6,7-dihydro-5h-pyrazolo[1,2-a]pyrazol-1-ones regulating inflammatory cytokines, (variants) and pharmaceutical composition

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and its pharmaceutically acceptable salts possessing properties of tumor necrosis factor (TNF-α) and to pharmaceutical composition based on thereof wherein R1 means substituted or unsubstituted phenyl wherein substitutes are chosen from halogen atoms or halide-(C1-C6)-alkyl; R4b is substituted or unsubstituted with 1-3 aryl substituted chosen from phenyl, naphthyl wherein substitutes are chosen from halogen atoms, (C1-C6)-alkyl, halide-(C1-C6)-alkyl, (C1-C6)-alkoxyl, cyano-, amino-, (C1-C6)-acylamino-group, (C1-C6)-alkanesulfonyl, or two adjacent substitutes in benzene ring form dioxol group, or unsubstituted or substituted 6-membered nitrogen-containing heteroaryl with 1-3 nitrogen atoms in ring wherein substitutes are chosen from halogen atoms.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 9 sch, 10 tbl, 15 ex

 

The present invention relates to 6,7-dihydro-5Npyrazolo[1,2-a]pyrazole-1-Onam, which inhibit extracellular secretion of inflammatory cytokines; these cytokines are responsible for one or more medical conditions of humans or higher mammals. The present invention relates also to compositions containing the aforementioned 6,7-dihydro-5Npyrazolo[1,2-a]pyrazole-1-ones, and the means of preventing, reducing or some type of regulation of enzymes, which are active components responsible for these conditions.

Interleukin-1 (IL-1) and factor-α tumor necrosis (TNF-α) are important biological substances, collectively known as "cytokines". These molecules act as intermediaries in the formation of the inflammatory response associated with immunological detection of infectious agents.

These Pro-inflammatory cytokines play a major role of mediators in many painful conditions and syndromes, among which are rheumatoid arthritis, osteoarthritis, irritable bowel syndrome (IBS), septic shock, cardiopulmonary dysfunction, acute respiratory disease, cachexia, and therefore responsible for the development and manifestation of symptoms of the person.

That is why there is a serious need for compounds and pharmaceutical whom such compositions, containing compounds, which are able to block, reduce, regulate, reduce or prevent the secretion of cytokines from the cells that produce them.

The present invention satisfies the specified requirement that has been unexpectedly discovered that certain bicyclic pyrazolones and their derivatives are effective inhibitors of the allocation of inflammatory cytokines, including interleukin-1 (IL-1) and tumor necrosis factor (TNF)from cells, and thus warn, reduce or otherwise regulate the enzymes, which are active components responsible for the described conditions.

The first aspect of the present invention are compounds, including their enantiomeric and diastereoisomeric forms, and pharmaceutically acceptable salts of these compounds having the formula:

in which R1means:

a) substituted or unsubstituted aryl; or

b) substituted or unsubstituted, heteroaryl;

each of R2chosen independently from the group consisting of:

a) hydrogen;

b) -(CH2)jO(CH2)nR8;

c) -(CH2)jNR9aR9b;

d) -(CH2)jCO2R10;

(e) -(CH2)jOCO2R10;

f) -(CH2)jCON(R10)2;

g) -(CH 2)jOCON(R10)2;

h) two of R2that may together form a carbonyl group;

i), and combinations thereof;

R8, R9a, R9band R10,eachindependently represents hydrogen, C1-C4alkyl and combinations thereof; R9aand R9btaken together, may form a 3-7-membered carbocyclic or heterocyclic ring; two of R10,taken together, may form a 3-7-membered carbocyclic or heterocyclic ring; j represents a number from 0 to 5, n represents a number from 0 to 5; Z represents O, S, NR11or NOR11; and R11denotes hydrogen or C1-C4alkyl;

R4bdenotes a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

Another aspect of the present invention are pharmaceutical compositions that are able to deliver the compounds according to the invention in the body of a human or higher mammal, moreover, these compositions contain:

a) an effective amount of one or more compounds according to the present invention and

b) one or more pharmaceutically acceptable excipients.

Another aspect of the present invention is a method of regulation of one or more inflammatory cytokines, which is posrednikami modulators of diseases or pathological States in mammals, and named the method involves the step of introducing a human or higher mammal an effective amount of a composition containing one or more compounds according to the present invention.

Another aspect of the present invention are forms of the compounds according to the invention, which under normal physiological conditions, release the compounds described above.

This and other objects of the invention, features and advantages will be more easily understood by the person skilled in the art upon reading further detailed description and appended claims. All the percentages, ratios and percentages are by weight, unless stated otherwise. All temperatures are expressed in degrees Celsius (° (C)unless otherwise stated. All cited documents with the relevant parts are included in the description by reference; the citation of any document should not be construed as a recognition of the fact that he is the closest prior art with respect to the present invention.

The present invention relates to compounds that are able to be intermediaries, regulators, or other extracellular inhibitors of certain cytokines, more specifically - inflammatory cytokines, and these cytokines play a role in stimulation, causes and p is oyavleniya diverse diseases, painful conditions or syndromes.

In the context of the present invention, the term "hydrocarbon" refers in this description to any organic group or link that contain atoms of carbon and hydrogen atoms. In this description, the term "hydrocarbon" includes heterocycles described below. Examples of different nheterocyclic unsubstituted hydrocarbon groups can be pentyl, 3-atelectasis, 1,3-dimetilfenil, cyclohexyl, CIS-3-hexyl, 7,7-dimethylbicyclo[2.2.1]-heptane-1-yl and naphthas-2-yl.

In this description, the term "hydrocarbon" includes aromatic (aryl) and non-aromatic ring, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl, cyclohexenyl, cycloheptenyl, bicyclo[0.1.1]butanal, bicyclo[0.1.2]pentanyl, bicyclo[0.1.3]hexanal (tuani), bicyclo[0.2.2]hexanal, bicyclo[0.1.4]heptanol (karani), bicyclo[2.2.1]heptenyl (norbornyl), bicyclo[0.2.4]octanol (caryophyllene), spiropentane, dicyclopentadienyl, decaline, phenyl, benzyl, naphthyl, indenyl, 2N-indenyl, azulene, tenantry, antril, fluorenyl, acenaphthylene, 1,2,3,4-tetrahydronaphthalene and others.

The term "heterocycle" includes both aromatic (heteroaryl)and non-aromatic heterocyclic ring, examples of which may include, without limitation: pyrrolyl 2N-pyrrolyl, 3H-pyrrole is, pyrazolyl 2N-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-Piran-2-he-yl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinil, s-triazinyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 1,4-oxazinyl, morpholinyl, azepine, oxepin, 4H-1,2-diazepine, indenyl 2N-indenyl, benzofuranyl, isobenzofuranyl, indolyl, 3H-indolyl, 1H-indolyl, benzoxazolyl 2N-1-benzopyranyl, chinoline, ethenolysis, hintline, 2H-1,4-benzoxazine, pyrrolidinyl, pyrrolyl, honokalani, furanyl, thiophenyl, benzimidazolyl and others, each of which may be substituted or not substituted.

An example of a group defined by the term "alkylaryl"is benzyl, having the formula:

as an example of a group defined by the term "acceleratorkey", is a 2-picolyl having the formula:

The term "substituted" used throughout the description text. In this description, the term "substituted" means "including links or groups that can replace one hydrogen atom, two hydrogen atoms or three hydrogen atoms in the hydrocarbon chain. Definition replaced also includes the replacement of hydrogen atoms on two adjacent carbon atoms with the formation of a new link or a new group". For example, substitutedthe group, whose mo is et to be replaced by only one hydrogen atom, includes halogen, hydroxyl, and others. Group, replacing two hydrogen atoms include carbonyl, oximino and others. Group, replacing two hydrogen atoms that are located on adjacent carbon atoms include apachegroup and others. Group, replacing three hydrogen atoms include cyano and others. The epoxy group is an example of a substituted group in which replacement of a hydrogen atom, located on adjacent carbon atoms. The term "substituted", as used herein, indicates that hydrocarbon link containing aromatic ring, the alkyl chain may have one or more hydrogen atoms replaced by a substituent. If the group is described as "substituted", there are any number of hydrogen atoms can be replaced. For example, 4-hydroxyphenyl is "substituted aromatic carbocyclic ring", (N,N-dimethyl-5-amino)-octanol is replaced With8is an alkyl group, 3-guanidinopropionic is replaced With3is an alkyl group and 2-carboxyphenyl is "substituted heteroaryl group". The following examples and are not restrictive, represent groups which can be replaced by hydrogen atoms, if the hydrocarbon group is defined as "replaced":

i) -[C(R12)2]p(CH=CH)qR12, gder denotes a number from 0 to 12; q denotes a number from 0 to 12;

ii) -C(Z)R12;

iii) -C(Z)2R12;

iv) -C(Z)CH=CH2;

v) -C(Z)N(R12)2;

vi) -C(Z)NR12N(R12)2;

vii) -CN;

viii) CNO;

ix) -CF3, -CCl3, -CBr3;

x) -N(R12)2;

xi) -NR12CN;

xii) -NR12C(Z)R12;

xiii) -NR12C(Z)N(R12)2;

xiv) -NHN(R12)2;

xv) -NHOR12;

xvi) -NCS;

xvii) -NO2;

xviii) -OR12;

xix) -OCN;

xx) -OCF3, -OCCl3; -OCBr3;

xxi) -F, -Cl, -Br, -I, and combinations thereof;

xxii) -SCN;

xxiii) -SO3M;

xxiv) -OSO3M;

xxv) -SO2N(R12)2;

xxvi) -SO2R12;

xxvii) -P(O)H2;

xxviii) -PO2;

xxix) -P(O)(OH)2;

xxx), and combinations thereof,

where R12denotes hydrogen, substituted or unsubstituted linear, branched C1-C20-alkyl, or cyclic alkyl, C6-C20-aryl, C7-C20-alkylaryl and combinations thereof; M represents hydrogen or a salt-forming cation; Z represents =O, =S, =NR11and combinations thereof. Suitable salt-forming cations can be a cation of sodium, lithium, potassium, calcium, magnesium, ammonium, and others.

The first aspect of the present invention relates to compounds of the formula:

which are 2-R1-substituted-3-(2-R-substituted-pyrimi the Jn-4-yl)-6,7-dihydro-5 N-pyrazolo[1,2-a]pyrazole-1-ons.

The second aspect of the present invention relates to compounds of the formula:

which are 2-R1-substituted-3-(2-R-substituted-pyrimidine-4-yl)-6,7-dihydro-5N-pyrazolo[1,2-a]pyrazole-1-thiones.

The third aspect of the invention relates to compounds of the formula:

which are 2-R1-substituted-3-(2-R-substituted-pyrimidine-4-yl)-6,7-dihydro-5N-pyrazolo[1,2-a]pyrazole-1-ylideneamino and their derivatives.

R is a substituent in position 2 of the ring pyrimidine-4-Il, in the General formula; R represents:

(a) a group of simple ester of the formula O[CH2]kR3; or

(b) a primary or secondary amine of the formula-NR4aR4b;

where R3denotes a substituted or unsubstituted With1-C4-alkyl, substituted or unsubstituted hydrocarbon cyclic group, a substituted or unsubstituted a heterocycle, a substituted or unsubstituted aryl or alkylaryl, substituted or unsubstituted heteroaryl or acceleratorkey; k denotes a number from 0 to 5.

The following describes the various aspects of the radical R of the present invention in the case when R is a simple ester of the formula

-O[CH2]kR3. However, the expert should not be limited to the given examples./p>

A) R is a group of simple ester of the formula OR3(k 0) and R3denotes a substituted or unsubstituted aryl.

i) According to one variant of this aspect of R is a group of simple ester of the formula OR3and R3is substituted or unsubstituted aryl. This option includes the following non-limiting examples of R: phenoxy, 2-fervency, 3 fervency, 4-fervency, 2,4-differencesi, 3 triptoreline, 4-triptoreline, 2,4-triptoreline and others.

ii) According to another variant of this aspect of R is a group of simple ester of the formula OR3and R3is substituted or unsubstituted aryl. This option includes the following non-limiting examples: 2-methylphenoxy, 3 methylphenoxy, 4-methylphenoxy, 2,4-dimethylphenoxy, 2-cianfrocca, 3 cianfrocca, 4-cianfrocca, 4-ethylenoxy and others.

iii) According to the following variant of this aspect of R is a group of simple ester of the formula OR3and R3is substituted or unsubstituted aryl. This option includes the following non-limiting examples: (2-methoxy)phenoxy, (3-methoxy)phenoxy, (4-methoxy)phenoxy, 3-[(N-acetyl)amino]-tenkasi, 3-benzo[1,3]dioxol-5-yl, and others.

C) R is a group of simple ester of the formula OR3(k 0) and R3is substituted sludge is unsubstituted heteroaryl.

i) According to the first embodiment of this aspect of R is a group of simple ester of the formula OR3and R3is unsubstituted heteroaryl. This option includes the following non-limiting examples: pyrimidine-2-yl, pyrimidine-4-yl, pyridine-2-yl, pyridin-3-yl, pyridine-4-yl, and others.

ii) According to the second variant of this aspect of R is a group of simple ester of the formula OR3and R3is replaced by heteroaryl. This option includes the following non-limiting examples: 2-aminopyrimidine-4-yl, and others.

C) R is a group of simple ester of the formula

-ORH2R3(k = 1) and R3is substituted or unsubstituted aryl.

i) According to the first embodiment of this aspect of R is a group of simple ester of the formula-OCH2R3and R3is substituted or unsubstituted heteroaryl. This option includes the following non-limiting examples: pyrimidine-2-yl, pyrimidine-4-yl, 2-aminopyrimidine-4-yl, 4-aminopyrimidine-6-yl, pyridin-2-yl, pyridin-3-yl, pyridine-4-yl, and others.

ii) According to the second variant of this aspect of R is a group of simple ester of the formula-OCH2R3andR3is substituted or unsubstituted alkyltetraalkyl. This option includes the following non-limiting examples: pyridine-3-retil, (methyl-2-pyridin-3-yl)ethyl, and others.

D) R is a group of simple ester of the formula OR3(k 0) and R3is substituted or unsubstituted With1-C4the alkyl.

i) According to the first embodiment of this aspect of R is a group of simple ester of the formula OR3and R3is unsubstituted linear, branched C1-C4the alkyl or cyclic alkyl. Non-limiting examples of this option are the following groups: methyl, ethyl, isopropyl, (S)-1-methylpropyl and others.

ii) According to the second variant of this aspect of R is a group of simple ester of the formula OR3and R3is substituted linear, branched C1-C4the alkyl or cyclic alkyl. Non-limiting examples of this option are the following group: 2-methoxyethyl, (S)-1-methyl-3-methoxypropyl and others.

The following describes the various aspects of R according to the present invention, when R denotes an amine of the formula-NR4aR4bwhere R4aand R4beach, independently of one another represent:

a) hydrogen or

b) -[C(R5aR5b)]mR6;

each of R5aand R5bindependently of one another denotes hydrogen or C1-C4alkyl, linear or branched, group OR7, -N(R7)2, -CO2R7, -CON(R7)2; cyclic and the keel, or a combination; R6denotes hydrogen, substituted or unsubstituted With1-C4alkyl, substituted or unsubstituted a heterocycle, a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; group-OR7, -N(R7)2, -CO2R7, -CON(R7)2where R7denotes hydrogen, a water-soluble cation, With1-C4alkyl or substituted or unsubstituted aryl; and m denotes a number from 0 to 5. However, the expert should not be restricted illustrated in this description of the meanings and examples.

A) R represents a chiral amino group, in which R4ais hydrogen, R5ais hydrogen and R5bis stands, and the group has the following formula:

and the indicated stereochemistry.

i) According to the first embodiment of this aspect of R is an amino group containing R6which is substituted or unsubstituted phenyl. Non-limiting examples of this option are: (S)-1-methyl-1-phenylethylamine, (S)-1-methyl-1-(4-forfinal)methylamino, (S)-1-methyl-1-(4-were)methylamino, (S)-1-methyl-1-(4-methoxyphenyl)methylamino, (S)-1-methyl-1-(2-AMINOPHENYL)methylamino, (S)-1-methyl-1-(4-AMINOPHENYL)methylamino and others.

ii) According to the second variant of this aspect of R is an amino group containing 6which is substituted or unsubstituted heteroaryl. Non-limiting examples of this option are: (S)-1-methyl-1-(pyridine-2-yl)methylamino, (S)-1-methyl-1-(pyridine-3-yl)methylamino, (S)-1-methyl-1-(pyridine-4-yl)methylamino, (S)-1-methyl-1-(furan-2-yl)methylamino, (S)-1-methyl-1-(3-benzo[1,3]dioxol-5-yl)methylamino and others.

iii) According to the third variant of this aspect of the invention, R represents an amino group containing R6which is substituted or unsubstituted C1-C4-alkyl. Non-limiting examples of this option are: (S)-1-methylpropylamine, (S)-1-methyl-2-(methoxy)ethylamino.

C) R represents a chiral amino group, in which R4adenotes hydrogen, and each of R5aand R5bis1-C4the alkyl, and the group has the formula:

and the specified stereochemistry, when R5a, R5band R6are not the same.

i) According to the first embodiment of this aspect of R is an amino group that does not contain a chiral center, non-limiting examples of this variant are 1,1-dimethylethylene, 1,1-dimethylbenzylamine and others.

ii) According to the second variant of this aspect of R is an amino group containing R6which is substituted or unsubstituted With1-C4what Kilom. Non-limiting examples of this option are: (S)-1-methyl-2-hydroxy-2-methylpropylamine, (S)-1-methyl-2-hydroxy-2-methylbutylamine and others.

C) R is alkylenediamine group, in which R4adenotes hydrogen, and both of the radical R5aand R5bin the group R4bdenote hydrogen, R6is substituted or unsubstituted aryl, and this group has the formula:

in which R11is hydrogen or a substituted group"defined above.

i) the First draft of this aspect includes the following non-limiting examples of values of R: benzylamino, (2-AMINOPHENYL)methylamino; (4-forfinal)methylamino, (4-methoxyphenyl)methylamino; (4-propanesulfonyl)methylamino and others.

ii) a Second variant of this aspect includes the following non-limiting examples of values of R: (2-were)methylamino; (3-were)methylamino; (4-were)methylamino and others.

D) R is an amino group, in which R4ais hydrogen, R4bcontains R5aequivalent to hydrogen, and R5bequivalent-CO2R7or-CON(R7)2and this group has the formula:

i) According to the first embodiment of this aspect of R is an amino group containing R6that which is substituted or unsubstituted phenyl. This option includes the following non-limiting examples of groups:

in which R11denotes hydrogen or "Deputy"defined above.

ii) According to the second variant of this aspect of R is an amino group containing R6which is substituted or unsubstituted alkyl. This option includes the following non-limiting examples of groups:

R1choose from:

a) substituted or unsubstituted aryl, or

b) substituted or unsubstituted heteroaryl.

According to the first aspect of R1represents phenyl, substituted with halogen, non-limiting examples of which are 4-forfinal, 2,4-differenl, 4-chlorophenyl, and others.

Each of R2chosen independently from the group consisting of:

a) hydrogen,

b) -(CH2)jO(CH2)nR8,

c) -(CH2)jNR9aR9b,

d) -(CH2)jCO2R10,

(e) -(CH2)jOCO2R10,

f) -(CH2)jCON(R10)2,

g) -(CH2)jOCON(R10)2,

h) two of R2taken together, which may form a carbonyl group,

i), and combinations thereof;

each of R8, R9a, R9band R10independently represents hydrogen, C 1-C4alkyl, and a combination thereof; R9aand R9btaken together, may form a carbocyclic or a heterocyclic ring containing 3-7 carbon atoms; two of R10taken together, may form a carbocyclic or a heterocyclic ring containing 3-7 carbon atoms; j represents a number from 0 to 5, n represents a number from 0 to 5.

The first aspect of the present invention related to R2includes the compounds of formula:

in which each of R2is hydrogen.

The second aspect of the invention relates to compounds of the formula:

in which R8is hydrogen or C1-C4the alkyl.

The third aspect of the invention relates to compounds of the formula:

in which each of R9aand R9bindependently denotes hydrogen, methyl, or R9aand R9b,taken together, constitute piperidino or morpholino ring.

A fourth aspect of the invention relates to compounds of the formula:

in which one of R2denotes-CO2R10and the other R2denotes hydrogen; one of R10denotes hydrogen or methyl.

