Compounds that inhibit releasing inflammatory cytokines

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

 

The scope of the invention

The invention relates to compounds which inhibit the extracellular release of inflammatory cytokines, and these cytokines are responsible for one or several pathological States in humans or higher mammals. The present invention further relates to compositions comprising these compounds, and the way to prevent, mitigate or control another through the action of enzymes that are supposed to be the active components responsible for the described in this description of the pathological condition.

Background of invention

Interleukin-1 (IL-1) and factor-α tumor necrosis (TNF-α) among the important biological substances known together as "cytokines". It is assumed that these molecules mediate the inflammatory response associated with immunological detection of infectious agents.

It is assumed that these proinflammatory cytokines are important mediators in many pathological conditions or syndromes, inter alia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease (IBS), septic shock, cardiopulmonary dysfunction, acute respiratory disease, cachexia and, therefore, are responsible for the development and royalene pathological conditions of the person.

There is therefore a long felt need in the compounds and pharmaceutical compositions that include the compounds, which may block, reduce, regulate, suppress, or prevent the release of cytokines from the cells that produce them.

Summary of the invention

The present invention satisfies the above needs, as it has been unexpectedly discovered that the [5,6]- and [5,6,6]-condensed pyrazolones and their derivatives are effective for inhibiting release of inflammatory cytokines, among others, interleukin-1 (IL-1) and tumor necrosis factor (TNF) from cells and thereby warn, weaken or otherwise regulate the action of enzymes that are supposed to be the active components responsible for the here described pathological conditions.

The first aspect of the present invention relates to compounds, including all of their enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts, and the compounds have the formula:

where R represents:

a) hydrogen;

b) -O(CH2)kR3or

C) -NR4aR4b;

R3represents a substituted or unsubstituted With1-C4alkyl, substituted or unsubstituted cyclizes the th hydrocarbon, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the index k is from 0 to 5;

R4aandR4brepresent, each independently:

a) hydrogen or

b) -[C(R5aR5b)]xR6;

each R5aandR5brepresents independently hydrogen, -OR7, -N(R7)2, -CO2R7, -CON(R7)2; an unbranched, branched or cyclic With1-C4alkyl and mixtures thereof; R6represents hydrogen, -OR7, -N(R7)2, -CO2R7, -CON(R7)2substituted or unsubstituted With1-C4alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7represents hydrogen, a water-soluble cation, With1-C4alkyl or substituted or unsubstituted aryl; the index x is equal to from 0 to 5;

R1represents:

a) substituted or unsubstituted aryl or

b) substituted or unsubstituted, heteroaryl;

links R2aand R2bselected, each independently, from the group consisting of:

a) hydrogen;

b) -O(CH2)jR8;

c) -(CH2)jN9aR9b;

d) -(CH2)jCO2R10;

(e) -(CH2)jOCO2R10;

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

g) carbonyl, when two links R2aor two-level R2bat the same carbon atom can be taken together with the formation of carbonyl management;

h) double bonds when one of R2aand one of R2btaken together with the formation of a double bond;

i) the ring when one of R2aand one of R2btaken together with the formation of substituted or unsubstituted ring comprising 4 to 8 atoms, with the specified ring selected from the group consisting of:

i) carbocyclic;

(ii) heterocyclic;

iii) aryl;

(iv) heteroaryl;

v) bicyclic and

vi) heterobicyclic rings

j) and mixtures thereof;

R8, R9a, R9band R10represent, each independently, hydrogen, C1-C4alkyl and mixtures thereof; R9aand R9bcan be taken together with the formation of a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two-level R10can be taken together with the formation of a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; m represents an index from 1 to 5; n represents an index from 1 to 5, m + n is from 2 to 6.

Another aspect of the present invention relates to pharmaceutical compositions that can deliver the compounds of the present invention in the body human the ESA or higher mammal, moreover, the compositions include:

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

b) one or more pharmaceutically acceptable excipients.

Another aspect of the present invention relates to methods of combating mediated by one or more inflammatory cytokines or modulated by inflammatory cytokines diseases or conditions mammals, and this method includes a step of introducing a human or higher mammal an effective amount of a composition comprising one or more compounds of the present invention.

These and other objectives, features and advantages will become apparent to the person skilled in the art after reading the following detailed description and the accompanying claims. All percentages, ratios and proportions are mass, unless otherwise noted. All temperatures are given in degrees Celsius (° (C)unless otherwise stated. All cited documents are in the appropriate part and incorporated herein by reference; the citation of any document should not be construed as an assumption that he is a well-known level regarding the present invention.

Detailed description of the invention

The present invention relates to link the m which is able to mediate, regulate or inhibit any other way extracellular release of some cytokines, especially of inflammatory cytokines, and these cytokines play a role in stimulation, the induction or expression of a large number of diseases, pathological conditions or syndromes.

For the purposes of the present invention, the term "hydrocarbon" is defined here as any organic link or a radical which consists of carbon atoms and hydrogen. In the term hydrocarbon included heterocycles, which are described below. Examples of various unsubstituted nheterocyclic hydrocarbonrich links include pentyl, 3-atelectasis, 1,3-dimetilfenil, cyclohexyl, CIS-3-hexyl, 7,7-dimethylbicyclo[2.2.1]heptane-1-yl and naphthas-2-yl.

In the definition of "hydrocarbon" includes aromatic (aryl) and non-aromatic carbocyclic ring, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexane, cyclohexanol, cycloheptanol, bicyclo[0.1.1]butanal, bicyclo[0.1.2]pentanyl, bicyclo[0.1.3]hexanal (trianel), 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, acenaphthyl the Nile, 1,2,3,4-tetrahydronaphthalene and the like.

The term "heterocycle" includes both aromatic (heteroaryl)and non-aromatic heterocyclic ring, non-limiting examples of which include: pyrrolyl 2N-pyrrolyl, 3H-pyrrolyl, pyrazolyl 2N-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-Piran-2-IMT, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinil, SIMM-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 the like, each of which may be substituted or unsubstituted.

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

while an example of a link defined by the term "acceleratorkey", is a 2-picoline link having the formula:

The term "substituted" used throughout the description. The term "substituted" is defined here as "covering radicals or links, the cat is who can replace a hydrogen atom, two atoms of hydrogen or three hydrogen atoms hidrocarburos radical. The term "substituted" may also include the replacement of hydrogen atoms at two adjacent carbon atoms with the formation of new radicals or link". For example, the substituted element, which requires the replacement of a single hydrogen atom, include halogen, hydroxyl and the like. Replacement of two hydrogen atoms include carbonyl, oximino and the like. Replacement of two hydrogen atoms from adjacent carbon atoms includes epoxy and the like. Replacement of three hydrogen atoms include cyano and the like. Epoxy bond is an example of the substituted element, which requires replacement of a hydrogen atom from the neighboring carbon atoms. The term "substituted"as used throughout the present description, indicates that hydrocarbonyl radical, among other things, an aromatic ring, the alkyl chain may have one or more hydrogen atoms replaced by a substituent. When the radical is described as "substituted"may be replaced by any number of hydrogen atoms. For example, 4-hydroxyphenyl represents a substituted aromatic carbocyclic ring, (N,N-dimethyl-5-amino)octanol represents a substituted C8alkyl link, 3-guanidinopropionic represents a substituted C3alkyl link, and 2-carboxyphenyl is a"substituted heteroaryl link". The following links represent non-limiting examples of units which can serve as a replacement of hydrogen atoms, when hidrocarburos link is described as "substituted".

i) -[C(R12)2]p(CH=CH)qR12where R is from 0 to 12; q is 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 mixtures 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 mixtures thereof,

where R12represents hydrogen, substituted or unsubstituted unbranched, branched or cyclic With1-C20alkyl, C6-C20aryl, C7-C20alkylaryl and mixtures thereof; M is a hydrogen or salt-forming cation; Z is a =O, =S, =NR12and mixtures thereof. Suitable soleobrazutaya cations include three is, lithium, potassium, calcium, magnesium, ammonium and the like.

The first aspect of the present invention, in General relates to new compounds suitable for inhibiting release of inflammatory cytokines, and these compounds have the formula:

R represents the substituent in position 2 of the pyrimidine-4-ilen part of a common basic structure, this link R represents:

(a) a simple ether having the formula- [CH2]kR3or

b) a primary or secondary aminothieno having the formula-NR4aR4b;

where R3represents a substituted or unsubstituted With1-C4alkyl, substituted or unsubstituted cyclic hydrocarbon, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, the index k is from 0 to 5.

Below are the different variants of the links R of the present invention, where R is a simple ether having the formula- [CH2]kR3. However, the person skilled in the art is not limited to the illustrative cases and examples of this specification.

A) the Links of R include ethers of the formula OR3(the index k is equal to 0), where R3represents a substituted or unsubstituted aryl.

i) One variant of this aspect of R including the AET ethers, having the formula-OR3where R3represents a substituted or unsubstituted aryl. This option includes the following non-limiting examples of R: phenoxy, 2-fervency, 3 fervency, 4-fervency, 2,4-divergence, 3 triptoreline, 4-triptoreline, 2,4-deformations and the like.

ii) Another variant of this aspect of R include ethers having the formula-OR3where R3represents a 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 the like.

iii) the Following variant of this aspect of R include ethers having the formula-OR3where R3represents a 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]phenoxy, 3-benzo[1,3]dioxol-5-yl, and the like.

B) the Links of R, including ethers having the formula-OR3(the index k is equal to 0), where R3represents a substituted or unsubstituted heteroaryl.

i) the First variant of this aspect of R include ethers having the formula-OR3where R3represents the unsubstituted heteroa the sludge. This option includes the following non-limiting examples: pyrimidine-2-yl, pyrimidine-4-yl, pyridine-2-yl, pyridin-3-yl, pyridine-4-yl and the like.

ii) a Second variant of this aspect of R include ethers having the formula-OR3where R3represents a substituted heteroaryl. This option includes the following non-limiting examples: 2-aminopyrimidine-4-yl and the like.

(C) the Links of R, including ethers having the formula-OCH2R3(the index k is equal to 1), where R3represents a substituted or unsubstituted aryl.

i) the First variant of this aspect of R include ethers having the formula-OCH2R3where R3represents a 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 the like.

ii) a Second variant of this aspect of R involves a simple ether having the formula-OCH2R3where R3represents a substituted or unsubstituted acceleratorkey. This option includes the following non-limiting examples: pyridine-3-retil, (2-methyl-2-pyridin-3-yl)ethyl and the like.

D) Links of R, including ethers having the formula-OR3(the index k is equal to 1), where R3the stand is made by a substituted or unsubstituted With 1-C4alkyl.

i) the First variant of this aspect of R is a simple ether having the formula-OR3where R3represents an unsubstituted unbranched, branched or cyclic With1-C4alkyl. This option includes the following non-limiting examples: methyl, ethyl, isopropyl, (S)-1-methylpropyl and the like.

ii) a Second variant of this aspect of R is a simple ether having the formula-OR3where R3represents a substituted unbranched, branched or cyclic With1-C4alkyl. This option includes the following non-limiting examples: 2-methoxyethyl, (S)-1-methyl-3-methoxypropyl and the like.

Below are the different aspects of the links R of the present invention, where R is an amine having the formula-NR4aR4b, R4aand R4brepresent, each independently:

a) hydrogen or

b) -[C(R5aR5b)]xR6;

each of R5aand R5brepresents, independently, hydrogen, -OR7, -N(R7)2, -CO2R7; -CON(R7)2; an unbranched, branched or cyclic With1-C4alkyl and mixtures thereof; R6represents hydrogen, -OR7, -N(R7)2, -CO2R7, -CON(R7)2; substituted or unsubstituted what th 1-C4alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7represents hydrogen, a water-soluble cation, With1-C4alkyl or substituted or unsubstituted aryl; the index x is equal to from 0 to 5. However, the person skilled in the art is not limited to the illustrative cases and examples of this specification.

A) the Links of R include chiral amino groups, where R4arepresents hydrogen, R5arepresents hydrogen and R5brepresents methyl, and these units have the formula:

and the indicated stereochemistry.

i) the First variant of this aspect of R is an amine, including R6that represents a substituted or unsubstituted phenyl. This option includes the following non-limiting examples: (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 the like.

ii) a Second embodiment of this aspect of R is an amine, including R6that represents a substituted or unsubstituted heteroaryl. This option includes the following non-limiting examples: (S)-1-methyl-1-(pyridine-2-yl)methylamino, (S)-1-methyl-1-(pyridin-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 the like.

iii) the Third variant of this aspect of R is an amine, including R6that represents a substituted or unsubstituted With1-C4alkyl. This option includes the following non-limiting examples: (S)-1-methylpropylamine, (S)-1-methyl-2-(methoxy)ethylamino.

B) the Links of R include chiral amino groups, where R4arepresents hydrogen, R5aand R5brepresent, each, With1-C4alkyl, and these units have the formula:

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

i) the First variant of this aspect of R is an amine that does not have a chiral center and non-limiting examples of which include 1,1-dimethylethylene, 1,1-dimethylbenzylamine and the like.

ii) a Second embodiment of this aspect of R is an amine, including R6that represents a substituted or unsubstituted With1-C4alkyl. This option includes the following non-limiting examples: (S)-1-methyl-2-hydroxy-2-methylpropylamine, (S)-1-methyl-2-hydroxy-2-methylbutylamine and the like.

(C) the Links of R, including alkylenediamine, where R4ais Soboh is hydrogen, both R5aand R5bthe radical R4brepresent hydrogen, R6represents a substituted or unsubstituted aryl, with the specified link has the formula:

where R11represents hydrogen or substituted link"as specified above.

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

i) the Second variant of this aspect includes the following non-limiting examples of links R: (2-were)methylamino; (3-were)methylamino, (4-were)methylamino and the like.

D) Links of R, including amines, where R4arepresents hydrogen, R4bincludes R5bequal to hydrogen, and R5bequal-CO2R7or-CON(R7)2with the specified link has the formula:

i) the First variant of this aspect of R is an amine, including R6that represents a substituted or unsubstituted phenyl. This option includes the following non-limiting examples:

where R11represents hydrogen or a substitute, as described above.

ii) the Second variant is this aspect of R is an amine, includes R6that represents a substituted or unsubstituted alkyl. This option includes the following non-limiting examples:

Links R1chosen from:

a) substituted or unsubstituted aryl or

b) substituted or unsubstituted heteroaryl.

The first aspect of the links R1covers halogen-substituted phenyl units, non-limiting examples of which include 4-forfinal, 2,4-differenl, 4-chlorophenyl, and the like. Links R2aand R2bselected, each independently, from the group consisting of:

a) hydrogen;

b) -O(CH2)jR8;

c) -(CH2)jN9aR9b;

d) -(CH2)jCO2R10;

(e) -(CH2)jOCO2R10;

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

g) carbonyl level, when two R2aor two R2bat the same carbon atom can be taken together with the formation of carbonyl management;

h) double bonds when one of R2aand one of R2btaken together with the formation of a double bond;

i) the ring when one of R2aand one of R2btaken together with the formation of substituted or unsubstituted ring comprising 4 to 8 atoms, with the specified ring selected from the group consisting of:

i) carbocyclic;

(ii) heterocyclic;

(iv) heteroaryl;

v) bicyclic and

vi) heterobicyclic ring;

l), and their mixtures;

R8, R9a, R9band R10represent, each independently, hydrogen, C1-C4alkyl and mixtures thereof; R9aand R9bcan be taken together with the formation of a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two-level R10can be taken together with the formation of a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5.

