Pyrazole derivatives for treatment of viral diseases

FIELD: organic chemistry, medicinal virology, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazole of the formula (I-A):

wherein R1 means (C1-C12)-alkyl that can be optionally substituted with 1-3 substitutes taken among fluorine, chlorine and bromine atoms, (C3-C8)-cycloalkyl, phenyl, pyridyl or (C1-C4)-alkyl substituted with phenyl; R2' means optionally substituted phenyl wherein phenyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano- and nitro-group; R3 means (C1-C12)-alkyl or (C1-C4)-alkoxy-(C1-C4)-alkyl; A' means (C1-C4)-alkyl optionally substituted with phenyl or optionally substituted with 4-pyridyl wherein phenyl or 4-pyridyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH2-U-heterocyclyl wherein U represents O, S or NR'' wherein R'' means hydrogen atom or (C1-C4)-alkyl and wherein heterocyclyl means pyridyl or pyrimidinyl that is optionally substituted with 1-2 substitutes taken among (C1-C4)-alkyl, fluorine, chlorine and bromine atoms, cyano-, nitro-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH(OH)-phenyl; or A' means the group CH=CHW wherein W means phenyl; X means S or O, and their pharmaceutically acceptable salts. These compounds are inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and, therefore, can be used in treatment of HIV-mediated diseases. Also, invention relates to a pharmaceutical composition used in treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 5 tbl, 32 ex

 

The invention relates to new and known derivatives of pyrazole, method of production thereof, to pharmaceutical compositions and to the use of such compounds in medicine, in particular in the treatment of viral diseases. In particular, these compounds are inhibitors of the reverse transcriptase of human immunodeficiency virus, i.e. inhibitors of the enzyme involved in the replication of the virus. Therefore, the compounds of the present invention can be successfully used as therapeutic agents for the treatment of diseases mediated by the human immunodeficiency virus (HIV).

The disease, acquired immune deficiency syndrome (AIDS)is the end result of infection by certain retroviruses, human immunodeficiency virus type-1 (HIV-1) or type 2 (HIV-2). Some important points in the life cycle of the virus have been identified as a possible target for therapeutic intervention. Inhibition of one of them, the transcription of viral RNA into viral DNA (reverse transcriptase, RT), has provided a range of modern treatment options used in the treatment of AIDS. Inhibition of reverse transcriptase provided a first type of HIV treatment with 3'-azido-3'-deoxythymidine (AZT). Have since been involved in several inhibitors, in General terms, representing two classes of analogs and nucleoside and non-nukes. As an example of the latter was found that some benzoxazinone, such as efavirenz, useful for the inhibition of HIV reverse transcriptase. However, an ongoing issue is the development of viral strains resistant to existing reverse transcriptase inhibitors. Therefore, an important goal is to develop compounds that are effective against resistant strains.

Derivatives of pyrazole described in the literature for various applications (for example, chemistry or for the treatment of stress-related diseases).

In the European patent EP 0627423 describes pyrazole derivatives and their use as biocides for agricultural garden plants.

Patent US 6005109 describes pyrazole derivatives and their use for the treatment of diseases associated with stress.

But have not yet been described in the literature pyrazole derivatives for the treatment of diseases mediated by the human immunodeficiency virus (HIV).

The aim of the present invention is to provide derivatives of pyrazole, which are potent inhibitors of the reverse transcriptase of human immunodeficiency virus, an enzyme involved in the replication of the virus, and which respectively have the ability to be effective as an antiviral drug.

Presents izopet the tion describes the use of compounds of formula I

where R1means optionally substituted (C1-C12)alkyl, (C3-C8)cycloalkyl, acyl, (C1-C4)alkylsulfonyl, optionally substituted phenylsulfonyl, aryl, heterocyclyl or (C1-C4)alkyl, substituted optionally substituted phenyl;

R2means aryl or optionally substituted phenyl;

R3means (C1-C12)alkyl or (C1-C4)alkoxy-(C1-C4)alkyl;

A represents a group selected from CH2-(aryl-/C1-C4/alkylamino), CH2-(aryl-/C1-C4/alkoxy), CH2-(heterocyclyl-/C1-C4/alkoxy), (C1-C4)alkyl, substituted optionally substituted aryl or optionally substituted heterocyclyl, or

A represents a group of formula CH2-U-heterocyclyl,

where U represents O, S or NR"where R" denotes hydrogen or (C1-C4)alkyl, or

A represents a group of formula CH(V)Z,

where V is IT or F and

where Z represents aryl or heterocyclyl, or

A represents a group of the formula CH=CHW,

where W denotes optionally substituted aryl or optionally substituted heterocyclyl;

X is S or O,

for the treatment of diseases mediated by the human immunodeficiency virus (HIV), or to receive, in addition to the state funds for such treatment.

The term "alkyl", as used in this context, means optionally substituted hydrocarbon residue with a straight or branched chain, containing from 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, including their various isomers. Preferably, the term "alkyl" means an optionally substituted hydrocarbon residue with a straight or branched chain, containing from 1 to 7 or 1 to 6 carbon atoms. Most preferably, the term "alkyl" means an optionally substituted hydrocarbon residue with a straight or branched chain, containing from 1 to 4 carbon atoms.

Suitable substituents for the alkyl chain can be selected from one or more substituents, such as aryl, heterocyclyl, alkoxyl, hydroxyl or halogen. The terms "aryl", "heterocyclyl", "alkoxy" and "halogen" is defined below. Preferred substituents for the alkyl chains are 1-5 substituents selected from fluorine, chlorine and bromine, more preferred 1-5 fluorine-containing substituents and preferred 1-3 fluorine-containing substituent.

In the case when more than one substituent is connected with the alkyl group, these substituents may be the same or may differ from the other.

Aryl (as defined below) as the substituent for the alkyl group may be substituted by 1-5 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine or bromine. More preferably the aryl is substituted by 1-3 substituents selected from methyl, ethyl, metoxygroup, ethoxypropan, hydroxyl, fluorine, chlorine or bromine.

Heterocyclyl (defined below) as the substituent for the alkyl group may be substituted by 1, 2, 3 or 4 (when chemically possible) substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine or bromine. More preferably heterocyclyl substituted by 1-2 substituents selected from methyl, ethyl, metoxygroup, ethoxypropan, hydroxyl, fluorine, chlorine or bromine.

Alkyl in R1is preferably optionally substituted hydrocarbon residue with a straight or branched chain, containing from 1 to 7, 1 to 6 or 1 to 4 carbon atoms as defined above. Suitable substituents for the alkyl group selected from aryl, heterocyclyl or halogen. Preferred substituents for the alkyl chains are 1-5 substituents selected from fluorine, chlorine and bromine, more preferred are 1-5 fluorine-containing substituents and most preferably 1-3 f is orderhash Deputy. More preferred alkyl in R1is methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, including their various isomers, trifluoromethyl or 2,2,2-triptorelin. The most preferred alkyl in R1is methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl.

Alkyl in R3preferably means unsubstituted hydrocarbon residue with a straight or branched chain, containing from 1 to 7 carbon atoms, and most preferred methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, including their various isomers. More preferred alkyl in R3is unsubstituted hydrocarbon residue with a straight or branched chain, containing from 1 to 4 carbon atoms.

The term "cycloalkyl", as used in this context, means optionally substituted cycloalkyl group containing from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, which may be condensed with an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle or carbocycle, for example, phenyl.

K is included deputies for cycloalkyl can be selected from one or more, above for alkyl.

Cycloalkyl in R1means, as defined above, preferably unsubstituted cycloalkyl group containing from 3 to 6 carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. More preferably cycloalkyl in R1means cyclopentyl or cyclohexyl.

The term "alkoxy", as used in this context, means not necessarily replaced alkyloxy straight or branched chain, containing from 1 to 7 carbon atoms, where represents the "alkyl" portion is as defined above. Examples of alkoxygroup are methoxy, ethoxy, h-propyloxy, isopropoxy, h-Butylochka-, 1-Deut-Butylochka, isobutoxy-, tert-Butylochka-, pentyloxy, hexyloxy, heptyloxy, including their various isomers.

Suitable substituents for alkoxygroup selected from aryl, hydroxyl, halogen or amino.

The term "alkoxyalkyl", as used in this context, means alkoxygroup containing from 1 to 4 carbon atoms as defined above which is connected with the alkyl group containing from 1 to 4 carbon atoms, preferably 1-2 carbon atoms), as defined above. Examples are methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropan, propylacetate, methoxybutyl, etexilate is, propylacetate, butylacetate, tert-butylacetyl, including their various isomers. Preferred alkoxyalkyl group in the framework of the present invention is (C1-C2)alkoxy-(C1-C2)alkyl.

Alkoxyalkyl in R3preferably means methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl.

The term "acyl", as used in this context, means a group of formula C(=O)H, C(=O)alkyl or C(=O)phenyl, where alkyl denotes optionally substituted hydrocarbon residue with a straight or branched chain, containing from 1 to 4 carbon atoms. The most preferred acyl groups are C(=O)H, C(=O)alkyl or C(=O)phenyl, where alkyl is unsubstituted hydrocarbon residue with a straight or branched chain, containing from 1 to 4 carbon atoms.

Acyl in R1means independently of one another preferably methoxycarbonyl (acetyl), ethylcarboxyl (propionyl), propylmalonic, butylcarbamoyl or phenylcarbinol (benzoyl).

The term "alkylsulfonyl"as used in the context, means a group of formula S(=O)2(alkyl), where alkyl denotes optionally substituted hydrocarbon residue with a straight or branched chain, containing from 1 to 4 carbon atoms, preferably denotes unsubstituted hydrocarbon residue with a straight or branched chain,containing from 1 to 4 carbon atoms. More preferred alkylsulfonyl groups are methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl, 1-second-butylsulfonyl, isobutylphenyl or tert-butylsulfonyl.

Alkylsulfonyl, R1means preferably methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl, 1-second-butylsulfonyl, isobutylphenyl or tert-butylsulfonyl.

The term "aryl", as used in this context, means optionally substituted phenyl and naphthyl, both optionally condensed on a benzene ring optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle or carbocycle, for example, cyclohexyl or cyclopentyl.

Suitable substituents for the aryl may be selected from 1, 2, 3, 4 or 5, preferably 1, 2 or 3 residues from those listed above for alkyl, preferably selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, nitro, S-(C1-C4)alkyl and NRR', where R and R' denote, independently of each other hydrogen or (C1-C4)alkyl. The substituents for the aryl may be selected from (C1-C4)alkyl, (C1-C4)alkoxyl, GI is Roxie, fluorine, chlorine or bromine.

When more than one substituent is connected with an aryl group, these substituents may be the same or may differ from each other.

Aryl in R1preferably means phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 1-forfinal, 2-forfinal or 3-forfinal. Most preferably the aryl in R1means phenyl.

Aryl in R2means preferably phenyl or naphthyl.

Optionally substituted phenyl, R2may be phenyl, substituted by 1-5 substituents, preferably 1, 2 or 3 residues selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup and nitro. The substituents for phenyl in R2can also be selected from (C1-C4)alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine or bromine. Examples of the optionally substituted phenyl is phenyl, 2-were, 3-were, 4-were, 2,3-dimetilfenil, 2,4-dimetilfenil, 2,5-dimetilfenil, 2,6-dimetilfenil, 3,4-dimetilfenil, 3, 5dimethylphenyl, 3,6-dimetilfenil, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-acid, 2,4-acid, 2,5-acid, 2,6-acid, 3,4-acid, 3,5-acid, 3,6-acid, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxide is l, 2.5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3,6-dihydroxyphenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2,3-differenl, 2,4-differenl, 2.5-differenl, 2,6-differenl, 3,4-differenl, 3,5-differenl, 2,3,4-tryptophanyl, 3,4,5-tryptophanyl, 2,3,4,5,6-pentafluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3,4-trichlorophenyl, 3,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,3-dibromophenyl, 2,4-dibromophenyl, 2.5-dibromophenyl, 2,6-dibromophenyl, 3,4-dibromophenyl, 3,5-dibromophenyl, 3,6-dibromophenyl, 2-tianfeng, 3-tianfeng, 4-tianfeng, 2,3-delapril, 2,4-delapril, 2.5-delapril, 2,6-delapril, 3,4-delapril, 3,5-delapril, 3,6-delapril, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3-dinitrophenyl, 2,4-dinitrophenyl, 2,5-dinitrophenyl, 2,6-dinitrophenyl, 3,4-dinitrophenyl, 3,5-dinitrophenyl, 3,6-dinitrophenyl, 1-chloro-2-methoxyphenyl, 1-chloro-3-methoxyphenyl, 1-chloro-4-methoxyphenyl, 1-chloro-5-methoxyphenyl, 2-chloro-1-methoxyphenyl, 2-chloro-3-methoxyphenyl, 2-chloro-4-methoxyphenyl, 2-chloro-5-methoxyphenyl, 3-chloro-1-methoxyphenyl, 3-chloro-2-methoxyphenyl, 3-chloro-4-methoxyphenyl, 3-chloro-5-methoxyphenyl. More preferred examples of the optionally substituted phenyl is phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-CHL is henil, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3,4-trichlorophenyl, 3,4,5-trichlorophenyl or 2,3,4,5,6-pentachlorophenyl. The most preferred examples of the optionally substituted phenyl is phenyl, 4-methoxyphenyl, 3-chlorophenyl or 3,5-dichlorophenyl.

The term "optionally substituted phenylsulfonyl", as used in this context, means a group of formula S(=O)2(phenyl, where phenyl optionally substituted by 1-5 substituents, preferably 1, 2 or 3 residues selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine or bromine. Examples of the optionally substituted phenyl are, as mentioned above, preferably phenylsulfonyl.

The term "(1-C4)alkyl, substituted optionally substituted aryl (preferably phenyl)," as it is used in context, means (C1-C4)alkyl as defined above which is substituted by an aryl group (preferably phenyl group) or a substituted aryl group (preferably a substituted phenyl group, which is substituted by 1, 2, 3, 4 or 5, preferably 1, 2 or 3, the remnants of the substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, S-(C1-C4)alkyl and NRR', where the R and R' independently of one another denote hydrogen or (C 1-C4)alkyl. The substituents for the substituted aryl (preferably phenyl) may also be selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine and langroup or substituents may optionally be selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine or bromine. When more than one substituent is connected with an aryl group (preferably phenyl group), these substituents may be the same or may differ from each other. Preferred substituents for substituted aryl (preferably phenyl) is selected from methyl, ethyl, metoxygroup, ethoxypropan, hydroxyl, fluorine, chlorine, bromine or substituents are selected from methyl, ethyl, metoxygroup, ethoxypropan, hydroxyl, fluorine, chlorine, bromine, langroup, amino, methylamino and dimethylaminopropyl. In the context of this invention "(1-C2)alkyl, substituted optionally substituted phenyl" is preferred. Examples are phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, trimethyl, triletal, tripropyl, tributyl, 2,3-dimethylformamid, 2,4-dimethylphenylamine, 2.5-dimethylformamid, 2,6-dimethylphenylamine, 3,4-dimethylphenylamine, 3,5-dimethylphenylamine, 3,6-dimethylformamid, methoxyphenethyl, methoxyphenethyl, marks ifeelfree, methoxyphenylacetyl, dimethoxyphenethyl, dimethoxyphenethyl, dimethoxyphosphoryl, dimethoxyphenyl, 2-hydroxyphenylethyl, 3-hydroxyphenylethyl, 4-hydroxyphenylethyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2.5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3,6-dihydroxyphenyl, 2-hydroxyphenylethyl, 3-hydroxyphenylethyl, 4-hydroxyphenylethyl, 2-hydroxyphenylpropionic, 3-hydroxyphenylpropionic, 4-hydroxyphenylpyruvic, 2-hydroxyphenylethyl, 3-hydroxyphenylethyl, 4-hydroxyphenylethyl, 2-performer, 3-performer, 4-performer, 2,3-differenlty, 2,4-differenlty, 2.5-differenlty, 2,6-differenlty, 3,4-differenlty, 3,5-differenlty, 3,6-differenlty, 2-florfenicol, 3-florfenicol, 4-florfenicol, 2-chloroformate, 3-chloroformate, 4-chloroformate, 2,3-dichlorophenylethyl, 2,4-dichlorophenylethyl, 2.5-dichlorophenylethyl, 2,6-dichlorophenylethyl, 3,4-dichlorophenylethyl, 3,5-dichlorophenylethyl, 3,6-dichlorophenylethyl, 2-chlorophenolate, 3-chloranilide, 4-chloranilide, 2-brompheniramine, 3-brompheniramine, 4-brompheniramine, 2,3-dibromophenyl, 2,4-dibromophenyl, 2.5-dibromophenyl, 2,6-dibromophenyl, 3,4-dibromophenyl, 3,5-dibromophenyl, 3,6-dibromophenyl, 2-bromperidol, 3-bromperidol, 4-bromperidol, 2-cianfanelli, 3-Tianhe ylmethyl, 4-cianfanelli, 2,3-disinformation, 2,4-disinformation, 2.5-disinformation, 2,6-disinformation, 3,4-disinformation, 3,5-disinformation, 3,6-disinformation, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 2,3-di-dimethylaminophenyl, 2,4-di-dimethylaminophenyl, 2,5-di-dimethylaminophenyl, 2,6-di-dimethylaminophenyl, 3,4-di-dimethylaminophenyl, 3,5-di-dimethylaminophenyl or 3,6-di-dimethylaminophenyl.

For R1(C1-C4)alkyl, substituted optionally substituted phenyl is as defined above, preferably vinylmation (benzyl).

(C1-C4)Alkali, substituted optionally substituted by phenyl, for Deputy And are as defined above, preferably they mean phenylmethyl (benzyl), 4-methylphenylethyl, 4-methoxyphenethyl, 4-nitrophenolate, 4-performer, 4-chloroformate, 4-brompheniramine, phenylethyl, 4-methylphenylethyl, 4-methoxyphenethyl, 4-nitrophenolate, 4-florfenicol, 4-chloranilide, 4-bromperidol, phenylpropyl, phenylbutyl, 2-cianfanelli, 3-cianfanelli, 4-cianfanelli, 2,3-disinformation, 2,4-disinformation, 2.5-disinformation, 2,6-disinformation, 3,4-disinformation, 3,5-disinformation, 3,6-disinformation, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dim is melaminoformal, 2,3-di-dimethylaminophenyl, 2,4-di-dimethylaminophenyl, 2,5-di-dimethylaminophenyl, 2,6-di-dimethylaminophenyl, 3,4-di-dimethylaminophenyl, 3,5-di-dimethylaminophenyl or 3,6-di-dimethylaminophenyl. More preferred examples are phenylmethyl (benzyl), phenylethyl, 2-cianfanelli, 3-cianfanelli, 4-cianfanelli, 2-dimethylaminophenyl, 3-dimethylaminophenyl or 4-dimethylaminophenyl.

Aryl in CH(OH)-aryl for substituent a is as defined above, preferably a phenyl, naphthyl or optionally substituted phenyl group. Suitable substituents for the aryl may be selected from 1, 2, 3, 4 or 5 substituents, such as (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine or bromine, preferably 1, 2 or 3 residues as methyl, ethyl, methoxy group, ethoxypropan, hydroxyl, fluorine, chlorine or bromine. Preferred aryl in CH(OH)-aryl for substituent a is phenyl.

Aryl in SN(F)-for aryl substituent And is therefore, as indicated above, is preferably phenyl, naphthyl or optionally substituted phenyl group. Suitable substituents for the aryl may be selected from 1, 2, 3, 4, or 5 substituents as (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine or bromine, preferably is 1, 2, or residue in the form of methyl, ethyl, metoxygroup, ethoxypropan, hydroxyl, fluorine, chlorine or bromine. Preferred aryl in SN(F)-for aryl substituent is phenyl.