Z represents O, S, NR11or NOR11; R11is hydrogen or the C 1-C4the alkyl. The first aspect of the present invention refers to the case where Z represents an oxygen atom, and includes 2-R1-substituted-3-(2-R-substituted-pyrimidine-4-yl)-6,7-dihydro-5Npyrazolo[1,2-a]pyrazole-1-ones, the second aspect of the present invention refers to the case where Z represents a sulfur atom, and provides 2-R1-substituted-3-(2-R-substituted-pyrimidine-4-yl)-6,7-dihydro-5Npyrazolo[1,2-a]pyrazole-1-thiones, the third aspect of the present invention refers to the case where Z represents a group NR11and provides 2-R1-substituted-3-(2-R-substituted-pyrimidine-4-yl)-6,7-dihydro-5Npyrazolo[1,2-a]pyrazole-1-ylideneamino and their derivatives.

The present invention is based on the surprising discovery that compounds that are included in Category IV of the present invention have a high inhibitory activity against cytokines. Compounds that are included in Category IV have the following formula:

in which R1represents:

a) substituted or unsubstituted aryl, or

b) substituted or unsubstituted, heteroaryl,

each of R2chosen independently from the group consisting of:

a) hydrogen,

b) -(CH2)jO(CH2)nR8,

c) -(CH2)jNR9aR9b,

d) -(CH2)jCO 2R10,

(e) -(CH2)jOCO2R10,

f) -(CH2)jCON(R10)2,

g) -(CH2)jOCON(R10)2,

h) two of R2taken together, which may form a carbonyl group,

i), and combinations thereof;

each of R8, R9a, R9band R10independently represents hydrogen, C1-C4alkyl and their combination;

R9aand R9btaken together, may form a carbocyclic or a heterocyclic ring containing 3-7 carbon atoms;

two of R10taken together, may form a carbocyclic or a heterocyclic ring containing 3-7 carbon atoms; j represents a number from 0 to 5, n represents a number from 0 to 5;

Z represents O, S, NR11or NOR11; R11is hydrogen or C1-C4by alkyl;

R4bdenotes a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

The first and second aspects of the compounds of Category IV are compounds of the formula

According to the first aspect of R1represents a substituted aryl selected from 4-ftoheia, 3-ftoheia, 2,4-dipthera, 4-chlorphenyl, 3-chlorphenyl, 2,4-dichlorophenyl or 3-tryptophanyl. Two particular values of R1that give the compounds of str is functioning to resist more effectively the secretion of the cytokine, include 4-forfinal and 3-triptoreline, especially 4-forfinal.

According to the first aspect of R4represents a substituted and unsubstituted aryl group.

The first draft of this aspect refers to an aryl group, or halogen-substituted aryl group selected from the group consisting of phenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2,4-differenl, 2,6-differenl, 3,5-differenl, 2,4,6-tryptophanyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, naphtalen-1-yl and naphtalen-2-yl.

The second variant of this aspect relates to substituted aryl group selected from the group consisting of 2-AMINOPHENYL, 3-AMINOPHENYL, 4-AMINOPHENYL, 2-were, 3-were, 4-were, 2,4-dimetilfenil, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-cyanophenyl, 3-cyanophenyl and 4-cyanophenyl.

The third variant of this aspect relates to substituted aryl group selected from the group consisting of 4-(methanesulfonyl)phenyl, 4-(econsultancy)phenyl, 4-(propanesulfonyl)phenyl, 2-(N-acylamino)phenyl, 3-(N-acylamino)phenyl, 4-(N-acylamino)phenyl and 3-benzo[1,3]dioxol-5-yl.

The fourth variant of this aspect refers to an aryl group selected from the group consisting of 2-triptoreline, 3-triptoreline, 4-triptoreline and 3,5-bis(trifluoromethyl)phenyl.

The second aspect of the values of R4from OSISA to substituted and unsubstituted aryl group.

The first draft of this aspect refers to an aryl group selected from the group consisting of 2-triptoreline, 3-triptoreline, 4-triptoreline and 3,5-bis(trifluoromethyl)phenyl.

The second variant of this aspect relates to heteroaryl or substituted heteroaryl group selected from the group consisting of pyridine-2-yl, pyridin-3-yl, pyridine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, 4,6-dichloropyrimidine-5-yl, ands-triazinyl.

Non-limiting examples of compounds of Category IV, which have a similar structure formula:

include the following compounds:

2-(4-forfinal)-3-(2-phenylaminopyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(2-forgenerating)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(3-forgenerating)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(4-forgenerating)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(2-chlorpheniramine)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(3-chlorpheniramine)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(4-chlorpheniramine)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(2-methylphenylimino)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-pyrazol-1-he,

3-[2-(3-methylphenylimino)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(4-methylphenylimino)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(2-cyanovinylene)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(3-cyanovinylene)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(4-cyanovinylene)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(2-chlorpheniramine)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(3-chlorpheniramine)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(4-chlorpheniramine)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(2,4-dipertanyakan)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(3,5-dipertanyakan)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(2,6-dipertanyakan)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

3-[2-(2,6-dichlorophenylamino)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he,

2-(4-forfinal)-3-[2-(pyridine-2-ylamino)-pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he

3-[2-(4,6-dichloropyrimidine-5-ylamino)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it.

the First category of compounds, inhibiting the secretion of inflammatory cytokine in accordance with the present invention, meets the following General formula:

in which R represents a group of simple ester of the formula OR3in which R1and R3have the meanings given in the following table I.

Table I
No.R1R
14-forfinalPhenoxy
24-forfinal2 fervency
34-forfinal3 fervency
44-forfinal4 fervency
54-forfinal2,6-divergence
64-forfinal2 cianfrocca
74-forfinal3 cianfrocca
84-forfinal2 triptoreline
94-forfinal4 triptoreline
104-forfinalN-methylpiperidin-4-yl
114-forfinal4 methylphenoxy
124-forfinal4 dimethylphenoxy
134-forfinal3-N-acetylaminophenol
144-forfinalPiran-4-yloxy
154-forfinal4 methoxyphenoxy
164-forfinal3-benzo[1,3]dioxol-5-yl
172,4-differenlPhenoxy
182,4-differenl2 fervency
192,4-differenl3 fervency
202,4-differenl4 fervency
212,4-differenl2,6-tryptophanate
222,4-differenl2 cianfrocca
232,4-differenl3 cianfrocca
242,4-differenl2 triptoreline
252,4-differenl4 triptoreline
262,4-differenlN-methylpiperidin-4-yl
272,4-differenl4 methylphenoxy
282,4-differenl2,4-dimethylphenoxy
292,4-differenl3-N-acetylaminophenol
302,4-differenlPiran-4-yloxy
312,4-differenl4 methoxyphenoxy
322,4-differenl3-benzo[1,3]dioxol-5-yl
333-triptorelinePhenoxy
343-triptoreline2 fervency
353-triptoreline3 fervency
363-triptoreline4 fervency
373-triptoreline2,6-divergence
383-triptoreline2 cianfrocca
393-triptoreline3 cianfrocca
403-triptoreline2 triptoreline
413-triptoreline4 triptoreline
423-triptorelineN-methylpiperidin-4-yl
433-triptoreline4 methylphenoxy
443-triptoreline2,4-dimethylphenoxy
453-triptoreline3-N-acetylaminophenol
46 3-triptorelinePiran-4-yloxy
473-triptoreline4 methoxyphenoxy
483-triptoreline3-benzo[1,3]dioxol-5-yl

Connection 1-48 and other similar compounds included in this category, can be obtained by the method described below. In the example below, R1denotes 4-forfinal, however, the specialist may use any other starting material, compatible with this method, such as, for example, methylphenylacetic, methyl-4-chlorophenylacetic and methyl-3-(trifluoromethyl)phenyl acetate.

The General scheme of obtaining intermediate compounds of Type I

EXAMPLE 1

Methyl ester of 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-3-oxopropanoic acid(3)

The following is a description of the method of obtaining 2-methylsulfonylamino-4-carbaldehyde1adapted in accordance with the method of H. Bredereck et al.,Chem.Ber.,97, pp3407-3417 (1964), included in the description by reference.

3-necked flask with a capacity of 12 l in an inert atmosphere enter dimethylacetal-N,N-dimethylformamide (801 g), dimethylacetal providemore aldehyde (779 g). The mixture is heated under reflux for 18 hours, at which those which the temperature decreases from about 109° With up to about 80°C. the Solution is cooled and added dropwise methanol (4 l) to dissolve the crude residue. The solution is then cooled to 20°and added thiourea (892 g, 11.7 mol). The mixture is left to mix for about 15 minutes and then injected the sodium methoxide (741 g, 13.7 mol) by 4 equivalent portions over 1 hour while maintaining the reaction temperature in the range of 18-28°C. the Mixture is stirred for 5 hours at room temperature, cooled to 20°, then enter odemeter (2 kg) for 1.25 hours while maintaining the reaction temperature in the range of 17-29°C. Stirring is continued for 18 hours at room temperature. The methanol and unreacted odemeter removed by heating the solution at a temperature of 35°and a pressure of 40 Torr to obtain approximately of 4.46 kg dark residue, which was partitioned between 14 l of water and 5 l of ethyl acetate. The aqueous fraction is extracted twice with ethyl acetate, the organic layers combined and concentrated in vacuo to obtain 685 g of oil, which is purified on silica and receive 522 g of 4-dimethoxymethyl-2-methylsulfonylamino.

Obtained above, dimethylacetal then hydrolyzing to obtain the free aldehyde by heating to 60°C for 3 hours in 1M HCl solution. Bring the environment up to neutral reaction using ethyl acetate and extracted the product with the receipt of 347 g of crude product, which purify on silica and receive 401 g 2-methylsulfonylamino-4-carbaldehyde1.

Obtain methyl ester of 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-3-hydroxypropionic acid(2)

To a cooled (-78° (C) the solution sitedisability (21,4 ml of 2M solution in THF, 42.8 mmol) in THF (70 ml) is added dropwise a solution of methyl-4-pertenecerte (6.0 g, to 35.7 mmol) in THF (30 ml). The solution is stirred for 1 hour at -78°C, after which the reaction mixture was added dropwise a solution of 2-methylsulfonylamino-4-carbaldehyde1,(6.0 g, or 39.3 mmol) in THF (30 ml). Stirring is continued for 45 minutes at -78°C, then the reaction quenched by injection of the reaction solution in a saturated aqueous solution of NH4Cl. The aqueous phase is extracted with ethyl acetate. The combined organic phases, dried (MgSO4), filtered and concentrated in vacuo. The crude residue purified on silica (33% EtOAc/hexane) and obtain 8.7 g (76%) of the desired product as a mixture (1:1) diastereoisomers.

Obtain methyl ester of 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-3-oxopropanoic acid(3).

In the suspension CrO3in CH2Cl2(300 ml) was injected pyridine. The mixture is intensively stirred for 1 hour at room temperature. A solution of the crude methyl ester of 2-(4-forfinal)-3-(2-METI sulfanilamide-4-yl)-3-hydroxypropionic acid 2,obtained above, in CH2Cl2(50 ml) was added dropwise to a suspension containing chromium. The reaction mixture was stirred at room temperature for 16 hours,diluted with ether (1 l) and filtered through a layer of celite.The filtrate was concentrated in vacuo and the resulting residue purified on silica (25% ETOAc/hexane) and obtain 3.7 g (yield 43%) of the desired product as a solid yellow color.

The following examples are to obtain 6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-about cyclic system using pyrazolidine, however, the specialist may use substituted cyclic hydrazine powered reagents for other structures with cyclic groups R2that is not a hydrogen, among which 3-methylpyrazole.

The General scheme of obtaining an intermediate product of Type II

EXAMPLE 2

2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5N-pyrazolo[1,2-a]pyrazole-1-he(5)

Obtaining 2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5N-pyrazolo[1,2-a]pyrazole-1-he(4):To a solution of pyrazolidine (7,8 g, 54.16 per mmol) in pyridine (100 ml) is added methyl ether 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-3-oxopropanoic acid3,(11.5g, 36,1 mmol). The reaction mixture is heated p and 90° C for 16 hours. The solvent is removed in vacuo and the resulting residue purified on silica (100% ETOAc, then 10% MeOH/ETOAc) and gain of 3.9 g (yield 37%) of the desired product as a solid yellow color.

Obtaining 2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5N-pyrazolo[1,2-a]pyrazole-1-it(5):To a solution of 2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5N-pyrazolo[1,2-a]pyrazole-1-it4,(1.3 g, 3.8 mmol) in a mixture of THF:methanol (56 ml of a mixture 1:1) was added dropwise a solution of Oxone®(peroxymonosulfate potassium) (9,34 g of 15.2 mmol) in water (42 ml). The reaction mixture is stirred for 1 hour at room temperature, diluted with aqueous solution of NaHCO3and extracted three times with ethyl acetate. The organic layers are combined, dried and concentrated in vacuo to obtain the crude desired product which is used without further purification.

The following text presents the method in which intermediate compounds of Type II can be used to obtain compounds of Category I, which are inhibitors of the allocation of inflammatory cytokines.

EXAMPLE 3

2-(4-Forfinal)-3-(2-phenoxypyridine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he(6)

Obtaining 2-(4-forfinal)-3-(2-phenoxypyridine-4-yl)-6,7-dihydro-5H-pyrazolo[12-a]pyrazole-1-it (6):To a solution of phenol (0.66 g, was 7.08 mmol) in THF (5 ml) is added NaH (0.24 g, 5,91 mmol) followed by addition of a solution of the crude 2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5N-pyrazolo[1,2-a]pyrazole-1-it5,obtained as described above (0.25 g, 0.67 mmol)in THF (2 ml). The reaction mixture was stirred for 1.5 hours at room temperature, diluted with aqueous solution of NaHCO3and extracted twice with ethyl acetate. The organic layers are combined, dried over MgSO4and concentrated in vacuo to obtain the crude product, which was purified on silica (100% EtOAc, then 10% MeOH/EtOAc) and obtain 0.35 g (yield 38%) of the desired product as a solid yellow color.

1H NMR (300 MHz, CDCl3) δ of 8.47 (d, J=5,1 Hz, 1H), 7,49 (DD, J=7,8, and 7.8 Hz, 2H), 7,40 (DDD, J=5,4, a 5.4 Hz, 2H), 7,35-7,22 (m, 3H), 7,10 (DD, J=8,4, and 8.4 Hz, 2H), make 6.90 (d, J=6,8 Hz, 1H), of 4.05 (t, J=7.2 Hz, 2H), 3,86 (t, J=7.2 Hz, 2H), 2,59 (dt, J=7,2, 7.2 Hz, 2H); HRMSfor C22H18FN4O2(M+H)+designed 389,1414; found 389,1407. This compound corresponds to the compound 1 in table I.

The following compounds related in the first aspect, the compounds I can be obtained according to the procedure described above.

N-(3-{4-[2-(4-Forfinal)-3-oxo-6,7-dihydro-3H,5H-pyrazolo[1,2-a]pyrazole-1-yl]-pyrimidine-2-yloxy}-phenyl)-ndimethylacetamide;1H NMR (300 MHz, d6-DMSO) δ 10,11 (s,1H), 8,66 (d, J=5,1 Hz, 1H), to 7.64 (m, 1H), 7,41-7,34 (m, 4H), 7,17 (t, J=9.0 Hz, 2H), 7,02 (d, J=5,1 Hz, 6,92-to 6.80 (m, 1 H), of 3.84 (t, J=6.9 Hz, 2H), 3,81 (t, J=6.9 Hz, 2H), 2,46 (m, 2H), 2.06 to (s, 3H); HRMSfor C24H20FN5O3(M+H)+designed 446,1628; found 446,1606.

2-(4-Forfinal)-3-[2-(2,4-dimethylphenoxy)pyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ 8,44 (DD, J=5,4, 1.5 Hz, 1H), 7,43-7,38 (m, 2H), 7,14-7,00 (m, 5H), to 6.88 (DD, J=5,1, 1.5 Hz, 1H), was 4.02 (t, J=7.2 Hz, 2H), 3,86 (t, J=7.2 Hz, 2H), 2,59 (dt, J=7,2, 7.2 Hz, 2H), of 2.38 (s, 3H), 2,19 (s, 3H); HRMSfor C24H21FN4O2(M+H)+designed 417,1727; found 417,1727.

2-(2,4-Differenl)-3-(2-phenoxypyridine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it.1H NMR (300 MHz, CDCl3) δ charged 8.52 (d, J=5,1 Hz, 1H), 7,60-7,46 (m, 3H), 7,33 (d, J=7.5 Hz, 1H), 7.23 percent (d, J=7.5 Hz, 2H), 7,01 (t, J=8,1 Hz, 1H), 6,91-6,83 (m, 2H), 4.09 to (t, J=6.6 Hz, 2H), 3,92 (t, J=6.9 Hz, 2H), 2,59 (t, J=6,9 Hz, 2H): MS (M+H)+407,2.

2-(4-forfinal)-3-[2-(4-pertenece)pyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo-[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ 8,51 (d, J=5,1 Hz, 1H), 7,39 (DD, J=8,7, 5,4 Hz, 2H), 7,21-7,10 (m, 5H), 6,91 (d, J=5,1 Hz, 1H), 4,42 is 4.35 (m, 2H), 4,10-Android 4.04 (t, J=7.2 Hz, 2H), 2,71 (dt, J=7,2, 7.2 Hz, 2H); MS (M+H)+406,9.

2-(4-forfinal)-3-[2-(2,6-divergence)pyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo-[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ charged 8.52 (d, J=5,1 Hz, 1H), 7,41 (DD, J=8,7, 5,4 Hz, 2H), 7,15-7,07 (m, 5H), 6,98 (d, J=5,1 Hz, 1H), or 4.31 (t, J=8,2 Hz, 2H), 4.09 to (t, J=8,2 Hz, 2H), 2,70 (dt, J=8,2, 8,2 Hz, 2H); MS (M+H)+425,2.

2-(4-fluoro who enyl)-3-[2-(2-pertenece)pyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo-[1,2-a]pyrazole-1-he; 1H NMR (300 MHz, CDCl3) δ 8,51 (d, J=5,1 Hz, 1H), 7,41-of 7.23 (m, 6H), 7,11 (t, J=8.7 Hz, 2H), 6,94 (d, J=5,1 Hz, 1H), 4,27 (t, J=8,2 Hz, 2H), 4.00 points (t, J=8,2 Hz, 2H), 2,66 (dt, J=8,2, 8,2 Hz, 2H); MS (M+H)+407,2.

2-(4-forfinal)-3-[2-(3-pertenece)pyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo-[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ 8,49 (d, J=5,1 Hz, 1H), 7,49-7,38 (m, 3H), 7,11 (t, J=8.7 Hz, 2H),? 7.04 baby mortality-6,98 (m, 3H), 6,94 (d, J=5,1 Hz, 1H), 4,13 (t, J=6.9 Hz, 2H), 3,97 (t, J=6.9 Hz, 2H), 2,66 (dt, J=6,9, 6,9 Hz, 2H); MS (M+H)+406,9.

According to the second aspect of the connection Category I, which are inhibitors of the allocation of the inflammatory cytokine, according to this invention have the following General formula:

in which R is an amino group of formula-NR4a[CHR5b]R6and R1, R4a, R5band R6have the meanings given below in table II. The stereochemistry of R5bhas the above configuration, when R5band R6are not hydrogen atoms.

