1,2,3,4-tetrahydropyrazolo [5,1-c](1,2,4)triazine or its pharmaceutically acceptable salt, its production method, pharmaceutical composition, inhibiting the production of interleukin-1 and tumor necrosis factor, a method of prophylactic or therapeutic treatment of diseases mediated by interleukin-1 and tumor necrosis factor

 

(57) Abstract:

New derivatives of pyrazole of the formula I, where R1and R2- phenyl, possibly substituted by halogen or pyridinyl, possibly substituted by halogen or lower alkoxy; R3is hydrogen or lower alkanoyl; R4- H, lower alkyl, cyclo(lower) alkyl, cyclo-(lower)alkyl(lower)alkyl, lower alkoxycarbonyl, phenylalkyl; substituted, phenylalkyl, tetrahydropyranyl, piperidyl or dissapionting, indanyl, lower alkanoyl, lower alkoxycarbonyl, lower alkoxyglycerols, lower alkylsulfonyl, cyclo(lower)alkylaryl, benzoyl, phenyl(lower)alkanoyl, phenylthio(lower)alkanoyl, phenylcarbamoyl, phenyl-thiocarbamoyl, phenylglyoxylic, carbarnoyl, morpholinylcarbonyl, indolyl(lower)alkanoyl; R5- H or lower alkyl, or its pharmaceutically acceptable salt. The compounds of formula I can be used as a drug for the prophylactic and therapeutic treatment of diseases mediated by IL - 1 and TNF, such as chronic inflammatory diseases, specific autoimmune disease caused by sepsis damage to the body in humans and animals. 4 C. and 3 h.p. f-crystals.

The invention relates medicines.

The invention relates to new heterocyclic derivatives. In particular, the invention relates to the derivatives of pyrazole and their pharmaceutically acceptable salts, which possess pharmacological activity, to processes for their preparation, to pharmaceutical compositions comprising pyrazole derivatives and their salts, and their use.

The aim of the invention is the development of new and useful derivatives of pyrazole and their pharmaceutically acceptable salts, which have a high inhibitory activity on production of Interleukin -1 (1L-1, IL-1) and a high inhibitory activity on production of tumor necrosis factor (TNF, TNF).

Another aim of the invention is to develop methods of obtaining derivatives of pyrazole and its salts.

Another aim of the invention is to develop pharmaceutical compositions comprising these pyrazole derivatives or their pharmaceutically acceptable salts.

Another object of the invention is to provide a use specified derivatives of pyrazole or its pharmaceutically acceptable salts as a drug for the prophylactic and therapeutic treatment of diseases mediated 1L damage to the body, and the like, in humans and animals.

Target derivatives of the invention are new and can be represented by the following General formula I:

< / BR>
where

R1means aryl which may have suitable substituent (s) or heterocyclic group which may have suitable substituent (s);

R2means aryl which may have suitable substituent (s) or heterocyclic group which may have suitable substituent (s);

R3means hydrogen or aryl;

R4means hydrogen, lower alkyl, cyclo(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl, ar(lower)alkyl which may have suitable substituent (s), ar(lower)alkenyl directly connected to the bridge connection tricyclic alkyl, heterocyclic group which may have suitable substituent (s), aryl, or a group of the formula

< / BR>
where

A denotes the lower alkylen:

R5means hydrogen or lower alkyl.

The target compound I of the invention can be obtained by methods 1 to 7, provided at the end of the description,

where

R1, R2, R3and R5- each as defined above is, having hydroxyl;

R4- acyl, having a protected amino group;

R4e- acyl having Eminescu;

R4- acyl having tsepliaeva group;

R4- acyl having N-containing heterocyclic group;

R6is hydrogen, C1-C5alkyl, cyclo(lower)alkyl, cyclo(lower)alkyl-(C1-C5)alkyl, aryl which may have suitable substituent (s) or ar(C1-C5)alkyl which may have suitable substituent (s),

a group of the formula:

< / BR>
is lower alkyl, cyclo(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl, ar(lower)alkyl which may have suitable substituent (s) ar(lower)alkenyl directly connected to the bridge connection tricyclic alkyl, heterocyclic group which may have suitable substituent (s), or a group of the formula

< / BR>
where

A - lowest alkylen;

X10anion;

N-containing heterocyclic group.

The initial compounds or their salts can be obtained by methods A - I are presented in the end of the description,

where

R1, R2, R3X1-and

each is as defined visi alkyl;

R11is lower alkyl or aryl;

X4acid residue.

Suitable pharmaceutically acceptable salts of the proposed compounds I are standard non-toxic salts, and they can be the salt of the base or the acid salt of the merger, such as a salt with an inorganic base, such as alkali metal salt (e.g. sodium salt, potassium salt, etc), salt, alkaline earth metal (e.g. calcium salt, magnesium salt, etc.,), ammonium salt, salt with organic base, for example salt of organic amine (for example, salt of triethylamine, salt, pyridine salt of Tsikolin, ethanolamine salt, triethanolamine salt, salt dicyclohexylamine, salt N, N'-dibenziletilendiaminom and so on), salt accession with inorganic carboxylic acid or acid (e.g., formate, acetate, triptorelin, maleate, tartrate, fumarate, methanesulfonate, bansilalpet, toluensulfonate and so on), salt with basic or acidic amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.,).

In the above and subsequent description of the invention examples and illustrations of the various definitions, which are assumed not to go beyond the frames of terasul from 1 to 6 carbon atoms, unless otherwise requested.

The term "higher" is used, referring to a group containing 7 to 20 carbon atoms, unless otherwise stated.

Suitable "lower alkyl" and "lower alkyl part" in terms of "cyclo(lower)alkyl(lower)alkyl", "carboxy(lower)alkyl", carboxy(lower)alkyl" and "ar(lower)alkyl" may include unbranched or branched alkyl having from 1 to 6 carbon atom(s) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, etc.

The corresponding "lower Alchemilla part" in the term "ar(lower)alkenyl" may include vinyl, 1-(or 2-)propenyl, 1-(or 2-or 3-)butenyl, 1-(or 2-or 3-, or 4-)pentenyl, 1-(or 2-or 3-, or 4-, or 5-)hexenyl, methylvinyl, ethyl vinyl, 1-(or 2-or 3-)methyl/1 (or 2)-propenyl, 1-(or 2-or 3-)ethyl-1-(or 2-)propenyl, 1-(or 2-or 3-, or 4-)-methyl-1-(or 2-or 3-)butenyl, and so on, of which more preferred may be C2-C4quinil.

Suitable "protected amino" and "protected amino" in the term "acyl having protected amino" may include acylamino or amino group, substituted obier, benzyl, trityl and so on) or the like.

Suitable "acyl" and "acyl part" in the term "acylamino", "acyl having protected hydroxy", and acyl having hydroxy, acyl having protected amino, acyl having amino, acyl having tsepliaeva group" and "acyl having N-containing heterocyclic group" may include carbarnoyl, cyclo(lower)allylcarbamate, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, referred to as heterocyclic acyl.

Suitable examples of illustrations acyl can be the following: carbarnoyl, thiocarbamoyl, cyclo(lower)alkylaryl (for example, cyclopropanecarbonyl, cyclohexylcarbonyl, and so on), aliphatic acyl, such as lower or higher alkanoyl (for example, formyl, acetyl, propanol, isobutyryl, butanoyl, pivaloyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, 3,3-dimethylbutanol, 2,2-dimethylbutanol, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanol, deletion, pentadecanol, hexadecanol, heptadecanol, octadecanol, nonadecanoic, icoanei and so on), or lower , the-pentyloxybenzoyl, heptyloxybiphenyl and so on), low alkoxyglycerols (for example, ethoxalyl, ethoxalyl and so on), lower or higher alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl and so on ), lower or higher alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl and so on) or the like, an aromatic acyl such as aroyl (for example, benzoyl, toluoyl, naphtol and so on ), ar(lower) alkanoyl (for example, phenyl(lower)alkanoyl (for example, phenylacetyl: phenylpropanol, phenylmethanol, phenylethanol, phenylpentane, phenylhexanoic and so on), naphthyl(lower)alkanoyl (for example, naphthylacetyl, afterrepair, afterburner and so on ), ar(lower)aleneil (for example, phenyl(lower)alkanoyl (for example, phenylpropenoyl, phenylmethanol, phenylmethanol, phenylmethanol, phenylhexanoic and so on ), naphthyl(lower)alkanoyl (for example, afterproperties, afterburner, and so on), ar(lower)alkoxycarbonyl (for example, phenyl(lower)alkoxycarbonyl (for example, benzyloxycarbonyl and so on ), aryloxyalkyl (for example, phenoxycarbonyl, naphthalocyanines and so on ), arieti(lower)alkanoyl (for example, phenylthio(lower)alkanoyl (for example, phenylthiourea, phenylthiocarbamoyl and so on), and so on), aryloxy(lower)alkanoyl (for example, feimer, phenyl-thiocarbamoyl and so on), acilglycerol (for example, phenylglyoxylic, afterpotential, and so on), arylsulfonyl (for example, phenylsulfonyl, p-tamilselvan, and so on), or the like, heterocyclic acyl, such as heterocyclic carbonyl, heterocyclic carbarnoyl, heterocyclic (lower)alkanoyl (for example, heterocyclic acetyl, heterocyclic propanol, heterocyclic butanol, heterocyclic pentanoyl, heterocyclic hexanoyl, and so on), heterocyclic (lower)alkanoyl (for example, heterocyclic propanol, heterocyclic butanol, heterocyclic pentanoyl, heterocyclic hexanoyl, and so on), heterocyclic glycerol, or the like, in which the heterocyclic part of the" in the terms "heterocyclic carbonyl", heterocyclic carbarnoyl", "heterocyclic (lower)alkyl", heterocyclic (lower)alkanoyl" and "heterocyclic glyoxylyl" mentioned above means in more detail saturated or unsaturated, monocyclic or polycyclic group containing at least one heteroatom such as oxygen atom, sulfur atom, nitrogen atom and the like.

Especially preferred heteros is preferably 5 or 6-membered) heterophilically group, containing from 1 to 4 atom(s) of nitrogen, for example, pyrrolyl, pyrrolidyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridin, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl and so on ), tetrazolyl (for example, 1H-tetrazolyl, 2H-tetrazolyl and so on and so forth, saturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group, containing from 1 to 4 atom(s) of nitrogen, for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinil and so on, unsaturated condensed heterocyclic group containing from 1 to 4 atom(s) of nitrogen, for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, hinely, ethanolic, indazoles, benzotriazolyl and so on, unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group containing from 1 to 2 atom(s) oxygen and from 1 to 3 atom(s) of nitrogen, for example, oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl and so on), and so on, saturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group containing from 1 to 2 atom(s) of oxygen and from 1 to 3 atom(s) of nitrogen, for example, morpholinyl, sindoni etc. unsaturated to the example benzoxazolyl, benzoxadiazole and so on, unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group containing from 1 to 2 atom(s) of sulfur, and from 3 atom(s) of nitrogen, for example thiazolyl, isothiazolin, thiadiazolyl, (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and so on, dihydrothiazine etc., saturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group, containing from 1 to 2 atom(s) of sulfur and 1 to 3 atom(s) of nitrogen, such as diazolidinyl and so on, unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group containing from 1 to 2 atom(s) of sulfur, such as thienyl, dehydrodidemnin, dehydrodidemnin etc., saturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group containing from 1 to 2 atom(s) of oxygen, such as tetrahydrofuryl, tetrahydropyranyl and so on, unsaturated condensed heterocyclic group containing 1 to 2 atom(s) of sulfur and 1 to 3 atom(s) of nitrogen, for example, benzothiazolyl, benzothiadiazole and so on , unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group containing from 1 to 2 atom(s) of oxygen, e.g. is undecanol (for example, 1.5-dioxaspiro(5,5)undecane and so on) and so on, unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heterophilically group containing an oxygen atom and 1 to 2 atom(s) of sulfur, such as dihydroartemisinin and so on, unsaturated condensed heterocyclic group containing 1 to 2 atom(s) of sulfur, for example benzothiazyl, benzodithiol and so on, ninasimone condensed heterocyclic group containing an oxygen atom and 1 to 2 atom(s) of sulfur, for example benzoxanthenes etc. or the like.

Acyl portion, as defined above, can have from one to ten, same or different, suitable substituent(s) such as lower alkyl (e.g. methyl, ethyl, propyl, and so on), lower alkoxy (e.g. methoxy, ethoxy, propoxy, and so on), lower alkylthio (for example, methylthio, ethylthio and so on ), lower alkylamino (for example, methylamino, ethylamino, propylamino and so on ), mono(or di or three)halo(lower)alkyl (e.g., vermeil, deformity, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, methyl bromide, dibromomethyl, tribromoethyl, 1 - or 2-foretel, 1 - or 2-bromacil, 1 - or 2-chloroethyl, 1,1-dottorati, 2,2-dottorati and so on ), di(lower)alkylamino (for example, dimethylamino, diethylamino, measures, cyclohexenyl, cyclohexadienyl, and so on), halogen (e.g. fluorine, bromine, iodine), amino, protected amino, mentioned above, hydroxy, protected carboxy, mentioned below, sulfo, aryl (e.g. phenyl, naphthyl and so on), sulfamoyl, imino, oxo, amino(lower)alkyl (e.g., aminomethyl, aminoethyl and so on ), chromolox, hydroxy(lower)alkyl (e.g. hydroxymethyl, 1 - or 2-hydroxyethyl, 1 - or 2 - or 3-hydroxypropyl, and so on) or the like.

Suitable "hydroxy protective group" in the term "protected hydroxy" and "acyl having protected hydroxy" may include the above-mentioned acyl, phenyl(lower)alkyl which may have one or more substituent(s) (e.g. benzyl, 4-methoxybenzyl, trityl and so on), tizamidine silyl (for example, three(lower)alkylsilane (for example, triethylsilyl, t-butyldimethylsilyl and so on), and so on), tetrahydropyranyl or the like.

Suitable "aryl" and "aryl part" in the terms "ar(lower)alkyl", ar(lower)alkenyl" and "ar(C1-C5)alkyl" may include phenyl, naphthyl and the like.

Accordingly tsepliaeva group" and "tsepliaeva part of the group" in the term "acyl having tsepliaeva group" may include an acid residue and the like.

Suitable "halogen" may include fluorine, bromine, chlorine, iodine.

Suitable "protected carboxy" and "protected carboxy part" in the term "protected carboxy(lower)alkyl" may include esterification carboxy and the like. A suitable example of the specified complex ester may be an ester, such as lower alkilany ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentalogy ester, t-pentalogy ester, hexyl ester, etc.,), the lower alkenilovyh ester (e.g. vinyl ester, allyl ether, and so on), the lower alkinilovymi ester (for example, atinlay ester, propenyloxy ester and so on), lower alkoxy(lower)alkilany ester (for example, methoxymethyl ether, ethoxymethyl ester, isopropoxy ester, 1-methoxyethoxy ester, 1-ethoxyethyl ester, and so on), lower alkylthio(lower)levy ester, isopropoxytitanium ester and so on), mono(or di or three)halo(lower)alkilany ester (for example, 2-iodoethylene ester, 2,2,2-trichlorethylene ester and so on ), lower alkanoyloxy(lower)alkilany ester (for example, acetoxymethyl ester, propionylacetate ester, butyrylacetate complex, veterinarinary ester, pivaloyloxymethyl ester, hexaniacinate ester, 1-ecotoxicology ester, 2-ecotoxicology ester, 2-propionylacetate ester and so on ), cyclo(lower)alkilany ester (for example, cyclopropylethyl ester, cyclopentyloxy ester, cyclohexyloxy ester and so on), lower alkoxycarbonyl(lower)alkilany ester (for example, methoxycarbonylmethyl ester, ethoxycarbonylmethyl ester, propoxycarbazone ester, 1-(or 2-) (methoxycarbonylamino)ethyl ester, 1-(or 2-) (ethoxycarbonyl)ethyl ester, 1-(or 2-) (propoxycarbonyl)ethyl ester, 1-(or 2-) (isopropoxycarbonyl) ethyl ester, and so on) of the lower alkanesulfonyl (lower)alkilany ester (for example, melony ether (for example, methoxycarbonylmethyl ester, ethoxycarbonylmethyl ester, propoxycarbazone ester, t-butoxycarbonyloxyimino ester, 1- (or 2-)methoxycarbonylmethyl ester, 1- (or 2-)-methoxycarbonylmethyl ester, 1- (or 2-) ethoxycarbonylmethyl ester, 1- (or 2-) isopropoxycarbonyloxymethyl ester, and so on), thalidomide-(lower)alkilany ester, or (5-lower alkyl-2-oxo-1,3-dioxo-4-yl) (lower)alkilany ester, such as (5-methyl)-2-oxo-1,3-dioxo-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxo-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxo-4-yl)ethyl ester, and so on), ar (lower) alkilany ester such as phenyl(lower)alkilany ester, which may have one or more suitable substituent(s) (e.g. benzyl ester, 4-methoxybenzyloxy ester, 4-nitrobenzyl ester, finitely ester, trailovic ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hidroxi-3,5-di-t-butylbenzyl ester and so on), arrowy ester which may have one or more approach tallowy ether, t-BUTYLPEROXY ether, Kilroy ether, mesityloxy ether, comenjoy ether, 4-hlorfenilovy ether, 4-methoxyphenacyl ether and so on), three(lower)alkyl silloway ester, lower alkylthiomethyl (for example, methylthioethyl, ethylthioethyl and so on), and the like.