Aryl in CH=CH-aryl for substituent a is as defined above, preferably a phenyl or optionally substituted phenyl group. Tendilla group (-CH=CH-) can be (E)- or (Z)-configuration. Both isomeric forms of these compounds covered by the present invention. The preferred configuration etendering group in the framework of the invention is (E)-configuration. Suitable substituents for the aryl may be selected from 1, 2, 3, 4 or 5 substituents, such as (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine or bromine, preferably is 1, 2 or 3 balance as methyl, ethyl, metoxygroup, ethoxypropan, hydroxyl, fluorine, chlorine or bromine. Preferred aryl in CH=CH-aryl for substituent a is phenyl, 4-were, 4-methoxyphenyl, 4-forfinal or 4-chlorophenyl. The most preferred aryl in CH=CH-aryl for substituent a is phenyl.

The term "Allakaket", as used in this context, means an aryl, or optionally substituted aryl group, as defined above, associated with alkoxygroup containing from 1 to 4 carbon atoms, as defined above. Preferred examples are phenyl who atelocerata (phenylmethoxy or benzyloxy), 4-methylphenylsiloxane, 4-methoxyphenylacetate, 4-performance.group or 4-khlorfenilalanina. The most preferred example is phenylmethoxy.

The term "arylalkylamine", as used in this context, means a group of formula N(R)-(C1-C4)alkylaryl, where the aryl or optionally substituted aryl group, as defined above, is connected with the alkyl group containing from 1 to 4 carbon atoms, which is linked to the amino group. The amino group is also substituted by R, where R is hydrogen or unsubstituted hydrocarbon residue with a straight or branched chain, containing from 1 to 4 carbon atoms. An example is phenylethylamine(methyl) (benzylaminopurine).

The term "heterocyclyl", as used in this context, means optionally substituted aromatic or non-aromatic monocyclic or bicyclic a heterocycle that contains one or more heteroatoms selected from nitrogen, oxygen and sulfur. Also included in the scope of the presented invention heterocyclic compounds with oxo(=O)-group. Examples of suitable heterocycles are furyl, 1-pyrrolyl, 2-pyrrolyl, 1-thiophenyl, 2-thiophenyl, 2-pyridinyl (2-pyridyl), 3-pyridinyl (3-pyridyl), 4-pyridinyl (4-pyridyl), 1H-pyridine-2-he, 1H-pyridin-4-one, 3H-pyrimidine-4-one, pyridazine (1,2-diazen), pyrimidine (1,3-is Yasin), pyrazin (1,4-diazen), oxazole or isoxazol (ISO-oxazol).

Suitable substituents for heterocyclyl can be selected from 1, 2, 3 or 4 (when chemically possible), more preferably from 1, 2 or 3, most preferably 1 or 2 substituents selected from (C1-C4)alkyl, fluorine, chlorine, bromine, langroup, nitro and NRR', where R and R' independently of one another denote hydrogen or (C1-C4)alkyl. The substituents for the substituted heterocyclyl can also be selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, langroup, fluorine, chlorine and bromine, or the substituents may optionally be selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine and bromine. In the case where more than one Deputy is connected with heterocyclyl group, these substituents may be the same or different from each other. For all the examples for "heterocyclyl" these substituents can be in any chemically possible position. For example, methylpyridyl means that methyl Deputy can be connected to 3, 4, 5 or 6 position 2-pyridyl, or 2, 4, 5 or 6 position 3-pyridyl, or 2, 3, 5, or 6 position 4-pyridyl.

The term "(1-C4)alkyl, substituted optionally substituted by heterocyclyl", as used in the text for the Deputy And, means (C1-C4)alkyl as defined above which is substituted heterocyclyl group or substituted heterocyclyl group, which is substituted by 1, 2, 3 or 4 (when chemically possible), more preferably 1, 2 or 3, most preferably 1 or 2 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, S-(C1-C4)alkyl and NRR', where R and R' independently of one another denote hydrogen or (C1-C4)alkyl. The substituents for the substituted heterocyclyl can also be selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine and bromine. In this invention the preferred alkyl with 1 carbon atom, (C1-C2)- and (C3-C4)alkyl, substituted optionally substituted by heterocyclyl. Examples are furylmethyl, purolater, fullprofile, furylmethyl, methylphenylethyl, methylphenylethyl, dimethylformamid, ethylformate, methoxyphenethyl, methoxyphenethyl, dimethoxyphenethyl, hydroxyphenylethyl, hydroxyphenylethyl, dihydroxypyrimidine, performer, deformability, chlortrimeton, corporeality, dichlorodimethyl, bromperidol, dibromodimethyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidin, methylpyrrolidinyl, methylpyrrole the Tyl, dimethylpyrrole, ethylpyrrolidin, methoxypropylamine, methoxypropylamine, dimethoxypyrimidine, hydroxypropylmethyl, hydroxypropylmethyl, dihydroxypyrrolidine, forparallel, differentally, harpercollin, herpersonality, dichloropropylene, pompermayer, dibromopropylether, thienylmethyl (2-thienylmethyl, 3-thienylmethyl), thiophenolate, thiophenolate, thienylmethyl, methyldiphenylamine, methylthiofentanyl, dimethylthioformamide, ethylthiomethyl, methoxythiophene, methoxythiophene, dimethoxyphenethyl, hydroxydiphenylmethyl, hydroxydiphenylmethyl, dihydroxydiphenylmethane, portefeuilles, divertimenti, chlorothioformate, horripilate, dichlorodiphenylmethane, bronchiodilator, dibromomannitol, pyridinylmethyl (2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl), pyridinylmethyl, pyridinylmethyl, pyridinylmethyl, 3-methyl-2-pyridinylmethyl, 4-methyl-2-pyridinylmethyl, 5-methyl-2-pyridinylmethyl, 6-methyl-2-pyridinylmethyl, 2-methyl-3-pyridinylmethyl, 4-methyl-3-pyridinylmethyl, 5-methyl-3-pyridinylmethyl, 6-methyl-3-pyridinylmethyl, 2-methyl-4-pyridinylmethyl, 3-methyl-4-pyridinylmethyl, 5-methyl-4-pyridinylmethyl, 6-methyl-4-pyridinylmethyl, 3-methoxy-2-pyridinylmethyl, 4-methoxy-2-pyridinylmethyl, 5-methoxy-2-pyridinylmethyl, 6-methoxy-2-pyridinylmethyl is, 2-methoxy-3-pyridinylmethyl, 4-methoxy-3-pyridylmethyl, 5-methoxy-3-pyridinylmethyl, 6-methoxy-3-pyridinylmethyl, 2-methoxy-4-pyridinylmethyl, 3-methoxy-4-pyridinylmethyl, 5-methoxy-4-pyridinylmethyl, 6-methoxy-4-pyridinylmethyl, 3-fluoro-2-pyridinylmethyl, 4-fluoro-2-pyridinylmethyl, 5-fluoro-2-pyridinylmethyl, 6-fluoro-2-pyridinylmethyl, 2-fluoro-3-pyridinylmethyl, 4-fluoro-3-pyridinylmethyl, 5-fluoro-3-pyridinylmethyl, 6-fluoro-3-pyridinylmethyl, 2-fluoro-4-pyridinylmethyl, 3-fluoro-4-pyridinylmethyl, 5-fluoro-4-pyridinylmethyl, 6-fluoro-4-pyridinylmethyl, 3-chloro-2-pyridinylmethyl, 4-chloro-2-pyridinylmethyl, 5-chloro-2-pyridinylmethyl, 6-chloro-2-pyridinylmethyl, 2-chloro-3-pyridinylmethyl, 4-chloro-3-pyridinylmethyl, 5-chloro-3-pyridinylmethyl, 6-chloro-3-pyridinylmethyl, 2-chloro-4-pyridinylmethyl, 3-chloro-4-pyridinylmethyl, 5-chloro-4-pyridinylmethyl, 6-chloro-4-pyridinylmethyl, 3-bromo-2-pyridinylmethyl, 4-bromo-2-pyridinylmethyl, 5-bromo-2-pyridinylmethyl, 6-bromo-2-pyridinylmethyl, 2-bromo-3-pyridinylmethyl, 4-bromo-3-pyridinylmethyl, 5-bromo-3-pyridinylmethyl, 6-bromo-3-pyridinylmethyl, 2-bromo-4-pyridinylmethyl, 3-bromo-4-pyridinylmethyl, 5-bromo-4-pyridinylmethyl, 6-bromo-4-pyridinylmethyl, 3-cyan-2-pyridinylmethyl, 4-cyan-2-pyridinylmethyl, 5-cyan-2-pyridinylmethyl, 6-cyan-2-pyridinylmethyl, 2-cyan-3-pyridinylmethyl, 4-cyan-3-pyridinylmethyl, 5-cyan-3-pyridinylmethyl, 6-cyan-3-pyridinylmethyl, 2-cyan-4-pyridinylmethyl, 3-cyan-4-pyridinylmethyl, 5-cyan-4-pyridine is methyl, 6-cyan-4-pyridinylmethyl, 3-(methylthio)-2-pyridinylmethyl, 4-(methylthio)-2-pyridinylmethyl, 5-(methylthio)-2-pyridinylmethyl, 6-(methylthio)-2-pyridinylmethyl, 2-(methylthio)-3-pyridinylmethyl, 4-(methylthio)-3-pyridinylmethyl, 5-(methylthio)-3-pyridinylmethyl, 6-(methylthio)-3-pyridinylmethyl, 2-(methylthio)-4-pyridinylmethyl, 3-(methylthio)-4-pyridinylmethyl, 5-(methylthio)-4-pyridinylmethyl, 6-(methylthio)-4-pyridinylmethyl, 2-chloro-3-methyl-4-pyridinylmethyl, 2-chloro-5-methyl-4-pyridinylmethyl, 2-chloro-6-methyl-4-pyridinylmethyl, 3-chloro-5-methyl-4-pyridinylmethyl, 3-chloro-6-methyl-4-pyridinylmethyl, 5-chloro-6-methyl-4-pyridinylmethyl, methylpyridinium, dimethylpyridinium, ethylpyridinium, methoxypyridine, methoxypyridine, dimethoxypyridine, hydroxypropylmethyl, hydroxypyridine, dihydroxypyridine, ftoropirimidinami, diferentially, chloropyridinyl, chloropyridinyl, dichlorophenylethyl, bromopyridine, dibromopyridine, indolylmethane, indocility, intelliprofile, indolylbutyric, methylindoline, methylindoline, dimethylindoline, acylindrical, methoxyindole, methoxyindole, dimethoxyindole, hydroxyindoleacetic, hydroxyindoleacetic, dihydroxyindoline, perindopril, differentally, gloryholestation, chlorinolysis, dichloroindophenol, brandalley, Deeb is mindalinami, 2-bromopyrimidine-4-yl, 5-bromopyrimidine-4-yl, 6-bromopyrimidine-4-yl, oxazolyl, 3-methyloxazolidine, 4-methyloxazolidine, 5-methyloxazolidine, 3,5-dimethyloxazolidine, 3,4-dimethyloxazolidine, 4,5-dimethyloxazole or isoxazolyl. Preferred examples are furylmethyl, purolater, pyrrolidinyl, pyrrolidinyl, pyridinylmethyl (2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl), 4-pyridinylmethyl, indolylmethane, indocility, 2-bromopyrimidine-4-yl, 5-bromopyrimidine-4-yl, 6-bromopyrimidine-4-yl, thienylmethyl (2-thienylmethyl, 3-thienylmethyl), thiophenolate, 6-bromopyrimidine-4-yl, oxazolyl, 3-methyloxazolidine, 4-methyloxazolidine, 5-methyloxazolidine, 3,5-dimethyloxazolidine, 3,4-dimethyloxazolidine, 4,5-dimethyloxazole, isoxazolyl, 3-methoxy-4-pyridinylmethyl, 2-fluoro-4-pyridinylmethyl, 2-chloro-4-pyridinylmethyl, 3-chloro-4-pyridinylmethyl, 5-bromo-3-pyridinylmethyl, 3-cyan-2-pyridinylmethyl, 2-(methylthio)-3-pyridinylmethyl, 3-chloro-5-methyl-4-pyridinylmethyl and most preferred examples are 4-pyridinylmethyl and 4-pyridinylmethyl.

The formula "CH2-U-heterocyclyl"as it is used in the context for Deputy And means heterocyclyl group, as defined above, which is connected with the group "U", which means O, S or NR"where R" denotes hydrogen or (C1-C )alkyl. Component "heterocyclyl-U" is connected with a methyl group. The above heterocyclyl group optionally substituted 1-4, preferably 1-3, more preferably 1-2 substituents selected from (C1-C4)alkyl, fluorine, chlorine, bromine, langroup, nitro and NRR', where R and R' independently of one another denote hydrogen or (C1-C4)alkyl. Preferred examples of component "heterocyclyl-U" is the 4-pyridyloxy-, 3-pyridyloxy-, 2-pyridyloxy-, 2-nitro-3-pyridyloxy-, 2-amino-3-pyridyloxy-, 4-methyl-3-pyridyloxy-, 5-chloro-3-pyridyloxy-, 2-amino-6-methyl-1,3-pyrimidine-4-roxyrama, 4-pyridylamino-, 3-pyridylamino-, 2-pyridyldithio, 4-pyridylamino-, 3-pyridylamino or 2-pyridylamino.

Heterocyclyl in CH(OH)-heterocyclyl for the substituent a is as defined above, is preferably furyl, 1-pyrrolyl, 2-pyrrolyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl or optionally substituted heterocyclyl group. Suitable substituents for heterocyclyl can be selected from 1, 2, 3 or 4 (when chemically possible) deputies from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine or bromine, preferably 1 or 2 substituents, such as methyl, ethyl, methoxy group, ethoxypropan, hydroxyl, fluorine, chlorine or bromine. Preferred and heterocyclyl residues in CH(OH)-heterocyclyl for Deputy And are 2-pyridinyl, 3-pyridinyl or 4-pyridinyl.

Heterocyclyl in SN(F)-heterocyclyl for the substituent a is as defined above, is preferably furyl, 1-pyrrolyl, 2-pyrrolyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl or optionally substituted heterocyclyl group. Suitable substituents for heterocyclyl can be selected from 1, 2, 3 or 4 (when chemically possible) deputies from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine or bromine, preferably 1 or 2 substituents, such as methyl, ethyl, methoxy group, ethoxypropan, hydroxyl, fluorine, chlorine or bromine. Preferred heterocyclyl balance in CH(R)-heterocyclyl for Deputy And is 4-pyridinyl.

Heterocyclyl in CH=CH-heterocyclyl for the substituent a is as defined above, is preferably pyridinyl or optionally substituted pyridinoline group. Ethylendiamine group (-CH=CH-) can be (E)- or (Z)-configuration. Both isomeric forms of such compounds are encompassed by the present invention. The preferred configuration ethylendiamine group in this invention is (E)-configuration. Suitable substituents for heterocyclyl can be selected from 1, 2, 3 or 4 (when chemically possible) deputies from (C1-C4)alkyl, (C1-C4)alkoxyl, Hydra is xela, fluorine, chlorine or bromine, preferably 1 or 2 substituents, such as methyl, ethyl, methoxy group, ethoxypropan, hydroxyl, fluorine, chlorine or bromine. Preferred heterocyclyl balance SN=SN-heterocyclyl for Deputy And is pyridinyl, 4-methylpyridine, 4-methoxypyridine, 4-herperidin or 4-chloropyridinyl. The most preferred heterocyclyl balance SN=SN-heterocyclyl for Deputy And is pyridinyl.

The term "geterotsiklicheskikh", as used in this context, means an aryl or optionally substituted heterocyclyl group, as defined above, which is associated with alkoxygroup containing from 1 to 4 carbon atoms, as defined above. Preferred examples are 4-pyridylmethylamine (4-pyridylmethyl), 3-pyridylmethylamine (3-pyridyloxy), 2-pyridylmethylamine (2-pyridyloxy).

The term "halogen" means fluorine, chlorine, bromine and iodine. More preferably halogen means fluorine, chlorine or bromine, and most preferably halogen means fluorine or chlorine.

In the framework of this invention, the term X represents S or O, preferably s

Any functional (i.e., reactive) group present in the side chain can be protected with a protective group which is known per se, for example the EP, described in the book "Protective groups in organic synthesis", 2nd edition, T.W.Greene and P.G.M.Wuts, John Wiley & Sons, new York, new York, 1991. For example, the amino group may be protected by tert-butoxycarbonyl (VOS) or benzyloxycarbonyl (Z).

Compounds according to this invention may contain one or more asymmetric carbon atoms and can therefore exist in the form of racemates or racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In addition, if the connection according to the invention contains olefinic double bond, then we can talk about (E)-or (Z)-configuration. Also, each chiral center may be characterized (R)- or (S)-configuration. All of these isomeric forms of such compounds are encompassed by the present invention.

The compounds of formula I, which are acids, can form pharmaceutically acceptable salts with bases, such as hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide, hydroxides of alkaline earth metals such as calcium hydroxide, barium hydroxide and magnesium hydroxide and the like, with organic bases, for example N-ethylpiperidine, dibenzylamine and the like. The compounds of formula I which are basic can form pharmaceutically acceptable salts with inorganic acid is Tami, for example kaleidotrope acids, such as hydrochloric acid and Hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid and the like, and with organic acids, for example acetic acid, formic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulfonate and p-toluensulfonate, and the like. Education and the provision of such salts can be carried out according to methods known in this field.

The preferred embodiment of the invention is the use of compounds of formula I

where R1means optionally substituted (C1-C12)alkyl, (C3-C8)cycloalkyl, acyl, (C1-C4)alkylsulfonyl, optionally substituted phenylsulfonyl, aryl, heterocyclyl or (C1-C4)alkyl, substituted optionally substituted by phenyl,

where (C1-C12)alkyl may be substituted by 1-5 substituents selected from fluorine, chlorine and bromine, and

where phenyl may be substituted by 1-5 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine and langroup;

R2means substituted phenyl,

defanyl may be substituted by 1-5 substituents, selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup and nitroguy;

R3means (C1-C12)alkyl or (C1-C4)alkoxy-(C1-C4)alkyl;

A represents a group selected from CH2-(aryl-/C1-C4/alkylamino), CH2-(aryl-/C1-C4/alkoxy), CH2-(heterocyclyl-/C1-C4/alkoxy), (C1-C4)alkyl, substituted optionally substituted aryl or optionally substituted heterocyclyl,

where aryl may be substituted by 1-5 substituents or heterocyclyl substituted by 1-4 substituents and the substituents are selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, S-(C1-C4)alkyl and NRR', where R and R' denote, independently of each other hydrogen or (C1-C4)alkyl, or

A represents a group of formula CH2-U-heterocyclyl,

where U represents O, S or NR"where R" denotes hydrogen or (C1-C4)alkyl, and where heterocyclyl optionally substituted by 1-4 substituents selected from (C1-C4)alkyl, fluorine, chlorine, bromine, langroup, nitro and NRR', where R and R' independently of one another denote hydrogen or (C1-C4)alkyl, or

A represents a group of formula CH(V)Z,

where V means HE or F and

g is e Z signifies aryl or heterocyclyl, or

A represents a group of the formula CH=CHW,

where W denotes optionally substituted aryl or optionally substituted heterocyclyl and

where aryl may be substituted by 1-5 substituents or heterocyclyl may be substituted by 1-4 substituents and the substituents are selected from (C1-C4)alkyl, (C1-C4)-alkoxyl, hydroxyl, langroup, fluorine, chlorine and bromine;

X is S or O;

for the treatment of diseases mediated by the human immunodeficiency virus (HIV), or to obtain drugs for such treatment.