Methyl
Table II
No.R1R4aR5bR6
494-forfinalHHPhenyl
504-forfinalHH4-forfinal
514-fluoro who Anil HH2-AMINOPHENYL
524-forfinalHH2-were
534-forfinalHH4-were
544-forfinalHH4-methoxyphenyl
554-forfinalHH4-(propanesulfonyl)phenyl
564-forfinalHH3-benzo[1,3]dioxol-5-yl
574-forfinalHHPyridine-2-yl
584-forfinalHHPyridine-3-yl
594-forfinalHMethylPhenyl
604-forfinalHMethyl4-forfinal
614-forfinalHMethyl2-AMINOPHENYL
624-forfinalHMethyl2-were
634-forfinalHMethyl4-were
644-forfinalH4-methoxyphenyl
654-forfinalHMethyl4-(propanesulfonyl)phenyl
664-forfinalHMethyl3-benzo[1,3]dioxol-5-yl
674-forfinalHMethylPyridine-2-yl
684-forfinalHMethylpyridine-3-yl
694-forfinalHHH
704-forfinalHHMethyl
714-forfinalHHEthyl
724-forfinalHHVinyl
734-forfinalHHCyclopropyl
744-forfinalHHCyclohexyl
754-forfinalHHMethoxymethyl
764-forfinalHHMethoxyethyl
774-forfinalHH1-hydroxy-1-methylethyl
784-forfinalHH-CO2H
794-forfinalHMethylH
804-forfinalHMethylMethyl
814-forfinalHMethylEthyl
824-forfinalHMethylVinyl
834-forfinalHMethylCyclopropyl
844-forfinalHMethylCyclohexyl
854-forfinalHMethylMethoxymethyl
864-forfinalHMethylMethoxyethyl
874-forfinalHMethyl1-hydroxy-1-methylethyl
884-forfinalHMethyl-CO2H
893-triptorelineHMethylPhenyl
903-triptorelineHMethyl4-forfinal
3-triptorelineHMethyl2-AMINOPHENYL
923-triptorelineHMethyl2-were
933-triptorelineHMethyl4-were
943-triptorelineHMethyl4-methoxyphenyl
953-triptorelineHMethyl4-(propanesulfonyl)phenyl
963-triptorelineHMethyl3-benzo[1,3]dioxol-5-yl
973-triptorelineHMethylPyridine-2-yl
983-triptorelineHMethylPyridine-3-yl
993-triptorelineHMethylH
1003-triptorelineHMethylMethyl
1013-triptorelineHMethylEthyl
1023-triptorelineHMethylVinyl
103 3-triptorelineHMethylCyclopropyl
1043-triptorelineHMethylCyclohexyl
1053-triptorelineHMethylMethoxymethyl
1063-triptorelineHMethylMethoxyethyl
1073-triptorelineHMethyl1-hydroxy-1-methylethyl
1083-triptorelineHMethyl-CO2H

Using intermediate compounds, such as connection5asrelevant source materials, compounds 49-108 and other compounds of the same category, described herein, can be obtained using the procedures described below. In the following example, R1denotes 4-forfinal, however, the specialist may use any other source material that is compatible with this method, such as, for example, methylphenylacetic, methyl-4-chlorophenylacetic and 3-(trifluoromethyl)phenyl acetate.

EXAMPLE 4

2-(4-forfinal)-3-[2-(S)-(1-phenylethylamine)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]is irsol-1-he (7)

Obtaining 2-(4-forfinal)-3-[2-(S)-(1-phenylethylamine)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it(7):A solution of the crude 2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5N-pyrazolo[1,2-a]pyrazole-1-it5obtained as described above (0,86 g,2.3 mmol)and (S)-(-)-α-methylbenzylamine (10,5 ml of 81.6 mmol) dissolved in toluene (18 ml). The resulting mixture was heated to 140°C for 12 hours, cooled to room temperature and the solvent is removed under vacuum. The resulting residue is purified on silica (1:1 ETOAc/hexane) and get the desired product that corresponds to the connection 59 table II.

1H NMR (300 MHz, CDCl3) δ 8,18 (d, J=5,1 Hz, 1H), 7,42-7,34 (m, 7H),? 7.04 baby mortality (DDD, J=9,0, to 6.9, 2.1 Hz, 2H), to 6.39 (d,J=5,1 Hz, 1H), 5,68 (user. s, 1H), 5,10 (m, 1H), 3,97 (dt, J=7,5, to 7.5, 7.5 Hz, 2H), 2,45 (user. s, 2H), 1,67 (m, 2H), 1,60 (d, J=7.5 Hz, 3H); HRMS for C24H22FN5O (M+N)+designed 416,1887; found 416,1897.

The following compounds related to the second aspect of the compounds I can be obtained according to the method described above.

2-(4-forfinal)-3-[2-(N'-methyl-N'-phenyl)-pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ 8,29 (d, J=5,1 Hz, 1H), 7,40 (DD, J=8,4, a 5.4 Hz, 2H), 7,29-7,25 (m, 2H), 7,06 (DD, J=8,4, and 8.4 Hz, 2H), 6,91 (d, J=9.0 Hz, 2H), 6,85 (t, 7.8 Hz, 1H), to 6.57 (d, J=5,1 Hz, 1H), 4.00 points (t, J=6.9 Hz, 4H), 3,39 (s, 3H), 2,48 is 2.33 (m, 2H); MS (M+H) +417,2.

Methyl ester of (R)-{4-[2-(4-forfinal)-3-oxo-6,7-dihydro-3H,5H-pyrazolo[1,2-a]pyrazole-1-yl]-pyrimidine-2-ylamino}-phenylacetic acid;1H NMR (300 MHz, CDCl3) δ compared to 8.26 (d, J=8,4 Hz, 7,54-7,24 (m, 7H),? 7.04 baby mortality (t, J=8,4 Hz, 2H), 6,47 (d, J=4,8 Hz, 1H), 5,65-to 5.58 (m, 2H), 4,05-4,00 (m, 2H), 3,79 (s, 3H), 3,78-3,68 (m, 2H), 1,67 (m, 2H); MS (M+H)+460,0.

2-(4-forfinal)-3-(2-benzylaminopurine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ 8,21 (d, J=4.5 Hz, 1H), 7,45-7,29 (m, 9H), 7,06 (DD, J=9,0, an 8.4 Hz, 2H), 6,47 (d, J=5.4 Hz, 1H), 4,70 (d, J=6.0 Hz, 2H), Android 4.04 (t, J=7.2 Hz, 2H), 3,80-the 3.65 (m, 2H), 2,65-2,52 (m, 2H); MS (M+H)+402,1.

2-(4-forfinal)-3-[2-(1-(S)-methylethylamine)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1HNMR (300 MHz, CDCl3) δ 8,17 (d, J=4,8 Hz, 7,46-7,40 (m, 2H), 7,05 (dt, J=8,7, 2.4 Hz, 2H), 6,38 (DD, J=4,8, 3.0 Hz, 1H), 5,11 (user. s, 1H), 4,13-of 3.96 (m, 5H), by 2.73 (dt, J=6,9, 6,9 Hz, 2H), 1,66-of 1.55 (m, 2H), 1,24 (d, J=6.3 Hz, 3H), 0,99 (t, J=7.2 Hz, 3H); HRMS for C20H22FN5O (M+N)+designed 368,1886; found 386,1880.

2-(4-forfinal)-3-[2-(allylamino)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ to 8.20 (d, J=5,1 Hz, 1H), 7,43 (DD, J=9,0, a 5.4 Hz, 2H), 7,05 (t, J=8.7 Hz, 2H), to 6.43 (d, J=5,1 Hz, 1H), 6,00 (dddd, J=7.2V 7.2V 7.2V, 5,1 Hz, 1H), 5,45 (user. s, 1H), 5,28 (DD, J =17,1, 1.5 Hz, 1H), 5,20 (DD, J=10,2, 1.5 Hz, 1H), 4,13-Android 4.04 (m, 6H), 2,71 (dt, J=7,2, 7.2 Hz, 2H);HRMS for C19H18FN5O (M+N)+designed 352,1573; found 352,1582.

2-(4-forfinal)-3-{2-[1-(S)-(4-were)atilim is but]pyrimidine-4-yl}-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he; 1H NMR (300 MHz, CDCl3) δ 8,15 (d, J=5.4 Hz, 1H), 7,40 (DD, J=8,7, 5.7 Hz, 2H), 7,28-7,27 (m, 2H), 7,17 (d, J=7.8 Hz, 2H),? 7.04 baby mortality (t, J=9.0 Hz, 2H), 6,41 (d, J =5.4 Hz, 1H), 5,20 (m, 1H), was 4.02-of 3.96 (m, 4H), 2,52 at 2.45 (m, 2H), a 2.36 (s, 3H), 1,60 (d, J=6.9 Hz, 3H); HRMS for C25H24FN5O (M+N)+designed 430,2043; found 430,2057.

2-(4-forfinal)-3-[2-(1-(S)-cyclohexylethylamine)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ is 8.16 (d, J=4,8 Hz, 1H), 7,44 (DD, J=9,0, 5.7 Hz, 2H), 7,05 (t, J=8.7 Hz, 2H), 6,37 (d, J=5,1 Hz, 1H), 5,12 (user. s, 1H), 4,14-was 4.02 (m, 4H), 3,99-to 3.92 (m, 1H), 2,73 (dt, J=6,9, 6,9 Hz, 2H), 1,88-to 1.63 (m, 4H), 1,54-of 1.40 (m, 1H), 1,28-of 1.03 (m, 6H), 1,20 (d, J=6.9 Hz, 3H); HRMS for C24H28FN5O (M+N)+designed 421,2279; found 421,2264.

2-(4-forfinal)-3-[2-(1-(R)-phenylethylamine)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ 8,11 (d, J=5.4 Hz, 1H), 7,43-of 7.23 (m, 7H), 7,05 (t, J=8,4 Hz, 2H), to 6.43 (d, J=5.4 Hz, 1H), 5,13 (m, 1H), 4,16-of 3.94 (m, 2H), 2,58-of 2.38 (m, 2H), and 1.63 (d, J=6.9 Hz, 3H); MS (M+H)+416,0.

2-(4-forfinal)-3-[2-(tert-butylamino)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ 8,11 (d, J=5.4 Hz, 1H), 7,43 (DD, J=6,9, 3,3 Hz, 2H), was 7.08 (t, J=6.6 Hz, 2H), 6,45 (d, J=5.7 Hz, 1H), 4,12-was 4.02 (m, 4H), 2,77 (dt, J=7,2, 7.2 Hz, 2H), of 1.52 (s, 9H); MS (M+H)+368,1.

2-(4-forfinal)-3-[2-(2-hydroxy-1,2-dimethylpropylene)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ 7,99 (m, 1H), 7,40 (DD, J=9,0, 5.7 Hz, 2H), 7,10 (t, J=8.7 Hz, 2H), 6,55 (d, J=5,4 Hz, 1H), 4,24-4,10 (m, 5H), and 2.83 (dt, J=8,4, and 8.4 Hz, 2H), 1,51-of 1.36 (m,9H); MS (M+H)+398,1.

2-(4-forfinal)-3-[(2-cyclopropylamino)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ 8,17 (m, 1H), 7,42 (DD, J=8,7, 5,4 Hz, 2H), 7,12 (t, J=8.7 Hz, 2H), of 6.52 (d, J=5.4 Hz, 1H), 4,27 (m, 2H), 4,15 (t, J=8,4 Hz, 2H), 2,88-of 2.81 (m, 1H), 2,77 (dt, J=8,4, and 8.4 Hz, 2H), of 0.93-0.87 (m, 2H), 0,71-0,66 (m, 2H); MS (M+H)+352,0.

2-(4-forfinal)-3-[(2-cyclopropylethyl)aminopyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ 8,17 (d, J=5,1 Hz, 1H), 7,41 (DD, J=8,7, 5,4 Hz, 2H), 7,07 (t, J=8.7 Hz, 2H), 6,41 (d, J=5,1 Hz, 1H), 5,55 (user. s, 1H), 4,15-of 4.05 (m, 4H), and 3.31 (t, J=5.4 Hz, 2H), 2,78 (dt, J=6,9, 6,9 Hz, 2H), 1,18 (m, 1H), 0,60 (m, 2H), 0,30 (m, 2H); MS (M+H)+366,0.

2-(4-forfinal)-3-[(2-methoxyethylamine)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ 8,18 (d, J=5,1 Hz, 1H), 7,42 (DD, J=8,7, 5.7 Hz, 2H), 7,06 (t, J=8.7 Hz, 2H), 6.42 per (d, J=5.4 Hz, 1H), 4,20-a 4.03 (m, 4H), 3,68-to 3.41 (m, 4H), 3,42 (s, 3H), 2,74 (dt, J=6,9, 6,9 Hz, 2H); MS (M+H)+370,0.

2-(4-forfinal)-3-[2-(2-methoxy-1-(S)-methylethylamine)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, CDCl3) δ 8,18 (d, J=4,8 Hz, 1H), 7,42 (DD, J=8,1, 5,4 Hz, 2H),? 7.04 baby mortality (t, J=8.7 Hz, 2H), to 6.39 (d, J=4,8 Hz, 1H), 5,49 (d, J=7.8 Hz, 1H), 4.26 deaths (m, 1H), 4,13 (t, J=6.9 Hz, 2H), 4,06 (t, J=6.9 Hz, 2H), 3.46 in (d, J=4,8 Hz, 2H), 3,41 (s, 3H), of 2.72 (dt, J=6,9, 6,9 Hz, 2H), 1,30 (s, 3H); MS (M+H)+384,0.

2-(4-forfinal)-3-{2-[1-(S)-(4-forfinal)ethylamino]pyrimidine-4-yl}-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H the Mr (300 MHz, CDCl3) δ 8,10 (d, J=5,1 Hz, 1H), 7,39 (DD, J=7,8, 5,1 Hz, 2H), 7,07 (t, J=7.8 Hz, 2H), 6.48 in (d, J=5,1 Hz, 1H), 5,12 (m, 1H), 4,18-3,98 (m, 2H), 2,61 at 2.45 (m, 2H), 1,64 (d, J=6.9 Hz, 3H); MS (M+H)+433,9.

2-(4-forfinal)-3-{2-[(pyridine-3-ylmethyl)amino]pyrimidine-4-yl}-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he;1H NMR (300 MHz, d6-DMSO) δ 8,69-8,51 (m, 2H), by 8.22 (d, J=5,1 Hz, 1H), 7,73-to 7.68 (m, 1H), 7,42 (DD, J=8,7, 5,4 Hz, 2H), 7,33-7,26 (m, 1H),? 7.04 baby mortality (t, J=8.7 Hz, 2H), 6.48 in (d, J=5,1 Hz, 1H), 5,77 (user. s, 1H), 4,69 (d, J=6.3 Hz, 2H), was 4.02 (t, J=6.9 Hz, 2H), 3,80 (m, 2H), 2,62 (dt, J=8,7, to 8.7 Hz, 2H); MS (M+H)+403,1.

The second category of compounds which are inhibitors of the allocation of the inflammatory cytokine, according to the invention has the following General formula:

in which R is a group of simple ester of the formula OR3and R9aand R9btaken together form a ring, are described below in table III.

Table III
No.R1R3The ring R9a/R9b
1094-forfinalPhenoxyMorpholinyl
1104-forfinal2 fervencyMorpholinyl
1114-forfinal3 fervencyMorpholinyl
1124-forfinalFervency Morpholinyl
1134-forfinal2,6-divergenceMorpholinyl
1144-forfinal2 cianfroccaMorpholinyl
1154-forfinal3 cianfroccaMorpholinyl
1164-forfinal2 triptorelineMorpholinyl
1174-forfinal4 triptorelineMorpholinyl
1184-forfinal2 methylphenoxyMorpholinyl
1194-forfinal4 methylphenoxyMorpholinyl
1204-forfinal2,4-dimethylphenoxyMorpholinyl
1214-forfinal3-N-acetylaminophenolMorpholinyl
1224-forfinal2 methoxyphenoxyMorpholinyl
1234-forfinal4 methoxyphenoxyMorpholinyl
1244-forfinal3-benzo[1,3]dioxol-5-ylMorpholinyl
1254-forfinalPhenoxyPiperidine-1-yl
1264-forfinal2 fervencyPiperidine-1-yl
1274-forfinal3 triterpenoicPiperidine-1-yl
1284-forfinal4 fervencyPiperidine-1-yl
1294-forfinal2,6-divergencePiperidine-1-yl
1304-forfinal2 cianfroccaPiperidine-1-yl
1314-forfinal3 cianfroccaPiperidine-1-yl
1324-forfinal2 tripterocalyxPiperidine-1-yl
1334-forfinal4 triptorelinePiperidine-1-yl
1344-forfinal2 methylphenoxyPiperidine-1-yl
1354-forfinal4 methylphenoxyPiperidine-1-yl
1364-forfinal2,4-dimethylphenoxyPiperidine-1-yl
1374-forfinal3-N-acetylaminophenolPiperidine-1-yl
1384-forfinal2 methoxyphenoxyPiperidine-1-yl
1394-forfinal4 methoxyphenoxyPiperidine-1-yl
1404-forfinal3-benzo[1,3]dioxol-5-ylPiperidine-1-yl
1414-forfinalPhenoxyPiperazine-1-Il
1424-forfinal2 fervencyPiperazine-1-Il
1434-forfinal3 fervencyPiperazine-1-Il
1444-forfinal4 fervencyPiperazine-1-Il
1454-forfinal2,6-divergencePiperazine-1-Il
1464-forfinal2 cianfroccaPiperazine-1-Il
1474-forfinal3 cianfroccaPiperazine-1-Il
1484-forfinal2 triptorelinePiperazine-1-Il
1494-forfinal4 triptorelinePiperazine-1-Il
1504-forfinal2 methylphenoxyPiperazine-1-Il
1514-forfinal4 methylphenoxyPiperazine-1-Il
1524-forfinal2,4-dimethylphenoxyPiperazine-1-Il
1534-forfinal3-N-acetylaminophenolPiperazine-1-Il
1544-forfinal2 methoxyphenoxyPiperazine-1-Il
1554-forfinal4 methoxyphenoxyPiperazine-1-Il
1564-forfinal3-benzo[1,3]dioxol-5-ylPiperazine-1-Il
1574-forfinalPhenoxyPyrrolidin-1-yl
1584-forfinal2 fervencyPyrrolidin-1-yl
1594-forfinal3 fervencyPyrrolidin-1-yl
1604-forfinal4 fervencyPyrrolidin-1-yl
1614-forfinal2,6-divergencePyrrolidin-1-yl
1624-forfinal2 cianfroccaPyrrolidin-1-yl
1634-forfinal3 cianfroccaPyrrolidin-1-yl
1644-forfinal2 triptorelinePyrrolidin-1-yl
1654-forfinal4 triptorelinePyrrolidin-1-yl
1664-forfinal2 methylphenoxyPyrrolidin-1-yl
1674-forfinal4 methylphenoxyPyrrolidin-1-yl
1674-forfinal2,4-dimethylphenoxyPyrrolidin-1-yl
1694-forfinal3-N-acetylaminophenolPyrrolidin-1-yl
1704-forfinal2 methoxyphenoxyPyrrolidin-1-yl
1714-forfinal4 methoxyphenoxyPyrrolidin-1-yl
1724-forfinal3-benzo[1,3]dioxol-5-ylPyrrolidin-1-yl

Below is a scheme of obtaining compounds relating to the first aspect of the compounds of Category II according to the invention. At the first stage envisages the use of the intermediate compounds of type III introduction to R1(in this example, 4-ftoheia) in the molecule. Intermediate ketones, such as connection11can be used in the next step for introducing selected amino group in position 6 pyrazolo[1,2-a]pyrazole-1-about cyclic system.

The General scheme of obtaining between the exact connection type III

EXAMPLE 5

Benzyl ether of 2-[2-(4-forfinal)acetyl]-4-oxo-pyrazolidine-1-carboxylic acid(11)

Obtain 1-benzyl ester 2-tert-butyloxycarbonyl-4-metrobidazole-1,2-dicarboxylic acid(8):To a suspension of NaH (3,81 g of 95.4 mmol) in DMF (80 ml) was added dropwise a solution of N-Cbz-N'-Boc-hydrazine (12.1 g, to 45.4 mmol) in DMF (20 ml). The reaction mixture is stirred for about 20 minutes and added dropwise 3-chloro-2-chloromethylated (5.8 ml, 50 mmol) and the reaction mixture is allowed to mix at room temperature until completion of the reaction by thin-layer chromatography, approximately 12 hours. The reaction solution was distributed between ethyl acetate and water, the aqueous layer was extracted several times with a solvent. The organic layers are combined, dried, filtered and concentrated to obtain the desired product as a clear oil which is used in the subsequent steps without purification.

Obtain 1-benzyl ester 4-metrobidazole-1 - carboxylic acid(9):To a solution of crude 1-benzyl ester 2-tert-butyloxycarbonyl-4-metrobidazole-1,2-dicarboxylic acid8,(30 g) in methanol (300 ml) was added dropwise at 0°With thionyl chloride. The reaction mixture was left to warm to room temperature and stirred for 18 hours. After koncentraciis vacuum reaction mixture get oil yellow, which crystallizes in the keeping with 23 g (yield 97%) of the desired product as HCl salt.