Suitable "lower alkylene" may include unbranched or branched alkylene, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, METROTILE, ethylethylene, propylene, and the like, among which more preferred example may be C1-C4alkylen.

Suitable "heterocyclic group" may be assigned to groups illustrated above.

Suitable "connected to the bridge connection tricyclic alkyl" may include tricyclazole, thrillometer, tricyclohexyl, tricyclohexyl, tricyclohexyl, tricyclodecane, tricyclodecane (for example, adamantyl and so on), tricyclodecane etc.

Suitable "cyclo(lower)alkyl" and "cyclo(lower)alkyl part" in terms of "cyclo(lower)alkyl(lower)alkyl" and "cyclo-(lower)alkyl-(C1-C5)alkyl" may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

1-C5) and ar(C1-C5)alkyl" may include unbranched or branched alkyl having from 1 to 5 carbon atom(s) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, neopentyl and the like.

Suitable "N-containing heterocyclic group" and "N-containing heterocyclic group" in the term "acyl having N-containing heterocyclic group" may include unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heterogenities group containing from 1 to 4 atom(s) of nitrogen, for example pyrrolyl, pyrrolidyl, imidazole, pyrazolyl, dihydropyridin, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl and so on), tetrazolyl (for example, 1H-tetrazolyl, 2H-tetrazolyl and so on and so forth, saturated 3 to 8-membered (more preferably 5 or 6-membered) heterogenities group containing from 1 to 4 atom(s) of nitrogen, for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinil and so on , unsaturated condensed heterocyclic group containing from 1 to 4 atom(s) of nitrogen, for example, indolyl, isoindolyl, indolinyl, and so on, saturated 3 to 8-membered (more preferably 5 or 6-membered)GE the Nile and so on, saturated 3 to 6-membered (more preferably 5 or 6-membered) heterogenities group containing from 1 to 2 atom(s) of sulfur and 1 to 3 atom(s) of nitrogen, such as diazolidinyl etc. or the like.

Suitable "Deputy" in the term "heterocyclic group which may have suitable substituent(s)" may include lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl and so on), lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, t-butoxy, pentyloxy, neopentylene, t-pentyloxy, hexyloxy and so on), lower alkenyl (for example, vinyl, 1-propenyl, allyl), 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5 hexenyl and so on), the lower quinil (for example, ethinyl, 1-PROPYNYL, propargyl, 1-methylpropenyl, 1-methylpropenyl, 1 or 2 or 3 butynyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl and so on ), mono (or di or three)halo (lower alkyl) (for example, vermeil, deformity, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, methyl bromide, dibromomethyl, three methyl bromide, 1-or 2-foretel, 1 or 2-bromacil, 1 or 2-chloroethyl, 1,1-dottorati, 2,2-dottorati and so on), halogen (e.g. chlorine, bromine, ft is ISSI)alkyl, such as phenyl(lower)alkyl (e.g. benzyl, phenethyl, phenylpropyl and so on ), carboxy(lower)alkyl, protected carboxy(lower)alkyl, nitro, amino, protected amino, di(lower)alkylamino (for example, dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, isopropylethylene, ethylmethylamino, ethylpropylamine and so on ), hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, acyl, mentioned above, cyano, mercapto, lower alkylthio (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio and so on), imino and the like.

Suitable "Deputy" in the term "aryl which may have suitable out of office assistant", "ar(lower)alkyl which may have suitable substituent(s)" and "ar(C1-C5)alkyl which may have suitable substituent(s)" may include lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl and so on), lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, t-butoxy, pentyloxy, neopentylene, t-pentyloxy, hexyloxy and so on ), lower alkenyl (for example, vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5 hexenyl and so on), h is or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 5-hexenyl and so on), mono(or di or three)halo(lower)alkyl (e.g., vermeil, deformity, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, methyl bromide, dibromomethyl, tribromoethyl, 1 or 2-foretel, 1 or 2-bromacil, 1 or 2-chloroethyl, 1,1-dottorati, 2,2-dottorati and so on ), halogen (e.g. chlorine, bromine, fluorine, iodine), carboxy, protected carboxy, hydroxy, protected hydroxy, aryl (e.g. phenyl, naphthyl and so on ), ar(lower)alkyl such as phenyl(lower)alkyl (e.g. benzyl, phenethyl, phenylpropyl and so on), carboxy(lower)alkyl, protected carboxy(lower)alkyl, nitro, amino, protected amino, di(lower)allylamine (for example, dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, isopropylethylene, ethylmethylamino, ethylpropylamine and so on ), hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, acyl, mentioned above, cyano, mercapto, lower alkylthio (for example, methylthio, ethylthio), propylthio, isopropylthio, butylthio and so on), imino and the like.

Methods of obtaining and offer parent compounds are discussed in detail below.

Method (1).

The compound (Ia) or its salt can be obtained by subjecting reduction reaction of the compound (II) or its salt.

the field.

Suitable regenerating agent used in chemical reduction are hydrides (for example, modesty hydrogen, soulful hydrogen, sociallyengaged, sodium borohydride, sodium cyanoborohydride and so on), the combination of borane, and tetrahydrofuran, or di(lower)aklil sulfide (for example, dimethyl sulfide, and so on), or a combination of metal (e.g. tin, zinc, iron, and so on), or compounds of the metal (e.g. chromium chloride, chromium acetate, etc. and organic acid or inorganic acid (e.g. formic acid, acetic acid, propionic acid, triperoxonane acid, p-toluensulfonate, hydrochloric acid, Hydrobromic acid, and so on).

Suitable catalysts used in catalytic reduction are conventional catalysts such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, and so on), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, and so on), Nickel catalysts (which set out the cobalt, the Raney cobalt, and so on), iron catalysts (e.g. reduced iron, Raney copper, Ullman copper, and so on), and the like.

The restoration carried out in a standard solvent which has no adverse effect on the reaction, such as water, alcohol (e.g. methanol, ethanol, propanol, etc. ), tetrahydrofuran, dioxane, N,N-dimethylformamide or a mixture of them.

In addition, in the case where the above-mentioned acid to be used, chemical recovery, are liquids, they can also be used as solvent.

The reaction temperature is not significant, and the reaction is usually carried out under cooling to heating.

Method (2).

The compound (Ic) or its salt can be obtained by subjecting the compound (Ib) or its reactive derivative or its salt of the reaction of acylation on the imino group.

Suitable allermuir agent used in this reaction, acylation, can serve as a compound of the formula:

< / BR>
where

R4ameans acyl or its reactive derivative or its salt.

Suitable reactive derivative at the imino group of the compound (Ib) can slis(trimethylsilyl)acetamide", she N-trimethylsilylacetamide or the like, a derivative obtained by the interaction of the compound (Ib) with phosphorus trichloride or phosgene, or etc.

Suitable reactive derivative of compound (XIX) can be galoyanized, acid anhydride, activated ester, isothiocyanate, isocyanate, etc., a Suitable example may be an acid chloride, acid azide, mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphorous acid, phenylphosphine acid, diphenylphosphoryl acid, dibenzylamine acid, halogenated phosphoric acid, etc.,), dialkylphosphorous acid, sulfurous acid, tisera acid, Alcantara acid (such as methanesulfonate, econsultation, and so on), sulfuric acid, alkaluria acid, aliphatic carboxylic acid (e.g., pavlikova acid, pentane acid, isopentane acid, 2-ethylmalonate acid, trichloroacetic acid, and so on), aromatic carboxylic acid (e.g. benzoic acid, etc.,), a symmetric acid anhydride, activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, activated complex e is SUB>N+=CH-) ester, vinyl ester, propargilovyh ester, p-nitrophenyloctyl ester, 2,4-dinitrophenoxy ester, trichloranisole ester, pentachlorphenol ester, methylphenacyl ester, phenylazophenyl ester, phenylthiomethyl, p-nitrophenyloctyl tiefer, p-crazily tiefer, carboxymethoxy tiefer, paranjoy ether, pyridyloxy ether, piperidinyl ether, 8-hinolinovy tiefer, and so on), ester with N-hydroxy compound (e.g. N, N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N - hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, and so on), substituted or unsubstituted aryl isocyanate, substituted or unsubstituted aryl isothiocyanate, etc. These reactive derivatives can be arbitrarily choose among them based on the type of compound (XIX) to be used.

The reaction is usually carried out in a standard solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, telengard, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which are not harmful line for the reaction. This standard is in free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'- morpholinobutyrophenone, N-cyclohexyl-N'-(4 - diethylaminoethoxy)carbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, N, N-carbonyl-bis(2 - Mei), pentamethylene-N-cyclohexylamine, diphenylmethan-N - cyclohexylamine, ethoxyacetylene, 1-alkoxy-1-chlorethylene, trialkyl postit, isopropyl polyphosphate, phosphorus oxychloride (chlorine phosphoryl), phosphor trichloride, thionyl, chloride, oxalyl, triphenylphosphite, salt of 2-ethyl-7-hydroxybenzotriazole, intra-molecular salt hydroxide 2-ethyl-5-(m-sulfophenyl)-isoxazole, 1-(p-chlorobenzenesulfonate)-6-chloro-1H-benzotriazol, the so-called Vilsmerier reagent obtained by reacting N,N-dimethylformamide with chloride tiomila, phosgene, phosphorous oxychloride, and so on, or, etc.

The reaction can be carried out in the presence of inorganic or organic bases, such as alkali metal (e.g. sodium, potassium and so on), hydroxide of alkaline metal (for example, sodium hydroxide, potassium hydroxide and so on), acid carbonate of an alkali metal (for example, acid carbonate is.D.), three(lower)alkylamine (for example, trimethylamine, triethylamine, diisopropylethylamine and so on), alkali metal hydride (e.g. sodium hydride, etc. ), (lower)alkoxide of an alkali metal (e.g. sodium methoxide, sodium ethoxide and so on), pyridine, lutidine, picoline, dimethylaminopyridine, N-(lower)alkalifying, N,N-di(lower)alkylbenzenes, N,N-di(lower)alkylamino, N-(lower)alkylpyridine (for example, N,N-methyl-2-pyrrolidone, etc. or etc.

The reaction can be carried out in the presence of an acid including Lewis acid.

Suitable acid may be an organic acid (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, triperoxonane acid, and so on) and inorganic acid (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g. zinc chloride, zinc bromide, and so on), etc.

When the acid, base and/or the original connection are liquid, they can be used as a solvent.

The reaction temperature is not significant, and the reaction is usually carried out under cooling to heating.

The invention in which the group during the reaction.

Method (3).

The compound (Ie) or its salt can be obtained by subjecting the compound (Id) or its salt reaction recovery.

This recovery can be performed according to the method similar to the above-mentioned method (1), and therefore, you can use the reagents and reaction conditions (e.g. solvent, reaction temperature and so on), is similar to method (1).

Method (4).

The compound (If) or its salt can be obtained by subjecting the compound (III) or its salt reaction recovery.

This recovery can be performed according to the method similar to the above-mentioned method (1), and therefore, you can use the reagents and reaction conditions (e.g. solvent, reaction temperature and so on), is similar to method (1).

Method (5).

The compound (Ih) or its salt can be obtained by subjecting the compound (Ig) or its salt of the elimination reaction of the hydroxy protective group.

Suitable means such reactions elimination can be a conventional method such as hydrolysis, recovery, etc.

(i) For hydrolysis.

The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.

Suitable acid may serve as an organic acid (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, triperoxonane acid), and inorganic acid (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, and so on).

The elimination using Lewis acid, such as triglossia acid (e.g., trichloroacetic acid, trifurcula acid and so on), or so forth , is preferably carried out in the presence of agents that monitor cation (e.g. anisole, phenol and so on).

The reaction is usually carried out in a standard solvent such as water, alcohol (e.g. methanol, ethanol, isopropyl alcohol, and so on), tetrahydrofuran, dioxane, dichloromethane, ethylene dichloride, chloroform, N,N-dimethylformamide, N, N-dimethylacetamide or any other organic solvent which has no adverse effect on the reaction.

Of these solvents are significant and the reaction is usually carried out under cooling to heating.

(ii) To restore.

The restoration carried out in a standard way, including chemical reduction and catalytic reduction.

Suitable regenerating reagent to be used in chemical reduction are hydrides (for example, modesty hydrogen, hydrogen sulfide, sociallyengaged, sodium borohydride, sodium cyanoborohydride and so on), or a combination of metal (e.g. tin, zinc, iron, and so on ), or compounds of the metal (e.g. chromium chloride, chromium acetate, etc. and organic acid or inorganic acid (e.g. formic acid, acetic acid, propionic acid, triperoxonane acid, p-toluensulfonate, hydrochloric acid, Hydrobromic acid, and so on).

Suitable catalysts to be used in catalytic reduction are standard catalysts such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, and so on), palladium catalysts (e.g. spongy palladium, palladium on barium carbonate, and so on), Nickel catalysts (e.g., the recovered Nickel, Nickel oxide, Raney Nickel, etc.), cobalt catalysts (e.g., the recovered cobalt, Raney cobalt, and so on), iron catalysts (e.g. reduced iron, and so on), etc.

Recovery is usually carried out in a standard solvent which has no adverse effect on the reaction, such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), N,N-dimethylformamide, tetrahydrofuran, methylene dichloride, chloroform, dioxane or a mixture of them.

In addition, in the case when the above-mentioned acid to be used in chemical reduction are liquids, they can also be used as solvent.

The reaction temperature recovery is not significant, and the reaction is usually carried out under cooling to heating.

Method (6).

The compound (Ij) or its salt can be obtained by subjecting the compound (Ii) or its salt of the elimination reaction of amino protective group.

This reaction can be performed according to the method similar to the above method (5), and therefore, you can use the reagents and reaction conditions (e.g. solvent, can be obtained by interaction of the compound (Ik) or its salt with the compound (Iv) or its salt.

This reaction is usually conducted in a solvent such as water, alcohol (e.g. methanol, ethanol and so on), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride: chloroform, dioxane, diethyl ether or any other solvent which does not exert adverse influence on the reaction. These standard solvents can also be used in mixture with water.

The reaction temperature is not significant, and the reaction is usually carried out under cooling to heating.

The reaction is usually carried out in the presence of inorganic or organic bases, such as alkali metal (e.g. sodium, potassium and so on), hydroxide of alkaline metal (for example, sodium hydroxide, potassium hydroxide and so on ), acid carbonate of an alkali metal (e.g. sodium acid carbonate, potassium acid carbonate, and so on), a carbonate of an alkali metal (e.g. sodium carbonate, potassium carbonate and so on), three(lower)alkylamine (for example, trimethylamine, triethylamine, diisopropylethylamine and so on), alkali metal hydride (for example, sodium hydride and so on ), alkali metal (lower) alkoxide (e.g. sodium methoxide, ethoxide sodium and so on), pyridine, lutidine, picoline, dimethylaminopyridine, N-(lower)alkilani/or the original connection are fluid, they can also be used as solvent.

Method (A).

The compound (VII) or its salt can be obtained by reacting compound (V) or its salt with a compound (VI) or its salt.

This reaction can be performed according to the method, opened in obtaining drug 2 or similar methods.

Method (B).

The compound (IX) or its salt can be obtained by reacting compound (VII) or its salt with the compound (VIII) or its salt.

This reaction can be performed according to the method described in preparation 3 or similar methods.

Method (C).

The compound (X) or its salt can be obtained by subjecting the compound (IX) or its salt cleavage reaction O-N bond.

This reaction can be carried out by the method described in preparation 4 or similar ways.

Method (D) (1).

The compound (XI) or its salt can be obtained by subjecting the compound (X) or its salt of the reaction of halogenation.

Halogenoalkane usually carried out using standard halogenation agent, such as halogen (e.g. chlorine, bromine, etc.,), triploid phosphorus (for example, tribromide phosphorus trichloride, FASTA (for example, phosphoryl trichloride, phosphoryl monochloride, and so on), thionyl halide (for example, thionyl chloride thionyl bromide, and so on, oxalyl halide (for example, oxalyl chloride, oxalyl bromide, and so on), etc.

This reaction is usually conducted in a solvent such as water, alcohol (e.g. methanol, ethanol, isopropyl ether, etc.,), benzene, dioxane, N, N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene dichloride, chloroform, diethyl ether or any other solvent which does not exert adverse influence on the reaction.

The reaction temperature is not significant, and the reaction is usually carried out under cooling to warming.

Method (D) (2)

The compound (XIII) or its salt can be obtained by reacting compound (XI) or its salt with the compound (XII) or its salt.

This reaction is usually conducted in a solvent such as water, alcohol (e.g. methanol, ethanol and so on), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, diethyl ether or any other solvent which does not exert adverse influence on the reaction.

The reaction temperature is not significant, and the reaction is usually carried out under cooling to warming.

This reaction is usually conducted in a solvent such as water, alcohol (for example, methanol, ethanol, and so on), benzene, N,N-/dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvent which does not exert adverse influence on the reaction. These standard solvents can also be used in mixture with water.

The reaction temperature is not significant, and the reaction is usually carried out by heating to heating.