Other preferred variants of the invention is the use of compounds of formula I, where

R1means optionally substituted (C1-C12)alkyl, (C3-C8)cycloalkyl, aryl, heterocyclyl or (C1-C4)alkyl, substituted phenyl,

where (C1-C12)alkyl may be substituted by 1-5 fluorine-containing substituents, preferably, when

R1means optionally substituted (C1-C7)alkyl, (C3-C8)cycloalkyl, aryl, heterocyclyl or (C1-C4)alkyl, substituted phenyl,

where (C1-C7)alkyl may be substituted by 1-3 fluorine-containing substituents,

more preferably, when

R1means optionally substituted (C1-C7)alkyl, (C -C6)cycloalkyl, phenyl, pyridyl or benzyl,

where (C1-C7)alkyl may be substituted by 1-3 fluorine-containing substituents,

most preferably, when

R1means (C1-C7)alkyl;

R2means substituted phenyl, substituted by 1-5 substituents selected from the

(C1-C4)alkyl, (C1-C4)alkoxyl, fluorine, chlorine, bromine, langroup and nitroguy,

preferably, when

R2means substituted phenyl, substituted with 1-3 substituents selected from the

(C1-C4)alkyl, (C1-C4)alkoxyl, fluorine, chlorine, bromine, langroup and nitroguy,

more preferably, when

R2means substituted phenyl, substituted with 1-3 substituents selected from the

(C1-C2)alkyl, fluorine, chlorine and langroup,

most preferably, when

R2means substituted phenyl, substituted with 1-3 substituents selected from chlorine and langroup;

R3means (C1-C12)alkyl or (C1-C4)alkoxy-(C1-C4)alkyl, preferably, when

R3means (C1-C7)alkyl or (C1-C4)alkoxy-(C1-C2)alkyl, more preferably, when

R3means (C1-C7)alkyl or (C1-C2)alkoxy-(C1-C2)alkyl,

p> most preferably, when

R3means (C1-C7)alkyl;

A represents a group selected from CH2-(aryl-/C1-C4/alkoxy), CH2-(heterocyclyl-/C1-C4/alkoxy), (C1-C4)alkyl, substituted optionally substituted phenyl or optionally substituted heterocyclyl, where phenyl may be substituted by 1-5 substituents or heterocyclyl substituted by 1-4 substituents and the substituents are selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, S-(C1-C4)alkyl and NRR', where R and R' denote, independently of each other hydrogen or (C1-C4)alkyl, or

A represents a group of formula CH2-U-heterocyclyl,

where U represents O, S or NR"where R" denotes hydrogen or (C1-C4)alkyl and where heterocyclyl optionally substituted by 1-4 substituents selected from (C1-C4)alkyl, fluorine, chlorine, bromine, langroup, nitro and NRR', where R and R' independently of one another denote hydrogen or (C1-C4)alkyl, or

A represents a group of formula CH(V)heterocyclyl,

where V means HE or F, or

A represents a group of the formula CH=CHW,

where W stands for optionally substituted aryl, substituted by 1-5 substituents, and the substituents are selected from (C1-C4)alkyl, (C1-C4)al is oxyl, hydroxyl, langroup, fluorine, chlorine and bromine, preferably, when

A represents a group selected from CH2-(phenyl-/C1-C2/alkoxy), CH2-(pyridyl-/C1-C2/alkoxy), (C1-C2)alkyl, substituted optionally substituted phenyl or optionally substituted heterocyclyl, where phenyl may be substituted by 1-3 substituents or heterocyclyl substituted with 1-2 substituents and the substituents are selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, S-(C1-C4)alkyl and NRR', where R and R' independently of one another denote hydrogen or (C1-C4)alkyl, or

A represents a group of formula CH2-U-heterocyclyl,

where U represents O, S or NR"where R" denotes hydrogen or (C1-C4)alkyl and where heterocyclyl optionally substituted by 1-2 substituents selected from (C1-C4)alkyl, fluorine, chlorine, bromine, langroup, nitro and NRR', where R and R' independently of one another denote hydrogen or (C1-C4)alkyl, or

A represents a group of formula CH(F)heterocyclyl,

more preferably, when

A represents a group selected from CH2-(phenyl-/C1-C2/alkoxy), CH2-(pyridyl-/C1-C2/alkoxy), (C1-C2)alkyl, substituted optionally substituted by phenyl which do not necessarily replaced by heterocyclyl,

where phenyl may be substituted by 1-3 substituents or heterocyclyl substituted with 1-2 substituents and the substituents are selected from (C1-C2)alkyl, (C1-C2)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, S-(C1-C2)alkyl and NRR', where R and R' independently of one another denote hydrogen or (C1-C2)alkyl, or

A represents a group of formula CH(F)Z,

where Z means heterocyclyl,

most preferably, when

A represents a group selected from CH2-(phenyl-/C1-C2/alkoxy), CH2-(pyridyl-/C1-C2/alkoxy), (C1-C2)alkyl, substituted optionally substituted by heterocyclyl,

where heterocyclyl substituted with 1-2 substituents and the substituents are selected from (C1-C2)alkyl, (C1-C2)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, S-(C1-C2)alkyl and NRR', where R and R' independently of one another denote hydrogen or (C1-C2)alkyl;

X is S or O,

for the treatment of diseases mediated by the human immunodeficiency virus (HIV), or to obtain drugs for such treatment.

Other preferred variants of the invention is the use of compounds of formula I, where

R1means (C1-C4)alkyl,

preferably, when

R1 means ethyl or isopropyl;

R2means substituted phenyl, substituted 1-3 chlorine substituents,

preferably, when

R2means 3,5-dichlorophenyl;

R3means (C1-C4)alkyl,

preferably, when

R3means methyl;

And means a group in the form (1-C2)alkyl, substituted optionally substituted by heterocyclyl,

where heterocyclyl substituted with 1-2 substituents and the substituents are selected from (C1-C2)alkyl and chlorine

preferably, when

And means a group in the form (1-C2)alkyl, substituted optionally substituted by heterocyclyl,

where heterocyclyl substituted with 1-2 substituents and the substituents are selected from (C1-C2)alkyl and chlorine;

X is S or O.

The preferred embodiment of the invention is the use of compounds of formula I, where X is S.

Also part of the presents invention is the use of compounds of formula I

where R1means (C1-C12)alkyl, (C3-C8)cycloalkyl, acyl, (C1-C4)alkylsulfonyl, optionally substituted phenylsulfonyl, aryl or (C1-C4)alkyl, substituted optionally substituted by phenyl,

where phenyl may be substituted by 1-5 C is Mascitelli, selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine and bromine;

R2means aryl or optionally substituted phenyl,

where phenyl may be substituted by 1-5 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine and bromine;

R3means (C1-C12)alkyl or (C1-C4)alkoxy-(C1-C4)alkyl;

A represents a group selected from CH2-(aryl-/C1-C4/alkylamino), CH2-(aryl-/C1-C4/alkoxy), (C1-C4)alkyl, substituted optionally substituted aryl or optionally substituted heterocyclyl,

where aryl may be substituted by 1-5 substituents or heterocyclyl substituted by 1-4 substituents and the substituents are selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine and bromine, or

A represents a group of formula CH(OH)Z,

where Z denotes aryl or heterocyclyl, or

A represents a group of the formula CH=CHW,

where W represents optionally substituted aryl or optionally substituted heterocyclyl, and

where aryl may be substituted by 1-5 substituents or heterocyclyl may be substituted by 1-4 substituents and the substituents are selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, PI is RA and bromine;

X is S or O;

for the treatment of diseases mediated by the human immunodeficiency virus (HIV), or to obtain drugs for such treatment.

Preferred embodiments of the invention to use the compounds of formula I for the treatment of diseases mediated by the human immunodeficiency virus (HIV), or to obtain drugs for such treatment are presented in table 1.

Table 1
STRUCTUREThe SYSTEMATIC NAME
5-(3-Chlorophenylthio)-3-methoxymethyl-1-methyl-4-styryl-1H-pyrazole
(E)-5-(3,5-Dichlorophenylthio)-3-(methoxymethyl)-1-phenyl-4-styryl-1H-pyrazole
5-(3,5-Dichlorophenylthio)-3-methyl-1-phenyl-4-styryl-1H-pyrazole
4-Benzyl-5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole
5-(3,5-Dichlorophenylthio)-3-methyl-4-(2-phenylethyl)-1-phenyl-1H-pyrazole
5-(3,5-Dichlorophenylthio)-3-(methoxymethyl)-1-phenyl-4-(2-peneliti is)-1H-pyrazole
[5-(3,5-Dichlorophenylthio)-3-(methoxymethyl)-1-methyl-1H-pyrazole-4-yl]phenylmethanol
[5-(3,5-Dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-yl]phenylmethanol
[5-(3,5-Dichlorophenylthio)-1-ethyl-3-(methoxymethyl)-1H-pyrazole-4-yl]phenylmethanol
4-Benzyl-5-(3,5-dichlorophenylthio)-1-ethyl-3-(methoxymethyl)-1H-pyrazole
4-Benzyl-5-(3,5-dichlorophenylthio)-3-methoxymethyl-1-methyl-1H-pyrazole
5-(3,5-Dichlorophenylthio)-3-methyl-α(RS)-phenyl-1H-pyrazole-4-methanol
1,4-Dibenzyl-5-(3,5-dichlorophenylthio)-3-methyl-1H-pyrazole
4-Benzyl-5-(3,5-dichlorophenylthio)-1-isopropyl-3-methyl-1H-pyrazole
4-Benzyl-5-(3,5-dichlorophenylthio)-1-ethyl-3-methyl-1H-pyrazole
4-Benzyl-1-sec-butyl-5-(3,5-dichlorophenylthio)-3-methyl-lH-pyrazole
4-[5-(3,5-Diclofe is ylthio)-3-methyl-1-phenyl-4-[(4-pyridyl)methyl]-1H-pyrazole
5-(3,5-Dichlorophenylthio)-1-ethyl-3-methyl-4-(2-phenylethyl)-1H-pyrazole
4-[5-(3,5-Dichlorophenylthio)-1-ethyl-3-methyl-[(4-pyridyl)methyl]-1H-pyrazole
4-Benzyl-1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazole
4-Benzyl-1-cyclopentyl-5-(3,5-dichlorophenylthio)-3-methyl-1H-pyrazole
4-Benzyl-1-cyclohexyl-5-(3,5-dichlorophenylthio)-3-methyl-1H-pyrazole
4-Benzyl-5-(3,5-dichlorophenylthio)-1-isobutyl-3-methyl-1H-pyrazole
4-Benzoyloxymethyl-5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole
2-[4-Benzyl-5-(3,5-dichlorobenzenesulfonyl)-3-methylpyrazole-1-yl]pyridine
4-Benzyl-3-methyl-5-(3-nitrophenoxy)-1-phenyl-1H-pyrazole
3-(4-Benzyl-5-methyl-2-phenyl-2H-pyrazole-3-yloxy)benzonitrile
2-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-methyl-1H-pyrazole-4-ylmethyl]pyridine
4-Benzoyloxymethyl-5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole
2-[5-(3,5-Dimethylbenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine
2-[5-(3-Chlorophenylsulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine
2-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylethoxy]pyridine
3-Chloro-5-[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylethoxy]pyridine
1-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-1H-pyridine-2-he
3-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine
3-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-3H-pyrimidine-4-one
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ileocecal]pyridine
3-(4-Benzyl-5-methyl-2-phenyl-2H-pyrazole-3-ylsulphonyl)benzonitrile
3-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl] pyridine
[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]pyridine-2-ylmethanol
[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]pyridine-4-ylmethanol
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-elmersolver]pyridine
4-Benzyl-5-(3,5-dichlorobenzenesulfonyl)-3-methyl-1-(2,2,2-triptorelin)-1H-pyrazole
4-{[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]vermeil}pyridine
5-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylethoxy]-2-methylpyridin
5-Bromo-4-[5-(3,5-dichlorobenzenesulfonyl)-1-from ropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyrimidine
3-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylethoxy]-2-nitropyridine
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-elmersolver]pyridine
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylethoxy]pyridine
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyrimidine
3-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylethoxy]pyridine-2-ylamine
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylethoxy]pyridine
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-3-herperidin
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylmethyl]-3-herperidin
3-Chloro-4-[5-(3,5-dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine
3-Chloro-4-[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylethoxy]-6-methylpyrimidin-2-ylamine
3-Bromo-5-[5-(3,5-dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine
[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine-3-ylamine
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]benzonitrile
2-Chloro-4-[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine
2-Chloro-4-[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-6-methylpyridin
2-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyrazin
4-[5-(3-Chloro-5-methoxybenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-2-methoxypyridine
3-[[5-(3,5-Dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-yl]methyl]-2-(methylthio)pyridine
4-[5-(3-Brompheniramine)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-3-chloropyridin
3-Chloro-4-(1-isopropyl-3-methyl-5-m-tamilselvan-1H-pyrazole-4-ylmethyl)pyridine
3-Chloro-4-[5-(3,5-dimethylbenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine
4-[5-(3-Brompheniramine)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-3-herperidin
3-Fluoro-4-(1-isopropyl-3-methyl-5-m-tamilselvan-1H-pyrazole-4-ylmethyl)pyridine
4-[5-(3,5-Dimethylbenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-3-herperidin
5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-4-thiophene-3-ylmethyl-1H-pyrazole
{3-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]phenyl}dimethylamine
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-ethyl-1H-pyrazole-4-ylmethyl]for 3,5-dimethylisoxazol
6-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine-2-carbonitrile

Part of the present invention are also new pyrazole derivatives, method of production thereof, pharmaceutical compositions and the use of such compounds in medicine. In particular, these compounds are inhibitors of the reverse transcriptase of human immunodeficiency virus, i.e. inhibitors of the enzyme involved in the replication of the virus.

The new compounds of this invention are the compounds of formula I-A

where R1means optionally substituted (C1-C12)alkyl, (C3-C8)cycloalkyl, acyl, (C1-C4)alkylsulfonyl, optionally substituted phenylsulfonyl, aryl, heterocyclyl or (C1-C4)alkyl, substituted phenyl,

where (C1-C12)alkyl may be substituted by 1-5 substituents selected from fluorine, chlorine and bromine, and

where phenyl may be substituted by 1-5 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine and langroup;

R2'means optionally substituted phenyl,

where phenyl may be substituted by 1-5 substituents selected from (C1-C4)alkyl, (C1- 4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup and nitro;

R3means (C1-C12)alkyl or (C1-C4)alkoxy-(C1-C4)alkyl;

And' means a group selected from CH2-(aryl-/C1-C4/alkylamino), CH2-(aryl-/C1-C4/alkoxy), CH2-(heterocyclyl-/C1-C4/alkoxy), (C1-C4)alkyl, substituted optionally substituted aryl or optionally substituted 4-pyridium,

where aryl may be substituted by 1-5 substituents or 4-pyridyl substituted by 1-4 substituents and the substituents are selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, S-(C1-C4)alkyl and NRR', where R and R' denote, independently of each other hydrogen or (C1-C4)alkyl, or

And' means a group of the formula CH2-U-heterocyclyl,

where U represents O, S or NR"where R" denotes hydrogen or (C1-C4)alkyl and where heterocyclyl optionally substituted by 1-4 substituents selected from (C1-C4)alkyl, fluorine, chlorine, bromine, langroup, nitro and NRR', where R and R' denote, independently of each other hydrogen or (C1-C4)alkyl,

or

And' means a group of formula CH(OH)aryl, or

And' means a group of the formula CH=CHW,

where W denotes optional samisen the th aryl or optionally substituted heterocyclyl, and

where aryl may be substituted by 1-5 substituents or heterocyclyl may be substituted by 1-4 substituents and the substituents are selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, langroup, fluorine, chlorine and bromine;

X is S or O,

their hydrolyzable complex or simple esters and their pharmaceutically acceptable salts.

The terms used for the substituents of new derivatives of pyrazole, are such as defined above.

Other variants of the invention are new compounds of formula I-A, where

R1means optionally substituted (C1-C12)alkyl, (C3-C8)cycloalkyl, aryl, heterocyclyl or (C1-C4)alkyl, substituted phenyl,

where (C1-C12)alkyl may be substituted by 1-5 fluorine-containing substituents, preferably, when

R1means optionally substituted (C1-C7)alkyl, (C3-C8)cycloalkyl, aryl, heterocyclyl or (C1-C4)alkyl, substituted optionally substituted by phenyl,

where (C1-C7)alkyl may be substituted by 1-3 fluorine-containing substituents,

more preferably, when

R1means optionally substituted (C1-C7)alkyl, (C3-C8)cycloalkyl,

phenyl, pyridyl or benzyl,

where (C1- 7)alkyl may be substituted by 1-3 fluorine-containing substituents,

most preferably, when

R1means (C1-C7)alkyl;

R2'means substituted phenyl, substituted by 1-5 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, fluorine, chlorine, bromine, langroup and nitro-group,

preferably, when

R2'means substituted phenyl, substituted with 1-3 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, fluorine, chlorine, bromine, langroup and nitroguy,

more preferably, when

R2'means substituted phenyl, substituted with 1-3 substituents selected from (C1-C2)alkyl, fluorine, chlorine and langroup,

most preferably, when

R2'means substituted phenyl, substituted with 1-3 substituents selected from chlorine and langroup;

R3means (C1-C12)alkyl or (C1-C4)alkoxy-(C1-C4)alkyl,

preferably, when

R3means (C1-C7)alkyl or (C1-C4)alkoxy-(C1-C2)alkyl,

more preferably, when

R3means (C1-C7)alkyl or (C1-C2)alkoxy-(C1-C2)alkyl,

most preferably, when

R3means (C1-C )alkyl;

And' means a group selected from CH2-(phenyl-/C1-C4/alkoxy), CH2-(pyridyl-/C1-C4/alkoxy), (C1-C4)alkyl, substituted optionally substituted aryl or optionally substituted 4-pyridium,

where aryl may be substituted by 1-5 substituents or 4-pyridyl substituted by 1-4 substituents and the substituents are selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, S-(C1-C4)alkyl and NRR', where R and R' denote, independently of each other hydrogen or (C1-C4)alkyl, or

And' means a group of the formula CH2-U-heterocyclyl,

where U represents O, S or NR"where R" denotes hydrogen or (C1-C4)alkyl and where heterocyclyl optionally substituted by 1-4 substituents selected from (C1-C4)alkyl, fluorine, chlorine, bromine, langroup, nitro and NRR', where R and R' denote, independently of each other hydrogen or (C1-C4)alkyl, or

And' means a group of formula CH(OH)aryl, or

And' means a group of the formula CH=CHW,

where W represents optionally substituted aryl, substituted by 1-5 substituents and the substituents are selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, langroup, fluorine, chlorine and bromine,

preferably, when

And' means a group selected the th of CH 2-(phenyl-/C1-C4/alkoxy), CH2-(pyridyl-/C1-C4/alkoxy), methyl, substituted by an optionally substituted phenyl or optionally substituted 4-pyridium, where phenyl may be substituted by 1-3 substituents or 4-pyridyl substituted with 1-2 substituents and the substituents are selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, S-(C1-C4)alkyl and NRR', where R and R'

mean independently from each other hydrogen or (C1-C4)alkyl, or

And' means a group of the formula CH2-U-heterocyclyl,

where U represents O, S or NR"where R" denotes hydrogen or (C1-C4)alkyl, and where heterocyclyl optionally substituted by 1-2 substituents selected from (C1-C4)alkyl, fluorine, chlorine, bromine, langroup, nitro and NRR', where R and R' denote, independently of each other hydrogen or (C1-C4)alkyl,

more preferably, when

And' means a group selected from CH2-(phenyl-/C1-C2/alkoxy), CH2-(pyridyl-/C1-C2/alkoxy), methyl, substituted by an optionally substituted phenyl or optionally substituted 4-pyridium,

where phenyl may be substituted by 1-3 substituents or 4-pyridyl substituted with 1-2 substituents and the substituents are selected from (C1-C2)alkyl, (C1-C2)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, S-(C1-C2)alkyl and NRR', where R and R' independently of one another denote hydrogen or (C1-C2)alkyl,

most preferably, when

And' means a group selected from CH2-(aryl-/C1-C2/alkoxy), CH2-(heterocyclyl-/C1-C2/alkoxy), methyl, substituted by an optionally substituted 4-pyridium,

where 4-pyridyl substituted with 1-2 substituents and the substituents are selected from (C1-C2)alkyl, (C1-C2)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, S-(C1-C2)alkyl and NRR', where R and R' independently of one another denote hydrogen or (C1-C2)alkyl;

X is S or O;

their hydrolyzable complex or simple esters and their pharmaceutically acceptable salts.