Getting benzyl ester 2-[2-(4-forfinal)acetyl]-4-metrobidazole-1-carboxylic acid(10):Sodium hydroxide (0.12 g, 3 mmol) dissolved in a mixture of 1:2 water with methylene chloride (30 ml) under vigorous stirring and added 1-benzyl ether4-metrobidazole-1-carboxylic acid9,(of 0.62 g, 2.8 mmol) at room temperature. Add (4-forfinal)acetylchloride (of 0.39 ml, 4.2 mmol) and the reaction continued with stirring for 18 hours, then the reaction mixture was diluted with water (10 ml) and allow the mixture to separate into layers. The aqueous layer was extracted with methylene chloride, the organic layers combined, dried and filtered. Concentrated in vacuo and get the crude product, which was purified on silica (1:3 ethyl acetate/hexane) and gain of 0.54 g (yield 62%) of the desired product.

Getting benzyl ester 2-[2-(4-forfinal)acetyl]-4-oxo-pyrazolidine-1-carboxylic acid(11):Bubbled ozone gas through a solution of benzyl ester 2-[2-(4-forfinal)acetyl]-4-metrobidazole-1-carboxylic acid10,(0.28 g, 0.8 mmol) in methylene chloride (15 ml) at -78°until the blue color of the solution. Remove the source of ozone and add dimethylsulfoxide (0,23 ml), the reaction mixture is brought to room temperature and stirred for 18 hours. The solvent is distilled off in vacuum and the resulting oil purified on silica (1:3 ethyl acetate/hexane) and obtain 0.15 g (yield 53%) of the desired product as a clear oil.

Synthesized intermediates of type III, as, for example, the connection11can be used as a template for introduction into the desired position 6 of the amino group, as described below in the example.

The General scheme of obtaining the intermediate compounds of type IV:

the introduction of the 6-amino group in the structure compounds

corresponding to the first aspect of the compounds of Category II.

EXAMPLE 6

2-(4-forfinal)-1-(4-(morpholine-4-yl-pyrazolidine-1-yl)-alanon(13)

Getting benzyl ester 2-[2-(4-forfinal)acetyl]-4-morpholine-4-yl-pyrazolidine-1-carboxylic acid(12):To a solution of benzyl ester 2-[2-(4-forfinal)acetyl]-4-oxo-pyrazolidine-1-carboxylic acid11,(0.14 g, 0.4 mmol) and research (0,038 ml, 0.43 mmol) in THF added at room temperature Na(OAc)3BH (0.125 g, 0.6 mmol) and the SPLA (of 0.022 ml, 0.4 mmol).

The solution was stirred for 12 hours, then the mixture is distributed between diethyl ether and NaHCO3. The aqueous layer was extracted several times with simple ether and combine the organic layers, dried and concentrated in vacuo to obtain a clear oil, which again R is straut in the air, and add 1 equivalent of HCl in ether and get a solid white product. Separate the solid product by filtration and produce the desired product in the amount of 100 mg (yield 60%) as HCl salt.

Obtaining 2-(4-forfinal)-1-(4-(morpholine-4-yl-pyrazolidine-1-yl)-ethanone(13):Benzyl ether of 2-[2-(4-forfinal)acetyl]-4-morpholine-4-yl-pyrazolidine-1-carboxylic acid in the form of HCl salt12,(100 mg, 0.2 mmol) is dissolved in methanol and added Pd/C (5 mg). The solution is then givenout apparatus Parr Hydrogenation Apparatus for 3 days, after which the catalyst was removed by filtration and the filtrate was concentrated in vacuo to obtain 55 mg (yield 81%) of the desired product in the form of a solid product is yellowish-brown color.

Because the amino group is in position 6 2-R'-substituted-pyrazolo[1,2-a]pyrazole-1-about the structure, the fragments of the final compounds containing selected R groups can be introduced at an appropriate stage of the synthesis. At this stage the use of intermediate compounds of type V General formula:

entering thus into the structure of the desired group OR3and named the intermediate compounds of type V can be obtained according to the method shown in the diagram below.

The General scheme of obtaining intermediate compounds of type V

EXAMPLE 7

2-Phenoxypyridine-4-carbonylchloride(18)

Obtaining methyl ester 2-methylsulfonylamino-4-carboxylic acid(14):To a suspension of 2-methylsulfonylamino-4-carboxylic acid (15 g, 88 mmol) in methanol (200 ml) was added dropwise thionyl chloride (25 ml). The solution is allowed to warm to room temperature and stirred for 12 hours. The solution is then concentrated in vacuo, and the residue solid yellow color, which can be treated with methylene chloride and re-subjected to concentration to obtain 19 g (yield 97%) of the HCl salt of the desired product as a solid white color.

Obtaining methyl ester 2-methanesulfonamido-4-carboxylic acid (15):An aqueous solution (1 l) Oxone®(211,7 g, 344 mmol) was injected dropwise at 0°in a solution of methyl ester 2-methylsulfonylamino-4-carboxylic acid14,(19 grams of 86.1 mmol) in a mixture of 1:1 methanol with THF (1 l). The reaction solution is brought to room temperature and stirred for 1.5 hours. The resulting suspension is distributed between methylene chloride and water. The aqueous phase is alkalinized by addition of NaOH and re-extracted with a solvent. The organic layers are combined and then dried, filtered and concentrated in vacuo to obtain an 18.4 g of the desired product is in the form of a yellow oil.

Obtaining methyl ester 2-phenoxypyridine-4-carboxylic acid(16):NaH (3.5 g of 60%suspension, which is 87.4 mmol)ofadded to a solution of phenol (8,23 g, which is 87.4 mmol) in THF (100 ml) at room temperature. Methyl ester 2-methanesulfonamido-4-carboxylic acid15,(6.3 g, of 29.1 mmol) dissolved in THF (60 ml) and added dropwise a solution of phenol. The reaction proceeds under stirring for 12 hours, then quenched by adding saturated aqueous solution of NH4Cl. The aqueous phase is extracted with methylene chloride and the combined organic layers dried, filtered and concentrated in vacuo to obtain a crude oil which was purified on silica (ethyl acetate/hexane 2:3) to obtain the 1,72 g (yield 25%) of the desired product as a white solid.

Getting 2-phenoxypyridine-4-carboxylic acid(17):To a solution of methyl ester 2 phenoxypyridine-4-carboxylic acid (16)(1,72 g, 74,8 mmol) in methanol (50 ml) is added 50%NaOH solution (10 ml) at room temperature. After stirring for 1.5 hours the solvent is distilled off in vacuum and the remaining aqueous phase is extracted with ethyl acetate. The aqueous phase can then carefully acidified using concentrated HCl and the resulting white solid is extracted twice with ethyl acetate. The organic layers are combined, dried is concentrated in vacuo to obtain 0.95 g (yield 60%) of the desired product in the form of a solid white color.

Getting 2-phenoxypyridine-4-carbonylchloride(18):To a solution of 2-phenoxypyridine-4-carboxylic acid17,(0,19 g, 0.89 mmol) in methylene chloride (10 ml)containing a few drops of DMF, add oxalicacid (0.1 ml). The solution is stirred for 2 hours at room temperature and concentrated in vacuo to obtain the desired product which is used without further purification.

The final stage of producing compounds that are in the first aspect of the compounds of Category II in accordance with the present invention, can be performed by a method described below. This method includes a step of interaction between the first component that contains the selected group, R1and the amino group in position 6, for example an intermediate connection13,and a second component containing end group R already entered in the pyrimidine ring, for example an intermediate connection18.

EXAMPLE 8

2-(4-forfinal)-6-morpholine-4-yl-3-(2-phenoxypyridine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he(20)

Obtaining 2-(4-forfinal)-1-[4-morpholine-4-yl-2-(2-phenoxypyridine-4-carbonyl)pyrazolidine-1-yl]ethanone(19):2-phenoxypyridine-4-carbonylchloride18(0.07 g, 0.28 mmol) in methylene chloride (1.5 ml) is added dropwise to a suspension of 2-(4-forfinal)-1-(4-(morpholine-4-the l-pyrazolidine-1-yl)ethanone 13(0.06 g, 0.18 mmol) in a solution of 2:5 water in CH2Cl2(7 ml)containing NaOH (0,0112 g, 0.28 mmol)at room temperature. The solution is stirred for 18 hours and diluted with an additional mixture of 2:5 water in CH2Cl2. The layers allowed to separate and the aqueous phase extracted with more methylene chloride. The organic layers are combined, dried, filtered and concentrated in vacuo to obtain a solid substance, yellowish-brown, which is purified by preparative HPLC, and get 0,021 g (yield 23%) of the desired product as an oily solid.

Obtaining 2-(4-forfinal)-6-morpholine-4-yl-3-(2-phenoxypyridine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it(20):

To a solution of 2-(4-forfinal)-1-[4-morpholine-4-yl-2-(2-phenoxypyridine-4-carbonyl)pyrazolidine-1-yl]ethanone19,(0.2 g, 0.4 mmol) in DMF (10 ml) at 0°add NaH (0,024 g, 0.6 mmol) and the resulting solution was stirred for 2 hours. The solvent is distilled off in vacuum, the residue is dissolved in methylene chloride and extracted with water, dried and re-concentrated to obtain 37 mg (yield 20%) of the desired product as a solid yellow color.

The following compounds relating to the first aspect of the compounds of Category II can be obtained by the method described above.

2-(4-Forfinal)-6-morpholine-4-yl-3-[2-(4-pertenece)-p is rimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he: 1H NMR (CDCl3, 300 MHz) δ to 1.61 (s, 4H), 2,58 (s, 4H), 3,70-3,99 (m, 4H), 4,23-425 (m, 1H), 6,94 (d, 1H, J=5,1 Hz), 7,10 (t, 2H, J=8.7 Hz), 7,26-7,41 (m, 6H), and 8.50 (d, 1H, J=5,1 Hz), ECI+MS: m/z (relates. intensity) 491,9 (100, M++H)

Analysis: With26H23F2N5O30.5 H2O:calculated C, 62,39; H, a 4.83; N, 13,99; found C, 62,02; H, to 4.38; N, 13,62.

The second aspect of the compounds of Category II relates to the compounds of the formula:

in which R is an amino group indicated in the formula. Similar compounds of table IV contains the group R having the formula-NHC(HR5bR6in which R4adenotes hydrogen and R1, R5b, R6, R9aand R9bhave the values listed in the table.

4-forfinal
Table IV
No.R1R5bR6R9aR9b
1734-forfinalHPhenylHH
1744-forfinalH4-forfinalHH
1754-forfinalH2-AMINOPHENYLHH
1764-forfinalH2-methylphe the Il HH
1774-forfinalH4-wereHH
1784-forfinalH4-methoxyphenylHH
1794-forfinalH4-(propanesulfonyl)phenylHH
1804-forfinalH3-benzo[1,3]dioxol-5-ylHH
1814-forfinalHPyridine-2-ylHH
1824-forfinalHPyridine-3-ylHH
1834-forfinalMethylPhenylHH
1844-forfinalMethyl4-forfinalHH
1854-forfinalMethyl2-AMINOPHENYLHH
1864-forfinalMethyl2-wereHH
1874-forfinalMethyl4-wereHH
188 4-forfinalMethyl4-methoxyphenylHH
1894-forfinalMethyl4-(propanesulfonyl)phenylHH
1904-forfinalMethyl3-benzo[1,3]dioxol-5-ylHH
1914-forfinalMethylPyridine-2-ylHH
1924-forfinalMethylPyridine-3-ylHH
1934-forfinalHPhenylMethylMethyl
1944-forfinalH4-forfinalMethylMethyl
1954-forfinalH2-AMINOPHENYLMethylMethyl
1964-forfinalH2-wereMethylMethyl
1974-forfinalH4-wereMethylMethyl
1984-forfinalH4-methoxyphenylMethylMethyl
199H4-(propanesulfonyl)phenylMethylMethyl
2004-forfinalH3-benzo[1,3]dioxol-5-ylMethylMethyl
2014-forfinalHPyridine-2-ylMethylMethyl
2024-forfinalHpyridine-3-ylMethylMethyl
2034-forfinalMethylPhenylMethylMethyl
2044-forfinalMethyl4-forfinalMethylMethyl
2054-forfinalMethyl2-AMINOPHENYLMethylMethyl
2064-forfinalMethyl2-wereMethylMethyl
2074-forfinalMethyl4-wereMethylMethyl
2084-forfinalMethyl4-methoxyphenylMethylMethyl
2094-forfinalMethyl4-(propanesultone is)phenyl MethylMethyl
2104-forfinalMethyl3-benzo[1,3]dioxol-5-ylMethylMethyl
2114-forfinalMethylPyridine-2-ylMethylMethyl
2124-forfinalMethylPyridine-3-ylMethylMethyl
2134-forfinal-CO2CH3PhenylHH
2144-forfinal-CO2CH34-forfinalHH
2154-forfinal-CO2CH32-AMINOPHENYLHH
2164-forfinal-CO2CH32-wereHH
2174-forfinal-CO2CH34-wereHH
2184-forfinal-CO2CH34-methoxyphenylHH
2194-forfinal-CO2CH34-(propanesulfonyl)phenylH H
2204-forfinal-CO2CH33-benzo[1,3]dioxol-5-ylHH
2214-forfinal-CO2CH3Pyridine-2-ylHH
2224-forfinal-CO2CH3Pyridine-3-ylHH
2234-forfinal-CO2CH3PhenylMethylMethyl
2244-forfinal-CO2CH34-forfinalMethylMethyl
2254-forfinal-CO2CH32-AMINOPHENYLMethylMethyl
2264-forfinal-CO2CH32-wereMethylMethyl
2274-forfinal-CO2CH34-wereMethylMethyl
2284-forfinal-CO2CH34-methoxyphenylMethylMethyl
2294-forfinal-CO2CH3 4-(propanesulfonyl)phenylMethylMethyl
2304-forfinal-CO2CH33-benzo[1,3]dioxol-5-ylMethylMethyl
2314-forfinal-CO2CH3Pyridine-2-ylMethylMethyl
2324-forfinal-CO2CH3Pyridine-3-ylMethylMethyl

Compounds, which are compounds of the second aspect of Category II, in which R is an amino group can be obtained according to the scheme described below, based on the total intermediate11.In the following example, R9aand R9beach represent methyl and R stands for (S)-(1-phenyl)ethylamino.

EXAMPLE 9

6-Dimethylamino-2-(4-forfinal)-3-[2-(1-phenylethylamine)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he(26)

Getting benzyl ester 4-dimethylamino-2-[2-(4-forfinal)acetyl]-pyrazolidine-1-carboxylic acid(21):To a solution of benzyl ester 2-[2-(4-forfinal)acetyl-4-oxo-pyrazolidine-1-carboxylic sour the s 11(3.6 g, 10 mmol) and dimethylamine (10 ml of 2M solution, 20 mmol) in THF added at room temperature Na(OAc)3BH (3.1 g, 15 mmol) and the SPLA (0.6 g, 10 mmol). The solution was stirred for 12 hours, then partitioned between diethyl ether and NaHCO3. The aqueous layers extracted several times with ether and the organic layers combined, dried and concentrated in vacuo to obtain a clear oil, which was re-dissolved in ether, enter 1 equivalent of HCl in ether with the formation of a solid white color. The solid is filtered off and get the desired product as HCl salt.

Obtaining 1-(4-dimethylaminopyridine-1-yl)-2-(4-forfinal)-ethanone(22):Benzyl ether of 4-dimethylamino-2-[2-(4-forfinal)acetyl]-pyrazolidine-1-carboxylic acid, HCl salt, (21) (4,22 g, 10 mmol) is dissolved in methanol and added Pd/C (100 mg). The solution is then hydronaut on the Parr apparatus®Hydrogenation Apparatus for 18 hours, after which the catalyst was removed by filtration and the filtrate was concentrated in vacuo to obtain the desired product.

Obtaining 1-[4-dimethylamino-2-(2-methylsulfonylamino-4-carbonyl)-pyrazolidine-1-yl]-2-(4-forfinal)-ethanone(23):

To a solution of 1-(4-dimethylaminopyridine-1-yl)-2-(4-forfinal)-ethanone22(2.5 g, 10 mmol) in dichloromethane (20 ml) is added 2-methylsulfonylamino-4-carbonylchloride (3.7 g 20 mmol) followed by precapitalism of 1.0 N aqueous sodium hydroxide solution (35 ml). The mixture is intensively stirred at room temperature for 12 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed with water (100 ml). The aqueous layer was subjected to reverse extraction with dichloromethane (100 ml). The combined organic layers washed with saturated aqueous sodium bicarbonate (100 ml) and brine (100 ml), dried, filtered and concentrated in vacuo. The resulting crude substance is purified on silica (1:1 hexane/ethyl acetate to 100% ethyl acetate) to obtain the desired product.

Getting 6-dimethylamino-2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it(24):

1-[4-Dimethylamino-2-(2-methylsulfonylamino-4-carbonyl)-pyrazolidine-1-yl]-2-(4-forfinal)-alanon23(4.0 g, 10 mmol) dissolved in THF (75 ml). This solution is introduced dropwise via cannula to a suspension of NaH (0,440 g 60%dispersion in mineral oil, 11 mmol) at -30°C. the Reaction mixture is gradually brought up to 0°C for 3 hours. The reaction is quenched using NH4Cl (saturated aqueous solution) (15 ml). The mixture is stirred at room temperature, then concentrated in vacuo. The residue was diluted with tetrahydrofuran (250 ml) and the mixture is filtered through a layer of celite. The filtrate was concentrated in vacuo to obtain an oily substance. The crude product is purified on the silicon dioxide is (100%ethyl acetate to mixtures of 5%, 10%, 20% methyl alcohol/ethyl acetate) to obtain the desired product.

Getting 6-dimethylamino-2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it(25):

To a solution of 6-dimethylamino-2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it24,(3.9 g, 10 mmol)inin a mixture of THF:methanol (150 ml of a mixture 1:1) was added dropwise a solution of Oxone®(peroxymonosulfate potassium) (24.3 g, to 39.5 mmol) in water (100 ml). The reaction mixture was stirred at room temperature for 1 hour, diluted with aqueous solution of NaHCO3and extracted three times with ethyl acetate. The organic layers are combined, dried and concentrated in vacuo and receive crude desired product which is used without further purification.

Getting 6-dimethylamino-2-(4-forfinal)-3-[2-(1-(S)-phenylethylamine)-pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it(26):A solution of the crude 6-dimethylamino-2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it25,obtained as described above (4,2 g, 10 mmol)and (S)-(-)α-methylbenzylamine (45,2 ml, 351 mmol) dissolved in toluene (100 ml). The resulting mixture was heated to 140°C for 12 hours, cooled to room temperature and the solvent is distilled off in vacuum. The obtained residue is purified on silica (11 EtOAc/hexane) to obtain the desired product.

Connection Category III, which are inhibitors of the allocation of inflammatory cytokines, in accordance with the present invention is characterized by a common structure, which is described by the formula:

and in accordance with the first aspect related to the ether analogues of the formula:

in which R and R1have the values listed in table IV.

td align="left"> 3-N-acetylaminophenol
Table IV
No.R1R
2334-forfinalPhenoxy
2344-forfinal2 fervency
2354-forfinal3 fervency
2364-forfinal4 fervency
2374-forfinal2,6-divergence
2384-forfinal2 cianfrocca
2394-forfinal3 cianfrocca
2404-forfinal2 triptoreline
2414-forfinal4 triptoreline
2424-forfinal2 methylphenoxy
2434-forfei the 4 methylphenoxy
2444-forfinal2,4-dimethylphenoxy
2454-forfinal3-N-acetylaminophenol
2464-forfinal2 methoxyphenoxy
2474-forfinal4 methoxyphenoxy
2484-forfinal3-benzo[1,3]dioxol-5-yl
2493-forfinalPhenoxy
2503-forfinal2 fervency
2513-forfinal3 fervency
2523-forfinal4 fervency
2533-forfinal2,6-divergence
2543-forfinal2 cianfrocca
2553-forfinal3 cianfrocca
2563-forfinal2 triptoreline
2573-forfinal4 triptoreline
2583-forfinal2 methylphenoxy
2593-forfinal4 methylphenoxy
2603-forfinal2,4-dimethylphenoxy
261 3-forfinal3-N-acetylaminophenol
2623-forfinal2 methoxyphenoxy
2633-forfinal4 methoxyphenoxy
2643-forfinal3-benzo[1,3]dioxol-5-yl
2653-triptorelinePhenoxy
2663-triptoreline2 fervency
2673-triptoreline3 fervency
2683-triptoreline4 fervency
2693-triptoreline2,6-divergence
2703-triptoreline2 cianfrocca
2713-triptoreline3 cianfrocca
2723-triptoreline2 triptoreline
2733-triptoreline4 triptoreline
2743-triptoreline2 methylphenoxy
2753-triptoreline4 methylphenoxy
2763-triptoreline2,4-dimethylphenoxy
2773-triptoreline
2783-triptoreline2 methoxyphenoxy
2793-triptoreline4 methoxyphenoxy
2803-triptoreline3-benzo[1,3]dioxol-5-yl

Compounds which correspond to the first aspect of the compounds of Category III can be obtained according to the scheme described below, using the intermediate8as a relevant source material.