System [5,6]-condensed rings

The first aspect of the present invention relates to cyclic underlying structures, in which the indices m and n are each equal to 2, thereby including the hulls of 2-(R1-substituted)-3-(2-R-substituted-pyrimidine-4-yl)-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it, having the formula:

where the links R2aand R2brepresent, each independently, hydrogen, -(CH2)jCO2R10, -(CH2)jCON(R10)2and mixtures thereof.

Variations of this basic structure include cyclic backbone having the formula:

being in position 8 esters and amides 5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it, having the formula:

as well as being in position 5 esters and amides 5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it, having the formula:

The second aspect of the present invention, when it refers to the links of R2aand R2bincludes frames of 2-(R1-substituted)-3-(2-R-substituted-pyrimidine-4-yl)-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it, having the formula:

where each of the links R2aand R2bindependently selected from the group consisting of:

a) hydrogen;

b) -O(CH2)jR8and

(C) -(CH2)jNR9aR9b.

Variants of this aspect include 6-hydroxy-2-(R1-substituted)-3-(2-R-substituted-pyrimidine-4-yl)-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-ones, 7-hydroxy-2-(R1-substituted)-3-(2-R-substituted-pyrimidine-4-yl)-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-ones, 6-(dimethylamino)-2-(R1-substituted)-3-(2-R-substituted-pyrimidine-4-yl)-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-ones, 6-morpholino-2-(R1-substituted)-3-(2-R-substituted-pyrimidine-4-yl)-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-ons.

The third aspect of the present invention, when it refers to the links of R2aand R2bincludes the basic structure, in which two adjacent link R2aand R2btaken together with the formation of a double bond, such as the hulls of 2-(R1 -substituted)-3-(2-R-substituted-pyrimidine-4-yl)-5,8-dihydropyrazolo[1,2-a]pyridazin-1-it, having the formula:

System [5,6,X]-condensed rings

The present invention relates also to [5,6,X]-condensed ring systems, where X represents a ring formed when one of R2aand one of R2btaken together with the formation of substituted or unsubstituted ring comprising 4 to 8 atoms. Educated rings selected from the group consisting of:

i) carbocyclic;

(ii) heterocyclic;

iii) aryl;

(iv) heteroaryl;

v) bicyclic and

vi) heterobicyclic rings.

The first version of the implementation of this aspect refers to ring systems in which one of R2aand one of R2btaken together with the formation of 6-membered aryl ring, among other things, the system [5,6,6]-condensed rings; 2-(R1-substituted)-3-(2-R-substituted-pyrimidine-4-yl)-5,10-dihydropyrazolo[1,2-b]phthalazine-1-ONU having the formula:

Variants of this aspect include analogues, which are substituted in the C-ring, such as compounds having the formula:

where R12is a Deputy, as described above. Non-limiting examples [5,6,6]-cyclical basic structures is altoadige of the invention are cyclic skeletons 2-(R 1-substituted)-3-(2-R-substituted-pyrimidine-4-yl)-5,10-dihydropyrazolo[1,2-b]phthalazine-1-it is, for example, a compound having the formula:

The first aspect analogues category 1, is able to inhibit the release of inflammatory cytokines present invention relates to compounds, including the skeleton of 5,10-dihydropyrazolo[1,2-b]phthalazine-1-it, having the formula:

where the units of R are amines having the formula-NH[CHR5]R6and R1, R4a, R5and R6have the values listed below in table I. the Stereochemistry of R5bis the configuration shown, when R5bis not hydrogen.

methyl
TABLE I
No.R1R4aR5bR6
14-forfinalNNphenyl
24-forfinalNN4-forfinal
34-forfinalNN2-AMINOPHENYL
44-forfinalNN2-were
5NN4-were
64-forfinalNN4-methoxyphenyl
74-forfinalNN4-(propanesulfonyl)phenyl
84-forfinalNN3-benzo[1,3]dioxol-5-yl
94-forfinalNNpyridine-2-yl
104-forfinalNNpyridine-3-yl
114-forfinalNNN
124-forfinalNNmethyl
134-forfinalNNethyl
144-forfinalNNvinyl
154-forfinalNNcyclopropyl
164-forfinalNNcyclohexyl
174-forfinalNNmethoxymethyl
184-forfinalNNmethoxyethyl
194-forfinalNN1-hydroxy-1-methylethyl
204-forfinalNN-CO2N
214-forfinalNmethylphenyl
224-forfinalNmethyl4-forfinal
234-forfinalNmethyl2-AMINOPHENYL
244-forfinalNmethyl2-were
254-forfinalNmethyl4-were
264-forfinalNmethyl4-methoxyphenyl
274-forfinalNmethyl4-(propanesulfonyl)phenyl
284-forfinalNmethyl3-benzo[1,3]dioxol-5-yl
294-forfinalNmethylpyridine-2-yl
30 4-forfinalNmethylpyridine-3-yl
314-forfinalNmethylN
324-forfinalNmethylmethyl
334-forfinalNmethylethyl
344-forfinalNmethylvinyl
354-forfinalNmethylcyclopropyl
364-forfinalNmethylcyclohexyl
374-forfinalNmethylmethoxymethyl
384-forfinalNmethylmethoxyethyl
394-forfinalNmethyl1-hydroxy-1-methylethyl
404-forfinalNmethyl-CO2N
413-triptorelineNmethylphenyl
423-triptorelineN4-forfinal
433-triptorelineNmethyl2-AMINOPHENYL
443-triptorelineNmethyl2-were
453-triptorelineNmethyl4-were
463-triptorelineNmethyl4-methoxyphenyl
473-triptorelineNmethyl4-(propanesulfonyl)phenyl
483-triptorelineNmethyl3-benzo[1,3]dioxol-5-yl
493-triptorelineNmethylpyridine-2-yl
503-triptorelineNmethylpyridine-3-yl
513-triptorelineNmethylN
523-triptorelineNmethylmethyl
533-triptorelineNmethylethyl
543-triptorelineNmethylvinyl
553-triptorelineNmethylcyclopropyl
563-triptorelineNmethylcyclohexyl
573-triptorelineNmethylmethoxymethyl
583-triptorelineNmethylmethoxyethyl
593-triptorelineNmethyl1-hydroxy-1-methylethyl
603-triptorelineNmethyl-CO2N

Below is the scheme of obtaining compounds relating to the first aspect of category I of the present invention. The first stage involves the use of intermediate compounds of type I, for example, intermediate compounds 3 for introducing the selected link R1in connecting the basic structure.

The General scheme to obtain the intermediate compounds of type I

Reagents and conditions: (a) LDA, THF, -78°C, 45 minutes

Reagents and conditions: (b) CrO3CH2Cl2, room temperature, 16 h.

EXAMPLE 1

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

Below is the method of obtaining 2-methylsulfonylamino-4-carbaldehyde,1adapted from the methodology H.Bredereck et al.,Chem. Ber.,97pp 3407-3417 (1964), are included in this description by reference.

3-necked flask with a volume of 12 l in an inert atmosphere to download dimethylacetal-N,N-dimethylformamide (801 g), dimethylacetal pyruvic aldehyde (779 g). The mixture is heated at the boil under reflux for 18 hours, during which time the temperature is reduced from approximately 109°C 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°C and add thiourea (892 g, 11.7 mol). After stirring the mixture for about 15 minutes add sodium methoxide (741 g, 13.7 mol) of 4 equal portions over 1 hour, maintaining the temperature of the solution in the range of 18-28°C. the Mixture is stirred for 5 hours at room temperature, cooled to 20°C, then for 1.25 hours add methyliodide (2 kg), maintaining the reaction temperature in the range 17-29°C. Stirring is continued at t the value of 18 hours at room temperature. The methanol and unreacted methyliodide removed by heating the solution at 35°C and 40 mm RT. Art., receiving approximately 4,46 kg dark residue, which was partitioned between 14 l of water and 5 l of ethyl acetate. The aqueous fraction is extracted a second time with ethyl acetate, the organic layers combined and concentrated in vacuo to obtain 685 g of oil, which is purified on silica, getting 522 g of 4-dimethoxymethyl-2-methylsulfonylamino.

Obtained above, dimethylacetal then hydrolyzing in the free aldehyde by heating to 60°C for 3 hours in 1M HCl. Neutralization and extraction of the product using ethyl acetate gives 347 g of the crude product, which was purified on silica, getting 401 g 2-methylsulfonylamino-4-carbaldehyde,1.

Obtain methyl ester of 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-3-hydroxypropionic acid (2):To a cold (-78° (C) the solution diisopropylamide lithium (21,4 ml of 2M solution in THF, 42.8 mmol) in THF (70 ml) was 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 is added dropwise a solution of 2-methylsulfonylamino-4-carbaldehyde,1(6.0 g, or 39.3 mmol) in THF (30 ml). Stirring is continued for 45 minutes at -78°C, then the reaction mixture is quenched, you is Eva reaction solution in water saturated NH 4Cl. 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)to give 8.7 g (76%) of the desired product as a mixture (1:1) of diastereomers.

Obtain methyl ester of 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-3-oxopropanoic acid (3):To a suspension CrO3in CH2Cl2(300 ml) is added pyridine. The mixture is vigorously stirred for 1 hour at room temperature. To hromsoderzhashchej suspension is added dropwise a solution of the crude methyl ester of 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-3-hydroxypropionic acid,2obtained above, in CH2Cl2(50 ml). 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)to give 3.7 g (yield 43%) of the desired product as a yellow solid.

The following example relates to the formation of 6,7-dihydro-5H-pyrazolo[1,2-a]pyrazole-1-nowych ring systems using pyrazolidine, however, the person skilled in the art can replace it with other cyclic hydrazine powered reagents to obtain other cyclizes the x systems of the present invention, among other things, specifies the use of hexahydropyridine to get 5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-ones. In the example below, the intermediate connection3obtained by the method described above is used for introduction as R14-tarpenring level, however, the substitution for such a link can be performed while obtaining the intermediate complex β-keeeper.

The following diagram illustrates the production of intermediate compounds of type II, for example, intermediate compounds5that includes rings and With the basic structure.

The General scheme of obtaining intermediate compounds of type II

Reagents and conditions: (a) NaH, DMF, 90°C, 3 hours.

Reagents and conditions: (b) SOCl2, Meon, room temperature, 72 hours.

EXAMPLE 2

1,2,3,4-Tetrahydropyrazin (5)

Obtaining di-tert-butyl ether, 1,4-dihydrophenazine-2,3-dicarboxylic acid (4):To a solution of di-tert-butylhypochlorite (3.0 g, 13,0 mmol) in DMF (20 ml) at room temperature add NaH (0.5 g, 13,0 mmol). After stirring 1 hour at room temperature to the reaction mixture are added 1,2-vibrometer (3.4 g, 13,0 mmol). After stirring 1 hour at room temperature to the reaction mixture add drugaware NaH (0.5 g, 13,0 mmol). The mixture was then heated to 90°C for 3 hours, allow it to cool to room temperature and stirring is continued at room temperature for 15 hours. The reaction mixture is then extinguish, pouring the reaction solution into water saturated NH4Cl. The aqueous phase is extracted with ether, the organic phase is dried (MgSO4), filtered and concentrated in vacuo. The crude residue purified on silica (5% EtOAc/hexane)to give 1.0 g (yield 23%) of the desired product as a clear oil.

Getting 1,2,3,4-tetrahydropyrazino (5):Di-tert-butyl ether, 1,4-dihydrophenazine-2,3-dicarboxylic acid,4, (1.0 g, 3 mmol) dissolved in Meon (20 ml) and added dropwise SOCl2(0.5 ml). After stirring at room temperature for 72 hours, the solvent is removed in vacuum, obtaining 0.6 g of the desired product as a white solid.

The following diagram illustrates the Assembly of the skeleton of the 3-pyrimidine-4-yl-5,10-dihydropyrazolo[1,2-b]phthalazine-1-she convergent stage, in which condense the intermediate3and5. The resulting intermediate compound is then converted into the target compound with the selected link R.

Reagents and conditions: (C) pyridine, boiling under reflux for 16 hours.

Reagents and conditions: (d) OXONE®, THF/Meon, room temperature, 2 hours.

Reagents and conditions: (e) toluene, 140°C, 12 h.

EXAMPLE 3

2-(4-Forfinal)-3-[2-(S)-(1-phenylethylamine)pyrimidine-4-yl]-5,10-dihydropyrazolo[1,2-b]phthalazine-1-he (8)

Obtaining 1-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-5,10-dihydropyrazolo[1,2-b]phthalazine-1-she (6):To a solution of 1,2,3,4-tetrahydropyrazino,5(0.3 g, 1.4 mmol)in pyridine (5 ml) is added methyl ether 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-3-oxopropanoic acid,3(0.4 g, 1.4 mmol). The reaction mixture is then heated to boiling under reflux for 16 hours. The solvent is removed in vacuo and the resulting residue purified preparative HPLC, receiving 0.2 g (yield 45%) of the desired product as a tan solid.

Obtaining 2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-5,10-dihydropyrazolo[1,2-b]phthalazine-1-it (7):To a solution of 1-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-5,10-dihydropyrazolo[1,2-b]phthalazine-1-it,6(2.4 g, 6.8 mmol) in a mixture of THF:Meon (80 ml of a mixture 1:1) added dropwise a solution of OXONE®(16,8 g of 27.2 mmol) in N2O (80 ml). After stirring for 2 hours at room temperature, the reaction mixture was diluted with aqueous saturated NaHCO3and extra the shape three times with ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated in vacuo, obtaining 1.5 g (yield 58%) of the desired product as a yellow solid.

Obtaining 2-(4-forfinal)-3-[2-(S)-(1-phenylethylamine)pyrimidine-4-yl]-5,10-dihydropyrazolo[1,2-b]phthalazine-1-it (8):2-(4-Forfinal)-3-(2-methanesulfonamido-4-yl)-5,10-dihydropyrazolo[1,2-b]phthalazine-1-it,7(0.9 g, 2.3 mmol) dissolved in toluene (18 ml) together with (S)-(-)-α-methylbenzylamine (10,5 ml of 81.6 mmol). The resulting mixture is heated to 140°C for 12 hours, cooled to room temperature and the solvent is removed in vacuum. The resulting residue is purified on silica (EtOAc/hexane, 1:1)to give 0.8 g (yield 80%) of the desired product as a red sticky solid.