The reaction is usually carried out in the presence of inorganic or organic bases, such as alkali metal (e.g. sodium, potassium and so on), hydroxide of alkaline metal (for example, sodium hydroxide, potassium hydroxide and so on ), acid carbonate of an alkali metal (e.g. sodium acid carbonate, potassium acid carbonate, and so on), a carbonate of an alkali metal (e.g. sodium carbonate, potassium carbonate, and so on), three (lower)alkylamino, (for example, trimethylamine, triethylamine, diisopropylethylamine, and so on), the alkali metal hydride (e.g. sodium hydride, and so on), alkali metal(lower)alkoxide (e.g. sodium methoxide, ethoxide sodium, and so on), pyridine, lutidine, picoline, dimethylaminopyridine, N-(lower)alcelam the e and/or the original connection are liquids, they can be also as a solvent.

Method (F).

The compound (XIII) or its salt can be obtained by reacting compound (X) or its salt with the compound (XII) or its salt.

This reaction is usually conducted in a solvent such as benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvent which does not exert adverse influence on the reaction.

The reaction temperature is not significant, and the reaction is usually carried out by heating to heating.

The reaction is usually carried out in the presence of an acid including Lewis acid.

Suitable acid may couple an organic acid (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, triperoxonane acid, and so on), inorganic acid (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g. zinc chloride, zinc bromide, and so on), and so on), etc.

In this case, when the acid and/or the original connection are liquids, they can be also as the tion (XIII) or its salt of the reaction of diazotization.

The reaction is usually carried out using standard diasterous agent, such as a combination of alkali metal nitrite (e.g. sodium nitrite, and so on ) and inorganic acid (e.g. hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid and so on), the combination of isopentyl nitrite and organic acids (e.g. acetic acid, benzoic acid, and so on), etc.

This reaction is usually conducted in a solvent such as water, alcohol (e.g. methanol, ethanol and so on), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvent which does not exert adverse influence on the reaction.

The reaction temperature is not significant, and the reaction is usually carried out under cooling.

Method (H).

The compound (IIa) or its salt can be obtained by reacting compound (XVI) or its salt with the compound (XVII) or its salt.

This reaction is usually conducted in a solvent such as water, alcohol (e.g. methanol, ethanol and so on), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, diethyl ether or any daysa significant, and the reaction is usually carried out under cooling to warming.

Method (I).

The compound (III) or its salt can be obtained by reacting compound (Ib) or its salt with the compound (XVIII) or its salt.

This reaction is usually conducted in a solvent such as water, alcohol (e.g. methanol, ethanol and so on), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvent which does not exert adverse influence on the reaction. These standard solvents can also be used in mixture with water.

The reaction temperature is not significant, and the reaction is usually carried out under cooling to heating.

The reaction is usually carried out in the presence of an acid including Lewis acid.

Suitable acid may serve as an organic acid (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, triperoxonane acid and so on) and inorganic acid (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g. zinc chloride, zinc bromide, and so Z can be also used as a solvent.

Appropriate anion can serve as an anion derived from substances used in the reaction, such as acid residue (for example, halogen (e.g. fluorine, chlorine, bromine, iodine and so on), OH-etc.

Suitable salts of the proposed and reference compounds in method (1) to (7) and (A) - (I) can be attributed salt exemplified for the compound (I).

New pyrazol derivatives (1) and their pharmaceutically acceptable salts of the present invention have a high inhibitory activity on the production of Interleukin-1 (IL-1, IL-1) and a high inhibitory activity on the production of tumor necrosis factor (TNF, TNF), and therefore are useful as an inhibitor on the production of Interleukin-1 (IL-1, IL-1) and inhibitor on the production of tumor necrosis factor (TNF, TNF).

Finally, the new derivatives of pyrazole (1) and their pharmaceutically acceptable salts can be used for prophylactic and therapeutic treatment of diseases mediated by IL-1 and TNF, such as chronic inflammatory diseases (e.g. rheumatoid arthritis, osteoarthritis, and so on), osteoporosis, rejection after transplantation, asthma, bacterial endotoxin-toxic shock syndrome-specific autoimmune diseases (anemia, gipoplasticheskaya anemia, often erythrocyte anemia, idiopathic thrombosis(cyto)singing and so on), systemic lupus erythematosus, inflammation of several cartilages, polychondritis scleroderma, wegener Wegener, dermatomyositis, chronic active hepatitis, muscle weakness, myasthenia gravis, psoriasis, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease, and so on), endocrine ophthalmopathy, graves disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type 1), Reiter syndrome, non-infectious uveitis, autoimmune keratitis (keratoconjunctivitis sicca, vernal keratoconjunctivitis, and so on), interstitially lung fibrosis, psoriatic arthritis, glomerulonephritis (e.g., nephrotic syndrome, minimal change nephropathy, and so on), and so on), etc.) tumor (cancer) cachexia, AIDS cachexia, thrombosis, etc.

To demonstrate the usefulness of derivatives of pyrazole (1) and their pharmaceutically acceptable salts of the present invention are illustrated below, the results of pharmacological tests of typical compounds pyrazol derivatives (1).

Under the terms of each of the example 16 - (5 is therefore, its.

(a) Inhibiting activity production of Interleukin-1 (IL-1, IL-1).

1. Test method.

Purified monocytes in human peripheral blood stimulated with bacterial lipopolysaccharide (1 μg/104cells) in the absence or presence accordingly dissolved the test compounds for 2 days at 37oC in humidified 5% CO2atmosphere. Cultural supernatant analyzed by IL-1 (IL-1) by the method of enzyme-linked immunosorbent assay (ELISA).

The test compound dissolved in absolute DMSO (dimethyl sulfoxide) to obtain 10 mm initial solutions and then diluted in free serum PRM11640.

IL-1 levels were quantified using a commercial FLISA kit (Ohtsuka assay, Japan), using the technique of sandwich. The levels of sensitivity for determination of IL-1B was 20 PG/ml

Inhibitory concentration that causes 50% inhibition (IC50), estimated using a regression analysis of the results of dose-response.

2. The results of the test.

Test connection - IC50(M)

Example 16 - (5) - 9,2 10-8< / BR>
Example 18 - (2) - 8,8 20-8< / BR>
(b) Inhibi peripheral blood stimulated with bacterial lipopolysaccharide (1 μg/104cells) in the absence or presence accordingly dissolved the test compounds for 2 days at 37oC in humidified 5% CO2atmosphere. Cultural supernatant analyzed for TNF (TNF) by the method of enzyme-linked immunosorbent assay (ELISA).

TNF (TNF) levels were quantified using a commercial ELISA kit (Endogen, Inc. USA) using the technique of sandwich. The levels of sensitivity for the determination of TNF was 12 PG/ml

Inhibitory concentration that causes 50% inhibition (IC50), estimated using a regression analysis of the results of dose-response.

2. The results of the test.

Test connection - 1C50(M)

Example 16-(5) - 9,1 10-8< / BR>
Example 18-(2) - 1,1 10-7< / BR>
For therapeutic treatment of the drug product the proposed compound (I) of the invention and their pharmaceutically acceptable salts are used in the form of standard pharmaceutical product in a mixture with conventional pharmaceutically acceptable carrier such as an organic or inorganic solid, or each filler which is suitable for oral, parenteral or external the TKA, pills or suppositories, or in liquid form such as solution, suspension or emulsion for injection, swallowing (ingestion), eye drops, etc. If necessary, in the above preparation may include excipients, such as a stabilizing agent, wetting or emulsifying agent, buffer, or any other commonly used additives.

Effective ingredient can usually be introduced with a standard dose of 0.001 mg/kg to 500 mg/kg, preferably from 0.01 mg/kg to 10 mg/kg, 1 to 4 times a day. However, the above dose may be increased or decreased, based on age, weight and condition of the patient or the method of administration of the drug.

Preferred variants of the proposed compound (I) are the following.

R1there is phenyl which may have 1 to 3 (more preferably one or two) suitable substituent(s) (more preferably phenyl, which may be from 1 to 3 (more preferably one or two; most preferably one) substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyl, lower quinil, mono(or di or three)halo(lower)alkyl, halogen, carboxy, zasio carboxy(lower)alkyl, amino, protected amino, di(lower)alkylamino, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, nitro, acyl, cyano, mercapto, lower alkylthio and imino, most preferably halophenol, or pyridyl which may have 1 to 3 (more preferably one or two) suitable substituent(s) (more preferably pyridyl which may have 1 to 3 (more preferably one or two, most preferably one, substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyl, lower quinil, mono(or di or three)halo(lower)alkyl, halogen, carboxy, protected carboxy, hydroxy, protected hydroxy, aryl, ar(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl, amino, protected amino, di(lower)alkylamino, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, nitro, acyl, cyano, mercapto, lower alkylthio and imino, most preferably pyridyl, R2means phenyl which may have 1 to 3 (more preferably one or two) suitable substituent(s) (more preferably phenyl which may have 1 to 3 (more preferably one or two; most preferably one) substituent(s is(or di or three)halo(lower)alkyl, halogen, carboxy, protected carboxy, hydroxy, protected hydroxy, aryl, ar(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl, amino, protected amino, di(lower)alkylamino, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, nitro, acyl, cyano, mercapto, lower alkylthio and imino), most preferably halophenol), or pyridyl which may have 1 to 3 (more preferably one or two) suitable substituent(s) (more preferably pyridyl which may have 1 to 3 (more preferably one or two; most preferably one) substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyl, lower quinil, mono(or di or three)halo(lower)alkyl, halogen, carboxy, protected carboxy, hydroxy, protected hydroxy, aryl, ar(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl, amino, protected amino, di(lower)alkylamino, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, nitro, acyl, cyano, mercapto, lower alkylthio and imino, most preferably pyridyl, haloperidol or lower alkoxyphenyl), R3means hydrogen or lower alkanoyl, R4about arificially carboxy(lower)alkyl (more preferably lower alkoxycarbonyl(lower)alkyl), phenyl(lower)alkyl which may have 1 to 3 (more preferably one or two) suitable substituent(s) (more preferably phenyl(lower)alkyl which may have 1 to 3 (more preferably one or two) substituent(s) selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkenyl, lower quinil, mono(or di or three)halo(lower)alkyl and di(lower)alkylamino, most preferably mono(or di)halophenol(lower)alkyl), adamantyl, phenyl(lower)alkenyl, tetrahydropyranyl, piperidyl or dissapionting, each of which may have 1 to 3 (more preferably one or two) substituent(s) selected from the group consisting of lower alkyl and acyl (more preferably tetrahydropyranyl, piperidyl or dissapionting, each of which may have one or two substituent(s) selected from the group consisting of lower alkyl and lower alkanoyl, most preferably tetrahydrofuranyl lowest alkylpiperidines lowest alkanolamides, or di(lower)alkylcyclohexanes), indanyl, lower alkanoyl, which may have from 1 to 3 (more preferably one or two) suitable substituent(s) (more preferably the bottom of the substituent(s), selected from the group consisting of carboxy, protected carboxy, lower alkoxy, halogen, protected amino, amino, hydroxy, protected hydroxy, di(lower)alkylamino, most preferably lower alkanoyl, which may have a Deputy selected from the group consisting of carboxy, esterified carboxy, lower alkoxy, halogen, lower alkoxycarbonyl, lower alkanolamine, amino, hydroxy, acyloxy (more preferably lower alkanoyloxy or cyclo(lower)alkylcarboxylic, and di(lower)alkylamino, lower alkoxycarbonyl, lower alkoxyglycerols, lower alkylsulfonyl, cyclo(lower)alkylaryl, aroyl, which may have from 1 to 3 (more preferably one or two) suitable substituent(s) (more preferably benzoyl which may have from 1 to 3 (more preferably one or two) substituent(s) selected from the group consisting of mono(or di or three)halo(lower)alkyl, halogen, protected hydroxy and hydroxy, most preferably benzoyl which may have one or two substituent(s) selected from the group consisting of was trihalo(lower)alkyl, halogen, acyloxy (more preferably lower alkanoyloxy) and hydroxy), ar(lower)alkanoyl, koto phenyl(lower)alkanoyl, which may have from 1 to 3 (more preferably one or two) substituent(s) selected from the group consisting of lower alkoxy, aryl, halogen and mono(or di or three)halo(lower) alkyl, most preferably phenyl(lower)alkanoyl, which may have one or two substituent(s) selected from the group consisting of lower alkoxy, phenyl, halogen and trihalo(lower)alkyl, ar(lower)alkanoyl (more preferably phenyl(lower)alkanoyl), aaltio(lower)alkanoyl (more preferably, phenylthio(lower)alkanoyl), arylcarbamoyl (more preferably phenylcarbamoyl), aryl-thiocarbamoyl (more preferably phenyl-thiocarbamoyl), allpication, which may have from 1 to 3 (more preferably one or two) suitable substituent(s) (more preferably phenylglyoxylic, which may have from 1 to 3 (more preferably one or two, most preferably one, substituent(s) selected from the group consisting of mono(or di or three)halo(lower)the alkyl and lower alkoxy, most preferably phenylglyoxylic, which may have a Deputy selected from the group consisting of was trihalo(lower)alkyl and lower alkoxy), carbarnoyl, which may have one or two suitable Zam is SSI)alkyl, (more preferably, acyloxy(lower)alkyl, lower alkoxy and cyclo(lower)alkyl, heterocyclic carbonyl (more preferably morpholinylcarbonyl), heterocyclic (lower)alkanoyl (more preferably indolyl(lower)alkanoyl or morpholinyl(lower)alkanoyl, or heterocyclic carbarnoyl (more preferably piperidinylcarbonyl), and R5is hydrogen or lower alkyl.

The following preparations and examples are provided to more detailed illustration of the invention.

Preparation 1. To a solution of 4-methylpyridine (74,4 g) and ethyl 4-perbenzoate (134,54 g) in dry tetrahydrofuran (600 ml) under ice cooling are added dropwise 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.6 l). The mixture was stirred at ambient temperature for 30 minutes To the reaction mixture hexane (2.2 l), and the separated solid is collected, washed with hexane and dried. The obtained solid substance was dissolved in 3N-hydrochloric acid (800 ml) and the solution neutralized aqueous saturated sodium bicarbonate solution. Separated solid is collected, washed with water and dried, obtaining 1-(4-forfinal)-2-(pyridin-4-yl)Ethan-1-he (148 g). So pl. 93 - 94oC.

oC for 3 h in nitrogen atmosphere. The cooled mixture was concentrated in vacuo. The residue is recrystallized from isopropyl ether, receiving 3-dimethylamino-1-(4 - forfinal)-2-(pyridin-4-yl)-2-propen-1-he (x 6.15 g).

NMR (CDCl3, ): 2,82 (6H, s), of 6.99 (2H, t, J = 9 Hz), 7,03 (2H, d, J = 6 Hz), 7,35 - of 7.55 (3H, m), 8,48 (2H, sh).

Preparation of 3. A mixture of 3-dimethylamino-1-(4-forfinal)-2-(pyridin-4-yl)-propen-1-it (x 6.15 g) and hydroxylamine hydrochloride (4,75 g) in dry ethanol (40 ml) is boiled with a reverse refrigerator for 20 minutes the Mixture is cooled and concentrated in vacuo. The residue is dissolved in dilute hydrochloric acid and then treated with an aqueous saturated solution of sodium bicarbonate. Precipitation is collected by filtration, washed with water, and dried, obtaining 5-(4-forfinal)-4-(pyridin-4-yl)isoxazol (5.35 g). So pl. 95 - 97oC.

NMR (CDCl3, ): 7,15 (2H, t, J 9 Hz), 7,37 (2H, d, J = 6 Hz), to 7.61 (2H, DD, J = 5 Hz and 9 Hz), 8,46 (1H, s), 8,67 (2H, d, J = 6 Hz).

Preparation 4. A suspension of 5-(4-forfinal)-4-(pyridin-4-yl)-isoxazol (5.35 g) in 1N aqueous sodium hydroxide solution (50 ml) is stirred for 1 h at 60oC. the Solution is cooled, the dried, getting 3-(4-forfinal)-3-oxo-2-(pyridin-4-yl)propanenitrile (5,27 g). So pl. 222 - 225oC.

NMR (CDCl3+ CD3OD, ): 7,11 (2H, t, J = 9 Hz), to 7.77 (2H, DD, J = 5 Hz and 9 Hz), 7,82 (2H, d, J = 6 Hz), 8,11 (2H, d, J = 6 Hz).

Preparation 5. A solution of 3-(4-forfinal)-3-oxo-2-(pyridin-4-yl)propanenitrile (240 mg) in phosphoryl trichloride (3 ml) is stirred for 15 min at 100oC and then evaporated under reduced pressure. To the residue is added toluene and concentrated in vacuo, and the residue is dissolved in ethanol (2 ml). To the mixture is added hydrazine monohydrate (150 mg). The mixture is refluxed for 3 h, cooled, and poured into aqueous saturated sodium bicarbonate solution. Separated oil is extracted with a mixture of ethanol and dichloromethane (2:8). The extract is washed with water, dried and concentrated in vacuo. The residue is recrystallized from methanol, obtaining 5-amino-3-(4-forfinal)-4-(pyridin-4-yl)pyrazole (110 mg). So pl. > 250oC.

NMR CDCl3+ CD3OD, ): was 7.08 (2H, t, J = 9 Hz), 7.23 percent (2H, d, J = 6 Hz), 7,33 (2H, DD, J = 5 Hz and 9 Hz), 8,42 (2H, d, J = 6 Hz).