Another preferred embodiment of the invention are new compounds of formula I-A, where

R1means (C1-C4)alkyl;

R2'means substituted phenyl, substituted 1-3 chlorine substituents;

R3means (C1-C4)alkyl;

And' means a methyl group substituted by an optionally substituted 4-pyridium, where 4-pyridyl substituted with 1-2 substituents and the substituents are selected from (C1-C2)alkyl and chlorine;

X is S or O;

their hydrolyzable complex or p is Ostia esters and their pharmaceutically acceptable salts.

A further preferred embodiment of the invention are new compounds of formula I-A, where

R1means (C1-C12)alkyl, (C3-C8)cycloalkyl, acyl, (C1-C4)alkylsulfonyl, optionally substituted phenylsulfonyl, aryl or (C1-C4)alkyl, substituted optionally substituted by phenyl,

where phenyl may be substituted by 1-5 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine or bromine;

R2'means optionally substituted phenyl,

where phenyl may be substituted by 1-5 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine or bromine;

R3means (C1-C12)alkyl or (C1-C4)alkoxy-(C1-C4)alkyl;

And' means a group selected from CH2-(aryl-/C1-C4/alkylamino), CH2-(aryl-/C1-C4/alkoxy), (C1-C4)alkyl, substituted optionally substituted aryl or optionally substituted 4-pyridium,

where aryl may be substituted by 1-5 substituents or 4-pyridyl substituted by 1-4 substituents and the substituents are selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine or bromine, or

And' means a group of the form is s CH(OH)Z'

where Z' is aryl, or

And' means a group of the formula CH=CHW,

where W denotes optionally substituted aryl or optionally substituted heterocyclyl, and

where aryl may be substituted by 1-5 substituents or heterocyclyl may be substituted by 1-4 substituents and the substituents are selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine or bromine;

X is S or O;

their hydrolyzable complex or simple esters and their pharmaceutically acceptable salts.

The preferred embodiment of the invention are new compounds of formula I-A, where

And' means a group selected from CH2-(aryl-/C1-C4/alkylamino), CH2-(aryl-/C1-C4/alkoxy), CH2-(heterocyclyl-/C1-C2/alkoxy), (C1-C4)alkyl, substituted optionally substituted aryl,

where aryl may be substituted by 1-5 substituents and the substituents are selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, S-(C1-C4)alkyl and NRR', where R and R' independently of one another denote hydrogen or (C1-C4)alkyl, or

And' means a group of the formula CH2-U-heterocyclyl,

where U represents O, S or NR"where R" denotes hydrogen or (C1-C4)alkyl, and where heterocyclyl the long is correctly substituted by 1-4 substituents, selected from (C1-C4)alkyl, fluorine, chlorine, bromine, langroup, nitro and NRR', where R and R' denote, independently of each other hydrogen or (C1-C4)alkyl,

or

And' means a group of formula CH(OH)aryl, or

And' means a group of the formula CH=CHW,

where W denotes optionally substituted aryl or optionally substituted heterocyclyl; and

where aryl may be substituted by 1-5 substituents or heterocyclyl may be substituted by 1-4 substituents and the substituents are selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, langroup, fluorine, chlorine and bromine;

X is S or O,

their hydrolyzable complex or simple esters and their pharmaceutically acceptable salts.

Especially preferred embodiment of the invention are new compounds of formula I-A, where

X is S.

Preferred variants of the invention are new compounds of formula I-A are presented in table 1 (see above).

Derivatives of pyrazole provided by the present invention that are useful for therapeutic treatment of the human or animal, and specifically these compounds are inhibitors of the reverse transcriptase enzyme of the human immunodeficiency virus. Accordingly, presents pyrazole derivatives are therapeutically active and substances for the treatment of diseases, mediated by human immunodeficiency virus, celovec (HIV), and can be used as medicines for the treatment of such diseases.

They can be used as medicines, especially for the treatment of viral diseases mediated immunity conditions or diseases, bacterial diseases, parasitic diseases, inflammatory diseases, hyperproliferative vascular diseases, tumors and cancer.

In particular, the compounds of the present invention and containing pharmaceutical compositions suitable as chemotherapeutic agents, inhibitors of viral replication and modulators of the immune system and can be applied for the treatment of diseases mediated by the human immunodeficiency virus (HIV), other viral diseases, such as, for example, retroviral infection (either alone or in combination with other antiviral agents, such as interferon or its derivatives, such as, for example, conjugates with polyethylene glycol).

They can be used alone or in combination with other therapeutically active means such as immunosuppressant, a chemotherapeutic agent, an antiviral agent, antibiotic, anti-parasitic agent, an anti-inflammatory, antifungal medium spans the PTO and/or remedy against vascular hyperproliferation.

Connection, whenever they obtained by means of the present invention, are also the object of the present invention.

Compounds of the present invention can be obtained, as shown in the following reaction schemes. The reaction can be conducted in conventional manner, known to specialists in this field. The initial compounds required for the preparation of compounds of formula I are commercially available or can be easily obtained according to methods known in this field.

In the present specification "includes" means "includes" and "covering" means "including".

Reaction scheme 1:

where R1, R2, R3and X are as defined for compounds of formula I, and R5means aryl or heterocyclyl.

In reaction scheme 1 the first stage reaction is carried out in such a way that the derived 5-hydroxypyrazol formula II (commercially available or synthesized in the usual way known to specialists in this field, as described, for example, in international patent application WO 9842678 or J. DeRuiter, etc., J. Heterocyclic Chem., 1987, 24, 149) are subjected to reaction with R5COCl (commercially available or synthesized according to methods known from textbooks on organic chemistry e.g. from training the ICA J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons), where R5so, as stated above, in a suitable solvent, receive the derived 5-hydroxypyrazol formula III, substituted in position 4 by a Deputy with exography. The reaction is conveniently carried out under conditions known for the acylation reactions, for example in an inert solvent, such as, for example, ethers, such as anhydrous tetrahydrofuran, diethyl ether, disutility ether, dioxane, preferably dioxane, or a mixture of the mentioned solvents, at the reaction temperature from room temperature to the boiling temperature of the reaction mixture in the presence of a catalyst, such as calcium hydroxide, potassium carbonate, aluminum chloride, boron TRIFLUORIDE, ferric chloride (3), tin tetrachloride or zinc chloride, preferably calcium hydroxide.

In the second stage reaction carry out the chlorination substituted by a hydroxyl group in position 5 of the compounds of formula III using glorieuses agent, such as (COCl)2, HCl, PCl5, PCl3, SOCl2or POCl3and get derivatives of 5-chloropyrazole formula IV. The reaction is conveniently carried out in an atmosphere of inert gas, such as nitrogen or argon, at the reaction temperature from room temperature up to the boiling temperature of the reaction mixture. Preferably reacts the Yu is carried out in the presence of POCl 3when the reaction temperature from about 50°With up to approximately 180°C. Optionally, the reaction can be carried out in an organic solvent, such as halogenated hydrocarbons (e.g. dichloromethane or trichloromethane), hydrocarbons (e.g. cyclohexane, methylcyclohexane, decalin, benzene, toluene, o-xylene, m-xylene or p-xylene), or mixtures of the mentioned solvents.

In the third stage, the reaction of the compound of formula IV is subjected to reaction with R2SH or R2HE (both reagents are commercially available or can be synthesized by methods known from textbooks on organic chemistry e.g. from a textbook J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons), where R2is as defined for compounds of formula I, get a pyrazole derivative of the formula V. the Reaction is carried out in a suitable solvent in the presence of a base, such as n-BuLi, sodium hydride, trialkylamine, as, for example, trimethylamine or triethylamine, potassium carbonate, sodium carbonate, magnesium carbonate, calcium carbonate, preferably potassium carbonate. The reaction is usually carried out in an atmosphere of inert gas, such as, for example, in an atmosphere of nitrogen or argon, at a temperature of from 0°C to the boiling temperature of the reaction mixture, preferably at a temperature between about 10 and 180°C. Appropriate RA is the founders for the reaction are tetrahydrofuran or polar aprotic solvents, as, for example, dimethylsulfoxide (DMSO), dimethylacetamide or N,N-dimethylformamide (DMF), preferably DMF.

In the fourth stage of the reaction oxoprop the compounds of formula V restore to obtain the corresponding hydroxyl-containing compounds of the formula Ia. The reaction is usually carried out with a base, such as sodium borohydride, lithium borohydride, or preferably with sodium borohydride in an organic solvent such as an alcohol solvent, such as methanol, ethanol, propanol, butanol, octanol or cyclohexanol, preferably in methanol, or ethers (e.g. tetrahydrofuran, diethyl ether, debutalbum ether, dioxane or diglyme) at a temperature of from 0°C to the boiling temperature of the reaction mixture, preferably at a temperature of reaction between about 5 and 80°C. the Reaction recovery carried out as described in textbooks of organic chemistry, for example in the textbook by J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons).

At the fifth stage of the reaction oxymethylene group of compounds of formula Ia restore next to the corresponding methylene group and get the connection formula Ib. The reaction is conveniently carried out in the presence of trialkylsilanes, as, for example, trimethylsilane, triethylsilane or Tripropylene, preferably of triethylsilane, dissolve the military in mineral acids, as, for example, triperoxonane acid (TFA), or Lewis acids, such as tin tetrachloride (described D.L.Comins and others in Tet. Lett., 1986, 27, 1869), at the reaction temperature from 0 to 80°C, preferably at a temperature of between approximately 5 and 50°C.

The reduction can also be carried out in the presence of iodine sodium, trimethylsilylpropyne and methyl hydrogen or, as described in textbooks of organic chemistry, for example, in the textbook by J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons). When the hydroxyl group is converted into a leaving group, such as mesilate or sulfonate, preferably mesilate, the reaction can then be carried out in the presence of zinc and acetic acid (described J..Lynch and others, in J. Org. Chem., 1997, 62, 9223-9228).

Optional oxoproline the compounds of formula V directly restore to the corresponding methylene derivative of the formula Ib. Such methods for direct reduction are, for example, the recovery Clemmensen, restoring the wolf-Kijner, hydrogenolysis of thioacetals or restore using trialkylsilanes, as, for example, trimethylsilane, triethylsilane or Tripropylene, preferably of triethylsilane dissolved in mineral acids, such as, for example, triperoxonane acid (TFA).

At the sixth stage of the PE the work oxymethylene group of compounds of formula Ia is transformed into the corresponding formatrecovery group to obtain the compounds of formula Iz. The reaction is carried out by treating the compounds of formula Ia with a suitable fluorinating agent, such as, for example, dialkylaminoalkyl (R7)2NSF3formula XIV, where R7may be (C1-C4)alkyl (e.g. ethyl) or (R7)2N can be a cyclic amino group (e.g., morpholine). Fluorinating agent is commercially available (for example, diethylaminoacetate will GIVE) or can be synthesized according to known in this field. The fluorination reaction can be carried out, as described in textbooks of organic chemistry, for example in the textbook by J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons).

Reaction scheme 2:

where R1, R2, R3U and X are as defined for compounds of formula I, R5, R6and R8means aryl or heterocyclyl and R9means of CH2-(aryl/C1-C4/alkylamino).

In reaction scheme 2, the first reaction stage is carried out in such a way that the derived 5-hydroxypyrazol formula II (commercially available or synthesized in the usual way known to specialists in this field, as described, for example, in international patent application WO 9842678 or J. DeRuiter, etc., J. Heterocyclic Chem., 1987, 24, 149) is transformed into derivatives of 4-Karbala the guide-5-chloropyrazole formula VI. A reaction that involves the exchange of the hydroxyl/chlorine in position 5 and the introduction of the group C(=O)H in position 4 of the pyrazole, usually carried out with the use of disubstituted formamide, such as N,N-dimethylformamide, N,N-methylphenylamine or N,N-diphenylformamidine, in the presence of phosphorus oxychloride in accordance with the reaction Vilsmaier. The reaction is carried out in an inert atmosphere, such as, for example, in an atmosphere of nitrogen or argon, at a temperature from room temperature up to the boiling temperature of the reaction mixture, preferably at a temperature between about 50 and 150°C. Optionally, the reaction can be carried out in an inert organic solvent, such as ethers (e.g. tetrahydrofuran, diethyl ether, disutility ether or dioxane), in polar aprotic solvents, such as dimethyl sulfoxide (DMSO) or N,N-dimethylacetamide, halogenated hydrocarbons (e.g. dichloromethane or trichloromethane), in hydrocarbons (e.g. cyclohexane, methylcyclohexane, decalin, benzene, toluene, o-xylene, m-xylene or p-xylene) or mixtures of the mentioned solvents. The chlorination reaction can also be carried out in accordance with the method described for reaction scheme 1 (stage 2), the application of such gloriously agents, as (COCl)2, HCl, PCl5, PCl3, SOCl2. The introduction of the group C(=O)N (reaction formirovaniya) in PR is izvozna of pyrazole can be also carried out according to the methods known from textbooks on organic chemistry (J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons). Such methods are, for example, the reaction of the Friedel -, reaction Vilsmeier-khaak, the reaction of Gatterman, the reaction of Gatterman-Koch reaction of Guben-Hash or reaction Rimera-Timan.

In the second stage of the reaction the compound of formula VI interacts with R2SH or R2HE (both reagents are commercially available or can be synthesized according to methods known from textbooks on organic chemistry e.g. from a textbook J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons), where R2is as defined for compounds of formula I, to obtain a derivative of pyrazole of the formula VII. The reaction is carried out according to the method described for reaction scheme 1 (stage 3).

In the third stage, the reaction of the compound of formula VII by the aldehyde group interacts by the reaction of the Wittig-Horner with dialkylphosphate formula (EtO)2P(=O)(CH2)nR6where n is the number 1, 2 or 3, with the formation of olefinic compounds of the formula Ic. The reaction is carried out analogously to the method described in the literature, for example, in the presence of a strong base, such as n-utility or preferably sodium hydride, in an organic solvent, such as anhydrous who ethers, as, for example, diethyl ether, disutility ether, dioxane, preferably in anhydrous tetrahydrofuran in an atmosphere of inert gas, such as nitrogen or argon, at a reaction temperature from 0 to 80°C, preferably at a temperature of between approximately 5 and 50°C. Optional olefinic compound of the formula Ic can be obtained by using other reactions combination, for example by Wittig reaction.

In the fourth stage of the reaction of olefinic group of the compounds of formula Ic hydronaut into the corresponding compound of formula Id. The reaction is carried out by methods similar to those described in the literature, for example, in a hydrogen atmosphere in the presence of a hydrogenation catalyst in a suitable solvent at a temperature from 0 to 80°C, preferably at a temperature of between approximately 5 and 50°C. the hydrogen Pressure may be between about 0 ATM and about 100 atmospheres, preferably between about 0 MPa and about 50 MPa, and most preferably between about 0 MPa and about 20 MPa. The hydrogenation catalyst used for this reaction may be any of the commonly known catalysts, such as noble metals (e.g. platinum, palladium or rhodium), on the media, such as activated carbon or alumina, or usually described in textbooks of organic chemistry, for example, J. March (1992), "Advanced Organic Cheistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons). Preferred hydrogenation catalysts are palladium on charcoal or Nickel catalyst of the Raney. Suitable solvents for hydrogenation reactions are organic solvents, such as alcohols (e.g. methanol, ethanol, propanol, butanol, octanol or cyclohexanol), ethers (e.g. tetrahydrofuran, diethyl ether, disutility ether or dioxane), ketones (e.g. acetone, butanone or cyclohexanone), polar aprotic solvents, such as dimethyl sulfoxide (DMSO) or N,N-dimethylacetamide, esters (e.g. ethyl acetate), halogenated hydrocarbons (e.g. dichloromethane or trichloromethane), hydrocarbons (e.g. cyclohexane, methylcyclohexane, decalin, benzene, toluene, o-xylene, m-xylene or p-xylene or mixtures of the mentioned solvents. Preferred solvents are esters, the preferred solvent is ethyl acetate.

At the fifth stage, the reaction of pyrazole of the formula VII is subjected to derivatization with Grignard reagent R5MgHal formula XV, where R5means aryl or heterocyclyl as defined for compounds of formula I, and Hal means chlorine, bromine or iodine, preferably chlorine (commercially available or synthesized according to the textbooks on organic is chemistry, for example, J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons), to obtain the corresponding oxymethylene pyrazole derivative of the formula Ia. The derivatization reaction is usually carried out in an inert solvent, for example in ethers, such as tetrahydrofuran, diethyl ether, disutility ether, dioxane, diglyme or mixtures of the abovementioned solvents, preferably in tetrahydrofuran, at a temperature between about -10 and 60°C, preferably at a temperature between about 0 and 40°S, more preferably at room temperature. Usually the derivatization reaction can be also carried out as described in textbooks of organic chemistry, for example in the textbook by J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons. Instead of a Grignard reagent R5MgHal formula XV can also be applied reagent of the formula LiR5.

In the sixth stage of the reaction, the recovery is carried out as described in reaction scheme 1 (stage 5), or may also be carried out in the presence of P2I4as described in the European patent EP 0627423.

For the synthesis of compounds of formula I, where R1, R2, R3and X are as in claim 1, and a represents CH2-(aryl-/C1-C4/alkoxy) or CH2-(heterocyclyl-/C1-C4/alkoxy), the compounds of formula VII PR who rotate through the recovery and subsequent esterification reaction into the corresponding compounds of formula I, where R1, R2, R3and X are as in claim 1, and a represents CH2-(aryl-/C1-C4/alkoxy) or CH2-(heterocyclyl-/C1-C4/alkoxy). Both reactions known from textbooks on organic chemistry e.g. from a textbook J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons. For example, the compounds of formula VII first restore using a suitable reducing agent (e.g. sodium borohydride in an alcohol solvent, such as methanol) in the corresponding derived alcohol and then subjected to reaction with aryl-(C1-C4)alkylhalogenide or heterocyclyl-(C1-C4)alkylhalogenide in basic conditions (e.g. sodium hydride in a polar aprotic solvent, such as dimethylformamide) to obtain the corresponding compounds of formula I, where R1, R2, R3and X are as in claim 1, and a represents CH2-(aryl-/C1-C4/alkoxy) or CH2-(heterocyclyl-/C1-C4/alkoxy).

The above reaction is described in more detail in the stages 7-9.