The first aspect analogues category II of the present invention, is able to inhibit the release of inflammatory cytokines, refers to compounds comprising frame 5,8-dihydropyrazolo[1,2-a]pyridazin-1-it, where R2aand R2btaken together form a double bond, and the specified frame has the formula:

where R1, R5band R6described in table II. The stereochemistry of R5bis the configuration shown, when R5bor R6is not hydrogen.

td align="right" namest="c0" nameend="c3"> TABLE II
No.R1R5bR6
614-forfinalNphenyl
624-forfinalN4-forfinal
634-forfinalN2-AMINOPHENYL
644-forfinalN2-were
654-forfinalN4-were
664-forfinalN4-methoxyphenyl
674-forfinalN4-(propanesulfonyl)phenyl
684-forfinalN3-benzo[1,3]dioxol-5-yl
694-forfinalNpyridine-2-yl
704-forfinalNpyridine-3-yl
714-forfinalNN
724-forfinalNmethyl
734-forfinalNethyl
744-forfinalNwines is l
754-forfinalNcyclopropyl
764-forfinalNcyclohexyl
774-forfinalNmethoxymethyl
784-forfinalNmethoxyethyl
794-forfinalN1-hydroxy-1-methylethyl
804-forfinalN-CO2N
814-forfinalmethylphenyl
824-forfinalmethyl4-forfinal
834-forfinalmethyl2-AMINOPHENYL
844-forfinalmethyl2-were
854-forfinalmethyl4-were
864-forfinalmethyl4-methoxyphenyl
874-forfinalmethyl4-(propanesulfonyl)phenyl
884-forfinalmethyl3-benzo[1,3]dioxol-5-yl
89 4-forfinalmethylpyridine-2-yl
904-forfinalmethylpyridine-3-yl
914-forfinalmethylN
924-forfinalmethylmethyl
934-forfinalmethylethyl
944-forfinalmethylvinyl
954-forfinalmethylcyclopropyl
964-forfinalmethylcyclohexyl
974-forfinalmethylmethoxymethyl
984-forfinalmethylmethoxyethyl
994-forfinalmethyl1-hydroxy-1-methylethyl
1004-forfinalmethyl-CO2N

Compounds that include analogues of the first aspect of category II can be obtained by the synthesis shown below in the following diagram.

Reagents and conditions: (a) NaH, DMF; 0°C to 90°C, 4 hours.

img src="https://img.russianpatents.com/830/8308590-s.jpg" height="22" width="59" >

Reagents and conditions: (b) SOCl2, MeOH; 0°C, 17 h.

Reagents and conditions: (C) pyridine, 90°C, 16 h.

Reagents and conditions: (d) OXONE®, THF/Meon/water, room temperature, 2 hours.

Reagents and conditions: (e) (S)-(-)-α-methylbenzylamine, toluene; 140°C for 12 h.

EXAMPLE 4

2-(4-Forfinal)-3-[2-(1-phenylethylamine)pyrimidine-4-yl]-5,8-dihydropyrazolo[1,2-a]pyridazin-1-he (13)

Obtaining di-tert-butyl ether, 3,6-dihydropyridin-1,2-dicarboxylic acid (9):To a solution of di-tert-butylhypochlorite (18.6 g, 80,0 mmol) in DMF (220 ml), cooled to 0°C, portions add NaH (8.0 g of 60% suspension in mineral oil, 200.0 mmol). After the solution is allowed to warm up and stirring 45 minutes at room temperature, the reaction mixture is added dropwise CIS-1,4-dichloro-2-butene (8,4 ml, 80,0 mmol). The mixture was then heated at 90°C for 4 hours, cooled to room temperature and stirred for additional 15 hours. The reaction mixture is quenched, pouring the contents of the reaction vessel into the icy water. The resulting aqueous phase is extracted with ether, the combined organic phases are washed with aqueous saturated NaHCO3, dried, filtered and concentrated in vacuo. Received neo is ewenny product is dissolved in hexane and the resulting solid substance produce by filtration, getting 24 grams of the desired product as a white powder.

Getting 1,2,3,4-tetrahydropyridine (10):To a solution of di-tert-butyl ether, 3,6-dihydropyridin-1,2-dicarboxylic acid,9(10.0 g, of 35.2 mmol) in Meon (140 ml) at 0°C is added dropwise SOCl2(22,0 ml). After gradual warming to room temperature and stirring for 17 hours, the solvent is removed in vacuum, getting a tan solid. The selected solid is then dissolved in the Meon (10 ml) and diluted with ether (250 ml). The resulting white solid is filtered, obtaining 4.3 g (yield 79%) of the desired product as a salt of di-HCl.

Obtaining 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-2,3,5,8-tetrahydropyrazolo[1,2-a]pyridazin-1-she (11):To a solution of 1,2,3,4-tetrahydropyridine,5(5,4 g of 34.2 mmol) in pyridine (100 ml) is added methyl ether 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-3-oxopropanoic acid,3, (7,3 g of 22.8 mmol). The reaction mixture is heated to 90°C for 16 hours. The solvent is then removed in vacuo and the resulting residue purified on silica (100% EtOAc)to give 3.5 g (yield 43%) of the desired product as a yellow solid.

Obtaining 2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-2,3,5,8-tetrahydropyrazolo[1,2-a]pyridazin-1-she (12):To a solution of 2-(4-Fortini is)-3-(2-methylsulfonylamino-4-yl)-2,3,5,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it, 11(2.4 g, 6.8 mmol)in a mixture of THF/Meon (80 ml of a mixture 1:1) is added dropwise a solution of OXONE®(16,8 g of 27.2 mmol) in N2O (80 ml). After stirring for 2 hours at room temperature, the reaction mixture was diluted with aqueous saturated NaHCO3and extracted with EtOAc (3x). The combined organic phases are dried, filtered and concentrated in vacuo, obtaining 1.5 g (yield 58%) of the desired product as a yellow solid.

Obtaining 2-(4-forfinal)-3-[2-(1-(S)-phenylethylamine)pyrimidine-4-yl]-5,8-dihydropyrazolo[1,2-a]pyridazin-1-it (13):2-(4-Forfinal)-3-(2-methanesulfonamido-4-yl)-2,3,5,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it,12, (0.9 g, 2.3 mmol) dissolved in toluene (18 ml) and to the solution was added (S)-(-)-α-methylbenzylamine (10,5 ml of 81.6 mmol). The resulting mixture is heated to 140°C for 12 hours, cooled and the solvent is removed in vacuum. The resulting crude product is purified on silica (EtOAc/hexane, 1:1)to give 0.8 g (yield 80%) of the desired product as a red sticky solid.

The second aspect analogues category II of the present invention, is able to inhibit the release of inflammatory cytokines, refers to compounds comprising frame 5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it and having the formula:

where R, R1, R2aand Rb described in table III.

-Och3
TABLE III
No.R1R2aR2bR
1014-forfinalN-HE1-(S)-phenylethylamine
1024-forfinalN-HE1-(S)-(4-forfinal)ethylamino
1034-forfinalN-HE1-(S)-(2-AMINOPHENYL)ethylamino
1044-forfinalN-HE1-(S)-(2-were)ethylamino
1054-forfinalN-HE1-(S)-(4-were)ethylamino
1064-forfinalN-HE1-(S)-(4-methoxyphenyl)ethylamino
1074-forfinalN-HE1-(S)-(4-propanesulfonyl)ethylamino
1084-forfinalN-HE1-(S)-(3-benzo[1,3]dioxol-5-yl)ethylamino
1094-forfinalN-HE1-(S)-(pyridin-2-yl)ethylamino
1104-forfinalN-HE1-(S)-(pyridin-3-yl)ethylamino
1114-forfinalN-HEmethylamino
1124-forfinalN-HEethylamino
1134-forfinalN-HEpropylamino
1144-forfinalN-HEcyclopropylamino
1154-forfinalN-HEcyclopropanemethylamine
1164-forfinalN-HEtert-butylamino
1174-forfinalN-HE1-(S)-(cyclopropyl)ethylamino
1184-forfinalN-HE1-(S)-(cyclopropylmethyl)ethylamino
1194-forfinalN-HE1-(R)-(α)-(carboxy)benzylamino
1204-forfinalN-HE1-(S)-(α)-(methyl)benzylamino
1214-forfinal-HE -HE1-(S)-phenylethylamine
1224-forfinal-HE-HE1-(S)-(4-forfinal)ethylamino
1234-forfinal-HE-HE1-(S)-(2-AMINOPHENYL)ethylamino
1244-forfinal-HE-HE1-(S)-(2-were)ethylamino
1254-forfinal-HE-HE1-(S)-(4-were)ethylamino
1264-forfinal-HE-HE1-(S)-(4-methoxyphenyl)ethylamino
1274-forfinal-HE-HE1-(S)-(4-propanesulfonyl)ethylamino
1284-forfinal-HE-HE1-(S)-(3-benzo[1,3]dioxol-5-yl)ethylamino
1294-forfinal-HE-HE1-(S)-(pyridin-2-yl)ethylamino
1304-forfinal-HE-HE1-(S)-(pyridin-3-yl)ethylamino
1314-forfinal-HE-HEmethylamino
1324-forfinal -HE-HEethylamino
1334-forfinal-HE-HEpropylamino
1344-forfinal-HE-HEcyclopropylamino
1354-forfinal-HE-HEcyclopropanemethylamine
1364-forfinal-HE-HEtert-butylamino
1374-forfinal-HE-HE1-(S)-(cyclopropyl)ethylamino
1384-forfinal-HE-HE1-(S)-(cyclopropylmethyl)ethylamino
1394-forfinal-HE-HE1-(R)-(α)-(carboxy)benzylamino
1404-forfinal-HE-HE1-(S)-(α)-(methyl)benzylamino
1414-forfinal-Och3-Och31-(S)-phenylethylamine
1424-forfinal-Och3-Och31-(S)-(4-forfinal)ethylamino
1434-forfinal-Och31-(S)-(2-AMINOPHENYL)ethylamino
1444-forfinal-Och3-Och31-(S)-(2-were)ethylamino
1454-forfinal-Och3-Och31-(S)-(4-were)ethylamino
1464-forfinal-Och3-Och31-(S)-(4-methoxyphenyl)ethylamino
1474-forfinal-Och3-Och31-(S)-(4-propanesulfonyl)ethylamino
1484-forfinal-Och3-Och31-(S)-(3-benzo[1,3]dioxol-5-yl)ethylamino
1494-forfinal-Och3-Och31-(S)-(pyridin-2-yl)ethylamino
1504-forfinal-Och3-Och31-(S)-(pyridin-3-yl)ethylamino
1514-forfinal-Och3-Och3methylamino
1524-forfinal-Och3-Och3ethyl is Ino
1534-forfinal-Och3-Och3propylamino
1544-forfinal-Och3-Och3cyclopropylamino
1554-forfinal-Och3-Och3cyclopropanemethylamine
1564-forfinal-Och3-Och3tert-butylamino
1574-forfinal-Och3-Och31-(S)-(cyclopropyl)ethylamino
1584-forfinal-Och3-Och31-(S)-(cyclopropylmethyl)ethylamino
1594-forfinal-Och3-Och31-(R)-(α)-(carboxy)benzylamino
1604-forfinal-Och3-Och31-(S)-(α)-(methyl)benzylamino

For the second aspect of category II intermediate connections, such as connection13can be used for obtaining analogs listed in table IV, for example the connection14.

Reagents and conditions: (a) OsO4, K3Fe(CN)6; tert-BuOH:H2O, room temperature, 12 h.

EXAMPLE 5

2-(4-Forfinal)-6,7-dihydroxy-3-[2-(1-phenylethylamine)pyrimidine-4-yl]-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-he (14)

Obtaining 2-(4-forfinal)-6,7-dihydroxy-3-[2-(1-phenylethylamine)pyrimidine-4-yl]-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-she (14):To a solution of 2-(4-forfinal)-3-[2-(1-phenylethylamine)pyrimidine-4-yl]-5,8-dihydropyrazolo[1,2-a]pyridazin-1-it,13(0.8 g, 1.88 mmol)in a mixture of tert-BuOH:H2O (24 ml of a mixture 1:1) add K3Fe(CN)6(1.9 grams, 5,64 mmol), K2CO3(0.8 g, 5.6 mmol) and NaHCO3(0.5 g, 5.6 mmol) followed by the addition of osmium tetroxide (0.1 g, 0.3 mmol). The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched by addition of an aqueous saturated solution of KHSO4(10 ml). The aqueous phase is extracted with EtOAc (3x) and the combined organic phases are dried, filtered and concentrated in vacuo. The resulting crude product is purified on silica (100% EtOAc)to give 0.4 g (yield 48%) of the desired product.

In addition, such a connection as14may be itself used as intermediate compounds for other analogues, such as connection15.

Reagents and conditions: (a) NaH, CH3I, toluene, room temperature, 62 hours.

EXAMPLE 6

2-(4-Forfinal)-6,7-dimethoxy-3-[2-(1-(S)-phenylethylamine)pyrimidine-4-yl]-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-he (15)

Obtaining 2-(4-forfinal)-6,7-dimethoxy-3-[2-(1-(S)-phenylethylamine)pyrimidine-4-yl]-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it (15):To a solution of 2-(4-forfinal)-6,7-dihydroxy-3-[2-(1-phenylethylamine)pyrimidine-4-yl]-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it,14(0,42 g of 0.91 mmol)in THF (2 ml) is added NaH (0.09 g, 2,30 mmol). After stirring at room temperature for 1 hour the reaction mixture is added dropwise methyliodide (0.14 g, 2,30 mmol). After stirring for 62 hours at room temperature the mixture was concentrated in vacuo, dissolved in EtOAc and washed with aqueous saturated NaHCO3. The organic phase is dried, filtered, concentrated in vacuo and the resulting residue purified on silica (100% EtOAc)to give 0.07 g (yield 16%) of the desired product as a yellow solid.

The first aspect analogues category III of the present invention, is able to inhibit the release of inflammatory cytokines, refers to compounds comprising frame 5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it and having the formula:

where R is a simple ester, R, R1and R10OPI is Ana below in table IV and analogues have indicated stereochemistry.

