improved method of synthesis, valuable properties of derivatives.

18 cl, 3 tbl, 91 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, anti-microbial preparations.

SUBSTANCE: invention relates to compounds useful as anti-microbial agents. Claimed compounds are effective against to certain human and animal pathogens, including Gram-positive aerobic bacteria such as multi-resistant staphylococcus, streptococcus and enterococcus, as well as anaerobic organisms such as species Bacterioides spp. and Clostridia spp., and acid resistant organisms such as Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium spp.

EFFECT: new anti-microbial agents.

2 ex, 5 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted indoles or its pharmaceutically acceptable salts of the formula (I): , wherein R1 means hydrogen (H) atom, halogen atom, -CN, nitro-group, -SO2R4, -OH, -OR4, -SO2NR5R6, -CONR5R6, -COOH, -COOCH3, -NR5R6, phenyl, naphthyl or (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atom, -OR8 and -NR5R6 wherein x = 2; R2 means (C1-C7)-alkyl; R3 means phenyl, naphthyl or heteroaryl and each of them is possibly substituted with one or more substitutes chosen independently from H, halogen atom, -CN, -OH, -SO2R4, -OR4, -SO2NR5R6, -CONR5R6, phenyl, naphthyl, (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atoms, -OR8 and -NR5R6, -S(O)xR7 wherein x = 2; R4 means (C1-C6)-alkyl; R5 and R6 mean independently H, (C1-C6)-alkyl, or R5 and R6 in common with nitrogen atom to which they are bound can form 6-membered saturated heterocyclic ring comprising one atom chosen from -NR16; R7 means (C1-C6)-alkyl; R8 means H, (C1-C6)-alkyl; R16 means H, -COY-(C1-C4)-alkyl wherein Y means oxygen atom (O) and wherein alkyl group in the substitute group can be direct, branched or cyclic, and wherein heteroaryl means 5-6-membered heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms, or means 6,6-condensed bicyclic aromatic ring system comprising one nitrogen atom. Compounds of the formula (I) can be used in production of a medicinal agent used in treatment of asthma and chronic obstructive disease.

EFFECT: valuable medicinal properties of compounds.

7 cl, 2 tbl, 59 ex

FIELD: chemistry of heterocyclic organic compounds, medicine.

SUBSTANCE: invention relates to a novel heterocyclic derivative of the formula (I'): , wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents-CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom; R5 represents (C2-C8)-alkenyl; R3 represents hydrogen atom or (C1-C4)-alkyl; X represents oxygen atom or sulfur atom; R20 represents phenyl substituted with unsubstituted (C1-C6)-alkyl, (C1-C6)-alkyl substituted with fluorine atom, (C1-C4)-alkoxy-group, phenyl-(C1-C4)-alkoxy-group, hydroxyl group, halogen atom, nitro-group, unsubstituted amino-group or amino-group substituted with (C1-C4)-alkyl; n means a whole number from 1 to 4, or to its pharmaceutically acceptable salt. Also, invention relates to heterocyclic derivative of the formula (I): , wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents -CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom; R represents (C4-C8)-alkyl or (C2-C8)-alkenyl or -CO-C≡C-R6 wherein R6 represents (C1-C8)-alkyl; R3 represents hydrogen atom or (C1-C4)-alkyl; X represents oxygen atom or sulfur atom; n means a whole number from 1 to 4, or its pharmaceutically acceptable salt. Compounds of the formulas (I') and (I) are effective as a hypoglycemic agent, hypolipidemic agent, agent improving resistance to insulin, therapeutic agent in treatment of diabetes mellitus, therapeutic agent in treatment of diabetes mellitus complications, agents enhancing tolerance to glucose, anti-arteriosclerotic agent, agents against obesity or agent for X syndrome.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 2 tbl, 56 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

Up!