EXAMPLE 10

2-(4-Forfinal)-6-hydroxy-3-(2-phenoxypyridine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he(36)

Obtain 1-benzyl ester 2-tert-butyloxycarbonyl-4-oxo-pyrazolidine-1,2-dicarboxylic acid(27):1-benzyl ester 2-tert-butyloxycarbonyl-4-metrobidazole-1,2-dicarboxylic acid8(23.9 g, a 75.1 mmol) dissolved in dichloromethane (200 ml). The solution is cooled to -78°and rinsed with oxygen for 5 minutes. Ozone gas is bubbled through a solution ofuntil then, until the solution acquires a thick blue color (about 20 minutes). The solution is rinsed with oxygen and argon, is then introduced 40 ml of dimethyl sulfide. About ladusaw bath resolve and the solution stirred at room temperature for 12 hours. The reaction solution is then concentrated in vacuo and the resulting oil purified on silica (3:1-2:1 hexane/ethyl acetate) to obtain 13.5 g (yield 56%) of the desired product as a viscous clear oil.

Obtain 1-benzyl ester 2-tert-butyloxycarbonyl-4-hydroxypyrrolidine-1,2-dicarboxylic acid(28):1-benzyl ester 2-tert-butyloxycarbonyl-4-oxo-pyrazolidine-1,2-dicarboxylic acid27(5.0 g, 15.6 mmol) dissolved in tetrahydrofuran (150 ml) and the solution cooled to -78°C. Adds dropwise with a syringe 5M solution of a complex of borane-dimethyl sulfide in the air (6,24 ml, and 31.2 mmol). After keeping the reaction at -78°C for 40 minutes the reaction is quenched by slowly adding saturated aqueous solution of ammonium chloride (20 ml). The cooling bath is eliminated and the mixture is brought to room temperature under vigorous stirring. The solvent is distilled off in vacuum and the residue diluted with dichloromethane (200 ml). The mixture was washed with water (150 ml) and saturated aqueous sodium bicarbonate (150 ml), water and brine. The combined aqueous layers extracted with dichloromethane (200 ml), water (150 ml), NaCl (saturated) (200 ml), dried over sodium sulfate, filtered and concentrated in vacuo to obtain of 4.66 g (yield 93%) of the desired product as a viscous clear oil.

Paul is the significance of 1-benzyl ester 2-tert-butyloxycarbonyl-4-(2,2-dimethylpropionic)pyrazolidine-1,2-dicarboxylic acid(29):

1-benzyl ester 2-tert-butyloxycarbonyl-4-hydroxypyrrolidine-1,2-dicarboxylic acid28(1,42 mg, 4.40 mmol)indissolved in pyridine (22 ml). Add 4-dimethylaminopyridine (10 mg), then trimethylacetylchloride (1,63 ml, 13,2 mmol). The reaction medium is stirred at room temperature for 12 hours. The turbid reaction mixture was then concentrated in vacuo and get the rest white. To the residue is added dichloromethane (75 ml) and the mixture was washed with 1N aqueous solution of hydrochloric acid (75 ml). The aqueous layer was extracted with dichloromethane (75 ml), the combined organic layers washed with saturated aqueous NaHCO3(75 ml), water (75 ml), brine (75 ml), then dried, filtered and concentrated in vacuo to obtain the crude product. The crude product is purified on silica (4:1-1:1 hexane/ethyl acetate) and gain of 1.76 g (yield 98%) of the desired product as a clear viscous oil.

Obtain 1-benzyl ester 4-(2,2-dimethylpropionic)pyrazolidine-1-carboxylic acid(30):

1-Benzyl ester 2-tert-butyloxycarbonyl-4-(2,2-dimethylpropionic)pyrazolidine-1,2-dicarboxylic acid29(1,76 g, 4,33 mmol) dissolved in methanol (40 ml) and the solution cooled to 0°C. is Added dropwise thionyl chloride (3,16 ml of 43.3 mmol), the reaction medium is brought to room temperature the s and stirring is continued for 12 hours. The reaction solution was concentrated in vacuo to obtain 1.45 g (yield 98%) of the desired product as HCl salt, representing the solid is not quite white.

Obtain 1-benzyl ester 2-[2-(4-forfinal)acetyl]-4-(2,2-dimethylpropionic)pyrazolidine-1-carboxylic acid(31):

1-Benzyl ester 4-(2,2-dimethylpropionic)pyrazolidine-1-carboxylic acid30(1.45 g, to 4.23 mmol) dissolved in dichloromethane (21 ml). The solution is cooled to 0°and added dropwise the triethylamine (1,30 ml, 9,31 mmol) via syringe. The cooling bath is eliminated and the reaction medium is brought to room temperature and stirring is continued for 20 minutes. Enter 4-florfenicol acid (848 mg, of 5.50 mmol). After stirring for 5 minutes the reaction mixture was transferred via cannula into a solution of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide in dichloromethane (21 ml), maintaining the temperature at 0°C. the Reaction medium is left to mix, gradually bringing the temperature to room for more than 12 hours. The reaction medium is washed with 5%aqueous solution of Na2CO3(2x50 ml). The combined aqueous layers extracted several times with dichloromethane (50 ml) and the combined organic layers washed with brine, dried, filtered and concentrated in vacuo. The crude product is purified on silica (2:1-1:1 GE the San/ethyl acetate) and get 1,71 g (yield 91%) of the desired product in the form of a solid white color.

Obtaining 1-[2-(4-forfinal)acetyl]-pyrazolidine-4-silt ether of 2,2-dimethylpropionic acid(32):1-benzyl ester 2-[2-(4-forfinal)acetyl]-4-(2,2-dimethylpropionic)pyrazolidine-1-carboxylic acid31(1,71 g, 3,86 mmol) dissolved in methanol (40 ml). The flask is flushed with nitrogen and injected with 10%palladium on coal (300 mg). The reaction flask is strongly shaken at room temperature and a pressure of 1 ATM of hydrogen for 6 hours. The flask is flushed with nitrogen and the reaction mixture is filtered through a layer of celite, rinsing with ethyl acetate (100 mg). The filtrate was concentrated in vacuo to obtain 1.18 g (yield 98%) of the desired product as a yellowish brown solid.

Obtaining 1-[2-(4-forfinal)acetyl]-2-(methylsulfonylamino-4-carbonyl)-pyrazolidine-4-silt ether of 2,2-dimethylpropionic acid(33):To a solution of 1-[2-(4-forfinal)acetyl]-pyrazolidine-4-silt ether of 2,2-dimethylpropionic acid32(427 mg, to 1.79 mmol) in dichloromethane (3 ml) is added 2-methylsulfonylamino-4-carbonylchloride (676 mg, 3.58 mmol), then added dropwise 1N aqueous sodium hydroxide solution (6 ml). The mixture is intensively stirred at room temperature for 12 hours. The reaction mixture was diluted with dichloromethane (25 ml) and washed with water (25 ml). The aqueous layers are subjected to reverse the former is regirovannyy dichloromethane (25 ml). The combined organic layers washed with saturated aqueous sodium bicarbonate (25 ml) and brine (25 ml), dried, filtered and concentrated in vacuo. The resulting crude substance is purified on silica (1:1 hexane/ethyl acetate to 100% ethyl acetate) and receive 464 mg (yield 96,6%) of the desired product as a viscous brown oil.

Getting 6-(4-forfinal)-7-(2-methylsulfonylamino-4-yl)-5-oxo-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-silt ether of 2,2-dimethylpropionic acid(34):1-[2-(4-forfinal)acetyl]-2-(methylsulfonylamino-4-carbonyl)-pyrazolidine-4-silt ether2,2-dimethylpropionic acid33(300 mg, 0,651 mmol)dissolved in THF (6 ml). This solution then add via cannula dropwise to a suspension of NaH (29 mg, 60%dispersion in mineral oil, 0,716 mmol) at -30°C. the Reaction mixture gradually over 3 hours is brought to a temperature 0°C. the Reaction is quenched with NH4Cl (saturated aqueous solution) (1 ml). The mixture is stirred at room temperature, then concentrated in vacuo. The residue was diluted with tetrahydrofuran (50 ml) and the mixture filtered through celite. The filtrate was concentrated in vacuo to obtain an orange oil. The crude product is purified on silica (100% ethyl acetate to 5%, 10%, 20% methyl alcohol/ethyl acetate) to obtain 87 mg (yield 30%) require the constituent of the product in a solid yellow color.

Getting 6-(4-forfinal)-7-(2-methanesulfonamido-4-yl)-5-oxo-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-silt ether of 2,2-dimethylpropionic acid(35):6-(4-forfinal)-7-(2-methylsulfonylamino-4-yl)-5-oxo-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-silt ether of 2,2-dimethylpropionicacid34(96 mg, 0,217 mmol) dissolved in chloroform (2 ml).

The solution is cooled to 0°and added dropwise to the yellow suspension a solution of 3-chlormadinone acid (117 mg with a purity of about 77%, 0,521 mmol) in chloroform (3 ml). The reaction medium is stirred at 0°C for 3 hours, then at room temperature for 12 hours. The reaction solution colored in yellow, washed with NaHSO3(saturated aqueous solution) (g ml). The layers are separated and the aqueous layer was extracted with chloroform (CH ml). The combined organic layers washed with NaHCO3(saturated aqueous solution), dried, filtered and concentrated in vacuo to obtain 50 mg (yield 48%) of the desired product as yellow oil.

Obtaining 2-(4-Forfinal)-6-hydroxy-3-(2-phenoxypyridine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it(36):Solution6-(4-forfinal)-7-(2-methanesulfonamido-4-yl)-5-oxo-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-siltether of 2,2-dimethylpropionic acid35(50 mg, 0,105 mmol) in THF (1 ml) slowly drain the t via cannula into a solution of sodium phenolate in THF (1 ml) at 0° C. the Cooling bath is removed and the reaction medium is stirred at room temperature for 1 hour. The reaction is quenched with NH4Cl (saturated aqueous solution) (500 μl). The reaction mixture was concentrated in vacuo and the residue was diluted in ethyl acetate (15 ml). The solution was washed with water (20 ml) and 5%aqueous solution of Na2CO3(20 ml). The combined aqueous layers are extracted with ethyl acetate (25 ml) and brine (20 ml), dried, filtered and concentrated in vacuo. The crude substance is purified on silica (100% ethyl acetate to 5, 10, 20% methyl alcohol/ethyl acetate) to obtain 9 mg (yield 21%) of the desired product as a solid yellow color.1H NMR (300 MHz, CDCl3) δ 8,43 (d, J=5,2 Hz, 1H), 7,46 (t, J=7.8 Hz, 2H), 7,31-7,27 (m, 3H), 7,19 (d, J=8,2 Hz, 2H), 7,03 (t, J=8.6 Hz, 2H), 6,80 (d, J=5,2 Hz, 1H), 5,41 (user. s, 1H), 4,82(m, 1H), 4,23 (d, J=12,4 Hz, 1H), 3.95 to of 3.85 (m, 2H), 3,76 (DD, J=12,4, 4,4 Hz, 1H); HRMSm/zfor C22H18FN4O3(MN)+designed 405,1363; found 405,1365.

This procedure can be used to obtain similar compounds Category III according to the first aspect, in which R8represents a C1-C4the alkyl. Conversion of intermediate compounds28tointermediate compounds of type IV, for example, to the methoxy analogue37using the procedures set out below, allows the specialist to obtain 6-alkoxyl the cyclic analogue connections Category III.

EXAMPLE 11

Obtain 1-benzyl ester 2-tert-butyloxycarbonyl-4-methoxypiperidine-1,2-dicarboxylic acid(37):1-Benzyl ester 2-tert-butyloxycarbonyl-4-hydroxypyrrolidine-1,2-dicarboxylic acid28(2.55 g, to $ 7.91 mmol) dissolved in dimethylformamide (40 ml). Add methyliodide (1.97 ml of 31.6 mmol) and then the silver oxide (3,67 g, 15.8 mmol). The flask was covered with foil and shaken for 12 hours in the absence of light. The reaction mixture was poured into ether (150 ml). The mixture is intensively stirred at room temperature and filtered through a layer of celite. The filtrate is washed with water (I ml) and brine (150 ml), dried, filtered and concentrated in vacuo to obtain 2.58 g (yield 97%) of the desired product in the form of a clear yellow oil.

According to the second aspect of the connection Category III refers to the structure in which the substituent R2in position 6 pyrazolo[1,2-a]pyrazole-1-about cyclic system which contains a carbonyl group selected from the group consisting of -(CH2)jCO2R10; -(CH2)jOCO2R10; -(CH2)jCON(R10)2and -(CH2)jOCON(R10)2in which R10matter described above. A non-limiting example is similar to the connection according to the second aspect of the connection is the second Category III has the formula:

Table VII illustrates examples of compounds of this aspect according to the present invention, in which two Deputy R10,taken together, form a loop.

4-forfinal
Table VII
No.R1R3R10ring
2814-forfinalPhenylMorpholine-1-yl
2824-forfinal4-forfinalMorpholine-1-yl
2834-forfinal2-AMINOPHENYLMorpholine-1-yl
2844-forfinal2-wereMorpholine-1-yl
2854-forfinal4-wereMorpholine-1-yl
2864-forfinal4-methoxyphenylMorpholine-1-yl
2874-forfinal4-(propanesulfonyl)phenylMorpholine-1-yl
2884-forfinal3-benzo[1,3]dioxol-5-ylMorpholine-1-yl
2894-forfinalPyridine-2-ylMorpholine-1-yl
2904-forfinalP is ridin-3-yl Morpholine-1-yl
2914-forfinalPhenylPiperidine-1-yl
2924-forfinal4-forfinalPiperidine-1-yl
2934-forfinal2-AMINOPHENYLPiperidine-1-yl
2944-forfinal2-werePiperidine-1-yl
2954-forfinal4-werePiperidine-1-yl
2964-forfinal4-methoxyphenylPiperidine-1-yl
2974-forfinal4-(propanesulfonyl)phenylPiperidine-1-yl
2984-forfinal3-benzo[1,3]dioxol-5-ylPiperidine-1-yl
2994-forfinalPyridine-2-ylPiperidine-1-yl
3004-forfinalPyridine-3-ylPiperidine-1-yl
3014-forfinalPhenylPiperazine-1-Il
3024-forfinal4-forfinalPiperazine-1-Il
3034-forfinal2-AMINOPHENYLPiperazine-1-Il
3042-werePiperazine-1-Il
3054-forfinal4-werePiperazine-1-Il
3064-forfinal4-methoxyphenylPiperazine-1-Il
3074-forfinal4-(propanesulfonyl)phenylPiperazine-1-Il
3084-forfinal3-benzo[1,3]dioxol-5-ylPiperazine-1-Il
3094-forfinalPyridine-2-ylPiperazine-1-Il
3104-forfinalPyridine-3-ylPiperazine-1-Il

As described above, the method of obtaining the compounds included in the first aspect of the compounds of Category III includes the final stage at which the O-protective group, such as, for example, C(O)C(CH3)3removed, at the same time, group-OR3is entered in the connection structure, for example, in the conversion process connection35in connection36. As for the compounds of the second aspect, the following procedure is used to obtain compounds in which one of R2in position 6 represents a carbonyl group, described above, as related to the second aspect of the compounds of Category III.

Following with the EMA illustrates the formation of compounds, above, on the basis of the intermediate compound (11).

EXAMPLE 12

6-(4-forfinal)-5-oxo-7-(2-phenoxypyridine-4-yl)-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-silt ether morpholine-4-carboxylic acid(43)

Getting benzyl ester 2-[2-(4-forfinal)acetyl]-4-hydroxypyrrolidine-1-carboxylic acid(38):Benzyl ether of 2-[2-(4-forfinal)acetyl]-4-oxo-pyrazolidine-1-carboxylic acid11(1.0 g, of 2.81 mmol) dissolved in THF (30 ml) and the solution cooled to -78°C. was added dropwise 5M solution of a complex of borane-dimethyl sulfide in ether (1.2 ml, 5,61 mmol). After keeping the reaction at a temperature of -78°C for 1 hour the reaction is quenched by slow addition of NH4Cl (saturated aqueous solution) (10 ml). The cooling bath removed and the mixture is brought to room temperature under vigorous stirring. Distilled tetrahydrofuran in vacuo and the residue diluted with water (50 ml). The mixture is extracted with ethyl acetate (2×100 ml), dried, filtered and concentrated in vacuo to obtain a yellow oil, which was purified on silica (1:1-1:2 hexane/ethyl acetate to 100% ethyl acetate) and receive 731 mg (yield 73%) of the desired product as a clear viscous oil.

Getting benzyl ester 2-[2-(4-forfinal)acetyl]-4-(4-nitrophen dicarbonyl)-pyrazolidine-1-carboxylic acid (39):

Benzyl ether of 2-[2-(4-forfinal)acetyl]-4-hydroxypyrrolidine-1-carboxylic acid38(366 mg, of 1.02 mmol) dissolved in dichloromethane (10 ml). The solution is cooled to 0°and add one portion of p-nitrophenylphosphate (411 mg, 2.04 mmol). The solution was stirred at 0°and add pyridine (198 μl, 2.45 mmol). Stirring is continued at 0°C for 1 hour, followed by stirring at room temperature for 12 hours. The reaction medium is diluted with water (40 ml) and extracted with dichloromethane (40 ml). The organic layer was washed with 0,5N NaOH (2×40 ml). The combined aqueous layers extracted with dichloromethane (30 ml). The combined organic layers washed with brine (30 ml), dried, filtered and concentrated in vacuo. The crude substance is purified on silica(3:1, 2:1, 1:1 hexane/ethyl acetate) and receive 462 mg (yield 86%) of the desired product as white foam.

Getting 1-benzyloxycarbonyl-2-[2-(4-forfinal)acetyl]-pyrazolidine-4-silt ether morpholine-4-carboxylic acid(40):

Benzyl ether of 2-[2-(4-forfinal)acetyl]-4-(4-nitrophenoxyacetic)-pyrazolidine-1-carboxylic acid39(462 mg,0,882 mmol) dissolved in dichloromethane (9 ml). Add morpholine (770 μl, 8,82 mmol)and the reaction medium immediately becomes pale yellow color. After stirring for about 1.5 hours at room themes is the temperature value of the reaction medium is diluted with dichloromethane (20 ml) and washed with 5%solution of Na 2CO3(2×20 ml). The combined aqueous layers extracted with dichloromethane (20 ml), organic layers combined, washed with water, brine and dried. The solvent is distilled off in vacuum and get 414 mg of the desired product as a clear oil.

Obtaining 1-[2-(4-forfinal)acetyl]-pyrazolidine-4-silt ether morpholine-4-carboxylic acid(41):1-benzyloxycarbonyl-2-[2-(4-forfinal)acetyl]-pyrazolidine-4-silt ether morpholine-4-carboxylic acid40(512 mg, of 1.09 mmol) was dissolved in methanol (10 ml) and the flask is flushed with nitrogen, then load 10%palladium on coal (103 mg). The reaction mixture is intensively stirred and hydronaut at a pressure of 1 ATM for 2.5 hours at room temperature. The reaction mixture was filtered through a layer of celite, rinse with ethyl acetate (100 ml) and concentrated in vacuo to obtain 354 mg of the desired product as a white powder.

Obtaining 1-[2-(4-forfinal)acetyl]-2-(2-phenoxypyridine-4-carbonyl)-pyrazolidine-4-silt ether morpholine-4-carboxylic acid(42): 1-[2-(4-forfinal)acetyl]-pyrazolidine-4-siltether morpholine-4-carboxylic acid(41)(354 mg, 1.05 mmol) and 2-phenoxypyridine-4-carbonylchloride18(345 mg, about 1.47 mmol) dissolved in dichloromethane (2 ml). Under vigorous stirring was added dropwise 1N NaOH solution (3 ml) at room temperature. The reaction proceeds in the tech is of 12 hours, then enter the additional amount of acid chloride18and continue stirring for 3 hours. Enter again (83 mg) acid chloride18and continue stirring for another 12 hours. Then the reaction medium is diluted with dichloromethane (50 ml) and washed with water (50 ml). The combined organic layers washed with NaHCO3(saturated solution) (50 ml) and brine (50 ml), dried, filtered and concentrated to obtain a brown oil. The crude substance is purified on silica (100% ethyl acetate-5% methyl alcohol/ethyl acetate) and obtain 348 mg (yield 61%) of the desired product as a viscous oil.