TABLE IV
No.R10R1R
61N4-forfinalphenoxy
62N4-forfinal2 fervency
63N4-forfinal3 fervency
64N4-forfinal4 fervency
65N4-forfinal2,6-divergence
66N4-forfinal2 cianfrocca
67N4-forfinal3 cianfrocca
68N4-forfinal2 triptoreline
69N4-forfinal4 triptoreline
70N4-forfinal2 methylphenoxy
71N4-forfinal4 methylphenoxy
72N4-forfinal2,4-dimethylphenoxy
73N4-FPO is phenyl 3-N-acetylaminophenol
74N4-forfinal2 methoxyphenoxy
75N4-forfinal4 methoxyphenoxy
76N4-forfinal3-benzo[1,3]dioxol-5-yl
77methyl4-forfinalphenoxy
78methyl4-forfinal2 fervency
79methyl4-forfinal3 fervency
80methyl4-forfinal4 fervency
81methyl4-forfinal2,6-divergence
82methyl4-forfinal2 cianfrocca
83methyl4-forfinal3 cianfrocca
84methyl4-forfinal2 triptoreline
85methyl4-forfinal4 triptoreline
86methyl4-forfinal2 methylphenoxy
87methyl 4-forfinal4 methylphenoxy
88methyl4-forfinal2,4-dimethylphenoxy
89methyl4-forfinal3-N-acetylaminophenol
90methyl4-forfinal2 methoxyphenoxy
91methyl4-forfinal4 methoxyphenoxy
92methyl4-forfinal3-benzo[1,3]dioxol-5-yl
93N4-chlorophenylphenoxy
94N4-chlorophenyl2 fervency
95N4-chlorophenyl3 fervency
96N4-chlorophenyl4 fervency
97N4-chlorophenyl2,6-divergence
98N4-chlorophenyl2 cianfrocca
99N4-chlorophenyl3 cianfrocca
100N4-chlorophenyl2 triptoreline
101N4-chlorine is phenyl 4 triptoreline
102N4-chlorophenyl2 methylphenoxy
103N4-chlorophenyl4 methylphenoxy
104N4-chlorophenyl2,4-dimethylphenoxy
105N4-chlorophenyl3-N-acetylaminophenol
106N4-chlorophenyl2 methoxyphenoxy
107N4-chlorophenyl4 methoxyphenoxy
108N4-chlorophenyl3-benzo[1,3]dioxol-5-yl
109methyl4-chlorophenylphenoxy
110methyl4-chlorophenyl2 fervency
111methyl4-chlorophenyl3 fervency
112methyl4-chlorophenyl4 fervency
113methyl4-chlorophenyl2,6-divergence
114methyl4-chlorophenyl2 cianfrocca
115methyl4 is arvanil 3 cianfrocca
116methyl4-chlorophenyl2 triptoreline
117methyl4-chlorophenyl4 triptoreline
118methyl4-chlorophenyl2 methylphenoxy
119methyl4-chlorophenyl4 methylphenoxy
120methyl4-chlorophenyl2,4-dimethylphenoxy
121methyl4-chlorophenyl3-N-acetylaminophenol
122methyl4-chlorophenyl2 methoxyphenoxy
123methyl4-chlorophenyl4 methoxyphenoxy
124methyl4-chlorophenyl3-benzo[1,3]dioxol-5-yl

Compounds that include analogues of the first aspect of category III can be obtained by the synthesis shown below in the following diagram.

Reagents and conditions: (a)2About2Cl2CH2Cl2; room temperature, 18 h.

Reagents and conditions: (b) CH2Cl2, room temperature, 3 hours.

Reagents and conditions: (C) TEM, CH2Cl2; room temperature, 18 h.

Reagents and conditions: (d) NaOH, Meon, room temperature, 20 minutes

Reagents and conditions: (e) TMS-CHN2CH2Cl2/Meon; 20 min, room temperature

Reagents and conditions: (f) OXONE®, THF/Meon, room temperature, 4 hours.

Reagents and conditions: (g) phenol, NaH, THF, room temperature, 1 hour.

EXAMPLE 7

Methyl ester of 2-(4-forfinal)-3-oxo-1-(3-phenoxyphenyl-4-yl)-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (22)

Getting 2-methylsulfonylamino-4-carbonylchloride (16):To a solution of 2-methylsulfonylamino-4-carboxylic acid (20 g, of 117.7 mmol) in CH2Cl2(100 ml) add oxalicacid (17,2 g, 197 mmol) and DMF (20 drops). The reaction solution was stirred at room temperature for 18 hours, after which the solvent is removed in vacuum, obtaining of 21.2 g (yield 95%) of the desired product as a dark green solid.

Obtaining methyl ester 1-(methylsulfonylamino-4-carbonyl)hexahydropyridine-3-carboxylic acid (17):To a solution of methyl ester hexahydropyridine-3-carbon is Oh acid (1.5 g, 8.3 mmol) in CH2Cl2(80 ml) is added 2-methylsulfonylamino-4-carbonylchloride, 16 (1,41 g, 7.5 mmol), and triethylamine (1.2 ml, 8.3 mmol). The mixture is stirred at room temperature for 3 hours. The reaction solution is then diluted with 1 n HCl (100 ml) and the organic phase is decanted. The aqueous phase is extracted with additional solvent and the organic layers combined, dried and concentrated in vacuo. The crude product was then purified on silica (ethyl acetate/hexane, 1:1)to give 0.9 g (yield 36%) of the desired product as a yellow solid.

Obtain methyl ester of 2-(4-perbenzoic)-1-(2-methylsulfonylamino-4-carbonyl)hexahydropyridine-3-carboxylic acid (18):To a solution of methyl ester 1-(methylsulfonylamino-4-carbonyl)hexahydropyridine-3-carboxylic acid,17(0.9 g, 3 mmol)in CH2Cl2(80 ml) is added 4-perforazione (0.63 ml, 4.6 mmol) and triethylamine 0,55 ml, 3.6 mmol). The reaction solution was stirred at room temperature for 18 hours, then diluted 1 N. HCl (50 ml) and the organic layer decanted. The organic phase is extracted with additional solvent, the organic layers combined, dried and concentrated in vacuo, obtaining the crude product. The crude substance is purified on silica (ethyl acetate/hexane, 1:1)getting to 1.15 g (yield 89% of the desired product as a yellow solid.

Obtaining 2-(4-forfinal)-1-(3-methylsulfonylamino-4-yl)-3-oxo-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (19):To a solution of methyl ester of 2-(4-perbenzoic)-1-(2-methylsulfonylamino-4-carbonyl)hexahydropyridine-3-carboxylic acid,18(1.13 g, 2,62 mmol), in methanol (40 ml) is added NaOH (1.26 g, of 31.4 mmol). The reaction mixture was stirred at room temperature for 20 minutes, then diluted 1 N. HCl (50 ml). The solution is extracted with ethyl acetate (3 x 250 ml), organic layers combined, dried and concentrated in vacuo, obtaining of 0.83 g (yield 79%) of oil which is used without further purification.

Obtain methyl ester of 2-(4-forfinal)-1-(3-methylsulfonylamino-4-yl)-3-oxo-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (20):To a solution of 2-(4-forfinal)-1-(3-methylsulfinylphenyl)-3-oxo-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid,19(0,83 g, 2.1 mmol)in methylene chloride (50 ml) is added trimethylsilyldiazomethane (1.5 ml, 2M solution in hexane, 3 mmol). The reaction mixture is stirred for 20 minutes at room temperature, then concentrated in vacuo to obtain the crude product in the form of oil, which is purified on silica (hexane/ethyl acetate, 1:4)to give 0.51 g (yield 59%) of the desired product as a yellow foam.

Getting metropoleopera 2-(4-forfinal)-1-(3-methanesulfonamido-4-yl)-3-oxo-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (21): Mix a solution of methyl ester of 2-(4-forfinal)-1-(3-methylsulfinylphenyl)-3-oxo-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid,20(0.51 g, of 1.23 mmol)in methanol (30 ml) cooled to 0°C. Oxone®of 2.27 g, 3.7 mmol) dissolved in water (30 ml) and added dropwise to the reaction solution over 1 hour. The solution is allowed to warm to room temperature and additionally stirred for 3 hours. Add NaHCO3(feast upon.) to a pH of approximately 7. The reaction solution is then extracted several times with ethyl acetate, the combined organic phases, dried and concentrated in vacuo, receiving 0.5 g (yield 91%) of the desired product as a yellow foam.

Obtain methyl ester of 2-(4-forfinal)-1-(2-phenoxypyridine-4-yl)-3-oxo-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (22):To a solution of methyl ester of 2-(4-forfinal)-1-(3-methanesulfonamido-4-yl)-3-oxo-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid,21(0,033 g 0,074 mmol) in THF (3 ml) was added phenol and NaH (0,009 g, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding 1 n HCl (20 ml) and the solution extracted with ethyl acetate (3 x 25 ml). The combined organic phases are washed with saturated salt solution, dried and concentrated in vacuo, obtaining the crude about the SPS, which purify on silica (hexane/ethyl acetate, 1:3), receiving 0,012 g (yield 35%) of the desired product as a white solid.1H-NMR (300 MHz, CDCl3) δ 8,64 (d, J=4,6 Hz, 1H), to 7.59-7,63 (m, 2H), 7,40 was 7.45 (m, 3H), 7,28-7,30 (m, 1H), 7,18 (d, J=8,4 Hz, 2H), 7.03 is-was 7.08 (m, 2H), 4,50-4,56 (m, 1H), 3,99-Android 4.04 (m, 1H), 3,86 (s, 1H), 3,01-3,10 (m, 1H), 2,33-to 2.41 (m, 1H), 1,86 (USS, 2H), 1,64 (USS, 3H); ESI/MS: 461 (M+H).

Other compounds in accordance with this aspect of category III can be obtained by the following method.

Reagents and conditions: (a) LiOH, Meon/water, room temperature, 3 hours.

EXAMPLE 8

Obtaining 2-(4-forfinal)-1-(2-phenoxypyridine-4-yl)-3-oxo-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (23):To a solution of methyl ester of 2-(4-forfinal)-1-(2-phenoxypyridine-4-yl)-3-oxo-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid,22, (0.02 g, 0,0143 mmol) in methanol (1 ml) and water (1 ml) is added LiOH (0,016 g of 0.65 mmol). The reaction solution was stirred at room temperature for 3 hours, then quenched by addition of 1 N. HCl (20 ml). The reaction solution is extracted with ethyl acetate (3 x 50 ml), organic layers combined, washed with saturated salt solution, dried and concentrated in vacuo, getting 0,012 g (yield 63%) of the desired product as a yellow solid.1H-NMR (300 MHz, CDCl3) δ to 8.45 (DD, J=4,6, and 2.1 Hz, 1H), 7,4-7,44 (m, 7H), 6,84-6,,95 (m, 3H), is 4.93 (DD, J=11,7, and 9.3 Hz, 1H), 4,23 (USD, J=12.9 Hz, 1H), 3.04 from-3,11 (m, 1H), 2,46-2,52 (m, 2H), 1,71-of 1.93 (m, 2H), APCI/MS: 447 (M +H).

2-(4-Forfinal)-1-[2-(4-pertenece)pyrimidine-4-yl]-3-oxo-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid:1H-NMR (300 MHz, CDCl3) δ and 8.50 (d, J=5,1 Hz, 1H), was 7.36 (DD, J=8,7, 5,4 Hz, 2H), 7,20-7,31 (m, 4H), 7,02 (t, J=8.7 Hz, 2H), 6,97 (d, J=5,1 Hz, 1H), 5,23-a 5.25 (m, 1H), 4,24 (d, J=11,4 Hz, 1H), 3,74 (s, 3H), 2,94-2,99 (m, 1H), 2,54 at 2.59 (m, 1H), 1,82 is 2.00 (m, 3H); ESI/MS: 479 (M+H).

The second aspect analogues category III of the present invention, is able to inhibit the release of inflammatory cytokines, refers to compounds comprising frame 5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it and having the formula:

where the units of R are amines having the formula-NH[CHR5b]R6and R1, R5b, R6and R10described herein below in table V. Stereochemistry of R5bis the configuration shown, when R5bis not hydrogen.

4-forfinal
TABLE V
No.R1R5bR6R10
1254-forfinalNHN
1264-forfinalNmethylN
1274-forfinalNethylN
1284-forfinalNvinylN
1294-forfinalNcyclopropylN
1304-forfinalNcyclohexylN
1314-forfinalNmethoxymethylN
1324-forfinalNmethoxyethylN
1334-forfinalN1-hydroxy-1-methylethylN
1344-forfinalN-CO2NN
1354-forfinalNphenylN
1364-forfinalN4-forfinalN
1374-forfinalN2-AMINOPHENYLN
1384-forfinalN2-wereN
1394-forfinalN4-methylpheni the N
1404-forfinalN4-methoxyphenylN
1414-forfinalN4-(propanesulfonyl)phenylN
1424-forfinalN3-benzo[1,3]dioxol-5-ylN
1434-forfinalNpyridine-2-ylN
1444-forfinalNpyridine-3-ylN
1454-forfinalmethylHN
1464-forfinalmethylmethylN
1474-forfinalmethylethylN
1484-forfinalmethylvinylN
1494-forfinalmethylcyclopropylN
1504-forfinalmethylcyclohexylN
1514-forfinalmethylmethoxymethylN
152 4-forfinalmethylmethoxyethylN
1534-forfinalmethyl1-hydroxy-1-methylethylN
1544-forfinalmethyl-CO2NN
1554-forfinalmethylphenylN
1564-forfinalmethyl4-forfinalN
1574-forfinalmethyl2-AMINOPHENYLN
1584-forfinalmethyl2-wereN
1594-forfinalmethyl4-wereN
1604-forfinalmethyl4-methoxyphenylN
1614-forfinalmethyl4-(propanesulfonyl)phenylN
1624-forfinalmethyl3-benzo[1,3]dioxol-5-ylN
1634-forfinalmethylpyridine-2-ylN
164methylpyridine-3-ylN
1654-forfinalNHmethyl
1664-forfinalNmethylmethyl
1674-forfinalNethylmethyl
1684-forfinalNvinylmethyl
1694-forfinalNcyclopropylmethyl
1704-forfinalNcyclohexylmethyl
1714-forfinalNmethoxymethylmethyl
1724-forfinalNmethoxyethylmethyl
1734-forfinalN1-hydroxy-1-methylethylmethyl
1744-forfinalN-CO2Nmethyl
1754-forfinalNphenylmethyl
1764-forfinalN4-f is arvanil methyl
1774-forfinalN2-AMINOPHENYLmethyl
1784-forfinalN2-weremethyl
1794-forfinalN4-weremethyl
1804-forfinalN4-methoxyphenylmethyl
1814-forfinalN4-(propanesulfonyl)phenylmethyl
1824-forfinalN3-benzo[1,3]dioxol-5-ylmethyl
1834-forfinalNpyridine-2-ylmethyl
1844-forfinalNpyridine-3-ylmethyl
1854-forfinalmethylHmethyl
1864-forfinalmethylmethylmethyl
1874-forfinalmethylethylmethyl
1884-forfinalmethylvinyl methyl
1894-forfinalmethylcyclopropylmethyl
1904-forfinalmethylcyclohexylmethyl
1914-forfinalmethylmethoxymethylmethyl
1924-forfinalmethylmethoxyethylmethyl
1934-forfinalmethyl1-hydroxy-1-methylethylmethyl
1944-forfinalmethyl-CO2Nmethyl
1954-forfinalmethylphenylmethyl
1964-forfinalmethyl4-forfinalmethyl
1974-forfinalmethyl2-AMINOPHENYLmethyl
1984-forfinalmethyl2-weremethyl
1994-forfinalmethyl4-weremethyl
2004-forfinalmate the 4-methoxyphenylmethyl
2014-forfinalmethyl4-(propanesulfonyl)phenylmethyl
2024-forfinalmethyl3-benzo[1,3]dioxol-5-ylmethyl
2034-forfinalmethylpyridine-2-ylmethyl
2044-forfinalmethylpyridine-3-ylmethyl

Compounds that include analogues of the second aspect of category III can be obtained by the synthesis shown below in the following diagram.