At the seventh stage of the reaction, the aldehyde of formula VII restored in the presence of a reducing agent to obtain the corresponding oxymethylene derivative of formula XVI. Regenerating means, usually use the mi for this reaction, preferred are sodium borohydride or other reducing agents, such as lithium borohydride, triacetoxyborohydride sodium, hydrogen along with catalyst, or restoring means, known in the field and applied according to known methods described in textbooks of organic chemistry, for example, in J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons. The reduction is usually carried out in an organic solvent such as an alcohol solvent, such as methanol, ethanol, propanol, butanol, octanol or cyclohexanol, preferably in methanol or ethanol, or ethers, such as tetrahydrofuran, diethyl ether, disutility ether, dioxane or diglyme, preferably in tetrahydrofuran, or mixtures of the mentioned solvents, such as methanol and tetrahydrofuran or ethanol and tetrahydrofuran. The reaction is carried out at a temperature between about -10 and 60°C, preferably at room temperature. The reduction can also be carried out as described in textbooks of organic chemistry, for example, in J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons.

At the eighth stage of the reaction oxymethylene group of compounds of formula XVI is converted into the corresponding bromatology group and get promoterdriven the second formula XVII, this is carried out in accordance with standard techniques according to methods known from textbooks on organic chemistry e.g. from a textbook J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons. Possible way to obtain bromo derivatives of formula XVII is the use of tetrabromomethane in the presence of triphenylphosphine in dichloromethane at room temperature.

At the ninth stage of the reaction, the bromide of formula XVII is subjected to reaction with arimethea or heterocyclisation HOCH2R8formula XVIII with in order to obtain the corresponding derivative of pyrazole of the formula IV. The reaction is usually carried out according to methods known from textbooks on organic chemistry e.g. from J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons. The reaction is carried out, for example, in the presence of a base, such as sodium hydride, lithium hydride, potassium carbonate or triethylamine, in a suitable organic solvent, such as tetrahydrofuran (THF), or in polar aprotic solvents such as dimethylsulfoxide (DMSO), N,N-dimethylacetamide or N,N-dimethylformamide (DMF), preferably DMF or THF, at temperatures between about -10 and 60°C, preferably at room temperature.

At the tenth stage of reaction derived oxymethylphenyl formula XVI with vzaimode istii with bromide BrCH 2R8directly transformed into the corresponding pyrazole derivative of the formula IV. The reaction is carried out in accordance with standard techniques according to methods known from textbooks on organic chemistry e.g. from J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons. Possible way to obtain a derivative of pyrazole of the formula Iy is the reaction oxymethylene pyrazole derivative of the formula XVI with arylmethylidene or heterocyclisation formula XIX in the presence of a base. The reaction may preferably be carried out in an organic solvent, such as, for example, polar aprotic solvents like N,N-dimethylacetamide or N,N-dimethylformamide (DMF), dichloromethane or tetrahydrofuran, using bases, such as sodium hydride, lithium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate, or organic amines, such as triethylamine, morpholine or N-alkylboronic, as, for example, N-methylmorpholine, at a temperature between about -10 and 60°C, preferably at room temperature.

On the eleventh stage of the reaction derived oxymethylphenyl formula XVI is converted by the reaction of Mitsunobu into the corresponding compounds of formula Ix. The reaction is known to specialists in this field (D.L. Hughes, Organic Preparations and Procedures International, 1996, 2, 127; Mitsunobu, Synthesis 1981, 1). The reaction is carried out in the presence of trialkyl or triarylphosphine, as, for example, triphenylphosphine, and a reagent of the formula RC(O)N=NC(O)R [R=alkoxy - or dialkylamino], as, for example, diethylazodicarboxylate. The reaction is carried out in a suitable organic solvent, such as dichloromethane, tetrahydrofuran (THF), or in polar aprotic solvents like N,N-dimethylacetamide or N,N-dimethylformamide (DMF), preferably DMF or THF, at temperatures between about -10 and 60°C, preferably at room temperature.

The compounds of formula Ix, where U means S, synthesize, based on bromatologia intermediate compounds XVII, applying the alkylation reaction using mercaptotetrazole (togetherall formula Het-SH). This reaction is carried out according to standard methods in accordance with the methods known from textbooks on organic chemistry e.g. from J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons. The reaction is preferably carried out in an organic solvent, such as, for example, polar aprotic solvents, such as N,N-dimethylacetamide or N,N-dimethylformamide (DMF), dichloromethane or tetrahydrofuran, using a base, such as sodium hydride, lithium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate or organically the amines, as, for example, triethylamine, morpholine or N-alkylboronic, as, for example, N-methylmorpholine, when the reaction temperature between about -10 and 60°C, preferably at room temperature.

At the twelfth stage of the reaction the compound of formula VII transformed using the reaction of reductive amination into the corresponding compounds of formula Iw, where R1, R2, R3and X are as in claim 1, and R9means of CH2-(aryl-/C1-C4/alkylamino). The reaction of reductive amination known from textbooks on organic chemistry e.g. from a textbook J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons. For example, the compound of formula VII is reacted with a derivative of arylamine, forming the corresponding derived imine, followed by reduction with, for example, NaBH(OAc)3leads to compounds of formula Iw, where R1, R2, R3and X are as in claim 1, and R9means of CH2-(aryl-/C1-C4/alkylamino). The secondary amine may not necessarily be proaccelerin using (C1-C4)alkylhalogenide in the corresponding (1-C4)alkylated compounds of formula Iw. The alkylation reaction is known from textbooks on organic chemistry e.g. from J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th and the doctor, John Wiley & Sons.

Reaction scheme 3:

where R1, R2, R3and X are such as defined for compounds of formula I, and R5means aryl or heterocyclyl.

In reaction scheme 3, the first reaction stage is carried out in such a way that p-CH3About(C6H4)CH2NHNH2·2HCl (receipt see example 3) is subjected to reaction with compounds of formula VIII to obtain derivatives of pyrazole of the formula IX. The reaction is usually carried out in the presence of a base, for example potassium carbonate, sodium carbonate, magnesium carbonate, calcium carbonate, potassium hydroxide, sodium hydroxide, magnesium hydroxide, calcium hydroxide, trimethylamine, triethylamine, three(n-propyl)amine, three(isopropyl)amine, preferably of trialkylamine, in a suitable solvent, such as halogenated hydrocarbons (e.g. dichloromethane or trichloromethane) or hydrocarbons (e.g. cyclohexane, methylcyclohexane, decalin, benzene, toluene, o-xylene, m-xylene or p-xylene), preferably in the toluene. The reaction is carried out at a temperature from room temperature up to the boiling temperature of the reaction mixture, preferably at a temperature between about 50 and 150°C.

In the second stage of the reaction the compound of formula IX is reacted with R5COCl (which is commercially available or synthesized in with the accordance with the methods, known from textbooks on organic chemistry e.g. from J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons), where R5is the same as defined above, in a suitable solvent, get a pyrazole derivative of the formula X, substituted at the 4th position of Deputy with exography. The reaction is carried out under the same conditions described for reaction scheme 1 (stage 1).

At the third stage reaction carry out the chlorination in position 5 of the compounds of formula X having a hydroxyl group in this position, using glorieuses agent, such as (COCl)2, HCl, PCl5, PCl3, SOCl2or POCl3get derivatives of 5-chloropyrazole formula XI. The reaction can usually be carried out with the use of POCl3at a temperature between about 0°and the boiling temperature of the reaction mixture, preferably between about 5 and 100°C. the Reaction may not be carried out in an atmosphere of inert gas, such as, for example, in an atmosphere of nitrogen or argon in an organic solvent, such as ethers (e.g. tetrahydrofuran, diethyl ether, disutility ether or dioxane), halogenated hydrocarbons (e.g. dichloromethane or trichloromethane), hydrocarbons (e.g. cyclohexane, methylcyclohexane, decalin, benzene, toluene, o-xylene, m-xylene or p-xylene), or see the si mentioned solvents.

In the fourth stage of the reaction the compound of formula XI is subjected to interaction with R2SH or R2HE (both reagents are commercially available or can be synthesized according to methods known from textbooks on organic chemistry e.g. from J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons), where R2is as defined for compounds of formula I, get a pyrazole derivative of the formula XII. The reaction is carried out in a suitable solvent in the presence of a base, such as n-BuLi, sodium hydride, trialkylamine, as, for example, trimethylamine or triethylamine, potassium carbonate, sodium carbonate, magnesium carbonate, calcium carbonate, preferably potassium carbonate. The reaction is carried out in a suitable solvent in the presence of a base, such as sodium hydride, trialkylamine, as, for example, trimethylamine or triethylamine, potassium carbonate, sodium carbonate, magnesium carbonate, calcium carbonate, preferably potassium carbonate. The reaction is usually carried out at a temperature of from 0°C to the boiling temperature of the reaction mixture, preferably at a reaction temperature between room temperature and about 180°C. Suitable solvents for the reaction are tetrahydrofuran or polar aprotic solvents, such as dimethyl sulfoxide (DMSO), dimethylacetamide or N,N-dim is telharmonic (DMF), preferred DMF.

At the fifth stage of the reaction the compound of formula XII is subjected to reaction with triperoxonane acid to remove 4-methoxybenzyloxy group pyrazol derivative and to obtain unsecured pyrazole derivative of the formula XIII. The reaction can also be carried out in mineral acids, such as hydrochloric acid, in a suitable solvent, such as dioxane, diethyl ether, ethyl acetate or methanol. The reaction is conveniently carried out at temperatures from room temperature up to the boiling temperature of the reaction mixture, preferably at temperatures between 40°and about 150°C. the Reaction may not necessarily be carried out in an inert atmosphere, such as, for example, in an atmosphere of nitrogen or argon in an organic solvent, such as alcohols (e.g. methanol, ethanol, propanol, butanol, octanol or cyclohexanol), ethers (e.g. tetrahydrofuran, diethyl ether, disutility ether or dioxane), ketones (e.g. acetone, butanone or cyclohexanone), esters (e.g. ethyl acetate), halogenated hydrocarbons (e.g. dichloromethane or trichloromethane), hydrocarbons (e.g. cyclohexane, methylcyclohexane, decalin, benzene, toluene, o-xylene, m-xylene or p-xylene) or a mixture of the mentioned solvents.

In the sixth stage of the reaction the compound of formula XIII is exposed to usaimage the action with an alkylating agent of formula R 1L, where L is a leaving group, such as chlorine, bromine, iodine, mesilate or toilet, to obtain the N-substituted pyrazole derivative of the formula V. the Reaction is usually carried out in a suitable solvent, in the atmosphere of inert gas, such as, for example, in an atmosphere of nitrogen or argon, in the presence of a strong base, such as sodium hydride or lithium hydride, preferably sodium hydride. The reaction temperature is preferably a temperature from 0°C to the boiling temperature of the reaction mixture, preferably the reaction is carried out at a temperature between 10°and about 150°C. Suitable solvents for the reaction are anhydrous polar aprotic solvents, such as tetrahydrofuran, dimethyl sulfoxide (DMSO), dimethylacetamide or N,N-dimethylformamide (DMF), preferably DMF.

At the seventh stage of the reaction oxoprop the compounds of formula V restore to obtain the corresponding compound with a hydroxyl group of formula Ia. The reaction is carried out under conditions similar to those described for reaction scheme 1 (stage 4).

At the eighth stage oxymethylene group of compounds of formula Ia then restore to the corresponding methylene group and get the connection formula Ib. The reaction is carried out under the same conditions described for reaction scheme 1 (stage 5).

The synthesis of compounds is ormula I, where R1means acyl, (C1-C4)alkylsulfonyl or optionally substituted phenylsulfonyl, R2, R3and X are as defined for compounds of formula I, and R5means aryl or heterocyclyl, preferably carried out in such a way that the compounds of formula XIII is subjected to acylation or sulfonylamino to obtain the corresponding compounds of formula I, where R1means acyl, (C1-C4)alkylsulfonyl or optionally substituted phenylsulfonyl. The reaction of acylation or sulfonylurea known from textbooks on organic chemistry e.g. from J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed., John Wiley & Sons. Further stages of the reaction are carried out in accordance with the reaction described in reaction scheme 3.

As indicated above, the compounds of formula I and their hydrolyzable complex or simple esters or pharmaceutically acceptable salts are inhibitors of the enzyme, reverse transcriptase, human immunodeficiency virus both in vitro and in vivo, and can be applied for disease control or prevention of diseases mediated by the human immunodeficiency virus (HIV).

The activity of compounds of the formula I for the treatment of diseases mediated by the human immunodeficiency virus (HIV), can be demonstrated using the SL is blowing analytical methods.

Method of analysis: analysis of the reverse transcriptase (RT) of HIV-1: the definition of the IC50inhibitor

Analysis of the reverse transcriptase of HIV-1 was performed in 96-cell plates (Millipore filtermat NOB50), using the purified recombinant enzyme and poly(rA)/oligo(dT)16-matrix as a seed crystal in a total volume of 50 µl. Components for analysis were 50 mm Tris/HCl, 50 mm NaCl, 1 mm ethylenediaminetetraacetic acid (edtc), 6 mm MgCl2, 5 μm dTTP, of 0.1 µci [3H] dTTP, 5 μg/ml poly(rA)pre-hybridizing with 2.5 μg/ml oligo(dT)16and inhibitors in this concentration range, so that the final concentration was 10% in DMSO. The reaction was initiated by adding 5 nm reverse transcriptase of HIV-1, and after incubation at 37°C for 30 minutes the reaction was stopped with the addition of 50 µl of chilled to the temperature of the ice 20%trichloroacetic acid (THUK) and left to precipitate at 4°C for 30 minutes. Rainfall tablet was collected using a vacuum and then washed 2×200 ál of 10%of THOK and 2×200 ál of 70%ethanol. Finally, the tablets were dried and counted for radioactivity in a Wallac Microbeta 1450 after addition of 15 μl of scintillation fluid in each cell. The values of the IC50(concentrations causing 50%inhibition) was calculated by curve % inhibition of the decimal logarithm of the concentration of the inhibitor.

Method of analysis of the antiviral activity

Antiviral activity against HIV was determined using adaptation techniques Pauwels, etc. {Pauwels and others, 1988, J. Virol Methods 20:309-321}. The method is based on the ability of compounds to protect HIV-infected T-lymphoblastoid cells (cells MT4) from cell necrosis, oposredovannogo infection. The cutoff point was calculated as the concentration at which cell viability of the culture was maintained at 50% (the concentration that causes 50%inhibition", IC50) Cell viability of the culture was determined using the absorption of soluble bromide 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium (MTT) yellow and recovered in the insoluble salt with formosanum purple. After solubilization used spectrophotometric methods for measuring the amount of formisano product.

The MT4 cells were prepared so that they were in the logarithmic growth phase and to a total of 2×10 cells infected with strain NHV of human immunodeficiency virus at a multiplicity of 0.0001 infectious units of virus per cell was contained in a total volume of 200 to 500 ál. Cells were incubated with virus for one hour at 37°to remove the virus. The cells were then washed in buffered 0.01 M phosphate physiological races of the thief, pH of 7.2, before being re-suspended in culture medium for incubation in culture with serial dilutions of tested compound. Was used culture medium RPMI 1640 without phenol red, supplemented with penicillin, streptomycin, L-glutamine and 10%amniotic calf serum (GM10).

The compounds were prepared as 2 mm solutions in dimethylsulfoxide (DMSO). Then prepare 4 copies of serial 2-fold dilutions in GM10 and quantity of 50 μl were placed in a 96-cell tablets over the final nanomolar limit concentrations 625-1,22. Fifty microlitres GM10 and 3.5×104infected cells were then added to each cell. Also prepared a control culture containing no cells (blind experiment)containing uninfected cells (100% viability; 4 copies) and infected cells without compounds (total necrosis of cell-mediated virus; 4 copies). The culture is then incubated at 37°C for 5 days in the humid air with 5% carbon dioxide.

Preparing a fresh solution of 5 mg/ml MTT in buffered 0.01 M phosphate saline solution, pH of 7.2, was added 20 μl of each culture. The culture is then incubated as previously, within 2 hours. Then mixed them, selecting the eyedropper tool and releasing it, and 170 μl of Triton X-100 in acidified isopropanol (1% vol./about. Triton X-100 in a mixture of 1:250 conc. hydrochloric acid in isopropanol). When formosanus layer was completely solubilization with further mixing, measured the absorbance (OD) of cultures at a wavelength of 540 and 690 nm (read at 690 nm was used as control samples for artifacts between cells). The percentage of protection for each treated culture was then calculated from the equation:

The values of the IC50can be obtained from the graphs of the percentage of protection in terms of the decimal logarithm of the concentration of the medicine.

In both assays the activity of compounds of the formula I, expressed by the value of the IC50, is in the range from about 0.5 to 10000 nm, or from about 0.5 to about 5000 nm, the preferred compounds are characterized by a range of activity from about 0.5 to 750 nm, more preferably from about 0.5 to 300 nm, and most preferably from about 0.5 to 50 nm.

Table 2
StructureRT IC50[nm]HIV IC50[nm]
2060403
3420592
8040453
27024
10536
849
107075
349100
95064
313110
650203
1123,6
57214,6
762,7
29234,1
45613,5
25220
37311,1
17751,7
398124
17611,9
10915
88028
27013,9
29831,5
5200-
1082-
607-
46319
48019
908,1

Derivatives of pyrazole provided the presented invention is useful for therapeutic treatment of the human or animal, they are particularly useful as inhibitors of reverse transcriptase, an enzyme of the human immunodeficiency virus. Accordingly, the production presents adnie of pyrazole are therapeutically active substances for the treatment of diseases, mediated by human immunodeficiency virus (HIV), and can be used as medicines for the treatment of such diseases.

They can be used as drugs primarily for the treatment of viral diseases caused by immune system conditions or diseases, bacterial diseases, parasitic diseases, inflammatory diseases, hyperproliferative vascular diseases, tumors and cancer.

In particular, the compounds of the present invention and containing pharmaceutical compositions are useful as chemotherapeutic agents, inhibitors of viral replication and modulators of the immune system and can be applied for the treatment of diseases caused by human immunodeficiency virus (HIV), other viral diseases, such as, for example, retroviral infection or when they are alone, or in combination with other antiviral agents, such as interferon or its derivatives, such as, for example, conjugates with polyethylene glycol).

These compounds can be used alone or in combination with other therapeutically active means such as immunosuppressant, a chemotherapeutic agent, an antiviral agent, antibiotic, antiparasitic agent, anti-inflammatory drugs is m, with fungicide and/or remedy against hyperproliferative vessels.

Compounds according to the invention can be used as medicines, for example in the form of pharmaceutical preparations which contain them or their salts in a mixture with a pharmaceutical organic or inorganic carrier, which is suitable for parenteral administration or administration into the small intestine, as, for example, water, gelatin, Arabic gum, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, etc. Pharmaceutical preparations can be provided in solid form, for example in the form of tablets, pills, suppositories, capsules, or in liquid form, for example in the form of solutions, suspensions or emulsions. They may be sterilized and/or may contain adjuvants, such as preservatives, stabilizers, wetting or emulsifying means, salts for modifying the osmotic pressure, painkillers or buffers. The compounds of formula I and their salts are preferably provided for oral administration and for this purpose one of them prepare the finished dosage form.