Getting 6-(4-forfinal)-5-oxo-7-(2-phenoxypyridine-4-yl)-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-silt ether morpholine-4-carboxylic acid(43):Solution1-[2-(4-forfinal)acetyl]-2-(2-phenoxypyridine-4-carbonyl)-pyrazolidine-4-silt ether morpholine-4-carboxylic acid42(154 mg, 0,287 mmol) in dimethylformamide (3 ml) was added dropwise at -10°to a suspension of sodium hydride (16,4 mg of 60%dispersion in mineral oil, 0,410 mmol) in tetrahydrofuran (3 ml). After keeping at -10°within hours, the reaction medium is heated to 0°C for 2 hours. The orange solution is then quenched by slow addition of a saturated solution of NH4Cl (400 ml). The cooling bath is eliminated and the solution allowed to warm up to matnog temperature. The reaction mixture was concentrated in vacuo and the resulting residue is dissolved in THF (25 ml) and filtered through a layer of celite.The filtrate was concentrated in vacuo and the residue purified using preparative HPLC to obtain 47 mg (yield 32%) of the desired product as a solid yellow color.1H NMR (300 MHz, CDCl3) δ 8,46 (d, J=4.9 Hz, 1H), 7,47-to 7.18 (m, 9H), was 7.08 (t, J=8.7 Hz, 2H), 6.89 in (d, J=4.9 Hz, 1H), to 5.66 (m, 1H), 4,16 (m, 2H), was 4.02 (d, J=12.9 Hz, 1H), a 3.87 (DD, J=12,9, 5,1 Hz, 1H), 3,79-3,30 (m, 8H); HRMS m/z for C27H25FN5O5(MH+) calculated 518,1840 found 518,1815.

According treemo aspect of the connection Category III refers to amino analogues corresponding to the formula:

in which groups R are amino groups of the formula

-NH[CHR5b]R6and R1, R5b, R6and R8have the values listed in table VIII.

tr>
Table VIII
No.R1R5bR6R8
3114-forfinalHPhenylMethyl
3124-forfinalH4-forfinalMethyl
3134-forfinalH2-aminophe the Il Methyl
3144-forfinalH2-wereMethyl
3154-forfinalH4-wereMethyl
3164-forfinalH4-methoxyphenylMethyl
3174-forfinalH4-(propanesulfonyl)phenylMethyl
3184-forfinalH3-benzo[1,3]dioxol-5-ylMethyl
3194-forfinalHPyridine-2-ylMethyl
3204-forfinalHPyridine-3-ylMethyl
3214-forfinalHHMethyl
3224-forfinalHMethylMethyl
3234-forfinalHEthylMethyl
3244-forfinalHVinylMethyl
3254-forfinalHCyclopropylMethyl
3264-forfinalHCollege the forces Methyl
3274-forfinalHMethoxymethylMethyl
3284-forfinalHMethoxyethylMethyl
3294-forfinalH1-hydroxy-1-methylethylMethyl
3304-forfinalH-CO2HMethyl
3314-forfinalMethylPhenylMethyl
3324-forfinalMethyl4-forfinalMethyl
3334-forfinalMethyl2-AMINOPHENYLMethyl
3344-forfinalMethyl2-wereMethyl
3354-forfinalMethyl4-wereMethyl
3364-forfinalMethyl4-methoxyphenylMethyl
3374-forfinalMethyl4-(propanesulfonyl)phenylMethyl
3384-forfinalMethyl3-benzo[1,3]dioxol-5-ylMethyl
3394-forfinalMethylPyridine-2-ylMethyl
3404-forfinalMethylPyridine-3-ylMethyl
3414-forfinalMethylHMethyl
3424-forfinalMethylMethylMethyl
3434-forfinalMethylEthylMethyl
3444-forfinalMethylVinylMethyl
3454-forfinalMethylCyclopropylMethyl
3464-forfinalMethylCyclohexylMethyl
3474-forfinalMethylMethoxymethylMethyl
3484-forfinalMethylMethoxyethylMethyl
3494-forfinalMethyl1-hydroxy-1-methylethylMethyl
3504-forfinalMethyl-CO2HMethyl

The connections relating to the third aspect is soedinenii Category III of the present invention, can be obtained by the method described below, using as starting compound intermediate28.

EXAMPLE 13

2-(4-forfinal)-6-methoxy-3-[2-(2-(S)-methoxy-1-methylethylamine)-pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he(51)

Getting benzyl ester 2-[2-(4-forfinal)acetyl]-4-methoxypiperidine-1-carboxylic acid(44):1-benzyl ester 2-tert-butyloxycarbonyl-4-hydroxypyrrolidine-1,2-dicarboxylic acid28(2.55 g, to $ 7.91 mmol)ofdissolved in dimethylformamide (40 ml). Add methyliodide (1.97 ml of 31.6 mmol) followed by the addition of silver oxide (3,67 g, 15.8 mmol). The flask was covered with foil and stirred the mixture overnight in the absence of light. The reaction mixture was poured into ether (150 ml). The mixture is intensively stirred at room temperature and filtered through a layer of celite. The filtrate is washed with water (2×150 ml) and brine (150 ml), dried over sodium sulfate, filtered and concentrated in vacuo to obtain 2.58 g (yield 97%) of the desired product in the form of a clear yellow oil.

Getting benzyl ester 2-[2-(4-forfinal)acetyl]-4-(4-methoxy)-pyrazolidine-1-carboxylic acid(45)b> :Benzyl ether of 2-[2-(4-forfinal)acetyl]-4-methoxypiperidine-1-carboxylicacid44, (to 2.57 g of 7.64 mmol) is dissolved in methyl alcohol (75 ml) and the solution cooled to 0°C. is Added dropwise thionyl chloride (5,58 ml, to 76.4 mmol) and the temperature of the reaction medium is brought to room during the night. The reaction solution was concentrated in vacuo and get 2,07 g (yield 99%) of the desired product as HCl salt, representing the solid is not quite white.

Getting benzyl ester 2-[2-(4-forfinal)acetyl]-4-methoxypiperidine-1-carboxylic acid(46):Benzyl ether of 2-[2-(4-forfinal)acetyl]-4-(4-methoxy)-pyrazolidine-1-carboxylic acid45,(8,81 g, and 32.3 mmol) dissolved in dichloromethane (150 ml). Add 4-perforazione (5.31g, to 38.8 mmol), then add 0,5N aqueous sodium hydroxide solution (150 ml). The mixture is intensively stirred at room temperature for 6 hours. The reaction medium is diluted with dichloromethane (200 ml) and washed with water (200 ml). The aqueous layer was extracted with dichloromethane (2×200 ml). The combined organic layers washed with 5%aqueous solution of sodium carbonate (250 ml) and brine (250 ml), dried over sodium sulfate, filtered and concentrated in vacuo to obtain 12.0 g of the desired product as a viscous oil yellowish-brown color.

Receiving -(4-forfinal)-1-(4-methoxypiperidine-1-yl)-ethanone (47):Benzyl ether of 2-[2-(4-forfinal)acetyl]-4-methoxypiperidine-1-carboxylic acid46(12.0 g, to 32.2 mmol) is dissolved in methyl alcohol (300 ml). The flask is rinsed with nitrogen and load 10%palladium on coal (1.2 g). The reaction mixture is intensively stirred at room temperature under hydrogen pressure of 1 ATM for 3 hours. The flask is rinsed with nitrogen and the reaction mixture is filtered through a layer of celite, rinse with ethyl acetate (100 ml). The filtrate was concentrated in vacuo to obtain to 7.67 g of the desired product as a viscous clear oil.

Obtaining 2-(4-forfinal)-1-[4-methoxy-2-(2-methylsulfonylamino-4-carbonyl)pyrazolidine-1-yl]-ethanone(48):2-(4-forfinal)-1-(4-methoxypiperidine-1-yl)-alanon47,(to 7.67 g is 32.2 mmol) and 2-methylsulfonylamino-4-carbonylchloride (9,11 g, to 48.3 mmol) dissolved in dichloromethane (150 ml). Slowly add 0,5N aqueous sodium hydroxide solution (150 ml) using a funnel and the mixture is intensively stirred at room temperature for 4 hours. The reaction mixture was diluted with 5%aqueous solution of sodium carbonate (1 l). The mixture is extracted with dichloromethane (I ml). The combined organic layers are dried over magnesium sulfate, filtered and concentrated to obtain a red oil. The crude substance is purified on silica (1:1-1:3 hexane/ethyl acetate to 100% ethyl acetate) to acquire the Oia 10.3 g of the desired product as a viscous brown oil.

Obtaining 2-(4-forfinal)-6-methoxy-3-(2-methylsulfonylamino-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it(49):

A solution of 2-(4-forfinal)-1-[4-methoxy-2-(2-methylsulfonylamino-4-carbonyl)pyrazolidine-1-yl]-ethanone48,(2,04 g, with 5.22 mmol) in a mixture of dimethylformamide and tetrahydrofuran 1:1 (30 ml) was added dropwise at 0°to a suspension of sodium hydride (230 mg, 60%dispersion in mineral oil, of 5.75 mmol) in dimethylformamide (60 ml). After the reaction for 2 hours at 0°with the formation of a bright red solution of the reaction quenched by the slow introduction of a saturated aqueous solution of ammonium chloride (5 ml). The cooling bath is eliminated and the solution is brought to room temperature. The reaction mixture was concentrated in vacuo and the resulting residue diluted with ethyl acetate (175 ml). The mixture was washed with saturated aqueous ammonium chloride (150 ml). The aqueous layer was extracted with ethyl acetate (CH ml). The combined organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude substance is purified on silica (100% ethyl acetate to 5, 10, 20% methyl alcohol/ethyl acetate) to obtain 1.1 g (yield 57%) of the desired product as an orange oil.

Obtaining 2-(4-forfinal)-6-methoxy-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it(50):2-(4-forfinal)-6-methoxy--(2-methylsulfonylamino-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he 49(1.10 g, 2,95 mmol) diluted with dichloromethane (60 ml). Add 3-chlormadinone acid (662 mg with a purity of about 77%, 2,95 mmol) in one step with the formation of a yellow suspension. After 20 minutes introduce additional amount of 3-chlormadinone acid (240 mg, 1.07 mmol). After 10 minutes the resulting clear yellow solution was poured into 10%aqueous solution of bisulfite sodium (60 ml). The layers are separated and the aqueous layer was extracted with dichloromethane (2×50 ml). The combined organic layers washed with saturated aqueous sodium bicarbonate (2×50 ml), dried over sodium sulfate, filtered and concentrated in vacuo to obtain 948 mg of a mixture of the corresponding sulfoxide and sulfone as a yellow solid. Use the following steps in the same form as received.

Obtaining 2-(4-forfinal)-6-methoxy-3-[2-(2-(S)-methoxy-1-methylethylamine)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it(51):2-(4-Forfinal)-6-methoxy-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it is in the form of a mixture of50(948 mg, 2,44 mmol) and (S)-2-amino-1-methoxypropane (652 mg, to 7.32 mmol) diluted with toluene (16 ml). The mixture is heated at 120°within 2 hours.

The orange solution is allowed to cool to room temperature, then concentrated in vacuo to obtain a residue of orange color. Raw substances what about the cleanse on silica (5%, 10% methyl alcohol/dichloromethane) and obtain 550 mg of the desired product in the form of a solid fluorescent yellow substance.1H NMR (300 MHz, CDCl3) δ is 8.16 (d, J=5,1 Hz, 1H), 7,40 (DD, J=8,8, 5.5 Hz, 2H), 7,03 (t, J=8,8 Hz, 2H), to 6.39 (d, J=5,1 Hz, 1H), 5,39 (user. d, J=8.0 Hz, 1H), 4,57 (m, 1H), 4,30-was 4.02 (m, 5H), of 3.45 (d, J=4,6 Hz, 2H), 3,42 (s, 3H), 3,39 (s, 3H), of 1.28 (d, J=6.6 Hz, 3H); HRMS, m/z for C21H25FN5About3(MN+) calculated 414,1941 found 414,1945.

Using an intermediate connection10that includes the 6-methylene group, can be obtained according to the above procedure with the following connection:

2-(4-forfinal)-6-methylene-3-[2-(2-(S)-phenyl-1-methylethylamine)-pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it52;1H NMR (CDCl3, 300 MHz) δ and 1.60 (d, 3H, J=6.9 Hz), to 4.52 (DD, 2H, J=15,9, 24 Hz), 5.08 to further 5.15 (m, 2H), 5,26 (s, 1H), 6,03 (s, 1H), 6,38 (d, 1H, J=5,1 Hz), 7,00-7,05 (m, 2H), 7,22-7,42 (m, 8H), 8,16 (d, 1H, J=5,1 Hz) HRMS: exact mass25H22FN5O 428,1887 (M++H), found 428,1871.

The intermediate connection10you can also oxidize with OsO4in standardthe conditions to obtain an intermediate compound53in accordance with the following scheme:

which can be used for the following connections:

2-(4-forfinal)-6-hydroxy-6-hydroxymethyl-3-(2-phenoxypyridine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he54;1 H NMR (DMSO-d6, 300 MHz) δ 3,41-to 3.52 (m, 2H), 3.72 points-3,86 (m, 3H), of 3.94 (d, 1H, J=11,1 Hz), 5,23 (t, 1H, J=5.7 Hz), 5,71 (s, 1H), 7,06 (d, 1H, J=4,8 Hz), 7.18 in-7,34 (m, 5H), 7,40-to 7.50 (m, 4H), 8,69 (d, 1H, J=4,8 Hz),ESI=MS: m/z (relative intensity)435,32 (100, M++H) Analysis for C23H19FN4O40,5H2O: calculated C, 62,30; H, 4,55; N, 12,63. Found: C, 62,33; H, 4,13; N, 12,41.

According to the procedure described above, or by its modifications it is possible to obtain other compounds according to the present invention, among which are the following:

2-(3-formationl)-3-(2-phenoxypyridine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it;

2-(4-propenyl)-3-(2-(6-aminopyrimidine-4-yloxy)pyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it;

2-(4-forfinal)-3-[2-(3-pertenece)pyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it;

2-(4-forfinal)-3-[2-(2,4-dimethylphenoxy)pyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it;

2-(2,4-differenl)-3-(2-phenoxypyridine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it;

2-(4-forfinal)-3-[2-(4-chlorophenoxy)pyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it;

2-(4-forfinal)-3-{2-[1-(R,S)-(4-forfinal)ethylamino]pyrimidine-4-yl}-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it;

2-{4-[2-(4-forfinal)-3-oxo-6,7-dihydro-3H,5H-pyrazolo[1,2-a]pyrazole-1-yl]-pyrimidine-2-ylamino}-propionic acid;

2-{4-[2-(4-forfinal)-3-oxo-6,7-dihydro-3H,5H-pyrazolo[1,2-a]pyrazole-1-yl]-pyrimidine-2-ylamino}-N-dimethylpropionic acid;

2-(4-forfinal)-3-(2-([1,3,4]thiadiazole-2-ylamino)pyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it;

2-(4-forfinal)-3-{2-[(pyridine-2-ylmethyl)amino]pyrimidine-4-yl}-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it;

2-(4-forfinal)-3-[(2-methoxypropylamine)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it;

2-(4-forfinal)-3-{2-[(furan-2-ylmethyl)amino]pyrimidine-4-yl}-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it;

2-(4-forfinal)-3-{2-[(3-benzo[1,3]dioxol-5-yl)amino]pyrimidine-4-yl}-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it;

2-(4-forfinal)-3-{2-[(1-(propane-1-sulfonyl)piperidine-4-ylamino]pyrimidine-4-yl}-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he; and

2-(4-forfinal)-3-{2-[(4-methoxybenzylamine)amino]pyrimidine-4-yl}-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it;

Compounds of Category IV, which are inhibitors of the allocation of the inflammatory cytokine, in accordance with the present invention has the General structure corresponding to the formula:

and according to the first aspect are compounds in which the radicals R1and R4bhave the values listed in the following table IX.

2-forfinaltd align="left"> 4-forfinal 389
Table IX
No.R1R4b
3514-forfinalPhenyl
3524-forfinal
3534-forfinal3-forfinal
3544-forfinal4-forfinal
3554-forfinal2-chlorophenyl
3564-forfinal3-chlorophenyl
3574-forfinal4-chlorophenyl
3584-forfinal2,4-differenl
3594-forfinal2,6-differenl
3604-forfinal3,5-differenl
3614-forfinal2,4,6-tryptophanyl
3624-forfinal2,4-dichlorophenyl
3634-forfinal2,6-dichlorophenyl
3644-forfinal3,5-dichlorophenyl
3654-forfinal2,4,6-trichlorphenol
3664-forfinalNaphtalen-1-yl
3674-forfinalNaphtalen-2-yl
3684-forfinal2-AMINOPHENYL
3694-forfinal3-AMINOPHENYL
3704-forfinal4-AMINOPHENYL
3712-cyanophenyl
3724-forfinal3-cyanophenyl
3734-forfinal4-cyanophenyl
3744-forfinal2-were
3754-forfinal3-were
3764-forfinal4-were
3774-forfinal2-methoxyphenyl
3784-forfinal3-methoxyphenyl
3794-forfinal4-methoxyphenyl
3804-forfinal2 methoxyphenoxy
3814-forfinal4 methoxyphenoxy
3824-forfinal2-(N-acylamino)phenyl
3834-forfinal3-(N-acylamino)phenyl
3844-forfinal4-(N-acylamino)phenyl
3854-forfinal4-(methanesulfonyl)phenyl
3864-forfinal4-(econsultancy)phenyl
3874-forfinal4-(propanesulfonyl)phenyl
3884-forfinal2-triptoreline
4-forfinal3-triptoreline
3904-forfinal4-triptoreline
3914-forfinal3,5-bis(trifluoromethyl)phenyl
3924-forfinal3-benzo[1,3]dioxol-5-yl
3933-triptorelinePhenyl
3943-triptoreline2-forfinal
3953-triptoreline3-forfinal
3963-triptoreline4-forfinal
3973-triptoreline2-chlorophenyl
3983-triptoreline3-chlorophenyl
3993-triptoreline4-chlorophenyl
4003-triptoreline2,4-differenl
4013-triptoreline2,6-differenl
4023-triptoreline3,5-differenl
4033-triptoreline2,4,6-tryptophanyl
4043-triptoreline2,4-dichlorophenyl
4053-triptoreline2,6-is chlorphenyl
4063-triptoreline3,5-dichlorophenyl
4073-triptoreline2,4,6-trichlorphenol
4083-triptorelineNaphtalen-1-yl
4093-triptorelineNaphtalen-2-yl
4103-triptoreline2-AMINOPHENYL
4113-triptoreline3-AMINOPHENYL
4123-triptoreline4-AMINOPHENYL
4133-triptoreline2-cyanophenyl
4143-triptoreline3-cyanophenyl
4153-triptoreline4-cyanophenyl
4163-triptoreline2-were
4173-triptoreline3-were
4183-triptoreline4-were
4193-triptoreline2-methoxyphenyl
4203-triptoreline3-methoxyphenyl
4213-triptoreline4-methoxyphenyl
4223-thrift methylphenyl 2 methoxyphenoxy
4233-triptoreline4 methoxyphenoxy
4243-triptoreline2-(N-acylamino)phenyl
4253-triptoreline3-(N-acylamino)phenyl
4263-triptoreline4-(N-acylamino)phenyl
4273-triptoreline4-(methanesulfonyl)phenyl
4283-triptoreline4-(econsultancy)phenyl
4293-triptoreline4-(propanesulfonyl)phenyl
4303-triptoreline2-triptoreline
4313-triptoreline3-triptoreline
4323-triptoreline4-triptoreline
4333-triptoreline3,5-bis(trifluoromethyl)phenyl
4343-triptoreline3-benzo[1,3]dioxol-5-yl

Compounds that belong to the first aspect of the compounds of Category IV can be obtained according to the scheme below, by using the intermediate connection5as a suitable source of product.