Reagents and conditions: (a) (S)-(-)-α-methylbenzylamine, toluene; 100°C, 4 hours.

Reagents and conditions: (b) LiOH, Meon/water, room temperature, 3 hours.

EXAMPLE 9

Methyl ester of 2-(4-forfinal)-3-oxo-1-[2-(1-(S)-(phenylethylamine)pyrimidine-4-yl]-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (24)

Receivingmethyl ester of 2-(4-forfinal)-3-oxo-1-[2-(1-(S)-(phenylethylamine)pyrimidine-4-yl]-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (24):To a solution of methyl ester of 2-(4-forfinal)-1-(3-methanesulfonamido-4-yl)-3-oxo-5,6,7,8-tetrahydro-3H-is irazola[1,2-a]pyridazine-5-carboxylic acid, 21, (0.10 g, 0.22 mmol) in toluene (1.4 ml) is added (S)-(-)-α-methylbenzylamine (1,4 ml, 1.12 mmol). The reaction solution is heated to 100°C for 4 hours, after which the reaction mixture is cooled and diluted with 1 N. HCl. The resulting solution is extracted with ethyl acetate (3 x 25 ml), organic layers combined, dried and concentrated in vacuo, getting 0,071 g (yield 66%) of the desired product as a yellow solid.1H-NMR (300 MHz, CDCl3) δ by 8.22 (DDD, J=11,4, 5,1, 2.1 Hz, 1H), 7,22-7,37 (m, 7H), 6,97 (dt, J=8,7, 2,1 Hz, 2H), 6,41 (DDD, J=15,6, 5,1, 2.1 Hz, 1H), 5,72-of 5.83 (m, 1H), 5,2 (USS, 2H), 5,52-5,62 (m, 1H), of 3.77 (s, 3H), 3,47 (d, J=2.7 Hz, 1H), 2,47 is 2.51 (m, 2H), 2.00 (evens OSS, 1H); of 1.41 (d, J=6.6 Hz, 3H); APCI/MS: 487 (M+H).

EXAMPLE 10

2-(4-Forfinal)-3-oxo-1-[2-(1-(S)-(phenylethylamine)pyrimidine-4-yl]-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (25)

Receiving2-(4-forfinal)-3-oxo-1-[2-(1-(S)-(phenylethylamine)pyrimidine-4-yl]-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (25):To a solution of methyl ester of 2-(4-forfinal)-3-oxo-1-[2-(S)-(1-phenylethylamine)pyrimidine-4-yl]-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid,24(of 0.066 g, 0.14 mmol), in methanol (2 ml) and water (2 ml) is added LiOH (0,033 g of 1.36 mmol). The mixture is stirred at room temperature for 3 hours, then diluted 1 N. HCl (25 ml), and the solution was extracted with ethyl acetate (3 x 50 ml). The combined organization is a mini-layers washed with saturated salt solution, dried and concentrated in vacuo, getting 0,043 g (yield 65%) of the desired product as a yellow solid.1H-NMR (300 MHz, CDCl3) δ 8,13-8,19 (m, 1H), 7,22-7,34 (m, 7H), 6,97 (t, J=8.7 Hz, 2H), 6,34 (DD, J=15,3, 5,1 Hz, 1H), 5,11-5,24 (m, 2H), 3,56 (USS, 1H), 2,96 (USS, 1H), 2,52-of 2.64 (m, 2H), 1,79 is 1.96 (m, 2H), 1,57 (d, J=6.9 Hz, 3H): ESI/MS: 474 (M+H).

Methyl ester of 2-(4-forfinal)-3-oxo-1-[2-(1-(S)-methylmethcathinone)pyrimidine-4-yl]-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid:1H-NMR (300 MHz, CDCl3) δ of 8.25 (d, J=5,1 Hz, 1H), 7,43 (DD, J=9,0,7 Hz, 2H), 6,99 (t, J=9.0 Hz, 2H), 6,44 (d, J=5,1 Hz, 1H), 5,50 is 5.54 (m, 1H), 5,26 (d, J=3,Hz, 1H), 4,15-of 4.25 (m, 2H), 3,76 (s, 3H), 3,37-3,47 (m, 4H), 2,95-of 3.06 (m, 1H), of 2.51-2,62 (m, 1H), 1,92-2,02 (m, 3H), 1,23-of 1.30 (m, 3H); ESI/MS: 456 (M+H).

The third aspect analogues category III of the present invention, is able to inhibit the release of inflammatory cytokines, refers to compounds comprising frame 5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it and having the formula:

where R is an ether group of the formula: -OR3. Table VI summarizes the various values of R, R1and R10.

TABLE VI
No.R10R1R
205N4-forfinalphenoxy
N4-forfinal2 fervency
207N4-forfinal3 fervency
208N4-forfinal4 fervency
209N4-forfinal2,6-divergence
210N4-forfinal2 cianfrocca
211N4-forfinal3 cianfrocca
212N4-forfinal2 triptoreline
213N4-forfinal4 triptoreline
214N4-forfinal2 methylphenoxy
215N4-forfinal4 methylphenoxy
216N4-forfinal2,4-dimethylphenoxy
217N4-forfinal3-N-acetylaminophenol
218N4-forfinal2 methoxyphenoxy
219N4-forfinal4 methoxyphenoxy
220 N4-forfinal3-benzo[1,3]dioxol-5-yl
221methyl4-forfinalphenoxy
222methyl4-forfinal2 fervency
223methyl4-forfinal3 fervency
224methyl4-forfinal4 fervency
225methyl4-forfinal2,6-divergence
226methyl4-forfinal2 cianfrocca
227methyl4-forfinal3 cianfrocca
228methyl4-forfinal2 triptoreline
229methyl4-forfinal4 triptoreline
230methyl4-forfinal2 methylphenoxy
231methyl4-forfinal4 methylphenoxy
232methyl4-forfinal2,4-dimethylphenoxy
233methyl4-forfinal3-N-acetaminophen is XI
234methyl4-forfinal2 methoxyphenoxy
235methyl4-forfinal4 methoxyphenoxy
236methyl4-forfinal3-benzo[1,3]dioxol-5-yl

Compounds that include a third aspect of analogues of category III can be obtained by the method shown in the following diagram.

Reagents and conditions: (a) (VOS)2Oh, Thea, CH2Cl2, room temperature, 12 h.

Reagents and conditions: (b) CH2Cl2, Thea, room temperature, 10 h.

Reagents and conditions: (C) TFU, CH2Cl2/water; 0°C 2 hours, room temperature 1 hour.

Reagents and conditions: (d) TEM, CH2Cl2; room temperature 12 hours.

Reagents and conditions: (e) NaOH, Meon; room temperature 15 h.

Reagents and conditions: (f) CH2N2Et2O/EtOAc, room temperature 5 minutes

Reagents and conditions: (g) Oxone®, THF/Meon/water; room temperature 5 hours.

p> Reagents and conditions: (h) phenol, NaOH, THF, room temperature 8 hours.

EXAMPLE 11

Methyl ester of 2-(4-forfinal)-1-oxo-3-(2-phenoxypyridine-4-yl)-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazin-5-(S)-carboxylic acid (33)

Obtaining 3-(S)-methyl ester 1-tert-butyl ether tetrahydropyrimidin-1,3-dicarboxylic acid (26):To methyl ether piperazinone acid (3,44 g, 19 mmol) in methylene chloride (150 ml) is added (BOC)2On (4,2 g, 19 mmol) and triethylamine (2.65 ml, 19 mmol). The reaction mixture was stirred for 12 hours, concentrated in vacuo to obtain a yellow oil, which was purified on silica (ethyl acetate/hexane, 1:1)to give 4.5 g (yield 98%) of the desired product as a pale yellow oil.

Obtaining 3-(S)-methyl ester 1-tert-butyl ether 2-(2-methylsulfonylamino-4-carbonyl)tetrahydropyrimidin-1,3-dicarboxylic acid (27):To a solution of 3-(S)-methyl ester 1-tert-butyl ether tetrahydropyrimidin-1,3-dicarboxylic acid,26(3,91 g, 15.9 mmol)in methylene chloride (200 ml) is added 2-methanesulfonamido-4-carbonylchloride,16, (3,32 g, 17.6 mmol) and triethylamine (3.5 ml, with 25.3 mmol) so that the pH was approximately neutral. The resulting mixture is stirred for 10 hours at room temperature and the mixture washed with water (100 ml), saturated salt solution (100 ml), dried and conc the Ute in vacuum to obtain oil, which purify on silica (ethyl acetate/hexane, 1:1), receiving with 5.22 g (yield 83%) of the desired product as a yellow oil.

Obtaining 3-(S)-methyl ester 2-(2-methylsulfonylamino-4-carbonyl)tetrahydropyrimidin-1,3-dicarboxylic acid (28):To a solution of 3-(S)-methyl ester 1-tert-butyl ether 2-(2-methylsulfonylamino-4-carbonyl)tetrahydropyrimidin-1,3-dicarboxylic acid,27(7 g, 17.6 mmol)in methylene chloride (50 ml) is added triperoxonane acid (50 ml) at 0°C. the Reaction mixture is stirred for 2 hours while cooling, for 1 hour at room temperature, then concentrated in vacuo, obtaining a residue that can be dissolved in toluene and again concentrated to obtain 7.2 g (yield 100%) of the desired compound in the form triptoreline salt in the form of a yellow oil which is used without further purification.

Obtaining 1-[2-(4-forfinal)-2-oxoethyl]-2-(2-methylsulfonylamino-4-carbonyl)hexahydropyridine-3-(S)-carboxylic acid (29):To a solution of 3-(S)-methyl ester 2-(2-methylsulfonylamino-4-carbonyl)tetrahydropyrimidin-1,3-dicarboxylic acid,28(7.2 g, 17.6 mmol)in methylene chloride (150 ml) is added 4-perforazione (3 g, 17.6 mmol) and triethylamine (3,65 ml of 26.4 mmol). The resulting mixture is stirred for 12 hours, then concentrated in vacuo, obtaining the cor is cinevue oil. The crude residue purified preparative HPLC, getting 5,33 g (yield 70%) of the desired product as a yellow oil.

Obtaining 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-1-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazin-5-(S)-carboxylic acid (30):To a solution of 1-[2-(4-forfinal)-2-oxoethyl]-2-(2-methylsulfonylamino-4-carbonyl)hexahydropyridine-3-(S)-carboxylic acid,29(1 g)in methanol (170 ml) is added NaOH (0,23 g, 5.8 mmol). The resulting mixture is stirred for 15 hours and the mixture was concentrated in vacuo to obtain a residue which is dissolved in water (150 ml). The solution is acidified with 3 N. HCl to pH 1 and extracted with ethyl acetate (300 ml). The organic layer was concentrated in vacuo and the resulting crude substance purified preparative HPLC, getting 7.0 g (yield 76%) of the desired product as a cream solid color.

Obtain methyl ester of 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-1-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazin-5-(S)-carboxylic acid (31):To a solution of 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-1-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid,30in a mixture of diethyl ether/ethyl acetate (2,5:1, 70 ml) is added freshly prepared diazomethane in diethyl ether (5 ml). The reaction mixture is stirred for 5 minutes, then quenched by the addition of the SPLA 0.5 ml). The resulting solution was washed with NaHCO3saturated salt solution, dried and concentrated in vacuo, receiving 1 g (yield 98%) of the desired product as a pale yellow solid.

Obtain methyl ester of 2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-1-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazin-5-(S)-carboxylic acid (32):To a solution of methyl ester of 2-(4-forfinal)-3-(2-methylsulfonylamino-4-yl)-1-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid,31(0,48 g of 1.16 mmol)in a mixture of THF/methanol, 1:1, 50 ml) is added Oxone®(2.14 g, 3.5 mmol) in water (50 ml). The reaction mixture is stirred for 5 hours at room temperature, reduce the volume in vacuo to about 25 ml and add ethyl acetate (200 ml). The organic phase is treated with NaHCO3saturated salt solution, dried and concentrated in vacuo, obtaining 0.5 g of the desired product as a yellow solid.

Obtain methyl ester of 2-(4-forfinal)-3-(2-phenoxypyridine-4-yl)-1-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazin-5-(S)-carboxylic acid (33):NaOH (0,112 g, 2.8 mmol) are added to a solution of phenol (0,316 g, to 3.36 mmol) in THF (100 ml). Methyl ester of 2-(4-forfinal)-3-(2-methanesulfonamido-4-yl)-1-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid,32(0.5 g)dissolved in THF (50 ml) and add n who drops to the solution over 5 minutes. The resulting mixture was stirred at room temperature for 8 hours, then add water (20 ml). The solution is extracted with ethyl acetate (100 ml), the organic layer was washed with saturated salt solution (50 ml) and concentrated in vacuo, getting 0,278 g (yield 54%) of the desired product as a yellow solid.1H-NMR (300 MHz, CDCl3) δ to 1.75 (m, 2H), of 1.97 (m, 1H), 2,42 (d, J=12,8 Hz, 1H), 3.27 to (m, 1H), 3.27 to (m, 1H), 3,6 (s, 3H), 4,5 (USD, J=12,8 Hz, 1H), 5.25 in (m, 1H), 6.87 in (d, J=5.7 Hz, 1H), 7,05 (m, 2H), 7.23 percent (m, 2H), 7,35 (m, 3H), 7,52 (m, 2H), 8,42 (d, J=5.7 Hz, 1H): exact mass calculated for C25H21FN4O4, 460,46, MS-ESI (M+1) 461.

A fourth aspect analogues category III of the present invention, is able to inhibit the release of inflammatory cytokines, refers to compounds comprising frame 5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it and having the formula:

where the units of R are amines having the formula-NH[CHR5b]R6and R1, R5b, R6and R10have the values listed here below in table VII. The stereochemistry of R5bis the configuration shown, when R5bis not hydrogen.