Preparation 6. Sodium (2,48 g) dissolved in dry ethanol (37 ml) under nitrogen atmosphere. To the solution was added 4-perforaciones (11,65 g) and ethyl isonicotinate (16,41 ml) and the solution is boiled with obratena pressure. The resulting aqueous solution is washed with ether and neutralized with diluted hydrochloric acid. Separated solid is collected, washed with water and dried, obtaining 2-(4-forfinal)-3-oxo-3-(pyridin-4-yl)propanenitrile (16,43 g). So pl. 230 - 232oC.

NMR (CDCl3+ CD3OD, ): for 7.12(2H, t, J = 9 Hz), to 7.68 (2H, d, J = 6 Hz), to 7.84 (2H, DD, J = 5 Hz and 9 Hz), 8,69 (2H, d, J = 6 Hz).

Preparation 7. A mixture of 2-(4-forfinal)-3-oxo-3-(pyridin-4-yl)propanenitrile (10 g), hydrazine monohydrate (2.4 ml) and acetic acid (5.2 ml) in dry benzene (100 ml) was boiled for 4 h, the Reaction mixture is cooled and extracted with 3N-hydrochloric acid (80 ml 3). The extracts concentrated in vacuo to a volume of 100 ml, and the solution is neutralized with an aqueous solution of ammonia. Separated solid is collected, washed with water and dried, obtaining 5-amino-4-(4-forefeel)-3-(pyridin-4-yl)pyrazole (2,02 g). So pl. 116 - 118oC.

NMR (CDCl3+ CD3OD, ): for 7.12 (2H, t, J = 9 Hz), 7,25 (2H, DD, J = 5 Hz and 9 Hz), 7,38 (2H, d, J = 6 Hz), 8,46 (2H, d, J = 6 Hz).

Preparation 8. To a mixture of 5-amino-4-(4-forefeel)-3-(pyridin-4-yl)pyrazole (100 mg) and concentrated hydrochloric acid (0.2 ml) in water (0.4 ml) is added sodium nitrite (28 mg) in water (0,12 ml) under cooling with ice. The mixture is displaced is the sodium (2 ml) and 1-(triphenylphosphonio)-2-propanone (126 mg) in dichloromethane (2 ml). The mixture was stirred at 10oC for 2 hours the Organic layer is separated, dried and concentrated in vacuo. The residue is purified by column chromatography on silica gel and the obtained oil is recrystallized from diisopropyl ether, receiving 8-(4-forefeel)-4-methyl-7-(pyridin-4-yl)pyrazolo-(5,1-C) (1,2,4)triazine (41 mg). So pl. 202,5 - 204,0oC.

NMR (CDCl3, ): only 2.91 (3H, s), 7,18 (2H, t, J = 9 Hz), a 7.62 (2H, DD, J = 5 Hz and 9 Hz), to 7.68 (2H, d, J = 6 Hz), at 8.60 (2H, d, J = 6 Hz), 8,79 (1H, s).

Preparation 9. The following compounds get by the method similar to the method of preparation 8.

(1) 8-(4-forefeel)-7-(pyridin-4-yl)pyrazolo(5,1-C)(1,2,4-triazine. So pl. 180 - 182oC.

NMR (CDCl3, 2): 7,20 (2H, t, J = 9 Hz), 7,55 - of 7.70 (4H, m), 8,59 (1H, d, J = 5 Hz), to 8.70 (2H, d, J = 6 Hz), of 8.90 (1H, d, J = 5 Hz).

(2) 7-(4-forefeel)-4-methyl-8-(pyridin-4-yl)pyrazolo-(5,1-C) (1,2,4)triazine. So pl. 220 - 223oC.

NMR (CDCl3, ): 2,90 (3H, s), 7,17 (2H, t, J = 9 Hz), 7,60 to 7.75 (4H, m), 8,67 (2H, d, J = 6 Hz), 8,81 (1H, m)

(3) 7-(4-forefeel)-8-(pyridin-4-yl)pyrazolo(5,1-C)(1,2,4-triazine.

NMR (CDCl3, ): 7,18 (2H, t, J = 9 Hz), 7,60 to 7.75 (4H, m), 8,59 (1H, d, J = 4 Hz), 8,68 (2H, d, J = 6 Hz), 8,93 (1H, d, J = 4 Hz).

Preparation 10. The following compounds get the technique similar to the technique wearable is>, ): to 4.28 (2H, s), 7,11 - 7,22 (3H, m), 7,27 (1H, s), 8,03 (2H, DD, J = 6 Hz and 9 Hz), of 8.37 (1H, d, J = 6 Hz).

(2) 2-(2-bromopyridin-4-yl)-1-(4-forefeel)ethane-1-it. So pl. 100 - 104oC.

NMR (CDCl3, ): of 4.25 (2H, s), 7,14 - 7,24 (3H, m), 7,40 (1H, s), 8,02 (2H, DD, J = 6 Hz and 9 Hz), 8,35 (1H, d, J = 6 Hz).

Preparation 11. The following compounds are obtained by methods similar to the method of preparation 2 and 3.

(1) 4-(2-chloropyridin-4-yl)-5-(4-forefeel)isoxazol. So pl. 94 - 96oC.

NMR (CDCl3, ): 7,17 (2H, t, J = 9 Hz), 7,22 (1H, d, J = 6 Hz), was 7.36 (1H, s), a 7.62 (2H, DD, J = 6 Hz and 9 Hz), to 8.41 (1H, d, J = 6 Hz), 8,43 (1H, s).

(2) 4-(2-bromopyridin-4-yl)-6-(4-forefeel)isoxazol, So pl. 136 - 138oC.

NMR (CDCl3, ): 7,28 (2H, t, J = 9 Hz), 7,24 (1H, d, J = 6 Hz), 7,53 (1H, s), 7,63 (2H, DD, J = 6 Hz and 9 Hz), 8,39 (1H, d, J = 6 Hz), 8,44 (1H, s).

Preparation 12. The following compounds get on techniques similar to the methods of preparation 4 and 6.

(1) 2-(2-chloropyridin-4-yl)-3-(4-forefeel)-3-oxopropanenitrile. So pl. 204 - 206oC (decomp.).

NMR (CDCl3, + CD3OD, ): 7,13 (2H, t, J = 9 Hz), 7,72 (2H, DD, J = 6 Hz and 9 Hz), 7,73 - of 7.90 (2H, m), of 8.06 (1H, m).

(2) 2-(2-bromopyridin-4-yl)-3-(4-forfinal)-3-oxopropanenitrile So pl. 217 - 219oC (decomp.).

NMR (CDCl3, + CD3OD, ): 7,13 (2H, t, J = 9 Hz the methods, similar methods of preparation 5 and 7.

(1) 5-amino-4-(2-chloropyridin-4-yl)-3-(4-forefeel)pyrazole. So pl. 213 - 216oC.

NMR (CDCl3, + CD3OD, ): 7,03 - 7,14 (3H, m), 7,29 - 7,38 (3H, m), 8,23 (1H, d, J = 6 Hz).

(2) 5-amino-4-(2-bromopyridin-4-yl)-3-(4-forefeel)-pyrazole. So pl. 213 - 215oC.

NMR (CDCl3, + CD3OD, ): 7,01 - 7,14 (3H, m), 7,28 - 7,47 (3H, m), 8,24 (1H, d, J = 6 Hz).

Preparation 14. The following compounds get by the method similar to the method of preparation 8.

(1) 8-(2-chloropyridin-4-yl)-7-(4-forefeel)pyrazolo-(5,1-C) (1,2,4)triazine. So pl. > 250oC.

NMR (DMCO-d6, / ): 7,40 (2H, t, J = 9 Hz), to 7.68 (1H, d, J = 6 Hz), of 7.70 (2H, DD, J = 6 Hz and 9 Hz), 7,60 (1H, s), 8,49 (1H, d, J = 6 Hz), 9,20 (1H, d, J = 5 Hz), 9,40 (1H, d, J = 5 Hz).

(2) 8-(2-bromopyridin-4-yl)-7-(4-forfinal)pyrazolo(5,1-c) (1,2,4)triazine. So pl. 258oC (decomp.).

NMR (DMCO-d6, ): 7,42 (2H, t, J = 9 Hz), 7,58 (1H, d, J = 6 Hz), 7,71 (2H, DD, J = 6 Hz and 9 Hz), 7,80 (1H, s), and 8.50 (1H, d, J = 6 Hz), 9,20 (1H, d, J = 5 Hz), 9,43 (1H, d, J = 5 Hz).

(3) 7-(4-forefeel)-8-(2-foroperation-4-yl)pyrazolo(5,1-c) (1,2,4)triazine. So pl. 240 - 242oC.

NMR (CDCl3: CD3OD = 9:1 ): of 7.23 (2H, t, J = 9 Hz), 7,42 (1H, s), EUR 7.57 (1H, d, J = 6 Hz), 7,69 (2H, DD, J = 6 Hz and 9 Hz), 8,24 (1H, d, J = 6 Hz), 8,78 (1H, d, J = 4 Hz), 9,01 (1H, d, J = 4 Hz).

Sentence is ablaut dropwise concentrated acid (0,32 ml). The mixture is refluxed for 1 h, cooled and poured into cold water. The aqueous solution is neutralized aqueous saturated sodium bicarbonate solution and separated oil is extracted with dichloromethane. The extract is washed with brine, dried and concentrated in vacuo. The residue is purified by column chromatography on silica gel, and the oil obtained is recrystallized from methanol, receiving 7-(4-forefeel)-8-(2-methoxypyridine - 4-yl)pyrazolo(5,1-c)(1,2,4)triazine (220 mg). So pl. 223 - 225oC.

NMR (CDCl3:CD3OD = 9:1, ): 3,99 (3H, s), 7,10-of 7.25 (4H, m), 7,69 (2H, DD, J = 6 Hz and 9 Hz), 8,21 (1H, d, J = 6 Hz), 8,68 (1H, d, J = 4 Hz), 8,93 (1H, d, J = 4 Hz).

Example 1. To a suspension of 7-(4-forefeel)-8-(pyridin - 4-yl)pyrazolo(5,1-c)(1,2,4)triazine (2.2 g) in methanol (20 ml) add cyanoborohydride sodium (480 mg), pH of the mixture support for 3 - 4 for 2 h with 1N hydrochloric acid. The procedure is repeated three more times to complete the restoration. The mixture is then concentrated in vacuo, and the residue dissolved in 2N hydrochloric acid. The mixture was stirred at 80oC for 30 min and cooled. The solution is neutralized aqueous saturated sodium bicarbonate solution. Separated solid substance was the 4)triazine (of 2.06 g). So pl. 233 - 235oC.

NMR (CDCl3:CD3OD = 9:1, ): 3,37 (2H, t, J = 6 Hz), 4,17 (2H, t, J = 6 Hz), 7,13 (2H, t, J = 9 Hz), 7,30 is 7.50 (4H, m), 8,24 (2H, d, J = 6 Hz).

Example 2. The following compounds get the technique similar to the technique of example 1.

(1) 7-(4-forefeel)-4-methyl-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 219 - 221oC.

NMR (CDCl3:CD3OD = 9:1, ): 1,60 (3H, d, J = 7 Hz), 3,05 (1H, DD, J = 6 Hz and 14 Hz), to 3.38 (1H, DD, J = 4 Hz and 14 Hz), 4,33 (1H, m), 7,06 (2H, t, J = 9 Hz), 7,12 (2H, d, J = 6 Hz), 7,40 (2H, DD, J = 9 Hz), of 8.37 (2H, d, J = 6 Hz).

(2) 8-(4-forefeel)-7-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. >250oC.

NMR (CDCl3, ): to 3.38 (2H, K, J = 6 Hz), 3,60 (1H, m), is 4.21 (2H, t, J = 6 Hz), vs. 5.47 (1H, d, J = 5 Hz), 7,06 (2H, t, J = 9 Hz), 7,19 (2H, DD, J = 6 Hz and 9 Hz), 7,35 (2H, d, J = 6 Hz), 8,49 (2H, d, J = 6 Hz).

Example 3. To a solution of 7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine (207 mg) in acetic acid (2 ml) was added under ice cooling, acetic anhydride (75 mg). The solution was stirred at ambient temperature for 1 h and concentrated in vacuo. The residue is dissolved in water (3 ml) and the solution neutralized aqueous saturated sodium bicarbonate solution. Separated oil is extracted with dichloromethane, and the ex-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine (195 mg). So pl. 216 - 218oC.

NMR (CDCl3:CD3OD = 9:1, ): 2,28 (3H, s), of 4.13 (2H, t, J = 6 Hz), 4.26 deaths (2H, t, J = 6 Hz), 7,05 (2H, t, J = 9 Hz), 7,27 (2H, t, J = 6 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz), 8,42 (2H, d, J = 6 Hz).

Example 4. The following compounds get by the method similar to the method of example 3.

(1) 2-acetyl-8-(4-forefeel)-7-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 115 - 120oC.

NMR (CDCl3, ): 2,28 (3H, s), 4,14 (2H, t, J = 6 Hz), 4,28 (2H, t, J = 6 Hz), between 6.08 (1H, s), to 7.09 (2H, t, J = 9 Hz), 7.23 percent (2H, DD, J = 6 Hz and 9 Hz), 7,35 (2H, d, J = 6 Hz), 8,49 (2H, d, J = 6 Hz).

(2) 7-(4-forefeel)-2-formyl-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 233 - 235oC.

NMR (CDCl3, ): 4,10-4,20 (2H, m), 4,25-and 4.40 (2H, m), 6,50 (1H, sh.C), 7,05 (2H, t, J = 9 Hz), to 7.15 (2H, d, J = 6 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz), to 8.45 (2H, d, J = 6 Hz), 8,55 (1H, s).

Example 5. To a mixture of 7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine (148 mg) and triethylamine (101 mg) in dry dichloromethane added acetic anhydride (54 mg). The reaction mixture was stirred at ambient temperature for 4 h, and then to the mixture is added methanol (1 ml). After keeping for 300 min, the mixture was concentrated in vacuo. The residue is purified by column chromatography on silica gel. Per is-hexane, receiving 1,2-diacetyl-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine (22 mg). So pl. 162 - 164oC.

NMR (CDCl3, ): 2,11 (3H, s), 2,22 (3H, s), 3,40 (1H, m), 4,20 is 4.45 (2H, m), 5,07 (1H, DD, J = 6 Hz and 9 Hz), 7,10 (2H, t, J = 9 Hz), 7,14 (2H, d, J = 6 Hz), 7,33 (2H, DD, J = 6 Hz and 9 Hz), 8,58 (2H, d, J = 6 Hz).

The second fraction was concentrated in vacuo, and the oil obtained is recrystallized from ethyl acetate, receiving 2-acetyl-7-(4-forefeel)- 8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo(5,1-c)(1,2,4)triazine (101 mg). So pl. 216 - 218oC.

NMR (CDCl3:CD3OD = 9:1, ): 2,28 (3H, s), of 4.12 (2H, t, J = 6 Hz), 4,25 (2H, t, J = 6 Hz), 7,07 (2H, t, J = 9 Hz), 7,20 (2H, d, J = 6 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz), 8,42 (2H, d, J = 6 Hz).

Example 6. The following two compounds obtained by the reaction of 7-(4-forefeel)-4-methyl-8-(pyridin-4-yl)-1,1,3,4-tetrahydro (5,1-c)(1,2,4)triazine according to methods analogous to the methods of example 5.

2-acetyl-7-(4-forefeel)-4-methyl-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 247 - 249oC.

NMR (CDCl3:CD3OD = 9:1, ): 1,60 (3H, d, J = 7 Hz), is 2.30 (3H, s), 3,93 (1H, DD, J = 6 Hz and 13 Hz), 4,10 (1H, DD, J = 5 Hz and 13 Hz), 4,46 (1H, m), 7,06 (2H, t, J = 9 Hz), 7,21 (2H, d, J = 6 Hz), 7,41 (2H, DD, J = 6 Hz and 9 Hz), 8,42 (2H, d, J = 6 Hz).

1,2-diacetyl-7-(4-forefeel)-4-methyl-8-(pyridin-4-yl)-1,1,3,4 - tetrahydropyran the 11 Hz and 13 Hz), 4,43 (1H, m), of 5.05 (1H, DD, J = 6 Hz and 13 Hz), 7,00 (2H, t, J = 9 Hz), 7,13 (2H, d, J = 6 Hz), was 7.36 (2H, DD, J = 6 Hz and 9 Hz), 8,58 (2H, d, J = 6 Hz).

Example 7. To a mixture of 7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine (100 mg, 0,339 mmol) and pyridine (54 mg, 0,678 mmol) in N-methyl-2-pyrrolidone (1.5 ml) add acetoxyacetyl chloride (60 mg, 0,441 mmol) in N-methyl-2-pyrrolidone (0.5 ml) in nitrogen atmosphere under ice cooling. After stirring for 30 min, the reaction mixture was diluted with aqueous saturated sodium bicarbonate solution, then extracted with ethyl acetate. The organic phase is washed with water and with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by chromatography on silica gel (eluent: dichloro-methane/methanol: 100/1-20/1), and the resulting amorphous product is recrystallized from diisopropyl ether, receiving 2-acetoxyacetyl-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine (76 mg). So pl. 121oC.

NMR (DMCO-d6, ): 2,10 (3H, s), 3.95 to of 4.05 (2H, m), 4,10-4,20 (2H, m), the 4.90 (2H, s), 7,15-7,30 (4H, m), 7,35-7,45 (2H, m), to 8.45 (2H, d, J = 6 Hz), to 8.70 (1H, s).