EXAMPLE 14

2-(4-forfinal)-3-(2-phenylaminopyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo-[1,2-a]pyrazole-1-he(2)

Obtaining 2-(4-forfinal)-3-(2-phenylaminopyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it(55):To a solution of aniline (0,12 ml of 1.34 mmol) in THF (4 ml) is added NaH (0.07 g, 1.00 mmol). After stirring the mixture for 5 minutes at room temperature, it was added 2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he5(0.25 g, 0.67 mmol). The reaction mixture is refluxed and stirred for 1 hour. The mixture is diluted with saturated aqueous NH4Cl and extracted twice with chloroform. The organic layers are combined, dried over MgSO4and concentrated in vacuo to obtain the crude substance, which is then purified on silica (5% Meon/chloroform) and obtain 0.05 g (yield 20%) of the desired product as a solid yellow1H NMR (300 MHz, CDCl3) δ a 8.34 (d, J=5,1 Hz, 1H), EUR 7.57 (DD, J=8,7, 1.2 Hz, 2H), 7,47-7,29 (m, 4H), 7,16-7,05 (m, 3H), 6,62 (d, J=5,1 Hz, 1H), 4,11 (t, J=6.9 Hz, 2H), 4,06 (t, J=6.9 Hz, 2H), 2,70 (dddd, J=6,9, of 6.9 and 6.9, 6.9 Hz, 2H),ESI+MS m/z (relative intensity) 388,1 (100, M++N). Analysis for C22H18FN5O 0,5H2O: calculated C, 66,66; H, a 4.83; N, 17,67; found: C, 66,55; H, 4,49; N, 17,39. This connection is suitable for the t same connection 351 in table IX.

According to the method described above can be obtained the following compounds relating to the first aspect of the compounds of Category IV.

3-[2-(2,6-dipertanyakan)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he:1H NMR (300 MHz, d6-DMSO) δ 9,36 (s, NH), scored 8.38 (d, J=5,1 Hz, 1H), 7,40-7,33 (m, 3H), 7,21-7,11 (m, 4H), to 6.58 (d, J=5,1 Hz, 1H), 3,90-3,82 (m, 4H), 2,55 is 2.51 (m, 2H),ESI+MS m/z (relative intensity) 424,1 (100, M++N). Analysis for C22H16F3N5O 0,5H2O: calculated C, 61,11; H, of 3.96; N, 16,20; found C, 61,67; H, a 4.03; N, 15,73.

3-[2-(2,6-dichlorophenylamino)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he:1H NMR (300 MHz, CDCl3) δ 8,32 (d, J=5,1 Hz, 1H), 7,47 (d, J=8.1 Hz, 2H), 7,41 (DD, J=8,7, 5,4 Hz, 2H), 7,29-7,25 (m, 1H), was 7.08 (t, J=8.7 Hz, 2H), 6,93 (user. s, NH), only 6.64 (d, J=5,1 Hz, 1H), 4,06 (t, J=6.9 Hz, 2H), 3,93 (t, J=6.9 Hz, 2H), 2,61 (dddd, J=6,9, of 6.9 and 6.9, 6.9 Hz, 2H),ESI+MS m/z (relative intensity) 433,1 (100, M++N). Analysis for C22H16FCl2N5O 0,5H2O: calculated C, 56,79; H, 3,68; N, 15,05; found C, 56,50; H, 3,63; N, 14,59.

2-(4-forfinal)-3-[2-(pyridine-2-ylamino)pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he:1H NMR (300 MHz, CDCl3) δ 8,46 (d, J=5,1 Hz, 1H), scored 8.38-at 8.36 (m, 2H), by 8.22 (d, J=8.7 Hz, 1H), 7,69 (DDD, J=9,0, to 7.5, 1.8 Hz, 1H), 7,45 (DD, J=8,7, 5,4 Hz, 2H), 7,07 (DD, J=8,7, to 8.7 Hz, 2H), 7,02-6,98 (m, 1H), 6,72 (d, J=5,1 Hz, 1H), 4.09 to (t, J=6.9 Hz, 2H), 4,06 (t, J=6.9 Hz, 2H), 2,73 (dddd, J=6,9, of 6.9 and 6.9, 6.9 Hz, 2H),ESI MS m/z (relative intensity) 389,1 (70, M++N). Analysis for C21H17FN6O H2O: calculated C, 62,06; H, 4,71; N, 20,68; found C, 61,77; H, 4.26 deaths; N, 20,05.

According to the second aspect of the compounds of this Category are compounds in which the radicals R1and R4bhave the values listed in the following table X.

Table X
No.R1R4b
4354-forfinalPyridine-2-yl
4364-forfinalPyridine-3-yl
4374-forfinalPyridine-4-yl
4384-forfinalPyrimidine-2-yl
4394-forfinalPyrimidine-4-yl
4404-forfinalPyrimidine-5-yl
4414-forfinal4,6-dichloropyrimidine-5-yl
4424-forfinals-triazinyl
4433-triptorelinePyridine-2-yl
4443-triptorelinePyridine-3-yl
4453-triptorelinePyridine-4-yl
4463-tripto who were Pyrimidine-2-yl
4473-triptorelinePyrimidine-4-yl
4483-triptorelinePyrimidine-5-yl
4493-triptoreline4,6-dichloropyrimidine-5-yl
4503-triptorelines-triazinyl

Compounds that belong to the second aspect of the compounds of Category IV can be obtained according to the scheme given below, using the intermediate5as a suitable source of product.

EXAMPLE 15

3-[2-(4,6-Dichloropyrimidine-5-ylamino)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he(56)

Obtain 3-[2-(4,6-dichloropyrimidine-5-ylamino)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it(56):

To a solution of 5-amino-4,6-dichloropyrimidine (219 mg, of 1.34 mmol) in THF (4 ml) is added NaH (0.07 g, 1.00 mmol). After stirring the mixture for 5 minutes at room temperature added to the reaction mixture of 2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-he5(0.25 g, 0.67 mmol). The reaction medium is brought to the boiling temperature under reflux and stirred the mixture for 1 hour. The mixture Rabaul who have saturated aqueous NH 4Cl and extracted twice with chloroform. The organic layers are combined, dried over MgSO4and concentrated in vacuo to obtain the crude product, which was purified on silica (5% Meon/chloroform) and get the desired product in the form of a solid yellow color.1H NMR (300 MHz, CDCl3) δ 8,77 (s, 1 H), 8,35 (d, J=5,1 Hz, 1H), 7,35 (DD, J=9,0, 5,1 Hz, 1H), 7,10 (DD, J=8,7, to 8.7 Hz, 2H), of 6.71 (d, J=5,1 Hz, 1H), 4,25 (t, J=6.9 Hz, 2H), 4,12 (t, J=6.9 Hz, 2H), 2,74 (dddd, J=6,9, 6,9, 6,9 and 6.9 Hz, 2H),ESI+MS m/z (relative intensity) 458,1 (100, M++N). This connection corresponds to the same connection 441 in table X.

Compounds according to the present invention is divided into several categories in order to provide an opportunity for the specialist to apply rational strategy synthesis for the preparation of similar compounds that were not specifically illustrated by the examples in this description. The distribution of connections across categories does not imply an increase or decrease in the efficiency of any of the compositions on their basis, which are given in this specification.

It was found that the above compounds have demonstrated in many examples, the activity (IC50in the cell based on the example below, or in the examples that link in this description) at concentrations below 1 m is cromoly (μm).

Compounds according to the present invention can effectively block the production of inflammatory cytokines from cells, which thus reduces, softens, regulates, reduces, inhibits or prevents one or more medical conditions or syndromes that are associated with extracellular secretion of one or more cytokines. Inflammatory painful conditions include those that are associated with the following non-limiting examples:

(i) Interleukin-1 (IL-1): participates as the molecule responsible for a large number of painful conditions, among which are rheumatoid arthritis, osteoarthritis, as well as other painful conditions that are associated with the destruction of the connective tissue.

(ii) the Cyclooxygenase-2 (SOH-2)inhibitors allocation of cytokine proposed as inhibitors induced the expression of MOR-2, which increases under the action of cytokines. M.K.O'Banlon et al.,Proc. Natl. Acad. Sci. USA.89, 4888 (1998).

(iii) Factor-α tumor necrosis (TNF-α): This proinflammatory cytokine is considered the main mediator in many painful conditions or syndromes, among which are rheumatoid arthritis, osteoarthritis, irritable bowel syndrome (IBS), septic shock, cardiopulmonary dysfunction, acute respiratory disease and cachexia.

Each of the painful situation of the deposits, which the expert wishes to cure, may require different amounts or concentrations of compounds described in this invention, to achieve a therapeutic result. You can determine this number by any known method of testing, which mark simple lab assistant.

The present invention relates also to the forms in which are produced the compounds according to the present invention, which, depending on the physiological conditions of the human or higher mammal, is capable of releasing the described connections. One variant of this aspect of the invention includes pharmaceutically acceptable salts of these compounds. Specialist for reasons of compatibility with the method of delivery, excipients and the like, can choose one salt form of these compounds, among others, since the compounds are active ingredients that soften the development of the mentioned pathological processes.

This aspect of the invention include numerous "Proletarskoye" forms of the compounds according to the invention. In the preparation of the compositions may be appropriate to produce compounds according to the invention in the form of such chemical forms that are not active in relation to the activity of the cytokine described in this invention,but instead compounds according to the invention are in the form, which, when introduced into the body of a human or higher mammal, undergo a chemical reaction catalyzed in the normal functioning of the body, for example, enzymes in the stomach, blood serum, and the chemical reaction releases related analogue. The term "prodrug" refers to those forms, which are converted in vivo to the active drug form.

Composition

The present invention relates also to compositions or formulations which contain compounds according to the invention, inhibiting the secretion of inflammatory cytokines. In General, the compositions according to the present invention contain:

a) an effective amount of one or more bicyclic pyrazolones and their derivatives according to the invention, which is effective in inhibiting the excretion of inflammatory cytokines; and

b) one or more pharmaceutically acceptable excipients.

In accordance with the present invention the terms "excipient" and "carrier" are used interchangeably herein and refer to the ingredients that are used in the practice of creating safe and effective pharmaceutical compositions.

Specialist clear that the excipients used in the first place in order to ensure the safe, tamilnew delivery and functionality of a pharmaceutical product this assignment is not only to fulfill the role of General vehicle upon delivery, but also to ensure effective absorption recipient of the active substance. Excipient can play simple and direct role inert carrier or to act as a pH stabilizer system or covering agent to ensure the safety of the stomach upon delivery of the ingredients. The specialist may also take advantage of the fact that the compounds according to the present invention improves cellular potency, pharmacokinetic properties, and also improves the bioavailability for oral use of the drug.

The present invention relates also to compositions or formulations which contain the predecessor or Palekastro" form compounds, which are inhibitors of the allocation of inflammatory cytokine according to the present invention. In General, the composition containing the precursor according to the present invention contains:

a) an effective amount of one or more derivatives of bicyclic pyrazolones according to the invention, which cause the selectionin vivothe corresponding analogue that is effective in inhibiting the inflammatory cytokines; and

b) one or more pharmaceutically acceptable excipio the tov.

Method of use

The present invention relates also to a method of regulating the level of one or more cytokines that induce inflammation, including Interleukin-1 (IL-1), factor-α tumor necrosis (TNF-α) and Interleukin-8 (IL-8), and thus enabling control, mediation or mitigate the painful condition affecting the amount of extracellular inflammatory cytokines. The present method includes the step of introducing a human or higher mammal an effective amount of a composition containing one or more inhibitors of the inflammatory cytokine according to the invention.

As inhibitors of inflammatory cytokines according to the present invention can be delivered by a method, which can be achieved in more than one area of the control, you can affect more than one painful condition at the same time. Non-limiting examples of diseases that are amenable to regulation or inhibition by inhibitors of the inflammatory cytokine, can be called diseases such as osteoarthritis, rheumatoid arthritis, diabetes, viral human immunodeficiency (HIV)infection.

Procedures

Compounds of the present invention can be evaluated for their effectiveness, for example, by measuring the inhibition constants of cytokine K iand indicators IC50that can be carried out by the method chosen by the expert.

Non-limiting examples of suitable methods include:

i) the Method of determining the enzyme activity on the substrate, visible in the UV region, described by the authors L.Al Relter,Int.J.Peptide Protein Res.,43, 87-96 (1994).

ii) Method for the determination of enzyme activity by fluorescent substrate described Thornberry et al.,Nature,356,768-774 (1992).

iii) Cell method PBMC, as described in US 6204261 B1 Batchelor et al., on March 20, 2001

Each of these methods are included in this description by reference.

In addition, in the case of factor-α tumor necrosis (TNF-α) inhibition can be measured using lipopolysaccharide (LPS), macrophage stimulating human cells (TPR-1), as described in the document:

i) K.M.Mohler et al., "Protection Against a Lethal Dose of Endotoxin by an Inhibitor of Tumour Necrosis Factor processing",Nature,370,pp. 218-220 (1994).

ii) US 6297381 B1 Cirillo et al., from 2 October 2001, a method is included by reference and reproduced below relevant part.

Inhibition of cytokine production can be observed by measuring the inhibition of TNF-α in cells TNR stimulated by lipopolysaccharide. All cells and reagents were diluted in RPMI 1640 phenol red and L-glutamine, supplemented with additional L-glutamine (General: 4 mm), penicillin, streptomycin the Ohm (each 50 units/ml) and amniotic bovine serum (FBS 3%) (GIBCO, to final concentration). The experiment was carried out in sterile conditions, only drug tested compound was not sterile. The original stock solutions prepared in DMSO with subsequent dilution in RPMI 1640 to a concentration of 2 times higher than the desired final concentration of experience. Cell suspension TNR-1 (2x106cells/ml, final concentration; American Type Culture Company, Rockville, Md.) placed in 96-well polypropylene round flat-bottomed culture tablet (Costar 3790; sterile)containing 125 μl of tested compound (double concentrated) or DMSO as a filler (test sample blank sample). The final concentration of DMSO should not exceed 0.2%. The mixture of cells was subjected to incubation for 30 minutes at a temperature of 37°and the concentration of CO25%, and then stimulation with lipopolysaccharide (LPS, final concentration 1 μg/ml; Sigma L-2630, fromE. coliserotype V; kept in a concentration of 1 mg/ml stock solution in the sorted endotoxin, diluted with H2About as a carrier at -80°). Blank sample (estimulando) was obtained with N2About the media; final incubation volume was 250 μl. Incubation (4 hours) was performed, as described above. At the end of the experiment was carried out by centrifugation for 5 minutes at room temperature at a speed of 1600 rpm (4033 g); supernatant razmeshali clean 96-well tablets and stored at -80° Since then analyzed for factor-α tumor necrosis person (TNF-α), using the corresponding commercially available ELISA kit (biostatic #CNS, Camarillo, Ca.). The calculated values of the IC50meanthe concentration of the compounds in which there is a 50%reduction in the maximum production of TNF-α.

Although there have been illustrated and described specific embodiments of the present invention, of course that the person skilled in the art may make various other changes and modifications without leaving the scope of the invention. This meant that the attached claims cover all changes and modifications are included in the scope of the present invention.

1. The compound of the formula

and its pharmaceutically acceptable salt,

in which R1means:

a) substituted or unsubstituted phenyl, where the substituents are selected from halogen atoms or keloids1-6of alkyl;

R4bis substituted or unsubstituted 1-3 substituents of the aryl selected from phenyl, naphthyl, where the substituents are selected from halogen atoms, C1-6of alkyl, halogen With1-6of alkyl, C1-6alkoxyl, cyano, amino, C1-6acylamino, C1-6alkanesulfonyl, or two adjacent substituent in anzalna ring form DIOXOLANYL group; or unsubstituted or substituted 6-membered nitrogen-containing heteroaryl with a 1-3 nitrogen atoms in the ring, where the substituents are selected from halogen atoms.

2. The compound according to claim 1, in which R1denotes 4-forfinal, 3-forfinal, 2,4-differenl, 4-chlorophenyl, 3-chlorophenyl, 2,4-dichlorophenyl or 3-tryptophanyl.

3. The compound according to claim 2, in which R1is a 4-florfenicol.

4. The compound according to claim 1, in which R4bdenotes aryl or halogen-substituted aryl selected from the group consisting of phenyl, 2-ftoheia, 3-ftoheia, 4-ftoheia, 2,4-dipthera, 2,6-dipthera, 3,5-dipthera, 2,4,6-tryptophanyl, 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, naphtalen-1-yl and naphtalen-2-yl.

5. The compound according to claim 1, in which R4bdenotes a substituted aryl selected from the group consisting of 2-AMINOPHENYL, 3-AMINOPHENYL, 4-AMINOPHENYL, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimetilfenil, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-cyanophenyl, 3-cyanophenyl and 4-cyanophenyl.

6. The compound according to claim 1, in which R4bdenotes a substituted aryl selected from the group consisting of 4-(methanesulfonyl)phenyl, 4-(econsultancy)phenyl, 4-(propanesulfonyl)phenyl, 2-(N-acylamino)phenyl, 3-(N-acylamino)phenyl, 4-(N-acylamino)phenyl and 3-benzo[1,3]dioxol-5-yl.

7. With the unity according to claim 1, in which R4bdenotes aryl selected from the group consisting of 2-triptoreline, 3-triptoreline, 4-trifloromethyl and 3,5-bis(trifluoromethyl)phenyl.

8. The compound according to claim 1, in which R4bdenotes heteroaryl or substituted heteroaryl selected from the group consisting of pyridine-2-yl, pyridin-3-yl, pyridine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, 4,6-dichloropyrimidine-5-yl, and s-triazinyl.

9. The compound of the formula

in which R4bis unsubstituted or substituted by 1-3 substituents of the aryl selected from phenyl, naphthyl, where the substituents are selected from halogen atoms, C1-6of alkyl, haloids1-6of alkyl, C1-6alkoxyl, cyano, amino, C1-6acylamino, C1-6alkanesulfonyl, or two adjacent substituent in the benzene ring form DIOXOLANYL group; or

unsubstituted or substituted 6-membered nitrogen-containing heteroaryl with a 1-3 nitrogen atoms in the ring, where the substituents are selected from halogen atoms,

and their pharmaceutically acceptable salts.

10. The connection according to claim 9, wherein said aryl or substituted aryl denotes phenyl or naphthyl.

11. The connection of claim 10, wherein said aryl or substituted aryl selected from the group consisting of phenyl, 2-ftoheia, 3-ftoheia, 4-ftoheia, 2,6-ditto is phenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 2,4-dimetilfenil, 3-triptoreline, 4-trifloromethyl,4-methylphenyl,4-methoxyphenyl and 3-benzo[1,3]dioxol-5-yl.

12. The connection of claim 10, in which heteroaryl or substituted heteroaryl denotes pyridyl,pyrimidinyl or triazinyl.

13. The connection 12, wherein said heteroaryl or substituted heteroaryl selected from the group consisting of pyridine-2-yl, pyridin-3-yl, pyridine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl and 4,6-dichloropyrimidine-5-yl.

14. The connection according to claim 9, in which R4bdenotes phenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2,6-differenl, 2,6-dichlorophenyl, 3-cyanophenyl, 2,4-dimetilfenil, 3-triptoreline, 4-triptoreline, 4-were, 4-methoxyphenyl, 3-(N-acylamino)phenyl, 4,6-dichloropyrimidine-5-yl and 3-benzo[1,3]-dioxol-5-yl.

15. The compound and its pharmaceutically acceptable salt selected from the group consisting of

2-(4-forfinal)-3-(2-phenylaminopyrimidine-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a] pyrazole-1-it,

3-[2-(2,6-dipertanyakan)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it,

3-[2-(2,6-dichlorophenylamino)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it,

2-(4-forfinal)-3-[2-(pyridine-2-ylamino)-pyrimidine-4-yl]-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it, and

3-[2-(4,6-dichloropyrimidine-5-Ilam is but)-pyrimidine-4-yl]-2-(4-forfinal)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-it.