The amount of the compounds of formula I, required for the treatment of viral diseases, especially diseases caused by human immunodeficiency virus (HIV), or other in which diseases originate, depends on a number of factors, including the severity of the disease and authenticity, gender and weight of the recipient, and is entirely at the discretion of the attending physician. In General, however, a suitable effective dose is in the range from 0.1 to 100 mg per kilogram of body weight of the recipient per day, preferably in the range from 0.5 to 50 mg per kilogram of body weight per day and most preferably in the range from 1.0 to 30 mg per kilogram of body weight per day. The optimum dose is about 5 to 25 mg per kilogram of body weight per day. The desired dose is preferably presented as one, two, three, four, five, six or more subds entered at intervals during the day, preferably it is one, two, three, four or five subdot and most preferably one, two or three curiosi. These subdata can be introduced in the form of dosage forms with standard doses, for example, containing from 1 to 1500 mg, preferably from 100 to 1400 mg, most preferably from 400 to 1000 mg of active ingredient in the dosage form with the standard dose.

The dosage of the compounds of General formula I and their pharmaceutically compatible salts with bases can vary within wide limits and in each case, of course, selected in accordance with the individual requirements and the causative agent of the disease, which Presto the fight.

As mentioned previously, the medicinal product containing the compound of General formula I or its pharmaceutically compatible salt, are also the object of the present invention, in addition, also the method of obtaining such drugs, which is characterized by the fact that combine one or more compounds of General formula I or their pharmaceutically compatible salts and, if desired, one or more other therapeutically valuable substances in herbal form for injection.

Preferably the compound of formula I in a pharmaceutical form. Finished dosage forms of the present invention include at least one active ingredient of the formula I together with one or more pharmaceutically acceptable excipients, and optionally one or more other therapeutic agents. Finished dosage forms for oral administration can be capsules, starch wafers or tablets, each of which contains a given number of active(s) ingredient(s), such forms can be obtained by any method well known in pharmacy. As the active ingredient(s), forms for oral administration may contain a binder (e.g. povidone, gelatin, hypromellose), a lubricating substance, an inert solvent is, the preservative substance conducive to grinding (for example, starch glycolate, sodium, povidone cross-stitching, sodium carboxymethyl cellulose cross-linking), or dispersing agent. Finished dosage forms for oral administration may also include tabularasa means to neutralize acidity in the stomach.

Used in the following examples, the abbreviations have the following meanings:

MSmass spectroscopy (MS)
ESelektrorazpredelenie
EIe-shock
NMRspectroscopy nuclear magnetic resonance (NMR)
DMFN,N-dimethylformamide (DMF)
DMSOdimethyl sulfoxide (DMSO)
rtroom temperature
minminute(s)
hhour(s)

All temperatures are given in degrees Celsius (°).

Described NMR spectra were recorded on a spectrometer Bruker DRX 400 MHz at a temperature of 300 K.

Mass spectra indicated by "(M+; EI)", starred in the conditions of electron impact ionization (EI) on the device THERMOQUEST MAT95 S at the temperature of the ion source 200°C. Other mass spectra were taken the ü when ionization elektrorazpredelenie (ESI) for one of the following devices:

a) THERMOQUEST SSQ 7000 [solvent of 0.085% triperoxonane acid (TFA) to 90% acetonitrile/water; flow rate 100 microlitres min; capillary 250°C; voltage spray 5 kV; gas layer 5,625 kg/cm2] or

b) liquid chromatography-mass spectrometry (LC-MS (liquid chromatograph connected to a mass spectrometer) THERMOQUEST TSQ 7000 ELECTROSPRAY or MICROMASS PLATFORM ELECTROSPRAY [solvent a 0.1% TFA in water, or of 0.085% TFA in 90% acetonitrile/water or of 0.085% TFA in acetonitrile].

Connection, whenever they get the methods of the present invention, are also the object of the present invention.

The following examples illustrate the present invention:

Example 1

4-Benzyl-5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole

A solution containing 80 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-yl]phenylmethanol and 64 μl of triethylsilane in 2 ml triperoxonane acid, was stirred 15 h at room temperature. The mixture was concentrated, diluted with 10 ml saturated sodium bicarbonate solution and was extracted twice with 10 ml dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified using flash chromatography on silica gel by elution ethyl acetate/petroleum spirit 40-60°C (1:10), received 60 mg of 4-benzyl-5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole in the ideal colorless resin. MS (EI) m/z 424 [M]+.1H-NMR (DMSO-d6): of 2.26 (s, 3H), 3,88 (s, 2H), 6,77 (d, 2H), 7,13 (m, 3H), 7,20 (m, 2H), 7,32 (t, 1H), 7,35-of 7.48 (m, 5H).

Starting material [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-yl]phenylmethanol was prepared as follows.

(A) a Solution containing 2.0 g of 4-benzoyl-3-methyl-1-phenyl-2-pyrazolin-5-it (commercially available, for example, from the firm Aldrich 15,660-4) in 4 ml of phosphorus oxychloride was stirred in nitrogen atmosphere at 100°C for 30 minutes. The mixture was poured into 40 ml of saturated sodium bicarbonate solution and was extracted three times with 30 ml of dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and evaporated, received 2.0 g (5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-yl)phenylmethanone in the form of a yellow oil which was used without further purification.

(B) a Solution containing 2.0 g (5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-yl)phenylmethanone, 2.0 g of 3, 5-dichlorothiophene and 1.7 g of potassium carbonate in 50 ml of N,N-dimethylformamide, was stirred at 60°C for 19 hours. The mixture was distributed between 100 ml of water and 100 ml dichloromethane. The organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified using flash chromatography on silica gel using methanol/dichloromethane for the elution, was obtained 2.2 g of [5-(3,5-dichlorobenzenesulfonyl)-3-methyl-1-phenyl-1H-pyrazole-4-yl]phenylmethanone in the form of a yellow oil. Mass spec is p (ES) m/z 439 [M+H] +, 480 [M+H+CH3CN]+.

(C) a Solution of 100 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-yl]phenylmethanone and 23 mg of sodium borohydride in 5 ml of methanol was stirred 17 hours at room temperature. The mixture was diluted with 4 ml water and was extracted 4 times with diethyl ether. The combined extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified using flash chromatography on silica gel by elution ethyl acetate/petroleum spirit 40-60°received 84 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-yl]phenylmethanol in the form of a colourless resin. Mass spectrum (EI) m/z 440 [M]+.

Examples 2-11

Compounds shown in table 3, obtained by the method similar to that described in example 1.

Table 3
When-MerStructureNameMS (ES) (M+N)+
2[5-(3,5-Dichlorophenylthio)-3-(methoxymethyl)-1-methyl-1H-pyrazole-4-yl]phenylmethanol408 (M+; EI)
35-(3,5-Dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-yl]phenylmethanol440 (M+; EI)
4 [5-(3,5-Dichlorophenylthio)-1-ethyl-3-(methoxymethyl)-1H-pyrazole-4-yl]phenylmethanol422 (M+; EI)
54-Benzyl-5-(3,5-dichlorophenylthio)-1-ethyl-3-(methoxymethyl)-1H-pyrazole406 (M+; EI)
64-Benzyl-5-(3,5-dichlorophenylthio)-3-methoxymethyl-1-methyl-1H-pyrazole322 (M+; EI)
7[5-(3,5-Dichlorophenylthio)-3-methyl-1H-pyrazole-4-yl]phenylmethanol455
81,4-Dibenzyl-5-(3,5-dichlorophenylthio)-3-methyl-1H-pyrazole439
94-[5-(3,5-Dichlorophenylthio)-3-methyl-1-phenyl-4-[(4-pyridyl)methyl]-1H-pyrazole426
104-Benzyl-5-(3,5-dichlorophenylthio)-1-ethyl-3-methyl-1H-pyrazole376 (M+; EI)
114-[5-(3,5-Dichlorophenylthio)-1-ethyl-3-methyl-[(4-pyridyl)methyl]-1H-pyrazole377 (M+; EI)

Example 12

5-(3,5-Dichlorophenylthio)-3-methyl-4-(2-phenylethyl)-1-phenyl-1H-piraso the

The suspension containing 95 mg of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-4-styryl-1H-pyrazole and 75 mg of 10% palladium on charcoal in 10 ml of ethyl acetate was stirred in hydrogen atmosphere (1 ATM) at room temperature for 40 hours. The suspension was filtered through celite®and the filtrate was evaporated, received 89 mg of 5-(3,5-dichlorophenylthio)-3-methyl-4-(2-phenylethyl)-1-phenyl-1H-pyrazole as a colourless resin. Mass spectrum (EI) m/z 438 [M]+.1H-NMR (DMSO-d6): and 2.14 (s, 3H), 2,68 (t, 2H), 2,77 (t, 2H), 6,85 (d, 2H), 7, 09 (d, 2H), 7,16 (t, 1H), 7,24 (t, 2H), 7,33-of 7.48 (m, 6H).

The original substance is 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-4-styryl-1H-pyrazole - received, as described below.

(A) a Solution containing 1.0 g of 5-methyl-2-phenyl-2H-pyrazole-3-ol (commercially available, for example, from the firm Aldrich M7,080-0) and 2.1 ml of phosphorus oxychloride in 10 ml of anhydrous N,N-dimethylformamide, was stirred under nitrogen at 100°C for 4 hours. The mixture was poured into 70 ml of saturated sodium bicarbonate solution and was extracted three times with 60 ml of dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel by elution of dichloromethane/methanol, received 177 mg of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde in the form of needle crystals of yellow color.

(B) a Solution containing 175 mg of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-is carbaldehyde, 142 mg of 3,5-dichlorothiophene and 132 mg of potassium carbonate in 5 ml of anhydrous N,N-dimethylformamide, was stirred in nitrogen atmosphere for 2 hours at 60°C. the Mixture was diluted with 10 ml water and was extracted three times with 8 ml of dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified using flash chromatography on silica gel by elution dichloromethane, received 164 mg of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde in the form of a yellow oil. Mass spectrum (EI) m/z 362 [M]+.

(B) a Solution containing 164 mg of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde, 103 mg determenirovana and 27 mg of sodium hydride (60% in mineral oil) in 5 ml of anhydrous tetrahydrofuran was stirred under nitrogen atmosphere for 16 hours at room temperature. The solvent is evaporated and the residue was purified using flash chromatography on silica gel by elution ethyl acetate/petroleum spirit 40-60°C (1:10), received 162 mg of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-4-styryl-1H-pyrazole in the form of a solid pale yellow color. Mass spectrum (EI) m/z 436 [M]+.

Examples 13-17

Compounds in table 4 were obtained by the method similar to that described in example 12.

Table 4
When-Mer StructureNameMS (ES) (M+N)+
135-(3-Chlorophenylthio)-3-methoxymethyl-1-methyl-4-styryl-1H-pyrazole371
14(E)-5-(3,5-Dichlorophenylthio)-3-(methoxymethyl)-1-phenyl-4-styryl-1H-pyrazole467
155-(3,5-Dichlorophenylthio)-3-methyl-1-phenyl-4-styryl-1H-pyrazole436 (M+: El)
165-(3,5-Dichlorophenylthio)-3-(methoxymethyl)-1-phenyl-4-(2-phenylethyl)-1H-pyrazole469
175-(3,5-Dichlorophenylthio)-1-ethyl-3-methyl-4-(2-phenylethyl)-1H-pyrazole390 (M+; El)

Example 18

4-Benzyl-5-(3,5-dichlorophenylthio)-1-isopropyl-3-methyl-1H-pyrazole

A solution containing 30 mg of [5-(3,5-dichlorophenylthio)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]phenylmethanol in 1 ml triperoxonane acid, was treated with 14 ál of triethylsilane. The mixture was stirred at room temperature for 15 minutes. The solvent is evaporated in vacuum and then the residue was distributed between diethyl ether/saturated sodium bicarbonate solution and three times extra is Aravali. The combined extracts were washed with brine, then dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified using flash chromatography on silica gel by elution diethyl ether/hexane (1:7), received 15 mg of a colorless resin. Mass spectrum (ES) m/z 391 [M+H]+.1H-NMR (DMSO-d6): of 1.27 (d, 6H), of 2.20 (s, 3H), 3,79 (s, 2H), 4,67 (m, 1H), PC 6.82 (d, 2H), 7,05 (d, 2H), to 7.09 (t, 1H), 7,17 (t, 2H), 7,38 (t, 1H).

Starting material [5-(3,5-dichlorophenylthio)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]phenylmethanol received, as described below.

(A) a Solution containing 7.9 ml of hydrazine hydrate is added in 80 ml of ethanol was treated with 3.7 ml of 4-methoxybenzylamine and heated for 2.0 hours at 90°C. the Solvent is evaporated in vacuum and then the resulting residue was dissolved in 30 ml of ethanol. The solution was acidified with 30 ml of 5 N. hydrochloric acid at 0°and fell precipitate white. Solid white color was filtered and dried, received a 2.75 g of the dihydrochloride (4-methoxybenzyl)hydrazine (PMBNHNH2·2HCl), which was used without further purification.

(B) a Solution containing a 2.75 g of the dihydrochloride (4-methoxybenzyl)of hydrazine in 50 ml of toluene was treated with 1.7 ml of triethylamine at room temperature and then stirred for 5 minutes. The mixture is then processed to 1.32 ml of methyl ester of acetoacetic acid and heated at 100°within 15 m of the nut. The solvent is evaporated in vacuum and then the residue was distributed between dichloromethane/10%citric acid, and was extracted three times. The combined extracts were washed with brine, then dried over anhydrous magnesium sulfate, filtered and evaporated, received a solid yellow color. The solid was purified using flash chromatography on silica gel by elution of methanol/dichloromethane (1:49), was obtained 2.3 g of 2-(4-methoxybenzyl)-5-methyl-2H-pyrazole-3-ol in the form of a solid white color. Mass spectrum (ES) m/z 219 [M+H]+.

(B) a Solution containing 1.0 g of 2-(4-methoxybenzyl)-5-methyl-2H-pyrazole-3-ol in 30 ml of dioxane, treated 679 mg of calcium hydroxide and 800 μl of benzoyl chloride, and then heated for 2 hours at 110°C. To the mixture was added 20 drops of water and the mixture was heated for another 2 hours. The solvent is evaporated in vacuum and the residue was distributed between dichloromethane/10%citric acid. The organic phase was washed with brine, then dried over anhydrous magnesium sulfate, filtered and evaporated to obtain a yellow oil. The oil was twice purified using flash chromatography on silica gel, using first for elution of methanol/dichloromethane (1:49), were solid red, then suirable with ethyl acetate/hexane (from 1:1 to 2:1) and received 400 mg of [5-hydroxy-1-(4-methoxybenzo the l)-3-methyl-1H-pyrazole-4-yl]phenylmethanone in the form of a yellow resin. Mass spectrum (ES) m/z 323 [M+H]+.

(G) a Solution containing 400 mg of [5-hydroxy-1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-yl]phenylmethanone in 5 ml of phosphorus oxychloride was heated for 30 minutes at 40°C. the Mixture was poured into cooled to the temperature of ice saturated sodium bicarbonate solution and was extracted three times with dichloromethane. The combined extracts were washed with brine, then dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified using flash chromatography on silica gel using diethyl ether/hexane (1:3) for the elution, were obtained 170 mg of [5-chloro-1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-yl]phenylmethanone in the form of a yellow resin. Mass spectrum (ES) m/z 341 [M+H]+.

(D) a Solution containing 170 mg of [5-chloro-1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-yl]phenylmethanone in 10 ml of N,N-dimethylformamide, and treated with 83 mg of potassium carbonate and 107 mg of 3,5-Dichlorotoluene. The mixture was heated 4 hours at 100°C. the Mixture was treated with another 83 mg of potassium carbonate and 107 mg of 3,5-Dichlorotoluene. The mixture then was heated at 50°C for 64 hours. The mixture then was treated with 83 mg of potassium carbonate and 107 mg of 3,5-Dichlorotoluene. Then the mixture was heated 2 hours at 100°C. the Solvent was removed in vacuum and the residue was distributed between dichloromethane/ water, washed with brine, then dried over anhydrous magnesium sulfate, filter the if and evaporated. The residue was purified using flash chromatography on silica gel using diethyl ether/petroleum ether (from 1:4 to 1:3), received 140 mg of [5-(3,5-dichlorophenylthio)-1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-yl]phenylmethanone in the form of a colorless oil. Mass spectrum (ES) m/z 483 [M+H]+.

(E) was Treated with 140 mg of [5-(3,5-dichlorophenylthio)-1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-yl]phenylmethanone 4 ml triperoxonane acid. The solution is then boiled under reflux for 2 hours. The solvent is evaporated in vacuum. The remainder is then distributed between dichloromethane/saturated sodium bicarbonate solution, washed with brine, then dried over anhydrous magnesium sulfate, filtered and evaporated, received 75 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1H-pyrazole-4-yl]phenylmethanone in a solid yellow color, which was used without further purification. Mass spectrum (ES) m/z 363 [M+H]+.

(G) a Solution containing 75 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1H-pyrazole-4-yl]phenylmethanone in 2 ml of anhydrous N,N-dimethylformamide (DMF)was treated at room temperature in a nitrogen atmosphere to 12 mg of sodium hydride. The mixture was then stirred for 2 minutes. To the mixture was added 25 μl of 2-iodopropane. The mixture was then stirred for 20 minutes. To the mixture was added 2 ml of water and then the mixture was extracted three times with ethyl acetate. The combined extracts were washed salt-Rast is a PR, then was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified using flash chromatography on silica gel by elution diethyl ether/hexane (1:7), received 32 mg of [5-(3,5-dichlorophenylthio)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]phenylmethanone in the form of a colorless oil. Mass spectrum (ES) m/z 405 [M+H]+.

(C) a Solution containing 32 mg of [5-(3,5-dichlorophenylthio)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]phenylmethanone in 2 ml of methanol was treated with 6 mg of sodium borohydride at room temperature in a nitrogen atmosphere. The mixture was then stirred at room temperature overnight. To the mixture was added 2 ml of water and then was extracted three times with diethyl ether. The combined extracts were washed with brine, then dried over anhydrous magnesium sulfate, filtered and evaporated, received 30 mg of [5-(3,5-dichlorophenylthio)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]phenylmethanol in a solid white color, which was used without further purification. Mass spectrum (ES) m/z 407 [M+H]+.

Examples 19-22

Compounds in table 5 were obtained by the method similar to that described in example 18.

Table 5
When-MerStructureNameMS (ES) (M+N)+
194-Benzyl-1-sec-butyl-5-(3,5-dichlorophenylthio)-3-methyl-1H-pyrazole405
204-Benzyl-1-cyclopentyl-5-(3,5-dichlorophenylthio)-3-methyl-1H-pyrazole417
214-Benzyl-1-cyclohexyl-5-(3,5-dichlorophenylthio)-3-methyl-1H-pyrazole431
224-Benzyl-5-(3,5-dichlorophenylthio)-1-isobutyl-3-methyl-1H-pyrazole405

Example 23

4-Benzyl-1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazole

A solution containing 54 mg of [1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazole-4-yl]phenylmethanol and 28 μl of triethylsilane in 2 ml triperoxonane acid, was stirred 22 hours at room temperature. The mixture was concentrated and added a saturated solution of sodium bicarbonate (6 ml). The mixture was extracted three times with 8 ml of dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified using flash chromatography on silica gel by elution ethyl acetate/petroleum ether (TKip40-60° (C) (1:4), was obtained 33 mg of 4-benzyl-1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazole in the form of a yellow oil. Mass when ECTR (ES) m/z 323 [M+H] +, 364 [M+H+CH3CN]+.1H-NMR (DMSO-d6): to 1.19 (t, 3H), of 2.20 (s, 3H), 3.46 in (s, 2H), 3,70 (s, 3H), 3,80 (q, 2H), PC 6.82-6.89 in (m, 4H), 7,01 (d, 2H), 7,12 (t, 1H), 7,20 (t, 2H).

The original substance [1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazole-4-yl]phenylmethanol was prepared as follows.