Example 8. The following compounds get by the method similar to the method of example 7.

(1) 7-(4-forefeel)-2-methylsulphonyl-8-(pyridine-4(3H, C) a 4.03 (2H, t, J = 6 Hz), to 4.33 (2H, t, J = 6 Hz), was 7.08 (2H, t, J = 9 Hz), 7,30-to 8.45 (4H, m), 8,40 (2H, d, J = 6 Hz).

(2) 7-(4-forefeel)-2-methoxycarbonyl-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 215 - 216oC.

NMR (DMCO-d6, ): the 3.65 (3H, s), 3,90-4,00 (2H, m), 4,10-of 4.25 (2H, m), to 7.15 (2H, d, J = 6 Hz), 7,20 (2H, t, J = 9 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz), to 8.45 (2H, d, J = 6 Hz), 8,55 (1H, s).

(3) 7-(4-forefeel)-8-(pyridin-4-yl)-2-(4-(trifloromethyl)benzoyl)- 1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 207 - 209oC.

NMR (DMCO-d6, ): 4,10-and 4.40 (4H, m), 6.75 in-6,90 (2H, m), 7,10 was 7.45 (4H, m), 7,75-a 7.85 (4H, m), 8,20-8,35 (2H, m).

(4) 2-cinnamoyl-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 228 - 230oC.

NMR (CDCl3, ): 4,25-and 4.40 (4H, m), and 6.25 (1H, sh.C), 7,05 (2H, t, J = 9 Hz), 7,20 (2H, d, J = 6 Hz), 7,30-of 7.60 (8H, m), 7,80 (1H, d, J = 15 Hz), 8,55 (2H, d, J = 6 Hz).

(5) 2-benzoyl-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 141oC (decomp.).

NMR (CDCl3, ): 4,20-and 4.40 (4H, m), 6,85-7,10 (4H, m), 7,40 (2H, DD, J = 6 Hz and 9 Hz), 7,45-the 7.65 (5H, m), 8,30-to 8.45 (2H, m).

(6) 2-(4-(acetoxy)benzoyl)-7-(4-forefeel)-8-(pyridin-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 148oC (decomp.).

NMR (CDCl3, ): 2,35 (3H, s), 4,25-and 4.40 (4H, m), 6.90 to-7,10 (4H, m), 7,20 (2H, t, J = 9 Hz), 7,40 (2H, DD, J = 6 is tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 214 - 215oC.

NMR (DMCO-d6, ): of 2.45 (2H, t, J = 6 Hz), of 2.72 (2H, t, J = 6 Hz), was 4.02 (2H, t, J = 5 Hz), is 4.15 (2H, t, J = 5 Hz), 7,10-7,30 (4H, m), 7,40 (2H, DD, J = 6 Hz and 9 Hz), 8,49 (2H, d, J = 6 Hz), to 8.70 (1H, s).

(8) 2-chloroacetyl-7-(4-forefeel)-8-(pyridin-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-c)(1,2,4)triazine.

NMR (CDCl3, ): 4,15-of 4.25 (2H, m), 4,25 is 4.35 (2H, m), and 4.40 (2H, s), of 6.45 (1H, s), 7,00 (2H, t, J = 9 Hz), to 7.15 (2H, d, J = 6 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz) and 8.50 (2H, d, J = 6 Hz).

(9) 7-(4-forefeel)-2-methoxyacetyl-8-(pyridin-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 219oC (decomp.).

NMR (CDCl3, ): of 3.45 (3H, s), 4,10-of 7.25 (2H, m), 4,25 is 4.35 (2H, m), and 4.40 (2H, s), of 6.45 (1H, sh.C), 7,05 (2H, t, J = 9 Hz), to 7.15 (2H, d, J = 6 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz) and 8.50 (2H, d, J = 6 Hz).

(10) 7-(4-forefeel)-2-pivaloyl-8-(pyridin-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 248 - 250oC.

NMR (CDCl3, ): of 1.30 (9H, s), 4,10-4,20 (2H, m), 4,22-4,32 (2H, m), 6,28 (1H, sh. C)? 7.04 baby mortality (2H, t, J = 9 Hz), 7,14 (2H, d, J = 6 Hz), 7,41 (2H, DD, J = 6 Hz and 9 Hz) and 8.50 (2H, d, J = 6 Hz).

(11) 2-cyclohexylcarbonyl-7-(4-forefeel)-8-(pyridin-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 209 - 211oC.

NMR (CDCl3, ): 1,20-1,60 (6H, m), 1,70-1,90 (4H, m), 2.95 and-3,10 (1H, m), 4,10-4,20 (4H, m), x 6.15 (1H, sh.C), 7,05 (2H, t, J = 9 Hz), to 7.15 (2H, d, J = 6 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz) and 8.50 (2H, d, J = 6 Hz).

(12) 2-CEC is UP>oC.

NMR (CDCl3, ): 1,20-to 1.83 (8H, m), 1,90-of 2.05 (2H, m), 2,35-2,52 (1H, m), 4,10-4,20 (2H, m), 4,24 is 4.35 (2H, m) to 5.00 (2H, s), is 6.54 (1H, c), 7,05 (2H, t, J = 9 Hz), 7,12 (2H, d, J = 6 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz), and 8.50 (2H, d, J = 6 Hz).

(13) 2-cyclopropanecarbonyl-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine. So pl. 192 - 194o.

NMR (CDCl3, ): 0,80-of 1.15 (4H, m), 2,52 (1H, m), 4,10-to 7.35 (4H, m), of 6.52 (1H, s),? 7.04 baby mortality (2H, t, J = 9 Hz), 7,17 (2H, d, J = 6 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz), 8,49 (2H, d, J = 6 Hz).

(14) 2-(3,3-dimethylbutyryl)-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine. So pl. 120oC (decomp).

NMR (CDCl3, ): of 1.03 (9H, s) of 2.50 (2H, s), 4,14-4,30 (4H, m), between 6.08 (1H, s), 7,03 (2H, t, J = 9 Hz), 7,17 (2H, d, J = 6 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz) and 8.50 (2H, d, J = 6 Hz).

(15) 7-(4-forefeel)-2-isopropylaminocarbonyl-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine. So pl. 170 - 172oC.

NMR (CDCl3, ): to 1.32 (6H, d, J = 6 Hz), 4,10 (2H, t, J = 5 Hz), 4,25 (2H, t, J = 5 Hz), free 5.01 (1H, Quint, J = 6 Hz), 6,0 (1H, sh.C.), 7,03 (2H, t, J = 9 Hz), 7,16 (2H, d, J = 6 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz), 8,51 (2H, d, J = 6 Hz).

(16) 2-(3-chloro-2,2-dimethylpropanoyl)-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4) triazine. So pl. 188 - 189oC.

NMR (CDCl3, ): of 1.20 (6H, s), 3,20 (2H, s), 4,14 (2H, t, J = 5 Hz), 4,32 (2H, t, J = 5.5 Hz), 7,00 (2H) - Rev.)-8-pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine. So pl. 204oC (sec).

NMR (CDCl3, ): of 0.79 (3H, t, J = 9 Hz), 1.27mm (6H, s) to 1.70 (2H, K, J = 9 Hz), 4,12-is 4.21 (2H, m), 4,24-to 4.33 (2H, m), of 6.20 (1H, sh.C.), ? 7.04 baby mortality (2H, t, J = 9 Hz), 7,13 (2H, d, J = 6 Hz), the 7.43 (2H, DD, J = 6 Hz and 9 Hz), charged 8.52 (2H, d, J = 6 Hz).

(18) 2-ethoxalyl-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo (5,1-C) (1,2,4)triazine. So pl. 174 - 176oC.

NMR (CDCl3, ): of 1.29 (3H, t, J = 7 Hz), 4,18 (2H, t, J = 6 Hz), 4,25 is 4.45 (4H, m), 6,95-to 7.15 (4H, m), 7,39 (2H, DD, J = 6 Hz and 9 Hz), 6,37 (7H, d, J = 6 Hz).

(19) 7-(4-forefeel)-2-(3-methoxyphenyl)-glyoxylyl)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine hydrochloride. So pl. 270 - 279oC (sec.).

NMR (CDCl3, + CD3OD, ): of 3.80 (3H, s), 4,30-and 4.40 (2H, m), 4,40-4,50 (2H, m), 7,07-7,19 (3H, m), 7,25-7,40 (7H, m), by 8.22 (2H, d, J = 6 Hz).

(20) 2-acetoxyacetyl-8-(4-forefeel)-7-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine. So pl. 231 - 232oC.

NMR (CDCl3: CD3OD = 9:1, ): to 2.18 (3H, s), of 4.13 (2H, t, J = 6 Hz), 4,30 (2H, t, J = 6 Hz), to 4.92 (2H, s), to 7.09 (2H, t, J = 9 Hz), 7,21 (2H, DD, J = 6 Hz and 9 Hz), was 7.36 (2H, d, J = 6 Hz), 8,48 (2H, d, J = 6 Hz),< / BR>
Example 9. A mixture of 7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine (118 mg) and ethyl isocyanate (30 mg) in dichloromethane (2 ml) was stirred at ambient temperature for 1 h the Mixture was concentrated in vacuo, and the residue p is Asolo (5,1-C) (1,2,4)triazine (120 mg). So pl. 235 - 240oC.

NMR (CDCl3: CD3OD = 9:1, ): of 1.12 (3H, t, J = 7 Hz) at 3.25 (2H, K, J = 7 Hz), 4,07 (2H, t, J = 6 Hz), 4,20 (2H, t, J = 6 Hz),? 7.04 baby mortality (2H, t, J = 9 Hz), 7,14 (2H, d, J = 6 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz), of 8.47 (2H, d, J = 6 Hz).

Example 10. The following compounds get by the method similar to the method of example 9.

(1) 7-(4-forefeel)-2-(phenyl(thiocarbamoyl))-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine. So pl. 197 - 200oC.

NMR (CDCl3, ): and 4.40 (2H, t, J = 6 Hz), a 4.83 (2H, t, J = 6 Hz), 7,06 (2H, t, J = 9 Hz), 7,15-to 7.50 (10H, m), 8,48 (2H, d, J = 6 Hz), 9,20 (1H, s),

(2) 7-(4-forefeel)-2-phenylcarbamoyl-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine. So pl. 180 - 182oC.

NMR (CDCl3, ): to 4.17 (2H, t, J = 6 Hz), 4,28 (2H, t, J = 6 Hz), 6,95-7,10 (3H, m), 7,15-7,45 (N, m) to 8.12 (1H, s), 8,51 (2H, d, J = 6 Hz).

(3) 2-carbarnoyl-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine. So pl. 141 - 145oC.

NMR (CDCl3: CD3OD = 9:1, ): 4,06 (2H, t, J = 6 Hz) to 4.23 (2H, t, J = 6 Hz), 7,07 (2H, t, J = 9 Hz), 7,25 (2H, d, J = 6 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz), 8,43 (2H, d, J = 6 Hz).

Example 11. A mixture of 7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine (74 mg) and N,N'-disuccinimidylsulfite (77 mg) in dry N,N-dimethylformamide (2 ml) is stirred at a temperature of Okuma environment for 3 hours The reaction mixture was poured into cold water and the separated oil is extracted with ethyl acetate. The extract is washed with brine, dried and concentrated in vacuo. The residue is recrystallized from ethyl acetate, receiving 2-diethylcarbamoyl-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine (80 mg). So pl. 223 - 226oC.

NMR (CDCl3: CD3OD = 9:1, ) : a 1.01 (6H, t, J=7 Hz), with 3.27 (4H, K, J = 7 Hz), a-3.84 (2H, so J = 6 Hz), 4,35 (2H, t, J = 6 Hz), 7,03 (2H, t, J = 9 Hz), to 7.15 (2H, d, J = 6 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz), 8,40 (2H, d, J = 6 Hz).

Example 12. The following compounds get by the method similar to the method of example 11.

(1) 7-(4-forefeel)-2-morpholinomethyl-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo (5,1-C) (1,2,4)triazine. So pl. 232 - 234oC.

NMR (CDCl3: CD3OD = 9:1, ): to 3.52 (4H, t, J = 6 Hz), 3,63 (4H, t, J = 6 Hz), 3,66 (2H, t, J = 6 Hz), 4,35 (2H, t, J = 6 Hz), 7,06 (2H, t, J = 9 Hz), 7,17 (2H, d, J = 6 Hz), 7,41 (2H, DD, J = 6 Hz and 9 Hz), to 8.41 (2H, d, J = 6 Hz).

(2) 2-bis-(2-hydroxyethyl)carbarnoyl-7-(4-forefeel)-8-pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo (5,1-C) (1,2,4) triazine. So pl. 118 - 121oC.

NMR (CDCl3:CD3OD = 9:1, ) : 3,50 (4H, t, J = 6 Hz), 3,62 (4H, t, J = 6 Hz), with 3.89 (2H, t, J = 6 Hz), 7,07 (2H, t, = 9 Hz), 7,18 (2H, d, J = 6 Hz), 7,38 (2H, DD, J = 6 Hz and 9 Hz), 8,49 (2H, d, J = 6 Hz).

(3) 2-CEC

NMR (CDCl3, ): 1,00-1,50 (4H, m), 1,50-1,80 (4H, m), 1,80-2,00 (2H, m), of 3.60 (1H, m), 4,07 (2H, t, J = 6 Hz), to 4.23 (2H, t, J = 6 Hz), 5,9 (1H, d, J = 8 Hz), 6,10 (1H, s), 7,03 (2H, t, J = 9 Hz), 7,11 (2H, d, J = 6 Hz), 7,42 (2H, DD, J = 6 Hz and 9 Hz), 8,53 (2H, d, J = 6 Hz).

(4) 7-(4-forefeel)-2-piperidine-4-yl)carbarnoyl-8-pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine. So pl. 140 - 141oC.

NMR (CDCl3:CD3OD = 9:1, ): of 1.39 (2H, m), of 1.65 (4H, m), 2,70 (4H, t, J = 5 Hz), 4,30 (2H, t, J = 6 Hz), to 4.23 (2H, t, J = 6 Hz), 7,07 (2H, t, J = 9 Hz), to 7.15 (2H, d, J = 6 Hz), 7,38 (2H, DD, J = 6 Hz and 9 Hz), of 8.47 (2H, d, J = 6 Hz).

(5) 7-(4-forefeel)-2-methoxycarbonyl-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine. So pl. 209 - 210oC.

NMR (CDCl3:CD3OD, ): to 3.73 (3H, s) 4,07 (2H, t, J = 6 Hz), 4.26 deaths (2H, t, J = 6 Hz), 7,07 (2H, t, J = 9 Hz), 7,18 (2H, d, J = 6 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz), 8,42 (2H, d, J = 6 Hz).

(6) 7-(4-forefeel)-2-(2-hydrooximethylcarbamil)-8-pyridin-4-yl)-1,2,3,4 - tetrahydrocarbazole(5,1 - C) (1,2,4)triazine. So pl. 139 - 140oC (decomp.).

NMR (DMCO-d6, ): 3,13 (2H, m) to 3.38 (2H, m), 3,85 (2H, t, J = 6 Hz), 4,07 (2H, t, J = 6 Hz) and 4.65 (1H, t, J = 5 Hz), 6,85 (1H, t, J = 5 Hz), 7,20 (2H, t, J = 9 Hz), 7,27 (2H, d, J = 5 Hz), 7,27 (2H, DD, J = 6 Hz and 9 Hz), of 8.47 (2H, d, J = 5 Hz) and 8.50 (1H, s).

Example 13. A mixture of 3-indolylacetic acid (57 mg, 0,325 mmol), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide (50 ml, 0,325 mmol) and 1-hidroxi the th environment. Then added to the mixture of 7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo (5,1-C) (1,2,4) triazine (80 mg, 0,271 mmol) in N,N-dimethylformamide (1 ml). After stirring for 2 h, the mixture was diluted with water and extracted with ethyl acetate. The organic phase is washed with water and with brine, dried over sodium sulfate and concentrated in vacuo. The residue is purified by recrystallization from ethyl acetate, receiving 7-(4-forefeel)-2-(3-indolylacetic)-8-pyridin-4-yl)-12,3,4 - tetrahydrocarbazole(5,1-C) (1,2,4)triazine (87 mg). So pl. 212 - 214oC.

NMR (CDCl3+ CD3OD, ): as 4.02 is 4.13 (4H, m), 4,18 - 4,27 (2H, m), of 6.96 - 7,24 (7H, m), 7,32 - 7,42 (3H, m), 7,58 (1H, d, J = 8 Hz), of 8.37 (2H, d, J = 6 Hz).

Example 14. The following compounds get by the method similar to the method of example 13.

(1) 2-tert-butoxycarbonylamino-7-(4-forefeel)-8-(pyridin-4-yl) -1,2,3,4-tetrahydropyrazolo(5,1 - C) (1,2,4) triazine.

NMR (CDCl3, ): a 1.45 (9H, s), 4,10 - 4,20 (2H, m), 4,20 is 4.35 (4H, m), 5,20 - and 5.30 (1H, m), 6,70 (1H, sh.C.), 7,05 (2H, t, J = 9 Hz), to 7.15 (2H, d, J = 6 Hz), 7,35 (2H, DD, J = 6 Hz and 9 Hz), to 8.45 (2H, d, J = 6 Hz).