16. Pharmaceutical composition having properties of tumor necrosis factor (TNF-α), containing

a) an effective amount of one or more bicyclic pyrazolones or their pharmaceutically acceptable salts, with the specified connection has the formula

in which R1means:

a) substituted or unsubstituted phenyl, where the substituents are selected from halogen atoms or halogen With1-6of alkyl;

R4bis substituted or unsubstituted 1-3 substituents of the aryl selected from phenyl, naphthyl, where the substituents are selected from halogen atoms, C1-6of alkyl, haloids1-6of alkyl, C1-6alkoxyl, cyano, amino, C1-6acylamino, C1-6alkanesulfonyl, or two adjacent substituent in the benzene ring form DIOXOLANYL group; or unsubstituted or substituted 6-membered nitrogen-containing heteroaryl with a 1-3 nitrogen atoms in the ring, where the substituents are selected from halogen atoms,

b) one or more pharmaceutically acceptable excipients.



 

Same patents:

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel pyrimidotriazines of the general formula (I):

wherein each R1 and R2 is chosen from the group comprising hydrogen atom, or R1 and R2 form in common chemical bond, -CH2-Ar and Ar is chosen from the group comprising unsubstituted phenyl, unsubstituted naphthyl, phenyl, mono- or disubstituted with (lower)-alkoxy-group and naphthyl mono- or disubstituted with (lower)-alkyl, or their pharmaceutically acceptable salts. Also, invention relates to a method for synthesis of these compounds, pharmaceutical composition based on thereof and to using novel pyrimidotriazines for prophylaxis and/or treatment of diabetes mellitus as these compounds possess the strong expressed inhibitory effect on activity of protein tyrosine phosphatase PTP1B.

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

15 cl, 27 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: chemical industry; method of production of the fluorine-containing compounds.

SUBSTANCE: the invention is pertaining to the chemical industry, in particular, to the improved method of production of fluorine-containing compounds from the halogen-containing, compounds, preferably, from chlorine-containing compounds due to an exchange of halogen for fluorine at presence of the HF-additional compound of the mono- or bicyclic amine with at least two atoms of nitrogen. At that at least one atom of nitrogen is built in the cyclic system as the fluorating agent; or at presence of anhydrous hydrogen fluoride - as the fluorating agent and the indicated HF-additional compound of the mono- or bicyclic amine as the catalyst. At usage of the applicable solvents the reaction mixtures can be divided into two phases and thus to simplify the reprocessing of the products. The invention also is pertaining to the HF-additional compounds of 1.5-diazabicyclo[4.3.0]non-5-en and N,N-dialkylaminopiridin, where alkyl represents C1-C4alkyl and where the molar ratio of HF to amine makes 1:1, and to HF- additional compounds 1.8- diazabicyclo[5.4.0]undecyl-7-ene, where the molar ratio of HF to amine compounds more than 1:1.

EFFECT: the invention ensures at usage of the applicable solvents to divide the reaction mixture into two phases and thus to simplify reprocessing of the products.

17 cl, 13 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel derivative of 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]benzimidazole, namely its hydrobromide, eliciting properties of antagonist of serotonin 5-HT3-receptors that can be used in therapy of cytotoxic nausea and vomiting. New salt is low toxic and exceeds bemesetron by anti-serotonin activity that is a selective 5-HT3- antagonist.

EFFECT: improved and valuable medicinal properties of derivative.

2 cl, 2 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anellated carbamoylazaheterocycles of the general formula (1) that possess inhibitory property of kinase activity and eliciting, for example, an anticancer activity. Also, compounds can be used as agonists, antagonists, receptor modulating agents, antiparasitic and antibacterial agents. Also, invention relates to a method for synthesis of compounds of the formula (1), a pharmaceutical composition based on thereof and a focused library for assay of leader-compounds. In compounds of the general formula (1) W represents 6-oxopiperazine, [1,4]-thiazepane, [1,4]-oxazepane or [1,4]-diazepane cycle anellated with at least one optionally substituted and optionally condensed heterocycle or carbocycle Q; Q represents optionally substituted thiophene, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrrolidine, optionally substituted indole, optionally substituted benzofuran, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene or optionally substituted naphthalene cycle; R1, R2 and R represent independently of each another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

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

15 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention relates to new compounds of the formula (I) wherein R1 and R2 can be similar or different and represent independently (C1-C6)-alkyl that are selective inhibitors of enzyme phosphodiesterase, and to their pharmaceutically acceptable salts or stereoisomers. Also, invention involves a method for preparing the preferable compound, i. e. 5-[[2-ethoxy-5-(cis-2,6-dimethylpiperazin-4-ylsulfonyl)phenyl]]-1-methyl-3-n-propyl-7,6-dihydro-1H-pyrazolo[4,3-d]pyrimidine-7-one. Also, invention proposes new intermediate compounds used in method for synthesis of this compound. Compounds of the formula (I) show very high effectiveness in treatment of diseases associated with impotence, such as the male erectile sterility but they exhibit such features as prolonged therapeutic effectiveness and lower toxicity. Also, invention relates to a pharmaceutical composition used in treatment of impotence and using compound of the formula (I) in preparing the medicinal preparation designated for treatment of diseases associated with impotence.

EFFECT: valuable medicinal properties of compound.

8 cl, 7 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a compound and to all its enantiomeric and diastereomeric forms and pharmaceutically acceptable salts that are able to prevent extracellular release of inflammatory cytokines. Proposed compounds have the formula (I): wherein R represents: (a) -OR3 or (b) -NR4aR4b; R3 represents unsubstituted or substituted phenyl wherein substitutes are: (i) halogen atom; (ii) (C1-C6)-alkyl; (iii) trifluoromethyl; (iv) trichloromethyl; (v) tribromomethyl; (vi) cyano-group, and (vii) (C1-C6)-alkoxy-group; each R4a and Rb represents independently: (a) hydrogen atom or (b) -[C(R5aR5b)]xR6 wherein index x = 0-5; each R5a and R5b represents independently hydrogen atom, linear or branched (C1-C4)-alkyl, (C3-C7)-cyclic alkyl; R6 represents -OR7 or (C1-C4)-alkyl; R7 represents hydrogen atom or (C1-C4)-alkyl; R1 represents halogen-substituted phenyl; each among links R2a and R2b is chosen independently from the groups consisting of: (a) hydrogen atom; (b) -O(CH2)jR8; (c) -(CH2)jCO2R10; (d) -(CH2)jCON(R10)2; (e) a double bond when R2a and one R2b are chosen with formation of a double bond; (f) a ring when one R2a and one R2b are chosen with formation a ring and indicated ring is chosen from the group consisting of: (i) benzene and (ii) dioxalane; each R8 and R10 represents independently hydrogen atom or (C1-C4)-alkyl; j represents index from 0 to 5; m represents index from 1 to 3; n represents index from 1 to 3, and m + n = 4. Also, invention relates to a pharmaceutical composition based on abovementioned compounds that inhibits extracellular release of inflammatory cytokines, and a method for regulation of extracellular release of inflammatory cytokines.

EFFECT: valuable medicinal properties of compounds.

10 cl, 9 tbl, 11 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to bicyclic heterocyclic substituted phenyloxazolidinones that represent compounds of the formula (I): wherein R is taken from the group consisting of -OH, O-heteroaryl, -N3, -OSO2R'', -NR'''R'''', or the formula: wherein: (ii) R'' represents direct or branched alkyl comprising up to 5 carbon atoms; (iii) R''' and R'''' are taken independently from the group consisting of hydrogen atom (H), -CO2-R1, -CO-R1, -CS-R1 and -SO2-R4 wherein R1 is taken among the group consisting of cycloalkyl comprising from 3 to 6 carbon atoms and direct or branched alkyl comprising up to 6 carbon atoms; R4 is taken from direct or branched alkyl comprising up to 4 carbon atoms; and R4a represents -CN or -NO2; R4b represents -SR4c, amino-group, -NHR4c or -NR4cR4d wherein R4c and R4d are taken independently from hydrogen atom (H) or alkyl; X represents from 0 to 4 members taken independently from the group consisting of halogen atom; and Y represents radical of the formula (II): or (III): wherein R5, R6, R7 and R8 represent independently hydrogen atom (H), or R and R6 and/or R7 and R8 form in common oxo-group; R9 and R10 represent independently hydrogen atom (H); A, B, C and D are taken from carbon atom (C) and nitrogen atom (N) to form phenyl ring or 5-6-membered heteroaromatic ring wherein the indicated heteroaromatic ring comprises from 1 to 4 members taken from the group consisting of nitrogen atom (N); Z is taken from alkyl, heteroaryl comprising nitrogen atom (N); and m represents 0 or 1. These compounds are useful as antibacterial agents and can be used for treatment of patient with the state caused the bacterial infection or with the bacterial infection caused by S. aureus and E. faecium.

EFFECT: valuable medicinal properties of compounds.

45 cl, 1 tbl, 50 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (1): and its salts wherein X means unsubstituted monocyclic (5-6-membered) ring system comprising nitrogen atom (N); or X means condensed bicyclic (9-12-membered) ring system comprising N-atom that can be substituted with substitute -SO2-phenyl; Z represents hydrogen atom (H) or means a condensed bicyclic (9-12-membered) unsubstituted or substituted ring system comprising at least one heteroatom, N-atom; Ar represents unsubstituted phenyl ring; each among L1, L2 and L3 represents independently a bond, -CO, -SO2 or -CH2 wherein at least one among L2 and L3 must involve -CO or -SO2; L2 and L3 can represent can represent independently -CONH or -CONHCH2 also; n = 0, 1 or 2; each R1 and R2 represents independently hydrogen atom (H) or a direct (C1-C6)-alkyl chain; Y comprises at least one substituted or unsubstituted phenyl ring or 5-6-membered heteroaromatic ring comprising at least one N-atom as a heteroatom; wherein optional substituted are chosen among the group consisting of halogen atom, alkyl, -COOH, -OH or -NH2; or Y represents 6,7-dihydropyrrolo[3,4-b]pyridine-5-one; wherein ring nitrogen atom can be oxidized optionally. Also, invention relates to a pharmaceutical composition used in treatment states regulated by chemokine CXCR4 or CCR5 receptors based on these compounds. Invention provides preparing new compounds and medicinal agents based on thereof for aims in treatment of HIV- and FIV-infected patients.

EFFECT: valuable medicinal properties of compounds and composition.

15 cl, 57 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 5-amino-1-pentene-3-ol of the general formula (I)

as a free form or as their physiologically compatible salts possessing the analgesic effect. In general formula (I) each R1 and R2 means independently of one another (C1-C6)-alkyl that can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or multi-substituted; or R1 and R2 form in common -(CH2)2-9-mono- or bicyclic ring; each R3 and R4 means independently of one another (C1-C6)-alkyl, or R3 and R4 form in common a ring and mean the group -CH2CH2NR22CH2CH2 wherein R22 represents (C1-C10)-alkyl; R5 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched, mono- or multi-substituted or unsubstituted, (C3-C9)-cycloalkyl that is saturated or means phenyl, heteroaryl that can be condensed with benzene ring and chosen from 5-membered heteroaryl with sulfur or oxygen atom as a heteroatom bound through saturated (C1-C3)-alkyl, phenyl bound through saturated (C1-C3)-alkyl-(C3-C10)-cycloalkyl wherein each among all these alkyl, phenyl, heteroaryl and cycloalkyl residues and independently of others can be unsubstituted or mono- or multi-substituted residues chosen independently of one another from the group comprising atoms F, Cl, Br, J, groups -OR18, (C1-C3)-alkyl) that is saturated or branched or unbranched, mono- or multi-substituted halide, or unsubstituted and wherein R18 represents hydrogen atom (H), (C1-C10)-alkyl that is saturated, branched or unbranched; R6 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched and unsubstituted, phenyl or heteroaryl that is chosen from 5-membered heteroaryl with oxygen atom as a heteroatom wherein each of them is unsubstituted or mono- or multi-substituted as indicated above; R7 means H. Also, invention relates to a medicinal agent based on proposed compounds and to a method for their synthesis.

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

10 cl, 493 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R1 represents alkyl; R2 represents halogen atom, formyl, substituted or unsubstituted alkyl, hydroxyl, (C1-C6)-alkoxy-group, halogenalkyl; or R and R2 in common with atom to which they are bound form unsubstituted 5-7-membered structure of the formula: -CH2-(CH2)nS- wherein n = 1 or 2; R3 represents hydrogen atom, halogen atom or alkyl; R4 represents alkoxy-group or unsubstituted aryl or aryl substituted with halogen atom, (C1-C6)-alkyl, halogenated (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl; R5 represents hydrogen atom, hydroxyl, alkyl, alkenyl or alkoxy-group; R6 represents hydrogen atom or alkyl; or R5 and R6 represent in common =O; X represents oxygen atom or -NR8 wherein R8 represents aryl substituted with halogen atom; m means a whole number in the range from 0 to 2, and its pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on these compounds, method for treatment of diseases mediated by cyclooxygenase and to a method for inhibition of cyclooxygenase activity in cells. Invention provides preparing novel compounds possessing valuable biological effect.

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

11 cl, 98 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel triazole derivative of the general formula (I): wherein R1 represents phenyl group optionally substituted with one or two groups chosen from (C1-C6)-alkyl group, (C1-C6)-halogenalkyl group, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkoxy-group, halogen atom, nitro-group or cyano-group, styrenyl group, (C1-C6)-alkoxystyrenyl-group or pyridyl group; R2 represents methyl or amino-group; A and B are carbon atoms; C and D represent independently carbon or nitrogen atom, and its nontoxic salt and pharmaceutical composition based on thereof. Also, invention relates to methods for synthesis of novel compounds, novel intermediate substances of the formula: wherein R2, A, B, C and D have above given values; n means a whole number from 0 to 2, and to a method for their synthesis. Compounds of the formula (I) possess anti-inflammatory activity and can be used potentially in treatment of fever, pain and inflammation.

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

9 cl, 2 tbl, 50 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 1-aminobutane-3-ol of the general formula (I): and their physiologically acceptable salts possessing analgesic effect and capacity for binding habapentin-site. In the general formula (I) R1 and R2 form in common (CH2)2-9-ring; each R3 and R4 independently of one another means (C1-C6)-alkyl that is branched or direct, saturated or unsubstituted, benzyl or phenethyl that are unsubstituted; R5 means (C1-C10)-alkyl that can be saturated, unsaturated, branched or direct or unsubstituted, (C3-C9)-cycloalkyl that is saturated, phenyl or 5-membered sulfur-containing heteroaryl possibly condensed with benzene ring, (C3-C6)-cycloalkyl bound through saturated or unsaturated (C1-C3)-alkyl, 5-membered possibly condensed with benzene ring sulfur-containing heteroaryl bound through saturated or unsaturated (C1-C3)-alkyl wherein each aryl, heteroaryl and cycloalkyl residue independently of one another can be unsubstituted or mono- or multi-substituted with residues chosen independently of one another from the group comprising atoms F, Cl, Br, J, -OR18, (C1-C10)-alkyl that is saturated or unsaturated, branched or direct and can be mono- or multi-substituted with halogen atoms wherein R18 represents hydrogen atom (H), (C1-C10)-alkyl that is saturated, branched or direct or unsubstituted; R6 means H; R7 means (C1-C6)-alkyl that is branched or direct, saturated or unsaturated or unsubstituted, (C3-C9)-cycloalkyl that is saturated or unsubstituted, phenyl that is unsubstituted or mono- or multi-substituted or phenyl bound through saturated (C1-C3)-alkyl that can be unsubstituted or mono- or multi-substituted wherein these substitutes can be chosen independently from the group comprising atoms F, Cl, Br, J, -OR18, (C1-C10)-alkyl that is saturated or unsaturated, branched or direct, in free form as their physiologically acceptable salts. Proposed compounds can be used in treatment of pain and first of all neuropathic, chronic and acute pain. Also, invention relates to a method for synthesis of compounds and preparing a medicinal agent.

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

9 cl, 89 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: the present innovation deals with developing preparations based upon essential oils to treat inflammatory diseases of respiratory organs and motor system. The composition suggested contains chitosan and essential oils of different plants upon emulsion foundation. The method suggested could be applied as an additional remedy for external application at treating inflammatory diseases of respiratory organs, degenerative and inflammatory diseases of motor system. The composition is of high spectrum of action and prolonged analgesic effect.

EFFECT: higher efficiency of application.

11 ex

FIELD: veterinary science.

SUBSTANCE: the present innovation refers to medicinal preparations applied for treating puerperal purulent-catarrhal endometritis and mastitis in cows and to the method of applying the present medicinal preparations. The suggested preparation for treating puerperal purulent-catarrhal endometritis, serous, seroso-catarrhal and subclinical mastitis in cows includes 1.4-di-N-oxide 2.3-bis-(oxymethyl) quinoxaline, trecresan (cresacin), dimethyl sulfoxide, propandiol 1.2 at the following ratio, (g/%): 1.4-di-N-oxide 2.3-bis-(oxymethyl) quinoxaline 1.0-1.2; trecresan (cresacin) 3.0-3.18; dimethyl sulfoxide 10.0-10.5; propandiol 1.2 20-25; distilled water - the rest. The innovation deals with intra-uterine introduction of the preparation suggested at the dosage of about 70-100 ml once daily for about 4-5 d. Moreover, this preparation should be introduced into affected part of the udder at the dosage of 10 ml once daily for 3-5 d. The innovation enables to shorten the multiplicity of introduction and accelerate the terms of recovery.

EFFECT: higher efficiency of therapy.

4 cl, 2 ex, 6 tbl

FIELD: organic chemistry, amino acids.

SUBSTANCE: invention proposes the novel derivatives of phenylalanine of the formula (I) and (II) possessing with antagonistic activity with respect to α4-integrin. Derivatives of phenylalanine are used as therapeutic agents in different diseases associated with α4-integrin.

EFFECT: valuable medicinal properties of compounds.

37 cl, 30 tbl, 215 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to novel O-substituted derivatives of 6-methyltramadol of the general formula (I) being optionally as their racemates, their pure stereoisomers but primarily as enantiomers or diastereomers, or as mixtures of stereomers being primarily as enantiomers or disatereomers in any their ratio in the mixture as a presented formulation or as their physiologically compatible salts. In the general formula (I) the value R means hydrogen atom (H), (C1-C3)-alkyl that can be saturated or unsaturated, branched or a direct, unsubstituted or substituted with -O-(C1-C3)-alkyl-group or OH-group, -CH2-(C4-C6)-cycloalkyl, (C4-C6)-cycloalkyl or thienyl group. Also, the invention relates to a method for synthesis of compounds of the general formula (I) by interaction of 2-dimethylaminomethyl-6-methylcyclohexanone of the formula (I) with metal-organic compound of the formula (III) wherein Z means Li; R has values given in the formula (I). The synthesized compounds of the formula (I) if necessary are converted to their physiologically compatible salts and/or racemates that are subjected for cleaving. Also, invention relates to a pharmaceutical composition.

EFFECT: improve method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 2 sch, 2 tbl, 30 ex

FIELD: chemical-pharmaceutical industry, medicine, peptides.

SUBSTANCE: invention relates to preparing and using peptides of the formula (I) possessing analgesic activity: A-B-Tyr-Pro(D-Pro, dHPro, D-dHPro, DL-dHPro, Hyp)-C-X wherein A means -O, -Ala, -Asp, -Glu, -Phe, -Gly, -His, -He, -Lys, -Leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; B means 0, -Ala, -Asp, -Glu, -Phe, -Gly, -His, -He, -Lys, -leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; C means 0, -Ala, -Asp, -Glu, -Phe, -Gly, -His, -He, -Lys, -Leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; X means -OH, -OCH3, -NH2. Proposed peptides can be used for design of new medicinal preparations. Peptides possess the enhanced activity as compared with pentalgin, analgin and morphine and have no toxic properties.

EFFECT: improved and valuable medicinal properties of peptides.

5 tbl, 4 ex

FIELD: pharmaceutical industry, in particular analgesic, vasodilatation, anti-inflammation ointment for topical application.

SUBSTANCE: claimed ointment is prepared in form of fine dispersed formulation containing bee venom extract melittin, lavender oil, camphor, arnica tincture, rosemary oil, eucalyptus oil, revitalin, carbopol, 30 % solution of sodium hydroxide, hydrophilic anionic ointment, soy lecithin, glycerol, conserving solution, ethanol, distilled water.

EFFECT: reduced toxicity of bee venom, decreased side effects and improved therapeutic effect.

2 tbl, 3 ex

FIELD: organic chemistry, medicine, allergology.

SUBSTANCE: invention relates to a method for treatment of allergy by administration to patient the therapeutically effective dose of a pharmaceutical composition comprising compound of the formula (I) . Invention provides the enhanced effectiveness of treatment.

EFFECT: improved treatment method.

7 cl, 3 dwg, 49 ex

Up!