(A) a Suspension of 3.9 g of ethyl ester of hydrazine and 3.6 ml of triethylamine in 80 ml of toluene was stirred at room temperature for 15 minutes. Was added to 2.8 ml of methyl ester of acetoacetic acid and the mixture is brought up to the azeotropic composition for 1.5 hours. The mixture was evaporated and the residue was purified using flash chromatography on silica gel by elution of dichloromethane/methanol (97:3), was obtained 3.1 g of 2-ethyl-5-methyl-2H-pyrazole-3-ol in the form of a solid orange color.

(B) a Suspension of 1.4 g of 2-ethyl-5-methyl-2H-pyrazole-3-ol, 1.6 g of calcium hydroxide and 1.3 ml of benzoyl chloride in 70 ml of 1,4-dioxane was stirred at 110°C for 3.5 hours. Was added 1 ml of water and the mixture was stirred at 110°C for 2 hours. Was added 25 ml of 2 N. hydrochloric acid. The mixture was stirred at room temperature for 16 hours, and three times was extracted with 60 ml ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and evaporated, was obtained 3.1 g (1-ethyl-5-hydroxy-3-methyl-1H-pyrazole-4-yl)phenylmethanone in the form of a yellow oil which was used without additional clear what I. Mass spectrum (ES) m/z 231 [M+H]+, 272 [M+H+CH3CN]+.

(C) a Solution of 2.6 g (1-ethyl-5-hydroxy-3-methyl-1H-pyrazole-4-yl)phenylmethanone in 4 ml of phosphorus oxychloride was stirred at 80°C for 1.5 hours. The mixture was poured into 300 ml of saturated sodium bicarbonate solution and was extracted three times with 70 ml of dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified using flash chromatography on silica gel by elution ethyl acetate/petroleum ether (TKip40-60° (C) (1:4), received 1,74 g (5-chloro-1-ethyl-3-methyl-1H-pyrazole-4-yl)phenylmethanone liquid pale yellow color. Mass spectrum (ES) m/z 249 [M+H]+, 290 [M+H+CH3CN]+.

(G) a Mixture of 129 mg (5-chloro-1-ethyl-3-methyl-1H-pyrazole-4-yl)phenylmethanone, 141 mg of 4-methoxyphenol and 33 mg of sodium hydride (60% in mineral oil) in 3 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen atmosphere at 110°C for 5 hours. Was added water (8 ml) and the mixture was extracted three times with 10 ml dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified using flash chromatography on silica gel by elution ethyl acetate/petroleum ether (TKip40-60° (C) (1:3), received 100 mg of [1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazole-4-yl]phenylmethanone in the form of a yellow oil. Mac the spectrum (ES) m/z 337 [M] +, 378 [M+H+CH3CN]+.

(D) a Solution of 77 mg of [1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazole-4-yl]phenylmethanone and 119 mg of sodium borohydride in 5 ml of methanol was stirred at room temperature for 24 hours. Was added 20 ml of water and the mixture was extracted three times with 15 ml of diethyl ether. The combined extracts were dried over magnesium sulfate, filtered and evaporated, received 54 mg of [1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazole-4-yl]phenylmethanol in the form of a colorless gum, which was used without further purification. Mass spectrum (ES) m/z 339 [M+H]+. 380 [M+H+CH3CN]+.

Example 24

4-Benzoyloxymethyl-5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole

A solution containing 115 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-yl]methanol, 54 mg of benzyl bromide and 38 mg of sodium hydride (60% in mineral oil) in 3 ml of anhydrous N,N-dimethylformamide, was stirred in nitrogen atmosphere at 100°C for 2 hours. Was added 10 ml of water and the mixture was extracted three times with 8 ml of dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and evaporated. The residue was twice purified using flash chromatography on silica gel by elution ethyl acetate/petroleum ether (TKip40-60° (C) (1:4), and then dichloromethane was received 35 mg 4-benzoyloxymethyl-5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-lH-pyrazole as a colourless resin Mass spectrum (ES) m/z 455 [M+H] +, 496 [M+H+CH3CN]+.1H-NMR (DMSO-d6): a 2.36 (s, 3H), 4,47(s, 2H), 4,49 (s, 2H), of 6.96 (d, 2H), 7.24 to 7,47 (m, 11H).

Starting material [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-yl]methanol was prepared as follows.

A mixture of 1.35 g of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-carboxaldehyde and 0.84 g of sodium borohydride in 10 ml of methanol was stirred at room temperature for 30 minutes. Was added water (10 ml) and the mixture was extracted four times with 15 ml of diethyl ether. The combined extracts were dried over magnesium sulfate, filtered and evaporated, got 670 mg of [5-(3,5-dichlorobenzenesulfonyl)-3-methyl-1-phenyl-1H-pyrazole-4-yl]methanol in the form of paste is gray, which was used without further purification. Mass spectrum (ES) m/z 365 [M+H]+, 406 [M+H+CH3CN]+.

Example 25

2-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylethoxy]pyridine

To a solution of 75 mg of [5-(3,5-dichlorophenyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]methanol in 8 ml of tetrahydrofuran was added 24 mg of 3-hydroxypyridine, 71 mg of triphenylphosphine and 43 μl of diethylazodicarboxylate. The reaction mixture was stirred at room temperature for 3 hours. Additionally, there was added 24 mg of 3-hydroxypyridine, 71 mg of triphenylphosphine and 43 μl of diethylazodicarboxylate and the reaction mixture was stirred over night at room temperature. The solvent is evaporated the residue was distributed between dichloromethane and water. The aqueous phase was extracted three times with 10 ml dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified twice using flash chromatography on silica gel by elution diethyl ether/hexane (1:2 then 2:1), received 100 mg of 2-[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylethoxy] pyridine in the form of a yellow resin. Mass spectrum (ES) m/z 408 [M+H]+.

Starting material [5-(3,5-dichlorophenyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]methanol was prepared as follows.

(A) a Mixture of 1.27 g of 5-hydroxy-1-isopropyl-3-methyl-1H-pyrazole, 3,4 ml of phosphorus oxychloride and 5.2 ml of dimethylformamide was heated at 100°C in nitrogen atmosphere for 1 hour. Then the reaction mixture was allowed to cool to room temperature and then distributed among 20 ml saturated sodium bicarbonate solution and 20 ml of dichloromethane. The aqueous phase was twice extracted with 20 ml dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and evaporated. The yellow residue was purified using flash chromatography on silica gel by elution of ethyl acetate/diethyl ether (1:5, then 1:4), received 213 mg (5-chloro-1-isopropyl-3-methyl-1H-pyrazole-4-yl)carbaldehyde in the form of a solid white color. Mass spectrum (ES) m/z 228 [M+H+MeCN]+.

(B) To a solution of 213 mg (5-chloro-1-isopropyl-3-METI what-1H-pyrazole-4-yl)carbaldehyde in 3 ml of N,N-dimethylformamide was added 245 mg of 3,5-dichlorothiophene and 190 mg of potassium carbonate. The reaction mixture was heated 2 hours at 60°With, then was added 125 mg of 3,5-dichlorothiophene and 95 mg of potassium carbonate. The mixture was heated at 60°With a further 1 hour, then cooled to room temperature over night. The solvent is evaporated and the residue was distributed between 20 ml dichloromethane and 20 ml of water. The aqueous phase was extracted twice with 10 ml dichloromethane and the combined extracts were washed with brine, dried, filtered and evaporated, received a yellow oil, which was purified using flash chromatography on silica gel by elution diethyl ether/hexane (1:7, then 1:5), received 317 mg of [5-(3,5-dichlorophenyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]carbaldehyde in the form of a solid white color. Mass spectrum (ES) m/z 329 [M+H]+.

(C) To a solution of 1.07 g of [5-(3,5-dichlorophenyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]carbaldehyde in 30 ml of methanol at room temperature was added in portions 740 mg sodium borohydride. The reaction mixture was stirred at room temperature for 5 hours, then mixed with 5 ml of water. The aqueous phase was extracted three times with 10 ml ethyl acetate and the combined extracts were washed with brine, dried, filtered and evaporated, received [5-(3,5-dichlorophenyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]methanol as a colourless oil. Mass spectrum (ES) m/z 331 [M+H]+.

Example 26

1-[5-(3,5-Dichlorphenol panel)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-1H-pyridine-2-he

To a solution of 119 mg of [5-(3,5-dichlorophenyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]methanol in 5 ml of dichloromethane was added 43 mg of 2-hydroxypyridine, 113 μl of tributylphosphine and 78 mg TMAD. The reaction mixture was stirred at room temperature for 2 hours, then the solvent evaporated. The residue was purified using flash chromatography on silica gel by elution diethyl ether/petrol (1:5 to 3:1), received 317 mg 1-[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-1H-pyridine-2-it is in the form of a colourless resin. Mass spectrum (ES) m/z 329 [M+H]+.

Example 27

4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ileocecal]pyridine

To a solution of 100 mg of [5-(3,5-dichlorophenyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]methanol in 3 ml of N,N-dimethylformamide was added 24 mg of sodium hydride (60%dispersion in oil). The mixture was stirred 5 minutes, then was added 96 mg hydrobromide 4-pommerellen. The reaction mixture was stirred at room temperature for 1 hour, then mixed with 5 ml of water. The aqueous phase was extracted three times with 10 ml dichloromethane and the combined extracts were washed with brine, dried, filtered and evaporated, received oil red, which was purified using flash chromatography on silica gel by elution ethyl acetate/hexane (1:2, then 1:1)were 62 mg of 4-[5-(3,5-dichlorphenol the Anil)-1-isopropyl-3-methyl-1H-pyrazole-4-ileocecal]pyridine as a colourless resin. Mass spectrum (ES) m/z 422 [M+H]+, 463 [M+H+MeCN]+.

Example 28

4-[[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]hydroxymethyl]pyridine

Processed 593 mg hydrobromide 4-bromopyridine 15 ml of 5%aqueous sodium bicarbonate solution and was extracted three times with 20 ml diethyl ether, the combined extracts were washed with brine, dried, filtered and evaporated, received a colorless oil, which was dissolved in 3 ml of tetrahydrofuran. To this solution under nitrogen atmosphere at room temperature was added of 1.52 ml of 3.0 M solution of isopropylacrylamide in diethyl ether. The reaction mixture was stirred at room temperature for 1.5 hours, then was added a solution of 1.0 g of [5-(3,5-dichlorophenyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]carbaldehyde in 10 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature overnight, then added 20 ml of water. The aqueous phase was extracted three times with 10 ml dichloromethane and the combined extracts were washed with brine, dried, filtered and evaporated, received a yellow oil, which was purified using flash chromatography on silica gel by elution ethyl acetate/hexane (1:2 then 2:1), received 835 mg of 4-[[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]hydroxymethyl]pyridine as a colourless resin. Mass spectrum (ES) mz 408 [M+H] +, 449 [M+H+MeCN]+.

Example 29

4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine

A solution of 466 mg tetraiodide phosphorus in 15 ml of benzene was heated at 80°C for 15 minutes. To this solution was added dropwise a solution of 400 mg of 4-[[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]hydroxymethyl]pyridine in 10 ml of benzene. The mixture was then heated for 1 hour at 80°With, then leave the mixture to cool to room temperature. Then there was added 8 ml of 10%aqueous solution of sodium bisulfite and the biphasic mixture was stirred for 1 hour. The aqueous phase was extracted three times with 30 ml ethyl acetate and the combined extracts were washed with brine, dried, filtered and evaporated, received a yellow residue, which was purified using flash chromatography on silica gel by elution ethyl acetate/hexane (1:1, then 2:1), received 238 mg of 4-[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl] pyridine in the form of a solid white color. Mass spectrum (ES) m/z 392 [M+H]+, 433 [M+H+MeCN]+.

Example 30

4-[[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]formetal]pyridine

To a solution of 200 mg of 4-[[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]hydroxymethyl]pyridine in 5 ml of dichloromethane with a temperature of -78°With added 68 μl TRIFLUORIDE d is ethylmercury. The reaction mixture was stirred 1 hour at -78°With, then was added a saturated aqueous solution of sodium bicarbonate. The aqueous phase was extracted three times with 10 ml dichloromethane and the combined extracts were washed with brine, dried, filtered and evaporated, got pitch dark blue color, which was purified using flash chromatography on silica gel by elution diethyl ether/hexane (1:2, then 1:1), received 118 mg of 4-[[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]formetal]pyridine as a colourless oil. Mass spectrum (ES) m/z 410 [M+H]+, 451 [M+H+MeCN]+.

Example 31

4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-3-herperidin

A solution of 278 mg of tetraiodide phosphorus in 10 ml of toluene was heated at 80°C for 20 minutes. To this solution was added dropwise a solution of 259 mg of 4-[[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]hydroxymethyl]-3-herperidin in 5 ml of benzene. The mixture then was heated at 80°C for 20 minutes, then the mixture was left to cool to room temperature. Then was added 10 ml of 10%aqueous solution of sodium bisulfite and the biphasic mixture was stirred for 1 hour. The aqueous phase was extracted with three times 20 ml of ethyl acetate and the combined extracts were washed with brine, dried, filtered and evaporated, got the butter yellow is a, which was purified using flash chromatography on silica gel by elution diethyl ether/hexane (1:1, then 2:1), was obtained 35 mg of 4-[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-3-herperidin in the form of a solid pale yellow color. Mass spectrum (ES) m/z 410 [M+H]+, 451 [M+H+MeCN]+.

Starting material 4-[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-hydroxymethyl-1H-pyrazole-4-ylmethyl]-3-herperidin was prepared as follows.

To a solution of 65 μl of 3-herperidin in 2.5 ml of anhydrous tetrahydrofuran with a temperature of -78°With added 381 μl of 2 M solution of diisopropylamide lithium in heptane/tetrahydrofuran/ethylbenzene. The mixture was stirred at -78°C for 1 hour, then treated dropwise with a solution of 250 mg of [5-(3,5-dichlorophenyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]carbaldehyde in 2 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred for 30 minutes, then it was allowed to warm to room temperature, after which the reaction was stopped by adding water. The aqueous phase was extracted three times with 20 ml diethyl ether and the combined extracts were washed with brine, dried, filtered and evaporated, received a yellow oil, which was purified using flash chromatography on silica gel by elution ethyl acetate/hexane (1:3, then 1:1), received 259 mg of 4-[5-(3,5-dichlorophenyl hanil)-1-isopropyl-3-hydroxymethyl-1H-pyrazole-4-ylmethyl]-3-herperidin in the form of a colorless oil. Mass spectrum (ES) m/z 426 [M+H]+, 467 [M+H+MeCN]+.

Example 32

[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine-3-ylamine

A mixture of 227 mg of 4-methyl bromide-5-(3,5-dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole, 62 mg of 3-aminopyridine and 36 mg of sodium hydride (60% in mineral oil) in 3 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen atmosphere at 110°C for 15 minutes. Was added water (10 ml) and the mixture was extracted three times with 8 ml of dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified using flash chromatography on silica gel by elution of dichloromethane/methanol, received 17 mg of [5-(3,5-dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine-3-ylamine in the form of a brown resin.1H-NMR (DMSO-d6): to 1.19 (t, 3H), and 2.27 (s, 3H), 4,05-4,11 (m, 4H), 6,03 (t, 1H), 6.87 in (d, 1H), 6,99 (m, 1H),? 7.04 baby mortality (d, 2H), 7,44 (t, 1H), 7,72 (dd, 1H), 7,94 (d, 1H).

The educt - 4-methyl bromide-5-(3,5-dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole were obtained as follows.

(A) a Suspension of 23 g of ethyl ester of hydrazine and 22 ml of triethylamine in 500 ml of toluene was stirred at room temperature for 15 minutes. Was added 17 ml of methyl ester of acetoacetic acid and the mixture is brought up to the azeotropic composition for 1.5 hours. The mixture was evaporated and the residue was purified using flash chromatogr is the philosophy on silica gel, using for elution of dichloromethane/methanol (97:3), was obtained 19 g of 2-ethyl-5-methyl-2H-pyrazole-3-ol in the form of a solid orange color.

(B) To 28,7 ml of anhydrous N,N-dimethylformamide at 0°slowly added 80,7 ml of phosphorus oxychloride, then 15.6 g of 2-ethyl-5-methyl-2H-pyrazole-3-ol. The mixture was stirred in nitrogen atmosphere at 80°C for 1 h, then poured into 700 ml of water at 0°With, then was extracted six times with 350 ml of diethyl ether. The combined extracts were dried over magnesium sulfate, filtered and evaporated, obtained 9.3 g of 5-chloro-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde in the form of liquid orange, which was used without further purification.

(C) a Mixture of 9.2 g of 5-chloro-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde, 14.3 g of 3,5-dichlorothiophene and 11.8 g of potassium carbonate in 40 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen atmosphere at 100°C for 18 hours. Was added water (200 ml) and the mixture was extracted three times with 100 ml dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified using flash chromatography on silica gel by elution of dichloromethane/ petroleum ether (TKip40-60° (C)received 12, 2 g of 5-(3,5-dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde in the form of a solid orange color. Mass spectrum (ES) m/z 356 [M+CH3CN+H]+ .

(G) a Mixture of 1.1 g of 5-(3,5-dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde and of 0.53 g of sodium borohydride in 25 ml of anhydrous methanol was stirred under nitrogen atmosphere at room temperature for 15 minutes. Was added water (25 ml) and the mixture was extracted three times with 20 ml diethyl ether. The combined extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified using flash chromatography on silica gel by elution ethyl acetate/petroleum ether (TKip40-60° (C) (1:3), received 902 mg of [5-(3,5-dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-yl]methanol in the form of a yellow oil. Mass spectrum (ES) m/z 317 [M+H]+.

(D) a Mixture of 460 mg of [5-(3,5-dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-yl]methanol, 481 mg chetyrehpostovye carbon and 380 mg of triphenylphosphine in 20 ml of dichloromethane was stirred at room temperature for 24 hours. The solvent is evaporated. The residue was purified using flash chromatography on silica gel by elution ethyl acetate/petroleum ether (TKip40-60° (C) (1:4), received 392 mg 4-bromacil-5-(3,5-dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole in the form of oil pale yellow color. Mass spectrum (ES) m/z 317 [M-Br+H2On]+.

Compounds in table 6 were obtained by the method similar to that described above.