(2) 7-(4-forefeel)-2-(2-methoxy-2-methylpropionyl)-8-(pyridin-4-yl)- 1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine. So pl. 114 - 116oC.

NMR (CDCl3, ): 1,50 (6H, s), or 3.28 (3H, s), 4,20 is 4.36 (3H, m), with 4.64 of 4.83 (1H, m), 7 droperidol(5,1-C) (1,2,4)triazine. So pl. 213 - 215oC.

NMR (CDCl3, ) : to 3.34 (3H, s), 3,70 - 3,88 (1H, m), 4,20 - 4,30 (2H, m), 4,45 - 4,58 (1H, m), 5,77 (1H, s), 5,88 (1H, s), 6,98 - was 7.08 (4H, m), 7,27 - 7,33 (5H, m), 7,38 (2H, DD, J = 6 Hz and 9 Hz), 8,56 (2H, d, J = 6 Hz).

(4) 2-(biphenyl-4-yl)acetyl)-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine. So pl. 153oC.

NMR (CDCl3, ): 3,98 (2H, s), 4,12 - 4,20 (2H, m), 4,20 - 4,32 (2H, m), 6,04 (1H, s), 7,03 (2H, t, J = 9 Hz), was 7.08 (2H, d, J = 6 Hz), 7.23 percent - EUR 7.57 (11H, m), and 8.50 (2H, d, J = 6 Hz).

(5) 2-((2,6-dichlorophenyl)acetyl)-7-(4-forefeel)-8-(pyridin-4-yl)- 1,2,3,4-tetrahydropyrazolo (5,1-C) (1,2,4)triazine. So pl.> 250 oC.

NMR (CDCl3+ CD3OD, ): 4,15 - 4,24 (2H, m), 4,24 - 4,37 (4H, m), 7,06 (2H, t, J = 9 Hz), 7,10 - 7,33 (5H, m), the 7.43 (2H, DD, J = 6 Hz and 9 Hz), 8,48 (2H, d, J = 6 Hz).

(6) 2-(N,N-dimethylaminoacetyl)-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo (5,1-C) (1,2,4)triazine the dihydrochloride. So pl. > 250oC.

NMR (DMCO-d6, ): 2,82 (6H, s), 4,10 (2H, t, J = 5 Hz), 4,25 (2H, t, J = 5 Hz), and 4.40 (2H, s), 7,30 (2H, t, J = 9 Hz), 7,47 (2H, DD, J = 6 Hz and 9 Hz), 7,79 (2H, d, J = 6 Hz), to 8.70 (2H, d, J = 6 Hz), 10,12 (1H, s).

(7) 7-(4-forefeel)-2-(phenylthiomethyl)-8-pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo (5,1 - C) (1,2,4) triazine hydrochloride. So pl. 235 - 238oC.

NMR (DMCO-d6, ): 3,95 -4,20 (6H, m), 7,10 - 7,40 (7H, m), 7,49 (2H, DD, J = 6 Hz and 9 Hz), 7,69 (2H, d, J = 6 Hz), 8,68 (2H, d,gold(5,1-C) (1,2,4)triazine hydrochloride. So pl. 254oC (decomp.).

NMR (CDCl3+ CD3OD, ): of 4.05 (2H, s), 4,17 - 4,39 (4H, m), 7,13 (2H, t, J = 9 Hz), 7.24 to 7,42 (6H, m), 7,62 - 7,74 (2H, m), 8,32-of 8.50 (2H, m)

(9) 2-((3,4-acid)acetyl)-7-(4-forefeel)-8-(pyridin - 4-yl)-1,2,3,4-tetrahydropyrazolo(5,1-C)(1,2,4-triazine hydrochloride.

NMR (CDCl3, ): to 3.73 (6H, s), of 3.96 (2H, s), 4,18-4.26 deaths (4H, m), 6,62 (1H, m), only 6.64 (2H, d, J = 8 Hz), 7,13 (2H, t, J = 9 Hz), 7,37 (2H, DD, J = 6 Hz and 9 Hz), 7,70-to 7.77 (2H, m), 8,1 P-to 8.20(2H, m), 9,60 (1H, sh.S.).

(10) 2-acetylaminophenol)-7-(4-forefeel)-8-(pyridin-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-C)(1,2,4)triazine hydrochloride. So pl. 239 - 243oC.

NMR (DMCO-d6, ): to 1.87 (3H, s) to 4.01 (2H, t, J = 5 Hz), 4,12 (2H, d, J = 6 Hz), 4,20 (2H, t, J = 5 Hz), 7,30 (2H, t, J = 9 Hz), of 7.48 (2H, DD, J = 6 Hz and 9 Hz), 7,69 (2H, d, J = 6 Hz), 8,11 (1H, t, J = 6 Hz), of 7.69 (2H, d, J = 6 Hz), 8,11 (1H, t, J = 6 Hz), to 8.70 (2H, d, J = 6 Hz), for 9.64 (1H, s).

Example 15. To a solution of 2-acetyl-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine (59 mg) in tetrahydrofuran is added dropwise borane-tertrahydrofuran ring complex (1.0 M solution in tetrahydrofuran, 1 ml). The solution was stirred at ambient temperature for 5 h, and to the solution is added dropwise 1N-hydrochloric acid (3 ml). The solution was stirred at 80oC for 20 min, and the tetrahydrofuran is evaporated. Then water Rusticana. The extract is dried and concentrated in vacuo. The residue is purified by column chromatography on silica gel, and the oil obtained is recrystallized from ethyl acetate, receiving 2-ethyl-7-(4-forefeel)-8-(pyridin-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-c)(1,2,4)triazine (30 ml). So pl. 144 - 145oC.

NMR (CDCl3, / ): of 1.23 (3H, t, J = 7 Hz), 2,28 (2H, K, J = 7 Hz), 3,37 (2H, t, J = 6 Hz), 4,25 (2H, t, J = 6 Hz), of 6.02 (1H, s),? 7.04 baby mortality (2H, t, J = 9 Hz), 7,22 (2H, d, J = 6 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz), to 8.40 (2H, d, J = 6 Hz).

Example 16. The following compounds get by the method similar to the method of example 15.

(1) 2-(3,4-dichlorophenyl)methyl-7-(4-forefeel)-8-(pyridin-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-c) (1,2,4)triazine. So pl. 188 - 191oC.

NMR (CDCl3, ): 3,40 (2H, t, J = 6 Hz), 3,93 (2H, s), 4,30 (2H, t, J = 6 Hz), of 5.68 (1H, s), of 6.99 (2H, d, J = 6 Hz), 7,05 (2H, t, J = 9 Hz), 7,20 (1H, d, J = 8 Hz), 7,35-of 7.55 (4H, m), to 8.41 (2H, d, J = 6 Hz).

(2) 7-(4-forefeel)-2-isobutyl-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 159 - 162oC.

NMR (CDCl3, ): 0,98 (6H, d, J = 7 Hz), was 1.94 (1H, Quint, J = 7 Hz), 2,58 (2H, d, J = 7 Hz), 3,32 (2H, t, J = 6 Hz), 4,25 (2H, t, J = 6 Hz), 558 (1H, s), 7,03 (2H, t, J = 9 Hz), to 7.09 (2H, d, J = 6 Hz), the 7.43 (2H, DD, J = 6 Hz and 9 Hz), of 8.47 (2H, d, J = 6 Hz).

(3) 2-cyclopropylmethyl-7-(4-forefeel)-8-(pyridin-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-c)(1,2,4) is, ,23 (2H, t, J = 6 Hz), 5,95 (1H, s), 7,03 (2H, t, J = 9 Hz), to 7.09 (2H, d, J = 6 Hz), 7,42 (2H, DD, J = 6 Hz and 9 Hz) and 8.50 (2H, d, J = 6 Hz).

(4) 2-(3,3-dimethylbutyl)-7-(4-forefeel)-8-(pyridin-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 185oC (decomp.).

NMR (CDCl3, ): 0,94 (9H, s), 1,50-1,60 (2H, m), of 2,75 2,85 (2H, m) to 3.35 (2H, t, J = 6 Hz), 4,25 (2H, t, J = 6 Hz), 7,02 (2H, t, J = 9 Hz), 7,10 (2H, d, J = 6 Hz), the 7.43 (2H, DD, J = 6 Hz and 9 Hz), 8,48 (2H, d, J = 6 Hz).

(5) 7-(4-forefeel)-2-neopentyl-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 174oC (decomp).

NMR (CDCl3, ): 1,00 (9H, s), 2,59 (2H, s), 3,30 (2H, t, J = 5 Hz), 4,25 (2H, t, J = 5 Hz), 5,70 (1H, s), 7,03 (2H, t, J = 9 Hz), was 7.08 (2H, d, J = 6 Hz), the 7.43 (2H, DD, J = 6 Hz and 9 Hz), 8,46 (2H, d, J = 6 Hz).

(6) 2-cyclohexylmethyl-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 120 - 135oC (decomp.).

NMR (CDCl3, ): 0,84-1,P5 (2H, m), 1,13-of 1.40 (4H, m), 1,54-1,90 (5H, m) 2,60 (2H, d, J = 6 Hz), 3,29 (2H, t, J = 6 Hz), 4,24 (2H, t, J = 6 Hz), to 5.56 (1H, s), 7,02 (2H, t, J = 9 Hz), was 7.08 (2H, d, J = 6 Hz), the 7.43 (2H, DD, J = 6 Hz and 9 Hz), of 8.47 (2H, d, J = 6 Hz).

(7) 2-(2,2-dimethylbutyl)-7-(4-forefeel)-8-(pyridin-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-c)(1,2,4)triazine. So pl. 148 - 151oC (decomp.).

NMR (CDCl3, ): or 0.83 (3H, t, J = 8 Hz), were 0.94 (6H, s) of 1.36 (2H, K, J = 8 Hz), 2,59 (2H, s), 3,26 (2H, t, J = 6 Hz), 4,25 (2H, t, J = 6 Hz), 5,67 (1H, s), 7,02 (2H, t, J = 9 Hz), 7,07 (2H, tetrahydropyrazolo(5,1-c)(1,2,4)triazine (89 mg) and cyanoborohydride sodium (63 mg) in methanol (1 ml) was added acetone (0.1 ml) under cooling. the pH of the mixture was adjusted to 3-4 1N hydrochloric acid, and the solution stirred at 4oC for 30 minutes and Then the solution is neutralized aqueous saturated sodium bicarbonate solution and poured into cold water. Separated oil is extracted with ethyl acetate, the extract washed with brine, dried and concentrated in vacuo. The residue is recrystallized from diethyl ether, receiving 7-(4-forefeel)-2-isopropyl-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine (75 mg).

NMR (CDCl3, ): of 1.20 (6H, d, J = 7 Hz), to 3.09 (1H, m), 3,42 (2H, t, J = 6 Hz), is 4.21 (2H, t, J = 6 Hz), 5,62 (1H, s), 7,03 (2H, t, J = 9 Hz), 7,10 (2H, d, J = 6 Hz), 7,42 (2H, DD, J = 6 Hz and 9 Hz), 8,48 (2H, d, J = 6 Hz).

Example 18. The following compounds get the technique similar to the technique of example 17.

(1) 2-(adamantane-2-yl)-7-(4-forefeel)-8-(pyridin-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-C)(1,2,4)triazine. So pl. 224oC (decomp.).

NMR (CDCl3, ) : 1,47 - 2,18 (14H, m), 2,90 (1H, m), 3,44 (2H, t, J=6 Hz), 4,18 (2H, t, J=6 Hz), 5,63 (1H, s), 7,03 (2H, t, J=9 Hz), was 7.08 (2H, d, J=6 Hz), 7,44 (2H, DD, J=6 Hz and 9 Hz), 8,48 (2H, d, J=6 Hz).

(2) 2-cyclohexyl-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-c)(1,2,4)triazine.

NMR (CDCl3, ) : 1,10 - 1,40 (4H, m), 1.55V is 2.10 (6H, m), 2,73 (1H, m), of 3.45 (2H, t, J=6 Hz), 4,19 (2H, t, J=6 Hz), 5,67 (1H, s), 7,03 (Iran-4-yl), -1,2,3,4-tetrahydropyrazolo(5,1-C)(1,2,4)triazine.

NMR (CDCl3, ) : 1,50 - 1,80 (2H, m), 1.85 to 2.05 is (2H, m), 2,98 (1H, m), 3,30 - to 3.50 (4H, m), 3.95 to - 4,10 (2H, m), is 4.21 (2H, t, J=6 Hz), 5,70 (1H, s), 7,03 (2H, t, J=9 Hz), 70,9 (2H, d, J= 6 Hz), to 4.41 (2H, DD, J=6 Hz and 9 Hz), 8,48 (2H, d, J=6 Hz).

(4) 2-(1-acetylpiperidine-4-yl)-7-(4-forefeel)-8-(pyridin-4-yl) -1,2,3,4-tetrahydropyrazolo(5,1-C)triazine.

NMR (CDCl3) : of 1.52 (2H, m) to 1.99 (2H, m), 2,11 (3H, s), 2,78 (1H, m), 2,98 (1H, m) and 3.15 (1H, m), 3,47 (2H, t, J=6 Hz), 3,85 (1H, m), 4,22 (2H, t, J= 6 Hz), 4,51 (1H, m), 5,69 (1H, s), 7,03 (2H, t, J=9 Hz), to 7.09 (2H, d, J=6 Hz), 7,41 (2H, DD, J= 6 Hz), of 8.47 (2H, d, J=6 Hz).

(5) 7-(4-forefeel)-2-(1-methylpiperidin-4-yl)-8-(pyridin-4-yl) -1,2,3,4-tetrahydropyrazolo(5,1-C)(1,2,4) triazine.

NMR (CDCl3: CD3OD= 9:1, ) : 1,50 - 1,75 (2H, m), 1,90 - of 2.15 (4H, m), is 2.30 (3H, s), 2,65 - of 3.00 (3H, m), of 3.46 (2H, t, J=6 Hz), 4,19 (2H, t, J=6 Hz), 7,07 (2H, t, J=9 Hz), 7,12 (2H, d, J=6 Hz), 7,39 (2H, DD, J=6 Hz and 9 Hz), scored 8.38 (2H, d, J=6 Hz).

(6) 7-(4-forefeel)-2-(1-methoxycarbonylethyl)-8-(pyridin-4-yl) -1,2,3,4-tetrahydropyrazolo(5,1-C)(1,2,4)triazine. So pl. 132 - 134oC.

NMR (CDCl3, ) : a 1.50 (3H, d, J=7 Hz), 3.27 to to 3.58 (2H, m), of 3.78 (3H, s), 3,82 (1H,, J=7 Hz), 4,10 - and 4.40 (2H, m), 6,04 (1H, s), 7,03 (2H, t, J= 9 Hz), 7,10 (2H, d, J=6 Hz), 7,41 (2H, DD, J=6 Hz and 9 Hz), 8,48 (2H, d, J=6 Hz).

(7) 7-(4-forefeel)-2-(indan-2-yl)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C)(1,2,4)triazine. So pl. 232oC (decomp.).

7,15 - of 7.25 (4H, m), 7,41 (2H, DD, J=6 Hz and 9 Hz), 8,48 (2H, d, J=6 Hz).

(8) 2-((E)-cinnamyl)-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C)(1,2,4)triazine. So pl. 178 - 183oC.

NMR (CDCl3, ) : of 3.43 (2H, t, J=6 Hz), 3,63 (2H, d, J=6 Hz), 4,27 (2H, t, J=6 Hz), 5,80 (1H, sh.C.), 6,27 (1H, dt, J=6 Hz and 15 Hz), 6,0 (1H, d, J=15 Hz), 6,98 - to 7.09 (4H, m), 7,27 and 7.36 (5H, m), the 7.43 (2H, DD, J=6 Hz and 9 Hz), 8,40 (2H, d, J=6 Hz).

(9) 2-(3,3-dimethyl-1,5-dioxaspiro(5,5)indecon-9-yl)-7-(4 - forefeel)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo-(5,1-C)(1,2,4)triazine. So pl. 186oC (decomp.).

NMR (CDCl3, ) : 0,98 (6H, s), 1,44 to 1.76 (4H, m), 1.85 to to 1.98 (2H, m), 2,15 - of 2.28 (2H, m), 2,78 - only 2.91 (1H, m), of 3.46 (2H, t, J=6 Hz), 3,52 (4H, d, J=4 Hz), 4,20 (2H, t, J=6 Hz), ceiling of 5.60 (1H, s), 7,03 (2H, t, J=9 Hz), to 7.09 (2H, d, J=6 Hz), 7,41 (24, DD, J=6 Hz and 9 Hz), 8,46 (2H, d, J=6 Hz).

Example 19. The mixture acetoxyacetyl-7-(4-forefeel)-8-pyridin-4-yl) -1,2,3,4-tetrahydropyrazolo(5,1-C)(1,2,4)triazine (75 mg), 0,190 mmol and an aqueous solution of sodium hydroxide (1M, of 0.38 ml, 0,380 mmol) in ethanol (1.5 ml) is stirred for 30 min at ambient temperature. After dilution aqueous saturated solution of ammonium chloride, the mixture is extracted with ethyl acetate. The extracts are dried over sodium sulfate and concentrated in vacuum. The residue dichloromethane: methanol 50/1-10/1), and the resulting amorphous product is crystallized from diiso asin (20 mg). So pl. 133oC (decomp.).