TABLE VII
No.R1R5bR6R10
2374-forfinalNHN
2384-forfinalNmethylN
2394-forfinalNethylN
2404-forfinalNvinylN
2414-forfinalNcyclopropylN
2424-forfinalNcyclohexylN
2434-forfinalNmethoxymethylN
2444-forfinalNmethoxyethylN
2454-forfinalN1-hydroxy-1-methylethylN
2464-forfinalN-CO2NN
2474-forfinalNphenylN
2484-forfinalN4-forfinalN
2494-forfinalN2-AMINOPHENYL N
2504-forfinalN2-wereN
2514-forfinalN4-wereN
2524-forfinalN4-methoxyphenylN
2534-forfinalN4-(propanesulfonyl)phenylN
2544-forfinalN3-benzo[1,3]dioxol-5-ylN
2554-forfinalNpyridine-2-ylN
2564-forfinalNpyridine-3-ylN
2574-forfinalmethylHN
2584-forfinalmethylmethylN
2594-forfinalmethylethylN
2604-forfinalmethylvinylN
2614-forfinalmethylcyclopropylN
2624-forfinal methylcyclohexylN
2634-forfinalmethylmethoxymethylN
2644-forfinalmethylmethoxyethylN
2654-forfinalmethyl1-hydroxy-1-methylethylN
2664-forfinalmethyl-CO2NN
2674-forfinalmethylphenylN
2684-forfinalmethyl4-forfinalN
2694-forfinalmethyl2-AMINOPHENYLN
2704-forfinalmethyl2-wereN
2714-forfinalmethyl4-wereN
2724-forfinalmethyl4-methoxyphenylN
2734-forfinalmethyl4-(propanesulfonyl)phenylN
2744-forfinal methyl3-benzo[1,3]dioxol-5-ylN
2754-forfinalmethylpyridine-2-ylN
2764-forfinalmethylpyridine-3-ylN
2774-forfinalNHmethyl
2784-forfinalNmethylmethyl
2794-forfinalNethylmethyl
2804-forfinalNvinylmethyl
2814-forfinalNcyclopropylmethyl
2824-forfinalNcyclohexylmethyl
2834-forfinalNmethoxymethylmethyl
2844-forfinalNmethoxyethylmethyl
2854-forfinalN1-hydroxy-1-methylethylmethyl
2864-forfinalN-CO2N methyl
2874-forfinalNphenylmethyl
2884-forfinalN4-forfinalmethyl
2894-forfinalN2-AMINOPHENYLmethyl
2904-forfinalN2-weremethyl
2914-forfinalN4-weremethyl
2924-forfinalN4-methoxyphenylmethyl
2934-forfinalN4-(propanesulfonyl)phenylmethyl
2944-forfinalN3-benzo[1,3]dioxol-5-ylmethyl
2954-forfinalNpyridine-2-ylmethyl
2964-forfinalNpyridine-3-ylmethyl
2974-forfinalmethylHmethyl
2984-forfinalmethylmethyl methyl
2994-forfinalmethylethylmethyl
3004-forfinalmethylvinylmethyl
3014-forfinalmethylcyclopropylmethyl
3024-forfinalmethylcyclohexylmethyl
3034-forfinalmethylmethoxymethylmethyl
3044-forfinalmethylmethoxyethylmethyl
3054-forfinalmethyl1-hydroxy-1-methylethylmethyl
3064-forfinalmethyl-CO2Nmethyl
3074-forfinalmethylphenylmethyl
3084-forfinalmethyl4-forfinalmethyl
3094-forfinalmethyl2-AMINOPHENYLmethyl
3104-forfinalmethyl methyl
3114-forfinalmethyl4-weremethyl
3124-forfinalmethyl4-methoxyphenylmethyl
3134-forfinalmethyl4-(propanesulfonyl)phenylmethyl
3144-forfinalmethyl3-benzo[1,3]dioxol-5-ylmethyl
3154-forfinalmethylpyridine-2-ylmethyl
3164-forfinalmethylpyridine-3-ylmethyl

Compounds that include analogues of the fourth aspect of category III can be obtained by synthesis, shown here below in the following diagram, starting with the intermediate connection32.

The fifth aspect analogues category III of the present invention, is able to inhibit the release of inflammatory cytokines, refers to compounds comprising frame 5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it and having the formula:

where R, R1, R9aand R9bhave the values listed below in table VIII.

td align="center"> methyl
TABLE VIII
No.R1RR9aR9b
3174-forfinalphenoxyNN
3184-forfinal2 fervencyNN
3194-forfinal3 fervencyNN
3204-forfinal4 fervencyNN
3214-forfinal2,6-divergenceNN
3224-forfinal2 cianfroccaNN
3234-forfinal3 cianfroccaNN
3244-forfinal2 triptorelineNN
3254-forfinal4 triptorelineNN
3264-forfinal2 methylphenoxyNN
3274-forfinal 4 methylphenoxyNN
3284-forfinal2,4-dimethylphenoxyNN
3294-forfinal3-N-acetylaminophenolNN
3304-forfinal2 methoxyphenoxyNN
3314-forfinal4 methoxyphenoxyNN
3324-forfinal3-benzo[1,3]dioxol-5-ylNN
3334-forfinalphenoxymethylmethyl
3344-forfinal2 fervencymethylmethyl
3354-forfinal3 fervencymethylmethyl
3364-forfinal4 fervencymethylmethyl
3374-forfinal2,6-divergencemethylmethyl
3384-forfinal2 cianfroccamethylmethyl
339 4-forfinal3 cianfroccamethylmethyl
3404-forfinal2 triptorelinemethylmethyl
3414-forfinal4 triptorelinemethylmethyl
3424-forfinal2 methylphenoxymethylmethyl
3434-forfinal4 methylphenoxymethylmethyl
3444-forfinal2,4-dimethylphenoxymethylmethyl
3454-forfinal3-N-acetylaminophenolmethylmethyl
3464-forfinal2 methoxyphenoxymethylmethyl
3474-forfinal4 methoxyphenoxymethylmethyl
3484-forfinal3-benzo[1,3]dioxol-5-ylmethylmethyl
3494-forfinal1-(S)-phenylethylamineNN
3504-forfinal 1-(S)-(4-forfinal)ethylaminoNN
3514-forfinal1-(S)-(2-AMINOPHENYL)ethylaminoNN
3524-forfinal1-(S)-(2-were)ethylaminoNN
3534-forfinal1-(S)-(4-were)ethylaminoNN
3544-forfinal1-(S)-(4-methoxyphenyl)ethylaminoNN
3554-forfinal1-(S)-(4-propanesulfonyl)ethylaminoNN
3564-forfinal1-(S)-(3-benzo[1,3]dioxol-5-yl)ethylaminoNN
3574-forfinal1-(S)-(pyridin-2-yl)ethylaminoNN
3584-forfinal1-(S)-(pyridin-3-yl)ethylaminoNN
3594-forfinalmethylaminoNN
3604-forfinalethylaminoNN
3614-forfinalpropylamino N
3624-forfinalcyclopropylaminoNN
3634-forfinalcyclopropanemethylamineNN
3644-forfinaltert-butylaminoNN
3654-forfinal1-(S)-(cyclopropyl)ethylaminoNN
3664-forfinal1-(S)-(cyclopropylmethyl)ethylaminoNN
3674-forfinal1-(R)-(α)-(carboxy)benzylaminoNN
3684-forfinal1-(S)-(α)-(methyl)benzylaminoNN
3694-forfinal1-(S)-phenylethylaminemethylmethyl
3704-forfinal1-(S)-(4-forfinal)ethylaminomethylmethyl
3714-forfinal1-(S)-(2-AMINOPHENYL)ethylaminomethylmethyl
3724-forfinal1-(S)-(2-were)ethylaminomethyl
3734-forfinal1-(S)-(4-were)ethylaminomethylmethyl
3744-forfinal1-(S)-(4-methoxyphenyl)ethylaminomethylmethyl
3754-forfinal1-(S)-(4-propanesulfonyl)ethylaminomethylmethyl
3764-forfinal1-(S)-(3-benzo[1,3]dioxol-5-yl)ethylaminomethylmethyl
3774-forfinal1-(S)-(pyridin-2-yl)ethylaminomethylmethyl
3784-forfinal1-(S)-(pyridin-3-yl)ethylaminomethylmethyl
3794-forfinalmethylaminomethylmethyl
3804-forfinalethylaminomethylmethyl
3814-forfinalpropylaminomethylmethyl
3824-forfinalcyclopropylaminomethylmethyl
3834-forfinalcyclopropa methylamino methylmethyl
3844-forfinaltert-butylaminomethylmethyl
3854-forfinal1-(S)-(cyclopropyl)ethylaminomethylmethyl
3864-forfinal1-(S)-(cyclopropylmethyl)ethylaminomethylmethyl
3874-forfinal1-(R)-(α)-(carboxy)benzylaminomethylmethyl
3884-forfinal1-(S)-(α)-(methyl)benzylaminomethylmethyl

Another variant of this aspect relates to compounds, in which R9aand R9btaken together form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms. In table IX describes the connection is enabled in this version of the fifth aspect of category III.

cyclohexyl
TABLE IX
No.R1RR9a-R9b-ring
3894-forfinalphenoxymorpholine-4-yl
3904-forfinal2-forfe the hydroxy morpholine-4-yl
3914-forfinal3 fervencymorpholine-4-yl
3924-forfinal4 fervencymorpholine-4-yl
3934-forfinal3 cianfroccamorpholine-4-yl
3944-forfinal4 methylphenoxymorpholine-4-yl
3954-forfinal3-N-acetylaminophenolmorpholine-4-yl
3964-forfinal4 methoxyphenoxymorpholine-4-yl
3974-forfinalphenoxypiperidine-1-yl
3984-forfinal2 fervencypiperidine-1-yl
3994-forfinal3 fervencypiperidine-1-yl
4004-forfinal4 fervencypiperidine-1-yl
4014-forfinal3 cianfroccapiperidine-1-yl
4024-forfinal4 methylphenoxypiperidine-1-yl
4034-forfinal 3-N-acetylaminophenolpiperidine-1-yl
4044-forfinal4 methoxyphenoxypiperidine-1-yl
4054-forfinalphenoxypiperazine-1-Il
4064-forfinal2 fervencypiperazine-1-Il
4074-forfinal3 fervencypiperazine-1-Il
4084-forfinal4 fervencypiperazine-1-Il
4094-forfinal3 cianfroccapiperazine-1-Il
4104-forfinal4 methylphenoxypiperazine-1-Il
4114-forfinal3-N-acetylaminophenolpiperazine-1-Il
4124-forfinal4 methoxyphenoxypiperazine-1-Il
4134-forfinalphenoxycyclohexyl
4144-forfinal2 fervencycyclohexyl
4154-forfinal3 fervencycyclohexyl
416 4-forfinal4 fervencycyclohexyl
4174-forfinal3 cianfroccacyclohexyl
4184-forfinal4 methylphenoxycyclohexyl
4194-forfinal3-N-acetylaminophenolcyclohexyl
4204-forfinal4 methoxyphenoxycyclohexyl
4214-forfinal1-(S)-phenylethylaminemorpholine-4-yl
4224-forfinal1-(S)-(4-forfinal)ethylaminomorpholine-4-yl
4234-forfinal1-(S)-(pyridin-2-yl)ethylaminomorpholine-4-yl
4244-forfinal1-(S)-(pyridin-3-yl)ethylaminomorpholine-4-yl
4254-forfinalethylaminomorpholine-4-yl
4264-forfinalpropylaminomorpholine-4-yl
4274-forfinalcyclopropylaminomorpholine-4-yl
4284-forfinalcyclopropylmethyl the Ino morpholine-4-yl
4294-forfinaltert-butylaminomorpholine-4-yl
4304-forfinal1-(S)-(α)-(methyl)benzylaminomorpholine-4-yl
4314-forfinal1-(S)-phenylethylaminepiperidine-1-yl
4324-forfinal1-(S)-(4-forfinal)ethylaminopiperidine-1-yl
4334-forfinal1-(S)-(pyridin-2-yl)ethylaminopiperidine-1-yl
4344-forfinal1-(S)-(pyridin-3-yl)ethylaminopiperidine-1-yl
4354-forfinalethylaminopiperidine-1-yl
4364-forfinalpropylaminopiperidine-1-yl
4374-forfinalcyclopropylaminopiperidine-1-yl
4384-forfinalcyclopropanemethylaminepiperidine-1-yl
4394-forfinaltert-butylaminopiperidine-1-yl
44024414-forfinal1-(S)-(α)-(methyl)benzylamino piperidine-1-yl
4424-forfinal1-(S)-phenylethylaminepiperazine-1-Il
4434-forfinal1-(S)-(4-forfinal)ethylaminopiperazine-1-Il
4444-forfinal1-(S)-(pyridin-2-yl)ethylaminopiperazine-1-Il
4454-forfinal1-(S)-(pyridin-3-yl)ethylaminopiperazine-1-Il
4464-forfinalethylaminopiperazine-1-Il
4474-forfinalpropylaminopiperazine-1-Il
4484-forfinalcyclopropylaminopiperazine-1-Il
4494-forfinalcyclopropanemethylaminepiperazine-1-Il
4504-forfinaltert-butylaminopiperazine-1-Il
4514-forfinal1-(S)-(α)-(methyl)benzylaminopiperazine-1-Il
4524-forfinal1-(S)-phenylethylaminecyclohexyl
4534-forfinal1-(S)-(4-forfinal)ethylamino
4544-forfinal1-(S)-(pyridin-2-yl)ethylaminocyclohexyl
4554-forfinal1-(S)-(pyridin-3-yl)ethylaminocyclohexyl
4564-forfinalethylaminocyclohexyl
4574-forfinalpropylaminocyclohexyl
4584-forfinalcyclopropylaminocyclohexyl
4594-forfinalcyclopropanemethylaminecyclohexyl
4604-forfinaltert-butylaminocyclohexyl
4614-forfinal1-(S)-(α)-(methyl)benzylaminocyclohexyl

Other compounds of the present invention include:

2-(4-forfinal)-5-(piperazine-1-carbonyl)-3-(2-phenoxypyridine-4-yl)-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazin-1-it;

2-(4-forfinal)-8-(piperazine-1-carbonyl)-3-(2-phenoxypyridine-4-yl)-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it;

2-(4-forfinal)-8-(morpholine-4-carbonyl)-3-(2-phenoxypyridine-4-yl)-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it;

2-(4-forfinal)-5-(morpholine-4-carbonyl)-3-[2-(4-f is orphenochs)pyrimidine-4-yl]-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-he;

2-(4-forfinal)-8-(morpholine-4-carbonyl)-3-[2-(4-pertenece)pyrimidine-4-yl]-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it;

2-(4-forfinal)-5-(morpholine-4-carbonyl)-3-{2-[1-(S)-(α)-(methyl)benzylamino]pyrimidine-4-yl}-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it;

2-(4-forfinal)-8-(morpholine-4-carbonyl)-3-{2-[1-(S)-(α)-(methyl)benzylamino]pyrimidine-4-yl}-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-1-it.

Analogues (compounds) of the present invention are divided into several categories to help the person skilled in the art to apply a rational synthetic strategy to obtain analogues that are not explicitly given in this description and in the examples. Location categories does not mean increased or reduced efficiency for any of the described and considered compositions.

In many cases, it was found that the compounds listed and described here above, are active (IC50in the following analysis, cell-based or in the analyses, which are contained in references) at the level below 1 micromolar (μm).