411
Table 6
When-MerStructureNameMS ES (M+N)+
2-[4-Benzyl-5-(3,5-dichlorobenzenesulfonyl)-3-methylpyrazole-1-yl]pyridine427
4-Benzyl-3-methyl-5-(3-nitrophenoxy)-1-phenyl-1H-pyrazole386
3-(4-Benzyl-5-methyl-2-phenyl-2H-pyrazole-3-yloxy)benzonitrile366
2-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine393
4-Benzoyloxymethyl-5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole422
2-[5-(3,5-Dimethylbenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine352
2-[5-(3-Chlorophenylsulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine359
25 2-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylethoxy]pyridine409
3-Chloro-5-[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylethoxy]pyridine443
261-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-1H-pyridine-2-he409
3-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine379
3-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-3H-pyrimidine-4-one379
274-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ileocecal]pyridine423
3-(4-Benzyl-5-methyl-2-phenyl-2H-pyrazole-3-ylsulphonyl)benzonitrile382
3-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine 393
[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]pyridine-2-ylmethanol409
[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]pyridine-4-ylmethanol
294-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine392
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-elmersolver]pyridine
4-Benzyl-5-(3,5-dichlorobenzenesulfonyl)-3-methyl-1-(2,2,2-triptorelin)-1H-pyrazole
304-{[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-yl]vermeil}pyridine410
5-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylethoxy]-2-methylpyridin
5-Bromo-4-[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyrimidine
3-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylethoxy]-2-nitropyridine
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-elmersolver]pyridine411
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylethoxy]pyridine395
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyrimidine394
3-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylethoxy]pyridine-2-ylamine410
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylethoxy]pyridine409
314-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-3-herperidin
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylmethyl]-3-herperidin397
3-Chloro-4-[5-(3,5-dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine413
3-Chloro-4-[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine427
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylethoxy]-6-methylpyrimidin-2-ylamine425
3-Bromo-5-[5-(3,5-dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine458
32[5-(3,5-Dichlorobenzenesulfonyl)-1-ethyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine-3-ylamine394
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]benzonitrile417
2-Chloro-4-[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine427
2-Chloro-4-[5-(3,5-dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-6-methylpyridin441
2-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyrazin394
4-[5-(3-Chloro-5-methoxybenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-2-methoxypyridine419
3-[[5-(3,5-Dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-yl]methyl]-2-(methylthio)pyridine473
4-[5-(3-Brompheniramine)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-3-chloropyridin437
3-Chloro-4-(1-isopropyl-3-methyl-5-m-tamilselvan-1H-pyrazole-4-ylmethyl)pyridine373
3-Chloro-4-[5-(3,5-dimethylbenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ileti is]pyridine 387
4-[5-(3-Brompheniramine)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-3-herperidin421
3-Fluoro-4-(1-isopropyl-3-methyl-5-m-tamilselvan-1H-pyrazole-4-ylmethyl)pyridine356
4-[5-(3,5-Dimethylbenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]-3-herperidin370
5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-4-thiophene-3-ylmethyl-1H-pyrazole398
{3-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]phenyl}dimethylamine435
4-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]for 3,5-dimethylisoxazol411
6-[5-(3,5-Dichlorobenzenesulfonyl)-1-isopropyl-3-methyl-1H-pyrazole-4-ylmethyl]pyridine-2-carbonitrile418

1. The compounds of formula I-A

where R1means (C1-C12)alkyl, which optionally may be substituted by 1-3 substituents selected from fluorine, chlorine and bromine, (C3-C8)cycloalkyl, phenyl, pyridyl, or (C1-C4)alkyl substituted by phenyl;

R2means optionally substituted phenyl, where phenyl may be substituted by 1-2 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup and nitro;

R3means (C1-C12)alkyl or (C1-C4)alkoxy(C1-C4)alkyl;

And' means (C1-C4)alkyl, substituted optionally substituted phenyl or optionally samemanner 4-pyridium, where phenyl or 4-pyridyl may be substituted by 1-2 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup and NRR', where R and R' independently of one another denote hydrogen or (C1-C4)alkyl; or

And' means a group of the formula CH2-U-heterocyclyl, where U represents O, S or NR"where R" denotes hydrogen or (C1-C4)alkyl and where heterocyclyl means pyridyl or pyrimidinyl, which optionally is substituted by 1-2 substituents selected from (C1-C4)alkyl, fluorine, chlorine, bromine, zengru the dust, nitro and NRR', where R and R' independently of one another denote hydrogen or (C1-C4)alkyl; or

And' means a group of formula CH(OH)phenyl; or

And' means a group CH=CHW, where W denotes phenyl;

X is S or O;

and their pharmaceutically acceptable salts.

2. The compounds of formula I-A according to claim 1, where R1means optionally substituted (C1-C12)alkyl, (C3-C8)cycloalkyl, phenyl, pyridyl or (C1-C4)alkyl, substituted phenyl, where (C1-C12)alkyl may be substituted by 1-3 fluorine atoms; R2means phenyl substituted with 1-2 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, fluorine, chlorine, bromine, langroup and nitro; R3means (C1-C12)alkyl or (C1-C4)alkoxy-(C1-C4)alkyl; And' means (C1-C4)alkyl, substituted optionally substituted phenyl or optionally substituted 4-pyridium, where phenyl or 4-pyridyl may be substituted by 1-2 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup and NRR', where R and R' denote, independently of each other hydrogen or (C1-C4)alkyl; or A' signifies a group of the formula CH2-U-heterocyclyl, where U represents O, S or NR"where R" means in Gorod or (C 1-C4)alkyl, and where heterocyclyl denotes pyridyl or pyrimidyl, optionally substituted with 1-2 substituents selected from (C1-C4)alkyl, fluorine, chlorine, bromine, langroup, nitro and NRR', where R and R' denote, independently of each other hydrogen or (C1-C4)alkyl; or A' signifies a group of formula CH(OH)phenyl; or A' signifies a group of the formula CH=CHW, where W stands for optionally substituted phenyl; X is S or O.

3. The compounds of formula I-A according to claim 1 or 2, where R1means (C1-C7)alkyl, which optionally may be substituted by 1-3 fluorine atoms, (C3-C8)cycloalkyl, phenyl, pyridyl or (C1-C4)alkyl substituted by phenyl;

R2means phenyl substituted with 1-2 substituents selected from (C1-C4)alkyl,

(C1-C4)alkoxyl, fluorine, chlorine, bromine, langroup and nitro;

R3means (C1-C7)alkyl or (C1-C4)alkoxy-(C1-C4)alkyl;

And' means methyl, substituted by an optionally substituted phenyl or optionally substituted 4-pyridium,

where phenyl or 4-pyridyl may be substituted by 1-2 substituents selected from the

(C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup and

NRR', where R and R' independently researched the Simo from each other denote hydrogen or (C 1-C4)alkyl; or A' signifies a group of the formula CH2-U-heterocyclyl, where U represents O, S or NR"where R" denotes hydrogen or (C1-C4)alkyl, and where heterocyclyl denotes pyridyl or pyrimidyl, which optionally is substituted by 1-2 substituents selected from (C1-C4)alkyl, fluorine, chlorine, bromine, langroup, nitro and NRR', where R and R' independently of one another denote hydrogen or (C1-C4)alkyl;

X is S or O.

4. The compounds of formula I-A according to any one of claims 1 to 3, where

R1means optionally substituted (C1-C7)alkyl, (C3-C8)pilooski, phenyl, pyridyl or benzyl,

where (C1-C7)alkyl may be substituted by 1-3 fluorine atoms;

R2means phenyl, substituted by 1-2 substituents which may be selected from (C1-C2)alkyl, fluorine, chlorine and langroup;

R3means (C1-C7)alkyl or (C1-C2)alkoxy-(C1-C2)alkyl;

And' means methyl, substituted by an optionally substituted phenyl or

optionally substituted 4-pyridium, where phenyl or 4-pyridyl may be substituted by 1-2 substituents selected from the

(C1-C2)alkyl, (C1-C2)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, and

NRR', where R and R' independently researched the Simo from each other denote hydrogen or (C 1-C2)alkyl;

X is S or O.

5. The compound of formula I-A according to any one of claims 1 to 4, where

R1means (C1-C7)alkyl;

R2means phenyl substituted with 1-2 substituents selected from chlorine and langroup;

R3means (C1-C7)alkyl;

And' means methyl, substituted by an optionally substituted 4-pyridium, where 4-pyridyl substituted by 1-2 substituents selected from (C1-C2)-alkyl,

(C1-C2)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup and NRR',

where R and R' independently of one another denote hydrogen or (C1-C2)alkyl;

X is S or O.

6. The compounds of formula I-A according to any one of claims 1 to 5, where

R1means (C1-C4)alkyl;

R is phenyl, substituted by 1-2 chlorine atoms;

R3means (C1-C4)alkyl;

And' means methyl, substituted by an optionally substituted 4-pyridium, where 4-pyridyl substituted with 1-2 substituents and the substituents are selected from (C1-C2)-alkyl and chlorine;

X is S or O.

7. The compounds of formula I-A according to claim 1, where

And' means (C1-C4)alkyl, substituted optionally substituted by phenyl,

where phenyl may be substituted by 1-2 substituents selected from (C1-C4)Alki is a, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine, bromine, langroup, and NRR', where R and R' independently of one another denote hydrogen or (C1-C4)alkyl; or

And' means a group of the formula CH2-U-heterocyclyl,

where U represents O, S or NR"where R" denotes hydrogen or (C1-C4)alkyl, and

where heterocyclyl denotes pyridyl or pyrimidyl, which optionally is substituted by 1-2 substituents selected from (C1-C4)alkyl, fluorine, chlorine, bromine, langroup, nitro and NRR', where R and R' independently of one another denote hydrogen or (C1-C4)alkyl; or

And' means a group of formula CH(OH)phenyl; or

And' means a group of the formula CH=CHW,

where W denotes phenyl;

X is S or O;

and their pharmaceutically acceptable salts.

8. The compounds of formula I-A according to claim 1

where R1means (C1-C12)alkyl, (C3-C8)cycloalkyl, phenyl or (C1-C4)alkyl substituted by phenyl;

R2means optionally substituted phenyl, where phenyl may be substituted by 1-2 substituents selected from (C1-C4)-alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine or bromine;

R3means (C1-C12)alkyl or (C1-C4)Ala the XI-(C 1-C4)alkyl;

And' means (C1-C4)alkyl, substituted optionally substituted phenyl or optionally samemanner 4-pyridium, where phenyl or 4-pyridyl may be substituted by 1-2 substituents selected from (C1-C4)alkyl, (C1-C4)alkoxyl, hydroxyl, fluorine, chlorine or bromine; or

And' means a group of formula CH(OH)phenyl;

or

And' means a group of the formula CH=CHW, where W represents phenyl;

X is S or O;

and their pharmaceutically acceptable salts.

9. The compounds of formula I-A according to any one of claims 1 to 8, wherein X is S.

10. The compound according to any one of claims 1 to 9 for use in the treatment of diseases mediated by the human immunodeficiency virus (HIV).

11. Pharmaceutical composition for use in the treatment of diseases mediated by the human immunodeficiency virus (HIV), comprising a pharmaceutically effective amount of the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 9 and, if desired, pharmaceutically inert carrier.



 

Same patents:

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes analgesic agent possessing the analgesic effect showing effectiveness against the pain by effect on nociceptors. As an active component the proposed analgesic agent comprises compound represented by the general formula (1) or its salt wherein X, Y, E, Q, A1, A2, R1, R3, R4, R5, R2A, R2C, R2D and R2B re determined in the invention claim.

EFFECT: valuable medicinal properties of agents.

3 tbl, 70 ex

FIELD: organic chemistry, chemical technology, herbicides, agriculture.

SUBSTANCE: invention relates to new sulfonamides of the formula (I):

and their salt wherein A represents substituted or unsubstituted benzene ring or 5-membered, or 6-membered substituted or unsubstituted heteroaromatic ring taken among the group comprising thienyl, pyrazolyl, imidazolyl, pyridyl wherein optional substitutes are taken among the group consisting of halogen atom, substituted or unsubstituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy-group, nitro-group, phenyl, phenoxy-group, benzoyl and (C1-C4)-alkylcarboxylate when any alkyl fragment in the latter indicated substituted is substituted with one or some halogen atoms, (C1-C4)-alkoxy-groups, cyano-group and phenyl; Q represents -O-, -S- or group of the formula: -CXX' wherein X and X' can be similar or different and each represents hydrogen atom, halogen atom, cyano-group, alkyl comprising 1-8 carbon atoms, or the group -ORa, -SRa; or one of X and X' represents hydroxy-group and another has values determine above; Ra means (C1-C8)-alkyl, phenyl; Rb means (C1-C8)-alkyl, phenyl; Y means nitrogen atom or the group CR9; R1 means unsubstituted (C1-C8)-alkyl or that substituted with halogen atom, cyano-group, phenyl or (C1-C4)-alkoxycarbonylamino-group, or it represents phenyl; R2 means hydrogen atom (H), (C1-C4)-alkyl; R3 and R4 can be similar or different and each represents (C1-C4)-alkyl, (C1-C4)-alkoxy-group, halogen atom; R9 means hydrogen atom (H) under condition that when Q represents oxygen atom (O) or -S- then ring A represents 5-membered substituted or unsubstituted heteroaromatic ring and determined above. Compounds of the formula (I) possess the herbicide activity that allows their using for eradication of weeds. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

FIELD: organic chemistry, medicine, pharmacy.

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

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

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

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

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds that inhibit binding ligands with α4β1-integrin (VLA-4) selectively. Compounds have the formula (I):

wherein W means unsubstituted phenyl or phenyl substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom, (C1-C4)-alkoxy-group and halogen alkyl; W1 means unsubstituted phenylene or phenylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, pyridylene, pyridylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, 2-oxopyrrolylene or thiazolylene; A means oxygen atom (O); R means -(CH2)n- wherein n = 1 or 2; X means -C(O)-; M is taken among the following groups: a)

wherein means divalent 5- or 6-membered heterocyclic radical wherein nitrogen atom is located in the joining point to X wherein Q represents -CH2-, -O- or -S-; R1, R2 and R3 are taken independently among the group involving: hydrogen atom (-H), hydroxyl group (-OH), quinolinyloxy-group, -NH2, mono- or dialkylamino-group, (C1-C6)-alkylsulfonylamino-, arylsulfonylamino-, naphthyloxy-, phenyloxy-group substituted optionally with di-(C1-C6)-alkylamine, (C1-C6)-alkyl, benzyloxymethyl, halogen atom, phenyl, (C1-C4)-alkoxy-group; or two adjacent R1, R2 and R3 taken in common can form alkylene- or alkylenenedioxy-group substituted optionally with 1-3 alkyl groups; R4 means hydrogen atom (H), lower alkyl; Y is taken among a bond, (C2-C8)-alkenylene group, (C2-C8)-alkynylene group, -C(O)-, -C(O)NH- and -(CH2)kY2 wherein k is taken among 1, 2 and 3; Y2 means a direct bond or divalent radical taken among -O-, -S-, -S(O)-, -S(O)2- and -NY3- wherein Y3 is taken among hydrogen atom (H), lower alkyl; Z means (C3-C8)-cycloalkylene, optionally substituted phenylene, pyridylene, piperidylene, piperazinylene; A1 means a direct bond, -(CH2)t-alkynyl wherein t is taken among 1, 2 and 3; R5 means -OH, lower alkoxy-group, , ; b) means wherein R11 is taken among , -NR12- wherein R12 is taken among hydrogen atom (-H), optionally substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl; Z3 is taken among a direct bond, (C1-C12)-alkyl wherein one or some carbon atoms can be replaced with -O- or -NR13- wherein R13 means hydrogen atom (-H), lower alkyl, wherein x = 0 or 1; y = 1, 2 or 3; R14 means hydrogen atom (-H), ; and when R11 means NR12 then Z3 is taken among: wherein 14Ra means hydrogen (H), halogen atom; , and ; Q2 means wherein R17 and R18 mean hydrogen atom (H), lower alkyl; or phenylene that can be substituted; L1 means -COOH or -COOR19 wherein R19 means lower alkyl. Compounds of the formula (I) inhibit activity of VLA-4-mediated adhesion of cells that allows their using in pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and compositions.

21 cl, 11 tbl, 283 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to R-2-aminoarylpropionic acid amides and pharmaceutical composition comprising thereof that can be used for prophylaxis and inhibition of recruiting and activation of leukocytes, and in treatment of pathologies directly dependent on indicated activation. Invention proposes compound of the general formula (1): wherein A, q, Ph and R have corresponding values, or its pharmaceutically acceptable salt. Also, invention describes a method for preparing amide of the formula (1) and pharmaceutical composition used in prophylaxis of leukocytes activation. Invention provides the development of pharmaceutical composition that can be used for prophylaxis and treatment of damaged tissues caused by enhancing activation of neutrophile granulocytes (polymorphonuclear leukocytes) in inflammation foci. Also, the invention relates to R-enantiomers 2-(aminoaryl)-propionylamides of the formula (1) that can be used for suppression of neutrophyles hemotaxis caused by IL-8. Also, compounds of this invention can be sued in treatment of psoriasis, ulcerous colitis, glomerulonephritis, acute respiratory insufficiency and rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds.

8 cl, 16 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-aminomethylquinolone-2 of the general formula (1)

(2)

or (3) wherein R1 means hydrogen atom (H) or Alk; R2 is taken among Alk; -OAlk, -SCH3, -Hal, -CF3, 3,4-OCH2CH2O-, 3,4-OCH2O-, 4-OCF3, 2-Ph, -OPh, -NHCOR, 2-OCH3, 5-Ph, 4-Obzk, 3-NO2, 2-CH3, 5-iPr, di-OAlk, di-Hal; or R2 represents halogen atom and alkyl group, or halogen atom and alkoxy-group taken simultaneously and independently of one another; or R2 represents the group -CONR4R5 wherein each R4 and R5 means independently of one another the group Alk, or they form the group -(CH2)n- wherein n = 2-6. R means -CH3; R3 means hydrogen atom (H); X is taken among hydrogen atom (H), 6-(C1-C3)-Alk, 6-iPr, 6-iBu; 7-(C1-C2)-Alk, 8-(C1-C2)-Alk, 6-(C1-C2)-OAlk, 6-OCF3, 7-(C1-C2)-Alk, 7-SCH3, 6,7-OCH2O-, 6,7-OCH2CH2O-, 5,6,7-OCH3, 6-F; X and Y are similar or different and taken among 7,8-CH3, 6,8-CH3, 5,8-CH3, 5,7-CH3, 6,7-CH3, 6,7-OCH3, 6-CH3, 7-Cl. Also, invention relates to a method for preparing indicated compounds and to pharmaceutical composition inhibiting activity of NO-synthetase based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof for aims preparing medicinal agents for treatment diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

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

19 cl, 1 tbl, 95 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

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

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

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

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention describes derivative of 1-aryl-3-cyano-5-pyridylalkylaminopyrazole represented by the following formula (1): wherein X represents C-halogen; R1 represents halogenalkyl group comprising from 1 to 4 carbon atoms with exception of perhalogenalkyl group; R2 represents hydrogen atom; R3 represents hydrogen atom; R4 represents hydrogen atom. Also, invention describes an agent used for control of insects comprising this derivative as an active component. Invention describes two methods for preparing compound of the formula 91). Compounds of the formula (1) are useful for control of insects in agriculture and for domestic animals.

EFFECT: improved preparing methods, valuable properties of compound and agent.

7 cl, 7 tbl, 7 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

FIELD: organic chemistry, medicine, pharmacy.

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

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

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

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

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a new improved method for preparing derivatives of 3,3-diarylpropylamines of the general formula (I) and sterically highly pure stable intermediate substances and their using for preparing pharmaceutical compositions. Method for preparing 3,3-diarylpropylamines of the general formula (I) wherein R means hydrogen atom, linear or branched (C1-C6)-alkyl but preferably methyl or isopropyl; R' and R'' can be similar or different and mean linear or branched (C1-C6)-alkyl but preferably methyl or isopropyl. Method involves condensation of cinnamic acid with compound of the general formula (1) to form compound of the general formula (2a) and the following reaction of the latter with chiral tertiary amine - cinchonidine to yield the corresponding salt of compound of the general formula (2b): and then from this compound the crystalline form of compound of the formula (3): is isolated followed by its either direct reduction with equivalent excess of hydride to yield lactol of the formula (5a) or via intermediate step by formation of corresponding acid chloroanhydride to form ester with alcohols of type R-OH wherein R is given above and the following conversion to compound of the formula (4): and the latter is hydrogenated with diisobutylaluminum-hydride or tri-tert.-butoxyaluminum-hydride to yield lactol of the formula (5) . Prepared lactols of the formula (5a) or (5) after reductive amination with secondary amine form compounds of the formula (I).

EFFECT: improved preparing method.

10 cl, 1 sch, 1 tbl, 13 ex

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