NMR (DMCO-d6, ) : 3,95 - of 4.05 (2H, m), 4,10 - 4,20 (2H, m), 4,25 (2H, d, J= 6 Hz), and 4.75 (1H, t, J=6 Hz), to 7.15 (2H, d, J=6 Hz), 7,25 (2H, t, J=9 Hz), 7,40 (2H, DD, J=6 Hz and 9 Hz) and 8.50 (2H, d, J=6 Hz), 8,55 (1H, C).

Example 20. A mixture of 2-(4-acetoxybenzoic)-7-(4-forefeel)-8-pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C)(1,2,4)triazine (65 mg, 0,142 mmol) and potassium carbonate (220 mg, 0,142 mmol) in methanol (1.3 ml) is stirred for 30 min at ambient temperature. The mixture down to pH 6 aqueous saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase is washed with water and with brine, dried over sodium sulfate and concentrated in vacuo. The residue is purified by chromatography on silica gel (eluent: dichloromethane/methanol 30/1-20/1), and the resulting amorphous product is crystallized from diisopropyl ether, receiving 7(4-forefeel)-2-(4-hydroxybenzoyl)-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C)(1,2,4)triazine (37 mg). So pl. 222oC (decomp.).

NMR (CDCl3+CD3OD, ) : 4,20 - and 4.40 (4H, m), 6,85 (2H, d, J=9 Hz), 6,95 - 7,10 (4H, m), 7,35 (2H, DD, J=6 Hz and 9 Hz), 7,55 (2H, d, J=9 Hz), 8,30 (2H, d, J=6 Hz)

Example 21. 2-Tert-butoxycarbonylamino-7-(4-forefeel)-8-(pyridin-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-C)(1,2,4)triazine (50 mg) is dissolved in triperoxonane ke. The residue is dissolved in water and the solution neutralized aqueous saturated sodium bicarbonate solution. Separated oil is extracted with a mixture of dichloromethane and benchmark (7:3), and the extract washed with water, dried and concentrated in vacuo. The residue is crystallized from ethyl acetate, obtaining 2-amino-acetyl-7-(4-forefeel)-8-(pyridin-4-yl)1,2,3,4-tetrahydropyrazolo(5,1-C)(1,2,4)triazine (30 mg). So pl. 208 - 211oC.

NMR (DMCO-d6, ): 3,50 (2H) to 4.01 (2H, t, J= 6 Hz), of 4.16 (2H, t, J= 6 Hz), 7,19 (2H, d, J= 6 Hz), 7,22 (2H, t, J= 9 Hz), 7,40 (2H, DD, J= 6 Hz and 9 Hz), 8,49 (2H, d, J= 6 Hz).

Example 22. A mixture of 2-chloroacetyl-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazin(5,1-C) (1,2,4)triazine (80 mg, 0,215 mmol), research (37 mg, 0,430 mmol) and triethylamine (22 mg, 0,215 mmol) in 1,2-dichloroethane (2 ml) is stirred for 24 h at ambient temperature. After dilution with dichloromethane, the mixture was washed with aqueous saturated sodium bicarbonate solution and saline. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is purified using chromatography on silica gel (eluent: ethyl acetate-ethyl acetate/methanol, 20/1), and the oil obtained is crystallized from diisopropyl ether, receiving 7-(4-forefeel)-2-morpholinoethyl-8-(pyridin-4-yl)-1,2,3,4-tetrahydro is), 4,30 (2H, d, J= 6 Hz), 7,05 (2H, t, J= 9 Hz), 7,10 (2H, d, J= 6 Hz), 7,40 (2H, DD, J= 6 Hz and 9 Hz), 7,95 (1H, sh.C.), of 8.50 (2H, d, J= 6 Hz).

Example 23. To a mixture of 7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo(5,1-C)(1,2,4)triazine (118 mg) and pyridine (64 mg) in N-methyl-1-pyrrolidone (2 ml) was added under ice cooling phenylacetyl chloride (65 mg) in a nitrogen atmosphere. After stirring for 1 h at 4oC the reaction mixture was poured into cold water. Separated oil is extracted with ethyl acetate, and the extract is washed with brine, dried and concentrated in vacuo. The residue is purified using column chromatography on silica gel and the obtained oil was dissolved in 10% methanolic solution of hydrogen chloride (1 ml). The resulting clear solution was concentrated in vacuo. The residue is crystallized from ethyl acetate, receiving 7-(4-forefeel)-2-phenylacetyl-8-(pyridin-4-yl) -1,2,3,4-tetrahydro-pyrazolo (5,1-C) (1,2,4)triazine hydrochloride (130 mg). So pl. 208 - 212oC.

NMR (DMCO-d6, ): a 3.87 (2H, s) 4,07 (2H, t, J=5 Hz), 4,18 (2H, t, J= 5 Hz), 7,00-7,20 (5H, m), 7,29 (2H, t, J= 9 Hz), the 7.43 (2H, DD, J= 6 Hz and 9 Hz), 7,66 (2H, d, J= 6 Hz), 8,71 (2H, d, J= 6 Hz), 9,63 (1H, s).

Example 24. The following compounds get by the method similar to the method of example 23.

(1) 7-(4-forefeel)-2-pentenol-8 - (the ): from 0.90 (3H, t, J= 6 Hz), 1,25-1,45 (2H, m), 1,55-1,70 (2H, m) to 2.55 (2H, t, J= 6 Hz), 4,10-4,30 (4H, m), to 7.15 (2H, t, J= 9 Hz), 7,40 (2H, DD, J= 6 Hz and 9 Hz), 7,80 - of 7.90 (2H, m), 8,10-of 8.25 (2H, m), 9,60 (1H, sh.S.).

(2) 7-(4-forefeel)-2-isobutyryl-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo (5,1-C) (1,2,4)triazine hydrochloride.

NMR (CDCl3, ): to 1.15 (6H, d, J= 7 Hz), 3,30 is 3.40 (1H, m), 4,15-4,30 (4H, m), to 7.15(2H, t, J= 9 Hz), 7,40 (2H, DD, J= 6 Hz and 9 Hz), 7,80-of 7.90 (2H, m), 8,15-8,30 (2H, m), 9,50(1H, sh.S.).

(3) 2-(3,4-dichlorobenzoyl)-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo (5,1-C) (1,2,4)triazine hydrochloride.

NMR (DMCO-d6, ): 4,22(2H, t, J= 6 Hz), to 4.33 (2H, t, J= 6 Hz), 7,29 (2H, t, J= 9 Hz), 7,40-of 7.60 (4H, m), of 7.70 (2H, m), 7,94 (1H, s), 8,63 (2H, d, J= 6 Hz), 9,99 (1H, s).

(4) 7-(4-forfinal)-2-phenylglycinol-8-(pyridin-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-C) (1,2,4)triazine hydrochloride.

So pl. 18 - 191oC (decomp.).

NMR (DMCO-d6, ): 4,24 (2H, t, J= 6 Hz), of 4.49 (2H, t, J= 6 Hz), 7,16 (2H, d, J= 7 Hz), 7,26 (2H, t, J= 9 Hz), 7,30 was 7.45 (4H, m), 7,50-the 7.65 (3H, m), to 8.57 (2H, d, J= 7 Hz), made up 9.77 (1H, s).

(5) 7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4-tetrahydro-2-(4 - trifluromethyl)glyoxylyl-pyrazolo(5,1-C)(1,2,4)triazine hydrochloride. So pl. 260 - 265oC (decomp.).

NMR (CDCl3+ CD3OD, ): 4,32-4,50 (4H, m), 7,13 (2H, t, J= 9 Hz), 7,30-the 7.43 (4H, m). 7,79 (2H, d, J= 9 Hz), to 7.93 (2H, d, J= 9 Hz), by 8.22 (2H, d, J= 6 Hz).

Example 25. To a mixture of 7-(4-ft mmol) in N-methyl-2-pyrrolidone (1.2 ml) add acetylchloride (19 mg, 0,239 mmol) in N-methyl-2-pyrrolidone (0.3 ml) at ambient temperature. The reaction mixture was stirred for 1 h, then to it was added aqueous saturated sodium bicarbonate solution and ethyl acetate. The organic phase is separated and washed with water, salt solution, and dried over sodium sulfate. The solvent is evaporated and the resulting residue purified using column chromatography on silica gel (eluent: dichloromethane/methanol, 100/1-40/1). Fractions containing the proposed connection, concentrated in vacuo and the resulting oil is crystallized from diisopropyl ether, receiving 1-acetyl-7-(4-forefeel)-2-isobutyl-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo(5,1-C) (1,2,4)triazine (57,0 mg). So pl. 194 - 197oC (decomp.).

NMR (CDCl3, ) : of 1.05 (3H, d, J= 6 Hz), of 1.12 (3H, d, J= 6 Hz), 1,90 (1H, m), of 2.25 (3H, s), 2.57 m-2,69 (1H, m), 2,75-of 2.86 (1H, m), 3,43 - 3,70 (2H, m), 4,13-4,24 (1H, m), 4,33-4,50 (1H, m), 6,95-7,05 (4H, m), 7,34 (2H, DD, J= 6 Hz and 9 Hz) and 8.50 (2H, d, J= 6 Hz).

Example 26. The following compounds get the technique similar to the technique of example 1.

(1) 8-(2-chloropyridin-4-yl)-7-(4-forefeel)-1,2,3,4 - tetrahydropyrazolo(5,1-C) (1,2,4)triazine. So pl. 219 - 221oC.

NMR (CDCl3, ): 3,48 (2H, K, J= 5 Hz), 3,68 (1H,, J= 5 Hz), 4,20 (2H, t, J= 5 Hz), the 5.65 (1H, d, J= 5 Hz), 6,94 (1H, d, J= 6 Hz), 7,06 (2H, t, J= 9 Hz), 7,Rotolo (5,1-C) (1,2,4) triazine. So pl. 212 - 216oC.

NMR (CDCl3, ): 3,32/3,44 (2H, m), 3,68 (1H, m), 4,20 (2H, t, J= 5 Hz), 5,67 (1H, sh. C.), to 6.95 (1H, d, J= 6 Hz), 7,07 (2H, t, J= 9 Hz), 7,17 (1H, s), 7,40 (2H, DD, J= 6 Hz, 9 Hz), 8,21 (1H, d, J= 6 Hz).

(3) 7-(4-forefeel)-8-(2-methoxypyridine-4-yl)-1,2,3,4-tetrahydropyrazolo (5,1-C) (1,2,4) triazine. So pl. 205 - 209oC.

NMR (CDCl3: CD3OD = 9:1, ): at 3.35 (2H, t, J= 6 Hz), with 3.89 (3H, s) to 4.17 (2H, t, J= 6 Hz), 6,60 (1H, s), of 6.68 (1H, d, J= 6 Hz), 7,05 (2H, t, J= 9 Hz), 7,42 (2H, DD, J= 6 Hz and 9 Hz), 7,98 (1H, d, J= 6 Hz).

(4) 7-(4-forefeel)-8-(2-foroperation-4-yl)-1,2,3,4-tetrahydropyrazolo (5,1-C)(1,2,4)triazine. So pl. 230 - 232oC.

NMR(CDCl3:CD3OD = 9:1, ): 3,37 (2H, t, J=6 Hz), 4,18 (2H, t, J = 6 Hz), 6,77 (1H,s), to 6.95 (1H, d, J = 6 Hz), was 7.08 (2H, t, J = 9 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz), 8,02 (1H, d, J = 9 Hz), 8,02(1H, d, J = 6 Hz).

Example 27. The following compounds get by the method similar to the method of examples 3, 7 and 13.

(1) 2-acetyl-8-(2-chloropyridin-4-yl)-7-(4-forefeel) is 1.2.3,4-tetrahydropyrazolo (5,1-C) (1,2,4)triazine. So pl. 208 - 209oC.

NMR (CDCl3, ): of 2.34 (3H, c), 4,13-4,20 (2H, m), 4,20-or 4.31 (2H, m), 6,30 (1H, sh.C.), 7,00-7,11 (3H, m), 7,24 (1H, s), 7,40 (2H, DD, J = 6 Hz and 9 Hz), 8,23 (1H, d, J = 6 Hz).

(2) 8-(2-chloropyridin-4-yl)-7-(4-forefeel)-2-phenylglycinol-1,2,3,4 - tetrahydropyrazolo(5,1-C)(1,2,4)triazine.

NMR (CDCl3, ) : 4,30 (2H, t, J = 5 Hz), 4,45 (acetyl-8-(2-bromopyridin-4-yl)-7-(4-forefeel)-1,2,3,4 - tetrahydropyrazolo(5,1-C)(1,2,4)triazine. So pl. 210 - 211oC.

NMR (CDCl3, ) : 2,35 (3H, s), 4,12-4,32 (4H, m), 6,30 (1H, sh.C.), 7,00 for 7.12 (3H, m), 7.23 percent (1H, s), 7,40 (2H, DD, J = 6 Hz and 9 Hz), 8,24 (1H, d, J = 6 Hz).

(4) 8-(2-bromopyridin-4-yl)-7-(4-forefeel)-2-phenylglycinol-1,2,3,4 - tetrahydropyrazolo(5,1-C)(1,2,4)triazine.

NMR (CDCl3, ): 4,30 (2H, t, J = 5 Hz), of 4.45 (2H, t, J = 5 Hz), 6,53-of 6.61 (2H, m), of 6.68 (1H, s), 7,02 (2H, t, J = 9 Hz), 7,25-to 7.35 (2H, m), 7,53 (2H, t, J = 9 Hz), 7,66 (1H, t, J = 9 Hz), 7,88-of 7.97 (3H, m).

(5) 7-(4-forefeel)-2-((2-methoxyphenyl)Glyoxylic)-8-(pyridin-4-yl)-1,2, 3.4-tetrahydropyrazolo(5,1-C)(1,2,4)triazine. So pl. 231 - 245oC (decomp.).

NMR (CDCl3, ): 3,48 (3H, s), 4,24 (2H, t, J = 6 Hz), 4,43 (2H, t, J = 6 Hz), 6.48 in (2H, d, J = 6 Hz), 6,77 (1H, s), at 6.84 (1H, d, J = 9 Hz), 7,01 (2H, t, J = 9 Hz), to 7.15 (1H, dt, J = 2 Hz and 9 Hz), 7,32 (2H, DD, J = 6 Hz and 9 Hz), EUR 7.57 (1H, dt, J = 2 Hz and 9 Hz), 8,06-8,13 (3H, m).

(6) 2-acetyl-7-(4-forefeel)-8-2-methoxypyridine-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-C)(1,2,4)triazine. So pl. 148 - 150oC.

NMR (CDCl3:CD3OD = 9:1, ): 2,28 (3H, s), 3,91 (3H, s), of 4.12 (2H, t, J = 6 Hz), 4,25 (2H, t, J = 6 Hz), to 6.67 (1H, s), 6,72 (1H, d, J = 6 Hz), 7,06 (2H, t, J = 9 Hz), 7,41 (2H, DD, J = 6 Hz and 9 Hz), 8,02 (1H, d, J = 6 Hz).

(7) 7-(4-forefeel)-8-(2-methoxypyridine-4-yl)-2-phenylglycinol - 1,2,3,4-tetrahydropyrazolo(5,1-C)(1,2,4)triazine. So pl. 129 - 122oC.

NMR (CDCl3: CD3OD = 9:1, ): 3,81 (3H,s), 4,25 (2H, t, J = 6 Hz), 4,42 ).

(8) 2-acetyl-7-(4-forefeel)-8-(2-foroperation-4-yl)- 1,2,3,4-tetrahydropyrazolo(5,1-C)(1,2,4)triazine. So pl. 204 - 206oC.

NMR (CDCl3: CD3OD = 9:1, ): 2,28 (3H,s), 4,14 (2H, t, J = 6 Hz), 4.26 deaths (2H, t, J = 6 Hz), 7,02 (1H, d, J = 6 Hz), 7,10 (2H, t, J = 9 Hz),? 7.04 baby mortality (2H, DD, J = 6 Hz and 9 Hz), with 8.05 (1H, d, J = 6 Hz).

(9) 7-(forefeel)-8-(2-herperidin-4-yl)-2-phenylglycinol-1,2,3,4 - tetrahydropyrazolo(5,1-C)(1,2,4)triazine. So pl. 238 - 240oC.

NMR (CDCl3:CD3OD = 9:1, ): to 4.28 (2H, t, J = 6 Hz), 4,43 (2H, t, J = 6 Hz), 6.35mm (1H,s), 6,60 (1H, d, J = 6 Hz), 7,05 (2H, t, J = 9 Hz), of 7.48 (2H, t, J = 8 Hz), a 7.62 (1H, t, J = 8 Hz), 7,75-of 7.90 (3H,m).

(10) 2-acetyl-7-(4-forefeel)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo (5,1-C)(1,2,4)triazine hydrochloride. So pl. 262 - 270oC.

NMR (CDCl3, ): to 2.29 (3H,s), 4,11-4,27 (4H, m), 7,12 (2H, t, J = 9 Hz), 7,40 (2H, DD, J = 6 Hz and 9 Hz), 7,80 (2H, d, J = 6 Hz), 8,49 (2H, d, J = 6 Hz), to 9.57 (1H, sh.S.).