Compounds of the present invention can effectively block the production of inflammatory cytokines from the cells, thus, provides the possibility of suppression, extinction, cessation, slow down or prevent the development of one or more pathological with the of Taani or syndromes, related to extracellular release of one or more cytokines. Inflammatory pathological conditions include conditions that relate to the following non-limiting examples of molecules:

i) Interleukin-1 (IL-1): participates as molecules responsible for a large number of pathological conditions, inter alia, rheumatoid arthritis, osteoarthritis, and other pathological conditions, which relate to the destruction of connective tissue.

ii) the Cyclooxygenase-2 (SOH-2)inhibitors of cytokine release proposed as inhibitors induced the expression of MOR-2, which was detected, is increased by cytokines. M.K. O Banion et al.,Proc. Natl. Acad. Sci. U.S.A.,89, 4888 (1998).

iii) Factor-α tumor necrosis (TNF-α): it is assumed that the proinflammatory cytokine is an important mediator in many pathological conditions or syndromes, inter alia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease (IBS), septic shock, cardiopulmonary dysfunction, acute respiratory disease and cachexia.

Each of pathological conditions that specialist in this area is required to cure, may require a different level or amount of the compounds described herein, to achieve therapeutic is equal. The person skilled in the art can determine this amount by any known testing methods, well-known specialist in this field.

The present invention further relates to forms of these compounds, which in the normal or higher mammal physiological conditions release of the described compounds. One variant of this aspect includes pharmaceutically acceptable salt described analogues. For the purpose of compatibility with the method of delivery, excipients and the like, the person skilled in the art may choose one form of salts of these analogues among others, because the connections are active compounds that inhibit described in this description of the disease processes.

To this aspect have different "Proletarskoye forms predecessors analogues of the present invention. Compounds of the present invention can be preferably obtained in the form of chemical derivatives, which are not active against the described activity of cytokines, but instead are forms of these analogues, which upon delivery to the human or higher animal will be subjected to a chemical reaction catalyzed by the normal function of the body, among other things, the enzymes present in the stomach, serum CROs and, moreover, the specified chemical reaction releases the main active connection. The term "prodrug" refers to compounds that are transformedin vivoin the active pharmaceutical agent.

COMPOSITION

The present invention relates also to compositions or ready preparative forms, which include the compounds of the present invention, inhibiting the release of inflammatory cytokines. In General, the compositions of the present invention include:

a) an effective amount of one or more bicyclic pyrazolones and their derivatives of the present invention, which are effective for inhibiting release of inflammatory cytokines, and

b) one or more pharmaceutically acceptable excipients.

For the purposes of the present invention, the term "excipient" and "carrier" are used interchangeably throughout the description of the present invention, and the terms defined in this description as "ingredients that are used in the practice of making safe and effective pharmaceutical compositions.

The specialist must understand that the excipients used mainly for the fact that they were used for delivering secure, stable and functional pharmaceuticals, being not only part of the total voltage is nitela for delivery, but it is also a means to achieve efficient absorption recipient of the active ingredient. Excipient can act as a simple and direct inert filler, or excipient used in this description, may be part of stabilizing the pH of the system or cover to guarantee safe delivery of the ingredients in the stomach. The specialist may also take advantage of the fact that the compounds of the present invention have an increased cell efficiency, improved pharmacokinetic properties, and improved oral bioavailability.

The present invention relates also to compositions or ready preparative forms, which include the form of a precursor or "prodrugs" of the compounds of the present invention, inhibiting the release of inflammatory cytokines. In General, such containing precursor compositions of the present invention include:

a) an effective amount of one or more derivatives of bicyclic pyrazolones of the present invention that act, releasingin vivothe corresponding analogue that is effective in the inhibition of release of inflammatory cytokines, and

b) one or more pharmaceutically acceptable excipients.

METHOD of USE

The present invention relates whom I also to a method of regulating the level of one or more inducing inflammation cytokines, among others, interleukin-1 (IL-1), factor-α tumor necrosis (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8) and, thus, the method of treatment or prevention, modulation or attenuation of pathological conditions that affect the extracellular levels of inflammatory cytokines. This method involves the step of introducing a human or higher mammal an effective amount of a composition comprising one or more inhibitors of inflammatory cytokines of the present invention.

As inhibitors of inflammatory cytokines of the present invention can be delivered in a way that can be achieved in more than one site of regulation, at the same time can be modulated by more than one pathological condition. Limitiruyuschie examples of diseases that are affected by regulation or inhibition, the inhibitor of inflammatory cytokines, whereby modulated by excessive activity of cytokines include osteoarthritis, rheumatoid arthritis, diabetes, disease caused by human immunodeficiency virus (HIV).

METHODS

Evaluation of the effectiveness of the compounds of the present invention can be carried out, for example, by measuring the constants of inhibition of cytokines and value of the IC50any method for the selection of a specialist.

Limitiruyuschie examples p is Chadasha analyses include:

i) Enzymatic analysis with the substrate in the UV-visible range of the spectrum, as described L. AI Reiter,Int. J. Peptide Protein Res.,43, 87-96 (1994).

ii) Enzymatic analysis with fluorescent substrate, as described Thornberry et al.,Nature,356, 768-774 (1992).

iii) Analysis using cells MCPC (RSV), as described in U.S. patent 6204261 B1, Batchelor et al., issued March 20, 2001.

Each of these materials included in this description by reference.

In addition, inhibition of tumor necrosis factor, TNF-α, can be measured using stimulated by lipopolysaccharide (LPS) monocytic human cell, as described in:

i) C.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) U.S. patent 6297381 B1, Cirillo et al., issued October 2, 2001, incorporated by reference and are reproduced herein below in the relevant part of it.

Inhibition of the production of cytokines can be detected by measuring the inhibition of TNF-α in lipopolysaccharide-stimulated cells TNR. All cells and reagents dissolved in RPMI 1640 with Phenol red and L-glutamine, supplemented with additional L-glutamine (total: 4 mm), penicillin and streptomycin (each 50 units/ml) and fetal bovine serum (3% FBS) (GIBCO, all concentrations are specified destination). The analysis is performed to erase the selected conditions, only the preparation of the test compounds is not sterile. Original solutions prepared in DMSO followed by dilution in RPMI 1640 to 2 times higher than the desired final concentration for analysis. Confluent cells TNR (2 x 106cells/ml, final concentration; American Type Culture Company, Rockville, Md) is added to 96-well polypropylene round-bottom culture plates (Costar 3790; sterile)containing 125 μl of the test compounds (2-fold concentrated) or filler DMSO (controls, blind experiments). The concentration of DMSO should not exceed 0.2% of the final. The cell mixture preincubated for 30 minutes at 37°C, 5% CO2before stimulation with lipopolysaccharide (LPS, 1 μg/ml; Sigma L-2630, from serotype V E. Coli; save as initial solution concentration of 1 mg/ml in protected from endotoxin, diluted with H2About the filler at -80°C). Blind experiments (estimulando) receive carrier H2About; the final volume of the incubation, 250 μl. Incubation (4 hours) occurs as described above. The analysis should be completed by centrifugation tablets for 5 minutes at room temperature, 1600 rpm./min (4033 g); the supernatant is then transferred to a clear 96-well plates and maintained at -80°C until analysis of TNF-α person commercially available kit for TYPHOID (Biosource #CNS, Camarillo, Ca). Vicis the military value IC 50is the concentration of test compound that causes a 50% reduction in the maximum production of TNF-α.

Although specific embodiments of the present invention have been illustrated and described, for specialists in this field should be obvious that they can be made of various other changes and modifications without going beyond the nature and scope of the invention. Therefore, the attached claims cover all such changes and modifications are included in the scope of the present invention.

1. Connection, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts, with the specified connection has the formula

where R represents a

a) -OR3or

b) -NR4aR4b;

R3represents a substituted or unsubstituted phenyl, where the substituents are

i) halogen;

ii) C1-C6alkyl;

iii) trifluoromethyl;

iv) trichloromethyl;

v) tribromoethyl;

vi) cyano, and

vii) C1-C6alkoxy;

R4aand R4brepresent each independently

a) hydrogen or

b) -[C(R5aR5b)]xR6;

the index x is equal to from 0 to 5;

ka is every R 5aand R5brepresents, independently, hydrogen, an unbranched or branched C1-C4alkyl, C3-C7cyclic alkyl;

R6represents-OR7or1-C4alkyl;

R7represents hydrogen or C1-C4alkyl;

R1represents a halogen-substituted phenyl;

links R2aand R2bselected each independently from the group consisting of

a) hydrogen;

b) -O(CH2)jR8;

c) -(CH2)jCO2R10;

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

e) double bonds when one of R2aand one of R2btaken together with the formation of a double bond;

f) ring, when one of R2aand one of R2btaken together with the formation of rings, and the specified ring selected from the group consisting of

i) benzene and

ii) dioxolane;

R8and R10are each independently hydrogen or C1-C4alkyl;

j is an index from 0 to 5;

m represents an index from 1 to 3;

n is an index from 1 to 3;

m+n is 4.

2. The compound according to claim 1, having the formula

where R represents a

a) -OR3or

b) -NR4aR4b;

R3represents a substituted or unsubstituted phenyl;

R4aand R4beach independently represent

a) hydrogen or

b) -[C(R5aR5b)]xR6;

the index x is equal to from 0 to 5;

each R5aand R5brepresents independently hydrogen, an unbranched or branched C1-C4alkyl, C3-C7cyclic alkyl;

R6represents a C1-C4alkyl;

R7represents hydrogen or C1-C1alkyl;

R1selected from the group consisting of 4-ftoheia, 2,4-diphthera and 4-chlorphenyl;

each link R2aor R2bindependently selected from the group consisting of

a) hydrogen and

b) -O(CH2)jR8;

j is 0.

3. The compound according to claim 2, where R2aor R2brepresents-CO2H, -CO2CH3, -CONH2or-CON(CH3)2.

4. The compound according to claim 1 or 2, where

R1is a 4-forfinal;

R is a simple essential element selected from the group consisting of phenoxy, 2-fervency, 3 fervency, 4-fervency, 2,6-divergence, 2-cianfrocca, 3 cianfrocca, 2-triptoreline, 4-triptoreline, 2-methylphenoxy, 4-is ethylenoxy, 2,4-dimethylphenoxy, 2-methoxyphenoxy, 4-methoxyphenoxy, or

R represents aminothieno selected from the group consisting of methylamino, ethylamino, propylamino, cyclopropylamino, cyclopropylmethyl-amino, tert-butylamine and 1-(S)-(cyclopropyl)ethylamino.

5. The compound according to claim 1, having the formula

where R represents a

(a) a simple ether having the formula-OR3or

b) -NR4aR4b;

R3represents a substituted or unsubstituted phenyl;

R4aand R4beach independently represents a

a) hydrogen or

b) -[C(R5aR5b)]xR6;

the index x is equal to from 0 to 5;

each R5aand R5brepresents independently hydrogen, an unbranched or branched C1-C4alkyl, C3-C7cyclic alkyl;

R6represents-OR7or C1-C4alkyl;

R7represents hydrogen or C1-C1alkyl;

R1selected from the group consisting of 4-ftoheia, 2,4-diphthera and 4-chlorphenyl;

each link R2aor R2bindependently selected from the group consisting of

a) hydrogen;

b) ring, when one of R2aand one of R2btaken together OBR is reattaching the ring, moreover, the specified ring selected from the group consisting of

i) benzene;

ii) dioxolane;

(C) double bonds when one of R2aand one of R2btaken together with the formation of a double bond;

j is 0.

6. The compound according to claim 5, where

R1is a 4-forfinal;

R is a simple essential element selected from the group consisting of phenoxy, 2-fervency, 3 fervency, 4-fervency, 2,6-divergence, 2-cianfrocca, 3 cianfrocca, 2-triptoreline, 4-trifluoromethyl-phenoxy, 2-methylphenoxy, 4-methylphenoxy, 2,4-dimethylphenoxy, 2-methoxy-phenoxy, 4-methoxyphenoxy, or

R represents aminothieno selected from the group consisting of methylamino, ethylamino, propylamino, cyclopropylamino, cyclopropylmethyl-amino, tert-butylamine and 1-(S)-(cyclopropyl)ethylamino.

7. The compound according to claim 1, having the formula

where R represents a

a) simple ether having the formula-OR3or

(b) amine having the formula-NR4aR4b;

R3represents a substituted or unsubstituted phenyl;

R4aand R4beach independently represents a

a) hydrogen or

b) -[C(R5aR5b)]xR6;

the index x is equal to 0;

ka is every R 5aand R5brepresents independently hydrogen, an unbranched or branched C1-C4alkyl, cyclic3-C7alkyl;

R6represents-OR7or1-C4alkyl;

R7represents hydrogen or C1-C1alkyl;

R1selected from the group consisting of 4-ftoheia, 2,4-diphthera and 4-chlorphenyl;

R11represents hydrogen.

8. The connection according to claim 7, where

R1is a 4-forfinal;

R is a simple essential element selected from the group consisting of phenoxy, 2-fervency, 3 fervency, 4-fervency, 2,6-divergence, 2-cianfrocca, 3 cianfrocca, 2-triptoreline, 4-triptoreline, 2-methylphenoxy, 4-methylphenoxy, 2,4-dimethylphenoxy, 2-methoxyphenoxy and 4 methoxyphenoxy, or

R represents aminothieno selected from the group consisting of methylamino, ethylamino, propylamino, cyclopropylamino, cyclopropylmethyl-amino, tert-butylamine and 1-(S)-(cyclopropyl)ethylamino.

9. Composition, inhibiting the extracellular release of inflammatory cytokines, including

a) an effective amount of one or more compounds according to claim 1, and

b) one or more pharmaceutically acceptable excipients.

10. The way to regulate the Finance extracellular release of inflammatory cytokines, moreover, this method involves the step of introducing a human or higher mammal composition, including

a) an effective amount of one or more compounds according to claim 1 and (b) one or more pharmaceutically acceptable excipients.



 

Same patents:

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 new amide derivatives of carboxylic acid that are antagonists of NMDA receptors of the formula (I): , wherein one radical among R1, R2, R3 and R4 represents -OH or NH2-group and others are hydrogen atoms; or two adjacent groups R1, R2, R3 and R4 in this case in common with one or more similar or different additional heteroatoms and -CH= and/or -CH2-groups form 5-6-membvered homo- or heterocyclic ring but preferably pyrrole, pyrazole, imidazole, oxazole, oxooxazolidine or 3-oxo-1,4-oxazine ring; two other groups among R1, R2, R3 and R4 radicals represent hydrogen atoms; R5 and R6 in common with nitrogen atom between them form saturated or unsaturated 4-6-membered heterocyclic ring that is substituted with phenoxy-, phenyl-[(C1-C4)-alkoxy]-, phenoxy-[(C1-C4)-alkyl]-, benzoyl-group optionally substituted in aromatic ring with one or more halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; X and Y mean independently oxygen, nitrogen atom or group -CH=, and to their salts formed with acids and bases. Also, invention relates to a method for preparing compounds of the formula (I) and pharmaceutical compositions showing activity as selective antagonists of NR2B receptor based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of the following diseases: chronic neurodegenerative diseases, chronic painful states, bacterial and viral infections.

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

11 cl, 2 tbl, 27 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to 5-aminoalkylpyrazolo[4,3-d]pyrimidines of the general formula (I): wherein R1 and R2 are similar or different and represent independently of one another (C1-C8)-alkyl group; R3 and R4 are similar or different and represent independently of one another (C1-C8)-alkoxy-group or halogen atom; R5 and R6 can be similar or different and represent independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl group that can be substituted with one or more hydroxyl groups, (C1-C8)-alkoxy-, amino-, mono-(C1-C8)-alkyl-amino-, di-[(C1-C8)-alkyl]-amino-, N-morpholino- or pyridyl groups or in common with nitrogen atom to which they are bound form unsaturated heterocyclic ring that comprises optionally one or more additional atoms of nitrogen and/or oxygen and substituted with one or more hydroxyl, (C1-C8)-alkylol, (C1-C6)-oligohydroxyalkyl, amino-, mono-[(C1-C8)-alkyl]-amino- or di-[(C1-C8)-alkyl]-amino-groups. Proposed compounds inhibit activity of cGMP-phosphodiesterase and can be used in treatment of states of cardiovascular system and for treatment in potency disturbances. Also, invention relates to a medicinal preparation used for inhibition of activity of cGMP-phosphodiesterase based on indicated compounds, a method for preparing compounds of the formula (I) and a method for preparing the medicinal preparation.

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

7 cl, 15 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes phenyl-substituted heterocyclic 1,3-ketoenols of the formula (I): wherein R1 and R3 mean independently of one another ethyl or (C1-C2)-alkoxy-group; Q means the group of the formula (Q1): or (Q2): wherein R4 and R5 in common with atoms to which they are joined form 5-7-membered cycle that can comprise additionally anellated alkylene chain consisting of 2-6 carbon atoms that, in turn, can comprise two heteroatoms taken among oxygen atom, and indicated cycle can be substituted with halogen atom, hydroxy-group, (C1-C6)-alkoxy-group, (C1-C6)-alkoxy-(C1-C6)-alkoxy-group, (C1-C4)-alkylcarbonyloxy-group, hydroxy-(C1-C4)-alkoxy-group, hydroxycarbonyl-(C1-C2)-alkoxy-group, methoxycarbonyl-(C1-C2)-alkoxy-group, methoxyimino-, methoxyethoxyethoxy-group; R6 and R7 means (C1-C10)-alkyl; R8 means hydrogen atom; X means oxygen atom; R20 means (C1-C10)-alkyl, and also agronomically acceptable salts and isomers of these compounds. Also, invention describes a method for preparing compounds of the formula (I), herbicide agent and a method for control of weed growth based on compounds of the formula (I). Invention provides preparing compounds possessing the herbicide activity.

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

5 cl, 28 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

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

38 cl, 3 tbl, 116 ex

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

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

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, amino acids, medicine, pharmacy.

SUBSTANCE: invention relates to using derivatives of cysteine for preparing a medicinal agent. The proposed agent is designated for treatment of diseases arising as a result of formation of heterotrimeric protein G, and to new derivatives of cysteine, and pharmaceutical composition based on thereof. Derivatives of cysteine, in particular, involve the following compounds: bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[2,2a]-pyrazine]-disulfide and bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-2-91-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo-[1,2a]-pyrazine-7-yl]-disulfide. Invention provides high effectiveness of treatment.

EFFECT: valuable medicinal properties of compounds.

6 cl, 7 dwg, 2 tbl, 7 ex

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

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

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

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to the substituted pyrazoles, pharmaceutical compositions comprising these compounds and methods for their using in treatment of autoimmune diseases wherein cathepsin S is their mediating agent. Described substituted pyrazoles represent compounds of the formula (I): wherein a dotted line is placed near the group -C-R6 or absent, or it represents a bond; Y represents nitrogen atom or -CR20; Z represents nitrogen atom or -CR21; T represents nitrogen atom or -CR2; S represents nitrogen atom or -CR3 under condition that from 0 to 3 among S, T, Y and Z represent nitrogen atom, and additionally under condition that one among S, T, Y and Z can represent the group =N+-O- if other three are not nitrogen atom; R20 is chosen from hydrogen, halogen atom, hydroxy-, cyano-group, 4-7-membered heterocycle comprising nitrogen and oxygen atom; R21 represents hydrogen atom; R2 is chosen from hydrogen, halogen atom and hydroxy-group; R3 is chosen from hydrogen, halogen atom, (C1-C5)-alkoxy-group, (C1-C5)-alkyl, cyano-group, -RgRhN, 4-7-membered heterocyclyl comprising nitrogen and oxygen atom and -R17OC=O; R5 and R6 represent hydrogen atom; R7 and R8 can be combined in common and form optionally substituted 5-7-membered carbocylic or heterocyclic ring comprising nitrogen atom and wherein the indicated ring can be unsaturated or aromatic and this ring is substituted optionally with -Rt(C=O)- or -RtSO2; Rt represents (C1-C6)-alkyl; Rg, Rh and R17 represent (C1-C5)-alkyl; G represents (C3-C6)-alkanediyl; Ar represents monocyclic aryl ring optionally substituted from 1 to 3 substitutes chosen independently from halogen atom, (C1-C5)-alkyl and (C1-C5)-halogenalkyl; R32 represents hydrogen atom, (C1-C5)-alkyl, cyano-group, C1-C5)-hydroxyalkyl, -(C=O)NRvRx, -CHO or (C1-C6)-alkoxycarbonyl wherein each from Rv and Rx is chosen independently from hydrogen atom (H), (C1-C5)-alkyl, (C1-C5)-hydroxyalkyl, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom-(C1-C5)-alkylene, (C1-C5)-aminoalkylene; Q represents -NR33, sulfur (S) or oxygen (O) atom; R33 represents hydrogen atom, (C1-C5)-alkyl, (C2-C5)-heterocyclyl comprising oxygen atom-(C1-C5)-alkylene, -R35OC=O and -R35OC=O; R35 represents (C1-C5)-alkyl, or their pharmaceutically acceptable salts, amides and esters, or their stereoisomeric forms.

EFFECT: improved for inhibition, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

25 cl, 3 tbl, 135 ex

FIELD: veterinary science.

SUBSTANCE: the present innovation deals with treating and preventing acute and chronic septic processes of any localization in animals, especially in case of inflammatory diseases of reproductive organs if females and, firstly, in cattle. It has been suggested a new homeopathic antiphlogistic veterinary preparation that contains Lachesis mutus, Pulsatilla, Sabina, Sepia and ACD-2 taken at equal ratios at the following dilutions of components: Pulsatilla D15, Sepia D6, Lachesis mutus D8,Sabina D3, ACD-2 D9. The innovation provides broadened variety of veterinary homeopathic antiphlogistic preparations.

EFFECT: higher efficiency of therapy.

3 ex, 4 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (1): and their pharmaceutically acceptable salts wherein represents a double bond; Z1 represents nitrogen atom (N), -CR5 wherein R5 represents hydrogen atom (H), (C1-C6)-alkyl, hydroxy-group (OH),(C1-C6)-alkoxy-group or halogen atom; Z2 at position 2 represents CR1 and at position it represents CA wherein each R1 means independently (C1-C6)-alkyl; A represents -Wi-COXjY wherein Y means -COR2 wherein R2 means -OR, -NR2, -NRNR2 or -NROR wherein each R represents independently hydrogen atom (H), (C1-C6)-alkyl, or (C5-C6)-heteroaryl comprising one or two heteroatoms in ring chosen from atoms N, O and S wherein each of them is substituted with one or some groups chosen from -NR'2, -OR', -COOR', (C1-C6)-alkyl, -CN, =O, and -SR' wherein each R' represents hydrogen atom (H) or (C1-C6)-alkyl and wherein two R or R' jointed to the same nitrogen atom (N) can form 3-8-membered ring chosen from the group comprising piperazine ring, morpholine ring, thiazolidine ring, oxazolidine ring, pyrrolidine ring, piperidine ring, azacyclopropane ring, azacyclobutane ring and azacyclooctane ring and wherein indicated ring can be substituted additionally with (C1-C6)-alkyl or -COO-(C1-C6)-alkyl; X represents unsubstituted (C1-C6)-alkylene, or Y means imidazole substituted with methyl group; i = 0; j = 0 or 1; R7 means hydrogen atom (H) or (C1-C6)-alkyl, -SOR, -SO2R, -RCO, -COOR, (C1-C6)-alkyl-COR, -CONR2, -SO2NR2,-CN, -OR, (C1-C6)-alkyl-SR, (C1-C6)-alkyl-OCOR, (C1-C6)-alkyl-COOR, (C1-C6)-alkyl-CN, or (C1-C6)-alkyl-CONR2 wherein each R represent independently hydrogen atom (H), (C1-C6)-alkyl or aryl that is substituted optionally with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; or R7 represents methoxymethyl, methoxyethyl, ethoxymethyl, benzyloxymethyl or 2-methoxyethyloxymethyl; each R3 represent independently halogen atom, (C1-C6)-alkyl, -OR, -SR or -NR2 wherein R represents hydrogen atom (H) or (C1-C6)-alkyl; n = 0-3; L1 means -CO; L2 means (C1-C4)-alkylene optionally substituted with one or two groups of (C1-C4)-alkyl; each R4 is chosen independently from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2, -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl; or R4 represents =O; m = 0-4; Ar means aryl group substituted with from 0 to 5 substitutes chosen from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2 and -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl. Compounds of the formula (I) possess the inhibitory activity with respect to p38-α kinase that allows their using as components of the pharmaceutical composition.

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

63 cl, 3 tbl, 9 sch, 16 ex

FIELD: medicine, pharmaceutical industry.

SUBSTANCE: the suggested preparation for treating inflammatory skin diseases contains mud volcano mud as an active substance to be introduced into polymeric mixture, moreover, the mud should be introduced into swollen polymers during mixing and homogenization till the development of homogeneous gel mass at the ratio of 15-30:1.5-2.5 in weight portions, and, also, a conservant and a pharmaceutically acceptable solvent. Additionally, the preparation contains plant and/or mineral oils and an emulsifier.

EFFECT: higher efficiency of therapy.

4 cl, 4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a soluble, carbonated, anti-inflammatory, analgesic and antipyretic agent as a tablet. Agent comprises acetylsalicylic acid, caffeine, ascorbic acid, paracetamol, basic component, acidic component and accessory substances. Invention provides the possibility of rapid release of the preparation in blood, decreasing time for undesirable contact of the preparation with stomach mucosa and its high activity.

EFFECT: valuable medicinal and pharmaceutical properties of agent.

6 cl, 6 tbl, 11 ex

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to an anti-inflammatory ointment with hypolipidemic effect. Proposed ointment comprises ephthylline-base for ointment, a statin wherein lescol (fluvastatin) is used as statin, and ephthylline comprises 40% of ephthiderm. Invention provides enhancing the curative effect and hypolipidemic effect and effects on enzymatic systems of biological membranes that results to prolongation of curative effect of ointment.

EFFECT: valuable medicinal properties of ointment.

3 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of piperidine of the general formula (I): or their nontoxic salts wherein R1 represents hydrogen atom, cyano-group; each R2 and R3 represents (C1-C8)-alkyl, (C3-C7)-cycloalkyl and others; each R4 and R5 represents hydrogen atom, (C1-C8)-alkyl and others; R6 represents hydroxyl group, (C1-C8)-alkoxy-group and others; m represents 0 or a whole number 1-4. Compounds of the formula (I) possess inhibitory activity with respect to PDE4 and can be used in medicine in treatment of inflammatory, diabetic, allergic and other diseases.

EFFECT: valuable medicinal properties of compounds.

10 cl, 11 tbl, 111 ex

FIELD: pharmaceutical industry and technology.

SUBSTANCE: invention relates to a method for preparing oily extracts from vegetable raw. Method for preparing gum-tree oily extract involves drying branches with 70% of leaves, not less, to the definite moisture index and milled followed by their treatment with electric activated liquid at the definite pH value and in the definite amount of raw mass at stirring and keeping for a definite time. Then prepared mass is wetted with ethyl alcohol, dried to the definite moisture value and extraction is carried out under definite conditions and filtered. Method allows decreasing extraction time and enhancing the yield of total amount of extractive substances.

EFFECT: improved preparing method of extracts.

5 tbl, 9 dwg, 16 ex

FIELD: medicine.

SUBSTANCE: method involves administering fluoroquinolone-series antibiotic like Ciproflaxin at a dose of 100-250 mg twice a day during 3-5 days and non-steroid anti-inflammatory preparation of Diclophenac at a dose of 75-150 mg/day during 3-7 days are sequentially introduced in preparing patient to diagnostic examination.

EFFECT: enhanced effectiveness in increasing method sensitivity.

2 tbl

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

SUBSTANCE: invention relates to methods for preparing 2-phenylamino-5-alkylphenylacetic acids of the general formula (I)

intermediate compounds for their preparing, their pharmaceutically acceptable salts and pharmaceutically acceptable prodrug esters wherein R, R1, R2, R3, R4 and R5 have corresponding values. Compound of the general formula (I) is prepared by splitting lactam of the formula (II): wherein symbols have values given in the description with a base, its precursors and methods for preparing these precursors. Abovementioned methods can comprise if necessary the temporal protection of all reaction groups showing effect followed by isolation of the prepared compound. Invention provides preparing compounds of the general formula (I) representing pharmaceutically active compounds that represent selective inhibitors of cyclooxygenase-2.

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

10 cl, 1 sch, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of N-heterocyclic compounds of the formula: , wherein n and m mean independently a whole number from 1 to 4; A means -C(O)OR1 or -C(O)N(R1)R2; W means -CH; R1 means hydrogen atom or (C1-C8)-alkyl; R means hydrogen atom, (C1-C8)-alkyl, heterocyclyl-(C1-C4)-alkyl chosen from the group comprising benzodioxolyl-, benzodioxanyl- or dihydrobenzofuranylalkyl or phenyl-(C1-C4)-alkyl substituted possibly with alkoxy-group; R4 means cyano-group or heterocyclyl chosen from the group comprising pyridinyl, morpholinyl, benzodioxolyl or benzodioxanyl-radical if m = 1; if m means from 2 to 4 then R4 can mean additionally hydroxy-group, -NR1R2 wherein R1 and R2 mean independently hydrogen atom, (C1-C8)-alkyl or benzyl-radical, -N(R1)-C(O)-R1, -N(R1)-C(O)-OR1, -N(R1)-S(O)t-R1 wherein R1 means hydrogen atom or (C1-C8)-alkyl, -N(R1)-C(O)-N(R1)2 wherein R1 means hydrogen atom; R5 means (C1-C8)-alkyl; t = 2, and their stereoisomers and pharmaceutically acceptable salts, pharmaceutical composition based on thereof and a method for treatment of diseases, in particular, rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds and composition.

12 cl

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