(11) 7-(4-forefeel)-2-phenylglycinol-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C)(1,2,4)triazine. So pl. to 240.5 - 242,0oC.

NMR (CDCl3:CD3OD = 9:1, ): 4,27 (2H, t, J = 6 Hz), of 4.45 (2H, t, J = 6 Hz), 6,70 (2H, d, J = 6 Hz), 7,01 (2H, t, J = 9 Hz), 7,30 (2H, DD, J = 6 Hz and 9 Hz), 7,47 (2H, t, J = 8 Hz), 7,63 (1H, t, J = 8 Hz), 7,81 (2H, d, J = 8 Hz), 8,18 (2H, d, J = 6 Hz).

Example 28. To a suspension of 7-(4-forefeel)-2-phenylglycinol-8-(pyridin-4-yl-1,2,3,4 - tetrahydropyrazolo(5,1-C)(1,2,4 resulting transparent solution was added ethyl acetate (30 ml) and the solution stirred at ambient temperature for 4 hours Separated solid is collected and recrystallized from aqueous acetonitrile, receiving 7-(4-forefeel)-2-phenylglycinol-8-(pyridin-4-yl)-1,2,3,4 - tetrahydropyrazolo(5,1-C)(1,2,4)triazine sulfate (2.7 g). So pl. 155 - 157oC.

NMR (DMCO-d6, ) : of 4.25 (2H,m), 4,49 (2H,m), 7,12 (2H, d, J = 7 Hz), 7,15-to 7.50 (6H,m), 7,50-of 7.70 (3H,m), 8,56 (2H, d, J = 7 Hz), 9,43 (1H,s).

11. 1,2,3,4,-tetrahydropyrazolo [5,1-c] [1,2,4]triazine of the formula I

< / BR>
where R1is phenyl which may be substituted by halogen, or pyridinyl which can be substituted by halogen or lower alkoxy;

R2is phenyl which may be substituted by halogen, or pyridinyl which can be substituted by halogen or lower alkoxy;

R3is hydrogen or lower alkanoyl;

R4is hydrogen, lower alkyl, cyclo(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, lower alkoxycarbonyl-(lower)aklil, phenyl-(lower)alkyl which may be substituted by 1-3 Halogens; adamantyl, phenyl(lower)alkenyl, tetrahydropyranyl, piperidyl or dissapionting, each of which may have one or two substituent selected from lower alkyl and lower alkanoyl; indanyl, lower alkanoyl, which may be substituted by carboxy, lower alkoxy, halogen, amino, hydroxy, ness the Chille)alkylamino; lowest alkoxycarbonyl, lower alkoxyglycerols, lower alkylsulfonyl, cyclo(lower)alkylaryl, benzoyl which may have 1-3 substituent selected from had trihalo(lower)alkyl, halogen, hydroxy and lower alkanoyloxy; phenyl(lower)alkanoyl, which may have 1-3 substituent selected from lower alkoxy, phenyl, halogen or trihalo(lower)alkyl; phenyl(lower)alkanoyl, phenylthio(lower)alkanoyl, phenylcarbamoyl, phenyl-thiocarbamoyl, phenylglyoxylic, which may have 1-3 substituent selected from had trihalo(lower)the alkyl and lower alkoxy; carbarnoyl, which may have one or two substituent selected from lower alkyl, hydroxy(lower)alkyl, lower alkoxy and cyclo(lower)alkyl; morpholinylcarbonyl, indolyl(lower)alkanoyl, morpholinyl(lower)alkanoyl, piperidinylcarbonyl;

R5is hydrogen or lower alkyl,

or its pharmaceutically acceptable salt,

2. Connection on p. 1, in which R4hydrogen, lower alkyl, cyclo(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, lower alkoxycarbonyl-(lower)alkyl, mono(or di)halophenol(lower)alkyl, adamantyl, phenyl(lower)alkenyl, tetrahydropyranyl lowest alkylpiperidines lowest alkanolamides, di(lower)ALCALDIA from carboxy, lower alkoxy, halogen, lower alkoxycarbonyl, lower alkanolamine, amino, hydroxy, lower alkanoyloxy, cyclo(lower)alkylcarboxylic and di(lower)alkylamino; lower alkoxycarbonyl, lower alkoxyglycerols, lower alkylsulfonyl, cyclo(lower)alkylaryl, benzoyl which may have one or two substituent(s) selected from the group consisting of was trihalo(lower)alkyl, halogen, lower alkanoyloxy and hydroxy; phenyl(lower)alkanoyl, which may have one or two substituent(s) selected from the group consisting of lower alkoxy, phenyl, halogen and trihalo(lower)alkyl; phenyl(lower)alkanoyl, phenylthio(lower)alkanoyl, phenylcarbamoyl, phenylthiocarbamoyl, phenylglyoxylic, which may have a Deputy selected from the group consisting of was trihalo(lower)alkyl and lower alkoxy; carbarnoyl, which may have one or two suitable substituent(s) selected from the group consisting of lower alkyl, hydroxy(lower)alkyl, acyloxy(lower)alkyl, lower alkoxy and cyclo(lower)alkyl; morpholinylcarbonyl, indolyl(lower)-alkanoyl, morpholinyl(lower)alkanoyl or piperidinylcarbonyl.

3. Connection on p. 2, in which R1- halophenol, R2- pyridyl, R3
(1) 7-(4-forefeel)-2-phenylglycinol-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c] [1,2,4]triazine,

(2) of the hydrochloride of 7-(4-forefeel)-2-phenylglycinol-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c] [1,2,4]triazine and

(3) sulfate 7-(4-forefeel)-2-phenylglycinol-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c] [1,2,4]triazine.

5. The method of obtaining the compounds of formula

< / BR>
where R1is phenyl which may be substituted by halogen, or pyridinyl which can be substituted by halogen or lower alkoxy;

R2is phenyl which may be substituted by halogen, or pyridinyl which can be substituted by halogen or lower alkoxy;

R3is hydrogen or lower alkanoyl;

R4lowest alkanoyl, which may be substituted by carboxy, lower alkoxy, halogen, amino, hydroxy, lower alkanoyloxy, cyclo(lower)alkylcarboxylic, lower alkanolamine, lower alkoxycarbonyl and di(lower)alkylamino; lower alkoxycarbonyl, lower alkoxyglycerols, lower alkylsulfonyl, cyclo(lower)alkylaryl, benzoyl which may have 1-3 substituent selected from had trihalo(lower)alkyl, halogen, hydroxy and lower alkanoyloxy; phenyl(lower)alkanoyl, which can genoil, phenyl-thio(lower)alkanoyl, phenylcarbamoyl, phenyl-thiocarbamoyl, phenylglyoxylic, which may have 1-3 substituent selected from had trihalo(lower)alkyl and lower alkoxy; carbarnoyl, which may have one or two substituent selected from lower alkyl, hydroxy(lower)alkyl, lower alkoxy and cyclo(lower)alkyl; morpholinylcarbonyl, indolyl(lower)alkanoyl, morpholinyl(lower)alkanoyl, piperidinylcarbonyl;

R5is hydrogen or lower alkyl,

or its pharmaceutically acceptable salts, characterized in that conduct the acylation of compounds of formula

< / BR>
where R1, R2, R3and R5each has the above values.

6. The pharmaceutical composition inhibiting the production of Interleukin 1 and tumor necrosis factor, characterized in that it comprises as active ingredient an effective amount of the compounds under item 1 or its pharmaceutically acceptable salt in a mixture with pharmaceutically acceptable carriers.

7. A method of prophylactic or therapeutic treatment of diseases mediated by Interleukin-1 (IL-1) and tumor necrosis factor (TWF), which includes the introduction of a connection on p. 1 or pharmaceutically acceptable salts thereof is

 

Same patents:

The invention relates to pyrazolopyrimidines General formula I and their pharmaceutically acceptable salts, where A is the group NR1R2or CR'1R'2R11, R1- H or C1-C6-alkyl, unsubstituted or substituted certain substituents, such as HE, F, CL and others, or C2-C6alkenyl; or C2-C6-quinil; R2-C1-C6-alkyl, unsubstituted or substituted certain substituents, such as HE, C1-C6-alkoxy and others; or C2-C6alkenyl or2-C6-quinil, or furanyl; and (C1-C4-alkylene)phenyl which may be substituted by 1 to 3 substituents: CL, F, C1-C4-alkyl, and one Deputy:1-C6-alkoxy, CF3, NO2, NH2; or (C1-C4-alkylen) hetaryl where hetaryl - thienyl, possibly substituted by CL, benzothiazyl, pyridyl, chinoline, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrrolidinyl, 1-benzylpiperidine, tetrahydropyranyl; or (C1-C4-alkylen)cyclopropyl; or NR1R2form hetaryl selected from the group consisting of pyrrolidyl, possibly substituted benzyl, pyrrolidinyl, possibly substituted by benzyl or HE, the IIR>-C6-alkyl; R3is hydrogen, C1-C6-alkyl, O-(C1-C6alkyl), S(C1-C4- alkyl); R4- C1-C6- alkyl, or S(O)n(C1-C6)-alkyl, where n= 0-2, R5- 2,4,6-substituted phenyl CL, C1-C6-alkyl, CF3; R11-N., HE, or COO- (C1-C2alkyl), provided that the group CR'1R'2R11not an alkyl straight chain; and when R3is N, then R4isn't C1-C6the alkyl

The invention relates to pharmaceutical compositions for the treatment of inflammatory diseases, for example asthma, arthritis and allergies; fear; depression; fatigue syndrome; headache; pain; cancer; irritable bowel syndrome, including Crohn's disease, mucous colitis and symptoms of irritation of the colon; deregulation of the immune system; infections caused by human immunodeficiency virus (HIV); neurovirology diseases, such as Alzheimer's disease; gastrointestinal diseases; disorders of appetite, such as anorexia nervous system; stress caused by bleeding; symptoms of drug and alcohol withdrawal symptoms; addiction to the excessive use of drugs; stress-induced psychotic States and problems of fertilization, containing the above compound of formula I is effective for the treatment of these diseases the number and pharmaceutically acceptable carrier

-aminocarbonyl acids possessing antiarrhythmic and antifibrillatory activity" target="_blank">

The invention relates to the field of chemistry of biologically active substances, which may have application in medicine

The invention relates to new derivatives of pyrazolo/4,3-d/pyrimidine-7-it formula I, where R1- H, CH3C2H5, R2- CH3CH2OH, CH2OCH3or n - C3H7, R3- C2H5CH2= CH - CH2, R4together with the nitrogen atom to which it is attached is 4-(R5)-piperidino - or 4-N (R6)-piperazino group, R5- H, N(CH3)2, CONH2, R6- H, CH3i - C3H7CH2CH2OH, CSNH2C(NH)NHCH3or C(NH)S CH3and their pharmaceutically acceptable salts, pharmaceutical compositions showing inhibitory activity against cyclic guanosin-31,51-monophosphatase (CGMP), which contains 1-400 mg per single dose of the compounds of formula (I) in a mixture with a pharmaceutically acceptable diluent or carrier; the method of treatment or prevention of conditions caused by the activity of CGMP, the essence of which consists in assigning to the person an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or above compositions

The invention relates to medicine, refers to medicines and can be used for the treatment of gunshot and infected wounds

The invention relates to the field of medicine and relates to a pharmaceutical composition having anticonvulsive and analgesic activity

The invention relates to new chemical substances possessing valuable properties, in particular derivatives pyridyl General formula (I)

< / BR>
where

n is the number 2, 3, 4 or 5,

A - uglerodsesola communication or unbranched Allenova group with 1 to 4 carbon atoms, unsubstituted or substituted by one or two alkyl groups,

X - nitromethylene group, cyanomethylene group, unsubstituted or substituted by a residue R6with the following for R4values except tetrazole, or a group of formula =N-R7where R7is cyano, alkanesulfonyl group, phenylsulfonyl group, phenylalkylamine group, aminosulfonyl group, alkylaminocarbonyl group, dialkylaminoalkyl group, phenylcarbonylamino group, aminocarbonyl group, alkylaminocarbonyl group or dialkylaminoalkyl group,

Y - alkoxygroup, fenoxaprop, allylthiourea, phenylthiourea or a group of the formula-R8NR9where R8means a hydrogen atom, an unbranched or branched alkyl group with 1 to 10 carbon atoms, which is in the 2nd, 3rd or 4th position can be C is POI or peredelnoj group, alkyl group with 1 to 4 carbon atoms, which may optionally be substituted with hydroxyl group in the 2 nd, 3rd or 4th position, cycloalkyl group with 3 or 4 carbon atoms, cycloalkyl group with 5-8 carbon atoms, in which one ethylene bridge can be replaced on-phenylenebis group, bicycloalkyl group with 6 to 8 carbon atoms, unsubstituted or substituted 1, 2 or 3 alkyl groups, adamantly group, alkoxygroup or trimethylsilylethynyl group, and R9is a hydrogen atom or an unbranched alkyl group, or R8and R9together with in between the nitrogen atoms form an unsubstituted or substituted by one or two alkyl groups or phenyl group, cyclic alkalinising with 4 to 6 carbon atoms, in which one ethylene bridge in the provisions of 3.4 can be replaced on-phenylenebis group, morpholinopropan or piperazinone, unsubstituted or substituted in the 4-position of the alkyl group with 1 to 3 carbon atoms or phenyl group,

R1is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms,

R2and R3is a hydrogen atom or together form a carbon-carbon bond,

Pyr - Peregrina group, unsubstituted or sameena the group, alkylaminocarbonyl group, dialkylaminoalkyl group, group, translated in vivo metabolic by carboxyl group or carboxyl group, if Y represents the group R8NR9where R8and R9have the above meaning,

R5is a hydrogen atom or the halogen, alkyl, alkoxy or trifluoromethyl,

all of the aforementioned alkyl and CNS remains, if nothing else is mentioned, have 1 to 3 carbon atoms, and, if nothing else is mentioned, all the above-mentioned phenyl nuclei may be mono - or tizamidine identical or different substituents from the group comprising an atom of fluorine, chlorine, or bromine, alkyl, hydroxyl, alkoxyl, carboxyl, phenyl, nitro-, amino-, alkylamino, dialkylamino, alkanolamine, cyano, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl and dialkylaminoalkyl,< / BR>
their enantiomers, CIS - or TRANS-isomers, if R2and R3together denote a carbon-carbon bond, and their salts

The invention relates to 1,4-disubstituted the piperazines of General formula (I), which means the group-CO - or-CH2-OCO; D - heteroaryl selected from a range including 1, 3, 5-triazinyl, pyrimidinyl and pyridinyl, possibly substituted by one or two substituents selected from a range, including mono-(C1-C6)-alkylamino, mono-(C3-C7)- alkynylamino-, di-(C1-C6)-alkylamino-,

(C1-C6)-alkyl-(C3-C7)-alkylamino and pyrrolidin-I-yl group; Raand Rbis a hydrogen atom or (C1-C3)-alkyl; n is an integer from 1 to 4; their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to medicine, namely to otolaryngology

The invention relates to the derivatives of triazole, exhibiting antifungal activity

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes a method for prophylaxis or treatment of states wherein inhibition of enzyme activity is required wherein this enzyme catalyzes hydrolysis reaction of ester functional groups and wherein indicated disorder represents obesity or accompanying disease. Method involves prescribing compound of the formula (1):

or its pharmaceutically acceptable salt, ester, amide or precursor wherein in the formula (1) a means six-membered aromatic or heteroaromatic ring; R1 means a branched or unbranched alkyl (its carbon chain can be broken possibly by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or their substituted derivative wherein a substitute represents one or more group taken independently among the following group: halogen atom, alkyl, halogen-substituted alkyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy-, cyano-, -C(O)R4, -CO2R4, -SOR4, -SO2R4, -NR6R7, -OR6, -SR6, -C(O)CX1X2NR6R7, -C(O)NR4R5, -C(O)N(OR5)R6, -NR6C(O)R4, -CR6(NH2)CO2R6, -NCX1X2CO2R6, -N(OH)C(O)NR6R7, -N(OH)C(O)R4, -NHC(O)NR6R7, -C(O)NHNR6R7, -C(O)N(OR5)R6, or lipid or steroid (natural or synthetic one) under condition that any substituting heteroatom in R1 or R2 must be segregated from nitrogen exocyclic atom by at least two carbon atoms (preferably, saturated ones); R2 means hydrogen atom or group, such as determined for R1 and wherein R4 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl, OR6, NHCX1X2CO2R6 or NR6R7; R5 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl; R6 and R7 are taken independently among hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylakyl, reduced heteroarylalkyl or -(CH2)n(OR5)m wherein n = from 1 to 12 but preferably from 2 to 10; m = from 1 to 3; for R5 (C2-C10)-alkyl is preferable; X1 and X2 represent independently hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl or reduced heteroarylalkyl. Also, invention describes compounds of formulas (II), (IIa), (IIb) given in the invention description, method for preparing compound of the formula (II), pharmaceutical composition used for prophylaxis or treatment of obesity or accompanying disorder, the nutrition foodstuff, method for prophylaxis or treatment of obesity or accompanying disorders, method for inhibition of enzymes activity, method for reducing the fat content in animals, cosmetic method for maintaining this weight of animals. Invention discloses the possibility for prophylaxis or treatment of obesity or accompanying disorders.

EFFECT: valuable medicinal properties of compounds.

30 cl, 1 dwg, 2 tbl, 5 ex

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